Heteroaromatic amine compound, pharmaceutical composition thereof and use thereof

Abstract

Disclosed in the present invention are a heteroaromatic amine compound, a pharmaceutical composition thereof and the use thereof. Specifically, disclosed are a compound represented by formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof. The compound of the present invention has one or more of the following advantages: (1) excellent agonistic activity on 5-hydroxytryptamine 4 receptor; (2) good selective agonistic activity on 5-hydroxytryptamine 4 receptor; (3) capability of significantly reducing the risk of cardiotoxicity caused by hERG channel suppression; and (4) excellent intestinal tissue selectivity and low system exposure, which can reduce the safety risk of the circulatory system.

Description

Heteroaromatic amine compounds, pharmaceutical compositions thereof and uses thereof

[0001] This application claims priority to Chinese Patent Application No. 2024113070114, filed on September 19, 2024, and Chinese Patent Application No. 2025113041633, filed on September 12, 2025. This application incorporates the entirety of the above-mentioned Chinese Patent Applications. TECHNICAL FIELD

[0002] The present application relates to heteroaromatic amine compounds, pharmaceutical compositions thereof and uses thereof. BACKGROUND

[0003] Serotonin (5-HT) receptors are a group of G protein-coupled receptors and ligand-gated ion channels that are present in the central nervous system and peripheral nervous system. To date, seven serotonin (5-HT) receptors, 5HT1, 5HT2, 5HT3, 5HT4, 5HT5, 5HT6 and 5HT7, have been discovered. Except for 5HT3 receptor, which is a ligand-gated ion channel, the other six belong to G protein-coupled receptors. Since 5HT4 receptor (FASEB Journal 1996, 10, 1398-1407) was discovered in 1988, it has attracted the attention of many pharmaceutical companies as a target for new drug development. In addition to the central nervous system, peripheral nervous system and cardiovascular system, 5HT4 receptors are also widely present in the gastrointestinal system.

[0004] Several selective 5-HT4 receptor agonists and antagonists have been developed for the treatment of peripheral diseases such as irritable bowel syndrome, gastroparesis, urinary system diseases urinary incontinence and cardiac arrhythmia. 5-HT4 receptor has been a target for drug development in the treatment of chronic constipation and enteric syndrome associated with constipation. Known disclosed 5-HT4 receptor agonists include cisapride (US 4,962,115), prucalopride (EP 0445862) and tegaserod (US 5,510,353) and the like. These compounds can stimulate gastrointestinal peristalsis to achieve the purpose of treating constipation. However, since most of these compounds lack high selectivity for 5-HT4 receptors, such as lack of selectivity for 5-HT family 5-HT1 and 5-HT2 receptors, the risk of side effects generated in clinical use cannot be ignored. In addition to lacking selectivity for 5-HT family such as 5-HT1 and 5-HT2 receptors, there is also a lack of inhibition selectivity for channels or transporters such as human ether-a-go-go-related gene (hERG). The lack of inhibition selectivity for hERG channels can lead to adverse side effects observed in clinical practice, such as cardiovascular side effects. In recent years, the drug development field has chosen to evaluate the inhibitory properties of drugs on the hERG channel before proceeding to in vivo animal experiments, which helps to avoid the discovery of safety risks in the cardiovascular system after the drug enters the later clinical trials. SUMMARY

[0005] The technical problem to be solved by the present application is to provide a heteroaromatic amine compound with a novel structure, a pharmaceutical composition thereof and an application thereof, in view of the lack of 5-hydroxytryptamine 4 receptor agonists in the prior art. The compound of the present application has one or more of the following advantages: (1) excellent agonistic activity on 5-hydroxytryptamine 4 receptor; (2) weak inhibitory activity on hERG.

[0006] The present application solves the above technical problem by the following technical scheme.

[0007] The present application provides a compound as shown in formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof:

[0008] wherein,

[0009] R 1 -S(=O)2R m or -S(=O)R m ;

[0010] R m is independently C1-C6 alkyl, C3-C6 cycloalkyl, substituted with one or more Rm1 Substituted C1-C6 alkyl groups or those with one or more R m1 Substituted C3-C6 cycloalkyl groups;

[0011] R m1 It is a halogen;

[0012] for

[0013] R 2 R X4 and R X6 Independently -H, halogen, -NR f R g C1-C6 alkyl or C1-C6 alkyl substituted with one or more halogens;

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

[0015] R X5 Independently -H, halogen, -NR f R g C1-C6 alkyl or C1-C6 alkyl substituted with one or more halogens;

[0016] Or, R m R X5 Together with the intermediary atoms connected to them, they form

[0017] m1 is 1 or 2;

[0018] m2 can be 0, 1, 2, 3, 4, 5, or 6;

[0019] R 4 It is a C1-C6 alkyl group;

[0020] Ring A is a 5, 6, or 7-membered monocyclic saturated heterocycle; or a 6, 7, 8, or 9-membered bicyclic saturated heterocycle; in addition to the N atom attached to it, ring A also contains 0, 1, or 2 O atoms.

[0021] R N and Connected to the same ring atom, or, R N and They are respectively attached to two adjacent ring atoms;

[0022] R N It is -H, -OH, halogen, C1-C6 alkyl, or formed by one or more R groups. e Substituted C1-C6 alkyl groups;

[0023] R e Independently -OH, C1-C6 alkoxy, -S-C1-C6 alkyl, or -NR e1 R e2 ;

[0024] R e1 and R e2 Each is independently -H or C1-C6 alkyl;

[0025] R 8a -H;

[0026] or,

[0027] R N R 8a Together with the intermediary atoms they are connected to, they form a ring B or are bounded by one or more R atoms. s1 Replaced ring B;

[0028] Ring B is a 4, 5, or 6-membered monocyclic saturated heterocycle; in addition to the N atom attached to it, ring B also contains 0, 1, or 2 O atoms.

[0029] R s1 Independently, it is either =O or C1-C6 alkyl;

[0030] R 8b -H, C1-C6 alkyl, C3-C6 cycloalkyl, -C(=O)R 8-1 -S(=O)2R 8-1 , by one or more R 8-2 Substituted C1-C6 alkyl groups or those with one or more R 8-2 Substituted C3-C6 cycloalkyl groups;

[0031] R 8-1 Independently C1-C6 alkyl or composed of one or more R 8-1a Substituted C1-C6 alkyl groups;

[0032] R 8-1a Independently -OH or halogen;

[0033] R 8-2 Independently -OH or halogen;

[0034] n is 0, 1, 2, or 3;

[0035] R M Independently -OH, halogen, C1-C6 alkyl, or surrounded by one or more R e Substituted C1-C6 alkyl groups.

[0036] In certain preferred embodiments of the application, certain groups in the compounds of Formula (I), pharmaceutically acceptable salts thereof, solvates thereof, or solvates of the pharmaceutically acceptable salts of the compounds of Formula (I) are defined as follows: groups not mentioned are as described in any of the Schemes of the application (simply "in a Scheme of the application").

[0037] In a Scheme of the application, each "C1-C6alkyl" and "substituted C1-C6alkyl" is independently methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, n-butyl, or t-butyl, preferably methyl, ethyl, or i-propyl.

[0038] In a Scheme of the application, each "C3-C6cycloalkyl" and "substituted C3-C6cycloalkyl" is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, for example cyclopropyl.

[0039] In a Scheme of the application, each "halogen" is independently F, Cl, Br, or I, for example F or Cl.

[0040] In a Scheme of the application, each "C1-C6alkoxy" is independently methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, n-butoxy, or t-butoxy, preferably methoxy.

[0041] In a Scheme of the application, in ring A, the "5-membered monocyclic saturated heterocyclic ring" is

[0042] In a Scheme of the application, in ring A, the "6-membered monocyclic saturated heterocyclic ring" is

[0043] In a Scheme of the application, in ring A, the "7-membered monocyclic saturated heterocyclic ring" is

[0044] In a Scheme of the application, in ring A, the "6-membered bicyclic saturated heterocyclic ring" is The configuration of the carbon atom marked "*" is independently R, S, or a mixture thereof, and the "6-membered bicyclic saturated heterocyclic ring" is, for example,

[0045] In a Scheme of the application, in ring A, the "7-membered bicyclic saturated heterocyclic ring" is The configuration of the carbon atom marked "*" is independently R, S, or a mixture thereof, and the "7-membered bicyclic saturated heterocyclic ring" is, for example,

[0046] In a Scheme of the application, in ring A, the "8-membered bicyclic saturated heterocyclic ring" is

[0047] In a preferred embodiment of the present application, in ring B, the "4-membered monocyclic saturated heterocycle" is the configuration of the carbon atom marked "*" is R-configuration, S-configuration or a mixture thereof, and the "4-membered monocyclic saturated heterocycle" is, for example,

[0048] In a preferred embodiment of the present application, in ring B, the "5-membered monocyclic saturated heterocycle" is the configuration of the carbon atom marked "*" is independently R-configuration, S-configuration or a mixture thereof, and the "5-membered monocyclic saturated heterocycle" is, for example,

[0049] In a preferred embodiment of the present application, in ring B, the "6-membered monocyclic saturated heterocycle" is the configuration of the carbon atom marked "*" is independently R-configuration, S-configuration or a mixture thereof, and the "6-membered monocyclic saturated heterocycle" is, for example,

[0050] In a preferred embodiment of the present application, R 1 is -S(=O)2R m .

[0051] In a preferred embodiment of the present application, R m is C1-C6 alkyl, C3-C6 cycloalkyl or C1-C6 alkyl substituted by one or more R m1 , for example -CH3, -CH2CH3, -CH(CH3)2, -CF3 or preferably -CH3.

[0052] In a preferred embodiment of the present application, is preferably

[0053] In a preferred embodiment of the present application, R 2 is independently -H, halogen or -NR f R g , for example -H, -NH2 or -Cl.

[0054] In a preferred embodiment of the present application, R X4 is independently -H or halogen, for example -H, -Cl or -F, further for example H.

[0055] In a preferred embodiment of the present application, R X6independently -H, -Cl, -F, -CH3, -NH2, or -CHF2, for example H.

[0056] In one embodiment of the application, R X5 independently -H, -Cl, -F, -CH3, -NH2, or -CHF2,

[0057] or, R m , R X5 and the intervening atoms to which they are attached collectively form

[0058] In one embodiment of the application, is R X5 is halogen, -NR f R g , C1-C6 alkyl or C1-C6 alkyl substituted with one or more halogens, R 2 is -H, halogen or -NR f R g , R X4 is -H or halogen; preferably, R X5 is C1-C6 alkyl, R 2 is -H, R X4 is -H.

[0059] In one embodiment of the application, R 4 is

[0060] In one embodiment of the application, is preferably the configuration of the carbon atom marked with an “*” is independently in the R configuration, the S configuration, or a mixture thereof;

[0061] R 5 , R 5’ , R 6 , R 7 , R 9 , R 10 , R 10’ , R 11 and R 11’ are each independently H, -OH, halogen, C1-C6 alkyl or C1-C6 alkyl substituted with one or more R e ;

[0062] R e is independently -OH, C1-C6 alkoxy, -S-C1-C6 alkyl or -NR e1 R e2 ;

[0063] R e1 and R e2 each independently H or C1-C6 alkyl;

[0064] or, "R 7 and R 9 ", "R 5 and R 9 ", "R 7 and R 10 ", or "R 9 and R 10 " are joined to form -(CH2) 1-2 -;

[0065] R 8a is H;

[0066] or, "R 8a and R 9 " or "R 8a and R 10 ", together with the intervening atoms to which they are attached, form a ring B or ring B substituted with one or more R s1 ;

[0067] ring B is a 4-, 5-, or 6-membered monocyclic saturated heterocyclic ring; in ring B, in addition to the attached N atom, 0, 1, or 2 O atoms are additionally included;

[0068] R s1 independently =O or C1-C6 alkyl;

[0069] R 8b is -H, C1-C6 alkyl, C3-C6 cycloalkyl, -C(=O)R 8-1 , -S(=O)2R 8-1 , C1-C6 alkyl substituted with one or more R 8-2 or C3-C6 cycloalkyl substituted with one or more R 8-2 ;

[0070] R 8-1 independently C1-C6 alkyl or C1-C6 alkyl substituted with one or more R 8-1a ;

[0071] R 8-1a independently -OH or halogen;

[0072] R 8-2 independently -OH or halogen;

[0073] B 1 and B 2 each independently a bond, -O-, or -CR B3 RB4 -;

[0074] R B3 and R B4 are each independently H, -OH, halogen, C1-C6alkyl or C1-C6alkyl substituted with one or more R e .

[0075] In one embodiment of the application, R 5 is H, or, "R 5 and R 9 " are joined to form -(CH2) 1-2 -, preferably H.

[0076] In one embodiment of the application, R 5’ is H.

[0077] In one embodiment of the application, R 6 is H, -OH or halogen, for example -H, -F or -OH, preferably H.

[0078] In one embodiment of the application, R 7 is H or halogen (for example H or F, preferably H); or,

[0079] "R 7 and R 9 " or "R 7 and R 10 " are joined to form -(CH2)1-2-;

[0080] R 7 is preferably H.

[0081] In one embodiment of the application, B 1 is a bond, -O or -CH2-, preferably a bond.

[0082] In one embodiment of the application, B 2 is a bond or -CH2-, preferably a bond.

[0083] In one embodiment of the application, R 8b is -H, C1-C6alkyl, C3-C6cycloalkyl, -C(=O)R 8-1 , -S(=O)2R 8-1 or C1-C6alkyl substituted with one or more R 8-2 , preferably -C(=O)R 8-1 .

[0084] In one embodiment of the application, R 8-1 is C1-C6alkyl.

[0085] In one embodiment of the application, R8b -H, preferably for example

[0086] In certain embodiments of the application, R 8a -H,

[0087] R 9 -H or -Ci-C6alkyl;

[0088] or, "R 9 and R 7 " or "R 9 and R 5 " are joined to form -(CH2) 1-2 -;

[0089] R 10 is H, Ci-C6alkyl or Ci-C6alkyl substituted with one or more R e ; or,

[0090] "R 10 and R 9 " are joined to form -(CH2) 1-2 -;

[0091] R e is independently -OH or Ci-C6alkoxy;

[0092] R 10’ is -H.

[0093] In certain embodiments of the application,

[0094] R 8a and R 10 , together with the intervening atoms to which they are attached, form a ring B or a ring B substituted with one or more R s1 ;

[0095] R s1 is independently Ci-C6alkyl;

[0096] R 9 is -H;

[0097] R 10’ is -H.

[0098] In certain embodiments of the application,

[0099] R 8a and R 9 , together with the intervening atoms to which they are attached, form a ring B or a ring B substituted with one or more R s1 ;

[0100] R s1 independently =0;

[0101] R 10 is -H

[0102] R 10’ is -H.

[0103] in a certain embodiment of the present application, R 11 is -H.

[0104] in a certain embodiment of the present application, R 11’ is -H.

[0105] in a certain embodiment of the present application, is n1 is 0, 1 or 2, preferably 0;

[0106] is preferably is further preferably the configuration of the carbon atom marked "*" is the R configuration, the S configuration or a mixture thereof;

[0107] wherein the definitions of the substituents are independently as described in any of the embodiments of the present application.

[0108] in a certain embodiment of the present application, R 9 is H or CrC6alkyl, for example H or -CH3, preferably H;

[0109] in a certain embodiment of the present application, R 10 is H, CrC6alkyl or CrC6alkyl substituted by one or more R e for example H, -CH3, is preferably H;

[0110] in a certain embodiment of the present application, R s1 is CrC6alkyl, for example methyl.

[0111] in a certain embodiment of the present application, is wherein the definitions of the substituents are independently as described in any of the embodiments of the present application.

[0112] preferably, R 8a is hydrogen and R 8b is CrC6alkyl.

[0113] in a certain embodiment of the present application, is wherein the carbon atom marked with an asterisk is in the R configuration, the S configuration, or a mixture thereof;

[0114] preferably

[0115] wherein R 8b is as defined in any of the aspects of the application.

[0116] In an aspect of the application, is

[0117] In an aspect of the application, the compound of formula (I) is a compound of formula (I-1):

[0118] wherein the definitions of the substituents are independently as defined in any of the aspects of the application.

[0119] Preferably, in formula (I-1),

[0120] B 1 is a bond, -O- or -CR B3 R B4 -;

[0121] R B3 and R B4 are each independently H, C1-C6 alkyl or C1-C6 alkyl substituted with one or more R e ;

[0122] R e is independently -OH, C1-C6 alkoxy, -S-C1-C6 alkyl or -NR e1 R e2 ;

[0123] R e1 and R e2 are each independently -H or C1-C6 alkyl;

[0124] R 8a is H;

[0125] R 8 b is -C(=O)R 8-1 , -S(=O)2R 8-1 or

[0126] R 8-1 is independently C1-C6 alkyl or C1-C6 alkyl substituted with one or more R 8-1a ;

[0127] R 8-1a independently -OH;

[0128] R 5 , R 5 , R 6 , R 7 , R 9 , R 10 and R 10 each independently H, C1-C6 alkyl, C1-C6 alkyl substituted with one or more R e ;

[0129] R 1 is -S(=O)2R m ;

[0130] R m is C1-C6 alkyl;

[0131] R 2 , R X4 and R X5 each independently H, halogen, -NR f R g , C1-C4 alkyl or C1-C4 alkyl substituted with one or more halogen;

[0132] R f and R g each independently H or C1-C6 alkyl;

[0133] R 4 is C1-C4 alkyl.

[0134] In one embodiment of the present application, the compound of formula (I-1) is a compound of formula (I-1-1): 1 is a bond.

[0135] In one embodiment of the present application, the compound of formula (I-1) is a compound of formula (I-1-1):

[0136] wherein the carbon atom marked with “*” has the R configuration, the S configuration or a mixture thereof.

[0137] In one embodiment of the present application, the compound of formula (I-1) is a compound of formula (I-1-1): 8-1 is methyl, ethyl or hydroxymethyl.

[0138] In one embodiment of the present application, the compound of formula (I-1) is a compound of formula (I-1-1): e is methoxy.

[0139] In one embodiment of the present application, the compound of formula (I-1) is a compound of formula (I-1-1):1 For

[0140] In one embodiment of the application, in the compound of formula (I-1), R 2 , R X4 and R X5 are each independently H, -F, -Cl, -NH2, -NHCH3, or methyl.

[0141] In one embodiment of the application, the compound of formula (I) is a compound of formula (I-2), (I-3), (I-4) or (I-5):

[0142] wherein the definitions of the substituents are independently as described in any of the embodiments of the application.

[0143] Preferably, in the compound of formula (I-2), (I-3), (I-4) or (I-5),

[0144] B 1 is a bond, -O- or -CR B3 R B4 -;

[0145] R B3 and R B4 are each independently H, C1-C6 alkyl or C1-C6 alkyl substituted with one or more R e ;

[0146] R e is independently -OH, C1-C6 alkoxy, -S-C1-C6 alkyl or -NR e1 R e2 ;

[0147] R e1 and R e2 are each independently -H or C1-C6 alkyl;

[0148] R 8-1 is independently C1-C6 alkyl or C1-C6 alkyl substituted with one or more R 8-1a ;

[0149] R 8-1a is independently -OH;

[0150] R 5 , R 5’ , R 6 , R 7 , R 9 , R 10 and R 10’each independently H, C1-C6alkyl, C1-C6alkyl substituted with one or more R e substituted C1-C6alkyl;

[0151] R 1 is -S(=O)2R m ;

[0152] R m is C1-C6alkyl;

[0153] R 2 , R X4 , R X5 and R X6 each independently H, halogen, -NR f R g , C1-C4alkyl or C1-C4alkyl substituted with one or more halogen;

[0154] R f and R g each independently H or C1-C6alkyl;

[0155] R 4 is C1-C4alkyl.

[0156] In an embodiment of the present application, in the compound of formula (I-2), (I-3), (I-4) or (I-5), B 1 is a bond.

[0157] In an embodiment of the present application, the compound of formula (I-3) is a compound of formula (I-3-1):

[0158] wherein the carbon atom marked with “*” has R configuration, S configuration or a mixture thereof.

[0159] In an embodiment of the present application, in the compound of formula (I-2), (I-3), (I-4) or (I-5), R 8-1 is independently methyl, ethyl or hydroxymethyl.

[0160] In an embodiment of the present application, in the compound of formula (I-2), (I-3), (I-4) or (I-5), R 1 is

[0161] In an embodiment of the present application, in the compound of formula (I-2), (I-3), (I-4) or (I-5), R 2 , R X4 , R X5 and R X6each independently H, -F, -CI, -NH2, -NHCH3, or methyl.

[0162] In one embodiment of the application, the compound of formula (I) is a compound of formula (I-6):

[0163] wherein the definitions of the substituents are independently as described in any of the embodiments of the application.

[0164] Preferably, in formula (I-6),

[0165] R 8-1 is independently C1-C6 alkyl or C1-C6 alkyl substituted by one or more R 8-1a ;

[0166] R 8-1a is independently -OH;

[0167] R 9 is C1-C6 alkyl or C1-C6 alkyl substituted by one or more R e ;

[0168] R e is independently -OH, C1-C6 alkoxy, -S-C1-C6 alkyl or -NR e1 R e2 ;

[0169] R e1 and R e2 are each independently -H or C1-C6 alkyl;

[0170] R 1 is -S(=0)2R m ;

[0171] R m is C1-C6 alkyl;

[0172] R 2 , R X4 , R X5 and R X6 are each independently H, halogen, -NR f R g , C1-C4 alkyl or C1-C4 alkyl substituted by one or more halogen;

[0173] R f and R g are each independently H or C1-C6 alkyl;

[0174] R 4 is C1-C4 alkyl.

[0175] In an embodiment of the present application, in the compound of formula (I-6), R 1 is

[0176] In an embodiment of the present application, in the compound of formula (I-6), R 2 , R X4 , R X5 and R X6 are each independently H, -F, -Cl, -NH2, -NHCH3, or methyl.

[0177] In an embodiment of the present application, in the compound of formula (I-6), R 9 is C1-C6 alkyl, for example methyl.

[0178] In an embodiment of the present application, in the compound of formula (I-6), is

[0179] In an embodiment of the present application, the compound of formula (I) is selected from any one of the following compounds:

[0180] The present application also provides a pharmaceutical composition comprising a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, as described in any one of the above embodiments, and a pharmaceutically acceptable excipient.

[0181] The present application also provides use of a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition, as described in any one of the above embodiments, in the manufacture of a 5-hydroxytryptamine 4 (5-HT4) receptor agonist.

[0182] The present application also provides use of a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition, as described in any one of the above embodiments, in the manufacture of a medicament for preventing and / or treating a disease associated with 5-hydroxytryptamine 4 receptor, for example, a gastrointestinal motility dysfunction, further for example, gastroesophageal reflux disease (GERD), constipation, irritable bowel syndrome (IBS), dyspepsia, postoperative ileus, delayed gastric emptying, gastroparesis, pseudo-obstruction, drug-induced transit delay, or diabetic gastroparesis.

[0183] The present application also provides a use of the compound of formula (I), the pharmaceutically acceptable salt thereof, the solvate thereof, the solvate of the pharmaceutically acceptable salt thereof or the pharmaceutical composition as described in any of the above aspects in the preparation of a medicament for preventing and / or treating gastrointestinal motility dysfunction, preferably, the gastrointestinal motility dysfunction is gastroesophageal reflux disease (GERD), constipation, irritable bowel syndrome (IBS), dyspepsia, postoperative ileus, delayed gastric emptying, gastroparesis, pseudo-obstruction, drug-induced transit delay or diabetic gastroparesis.

[0184] As will be understood by those skilled in the art, the use of means that the corresponding group is attached to the rest of the molecule by this site.

[0185] As used herein, a substituent group can be preceded by a single dash "-" to indicate that the named substituent is attached to the parent moiety by a single bond. A substituent group can be preceded by a double dash "==" to indicate that the named substituent is attached to the parent moiety by a double bond.

[0186] The term "alkyl" refers to a straight or branched chain saturated hydrocarbon group having the indicated number of carbon atoms. In some embodiments, the alkyl group is C 1-6 alkyl, e.g., C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl, C 1-2 alkyl, etc. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, sec-butyl, n-pentyl, n-hexyl, and the like.

[0187] The term "alkyl" refers to a straight or branched chain saturated hydrocarbon group having the indicated number of carbon atoms. In some embodiments, the alkyl group is C 1-6 alkyl, e.g., C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl, C 1-2 alkyl, etc. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, sec-butyl, n-pentyl, n-hexyl, and the like.

[0188] The term "alkoxy" refers to the group -O-R X where R X is alkyl as defined above.

[0189] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0190] The term "saturated heterocycle" refers to a saturated cyclic group having the specified number of ring atoms (e.g., 4-, 5-, 6-, 7-, 8-, 9-membered), the specified number of heteroatoms (e.g., 1, 2, or 3), and the specified type of heteroatoms (in addition to N, O atoms can also be present).

[0191] The term "pharmaceutically acceptable salt" refers to those salts of the compounds of the present application which are relatively non-toxic, pharmaceutically acceptable salts derived from pharmaceutically acceptable acids or bases. When the compounds of the present application contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the pharmaceutically acceptable base in a pure solution or in a suitable inert solvent. When the compounds of the present application contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the pharmaceutically acceptable acid in a pure solution or in a suitable inert solvent.

[0192] The term "solvate" refers to a compound in combination with a solvent (a substance formed by the combination of a solvent and a solute. Solvates are classified into stoichiometric solvates and non-stoichiometric solvates.

[0193] The term "solvate of a pharmaceutically acceptable salt" refers to a compound in combination with a pharmaceutically acceptable acid or base, a solvent. The amount of solvent can be stoichiometric or non-stoichiometric.

[0194] The term "pharmaceutically acceptable excipient" refers to excipients and additives used in the manufacture of pharmaceutical products and the formulation of prescriptions, which are all substances contained in pharmaceutical preparations other than active ingredients. Please refer to the Pharmacopoeia of the People's Republic of China (2020 Edition) Volume IV, or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).

[0195] The term "prevention" refers to a reduction in the risk of acquiring or developing a disease or disorder.

[0196] The term "treatment" refers to therapeutic treatment. In reference to a particular condition, treatment refers to: (1) relieving one or more of the signs or symptoms of the disease or condition, (2) interfering with (a) one or more points in a biological cascade that leads to or causes the condition or (b) one or more of the biological manifestations of the condition, (3) ameliorating one or more symptoms, effects, or side effects associated with the condition or one or more symptoms, effects, or side effects associated with treatment of the condition, or (4) slowing the development of the condition or one or more of the biological manifestations of the condition.

[0197] In the application, the agonist drug can be used in vivo in a mammal; it can also be used in vitro, mainly for experimental purposes, such as providing a standard or control sample for comparison, or being prepared into a kit according to the conventional method in the art for rapid detection of the agonistic effect of the 5-hydroxytryptamine 4 receptor.

[0198] On the basis of common knowledge in the art, the above-mentioned preferred conditions can be combined arbitrarily, thereby obtaining various preferred examples of the present application.

[0199] The reagents and raw materials used in the present application are commercially available.

[0200] On the basis of common knowledge in the art, the above-mentioned preferred conditions can be combined arbitrarily, thereby obtaining various preferred examples of the present application.

[0201] The reagents and raw materials used in the present application are commercially available.

[0202] The positive progress effect of the present application is that the compound of the present application has one or more of the following advantages:

[0203] (1) The compound of the present application has excellent agonistic activity on the 5-hydroxytryptamine 4 receptor;

[0204] (2) The compound of the present application has good selective agonistic activity on the 5-hydroxytryptamine 4 receptor;

[0205] (3) The compound of the present application can significantly reduce the risk of cardiotoxicity caused by hERG channel inhibition;

[0206] (4) The compound of the present application has excellent intestinal tissue selectivity and low systemic exposure, thereby reducing the safety risk of the circulatory system. DETAILED DESCRIPTION

[0207] The present application will be further described by way of examples below, but the present application is not limited to the scope of the examples described. The experimental methods in the following examples, for which no specific conditions are indicated, are selected according to conventional methods and conditions, or according to the instructions of the goods.

[0208] Example 1:

[0209] Preparation of (S)-N-(1-(4-(4-amino-5-chloro-6-(methylsulfonyl)pyridin-2-ylamino)-6- propylpyridin-2-ylpyrrolidin-3-yl)acetamide (Compound 1)

[0210] Step 1:

[0211] Compound 1-1 (1.00 g, 5.1 mmol; CAS: 874491-78-8, purchased directly from Jinan Qiyebio- tech Co., Ltd.) and cuprous iodide (289 mg, 1.52 mmol), sodium methanesulfinate (1.03 g, 10.1 mmol), cesium carbonate (495 mg, 1.52 mmol) and L-proline (174 mg, 1.52 mmol) were dissolved in dimethyl sulfoxide (12 mL) at room temperature under nitrogen atmosphere. The reaction system was heated to 130 °C under nitrogen atmosphere, then stirred at this condition for 4 hours. The reaction progress was monitored by liquid chromatography-mass spectrometry. After the reaction was completed, the reaction mixture was filtered, and the filtrate was directly purified by reverse phase column C18. The purification conditions were as follows: 80 g C18 reverse phase column; mobile phase: acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate: 60 mL / min; gradient: acetonitrile increased from 5% to 60% in 30 minutes; detection wavelength: 254 nm. After confirmation by liquid chromatography-mass spectrometry, the fraction of the product was collected, concentrated under reduced pressure and lyophilized to obtain 220 mg of compound 1-2 (white solid, yield 18%).

[0212] MS (ESI, m / z): [M+H] + = 241.05 / 243.05.

[0213] Step 2:

[0214] Compound 1-2 (200 mg, 0.83 mmol) was dissolved in tetrahydrofuran (2 mL) at room temperature, then di-tert-butyl dicarbonate (362.3 mg, 1.66 mmol) and 4-dimethylaminopyridine (50.0 mg, 0.41 mmol) were added to the above reaction solution. The reaction system was heated to 60 °C, then stirred at this condition for 15 hours. The reaction progress was monitored by liquid chromatography-mass spectrometry. After the reaction was completed, the reaction system was concentrated under reduced pressure. The residue was directly purified by silica gel column (eluent: petroleum ether / ethyl acetate = 8 / 1), and the obtained fraction was concentrated under reduced pressure to obtain 200 mg of compound 1-3 (white solid, yield 54%).

[0215] MS (ESI, m / z): [M+H] + = 441.05 / 443.00 / 445.05.

[0216] 1 H NMR (400MHz, CDCl3) δ 7.43 (s, 1H), 3.43 (s, 3H), 1.45 (s, 18H).

[0217] Step 3:

[0218] The starting material 1-4 (20.0 g, 104 mmol, CAS: 25194-01-8; directly purchased from the supplier Shanghai Bide Pharmaceutical Technology Co., Ltd.) was dissolved in dichloromethane (300 mL) at 0°C, and then 1-5 (19.3 g, 104 mmol; CAS: 122536-76-9, directly purchased from the supplier Shanghai Shaoyuan Technology Co., Ltd.) and N, N-diisopropyl ethylamine (40.3 g, 312 mmol) were added to the above reaction solution in turn. After the addition was completed, the reaction system was removed from the ice bath, the temperature was naturally increased to room temperature, and stirring was performed under this condition for 4 hours. The reaction progress was monitored by liquid chromatography. After the reaction was completed, the reaction system was concentrated under reduced pressure. The residue was directly purified by silica gel column (eluent: petroleum ether / ethyl acetate = 5 / 1), and the obtained fraction was concentrated under reduced pressure to obtain 7.00 g of compound 1-6 (yellow solid, yield 20%).

[0219] MS (ESI, m / z): [M+H] + = 343.15 / 345.10.

[0220] 1 H NMR (400 MHz, CDCl3) δ 7.21 (d, J = 1.6 Hz, 1H), 6.93 (d, J = 1.6 Hz, 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).

[0221] Step 4:

[0222] Compound 1-6 (7.00 g, 20.5 mmol) was dissolved in 1,4-dioxane (80 mL) at room temperature under nitrogen atmosphere, then n-propylboronic acid (1.80 g, 20.5 mmol), 1,1'- bis(diphenylphosphino)ferrocenedichloropalladium complex (1.50 g, 2.05 mmol) and potassium carbonate (8.49 g, 61.5 mmol) were added successively into the above reaction solution. The reaction system was heated to 100 °C and stirred at this temperature for 16 hours. The reaction progress was monitored by LC-MS. After the reaction was completed, the reaction system was cooled to room temperature naturally, moved to ice bath and quenched with water (200 mL) at 0 °C. Extracted with ethyl acetate (300 mL x 3), the combined organic phase was washed with saturated sodium chloride aqueous solution (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was directly purified by silica gel column (eluent: petroleum ether / ethyl acetate = 4 / 1) to give 6.00 g of compound 1-7 (yellow solid, yield 84%).

[0223] MS (ESI, m / z): [M+H] + = 351.20.

[0224] 1 H NMR (400 MHz, CDC13) δ 7.07 (d, J = 1.6 Hz, 1H), 6.85 (d, J = 1.6 Hz, 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).

[0225] Step 5:

[0226] Compound 1-7 (6.00 g, 17.1 mmol) was dissolved in dichloromethane (70 mL) at 0 °C, then trifluoroacetic acid (10 mL) was added slowly dropwise into the above reaction solution. After the addition was completed, the reaction system was moved out of the ice bath, the temperature was naturally increased to room temperature and stirred at this temperature for 5 hours. The reaction progress was monitored by LC-MS. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to give 6.3 g of trifluoroacetate salt of compound 1-8 (brown oil, yield 101%, crude).

[0227] MS (ESI, m / z): [M-CF3COOH+H] += 251.20.

[0228] Step 6:

[0229] Compound 1-8 trifluoroacetate (6.3 g, 17.3 mmol) was dissolved in dichloromethane (65 mL) at 0 °C, then acetic anhydride (0.8 g, 8.0 mmol) and triethylamine (5.2 g, 52 mmol) were added into the above solution respectively. After the addition was completed, the reaction system was removed from the ice bath, the temperature was naturally increased to room temperature and stirred for 2 hours under this condition. The reaction progress was monitored by liquid chromatography-mass spectrometry. After the reaction was completed, the reaction system was directly concentrated under reduced pressure, and the residue was directly purified by silica gel column (eluent: dichloromethane / methanol = 10 / 1). The product fraction was collected and concentrated under reduced pressure to obtain 5.0 g of compound 1-9 (red solid, yield 99%).

[0230] MS (ESI, m / z): [M+H] + = 293.10.

[0231] Step 7:

[0232] Compound 1-9 (5.0 g, 17.1 mmol) was dissolved in ethanol (50 mL) and water (12 mL) at room temperature, and ammonium chloride (4.57 g, 85.5 mmol) and iron powder (4.78 g, 85.5 mmol) were added into the above reaction solution respectively. The reaction system was heated at 80 °C and stirred for 1 hour. The reaction progress was monitored by liquid chromatography-mass spectrometry. After the reaction was completed, the reaction system was naturally cooled to perform filtration, the filter cake was washed with methanol (100 mL x 2), and the filtrate and methanol washing liquid were combined and concentrated under reduced pressure. The obtained residue was directly purified by silica gel column (eluent: dichloromethane / methanol = 10 / 1). The obtained fraction was concentrated under reduced pressure to obtain 3.10 g of compound 1-10 (orange red solid, yield 69%).

[0233] MS (ESI, m / z): [M+H] + = 263.20.

[0234] 1H NMR (400 MHz, DMSO-d6) δ 8.08 (d, J = 6.8 Hz, 1H), 5.71 (d, J = 1.6 Hz, 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).

[0235] Step 8:

[0236] Step 8: To a solution of 1-10 (100 mg, 0.38 mmol) and 1-3 (143 mg, 0.33 mmol) in 1,4-dioxane (1 mL) was added successively tris(dibenzylideneacetone)dipalladium (60 mg, 0.06 mmol), cesium carbonate (215 mg, 0.66 mmol) and 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl (50 mg, 0.12 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was heated to 100 °C and stirred at this temperature for 8 h. The reaction progress was monitored by LC-MS. After completion of the reaction, the reaction mixture was allowed to cool to room temperature and filtered. The filter cake was washed with methanol (15 mL x 3). The combined washings and filtrate were concentrated under reduced pressure. The residue was purified by reverse phase C18 column. The purification conditions were as follows: 80 g C18 reverse phase column; mobile phase: acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate: 25 mL / min; gradient: acetonitrile increased from 5% to 95% in 45 min; detection wavelength: 254 nm. The product fractions were collected, concentrated under reduced pressure and lyophilized to give 75 mg of compound 1-11 (yellow solid, yield 35%).

[0237] MS (ESI, m / z): [M+H] + = 667.20 / 669.15.

[0238] Step 9:

[0239] According to the synthesis method of Step 5 in Example 1, the starting material was replaced with compound 1-11 (60 mg, 0.10 mmol) accordingly. After the reaction was completed, it was purified by preparative liquid chromatography. The purification conditions were as follows: column type X Bridge Prep OBD C18 Column 30 x 150 mm, 5 μm; mobile phase acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate 60 mL / min; gradient acetonitrile from 17% to 34% in 10 min, then 34% acetonitrile for 10 min; detection wavelength 254 nm / 220 nm, retention time 11.8 min. The product fractions were collected, concentrated under reduced pressure and lyophilized to obtain 20.0 mg of compound 1 (white solid, yield 48%).

[0240] MS (ESI, m / z): [M+H] + = 467.20 / 469.15.

[0241] 1 H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.10 (d, J = 6.8 Hz, 1H), 6.72 (s, 2H), 6.58 (d, J = 1.6 Hz, 1H), 6.53 (d, J = 1.6 Hz, 1H), 6.37 (s, 1H), 4.32-4.23 (m, 1H), 3.62-3.53 (m, 1H), 3.49-3.37 (m, 2H), 3.32 (s, 3H), 3.23-3.15 (m, 1H), 2.42 (t, J = 7.6 Hz, 2H), 2.16-2.07 (m, 1H), 1.89-1.80 (m, 1H), 1.81 (s, 3H), 1.68-1.58 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H).

[0242] Examples 2a and 2b:

[0243] N-((S)-1-(4-((4-amino-5-chloro-6-((R or S)-methylsulfinyl)pyridin-2-yl)amino)-6- propylpyridin-2-yl)pyrrolidin-3-yl)acetamide (compound 2a);

[0244] Preparation of N-((S)-1-(4-((4-amino-5-chloro-6-((S or R)-methylsulfinyl)pyridin-2- yl)amino)-6-propylpyridin-2-yl)pyrrolidin-3-yl)acetamide (compound 2b)

[0245] Step 1:

[0246] Compound 1-1 (3.0 g, 15.2 mmol; CAS: 874491-78-8, which can be directly purchased from Jinan Qiyebio Pharmaceutical Technology Co., Ltd.) was dissolved in N, N-dimethylformamide (60 mL) and water (24 mL) at room temperature, and then sodium methanethiolate (1.17 g, 16.7 mmol) was added to the above reaction solution. The reaction system was stirred at 120 °C for 15 hours. The reaction progress was monitored by liquid chromatography-mass spectrometry. After the reaction was completed, the reaction solution was cooled to room temperature, then poured into water (100 mL), and after standing, filtered, and the filter cake was further purified by silica gel column (eluent: petroleum ether / ethyl acetate = 4 / 1), and the obtained fraction was concentrated under reduced pressure to obtain 2.0 g of compound 2-1 (red solid, yield 63%).

[0247] MS (ESI, m / z): [M+H] + = 209.10 / 211.10 / 213.05.

[0248] 1 H NMR (400 MHz, CDCl3) δ 6.42 (s, 1H), 2.54 (s, 3H).

[0249] Step 2:

[0250] According to the synthesis method of Step 2 in Example 1, the raw materials were replaced with compound 2-1 (2.0 g, 9.61 mmol) to prepare 2.80 g of compound 2-2 (red liquid, yield 71%).

[0251] MS (ESI, m / z): [M-Boc+H] + = 309.15 / 311.05 / 313.15.

[0252] 1 H NMR (400 MHz, CDCl3) δ 6.92 (s, 1H), 2.58 (s, 3H), 1.43 (s, 18H).

[0253] Step 3:

[0254] Compound 2-2 (500 mg, 1.22 mmol) was dissolved in dichloromethane (5 mL) at 0 °C, then m-chloroperoxybenzoic acid (211 mg, 1.22 mmol) was added into the above solution in batches. The reaction system was stirred at room temperature for 3 hours. The reaction was monitored by liquid chromatography-mass spectrometry. After the reaction was completed, the reaction system was neutralized to pH 10-11 with saturated aqueous sodium bicarbonate solution at 0 °C, then extracted with ethyl acetate (30 mL x 3), the combined organic phase was washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was directly purified by silica gel column (eluent: petroleum ether / ethyl acetate = 2 / 1) to give 175 mg of compound 2-3 (racemic, white solid, yield 33%).

[0255] MS (ESI, m / z): [M+H] + = 425.00 / 427.00 / 429.05.

[0256] 1 H NMR (400 MHz, CDCI3) d 7.37 (s, 1 H), 2.90 (s, 3 H), 1.44 (s, 18 H).

[0257] Step 4:

[0258] According to the synthetic method of Step 8 in Example 1, the raw materials were replaced by compound 2-3 (288 mg, 0.67 mmol) and compound 1-10 (160 mg, 0.61 mmol) to give 222 mg of compound 2-4 (white solid, yield 50%).

[0259] MS (ESI, m / z): [M+H] + = 651.30 / 653.30.

[0260] 1H NMR (400 MHz, CDC13) δ 7.41 (d, J = 3.2 Hz, 1H), 7.29 (s, 1H), 6.81 - 6.74 (m, 1H), 6.59 - 6.53 (m, 1H), 5.87 - 5.71 (m, 1H), 4.65 - 4.56 (m, 1H), 3.80 - 3.70 (m, 1H), 3.62 - 3.51 (m, 2H), 3.50 - 3.43 (m, 1H), 2.86 (d, J = 3.2 Hz, 3H), 2.62 (t, J = 7.6 Hz, 2H), 2.37 - 2.24 (m, 1H), 2.06 - 1.97 (m, 4H), 1.82 - 1.68 (m, 2H), 1.46 (s, 18H), 0.99 (t, J = 7.2 Hz, 3H).

[0261] Step 5:

[0262] According to the synthesis method of Step 5 in Example 1, with the raw material corresponding replaced by compound 2-4 (180 mg, 0.27 mmol), 62 mg of compound 2 (diastereoisomer mixture, white solid, yield 51%) was prepared.

[0263] MS (ESI, m / z): [M+H] + = 451.25 / 453.20.

[0264] 1 H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 8.12 (d, J = 6.4 Hz, 1H), 6.86 (s, 1H), 6.78 - 6.71 (m, 4H), 4.33 - 4.24 (m, 1H), 3.61 - 3.52 (m, 1H), 3.49 - 3.34 (m, 2H), 3.22 - 3.15 (m, 1H), 2.75 (s, 3H), 2.43 (t, J = 7.6 Hz, 2H), 2.19 - 2.06 (m, 1H), 1.92 - 1.79 (m, 4H), 1.71 - 1.57 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H).

[0265] Step 6:

[0266] The diastereomeric mixture 2 (62 mg, 0.13 mmol) was subjected to chiral resolution. Resolution conditions were as follows: chiral column CHIRALART 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: isocratic 30% B; detection wavelength 240 / 250 nm; retention time 7.9 min for the fore peak fraction, which was concentrated under reduced pressure and lyophilized to give 22 mg of optically pure compound 2a (white solid, yield 35%); retention time 10.6 min for the back peak fraction, which was concentrated under reduced pressure and lyophilized to give 20 mg of optically pure compound 2b (white solid, yield 32%).

[0267] Compound 2a:

[0268] MS (ESI, m / z): [M+H] + = 451.25 / 453.25.

[0269] 1 H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 1H), 8.12 (d, J = 6.4 Hz, 1H), 6.86 (s, 1H), 6.79-6.70 (m, 4H), 4.35-4.24 (m, 1H), 3.61-3.52 (m, 1H), 3.49-3.33 (m, 2H), 3.23-3.15 (m, 1H), 2.75 (s, 3H), 2.43 (t, J = 7.6 Hz, 2H), 2.19-2.06 (m, 1H), 1.91-1.82 (m, 1H), 1.81 (s, 3H), 1.72-1.57 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H).

[0270] Compound 2b:

[0271] MS (ESI, m / z): [M+H] + = 451.25 / 453.25.

[0272] 1H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 1H), 8.12 (d, J = 6.4 Hz, 1H), 6.86 (s, 1H), 6.78 - 6.69 (m, 4H), 4.34 - 4.23 (m, 1H), 3.61 - 3.52 (m, 1H), 3.49 - 3.33 (m, 2H), 3.23 - 3.15 (m, 1H), 2.75 (s, 3H), 2.43 (t, J = 7.6 Hz, 2H), 2.19 - 2.06 (m, 1H), 1.91 - 1.82 (m, 1H), 1.81 (s, 3H), 1.71 - 1.56 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H).

[0273] Examples 3a and 3b:

[0274] (S or R)-N-(1-(4-((4-amino-5-fluoro-6-(methylsulfonyl)pyridin-2-yl)amino)-6- propylpyridin-2-yl)piperidin-3-yl)acetamide (Compound 3a); and

[0275] (R or S)-N-(1-((4-(4-amino-5-fluoro-6-(methylsulfonyl)pyridin-2-yl)amino)-6- propylpyridin-2-yl)piperidin-3-yl)acetamide (Compound 3b)

[0276] Step 1:

[0277] According to the synthesis method of Step 1 in Example 1, 300 mg of Compound 3-2 (brown solid, yield 12%) was prepared by replacing the starting material with Compound 3-1 (2.00 g, 11.0 mmol; CAS: 2051921-49-2, directly purchased from Shanghai Hauhon Biotech Co., Ltd.) accordingly.

[0278] MS (ESI, m / z): [M+H] + = 225.05 / 227.05.

[0279] Step 2:

[0280] Compound 3-2 (300 mg, 1.34 mmol), 4-dimethylaminopyridine (16 mg, 0.13 mmol), triethylamine (0.4 g, 4.02 mmol) and di-tert-butyl dicarbonate (0.7 g, 3.35 mmol) were dissolved in tetrahydrofuran (3 mL) at 0 °C, the reaction system was removed from the ice bath, the temperature was naturally increased to room temperature, and stirred at this condition for 2 hours. The reaction progress was monitored by liquid chromatography-mass spectrometry. After the reaction was completed, the reaction mixture was directly concentrated under reduced pressure, and the obtained residue was directly purified by silica gel column (eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain 260 mg of compound 3-3 (brown solid, yield 45%).

[0281] MS (ESI, m / z): [M+H] + = 425.00 / 427.00.

[0282] 1 H NMR (400 MHz, CDCI3) δ 7.44 (d, J = 4.4 Hz, 1 H), 3.36 (s, 3 H), 1.48 (s, 18 H).

[0283] Step 3:

[0284] According to the synthetic method of Step 4 in Example 1, the raw materials were replaced with compound 3-4 (15.0 g, 77.7 mmol) to prepare 4.0 g of compound 3-5 (yellow liquid, yield 26%).

[0285] 1 H NMR (400 MHz, CDCI3) δ 7.44 (d, J = 4.4 Hz, 1 H), 3.36 (s, 3 H), 1.48 (s, 18 H).

[0286] Step 4:

[0287] According to the synthetic method of Step 8 in Example 1, the raw materials were replaced with compound 3-5 (1.06 g, 5.30 mmol) and compound 3-6 (1.5 g, 10.5 mmol; CAS: 5810-55-9, directly purchased from Shanghai Lixi'ai Chemical Industry Development Co., Ltd.) to prepare 1.5 g of compound 3-7 (yellow solid, yield 92%).

[0288] MS (ESI, m / z): [M+H] + = 307.10.

[0289] MS (ESI, m / z): [M+H]1 H NMR (400 MHz, CDC13) δ 7.18 (d, J = 1.6 Hz, 1H), 7.11 (d, J = 1.6 Hz, 1H), 5.80 (d, J = 7.6 Hz, 1H), 4.15 - 4.04 (m, 1H), 3.86 - 3.77 (m, 1H), 3.73 - 3.63 (m, 1H), 3.63 - 3.48 (m, 2H), 2.70 (t, J = 7.6 Hz, 2H), 1.97 (s, 3H), 1.96 - 1.85 (m, 1H), 1.84 - 1.63 (m, 5H), 0.97 (t, J = 7.2 Hz, 3H).

[0290] Step 5:

[0291] According to the synthetic method of Step 7 in Example 1, with corresponding replacement of raw materials by compound 3-7 (1.5 g, 4.90 mmol), 1.0 g of compound 3-8 (yellow solid, yield 74%) was prepared.

[0292] MS (ESI, m / z): [M+H] + = 277.20.

[0293] 1 H NMR (400 MHz, CDC13) δ 6.55 (d, J = 7.2 Hz, 1H), 5.89 (d, J = 1.6 Hz, 1H), 5.78 (d, J = 1.6 Hz, 1H), 4.10 - 4.00 (m, 3H), 3.80 - 3.71 (m, 1H), 3.71 - 3.61 (m, 1H), 3.35 - 3.20 (m, 2H), 2.54 - 2.46 (m, 2H), 1.95 (s, 3H), 1.91 - 1.81 (m, 1H), 1.76 - 1.64 (m, 4H), 1.61 - 1.54 (m, 1H), 0.95 (t, J = 7.2 Hz, 3H).

[0294] Step 6:

[0295] According to the synthetic method of Step 8 in Example 1, with corresponding replacement of raw materials by compound 3-8 (110 mg, 0.39 mmol) and compound 3-3 (169 mg, 0.39 mmol), 230 mg of compound 3-9 (brown solid, yield 88%) was prepared.

[0296] MS (ESI, m / z): [M+H] + = 665.30.

[0297] Step 7:

[0298] According to the synthetic method of Step 5 in Example 1, by replacing the starting materials with compound 3-9 (230 mg, 0.34 mmol) accordingly, 60.1 mg of compound 3 (racemate, white solid, yield 38%) was prepared.

[0299] MS (ESI, m / z): [M+H] + = 465.20.

[0300] Step 8:

[0301] Chiral resolution of racemate 3 (60 mg, 0.13 mmol) was performed with the following resolution 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; flow rate 40 mL / min; gradient: isocratic 20% B; detection wavelength 270 / 240 nm; the front peak fraction was obtained with a retention time of 18.1 min, and 43.7 mg of optically pure compound 3a (white solid, yield 73%) was obtained after concentration under reduced pressure and lyophilization; the back peak fraction was obtained with a retention time of 26.1 min, and 10.2 mg of optically pure compound 3b (white solid, yield 17%) was obtained after concentration under reduced pressure and lyophilization.

[0302] Compound 3a:

[0303] MS (ESI, m / z): [M+H] + = 465.25.

[0304] 1 H NMR (400 MHz, DMSO-d6) δ 9.13 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.08 (d, J = 1.6 Hz, 1H), 6.65 (s, 2H), 6.62-6.59 (m, 1H), 6.39 (d, J = 5.6 Hz, 1H), 4.13-4.05 (m, 1H), 4.04-3.97 (m, 1H), 3.71-3.60 (m, 1H), 3.28 (s, 3H), 2.86-2.75 (m, 1H), 2.67-2.57 (m, 1H), 2.42 (t, J = 7.6 Hz, 2H), 1.88-1.79 (m, 4H), 1.75-1.68 (m, 1H), 1.71-1.56 (m, 2H), 1.51-1.44 (m, 1H), 1.44-1.30 (m, 1H), 0.89 (t, J = 7.2 Hz, 3H).

[0305] 19F NMR (377 MHz, DMSO-d6) d -154.12.

[0306] Compound 3b:

[0307] MS (ESI, m / z): [M+H] + = 465.25.

[0308] 1 H NMR (400 MHz, DMSO-d6) d 9.13 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.08 (d, J = 1.6 Hz, 1H), 6.65 (s, 2H), 6.62 - 6.59 (m, 1H), 6.39 (d, J = 5.6 Hz, 1H), 4.13 - 4.05 (m, 1H), 4.04 - 3.97 (m, 1H), 3.74 - 3.56 (m, 1H), 3.27 (s, 3H), 2.85 - 2.75 (m, 1H), 2.67 - 2.57 (m, 1H), 2.42 (t, J = 7.6 Hz, 2H), 1.88 - 1.79 (m, 4H), 1.75 - 1.68 (m, 1H), 1.68 - 1.56 (m, 2H), 1.51 - 1.44 (m, 1H), 1.44 - 1.30 (m, 1H), 0.89 (t, J = 7.2 Hz, 3H).

[0309] 19 F NMR (377 MHz, DMSO-d6) d -154.12.

[0310] Example 4:

[0311] Preparation of (S)-N-(l-(4-((5-chloro-6-(methylsulfonyl)pyridin-2-yl)amino)-6- propylpyridin-2-yl)pyrrolidin-3-yl)acetamide (Compound 4)

[0312] Step 1:

[0313] According to the synthetic method of Step 1 in Example 1, with raw material corresponding replaced by compound 4-1 (5.0 g, 27.4 mmol; CAS: 29154-14-1, directly purchased from Shanghai Titan Technology Co., Ltd.), 840 mg of compound 4-2 (brown solid, yield 14%) was prepared.

[0314] MS (ESI, m / z): [M+H] + = 225.90 / 227.90 / 229.85.

[0315] 1H NMR (400 MHz, CDC13) δ 7.86 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 3.41 (s, 3H).

[0316] Step 2:

[0317] According to the synthetic method of Step 8 in Example 1, the starting materials were replaced with compound 1-10 (150 mg, 0.57 mmol) and compound 4-2 (185 mg, 0.82 mmol). After the reaction was completed, purification was performed by preparative liquid chromatography. The purification conditions were as follows: column type X Bridge Shield OBD C18 Column 30 x 150 mm, 5 μm; mobile phase acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate 60 mL / min; gradient acetonitrile from 29% to 59% in 10 min; detection wavelength 254 nm / 220 nm, retention time 6.5 min. The product fractions were collected and concentrated under reduced pressure to prepare 33.7 mg of compound 4 (white solid, yield 13%).

[0318] MS (ESI, m / z): [M+H] + = 452.20 / 454.15.

[0319] 1 H NMR (400 MHz, DMSO-d6) δ 9.76 (s, 1H), 8.13 (d, J = 6.8 Hz, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.13 (d, J = 8.8 Hz, 1H), 6.80 (d, J = 1.6 Hz, 1H), 6.58 (d, J = 1.6 Hz, 1H), 4.33-4.25 (m, 1H), 3.65-3.56 (m, 1H), 3.51-3.43 (m, 1H), 3.42 (s, 3H), 3.41-3.37 (m, 1H), 3.27-3.19 (m, 1H), 2.46 (t, J = 7.6 Hz, 2H), 2.19-2.05 (m, 1H), 1.91-1.82 (m, 1H), 1.81 (s, 3H), 1.72-1.58 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H).

[0320] Examples 5a and 5b:

[0321] 2-((3aR or 3aS, 6aR or 6aS)-4-(4-((5-fluoro-6-(methylsulfonyl)pyridin-2-yl)amino)-6- propylpyridin-2-yl)hexahydropyrrolo[3,2-b]pyrrol-l(2H)-yl)ethanol-l-ol (Compound 5a); and

[0322] 2-((3aS or 3aR, 6aS or 6aR)-4-(4-((5-fluoro-6-(methylsulfonyl)pyridin-2-yl)amino)-6- propylpyridin-2-yl)hexahydropyrrolo[3,2-b]pyrrol-l(2H)-yl)ethanol-l-ol compound (Compound 5b)

[0323] Step 1:

[0324] Compound 5-1 (1.06 g, 4.98 mmol; CAS: 885277-81-6, directly purchased from Shanghai Carl Chemical Co., Ltd.) and compound 3-5 (1.00 g, 4.98 mmol) were dissolved in 1,4-dioxane (15 mL) at room temperature under nitrogen atmosphere. To the above solution, catalyst dichloro[l,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridinyl)palladium(II) (395 mg, 0.5 mmol) and cesium carbonate (4.9 g, 15 mmol) were added respectively. The reaction system was heated to 100 °C, then stirred at this condition for 3 hours. The reaction progress was monitored by LC-MS. After the reaction was completed, the reaction system was cooled to room temperature, filtered, the filter cake was washed with methanol (10 mL x 3), the filtrate and washing liquid were combined and concentrated under reduced pressure. The residue was directly purified by reverse phase column C18. The purification conditions were as follows: 40 g C18 reverse phase column; mobile phase acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate 30 mL / min; gradient acetonitrile from 10% to 95% in 20 min; detection wavelength 254 nm. After confirmation by LC-MS, the product fraction was collected, concentrated under reduced pressure and lyophilized to obtain 1.80 g of compound 5-2 (yellow oil, yield 96%).

[0325] MS (ESI, m / z): [M+H] + = 377.15.

[0326] 1 H NMR (400 MHz, CDC13) δ 7.01 (d, J = 1.6 Hz, 1H), 6.81 (d, J = 1.6 Hz, 1H), 4.57-4.53 (m, 1H), 4.45-4.30 (m, 1H), 3.67-3.49 (m, 2H), 3.43-3.31 (m, 1H), 3.17-3.05 (m, 1H), 2.72-2.56 (m, 2H), 2.38-2.16 (m, 1H), 2.16-1.98 (m, 3H), 1.77-1.65 (m, 2H), 1.43 (s, 9H), 0.90 (t, J = 7.2 Hz, 3H).

[0327] Step 2:

[0328] According to the synthetic method of Step 5 in Example 1, the raw material was replaced by compound 5-2 (1.80 g, 4.78 mmol) to produce 1.30 g of compound 5-3 (orange yellow oil, yield 98%).

[0329] MS (ESI, m / z): [M+H] + = 277.10.

[0330] 1 H NMR (400 MHz, CDC13) δ 7.24-7.13 (m, 1H), 6.63-6.43 (m, 1H), 6.33 (s, 1H), 4.47-4.33 (m, 1H), 3.59-3.44 (m, 1H), 3.09-3.00 (m, 1H), 2.58-2.48 (m, 2H), 2.47-2.37 (m, 1H), 2.13-1.94 (m, 4H), 1.80-1.67 (m, 2H), 1.60 (s, 2H), 0.95 (t, J = 7.2 Hz, 3H).

[0331] Step 3:

[0332] Compound 5-3 (1.80 g, 6.51 mmol) was dissolved in solvent N,N-dimethylformamide (30 mL) at 0 °C under nitrogen atmosphere. Then sodium hydride (391 mg, 9.7 mmol, 60% dispersion in mineral oil) was added into the above reaction system in batches. The reaction system was stirred at 0 °C for 20 minutes, and then compound 5-4 (1.21 g, 7.24 mmol; CAS: 927-68-4, directly purchased from the supplier Shanghai Tixi'ai Chemical Industry Development Co., Ltd.) was added into the above reaction solution. The reaction system was removed from the ice bath, and the temperature was naturally increased to room temperature under nitrogen atmosphere. The reaction was stirred at room temperature for 3 hours. The reaction progress was monitored by liquid chromatography-mass spectrometry. After the reaction was completed, the reaction system was cooled to 0 °C with an ice water bath, and then quenched with water (20 mL). Ethyl acetate (100 mL x 3) was used for extraction, and the combined organic phase was washed with saturated sodium chloride aqueous solution (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was directly purified by a reverse phase C18 column. The purification conditions were as follows: 120 g C18 reverse phase column; mobile phase: acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate: 40 mL / min; gradient: acetonitrile increased from 30% to 80% in 35 minutes; detection wavelength: 254 nm. After liquid chromatography-mass spectrometry confirmation, the product fraction was collected and concentrated under reduced pressure to obtain 1.0 g of compound 5-5 (orange yellow oil, yield 42%).

[0333] MS (ESI, m / z): [M+H] + = 363.10.

[0334] Step 4:

[0335] According to the synthetic method of Step 7 in Example 1, substituting the starting materials correspondingly with compound 5-5 (1.0 g, 2.76 mmol), 400 mg of compound 5-6 (colorless oil, yield 44%) was prepared.

[0336] MS (ESI, m / z): [M+H] + = 333.10.

[0337] 1 H NMR (400 MHz, CDCl3) δ 5.97-5.78 (m, 3H), 5.53 (d, J = 2.0 Hz, 1H), 4.61-4.53 (m, 1H), 4.29-4.18 (m, 1H), 4.15-4.05 (m, 1H), 3.67-3.62 (m, 1H), 3.60-3.49 (m, 2H), 3.21-3.12 (m, 2H), 3.05-2.94 (m, 1H), 2.80-2.69 (m, 1H), 2.58-2.45 (m, 2H), 2.36-2.25 (m, 1H), 2.06 (s, 3H), 2.04-1.96 (m, 1H), 1.92-1.78 (m, 1H), 1.68-1.55 (m, 2H), 1.58-1.47 (m, 1H), 0.92 (t, J = 7.2 Hz, 3H).

[0338] Step 5:

[0339] According to the synthetic method of Step 8 in Example 1, substituting the starting materials correspondingly with compound 5-7 (2.0 g, 12.1 mmol) and sodium thiomethoxide (930 mg, 13.3 mmol; CAS: 5188-07-8, directly purchased from Beijing Sihai Longxing Petroleum Chemical Co., Ltd.), 830 mg of compound 5-8 (colorless oil, yield 39%) was prepared.

[0340] 1 H NMR (400 MHz, CDCl3) δ 7.21-7.16 (m, 1H), 7.00-6.96 (m, 1H), 2.58 (s, 3H).

[0341] 19 F NMR (377 MHz, CDCl3) δ -125.52.

[0342] Step 6:

[0343] According to the synthetic method of Step 3 in Example 2, with the corresponding raw materials replaced by 5-8 (830 mg, 4.67 mmol), 600 mg of compound 5-9 (white solid, yield 61%) was prepared.

[0344] 1 H NMR (400 MHz, DMSO-d6) δ 8.26 - 8.17 (m, 1H), 8.05 - 7.97 (m, 1H), 3.42 (s, 3H).

[0345] 19 F NMR (377 MHz, DMSO-d6) δ -121.27.

[0346] Step 7:

[0347] According to the synthetic method of Step 8 in Example 1, with the corresponding raw materials replaced by compound 5-6 (300 mg, 0.90 mmol) and compound 5-9 (189 mg, 0.90 mmol), 400 mg of compound 5-10 (brown oil, yield 88%) was prepared.

[0348] MS (ESI, m / z): [M+H] + = 506.05.

[0349] Step 8:

[0350] Compound 5-10 (400 mg, 0.79 mmol) and lithium hydroxide (237 mg, 9.90 mmol) were dissolved in methanol (2 mL), tetrahydrofuran (2 mL) and water (2 mL) at 0 °C. The reaction system was removed from the ice bath, and the temperature was naturally increased to room temperature, and stirred at this condition for 1 hour. The reaction progress was monitored by liquid chromatography. After the reaction was completed, water (6 mL) was added to the reaction system at room temperature, extracted with ethyl acetate (30 mL x 3), the combined organic phase was washed with saturated aqueous sodium chloride solution (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was directly purified with a silica gel column (eluent: dichloromethane / methanol = 10 / 1), the product fraction was collected and concentrated under reduced pressure to obtain 88 mg of compound 5 (racemate, white solid, yield 24%).

[0351] MS (ESI, m / z): [M+H] + = 464.20.

[0352] Step 9:

[0353] Chiral resolution of racemic 5 (80 mg, 0.17 mmol) was performed with the following conditions: Chiral column CHIRALPAK IG, 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: isocratic 30% B; detection wavelength 220 / 254 nm; the front peak fraction was obtained with retention time 9.2 min, and 34.4 mg of optically pure compound 5a (white solid, yield 43%) was obtained after concentration under reduced pressure and lyophilization; the back peak fraction was obtained with retention time 12.7 min, and 30 mg of optically pure compound 5b (white solid, yield 37%) was obtained after concentration under reduced pressure and lyophilization.

[0354] Compound 5a:

[0355] MS (ESI, m / z): [M+H] + = 464.10.

[0356] 1 H NMR (400 MHz, DMSO-d6) δ 9.64 (s, 1H), 7.90-7.83 (m, 1H), 7.24-7.16 (m, 1H), 7.03 (d, J = 1.6 Hz, 1H), 6.48 (d, J = 1.6 Hz, 1H), 4.43 (t, J = 5.2 Hz, 1H), 4.35-4.29 (m, 1H), 3.65-3.56 (m, 1H), 3.55-3.46 (m, 2H), 3.36 (s, 3H), 3.32-3.24 (m, 1H), 3.13-3.05 (m, 1H), 3.03-2.94 (m, 1H), 2.84-2.73 (m, 1H), 2.49-2.36 (m, 2H), 2.39-2.26 (m, 2H), 2.24-2.13 (m, 1H), 1.92-1.83 (m, 1H), 1.81-1.73 (m, 1H), 1.73-1.59 (m, 2H), 1.44-1.31 (m, 1H), 0.90 (t, J = 7.2 Hz, 3H).

[0357] 19 F NMR (377 MHz, DMSO-d6) δ -132.05.

[0358] Compound 5b:

[0359] MS (ESI, m / z): [M+H] + = 464.10.

[0360] 1H NMR (400 MHz, DMSO-d6) δ 9.64 (s, 1H), 7.90-7.83 (m, 1H), 7.24-7.16 (m, 1H), 7.03 (d, J = 1.6 Hz, 1H), 6.48 (d, J = 1.6 Hz, 1H), 4.43 (t, J = 5.2 Hz, 1H), 4.37-4.27 (m, 1H), 3.65-3.56 (m, 1H), 3.55-3.46 (m, 2H), 3.36 (s, 3H), 3.32-3.24 (m, 1H), 3.13-3.05 (m, 1H), 3.03-2.94 (m, 1H), 2.84-2.73 (m, 1H), 2.49-2.38 (m, 2H), 2.41-2.26 (m, 2H), 2.24-2.13 (m, 1H), 1.92-1.83 (m, 1H), 1.83-1.74 (m, 1H), 1.74-1.59 (m, 2H), 1.44-1.34 (m, 1H), 0.90 (t, J = 7.2 Hz, 3H).

[0361] 19 F NMR (377 MHz, DMSO-d6) δ -132.05.

[0362] Example 6a and 6b:

[0363] (S or R)-N-(1-(4-((4-amino-5-chloro-6-(methylsulfonyl)pyridin-2-yl)amino)-6- propylpyridin-2-yl)piperidin-3-yl)acetamide (Compound 6a); and

[0364] (R or S)-N-(1-(4-((4-amino-5-chloro-6-(methylsulfonyl)pyridin-2-yl)amino)-6- propylpyridin-2-yl)piperidin-3-yl)acetamide (Compound 6b)

[0365] Step 1:

[0366] According to the synthetic method of Step 8 in Example 1, with the raw materials being replaced by Compound 3-8 (120 mg, 0.43 mmol) and Compound 1-3 (210 mg, 0.48 mmol) accordingly, 100 mg of Compound 6-1 (white solid, yield 34%) was prepared.

[0367] MS (ESI, m / z): [M+H] + = 681.25 / 683.20.

[0368] Step 2:

[0369] According to the synthetic method of Step 5 in Example 1, by replacing the starting materials with compound 6-1 (120 mg, 0.176 mmol) accordingly, 60 mg of compound 6 (racemate, white solid, yield 71%) was prepared.

[0370] MS (ESI, m / z): [M+H] + = 481.10 / 483.10.

[0371] Step 3:

[0372] Chiral resolution of racemate 6 (60 mg, 0.125 mmol) was performed under the following resolution conditions: Chiral column CHIRAL ART Cellulose-SB, 3x25 cm, 5 μm; mobile phase A: n-hexane / methyl-tert-butyl ether = 1 / 1, mobile phase B: ethanol; flow rate 40 mL / min; gradient: isocratic 8% B; detection wavelength 270 / 250 nm; the front peak fraction was obtained with a retention time of 10.0 min, and after concentration under reduced pressure and lyophilization, 16.7 mg of optically pure compound 6a (white solid, yield 28%) was obtained; the back peak fraction was obtained with a retention time of 11.6 min, and after concentration under reduced pressure and lyophilization, 5.1 mg of optically pure compound 6b (white solid, yield 9%) was obtained.

[0373] Compound 6a:

[0374] MS (ESI, m / z): [M+H] + = 481.20 / 483.10.

[0375] 1 H NMR (400 MHz, DMSO-d6) δ 9.21 (s, 1H), 7.85 (d, J = 7.6 Hz, 1H), 6.83 (s, 1H), 6.75 (s, 2H), 6.65 (d, J = 1.6 Hz, 1H), 6.42 - 6.37 (m, 1H), 4.10 - 3.98 (m, 2H), 3.72 - 3.61 (m, 1H), 3.34 (s, 3H), 2.87 - 2.76 (m, 1H), 2.68 - 2.58 (m, 1H), 2.43 (t, J = 7.6 Hz, 2H), 1.87 - 1.79 (m, 4H), 1.76 - 1.69 (m, 1H), 1.69 - 1.56 (m, 2H), 1.47 - 1.37 (m, 2H), 0.89 (t, J = 7.2 Hz, 3H).

[0376] Compound 6b:

[0377] MS (ESI, m / z): [M+H] + = 481.15 / 483.10.

[0378] 1 H NMR (400 MHz, DMSO-d6) δ 9.20 (s, 1H), 7.85 (d, J = 7.6 Hz, 1H), 6.83 (s, 1H), 6.74 (s, 2H), 6.65 (d, J = 1.6 Hz, 1H), 6.39 (d, J = 1.6 Hz, 1H), 4.10-3.98 (m, 2H), 3.69-3.62 (m, 1H), 3.33 (s, 3H), 2.86-2.76 (m, 1H), 2.68-2.58 (m, 1H), 2.43 (t, J = 7.6 Hz, 2H), 1.86-1.77 (m, 4H), 1.75-1.68 (m, 1H), 1.67-1.55 (m, 2H), 1.52-1.31 (m, 2H), 0.89 (t, J = 7.2 Hz, 3H).

[0379] Examples 7a and 7b:

[0380] 5-chloro-6-(methylsulfonyl)-N2-(2-((3aR or 3aS, 7aR or 7aS)-octahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-6-propylpyridin-4-yl)pyridine-2,4-diamine (Compound 7a); and

[0381] Preparation of 5-chloro-6-(methylsulfonyl)-N2-(2-((3aS or 3aR, 7aS or 7aR)-octahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-6-propylpyridin-4-yl)pyridine-2,4-diamine (Compound 7b)

[0382] Step 1:

[0383] According to the synthesis method of Step 1 in Example 5, with the raw materials being replaced by Compound 3-5 (833 mg, 4.15 mmol) and Compound 7-1 (940 mg, 4.15 mmol, CAS: 1211583-65-1, directly purchased from Nanjing Nari Technology Co., Ltd.), 560 mg of Compound 7-2 (yellow oil, yield 35%) was prepared.

[0384] MS (ESI, m / z): [M+H] + = 391.35.

[0385] 1H NMR (400 MHz, CDC13) δ 7.03 (d, J = 2.0 Hz, 1H), 6.80 (d, J = 2.0 Hz, 1H), 4.78-4.49 (m, 1H), 4.21-3.91 (m, 3H), 3.63-3.52 (m, 1H), 3.52-3.36 (m, 1H), 2.68 (t, J = 7.6 Hz, 2H), 2.42-2.32 (m, 1H), 2.24-2.08 (m, 2H), 1.80-1.74 (m, 2H), 1.72-1.61 (m, 2H), 1.55-1.49 (m, 1H), 1.48 (s, 9H), 0.97 (t, J = 7.2 Hz, 3H).

[0386] Step 2:

[0387] According to the synthetic method of Step 7 in Example 1, by replacing the raw materials with compound 7-2 (530 mg, 1.36 mmol) accordingly, 314 mg of compound 7-3 (pale yellow oil, yield 64%) was prepared.

[0388] MS (ESI, m / z): [M+H] + = 361.25.

[0389] Step 3:

[0390] The raw materials 7-3 (100 mg, 0.28 mmol) and 1-3 (123 mg, 0.28 mmol) were dissolved in toluene (4 mL) at room temperature under nitrogen atmosphere. Tris(dibenzylideneacetone)dipalladium (25.4 mg, 0.028 mmol), cesium carbonate (181 mg, 0.55 mmol) and 1,1'-binaphthalene-2,2'-diphenylphosphine (35 mg, 0.056 mmol) were added into the above reaction solution successively. The reaction system was heated to 100 °C and stirred for 15 hours under this condition. The reaction progress was monitored by liquid chromatography-mass spectrometry. After the reaction was completed, the reaction system was cooled to room temperature, filtered, the filter cake was washed with methanol (15 mL x 3), and the washing solution and the filtrate were combined and concentrated under reduced pressure. The obtained residue was directly purified by silica gel column (eluent: petroleum ether / ethyl acetate = 10 / 1) to obtain 160 mg of compound 7-4 (white solid, yield 87%).

[0391] MS (ESI, m / z): [M+H] + = 665.25 / 667.15.

[0392] Step 4:

[0393] According to the synthetic method of Step 5 in Example 1, starting material was replaced with compound 7-4 (160 mg, 0.24 mmol) to produce 90 mg of compound 7 (racemate, white solid, yield 80%).

[0394] MS (ESI, m / z): [M+H] + = 465.05 / 467.00.

[0395] Step 5:

[0396] Chiral resolution of racemate 7 (90 mg, 0.19 mmol) was performed under the following resolution conditions: Chiral column CHIRALPAK IG, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isocratic 50% B; detection wavelength 200 / 210 nm; the front peak fraction was obtained at a retention time of 6.0 min, and after concentration under reduced pressure and lyophilization, 31.7 mg of optically pure compound 7a (white solid, yield 35%) was obtained; the back peak fraction was obtained at a retention time of 8.2 min, and after concentration under reduced pressure and lyophilization, 35 mg of optically pure compound 7b (white solid, yield 39%) was obtained.

[0397] Compound 7a:

[0398] MS (ESI, m / z): [M+H] + = 465.20 / 467.20.

[0399] 1 H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 6.68 (s, 2H), 6.53-6.48 (m, 2H), 6.36 (s, 1H), 3.80-3.74 (m, 1H), 3.48-3.35 (m, 2H), 3.34 (s, 3H), 3.30-3.21 (m, 2H), 2.73-2.56 (m, 1H), 2.44-2.36 (m, 2H), 2.17-2.01 (m, 2H), 1.78-1.70 (m, 1H), 1.70-1.56 (m, 2H), 1.52-1.39 (m, 2H), 1.34-1.23 (m, 1H), 0.89 (t, J = 7.2 Hz, 3H).

[0400] Compound 7b:

[0401] MS (ESI, m / z): [M+H] + = 465.25 / 467.20.

[0402] 1H NMR (400 MHz, DMSO-d6) δ 9.11 (s, 1H), 6.70 (s, 2H), 6.56-6.48 (m, 2H), 6.36 (s, 1H), 3.83-3.74 (m, 1H), 3.45-3.36 (m, 2H), 3.35 (s, 3H), 3.30-3.21 (m, 2H), 2.73-2.57 (m, 1H), 2.44-2.32 (m, 2H), 2.19-2.05 (m, 2H), 1.77-1.72 (m, 1H), 1.69-1.56 (m, 2H), 1.48-1.40 (m, 2H), 1.32-1.28 (m, 1H), 0.89 (t, J = 7.2 Hz, 3H).

[0403] Example 8:

[0404] Preparation of (S)-N-(2-(3-(ethylamino)pyrrolidin-1-yl)-6-propylpyridin-4-yl)-5- fluoro-6-(methylsulfonyl)pyridin-2-amine (Compound 8)

[0405] Step 1:

[0406] According to the synthesis method of Step 3 in Example 5, with raw materials replaced by Compound 1-7 (1.00 g, 2.85 mmol) and iodoethane (667 mg, 4.28 mmol; CAS: 75-03-6, directly purchased from Anhui Zesheng Science and Technology Co., Ltd.), 900 mg of Compound 8-1 (brown oil, yield 83%) was prepared.

[0407] MS (ESI, m / z): [M+H] + = 379.20.

[0408] 1 H NMR (400 MHz, CDCl3) δ 7.07 (d, J = 1.6 Hz, 1H), 6.86 (d, J = 1.6 Hz, 1H), 4.80-4.65 (m, 1H), 3.84-3.75 (m, 2H), 3.52-3.35 (m, 2H), 3.32-3.12 (m, 2H), 2.74 (t, J = 7.6 Hz, 2H), 2.27-2.13 (m, 2H), 1.84-1.70 (m, 2H), 1.48 (s, 9H), 1.17 (t, J = 6.8 Hz, 3H), 0.98 (t, J = 7.2 Hz, 3H).

[0409] Step 2:

[0410] According to the method for synthesizing of Step 7 in Example 1, substituting the raw materials correspondingly with compound 8-1 (900 mg, 2.38 mmol), 106 mg of compound 8-2 (white solid, yield 13%) was prepared.

[0411] MS (ESI, m / z): [M+H] + = 349.10.

[0412] Step 3:

[0413] According to the method for synthesizing of Step 8 in Example 1, substituting the raw materials correspondingly with 8-2 (100 mg, 0.29 mmol) and 5-8 (60 mg, 0.29 mmol), 80 mg of compound 8-3 (brown oil, yield 53%) was prepared.

[0414] MS (ESI, m / z): [M+H] + = 522.25.

[0415] 1 H NMR (400 MHz, CDCl3) δ 7.55-7.46 (m, 1H), 7.24-7.13 (m, 1H), 6.84-6.58 (m, 1H), 6.35 (s, 1H), 4.76-4.58 (m, 1H), 3.77-3.65 (m, 2H), 3.48-3.31 (m, 2H), 3.27 (s, 3H), 3.23-3.16 (m, 1H), 2.66-2.49 (m, 2H), 2.23-2.05 (m, 2H), 1.78-1.61 (m, 3H), 1.50-1.47 (s, 9H), 1.16 (t, J = 6.8 Hz, 3H), 0.99-0.90 (m, 3H).

[0416] 19 F NMR (377 MHz, CDCl3) δ -129.75.

[0417] Step 4:

[0418] According to the synthesis method of Step 5 in Example 1, the starting material was replaced with compound 8-3 (80 mg, 0.15 mmol) accordingly. After the reaction was completed, it was purified by preparative liquid chromatography. The purification conditions were as follows: column type X Bridge Shield RP18 OBD Column 30 x 150 mm, 5 μm; mobile phase acetonitrile and water (10 mmol / L ammonium bicarbonate + 0.05% ammonia water); flow rate 60 mL / min; gradient acetonitrile from 23% to 53% in 10 min; detection wavelength 254 nm / 220 nm, retention time 8.5 min. The product fractions were collected and concentrated under reduced pressure to give 22 mg of compound 8 (yellow semi-solid, yield 34%).

[0419] MS (ESI, m / z): [M+H] + = 422.20.

[0420] 1 H NMR (400 MHz, DMSO-d6) δ 9.63 (s, 1H), 7.88-7.83 (m, 1H), 7.24-7.16 (m, 1H), 6.97 (d, J = 1.6 Hz, 1H), 6.48 (d, J = 1.6 Hz, 1H), 3.60-3.51 (m, 1H), 3.51-3.41 (m, 1H), 3.37 (s, 3H), 3.35-3.30 (m, 2H), 3.16-3.08 (m, 1H), 2.64-2.51 (m, 2H), 2.49-2.40 (m, 2H), 2.12-2.00 (m, 1H), 1.80-1.58 (m, 4H), 1.02 (t, J = 7.2 Hz, 3H), 0.91 (t, J = 7.2 Hz, 3H).

[0421] 19 F NMR (377 MHz, DMSO-d6) δ -132.39.

[0422] Example 9:

[0423] (S)-5-chloro-N 2 Preparation of (S)-5-chloro-N

[0424] Step 1:

[0425] The starting material 8-2 (100 mg, 0.28 mmol) and 1-3 (126 mg, 0.28 mmol) were dissolved in 1,4-dioxane (2 mL) at room temperature under nitrogen atmosphere. To the above solution were added successively tris(dibenzylideneacetone)dipalladium (26 mg, 0.029 mmol), cesium carbonate (187 mg, 0.57 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (33 mg, 0.057 mmol). The reaction system was heated to 100 °C and stirred for 3 h. The reaction progress was monitored by LC-MS. The reaction system was allowed to cool down to room temperature, filtered, the filter cake was washed with dichloromethane (5 mL x 3), and the combined washings and filtrate were concentrated under reduced pressure. The residue was directly purified by silica gel column (eluent: dichloromethane / methanol = 10 / 1) to give 120 mg of compound 9-1 (brown oil, yield 64%).

[0426] MS (ESI, m / z): [M+H] + = 653.25 / 655.20.

[0427] Step 2:

[0428] According to the synthetic method of Step 5 in Example 1, the starting material was replaced by compound 9-1 (100 mg, 0.15 mmol) accordingly. After the reaction was completed, it was purified by preparative liquid chromatography. The purification conditions were as follows: column type X Bridge Shield RP18 OBD Column 30 x 150 mm, 5 μm; mobile phase acetonitrile and water (10 mmol / L ammonium bicarbonate + 0.05% ammonia water); flow rate 60 mL / min; gradient acetonitrile from 22% to 41% in 10 min; detection wavelength 254 nm / 220 nm, retention time 10.6 min. The product fractions were collected and concentrated under reduced pressure to give 40 mg of compound 9 (white solid, yield 58%).

[0429] MS (ESI, m / z): [M+H] + = 453.25 / 455.20.

[0430] 1H NMR (400 MHz, DMSO-d6) δ 9.15 (d, J = 2.4 Hz, 1H), 6.71 (s, 2H), 6.56 (s, 1H), 6.48 (s, 1H), 6.39 - 6.36 (m, 1H), 3.57 - 3.48 (m, 1H), 3.48 - 3.38 (m, 1H), 3.36 (s, 3H), 3.34 - 3.24 (m, 3H), 3.12 - 3.04 (m, 1H), 2.65 - 2.51 (m, 2H), 2.46 - 2.37 (m, 2H), 2.11 - 2.00 (m, 1H), 1.79 - 1.56 (m, 3H), 1.02 (t, J = 7.2 Hz, 3H), 0.90 (t, J = 7.2 Hz, 3H).

[0431] Example 10:

[0432] Preparation of (S)-5-fluoro-N-(2-(3-(methylamino)pyrrolidin-1-yl)-6- propylpyridin-4-yl)-6-(methylsulfonyl)pyridin-2-amine (Compound 10)

[0433] Step 1:

[0434] According to the synthesis method of Step 3 in Example 5, with raw materials replaced by Compound 1-7 (1.0 g, 2.85 mmol) and iodomethane (607 mg, 4.28 mmol) accordingly, 800 mg of Compound 10-1 (yellow solid, yield 77%) was prepared.

[0435] MS (ESI, m / z): [M+H] + = 365.15.

[0436] 1 H NMR (400 MHz, CDCl3) δ 7.08 (d, J = 1.6 Hz, 1H), 6.85 (d, J = 1.6 Hz, 1H), 5.02 - 4.83 (m, 1H), 3.78 - 3.69 (m, 2H), 3.53 - 3.36 (m, 2H), 2.83 (s, 3H), 2.71 (t, J = 7.6 Hz, 2H), 2.28 - 2.07 (m, 2H), 1.83 - 1.70 (m, 2H), 1.49 (s, 9H), 0.97 (t, J = 7.2 Hz, 3H).

[0437] Step 2:

[0438] Following the procedure of Step 7 in Example 1, starting from compound 10-1 (600 mg, 1.65 mmol) instead, 500 mg of compound 10-2 (off-white oil, 91% yield) was prepared.

[0439] MS (ESI, m / z): [M+H] + = 335.10.

[0440] 1 H NMR (400 MHz, CDCl3) δ 6.01 (s, 1H), 5.65 (s, 1H), 4.87-4.74 (m, 1H), 3.80-3.50 (m, 3H), 3.48 (s, 3H), 3.46-3.37 (m, 1H), 2.90-2.69 (m, 4H), 2.18-2.03 (m, 2H), 1.75-1.62 (m, 2H), 1.47 (s, 9H), 0.95 (t, J = 7.2 Hz, 3H).

[0441] Step 3:

[0442] Following the procedure of Step 8 in Example 1, starting from compound 10-2 (150 mg, 0.45 mmol) and compound 5-9 (94 mg, 0.45 mmol) instead, 90 mg of compound 10-3 (yellow solid, 40% yield) was prepared.

[0443] MS (ESI, m / z): [M+H] + = 508.35.

[0444] 1 H NMR (400 MHz, CDCl3) δ 7.47 (t, J = 8.8 Hz, 1H), 7.32-7.28 (m, 1H), 7.14-7.09 (m, 1H), 6.67 (s, 1H), 6.32 (d, J = 1.6 Hz, 1H), 4.93-4.77 (m, 1H), 3.74-3.60 (m, 2H), 3.46-3.32 (m, 2H), 3.27 (s, 3H), 2.81 (s, 3H), 2.54 (t, J = 7.2 Hz, 2H), 2.20-2.05 (m, 2H), 1.76-1.66 (m, 2H), 1.48 (s, 9H), 0.95 (t, J = 7.2 Hz, 3H).

[0445] 19 F NMR (377 MHz, CDCl3) δ -130.58.

[0446] Step 4:

[0447] Synthesized according to the procedure of Step 5 in Example 1, with the corresponding starting materials replaced by compound 10-3 (91 mg, 0.18 mmol). After the reaction was complete, it was purified by preparative liquid chromatography. The purification conditions were as follows: column type X Bridge Shield OBD C18 Column 30 x 150 mm, 5 pm; mobile phase acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate 60 mL / min; gradient acetonitrile from 13% to 43% in 10 min; detection wavelength 254 / 220 nm, retention time 8.8 min. The product fractions were collected and concentrated under reduced pressure to give 30 mg of compound 10 (white solid, yield 41%).

[0448] MS (ESI, m / z): [M+H] + = 408.15.

[0449] 1 H NMR (400 MHz, DMSO-d6) δ 9.64 (s, 1H), 7.86 (t, J = 9.2 Hz, 1H), 7.24 - 7.16 (m, 1H), 6.98 (d, J = 1.6 Hz, 1H), 6.47 (d, J = 1.6 Hz, 1H), 3.57 - 3.50 (m, 1H), 3.49 - 3.41 (m, 1H), 3.37 (s, 3H), 3.36 - 3.33 (m, 1H), 3.25 - 3.10 (m, 2H), 2.44 (t, J = 7.6 Hz, 2H), 2.30 (s, 3H), 2.10 - 1.98 (m, 1H), 1.81 - 1.67 (m, 1H), 1.70 - 1.58 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H).

[0450] 19 F NMR (377 MHz, DMSO-d6) δ -132.37.

[0451] Example 11:

[0452] Preparation of (S)-5-chloro-N-(2-(3-(methylamino)pyrrolidin-1-yl)-6- propylpyridin-4-yl)-6-(methylsulfonyl)pyridin-2-amine (Compound 11)

[0453] Step 1:

[0454] Synthesized according to the method of Step 8 in Example 1 with the corresponding starting materials replaced by compound 10-2 (100 mg, 0.30 mmol) and compound 4-2 (74.4 mg, 0.33 mmol) to give 50 mg of compound 11-1 (white solid, yield 32%).

[0455] MS (ESI, m / z): [M-H] - = 522.15 / 524.10.

[0456] Step 2:

[0457] Synthesized according to the method of Step 5 in Example 1 with the corresponding starting materials replaced by compound 11-1 (20 mg, 0.038 mmol). After the reaction was complete, it was purified by preparative liquid chromatography. The purification conditions were as follows: column type X Bridge Shield OBD C18 Column 30 x 150 mm, 5 pm; mobile phase acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate 60 mL / min; gradient acetonitrile from 19% to 49% in 10 min; detection wavelength 254 / 220 nm, retention time 8.6 min. The product fractions were collected and concentrated under reduced pressure to give 6.9 mg of compound 11 (white solid, yield 43%).

[0458] MS (ESI, m / z): [M+H] + = 424.10 / 426.15.

[0459] 1 H NMR (400 MHz, DMSO-d6) δ 9.73 (s, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.13 (d, J = 8.8 Hz, 1H), 6.80 (d, J = 1.6 Hz, 1H), 6.53 (d, J = 1.6 Hz, 1H), 3.57 - 3.49 (m, 1H), 3.48 - 3.43 (m, 1H), 3.42 (s, 3H), 3.37 - 3.32 (m, 2H), 3.23 - 3.11 (m, 2H), 2.45 (t, J = 7.6 Hz, 2H), 2.30 (s, 3H), 2.08 - 2.00 (m, 1H), 1.81 - 1.71 (m, 1H), 1.71 - 1.58 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H).

[0460] Example 12:

[0461] Preparation of (S)-5-methyl-N-(2-(3-(methylamino)pyrrolidin-1-yl)-6- propylpyridin-4-yl)-6-(methylsulfonyl)pyridin-2-amine (Compound 12)

[0462] Step 1:

[0463] According to the synthetic method in Step 1 in Embodiment 1, the raw material was replaced with compound 12-1 (5.0 g, 35.1 mmol; CAS: 442129-37-5, directly purchased from Shanghai Biotech Co., Ltd.) to prepare 1.8 g of compound 12-2 (light green solid, yield 28%).

[0464] MS (ESI, m / z): [M+H] + = 187.05.

[0465] 1 H NMR (400 MHz, CDC13) δ 7.38 (d, J = 8.4 Hz, 1H), 6.60 (d, J = 8.4 Hz, 1H), 4.41 (s, 2H), 3.26 (s, 3H), 2.54 (s, 3H).

[0466] Step 2:

[0467] The raw material 12-2 (900 mg, 4.83 mmol) was dissolved in acetonitrile (8 mL) at room temperature, and then hydrobromic acid (3.28 mL, 29.0 mmol, mass fraction 48%) was added to the above reaction solution by syringe. The reaction system was cooled to -10°C, liquid bromine (0.62 mL, 12.1 mmol) was added dropwise to the above reaction system, and stirred for 2 hours under this condition, then the reaction system was moved to an ice water bath, and aqueous sodium nitrite solution (1.6 mL, 7.5 mol / L) was added to the above reaction solution and stirred for 2 hours under this condition. The reaction progress was monitored by liquid chromatography, and after the reaction was completed, the reaction was quenched with saturated aqueous sodium thiosulfate solution (50 mL) at 0°C, and then the pH of the reaction system was adjusted to 11-12 with saturated aqueous sodium bicarbonate solution. Then extracted with ethyl acetate (50 mL x 3), the combined organic phase was washed with saturated aqueous sodium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was directly purified by silica gel column (eluent: petroleum ether / ethyl acetate = 7 / 3), and the obtained fraction was concentrated under reduced pressure to obtain 500 mg of compound 12-3 (yellow solid, yield 42%).

[0468] MS (ESI, m / z): [M+H] + = 249.90 / 251.80.

[0469] 1H NMR (400 MHz, CDC13) δ 7.60-7.51 (m, 2H), 3.38 (s, 3H), 2.66 (s, 3H).

[0470] Step 3:

[0471] According to the method of Step 8 in Example 1, with corresponding raw materials replaced by compound 10-2 (110 mg, 0.33 mmol) and compound 12-3 (83 mg, 0.33 mmol), 140 mg of compound 12-4 (light yellow solid, yield 84%) was prepared.

[0472] MS (ESI, m / z): [M+H] + = 504.35.

[0473] Step 4:

[0474] According to the method of Step 5 in Example 1, with corresponding raw materials replaced by compound 12-4 (160 mg, 0.32 mmol). After the reaction was completed, it was directly purified by reverse phase column C18. The purification conditions were as follows: 120 g C18 reverse phase column; mobile phase acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate 35 mL / min; gradient acetonitrile from 30% to 50% in 30 min; detection wavelength 254 nm. After confirmation by liquid chromatography-mass spectrometry, the product fraction was collected and concentrated under reduced pressure to obtain 46 mg of compound 12 (white solid, yield 35%).

[0475] MS (ESI, m / z): [M+H] + = 404.25.

[0476] 1 H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.73 (d, J = 1.6 Hz, 1H), 6.52 (d, J = 1.6 Hz, 1H), 3.56-3.33 (m, 3H), 3.34 (s, 3H), 3.25-3.14 (m, 1H), 3.17-3.09 (m, 1H), 2.49 (s, 3H), 2.47-2.40 (m, 2H), 2.30 (s, 3H), 2.10-1.98 (m, 1H), 1.97-1.82 (m, 1H), 1.81-1.70 (m, 1H), 1.73-1.58 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H).

[0477] Example 13a and 13b:

[0478] 5-chloro-N 2 - (2-((3aR or 3aS, 6aR or 6aS)- hexahydropyrrolo [3, 2-b] pyrrol-l- (2H)-yl)-6-propylpyridin-4-yl)-6- (methylsulfonyl)pyridine-2, 4-diamine (Compound 13a); and

[0479] 5-chloro-N 2 - (2-((3aS or 3aR, 6aS or 6aR)- hexahydropyrrolo [3, 2-b] pyrrol-l- (2H)-yl)-6-propylpyridin-4-yl)-6- (methylsulfonyl)pyridine-2, 4-diamine (Compound 13b)

[0480] Step 1:

[0481] According to the method of synthesis of Step 7 in Example 1, substituting the starting materials accordingly with Compound 5-2 (700 mg, 1.86 mmol), 600 mg of Compound 13-1 (brown solid, yield 93%) was prepared.

[0482] MS (ESI, m / z): [M-H] - = 345.25.

[0483] 1 H NMR (400 MHz, DMSO-d6) δ 7.33 (s, 2H), 6.07 (d, J = 2.0 Hz, 1H), 5.71 (d, J = 2.0 Hz, 1H), 4.67 - 4.63 (m, 1H), 4.41 - 4.37 (m, 1H), 3.67 - 3.48 (m, 2H), 3.46 - 3.38 (m, 1H), 3.11 - 3.04 (m, 1H), 2.80 - 2.68 (m, 1H), 2.65 - 2.53 (m, 1H), 2.22 - 1.98 (m, 3H), 1.94 - 1.88 (m, 1H), 1.68 - 1.53 (m, 2H), 1.43 (s, 9H), 0.92 (t, J = 7.2 Hz, 3H).

[0484] Step 2:

[0485] According to the method of synthesis of Step 1 in Example 9, substituting the starting materials accordingly with Compound 13-1 (173 mg, 0.50 mmol) and Compound 1-3 (220 mg, 0.50 mmol), 300 mg of Compound 13-2 (brown solid, yield 93%) was prepared.

[0486] MS (ESI, m / z): [M+H] += 651.30 / 653.20.

[0487] 1 H NMR (400 MHz, CDC13) δ 8.19 - 8.11 (m, 1H), 7.39 (s, 1H), 6.79 - 6.64 (m, 1H), 6.44 - 6.36 (m, 1H), 6.30 (s, 1H), 4.69 - 4.60 (m, 1H), 4.47 - 4.33 (m, 1H), 3.74 - 3.49 (m, 2H), 3.45 - 3.38 (m, 1H), 3.34 (s, 3H), 3.24 - 3.13 (m, 1H), 2.68 - 2.47 (m, 2H), 2.19 - 1.99 (m, 4H), 1.81 - 1.68 (m, 2H), 1.56 - 1.44 (m, 18H), 0.97 (t, J = 7.2 Hz, 3H).

[0488] Step 3:

[0489] Compound 13-2 (300 mg, 0.46 mmol) was dissolved in methanol (5 mL) at 0 °C, then 4 mol / L hydrochloric acid 1,4-dioxane solution (3 mL) was added to the above reaction solution. The reaction system was removed from the ice bath, and the temperature was naturally increased to room temperature, and stirred for 16 hours under this condition. The reaction progress was monitored by liquid chromatography. After the reaction was completed, the reaction mixture was concentrated under reduced pressure and freeze-dried, and the obtained residue was directly purified by reverse phase column C18. The purification conditions were as follows: 120 g C18 reverse phase column; mobile phase acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate 35 mL / min; gradient acetonitrile from 30% to 60% in 30 min; detection wavelength 254 nm. After confirmation by liquid chromatography, the product fraction was collected and concentrated under reduced pressure to obtain 80 mg of compound 13 (white solid, yield 39%).

[0490] MS (ESI, m / z): [M+H] + = 451.20 / 453.20.

[0491] Step 4:

[0492] Chiral resolution of racemic 13 (80 mg, 0.18 mmol) was performed under the following conditions: Chiral column Enantiocel-A4-5, 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: isocratic 20% B; detection wavelength 272 / 214 nm; the front peak fraction was obtained with a retention time of 20.8 min, and after concentration under reduced pressure and lyophilization, 32 mg of optically pure compound 13a (white solid, yield 40%) was obtained; the back peak fraction was obtained with a retention time of 25.8 min, and after concentration under reduced pressure and lyophilization, 33 mg of optically pure compound 13b (white solid, yield 41%) was obtained.

[0493] Compound 13a:

[0494] MS (ESI, m / z): [M+H] + = 451.20 / 453.20.

[0495] 1 H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 1H), 6.57-6.54 (m, 1H), 6.51 (s, 1H), 6.45 (s, 2H), 6.41 (s, 1H), 4.27-4.19 (m, 1H), 3.85-3.78 (m, 1H), 3.55-3.45 (m, 1H), 3.41-3.30 (m, 1H), 3.08-2.94 (m, 4H), 2.76 (t, J = 6.4 Hz, 2H), 2.49-2.41 (m, 2H), 2.01-1.87 (m, 2H), 1.78-1.74 (m, 1H), 1.74-1.60 (m, 3H), 0.91 (t, J = 7.2 Hz, 3H).

[0496] Compound 13b:

[0497] MS (ESI, m / z): [M+H] + = 451.20 / 453.20.

[0498] 1H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 1H), 6.57-6.54 (m, 1H), 6.51 (s, 1H), 6.45 (s, 2H), 6.41 (s, 1H), 4.24-4.20 (m, 1H), 3.83-3.78 (m, 1H), 3.55-3.45 (m, 1H), 3.41-3.33 (m, 1H), 3.07-2.97 (m, 4H), 2.76 (t, J = 6.4 Hz, 2H), 2.49-2.38 (m, 2H), 2.01-1.87 (m, 2H), 1.79-1.74 (m, 1H), 1.74-1.60 (m, 3H), 0.91 (t, J = 7.2 Hz, 3H).

[0499] Examples 14a and 14b:

[0500] N 2 (2-((3aR or 3aS, 6aR or 6aS)-hexahydropyrrolo[3,2-b]pyrrol-l(2H)-yl)-6- propylpyridin-4-yl)-5-methyl-6-(methylsulfonyl)pyridine-2,4-diamine (Compound 14a); and 2 (2-((3aS or 3aR, 6aS or 6aR)-hexahydropyrrolo[3,2-b]pyrrol-l(2H)-yl)-6- propylpyridin-4-yl)-5-methyl-6-(methylsulfonyl)pyridine-2,4-diamine (Compound 14b)

[0501] Step 1:

[0502] Compound 14-1 (20 g, 123 mmol; CAS: 2587-02-2, directly purchased from Shanghai Biotech Co., Ltd.) was dissolved in acetonitrile (6 mL) at room temperature, and then N-chlorosuccinimide (21.9 g, 123 mmol) was added to the above reaction solution. The reaction system was heated to 80 °C, and stirred at this condition for 4 hours. The reaction progress was monitored by liquid chromatography-mass spectrometry. After the reaction was completed, the reaction mixture was directly concentrated under reduced pressure, and the obtained residue was directly purified by silica gel column (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain 22 g of compound 14-2 (yellow solid, yield 74%).

[0503] MS (ESI, m / z): [M+H] + = 242.95 / 244.95 / 246.85.

[0504] 1 H NMR (300 MHz, CD3OD) δ 6.65 (s, 1H).

[0505] Step 2:

[0506] Synthesized according to the method of Step 1 in Example 2, with the corresponding starting materials replaced by compound 14-2 (5.0 g, 20.7 mmol), to produce 3.5 g of compound 14-3 (white solid, yield 67%).

[0507] MS (ESI, m / z): [M+H] + = 254.80 / 256.75 / 258.70.

[0508] 1 H NMR (300 MHz, CD3OD) δ 6.44 (s, 1H), 2.43 (s, 3H).

[0509] Step 3:

[0510] Synthesized according to the method of Step 2 in Example 3, with the corresponding starting materials replaced by compound 14-3 (3.5 g, 13.8 mmol), to produce 5.0 g of compound 14-4 (white solid, yield 80%).

[0511] 1 H NMR (400 MHz, DMSO-d6) δ 7.59 (s, 1H), 2.53 (s, 3H), 1.37 (s, 18H).

[0512] Step 4:

[0513] Compound 14-4 (2.0 g, 4.41 mmol) and methylboronic acid (320 mg, 5.29 mmol) were dissolved in toluene (20 mL) and water (42 mL) at room temperature under nitrogen atmosphere. To the above solution, palladium acetate (100 mg, 0.44 mmol), tricyclohexylphosphine (120 mg, 0.43 mmol) and potassium phosphate (180 mg, 0.85 mmol) were added successively. The reaction system was heated to 100 °C and stirred for 16 hours. The reaction progress was monitored by LC-MS. After the reaction was completed, the reaction was quenched with water (30 mL). The combined organic phase was extracted with ethyl acetate (100 mL x 3), washed with saturated sodium chloride aqueous solution (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was directly purified by silica gel column (eluent: petroleum ether / ethyl acetate = 9 / 1) to obtain 1.5 g of compound 14-5 (yellow liquid, yield 88%).

[0514] MS (ESI, m / z): [M+H]+ = 389.30 / 391.20.

[0515] 1 H NMR (400 MHz, DMSO-d6) d 7.30 (s, 1H), 2.53 (s, 3H), 1.99 (s, 3H), 1.38 (s, 18H).

[0516] Step 5:

[0517] Synthesized according to the method of Step 3 in Example 2, with the corresponding replacement of starting materials to compound 14-5 (400 mg, 1.03 mmol), to give 300 mg of compound 14-6 (white solid, yield 69%).

[0518] MS (ESI, m / z): [M+H] + = 421.10 / 423.05.

[0519] Step 6:

[0520] Synthesized according to the method of Step 8 in Example 1, with the corresponding replacement of starting materials to 13-1 (100 mg, 0.29 mmol) and 14-6 (160 mg, 0.38 mmol), to give 150 mg of compound 14-7 (brown solid, yield 71%).

[0521] MS (ESI, m / z): [M+H] + = 631.15.

[0522] Step 7:

[0523] Synthesized according to the method of Step 5 in Example 1, with the corresponding replacement of starting materials to 14-7 (150 mg, 0.24 mmol), to give 40 mg of compound 14 (white solid, yield 39%).

[0524] MS (ESI, m / z): [M+H] + = 431.20.

[0525] Step 8:

[0526] Racemic 14 (40 mg, 0.09 mmol) was subjected to chiral resolution. Resolution conditions were as follows: Chiral column CHIRALPAK ID, 250 x 30 mm, 5 μm; mobile phase A: n-hexane (10 mM ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isocratic 30% B; detection wavelength 205 / 210 nm; retention time 13 min for the fore peak fraction, which was concentrated under reduced pressure and lyophilized to give 14.6 mg of optically pure compound 14a (white solid, yield 37%); retention time 18 min for the back peak fraction, which was concentrated under reduced pressure and lyophilized to give 8.6 mg of optically pure compound 14b (white solid, yield 22%).

[0527] Compound 14a:

[0528] MS (ESI, m / z): [M+H] + = 431.30.

[0529] 1 H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 6.57 (d, J = 1.6 Hz, 1H), 6.44 (d, J = 1.6 Hz, 1H), 6.29 (s, 1H), 5.99 (s, 2H), 4.26 - 4.17 (m, 1H), 3.86 - 3.77 (m, 1H), 3.51 - 3.45 (m, 1H), 3.39 - 3.32 (m, 1H), 3.24 (s, 3H), 2.81 - 2.73 (m, 2H), 2.48 - 2.36 (m, 2H), 2.26 (s, 3H), 2.01 - 1.87 (m, 2H), 1.81 - 1.73 (m, 1H), 1.73 - 1.61 (m, 3H), 0.91 (t, J = 7.2 Hz, 3H).

[0530] Compound 14b:

[0531] MS (ESI, m / z): [M+H] + = 431.30.

[0532] 1H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H), 6.55 (d, J = 1.6 Hz, 1H), 6.42 (d, J = 1.6 Hz, 1H), 6.30 (s, 1H), 5.89 (s, 2H), 4.27-4.18 (m, 1H), 3.86-3.77 (m, 1H), 3.54-3.44 (m, 1H), 3.42-3.31 (m, 1H), 3.23 (s, 3H), 2.78 (t, J = 6.4 Hz, 2H), 2.48-2.36 (m, 2H), 2.27 (s, 3H), 2.02-1.88 (m, 2H), 1.79-1.74 (m, 1H), 1.73-1.62 (m, 3H), 0.91 (t, J = 7.2 Hz, 3H).

[0533] Examples 15a and 15b:

[0534] 5-chloro-6-(ethylsulfonyl)-N 2 -(2-((3aS or 3aR, 7aS or 7aR)-octahydro-lH-pyrrolo[3,2-b]pyridin-l-yl)-6- propylpyridin-4-yl)pyridine-2,4-diamine (Compound 15a); and 5-chloro-6-(ethylsulfonyl)-N 2 -(2-((3aR or 3aS, 7aR or 7aS)-octahydro-lH-pyrrolo[3,2-b]pyridin-l-yl)-6- propylpyridin-4-yl)pyridine-2,4-diamine (Compound 15b)

[0535] Step 1:

[0536] Synthesized according to the method of Step 1 in Example 1 with the corresponding starting materials replaced by Compound 1-1 (500 mg, 2.53 mmol) and sodium ethanesulfinate (588 mg, 5.06 mmol) to give 230 mg of Compound 15-1 (white solid, 36% yield).

[0537] MS (ESI, m / z): [M+H] + = 254.95 / 256.95 / 258.90.

[0538] Step 2:

[0539] Synthesized according to the method of Step 2 in Example 1 with the corresponding starting materials replaced by Compound 15-1 (500 mg, 1.97 mmol) to give 230 mg of Compound 15-2 (white solid, 26% yield).

[0540] MS (ESI, m / z): [M+H]+ = 455.15 / 457.15 / 459.10.

[0541] 1 H NMR (400 MHz, CDC13) δ 7.42 (s, 1H), 3.69-3.59 (m, 2H), 1.48 (t, J = 7.2 Hz, 3H), 1.45 (s, 18H).

[0542] Step 3:

[0543] According to the synthetic method of Step 1 in Example 5, with the raw materials correspondingly replaced by compound 3-5 (833 mg, 4.15 mmol) and compound 15-3 (940 mg, 4.15 mmol, CAS: 1211583-65-1, directly purchased from Nanjing Huashitai Technology Co., Ltd.), 560 mg of compound 15-4 (yellow oil, yield 35%) was prepared.

[0544] MS (ESI, m / z): [M+H] + = 391.35.

[0545] 1 H NMR (400 MHz, CDC13) δ 7.03 (d, J = 2.0 Hz, 1H), 6.80 (d, J = 2.0 Hz, 1H), 4.78-4.49 (m, 1H), 4.21-3.91 (m, 3H), 3.63-3.52 (m, 1H), 3.52-3.36 (m, 1H), 2.68 (t, J = 7.6 Hz, 2H), 2.42-2.32 (m, 1H), 2.24-2.08 (m, 2H), 1.80-1.74 (m, 2H), 1.72-1.61 (m, 2H), 1.55-1.49 (m, 1H), 1.48 (s, 9H), 0.97 (t, J = 7.2 Hz, 3H).

[0546] Step 4:

[0547] According to the synthetic method of Step 7 in Example 1, with the raw materials correspondingly replaced by compound 15-4 (530 mg, 1.36 mmol), 314 mg of compound 15-5 (pale yellow oil, yield 64%) was prepared.

[0548] MS (ESI, m / z): [M+H] + = 361.25.

[0549] Step 5:

[0550] Synthesized according to the method of Step 1 in Example 9, with the corresponding starting materials replaced by compound 15-5 (214 mg, 0.59 mmol) and compound 15-2 (170 mg, 0.37 mmol) to give 160 mg of compound 15-6 (white solid, yield 55%).

[0551] MS (ESI, m / z): [M+H] + = 779.50 / 781.50.

[0552] Step 6:

[0553] Synthesized according to the method of Step 5 in Example 1, with the corresponding starting material replaced by compound 15-6 (160 mg, 0.20 mmol) to give 80 mg of compound 15 (racemate, white solid, yield 81%).

[0554] MS (ESI, m / z): [M+H] + = 479.10 / 481.10.

[0555] Step 7:

[0556] Chiral resolution of racemate 15 (80 mg, 0.167 mmol) was performed with the following resolution conditions: Chiral column CHIRALPAK IG, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isocratic 30% B; detection wavelength 270 / 260 nm; the front peak fraction was obtained with a retention time of 12.8 min, which after concentration under reduced pressure and lyophilization gave 17 mg of optically pure compound 15a (white solid, yield 21%); the back peak fraction was obtained with a retention time of 17.2 min, which after concentration under reduced pressure and lyophilization gave 21 mg of optically pure compound 15b (white solid, yield 26%).

[0557] Compound 15a:

[0558] MS (ESI, m / z): [M+H] + = 479.25 / 481.10.

[0559] 1H NMR (400 MHz, DMSO-d6) δ 9.11 (s, 1 H), 6.70 (s, 2 H), 6.58 (d, J = 1.6 Hz, 1 H), 6.48 (d, J = 1.6 Hz, 1 H), 6.36 (s, 1 H), 4.01 - 3.83 (m, 1 H), 3.82 - 3.73 (m, 1 H), 3.59 - 3.48 (m, 2 H), 3.48 - 3.35 (m, 2 H), 3.29 - 3.21 (m, 1 H), 2.73 - 2.56 (m, 2 H), 2.46 - 2.34 (m, 2 H), 2.19 - 2.03 (m, 2 H), 1.76 - 1.70 (m, 1 H), 1.70 - 1.56 (m, 2 H), 1.48 - 1.41 (m, 2 H), 1.36 - 1.27 (m, 1 H), 1.24 (t, J = 7.2 Hz, 3 H), 0.90 (t, J = 7.2 Hz, 3 H).

[0560] Compound 15b:

[0561] MS (ESI, m / z): [M+H] + = 479.25 / 481.10.

[0562] 1 H NMR (400 MHz, DMSO-d6) δ 9.11 (s, 1 H), 6.70 (s, 2 H), 6.58 (d, J = 1.6 Hz, 1 H), 6.48 (d, J = 1.6 Hz, 1 H), 6.36 (s, 1 H), 4.01 - 3.83 (m, 1 H), 3.82 - 3.73 (m, 1 H), 3.59 - 3.48 (m, 2 H), 3.48 - 3.35 (m, 2 H), 3.29 - 3.21 (m, 1 H), 2.73 - 2.56 (m, 2 H), 2.46 - 2.34 (m, 2 H), 2.19 - 2.03 (m, 2 H), 1.76 - 1.70 (m, 1 H), 1.70 - 1.56 (m, 2 H), 1.48 - 1.41 (m, 2 H), 1.36 - 1.27 (m, 1 H), 1.24 (t, J = 7.2 Hz, 3 H), 0.90 (t, J = 7.2 Hz, 3 H).

[0563] Examples 16a and 16b:

[0564] 4-chloro-N 1 (2-((3aS or 3aR, 7aS or 7aR)-4-methyloctahydro-lH-pyrrolo[3,2-b]pyridin-l-yl)-6- propylpyridin-4-yl)-5-(methylsulfonyl)benzen- 1,3 -diamine (Compound 16a); and 4-chloro-N 1Preparation of (2-((3aR or 3aS, 7aR or 7aS)-4-methyloctahydro-lH-pyrrolo[3,2- b]pyridin-l-yl)-6-propylpyridin-4-yl)-5-(methylsulfonyl)benzene-l,3-diamine (Compound 16b)

[0565] Step 1:

[0566] Synthesized according to the method of Step 5 in Example 1, with the raw material replaced by Compound 15-4 (1.5 g, 3.84 mmol) to give 800 mg of Compound 16-1 (red oil, yield 72%).

[0567] MS (ESI, m / z): [M+H] + = 291.20.

[0568] Step 2:

[0569] Compound 16-1 (500 mg, 1.72 mmol) was dissolved in 1,2-dichloroethane (5 mL) at room temperature, and then formaldehyde aqueous solution (139 mg, 1.72 mmol) and sodium cyanoborohydride (433 mg, 6.89 mmol) were added. 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 completed, it was quenched by pouring into water (100 mL), extracted with ethyl acetate (30 mL x 3), and the combined organic phase was washed with saturated sodium chloride aqueous solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was directly purified by silica gel column (eluent: petroleum ether / ethyl acetate = 1 / 1), and the obtained fraction was concentrated under reduced pressure to give 450 mg of Compound 16-2 (white solid, yield 86%).

[0570] MS (ESI, m / z): [M+H] + = 305.25.

[0571] 1 H NMR (400 MHz, CDC13) δ 7.01 (d, J = 1.2 Hz, 1H), 6.80 (d, J = 1.2 Hz, 1H), 4.23 - 4.07 (m, 2H), 3.69 - 3.59 (m, 1H), 3.48 - 3.37 (m, 2H), 3.02 - 2.72 (m, 2H), 2.68 (t, J = 7.2 Hz, 1H), 2.64 - 2.50 (m, 2H), 2.26 - 2.13 (m, 1H), 2.02 - 1.92 (m, 1H), 1.81 - 1.50 (m, 5H), 1.37 - 1.30 (m, 1H), 0.97 (t, J = 7.2 Hz, 3H).

[0572] Step 3:

[0573] Synthesized according to the method of Step 7 in Example 1 with corresponding replacement of raw materials by compound 16-2 (450 mg, 1.48 mmol) to produce 400 mg of compound 16-3 (yellow solid, yield 99%).

[0574] MS (ESI, m / z): [M+H] + = 275.05.

[0575] 1 H NMR (400 MHz, DMSO-d6) δ 7.27 (s, 2H), 6.01 (s, 1H), 5.65 (s, 1H), 4.37 - 4.17 (m, 1H), 3.87 - 3.44 (m, 5H), 3.04 - 2.56 (m, 5H), 2.38 - 2.18 (m, 1H), 2.13 - 1.91 (m, 2H), 1.72 - 1.54 (m, 4H), 1.37 - 1.21 (m, 1H), 0.92 (t, J=7.2 Hz, 3H).

[0576] Step 4:

[0577] Synthesized according to the method of Step 1 in Example 9 with corresponding replacement of raw materials by compound 16-4 (214 mg, 0.68 mmol; CAS: 20098-47-9, directly purchased from the supplier Shanghai Biotech Co., Ltd.) to produce 160 mg of compound 16-5 (brown solid, yield 67%).

[0578] MS (ESI, m / z): [M+H] + = 350.95 / 352.90 / 354.95.

[0579] 1 H NMR (400 MHz, CDCl3) δ 9.14 (d, J=2.4 Hz, 1H), 8.16 (d, J=2.4 Hz, 1H), 7.14 - 7.06 (m, 1H), 1.56 (s, 9H).

[0580] Step 5:

[0581] Compound 16-5 (2.0 g, 5.68 mmol) was dissolved in 1,4-dioxane (25 mL) under nitrogen at room temperature, and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (329 mg, 0.57 mmol), palladium acetate (127 mg, 0.57 mmol), N,N-diisopropylethylamine (1.47 g, 11.3 mmol) and sodium thiomethoxide (438 mg, 6.25 mmol) were added successively to the above reaction solution. The reaction system was stirred at 100 °C for 16 hours, and the reaction progress was monitored by thin layer chromatography (mobile phase: petroleum ether / ethyl acetate = 10 / 1). After the reaction was completed, the reaction mixture was filtered, the filter cake was washed with ethyl acetate (40 mL x 2), and the filtrate was concentrated under reduced pressure. The residue was directly purified by silica gel column (eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain 1.1 g of compound 16-6 (pale yellow solid, yield 61%).

[0582] MS (ESI, m / z): [M-H]- = 317.05 / 319.00.

[0583] 1 H NMR (400 MHz, CDCl3) δ 8.91 (d, J = 2.4 Hz, 1H), 7.69-7.64 (m, 1H), 7.17 (s, 1H), 2.57 (s, 3H), 1.56 (s, 9H).

[0584] Step 6:

[0585] Synthesized according to the method of Step 3 in Example 2, with the raw materials replaced by compound 16-6 (1.1 g, 3.45 mmol) to prepare 700 mg of compound 16-7 (yellow oil, yield 58%).

[0586] MS (ESI, m / z): [M-H]- = 349.00 / 351.00.

[0587] 1 H NMR (400 MHz, CDCl3) δ 9.45 (d, J = 2.8 Hz, 1H), 8.66 (d, J = 2.8 Hz, 1H), 7.37 (s, 1H), 3.30 (s, 3H), 1.58 (s, 9H).

[0588] Step 7:

[0589] Synthesized according to the method of Step 7 in Example 1 with corresponding replacement of starting materials by compound 16-7 (640 mg, 1.83 mmol) to give 440 mg of compound 16-8 (brown oil solid, yield 75%).

[0590] MS (ESI, m / z): [M-H] - = 318.95 / 320.90.

[0591] 1 H NMR (400 MHz, CDC13) δ 7.86 (d, J = 2.8 Hz, 1H), 7.17-7.13 (m, 2H), 3.22 (s, 3H), 1.54 (s, 9H).

[0592] Step 8:

[0593] Compound 16-8 (430 mg, 1.34 mmol) and cuprous bromide (211 mg, 1.47 mmol), tert-butyl nitrite (276 mg, 2.56 mmol) were dissolved in acetonitrile (3.5 mL) at room temperature under nitrogen atmosphere. The reaction was heated to 60 °C under nitrogen atmosphere, then stirred at this condition for 4 hours. The reaction progress was monitored by LC-MS. After completion, it was cooled to room temperature, concentrated under reduced pressure. The residue was directly purified by silica gel column (eluent: petroleum ether / ethyl acetate = 1 / 1), the fractions were concentrated under reduced pressure to give 260 mg of compound 16-9 (white solid, yield 54%).

[0594] 1 H NMR (400 MHz, CDC13) δ 8.67 (d, J = 2.4 Hz, 1H), 7.89 (d, J = 2.4 Hz, 1H), 7.13 (s, 1H), 3.18 (s, 3H), 1.48 (s, 9H).

[0595] Step 9:

[0596] Synthesized according to the method of Step 1 in Example 9 with corresponding replacement of starting materials by compound 16-3 (293 mg, 1.07 mmol) and 16-9 (410 mg, 1.07 mmol) to give 300 mg of compound 16-10 (light green oil, yield 48%).

[0597] MS (ESI, m / z): [M+H] + = 579.25 / 581.25.

[0598] Step 10:

[0599] Synthesized according to the procedure of Step 5 in Example 1 with corresponding starting materials replaced by compound 16-10 (200 mg, 0.34 mmol) to give 100 mg of compound 16 (yellow solid, yield 60%).

[0600] MS (ESI, m / z): [M+H] + = 479.20 / 481.20.

[0601] Step 11:

[0602] Chiral resolution of racemic 16 (70 mg, 0.14 mmol) was performed with the following resolution conditions: Chiral column CHIRALART Cellulose-SZ, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isocratic 30% B; detection wavelength 260 / 270 nm; the front peak fraction was obtained with a retention time of 10.8 min, which after concentration under reduced pressure and lyophilization gave 24 mg of optically pure compound 16a (white solid, yield 34%); the back peak fraction was obtained with a retention time of 13.2 min, which after concentration under reduced pressure and lyophilization gave 21 mg of optically pure compound 16b (white solid, yield 30%).

[0603] Compound 16a:

[0604] MS (ESI, m / z): [M+H] + = 479.20 / 481.20.

[0605] 1 H NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H), 6.70 (s, 2H), 6.60-6.54 (m, 1H), 6.50-6.46 (m, 1H), 6.36 (s, 1H), 4.02-3.88 (m, 1H), 3.51-3.40 (m, 1H), 3.34 (s, 3H), 3.29-3.13 (m, 2H), 2.44-2.35 (m, 4H), 2.29 (s, 3H), 2.10-1.97 (m, 2H), 1.84-1.71 (m, 1H), 1.69-1.57 (m, 2H), 1.55-1.39 (m, 2H), 1.28-1.14 (m, 1H), 0.89 (t, J = 7.2 Hz, 3H).

[0606] Compound 16b:

[0607] MS (ESI, m / z): [M+H] + = 479.20 / 481.20.

[0608] 1 H NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H), 6.70 (s, 2H), 6.61-6.54 (m, 1H), 6.52-6.47 (m, 1H), 6.36 (s, 1H), 3.98-3.88 (m, 1H), 3.52-3.41 (m, 1H), 3.34 (s, 3H), 3.28-3.14 (m, 2H), 2.46-2.35 (m, 4H), 2.29 (s, 3H), 2.10-1.96 (m, 2H), 1.85-1.72 (m, 1H), 1.68-1.56 (m, 2H), 1.54-1.38 (m, 2H), 1.29-1.13 (m, 1H), 0.89 (t, J = 7.2 Hz, 3H).

[0609] Example 17:

[0610] (S)-5-chloro-6-(methylsulfonyl)-N 2 Preparation of (S)-5-chloro-6-(methylsulfonyl)-N

[0611] Step 1:

[0612] Compound 1-8 (2.9 g, 7.96 mmol) was dissolved in dichloromethane (25 mL) at 0 °C under nitrogen atmosphere, and triethylamine (2.4 g, 24.0 mmol) and trifluoroacetic anhydride (2.0 g, 9.59 mmol) were added to the above reaction solution by syringe. The reaction system was stirred at 0 °C for 2 hours, and the reaction progress was monitored by liquid chromatography-mass spectrometry. After the reaction was completed, the reaction was quenched with saturated aqueous sodium carbonate solution (50 mL) at 0 °C, extracted with ethyl acetate (200 mL x 3), and the combined organic phase was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was directly purified by silica gel column (eluent: petroleum ether / ethyl acetate = 2 / 1), and the obtained fraction was concentrated under reduced pressure to obtain 1.45 g of compound 17-1 (yellow solid, yield 52%).

[0613] MS (ESI, m / z): [M+H] + = 347.15.

[0614] 1H NMR (400 MHz, CDCI3) δ 7.12 (d, J = 1.6 Hz, 1 H), 6.88 (d, J = 1.6 Hz, 1 H), 6.66-6.53 (m, 1 H), 4.73-4.63 (m, 1 H), 3.95-3.85 (m, 1 H), 3.75-3.54 (m, 3 H), 2.72 (t, J = 7.6 Hz, 2 H), 2.51-2.38 (m, 1 H), 2.23-2.09 (m, 1 H), 1.83-1.70 (m, 2 H), 0.98 (t, J = 7.2 Hz, 3 H).

[0615] 19 F NMR (377 MHz, CDCI3) δ -75.75.

[0616] Step 2:

[0617] The starting material 17-1 (500 mg, 1.44 mmol) was dissolved in tetrahydrofuran (10 mL) under nitrogen atmosphere at room temperature, and then borane tetrahydrofuran complex (1 mmol / L tetrahydrofuran solution, 5.8 mL) was added into the above reaction system. The temperature was raised to 65 °C, and the reaction was carried out under this condition for 5 hours. The reaction progress was monitored by liquid chromatography-mass spectrometry. After the reaction was completed, the reaction system was naturally cooled to room temperature. The reaction was quenched with saturated aqueous ammonium chloride solution (50 mL), extracted with ethyl acetate (20 mL), and the combined organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was directly purified by silica gel column (eluent: petroleum ether / ethyl acetate = 2 / 1), and the obtained fraction was concentrated under reduced pressure to obtain 450 mg of compound 17-2 (yellow solid, yield 93%).

[0618] MS (ESI, m / z): [M+H] + = 333.20.

[0619] 1 H NMR (400 MHz, CDCI3) δ 7.07 (d, J = 1.6 Hz, 1 H), 6.86 (d, J = 1.6 Hz, 1 H), 3.84-3.76 (m, 1 H), 3.71-3.62 (m, 2 H), 3.60-3.52 (m, 1 H), 3.46-3.39 (m, 1 H), 3.33-3.23 (m, 2 H), 2.74 (t, J = 7.6 Hz, 2 H), 2.34-2.20 (m, 1 H), 2.07-1.92 (m, 1 H), 1.84-1.70 (m, 2 H), 0.98 (t, J = 7.2 Hz, 3 H).

[0620] 19F NMR (377 MHz, CDCI3) δ -71.61.

[0621] Step 3:

[0622] Synthesized according to the method of Example 1, Step 2 with the corresponding replacement of starting material 17-2 (600 mg, 1.8 mmol) to produce 300 mg of compound 17-3 (yellow solid, 38% yield).

[0623] MS (ESI, m / z): [M+H] + = 433.20.

[0624] 1 H NMR (400 MHz, CDCI3) δ 7.09 (d, J = 1.6 Hz, 1H), 6.89 (s, 1H), 4.52 - 4.37 (m, 1H), 3.98 - 3.77 (m, 4H), 3.60 - 3.48 (m, 2H), 2.82 - 2.74 (m, 2H), 2.41 - 2.29 (m, 2H), 1.84 - 1.72 (m, 2H), 1.48 (s, 9H), 0.98 (t, J = 7.2 Hz, 3H).

[0625] 19 F NMR (377 MHz, CDCI3) δ -70.27.

[0626] Step 4:

[0627] Synthesized according to the method of Example 1, Step 7 with the corresponding replacement of starting material compound 17-3 (300 mg, 0.69 mmol) to produce 130 mg of compound 17-4 (pink solid, 46% yield).

[0628] MS (ESI, m / z): [M+H] + = 403.20.

[0629] Step 5:

[0630] Synthesized according to the method of Example 9, Step 1 with the corresponding replacement of starting material compound 17-4 (70 mg, 0.17 mmol) and compound 1-3 (84 mg, 0.19 mmol) to produce 70 mg of compound 17-5 (pink solid, 50% yield).

[0631] MS (ESI, m / z): [M+H] + = 707.25 / 709.15.

[0632] Step 6:

[0633] Synthesized according to the procedure of Step 5 in Example 1, with the corresponding starting materials replaced by compound 17-5 (90 mg, 0.11 mmol). After the reaction was complete, it was purified by preparative liquid chromatography. The purification conditions were as follows: Column type X Bridge Shield RP18 OBD Column 30 x 150 mm, 5 pm; mobile phase acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate 60 mL / min; gradient acetonitrile from 35% to 50% in 17 min; detection wavelength 254 / 220 nm, retention time 11.0 min. The product fractions were collected and concentrated under reduced pressure to give 16 mg of compound 17 (white solid, yield 28%).

[0634] MS (ESI, m / z): [M+H] + = 507.20 / 509.20.

[0635] 1 H NMR (400 MHz, DMSO-d6) d 9.15 (s, 1H), 6.71 (s, 2H), 6.58 (d, J = 1.6 Hz, 1H), 6.49 (d, J = 1.6 Hz, 1H), 6.37 (s, 1H), 3.60 - 3.52 (m, 1H), 3.47 - 3.38 (m, 2H), 3.35 (s, 3H), 3.31 - 3.22 (m, 2H), 3.19 - 3.07 (m, 1H), 2.67 - 2.57 (m, 1H), 2.41 (t, J = 7.6 Hz, 2H), 2.12 - 2.00 (m, 1H), 1.84 - 1.71 (m, 1H), 1.70 - 1.56 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H).

[0636] 19 F NMR (377 MHz, DMSO-d6) d -70.47.

[0637] Example 18:

[0638] (S)-5-chloro-N 2 Preparation of (S)-5-chloro-N

[0639] Step 1:

[0640] Compound 1-8 (652 mg, 1.79 mmol) and acetone (1.3 mL, 17.7 mmol) were dissolved in methanol (5 mL) at room temperature, and then sodium cyanoborohydride (225 mg, 3.58 mmol) and acetic acid (0.2 mL, 3.49 mmol) were 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 completed, it was quenched by pouring into water (100 mL), and then extracted with ethyl acetate (100 mL x 3), and the combined organic phase was washed with saturated aqueous sodium chloride solution (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was directly purified by silica gel column (eluent: petroleum ether / ethyl acetate = 1 / 4) to obtain 450 mg of compound 18-1 (pale yellow oil, yield 86%).

[0641] MS (ESI, m / z): [M+H] + = 293.10.

[0642] 1 H NMR (400 MHz, CDCl3) δ 7.04 (d, J = 1.6 Hz, 1H), 6.82 (d, J = 1.6 Hz, 1H), 3.87-3.78 (m, 1H), 3.73-3.57 (m, 2H), 3.55-3.44 (m, 1H), 3.32-3.24 (m, 1H), 3.06-2.93 (m, 1H), 2.69 (t, J = 7.6 Hz, 2H), 2.36-2.23 (m, 1H), 2.03 (s, 1H), 1.99-1.85 (m, 1H), 1.83-1.69 (m, 2H), 1.17-1.13 (m, 6H), 0.97 (t, J = 7.2 Hz, 3H).

[0643] Step 2:

[0644] Synthesized according to the method of Step 7 in Example 1, with the raw materials replaced with compound 18-1 (200 mg, 0.68 mmol) to prepare 160 mg of compound 18-2 (pale yellow solid, yield 89%).

[0645] MS (ESI, m / z): [M+H] + = 263.20.

[0646] Step 3:

[0647] Synthesized according to the procedure of Step 1 in Example 9 with the corresponding starting materials replaced by compound 18-2 (100 mg, 0.38 mmol) and 1-3 (168 mg, 0.38 mmol) to give 130 mg of compound 18-3 (yellowish solid, yield 60%).

[0648] MS (ESI, m / z): [M+H] + = 567.25 / 569.20.

[0649] Step 4:

[0650] Synthesized according to the procedure of Step 5 in Example 1 with the corresponding starting materials replaced by compound 18-3 (110 mg, 0.19 mmol). After the reaction was complete, it was directly purified by reverse phase column C18. The purification conditions were as follows: 120 g C18 reverse phase column; mobile phase acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate 35 mL / min; gradient acetonitrile from 30% to 80% in 25 min; detection wavelength 254 nm. After confirmation by LC-MS, the fractions of the product were collected and concentrated under reduced pressure to give 59 mg of compound 18 (yellow oil, yield 66%).

[0651] MS (ESI, m / z): [M+H] + = 467.25 / 469.20.

[0652] 1 H NMR (400 MHz, DMSO-d6) δ 9.15 (s, 1H), 6.72 (s, 2H), 6.55 (d, J = 1.6 Hz, 1H), 6.49 (d, J = 1.6 Hz, 1H), 6.37 (s, 1H), 3.60-3.55 (m, 1H), 3.48-3.39 (m, 2H), 3.36 (s, 3H), 3.31-3.25 (m, 1H), 3.05-2.97 (m, 1H), 2.87-2.79 (m, 1H), 2.41 (t, J = 7.6 Hz, 2H), 2.13-2.01 (m, 1H), 1.79-1.49 (m, 4H), 1.03-0.96 (m, 6H), 0.89 (t, J = 7.2 Hz, 3H).

[0653] Example 19:

[0654] Preparation of (S)-5-chloro-N-(2-(3-(ethylamino)pyrrolidin-1-yl)-6- propylpyridin-4-yl)-6-(methylsulfonyl)pyridin-2-amine (Compound 19)

[0655] Step 1:

[0656] Synthesized according to the procedure of Step 8 in Example 1 with the corresponding starting materials replaced by compound 8-2 (100 mg, 0.29 mmol) and compound 4-2 (65 mg, 0.29 mmol) to give 75 mg of compound 19-1 (pale yellow solid, 48% yield).

[0657] MS (ESI, m / z): [M+H] + = 538.10 / 540.20.

[0658] Step 2:

[0659] Synthesized according to the procedure of Step 5 in Example 1 with the corresponding starting materials replaced by compound 19-1 (75 mg, 0.14 mmol). After the reaction was complete, it was purified by preparative liquid chromatography. The purification conditions were as follows: Column type X Bridge Prep OBD C18 Column 30 x 150 mm, 5 μm; mobile phase acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate 60 mL / min; gradient acetonitrile from 32% to 36% in 10 minutes, then 36% acetonitrile for 5 minutes; detection wavelength 254 nm / 220 nm, retention time 8.7 minutes. The product fractions were collected, concentrated under reduced pressure and lyophilized to give 20 mg of compound 19 (white solid, 33% yield).

[0660] MS (ESI, m / z): [M+H] + = 438.20 / 440.30.

[0661] 1 H NMR (400 MHz, DMSO-d6) δ 9.72 (s, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.13 (d, J = 8.8 Hz, 1H), 6.78 (d, J = 1.6 Hz, 1H), 6.54 (d, J = 1.6 Hz, 1H), 3.59 - 3.51 (m, 1H), 3.51 - 3.43 (m, 1H), 3.42 (s, 3H), 3.39 - 3.33 (m, 2H), 3.16 - 3.07 (m, 1H), 2.64 - 2.52 (m, 2H), 2.45 (t, J = 7.6 Hz, 2H), 2.12 - 2.00 (m, 1H), 1.80 - 1.67 (m, 1H), 1.70 - 1.58 (m, 2H), 1.02 (t, J = 7.2 Hz, 3H), 0.90 (t, J = 7.2 Hz, 3H).

[0662] Example 20a and 20b:

[0663] 5-chloro-6-(cyclopropylsulfonyl)-N2 (2-(3aS or 3aR, 7aS or 7aR)-octahydro-lH-pyrrolo[3,2-b]pyridin-l-yl)-6- propylpyridin-4-yl)pyridine-2,4-diamine (Compound 20a); and 5-chloro-6-(cyclopropylsulfonyl)-N 2 (2-(3aR or 3aS, 7aR or 7aS)-octahydro-lH-pyrrolo[3,2-b]pyridin-l-yl)-6- propylpyridin-4-yl)pyridine-2,4-diamine (Compound 20b)

[0664] Step 1:

[0665] Synthesized according to the method of Step 1 in Example 1, with the corresponding starting materials replaced by Compound 1-1 (1.0 g, 5.06 mmol) and sodium cyclopropylsulfinate (1.3 g, 10.1 mmol; CAS: 910209-21-1, purchased directly from Shanghai Titan Scientific Co., Ltd.), to give 300 mg of Compound 20-1 (white solid, yield 22%).

[0666] MS (ESI, m / z): [M+H] + = 266.90 / 268.85 / 270.85.

[0667] 1 H NMR (400 MHz, CDCl3) δ 6.80 (s, 1H), 5.10 (s, 2H), 3.20-2.86 (m, 1H), 1.44-1.33 (m, 2H), 1.24-1.02 (m, 2H).

[0668] Step 2:

[0669] Synthesized according to the method of Step 2 in Example 1, with the corresponding starting materials replaced by Compound 20-1 (300 mg, 1.13 mmol), to give 420 mg of Compound 20-2 (white solid, yield 80%).

[0670] MS (ESI, m / z): [M+H] + = 467.20 / 469.25 / 471.20.

[0671] 1 H NMR (400 MHz, CDCl3) δ 7.41 (s, 1H), 4.20-4.03 (m, 1H), 1.45 (s, 18H), 1.32-1.15 (m, 4H).

[0672] Step 3:

[0673] Synthesized according to the method of Step 1 in Example 9, with the corresponding starting materials replaced by compound 15-5 (50 mg, 0.14 mmol) and compound 20-2 (71 mg, 0.15 mmol) to give 40 mg of compound 20-3 (white solid, yield 36%).

[0674] MS (ESI, m / z): [M+H] + = 791.40 / 793.30.

[0675] Step 4:

[0676] Synthesized according to the method of Step 5 in Example 1, with the corresponding starting material replaced by compound 20-3 (40 mg, 0.05 mmol) to give 20 mg of compound 20 (racemate, white solid, yield 81%).

[0677] MS (ESI, m / z): [M+H] + = 491.20 / 493.15.

[0678] Step 5:

[0679] Chiral resolution of racemate 20 (20 mg, 0.04 mmol) was performed with the following conditions: Chiral column CHIRALPAK IG, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (0.5% 2 mol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isocratic 25% B; detection wavelength 210 / 271 nm; the front peak fraction was obtained with retention time 6.1 min, and after concentration under reduced pressure and lyophilization, 4.2 mg of optically pure compound 20a (white solid, yield 21%) was obtained; the back peak fraction was obtained with retention time 8.4 min, and after concentration under reduced pressure and lyophilization, 4.9 mg of optically pure compound 20b (white solid, yield 25%) was obtained.

[0680] Compound 20a:

[0681] MS (ESI, m / z): [M+H] + = 491.25 / 493.20.

[0682] 1H NMR (400 MHz, DMSO-d6) δ 9.11 (s, IH), 6.74 (d, J = 1.6 Hz, IH), 6.68 (s, 2H), 6.52 (d, J = 1.6 Hz, IH), 6.36 (s, IH), 3.83-3.73 (m, IH), 3.50-3.38 (m, 2H), 3.31-3.20 (m, 2H), 3.14-3.01 (m, IH), 2.74-2.54 (m, 2H), 2.44-2.29 (m, 2H), 2.20-2.01 (m, 2H), 1.80-1.68 (m, IH), 1.71-1.52 (m, 2H), 1.50-1.38 (m, 2H), 1.38-1.20 (m, IH), 1.18-1.04 (m, 4H), 0.89 (t, J = 7.2 Hz, 3H).

[0683] Compound 20b:

[0684] MS (ESI, m / z): [M+H] + = 491.25 / 493.15.

[0685] 1 H NMR (400 MHz, DMSO-d6) δ 9.13 (s, IH), 6.76 (d, J = 1.6 Hz, IH), 6.68 (s, 2H), 6.53 (d, J = 1.6 Hz, IH), 6.36 (s, IH), 3.90-3.76 (m, IH), 3.57-3.40 (m, 2H), 3.35-3.22 (m, 2H), 3.12-2.99 (m, IH), 2.79-2.61 (m, 2H), 2.42-2.35 (m, 2H), 2.23-2.05 (m, 2H), 1.82-1.72 (m, IH), 1.69-1.54 (m, 2H), 1.54-1.24 (m, 3H), 1.18-1.05 (m, 4H), 0.89 (t, J = 7.2 Hz, 3H).

[0686] Examples 21a and 21b:

[0687] 5-chloro-6-(ethylsulfonyl)-N 2 -(2-(3aR or 3aS, 6aR or 6aS)-hexahydropyrrolo[3,2-b]pyrrol-l(2H)-yl)-6- propylpyridin-4-yl)pyridine-2,4-diamine (Compound 21a); and

[0688] 5-chloro-6-(ethylsulfonyl)-N 2Preparation of (2-(3aS or 3aR, 6aS or 6aR)-hexahydropyrrolo[3,2-b]pyrrol-l(2H)-yl)-6- propylpyridin-4-yl)pyridine-2,4-diamine (Compound 21b)

[0689] Step 1:

[0690] Synthesized according to the method of Step 1 in Example 9, with the corresponding replacement of starting materials to Compound 13-1 (100 mg, 0.29 mmol) and Compound 15-2 (144 mg, 0.32 mmol), to give 120 mg of Compound 21-1 (white solid, yield 54%).

[0691] MS (ESI, m / z): [M+H] + = 765.30 / 767.20.

[0692] Step 2:

[0693] Synthesized according to the method of Step 5 in Example 1, with the corresponding replacement of starting materials to Compound 21-1 (120 mg, 0.16 mmol), to give 60 mg of Compound 21 (racemate, yellow oil, yield 82%).

[0694] MS (ESI, m / z): [M+H] + = 465.20 / 467.20.

[0695] Step 3:

[0696] Chiral resolution of racemic Compound 21 (60 mg, 0.13 mmol) was performed under the following resolution conditions: Chiral column Lux 5u Cellulose-2, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (0.5% 2 mol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isocratic 20% B; detection wavelength 286 / 248 nm; the front peak fraction was obtained at retention time 18.6 min, to give 18.2 mg of optically pure Compound 21a (white solid, yield 30%) after concentration under reduced pressure and lyophilization; the back peak fraction was obtained at retention time 24.2 min, to give 16.6 mg of optically pure Compound 21b (pale yellow solid, yield 28%) after concentration under reduced pressure and lyophilization.

[0697] Compound 21a:

[0698] MS (ESI, m / z): [M+H] + = 465.25 / 467.20.

[0699] 1 H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 6.76 - 6.67 (m, 2H), 6.64 (d, J = 1.6 Hz, 1H), 6.55 (d, J = 1.6 Hz, 1H), 6.37 (s, 1H), 4.58 - 3.74 (m, 2H), 3.59 - 3.43 (m, 3H), 3.39 - 3.01 (m, 2H), 2.80 - 2.65 (m, 2H), 2.47 - 2.33 (m, 2H), 2.18 - 1.71 (m, 3H), 1.72 - 1.54 (m, 3H), 1.24 (t, J = 7.2 Hz, 3H), 0.90 (t, J = 7.2 Hz, 3H).

[0700] Compound 21b:

[0701] MS (ESI, m / z): [M+H] + = 465.25 / 467.20.

[0702] 1 H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 6.76 - 6.67 (m, 2H), 6.64 (d, J = 1.6 Hz, 1H), 6.55 (d, J = 1.6 Hz, 1H), 6.37 (s, 1H), 4.58 - 3.74 (m, 2H), 3.59 - 3.43 (m, 3H), 3.39 - 3.01 (m, 2H), 2.80 - 2.65 (m, 2H), 2.47 - 2.33 (m, 2H), 2.18 - 1.71 (m, 3H), 1.72 - 1.54 (m, 3H), 1.24 (t, J = 7.2 Hz, 3H), 0.90 (t, J = 7.2 Hz, 3H).

[0703] Example 22a and 22a:

[0704] 5-chloro-6-(isopropylsulfonyl)-N 2 -(2-(3aS or 3aR, 7aS or 7aR)-octahydro-lH-pyrrolo[3,2-b]pyridin-l-yl)-6- propylpyridin-4-yl)pyridine-2,4-diamine (Compound 22a); and 5-chloro-6-(isopropylsulfonyl)-N 2 -(2-(3aR or 3aS, 7aR or 7aS)-octahydro-lH-pyrrolo[3,2-b]pyridin-l-yl)-6- propylpyridin-4-yl)pyridine-2,4-diamine (Compound 22b)

[0705] Step 1:

[0706] Synthesized according to the method of Step 1 in Example 1, with the corresponding replacement of starting materials to compound 1-1 (2.0 g, 10.1 mmol) and sodium isopropylsulfinate (2.69 g, 20.4 mmol; CAS: 4160-19-4, directly purchased from Shanghai Biotech Co., Ltd.), to give 330 mg of compound 22-1 (white solid, yield 12%).

[0707] MS (ESI, m / z): [M+H] + = 268.95 / 270.90 / 272.85.

[0708] 1 H NMR (300 MHz, CDCl3) δ 6.80 (s, 1H), 5.17 (s, 2H), 4.18-3.97 (m, 1H), 1.44 (d, J = 6.9 Hz, 6H).

[0709] Step 2:

[0710] Synthesized according to the method of Step 2 in Example 1, with the corresponding replacement of starting materials to compound 22-1 (330 mg, 1.23 mmol), to give 420 mg of compound 22-2 (white solid, yield 73%).

[0711] MS (ESI, m / z): [M+H] + = 469.15 / 471.10 / 473.05.

[0712] Step 3:

[0713] Synthesized according to the method of Step 1 in Example 9, with the corresponding replacement of starting materials to compound 15-5 (90 mg, 0.25 mmol) and compound 22-2 (129 mg, 0.27 mmol), to give 130 mg of compound 22-3 (white solid, yield 66%).

[0714] MS (ESI, m / z): [M+H] + = 793.35 / 795.30.

[0715] Step 4:

[0716] Synthesized according to the method of Step 5 in Example 1, with the corresponding replacement of starting materials to compound 22-3 (130 mg, 0.16 mmol), to give 60 mg of compound 22 (racemate, white solid, yield 74%).

[0717] MS (ESI, m / z): [M+H]+ = 493.25 / 495.20.

[0718] Step 5:

[0719] The racemic compound 22 (60 mg, 0.12 mmol) was subjected to chiral resolution with the following resolution conditions: chiral column CHIRALPAK ID, 3 x 25 cm, 5 μm; mobile phase A: methyl tert-butyl ether (10 mol / L ammonia), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isocratic 20% B; detection wavelength 270 / 244 nm; the front peak fraction was obtained with a retention time of 5.3 min, and after concentration under reduced pressure and lyophilization, 14 mg of optically pure compound 22a (white solid, yield 23%) was obtained; the back peak fraction was obtained with a retention time of 6.7 min, and after concentration under reduced pressure and lyophilization, 13 mg of optically pure compound 22b (white solid, yield 22%) was obtained.

[0720] Compound 22a:

[0721] MS (ESI, m / z): [M+H] + = 493.25 / 495.20.

[0722] 1 H NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H), 6.79 (s, 1H), 6.69 (s, 2H), 6.43 (s, 1H), 6.36 (s, 1H), 3.97-3.82 (m, 1H), 3.82-3.71 (m, 1H), 3.49-3.35 (m, 2H), 3.31-3.21 (m, 2H), 2.73-2.55 (m, 2H), 2.44-2.31 (m, 2H), 2.19-2.02 (m, 2H), 1.79-1.70 (m, 1H), 1.68-1.54 (m, 2H), 1.49-1.39 (m, 2H), 1.41-1.31 (m, 1H), 1.33-1.17 (m, 6H), 0.90 (t, J = 7.2 Hz, 3H).

[0723] Compound 22b:

[0724] MS (ESI, m / z): [M+H] + = 493.25 / 495.20.

[0725] 1H NMR (400 MHz, DMSO-d6) δ 9.13 (s, 1H), 6.79 (s, 1H), 6.69 (s, 2H), 6.43 (s, 1H), 6.36 (s, 1H), 4.01 - 3.85 (m, 1H), 3.85 - 3.70 (m, 1H), 3.54 - 3.37 (m, 2H), 3.33 - 3.22 (m, 2H), 2.72 - 2.56 (m, 2H), 2.46 - 2.34 (m, 2H), 2.18 - 2.06 (m, 2H), 2.00 - 1.70 (m, 1H), 1.69 - 1.54 (m, 2H), 1.52 - 1.39 (m, 2H), 1.40 - 1.28 (m, 1H), 1.28 - 1.17 (m, 6H), 0.90 (t, J = 7.2 Hz, 3H).

[0726] Examples 23a and 23b:

[0727] (S or R)-5-chloro-N 2 - (2-(3-(ethylamino)-3-methylpyrrolidin-1-yl)-6-propylpyridin-4-yl)-6- (methylsulfonyl)pyridazine (Compound 23a); and

[0728] (R or S)-5-chloro-N 2 Preparation of (R or S)-5-chloro-N

[0729] Step 1:

[0730] Synthesized according to the method of Step 8 in Example 1 with the corresponding replacement of starting materials Compound 3-5 (1.0 g, 4.98 mmol) and Compound 23-1 (1.0 g, 4.98 mmol; CAS: 147459-52-7, directly purchased from the supplier Shanghai Biotech Co., Ltd.) to prepare 1.6 g of Compound 23-2 (orange solid, yield 88%).

[0731] MS (ESI, m / z): [M+H] + = 365.15.

[0732] Step 2:

[0733] Synthesized according to the method of Step 3 in Example 5 with the corresponding replacement of starting materials Compound 23-2 (600 mg, 1.65 mmol) and iodoethane (256 mg, 1.64 mmol) to prepare 360 mg of Compound 23-3 (yellow solid, yield 56%).

[0734] MS (ESI, m / z): [M+H] + = 393.25.

[0735] 1 H NMR (400 MHz, CDC13) δ 7.10 - 7.03 (m, 1H), 6.87 (s, 1H), 4.15 - 4.03 (m, 1H), 3.84 - 3.64 (m, 1H), 3.59 - 3.57 (m, 1H), 3.54 - 3.40 (m, 1H), 3.41 - 3.19 (m, 2H), 2.73 (t, J=7.6 Hz, 2H), 2.42 - 2.29 (m, 1H), 2.25 - 2.16 (m, 1H), 1.84 - 1.70 (m, 2H), 1.51 (s, 9H), 1.39 (s, 3H), 1.20 (t, J=7.2 Hz, 3H), 0.98 (t, J=7.2 Hz, 3H).

[0736] Step 3:

[0737] Synthesized according to the method of Step 7 in Example 1 with corresponding replacement of starting materials with compound 23-3 (350 mg, 0.89 mmol) to produce 220 mg of compound 23-4 (pale yellow solid, yield 68%).

[0738] MS (ESI, m / z): [M+H] + = 363.25.

[0739] Step 4:

[0740] Synthesized according to the method of Step 1 in Example 9 with corresponding replacement of starting materials with compound 23-4 (200 mg, 0.55 mmol) and compound 1-3 (188 mg, 0.55 mmol) to produce 250 mg of compound 23-5 (pale yellow solid, yield 68%).

[0741] MS (ESI, m / z): [M+H] + = 667.30 / 669.30.

[0742] Step 5:

[0743] Synthesized according to the method of Step 5 in Example 1 with corresponding replacement of starting materials with compound 23-5 (200 mg, 0.30 mmol) to produce 90 mg of compound 23 (racemate, white solid, yield 64%).

[0744] MS (ESI, m / z): [M+H] + = 467.15 / 469.20.

[0745] Step 6:

[0746] Racemic 23 (90 mg, 0.19 mmol) was subjected to chiral resolution with the following resolution conditions: Chiral column CHIRALART Cellulose-SZ, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (0.5% of 2 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isocratic 30% B; detection wavelength 284 / 248 nm; the front peak fraction was obtained with a retention time of 10.1 min, and after concentration under reduced pressure and lyophilization, 29 mg of optically pure compound 23a (white solid, yield 32%) was obtained; the back peak fraction was obtained with a retention time of 12.6 min, and after concentration under reduced pressure and lyophilization, 32 mg of optically pure compound 23b (white solid, yield 36%) was obtained.

[0747] Compound 23a:

[0748] MS (ESI, m / z): [M+H] + = 467.20 / 469.15.

[0749] 1 H NMR (400 MHz, DMSO-d6) δ 9.13 (s, 1H), 6.71 (s, 2H), 6.54 (d, J = 1.2 Hz, 1H), 6.47 (d, J = 1.2 Hz, 1H), 6.37 (s, 1H), 3.50 - 3.39 (m, 1H), 3.38 - 3.34 (m, 4H), 3.31 - 3.24 (m, 1H), 3.22 - 3.15 (m, 1H), 2.62 - 2.51 (m, 2H), 2.45 - 2.37 (m, 2H), 1.96 - 1.85 (m, 1H), 1.79 - 1.69 (m, 1H), 1.69 - 1.56 (m, 2H), 1.18 (s, 3H), 1.00 (t, J = 7.2 Hz, 3H), 0.90 (t, J = 7.2 Hz, 3H).

[0750] Compound 23b:

[0751] MS (ESI, m / z): [M+H] + = 467.25 / 469.15.

[0752] 1H NMR (400 MHz, DMSO-d6) δ 9.13 (s, 1H), 6.71 (s, 2H), 6.54 (d, J = 1.2 Hz, 1H), 6.47 (d, J = 1.2 Hz, 1H), 6.37 (s, 1H), 3.50 - 3.39 (m, 1H), 3.39 - 3.34 (m, 4H), 3.31 - 3.24 (m, 1H), 3.22 - 3.15 (m, 1H), 2.62 - 2.51 (m, 2H), 2.45 - 2.37 (m, 2H), 1.96 - 1.85 (m, 1H), 1.80 - 1.69 (m, 1H), 1.69 - 1.56 (m, 2H), 1.18 (s, 3H), 1.00 (t, J = 7.2 Hz, 3H), 0.90 (t, J = 7.2 Hz, 3H).

[0753] Example 24:

[0754] (S)-5-chloro-N 2 Preparation of (S)-5-chloro-N

[0755] Step 1:

[0756] Synthesized according to the method of Step 1 in Example 9 with raw materials replaced by compound 8-2 (60 mg, 0.17 mmol) and compound 15-2 (77 mg, 0.17 mmol) to give 50 mg of compound 24-1 (brown solid, yield 38%).

[0757] MS (ESI, m / z): [M+H] + = 767.40 / 769.30.

[0758] Step 2:

[0759] Compound 24-1 (50 mg, 0.065 mmol) was dissolved in dichloromethane (1.0 mL) at 0 °C, and trifluoroacetic acid (0.3 mL) was added slowly by syringe. After the addition was complete, the reaction was allowed to warm to room temperature and stirred for 2 h. The reaction was monitored by LC-MS. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was purified directly by preparative liquid chromatography. The purification conditions were as follows: column type X Bridge Prep OBD C18 30 x 150 mm, 5 μm; mobile phase acetonitrile and water (0.05% ammonia); flow rate 60 mL / min; gradient acetonitrile from 30% to 42% over 17 min; detection wavelength 254 nm / 220 nm, retention time 10.5 min. The product fractions were collected, concentrated under reduced pressure, and lyophilized to give 10 mg of compound 24 (racemic, white solid, 33% yield).

[0760] MS (ESI, m / z): [M+H] + = 467.30 / 469.20.

[0761] 1 H NMR (400 MHz, DMSO-d6) δ 9.14 (s, 1H), 6.70 (s, 2H), 6.63 (d, J = 1.6 Hz, 1H), 6.46 (d, J = 1.6 Hz, 1H), 6.37 (s, 1H), 3.58 - 3.49 (m, 3H), 3.49 - 3.39 (m, 1H), 3.32 - 3.26 (m, 2H), 3.13 - 3.04 (m, 1H), 2.62 - 2.52 (m, 2H), 2.41 (d, J = 7.2 Hz, 2H), 2.11 - 1.99 (m, 1H), 1.77 - 1.69 (m, 1H), 1.67 - 1.58 (m, 2H), 1.24 (t, J = 7.2 Hz, 3H), 1.02 (t, J = 7.2 Hz, 3H), 0.90 (t, J = 7.2 Hz, 3H).

[0762] Examples 25a and 25b:

[0763] (S or R)-5-chloro-N 2 -(2-(3-(cyclopropylamino)pyrrolidin-1-yl)-6-propylpyridin-4-yl)-6- (methylsulfonyl)pyridazine (Compound 25a); and

[0764] (R or S)-5-chloro-N 2 -(2-(3-(cyclopropylamino)pyrrolidin-1-yl)-6-propylpyridin-4-yl)-6- (methylsulfonyl)pyridazine (Compound 25b)

[0765] Step 1:

[0766] Synthesized according to the method in Step 3 in Example 13, with the corresponding replacement of raw materials to compound 25-1 (1.0 g, 4.42 mmol; CAS: 887587-25-9, directly purchased from Shanghai Xinyuan Pharmaceutical Technology Co., Ltd.), to prepare 1.0 g of hydrochloride compound 25-2 (brown oil, yield 139%, crude).

[0767] 1 H NMR (400 MHz, D20) δ 6.24-6.10 (m, 1H), 5.77-5.71 (m, 1H), 5.66 (m, 2H), 5.49-5.40 (m, 1H), 5.03-4.91 (m, 1H), 4.61-4.38 (m, 2H), 3.26-3.14 (m, 2H), 2.98 (m, 2H).

[0768] Step 2:

[0769] Synthesized according to the method in Step 8 in Example 1, with the corresponding replacement of raw materials to compound 25-2 (643 mg, 3.97 mmol) and compound 3-5 (795 mg, 3.97 mmol), to prepare 400 mg of compound 25-3 (yellow oil, yield 35%).

[0770] MS (ESI, m / z): [M+H] + = 291.15.

[0771] 1 H NMR (400 MHz, CDCl3) δ 7.04 (d, J = 1.6 Hz, 1H), 6.83 (d, J = 1.6 Hz, 1H), 3.84-3.75 (m, 1H), 3.72-3.60 (m, 2H), 3.56-3.39 (m, 2H), 2.69 (d, J = 7.6 Hz, 2H), 2.34-2.21 (m, 2H), 2.09-1.98 (m, 1H), 1.76 (m, 2H), 0.97 (d, J = 7.2 Hz, 3H), 0.60-0.42 (m, 4H).

[0772] Step 3:

[0773] Synthesized according to the method in Step 7 in Example 1, with the corresponding replacement of raw materials to compound 25-3 (200 mg, 0.69 mmol), to prepare 150 mg of compound 25-4 (yellow oil, yield 84%).

[0774] MS (ESI, m / z): [M+H] + = 261.20.

[0775] 1 H NMR (400 MHz, CDC13) δ 5.82 (d, J = 1.6 Hz, 1H), 5.44 (d, J = 1.6 Hz, 1H), 4.01 - 3.82 (m, 1H), 3.78 - 3.67 (m, 1H), 3.62 - 3.48 (m, 2H), 3.47 - 3.37 (m, 1H), 3.31 - 3.20 (m, 1H), 2.64 - 2.43 (m, 2H), 2.25 - 2.09 (m, 2H), 1.92 - 1.80 (m, 1H), 1.78 - 1.40 (m, 4H), 0.96 (t, J = 7.2 Hz, 3H), 0.50 - 0.43 (m, 2H), 0.40 - 0.33 (m, 2H).

[0776] Step 4:

[0777] Synthesized according to the method of Step 8 in Example 1, with the corresponding replacement of starting materials compound 25-4 (150 mg, 0.57 mmol) and compound 1-3 (251 mg, 0.57 mmol), to give 90 mg of compound 25-5 (yellow solid, yield 28%).

[0778] MS (ESI, m / z): [M+H] + = 565.25 / 567.20.

[0779] Step 5:

[0780] Synthesized according to the method of Step 5 in Example 1, with the corresponding replacement of starting materials compound 25-5 (90 mg, 0.16 mmol), to give 60 mg of compound 25 (racemate, yellow solid, yield 81%).

[0781] MS (ESI, m / z): [M+H] + = 465.20 / 467.10.

[0782] Step 6:

[0783] Chiral resolution of racemic 25 (50 mg, 0.11 mmol) was performed with the following conditions: Chiral column CHIRALPAK IM, 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: isocratic 30% B; detection wavelength 230 / 272 nm; retention time 11.6 min for the fore peak fraction, which gave 3.4 mg of optically pure compound 25a (white solid, yield 7%) after concentration under reduced pressure and lyophilization; retention time 13.1 min for the back peak fraction, which gave 4.1 mg of optically pure compound 25b (white solid, yield 8%) after concentration under reduced pressure and lyophilization.

[0784] Compound 25a:

[0785] MS (ESI, m / z): [M+H] + = 465.20 / 467.15.

[0786] 1 H NMR (400 MHz, DMSO-d6) δ 9.14 (s, 1H), 6.70 (s, 2H), 6.58-6.51 (m, 1H), 6.51-6.44 (m, 1H), 6.36 (s, 1H), 3.60-3.47 (m, 2H), 3.30-3.25 (m, 3H), 3.22-3.08 (m, 3H), 2.44-2.36 (m, 2H), 2.12-1.97 (m, 2H), 1.90-1.73 (m, 1H), 1.70-1.52 (m, 2H), 0.89 (t, J = 7.2 Hz, 3H), 0.44-0.32 (m, 2H), 0.30-0.15 (m, 2H).

[0787] Compound 25b:

[0788] MS (ESI, m / z): [M+H] + = 465.20 / 467.15.

[0789] 1H NMR (400 MHz, DMSO-d6) δ 9.14 (s, 1H), 6.71 (s, 2H), 6.54 (s, 1H), 6.48 (d, J = 1.6 Hz, 1H), 6.37 (s, 1H), 3.62 - 3.50 (m, 2H), 3.44 - 3.35 (m, 3H), 3.24 - 3.09 (m, 3H), 2.45 - 2.30 (m, 2H), 2.13 - 1.97 (m, 2H), 1.85 - 1.69 (m, 1H), 1.69 - 1.54 (m, 2H), 0.89 (t, J = 7.2 Hz, 3H), 0.43 - 0.31 (m, 2H), 0.25 - 0.18 (m, 2H).

[0790] Example 26:

[0791] (S)-N-(1-(4-(5-amino-4-chloro-6-(methylsulfonyl)pyridin-2-yl)amino)-6- propylpyridin-2-yl)pyrrolidin-3-yl)acetamide (Compound 26a); and

[0792] (S)-N-(1-(4-(3-amino-6-chloro-2-(methylsulfonyl)pyridin-4-yl)amino)-6- propylpyridin-2-yl)pyrrolidin-3-yl)acetamide (Compound 26b)

[0793] Step 1:

[0794] Synthesized according to the method of Step 1 in Example 1, with the raw material replaced accordingly to Compound 26-1 (10.0 g, 61.4 mmol; CAS: 62476-56-6, directly purchased from Shanghai Biotech Co., Ltd.), to prepare 1.0 g of Compound 26-2 (brown solid, yield 8%).

[0795] MS (ESI, m / z): [M+H] + = 206.90 / 208.80.

[0796] 1 H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H), 4.92 - 4.37 (m, 2H), 3.17 (s, 3H).

[0797] Step 2:

[0798] Compound 26-2 (800 mg, 3.87 mmol) and trifluoromethanesulfonic acid were dissolved in hexafluoroisopropanol (8 mL) at room temperature, and then trichloroisocyanuric acid (1.1 g, 4.74 mmol; CAS: 87-90-1, directly purchased from Anhui Zesheng Technology Co., Ltd.) was slowly added dropwise into the above reaction solution. After the addition was completed, the reaction system was heated to 60°C, and stirred at this condition for 3 hours. The reaction system was monitored by liquid chromatography-mass spectrometry. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The obtained residue was directly purified by 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 increased from 5% to 15% in 20 minutes; detection wavelength: 254 nm. The fraction of the product was collected, concentrated under reduced pressure and lyophilized to obtain 250 mg of compound 26-3 (brown solid, yield 27%).

[0799] MS (ESI, m / z): [M-H] - = 238.90 / 240.90 / 242.90.

[0800] Step 3:

[0801] Synthesized according to the method in step 2 in example 3, with the raw materials replaced accordingly by compound 26-3 (250 mg, 1.04 mmol), to prepare 150 mg of compound 26-4 (brown solid, yield 42%).

[0802] MS (ESI, m / z): [M+H] + = 341.05 / 343.00 / 345.00.

[0803] Step 4:

[0804] Synthesized according to the method in step 8 in example 1, with the raw materials replaced accordingly by compound 1-10 (123 mg, 0.47 mmol) and 26-4 (159 mg, 0.47 mmol). After the reaction was completed, direct purification was performed by a silica gel column (eluent: dichloromethane / methanol = 10 / 1), and the obtained fraction was concentrated under reduced pressure to obtain 100 mg of compound 26-5a (brown solid, yield 38%) and 20 mg of compound 26-5b (brown solid, yield 8%).

[0805] Compound 26-5a:

[0806] MS (ESI, m / z): [M+H] + = 567.20 / 569.15.

[0807] Compound 26-5b:

[0808] MS (ESI, m / z): [M+H] + = 567.15 / 569.20.

[0809] Step 5:

[0810] The starting material 26-5a (20 mg, 0.035 mmol) was dissolved in acetonitrile (1 mL) at room temperature under nitrogen atmosphere. To the above solution, sodium iodide (10.4 mg, 0.07 mmol) and chlorotrimethylsilane (5.4 mg, 0.05 mmol) were added sequentially. The reaction was heated to 80 °C and stirred for 3 hours. The reaction progress was monitored by LCMS. After the reaction was completed, the reaction was allowed to cool to room temperature and concentrated under reduced pressure. The residue was directly purified by preparative liquid chromatography. The purification conditions were as follows: Column type X Bridge Prep OBD C18 Column 30 x 150 mm, 5 mm; mobile phase acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate 60 mL / min; gradient acetonitrile from 17% to 47% in 10 minutes, then 34% acetonitrile for 10 minutes; detection wavelength 254 nm / 220 nm, retention time 7.9 minutes. The product fractions were collected, concentrated under reduced pressure and lyophilized to give 9.5 mg of compound 26a (light yellow solid, yield 58%).

[0811] MS (ESI, m / z): [M+H] + = 467.20 / 469.15.

[0812] 1 H NMR (400 MHz, DMSO-d6) δ 9.57 - 9.29 (m, 1H), 8.12 (d, J = 6.8 Hz, 1H), 7.64 (s, 1H), 6.88 (d, J = 1.6 Hz, 1H), 6.77 (s, 2H), 6.55 (d, J = 1.6 Hz, 1H), 4.39 - 4.24 (m, 1H), 3.62 - 3.39 (m, 3H), 3.26 - 3.17 (m, 1H), 3.00 (s, 3H), 2.46 - 2.41 (m, 2H), 2.19 - 2.09 (m, 1H), 1.90 - 1.74 (m, 4H), 1.71 - 1.57 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H).

[0813] Step 6:

[0814] Synthesized according to the procedure of Step 5 in Example 26, with the corresponding starting materials replaced by compound 26-5b (20 mg, 0.035 mmol). After the reaction was complete, it was purified by preparative liquid chromatography. The purification conditions were as follows: Column type X Bridge Prep OBD C18 Column 30 x 150 mm, 5 μm; mobile phase acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate: 60 mL / min; gradient acetonitrile from 26% to 42% in 10 min, detection wavelength 254 nm / 220 nm, retention time 10.2 min. The product fractions were collected, concentrated under reduced pressure and lyophilized to give 3 mg of compound 26b (white solid, yield 18%).

[0815] MS (ESI, m / z): [M+H] + = 467.20 / 469.20.

[0816] 1 H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.72-8.50 (m, 1H), 8.14 (d, J = 6.5 Hz, 1H), 7.62 (s, 1H), 7.05-6.87 (m, 2H), 6.71 (s, 1H), 4.40-4.26 (m, 1H), 3.66-3.57 (m, 1H), 3.55-3.38 (m, 2H), 3.28-3.21 (m, 1H), 3.00 (s, 3H), 2.53-2.51 (m, 2H), 2.21-2.10 (m, 1H), 1.92-1.79 (m, 4H), 1.73-1.57 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H).

[0817] Example 27a and 27b:

[0818] (S or R)-N-(1-(4-(5-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-6- propylpyridin-2-yl)piperidin-3-yl)acetamide (compound 27a); and

[0819] Preparation of (R or S)-N-(1-(4-(5-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-6- propylpyridin-2-yl)piperidin-3-yl)acetamide (compound 27b)

[0820] Step 1:

[0821] The procedure according to step 8 in example 1 was followed, replacing the starting materials accordingly with 3-8 (150 mg, 0.54 mmol) and compound 12-3 (136 mg, 0.54 mmol) to produce 150 mg of compound 27 (racemate, white solid, yield 62%).

[0822] MS (ESI, m / z): [M+H] + = 446.20.

[0823] 1 H NMR (400 MHz, CDC13) δ 7.53 (d, J = 8.4 Hz, 1H), 7.24 - 7.12 (m, 1H), 7.08 (d, J = 8.4 Hz, 1H), 6.76 (s, 1H), 6.61 - 6.56 (m, 1H), 6.23 (d, J = 6.8 Hz, 1H), 4.05 - 3.99 (m, 1H), 3.64 - 3.47 (m, 4H), 3.28 (s, 3H), 2.61 (s, 3H), 2.60 - 2.52 (m, 2H), 1.97 (s, 3H), 1.88 - 1.81 (m, 1H), 1.80 - 1.67 (m, 4H), 1.67 - 1.59 (m, 1H), 0.96 (t, J = 7.2 Hz, 3H).

[0824] Step 2:

[0825] The racemate 27 (150 mg, 0.34 mmol) was subjected to chiral resolution with the following resolution conditions: Chiral column CHIRALPAK ID, 3.0 x 50 mm, 3 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isocratic 20% B; detection wavelength 220 / 254 nm; the first peak fraction was obtained at a retention time of 16.7 min, which after concentration under reduced pressure and lyophilization gave 48 mg of optically pure compound 27a (white solid, yield 32%); the second peak fraction was obtained at a retention time of 21.9 min, which after concentration under reduced pressure and lyophilization gave 52 mg of optically pure compound 27b (white solid, yield 34%). a

[0826] Compound 27 a :

[0827] MS (ESI, m / z): [M+H] + = 446.25.

[0828] 1 ​H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.98 (s, 1H), 6.72 (d, J = 1.6 Hz, 1H), 4.14 - 3.98 (m, 2H), 3.72 - 3.61 (m, 1H), 3.31 (s, 3H), 2.89 - 2.78 (m, 1H), 2.70 - 2.60 (m, 1H), 2.49 - 2.48 (m, 3H), 2.47 - 2.41 (m, 2H), 1.89 - 1.78 (m, 4H), 1.75 - 1.67 (m, 1H), 1.67 - 1.57 (m, 2H), 1.55 - 1.30 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H).

[0829] Compound 27b:

[0830] MS (ESI, m / z): [M+H] + = 446.25.

[0831] 1 H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.98 (s, 1H), 6.72 (d, J = 1.6 Hz, 1H), 4.14 - 3.98 (m, 2H), 3.72 - 3.61 (m, 1H), 3.31 (s, 3H), 2.89 - 2.78 (m, 1H), 2.70 - 2.60 (m, 1H), 2.49 - 2.48 (m, 3H), 2.47 - 2.41 (m, 2H), 1.89 - 1.78 (m, 4H), 1.75 - 1.67 (m, 1H), 1.67 - 1.57 (m, 2H), 1.55 - 1.30 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H).

[0832] Example 28:

[0833] Preparation of (S)-N-(1-(6-(4-amino-3-chloro-6-(methylsulfonyl)pyridin-2-ylamino)-2- propylpyrimidin-4-yl)pyrrolidin-3-yl)acetamide (Compound 28)

[0834] Step 1:

[0835] According to the method for synthesizing Step 1 in Embodiment 1, the raw material was replaced by compound 28-1 (5.0 g, 30.7 mmol; CAS: 2587-02-2, directly purchased from Shanghai Hauhun Biomedical Technology Co., Ltd.) to prepare 1.5 g of compound 28-2 (white solid, yield 23%).

[0836] MS (ESI, m / z): [M+H] + = 206.90 / 208.85.

[0837] 1 H NMR (400 MHz, CDCl3) δ 7.23 (d, J = 2.0 Hz, 1H), 6.68 (d, J = 2.0 Hz, 1H), 4.73 (s, 2H), 3.20 (s, 3H).

[0838] Step 2:

[0839] Compound 28-2 (1.5 g, 7.26 mmol) was dissolved in acetonitrile (20 mL) at room temperature, and then N-chlorosuccinimide (970 mg, 7.26 mmol) was added to the above reaction solution. The reaction system was heated to 80°C, and stirred at this temperature for 4 hours. The reaction progress was monitored by liquid chromatography. After the reaction was completed, the reaction mixture was directly concentrated under reduced pressure, and the obtained residue was directly purified by silica gel column (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain 700 mg of compound 28-3 (white solid, yield 40%).

[0840] MS (ESI, m / z): [M+H] + = 241.00 / 243.00 / 245.05.

[0841] 1 H NMR (300 MHz, CDCl3) δ 7.35 (s, 1H), 5.17 (s, 2H), 3.20 (s, 3H).

[0842] Step 3:

[0843] According to the method for synthesizing Step 2 in Embodiment 3, the raw material was replaced by compound 28-3 (400 mg, 1.67 mmol) to prepare 300 mg of compound 28-4 (white solid, yield 53%).

[0844] MS (ESI, m / z): [M+H] + = 340.90 / 342.85 / 344.90.

[0845] 1 H NMR (300 MHz, CDC13) δ 8.94 (s, 1H), 7.43 (s, 1H), 3.22 (s, 3H), 1.55 (s, 9H).

[0846] Step 4:

[0847] Synthesized according to the method of Step 3 in Example 1, with the raw materials replaced accordingly with 28-5 (15.0 g, 81.8 mmol; CAS: 3764-01-0, purchased directly from the supplier Shanyou Technology Co., Ltd.) and 1-5 (15.2 g, 81.8 mmol; CAS: 122536-76-9, purchased directly from the supplier Shanyou Technology Co., Ltd.), to prepare 15.0 g of compound 28-6 (white solid, yield 55%).

[0848] MS (ESI, m / z): [M+H] + = 333.15.

[0849] 1 H NMR (400 MHz, CDC13) δ 6.22 (s, 1H), 4.71 (s, 1H), 4.39-4.19 (m, 1H), 4.03-3.09 (m, 4H), 2.43-1.79 (m, 2H), 1.45 (s, 9H).

[0850] Step 5:

[0851] Synthesized according to the method of Step 5 in Example 1, with the raw materials replaced accordingly with compound 28-6 (15.0 g, 45.0 mmol), to prepare 16.3 g of trifluoroacetate compound 28-7 (yellow oil, yield 104%, crude).

[0852] MS (ESI, m / z): [M+H] + = 233.15.

[0853] Step 6:

[0854] Synthesized according to the method of Step 6 in Example 1, with the raw materials replaced accordingly with compound 28-7 (10.0 g, 28.9 mmol, crude), to prepare 5.00 g of compound 28-8 (white solid, yield 63%).

[0855] MS (ESI, m / z): [M+H] + = 275.05.

[0856] 1H NMR (400 MHz, CDC13) δ 7.13 - 6.78 (m, 1H), 6.18 (d, J = 3.2 Hz, 1H), 4.73 - 4.52 (m, 1H), 3.91 - 3.46 (m, 3H), 3.44 - 3.28 (m, 1H), 2.39 - 2.04 (m, 2H), 2.03 (s, 3H).

[0857] Step 7:

[0858] Synthesized according to the method of Step 4 in Example 1, with the raw materials replaced accordingly to 28-8 (5.00 g, 18.2 mmol), to produce 250 mg of compound 28-9 (white solid, yield 5%) and 850 mg of compound 28-10 (white solid, yield 16%).

[0859] Compound 28-9:

[0860] MS (ESI, m / z): [M+H] + = 283.12.

[0861] 1 H NMR (400 MHz, CDC13) δ 6.08 (s, 1H), 4.66 - 4.53 (m, 1H), 3.85 - 3.54 (m, 3H), 3.43 - 3.25 (m, 1H), 2.66 (t, J = 7.6 Hz, 2H), 2.33 - 2.19 (m, 1H), 2.11 - 2.04 (m, 1H), 2.01 (s, 3H), 1.85 - 1.72 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H).

[0862] Compound 28-10:

[0863] MS (ESI, m / z): [M+H] + = 283.12.

[0864] 1 H NMR (400 MHz, CDC13) δ 6.84 (s, 1H), 5.99 (s, 1H), 4.57 - 4.53 (m, 1H), 3.70 - 3.46 (m, 3H), 3.42 - 3.26 (m, 1H), 2.49 (t, J = 7.6 Hz, 2H), 2.29 - 2.11 (m, 2H), 1.98 (s, 3H), 1.72 - 1.59 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H).

[0865] Step 8:

[0866] Compound 28-9 (400 mg, 1.4 mmol) was dissolved in dimethyl sulfoxide (5.0 mL) at room temperature under nitrogen atmosphere. Copper(I) iodide (541 mg, 2.8 mmol), proline (209 mg, 1.8 mmol) and sodium azide (110 mg, 1.7 mmol) were added successively into the above solution. The reaction system was heated to 100 °C and stirred at this temperature for 2 hours. The reaction progress was monitored by liquid chromatography-mass spectrometry. The heating was stopped after the reaction was completed. The reaction system was cooled to room temperature naturally, then put into ice bath, and quenched with saturated sodium hypochlorite aqueous solution (20 mL) at 0 °C. The extraction was performed with ethyl acetate (100 mL x 3), and the combined organic phase was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was directly purified by silica gel column (eluent: petroleum ether / ethyl acetate = 2 / 1) to give 320 mg of compound 28-11 (yellowish solid, yield 86%).

[0867] MS (ESI, m / z): [M+H] + = 264.10.

[0868] Step 9:

[0869] According to the synthetic method of Step 8 in Example 1, with the raw materials being replaced by compound 28-4 (388 mg, 1.14 mmol) and compound 28-11 (300 mg, 1.14 mmol) respectively, 150 mg of compound 28-12 (yellowish solid, yield 23%) was prepared.

[0870] MS (ESI, m / z): [M+H] + = 568.20 / 570.20.

[0871] Step 10:

[0872] Compound 28-12 (150 mg, 0.26 mmol) was dissolved in dichloromethane (1 mL) at 0 °C, and trifluoroacetic acid (0.3 mL) was added slowly by syringe. The reaction was stirred at room temperature for 3 h. The reaction was monitored by LC-MS. After the reaction was completed, the reaction mixture was directly concentrated under reduced pressure. The residue was directly purified by preparative liquid chromatography. The purification conditions were as follows: column type X Bridge Prep OBD C18 Column 30 x 150 mm, 5 pm; mobile phase acetonitrile and water (10 mmol / L ammonium bicarbonate and 0.05% ammonia water); flow rate 60 mL / min; gradient acetonitrile from 12% to 42% in 13 min; detection wavelength 254 nm / 220 nm, retention time 11.7 min. The product fractions were collected, concentrated under reduced pressure and lyophilized to give 25 mg of compound 28 (white solid, yield 20%).

[0873] MS (ESI, m / z): [M+H] + = 468.30 / 470.25.

[0874] 1 H NMR (400 MHz, DMSO-d6) d 8.15 (d, J = 6.4 Hz, 1H), 7.95 (s, 1H), 7.22 - 7.09 (m, 1H), 7.07 (s, 1H), 6.99 (s, 2H), 4.40 - 4.24 (m, 1H), 3.75 - 3.36 (m, 4H), 3.20 (s, 3H), 2.54 - 2.52 (m, 2H), 2.22 - 2.06 (m, 1H), 1.93 - 1.84 (m, 1H), 1.81 (s, 3H), 1.78 - 1.65 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H).

[0875] Example 29:

[0876] Preparation of (S)-N-(4-fluoro-3-(methylsulfonyl)phenyl)-2-(3- (methylamino)pyrrolidin-1-yl)-6-propylpyridin-4-amine (Compound 29)

[0877] Step 1:

[0878] Synthesized according to the method of Example 1, Step 9, with raw materials replaced accordingly to 10-2 (100 mg, 0.30 mmol) and 29-1 (91 mg, 0.36 mmol; CAS: 914636-38-7, directly purchased from the supplier Zhuhai Obokay Biomedical Technology Co., Ltd.), to give 80 mg of compound 29-2 (white solid, yield 53%).

[0879] MS (ESI, m / z): [M+H] + = 507.20.

[0880] Step 2:

[0881] Synthesized according to the procedure of Step 5 in Example 1 with the corresponding starting materials replaced by compound 29-2 (80 mg, 0.16 mmol). After the reaction was complete, it was directly purified by reverse phase C18 column. The purification conditions were as follows: 80 g C18 reverse phase column; mobile phase acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate 25 mL / min; gradient acetonitrile from 20% to 80% in 20 min; detection wavelength 254 nm. The fractions of the product were collected and concentrated under reduced pressure to give 31 mg of compound 29 (white solid, yield 48%).

[0882] MS (ESI, m / z): [M+H] + = 407.20.

[0883] 1 H NMR (400 MHz, DMSO-d6) δ 7.89 - 7.81 (m, 1H), 7.71 - 7.62 (m, 1H), 7.48 (m, 1H), 6.35 (d, J = 2.0 Hz, 1H), 5.98 (d, J = 2.0 Hz, 1H), 4.08 - 3.98 (m, 1H), 3.94 - 3.85 (m, 1H), 3.81 - 3.69 (m, 2H), 3.69 - 3.58 (m, 1H), 3.30 (s, 3H), 2.80 (s, 3H), 2.71 (t, J = 7.6 Hz, 2H), 2.62 - 2.49 (m, 1H), 2.41 - 2.29 (m, 1H), 1.80 - 1.65 (m, 2H), 1.03 (t, J = 7.2 Hz, 3H).

[0884] 19 F NMR (377 MHz, DMSO-d6) δ -121.49.

[0885] Example 30:

[0886] Preparation of (S)-N-(4-chloro-3-(methylsulfonyl)phenyl)-2-(3-(methylamino)pyrrolidin-1-yl)-6-propylpyridin-4-amine (Compound 30)

[0887] Step 1:

[0888] Synthesized according to the procedure of Example 1, Step 1 with the corresponding starting materials replaced with 30-1 (500 mg, 2.42 mmol; CAS: 823-54-1, purchased directly from Shanghai Shaoyuan Technology Co., Ltd.) to afford 100 mg of compound 30-2 (white solid, yield 20%).

[0889] 1 H NMR (400 MHz, CDC13) δ 7.42 (d, J = 2.8 Hz, 1H), 7.27 (d, J = 8.8 Hz, 1H), 6.86-6.76 (m, 1H), 4.00 (s, 2H), 3.25 (s, 3H).

[0890] Step 2:

[0891] Synthesized according to the procedure of Example 16, Step 8 with the corresponding starting materials replaced with 30-2 (100 mg, 0.49 mmol) to afford 80 mg of compound 30-3 (white solid, yield 61%).

[0892] 1 H NMR (400 MHz, CDC13) δ 8.28 (d, J = 2.4 Hz, 1H), 7.75-7.65 (m, 1H), 7.44 (d, J = 8.4 Hz, 1H), 3.28 (s, 3H).

[0893] Step 3:

[0894] Synthesized according to the procedure of Example 1, Step 8 with the corresponding starting materials replaced with 10-2 (40 mg, 0.12 mmol) and 30-3 (38 mg, 0.14 mmol) to afford 50 mg of compound 30-4 (white solid, yield 80%).

[0895] MS (ESI, m / z): [M+H] + = 523.20 / 525.20.

[0896] Step 4:

[0897] Synthesized according to the procedure of Example 1, Step 5 with the corresponding starting materials replaced with compound 30-4 (45 mg, 0.086 mmol). After the reaction was completed, it was directly purified by reverse phase column C18. The purification conditions were as follows: 20 g C18 reverse phase column; mobile phase acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate 25 mL / min; gradient acetonitrile from 10% to 70% in 20 min; detection wavelength 254 nm. The fractions of the product were collected and concentrated under reduced pressure to give 20 mg of compound 30 (white solid, yield 55%).

[0898] MS (ESI, m / z): [M+H] + = 423.20 / 425.20.

[0899] 1 H NMR (400 MHz, DMSO-d6) d 8.91 (s, 1H), 7.84 (d, J = 2.8 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.47 - 7.40 (m, 1H), 6.13 (d, J = 1.6 Hz, 1H), 5.86 (d, J = 1.6 Hz, 1H), 3.53 - 3.45 (m, 1H), 3.44 - 3.36 (m, 2H), 3.35 (s, 3H), 3.23 - 3.15 (m, 1H), 3.14 - 3.07 (m, 1H), 2.43 (t, J = 7.6 Hz, 2H), 2.29 (s, 3H), 2.10 - 1.98 (m, 1H), 1.81 - 1.70 (m, 1H), 1.73 - 1.56 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H).

[0900] Example 31:

[0901] Preparation of (S)-N-(1-(6-((4-chloro-3-(methylsulfonyl)phenyl)amino)-2- propylpyrimidin-4-yl)pyrrolidin-3-yl)acetamide (Compound 31)

[0902] Step 1:

[0903] Synthesized according to the procedure of Step 8 in Example 1 with raw materials replaced accordingly to Compound 28-9 (200 mg, 0.71 mmol) and 30-2 (175 mg, 0.85 mmol). After the reaction was complete, purified by preparative liquid chromatography. The purification conditions were as follows: Column type X Bridge Shield RP18 OBD Column 30 x 150 mm, 5 μm; mobile phase acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate 60 mL / min; gradient acetonitrile from 25% to 55% in 10 min; detection wavelength 254 nm / 220 nm, retention time 9.1 min. The fractions of the product were collected and concentrated under reduced pressure to give 21.6 mg of Compound 31 (white solid, yield 7%).

[0904] MS (ESI, m / z): [M+H] + = 452.00 / 454.00.

[0905] 1H NMR (400 MHz, DMSO-d6) δ 9.52 (s, 1H), 8.63 (d, J = 2.8 Hz, 1H), 8.13 (d, J = 6.4 Hz, 1H), 8.00 - 7.92 (m, 1H), 7.58 (d, J = 8.8 Hz, 1H), 5.54 (s, 1H), 4.32 - 4.27 (m, 1H), 3.68 - 3.38 (m, 2H), 3.34 (s, 3H), 3.28 - 3.12 (m, 1H), 2.55 (t, J = 7.6 Hz, 2H), 2.19 - 2.06 (m, 2H), 1.93 - 1.83 (m, 1H), 1.81 (s, 3H), 1.79 - 1.70 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H).

[0906] Example 32:

[0907] Preparation of (S)-N-(l-(4-(4-chloro-3-(methylsulfonyl)phenyl)amino)-6- propylpyridin-2-yl)pyrrolidin-3-yl)acetamide (Compound 32)

[0908] Step 1:

[0909] Synthesized according to the procedure of Step 8 in Example 1, with the raw materials replaced accordingly to Compound 1-10 (150 mg, 0.57 mmol) and 30-3 (184 mg, 0.68 mmol). After the reaction was complete, purified by preparative liquid chromatography. The purification conditions were as follows: Column type X Bridge Shield RP18 OBD Column 30 x 150 mm, 5 μm; mobile phase acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate 60 mL / min; gradient acetonitrile from 23% to 53% in 10 min; detection wavelength 254 nm / 220 nm, retention time 9.1 min. The product fractions were collected and concentrated under reduced pressure to give 38 mg of Compound 32 (white solid, yield 14%).

[0910] MS (ESI, m / z): [M+H] + = 451.25 / 453.20.

[0911] 1H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.13 (d, J = 6.8 Hz, 1H), 7.82 (d, J = 2.8 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.48 - 7.41 (m, 1H), 6.16 (d, J = 1.6 Hz, 1H), 5.86 (d, J = 1.6 Hz, 1H), 4.35 - 4.23 (m, 1H), 3.61 - 3.51 (m, 1H), 3.49 - 3.37 (m, 2H), 3.36 (s, 3H), 3.22 - 3.14 (m, 1H), 2.43 (t, J = 7.6 Hz, 2H), 2.18 - 2.06 (m, 1H), 1.89 - 1.76 (m, 4H), 1.68 - 1.59 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H).

[0912] Example 33:

[0913] Preparation of (S)-N-(l-(6-(4-amino-5-chloro-6-(methylsulfonyl)pyridin-2-yl)amino)-2- propylimidazol-4-yl)pyrrolidin-3-yl)acetamide (Compound 33)

[0914] Step 1:

[0915] Synthesized according to the method of Step 1 in Example 9, with the corresponding replacement of starting materials compound 28-11 (100 mg, 0.38 mmol) and compound 1-3 (167 mg, 0.38 mmol), to give 100 mg of compound 33-1 (brown oil, yield 46%).

[0916] MS (ESI, m / z): [M+H] + = 568.15 / 570.10.

[0917] Step 2:

[0918] Synthesized according to the method of Step 5 in Example 1, with the corresponding replacement of starting materials compound 33-1 (100 mg, 0.18 mmol). After the reaction was complete, purified by preparative liquid chromatography. The purification conditions were as follows: column XB ridge Shield RP18 OBD Column 30 x 150 mm, 5 μm; mobile phase methanol and water (10 mmol / L ammonium bicarbonate); flow rate 60 mL / min; gradient acetonitrile from 30% to 50% in 17 min; detection wavelength 254 nm / 220 nm, retention time 13.2 min. The product fractions were collected, concentrated under reduced pressure and lyophilized to give 48 mg of compound 33 (white solid, yield 57%).

[0919] MS (ESI, m / z): [M+H] + = 468.20 / 470.20.

[0920] 1 H NMR (400 MHz, DMSO-d6) δ 10.96 - 9.24 (s, 1H), 8.16 (d, J = 6.4 Hz, 1H), 7.61 - 6.05 (m, 4H), 4.36 - 4.26 (m, 1H), 3.96 - 3.47 (m, 4H), 3.38 (s, 3H), 2.71 - 2.53 (m, 2H), 2.19 - 2.10 (m, 1H), 2.01 - 1.86 (m, 1H), 1.82 (s, 3H), 1.78 - 1.68 (m, 2H), 0.94 (t, J = 7.2 Hz, 3H).

[0921] Example 34:

[0922] (S)-5-chloro-N 2 Preparation of (S)-5-chloro-N

[0923] Step 1:

[0924] Compound 34-1 (10 g, 81.5 mmol; CAS: 3020-81-3, directly purchased from Jiangsu Eicobio Biomedical Research and Development Co., Ltd.) and compound 34-2 (13 g, 81.5 mmol; CAS: 105-53-3, directly purchased from Shanghai Titan Technology Co., Ltd.) were dissolved in ethanol (100 mL) at room temperature, and then sodium ethoxide (11.1 g, 163 mmol) was added to the above reaction solution. The reaction system was heated at 85°C and stirred for 16 hours, and the reaction progress was monitored by liquid chromatography. After the reaction was completed, the reaction system was naturally cooled to room temperature, and the reaction system was concentrated under reduced pressure. Water (30 mL) was added to the mixture, and then the reaction system was placed in an ice water bath, and the pH of the reaction system was adjusted to 1-2 with concentrated hydrochloric acid. After filtration, the filter cake was washed with ice water (20 mL x 2), and the obtained solid was dried to obtain 10.4 g of compound 34-3 (white solid, yield 83%).

[0925] MS (ESI, m / z): [M+H] + = 155.05.

[0926] Step 2:

[0927] Compound 34-3 (10.4 g, 67.4 mmol) and N, N-diisopropyl ethylamine (21.7 g, 168.5 mmol) were dissolved in phosphorous oxychloride (100 mL) at 0 °C. The reaction system was removed from the ice bath and then heated to 100 °C, then stirred at this condition for 15 hours. The reaction progress was monitored by liquid chromatography-mass spectrometry. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to remove most of the phosphorous oxychloride. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1), and the obtained fraction was concentrated under reduced pressure to obtain 9.0 g of compound 34-4 (pale yellow oil, yield 70%).

[0928] MS (ESI, m / z): [M+H] + = 191.00 / 193.00 / 195.05.

[0929] 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).

[0930] Step 3:

[0931] Synthesized according to the method of Example 1, Step 4, with the corresponding starting materials replaced by compound 34-4 (2.0 g, 10.47 mmol) and compound 1-5 (1.96 g, 10.74 mmol; CAS: 122536-76-9, directly purchased from Shanghai Shao Yuan Technology Co., Ltd.), to prepare 3.5 g of compound 34-5 (yellow oil, yield 98%).

[0932] MS (ESI, m / z): [M+H] + = 341.30 / 343.30.

[0933] 1 H NMR (400 MHz, CDCl3) δ 6.10 (s, 1H), 4.72 (d, J = 6.8 Hz, 1H), 4.37-4.27 (m, 1H), 3.91-3.11 (m, 4H), 2.70-2.61 (m, 2H), 2.28-2.21 (m, 1H), 2.01-1.91 (m, 1H), 1.79-1.69 (m, 2H), 1.44 (s, 9H), 0.95 (t, J = 7.2 Hz, 3H).

[0934] Step 4:

[0935] According to the method for Step 3 in Example 5, with the corresponding starting materials replaced by compound 34-5 (1.7 g, 4.99 mmol) and iodoethane (933 mg, 5.98 mmol), 1.7 g of compound 34-6 (pale yellow oil, yield 93%) was prepared.

[0936] MS (ESI, m / z): [M+H] + = 369.30 / 371.25.

[0937] 1 H NMR (400 MHz, CDCl3) δ 6.12 (s, 1H), 4.73-4.59 (m, 1H), 4.03-3.83 (m, 1H), 3.53-3.34 (m, 3H), 3.30-3.10 (m, 2H), 2.73-2.65 (m, 2H), 2.27-2.07 (m, 2H), 1.86-1.72 (m, 2H), 1.48 (s, 9H), 1.15 (t, J = 6.8 Hz, 3H), 0.97 (t, J = 7.2 Hz, 3H).

[0938] Step 5:

[0939] According to the method for Step 8 in Example 28, with the corresponding starting materials replaced by compound 34-6 (1.5 g, 4.07 mmol), 900 mg of compound 34-7 (off-white solid, yield 63%) was prepared.

[0940] MS (ESI, m / z): [M+H] + = 350.20.

[0941] 1 H NMR (400 MHz, CDCl3) δ 6.12 (s, 1H), 4.73-4.59 (m, 1H), 4.03-3.83 (m, 1H), 3.53-3.34 (m, 3H), 3.30-3.10 (m, 2H), 2.73-2.65 (m, 2H), 2.27-2.07 (m, 2H), 1.86-1.72 (m, 2H), 1.48 (s, 9H), 1.15 (t, J = 6.8 Hz, 3H), 0.97 (t, J = 7.2 Hz, 3H).

[0942] Step 6:

[0943] Synthesized according to the method of Step 1 in Example 9, with the corresponding starting materials replaced by compound 34-7 (120 mg, 0.34 mmol) and compound 1-3 (151 mg, 0.34 mmol) to give 150 mg of compound 34-8 (brown oil, yield 67%).

[0944] 1 H NMR (400 MHz, CDC13) δ 8.51 (s, 1H), 7.43-7.37 (m, 1H), 7.23-6.92 (m, 1H), 6.62 (s, 1H), 4.81-4.54 (m, 1H), 4.06-3.60 (m, 1H), 3.45-3.33 (m, 1H), 3.31 (s, 3H), 3.29-3.15 (m, 2H), 2.71-2.58 (m, 2H), 2.26-2.05 (m, 2H), 1.90-1.76 (m, 2H), 1.75-1.63 (m, 2H), 1.55 (s, 9H), 1.48 (s, 9H), 1.16 (t, J = 7.2 Hz, 3H), 1.00 (t, J = 7.2 Hz, 3H).

[0945] Step 7:

[0946] Synthesized according to the method of Step 5 in Example 1, with the corresponding starting materials replaced by compound 34-8 (150 mg, 0.23 mmol). After the reaction was complete, it was purified by preparative liquid chromatography. The purification conditions were as follows: column type X Bridge Shield Phenyl OBD Column 30 x 150 mm, 5 pm; mobile phase acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate 60 mL / min; gradient acetonitrile from 23% to 38% in 17 min; detection wavelength 254 / 220 nm, retention time 5.5 min. The product fractions were collected and concentrated under reduced pressure to give 70 mg of compound 34 (white solid, yield 67%).

[0947] MS (ESI, m / z): [M+H] + = 454.25 / 456.20.

[0948] 1H NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 6.94 (s, 1H), 6.76 (s, 2H), 6.72 (s, 1H), 3.68-3.40 (m, 2H), 3.37 (s, 3H), 3.34-3.24 (m, 2H), 3.19-3.10 (m, 1H), 2.69-2.55 (m, 3H), 2.19-1.95 (m, 1H), 1.85-1.65 (m, 4H), 1.02 (t, J = 7.2 Hz, 3H), 0.93 (t, J = 7.2 Hz, 3H).

[0949] Examples 35a and 35b:

[0950] 4-chloro-5-(methylsulfonyl)-N 1 -(2-((3aS or 3aR, 7aS or 7aR)-octahydro-lH-pyrrolo[3,2-b]pyridin-l-yl)-6- propylpyridin-4-yl)benzene-l,3-diamine (Compound 35a); and

[0951] 4-chloro-5-(methylsulfonyl)-N 1 -(2-((3aR or 3aS, 7aR or 7aS)-octahydro-lH-pyrrolo[3,2-b]pyridin-l-yl)-6- propylpyridin-4-yl)benzene-l,3-diamine (Compound 35b)

[0952] Step 1:

[0953] Synthesized according to the method of Step 1 in Example 9, with the raw materials replaced accordingly to Compound 35-1 (4.0 g, 12.7 mmol; CAS: 20098-47-9, directly purchased from the supplier Shanghai Bide Pharmaceutical Technology Co., Ltd.) and Compound tert-butyl carbamate (1.6 g, 13.7 mmol; CAS: 4248-19-5, directly purchased from the supplier Shanghai Shaoyuan Technology Co., Ltd.), to prepare 2.5 g of Compound 35-2 (brown solid, yield 56%).

[0954] MS (ESI, m / z): [M-H] - = 348.95 / 350.90 / 352.95.

[0955] 1 H NMR (400 MHz, CDCl3) δ 9.14 (d, J = 2.4 Hz, 1H), 8.16 (d, J = 2.4 Hz, 1H), 7.14-7.06 (m, 1H), 1.56 (s, 9H).

[0956] Step 2:

[0957] Synthesized according to the method of step 5 in example 16 with corresponding replacement of starting materials with compound 35-2 (2.0 g, 5.72 mmol) to give 1.1 g of compound 35-3 (yellow solid, yield 60%).

[0958] 1 H NMR (400 MHz, CDCl3) δ 8.91 (d, J = 2.4 Hz, 1H), 7.69-7.64 (m, 1H), 7.17 (s, 1H), 2.57 (s, 3H), 1.56 (s, 9H).

[0959] Step 3:

[0960] Synthesized according to the method of step 3 in example 2 with corresponding replacement of starting materials with compound 35-3 (1.1 g, 3.46 mmol) to give 700 mg of compound 35-4 (yellow oil, yield 58%).

[0961] MS (ESI, m / z): [M-H] - = 349.00 / 351.05.

[0962] 1 H NMR (400 MHz, CDCl3) δ 9.45 (d, J = 2.8 Hz, 1H), 8.66 (d, J = 2.8 Hz, 1H), 7.37 (s, 1H), 3.30 (s, 3H), 1.58 (s, 9H).

[0963] Step 4:

[0964] Synthesized according to the method of step 7 in example 1 with corresponding replacement of starting materials with compound 35-4 (640 mg, 1.83 mmol) to give 440 mg of compound 35-5 (brown oil, yield 75%).

[0965] MS (ESI, m / z): [M-H] - = 319.00 / 321.00.

[0966] 1 H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 2.8 Hz, 1H), 7.17-7.13 (m, 2H), 3.22 (s, 3H), 1.54 (s, 9H).

[0967] Step 5:

[0968] Synthesized according to the method of step 8 in example 1 with the corresponding replacement of starting materials with compound 35-6 (213 mg, 0.56 mmol) and 15-5 (202 mg, 0.56 mmol) to give 112 mg of compound 35-7 (brown solid, yield 30%).

[0969] 1 H NMR (400 MHz, CDC13) δ 8.67 (d, J = 2.4 Hz, 1H), 7.89 (d, J = 2.4 Hz, 1H), 7.13 (s, 1H), 3.18 (s, 3H), 1.48 (s, 9H).

[0970] Step 6:

[0971] Synthesized according to the method of step 8 in example 1 with the corresponding replacement of starting materials with compound 35-6 (213 mg, 0.56 mmol) and 15-5 (202 mg, 0.56 mmol) to give 112 mg of compound 35-7 (brown solid, yield 30%).

[0972] MS (ESI, m / z): [M+H] + = 664.30 / 666.25.

[0973] Step 7:

[0974] Synthesized according to the method of step 5 in example 1 with the corresponding replacement of starting materials with compound 35-7 (113 mg, 0.17 mmol) to give 57 mg of compound 35 (racemate, yellow solid, yield 72%).

[0975] MS (ESI, m / z): [M+H] + = 464.20 / 466.15.

[0976] Step 8:

[0977] Chiral resolution of racemic compound 35 (57 mg, 0.12 mmol) was performed with the following resolution conditions: Chiral column CHIRALPAK IG, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isocratic 30% B; detection wavelength 210 / 220 nm; retention time 22.5 min to give the fore peak fraction, which after concentration under reduced pressure and lyophilization gave 14 mg of optically pure compound 35a (off-white solid, yield 25%); retention time 31.7 min to give the back peak fraction, which after concentration under reduced pressure and lyophilization gave 13 mg of optically pure compound 35b (off-white solid, yield 23%).

[0978] Compound 35a:

[0979] MS (ESI, m / z): [M+H] + = 464.15 / 466.15.

[0980] 1 H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 7.05 (d, J = 2.8 Hz, 1H), 6.90 (d, J = 2.8 Hz, 1H), 6.06 (s, 1H), 5.86 (s, 2H), 5.82 (s, 1H), 3.78-3.68 (m, 1H), 3.45-3.34 (m, 2H), 3.29 (s, 3H), 3.27-3.19 (m, 1H), 2.71-2.55 (m, 2H), 2.44-2.34 (m, 2H), 2.18-2.04 (m, 2H), 1.76-1.70 (m, 1H), 1.69-1.56 (m, 2H), 1.49-1.40 (m, 2H), 1.30-1.22 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H).

[0981] Compound 35b:

[0982] MS (ESI, m / z): [M+H] + = 464.20 / 466.15.

[0983] 1 H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 7.05 (d, J = 2.4 Hz, 1H), 6.90 (d, J = 2.4 Hz, 1H), 6.06 (d, J = 1.6 Hz, 1H), 5.86 (s, 2H), 5.82 (s, 1H), 3.78-3.68 (m, 1H), 3.45-3.34 (m, 2H), 3.29 (s, 3H), 3.27-3.19 (m, 1H), 2.73-2.56 (m, 2H), 2.44-2.35 (m, 2H), 2.18-2.04 (m, 2H), 1.75-1.71 (m, 1H), 1.69-1.56 (m, 2H), 1.47-1.42 (m, 2H), 1.30-1.21 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H).

[0984] Example 36:

[0985] Preparation of (S)-N-(1-(4-(3-amino-4-chloro-5-(methylsulfonyl)phenyl)amino)-6- propylpyridin-2-yl)pyrrolidin-3-yl)acetamide (Compound 36)

[0986] Step 1:

[0987] Synthesized according to the procedure of Step 1 in Example 9 with the corresponding starting materials replaced by 1-10 (100 mg, 0.38 mmol) and 35-6 (146 mg, 0.38 mmol) to give 120 mg of compound 36-1 (racemic, brown solid, yield 56%).

[0988] MS (ESI, m / z): [M+H] + = 566.25 / 568.25.

[0989] 1 H NMR (400 MHz, CDC13) δ 8.42 (d, J = 2.8 Hz, 1H), 7.59 (d, J = 2.8 Hz, 1H), 7.28-7.25 (m, 2H), 7.20 (s, 1H), 6.20 (d, J = 2.0 Hz, 1H), 6.06 (d, J = 2.0 Hz, 1H), 4.59-4.54 (m, 1H), 3.75-3.61 (m, 2H), 3.60-3.52 (m, 2H), 3.24 (s, 3H), 2.62-2.54 (m, 2H), 2.29-2.16 (m, 1H), 2.04-1.95 (m, 4H), 1.77-1.63 (m, 2H), 1.52 (s, 9H), 0.95 (t, J = 7.2 Hz, 3H).

[0990] Step 2:

[0991] Synthesized according to the procedure of Step 5 in Example 1 with the corresponding starting materials replaced by compound 36-1 (120 mg, 0.21 mmol). After the reaction was complete, it was purified by preparative liquid chromatography. The purification conditions were as follows: Column type X Bridge Shield RP18 OBD Column 30 x 150 mm, 5 pm; mobile phase acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate: 60 mL / min; gradient acetonitrile from 22% to 37% in 17 min, detection wavelength 254 nm / 220 nm, retention time 10.0 min. The product fractions were collected, concentrated under reduced pressure and lyophilized to give 60 mg of compound 36 (white solid, yield 61%).

[0992] MS (ESI, m / z): [M+H] + = 466.25 / 468.15.

[0993] 1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.11 (d, J = 6.8 Hz, 1H), 7.05 (d, J = 2.4 Hz, 1H), 6.94 (d, J = 2.4 Hz, 1H), 6.12 (d, J = 1.6 Hz, 1H), 5.88 (s, 2H), 5.83 (d, J = 1.6 Hz, 1H), 4.33 - 4.24 (m, 1H), 3.62 - 3.54 (m, 1H), 3.47 - 3.33 (m, 2H), 3.29 (s, 3H), 3.21 - 3.13 (m, 1H), 2.42 (t, J = 7.6 Hz, 2H), 2.19 - 2.05 (m, 1H), 1.89 - 1.80 (m, 1H), 1.81 (s, 3H), 1.70 - 1.56 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H).

[0994] Example 37:

[0995] Preparation of (S)-N-(l-(6-(3-amino-4-chloro-5-(methylsulfonyl)phenyl)amino)-2- propylimidazol-4-yl)pyrrolidin-3-yl)acetamide (Compound 37)

[0996] Step 1:

[0997] Synthesized according to the method of Step 1 in Example 9 with raw materials replaced by 28-11 (100 mg, 0.38 mmol) and 35-6 (146 mg, 0.38 mmol) to give 150 mg of Compound 37-1 (brown semi-solid, yield 70%).

[0998] MS (ESI, m / z): [M+H] + = 567.15 / 569.15.

[0999] 1 H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 7.85 - 7.79 (m, 1H), 7.22 - 7.13 (m, 2H), 5.98 - 5.83 (m, 1H), 5.79 - 5.69 (m, 1H), 4.62 - 4.57 (m, 1H), 3.75 - 3.68 (m, 1H), 3.60 - 3.55 (m, 2H), 3.46 - 3.41 (m, 1H), 3.24 (s, 3H), 2.67 - 2.59 (m, 2H), 2.27 - 2.22 (m, 1H), 2.03 - 2.00 (m, 1H), 1.99 (s, 3H), 1.89 - 1.75 (m, 2H), 1.53 (s, 9H), 1.02 - 0.97 (m, 3H).

[1000] Step 2:

[1001] Synthesized according to the procedure of Step 5 in Example 1 with the corresponding replacement of starting materials with compound 37-1 (120 mg, 0.21 mmol). After the reaction was complete, purified by preparative liquid chromatography. Purification conditions were as follows: Column type X Bridge Prep OBD C18 Column 30 x 150 mm, 5 μm; mobile phase acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate 60 mL / min; gradient acetonitrile from 15% to 45% in 10 min; detection wavelength 254 nm / 220 nm, retention time 8.8 min. The fractions containing the product were collected and concentrated under reduced pressure to give 50 mg of compound 37 (white solid, 51% yield).

[1002] MS (ESI, m / z): [M+H] + = 467.25 / 469.20.

[1003] 1 H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.13 (d, J = 6.4 Hz, 1H), 7.76 (d, J = 2.4 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H), 5.80 (s, 2H), 5.54 (s, 1H), 4.33 - 4.24 (m, 1H), 3.64 - 3.55 (m, 1H), 3.53 - 3.35 (m, 2H), 3.28 (s, 3H), 3.25 - 3.09 (m, 1H), 2.54 (t, J = 7.6 Hz, 2H), 2.17 - 2.07 (m, 1H), 1.89 - 1.83 (m, 1H), 1.81 (s, 3H), 1.80 - 1.72 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H).

[1004] Example 38:

[1005] Preparation of (S)-N-(l-(6-((4-amino-5-chloro-6-(ethylsulfonyl)pyridin-2-yl)amino)-2- propylpyrimidin-4-yl)pyrrolidin-3-yl)acetamide (Compound 38)

[1006] Step 1:

[1007] Synthesized according to the procedure of Step 1 in Example 9 with the corresponding replacement of starting materials with 28-11 (80 mg, 0.30 mmol) and 15-2 (138 mg, 0.30 mmol) to give 200 mg of compound 38-1 (white solid, 98% yield).

[1008] MS (ESI, m / z): [M+H] + = 682.30 / 684.30.

[1009] Step 2:

[1010] Synthesized according to the procedure of Step 5 in Example 1 with the corresponding starting materials replaced by compound 38-1 (200 mg, 0.29 mmol). After the reaction was complete, it was purified by preparative liquid chromatography. The purification conditions were as follows: Column type X Bridge Shield RP18 OBD Column 30 x 150 mm, 5 μm; mobile phase acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate: 60 mL / min; gradient acetonitrile from 43% to 58% in 10 min, detection wavelength 254 nm / 220 nm, retention time 8.1 min. The product fractions were collected, concentrated under reduced pressure and lyophilized to give 44 mg of compound 38 (white solid, yield 31%).

[1011] MS (ESI, m / z): [M+H] + = 482.25 / 484.20.

[1012] 1 H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 8.14 (d, J = 6.4 Hz, 1H), 6.97 (s, 1H), 6.89 - 6.68 (m, 3H), 4.40 - 4.20 (m, 1H), 3.66 - 3.58 (m, 1H), 3.58 - 3.40 (m, 3H), 3.40 - 3.28 (m, 2H), 2.57 - 2.50 (m, 2H), 2.24 - 2.01 (m, 1H), 1.93 - 1.83 (m, 1H), 1.81 (s, 3H), 1.79 - 1.66 (m, 2H), 1.24 (t, J = 7.2 Hz, 3H), 0.93 (t, J = 7.2 Hz, 3H).

[1013] Example 39a and 39b:

[1014] N-(4-methyl-3-(methylsulfonyl)phenyl)-2-((3aS or 3aR, 7aS or 7aR)-octahydro- 1 H-pyrrolo[3,2-b]pyridin-1-yl)-6-propylpyridin-4-amine (compound 39a); and

[1015] Preparation of N-(4-methyl-3-(methylsulfonyl)phenyl)-2-((3aR or 3aS,7aR or 7aS)- octahydro-lH-pyrrolo[3,2-b]pyridin-l-yl)-6-propylpyridin-4-amine (Compound 39b)

[1016] Step 1:

[1017] Synthesized according to the method of Example 1, Step 8, with raw materials replaced accordingly with 15-5 (120 mg, 0.33 mmol) and 39-1 (83 mg, 0.33 mmol; CAS: 254887-17-7, directly purchased from Shanghai Biotech Co., Ltd.), to give 140 mg of Compound 39-2 (brown solid, yield 80%).

[1018] MS (ESI, m / z): [M+H] + = 529.35.

[1019] Step 2:

[1020] Synthesized according to the method of Example 1, Step 5, with raw materials replaced accordingly with 39-2 (140 mg, 0.26 mmol), to give 50 mg of Compound 39 (racemate, white solid, yield 45%).

[1021] MS (ESI, m / z): [M+H] + = 429.25.

[1022] Step 3:

[1023] The racemate 39 (50 mg, 0.117 mmol) was subjected to chiral resolution. The resolution conditions were as follows: chiral column CHIRALART Cellulose-SB, 250 x 30 mm, 5 μm; mobile phase A: n-hexane (0.5% of 2 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isocratic 20% B; detection wavelength 250 / 260 nm; the front peak fraction was obtained with retention time 9.0 min, concentrated under reduced pressure and lyophilized to give 22 mg of optically pure Compound 39a (white solid, yield 44%); the back peak fraction was obtained with retention time 11.2 min, concentrated under reduced pressure and lyophilized to give 22 mg of optically pure Compound 39b (white solid, yield 44%).

[1024] Compound 39a:

[1025] MS (ESI, m / z): [M+H] + = 429.30.

[1026] 1 H NMR (400 MHz, DMSO-d6) δ 8.63 (s, 1H), 7.73 (d, J = 2.0 Hz, 1H), 7.35 - 7.32 (m, 2H), 6.06 (d, J = 1.6 Hz, 1H), 5.82 (d, J = 1.6 Hz, 1H), 3.77 - 3.67 (m, 1H), 3.45 - 3.34 (m, 2H), 3.30 - 3.21 (m, 2H), 3.19 (s, 3H), 2.73 - 2.57 (m, 2H), 2.55 (s, 3H), 2.45 - 2.34 (m, 2H), 2.18 - 2.02 (m, 2H), 1.78 - 1.68 (m, 1H), 1.68 - 1.54 (m, 2H), 1.53 - 1.39 (m, 2H), 1.29 - 1.25 (m, 1H), 0.90 (t, J = 7.2 Hz, 3H).

[1027] Compound 39b:

[1028] MS (ESI, m / z): [M+H] + = 429.30.

[1029] 1 H NMR (400 MHz, DMSO-d6) δ 8.63 (s, 1H), 7.73 (d, J = 2.0 Hz, 1H), 7.35 - 7.32 (m, 2H), 6.06 (d, J = 1.6 Hz, 1H), 5.82 (d, J = 1.6 Hz, 1H), 3.77 - 3.67 (m, 1H), 3.45 - 3.34 (m, 2H), 3.30 - 3.21 (m, 2H), 3.19 (s, 3H), 2.73 - 2.57 (m, 2H), 2.55 (s, 3H), 2.45 - 2.34 (m, 2H), 2.18 - 2.02 (m, 2H), 1.78 - 1.68 (m, 1H), 1.68 - 1.54 (m, 2H), 1.53 - 1.39 (m, 2H), 1.29 - 1.25 (m, 1H), 0.90 (t, J = 7.2 Hz, 3H).

[1030] Examples 40a and 40b:

[1031] 2-((3aS or 3aR, 6aS or 6aR)-5,5-dimethylhexahydropyrrolo[3,2-b]pyrrol-l(2H)-yl)-N-(4-methyl-3-(methylsulfonyl)phenyl)-6-propylpyridin-4-amine (Compound 40a); and 2-((3aR or 3aS, 6aR or 6aS)-5,5-dimethylhexahydropyrrolo[3,2-b]pyrrol-l(2H)-yl)-N-(4-methyl-3-(methylsulfonyl)phenyl)-6-propylpyridin-4-amine (Compound 40b)

[1032] Step 1:

[1033] Compound 40-1 (700 mg, 3.09 mmol; CAS: 1251021-42-7, purchased directly from Nanjing Huacheng Technology Co., Ltd.) was dissolved in N,N-dimethylformamide (7 mL) at 0 °C under nitrogen atmosphere, then sodium hydride (186 mg, 4.64 mmol, 60% dispersion in mineral oil) was added to the reaction solution in portions. The reaction system was stirred for 30 minutes under this condition. Then 4-methoxychlorobenzene (533 mg, 3.40 mmol) was added to the reaction solution, and the reaction system was stirred for 2 hours after returning to room temperature. The reaction progress was monitored by liquid chromatography-mass spectrometry. After the reaction was completed, the reaction system was quenched with saturated aqueous ammonium chloride solution (100 mL) at 0 °C. Then it was extracted with ethyl acetate (100 mL x 3), and the combined organic phase was washed with saturated aqueous sodium chloride solution (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by reverse phase column C18. The purification conditions were as follows: 20 g C18 reverse phase column; mobile phase: acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate: 25 mL / min; gradient: acetonitrile from 10% to 50% in 25 minutes; detection wavelength: 220 / 254 nm. The product fractions were collected and concentrated under reduced pressure to obtain 930 mg of compound 40-2 (brown solid, yield 86%).

[1034] MS (ESI, m / z): [2M+H] + = 693.40.

[1035] 1H NMR (400 MHz, CDC13) δ 7.21-7.14 (m, 2H), 6.90-6.82 (m, 2H), 4.86-4.71 (m, 1H), 4.31-4.16 (m, 1H), 4.15-4.01 (m, 2H), 3.79 (s, 3H), 3.67-3.50 (m, 1H), 3.24-3.08 (m, 1H), 2.76-2.55 (m, 2H), 2.05-1.99 (m, 1H), 1.85-1.71 (m, 1H), 1.45 (s, 9H).

[1036] Step 2:

[1037] Compound 40-2 (920 mg, 2.66 mmol) was dissolved in dichloromethane (10 mL), then triflic anhydride (899 mg, 3.19 mmol), 2,6-di-tert-butyl-4-methylpyridine (655 mg, 3.19 mmol) and methyl magnesium bromide (8.87 mL, 26.6 mmol, 3M in ethyl ether) were added to the reaction solution. The reaction system was allowed to return to room temperature and stirring was continued for 3 hours. After the reaction was completed, it was quenched with saturated aqueous ammonium chloride solution (100 mL), then extracted with ethyl acetate (200 mL x 3), the combined organic phase was washed with saturated aqueous sodium chloride solution (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase column C18. The purification conditions were as follows: 20 g C18 reverse phase column; mobile phase: acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate: 25 mL / min; gradient: acetonitrile from 10% to 90% in 30 min; detection wavelength: 220 / 254 nm. The product fractions were collected and concentrated under reduced pressure to obtain 500 mg of compound 40-3 (yellow solid, yield 52%).

[1038] MS (ESI, m / z): [M+H] + = 361.25.

[1039] Step 3:

[1040] According to the method of step 5 in Example 1, the starting material was replaced with 40-3 (500 mg, 1.39 mmol) to synthesize, to prepare 550 mg of trifluoroacetate compound 40-4 (brown oil, yield 106%, crude).

[1041] MS (ESI, m / z): [M-CF3COOH+H] + = 261.05.

[1042] Step 4:

[1043] Synthesized according to the method of Step 1 in Example 5, with the corresponding starting materials replaced by 40-4 (504 mg, 1.35 mmol) and 3-5 (282 mg, 1.41 mmol) to give 300 mg of compound 40-5 (yellow solid, yield 53%).

[1044] MS (ESI, m / z): [M+H] + = 425.30.

[1045] 1 H NMR (400 MHz, DMSO-d6) δ 7.31 - 7.25 (m, 2H), 7.07 - 7.01 (m, 1H), 6.90 - 6.83 (m, 3H), 4.52 - 4.42 (m, 1H), 3.85 (m, 1H), 3.74 (s, 3H), 3.63 - 3.50 (m, 2H), 3.31 - 3.24 (m, 2H), 2.65 (t, J = 7.4 Hz, 2H), 2.37 - 2.25 (m, 1H), 1.75 - 1.63 (m, 2H), 1.58 - 1.47 (m, 1H), 1.42 - 1.33 (m, 1H), 1.33 - 1.25 (m, 1H), 1.10 - 1.02 (m, 6H), 0.91 (t, J = 7.2 Hz, 3H).

[1046] Step 5:

[1047] The starting material 40-5 (300 mg, 0.71 mmol) was dissolved in methanol (6 mL) at room temperature under nitrogen atmosphere. To the above solution, palladium hydroxide (40 mg, 0.28 mmol) and ammonium formate (446 mg, 7.07 mmol) were added successively. The reaction system was heated to 80 °C and stirred for 3 hours under hydrogen atmosphere. The reaction progress was monitored by LC-MS. After the reaction was completed, the reaction system was naturally cooled to room temperature, filtered, the filter cake was washed with methanol (10 mL x 3), and the filtrate and methanol washing liquid were combined and concentrated under reduced pressure. The obtained residue was purified by reverse phase column C18. The purification conditions were as follows: 20 g C18 reverse phase column; mobile phase: acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate: 25 mL / min; gradient: acetonitrile increased from 10% to 50% in 25 min; detection wavelength: 254 nm. The product fractions were collected and concentrated under reduced pressure to give 60 mg of compound 40-6 (white solid, yield 30%).

[1048] MS (ESI, m / z): [M+H] + = 275.10.

[1049] 1H NMR (400 MHz, DMSO-d6) δ 5.69 (d, J = 0.8 Hz, 1H), 5.41 (s, 2H), 5.38 (d, J = 0.8 Hz, 1H), 4.37 - 4.20 (m, 1H), 4.01 - 3.92 (m, 1H), 3.66 - 3.45 (m, 1H), 3.39 - 3.22 (m, 1H), 2.37 - 2.21 (m, 2H), 2.15 - 2.01 (m, 1H), 1.90 - 1.78 (m, 1H), 1.76 - 1.66 (m, 1H), 1.64 - 1.52 (m, 2H), 1.23 - 1.16 (m, 1H), 1.14 - 1.02 (m, 6H), 0.88 (t, J = 7.2 Hz, 3H).

[1050] Step 6:

[1051] Synthesized according to the method of Step 8 in Example 1, with raw materials replaced accordingly to 40-6 (50 mg, 0.18 mmol) and 39-1 (45 mg, 0.18 mmol; CAS: 254887-17-7, directly purchased from Shanghai Biotech Co., Ltd.), to prepare 50 mg of compound 40 (racemate, white solid, yield 62%).

[1052] MS (ESI, m / z): [M+H] + = 443.30.

[1053] Step 7:

[1054] The racemate 40 (50 mg, 0.11 mmol) was subjected to chiral resolution. The resolution conditions were as follows: chiral column Lux 5u Cellulose-2, 250 x 30 mm, 5 pm; mobile phase A: n-hexane (0.5% of 2 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isocratic 30% B; detection wavelength 290 / 300 nm; the front peak fraction was obtained with retention time 9.0 min, concentrated under reduced pressure and lyophilized to obtain 20 mg of optically pure compound 40a (white solid, yield 40%); the back peak fraction was obtained with retention time 11.3 min, concentrated under reduced pressure and lyophilized to obtain 20 mg of optically pure compound 40b (white solid, yield 40%).

[1055] Compound 40a:

[1056] MS (ESI, m / z): [M+H] + = 443.25.

[1057] 1H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 7.74 (d, J = 2.4 Hz, 1H), 7.40-7.28 (m, 2H), 6.06 (d, J = 1.6 Hz, 1H), 5.85 (d, J = 1.6 Hz, 1H), 4.30-4.21 (m, 1H), 3.98-3.88 (m, 1H), 3.66-3.57 (m, 1H), 3.39-3.33 (m, 1H), 3.19 (s, 3H), 2.55 (s, 3H), 2.44-2.36 (m, 2H), 2.13-2.05 (m, 1H), 1.88-1.77 (m, 1H), 1.73-1.57 (m, 3H), 1.24-1.17 (m, 1H), 1.10 (s, 3H), 1.06 (s, 3H), 0.90 (t, J = 7.2 Hz, 3H).

[1058] Compound 40b:

[1059] MS (ESI, m / z): [M+H] + = 443.25.

[1060] 1 H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 7.74 (d, J = 2.4 Hz, 1H), 7.40-7.28 (m, 2H), 6.06 (d, J = 1.6 Hz, 1H), 5.85 (d, J = 1.6 Hz, 1H), 4.30-4.21 (m, 1H), 3.98-3.88 (m, 1H), 3.66-3.57 (m, 1H), 3.39-3.33 (m, 1H), 3.19 (s, 3H), 2.55 (s, 3H), 2.44-2.36 (m, 2H), 2.13-2.05 (m, 1H), 1.88-1.77 (m, 1H), 1.73-1.57 (m, 3H), 1.24-1.17 (m, 1H), 1.10 (s, 3H), 1.06 (s, 3H), 0.90 (t, J = 7.2 Hz, 3H).

[1061] Example 41a and 41b:

[1062] (S or R)-5-chloro-N-(2-(3-(ethylamino)-3-methylpyrrolidin-1-yl)-6- propylpyridin-4-yl)-6-(methylsulfonyl)pyridin-2-amine (Compound 41a); and

[1063] (R or S)-5-chloro-N-(2-(3-(ethylamino)-3-methylpyrrolidin-1-yl)-6- propylpyridin-4-yl)-6-(methylsulfonyl)pyridin-2-amine (Compound 41b)

[1064] Step 1:

[1065] Synthesized according to the method in Step 1 in Example 9, with the corresponding replacement of starting materials compound 23-4 (250 mg, 0.69 mmol) and compound 4-2 (203 mg, 0.90 mmol), yielded 200 mg of compound 41-1 (yellow solid, yield 52%).

[1066] MS (ESI, m / z): [M+H] + = 552.30 / 554.30.

[1067] 1 H NMR (400 MHz, CDC13) δ 7.79 - 7.70 (m, 2H), 7.28 (s, 1H), 7.25 (s, 1H), 4.17 - 4.08 (m, 1H), 3.92 (s, 1H), 3.65 (s, 1H), 3.50 - 3.42 (m, 1H), 3.41 - 3.28 (m, 2H), 3.27 - 3.18 (m, 1H), 3.07 (s, 3H), 2.65 - 2.54 (m, 2H), 2.35 - 2.23 (m, 1H), 2.20 - 2.08 (m, 1H), 1.77 - 1.66 (m, 2H), 1.37 (s, 3H), 1.32 - 1.23 (m, 2H), 1.19 (t, J=6.8 Hz, 3H), 0.95 (t, J=7.2 Hz, 3H).

[1068] Step 2:

[1069] Synthesized according to the method in Step 5 in Example 1, with the corresponding replacement of starting materials compound 41-1 (200 mg, 0.36 mmol), yielded 80 mg of compound 41 (racemate, white solid, yield 49%).

[1070] MS (ESI, m / z): [M+H] + = 452.20 / 454.25.

[1071] Step 3:

[1072] Chiral resolution of racemic 41 (80 mg, 0.17 mmol) was performed under the following conditions: Chiral column CHIRALPAK IG, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (0.5% of 2 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isocratic 30% B; detection wavelength 254 / 220 nm; the front peak fraction was obtained at a retention time of 15.2 min, and 7.2 mg of optically pure compound 41a (white solid, yield 9%) was obtained after concentration under reduced pressure and lyophilization; the back peak fraction was obtained at a retention time of 20.5 min, and 4 mg of optically pure compound 41b (white solid, yield 5%) was obtained after concentration under reduced pressure and lyophilization.

[1073] Compound 41a:

[1074] MS (ESI, m / z): [M+H] + = 452.25 / 454.15.

[1075] 1 H NMR (400 MHz, DMSO-d6) δ 9.72 (s, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.12 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 1.8 Hz, 1H), 6.59-6.50 (m, 1H), 3.51-3.36 (m, 5H), 3.30-3.17 (m, 3H), 2.68-2.55 (m, 2H), 2.48-2.41 (m, 2H), 1.96-1.86 (m, 1H), 1.80-1.71 (m, 1H), 1.70-1.59 (m, 2H), 1.19 (s, 3H), 1.00 (t, J = 7.2 Hz, 3H), 0.91 (t, J = 7.2 Hz, 3H).

[1076] Compound 41b:

[1077] MS (ESI, m / z): [M+H] + = 452.20 / 454.25.

[1078] 1H NMR (400 MHz, DMSO-d6) δ 9.72 (s, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.12 (d, J = 8.8 Hz, 1H), 6.76 (s, 1H), 6.53 (s, 1H), 3.53 - 3.36 (m, 5H), 3.30 - 3.16 (m, 3H), 2.64 - 2.54 (m, 2H), 2.46 - 2.41 (m, 2H), 1.96 - 1.87 (m, 1H), 1.80 - 1.71 (m, 1H), 1.71 - 1.59 (m, 2H), 1.19 (s, 3H), 1.00 (t, J = 7.2 Hz, 3H), 0.91 (t, J = 7.2 Hz, 3H). Example 42a and 42b:

[1079] (S or R)-N-(1-(4-(4-methyl-3-(methylsulfonyl)phenyl)amino)-6-propylpyridin-2- yl)piperidin-3-yl)acetamide (Compound 42a); and

[1080] (R or S)-N-(1-(4-(4-methyl-3-(methylsulfonyl)phenyl)amino)-6-propylpyridin-2- yl)piperidin-3-yl)acetamide (Compound 42b)

[1081] Step 1:

[1082] Synthesized according to the method of Example 1, Step 8, with the raw materials replaced accordingly to 3-8 (120 mg, 0.43) and 39-1 (119 mg, 0.48 mmol; CAS: 254887-17-7, directly purchased from the supplier Shanghai Biotech Co., Ltd.), to give 100 mg of Compound 42 (racemate, white solid, yield 52%).

[1083] MS (ESI, m / z): [M+H] + = 445.25.

[1084] Step 2:

[1085] Racemic 42 (120 mg, 0.27 mmol) was subjected to chiral resolution. Resolution conditions were as follows: Chiral column Lux 5u Cellulose-2, 3 x 25 cm, 5 pm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isocratic 20% B; detection wavelength 292 / 254 nm; retention time 17.8 min to obtain the fore peak fraction, which was concentrated under reduced pressure and lyophilized to obtain 50 mg of optically pure compound 42a (white solid, yield 42%); retention time 22.6 min to obtain the back peak fraction, which was concentrated under reduced pressure and lyophilized to obtain 50 mg of optically pure compound 42b (white solid, yield 42%).

[1086] Compound 42a:

[1087] MS (ESI, m / z): [M+H] + = 445.30.

[1088] 1 H NMR (400 MHz, DMSO-d6) δ 8.74 (s, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.79 - 7.66 (m, 1H), 7.44 - 7.27 (m, 2H), 6.23 - 6.10 (m, 2H), 4.08 - 3.88 (m, 2H), 3.70 - 3.57 (m, 1H), 3.20 (s, 3H), 2.99 - 2.75 (m, 1H), 2.71 - 2.61 (m, 1H), 2.56 (s, 3H), 2.46 - 2.38 (m, 2H), 1.89 - 1.82 (m, 1H), 1.81 (s, 3H), 1.77 - 1.67 (m, 1H), 1.67 - 1.55 (m, 2H), 1.52 - 1.32 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H).

[1089] Compound 42b:

[1090] MS (ESI, m / z): [M+H] + = 445.30.

[1091] 1H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H), 7.87-7.80 (m, 1H), 7.71-7.67 (m, 1H), 7.41-7.32 (m, 2H), 6.24-6.07 (m, 2H), 4.05-3.91 (m, 2H), 3.73-3.58 (m, 1H), 3.21 (s, 3H), 2.97-2.80 (m, 1H), 2.74-2.61 (m, 1H), 2.56 (s, 3H), 2.46-2.39 (m, 2H), 1.89-1.82 (m, 1H), 1.81 (s, 3H), 1.76-1.67 (m, 1H), 1.66-1.57 (m, 2H), 1.53-1.32 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H).

[1092] Examples 43a and 43b:

[1093] (S or R)-N-(1-(6-(4-methyl-3-(methylsulfonyl)phenyl)amino)-2- propylimidazol-4-yl)piperidin-3-yl)acetamide (Compound 43a); and

[1094] Preparation of (R or S)-N-(1-(6-(4-methyl-3-(methylsulfonyl)phenyl)amino)-2- propylimidazol-4-yl)piperidin-3-yl)acetamide (Compound 43b)

[1095] Step 1:

[1096] Synthesized according to the method of Example 1, Step 1, with the raw material replaced accordingly to 43-1 (500 mg, 2.69 mmol; CAS: 7745-91-7, directly purchased from Shanghai Shaoyuan Technology Co., Ltd.), to prepare 300 mg of Compound 43-2 (white solid, yield 60%).

[1097] MS (ESI, m / z): [M-H] - = 184.05.

[1098] 1 H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 2.4 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 6.84-6.77 (m, 1H), 3.49 (s, 2H), 3.05 (s, 3H), 2.56 (s, 3H).

[1099] Step 2:

[1100] Synthesized according to the method of Example 1, Step 4, with the corresponding replacement of starting materials to compound 43-3 (629 mg, 3.14 mmol; CAS: 172603-05-3, purchased directly from Shanghai Hauheng Biomedical Technology Co., Ltd.) and 34-4 (600 mg, 3.14 mmol), to produce 800 mg of compound 43-4 (white solid, yield 72%).

[1101] MS (ESI, m / z): [M+H] + = 355.20 / 357.10.

[1102] 1 H NMR (400 MHz, CDC13) δ 6.40 (s, 1H), 4.72-4.55 (m, 1H), 3.87-3.46 (m, 4H), 2.70 (t, J = 7.6 Hz, 2H), 2.00-1.88 (m, 1H), 1.86-1.70 (m, 3H), 1.71-1.57 (m, 2H), 1.45 (s, 9H), 0.98 (t, J = 7.2 Hz, 3H).

[1103] Step 3:

[1104] Synthesized according to the method of Example 1, Step 5, with the corresponding replacement of starting materials to 43-4 (800 mg, 2.25 mmol), to produce 900 mg of trifluoroacetate compound 43-5 (brown oil, yield 104%, crude).

[1105] MS (ESI, m / z): [M-CF3COOH+H] + = 255.15 / 257.15.

[1106] Step 4:

[1107] Synthesized according to the method of Example 1, Step 6, with the corresponding replacement of starting materials to 43-5 (1.2 g, 3.13 mmol), to produce 700 mg of compound 43-6 (yellow solid, yield 76%).

[1108] MS (ESI, m / z): [M+H] + = 297.20 / 299.15.

[1109] 1H NMR (400 MHz, CDC13) δ 6.41 (s, 1H), 5.70-5.60 (m, 1H), 4.05-3.96 (m, 1H), 3.88-3.67 (m, 2H), 3.62-3.47 (m, 2H), 2.73-2.65 (m, 2H), 1.97 (s, 3H), 1.96-1.89 (m, 1H), 1.84-1.60 (m, 5H), 0.97 (t, J = 7.2 Hz, 3H).

[1110] Step 5:

[1111] Synthesized according to the method of Example 1, Step 8, with the corresponding starting materials replaced by 43-6 (130 mg, 0.44 mmol) and 43-2 (81 mg, 0.44 mmol) to give 150 mg of compound 43 (orange solid, yield 77%).

[1112] MS (ESI, m / z): [M+H] + = 446.10.

[1113] Step 6:

[1114] Racemic 43 (150 mg, 0.33 mmol) was subjected to chiral resolution. Resolution conditions were as follows: Chiral column CHIRALPAK ID, 250 x 30 mm, 5 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isocratic 50% B; detection wavelength 296 / 238 nm; retention time 6.5 min for the fore fraction, which was concentrated under reduced pressure and lyophilized to give 100 mg of optically pure compound 43a (white solid, yield 67%); retention time 13.4 min for the back fraction, which was concentrated under reduced pressure and lyophilized to give 22 mg of optically pure compound 43b (white solid, yield 15%).

[1115] Compound 43a:

[1116] MS (ESI, m / z): [M+H] + = 446.15.

[1117] 1H NMR (400 MHz, DMSO-d6) δ 9.30 (s, 1H), 8.35 (d, J = 2.4 Hz, 1H), 7.94-7.75 (m, 2H), 7.32 (d, J = 8.4 Hz, 1H), 5.80 (s, 1H), 4.09-3.91 (m, 2H), 3.70-3.54 (m, 1H), 3.17 (s, 3H), 3.04-2.94 (m, 1H), 2.85-2.75 (m, 1H), 2.54 (s, 3H), 2.53-2.51 (m, 2H), 1.90-1.83 (m, 1H), 1.81 (s, 3H), 1.79-1.70 (m, 3H), 1.51-1.35 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H).

[1118] Compound 43b:

[1119] MS (ESI, m / z): [M+H] + = 446.20.

[1120] 1 H NMR (400 MHz, DMSO-d6) δ 9.30 (s, 1H), 8.35 (d, J = 2.4 Hz, 1H), 7.94-7.75 (m, 2H), 7.32 (d, J = 8.4 Hz, 1H), 5.80 (s, 1H), 4.09-3.91 (m, 2H), 3.70-3.54 (m, 1H), 3.17 (s, 3H), 3.04-2.94 (m, 1H), 2.85-2.75 (m, 1H), 2.54 (s, 3H), 2.53-2.51 (m, 2H), 1.90-1.83 (m, 1H), 1.81 (s, 3H), 1.79-1.70 (m, 3H), 1.51-1.35 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H).

[1121] Examples 44a and 44b:

[1122] (S or R)-N-(1-(4-((3-(ethylsulfonyl)-4-methylphenyl)amino)-6- propylpyridin-2-yl)piperidin-3-yl)acetamide (Compound 44a); and

[1123] Preparation of (R or S)-N-(1-(4-((3-(ethylsulfonyl)-4-methylphenyl)amino)-6- propylpyridin-2-yl)piperidin-3-yl)acetamide (Compound 44b)

[1124] Step 1:

[1125] Synthesized according to the method of step 8 in example 16 with corresponding replacement of starting materials with compound 3-8 (300 mg, 1.08 mmol) to prepare 120 mg of compound 44-1 (yellow oil, yield 33%).

[1126] MS (ESI, m / z): [M+H] + = 340.10 / 342.00.

[1127] 1 H NMR (400 MHz, CDC13) δ 6.68 (s, 1H), 6.64 (s, 1H), 6.06-5.92 (m, 1H), 4.24-4.02 (m, 1H), 3.72-3.66 (m, 1H), 3.64-3.49 (m, 3H), 3.48-3.89 (m, 1H), 2.66-2.51 (m, 2H), 1.96 (s, 3H), 1.87-1.51 (m, 5H), 0.96 (t, J = 7.2 Hz, 3H).

[1128] Step 2:

[1129] Synthesized according to the method of step 1 in example 1 with corresponding replacement of starting materials with compound 43-1 (500 mg, 2.68 mmol) and sodium ethylsulfinate (624 mg, 5.37 mmol) to prepare 300 mg of compound 44-2 (yellow solid, yield 56%).

[1130] MS (ESI, m / z): [M+H] + = 200.10.

[1131] Step 3:

[1132] Synthesized according to the method of step 8 in example 1 with corresponding replacement of starting materials with compound 44-1 (120 mg, 0.35 mmol) and 44-2 (84 mg, 0.42 mmol) to prepare 140 mg of compound 44 (racemate, yellowish solid, yield 87%).

[1133] MS (ESI, m / z): [M+H] + = 459.25.

[1134] Step 4:

[1135] Chiral resolution of racemic 44 (140 mg, 0.30 mmol) was performed with the following conditions: Chiral column CHIRALPAK AD-H, 3 x 25 cm, 5 μm; mobile phase A: CO2, mobile phase B: isopropanol (20 mmol / L ammonia); flow rate 65 mL / min; gradient: isocratic 38% B; detection wavelength 220 nm; retention time 6.1 min for the fore peak fraction, which gave 44 mg of optically pure compound 44a (white solid, yield 31%) after concentration under reduced pressure and lyophilization; retention time 7.3 min for the back peak fraction, which gave 12 mg of optically pure compound 44b (white solid, yield 8%) after concentration under reduced pressure and lyophilization.

[1136] Compound 44a:

[1137] MS (ESI, m / z): [M+H] + = 459.25.

[1138] 1 H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.69 - 7.59 (m, 1H), 7.37 (s, 1H), 7.36 (s, 1H), 6.23 - 6.04 (m, 2H), 4.12 - 3.83 (m, 2H), 3.79 - 3.61 (m, 1H), 3.31 - 3.25 (m, 2H), 2.87 - 2.76 (m, 1H), 2.68 - 2.60 (m, 1H), 2.53 (s, 3H), 2.45 - 2.38 (m, 2H), 1.87 - 1.82 (m, 1H), 1.81 (s, 3H), 1.76 - 1.66 (m, 1H), 1.66 - 1.55 (m, 2H), 1.51 - 1.30 (m, 2H), 1.11 (t, J = 7.2 Hz, 3H), 0.90 (t, J = 7.2 Hz, 3H).

[1139] Compound 44b:

[1140] MS (ESI, m / z): [M+H] + = 459.25.

[1141] 1H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.68-7.63 (m, 1H), 7.40-7.33 (m, 2H), 6.21-6.10 (m, 2H), 4.09-3.89 (m, 2H), 3.73-3.58 (m, 1H), 3.32-3.23 (m, 2H), 2.88-2.76 (m, 1H), 2.70-2.58 (m, 1H), 2.53 (s, 3H), 2.47-2.37 (m, 2H), 1.87-1.82 (m, 1H), 1.80 (s, 3H), 1.76-1.67 (m, 1H), 1.67-1.55 (m, 2H), 1.53-1.31 (m, 2H), 1.11 (t, J = 7.2 Hz, 3H), 0.90 (t, J = 7.2 Hz, 3H).

[1142] Examples 45a and 45b:

[1143] 2-((3aS or 3aR, 6aS or 6aR)-hexahydropyrrolo[3,2-b]pyrrol-l(2H)-yl)-N-(4-methyl-3- (methylsulfonyl)phenyl)-6-propylpyridin-4-amine (Compound 45a); and

[1144] Preparation of 2-((3aR or 3aS, 6aR or 6aS)-hexahydropyrrolo[3,2-b]pyrrol-l(2H)-yl)-N-(4- methyl-3-(methylsulfonyl)phenyl)-6-propylpyridin-4-amine (Compound 45b)

[1145] Step 1:

[1146] According to the synthetic method of Step 8 in Example 1, with corresponding replacement of the raw materials by Compound 13-1 (201 mg, 0.58 mmol) and Compound 39-1 (144 mg, 0.58 mmol), 110 mg of Compound 45-1 (yellow solid, yield 37%) was prepared.

[1147] MS (ESI, m / z): [M+H] + = 515.25.

[1148] Step 2:

[1149] According to the synthetic method of Step 5 in Example 1, with corresponding replacement of the raw materials by Compound 45-1 (100 mg, 0.19 mmol), 50 mg of Compound 45 (racemate, yellow solid, yield 63%) was prepared.

[1150] MS (ESI, m / z): [M+H] + = 415.15.

[1151] Step 3:

[1152] Racemic 45 (50 mg, 0.12 mmol) was subjected to chiral resolution with the following resolution conditions: Chiral column CHIRALPAK AD, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isocratic 10% B; detection wavelength 254 / 220 nm; retention time 30.2 min to give the fore peak fraction, which after concentration under reduced pressure and lyophilization gave 7.0 mg of optically pure compound 45a (white solid, yield 14%); retention time 36.8 min to give the back peak fraction, which after concentration under reduced pressure and lyophilization gave 7 mg of optically pure compound 45b (white solid, yield 14%).

[1153] Compound 45a:

[1154] MS (ESI, m / z): [M+H] + = 415.20.

[1155] 1 H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 7.76 - 7.71 (m, 1H), 7.37 - 7.33 (m, 2H), 6.11 (d, J = 1.6 Hz, 1H), 5.91 (d, J = 1.6 Hz, 1H), 4.20 - 4.09 (m, 1H), 3.90 - 3.82 (m, 1H), 3.64 - 3.46 (m, 3H), 3.19 (s, 3H), 2.87 - 2.72 (m, 2H), 2.55 (s, 3H), 2.45 - 2.38 (m, 2H), 2.01 - 1.85 (m, 2H), 1.84 - 1.68 (m, 2H), 1.67 - 1.59 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H).

[1156] Compound 45b:

[1157] MS (ESI, m / z): [M+H] + = 415.20.

[1158] 1H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 7.74-7.71 (m, 1H), 7.38-7.32 (m, 2H), 6.11 (d, J = 1.6 Hz, 1H), 5.91 (d, J = 1.6 Hz, 1H), 4.20-4.09 (m, 1H), 3.90-3.82 (m, 1H), 3.64-3.46 (m, 3H), 3.20 (s, 3H), 2.87-2.72 (m, 2H), 2.55 (s, 3H), 2.45-2.38 (m, 2H), 2.02-1.85 (m, 2H), 1.84-1.68 (m, 2H), 1.67-1.58 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H).

[1159] Examples 46a and 46b:

[1160] (S or R)-2-(3-(ethylamino)-3-methylpyrrolidin-1-yl)-N-(4-methyl-3- (methylsulfonyl)phenyl)-6-propylpyridin-4-amine (Compound 46a); and

[1161] Preparation of (R or S)-2-(3-(ethylamino)-3-methylpyrrolidin-1-yl)-N-(4-methyl-3- (methylsulfonyl)phenyl)-6-propylpyridin-4-amine (Compound 46b)

[1162] Step 1:

[1163] According to the synthesis method of Step 8 in Example 1, with corresponding replacement of raw materials by Compound 23-4 (80 mg, 0.22 mmol) and Compound 39-1 (61 mg, 0.24 mmol; CAS: 254887-17-7, directly purchased from Shanghai Biotech Co., Ltd.), 80 mg of Compound 46-1 (white solid, yield 68%) was prepared.

[1164] MS (ESI, m / z): [M+H] + = 531.30.

[1165] Step 2:

[1166] According to the synthesis method of Step 5 in Example 1, with corresponding replacement of raw materials by Compound 46-1 (70 mg, 0.13 mmol), 50 mg of Compound 46 (racemate, white solid, yield 89%) was prepared.

[1167] MS (ESI, m / z): [M+H] + = 431.25.

[1168] Step 3:

[1169] Chiral resolution of racemic compound 46 (40 mg, 0.093 mmol) was performed with the following conditions: Chiral column CHIRALPAK OD, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (0.5% of 2 mmol / L of ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isocratic 50% B; detection wavelength 254 / 220 nm; the front peak fraction was obtained with retention time 9.3 min, after concentration under reduced pressure and lyophilization, 10 mg of optically pure compound 46a (white solid, yield 25%) was obtained; the back peak fraction was obtained with retention time 12.7 min, after concentration under reduced pressure and lyophilization, 10 mg of optically pure compound 46b (white solid, yield 25%) was obtained.

[1170] Compound 46a:

[1171] MS (ESI, m / z): [M+H] + = 431.30.

[1172] 1 H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 7.76-7.65 (m, 1H), 7.43-7.28 (m, 2H), 6.12 (d, J = 1.6 Hz, 1H), 5.83 (d, J = 1.6 Hz, 1H), 3.50-3.45 (m, 4H), 3.20 (s, 3H), 2.80-2.69 (m, 2H), 2.56 (s, 3H), 2.45-2.36 (m, 2H), 2.12-2.01 (m, 1H), 1.94-1.82 (m, 1H), 1.69-1.54 (m, 2H), 1.29 (s, 3H), 1.09 (t, J = 7.2 Hz, 3H), 0.91 (t, J = 7.2 Hz, 3H).

[1173] Compound 46b:

[1174] MS (ESI, m / z): [M+H] + = 431.25.

[1175] 1H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 7.80-7.67 (m, 1H), 7.41-7.30 (m, 2H), 6.16-6.11 (m, 1H), 5.90-5.79 (m, 1H), 3.51-3.46 (m, 4H), 3.20 (s, 3H), 2.88-2.76 (m, 2H), 2.56 (s, 3H), 2.46-2.38 (m, 2H), 2.20-2.09 (m, 1H), 2.03-1.90 (m, 1H), 1.70-1.55 (m, 2H), 1.33 (s, 3H), 1.13 (t, J = 7.2 Hz, 3H), 0.91 (t, J = 7.2 Hz, 3H).

[1176] Examples 47a and 47b:

[1177] N 1 (4-((3aR or 3aS, 6aR or 6aS)-hexahydropyrrolo[3,2-b]pyrrol-l(2H)-yl)-6- propylpyrimidin-2-yl)-3-(methylsulfonyl)benzene-l,4-diamine (Compound 47a); and

[1178] N 1 (4-((3aS or 3aR, 6aS or 6aR)-hexahydropyrrolo[3,2-b]pyrrol-l(2H)-yl)-6- propylpyrimidin-2-yl)-3-(methylsulfonyl)benzene-l,4-diamine (Compound 47b)

[1179] Step 1:

[1180] Synthesized according to the method of Example 2, Step 1, with the corresponding starting materials replaced by Compound 47-1 (3.00 g, 19.2 mmol; CAS: 2369-13-3, directly purchased from Shanghai Hauhun Biomedical Technology Co., Ltd.), to give 2.8 g of Compound 47-2 (yellow solid, yield 79%).

[1181] MS (ESI, m / z): [M+H] + = 185.15.

[1182] Step 2:

[1183] Synthesized according to the method of Example 3, Step 2, with the corresponding starting materials replaced by Compound 47-2 (6.0 g, 32.6 mmol), to give 9.0 g of Compound 47-3 (yellow solid, yield 72%).

[1184] 1H NMR (400 MHz, CDCI3) δ 8.28 (d, J = 8.8 Hz, 1 H), 7.14 (d, J = 2.0 Hz, 1 H), 7.08 - 7.02 (m, 1 H), 2.47 (s, 3 H), 1.46 (s, 18 H).

[1185] Step 3:

[1186] Synthesized according to the method of Step 3 in Example 2 with corresponding replacement of starting materials with compound 47-3 (3.0 g, 7.80 mmol) to give 1.4 g of compound 47-4 (yellow solid, yield 43%).

[1187] 1 H NMR (400 MHz, CDCI3) δ 8.02 (d, J = 2.4 Hz, 1 H), 7.88 (d, J = 8.4 Hz, 1 H), 7.63 - 7.55 (m, 1 H), 3.45 (s, 3 H), 1.47 (s, 18 H).

[1188] Step 4:

[1189] Synthesized according to the method of Step 5 in Example 1 with corresponding replacement of starting materials with compound 47-4 (1.4 g, 3.36 mmol) to give 1.3 g of trifluoroacetate compound 47-5 (yellow solid, yield 117%, crude).

[1190] MS (ESI, m / z): [M-CF3COOH-H] - = 214.95.

[1191] Step 5:

[1192] Synthesized according to the method of Step 2 in Example 34 with corresponding replacement of starting materials with compound 47-6 (20.0 g, 117 mmol; CAS: 51-52-5, directly purchased from the supplier Shanghai Yuenye Biotech Co., Ltd.) to give 13.0 g of compound 47-7 (brown oil, yield 58%).

[1193] MS (ESI, m / z): [M+H] + = 191.20.

[1194] 1 H NMR (400 MHz, CDCI3) δ 7.15 (s, 1 H), 2.71 (t, J = 7.2 Hz, 2 H), 1.84 - 1.67 (m, 2 H), 0.99 (t, J = 7.2 Hz, 3 H).

[1195] Step 6:

[1196] The synthesis was carried out according to the method of Step 3 in Example 1, with the corresponding replacement of starting materials 47-7 (400 mg, 2.09 mmol) and 5-1 (444 mg, 2.09 mmol; CAS: 885277-81-6, purchased directly from Shanghai Chem-Express Co., Ltd.) to give 470 mg of compound 47-8 (colorless oil, 61% yield).

[1197] MS (ESI, m / z): [M+H] + = 367.30.

[1198] 1 H NMR (400 MHz, CDC13) δ 6.06 (s, 1H), 4.75 - 4.61 (m, 1H), 4.53 - 4.36 (m, 1H), 3.80 - 3.69 (m, 1H), 3.67 - 3.57 (m, 1H), 3.41 - 3.31 (m, 1H), 3.22 - 3.10 (m, 1H), 2.57 (t, J=8.0 Hz, 2H), 2.49 - 2.18 (m, 1H), 2.15 - 2.00 (m, 3H), 1.79 - 1.65 (m, 2H), 1.49 (s, 9H), 0.97 (t, J=7.6 Hz, 3H).

[1199] Step 7:

[1200] The synthesis was carried out according to the method of Step 8 in Example 1, with the corresponding replacement of starting materials compound 47-8 (800 mg, 2.18 mmol) and 47-5 (720 mg, 3.33 mmol) to give 1.0 g of compound 47-9 (brown solid, 84% yield).

[1201] MS (ESI, m / z): [M+H] + = 547.20.

[1202] 1H NMR (400 MHz, CDC13) δ 9.05 - 8.82 (m, 1H), 7.98 - 7.90 (m, 1H), 7.87 - 7.56 (m, 2H), 5.87 (s, 1H), 5.02 - 4.68 (m, 1H), 4.60 - 4.37 (m, 1H), 3.84 - 3.56 (m, 2H), 3.50 (s, 3H), 3.45 - 3.32 (m, 1H), 3.26 - 3.06 (m, 1H), 2.52 (t, J = 7.6 Hz, 2H), 2.47 - 2.06 (m, 4H), 1.81 - 1.67 (m, 2H), 1.50 (s, 9H), 0.99 (t, J = 7.2 Hz, 3H).

[1203] Step 8:

[1204] Synthesized according to the method of Step 7 in Example 1, with the corresponding starting materials replaced by compound 47-9 (1.0 g, 1.83 mmol), to give 500 mg of compound 47-10 (colorless solid, 53% yield).

[1205] MS (ESI, m / z): [M+H] + = 517.20.

[1206] Step 9:

[1207] Synthesized according to the method of Step 5 in Example 1, with the corresponding starting materials replaced by compound 47-10 (500 mg, 0.97 mmol), to give 220 mg of trifluoroacetate compound 47 (racemate, colorless oil, 43% yield).

[1208] MS (ESI, m / z): [M-CF3COOH+H] + = 417.30.

[1209] Step 10:

[1210] Chiral resolution of racemate 47 (220 mg, 0.41 mmol) was performed under the following conditions: Chiral column Chiral NQ (2), 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mM ammonia-methanol), mobile phase B: isopropanol; flow rate 40 mL / min; gradient: isocratic 50% B; detection wavelength 280 / 238 nm; retention time 13.7 min to give the fore peak fraction, which after concentration under reduced pressure and lyophilization gave 73 mg of optically pure compound 47a (white solid, 43% yield); retention time 18.9 min to give the back peak fraction, which after concentration under reduced pressure and lyophilization gave 73 mg of optically pure compound 47b (white solid, 43% yield).

[1211] Compound 47a:

[1212] MS (ESI, m / z): [M+H] + = 417.25.

[1213] 1 H NMR (400 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.44 (s, 1H), 7.56 - 7.46 (m, 1H), 6.80 (d, J = 8.8 Hz, 1H), 5.77 (s, 1H), 5.58 (s, 2H), 4.56 - 4.08 (m, 1H), 3.89 - 3.47 (m, 4H), 3.06 (s, 3H), 2.75 (t, J = 6.6 Hz, 2H), 2.37 (t, J = 7.6 Hz, 2H), 2.14 - 1.99 (m, 1H), 1.98 - 1.86 (m, 1H), 1.84 - 1.73 (m, 1H), 1.71 - 1.62 (m, 2H), 1.61 - 1.56 (m, 1H), 0.91 (t, J = 7.2 Hz, 3H). J = 7.2 Hz, 3H).

[1214] Compound 47b:

[1215] MS (ESI, m / z): [M+H] + = 417.30.

[1216] 1 H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.44 (s, 1H), 7.54 - 7.48 (m, 1H), 6.80 (d, J = 8.8 Hz, 1H), 5.77 (s, 1H), 5.58 (s, 2H), 4.22 - 4.18 (m, 1H), 3.86 - 3.76 (m, 1H), 3.48 - 3.45 (m, 3H), 3.06 (s, 3H), 2.75 (t, J = 6.6 Hz, 2H), 2.38 (t, J = 7.6 Hz, 2H), 2.07 - 2.02 (m, 1H), 1.93 - 1.87 (m, 1H), 1.82 - 1.78 (m, 1H), 1.73 - 1.59 (m, 3H), 0.91 (t, J = 7.2 Hz, 3H).

[1217] Examples 48a and 48b:

[1218] (S or R)-N-(1-(2-((4-methyl-3-(methylsulfonyl)phenyl)amino)-6- propylpyrimidin-4-yl)piperidin-3-yl)acetamide (Compound 48a); and

[1219] (R or S)-N-(1-(2-((4-methyl-3-(methylsulfonyl)phenyl)amino)-6-propylpyrimidin-4- yl)piperidin-3-yl)acetamide (Compound 48b)

[1220] Step 1:

[1221] Synthesized according to the method of Step 3 in Example 1, with the corresponding replacement of starting materials, compound 47-7 (500 mg, 2.62 mmol) and compound 43-3 (524 mg, 2.62 mmol; CAS: 172603-05-3, directly purchased from Shanghai Hauhun Biomedical Technology Co., Ltd.), to give 700 mg of compound 48-1 (yellow solid, yield 75%).

[1222] MS (ESI, m / z): [M+H] + = 355.20 / 357.10.

[1223] 1 H NMR (300 MHz, CDC13) 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).

[1224] Step 2:

[1225] Synthesized according to the method of Step 5 in Example 1, with the corresponding replacement of starting materials, compound 48-1 (700 mg, 1.98 mmol), to give 700 mg of trifluoroacetate compound 48-2 (brown oil, yield 96%, crude).

[1226] MS (ESI, m / z): [M-CF3COOH+H] + = 255.10 / 257.05.

[1227] Step 3:

[1228] Synthesized according to the method of Step 6 in Example 1, with the corresponding replacement of starting materials, compound 48-2 (700 mg, 1.90 mmol), to give 500 mg of compound 48-3 (yellow solid, yield 89%).

[1229] MS (ESI, m / z): [M+H] + = 297.10 / 299.05.

[1230] 1 H NMR (400 MHz, CDC13) 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).

[1231] Step 4:

[1232] According to the synthetic method of Step 8 in Example 1, with the raw materials correspondingly replaced by compound 48-3 (100 mg, 0.34 mmol) and compound 43-2 (63 mg, 0.34 mmol), 100 mg of compound 48 (racemate, white solid, yield 66%) was prepared.

[1233] MS (ESI, m / z): [M+H] + = 446.10.

[1234] 1 H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.65 (s, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.76-7.69 (m, 1H), 7.28 (d, J = 8.4 Hz, 1H), 6.13 (s, 1H), 4.15-4.02 (m, 2H), 3.67-3.60 (m, 1H), 3.21-3.08 (m, 4H), 2.97-2.87 (m, 1H), 2.54 (s, 3H), 2.42 (t, J = 7.6 Hz, 2H), 1.89-1.83 (m, 1H), 1.80 (s, 3H), 1.78-1.73 (m, 1H), 1.73-1.63 (m, 2H), 1.54-1.42 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H).

[1235] Step 5:

[1236] Chiral resolution of racemic 48 (100 mg, 0.22 mmol) was performed with the following conditions: Chiral column NB-CHIRALCEL OD-H, 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: isocratic 10% B; detection wavelength 254 / 228 nm; retention time 11.7 min for the fore peak fraction, which after concentration under reduced pressure and lyophilization gave 34 mg of optically pure compound 48a (white solid, yield 34%); retention time 15.0 min for the back peak fraction, which after concentration under reduced pressure and lyophilization gave 37 mg of optically pure compound 48b (white solid, yield 37%).

[1237] Compound 48a:

[1238] (c = 0.1 in EtOH).

[1239] MS (ESI, m / z): [M+H] + = 466.30.

[1240] 1 H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.65 (s, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.77 - 7.69 (m, 1H), 7.27 (d, J = 8.4 Hz, 1H), 6.13 (s, 1H), 4.17 - 4.02 (m, 2H), 3.70 - 3.59 (m, 1H), 3.21 - 3.08 (m, 4H), 2.97 - 2.87 (m, 1H), 2.54 (s, 3H), 2.42 (t, J = 7.6 Hz, 2H), 1.90 - 1.82 (m, 1H), 1.80 (s, 3H), 1.79 - 1.74 (m, 1H), 1.73 - 1.61 (m, 2H), 1.54 - 1.40 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H).

[1241] Compound 48b:

[1242] (c = 0.1 in EtOH).

[1243] MS (ESI, m / z): [M+H] + = 466.30.

[1244] 1H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.65 (s, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.77-7.69 (m, 1H), 7.28 (d, J = 8.4 Hz, 1H), 6.13 (s, 1H), 4.15-4.02 (m, 2H), 3.70-3.59 (m, 1H), 3.19-3.10 (m, 4H), 2.99-2.87 (m, 1H), 2.54 (s, 3H), 2.42 (t, J = 7.6 Hz, 2H), 1.90-1.82 (m, 1H), 1.80 (s, 3H), 1.78-1.73 (m, 1H), 1.75-1.61 (m, 2H), 1.54-1.40 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H).

[1245] Examples 49a and 49b:

[1246] N-(4-methyl-3-(methylsulfonyl)phenyl)-4-((3aS or 3aR, 7aS or 7aR)- octahydro-lH-pyrrolo[3,2-b]pyridin-l-yl)-6-propylpyrimidin-2-amine (Compound 49a); and

[1247] Preparation of N-(4-methyl-3-(methylsulfonyl)phenyl)-4-((3aR or 3aS, 7aR or 7aS)- octahydro-lH-pyrrolo[3,2-b]pyridin-l-yl)-6-propylpyrimidin-2-amine (Compound 49b)

[1248] Step 1:

[1249] According to the synthesis method of Step 3 in Example 1, with corresponding raw materials replaced by Compound 47-7 (169 mg, 0.88 mmol) and Compound 15-3 (200 mg, 0.88 mmol; CAS: 1211583-65-1, directly purchased from Nanjing Nari Technology Co., Ltd.), 120 mg of Compound 49-1 (white solid, yield 36%) was prepared.

[1250] MS (ESI, m / z): [M+H] + = 381.20 / 383.10.

[1251] Step 2:

[1252] According to the synthetic method of Step 8 in Example 1, with the corresponding starting materials replaced by compound 49-1 (100 mg, 0.26 mmol) and compound 43-2 (54 mg, 0.30 mmol), 80 mg of compound 49-2 (yellow solid, yield 58%) was prepared.

[1253] MS (ESI, m / z): [M+H] + = 530.30.

[1254] Step 3:

[1255] According to the synthetic method of Step 5 in Example 1, with the corresponding starting materials replaced by compound 49-2 (80 mg, 0.15 mmol), 60 mg of compound 49 (racemate, white solid, yield 93%) was prepared.

[1256] MS (ESI, m / z): [M+H] + = 430.10.

[1257] Step 4:

[1258] The racemic compound 49 (60 mg, 0.14 mmol) was subjected to chiral resolution. The resolution conditions were as follows: chiral column CHIRALPAK IN, 3x25 cm, 5 μm; mobile phase A: n-hexane (0.5% of 2 mmol / L of ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isocratic 50% B; detection wavelength 260 / 270 nm; the front peak fraction was obtained with a retention time of 14.0 min, and was concentrated under reduced pressure and lyophilized to obtain 25 mg of optically pure compound 49a (white solid, yield 42%); the back peak fraction was obtained with a retention time of 17.5 min, and was concentrated under reduced pressure and lyophilized to obtain 20 mg of optically pure compound 49b (white solid, yield 33%).

[1259] Compound 49a:

[1260] MS (ESI, m / z): [M+H] + = 430.30.

[1261] 1H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1H), 8.86-8.56 (m, 1H), 7.88-7.68 (m, 1H), 7.26 (d, J = 8.4 Hz, 1H), 5.83 (s, 1H), 3.99-3.41 (m, 4H), 3.14 (s, 3H), 2.72-2.58 (m, 2H), 2.54 (s, 3H), 2.44-2.36 (m, 2H), 2.25-2.06 (m, 2H), 1.82-1.60 (m, 3H), 1.53-1.29 (m, 3H), 0.91 (t, J = 7.2 Hz, 3H).

[1262] Compound 49b:

[1263] MS (ESI, m / z): [M+H] + = 430.30.

[1264] 1 H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1H), 8.86-8.56 (m, 1H), 7.88-7.68 (m, 1H), 7.26 (d, J = 8.4 Hz, 1H), 5.83 (s, 1H), 3.99-3.41 (m, 4H), 3.14 (s, 3H), 2.72-2.58 (m, 2H), 2.54 (s, 3H), 2.44-2.36 (m, 2H), 2.25-2.06 (m, 2H), 1.82-1.60 (m, 3H), 1.53-1.29 (m, 3H), 0.91 (t, J = 7.2 Hz, 3H).

[1265] Example 50:

[1266] Preparation of (S)-N-(l-(2-((4-methyl-3-(methylsulfonyl)phenyl)amino)-6- propylpyrimidin-4-yl)pyrrolidin-3-yl)acetamide (Compound 50)

[1267] Synthesized according to the procedure of Step 8 in Example 1 with raw materials replaced accordingly to compound 28-10 (100 mg, 0.35 mmol) and 43-2 (65 mg, 0.35 mmol). After the reaction was complete, it was directly purified by reverse phase column C18. The purification conditions were as follows: 80 g C18 reverse phase column; mobile phase acetonitrile and water (10 mmo / L ammonium bicarbonate); flow rate 25 mL / min; gradient acetonitrile from 30% to 50% in 25 min; detection wavelength 254 nm. The fractions of product were collected, concentrated under reduced pressure and lyophilized to give 60 mg of compound 50 (white solid, yield 40%).

[1268] MS (ESI, m / z): [M+H] + = 432.20.

[1269] 1 H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 9.01 - 8.70 (m, 1H), 8.17 (s, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 5.85 (s, 1H), 4.40 - 4.25 (m, 1H), 3.80 - 3.35 (m, 4H), 3.15 (s, 3H), 2.54 (s, 3H), 2.45 - 2.39 (m, 2H), 2.20 - 2.05 (m, 1H), 1.94 - 1.84 (m, 1H), 1.81 (s, 3H), 1.74 - 1.63 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H).

[1270] Example 51:

[1271] (R)-N-(1-(2-((4-methyl-3-(methylsulfonyl)phenyl)amino)-6-propylpyrimidin-4-yl)pyrrolidin-3-yl)acetamide (Compound 51) was prepared according to the procedure of Example 1, Step 6, with the raw materials replaced accordingly with Compound 51-1 (2 g, 10.7 mmol; CAS: 147081-49-0, purchased directly from Shanghai Shaoyuan Technology Co., Ltd.), to give 2 g of Compound 51-2 (brown oil, yield 82%, crude).

[1272] Step 1:

[1273] Synthesized according to the procedure of Example 1, Step 6, with the raw materials replaced accordingly with Compound 51-1 (2 g, 10.7 mmol; CAS: 147081-49-0, purchased directly from Shanghai Shaoyuan Technology Co., Ltd.), to give 2 g of Compound 51-2 (brown oil, yield 82%, crude).

[1274] MS (ESI, m / z): [M-H] - = 432.20.

[1275] Step 2:

[1276] Synthesized according to the procedure of Example 1, Step 5, with the raw materials replaced accordingly with Compound 51-2 (2 g, 8.76 mmol), to give 1.2 g of Compound 51-3 (light yellow oil, crude, yield 107%).

[1277] MS (ESI, m / z): [M+H] + = 432.20.

[1278] Step 3:

[1279] Compound 47-6 (5.0 g, 29.4 mmol; CAS: 51-52-5, purchased directly from Shanghai Hauheng Biomedical Technology Co., Ltd.) and thiophosgene (5.05 g, 43.9 mmol; CAS: 463-71-8, purchased directly from Shanghai Titan Scientific Co., Ltd.) were dissolved in tetrahydrofuran (50 mL) at room temperature. The reaction system was stirred at room temperature for 8 hours, and the reaction progress was monitored by liquid chromatography-mass spectrometry. After the reaction was completed, 5% NaOH aqueous solution was slowly added dropwise to the reaction solution at 0 °C to adjust the pH to 7-8, the aqueous phase was separated, the pH was adjusted to 2-3 with 1M hydrochloric acid, and ethyl acetate (50 mL x 2) was added for extraction, then the organic phases were combined, concentrated to a certain amount, and then n-heptane was added dropwise for solidification and beating, filtered, and the filter cake was dried at room temperature to obtain 4.6 g of compound 51-4 (pale yellow solid, yield 91%).

[1280] MS (ESI, m / z): [M+H] + = 173.10 / 175.00.

[1281] Step 4:

[1282] Compound 51-4 (2.0 g, 11.6 mmol) and compound 43-2 (2.15 g, 11.6 mmol) were dissolved in isopropanol (20 mL) at room temperature, and trifluoroacetic acid (1.32 g, 11.6 mmol) was added to the above reaction solution. The reaction system was stirred at room temperature for 5 hours, and the reaction progress was monitored by liquid chromatography-mass spectrometry. After the reaction was completed, it was concentrated under reduced pressure, and the residue was directly purified by silica gel column (eluent: petroleum ether / ethyl acetate = 2 / 1) to obtain 3.3 g of compound 51-5 (white solid, yield 89%).

[1283] MS (ESI, m / z): [M+H] + = 322.20.

[1284] Step 5:

[1285] To a solution of 51-5 (200 mg, 0.62 mmol) and triethylamine (0.13 mL, 0.93 mmol) in dichloromethane (2 mL) was added triflic anhydride (210 mg, 0.75 mmol) at 0 °C. After the addition was completed, the reaction mixture was removed from the ice bath and allowed to warm to room temperature and stirred for 2 h. Subsequently, N,N-diisopropylethylamine (0.54 mL, 3.11 mmol) and 51-3 (159 mg, 1.24 mmol) were added to the reaction mixture and stirred for 1 h. The reaction progress was monitored by LC-MS. After the reaction was completed, the reaction was quenched with water (5 mL) at room temperature, concentrated under reduced pressure, and the residue was purified directly by silica gel column (eluent: dichloromethane / methanol = 8 / 1) to give 1.3 g of crude product, which was further purified by LC prep. The purification conditions were as follows: Column type X Bridge Prep OBD C18 Column 30 x 150 mm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonium bicarbonate), mobile phase B: ethanol; flow rate 60 mL / min; gradient: isocratic 20% B; detection wavelength 220 / 254 nm; retention time 12.6 min to give the product fraction, which was concentrated under reduced pressure and lyophilized to give 187 mg of optically pure compound 51 (white solid, yield 70%).

[1286] MS (ESI, m / z): [M+H] + = 432.25.

[1287] 1 H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.97-8.63 (m, 1H), 8.15 (s, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 5.85 (s, 1H), 4.39-4.30 (m, 1H), 3.80-3.37 (m, 4H), 3.14 (s, 3H), 2.54 (s, 3H), 2.47-2.35 (m, 2H), 2.19-2.05 (m, 1H), 1.92-1.84 (m, 1H), 1.81 (s, 3H), 1.74-1.62 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H).

[1288] Example 52a and 52b:

[1289] (R or S)-7-(2-((4-methyl-3-(methylsulfonyl)phenyl)amino)-6-propylpyrimidin-4-yl)-1,7- diazaspiro[4.5]decane-2-one (Compound 52a); and (R or S)-7-(2-((4-methyl-3-(methylsulfonyl)phenyl)amino)-6-propylpyrimidin-4-yl)-1,7- diazaspiro[4.5]decane-2-one (Compound 52a); and

[1290] (S or R)-7-(2-((4-methyl-3-(methylsulfonyl)phenyl)amino)-6-propylpyrimidin-4-yl)- 1,7-diazaspiro[4.5]decane-2-one (Compound 52b)

[1291] Step 1:

[1292] According to the synthetic method of Step 5 in Example 1, substituting the starting materials accordingly with Compound 52-1 (300 mg, 1.18 mmol; CAS: 1158749-85-9, directly purchased from Shanghai TaiFu Pharmaceutical Technology Co., Ltd.), 260 mg of trifluoroacetate salt Compound 52-2 (brown oil, yield 82%, crude) was prepared.

[1293] MS (ESI, m / z): [M-CF3COOH+H] + = 155.20.

[1294] Step 2:

[1295] According to the synthetic method of Step 3 in Example 1, substituting the starting materials accordingly with Compound 52-2 (260 mg, 0.97 mmol, crude) and Compound 47-7 (322 mg, 1.69 mmol), 218 mg of Compound 52-3 (white solid, yield 73%) was prepared.

[1296] MS (ESI, m / z): [M+H] + = 309.15 / 311.10.

[1297] 1 H NMR (400 MHz, CDCl3) δ 6.63-6.50 (m, 1H), 6.28 (s, 1H), 3.77-3.68 (m, 1H), 3.67-3.54 (m, 2H), 3.54-3.44 (m, 1H), 2.61-2.52 (m, 2H), 2.48-2.35 (m, 2H), 2.07-1.95 (m, 1H), 1.91-1.80 (m, 2H), 1.79-1.66 (m, 5H), 0.96 (t, J = 7.2 Hz, 3H).

[1298] Step 3:

[1299] According to the synthetic method of Step 8 in Example 1, with the raw materials correspondingly replaced with compound 52-3 (120 mg, 0.39 mmol) and compound 43-2 (72 mg, 0.39 mmol), 150 mg of compound 52 (racemate, brown solid, yield 84%) was prepared.

[1300] MS (ESI, m / z): [M+H] + = 458.30.

[1301] Step 4:

[1302] The racemate compound 52 (50 mg, 0.11 mmol) was subjected to chiral resolution, and the resolution conditions were as follows: chiral column CHIRAL ART Cellulose-SZ, 3x25 cm, 5 μm; mobile phase A: n-hexane (0.5% of 2 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isocratic 50% B; detection wavelength 274 / 252 nm; the front peak fraction was obtained with a retention time of 9.9 min, and after concentration under reduced pressure and lyophilization, 15 mg of optically pure compound 52a (pale yellow solid, yield 30%) was obtained; the back peak fraction was obtained with a retention time of 13.5 min, and after concentration under reduced pressure and lyophilization, 17.0 mg of optically pure compound 52b (pale yellow solid, yield 34%) was obtained.

[1303] Compound 52a:

[1304] MS (ESI, m / z): [M+H] + = 458.30.

[1305] 1 H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.67 (d, J = 2.4 Hz, 1H), 7.94 (s, 1H), 7.74-7.67 (m, 1H), 7.27 (d, J = 8.4 Hz, 1H), 6.26 (s, 1H), 3.87-3.71 (m, 2H), 3.38-3.33 (m, 1H), 3.31-3.26 (m, 1H), 3.14 (s, 3H), 2.54 (s, 3H), 2.46-2.38 (m, 2H), 2.38-2.26 (m, 1H), 2.18-2.05 (m, 1H), 1.91-1.80 (m, 1H), 1.78-1.61 (m, 6H), 1.58-1.47 (m, 1H), 0.91 (t, J = 7.2 Hz, 3H).

[1306] Compound 52b:

[1307] MS (ESI, m / z): [M+H] + = 458.25.

[1308] 1 H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.67 (d, J = 2.4 Hz, 1H), 7.94 (s, 1H), 7.74 - 7.67 (m, 1H), 7.27 (d, J = 8.4 Hz, 1H), 6.26 (s, 1H), 3.89 - 3.68 (m, 2H), 3.40 - 3.34 (m, 1H), 3.34 - 3.32 (m, 1H), 3.14 (s, 3H), 2.54 (s, 3H), 2.46 - 2.38 (m, 2H), 2.38 - 2.26 (m, 1H), 2.18 - 2.05 (m, 1H), 1.91 - 1.80 (m, 1H), 1.78 - 1.60 (m, 6H), 1.57 - 1.48 (m, 1H), 0.91 (t, J = 7.2 Hz, 3H).

[1309] Examples 53a and 53b:

[1310] (S or R)-7-(2-((4-methyl-3-(methylsulfonyl)phenyl)amino)-6-propylpyrimidin-4-yl)- 1,7-diazaspiro[4.4]nonan-2-one (Compound 53a); and

[1311] Preparation of (R or S)-7-(2-((4-methyl-3-(methylsulfonyl)phenyl)amino)-6- propylpyrimidin-4-yl)-1,7-diazaspiro[4.4]nonan-2-one (Compound 53b)

[1312] Step 1 :

[1313] Synthesized according to the method of Example 1, Step 5, with the raw material replaced accordingly to 53-1 (600 mg, 2.50 mmol; CAS: 1160246-72-9, directly purchased from Shanghai TaiFu Pharmaceutical Technology Co., Ltd.), to produce 80 mg trifluoroacetate salt 53-2 (brown oil, yield 107%, crude).

[1314] MS (ESI, m / z): [M-CF3COOH+H] + = 141.05.

[1315] Step 2:

[1316] Synthesized according to the method of Example 1, Step 3, with the corresponding starting materials replaced by 47-7 (400 mg, 2.11 mmol) and 53-2 (590 mg, 2.32 mmol, crude), to give 360 mg of compound 53-3 (white solid, yield 58%).

[1317] MS (ESI, m / z): [M+H] + = 295.20.

[1318] 1 H NMR (400 MHz, CDC13) δ 6.79 (br s, 1H), 6.04 (s, 1H), 3.90-3.35 (m, 4H), 2.62-2.37 (m, 4H), 2.30-2.10 (m, 4H), 1.80-1.62 (m, 2H), 0.96 (t, J = 6.8 Hz, 3H).

[1319] Step 3:

[1320] Synthesized according to the method of Example 1, Step 8, with the corresponding starting materials replaced by compound 53-3 (168 mg, 0.57 mmol) and compound 43-2 (105 mg, 0.57 mmol), to give 230 mg of compound 53 (racemate, brown solid, yield 91%).

[1321] MS (ESI, m / z): [M+H] + = 444.20.

[1322] Step 4:

[1323] Chiral resolution of racemate 53 (230 mg, 0.52 mmol) was performed under the following conditions: Chiral column CHIRALPAK IM, 3.0 x 25 mm, 5 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isocratic 50% B; detection wavelength 270 / 280 nm; the first peak fraction was obtained at a retention time of 20.7 min, to give 99 mg of optically pure compound 53a (white solid, yield 43%); the second peak fraction was obtained at a retention time of 35.6 min, to give 99 mg of optically pure compound 53b (white solid, yield 43%) after concentration under reduced pressure and lyophilization.

[1324] Compound 53a:

[1325] MS (ESI, m / z): [M+H] + = 444.25.

[1326] 1 H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 9.01 - 8.80 (m, 1H), 8.12 (s, 1H), 7.77 - 7.54 (m, 1H), 7.27 (d, J = 8.4 Hz, 1H), 5.85 (s, 1H), 3.88 - 3.40 (m, 4H), 3.14 (s, 3H), 2.54 (s, 3H), 2.45 - 2.39 (m, 2H), 2.33 - 2.21 (m, 2H), 2.13 - 1.91 (m, 4H), 1.75 - 1.62 (m, 2H), 0.91 (t, J = 7.6 Hz, 3H).

[1327] Compound 53b:

[1328] MS (ESI, m / z): [M+H] + = 444.25.

[1329] 1 H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 9.01 - 8.80 (m, 1H), 8.12 (s, 1H), 7.77 - 7.54 (m, 1H), 7.27 (d, J = 8.4 Hz, 1H), 5.85 (s, 1H), 3.88 - 3.40 (m, 4H), 3.14 (s, 3H), 2.54 (s, 3H), 2.45 - 2.39 (m, 2H), 2.33 - 2.21 (m, 2H), 2.13 - 1.91 (m, 4H), 1.75 - 1.62 (m, 2H), 0.91 (t, J = 7.6 Hz, 3H).

[1330] Examples 54a and 54b:

[1331] (S or R)-N-(3-methyl-l-(2-(4-methyl-3-(methylsulfonyl)phenyl)amino)-6- propylpyrimidin-4-yl)piperidin-3-yl)acetamide (Compound 54a); and

[1332] (R or S)-N-(3-methyl-l-(2-(4-methyl-3-(methylsulfonyl)phenyl)amino)-6- propylpyrimidin-4-yl)piperidin-3-yl)acetamide (Compound 54b)

[1333] Step 1:

[1334] According to the synthetic method of Step 3 in Example 1, with the raw material correspondingly replaced with compound 54-1 (561 mg, 2.62 mmol; CAS: 169750-96-3, directly purchased from Shanghai Biotech Co., Ltd.) and compound 47-7 (500 mg, 2.62 mmol), 700 mg of compound 54-2 (yellow solid, yield 73%) was prepared.

[1335] MS (ESI, m / z): [M+H] + = 369.25 / 371.20.

[1336] 1 H NMR (400 MHz, CDCl3) δ 6.36 (s, 1H), 4.50-4.28 (m, 2H), 3.12-2.97 (m, 2H), 2.53-2.45 (m, 2H), 2.11-1.99 (m, 1H), 1.78-1.59 (m, 4H), 1.59-1.47 (m, 1H), 1.39 (s, 9H), 1.37 (s, 3H), 0.94 (t, J = 7.2 Hz, 3H).

[1337] Step 2:

[1338] According to the synthetic method of Step 5 in Example 1, with the raw material correspondingly replaced with compound 54-2 (700 mg, 1.90 mmol), 780 mg of trifluoroacetate compound 54-3 (brown oil, yield 107%, crude) was prepared.

[1339] MS (ESI, m / z): [M-CF3COOH+H] + = 269.15 / 271.10.

[1340] Step 3:

[1341] According to the synthetic method of Step 6 in Example 1, with the raw material correspondingly replaced with compound 54-3 (600 mg, 1.57 mmol, crude), 450 mg of compound 54-4 (white solid, yield 92%) was prepared.

[1342] MS (ESI, m / z): [M+H] + = 311.15 / 313.15.

[1343] 1H NMR (400 MHz, CDC13) δ 6.34 (s, 1H), 5.63 (s, 1H), 4.57-4.48 (m, 1H), 4.26-4.16 (m, 1H), 3.13-3.04 (m, 1H), 3.02-2.94 (m, 1H), 2.58-2.49 (m, 2H), 2.45-2.28 (m, 1H), 1.85 (s, 3H), 1.77-1.60 (m, 4H), 1.56-1.45 (m, 1H), 1.43 (s, 3H), 0.96 (t, J = 7.2 Hz, 3H).

[1344] Step 4:

[1345] According to the synthesis method of Step 8 in Example 1, with the raw materials correspondingly replaced by compound 54-4 (118 mg, 0.38 mmol) and compound 43-2 (70 mg, 0.38 mmol), 150 mg of compound 54 (yellow solid, yield 86%) was prepared.

[1346] MS (ESI, m / z): [M+H] + = 460.25.

[1347] 1 H NMR (400 MHz, CDC13) δ 6.34 (s, 1H), 5.63 (s, 1H), 4.57-4.48 (m, 1H), 4.26-4.16 (m, 1H), 3.13-3.04 (m, 1H), 3.02-2.94 (m, 1H), 2.58-2.49 (m, 2H), 2.45-2.28 (m, 1H), 1.85 (s, 3H), 1.77-1.60 (m, 4H), 1.56-1.45 (m, 1H), 1.43 (s, 3H), 0.96 (t, J = 7.2 Hz, 3H).

[1348] Step 5:

[1349] Chiral resolution of racemic 54 (150 mg, 0.33 mmol) was performed under the following conditions: Chiral column CHIRALPAK ID, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (0.5% 2M ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isocratic 30% B; detection wavelength 240 / 250 nm; retention time 15.0 min for the fore peak fraction, which after concentration under reduced pressure and lyophilization gave 61 mg of optically pure compound 54a (yellow solid, yield 41%); retention time 20.1 min for the back peak fraction, which after concentration under reduced pressure and lyophilization gave 63 mg of optically pure compound 54b (yellow solid, yield 42%).

[1350] Compound 54a:

[1351] MS (ESI, m / z): [M+H] + = 460.30.

[1352] 1 H NMR (400 MHz, DMSO-d6) δ 9.28 (s, 1H), 8.70 (d, J = 2.4 Hz, 1H), 7.74 - 7.66 (m, 1H), 7.33 (s, 1H), 7.29 (d, J = 8.4 Hz, 1H), 6.05 (s, 1H), 4.28 - 4.12 (m, 2H), 3.31 - 3.17 (m, 2H), 3.15 (s, 3H), 2.54 (s, 3H), 2.44 - 2.34 (m, 2H), 1.99 - 1.88 (m, 1H), 1.77 - 1.70 (m, 1H), 1.68 (s, 3H), 1.67 - 1.61 (m, 2H), 1.59 - 1.48 (m, 2H), 1.29 (s, 3H), 0.91 (t, J = 7.2 Hz, 3H).

[1353] Compound 54b:

[1354] MS (ESI, m / z): [M+H] + = 460.25.

[1355] 1H NMR (400 MHz, DMSO-d6) δ 9.28 (s, 1H), 8.70 (d, J = 2.4 Hz, 1H), 7.74 - 7.67 (m, 1H), 7.33 (s, 1H), 7.29 (d, J = 8.4 Hz, 1H), 6.05 (s, 1H), 4.28 - 4.14 (m, 2H), 3.29 - 3.16 (m, 2H), 3.15 (s, 3H), 2.54 (s, 3H), 2.44 - 2.34 (m, 2H), 1.98 - 1.86 (m, 1H), 1.75 - 1.71 (m, 1H), 1.69 (s, 3H), 1.67 - 1.62 (m, 2H), 1.60 - 1.47 (m, 2H), 1.29 (s, 3H), 0.91 (t, J = 7.2 Hz, 3H).

[1356] Examples 55a and 55b:

[1357] (R or S)-N-(1-(2-(3-amino-4-methyl-5-(methylsulfonyl)phenyl)amino)-6- propylpyrimidin-4-yl)piperidin-3-yl)acetamide (Compound 55a); and

[1358] Preparation of (S or R)-N-(1-(2-(3-amino-4-methyl-5-(methylsulfonyl)phenyl)amino)- 6-propylpyrimidin-4-yl)piperidin-3-yl)acetamide (Compound 55b)

[1359] Step 1:

[1360] According to the synthesis method of Step 1 in Example 9, with the corresponding raw materials replaced by Compound 55-1 (1.0 g, 3.40 mmol; CAS: 101581-06-0, purchased directly from Shanghai Haohong Biomedical Technology Co., Ltd.), 300 mg of Compound 55-2 (yellow solid, yield 27%) was prepared.

[1361] MS (ESI, m / z): [M+H] + = 330.95 / 332.95.

[1362] Step 2:

[1363] According to the synthesis method of Step 5 in Example 16, with the corresponding raw materials replaced by Compound 55-2 (300 mg, 0.91 mmol), 250 mg of Compound 55-3 (white solid, yield 92%) was prepared.

[1364] MS (ESI, m / z): [M-H] - = 297.05.

[1365] Step 3:

[1366] Synthesized according to the method of Step 3 in Example 2 with corresponding replacement of raw materials by compound 55-3 (250 mg, 0.84 mmol) to produce 230 mg of compound 55-4 (yellow solid, yield 83%).

[1367] MS (ESI, m / z): [M-H] - = 329.05.

[1368] 1 H NMR (400 MHz, CDC13) δ 9.11 (d, J = 2.4 Hz, 1H), 8.66 (d, J = 2.4 Hz, 1H), 6.59 (s, 1H), 3.15 (s, 3H), 2.71 (s, 3H), 1.56 (s, 9H).

[1369] Step 4:

[1370] Synthesized according to the method of Step 7 in Example 1 with corresponding replacement of raw materials by compound 55-4 (230 mg, 0.70 mmol) to produce 150 mg of compound 55-5 (white solid, yield 71%).

[1371] MS (ESI, m / z): [M-H] - = 299.10.

[1372] 1 H NMR (400 MHz, CDC13) δ 7.59 (d, J = 2.4 Hz, 1H), 7.23 (d, J = 2.4 Hz, 1H), 6.41 (s, 1H), 3.05 (s, 3H), 2.47 (s, 3H), 1.52 (s, 9H).

[1373] Step 5:

[1374] Synthesized according to the method of Step 8 in Example 1 with corresponding replacement of raw materials by compound 55-5 (150 mg, 0.50 mmol) and 48-3 (150 mg, 1.02 mmol) to produce 250 mg of compound 55-6 (white solid, yield 89%).

[1375] MS (ESI, m / z): [M+H] + = 561.30.

[1376] Step 6:

[1377] Synthesized according to the procedure of Step 5 in Example 1 with corresponding starting materials replaced by compound 55-6 (250 mg, 0.44 mmol) to give 150 mg of compound 55 (racemate, yellowish solid, yield 74%).

[1378] MS (ESI, m / z): [M+H] + = 461.25.

[1379] Step 7:

[1380] Chiral resolution of racemate 55 (150 mg, 0.32 mmol) was performed with the following conditions: Chiral column CHIRALPAK ID, 2 x 25 cm, 5 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate 20 mL / min; gradient: isocratic 50% B; detection wavelength 222 / 272 nm; the first peak fraction was obtained at retention time 8.0 min, which gave 49 mg of optically pure compound 55a (white solid, yield 33%) after concentration under reduced pressure and lyophilization; the second peak fraction was obtained at retention time 16.0 min, which gave 58 mg of optically pure compound 55b (white solid, yield 39%) after concentration under reduced pressure and lyophilization.

[1381] Compound 55a:

[1382] MS (ESI, m / z): [M+H] + = 461.25.

[1383] 1 H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 1H), 7.94 (d, J = 7.2 Hz, 1H), 7.72 (s, 1H), 7.25 (s, 1H), 6.08 (s, 1H), 5.24 (s, 2H), 4.32 - 4.11 (m, 1H), 4.09 - 3.90 (m, 1H), 3.73 - 3.56 (m, 1H), 3.15 - 3.01 (m, 4H), 2.94 - 2.77 (m, 1H), 2.45 - 2.35 (m, 2H), 2.27 (s, 3H), 1.90 - 1.84 (m, 1H), 1.82 (s, 3H), 1.79 - 1.72 (m, 1H), 1.72 - 1.60 (m, 2H), 1.55 - 1.38 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H).

[1384] Compound 55b:

[1385] MS (ESI, m / z): [M+H] + = 461.25.

[1386] 1 H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 7.95 (d, J = 7.2 Hz, 1H), 7.71 (s, 1H), 7.25 (s, 1H), 6.08 (s, 1H), 5.25 (s, 2H), 4.31-4.11 (m, 1H), 4.09-3.91 (m, 1H), 3.72-3.57 (m, 1H), 3.15-3.02 (m, 4H), 2.94-2.75 (m, 1H), 2.45-2.36 (m, 2H), 2.27 (s, 3H), 1.90-1.84 (m, 1H), 1.83 (s, 3H), 1.80-1.72 (m, 1H), 1.71-1.61 (m, 2H), 1.54-1.41 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H).

[1387] Example 56:

[1388] Preparation of N-(4-methyl-3-(methylsulfonyl)phenyl)-4-(4-(methylamino)piperidin-l-yl)-6- propylpyrimidin-2-amine (Compound 56)

[1389] Step 1:

[1390] Synthesized according to the method of Example 1, Step 3, with the raw materials replaced accordingly to 47-7 (500 mg, 2.62 mmol) and 56-1 (561 mg, 2.62 mmol; CAS: 108612-54-0, purchased directly from the supplier Shanghai Shaoyuan Technology Co., Ltd.), to prepare 500 mg of Compound 56-2 (yellow oil, yield 52%).

[1391] MS (ESI, m / z): [M+H] + = 369.05 / 371.10.

[1392] 1 H NMR (400 MHz, CDCl3) δ 6.23 (s, 1H), 4.63-4.38 (m, 2H), 4.37-4.18 (m, 1H), 3.01-2.82 (m, 2H), 2.70 (s, 3H), 2.55-2.46 (m, 2H), 1.79-1.57 (m, 6H), 1.48 (s, 9H), 0.94 (t, J = 7.2 Hz, 3H).

[1393] Step 2:

[1394] Synthesized according to the method of Example 1, Step 8, with the corresponding starting materials replaced by 56-2 (100 mg, 0.27 mmol) and 43-2 (50 mg, 0.27 mmol) to give 120 mg of compound 56-3 (yellow solid, yield 86%).

[1395] MS (ESI, m / z): [M+H] + = 518.15.

[1396] 1 H NMR (400 MHz, CDC13) δ 8.79 - 8.67 (m, 1H), 7.45 - 7.39 (m, 1H), 7.24 - 7.13 (m, 2H), 5.95 (s, 1H), 4.63 - 4.42 (m, 2H), 4.41 - 4.11 (m, 1H), 3.05 (s, 3H), 2.99 - 2.87 (m, 2H), 2.71 (s, 3H), 2.64 (s, 3H), 2.51 - 2.43 (m, 2H), 1.83 - 1.58 (m, 6H), 1.47 (s, 9H), 0.98 (t, J = 7.2 Hz, 3H).

[1397] Step 3:

[1398] Synthesized according to the method of Example 1, Step 5, with the corresponding starting materials replaced by compound 56-3 (100 mg, 0.19 mmol). After the reaction was complete, it was purified by preparative liquid chromatography. The purification conditions were as follows: column type X bridge Phenyl OBD Column 30 x 150 mm, 5 μm; mobile phase acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate: 60 mL / min; gradient acetonitrile from 21% to 36% in 17 min, detection wavelength 254 nm / 220 nm, retention time 8.5 min. The product fractions were collected, concentrated under reduced pressure and lyophilized to give 45 mg of compound 56 (white solid, yield 57%).

[1399] MS (ESI, m / z): [M+H] + = 418.30.

[1400] 1H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.75 (d, J = 2.4 Hz, 1H), 7.71 - 7.58 (m, 1H), 7.28 (d, J = 8.4 Hz, 1H), 6.17 (s, 1H), 4.32 - 4.17 (m, 2H), 3.14 (s, 3H), 3.11 - 2.96 (m, 2H), 2.56 - 2.52 (m, 4H), 2.46 - 2.36 (m, 2H), 2.29 (s, 3H), 1.91 - 1.78 (m, 2H), 1.75 - 1.61 (m, 2H), 1.26 - 1.10 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H).

[1401] Examples 57a and 57b:

[1402] (S or R)-N-(1-(2-((3-(ethylsulfonyl)-4-methylphenyl)amino)-6- propylpyrimidin-4-yl)piperidin-3-yl)acetamide (Compound 57a); and

[1403] Preparation of (R or S)-N-(1-(2-((3-(ethylsulfonyl)-4-methylphenyl)amino)-6- propylpyrimidin-4-yl)piperidin-3-yl)acetamide (Compound 57b)

[1404] Step 1:

[1405] Synthesized according to the method of Example 1, Step 1, with the raw materials replaced accordingly to 43-1 (500 mg, 2.69 mmol; CAS: 7745-91-7, directly purchased from Shanghai Shaoyuan Technology Co., Ltd.) and sodium ethanesulfinate (624 mg, 5.37 mmol; CAS: 20035-08-9, directly purchased from Shanghai Bide Pharmaceutical Technology Co., Ltd.) to prepare 300 mg of Compound 57-1 (pale yellow solid, yield 56%).

[1406] MS (ESI, m / z): [M+H] + = 200.10.

[1407] 1 H NMR (400 MHz, CDCl3) δ 7.34-7.28 (m, 1H), 7.18-6.94 (m, 1H), 6.85-6.76 (m, 1H), 3.76 (s, 2H), 3.13 (m, 2H), 2.57-2.50 (m, 3H), 1.36-1.18 (m, 3H).

[1408] Step 2:

[1409] Synthesized according to the procedure of Example 1, Step 8, with the corresponding starting materials replaced by 57-1 (150 mg, 0.75 mmol) and 48-3 (223 mg, 0.75 mmol) to give 120 mg of compound 57 (racemate, yellow solid, yield 35%).

[1410] MS (ESI, m / z): [M+H] + = 460.30.

[1411] Step 3:

[1412] Racemate 57 (120 mg, 0.26 mmol) was subjected to chiral resolution. Resolution conditions were as follows: Chiral column CHIRALPAK ID, 250 x 30 mm, 5 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isocratic 50% B; detection wavelength 270 / 280 nm; retention time 10.9 min to give the fore fraction, which was concentrated under reduced pressure and lyophilized to give 60 mg of optically pure compound 57a (pale white solid, yield 50%); retention time 16.2 min to give the later fraction, which was concentrated under reduced pressure and lyophilized to give 30 mg of optically pure compound 57b (pale white solid, yield 25%).

[1413] Compound 57a:

[1414] MS (ESI, m / z): [M+H] + = 460.20.

[1415] 1 H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.64 (s, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.75-7.68 (m, 1H), 7.28 (d, J = 8.4 Hz, 1H), 6.12 (s, 1H), 4.20-3.96 (m, 2H), 3.71-3.59 (m, 1H), 3.26-3.07 (m, 3H), 3.04-2.82 (m, 1H), 2.51 (s, 3H), 2.45-2.39 (m, 2H), 1.86-1.76 (m, 5H), 1.73-1.63 (m, 2H), 1.53-1.37 (m, 2H), 1.10 (t, J = 7.2 Hz, 3H), 0.91 (t, J = 7.2 Hz, 3H).

[1416] Compound 57b:

[1417] MS (ESI, m / z): [M+H] + = 460.20.

[1418] 1 H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.64 (s, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.77-7.68 (m, 1H), 7.28 (d, J = 8.4 Hz, 1H), 6.12 (s, 1H), 4.20-3.96 (m, 2H), 3.72-3.54 (m, 1H), 3.26-3.08 (m, 3H), 3.03-2.83 (m, 1H), 2.51 (s, 3H) 2.47-2.35 (m, 2H), 1.86-1.76 (m, 5H), 1.71-1.61 (m, 2H), 1.53-1.37 (m, 2H), 1.10 (t, J = 7.2 Hz, 3H), 0.91 (t, J = 7.2 Hz, 3H).

[1419] Examples 58a and 58b:

[1420] (S or R)-N-(4-methyl-3-(methylsulfonyl)phenyl)-4-(3-(methylamino)piperidin-l-yl)-6- propylpyrimidin-2-amine (Compound 58a); and

[1421] Preparation of (R or S)-N-(4-methyl-3-(methylsulfonyl)phenyl)-4-(3-(methylamino)piperidin-l-yl)-6-propylpyrimidin-2-amine (Compound 58b)

[1422] Step 1:

[1423] Synthesized according to the method of Example 1, Step 3, with the raw materials replaced accordingly to 47-7 (1.0 g, 5.23 mmol) and Compound 43-3 (1.0 g, 5.23 mmol) to produce 1.2 g of Compound 58-1 (racemate, light yellow solid, yield 64%).

[1424] MS (ESI, m / z): [M+H] + = 355.10 / 357.20.

[1425] 1 H NMR (400 MHz, CDCl3) δ.6.29 (s, 1H), 4.64-4.47 (m, 1H), 3.89-3.33 (m, 4H), 2.62-2.50 (m, 2H), 2.00-1.94 (m, 1H), 1.83-1.56 (m, 5H), 1.45 (s, 9H), 0.96 (t, J = 7.2 Hz, 3H).

[1426] Step 2:

[1427] Synthesized according to the method of Example 5, Step 3 with the corresponding starting materials replaced with 58-1 (500 mg, 1.41 mmol) to produce 480 mg of compound 58-2 (brown oil, 92% yield).

[1428] MS (ESI, m / z): [M+H] + = 369.10 / 371.05

[1429] 1 H NMR (400 MHz, CDC13) δ 6.27 (s, 1H), 4.66 - 4.17 (m, 2H), 4.03 - 3.68 (m, 1H), 2.98 - 2.88 (m, 1H), 2.85 - 2.82 (m, 3H), 2.79 - 2.71 (m, 1H), 2.63 - 2.54 (m, 2H), 2.00 - 1.85 (m, 2H), 1.83 - 1.68 (m, 3H), 1.65 - 1.54 (m, 1H), 1.48 (s, 9H), 1.01 - 0.93 (m, 3H).

[1430] Step 3:

[1431] Synthesized according to the method of Example 1, Step 8 with the corresponding starting materials replaced with 58-2 (250 mg, 0.68 mmol) and 43-2 (126 mg, 0.68 mmol) to produce 310 mg of compound 58-3 (light yellow solid, 88% yield).

[1432] MS (ESI, m / z): [M+H] + = 518.25.

[1433] Step 4:

[1434] Synthesized according to the method of Example 1, Step 5 with the corresponding starting materials replaced with 58-3 (300 mg, 0.58 mmol) to produce 200 mg of compound 58 (racemate, light white solid, 83% yield).

[1435] MS (ESI, m / z): [M+H] + = 418.05.

[1436] Step 5:

[1437] Racemic compound 58 (200 mg, 0.48 mmol) was subjected to chiral resolution. Resolution conditions were as follows: Chiral column CHIRALPAK ID, 250 x 30 mm, 5 μm; mobile phase A: n-hexane (0.5% of 2 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isocratic 50% B; detection wavelength 270 / 280 nm; retention time 12.2 min for the fore peak fraction, which was concentrated under reduced pressure and lyophilized to give 80 mg of optically pure compound 58a (light white solid, yield 40%); retention time 15.4 min for the back peak fraction, which was concentrated under reduced pressure and lyophilized to give 70 mg of optically pure compound 58b (light white solid, yield 35%).

[1438] Compound 58a:

[1439] MS (ESI, m / z): [M+H] + = 418.25.

[1440] 1 H NMR (400 MHz, DMSO-d6) δ 9.28 (s, 1H), 8.66 (d, J = 2.4 Hz, 1H), 7.77 - 7.67 (m, 1H), 7.27 (d, J = 8.4 Hz, 1H), 6.15 (s, 1H), 4.31 - 4.02 (m, 2H), 3.15 (s, 3H), 3.11 - 2.91 (m, 1H), 2.87 - 2.77 (m, 1H), 2.54 (s, 3H), 2.45 - 2.39 (m, 2H), 2.38 - 2.33 (m, 1H), 2.31 (s, 3H), 2.00 - 1.88 (m, 1H), 1.85 - 1.59 (m, 4H), 1.46 - 1.20 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H).

[1441] Compound 58b:

[1442] MS (ESI, m / z): [M+H] + = 418.25.

[1443] 1H NMR (400 MHz, DMSO-d6) δ 9.28 (s, 1H), 8.66 (d, J = 2.4 Hz, 1H), 7.78 - 7.66 (m, 1H), 7.27 (d, J = 8.4 Hz, 1H), 6.15 (s, 1H), 4.33 - 3.92 (m, 2H), 3.15 (s, 3H), 3.11 - 2.94 (m, 1H), 2.90 - 2.74 (m, 1H), 2.54 (s, 3H), 2.46 - 2.39 (m, 2H), 2.38 - 2.33 (m, 1H), 2.31 (s, 3H), 2.00 - 1.85 (m, 1H), 1.86 - 1.60 (m, 4H), 1.50 - 1.20 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H).

[1444] Example 59: Preparation of (S)-N-(4-methyl-3-(methylsulfonyl)phenyl)-4-(3- (methylamino)pyrrolidin-1-yl)-6-propylpyrimidin-2-amine (Compound 59)

[1445] Step 1:

[1446] According to the method of Example 1, Step 3, with raw materials replaced by 47-7 (10 g, 52.3 mmol) and 1-5 (11.7 g, 62.8 mmol; CAS: 122536-76-9, directly purchased from Shanghai Shao Yuan Technology Co., Ltd.), 11.5 g of Compound 59-1 (light white solid, yield 65%) was prepared.

[1447] MS (ESI, m / z): [M+H] + = 341.20 / 343.15.

[1448] Step 2:

[1449] According to the method of Example 5, Step 3, with raw materials replaced by 59-1 (2 g, 5.88 mmol), 1.9 g of Compound 59-2 (yellow oil, yield 91%) was prepared.

[1450] MS (ESI, m / z): [M+H] + = 355.25 / 357.15.

[1451] Step 3:

[1452] Synthesized according to the method of Example 1, Step 8, with the corresponding starting materials replaced with 59-2 (150 mg, 0.42 mmol) and 43-2 (86 mg, 0.46 mmol) to produce 80 mg of compound 59-3 (white solid, 38% yield).

[1453] MS (ESI, m / z): [M+H] + = 504.25.

[1454] Step 4:

[1455] Synthesized according to the method of Example 1, Step 5, with the corresponding starting materials replaced with compound 59-3 (80 mg, 0.159 mmol). After the reaction was complete, it was directly purified by reverse phase column C18. The purification conditions were as follows: 20 g C18 reverse phase column; mobile phase acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate 25 mL / min; gradient acetonitrile from 10% to 90% in 30 min; detection wavelength 254 nm. The product fractions were collected and concentrated under reduced pressure to give 23 mg of compound 59 (white solid, 36% yield).

[1456] MS (ESI, m / z): [M+H] + = 404.25.

[1457] 1 H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.88 (s, 1H), 7.77-7.62 (m, 1H), 7.35-7.16 (m, 1H), 5.82 (s, 1H), 3.75-3.42 (m, 3H), 3.41-3.31 (m, 2H), 3.14 (s, 3H), 2.54 (s, 3H), 2.45-2.38 (m, 2H), 2.33 (s, 3H), 2.13-1.98 (m, 1H), 1.91-1.74 (m, 1H), 1.74-1.61 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H).

[1458] Example 60a and 60b:

[1459] (S or R)-N-(1-(2-((4-chloro-3-(methylsulfonyl)phenyl)amino)-6- propylpyrimidin-4-yl)piperidin-3-yl)acetamide (Compound 60a); and

[1460] Preparation of (R or S)-N-(1-(2-((4-chloro-3-(methylsulfonyl)phenyl)amino)-6- propylpyrimidin-4-yl)piperidin-3-yl)acetamide (Compound 60b)

[1461] Step 1:

[1462] Synthesized according to the procedure of Example 28, Step 8, with the corresponding starting materials replaced by 48-3 (500 mg, 1.68 mmol) to produce 360 mg of compound 60-1 (brown oil, 77% yield).

[1463] MS (ESI, m / z): [M+H] + = 278.20.

[1464] Step 2:

[1465] Synthesized according to the procedure of Example 9, Step 1, with the corresponding starting materials replaced by 60-1 (150 mg, 0.54) and 30-3 (146 mg, 0.54 mmol) to produce 100 mg of compound 60 (racemate, yellow oil, 40% yield).

[1466] MS (ESI, m / z): [M+H] + = 466.15 / 468.15.

[1467] Step 3:

[1468] Chiral resolution of racemate 60 (80 mg, 0.17 mmol) was performed. Resolution conditions were as follows: Chiral column CHIRAL ART Cellulose-SC, 250 x 30 mm, 5 μm; mobile phase A: n-hexane (0.5% of 2 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isocratic 50% B; detection wavelength 278 / 232 nm; retention time 11.7 min for the fore peak fraction, which was concentrated under reduced pressure and lyophilized to give 30 mg of optically pure compound 60a (white solid, 37% yield); retention time 15.0 min for the back peak fraction, which was concentrated under reduced pressure and lyophilized to give 30 mg of optically pure compound 60b (white solid, 37% yield).

[1469] Compound 60a:

[1470] MS (ESI, m / z): [M+H] + = 466.25 / 468.10.

[1471] 1H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 8.84 (d, J = 2.8 Hz, 1H), 7.88 (s, 1H), 7.86 (s, 1H), 7.55 (d, J = 8.8 Hz, 1H), 6.18 (s, 1H), 4.25 - 3.98 (m, 2H), 3.69 - 3.60 (m, 1H), 3.32 (s, 3H), 3.22 - 3.09 (m, 1H), 2.97 - 2.87 (m, 1H), 2.47 - 2.39 (m, 2H), 1.90 - 1.83 (m, 1H), 1.81 (s, 3H), 1.79 - 1.73 (m, 1H), 1.73 - 1.62 (m, 2H), 1.55 - 1.43 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H).

[1472] Compound 60b:

[1473] MS (ESI, m / z): [M+H] + = 466.25 / 468.10.

[1474] 1 H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 8.84 (d, J = 2.8 Hz, 1H), 7.88 (s, 1H), 7.86 (s, 1H), 7.55 (d, J = 8.8 Hz, 1H), 6.18 (s, 1H), 4.25 - 3.98 (m, 2H), 3.69 - 3.60 (m, 1H), 3.32 (s, 3H), 3.22 - 3.09 (m, 1H), 2.97 - 2.87 (m, 1H), 2.47 - 2.39 (m, 2H), 1.90 - 1.83 (m, 1H), 1.81 (s, 3H), 1.79 - 1.73 (m, 1H), 1.73 - 1.62 (m, 2H), 1.55 - 1.43 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H).

[1475] Examples 61a and 61b:

[1476] (S or R)-N-(1-(2-((2-fluoro-4-methyl-5-(methylsulfonyl)phenyl)amino)-6- propylpyrimidin-4-yl)piperidin-3-yl)acetamide (Compound 61a); and

[1477] Preparation of (R or S)-N-(1-(2-((2-fluoro-4-methyl-5-(methylsulfonyl)phenyl)amino)-6- propylpyrimidin-4-yl)piperidin-3-yl)acetamide (Compound 61b)

[1478] Step 1:

[1479] Synthesized according to the method of Example 1, Step 1, with the corresponding starting materials replaced by 61-1 (1.0 g, 4.90 mmol; CAS; 945244-29-1, purchased directly from Shanghai Shaoyuan Technology Co., Ltd.), to produce 380 mg of compound 61-2 (pale yellow solid, yield 38%).

[1480] MS (ESI, m / z): [M-H] - = 202.00.

[1481] 1 H NMR (400 MHz, CDC13) δ 7.48 (d, J = 8.8 Hz, 1H), 6.95 (d, J = 11.2 Hz, 1H), 3.04 (s, 3H), 2.57 (s, 3H).

[1482] 19 F NMR (377 MHz, CDC13) δ -127.72.

[1483] Step 2:

[1484] Synthesized according to the method of Example 1, Step 8, with the corresponding starting materials replaced by 61-2 (114 mg, 0.56 mmol) and 48-3 (148 mg, 0.50 mmol), to produce 160 mg of compound 61 (racemate, pale yellow solid, yield 62%).

[1485] MS (ESI, m / z): [M+H] + = 464.25.

[1486] Step 3:

[1487] The racemate 61 (160 mg, 0.34 mmol) was subjected to chiral resolution. The resolution conditions were as follows: chiral column CHIRALPAK IH, 250 x 30 mm, 5 μm; mobile phase A: n-hexane (0.5% of 2 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isocratic 30% B; detection wavelength 272 / 210 nm; the front peak fraction was obtained with a retention time of 7.6 min, concentrated under reduced pressure and lyophilized to obtain 31 mg of optically pure compound 61a (white solid, yield 19%); the back peak fraction was obtained with a retention time of 11.8 min, concentrated under reduced pressure and lyophilized to obtain 77 mg of optically pure compound 61b (white solid, yield 48%).

[1488] Compound 61a:

[1489] MS (ESI, m / z): [M+H] + = 464.15.

[1490] 1 H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J = 8.2 Hz, 1H), 8.55 (s, 1H), 7.85 (d, J = 7.5 Hz, 1H), 7.32 (d, J = 11.8 Hz, 1H), 6.15 (s, 1H), 4.05 - 4.00 (m, 2H), 3.66 - 3.57 (m, 1H), 3.17 (s, 3H), 3.14 - 3.08 (m, 1H), 2.97 - 2.87 (m, 1H), 2.57 (s, 3H), 2.44 - 2.36 (m, 2H), 2.26 - 1.79 (m, 5H), 1.71 - 1.62 (m, 2H), 1.51 - 1.38 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H).

[1491] 19 F NMR (377 MHz, DMSO-d6) δ -118.92.

[1492] Compound 61b:

[1493] MS (ESI, m / z): [M+H] + = 464.15.

[1494] 1 H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J = 8.3 Hz, 1H), 8.56 (s, 1H), 7.85 (d, J = 7.5 Hz, 1H), 7.32 (d, J = 11.8 Hz, 1H), 6.15 (s, 1H), 4.05 - 4.00 (m, 2H), 3.66 - 3.57 (m, 1H), 3.17 (s, 3H), 3.14 - 3.08 (m, 1H), 2.97 - 2.87 (m, 1H), 2.57 (s, 3H), 2.44 - 2.36 (m, 2H), 1.86 - 1.71 (m, 5H), 1.71 - 1.62 (m, 2H), 1.51 - 1.38 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H).

[1495] 19 F NMR (377 MHz, DMSO-d6) δ -118.92.

[1496] Examples 62a, 62b, 62c and 62d:

[1497] N-((2R or 2S, 3S or 3R)-2-(hydroxymethyl)-l-(2-((4-methyl-3- (methylsulfonyl)phenyl)amino)-6-propylpyrimidin-4-yl)pyrrolidin-3-yl)acetamide (Compound 62a);

[1498] N-((2S or 2R, 3S or 3R)-2-(hydroxymethyl)-l-(2-((4-methyl-3- (methylsulfonyl)phenyl)amino)-6-propylpyrimidin-4-yl)pyrrolidin-3-yl)acetamide (Compound 62b);

[1499] N-((2S or 2R, 3S or 3R)-2-(hydroxymethyl)-l-(2-((4-methyl-3- (methylsulfonyl)phenyl)amino)-6-propylpyrimidin-4-yl)pyrrolidin-3-yl)acetamide (Compound 62b);

[1500] N-((2S or 2R, 3S or 3R)-2-(hydroxymethyl)-l-(2-((4-methyl-3- (methylsulfonyl)phenyl)amino)-6-propylpyrimidin-4-yl)pyrrolidin-3-yl)acetamide (Compound 62b);

[1501] Step 1:

[1502] Compound 62-1 (12.5 g, 48.6 mmol; CAS: 170123-25-8, purchased directly from Nanjing Hengjia Pharmaceutical Co., Ltd.) and hydroxylamine hydrochloride (10.1 g, 145 mmol) were dissolved in ethanol (125 mL) at room temperature under nitrogen atmosphere, and sodium bicarbonate (16.3 g, 194 mmol) was added to the above reaction solution. The reaction was stirred at 60 °C for 16 hours. The reaction progress was monitored by liquid chromatography-mass spectrometry. After the reaction was completed, the reaction system was concentrated under reduced pressure. The obtained residue was purified by reverse phase column C18. The purification conditions were as follows: 20 g C18 reverse phase column; mobile phase acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate 25 mL / min; gradient acetonitrile from 10% to 30% in 20 minutes; detection wavelength 220 / 200 nm. The product fraction was collected and concentrated under reduced pressure to obtain 10 g of compound 62-2 (white solid, yield 76%).

[1503] 1 H NMR (400 MHz, CDC13) δ 4.91-4.75 (m, 1H), 4.33-4.12 (m, 2H), 3.81-3.61 (m, 2H), 2.91-2.81 (m, 2H), 1.52-1.39 (m, 9H), 1.33-1.26 (m, 3H).

[1504] Step 2:

[1505] Compound 62-2 (9.0 g, 33.1 mmol) was dissolved in tetrahydrofuran (90 mL) at -78 °C under nitrogen atmosphere, then diisobutylaluminum hydride (1 mmol / mL in n-hexane, 116 mL, 116 mmol) was added into the reaction solution, followed by stirring at room temperature for 25 minutes. The reaction was monitored by LC-MS. After the reaction was completed, the reaction was naturally cooled to room temperature, then moved to an ice bath, quenched with saturated ammonium chloride aqueous solution (30 mL) at 0 °C. Then filtered, the filter cake was washed with methanol (20 mL x 2), the filtrate and methanol washing liquid were combined and concentrated under reduced pressure, the obtained residue was purified by reverse phase column C18. The purification conditions were as follows: 20 g C18 reverse phase column; mobile phase acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate 25 mL / min; gradient acetonitrile from 40% to 60% in 20 minutes; detection wavelength 220 / 200 nm. The product fraction was collected and concentrated under reduced pressure to obtain 1.5 g of compound 62-3 (green oil, yield 20%).

[1506] 1 H NMR (400 MHz, CD3OD) δ 4.31-4.22 (m, 1H), 4.03-3.89 (m, 1H), 3.78-3.62 (m, 2H), 3.59-3.45 (m, 1H), 2.91-2.61 (m, 2H), 1.48 (s, 9H).

[1507] Step 3:

[1508] The starting material 62-3 (1.3 g, 5.65 mmol) was dissolved in acetic acid (13 mL) at room temperature under nitrogen atmosphere. Platinum dioxide (385 mg, 1.57 mmol) was added into the above reaction solution. The reaction system was heated to 60 °C and stirred for 3 hours under hydrogen atmosphere (30 atm). The reaction progress was monitored by LC-MS. After the reaction was completed, the reaction was naturally cooled to room temperature, filtered, the filter cake was washed with methanol (30 mL x 3), the filtrate and methanol washing liquid were combined and concentrated under reduced pressure. The obtained residue was purified by reverse phase column C18. The purification conditions were as follows: 20 g C18 reverse phase column; mobile phase acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate 25 mL / min; gradient acetonitrile from 40% to 70% in 20 minutes; detection wavelength 254 nm. The product fraction was collected and concentrated under reduced pressure to obtain 800 mg of compound 62-4 (white solid, yield 65%).

[1509] MS (ESI, m / z): [M+H] + = 217.10.

[1510] Step 4:

[1511] The starting material 62-4 (400 mg, 1.85 mmol) and acetic acid (111 mg, 1.85 mmol) were dissolved in N,N-dimethylformamide (3 mL) at room temperature under nitrogen atmosphere. To the above solution, 2-(7-azobenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.1 g, 2.89 mmol) and triethylamine (561 mg, 5.54 mmol) were added successively. The reaction system was stirred for 2 hours under the above condition. The reaction progress was monitored by LC-MS. After the reaction was completed, the reaction system was naturally cooled to room temperature and concentrated under reduced pressure. The obtained residue was purified by reverse phase column C18. The purification conditions were as follows: 20 g C18 reverse phase column; mobile phase acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate 25 mL / min; gradient acetonitrile from 10% to 80% in 30 minutes; detection wavelength 220 / 200 nm. The product fraction was collected and concentrated under reduced pressure to obtain 400 mg of compound 62-5 (yellow oil, yield 85%).

[1512] MS (ESI, m / z): [M-H] - = 257.15.

[1513] 1 H NMR (400 MHz, CDC13) δ 6.70-6.30 (m, 1H), 4.64-4.49 (m, 1H), 4.01-3.85 (m, 2H), 3.73-3.60 (m, 1H), 3.51-3.40 (m, 1H), 3.39-3.27 (m, 1H), 2.27-2.11 (m, 1H), 2.01 (s, 3H), 1.97-1.83 (m, 1H), 1.47 (s, 9H), 1.37-1.22 (m, 1H).

[1514] Step 5:

[1515] Synthesized according to the method of Example 13, Step 3, with the starting material replaced by 62-5 (380 mg, 1.47 mmol) to prepare 280 mg of compound 62-6 hydrochloride (white solid, yield 70%, crude).

[1516] MS (ESI, m / z): [M-HCI+H] + = 159.15.

[1517] Step 6:

[1518] Synthesized according to the method of Example 1, Step 3, with the corresponding starting materials replaced by 62-6 (201 mg, 0.74 mmol, crude) and 47-7 (141 mg, 0.74 mmol), and the temperature adjusted to 50 °C, to give 150 mg of compound 62-7 (yellow oil, yield 65%).

[1519] MS (ESI, m / z): [M+H] + = 313.00 / 314.95.

[1520] Step 7:

[1521] Synthesized according to the method of Example 1, Step 8, with the corresponding starting materials replaced by 62-7 (150 mg, 0.48 mmol) and 43-2 (89 mg, 0.48 mmol), to give 100 mg of compound 62 (racemic mixture, yellow solid, yield 45%).

[1522] MS (ESI, m / z): [M+H] + = 462.25.

[1523] Step 8:

[1524] The racemic mixture 62 (100 mg, 0.22 mmol) was subjected to chiral resolution. Resolution conditions were as follows: Chiral column Enantiocel-A4-5, 250 x 30 mm, 5 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isocratic 50% B; detection wavelength 220 / 254 nm; first peak fraction with retention time 6.1 min gave 7 mg of optically pure compound 62a (white solid, yield 7%); second peak fraction with retention time 7.9 min gave 9 mg of optically pure compound 62b (white solid, yield 9%); third peak fraction with retention time 9.0 min gave 20 mg of optically pure compound 62c (white solid, yield 20%); fourth peak fraction with retention time 11.5 min gave 19 mg of optically pure compound 62d (white solid, yield 19%).

[1525] Compound 62a:

[1526] MS (ESI, m / z): [M+H] + = 462.25.

[1527] 1H NMR (300 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.65-8.55 (m, 1H), 7.94-7.84 (m, 1H), 7.83-7.71 (m, 1H), 7.26 (d, J = 8.4 Hz, 1H), 5.96-5.88 (m, 1H), 4.56-4.28 (m, 2H), 4.02-3.89 (m, 1H), 3.72-3.52 (m, 4H), 3.13 (s, 3H), 2.58 (s, 3H), 2.47-2.44 (m, 2H), 2.35-2.21 (m, 1H), 1.92-1.80 (m, 4H), 1.78-1.69 (m, 2H), 0.97 (t, J = 7.2 Hz, 3H).

[1528] Compound 62b:

[1529] MS (ESI, m / z): [M+H] + = 462.35.

[1530] 1 H NMR (300 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.65-8.43 (m, 1H), 7.96-7.84 (m, 1H), 7.80-7.64 (m, 1H), 7.26 (d, J = 8.4 Hz, 1H), 5.91 (s, 1H), 4.49-4.31 (m, 2H), 4.01-3.88 (m, 1H), 3.73-3.48 (m, 4H), 3.13 (s, 3H), 2.58 (s, 3H), 2.47-2.42 (m, 2H), 2.34-2.21 (m, 1H), 1.90-1.79 (m, 4H), 1.78-1.66 (m, 2H), 0.97 (t, J = 7.2 Hz, 3H).

[1531] Compound 62c:

[1532] MS (ESI, m / z): [M+H] + = 462.25.

[1533] 1H NMR (300 MHz, DMSO-d6) δ 8.82 (s, 1 H), 8.64 - 8.54 (m, 1 H), 7.92 - 7.80 (m, 1 H), 7.53 (s, 1 H), 7.26 (d, J = 8.7 Hz, 1 H), 5.93 (s, 1 H), 4.45 - 4.25 (m, 2 H), 4.22 - 4.13 (m, 1 H), 3.89 - 3.77 (m, 1 H), 3.68 - 3.38 (m, 3 H), 3.13 (s, 3 H), 2.57 (s, 3 H), 2.48 - 2.42 (m, 2 H), 2.21 - 2.07 (m, 2 H), 1.92 (s, 3 H), 1.82 - 1.65 (m, 2 H), 0.96 (t, J = 7.2 Hz, 3 H).

[1534] Compound 62d:

[1535] MS (ESI, m / z): [M+H] + = 462.30.

[1536] 1 H NMR (300 MHz, DMSO-d6) δ 8.82 (s, 1 H), 8.64 - 8.54 (m, 1 H), 7.92 - 7.80 (m, 1 H), 7.53 (s, 1 H), 7.26 (d, J = 8.7 Hz, 1 H), 5.93 (s, 1 H), 4.45 - 4.25 (m, 2 H), 4.22 - 4.13 (m, 1 H), 3.89 - 3.77 (m, 1 H), 3.68 - 3.38 (m, 3 H), 3.13 (s, 3 H), 2.57 (s, 3 H), 2.48 - 2.42 (m, 2 H), 2.21 - 2.07 (m, 2 H), 1.92 (s, 3 H), 1.82 - 1.65 (m, 2 H), 0.96 (t, J = 7.2 Hz, 3 H).

[1537] Examples 63a and 63b:

[1538] N-(4-methyl-3-(methylsulfonyl)phenyl)-4-((3aR or 3aS, 7aR or 7aS)- octahydro-4H-pyrrolo[3,2-b]pyridin-4-yl)-6-propylpyrimidin-2-amine (Compound 63a); and

[1539] N-(4-methyl-3-(methylsulfonyl)phenyl)-4-((3aR or 3aS, 7aR or 7aS)- octahydro-4H-pyrrolo[3,2-b]pyridin-4-yl)-6-propylpyrimidin-2-amine (Compound 63a); and

[1540] Step 1:

[1541] Synthesized according to the method of Example 1, Step 3, with the corresponding replacement of starting materials 63-1 (355 mg, 1.57 mmol; 1251010-63-5, purchased directly from the supplier Shanghai Biodech Pharmaceutical Technology Co., Ltd.) and 47-7 (300 mg, 1.57 mmol) to make 400 mg of compound 63-2 (brown oil, yield 67%).

[1542] MS (ESI, m / z): [M+H] + = 381.20 / 383.15.

[1543] 1 H NMR (400 MHz, CDC13) δ 6.24 (s, 1H), 3.97-3.84 (m, 1H), 3.84-3.74 (m, 1H), 3.60-3.32 (m, 2H), 2.97-2.79 (m, 1H), 2.73-2.58 (m, 1H), 2.54 (t, J = 7.6 Hz, 2H), 2.46-2.24 (m, 1H), 2.24-2.06 (m, 1H), 2.01-1.87 (m, 1H), 1.85-1.57 (m, 4H), 1.47 (s, 9H), 1.40-1.29 (m, 1H), 1.02-0.92 (m, 3H).

[1544] Step 2:

[1545] Synthesized according to the method of Example 9, Step 1, with the corresponding replacement of starting materials 63-2 (150 mg, 0.39 mmol) and 43-2 (72.9 mg, 0.39 mmol) to make 170 mg of compound 63-3 (brown solid, yield 82%).

[1546] MS (ESI, m / z): [M+H] + = 530.30.

[1547] Step 3:

[1548] Synthesized according to the method of Example 1, Step 5, with the corresponding replacement of starting material 63-3 (160 mg, 0.30 mmol) to make 80 mg of compound 63 (racemate, white solid, yield 62%).

[1549] MS (ESI, m / z): [M+H] + = 430.25.

[1550] Step 4:

[1551] Racemic 63 (80 mg, 0.18 mmol) was subjected to chiral resolution. Resolution conditions were as follows: Chiral column CHIRALPAK ID, 250 x 30 mm, 5 μm; mobile phase A: n-hexane (0.5% 2M ammonia-methanol), mobile phase B: ethanol; flow rate 20 mL / min; gradient: isocratic 50% B; detection wavelength 240 / 250 nm; retention time 7.8 min for the fore peak fraction, which was concentrated under reduced pressure and lyophilized to give 30 mg of optically pure compound 63a (white solid, yield 38%); retention time 15.5 min for the back peak fraction, which was concentrated under reduced pressure and lyophilized to give 31 mg of optically pure compound 63b (white solid, yield 39%).

[1552] Compound 63a:

[1553] MS (ESI, m / z): [M+H] + = 430.25.

[1554] 1 H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.76 (d, J = 2.4 Hz, 1H), 7.68 - 7.61 (m, 1H), 7.28 (d, J = 8.4 Hz, 1H), 6.12 (s, 1H), 4.82 - 4.54 (m, 1H), 4.28 - 4.02 (m, 1H), 3.43 - 3.20 (m, 1H), 3.16 (s, 3H), 3.10 - 3.00 (m, 1H), 2.99 - 2.86 (m, 2H), 2.86 - 2.77 (m, 1H), 2.54 (s, 3H), 2.42 (t, J = 7.2 Hz, 2H), 2.10 - 1.94 (m, 1H), 1.79 - 1.64 (m, 3H), 1.64 - 1.48 (m, 2H), 1.45 - 1.28 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H).

[1555] Compound 63b:

[1556] MS (ESI, m / z): [M+H] + = 430.25.

[1557] 1H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.76 (d, J = 2.4 Hz, 1H), 7.69 - 7.61 (m, 1H), 7.28 (d, J = 8.4 Hz, 1H), 6.12 (s, 1H), 4.79 - 4.55 (m, 1H), 4.29 - 4.05 (m, 1H), 3.42 - 3.20 (m, 1H), 3.16 (s, 3H), 3.10 - 3.00 (m, 1H), 2.99 - 2.85 (m, 2H), 2.87 - 2.74 (m, 1H), 2.54 (s, 3H), 2.42 (t, J = 7.6 Hz, 2H), 2.07 - 1.95 (m, 1H), 1.79 - 1.61 (m, 3H), 1.61 - 1.48 (m, 2H), 1.47 - 1.31 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H).

[1558] Example 64:

[1559] Preparation of N-(2-(2-((4-methyl-3-(methylsulfonyl)phenyl)amino)-6- propylpyrimidin-4-yl)-2-azabicyclo[2.2.2]oct-4-yl)acetamide (Compound 64)

[1560] Step 1:

[1561] Synthesized according to the method of Example 1, Step 3, starting from the corresponding 64-1 (486 mg, 2.87 mmol; CAS: 2306265-63-2; purchased directly from Nanjing Nari Science & Technology Co., Ltd.) and 47-7 (500 mg, 2.62 mmol) to give 550 mg of Compound 64-2 (white solid, 65% yield).

[1562] MS (ESI, m / z): [M+H] + = 324.15 / 326.10.

[1563] 1 H NMR (400 MHz, CDCl3) δ 6.03 (s, 1H), 4.99 - 4.88 (m, 1H), 3.74 (s, 3H), 3.52 - 3.37 (m, 1H), 2.61 - 2.47 (m, 2H), 2.12 - 1.59 (m, 11H), 0.97 (t, J = 7.2 Hz, 3H).

[1564] Step 2:

[1565] Synthesized according to the method of Example 5, Step 8, with the corresponding starting materials replaced with 64-2 (500 mg, 1.55 mmol) to produce 450 mg of compound 64-3 (white solid, 94% yield).

[1566] MS (ESI, m / z): [M+H] + = 310.25 / 312.20.

[1567] Step 3:

[1568] The starting material 64-3 (250 mg, 0.81 mmol) was dissolved in tert-butanol (5 mL) at room temperature under nitrogen atmosphere. Diphenyl phosphorazide (330 mg, 1.20 mmol) and triethylamine (243 mg, 2.40 mmol) were added successively to the above reaction solution. The reaction system was warmed to 90 °C and stirred for 2 hours. The reaction progress was monitored by LC-MS. After the reaction was completed, the reaction system was naturally cooled to room temperature, concentrated under reduced pressure, and the residue was directly purified by silica gel column (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain 90 mg of compound 64-4 (white solid, 29% yield).

[1569] MS (ESI, m / z): [M+H] + = 381.20 / 383.15.

[1570] 1 H NMR (400 MHz, CDCl3) δ 6.02 (s, 1H), 4.96-4.85 (m, 1H), 4.53-4.40 (m, 1H), 3.62 (s, 2H), 2.71-2.52 (m, 2H), 2.21-2.07 (m, 2H), 2.01-1.65 (m, 8H), 1.45 (s, 9H), 0.98 (t, J = 7.2 Hz, 3H).

[1571] Step 4:

[1572] Synthesized according to the method of Example 1, Step 5, with the corresponding starting materials replaced with 64-4 (80 mg, 0.21 mmol) to produce 100 mg of trifluoroacetate compound 64-5 (white solid, 121% yield, crude).

[1573] MS (ESI, m / z): [M-CF3COOH+H] + = 281.15 / 283.10.

[1574] Step 5:

[1575] Synthesized according to the procedure of Example 1, Step 6, with the corresponding starting materials replaced with 64-5 (100 mg, 0.25 mmol, crude) to give 50 mg of compound 64-6 (white solid, 62% yield).

[1576] MS (ESI, m / z): [M+H] + = 323.15 / 325.10.

[1577] Step 6:

[1578] Synthesized according to the procedure of Example 1, Step 8, with the corresponding starting materials replaced with compound 64-6 (71 mg, 0.22 mmol) and 43-2 (44 mg, 0.24 mmol). After the reaction was complete, it was purified by preparative liquid chromatography. The purification conditions were as follows: Column type XBridge Shield RP18 OBD Column 30 x 150 mm, 5 μm; mobile phase acetonitrile and water (10 mmol / L ammonium bicarbonate); flow rate: 60 mL / min; gradient acetonitrile from 37% to 48% in 10 min, detection wavelength 254 nm / 220 nm, retention time 9.7 min. The product fractions were collected, concentrated under reduced pressure and lyophilized to give 36 mg of compound 64 (white solid, 35% yield).

[1579] MS (ESI, m / z): [M+H] + = 472.30.

[1580] 1 H NMR (300 MHz, DMSO-d6) δ 9.07 (s, 1H), 8.78-8.74 (m, 1H), 7.73-7.61 (m, 1H), 7.51-7.32 (m, 1H), 7.26 (d, J = 8.4 Hz, 1H), 5.90-5.69 (m, 1H), 3.77-3.45 (m, 2H), 3.13 (s, 3H), 2.56 (s, 3H), 2.47-2.39 (m, 2H), 2.10-1.93 (m, 2H), 1.95-1.78 (m, 10H), 1.78-1.61 (m, 2H), 0.94 (t, J = 7.2 Hz, 3H).

[1581] Example 65a and 65b:

[1582] (S or R)-N-(1-(2-((3-(isopropylsulfonyl)-4-methylphenyl)amino)-6- propylpyrimidin-4-yl)piperidin-3-yl)acetamide (Compound 65a); and

[1583] (R or S)-N-(1-(2-((3-(isopropylsulfonyl)-4-methylphenyl)amino)-6- propylpyrimidin-4-yl)piperidin-3-yl)acetamide (Compound 65b) was prepared according to the procedure of Example 1, Step 1, with the corresponding starting materials replaced by Compound 43-1 (1.0 g, 5.37 mmol; CAS: 7745-91-7, purchased directly from Shanghai Shao Yuan Technology Co., Ltd.) and sodium 2-propanesulfonate (1.4 g, 10.6 mmol; CAS: 4160-19-4; purchased directly from Shanghai Bide Pharmaceutical Technology Co., Ltd.), to afford 400 mg of Compound 65-1 (white solid, 35% yield).

[1584] Step 1:

[1585] According to the procedure of Example 1, Step 1, with the corresponding starting materials replaced by Compound 43-1 (1.0 g, 5.37 mmol; CAS: 7745-91-7, purchased directly from Shanghai Shao Yuan Technology Co., Ltd.) and sodium 2-propanesulfonate (1.4 g, 10.6 mmol; CAS: 4160-19-4; purchased directly from Shanghai Bide Pharmaceutical Technology Co., Ltd.), to afford 400 mg of Compound 65-1 (white solid, 35% yield).

[1586] MS (ESI, m / z): [M+H] + = 214.10.

[1587] Step 2:

[1588] According to the procedure of Example 1, Step 8, with the corresponding starting materials replaced by 65-1 (86 mg, 0.40 mmol) and 48-3 (120 mg, 0.40 mmol), to afford 140 mg of Compound 65 (racemate, white solid, 74% yield).

[1589] MS (ESI, m / z): [M+H] + = 474.25.

[1590] 1 H NMR (400 MHz, CDCl3) δ 8.72-8.70 (m, 1H), 7.45-7.39 (m, 1H), 7.38-7.29 (m, 3H), 7.24-7.20 (m, 1H), 4.46-4.40 (m, 1H), 4.13-4.05 (m, 1H), 3.97-3.84 (m, 1H), 3.82-3.74 (m, 1H), 3.69-3.66 (m, 1H), 3.51-3.44 (m, 1H), 2.61 (s, 3H), 2.51-2.43 (m, 2H), 2.11 (s, 1H), 1.99-1.94 (m, 3H), 1.76-1.64 (m, 5H), 1.33-1.27 (m, 6H), 1.01-0.94 (m, 3H).

[1591] Step 3:

[1592] Racemic 65 (120 mg, 0.25 mmol) was subjected to chiral resolution. Resolution conditions were as follows: Chiral column CHIRALPAK ID, 250 x 30 mm, 5 μm; mobile phase A: n-hexane (0.5% of 2 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isocratic 30% B; detection wavelength 240 / 250 nm; retention time 7.8 min for the fore peak fraction, which was concentrated under reduced pressure and lyophilized to give 70 mg of optically pure compound 65a (white solid, yield 58%); retention time 15.5 min for the back peak fraction, which was concentrated under reduced pressure and lyophilized to give 30 mg of optically pure compound 65b (white solid, yield 25%).

[1593] Compound 65a:

[1594] MS (ESI, m / z): [M+H] + = 474.30.

[1595] 1 H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.65 (s, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 6.12 (s, 1H), 4.16 - 3.92 (m, 2H), 3.71 - 3.60 (m, 1H), 3.42 - 3.33 (m, 1H), 3.24 - 3.11 (m, 1H), 3.00 - 2.90 (m, 1H), 2.49 (s, 3H), 2.41 (d, J = 7.2 Hz, 2H), 1.92 - 1.83 (m, 1H), 1.81 (s, 3H), 1.78 - 1.72 (m, 1H), 1.72 - 1.61 (m, 2H), 1.55 - 1.41 (m, 2H), 1.16 (d, J = 6.8 Hz, 6H), 0.91 (t, J = 7.2 Hz, 3H).

[1596] Compound 65b:

[1597] MS (ESI, m / z): [M+H] + = 474.30.

[1598] 1H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.65 (s, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 6.12 (s, 1H), 4.16 - 3.90 (m, 2H), 3.69 - 3.61 (m, 1H), 3.44 - 3.34 (m, 1H), 3.24 - 3.11 (m, 1H), 3.00 - 2.90 (m, 1H), 2.49 (s, 3H) 2.45 - 2.37 (m, 2H), 1.92 - 1.82 (m, 1H), 1.81 (s, 3H), 1.79 - 1.72 (m, 1H), 1.72 - 1.61 (m, 2H), 1.55 - 1.41 (m, 2H), 1.16 (d, J = 6.8 Hz, 6H), 0.91 (t, J = 7.2 Hz, 3H).

[1599] Examples 66a and 66b:

[1600] (R or S)-N-(1-(2-((3-(cyclopropylsulfonyl)-4-methylphenyl)amino)-6- propylpyrimidin-4-yl)piperidin-3-yl)acetamide (Compound 66a); and

[1601] Preparation of (S or R)-N-(1-(2-((3-(cyclopropylsulfonyl)-4-methylphenyl)amino)-6- propylpyrimidin-4-yl)piperidin-3-yl)acetamide (Compound 66b)

[1602] Step 1:

[1603] Synthesized according to the procedure of Example 1, Step 1, with the raw materials replaced accordingly to Compound 43-1 (1.0 g, 5.37 mmol; CAS: 7745-91-7, purchased directly from Shanghai Shaoyuan Technology Co., Ltd.) and sodium cyclopropylsulfinate (1.37 g, 10.5 mmol; CAS: 910209-21-1, purchased directly from Shanghai Shaoyuan Technology Co., Ltd.) to afford 700 mg of Compound 66-1 (brown solid, yield 62%).

[1604] 1 H NMR (400 MHz, CDCl3) δ 7.25 (d, J = 2.4 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 6.85 - 6.73 (m, 1H), 4.22 - 3.33 (m, 2H), 2.64 - 2.50 (m, 4H), 1.35 - 1.26 (m, 2H), 1.06 - 0.95 (m, 2H).

[1605] Step 2:

[1606] Compound 66 was prepared according to the procedure of Step 8 in Example 1, with the corresponding starting materials replaced by 66-1 (209 mg, 0.70 mmol) and 48-3 (150 mg, 0.71 mmol), to give 100 mg of compound 66 (yellow solid, yield 30%).

[1607] MS (ESI, m / z): [M+H] + = 472.25.

[1608] Step 3:

[1609] Racemic compound 66 (100 mg, 0.21 mmol) was subjected to chiral resolution. Resolution conditions were as follows: Chiral column CHIRALPAK ID, 250 x 30 mm, 5 μm; mobile phase A: n-hexane (0.5% 2M ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isocratic 10% B; detection wavelength 220 / 254 nm; the fore peak fraction was obtained at a retention time of 7.4 min, concentrated under reduced pressure and lyophilized to give 66 mg of optically pure compound 66a (white solid, yield 66%); the back peak fraction was obtained at a retention time of 9.6 min, concentrated under reduced pressure and lyophilized to give 18 mg of optically pure compound 66b (racemic, white solid, yield 18%).

[1610] Compound 66a:

[1611] MS (ESI, m / z): [M+H] + = 472.25.

[1612] 1 H NMR (400 MHz, DMSO-d6) δ 9.28 (s, 1H), 8.55 (s, 1H), 7.88 (d, J = 7.2 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 6.12 (s, 1H), 4.10 - 3.99 (m, 2H), 3.73 - 3.51 (m, 1H), 3.23 - 3.05 (m, 1H), 3.02 - 2.77 (m, 2H), 2.58 (s, 3H), 2.41 (t, J = 7.2 Hz, 2H), 1.90 - 1.83 (m, 1H), 1.81 (s, 3H), 1.78 - 1.71 (m, 1H), 1.70 - 1.59 (m, 2H), 1.51 - 1.40 (m, 2H), 1.09 - 0.99 (m, 4H), 0.91 (t, J = 7.2 Hz, 3H).

[1613] Compound 66b:

[1614] MS (ESI, m / z): [M+H] + = 472.25.

[1615] 1 H NMR (400 MHz, DMSO-d6) δ 9.27 (s, 1H), 8.54 (s, 1H), 7.87 (d, J = 7.2 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 6.11 (s, 1H), 4.16 - 3.91 (m, 2H), 3.71 - 3.57 (m, 1H), 3.22 - 3.09 (m, 1H), 2.99 - 2.83 (m, 2H), 2.57 (s, 3H), 2.40 (t, J = 7.2 Hz, 2H), 1.92 - 1.83 (m, 1H), 1.80 (s, 3H), 1.77 - 1.60 (m, 3H), 1.54 - 1.39 (m, 2H), 1.07 - 0.97 (m, 4H), 0.90 (t, J = 7.2 Hz, 3H).

[1616] Examples 67a and 67b:

[1617] (S or R)-N-(3-methyl-l-(2-(4-methyl-3-(methylsulfonyl)phenyl)amino)-6- propylpyrimidin-4-yl)pyrrolidin-3-yl)acetamide (Compound 67a); and

[1618] (R or S)-N-(3-methyl-l-(2-(4-methyl-3-(methylsulfonyl)phenyl)amino)-6- propylpyrimidin-4-yl)pyrrolidin-3-yl)acetamide (Compound 67b)

[1619] Step 1:

[1620] Synthesized according to the procedure of Example 1, Step 3, with raw materials replaced accordingly to 47-7 (1.00 g, 5.23 mmol) and 23-1 (1.05 g, 5.23 mmol; CAS: 147459-52-7, purchased directly from the supplier Shanghai Hauhun Biomedical Technology Co., Ltd.), to prepare 990 mg of Compound 67-1 (yellow solid, yield 54%).

[1621] 1H NMR (400 MHz, CDC13) δ 6.03 (s, 1H), 4.72-4.49 (m, 1H), 3.89-3.26 (m, 5H), 2.58-2.50 (m, 2H), 1.95 (s, 1H), 1.78-1.64 (m, 2H), 1.44 (s, 9H), 1.00-0.92 (m, 3H).

[1622] Step 2:

[1623] Synthesized according to the method of Example 1, Step 5, with the corresponding starting materials replaced with 67-1 (250 mg, 0.70 mmol) to produce 230 mg of trifluoroacetate salt of compound 67-2 (brown oil, 89% yield, crude).

[1624] MS (ESI, m / z): [M-CF3COOH+H] + = 255.10 / 257.05.

[1625] Step 3:

[1626] Synthesized according to the method of Example 1, Step 6, with the corresponding starting materials replaced with 67-2 (230 mg, 0.62 mmol, crude) to produce 136 mg of compound 67-3 (racemic, white solid, 74% yield).

[1627] MS (ESI, m / z): [M+H] + = 297.15 / 299.10.

[1628] Step 4:

[1629] Synthesized according to the method of Example 1, Step 8, with the corresponding starting materials replaced with 67-3 (120 mg, 0.40 mmol) and 43-2 (75 mg, 0.40 mmol) to produce 120 mg of compound 67 (racemic, brown solid, 67% yield).

[1630] MS (ESI, m / z): [M+H] + = 446.20.

[1631] Step 5:

[1632] Racemic 67 (120 mg, 0.27 mmol) was subjected to chiral resolution. Resolution conditions were as follows: Chiral column CHIRALPAK IA, 250 x 30 mm, 5 μm; mobile phase A: n-hexane: methyl-tert-butyl ether (1 : 1, 0.1% diethylamine), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isocratic 10% B; detection wavelength 220 / 254 nm; retention time 10.9 min for the fore peak fraction, which was concentrated under reduced pressure and lyophilized to give 48 mg of optically pure compound 67a (white solid, yield 40%); retention time 17.3 min for the back peak fraction, which was concentrated under reduced pressure and lyophilized to give 63 mg of optically pure compound 67b (white solid, yield 52%).

[1633] Compound 67a:

[1634] MS (ESI, m / z): [M+H] + = 446.25.

[1635] 1 H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.95 - 8.75 (m, 1H), 8.01 - 7.79 (m, 1H), 7.77 - 7.66 (m, 1H), 7.27 (d, J=8.4 Hz, 1H), 5.87 - 5.65 (m, 1H), 4.08 - 3.57 (m, 2H), 3.52 - 3.21 (m, 2H), 3.16 (s, 3H), 2.54 (s, 3H), 2.42 (t, J=7.6 Hz, 2H), 2.38 - 2.23 (m, 1H), 1.95 - 1.85 (m, 1H), 1.78 (s, 3H), 1.74 - 1.61 (m, 2H), 1.43 (s, 3H), 0.91 (t, J=7.2 Hz, 3H).

[1636] Compound 67b:

[1637] MS (ESI, m / z): [M+H] + = 446.25.

[1638] 1H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.90-8.72 (m, 1H), 8.03-7.81 (m, 1H), 7.77-7.59 (m, 1H), 7.27 (d, J = 8.4 Hz, 1H), 5.94-5.68 (m, 1H), 4.10-3.55 (m, 2H), 3.52-3.21 (m, 2H), 3.16 (s, 3H), 2.54 (s, 3H), 2.42 (t, J = 7.6 Hz, 2H), 2.38-2.23 (m, 1H), 1.95-1.85 (m, 1H), 1.78 (s, 3H), 1.73-1.61 (m, 2H), 1.43 (s, 3H), 0.91 (t, J = 7.2 Hz, 3H).

[1639] Examples 68a and 68b:

[1640] (S or R)-2-hydroxy-N-(1-(2-((4-methyl-3-(methylsulfonyl)phenyl)amino)-6- propylpyrimidin-4-yl)piperidin-3-yl)acetamide (Compound 68a); and

[1641] Preparation of (R or S)-2-hydroxy-N-(1-(2-((4-methyl-3-(methylsulfonyl)phenyl)amino)-6- propylpyrimidin-4-yl)piperidin-3-yl)acetamide (Compound 68b)

[1642] Step 1:

[1643] Synthesized according to the method of Example 62, Step 4, with the raw materials replaced accordingly to 48-2 (199 mg, 0.78 mmol) and 68-1 (93 mg, 0.79 mmol; CAS: 13831-30-6, directly purchased from the supplier Shanghai Titan Scientific Co., Ltd.), to prepare 200 mg of Compound 68-2 (colorless oil, yield 72%).

[1644] MS (ESI, m / z): [M+H] + = 355.15 / 357.10.

[1645] 1H NMR (400 MHz, CDC13) δ 6.38 (d, J = 7.2 Hz, 1H), 6.31 (s, 1H), 4.08-4.00 (m, 1H), 3.89-3.75 (m, 2H), 3.64-3.50 (m, 2H), 2.82-2.79 (m, 1H), 2.57-2.48 (m, 2H), 2.35-2.25 (m, 1H), 2.09 (s, 3H), 2.03-1.93 (m, 1H), 1.84-1.57 (m, 5H), 0.94 (t, J = 7.2 Hz, 3H).

[1646] Step 2:

[1647] Synthesized according to the procedure of Example 1, Step 8, with the corresponding starting materials replaced by 68-2 (71 mg, 0.20 mmol) and 43-2 (37 mg, 0.20 mmol) to give 80 mg of compound 68 (racemic, colorless oil, 87% yield).

[1648] MS (ESI, m / z): [M+H] + = 462.20.

[1649] Step 3:

[1650] Racemic 68 (80 mg, 0.17 mmol) was subjected to chiral resolution. Resolution conditions were as follows: Chiral column CHIRALPAK ID, 250 x 30 mm, 5 μm; mobile phase A: n-hexane (0.5% 2M ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isocratic 40% B; detection wavelength 220 / 254 nm; retention time 11.4 min for the fore peak fraction, which was concentrated under reduced pressure and lyophilized to give 17 mg of optically pure compound 68a (white solid, 21% yield); retention time 16.1 min for the back peak fraction, which was concentrated under reduced pressure and lyophilized to give 19 mg of optically pure compound 68b (white solid, 23% yield).

[1651] Compound 68a:

[1652] MS (ESI, m / z): [M+H] + = 462.30.

[1653] 1H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.64 (s, 1H), 7.77-7.70 (m, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 6.16 (s, 1H), 5.47-5.41 (m, 1H), 4.26-4.04 (m, 2H), 3.81 (d, J = 5.6 Hz, 2H), 3.78-3.67 (m, 1H), 3.14 (s, 3H), 3.08-2.97 (m, 2H), 2.54 (s, 3H), 2.42 (t, J = 7.6 Hz, 2H), 1.89-1.79 (m, 1H), 1.76-1.55 (m, 4H), 1.53-1.39 (m, 1H), 0.91 (t, J = 7.2 Hz, 3H).

[1654] Compound 68b:

[1655] MS (ESI, m / z): [M+H] + = 462.30.

[1656] 1 H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.64 (s, 1H), 7.77-7.70 (m, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 6.16 (s, 1H), 5.47-5.41 (m, 1H), 4.26-4.04 (m, 2H), 3.81 (d, J = 5.6 Hz, 2H), 3.78-3.67 (m, 1H), 3.14 (s, 3H), 3.08-2.97 (m, 2H), 2.54 (s, 3H), 2.42 (t, J = 7.6 Hz, 2H), 1.89-1.79 (m, 1H), 1.76-1.55 (m, 4H), 1.53-1.39 (m, 1H), 0.91 (t, J = 7.2 Hz, 3H).

[1657] Examples 69a and 69b:

[1658] (S or R)-N-(1-(2-(3-amino-4-chloro-5-(methylsulfonyl)phenyl)amino)-6- propylpyrimidin-4-yl)piperidin-3-yl)acetamide (Compound 69a); and

[1659] Preparation of (R or S)-N-(1-(2-(3-amino-4-chloro-5-(methylsulfonyl)phenyl)amino)-6- propylpyrimidin-4-yl)piperidin-3-yl)acetamide (Compound 69b)

[1660] Step 1:

[1661] Synthesized according to the method of Example 9, Step 1 with the corresponding starting materials replaced with 60-1 (160 mg, 0.58 mmol) and 35-6 (222 mg, 0.58 mmol) to give 120 mg of compound 69-1 (racemate, white solid, 35% yield).

[1662] MS (ESI, m / z): [M+H] + = 581.25 / 583.20.

[1663] Step 2:

[1664] Synthesized according to the method of Example 1, Step 5 with the corresponding starting materials replaced with 69-1 (160 mg, 0.27 mmol) to give 55 mg of compound 69 (racemate, white solid, 42% yield).

[1665] MS (ESI, m / z): [M+H] + = 481.15 / 483.15.

[1666] Step 3:

[1667] Chiral resolution of racemate 69 (55 mg, 0.11 mmol). Resolution conditions: Chiral column Enantiocel-A4-5, 250 x 30 mm, 5 μm; mobile phase A: n-hexane (0.5% of 2 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isocratic 40% B; detection wavelength 220 / 254 nm; retention time 11.8 min to give the front peak fraction, which was concentrated under reduced pressure and lyophilized to give 21 mg of optically pure compound 69a (white solid, 38% yield); retention time 15.2 min to give the back peak fraction, which was concentrated under reduced pressure and lyophilized to give 3.4 mg of optically pure compound 69b (white solid, 6% yield).

[1668] Compound 69a:

[1669] MS (ESI, m / z): [M+H] + = 481.20 / 483.15.

[1670] 1H NMR (400 MHz, DMSO-d6) δ 9.27 (s, 1H), 7.97 (d, J = 7.2 Hz, 1H), 7.82 (s, 1H), 7.46 (s, 1H), 6.13 (s, 1H), 5.78 (s, 2H), 4.38 - 3.88 (m, 2H), 3.73 - 3.56 (m, 1H), 3.26 (s, 3H), 3.17 - 3.02 (m, 1H), 2.95 - 2.79 (m, 1H), 2.45 - 2.36 (m, 2H), 1.92 - 1.72 (m, 5H), 1.74 - 1.61 (m, 2H), 1.55 - 1.42 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H).

[1671] Compound 69b:

[1672] MS (ESI, m / z): [M+H] + = 481.25 / 483.20.

[1673] 1 H NMR (400 MHz, DMSO-d6) δ 9.27 (s, 1H), 7.97 (d, J = 7.2 Hz, 1H), 7.82 (s, 1H), 7.46 (s, 1H), 6.13 (s, 1H), 5.78 (s, 2H), 4.38 - 3.88 (m, 2H), 3.73 - 3.56 (m, 1H), 3.26 (s, 3H), 3.17 - 3.02 (m, 1H), 2.95 - 2.79 (m, 1H), 2.45 - 2.36 (m, 2H), 1.92 - 1.72 (m, 5H), 1.74 - 1.61 (m, 2H), 1.55 - 1.42 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H).

[1674] Examples 70a and 70b:

[1675] (S or R)-N-(1-(2-((4-amino-3-(methylsulfonyl)phenyl)amino)-6- propylpyrimidin-4-yl)piperidin-3-yl)acetamide (Compound 70a); and

[1676] Preparation of (R or S)-N-(1-(2-((4-amino-3-(methylsulfonyl)phenyl)amino)-6- propylpyrimidin-4-yl)piperidin-3-yl)acetamide (Compound 70b)

[1677] Step 1:

[1678] According to the method for synthesizing Step 8 in Embodiment 1, raw materials were replaced with compound 47-5 (144 mg, 0.67 mmol) and compound 48-3 (198 mg, 0.67 mmol) to prepare 160 mg of compound 70-1 (yellow solid, yield 50%).

[1679] MS (ESI, m / z): [M+H] + = 477.25.

[1680] Step 2:

[1681] Compound 70-1 (120 mg, 0.25 mmol) was dissolved in N,N-dimethylformamide (2 mL) at room temperature under a nitrogen atmosphere, and then tetrahydroxydiboron (67 mg, 0.75 mmol; CAS: 13675-18-8, purchased directly from Shanghai Shao Yuan Technology Co., Ltd.) and 4,4'-dipyridine (19 mg, 0.12 mmol; CAS: 553-26-4, purchased directly from Anhui Zesheng Technology Co., Ltd.) were added to the reaction solution. The reaction system was stirred for 10 minutes under these conditions. The reaction progress was monitored by liquid chromatography-mass spectrometry. After the reaction was completed, the reaction system was concentrated under reduced pressure, and the obtained residue was directly purified by a reverse-phase C18 column. The purification conditions were as follows: C18 reverse-phase column; mobile phase: acetonitrile and water (10 mmol / L ammonium bicarbonate); gradient: acetonitrile increased from 10% to 50% in 10 minutes; detection wavelength: 254 nm; the product fraction was collected, concentrated under reduced pressure, and lyophilized to obtain 70 mg of compound 70 (racemate, yellow solid, yield 62%).

[1682] MS (ESI, m / z): [M+H] + = 447.2.

[1683] Step 3:

[1684] Racemate 70 (50 mg, 0.11 mmol) was subjected to chiral resolution. The resolution conditions were as follows: chiral column CHIRALPAK IG, 2 x 25 cm, 5 μm; mobile phase A: n-hexane (0.5% 2M ammonia-methanol), mobile phase B: ethanol; flow rate: 20 mL / min; gradient: isocratic gradient 40% B; detection wavelength: 254 / 220 nm; the front peak fraction was obtained at a retention time of 10.3 minutes, concentrated under reduced pressure, and lyophilized to obtain 32 mg of optically pure compound 70a (yellow solid, yield 64%); the back peak fraction was obtained at a retention time of 15.7 minutes, concentrated under reduced pressure, and lyophilized to obtain 7 mg of optically pure compound 70b (yellow solid, yield 14%).

[1685] Compound 70a:

[1686] MS (ESI, m / z): [M+H] + = 447.10.

[1687] 1 H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.25 (d, J = 2.0 Hz, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.55 - 7.43 (m, 1H), 6.80 (d, J = 8.8 Hz, 1H), 6.03 (s, 1H), 5.61 (s, 2H), 4.08 - 4.02 (m, 2H), 3.64 - 3.60 (m, 1H), 3.13 - 3.05 (m, 4H), 2.94 - 2.79 (m, 1H), 2.42 - 2.32 (m, 2H), 1.95 - 1.77 (m, 4H), 1.77 - 1.70 (m, 1H), 1.70 - 1.59 (m, 2H), 1.52 - 1.34 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H).

[1688] Compound 70b:

[1689] MS (ESI, m / z): [M+H] + = 447.10.

[1690] 1 H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.25 (d, J = 2.0 Hz, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.55 - 7.43 (m, 1H), 6.80 (d, J = 8.8 Hz, 1H), 6.03 (s, 1H), 5.61 (s, 2H), 4.08 - 4.02 (m, 2H), 3.64 - 3.60 (m, 1H), 3.13 - 3.05 (m, 4H), 2.94 - 2.79 (m, 1H), 2.42 - 2.32 (m, 2H), 1.95 - 1.77 (m, 4H), 1.77 - 1.70 (m, 1H), 1.70 - 1.59 (m, 2H), 1.52 - 1.34 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H).

[1691] Examples 71a and 71b:

[1692] (S or R)-4-(3-(ethylamino)-3-methylpyrrolidin-l-yl)-N-(4-methyl-3- (methylsulfonyl)phenyl)-6-propylpyrimidin-2-amine (Compound 71a); and

[1693] (R or S)-4-(3-(ethylamino)-3-methylpyrrolidin-l-yl)-N-(4-methyl-3- (methylsulfonyl)phenyl)-6-propylpyrimidin-2-amine (Compound 71b)

[1694] Step 1:

[1695] Synthesized according to the method of Step 3 in Example 1 with the corresponding replacement of starting materials, compound 47-7 (1.0 g, 5.26 mmol) and compound 23-1 (1.0 g, 5.26 mmol; CAS: 147459-52-7, directly purchased from Shanghai Biotech Co., Ltd.), to afford 990 mg of compound 71-1 (yellow solid, 53% yield).

[1696] MS (ESI, m / z): [M+H] + = 355.20 / 357.15.

[1697] Step 2:

[1698] Synthesized according to the method of Step 3 in Example 5 with the corresponding replacement of starting materials, 71-1 (450 mg, 1.27 mmol) and iodoethane (396 mg, 2.54 mmol), to afford 460 mg of compound 71-2 (yellow solid, 95% yield).

[1699] MS (ESI, m / z): [M+H] + = 383.25 / 385.20.

[1700] Step 3:

[1701] Synthesized according to the method of Step 8 in Example 1 with the corresponding replacement of starting materials, compound 71-2 (110 mg, 0.29 mmol) and compound 43-2 (59 mg, 0.32 mmol), to afford 130 mg of compound 71-3 (pale yellow solid, 84% yield).

[1702] MS (ESI, m / z): [M+H] + = 532.35.

[1703] Step 4:

[1704] Synthesized according to the method of Step 5 in Example 1 with the corresponding replacement of starting materials, compound 71-3 (148 mg, 0.28 mmol), to afford 100 mg of compound 71 (yellow solid, 83% yield).

[1705] MS (ESI, m / z): [M+H] + = 432.30.

[1706] Step 5:

[1707] Racemic 71 (100 mg, 0.23 mmol) was subjected to chiral resolution with the following resolution conditions: Chiral column CHIRALART Cellulose-SZ, 2 x 25 cm, 5 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate 20 mL / min; gradient: isocratic 5% B; detection wavelength 254 / 220 nm; retention time 22.0 min to obtain the fore peak fraction, which after concentration under reduced pressure and lyophilization gave 30 mg of optically pure compound 71a (white solid, yield 30%); retention time 26.5 min to obtain the back peak fraction, which after concentration under reduced pressure and lyophilization gave 18 mg of optically pure compound 71b (white solid, yield 18%).

[1708] Compound 71a:

[1709] MS (ESI, m / z): [M+H] + = 432.25.

[1710] 1 H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.87 (d, J = 2.4 Hz, 1H), 7.69 (s, 1H), 7.27 (d, J = 8.4 Hz, 1H), 5.80 (s, 1H), 3.71-3.67 (m, 3H), 3.14 (s, 3H), 2.55-2.51 (m, 6H), 2.40 (t, J = 7.5 Hz, 2H), 1.96-1.93 (m, 1H), 1.79-1.75 (m, 1H), 1.68-1.64 (m, 2H), 1.21 (s, 3H), 1.00 (t, J = 7.0 Hz, 3H), 0.91 (t, J = 7.4 Hz, 3H).

[1711] Compound 71b:

[1712] MS (ESI, m / z): [M+H] + = 432.25.

[1713] 1H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.87 (d, J = 2.4 Hz, 1H), 7.69 (s, 1H), 7.27 (d, J = 8.3 Hz, 1H), 5.80 (s, 1H), 3.64-3.61 (m, 3H), 3.14 (s, 3H), 2.54-2.50 (m, 6H), 2.40 (t, J = 7.5 Hz, 2H), 1.96-1.93 (m, 1H), 1.79-1.75 (m, 1H), 1.68-1.65 (m, 2H), 1.21 (s, 3H), 1.00 (t, J = 7.0 Hz, 3H), 0.91 (t, J = 7.4 Hz, 3H).

[1714] Examples 72a and 72b:

[1715] (S or R)-4-(3-methyl-3-(methylamino)piperidin-l-yl)-N-(4-methyl-3- (methylsulfonyl)phenyl)-6-propylpyrimidin-2-amine (Compound 72a); and

[1716] Preparation of (R or S)-4-(3-methyl-3-(methylamino)piperidin-l-yl)-N-(4-methyl-3- (methylsulfonyl)phenyl)-6-propylpyrimidin-2-amine (Compound 72b)

[1717] Step 1:

[1718] Synthesized according to the method of Step 3 in Example 1, with the corresponding replacement of starting materials compound 47-7 (500 mg, 2.62 mmol) and compound 54-1 (560 mg, 2.62 mmol; CAS: 169750-96-3, directly purchased from Shanghai Biotech Co., Ltd.) to prepare 700 mg of compound 72-1 (yellow solid, yield 73%).

[1719] MS (ESI, m / z): [M+H] + = 369.25 / 371.20.

[1720] Step 2:

[1721] Synthesized according to the method of Step 3 in Example 5, with the corresponding replacement of starting materials 72-1 (298 mg, 0.81 mmol) and iodomethane (172 mg, 1.22 mmol) to prepare 200 mg of compound 72-2 (white solid, yield 64%).

[1722] MS (ESI, m / z): [M+H] + = 383.20 / 385.20.

[1723] Step 3:

[1724] Synthesized according to the method of Step 8 in Example 1 with the corresponding replacement of starting materials, compound 72-2 (199 mg, 0.52 mmol) and compound 43-2 (96 mg, 0.52 mmol), to give 120 mg of compound 72-3 (yellow oil, yield 43%).

[1725] MS (ESI, m / z): [M+H] + = 532.30.

[1726] Step 4:

[1727] Synthesized according to the method of Step 5 in Example 1 with the corresponding replacement of starting materials, compound 72-3 (196 mg, 0.37 mmol), to give 120 mg of compound 72 (racemate, white solid, yield 75%).

[1728] MS (ESI, m / z): [M+H] + = 432.20.

[1729] Step 5:

[1730] Chiral resolution of racemate 72 (100 mg, 0.23 mmol) was performed with the following resolution conditions: Chiral column CHIRALART Cellulose-SZ, 2 x 25 cm, 5 μm; mobile phase A: n-hexane (0.5% of 2 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isocratic 50% B; detection wavelength 254 / 220 nm; the front peak fraction was obtained with retention time 13.5 min, to give 41 mg of optically pure compound 72a (white solid, yield 41%) after concentration under reduced pressure and lyophilization; the back peak fraction was obtained with retention time 18.3 min, to give 44 mg of optically pure compound 72b (white solid, yield 44%) after concentration under reduced pressure and lyophilization.

[1731] Compound 72a:

[1732] MS (ESI, m / z): [M+H] + = 432.15.

[1733] 1H NMR (400 MHz, DMSO-d6) δ 9.25 (s, 1H), 8.70 (d, J = 2.4 Hz, 1H), 7.77-7.60 (m, 1H), 7.27 (d, J = 8.4 Hz, 1H), 6.14 (s, 1H), 3.76 (s, 1H), 3.69-3.54 (m, 1H), 3.42-3.34 (m, 1H). 3.29-3.18 (m, 1H), 3.15 (s, 3H), 2.54 (s, 3H), 2.44-2.37 (m, 2H), 2.16 (s, 3H), 1.73-1.57 (m, 4H), 1.54-1.33 (m, 3H), 0.97 (s, 3H), 0.91 (t, J = 7.2 Hz, 3H).

[1734] Compound 72b:

[1735] MS (ESI, m / z): [M+H] + = 432.10.

[1736] 1 H NMR (400 MHz, DMSO-d6) δ 9.27 (s, 1H), 8.71 (d, J = 2.4 Hz, 1H), 7.77-7.60 (m, 1H), 7.28 (d, J = 8.4 Hz, 1H), 6.16 (s, 1H), 3.78 (s, 1H), 3.69-3.54 (m, 1H), 3.42-3.34 (m, 1H) 3.29-3.18 (m, 1H), 3.15 (s, 3H), 2.54 (s, 3H), 2.45-2.37 (m, 2H), 2.20 (s, 3H), 1.74-1.58 (m, 4H), 1.57-1.20 (m, 3H), 1.00 (s, 3H), 0.91 (t, J = 7.2 Hz, 3H).

[1737] Examples 73a and 73b:

[1738] (S or R)-N-(1-(2-((4-chloro-3-(methylsulfonyl)phenyl)amino)-6-propylpyrimidin-4-yl)-3- methylpiperidin-3-yl)acetamide (Compound 73a); and

[1739] Preparation of (R or S)-N-(1-(2-((4-chloro-3-(methylsulfonyl)phenyl)amino)-6-propylpyrimidin-4- yl)-3-methylpiperidin-3-yl)acetamide (Compound 73b)

[1740] Step 1:

[1741] Synthesized according to the method of Step 8 in Example 1 with the corresponding starting materials replaced by compound 54-4 (118 mg, 0.38 mmol) and compound 30-2 (78 mg, 0.38 mmol) to give 100 mg of compound 73 (racemate, white solid, yield 54%).

[1742] MS (ESI, m / z): [M+H] + = 480.20 / 482.15.

[1743] Step 2:

[1744] Chiral resolution of racemate 73 (100 mg, 0.21 mmol) was performed with the following resolution conditions: Chiral column CHIRALPAK IG, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (0.5% of 2 mmol / L ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isocratic 30% B; detection wavelength 254 / 220 nm; the front peak fraction was obtained with retention time 15.2 min, which after concentration under reduced pressure and lyophilization gave 50 mg of optically pure compound 73a (yellow solid, yield 50%); the back peak fraction was obtained with retention time 20.5 min, which after concentration under reduced pressure and lyophilization gave 48 mg of optically pure compound 73b (yellow solid, yield 48%).

[1745] Compound 73a:

[1746] MS (ESI, m / z): [M+H] + = 480.25 / 482.20.

[1747] 1 H NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 8.87 (s, 1H), 7.88-7.82 (m, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.42-7.24 (m, 1H), 6.09 (s, 1H), 4.32-4.09 (m, 2H), 3.33 (s, 3H), 3.28-3.12 (m, 2H), 2.46-2.34 (m, 2H), 1.95-1.87 (m, 1H), 1.76-1.60 (m, 6H), 1.60-1.49 (m, 2H), 1.29 (s, 3H), 0.91 (t, J = 7.2 Hz, 3H).

[1748] Compound 73b:

[1749] MS (ESI, m / z): [M+H] + = 480.20 / 482.20.

[1750] 1 H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 8.87 (s, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.42-7.24 (m, 1H), 6.11 (s, 1H), 4.41-4.06 (m, 2H), 3.31 (s, 3H), 3.28-3.12 (m, 2H), 2.44-2.38 (m, 2H), 1.98-1.87 (m, 1H), 1.74-1.62 (m, 6H), 1.61-1.48 (m, 2H), 1.29 (s, 3H), 0.91 (t, J = 7.2 Hz, 3H).

[1751] Examples 74a and 74b:

[1752] (S or R)-N-(1-(2-((4-chloro-3-(trifluoromethyl)sulfonyl)phenyl)amino)-6- propylpyrimidin-4-yl)piperidin-3-yl)acetamide (Compound 74a); and

[1753] (R or S)-N-(1-(2-((4-chloro-3-(trifluoromethyl)sulfonyl)phenyl)amino)-6- propylpyrimidin-4-yl)piperidin-3-yl)acetamide (Compound 74b)

[1754] Step 1:

[1755] Compound 74-1 (7.0 g, 40.5 mmol; CAS: 6283-25-6, directly purchased from Shanghai Titan Scientific Co., Ltd.) was dissolved in ethanol (100 mL) at 0 °C, then fluoroboric acid (17.8 g, 81.0 mmol, 40% w / w) and tert-butyl nitrite (8.35 g, 81.1 mmol) were added. After the addition was completed, the ice bath was removed, and the temperature was naturally raised to room temperature, and stirred for 2 hours. After the reaction was completed, the reaction was quenched with isopropyl ether (100 mL), filtered, the filter cake was washed with isopropyl ether (50 mL x 3), and the filter cake was freeze-dried to obtain 7.2 g of compound 74-2 (yellow solid, crude product, yield 66%).

[1756] MS (ESI, m / z): [M-BF4 - ] + = 184.00 / 185.95.

[1757] Step 2:

[1758] Compound 74-2 (3.4 g, 12.5 mmol) was dissolved in dimethyl sulfoxide (150 mL) under nitrogen atmosphere at room temperature, then sodium trifluoromethylsulfinate (8.61 g, 54.5 mmol) and cuprous oxide (263 mg, 1.84 mmol) were added into the above reaction solution. The reaction system was stirred at room temperature under nitrogen atmosphere for 12 hours. After the reaction was completed, ethyl acetate (150 mL) was added into the reaction system, then washed with water (100 mL x 3) and saturated brine solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was directly purified by silica gel column (eluent: petroleum ether / ethyl acetate = 1 / 1), and the obtained fraction was concentrated under reduced pressure to obtain 350 mg of compound 74-3 (pale yellow solid, yield 10%).

[1759] 1 H NMR (400 MHz, DMSO-d6) δ 8.81-8.70 (m, 2H), 8.31-8.20 (m, 1H).

[1760] 19 F NMR (377 MHz, DMSO-d6) δ -75.46.

[1761] Step 3:

[1762] Synthesized according to the method of Step 7 in Example 1, with the raw material corresponding replaced by compound 74-3 (318 mg, 1.10 mmol), to prepare 200 mg of compound 74-4 (white solid, yield 70%).

[1763] MS (ESI, m / z): [M-H] - = 257.90 / 259.90.

[1764] 1 H NMR (400 MHz, DMSO-d6) δ 7.47 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 2.8 Hz, 1H), 7.09-7.02 (m, 1H), 6.15 (s, 2H).

[1765] 19 F NMR (377 MHz, DMSO-d6) δ -76.80.

[1766] Step 4:

[1767] Synthesized according to the procedure of Step 1 in Example 9 with the corresponding starting materials replaced by compound 48-3 (198 mg, 0.67 mmol) and compound 74-4 (173 mg, 0.67 mmol) to give 150 mg of compound 74 (racemate, yellowish solid, yield 43%).

[1768] MS (ESI, m / z): [M+H] + = 520.10 / 522.00.

[1769] 1 H NMR (400 MHz, DMSO-d6) δ 9.80 (s, 1H), 9.23 - 9.07 (m, 1H), 8.05 - 7.95 (m, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.75 (d, J = 8.8 Hz, 1H), 6.23 (s, 1H), 4.23 - 4.06 (m, 1H), 3.73 - 3.57 (m, 1H), 3.25 - 3.10 (m, 1H), 3.00 - 2.87 (m, 1H), 2.45 (d, J = 7.2 Hz, 2H), 1.91 - 1.63 (m, 7H), 1.56 - 1.42 (m, 2H), 1.37 - 1.21 (m, 1H), 0.91 (t, J = 7.2 Hz, 3H).

[1770] 19 F NMR (377 MHz, DMSO-d6) δ -76.74.

[1771] Step 5:

[1772] The racemic compound 74 (130 mg, 0.25 mmol) was chiral resolution with the following resolution conditions: chiral column CHIRALPAK IG, 3 x 25 cm, 5 pm; mobile phase A: n-hexane (0.5% of 2M ammonia-methanol), mobile phase B: ethanol; flow rate 40 mL / min; gradient: isocratic 10% B; detection wavelength 254 / 220 nm; the front peak fraction was obtained with retention time 13.3 min, after concentration under reduced pressure and lyophilization, 80 mg of optically pure compound 74a (yellowish solid, yield 61%) was obtained; the back peak fraction was obtained with retention time 21.0 min, after concentration under reduced pressure and lyophilization, 20 mg of optically pure compound 74b (white solid, yield 15%) was obtained.

[1773] Compound 74a:

[1774] MS (ESI, m / z): [M+H] + = 520.15 / 522.10.

[1775] 1H NMR (400 MHz, DMSO-d6) δ 9.80 (s, 1H), 9.17 (s, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.75 (d, J = 8.8 Hz, 1H), 6.23 (s, 1H), 4.27 - 3.91 (m, 2H), 3.75 - 3.57 (m, 1H), 3.27 - 3.12 (m, 1H), 3.02 - 2.86 (m, 1H), 2.45 (t, J = 7.6 Hz, 2H), 1.92 - 1.63 (m, 7H), 1.56 - 1.40 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H).

[1776] 19 F NMR (377 MHz, DMSO-d6) δ -76.74.

[1777] Compound 74b:

[1778] MS (ESI, m / z): [M+H] + = 520.15 / 522.15.

[1779] 1 H NMR (400 MHz, DMSO-d6) δ 9.80 (s, 1H), 9.16 (s, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.75 (d, J = 8.8 Hz, 1H), 6.22 (s, 1H), 4.27 - 3.91 (m, 2H), 3.75 - 3.57 (m, 1H), 3.23 - 3.05 (m, 1H), 3.03 - 2.85 (m, 1H), 2.44 (t, J = 7.6 Hz, 2H), 1.92 - 1.62 (m, 7H), 1.55 - 1.39 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H).

[1780] 19 F NMR (377 MHz, DMSO-d6) δ -76.72.

[1781] Examples 75a and 75b:

[1782] (S or R)-N-(1-(2-((4-methyl-3-(methylsulfonyl)phenyl)amino)-6- propylpyrimidin-4-yl)piperidin-3-yl)methanesulfonamide (Compound 75a); and

[1783] (R or S)-N-(1-(2-((4-methyl-3-(methylsulfonyl)phenyl)amino)-6- propylpyrimidin-4-yl)piperidin-3-yl)methanesulfonamide (Compound 75b)

[1784] Step 1:

[1785] Compound 48-2 (287 mg, 0.78 mmol), methylsulfonic anhydride (136 mg, 0.78 mmol) and triethylamine (319 mg, 3.16 mmol) were dissolved in dichloromethane (2 mL) at room temperature under nitrogen atmosphere, then the reaction system was stirred for 2 hours under this condition. The reaction progress was monitored by liquid chromatography-mass spectrometry. After the reaction was completed, the reaction system was concentrated under reduced pressure, and the obtained residue was directly purifi...

Claims

1. A compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof: wherein, R 1 -S(0)=0R m -S(0)=0R m -S(0)=0R R m independently C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkyl substituted with one or more R m1 independently C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkyl substituted with one or more R m1 independently C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkyl substituted with one or more R R m1 halogen; For R 2 , R X4 , and R X6 are independently -H, halogen, -NR f R g , C1-C6alkyl, or C1-C6alkyl substituted with one or more halogens; R f and R g each independently -H or C1-C6alkyl; R X5 independently -H, halogen, -NR f R g , C1-C6alkyl or C1-C6alkyl substituted with one or more halogens; or R m or R X5 and the intervening atoms to which they are attached m1 is 1 or 2; m2 is 0, 1, 2, 3, 4, 5 or 6; R 4 Ci-C6-alkyl; ring A is a 5-, 6- or 7-membered monocyclic saturated heterocycle; or a 6-, 7-, 8- or 9-membered bicyclic saturated heterocycle; in ring A, in addition to the N atom to which it is attached, there are additionally 0, 1 or 2 O atoms; R N With Connected to the same ring atom, or, R N and is attached to each of the two adjacent ring atoms, respectively; R N is -H, -OH, halogen, C1-C6 alkyl, C1-C6 alkyl substituted with one or more Re; R e independently -OH, C1-C6alkoxy, -S-C1-C6alkyl, or -NR e1 R e2 ; R e1 and R e2 each independently -H or C1-C6alkyl; R 8a -H; and R is -H. or, R N , R 8a , together with the intervening atoms to which they are attached, form a ring B or ring B substituted with one or more R s1 ; ring B is a 4-, 5- or 6-membered monocyclic saturated heterocycle; in ring B, in addition to the N atom to which it is attached, there are additionally 0, 1 or 2 O atoms; R s1 independently =0 or C1-C6alkyl; R 8b -H, C1-C6alkyl, C3-C6cycloalkyl, -C(=O)R 8-1 , -S(=O)2R 8-1 , substituted by one or more R 8-2 substituted by one or more R 8-2 substituted by one or more R substituted by one or more R substituted by one or more R substituted by one or more R substituted by one or more R substituted by one or more R substituted by one or more R substituted by one R 8-1 independently C1-C6alkyl or C1-C6alkyl substituted with one or more R 8-1a substituted C1-C6alkyl; R 8-1a independently -OH or halogen; R 8-2 independently -OH or halogen; n is 0, 1, 2 or 3; R M independently -OH, halogen, C1-C6alkyl, C1-C6alkyl substituted with one or more R e substituted C1-C6alkyl.

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, one or more of the following conditions are met: (1) R 1 -S(=O)2R m ; (2) R m is Ci-C6-alkyl, C3-C6-cycloalkyl or Ci-C6-alkyl substituted by one or more R m1 is, for example, -CH3, -CH2CH3, -CH(CH3)2, -CF3or preferably -CH3; (3) For preferably (4) R 2 independently -H, halogen, or -NR f R g , for example -H, -NH2, or -Cl; (5) R X4 independently -H or halogen, e.g., -H, -CI, or -F, further e.g., H; (6) R X6 independently -H, -Cl, -F, -CH3, -NH2, or -CHF2, for example H; (7) R X5 independently -H, -CI, -F, -CH3, -NH2, or -CHF2, or R m or R X5 and the intervening atoms, if any, that are connected thereto (8) R 4 For 3. The compound according to claim 1, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, represented by formula (I), wherein For R X5 halogen, -NR f R g , C1-C6alkyl or C1-C6alkyl substituted with one or more halogens, R2is -H, halogen or -NR f R g , R X4 is -H or halogen; preferably, R X5 is C1-C6alkyl, R2is -H and R X4 is -H.

4. The compound according to claim 1, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, represented by formula (I), wherein For Preferably the configuration of the carbon atom marked "*" is independently in the R configuration, the S configuration or a mixture thereof; R 5 , R 5' , R 6 , R 7 , R 9 , R 10 , R 10' , R 11 and R 11’ are each independently H, -OH, halogen, C1-C6alkyl, or C1-C6alkyl substituted with one or more R e ; R e independently -OH, C1-C6alkoxy, -S-C1-C6alkyl, or -NR e1 R e2 ; R e1 and R e2 each independently H or Ci-C6alkyl; or, "R 7 and R 9 ", "R 5 and R 9 ", "R 7 and R 10 ", or "R 9 and R 10 " are joined to form -(CH2) 1-2 -; R 8a is H; or, "R 8a and R 9 " together with the intervening atoms to which they are attached form a ring B or ring B substituted with one or more R 8a and R 10 " together with the intervening atoms to which they are attached form a ring B or ring B substituted with one or more R s1 ; ring B is a 4-, 5- or 6-membered monocyclic saturated heterocycle; in ring B, in addition to the N atom to which it is attached, there are additionally 0, 1 or 2 O atoms; R s1 independently =0 or C1-C6alkyl; R 8b -H, C1-C6alkyl, C3-C6cycloalkyl, -C(=O)R 8-1 , 8-1 , substituted by one or more R 8-2 substituted by one or more R 8-2 substituted by one or more R substituted by one or more R substituted by one or more R substituted by one or more R substituted by one or more R substituted by one or more R substituted by one or more R substituted by one R 8-1 independently C1-C6alkyl or C1-C6alkyl substituted with one or more R 8-1a substituted C1-C6alkyl; R 8-1a independently -OH or halogen; R 8-2 independently -OH or halogen; B 1 and B 2 each independently a bond, -O- or -CR B3 R B4 -; R B3 and R B4 each independently H, -OH, halogen, C1-C6alkyl, or C1-C6alkyl substituted with one or more R e substituents.

5. The compound of formula (I) as claimed in claim 4, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, one or more of the following conditions are met: (1) R 5 is H, or, "R 5 and R 9 " are joined to form -(CH2) 1-2 - is H; (2) R 5’ is H; (3) R 6 H, -OH, or halogen, for example -H, -F, or -OH, preferably H; (4)R 7 For H or halogen; or, "R" 7 and R 9 "or "R 7 and R 10 "Connection formed -(CH2)" 1-2 -;R 7 H is preferred; (5) B 1 is a bond, -O or -CH2-, preferably a bond; (6) B 2 is a bond or -CH2-, preferably a bond; (7) R 8b is -H, CrC6-alkyl, C3-C6-cycloalkyl, -C(=0)R 8-1 , -S(=0)2R 8-1 or CrC6-alkyl substituted by one or more R 8-2 , preferably -C(=0)R 8-1 ; (8) R 8-1 Ci-C6-alkyl; (9) R 8a , R 9 , R 10 , and R 10' are defined as any one of the following schemes: Scheme 1: R 8a is -H, R 9 -H or -Ci-C6alkyl; Or, "R 9 and R 7 "or "R 9 and R 5 "Connection formed -(CH2)" 1-2 -; R 10 H, Ci-C6alkyl or Ci-C6alkyl substituted with one or more R e H, Ci-C6alkyl or Ci-C6alkyl substituted with one or more R "R 10 and R 9 form together with the carbon atom to which they are attached a 5- or 6-membered heterocyclyl ring; and 1-2 -; R e independently -OH or C1-C6alkoxy; R 10' -H; and R is -H. Scheme 2: R 8a and R 10 with the intervening atoms to which they are attached form a ring B or ring B substituted with one or more R s1 substituted ring B; R s1 independently C1-C6alkyl; R 9 -H; and R is -H. R 10' -H; and R is -H. Scheme 3: R 8a and R 9 with the intervening atoms to which they are attached form a ring B or ring B substituted with one or more R s1 substituted ring B; R s1 independently =0; R 10 = -H R 10' -H; and R is -H. (10) R 11 -H; (11) R 11' is -H.

6. The compound of formula (I) as claimed in claim 4, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, one or more of the following conditions are met: (1) For n1 is 0, 1 or 2, preferably 0; Preferably Further preferred is the configuration of the carbon atom marked "*" is in the R configuration, the S configuration or a mixture thereof; (2) R 9 is H or C1-C6alkyl, for example H or -CH3, preferably H; (3) R 10 H, C1-C6 alkyl or C1-C6 alkyl substituted by one or more R e H, C1-C6 alkyl or C1-C6 alkyl substituted by one or more R preferably H; (4) R s1 is Ci-C6-alkyl, for example methyl; (6) For Preferably, R 8a is hydrogen, R 8b is C1-C6alkyl.

7. The compound of formula (I) as claimed in claim 4, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, one or more of the following conditions are met: (1) For wherein the configuration of the carbon atom marked "*" is in the R configuration, the S configuration or a mixture thereof; Preferably (2) R 8b -H, preferably For example 8. The compound according to claim 4, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, represented by formula (I), wherein For 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 as shown in formula (I) is a compound as shown in formula (I-1), (I-2), (I-3), (I-4), (I-5) or (I-6): wherein R 4 , R 1 , R 2 , R X4 , R X5 and R X6 are independently defined as in at least one of claims 1-3. B 1 , R 5 , R 5' , R 6 , R 7 , R 8a , R 8b , R 8-1 , R 9 , R 10 and R 10' are independently as defined in at least one of claims 4-8.

10. The compound according to claim 9, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, represented by formula (I), wherein in formula (I-1), B 1 is a bond, -O- or -CR B3 R B4 -; R B3 and R B4 each independently H, C1-C6alkyl, or C1-C6alkyl substituted with one or more Re; R e independently -OH, C1-C6alkoxy, -S-C1-C6alkyl, or -NR e1 R e2 ; R e1 and R e2 each independently -H or C1-C6alkyl; R 8a is H; R 8b -C(=O)R 8-1 -S(=O)2R 8-1 or R 8-1 independently C1-C6alkyl or C1-C6alkyl substituted with one or more R 8-1a substituted C1-C6alkyl; R 8-1a independently -OH; R 5 , R 5' , R 6 , R 7 , R 9 , R 10 , and R 10' are each independently H, C1-C6alkyl, C1-C6alkyl substituted with one or more R e ; R 1 -S(=O)2R m ; R m Ci-C6-alkyl; R 2 , R X4 , and R X5 are each independently H, halogen, -NR f R g , C1-C4 alkyl, or C1-C4 alkyl substituted with one or more halogens; R f and R g each independently H or Ci-C6alkyl; R 4 is C1-C4 alkyl; in formula (I-2), (I-3), (I-4) or (I-5), B 1 is a bond, -O- or -CR B3 R B4 -; R B3 and R B4 each independently H, C1-C6alkyl, or C1-C6alkyl substituted with one or more Re; R e independently -OH, C1-C6alkoxy, -S-C1-C6alkyl, or -NR e1 R e2 ; R e1 and R e2 each independently -H or Ci-C6alkyl; R 8-1 independently C1-C6alkyl or C1-C6alkyl substituted with one or more R 8-1a substituted C1-C6alkyl; R 8-1a independently -OH; R 5 , R 5' , R 6 , R 7 , R 9 , R 10 , and R 10' are each independently H, C1-C6alkyl, C1-C6alkyl substituted with one or more R e ; R 1 -S(=O)2R m ; R m Ci-C6-alkyl; R 2 , R X4 , R X5 , and R X6 are each independently H, halogen, -NR f R g , C1-C4 alkyl, or C1-C4 alkyl substituted with one or more halogens; R f and R g each independently H or Ci-C6alkyl; R 4 Ci-C4-alkyl; in formula (I-6), R 8-1 independently C1-C6alkyl or C1-C6alkyl substituted with one or more R 8-1a substituted C1-C6alkyl; R 8-1a independently -OH; R 9 C1-C6alkyl or C1-C6alkyl substituted by one or more R e substituted C1-C6alkyl; R e independently -OH, C1-C6alkoxy, -S-C1-C6alkyl, or -NR e1 R e2 ; R e1 and R e2 each independently -H or C1-C6alkyl; R 1 -S(=O)2R m ; R m Ci-C6-alkyl; R 2 , R X4 , R X5 , and R X6 are each independently H, halogen, -NR f R g , C1-C4 alkyl, or C1-C4 alkyl substituted with one or more halogens; R f and R g each independently H or Ci-C6alkyl; R 4 is C1-C4 alkyl.

11. The compound according to claim 10, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, represented by formula (I), wherein one or more of the following conditions are met for the compound represented by formula (I-1): (1) B 1 is a bond; Preferably, the compound as shown in formula (I-1) is a compound as shown in formula (I-1-1): wherein the configuration of the carbon atom marked "*" is in the R configuration, the S configuration or a mixture thereof; (2) R 8-1 is methyl, ethyl or hydroxymethyl; (3) R e is methoxy; (4) R 1 For (5) R 2 (6) R X4 (7) R X5 each independently H, -F, -CI, -NH2, -NHCH3, or methyl; one or more of the following conditions are met for the compound represented by formula (I-2), (I-3), (I-4) or (I-5): (1) B 1 is a bond; (2) R 8-1 independently methyl, ethyl or hydroxymethyl; (3) R 1 For (4) R 2 (4) R X4 (4) R X5 (4) R X6 each independently H, -F, -CI, -NH2, -NHCH3, or methyl; preferably, the compound as shown in formula (I-3) is a compound as shown in formula (I-3-1): wherein the configuration of the carbon atom marked "*" is in the R configuration, the S configuration or a mixture thereof; one or more of the following conditions are met for the compound represented by formula (I-6): (1) R 1 To (2) R 2 (3) R X4 (4) R X5 (5) R X6 each independently H, -F, -CI, -NH2, -NHCH3, or methyl; Preferably, For (3) R 9 is Ci-C6-alkyl, for example methyl.

12. The compound as shown in formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof according to claim 1, wherein, The compound as shown in formula (I) is selected from any one of the following compounds: ​ 13. A pharmaceutical composition comprising a compound according to at least one of claims 1 to 12, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.

14. Use of a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof or a pharmaceutical composition as defined in any one of claims 1 to 13 for the manufacture of a 5-hydroxytryptamine 4 receptor agonist.

15. Use of a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof or a pharmaceutical composition as defined in any one of claims 1 to 13 for the manufacture of a medicament for the prevention and / or treatment of a 5-hydroxytryptamine 4 receptor related disorder, such as a gastrointestinal motility disorder, further such as gastroesophageal reflux disease, constipation, irritable bowel syndrome, dyspepsia, postoperative ileus, delayed gastric emptying, gastroparesis, pseudo-obstruction, drug-induced transit delay or diabetic gastroparesis.

16. Use of a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof or a pharmaceutical composition as defined in any one of claims 1 to 13 for the manufacture of a medicament for the prevention and / or treatment of a gastrointestinal motility disorder, preferably gastroesophageal reflux disease, constipation, irritable bowel syndrome, dyspepsia, postoperative ileus, delayed gastric emptying, gastroparesis, pseudo-obstruction, drug-induced transit delay or diabetic gastroparesis.

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