Heteroaromatic ring compound as well as pharmaceutical composition and application thereof

Abstract

The invention provides a heteroaromatic ring compound as well as a pharmaceutical composition and application thereof. Specifically, the invention provides a compound shown as a formula (I), a pharmaceutically acceptable salt of the compound, a solvate of the compound or a solvate of the pharmaceutically acceptable salt of the compound. The heteroaromatic ring compound provided by the invention has one or more of the following advantages: good 5-HT4 receptor selective excitation activity and relatively weak hERG inhibitory activity.

Description

Technical Field

[0001] This invention relates to heterocyclic aromatic compounds, pharmaceutical compositions thereof, and their applications. Background Technology

[0002] 5-HT receptors are a group of G protein-coupled receptors and ligand-gated ion channels found in the central and peripheral nervous systems. To date, seven 5-HT receptors have been identified: 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6, and 5-HT7. Except for 5-HT3, which is a ligand-gated ion channel, the other six are G protein-coupled receptors. The 5-HT4 receptor (FASEB Journal 1996, 10, 1398–1407), since its discovery in 1988, has attracted considerable attention from pharmaceutical companies as a target for new drug development. Besides the central nervous system, peripheral nervous system, and cardiovascular system, the 5-HT4 receptor is also widely distributed in the gastrointestinal system.

[0003] Several selective 5-HT4 receptor agonists and antagonists have been developed for the treatment of peripheral diseases such as irritable bowel syndrome, gastroparesis, urinary incontinence, and arrhythmias. The 5-HT4 receptor has long been a target for drug development in the treatment of chronic constipation and peritoneal syndrome with constipation. Known publicly disclosed 5-HT4 receptor agonists include cisapride (US4,962,115), prucalopride (EP0445862), and tegaserod (US5,510,353). These compounds stimulate gastrointestinal motility to treat constipation. However, due to the lack of high selectivity for 5-HT4 receptors in most of these compounds, the risk of side effects during clinical use is not negligible. In addition to lacking selectivity for 5-HT family receptors such as 5-HT1 and 5-HT2, it also lacks inhibitory selectivity for channels or transporters such as the human ether-a-go-go-related gene (hERG). This lack of selectivity for hERG channel inhibition may lead to adverse side effects observed clinically, such as cardiovascular side effects. In recent years, the drug development field has increasingly opted to evaluate the inhibitory properties of drugs on hERG channels before in vivo animal experiments. This strategy helps avoid discovering cardiovascular safety risks after drugs have entered late-stage clinical trials. Summary of the Invention

[0004] The technical problem to be solved by this invention is to address the deficiency in the variety of 5-HT4 receptor agonists in the prior art by providing a novel heterocyclic compound, its pharmaceutical composition, and its application. The heterocyclic compound of this invention has one or more of the following advantages: good selective 5-HT4 receptor agonist activity and weak hERG inhibitory activity.

[0005] The present invention solves the above-mentioned technical problems through the following technical solutions.

[0006] This invention provides a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof:

[0007] ;

[0008] in,

[0009] X 1 For CR X1 Or N;

[0010] X 2 For CR X2 Or N;

[0011] X 3 For CR X3 Or N;

[0012] R X1 R X2 and R X3 Independently -H, halogen, C1-C6 alkyl, C2-C6 alkynyl, C2-C6 alkenyl, or influenced by one or more R groups. X1-1 Substituted C1-C6 alkyl groups;

[0013] R X1-1 Independent of halogen, -OH, -NR f R g Or C3-C6 cycloalkyl;

[0014] R f and R g Each is independently -H or C1-C6 alkyl;

[0015] R 4 It is a halogen, C1-C6 alkyl, C2-C6 alkynyl, C2-C6 alkenyl, or is oxidized by one or more R groups. 4-1 Substituted C1-C6 alkyl groups;

[0016] R 4-1 Independent of halogen, -OH, -NR f R g Or C3-C6 cycloalkyl;

[0017] Or, R X1 and R 4 The atoms connected to them together form C4-C7 carbon rings or 4-7 membered heterocycles. In the 4-7 membered heterocycles, the heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.

[0018] Or, R X2 and R 4 The atoms connected to them together form C4-C7 carbon rings or 4-7 membered heterocycles. In the 4-7 membered heterocycles, the heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.

[0019] for , , , or ;

[0020] B is a connector, -O-, -S-, , , -NR B2 -or CR B3 R B4 ;

[0021] R B1 R B2 R B3 R B4 R 5 R 5’ R 6 R 7 R 9 R 10 and R 10’ Each is independently -H, C1-C6 alkyl, or surrounded by one or more R e Substituted C1-C6 alkyl groups;

[0022] R 8 Independently for -H, C1-C6 alkyl or containing one or more R e Substituted C1-C6 alkyl groups;

[0023] R 8-1 Independently C1-C6 alkyl, C1-C6 alkoxy, or -NR h R i ;

[0024] R h and R i Each is independently -H or C1-C6 alkyl;

[0025] Re Independently -OH or C1-C6 alkoxy group;

[0026] Or, “R” 5 and R 5’ “R” 5 and R 6 “R” 6 and R 7 “R” 7 and R 8 “R” 8 and R 9 “R” 9 and R 10 "or "R 10 and R 10’ "The atoms connected to them together form 5-6 membered saturated heterocycles or are bounded by one or more R..." d The substituted 5-6 member saturated heterocycle, wherein the heteroatoms are each independently N and / or O, and the number of heteroatoms is each independently 1 or 2.

[0027] R d Independently equal to 0;

[0028] Ring A is C6-C 10 Aromatic ring or 5-10 membered heteroaromatic ring, wherein the 5-10 membered heteroaromatic ring is a 5-10 membered heteroaromatic ring in which the heteroatoms are selected from one, two or three kinds of N, O and S, and the number of heteroatoms is one, two or three.

[0029] R 1 for or ;

[0030] R a It is a C1-C4 alkyl or C3-C4 cycloalkyl;

[0031] R b -H, -CN, C1-C4 alkyl, or ;

[0032] R b-1 Independently, it is a C1-C4 alkyl group;

[0033] Independently -H, =O, -NR f R g -NO2, -OH, -CN, halogens, C1-C4 alkyl, C2-C4 alkynyl, C2-C4 alkenyl, C3-C4 cycloalkyl, C1-C4 alkoxy groups or those with one or more R groups 2-1Substituted C1-C4 alkyl groups;

[0034] R 2-1 Independent of halogen, -OH or NR f R g ;

[0035] Or, R 1 Adjacent R 2 The atoms connected to them together form , or p and q are each independently 1, 2 or 3;

[0036] m can be 1, 2, 3, 4, or 5.

[0037] In certain preferred embodiments of the present invention, certain groups in the compound represented by formula (I), its pharmaceutically acceptable salt, its solvate or a solvate of a pharmaceutically acceptable salt thereof are defined as follows, and groups not mentioned are as described in any embodiment of the present invention (hereinafter referred to as "in a certain embodiment of the present invention").

[0038] In one aspect of the invention, each "halogen" is independently F, Cl, Br or I, for example F or Cl.

[0039] In one embodiment of the invention, each “C1-C6 alkyl” is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl, ethyl, n-propyl, or n-butyl.

[0040] In one embodiment of the present invention, each “C2-C6 ynyl group” is independently ethynyl, propynyl or propynyl, for example propynyl.

[0041] In one embodiment of the invention, each “C2-C6 alkenyl” is independently vinyl, propenyl, or allyl, for example, propenyl.

[0042] In one embodiment of the present invention, each “C3-C6 cycloalkyl” is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl.

[0043] In one embodiment of the present invention, each “C1-C6 alkoxy” is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy, for example, methoxy.

[0044] In one aspect of the invention, each "5-6 member saturated heterocycle" is independently a tetrahydropyrrole ring or a piperidine ring, for example... , or In this case, the carbon atoms marked with "*" have the configuration of R, S, or a mixture thereof, for example... , , , , , , , or .

[0045] In one aspect of the present invention, the one or more R d The substituted 5-6 membered saturated heterocycles are independently a tetrahydropyrrole ring substituted with one =O or a piperidine ring substituted with one =O, for example... or In this case, the carbon atoms marked with "*" have the configuration of R, S, or a mixture thereof, for example... , , , , or .

[0046] In one embodiment of the present invention, each "C6-C" 10 Each aromatic ring can be a benzene ring or a naphthalene ring, for example, a benzene ring.

[0047] In one aspect of the present invention, each "5-10 member heteroaromatic ring" is independently a 5-6 member monocyclic heteroaromatic ring or an 8-10 member bicyclic heteroaromatic ring with N heteroatoms, and the number of heteroatoms is 1, 2 or 3. In the bicyclic heteroaromatic ring, each ring is aromatic or one of the rings is aromatic.

[0048] In one aspect of the invention, each "5-10 membered heteroaromatic ring" is independently a pyridine ring, a pyrimidine ring, an imidazopyridine ring, a pyrrolopyridine ring, or a dihydropyridopyridine ring, for example... , , , , , or .

[0049] In one embodiment of the invention, each “C1-C4 alkyl” is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl, ethyl, or isopropyl.

[0050] In one embodiment of the invention, each “C3-C4 cycloalkyl” is independently cyclopropyl or cyclobutyl, for example, cyclopropyl.

[0051] In one embodiment of the present invention, each “C1-C4 alkoxy” is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy, for example, methoxy.

[0052] In one aspect of the present invention,

[0053] X 1 For CR X1 Or N;

[0054] X 2 For CR X2 Or N;

[0055] X 3 For CR X3 Or N;

[0056] R X1 R X2 and R X3 Independently -H, halogen, C1-C6 alkyl, C2-C6 alkynyl, C2-C6 alkenyl, or influenced by one or more R groups. X1-1 Substituted C1-C6 alkyl groups;

[0057] R X1-1 Independent of halogen, -OH, -NR f R g Or C3-C6 cycloalkyl;

[0058] R f and R g Each is independently -H or C1-C6 alkyl;

[0059] R 4 It is a halogen, C1-C6 alkyl, C2-C6 alkynyl, C2-C6 alkenyl, or is oxidized by one or more R groups. 4-1 Substituted C1-C6 alkyl groups;

[0060] R 4-1 Independent of halogen, -OH, -NR f R g Or C3-C6 cycloalkyl;

[0061] Or, R X1 and R 4 The atoms connected to them together form C4-C7 carbon rings or 4-7 membered heterocycles. In the 4-7 membered heterocycles, the heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.

[0062] Or, R X2 and R 4The atoms connected to them together form C4-C7 carbon rings or 4-7 membered heterocycles. In the 4-7 membered heterocycles, the heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.

[0063] for , , , or ;

[0064] B is a connector, -O-, -S-, , , -NR B2 or CR B3 R B4 ;

[0065] R B1 R B2 R B3 R B4 R 5 R 5’ R 6 R 7 R 9 R 10 and R 10’ Each is independently -H, C1-C6 alkyl, or surrounded by one or more R e Substituted C1-C6 alkyl groups;

[0066] R 8 Independently for -H, C1-C6 alkyl or containing one or more R e Substituted C1-C6 alkyl groups;

[0067] R 8-1 Independently C1-C6 alkyl, C1-C6 alkoxy, or -NR h R i ;

[0068] R h and R i Each is independently -H or C1-C6 alkyl;

[0069] R e Independently -OH or C1-C6 alkoxy group;

[0070] Or, “R” 5 and R 5’ “R” 5 and R 6 “R” 6 and R 7 “R”7 and R 8 “R” 8 and R 9 “R” 9 and R 10 "or "R 10 and R 10’ "The atoms connected to them together form 5-6 member saturated heterocycles or are bounded by one or more R..." d The substituted 5-6 member saturated heterocycle, wherein the heteroatoms are each independently N and / or O, and the number of heteroatoms is each independently 1 or 2.

[0071] R d Independently equal to 0;

[0072] Ring A is C6-C 10 Aromatic ring or 5-10 membered heteroaromatic ring, wherein the 5-10 membered heteroaromatic ring is a 5-10 membered heteroaromatic ring in which the heteroatoms are selected from one, two or three kinds of N, O and S, and the number of heteroatoms is one, two or three.

[0073] R 1 for ;

[0074] R a It is a C1-C4 alkyl or C3-C4 cycloalkyl;

[0075] R b -H, C1-C4 alkyl, or ;

[0076] R b-1 Independently, it is a C1-C4 alkyl group;

[0077] Independently -H, =O, -NR f R g -NO2, -OH, -CN, halogens, C1-C4 alkyl, C2-C4 alkynyl, C2-C4 alkenyl, C3-C4 cycloalkyl, C1-C4 alkoxy groups or those with one or more R groups 2-1 Substituted C1-C4 alkyl groups;

[0078] R 2-1 Independently halogen, -OH or -NR f R g ;

[0079] Or, R 1 Adjacent R 2 The atoms connected to them together form or p and q are each independently 1, 2 or 3;

[0080] m can be 1, 2, 3, 4, or 5.

[0081] In one aspect of the present invention, for , , , , or ,For example , or .

[0082] In one aspect of the present invention, R 4 Halogen, C1-C4 alkyl, C3 alkynyl or R 4-1 It is a C3-C4 cycloalkyl group, such as Cl, methyl, n-propyl, n-butyl, or Preferred to be n-propyl, n-butyl or More preferably n-propyl.

[0083] In one aspect of the present invention, One or more of the following:

[0084] I: or The carbon atoms marked with "*" have the R configuration, S configuration, or a mixture thereof, for example... , , , , or Preferred , or , where R 8 for R 9 It is -H or C1-C6 alkyl;

[0085] II: , , , or The carbon atoms marked with "*" have the R configuration, S configuration, or a mixture thereof, for example... , , , , , , , , , , , , , , , , , , , or For example, , , , , , , , , , , , , , or Among them, "R" 5 and R 6 “R” 6 and R 7 “R” 7 and R 8 “R” 8 and R 9 "or "R 9 and R 10 "The atoms connected to them together form 5-6 membered saturated heterocycles or are bounded by one or more R..." d Substituted 5-6 member saturated heterocycles;

[0086] III: , or The carbon atoms marked with "*" have the R configuration, S configuration, or a mixture thereof, for example... , , , , , or R 5 and R 10 Each is independently a C1-C6 alkyl group or is composed of one or more R groups. e Substituted C1-C6 alkyl groups;

[0087] IV: The carbon atoms marked with "*" have the R configuration, S configuration, or a mixture thereof, for example... , or Preferred R 10 It is a C1-C6 alkyl group.

[0088] In one aspect of the present invention, One or more of the following:

[0089] I: , , , or The carbon atoms marked with "*" have the R configuration, S configuration, or a mixture thereof. , , , , , , , , , , , , , or For example, , , , , , , , , , , , or Preferred , or ;

[0090] II: , , , , or The carbon atoms marked with "*" have the R configuration, S configuration, or a mixture thereof, for example... , , , , , , , , , , , , , , , , or ;

[0091] III: , or The carbon atoms marked with "*" have the R configuration, S configuration, or a mixture thereof, for example... , , , , , or ;

[0092] IV: The carbon atoms marked with "*" have the R configuration, S configuration, or a mixture thereof, for example... , or Preferred .

[0093] In one embodiment of the present invention, ring A is a benzene ring, a 6-membered heteroaromatic ring, or an 8-10-membered bicyclic heteroaromatic ring, wherein each ring of the 8-10-membered bicyclic heteroaromatic ring is aromatic or one of the rings is aromatic.

[0094] In one embodiment of the present invention, ring A is a benzene ring, a pyridine ring, a pyrimidine ring, an imidazopyridine ring, a pyrrolopyridine ring, a dihydropyrrolopyridine ring, or a dihydropyridopyridine ring, for example... , , , , , , , or .

[0095] In one aspect of the present invention, for , , , , , , , , , , or ,For example , , , or .

[0096] In one aspect of the present invention, R 1 for The sulfur atoms marked with "*" have the configuration of R, S, or a mixture thereof, for example... , or Or, R 1 Adjacent R 2 The atoms connected to them together form The sulfur atoms marked with "*" have the configuration of R, S, or a mixture thereof, for example... , or Where the a-end represents R 1 The b-end represents R. 2 end.

[0097] In one aspect of the present invention, R 1 for , , , , , or The sulfur atoms marked with "*" have the configuration of R, S, or a mixture thereof, for example... , , , , , , , , , , , , , , , , , or .

[0098] In one aspect of the present invention, R 1 for , , , or The sulfur atoms marked with "*" have the configuration of R, S, or a mixture thereof, for example... , , , , , , , , , , , , , or ;

[0099] Or, R 1 Adjacent R 2 The atoms connected to them together form The sulfur atoms marked with "*" have the configuration of R, S, or a mixture thereof, for example... , or Where the a-end represents R 1 The b-end represents R. 2 end.

[0100] In one aspect of the present invention, R 2 To be independent of -H, =O, -NH2, -NO2, -OH, -CN, -F, -Cl, -CF3, methoxy or methyl.

[0101] In one aspect of the present invention, R 2 To be independent of -H, =O, -NH2, -NO2, -OH, -CN, -F, -Cl, methoxy or methyl, preferably -H, F, Cl, methyl or -NH2;

[0102] Or, R 1 Adjacent R 2 The atoms connected to them together form The sulfur atoms marked with "*" have the configuration of R, S, or a mixture thereof, for example... , or Where the a-end represents R 1 The b-end represents R. 2 end.

[0103] In one aspect of the present invention, the compound represented by formula (I) is a compound represented by formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), or (IJ):

[0104] , , , , , , , , or ;

[0105] Among them, the carbon atoms marked with "*" are in the R configuration, S configuration, or a mixture thereof;

[0106] X is CH or N, Z is CH2, NH, O or S, and m is 0, 1 or 2;

[0107] The definitions and positions of the remaining substituents are as described in any embodiment of the present invention.

[0108] In one aspect of the present invention, the compound represented by formula (I) is a compound represented by formula (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), or (I-8):

[0109] , , , , , , or ;

[0110] Where X is CH or N, and m is 0, 1 or 2;

[0111] The definitions and positions of the remaining substituents are as described in any embodiment of the present invention.

[0112] In one aspect of the present invention, the compound represented by formula (I) is any one of the following compounds:

[0113] , , , , , , , , , , , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , and .

[0114] In one aspect of the present invention, the compound represented by formula (I) is any one of the following compounds:

[0115] and The compound that elutes first under the following conditions: chiral column CHIRALCEL AY-H, 2 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: isopropanol; flow rate 40 mL / min; gradient: isogradient 50% B; preferably, the retention time of the compound that elutes first is 5.5 min.

[0116] and Compounds eluting later under the following conditions: chiral column CHIRALCEL AY-H, 2 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: isopropanol; flow rate 40 mL / min; gradient: isogradient 50% B; preferably, the retention time of the compounds eluting later is 13.2 min.

[0117] and The compound that elutes first under the following conditions: chiral column CHIRAL ART Cellulose-SZ, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the compound that elutes first is 11.0 min;

[0118] and Compounds eluting later under the following conditions: chiral column CHIRAL ART Cellulose-SZ, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the compounds eluting later is 13.8 min.

[0119] and The compound that elutes first under the following conditions: chiral column CHIRALPAK-IK, 3 x 25 mm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the compound that elutes first is 19.0 min.

[0120] and Compounds eluting later under the following conditions: chiral column CHIRALPAK-IK, 3 x 25 mm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the compound eluting later is 24.1 min.

[0121] and The compound that elutes first under the following conditions: chiral column HIRAL ART Cellulose-SB, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase ethanol; flow rate 40 mL / min; gradient: isogradient 25% B; preferably, the retention time of the compound that elutes first is 12.4 min.

[0122] and Compounds eluting later under the following conditions: chiral column HIRAL ART Cellulose-SB, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase ethanol; flow rate 40 mL / min; gradient: isogradient 25% B; preferably, the retention time of the compounds eluting later is 24.1 min.

[0123] A stereoisomer, wherein... The configuration of the S atom in compound A1 The S atom configuration is the same, and the compound A1 is... and The compound that elutes first under the following conditions: chiral column CHIRALPAK PAK AD-H, 30 x 250 mm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 50% B; preferably, the retention time of the compound that elutes first is 9.7 min;

[0124] A stereoisomer, wherein... The configuration of the S atom in compound A2 is similar to that in compound A2. The S atom configuration is the same, and the compound A2 is... and Compounds that elute later in the column under the following conditions: Chiral column CHIRALPAK PAK AD-H, 30 x 250 mm, 5 μm; Mobile phase A: n-hexane (10 mmol / L ammonia-methanol), Mobile phase B: ethanol; Flow rate 40 mL / min; Gradient: isogradient 50% B; Preferably, the retention time of the compound that elutes later in the column is 14.2 min.

[0125] and The first-eluting compound was selected under the following conditions: a chiral column CHIRAL ART Cellulose-SB, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: 30% B; preferably, the retention time of the first-eluting compound was 7.6 min.

[0126] and Compounds eluting later under the following conditions: chiral column CHIRAL ART Cellulose-SB, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: 30% B; preferably, the retention time of the compounds eluting later is 11.3 min.

[0127] A stereoisomer, wherein... The configuration of the S atom in compound A3 is similar to that in compound A3. The S atoms have the same configuration, and the compound A3 is... and The first-eluting compound was selected under the following conditions: a chiral column CHIRAL ART Cellulose-SB, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: 30% B; preferably, the retention time of the first-eluting compound was 7.6 min.

[0128] A stereoisomer, wherein... The configuration of the S atom in compound A4 is similar to that in compound A4. The S atoms have the same configuration, and the compound A4 is... and Compounds eluting later under the following conditions: chiral column CHIRAL ART Cellulose-SB, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: 30% B; preferably, the retention time of the compounds eluting later is 11.3 min.

[0129] and The compound that elutes first under the following conditions: chiral column CHIRAL ART Cellulose-SB, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the compound that elutes first is 15.1 min;

[0130] and Compounds that elute later in the column under the following conditions: chiral column CHIRAL ART Cellulose-SB, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the compounds that elute later in the column is 19 min.

[0131] and The compound that elutes first under the following conditions: chiral column Chiral NQ(2) 5u, 250 x 30 mm, 5 μm; mobile phase A: n-hexane (0.1% formic acid), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the compound that elutes first is 24.3 min;

[0132] and Compounds that elute later in the column under the following conditions: Chiral NQ(2) 5u, 250 x 30 mm, 5 μm; mobile phase A: n-hexane (0.1% formic acid), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the compound that elutes later in the column is 28.4 min.

[0133] and The compound that elutes first under the following conditions: chiral column: (S, S)-WHELK-O1, 2 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 20 mL / min; gradient: isogradient 40% B; preferably, the retention time of the compound that elutes first is 24.1 min;

[0134] and Compounds eluting later under the following conditions: chiral column: (S, S)-WHELK-O1, 2 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate: 20 mL / min; gradient: isogradient 40% B; preferably, the retention time of the compound eluting later is 30.0 min;

[0135] and The compound that elutes first under the following conditions: chiral column: CHIRAL ART Cellulose-SC, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol / acetonitrile = 5 / 1; flow rate: 40 mL / min; gradient: isogradient 20% B; preferably, the retention time of the compound that elutes first is 28.2 min;

[0136] and Compounds eluting later under the following conditions: chiral column: CHIRAL ART Cellulose-SC, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol / acetonitrile = 5 / 1; flow rate: 40 mL / min; gradient: isogradient 20% B; preferably, the retention time of the compound eluting later is 35.3 min;

[0137] and The compound that elutes first under the following conditions: chiral column CHIRAL ART Cellulose-SZ, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 40% B; preferably, the retention time of the compound that elutes first is 9.7 min.

[0138] and Compounds eluting later under the following conditions: chiral column CHIRAL ART Cellulose-SZ, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 40% B; preferably, the retention time of the compounds eluting later is 12.3 min.

[0139] A stereoisomer, wherein... The configuration of the S atom in compound A5 is similar to that in compound A5. The S atoms have the same configuration, and the compound A5 is... and The compound that elutes first under the following conditions: chiral column CHIRAL ART Cellulose-SZ, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 40% B; preferably, the retention time of the compound that elutes first is 9.7 min;

[0140] A stereoisomer, wherein... The configuration of the S atom in compound A6 is similar to that in compound A6. The S atoms have the same configuration, and the compound A6 is... and Compounds eluting later under the following conditions: chiral column CHIRAL ART Cellulose-SZ, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 40% B; preferably, the retention time of the compounds eluting later is 12.3 min.

[0141] and The compound that elutes first under the following conditions: chiral column: CHIRAL ART Cellulose-SZ, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the compound that elutes first is 13.4 min;

[0142] and Compounds eluting later under the following conditions: chiral column: CHIRAL ART Cellulose-SZ, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate: 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the compounds eluting later is 17.5 min.

[0143] and The compound that elutes first under the following conditions: chiral column: CHIRAL ART Cellulose-SZ, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: isopropanol; flow rate 40 mL / min; gradient: isogradient 50% B; preferably, the retention time of the compound that elutes first is 10.6 min;

[0144] and Compounds eluting later under the following conditions: chiral column: CHIRAL ART Cellulose-SZ, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: isopropanol; flow rate: 40 mL / min; gradient: isogradient 50% B; preferably, the retention time of the compound eluting later is 13.7 min.

[0145] and The compound that elutes first is selected under the following conditions: column: CHIRALPAK-IK, 3 x 25 mm, 5 μm; mobile phase A: carbon dioxide, mobile phase B: methanol (20 mmol / L ammonia); flow rate: 90 mL / min; gradient: isogradient 50% B; preferably, the retention time of the compound that elutes first is 8.3 min.

[0146] and Compounds eluting later under the following conditions: column: CHIRALPAK-IK, 3 x 25 mm, 5 μm; mobile phase A: carbon dioxide, mobile phase B: methanol (20 mmol / L ammonia); flow rate: 90 mL / min; gradient: isogradient 50% B; preferably, the retention time of the compound eluting later is 10.2 min.

[0147] A stereoisomer, wherein... The configuration of the S atom in compound A7 is similar to that in... The S atoms have the same configuration, and the compound A7 is... and The compound that elutes first is selected under the following conditions: column: CHIRALPAK-IK, 3 x 25 mm, 5 μm; mobile phase A: carbon dioxide, mobile phase B: methanol (20 mmol / L ammonia); flow rate: 90 mL / min; gradient: isogradient 50% B; preferably, the retention time of the compound that elutes first is 8.3 min.

[0148] A stereoisomer, wherein... The configuration of the S atom in compound A8 The S atoms have the same configuration, and the compound A8 is... and Compounds eluting later under the following conditions: column: CHIRALPAK-IK, 3 x 25 mm, 5 μm; mobile phase A: carbon dioxide, mobile phase B: methanol (20 mmol / L ammonia); flow rate: 90 mL / min; gradient: isogradient 50% B; preferably, the retention time of the compound eluting later is 10.2 min.

[0149] and The compound that elutes first under the following conditions: chiral column CHIRAL ART Cellulose-SZ, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (methanol with 10 mM ammonia), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 50% B; preferably, the retention time of the compound that elutes first is 8.8 min.

[0150] and Compounds that elute later in the column were selected under the following conditions: Chiral ART Cellulose-SZ column, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (methanol with 10 mM ammonia), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 50% B; preferably, the retention time of the compounds that elute later in the column was 13.6 min.

[0151] and The compound that elutes first under the following conditions: Chiral column CHIRAL ART Cellulose-SZ, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (methanol with 10 mM ammonia); mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 50% B; preferably, the retention time of the compound that elutes first is 7.8 min.

[0152] and Compounds that elute later in the column were selected under the following conditions: Chiral column CHIRAL ART Cellulose-SZ, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (methanol with 10 mM ammonia); mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 50% B; preferably, the retention time of the compounds that elute later in the column was 9.9 min.

[0153] and The compound that elutes first under the following conditions: chiral column CHIRALCEL AY-H, 2 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol); mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 50% B; preferably, the retention time of the compound that elutes first is 3.6 min.

[0154] and Compounds that elute later in the column were selected under the following conditions: chiral column CHIRALCEL AY-H, 2 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol); mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 50% B; preferably, the retention time of the compounds that elute later in the column was 6.8 min.

[0155] and The first eluting compound was selected under the following conditions: Chiral NX(2) chiral column, 250 x 30 mm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol); mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 40% B; preferably, the retention time of the first eluting compound was 10.1 min.

[0156] and Compounds that elute later in the column under the following conditions: Chiral NX(2), 250 x 30 mm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol); mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 40% B; preferably, the retention time of the compounds that elute later in the column is 14.0 min.

[0157] and The compound that elutes first under the following conditions: chiral column CHIRAL ART Cellulose-SZ, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 50% B; preferably, the retention time of the compound that elutes first is 6.7 min;

[0158] and Compounds that elute later in the column under the following conditions: chiral column CHIRAL ART Cellulose-SZ, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 50% B; preferably, the retention time of the compounds that elute later in the column is 11.0 min.

[0159] and The compound that elutes first under the following conditions: chiral column CHIRALPAK IA, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the compound that elutes first is 16.1 min;

[0160] and Compounds that elute later in the column were selected under the following conditions: chiral column CHIRALPAK IA, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the compounds that elute later in the column was 21.6 min.

[0161] , , and The first eluting compound was selected under the following conditions: chiral column Enantiocel-A4-5, 3.0 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the first eluting compound was 11.5 min.

[0162] , , and The second eluting compound was selected under the following conditions: chiral column Enantiocel-A4-5, 3.0 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the second eluting compound was 17.0 min.

[0163] , , and The third eluting compound was selected under the following conditions: chiral column Enantiocel-A4-5, 3.0 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the compound with the third eluting peak was 21.2 min.

[0164] , , and The substance that elutes second under condition A is further separated from the compound that elutes first under condition B. Condition A is: Enantiocel-A4-5 chiral column, 3.0 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the substance that elutes second is 17.0 min. Condition B is: CHIRALPAK IH column, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the compound that elutes first is 16.8 min.

[0165] , , and The compound that elutes the second peak under condition A is further separated under condition B. Condition A is: Enantiocel-A4-5 chiral column, 3.0 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the second peak is 17.0 min. Condition B is: CHIRALPAK IH 3 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the subsequent peak is 23.5 min.

[0166] and The first-eluting compound was selected under the following conditions: chiral column Lux 5um Cellulose-4 3×25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 50% ethanol; preferably, the retention time of the first-eluting compound was 11.8 min.

[0167] and Compounds eluting later under the following conditions: chiral column Lux 5um Cellulose-4 3×25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 50% ethanol; preferably, the retention time of the compounds eluting later is 14.5 min.

[0168] , , and The first eluting substance under the following conditions: chiral column CHIRALPAK-IK, 3.0 × 25 mm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the first eluting substance is 7.8 min;

[0169] , , and The second eluting substance was obtained under the following conditions: chiral column CHIRALPAK-IK, 3.0 × 25 mm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the second eluting substance was 17.0 min.

[0170] , , and The substance that elutes first under condition A is further separated into its initial peaks under condition B. Condition A is as follows: chiral column CHIRALPAK-IK, 3.0 × 25 mm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the first elute is 7.8 min. Condition B is as follows: chiral column CHIRALPAK IH, 3 × 25 cm, 5 μm; mobile phase A: carbon dioxide, mobile phase B: 20 ​​mmol / L ammonia-methanol; flow rate 100 mL / min; gradient: isogradient 35% 20 mmol / L ammonia-methanol solution; preferably, the retention time of the initial elute is 3.9 min.

[0171] , , and The substance that elutes first under condition A is further separated under condition B, and the resulting elutes are the substances that elute after further separation. Condition A is: chiral column CHIRALPAK-IK, 3.0 × 25 mm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the first elute is 7.8 min. Condition B is: chiral column CHIRALPAK IH, 3 × 25 cm, 5 μm; mobile phase A: carbon dioxide, mobile phase B: 20 ​​mmol / L ammonia-methanol; flow rate 100 mL / min; gradient: isogradient 35% 20 mmol / L ammonia-methanol solution; preferably, the retention time of the subsequent elutes is 5.2 min.

[0172] , , and The substance that elutes first under condition A is further separated under condition B, and the substance that elutes next under condition C is further separated from the first elute under condition C. Condition A is: chiral column CHIRALPAK-IK, 3.0 × 25 mm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the first elute is 7.8 min. Condition B is: chiral column CHIRALPAK IH, 3 × 25 cm, 5 μm; mobile phase A: carbon dioxide, mobile phase B: 20 ​​mmol / L ammonia-methanol; flow rate 100 mL / min; gradient: isogradient 35% 20 mmol / L ammonia-methanol solution; preferably, the retention time of the subsequent elutes is 5.2 min. Condition C is: chiral column CHIRALPAK IH, 3 × 25 cm, 5 μm; Mobile phase A: carbon dioxide, mobile phase B: 20 ​​mmol / L ammonia-isopropanol; flow rate 80 mL / min; gradient: isogradient 50% B; preferably, the retention time of the first eluting substance further separated under condition C is 5.8 min;

[0173] , , and The substance that elutes first under condition A, is further separated under condition B, and then further separated under condition C. Condition A is: chiral column CHIRALPAK-IK, 3.0 × 25 mm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the first elute is 7.8 min. Condition B is: chiral column CHIRALPAK IH, 3 × 25 cm, 5 μm; mobile phase A: carbon dioxide, mobile phase B: 20 ​​mmol / L ammonia-methanol; flow rate 100 mL / min; gradient: isogradient 35% 20 mmol / L ammonia-methanol solution; preferably, the retention time of the subsequent elutes is 5.2 min. Condition C is: chiral column CHIRALPAK IH, 3 × 25 cm, 5 μm; Mobile phase A: carbon dioxide, mobile phase B: 20 ​​mmol / L ammonia-isopropanol; flow rate 80 mL / min; gradient: isogradient 50% B; preferably, the retention time of the substance eluting after further separation under condition C is 7.2 min;

[0174] and The compound that elutes first under the following conditions: chiral column Lux 5u Cellulose-2 30 × 250 mm, 5.0 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% ethanol; preferably, the retention time of the compound that elutes first is 17.7 min.

[0175] and Compounds eluting later under the following conditions: chiral column Lux 5u Cellulose-2 30 × 250 mm, 5.0 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% ethanol; preferably, the retention time of the compound eluting later is 22.4 min.

[0176] and The first eluting compound was selected under the following conditions: chiral column Lux 5um Cellulose-4, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; gradient: isogradient 50% B; preferably, the retention time of the first eluting compound was 8.8 min.

[0177] and Compounds eluting later under the following conditions: chiral column Lux 5um Cellulose-4, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; gradient: isogradient 50% B; preferably, the retention time of the compound eluting later is 11.7 min.

[0178] and The first eluting compound was selected under the following conditions: chiral column CHIRALPAK AD-H, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: isopropanol; flow rate: 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the first eluting compound was 7.7 min.

[0179] and Compounds eluting later under the following conditions: chiral column CHIRALPAK AD-H, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: isopropanol; flow rate: 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the compound eluting later is 12.8 min;

[0180] , , and The first eluting compound was selected under the following conditions: chiral column CHIRAL ARTCellulose-SC, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate: 40 mL / min; gradient: isogradient 50% B; preferably, the retention time of the first eluting compound was 7.9 min.

[0181] , , and The second eluting compound was obtained under the following conditions: chiral column CHIRAL ARTCellulose-SC, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate: 40 mL / min; gradient: isogradient 50% B; preferably, the retention time of the second eluting compound was 9.6 min.

[0182] , , and The third eluting compound was observed under the following conditions: a chiral column CHIRAL ARTCellulose-SC, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate: 40 mL / min; gradient: isogradient 50% B; preferably, the retention time of the third eluting compound was 11.6 min.

[0183] , , and The fourth eluting compound was observed under the following conditions: a chiral column CHIRAL ARTCellulose-SC, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate: 40 mL / min; gradient: isogradient 50% B; preferably, the retention time of the fourth eluting compound was 24.2 min.

[0184] , , and The substance that elutes first under condition A is further separated into its initial peaks under condition B. Condition A is as follows: chiral column CHIRALPAK IN 3, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (0.5% in 2 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the first elute is 15.9 min. Condition B is as follows: chiral column CHIRALPAK IH, 3.0 × 50 mm, 3 μm; mobile phase A: carbon dioxide, mobile phase B: 20 ​​mM ammonia-methanol; flow rate 100 mL / min; gradient: isogradient 30% B; preferably, the retention time of the first elute is 3.12 min.

[0185] , , and The substance that elutes first under condition A is further separated under condition B, and the substance that elutes after further separation is described in condition A as follows: chiral column CHIRALPAK IN 3, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (0.5% in 2 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the first elute is 15.9 min. Condition B is described as follows: chiral column CHIRALPAK IH, 3.0 × 50 mm, 3 μm; mobile phase A: carbon dioxide, mobile phase B: 20 ​​mM ammonia-methanol; flow rate 100 mL / min; gradient: isogradient 30% B; preferably, the retention time of the subsequent elute is 4.10 min.

[0186] , , and The substance that elutes second under condition A is further separated from the substance that elutes first under condition C. Condition A is: chiral column CHIRALPAK IN 3, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (0.5% in 2 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the substance that elutes second is 25.4 min. Condition C is: chiral column CHIRALPAK IH, 3.0 × 50 mm, 3 μm; mobile phase A: carbon dioxide, mobile phase B: 20 ​​mM ammonia-methanol; flow rate 100 mL / min; gradient: isogradient 30% B; preferably, the retention time of the substance that elutes first is 3.0 min.

[0187] , , and The substance that elutes second under condition A is further separated under condition C, and the resulting elute is the substance with the second peak. Condition A is: chiral column CHIRALPAK IN 3, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (0.5% in 2 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the second elute is 25.4 min. Condition C is: chiral column CHIRALPAK IH, 3.0 × 50 mm, 3 μm; mobile phase A: carbon dioxide, mobile phase B: 20 ​​mM ammonia-methanol; flow rate 100 mL / min; gradient: isogradient 30% B; preferably, the retention time of the subsequent elute is 4.10 min.

[0188] , , and The substance that elutes first under condition A is further separated under condition B. Condition A is as follows: chiral column Enantiocel-A4-5, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (0.5% 2M ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 50% B; preferably, the retention time of the substance that elutes first under condition A is 8.9 min. Condition B is as follows: chiral column CHIRALPAKAY, 3.0 × 50 mm, 3 μm; mobile phase A: n-hexane (0.5% 2M ammonia-methanol), mobile phase B: ethanol / acetonitrile (5 / 1); flow rate 40 mL / min; gradient: isogradient 40% B; preferably, the retention time of the substance that elutes first under condition B is 5.4 min.

[0189] , , and The substance that elutes first under condition A is further separated under condition B, and the substance that elutes second under condition C is further separated under condition C. Condition A is: chiral column Enantiocel-A4-5, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (0.5% 2M ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 50% B; preferably, the retention time of the substance that elutes first under condition A is 8.9 min. Condition B is: chiral column CHIRALPAK AY, 3.0 × 50 mm, 3 μm; mobile phase A: n-hexane (0.5% 2M ammonia-methanol), mobile phase B: ethanol / acetonitrile (5 / 1); flow rate 40 mL / min; gradient: isogradient 40% B; preferably, the retention time of the substance that elutes second under condition B is 10.2 min; condition C is a chiral column CHIRALPAK... ID, 3.0 × 50 mm, 3 μm; Mobile phase A: n-hexane (20 mM ammonia-methanol), Mobile phase B: ethanol; Flow rate 40 mL / min; Gradient: isogradient 30% B; Preferably, the retention time of the first eluting substance further separated under condition C is 21 min;

[0190] , , and The substance that elutes first under condition A, is further separated into a second peak under condition B, and then further separated under condition C. Condition A is: chiral column Enantiocel-A4-5, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (0.5% 2M ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 50% B; preferably, the retention time of the first elute under condition A is 8.9 min. Condition B is: chiral column CHIRALPAK AY, 3.0 × 50 mm, 3 μm; mobile phase A: n-hexane (0.5% 2M ammonia-methanol), mobile phase B: ethanol / acetonitrile (5 / 1); flow rate 40 mL / min; gradient: isogradient 40% B; preferably, the retention time of the second elute after separation under condition B is 10.2 min; condition C is a chiral column CHIRALPAK... ID, 3.0 × 50 mm, 3 μm; Mobile phase A: n-hexane (20 mM ammonia-methanol), Mobile phase B: ethanol; Flow rate 40 mL / min; Gradient: isogradient 30% B; Preferably, the retention time of the substance eluting after further separation under condition C is 28.3 min;

[0191] , , and The substance that elutes the second peak under condition A, wherein condition A is: chiral column Enantiocel-A4-5, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (0.5% 2M ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 50% B; preferably, the retention time of the substance that elutes the second peak under condition A is 13.9 min;

[0192] , , and The substance that elutes first under condition A is further separated into its initial peaks under condition B. Condition A is as follows: column type: Lux 5um Cellulose-4, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (0.5% 2M ammonia-methanol), mobile phase B: ethanol; flow rate: 40 mL / min; gradient: isogradient 30%B; preferably, the retention time of the substance that elutes first under condition A is 16.3 min. Condition B is as follows: chiral column: CHIRALPAKID, 3.0 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate: 40 mL / min; gradient: isogradient 50%B; preferably, the retention time of the substance that elutes first under condition B is 9.0 min.

[0193] , , and The substance that elutes first under condition A is further separated under condition B, where condition A is: column type Lux 5um Cellulose-4, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (0.5% 2M ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the substance that elutes first under condition A is 16.3 min. Condition B is: chiral column CHIRALPAKID, 3.0 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 50% B; preferably, the retention time of the substance that elutes after further separation under condition B is 11.9 min.

[0194] , , and The substance that elutes second under condition A, wherein condition A is: column type Lux5um Cellulose-4, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (0.5% 2M ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the substance that elutes second under condition A is 22.4 min;

[0195] , , and The substance that elutes third under condition A, wherein condition A is: column type Lux5um Cellulose-4, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (0.5% 2M ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the substance that elutes third under condition A is 28.4 min.

[0196] The above retention time test conditions are not a limitation on the compound. As long as the above test conditions are used to determine the retention time, and the obtained retention time is the same as or within the error range described above, and the compound is a stereoisomer of the compound limited by the retention time described above, then it falls within the protection scope of this invention.

[0197] The present invention also provides a pharmaceutical composition comprising a compound of formula (I) as described in any of the above embodiments, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0198] The present invention also provides the use of a compound of formula (I) as described in any of the above embodiments, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition in the preparation of a 5-hydroxytryptamine 4 (5-HT4) receptor agonist.

[0199] The present invention also provides the use of any of the above-described compounds of formula (I), pharmaceutically acceptable salts thereof, solvates thereof, solvates of pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of medicaments for the prevention and / or treatment of diseases associated with serotonin 4 receptors, such as gastrointestinal motility disorders or gastrointestinal diseases, such as gastroesophageal reflux disease (GERD), constipation, irritable bowel syndrome (IBS), dyspepsia, postoperative intestinal obstruction, delayed gastric emptying, gastroparesis, pseudo-intestinal obstruction, drug-induced transit delay, or diabetic gastric atony.

[0200] The present invention also provides the use of the compound of formula (I) as described in any of the above embodiments, its pharmaceutically acceptable salt, its solvate, a solvate of its pharmaceutically acceptable salt, or the above pharmaceutical composition in the preparation of a medicament for the prevention and / or treatment of a disease, wherein the disease is a gastrointestinal motility disorder or a gastrointestinal disease, such as gastroesophageal reflux disease (GERD), constipation, irritable bowel syndrome (IBS), dyspepsia, postoperative intestinal obstruction, delayed gastric emptying, gastroparesis, pseudo-intestinal obstruction, drug-induced transit delay, or diabetic gastric atony.

[0201] Those skilled in the art will understand that, according to conventions used in the art, the use of "" in the structural formulas describing the functional groups in this invention is appropriate. "" refers to the fact that the corresponding group is connected to other fragments or groups in the compound through this site.

[0202] In this article, a single hyphen "-" can be added before the substituent to indicate that the named substituent is connected to the parent moiety by a single bond; a single hyphen "=" can be added before the substituent to indicate that the named substituent is connected to the parent moiety by a double bond.

[0203] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0204] The term "alkyl" refers to a straight-chain or branched saturated hydrocarbon group having a specified number of carbon atoms. In some embodiments, the alkyl group is C64. 1-6 Alkyl, such as C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl groups, etc. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl and similar alkyl groups.

[0205] The term "alkenyl" refers to a straight-chain or branched olefin having a specific number of carbon atoms, containing one or more carbon-carbon double bonds and no carbon-carbon triple bonds. The one or more carbon-carbon double bonds can be intermediate or terminal. Examples of alkenes include, but are not limited to, vinyl or allyl.

[0206] The term "alkynyl" refers to a straight-chain or branched hydrocarbon group (e.g., C2-C6 alkynyl, or C2-C4 alkynyl) with one or more triple bonds having a specific number of carbon atoms. These carbon-carbon triple bonds can be intermediate or terminal, such as in the propynyl group with the triple bond in the middle. Or a propynyl group at the end of the triple bond wait.

[0207] The term "cycloalkyl" refers to a saturated cyclic group having a specified number of carbon atoms in the ring (e.g., C3 to C6) and whose ring atoms consist only of carbon atoms. Monocycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0208] The term "alkoxy group" refers to the group -OR X , where R X It is an alkyl group as defined above.

[0209] The term "carbon ring" refers to a saturated or unsaturated ring with a specified number of ring atoms (e.g., 3-7), consisting of only carbon atoms.

[0210] The term "heterocycle" refers to a saturated or unsaturated ring having a specified number of ring atoms (e.g., 4-7), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (e.g., one or more selected from N, O, and S).

[0211] The term "aromatic ring" refers to a ring having a specified number of carbon atoms (e.g., C6~C1). 10 An unsaturated ring, which is a monocyclic or polycyclic ring (e.g., two or three). When it is a polycyclic ring, the monocyclic rings share two atoms and one bond, and each ring is aromatic.

[0212] The term "heteroaromatic ring" refers to an unsaturated ring having a specified number of ring atoms (e.g., 5 to 10), a specified number of heteroatoms (e.g., 1, 2 or 3), and a specified type of heteroatoms (1, 2 or 3 of N, O and S), which may be monocyclic or polycyclic, sharing two atoms and one bond between monocyclic rings, and (at least one ring / each ring) is aromatic.

[0213] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0214] The reagents and raw materials used in this invention are all commercially available.

[0215] The positive and progressive effects of the present invention are as follows: the compounds of the present invention have excellent agonistic activity against the 5-HT4 receptor, and furthermore, compared with the 5-HT1, 5-HT2, 5-HT3 and 5-HT6 receptors, the compounds of the present invention have good selective agonistic activity against the 5-HT4 receptor. Detailed Implementation

[0216] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0217] The abbreviations and their corresponding chemical names used in the embodiments of this invention are as follows: abbreviation describe <![CDATA[Pd(dppf)Cl2]]> [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride <![CDATA[Pd(dppf)Cl2·DCM]]> [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex <![CDATA[Boc2O]]> Ditert-butyl dicarbonate DIEA N,N-Diisopropylethylamine DMAP 4-Dimethylaminopyridine 1,4-Dioxane 1,4-Dioxane, <![CDATA[K2CO3]]> Potassium carbonate DMF N,N-dimethylformamide Fe iron <![CDATA[NH4Cl]]> ammonium chloride NaH Sodium hydride <![CDATA[Ac2O]]> Acetic anhydride <![CDATA[BBr3]]> Boron tribromide <![CDATA[POCl3]]> Phosphorus oxychloride <![CDATA[Pd2(dba)3]]> Di(2-benzylacetone)palladium TFA Trifluoroacetic acid <![CDATA[(CH3CO)2O]]> Acetic anhydride S-Phos 2-Dicyclohexylphosphine-2′,6′-dimethoxy-biphenyl <![CDATA[Cs2CO3]]> cesium carbonate <![CDATA[PhI(OAc)2]]> (diacetoxyiodine)benzene XantPhos 4,5-Bis(diphenylphosphine)-9,9-dimethyloxanthracene <![CDATA[Pd(OAc)2]]> Palladium acetate THF Tetrahydrofuran DMSO dimethyl sulfoxide ACN Acetonitrile NCS N-chlorosuccinimide <![CDATA[BocNH2]]> tert-butyl carbamate Pd-PEPPSI-IHeptCl Dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) <![CDATA[NH2COONH4]]> Ammonium carbamate X-Phos 2-Bicyclohexylphosphine-2',4',6'-triisopropylbiphenyl LiOH Lithium hydroxide Proline proline

[0218] The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE III HD 400 or Bruker AVANCE III HD 300 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as solvents, and tetramethylsilane (TMS) as the internal standard.

[0219] The determinations were performed using LC-MS with an electrospray ionization (ESI) source. The determinations were performed using a SHIMADZU LC-20 AP. XR And SPD-M20A high-performance liquid chromatography.

[0220] Thin-layer chromatography uses Yantai Xinnuo Chemical GF254 silica gel plates. The TLC standard is 0.15 mm to 0.20 mm. Column chromatography generally uses 200 to 300 mesh silica gel from Chenghua Chemical as the carrier.

[0221] The starting materials used in the embodiments of the present invention are known and commercially available, or can be synthesized using or in accordance with methods known in the art.

[0222] Example 1:

[0223] N-((S)-1-(2-((3-(((S or R)-S-methylsulfonylimino)phenyl)amino)-6-propylpyrimidin-4-yl)pyrrolidine-3-yl)acetamide (compound 1a)

[0224] Preparation of N-((S)-1-(2-((3-((R or S)-S-methylsulfonylimino)phenyl)amino)-6-propylpyrimidin-4-yl)pyrrolidine-3-yl)acetamide (compound 1b)

[0225] Step 1:

[0226]

[0227] In 0 o Under C conditions, compound 1-1 (20.0 g, 117 mmol; CAS: 51-52-5, purchased directly from supplier Shanghai Yuanye Biotechnology) and N,N-diisopropylethylamine (50 mL, 287 mmol) were dissolved in phosphine oxychloride (200 mL). The reaction system was heated at 100 °C. o The mixture was stirred at C for 15 hours. The reaction progress was monitored by liquid chromatography-mass spectrometry. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to remove most of the phosphine oxychloride. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1). The fraction obtained was concentrated under reduced pressure to give 13.0 g of compound 1-2 (brown oil, yield 58%).

[0228] MS (ESI, m / z): [M+H] + = 191.20 / 193.20 / 195.20.

[0229] 1 H NMR (400 MHz, CDCl3) δ 7.15 (s, 1H), 2.71 (t, J = 7.2 Hz, 2H), 1.84-1.67 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H).

[0230] Step 2:

[0231]

[0232] In 0 oUnder C conditions, compounds 1-2 (10.0 g, 52.3 mmol) were dissolved in dichloromethane (130 mL), and then (S)-pyrrolidine-3-ylcarbamate tert-butyl ester (11.7 g, 62.8 mmol; CAS: 122536-76-9, purchased directly from supplier Shanghai Shaoyuan Technology Co., Ltd.) and N,N-diisopropylethylamine (10.9 mL, 62.8 mmol) were added to the above reaction solution, respectively. The reaction system was stirred at room temperature for 3 hours. The reaction progress was monitored using liquid chromatography-mass spectrometry. After the reaction was complete, the reaction system was directly concentrated under reduced pressure, and the resulting residue was directly purified using a reversed-phase C18 column. The purification conditions were as follows: 330 g C18 reversed-phase column; mobile phase: acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate: 80 mL / min; gradient: acetonitrile increased from 10% to 70% within 20 minutes; detection wavelength: 254 nm. After liquid chromatography-mass spectrometry (LC-MS) confirmation, the fraction of the product was collected, concentrated under reduced pressure, and lyophilized to give 8.00 g of compound 1-3 (yellow solid, yield 45%).

[0233] MS (ESI, m / z): [M+H] + = 341.05 / 343.05.

[0234] 1 H NMR (400 MHz, CDCl3) δ 6.02 (s, 1H), 4.79-4.49 (m, 1H), 4.40-4.30(m, 1H), 3.70-3.20 (m, 4H), 2.55 (t, J = 7.2 Hz, 2H), 2.35-2.15 (m, 1H), 2.13-1.83 (m, 1H), 1.80-1.65 (m, 2H), 1.45 (s, 9H), 0.95 (t, J = 7.2 Hz, 3H).

[0235] Step 3:

[0236]

[0237] In 0 o Under C conditions, compound 1-3 (8.00 g, 23.5 mmol) was dissolved in dichloromethane (160 mL), and then trifluoroacetic acid (35.0 mL) was slowly added dropwise to the solution using a syringe. The reaction system was allowed to return to room temperature and stirred for 2 hours. The reaction progress was monitored using liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction system was concentrated under reduced pressure to obtain 8.80 g of trifluoroacetate 1-4 (pale yellow oil, yield 106%, crude product).

[0238] MS (ESI, m / z): [M-CF3COOH +H] + = 241.20 / 243.15.

[0239] 1 H NMR (400 MHz, CD3OD) δ 6.52 (s, 1H), 4.12-4.02 (m, 1H), 4.01-3.61(m, 4H), 2.64 (t, J = 7.2 Hz, 2H), 2.55-2.45 (m, 1H), 2.35-2.25 (m, 1H),1.79-1.68 (m, 2H), 0.98 (t, J = 7.2 Hz, 3H).

[0240] Step 4:

[0241]

[0242] Compounds 1-4 (8.80 g, 24.9 mmol, crude product) were dissolved in dichloromethane (110 mL) at room temperature. Acetic anhydride (3.74 g, 37.4 mmol) and triethylamine (17.0 mL, 124 mmol) were then added to the reaction solution. The reaction mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified directly using a C18 reversed-phase column. The purification conditions were as follows: 330 g C18 reversed-phase column; mobile phase: acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate: 80 mL / min; gradient: acetonitrile from 10% to 90% over 30 minutes; detection wavelength: 254 nm. After LC-MS confirmation, the product fraction was collected, concentrated under reduced pressure, and lyophilized to give 5.00 g of compound 1-5 (yellow solid, 71% yield).

[0243] MS (ESI, m / z): [M+H] + = 282.95 / 285.15.

[0244] 1H NMR (400 MHz, CDCl3) δ 6.37-6.19 (m, 1H), 6.03 (s, 1H), 4.62-4.52(m, 1H), 3.76-3.24 (m, 4H), 2.55 (t, J = 7.2 Hz, 2H), 2.30-2.20 (m, 1H), 2.18-2.08 (m, 1H), 2.02 (s, 3H), 1.76-1.65 (m, 2H), 0.98 (t, J = 7.2 Hz, 3H).

[0245] Step 5:

[0246]

[0247] Compounds 1-6 (3.00 g, 19.2 mmol; CAS: 2369-13-3, purchased directly from Shanghai Haohong Biomedical Technology Co., Ltd.) were dissolved in N,N-dimethylformamide (30.0 mL) at 0 °C, and sodium methanethiol (1.62 g, 23.1 mmol) was added in portions to the above solution. The reaction system was brought to room temperature and stirred for 1 hour at room temperature. The reaction progress was monitored by liquid chromatography-mass spectrometry. After the reaction was complete, the reaction system was quenched with water (300 mL) at 0 °C. The mixture was extracted with ethyl acetate (200 mL × 3), the organic phases were combined, washed with saturated sodium chloride aqueous solution (200 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 9 / 1), and the fraction was concentrated under reduced pressure to give 2.80 g of compounds 1-7 (yellow solid, yield 79%).

[0248] MS (ESI, m / z): [M+H] + = 185.15.

[0249] Step 6:

[0250]

[0251] Under a nitrogen atmosphere and at room temperature, starting materials 1-7 (400 mg, 2.17 mmol) and 1-5 (614 mg, 2.17 mmol) were dissolved in 1,4-dioxane (4 mL). Then, tris(dibenzylacetone)palladium (198 mg, 0.217 mmol), cesium carbonate (1.41 g, 4.34 mmol), and 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (178 mg, 0.434 mmol) were added sequentially to the reaction solution. The reaction mixture was stirred at 100 °C for 2 hours. The reaction progress was monitored using liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the mixture was brought to room temperature, filtered, and the filter cake was washed with methanol (10.0 mL × 3). The filtrate was concentrated under reduced pressure, and the residue was directly purified using a reverse-phase C18 column. The purification conditions were as follows: 40 g C18 reversed-phase column; mobile phase: acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate: 25 mL / min; gradient: acetonitrile increased from 5% to 95% over 45 minutes; detection wavelength: 254 nm. After confirmation by liquid chromatography-mass spectrometry, the product fraction was collected, concentrated under reduced pressure, and lyophilized to give 350 mg of compounds 1-8 (yellow solid, yield 37%).

[0252] MS (ESI, m / z): [M+H] + = 431.15.

[0253] 1 H NMR (300 MHz, DMSO-d6) δ 9.82 (s, 1H), 8.20 (d, J = 9.2 Hz, 1H), 8.14 (d, J = 6.8 Hz, 1H), 8.09 (s, 1H), 7.83 (s, 1H), 6.00 (s, 1H), 4.40-4.27(m, 1H), 3.75-3.40 (m, 4H), 3.27-3.05 (m, 1H), 2.48 (s, 3H), 2.47-2.43 (m,1H), 2.21-2.09 (m, 1H), 1.97-1.85 (m, 1H), 1.80 (s, 3H), 1.74-1.63 (m, 2H),0.93 (t, J = 7.2 Hz, 3H).

[0254] Step 7:

[0255]

[0256] Compounds 1-8 (350 mg, 0.813 mmol) were dissolved in methanol (5.00 mL) at room temperature. Ammonium carbamate (253 mg, 3.25 mmol) and (diacetoxyiodine)benzene (785 mg, 2.44 mmol) were added sequentially to the reaction solution. The reaction mixture was stirred for 1 hour at room temperature. The reaction progress was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction mixture was quenched with water (20.0 mL) at 0 °C. The mixture was extracted with ethyl acetate (50.0 mL × 3), and the combined organic phases were washed with saturated sodium chloride aqueous solution (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified directly using a reverse-phase C18 column. The purification conditions were as follows: 80 g C18 reversed-phase column; mobile phase: acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate: 40 mL / min; gradient: acetonitrile from 5% to 95% over 40 minutes; detection wavelength: 254 nm. After confirmation by liquid chromatography-mass spectrometry, the product fraction was collected, concentrated under reduced pressure, and lyophilized to give 200 mg of compounds 1-9 (yellow solid, yield 53%).

[0257] MS (ESI, m / z): [M+H] + = 462.20.

[0258] 1 H NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 8.97 (s, 1H), 8.14 (s, 1H), 8.00-7.77 (m, 2H), 5.97 (s, 1H), 4.59 (s, 1H), 4.43-4.33 (m, 1H), 3.74-3.36(m, 4H), 3.29 (s, 3H), 2.50-2.44 (m, 2H), 2.14-2.10 (m, 1H), 1.92-1.88 (m,1H), 1.86 (s, 3H) 1.68-1.73 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H).

[0259] Step 8:

[0260]

[0261] Compounds 1-9 (200 mg, 0.433 mmol) were dissolved in ethanol (3.2 mL) and water (0.8 mL) at room temperature. Ammonium chloride (116 mg, 2.17 mmol) and zinc powder (142 mg, 2.16 mmol) were added to the above reaction solution, respectively. The reaction system was stirred at room temperature for 1 hour. The reaction progress was monitored by liquid chromatography-mass spectrometry. After the reaction was complete, the reaction system was filtered, the filter cake was washed with ethanol (10.0 mL × 2), the filtrate was concentrated under reduced pressure, and the residue was directly purified by preparative liquid chromatography. The purification conditions were as follows: X Br sidge Shield RP18 OBD Column 30 × 150 mm, 5 μm; mobile phase: water (10 mmol / L ammonium bicarbonate + 0.05% ammonia) and acetonitrile; flow rate: 60 mL / min; gradient: acetonitrile from 10% to 30% over 10 min, then maintained at an isogradient of 30% acetonitrile for 10 min; detection wavelength: 254 nm / 220 nm; retention time: 11.2 min. The fraction was collected, concentrated under reduced pressure, and lyophilized to give 75 mg of compound 1 (a mixture of diastereomers, white solid, yield 40%).

[0262] MS (ESI, m / z): [M+H] + = 432.20.

[0263] Step 9:

[0264]

[0265] The diastereomer mixture 1 (75.0 mg, 0.174 mmol) was chirally resolved under the following conditions: chiral column CHIRALCEL AY-H, 2 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: isopropanol; flow rate 40 mL / min; gradient: isogradient 50% B; detection wavelength 209 / 282 nm; retention time 5.50 min for the forepeak fraction. After concentration under reduced pressure and lyophilization, 34.1 mg of optically pure compound 1a (white solid, 45% yield) was obtained. The latter fraction was obtained with a retention time of 13.2 min. After concentration under reduced pressure and lyophilization, 35.0 mg of optically pure compound 1b (white solid, 46% yield) was obtained.

[0266] Compound 1a:

[0267] MS (ESI, m / z): [M+H] + = 432.20.

[0268] 1 H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.40 (s, 1H), 8.13 (d, J =6.8 Hz, 1H), 7.46-7.43 (m, 1H), 6.74 (d, J = 8.8 Hz, 1H), 5.87 (s, 2H), 5.74(s, 1H), 4.36-4.23 (m, 1H), 4.12 (s, 1H), 3.51-3.18 (m, 4H), 2.97 (s, 3H), 2.37 (t, J = 7.2 Hz, 2H), 2.15-2.04 (m, 1H), 1.90-1.84 (m, 1H), 1.80 (s, 3H),1.69-1.60 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H).

[0269] Compound 1b:

[0270] [α] 25 D = -34.75 (c = 0.4, EtOH)

[0271] MS (ESI, m / z): [M+H] + = 432.20.

[0272] 1 H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.40 (s, 1H), 8.13 (d, J =6.8 Hz, 1H), 7.46-7.43 (m, 1H), 6.74 (d, J = 8.8 Hz, 1H), 5.87 (s, 2H), 5.74(s, 1H), 4.36-4.23 (m, 1H), 4.12 (s, 1H), 3.51-3.18 (m, 4H), 2.97 (s, 3H), 2.37 (t, J = 7.2 Hz, 2H), 2.15-2.04 (m, 1H), 1.90-1.84 (m, 1H), 1.80 (s, 3H),1.69-1.61 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H).

[0273] Example 2:

[0274] N-((S)-1-(2-((3-((S or R)-S-methylsulfonylimino)phenyl)amino)-6-propylpyrimidin-4-yl)pyrrolidine-3-yl)acetamide (compound 2a);

[0275] Preparation of N-((S)-1-(2-((3-((R or S)-S-methylsulfonylimino)phenyl)amino)-6-propylpyrimidin-4-yl)pyrrolidine-3-yl)acetamide (compound 2b)

[0276] Step 1:

[0277]

[0278] According to the synthesis method in step 6 of Example 1, the raw materials were replaced with 2-1 (60.0 mg, 0.431 mmol; CAS: 1783-81-9, purchased directly from supplier Shanghai Haohong Biomedical Technology) and 1-5 (122 mg, 0.431 mmol) respectively to prepare 130 mg of compound 2-2 (white solid, yield 78%).

[0279] MS (ESI, m / z): [M+H] + = 386.20.

[0280] 1 H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.15 (d, J = 6.8 Hz, 1H), 7.95 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.20-7.09 (m, 1H), 6.79-6.71 (m, 1H),5.83 (s, 1H), 4.41-4.27 (m, 1H), 4.13-4.02 (m, 1H), 3.79-3.34 (m, 3H), 2.44(s, 3H), 2.42-2.37 (m, 2H), 2.19-2.07 (m, 1H), 1.91-1.83 (m, 1H), 1.81(s,3H), 1.73-1.60 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H).

[0281] Step 2:

[0282]

[0283] According to step 7 of Example 1, the starting material was replaced with 2-2 (130 mg, 0.337 mmol) to prepare 55.0 mg of compound 2 (a mixture of diastereomers, white solid, yield 39%).

[0284] MS (ESI, m / z): [M+H] + = 417.15.

[0285] Step 3:

[0286]

[0287] The diastereomer mixture 2 (55.0 mg, 0.132 mmol) was chirally resolved. The resolution conditions were as follows: chiral column CHIRAL ART Cellulose-SZ, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; detection wavelength 211 / 271 nm. A retention time of 11.0 min yielded the forepeak fraction, which was concentrated under reduced pressure and lyophilized to give 15.1 mg of optically pure compound 2a (white solid, 27% yield); a retention time of 13.8 min yielded the hindpeak fraction, which was concentrated under reduced pressure and lyophilized to give 20.2 mg of optically pure compound 2b (white solid, 36% yield).

[0288] Compound 2a:

[0289] MS (ESI, m / z): [M+H] + = 417.15.

[0290] 1 H NMR (400 MHz, DMSO-d6) δ 9.37 (s, 1H), 8.82 (s, 1H), 8.23-8.08 (m,1H), 7.78 (d, J = 7.6 Hz, 1H), 7.48-7.33 (m, 2H), 5.86 (s, 1H), 4.37-4.27 (m,1H), 3.99 (s, 1H), 3.82-3.37 (m, 3H), 3.24-3.06 (m, 1H), 3.01 (s, 3H), 2.43(t, J = 7.2 Hz, 2H), 2.21-2.06 (m, 1H), 1.94 -1.85 (m,1H), 1.81 (s, 3H),1.77-1.61 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H).

[0291] Compound 2b:

[0292] MS (ESI, m / z): [M+H] + = 417.15.

[0293] 1 H NMR (400 MHz, DMSO-d6) δ 9.37 (s, 1H), 8.82 (s, 1H), 8.23-8.08 (m,1H), 7.78 (d, J = 7.6 Hz, 1H), 7.48-7.33 (m, 2H), 5.86 (s, 1H), 4.37-4.27 (m,1H), 3.99 (s, 1H), 3.82-3.37 (m, 3H), 3.24-3.06 (m, 1H), 3.01 (s, 3H), 2.43(t, J = 7.2 Hz, 2H), 2.21-2.06 (m, 1H), 1.94-1.85 (m,1H), 1.81 (s, 3H), 1.77-1.61 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H).

[0294] Example 3:

[0295] N-((S)-1-(2-((3-cyano-5-((R or S)-S-methylsulfonylimino)phenyl)amino)-6-propylpyrimidin-4-yl)pyrrolidine-3-yl)acetamide (compound 3a)

[0296] Preparation of N-((S)-1-(2-((3-cyano-5-((S or R)-S-methylsulfonylimino)phenyl)amino)-6-propylpyrimidin-4-yl)pyrrolidine-3-yl)acetamide (compound 3b)

[0297] Step 1:

[0298]

[0299] Under a nitrogen atmosphere, 3-1 (1.10 g, 5.58 mmol; CAS: 49674-16-0, purchased directly from Shanghai Haohong Biomedical Technology Co., Ltd.) was dissolved in 1,4-dioxane (15.0 mL). Then, palladium acetate (130 mg, 0.558 mmol), cesium carbonate (3.64 g, 11.2 mmol), sodium methanethiol (780 mg, 11.2 mmol), and the ligand 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene (320 mg, 0.558 mmol) were added sequentially to the reaction solution. The reaction system was stirred at 120 °C for 3 hours under a nitrogen atmosphere. The reaction progress was monitored using liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction system was quenched with water (30 mL) at 0 °C. Extracted with ethyl acetate (150 mL × 3), the combined organic phases were washed with saturated sodium chloride aqueous solution (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1), and the resulting fraction was concentrated under reduced pressure to give 600 mg of compound 3-2 (pale yellow solid, yield 63%).

[0300] MS (ESI, m / z): [MH] - = 163.10.

[0301] 1 H NMR (400 MHz, CDCl3) δ 6.85 (s, 1H), 6.72-6.70 (m, 1H), 6.67-6.65(m, 1H), 3.87 (br s, 2H), 2.46 (s, 3H).

[0302] Step 2:

[0303]

[0304] According to step 6 of Example 1, the starting materials were replaced with 3-2 (170 mg, 1.04 mmol) and 1-5 (293 mg, 1.04 mmol) respectively to prepare 270 mg of compound 3-3 (white solid, yield 64%).

[0305] MS (ESI, m / z): [M+H] + = 411.15.

[0306] 1H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 8.20-8.12 (m, 2H), 8.09-7.93(m, 1H), 7.15 (s, 1H), 5.91 (s, 1H), 4.41-4.28 (m, 1H), 3.73-3.53 (m, 2H),3.49-3.40 (m, 1H), 3.25-3.05 (m, 1H), 2.50 (s, 3H), 2.44 (t, J = 7.2 Hz, 2H),2.20-2.07 (m, 1H), 1.96-1.84 (m, 1H), 1.80 (s, 3H), 1.73-1.62 (m, 2H), 0.92(t, J = 7.2 Hz, 3H).

[0307] Step 3:

[0308]

[0309] According to step 7 of Example 1, the starting material was replaced with 3-3 (230 mg, 0.560 mmol) to prepare 100 mg of compound 3 (a diastereomer mixture, white solid, yield 40%).

[0310] MS (ESI, m / z): [M+H] + = 442.20.

[0311] 1 H NMR (400 MHz, CDCl3) δ 8.88 (s, 1H), 8.00 (s, 1H), 7.83-7.80 (m,1H), 5.93-5.83 (m, 1H), 5.82 (s, 1H), 4.62-4.53 (m, 1H), 3.93-3.42 (m, 4H),3.11 (s, 3H), 2.97-2.78 (m, 1H), 2.57-2.50 (t, J = 7.6 Hz, 2H), 2.44-2.31 (m,1H), 2.09-2.03 (m, 1H), 2.02 (s, 3H), 1.81-1.71 (m, 2H), 1.00 (t, J = 7.2 Hz, 3H).

[0312] Step 4:

[0313]

[0314] The diastereomer mixture 3 (100 mg, 0.226 mmol) was chirally resolved. The resolution conditions were as follows: chiral column CHIRALPAK-IK, 3 × 25 mm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; detection wavelength 208 / 240 nm; retention time 19.0 min yielded the forepeak fraction, which, after concentration under reduced pressure and lyophilization, yielded 32.2 mg of optically pure compound 3a (white solid, 32% yield); retention time 24.1 min yielded the hindpeak fraction, which, after concentration under reduced pressure and lyophilization, yielded 25.2 mg of optically pure compound 3b (white solid, 25% yield).

[0315] Compound 3a:

[0316] [α] 25 D = -15.25 (c = 0.4, EtOH)

[0317] MS (ESI, m / z): [M+H] + = 442.20.

[0318] 1 H NMR (400 MHz, DMSO-d6) δ 9.76 (s, 1H), 8.97 (s, 1H), 8.27 (s, 1H), 8.22-8.09 (m, 1H), 7.73 (s, 1H), 5.93 (s, 1H), 4.40-4.26 (m, 2H), 3.80-3.38(m, 4H), 3.08 (s, 3H), 2.46 (t, J = 7.6 Hz, 2H), 2.20-2.07 (m, 1H), 1.95-1.84(m, 1H), 1.81 (s, 3H), 1.75-1.63 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H).

[0319] Compound 3b:

[0320] [α] 25 D = -43.75 (c = 0.4, EtOH)

[0321] MS (ESI, m / z): [M+H] + = 442.20.

[0322] 1H NMR (400 MHz, DMSO-d6) δ 9.77 (s, 1H), 8.99 (s, 1H), 8.28 (s, 1H), 8.22-8.09 (m, 1H), 7.74 (s, 1H), 5.94 (s, 1H), 4.39-4.25 (m, 2H), 3.76-3.37(m, 4H), 3.08 (s, 3H), 2.46 (t, J = 7.6 Hz, 2H), 2.20-2.07 (m, 1H), 1.95-1.84(m, 1H), 1.80 (s, 3H), 1.74-1.63 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H).

[0323] Example 4:

[0324] N-((S)-1-(2-((3-((S or R)-S-methylsulfonylimide)-4-nitrophenyl)amino)-6-propylpyrimidin-4-yl)pyrrolidine-3-yl)acetamide (compound 4a)

[0325] Preparation of N-((S)-1-(2-((3-((R or S)-S-methylsulfonylimino)-4-nitrophenyl)amino)-6-propylpyrimidin-4-yl)pyrrolidine-3-yl)acetamide (compound 4b)

[0326] Step 1:

[0327]

[0328] Compounds 1-9 (a mixture of diastereomers, 110 mg, 0.238 mmol) were prepared according to the synthetic method in Example 1, and then subjected to chiral resolution. The resolution conditions were as follows: chiral column HIRAL ART Cellulose-SB, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase ethanol; flow rate 40 mL / min; gradient: isogradient 25% B; detection wavelength 240 / 206 nm; retention time 12.4 min yielded the forepeak fraction, which was concentrated under reduced pressure and lyophilized to give 40.5 mg of optically pure compound 4a (yellow solid, yield 36%); retention time 24.1 min yielded the hindpeak fraction, which was concentrated under reduced pressure and lyophilized to give 35.1 mg of optically pure compound 4b (yellow solid, yield 32%).

[0329] Compound 4a:

[0330] [α] 25D = -106.5 (c = 0.4, EtOH)

[0331] MS (ESI, m / z): [M+H] + = 462.15.

[0332] 1 H NMR (400 MHz, DMSO-d6) δ 9.97 (s, 1H), 8.95 (s, 1H), 8.22 - 8.07 (m,1H), 7.95 - 7.84 (m, 2H), 5.97 (s, 1H), 4.48 (br s, 1H), 4.39 - 4.26 (m, 1H),3.84 - 3.39 (m, 3H), 3.24 - 3.10 (m, 1H), 2.50 (s, 3H), 2.46 - 2.43 (m, 2H), 2.20 - 2.06 (m, 1H), 1.96 - 1.85 (m, 1H), 1.81 (s, 3H), 1.74 - 1.65 (m, 2H), 0.92 (t, J = 7.6 Hz, 3H).

[0333] Compound 4b:

[0334] [α] 25 D = +97.75 (c = 0.4, EtOH)

[0335] MS (ESI, m / z): [M+H] + = 462.15.

[0336] 1 H NMR (400 MHz, DMSO-d6) δ 9.99 (s, 1H), 9.09 - 8.84 (m, 1H), 8.24 - 8.05(m, 1H), 7.96 - 7.84 (m, 2H), 5.98 (s, 1H), 4.49 (br s, 1H), 4.40 - 4.25 (m, 1H),3.84 - 3.44 (m, 3H), 3.24 - 3.06 (m, 1H), 2.50 (s, 3H), 2.48 - 2.42 (m, 2H), 2.20 - 2.06 (m, 1H), 1.96 - 1.85 (m, 1H), 1.81 (s, 3H), 1.74 - 1.65 (m, 2H), 0.92 (t, J = 7.6 Hz, 3H).

[0337] Example 5:

[0338] N-((S)-1-(2-((4-amino-3-((R or S)-ethylsulfonylimino)phenyl)amino)-6-propylpyrimidin-4-yl)pyrrolidine-3-yl)acetamide (compound 5a)

[0339] Preparation of N-((S)-1-(2-((4-amino-3-((S or R)-ethylsulfonylimino)phenyl)amino)-6-propylpyrimidin-4-yl)pyrrolidine-3-yl)acetamide (compound 5b)

[0340] Step 1:

[0341]

[0342] According to step 5 of Example 1, the starting materials were replaced with 1-6 (5.00 g, 32.0 mmol) and sodium ethanethiol (3.23 g, 38.4 mmol) respectively to prepare 5.00 g of compound 5-1 (yellow solid, yield 78%).

[0343] 1 H NMR (300 MHz, CDCl3) δ 8.18 (d, J = 8.7 Hz, 1H), 6.48-6.43 (m, 2H), 4.41 (s, 2H), 2.99-2.88 (m, 2H), 1.43 (t, J = 7.5 Hz, 3H).

[0344] Step 2:

[0345]

[0346] Under a nitrogen atmosphere, starting materials 5-1 (500 mg, 2.52 mmol) and 1-5 (713 mg, 2.52 mmol) were dissolved in 1,4-dioxane (6.00 mL). Catalysts dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazolium-2-yl](3-chloropyridyl)palladium(II) (246 mg, 0.252 mmol) and cesium carbonate (1.64 g, 5.04 mmol) were added to the reaction mixture. The reaction system was stirred at 100 °C for 16 hours under a nitrogen atmosphere. The reaction progress was monitored using liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the system was allowed to return to room temperature. The filter cake was washed with methanol (20 mL × 3), the filtrate was concentrated under reduced pressure, and the residue was directly purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1). The fraction obtained was concentrated under reduced pressure to give 400 mg of compound 5-2 (white solid, yield 36%).

[0347] MS (ESI, m / z): [M+H] + = 445.20.

[0348] 1 H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 8.8 Hz, 1H), 7.93 (br s, 1H), 7.39-7.28 (m, 2H), 5.92-5.83 (m, 1H), 5.80 (s, 1H), 4.66-4.56 (m, 1H), 3.82-3.18 (m, 4H), 3.02-2.93 (m, 2H), 2.51 (t, J = 7.6 Hz, 2H), 2.35-2.25 (m, 1H), 2.08-2.04 (m, 1H), 2.03 (s, 3H), 1.79-1.69 (m, 2H), 1.43 (d, J = 7.6 Hz, 3H),1.00 (d, J = 7.6 Hz, 3H).

[0349] Step 3:

[0350]

[0351] According to step 7 of Example 1, the starting material was replaced with 5-2 (400 mg, 0.90 mmol) to prepare 220 mg of compound 5-3 (a mixture of diastereomers, yellow solid, yield 51%).

[0352] MS (ESI, m / z): [M+H] + = 476.25.

[0353] Step 4:

[0354]

[0355] The diastereomer mixture 5-3 (220 mg, 0.263 mmol) was chirally resolved. The resolution conditions were as follows: chiral column CHIRALPAK PAK AD-H, 30 × 250 mm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 50% B; detection wavelength 208 / 240 nm. A retention time of 9.7 min yielded the forepeak fraction, which was concentrated under reduced pressure and lyophilized to give 80.5 mg of optically pure compound 5-3a (white solid, 36% yield); a retention time of 14.2 min yielded the hindpeak fraction, which was concentrated under reduced pressure and lyophilized to give 81.0 mg of optically pure compound 5-3b (white solid, 37% yield).

[0356] Compound 5-3a:

[0357] MS (ESI, m / z): [M+H] + = 476.20.

[0358] 1 H NMR (400 MHz, CDCl3) δ 9.04 (s, 1H), 7.71-7.53 (m, 2H), 5.82 (s,1H), 4.64-4.51 (m, 1H), 3.96-3.82 (m, 2H), 3.81-3.70 (m, 1H), 3.68-3.55 (m,3H), 2.60 (t, J = 8.0 Hz, 2H), 2.47-2.36 (m, 1H), 2.15-2.06 (m, 1H), 2.03 (s,3H), 1.85-1.77 (m, 2H), 1.37 (t, J = 7.2 Hz, 3H), 1.02 (t, J = 7.2 Hz, 3H).

[0359] Compound 5-3b:

[0360] MS (ESI, m / z): [M+H] + = 476.20.

[0361] 1H NMR (400 MHz, CDCl3) δ 9.05 (s, 1H), 7.71-7.53 (m, 2H), 5.83 (s,1H), 4.65-4.52 (m, 1H), 3.98-3.83 (m, 2H), 3.82-3.70 (m, 1H), 3.69-3.55 (m,3H), 2.60 (t, J = 7.6 Hz, 2H), 2.48-2.36 (m, 1H), 2.15-2.06 (m, 1H), 2.03 (s,3H), 1.85-1.78 (m, 2H), 1.37 (t, J = 7.2 Hz, 3H), 1.02 (t, J = 7.2 Hz, 3H).

[0362] Step 5:

[0363]

[0364] Compound 5-3a (80.0 mg, 0.168 mmol) was dissolved in ethanol (1.20 mL) and water (0.30 mL) at room temperature. Ammonium chloride (45.3 mg, 0.840 mmol) and iron powder (47.1 mg, 0.840 mmol) were added to the above reaction solution, respectively. The reaction system was heated to 80 °C. o Stirring at C for 1 hour. The reaction progress was monitored by liquid chromatography-mass spectrometry. After the reaction was complete, the reaction system was filtered, the filter cake was washed with methanol (10 mL × 2), the filtrate was concentrated under reduced pressure, and the residue was directly purified using a C18 reversed-phase column. The purification conditions were as follows: 40 g C18 reversed-phase column; mobile phase: acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate: 35 mL / min; gradient: acetonitrile from 10% to 50% over 30 minutes; detection wavelength: 254 nm. The product fraction was collected, concentrated under reduced pressure, and lyophilized to give 29 mg of compound 5a (white solid, yield 39%).

[0365] MS (ESI, m / z): [M+H] + = 446.25.

[0366] 1H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.39 (s, 1H), 8.18-8.06 (m,1H), 7.45-7.40 (m, 1H), 6.72 (d, J = 8.8 Hz, 1H), 5.89 (s, 2H), 5.73 (s, 1H), 4.36-4.25 (m, 1H), 4.10 (s, 1H), 3.73-3.36 (m, 3H), 3.27-3.15 (m, 1H), 3.17-3.01 (m, 2H), 2.37 (t, J = 7.6 Hz, 2H), 2.15-2.04 (m, 1H), 1.90-1.82 (m, 1H), 1.80 (s, 3H), 1.71-1.60 (m, 2H), 1.06 (t, J = 7.6 Hz, 3H), 0.90 (t, J = 7.2Hz, 3H).

[0367] Step 6:

[0368]

[0369] According to the method in step 5 of Example 5, the starting material was replaced with 5-3b (80 mg, 0.168 mmol) to prepare 25 mg of compound 5b (yellow solid, yield 33%).

[0370] MS (ESI, m / z): [M+H] + = 446.25.

[0371] 1H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.38 (s, 1H), 8.18-8.06 (m,1H), 7.45-7.40 (m, 1H), 6.73 (d, J = 8.8 Hz, 1H), 5.89 (s, 2H), 5.73 (s, 1H), 4.36-4.25 (m, 1H), 4.10 (s, 1H), 3.73-3.35 (m, 3H), 3.27-3.16 (m, 1H), 3.18-3.02 (m, 2H), 2.37 (t, J = 7.6 Hz, 2H), 2.16-2.05 (m, 1H), 1.90-1.81 (m, 1H), 1.80 (s, 3H), 1.71-1.60 (m, 2H), 1.07 (t, J = 7.6 Hz, 3H), 0.90 (t, J = 7.2Hz, 3H).

[0372] Example 6:

[0373] N-((S)-1-(2-((4-nitro-3-((S or R)-propyl-2-ylsulfonylimino)phenyl)amino)-6-propylpyrimidin-4-yl)pyrrolidine-3-yl)acetamide (compound 6a)

[0374] Preparation of N-((S)-1-(2-((4-nitro-3-((R or S)-propyl-2-ylsulfonylimino)phenyl)amino)-6-propylpyrimidin-4-yl)pyrrolidine-3-yl)acetamide (compound 6b)

[0375] Step 1:

[0376]

[0377] According to step 5 of Example 1, the starting materials were replaced with 1-6 (5.00 g, 32.0 mmol) and sodium isopropanethiolate (4.17 g, 41.6 mmol) respectively to prepare 2.80 g of compound 6-1 (yellow solid, yield 41%).

[0378] MS (ESI, m / z): [M+H] + = 212.90.

[0379] 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 8.8 Hz, 1H), 6.55 (d, J = 2.4Hz, 1H), 6.44-6.39 (m, 1H), 4.61 (brs, 2H), 3.51-3.44 (m, 1H), 1.40 (d, J =6.8 Hz, 6H).

[0380] Step 2:

[0381]

[0382] According to the method in step 2 of Example 5, the starting materials were replaced with 1-5 (600 mg, 2.12 mmol) and 6-1 (495 mg, 2.33 mmol) respectively to prepare 650 mg of compound 6-2 (pale yellow solid, yield 67%).

[0383] MS (ESI, m / z): [M+H] + = 459.10.

[0384] 1 H NMR (300 MHz, DMSO-d6) δ 9.70 (s, 1H), 8.30-8.17 (m, 2H), 8.12 (d,J = 9.3 Hz, 1H), 7.93-7.63 (m, 1H), 5.97 (s, 1H), 4.37-4.28 (m, 1H), 4.13-3.60 (m, 3H), 3.53-3.03 (m, 2H), 2.45 (t, J = 7.5 Hz, 2H), 2.22-2.06 (m, 1H), 1.95-1.84 (m, 1H), 1.82 (s, 3H), 1.72-1.58 (m, 2H), 1.35 (d, J = 6.6 Hz, 6H),0.91 (t, J = 7.2 Hz, 3H).

[0385] Step 3:

[0386]

[0387] According to step 7 of Example 1, the starting material was replaced with 6-2 (600 mg, 1.30 mmol) to prepare 370 mg of compound 6 (a mixture of diastereomers, pale yellow solid, yield 58%).

[0388] MS (ESI, m / z): [M+H] + = 490.20

[0389] Step 4:

[0390]

[0391] The diastereomer mixture 6 (390 mg, 0.797 mmol) was chirally resolved. The resolution conditions were as follows: chiral column CHIRAL ART Cellulose-SB, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: 30% B; detection wavelength 210 / 240 nm. A retention time of 7.6 min yielded the forepeak fraction, which, after concentration under reduced pressure and lyophilization, gave 110 mg of optically pure compound 6a (yellow solid, 28% yield); a retention time of 11.3 min yielded the hindpeak fraction, which, after concentration under reduced pressure and lyophilization, gave 100 mg of optically pure compound 6b (yellow solid, 26% yield).

[0392] Compound 6a:

[0393] [α] 25 D = -34.75 (c = 0.4, EtOH)

[0394] MS (ESI, m / z): [M+H] + = 490.10.

[0395] 1 H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.97 (s, 1H), 8.19-8.10 (m,1H), 7.88-7.79 (m, 2H), 5.97 (s, 1H), 4.51-4.47 (m, 1H), 4.40-4.29 (m, 1H),3.83-3.72 (m, 1H), 3.70-3.35 (m, 3H), 3.26-3.07 (m, 1H), 2.45 (t, J = 7.6 Hz,2H), 2.22-2.07 (m, 1H), 1.96-1.84 (m, 1H), 1.81 (s, 3H), 1.77-1.64 (m, 2H), 1.27 (d, J = 6.8 Hz, 6H), 0.92 (t, J = 7.2 Hz, 3H).

[0396] Compound 6b:

[0397] [α] 25 D = -37.75 (c = 0.4, EtOH)

[0398] MS (ESI, m / z): [M+H] + = 490.15.

[0399] 1 H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 8.98 (s, 1H), 8.21-8.09 (m,1H), 7.88-7.79 (m, 2H), 5.96 (s, 1H), 4.55-4.43 (m, 1H), 4.41-4.31 (m, 1H),3.85-3.70 (m, 1H), 3.70-3.35 (m, 3H), 3.26-3.07 (m, 1H), 2.45 (t, J = 7.6 Hz,2H), 2.22-2.07 (m, 1H), 1.96-1.84 (m, 1H), 1.81 (s, 3H), 1.77-1.64 (m, 2H), 1.27 (d, J = 6.8 Hz, 6H), 0.92 (t, J = 7.2 Hz, 3H).

[0400] Example 7:

[0401] N-((S)-1-(2-((4-amino-3-((R or S)-propyl-2-ylsulfonylimino)phenyl)amino)-6-propylpyrimidin-4-yl)pyrrolidine-3-yl)acetamide (compound 7a)

[0402] Preparation of N-((S)-1-(2-((4-amino-3-((S or R)-propyl-2-ylsulfonylimino)phenyl)amino)-6-propylpyrimidin-4-yl)pyrrolidine-3-yl)acetamide (compound 7b)

[0403] Step 1:

[0404]

[0405] According to the method in step 5 of Example 5, the starting material was replaced with 6a (80.0 mg, 0.163 mmol) to prepare 35.5 mg of optically pure compound 7a (yellow solid, yield 47%).

[0406] MS (ESI, m / z): [M+H] += 460.15.

[0407] 1 H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.37 (s, 1H), 8.18-8.08 (m,1H), 7.46-7.33 (m, 1H), 6.70 (d, J = 8.8 Hz, 1H), 5.94 (s, 2H), 5.73 (s, 1H),4.38-4.28 (m, 1H), 4.07 (s, 1H), 3.75-3.35 (m, 3H), 3.30-3.21 (m, 2H), 2.37(t, J = 7.6 Hz, 2H), 2.19-2.04 (m, 1H), 1.92-1.78 (m, 1H), 1.77 (s, 3H), 1.73-1.59 (m, 2H), 1.21 (d, J = 6.8 Hz, 3H), 1.11 (d, J = 6.8 Hz, 3H), 0.90 (t, J = 7.2 Hz, 3H).

[0408] Step 2:

[0409]

[0410] Synthesized according to step 5 of Example 5, with the starting material replaced by 6b (80.0 mg, 0.163 mmol), yielding 35.2 mg of optically pure compound 7b (yellow solid, yield 47%).

[0411] MS (ESI, m / z): [M+H] + = 460.20.

[0412] 1H NMR (400 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.38 (s, 1H), 8.16-8.07 (m,1H), 7.46-7.35 (m, 1H), 6.68 (d, J = 8.8 Hz, 1H), 5.94 (s, 2H), 5.73 (s, 1H),4.37-4.27 (m, 1H), 4.06 (s, 1H), 3.78-3.32 (m, 3H), 3.30-3.21 (m, 2H), 2.37(t, J = 7.6 Hz, 2H), 2.17-2.04 (m, 1H), 1.90-1.76 (m, 1H), 1.75 (s, 3H), 1.72-1.59 (m, 2H), 1.21 (d, J = 6.8 Hz, 3H), 1.11 (d, J = 6.8 Hz, 3H), 0.90 (t, J = 7.2 Hz, 3H).

[0413] Example 8:

[0414] N-((S)-1-(4-((4-amino-3-((R or S)-S-methylsulfonylimino)phenyl)amino)-6-propylpyridin-2-yl)pyrrolidine-3-yl)acetamide (compound 8a)

[0415] Preparation of N-((S)-1-(4-((4-amino-3-((S or R)-S-methylsulfonylimino)phenyl)amino)-6-propylpyridin-2-yl)pyrrolidine-3-yl)acetamide (compound 8b)

[0416] Step 1:

[0417]

[0418] At 0 °C, raw material 8-1 (30.0 g, 164 mmol, CAS: 16063-69-7, directly purchased from supplier Shanghai Shaoyuan Technology Co., Ltd.) was dissolved in dichloromethane (300 mL). Then, (S)-pyrrolidine-3-ylcarbamate tert-butyl ester (23.4 g, 126 mmol; CAS: 122536-76-9, directly purchased from supplier Shanghai Shaoyuan Technology Co., Ltd.) and N,N-diisopropylethylamine (63.8 g, 493 mmol) were added to the above reaction solution sequentially. The reaction system was stirred at room temperature for 4 hours. The reaction progress was monitored by liquid chromatography-mass spectrometry. After the reaction was complete, the reaction system was concentrated under reduced pressure, and the residue was directly purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1). The obtained fraction was concentrated under reduced pressure to give 15.0 g of compound 8-2 (white solid, yield 27%).

[0419] MS (ESI, m / z): [M+H] + = 332.15 / 334.10 / 336.20.

[0420] 1 H NMR (400 MHz, CDCl3) δ 6.58 (s, 1H), 6.22 (s, 1H), 4.75-4.56 (m,1H), 4.42-4.21 (m, 1H), 3.74-3.66 (m, 1H), 3.58-3.45 (m, 2H), 3.35-3.27 (m,1H), 2.33-2.21 (m, 1H), 2.02-1.91 (m, 1H), 1.45 (s, 9H).

[0421] Step 2:

[0422]

[0423] Compound 8-2 (13.0 g, 39.1 mmol) was dissolved in dichloromethane (150 mL) at 0 °C. Trifluoroacetic acid (5.00 mL) was then slowly added dropwise to the reaction solution using a syringe. The reaction system was stirred at room temperature for 2 hours. After complete reaction of the reactants, the reaction solution was concentrated under reduced pressure to obtain 15.0 g of 8-3 trifluoroacetate compound (brown oil, yield 110%, crude product).

[0424] MS (ESI, m / z): [M-CF3COOH+H] += 232.05 / 234.05 / 236.15.

[0425] Step 3:

[0426]

[0427] Compound 8-3 trifluoroacetate (15.0 g, 43.48 mmol, crude product) was dissolved in dichloromethane (160 mL) at 0 °C. Acetic anhydride (9.85 g, 97.00 mmol) and triethylamine (32.70 g, 32.3 mmol) were then added to the solution. The reaction mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1). The product fraction was collected and concentrated under reduced pressure to give 11.0 g of compound 8-4 (yellow solid, 93% yield).

[0428] MS (ESI, m / z): [M+H] + = 274.15 / 276.10 / 278.05.

[0429] 1 H NMR (400 MHz, CDCl3) δ 6.59 (d, J = 1.2 Hz, 1H), 6.22 (d, J = 1.2Hz, 1H), 5.90-5.78 (m, 1H), 4.63-4.52 (m, 1H), 3.75-3.67 (m, 1H), 3.58-3.48(m, 2H), 3.39-3.31 (m, 1H), 2.35-2.24 (m, 1H), 2.03-1.95 (m, 4H).

[0430] Step 4:

[0431]

[0432] Compound 8-4 (100 mg, 0.360 mmol) was dissolved in 1,4-dioxane (1.0 mL) at room temperature and under a nitrogen atmosphere. Then, n-propylboronic acid (35.3 mg, 0.410 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (26.7 mg, 0.0360 mmol), and potassium carbonate (101 mg, 0.730 mmol) were added sequentially to the reaction solution. The reaction system was stirred at 100 °C for 16 hours. After liquid chromatography showed no remaining reactants, the reaction was quenched with water (20.0 mL) at 0 °C, extracted with ethyl acetate (20.0 mL × 3), and the combined organic phases were washed with saturated sodium chloride aqueous solution (20 mL × 2). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was directly purified using a reverse-phase C18 column. The purification conditions were as follows: 330 g C18 reversed-phase column; mobile phase: acetonitrile and water (0.1% formic acid); flow rate: 45 mL / min; gradient: acetonitrile from 5% to 20% over 20 minutes; detection wavelength: 254 nm. After confirmation by liquid chromatography-mass spectrometry, the product fraction was collected, concentrated under reduced pressure, and lyophilized to give 80.0 mg of compound 8-5 (yellow solid, yield 79%).

[0433] MS (ESI, m / z): [M+H] + = 282.15 / 284.10.

[0434] 1 H NMR (400 MHz, CDCl3) δ 6.91-6.71 (m, 1H), 6.52 (s, 1H), 6.43 (s,1H), 4.59 (s, 1H), 3.89-3.56 (m, 4H), 2.74 (t, J = 7.6 Hz, 2H), 2.36-2.07 (m,2H), 1.98 (s, 3H), 1.82-1.64 (m, 2H), 0.98 (t, J = 7.6 Hz, 3H).

[0435] Step 5:

[0436]

[0437] According to the method in step 2 of Example 5, the starting materials were replaced with 8-5 (1.60 g, 5.68 mmol) and 1-7 (1.05 g, 5.68 mmol) respectively to prepare 2.30 g of compound 8-6 (brown solid, yield 94%).

[0438] MS (ESI, m / z): [M+H] + = 430.20.

[0439] 1 H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 8.22 (d, J = 9.2 Hz, 1H), 8.13 (d, J = 6.8 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 7.06-6.99 (m, 1H), 6.33(d, J = 1.6 Hz, 1H), 6.01 (d, J = 1.6 Hz, 1H), 4.35-4.25 (m, 1H), 3.65-3.57(m, 1H), 3.53-3.36 (m, 2H), 3.26-3.15 (m, 1H), 2.50-2.46 (m, 2H), 2.45 (s,3H), 2.20-2.06 (m, 1H), 1.92-1.79 (m, 1H), 1.82 (s, 3H), 1.73-1.59 (m, 2H),0.92 (t, J = 7.2 Hz, 3H).

[0440] Step 6:

[0441]

[0442] According to step 7 of Example 1, the starting material was replaced with 8-6 (2.00 g, 4.66 mmol) to prepare 420 mg of compound 8-7 (brown solid, yield 19%).

[0443] MS (ESI, m / z): [M+H] + = 461.15.

[0444] 1H NMR (400 MHz, DMSO-d6) δ 9.44 (s, 1H), 8.13 (d, J = 6.8 Hz, 1H), 7.93-7.85 (m, 2H), 7.42-7.34 (m, 1H), 6.29 (d, J = 1.6 Hz, 1H), 6.00 (d, J =1.6 Hz, 1H), 4.61 (s, 1H), 4.33-4.25 (m, 1H), 3.64-3.55 (m, 1H), 3.51-3.37(m, 2H), 3.33 (s, 3H), 3.25-3.16 (m, 1H), 2.49-2.42 (m, 2H), 2.20-2.07 (m,1H), 1.90-1.83 (m, 1H), 1.81 (s, 3H), 1.71-1.58 (m, 2H), 0.92 (t, J = 7.2 Hz,3H)

[0445] Step 7:

[0446]

[0447] According to the method in step 5 of Example 5, the starting materials were replaced with 8-7 (400 mg, 0.869 mmol) to prepare 200 mg of compound 8 (a mixture of diastereomers, brown solid, yield 53%).

[0448] MS (ESI, m / z): [M+H] + = 431.15.

[0449] Step 8:

[0450]

[0451] The diastereomer mixture 8 (200 mg, 0.465 mmol) was chirally resolved. The resolution conditions were as follows: chiral column CHIRAL ART Cellulose-SB, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; detection wavelength 210 / 240 nm. A retention time of 15.1 min yielded the forepeak fraction, which, after concentration under reduced pressure and lyophilization, gave 61.1 mg of optically pure compound 8a (white solid, 31% yield); a retention time of 19.0 min yielded the stern fraction, which, after concentration under reduced pressure and lyophilization, gave 57.5 mg of optically pure compound 8b (white solid, 29% yield).

[0452] Compound 8a:

[0453] MS (ESI, m / z): [M+H] + = 431.25.

[0454] 1 H NMR (400 MHz, DMSO-d6) δ 8.08 (d, J = 6.8 Hz, 1H), 8.03 (s, 1H), 7.44 (d, J = 2.6 Hz, 1H), 7.17-7.12 (m, 1H), 6.84 (d, J = 8.6 Hz, 1H), 6.07(s, 2H), 5.91 (d, J = 1.6 Hz, 1H), 5.56 (d, J = 1.6 Hz, 1H), 4.31 (s, 1H), 4.29-4.20 (m, 1H), 3.55-3.35 (m, 3H), 3.14-3.08 (m, 1H), 3.00 (s, 3H), 2.35(t, J = 7.6 Hz, 2H), 2.15-2.03 (m, 1H), 1.84-1.81 (m, 1H), 1.80 (s, 3H), 1.65-1.54 (m, 2H), 0.89 (t, J = 7.2 Hz, 3H).

[0455] Compound 8b:

[0456] MS (ESI, m / z): [M+H] + = 431.20.

[0457] 1H NMR (400 MHz, DMSO-d6) δ 8.08 (d, J = 6.8 Hz, 1H), 8.03 (s, 1H), 7.44 (d, J = 2.6 Hz, 1H), 7.18-7.12 (m, 1H), 6.84 (d, J = 8.6 Hz, 1H), 6.07(s, 2H), 5.91 (d, J = 1.6 Hz, 1H), 5.56 (d, J = 1.6 Hz, 1H), 4.31 (s, 1H), 4.28-4.21 (m, 1H), 3.55-3.46 (m, 1H), 3.42-3.34 (m, 1H), 3.30-3.25 (m, 1H),3.14-3.06 (m, 1H), 3.00 (s, 3H), 2.35 (t, J = 7.6 Hz, 2H), 2.14-2.02 (m, 1H),1.85-1.80 (m, 1H), 1.79 (s, 3H), 1.65-1.53 (m, 2H), 0.89 (t, J = 7.2 Hz, 3H).

[0458] Example 9:

[0459] N-((S)-1-(2-((4-amino-3-((R or S)-N,S-dimethylsulfonylimide)phenyl)amino)-6-propylpyrimidin-4-yl)pyrrolidine-3-yl)acetamide (compound 9a)

[0460] Synthesis of N-((S)-1-(2-((4-amino-3-((S or R)-N,S-dimethylsulfonylimino)phenyl)amino)-6-propylpyrimidin-4-yl)pyrrolidine-3-yl)acetamide (compound 9b)

[0461] Step 1:

[0462]

[0463] Compounds 1-9 (750 mg, 1.625 mmol) were dissolved in 1,4-dioxane (16 mL) at room temperature. Methylboric acid (195 mg, 3.25 mmol), copper acetate (590 mg, 3.25 mmol), and pyridine (251 mg, 3.25 mmol) were then added sequentially to the reaction solution. The reaction system was stirred in an open container at 100 °C for 2 hours. The reaction progress was monitored using liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was directly purified using a reversed-phase C18 column. The purification conditions were as follows: 120 g C18 reversed-phase column; mobile phase: acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate: 40 mL / min; gradient: acetonitrile from 5% to 40% over 20 minutes, then from 40% to 95% over 30 minutes; detection wavelength: 254 nm. After liquid chromatography-mass spectrometry (LC-MS) confirmation, the fraction of the product was collected, concentrated under reduced pressure, and lyophilized to give 350 mg of compound 9-1 (a mixture of diastereomers, a yellow solid, yield 45%).

[0464] MS (ESI, m / z): [M+H] + = 476.20.

[0465] Step 2:

[0466]

[0467] The compound 9 was synthesized according to step 8 of Example 1, with the starting material replaced by 9-1 (240 mg, 0.505 mmol) to obtain 50.0 mg of compound 9 (a mixture of diastereomers, white solid, yield 22%).

[0468] MS (ESI, m / z): [M+H] + = 446.25.

[0469] Step 3:

[0470]

[0471] A mixture of diastereomers (9, 37 mg, 0.083 mmol) was chirally resolved. The resolution conditions were as follows: Chiral NQ(2) 5u chiral column, 250 × 30 mm, 5 μm; mobile phase A: n-hexane (0.1% formic acid), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; detection wavelength 208 / 282 nm; retention time 24.3 min. The formate fraction was obtained by concentration under reduced pressure, followed by purification and release via a reversed-phase C18 column. The purification conditions were as follows: 40 g C18 reversed-phase column; mobile phase: acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate 35 mL / min; gradient: acetonitrile increased from 10% to 50% over 30 min; detection wavelength 254 nm. After confirming the product fraction with liquid chromatography-mass spectrometry (LC-MS), the product was concentrated under reduced pressure and lyophilized to give 8.1 mg of optically pure compound 9a (white solid, 22% yield). A later peak fraction was obtained at a retention time of 28.4 min, which was concentrated under reduced pressure to give the formate, which was then purified and freed using a reversed-phase C18 column. The purification conditions were as follows: 40 g C18 reversed-phase column; mobile phase: acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate: 35 mL / min; gradient: acetonitrile from 10% to 50% over 30 min; detection wavelength: 254 nm. After confirming the product fraction with LC-MS, the product was collected, concentrated under reduced pressure, and lyophilized to give 9.2 mg of optically pure compound 9b (white solid, 24% yield).

[0472] Compound 9a:

[0473] MS (ESI, m / z): [M+H] + = 446.20.

[0474] 1H NMR (300 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.31 (br s, 1H), 8.13 (d, J= 6.6 Hz, 1H), 7.53-7.48 (m, 1H), 6.75 (d, J = 8.8 Hz, 1H), 5.78 (s, 2H),5.74 (s, 1H), 4.38-4.22 (m, 1H), 3.75-3.37 (m, 3H), 3.29-3.08 (m, 1H), 2.99(s, 3H), 2.51 (s, 3H), 2.38 (t, J = 7.6 Hz, 2H), 2.18-2.04 (m, 1H), 1.93-1.83(m, 1H), 1.80 (s, 3H), 1.73-1.59 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H).

[0475] Compound 9b:

[0476] MS (ESI, m / z): [M+H] + = 446.15.

[0477] 1 H NMR (300 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.32 (br s, 1H), 8.13 (d, J= 6.6 Hz, 1H), 7.53-7.47 (m, 1H), 6.75 (d, J = 8.7 Hz, 1H), 5.78 (s, 2H),5.74 (s, 1H), 4.37-4.24 (m, 1H), 3.70-3.39 (m, 3H), 3.29-3.08 (m, 1H), 2.99(s, 3H), 2.50 (s, 3H), 2.38 (t, J = 7.5 Hz, 2H), 2.17-2.03 (m, 1H), 1.93-1.83(m, 1H), 1.80 (s, 3H), 1.73-1.59 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H).

[0478] Example 10:

[0479] N-((S)-1-(4-((4-amino-5-chloro-6-((R or S)-S-methylsulfonylimide)pyridin-2-yl)amino)-6-propylpyridin-2-ylpyrrolidine-3-yl)acetamide (compound 10a)

[0480] Preparation of N-((S)-1-(4-(4-amino-5-chloro-6-((S or R)-S-methylsulfonylimide)pyridin-2-yl)amino)-6-propylpyridin-2-ylpyrrolidine-3-yl)acetamide (compound 10b)

[0481] Step 1:

[0482]

[0483] Compound 10⁻¹ (3.00 g, 15.2 mmol; CAS: 874491-78-8, available directly from Jinan Qianye Pharmaceutical Technology Co., Ltd.) was dissolved in N,N-dimethylformamide (60.0 mL) and water (24.0 mL) at room temperature. Sodium methanethiol (1.17 g, 16.7 mmol) was then added to the reaction mixture. The reaction system was stirred at 120 °C for 15 hours. The reaction progress was monitored using liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction mixture was cooled to room temperature and then poured into water (100 mL). After standing, the mixture was filtered. The filter cake was further purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4 / 1). The resulting fraction was concentrated under reduced pressure to give 2.00 g of compound 10⁻² (red solid, yield 63%).

[0484] MS (ESI, m / z): [M+H] + = 209.10 / 211.05 / 213.05.

[0485] 1 H NMR (400 MHz, CDCl3) δ 6.42 (s, 1H), 2.54 (s, 3H).

[0486] Step 2:

[0487]

[0488] Compound 10⁻² (2.00 g, 9.57 mmol) was dissolved in tetrahydrofuran (50.0 mL) at room temperature. The reaction mixture of di-tert-butyl dicarbonate (4.18 g, 19.1 mmol) and 4-dimethylaminopyridine (0.580 g, 4.78 mmol) was then stirred at 60 °C for 15 h. The reaction progress was monitored using liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was directly purified using a reversed-phase C18 column. The purification conditions were as follows: 120 g C18 reversed-phase column; mobile phase: acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate: 35 mL / min; gradient: acetonitrile from 10% to 70% over 30 min; detection wavelength: 254 nm. After LC-MS confirmation, the product fraction was collected, concentrated under reduced pressure, and lyophilized to give 2.80 g of compound 10⁻³ (red liquid, 72% yield).

[0489] MS (ESI, m / z): [M-Boc+H] + = 309.15 / 311.05 / 313.05.

[0490] 1 H NMR (400 MHz, CDCl3) δ 6.92 (s, 1H), 2.58 (s, 3H), 1.43 (s, 18H).

[0491] Step 3:

[0492]

[0493] According to the method in step 2 of Example 1, the starting materials were replaced with 10⁻⁴ (20.0 g, 10⁴ mmol, CAS: 25194-01-8; purchased directly from Shanghai Bid Pharmaceutical Technology Co., Ltd.) and (S)-pyrrolidine-3-ylcarbamate tert-butyl ester (19.3 g, 10⁴ mmol; CAS: 122536-76-9, purchased directly from Shanghai Shaoyuan Technology Co., Ltd.) to prepare 7.00 g of compound 10⁻⁵ (yellow solid, yield 20%).

[0494] MS (ESI, m / z): [M+H] + = 343.15 / 345.10.

[0495] 1H NMR (400 MHz, CDCl3) δ 7.21 (d, J = 1.6 Hz, 1H), 6.93 (d, J = 1.6Hz, 1H), 4.71-4.61 (m, 1H), 4.42-4.31 (m, 1H), 3.86-3.77 (m, 1H), 3.69-3.53(m, 2H), 3.44-3.34 (m, 1H), 2.39-2.26 (m, 1H), 2.07-1.96 (m, 1H), 1.46 (s,9H).

[0496] Step 4:

[0497]

[0498] According to step 4 of Example 8, the starting material was replaced with 10⁻⁵ (7.00 g, 20.4 mmol) to prepare 6.00 g of compound 10⁻⁶ (yellow solid, yield 84%).

[0499] MS (ESI, m / z): [M+H] + = 351.20.

[0500] 1 H NMR (400 MHz, CDCl3) δ 7.07 (d, J = 1.6 Hz, 1H), 6.85 (d, J = 1.6Hz, 1H), 4.78-4.59 (m, 1H), 4.41-4.30 (m, 1H), 3.85-3.76 (m, 1H), 3.68-3.53(m, 2H), 3.46-3.37 (m, 1H), 2.71 (t, J = 7.6 Hz, 2H), 2.36-2.24 (m, 1H), 2.05-1.95 (m, 1H), 1.82-1.69 (m, 2H), 1.46 (s, 9H), 0.97 (t, J = 7.2 Hz, 3H).

[0501] Step 5:

[0502]

[0503] According to the method in step 3 of Example 1, the starting material was replaced with 10⁻⁶ (6.00 g, 17.1 mmol) to prepare 6.30 g of trifluoroacetate of compound 10⁻⁷ (brown oily substance, yield 101%, crude product).

[0504] MS (ESI, m / z): [M-CF3COOH+H] + = 251.20.

[0505] Step 6:

[0506]

[0507] Synthesized according to step 4 of Example 1, with the starting material replaced by 10⁻⁷ (6.30 g, 17.3 mmol), yielding 5.00 g of compound 10⁻⁸ (red solid, 99% yield).

[0508] MS (ESI, m / z): [M+H] + = 293.10.

[0509] Step 7:

[0510]

[0511] According to the method in step 5 of Example 5, the starting material was replaced with 10-8 (5.00 g, 17.1 mmol) to prepare 3.10 g of compound 10-9 (red solid, yield 69%).

[0512] MS (ESI, m / z): [M+H] + = 263.20.

[0513] 1 H NMR (400 MHz, DMSO-d6) δ 8.08 (d, J = 6.8 Hz, 1H), 5.71 (d, J = 1.6Hz, 1H), 5.46 (s, 2H), 5.35 (d, J = 1.6 Hz, 1H), 4.15-4.05 (m, 1H), 3.58-3.48(m, 1H), 3.42-3.25 (m, 2H), 3.13-3.06 (m, 1H), 2.30 (t, J = 7.6 Hz, 2H), 2.13-2.03 (m, 1H), 1.85-1.74 (m, 4H), 1.63-1.52 (m, 2H), 0.88 (t, J = 7.2 Hz, 3H).

[0514] Step 8:

[0515]

[0516] According to step 6 of Example 1, the starting materials were replaced with 10⁻³ (3.11 g, 7.62 mmol) and 10⁻⁹ (2.00 g, 7.62 mmol) respectively to prepare 1.80 g of compound 10⁻¹⁰ (red liquid, yield 37%).

[0517] MS (ESI, m / z): [M+H] + = 635.30 / 637.25.

[0518] Step 9:

[0519]

[0520] According to step 7 of Example 1, the starting material was replaced with 10-10 (1.80 g, 2.83 mmol) to prepare 280 mg of compound 10-11 (red solid, yield 15%).

[0521] MS (ESI, m / z): [M+H] + = 666.30 / 668.30.

[0522] Step 10:

[0523]

[0524] Compound 10-11 (260 mg, 0.390 mmol) was dissolved in dichloromethane (4.00 mL) at 0 °C, and trifluoroacetic acid (1.70 mL) was slowly added dropwise to the reaction solution using a syringe. The reaction system was stirred at room temperature for 15 hours. The reaction system was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction mixture was directly concentrated under reduced pressure, and the residue was directly purified by preparative liquid chromatography (HPLC). The purification conditions were as follows: column type X Br sidge Prep OBDC18 Column 30 × 150 mm, 5 μm; mobile phase acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate 60 mL / min; gradient of acetonitrile from 12% to 30% over 10 minutes, then maintaining an isogradient of 30% for 10 minutes; detection wavelength 254 nm / 220 nm; retention time 11.95 minutes. The fraction of the product was collected, concentrated under reduced pressure, and lyophilized to give 60.0 mg of compound 10 (a mixture of diastereomers, white solid, yield 33%).

[0525] MS (ESI, m / z): [M+H] + = 466.35 / 468.40.

[0526] Step 11:

[0527]

[0528] The diastereomer mixture 10 (60.0 mg, 0.129 mmol) was chirally resolved. The resolution conditions were as follows: chiral column: (S, S)-WHELK-O1, 2 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate: 20 mL / min; gradient: isogradient 40% B; detection wavelength: 246 / 274 nm; retention time: 24.1 min yielded the forepeak fraction, which was concentrated under reduced pressure and lyophilized to give 16.0 mg of optically pure compound 10a (red solid, yield 27%); retention time: 30.0 min yielded the hindpeak fraction, which was concentrated under reduced pressure and lyophilized to give 16.6 mg of optically pure compound 10b (white solid, yield 28%).

[0529] Compound 10a:

[0530] MS (ESI, m / z): [M+H] + = 466.20 / 468.15.

[0531] 1 H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.11 (d, J = 6.8 Hz, 1H), 6.63 (s, 2H), 6.54 (d, J = 1.6 Hz, 1H), 6.48 (s, 1H), 6.31 (s, 1H), 4.32-4.21(m, 2H), 3.60-3.52 (m, 1H), 3.49-3.34 (m, 2H), 3.29 (s, 3H), 3.23-3.14 (m,1H), 2.41 (t, J = 7.6 Hz, 2H), 2.17-2.05 (m, 1H), 1.87-1.81 (m, 1H), 1.80 (s,3H), 1.69-1.56 (m, 2H), 0.89 (t, J = 7.2 Hz, 3H).

[0532] Compound 10b:

[0533] MS (ESI, m / z): [M+H] + = 466.15 / 468.10.

[0534] 1H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.11 (d, J = 6.8 Hz, 1H), 6.63 (s, 2H), 6.54 (d, J = 1.6 Hz, 1H), 6.48 (d, J = 1.6 Hz, 1H), 6.31 (s,1H), 4.31-4.21 (m, 2H), 3.61-3.52 (m, 1H), 3.48-3.38 (m, 1H), 3.36-3.33 (m,1H), 3.29 (s, 3H), 3.22-3.14 (m, 1H), 2.41 (t, J = 7.6, Hz, 2H), 2.17-2.04(m, 1H), 1.93-1.81 (m, 1H), 1.80 (s, 3H), 1.69-1.55 (m, 2H), 0.89 (t, J = 7.2Hz, 3H).

[0535] Example 11:

[0536] N-((S)-1-(4-(4-amino-5-(R or S)-S-methylsulfinyl)pyridin-2-yl)amino)-6-propylpyridin-2-ylpyrrolidine-3-yl)acetamide (compound 11a)

[0537] Preparation of N-((S)-1-(4-(4-amino-5-(S or R)-S-methylsulfinyl)pyridin-2-yl)amino)-6-propylpyridin-2-ylpyrrolidine-3-yl)acetamide (compound 11b)

[0538] Preparation

[0539] Step 1:

[0540]

[0541] Compound 11-1 (5.00 g, 24.1 mmol; CAS: 857730-21-3, purchased directly from Shanghai Bid Pharmaceutical Technology Co., Ltd.) was dissolved in dichloromethane (50.0 mL) at room temperature. Then, di-tert-butyl dicarbonate (7.89 g, 36.15 mmol), triethylamine (10.0 mL, 72.3 mmol), and 4-dimethylaminopyridine (290 mg, 2.41 mmol) were added sequentially to the reaction mixture. The reaction system was stirred at room temperature for 16 hours. The reaction progress was monitored using liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was purified directly by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1). The resulting fraction was concentrated under reduced pressure to give 5.50 g of compound 11-2 (white solid, 56% yield).

[0542] MS (ESI, m / z): [M+H] + = 407.10 / 409.10 / 411.10.

[0543] Step 2:

[0544]

[0545] Compound 11-2 (4.00 g, 9.81 mmol) was dissolved in 1,4-dioxane (50.0 mL) at room temperature and under a nitrogen atmosphere, followed by the sequential addition of sodium methanethiol (0.760 g, 10.7 mmol), palladium acetate (0.220 g, 0.981 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (0.570 g, 0.981 mmol), and N,N-diisopropylethylamine (5.07 g, 39.2 mmol). The reaction mixture was stirred at 100 °C for 4 hours under a nitrogen atmosphere. The reaction progress was monitored using liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction mixture was filtered, the filter cake was washed with ethyl acetate (20 mL × 3), and the filtrate was directly concentrated under reduced pressure. The residue was purified directly by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 9 / 1), and the resulting fraction was concentrated under reduced pressure to give 480 mg of compound 11-3 (pale yellow solid, yield 18%).

[0546] MS (ESI, m / z): [M+H] + = 274.95 / 277.00.

[0547] 1H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 8.21 (s, 1H), 7.89 (br s, 1H), 2.34 (s, 3H), 1.55 (s, 9H).

[0548] Step 3:

[0549]

[0550] According to step 6 of Example 1, the starting materials were replaced with 10-9 (528 mg, 1.92 mmol) and 11-3 (420 mg, 1.60 mmol) respectively to prepare 400 mg of compound 11-4 (white solid, yield 50%).

[0551] MS (ESI, m / z): [M+H] + = 501.30.

[0552] 1 H NMR (300 MHz, DMSO-d6) δ 9.30 (s, 1H), 8.27 (s, 1H), 8.18 (s, 1H), 8.12 (d, J = 6.9 Hz, 1H), 7.62 (s, 1H), 6.70 (d, J = 1.5 Hz, 1H), 6.66 (d, J= 1.5 Hz, 1H), 4.36-4.24 (m, 1H), 3.63-3.33 (m, 3H), 3.23-3.19 (m, 1H), 2.43(t, J = 8.4 Hz, 2H), 2.29 (s, 3H), 2.19-2.06 (m, 1H), 1.91-1.82 (m, 1H), 1.81(s, 3H), 1.71-1.57 (m, 2H), 1.51 (s, 9H), 0.91 (t, J = 7.5 Hz, 3H).

[0553] Step 4:

[0554]

[0555] According to step 7 of Example 1, the starting material was replaced with 11-4 (350 mg, 0.699 mmol) to prepare 180 mg of compound 11-5 (red solid, diastereomer mixture, yield 48%).

[0556] MS (ESI, m / z): [M+H]+ = 532.40.

[0557] Step 5:

[0558]

[0559] Compound 11-5 (180 mg, 0.338 mmol) was dissolved in dichloromethane (3.0 mL) at 0 °C, and trifluoroacetic acid (1.5 mL) was slowly added dropwise to the reaction solution using a syringe. The reaction system was stirred at room temperature for 16 hours. The reaction system was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was first dissolved in methanol (3.0 mL), and then triethylamine (1.5 mL) was added, and the mixture was stirred at room temperature for 3 minutes. This solution was directly purified using a C18 reversed-phase column. The purification conditions were as follows: 40 g C18 reversed-phase column; mobile phase: acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate: 35 mL / min; gradient: acetonitrile from 10% to 70% over 20 minutes; detection wavelength: 254 nm. After LC-MS confirmation, the product fraction was collected, concentrated under reduced pressure, and lyophilized to obtain 70 mg of crude product.

[0560] 70 mg of crude product was further purified by a non-chiral SFC under the following conditions: Column: Ultimate XB-NH23 cm × 250 mm, 5 μm; Mobile phase A: carbon dioxide; Mobile phase B: 20 ​​mmol / L ammonia-methanol; Flow rate: 100 mL / min; Gradient: isogradient 42% B; Back pressure: 100 hPa; Detection wavelength: 254 nm; Retention time: 4.02 min. The product fraction was concentrated under reduced pressure and lyophilized to give 35.0 mg of compound 11 (a mixture of diastereomers, white solid, yield 24%).

[0561] MS (ESI, m / z): [M+H] + = 432.15.

[0562] Step 6:

[0563]

[0564] The diastereomer mixture 11 (35.0 mg, 0.0813 mmol) was chirally resolved. The resolution conditions were as follows: chiral column: CHIRAL ART Cellulose-SC, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol / acetonitrile = 5 / 1; flow rate: 40 mL / min; gradient: isogradient 20% B; detection wavelength: 298 / 242 nm; retention time: 28.2 min to obtain the forepeak fraction, which was concentrated under reduced pressure and lyophilized to give 11.0 mg of optically pure compound 11a (white solid, yield 31%); retention time: 35.3 min to obtain the hindpeak fraction, which was concentrated under reduced pressure and lyophilized to give 12.5 mg of optically pure compound 11b (white solid, yield 36%).

[0565] Compound 11a:

[0566] MS (ESI, m / z): [M+H] + = 432.25.

[0567] 1 H NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H), 8.25 (s, 1H), 8.11 (d, J =6.8 Hz, 1H), 6.82 (s, 2H), 6.64 (s, 1H), 6.60 (s, 1H), 6.20 (s, 1H), 4.36 (s,1H), 4.34-4.25 (m, 1H), 3.62-3.53 (m, 1H), 3.53-3.34 (m, 2H), 3.22-3.14 (m,1H), 3.01 (s, 3H), 2.43 (t, J = 7.6 Hz, 2H), 2.19-2.06 (m, 1H), 1.90-1.82 (m,1H), 1.81 (s, 3H), 1.71-1.57 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H).

[0568] Compound 11b:

[0569] MS (ESI, m / z): [M+H] + = 432.20.

[0570] 1H NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H), 8.25 (s, 1H), 8.11 (d, J =6.8 Hz, 1H), 6.82 (s, 2H), 6.64 (s, 1H), 6.60 (s, 1H), 6.20 (s, 1H), 4.36 (s,1H), 4.33-4.25 (m, 1H), 3.62-3.53 (m, 1H), 3.53-3.42 (m, 1H), 3.42-3.34 (m,1H), 3.22-3.14 (m, 1H), 3.01 (s, 3H), 2.43 (t, J = 7.6 Hz, 2H), 2.19-2.07 (m,1H), 1.90-1.80 (m, 1H), 1.81 (s, 3H), 1.71-1.57 (m, 2H), 0.91 (t, J = 7.2 Hz,3H).

[0571] Example 12:

[0572] N-((S)-1-(2-((4-methoxy-3-((S or R)-S-methylsulfonylimino)phenyl)amino)-6-propylpyrimidin-4-yl)pyrrolidine-3-yl)acetamide (compound 12a)

[0573] Preparation of N-((S)-1-(2-((4-methoxy-3-((R or S)-S-methylsulfonylimino)phenyl)amino)-6-propylpyrimidin-4-yl)pyrrolidine-3-yl)acetamide (compound 12b)

[0574] Step 1:

[0575]

[0576] Compound 12-1 (2.00 g, 7.17 mmol; CAS: 5399-03-1, purchased directly from Shanghai Bide Pharmaceutical Technology Co., Ltd.) was dissolved in 1,4-dioxane (18.0 mL) under nitrogen atmosphere and room temperature. 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene (0.410 g, 0.717 mmol), tris(dibenzylideneacetone)dipalladium (0.660 g, 0.717 mmol), N,N-diisopropylethylamine (2.50 mL, 14.3 mmol), and sodium methanethiol (0.750 g, 10.7 mmol) were added sequentially to the above reaction solution. The reaction system was stirred at 80 °C for 2 hours. The reaction progress was monitored by thin-layer chromatography (mobile phase: petroleum ether / ethyl acetate = 10 / 1). After the reaction was complete, the reactant mixture was filtered, and the filter cake was washed with ethyl acetate (40 mL × 2). The filtrate was concentrated under reduced pressure. The residue was purified directly by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1). The resulting fraction was concentrated under reduced pressure to give 1.20 g of compound 12-2 (pale yellow solid, yield 84%).

[0577] 1 H NMR (400 MHz, CDCl3) δ 8.67 (d, J = 2.8 Hz, 1H), 8.28-8.24 (m, 1H), 8.08-8.04 (m, 1H), 4.00 (s, 3H), 2.51 (s, 3H).

[0578] Step 2:

[0579]

[0580] According to step 7 of Example 1, the starting material was replaced with 12-2 (900 mg, 4.52 mmol) to prepare 450 mg of compound 12-3 (white solid, yield 43%).

[0581] MS (ESI, m / z): [M+H] + = 231.00.

[0582] 1H NMR (400 MHz, DMSO-d6) δ 8.66 (d, J = 2.8 Hz, 1H), 8.51-8.47 (m,1H), 7.47 (d, J = 9.2 Hz, 1H), 4.68 (brs, 1H), 4.08 (s, 3H), 3.20 (s, 3H).

[0583] Step 3:

[0584]

[0585] Compound 12-3 (350.0 mg, 1.52 mmol) was dissolved in tetrahydrofuran (5.00 mL) at room temperature, followed by the addition of di-tert-butyl dicarbonate (665 mg, 3.038 mmol) and 4-dimethylaminopyridine (371 mg, 3.038 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was directly concentrated under reduced pressure, and the residue was directly purified using a reversed-phase C18 column under the following conditions: 80 g C18 reversed-phase column; mobile phase: acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate: 35 mL / min; gradient: acetonitrile from 5% to 90% over 30 minutes; detection wavelength: 254 nm. After confirmation by liquid chromatography-mass spectrometry, the product fraction was collected, concentrated under reduced pressure, and lyophilized to give 350 mg of compound 12-4 (white solid, 37% yield).

[0586] MS (ESI, m / z): [2M+Na] + = 683.20.

[0587] 1 H NMR (300 MHz, DMSO-d6) δ 8.64-8.59 (m, 1H), 8.58 (s, 1H), 7.56 (d,J = 9.3 Hz, 1H), 4.08 (s, 3H), 3.44 (s, 3H), 1.20 (s, 9H).

[0588] Step 4:

[0589]

[0590] According to step 8 of Example 1, the starting material was replaced with 12-4 (350 mg, 1.06 mmol) to prepare 250 mg of compound 12-5 (white solid, yield 78%).

[0591] MS (ESI, m / z): [M+H] + = 301.00.

[0592] 1 H NMR (400 MHz, CDCl3) δ 7.35 (s, 1H), 6.92-6.87 (m, 2H), 3.88 (s, 3H), 3.35 (s, 3H), 1.38 (s, 9H).

[0593] Step 5:

[0594]

[0595] According to step 6 of Example 1, the starting materials were replaced with 12-5 (230 mg, 0.766 mmol) and 1-5 (216 mg, 0.766 mmol) respectively to prepare 220 mg of compound 12-6 (pale yellow solid, yield 53%).

[0596] MS (ESI, m / z): [M+H] + = 547.20.

[0597] 1 H NMR (400 MHz, CDCl3) δ 8.93 (s, 1H), 7.52-7.47 (m, 1H), 7.01-6.98(m, 1H), 6.29-6.14 (m, 1H), 5.72 (s, 1H), 4.56-4.47 (m, 1H), 3.94 (s, 3H),3.87-3.46 (m, 4H), 3.39 (s, 3H), 2.51 (t, J = 7.6 Hz, 2H), 2.39-2.26 (m, 1H),2.08-2.03 (m, 1H), 2.01 (s, 3H), 1.80-1.70 (m, 2H), 1.36 (s, 9H), 0.98 (t, J = 7.6 Hz, 3H).

[0598] Step 6:

[0599]

[0600] Compound 12-6 (220 mg, 0.402 mmol) was dissolved in dichloromethane (5.00 mL) at 0 °C, and then trifluoroacetic acid (2.00 mL) was slowly added to the reaction solution using a syringe. The reaction system was stirred for 1 hour at room temperature. After the reaction mixture was cleared by liquid chromatography-mass spectrometry (LC-MS), the reaction solution was concentrated under reduced pressure. The residue was directly purified using a reversed-phase C18 column under the following conditions: 120 g C18 reversed-phase column; mobile phase: acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate: 35 mL / min; acetonitrile gradient increased from 20% to 90% over 40 minutes; detection wavelength: 254 nm. After LC-MS confirmation, the product fraction was collected, concentrated under reduced pressure, and lyophilized to give 160 mg of compound 12 (a mixture of diastereomers, white solid, yield 89%).

[0601] MS (ESI, m / z): [M+H] + = 447.20.

[0602] Step 7:

[0603]

[0604] The diastereomer mixture 12 (160 mg, 0.358 mmol) was chirally resolved. The resolution conditions were as follows: chiral column CHIRAL ART Cellulose-SZ, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 40% B; detection wavelength 210 / 274 nm. A retention time of 9.7 min yielded the forepeak fraction, which was concentrated under reduced pressure and lyophilized to give 75.1 mg of optically pure compound 12a (white solid, 47% yield); a retention time of 12.3 min yielded the hindpeak fraction, which was concentrated under reduced pressure and lyophilized to give 71.0 mg of optically pure compound 12b (white solid, 44% yield).

[0605] Compound 12a:

[0606] MS (ESI, m / z): [M+H] + = 447.10.

[0607] 1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.57 (s, 1H), 8.13 (d, J =5.6 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 9.2 Hz, 1H), 5.79 (s,1H), 4.39-4.25 (m, 1H), 3.90 (br s, 1H), 3.86 (s, 3H), 3.77-3.35 (m, 4H),3.13 (s, 3H), 2.40 (t, J = 7.6 Hz, 2H), 2.16-2.04 (m, 1H), 1.91-1.83 (m, 1H),1.81 (s, 3H), 1.73-1.62 (m, 2H), 0.91 (t, J = 7.6 Hz, 3H).

[0608] Compound 12b:

[0609] MS (ESI, m / z): [M+H] + = 447.15.

[0610] 1 H NMR (400 MHz, DMSO-d 6) δ 9.07 (s, 1H), 8.58 (s, 1H), 8.13 (d, J =5.6 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 9.2 Hz, 1H), 5.79 (s,1H), 4.39-4.24 (m, 1H), 3.92 (br s, 1H), 3.86 (s, 3H), 3.77-3.35 (m, 4H), 3.13 (s, 3H), 2.40 (t, J = 7.6 Hz, 2H), 2.16-2.05 (m, 1H), 1.91-1.83 (m, 1H),1.81 (s, 3H), 1.73-1.62 (m, 2H), 0.91 (t, J = 7.6 Hz, 3H).

[0611] Example 13:

[0612] N-((S)-1-(2-((4-hydroxy-3-((S or R)-S-methylsulfonylimino)phenyl)amino)-6-propylpyrimidin-4-yl)pyrrolidine-3-yl)acetamide (compound 13a)

[0613] Preparation of N-((S)-1-(2-((4-hydroxy-3-((R or S)-S-methylsulfonylimino)phenyl)amino)-6-propylpyrimidin-4-yl)pyrrolidine-3-yl)acetamide (compound 13b)

[0614] Step 1:

[0615]

[0616] Compound 12a (40.0 mg, 0.090 mmol) was dissolved in dry dichloromethane (3.00 mL) under a nitrogen atmosphere at -70 °C. Boron tribromide (0.80 mL) was then slowly added dropwise to the reaction mixture using a syringe. After the reaction system returned to room temperature, stirring was continued for 15 hours. The reaction progress was monitored using liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, methanol (20.0 mL) was added to the reaction system to quench the reaction at -70 °C. The reaction mixture was concentrated under reduced pressure, and the resulting residue was directly purified by preparative liquid chromatography (HPLC) under the following conditions: column type YMC-Actus Triart C18ExRS 30 × 150 mm, 5 μm; mobile phase: acetonitrile and water (10 mmol / L ammonium bicarbonate + 0.05% NH3). . H2O); flow rate 60 mL / min; gradient of acetonitrile from 9% to 31% over 10 min, then maintaining an isogradient of 31% acetonitrile for 10 min; detection wavelength 254 nm / 220 nm; retention time 13.52 min, product fraction collected. Concentrated under reduced pressure and lyophilized to give 16.5 mg of optically pure compound 13a (white solid, yield 42%).

[0617] MS (ESI, m / z): [M+H] + = 433.20.

[0618] 1H NMR (300 MHz, DMSO-d6) δ 9.01 (s, 1H), 8.63 (br s, 1H), 8.13 (d, J= 6.9 Hz, 1H), 7.63-7.57 (m, 1H), 6.83 (d, J = 9.0 Hz, 1H), 5.79 (s, 1H), 4.37-4.25 (m, 1H), 3.80-3.37 (m, 4H), 3.18 (s, 3H), 2.40 (t, J = 7.2 Hz, 2H), 2.18-2.04 (m, 1H), 1.98-1.83 (m, 1H), 1.81 (s, 3H), 1.73-1.61 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H).

[0619] Step 2:

[0620]

[0621] Compound 12b (40.0 mg, 0.0900 mmol) was dissolved in dry dichloromethane (3.00 mL) under a nitrogen atmosphere at -70 °C. Boron tribromide (0.80 mL) was then slowly added dropwise to the reaction solution using a syringe. After the reaction system was brought to room temperature, stirring was continued for 15 hours. The reaction progress was monitored using liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, it was quenched with methanol (20.0 mL) at -70 °C. The reaction mixture was concentrated under reduced pressure, and the resulting residue was directly purified by preparative liquid chromatography (HPLC) under the following conditions: column type X Br sidge Prep Phenyl OBDColumn 19 × 250 mm, 5 μm; mobile phase acetonitrile and water (10 mmol / L ammonium bicarbonate + 0.05% NH3). . H2O); flow rate 60 mL / min; gradient of acetonitrile from 33% to 48% over 10 min, then maintaining an isogradient of 48% acetonitrile for 10 min; detection wavelength 254 nm / 220 nm; retention time 9.5 min, product fraction collected. Concentrated under reduced pressure and lyophilized to give 13.2 mg of optically pure compound 13b (white solid, yield 34%).

[0622] MS (ESI, m / z): [M+H] + = 433.20.

[0623] 1H NMR (300 MHz, DMSO-d6) δ 9.01 (s, 1H), 8.63 (br s, 1H), 8.13 (d, J= 6.9 Hz, 1H), 7.63-7.57 (m, 1H), 6.83 (d, J = 9.0 Hz, 1H), 5.79 (s, 1H), 4.37-4.25 (m, 1H), 3.80-3.37 (m, 4H), 3.18 (s, 3H), 2.40 (t, J = 7.2 Hz, 2H), 2.18-2.04 (m, 1H), 1.98-1.83 (m, 1H), 1.81 (s, 3H), 1.73-1.61 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H).

[0624] Example 14:

[0625] N-((S)-1-(2-((4-methyl-3-((R or S)-S-methylsulfonylimino)phenyl)amino)-6-propylpyrimidin-4-yl)pyrrolidine-3-yl)acetamide (compound 14a)

[0626] Synthesis of N-((S)-1-(2-((4-methyl-3-((S or R)-S-methylsulfonylimino)phenyl)amino)-6-propylpyrimidin-4-yl)pyrrolidine-3-yl)acetamide (compound 14b)

[0627] Step 1:

[0628]

[0629] Under a nitrogen atmosphere and at room temperature, raw material 14-1 (10.0 g, 38.0 mmol; CAS: 7745-92-8, purchased directly from Shanghai Haohong Biomedical Technology Co., Ltd.) was dissolved in 1,4-dioxane (100 mL). 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (2.20 g, 3.80 mmol), palladium acetate (850 mg, 3.80 mmol), cesium carbonate (24.8 g, 76.0 mmol), and sodium methanethiol (4.00 g, 57.0 mmol) were added sequentially to the above reaction solution. The reaction system was stirred at 80 °C under a nitrogen atmosphere for 2 hours. The reaction progress was monitored using liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction system was brought back to room temperature, filtered, and the filter cake was washed with ethyl acetate (100 mL × 2). The filtrate was concentrated under reduced pressure, and the residue was directly purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 6 / 1). The resulting fraction was concentrated under reduced pressure to obtain 4 g of crude product methyl (2-methyl-5-nitrophenyl)sulfonamide (yellow solid).

[0630] At room temperature, 4 g of crude methyl(2-methyl-5-nitrophenyl)sulfanilamide was dissolved in methanol (40.0 mL). Ammonium carbamate (8.52 g, 109 mmol) and (diacetoxyiodine)benzene (21.1 g, 65.5 mmol) were added to the reaction solution. The reaction mixture was stirred at room temperature for 3 hours. The reaction progress was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the mixture was directly concentrated under reduced pressure. The resulting residue was purified directly by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1). The fraction was concentrated under reduced pressure to give 2.10 g of compound 14-2 (yellow solid, 26% yield).

[0631] MS (ESI, m / z): [M+H] + = 215.15.

[0632] 1 H NMR (400 MHz, CDCl3) δ 8.97 (d, J = 2.4 Hz, 1H), 8.37-8.27 (m, 1H), 7.55 (d, J = 8.4 Hz, 1H), 3.19 (s, 3H), 2.89 (s, 3H).

[0633] Step 2:

[0634]

[0635] Compound 14-2 (2.50 g, 11.7 mmol) was dissolved in tetrahydrofuran (50.0 mL) at room temperature. Then, di-tert-butyl dicarbonate (4.65 g, 21.3 mmol) and 4-dimethylaminopyridine (371 mg, 3.038 mmol) were added to the reaction solution, respectively. The reaction mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction was quenched with water (50.0 mL) at 0 °C, extracted with ethyl acetate (100 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified directly by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1). The resulting fraction was concentrated under reduced pressure to give 1.50 g of compound 14-3 (pale yellow solid, yield 24%).

[0636] MS (ESI, m / z): [M-Boc+H] + = 215.15.

[0637] 1 H NMR (400 MHz, CDCl3) δ 8.95 (d, J = 2.4 Hz, 1H), 8.40-8.35 (m, 1H), 7.58 (d, J = 8.4 Hz, 1H), 3.29 (s, 3H), 2.81 (s, 3H), 1.38 (s, 9H).

[0638] Step 3:

[0639]

[0640] According to step 8 of Example 1, the starting material was replaced with 14-3 (1.50 g, 4.48 mmol) to prepare 1.20 g of compound 14-4 (pale yellow solid, yield 88%).

[0641] MS (ESI, m / z): [M+H] + = 285.15.

[0642] 1 H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 2.4 Hz, 1H), 7.11 (d, J = 8.0Hz, 1H), 6.83-6.79 (m, 1H), 3.20 (s, 3H), 2.53 (s, 3H), 1.39 (s, 9H).

[0643] Step 4:

[0644]

[0645] According to step 6 of Example 1, the starting materials were replaced with 1-5 (200 mg, 0.709 mmol) and 14-4 (281 mg, 0.989 mmol) respectively to prepare 120 mg of compound 14-5 (pale yellow solid, yield 32%).

[0646] MS (ESI, m / z): [MH] - = 529.15.

[0647] Step 5:

[0648]

[0649] Compound 14-5 (120 mg, 0.226 mmol) was dissolved in dichloromethane (4.0 mL) at 0 °C, and trifluoroacetic acid (1.0 mL) was slowly added dropwise to the reaction solution using a syringe. The reaction system was stirred at room temperature for 1 hour. The reaction system was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was directly purified using a reversed-phase C18 column. The purification conditions were as follows: 40 g C18 reversed-phase column; mobile phase: acetonitrile and water (0.1% ammonia); flow rate: 35 mL / min; gradient of acetonitrile from 5% to 75% over 30 minutes; detection wavelength: 254 nm. After LC-MS confirmation, the product fraction was collected, concentrated under reduced pressure, and lyophilized to give 90.0 mg of compound 14 (a mixture of diastereomers, yellow solid, 93% yield).

[0650] MS (ESI, m / z): [M+H] + = 431.20.

[0651] Step 6:

[0652]

[0653] The diastereomer mixture 14 (90.0 mg, 0.210 mmol) was chirally resolved. The resolution conditions were as follows: chiral column: CHIRAL ART Cellulose-SZ, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate: 40 mL / min; gradient: isogradient 30% B; detection wavelength: 274 / 260 nm; retention time: 13.4 min yielded the forepeak fraction, which was concentrated under reduced pressure and lyophilized to give 29.5 mg of optically pure compound 14a (white solid, 32% yield); retention time: 17.5 min yielded the stern fraction, which was concentrated under reduced pressure and lyophilized to give 29.0 mg of optically pure compound 14b (white solid, 32% yield).

[0654] Compound 14a:

[0655] MS (ESI, m / z): [M+H] + = 431.20.

[0656] 1 H NMR (400 MHz, DMSO-d6) δ 9.20 (s, 1H), 8.76 (br s, 1H), 8.18-8.09(m, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 5.82 (s, 1H), 4.38-4.25 (m, 1H), 4.01-3.98 (m, 1H), 3.80-3.41 (m, 4H), 3.03 (d, J = 1.2 Hz, 3H), 2.58 (s, 3H), 2.41 (t, J = 7.6 Hz, 2H), 2.18-2.05 (m, 1H), 1.93-1.83 (m,1H), 1.81 (s, 3H), 1.75-1.61 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H).

[0657] Compound 14b:

[0658] MS (ESI, m / z): [M+H] + = 431.20.

[0659] 1H NMR (400 MHz, DMSO-d6) δ 9.20 (s, 1H), 8.77 (br s, 1H), 8.19-8.08(m, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 5.82 (s, 1H),4.37-4.26 (m, 1H), 3.99 (s, 1H), 3.80-3.40 (m, 4H), 3.03 (s, 3H), 2.58 (s,3H), 2.41 (t, J = 7.6 Hz, 2H), 2.18-2.06 (m, 1H), 1.93-1.83 (m, 1H), 1.81 (s,3H), 1.76-1.60 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H).

[0660] Example 15:

[0661] N-((S)-1-(2-((4-chloro-3-((R or S)-S-methylsulfonylimino)phenyl)amino)-6-propylpyrimidin-4-yl)pyrrolidine-3-yl)acetamide (compound 15a)

[0662] Preparation of N-(((S)-1-(2-((4-chloro-3-((S or R)-S-methylsulfonylimino)phenyl)amino)-6-propylpyrimidin-4-yl)pyrrolidine-3-yl)acetamide (compound 15b)

[0663] Step 1:

[0664]

[0665] Compound 15-1 (10.2 g, 42.9 mmol; CAS: 16588-26-4, purchased directly from Shanghai Haohong Biomedical Technology Co., Ltd.) was dissolved in 1,4-dioxane (100 mL) at room temperature and under a nitrogen atmosphere. The catalyst palladium acetate (1.05 g, 4.68 mmol), the ligand 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (2.48 g, 4.29 mmol), cesium carbonate (27.2 g, 83.5 mmol), and sodium methanethiol (4.36 g, 62.2 mmol) were added sequentially to the above reaction solution. The reaction system was stirred at 120 °C for 2 hours. The reaction system was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate (100 mL × 3). The filtrate was concentrated under reduced pressure, and the residue was directly purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1) to obtain 5 g of (2-chloro-5-nitrophenyl)(methyl)sulfanilamide (yellow solid, crude product).

[0666] At room temperature, 5 g of crude (2-chloro-5-nitrophenyl)(methyl)sulfanilamide was dissolved in methanol (60 mL). Ammonium carbamate (9.58 g, 123 mmol) and (diacetoxyiodine)benzene (23.7 g, 73.7 mmol) were added to the above reaction solution. The reaction system was reacted at room temperature for 3 hours. The reaction progress was monitored by liquid chromatography-mass spectrometry. After the reaction was complete, the reaction system was quenched with water (100 mL). The mixture was extracted with ethyl acetate (100 mL × 3), and the combined organic phases were washed with saturated sodium chloride aqueous solution (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was directly purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1). The resulting fraction was concentrated under reduced pressure to give 2.50 g of compound 15-2 (deep red oil, yield 25%).

[0667] MS (ESI, m / z): [M+H] + = 235.10 / 237.10.

[0668] Step 2:

[0669]

[0670] Compound 15-2 (2.50 g, 10.6 mmol) was dissolved in tetrahydrofuran (50.0 mL) at room temperature. Then, di-tert-butyl dicarbonate (4.65 g, 21.3 mmol) and 4-dimethylaminopyridine (130 mg, 1.06 mmol) were added to the reaction mixture, respectively. The reaction system was stirred at room temperature for 2 hours. The reaction progress was monitored using liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, it was quenched with water (50.0 mL) at room temperature. Extraction was performed with ethyl acetate (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was directly purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1). The resulting fraction was concentrated under reduced pressure to give 1.50 g of compound 15-3 (yellow solid, yield 42%).

[0671] MS (ESI, m / z): [M-Boc+H] + = 235.05 / 237.00.

[0672] 1 H NMR (400 MHz, CDCl3) δ 9.08 (d, J = 2.4 Hz, 1H), 8.45-8.42 (m, 1H), 7.77 (d, J = 8.4 Hz, 1H), 3.40 (s, 3H), 1.37 (s, 9H).

[0673] Step 3:

[0674]

[0675] According to step 8 of Example 1, the starting material was replaced with 15-3 (1.50 g, 4.48 mmol) to prepare 1.20 g of compound 15-4 (yellow solid, yield 88%).

[0676] MS (ESI, m / z): [M+H] + = 305.10 / 307.10.

[0677] 1 H NMR (400 MHz, DMSO-d6) δ 7.31-7.26 (m, 2H), 6.82-6.78 (m, 1H), 5.86 (s, 2H), 3.32 (s, 3H), 1.21 (s, 9H).

[0678] Step 4:

[0679]

[0680] According to step 6 of Example 1, the starting materials were replaced with 1-5 (200 mg, 0.709 mmol) and 15-4 (281 mg, 0.922 mmol) respectively to prepare 120 mg of compound 15-5 (yellow solid, yield 31%).

[0681] MS (ESI, m / z): [M+H] + = 551.25 / 553.20.

[0682] Step 5:

[0683]

[0684] According to the method in step 5 of Example 14, the starting material was replaced with 15-5 (200 mg, 0.226 mmol) to prepare 90.0 mg of compound 15 (a mixture of diastereomers, yellow solid, yield 55%).

[0685] MS (ESI, m / z): [M+H] + = 451.20 / 453.15.

[0686] Step 6:

[0687]

[0688] The diastereomer mixture 15 (90.0 mg, 0.200 mmol) was chirally resolved. The resolution conditions were as follows: chiral column: CHIRAL ART Cellulose-SZ, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: isopropanol; flow rate: 40 mL / min; gradient: isogradient 50% B; detection wavelength: 202 / 220 nm; retention time: 10.6 min yielded the forepeak fraction, which, after concentration under reduced pressure and lyophilization, yielded 29.0 mg of optically pure compound 15a (white solid, 32% yield); retention time: 13.7 min yielded the stern fraction, which, after concentration under reduced pressure and lyophilization, yielded 28.5 mg of optically pure compound 15b (white solid, 32% yield).

[0689] Compound 15a:

[0690] MS (ESI, m / z): [M+H] + = 451.15 / 453.10.

[0691] 1H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 8.91 (br s, 1H), 8.14 (d, J= 4.0 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 5.87 (s,1H), 4.37-4.27 (m, 2H), 3.80-3.37 (m, 4H), 3.19 (s, 3H), 2.43 (t, J = 7.6 Hz,2H), 2.17-2.06 (m, 1H), 1.92-1.83 (m, 1H), 1.81 (s, 3H), 1.73-1.63 (m, 2H),0.91 (t, J = 7.2 Hz, 3H).

[0692] Compound 15b:

[0693] MS (ESI, m / z): [M+H] + = 451.20 / 453.15.

[0694] 1 H NMR (400 MHz, DMSO-d6) δ 9.46 (s, 1H), 8.95 (br s, 1H), 8.15 (s,1H), 7.84-7.77 (m, 1H), 7.46 (d, J = 8.8 Hz, 1H), 5.86 (s, 1H), 4.38-4.24 (m,2H), 3.78-3.36 (m, 4H), 3.19 (s, 3H), 2.43 (t, J = 7.6 Hz, 2H), 2.17-2.07 (m,1H), 1.93-1.83 (m, 1H), 1.81 (s, 3H), 1.73-1.63 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H).

[0695] Example 16:

[0696] N-((S)-1-(2-((3-((S or R)-S-methylsulfonylimide)-5-nitrophenyl)amino)-6-propylpyrimidin-4-yl)pyrrolidine-3-yl)acetamide (compound 16a)

[0697] Preparation of N-((S)-1-(2-((3-((R or S)-S-methylsulfonylimino)-5-nitrophenyl)amino)-6-propylpyrimidin-4-yl)pyrrolidine-3-yl)acetamide (compound 16b)

[0698] Step 1:

[0699]

[0700] According to the method in step 1 of Example 15, the raw materials were replaced with compound 16-1 (15.0 g, 53.4 mmol; CAS: 6311-60-0, purchased directly from the supplier Haibide Pharmaceutical Technology Co., Ltd.) to prepare 1.20 g of compound 16-2 (brownish-yellow oily substance, yield 8%).

[0701] MS (ESI, m / z): [M+H] + = 279.00 / 280.95.

[0702] 1 H NMR (400 MHz, CDCl3) δ 8.78 (s, 1H), 8.60 (s, 1H), 8.47 (s, 1H), 3.18 (s, 3H).

[0703] Step 2:

[0704]

[0705] According to the method in step 2 of Example 15, the starting material was replaced with 16-2 (600 mg, 2.15 mmol) to prepare 650 mg of compound 16-3 (white solid, yield 80%).

[0706] 1 H NMR (400 MHz, CDCl3) δ 8.73 (s, 1H), 8.64 (s, 1H), 8.44 (s, 1H), 3.32 (s, 3H), 1.42 (s, 9H).

[0707] Step 3:

[0708]

[0709] Compound 16-3 (600 mg, 1.58 mmol) was dissolved in dimethyl sulfoxide (6.00 mL) at room temperature and under a nitrogen atmosphere. Cuprous iodide (602 mg, 3.16 mmol), proline (236 mg, 2.01 mmol), and sodium azide (206 mg, 3.16 mmol) were added sequentially to the solution. The reaction mixture was stirred at 100 °C for 2 hours. The reaction progress was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, it was quenched at 0 °C with a saturated sodium hypochlorite aqueous solution (5.00 mL). The mixture was extracted with ethyl acetate (100 mL × 3), and the combined organic phases were washed with saturated brine (100 mL × 2), dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue was directly purified using a reverse-phase C18 column. The purification conditions were as follows: 120 g C18 reversed-phase column; mobile phase: acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate: 35 mL / min; gradient: acetonitrile increased from 20% to 70% over 20 minutes; detection wavelength: 254 nm. After confirmation by liquid chromatography-mass spectrometry, the product fraction was collected, concentrated under reduced pressure, and lyophilized to give 450 mg of compound 16-4 (yellow solid, 90% yield).

[0710] MS (ESI, m / z): [MH] - = 314.10.

[0711] 1 H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 7.68 (s, 1H), 7.52 (s, 1H), 4.47 (br s, 2H), 3.26 (s, 3H), 1.41 (s, 9H).

[0712] Step 4:

[0713]

[0714] According to the synthesis method in step 6 of Example 1, the starting materials were replaced with 1-5 (330 mg, 1.17 mmol) and 16-4 (441 mg, 1.40 mmol) respectively to prepare 500 mg of compound 16-5 (yellow solid, yield 76%).

[0715] MS (ESI, m / z): [M+H] + = 562.20.

[0716] 1H NMR (400 MHz, CDCl3) δ 8.85 (s, 1H), 8.30-8.25 (m, 1H), 7.73 (s,1H), 5.82 (s, 1H), 4.65-4.44 (m, 1H), 3.97-3.55 (m, 3H), 3.46-3.33 (m, 1H),3.29 (s, 3H), 2.51 (t, J = 7.6 Hz, 2H), 2.46-2.26 (m, 1H), 2.12-2.04 (m, 1H),2.02 (s, 3H),1.78-1.68 (m, 2H), 1.36 (s, 9H), 0.98 (t, J = 7.2 Hz, 3H).

[0717] Step 5:

[0718]

[0719] Compound 16-5 (500 mg, 0.890 mmol) was dissolved in dichloromethane (10.00 mL) at 0 °C, and then trifluoroacetic acid (2.00 mL) was slowly added to the reaction solution using a syringe. The reaction system was stirred at room temperature for 2 hours. After the reaction mixture was cleared by liquid chromatography-mass spectrometry (LC-MS), the reaction solution was concentrated under reduced pressure, and the residue was directly purified using a reversed-phase C18 column under the following conditions: 120 g C18 reversed-phase column; mobile phase: acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate: 40 mL / min; acetonitrile concentration increased from 20% to 70% within 20 minutes; detection wavelength: 254 nm. After LC-MS confirmation, the product fraction was collected, concentrated under reduced pressure, and lyophilized to give 400 mg of compound 16 (a mixture of diastereomers, yellow solid, 97% yield).

[0720] MS (ESI, m / z): [M+H] + = 462.20.

[0721] Step 6:

[0722]

[0723] The diastereomer mixture 16 (400 mg, 0.867 mmol) was resolved by SFC. The resolution conditions were as follows: column: CHIRALPAK-IK, 3 x 25 mm, 5 μm; mobile phase A: carbon dioxide, mobile phase B: methanol (20 mmol / L ammonia); flow rate: 90 mL / min; gradient: isogradient 50% B; detection wavelength: 256 / 310 nm; retention time: 8.3 min to obtain the forepeak fraction, which was concentrated under reduced pressure and lyophilized to give 170 mg of optically pure compound 16a (white solid, yield 43%); retention time: 10.2 min to obtain the hindpeak fraction, which was concentrated under reduced pressure and lyophilized to give 195 mg of optically pure compound 16b (white solid, yield 49%).

[0724] Compound 16a:

[0725] [α] 25 D = -10.25 (c = 0.4, EtOH)

[0726] MS (ESI, m / z): [M+H] + = 462.25.

[0727] 1 H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H), 9.12 (br s, 1H), 8.88 (s,1H), 8.17 (br s, 1H), 8.11-8.09 (m, 1H), 5.97 (s, 1H), 4.45 (s, 1H), 4.40-4.28 (m, 1H), 3.82-3.37 (m, 3H), 3.23-3.14 (m, 1H), 3.11 (s, 3H), 2.47 (t, J= 7.6 Hz, 2H), 2.21-2.09 (m, 1H), 1.95-1.85 (m, 1H), 1.82 (s, 3H), 1.77-1.65(m, 2H), 0.92 (t, J = 7.2 Hz, 3H).

[0728] Compound 16b:

[0729] MS (ESI, m / z): [M+H] + = 462.20.

[0730] 1H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H), 9.12 (br s, 1H), 8.89 (s,1H), 8.17 (br s, 1H), 8.11-8.09 (m, 1H), 5.96 (s, 1H), 4.44 (s, 1H), 4.40-4.28 (m, 1H), 3.85-3.38 (m, 3H), 3.25-3.16 (m, 1H), 3.12 (s, 3H), 2.47 (t, J= 7.6 Hz, 2H), 2.21-2.10 (m, 1H), 1.95-1.86 (m, 1H), 1.82 (s, 3H), 1.77-1.66(m, 2H), 0.93 (t, J = 7.2 Hz, 3H).

[0731] Example 17:

[0732] N-((S)-1-(2-((3-amino-5-((S or R)-S-methylsulfonylimino)phenyl)amino)-6-propylpyrimidin-4-yl)pyrrolidine-3-yl)acetamide (compound 17a)

[0733] Preparation of N-((S)-1-(2-((3-amino-5-((R or S)-S-methylsulfonylimino)phenyl)amino)-6-propylpyrimidin-4-yl)pyrrolidine-3-yl)acetamide (compound 17b)

[0734] Step 1:

[0735]

[0736] According to the method in step 5 of Example 5, the starting material was replaced with 16a (90.0 mg, 0.195 mmol) to prepare 82.0 mg of optically pure compound 17a (white solid, yield 97%).

[0737] MS (ESI, m / z): [M+H] + = 432.20.

[0738] 1H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 1H), 8.14 (d, J = 4.8 Hz, 1H), 7.91 (br s, 1H), 7.03-6.99 (m, 1H), 6.70-6.66 (m, 1H), 5.81 (s, 1H), 5.34 (s,2H), 4.38-4.34 (m, 1H), 3.73 (br s, 1H), 3.67-3.37 (m, 3H), 3.28-3.02 (m,1H), 2.93 (s, 3H), 2.41 (t, J = 7.2 Hz, 2H), 2.18-2.05 (m, 1H), 1.93-1.84 (m,1H), 1.81 (s, 3H), 1.73-1.62 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H).

[0739] Step 2:

[0740]

[0741] According to the method in step 5 of Example 5, the starting material was replaced with 16b (115 mg, 0.249 mmol) to prepare 104 mg of optically pure compound 17b (white solid, yield 97%).

[0742] MS (ESI, m / z): [M+H] + = 432.25.

[0743] 1 H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 8.18-8.10 (m, 1H), 7.93 (brs, 1H), 7.03-6.99 (m, 1H), 6.70-6.66 (m, 1H), 5.81 (s, 1H), 5.34 (s, 2H),4.38-4.24 (m, 1H), 3.72 (br s, 1H), 3.67-3.38 (m, 3H), 3.22-3.04 (m, 1H),2.93 (s, 3H), 2.41 (t, J = 7.2 Hz, 2H), 2.17-2.05 (m, 1H), 1.92-1.83 (m, 1H),1.81 (s, 3H), 1.73-1.62 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H).

[0744] Example 18:

[0745] N-((S)-1-(2-(((R or S)-1-methyl-1-oxy-3H-1λ) 4 -Benz[d]isothiazolyl)amino)-6-propylpyrimidin-4-yl)pyrrolidine-3-yl)acetamide (compound 18a)

[0746] and N-((S)-1-(2-(((S or R)-1-methyl-1-oxid-3H-1λ) 4 Preparation of benzo[d]isothiazolyl)amino)-6-propylpyrimidin-4-yl)pyrrolidine-3-yl)acetamide (compound 18b)

[0747] Step 1:

[0748]

[0749] Compound 18-1 (6.00 g, 20.49 mmol; CAS: 89459-38-1, purchased directly from Shanghai Bid Pharmaceutical Technology Co., Ltd.) was dissolved in 1,4-dioxane (60.0 mL) at room temperature and under a nitrogen atmosphere. Then, sodium methanethiol (2.16 g, 30.6 mmol), palladium acetate (460 mg, 2.05 mmol), ligand 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene (1.10 g, 2.05 mmol), and N,N-diisopropylethylamine (14.4 mL, 81.9 mmol) were added sequentially to the reaction solution. The reaction system was stirred at 120 °C for 3 hours under a nitrogen atmosphere. The reaction progress was monitored using liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the mixture was filtered, the filter cake was washed with ethyl acetate (100 mL × 3), and the filtrate was concentrated under reduced pressure. The residue was purified directly using a silica gel column (eluent: dichloromethane / methanol = 9 / 1), and the resulting fraction was concentrated under reduced pressure to give 3.05 g of compound 18-2 (pale yellow solid, yield 70%).

[0750] MS (ESI, m / z): [MH] - = 211.90.

[0751] Step 2:

[0752]

[0753] Compound 18-2 (3.50 g, 16.4 mmol) was dissolved in ultradry tetrahydrofuran (35.0 mL) at 0 °C under a nitrogen atmosphere. 6.6 mL of boranetetrahydrofuran solution (1 mol / L) was added dropwise to the reaction mixture using a syringe. The reaction was stirred at room temperature for 15 hours. The reaction progress was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, it was quenched with water (20.0 mL) at 0 °C. The mixture was extracted with ethyl acetate (60.0 mL × 3), and the combined organic phases were washed with saturated sodium chloride aqueous solution (50.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified directly by silica gel column chromatography (eluent: dichloromethane / methanol = 9 / 1). The resulting fraction was concentrated under reduced pressure to give 960 mg of compound 18-3 (pale yellow oil, yield 29%).

[0754] MS (ESI, m / z): [MH] - = 197.95.

[0755] 1 H NMR (300 MHz, CDCl3) δ 8.04-7.99 (m, 2H), 7.67-7.63 (m, 1H), 4.80 (s, 2H), 2.59 (s, 3H).

[0756] Step 3:

[0757]

[0758] Compound 18-3 (900 mg, 4.52 mmol) was dissolved in dichloromethane (10.0 mL) at 0 °C under a nitrogen atmosphere. Then, thionyl chloride (0.53 mL, 6.78 mmol) was slowly added dropwise to the reaction solution using a syringe. The reaction system was stirred at room temperature for 15 hours. The reaction progress was monitored by thin-layer chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1). After the starting material disappeared, the reaction was quenched with water (10.0 mL) at 0 °C. Extraction was performed with ethyl acetate (50.0 mL × 3), and the combined organic phases were washed with saturated sodium chloride (50.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified directly by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4 / 1), and the resulting fraction was concentrated under reduced pressure to give 870 mg of compound 18-4 (pale yellow solid, 89% yield).

[0759] 1H NMR (300 MHz, CDCl3) δ 8.08 (d, J = 2.1 Hz, 1H), 8.03-7.96 (m, 1H), 7.57 (d, J = 8.4 Hz, 1H), 4.71 (s, 2H), 2.62 (s, 3H).

[0760] Step 4:

[0761]

[0762] According to step 7 of Example 1, the starting material was replaced with 18-4 (870 mg, 4.00 mmol) to prepare 720 mg of compound 18-5 (pale yellow solid, yield 72%).

[0763] MS (ESI, m / z): [M+H] + = 249.05 / 251.10.

[0764] 1 H NMR (300 MHz, CDCl3) δ 9.02 (d, J = 2.4 Hz, 1H), 8.48-8.42 (m, 1H), 7.85 (d, J = 8.4 Hz, 1H), 5.40-5.21 (m, 2H), 3.32 (s, 3H).

[0765] Step 5:

[0766]

[0767] Compound 18-5 (720 mg, 2.90 mmol) was dissolved in acetonitrile (8.00 mL) at room temperature. The reaction mixture was stirred at 80 °C for 5 hours. The reaction mixture was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was purified directly by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1), and the resulting fraction was concentrated under reduced pressure to give 500 mg of compound 18-6 (white liquid, 81% yield).

[0768] MS (ESI, m / z): [M+H] + = 213.05.

[0769] 1H NMR (300 MHz, CDCl3) δ 8.70 (d, J = 1.8 Hz, 1H), 8.52-8.47 (m, 1H), 7.71 (d, J = 8.4 Hz, 1H), 5.06-4.80 (m, 2H), 3.49 (s, 3H).

[0770] Step 6:

[0771]

[0772] According to the method in step 5 of Example 5, the starting material was replaced with 18-6 (470 mg, 2.22 mmol) to prepare 235 mg of compound 18-7 (pale yellow oil, yield 58%).

[0773] MS (ESI, m / z): [M+H] + = 183.10.

[0774] 1 H NMR (300 MHz, CDCl3) δ 7.24 (s, 1H), 7.03 (d, J = 2.1 Hz, 1H), 6.93-6.88 (m, 1H), 4.84-4.55 (m, 2H), 3.33 (s, 3H).

[0775] Step 7:

[0776]

[0777] According to step 6 of Example 1, the starting materials were replaced with 1-5 (150 mg, 0.530 mmol) and 18-7 (97.0 mg, 0.530 mmol) respectively to prepare 100 mg of compound 18 (a mixture of diastereomers, red solid, yield 44%).

[0778] MS (ESI, m / z): [M+H] + = 429.05.

[0779] Step 8:

[0780]

[0781] The mixture of diastereomers 18 (100 mg, 0.233 mmol) was chirally resolved under the following conditions: chiral column CHIRAL ART Cellulose-SZ, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (methanol with 10 mM ammonia), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 50% B; detection wavelength 210 / 254 nm. A retention time of 8.8 min yielded the forepeak fraction, which was concentrated under reduced pressure and lyophilized to give 28.0 mg of optically pure compound 18a (white solid, 28% yield); a retention time of 13.6 min yielded the hindpeak fraction, which was concentrated under reduced pressure and lyophilized to give 28.0 mg of optically pure compound 18b (white solid, 28% yield).

[0782] Compound 18a:

[0783] MS (ESI, m / z): [M+H] + = 429.20.

[0784] 1 H NMR (300 MHz, DMSO-d6) δ 9.49 (s, 1H), 8.72 (d, J = 0.9 Hz, 1H), 8.18 (d, J = 7.2 Hz, 1H), 7.76 (d, J = 8.7 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H),5.88 (s, 1H), 4.67-4.42 (m, 2H), 4.39-4.26 (m, 1H), 3.87-3.36 (m, 3H), 3.32(s, 3H), 3.25-3.12 (m, 1H), 2.45 (t, J = 8.1 Hz, 2H), 2.22-2.08 (m, 1H), 1.97-1.85 (m, 1H), 1.82 (s, 3H), 1.76-1.62 (m, 2H), 0.93 (t, J = 7.5 Hz, 3H).

[0785] Compound 18b:

[0786] MS (ESI, m / z): [M+H] + = 429.15.

[0787] 1H NMR (300 MHz, DMSO-d6) δ 9.49 (s, 1H), 8.76 (s, 1H), 8.17 (br s,1H), 7.74 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 5.89 (s, 1H), 4.67-4.43 (m, 2H), 4.38-4.26 (m, 1H), 3.77-3.36 (m, 3H), 3.32 (s, 3H), 3.25-3.12(m, 1H), 2.45 (t, J = 8.1 Hz, 2H), 2.22-2.08 (m, 1H), 1.97-1.85 (m, 1H), 1.81(s, 3H), 1.77-1.62 (m, 2H), 0.92 (t, J = 7.5 Hz, 3H).

[0788] Example 19:

[0789] N-(((S)-1-(2-((3-amino-4-fluoro-5-((((R or S)-S-methylsulfonylimino)phenyl)amino)-6-propylpyrimidin-4-yl)pyrrolidine-3-yl)acetamide (compound 19a)

[0790] Preparation of N-(((S)-1-(2-((3-amino-4-fluoro-5-((((S or R)-S-methylsulfonylimino)phenyl)amino)-6-propylpyrimidin-4-yl)pyrrolidine-3-yl)acetamide (compound 19b)

[0791] Step 1:

[0792]

[0793] Compound 19-1 (40.0 g, 134 mmol) was dissolved in 1,4-dioxane (400.0 mL) at room temperature and under a nitrogen atmosphere. Sodium methanethiol (9.38 g, 134 mmol), palladium acetate (3.00 g, 13.4 mmol), ligand 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene (15.5 g, 26.8 mmol), and N,N-diisopropylethylamine (34.6 g, 268 mmol) were then added sequentially to the reaction solution. The reaction mixture was stirred at 120 °C for 2 hours under a nitrogen atmosphere. The reaction progress was monitored using liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the mixture was filtered, the filter cake was washed with ethyl acetate (500 mL × 2), and the filtrate was concentrated under reduced pressure. The residue was purified directly by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 9 / 1), and the resulting fraction was concentrated under reduced pressure to give 25.0 g of compound 19-2 (pale yellow solid, 70% yield, crude product).

[0794] 1 H NMR (300 MHz, CDCl3) δ 8.28-8.24 (m, 1H), 8.06-8.02 (m, 1H), 2.59 (s, 3H).

[0795] Step 2:

[0796]

[0797] Compound 19-2 (25.0 g, 94.0 mmol, crude) was dissolved in 1,4-dioxane (60.0 mL) at room temperature and under a nitrogen atmosphere. Then, tert-butyl carbamate (11.0 g, 94.0 mmol), palladium acetate (2.11 g, 9.40 mmol), the ligand 2-bicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (8.96 g, 18.8 mmol), and cesium carbonate (61.2 g, 188 mmol) were added sequentially to the reaction solution. The reaction system was stirred at 100 °C for 2 hours under nitrogen atmosphere. The reaction progress was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction system was filtered, the filter cake was washed with methanol (100 mL × 2), the filtrate was concentrated under reduced pressure, and the residue was directly purified by reversing-phase column C18. The purification conditions were as follows: 330 g C18 reversed-phase column; mobile phase: acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate: 80 mL / min; gradient: acetonitrile from 50% to 95% over 30 minutes; detection wavelength: 254 nm. After confirmation by LC-MS, the product fraction was collected and concentrated under reduced pressure to give 1.60 g of compound 19-3 (white solid, yield 6%).

[0798] MS (ESI, m / z): [MH] - = 301.00.

[0799] 1 H NMR (400 MHz, CDCl3) δ 8.91-8.84 (m, 1H), 7.79-7.72 (m, 1H), 6.82 (s, 1H), 2.55 (s, 3H), 1.55 (s, 9H).

[0800] Step 3:

[0801]

[0802] According to the method in step 7 of Example 1, the starting material was replaced with 19-3 (1.60 g, 5.29 mmol) to prepare 1.00 g of compound 19-4 (yellow solid, yield 57%).

[0803] MS (ESI, m / z): [M+H] + = 334.20.

[0804] 1 H NMR (400 MHz, CDCl3) δ 9.37-9.30 (m, 1H), 8.49-8.41 (m, 1H), 6.99 (s, 1H), 3.30 (s, 3H), 3.20 (s, 1H), 1.57 (s, 9H).

[0805] Step 4:

[0806]

[0807] According to the method in step 5 of Example 5, the starting material was replaced with 19-4 (300 mg, 0.900 mmol) to prepare 180 mg of compound 19-5 (yellow solid, yield 66%).

[0808] MS (ESI, m / z): [M+H] + = 304.10.

[0809] Step 5:

[0810]

[0811] According to step 6 of Example 1, the starting materials were replaced with 1-5 (168 mg, 0.593 mmol) and 19-5 (180 mg, 0.593 mmol) respectively to prepare 180 mg of compound 19-6 (yellow solid, yield 55%).

[0812] MS (ESI, m / z): [M+H] + = 550.30.

[0813] 1 H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 9.08 (s, 1H), 8.35 (s, 1H), 8.23-8.09 (m, 2H), 5.84 (s, 1H), 4.44 (s, 1H), 4.36-4.23 (m, 1H), 3.77-3.34(m, 4H), 3.14 (s, 3H), 2.41 (t, J = 7.6 Hz, 2H), 2.16-2.03 (m, 1H), 1.90-1.80(m, 1H), 1.80 (s, 3H), 1.75-1.61 (m, 2H), 1.46 (s, 9H), 0.91 (t, J = 7.2 Hz, 3H).

[0814] Step 6:

[0815]

[0816] Compound 19-6 (180 mg, 0.327 mmol) was dissolved in dichloromethane (2.4 mL) at 0 °C, and trifluoroacetic acid (0.6 mL) was slowly added dropwise to the reaction solution using a syringe. The reaction system was stirred at room temperature for 2 hours. The reaction system was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was directly purified using a reversed-phase C18 column. The purification conditions were as follows: 40 g C18 reversed-phase column; mobile phase: acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate: 35 mL / min; gradient: acetonitrile from 20% to 60% over 30 minutes; detection wavelength: 254 nm. The product fraction was collected, concentrated under reduced pressure, and lyophilized to give 120 mg of compound 19 (a mixture of diastereomers, white solid, yield 82%).

[0817] MS (ESI, m / z): [M+H] + = 450.20.

[0818] Step 7:

[0819]

[0820] The diastereomer mixture 19 (120 mg, 0.267 mmol) was chirally resolved. The resolution conditions were as follows: chiral column CHIRAL ART Cellulose-SZ, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (methanol with 10 mM ammonia); mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 50% B; detection wavelength 254 / 220 nm; retention time 7.8 min yielded the forepeak fraction, which was concentrated under reduced pressure and lyophilized to give 24.8 mg of optically pure compound 19a (white solid, 21% yield); retention time 9.9 min yielded the hindpeak fraction, which was concentrated under reduced pressure and lyophilized to give 34.9 mg of optically pure compound 19b (white solid, 29% yield).

[0821] Compound 19a:

[0822] MS (ESI, m / z): [M+H] + = 450.15.

[0823] 1 H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.12 (d, J = 6.4 Hz, 1H), 7.79 (s, 1H), 7.26 (d, J = 6.8 Hz, 1H), 5.79 (s, 1H), 5.32 (s, 2H), 4.38-4.24(m, 1H), 4.18 (s, 1H), 3.78-3.36 (m, 4H), 3.11 (s, 3H), 2.40 (t, J = 7.6 Hz,2H), 2.18-2.03 (m, 1H), 1.90-1.82 (m, 1H), 1.81 (s, 3H), 1.74-1.60 (m, 2H),0.91 (t, J = 7.2 Hz, 3H).

[0824] 19 F NMR (377 MHz, DMSO-d6) δ -142.8

[0825] Compound 19b:

[0826] MS (ESI, m / z): [M+H] + = 450.15.

[0827] 1 H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.17-8.07 (m, 1H), 7.81 (s,1H), 7.29-7.22 (m, 1H), 5.79 (s, 1H), 5.32 (s, 2H), 4.39-4.24 (m, 1H), 4.18(s, 1H), 3.78-3.35 (m, 4H), 3.11 (s, 3H), 2.40 (t, J = 7.6 Hz, 2H), 2.19-2.04(m, 1H), 1.91-1.82 (m, 1H), 1.81 (s, 3H), 1.74-1.60 (m, 2H), 0.91 (t, J = 7.2Hz, 3H).

[0828] 19 F NMR (377 MHz, DMSO-d6) δ -142.8

[0829] Example 20:

[0830] N-((S)-1-(2-((4-amino-3-((R or S)-cyclopropanesulfonyl)phenyl)amino)-6-propylpyrimidin-4-yl)pyrrolidine-3-yl)acetamide (compound 20a)

[0831] Preparation of N-((S)-1-(2-((4-amino-3-((S or R)-cyclopropanesulfonyl)phenyl)amino)-6-propylpyrimidin-4-yl)pyrrolidine-3-yl)acetamide (compound 20b)

[0832] Step 1:

[0833]

[0834] Compound 20-1 (5.00 g, 22.7 mmol; CAS: 321-23-3, purchased directly from Shanghai Shaoyuan Technology Co., Ltd.) and tert-butyl mercaptan (2.66 g, 29.5 mmol) were dissolved in N,N-dimethylformamide (4.0 mL) at room temperature. Potassium carbonate (14.8 g, 45.5 mmol) was then added to the reaction mixture. The reaction system was stirred at room temperature for 2 hours. The reaction progress was monitored by thin-layer chromatography (mobile phase: petroleum ether: ethyl acetate = 20:1). After the starting material disappeared, the reaction was stopped at 0°C. oThe reaction was quenched with water (500 mL) under C conditions. Extraction was performed with ethyl acetate (500 mL × 3), and the combined organic phases were washed with saturated sodium chloride aqueous solution (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified directly by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1), and the resulting fraction was concentrated under reduced pressure to give 5.00 g of compound 20-2 (yellow oil, yield 76%).

[0835] 1 H NMR (300 MHz, DMSO-d6) δ 7.95-7.93 (m, 1H), 7.88 (d, J = 1.2 Hz,2H), 1.26 (s, 9H).

[0836] Step 2:

[0837]

[0838] Compound 20-2 (5.00 g, 17.2 mmol) was dissolved in dichloromethane (50.0 mL) at 0 °C. Trifluoroacetic acid (15.0 mL) was slowly added dropwise to the reaction solution using a syringe. The reaction system was stirred at room temperature for 48 hours. The reaction system was then concentrated under reduced pressure. Petroleum ether (50.0 mL) was added at room temperature, and the mixture was stirred for 5 minutes. After standing, a large amount of solid precipitated out. The mixture was then filtered, and the filter cake was washed with petroleum ether (50.0 mL × 3), dried, and yielded 2.50 g of compound 20-3 (yellow solid, yield 62%).

[0839] 1 H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 8.8 Hz, 1H), 7.62 (d, J = 2.0Hz, 1H), 7.42-7.38 (m, 1H), 4.00 (br s, 1H).

[0840] Step 3:

[0841]

[0842] Compound 20-3 (2.50 g, 8.53 mmol) and compound cyclopropylboronic acid (1.38 g, 16.0 mmol; CAS: 411235-57-9, purchased directly from Shanghai Bide Pharmaceutical Technology Co., Ltd.) were dissolved in 1,2-dichloroethane (100 mL) under nitrogen protection at room temperature. Copper acetate (1.94 g, 10.7 mmol), cesium carbonate (3.48 g, 10.7 mmol), and 2,2-bipyridine (1.67 g, 10.7 mmol) were then added to the reaction mixture. The reaction system was stirred at 80 °C for 16 hours. The reaction progress was monitored by thin-layer chromatography (mobile phase: petroleum ether / ethyl acetate = 20 / 1). After the reaction was complete, the reaction system was concentrated under reduced pressure. The residue was purified directly by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 40 / 1), and the resulting fraction was concentrated under reduced pressure to give compound 20-4 (yellow solid, yield 60%).

[0843] 1 H NMR (300 MHz, CDCl3) δ 8.05 (d, J = 8.8 Hz, 1H), 7.96 (d, J = 2.0Hz, 1H), 7.34-7.28 (m, 1H), 2.09-1.99 (m, 1H), 1.22-1.15 (m, 2H), 0.78-0.67(m, 2H).

[0844] Step 4:

[0845]

[0846] According to the method in step 3 of Example 16, the starting materials were replaced with compounds 1-5 (800 mg, 2.84 mmol) to prepare 500 mg of compound 20-5 (pale yellow solid, yield 67%).

[0847] MS (ESI, m / z): [M+H] + = 264.10.

[0848] 1H NMR (400 MHz, DMSO-d6) δ 8.10 (d, J = 6.4 Hz, 1H), 5.84 (s, 2H), 5.58 (s, 1H), 4.29-4.20 (m, 1H), 3.57-3.36 (m, 3H), 3.28-3.14 (m, 1H), 2.29(t, J = 7.2 Hz, 2H), 2.14-2.06 (m, 1H), 1.86-1.81 (m, 1H), 1.80 (s, 3H), 1.63-1.53 ​​(m, 2H), 0.87 (t, J = 7.2 Hz, 3H).

[0849] Step 5:

[0850]

[0851] According to step 6 of Example 1, the starting materials were replaced with compound 20-5 (321 mg, 1.22 mmol) and compound 20-4 (367 mg, 1.34 mmol) respectively to prepare 430 mg of compound 20-6 (white solid, yield 77%).

[0852] MS (ESI, m / z): [M+H] + = 457.15.

[0853] 1 H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 9.0 Hz, 1H), 7.86 (s, 1H), 7.84-7.79 (m, 1H), 7.37-7.30 (m, 1H), 5.93-5.85 (m, 1H), 5.80 (br s, 1H),4.68-4.55 (m, 1H), 3.88-3.70 (m, 1H), 3.66-3.48 (m, 2H), 3.47-3.28 (m, 1H),2.49 (t, J = 7.6 Hz, 2H), 2.37-2.24 (m, 1H), 2.12-2.06 (m, 1H), 2.04 (s, 3H),1.79-1.65 (m, 3H), 1.22-1.16 (m, 2H), 0.98 (t, J = 7.2 Hz, 3H), 0.81-0.72 (m,2H).

[0854] Step 6:

[0855]

[0856] According to step 7 of Example 1, the starting material was replaced with compound 20-6 (425 mg, 0.931 mmol) to prepare 290 mg of compound 20-7 (yellow solid, yield 64%).

[0857] MS (ESI, m / z): [M+H] + = 488.15.

[0858] 1 H NMR (400 MHz, CDCl3) δ 10.9 (br s, 1H), 8.99 (s, 1H), 7.82-7.37 (m,2H), 6.59-6.32 (m, 1H), 5.75 (d, J = 6.0 Hz, 1H), 4.69-4.46 (m, 1H), 3.91-3.66 (m, 2H), 3.63-3.38 (m, 2H), 3.38-3.24 (m, 1H), 2.51 (t, J = 7.8 Hz, 2H), 2.39-2.23 (m, 1H), 2.08-1.98 (m, 4H), 1.75-1.64 (m, 2H), 1.17-1.04 (m, 2H),1.00 (t, J = 7.2 Hz, 3H), 0.91-0.81 (m, 2H).

[0859] Step 7:

[0860]

[0861] According to the method in step 5 of Example 5, the starting material was replaced with 20-7 (250 mg, 0.513 mmol) to prepare 150 mg of compound 20 (a mixture of diastereomers, white solid, yield 64%).

[0862] MS (ESI, m / z): [M+H] + = 458.25.

[0863] Step 8:

[0864]

[0865] The diastereomer mixture 20 (120 mg, 0.164 mmol) was chirally resolved. The resolution conditions were as follows: chiral column CHIRALCEL AY-H, 2 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol); mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 50% B; detection wavelength 282 / 236 nm; retention time 3.6 min yielded the forepeak fraction, which, after concentration under reduced pressure and lyophilization, yielded 33.0 mg of optically pure compound 20a (white solid, 28% yield); retention time 6.8 min yielded the hindpeak fraction, which, after concentration under reduced pressure and lyophilization, yielded 33.0 mg of optically pure compound 20b (white solid, 28% yield).

[0866] Compound 20a:

[0867] [α] 25 D = +2.00 (c = 0.4, EtOH)

[0868] MS (ESI, m / z): [M+H] + = 458.10.

[0869] 1 H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.31 (s, 1H), 8.17-8.07 (m,1H), 7.46-7.38 (m, 1H), 6.70 (d, J = 8.8 Hz, 1H), 5.96 (s, 2H), 5.73 (s, 1H),4.35-4.27 (m, 1H), 4.14 (s, 1H), 3.76-3.37 (m, 4H), 2.78-2.69 (m, 1H), 2.37(t, J = 7.6 Hz, 2H), 2.17-2.04 (m, 1H), 1.89-1.82 (m, 1H), 1.80 (s, 3H),1.73-1.58 (m, 2H), 1.07-1.00 (m, 1H), 0.99-0.85 (m, 5H), 0.84-0.75 (m, 1H).

[0870] Compound 20b:

[0871] MS (ESI, m / z): [M+H] + = 458.15.

[0872] 1H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.31 (s, 1H), 8.17-8.07 (m,1H), 7.45-7.38 (m, 1H), 6.70 (d, J = 8.8 Hz, 1H), 5.96 (s, 2H), 5.73 (s, 1H),4.36-4.25 (m, 1H), 4.13 (s, 1H), 3.72-3.34 m, 4H), 2.78-2.69 (m, 1H), 2.37(t, J = 7.6 Hz, 2H), 2.18-2.02 (m, 1H), 1.91-1.81 (m, 1H), 1.80 (s, 3H),1.72-1.59 (m, 2H), 1.08-1.00 (m, 1H), 1.00-0.84 (m, 5H), 0.84-0.76 (m, 1H).

[0873] Example 21:

[0874] N-((S)-1-(4-(4-amino-6-((R or S)-S-methylsulfonylimide)pyridin-2-yl)amino)-6-propylpyridin-2-ylpyrrolidine-3-yl)acetamide (compound 21a)

[0875] Preparation of N-((S)-1-(4-(4-amino-6-((S or R)-S-methylsulfonylimide)pyridin-2-yl)amino)-6-propylpyridin-2-ylpyrrolidine-3-yl)acetamide (compound 21b)

[0876] Step 1:

[0877]

[0878] Compound 21-1 (10.0 g, 48.5 mmol) and sodium methanethiol (3.40 g, 48.5 mmol) were dissolved in N,N-dimethylformamide (200.0 mL) and water (80.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 15 hours. The reaction progress was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction mixture was quenched with water (300 mL) at room temperature. The mixture was filtered, the filter cake was washed with ice water (20 mL × 2), and dried to give 9.00 g of compound 21-2 (white solid, 85% yield).

[0879] MS (ESI, m / z): [M+H] + = 218.20 / 220.15.

[0880] 1 H NMR (300 MHz, CDCl3) δ 7.64 (d, J = 1.2 Hz, 1H), 7.51 (d, J = 1.2Hz, 1H), 3.95 (s, 3H), 2.59 (s, 3H).

[0881] Step 2:

[0882]

[0883] Compound 21-2 (5.00 g, 23.0 mmol) was dissolved in a mixed solvent of methanol (50.0 mL), tetrahydrofuran (25.0 mL), and water (25.0 mL) at 0 °C. Lithium hydroxide (2.75 g, 115 mmol) was then added to the reaction mixture. The reaction mixture was stirred at room temperature for 3 hours. The reaction progress was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the methanol and tetrahydrofuran were removed by concentration under reduced pressure. The pH of the reaction mixture was adjusted to 2-3 with 1 mol / L hydrochloric acid aqueous solution at 0 °C. After the solid had completely precipitated, the mixture was filtered, and the filter cake was washed with ice water (20 mL). After drying, 2.50 g of compound 21-3 (white solid, 53% yield) was obtained.

[0884] MS (ESI, m / z): [M+H] + = 204.05 / 206.10.

[0885] 1 H NMR (300 MHz, DMSO-d6) δ 14.08 (br s, 1H), 7.65 (d, J = 1.2 Hz, 1H), 7.50 (d, J = 1.2 Hz, 1H), 2.56 (s, 3H).

[0886] Step 3:

[0887]

[0888] Compound 21-3 (2.20 g, 10.8 mmol), triethylamine (3.0 mL), and diphenyl azidophosphate (3.5 mL) were dissolved in tert-butanol (25.0 mL) at room temperature and under a nitrogen atmosphere. The reaction mixture was stirred at 90 °C for 3 hours under a nitrogen atmosphere. The reaction progress was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was directly purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1). The resulting fraction was concentrated under reduced pressure to give 2.20 g of compound 21-4 (pale yellow oil, yield 74%).

[0889] MS (ESI, m / z): [M+H] + = 275.15 / 277.10.

[0890] 1 H NMR (400 MHz, CDCl3) δ 7.18 (d, J = 1.6 Hz, 1H), 7.06 (d, J = 1.6Hz, 1H), 6.65 (s, 1H), 2.53 (s, 3H), 1.52 (s, 9H).

[0891] Step 4:

[0892]

[0893] According to step 7 of Example 1, the starting material was replaced with 21-4 (1.80 g, 6.55 mmol) to prepare 1.10 g of compound 21-5 (white solid, yield 55%).

[0894] MS (ESI, m / z): [M+H] + = 306.10 / 308.00.

[0895] 1 H NMR (300 MHz, CDCl3) δ 7.89-7.82 (m, 2H), 7.39 (s, 1H), 3.26 (s,3H), 1.54 (s, 9H).

[0896] Step 5:

[0897]

[0898] Compound 21-5 (400 mg, 1.31 mmol) was dissolved in tetrahydrofuran (4.0 mL) at 0 °C under a nitrogen atmosphere. Sodium hydride (62.8 mg, 1.57 mmol, 60% dispersed in mineral oil) was then added in portions to the reaction mixture. The mixture was stirred at 0 °C for 30 minutes, and then di-tert-butyl dicarbonate (343 mg, 1.57 mmol) was added. The mixture was stirred at 60 °C for 2 hours under a nitrogen atmosphere. The reaction progress was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the mixture was cooled to 0 °C and then quenched with water (40.0 mL). Extraction was performed with ethyl acetate (100 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was directly purified using a reversed-phase C18 column under the following conditions: 40 g C18 reversed-phase column; mobile phase: acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate: 30 mL / min; gradient: acetonitrile increased from 5% to 95% over 35 minutes; detection wavelength: 254 nm. After confirmation by LC-MS, the product fraction was collected and concentrated under reduced pressure to give 200 mg of compound 21-6 (white solid, yield 38%).

[0899] MS (ESI, m / z): [M+H] + = 406.10 / 408.15.

[0900] Step 6:

[0901]

[0902] According to the synthesis method in step 6 of Example 1, the raw materials were replaced with compound 10-9 (165 mg, 0.629 mmol) and compound 21-6 (306 mg, 0.754 mmol) respectively to prepare 183 mg of compound 21-7 (red oil, yield 46%).

[0903] MS (ESI, m / z): [M+H] + = 632.40.

[0904] Step 7:

[0905]

[0906] Compound 21-7 (140 mg, 0.222 mmol) was dissolved in dichloromethane (3.0 mL) at 0 °C, and trifluoroacetic acid (0.8 mL) was slowly added dropwise to the reaction solution using a syringe. The reaction system was stirred at room temperature for 5 hours. The reaction system was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was directly purified by preparative liquid chromatography (HPLC). The purification conditions were as follows: column type: YMC-Actus Triart C18 ExRS 30 × 150 mm, 5 μm; mobile phase: acetonitrile and water (10 mmol / L ammonium bicarbonate + 0.05% NH3). . H2O); flow rate 60 mL / min; gradient of acetonitrile from 10% to 30% over 10 min, then maintaining an isogradient of 30% acetonitrile for 10 min; detection wavelength 254 nm / 220 nm, retention time 9.67 min; the fraction of product was collected, concentrated under reduced pressure and lyophilized to give 35.0 mg of compound 21 (a mixture of diastereomers, white solid, yield 37%).

[0907] MS (ESI, m / z): [M+H] + = 432.40

[0908] Step 8:

[0909]

[0910] The diastereomer mixture 21 (35.0 mg, 0.0770 mmol) was chirally resolved under the following conditions: chiral column Chiral NX(2), 250 × 30 mm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol); mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 40% B; detection wavelength 260 / 272 nm; retention time 10.1 min yielded the forepeak fraction, which, after concentration under reduced pressure and lyophilization, yielded 14.7 mg of optically pure compound 21a (white solid, 42% yield); retention time 14.0 min yielded the hindpeak fraction, which, after concentration under reduced pressure and lyophilization, yielded 14.2 mg of optically pure compound 21b (white solid, 41% yield).

[0911] Compound 21a:

[0912] MS (ESI, m / z): [M+H] + = 432.25.

[0913] 1H NMR (400 MHz, DMSO-d6) δ 8.96 (s, 1H), 8.06 (d, J = 6.8 Hz, 1H), 6.87 (s, 1H), 6.72 (d, J = 1.6 Hz, 1H), 6.44 (s, 1H), 6.33 (s, 2H), 6.01 (d,J = 2.0 Hz, 1H), 4.25-4.16 (m, 1H), 3.87 (s, 1H), 3.56-3.47 (m, 1H), 3.44-3.34 (m, 2H), 3.17-3.11 (m, 1H), 3.00 (s, 3H), 2.35 (t, J = 7.6 Hz, 2H), 2.11-1.99 (m, 1H), 1.83-1.74 (m, 1H), 1.74 (s, 3H), 1.63-1.51 (m, 2H), 0.84(t, J = 7.2 Hz, 3H).

[0914] Compound 21b:

[0915] MS (ESI, m / z): [M+H] + = 432.20.

[0916] 1 H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.13 (d, J = 6.8 Hz, 1H), 6.94 (s, 1H), 6.79 (d, J = 2.0 Hz, 1H), 6.51 (s, 1H), 6.40 (s, 2H), 6.08 (d,J = 2.0 Hz, 1H), 4.32-4.23 (m, 1H), 3.94 (s, 1H), 3.62-3.53 (m, 1H), 3.48-3.37 (m, 2H), 3.25-3.17 (m, 1H), 3.07 (s, 3H), 2.42 (t, J = 7.6 Hz, 2H), 2.18-2.05 (m, 1H), 1.90-1.81 (m, 1H), 1.81 (s, 3H), 1.71-1.57 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H).

[0917] Example 22:

[0918] N-((S)-1-(4-((4-(R or S)-S-methylsulfonylimino)-1H-imidazo[4,5-c]pyridin-6-yl)amino)-6-propylpyridin-2-yl)pyrrolidine-3-yl)acetamide (compound 22a)

[0919] Preparation of N-((S)-1-(4-((4-(S or R)-S-methylsulfonylimino)-1H-imidazo[4,5-c]pyridin-6-yl)amino)-6-propylpyridin-2-yl)pyrrolidine-3-yl)acetamide (compound 22b)

[0920] Step 1:

[0921]

[0922] Compound 22-1 (5.00 g, 26.6 mmol; CAS: 2589-12-0, purchased directly from Shanghai Bid Pharmaceutical Technology Co., Ltd.) was dissolved in N,N-dimethylformamide (50.0 mL) at room temperature, and then sodium methanethiol (9.32 g, 133 mmol) was added to the above reaction solution. The reaction system was stirred at 120 °C for 24 hours. The reaction progress was monitored by liquid chromatography-mass spectrometry. After the reaction was complete, the reaction system was quenched with water (500 mL) at 0 °C, extracted with ethyl acetate (300 mL × 3), and the combined organic phases were washed with saturated sodium chloride aqueous solution (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was directly purified by silica gel column chromatography (eluent: pure ethyl acetate) to give 2.50 g of compound 22-2 (white solid, yield 47%).

[0923] MS (ESI, m / z): [M+H] + = 199.90 / 201.85.

[0924] 1 H NMR (400 MHz, DMSO-d6) δ 13.09 (br s, 1H) 8.34 (s, 1H), 7.39 (s,1H), 2.60 (s, 3H).

[0925] Step 2:

[0926]

[0927] Compound 22-2 (2.50 g, 12.5 mmol) and potassium carbonate (4.33 g, 31.3 mmol) were dissolved in N,N-dimethylformamide (25.0 mL) and added to the above reaction solution at room temperature. Chloromethyltrimethylsilylethyl ether (2.09 g, 12.5 mmol) was added dropwise to the reaction solution using a syringe. The reaction system was stirred for 2 hours at room temperature. The reaction progress was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction mixture was filtered, the filter cake was washed with ethyl acetate (200 mL × 3), the filtrate was washed with water (100 mL × 4), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was directly purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 40 / 1) to give compound 22-4 (yellow solid, 44% yield).

[0928] MS (ESI, m / z): [M+H] + = 329.95 / 331.90.

[0929] 1 H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.15 (s, 1H), 5.42 (s, 2H), 3.49-3.41 (m, 2H), 2.66 (s, 3H), 0.88-0.84 (m, 2H), -0.07 (s, 9H).

[0930] Step 3:

[0931]

[0932] According to step 7 of Example 1, the starting material was replaced with compound 22-3 (1.60 g, 4.85 mmol) to prepare 520 mg of compound 22-4 (white solid, yield 30%).

[0933] MS (ESI, m / z): [M+H] + = 361.05 / 363.00.

[0934] 1H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 7.89 (s, 1H), 6.50 (d, J =11.0 Hz, 1H), 5.53 (d, J = 11.0 Hz, 1H), 3.62 (s, 3H), 3.58-3.32 (m, 2H),1.09-0.99 (m, 1H), 0.93-0.83 (m, 1H), 0.00 (s, 9H).

[0935] Step 4:

[0936]

[0937] According to the synthesis method in step 5 of Example 21, the raw materials were replaced with compound 22-4 (520 mg, 1.44 mmol) to prepare 260 mg of compound 22-5 (white solid, yield 39%).

[0938] MS (ESI, m / z): [M+H] + = 461.00 / 463.05.

[0939] 1 H NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 7.95 (s, 1H), 6.17 (d, J =10.4 Hz, 1H), 6.03 (d, J = 10.4 Hz, 1H), 3.68 (t, J = 8.4 Hz, 2H), 3.64 (s,3H), 1.40 (s, 9H), 1.06-0.95 (m, 2H), 0.00 (s, 9H).

[0940] Step 5:

[0941]

[0942] According to the method in step 2 of Example 5, the starting materials were replaced with 10-9 (130 mg, 0.496 mmol) and 22-5 (251 mg, 0.546 mmol) respectively to prepare 300 mg of compound 22-6 (a mixture of diastereomers, brown solid, yield 88%).

[0943] MS (ESI, m / z): [M+H] + = 687.30.

[0944] 1H NMR (400 MHz, CD3OD) δ 8.71 (s, 1H), 7.87-7.70 (s, 1H), 7.56 (s,1H), 6.52 (s, 1H), 6.28-6.21 (m, 1H), 5.88-5.80 (m, 1H), 4.58-4.49 (m, 1H), 4.09-3.94 (m, 1H), 3.92-3.83 (m, 1H), 3.77-3.58 (m, 1H), 3.57 (s, 3H), 3.54-3.46 (m, 1H), 3.37 (s, 2H), 2.71 (t, J = 7.6 Hz, 2H), 2.41-2.32 (m, 1H),2.19-2.11 (m, 1H), 1.99 (s, 3H), 1.86-1.71 (m, 2H), 1.13 (s, 9H), 1.05 (t, J= 7.2 Hz, 3H), 1.00-0.92 (m, 1H), 0.92-0.80 (m, 1H), 0.00 (s, 9H).

[0945] Step 6:

[0946]

[0947] Compound 22-6 (300 mg, 0.511 mmol) was dissolved in dichloromethane (5.00 mL) at 0 °C, and trifluoroacetic acid (2.00 mL) was slowly added dropwise to the reaction solution using a syringe. The reaction system was stirred at room temperature for 2 hours. The reaction system was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was directly purified using a reversed-phase C18 column. The purification conditions were as follows: 80 g C18 reversed-phase column; mobile phase: acetonitrile and water (0.1% formic acid); flow rate: 60 mL / min; gradient: acetonitrile from 5% to 95% over 30 minutes; detection wavelength: 254 nm / 220 nm. After LC-MS confirmation, the product fraction was collected, concentrated under reduced pressure, and lyophilized to obtain 180 mg of crude product.

[0948] The crude product was further purified by preparative liquid chromatography. The purification conditions were as follows: column type YMC-ActusTriart C18 ExRS 30 × 150 mm, 5 μm; mobile phase acetonitrile and water (10 mmol / L ammonium bicarbonate + 0.05% NH3). .H2O); flow rate 60 mL / min; gradient of acetonitrile from 2% to 14% over 10 min, then maintained at an isogradient of 14% acetonitrile for 10 min; detection wavelength 254 nm; retention time 10.9 min. The product fraction was collected, concentrated under reduced pressure, and lyophilized to give 60.0 mg of formate of compound 22 (a mixture of diastereomers, pale green solid, yield 23%).

[0949] MS (ESI, m / z): [M-HCOOH+H] + = 457.20.

[0950] Step 7:

[0951]

[0952] The formate (55.0 mg, 0.110 mmol) of the diastereomer mixture 22 was chirally resolved. The resolution conditions were as follows: chiral column CHIRAL ART Cellulose-SZ, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 50% B; detection wavelength 220 / 254 nm; retention time 6.7 min yielded the forepeak fraction, which, after concentration under reduced pressure and lyophilization, yielded 14.3 mg of optically pure compound 22a (white solid, 29% yield); retention time 11.0 min yielded the stern fraction, which, after concentration under reduced pressure and lyophilization, yielded 10.2 mg of optically pure compound 22b (white solid, 20% yield).

[0953] Compound 22a:

[0954] MS (ESI, m / z): [M+H] + = 457.20.

[0955] 1H NMR (400 MHz, DMSO-d6) δ 12.80 (s, 1H), 9.26 (s, 1H), 8.39 (s, 1H), 8.12 (d, J = 6.8 Hz, 1H), 7.25 (s, 1H), 6.90 (s, 1H), 6.54 (s, 1H), 4.62-4.09(m, 2H), 3.66-3.57 (m, 1H), 3.55-3.42 (m, 1H), 3.45-3.37 (m, 1H), 3.32 (s,3H), 3.28-3.19 (m, 1H), 2.45 (t, J = 7.6 Hz, 2H), 2.19-2.07 (m, 1H), 1.91-1.83 (m, 1H), 1.81 (s, 3H), 1.73-1.59 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H).

[0956] Compound 22b:

[0957] MS (ESI, m / z): [M+H] + = 457.20.

[0958] 1 H NMR (400 MHz, DMSO-d6) δ 12.75 (s, 1H), 9.25 (s, 1H), 8.38 (s, 1H), 8.12 (d, J = 6.8 Hz, 1H), 7.25 (s, 1H), 6.90 (s, 1H), 6.54 (s, 1H), 4.68-4.20(m, 2H), 3.65-3.56 (m, 1H), 3.54-3.37 (m, 2H), 3.32 (s, 3H), 3.29-3.20 (m,1H), 2.45 (t, J = 7.6 Hz, 2H), 2.19-2.06 (m, 1H), 1.91-1.83 (m, 1H), 1.81 (s,3H), 1.73-1.59 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H).

[0959] Example 23:

[0960] N-((S)-1-(4-((4-amino-5-fluoro-6-((R or S)-S-methylsulfonylimide)pyridin-2-yl)amino)-6-propylpyridin-2-ylpyrrolidine-3-yl)acetamide (compound 23a)

[0961] Preparation of N-((S)-1-(4-((4-amino-5-fluoro-6-((S or R)-S-methylsulfonylimide)pyridin-2-yl)amino)-6-propylpyridin-2-ylpyrrolidine-3-yl)acetamide (compound 23b)

[0962] Step 1:

[0963]

[0964] According to the synthesis method in step 1 of Example 10, the raw materials were replaced with compound 23-1 (5.00 g, 27.6 mmol; CAS: 2051921-49-2, purchased directly from the supplier Shanghai Bid Pharmaceutical Technology Co., Ltd.) to prepare 2.00 g of compound 23-2 (white solid, yield 38%).

[0965] MS (ESI, m / z): [M+H] + = 193.10 / 195.05.

[0966] 1 H NMR (400 MHz, CDCl3) δ 6.43 (d, J = 5.6 Hz, 1H), 4.26 (br s, 2H), 2.54 (s, 3H).

[0967] Step 2:

[0968]

[0969] According to the synthesis method in step 2 of Example 10, the starting material was replaced with compound 23-2 (2.00 g, 10.4 mmol) to prepare 2.60 g of compound 23-3 (white solid, yield 64%).

[0970] MS (ESI, m / z): [M+H] + = 393.10 / 395.00.

[0971] 1 H NMR (400 MHz, CDCl3) δ 6.87 (d, J = 4.4 Hz, 1H), 2.59 (s, 3H), 1.45 (s, 18H).

[0972] Step 3:

[0973]

[0974] According to the synthesis method in step 6 of Example 1, the raw materials were replaced with compound 23-3 (800 mg, 2.03 mmol) and compound 10-9 (534 mg, 2.03 mmol) respectively to prepare 600 mg of compound 23-4 (yellow solid, yield 57%).

[0975] MS (ESI, m / z): [M+H] + = 519.30.

[0976] 1 H NMR (300 MHz, CDCl3) δ 7.55 (d, J = 4.5 Hz, 1H), 7.01-6.61 (m, 2H), 6.47 (s, 1H), 6.40 (s, 1H), 6.30-5.93 (m, 1H), 4.67-4.51 (m, 1H), 3.75-3.41(m, 4H), 2.69-2.46 (m, 5H), 2.33-2.17 (m, 1H), 2.08-2.01 (m, 1H), 1.99 (s,3H), 1.78-1.62 (m, 2H), 1.50 (s, 9H), 0.96 (t, J = 7.2 Hz, 3H).

[0977] Step 4:

[0978]

[0979] According to the synthesis method in step 7 of Example 1, the starting material was replaced with compound 23-4 (600 mg, 1.15 mmol) to prepare 300 mg of compound 23-5 (brown solid, diastereomer mixture, yield 47%).

[0980] MS (ESI, m / z): [M+H] + = 550.30.

[0981] Step 5:

[0982]

[0983] Compound 23-5 (300 mg, 0.546 mmol) was dissolved in dichloromethane (2.0 mL) at 0 °C, and trifluoroacetic acid (0.5 mL) was slowly added dropwise to the reaction solution using a syringe. The reaction system was stirred at room temperature for 3 hours. The reaction system was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was directly purified by preparative liquid chromatography (HPLC). The purification conditions were as follows: column type: Xselect CSH F-Phenyl OBD column 30 x 250 mm, 5 μm; mobile phase: methanol and water (0.1% formic acid); flow rate: 60 mL / min; gradient: acetonitrile from 8% to 27% over 10 min, then maintained at an isogradient of 27% acetonitrile for 15 min; detection wavelength: 254 nm / 200 nm; retention time: 9.4 min. The fraction of the product was collected, concentrated under reduced pressure, and lyophilized to give 70.0 mg of compound 23 (a mixture of diastereomers, white solid, yield 29%).

[0984] MS (ESI, m / z): [M+H] + = 450.20.

[0985] Step 6:

[0986]

[0987] The diastereomer mixture 23 (70.0 mg, 0.156 mmol) was chirally resolved. The resolution conditions were as follows: chiral column CHIRALPAK IA, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; detection wavelength 260 / 220 nm; retention time 16.1 min yielded the forepeak fraction, which, after concentration under reduced pressure and lyophilization, yielded 12.7 mg of optically pure compound 23a (white solid, 18% yield); retention time 21.6 min yielded the hindpeak fraction, which, after concentration under reduced pressure and lyophilization, yielded 14.5 mg of optically pure compound 23b (white solid, 22% yield).

[0988] Compound 23a:

[0989] MS (ESI, m / z): [M+H] + = 450.20.

[0990] 1H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.17-8.09 (m, 1H), 6.83 (s,1H), 6.55 (s, 2H), 6.50 (s, 1H), 6.33 (d, J = 5.6 Hz, 1H), 4.34-4.19 (m, 2H),3.63-3.55 (m, 1H), 3.51-3.32 (m, 2H), 3.24-3.16 (m, 4H), 2.42 (t, J = 7.6 Hz,2H), 2.18-2.05 (m, 1H), 1.88-1.82 (m, 1H), 1.81 (s, 3H), 1.70-1.56 (m, 2H),0.90 (t, J = 7.2 Hz, 3H).

[0991] 19 F NMR (377 MHz, DMSO-d6) δ -154.02

[0992] Compound 23b:

[0993] MS (ESI, m / z): [M+H] + = 450.15.

[0994] 1 H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.16-8.09 (m, 1H), 6.82 (s,1H), 6.54 (s, 2H), 6.50 (s, 1H), 6.32 (d, J = 5.6 Hz, 1H), 4.33-4.22 (m, 2H), 3.62-3.53 (m, 1H), 3.50-3.38 (m, 2H), 3.25-3.22 (m, 1H), 3.21 (s, 3H), 2.42(t, J = 7.6 Hz, 2H), 2.17-2.05 (m, 1H), 1.89-1.82 (m, 1H), 1.81 (s, 3H),1.70-1.56 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H).

[0995] 19 F NMR (377 MHz, DMSO-d6) δ -154.10.

[0996] Example 24:

[0997] (R or S)-(4-amino-3-chloro-6-((2-((R or S)-2-methylpiperazin-1-yl)-6-propylpyridin-4-yl)amino)pyridin-2-yl)(imino)(methyl)-λ 6 -Aminosulfonone (compound 24a);

[0998] (S or R)-(4-amino-3-chloro-6-((2-((R or S)-2-methylpiperazin-1-yl)-6-propylpyridin-4-yl)amino)pyridin-2-yl)(imino)(methyl)-λ 6 -Aminosulfonone (compound 24b);

[0999] (R or S)-(4-amino-3-chloro-6-((2-((S or R)-2-methylpiperazin-1-yl)-6-propylpyridin-4-yl)amino)pyridin-2-yl)(imino)(methyl)-λ 6 -Aminosulfonone (compound 24c);

[1000] and (S or R)-(4-amino-3-chloro-6-((2-((S or R)-2-methylpiperazin-1-yl)-6-propylpyridin-4-yl)amino)pyridin-2-yl) (imino) (methyl)-λ 6 Preparation of -aminosulfonone (compound 24d)

[1001] Step 1:

[1002]

[1003] At room temperature, starting material 10⁻⁴ (40.0 g, 0.208 mol, CAS: 25194-01-8; purchased directly from Shanghai Bide Pharmaceutical Technology Co., Ltd.) and compound 24-1 (racemic mixture, 38.6 g, 0.200 mol; CAS: 120737-59-9, purchased directly from Shanghai Shaoyuan Technology Co., Ltd.) were dissolved in acetonitrile (400 mL), and then N,N-diisopropylethylamine (77.4 g, 0.598 mol) was added to the above reaction solution. The reaction system was stirred at 80 °C for 16 hours. The reaction progress was monitored by thin-layer chromatography (mobile phase: petroleum ether / ethyl acetate = 4 / 1). After the reaction was complete, the reaction system was cooled to room temperature and concentrated under reduced pressure. The residue was directly purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4 / 1). The obtained fraction was concentrated under reduced pressure to give 3.00 g of compound 24-2 (orange-red oil, yield 4%).

[1004] 1H NMR (400 MHz, CDCl3) δ 7.24 (d, J = 1.6 Hz, 1H), 7.15 (d, J = 1.6Hz, 1H), 4.53-4.41 (m, 1H), 4.30-4.12 (m, 1H), 4.11-4.03 (m, 1H), 4.01-3.86(m, 1H), 3.31-3.12 (m, 2H), 3.11-2.90 (m, 1H), 1.49 (s, 9H), 1.22 (d, J = 6.8Hz, 3H).

[1005] Step 2:

[1006]

[1007] Under a nitrogen atmosphere, starting material 24-2 (3.00 g, 8.4 mmol), n-propylboronic acid (1.10 g, 12.5 mmol), potassium carbonate (3.48 g, 25.2 mmol), and catalyst 1,1-bis(diphenylphosphine)ferrocene palladium dichloromethane complex (0.680 g, 0.83 mmol) were dissolved in 1,4-dioxane (50 mL). The reaction mixture was stirred at 100 °C for 16 hours under a nitrogen atmosphere. The reaction progress was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction mixture was filtered, the filter cake was washed with methanol (50 mL × 3), the filtrate was concentrated under reduced pressure, and the residue was directly purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1). The resulting fraction was concentrated under reduced pressure to give 2.20 g of compound 24-3 (red oil, yield 72%).

[1008] MS (ESI, m / z): [M+H] + = 365.25.

[1009] 1H NMR (400 MHz, CDCl3) δ 7.12 (d, J = 1.6 Hz, 1H), 7.09 (d, J = 1.6Hz, 1H), 4.63-4.48 (m, 1H), 4.31-3.88 (m, 3H), 3.30-3.12 (m, 2H), 3.12-2.89(m, 1H), 2.73 (t, J = 7.6 Hz, 2H), 1.83-1.69 (m, 2H), 1.49 (s, 9H), 1.18 (d,J = 6.8 Hz, 3H), 0.98 (t, J = 7.2 Hz, 3H).

[1010] Step 3:

[1011]

[1012] According to the method in step 5 of Example 5, the starting material was replaced with compound 24-3 (1.87 g, 5.13 mmol) to prepare 1.60 g of compound 24-4 (orange-red oily substance, racemic mixture, yield 93%).

[1013] MS (ESI, m / z): [M+H] + = 335.25.

[1014] 1 H NMR (400 MHz, CDCl3) δ 5.89 (d, J = 1.6 Hz, 1H), 5.66 (d, J = 1.6Hz, 1H), 4.61-4.37 (m, 1H), 4.08-3.71 (m, 5H), 3.26-2.88 (m, 3H), 2.61-2.43(m, 2H), 1.76-1.67 (m, 2H), 1.48 (s, 9H), 1.08 (d, J = 6.6 Hz, 3H), 0.94 (t,J = 7.2 Hz, 3H).

[1015] Step 4:

[1016]

[1017] According to step 6 of Example 1, the starting materials were replaced with compound 24-4 (1.60 g, 4.80 mmol) and compound 10-3 (1.96 g, 4.80 mmol) respectively to prepare 800 mg of compound 24-5 (pale yellow solid, racemic mixture, yield 28%).

[1018] MS (ESI, m / z): [M+H] + = 607.30 / 609.30.

[1019] 1 H NMR (400 MHz, CDCl3) δ 7.71 (s, 1H), 7.12 (s, 1H), 6.57 (s, 1H), 6.50 (s, 1H), 6.43 (s, 1H), 4.65-4.56 (m, 1H), 4.19-4.07 (m, 1H), 4.02-3.79(m, 2H), 3.25-2.91 (m, 3H), 2.56 (s, 3H), 2.55-2.49 (m, 2H), 1.80-1.68 (m,2H), 1.52 (s, 9H), 1.48 (s, 9H), 1.12 (d, J = 6.4 Hz, 3H), 0.96 (t, J = 7.2Hz, 3H).

[1020] Step 5:

[1021]

[1022] According to step 7 of Example 1, the starting material was replaced with compound 24-5 (800 mg, 1.32 mmol) to prepare 350 mg of compound 24-6 (racemic mixture, pale yellow liquid, yield 42%).

[1023] MS (ESI, m / z): [M+H] + = 638.15 / 640.10.

[1024] Step 6:

[1025]

[1026] Compound 24-6 (350 mg, 0.55 mmol) was dissolved in dichloromethane (5.0 mL) at 0 °C, and trifluoroacetic acid (2.0 mL) was slowly added dropwise to the reaction solution using a syringe. The reaction system was stirred at room temperature for 2 hours. The reaction system was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was directly purified using a reversed-phase C18 column. The purification conditions were as follows: 80 g C18 reversed-phase column; mobile phase: acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate: 60 mL / min; gradient of acetonitrile from 30% to 60% over 30 minutes; detection wavelength: 254 nm. After LC-MS confirmation, the product fraction was collected, concentrated under reduced pressure, and lyophilized to give 80.0 mg of compound 24 (racemic mixture, white solid, yield 33%).

[1027] MS (ESI, m / z): [M+H] + = 438.30 / 440.25.

[1028] Step 7:

[1029]

[1030] Mixture 24 (80.0 mg, 0.183 mmol) was subjected to chiral resolution. The resolution conditions were as follows: chiral column Enantiocel-A4-5, 3.0 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; detection wavelength 272 / 246 nm. Three fractions were obtained at retention times of 11.5 min, 17 min, and 21.2 min: the fraction from the first peak (retention time 11.5 min), after concentration under reduced pressure and lyophilization, yielded 7.0 mg of optically pure compound 24a (white solid, 9% yield); the fraction from the second peak (retention time 17.0 min), after concentration under reduced pressure and lyophilization, yielded a mixture of 30.0 mg (38% yield) of compound (a mixture of 24b and 24c), which required further chiral resolution; the fraction from the third peak (retention time 21.2 min), after concentration under reduced pressure and lyophilization, yielded 10.0 mg of optically pure compound 24d (white solid, 13% yield).

[1031] The second fraction (a mixture of compounds 24b and 24c) of 30.0 mg was subjected to a second chiral resolution under the following conditions: CHIRALPAK IH 3 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; detection wavelength 272 / 246 nm. A fraction with a retention time of 16.8 min was obtained, which was concentrated under reduced pressure and lyophilized to give 6.0 mg of optically pure compound 24b (white solid, 7% yield); a fraction with a retention time of 23.5 min was obtained, which was concentrated under reduced pressure and lyophilized to give 10.0 mg of optically pure compound 24c (white solid, 13% yield).

[1032] Compound 24a:

[1033] MS (ESI, m / z): [M+H] + = 438.10 / 440.05.

[1034] 1 H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 6.67-6.62 (m, 4H), 6.30 (s,1H), 4.37-4.32 (m, 1H), 4.22 (s, 1H), 3.83-3.76 (m, 1H), 3.27 (s, 3H), 2.97-2.89 (m, 1H), 2.87-2.67 (m, 4H), 2.63-2.56 (m, 1H), 2.42 (t, J = 7.2 Hz, 2H), 1.68-1.58 (m, 2H), 1.06 (d, J = 6.4 Hz, 3H), 0.89 (t, J = 7.2 Hz, 3H).

[1035] Compound 24b:

[1036] MS (ESI, m / z): [M+H] + = 438.15 / 440.10.

[1037] 1H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 6.70-6.60 (m, 4H), 6.31 (s,1H), 4.35 (s, 1H), 4.23-4.19 (m, 1H), 3.84-3.77 (m, 1H), 3.27 (s, 3H), 2.98-2.79 (m, 1H), 2.82-2.73 (m, 3H), 2.69- 2.54 (m, 2H), 2.47-2.38 (m, 2H), 1.70-1.56 (m, 2H), 1.07 (d, J = 6.4 Hz, 3H), 0.89 (t, J = 7.2 Hz, 3H).

[1038] Compound 24c:

[1039] MS (ESI, m / z): [M+H] + = 438.15 / 440.10.

[1040] 1 H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 6.70-6.60 (m, 4H), 6.31 (s,1H), 4.35 (s, 1H), 4.23-4.19 (m, 1H), 3.84-3.77 (m, 1H), 3.27 (s, 3H), 2.98-2.79 (m, 1H), 2.82-2.73 (m, 3H), 2.69- 2.54 (m, 2H), 2.47-2.38 (m, 2H), 1.70-1.56 (m, 2H), 1.07 (d, J = 6.4 Hz, 3H), 0.89 (t, J = 7.2 Hz, 3H).

[1041] Compound 24d:

[1042] MS (ESI, m / z): [M+H] + = 438.10 / 440.10

[1043] 1H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 6.69-6.60 (m, 4H), 6.31 (s,1H), 4.36-4.32 (m, 1H), 4.22 (s, 1H), 3.83-3.75 (m, 1H), 3.27 (s, 3H), 2.97-2.89 (m, 1H), 2.87-2.71 (m, 3H), 2.69-2.54 (m, 2H), 2.42 (t, J = 7.6 Hz, 2H), 1.69-1.56 (m, 2H), 1.06 (d, J = 6.4 Hz, 3H), 0.89 (t, J = 7.2 Hz, 3H).

[1044] Example 25:

[1045] N-((S)-1-(4-((3-amino-5-((R or S)-S-methylsulfonylimino)phenyl)amino)-6-propylpyridin-2-yl)pyrrolidine-3-yl)acetamide (compound 25a)

[1046] Preparation of N-((S)-1-(4-((3-amino-5-((S or R)-S-methylsulfonylimino)phenyl)amino)-6-propylpyridin-2-yl)pyrrolidine-3-yl)acetamide (compound 25b)

[1047] Step 1:

[1048]

[1049] According to the method in step 2 of Example 5, the starting materials were replaced with 10-9 (250 mg, 0.953 mmol) and 16-3 (433 mg, 1.14 mmol) respectively to prepare 200 mg of compound 25-1 (brown solid, yield 37%).

[1050] MS (ESI, m / z): [M+H] + = 561.20

[1051] 1H NMR (400 MHz, CDCl3) δ 8.21-8.13 (m, 2H), 8.09-7.97 (m, 1H), 6.48(s, 1H), 6.25-6.15 (m, 1H), 5.92-5.84 (m, 1H), 4.60-4.48 (m, 1H), 3.67- 3.52(m, 3H), 3.40-3.31 (m, 1H), 3.31- 3.28 (m, 3H), 2.61-2.50 (m, 2H), 2.30-2.15(m, 1H), 2.10-1.93 (m, 4H), 1.75-1.62 (m, 2H), 1.46-1.36 (m, 9H), 0.95 (t, J= 7.2 Hz, 3H).

[1052] Step 2:

[1053]

[1054] According to the method in step 5 of Example 5, the starting material was replaced with 25-1 (200 mg, 0.357 mmol) to prepare 150 mg of compound 25-2 (white solid, yield 79%).

[1055] MS (ESI, m / z): [M+H] + = 531.30

[1056] Step 3:

[1057]

[1058] Compound 25-2 (150 mg, 0.283 mmol) was dissolved in dichloromethane (2.0 mL) at 0 °C, and trifluoroacetic acid (0.5 mL) was slowly added dropwise to the reaction solution using a syringe. The reaction system was stirred at 0 °C for 2 hours. The reaction system was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was directly purified by a reversed-phase C18 column. The purification conditions were as follows: 40 g C18 reversed-phase column; mobile phase: acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate: 30 mL / min; gradient: acetonitrile from 20% to 80% over 25 minutes; detection wavelength: 254 nm. After LC-MS confirmation, the product fraction was collected, concentrated under reduced pressure, and lyophilized to give 100 mg of compound 25 (a mixture of diastereomers, white solid, 82% yield).

[1059] MS (ESI, m / z): [MH] += 431.10.

[1060] Step 4:

[1061]

[1062] The diastereomer mixture 25 (100 mg, 0.232 mmol) was chirally resolved. The resolution conditions were as follows: chiral column Lux 5um Cellulose-4 3×25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 50% ethanol; detection wavelength 250 / 260 nm; retention time 11.8 min yielded the forepeak fraction, which, after concentration under reduced pressure and lyophilization, yielded 40.0 mg of optically pure compound 25a (white solid, 40% yield); retention time 14.5 min yielded the hindpeak fraction, which, after concentration under reduced pressure and lyophilization, yielded 40.0 mg of optically pure compound 25b (white solid, 40% yield).

[1063] Compound 25a:

[1064] MS (ESI, m / z): [M+H] + = 431.30.

[1065] 1 H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H), 8.19-8.08 (m, 1H), 6.85 (s,1H), 6.70 (s, 1H), 6.58 (s, 1H), 6.12 (s, 1H), 5.83 (s, 1H), 5.56 (br, 2H),4.32-4.23 (m, 1H), 3.89 (br, 1H), 3.61-3.52 (m, 1H), 3.50-3.29 (m, 2H), 3.20-3.12 (m, 1H), 2.95 (s, 3H), 2.41 (t, J = 7.6 Hz, 2H), 2.18-2.05 (m, 1H),1.88-1.82 (m, 1H), 1.81 (s, 3H), 1.69-1.56 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H).

[1066] Compound 25b:

[1067] MS (ESI, m / z): [M+H] + = 431.25.

[1068] 1 H NMR (400 MHz, DMSO-d6) δ 8.46 (s, 1H), 8.17-8.08 (m, 1H), 6.85 (s,1H), 6.70 (s, 1H), 6.58 (s, 1H), 6.12 (s, 1H), 5.84 (s, 1H), 5.57 (s, 2H),4.33-4.23 (m, 1H), 3.90 (br, 1H), 3.61-3.52 (m, 1H), 3.49-3.26 (m, 2H), 3.20-3.12 (m, 1H), 2.96 (s, 3H), 2.41 (t, J = 7.6 Hz, 2H), 2.18-2.05 (m, 1H),1.89-1.82 (m, 1H), 1.81 (s, 3H), 1.69-1.56 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H).

[1069] Example 26: MYL-0185-00-01; MYL-0186-00-01; MYL-0187-00-01; MYL-0187-00-01

[1070] N-((S or R)-1-(4-((4-amino-5-chloro-6-((R or S)-S-methylsulfonylimino)pyridin-2-yl)amino)-6-propylpyridin-2-yl-(piperidin-3-yl)acetamide (compound 26a);

[1071] N-((R or S)-1-(4-(4-amino-5-chloro-6-((R or S)-S-methylsulfonylimino)pyridin-2-yl)amino)-6-propylpyridin-2-yl-(piperidin-3-yl)acetamide (compound 26b);

[1072] N-((R or S)-1-(4-((4-amino-5-chloro-6-((R or S)-S-methylsulfonylimino)pyridin-2-yl)amino)-6-propylpyridin-2-yl-(piperidin-3-yl)acetamide (compound 26c);

[1073] Preparation of N-((R or S)-1-(4-((4-amino-5-chloro-6-((S or R)-S-methylsulfonylimino)pyridin-2-yl)amino)-6-propylpyridin-2-yl-(piperidin-3-yl)acetamide (compound 26d)

[1074] Step 1:

[1075]

[1076] According to the method in step 2 of Example 1, the raw materials were replaced with 10-4 (20.0 g, 104 mmol, CAS: 25194-01-8; purchased directly from Shanghai Bid Pharmaceutical Technology Co., Ltd.) and 26-1 (20.8 g, 104 mmol; CAS: 172603-05-3, purchased directly from Shanghai Haohong Biomedical Technology Co., Ltd.) to prepare 5.20 g of compound 26-2 (orange solid, yield 14%).

[1077] MS (ESI, m / z): [M+H] + = 357.15 / 359.10.

[1078] 1 H NMR (400 MHz, CDCl3) δ 7.25 (s, 1H), 7.20 (d, J = 1.6 Hz, 1H), 4.68-4.49 (m, 1H), 3.97-3.65 (m, 3H), 3.58-3.31 (m, 2H), 2.06-1.92 (m, 1H),1.87-1.74 (m, 1H), 1.72-1.56 (m, 2H), 1.45 (s, 9H).

[1079] Step 2:

[1080]

[1081] According to the method in step 2 of Example 24, the starting material was replaced with 26-2 (3.00 g, 9.24 mmol) to prepare 2.64 g of compound 26-3 (orange solid, yield 78%).

[1082] MS (ESI, m / z): [M+H] + = 365.20.

[1083] 1H NMR (400 MHz, CDCl3) δ 7.18 (s, 1H), 7.09 (d, J = 1.6 Hz, 1H), 4.81-4.77 (m, 1H), 3.81-3.76 (m, 3H), 3.57-3.53 (m, 2H), 2.72 (d, J = 7.6 Hz, 2H), 2.00-1.88 (m, 1H), 1.85-1.71 (m, 3H), 1.70-1.58 (m, 2H), 1.45 (s, 9H), 0.98 (t, J = 7.2 Hz, 3H).

[1084] Step 3:

[1085]

[1086] According to the method in step 3 of Example 1, the raw material was replaced with 26-3 (2.64 g, 7.24 mmol) to prepare 2.90 g of trifluoroacetate compound 26-4 (light yellow liquid, yield 106%, crude product).

[1087] MS (ESI, m / z): [M-CF3COOH+H] + = 265.05.

[1088] Step 4:

[1089]

[1090] According to step 4 of Example 1, the starting material was replaced with 26-4 (2.73 g, 7.22 mmol, crude product) to prepare 2.15 g of compound 26-5 (orange solid, yield 97%).

[1091] MS (ESI, m / z): [M+H] + = 307.00.

[1092] 1H NMR (400 MHz, CDCl3) δ 7.19 (d, J = 1.6 Hz, 1H), 7.11 (d, J = 1.6Hz, 1H), 5.80-5.74 (m, 1H), 4.15-4.05 (m, 1H), 3.85-3.77 (m, 1H), 3.71-3.63(m, 1H), 3.62-3.51 (m, 2H), 2.71 (t, J = 7.6 Hz, 2H), 1.98 (s, 3H), 1.95-1.86(m, 1H), 1.85-1.65 (m, 5H), 0.98 (t, J = 7.2 Hz, 3H).

[1093] Step 5:

[1094]

[1095] According to the method in step 5 of Example 5, the starting material was replaced with 26-5 (2.15 g, 7.02 mmol) to prepare 1.65 g of compound 26-6 (white solid, yield 85%).

[1096] MS (ESI, m / z): [M+H] + = 277.05.

[1097] 1 H NMR (400 MHz, DMSO-d6) δ 7.81 (d, J = 7.6 Hz, 1H), 5.78-5.73 (m,1H), 5.69 (d, J = 1.6 Hz, 1H), 5.49 (s, 2H), 3.99-3.86 (m, 2H), 3.68-3.58 (m,1H), 2.77-2.66 (m, 1H), 2.58-2.47 (m, 1H), 2.31 (t, J = 7.6 Hz, 2H), 1.85-1.76 (m, 4H), 1.74-1.64 (m, 1H), 1.62-1.52 (m, 2H), 1.51-1.27 (m, 2H), 0.87 (t, J = 7.2 Hz, 3H).

[1098] Step 6:

[1099]

[1100] According to the synthesis method in step 6 of Example 1, the starting materials were replaced with 26-6 (1.65 g, 5.97 mmol) and 10-3 (2.69 g, 6.57 mmol) respectively to prepare compound 26-7 (brown solid, yield 49%).

[1101] MS (ESI, m / z): [M+H] + = 649.30 / 651.25.

[1102] Step 7:

[1103]

[1104] According to step 7 of Example 1, the starting material was replaced with 26-7 (1.60 g, 2.46 mmol) to prepare 320 mg of compound 26-8 (a mixture of diastereomers, white solid, yield 19%).

[1105] MS (ESI, m / z): [M+H] + = 680.20 / 682.15.

[1106] Step 8:

[1107]

[1108] Compound 26-8 (320 mg, 0.471 mmol) was dissolved in dichloromethane (6.0 mL) at 0 °C, and trifluoroacetic acid (2.0 mL) was slowly added dropwise to the reaction solution using a syringe. The reaction system was stirred for 3 hours. The reaction system was monitored by liquid chromatography-mass spectrometry. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was directly purified by silica gel column chromatography (eluent: dichloromethane / 7 mol / L ammonia-methanol = 10 / 1). The obtained fraction was concentrated under reduced pressure to obtain 120 mg of crude product. The crude product was further purified by preparative liquid chromatography. The purification conditions were as follows: YMC-Actus TriartC18 ExRS 30 × 150 mm, 5 μm; mobile phase: acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate: 60 mL / min; gradient of acetonitrile from 20% to 32% over 10 min, then maintaining an isogradient of 32% acetonitrile for 10 min; detection wavelength: 254 nm / 220 nm; retention time: 13.2 min; the product fraction was collected. The product was concentrated under reduced pressure and lyophilized to give 80.0 mg of compound 26 (racemic mixture, white solid, yield 36%).

[1109] MS (ESI, m / z): [M+H]+ = 480.30 / 482.25.

[1110] Step 9:

[1111]

[1112] The mixture 26 (80.0 mg, 0.167 mmol) was subjected to chiral resolution. The resolution conditions were as follows: chiral column CHIRALPAK-IK, 3.0 × 25 mm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; detection wavelength 274 / 212 nm. Two fractions were obtained (retention times 7.8 min and 17.0 min, respectively). The first fraction (retention time 7.8 min) was concentrated under reduced pressure and lyophilized to obtain a mixture of 51.3 mg of compounds 26a, 26b, and 26c, which required further resolution and purification. The second fraction (retention time 17.0 min) was concentrated under reduced pressure and lyophilized to obtain 16.1 mg of optically pure compound 26d (white solid, 20% yield).

[1113] The first fraction obtained above (51 mg, a mixture of compounds 26a, 26b, and 26c) was separated by SFC. The separation conditions were as follows: chiral column CHIRALPAK IH 3 × 25 cm, 5 μm; mobile phase A: carbon dioxide, mobile phase B: 20 ​​mmol / L ammonia-methanol; flow rate 100 mL / min; gradient: isogradient 35% 20 mmol / L ammonia-methanol solution; detection wavelength 202 / 270 nm. The fraction with the leading peak was obtained at a retention time of 3.9 min, concentrated under reduced pressure, and lyophilized to give 13 mg of optically pure compound 26a (white solid, yield 16%); the fraction with the trailing peak was obtained at a retention time of 5.2 min, concentrated under reduced pressure, and lyophilized to give a mixture (30.2 mg, a mixture of compounds 26b and 26c).

[1114] A mixture of 30 mg of compounds 26b and 26c was subjected to a third separation. The separation conditions were as follows: chiral column CHIRALPAK IH 3 × 25 cm, 5 μm; mobile phase A: carbon dioxide, mobile phase B: 20 ​​mmol / L ammonia-isopropanol; flow rate 80 mL / min; gradient: isogradient 50% B; detection wavelength 204 / 270 nm. A fraction with a retention time of 5.8 min was obtained, which was concentrated under reduced pressure and lyophilized to give 12.0 mg of optically pure compound 26b (white solid, 15% yield); a fraction with a retention time of 7.2 min was obtained, which was concentrated under reduced pressure and lyophilized to give 12.1 mg of optically pure compound 26c (white solid, 15% yield).

[1115] Compound 26a:

[1116] MS (ESI, m / z): [M+H] + = 480.15 / 482.10.

[1117] 1 H NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H), 7.85 (d, J = 7.6 Hz, 1H), 6.72 (s, 1H), 6.68 (s, 1H), 6.64 (s, 2H), 6.34 (s, 1H), 4.25-4.20 (m, 1H),4.08-3.97 (m, 2H), 3.71-3.59 (m, 1H), 3.26 (s, 3H), 2.85-2.76 (m, 1H), 2.67-2.58 (m, 1H), 2.43 (t, J = 7.6 Hz, 2H), 1.87-1.78 (m, 4H), 1.76-1.69 (m, 1H), 1.69-1.55 (m, 2H), 1.54-1.31 (m, 2H), 0.89 (t, J = 7.2 Hz, 3H).

[1118] Compound 26b:

[1119] MS (ESI, m / z): [M+H] + = 480.25 / 482.20.

[1120] 1H NMR (400 MHz, DMSO-d6) δ 9.13 (s, 1H), 7.87 (d, J = 7.6 Hz, 1H), 6.72 (s, 1H), 6.69 (s, 1H), 6.66 (s, 2H), 6.33 (s, 1H), 4.22 (s, 1H), 4.08-4.96 (m, 2H), 3.69-3.62 (m, 1H), 3.26 (s, 3H), 2.86-2.76 (m, 1H), 2.67-2.58(m, 1H), 2.43 (t, J = 7.6 Hz, 2H), 1.86-1.78 (m, 4H), 1.76-1.68 (m, 1H), 1.69-1.55 (m, 2H), 1.51-1.33 (m, 2H), 0.89 (t, J = 7.2 Hz, 3H).

[1121] Compound 26c:

[1122] MS (ESI, m / z): [M+H] + = 480.25 / 482.20.

[1123] 1 H NMR (400 MHz, DMSO-d6) δ 9.13 (s, 1H), 7.87 (d, J = 7.6 Hz, 1H), 6.72 (s, 1H), 6.68 (s, 1H), 6.66 (s, 2H), 6.34 (s, 1H), 4.23 (s, 1H), 4.06-3.96 (m, 2H), 3.68-3.63 (m, 1H), 3.27 (s, 3H), 2.86-2.76 (m, 1H), 2.67-2.58(m, 1H), 2.42 (t, J = 7.6 Hz, 2H), 1.86-1.80 (m, 4H), 1.77-1.68 (m, 1H), 1.68-1.55 (m, 2H), 1.53-1.31 (m, 2H), 0.89 (t, J = 7.2 Hz, 3H).

[1124] Compound 26d:

[1125] MS (ESI, m / z): [M+H] + = 480.20 / 482.15.

[1126] 1H NMR (400 MHz, DMSO-d6) δ 9.13 (s, 1H), 7.86 (d, J = 7.6 Hz, 1H), 6.73 (s, 1H), 6.68 (s, 1H), 6.65 (s, 2H), 6.34 (s, 1H), 4.21 (s, 1H), 4.07-3.96 (m, 2H), 3.69-3.63 (m, 1H), 3.26 (s, 3H), 2.87-2.76 (m, 1H), 2.69-2.58(m, 1H), 2.43 (t, J = 7.6 Hz, 2H), 1.88-1.78 (m, 4H), 1.77-1.69 (m, 1H), 1.69-1.55 (m, 2H), 1.54-1.31 (m, 2H), 0.89 (t, J = 7.2 Hz, 3H).

[1127] Example 27:

[1128] N-((S or R)-1-(4-((6-amino-2-((R or S)-S-methylsulfonylimino)pyrimidin-4-yl)amino)-6-propylpyridin-2-yl)pyrrolidine-3-yl)acetamide (compound 27a);

[1129] Preparation of N-((S or R)-1-(4-((6-amino-2-((S or R)-S-methylsulfonylimino)pyrimidin-4-yl)amino)-6-propylpyridin-2-yl)pyrrolidine-3-yl)acetamide (compound 27b)

[1130] Step 1:

[1131]

[1132] According to the synthesis method in step 1 of Example 22, the raw materials were replaced with compound 27-1 (15.0 g, 91.5 mmol; CAS: 10132-07-7, purchased directly from the supplier Shanghai Titan Technology Co., Ltd.) to prepare 4.50 g of compound 27-2 (white solid, yield 28%).

[1133] MS (ESI, m / z): [M+H] + = 176.00 / 178.05.

[1134] 1 H NMR (400 MHz, CDCl3) δ 6.16 (s, 1H), 5.02 (s, 2H), 2.51 (s, 3H).

[1135] Step 2:

[1136]

[1137] Compound 27-2 (4.50 g, 25.6 mmol) was dissolved in tetrahydrofuran (100 mL) at room temperature. Then, di-tert-butyl dicarbonate (14.0 g, 64.1 mmol), triethylamine (7.78 g, 76.9 mmol), and 4-dimethylaminopyridine (313 mg, 2.56 mmol) were added sequentially to the reaction mixture. The reaction mixture was stirred at room temperature for 2 hours. The reaction progress was monitored using liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was purified directly by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4 / 1). The resulting fraction was concentrated under reduced pressure to give 9.00 g of compound 27-3 (white solid, 94% yield).

[1138] MS (ESI, m / z): [M+H] + = 376.10 / 378.05.

[1139] 1 H NMR (400 MHz, CDCl3) δ 7.49 (s, 1H), 2.49 (s, 3H), 1.56 (s, 18H).

[1140] Step 3:

[1141]

[1142] According to the method in step 2 of Example 5, the starting materials were replaced with 10-9 (350 mg, 1.33 mmol) and 27-3 (501 mg, 1.33 mmol) respectively to prepare 600 mg of compound 27-4 (brown solid, yield 75%).

[1143] MS (ESI, m / z): [M+H] + = 602.35.

[1144] Step 4:

[1145]

[1146] According to step 7 of Example 1, the starting material was replaced with 27-4 (600 mg, 0.997 mmol) to prepare 300 mg of compound 27-5 (black solid, yield 48%).

[1147] MS (ESI, m / z): [M+H] + = 633.25.

[1148] Step 5:

[1149]

[1150] Compound 27-5 (300 mg, 0.474 mmol) was dissolved in dichloromethane (3.0 mL) at 0 °C, and trifluoroacetic acid (1.0 mL) was slowly added dropwise to the reaction solution using a syringe. The reaction system was stirred at room temperature for 16 hours. The reaction system was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was directly purified by preparative liquid chromatography (HPLC). The purification conditions were as follows: column type: X bridge Phenyl OBD Column, 30 × 150 mm, 5.0 μm; mobile phase: methanol and water (10 mmol / L ammonium bicarbonate + 0.1% NH3). . H2O); flow rate 60 mL / min; gradient of methanol from 35% to 50% over 17 min; detection wavelength 254 nm / 220 nm, retention time 10.7 min; the fraction of product was collected, concentrated under reduced pressure and lyophilized to give 30.0 mg of compound 27 (a mixture of diastereomers, white solid, yield 15%).

[1151] MS (ESI, m / z): [M+H] + = 433.30.

[1152] Step 6:

[1153]

[1154] The diastereomer mixture 27 (40 mg, 0.092 mmol) was chirally resolved. The resolution conditions were as follows: chiral column Lux 5u Cellulose-2 30 × 250 mm, 5.0 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% ethanol; detection wavelength 260 / 288 nm; retention time 17.7 min yielded the forepeak fraction, which, after concentration under reduced pressure and lyophilization, yielded 15.0 mg of optically pure compound 27a (white solid, 38% yield); retention time 22.4 min yielded the hindpeak fraction, which, after concentration under reduced pressure and lyophilization, yielded 15.1 mg of optically pure compound 27b (white solid, 38% yield).

[1155] Compound 27a:

[1156] MS (ESI, m / z): [M+H] + = 433.20.

[1157] 1 H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 8.11 (d, J = 6.8 Hz, 1H), 7.03 (s, 2H), 6.67 (s, 1H), 6.53 (d, J = 1.6 Hz, 1H), 5.89 (s, 1H), 4.33-4.24(m, 1H), 3.84 (s, 1H), 3.63-3.54 (m, 1H), 3.49-3.35 (m, 2H), 3.24-3.19 (m,1H), 3.18 (s, 3H), 2.45 (t, J = 7.6 Hz, 2H), 2.19-2.06 (m, 1H), 1.90-1.82 (m,1H), 1.81 (s, 3H), 1.71-1.57 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H).

[1158] Compound 27b:

[1159] MS (ESI, m / z): [M+H] + = 433.25.

[1160] 1 H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 8.11 (d, J = 6.8 Hz, 1H), 7.03 (s, 2H), 6.67 (s, 1H), 6.53 (d, J = 1.6 Hz, 1H), 5.89 (s, 1H), 4.33-4.24(m, 1H), 3.84 (s, 1H), 3.63-3.54 (m, 1H), 3.51-3.37 (m, 2H), 3.24-3.19 (m,1H), 3.18 (s, 3H), 2.45 (t, J = 7.6 Hz, 2H), 2.19-2.06 (m, 1H), 1.90-1.82 (m,1H), 1.81 (s, 3H), 1.71-1.57 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H).

[1161] Example 28:

[1162] Preparation of N-((3S)-1-(2-(4-amino-3-fluoro-5-(S-methylsulfonylimino)phenyl)amino)-6-propylpyrimidin-4-yl)pyrrolidine-3-yl)acetamide (compound 28)

[1163] Step 1:

[1164]

[1165] According to the synthesis method in step 3 of Example 16, the raw materials were replaced with compounds 1-5 (10 g, 35.4 mmol) to prepare 6 g of compound 28-1 (pale blue solid, yield 64%).

[1166] MS (ESI, m / z): [M+H] + = 264.10.

[1167] 1 H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 7.0 Hz, 1H), 5.84 (s, 2H), 5.58 (s, 1H), 4.29-4.20 (m, 1H), 3.57-3.36 (m, 3H), 3.28-3.14 (m, 1H), 2.29(t, J = 7.2 Hz, 2H), 2.14-2.06 (m, 1H), 1.86-1.81 (m, 1 H), 1.80 (s, 3H), 1.63-1.53 ​​(m, 2H), 0.87 (t, J = 7.2 Hz, 3H).

[1168] Step 2:

[1169]

[1170] According to the method in step 5 of Example 1, the raw material was replaced with 28-2 (5.0 g, 21.1 mmol; CAS: 147808-42-2, which can be purchased directly from the supplier Shanghai Shaoyuan Technology Co., Ltd.) to prepare 300 mg of compound 28-3 (yellow solid, yield 5%).

[1171] 1 H NMR (300 MHz, CDCl3) δ 7.26-7.19 (m, 2H), 2.53 (s, 3H).

[1172] Step 3:

[1173]

[1174] According to the method in step 6 of Example 1, the starting materials were replaced with 28-1 (110 mg, 0.418 mmol) and 28-3 (111 mg, 0.418 mmol) respectively to prepare 130 mg of compound 28-4 (yellow solid, yield 69%).

[1175] MS (ESI, m / z): [M+H] + = 449.15.

[1176] 1 H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 8.16 (d, J = 8.8 Hz, 1H), 7.57 (d, J = 10.4 Hz, 1H), 7.69 (s, 1H), 6.03 (s, 1H), 4.39-4.28 (m, 1H),3.75-3.36 (m, 4H), 2.62 (s, 3H), 2.48 (t, J = 7.2 Hz, 2H), 2.22-2.08 (m, 1H),1.95-1.86 (m, 1H), 1.81 (s, 3H), 1.72-1.64 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H).

[1177] 19 F NMR (377 MHz, DMSO-d6) δ -119.40.

[1178] Step 4:

[1179]

[1180] According to the method in step 7 of Example 1, the starting material was replaced with 28-4 (110 mg, 0.245 mmol) to prepare 40 mg of compound 28-5 (yellow solid, yield 34%).

[1181] MS (ESI, m / z): [M+H] + = 480.05.

[1182] 1H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.55 (s, 1H), 8.19-8.08 (m,2H), 6.00 (s, 1H), 4.78 (s, 1H), 4.39-4.28 (m, 1H), 3.81-3.39 (m, 4H), 3.22(s, 3H), 2.47 (t, J = 7.2 Hz, 2H), 2.21-2.06 (m, 1H), 1.95-1.85 (m, 1H) 1.81(s, 3H), 1.74-1.63 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H).

[1183] 19 F NMR (377 MHz, DMSO) δ -122.82.

[1184] Step 5:

[1185]

[1186] Compound 28-5 (40 mg, 0.083 mmol) was dissolved in ethanol (4 mL) and water (1 mL) at room temperature. Ammonium chloride (23 mg, 0.430 mmol) and zinc powder (30 mg, 0.456 mmol) were then added to the reaction solution. The reaction system was stirred at room temperature for 1 hour, and the reaction progress was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the solution was concentrated under reduced pressure, and the residue was purified using a C18 reversed-phase column. The purification conditions were as follows: C18 reversed-phase column; mobile phase: acetonitrile and water (10 mmol / L ammonium bicarbonate); gradient: acetonitrile increased from 20% to 60% over 20 minutes; detection wavelength: 254 nm. The product fraction was collected, concentrated under reduced pressure, and the crude product was further purified by preparative liquid chromatography (HPLC). The purification conditions were as follows: YMC-Actus Triart C18 ExRS Column, 30 × 150 mm, 5 μm; mobile phase: methanol and water (10 mmol / L ammonium bicarbonate); flow rate: 60 mL / min; gradient: methanol increased from 40% to 57% over 10 min; detection wavelength: 254 nm / 220 nm; retention time: 11.4 min. The product fraction was collected, concentrated under reduced pressure, and lyophilized to give 8 mg of compound 28 (a mixture of diastereomers, white solid, yield 21%).

[1187] MS (ESI, m / z): [M+H] + = 450.20.

[1188] 1 H NMR (400 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.21 (brs, 1H), 8.13 (d, J =6.6 Hz, 1H), 7.71 (d, J = 13.6 Hz, 1H), 5.78 (s, 1H), 5.74 (s, 2H), 4.39 (s,1H), 4.36-4.26 (m, 1H), 3.73-3.36 (m, 3H), 3.31-3.22 (m, 1H), 3.02 (s, 3H), 2.39 (t, J = 7.2 Hz, 2H), 2.17-2.05 (m, 1H), 1.91-1.83 (m, 1H) 1.81 (s, 3H),1.72-1.61 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H).

[1189] 19 F NMR (377 MHz, DMSO) δ -131.81.

[1190] Example 29:

[1191] Preparation of N-((3S)-1-(2-((3-(S-methylsulfonylimideyl)-4-(trifluoromethyl)phenyl)amino)-6-propylpyrimidin-4-yl)pyrrolidine-3-yl)acetamide (compound 29)

[1192] Step 1:

[1193]

[1194] According to the method in step 1 of Example 11, the raw material was replaced with 29-1 (3.00 g, 12.5 mmol; CAS: 172215-91-7, which can be purchased directly from the supplier Shanghai Shaoyuan Technology Co., Ltd.) to prepare 1.20 g of compound 29-2 (white solid, yield 28%).

[1195] MS (ESI, m / z): [MH] - = 338.00 / 339.95.

[1196] 1H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H), 8.01 (d, J = 2.0 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.60-7.56 (m, 1H), 1.49 (s, 9H).

[1197] Step 2:

[1198]

[1199] According to the method in step 1 of Example 3, the starting material was replaced with 29-2 (500 mg, 1.47 mmol) to prepare 100 mg of compound 29-3 (white solid, yield 22%).

[1200] MS (ESI, m / z): [MH] - = 306.15.

[1201] 1 H NMR (400 MHz, CDCl3) δ 7.57-7.47 (m, 2H), 7.10-7.05 (m, 1H), 6.63 (s, 1H), 2.52 (s, 3H), 1.53 (s, 9H).

[1202] 19 F NMR (376 MHz, CDCl3) δ -60.88.

[1203] Step 3:

[1204]

[1205] Compound 29-3 (100 mg, 0.325 mmol) was dissolved in ethyl acetate (4 mol / L, 1.5 mL) and dichloromethane (4 mL) at 0 °C. The reaction mixture was brought to room temperature and stirred for 3 hours. The reaction was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified using a C18 reversed-phase column. The purification conditions were as follows: C18 reversed-phase column; mobile phase: acetonitrile and water (10 mmol / L ammonium bicarbonate); gradient: acetonitrile from 10% to 50% over 15 minutes; detection wavelength: 254 nm. The product fraction was collected and concentrated under reduced pressure to give 50 mg of compound 29-4 (pale yellow solid, 74% yield).

[1206] MS (ESI, m / z): [MH] - = 206.05.

[1207] 1 H NMR (400 MHz, CDCl3) δ 7.38 (d, J = 8.4 Hz, 1H), 6.58 (d, J = 2.4Hz, 1H), 6.48-6.41 (m, 1H), 3.95 (brs, 2H), 2.47 (s, 3H).

[1208] 19 F NMR (377 MHz, CDCl3) δ -59.79.

[1209] Step 4:

[1210]

[1211] According to step 6 of Example 1, the starting materials were replaced with 29-4 (30.8 mg, 0.149 mmol) and 1-5 (42 mg, 0.149 mmol) respectively to prepare 40 mg of compound 29-5 (white solid, yield 59%).

[1212] MS (ESI, m / z): [M+H] + = 454.15.

[1213] 1 H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 8.15 (d, J = 6.4 Hz, 1H), 8.05 (s, 1H), 7.85-7.76 (m, 1H), 7.51-7.43 (m, 1H), 5.92 (s, 1H), 4.38-4.26(m, 1H), 3.79-3.37 (m, 4H), 2.51 (s, 3H), 2.45 (t, J = 7.4 Hz, 2H), 2.22-2.09(m, 1H), 1.90-1.82(m, 1H),1.81 (s, 3H), 1.74-1.60 (m, 2H), 0.92 (t, J = 7.4Hz, 3H).

[1214] 19 F NMR (377 MHz, DMSO-d6) δ -58.77.

[1215] Step 5:

[1216]

[1217] Compound 29-5 (35 mg, 0.077 mmol) was dissolved in methanol (2 mL) at room temperature. Ammonium carbamate (30.0 mg, 0.384 mmol) and (diacetoxyiodine)benzene (124 mg, 0.384 mmol) were added sequentially to the reaction solution. The reaction mixture was stirred for 16 hours at room temperature. The reaction progress was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction mixture was quenched with water (2 mL) at 0 °C, extracted with ethyl acetate (5 mL × 3), and the combined organic phases were washed with saturated sodium chloride aqueous solution (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was directly purified using a C18 reversed-phase column. The purification conditions were as follows: C18 reversed-phase column; mobile phase: acetonitrile and water (10 mmol / L ammonium bicarbonate); gradient: acetonitrile from 10% to 70% over 20 minutes; detection wavelength: 254 nm. The fraction of the product was collected, concentrated under reduced pressure, and lyophilized to give 17 mg of compound 29 (a mixture of diastereomers, white solid, yield 45%).

[1218] MS (ESI, m / z): [M+H] + = 485.25.

[1219] 1 H NMR (400 MHz, DMSO-d6) δ 9.82 (s, 1H), 9.05 (s, 1H), 8.16 (s, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 5.94 (s, 1H), 4.41-4.22(m, 2H), 3.88-3.39 (m, 3H), 3.25-3.12 (m, 1H), 3.08 (s, 3H), 2.45 (t, J = 7.4Hz, 2H), 2.22-2.07 (m, 1H), 1.96-1.87 (m, 1H), 1.81 (s, 3H), 1.75-1.62 (m,2H), 0.92 (t, J = 7.4 Hz, 3H).

[1220] 19 F NMR (377 MHz, DMSO) δ -53.42.

[1221] Example 30:

[1222] Preparation of N-((3S)-1-(2-(4-methyl-3-(methyldiiminosulfonyl)phenyl)amino)-6-propylpyrimidin-4-yl)pyrrolidine-3-yl)acetamide (compound 30)

[1223] Step 1:

[1224]

[1225] According to the method in step 1 of Example 3, the raw material was replaced with 30-1 (1.0 g, 3.49 mmol; CAS: 515813-02-2, purchased directly from the supplier Shanghai Haohong Biomedical Technology Co., Ltd.) to prepare 500 mg of compound 30-2 (yellow solid, yield 56%).

[1226] MS (ESI, m / z): [MH] - = 252.10.

[1227] 1 H NMR (400 MHz, DMSO-d6) δ 9.23 (s, 1H), 7.35 (s, 1H), 7.14 (d, J =7.4 Hz, 1H), 7.02 (d, J = 7.4 Hz, 1H), 2.39 (s, 3H), 2.15 (s, 3H), 1.46 (s,9H).

[1228] Step 2:

[1229]

[1230] According to the method in step 3 of Example 29, the starting material was replaced with 30-2 (307 mg, 1.21 mmol) to prepare 160 mg of compound 30-3 (yellow oil, yield 86%).

[1231] MS (ESI, m / z): [M+H] + = 154.30.

[1232] 1 H NMR (400 MHz, CDCl3) δ 6.91 (d, J = 8.0 Hz, 1H), 6.51 (d, J = 2.4Hz, 1H), 6.41-6.38 (m, 1H), 3.56 (brs, 2H), 2.39 (s, 3H), 2.15 (s, 3H).

[1233] Step 3:

[1234]

[1235] According to step 6 of Example 1, the starting materials were replaced with 30-3 (108 mg, 0.704 mmol) and 1-5 (200 mg, 0.707 mmol) respectively to prepare 200 mg of compound 30-4 (yellow solid, yield 71%).

[1236] MS (ESI, m / z): [M+H] + = 400.25.

[1237] 1 H NMR (400 MHz, CDCl3) δ 7.58 (s, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.04(d, J = 8.0 Hz, 1H), 5.79 (brs, 1H), 5.66 (s, 1H), 4.64-4.55 (m, 1H), 3.80-3.32 (m, 4H), 2.47 (s, 3H), 2.46 (t, J = 7.2 Hz, 2H), 2.34-2.30 (m, 1H), 2.28(s, 3H), 2.06-2.02 (m, 1H), 2.00 (s, 3H), 1.75-1.69 (m, 2H), 0.97 (t, J = 7.4Hz, 3H).

[1238] Step 4:

[1239]

[1240] Compound 30-4 (100 mg, 0.25 mmol) was dissolved in methanol (1 mL) at room temperature. Ammonium carbamate (78 mg, 1.0 mmol) and (diacetoxyiodine)benzene (241 mg, 0.75 mmol) were added sequentially to the reaction solution. The reaction mixture was stirred for 1 hour at room temperature. The reaction progress was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction mixture was quenched with water (1 mL) at 0 °C, extracted with ethyl acetate (2 mL × 3), and the combined organic phases were washed with saturated sodium chloride aqueous solution (5 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified directly by preparative liquid chromatography (PCLC). The purification conditions were as follows: X Bridge Prep Phenyl OBDColumn 19 × 25 mm, 5 μm; mobile phase: water (10 mmol / L ammonium bicarbonate) and acetonitrile; flow rate 60 mL / min; gradient of acetonitrile from 19% to 34% over 10 min; detection wavelength 254 nm / 220 nm; retention time 10.2 min. The product fraction was collected, concentrated under reduced pressure, and lyophilized to give 3.5 mg of compound 30 (yellow solid, yield 3%).

[1241] MS (ESI, m / z): [M+H] + = 430.25.

[1242] 1 H NMR (400 MHz, DMSO-d6) δ 8.13 (brs, 1H), 6.57-6.37 (m, 2H), 6.26-6.15 (m, 1H), 6.11-6.04 (m, 1H), 4.38-4.23 (m, 1H), 3.62-3.53 (m, 1H), 3.52-3.40 (m, 2H), 3.01-2.98 (m, 3H), 2.47-2.43 (m, 4H), 2.11-2.04 (m, 2H), 1.92-1.83 (m, 1H), 1.80 (s, 3H), 1.68-1.57 (m, 2H), 1.44-1.40 (m, 3H), 0.89 (t, J= 7.3 Hz, 3H).

[1243] Example 31:

[1244] Preparation of N-((3S)-1-(2-(3-(methyldiimidesulfonyl)-4-methoxyphenylamino)-6-propylpyrimidin-4-yl)pyrrolidine-3-yl)acetamide (compound 31)

[1245] Step 1:

[1246]

[1247] Compound 31-1 (3.0 g, 19.5 mmol; CAS: 99-57-0, available directly from Anhui Zesheng Technology Co., Ltd.), cuprous iodide (6.0 g, 31.5 mmol), and tert-butyl nitrite (2.5 g, 24.2 mmol) were dissolved in acetonitrile (50 mL) under a nitrogen atmosphere. The reaction system was heated to 80 °C under a nitrogen atmosphere and stirred for 2 hours, with the reaction progress monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, it was cooled to room temperature and concentrated under reduced pressure. The residue was directly purified using a C18 reversed-phase column. The purification conditions were as follows: C18 reversed-phase column; mobile phase: acetonitrile and water (10 mmol / L ammonium bicarbonate); gradient: acetonitrile from 10% to 50% over 30 minutes; detection wavelength: 254 nm. The product fraction was collected, concentrated under reduced pressure, and lyophilized to give 1.2 g of compound 31-2 (yellow solid, yield 23%).

[1248] MS (ESI, m / z): [MH] - = 263.80.

[1249] 1 H NMR (400 MHz, DMSO-d6) δ 12.0 (brs, 1H), 8.50 (d, J = 3.2 Hz, 1H), 8.17-8.13 (m, 1H), 7.02 (d, J = 9.4 Hz, 1H).

[1250] Step 2:

[1251]

[1252] At room temperature, 31-2 (1.0 g, 3.78 mmol) and N,N-diisopropylethylamine (974 mg, 7.54 mmol) were dissolved in dichloromethane (20 mL), and bromomethyl methyl ether (1.13 g, 9.04 mmol) was added to the above reaction solution. The reaction system was stirred at room temperature for 16 hours, and the reaction progress was monitored by liquid chromatography-mass spectrometry. After the reaction was complete, the reaction was quenched with water (20 mL), extracted with ethyl acetate (30 mL × 3), and the combined organic phases were washed with saturated sodium chloride aqueous solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was directly purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1). The resulting fraction was concentrated under reduced pressure to give 1.0 g of compound 31-3 (yellow solid, yield 86%).

[1253] 1 H NMR (400 MHz, CDCl3) δ 8.67 (d, J = 2.0 Hz, 1H), 8.23-8.19 (m, 1H), 7.14 (d, J = 9.2 Hz, 1H), 5.36 (s, 2H), 3.53 (s, 3H).

[1254] Step 3:

[1255]

[1256] According to the method in step 1 of Example 3, the starting material was replaced with 31-3 (1.0 g, 3.24 mmol) to prepare 600 mg of compound 31-4 (yellow solid, yield 81%).

[1257] 1 H NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 7.14 (d, J = 7.4 Hz, 1H), 7.07 (d, J = 7.4 Hz, 1H), 5.27 (s, 2H), 3.44 (s, 3H), 2.43 (s, 3H).

[1258] Step 4:

[1259]

[1260] Compound 31-4 (600 mg, 2.62 mmol) and 80% hydrazine hydrate (675 mg, 10.8 mmol) were dissolved in methanol (8 mL) at 0 °C under a nitrogen atmosphere, followed by the addition of Raney nickel (40 mg, 0.68 mmol). The reaction system was allowed to return to room temperature naturally and stirred for 1 hour under these conditions, with the reaction progress monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the mixture was filtered, and the filter cake was washed with methanol (10 mL × 3). The filtrate was concentrated under reduced pressure, and the resulting residue was directly purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1). The resulting fraction was concentrated under reduced pressure to give 500 mg of compound 31-5 (yellow solid, 96% yield).

[1261] MS (ESI, m / z): [M+H] + = 199.95.

[1262] Step 5:

[1263]

[1264] According to step 6 of Example 1, the starting materials were replaced with 31-5 (500 mg, 2.51 mmol) and 1-5 (708 mg, 2.51 mmol) respectively to prepare 250 mg of compound 31-6 (pale yellow solid, yield 22%).

[1265] MS (ESI, m / z): [M+H] + = 446.15.

[1266] 1 H NMR (400 MHz, CDCl3) δ 7.50 (s, 1H), 7.32 (d, J = 8.8 Hz, 1H), 7.01(d, J = 8.8 Hz, 1H), 6.05 (brs, 1H), 5.61 (s, 1H), 5.16 (s, 2H), 4.66-4.58(m, 1H), 3.84-3.54 (m, 4H), 3.51 (s, 3H), 2.47-2.40 (m, 5H), 2.33-2.23 (m,1H), 2.08-2.03 (m, 1H), 2.02 (s, 3H), 1.76-1.65 (m, 2H), 0.97 (t, J = 7.2 Hz, 3H).

[1267] Step 6:

[1268]

[1269] According to the method in step 3 of Example 1, the starting material was replaced with 31-6 (200 mg, 0.45 mmol) to prepare 150 mg of compound 31-7 (yellow solid, yield 83%, crude product).

[1270] MS (ESI, m / z): [M+H] + = 402.10.

[1271] Step 7:

[1272]

[1273] Compound 31-7 (112 mg, 0.28 mmol) and potassium carbonate (100 mg, 0.72 mmol) were dissolved in dry N,N-dicarboxamide (2 mL) under a nitrogen atmosphere at room temperature. Iodomethane (60 mg, 0.42 mmol) was then added to the reaction mixture. The reaction mixture was stirred for 1 hour, and the reaction progress was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was directly purified using a C18 reversed-phase column. The purification conditions were as follows: C18 reversed-phase column; mobile phase: acetonitrile and water (10 mmol / L ammonium bicarbonate); gradient: acetonitrile from 10% to 50% over 10 minutes; detection wavelength: 254 nm. The product fraction was collected and concentrated under reduced pressure to give 50 mg of compound 31-8 (yellow solid, 43% yield).

[1274] MS (ESI, m / z): [M+H] + = 416.25.

[1275] Step 8:

[1276]

[1277] Compound 31-8 (10 mg, 0.024 mmol) was dissolved in methanol (0.3 mL) at room temperature. Ammonium carbamate (7.6 mg, 0.096 mmol) and (diacetoxyiodine)benzene (23.0 mg, 0.071 mmol) were added sequentially to the reaction solution. The reaction mixture was stirred for 1 hour at room temperature. The reaction progress was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction mixture was quenched with water (1 mL) at 0 °C, extracted with ethyl acetate (2 mL × 3), and the combined organic phases were washed with saturated sodium chloride aqueous solution (5 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified directly by preparative liquid chromatography (PCLC). The purification conditions were as follows: X Bridge Prep PhenylOBD Column 19 × 25 mm, 5 μm; mobile phase: water (10 mmol / L ammonium bicarbonate) and acetonitrile; flow rate 60 mL / min; gradient of acetonitrile from 19% to 34% over 10 min; detection wavelength 254 nm / 220 nm; retention time 10.2 min. The product fraction was collected, concentrated under reduced pressure, and lyophilized to give 2.7 mg of compound 31 (pale yellow solid, yield 25%).

[1278] MS (ESI, m / z): [M+H] + = 446.20.

[1279] 1 H NMR (400 MHz, CD3OD) δ 6.88-6.71 (m, 1H), 6.60-6.36 (m, 2H), 6.19-6.10 (m, 1H), 4.50-4.38 (m, 1H), 3.83-3.49 (m, 3H), 3.26-3.18 (m, 5H), 2.59-2.50 (m, 2H), 2.45-2.42 (m, 1H), 2.32-2.18 (m, 1H), 2.15 (s, 1H), 2.07-1.96(m, 1H), 1.94 (s, 3H), 1.77-1.64 (m, 2H), 1.01-0.92 (m, 3H).

[1280] Example 32:

[1281] N-((S)-1-(6-((3-amino-5-((R or S)-S-methylsulfonylimino)phenyl)amino)-2-propylpyrimidin-4-yl)pyrrolidine-3-yl)acetamide (compound 32a);

[1282] Preparation of N-((S)-1-(6-((3-amino-5-((S or R)-S-methylsulfonylimino)phenyl)amino)-2-propylpyrimidin-4-yl)pyrrolidine-3-yl)acetamide (compound 32b)

[1283] Step 1:

[1284]

[1285] Compound 32-1 (10.0 g, 81.5 mmol; CAS: 3020-81-3, purchased directly from Jiangsu Aikon Biomedical R&D Co., Ltd.) and compound 32-2 (13.0 g, 81.5 mmol; CAS: 105-53-3, purchased directly from Shanghai Titan Technology Co., Ltd.) were dissolved in ethanol (100 mL) at room temperature. Sodium ethoxide (11.1 g, 163 mmol) was then added to the reaction solution. The reaction system was heated to 85 °C and stirred for 16 hours, and the reaction progress was monitored using liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction system was naturally cooled to room temperature. The reaction system was concentrated under reduced pressure, and water (30 mL) was added to the mixture. Then the mixture was transferred to an ice-water bath, and the pH of the reaction system was adjusted to 1-2 with concentrated hydrochloric acid. The mixture was filtered, and the filter cake was washed with ice water (20 mL × 2). The obtained solid was dried to give 10.4 g of compound 32-3 (white solid, yield 83%).

[1286] MS (ESI, m / z): [M+H] + = 155.05.

[1287] Step 2:

[1288]

[1289] According to the method in step 1 of Example 1, the starting material was replaced with 32-3 (10.4 g, 67.5 mmol) to prepare 9.0 g of compound 32-4 (pale yellow oil, yield 70%).

[1290] MS (ESI, m / z): [M+H] + = 191.05 / 193.10 / 195.05.

[1291] 1 H NMR (400 MHz, CDCl3) δ 7.24 (s, 1H), 2.95-2.86 (m, 2H), 1.90-1.79(m, 2H), 0.99 (t, J = 7.4 Hz, 3H).

[1292] Step 3:

[1293]

[1294] According to the method in step 2 of Example 1, the starting material was replaced with 32-4 (5.0 g, 26.3 mmol) to prepare 8.5 g of compound 32-6 (a grayish-white oily substance, yield 95%).

[1295] 1 H NMR (400 MHz, CDCl3) δ 6.10 (s, 1H), 4.81-4.62 (m, 1H), 4.40-4.24(m, 1H), 3.89-3.19 (m, 4H), 2.68-2.61 (m, 2H), 2.32-2.20 (m, 1H), 2.02-1.87(m, 1H), 1.82-1.69 (m, 2H), 1.44 (s, 9H), 0.95 (t, J = 7.4 Hz, 3H).

[1296] Step 4:

[1297]

[1298] Synthesized according to step 3 in Example 1, with the starting material replaced by 32-6 (3.6 g, 10.6 mmol), 3.6 g of trifluoroacetate compound 32-7 (brown oil, 96% yield, crude product) was obtained.

[1299] MS (ESI, m / z): [M+H] + = 241.10 / 243.05.

[1300] Step 5:

[1301]

[1302] According to step 4 of Example 1, the starting material was replaced with 32-7 (4 g, 11.3 mmol) to prepare 600 mg of compound 32-8 (grayish-white oil, yield 19%).

[1303] MS (ESI, m / z): [M+H] + = 283.25 / 285.20.

[1304] Step 6:

[1305]

[1306] According to the synthesis method in step 3 of Example 16, the raw materials were replaced with compound 32-8 (700 mg, 2.48 mmol) to prepare 500 mg of compound 32-9 (yellow solid, yield 77%).

[1307] MS (ESI, m / z): [M+H] + = 264.30.

[1308] Step 7:

[1309]

[1310] According to the method in step 2 of Example 5, the starting materials were replaced with 32-9 (150 mg, 0.57 mmol) and 16-3 (259 mg, 0.68 mmol) respectively to prepare 80.0 mg of optically pure compound 32-10 (yellow solid, yield 25%).

[1311] MS (ESI, m / z): [M+H] + = 562.20.

[1312] Step 8:

[1313]

[1314] Synthesized according to step 5 of Example 5, with the starting material replaced by 32-10 (85 mg, 0.15 mmol), yielding 60.0 mg of optically pure compound 32-11 (yellow solid, 75% yield).

[1315] MS (ESI, m / z): [M+H] + = 532.30.

[1316] 1H NMR (400 MHz, CDCl3) δ 7.42-7.34 (m, 1H), 6.95-6.82 (m, 2H), 6.30-6.00 (m, 1H), 5.65-5.52 (m, 1H), 4.62-4.47 (m, 1H), 4.09 (s, 2H), 3.75-3.33(m, 4H), 3.23 (s, 3H), 2.63 (t, J = 7.6 Hz, 2H), 2.33-2.18 (m, 1H), 2.04-1.96(m, 4H), 1.88-1.73 (m, 2H), 1.42 (s, 9H), 1.00 (t, J = 7.2 Hz, 3H).

[1317] Step 9:

[1318]

[1319] The product was synthesized according to step 3 of Example 1, with the starting material replaced by 32-11 (60.0 mg, 0.11 mmol). After the reaction was complete, it was purified directly using a reversed-phase C18 column. The purification conditions were as follows: C18 reversed-phase column; mobile phase: acetonitrile and water (10 mmol / L ammonium bicarbonate); gradient: acetonitrile from 50% to 75% over 25 minutes; detection wavelength: 254 / 220 nm. After confirmation by liquid chromatography-mass spectrometry, the product fraction was collected, concentrated under reduced pressure, and lyophilized to give 30 mg of compound 32 (a mixture of diastereomers, a grayish-white solid, yield 63%).

[1320] MS (ESI, m / z): [M+H] + = 432.10.

[1321] Step 10:

[1322]

[1323] The diastereomer mixture 32 (30 mg, 0.070 mmol) was chirally resolved. The resolution conditions were as follows: chiral column Lux 5um Cellulose-4, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), i.e., the concentration of (ammonia-methanol) in n-hexane was 10 mmol / L, such as 20 mL of 2 mol / L (ammonia-methanol) added to 4 L of n-hexane; mobile phase B: ethanol; gradient: isogradient 50% B; detection wavelength 250 / 294 nm; retention time 8.8 min yielded the forepeak fraction, which was concentrated under reduced pressure and lyophilized to give 13.0 mg of optically pure compound 32a (grayish-white solid, 43% yield); retention time 11.7 min yielded the hindpeak fraction, which was concentrated under reduced pressure and lyophilized to give 12 mg of optically pure compound 32b (grayish-white solid, 40% yield).

[1324] Compound 32a:

[1325] MS (ESI, m / z): [M+H] + = 432.30.

[1326] 1 H NMR (400 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.14 (d, J = 6.4 Hz, 1H), 7.46-7.41 (m, 1H), 7.03- 6.97 (m, 1H), 6.73-6.67 (m, 1H), 5.55 (s, 1H), 5.48(s, 2H), 4.31-4.25 (m, 1H), 3.93 (s, 1H), 3.61-3.38 (m, 3H), 3.24-3.10 (m,1H), 2.96 (s, 3H), 2.53 (t, J = 7.6 Hz, 2H), 2.15-2.07 (m, 1H), 1.90-1.79 (m,4H), 1.78-1.69 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H).

[1327] Compound 32b:

[1328] MS (ESI, m / z): [M+H] + = 432.25.

[1329] 1H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.17-8.11 (m, 1H), 7.46-7.41(m, 1H), 7.03-6.97 (m, 1H), 6.73-6.67 (m, 1H), 5.55 (s, 1H), 5.48 (s, 2H),4.31-4.25 (m, 1H), 3.94 (s, 1H), 3.64-3.37 (m, 3H), 3.26-3.09 (m, 1H), 2.96(s, 3H), 2.53 (t, J = 7.6 Hz, 2H), 2.16-2.07 (m, 1H), 1.88-1.82 (m, 1H), 1.81(s, 3H), 1.79-1.68 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H).

[1330] Example 33:

[1331] N-((S)-1-(6-((4-amino-5-methyl-6-((R or S)-S-methylsulfonylimino)pyridin-2-yl)amino)-2-propylpyrimidin-4-yl)pyrrolidine-3-yl)acetamide (compound 33a); and

[1332] Preparation of N-((S)-1-(6-((4-amino-5-methyl-6-(S or R)-S-methylsulfonylimino)pyridin-2-yl)amino)-2-propylpyrimidin-4-yl)pyrrolidine-3-yl)acetamide (compound 33b)

[1333] Step 1:

[1334]

[1335] Compound 33-1 (5.0 g, 30.7 mmol) was dissolved in acetonitrile (50 mL) at 0 °C, followed by the addition of N-bromosuccinimide (5.5 g, 30.9 mmol). The reaction mixture was stirred at 0 °C for 4 hours, and the reaction progress was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction mixture was directly concentrated under reduced pressure. The residue was purified directly by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1), and the fraction was concentrated under reduced pressure to give 7 g of compound 33-2 (white solid, 95% yield).

[1336] 1 H NMR (300 MHz, CDCl3) δ 6.65 (s, 1H)

[1337] Step 2:

[1338]

[1339] According to the method in step 5 of Example 1, the starting material was replaced with 33-2 (2.0 g, 8.3 mmol) to prepare 1.75 g of compound 33-3 (white solid, yield 84%).

[1340] 1 H NMR (300 MHz, CDCl3) δ 6.44 (s, 1H), 2.43 (s, 3H).

[1341] Step 3:

[1342]

[1343] Synthesized according to step 2 of Example 10, with the starting material replaced by 33-3 (1.0 g, 4.0 mmol), yielding 1.6 g of compound 33-4 (white solid, 88% yield).

[1344] 1 H NMR (400 MHz, DMSO-d6) δ 7.59 (s, 1H), 2.53 (s, 3H), 1.37 (s, 18H).

[1345] Step 4:

[1346]

[1347] Under a nitrogen atmosphere, starting material 33-4 (1.0 g, 2.2 mmol), methylboric acid (150 mg, 2.5 mmol), tricyclohexylphosphine (56 mg, 0.220 mmol), potassium phosphate (1.5 g, 7.1 mmol), and palladium acetate (22.4 mg, 0.1 mmol) were dissolved in toluene / water (10 / 1). The reaction mixture was stirred at 100 °C for 16 hours under a nitrogen atmosphere, and the reaction progress was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was directly purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 9 / 1). The resulting fraction was concentrated under reduced pressure to give 700 mg of compound 33-5 (white solid, 82% yield).

[1348] 1H NMR (400 MHz, CD3OD) δ 6.99 (s, 1H), 2.57 (s, 3H), 2.06 (s, 3H), 1.41 (s, 18H).

[1349] Step 5:

[1350]

[1351] According to step 6 of Example 1, the starting materials were replaced with 32-9 (200 mg, 0.76 mmol) and 33-5 (326 mg, 0.84 mmol) respectively to prepare 200 mg of compound 33-6 (brown solid, yield 43%).

[1352] MS (ESI, m / z): [M+H] + = 616.25.

[1353] Step 6:

[1354]

[1355] According to the method in step 7 of Example 1, the starting material was replaced with 33-6 (180 mg, 0.29 mmol) to prepare 100 mg of compound 33-7 (yellow solid, yield 53%).

[1356] MS (ESI, m / z): [M+H] + = 647.45.

[1357] Step 7:

[1358]

[1359] The synthesis was performed according to step 3 of Example 1, with the starting material replaced by 33-7 (77 mg, 0.12 mmol). After the reaction was complete, the mixture was purified by preparative liquid chromatography. The purification conditions were as follows: column type NB_CHIRALPAK AD-H Column 30 × 250 mm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: isopropanol; flow rate 40 mL / min; gradient: isogradient 30% B; detection wavelength 258 / 214 nm; 50 mg of compound 33 (a mixture of diastereomers, yellow solid, yield 93%) was obtained.

[1360] MS (ESI, m / z): [M+H] + = 447.25.

[1361] Step 8:

[1362]

[1363] The diastereomer mixture 33 (50 mg, 0.11 mmol) was chirally resolved. The resolution conditions were as follows: chiral column CHIRALPAK AD-H, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: isopropanol; flow rate: 40 mL / min; gradient: isogradient 30% B; detection wavelength: 258 / 214 nm; retention time of 7.7 min yielded the forepeak fraction, which was concentrated under reduced pressure and lyophilized to give 20 mg of optically pure compound 33a (white solid, 40% yield); retention time of 12.8 min yielded the stern fraction, which was concentrated under reduced pressure and lyophilized to give 28 mg of optically pure compound 33b (white solid, 56% yield).

[1364] Compound 33a:

[1365] MS (ESI, m / z): [M+H] + = 447.25.

[1366] 1 H NMR (400 MHz, DMSO-d6) δ 9.26 (s, 1H), 8.12 (d, J = 6.4 Hz, 1H), 6.77-6.58 (m, 2H), 6.16 (s, 2H), 4.34-4.13 (m, 2H), 3.71-3.36 (m, 3H), 3.28-3.14 (m, 4H), 2.49-2.45 (m, 2H), 2.27 (s, 3H), 2.18-2.05 (m, 1H), 1.90-1.78(m, 4H), 1.77-1.66 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H).

[1367] Compound 33b:

[1368] MS (ESI, m / z): [M+H] + = 447.30

[1369] 1H NMR (400 MHz, DMSO-d6) δ 9.26 (s, 1H), 8.12 (d, J = 6.6 Hz, 1H), 6.86-6.55 (m, 2H), 6.16 (s, 2H), 4.37-4.10 (m, 2H), 3.71-3.36 (m, 3H), 3.31-3.16 (m, 4H), 2.50-2.47 (m, 2H), 2.27 (s, 3H), 2.11 (s, 1H), 1.90-1.79 (m,4H), 1.78-1.65 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H).

[1370] Example 34:

[1371] (R or S)-(3-amino-5-((4-((S or R)-2-(methoxymethyl)pyrrolidin-1-yl)-6-propylpyrimidin-2-yl)amino)phenyl)(imino)(methyl)-λ 6 -Thione (compound 34a);

[1372] (R or S)-(3-amino-5-((4-((R or S)-2-(methoxymethyl)pyrrolidin-1-yl)-6-propylpyrimidin-2-yl)amino)phenyl)(imino)(methyl)-λ 6 -Thione (compound 34b);

[1373] (S or R)-(3-amino-5-((4-((S or R)-2-(methoxymethyl)pyrrolidin-1-yl)-6-propylpyrimidin-2-yl)amino)phenyl)(imino)(methyl)-λ 6 -Thione (compound 34c); and

[1374] (S or R)-(3-amino-5-((4-((R or S)-2-(methoxymethyl)pyrrolidin-1-yl)-6-propylpyrimidin-2-yl)amino)phenyl)(imino)(methyl)-λ 6 Preparation of thiophene (compound 34d)

[1375] Step 1:

[1376]

[1377] According to the method in step 2 of Example 1, the starting materials were replaced with 1-2 (3.0 g, 15.8 mmol) and 34-1 (2.62 g, 22.6 mmol) respectively, and 2.5 g of compound 34-2 (brown oil, yield 59%) was prepared.

[1378] MS (ESI, m / z): [M+H] + = 270.15 / 272.15.

[1379] 1 H NMR (400 MHz, CDCl3) δ 6.33-5.97 (m, 1H), 4.50-4.22 (m, 1H), 3.67-3.41 (m, 3H), 3.39-3.26 (m, 4H), 2.55-2.50 (m, 2H), 2.18-2.04 (m, 2H), 2.03-1.93 (m, 2H), 1.74-1.65 (m, 2H), 0.98-0.92 (m, 3H).

[1380] Step 2:

[1381]

[1382] According to the method in step 2 of Example 5, the starting materials were replaced with 34-2 (350 mg, 1.3 mmol) and 16-4 (410 mg, 1.3 mmol) respectively to prepare 340 mg of compound 34-3 (yellow solid, yield 48%).

[1383] MS (ESI, m / z): [M+H] + = 549.15.

[1384] 1 H NMR (400 MHz, CDCl3) δ 9.12-9.07 (m, 1H), 8.66-8.48 (m, 1H), 8.34-8.27 (m, 1H), 6.12-5.73 (m, 1H), 4.66-4.38 (m, 1H), 4.17-4.00 (m, 1H), 3.69-3.43 (m, 2H), 3.44-3.25 (m, 6H), 2.59-2.52 (m, 2H), 2.16-1.97 (m, 5H), 1.83-1.72 (m, 2H), 1.41 (s, 9H), 1.28-1.23 (m, 1H), 1.06-0.96 (m, 3H).

[1385] Step 3:

[1386]

[1387] Synthesized according to step 5 of Example 5, with the starting material replaced by 34-3 (340 mg, 0.62 mmol), yielding 300 mg of compound 34-4 (brown solid, 93% yield).

[1388] MS (ESI, m / z): [M+H] + = 519.20.

[1389] 1 H NMR (400 MHz, CDCl3) δ 8.16-7.87 (m, 1H), 7.69-7.42 (m, 1H), 7.22-7.02 (m, 1H), 6.80 (s, 1H), 5.74 (s, 1H), 4.60-4.36 (m, 1H), 4.24-4.01 (m,1H), 4.00-3.75 (m, 1H), 3.37 (s, 3H), 3.30-3.12 (m, 5H), 2.51-2.42 (m, 2H),2.12-1.94 (m, 4H), 1.76-1.65 (m, 2H), 1.41 (s, 9H), 1.02-0.94 (m, 3H).

[1390] Step 4:

[1391]

[1392] Compound 34-4 (300 mg, 0.58 mmol) was dissolved in dichloromethane (2.4 mL) at 0 °C. Trifluoroacetic acid (0.8 mL) was slowly added dropwise to the reaction solution using a syringe. The reaction system was then removed from the ice bath and allowed to rise naturally to room temperature, under which conditions the mixture was stirred for 16 hours. The reaction system was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was directly purified by preparative liquid chromatography (HPLC). The purification conditions were as follows: XBridge Shield RP18 OBD Column 30 × 150 mm, 5 μm; mobile phase: water (10 mmol / L ammonium bicarbonate + 0.05% ammonia) and acetonitrile; flow rate 60 mL / min; gradient of acetonitrile from 28% to 48% over 10 min; detection wavelength 254 nm / 220 nm; retention time 10.2 min. The product fraction was collected, concentrated under reduced pressure, and lyophilized to give 130 mg of compound 34 (racemic mixture, white solid, yield 54%).

[1393] MS (ESI, m / z): [M+H] + = 419.25.

[1394] Step 5:

[1395]

[1396] The racemic mixture 34 (130 mg, 0.31 mmol) was chirally resolved. The separation conditions were as follows: Chiral ART Cellulose-SC column, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate: 40 mL / min; gradient: isogradient 50% B; detection wavelength: 300 / 248 nm; retention time 7.9 min yielded the first fraction, which was concentrated under reduced pressure and lyophilized to give 25 mg of optically pure compound 34a (white solid, yield 19%); retention time 9.6 min yielded the second fraction, which was concentrated under reduced pressure and lyophilized to give 22 mg of optically pure compound 34b (white solid, yield 17%); retention time 11.6 min yielded the third fraction, which was concentrated under reduced pressure and lyophilized to give 24 mg of optically pure compound 34c (white solid, yield 18%); retention time 24.2 min yielded the fourth fraction, which was concentrated under reduced pressure and lyophilized to give 22 mg of optically pure compound 34d (white solid, yield 17%).

[1397] Compound 34a:

[1398] MS (ESI, m / z): [M+H] + = 419.25.

[1399] 1 H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 7.88-7.49 (m, 1H), 7.43-6.90(m, 1H), 6.71-6.61 (m, 1H), 5.91-5.78 (m, 1H), 5.30 (s, 2H), 4.54-4.19 (m,1H), 3.75 (s, 1H), 3.61-3.34 (m, 3H), 3.31-3.26 (m, 1H), 3.24 (s, 3H), 2.93(s, 3H), 2.43-2.38 (m, 2H), 2.09-1.85 (m, 4H), 1.72-1.60 (m, 2H), 0.94-0.88(m, 3H).

[1400] Compound 34b:

[1401] MS (ESI, m / z): [M+H]+ = 419.25.

[1402] 1 H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 7.88-7.49 (m, 1H), 7.43-6.90(m, 1H), 6.71-6.61 (m, 1H), 5.91-5.78 (m, 1H), 5.30 (s, 2H), 4.54-4.19 (m,1H), 3.75 (s, 1H), 3.61-3.34 (m, 3H), 3.31-3.26 (m, 1H), 3.24 (s, 3H), 2.93(s, 3H), 2.43-2.38 (m, 2H), 2.09-1.85 (m, 4H), 1.72-1.60 (m, 2H), 0.94-0.88(m, 3H).

[1403] Compound 34c:

[1404] MS (ESI, m / z): [M+H] + = 419.30.

[1405] 1 H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 7.88-7.49 (m, 1H), 7.43-6.90(m, 1H), 6.71-6.61 (m, 1H), 5.91-5.78 (m, 1H), 5.30 (s, 2H), 4.54-4.19 (m,1H), 3.75 (s, 1H), 3.61-3.34 (m, 3H), 3.31-3.26 (m, 1H), 3.24 (s, 3H), 2.93(s, 3H), 2.43-2.38 (m, 2H), 2.09-1.85 (m, 4H), 1.72-1.60 (m, 2H), 0.94-0.88(m, 3H).

[1406] Compound 34d:

[1407] MS (ESI, m / z): [M+H] + = 419.30.

[1408] 1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 7.88-7.49 (m, 1H), 7.43-6.90(m, 1H), 6.71-6.61 (m, 1H), 5.91-5.78 (m, 1H), 5.30 (s, 2H), 4.54-4.19 (m,1H), 3.75 (s, 1H), 3.61-3.34 (m, 3H), 3.31-3.26 (m, 1H), 3.24 (s, 3H), 2.93(s, 3H), 2.43-2.38 (m, 2H), 2.09-1.85 (m, 4H), 1.72-1.60 (m, 2H), 0.94-0.88(m, 3H).

[1409] Example 35:

[1410] N-((S or R)-1-(2-(4-methyl-3-((R or S)-S-methylsulfonylimino)phenyl)amino)-6-propylpyrimidin-4-yl)piperidin-3-yl)acetamide (compound 35a);

[1411] N-((S or R)-1-(2-(4-methyl-3-((S or R)-S-methylsulfonylimino)phenyl)amino)-6-propylpyrimidin-4-yl)piperidin-3-yl)acetamide (compound 35b);

[1412] N-((R or S)-1-(2-(4-methyl-3-((R or S)-S-methylsulfonylimino)phenyl)amino)-6-propylpyrimidin-4-yl)piperidin-3-yl)acetamide (compound 35c); and

[1413] Preparation of N-((R or S)-1-(2-(4-methyl-3-((S or R)-S-methylsulfonylimino)phenyl)amino)-6-propylpyrimidin-4-yl)piperidin-3-yl)acetamide (compound 35d)

[1414] Step 1:

[1415]

[1416] Under a nitrogen atmosphere and at room temperature, raw material 35-1 (10.0 g, 38.0 mmol; CAS: 7745-92-8, purchased directly from Shanghai Haohong Biomedical Technology Co., Ltd.) was dissolved in 1,4-dioxane (100 mL). 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (2.2 g, 3.8 mmol), palladium acetate (853 mg, 3.80 mmol), cesium carbonate (24.8 g, 76.1 mmol), and sodium methanethiol (4.0 g, 57.1 mmol) were added sequentially to the above reaction solution. The reaction system was stirred at 80 °C under a nitrogen atmosphere for 2 hours. The reaction progress was monitored using liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction system was brought back to room temperature, filtered, and the filter cake was washed with ethyl acetate (100 mL × 2). The filtrate was concentrated under reduced pressure. The residue was purified directly using a silica gel column (eluent: petroleum ether / ethyl acetate = 6 / 1). The resulting fraction was concentrated under reduced pressure to give 4.0 g of 1-methyl-2-(methylsulfonyl)-4-nitrobenzene (yellow solid, crude product, yield 49%).

[1417] At room temperature, 4.0 g of crude 1-methyl-2-(methanesulfonyl)-4-nitrobenzene was dissolved in methanol (40 mL). Ammonium carbamate (8.5 g, 109 mmol) and (diacetoxyiodine)benzene (21.1 g, 65.5 mmol) were added to the reaction solution. The reaction mixture was stirred at room temperature for 3 hours. The reaction progress was monitored by liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the mixture was directly concentrated under reduced pressure. The resulting residue was purified directly by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1). The fraction was concentrated under reduced pressure to give 2.1 g of compound 35-2 (yellow solid, 26% yield).

[1418] MS (ESI, m / z): [M+H] + = 215.15.

[1419] 1 H NMR (300 MHz, CDCl3) δ 8.94 (d, J = 2.4 Hz, 1H), 8.41-8.16 (m, 1H), 7.53 (d, J = 8.4 Hz, 1H), 3.18 (s, 3H), 2.87 (s, 3H).

[1420] Step 2:

[1421]

[1422] According to the method in step 2 of Example 10, the starting material was replaced with 35-2 (2.5 g, 11.7 mmol) to prepare 1.5 g of compound 35-3 (pale yellow solid, yield 41%).

[1423] MS (ESI, m / z): [M-Boc+H] + = 215.15.

[1424] 1 H NMR (300 MHz, CDCl3) δ 8.94 (d, J = 2.4 Hz, 1H), 8.41-8.34 (m, 1H), 7.57 (d, J = 8.4 Hz, 1H), 3.28 (s, 3H), 2.81 (s, 3H), 1.38 (s, 9H).

[1425] Step 3:

[1426]

[1427] According to step 8 of Example 1, the starting material was replaced with 35-3 (1.5 g, 4.8 mmol) to prepare 1.2 g of compound 35-4 (pale yellow solid, yield 88%).

[1428] MS (ESI, m / z): [M+H] + = 285.15.

[1429] 1 H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 2.6 Hz, 1H), 7.10 (d, J = 8.2Hz, 1H), 6.83-6.78 (m, 1H), 3.19 (s, 3H), 2.52 (s, 3H), 1.38 (s, 9H).

[1430] Step 4:

[1431]

[1432] According to the method in step 2 of Example 1, the starting materials were replaced with compounds 1-2 (500 mg, 2.63 mmol) and 26-1 (524 mg, 2.62 mmol; CAS: 172603-05-3, purchased directly from the supplier Shanghai Haohong Biomedical Technology Co., Ltd.) to prepare 700 mg of compound 35-5 (yellow solid, yield 75%).

[1433] MS (ESI, m / z): [M+H] + = 355.20 / 357.10.

[1434] 1 H NMR (300 MHz, CDCl3) δ 6.29 (s, 1H), 4.64-4.56 (m, 1H), 3.92-3.31(m, 4H), 2.58-2.47 (m, 2H), 2.08-1.90 (m, 2H), 1.79-1.55 (m, 4H), 1.45 (s,9H), 0.95 (t, J = 7.2 Hz, 3H).

[1435] Step 5:

[1436]

[1437] According to the method in step 3 of Example 1, the starting material was replaced with compound 35-5 (700 mg, 1.98 mmol) to prepare 700 mg of trifluoroacetate of compound 35-6 (brown oily substance, yield 96%, crude product).

[1438] MS (ESI, m / z): [M-CF3COOH+H] + = 255.15 / 257.15.

[1439] Step 6:

[1440]

[1441] According to the method in step 5 of Example 1, the starting material was replaced with compound 35-6 (700 mg, 1.90 mmol) to prepare 500 mg of compound 35-7 (yellow solid, yield 89%).

[1442] MS (ESI, m / z): [M+H] + = 297.10 / 299.10.

[1443] 1H NMR (400 MHz, CDCl3) δ 6.32 (s, 1H), 5.82-5.76 (m, 1H), 4.01-3.92(m, 1H), 3.91-3.82 (m, 1H), 3.57-3.47 (m, 1H), 3.45-3.36 (m, 2H), 2.59-2.50(m, 2H), 1.98 (s, 3H), 1.85-1.59 (m, 6H), 0.96 (t, J = 7.2 Hz, 3H).

[1444] Step 7:

[1445]

[1446] According to the method in step 7 of Example 1, the starting materials were replaced with 35-4 (230 mg, 0.81 mmol) and 35-7 (240 mg, 0.81 mmol) respectively to prepare 400 mg of compound 35-8 (yellow solid, yield 91%).

[1447] MS (ESI, m / z): [M+H] + = 545.25.

[1448] Step 8:

[1449]

[1450] According to the method in step 3 of Example 1, the starting material was replaced with 35-8 (400 mg, 0.73 mmol) to prepare 300 mg of compound 35 (racemic, yellow solid, yield 92%).

[1451] MS (ESI, m / z): [M+H] + = 445.20.

[1452] Step 9:

[1453]

[1454] The racemic mixture 35 (300 mg, 0.675 mmol) was chirally resolved under the following conditions: chiral column CHIRALPAK IN 3, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (0.5% in 2 M ammonia-methanol), i.e., n-hexane (10 mmol / L ammonia-methanol); mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; detection wavelength 254 / 270 nm; retention time 15.9 min yielded the first peak fraction, which was concentrated under reduced pressure and lyophilized to obtain a mixture of 120 mg of compounds 35a and 35b; retention time 25.4 min yielded the second peak fraction, which was concentrated under reduced pressure and lyophilized to obtain a mixture of 120 mg of compounds 35c and 35d.

[1455] A mixture of 120 mg of 35a and 35b was chirally separated under the following conditions: chiral column CHIRALPAKIH, 3.0 × 50 mm, 3 μm; mobile phase A: carbon dioxide, mobile phase B: 20 ​​mM ammonia-methanol; flow rate 100 mL / min; gradient: isogradient 30% B; detection wavelength 220 / 254 nm; retention time 3.12 min yielded the forepeak fraction, which was concentrated under reduced pressure and lyophilized to give 32.7 mg of optically pure compound 35a (white solid, yield 27%); retention time 4.10 min yielded the hindpeak fraction, which was concentrated under reduced pressure and lyophilized to give 61.7 mg of optically pure compound 35b (white solid, yield 51%).

[1456] A mixture of 120 mg of 35c and 35d was chirally separated under the following conditions: chiral column CHIRALPAKIH, 3.0 × 50 mm, 3 μm; mobile phase A: carbon dioxide, mobile phase B: 20 ​​mM ammonia-methanol; flow rate 100 mL / min; gradient: isogradient 35%B; detection wavelength 220 / 254 nm; retention time 3.0 min yielded the forepeak fraction, which was concentrated under reduced pressure and lyophilized to obtain 35.1 mg of optically pure compound 35c (white solid, yield 29%); retention time 4.1 min yielded the hindpeak fraction, which was concentrated under reduced pressure and lyophilized to obtain 64 mg of optically pure compound 35d (white solid, yield 53%).

[1457] Compound 35a:

[1458] MS (ESI, m / z): [M+H] + = 445.30.

[1459] 1H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 8.59 (s, 1H), 7.88 (d, J =7.2 Hz, 1H), 7.71-7.62 (m, 1H), 7.25 (d, J = 8.4 Hz, 1H), 6.18 (s, 1H), 4.24-3.84 (m, 2H), 3.72-3.58 (m, 1H), 3.24-3.13 (m, 1H), 3.05 (s, 3H), 3.03-2.95(m, 1H), 2.59 (s, 3H), 2.46-2.39 (m, 2H), 1.92-1.82 (m, 1H), 1.82-1.73 (m,4H), 1.72-1.62 (m, 2H), 1.53-1.41 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H).

[1460] Compound 35b:

[1461] MS (ESI, m / z): [M+H] + = 445.30.

[1462] 1 H NMR (400 MHz, DMSO-d6)δ 9.43 (s, 1H), 8.57 (s, 1H), 7.89 (d, J =7.6 Hz, 1H), 7.72-7.62 (m, 1H), 7.25 (d, J = 8.4 Hz, 1H), 6.19 (s, 1H), 4.23-3.84 (m, 2H), 3.74-3.55 (m, 1H), 3.26-3.13 (m, 1H), 3.05 (s, 3H), 3.03-2.92(m, 1H), 2.60 (s, 3H), 2.49-2.41 (m, 2H), 1.92-1.82 (m, 1H), 1.82-1.72 (m,4H), 1.73-1.62 (m, 2H), 1.54-1.41 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H).

[1463] Compound 35c:

[1464] MS (ESI, m / z): [M+H] + = 445.30.

[1465] 1H NMR (400 MHz, DMSO-d6)δ 9.33 (s, 1H), 8.59 (s, 1H), 7.88 (d, J =7.2 Hz, 1H), 7.72-7.62 (m, 1H), 7.23 (d, J = 8.4 Hz, 1H), 6.15 (s, 1H), 4.25-3.95 (m, 2H), 3.71-3.56 (m, 1H), 3.23-3.09 (m, 1H), 3.04 (s, 3H), 3.00-2.89(m, 1H), 2.59 (s, 3H), 2.47-2.35 (m, 2H), 1.91-1.83 (m, 1H), 1.80 (s, 3H),1.78-1.72 (m, 1H), 1.72 -1.61 (m, 2H), 1.54-1.39 (m, 2H), 0.91 (t, J = 7.2Hz, 3H).

[1466] Compound 35d:

[1467] MS (ESI, m / z): [M+H] + = 445.25.

[1468] 1 H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.60 (s, 1H), 7.88 (d, J =7.2 Hz, 1H), 7.71-7.62 (m, 1H), 7.24 (d, J = 8.4 Hz, 1H), 6.16 (s, 1H), 4.25-3.89 (m, 2H), 3.73-3.56 (m, 1H), 3.25-3.10 (m, 1H), 3.04 (s, 3H), 3.02-2.93(m, 1H), 2.59 (s, 3H), 2.48-2.38 (m, 2H), 1.94-1.82 (m, 1H), 1.80 (s, 3H),1.79-1.72 (m, 1H), 1.73-1.61 (m, 2H), 1.54-1.39 (m, 2H), 0.91 (t, J = 7.2 Hz,3H).

[1469] Example 36:

[1470] N-((S or R)-1-(2-((4-chloro-3-((R or S)-S-methylsulfonylimino)phenyl)amino)-6-propylpyrimidin-4-yl)piperidin-3-yl)acetamide (compound 36a);

[1471] N-((S or R)-1-(2-((4-chloro-3-((S or R)-S-methylsulfonylimino)phenyl)amino)-6-propylpyrimidin-4-yl)piperidin-3-yl)acetamide (compound 36b);

[1472] N-((R or S)-1-(2-((4-chloro-3-((R or S)-S-methylsulfonylimino)phenyl)amino)-6-propylpyrimidin-4-yl)piperidin-3-yl)acetamide (compound 36c); and

[1473] Preparation of N-((R or S)-1-(2-((4-chloro-3-((S or R)-S-methylsulfonylimino)phenyl)amino)-6-propylpyrimidin-4-yl)piperidin-3-yl)acetamide (compound 36d)

[1474] Step 1:

[1475]

[1476] According to the method in step 1 of Example 35, the raw material was replaced with 36-1 (10.2 g, 43.1 mmol; CAS: 16588-26-4, purchased directly from the supplier Shanghai Haohong Biomedical Technology Co., Ltd.) to prepare 2.5 g of compound 36-2 (dark red oily substance, yield 25%).

[1477] MS (ESI, m / z): [M+H] + = 235.05 / 237.05.

[1478] Step 2:

[1479]

[1480] According to the method in step 2 of Example 10, the starting material was replaced with 36-2 (2.5 g, 10.7 mmol) to prepare 1.5 g of compound 36-3 (yellow solid, yield 42%).

[1481] MS (ESI, m / z): [M-Boc+H] + = 235.10 / 237.10.

[1482] 1H NMR (400 MHz, CDCl3) δ 9.08 (d, J = 2.4 Hz, 1H), 8.45-8.42 (m, 1H), 7.77 (d, J = 8.4 Hz, 1H), 3.40 (s, 3H), 1.37 (s, 9H).

[1483] Step 3:

[1484]

[1485] According to step 8 of Example 1, the starting material was replaced with 36-3 (1.5 g, 4.49 mmol) to prepare 1.2 g of compound 37-4 (yellow solid, yield 88%).

[1486] MS (ESI, m / z): [M+H] + = 305.15 / 307.10.

[1487] 1 H NMR (400 MHz, DMSO-d6) δ 7.31-7.26 (m, 2H), 6.82-6.78 (m, 1H), 5.86 (s, 2H), 3.32 (s, 3H), 1.21 (s, 9H).

[1488] Step 4:

[1489]

[1490] According to the method in step 7 of Example 1, the starting materials were replaced with 35-7 (300 mg, 1.01 mmol) and 36-4 (308 mg, 1.01 mmol) respectively to prepare 500 mg of compound 36-5 (brown oil, yield 88%).

[1491] MS (ESI, m / z): [M+H] + = 565.30 / 567.25.

[1492] Step 5:

[1493]

[1494] According to the method in step 3 of Example 1, the starting material was replaced with 36-5 (500 mg, 0.886 mmol) to prepare 130 mg of compound 36 (racemic mixture, white solid, yield 32%).

[1495] MS (ESI, m / z): [M+H] + = 465.15 / 467.20.

[1496] Step 6:

[1497]

[1498] The racemic mixture 36 (130 mg, 0.28 mmol) was chirally resolved under the following conditions: chiral column Enantiocel-A4-5, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (0.5% 2M ammonia-methanol), i.e., n-hexane (10 mmol / L ammonia-methanol); mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 50% B; detection wavelength 220 / 254 nm; retention time 8.9 min yielded the first peak fraction, which was concentrated under reduced pressure and lyophilized to obtain a mixture of compounds 36a, 36b, and 36c; retention time 13.9 min yielded the second peak fraction, which was concentrated under reduced pressure and lyophilized to obtain 24 mg of compound 36d (white solid, yield 18%).

[1499] Chiral resolution was performed on a mixture of compounds 36a, 36b, and 36c under the following conditions: chiral column CHIRALPAK AY, 3.0 × 50 mm, 3 μm; mobile phase A: n-hexane (0.5% 2M ammonia-methanol), mobile phase B: ethanol / acetonitrile (5 / 1); flow rate 40 mL / min; gradient: isogradient 40% B; detection wavelength 220 / 254 nm; retention time 5.4 min yielded the forepeak fraction, which was concentrated under reduced pressure and lyophilized to give 22 mg of optically pure compound 36a (white solid, yield 17%); retention time 10.2 min yielded the hindpeak fraction, which was concentrated under reduced pressure and lyophilized to give a mixture of compounds 36b and 36c.

[1500] Chiral separation was performed on a mixture of 36b and 36c under the following conditions: chiral column CHIRALPAK ID, 3.0 × 50 mm, 3 μm; mobile phase A: n-hexane (20 mM ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; detection wavelength 220 / 254 nm; retention time 21 min yielded the last fraction, which was concentrated under reduced pressure and lyophilized to give 13 mg of optically pure compound 36b (white solid, 10% yield); retention time 28.3 min yielded the last fraction, which was concentrated under reduced pressure and lyophilized to give 12 mg of optically pure compound 36c (white solid, 9% yield).

[1501] Compound 36a:

[1502] MS (ESI, m / z): [M+H] + = 465.20 / 467.20.

[1503] 1 H NMR (400 MHz, DMSO-d6) δ 9.48 (s, 1H), 8.77 (s, 1H), 7.88 (d, J =7.2 Hz, 1H), 7.86 - 7.77 (m, 1H), 7.46 (d, J = 8.8 Hz, 1H), 6.16 (s, 1H), 4.31(s, 1H), 4.24 - 3.94 (m, 2H), 3.72 - 3.55 (m, 1H), 3.21 - 3.17 (m, 3H), 3.17 - 3.06(m, 1H), 2.96 - 2.85 (m, 1H), 2.46 - 2.38 (m, 2H), 1.90 - 1.83 (m, 1H), 1.81 (s,3H), 1.78 - 1.72 (m, 1H), 1.72 - 1.62 (m, 2H), 1.51 - 1.39 (m, 2H), 0.91 (t, J =7.2 Hz, 3H).

[1504] Compound 36b:

[1505] MS (ESI, m / z): [M+H] + = 465.25 / 467.25.

[1506] 1 H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.78 (s, 1H), 7.86 (d, J =7.2 Hz, 1H), 7.84 - 7.77 (m, 1H), 7.46 (d, J = 8.8 Hz, 1H), 6.16 (s, 1H), 4.32(s, 1H), 4.17 - 3.99 (m, 2H), 3.69 - 3.58 (m, 1H), 3.21 - 3.17 (m, 3H), 3.16 - 3.08(m, 1H), 3.00 - 2.85 (m, 1H), 2.46 - 2.38 (m, 2H), 1.92 - 1.82 (m, 1H), 1.80 (s,3H), 1.74 - 1.61 (m, 3H), 1.53 - 1.38 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H).

[1507] Compound 36c:

[1508] MS (ESI, m / z): [M+H] + = 465.20 / 467.20.

[1509] 1 H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.78 (s, 1H), 7.86 (d, J =7.2 Hz, 1H), 7.84-7.77 (m, 1H), 7.46 (d, J = 8.4 Hz, 1H), 6.16 (s, 1H), 4.32(s, 1H), 4.18-4.00 (m, 2H), 3.69-3.58 (m, 1H), 3.21-3.17 (m, 3H), 3.17-3.08(m, 1H), 3.03-2.78 (m, 1H), 2.45-2.37 (m, 2H), 1.92-1.83 (m, 1H), 1.80 (s,3H), 1.78-1.72 (m, 1H), 1.72-1.62 (m, 2H), 1.55-1.43 (m, 2H), 0.91 (t, J =7.2 Hz, 3H).

[1510] Compound 36d:

[1511] MS (ESI, m / z): [M+H] + = 465.25 / 467.25.

[1512] 1H NMR (400 MHz, DMSO-d6) δ 9.48 (s, 1H), 8.77 (s, 1H), 7.88 (d, J =7.2 Hz, 1H), 7.86-7.77 (m, 1H), 7.46 (d, J = 8.8 Hz, 1H), 6.16 (s, 1H), 4.31(s, 1H), 4.24-3.94 (m, 2H), 3.72-3.55 (m, 1H), 3.21-3.17 (m, 3H), 3.17-3.06(m, 1H), 2.96-2.85 (m, 1H), 2.46-2.38 (m, 2H), 1.90-1.83 (m, 1H), 1.81 (s,3H), 1.78-1.72 (m, 1H), 1.72-1.62 (m, 2H), 1.51-1.39 (m, 2H), 0.91 (t, J =7.2 Hz, 3H).

[1513] Example 37:

[1514] N-((S or R)-1-(2-((3-(((R or S)-N-cyano-S-methylsulfonylimino)-4-methylphenyl)amino)-6-propylpyrimidin-4-yl)piperidin-3-yl)acetamide (compound 37a);

[1515] N-((S or R)-1-(2-((3-(S or R)-N-cyano-S-methylsulfonylimino)-4-methylphenyl)amino)-6-propylpyrimidin-4-yl)piperidin-3-yl)acetamide (compound 37b);

[1516] N-((R or S)-1-(2-((3-(((S or R)-N-cyano-S-methylsulfonylimino)-4-methylphenyl)amino)-6-propylpyrimidin-4-yl)piperidin-3-yl)acetamide (compound 37c); and

[1517] Preparation of N-((R or S)-1-(2-((3-(R or S)-N-cyano-S-methylsulfonylimino)-4-methylphenyl)amino)-6-propylpyrimidin-4-yl)piperidin-3-yl)acetamide (compound 37d)

[1518] Step 1:

[1519]

[1520] Compound 14-2 (1.0 g, 4.67 mmol) was dissolved in dichloromethane (10 mL) at room temperature. Then, cyanogen bromide (989 mg, 9.34 mmol) and 4-dimethylaminopyridine (570 mg, 4.67 mmol) were added sequentially to the reaction mixture. The reaction mixture was stirred at room temperature for 2 hours, and the reaction progress was monitored using liquid chromatography-mass spectrometry (LC-MS). After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was directly purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 100). The fraction was concentrated under reduced pressure to give 700 mg of compound 37-1 (white solid, 63% yield).

[1521] MS (ESI, m / z): [M+H] + = 239.95.

[1522] 1 H NMR (400 MHz, CDCl3) δ 8.96 (d, J = 2.4 Hz, 1H), 8.52-8.45 (m, 1H), 7.69 (d, J = 8.4 Hz, 1H), 3.46 (s, 3H), 2.88 (s, 3H).

[1523] Step 2:

[1524]

[1525] According to the method in step 5 of Example 5, the starting material was replaced with 37-1 (700 mg, 2.93 mmol) to obtain 430 mg of compound 37-2 (yellow oil, 70% yield).

[1526] MS (ESI, m / z): [M+H] + = 210.10.

[1527] Step 3:

[1528]

[1529] The compound 37 was synthesized according to step 6 of Example 1, with the starting materials replaced by 37-2 (71.1 mg, 0.34 mmol) and 35-7 (100.7 mg, 0.34 mmol) respectively, to obtain 120 mg of compound 37 (racemic mixture, yellow solid, yield 75%).

[1530] MS (ESI, m / z): [M+H] + = 470.15.

[1531] 1 H NMR (400 MHz, CDCl3) δ 9.00-8.93 (m, 1H), 7.39-7.32 (m, 1H), 7.29(d, J = 8.4 Hz, 1H), 6.02 (s, 1H), 5.89-5.78 (m, 1H), 4.20-4.03 (m, 1H),4.03-3.90 (m, 1H), 3.84-3.74 (m, 1H), 3.52-3.40 (m, 1H), 3.32-3.24 (m, 1H),2.65 (s, 3H), 2.52-2.44 (m, 2H), 2.06-1.99 (m, 1H), 1.97-1.85 (m, 5H), 1.82-1.52 (m, 6H), 0.98 (t, J = 7.2 Hz, 3H).

[1532] Step 4:

[1533]

[1534] 120 mg of the racemic mixture 37 was chirally resolved under the following conditions: column type Lux 5um Cellulose-4, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (0.5% 2M ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; detection wavelength 254 / 220 nm; retention time 16.3 min yielded the first fraction, which, after concentration under reduced pressure and lyophilization, yielded 32 mg of a mixture of 37a and 37b; retention time 22.4 min yielded the second fraction, which, after concentration under reduced pressure and lyophilization, yielded 42.7 mg of optically pure compound 37c (white solid, 35% yield); retention time 28.4 min yielded the third fraction, which, after concentration under reduced pressure and lyophilization, yielded 41.4 mg of optically pure compound 37d (white solid, 34% yield).

[1535] Chiral resolution was performed on a mixture of 32 mg of 37a and 37b under the following conditions: chiral column CHIRALPAKID, 3.0 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 50% B; detection wavelength 254 / 220 nm; retention time 9.0 min yielded the forepeak fraction, which was concentrated under reduced pressure and lyophilized to give 18 mg of optically pure compound 37a (white solid, 15% yield); retention time 11.9 min yielded the hindpeak fraction, which was concentrated under reduced pressure and lyophilized to give 12 mg of optically pure compound 37b (white solid, 10% yield).

[1536] Compound 37a:

[1537] MS (ESI, m / z): [M+H] + = 470.25.

[1538] 1 H NMR (400 MHz, DMSO-d6) δ 9.48 (s, 1H), 8.84 (s, 1H), 7.88 (d, J =7.6 Hz, 1H), 7.82 (d, J =8.4 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 6.16 (s, 1H),4.19-3.97 (m, 2H), 3.70-3.57 (m, 4H), 3.23-3.10 (m, 1H), 3.01-2.91 (m, 1H),2.57 (s, 3H), 2.47-2.39 (m, 2H), 1.90-1.74 (m, 5H), 1.75-1.62 (m, 2H), 1.55-1.43 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H).

[1539] Compound 37b:

[1540] MS (ESI, m / z): [M+H] + = 470.30.

[1541] 1H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.83 (s, 1H), 7.87 (d, J =7.6 Hz, 1H), 7.83 (d, J =8.4 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 6.16 (s, 1H),4.22-3.96 (m, 2H), 3.73-3.57 (m, 4H), 3.22-3.09 (m, 1H), 2.99-2.89 (m, 1H),2.57 (s, 3H), 2.48-2.40 (m, 2H), 1.90-1.76 (m, 5H), 1.74-1.63 (m, 2H), 1.52-1.43 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H).

[1542] Compound 37c:

[1543] MS (ESI, m / z): [M+H] + = 470.25.

[1544] 1 H NMR (400 MHz, DMSO-d6) δ 9.49 (s, 1H), 8.82 (s, 1H), 7.88 (d, J =7.6 Hz, 1H), 7.83 (d, J =8.4 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 6.17 (s, 1H),4.24-3.97 (m, 2H), 3.77-3.57 (m, 4H), 3.22-3.11 (m, 1H), 2.99-2.89 (m, 1H),2.57 (s, 3H), 2.48-2.40 (m, 2H), 1.95-1.74 (m, 5H), 1.73-1.64 (m, 2H), 1.55-1.43 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H).

[1545] Compound 37d:

[1546] MS (ESI, m / z): [M+H] + = 470.25.

[1547] 1H NMR (400 MHz, DMSO-d6) δ 9.49 (s, 1H), 8.83 (s, 1H), 7.88 (d, J =7.6 Hz, 1H), 7.82 (d, J =8.4 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 6.17 (s, 1H),4.25-3.94 (m, 2H), 3.73-3.57 (m, 4H), 3.24-3.10 (m, 1H), 3.01-2.91 (m, 1H),2.57 (s, 3H), 2.48-2.40 (m, 2H), 1.96-1.74 (m, 5H), 1.73-1.62 (m, 2H), 1.52-1.43 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H).

[1548] In vitro biological experimental methods

[1549] 1.5-HT 4a Procedure for Radioligand Binding Assay

[1550] 1) Add 48 µL / well assay buffer (50 mM HEPES, pH 7.4, 0.1% BSA) and 2 µL / well test compound (DMSO final concentration 1%) to a 96-well deep plate, and shake at 500 rpm for 5 minutes to completely mix the reaction system.

[1551] 2) Add 99.5 μL of 5-HT containing 0.5 µL to each well. 4a Prepare the membrane protein assay buffer and vortex at 500 rpm for 5 minutes.

[1552] 3) Add 50 µL of [[] to each well 3 Prepare assay buffer of H]-GR113808 (final concentration 0.25 nM) and vortex at 500 rpm for 5 minutes.

[1553] 4) Incubate the plate at 27 ℃ for 1 hour.

[1554] 5) Pre-incubate the UNIFILTER-96 GF / C filter plate with 0.5% PEI at 4 ℃ for 1 hour.

[1555] 6) Wash the UNIFILTER-96 GF / C filter plate twice with 1 mL of washing buffer (50 mM HEPES, pH 7.4) per well, and transfer the membrane mixture to the UNIFILTER-96 GF / C filter.

[1556] 7) Dry the plate at 55 ℃ for 10 minutes.

[1557] 8) Add 40 µL of ULTIMA GOLD to each well and read the CPM value using a Microbeta-2.

[1558] 9) Use Graphpad for data processing and analysis and calculate IC. 50 (nM) and Ki value.

[1559] 2.5-HT4a Tag-lite method combined with experimental procedures

[1560] 1) Dilute 5X TLB buffer to 1X TLB buffer using ddH2O.

[1561] 2) Prepare a 15 ml centrifuge tube and add 10 ml of 1X TLB buffer. Thaw two frozen Tag-lite angiotensin 5HT4A-labeled cells in a 37 ℃ water bath until the ice is completely thawed (1-2 minutes). Quickly transfer the cells to a 15 ml centrifuge tube and centrifuge at 1200 g at room temperature for 5 minutes.

[1562] 3) Gently aspirate the supernatant. Resuspend the cell pellet in 1 ml of 1X TLB buffer, mix gently, then add 2.7 ml of 1X TLB buffer and invert to mix several times.

[1563] 4) Dilute Tag-lite angiotensin receptor red agonist (8600 nM stock solution) to 12 nM (2X) with 1X TLB buffer and set aside for use.

[1564] 5) Transfer the serially diluted compound to a 384-well plate at 20 nl / well and centrifuge at 200 g for 1 minute at room temperature.

[1565] 6) Add 10 μl of labeled cells per well to a 384-well plate and centrifuge at 200 g for 3-5 seconds at room temperature.

[1566] 7) Add 10 μl of 2X Tag-lite angiotensin reactivator red agonist to all wells according to the plate layout.

[1567] 8) Centrifuge the test plate at room temperature for 1 minute at 200 g, and then incubate at 25°C for 1 hour.

[1568] 9) Read the plates at wavelengths of 665 nm and 615 nm on the Envision 2105 plate reader.

[1569] 10) Use Graphpad to process and analyze the data and calculate IC50 (nM).

[1570] 3.5-HT 4a cAMP assay experimental procedure

[1571] 1) HEK293 cells were cultured in complete medium at 37 ℃ and 5% CO2, and the cell density was maintained in a sub-convergence state.

[1572] 2) After TrypLE digestion, HEK293 cells were resuspended in cell transfection medium, and 6 x 10⁻⁶ cells were added. 6 The cells were seeded into T-75 cell culture flasks and then cultured overnight at 37 ℃ and 5% CO2.

[1573] 3) Add 10 μg of 5-HT 4a HEK293 cells were transfected with the pIRESpuro3 plasmid and incubated at 37 °C and 5% CO2 for 5 hours. The transfection reagent used was Lipofectamine™ LTX & Plus reagent, with a DNA to LTX ratio of 1:3.

[1574] 4) Dilute the analyte 3-fold with DMSO to obtain 10 concentrations. Transfer 50 nL / well of the compound to a 384-well plate using an Echo.

[1575] 5) Five hours after transfection, HEK293 cells were digested with TrypLE and resuspended in experimental buffer. Then, 8000 cells / well / 20 μL were added to the 384-well plate prepared in step 4 and incubated at 37 °C for 30 minutes.

[1576] 6) Dilute cAMP-d2 1 / 20 with lysis buffer and add 5 μL to each well of a 384-well plate.

[1577] 7) Dilute Eu-Cryptate antibody 1 / 20 with lysis buffer and add 5 μL to each well of a 384-well plate.

[1578] 8) Incubate the 384-well plate at room temperature for 1 hour.

[1579] 9) Read the plates at wavelengths of 665 nm and 615 nm on the Envision 2105 plate reader.

[1580] 10) Use Graphpad for data processing and analysis and calculate EC.50 (nM).

[1581] 4.5-HT 1a cAMP assay experimental procedure

[1582] 1) The HTR1A-CHO-k1 stable cell line was cultured in complete medium (Ham's F-12K + 10% fetal bovine serum + 1x penicillin-streptomycin + 600 μg / mL hygromycin B) under culture conditions of 37 ℃ and 5% CO2, and the cell confluence was maintained at 80%-90%.

[1583] 2) Dilute the 10 mM DMSO stock solution of the test compound five times to obtain a total of 10 concentrations.

[1584] 3) Use Echo to transfer 20 nL / well of the analyte to a 384-well assay plate.

[1585] 4) After digesting the HTR1A-CHO-k1 stable cells, resuspend them in assay buffer (1X HBSS + 20 mM HEPES + 0.1% BSA + 500 μM IBMX), and seed 1000 cells / well / 15 μL into the assay plate prepared in step 3, and incubate at 37 ℃ for 10 minutes.

[1586] 5) Prepare a 16 μM Forskolin solution in the assay buffer.

[1587] 6) Add 5 μL of 16 μM Forskolin working solution to each well and incubate at 37 °C for 30 minutes.

[1588] 7) Preparation of working solution for detection reagent: Dilute Eu-cAMP tracer to 1 / 50 with detection buffer, and dilute Ulight anti-cAMP to 1 / 150 with the same buffer.

[1589] 8) Add 5 μL of Eu-cAMP tracer and 5 μL of Ulight anti-cAMP working solution to each well and incubate at 25 °C for 1 hour.

[1590] 9) Collect data using the Envision 2105 microboard reader and HTRF module.

[1591] 10) Use Graphpad for data processing and analysis and calculate EC. 50 (nM).

[1592] 5.5-HT 2a FLIPR Calcium Flow Measurement Experimental Procedure

[1593] 1) Flp-In-CHO-5HT was cultured in complete medium (Ham's F-12K + 10% fetal bovine serum + 1x penicillin-streptomycin + 600 μg / mL hygromycin B) under culture conditions of 37 ℃ and 5% CO2. 2a The cell lines were stabilized and maintained at 80%-90% cell confluence.

[1594] 2) Inoculate 10,000 cells / well / 25 μL of cell seeding medium (Ham's F-12K+ 10% dialyzed fetal bovine serum) into 384-well cell plates and incubate overnight at 37 ℃ and 5% CO2.

[1595] 3) Prepare 2x component A (Ca) in assay buffer (1x HBSS + 20 mM HEPES). 2+ (Probe) solution.

[1596] 4) Replace the inoculation medium in the cell plate with 20 μL / well assay buffer.

[1597] 5) Add an equal volume of 2x component A to each well, and then incubate the cell plate at 37°C for 2 hours.

[1598] 6) Prepare a 5x working solution of the test compound in the assay buffer.

[1599] 7) Add 10 μL of the 5x compound working solution to the assay plate using FLIPR Penta and collect the fluorescence signal immediately.

[1600] 8) Use Graphpad for data processing and analysis, and calculate EC. 50 (nM).

[1601] 6.5-HT 2b FLIPR Calcium Flow Measurement Experimental Procedure

[1602] 1) Flp-In-CHO-5HT was cultured in complete medium (Ham's F-12K + 10% fetal bovine serum + 1x penicillin-streptomycin + 600 μg / mL hygromycin B) under culture conditions of 37 ℃ and 5% CO2. 2b The cell lines were stabilized and maintained at 80%-90% cell confluence.

[1603] 2) Inoculate 7,500 cells / well / 25 μL of cell seeding medium (Ham's F-12K + 10% dialyzed fetal bovine serum) into 384-well cell plates and incubate overnight at 37°C and 5% CO2.

[1604] 3) Prepare 2x component A (Ca) in assay buffer (1x HBSS + 20 mM HEPES). 2+ (Probe) solution.

[1605] 4) Replace the inoculation medium in the cell plate with 20 μl / well of assay buffer.

[1606] 5) Add an equal volume of 2x component A to each well, and then incubate the cell plate at 37°C for 2 hours.

[1607] 6) Prepare a 5x working solution of the test compound in the assay buffer.

[1608] 7) Add 10 μL of the 5x compound working solution to the assay plate using FLIPR Penta and collect the fluorescence signal immediately.

[1609] 8) Use Graphpad for data processing and analysis, and calculate EC. 50 (nM).

[1610] 7.5-HT 2c FLIPR Calcium Flow Measurement Experimental Procedure

[1611] 1) Flp-In-CHO-5-HT was cultured in complete medium (Ham's F-12K + 10% fetal bovine serum + 1x penicillin-streptomycin + 600 μg / mL hygromycin B) under culture conditions of 37℃ and 5% CO2. 2c The cell lines were stabilized and maintained at 80%-90% cell confluence.

[1612] 2) Inoculate 10,000 cells / well / 25 μL of cell seeding medium (Ham's F-12K+ 10% dialyzed fetal bovine serum) into 384-well cell plates and incubate overnight at 37 ℃ and 5% CO2.

[1613] 3) Prepare 2x component A (Ca) in assay buffer (1x HBSS + 20 mM HEPES). 2+ (Probe) solution.

[1614] 4) Replace the inoculation medium in the cell plate with 20 μL / well assay buffer.

[1615] 5) Add an equal volume of 2x component A to each well, and then incubate the cell plate at 37 °C for 2 hours.

[1616] 6) Prepare a 5x working solution of the test compound in the assay buffer.

[1617] 7) Add 10 μL of the 5x compound working solution to the assay plate using FLIPR Penta and collect the fluorescence signal immediately.

[1618] 8) Use Graphpad for data processing and analysis, and calculate EC. 50 (nM).

[1619] 8.5-HT3 Radioligand Binding Determination Experimental Procedure

[1620] 1) Add 48 µL / well assay buffer (50 mM HEPES, pH 7.4, 0.1% BSA) and 2 µL / well test compound (DMSO final concentration 1%) to a 96-well deep plate, and shake at 500 rpm for 5 minutes to completely mix the reaction system.

[1621] 2) Add 99 μL of assay buffer containing 1 µL of 5-HT3 membrane protein to each well and vortex at 500 rpm for 5 minutes.

[1622] 3) Add 50 µL of [[] to each well 3 Prepare assay buffer of H]-GR65630 (final concentration 1 nM) and shake at 500 rpm for 5 minutes.

[1623] 4) Incubate the plate at 27 ℃ for 1 hour.

[1624] 5) Pre-incubate the UNIFILTER-96 GF / C filter plate with 0.5% PEI at 4 ℃ for 1 hour.

[1625] 6) Wash the UNIFILTER-96 GF / C filter plate twice with 1 mL of washing buffer (50 mM HEPES, pH 7.4) per well, and transfer the membrane mixture to the UNIFILTER-96 GF / C filter.

[1626] 7) Dry the plate at 55 ℃ for 10 minutes.

[1627] 8) Add 40 µL of ULTIMA GOLD to each well and read the CPM value using a Microbeta-2.

[1628] 9) Use Graphpad for data processing and analysis and calculate IC. 50 (nM) and Ki value.

[1629] 9.5-HT6cAMP assay procedure

[1630] 1) Dilute the 10 mM DMSO stock solution of the test compound five-fold to obtain 10 concentrations. 2) Use an Echo to transfer 20 nL / well of the test compound to a 384-well assay plate.

[1631] 3) Remove 5-HT6 cells from liquid nitrogen, revive them, and wash them twice with PBS to collect the cells.

[1632] 4) Resuspend the cells in assay buffer (1x HBSS + 20 mM HEPES) and seed 1000 cells / well / 15 μL into the assay plate prepared in step 2, and incubate at 37 °C for 30 minutes.

[1633] 5) Preparation of working solution for detection reagent: Dilute Eu-cAMP tracer to 1 / 50 with detection buffer, and dilute Ulight anti-cAMP to 1 / 150 with the same buffer.

[1634] 6) Add 5 μL of Eu-cAMP tracer and 5 μL of Ulight anti-cAMP working solution to each well and incubate at 25 °C for 1 hour.

[1635] 7) Collect data using the Envision 2105 microboard reader and HTRF module.

[1636] 8) Use Graphpad for data processing and analysis, and calculate EC. 50 (nM).

[1637] 10. Manual patch-clamp assay for the inhibition of hERG potassium ion channels by the test compound (single concentration test)

[1638] (1) Materials and instruments

[1639]

[1640] (2) Cell lines and cell culture

[1641] HEK293 cell line (catalog number: K1236) stably expressing hERG ion channels was purchased from Invitrogen. This cell line was cultured in a medium containing 85% DMEM, 10% dialyzed fetal bovine serum, 0.1 mM non-essential amino acid solution, 100 U / mL penicillin-streptomycin solution, 25 mM HEPES, 5 μg / mL blastcin, and 400 μg / mL genimycin. When the cell density reached 40%–80% of the culture dish bottom area, the cells were digested with trypsin and passaged three times per week. Before the experiment, the cells were cultured at a density of 5 × 10⁶ cells / mL. 5Cells were cultured at high density in 6 cm culture dishes, induced with 1 μg / mL doxycycline for 48 hours, then digested and seeded on slides for subsequent manual patch-clamp experiments.

[1642] (3) Solution preparation

[1643] 1) Extracellular fluid (in mM): 132 sodium chloride, 4 potassium chloride, 3 calcium chloride, 0.5 magnesium chloride, 11.1 glucose and 10 HEPES (pH adjusted to 7.35 with sodium hydroxide).

[1644] 2) Intracellular fluid (in mM): 140 potassium chloride, 2 magnesium chloride, 10 EGTA, 5 magnesium ATP and 10 HEPES (pH adjusted to 7.35 with potassium hydroxide).

[1645] Note: The osmotic pressure of the solution should be controlled between 280 and 300 mOsmol / kg. The solution needs to be filtered and stored at 4°C before use. o Store at -20°C. Prepare a 100 mM stock solution of magnesium ATP, aliquot, and store at -20°C. o Refrigerate at C. On the day of the experiment, take a certain amount and add it to the intracellular fluid; prepare and use immediately.

[1646] (4) Preparation of the solution of the compound to be tested

[1647] 1) In accordance with the standard operating procedure SOP-ADMET-MAN-007, the compound to be tested is dissolved in DMSO and prepared into a stock solution with a final concentration of 10 mM.

[1648] 2) Before the experiment, the intermediate solution of the test compound gradient was diluted again with extracellular fluid at a ratio of 1:1000 to 10 μM. The content of DMSO in the working solution was 0.1% (volume ratio).

[1649] Note: The content of DMSO in the working solution should be controlled within 1% (volume ratio) to avoid cytotoxicity.

[1650] 3) After preparing the working solution, visually inspect it for any precipitate or turbidity. If present, sonicate it in a water bath for 30 minutes to improve its solubility.

[1651] (5) Experimental steps

[1652] 1) Place the small glass slide containing HEK293 cells in the culture dish into the perfusion tank of the micromanipulation table.

[1653] 2) Using an Olympus IX51, IX71, or IX73 inverted microscope...

Claims

1. A compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof: ； in, X 1 For CR X1 Or N; X 2 For CR X2 Or N; X 3 For CR X3 Or N; R X1 R X2 and R X3 Independently -H, halogen, C1-C6 alkyl, C2-C6 alkynyl, C2-C6 alkenyl, or influenced by one or more R groups. X1-1 Substituted C1-C6 alkyl groups; R X1-1 Independent of halogen, -OH, -NR f R g Or C3-C6 cycloalkyl; R f and R g Each is independently -H or C1-C6 alkyl; R 4 It is a halogen, C1-C6 alkyl, C2-C6 alkynyl, C2-C6 alkenyl, or is oxidized by one or more R groups. 4-1 Substituted C1-C6 alkyl groups; R 4-1 Independent of halogen, -OH, -NR f R g Or C3-C6 cycloalkyl; Or, R X1 and R 4 The atoms connected to them together form C4-C7 carbon rings or 4-7 membered heterocycles. In the 4-7 membered heterocycles, the heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3. Or, R X2 and R 4 The atoms connected to them together form C4-C7 carbon rings or 4-7 membered heterocycles. In the 4-7 membered heterocycles, the heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3. for , , , or ; B is a connector, -O-, -S-, , , -NR B2 or CR B3 R B4 ; R B1 R B2 R B3 R B4 R 5 R 5’ R 6 R 7 R 9 R 10 and R 10’ Each is independently -H, C1-C6 alkyl, or surrounded by one or more R e Substituted C1-C6 alkyl groups; R 8 Independently for -H, C1-C6 alkyl or containing one or more R e Substituted C1-C6 alkyl groups; R 8-1 Independently C1-C6 alkyl, C1-C6 alkoxy, or -NR h R i ; R h and R i Each is independently -H or C1-C6 alkyl; R e Independently -OH or C1-C6 alkoxy group; Or, "R 5 and R 5’ ", "R 5 and R 6 ", "R 6 and R 7 ", "R 5 and R 8 ", "R 7 and R 8 ", "R 8 and R 9 ", "R 9 and R 10 "or "R 10 and R 10’ "The atoms connected to them together form 5-6 member saturated heterocycles or are bounded by one or more R..." d The substituted 5-6 member saturated heterocycle, wherein the heteroatoms are each independently N and / or O, and the number of heteroatoms is each independently 1 or 2. R d Independently equal to 0; Ring A is C6-C 10 Aromatic ring or 5-10 membered heteroaromatic ring, wherein the 5-10 membered heteroaromatic ring is a 5-10 membered heteroaromatic ring in which the heteroatoms are selected from one, two or three kinds of N, O and S, and the number of heteroatoms is one, two or three. R 1 for or ; R a It is a C1-C4 alkyl or C3-C4 cycloalkyl; R b -H, -CN, C1-C4 alkyl, or ; R b-1 Independently, it is a C1-C4 alkyl group; Independently -H, =O, -NR f R g -NO2, -OH, -CN, halogens, C1-C4 alkyl, C2-C4 alkynyl, C2-C4 alkenyl, C3-C4 cycloalkyl, C1-C4 alkoxy groups or those with one or more R groups 2-1 Substituted C1-C4 alkyl groups; R 2-1 Independently halogen, -OH or -NR f R g ; Or, R 1 Adjacent R 2 The atoms connected to them together form , or p and q are each independently 1, 2 or 3; m can be 1, 2, 3, 4, or 5.

2. The compound of formula (I) as claimed in claim 1, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, X 1 For CR X1 Or N; X 2 For CR X2 Or N; X 3 For CR X3 Or N; R X1 R X2 and R X3 Independently -H, halogen, C1-C6 alkyl, C2-C6 alkynyl, C2-C6 alkenyl, or influenced by one or more R groups. X1-1 Substituted C1-C6 alkyl groups; R X1-1 Independent of halogen, -OH, -NR f R g Or C3-C6 cycloalkyl; R f and R g Each is independently -H or C1-C6 alkyl; R 4 It is a halogen, C1-C6 alkyl, C2-C6 alkynyl, C2-C6 alkenyl, or is oxidized by one or more R groups. 4-1 Substituted C1-C6 alkyl groups; R 4-1 Independent of halogen, -OH, -NR f R g Or C3-C6 cycloalkyl; Or, R X1 and R 4 The atoms connected to them together form C4-C7 carbon rings or 4-7 membered heterocycles. In the 4-7 membered heterocycles, the heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3. Or, R X2 and R 4 The atoms connected to them together form C4-C7 carbon rings or 4-7 membered heterocycles. In the 4-7 membered heterocycles, the heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3. for , , , or ; B is a connector, -O-, -S-, , , -NR B2 or CR B3 R B4 ; R B1 R B2 R B3 R B4 R 5 R 5’ R 6 R 7 R 9 R 10 and R 10’ Each is independently -H, C1-C6 alkyl, or surrounded by one or more R e Substituted C1-C6 alkyl groups; R 8 Independently for -H, C1-C6 alkyl or containing one or more R e Substituted C1-C6 alkyl groups; R 8-1 Independently C1-C6 alkyl, C1-C6 alkoxy, or -NR h R i ; R h and R i Each is independently -H or C1-C6 alkyl; R e Independently -OH or C1-C6 alkoxy group; Or, "R 5 and R 5’ ", "R 5 and R 6 ", "R 6 and R 7 ", "R 7 and R 8 ", "R 8 and R 9 ", "R 9 and R 10 "or "R 10 and R 10’ "The atoms connected to them together form 5-6 member saturated heterocycles or are bounded by one or more R..." d The substituted 5-6 member saturated heterocycle, wherein the heteroatoms are each independently N and / or O, and the number of heteroatoms is each independently 1 or 2. R d Independently equal to 0; Ring A is C6-C 10 Aromatic ring or 5-10 membered heteroaromatic ring, wherein the 5-10 membered heteroaromatic ring is a 5-10 membered heteroaromatic ring in which the heteroatoms are selected from one, two or three kinds of N, O and S, and the number of heteroatoms is one, two or three. R 1 for ; R a It is a C1-C4 alkyl or C3-C4 cycloalkyl; R b -H, C1-C4 alkyl, or ; R b-1 Independently, it is a C1-C4 alkyl group; Independently -H, =O, -NR f R g -NO2, -OH, -CN, halogens, C1-C4 alkyl, C2-C4 alkynyl, C2-C4 alkenyl, C3-C4 cycloalkyl, C1-C4 alkoxy groups or those with one or more R groups 2-1 Substituted C1-C4 alkyl groups; R 2-1 Independently halogen, -OH or -NR f R g ; Or, R 1 Adjacent R 2 The atoms connected to them together form or p and q are each independently 1, 2 or 3; m can be 1, 2, 3, 4, or 5.

3. The compound of formula (I) as described in claim 1 or 2, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1) Each "halogen" is independently F, Cl, Br or I, for example F or Cl; (2) Each "C1-C6 alkyl" is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl, ethyl, n-propyl or n-butyl; (3) Each "C2-C6 ynyl group" is independently ethynyl, propynyl or propynyl, for example propynyl; (4) Each "C2-C6 alkenyl" is independently vinyl, propenyl or allyl, for example propenyl; (5) Each "C3-C6 cycloalkyl" is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl; (6) Each "C1-C6 alkoxy" is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example methoxy; (7) Each "5-6 member saturated heterocycle" is independently a tetrahydropyrrole ring or a piperidine ring, for example , or In this case, the carbon atoms marked with "*" have the configuration of R, S, or a mixture thereof, for example... , , , , , , , or ; (8) The one or more R d The substituted 5-6 membered saturated heterocycles are independently a tetrahydropyrrole ring substituted with one =O or a piperidine ring substituted with one =O, for example... or In this case, the carbon atoms marked with "*" have the configuration of R, S, or a mixture thereof, for example... , , , , or ; (9) Each "C6-C 10 Each aromatic ring can be independently a benzene ring or a naphthalene ring, for example, a benzene ring; (10) Each "5-10 membered heteroaromatic ring" is independently a 5-6 membered monocyclic heteroaromatic ring or an 8-10 membered bicyclic heteroaromatic ring, wherein each ring of the bicyclic heteroaromatic ring is aromatic or one of the rings is aromatic; for example, a pyridine ring, a pyrimidine ring, an imidazopyridine ring, a pyrrolopyridine ring, or a dihydropyridopyridine ring, for example , , , , , or ; (11) Each "C1-C4 alkyl" is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl, ethyl or isopropyl; (12) Each "C3-C4 cycloalkyl" is independently cyclopropyl or cyclobutyl, for example cyclopropyl; (13) Each "C1-C4 alkoxy" is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example methoxy.

4. The compound of formula (I) as described in claim 1 or 2, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1) for , , , , or ,For example , or ; (2) R 4 Halogen, C1-C4 alkyl, C3 alkynyl or R 4-1 It is a C3-C4 cycloalkyl group, such as Cl, methyl, n-propyl, n-butyl, or Preferred to be n-propyl, n-butyl or More preferably n-propyl; (3) One or more of the following: I: or The carbon atoms marked with "*" have the R configuration, S configuration, or a mixture thereof, for example... , , , , or Preferred , or , where R 8 for R 9 It is -H or C1-C6 alkyl; II: , , , or The carbon atoms marked with "*" have the R configuration, S configuration, or a mixture thereof, for example... , , , , , , , , , , , , , , , , , , , or For example, , , , , , , , , , , , , , or , among which, "R 5 and R 6 ", "R 6 and R 7 ", "R 7 and R 8 ", "R 8 and R 9 "or "R 9 and R 10 "The atoms connected to them together form 5-6 membered saturated heterocycles or are bounded by one or more R..." d Substituted 5-6 member saturated heterocycles; III: , or The carbon atoms marked with "*" have the R configuration, S configuration, or a mixture thereof, for example... , , , , , or R 5 and R 10 Each is independently a C1-C6 alkyl group or is composed of one or more R groups. e Substituted C1-C6 alkyl groups; IV: The carbon atoms marked with "*" have the R configuration, S configuration, or a mixture thereof, for example... , or Preferred R 10 It is a C1-C6 alkyl group; (4) Ring A is a benzene ring, a 6-membered heteroaromatic ring, or an 8-10-membered bicyclic heteroaromatic ring. In the 8-10-membered bicyclic heteroaromatic ring, each ring is aromatic or one of the rings is aromatic, for example, a benzene ring, a pyridine ring, a pyrimidine ring, an imidazopyridine ring, a pyrrolopyridine ring, a dihydropyrrolopyridine ring, or a dihydropyridopyridine ring. , , , , , , , or ; (5) R 1 for The sulfur atoms marked with "*" have the configuration of R, S, or a mixture thereof, for example... , or Or, R 1 Adjacent R 2 The atoms connected to them together form The sulfur atoms marked with "*" have the configuration of R, S, or a mixture thereof, for example... , or Where the a-end represents R 1 The b-end represents R. 2 end.

5. The compound of formula (I) as claimed in claim 1, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1) R 1 for , , , , , or The sulfur atoms marked with "*" have the configuration of R, S, or a mixture thereof, for example... , , , , , , , , , , , , , , , , , or ; (2) R 2 To be independent of -H, =O, -NH2, -NO2, -OH, -CN, -F, -Cl, -CF3, methoxy or methyl.

6. The compound of formula (I) as claimed in claim 1 or 2, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1) One or more of the following: I: , , , or The carbon atoms marked with "*" have the R configuration, S configuration, or a mixture thereof, for example... , , , , , , , , , , , , , or For example, , , , , , , , , , , , or Preferred , or ; II: , , , , or The carbon atoms marked with "*" have the R configuration, S configuration, or a mixture thereof, for example... , , , , , , , , , , , , , , , , or ; III: , or The carbon atoms marked with "*" have the R configuration, S configuration, or a mixture thereof, for example... , , , , , or ; IV: The carbon atoms marked with "*" have the R configuration, S configuration, or a mixture thereof, for example... , or Preferred ; (2) for , , , , , , , , , , or ,For example , , , or ; (3) R 1 for , , , or The sulfur atoms marked with "*" have the configuration of R, S, or a mixture thereof, for example... , , , , , , , , , , , , , or ; Or, R 1 Adjacent R 2 The atoms connected to them together form The sulfur atoms marked with "*" have the configuration of R, S, or a mixture thereof, for example... , or Where the a-end represents R 1 The b-end represents R. 2 end; (4) R 2 To be independent of -H, =O, -NH2, -NO2, -OH, -CN, -F, -Cl, methoxy or methyl, preferably -H, F, Cl, methyl or -NH2; Or, R 1 Adjacent R 2 The atoms connected to them together form The sulfur atoms marked with "*" have the configuration of R, S, or a mixture thereof, for example... , or Where the a-end represents R 1 The b-end represents R. 2 end.

7. The compound of formula (I) as claimed in any one of claims 1-6, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by formula (I) is a compound represented by formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), or (IJ): , , , , , , , , or ; Among them, the carbon atoms marked with "*" are in the R configuration, S configuration, or a mixture thereof; X is CH or N, Z is CH2, NH, O or S, and m is 0, 1 or 2; The definitions and positions of the remaining substituents are as described in any one of claims 1-6.

8. The compound of formula (I) as claimed in any one of claims 1-6, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by formula (I) is a compound represented by formula (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), or (I-8): , , , , , , or ; Where X is CH or N, and m is 0, 1 or 2; The definitions and positions of the remaining substituents are as described in any one of claims 1-6.

9. The compound of formula (I) as claimed in claim 1, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by formula (I) is any one of the following compounds: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

10. The compound of formula (I) as claimed in claim 1, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by formula (I) is any one of the following compounds: and The compound that elutes first under the following conditions: chiral column CHIRALCEL AY-H, 2 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: isopropanol; flow rate 40 mL / min; gradient: isogradient 50% B; preferably, the retention time of the compound that elutes first is 5.5 min. and Compounds eluting later under the following conditions: chiral column CHIRALCEL AY-H, 2 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: isopropanol; flow rate 40 mL / min; gradient: isogradient 50% B; preferably, the retention time of the compounds eluting later is 13.2 min. and The compound that elutes first under the following conditions: chiral column CHIRAL ART Cellulose-SZ, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the compound that elutes first is 11.0 min; and Compounds eluting later under the following conditions: chiral column CHIRAL ART Cellulose-SZ, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the compounds eluting later is 13.8 min. and The compound that elutes first under the following conditions: chiral column CHIRALPAK-IK, 3 x 25 mm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the compound that elutes first is 19.0 min. and Compounds eluting later under the following conditions: chiral column CHIRALPAK-IK, 3 x 25 mm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the compound eluting later is 24.1 min. and The compound that elutes first under the following conditions: chiral column HIRAL ART Cellulose-SB, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase ethanol; flow rate 40 mL / min; gradient: isogradient 25% B; preferably, the retention time of the compound that elutes first is 12.4 min. and Compounds eluting later under the following conditions: chiral column HIRAL ART Cellulose-SB, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase ethanol; flow rate 40 mL / min; gradient: isogradient 25% B; preferably, the retention time of the compounds eluting later is 24.1 min. A stereoisomer, wherein... The configuration of the S atom in compound A1 The S atom configuration is the same, and the compound A1 is... and The compound that elutes first under the following conditions: chiral column CHIRALPAK PAK AD-H, 30 x 250 mm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 50% B; preferably, the retention time of the compound that elutes first is 9.7 min; A stereoisomer, wherein... The configuration of the S atom in compound A2 is similar to that in compound A2. The S atom configuration is the same, and the compound A2 is... and Compounds that elute later in the column under the following conditions: Chiral column CHIRALPAK PAK AD-H, 30 x 250 mm, 5 μm; Mobile phase A: n-hexane (10 mmol / L ammonia-methanol), Mobile phase B: ethanol; Flow rate 40 mL / min; Gradient: isogradient 50% B; Preferably, the retention time of the compound that elutes later in the column is 14.2 min. and The first-eluting compound was selected under the following conditions: a chiral column CHIRAL ART Cellulose-SB, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: 30% B; preferably, the retention time of the first-eluting compound was 7.6 min. and Compounds eluting later under the following conditions: chiral column CHIRAL ART Cellulose-SB, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: 30% B; preferably, the retention time of the compounds eluting later is 11.3 min. A stereoisomer, wherein... The configuration of the S atom in compound A3 is similar to that in compound A3. The S atoms have the same configuration, and the compound A3 is... and The first-eluting compound was selected under the following conditions: a chiral column CHIRAL ART Cellulose-SB, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: 30% B; preferably, the retention time of the first-eluting compound was 7.6 min. A stereoisomer, wherein... The configuration of the S atom in compound A4 is similar to that in compound A4. The S atoms have the same configuration, and the compound A4 is... and Compounds eluting later under the following conditions: chiral column CHIRAL ART Cellulose-SB, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: 30% B; preferably, the retention time of the compounds eluting later is 11.3 min. and The compound that elutes first under the following conditions: chiral column CHIRAL ART Cellulose-SB, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the compound that elutes first is 15.1 min; and Compounds that elute later in the column under the following conditions: chiral column CHIRAL ART Cellulose-SB, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the compounds that elute later in the column is 19 min. and The compound that elutes first under the following conditions: chiral column Chiral NQ(2) 5u, 250 x 30 mm, 5 μm; mobile phase A: n-hexane (0.1% formic acid), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the compound that elutes first is 24.3 min; and Compounds that elute later in the column under the following conditions: Chiral NQ(2) 5u, 250 x 30 mm, 5 μm; mobile phase A: n-hexane (0.1% formic acid), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the compound that elutes later in the column is 28.4 min. and The compound that elutes first under the following conditions: chiral column: (S, S)-WHELK-O1, 2 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 20 mL / min; gradient: isogradient 40% B; preferably, the retention time of the compound that elutes first is 24.1 min; and Compounds eluting later under the following conditions: chiral column: (S, S)-WHELK-O1, 2 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate: 20 mL / min; gradient: isogradient 40% B; preferably, the retention time of the compound eluting later is 30.0 min; and The compound that elutes first under the following conditions: chiral column: CHIRAL ART Cellulose-SC, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol / acetonitrile = 5 / 1; flow rate: 40 mL / min; gradient: isogradient 20% B; preferably, the retention time of the compound that elutes first is 28.2 min; and Compounds eluting later under the following conditions: chiral column: CHIRAL ART Cellulose-SC, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol / acetonitrile = 5 / 1; flow rate: 40 mL / min; gradient: isogradient 20% B; preferably, the retention time of the compound eluting later is 35.3 min; and The compound that elutes first under the following conditions: chiral column CHIRAL ART Cellulose-SZ, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 40% B; preferably, the retention time of the compound that elutes first is 9.7 min; and Compounds eluting later under the following conditions: chiral column CHIRAL ART Cellulose-SZ, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 40% B; preferably, the retention time of the compounds eluting later is 12.3 min. A stereoisomer, wherein... The configuration of the S atom in compound A5 is similar to that in compound A5. The S atoms have the same configuration, and the compound A5 is... and The compound that elutes first under the following conditions: chiral column CHIRAL ART Cellulose-SZ, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 40% B; preferably, the retention time of the compound that elutes first is 9.7 min; A stereoisomer, wherein... The configuration of the S atom in compound A6 is similar to that in compound A6. The S atoms have the same configuration, and the compound A6 is... and Compounds eluting later under the following conditions: chiral column CHIRAL ART Cellulose-SZ, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 40% B; preferably, the retention time of the compounds eluting later is 12.3 min. and The compound that elutes first under the following conditions: chiral column: CHIRAL ART Cellulose-SZ, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the compound that elutes first is 13.4 min; and Compounds eluting later under the following conditions: chiral column: CHIRAL ART Cellulose-SZ, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate: 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the compounds eluting later is 17.5 min. and The compound that elutes first under the following conditions: chiral column: CHIRAL ART Cellulose-SZ, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: isopropanol; flow rate 40 mL / min; gradient: isogradient 50% B; preferably, the retention time of the compound that elutes first is 10.6 min; and Compounds eluting later under the following conditions: chiral column: CHIRAL ART Cellulose-SZ, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: isopropanol; flow rate: 40 mL / min; gradient: isogradient 50% B; preferably, the retention time of the compound eluting later is 13.7 min; and The compound that elutes first is selected under the following conditions: column: CHIRALPAK-IK, 3 x 25 mm, 5 μm; mobile phase A: carbon dioxide, mobile phase B: methanol (20 mmol / L ammonia); flow rate: 90 mL / min; gradient: isogradient 50% B; preferably, the retention time of the compound that elutes first is 8.3 min. and Compounds eluting later under the following conditions: column: CHIRALPAK-IK, 3 x 25 mm, 5 μm; mobile phase A: carbon dioxide, mobile phase B: methanol (20 mmol / L ammonia); flow rate: 90 mL / min; gradient: isogradient 50% B; preferably, the retention time of the compound eluting later is 10.2 min. A stereoisomer, wherein... The configuration of the S atom in compound A7 is similar to that in... The S atoms have the same configuration, and the compound A7 is... and The compound that elutes first is selected under the following conditions: column: CHIRALPAK-IK, 3 x 25 mm, 5 μm; mobile phase A: carbon dioxide, mobile phase B: methanol (20 mmol / L ammonia); flow rate: 90 mL / min; gradient: isogradient 50% B; preferably, the retention time of the compound that elutes first is 8.3 min. A stereoisomer, wherein... The configuration of the S atom in compound A8 The S atoms have the same configuration, and the compound A8 is... and Compounds eluting later under the following conditions: column: CHIRALPAK-IK, 3 x 25 mm, 5 μm; mobile phase A: carbon dioxide, mobile phase B: methanol (20 mmol / L ammonia); flow rate: 90 mL / min; gradient: isogradient 50% B; preferably, the retention time of the compound eluting later is 10.2 min. and The compound that elutes first under the following conditions: chiral column CHIRAL ART Cellulose-SZ, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (methanol with 10 mM ammonia), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 50% B; preferably, the retention time of the compound that elutes first is 8.8 min. and Compounds that elute later in the column were selected under the following conditions: Chiral ART Cellulose-SZ column, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (methanol with 10 mM ammonia), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 50% B; preferably, the retention time of the compounds that elute later in the column was 13.6 min. and The compound that elutes first under the following conditions: chiral column CHIRAL ART Cellulose-SZ, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (methanol with 10 mM ammonia); mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 50% B; preferably, the retention time of the compound that elutes first is 7.8 min. and Compounds that elute later in the column under the following conditions: Chiral column CHIRAL ART Cellulose-SZ, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (methanol with 10 mM ammonia); mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 50% B; preferably, the retention time of the compounds that elute later in the column is 9.9 min. and The compound that elutes first under the following conditions: chiral column CHIRALCEL AY-H, 2 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol); mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 50% B; preferably, the retention time of the compound that elutes first is 3.6 min. and Compounds that elute later in the column were selected under the following conditions: chiral column CHIRALCEL AY-H, 2 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol); mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 50% B; preferably, the retention time of the compounds that elute later in the column was 6.8 min. and The first eluting compound was selected under the following conditions: Chiral NX(2) chiral column, 250 x 30 mm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol); mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 40% B; preferably, the retention time of the first eluting compound was 10.1 min. and Compounds that elute later in the column under the following conditions: Chiral NX(2), 250 x 30 mm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol); mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 40% B; preferably, the retention time of the compounds that elute later in the column is 14.0 min. and The compound that elutes first under the following conditions: chiral column CHIRAL ART Cellulose-SZ, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 50% B; preferably, the retention time of the compound that elutes first is 6.7 min; and Compounds that elute later in the column under the following conditions: chiral column CHIRAL ART Cellulose-SZ, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 50% B; preferably, the retention time of the compounds that elute later in the column is 11.0 min. and The compound that elutes first under the following conditions: chiral column CHIRALPAK IA, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the compound that elutes first is 16.1 min; and Compounds that elute later in the column were selected under the following conditions: chiral column CHIRALPAK IA, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the compounds that elute later in the column was 21.6 min. , , and The first eluting compound was selected under the following conditions: chiral column Enantiocel-A4-5, 3.0 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the first eluting compound was 11.5 min. , , and The second eluting compound was selected under the following conditions: chiral column Enantiocel-A4-5, 3.0 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the second eluting compound was 17.0 min. , , and The third eluting compound was selected under the following conditions: chiral column Enantiocel-A4-5, 3.0 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the compound with the third eluting peak was 21.2 min. , , and The substance that elutes second under condition A is further separated from the compound that elutes first under condition B. Condition A is: Enantiocel-A4-5 chiral column, 3.0 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the substance that elutes second is 17.0 min. Condition B is: CHIRALPAK IH column, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the compound that elutes first is 16.8 min. , , and The compound that elutes the second peak under condition A is further separated under condition B. Condition A is: Enantiocel-A4-5 chiral column, 3.0 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the second peak is 17.0 min. Condition B is: CHIRALPAK IH 3 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the subsequent peak is 23.5 min. and The first-eluting compound was selected under the following conditions: chiral column Lux 5um Cellulose-4 3×25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 50% ethanol; preferably, the retention time of the first-eluting compound was 11.8 min. and Compounds eluting later under the following conditions: chiral column Lux 5um Cellulose-4 3×25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 50% ethanol; preferably, the retention time of the compounds eluting later is 14.5 min. , , and The first eluting substance under the following conditions: chiral column CHIRALPAK-IK, 3.0 × 25 mm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the first eluting substance is 7.8 min; , , and The second eluting substance was obtained under the following conditions: chiral column CHIRALPAK-IK, 3.0 × 25 mm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the second eluting substance was 17.0 min. , , and The substance that elutes first under condition A is further separated into its initial peaks under condition B. Condition A is as follows: chiral column CHIRALPAK-IK, 3.0 × 25 mm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the first elute is 7.8 min. Condition B is as follows: chiral column CHIRALPAK IH, 3 × 25 cm, 5 μm; mobile phase A: carbon dioxide, mobile phase B: 20 ​​mmol / L ammonia-methanol; flow rate 100 mL / min; gradient: isogradient 35% 20 mmol / L ammonia-methanol solution; preferably, the retention time of the initial elute is 3.9 min. , , and The substance that elutes first under condition A is further separated under condition B, and the resulting elutes are the substances that elute after further separation. Condition A is: chiral column CHIRALPAK-IK, 3.0 × 25 mm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the first elute is 7.8 min. Condition B is: chiral column CHIRALPAK IH, 3 × 25 cm, 5 μm; mobile phase A: carbon dioxide, mobile phase B: 20 ​​mmol / L ammonia-methanol; flow rate 100 mL / min; gradient: isogradient 35% 20 mmol / L ammonia-methanol solution; preferably, the retention time of the subsequent elutes is 5.2 min. , , and The substance that elutes first under condition A is further separated under condition B, and the substance that elutes next under condition C is further separated from the first elute under condition C. Condition A is: chiral column CHIRALPAK-IK, 3.0 × 25 mm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the first elute is 7.8 min. Condition B is: chiral column CHIRALPAK IH, 3 × 25 cm, 5 μm; mobile phase A: carbon dioxide, mobile phase B: 20 ​​mmol / L ammonia-methanol; flow rate 100 mL / min; gradient: isogradient 35% 20 mmol / L ammonia-methanol solution; preferably, the retention time of the subsequent elute is 5.2 min. Condition C is: chiral column CHIRALPAK IH, 3 × 25 cm, 5 μm; Mobile phase A: carbon dioxide, mobile phase B: 20 ​​mmol / L ammonia-isopropanol; flow rate 80 mL / min; gradient: isogradient 50% B; preferably, the retention time of the first eluting substance further separated under condition C is 5.8 min; , , and The substance that elutes first under condition A, is further separated under condition B, and then further separated under condition C. Condition A is: chiral column CHIRALPAK-IK, 3.0 × 25 mm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the first elute is 7.8 min. Condition B is: chiral column CHIRALPAK IH, 3 × 25 cm, 5 μm; mobile phase A: carbon dioxide, mobile phase B: 20 ​​mmol / L ammonia-methanol; flow rate 100 mL / min; gradient: isogradient 35% 20 mmol / L ammonia-methanol solution; preferably, the retention time of the subsequent elutes is 5.2 min. Condition C is: chiral column CHIRALPAK IH, 3 × 25 cm, 5 μm; Mobile phase A: carbon dioxide, mobile phase B: 20 ​​mmol / L ammonia-isopropanol; flow rate 80 mL / min; gradient: isogradient 50% B; preferably, the retention time of the substance eluting after further separation under condition C is 7.2 min; and The compound that elutes first under the following conditions: chiral column Lux 5u Cellulose-2 30 × 250 mm, 5.0 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% ethanol; preferably, the retention time of the compound that elutes first is 17.7 min. and Compounds eluting later under the following conditions: chiral column Lux 5u Cellulose-2 30 × 250 mm, 5.0 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% ethanol; preferably, the retention time of the compound eluting later is 22.4 min. and The first eluting compound was selected under the following conditions: chiral column Lux 5um Cellulose-4, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; gradient: isogradient 50% B; preferably, the retention time of the first eluting compound was 8.8 min. and Compounds eluting later under the following conditions: chiral column Lux 5um Cellulose-4, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; gradient: isogradient 50% B; preferably, the retention time of the compound eluting later is 11.7 min. and The first eluting compound was selected under the following conditions: chiral column CHIRALPAK AD-H, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: isopropanol; flow rate: 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the first eluting compound was 7.7 min. and Compounds eluting later under the following conditions: chiral column CHIRALPAK AD-H, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: isopropanol; flow rate: 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the compound eluting later is 12.8 min; , , and The first eluting compound was selected under the following conditions: chiral column CHIRAL ARTCellulose-SC, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate: 40 mL / min; gradient: isogradient 50% B; preferably, the retention time of the first eluting compound was 7.9 min. , , and The second eluting compound was obtained under the following conditions: chiral column CHIRAL ARTCellulose-SC, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate: 40 mL / min; gradient: isogradient 50% B; preferably, the retention time of the second eluting compound was 9.6 min. , , and The third eluting compound was observed under the following conditions: a chiral column CHIRAL ARTCellulose-SC, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate: 40 mL / min; gradient: isogradient 50% B; preferably, the retention time of the third eluting compound was 11.6 min. , , and The fourth eluting compound was observed under the following conditions: a chiral column CHIRAL ARTCellulose-SC, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate: 40 mL / min; gradient: isogradient 50% B; preferably, the retention time of the fourth eluting compound was 24.2 min. , , and The substance that elutes first under condition A is further separated into its initial peaks under condition B. Condition A is as follows: chiral column CHIRALPAK IN 3, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (0.5% in 2 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the first elute is 15.9 min. Condition B is as follows: chiral column CHIRALPAK IH, 3.0 × 50 mm, 3 μm; mobile phase A: carbon dioxide, mobile phase B: 20 ​​mM ammonia-methanol; flow rate 100 mL / min; gradient: isogradient 30% B; preferably, the retention time of the first elute is 3.12 min. , , and The substance that elutes first under condition A is further separated under condition B, and the substance that elutes after further separation is described in condition A as follows: chiral column CHIRALPAK IN 3, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (0.5% in 2 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the first elute is 15.9 min. Condition B is described as follows: chiral column CHIRALPAK IH, 3.0 × 50 mm, 3 μm; mobile phase A: carbon dioxide, mobile phase B: 20 ​​mM ammonia-methanol; flow rate 100 mL / min; gradient: isogradient 30% B; preferably, the retention time of the subsequent elute is 4.10 min. , , and The substance that elutes second under condition A is further separated from the substance that elutes first under condition C. Condition A is: chiral column CHIRALPAK IN 3, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (0.5% in 2 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the substance that elutes second is 25.4 min. Condition C is: chiral column CHIRALPAK IH, 3.0 × 50 mm, 3 μm; mobile phase A: carbon dioxide, mobile phase B: 20 ​​mM ammonia-methanol; flow rate 100 mL / min; gradient: isogradient 30% B; preferably, the retention time of the substance that elutes first is 3.0 min. , , and The substance that elutes second under condition A is further separated under condition C, and the resulting elute is the substance with the second peak. Condition A is: chiral column CHIRALPAK IN 3, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (0.5% in 2 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the second elute is 25.4 min. Condition C is: chiral column CHIRALPAK IH, 3.0 × 50 mm, 3 μm; mobile phase A: carbon dioxide, mobile phase B: 20 ​​mM ammonia-methanol; flow rate 100 mL / min; gradient: isogradient 30% B; preferably, the retention time of the subsequent elute is 4.10 min. , , and The substance that elutes first under condition A is further separated under condition B. Condition A is: chiral column Enantiocel-A4-5, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (0.5% 2M ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 50% B; preferably, the retention time of the substance that elutes first under condition A is 8.9 min. Condition B is: chiral column CHIRALPAK AY, 3.0 × 50 mm, 3 μm; mobile phase A: n-hexane (0.5% 2M ammonia-methanol), mobile phase B: ethanol / acetonitrile (5 / 1); flow rate 40 mL / min; gradient: isogradient 40% B; preferably, the retention time of the substance that elutes first under condition B is 5.4 min. , , and The substance that elutes first under condition A is further separated under condition B, and the substance that elutes second under condition C is further separated under condition C. Condition A is: chiral column Enantiocel-A4-5, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (0.5% 2M ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 50% B; preferably, the retention time of the substance that elutes first under condition A is 8.9 min. Condition B is: chiral column CHIRALPAK AY, 3.0 × 50 mm, 3 μm; mobile phase A: n-hexane (0.5% 2M ammonia-methanol), mobile phase B: ethanol / acetonitrile (5 / 1); flow rate 40 mL / min; gradient: isogradient 40% B; preferably, the retention time of the substance that elutes second under condition B is 10.2 min; condition C is a chiral column CHIRALPAK... ID, 3.0 × 50 mm, 3 μm; Mobile phase A: n-hexane (20 mM ammonia-methanol), Mobile phase B: ethanol; Flow rate 40 mL / min; Gradient: isogradient 30% B; Preferably, the retention time of the first eluting substance further separated under condition C is 21 min; , , and The substance that elutes first under condition A, is further separated into a second peak under condition B, and then further separated under condition C. Condition A is: chiral column Enantiocel-A4-5, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (0.5% 2M ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 50% B; preferably, the retention time of the first elute under condition A is 8.9 min. Condition B is: chiral column CHIRALPAK AY, 3.0 × 50 mm, 3 μm; mobile phase A: n-hexane (0.5% 2M ammonia-methanol), mobile phase B: ethanol / acetonitrile (5 / 1); flow rate 40 mL / min; gradient: isogradient 40% B; preferably, the retention time of the second elute after separation under condition B is 10.2 min; condition C is a chiral column CHIRALPAK... ID, 3.0 × 50 mm, 3 μm; Mobile phase A: n-hexane (20 mM ammonia-methanol), Mobile phase B: ethanol; Flow rate 40 mL / min; Gradient: isogradient 30% B; Preferably, the retention time of the substance eluting after further separation under condition C is 28.3 min; , , and The substance that elutes the second peak under condition A, wherein condition A is: chiral column Enantiocel-A4-5, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (0.5% 2M ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 50% B; preferably, the retention time of the substance that elutes the second peak under condition A is 13.9 min; , , and The substance that elutes first under condition A is further separated into its initial peaks under condition B. Condition A is as follows: column type: Lux 5um Cellulose-4, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (0.5% 2M ammonia-methanol), mobile phase B: ethanol; flow rate: 40 mL / min; gradient: isogradient 30%B; preferably, the retention time of the substance that elutes first under condition A is 16.3 min. Condition B is as follows: chiral column: CHIRALPAKID, 3.0 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate: 40 mL / min; gradient: isogradient 50%B; preferably, the retention time of the substance that elutes first under condition B is 9.0 min. , , and The substance that elutes first under condition A is further separated under condition B, where condition A is: column type Lux 5um Cellulose-4, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (0.5% 2M ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the substance that elutes first under condition A is 16.3 min. Condition B is: chiral column CHIRALPAKID, 3.0 × 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 50% B; preferably, the retention time of the substance that elutes after further separation under condition B is 11.9 min. , , and The substance that elutes second under condition A, wherein condition A is: column type Lux5um Cellulose-4, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (0.5% 2M ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the substance that elutes second under condition A is 22.4 min; , , and The substance that elutes third under condition A, wherein condition A is: column type Lux5um Cellulose-4, 3 × 25 cm, 5 μm; mobile phase A: n-hexane (0.5% 2M ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isogradient 30% B; preferably, the retention time of the substance that elutes third under condition A is 28.4 min.

11. A pharmaceutical composition comprising a compound of formula (I) as claimed in any one of claims 1-10, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

12. The use of the compound of formula (I) as claimed in any one of claims 1-10, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as claimed in claim 11 in the preparation of a 5-hydroxytryptamine 4 (5-HT4) receptor agonist.

13. The use of the compound of formula (I) as described in any one of claims 1-10, its pharmaceutically acceptable salt, its solvate, a solvate of its pharmaceutically acceptable salt, or the pharmaceutical composition as described in claim 11 in the preparation of a medicament for the prevention and / or treatment of diseases associated with serotonin 4 receptors, such as gastrointestinal motility disorders or gastrointestinal diseases, such as gastroesophageal reflux disease (GERD), constipation, irritable bowel syndrome (IBS), dyspepsia, postoperative intestinal obstruction, delayed gastric emptying, gastroparesis, pseudo-intestinal obstruction, drug-induced transit delay, or diabetic gastric atony.

14. The use of the compound of formula (I) as described in any one of claims 1-10, its pharmaceutically acceptable salt, its solvate, a solvate of its pharmaceutically acceptable salt, or the pharmaceutical composition as described in claim 11 in the preparation of a medicament for the prevention and / or treatment of a disease, wherein the disease is a gastrointestinal motility disorder or a gastrointestinal disease, such as gastroesophageal reflux disease (GERD), constipation, irritable bowel syndrome (IBS), dyspepsia, postoperative intestinal obstruction, delayed gastric emptying, gastroparesis, pseudo-intestinal obstruction, drug-induced transit delay, or diabetic gastric atony.

Images