Aromatic ring-containing compound as WRN inhibitor and use thereof

Abstract

The present invention relates to an aromatic ring-containing compound as a WRN inhibitor and use thereof, and specifically relates to a compound represented by formula (I), a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt, or a prodrug thereof, a preparation method therefor, and use thereof in the preparation of a drug for treating WRN-related diseases.

Description

Aromatic ring compounds as WRN inhibitors and their applications

[0001] Priority information

[0002] This application requests patent applications filed with the China National Intellectual Property Administration (CNIPA) on June 28, 2024 (202410858909.4), November 15, 2024 (202411646381.0), February 8, 2025 (202510142098.2), and March 28, 2025 (2025).

[0003] Priority and rights of 202510388393.6, and its full text is incorporated herein by reference. Technical Field

[0004] This invention relates to the pharmaceutical field, and more specifically, to a class of aromatic ring-containing compounds as WRN inhibitors and their applications. Background Technology

[0005] Microsatellites (MS) are tandemly repetitive sequences (1-6 repeat units) in the human genome. Under normal conditions, the length and order of microsatellites remain unchanged and are stably inherited. Microsatellite instability (MSI) refers to changes in the length of microsatellite (MS) sequences caused by insertion or deletion mutations during DNA replication, often due to mismatch repair (MMR) defects. Based on the frequency of MSI occurrence, it can be classified into three types: high microsatellite instability (MSI-H), low microsatellite instability (MSI-L), and stable microsatellite (MSS).

[0006] MSI is a common feature of tumor cells, with hundreds of thousands of MSI-positive tumors diagnosed globally each year. In a sample study from the TCGA database, the highest MSI positivity rates were found in colorectal cancer (10.2%), endometrial cancer (21.9%), gastric cancer (8.5%), and small bowel cancer (14.3%).

[0007] The growth of MSI malignant tumor is highly dependent on Werner syndrome RecQ-like helicase (WRN), tandem repeats are highly unstable in MSI cells and can be massively amplified, the amplified tandem repeats form abnormal secondary structures, which prevent replication forks and activate ATR checkpoint kinase, and normal replication requires WRN helicase to unwind, in the case of WRN inhibition, the amplified tandem repeats are easily cut by MUS81 nuclease, resulting in a large number of chromosome fragmentation. Using RNA interference technology to simultaneously silence the WRN gene in various MSI-H cells and MSS cells and detect cell apoptosis, after WRN silencing in MSI-H cells, the cells undergo obvious apoptosis, while no cell apoptosis is observed in MSS cells, which indicates that WRN is a potential synthetic lethal target of MSI malignant tumor. In another large functional genomics study, it was found that WRN enzyme is essential for the survival of MSI-H cell lines with mismatch repair defects, which also proves that WRN has synthetic lethality to MSI tumor. These all indicate that developing new WRN inhibitors for treating MSI-H tumor is a potential direction. SUMMARY

[0008] In a first aspect, the present application provides a compound, which is a compound represented by formula (I), a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof,

[0009] wherein,

[0010] X1 is N or CR x1 ;

[0011] X2 is N or CR x2 ;

[0012] X3 is N or CR x3 ;

[0013] X4 is N or CR x4 ;

[0014] X5 is N or CR x5 ;

[0015] R x1 is H, halogen, OH, NH2, CN, COOH, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 alkylamino, -S-C 1-6 alkyl, C 3-8 cycloalkyl, -O-C 3-8 cycloalkyl, C 3-8cycloalkenyl, C 6-10 aryl, -O-(3-8 membered cycloalkyl), 4-8 membered heterocycloalkenyl, -O-(4-8 membered heterocycloalkyl), 5-10 membered heteroaryl, or -O-(5-10 membered heteroaryl), each of which is independently optionally substituted with 1, 2, 3, or 4 R 6-10 aryl, -O-(3-8 membered cycloalkyl), 4-8 membered heterocycloalkenyl, -O-(4-8 membered heterocycloalkyl), 5-10 membered heteroaryl, or -O-(5-10 membered heteroaryl), each of which is independently optionally substituted with 1, 2, 3, or 4 R 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 alkylamino, -S-C 1-6 alkyl, C 3-8 cycloalkyl, -O-C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 6-10 aryl, -O-C 6- 10 aryl, -O-(3-8 membered cycloalkyl), 4-8 membered heterocycloalkenyl, -O-(4-8 membered heterocycloalkyl), 5-10 membered heteroaryl, or -O-(5-10 membered heteroaryl), each of which is independently optionally substituted with 1, 2, 3, or 4 R m substituted;

[0016] R x3 is H, halogen, OH, NH2, CN, COOH, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 alkylamino, -S-C 1-6 alkyl, C 3-8 cycloalkyl, -O-C 3-8 cycloalkyl, or C 3-8 cycloalkenyl, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 alkylamino, -S-C 1-6 alkyl, C 3-8 cycloalkyl, -O-C 3-8 cycloalkyl, and C 3-8 cycloalkenyl, each of which is independently optionally substituted with 1, 2, 3, or 4 R n substituted;

[0017] R x2 , R x4 , and R x5 are each independently H, halogen, OH, NH2, CN, COOH, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2- 6alkynyl, C 1-6 alkoxy, C1-6 Alkylamino, -NHR ee -C 0-6 Alkylene-C(=O)-NR e1 R e2 -C 0-6 Alkylene-NR e1 -C(=O)-C 1-6 Alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylamino, -NHR ee -C 0-6 Alkylene-C(=O)-NR e1 R e2 -C 0-6 Alkylene-NR e1 -C(=O)-C 1-6 Alkyl, C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl groups are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. y replace;

[0018] R ee -C 0-6 Alkylene-S(=O)2-R ee1 -C 1-6 alkylene-5-10-membered heteroaryl or ring A, wherein ring A is C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl, 4-8 membered heterocyclic alkenyl or 5-10 membered heteroaryl;

[0019] R ee1 For H or C 1-6 alkyl;

[0020] Each R e1 and R e2 H or C, independently respectively 1-6 alkyl;

[0021] Each R m R n and R y The independent components are H, halogen, OH, NH2, CN, COOH, and C, respectively. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, -S(=O)2-R or C 3-8 cycloalkyl;

[0022] R is H, -NR d1 R d2 , C 1-6 alkyl or -C 1-6 alkylene-OH;

[0023] L is a single bond, -O-, -S-, -NH-, -S(=O)- or -S(=O)2-;

[0024] R 11 and R 12 are each independently H, halogen, OH, NH2, CN, COOH, C 1-6 alkyl, C 3-8 cycloalkyl, 5-6 membered heterocycloalkyl or 5-6 membered heterocycloalkenyl, said C 1-6 alkyl, C 3-8 cycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkenyl are each independently optionally substituted with 1, 2, 3 or 4 R a ;

[0025] R2is H, halogen, OH, NH2, CN, COOH, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkylamino, said C 1-6 alkyl, C 1-6 alkoxy and C 1-6 alkylamino are each independently optionally substituted with 1, 2, 3 or 4 R b ;

[0026] R 31 and R 32 are each independently H, halogen, CN, C 1-6 alkyl, -C 0-6 alkylene-S(=O)2-NR e3 R e4 , -C 1-6 alkylene-S(=O)2-R e5 , -S(=O)2-R e6 , -C 0-6 alkylene-S(=O)(=NR e7 )-R e8 , -C 0-6 alkylene-S(=O)-NR e3 R e4 , -C 0-6 alkylene-S(=O)-R e5 , -C 0-6 alkylene-C(=O)-NR e3 R e4 , -C 0-6 alkylene-C(=O)-Re5 -C 0-6 alkylene-NR e3 -C(=O)-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl or 5-6 membered heteroaryl, said C 1-6 alkyl, -C 0-6 alkylene-S(=O)2-NR e3 R e4 -C 1-6 alkylene-S(=O)2-R e5 -S(=O)2-R e6 -C 0-6 alkylene-S(=O)(=NR e7 )-R e8 -C 0-6 alkylene-S(=O)-NR e3 R e4 -C 0-6 alkylene-S(=O)-R e5 -C 0-6 alkylene-C(=O)-NR e3 R e4 -C 0-6 alkylene-C(=O)-R e5 -C 0-6 alkylene-NR e3 -C(=O)-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl and 5-6 membered heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 R c substituents;

[0027] each R e3 and R e4 are each independently H or C 1-6 alkyl;

[0028] each R e5 and R e8 are each independently H, OH, C 1-6 alkyl, C 3-8 cycloalkyl, 5-6 membered heterocycloalkyl or 5-6 membered heterocycloalkenyl;

[0029] each R e6 is each independently H, C 1-6 alkyl, C 3-8cycloalkyl, 4-6 membered heterocycloalkyl or 4-6 membered heterocycloalkenyl;

[0030] each R e7 is independently H, CN or C 1-6 alkyl;

[0031] each R a , R b and R c are independently H, halogen, OH, NH2, CN, =0, COOH or C 1-6 alkyl;

[0032] each R d1 and R d2 are independently H or C 1-6 alkyl;

[0033] p is 0, 1, 2, 3 or 4;

[0034] and, said R 31 , R 32 , X4, R x4 , X5, R x5 satisfy one of the following conditions:

[0035] a) when one of R 31 and R 32 is H, the other is not CN; or,

[0036] b) when one of R 31 and R 32 is -S(=0)2-R e6 , R e6 is C 1-6 alkyl, C 3-8 cycloalkyl or 5-6 membered heterocycloalkyl, the other is H, X4is CR x4 , R x4 is C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylamino or C 3-8 cycloalkyl; or,

[0037] c) when one of R 31 and R 32 is -S(=0)2-R e6 , R e6 is C 1-6 alkyl, C 3-8 cycloalkyl or 5-6 membered heterocycloalkyl, the other is H, X5is CR x5 , R x5 is -NHRee ;

[0038] The heteroatoms in the "heterocycloalkyl", "heterocycloalkenyl" and "heteroaryl" include N, O, S, the S heteroatom is optionally oxidized to S(=O), S(=O)2 or S(=O)(=NH), the number of the heteroatoms is 1, 2, 3 or 4; when the number of the heteroatoms is multiple, the heteroatoms are the same or different.

[0039] In a first aspect, the present application provides a compound, which is a compound represented by formula (I), a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof,

[0040] wherein,

[0041] X1is N or CR x1 ;

[0042] X2is N or CR x2 ;

[0043] X3is N or CR x3 ;

[0044] X4is N or CR x4 ;

[0045] X5is N or CR x5 ;

[0046] R x1 is H, halogen, OH, NH2, CN, COOH, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 alkylamino, -S-C 1-6 alkyl, C 3-8 cycloalkyl, -O-C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 6-10 aryl, -O-C 6-10 aryl, 3-8 membered heterocycloalkyl, -O-(3-8 membered heterocycloalkyl), 4-8 membered heterocycloalkenyl, -O-(4-8 membered heterocycloalkenyl), 5-10 membered heteroaryl or -O-(5-10 membered heteroaryl), the C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 alkylamino, -S-C 1-6 alkyl, C 3-8 cycloalkyl, -O-C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C6-10 aryl, -O-C 6- 10 aryl, 3-8 membered heterocycloalkyl, -O-(3-8 membered heterocycloalkyl), 4-8 membered heterocycloalkenyl, -O-(4-8 membered heterocycloalkyl), 5-10 membered heteroaryl, and -O-(5-10 membered heteroaryl) are each independently optionally substituted with 1, 2, 3, or 4 R m substituents;

[0047] R x3 H, halogen, OH, NH2, CN, COOH, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 alkylamino, -S-C 1-6 alkyl, C 3-8 cycloalkyl, -O-C 3-8 cycloalkyl, or C 3-8 cycloalkenyl, said C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 alkylamino, -S-C 1-6 alkyl, C 3-8 cycloalkyl, -O-C 3-8 cycloalkyl, and C 3-8 cycloalkenyl are each independently optionally substituted with 1, 2, 3, or 4 R n substituents;

[0048] R x2 , R x4 , and R x5 are each independently H, halogen, OH, NH2, CN, COOH, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2- alkynyl, C 1-6 alkoxy, C 1-6 alkylamino, -NHR ee , -C 0-6 alkylene-C(=O)-NR e1 R e2 , -C 0-6 alkylene-NR e1 -C(=O)-C 1-6 alkyl, C 3-8 cycloalkyl, or 3-8 membered heterocycloalkyl, said C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C1-6 Alkylamino, -NHR ee -C 0-6 Alkylene-C(=O)-NR e1 R e2 -C 0-6 Alkylene-NR e1 -C(=O)-C 1-6 Alkyl, C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl groups are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. y replace;

[0049] R ee -C 0-6 Alkylene-S(=O)2-R ee1 -C 0-6 alkylene-5-10-membered heteroaryl or ring A, wherein ring A is C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl, 4-8 membered heterocyclic alkenyl or 5-10 membered heteroaryl;

[0050] R ee1 For H or C 1-6 alkyl;

[0051] Each R e1 and R e2 H or C, independently respectively 1-6 alkyl;

[0052] Each R m R n and R y The independent components are H, halogen, OH, NH2, CN, COOH, and C, respectively. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, -S(=O)2-R or C 3-8 cycloalkyl;

[0053] R represents H and C. 1-6 Alkyl or C 1-6 alkyl;

[0054] L can be a single bond, -O-, -S-, -NH-, -S(=O)-, or -S(=O)2-;

[0055] R 11 and R 12 The independent components are H, halogen, OH, NH2, CN, COOH, and C, respectively. 1-6 Alkyl, C 3-8 Cycloalkyl, 5-6 membered heterocycloalkyl or 5-6 membered heterocycloalkenyl, wherein C 1-6alkyl, C 3-8 cycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkenyl are each independently optionally substituted with 1, 2, 3 or 4 R a substituents;

[0056] R2is H, halogen, OH, NH2, CN, COOH, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkoxy and C 1-6 alkyl, C b substituents;

[0057] R 31 and R 32 are each independently H, halogen, CN, C 1-6 alkyl, -C 0-6 alkylene-S(=0)2-NR e3 R e4 , -C 1-6 alkylene-S(=0)2-R e5 , -S(=0)2-R e6 , -C 0-6 alkylene-S(=0)(=NR e7 )-R e8 , -C 0-6 alkylene-S(=0)-NR e3 R e4 , -C 0-6 alkylene-S(=0)-R e5 , -C 0-6 alkylene-C(=0)-NR e3 R e4 , -C 0-6 alkylene-C(=0)-R e5 , -C 0-6 alkylene-NR e3 -C(=0)-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl, C 3-8 cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl or 5-6 membered heteroaryl, said C 1-6 alkyl, -C 0-6 alkylene-S(=0)2-NR e3 R e4 , -C 1-6 alkylene-S(=0)2-R e5 , -S(=0)2-R e6 , -C0-6 alkylene-S(=O)(=NR e7 )-R e8 , -C 0-6 alkylene-S(=O)-NR e3 R e4 , -C 0-6 alkylene-S(=O)-R e5 , -C 0-6 alkylene-C(=O)-NR e3 R e4 , -C 0-6 alkylene-C(=O)-R e5 , -C 0-6 alkylene-NR e3 -C(=O)-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl and 5-6 membered heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 R c ;

[0058] each R e3 and R e4 is independently H or C 1-6 alkyl;

[0059] each R e5 and R e8 is independently H, OH, C 1-6 alkyl, C 3-8 cycloalkyl, 5-6 membered heterocycloalkyl or 5-6 membered heterocycloalkenyl;

[0060] each R e6 is independently H, C 1-6 alkyl, C 3-8 cycloalkyl, 4-6 membered heterocycloalkyl or 4-6 membered heterocycloalkenyl;

[0061] each R e7 is independently H, CN or C 1-6 alkyl;

[0062] each R a , R b and R c is independently H, halogen, OH, NH2, CN, =O, COOH or C 1-6 alkyl;

[0063] p is 0, 1, 2, 3 or 4;

[0064] and, the R 31 , R 32X4, R x4 X5, R x5 One of the following conditions must be met:

[0065] a) when R 31 and R 32 are H, the other is not CN; or,

[0066] b) when one of R 31 and R 32 is -S(=O)2-R e6 , R e6 is C 1-6 alkyl, C 3-8 cycloalkyl or 5-6 membered heterocycloalkyl, the other is H, X4 is CR x4 , R x4 is C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylamino or C 3-8 cycloalkyl; or,

[0067] c) when one of R 31 and R 32 is -S(=O)2-R e6 , R e6 is C 1-6 alkyl, C 3-8 cycloalkyl or 5-6 membered heterocycloalkyl, the other is H, X5 is CR x5 , R x5 is -NHR ee ;

[0068] The heteroatoms in the "heterocycloalkyl", "heterocycloalkenyl" and "heteroaryl" include N, O, S, the S heteroatom is optionally oxidized to S(=O), S(=O)2 or S(=O)(=NH), the number of heteroatoms is 1, 2, 3 or 4; when the number of heteroatoms is more than one, the heteroatoms are the same or different.

[0069] In a first aspect of the present application, the present application provides a compound, which is a compound represented by formula (I), a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof,

[0070] wherein,

[0071] X1 is N or CR x1 ;

[0072] X2 is N or CR x2 ;

[0073] X3is N or CR x3 ;

[0074] X4is N or CR x4 ;

[0075] X5is N or CR x5 ;

[0076] R x1 is H, halogen, OH, NH2, CN, COOH, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 alkylamino, -S-C 1-6 alkyl, C 3-8 cycloalkyl, -O-C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 6-10 aryl, -O-C 6-10 aryl, 3-8 membered heterocycloalkyl, -O-(3-8 membered heterocycloalkyl), 4-8 membered heterocycloalkenyl, -O-(4-8 membered heterocycloalkenyl), 5-10 membered heteroaryl or -O-(5-10 membered heteroaryl), each independently optionally substituted with 1, 2, 3 or 4 R 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 alkylamino, -S-C 1-6 alkyl, C 3-8 cycloalkyl, -O-C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 6-10 aryl, -O-C 6- 10 aryl, 3-8 membered heterocycloalkyl, -O-(3-8 membered heterocycloalkyl), 4-8 membered heterocycloalkenyl, -O-(4-8 membered heterocycloalkyl), 5-10 membered heteroaryl and -O-(5-10 membered heteroaryl) are each independently optionally substituted with 1, 2, 3 or 4 R m substituents;

[0077] R x3 is H, halogen, OH, NH2, CN, COOH, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 alkylamino, -S-C 1-6 alkyl, C 3-8 cycloalkyl, -O-C 3-8 cycloalkyl or C 3-8 cycloalkenyl, C 1-6 alkyl, C 2-6alkenyl, C 1-6 alkoxy, C 1-6 alkylamino, -S-C 1-6 alkyl, C 3-8 cycloalkyl, -O-C 3-8 cycloalkyl and C 3-8 cycloalkenyl are each independently optionally substituted with 1, 2, 3, or 4 R n substituents;

[0078] R x2 , R x4 and R x5 are each independently H, halogen, OH, NH2, CN, COOH, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2- 6alkynyl, C 1-6 alkoxy, C 1-6 alkylamino, -NHR ee , -C 0-6 alkyl-C(=O)-NR e1 R e2 , -C 0-6 alkyl-NR e1 -C(=O)-C 1-6 alkyl and C 3- 8cycloalkyl, said C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylamino, -NHR ee , -C 0-6 alkyl-C(=O)-NR e1 R e2 , -C 0-6 alkyl-NR e1 -C(=O)-C 1-6 alkyl and C 3-8 cycloalkyl are each independently optionally substituted with 1, 2, 3, or 4 R y substituents;

[0079] R ee is ring A, which is C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 4-8 membered heterocycloalkenyl, or 5-10 membered heteroaryl;

[0080] each R e1 and R e2 is independently H or C 1-6 alkyl;

[0081] each R m , R n , and R y is independently H, halogen, OH, NH2, CN, COOH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylamino, -S(=O)2-R, or C 3-8 cycloalkyl;

[0082] R is H or C 1-6 alkyl; L is a single bond, -O-, -S-, -NH-, -S(=O)-, or -S(=O)2-;

[0083] R 11 and R 12 are each independently H, halogen, OH, NH2, CN, COOH, C 1-6 alkyl, C 3-8 cycloalkyl, 5-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkenyl, said C 1-6 alkyl, C 3-8 cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heterocycloalkenyl are each independently optionally substituted with 1, 2, 3, or 4 R a ;

[0084] R2is H, halogen, OH, NH2, CN, COOH, C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkylamino, said C 1-6 alkyl, C 1-6 alkoxy, and C 1-6 alkylamino are each independently optionally substituted with 1, 2, 3, or 4 R b ;

[0085] R 31 and R 32 are each independently H, halogen, CN, C 1-6 alkyl, -C 0-6 alkyl-S(=O)2-NR e3 R e4 , -C 1-6 alkyl-S(=O)2-R e5 , -S(=O)2-R e6 , -C 0-6 alkyl-S(=O)(=NR e7 )-R e8 , -C 0-6 alkyl-S(=O)-NR e3 R e4 , -C0-6 alkyl-S(=0)-R e5 , -C 0-6 alkyl-C(=0)-NR e3 R e4 , -C 0-6 alkyl-C(=0)-R e5 , -C 0-6 alkyl-NR e3 -C(=0)-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl or 5-6 membered heteroaryl, said C 1-6 alkyl, -C 0-6 alkyl-S(=0)2-NR e3 R e4 , -C 1-6 alkyl-S(=0)2-R e5 , -S(=0)2-R e6 , -C 0-6 alkyl-S(=0)(=NR e7 )-R e8 , -C 0-6 alkyl-S(=0)-NR e3 R e4 , -C 0-6 alkyl-S(=0)-R e5 , -C 0-6 alkyl-C(=0)-NR e3 R e4 , -C 0-6 alkyl-C(=0)-R e5 , -C 0-6 alkyl-NR e3 -C(=0)-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl and 5-6 membered heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 R c substituents;

[0086] each R e3 and R e4 is independently H or C 1-6 alkyl;

[0087] each R e5 and R e8 is independently H, OH, C 1-6 alkyl, C 3-8cycloalkyl, 4-6 membered heterocycloalkyl or 4-6 membered heterocycloalkenyl;

[0088] each R e6 is independently H, CN or C 1-6 alkyl, C 3-8 cycloalkyl, 4-6 membered heterocycloalkyl or 4-6 membered heterocycloalkenyl;

[0089] each R e7 is independently H, CN or C 1-6 alkyl;

[0090] each R a , R b and R c are independently H, halogen, OH, NH2, CN, =0, COOH or C 1-6 alkyl;

[0091] p is 0, 1, 2, 3 or 4;

[0092] and, said R 31 , R 32 , X4, R x4 , X5, R x5 have to fulfill one of the following conditions:

[0093] a) when one of R 31 and R 32 is H, the other is not CN;

[0094] b) when one of R 31 and R 32 is -S(=0)2-R e6 , R e6 is C 1-6 alkyl, C 3-8 cycloalkyl or 5-6 membered heterocycloalkyl, the other is H, X4 is CR x4 , R x4 is C 1-6 halogenated alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylamino or C 3-8 cycloalkyl;

[0095] c) when one of R 31 and R 32 is -S(=0)2-R e6 , R e6 is C 1-6 alkyl, C 3-8 cycloalkyl or 5-6 membered heterocycloalkyl, the other is H, X5 is CR x5 , Rx5 -NHR ee ;

[0096] The heteroatoms in the "heterocycloalkyl", "heterocycloalkenyl" and "heteroaryl" include N, O, S, the S heteroatom is optionally oxidized to S(=O), S(=O)2 or S(=O)(=NH), the number of the heteroatoms is 1, 2, 3 or 4; when the number of the heteroatoms is multiple, the heteroatoms are the same or different.

[0097] In a first aspect, the present application provides a compound, which is a compound represented by formula (I), a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof,

[0098] wherein,

[0099] X1is N or CR x1 ;

[0100] X2is N or CR x2 ;

[0101] X3is N or CR x3 ;

[0102] X4is N or CR x4 ;

[0103] X5is N or CR x5 ;

[0104] R x1 is H, halogen, OH, NH2, CN, COOH, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 alkylamino, -S-C 1-6 alkyl, C 3-8 cycloalkyl, -O-C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 6-10 aryl, -O-C 6-10 aryl, 3-8 membered heterocycloalkyl, -O-(3-8 membered heterocycloalkyl), 4-8 membered heterocycloalkenyl, -O-(4-8 membered heterocycloalkenyl), 5-10 membered heteroaryl or -O-(5-10 membered heteroaryl), the C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 alkylamino, -S-C 1-6 alkyl, C 3-8 cycloalkyl, -O-C 3-8 cycloalkyl, C 3-8cycloalkenyl, C 6-10 aryl, -O-C 6- 10 aryl, 3-8 membered heterocycloalkyl, -O-(3-8 membered heterocycloalkyl), 4-8 membered heterocycloalkenyl, -O-(4-8 membered heterocycloalkyl), 5-10 membered heteroaryl and -O-(5-10 membered heteroaryl) are each independently optionally substituted with 1, 2, 3, or 4 R m substituents;

[0105] R x3 is H, halogen, OH, NH2, CN, COOH, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 alkylamino, -S-C 1-6 alkyl, C 3-8 cycloalkyl, -O-C 3-8 cycloalkyl or C 3-8 cycloalkenyl, said C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 alkylamino, -S-C 1-6 alkyl, C 3-8 cycloalkyl, -O-C 3-8 cycloalkyl and C 3-8 cycloalkenyl are each independently optionally substituted with 1, 2, 3, or 4 R n substituents;

[0106] R x2 , R x4 and R x5 are each independently H, halogen, OH, NH2, CN, COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylamino, -C 0-6 alkyl-C(=O)-NR e1 R e2 , -C 0-6 alkyl-NR e1 -C(=O)-C 1-6 alkyl or C 3-8 cycloalkyl, said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylamino, -C 0-6 alkyl-C(=O)-NR e1 R e2, -C 0-6 alkyl-NR e1 -C(=O)-C 1-6 alkyl and C 3-8 cycloalkyl are each independently optionally substituted with 1, 2, 3, or 4 R y substituents;

[0107] each R e1 and R e2 are each independently H or C 1-6 alkyl;

[0108] each R m , R n and R y are each independently H, halogen, OH, NH2, CN, COOH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, or C 3-8 cycloalkyl;

[0109] L is a single bond, -O-, -S-, -NH-, -S(=O)-, or -S(=O)2-;

[0110] R 11 and R 12 are each independently H, halogen, OH, NH2, CN, COOH, C 1-6 alkyl, C 3-8 cycloalkyl, 5-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkenyl, said C 1-6 alkyl, C 3-8 cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heterocycloalkenyl are each independently optionally substituted with 1, 2, 3, or 4 R a substituents;

[0111] R2is H, halogen, OH, NH2, CN, COOH, C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkylamino, said C 1-6 alkyl, C 1-6 alkoxy, and C 1-6 alkylamino are each independently optionally substituted with 1, 2, 3, or 4 R b substituents;

[0112] R 31 and R 32 are each independently H, halogen, CN, C 1-6 alkyl, -C 0-6 alkyl-S(=O)2-NR e3 R e4 , -C 1-6 alkyl-S(=O)2-Re5 -S(=O)2-R e6 -C(=O)-R 0-6 alkyl-S(=O)(=NR e7 )-R e8 -C(=O)-NR 0-6 alkyl-S(=O)-NR e3 R e4 -C(=O)-R 0-6 alkyl-S(=O)-R e5 -C(=O)-NR 0-6 alkyl-C(=O)-NR e3 R e4 -C(=O)-R 0-6 alkyl-C(=O)-R e5 -C(=O)-NR 0-6 alkyl-NR e3 -C(=O)-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl or 5-6 membered heteroaryl, each independently optionally substituted with 1, 2, 3 or 4 R 1-6 alkyl, -C 0-6 alkyl-S(=O)2-NR e3 R e4 -C(=O)-R 1-6 alkyl-S(=O)2-R e5 -S(=O)2-R e6 -C(=O)-NR 0-6 alkyl-S(=O)(=NR e7 )-R e8 -C(=O)-NR 0-6 alkyl-S(=O)-NR e3 R e4 -C(=O)-R 0-6 alkyl-S(=O)-R e5 -C(=O)-NR 0-6 alkyl-C(=O)-NR e3 R e4 -C(=O)-R 0-6 alkyl-C(=O)-R e5 -C(=O)-NR 0-6 alkyl-NR e3 -C(=O)-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl and 5-6 membered heteroaryl, each independently optionally substituted with 1, 2, 3 or 4 R c substituents;

[0113] each Re3 and R e4 are each independently H or C 1-6 alkyl;

[0114] each R e5 and R e8 are each independently H, OH, C 1-6 alkyl, C 3-8 cycloalkyl, 5-6 membered heterocycloalkyl or 5-6 membered heterocycloalkenyl;

[0115] each R e6 are each independently H, C 1-6 alkyl, C 3-8 cycloalkyl, 4-6 membered heterocycloalkyl or 4-6 membered heterocycloalkenyl;

[0116] each R e7 are each independently H, CN or C 1-6 alkyl;

[0117] each R a , R b and R c are each independently H, halogen, OH, NH2, CN, =0, COOH or C 1-6 alkyl;

[0118] p is 0, 1, 2, 3 or 4;

[0119] and, the R 31 , R 32 , R x4 must satisfy one of the following conditions:

[0120] a) when one of R 31 and R 32 is H, the other is not CN;

[0121] b) when one of R 31 and R 32 is -S(=0)2-R e6 , R e6 is C 1-6 alkyl, C 3-8 cycloalkyl or 5-6 membered heterocycloalkyl, the other is H, R x4 is C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylamino or C 3-8 cycloalkyl.

[0122] In a first aspect, the present application provides a compound, which is a compound of formula (I), a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof,

[0123] wherein,

[0124] X1is N or CR x1 ;

[0125] X2is N or CR x2 ;

[0126] X3is N or CR x3 ;

[0127] X4is N or CR x4 ;

[0128] X5is N or CR x5 ;

[0129] R x1 is H, halogen, OH, NH2, CN, COOH, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 alkylamino, -S-C 1-6 alkyl, C 3-8 cycloalkyl, -O-C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 6-10 aryl, -O-C 6-10 aryl, 3-8 membered heterocycloalkyl, -O-(3-8 membered heterocycloalkyl), 4-8 membered heterocycloalkenyl, -O-(4-8 membered heterocycloalkenyl), 5-10 membered heteroaryl or -O-(5-10 membered heteroaryl), each of said C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 alkylamino, -S-C 1-6 alkyl, C 3-8 cycloalkyl, -O-C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 6-10 aryl, -O-C 6- 10 aryl, 3-8 membered heterocycloalkyl, -O-(3-8 membered heterocycloalkyl), 4-8 membered heterocycloalkenyl, -O-(4-8 membered heterocycloalkenyl), 5-10 membered heteroaryl and -O-(5-10 membered heteroaryl) are independently optionally substituted with 1, 2, 3 or 4 R m ;

[0130] R x3For H, halogen, OH, NH2, CN, COOH, C 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Alkoxy, C 1-6 Alkylamino, -SC 1-6 Alkyl, C 3-8 cycloalkyl, -OC 3-8 cycloalkyl or C 3-8 Cycloalkenyl, the C 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Alkoxy, C 1-6 Alkylamino, -SC 1-6 Alkyl, C 3-8 cycloalkyl, -OC 3-8 cycloalkyl and C 3-8 The cycloalkene groups are independently and optionally surrounded by 1, 2, 3 or 4 R groups. n Replace; R x2 R x4 and R x5 The independent components are H, halogen, OH, NH2, CN, COOH, and C, respectively. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, -C 0-6 Alkyl-C(=O)-NR e1 R e2 -C 0-6 Alkyl-NR e1 -C(=O)-C 1-6 Alkyl or C 3-8 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, -C 0-6 Alkyl-C(=O)-NR e1 R e2 -C 0-6 Alkyl-NR e1 -C(=O)-C 1-6 Alkyl and C 3-8 The cycloalkyl groups are each independently and optionally marked with 1, 2, 3 or 4 R groups. y replace;

[0131] Each R e1 and R e2 H or C, independently respectively 1-6 alkyl;

[0132] Each R m R n and R y The independent components are H, halogen, OH, NH2, CN, COOH, and C, respectively.1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino or C 3-8 cycloalkyl;

[0133] L can be a single bond, -O-, -S-, -NH-, -S(=O)-, or -S(=O)2-;

[0134] R 11 and R 12 The independent components are H, halogen, OH, NH2, CN, COOH, and C, respectively. 1-6 Alkyl, C 3-8 Cycloalkyl, 5-6 membered heterocycloalkyl or 5-6 membered heterocycloalkenyl, wherein C 1-6 Alkyl, C 3-8 Cycloalkyl, 5-6 membered heterocyclic alkyl, and 5-6 membered heterocyclic alkenyl groups are each independently and optionally surrounded by 1, 2, 3, or 4 R groups. a replace;

[0135] R2 can be H, halogen, OH, NH2, CN, COOH, or C. 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkylamino, the C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Alkylamino groups are independently and optionally surrounded by 1, 2, 3 or 4 R groups. b Replace; R 31 and R 32 Each is independently H, halogen, CN, C 1- 6-alkyl, -C 0-6 Alkyl-S(=O)2-NR e3 R e4 -C 1-6 Alkyl-S(=O)2-R e5 -C 0-6 Alkyl-S(=O)-NR e3 R e4 -C 0-6 Alkyl-S(=O)-R e5 -C 0-6 Alkyl-C(=O)-NR e3 R e4 -C 0-6 Alkyl-C(=O)-R e5 -C 0-6 Alkyl-NR e3 -C(=O)-C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-8cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl or 5-6 membered heteroaryl, which C 1-6 alkyl, -C 0-6 alkyl-S(=O)2-NR e3 R e4 , -C 1-6 alkyl-S(=O)2-R e5 , -C 0-6 alkyl-S(=O)-NR e3 R e4 , -C 0-6 alkyl-S(=O)-R e5 , -C 0-6 alkyl-C(=O)-NR e3 R e4 , -C 0-6 alkyl-C(=O)-R e5 , -C 0-6 alkyl-NR e3 -C(=O)-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl and 5-6 membered heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 R c substituents;

[0136] and, when one of R 31 and R 32 is H, the other is not CN;

[0137] each R e3 and R e4 is independently H or C 1-6 alkyl; each R e5 is independently H, OH, C 1-6 alkyl, C 3-8 cycloalkyl, 5-6 membered heterocycloalkyl or 5-6 membered heterocycloalkenyl; each R a , R b and R c is independently H, halogen, OH, NH2, CN, =O, COOH or C 1-6 alkyl;

[0138] p is 0, 1, 2, 3 or 4.

[0139] According to an embodiment of the present application, the above-mentioned compound can further include at least one of the following technical features:

[0140] In an optional embodiment of the present application, at least one of X1, X2, X3, X4and X5is N.

[0141] In an alternative embodiment of the application, one or two of X1, X2, X3, X4and X5are N.

[0142] In an alternative embodiment of the application, X1is CR x1 , X2is N, X3is CR x3 , X4is N or CR x4 , and X5is CR x5 .

[0143] In an alternative embodiment of the application, X1is CR x1 , X2is N, X3is CR x3 , X4is N, and X5is CR x5 .

[0144] In an alternative embodiment of the application, X1is CR x1 , X2is N, X3is CR x3 , X4is CR x4 , and X5is CH.

[0145] In an alternative embodiment of the application, R x1 is H, halogen, OH, NH2, CN, COOH, C 1-4 alkyl, C 2-4 alkenyl, C 1-4 alkoxy, C 1-4 alkylamino, -S-C 1-4 alkyl, C 3-6 cycloalkyl, -O-C 3-6 cycloalkyl, C 3-6 cycloalkenyl, C 6-10 aryl, -O-C 6-10 aryl, 5-6 membered heterocycloalkyl, -O-(5-6 membered heterocycloalkyl), 5-6 membered heterocycloalkenyl, -O-(5-6 membered heterocycloalkenyl), 5-6 membered heteroaryl, or -O-(5-6 membered heteroaryl), each of said C 1-4 alkyl, C 2-4 alkenyl, C 1-4 alkoxy, C 1-4 alkylamino, -S-C 1-4 alkyl, C 3-6 cycloalkyl, -O-C 3-6 cycloalkyl, C 3- 6cycloalkenyl, C 6-10 aryl, -O-C 6-10 aryl, 5-6 membered heterocycloalkyl, -O-(5-6 membered heterocycloalkyl), 5-6 membered heterocycloalkenyl, -O-(5-6 membered heterocycloalkenyl), 5-6 membered heteroaryl, and -O-(5-6 membered heteroaryl) is independently optionally substituted with 1, 2, 3, or 4 R m .

[0146] In an optional embodiment of the application, R x1 is H, halogen, OH, NH2, CN, COOH, C 1-4 alkyl, C 3-6 cycloalkyl, phenyl, -O-phenyl, 5-6 membered heteroaryl or -O-(5-6 membered heteroaryl), each independently optionally substituted with 1, 2, 3 or 4 R 1-4 alkyl, C 3-6 cycloalkyl, phenyl, -O-phenyl, 5-6 membered heteroaryl and -O-(5-6 membered heteroaryl), each independently optionally substituted with 1, 2, 3 or 4 R m substituents.

[0147] In an optional embodiment of the application, R x1 is H, F, Cl, Br, methyl, ethyl, phenyl or -O-phenyl, each independently optionally substituted with 1, 2, 3 or 4 R m substituents.

[0148] In an optional embodiment of the application, each R m is independently H, halogen, OH, NH2, CN, COOH, C 1-3 alkyl.

[0149] In an optional embodiment of the application, each R m is independently H, F, Cl, Br, OH, NH2, CN, COOH, methyl or ethyl.

[0150] In an optional embodiment of the application, R x1 is

[0151] In an optional embodiment of the application, R x1 is

[0152] In an optional embodiment of the application, R x3 is H, halogen, OH, NH2, CN, COOH, C 1-4 alkyl, C 2-4 alkenyl, C 1-4 alkoxy, C 1-4 alkylamino, -S-C 1-4 alkyl, C 3-6 cycloalkyl, -O-C 3-6 cycloalkyl or C 3-6 cycloalkenyl, each independently optionally substituted with 1, 2, 3 or 4 R 1-4 alkyl, C 2-4 alkenyl, C 1-4 alkoxy, C 1-4 alkylamino, -S-C 1-4alkyl, C 3-6 cycloalkyl, -O-C 3-6 cycloalkyl and C 3-6 cycloalkenyl are each independently optionally substituted with 1, 2, 3, or 4 R n substituents;

[0153] In an alternative embodiment of the application, R x3 is H, halogen, C 1-4 alkyl, or C 3-6 cycloalkyl, said C 1-4 alkyl and C 3-6 cycloalkyl are each independently optionally substituted with 1, 2, 3, or 4 R n substituents;

[0154] In an alternative embodiment of the application, R x3 is H, F, Cl, Br, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, said methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl are each independently optionally substituted with 1, 2, 3, or 4 R n substituents.

[0155] In an alternative embodiment of the application, each R n is independently H, halogen, OH, NH2, CN, COOH, C 1-3 alkyl, or C 3- 6cycloalkyl.

[0156] In an alternative embodiment of the application, each R n is independently H, F, Cl, Br, OH, NH2, CN, COOH, methyl, ethyl, propyl, cyclopropyl, or cyclobutyl.

[0157] In an alternative embodiment of the application, R x3 is H, methyl, ethyl, cyclopentyl,

[0158] In an alternative embodiment of the application, R x3 is H, cyclopentyl, or

[0159] In an alternative embodiment of the application, R x2 , R x4 , and R x5 are each independently H, halogen, OH, NH2, CN, COOH, C 1-3 alkyl, C 1-3 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkoxy, C 1-3alkyl, C ee alkylene-C(=O)-NR 0-3 R e1 alkyl, C e2 alkylene-NR 0-3 -C(=O)-C e1 alkyl, C 1-3 cycloalkyl and 4-6 membered heterocycloalkyl are each independently optionally substituted with 1, 2, 3, or 4 R 3-6 alkyl, C 1-3 haloalkyl, C 1-3 alkenyl, C 2-4 alkynyl, C 2-4 alkoxy, C 1-3 alkyl, C 1-3 alkylene-NR ee -C(=O)-C 0-3 alkyl, C e1 alkylene-C(=O)-NR e2 R 0-3 alkylene-NR e1 -C(=O)-C 1- alkyl, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl are each independently optionally substituted with 1, 2, 3, or 4 R y substituents.

[0160] In an optional embodiment of the application, R x2 is H, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl or C 1-3 alkoxy, C 1-3 alkyl, C 1-3 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl and C 1-3 alkoxy are each independently optionally substituted with 1, 2, 3, or 4 R y substituents.

[0161] In an optional embodiment of the application, R x4 is H, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl or C 1-3 alkoxy, C 1-3 alkyl, C 1-3 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl and C 1-3 alkoxy are each independently optionally substituted with 1, 2, 3, or 4 R ysubstituted.

[0162] In an optional embodiment of the application, R x5 is H, halogen, NH2, C 1-3 alkyl, C 1-3 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkoxy, -NHR ee or 4-6 membered heterocycloalkyl, said C 1-3 alkyl, C 1-3 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkoxy, -NHR ee and 4-6 membered heterocycloalkyl are each independently optionally substituted with 1, 2, 3, or 4 R y substituents.

[0163] In an optional embodiment of the application, R x5 is H or -NHR ee , said -NHR ee is optionally substituted with 1, 2, 3, or 4 R y substituents.

[0164] In an optional embodiment of the application, R x5 is -NHR ee , said -NHR ee is optionally substituted with 1, 2, 3, or 4 R y substituents.

[0165] In an optional embodiment of the application, R x2 , R x4 and R x5 are each independently H, halogen, OH, NH2, CN, COOH, C 1-3 alkyl, C 1-3 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkoxy, C 1-3 alkylamino, -NHR ee , -C 0-3 alkyl-C(=O)-NR e1 R e2 , -C 0-3 alkyl-NR e1 -C(=O)-C 1-3 alkyl or C 3-6 cycloalkyl, said C 1-3 alkyl, C 1-3 haloalkyl, C 2-4 alkenyl, C2-4 alkynyl, C 1-3 alkoxy, C 1-3 alkylamino, -NHR ee , -C 0-3 alkyl-C(=O)-NR e1 R e2 , -C 0-3 alkyl-NR e1 -C(=O)-C 1-3 alkyl and C 3-6 cycloalkyl are each independently optionally substituted with 1, 2, 3, or 4 R y substituents;

[0166] In an alternative embodiment of the application, R x2 , R x4 and R x5 are each independently H, halogen, OH, NH2, CN, COOH, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkoxy, C 1-3 alkylamino, -C 0-3 alkyl-C(=O)-NR e1 R e2 , -C 0-3 alkyl-NR e1 -C(=O)-C 1-3 alkyl or C 3-6 cycloalkyl, said C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkoxy, C 1-3 alkylamino, -C 0-3 alkyl-C(=O)-NR e1 R e2 , -C 0-3 alkyl-NR e1 -C(=O)-C 1-3 alkyl and C 3-6 cycloalkyl are each independently optionally substituted with 1, 2, 3, or 4 R y substituents.

[0167] In an alternative embodiment of the application, R x2 , R x4 and R x5 are each independently H, halogen, OH, NH2, CN, COOH, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, -C 0-3 alkyl-C(=O)-NRe1 R e2 , -C 0-3 alkyl-NR e1 -C(=O)-C 1-3 alkyl and C 3-6 cycloalkyl are each independently optionally substituted with 1, 2, 3, or 4 R 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, -C 0-3 alkyl-C(=O)-NR e1 R e2 , -C 0-3 alkyl-NR e1 -C(=O)-C 1-3 alkyl and C 3-6 cycloalkyl are each independently optionally substituted with 1, 2, 3, or 4 R y substituents.

[0168] In an alternative embodiment of the application, each R y is independently H, F, Cl, or Br.

[0169] In an alternative embodiment of the application, each R y is independently H, OH, F, Cl, Br, oxo (=O), C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 alkylamino, -S(=O)2-R, or C 3-6 cycloalkyl.

[0170] In an alternative embodiment of the application, each R y is independently H, F, Cl, Br, CN, C 1-3 alkyl, C 1-3 haloalkyl, C 1- alkoxy, C 1-3 alkylamino, -S(=O)2-R, or C 3-6 cycloalkyl.

[0171] In an alternative embodiment of the application, each R y is independently H, F, Cl, Br, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 alkylamino, -S(=O)2-R, or C 3-6 cycloalkyl.

[0172] In an alternative embodiment of the application, R is H, -NHR d2 , C 1-3 alkyl, or -C1-3 alkylene-OH, wherein R d2 is H or C 1-6 alkyl.

[0173] In an alternative embodiment of the application, R is H, -NH(CH3), methyl or -CH2CH2(OH).

[0174] In an alternative embodiment of the application, R is H or C 1-3 alkyl.

[0175] In an alternative embodiment of the application, R is H or methyl.

[0176] In an alternative embodiment of the application, each R y is independently H, OH, F, CI, CN, oxo (=0), methyl, -CHF2, -CH2CF3, -S(=0)2-CH3, S(=0)2-NH(CH3) or S(=0)2-CH2-CH2(OH).

[0177] In an alternative embodiment of the application, each R y is independently H, F, CI, CN, methyl, -CHF2, -CH2CF3 or -S(=0)2-CH3.

[0178] In an alternative embodiment of the application, each R y is independently H, F, methyl, -CHF2, -CH2CF3 or -S(=0)2-CH3.

[0179] In an alternative embodiment of the application, R ee is -C 0-3 alkylene-S(=0)2-R ee1 , -C 0-3 alkylene-5-6 membered heteroaryl or ring A, which is C 3-6 cycloalkyl, 4-8 membered heterocycloalkyl, phenyl, 5-6 membered heterocycloalkenyl or 5-6 membered heteroaryl.

[0180] In an alternative embodiment of the application, R ee is -C 0-3 alkylene-S(=0)2-R ee1 , -C 1-3 alkylene-5-6 membered heteroaryl or ring A, which is C 3-6 cycloalkyl, 4-8 membered heterocycloalkyl, phenyl, 5-6 membered heterocycloalkenyl or 5-6 membered heteroaryl, wherein R ee is optionally substituted with 1, 2, 3 or 4 R y .

[0181] In an alternative embodiment of the application, Ree -C 0-3 alkylene-S(=0)2-R ee1 -C 0-3 alkylene-5-6 membered heteroaryl or ring A, which is C 3-6 cycloalkyl, 4-6 membered monocyclic heterocycloalkyl, 6-8 membered spiro heterocycloalkyl, 6-8 membered fused heterocycloalkyl, phenyl, 5-6 membered heterocycloalkenyl or 5-6 membered heteroaryl.

[0182] In an optional embodiment of the application, R ee -C 0-3 alkylene-S(=0)2-R ee1 -C 1-3 alkylene-5-6 membered heteroaryl or ring A, which is C 3-6 cycloalkyl, 4-6 membered monocyclic heterocycloalkyl, 6-8 membered spiro heterocycloalkyl, 6-8 membered fused heterocycloalkyl, phenyl, 5-6 membered heterocycloalkenyl or 5-6 membered heteroaryl, wherein R ee is optionally substituted with 1, 2, 3 or 4 R y .

[0183] In an optional embodiment of the application, R ee -C 0-3 alkylene-S(=0)2-R ee1 -C 1-3 alkylene-5-6 membered heteroaryl or ring A, which is C 3-6 cycloalkyl, 4-8 membered heterocycloalkyl, phenyl, 5-6 membered heterocycloalkenyl or 5-6 membered heteroaryl, wherein R ee is optionally substituted with 1, 2, 3 or 4 R y .

[0184] In an optional embodiment of the application, R ee -C 0-3 alkylene-S(=0)2-R ee1 -C 1-3 alkylene-5-6 membered heteroaryl or ring A, which is C 3-6 monocyclic cycloalkyl, C 5-6 bridged cycloalkyl, 4-6 membered monocyclic heterocycloalkyl, 6-8 membered spiro heterocycloalkyl, 6-8 membered fused heterocycloalkyl, phenyl, 5-6 membered heterocycloalkenyl or 5-6 membered heteroaryl, wherein R ee is optionally substituted with 1, 2, 3 or 4 R y .

[0185] In an optional embodiment of the application, R ee -C 0-3 alkylene-S(=0)2-R ee1 -C 0-3alkylene-5-6 membered heteroaryl or ring A, which is C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heterocycloalkenyl or 5-6 membered heteroaryl.

[0186] In an optional embodiment of the application, R ee is -C 0-3 alkylene-S(=O)2-R ee1 , -C 1-3 alkylene-5-6 membered heteroaryl or ring A, which is C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heterocycloalkenyl or 5-6 membered heteroaryl, wherein R ee is optionally substituted with 1, 2, 3 or 4 R y substituents.

[0187] In an optional embodiment of the application, R ee is -C 0-3 alkylene-S(=O)2-R ee1 , -C 1-3 alkylene-5-6 membered heteroaryl or ring A, which is C 3-6 monocyclic cycloalkyl, C 5-6 bridged cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heterocycloalkenyl or 5-6 membered heteroaryl, wherein R ee is optionally substituted with 1, 2, 3 or 4 R y substituents.

[0188] In an optional embodiment of the application, R ee is -C 1-3 alkylene-S(=O)2(C 1-3 alkyl) or C 1-3 cycloalkyl substituted with -S(=O)2(C 3-6 alkyl).

[0189] In an optional embodiment of the application, R ee is 4-6 membered monocyclic heterocycloalkyl, which is substituted with one or more oxo (=O) and / or OH when S is contained in the 4-6 membered monocyclic heterocycloalkyl.

[0190] In an optional embodiment of the application, R ee is 4-6 membered monocyclic heterocycloalkyl, which is substituted with -S(=O)2(C 1-3 alkyl), S(=O)2-NH(C 1-3 alkyl) or -S(=O)2-C 1-3 alkylene-CH2(OH) when N is contained in the 4-6 membered monocyclic heterocycloalkyl.

[0191] In an optional embodiment of the present invention, R ee It is a 4-6 member monocyclic heterocyclic alkyl group, wherein when the 4-6 member monocyclic heterocyclic alkyl group contains O, the 4-5 member monocyclic heterocyclic alkyl group is unsubstituted.

[0192] In an optional embodiment of the present invention, R ee It is a 5-6 membered heteroaryl group, wherein the 5-6 membered heteroaryl group is optionally C 1-3 Alkyl, halomethyl or -S(=O)2(C 1-3 Alkyl) substitution.

[0193] In an optional embodiment of the present invention, R ee -C 1-3 Alkylene-S(=O)2(C 1-3 Alkyl), -S(=O)2(C 1-3 alkyl) substituted C 3-6 Cycloalkyl, 4-6 membered monocyclic heterocyclic alkyl, or 5-6 membered heteroaryl; wherein, when the 4-6 membered monocyclic heterocyclic alkyl contains S, the 4-6 membered monocyclic heterocyclic alkyl is substituted by one or more oxo (=O) and / or OH; when the 4-6 membered monocyclic heterocyclic alkyl contains N, the 4-6 membered monocyclic heterocyclic alkyl is substituted by -S(=O)2(C 1-3 Alkyl group, S(=O)2-NH(CH3) or -S(=O)2-CH2-CH2(OH) substituted; when the 4-6 membered monocyclic heterocyclic alkyl group contains O, the 4-5 membered monocyclic heterocyclic alkyl group is unsubstituted, and the 5-6 membered heteroaryl group is optionally C 1-3 Alkyl, halomethyl or -S(=O)2(C 1-3 Alkyl) substitution.

[0194] In an optional embodiment of the present invention, R ee -C 1-3 Alkylene-S(=O)2(C 1-3 Alkyl), -S(=O)2(C 1-3 alkyl) substituted C 3-6 Cycloalkyl or 4-6 membered monocyclic heterocyclic alkyl; wherein, when the 4-6 membered monocyclic heterocyclic alkyl contains S, the 4-6 membered monocyclic heterocyclic alkyl is substituted by one or more oxo (=O); when the 4-6 membered monocyclic heterocyclic alkyl contains N, the 4-6 membered monocyclic heterocyclic alkyl is substituted by -S(=O)2(C 1-3 Alkyl) substitution.

[0195] In an optional embodiment of the present invention, when R ee -C 1-3 Alkylene-S(=O)2-C 1-3 When alkyl, R 31 For H, R 32-S(=O)2-R e6 .

[0196] In an optional embodiment of the present invention, R ee1 For H or C 1-3 alkyl.

[0197] In an optional embodiment of the present invention, R ee1 It is H or methyl.

[0198] In an optional embodiment of the present invention, R ee It is -(CH2)2-S(=O)2-CH3, Or ring A, wherein ring A is

[0199] In an optional embodiment of the present invention, R ee It is -(CH2)2-S(=O)2-CH3, Or ring A, wherein ring A is Where R ee Can be arbitrarily divided by 1, 2, 3 or 4 Rs y replace.

[0200] In an optional embodiment of the present invention, R ee It is -(CH2)2-S(=O)2-CH3, Or ring A, wherein ring A is

[0201] In an optional embodiment of the present invention, R ee It is -(CH2)2-S(=O)2-CH3, Or ring A, wherein ring A is

[0202] In an optional embodiment of the present invention, R ee It is -(CH2)2-S(=O)2-CH3, Or ring A, wherein ring A is

[0203] In an optional embodiment of the present invention, R ee It is -(CH2)2-S(=O)2-CH3, Or ring A, wherein ring A is Where R eeoptionally substituted with 1, 2, 3, or 4 R y substituted.

[0204] In an optional embodiment of the application, R ee is -(CH2)2-S(=O)2-CH3, or ring A is

[0205] In an optional embodiment of the application, R ee is -(CH2)2-S(=O)2-CH3, or ring A is

[0206] In an optional embodiment of the application, R ee is ring A which is C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heterocycloalkenyl, or 5-6 membered heteroaryl.

[0207] In an optional embodiment of the application, R ee is ring A which is

[0208] In an optional embodiment of the application, R ee is ring A which is

[0209] In an optional embodiment of the application, R ee is ring A which is

[0210] In an optional embodiment of the application, R ee is ring A which is

[0211] In an optional embodiment of the application, R x2 , R x4 , and R x5 are each independently H, F, Cl, Br, methyl, ethyl, -CF3, -CHF2, vinyl, ethynyl, or methoxy.

[0212] In an optional embodiment of the application, R x2 , R x4 , and R x5 are each independently H, F, Cl, Br, methyl, or ethyl.

[0213] In an alternative embodiment of the application, each R e1 and R e2 are each independently H or C 1-3 alkyl.

[0214] In an alternative embodiment of the application, each R e1 and R e2 are each independently H, methyl, ethyl or propyl.

[0215] In an alternative embodiment of the application, R x2 is H, F, Cl, Br, methyl, ethyl, -CF3, -CHF2, vinyl, ethynyl or methoxy.

[0216] In an alternative embodiment of the application, R x4 is H, F, Cl, Br, methyl, ethyl, -CF3, -CHF2, vinyl, ethynyl or methoxy.

[0217] In an alternative embodiment of the application, R x5 is H, F, Cl, Br, NH2, methyl, ethyl, -CF3, -CHF2, vinyl, ethynyl, methoxy, -NH-(CH2)2-S(=O)2-CH3,

[0218] In an alternative embodiment of the application, R x5 is H, F, Cl, Br, NH2, methyl, ethyl, -CF3, -CHF2, vinyl, ethynyl, methoxy, -NH-(CH2)2-S(=O)2-CH3,

[0219] In an alternative embodiment of the application, R x5 is H, F, Cl, Br, NH2, methyl, ethyl, -CF3, -CHF2, vinyl, ethynyl, methoxy, -NH-(CH2)2-S(=O)2-CH3,

[0220] In an alternative embodiment of the application, R x5 is H, F, Cl, Br, methyl, ethyl, -CF3, -CHF2, vinyl, ethynyl, methoxy,

[0221] In an alternative embodiment of the application, R x5 is or -NH-(CH2)2-S(=O)2-CH3.

[0222] In an alternative embodiment of the application, L is -NH-.

[0223] In an alternative embodiment of the application, R 11 and R 12 are each independently H, halogen, OH, NH2, CN, COOH, C 1-3 alkyl or C 3-6 cycloalkyl, each of said C 1-3 alkyl and C 3-6 cycloalkyl being independently optionally substituted with 1, 2, 3 or 4 R a groups.

[0224] In an alternative embodiment of the application, R 11 and R 12 are each independently H, F, Cl, Br, OH, NH2, CN, COOH, methyl, ethyl, propyl, cyclopropyl or cyclobutyl, each of said methyl, ethyl, propyl, cyclopropyl and cyclobutyl being independently optionally substituted with 1, 2, 3 or 4 R a groups.

[0225] In an alternative embodiment of the application, each R a is independently H, F, Cl, Br, OH, NH2, CN, =O or COOH.

[0226] In an alternative embodiment of the application, R 11 and R 12 are each independently H, cyclopropyl or

[0227] In an alternative embodiment of the application, R 11 is H and R 12 is cyclopropyl.

[0228] In an alternative embodiment of the application, R 11 is cyclopropyl and R 12 is H.

[0229] In an alternative embodiment of the application, R2is H, F, Cl, Br, OH, NH2, CN, COOH or C 1-3 alkyl, said C 1-3 alkyl being independently optionally substituted with 1, 2, 3 or 4 R b groups.

[0230] In an alternative embodiment of the application, each R b is independently H, F, Cl or Br.

[0231] In an alternative embodiment of the application, R2is H.

[0232] In an alternative embodiment of the application, R 31 and R 32 are each independently H, halogen, CN, C 1-3 alkyl, -C 0-3 alkylene-S(=O)2-NR e3 R e4 , -C 1-3 alkylene-S(=O)2-R e5 , -S(=O)2-R e6 , -C 0-3 alkylene-S(=O)(=NR e7 )-R e8 , -C 0-3 alkylene-S(=O)-NR e3 R e4 , -C 0-3 alkylene-S(=O)-R e5 , -C 0-3 alkylene-C(=O)-NR e3 R e4 , -C 0-3 alkylene-C(=O)-R e5 , -C 0-3 alkylene-NR e3 -C(=O)-C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, C 3-6 cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl or 5-6 membered heteroaryl, said C 1-3 alkyl, -C 0-3 alkylene-S(=O)2-NR e3 R e4 , -C 1-3 alkylene-S(=O)2-R e5 , -S(=O)2-R e6 , -C 0-3 alkylene-S(=O)(=NR e7 )-R e8 , -C 0-3 alkylene-S(=O)-NR e3 R e4 , -C 0-3 alkylene-S(=O)-R e5 , -C 0-3 alkylene-C(=O)-NR e3 R e4 , -C0-3 alkylene-C(=O)-R e5 , -C 0-3 alkylene-NR e3 -C(=O)-C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, C 3-6 cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl and 5-6 membered heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 R c substituents.

[0233] In an optional embodiment of the application, R 31 and R 32 are each independently H, halogen, CN, C 1-3 alkyl, -C 0-3 alkyl-S(=O)2-NR e3 R e4 , -C 1-3 alkyl-S(=O)2-R e5 , -S(=O)2-R e6 , -C 0-3 alkyl-S(=O)(=NR e7 )-R e8 , -C 0-3 alkyl-S(=O)-NR e3 R e4 , -C 0- 3alkyl-S(=O)-R e5 , -C 0-3 alkyl-C(=O)-NR e3 R e4 , -C 0-3 alkyl-C(=O)-R e5 , -C 0-3 alkyl-NR e3 -C(=O)-C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, C 3-6 cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl or 5-6 membered heteroaryl, said C 1-3 alkyl, -C 0-3 alkyl-S(=O)2-NR e3 R e4 , -C 1-3 alkyl-S(=O)2-R e5 , -S(=O)2-R e6 , -C 0-3 alkyl-S(=O)(=NR e7 )-R e8 , -C0-3 alkyl-S(=0)-NR e3 R e4 -C 0-3 alkyl-S(=0)-R e5 -C 0-3 alkyl-C(=0)-NR e3 R e4 -C 0-3 alkyl-C(=0)-R e5 -C 0-3 alkyl-NR e3 -C(=0)-C 1-3 alkyl, C 1- 3alkoxy, C 1-3 alkylamino, C 3-6 cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl and 5-6 membered heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 R c substituents.

[0234] In an optional embodiment of the application, R 31 and R 32 are each independently H, halogen, CN, C 1-3 alkyl, -C 0-3 alkyl-S(=0)2-NR e3 R e4 -C 1-3 alkyl-S(=0)2-R e5 -C 0-3 alkyl-S(=0)-NR e3 R e4 -C 0-3 alkyl-S(=0)-R e5 -C 0-3 alkyl-C(=0)-NR e3 R e4 -C 0-3 alkyl-C(=0)-R e5 -C 0-3 alkyl-NR e3 -C(=0)-C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, C 3-6 cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl or 5-6 membered heteroaryl, said C 1-3 alkyl, -C 0-3 alkyl-S(=0)2-NR e3 R e4 -C 1-3 alkyl-S(=0)2-R e5 -C 0-3alkyl-S(=0)-NR e3 R e4 , -C 0-3 alkyl-S(=0)-R e5 , -C 0-3 alkyl-C(=0)-NR e3 R e4 , -C 0-3 alkyl-C(=0)-R e5 , -C 0-3 alkyl-NR e3 -C(=0)-C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, C 3-6 cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl and 5-6 membered heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 R c substituents.

[0235] In an optional embodiment of the application, R 31 and R 32 are each independently H, F, Cl, Br, CN, C 1-3 alkyl, -S(=0)2-NR e3 R e4 , -S(=0)-R e5 , -S(=0)2-R e6 , -S(=0)(=NR e7 )-R e8 , -C(=0)-NR e3 R e4 , -C(=0)-R e5 , -NR e3 -C(=0)-C 1-3 alkyl, C 1-3 alkoxy, or C 1-3 alkylamino, said C 1-3 alkyl, -S(=0)2-NR e3 R e4 , -S(=0)-R e5 , -S(=0)2-R e6 , -S(=0)(=NR e7 )-R e8 , -C(=0)-NR e3 R e4 , -C(=0)-R e5 , -NR e3 -C(=0)-C 1-3 alkyl, C 1-3 alkoxy, and C 1-3 alkylamino are each independently optionally substituted with 1, 2, 3, or 4 Rc replace.

[0236] In an optional embodiment of the present invention, R 31 and R 32 They are H, F, Cl, Br, CN, and C, respectively. 1-3 Alkyl group, -S(=O)2-NR e3 R e4 -S(=O)-R e5 -C(=O)-NR e3 R e4 -C(=O)-R e5 -NR e3 -C(=O)-C 1-3 Alkyl, C 1-3 Alkoxy or C 1-3 Alkylamino, the C 1-3 Alkyl group, -S(=O)2-NR e3 R e4 -S(=O)-R e5 -C(=O)-NR e3 R e4 -C(=O)-R e5 -NR e3 -C(=O)-C 1-3 Alkyl, C 1-3 Alkoxy and C 1- The 3 alkylamino groups are independently and optionally surrounded by 1, 2, 3 or 4 R groups. c replace.

[0237] In an optional embodiment of the present invention, R 31 For H, F, Cl, Br, CN, C 1-3 Alkyl, C 1-3 Alkoxy or C 1-3 Alkylamino, the C 1-3 Alkyl, C 1-3 Alkoxy and C 1-3 Alkylamino groups are independently and optionally surrounded by 1, 2, 3 or 4 R groups. c replace.

[0238] In an optional embodiment of the present invention, R 31 It can be H, F, methyl, ethyl, or propyl.

[0239] In an optional embodiment of the present invention, R 31 It can be H, methyl, ethyl, or propyl.

[0240] In an optional embodiment of the present invention, R 32 For H, F, Cl, Br, CN, C 1-3 Alkyl group, -S(=O)2-NRe3 R e4 -S(=O)-R e5 -S(=O)2-R e6 -S(=O)(=NR) e7 )-R e8 -C(=O)-NR e3 R e4 -C(=O)-R e5 or -NR e3 -C(=O)-C 1-3 Alkyl, the C 1-3 Alkyl group, -S(=O)2-NR e3 R e4 -S(=O)-R e5 -S(=O)2-R e6 -S(=O)(=NR) e7 )-R e8 -C(=O)-NR e3 R e4 -C(=O)-R e5 and -NR e3 -C(=O)-C 1-3 Alkyl groups are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. c replace.

[0241] In an optional embodiment of the present invention, R 32 For H, F, Cl, Br, CN, C 1-3 Alkyl group, -S(=O)2-NR e3 R e4 -S(=O)-R e5 -C(=O)-NR e3 R e4 -C(=O)-R e5 or -NR e3 -C(=O)-C 1-3 Alkyl, the C 1-3 Alkyl group, -S(=O)2-NR e3 R e4 -S(=O)-R e5 -C(=O)-NR e3 R e4 -C(=O)-R e5 and -NR e3 -C(=O)-C 1-3 Alkyl groups are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. c replace.

[0242] In an optional embodiment of the present invention, R 32-S(=O)2-NR e3 R e4 -S(=O)2-R e6 -S(=O)(=NR e7 )-R e8 -C(=O)-NR e3 R e4 -S(=O)2-NR e3 R e4 -S(=O)2-R e6 -S(=O)(=NR e7 )-R e8 -C(=O)-NR e3 R e4 are each independently optionally substituted with 1, 2, 3, or 4 R c .

[0243] In an optional embodiment of the application, each R e3 and R e4 is independently H or C 1-3 alkyl.

[0244] In an optional embodiment of the application, each R e3 and R e4 is independently H, methyl, ethyl, or propyl.

[0245] In an optional embodiment of the application, each R e5 and R e8 is independently H, OH, C 1-3 alkyl, or C 3-6 cycloalkyl.

[0246] In an optional embodiment of the application, each R e5 is independently H, OH, C 1-3 alkyl, or C 3-6 cycloalkyl.

[0247] In an optional embodiment of the application, each R e5 and R e8 is independently H, OH, methyl, ethyl, or cyclopropyl.

[0248] In an optional embodiment of the application, each R e5 is independently H, OH, methyl, ethyl, or cyclopropyl.

[0249] In an optional embodiment of the application, each R e6 is independently H, C 1-3 alkyl, C 3-6 cycloalkyl, or 4-membered heterocycloalkyl.

[0250] In an optional embodiment of the application, each R e6 is independently H, methyl, ethyl, cyclopropyl or

[0251] In an optional embodiment of the application, each R e7 is independently H, CN or C 1-3 alkyl.

[0252] In an optional embodiment of the application, each R e7 is independently CN.

[0253] In an optional embodiment of the application, each R c is independently H, F, Cl, Br, OH, NH2, CN or COOH.

[0254] In an optional embodiment of the application, R 32 is -S(=O)2-NR e3 R e4 .

[0255] In an optional embodiment of the application, R 32 is -S(=O)2-N(CH3)2, -C(=O)-N(CH3)2, -S(=O)2-CH3, -S(=O)(=N-CN)-CH3 or

[0256] In an optional embodiment of the application, R 32 is -S(=O)2-N(CH3)2.

[0257] In an optional embodiment of the application, R 31 is H or F, and R 32 is -S(=O)2-CH3.

[0258] In an optional embodiment of the application, the compound of formula (I) has the structural formula (I-A):

[0259] wherein,

[0260] R x1 , R x3 , X4, R 11 , R 12 , R2, R 31 , R 32 and p are as defined in the application.

[0261] In an optional embodiment of the application, the compound of formula (I) has the structural formula (I-AA):

[0262] in,

[0263] q is 1, 2, 3, or 4;

[0264] R m R x3 X4, R 11 R 12 R2, R 31 and R 32 As defined in this invention.

[0265] In an optional embodiment of the present invention, the compound represented by formula (Ⅰ) has the structural formula (Ⅰ-AA1):

[0266] in,

[0267] q is 1, 2, 3, or 4;

[0268] R m R x3 X4, R 11 R 12 R2, R 31 and R 32 As defined in this invention. In an optional embodiment of this invention, the compound represented by formula (I) has the structural formula (I-1):

[0269] in,

[0270] R x1 R x3 X4, R 11 R 12 R2, R 31 R 32 p is as defined in this invention.

[0271] In an optional embodiment of the present invention, the compound represented by formula (I) has structural formula (I-2):

[0272] in,

[0273] q is 1, 2, 3, or 4;

[0274] R m R x3 X4, R 11 R 12 R2, R 31 R e3 and R e4 As defined in this invention.

[0275] In an optional embodiment of the present invention, the compound represented by formula (I) has structural formula (I-3):

[0276] wherein

[0277] q is 1, 2, 3, or 4;

[0278] R m , R x3 , X4, R 11 , R 12 , R2, R 31 , and R e6 are as defined herein.

[0279] In an optional embodiment of the application, the compound of formula (I) has the structural formula (I-4):

[0280] wherein

[0281] q is 1, 2, 3, or 4;

[0282] w is 1, 2, 3, or 4;

[0283] R m , R x3 , R 11 , R 12 , R2, R 31 , R e6 , ring A, and R y are as defined herein.

[0284] In an optional embodiment of the application, R 31 is H, halogen, or C 1-6 alkyl.

[0285] In an optional embodiment of the application, R 31 is H or F.

[0286] In an optional embodiment of the application, R m is H.

[0287] In an optional embodiment of the application, ring A is

[0288] In an optional embodiment of the application, each R y is independently H, OH, oxo (=0), methyl, -CHF2, -S(=0)2-CH3, -S(=0)2-NH(CH3), or -S(=0)2-CH2-CH2(OH).

[0289] In an optional embodiment of the application, the compound of formula (I) has the structural formula (I-2A):

[0290] wherein

[0291] q is 1, 2, 3, or 4;

[0292] R 11 is halogen, OH, NH2, CN, COOH, C 1-6 alkyl, C 3-8 cycloalkyl, 5-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkenyl, each of which is independently optionally substituted with 1, 2, 3, or 4 R 1- 6alkyl, C 3-8 cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heterocycloalkenyl is independently optionally substituted with 1, 2, 3, or 4 R a substituents;

[0293] each R a is independently H, halogen, OH, NH2, CN, =O, COOH, or C 1-6 alkyl;

[0294] R m , R x3 , X4, R 12 , R2, R 31 , R e3 , and R e4 are as defined herein.

[0295] In an optional embodiment of the application, the compound of formula (I) has the structural formula (I-2A):

[0296] wherein,

[0297] q is 1, 2, 3, or 4;

[0298] R m , R x3 , X4, R 11 , R 12 , R2, R 31 , R e3 , and R e4 are as defined herein.

[0299] In an optional embodiment of the application, the compound of formula (I) has the structural formula (I-3A):

[0300] wherein,

[0301] q is 1, 2, 3, or 4;

[0302] R m , R x3 , X4, R 11 , R 12 , R2, R 31 , and R e6As defined in this invention.

[0303] In an optional embodiment of the present invention, the compound represented by formula (Ⅰ) has the structural formula (Ⅰ-4A):

[0304] in,

[0305] q is 1, 2, 3, or 4;

[0306] w is 1, 2, 3, or 4;

[0307] R m R x3 R 11 R 12 R2, R 31 R e6 Ring A and R y As defined in this invention.

[0308] In an optional embodiment of the present invention, R 11 Halogen, OH, NH2, CN, COOH, C 1-3 Alkyl or C 3-6 cycloalkyl, the C 1- 3-alkyl and C 3-6 The cycloalkyl groups are each independently and optionally marked with 1, 2, 3 or 4 R's. a replace.

[0309] In an optional embodiment of the present invention, R 11 The radicals are F, Cl, Br, OH, NH2, CN, COOH, methyl, ethyl, propyl, cyclopropyl, or cyclobutyl, wherein the methyl, ethyl, propyl, cyclopropyl, and cyclobutyl groups are each independently and optionally converted by 1, 2, 3, or 4 R radicals. a replace.

[0310] In an optional embodiment of the present invention, each R a They can be H, F, Cl, Br, OH, NH2, CN, =O or COOH, respectively.

[0311] In an optional embodiment of the present invention, R 11 Cyclopropyl or

[0312] In an optional embodiment of the present invention, R m For H.

[0313] In an optional embodiment of the present invention, ring A is...

[0314] In an optional embodiment of the present invention, each R yindependently H, OH, oxo (=0), methyl, -CHF2, -S(=0)2-CH3, -S(=0)2-NH(CH3), or -S(=0)2-CH2-CH2(OH).

[0315] In an optional embodiment of the application, the compound of formula (I) has the structural formula (I-5):

[0316] wherein,

[0317] q is 1, 2, 3, or 4;

[0318] R ee is -C 0-6 alkylene-S(=0)2-R ee1 , -C 0-6 alkylene-5-10 membered heteroaryl or ring A, said R ee is optionally substituted with 1, 2, 3, or 4 R y ;

[0319] R 31 is H, halogen, or C 1-6 alkyl;

[0320] R m , R x3 , R 11 , R 12 , R2, R e6 , R ee1 , ring A, and R y are as defined in the application.

[0321] In an optional embodiment of the application, -C 0-6 alkylene-S(=0)2-R ee1 , -C 1-6 alkylene-5-10 membered heteroaryl or ring A, said R ee is optionally substituted with 1, 2, 3, or 4 R y .

[0322] In an optional embodiment of the application, R ee is -C 0-3 alkylene-S(=0)2-R ee1 , -C 0-3 alkylene-5-6 membered heteroaryl or ring A, said R ee is optionally substituted with 1, 2, 3, or 4 R y .

[0323] In an optional embodiment of the application, R ee is -C 0-3 alkylene-S(=0)2-R ee1 , -C1-3 alkylene-5-6 membered heteroaryl or ring A, said R ee is optionally substituted with 1, 2, 3, or 4 R y substituents.

[0324] In an optional embodiment of the application, R 31 is H or F;

[0325] In an optional embodiment of the application, the compound of formula (I) has the structural formula (I-6):

[0326] wherein,

[0327] q is 1, 2, 3, or 4;

[0328] R 31 is halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, or C 3-8 cycloalkyl, said C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, and C 3-8 cycloalkyl are each independently optionally substituted with 1, 2, 3, or 4 R c substituents;

[0329] R x5 is H, halogen, OH, NH2, CN, COOH, or C 1-6 alkyl, said C 1-6 alkyl is optionally substituted with 1, 2, 3, or 4 R y substituents;

[0330] R m , R x3 , X4, R 11 , R 12 , R2, R e6 , R c , and R y are as defined in the application.

[0331] In an optional embodiment of the application, R 31 is F, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, or C 3-6 cycloalkyl, said C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, and C 3-6 cycloalkyl are each independently optionally substituted with 1, 2, 3, or 4 R c substituents.

[0332] In an alternative embodiment of the application, R 31 is F or methyl.

[0333] In an alternative embodiment of the application, R x5 is H or NH2.

[0334] In an alternative embodiment of the application, the compound of formula (I) has the structural formula (I-7):

[0335] wherein,

[0336] q is 1, 2, 3 or 4;

[0337] R x4 is C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylamino or C 3-8 cycloalkyl, said C 1-6 haloalkyl, C 2- 6alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylamino or C 3-8 cycloalkyl is each independently optionally substituted with 1, 2, 3 or 4 R y , R m , R x3 , R 11 , R 12 , R2, R e6 and R y are as defined in the application.

[0338] In an alternative embodiment of the application, R x4 is -CF3, vinyl, ethynyl or methoxy.

[0339] In an alternative embodiment of the application, the compound of formula (I) has the structural formula (I-8):

[0340] wherein,

[0341] q is 1, 2, 3 or 4;

[0342] R e6 is 4-membered heterocycloalkyl or 4-membered heterocycloalkenyl, said R e6 is optionally substituted with 1, 2, 3 or 4 R c ;

[0343] R m , R x3 , R11 , R 12 , R2and R c as defined herein.

[0344] In an optional embodiment of the application, R e6 is

[0345] In an optional embodiment of the application, the compound of formula (I) has the structural formula (I-5A):

[0346] wherein,

[0347] q is 1, 2, 3 or 4;

[0348] R ee is -C 0-6 alkylene-S(=0)2-R ee1 , -C 0-6 alkylene-5-10 membered heteroaryl or ring A, said R ee is optionally substituted with 1, 2, 3 or 4 R y ;

[0349] R 31 is H, halogen or C 1-6 alkyl;

[0350] R m , R x3 , R 11 , R 12 , R2, R e6 , R ee1 , ring A and R y are as defined herein.

[0351] In an optional embodiment of the application, R ee is -C 0-6 alkylene-S(=0)2-R ee1 , -C 1-6 alkylene-5-10 membered heteroaryl or ring A, said R ee is optionally substituted with 1, 2, 3 or 4 R y .

[0352] In an optional embodiment of the application, the compound of formula (I) has the structural formula (I-6A):

[0353] wherein,

[0354] q is 1, 2, 3 or 4;

[0355] R 31 is halogen, C 1-6 alkyl, C1-6 Alkoxy, C 1-6 Alkylamino or C 3-8 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino and C 3-8 The cycloalkyl groups are each independently and optionally marked with 1, 2, 3 or 4 R groups. c replace;

[0356] R x5 It can be H, halogen, OH, NH2, CN, COOH or C 1-6 Alkyl, the C 1-6 Alkyl groups are optionally surrounded by 1, 2, 3 or 4 R's. y replace;

[0357] R m R x3 X4, R 11 R 12 R2, R e6 R c and R y As defined in this invention.

[0358] In an optional embodiment of the present invention, the compound represented by formula (Ⅰ) has the structural formula (Ⅰ-7A):

[0359] in,

[0360] q is 1, 2, 3, or 4;

[0361] R x4 C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylamino or C 3-8 cycloalkyl, the C 1-6 Haloalkyl, C 2- 6-alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylamino or C 3-8 The cycloalkyl groups are each independently and optionally marked with 1, 2, 3 or 4 R groups. y replace;

[0362] R m R x3 R 11 R 12 R2, R e6 and R y As defined in this invention.

[0363] In an optional embodiment of the present application, the compound of formula (I) has the structural formula (I-8A):

[0364] wherein,

[0365] q is 1, 2, 3, or 4;

[0366] R e6 is 4-membered heterocycloalkyl or 4-membered heterocycloalkenyl, said R e6 is optionally substituted with 1, 2, 3, or 4 R c ;

[0367] R m , R x3 , R 11 , R 12 , R2, and R c are as defined in the present application.

[0368] In an optional embodiment of the present application, R x5 is not H.

[0369] In an optional embodiment of the present application, when R x5 is H, R 31 and R 32 are not H.

[0370] In an optional embodiment of the present application, when R x5 is H, R 31 is F, and R 32 is -S(=O)2-CH3.

[0371] In an optional embodiment of the present application, the compound of formula (I) is not

[0372] In an optional embodiment of the present application, the compound is selected from any one of the following compounds or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof:

[0373] In an optional embodiment of the present application, the compound is selected from any one of the following compounds or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof:

[0374] In another aspect of the present application, the present application provides a method for preparing an intermediate compound of formula (II) or a salt thereof,

[0375] The method comprises:

[0376] S1, reacting a compound of formula (III) with a compound of formula (IV) to form a compound of formula (V):

[0377] wherein R6 is C 3-8 cycloalkyl or C 6-10 aryl, said C 3-8 cycloalkyl and C 6-10 aryl are each independently optionally substituted with 1, 2, 3 or 4 R f ;

[0378] R7 and R8 are each independently C 1-6 alkyl or C 3-8 cycloalkyl, said C 1-6 alkyl and C 3-8 cycloalkyl are each independently optionally substituted with 1, 2, 3 or 4 R g ;

[0379] each R f and R g is independently H, halogen, OH, NH2, CN, COOH or C 1-6 alkyl.

[0380] In an optional embodiment of the present application, the reaction in S1 of the above preparation method is carried out in the presence of a catalyst.

[0381] In an optional embodiment of the present application, the catalyst in S1 of the above preparation method is a palladium catalyst.

[0382] In an optional embodiment of the present application, the palladium catalyst in S1 of the above preparation method is Pd(PPh3)4, Pd2dba3 or Pd(OAc)2.

[0383] In an optional embodiment of the present application, the solvent used in the reaction in S1 of the above preparation method is dioxane, tetrahydrofuran or toluene.

[0384] In an optional embodiment of the present application, the reaction temperature of the reaction in S1 of the above preparation method is 40-150°C.

[0385] In an optional embodiment of the present application, the reaction temperature of the reaction in S1 of the above preparation method is 80-120°C.

[0386] In an optional embodiment of the present application, the reaction temperature of the reaction in S1 of the above preparation method is 100°C.

[0387] In an optional embodiment of the present application, the above preparation method further comprises:

[0388] S2, reacting the compound shown in formula (V) with an acid to generate a compound shown in formula (VI):

[0389] wherein R6, R7 and R8 are defined as in the above preparation method.

[0390] In an optional embodiment of the present application, the acid in S2 of the above preparation method is hydrochloric acid or trifluoroacetic acid.

[0391] In an optional embodiment of the present application, the above preparation method further comprises:

[0392] S3, reacting the compound shown in formula (VI) with a fluorinating agent to generate a compound shown in formula (II):

[0393] wherein R6 and R7 are defined as in the above preparation method.

[0394] In an optional embodiment of the present application, the fluorinating agent in S3 of the above preparation method is diethylaminosulfur trifluoride or bis(2-methoxyethyl)aminosulfur trifluoride.

[0395] In an optional embodiment of the present application, the compound shown in formula (III) is obtained by reacting the compound shown in formula (VII) with R6-ONa to generate a compound shown in formula (III):

[0396] wherein R6 and R7 are defined as in the above preparation method.

[0397] In an optional embodiment of the present application, R6 is phenyl.

[0398] In an optional embodiment of the present application, R7 is ethyl.

[0399] In an optional embodiment of the present application, R8 is ethyl, propyl, n-butyl, isobutyl or cyclohexyl.

[0400] In an optional embodiment of the present application, R8 is ethyl or n-butyl.

[0401] In an optional embodiment of the present application, R8 is ethyl.

[0402] In a second aspect of the present application, the present application provides a pharmaceutical composition comprising the compound of the first aspect described above, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof.

[0403] In an optional embodiment of the present application, the pharmaceutical composition described above further comprises a pharmaceutically acceptable carrier or excipient.

[0404] In a third aspect of the present application, the compound of the first aspect described above, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition of the second aspect of the present application, is used as a medicament for inhibiting WRN and / or treating a WRN-related disease.

[0405] The use of the compound of the first aspect described above, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition of the second aspect of the present application, comprises:

[0406] inhibiting WRN; and / or,

[0407] treating a WRN-related disease.

[0408] The use of the compound of the first aspect described above, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition of the second aspect of the present application, comprises:

[0409] preparing a medicament for treating a WRN-related disease; and / or,

[0410] preparing a WRN inhibitor.

[0411] In an optional embodiment of the present application, the WRN-related disease comprises a microsatellite instability-high or mismatch repair gene-deficient solid tumor.

[0412] In a fourth aspect of the present application, the present application provides a method for inhibiting WRN, comprising: introducing the compound of the first aspect described above, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition of the second aspect described above, into a cell.

[0413] In an optional embodiment of the present application, the WRN-related disease comprises a microsatellite instability-high or mismatch repair gene-deficient solid tumor.

[0414] In a fifth aspect, the present application provides a method for treating a WRN-related disease, comprising: administering to a subject a pharmaceutically acceptable dose of the compound of the first aspect or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition of the second aspect.

[0415] In an optional embodiment of the present application, the WRN-related disease comprises a microsatellite instability-high or mismatch repair gene-deficient solid tumor.

[0416] Terms and definitions

[0417] Unless otherwise indicated, the terms and definitions recited in the present application, including the specification and claims of the present application, are as follows.

[0418] As understood by one skilled in the art, in the structural formulae of the present application, are used to depict the point of attachment of a moiety or substituent to the core structure or backbone structure. As used herein, "R1", "R1", and "R 1 " have the same meaning and are interchangeable with each other. Similar definitions apply to other symbols such as R2, etc.

[0419] Unless otherwise specified, the term "pharmaceutically acceptable" pertains to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0420] Unless otherwise specified, the term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable, nontoxic acid or base salt, including salts of inorganic acids and bases, salts of organic acids and bases.

[0421] In addition to pharmaceutically acceptable salts, other salts are also contemplated. They can serve as intermediates in the purification of the compounds or in the preparation of other pharmaceutically acceptable salts, or they can be useful in the identification, characterization, or purification of the compounds of the present application.

[0422] Unless otherwise specified, the term "pharmaceutical composition" denotes a mixture of one or more of the compounds described herein or physiologically / pharmaceutically acceptable salts or prodrugs thereof with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The objective of a pharmaceutical composition is to facilitate administration of the compound to an organism.

[0423] The term "excipient" is meant to include any ingredient other than the active compound(s) of the drug. Examples of classes of excipients include binders, disintegrants, lubricants, glidants, stabilizers, fillers, and diluents, among others. Excipients can enhance the handling properties of a pharmaceutical formulation, i.e., make the formulation more amenable to direct compression by increasing flow and / or cohesion.

[0424] The term "prodrug" means a compound which can be converted under physiological conditions or by solvoiytic cleavage to provide a biologically or pharmaceutically active compound of the application. Prodrugs of the application are prepared by modifying functional groups in such a way that their solubility characteristics are altered but undergo in vivo conversion to the parent compound. Prodrugs include compounds of the application wherein a hydroxy or amino group is bonded to any group that, when administered to a mammalian subject, is cleaved to form a free hydroxyl or aminogroup.

[0425] The term "stereoisomers" means isomers that have the same molecular formula but different structures, resulting from the spatial arrangement of the atoms. Stereoisomers include enantiomeric or optical isomers, diastereomeric isomers, and conformational isomers.

[0426] Depending on the choice of raw materials and methods, the compounds of the application can be present in the form of one or more of the possible isomers or as a mixture of isomers, for example, as pure optical isomers, or as a mixture of isomers, such as, for example, as racemic mixtures, or as mixtures of diastereoisomers, depending on the number of asymmetric carbon atoms. When describing compounds having optical activity, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to one chiral center (or multiple chiral centers) in the molecule. The prefixes D and L or (+) and (-) are used to designate the optical rotation of a compound, where (-) or L indicates that the compound is levorotatory. A compound with the prefix (+) or D is dextrorotary. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers are also referred to as enantiomers, and mixtures of such isomers are often referred to as enantiomeric mixtures. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which can occur when there has been no stereo selection or stereo specificity in a chemical reaction or process. Many geometric isomers of olefins, C=N double bonds, and the like can also exist; all such stable isomers are contemplated in the present application. When the compounds described herein contain olefinic double bonds, unless otherwise specified, these double bonds are understood to include both E and Z geometric isomers. If compounds contain diastereomeric ring alkyl groups, the substituents can be in the cis- or trans- (or "s" or "t") configuration.

[0427] When bonds to chiral carbons in the formulas of the application are depicted as lines, it is understood that both the (R) and (S) configurations of the chiral carbons and the enantiomerically pure compounds and mixtures resulting therefrom are included within the scope of the general formulas. The graphic representation of racemates or enantiomerically pure compounds herein is from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated, the absolute configuration of a stereogenic center is represented by a wedge and dashed line bond.

[0428] The optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Compounds of the application containing asymmetrically substituted carbon atoms can be isolated in optically active form or as racemates. Resolution of racemic mixtures of the compounds can be achieved by any of a number of methods known in the art. Exemplary methods include fractional crystallization using chiral resolving acids, which are optically active, salt-forming organic acids. Suitable resolving agents for fractional crystallization procedures are, for example, the optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, binolyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids. Other resolving agents suitable for fractional crystallization procedures include the stereoisomerically pure forms of α-methyl- benzylamine (e.g., the S and R forms or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like. Resolution of racemic mixtures can also be achieved by elution of a chromatography column packed with an optically active resolving agent (e.g., a dinitrobenzoylphenylglycine). Resolution can be achieved using high performance liquid chromatography (HPLC) or supercritical fluid chromatography (SFC). The choice of the particular method and elution conditions, as well as the choice of the chromatography column, can be selected by one skilled in the art based on the structure of the compound and the results of the test. Further, any enantiomer or diastereomer of a compound described herein can be obtained by stereochemically organized synthesis using optically pure starting materials or reagents of known configuration.

[0429] The term "tautomers" refers to isomers that differ in the position of a proton, unless otherwise specified. Compounds of the application can exhibit tautomerism. Tautomeric compounds can exist in two or more interconvertible forms. Proton- shifting tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in an equilibrium, and attempts to isolate a single tautomer usually result in a mixture whose physical and chemical properties are consistent with mixtures of compounds. The position of equilibrium depends on the chemical environment within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates; in phenols, the enol form predominates. The present application includes all tautomeric forms of the compounds.

[0430] In examples of the present application, the proton can occupy two or more positions in a cyclic form of the heterocyclic ring system, for example, 1H- and 3H-imidazole, 1H-, 2H-, and 4H-1,2,4-triazole, 1H- and 2H-isoindole, tetrazole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or spatially fixed in one form by appropriate substitution. For example:

[0431] Unless otherwise indicated, the term "wedge" is used to represent a solid line bond and a dashed line bond is used to represent the absolute configuration of a stereocenter, and the term "straight" is used to represent a solid line bond and a dashed line bond is used to represent the relative configuration of a stereocenter.

[0432] Unless otherwise specified, the term "solvate" means a compound of the present application or a salt thereof, including a stoichiometric or non-stoichiometric amount of solvent, when the solvent is water, then a hydrate.

[0433] The compounds of the present application can contain unnatural proportions of atomic isotopes at one or more of the atoms in a compound, for example, deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). All isotopic variations of the compounds of the present application, whether radioactive or not, are encompassed within the scope of the present application.

[0434] The term "effective amount" or "therapeutically effective amount" with respect to a pharmaceutical or pharmacological agent means a sufficient amount of the agent to provide the desired effect, without being toxic to the recipient. For oral dosage forms of the present application, an "effective amount" of one active agent in a composition means the amount needed to achieve the desired effect in conjunction with another active agent in the composition. The determination of an effective amount is dependent on the age and general condition of the recipient, as well as the particular active agent, and an effective amount for a particular case can be determined by one of ordinary skill in the art using routine testing.

[0435] The term "active ingredient", "therapeutic agent", "active agent" or "active agent" means a chemical entity that is effective in treating a disorder, disease or condition of interest, unless otherwise specified.

[0436] The term "substituted," unless otherwise specified, means that any one or more hydrogen atoms on the designated atom is replaced with a substituent group, including heavy isotopes and variations of hydrogen, as long as the valency of the designated atom is not changed. When the substituent is a keto group (i.e., =0), it means that two hydrogen atoms are replaced. Keto substitution does not occur on aromatic groups.

[0437] The term "optionally" or "optional," unless otherwise specified, means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0438] The term "optionally substituted," "optionally substituted with," or "optionally substituted by," unless otherwise specified, means that the group can or can not be substituted and that the type and number of substituents, unless otherwise specified, can be any chemically possible groups and number.

[0439] When any variable (e.g., R) occurs more than one time in a compound or substituent, its definition in each instance is independent of the definition of the other. Thus, for example, if a group is substituted with 0-2 R groups, then the group can optionally be substituted with up to two R groups, and each R group is selected independently of the other. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. In addition, when a multiple ring (fused, spiro, or bridged) is substituted with a substituent, it is intended that each ring in the multiple ring system can be independently substituted with the substituent.

[0440] The term "alkyl," unless otherwise specified, represents a straight or branched chain monovalent hydrocarbon group containing from 1 to 20 carbon atoms, wherein the alkyl group can optionally be substituted with one or more substituents described herein. In some embodiments, the alkyl group contains 1-20 carbon atoms (C 1-20 ). In some embodiments, the alkyl group contains 1-12 carbon atoms (C 1-12 ). In some embodiments, the alkyl group contains 1-10 carbon atoms (C 1-10 ). In some embodiments, the alkyl group contains 1-6 carbon atoms (C 1-6 ). In some embodiments, the alkyl group contains 1-3 carbon atoms (C 1-3Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, t-butyl, isopentyl, 2-methylbutyl, 1- methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4- methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1- ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, 1,2-dimethylbutyl, and the like.

[0441] In the present application, the term "C α-β "alkyl" means an alkyl group containing a minimum of a and a maximum of β carbon atoms, wherein a and β represent an integer, which can also be indicated in the form "C α -C β alkyl" groups. A Co alkyl group represents a direct bond.

[0442] Unless otherwise specified, the term "alkenyl" means a straight or branched chain monovalent hydrocarbon group of from 2 to 12 carbon atoms containing at least one site of 2 double bond, wherein the alkenyl group can optionally be substituted with one or more substituents described herein, including "cis" and "trans" positioning, or "E" and "Z" positioning. In some embodiments, the alkenyl group contains from 2 to 12 carbon atoms (C 2-12 ). In some embodiments, the alkenyl group contains from 2 to 8 carbon atoms (C 2-8 ). In some embodiments, the alkenyl group contains from 2 to 6 carbon atoms (C 2-6 ). In some embodiments, the alkenyl group contains from 2 to 4 carbon atoms (C 2-4 ). Examples of alkenyl groups include, but are not limited to, ethenyl (-CH=CH2), allyl (-CH2CH=CH2), and the like.

[0443] Unless otherwise specified, the term "alkynyl" means a straight or branched chain monovalent hydrocarbon group of from 2 to 12 carbon atoms containing at least one site of 2-12 unsaturation, i.e., one carbon-carbon sp triple bond, wherein the alkynyl group can optionally be substituted with one or more substituents described herein. In some embodiments, the alkynyl group contains from 2 to 12 carbon atoms (C 2-8 ). In some embodiments, the alkynyl group contains from 2 to 8 carbon atoms (C 2-6 ). In some embodiments, the alkynyl group contains from 2 to 6 carbon atoms (C 2-4 . In some embodiments, the alkynyl group contains from 2 to 4 carbon atoms (CExamples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propynyl (-CH2C≡CH), 1-propynyl (-C≡C-CH3), and the like.

[0444] Unless otherwise specified, the term "alkylene" denotes a saturated, divalent hydrocarbon radical resulting from the removal of two hydrogen atoms from a saturated, straight- chain or branched-chain hydrocarbon group, wherein the alkylene group can be optionally substituted with one or more substituents described herein. In some embodiments, the alkylene group contains 1-12 carbon atoms (C1-C12alkylene). 1-12 In some embodiments, the alkylene group contains 1-6 carbon atoms (C1-C6alkylene). 1-10 In some embodiments, the alkylene group contains 1-6 carbon atoms (C1-C6alkylene). 1-6 In some embodiments, the alkylene group contains 1-4 carbon atoms (C1-C4alkylene). 1-4 In some embodiments, the alkylene group contains 1-3 carbon atoms (C1-C3alkylene). 1-3 In some embodiments, the alkylene group contains 1-2 carbon atoms (C1-C2alkylene). 1-2 Examples of alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), isopropylene (-CH(CH3)CH2-), and the like.

[0445] Unless otherwise specified, the term "alkoxy" denotes an alkyl group attached to the remainder of the molecule through an oxygen atom, or denotes an alkyl-O-alkyl group, the oxygen atom can be attached to any one of the carbon atoms of the alkyl group in either straight or branched chain, wherein alkyl has the meaning as described herein. In some embodiments, the alkoxy group contains 1-12 carbon atoms (C1-C12alkoxy). 1-12 In some embodiments, the alkoxy group contains 1-6 carbon atoms (C1-C6alkoxy). 1-6 In some embodiments, the alkoxy group contains 1-4 carbon atoms (C1-C4alkoxy). 1-4 In some embodiments, the alkoxy group contains 1-3 carbon atoms (C1-C3alkoxy). 1-3 The alkoxy group can be optionally substituted with one or more substituents described herein. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, 2-methyl-2-propoxy, 1-pentoxy, 2-pentoxy, 3-pentoxy, 2-methyl-2-butoxy, 3-methyl-2-butoxy, 3-methyl-l-butoxy, 2-methyl-l-butoxy, CH3-O-CH2-, and the like.

[0446] Unless otherwise specified, the term "alkylamino" means an alkyl group attached to the remainder of the molecule through an amino group, wherein alkyl has the meaning as described herein. In some embodiments, the alkylamino group contains 1 to 12 carbon atoms (C 1-12 ). In some embodiments, the alkylamino group contains 1 to 6 carbon atoms (C 1-6 ). In some embodiments, the alkylamino group contains 1 to 4 carbon atoms (C 1-4 ). In some embodiments, the alkylamino group contains 1 to 3 carbon atoms (C 1-3 ). The alkylamino group can optionally be substituted with one or more substituents described herein. Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -NHCH2CH2CH3, -NHCH(CH3)2, -NHCH2CH(CH3)2, and the like.

[0447] Unless otherwise specified, the term "haloalkyl", "haloalkenyl", or "haloalkoxy" means an alkyl, alkenyl, or alkoxy group substituted with one or more halogen atoms. Examples include, but are not limited to, trifluoromethyl, trifluoromethoxy, and the like.

[0448] Unless otherwise specified, the term "cycloalkyl" means a monovalent or multivalent saturated monocyclic, bicyclic, or tricyclic ring system containing 3 to 12 carbon atoms, wherein the bicyclic or tricyclic ring system includes spiro, fused, and bridged rings. In some embodiments, the cycloalkyl group contains 3 to 12 carbon atoms (C 3-12 ). In some embodiments, the cycloalkyl group contains 3 to 8 carbon atoms (C 3-8 ). In some embodiments, the cycloalkyl group contains 3 to 6 carbon atoms (C 3-6 ). The cycloalkyl group can be independently unsubstituted or substituted with one or more substituents described herein. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2]bicyclooctane, and the like.

[0449] Unless otherwise specified, the term "bridged cycloalkyl" refers to a saturated bicyclic or polycyclic cyclic hydrocarbon substituent formed by the connection of two or more cyclic structures through the sharing of two non-adjacent ring atoms, all of which are C. Examples of bridged cycloalkyl groups include, but are not limited to, and the like.

[0450] Unless otherwise specified, the term "cycloalkenyl" means a monovalent or multivalent non-aromatic unsaturated monocyclic, bicyclic, or tricyclic ring system containing 3 to 12 carbon atoms. In some embodiments, the cycloalkenyl group contains 3 to 12 carbon atoms (C 3-12). In some embodiments, the cycloalkenyl group comprises 3-8 carbon atoms (C 3-8 ). In some embodiments, the cycloalkenyl group comprises 3-6 carbon atoms (C 3-6 ). The cycloalkenyl group can be independently unsubstituted or substituted with one or more substituents described herein. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, cyclooctenyl, cyclopentadienyl, and the like.

[0451] Unless otherwise specified, the term "aryl" means a monocyclic, bicyclic and tricyclic carbocyclic ring system containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system contains 3-7 atoms in a ring, and has one or more points of attachment to the rest of the molecule. In some embodiments, the aryl group comprises 6-14 carbon atoms (C 6-14 ). In some embodiments, the aryl group comprises 6-12 carbon atoms (C 6-12 ). In some embodiments, the aryl group comprises 6-10 carbon atoms (C 6-10 ). The aryl group can be independently unsubstituted or substituted with one or more substituents described herein. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, and the like.

[0452] Unless otherwise specified, Cn-n+m or Cn-Cn+m includes any one particular case of n to n+m carbons, for example C 1-12 includes C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , and C 12 also includes any one range of n to n+m, for example C 1-12 includes C 1- 3, C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 and so on; likewise, n-membered to n+m-membered means the number of atoms in a ring is n to n+m, for example 3-12 membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, and 12-membered ring, also includes any one range of n to n+m, for example 3-12 membered ring includes 3-6 membered ring, 3-9 membered ring, 5-6 membered ring, 5-7 membered ring, 6-7 membered ring, 6-8 membered ring, and 6-10 membered ring, and so on.

[0453] Unless otherwise specified, the terms "heteroaryl," "heteroaromatic," or "heteroaromatic ring" are used interchangeably and mean a monocyclic, bicyclic, or polycyclic ring system containing 5 to 12 ring atoms, at least one ring system having aromaticity, preferably 5 to 10 ring atoms, more preferably 5 to 6 ring atoms, wherein 1, 2, 3, or more ring atoms are heteroatoms and the remainder are carbon, the heteroatoms being independently selected from O, N, or S, preferably 1, 2, or 3 in number, wherein a N or S ring atom can optionally be oxidized to form an N-oxide (e.g., NO) or S-oxide (e.g., S(O) p , p is 1 or 2), and a N ring atom can optionally be quaternized. The "heteroaryl," "heteroaromatic," or "heteroaromatic ring" is optionally substituted with one or more substituents described herein. Examples of "heteroaryl," "heteroaromatic," and "heteroaromatic ring" include, but are not limited to, 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thiophenyl, 3-thiophenyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyrazinyl, 1,3,5-triazinyl; and also bicyclic rings, but not limited to these: benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl), imidazo[l,2-a]pyridinyl, pyrazolo[l,5-a]pyridinyl, pyrazolo[l,5-a]pyrimidinyl, imidazo[l,2-b]pyridazinyl, [l,2,4]triazolo[4,3-b]pyridazinyl, [l,2,4]triazolo[l,5-a]pyrimidinyl, [l,2,4]triazolo[l,5-a]pyridinyl, and the like.

[0454] Unless otherwise specified, the term "heteroaryl" means a monocyclic, bicyclic or polycyclic ring system having 3 to 20 ring atoms, wherein 1, 2, 3 or more ring atoms are selected from N, O or S, and the remainder of the ring atoms are C, wherein the N heteroatom or S heteroatom on the ring can optionally be oxidized to form an N-oxide (e.g., NO) or S-oxide (e.g., S(O) p , p is 1 or 2), and the N heteroatom on the ring can optionally be quaternized. The heteroaryl group is optionally substituted with one or more substituents described herein. Preferably, the heteroaryl group contains 3 to 12 ring atoms (3- to 12-membered heteroaryl), further preferably 3 to 10 ring atoms (3- to 10-membered heteroaryl), or 3 to 8 ring atoms (3- to 8-membered heteroaryl), or 3 to 6 ring atoms (3- to 6-membered heteroaryl), or 4 to 6 ring atoms (4- to 6-membered heteroaryl), or 5 to 6 ring atoms (5- to 6-membered heteroaryl). Preferably, there are 1 to 4, more preferably 1 to 3 (i.e., 1, 2, or 3) heteroatoms. Examples of monocyclic heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, and pyrazinyl. Bicyclic or polycyclic heteroaryl groups include spiro, fused, and bridged heteroaryl groups.

[0455] Unless otherwise specified, the term "heteroalkyl" means a saturated "heteroalkyl" group as defined above containing 3 to 20 ring atoms, wherein 1, 2, 3 or more ring atoms are selected from N, O or S, and the remainder of the ring atoms are C, wherein the N heteroatom or S heteroatom on the ring can optionally be oxidized to form an N-oxide (e.g., NO) or S-oxide (e.g., S(O) p, p is 1 or 2, and the N heteroatom on the ring can optionally be quaternized. The heterocycloalkyl group is optionally substituted with one or more substituents described herein. Preferred are those comprising 3-12 ring atoms (3-12 membered heterocycloalkyl), further preferred are those comprising 3-8 ring atoms (3-8 membered heterocycloalkyl), or 5-10 ring atoms (5-10 membered heterocycloalkyl), or 5-7 ring atoms (5-7 membered heterocycloalkyl), or 4-6 ring atoms (4-6 membered heterocycloalkyl), or 5-6 ring atoms (5-6 membered heterocycloalkyl). The number of heteroatoms is preferably 1-4, more preferably 1-3 (i.e. 1, 2, or 3). Examples of heterocycloalkyl groups include, but are not limited to, oxiranyl, aziridinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, and the like.

[0456] Unless otherwise specified, the term "spiroheterocycloalkyl" refers to a saturated bicyclic or polycyclic cyclic hydrocarbon substituent formed from two or more cyclic structures sharing one ring atom, wherein 1, 2, 3, or more ring atoms are selected from N, O, or S, with the remainder of the ring atoms being C, wherein the N or S heteroatom on the ring can optionally be oxidized to form an N-oxide (e.g., NO) or S-oxide (e.g., S(O) p , p is 1 or 2, and the N heteroatom on the ring can optionally be quaternized. Examples of spiroheterocycloalkyl groups include, but are not limited to,

[0457] Unless otherwise specified, the term "fused heterocycloalkyl" refers to a saturated bicyclic or polycyclic cyclic hydrocarbon substituent formed from two or more cyclic structures sharing two adjacent ring atoms, wherein 1, 2, 3, or more ring atoms are selected from N, O, or S, with the remainder of the ring atoms being C, wherein the N or S heteroatom on the ring can optionally be oxidized to form an N-oxide (e.g., NO) or S-oxide (e.g., S(O) p , p is 1 or 2, and the N heteroatom on the ring can optionally be quaternized.

[0458] Unless otherwise specified, the term "heteroaryloxy" means a heteroaryl group, as defined above, attached through an oxygen atom. The heteroaryloxy group is optionally substituted with one or more substituents described herein. Preferably, the heteroaryloxy group contains 4 to 20 ring atoms (4 to 20 membered heteroaryloxy), further preferably 5 to 10 ring atoms (5 to 10 membered heteroaryloxy), or 5 to 8 ring atoms (5 to 8 membered heteroaryloxy), 4 to 8 ring atoms (4 to 8 membered heteroaryloxy), or 5 to 6 ring atoms (5 to 6 membered heteroaryloxy), or 7 ring atoms (7 membered heteroaryloxy). Preferably, the heteroaryloxy group contains 1 to 4, more preferably 1 to 3 (i.e. 1, 2 or 3) heteroatoms. p , p is 1 or 2), and the N heteroatom on the ring can optionally be quaternized. The heteroaryloxy group is optionally substituted with one or more substituents described herein. Preferably, the heteroaryloxy group contains 4 to 20 ring atoms (4 to 20 membered heteroaryloxy), further preferably 5 to 10 ring atoms (5 to 10 membered heteroaryloxy), or 5 to 8 ring atoms (5 to 8 membered heteroaryloxy), 4 to 8 ring atoms (4 to 8 membered heteroaryloxy), or 5 to 6 ring atoms (5 to 6 membered heteroaryloxy), or 7 ring atoms (7 membered heteroaryloxy). Preferably, the heteroaryloxy group contains 1 to 4, more preferably 1 to 3 (i.e. 1, 2 or 3) heteroatoms.

[0459] Unless otherwise specified, the term "monocyclic" means a group having only one ring which can be saturated, unsaturated, or partially saturated, and can be carbocyclic (all ring atoms are carbon atoms) or heterocyclic (in addition to carbon atoms, ring atoms include, for example, 1, 2, or 3 heteroatoms, for example N, O, or S).

[0460] Unless otherwise specified, the term "halo" or "halogen" is fluorine, chlorine, bromine, and iodine.

[0461] Further, it is noted that the descriptive manner "independently" as employed in the present application is to be interpreted broadly, i.e. it means that each individual described is independent of the other, and can be the same or different specific group independently. In more detail, the descriptive manner "independently" can mean that the specific options expressed between the same symbols in different groups do not influence each other, or it can mean that the specific options expressed between the same symbols in the same group do not influence each other.

[0462] Unless otherwise specified, the term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine; cattle, goats, horses, or primates, most preferably humans.

[0463] The term "therapeutically effective amount" means that amount of an active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of: (1) preventing the disease: for example, preventing a disease, disorder, or condition from occurring in an individual that is predisposed or does not yet experience or display symptoms of the disease pathology; (2) inhibiting the disease: for example, arresting the development of a disease, disorder, or condition (i.e., stopping the pathology and / or symptoms from developing further) in an individual that is experiencing or displays symptoms of the disease pathology; (3) relieving the disease: for example, causing regression of a disease, disorder, or condition (i.e., reversing the pathology and / or symptoms) in an individual that is experiencing or displays symptoms of the disease pathology.

[0464] The terms "treat" and other similar terms as used herein include the following meanings:

[0465] (i) preventing the disease or condition from occurring in a mammal, in particular, when such mammal is predisposed or at risk to developing the disease or condition but has not yet been diagnosed as having it;

[0466] (ii) inhibiting the disease or condition, i.e., arresting its development;

[0467] (iii) relieving the disease or condition, i.e., causing regression of the state of the disease or condition; or

[0468] (iv) relieving the symptoms of the disease or condition.

[0469] The definitions of the abbreviations used in the present application are as follows: KHMDS represents potassium bis(trimethylsilyl)amide; Boc represents tert-butyloxycarbonyl; TFA represents trifluoroacetic acid; PhONa represents sodium phenoxide; DAST represents diethylaminosulfur trifluoride; CMPI represents 2-chloro-1-methylpyridine iodide; DIPEA represents N,N-diisopropylethylamine; CDCl3 represents deuterated chloroform; MeI represents methyl iodide; nBuLi represents n-butyllithium; m-CPBA represents meta-chloroperoxybenzoic acid; DMSO represents dimethyl sulfoxide; DMSO-d6 represents deuterated dimethyl sulfoxide; DMF represents N,N-dimethylformamide; UHP represents urea hydrogen peroxide; TFAA trifluoroacetic anhydride; DIBAL-H represents diisobutylaluminum hydride; Me represents methyl; Bu represents butyl; PMB represents p-methoxybenzyl; Bn represents benzyl; Ph represents phenyl; HATU represents 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; NCS represents N-chlorosuccinimide; HMPA represents hexamethylphosphoramide; MsCl represents methylsulfonyl chloride; SEMCl represents 2-(trimethylsilyl)ethoxymethyl chloride; Pd(PPh3)4 represents tetrakis(triphenylphosphine)palladium; Pd2dba3 represents tris(dibenzylideneacetone)dipalladium; Pd(OAc)2 represents palladium acetate. Advantages

[0470] According to the embodiments of the present application, the present application has at least one of the following technical effects:

[0471] The present application provides a compound with novel structure, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, which has excellent pharmacokinetic properties, low clearance rate, high tissue distribution, high plasma exposure, good drug efficacy and drugability, and can effectively treat WRN related diseases. The compound of the present application has strong inhibition on WRN, and can significantly inhibit WRN enzyme activity, SW48 cell proliferation and HCT116 cell proliferation. DETAILED DESCRIPTION

[0472] The present application will be further described below in conjunction with specific examples. It should be understood that the following description is only the most preferred embodiment of the present application, and should not be considered as a limitation on the scope of protection of the present application. Based on a full understanding of the present application, the experimental methods not specified in the following examples are generally carried out under conventional conditions, or under the conditions recommended by the manufacturer, and the skilled person in the art can make non-essential modifications to the technical solutions of the present application. Such modifications should be considered to be within the scope of protection of the present application.

[0473] Preparation of intermediate 01d-P1:

[0474] The synthetic route of intermediate 01d-P1 is shown below:

[0475] First step: Synthesis of (S,E)-(1-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl) tert-butylcarbamate / (R,E)-(1-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl) tert-butylcarbamate (01c-P1 / 01c-P2)

[0476] Compound 01c-P1 is one of the two structural formulas above, and compound 01c-P2 is the other structural formula;

[0477] Dissolve (E)-(1-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl) tert-butylcarbamate (01c) (1.30 g, 4.43 mmol) in methanol (40 mL), then purify by chiral separation (column: DAICEL CHIRALPAK IG (250 mm*50 mm, 10 μm); aqueous-organic phase: CO2-IPA (0.1% NH 3. H2O); gradient: 15%-15%, 4.8 min) to obtain compound (S,E)-(1-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl) tert-butylcarbamate and compound (R,E)-(1-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl) tert-butylcarbamate, one of which is 01c-P1 (retention time: 2.560 min) and the other is 01c-P2 (retention time: 2.739 min).

[0478] Second step: Synthesis of 01d-P1

[0479] Compound 01d-P1 is one of the two structural formulas above;

[0480] Dissolve 01c-P1 in dichloromethane (10 mL), and add trifluoroacetic acid (2 mL). The reaction solution is reacted at 25°C for 5 hours, and TLC detection shows that the reaction is complete. The reaction solution is concentrated under reduced pressure to obtain the crude trifluoroacetate salt of 01d-P1.

[0481] Example 01: Preparation of target compounds 01A / 01B

[0482] (S,E)-N-(1-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4- phenoxy pyrimidine-5-carboxamide / (R,E)-N-(1-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-phenoxy pyrimidine-5-carboxamide

[0483] Compound 01A is one of the two structural formulas above, and Compound 01B is the other structural formula;

[0484] The synthesis route of Compound 01A and 01B is shown as follows:

[0485] First step: synthesis of diethyl (fluoro(methylsulfonyl)methyl)phosphonate (01b)

[0486] Diethyl (methylsulfonyl)methyl)phosphonate (01a) (1.50 g, 6.52 mmol) was dissolved in tetrahydrofuran (18 mL), and the reaction solution was cooled to -78 °C. Potassium bis(trimethylsilyl)amide (8.15 mL, 8.15 mmol, 1 M tetrahydrofuran solution) was added, and the reaction solution was reacted at -78 °C for 1 hour. 1-Chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt (Selectfluor) (1.83 g, 23.7 mmol) was added. The reaction solution was reacted at -78 °C for 10 minutes, and then DMF (12 mL) was added. The reaction solution was warmed to 20 °C and reacted for 14 hours. LC-MS detection showed that the reaction was complete, and the reaction solution was added to water (50 mL). Extraction was performed with ethyl acetate (50 mL x 3), the organic layers were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain diethyl (fluoro(methylsulfonyl)methyl)phosphonate (01b) (1.50 g, yield 46%, purity 50%). The crude product was directly used in the next step.

[0487] Second step: synthesis of tert-butyl (E)-(1-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)carbamate (01c)

[0488] Diethyl (fluoro(methylsulfonyl)methyl)phosphonate (01b) (1.70 g, 4.11 mmol, purity 50%) and tert-butyl (S)-(1-cyclopropyl-2-oxoethyl)carbamate (820 mg, 4.11 mmol) were dissolved in tetrahydrofuran (40 mL), and anhydrous potassium carbonate (1.70 g, 12.3 mmol) was added. The reaction solution was reacted at 60 °C for 4 hours. LC-MS detection showed that the reaction was complete, water (50 mL) was added to the reaction system, extraction was performed with ethyl acetate (50 mL x 3), the organic layers were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Purification was performed by silica gel column separation (petroleum ether: ethyl acetate (V / V) = 100:0-80:20, gradient elution) to obtain tert-butyl (E)-(1-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)carbamate (01c) (180 mg, yield 9%).

[0489] Compound (01c): 1 H NMR (400 MHz, CDC13): δ 6.01 (dd, J = 32.4, 8.8 Hz, 1H), 3.82 (s, 1H), 2.98 (s, 3H), 1.37 (s, 9H), 0.96 - 0.87 (m, 1H), 0.60 - 0.50 (m, 2H), 0.42 - 0.30 (m, 2H).

[0490] Step 3: Synthesis of (E)-1-cyclopropyl-3-fluoro-3-(methylsulfonyl)propyl-2- en-1-amine (01d)

[0491] (E)-(1-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)carbamic acid tert-butyl ester (01c) (180 mg, 0.61 mmol) was dissolved in dichloromethane (2.5 mL), trifluoroacetic acid (0.5 mL) was added. The reaction was stirred at 20 °C for 5 h. LC-MS showed the reaction was completed. The reaction was concentrated under reduced pressure to give (E)-1-cyclopropyl-3-fluoro-3-(methylsulfonyl)propyl-2-en-1-amine (01d) trifluoroacetate salt (200 mg, yield 75%, purity 50%).

[0492] LC-MS, M / Z (ESI): 194.0 [M-Boc+H] + .

[0493] Step 4: Synthesis of 2-chloro-4-phenoxy-pyrimidine-5-carboxylic acid ethyl ester (01e)

[0494] 2,4-dichloro-pyrimidine-5-carboxylic acid ethyl ester (5.00 g, 22.7 mmol) was dissolved in tetrahydrofuran (30 mL), sodium phenoxide (2.77 g, 23.9 mmol) was added. The reaction was stirred at 0 °C for 6 h. LC-MS showed the reaction was completed. The reaction was poured into water (50 mL), extracted with ethyl acetate (50 mL x 3), the combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 20:1-6:1, gradient elution) to give 2-chloro-4-phenoxy-pyrimidine-5-carboxylic acid ethyl ester (01e) (4.67 g, yield 74%).

[0495] Step 5: Synthesis of 2-(1-ethoxy-vinyl)-4-phenoxy-pyrimidine-5-carboxylic acid ethyl ester (01f)

[0496] Ethyl 2-acetyl-4-phenoxy pyrimidine-5-carboxylate (01g) was synthesized according to the following procedure. Ethyl 2-chloro-4-phenoxy pyrimidine-5-carboxylate (01e) (4.50 g, 16.2 mmol), tributyl(1-ethoxyvinyl)tin (7.01 g, 19.4 mmol) and tetrakis(triphenylphosphine)palladium (1.87 g, 1.62 mmol) were dissolved in 1,4-dioxane (30 mL) and the reaction was stirred at 100 °C for 8 h. LC-MS indicated the reaction was completed. Saturated potassium fluoride (30 mL) aqueous solution was added and stirred for 12 h. The reaction mixture was extracted with ethyl acetate (40 mL x 3), the organic layers were combined and washed with saturated brine (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 20:1-6:1, gradient elution) to give ethyl 2-(1-ethoxyvinyl)-4-phenoxy pyrimidine-5-carboxylate (01f) (3.10 g, 61% yield).

[0497] Step 6: Synthesis of ethyl 2-acetyl-4-phenoxy pyrimidine-5-carboxylate (01g)

[0498] Ethyl 2-(1-ethoxyvinyl)-4-phenoxy pyrimidine-5-carboxylate (01f) (3.10 g, 9.87 mmol) was dissolved in 2 M HC1 in 1,4-dioxane (50 mL) and stirred at room temperature for 16 h. LC-MS indicated the reaction was completed. The reaction mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 20:1-5:1, gradient elution) to give ethyl 2-acetyl-4-phenoxy pyrimidine-5-carboxylate (01g) (1.35 g, 48% yield).

[0499] Step 7: Synthesis of ethyl 2-(1,1-difluoroethyl)-4-phenoxy pyrimidine-5-carboxylate (01h)

[0500] Ethyl 2-acetyl-4-phenoxy pyrimidine-5-carboxylate (01g) (1.35 g, 4.74 mmol) was dissolved in dichloromethane (15 mL) and diethylaminosulfur trifluoride (DAST) (1.52 g, 9.78 mmol) was added. The reaction was stirred at 25 °C for 6 h. LC-MS indicated the reaction was completed. The reaction mixture was poured into water (20 mL) and extracted with dichloromethane (20 mL x 3). The organic layers were combined, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 20:1-5:1, gradient elution) to give ethyl 2-(1,1-difluoroethyl)-4-phenoxy pyrimidine-5-carboxylate (01h) (1.16 g, 83% yield).

[0501] Step 8: Synthesis of 2-(l,l-difluoroethyl)-4-phenoxy-pyrimidine-5-carboxylic acid (01i)

[0502] Ethyl 2-(l,l-difluoroethyl)-4-phenoxy-pyrimidine-5-carboxylate (01h) (1.16 g, 3.92 mmol) was dissolved in water / tetrahydrofuran (5 mL / 15 mL), lithium hydroxide (0.18 g, 7.84 mmol) was added, and the mixture was stirred at room temperature for 8 hours. LC-MS indicated that the reaction was complete. The reaction solution was diluted with 1 M hydrochloric acid to adjust the pH to <7, and then extracted with ethyl acetate (30 mL x 3). The organic layers were combined, washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 2-(l,l-difluoroethyl)-4-phenoxy-pyrimidine-5-carboxylic acid (01i) (0.97 g, yield 88%).

[0503] Step 9: Synthesis of (S,E)-N-(l-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-2-(l,l- difluoroethyl)-4-phenoxy-pyrimidine-5-carboxamide / (R,E)-N-(l-cyclopropyl-3-fluoro-3- (methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-4-phenoxy-pyrimidine-5-carboxamide (01A / 01B)

[0504] To a solution of 2-(1,1-difluoroethyl)-4-(phenyloxy)pyrimidine-5-carboxylic acid (01i) (72 mg, 0.26 mmol) and (E)-1-cyclopropyl-3-fluoro-3-(methylsulfonyl)propyl-2- en-1-amine trifluoroacetate salt (150 mg, 0.26 mmol, purity 50%) in dichloromethane (3 mL) was added N,N-diisopropylethylamine (DIPEA) (165 mg, 1.28 mmol) and 2-chloro-1-methylpyridine iodide (CMP I) (98 mg, 0.38 mmol) and the reaction was stirred at 20 °C under N2for 2 h. LC-MS indicated the reaction was complete. The reaction was concentrated under reduced pressure and purified by HPLC to give racemate. The racemate was separated by SFC (Daicel ChiralPak IF, 40 mm 1.D. x 250 mm, 10 um; n-Hexane-Ethanol; 0-50; 80 mL / min) to give (S,E)-N-(1-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4- phenoxy pyrimidine-5-carboxamide and (R,E)-N-(1-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-phenoxy pyrimidine-5-carboxamide, one of which was 01A (retention time: 3.584 min) and the other was 01B (retention time: 2.846 min).

[0505] 01A: 1 H NMR (400 MHz, DMSO-d6): δ 9.01 (s, 1H), 8.94 (d, J = 8.0 Hz, 1H), 7.60 - 7.42 (m, 2H), 7.39 - 7.16 (m, 3H), 6.33 (dd, J = 34.4, 8.8 Hz, 1H), 4.56 - 4.32 (m, 1H), 3.25 (s, 3H), 1.86 (t, J = 19.2 Hz, 3H), 1.30 - 1.24 (m, 1H), 0.61 - 0.49 (m, 2H), 0.49 - 0.32 (m, 2H).

[0506] LC-MS, M / Z (ESI): 456.2 [M+H] + .

[0507] 01B: 1H NMR (400 MHz, DMSO-d6): δ 9.01 (s, 1H), 8.99-8.90 (m, 1H), 7.51-7.47 (m, 2H), 7.38-7.31 (m, 3H), 6.34 (dd, J = 34.4, 8.8 Hz, 1H), 4.54-4.38 (m, 1H), 3.25 (s, 3H), 1.90-1.80 (m, 3H), 1.35-1.29 (m, 1H), 0.63-0.49 (m, 2H), 0.49-0.28 (m, 2H).

[0508] LC-MS, M / Z (ESI): 456.4 [M+H] + .

[0509] Example 02: Preparation of the target compounds 02A / 02B

[0510] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)but-2-en-1-yl)-2-(1,1-difluoroethyl)-4- phenoxy pyrimidine-5-carboxamide / (R,E)-N-(1-cyclopropyl-3-(methylsulfonyl)but-2-en-1- yl)-2-(1,1-difluoroethyl)-4-phenoxy pyrimidine-5-carboxamide

[0511] Compound 02A is one of the above two structural formulas, and compound 02B is the other structural formula.

[0512] The synthesis route of compound 02 is as follows:

[0513] First step: synthesis of diethyl (1-(methylthio)ethyl)phosphonate (02b)

[0514] Diethyl (methylthio)methyl)phosphonate (02a) (10.0 g, 50.4 mmol) was dissolved in tetrahydrofuran (100 mL) solvent, and the reaction solution was cooled to -78°C. n-Butyllithium (24.2 mL, 60.5 mmol, 2.5M tetrahydrofuran solution) was added, and the reaction solution was reacted at -78°C for 3 hours. Iodomethane (7.88 g, 55.5 mmol) was slowly added dropwise. The reaction solution was naturally warmed to 20°C and reacted for 14 hours. LC-MS detection showed that the reaction was complete. The reaction solution was added to water (50 mL), extracted with ethyl acetate (200 mL x 3), the organic layers were combined, washed with saturated brine (70 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Purification was performed by silica gel column separation (petroleum ether: ethyl acetate (V / V) = 100:0-50:50, gradient elution) to obtain diethyl (1-(methylthio)ethyl)phosphonate (02b) (8.00 g, yield 52%).

[0515] Second Step: Synthesis of Diethyl (1-(methylsulfonyl)ethyl)phosphonate (02c)

[0516] Diethyl (1-(methylthio)ethyl)phosphonate (02b) (8.00 g, 26.4 mmol) was dissolved in dichloromethane (100 mL), cooled to 0 °C, and m-chloroperoxybenzoic acid (13.4 g, 65.9 mmol) was added. The reaction was stirred at 20 °C for 3 h. TLC detection showed that the reaction was completed. The reaction was added to saturated sodium thiosulfate solution (100 mL), and extracted with ethyl acetate (100 mL x 3). The organic layers were combined, washed with saturated sodium bicarbonate (50 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Purification was performed by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 100:0-50:50, gradient elution) to obtain diethyl (1-(methylsulfonyl)ethyl)phosphonate (02c) (6.00 g, yield 93.0%).

[0517] Third Step: Synthesis of (E)-(1-cyclopropyl-3-(methylsulfonyl)but-2-en-1-yl)carbamic acid tert-butyl ester (02d)

[0518] Diethyl (1-(methylsulfonyl)ethyl)phosphonate (02c) (613 mg, 2.51 mmol) and (S)-(1-cyclopropyl-2-oxoethyl)carbamic acid tert-butyl ester (500 mg, 2.51 mmol) were dissolved in tetrahydrofuran (5 mL), and anhydrous potassium carbonate (1.04 g, 7.53 mmol) was added. The reaction was stirred at 60 °C for 5 h. LC-MS detection showed that the reaction was completed. Water (50 mL) was added to the reaction system, and extracted with ethyl acetate (50 mL x 3). The organic layers were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Purification was performed by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 100:0-65:35, gradient elution) to obtain (E)-(1-cyclopropyl-3-(methylsulfonyl)but-2-en-1-yl)carbamic acid tert-butyl ester (02d) (100 mg, yield 14%).

[0519] Fourth Step: Synthesis of (E)-1-cyclopropyl-3-(methylsulfonyl)but-2-en-1-amine (02e)

[0520] Tert-butyl (E)-(l-cyclopropyl-3-(methylsulfonyl)but-2-en-l- yl)carbamate (02d) (150 mg, 0.52 mmol) was dissolved in dichloromethane (2.5 mL), trifluoroacetic acid (0.5 mL) was added, and the reaction was stirred at 20 °C for 5 h. LC-MS indicated the reaction was complete, and the reaction was concentrated to give crude (E)-l-cyclopropyl-3-(methylsulfonyl)but-2-en-l-amine trifluoroacetate salt (02e) (150 mg, 91% yield).

[0521] Fifth step: Synthesis of (S,E)-N-(l-cyclopropyl-3-(methylsulfonyl)but-2-en-l-yl)-2-(l,l- difluoroethyl)-4-phenoxy pyrimidine-5-carboxamide / (R,E)-N-(l-cyclopropyl-3-(methylsulfonyl)but-2-en-l-yl)-2-(l,l-difluoroethyl)-4-phenoxy pyrimidine-5-carboxamide (02A / 02B)

[0522] Tert-butyl (E)-(l-cyclopropyl-3-(methylsulfonyl)but-2-en-l- yl)carbamate (02d) (150 mg, 0.52 mmol) was dissolved in dichloromethane (2.5 mL), trifluoroacetic acid (0.5 mL) was added, and the reaction was stirred at 20 °C for 5 h. LC-MS indicated the reaction was complete, and the reaction was concentrated to give crude (E)-l-cyclopropyl-3-(methylsulfonyl)but-2-en-l-amine trifluoroacetate salt (02e) (150 mg, 91% yield).

[0523] 02A: 1H NMR (400 MHz, DMSO-d6): δ 8.97 (s, 1H), 8.87 (d, J = 8.0 Hz, 1H), 8.87 (d, J = 8.0 Hz, 1H), 7.53 - 7.46 (m, 2H), 7.34 - 7.29 (m, 3H), 6.59 (dd, J = 9.2, 1.2 Hz, 1H), 4.46 - 4.38 (m, 1H), 2.96 (s, 3H), 2.10 (d, J = 1.2 Hz, 3H), 1.85 (t, J = 19.2 Hz, 3H), 1.19 - 1.14 (m, 1H), 0.54 - 0.45 (m, 2H), 0.44 - 0.34 (m, 2H).

[0524] LC-MS, M / Z (ESI): 452.2 [M+H] + .

[0525] 02B: 1 H NMR (400 MHz, DMSO-d6): δ 8.97 (s, 1H), 8.87 (d, J = 8.0 Hz, 1H), 8.87 (d, J = 8.0 Hz, 1H), 7.53 - 7.46 (m, 2H), 7.34 - 7.29 (m, 3H), 6.59 (dd, J = 9.2, 1.2 Hz, 1H), 4.46 - 4.38 (m, 1H), 2.96 (s, 3H), 2.10 (d, J = 1.2 Hz, 3H), 1.85 (t, J = 19.2 Hz, 3H), 1.19 - 1.14 (m, 1H), 0.54 - 0.45 (m, 2H), 0.44 - 0.34 (m, 2H).

[0526] LC-MS, M / Z (ESI): 452.2 [M+H] + .

[0527] Example 03: Preparation of the target compound 03

[0528] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-6-ethyl-2-phenoxy-5- (trifluoromethyl)nicotinamide (03)

[0529] The synthetic route of compound 03 is shown below:

[0530] First step: Synthesis of methyl 2-phenoxy-5-(trifluoromethyl)nicotinate (03b)

[0531] To a solution of methyl 2-chloro-5-(trifluoromethyl)nicotinate (03a) (5.00 g, 20.8 mmol) and phenol (3.93 g, 41.7 mmol) in N-methylpyrrolidine (30 mL) was added anhydrous potassium carbonate (8.65 g, 62.6 mmol). The reaction was stirred at 100 °C for 3.5 h. LC-MS indicated the reaction was completed. The reaction was quenched with saturated aqueous sodium chloride solution (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 100:0-80:20, gradient elution) to give methyl 2-phenoxy-5-(trifluoromethyl)nicotinate (03b) (3.30 g, 53% yield).

[0532] Second Step: Synthesis of 3-(methoxycarbonyl)-2-phenoxy-5- (trifluoromethyl)pyridine 1-oxide (03c)

[0533] To a solution of methyl 2-phenoxy-5-(trifluoromethyl)nicotinate (03b) (1.70 g, 5.72 mmol) in dichloromethane (60 mL) was added oxone (1.13 g, 12.0 mmol) and trifluoroacetic anhydride (2.40 g, 11.4 mmol). The reaction was stirred at room temperature for 18 h. LC-MS indicated the reaction was completed. The resulting mixture was diluted with saturated aqueous sodium bicarbonate solution (40 mL) and extracted with dichloromethane (30 mL x 3). The combined organic layers were washed with saturated aqueous sodium chloride solution (80 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase C18 column (water: acetonitrile (V / V) = 100:0-60:40, gradient elution) to give 3-(methoxycarbonyl)-2-phenoxy-5-(trifluoromethyl)pyridine 1-oxide (03c) (200 mg, 11% yield).

[0534] Third Step: Synthesis of methyl 6-chloro-2-phenoxy-5-(trifluoromethyl)nicotinate (03d)

[0535] A solution of 3-(methoxycarbonyl)-2-phenoxy-5-(trifluoromethyl)pyridine 1-oxide (03c) (200 mg, 0.64 mmol) in phosphorus oxychloride (2 mL) was stirred at 80 °C for 2 h under nitrogen atmosphere. LC-MS indicated the reaction was completed. The reaction was cooled to room temperature and quenched by the addition of water (5 mL) and methanol (5 mL). The mixture was extracted with dichloromethane (10 mL x 3). The organic layers were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 100:0 to 60:40, gradient elution) to give methyl 6-chloro-2-phenoxy-5-(trifluoromethyl)nicotinate (03d) (160 mg, 68% yield).

[0536] Fourth Step: Synthesis of methyl 2-phenoxy-5-(trifluoromethyl)-6-vinyl nicotinate (03e)

[0537] To a solution of methyl 6-chloro-2-phenoxy-5-(trifluoromethyl)nicotinate (03d) (160 mg, 0.48 mmol) and tributyl(vinyl)tin (184 mg, 0.579 mmol) in toluene (2 mL) was added tetrakis(triphenylphosphine) palladium (55.7 mg, 0.05 mmol) under nitrogen atmosphere. The reaction was stirred at 110 °C for 18 h under nitrogen atmosphere. LC-MS indicated the reaction was completed. The reaction was cooled to room temperature and diluted with water (10 mL). The mixture was extracted with ethyl acetate (10 mL x 3). The organic layers were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 100:0 to 50:50, gradient elution) to give methyl 2-phenoxy-5-(trifluoromethyl)-6-vinyl nicotinate (03e) (120 mg, 77% yield).

[0538] Fifth Step: Synthesis of methyl 6-ethyl-2-phenoxy-5-(trifluoromethyl)nicotinate (03f)

[0539] To a solution of methyl 2-phenoxy-5-(trifluoromethyl)-6-vinyl nicotinate (03e) (80.0 mg, 0.17 mmol) in methanol (1 mL) was added Pd / C (18.4 mg, 10% Wt, 55% water). The reaction was stirred at room temperature for 18 h under hydrogen atmosphere. LC-MS indicated the reaction was completed. The reaction was filtered and the filtrate was concentrated under reduced pressure to give methyl 6-ethyl-2-phenoxy-5-(trifluoromethyl)nicotinate (03f) (40.0 mg, 71% yield). The crude product was used directly in the next step without purification.

[0540] Step 6: Synthesis of 6-ethyl-2-phenoxy-5-(trifluoromethyl)nicotinic acid (03g)

[0541] To a mixture solution of methyl 6-ethyl-2-phenoxy-5-(trifluoromethyl)nicotinate (03f) (55.0 mg, 0.17 mmol) in methanol (2 mL) and water (1 mL) was added lithium hydroxide (21.3 mg, 0.51 mmol). The reaction was stirred at room temperature for 1 hour. LC-MS detection showed the reaction was completed. The reaction was adjusted to pH = 3 with 1 M hydrochloric acid, then extracted with ethyl acetate (10 mL x 3), the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 6-ethyl-2-phenoxy-5-(trifluoromethyl)nicotinic acid (03g) (60.0 mg, yield 91%) as a crude product, which was used directly in the next step without purification.

[0542] Step 7: Synthesis of (S)-(1-cyclopropyl-2-(methoxy(methyl)amino)-2-oxoethyl) carbamic acid tert-butyl ester (03h)

[0543] To a solution of (S)-2-((tert-butoxycarbonyl)amino)-2-cyclopropylacetic acid (10.00 g, 46.5 mmol) in dichloromethane (40 mL) was added N,N'-carbonyldiimidazole (CDI) (11.30 g, 69.8 mmol) and stirred at room temperature for 2 hours, then N,O-dimethylhydroxylamine hydrochloride (6.80 g, 69.8 mmol) was added and the reaction was continued at room temperature for 10 hours. TLC detection showed the reaction was completed. After cooling to room temperature, the reaction was diluted with water (100 mL) and extracted with dichloromethane (100 mL x 3). The combined organic layers were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 100:0-70:30, gradient elution) to give (S)-(1-cyclopropyl-2-(methoxy(methyl)amino)-2-oxoethyl) carbamic acid tert-butyl ester (03h) (10.32 g, yield 86%).

[0544] Step 8: Synthesis of (S)-(1-cyclopropyl-2-oxoethyl)carbamic acid tert-butyl ester (03i)

[0545] (S)-(l-cyclopropyl-2-oxoethyl)carbamic acid tert-butyl ester (03i) (5.17 g, 26.0 mmol) and diethyl (methylsulfonyl)methyl)phosphonate (6.57 g, 28.6 mmol) were dissolved in tetrahydrofuran (30 mL), anhydrous potassium carbonate (7.17 g, 52.0 mmol) was added, and the reaction was stirred at 60 °C for 8 h. The reaction was monitored by TLC, and upon completion, the reaction was cooled to room temperature and diluted with water (80 mL). The reaction was extracted with ethyl acetate (80 mL x 3). The organic layers were combined and washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 100:0 to 80:20, gradient elution) to give (S,E)-(l-cyclopropyl-3-(methylsulfonyl)allyl)carbamic acid tert-butyl ester (03j) (3.79 g, 53% yield).

[0546] Ninth step: Synthesis of (S,E)-(l-cyclopropyl-3-(methylsulfonyl)allyl)carbamic acid tert-butyl ester (03j)

[0547] (S)-(l-cyclopropyl-2-oxoethyl)carbamic acid tert-butyl ester (03i) (5.17 g, 26.0 mmol) and diethyl (methylsulfonyl)methyl)phosphonate (6.57 g, 28.6 mmol) were dissolved in tetrahydrofuran (30 mL), anhydrous potassium carbonate (7.17 g, 52.0 mmol) was added, and the reaction was stirred at 60 °C for 8 h. The reaction was monitored by TLC, and upon completion, the reaction was cooled to room temperature and diluted with water (80 mL). The reaction was extracted with ethyl acetate (80 mL x 3). The organic layers were combined and washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 100:0 to 80:20, gradient elution) to give (S,E)-(l-cyclopropyl-3-(methylsulfonyl)allyl)carbamic acid tert-butyl ester (03j) (3.79 g, 53% yield).

[0548] Tenth step: Synthesis of (S,E)-l-cyclopropyl-3-(methylsulfonyl)prop-2-en-l-amine (03k)

[0549] (S, E)-(l-cyclopropyl-3-(methylsulfonyl)allyl)carbamic acid tert-butyl ester (03j) (3.79 g, 13.8 mmol) was dissolved in trifluoroacetic acid / dichloromethane (5 mL / 10 mL) and reacted at room temperature for 4 hours. The reaction was checked by TLC and the reaction solution was concentrated under reduced pressure to obtain crude (S, E)-l-cyclopropyl-3-(methylsulfonyl)prop-2-en-l-amine trifluoroacetate salt (03k) (4.00 g, yield 100%), which was used directly in the next step without purification.

[0550] Tenth step: synthesis of (S, E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6- ethyl-2-phenoxy-5-(trifluoromethyl)nicotinamide (03)

[0551] To a solution of 6-ethyl-2-phenoxy-5-(trifluoromethyl)nicotinic acid (03g) (60.0 mg, 0.19 mmol) and (S, E)-l-cyclopropyl-3-(methylsulfonyl)prop-2-en-l-amine trifluoroacetate salt (40.5 mg, 0.231 mmol) in dichloromethane (2 mL) was added 2-chloro-l-methylpyridinium iodide (98.5 mg, 0.39 mmol) and N, N-diisopropylethylamine (DIPEA) (0.096 mL, 0.58 mmol) and the resulting mixture was stirred at room temperature for 1 hour. The reaction was checked by LC-MS and the reaction solution was concentrated under reduced pressure to obtain a crude product, which was separated and purified by HPLC to obtain (S, E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-ethyl-2-phenoxy-5- (trifluoromethyl)nicotinamide (03).

[0552] 1 H NMR (400 MHz, CD3OD): δ 8.43 (s, 1H), 7.53 - 7.44 (m, 2H), 7.35 - 7.20 (m, 3H), 7.02 (dd, J = 15.2, 4.8 Hz, 1H), 6.86 (dd, J = 15.2, 1.6 Hz, 1H), 4.27 - 4.12 (m, 1H), 2.95 (s, 3H), 2.81 (q, J = 7.2 Hz, 2H), 1.23 - 1.15 (m, 1H), 1.10 (t, J = 7.2 Hz, 3H), 0.75 - 0.59 (m, 2H), 0.57 - 0.45 (m, 2H).

[0553] LC-MS, M / Z (ESI): 469.2 [M+H] + .

[0554] Example 04: preparation of target compound 04

[0555] (S, E)-N-(1-cyclopropyl-3-(oxetan-3-ylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4- phenoxy pyrimidine-5-carboxamide (04)

[0556] The synthetic route of compound 04 is shown below:

[0557] First step: Synthesis of S-((diethoxyphosphoryl)methyl) ethyl sulfide (04b)

[0558] To a solution of iodomethyl phosphoric acid diethyl ester (04a) (13.0 g, 49.2 mmol) and potassium thioacetate (10.8 g, 93.5 mmol) in tetrahydrofuran (130 mL) was added tetrabutylammonium iodide (20.7 g, 56.1 mmol) and the reaction was stirred at 70 °C for 4.5 h. LC-MS indicated the reaction was complete. The reaction was quenched with aqueous solution (100 mL) at room temperature and extracted with ethyl acetate (150 mL x 3). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 100:0-100:1, gradient elution) to give S-((diethoxyphosphoryl)methyl) ethyl sulfide (04b) (5.00 g, yield 40%).

[0559] Second step: Synthesis of (mercaptomethyl) phosphonic acid diethyl ester (04c)

[0560] To a solution of S-((diethoxyphosphoryl)methyl) ethyl sulfide (04b) (5.00 g, 22.1 mmol) in methanol (60 mL) and water (20 mL) was added potassium hydroxide (2.48 g, 44.2 mmol). The reaction was stirred at room temperature for 2 h. LC-MS indicated the reaction was complete. The resulting mixture was adjusted to pH = 1 with 2 M hydrochloric acid and extracted with ethyl acetate (100 mL x 3). The organic layers were combined and washed with saturated brine (250 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude (mercaptomethyl) phosphonic acid diethyl ester (04c) (4.00 g, yield 69%). The crude product was used directly in the next step without purification.

[0561] Third step: Synthesis of (oxetan-3-ylthio)methyl) phosphonic acid diethyl ester (04d)

[0562] To a solution of (thioxomethyl)phosphinic acid diethyl ester (04c) (2.00 g, 10.8 mmol) and 3-iodooxetane (3.00 g, 16.3 mmol) in DMF (20 mL) was added anhydrous potassium carbonate (4.50 g, 32.6 mmol) under nitrogen protection. The reaction was stirred at room temperature for 3 h. LC-MS detection showed the reaction was completed. The reaction was concentrated under reduced pressure. The crude product was separated and purified by C18 column (water: acetonitrile V / V = 100:0-50:50, gradient elution) to give (oxetan-3-ylthio)methyl)phosphinic acid diethyl ester (04d) (1.70 g, yield 65%).

[0563] Fourth step: synthesis of (oxetan-3-ylsulfonyl)methyl)phosphinic acid diethyl ester (04e)

[0564] To a solution of (oxetan-3-ylthio)methyl)phosphinic acid diethyl ester (04d) (700 mg, 2.91 mmol) in ethanol (10 mL) and water (1 mL) was added potassium peroxymonosulfate (5.7 mL, 58.3 mmol) under nitrogen protection. The reaction was stirred at room temperature for 18 h. LC-MS detection showed the reaction was completed. The mixture was filtered and concentrated under reduced pressure to give the crude product. The crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 100:0-80:20, gradient elution) to give (oxetan-3-ylsulfonyl)methyl)phosphinic acid diethyl ester (04e) (700 mg, yield 88%).

[0565] Fifth step: synthesis of (S,E)-(1-cyclopropyl-3-(oxetan-3-ylsulfonyl)allyl) tert-butyl carbamate (04f)

[0566] To a solution of (oxetan-3-ylsulfonyl)methyl)phosphinic acid diethyl ester (04e) (136 mg, 0.502 mmol) and (S)-(1-cyclopropyl-2-oxoethyl) tert-butyl carbamate (100 mg, 0.50 mmol) in tetrahydrofuran (2 mL) was added anhydrous potassium carbonate (69.4 mg, 0.50 mmol). The mixture was stirred at 60 °C for 2 h. LC-MS detection showed the reaction was completed. The mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined and washed with saturated brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (S,E)-(1-cyclopropyl-3-(oxetan-3-ylsulfonyl)allyl) tert-butyl carbamate (04f) (130 mg, yield 82%), which was used directly in the next step without purification.

[0567] Step 6: Synthesis of (S,E)-1-cyclopropyl-3-(oxetan-3-ylsulfonyl)prop-2-en-1-amine (04g)

[0568] To a solution of (S,E)-tert-butyl (1-cyclopropyl-3-(oxetan-3-ylsulfonyl)allyl)carbamate (04f) (50.0 mg, 0.16 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.2 mL), the resulting mixture was stirred at room temperature for 1 hour. LC-MS indicated the reaction was complete, the reaction was concentrated under reduced pressure to give (S,E)-1-cyclopropyl-3-(oxetan-3-ylsulfonyl)prop-2-en-1-amine trifluoroacetate salt (40.0 mg, yield 82%) which was used directly in the next step without purification.

[0569] Step 7: Synthesis of (S,E)-N-(1-cyclopropyl-3-(oxetan-3-ylsulfonyl)allyl)-2-(1,1- difluoroethyl)-4-phenoxy pyrimidine-5-carboxamide (04)

[0570] To a solution of (S,E)-1-cyclopropyl-3-(oxetan-3-ylsulfonyl)prop-2-en-1-amine trifluoroacetate salt (370 mg, 1.70 mmol) and 2-(1,1-difluoroethyl)-4-phenoxy pyrimidine-5- carboxylic acid (01i) (326 mg, 1.16 mmol) in dichloromethane (5 mL) was added N,N- diisopropylethylamine (DIPEA) (1.41 mL, 8.51 mmol) and 2-chloro-1-methylpyridinium iodide (653 mg, 2.55 mmol). The resulting mixture was stirred at room temperature for 3 hours under nitrogen protection. LC-MS indicated the reaction was complete, the reaction was concentrated under reduced pressure to give a crude product. The crude product was purified by HPLC separation and then by SFC resolution (Daicel ChiralCel OJ, 40 mm l.D, x 250 mm, 10 μm; n-hexane ethanol dichloromethane; 10-10; 90 mL / min) to give (S,E)-N-(1-cyclopropyl-3-(oxetan-3-ylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4- phenoxy pyrimidine-5-carboxamide (04).

[0571] 1H NMR (400 MHz, CD3OD): δ 9.00 (s, 1H), 7.51-7.46 (m, 2H), 7.36-7.27 (m, 3H), 7.09 (dd, J = 15.2, 5.2 Hz, 1H), 6.76 (dd, J = 15.2, 1.6 Hz, 1H), 4.84-4.79 (m, 2H), 4.74-4.68 (m, 2H), 4.51-4.41 (m, 1H), 4.22-4.16 (m, 1H), 1.81 (t, J = 18.4 Hz, 3H), 1.31-1.27 (m, 1H), 1.21-1.12 (m, 1H), 0.74-0.62 (m, 2H), 0.55-0.48 (m, 2H).

[0572] LC-MS, M / Z (ESI): 480.2 [M+H] + .

[0573] Example 05: Preparation of the target compound 05

[0574] (S, E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4- phenoxy-6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-5-carboxamide (05)

[0575] The synthetic route of compound 05 is shown as follows:

[0576] First step: synthesis of 2,4-dichloro-6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine- 5-carboxylic acid (05b)

[0577] 2,4,6-trichloropyrimidine-5-carboxylic acid (05a) (3.00 g, 13.3 mmol) and tetrahydro-2H-pyran-4-amine (1.34 g, 13.3 mmol) were dissolved in DMF (20 mL), then N,N-diisopropylethylamine (DIPEA) (4.28 g, 33.2 mmol) was added, and the reaction was carried out at room temperature for 3 hours. After the reaction was completed by LC-MS detection, the reaction solution was poured into water (50 mL), adjusted to pH = 3 with 1M hydrochloric acid, extracted with ethyl acetate (50 mL x 3), the organic phase was combined and washed with saturated brine (100 mL x 2), and dried over anhydrous sodium sulfate. The crude product 2,4-dichloro-6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-5-carboxylic acid (05b) (3.2 g, purity: 90%) was obtained by concentration under reduced pressure, which was directly used for the next step without purification.

[0578] Step 2: Synthesis of methyl 2-chloro-4-phenoxy-6-((tetrahydro-2H-pyran-4- yl)amino)pyrimidine-5-carboxylate (05d)

[0579] Methyl 2,4-dichloro-6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-5- carboxylate (05c) (2.48 g, 8.1 mmol) and sodium phenoxide (0.94 g, 8.1 mmol) were dissolved in tetrahydrofuran (20 mL) and reacted for 4 hours under ice water bath. After the reaction was completed by LC-MS detection, the reaction solution was poured into water (30 mL), and extracted with ethyl acetate (30 mL x 3). The organic phase was combined, washed with saturated brine (90 mL), and dried over anhydrous sodium sulfate. The crude product was obtained by concentration under reduced pressure, and purified by silica gel column separation (petroleum ether: ethyl acetate (V / V) = 100:0-90:10, gradient elution) to obtain methyl 2-chloro-4-phenoxy-6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-5-carboxylate (05d) (1.60 g, yield 54%).

[0580] Step 3: Synthesis of methyl 4-phenoxy-2-(prop-1-en-2-yl)-6-((tetrahydro-2H-pyran-4- yl)amino)pyrimidine-5-carboxylate (05e)

[0581] Methyl 2,4-dichloro-6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-5- carboxylate (05c) (2.48 g, 8.1 mmol) and sodium phenoxide (0.94 g, 8.1 mmol) were dissolved in tetrahydrofuran (20 mL) and reacted for 4 hours under ice water bath. After the reaction was completed by LC-MS detection, the reaction solution was poured into water (30 mL), and extracted with ethyl acetate (30 mL x 3). The organic phase was combined, washed with saturated brine (90 mL), and dried over anhydrous sodium sulfate. The crude product was obtained by concentration under reduced pressure, and purified by silica gel column separation (petroleum ether: ethyl acetate (V / V) = 100:0-90:10, gradient elution) to obtain methyl 2-chloro-4-phenoxy-6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-5-carboxylate (05d) (1.60 g, yield 54%).

[0582] Step 4: Synthesis of methyl 4-phenoxy-2-(prop-1-en-2-yl)-6-((tetrahydro-2H-pyran-4- yl)amino)pyrimidine-5-carboxylate (05e)

[0583] Methyl 2-acetyl-4-phenoxy-6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-5- carboxylate (05f) was synthesized according to the following procedure: Methyl 4-phenoxy-2-(prop-1-en-2-yl)-6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-5- carboxylate (05e) (1.06 g, 2.9 mmol), 2,6-dimethylpyridine (0.46 g, 4.3 mmol), sodium periodate (1.84 g, 8.6 mmol) and ruthenium trichloride (0.19 g, 0.6 mmol) were dissolved in tetrahydrofuran / water (20 mL / 5 mL) and reacted at room temperature for 2 hours. After the reaction was completed by LC-MS detection, the reaction solution was poured into 20 mL of water, adjusted to pH = 3 with 1 M hydrochloric acid, extracted with ethyl acetate (30 mL x 3), and the organic phase was combined, washed with saturated brine (80 mL), and dried over anhydrous sodium sulfate. The crude product was obtained by concentration under reduced pressure, and purified by silica gel column separation (petroleum ether: ethyl acetate (V / V) = 100:0-80:20, gradient elution) to obtain methyl 2-acetyl-4-phenoxy-6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-5-carboxylate (05f) (0.68 g, yield 64%).

[0584] Fifth step: Synthesis of methyl 2-acetyl-4-phenoxy-6-((tetrahydro-2H-pyran-4- yl)amino)pyrimidine-5-carboxylate (05f)

[0585] Methyl 2-acetyl-4-phenoxy-6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-5- carboxylate (05f) was synthesized according to the following procedure: Methyl 4-phenoxy-2-(prop-1-en-2-yl)-6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-5- carboxylate (05e) (1.06 g, 2.9 mmol), 2,6-dimethylpyridine (0.46 g, 4.3 mmol), sodium periodate (1.84 g, 8.6 mmol) and ruthenium trichloride (0.19 g, 0.6 mmol) were dissolved in tetrahydrofuran / water (20 mL / 5 mL) and reacted at room temperature for 2 hours. After the reaction was completed by LC-MS detection, the reaction solution was poured into 20 mL of water, adjusted to pH = 3 with 1 M hydrochloric acid, extracted with ethyl acetate (30 mL x 3), and the organic phase was combined, washed with saturated brine (80 mL), and dried over anhydrous sodium sulfate. The crude product was obtained by concentration under reduced pressure, and purified by silica gel column separation (petroleum ether: ethyl acetate (V / V) = 100:0-80:20, gradient elution) to obtain methyl 2-acetyl-4-phenoxy-6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-5-carboxylate (05f) (0.68 g, yield 64%).

[0586] Sixth step: Synthesis of methyl 2-(1,1-difluoroethyl)-4-phenoxy-6-((tetrahydro-2H- pyran-4-yl)amino)pyrimidine-5-carboxylate (05g)

[0587] Methyl 2-acetyl-4-phenoxy-6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-5- carboxylate (05f) (0.68 g, 1.8 mmol) and diethylaminosulfur trifluoride (DAST) (1.48 g, 9.2 mmol) were dissolved in dichloromethane (15 mL) and reacted at room temperature for 8 hours. After the reaction was completed as detected by LC-MS, the reaction solution was poured into 20 mL of water, extracted with dichloromethane (20 mL x 3), and the organic phase was combined, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 100:0-90:10, gradient elution) to obtain methyl 2-(1,1-difluoroethyl)-4-phenoxy-6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-5-carboxylate (05g) (0.52 g, yield 72%).

[0588] Seventh step: synthesis of 2-(1,1-difluoroethyl)-4-phenoxy-6-((tetrahydro-2H-pyran-4- yl)amino)pyrimidine-5-carboxylic acid (05h)

[0589] Methyl 2-(1,1-difluoroethyl)-4-phenoxy-6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-5- carboxylate (05g) (0.52 g, 1.3 mmol) and lithium hydroxide (0.13 g, 5.3 mmol) were dissolved in tetrahydrofuran / water (10 mL / 5 mL) and reacted at room temperature for 4 hours. After the reaction was completed as detected by LC-MS, the reaction solution was poured into 10 mL of water, adjusted to pH = 3 with 1M hydrochloric acid, extracted with ethyl acetate (15 mL x 3), and the organic phase was combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude 2-(1,1-difluoroethyl)-4-phenoxy-6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-5-carboxylic acid (05h) (0.48 g, yield 95%), which was used directly in the next step without purification.

[0590] Eighth step: synthesis of (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1- difluoroethyl)-4-phenoxy-6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-5-carboxamide (05)

[0591] A mixture of 2-(1,1-difluoroethyl)-4-phenoxy-6-((tetrahydro-2H-pyran-4- yl)amino)pyrimidine-5-carboxylic acid (05h) (0.10 g, 0.3 mmol), trifluoroacetate salt of (S,E)-1-cyclopropyl-3-(methylsulfonyl)prop-2-en-1-amine (03k) (0.14 g, 0.4 mmol), HATU (0.15 g, 0.4 mmol) and N,N-diisopropylethylamine (DIPEA) (0.10 g, 0.8 mmol) was dissolved in DMF (3 mL) and reacted at room temperature for 2 hours. After the reaction was completed by LC-MS, the reaction solution was poured into 15 mL of water, extracted with ethyl acetate (15 mL x 3), and the organic phase was combined, washed with saturated brine (45 mL), and dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure and purified by HPLC to obtain (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-phenoxy-6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-5-carboxamide (05).

[0592] 1 H NMR (400 MHz, DMSO-d6) δ 8.67 (d, J = 8.2 Hz, 1H), 8.39 (d, J = 7.4 Hz, 1H), 7.44 (dd, J = 8.7, 7.2 Hz, 2H), 7.27 (d, J = 7.9 Hz, 3H), 6.96 - 6.72 (m, 2H), 4.34 - 4.11 (m, 2H), 3.85 (d, J = 11.8 Hz, 2H), 3.48 - 3.39 (m, 2H), 2.94 (s, 2H), 1.88 (d, J = 10.7 Hz, 2H), 1.78 (t, J = 18.9 Hz, 3H), 1.62 - 1.49 (m, 2H), 1.19 - 1.02 (m, 1H), 0.58 - 0.29 (m, 4H).

[0593] LC-MS, M / Z (ESI): 537.1 [M+H] + .

[0594] Example 06: Preparation of the target compound 06

[0595] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-((3,3-difluorocyclobutyl)amino)-2-(1,1-difluoroethyl)-6-phenoxy-pyrimidine-5-carboxamide (06)

[0596] The synthetic route of compound 06 is shown below:

[0597] The first to eighth steps were carried out according to the synthetic method of compound 05, replacing tetrahydro-2H-pyran-4-amine with 3,3-difluorocyclobutane-1-amine, to obtain (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-((3,3-difluorocyclobutyl)amino)-2-(1,1-difluoroethyl)-6-phenoxy-pyrimidine-5-carboxamide (06).

[0598] 06: 1 H NMR (400 MHz, DMSO-d6) δ 8.77 (d, J = 8.3 Hz, 1H), 8.41 (d, J = 6.2 Hz, 1H), 7.44 (dd, J = 8.5, 7.5 Hz, 2H), 7.36 - 7.15 (m, 3H), 7.00 - 6.68 (m, 2H), 4.48 - 4.07 (m, 2H), 3.05 - 2.92 (m, 2H), 2.91 (s, 3H), 2.87 - 2.72 (m, 2H), 1.80 (t, J = 18.9 Hz, 3H), 1.14 - 1.04 (m, 2H), 0.62 - 0.35 (m, 4H).

[0599] LC-MS, M / Z (ESI): 543.1 [M+H] + .

[0600] Example 07: Preparation of the target compound 07

[0601] (S,E)-4-((1H-pyrazol-4-yl)amino)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-6-phenoxy-pyrimidine-5-carboxamide (07)

[0602] The synthetic route of compound 07 is shown as follows:

[0603] The first to sixth steps were carried out according to the synthetic method of compound 05, replacing tetrahydro-2H-pyran-4-amine with (4-methoxyphenyl)methanamine, to obtain methyl 2-(1,1-difluoroethyl)-4-((4-methoxybenzyl)amino)-6-phenoxy-pyrimidine-5-carboxylate (07g).

[0604] Seventh step: synthesis of methyl 4-amino-2-(1,1-difluoroethyl)-6-phenoxy-pyrimidine-5-carboxylate (07h)

[0605] Methyl 4-amino-2-(l,l-difluoroethyl)-6-phenoxy pyrimidine-5-carboxylate (07h) (0.34 g, 1.1 mmol), isoamyl nitrite (0.26 g, 2.2 mmol) and cuprous chloride (0.22 g, 8.6 mmol) were dissolved in acetonitrile (10 mL) and reacted at 80 °C for 2 hours. After the reaction was completed by LC-MS detection, the reaction solution was poured into 15 mL of water, extracted with ethyl acetate (15 mL x 3), and the organic phase was combined, washed with saturated brine (45 mL), and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the crude product was purified by silica gel column separation (petroleum ether: ethyl acetate (V / V) = 100:0-90:10, gradient elution) to obtain methyl 4-chloro-2-(l,l-difluoroethyl)-6-phenoxy pyrimidine-5-carboxylate (07i) (0.21 g, yield 58%).

[0606] Eighth step: synthesis of methyl 4-chloro-2-(l,l-difluoroethyl)-6-phenoxy pyrimidine-5-carboxylate (07i)

[0607] Methyl 4-amino-2-(l,l-difluoroethyl)-6-phenoxy pyrimidine-5-carboxylate (07h) (0.34 g, 1.1 mmol), isoamyl nitrite (0.26 g, 2.2 mmol) and cuprous chloride (0.22 g, 8.6 mmol) were dissolved in acetonitrile (10 mL) and reacted at 80 °C for 2 hours. After the reaction was completed by LC-MS detection, the reaction solution was poured into 15 mL of water, extracted with ethyl acetate (15 mL x 3), and the organic phase was combined, washed with saturated brine (45 mL), and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the crude product was purified by silica gel column separation (petroleum ether: ethyl acetate (V / V) = 100:0-90:10, gradient elution) to obtain methyl 4-chloro-2-(l,l-difluoroethyl)-6-phenoxy pyrimidine-5-carboxylate (07i) (0.21 g, yield 58%).

[0608] Ninth step: synthesis of methyl 4-((l-(tert-butoxycarbonyl)-lH-pyrazol-4-yl)amino)-2-(l,l-difluoroethyl)-6-phenoxy pyrimidine-5-carboxylate (07j)

[0609] Methyl 4-chloro-2-(l,l-difluoroethyl)-6-phenoxy pyrimidine-5-carboxylate (07i) (0.21 g, 0.6 mmol), tert-butyl 4-amino-lH-pyrazole-l-carboxylate (0.18 g, 1.0 mmol) and N,N-diisopropyl ethylamine (DIPEA) (0.17 g, 1.3 mmol) were dissolved in tetrahydrofuran (10 mL) and reacted at 80 °C for 6 hours. After the reaction was completed by LC-MS detection, the reaction solution was poured into 10 mL of water, extracted with ethyl acetate (15 mL x 3), and the organic phase was combined, washed with saturated brine (45 mL), and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the crude product was purified by silica gel column separation (petroleum ether: ethyl acetate (V / V) = 100:0-80:20, gradient elution) to obtain methyl 4-((l-(tert-butoxycarbonyl)-lH-pyrazol-4-yl)amino)-2-(l,l-difluoroethyl)-6-phenoxy pyrimidine-5-carboxylate (07j) (0.20 g, yield 66%).

[0610] Step 10: Synthesis of 4-((lH-pyrazol-4-yl)amino)-2-(l,l-difluoroethyl)-6-phenoxy pyrimidine-5-carboxylic acid (07k)

[0611] Methyl 4-((l-(tert-butoxycarbonyl)-lH-pyrazol-4-yl)amino)-2-(l,l-difluoroethyl)-6-phenoxy pyrimidine-5-carboxylate (07j) (0.20 g, 0.4 mmol) was dissolved in trifluoroacetic acid / dichloromethane (2 mL / 6 mL) and reacted at room temperature for 2 hours. After the reaction was completed by LC-MS detection, the crude product was concentrated under reduced pressure, dissolved in tetrahydrofuran / water (4 mL / 1 mL), and lithium hydroxide (0.02 g, 0.8 mmol) was added, and reacted at room temperature for 6 hours. After the reaction was completed by LC-MS detection, the reaction solution was poured into 10 mL of water, adjusted to pH = 3 with 1M hydrochloric acid, extracted with ethyl acetate (10 mL x 3), and the organic phase was combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 4-((lH-pyrazol-4-yl)amino)-2-(l,l-difluoroethyl)-6-phenoxy pyrimidine-5-carboxylic acid (07k) (0.14 g, yield 95%), which was used directly in the next step without purification.

[0612] Step 10: Synthesis of (S,E)-4-((lH-pyrazol-4-yl)amino)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-6-phenoxy pyrimidine-5-carboxamide (07)

[0613] A mixture of 4-((1H-pyrazol-4-yl)amino)-2-(1,1-difluoroethyl)-6- phenoxy pyrimidine-5-carboxylic acid (07k) (0.05 g, 0.1 mmol), (S,E)-1- cyclopropyl-3-(methylsulfonyl)prop-2-en-1-amine trifluoroacetate salt (0.06 g, 0.2 mmol), HATU (0.08 g, 0.2 mmol) and N,N-diisopropyl ethylamine (DIPEA) (0.05 g, 0.4 mmol) was dissolved in DMF (3 mL) and reacted at room temperature for 2 hours. After the reaction was completed by LC-MS detection, the reaction solution was poured into 15 mL of water, extracted with dichloromethane (15 mL x 3), and the organic phase was combined, washed with saturated brine (45 mL), and dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure, and (S,E)-4-((1H-pyrazol-4-yl)amino)-N-(1-cyclopropyl-3- (methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-6-phenoxy pyrimidine-5-carboxamide (07) was obtained by separation and purification with HPLC.

[0614] 1 H NMR (400 MHz, DMSO-d6) δ 12.65 (s, 1H), 10.13 (s, 1H), 8.83 (d, J = 8.2 Hz, 1H), 8.03 (s, 1H), 7.78 (s, 1H), 7.53 - 7.33 (m, 2H), 7.33 - 7.12 (m, 3H), 6.96 - 6.59 (m, 2H), 4.34 - 4.26 (m, 1H), 2.90 (s, 3H), 1.80 (t, J = 19.0 Hz, 3H), 1.14 - 1.04 (m, 1H), 0.60 - 0.33 (m, 4H).

[0615] LC-MS, M / Z (ESI): 519.1 [M+H] + .

[0616] Example 08: Preparation of the target compound 08

[0617] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-(cyclopropylamino)-2-(1,1- difluoroethyl)-6-phenoxy pyrimidine-5-carboxamide (08)

[0618] The synthetic route of compound 08 is shown below:

[0619] The first to eighth steps were carried out completely according to the synthetic method of compound 05, replacing tetrahydro-2H-pyran-4-amine with cyclopropylamine to obtain (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-(cyclopropylamino)-2-(1,1-difluoroethyl)-6-phenoxy-pyrimidine-5-carboxamide (08)

[0620] 1 H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J = 8.0 Hz, 1H), 8.25 (d, J = 3.9 Hz, 1H), 7.58 - 7.36 (m, 2H), 7.35 - 7.17 (m, 3H), 6.95 - 6.67 (m, 2H), 4.24 (td, J = 8.2, 3.8 Hz, 1H), 2.91 (s, 3H), 2.12 - 1.91 (m, 1H), 1.80 (t, J = 18.9 Hz, 3H), 1.06 (dd, J = 13.0, 8.1 Hz, 3H), 0.85 - 0.68 (m, 3H), 0.58 - 0.32 (m, 6H).

[0621] LC-MS, M / Z (ESI): 493.2 [M+H] + .

[0622] Example 09: Preparation of the target compound 09

[0623] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-(oxetan-3-ylamino)-6-phenoxy-pyrimidine-5-carboxamide (09)

[0624] The synthetic route of compound 09 is shown as follows:

[0625] The first to eighth steps were carried out completely according to the synthetic method of compound 05, replacing tetrahydro-2H-pyran-4-amine with cyclopropylamine to obtain (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-(cyclopropylamino)-2-(1,1-difluoroethyl)-6-phenoxy-pyrimidine-5-carboxamide (08)

[0626] 1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J = 8.3 Hz, 1H), 8.65 (d, J = 5.0 Hz, 1H), 7.56 - 7.37 (m, 2H), 7.37 - 7.17 (m, 3H), 7.03 - 6.61 (m, 2H), 5.15 - 4.87 (m, 1H), 4.78 (t, J = 6.9 Hz, 2H), 4.56 (t, J = 6.5 Hz, 2H), 4.30 (td, J = 8.1, 4.1 Hz, 1H), 2.92 (s, 3H), 1.77 (t, J = 19.0 Hz, 3H), 1.15 - 1.05 (m, 1H), 0.61 - 0.28 (m, 4H).

[0627] LC-MS, M / Z (ESI): 509.1 [M+H] + .

[0628] Example 10: Preparation of the target compound 10

[0629] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-6-methyl-2-phenoxy-5- (trifluoromethyl)nicotinamide (10)

[0630] The synthetic route of compound 10 is shown as follows:

[0631] First step: synthesis of ethyl 6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate (10b)

[0632] Ethyl 6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate (10b) (4.10 g, purity: 90%) was obtained by dissolving 6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (10a) (5.00 g, 32.7 mmol) in ethanol (60 mL), then slowly adding SOCl2 (7.71 g, 65.4 mmol) dropwise under an ice water bath, and the reaction liquid was warmed to 80 °C for 16 hours. After the reaction was completed by LC-MS detection, the reaction liquid was concentrated under reduced pressure to remove most of the solvent, then poured into water (80 mL), extracted with ethyl acetate (80 mL x 3), the organic phase was combined, washed with saturated brine (200 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave ethyl 6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate (10b) (4.10 g, purity: 90%), which was used directly for the next step without purification.

[0633] Second step: synthesis of ethyl 5-bromo-6-methyl-2-oxo-1,2-dihydropyridine-3- carboxylate (10c)

[0634] Ethyl 6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate (10b) (3.69 g, 20.4 mmol) and N-bromosuccinimide (NBS) (5.41 g, 30.6 mmol) were dissolved in acetonitrile (40 mL) and reacted at 80 °C for 4 hours. After the reaction was completed by LC-MS detection, it was poured into water (50 mL) and extracted with ethyl acetate (60 mL x 3). The organic phase was combined, washed with saturated brine (150 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave a crude product, which was purified by silica gel column separation (dichloromethane:methanol (V / V) = 100:0-95:5, gradient elution) to give ethyl 5-bromo-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate (10c) (3.41 g, yield 65%).

[0635] Third step: synthesis of ethyl 5-bromo-2-chloro-6-methylnicotinate (10d)

[0636] Ethyl 5-bromo-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate (10c) (3.41 g, 13.2 mmol) was dissolved in 1,4-dioxane (30 mL), and then POCl3(10.0 g, 131.7 mmol) was added dropwise. The reaction was carried out at 100 °C for 6 hours. After the reaction was completed by LC-MS detection, it was slowly poured into water (60 mL) to quench, extracted with ethyl acetate (60 mL x 3), and the organic phase was combined, washed with saturated brine (150 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave a crude product, which was purified by silica gel column separation (petroleum ether: ethyl acetate (V / V) = 100:0-90:10, gradient elution) to give ethyl 5-bromo-2-chloro-6-methylnicotinate (10d) (2.63 g, yield 72%).

[0637] Fourth step: synthesis of ethyl 5-bromo-6-methyl-2-phenoxy nicotinate (10e)

[0638] Ethyl 5-bromo-2-chloro-6-methylnicotinate (10d) (2.63 g, 9.5 mmol) was dissolved in tetrahydrofuran (30 mL), and then sodium phenolate (1.10 g, 9.5 mmol) was added. The reaction was carried out at room temperature for 6 hours. After the reaction was completed by LC-MS detection, it was slowly poured into water (60 mL) to quench, extracted with ethyl acetate (60 mL x 3), and the organic phase was combined, washed with saturated brine (150 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave a crude product, which was purified by silica gel column separation (petroleum ether: ethyl acetate (V / V) = 100:0-90:10, gradient elution) to give ethyl 5-bromo-6-methyl-2-phenoxy nicotinate (10e) (1.65 g, yield 52%).

[0639] Step 5: Synthesis of ethyl 6-methyl-2-phenoxy-5-(trifluoromethyl)nicotinate (10f)

[0640] Ethyl 5-bromo-6-methyl-2-phenoxy nicotinate (10e) (0.80 g, 2.4 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (1.83 g, 12.0 mmol), hexamethylphosphoric triamide (HMPA) (0.42 g, 2.4 mmol) and CuI (0.09 g, 0.5 mmol) were dissolved in N-methylpyrrolidone (8 mL) under nitrogen protection, and reacted at 150 °C for 6 h. After the reaction was completed by LC-MS detection, it was then slowly poured into water (20 mL), extracted with ethyl acetate (20 mL x 3), the organic phase was combined, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure, and purified by silica gel column separation (petroleum ether: ethyl acetate (V / V) = 100:0-90:10, gradient elution) to obtain ethyl 6-methyl-2-phenoxy-5-(trifluoromethyl)nicotinate (10f) (0.24 g, yield 31%).

[0641] Step 6: Synthesis of 6-methyl-2-phenoxy-5-(trifluoromethyl)nicotinic acid (10g)

[0642] Ethyl 6-methyl-2-phenoxy-5-(trifluoromethyl)nicotinate (10f) (0.10 g, 0.3 mmol) and lithium hydroxide (0.03 g, 1.2 mmol) were dissolved in tetrahydrofuran / water (10 mL / 5 mL) and reacted at room temperature for 6 h. After the reaction was completed by LC-MS detection, the reaction solution was poured into 10 mL of water, adjusted to pH = 3 with 1M hydrochloric acid, extracted with ethyl acetate (15 mL x 3), the organic phase was combined, washed with saturated brine (45 mL), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product 6-methyl-2-phenoxy-5-(trifluoromethyl)nicotinic acid (10g) (86.8 g, yield 95%), which was directly used in the next step without purification.

[0643] Step 7: Synthesis of (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-6-methyl-2-phenoxy-5-(trifluoromethyl)nicotinamide (10)

[0644] To a solution of 6-methyl-2-phenoxy-5-(trifluoromethyl)nicotinic acid (10 g) (86.8 mg, 0.3 mmol), (S,E)-1-cyclopropyl-3-(methylsulfonyl)prop-2-en-1-amine trifluoroacetate salt (0.13 g, 0.4 mmol), HATU (0.16 g, 0.4 mmol) and N,N-diisopropyl ethylamine (DIPEA) (0.11 g, 0.9 mmol) in DMF (3 mL) was stirred at room temperature for 2 hours. After the reaction was detected by LC-MS, the reaction solution was poured into 10 mL of water, extracted with ethyl acetate (10 mL x 3), the organic phase was combined, washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure, and purified by HPLC to obtain (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-6-methyl-2-phenoxy-5- (trifluoromethyl)nicotinamide (10).

[0645] 1 H NMR (400 MHz, DMSO-d6) δ 8.75 (d, J = 8.2 Hz, 1H), 8.28 (s, 1H), 7.43 (dd, J = 8.5, 7.3 Hz, 2H), 7.31 - 7.16 (m, 3H), 6.98 - 6.65 (m, 2H), 4.22 (tt, J = 8.4, 1.5 Hz, 1H), 2.93 (s, 3H), 2.40 (d, J = 1.7 Hz, 3H), 1.15 - 1.00 (m, 1H), 0.68 - 0.23 (m, 4H).

[0646] LC-MS, M / Z (ESI): 455.1 [M+H] + .

[0647] Example 11: Preparation of target compound 11

[0648] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-6-methyl-2-phenoxy-5-vinyl nicotinamide (11)

[0649] The synthetic route of compound 11 is shown as follows:

[0650] First step: synthesis of ethyl 6-methyl-2-phenoxy-5-vinyl nicotinate (11b)

[0651] Ethyl 5-bromo-6-methyl-2-phenoxy nicotinate (10e) (0.20 g, 0.6 mmol), potassium vinyltrifluoroborate (0.12 g, 9 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (Pd(dppf)Cl2) (0.04 g, 0.1 mmol) and anhydrous potassium carbonate (0.25 g, 1.8 mmol) were dissolved in 1,4-dioxane / water (8 mL / 2 mL) and reacted at 100 °C for 4 hours. After the reaction was detected by LC-MS, the reaction solution was poured into 10 mL of water, extracted with ethyl acetate (10 mL x 3), and the organic phase was combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure and purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 100:0-80:20, gradient elution) to obtain ethyl 6-methyl-2-phenoxy-5-vinyl nicotinate (11b) (0.17 g, yield 73%).

[0652] Second step: synthesis of 6-methyl-2-phenoxy-5-vinyl nicotinic acid (11c)

[0653] Ethyl 6-methyl-2-phenoxy-5-vinyl nicotinate (11b) (0.10 g, 0.3 mmol) and lithium hydroxide (0.03 g, 1.2 mmol) were dissolved in tetrahydrofuran / water (6 mL / 3 mL) and reacted at room temperature for 6 hours. After the reaction was detected by LC-MS, the reaction solution was poured into 10 mL of water, adjusted to pH = 3 with 1M hydrochloric acid, extracted with ethyl acetate (10 mL x 3), and the organic phase was combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The crude product 6-methyl-2-phenoxy-5-vinyl nicotinic acid (11c) (86 mg, yield 95%) was obtained by concentration under reduced pressure and directly used in the next step without purification.

[0654] Third step: synthesis of (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-6-methyl-2-phenoxy-5-vinyl nicotinamide (11)

[0655] A mixture of 6-methyl-2-phenoxy-5-vinyl nicotinic acid (11c) (86 mg, 0.3 mmol), trifluoroacetate salt of (S,E)-1-cyclopropyl-3-(methylsulfonyl)prop-2-en-1-amine (03k) (0.13 g, 0.4 mmol), HATU (0.16 g, 0.4 mmol) and N,N-diisopropyl ethylamine (DIPEA) (0.11 g, 0.9 mmol) was dissolved in DMF (3 mL) and reacted at room temperature for 2 hours. After the reaction was completed by LC-MS detection, the reaction solution was poured into 10 mL of water, extracted with ethyl acetate (10 mL x 3), the organic phase was combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure, and (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-6-methyl-2-phenoxy-5-vinyl nicotinamide (11) was obtained by HPLC separation and purification.

[0656] 1 H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J = 8.2 Hz, 1H), 8.14 (s, 1H), 7.39 (dd, J = 8.8, 7.1 Hz, 2H), 7.24 - 7.09 (m, 3H), 6.99 - 6.67 (m, 3H), 5.80 (dd, J = 17.5, 1.1 Hz, 1H), 5.37 (dd, J = 11.0, 1.1 Hz, 1H), 4.20 (td, J = 8.3, 3.1 Hz, 1H), 2.91 (s, 3H), 2.31 (s, 3H), 1.19 - 0.98 (m, 1H), 0.67 - 0.23 (m, 4H).

[0657] LC-MS, M / Z (ESI): 413.1 [M+H] + .

[0658] Example 12: Preparation of target compound 12

[0659] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-6-(1,1-difluoroethyl)-5-ethynyl-2-phenoxy nicotinamide (12)

[0660] The synthetic route of compound 12 is shown as follows:

[0661] First step: synthesis of 2-(benzyloxy)-6-chloronicotinic acid methyl ester (12b)

[0662] Methyl 6-chloro-2-fluoro-nicotinate (12a) (5.00 g, 26.5 mmol) and benzyl alcohol (3.14 g, 29.1 mmol) were dissolved in tetrahydrofuran (50 mL), then NaH (1.16 g, 29.1 mmol, content 60%) was added, and the reaction was carried out at room temperature for 6 hours. After the reaction was completed by LC-MS detection, it was poured into water (80 mL), extracted with ethyl acetate (80 mL x 3), the organic phase was combined, washed with saturated brine (200 mL), and dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure, and purified by silica gel column separation (petroleum ether: ethyl acetate (V / V) = 100:0-90:10, gradient elution) to obtain methyl 2-(benzyloxy)-6-chloronicotinate (12b) (2.56 g, yield 35%).

[0663] Second step: synthesis of methyl 2-(benzyloxy)-6-(1-ethoxyvinyl)nicotinate (12c)

[0664] Methyl 2-(benzyloxy)-6-chloronicotinate (12b) (2.56 g, 9.2 mmol), tributyl(1-ethoxyvinyl)tin (5.00 g, 13.9 mmol), and tetrakis(triphenylphosphine)palladium (1.07 g, 0.9 mmol) were dissolved in 1,4-dioxane (30 mL) under nitrogen protection, and the reaction was carried out at 100°C for 6 hours. After the reaction was completed by LC-MS detection, it was poured into saturated aqueous potassium fluoride solution (50 mL), and stirred for 24 hours. Then it was extracted with ethyl acetate (50 mL x 3), the organic phase was combined, washed with saturated brine (120 mL), and dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure, and purified by silica gel column separation (petroleum ether: ethyl acetate (V / V) = 100:0-90:10, gradient elution) to obtain methyl 2-(benzyloxy)-6-(1-ethoxyvinyl)nicotinate (12c) (2.02 g, yield 70%).

[0665] Third step: synthesis of methyl 6-acetyl-2-(benzyloxy)nicotinate (12d)

[0666] Methyl 2-(benzyloxy)-6-(1-ethoxyvinyl)nicotinate (12c) (2.02 g, 6.5 mmol) was dissolved in a 1,4-dioxane solution of HCl (2.0 M, 20 mL), and the reaction was carried out at room temperature for 6 hours. After the reaction was completed by LC-MS detection, it was concentrated under reduced pressure to obtain methyl 6-acetyl-2-(benzyloxy)nicotinate (12d) (1.66 g, yield 90%), which was directly used in the next step without purification.

[0667] Fourth step: synthesis of methyl 2-(benzyloxy)-6-(1,1-difluoroethyl)nicotinate (12e)

[0668] Methyl 6-acetyl-2-(benzyloxy)nicotinate (12d) (1.66 g, 5.8 mmol) and diethylaminosulfur trifluoride (DAST) (2.81 g, 17.5 mmol) were dissolved in dichloroethane (15 mL) and reacted at 70 °C for 16 h. After the reaction was completed by LC-MS detection, the reaction solution was poured into 20 mL of water, extracted with dichloromethane (20 mL x 3), and the organic phase was combined, washed with saturated brine (60 mL), and dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure and purified by silica gel column separation (petroleum ether: ethyl acetate (V / V) = 100:0-90:10, gradient elution) to obtain methyl 2-(benzyloxy)-6-(l,l-difluoroethyl)nicotinate (12e) (1.40 g, yield 78%).

[0669] Fifth step: synthesis of methyl 6-(l,l-difluoroethyl)-2-oxo-l,2-dihydropyridine-3-carboxylate (12f)

[0670] Methyl 6-(l,l-difluoroethyl)-2-oxo-l,2-dihydropyridine-3-carboxylate (12f) (0.87 g, 4.0 mmol) and N-bromosuccinimide (NBS) (1.06 g, 6.0 mmol) were dissolved in acetonitrile (20 mL) and reacted at 80 °C for 4 h. After the reaction was completed by LC-MS detection, it was then poured into water (20 mL), extracted with ethyl acetate (20 mL x 3), and the organic phase was combined, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure and purified by silica gel column separation (dichloromethane:methanol (V / V) = 100:0-95:5, gradient elution) to obtain methyl 5-bromo-6-(l,l-difluoroethyl)-2-oxo-l,2-dihydropyridine-3-carboxylate (12g) (0.89 g, yield 75%).

[0671] Sixth step: synthesis of methyl 5-bromo-6-(l,l-difluoroethyl)-2-oxo-l,2-dihydropyridine-3-carboxylate (12g)

[0672] Methyl 6-(l,l-difluoroethyl)-2-oxo-l,2-dihydropyridine-3-carboxylate (12f) (0.87 g, 4.0 mmol) and N-bromosuccinimide (NBS) (1.06 g, 6.0 mmol) were dissolved in acetonitrile (20 mL) and reacted at 80 °C for 4 h. After the reaction was completed by LC-MS detection, it was then poured into water (20 mL), extracted with ethyl acetate (20 mL x 3), and the organic phase was combined, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure and purified by silica gel column separation (dichloromethane:methanol (V / V) = 100:0-95:5, gradient elution) to obtain methyl 5-bromo-6-(l,l-difluoroethyl)-2-oxo-l,2-dihydropyridine-3-carboxylate (12g) (0.89 g, yield 75%).

[0673] Step 7: Synthesis of methyl 5-bromo-2-chloro-6-(l,l-difluoroethyl)nicotinate (12h)

[0674] Methyl 5-bromo-6-(l,l-difluoroethyl)-2-oxo-l,2-dihydropyridine-3-carboxylate (12g) (0.89 g, 3.0 mmol) was dissolved in 1,4-dioxane (10 mL), then POCl3(4.57 g, 30.1 mmol) was added dropwise, and the reaction was carried out at 100 °C for 6 h. After the reaction was completed by LC-MS detection, the reaction solution was slowly poured into water (20 mL), extracted with ethyl acetate (20 mL x 3), and the organic phase was combined, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure, and purified by silica gel column separation (petroleum ether: ethyl acetate (V / V) = 100:0-90:10, gradient elution) to obtain methyl 5-bromo-2-chloro-6-(l,l-difluoroethyl)nicotinate (12h) (0.61 g, yield 65%).

[0675] Step 8: Synthesis of methyl 5-bromo-6-(l,l-difluoroethyl)-2-phenoxy nicotinate (12i)

[0676] Methyl 5-bromo-2-chloro-6-(l,l-difluoroethyl)nicotinate (12h) (0.61 g, 1.9 mmol) was dissolved in tetrahydrofuran (15 mL), then sodium phenolate (0.27 g, 1.9 mmol) was added, and the reaction was carried out at room temperature for 6 h. After the reaction was completed by LC-MS detection, it was slowly poured into water (15 mL), extracted with ethyl acetate (15 mL x 3), and the organic phase was combined, washed with saturated brine (40 mL), and dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure, and purified by silica gel column separation (petroleum ether: ethyl acetate (V / V) = 100:0-90:10, gradient elution) to obtain methyl 5-bromo-6-(l,l-difluoroethyl)-2-phenoxy nicotinate (12i) (0.30 g, yield 41%).

[0677] Step 9: Synthesis of methyl 6-(l,l-difluoroethyl)-5-ethynyl-2-phenoxy nicotinate (12j)

[0678] Methyl 6-(1,1 -difluoroethyl)-5-ethynyl-2-phenoxy nicotinate (12j) (0.18 g, 0.6 mmol) and lithium hydroxide (0.05 g, 2.4 mmol) were dissolved in tetrahydrofuran / water (10 mL / 5 mL) and reacted at room temperature for 6 hours. After the reaction was completed by LC-MS detection, the reaction solution was poured into 10 mL of water, adjusted to pH = 3 with 1 M hydrochloric acid, extracted with ethyl acetate (15 mL x 3), the organic phase was combined and washed with saturated brine (45 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude 6-(1,1 -difluoroethyl)-5-ethynyl-2-phenoxy nicotinic acid (12k) (0.17 g, 95% yield), which was used directly in the next step without purification.

[0679] Tenth step: Synthesis of 6-(1,1 -difluoroethyl)-5-ethynyl-2-phenoxy nicotinic acid (12k)

[0680] Methyl 6-(1,1 -difluoroethyl)-5-ethynyl-2-phenoxy nicotinate (12j) (0.18 g, 0.6 mmol) and lithium hydroxide (0.05 g, 2.4 mmol) were dissolved in tetrahydrofuran / water (10 mL / 5 mL) and reacted at room temperature for 6 hours. After the reaction was completed by LC-MS detection, the reaction solution was poured into 10 mL of water, adjusted to pH = 3 with 1 M hydrochloric acid, extracted with ethyl acetate (15 mL x 3), the organic phase was combined and washed with saturated brine (45 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude 6-(1,1 -difluoroethyl)-5-ethynyl-2-phenoxy nicotinic acid (12k) (0.17 g, 95% yield), which was used directly in the next step without purification.

[0681] Tenth step: Synthesis of 6-(1,1 -difluoroethyl)-5-ethynyl-2-phenoxy nicotinic acid (12k)

[0682] A mixture of 6-(1,1 -difluoroethyl)-5-ethynyl-2-phenoxy nicotinic acid (12k) (100 mg, 0.3 mmol), (S,E)-1 -cyclopropyl-3-(methylsulfonyl)prop-2-en-1 -amine trifluoroacetate salt (0.14 g, 0.4 mmol), HATU (0.19 g, 0.4 mmol) and N,N-diisopropylethylamine (DIPEA) (0.13 g, 0.9 mmol) in DMF (3 mL) was stirred at room temperature for 2 h. After the reaction was completed by LC-MS, the reaction mixture was poured into 10 mL of water, extracted with ethyl acetate (10 mL x 3), the organic phase was combined, washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure and purified by HPLC to give (S,E)-N-(1 -cyclopropyl-3-(methylsulfonyl)allyl)-6-(1,1 -difluoroethyl)-5-ethynyl-2-phenoxy nicotinamide (12).

[0683] 1 H NMR (400 MHz, DMSO-d6) d 8.88 (d, J = 8.2 Hz, 1 H), 8.28 (s, 1 H), 7.59 - 7.33 (m, 2H), 7.33 - 7.08 (m, 3H), 6.98 - 6.74 (m, 2H), 4.64 (s, 1 H), 4.26 (td, J = 8.3, 3.3 Hz, 1 H), 2.98 (s, 3H), 1.76 (t, J = 19.0 Hz, 3H), 1.08 (dd, J = 9.1, 3.9 Hz, 1 H), 0.70 - 0.28 (m, 4H).

[0684] LC-MS, M / Z (ESI): 461.1 [M+H] + .

[0685] Example 13: Preparation of the target compound 13

[0686] (S,E)-N-(1 -cyclopropyl-4-(dimethylamino)-4-oxobut-2-en-1 -yl)-2-(1,1 - difluoroethyl)-4-phenoxy pyrimidine-5-carboxamide (13)

[0687] The synthetic route of compound 13 is shown as follows:

[0688] First step: Synthesis of N,N-dimethyl-2-(triphenyl-λ 5 - phosphinyl)acetamide (13b)

[0689] Compound 2-chloro-N,N-dimethylacetamide (13a) (6.06 g, 50 mmol) and triphenylphosphine (13.10 g, 50 mmol) were dissolved in tetrahydrofuran (70 mL) and the reaction was refluxed at 70 °C for 48 h. After the reaction mixture was cooled to room temperature, 5% NaOH solution (50 mL) was added dropwise and the reaction was stirred for 30 min. The reaction mixture was concentrated under reduced pressure and water (50 mL) was added to the suspension to extract the product with dichloromethane (100 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain N,N-dimethyl-2-(triphenyl-λ 5 -phosphoranylidene)acetamide (13b) (16.57 g, 95% yield) which was used directly in the next step without purification.

[0690] Second step: Synthesis of (S,E)-(1-cyclopropyl-4-(dimethylamino)-4-oxobut-2-en-1- yl)carbamic acid tert-butyl ester (13c)

[0691] Compound N,N-dimethyl-2-(triphenyl-λ 5 -phosphoranylidene)acetamide (13b) (400 mg, 2.0 mmol) was dissolved in dichloromethane (10.0 mL) and triethylamine (2.0 mL) was added dropwise with stirring at room temperature. Intermediate (S)-(1-cyclopropyl-2-oxoethyl)carbamic acid tert-butyl ester was added and the reaction was stirred at 60 °C for 6 h. The reaction was monitored by LC-MS and the organic phase was removed by concentration under reduced pressure. The product was purified by preparative HPLC to obtain (S,E)-(1-cyclopropyl-4-(dimethylamino)-4-oxobut-2-en-1-yl)carbamic acid tert-butyl ester (13c) as a colorless oil (401 mg, 75% yield).

[0692] Third step: Synthesis of (S,E)-4-amino-4-cyclopropyl-N,N-dimethylbut-2-enamide (13d)

[0693] (S,E)-(1-cyclopropyl-4-(dimethylamino)-4-oxobut-2-en-1-yl)carbamic acid tert-butyl ester (13c) (400 mg, 1.5 mmol) was dissolved in dichloromethane (10.0 mL) and 4 M HCl solution in 1,4-dioxane (2.0 mL) was added dropwise with stirring at room temperature. The reaction was stirred for 30 min and the reaction was monitored by TLC. The organic phase was removed by concentration under reduced pressure and excess HCl was removed by concentration with dichloromethane several times to obtain (S,E)-4-amino-4-cyclopropyl-N,N-dimethylbut-2-enamide (13d) (250 mg, 100% yield) which was used directly in the next step without purification.

[0694] Step 4: Synthesis of (S, E)-N-(1-cyclopropyl-4-(dimethylamino)-4-oxobut-2-en-1-yl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide (13)

[0695] (S, E)-4-amino-4-cyclopropyl-N,N-dimethylbut-2-enamide (13d) (41 mg, 0.24 mmol) was dissolved in DMF (3 mL), 2-(1,1-difluoroethyl)-4-phenoxy-pyrimidine-5-carboxylic acid (01i) (45 mg, 0.16 mmol) was added, triethylamine (81 mg, 0.80 mmol) was added dropwise, HATU (153 mg, 0.40 mmol) was added under stirring, and the reaction was allowed to proceed at room temperature for 1 hour. The reaction was detected by LC-Ms, 10 mL of saturated brine solution was added to the reaction solution, and the product was extracted with ethyl acetate (10 mL x 3). After the organic phase was concentrated under reduced pressure, HPLC was used for separation and purification, and (S, E)-N-(1-cyclopropyl-4-(dimethylamino)-4-oxobut-2-en-1-yl)-2-(1,1-difluoroethyl)-4-phenoxy-pyrimidine-5-carboxamide (13) was obtained.

[0696] 1 H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.83 (d, J = 8.3 Hz, 1H), 7.46 (t, J = 7.9 Hz, 2H), 7.31 - 7.27 (m, 3H), 6.72 - 6.67 (m, 1H), 6.55 (d, J = 15.4 Hz, 1H), 4.21 (d, J = 6.0 Hz, 1H), 2.81 (d, J = 14.7 Hz, 6H), 1.82 (t, J = 19.0 Hz, 3H), 1.05 - 1.00 (m, 1H), 0.49 - 0.34 (m, 4H).

[0697] LC-MS, M / Z (ESI): 431.1 [M+H] + .

[0698] Example 14: Preparation of target compound 14

[0699] (S, E)-N-(1-cyclopropyl-3-(N,N-dimethylsulfamoyl)allyl)-2-(1,1-difluoroethyl)-4- phenoxy-pyrimidine-5-carboxamide (14)

[0700] The synthesis route of compound 14 is shown as follows:

[0701] Step 1: Synthesis of diethyl chlorophosphine (14b)

[0702] To a solution of diethyl phosphite (14a) (10.0 g, 18.7 mmol) in carbon tetrachloride (50 mL) was added N-chlorosuccinimide (3.66 g, 18.7 mmol) and the resulting mixture was stirred at 40 °C for 12 h. TLC detection showed the reaction was complete. The resulting mixture was diluted with water (100 mL) and then extracted with dichloromethane (100 mL x 3). The combined organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate and concentrated to give the crude product. The crude product was purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 100:0-70:30, gradient elution) to give diethyl (N,N-dimethylsulfamoyl)methyl)phosphonate (14b) (8.00 g, yield 56%).

[0703] Second Step: Synthesis of diethyl (N,N-dimethylsulfamoyl)methyl)phosphonate (14c)

[0704] To a solution of N,N-dimethylmethanesulfonamide (25.0 g, 203 mmol) in tetrahydrofuran (400 mL) was added dropwise n-butyllithium (97.4 mL, 2.5 M in tetrahydrofuran) and a solution of diethyl phosphite (14b) (35.0 g, 203 mmol) in tetrahydrofuran at -78 °C. The resulting mixture was stirred at room temperature for 2 h. LC-MS detection showed the reaction was complete. The reaction was quenched with water (300 mL) and then extracted with ethyl acetate (300 mL x 3). The combined organic phase was washed with saturated brine (600 mL), dried over anhydrous sodium sulfate and concentrated to give the crude product. The crude product was purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 100:0-70:30, gradient elution) to give diethyl (N,N-dimethylsulfamoyl)methyl)phosphonate (14c) (500.0 mg, yield 1%).

[0705] Third Step: Synthesis of (S,E)-(1-cyclopropyl-3-(N,N-dimethylsulfamoyl)allyl)carbamic acid tert-butyl ester (14d)

[0706] To a solution of diethyl (N,N-dimethylsulfamoyl)methyl)phosphonate (14c) (3.00 g, 11.6 mmol), (S)-(l-cyclopropyl-2-oxoethyl) tert-butylcarbamate (2.31 g, 11.6 mmol) in tetrahydrofuran (30 mL) was added anhydrous potassium carbonate (4.80 g, 34.7 mmol), the resulting mixture was stirred at 60 °C for 4 h. LC-MS indicated the reaction was complete, the reaction was diluted with water (50 mL), then extracted with ethyl acetate (50 mL x 3), the combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate and concentrated to give the crude product. The crude product was purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 100:0-70:30, gradient elution) to give (S,E)-(l-cyclopropyl-3-(N,N-dimethylsulfamoyl)allyl) tert-butylcarbamate (14d) (1.40 g, yield 36%).

[0707] Fourth Step: Synthesis of (S,E)-3-amino-3-cyclopropyl-N,N-dimethylpropyl-1-en-1- sulfonamide (14e)

[0708] To a solution of (S,E)-(l-cyclopropyl-3-(N,N-dimethylsulfamoyl)allyl) tert-butylcarbamate (14d) (660 mg, 2.14 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (3 mL), the resulting mixture was stirred at room temperature for 2 h. LC-MS indicated the reaction was complete, the reaction was concentrated to give the crude (S,E)-3-amino-3-cyclopropyl-N,N-dimethylpropyl-1-en-1-sulfonamide (14e) (410 mg, yield 74%), which was used directly in the next step without purification.

[0709] Fifth Step: Synthesis of (S,E)-N-(l-cyclopropyl-3-(N,N-dimethylsulfamoyl)allyl)-2-(l,l- difluoroethyl)-4-phenoxy pyrimidine-5-carboxamide (14)

[0710] (S, E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1, 1-difluoroethyl)-4-((1, 1-dioxidothiophen-3-yl)amino)-6-phenoxypyrimidine-5-carboxamide (15)

[0711] 1 H NMR (400 MHz, DMSO-d6) δ 8.97 (s, 1H), 8.93 (d, J = 8.1 Hz, 1H), 7.48 - 7.44 (m, 2H), 7.30 - 7.27 (m, 3H), 6.70 (dd, J = 15.3, 5.0 Hz, 1H), 6.55 - 6.50 (m, 1H), 4.28 - 4.23 (m, 1H), 2.52 (d, J = 1.0 Hz, 6H), 1.85 (d, J = 19.0 Hz, 3H), 1.09 (dq, J = 8.4, 4.8, 3.9 Hz, 1H), 0.50 (ddd, J = 18.5, 8.8, 3.2 Hz, 3H), 0.38 (t, J = 6.0 Hz, 1H).

[0712] LC-MS, M / Z (ESI): 467.1 [M+H] + .

[0713] Example 15: Preparation of the target compound 15

[0714] (S, E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1, 1-difluoroethyl)-4-((1, 1-dioxidothiophen-3-yl)amino)-6-phenoxypyrimidine-5-carboxamide (15)

[0715] The synthetic route of compound 15 is shown as follows:

[0716] Step 1: Synthesis of methyl 2-(1,1 -difluoroethyl)-4-((1,1 -dioxidothiophen-3- yl)amino)-6-phenoxy pyrimidine-5-carboxylate (15a)

[0717] Methyl 4-chloro-2-(1,1 -difluoroethyl)-6-phenoxy pyrimidine-5-carboxylate (07i) (80 mg, 0.2 mmol), 3-aminothiophene-1,1 -dioxide (59 mg, 0.5 mmol) and N,N- diisopropylethylamine (DIPEA) (63 mg, 0.5 mmol) were dissolved in tetrahydrofuran (5 mL) and reacted at 80 °C for 8 hours. After the reaction was completed by LC-MS detection, the reaction solution was poured into 10 mL of water, extracted with ethyl acetate (10 mL x 3), and the organic phase was combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure and purified by silica gel column separation (petroleum ether: ethyl acetate (V / V) = 100:0-75:25, gradient elution) to obtain methyl 2-(1,1 -difluoroethyl)-4-((1,1 -dioxidothiophen-3-yl)amino)-6- phenoxy pyrimidine-5-carboxylate (15a) (86 mg, yield 85%).

[0718] Step 2: Synthesis of 2-(1,1 -difluoroethyl)-4-((1,1 -dioxidothiophen-3-yl)amino)-6- phenoxy pyrimidine-5-carboxylic acid (15b)

[0719] Methyl 2-(1,1 -difluoroethyl)-4-((1,1 -dioxidothiophen-3-yl)amino)-6-phenoxy pyrimidine-5-carboxylate (15a) (86 mg, 0.2 mmol) was dissolved in tetrahydrofuran / water (4 mL / 1 mL), and lithium hydroxide (25 mg, 0.6 mmol) was added, and the reaction was carried out at room temperature for 6 hours. After the reaction was completed by LC-MS detection, the reaction solution was poured into 10 mL of water, adjusted to pH = 3 with 1 M hydrochloric acid, extracted with ethyl acetate (10 mL x 3), and the organic phase was combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. 2-(1,1 -difluoroethyl)-4-((1,1 -dioxidothiophen-3-yl)amino)-6-phenoxy pyrimidine-5-carboxylic acid (15b) (78 mg, yield 95%) was obtained by concentration under reduced pressure, and the next step was carried out directly without purification.

[0720] Step 3: Synthesis of (S,E)-N-(1 -cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1 - difluoroethyl)-4-((1,1 -dioxidothiophen-3-yl)amino)-6-phenoxy pyrimidine-5-carboxamide (15)

[0721] A mixture of 2-(1,1-difluoroethyl)-4-((1,1-dioxide thien-3-yl)amino)-6- phenoxy pyrimidine-5-carboxylic acid (15b) (78 mg, 0.2 mmol), (S,E)-1- cyclopropyl-3-(methylsulfonyl)prop-2-en-1-amine trifluoroacetate salt (85 mg, 0.3 mmol), HATU (112 mg, 0.3 mmol) and N,N-diisopropyl ethylamine (DIPEA) (76 mg, 0.6 mmol) were dissolved in DMF (3 mL) and reacted at room temperature for 2 hours. After the reaction was completed as detected by LC-MS, the reaction solution was poured into 10 mL of water, extracted with ethyl acetate (10 mL x 3), and the organic phase was combined, washed with saturated brine (25 mL), and dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure and purified by HPLC to obtain (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-((1,1-dioxide thien-3-yl)amino)-6-phenoxy pyrimidine-5-carboxamide (15).

[0722] 1 H NMR (400 MHz, DMSO-d6) δ 8.80 (d, J = 8.3 Hz, 1H), 8.64 (d, J = 5.6 Hz, 1H), 7.44 (t, J = 7.9 Hz, 2H), 7.26 (t, J = 7.8 Hz, 3H), 6.97 - 6.72 (m, 2H), 4.74 (tt, J = 10.7, 5.3 Hz, 1H), 4.58 (dd, J = 14.5, 8.6 Hz, 2H), 4.43 - 4.22 (m, 3H), 2.92 (s, 3H), 1.82 (t, J = 19.0 Hz, 3H), 1.10 (tt, J = 13.5, 6.7 Hz, 1H), 0.63 - 0.33 (m, 4H).

[0723] LC-MS, M / Z (ESI): 557.1 [M+H] + .

[0724] Example 16: Preparation of the target compound 16

[0725] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-((1-methyl-1H- pyrazol-4-yl)amino)-6-phenoxy pyrimidine-5-carboxamide (16)

[0726] The synthetic route of compound 16 is shown as follows:

[0727] The synthesis of compound 16 was carried out exactly as per the synthetic procedure of compound 15, only replacing 3-aminothiophene-1,1 -dioxide with 1 -methyl- 1H-pyrazol-4-amine to obtain (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-((1-methyl-1H-pyrazol-4-yl)amino)-6-phenoxy-pyrimidine-5-carboxamide (16)

[0728] Compound 16: 1 H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.86 (d, J = 8.2 Hz, 1H), 7.99 (s, 1H), 7.71 (s, 1H), 7.45 (dd, J = 8.6, 7.3 Hz, 2H), 7.28 (d, J = 8.5 Hz, 3H), 6.99 - 6.72 (m, 2H), 4.33 (td, J = 8.1, 3.9 Hz, 1H), 3.83 (s, 3H), 2.92 (s, 3H), 1.84 (t, J = 19.0 Hz, 3H), 1.13 (tt, J = 9.7, 5.1 Hz, 1H), 0.64 - 0.31 (m, 4H).

[0729] LC-MS, M / Z (ESI): 533.1 [M+H] + .

[0730] Example 17: Preparation of the target compound 17

[0731] ((S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-phenoxy-6-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)amino)pyrimidine-5-carboxamide (17)

[0732] The synthetic route of compound 17 is shown below:

[0733] The synthesis of compound 17 was carried out exactly as per the synthetic procedure of compound 15, only replacing 3-aminothiophene-1,1 -dioxide with 1 -(2,2,2-trifluoroethyl)- 1H-pyrazol-4-amine to obtain ((S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-phenoxy-6-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)amino)pyrimidine-5-carboxamide (17)

[0734] Compound 17: 1H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.90 (d, J = 8.2 Hz, 1H), 8.19 (s, 1H), 7.88 (s, 1H), 7.61 - 7.41 (m, 2H), 7.28 (d, J = 7.9 Hz, 3H), 7.10 - 6.61 (m, 2H), 5.16 (q, J = 9.1 Hz, 2H), 4.34 (td, J = 8.1, 4.0 Hz, 1H), 2.92 (s, 3H), 1.85 (t, J = 19.0 Hz, 3H), 1.16 - 1.05 (m, 1H), 0.75 - 0.27 (m, 4H).

[0735] LC-MS, M / Z (ESI): 601.0 [M+H] + .

[0736] Example 18: Preparation of Compound 18

[0737] (S,E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-4-((l- (methylsulfonyl)azetidin-3-yl)amino)-6-phenoxy pyrimidine-5-carboxamide (18)

[0738] The synthesis of compound 18 is shown below:

[0739] The synthesis of compound 18 was carried out exactly as described for the synthesis of compound 15, replacing 3-aminothiophene-1,1-dioxide with 1- (methylsulfonyl)azetidin-3-amine to give (S,E)-N-(l-cyclopropyl-3- (methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-4-((l-(methylsulfonyl)azetidin-3- yl)amino)-6-phenoxy pyrimidine-5-carboxamide (18)

[0740] Compound 18: 1H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J = 8.3 Hz, 1H), 8.54 (d, J = 5.5 Hz, 1H), 7.65 - 7.33 (m, 2H), 7.26 (t, J = 7.8 Hz, 3H), 6.99 - 6.72 (m, 2H), 4.74 (q, J = 7.0 Hz, 1H), 4.31 (td, J = 8.2, 4.2 Hz, 1H), 4.13 (t, J = 8.1 Hz, 2H), 3.94 (dd, J = 6.3, 2.5 Hz, 2H), 3.05 (s, 3H), 2.92 (s, 3H), 1.81 (t, J = 19.0 Hz, 3H), 1.17 - 1.04 (m, 1H), 0.74 - 0.31 (m, 4H).

[0741] LC-MS, M / Z (ESI): 586.0 [M+H] + .

[0742] Example 19: Preparation of the target compound 19

[0743] (S,E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-4-((l-(methylsulfonyl)-lH-pyrazol-4-yl)amino)-6-phenoxy-pyrimidine-5-carboxamide (19)

[0744] The synthetic route of compound 19 is shown below:

[0745] First Step: Synthesis of 2-(l,l-difluoroethyl)-4-((l-(methylsulfonyl)-lH-pyrazol-4-yl)amino)-6-phenoxy-pyrimidine-5-carboxylic acid (19a)

[0746] Methyl 4-((l-(tert-butoxycarbonyl)-lH-pyrazol-4-yl)amino)-2-(l,l- difluoroethyl)-6-phenoxy pyrimidine-5-carboxylate (07j) (60 mg, 0.1 mmol) was dissolved in trifluoroacetic acid / dichloromethane (1 mL / 2 mL) and reacted at room temperature for 2 hours. After the reaction was completed as detected by LC-MS, the trifluoroacetic acid was removed by concentration under reduced pressure to obtain a crude product. The crude product was dissolved in dichloromethane (3 mL), N,N-diisopropylethylamine (DIPEA) (41 mg, 0.3 mmol) and methanesulfonyl chloride (MsCl) (18 mg, 0.2 mmol) were added, and then the reaction was allowed to proceed at room temperature for 1 hour. After the reaction was completed as detected by LC-MS, the solvent was removed by concentration under reduced pressure, and the crude product was dissolved in tetrahydrofuran / water (3 mL / 1 mL), LiOH (15 mg, 0.4 mmol) was added, and the reaction was allowed to proceed at room temperature for 4 hours. After the reaction was completed as detected by LC-MS, the reaction solution was poured into water (5 mL), and the pH was adjusted to 3 with 1M hydrochloric acid. The organic phase was extracted with ethyl acetate (10 mL x 3), combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave 2-(l,l-difluoroethyl)-4-((l-(methylsulfonyl)-lH-pyrazol-4-yl)amino)-6- phenoxy pyrimidine-5-carboxylic acid (19a) (47 mg, 85% yield). The next step was performed without purification.

[0747] Second Step: Synthesis of (S,E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l- difluoroethyl)-4-((l-(methylsulfonyl)-lH-pyrazol-4-yl)amino)-6-phenoxy pyrimidine-5- carboxamide (19)

[0748] A mixture of 2-(1,1-difluoroethyl)-4-((1-(methylsulfonyl)-1H-pyrazol-4-yl)amino)- 6-phenoxy pyrimidine-5-carboxylic acid (19a) (47 mg, 0.1 mmol), (S,E)-1- cyclopropyl-3-(methylsulfonyl)prop-2-en-1-amine trifluoroacetate salt (47 mg, 0.2 mmol), HATU (62 mg, 0.2 mmol) and N,N-diisopropyl ethylamine (DIPEA) (42 mg, 0.3 mmol) were dissolved in DMF (3 mL) and reacted at room temperature for 2 hours. After the reaction was completed as detected by LC-MS, the reaction solution was poured into 10 mL of water, extracted with ethyl acetate (10 mL x 3), and the organic phase was combined, washed with saturated brine (25 mL), and dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure and purified by HPLC to obtain (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-((1- (methylsulfonyl)-1H-pyrazol-4-yl)amino)-6-phenoxy pyrimidine-5-carboxamide (19).

[0749] 1 H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.95 (d, J = 8.1 Hz, 1H), 8.62 (s, 1H), 8.29 (s, 1H), 7.61 - 7.39 (m, 2H), 7.29 (d, J = 7.9 Hz, 3H), 7.05 - 6.69 (m, 2H), 4.37 (td, J = 8.0, 3.8 Hz, 1H), 3.52 (s, 3H), 2.92 (s, 3H), 1.84 (t, J = 19.0 Hz, 3H), 1.11 (dt, J = 13.4, 6.5 Hz, 1H), 0.67 - 0.29 (m, 4H).

[0750] LC-MS, M / Z (ESI): 597.1 [M+H] + .

[0751] Example 20: Preparation of target compound 20

[0752] N-((S,E)-1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-((1,1- dioxidothiopyran-3-yl)amino)-6-phenoxy pyrimidine-5-carboxamide (20)

[0753] The synthetic route of compound 20 is shown below:

[0754] The synthesis of compound 20 was carried out exactly as for compound 15, replacing 3- aminothiophene-1,1 -dioxide with 3-amino-tetrahydrothiophene 1,1 -dioxide to give (N-((S,E)-1 -cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1 -difluoroethyl)-4-((1,1 - dioxotetrahydrothiophen-3-yl)amino)-6-phenoxy-pyrimidine-5-carboxamide (20)

[0755] Compound 20: 1 H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J = 8.2 Hz, 1 H), 8.66 - 8.33 (m, 1 H), 7.44 (t, J = 7.8 Hz, 2H), 7.26 (d, J = 8.4 Hz, 3H), 6.99 - 6.63 (m, 2H), 5.14 - 4.72 (m, 1 H), 4.48 - 4.11 (m, 1 H), 3.52 (dd, J = 13.1, 7.7 Hz, 1 H), 3.32 - 3.02 (m, 3H), 2.50 (s, 1 H), 2.27 (ddd, J = 13.6, 11.6, 7.0 Hz, 1 H), 1.81 (t, J = 19.0 Hz, 3H), 1.10 (dd, J = 8.6, 4.0 Hz, 1 H), 0.66 - 0.29 (m, 4H).

[0756] LC-MS, M / Z (ESI): 571.0 [M+H] + .

[0757] Example 21 : Preparation of target compound 21

[0758] (E)-4-amino-N-(1 -cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-2-(1,1 - difluoroethyl)-6-phenoxy-pyrimidine-5-carboxamide (21)

[0759] The synthetic route of compound 21 is shown below:

[0760] The synthesis of compound 21 was carried out exactly as for compound 15 to give (E)-4-amino-N-(1 -cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-2-(1,1 - difluoroethyl)-6-phenoxy-pyrimidine-5-carboxamide (21)

[0761] Compound 21: 1H NMR (400 MHz, DMSO-d6) δ 8.68 (d, J = 8.0 Hz, 1H), 7.89 (s, 2H), 7.44 (dd, J = 9.4, 6.5 Hz, 2H), 7.29 - 7.23 (m, 3H), 6.35 (dd, J = 34.6, 8.9 Hz, 1H), 4.49 (q, J = 8.3 Hz, 1H), 3.24 (s, 3H), 1.74 (t, J = 18.9 Hz, 3H), 1.23 (d, J = 4.8 Hz, 1H), 0.51 - 0.31 (m, 4H).

[0762] LC-MS, M / Z (ESI): 471.0 [M+1] + .

[0763] Example 22: Preparation of Compound 22

[0764] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-((1- (difluoromethyl)-1H-pyrazol-4-yl)amino)-6-phenoxy pyrimidine-5-carboxamide (22)

[0765] The synthetic route of compound 22 is shown below:

[0766] The synthesis of compound 22 was carried out exactly as described for the synthesis of compound 15, replacing 3-aminothiophene-1,1-dioxide with 1-(difluoromethyl)-1H-pyrazol-4-amine to give (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-((1- (difluoromethyl)-1H-pyrazol-4-yl)amino)-6-phenoxy pyrimidine-5-carboxamide (22)

[0767] Compound 22: 1 H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.95 (d, J = 8.3 Hz, 1H), 8.49 (s, 1H), 8.11 (s, 1H), 7.84 (s, 1H), 7.49 - 7.43 (m, 2H), 7.31 - 7.25 (m, 3H), 6.93 - 6.83 (m, 2H), 4.36 (td, J = 8.0, 3.9 Hz, 1H), 2.92 (s, 3H), 1.85 (t, J = 19.0 Hz, 3H), 1.17 - 1.09 (m, 1H), 0.58 - 0.43 (m, 4H).

[0768] LC-MS, M / Z (ESI): 569.0 [M+1] + .

[0769] Example 23: Preparation of the target compound 23

[0770] (S,E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-4- phenoxy-6-(thiazol-5-ylamino)pyrimidine-5-carboxamide (23)

[0771] The synthetic route of compound 23 is shown below:

[0772] The synthesis of compound 23 was carried out exactly as described for compound 15, replacing 3-aminothiophene-1,1-dioxide with 5-aminothiazole to give ((S,E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-4- phenoxy-6-(thiazol-5-ylamino)pyrimidine-5-carboxamide (23)

[0773] Compound 23: 1 H NMR (400 MHz, DMSO-d6) δ 11.17 (s, 1H), 8.97 (s, 1H), 8.62 (s, 1H), 7.86 (s, 1H), 7.43 (t, J = 7.8 Hz, 2H), 7.28 - 7.23 (m, 3H), 6.91 - 6.82 (m, 2H), 4.33 (dt, J = 8.2, 4.1 Hz, 1H), 2.91 (s, 3H), 1.88 (t, J = 18.9 Hz, 3H), 1.13 - 1.07 (m, 1H), 0.58 - 0.49 (m 1H), 0.44 (dd, J = 8.0, 3.2 Hz, 3H).

[0774] LC-MS, M / Z (ESI): 536.1 [M+1] + .

[0775] Example 24: Preparation of the target compound 24

[0776] (S,E)-4-((5-cyano-lH-pyrazol-4-yl)amino)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)- 2-(l,l-difluoroethyl)-6-phenoxyprimidine-5-carboxamide (24)

[0777] The synthetic route of compound 24 is shown below:

[0778] The synthesis of compound 24 was carried out exactly as described for compound 15, except that 3-aminothiophene-1,1 -dioxide was replaced by 4-amino-1 H- pyrazole-3-carbonitrile to give (S,E)-4-((5-cyano-1 H-pyrazol-4-yl)amino)-N-(1 - cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1 -difluoroethyl)-6-phenoxy-pyrimidine-5- carboxamide (24)

[0779] Compound 24: 1 H NMR (400 MHz, DMSO-d6) δ 10.52 (s, 1 H), 8.88 (d, J = 7.9 Hz, 1 H), 8.17 (s, 1 H), 7.46 - 7.40 (m, 2 H), 7.30 - 7.23 (m, 3 H), 6.90 - 6.81 (m, 2 H), 4.29 (td, J = 8.3, 3.1 Hz, 1 H), 2.91 (s, 3 H), 1.76 (t, J = 19.0 Hz, 3 H), 1.16 - 1.09 (m, 1 H), 0.51 (dt, J = 8.4, 3.0 Hz, 1 H), 0.53 - 0.40 (m, 3 H).

[0780] LC-MS, M / Z (ESI): 544.1 [M+1 ] + .

[0781] Example 25: Preparation of the target compound 25

[0782] (S,E)-4-((2H-tetrazol-5-yl)methyl)amino)-N-(1 -cyclopropyl-3-(methylsulfonyl)allyl)- 2-(1,1 -difluoroethyl)-6-phenoxy-pyrimidine-5-carboxamide (25)

[0783] The synthetic route of compound 25 is shown below:

[0784] The synthesis of compound 25 was carried out exactly as described for compound 15, except that 3-aminothiophene-1,1 -dioxide was replaced by (2H-tetrazol-5- yl)methanamine to give (S,E)-4-((2H-tetrazol-5-yl)methyl)amino)-N-(1 -cyclopropyl- 3-(methylsulfonyl)allyl)-2-(1,1 -difluoroethyl)-6-phenoxy-pyrimidine-5-carboxamide (25)

[0785] Compound 25: 1H NMR (400 MHz, DMSO-d6) δ 8.89 - 8.72 (m, 2H), 7.44 (td, J = 7.2, 2.1 Hz, 2H), 7.34 - 7.19 (m, 3H), 6.97 - 6.71 (m, 2H), 5.02 - 4.82 (m, 2H), 4.30 (td, J = 8.3, 4.1 Hz, 1H), 2.94 (s, 3H), 1.65 (t, J = 19.0 Hz, 3H), 1.20 - 1.03 (m, 1H), 0.64 - 0.31 (m, 4H).

[0786] LC-MS, M / Z (ESI): 535.0 [M+H] + .

[0787] Example 26: Preparation of the target compound 26

[0788] N-((S,E)-1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-(((1R,3R)-3- (methylsulfonyl)cyclobutyl)amino)-6-phenoxy pyrimidine-5-carboxamide (26)

[0789] The synthetic route of compound 26 is shown below:

[0790] The synthesis of compound 26 was carried out exactly as described for the synthesis of compound 15, only replacing 3-aminothiophene-1,1-dioxide with (1R,3R)-3- (methylsulfonyl)cyclobutane-1 -amine to give N-((S,E)-1-cyclopropyl-3-(methylsulfonyl)allyl)- 2-(1,1-difluoroethyl)-4-(((1R,3R)-3-(methylsulfonyl)cyclobutyl)amino)-6-phenoxy pyrimidine- 5-carboxamide (26)

[0791] Compound 26: 1 H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J = 8.3 Hz, 1H), 8.41 (d, J = 7.1 Hz, 1H), 7.59 - 7.32 (m, 2H), 7.25 (dd, J = 7.7, 5.5 Hz, 3H), 7.05 - 6.71 (m, 2H), 4.89 - 4.53 (m, 1H), 4.30 (td, J = 8.0, 3.9 Hz, 1H), 3.98 - 3.71 (m, 1H), 2.97 (s, 3H), 2.92 (s, 3H), 2.82 - 2.50 (m, 4H), 1.78 (t, J = 18.9 Hz, 3H), 1.10 (td, J = 13.4, 8.1 Hz, 1H), 0.49 (dq, J = 37.4, 6.1, 4.8 Hz, 4H).

[0792] LC-MS, M / Z (ESI): 585.0 [M+H] + .

[0793] Example 27: Preparation of the target compound 27

[0794] (S, E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-6-(1,1-difluoroethyl)-2-phenoxy-5- (trifluoromethyl)nicotinamide (27)

[0795] The synthetic route of compound 27 is shown as follows:

[0796] First Step: Synthesis of methyl 2-phenoxy-5-(trifluoromethyl)nicotinate (27a)

[0797] To a solution of methyl 2-chloro-5-trifluoromethyl nicotinate (10.0 g, 41.7 mmol) in N-methyl pyrrolidine (120 mL) was added phenol (7.85 g, 83.5 mmol) and N,N- diisopropyl ethylamine (20.7 mL, 125 mmol) and the resulting mixture was stirred at 80 °C for 18 h. TLC indicated the reaction was complete. The reaction was diluted with water (300 mL) and extracted with ethyl acetate (200 mL x 3), and the combined organic layers were concentrated under reduced pressure to give a crude product, which was purified by silica gel column (petroleum ether: ethyl acetate = 100:0-80:20, gradient elution) to give methyl 2-phenoxy-5-(trifluoromethyl)nicotinate (27a) (8.20 g, yield 70%).

[0798] Second Step: Synthesis of 3-(methoxycarbonyl)-2-phenoxy-5-(trifluoromethyl)pyridine 1- oxide (27b)

[0799] To a solution of methyl 2-phenoxy-5-(trifluoromethyl)nicotinate (27a) (8.20 g, 22.1 mmol) in dichloromethane (100 mL) was added urea hydrogen peroxide (4.36 g, 46.3 mmol) and trifluoroacetic anhydride (9.27 g, 44.1 mmol) at 0 °C and the resulting mixture was stirred at 25 °C for 18 h. LC-MS indicated 10% conversion. The reaction was quenched with saturated aqueous sodium sulfite (300 mL) and extracted with dichloromethane (100 mL x 3). The combined organic layers were concentrated under reduced pressure to give a crude product, which was purified by silica gel column (petroleum ether: ethyl acetate = 100:0-50:50, gradient elution) to give 3-(methoxycarbonyl)-2-phenoxy-5-(trifluoromethyl)pyridine 1-oxide (27b) (700 mg, yield 10%).

[0800] Step 3: Synthesis of methyl 6-chloro-2-phenoxy-5-(trifluoromethyl)nicotinate (27c)

[0801] To a solution of methyl 3-(methoxycarbonyl)-2-phenoxy-5- (trifluoromethyl)pyridine 1-oxide (27b) (700 mg, 2.24 mmol) in dichloromethane (10 mL) was added phosphorus oxychloride (2.08 mL, 22.3 mmol) at 0 °C, the resulting mixture was stirred at 80 °C for 48 h. LC-MS indicated the reaction was completed. The reaction was quenched with ice water, extracted with dichloromethane (30 mL x 3), the combined organic layers were concentrated under reduced pressure to give the crude product, which was purified by silica gel column (petroleum ether: ethyl acetate = 100:0-80:20, gradient elution) to give methyl 6-chloro-2-phenoxy-5-(trifluoromethyl)nicotinate (27c) (250 mg, yield 34%).

[0802] Step 4: Synthesis of methyl 6-(1-ethoxyvinyl)-2-phenoxy-5- (trifluoromethyl)nicotinate (27d)

[0803] To a solution of methyl 6-chloro-2-phenoxy-5-(trifluoromethyl)nicotinate (27c) (220 mg, 0.66 mmol) and tributyl(1-ethoxyvinyl)tin (287 mg, 0.80 mmol) in DMF (6 mL) was added tetrakis(triphenylphosphine)palladium (76.7 mg, 0.07 mmol), the resulting mixture was stirred at 110 °C for 18 h. LC-MS indicated the reaction was completed. The reaction was diluted with water (30 mL), extracted with ethyl acetate (20 mL x 3), the combined organic layers were concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column (petroleum ether: ethyl acetate = 100:0-90:10, gradient elution) to give methyl 6-(1-ethoxyvinyl)-2-phenoxy-5-(trifluoromethyl)nicotinate (27d) (160 mg, yield 66%).

[0804] Step 5: Synthesis of methyl 6-acetyl-2-phenoxy-5-(trifluoromethyl)nicotinate (27e)

[0805] To a solution of methyl 6-(1-ethoxyvinyl)-2-phenoxy-5-(trifluoromethyl)nicotinate (27d) (60.0 mg, 0.16 mmol) was added hydrochloric acid (2 mL, 4 M in dioxane), the resulting mixture was stirred at 35 °C for 2 h. LC-MS indicated the reaction was completed. The reaction was directly concentrated under reduced pressure to give methyl 6-(1-ethoxyvinyl)-2-phenoxy-5-(trifluoromethyl)nicotinate (27e) (55.0 mg, yield 70%). The crude product was used directly in the next step without purification.

[0806] Step 6: Synthesis of methyl 6-(1,1 -difluoroethyl)-2-phenoxy-5- (trifluoromethyl)nicotinate (27f)

[0807] To a solution of methyl 6-(1-ethoxyvinyl)-2-phenoxy-5-(trifluoromethyl)nicotinate (27e) (90.0 mg, 0.27 mmol) in dichloromethane (1 mL) was added diethylamine sulfide trifluoride (5.00 mL, 0.27 mmol) at -78 °C, the resulting mixture was stirred at 40 °C for 48 h. LC-MS indicated the reaction was completed. The reaction was quenched with methanol, diluted with water (50 mL), extracted with ethyl acetate (20 mL x 3), the combined organic layers were concentrated under reduced pressure to give a crude product, which was purified by silica gel column (petroleum ether: ethyl acetate = 100:0-80:20, gradient elution) to give methyl 6-(1,1 -difluoroethyl)-2-phenoxy-5- (trifluoromethyl)nicotinate (27f) (87.0 mg, yield 91 %).

[0808] Step 7: Synthesis of 6-(1,1 -difluoroethyl)-2-phenoxy-5-(trifluoromethyl)nicotinic acid (27g)

[0809] To a solution of methyl 6-(1,1 -difluoroethyl)-2-phenoxy-5- (trifluoromethyl)nicotinate (27f) (80.0 mg, 0.22 mmol) in methanol (2 mL) and water (1 mL) was added lithium hydroxide (10.6 mg, 0.44 mmol), the resulting mixture was stirred at 25 °C for 1 h. LC-MS indicated the reaction was completed. The reaction was diluted with 1 M aqueous solution (20 mL), extracted with dichloromethane (10 mL x 3), the combined organic layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure to give 6-(1,1 -difluoroethyl)-2-phenoxy-5- (trifluoromethyl)nicotinic acid (27g) (70.0 mg, yield 91 %).

[0810] Step 8: Synthesis of (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-6-(1,1 - difluoroethyl)-2-phenoxy-5-(trifluoromethyl)nicotinamide (27)

[0811] To a solution of 6-(1,1-difluoroethyl)-2-phenoxy-5-(trifluoromethyl)nicotinic acid (27 g) (70.0 mg, 0.20 mmol) and (S,E)-1-cyclopropyl-3-(methylsulfonyl)prop-2-en-1-amine (03k) trifluoroacetate salt (35.4 mg, 0.20 mmol) in dichloromethane (2 mL) was added 2-chloro-1-methylpyridinium iodide (103 mg, 0.40 mmol) and N,N-diisopropylethylamine (78.3 mg, 0.61 mmol) and the resulting mixture was stirred at 25 °C for 1 h. LC-MS indicated the reaction was complete. The reaction was directly concentrated under reduced pressure to give a crude product, which was purified by HPLC to give (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-6-(1,1-difluoroethyl)-2-phenoxy-5- (trifluoromethyl)nicotinamide (27).

[0812] 1 H NMR (400 MHz, MeOD): δ 8.60 (s, 1H), 7.57-7.38 (m, 2H), 7.37-7.20 (m, 3H), 7.00 (dd, J = 15.2, 4.8 Hz, 1H), 6.86 (dd, J = 15.2, 1.6 Hz, 1H), 4.29-4.12 (m, 1H), 2.93 (s, 3H), 1.69 (t, J = 18.8 Hz, 3H), 1.22-1.10 (m, 1H), 0.74-0.68 (m, 1H), 0.68-0.58 (m, 1H), 0.56-0.43 (m, 2H).

[0813] LC-MS, M / Z (ESI): 505.0 [M+H] + .

[0814] Example 28: Preparation of the target compound 28

[0815] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-(3- (methylsulfonyl)azetidin-1-yl)-6-phenoxy-pyrimidine-5-carboxamide (28)

[0816] The synthetic route of compound 28 is shown below:

[0817] The synthesis of compound 28 was carried out exactly as the synthesis of compound 15, only replacing 3-aminothiophene-1,1 -dioxide with 3-(methylsulfonyl)azetidine to give (S,E)-N-(1 -cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1 -difluoroethyl)-4-(3-(methylsulfonyl)azetidin-1 -yl)-6-phenoxy-pyrimidine-5-carboxamide (28).

[0818] Compound 28: 1 H NMR (400 MHz, CDC13) δ 7.38 (t, 2H), 7.13 (d, 2H), 6.95 (dd, 1H), 6.69 (t, 2H), 4.63 - 4.44 (m, 3H), 4.36 (s, 1H), 4.20 - 3.97 (m, 2H), 2.92 (s, 3H), 2.86 - 2.75 (m, 3H), 1.73 (dd, 3H), 1.23 (s, 1H), 1.06 - 0.95 (m, 1H), 0.65 (dd, 2H), 0.43 (d, 2H).

[0819] LC-MS, M / Z (ESI): 571.2 [M+H] + .

[0820] Example 29: Preparation of target compound 29 / 29-P1 / 29-P2

[0821] (E)-N-(1-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-((1-(methylsulfonyl)azetidin-3-yl)amino)-6-phenoxy-pyrimidine-5-carboxamide (29)

[0822] (S,E)-N-(1-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-((1-(methylsulfonyl)azetidin-3-yl)amino)-6-phenoxy-pyrimidine-5-carboxamide / (R,E)-N-(1-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-((1-(methylsulfonyl)azetidin-3-yl)amino)-6-phenoxy-pyrimidine-5-carboxamide

[0823] Compound 29-P1 is one of the two structural formulas above, and compound 29-P2 is the other structural formula;

[0824] The synthesis route of compound 29 is shown below:

[0825] Step 1: Synthesis of methyl 2-(1,1-difluoroethyl)-4-((1-(methylsulfonyl)azetidin-3- yl)amino)-6-phenoxy pyrimidine-5-carboxylate (29a)

[0826] Methyl 4-chloro-2-(1,1-difluoroethyl)-6-phenoxy pyrimidine-5-carboxylate (07i) (60 mg, 0.18 mmol) was dissolved in tetrahydrofuran (5.0 mL), DIPEA (72 mg, 0.54 mmol) and 1-(methylsulfonyl)azetidin-3-amine (42 mg, 0.27 mmol) were added successively, the resulting mixture was heated at 60 °C for 4 h, the reaction was monitored by LC-MS, after the reaction was completed, the mixture was cooled to room temperature, water (20 mL) was added, the organic layer was extracted with ethyl acetate (10.0 mL x 3), the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give methyl 2-(1,1-difluoroethyl)-4-((1-(methylsulfonyl)azetidin-3-yl)amino)-6-phenoxy pyrimidine-5-carboxylate (29a) (80 mg, yield 99%), which was used directly in the next step.

[0827] Step 2: Synthesis of 2-(1,1-difluoroethyl)-4-((1-(methylsulfonyl)azetidin-3-yl)amino)-6- phenoxy pyrimidine-5-carboxylic acid (29b)

[0828] Methyl 2-(1,1-difluoroethyl)-4-((1-(methylsulfonyl)azetidin-3-yl)amino)-6-phenoxy pyrimidine-5-carboxylate (29a) (80 mg, 0.18 mmol) was dissolved in tetrahydrofuran (5.0 mL) and water (1.0 mL), then lithium hydroxide monohydrate (23 mg, 0.54 mmol) was added, the resulting mixture was heated at 70 °C for 3 h, the reaction was monitored by LC-MS, after the reaction was completed, the mixture was cooled to room temperature, water (20 mL) was added, and dilute hydrochloric acid was added dropwise to adjust the pH to about 3, the organic layer was extracted with ethyl acetate (10 mL x 3), the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2-(1,1-difluoroethyl)-4-((1-(methylsulfonyl)azetidin-3-yl)amino)-6-phenoxy pyrimidine-5-carboxylic acid (29b) (77 mg, yield 100%), which was used directly in the next step.

[0829] Step 3: Synthesis of (E)-N-(1-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-((1-(methylsulfonyl)azetidin-3-yl)amino)-6-phenoxy pyrimidine-5-carboxamide (29)

[0830] Compound 2-(1,1 -difluoroethyl)-4-((1 -(methylsulfonyl)azetidin-3-yl)amino)-6- phenoxy pyrimidine-5-carboxylic acid (29b) (77 mg, 0.18 mmol) was dissolved in DMF (7.0 mL), and intermediate (E)-1 -cyclopropyl-3-fluoro-3-(methylsulfonyl)propyl-2-en-1 -amine trifluoroacetate salt (01 d) (53 mg, 0.27 mmol) was added, followed by TEA (93 mg, 0.92 mmol) and HATU (175 mg, 0.45 mmol) with stirring at room temperature. The resulting mixture was continuously reacted at room temperature for 1 h, and LC-MS was used to detect the end of the reaction. To the reaction solution was added 20 mL of saturated NaCI solution, and the product was extracted with ethyl acetate (10 mL x 3). The organic phase was concentrated and then purified by reverse phase chromatography to obtain compound (E)-N-(1 -cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-2-(1,1 - difluoroethyl)-4-((1 -(methylsulfonyl)azetidin-3-yl)amino)-6-phenoxy pyrimidine-5-carboxamide (29).

[0831] 1 H NMR (400 MHz, DMSO-d6) δ 8.77 (dd, J = 15.6, 6.7 Hz, 2H), 7.41 (t, J = 7.9 Hz, 2H), 7.28 - 7.16 (m, 3H), 6.32 (dd, J = 34.6, 8.9 Hz, 1H), 4.72 - 4.64 (m, 1H), 4.49 (d, J = 8.4 Hz, 1H), 4.10 (t, J = 8.1 Hz, 2H), 3.93 - 3.84 (m, 2H), 3.20 (s, 3H), 3.01 (s, 3H), 1.76 (t, J = 19.0 Hz, 3H), 1.19 (d, J = 7.6 Hz, 1H), 0.50 - 0.28 (m, 4H).

[0832] LC-MS, M / Z (ESI): 604.1 [M+1] + .

[0833] Fourth step: (S, E)-N-(1 -cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-2-(1,1 - difluoroethyl)-4-((1 -(methylsulfonyl)azetidin-3-yl)amino)-6-phenoxy pyrimidine-5- carboxamide / (R, E)-N-(1 -cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-2-(1,1 - difluoroethyl)-4-((1 -(methylsulfonyl)azetidin-3-yl)amino)-6-phenoxy pyrimidine-5- carboxamide (29-P1 / 29-P2)

[0834] (E)-N-(1-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-(3- (methylsulfonamido)azetidin-1-yl)-6-phenoxy pyrimidine-5-carboxamide (29) was prepared by normal phase via SFC (Daicel ChiralPak AS, 40 mm l.D. x 250 mm, 10 pm; n-Hexane- Isopropanol; 50%; 110 mL / min), the resulting two products were further prepared by reverse phase (Xtimate C18, 50*250 mm, 10 pm; 0.1% FA-ACN; 50-80; 70 mL / min), respectively, to give (S,E)-N-(1-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4- ((1-(methylsulfonyl)azetidin-3-yl)amino)-6-phenoxy pyrimidine-5-carboxamide and (R,E)-N-(1-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-((1- (methylsulfonyl)azetidin-3-yl)amino)-6-phenoxy pyrimidine-5-carboxamide, one of which is 29-P1 (Daicel ChiralPak AS, 40 mm l.D. x 250 mm, 10 pm; n-Hexane-Isopropanol; 50%; 110 mL / min, retention time: 12.118 min) and the other is 29-P2 (Daicel ChiralPak AS, 40 mm l.D. x 250 mm, 10 pm; n-Hexane-Isopropanol; 50%; 110 mL / min, retention time: 19.410 min).

[0835] 29-P1: 1 H NMR (400 MHz, DMSO-d6): δ 8.82 (d, J = 5.2 Hz, 1H), 8.77 (d, J = 8.0 Hz, 1H), 7.47 - 7.42 (m, 2H), 7.29 - 7.22 (m, 3H), 6.35 (dd, J = 34.4, 8.8 Hz, 1H), 4.76 - 4.67 (m, 1H), 4.56 - 4.49 (m, 1H), 4.16 - 4.10 (m, 2H), 3.94 - 3.89 (m, 2H), 3.24 (s, 3H), 3.04 (s, 3H), 1.79 (t, J = 19.2 Hz, 3H), 1.26 - 1.19 (m, 1H), 0.53 - 0.40 (m, 3H), 0.37 - 0.30 (m, 1H).

[0836] LC-MS, M / Z (ESI): 604.2 [M+H]+ .

[0837] 29-P2: 1 H NMR (400 MHz, DMSO-d6): δ 8.82 (d, J = 5.2 Hz, 1H), 8.77 (d, J = 8.0 Hz, 1H), 7.48 - 7.41 (m, 2H), 7.30 - 7.19 (m, 3H), 6.35 (dd, J = 34.6, 8.8 Hz, 1H), 4.80 - 4.64 (m, 1H), 4.59 - 4.43 (m, 1H), 4.20 - 4.08 (m, 2H), 3.95 - 3.88 (m, 2H), 3.24 (s, 3H), 3.04 (s, 3H), 1.79 (t, J = 19.2 Hz, 3H), 1.27 - 1.18 (m, 1H), 0.54 - 0.41 (m, 3H), 0.38 - 0.27 (m, 1H).

[0838] LC-MS, M / Z (ESI): 604.2 [M+H] + .

[0839] Example 30: Preparation of the target compound 30

[0840] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-((2- (methylsulfonyl)ethyl)amino)-6-phenoxy pyrimidine-5-carboxamide (30)

[0841] The synthetic route of compound 30 is shown below:

[0842] The synthesis of compound 30 was completed according to the synthetic procedure of compound 15, only replacing 3-aminothiophene-1,1-dioxide with 2- (methylsulfonyl)ethan-1-amine to give (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-((2-(methylsulfonyl)ethyl)amino)-6-phenoxy pyrimidine-5-carboxamide (30)

[0843] Compound 30: 1H NMR (400 MHz, DMSO-d6) δ 8.69 (d, J = 8.3 Hz, 1H), 8.30 (t, J = 5.8 Hz, 1H), 7.44 - 7.37 (m, 2H), 7.22 (t, J = 7.9 Hz, 3H), 6.85 - 6.73 (m, 2H), 4.25 (td, J = 8.2, 4.3 Hz, 1H), 3.85 (dd, J = 12.7, 6.4 Hz, 2H), 3.37 (t, J = 6.6 Hz, 2H), 3.00 (s, 3H), 2.88 (s, 3H), 1.77 (t, J = 19.0 Hz, 3H), 1.09 - 1.02 (m, 1H), 0.53 - 0.35 (m, 4H).

[0844] LC-MS, M / Z (ESI): 559.1 [M+H] + .

[0845] Example 31: Preparation of the target compound 31

[0846] (S,E)-4-((2H-1,2,3-triazol-4-yl)amino)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1- difluoroethyl)-6-phenoxy pyrimidine-5-carboxamide (31)

[0847] The synthetic route of compound 31 is shown below:

[0848] First Step: Synthesis of methyl 2-(1,1-difluoroethyl)-4-phenoxy-6-((2-(2- (trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-yl)amino)pyrimidine-5-carboxylate (31a)

[0849] Methyl 4-bromo-2-(l,l-difluoroethyl)-6-phenoxy pyrimidine-5-carboxylate (33i) (120 mg, 0.32 mmol), 2-(2-trimethylsilylethoxymethyl)triazole-4-amine (138 mg, 0.64 mmol), tris(dibenzylideneacetone)dipalladium (44 mg, 0.048 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (37 mg, 0.064 mmol) and cesium carbonate (262 mg, 0.8 mmol) were added into a mixture of 1,4-dioxane (15 mL) under nitrogen protection. The reaction mixture was stirred at 100 °C for 2 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 4: 1-1: 1, gradient elution) to give methyl 2-(l,l-difluoroethyl)-4-phenoxy-6-((2-(2-(trimethylsilyl)ethoxy)methyl)-2H-l,2,3-triazol-4-yl)amino)pyrimidine-5-carboxylate (31a) (120 mg, yield 74%).

[0850] Step 2: Synthesis of 2-(l,l-difluoroethyl)-4-phenoxy-6-((2-(2-(trimethylsilyl)ethoxy)methyl)-2H-l,2,3-triazol-4-yl)amino)pyrimidine-5-carboxylic acid (31b)

[0851] Methyl 2-(l,l-difluoroethyl)-4-phenoxy-6-((2-(2-(trimethylsilyl)ethoxy)methyl)-2H-l,2,3-triazol-4-yl)amino)pyrimidine-5-carboxylate (31a) (120 mg, 0.24 mmol) was added into a mixture of tetrahydrofuran: water = 4: 1 (8 mL) under nitrogen protection, then lithium hydroxide (17 mg, 0.71 mmol) was added. The reaction mixture was stirred at 60 °C for 2 h. After completion of the reaction, the pH was adjusted to 2 with 1 M hydrochloric acid. The reaction mixture was poured into 10 mL of water and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with 40 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product 2-(l,l-difluoroethyl)-4-phenoxy-6-((2-(2-(trimethylsilyl)ethoxy)methyl)-2H-l,2,3-triazol-4-yl)amino)pyrimidine-5-carboxylic acid (31b) (110 mg, yield 94%).

[0852] Step 3: Synthesis of 4-((2H-l,2,3-triazol-4-yl)amino)-2-(l,l-difluoroethyl)-6-phenoxy pyrimidine-5-carboxylic acid (31c)

[0853] To a solution of 2-(l,l-difluoroethyl)-4-phenoxy-6-((2-(2-(trimethylsilyl)ethoxy)methyl)- 2H-l,2,3-triazol-4-yl)amino)pyrimidine-5-carboxylic acid (31b) (116 mg, 0.24 mmol) in 4 M hydrochloric acid in dioxane 10 mL, was heated to 60 °C for 2 h under nitrogen atmosphere. After completion of the reaction, the reaction mixture was directly concentrated under reduced pressure to get the crude 4-((2H-l,2,3-triazol-4-yl)amino)-2-(l,l-difluoroethyl)-6-phenoxy pyrimidine-5-carboxylic acid (31c) (85 mg, yield 100%).

[0854] Fourth step: (S,E)-4-((2H-l,2,3-triazol-4-yl)amino)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)- 2-(l,l-difluoroethyl)-6-phenoxy pyrimidine-5-carboxamide (31)

[0855] To a solution of 4-((2H-l,2,3-triazol-4-yl)amino)-2-(l,l-difluoroethyl)-6-phenoxy pyrimidine-5- carboxylic acid (31c) (80 mg, 0.22 mmol) in DMF (5 mL) was added (S,E)-l-cyclopropyl-3- (methylsulfonyl)prop-2-en-l-amine trifluoroacetate salt (116 mg, 0.66 mmol), N,N- diisopropylethylamine (142 mg, 1.1 mmol) and 2-(7-azabenzotriazol-l-yl)-l,l,3,3- tetramethyl uronium hexafluorophosphate (HATU) (167 mg, 0.44 mmol). The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was poured into 15 mL of water and extracted with ethyl acetate (20 mL x 3), the organic layer was washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to get the crude. The compound (S,E)-4-((2H-l,2,3-triazol-4-yl)amino)-N-(l-cyclopropyl-3- (methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-6-phenoxy pyrimidine-5-carboxamide (31) was purified by HPLC.

[0856] 1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.84 (d, J = 8.1 Hz, 1H), 8.09 (d, J = 4.3 Hz, 1H), 7.47 - 7.39 (m, 2H), 7.32 - 7.22 (m, 3H), 6.93 - 6.81 (m, 2H), 4.28 (td, J = 8.3, 3.2 Hz, 1H), 2.92 (s, 3H), 1.80 (t, J = 19.0 Hz, 3H), 1.34 (d, J = 5.8 Hz, 1H), 1.12 (dd, J = 8.6, 4.4 Hz, 1H), 0.57 - 0.50 (m, 1H), 0.47 - 0.40 (m, 2H).

[0857] LC-MS, M / Z (ESI): 520.0 [M+H] + .

[0858] Example 32: Preparation of the target compound 32

[0859] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-phenoxy-6- (pyrimidin-5-ylamino)pyrimidine-5-carboxamide (32)

[0860] The synthetic route of compound 32 is shown as follows:

[0861] First Step: Synthesis of methyl 2-(1,1-difluoroethyl)-4-phenoxy-6-(pyrimidin-5- ylamino)pyrimidine-5-carboxylate (32a)

[0862] To a solution of methyl 4-bromo-2-(1,1-difluoroethyl)-6-phenoxy pyrimidine-5- carboxylate (33i) (120 mg, 0.32 mmol) in DMF (3 mL) was added 5-aminopyrimidine (45.9 mg, 0.48 mmol), Ruphos pd G4 (54.7 mg, 0.064 mmol) and cesium carbonate (209 mg, 0.64 mmol), the resulting mixture was stirred at 80 °C for 18 hours. LC-MS detected that the reaction was completed. The reaction was diluted with water (20 mL), extracted with ethyl acetate (10 mL x 3), the combined organic layers were concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column (petroleum ether: ethyl acetate = 100:0-10:90, gradient elution) to give methyl 2-(1,1-difluoroethyl)-4-phenoxy-6-(pyrimidin-5-ylamino)pyrimidine-5-carboxylate (32a) (50.0 mg, yield 40%).

[0863] Step 2: Synthesis of 2-(l,l-difluoroethyl)-4-phenoxy-6-(pyrimidin-5- ylamino)pyrimidine-5-carboxylic acid (32b)

[0864] To a solution of methyl 2-(l,l-difluoroethyl)-4-phenoxy-6-(pyridazin-4- ylamino)pyrimidine-5-carboxylate (32a) (50.0 mg, 0.13 mmol) in tetrahydrofuran (1 mL) and water (0.3 mL) was added lithium hydroxide (10.8 mg, 0.26 mmol) and the resulting mixture was stirred at 25 °C for 1 hour. LC-MS indicated the reaction was complete. The reaction was diluted with water (20 mL), then adjusted to pH = 5 with 1 M hydrochloric acid, extracted with dichloromethane (10 mL x 3), and the combined organic layers were concentrated to give 2-(l,l-difluoroethyl)-4-phenoxy-6-(pyridazin-4-ylamino)pyrimidine-5-carboxylic acid (32b) (40 mg, crude). The crude product was used directly in the next step without purification.

[0865] Step 3: Synthesis of (S,E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l- difluoroethyl)-4-phenoxy-6-(pyrimidin-5-ylamino)pyrimidine-5-carboxamide (32)

[0866] To a solution of 2-(l,l-difluoroethyl)-4-phenoxy-6-(pyridazin-4- ylamino)pyrimidine-5-carboxylic acid (32b) (40.0 mg, 0.11 mmol) and (S,E)-l- cyclopropyl-3-(methylsulfonyl)prop-2-en-l -amine trifluoroacetate salt (16.9 mg, 0.10 mmol) in dichloromethane (2 mL) was added 2-chloro-l-methylpyridine iodide (54.8 mg, 0.21 mmol) and N,N-diisopropylethylamine (0.053 mL, 0.32 mmol). The resulting mixture was stirred at 25 °C for 2 hours. LC-MS indicated the reaction was complete. The resulting mixture was concentrated to give a crude product, which was purified by HPLC to give (S,E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-4-phenoxy-6-(pyrimidin-5-ylamino)pyrimidine-5-carboxamide (32).

[0867] 1H NMR (400 MHz, MeOD): δ 9.23 (s, 2H), 8.87 (s, 1H), 7.52-7.42 (m, 2H), 7.36-7.26 (m, 3H), 7.02 (dd, J = 15.2, 4.8 Hz, 1H), 6.86 (dd, J = 15.2, 1.6 Hz, 1H), 4.30-4.24 (m, 1H), 2.93 (s, 3H), 1.76 (t, J = 18.4 Hz, 3H), 1.25-1.13 (m, 1H), 0.74-0.67 (m, 1H), 0.66-0.58 (m, 1H), 0.56-0.46 (m, 2H).

[0868] LC-MS, M / Z (ESI): 531.2 [M+H] + .

[0869] Example 33: Preparation of the target compound 33

[0870] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4- phenoxy-6-(pyridazin-4-ylamino)pyrimidine-5-carboxamide (33)

[0871] The synthetic route of compound 33 is shown as follows:

[0872] First Step: Synthesis of methyl 4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylate (33a)

[0873] To a solution of 4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylic acid (21.0 g, 87.8 mmol) in DMF (250 mL) was added iodomethane (15.6 g, 109 mmol) and anhydrous potassium carbonate (14.6 g, 105 mmol), the resulting mixture was stirred at 25 °C for 18 hours. LC-MS detection showed the reaction was completed. The reaction solution was diluted with saturated brine (300 mL), extracted with ethyl acetate (200 mL x 3), the combined organic layers were concentrated under reduced pressure to give the crude product, which was purified by silica gel column (petroleum ether: ethyl acetate = 100:0-80:20, gradient elution) to give methyl 4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylate (33a) (22.0 g, yield 98%).

[0874] Second Step: Synthesis of methyl 4-chloro-2-(methylthio)-6-phenoxy pyrimidine-5-carboxylate (33b)

[0875] To a solution of methyl 4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylate (33a) (20.0 g, 79.0 mmol) and cesium carbonate (25.8 g, 79.0 mmol) in tetrahydrofuran (190 mL) was added phenol (6.25 mL, 71.1 mmol) at 0 °C. The resulting mixture was stirred at 25 °C for 18 h. LC-MS indicated the reaction was completed. The reaction was diluted with water (300 mL), and extracted with ethyl acetate (100 mL x 3). The combined organic layers were concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column (petroleum ether: ethyl acetate = 100:0-70:30, gradient elution) to give methyl 4-chloro-2-(methylthio)-6-phenoxy-pyrimidine-5-carboxylate (33b) (23.0 g, yield 88%).

[0876] Step 3: Synthesis of methyl 4-methoxy-2-(methylthio)-6-phenoxy-pyrimidine-5-carboxylate (33c)

[0877] To a solution of methyl 4-chloro-2-(methylthio)-6-phenoxy-pyrimidine-5-carboxylate (33b) (20.0 g, 60.5 mmol) in methanol (200 mL) was added sodium methoxide (10.1 mL, 54.4 mmol, 5.5 M in methanol) at 0 °C. The resulting mixture was stirred at 25 °C for 18 h. LC-MS indicated the reaction was completed. The reaction was diluted with water (500 mL), and extracted with ethyl acetate (300 mL x 3). The combined organic layers were concentrated under reduced pressure to give a crude product. The crude product was purified by C18 column (water: acetonitrile = 100:0-40:60, gradient elution) to give methyl 4-methoxy-2-(methylthio)-6-phenoxy-pyrimidine-5-carboxylate (33c) (5.60 g, yield 30%).

[0878] Step 4: Synthesis of methyl 2-chloro-4-methoxy-6-phenoxy-pyrimidine-5-carboxylate (33d)

[0879] To a solution of methyl 4-methoxy-2-(methylthio)-6-phenoxy-pyrimidine-5-carboxylate (33c) (8.00 g, 26.1 mmol) in acetonitrile (40 mL) was added sulfuryl chloride (17.6 g, 131 mmol) at 0 °C. The resulting mixture was stirred at 25 °C for 3 h. LC-MS indicated the reaction was completed. The reaction was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column (petroleum ether: ethyl acetate = 100:0-75-25) to give methyl 2-chloro-4-methoxy-6-phenoxy-pyrimidine-5-carboxylate (33d) (1.90 g, yield 25%).

[0880] Step 5: Synthesis of methyl 2-(1-ethoxyvinyl)-4-methoxy-6-phenoxy-pyrimidine-5-carboxylate (33e)

[0881] To a solution of methyl 2-chloro-4-methoxy-6-phenoxy pyrimidine-5-carboxylate (33d) (4.10 g, 13.9 mmol) in DMF (40 mL) was added tributyl(1-ethoxyvinyl)tin (7.54 g, 20.9 mmol), tetrakis(triphenylphosphine)palladium (1.61 g, 1.4 mmol), the resulting mixture was stirred at 110 °C for 14 h under nitrogen. LC-MS indicated the reaction was completed. The reaction was quenched with water (60 mL), then extracted with ethyl acetate (60 mL x 3), the combined organic layers were concentrated under reduced pressure to give a crude product, which was purified by silica gel column (petroleum ether: ethyl acetate = 100:0-90:10, gradient elution) to give methyl 2-(1-ethoxyvinyl)-4-methoxy-6-phenoxy pyrimidine-5-carboxylate (33e) (3.10 g, yield 67%).

[0882] Step 6: Synthesis of methyl 2-acetyl-4-methoxy-6-phenoxy pyrimidine-5-carboxylate (33f)

[0883] To a solution of methyl 2-(1-ethoxyvinyl)-4-methoxy-6-phenoxy pyrimidine-5-carboxylate (33e) (3.10 g, 9.4 mmol) in dioxane (6 mL) was added hydrochloric acid (6 mL, 4 M in dioxane), the resulting mixture was stirred at 15 °C for 3 h. LC-MS indicated the reaction was completed. The reaction was concentrated under reduced pressure to give a crude product, which was purified by silica gel column (petroleum ether: ethyl acetate = 100:0-75:25, gradient elution) to give methyl 2-acetyl-4-methoxy-6-phenoxy pyrimidine-5-carboxylate (33f) (2.00 g, yield 71%).

[0884] Step 7: Synthesis of methyl 2-(1,1-difluoroethyl)-4-methoxy-6-phenoxy pyrimidine-5-carboxylate (33g)

[0885] To a solution of methyl 2-acetyl-4-methoxy-6-phenoxy pyrimidine-5-carboxylate (33f) (500 mg, 1.65 mmol) in dichloromethane (2 mL) was added DAST (5 mL) dropwise at -78 °C, the resulting mixture was stirred at 30 °C for 18 h. LC-MS indicated the reaction was completed. The reaction was quenched with methanol, then diluted with water (100 mL), extracted with ethyl acetate (50 mL x 3), concentrated under reduced pressure to give a crude product, which was purified by silica gel column (petroleum ether: ethyl acetate = 100:0-70:30, gradient elution) to give methyl 2-(1,1-difluoroethyl)-4-methoxy-6-phenoxy pyrimidine-5-carboxylate (33g) (400 mg, yield 75%).

[0886] Eighth Step: Synthesis of methyl 2-(1,1 -difluoroethyl)-4-hydroxy-6- phenoxy pyrimidine-5-carboxylate (33h)

[0887] To a solution of methyl 2-(1,1 -difluoroethyl)-4-methoxy-6-phenoxy pyrimidine-5- carboxylate (33g) (680 mg, 2.09 mmol) in dichloromethane (10 mL) was added boron tribromide (2.62 g, 10.45 mmol) dropwise at -78 °C, the resulting mixture was stirred at -78 °C for 30 min. LC-MS indicated the reaction was completed. The reaction was quenched with MeOH at -78 °C, then diluted with water (30 mL), extracted with dichloromethane (20 mL x 3), the combined organic layers were concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column (petroleum ether: ethyl acetate = 100:0-65:35, gradient elution) to give methyl 2-(1,1 -difluoroethyl)-4-hydroxy-6-phenoxy pyrimidine-5-carboxylate (33h) (colorless oil, 410 mg, 63% yield).

[0888] Ninth Step: Synthesis of methyl 4-bromo-2-(1,1 -difluoroethyl)-6-phenoxy pyrimidine-5- carboxylate (33i)

[0889] To a solution of methyl 2-(1,1 -difluoroethyl)-4-hydroxy-6-phenoxy pyrimidine-5- carboxylate (33h) (310 mg, 1.00 mmol) in phosphorous tribromide (5 mL) was added phosphorous oxybromide (2.86 g, 9.99 mmol), the resulting mixture was stirred at 90 °C for 4 h. LC-MS indicated the reaction was completed. The reaction was quenched with MeOH at -78 °C, then diluted with water (20 mL), extracted with ethyl acetate (10 mL x 3), the combined organic layers were concentrated under reduced pressure to give the crude product, which was purified by silica gel column (petroleum ether: ethyl acetate = 100:0-90:10, gradient elution) to give methyl 4-bromo-2-(1,1 -difluoroethyl)-6-phenoxy pyrimidine-5-carboxylate (33i) (250 mg, 67% yield).

[0890] Tenth Step: Synthesis of methyl 2-(1,1 -difluoroethyl)-4-phenoxy-6-(pyridazin-4- ylamino) pyrimidine-5-carboxylate (33j)

[0891] To a solution of methyl 4-bromo-2-(l,l-difluoroethyl)-6-phenoxy pyrimidine-5- carboxylate (33i) (80.0 mg, 0.214 mmol) in DMF (1 mL) was added 4-aminopyridazine (30.6 mg, 0.32 mmol), Ruphos Pd G4 (36.5 mg, 0.04 mmol) and cesium carbonate (140 mg, 0.43 mmol), the resulting mixture was stirred at 80 °C for 18 h. LC-MS indicated the reaction was completed. The reaction was diluted with water (20 mL), extracted with ethyl acetate (10 mL x 3), the combined organic layers were concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column (petroleum ether: ethyl acetate = 100:0-10:90, gradient elution) to give methyl 2-(l,l-difluoroethyl)-4-phenoxy-6-(pyridazin-4-ylamino) pyrimidine-5-carboxylate (33j) (40.0 mg, yield 48%).

[0892] Tenth step: synthesis of 2-(l,l-difluoroethyl)-4-phenoxy-6-(pyridazin-4- ylamino) pyrimidine-5-carboxylic acid (33k)

[0893] To a solution of methyl 2-(l,l-difluoroethyl)-4-phenoxy-6-(pyridazin-4- ylamino) pyrimidine-5-carboxylate (33j) (30.0 mg, 0.08 mmol) in a mixture of tetrahydrofuran (1 mL) and water (0.2 mL) was added lithium hydroxide (6.54 mg, 0.156 mmol), the resulting mixture was stirred at 40 °C for 1 h. LC-MS indicated the reaction was completed. The reaction was diluted with water (20 mL), then adjusted to pH = 3 with 1 M hydrochloric acid, extracted with dichloromethane (10 mL x 3), the combined organic layers were concentrated under reduced pressure to give 2-(l,l-difluoroethyl)-4-phenoxy-6-(pyridazin-4-ylamino) pyrimidine-5-carboxylic acid (33k) (30 mg, crude). The crude product was used directly in the next step without purification.

[0894] Twelfth step: synthesis of (S,E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l- difluoroethyl)-4-phenoxy-6-(pyridazin-4-ylamino) pyrimidine-5-carboxamide (33)

[0895] To a solution of 2-(1,1-difluoroethyl)-4-phenoxy-6-(pyridazin-4-ylamino)pyrimidine-5- carboxylic acid (33k) (30.0 mg, 0.08 mmol) and (S,E)-1-cyclopropyl-3-(methylsulfonyl)prop-2- en-1-amine trifluoroacetate salt (16.9 mg, 0.10 mmol) in dichloromethane (2 mL) was added 2-chloro-1-methylpyridinium iodide (41.1 mg, 0.161 mmol) and N,N-diisopropylethylamine (0.027 mL, 0.02 mmol). The resulting mixture was stirred at 25 °C for 2 h. LC-MS indicated the reaction was complete. The resulting mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by HPLC to give (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-phenoxy-6- (pyridazin-4-ylamino)pyrimidine-5-carboxamide (33).

[0896] 1 H NMR (400 MHz, MeOD): δ 9.54 (d, J = 2.4 Hz, 1H), 9.15 (d, J = 6.4 Hz, 1H), 8.68 (d, J = 3.6 Hz, 1H), 7.54 - 7.45 (m, 2H), 7.38 - 7.29 (m, 3H), 7.03 (dd, J = 15.2, 4.8 Hz, 1H), 6.88 (dd, J = 15.2, 1.5 Hz, 1H), 2.94 (s, 3H), 1.82 (t, J = 18.4 Hz, 3H), 1.23 - 1.18 (m, 1H), 0.74 - 0.68 (m, 1H), 0.65 - 0.59 (m, 1H), 0.56 - 0.49 (m, 2H).

[0897] LC-MS, M / Z (ESI): 531.2 [M+H] + .

[0898] Example 34: Preparation of the target compound 34

[0899] (S,E)-4-((3-chloro-1H-pyrazol-4-yl)amino)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2- (1,1-difluoroethyl)-6-phenoxyyrimidine-5-carboxamide (34)

[0900] The synthetic route of compound 34 is shown as follows:

[0901] First Step: Synthesis of 3-chloro-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazole (34a)

[0902] To a solution of 3-chloro-4-nitro-lH-pyrazole (400 mg, 3.54 mmol) in tetrahydrofuran (5 mL) was added sodium hydride (283 mg, 7.07 mmol) at 0 °C. The reaction was stirred at 0 °C for 0.5 h. Then 2-(trimethylsilyl)ethoxymethyl chloride (885 mg, 5.31 mmol) was added to the reaction mixture. The reaction was stirred at 15 °C for 2 h. LC-MS was used to monitor the reaction. The reaction was completed. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 100:0-90:10, gradient elution) to give 3-chloro-4-nitro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazole (34a) (650 mg, 76% yield).

[0903] Second Step: Synthesis of 3-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-4-amine (34b)

[0904] To a solution of 3-chloro-4-nitro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazole (34a) (500 mg, 1.80 mmol) in ethanol (5 mL) and water (1 mL) was added iron powder (805 mg, 14.4 mmol) and ammonium chloride (963 mg, 18.0 mmol). The reaction was stirred at 15 °C for 18 h. LC-MS was used to monitor the reaction. The reaction was completed. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (dichloromethane: methanol (V / V) = 100:0-90:10, gradient elution) to give 3-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-4-amine (34b) (500 mg, 76% yield).

[0905] Third Step: Synthesis of methyl 4-((3-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-4-yl)amino)-2-(l,l-difluoroethyl)-6-phenoxy-pyrimidine-5-carboxylate (34c)

[0906] To a solution of methyl 4-bromo-2-(l,l-difluoroethyl)-6- phenoxy pyrimidine-5-carboxylate (33i) (100 mg, 0.268 mmol) and 3-chloro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrazol-4-amine (34b) (66.4 mg, 0.268 mmol) in N,N- dimethylformamide (3 mL) was added methane sulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri- isopropyl- 1, 1 '-biphenyl) (2'-amino- 1, 1 '-biphenyl-2-yl)palladium(II) (22.8 mg, 0.03 mmol) and cesium carbonate (175 mg, 0.536 mmol) and the resulting mixture was stirred at 80 °C for 18 h under nitrogen. The reaction was checked by LC-MS and was complete. The reaction was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined and concentrated to give a crude product. The crude product was purified by silica gel column (petroleum ether: ethyl acetate = 100:0-70:30, gradient elution) to give methyl 4-((3-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-4-yl)amino)-2-(l,l- difluoroethyl)-6-phenoxy pyrimidine-5-carboxylate (34c) (50 mg, 35% yield).

[0907] Fourth Step: Synthesis of 4-((3-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-4- yl)amino)-2-(l,l-difluoroethyl)-6-phenoxy pyrimidine-5-carboxylic acid (34d)

[0908] Methyl 4-((3-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-4-yl)amino)-2-(l,l- difluoroethyl)-6-phenoxy pyrimidine-5-carboxylate (34c) (30 mg, 0.06 mmol) was dissolved in a mixture of isopropanol (2 mL), tetrahydrofuran (2 mL) and water (0.5 mL), and lithium hydroxide (7.05 mg, 0.17 mmol) was added. The reaction was stirred at 40 °C for 2 h. The reaction was checked by LC-MS and was complete. To the reaction was added 2M hydrochloric acid solution to adjust the pH to 3, and extracted with dichloromethane (20 mL x 3). The organic layers were combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to give a crude product, 4-((3-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-4-yl)amino)-2-(l,l- difluoroethyl)-6-phenoxy pyrimidine-5-carboxylic acid (34d) (25 mg, 86% yield).

[0909] Step 5: Synthesis of (S, E)-4-((3-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- pyrazol-4-yl)amino)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l- difluoroethyl)-6-phenoxy pyrimidine-5-carboxamide (34e)

[0910] (S, E)-4-((3-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-4-yl)amino)- N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-6-phenoxy pyrimidine- 5-carboxylic acid (34d) (20.0 mg, 0.04 mmol) and (S, E)-l-cyclopropyl-3- (methylsulfonyl)prop-2-en-l-amine trifluoroacetate salt (6.66 mg, 0.04 mmol) were dissolved in dimethyl sulfoxide (0.5 mL); N, N-diisopropyl ethylamine (9.83 mg, 0.08 mmol) and N, N, N', N'-tetramethyl-O-(7-azabenzotriazol-l-yl) urea hexafluorophosphate (21.7 mg, 0.06 mmol) were added to the reaction. The reaction was stirred at 15 °C for 3 hours. LC-MS indicated the reaction was complete. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined and washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The organic solvent was concentrated to give (S, E)-4-((3-chloro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrazol-4-yl)amino)-N-(l-cyclopropyl-3- (methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-6-phenoxy pyrimidine-5-carboxamide (34e) (20 mg, 77% yield) as a crude product.

[0911] Step 6: (S, E)-4-((3-chloro-lH-pyrazol-4-yl)amino)-N-(l-cyclopropyl-3- (methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-6-phenoxy pyrimidine-5-carboxamide (34)

[0912] (S, E)-4-((3-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-4-yl)amino)- N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-6-phenoxy-pyrimidine-5- carboxamide (20.0 mg, 0.03 mmol) was dissolved in a solution of hydrochloric acid in dioxane (2 mL, 4 mol / L). The reaction was stirred at 15 °C under N2for 24 h. LC-MS showed the formation of the target product. The reaction was concentrated under reduced pressure, and purified by HPLC to give (S, E)-4-((3-chloro-lH-pyrazol-4-yl)amino)-N-(l-cyclopropyl-3- (methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-6-phenoxy-pyrimidine-5-carboxamide (34).

[0913] 1 H NMR (400 MHz, MeOD): δ 8.32 (s, 1H), 7.50-7.43 (m, 2H), 7.35-7.25 (m, 3H), 7.01 (dd, J = 15.2, 4.8 Hz, 1H), 6.84 (d, J = 15.2 Hz, 1H), 4.27-4.22 (m, 1H), 2.95 (s, 3H), 1.75 (t, J = 18.4 Hz, 3H), 1.23-1.15 (m, 1H), 0.73-0.66 (m, 1H), 0.65-0.59 (m, 1H), 0.54-0.47 (m, 2H).

[0914] LC-MS, M / Z (ESI): 553.2 [M+H] + .

[0915] Example 35: Preparation of the target compound 35

[0916] Compound 35 is one of the two structural formulas above;

[0917] The synthetic route of compound 35 is shown below:

[0918] Compound 36 is one of the two structural formulae above;

[0919] 1 H NMR (400 MHz, DMSO-d6) δ 8.94 (d, J = 5.6 Hz, 1H), 8.80 (d, J = 8.1 Hz, 1H), 7.45 (t, J = 7.9 Hz, 2H), 7.37 - 7.12 (m, 3H), 6.36 (dd, J = 34.6, 8.9 Hz, 1H), 4.85 - 4.66 (m, 1H), 4.64 - 4.45 (m, 3H), 4.40 - 4.22 (m, 2H), 3.24 (s, 3H), 1.80 (t, J = 19.0 Hz, 3H), 1.23 (dd, J = 8.3, 4.2 Hz, 1H), 0.57 - 0.24 (m, 4H).

[0920] LC-MS, M / Z (ESI): 575.1 [M+H] + .

[0921] Example 36: Preparation of target compound 36

[0922] Compound 36 is one of the two structural formulae above;

[0923] The synthetic route of compound 36 is shown as follows:

[0924] Compound 36 was prepared according to the following procedure: 4-((1H- Pyrazol-4-yl)amino)-2-(1,1-difluoroethyl)-6-phenoxy-pyrimidine-5-carboxylic acid (07k) (43 mg, 0.12 mmol), trifluoroacetate salt of compound 01d-P1 (36 mg, 0.12 mmol), HATU (72 mg, 0.19 mmol) and N,N-diisopropyl ethylamine (DIPEA) (38 mg, 0.36 mmol) were dissolved in DMF (2 mL) and reacted at room temperature for 2 hours. After the reaction was completed as detected by LC-MS, the reaction solution was poured into 10 mL of water, extracted with ethyl acetate (10 mL x 3), and the organic phase was combined, washed with saturated brine (25 mL), and dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure, and purified by HPLC to obtain compound 36.

[0925] 1 H NMR (400 MHz, DMSO-d6) δ 10.49 (s, 1H), 8.87 (d, J = 8.0 Hz, 1H), 7.95 (s, 2H), 7.46 (t, J = 7.9 Hz, 2H), 7.27 (dd, J = 7.4, 4.2 Hz, 3H), 6.39 (dd, J = 34.7, 8.9 Hz, 1H), 4.55 (dd, J = 16.8, 8.4 Hz, 1H), 3.25 (s, 3H), 1.81 (t, J = 19.0 Hz, 3H), 1.21 - 1.05 (m, 1H), 0.55 - 0.33 (m, 4H).

[0926] LC-MS, M / Z (ESI): 537.2 [M+H] + .

[0927] Example 37: Preparation of target compound 37

[0928] Compound 37 is one of the two structural formulas above;

[0929] The synthetic route of compound 37 is shown below:

[0930] Compound 37 was prepared according to the following procedure: 2-(1,1-difluoroethyl)-4-(((1R,3R)-3-(methylsulfonyl)cyclobutyl)amino)-6- phenoxy pyrimidine-5-carboxylic acid (26b) (51 mg, 0.12 mmol), trifluoroacetate salt of compound 01d-P1 (36 mg, 0.12 mmol), HATU (72 mg, 0.19 mmol) and N,N-diisopropyl ethylamine (DIPEA) (38 mg, 0.36 mmol) were dissolved in DMF (2 mL) and reacted at room temperature for 2 hours. After the reaction was detected by LC-MS, the reaction solution was poured into 10 mL of water, extracted with ethyl acetate (10 mL x 3), and the organic phase was combined, washed with saturated brine (25 mL), and dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure, and compound 37 was obtained by separation and purification with HPLC.

[0931] 1 H NMR (400 MHz, DMSO-d6) δ 8.73 (t, J = 6.8 Hz, 2H), 7.42 (t, J = 7.8 Hz, 2H), 7.26 - 7.20 (m, 3H), 6.38 - 6.31 (m, 1H), 4.71 (q, J = 7.9 Hz, 1H), 4.49 (q, J = 8.4 Hz, 1H), 3.85 - 3.81 (m, 1H), 3.23 (s, 3H), 2.94 (s, 3H), 2.70 (tt, J = 8.7, 4.0 Hz, 2H), 2.58 - 2.52 (m, 2H), 1.75 (t, J = 18.9 Hz, 3H), 1.21 (dq, J = 8.7, 4.8, 4.1 Hz, 1H), 0.51 - 0.40 (m, 3H), 0.32 (dt, J = 9.5, 4.8 Hz, 1H).

[0932] LC-MS, M / Z (ESI): 603.0 [M+H] + .

[0933] Example 38: Preparation of target compound 38

[0934] Compound 38 is one of the two structural formulas above;

[0935] The synthetic route of compound 38 is shown below:

[0936] Compound 38 was prepared according to the following procedure: 2-(1,1-difluoroethyl)-4-((2-(methylsulfonyl)ethyl)amino)-6-phenoxy pyrimidine-5-carboxylic acid (30b) (48 mg, 0.12 mmol), trifluoroacetate salt of compound 01d-P1 (36 mg, 0.12 mmol), HATU (72 mg, 0.19 mmol) and N,N-diisopropyl ethylamine (DIPEA) (38 mg, 0.36 mmol) were dissolved in DMF (2 mL) and reacted at room temperature for 2 hours. After the reaction was detected by LC-MS, the reaction solution was poured into 10 mL of water, extracted with ethyl acetate (10 mL x 3), and the organic phase was combined, washed with saturated brine (25 mL), and dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure, and compound 38 was obtained by separation and purification with HPLC.

[0937] 1 H NMR (400 MHz, DMSO-d6) δ 8.69 (d, J = 7.4 Hz, 2H), 7.43 (t, J = 7.8 Hz, 2H), 7.24 (t, J = 8.1 Hz, 3H), 6.34 (dd, J = 34.5, 9.0 Hz, 1H), 4.49 - 4.45 (m, 1H), 3.87 (dd, J = 12.8, 6.5 Hz, 2H), 3.38 (t, J = 6.7 Hz, 2H), 3.22 (s, 3H), 3.01 (s, 3H), 1.78 (t, J = 19.0 Hz, 3H), 1.21 (s, 1H), 0.46 - 0.30 (m, 4H).

[0938] LC-MS, M / Z (ESI): 577.1 [M+H] + .

[0939] Example 39: Preparation of target compound 39

[0940] Compound 39 is one of the two structural formulas above;

[0941] Compound 39-P1 is one of the two structural formulas above;

[0942] Compound 39-P2 is one of the two structural formulas above;

[0943] The synthetic route of compound 39 is shown below:

[0944] Compound 39-P1: 1H NMR (400 MHz, DMSO-d6) δ 8.82 - 8.79 (m, 1H), 8.76 - 8.73 (m, 1H), 7.43 (t, J = 7.8 Hz, 2H), 7.24 (dd, J = 15.3, 7.8 Hz, 3H), 6.36 (ddd, J = 34.6, 8.8, 4.5 Hz, 1H), 4.86 (dd, J = 14.5, 7.2 Hz, 1H), 4.50 - 4.45 (m, 1H), 3.50 (dd, J = 13.2, 6.7 Hz, 1H), 3.33 - 3.28 (m, 2H), 3.22 (s, 3H), 3.17 (dd, J = 11.8, 6.9 Hz, 2H), 2.27 - 2.22 (m, 1H), 1.77 (t, J = 19.0 Hz, 3H), 1.21 (s, 1H), 0.52 - 0.44 (m, 2H), 0.41 - 0.30 (m, 2H).

[0945] Compound 39-P2: 1H NMR (400 MHz, DMSO-d6) δ 8.82 - 8.79 (m, 1H), 8.76 - 8.73 (m, 1H), 7.43 (t, J = 7.8 Hz, 2H), 7.24 (dd, J = 15.3, 7.8 Hz, 3H), 6.36 (ddd, J = 34.6, 8.8, 4.5 Hz, 1H), 4.86 (dd, J = 14.5, 7.2 Hz, 1H), 4.50 - 4.45 (m, 1H), 3.50 (dd, J = 13.2, 6.7 Hz, 1H), 3.33 - 3.28 (m, 2H), 3.22 (s, 3H), 3.17 (dd, J = 11.8, 6.9 Hz, 2H), 2.27 - 2.22 (m, 1H), 1.77 (t, J = 19.0 Hz, 3H), 1.21 (s, 1H), 0.52 - 0.44 (m, 2H), 0.41 - 0.30 (m, 2H). 1 H NMR (400 MHz, DMSO-d6) δ 8.82 - 8.79 (m, 1H), 8.76 - 8.73 (m, 1H), 7.43 (t, J = 7.8 Hz, 2H), 7.24 (dd, J = 15.3, 7.8 Hz, 3H), 6.36 (ddd, J = 34.6, 8.8, 4.5 Hz, 1H), 4.86 (dd, J = 14.5, 7.2 Hz, 1H), 4.50 - 4.45 (m, 1H), 3.50 (dd, J = 13.2, 6.7 Hz, 1H), 3.33 - 3.28 (m, 2H), 3.22 (s, 3H), 3.17 (dd, J = 11.8, 6.9 Hz, 2H), 2.27 - 2.22 (m, 1H), 1.77 (t, J = 19.0 Hz, 3H), 1.21 (s, 1H), 0.52 - 0.44 (m, 2H), 0.41 - 0.30 (m, 2H).

[0946] LC-MS, M / Z (ESI): 589.1 [M+H] + .

[0947] Compound 39-P1: 1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J = 7.2 Hz, 1H), 8.74 (d, J = 8.0 Hz, 1H), 7.59 - 7.39 (m, 2H), 7.37 - 7.18 (m, 3H), 6.38 (dd, J = 34.7, 8.9 Hz, 1H), 5.07 - 4.68 (m, 1H), 4.50 (q, J = 8.4 Hz, 1H), 3.51 (dd, J = 13.3, 7.6 Hz, 1H), 3.32 - 3.10 (m, 7H), 2.37 - 2.13 (m, 1H), 1.79 (t, J = 19.0 Hz, 3H), 1.40 - 1.17 (m, 1H), 0.59 - 0.25 (m, 4H).

[0948] LC-MS, M / Z (ESI): 589.1 [M+H] + .

[0949] Compound 39-P2: 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J = 7.2 Hz, 1H), 8.74 (d, J = 8.0 Hz, 1H), 7.58 - 7.35 (m, 2H), 7.36 - 7.09 (m, 3H), 6.37 (dd, J = 34.7, 8.9 Hz, 1H), 4.88 (dd, J = 15.0, 7.3 Hz, 1H), 4.49 (q, J = 8.4 Hz, 1H), 3.52 (dd, J = 13.2, 7.6 Hz, 1H), 3.30 - 3.10 (m, 7H), 2.25 (dq, J = 13.1, 8.7 Hz, 1H), 1.79 (t, J = 19.0 Hz, 3H), 1.37 - 1.09 (m, 1H), 0.61 - 0.24 (m, 4H).

[0950] LC-MS, M / Z (ESI): 589.1 [M+H] + .

[0951] Example 40: Preparation of target compound 40

[0952] Compound 40 is one of the two structures above;

[0953] The synthetic route of compound 40 is shown below:

[0954] First step: synthesis of methyl 2-(1,1-difluoroethyl)-4-((2,2-dioxide-2- thiaspiro[3.3]heptan-6-yl)amino)-6-phenoxy pyrimidine-5-carboxylate (40a)

[0955] Methyl 4-chloro-2-(l,l-difluoroethyl)-6-phenoxy pyrimidine-5-carboxylate (07i) (80 mg, 0.2 mmol), 6-amino-2-thiasprio[3.3]heptane 2,2-dioxide (98 mg, 0.5 mmol) and N,N-diisopropyl ethylamine (DIPEA) (63 mg, 0.5 mmol) were dissolved in tetrahydrofuran (5 mL) and reacted at 80 °C for 6 hours. After the reaction was completed by LC-MS detection, the reaction solution was poured into 10 mL of water, extracted with ethyl acetate (10 mL x 3), the organic phase was combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure, and purified by silica gel column separation (petroleum ether: ethyl acetate (V / V) = 100:0-75:25, gradient elution) to obtain methyl 2-(l,l-difluoroethyl)-4-((2,2-dioxide-2-thiaspiro[3.3]heptan-6-yl)amino)-6-phenoxy pyrimidine-5-carboxylate (40a) (100 mg, yield 85%).

[0956] Second step: synthesis of 2-(l,l-difluoroethyl)-4-((2,2-dioxide-2-thiaspiro[3.3]heptan-6-yl)amino)-6-phenoxy pyrimidine-5-carboxylic acid (40b)

[0957] Methyl 2-(l,l-difluoroethyl)-4-((2,2-dioxide-2-thiaspiro[3.3]heptan-6-yl)amino)-6-phenoxy pyrimidine-5-carboxylate (40a) (100 mg, 0.2 mmol) was dissolved in tetrahydrofuran / water (4 mL / 1 mL), lithium hydroxide (25 mg, 0.6 mmol) was added, and the reaction was carried out at room temperature for 6 hours. After the reaction was completed by LC-MS detection, the reaction solution was poured into 10 mL of water, adjusted to pH = 3 with 1 M hydrochloric acid, extracted with ethyl acetate (10 mL x 3), the organic phase was combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 2-(l,l-difluoroethyl)-4-((2,2-dioxide-2-thiaspiro[3.3]heptan-6-yl)amino)-6-phenoxy pyrimidine-5-carboxylic acid (40b) (92 mg, yield 95%), which was directly used in the next step without purification.

[0958] Third step: synthesis of compound 40

[0959] Compound 40 is one of the two structures above;

[0960] Compound 40 was prepared according to the following reaction scheme:

[0961] 1 H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J = 7.7 Hz, 2H), 7.44 (t, J = 7.9 Hz, 2H), 7.25 (dd, J = 14.9, 7.6 Hz, 3H), 6.36 (dd, J = 34.7, 8.9 Hz, 1H), 4.63 - 4.41 (m, 2H), 4.32 (s, 2H), 4.20 (s, 2H), 3.24 (s, 3H), 2.68 (dd, J = 11.8, 7.9 Hz, 2H), 2.44 (t, J = 9.4 Hz, 2H), 1.77 (t, J = 18.9 Hz, 3H), 1.27 - 1.11 (m, 1H), 0.58 - 0.28 (m, 4H).

[0962] LC-MS, M / Z (ESI): 615.1 [M+H] + .

[0963] Example 41: Preparation of Compound 41

[0964] Compound 41 is one of the two structures above;

[0965] The synthetic route of Compound 41 is shown below:

[0966] First Step: Synthesis of Methyl 2-(1,1-difluoroethyl)-4-((1,1-dioxidetetrahydro-2H- thiopyran-4-yl)amino)-6-phenoxy pyrimidine-5-carboxylate (41a)

[0967] Methyl 4-chloro-2-(1,1 -difluoroethyl)-6-phenoxy pyrimidine-5-carboxylate (07i) (50 mg, 0.15 mmol), 4-amino tetrahydro-2H-thiopyran 1,1 -dioxide (36 mg, 0.27 mmol) and N,N-diisopropyl ethylamine (DIPEA) (60 mg, 0.45 mmol) were dissolved in tetrahydrofuran (5 mL) and reacted at 80 °C for 6 hours. After the reaction was completed by LC-MS detection, the reaction solution was poured into 10 mL of water, extracted with ethyl acetate (10 mL x 3), the organic phase was combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure and purified by silica gel column separation (petroleum ether: ethyl acetate (V / V) = 100:0-75:25, gradient elution) to obtain methyl 2-(1,1 -difluoroethyl)-4-((1,1 -dioxotetrahydro-2H-thiopyran-4-yl)amino)-6-phenoxy pyrimidine-5-carboxylate (41a) (54 mg, yield 99%).

[0968] Second step: synthesis of 2-(1,1 -difluoroethyl)-4-((1,1 -dioxotetrahydro-2H- thiopyran-4-yl)amino)-6-phenoxy pyrimidine-5-carboxylic acid (41b)

[0969] Methyl 2-(1,1 -difluoroethyl)-4-((1,1 -dioxotetrahydro-2H-thiopyran-4-yl)amino)-6- phenoxy pyrimidine-5-carboxylate (41a) (54 mg, 0.15 mmol) was dissolved in tetrahydrofuran / water (4 mL / 1 mL), lithium hydroxide (19 mg, 0.45 mmol) was added, and the reaction was carried out at room temperature for 6 hours. After the reaction was completed by LC-MS detection, the reaction solution was poured into 10 mL of water, adjusted to pH = 3 with 1 M hydrochloric acid, extracted with ethyl acetate (10 mL x 3), the organic phase was combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. 2-(1,1 -difluoroethyl)-4-((1,1 -dioxotetrahydro-2H-thiopyran-4-yl)amino)-6-phenoxy pyrimidine-5-carboxylic acid (41b) (52 mg, yield 100%) was obtained by concentration under reduced pressure, and the next step was carried out directly without purification.

[0970] Third step: synthesis of compound 41

[0971] Compound 41 is one of the two structures above;

[0972] Compound 41 was prepared according to the following reaction scheme:

[0973] 1 H NMR (400 MHz, DMSO-d6) δ 8.73 (d, J = 7.9 Hz, 1H), 8.62 (d, J = 7.2 Hz, 1H), 7.44 (t, J = 7.8 Hz, 2H), 7.26 (dd, J = 16.9, 7.8 Hz, 3H), 6.37 (dd, J = 34.7, 8.8 Hz, 1H), 4.48 (dd, J = 16.6, 8.3 Hz, 1H), 4.33 (d, J = 6.9 Hz, 1H), 3.23 (s, 3H), 3.08 (d, J = 13.6 Hz, 2H), 2.22 (d, J = 11.2 Hz, 2H), 2.12 - 2.05 (m, 2H), 1.81 (t, J = 19.0 Hz, 3H), 1.23 (s, 2H), 0.58 - 0.36 (m, 4H), 0.35 - 0.31 (m, 1H).

[0974] LC-MS, M / Z (ESI): 603.0 [M+H] + .

[0975] Example 42: Preparation of Compound 42

[0976] Compound 42 is one of the two structures above

[0977] The synthetic route of Compound 42 is shown below:

[0978] Step 1: Synthesis of methyl 2-(1,1-difluoroethyl)-4-((3-(methylsulfonyl)dicyclo[1.1.1] pentan-1-yl)amino)-6-phenoxy pyrimidine-5-carboxylate (42a)

[0979] Methyl 4-chloro-2-(l,l-difluoroethyl)-6-phenoxy pyrimidine-5-carboxylate (07i) (80 mg, 0.2 mmol), 3-(methylsulfonyl)bicyclo[l. l. l]pentan-l -amine (60 mg, 0.4 mmol) and N,N-diisopropylethylamine (DIPEA) (63 mg, 0.5 mmol) were dissolved in tetrahydrofuran (5 mL) and reacted at 80 °C for 6 hours. After the reaction was completed by LC-MS detection, the reaction solution was poured into 10 mL of water, extracted with ethyl acetate (10 mL x 3), and the organic phase was combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure and purified by silica gel column separation (petroleum ether: ethyl acetate (V / V) = 100:0-75:25, gradient elution) to obtain methyl 2-(l,l-difluoroethyl)-4-((3-(methylsulfonyl)bicyclo[l. l. l]pentan-l -yl)amino)-6-phenoxy pyrimidine-5-carboxylate (42a) (99 mg, yield 90%).

[0980] Second step: synthesis of 2-(l,l-difluoroethyl)-4-((3-(methylsulfonyl)bicyclo[l. l. l]pentan-l -yl)amino)-6-phenoxy pyrimidine-5-carboxylic acid (42b)

[0981] Methyl 2-(l,l-difluoroethyl)-4-((3-(methylsulfonyl)bicyclo[l. l. l]pentan-l -yl)amino)-6-phenoxy pyrimidine-5-carboxylate (42a) (99 mg, 0.2 mmol) was dissolved in tetrahydrofuran / water (4 mL / 1 mL), lithium hydroxide (28 mg, 0.6 mmol) was added, and the reaction was carried out at room temperature for 6 hours. After the reaction was completed by LC-MS detection, the reaction solution was poured into 10 mL of water, adjusted to pH = 3 with 1 M hydrochloric acid, extracted with ethyl acetate (10 mL x 3), and the organic phase was combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. 2-(l,l-difluoroethyl)-4-((3-(methylsulfonyl)bicyclo[l. l. l]pentan-l -yl)amino)-6-phenoxy pyrimidine-5-carboxylic acid (42b) (92 mg, crude) was obtained by concentration under reduced pressure, and the next step was carried out without purification.

[0982] Third step: synthesis of compound 42

[0983] Compound 42 is one of the two structures above

[0984] Compound 42 was prepared according to the following reaction scheme:

[0985] 1 H NMR (600 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.79 (d, J = 8.0 Hz, 1H), 7.44 (t, J = 7.8 Hz, 2H), 7.34 - 7.14 (m, 3H), 6.33 (dd, J = 34.6, 8.9 Hz, 1H), 4.49 (q, J = 8.3 Hz, 1H), 3.23 (s, 3H), 3.01 (s, 3H), 2.53 (s, 6H), 1.81 (t, J = 18.9 Hz, 3H), 1.24 - 1.16 (m, 1H), 0.57 - 0.25 (m, 4H).

[0986] LC-MS, M / Z (ESI): 615.1 [M+H] + .

[0987] Example 43: Preparation of target compound 43

[0988] Compound 43 is one of the two structures above

[0989] The synthetic route of compound 43 is shown below:

[0990] First step: synthesis of tert-butyl (1-(N-methylsulfamoyl)azetidin-3-yl)carbamate (43a)

[0991] tert-Butyl azetidin-3-ylcarbamate (1.00 g, 5.81 mmol) and N,N-diisopropylethylamine (DIPEA) (1.13 g, 8.72 mmol) were dissolved in dichloromethane (10 mL), methyl sulfamoyl chloride (0.75 g, 5.81 mmol) was added dropwise slowly, and the reaction was allowed to proceed at room temperature for 4 hours. After the reaction was completed as determined by TLC, the reaction solution was poured into 20 mL of water, extracted with dichloromethane (15 mL x 3), and the organic phase was combined, washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. The crude product was obtained by concentration under reduced pressure, and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 100:0-75:25, gradient elution) to obtain tert-butyl (1-(N-methylsulfamoyl)azetidin-3-yl)carbamate (43a) (0.49 g, yield 41%).

[0992] Second Step: Synthesis of 3-amino-N-methylazetidine-1-sulfonamide (43b)

[0993] tert-Butyl (1-(N-methylsulfamoyl)azetidin-3-yl)carbamate (43a) (0.49 g, 1.86 mmol) was dissolved in trifluoroacetic acid / dichloromethane (4 mL / 2 mL), and the reaction was allowed to proceed at room temperature for 3 hours. After the reaction was completed as determined by TLC, the reaction solution was concentrated under reduced pressure to obtain 3-amino-N-methylazetidine-1-sulfonamide (43b) (0.45 g, crude), which was used directly in the next step without purification.

[0994] Third Step: Synthesis of methyl 2-(1,1-difluoroethyl)-4-((1-(N-methylsulfamoyl)azetidin-3-yl)amino)-6-phenoxy-pyrimidine-5-carboxylate (43c)

[0995] Methyl 2-(1,1 -difluoroethyl)-4-((1 -(N-methylsulfamoyl)azetidin-3-yl)amino)- 6-phenoxy pyrimidine-5-carboxylate (43c) (64 mg, 92% yield) was obtained by dissolving methyl 4-chloro-2-(1,1 -difluoroethyl)-6-phenoxy pyrimidine-5-carboxylate (07i) (50 mg, 0.15 mmol), 3-amino-N-methylazetidine-1 -sulfonamide (43b) (39 mg, 0.23 mmol) and N,N-diisopropylethylamine (DIPEA) (60 mg, 0.45 mmol) in tetrahydrofuran (5 mL) and reacting at 80 °C for 6 h. After the reaction was completed by LC-MS detection, the reaction solution was poured into 10 mL of water, extracted with ethyl acetate (10 mL x 3), the organic phase was combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the crude product was purified by silica gel column separation (petroleum ether: ethyl acetate (V / V) = 100:0-75:25, gradient elution) to obtain methyl 2-(1,1 -difluoroethyl)-4-((1 -(N-methylsulfamoyl)azetidin-3-yl)amino)- 6-phenoxy pyrimidine-5-carboxylate (43c) (64 mg, 92% yield).

[0996] Fourth step: synthesis of 2-(1,1 -difluoroethyl)-4-((1 -(N-methylsulfamoyl)azetidin-3-yl)amino)-6-phenoxy pyrimidine-5-carboxylic acid (43d)

[0997] Methyl 2-(1,1 -difluoroethyl)-4-((1 -(N-methylsulfamoyl)azetidin-3-yl)amino)- 6-phenoxy pyrimidine-5-carboxylate (43c) (64 mg, 0.14 mmol) was dissolved in tetrahydrofuran / water (4 mL / 1 mL), lithium hydroxide (18 mg, 0.42 mmol) was added, and the reaction was carried out at room temperature for 6 h. After the reaction was completed by LC-MS detection, the reaction solution was poured into 10 mL of water, adjusted to pH = 3 with 1 M hydrochloric acid, extracted with ethyl acetate (10 mL x 3), the organic phase was combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. After concentration under reduced pressure, 2-(1,1 -difluoroethyl)-4-((1 -(N-methylsulfamoyl)azetidin-3-yl)amino)-6-phenoxy pyrimidine-5-carboxylic acid (43d) (56 mg, crude) was obtained without purification for the next step.

[0998] Fifth step: synthesis of compound 43

[0999] Compound 43 is one of the two structures above

[1000] Compound 43 was prepared according to the following reaction scheme:

[1001] 1 H NMR (600 MHz, DMSO-d6) δ 8.80 (dd, J = 24.6, 6.5 Hz, 2H), 7.44 (t, J = 7.9 Hz, 2H), 7.25 (dd, J = 16.3, 7.9 Hz, 3H), 7.15 (q, J = 4.8 Hz, 1H), 6.35 (dd, J = 34.6, 8.9 Hz, 1H), 4.74 - 4.58 (m, 1H), 4.51 (q, J = 8.3 Hz, 1H), 3.99 (td, J = 7.6, 3.5 Hz, 2H), 3.77 (q, J = 8.2 Hz, 2H), 3.23 (s, 3H), 2.58 (d, J = 4.9 Hz, 3H), 1.78 (t, J = 19.0 Hz, 3H), 1.31 - 1.15 (m, 1H), 0.62 - 0.21 (m, 4H).

[1002] LC-MS, M / Z (ESI): 619.0 [M+H] + .

[1003] Example 44: Preparation of target compound 44

[1004] Compound 44 is one of the two structures above

[1005] The synthetic route of compound 44 is shown below:

[1006] First step: synthesis of methyl 2-((3-(tert-butoxycarbonyl)amino)azetidin-1-yl)sulfonyl)acetate (44a)

[1007] tert-Butyl azetidin-3-ylcarbamate (1.00 g, 5.81 mmol) and N,N-diisopropylethylamine (DIPEA) (1.13 g, 8.72 mmol) were dissolved in dichloromethane (10 mL), and methyl 2-(chlorosulfonyl)acetate (1.00 g, 5.81 mmol) was added dropwise slowly. The reaction was stirred at room temperature for 4 hours. After the reaction was completed by TLC detection, the reaction solution was poured into 20 mL of water, and extracted with dichloromethane (15 mL x 3). The organic phase was combined, washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure, and purified by silica gel column separation (petroleum ether: ethyl acetate (V / V) = 100:0-75:25, gradient elution) to obtain methyl (2-((3-(tert-butoxycarbonyl)amino)azetidin-1-yl)sulfonyl)acetate (44a) (0.90 g, yield 51%).

[1008] Second step: synthesis of tert-butyl (1-((2-hydroxyethyl)sulfonyl)azetidin-3-yl)carbamate (44b)

[1009] Methyl (2-((3-(tert-butoxycarbonyl)amino)azetidin-1-yl)sulfonyl)acetate (44a) (0.90 g, 2.91 mmol) and calcium chloride (0.65 g, 5.81 mmol) were dissolved in tetrahydrofuran (10 mL), and sodium borohydride (0.22 g, 5.81 mmol) was added dropwise slowly. The reaction was stirred at room temperature for 12 hours. After the reaction was completed by TLC detection, the reaction solution was poured into 20 mL of water, and extracted with dichloromethane (15 mL x 3). The organic phase was combined, washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure, and purified by silica gel column separation (petroleum ether: ethyl acetate (V / V) = 100:0-60:40, gradient elution) to obtain tert-butyl (1-((2-hydroxyethyl)sulfonyl)azetidin-3-yl)carbamate (44b) (0.28 g, yield 35%).

[1010] Third step: synthesis of 2-((3-aminoazetidin-1-yl)sulfonyl)ethan-1-ol (44c)

[1011] Tert-butyl (1-((2-hydroxyethyl)sulfonyl)azetidin-3-yl)carbamate (44b) (0.28 g, 1.02 mmol) was dissolved in trifluoroacetic acid / dichloromethane (4 mL / 2 mL), and the reaction was stirred at room temperature for 3 hours. After the reaction was completed by TLC detection, the reaction solution was concentrated under reduced pressure to obtain 2-((3-aminoazetidin-1-yl)sulfonyl)ethan-1-ol (44c) (0.19 g, crude product), which was directly used in the next step without purification.

[1012] Step 4: Synthesis of methyl 2-(1,1-difluoroethyl)-4-((1-((2- hydroxyethyl)sulfonyl)azetidin-3-yl)amino)-6-phenoxy pyrimidine-5-carboxylate (44d)

[1013] Methyl 4-chloro-2-(1,1-difluoroethyl)-6-phenoxy pyrimidine-5-carboxylate (07i) (50 mg, 0.15 mmol), 2-((3-aminoazetidin-1-yl)sulfonyl)ethanol-1-ol (44c) (42 mg, 0.23 mmol) and N,N-diisopropylethylamine (DIPEA) (60 mg, 0.45 mmol) were dissolved in tetrahydrofuran (5 mL) and reacted at 80 °C for 6 hours. After the reaction was completed by LC-MS detection, the reaction solution was poured into 10 mL of water, extracted with ethyl acetate (10 mL x 3), and the organic phase was combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure and purified by silica gel column separation (petroleum ether: ethyl acetate (V / V) = 100:0-70:30, gradient elution) to obtain methyl 2-(1,1-difluoroethyl)-4-((1-((2-hydroxyethyl)sulfonyl)azetidin-3-yl)amino)-6-phenoxy pyrimidine-5-carboxylate (44d) (69 mg, yield 95%).

[1014] Step 5: Synthesis of 2-(1,1-difluoroethyl)-4-((1-((2-hydroxyethyl)sulfonyl)azetidin-3-yl)amino)-6-phenoxy pyrimidine-5-carboxylic acid (44e)

[1015] Methyl 2-(1,1-difluoroethyl)-4-((1-(N-methylsulfamoyl)azetidin-3-yl)amino)-6-phenoxy pyrimidine-5-carboxylate (43c) (69 mg, 0.15 mmol) was dissolved in tetrahydrofuran / water (4 mL / 1 mL), and lithium hydroxide (19 mg, 0.44 mmol) was added, and the reaction was carried out at room temperature for 6 hours. After the reaction was completed by LC-MS detection, the reaction solution was poured into 10 mL of water, adjusted to pH = 3 with 1M hydrochloric acid, extracted with ethyl acetate (10 mL x 3), and the organic phase was combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. 2-(1,1-Difluoroethyl)-4-((1-((2-hydroxyethyl)sulfonyl)azetidin-3-yl)amino)-6-phenoxy pyrimidine-5-carboxylic acid (44e) (66 mg, crude) was obtained by concentration under reduced pressure, and the next step was carried out without purification.

[1016] Step 6: Synthesis of compound 44

[1017] Compound 44 is one of the two structures above

[1018] Compound 44 was prepared according to the following reaction scheme:

[1019] 1 H NMR (600 MHz, DMSO-d6) δ 8.81 (d, J = 5.5 Hz, 1H), 8.78 (d, J = 8.0 Hz, 1H), 7.44 (t, J = 7.9 Hz, 2H), 7.25 (dd, J = 17.0, 8.0 Hz, 3H), 6.36 (dd, J = 34.6, 8.9 Hz, 1H), 5.10 (t, J = 5.4 Hz, 1H), 4.72 (q, J = 6.8 Hz, 1H), 4.52 (q, J = 8.3 Hz, 1H), 4.14 (td, J = 7.8, 3.3 Hz, 2H), 3.95 (q, J = 7.9 Hz, 2H), 3.77 (q, J = 6.1 Hz, 2H), 3.35 (s, 2H), 3.24 (s, 3H), 1.79 (t, J = 19.0 Hz, 3H), 1.26 - 1.18 (dtd, J = 11.2, 8.0, 4.0 Hz, 1H), 0.59 - 0.31 (m, 4H).

[1020] LC-MS, M / Z (ESI): 634.0 [M+H] + .

[1021] Example 45: Preparation of target compound 45

[1022] Compound 45 is one of the two structures above

[1023] The synthetic route of compound 45 is shown below:

[1024] First step: synthesis of methyl 2-(1,1-difluoroethyl)-4-((3-(methylsulfonyl)phenyl)amino)-6- phenoxy pyrimidine-5-carboxylate (45a)

[1025] Methyl 4-chloro-2-(l,l-difluoroethyl)-6-phenoxy pyrimidine-5-carboxylate (07i) (50 mg, 0.15 mmol), 3-(methylsulfonyl)aniline (39 mg, 0.23 mmol) and N,N- diisopropylethylamine (DIPEA) (59 mg, 0.45 mmol) were dissolved in tetrahydrofuran (5 mL) and reacted at 80 °C for 6 hours. After the reaction was completed by LC-MS detection, the reaction solution was poured into 10 mL of water, extracted with ethyl acetate (10 mL x 3), and the organic phase was combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure and purified by silica gel column separation (petroleum ether: ethyl acetate (V / V) = 100:0-75:25, gradient elution) to obtain methyl 2-(l,l-difluoroethyl)-4-((3-(methylsulfonyl)phenyl)amino)-6-phenoxy pyrimidine-5-carboxylate (45a) (71 mg, yield 99%).

[1026] Second step: synthesis of 2-(l,l-difluoroethyl)-4-((3-(methylsulfonyl)phenyl)amino)-6-phenoxy pyrimidine-5-carboxylic acid (45b)

[1027] Methyl 2-(l,l-difluoroethyl)-4-((3-(methylsulfonyl)phenyl)amino)-6-phenoxy pyrimidine-5-carboxylate (45a) (71 mg, 0.15 mmol) was dissolved in tetrahydrofuran / water (4 mL / 1 mL), lithium hydroxide (19 mg, 0.45 mmol) was added, and the reaction was carried out at 70 °C for 3 hours. After the reaction was completed by LC-MS detection, the reaction solution was poured into 10 mL of water, adjusted to pH = 3 with 1M hydrochloric acid, extracted with ethyl acetate (10 mL x 3), and the organic phase was combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. 2-(l,l-difluoroethyl)-4-((3-(methylsulfonyl)phenyl)amino)-6-phenoxy pyrimidine-5-carboxylic acid (45b) (69 mg, crude) was obtained by concentration under reduced pressure, and the next step was carried out without purification.

[1028] Third step: synthesis of compound 45

[1029] Compound 45 is one of the two structures above

[1030] Compound 45 was prepared according to the procedure described in Example 1, using 2-(1,1-difluoroethyl)-4-((3-(methylsulfonyl)phenyl)amino)-6- phenoxy pyrimidine-5-carboxylic acid (45b) (69 mg, 0.15 mmol), trifluoroacetate salt of compound 01d-P1 (56 mg, 0.18 mmol), HATU (88 mg, 0.23 mmol) and N,N-diisopropyl ethylamine (DIPEA) (59 mg, 0.46 mmol) in DMF (2 mL) at room temperature for 2 hours. After the reaction was completed by LC-MS detection, the reaction solution was poured into 10 mL of water, extracted with ethyl acetate (10 mL x 3), the organic phase was combined, washed with saturated brine (25 mL) and dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure, and purified by HPLC to obtain compound 45.

[1031] 1 H NMR (400 MHz, CDCl3) δ 12.37 (s, 1H), 8.49 (s, 1H), 8.38 (d, J = 6.6 Hz, 1H), 7.89 (d, J = 8.3 Hz, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.47 (t, J = 7.8 Hz, 2H), 7.34 (d, J = 7.4 Hz, 1H), 7.19 (d, J = 8.1 Hz, 2H), 6.21 (d, J = 23.9 Hz, 1H), 4.35 (d, J = 7.2 Hz, 1H), 3.08 (d, J = 2.1 Hz, 6H), 1.78 (t, J = 18.6 Hz, 3H), 0.87 (s, 1H), 0.69 - 0.63 (m, 2H), 0.47 (d, J = 4.5 Hz, 2H).

[1032] LC-MS, M / Z (ESI): 624.1 [M+H] + .

[1033] Example 46: Preparation of target compound 46

[1034] Compound 46 is one of the two structures above

[1035] The synthetic route of compound 46 is shown below:

[1036] First step: synthesis of 3-thioxabicyclo[3.1.0]hexane 3,3-dioxide (46a)

[1037] Dichloromethane (25 mL) and 2,5-dihydrothiophene-1,1 -dioxide (2.00 g, 16.95 mmol) was added m-chloroperoxybenzoic acid (5.85 g, 33.90 mmol, 85% content) slowly and the reaction was stirred at room temperature for 48 h. After the reaction was completed by TLC detection, the reaction solution was poured into 25 mL saturated aqueous sodium thiosulfate solution and stirred for another 3 h. The mixture was extracted with dichloromethane (25 mL x 3), and the combined organic phase was washed with saturated brine (45 mL) and dried over anhydrous sodium sulfate. The crude product was obtained by concentration under reduced pressure and purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 100:0-70:30, gradient elution) to give 3-thiabicyclo[3.1.0]hexane 3,3-dioxide (46a) (0.49 g, yield 22%).

[1038] Second Step: Synthesis of 3-amino-4-hydroxythiophene 1,1 -dioxide (46b)

[1039] 3-thiabicyclo[3.1.0]hexane 3,3-dioxide (46a) (0.49 g, 1.86 mmol) was dissolved in ammonia water (4 mL) and the reaction was stirred at 70 °C for 12 h. After the reaction was completed by TLC detection, the reaction solution was concentrated under reduced pressure to give 3-amino-4-hydroxythiophene 1,1 -dioxide (46b) (0.55 g, crude), which was used directly in the next step without purification.

[1040] Third Step: Synthesis of methyl 2-(1,1 -difluoroethyl)-4-((4-hydroxy-1,1 -dioxidothiophen-3- yl)amino)-6-phenoxy pyrimidine-5-carboxylate (46c)

[1041] Methyl 4-chloro-2-(1,1 -difluoroethyl)-6-phenoxy pyrimidine-5-carboxylate (07i) (400 mg, 1.22 mmol), 3-amino-4-hydroxythiophene 1,1 -dioxide (46b) (277 mg, 1.83 mmol) and N,N-diisopropylethylamine (DIPEA) (316 mg, 2.45 mmol) were dissolved in tetrahydrofuran (10 mL) and the reaction was stirred at 70 °C for 12 h. After the reaction was completed by LC-MS detection, the reaction solution was poured into 15 mL water, extracted with ethyl acetate (15 mL x 3), and the combined organic phase was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. The crude product was obtained by concentration under reduced pressure and purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 100:0-60:40, gradient elution) to give methyl 2-(1,1 -difluoroethyl)-4-((4-hydroxy-1,1 -dioxidothiophen-3-yl)amino)-6- phenoxy pyrimidine-5-carboxylate (46c) (406 mg, yield 75%).

[1042] Step 4: Synthesis of 2-(1,1-difluoroethyl)-4-((1-(N-methylsulfamoyl)azetidin-3- yl)amino)-6-phenoxy pyrimidine-5-carboxylic acid (46d)

[1043] Methyl 2-(1,1-difluoroethyl)-4-((4-hydroxy-1,1-dioxide thiolane-3-yl)amino)-6- phenoxy pyrimidine-5-carboxylate (46c) (406 mg, 9.2 mmol) was dissolved in tetrahydrofuran / water (10 mL / 2 mL), lithium hydroxide (116 mg, 2.8 mmol) was added, and the reaction was allowed to proceed at room temperature for 6 hours. After the reaction was completed as determined by LC-MS, the reaction solution was poured into 10 mL of water, adjusted to pH = 3 with 1M hydrochloric acid, extracted with ethyl acetate (15 mL x 3), the organic phase was combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 2-(1,1-difluoroethyl)-4-((1-(N-methylsulfamoyl)azetidin-3-yl)amino)-6-phenoxy pyrimidine-5-carboxylic acid (46d) (370 mg, crude), which was used directly in the next step without purification.

[1044] Step 5: Synthesis of compound 46

[1045] Compound 46 is one of the two structures above

[1046] Methyl 2-(1,1-difluoroethyl)-4-((1-(N-methylsulfamoyl)azetidin-3-yl)amino)-6- phenoxy pyrimidine-5-carboxylate (46d) (50 mg, 0.11 mmol), trifluoroacetate salt of compound 01d-P1 (52 mg, 0.17 mmol), HATU (65 mg, 0.17 mmol), and N,N- diisopropylethylamine (DIPEA) (44 mg, 0.34 mmol) were dissolved in DMF (2 mL), and the reaction was allowed to proceed at room temperature for 2 hours. After the reaction was completed as determined by LC-MS, the reaction solution was poured into 10 mL of water, extracted with ethyl acetate (10 mL x 3), the organic phase was combined, washed with saturated brine (25 mL), and dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure, and compound 46 was obtained by separation and purification with HPLC.

[1047] 1H NMR (600 MHz, DMSO-d6) δ 9.32 (d, J = 7.3 Hz, 1H), 9.03 (d, J = 7.0 Hz, 1H), 8.87 - 8.60 (m, 1H), 7.57 - 7.39 (m, 2H), 7.28 (dd, J = 17.8, 7.9 Hz, 3H), 6.56 - 6.24 (m, 2H), 4.92 - 4.34 (m, 4H), 3.70 - 2.94 (m, 7H), 1.86 - 1, 75 (m, 2H), 1.32 - 1.20 (m, 1H), 0.57 - 0.24 (m, 3H).

[1048] LC-MS, M / Z (ESI): 604.0 [M+H] + .

[1049] The preparation method of the following compound is for Reference Example 14

[1050] The preparation method of the following compound is for Reference Example 01

[1051] The preparation method of the following compound is for Reference Example 12

[1052] The preparation method of the following compound is for Reference Example 07

[1053] Biological test:

[1054] Test Example 1: Inhibition test of compound on WRN enzyme activity

[1055] The compound was gradiently diluted with DMSO in a 384-well compound dilution plate, 0.15 μL of the compound was transferred to a 384-reaction microplate using Echo, 5 μL of WRN (517-1238) enzyme solution (containing 0.20 mM ATP) was added to each well of the 384-reaction microplate, and it was incubated at 25°C for 4 hours. The wells containing DMSO and enzyme were used as high value controls, and the wells containing only DMSO and buffer were used as low value controls. 5 μL of double-stranded DNA and capture DNA mixed solution was added to each well, and after centrifugation, 5 μL of ATP solution was added, and it was incubated at 25°C for 30 minutes. Then the fluorescence signal value (excitation wavelength: 620 nm, emission wavelength: 685 nm) was read on the BMG (CLARIO Star Plus acu) enzyme marker. The inhibition rate of the compound was calculated according to the following formula, and then the four-parameter IC 50 curve was fitted and analyzed by XLfit 5.5.0.

[1056] Inhibition rate % = (signal value 高值对照 - signal value 化合物处理 ) / (signal value 高值对照 - signal value 低值对照 )*100%

[1057] Table 1 Test compound on WRN enzyme inhibition activity

[1058] The test results show that the compound of the present application can significantly inhibit the activity of WRN enzyme, and has good drug property.

[1059] Test Example 2: Compound on SW48 cell proliferation inhibition test

[1060] SW48 cells (ATCC, CCL-231) were cultured in Leibovitz's L-15 + 10% FBS + 1% PS as complete medium, and the logarithmic phase SW48 cells were inoculated into 96-well microplate at 3000 cells / well, and cultured in 37℃, 5% CO2 cell incubator overnight. The compound diluted with cell culture medium was added to the cell plate for continuous culture for 5 days. After incubation, the cell viability was detected using Cell Counting-Lite 2.0 luminescent cell viability assay kit (Vazyme, DD1101-03) according to the instructions provided by the supplier, and the signal value was detected on BMG (PHERAstar FSX). The wells containing only cell culture medium were used as low control, and the wells containing cells and the same proportion of DMSO were used as high control. The inhibition rate of the compound was calculated according to the following formula, and the IC 50 value was calculated by fitting four-parameter logistic model or Excel.

[1061] Inhibition rate % = (signal value 高值对照 - signal value 化合物处理 ) / (signal value 高值对照 - signal value 低值对照 )*100%

[1062] Table 2 Test compound on SW48 cell proliferation inhibition activity

[1063] The test results show that the compound of the present application can significantly inhibit the proliferation of SW48 cells, and has good drug property.

[1064] Test Example 3: Compound on HCT116 cell proliferation inhibition test

[1065] HCT116 cells (ATCC) were cultured in McCoy's 5A + 10% FBS + 1% PS as complete medium, and the logarithmic phase HCT116 cells were seeded into 96-well microplates at 500 cells / well, and incubated at 37°C, 5% CO2 cell incubator overnight. The compounds diluted with cell culture medium were added to the cell plate for continuous culture for 5d. After incubation, the cell viability was detected using CellTiter-Glo 2.0 Luminescent Cell Viability Assay Kit (Promega, G924C) and following the instructions provided by the supplier, and the signal value was detected on a multifunctional microplate reader (SpectraMax iD5). The wells containing only cell culture medium were used as low control, and the wells containing cells and the same proportion of DMSO were used as high control. The inhibition rate of the compound was calculated according to the following formula, and the IC 50 value was calculated by fitting a four-parameter logistic model or Excel.

[1066] Inhibition rate % = (signal value high control - signal value compound treatment) / (signal value high control - signal value low control) * 100%

[1067] Table 3 Test compound inhibitory activity on HCT116 cell proliferation

[1068] Table 3-1 Test compound inhibitory activity on HCT116 cell proliferation

[1069] The activity ranges A, B and C refer to the IC 50 values in patch clamp detection, as follows: "A": IC 50 < 1 μM; "B": 1 μM ≤ IC 50 < 10 μM; "C": IC 50 ≥ 10 μM.

[1070] The test results show that the compounds of the present application can significantly inhibit the proliferation of HCT116 cells, and have good drug properties.

[1071] Test Example 4: Mouse pharmacokinetic test (oral)

[1072] Mouse pharmacokinetic test, male ICR mice, 20-25 g, fasted overnight. Take 3 mice, oral gavage administration of 10 mg / kg. Blood samples were taken before administration and at 15, 30 minutes and 1, 2, 4, 8, 24 hours after administration. Blood samples were centrifuged at 6800 g, 2-8℃ for 6 minutes, and the plasma was collected and stored at -80℃. Take the plasma at each time point, add 3-5 times the amount of internal standard acetonitrile solution, mix, vortex mix for 1 minute, centrifuge at 13000 rpm for 10 minutes at 4℃, take the supernatant and add 3 times the amount of water, take an appropriate amount of mixture for LC-MS / MS analysis. The main pharmacokinetic parameters were analyzed by WinNonlin 7.0 software non-compartment model.

[1073] Table 4 Mouse pharmacokinetic test results (oral)

[1074] The results of the mouse pharmacokinetic test show that the compounds of the present application exhibit excellent pharmacokinetic properties, with high plasma exposure and good drug development potential.

[1075] Test Example 5: Rat pharmacokinetic test (oral)

[1076] Rat pharmacokinetic test, male SD rats, 180-240 g, fasted overnight. Take 3 rats, oral gavage administration of 10 mg / kg. Blood samples were taken before administration and at 15, 30 minutes and 1, 2, 4, 8, 24 hours after administration. Blood samples were centrifuged at 6800 g, 2-8℃ for 6 minutes, and the plasma was collected and stored at -80℃. Take the plasma at each time point, add 3-5 times the amount of internal standard acetonitrile solution, mix, vortex mix for 1 minute, centrifuge at 13000 rpm for 10 minutes at 4℃, take the supernatant and add 3 times the amount of water, take an appropriate amount of mixture for LC-MS / MS analysis. The main pharmacokinetic parameters were analyzed by WinNonlin 7.0 software non-compartment model.

[1077] Table 5 Rat pharmacokinetic test results (oral)

[1078] The results of the rat pharmacokinetic test show that the compounds of the present application exhibit excellent rat pharmacokinetic properties, with high plasma exposure and good drug development potential.

[1079] Test Example 6: Dog pharmacokinetic test (oral)

[1080] Dog pharmacokinetic test, male Beagle dogs, 8-10 kg, overnight fasting. Take 3 Beagle dogs, oral gavage administration of 5 mg / kg, before administration and after administration of 15, 30 minutes and 1, 2, 4, 8, 24 hours of blood. Blood samples were centrifuged at 6800g, 2-80 for 6 minutes, and the plasma was collected and stored at -80. Take the plasma at each time point, add 3-5 times the amount of internal standard acetonitrile solution, mix, vortex mix for 1 minute, centrifuge at 13000 rpm for 4 minutes, take the supernatant and add 3 times the amount of water, take the appropriate amount of mixture for LC-MS / MS analysis. The main pharmacokinetic parameters were analyzed by WinNonlin 7.0 software non-compartment model.

[1081] Table 6 Dog pharmacokinetic test results (oral)

[1082] The results of the dog pharmacokinetic test show that the compounds of the present application exhibit excellent dog pharmacokinetic properties, high plasma exposure, and good drug development.

[1083] Test Example 7: Monkey pharmacokinetic test (oral)

[1084] Monkey pharmacokinetic test, male cynomolgus monkeys, 3-5 kg, overnight fasting. Take 3 cynomolgus monkeys, oral gavage administration of 5 mg / kg, before administration and after administration of 15, 30 minutes and 1, 2, 4, 8, 24 hours of blood. Blood samples were centrifuged at 6800g, 2-80 for 6 minutes, and the plasma was collected and stored at -80. Take the plasma at each time point, add 3-5 times the amount of internal standard acetonitrile solution, mix, vortex mix for 1 minute, centrifuge at 13000 rpm for 4 minutes, take the supernatant and add 3 times the amount of water, take the appropriate amount of mixture for LC-MS / MS analysis. The main pharmacokinetic parameters were analyzed by WinNonlin 7.0 software non-compartment model.

[1085] Table 7 Monkey pharmacokinetic test results (oral)

[1086] The results of the monkey pharmacokinetic test show that the compounds of the present application exhibit excellent monkey pharmacokinetic properties, high plasma exposure, and good drug development.

[1087] Test Example 8: Mouse pharmacokinetic test (intravenous injection)

[1088] Mouse pharmacokinetic test, male ICR mice, 20-25 g, fasted overnight. Take 3 mice, intravenous injection of 1 mg / kg, before administration and at 15, 30 minutes and 1, 2, 4, 8, 24 hours after administration. Blood samples were centrifuged at 6800 g, 2-8℃ for 6 minutes, and the plasma was collected and stored at -80℃. Take the plasma at each time point, add 3-5 times the amount of internal standard acetonitrile solution, mix, vortex mix for 1 minute, centrifuge at 13000 rpm for 10 minutes at 4℃, take the supernatant and add 3 times the amount of water, take an appropriate amount of mixture for LC-MS / MS analysis. The main pharmacokinetic parameters were analyzed by WinNonlin 7.0 software non-compartment model.

[1089] Table 8 Mouse pharmacokinetic test results (intravenous injection)

[1090] The results of the mouse pharmacokinetic test show that the compounds of the present application exhibit excellent pharmacokinetic properties, with low clearance, high tissue distribution, and good drug formation.

[1091] Test Example 9: Rat pharmacokinetic test (intravenous injection)

[1092] Rat pharmacokinetic test, male SD rats, 180-240 g, fasted overnight. Take 3 rats, intravenous injection of 1 mg / kg, before administration and at 15, 30 minutes and 1, 2, 4, 8, 24 hours after administration. Blood samples were centrifuged at 6800 g, 2-8℃ for 6 minutes, and the plasma was collected and stored at -80℃. Take the plasma at each time point, add 3-5 times the amount of internal standard acetonitrile solution, mix, vortex mix for 1 minute, centrifuge at 13000 rpm for 10 minutes at 4℃, take the supernatant and add 3 times the amount of water, take an appropriate amount of mixture for LC-MS / MS analysis. The main pharmacokinetic parameters were analyzed by WinNonlin 7.0 software non-compartment model.

[1093] Table 9 Rat pharmacokinetic test results (intravenous injection)

[1094] The results of the rat pharmacokinetic test show that the compounds of the present application exhibit excellent rat pharmacokinetic properties, with low clearance, high tissue distribution, and good drug formation.

Claims

1. The compound represented by formula (Ⅰ), its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, in, X1 is N or CR x1 ; X2 is N or CR x2 ; X3 is N or CR x3 ; X4 is N or CR x4 ; X5 is N or CR x5 ; R x1 For H, halogen, OH, NH2, CN, COOH, C 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Alkoxy, C 1-6 Alkylamino, -SC 1-6 Alkyl, C 3-8 cycloalkyl, -OC 3-8 cycloalkyl, C 3-8 Cycloalkenyl, C 6-10 Aryl, -OC 6-10 Aryl, 3-8 membered heterocyclic alkyl, -O-(3-8 membered heterocyclic alkyl), 4-8 membered heterocyclic alkenyl, -O-(4-8 membered heterocyclic alkenyl), 5-10 membered heteroaryl or -O-(5-10 membered heteroaryl), wherein C 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Alkoxy, C 1-6 Alkylamino, -SC 1-6 Alkyl, C 3-8 cycloalkyl, -OC 3-8 cycloalkyl, C 3-8 Cycloalkenyl, C 6-10 Aryl, -OC 6- 10 Aryl, 3-8-membered heterocyclic alkyl, -O-(3-8-membered heterocyclic alkyl), 4-8-membered heterocyclic alkenyl, -O-(4-8-membered heterocyclic alkyl), 5-10-membered heteroaryl and -O-(5-10-membered heteroaryl) are each independently and optionally surrounded by 1, 2, 3 or 4 R's. m replace; R x3 For H, halogen, OH, NH2, CN, COOH, C 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Alkoxy, C 1-6 Alkylamino, -SC 1-6 Alkyl, C 3-8 cycloalkyl, -OC 3-8 cycloalkyl or C 3-8 Cycloalkenyl, the C 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Alkoxy, C 1-6 Alkylamino, -SC 1-6 Alkyl, C 3-8 cycloalkyl, -OC 3-8 cycloalkyl and C 3-8 The cycloalkene groups are independently and optionally surrounded by 1, 2, 3 or 4 R groups. n replace; R x2 R x4 and R x5 The independent components are H, halogen, OH, NH2, CN, COOH, and C, respectively. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2- 6-acetylinyl, C 1-6 Alkoxy, C 1-6 Alkylamino, -NHR ee -C 0-6 Alkylene-C(=O)-NR e1 R e2 -C 0-6 Alkylene-NR e1 -C(=O)-C 1-6 Alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylamino, -NHR ee -C 0-6 Alkylene-C(=O)-NR e1 R e2 -C 0-6 Alkylene-NR e1 -C(=O)-C 1-6 Alkyl, C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl groups are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. y replace; R ee -C 0-6 Alkylene-S(=O)2-R ee1 -C 1-6 alkylene-5-10-membered heteroaryl or ring A, wherein ring A is C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl, 4-8 membered heterocyclic alkenyl or 5-10 membered heteroaryl; R ee1 For H or C 1-6 alkyl; Each R e1 and R e2 H or C, independently respectively 1-6 alkyl; Each R m R n and R y The independent components are H, halogen, OH, NH2, CN, COOH, oxo (=O), and C, respectively. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, -S(=O)2-R or C 3-8 cycloalkyl; R is H, -NR d1 R d2 C 1-6 Alkyl or -C 1-6 alkylene-OH; L can be a single bond, -O-, -S-, -NH-, -S(=O)-, or -S(=O)2-; R 11 and R 12 The independent components are H, halogen, OH, NH2, CN, COOH, and C, respectively. 1-6 Alkyl, C 3-8 Cycloalkyl, 5-6 membered heterocycloalkyl or 5-6 membered heterocycloalkenyl, wherein C 1-6 Alkyl, C 3-8 Cycloalkyl, 5-6 membered heterocyclic alkyl, and 5-6 membered heterocyclic alkenyl groups are each independently and optionally surrounded by 1, 2, 3, or 4 R groups. a replace; R2 can be H, halogen, OH, NH2, CN, COOH, or C. 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkylamino, the C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Alkylamino groups are independently and optionally surrounded by 1, 2, 3 or 4 R groups. b replace; R 31 and R 32 Each is independently H, halogen, CN, C 1-6 Alkyl, -C 0-6 Alkylene-S(=O)2-NR e3 R e4 -C 1-6 Alkylene-S(=O)2-R e5 -S(=O)2-R e6 -C 0-6 Alkylene-S(=O)(=NR) e7 )-R e8 -C 0-6 Alkylene-S(=O)-NR e3 R e4 -C 0-6 Alkylene-S(=O)-R e5 -C 0-6 Alkylene-C(=O)-NR e3 R e4 -C 0-6 Alkylene-C(=O)-R e5 -C 0-6 Alkylene-NR e3 -C(=O)-C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-8 Cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl or 5-6 membered heteroaryl, wherein C 1-6 Alkyl, -C 0-6 Alkylene-S(=O)2-NR e3 R e4 -C 1-6 Alkylene-S(=O)2-R e5 -S(=O)2-R e6 -C 0-6 Alkylene-S(=O)(=NR) e7 )-R e8 -C 0-6 Alkylene-S(=O)-NR e3 R e4 -C 0-6 Alkylene-S(=O)-R e5 -C 0-6 Alkylene-C(=O)-NR e3 R e4 -C 0-6 Alkylene-C(=O)-R e5 -C 0-6 Alkylene-NR e3 -C(=O)-C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-8 Cycloalkyl, 5-6-membered heterocycloalkyl, 5-6-membered heterocycloalkenyl, and 5-6-membered heteroaryl groups are each independently and optionally surrounded by 1, 2, 3, or 4 R groups. c replace; Each R e3 and R e4 H or C, independently respectively 1-6 alkyl; Each R e5 and R e8 They are H, OH, and C, respectively. 1-6 Alkyl, C 3-8 Cycloalkyl, 5-6 membered heterocycloalkyl or 5-6 membered heterocycloalkenyl; Each R e6 H and C are independent of each other. 1-6 Alkyl, C 3-8 Cycloalkyl, 4-6 membered heterocycloalkyl or 4-6 membered heterocycloalkenyl; Each R e7 Each independently can be H, CN, or C. 1-6 alkyl; Each R a R b and R c Each can be independently H, halogen, OH, NH2, CN, =O, COOH, or C. 1-6 alkyl; Each R d1 and R d2 H or C, independently respectively 1-6 alkyl; p is 0, 1, 2, 3 or 4; Furthermore, the R 31 R 32 X4, R x4 X5, R x5 One of the following conditions must be met: a) When R 31 and R 32 If one of them is H, the other is not CN; or, b) When R 31 and R 32 One of them is -S(=O)2-R e6 R e6 C 1-6 Alkyl, C 3-8 When the cycloalkyl or 5-6 membered heterocycloalkyl group has an H atom, X4 is CR. x4 R x4 C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylamino or C 3-8 cycloalkyl; or, c) When R 31 and R 32 One of them is -S(=O)2-R e6 R e6 C 1-6 Alkyl, C 3-8 When the other alkyl group is a cycloalkyl group or a 5-6 membered heterocycloalkyl group, and the other alkyl group is H, then X5 is CR. x5 R x5 -NHR ee ; The heteroatoms in the "heterocyclic alkyl", "heterocyclic alkenyl" and "heteroaryl" include N, O and S, and the S heteroatoms are optionally oxidized to S(=O), S(=O)2 or S(=O)(=NH), and the number of heteroatoms is 1, 2, 3 or 4; when the number of heteroatoms is multiple, the heteroatoms may be the same or different.

2. The compound according to claim 1, characterized in that, At least one of X1, X2, X3, X4, and X5 is N; And / or, one or two of X1, X2, X3, X4 and X5 are N; And / or, X1 is CR x1 X2 is N, X3 is CR x3 X4 is N or CR x4 X5 is CR x5 ; And / or, X1 is CR x1 X2 is N, X3 is CR x3 X4 is N, X5 is CR x5 ; And / or, X1 is CR x1 X2 is N, X3 is CR x3 X4 is CR x4 X5 is CH; And / or, R x1 For H, halogen, OH, NH2, CN, COOH, C 1-4 Alkyl, C 2-4 alkenyl, C 1-4 Alkoxy, C 1-4 Alkylamino, -SC 1-4 Alkyl, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, C 3-6 Cycloalkenyl, C 6-10 Aryl, -OC 6-10 Aryl, 5-6 membered heterocyclic alkyl, -O-(5-6 membered heterocyclic alkyl), 5-6 membered heterocyclic alkenyl, -O-(5-6 membered heterocyclic alkenyl), 5-6 membered heteroaryl or -O-(5-6 membered heteroaryl), wherein C 1-4 Alkyl, C 2- 4-Alkenyl, C 1-4 Alkoxy, C 1-4 Alkylamino, -SC 1-4 Alkyl, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, C 3-6 Cycloalkenyl, C 6-10 Aryl, -OC 6-10 Aryl, 5-6-membered heterocyclic alkyl, -O-(5-6-membered heterocyclic alkyl), 5-6-membered heterocyclic alkenyl, -O-(5-6-membered heterocyclic alkenyl), 5-6-membered heteroaryl and -O-(5-6-membered heteroaryl) are each independently and optionally surrounded by 1, 2, 3 or 4 Rs. m replace; And / or, R x1 For H, halogen, OH, NH2, CN, COOH, C 1-4 Alkyl, C 3-6 Cycloalkyl, phenyl, -O-phenyl, 5-6 heteroaryl, or -O-(5-6 heteroaryl), wherein C 1-4 Alkyl, C 3-6 Cycloalkyl, phenyl, -O-phenyl, 5-6 heteroaryl, and -O-(5-6 heteroaryl) are each independently and optionally surrounded by 1, 2, 3, or 4 R groups. m replace; And / or, R x1 The derivative is H, F, Cl, Br, methyl, ethyl, phenyl, or -O-phenyl, wherein the methyl, ethyl, phenyl, and -O-phenyl groups are each independently and optionally separated by 1, 2, 3, or 4 R groups. m replace; And / or, each R m The independent components are H, halogen, OH, NH2, CN, COOH, and C, respectively. 1-3 alkyl; And / or, each R m They can be independently H, F, Cl, Br, OH, NH2, CN, COOH, methyl or ethyl; And / or, R x1 for And / or, R x1 for And / or, R x3 For H, halogen, OH, NH2, CN, COOH, C 1-4 Alkyl, C 2-4 alkenyl, C 1-4 Alkoxy, C 1-4 Alkylamino, -SC 1-4 Alkyl, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl or C 3-6 Cycloalkenyl, the C 1-4 Alkyl, C 2-4 alkenyl, C 1-4 Alkoxy, C 1-4 Alkylamino, -SC 1-4 Alkyl, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl and C 3-6 The cycloalkene groups are independently and optionally surrounded by 1, 2, 3 or 4 R groups. n replace; And / or, R x3 H, halogen, C 1-4 Alkyl or C 3-6 cycloalkyl, the C 1-4 Alkyl and C 3-6 The cycloalkyl groups are each independently and optionally marked with 1, 2, 3 or 4 R groups. n replace; And / or, R x3 The derivatives are H, F, Cl, Br, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein the methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl groups are each independently and optionally converted by 1, 2, 3, or 4 R groups. n replace; And / or, each R n The independent components are H, halogen, OH, NH2, CN, COOH, and C, respectively. 1-3 Alkyl or C 3-6 cycloalkyl; And / or, each R n They can be independently H, F, Cl, Br, OH, NH2, CN, COOH, methyl, ethyl, propyl, cyclopropyl, or cyclobutyl; And / or, R x3 H, methyl, ethyl, cyclopentyl, 3. The compound according to claim 1, characterized in that, R x2 R x4 and R x5 They are independently H, halogen, OH, NH2, CN, COOH, C 1-3 Alkyl, C 1-3 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 1-3 Alkylamino, -NHR ee -C 0-3 Alkylene-C(=O)-NR e1 R e2 -C 0-3 Alkylene-NR e1 -C(=O)-C 1-3 Alkyl, C 3-6 Cycloalkyl or 4-6 membered heterocycloalkyl, wherein C 1-3 Alkyl, C 1-3 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 1-3 Alkylamino, -NHR ee -C 0-3 Alkylene-C(=O)-NR e1 R e2 -C 0- 3-alkylene-NR e1 -C(=O)-C 1-3 Alkyl, C 3-6 Cycloalkyl and 4-6 membered heterocycloalkyl groups are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. y replace; And / or, R x2 H, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl or C 1-3 Alkoxy, the C 1-3 Alkyl, C 1- 3-Hydroalkyl, C 2-4 alkenyl, C 2-4 alkynyl group and C 1-3 The alkoxy groups are independently and optionally surrounded by 1, 2, 3 or 4 R groups. y replace; And / or, R x2 It can be H, F, Cl, Br, methyl, ethyl, -CF3, -CHF2, vinyl, ethynyl, or methoxy; And / or, R x4 H, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl or C 1-3 Alkoxy, the C 1-3 Alkyl, C 1- 3-Hydroalkyl, C 2-4 alkenyl, C 2-4 alkynyl group and C 1-3 The alkoxy groups are independently and optionally surrounded by 1, 2, 3 or 4 R groups. y replace; And / or, R x4 It can be H, F, Cl, Br, methyl, ethyl, -CF3, -CHF2, vinyl, ethynyl, or methoxy; And / or, R x5 H, halogens, NH2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, -NHR ee Or 4-6 membered heterocyclic alkyl groups, wherein C 1-3 Alkyl, C 1-3 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, -NHR ee Each of the 4-6 membered heterocyclic alkyl groups is independently and optionally surrounded by 1, 2, 3 or 4 R groups. y replace; And / or, R x5 For H or -NHR ee The -NHR ee Optionally divided by 1, 2, 3 or 4 R y replace; And / or, R ee -C 0-3 Alkylene-S(=O)2-R ee1 -C 1-3 alkylene-5-6-membered heteroaryl or ring A, wherein ring A is C 3-6 Cycloalkyl, 4-8 membered heterocycloalkyl, phenyl, 5-6 membered heterocycloalkenyl or 5-6 membered heteroaryl, wherein R ee Optionally divided by 1, 2, 3 or 4 R y replace; And / or, R ee -C 0-3 Alkylene-S(=O)2-R ee1 -C 1-3 alkylene-5-6-membered heteroaryl or ring A, wherein ring A is C 3-6 Monocyclic cycloalkyl, C 5-6 Bridged cycloalkyl, 4-6 membered monocyclic heterocyclic alkyl, 6-8 membered spirocyclic alkyl, 6-8 membered fused heterocyclic alkyl, phenyl, 5-6 membered heterocyclic alkenyl or 5-6 membered heteroaryl, wherein R ee Optionally divided by 1, 2, 3 or 4 R y replace; And / or, R ee1 For H or C 1-3 alkyl; And / or, R ee1 It is H or methyl; And / or, R ee It is -(CH2)2-S(=O)2-CH3, Or ring A, wherein ring A is Where R ee Optionally divided by 1, 2, 3 or 4 R y replace; And / or, R ee It is -(CH2)2-S(=O)2-CH3, Or ring A, wherein ring A is Where R ee Optionally divided by 1, 2, 3 or 4 R y replace; And / or, each R e1 and R e2 H or C, independently respectively 1-3 alkyl; And / or, each R e1 and R e2 Each can be independently H, methyl, ethyl, or propyl; And / or, each R y They are, independently, H, OH, F, Cl, Br, CN, oxo (=O), and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, -S(=O)2-R or C 3-6 cycloalkyl; And / or, R is H, -NHR d2 C 1-3 Alkyl or -C 1-3 alkylene-OH, wherein R d2 For H or C 1-6 alkyl; And / or, R is H, -NH(CH3), methyl, or -CH2CH2(OH); And / or, each R y They can be independently H, OH, F, Cl, CN, oxo(=O), methyl, -CHF2, -CH2CF3, -S(=O)2-CH3, -S(=O)2-NH(CH3) or -S(=O)2-CH2-CH2(OH); And / or, R ee -C 1-3 Alkylene-S(=O)2(C 1-3 Alkyl), -S(=O)2(C 1-3 alkyl) substituted C 3-6 Cycloalkyl, 4-6 membered monocyclic heterocyclic alkyl, or 5-6 membered heteroaryl; wherein... When the 4-6 membered monocyclic heterocyclic alkyl group contains S, the 4-6 membered monocyclic heterocyclic alkyl group is substituted by one or more oxo (=O) and / or OH; When the 4-6 membered monocyclic heterocyclic alkyl group contains N, the 4-6 membered monocyclic heterocyclic alkyl group is coated with -S(=O)2(C 1-3 Alkyl), S(=O)2-NH(CH3) or -S(=O)2-CH2-CH2(OH) substitution; When the 4-6 member monocyclic heterocyclic alkyl group contains O, the 4-5 member monocyclic heterocyclic alkyl group is unsubstituted; The 5-6 quinone heteroaryl group is optionally coated with C. 1-3 Alkyl, halomethyl or -S(=O)2(C 1-3 Alkyl) substitution; And / or, R ee -C 1-3 Alkylene-S(=O)2(C 1-3 Alkyl), -S(=O)2(C 1-3 alkyl) substituted C 3-6 Cycloalkyl or 4-6 membered monocyclic heterocyclic alkyl; wherein, When the 4-6 membered monocyclic heterocyclic alkyl group contains S, the 4-6 membered monocyclic heterocyclic alkyl group is substituted by one or more oxo (=O); When the 4-6 membered monocyclic heterocyclic alkyl group contains N, the 4-6 membered monocyclic heterocyclic alkyl group is coated with -S(=O)2(C 1-3 Alkyl) substitution; And / or, when R ee -C 1-3 Alkylene-S(=O)2-C 1-3 When alkyl, R 31 For H, R 32 -S(=O)2-R e6 ; And / or, R x5 For H, F, Cl, Br, NH2, methyl, ethyl, -CF3, -CHF2, vinyl, ethynyl, methoxy, -NH-(CH2)2-S(=O)2-CH3, And / or, R x5 for -NH-(CH2)2-S(=O)2-CH3.

4. The compound according to claim 1, characterized in that, L is -NH-; And / or, R 11 and R 12 The independent components are H, halogen, OH, NH2, CN, COOH, and C, respectively. 1-3 Alkyl or C 3-6 cycloalkyl, the C 1-3 Alkyl and C 3-6 The cycloalkyl groups are each independently and optionally marked with 1, 2, 3 or 4 R groups. a replace; And / or, R 11 and R 12 Each of the following is independently H, F, Cl, Br, OH, NH2, CN, COOH, methyl, ethyl, propyl, cyclopropyl, or cyclobutyl, wherein the methyl, ethyl, propyl, cyclopropyl, and cyclobutyl groups are each optionally independently converted by 1, 2, 3, or 4 R groups. a replace; And / or, each R a They can be independently H, F, Cl, Br, OH, NH2, CN, =O, or COOH; And / or, R 11 and R 12 Independently H, cyclopropyl or And / or, R 11 For H, R 12 It is cyclopropyl; And / or, R 11 It is cyclopropyl, R 12 For H.

5. The compound according to claim 1, characterized in that, R2 can be H, F, Cl, Br, OH, NH2, CN, COOH, or C. 1-3 Alkyl, the C 1-3 Alkyl groups are independently and optionally surrounded by 1, 2, 3 or 4 R groups. b replace; And / or, each R b They can be H, F, Cl, or Br, respectively. And / or, R2 is H; And / or, R 31 and R 32 Each is independently H, halogen, CN, C 1-3 Alkyl, -C 0-3 Alkylene-S(=O)2-NR e3 R e4 -C 1-3 Alkylene-S(=O)2-R e5 -S(=O)2-R e6 -C 0-3 Alkylene-S(=O)(=NR) e7 )-R e8 -C 0-3 Alkylene-S(=O)-NR e3 R e4 -C 0-3 Alkylene-S(=O)-R e5 -C 0- 3-alkylene-C(=O)-NR e3 R e4 -C 0-3 Alkylene-C(=O)-R e5 -C 0-3 Alkylene-NR e3 -C(=O)-C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl or 5-6 membered heteroaryl, wherein C 1-3 Alkyl, -C 0-3 Alkylene-S(=O)2-NR e3 R e4 -C 1-3 Alkylene-S(=O)2-R e5 -S(=O)2-R e6 -C 0-3 Alkylene-S(=O)(=NR) e7 )-R e8 -C 0-3 Alkylene-S(=O)-NR e3 R e4 -C 0-3 Alkylene-S(=O)-R e5 -C 0-3 Alkylene-C(=O)-NR e3 R e4 -C 0-3 Alkylene-C(=O)-R e5 -C 0-3 Alkylene-NR e3 -C(=O)-C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 3-6 Cycloalkyl, 5-6-membered heterocycloalkyl, 5-6-membered heterocycloalkenyl, and 5-6-membered heteroaryl groups are each independently and optionally surrounded by 1, 2, 3, or 4 R groups. c replace; And / or, R 31 and R 32 They are H, F, Cl, Br, CN, and C, respectively. 1-3 Alkyl group, -S(=O)2-NR e3 R e4 -S(=O)-R e5 -S(=O)2-R e6 -S(=O)(=NR) e7 )-R e8 -C(=O)-NR e3 R e4 -C(=O)-R e5 -NR e3 -C(=O)-C 1-3 Alkyl, C 1-3 Alkoxy or C 1-3 Alkylamino, the C 1-3 Alkyl group, -S(=O)2-NR e3 R e4 -S(=O)-R e5 -S(=O)2-R e6 -S(=O)(=NR) e7 )-R e8 -C(=O)-NR e3 R e4 -C(=O)-R e5 -NR e3 -C(=O)-C 1-3 Alkyl, C 1-3 Alkoxy and C 1-3 Alkylamino groups are independently and optionally surrounded by 1, 2, 3 or 4 R groups. c replace; And / or, R 31 For H, F, Cl, Br, CN, C 1-3 Alkyl, C 1-3 Alkoxy or C 1-3 Alkylamino, the C 1-3 Alkyl, C 1-3 Alkoxy and C 1- The 3 alkylamino groups are independently and optionally surrounded by 1, 2, 3 or 4 R groups. c replace; And / or, R 31 It can be H, F, methyl, ethyl, or propyl; And / or, R 32 For H, F, Cl, Br, CN, C 1-3 Alkyl group, -S(=O)2-NR e3 R e4 -S(=O)-R e5 -S(=O)2-R e6 -S(=O)(=NR) e7 )-R e8 -C(=O)-NR e3 R e4 -C(=O)-R e5 or -NR e3 -C(=O)-C 1-3 Alkyl, the C 1-3 Alkyl group, -S(=O)2-NR e3 R e4 -S(=O)-R e5 -S(=O)2-R e6 -S(=O)(=NR) e7 )-R e8 -C(=O)-NR e3 R e4 -C(=O)-R e5 and -NR e3 -C(=O)-C 1-3 Alkyl groups are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. c replace; And / or, R 32 -S(=O)2-NR e3 R e4 -S(=O)2-R e6 -S(=O)(=NR) e7 )-R e8 or -C(=O)-NR e3 R e4 The -S(=O)2-NR e3 R e4 -S(=O)2-R e6 -S(=O)(=NR) e7 )-R e8 and -C(=O)-NR e3 R e4 Each can be independently and arbitrarily assigned to 1, 2, 3, or 4 R's. c replace; And / or, each R e3 and R e4 H or C, independently respectively 1-3 alkyl; And / or, each R e3 and R e4 Each can be independently H, methyl, ethyl, or propyl; And / or, each R e5 and R e8 They are H, OH, and C, respectively. 1-3 Alkyl or C 3-6 cycloalkyl; And / or, each R e5 and R e8 Each can be independently H, OH, methyl, ethyl, or cyclopropyl; And / or, each R e6 H and C are independent of each other. 1-3 Alkyl, C 3-6 cycloalkyl or 4-membered heterocycloalkyl; And / or, each R e6 Each is independently H, methyl, ethyl, cyclopropyl or And / or, each R e7 Each independently can be H, CN, or C. 1-3 alkyl; And / or, each R e7 Each is independently designated as CN; And / or, each R c They can be independently H, F, Cl, Br, OH, NH2, CN, or COOH; sum / or, R 32 For -S(=O)2-N(CH3)2, -C(=O)-N(CH3)2, -S(=O)2-CH3, -S(=O)(=N-CN)-CH3 or And / or, R 31 For H or F, R 32 It is -S(=O)2-CH3.

6. The compound according to claim 1, characterized in that, The compound shown in formula (Ⅰ) has the structural formula (Ⅰ-A): in, R x1 R x3 X4, R 11 R 12 R2, R 31 R 32 and p as defined in claim 1; Preferably, the compound shown in formula (Ⅰ) has the structural formula (Ⅰ-AA): in, q is 1, 2, 3, or 4; R m R x3 X4, R 11 R 12 R2, R 31 and R 32 As defined in claim 1; Preferably, the compound shown in formula (Ⅰ) has the structural formula (Ⅰ-AA1): in, q is 1, 2, 3, or 4; R m R x3 X4, R 11 R 12 R2, R 31 and R 32 As defined in claim 1.

7. The compound according to claim 1, characterized in that, The compound shown in formula (Ⅰ) has structural formula (Ⅰ-1): in, R x1 R x3 X4, R 11 R 12 R2, R 31 R e3 R e4 and p as defined in claim 1; And / or, the compound shown in formula (I) has structural formula (I-2), structural formula (I-3), or structural formula (I-4): in, q is 1, 2, 3, or 4; R m R x3 X4, R 11 R 12 R2, R 31 R e3 R e4 R e6 As defined in claim 1; in, q is 1, 2, 3, or 4; w is 1, 2, 3, or 4; R 31 H, halogen or C 1-6 alkyl; R m R x3 R 11 R 12 R2, R e6 Ring A and R y As defined in claim 1; And / or, R 31 For H or F; And / or, R m For H; And / or, ring A is And / or, each R y They can be independently H, OH, oxo (=O), methyl, -CHF2, -S(=O)2-CH3, -S(=O)2-NH(CH3) or -S(=O)2-CH2-CH2(OH); Preferably, the compound shown in formula (I) has structural formula (I-2A), structural formula (I-3A), or structural formula (I-4A): in, q is 1, 2, 3, or 4; R m R x3 X4, R 11 R 12 R2, R 31 R e3 R e4 R e6 As defined in claim 1; in, q is 1, 2, 3, or 4; w is 1, 2, 3, or 4; R 31 H, halogen or C 1-6 alkyl; R m R x3 R 11 R 12 R2, R e6 Ring A and R y As defined in claim 1; And / or, R m For H; And / or, ring A is And / or, each R y They can be independently H, OH, oxo (=O), methyl, -CHF2, -S(=O)2-CH3, -S(=O)2-NH(CH3) or -S(=O)2-CH2-CH2(OH).

8. The compound according to claim 1, characterized in that, The compound represented by formula (Ⅰ) is selected from any of the following schemes: Option 1: The compound shown in formula (Ⅰ) has the structural formula (Ⅰ-5): in, q is 1, 2, 3, or 4; R ee -C 0-6 Alkylene-S(=O)2-R ee1 -C 1-6 alkylene-5-10-membered heteroaryl or cyclic A, wherein R ee Optionally divided by 1, 2, 3 or 4 R y replace; R 31 H, halogen or C 1-6 alkyl; R m R x3 R 11 R 12 R2, R e6 R ee1 Ring A and R y As defined in claim 1; And / or, R ee -C 0-3 Alkylene-S(=O)2-R ee1 -C 1-3 alkylene-5-6-membered heteroaryl or cyclic A, wherein R ee Optionally divided by 1, 2, 3 or 4 R y replace; And / or, R 31 For H or F; Option 2: The compound shown in formula (Ⅰ) has the structural formula (Ⅰ-6): in, q is 1, 2, 3, or 4; R 31 Halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino or C 3-8 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino and C 3-8 The cycloalkyl groups are each independently and optionally marked with 1, 2, 3 or 4 R groups. c replace; R x5 It can be H, halogen, OH, NH2, CN, COOH or C 1-6 Alkyl, the C 1-6 Alkyl groups are optionally surrounded by 1, 2, 3 or 4 R's. y replace; R m R x3 X4, R 11 R 12 R2, R e6 R c and R y As defined in claim 1; And / or, R 31 For F, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino or C 3-6 cycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino and C 3-6 The cycloalkyl groups are each independently and optionally marked with 1, 2, 3 or 4 R groups. c replace; And / or, R 31 It is F or methyl; And / or, R x5 It is H or NH2; Option 3: The compound shown in formula (Ⅰ) has the structural formula (Ⅰ-7): in, q is 1, 2, 3, or 4; R x4 C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylamino or C 3-8 cycloalkyl, the C 1-6 Haloalkyl, C 2- 6-alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylamino or C 3-8 The cycloalkyl groups are each independently and optionally marked with 1, 2, 3 or 4 R groups. y replace; R m R x3 R 11 R 12 R2, R e6 and R y As defined in claim 1; And / or, R x4 It can be -CF3, vinyl, ethynyl, or methoxy; Option 4: The compound shown in formula (Ⅰ) has the structural formula (Ⅰ-8): in, q is 1, 2, 3, or 4; R e6 The R is a 4-membered heterocyclic alkyl or a 4-membered heterocyclic alkenyl group. e6 Optionally divided by 1, 2, 3 or 4 R c replace; R m R x3 R 11 R 12 R2 and R c As defined in claim 1; And / or, R e6 for 9. The compound according to claim 1, characterized in that, The compound represented by formula (Ⅰ) is selected from any of the following schemes: Option 5: The compound shown in formula (Ⅰ) has the structural formula (Ⅰ-5A): in, q is 1, 2, 3, or 4; R ee -C 0-6 Alkylene-S(=O)2-R ee1 -C 1-6 alkylene-5-10-membered heteroaryl or cyclic A, wherein R ee Optionally divided by 1, 2, 3 or 4 R y replace; R 31 H, halogen or C 1-6 alkyl; R m R x3 R 11 R 12 R2, R e6 R ee1 Ring A and R y As defined in claim 1; Option 6: The compound shown in formula (Ⅰ) has the structural formula (Ⅰ-6A): in, q is 1, 2, 3, or 4; R 31 Halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino or C 3-8 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino and C 3-8 The cycloalkyl groups are each independently and optionally marked with 1, 2, 3 or 4 R groups. c replace; R x5 It can be H, halogen, OH, NH2, CN, COOH or C 1-6 Alkyl, the C 1-6 Alkyl groups are optionally surrounded by 1, 2, 3 or 4 R's. y replace; R m R x3 X4, R 11 R 12 R2, R e6 R c and R y As defined in claim 1; Option 7: The compound shown in formula (Ⅰ) has the structural formula (Ⅰ-7A): in, q is 1, 2, 3, or 4; R x4 C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylamino or C 3-8 cycloalkyl, the C 1-6 Haloalkyl, C 2- 6-alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylamino or C 3-8 The cycloalkyl groups are each independently and optionally marked with 1, 2, 3 or 4 R groups. y replace; R m R x3 R 11 R 12 R2, R e6 and R y As defined in claim 1; Option 8: The compound shown in formula (Ⅰ) has the structural formula (Ⅰ-8A): in, q is 1, 2, 3, or 4; R e6 The R is a 4-membered heterocyclic alkyl or a 4-membered heterocyclic alkenyl group. e6 Optionally divided by 1, 2, 3 or 4 R c replace; R m R x3 R 11 R 12 R2 and R c As defined in claim 1.

10. The compound according to claim 1, characterized in that, Selected from any of the following compounds or their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs:

11. The compound according to claim 1, characterized in that, Selected from any of the following compounds or their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs:

12. A method for preparing a compound of intermediate formula (II) or a salt thereof, The preparation method includes: S1. The step of reacting the compound shown in formula (III) with the compound shown in formula (IV) to produce the compound shown in formula (V): Where R6 is C 3-8 cycloalkyl or C 6-10 Aryl, the C 3-8 cycloalkyl and C 6-10 The aryl group is independently and optionally bounded by 1, 2, 3 or 4 R groups. f replace; R7 and R8 are each independently C 1-6 Alkyl or C 3-8 cycloalkyl, the C 1-6 Alkyl and C 3-8 The cycloalkyl groups are each independently and optionally marked with 1, 2, 3 or 4 R groups. g replace; Each R f and R g Each can be independently H, halogen, OH, NH2, CN, COOH, or C. 1-6 alkyl.

13. The preparation method according to claim 12, characterized in that, In S1, the reaction is carried out in the presence of a catalyst; preferably, the catalyst is a palladium catalyst; preferably, the palladium catalyst is Pd(PPh3)4, Pd2dba3 or Pd(OAc)2; And / or, in S1, the solvent used in the reaction is dioxane, tetrahydrofuran, or toluene; And / or, in S1, the reaction temperature is 40–150°C; preferably, the reaction temperature is 80–120°C; preferably, the reaction temperature is 100°C.

14. The preparation method according to claim 12, characterized in that, The preparation method further includes: S2. The steps of reacting the compound shown in formula (V) with an acid to produce the compound shown in formula (VI): And / or, the preparation method further includes: S3. The steps of reacting the compound shown in formula (VI) with a fluorinating agent to produce the compound shown in formula (II): And / or, the compound represented by formula (III) is obtained by reacting the compound represented by formula (VII) with R6-ONa, the steps for generating the compound represented by formula (III): R6, R7 and R8 are as defined in claim 12; Preferably, in S2, the acid is hydrochloric acid or trifluoroacetic acid; Preferably, in S3, the fluorinating agent is diethylaminosulfur trifluoride or bis(2-methoxyethyl)aminosulfur trifluoride.

15. The preparation method according to claim 12 or 14, wherein, R6 is a phenyl group; And / or, R7 is ethyl; And / or, R8 is ethyl, propyl, n-butyl, isobutyl or cyclohexyl; preferably, R8 is ethyl or n-butyl; preferably, R8 is ethyl.

16. A pharmaceutical composition, characterized in that, It comprises the compound of any one of claims 1-11 or its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs; and a pharmaceutically acceptable carrier.

17. The compound according to any one of claims 1-11, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition of claim 16, for use in inhibiting WRN and / or treating WRN-related diseases, or having the following uses: Suppress WRN; and / or, Prepare drugs for the treatment of WRN-related diseases; and / or, Preparation of WRN inhibitors; and / or, Used to treat WRN-related diseases.

18. A method for suppressing WRN, characterized in that, include: Introduce the compound of any one of claims 1-11 or its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition of claim 16 into cells.

19. A method for treating WRN-related diseases, characterized in that, include: Administering to a subject a pharmaceutically acceptable dose of any of the compounds of claims 1-11 or their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition of claim 16.

20. The use according to claim 17 or the method according to any one of claims 18-19, characterized in that, The WRN-related diseases include solid tumors with microsatellite instability or mismatch repair gene defects.

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