Macrocyclic ALK inhibitor, preparation method therefor and use thereof

Abstract

Provided are a macrocyclic ALK inhibitor, a preparation method therefor, a pharmaceutical composition containing the inhibitor, and the use thereof in the prevention or treatment of ALK-related diseases.

Description

Macrocyclic alk inhibitors, methods of making and uses thereof

[0001] Cross-reference to related applications

[0002] This application claims priority to and the benefit of the following Chinese patent applications, the contents of which are incorporated herein by reference in their entirety:

[0003] Chinese Patent Application No. 202411024920.7, filed July 29, 2024, to the China National Intellectual Property Office;

[0004] Chinese Patent Application No. 202411372534.7, filed September 29, 2024, to the China National Intellectual Property Office;

[0005] Chinese Patent Application No. 202411841863.1, filed December 13, 2024, to the China National Intellectual Property Office;

[0006] Chinese Patent Application No. 202510404157.9, filed April 1, 2025, to the China National Intellectual Property Office; and

[0007] Chinese Patent Application No. 202510853604.9, filed June 24, 2025, to the China National Intellectual Property Office. TECHNICAL FIELD

[0008] The present disclosure relates to macrocyclic ALK inhibitors, methods of making the same, pharmaceutical compositions containing the same, and uses thereof in the prevention or treatment of ALK-related diseases. BACKGROUND

[0009] Lung cancer is the most common cancer worldwide, with more than 2 million new cases each year, of which non-small cell lung cancer patients account for 80-85%. In the past few years, the incidence of lung cancer in China has shown an increasing trend year by year. The main driver genes of lung cancer include EGFR, KRAS, ALK, ROS1, BRAF, etc.

[0010] Anaplastic lymphoma kinase (ALK) is a member of the receptor tyrosine kinase family, which is activated after binding to extracellular ligands to regulate cell growth. The ALK protein contains 1620 amino acids, including an extracellular domain for ligand recognition and a tyrosine kinase domain (TKD) for signal transduction. In non-small cell lung cancer, ALK forms a driver gene after fusion with microtubule-associated protein-like 4 (EML4) gene. The incidence of EML4-ALK gene fusion in non-small cell lung cancer is 3%-5%.

[0011] In recent years, the treatment strategy for ALK-positive non-small cell lung cancer has developed rapidly, and ALK tyrosine kinase inhibitors with stronger activity and selectivity have emerged. Multiple randomized studies have shown that the new generation of ALK tyrosine kinase inhibitors exhibits better efficacy for patients with ALK-positive non-small cell lung cancer who receive initial treatment, and the survival rate of patients has been greatly improved. At present, several ALK tyrosine kinase inhibitors have been approved as first-line treatment for ALK-positive tumors.

[0012] Although most patients have a good clinical response when they receive ALK tyrosine kinase inhibitor treatment for the first time, the emergence of drug resistance mutations during treatment will cause ALK to be reactivated and thus cause disease progression. About 50%-60% of patients will develop drug resistance mutations during treatment with second-generation ALK tyrosine kinase inhibitors, and some mutations such as L1196M mutation and G1202R mutation combination may be resistant to approved drugs. Therefore, the development of ALK tyrosine kinase inhibitors with high activity, high selectivity and obvious inhibition of ALK drug resistance mutations can further meet the market demand for ALK-positive non-small cell lung cancer. SUMMARY

[0013] The present disclosure relates to a compound of Formula (A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0014] wherein,

[0015] X1, X2, X3are independently selected from CH or N;

[0016] Ring A is selected from phenylene or 5-6 membered heteroarylene;

[0017] Ring B is selected from 5-membered heteroarylene comprising at least one N atom;

[0018] Ring C is selected from 5-15 membered heterocyclylene or 5-12 membered heteroarylene;

[0019] Y 1 is selected from O, NR 6 or CR 7 R 7b ;

[0020] Y 2 is selected from O, NR 8 or CR 9 R 9b ;

[0021] R 1 and R 2 are independently selected from H or C1-C6alkyl;

[0022] each R 3 is independently selected from CN, halogen, OH, NH2, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, or phenyl, optionally substituted with R 3a ;

[0023] or, R 1 , R 3 and the atom to which they are attached together form a C5-C 10 unsaturated carbocyclic ring or 5-10 membered heterocyclyl;

[0024] each R 3a is independently selected from CN, halogen, OH, NH2, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, or phenyl, optionally substituted with R 3b ;

[0025] each R 3b is independently selected from CN, halogen, OH, NH2, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or 4-7 membered heterocyclyl, optionally substituted with R 3c ;

[0026] each R 3c is independently selected from CN, OH, NH2, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6alkylamino;

[0027] each R 4independently selected from CN, halogen, OH, NH2, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl or phenyl, said OH, NH2, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl or phenyl being optionally substituted with R 12 cycloalkyl, 4-12 membered heterocyclyl, 5-6 membered heteroaryl or phenyl, said OH, NH2, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl or phenyl being optionally substituted with R 12 cycloalkyl, 4-12 membered heterocyclyl, 5-6 membered heteroaryl or phenyl, said OH, NH2, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl or phenyl being optionally substituted with R 4a substituted;

[0028] or, R 3 , R 4 and the atom to which they are attached together form a C5-C 10 unsaturated carbocyclic or 5-10 membered heterocyclyl ring;

[0029] each R 4a is independently selected from CN, halogen, OH, NH2, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl or phenyl, said OH, NH2, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl or phenyl being optionally substituted with R 4b substituted;

[0030] each R 4b is independently selected from CN, halogen, OH, NH2, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl or 4-7 membered heterocyclyl, said OH, NH2, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl or 4-7 membered heterocyclyl being optionally substituted with R 4c substituted;

[0031] each R 4c is independently selected from CN, OH, NH2, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy or C1-C6alkylamino;

[0032] each R 5 is independently selected from CN, halogen, OH, NH2, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl or phenyl, said OH, NH2, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl or phenyl being optionally substituted with R 12 cycloalkyl, 4-12 membered heterocyclyl, 5-6 membered heteroaryl or phenyl, said OH, NH2, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl or phenyl being optionally substituted with R 12 cycloalkyl, 4-12 membered heterocyclyl, 5-6 membered heteroaryl or phenyl, said OH, NH2, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl or phenyl being optionally substituted with R 5a substituted;

[0033] each R 5aindependently selected from CN, halogen, OH, NH2, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, or phenyl, said OH, NH2, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, or phenyl optionally substituted with R 5b substituted;

[0034] each R 5b is independently selected from CN, halogen, OH, NH2, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or 4-7 membered heterocyclyl, said OH, NH2, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or 4-7 membered heterocyclyl optionally substituted with R 5c substituted;

[0035] each R 5c is independently selected from CN, OH, NH2, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6alkylamino;

[0036] R 6 and R 8 is independently selected from H or C1-C6alkyl, said C1-C6alkyl optionally substituted with R 8a substituted;

[0037] each R 8a is independently selected from halogen, C3-C6cycloalkyl, or 4-7 membered heterocyclyl;

[0038] R 7 , R 7b , R 9 , R 9b is independently selected from H, halogen, or C1-C6alkyl, said C1-C6alkyl optionally substituted with halogen; or, R 9 , R 9b together with the atom to which they are attached form or C3-C6cycloalkyl, said or C3-C6cycloalkyl optionally substituted with halogen or C1-C6alkyl; or, R 5 , R 9 together with the atom to which they are attached form C5-C 10 unsaturated carbocyclic or 5-10 membered heterocyclyl;

[0039] m, n and p are independently selected from an integer from 0 to 3.

[0040] In some embodiments, X1is N, X2, X3is CH; or X1, X3is N, X2is CH.

[0041] In some embodiments, X1is N, X2, X3is CH.

[0042] In some embodiments, ring A is selected from phenylene, thiazolylene, or thiophenylene. In some embodiments, ring A is selected from

[0043] In some embodiments, R 1 is selected from C1-C3alkyl. In some embodiments, R 1 is methyl.

[0044] In some embodiments, R 2 is H.

[0045] In some embodiments, R 1 is methyl and R 2 is H.

[0046] In some embodiments, the carbon atom to which R 1 and R 2 are attached is in the R configuration.

[0047] In some embodiments, each R 3 is independently selected from halogen or C1-C6alkyl. In some embodiments, R 3 is selected from halogen or C1-C3alkyl. In some embodiments, R 3 is selected from F or methyl. In some embodiments, R 3 is selected from F. In some embodiments, R 3 is selected from methyl.

[0048] In some embodiments, n is 1 and R 3 is selected from F or methyl. In some embodiments, n is 1 and R 3 is selected from F.

[0049] In some embodiments, is selected from In the above embodiments, wherein the lower end of the structural fragment is attached to ring B. In some embodiments, is wherein b represents the position of attachment to ring B.

[0050] In some embodiments, R 1 , R 3 and the atom to which they are attached collectively form a cyclohexenyl group.

[0051] In some embodiments, R 4 is selected from halogen, C1-C6alkyl, or C3-C6cycloalkyl. In some embodiments, R 4selected from halogen or Ci-C6alkyl. In some embodiments, R 4 selected from Ci-C6alkyl or C3-C6cycloalkyl. In some embodiments, R 4 selected from Ci-C6alkyl. In some embodiments, R 4 selected from Ci-C3alkyl. In some embodiments, R 4 selected from CI, methyl or cyclopropyl. In some embodiments, R 4 selected from methyl or cyclopropyl. In some embodiments, R 4 selected from methyl.

[0052] In some embodiments, R 4 selected from halogen or Ci-C3alkyl. In some embodiments, R 4 selected from CI or methyl.

[0053] In some embodiments, m is 1 and R 4 selected from halogen, Ci-C6alkyl or C3-C6cycloalkyl. In some embodiments, m is 1 and R 4 selected from CI, methyl or cyclopropyl. In some embodiments, m is 1 and R 4 is methyl.

[0054] In some embodiments, R 3 , R 4 together with the atom to which they are attached form an 8-membered heterocyclyl.

[0055] In some embodiments, ring B is selected from pyrazolylene, imidazolylene or thiazolylene. In some embodiments, ring B is selected from pyrazolylene or thiazolylene. In some embodiments, ring B is selected from pyrazolylene or imidazolylene. In some embodiments, ring B is selected from pyrazolylene. In some embodiments, ring B is selected from In some embodiments, ring B is selected from wherein b represents the position of attachment to ring A. In some embodiments, ring B is selected from In some embodiments, ring B is selected from wherein b represents the position of attachment to ring A.

[0056] In some embodiments, selected from In some embodiments, selected from In some embodiments, selected from In the above embodiments, the upper end connection site of the structural fragment is connected to ring A. In some embodiments, is selected from wherein b represents the position of attachment to ring A.

[0057] In some embodiments, ring C is selected from 5-12 membered heterocyclylene or 5-10 membered heteroarylene.

[0058] In some embodiments, ring C is selected from In the above embodiments, the right end connection site of the structural fragment is connected to Y 2 .

[0059] In some embodiments, ring C is selected from wherein c represents the position of attachment to Y 2 .

[0060] In some embodiments, ring C is selected from wherein c represents the position of attachment to Y 2 .

[0061] In some embodiments, ring C is selected from In the above embodiments, the right end connection site of the structural fragment is connected to Y 2 .

[0062] In some embodiments, ring C is selected from In the above embodiments, the right end connection site of the structural fragment is connected to Y 2 .

[0063] In some embodiments, ring C is selected from In the above embodiments, the right end connection site of the structural fragment is connected to Y 2 .

[0064] In some embodiments, ring C is selected from In some embodiments, ring C is selected from wherein c represents the position of attachment to Y 2 .

[0065] In some embodiments, each R 5independently selected from CN, halogen, OH, NH2, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, or phenyl, said OH, NH2, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, or phenyl being optionally substituted with R 5a substituted.

[0066] In some embodiments, each R 5 is independently selected from CN, halogen, OH, NH2, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, or phenyl, said OH, NH2, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, or phenyl being optionally substituted with R 5a substituted.

[0067] In some embodiments, each R 5 is independently selected from halogen, OH, NH2, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or 4-7 membered heterocyclyl, said OH, NH2, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or 4-7 membered heterocyclyl being optionally substituted with R 5a substituted. In some embodiments, each R 5a is independently selected from halogen, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or 4-7 membered heterocyclyl.

[0068] In some embodiments, p is 1 or 2, and there is one R 5 is selected from -O-C3-C6cycloalkyl, -O-4-7 membered heterocyclyl, 5-9 membered heterocyclyl, or 5-6 membered heteroaryl, said -O-C3-C6cycloalkyl, -O-4-7 membered heterocyclyl, 5-9 membered heterocyclyl, or 5-6 membered heteroaryl being optionally substituted with R 5a substituted.

[0069] In some embodiments, p is 2, and there is one R 5 is selected from 5-6 membered heteroaryl optionally substituted with R 5a substituted.

[0070] In some embodiments, p is 2, and there is one R 5 is selected from 5-6 membered heteroaryl optionally substituted with R 5a substituted.

[0071] In some embodiments, each R 5 is independently selected from CN, halogen, OH, NH2, C1-C6alkyl, said OH, NH2, optionally substituted with R 5a .

[0072] In some embodiments, each R 5a is independently selected from halogen, OH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, 5b .

[0073] In some embodiments, each R 5a is independently selected from halogen, OH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, said OH, NH2, optionally substituted with R 5b .

[0074] In some embodiments, each R 5b is independently selected from NH2, halogen, C1-C6 alkyl, or 4-7 membered heterocyclyl, said NH2, C1-C6 alkyl, or 4-7 membered heterocyclyl optionally substituted with R 5c .

[0075] In some embodiments, each R 5b is independently selected from halogen, C1-C6 alkyl, or 4-7 membered heterocyclyl, said C1-C6 alkyl or 4-7 membered heterocyclyl optionally substituted with R 5c .

[0076] In some embodiments, each R 5b is independently selected from halogen, methyl, or said optionally substituted with R 5c .

[0077] In some embodiments, each R 5c is independently selected from C1-C6 alkyl.

[0078] In some embodiments, is wherein R 5selected from CN, halogen, OH, NH2, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, 4-9 membered heterocyclyl, or 5-6 membered heteroaryl, said OH, NH2, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, 4-9 membered heterocyclyl, or 5-6 membered heteroaryl optionally substituted with R 5a substituted.

[0079] In some embodiments, each R 5a is independently selected from OH, NH2, halogen, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or 4-7 membered heterocyclyl, said NH2, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or 4-7 membered heterocyclyl optionally substituted with R 5b substituted. In some embodiments, each R 5b is independently selected from halogen and C1-C6alkyl.

[0080] In some embodiments, is selected from In the above embodiments, the right-hand connection site of the structural fragment is connected to Y 2 .

[0081] In some embodiments, is selected from In the above embodiments, the right-hand connection site of the structural fragment is connected to Y 2 .

[0082] In some embodiments, is selected from In the above embodiments, the right-hand connection site of the structural fragment is connected to Y 2 .

[0083] In some embodiments, is selected from In the above embodiments, the right-hand connection site of the structural fragment is connected to Y 2 .

[0084] In some implementation schemes, Selected from In the above implementation scheme, the right-side connection site of the structural segment is related to Y. 2 Connected.

[0085] In some implementation schemes, Selected from In the above implementation scheme, the right-side connection site of the structural segment is related to Y. 2 Connected.

[0086] In some implementation schemes, Y 1 Selected from O or CR 7 R 7b .

[0087] In some implementation schemes, Y 1 Selected from O, CHF, or CF2.

[0088] In some implementation schemes, Y 1 Selected from O.

[0089] In some implementation schemes, R 7 R 7b It is independently selected from H or halogens.

[0090] In some implementation schemes, R 7 R 7b Independently selected from H or F.

[0091] In some implementation schemes, Y 2 Selected from NR 8 or CR 9 R 9b .

[0092] In some implementation schemes, Y 2 Selected from CR 9 R 9b .

[0093] In some implementation schemes, R 6 and R 8 It is independently selected from H or C1-C6 alkyl groups.

[0094] In some implementation schemes, R 8 It can be H, CH3 or CH2CF3.

[0095] In some implementation schemes, R 8 It is CH3.

[0096] In some implementation schemes, R 9 R 9b Independently selected from H or C1-C3 alkyl; or, R9 R 9b and the atom to which they are attached together form or cyclopropyl, said or cyclopropyl is optionally substituted with halo or C1-C6 alkyl; or, R 5 R 9 and the atom to which they are attached together form a C5-C6 unsaturated carbocyclic ring or a 5-6 membered heterocyclyl.

[0097] In some embodiments, R 9 R 9b are independently selected from H or C1-C3 alkyl; or, R 9 R 9b and the atom to which they are attached together form or cyclopropyl, said or cyclopropyl is optionally substituted with halo or C1-C6 alkyl; or, R 5 R 9 and the atom to which they are attached together form a C5-C6 unsaturated carbocyclic ring.

[0098] In some embodiments, R 9 R 9b are independently selected from H or methyl; or, R 9 R 9b and the atom to which they are attached together form or, R 5 R 9 and the atom to which they are attached together form a cyclopentenyl, a cyclohexenyl or

[0099] In some embodiments, R 9 R 9b are independently selected from H or methyl; or, R 9 R 9b and the atom to which they are attached together form or, R 5 R 9 and the atom to which they are attached together form a cyclopentenyl or a cyclohexenyl.

[0100] In some embodiments, Y 2 is selected from -CH(CH3)-, -CH2-, -N(CH3)-, -NH-, -N(CH2CF3)-,

[0101] In some embodiments, Y 2 is -CH(CH3)-, -CH2-, -N(CH3)- or

[0102] In some embodiments, Y 2 is selected from -CH(CH3)-, -CH2-, -N(CH3)-, -NH-, or -N(CH2CF3)-.

[0103] In some embodiments, Y 2 is selected from In some embodiments, Y 2 is

[0104] In some embodiments, n is 1, m is 1, and / or p is 0, 1, or 2. In some embodiments, n is 1. In some embodiments, m is 1. In some embodiments, p is 1 or 2. In some embodiments, p is 2.

[0105] In some embodiments, X1is N, X2, X3are CH; Y 1 is O; R 1 is methyl, R 2 is H; is wherein the lower end attachment site of the structural fragment is attached to ring B; and / or, is wherein the upper end attachment site of the structural fragment is attached to ring A. In the above embodiments, Y 2 is -CH(CH3)-, -CH2-, -N(CH3)-, or or Y 2 is In the above embodiments, ring C, R 5 and p are as previously defined; or is R 5 is as previously defined. In the above embodiments, the carbon atom to which R 1 and R 2 are attached is in the R configuration.

[0106] In some embodiments, the compound of formula (A), stereoisomer thereof, or pharmaceutically acceptable salt thereof, is selected from the group consisting of a compound of formula (I), stereoisomer thereof, or pharmaceutically acceptable salt thereof,

[0107] wherein, ring A, ring B, ring C, Y 1 , Y 2 , R 1 , R 2 , R 3 , R 4 , R5 , m, n and p are as defined in formula (A).

[0108] In some embodiments, the compound of formula (I), stereoisomer thereof, or pharmaceutically acceptable salt thereof is selected from a compound of formula (II), stereoisomer thereof, or pharmaceutically acceptable salt thereof,

[0109] wherein,

[0110] Y 2 is as defined in formula (I), with the proviso that Y 2 is not CH2.

[0111] In some embodiments, the compound of formula (A), stereoisomer thereof, or pharmaceutically acceptable salt thereof is selected from a compound of formula (A-1), stereoisomer thereof, or pharmaceutically acceptable salt thereof,

[0112] wherein, R 7c and R 7d are independently selected from H, halogen, or C1-C6 alkyl; ring A, ring B, ring C, X3, Y 1 , R 1 , R 2 , R 3 , R 4 , R 5 , m, n and p are as defined in formula (A).

[0113] In some embodiments, the compound of formula (A), stereoisomer thereof, or pharmaceutically acceptable salt thereof is selected from a compound of formula (A-2), stereoisomer thereof, or pharmaceutically acceptable salt thereof,

[0114] wherein, R 7c and R 7d are independently selected from H, halogen, or C1-C6 alkyl; ring B, ring C, X3, R 3 , R 4 , R 5 , m, n and p are as defined in formula (A).

[0115] In some embodiments, the compound of formula (A), stereoisomer thereof, or pharmaceutically acceptable salt thereof is selected from a compound of formula (III), stereoisomer thereof, or pharmaceutically acceptable salt thereof,

[0116] wherein, R 7c and R 7d are independently selected from H, halogen, or C1-C6 alkyl; ring A, ring B, ring C, Y 1 , R 1 , R 2 , R3 , R 4 , R 5 , m, n and p are as defined in formula (A).

[0117] In some embodiments, the "heteroaryl" or "heteroarylene" as described above contains 1, 2, or 3 heteroatoms independently selected from N, O, or S; or contains 1 or 2 heteroatoms independently selected from N or O; or contains 1 or 2 N atoms.

[0118] In some embodiments, the "heterocyclyl" or "heterocyclylene" as described above contains 1, 2, or 3 heteroatoms independently selected from N, O, or S; or contains 1 or 2 heteroatoms independently selected from N or O; or contains 1 or 2 N atoms.

[0119] In some embodiments, the compound of formula (A), stereoisomer thereof, or pharmaceutically acceptable salt thereof of the present disclosure is selected from the following compounds or stereoisomers thereof, or pharmaceutically acceptable salts thereof:

[0120] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of formula (A), formula (A-1), formula (A-2), formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0121] In another aspect, the present disclosure provides a method of treating a disease associated with ALK in a mammal, comprising administering to a mammal, preferably a human, in need of such treatment, a therapeutically effective amount of a compound of formula (A), formula (A-1), formula (A-2), formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0122] In another aspect, the present disclosure provides the use of a compound of formula (A), formula (A-1), formula (A-2), formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the preparation of a medicament for the prevention or treatment of a disease associated with ALK.

[0123] In another aspect, the present disclosure provides use of a compound of Formula (A), Formula (A-1), Formula (A-2), Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the prevention or treatment of an ALK-related disease.

[0124] In another aspect, the present disclosure provides a compound of Formula (A), Formula (A-1), Formula (A-2), Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the prevention or treatment of an ALK-related disease.

[0125] In some embodiments, the ALK-related disease is selected from a tumor, preferably lung cancer, more preferably non-small cell lung cancer.

[0126] In some embodiments, the ALK-related disease is selected from a tumor with ALK mutation.

[0127] In some embodiments, the ALK mutation is EML4-ALK, a fusion between the echinoderm microtubule-associated protein-like 4 (EML4) gene and the ALK tyrosine kinase domain. In some embodiments, the ALK mutation is EML4-ALK v1. In some embodiments, the ALK mutation is EML4-ALK G1202R. In some embodiments, the ALK mutation is EML4-ALK L1196M. In some embodiments, the ALK mutation is EML4-ALK G1202R / L1196M.

[0128] The compounds of the present disclosure have at least one of the following beneficial effects:

[0129] (1) The compounds of the present disclosure have excellent inhibitory effects on ALK WT and ALK [G1202R / L1196M] mutant tumor cells;

[0130] (2) The compounds of the present disclosure have high ALK selectivity on ALK WT and ALK [G1202R / L1196M] mutant tumor cells;

[0131] (3) The compounds of the present disclosure have better metabolic stability;

[0132] (4) The compounds of the present disclosure have lower cardiotoxicity;

[0133] (5) The compounds of the present disclosure have longer half-lives;

[0134] (6) The compounds of the present disclosure have good drugability.

[0135] In some embodiments, the compounds of the present disclosure have good drugability, excellent inhibitory effect on ALK WT and ALK[G1202R / L1196M] mutant tumor cells, high ALK selectivity, long half-life, and low cardiotoxicity.

[0136] Definitions and explanations of terms

[0137] Unless otherwise indicated, the terms used in the present disclosure have the following meanings, and the definitions of the groups and terms described in the present disclosure, including the definitions as examples, exemplary definitions, preferred definitions, definitions described in tables, definitions of specific compounds in examples, etc., can be combined and integrated with each other arbitrarily. A specific term should not be considered indefinite or unclear without a specific definition, but should be understood according to the ordinary meaning in the art. When a trade name appears herein, it is intended to refer to its corresponding product or active ingredient thereof.

[0138] Herein represents a point of attachment.

[0139] The graphical representation of racemates or enantiomerically pure compounds herein is from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated, the wedge and hashed wedges represents the absolute configuration of a stereocenter.

[0140] The term "stereoisomer" refers to isomers that have the same molecular formula but different structures, due to having a different spatial arrangement of their atoms. Stereoisomers include enantiomers (which are mirror images of one another) and diastereomers (which are not mirror images of one another). The term "geometric isomer" refers to isomers that have the same molecular formula and the same order of atoms but differ in the spatial arrangement of their atoms. Geometric isomers include cis- and trans-isomers.

[0141] The compounds of the present disclosure can have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms, or asymmetric double bonds, and thus the compounds of the present disclosure can exist in particular geometric or stereoisomeric forms. The particular geometric or stereoisomeric forms can be cis- and trans-isomers, E- and Z- geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, as well as racemic mixtures or other mixtures thereof, such as those that are enantiomerically or diastereomerically enriched. Additional asymmetric carbon, sulfur, nitrogen, or phosphorus atoms or atoms that bear stereogenic groups can be present in a substituent such as an alkyl group, and all of these isomers are intended to be included within the scope of the present disclosure. The compounds of the present disclosure containing an asymmetric atom can be isolated in optically active or racemic forms. This isolation can be achieved by classical separation techniques or by the synthesis of an essentially pure optical form (single race) using chiral reagents in place of achiral reagents.

[0142] The term "substituted" means that any one or more hydrogen atoms on a particular atom is replaced with a substituent, provided that the valence of the particular atom is not normally exceeded, and that the substituted compound is stable.

[0143] The term "optionally" or "optional" means that the subsequently described event or circumstance can or can not occur, and this description includes instances in which the event or circumstance occurs and instances in which it does not. For example, an ethyl group "optionally" substituted with a halogen means that the ethyl group can be unsubstituted (CH2CH3), mono-substituted (CH2CH2F, CH2CH2C1, etc.), poly-substituted (CHFCH2F, CH2CHF2, CHFCH2C1, CH2CHC12, etc.), or fully substituted (CF2CF3, CF2CC13, CC12CC13, etc.). One skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern will be introduced that results in a sterically impossible or synthetically impossible structure.

[0144] When any variable (e.g., R 3 , R 4 ) occurs more than one time in a compound; each occurrence is independent of the others. For example, if a group is substituted with 2 R 3 groups, each R 3 is selected independently.

[0145] When a bond to a substituent interposes two atoms of a ring, that substituent can be bonded to either atom of the ring. For example, the structural element indicates that R 3 may be substituted for any available position on the phenyl ring.

[0146] C m -C n herein means an integer from m to n carbon atoms. For example "C1-C6" means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.

[0147] The term "alkyl" means a straight, branched, or cyclic hydrocarbon group having the general formula C n H 2n+1alkyl group, which can be straight-chained or branched. The term "C1-C6alkyl" is understood to mean a straight-chained or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms, specific examples including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, and the like. The term "C1-C3alkyl" is understood to mean a straight-chained or branched saturated monovalent hydrocarbon group having 1 to 3 carbon atoms. The "C1-C6alkyl" group can further comprise a "C1-C3alkyl" group.

[0148] The term "haloalkyl" comprises a mono- or polyhalogenated alkyl group, specific examples including but not limited to trifluoromethyl, 2,2,2-trichloroethyl, or 3-fluoropropyl, and the like. The term "C1-C6haloalkyl" is understood to mean a mono- or polyhalogenated alkyl group having 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

[0149] The term "alkoxy" is "-O-alkyl", the alkyl group being as defined above. The term "C1-C6alkoxy" means "-O-C1-C6alkyl", for example -OCH3.

[0150] The term "cycloalkyl" means a fully saturated or partially saturated monocyclic or polycyclic cyclic hydrocarbon substituent, polycyclic cyclic hydrocarbons including cyclic hydrocarbons in the form of fused, bridged or spirocyclic, and the like. The term "C3-C6cycloalkyl" is understood to mean a fully saturated or partially saturated monocyclic, fused, spirocyclic or bridged ring having 3, 4, 5, or 6 carbon atoms. Specific examples of cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, and the like.

[0151] The term "unsaturated carbocyclic" means a ring substituent composed of carbon atoms and hydrogen atoms, and the cyclic portion is an unsaturated ring, for example, aryl or cycloalkenyl, and the like. The term "C5-C10unsaturated carbocyclic" is understood to mean a ring substituent composed of carbon atoms and hydrogen atoms, and the cyclic portion is an unsaturated ring having 5, 6, 7, 8, 9, or 10 carbon atoms. 10 Specific examples of "unsaturated carbocyclic" groups include but are not limited to cyclobutenyl (e.g., 1-cyclobutenyl), cyclopentenyl (e.g., 1-cyclopenten-1-yl, 2-cyclopenten-1-yl, and 3-cyclopenten-1-yl), cyclohexenyl (e.g., 1-cyclohexen-1-yl, 2-cyclohexen-1-yl, and 3-cyclohexen-1-yl), and the like.

[0152] The term "heterocyclyl" refers to a fully saturated or partially saturated (not an aromatic heteroaromatic overall) monovalent monocyclic, fused ring, spirocyclic, or bridged ring radical containing from 1 to 5 heteroatoms or heteroatom groups (i.e., groups of atoms containing a heteroatom) in its ring atom count, including but not limited to nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), boron (B), -S(=0)2-, -S(=0)-, and optionally substituted -NH-, -S(=0)(=NH)-, -C(=0)NH-, -C(=NH)-, -S(=0)2NH-, S(=0)NH-, or -NHC(=0)NH-, and the like, in its ring atoms. The term "5-15 membered heterocyclyl" refers to a heterocyclyl group having a ring atom count of 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, and containing 1, 2, 3, 4, or 5 heteroatoms or heteroatom groups independently selected from those described above in its ring atoms. The term "4-7 membered heterocyclyl" refers to a heterocyclyl group having a ring atom count of 4, 5, 6, or 7, and containing 1, 2, or 3 heteroatoms or heteroatom groups independently selected from those described above in its ring atoms. Specific examples of 5-membered heterocyclyl groups include, but are not limited to, tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4,5-dihydrooxazolyl, or 2,5-dihydro-lH-pyrrolyl; specific examples of 6-membered heterocyclyl groups include, but are not limited to, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridinyl, or 4H-[l,3,4]thiadiazinyl; specific examples of 7-membered heterocyclyl groups include, but are not limited to, diazepanyl; specific examples of 8-membered heterocyclyl groups include, but are not limited to, The heterocyclyl group can also be a bicyclic group, where specific examples of 5,5-membered bicyclic groups include, but are not limited to, hexahydrocyclopenta[c]pyrrol-2(lH)-yl; specific examples of 5,6-membered bicyclic groups include, but are not limited to, hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl, 5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyrazinyl, or 5,6,7,8-tetrahydroimidazo[l,5-a]pyrazinyl. Optionally, the heterocyclyl group can be a benzo-fused ring of the above 4-7-membered heterocyclyl groups, specific examples include, but are not limited to, dihydroisoquinolinyl and the like. The "5-15 membered heterocyclyl" group can include the "5-10 membered heterocyclyl", "5-6 membered heterocyclyl", "6-8 membered heterocyclyl" and the like ranges, the "5-12 membered heterocyclyl" group can include the "5-10 membered heterocyclyl", "5-6 membered heterocyclyl", "6-8 membered heterocyclyl" and the like ranges, the "5-10 membered heterocyclyl" group can include the "5-6 membered heterocyclyl", "6-8 membered heterocyclyl" and the like ranges, and the "4-7 membered heterocyclyl" group can further include the "4-6 membered heterocyclyl", "5-6 membered heterocyclyl" and the like ranges. Although some bicyclic heterocyclyl moieties in the present disclosure contain a benzene ring or a heteroaromatic ring partially, the heterocyclyl group as a whole is still non-aromatic. The term "heterocyclyl" or "heterocyclylene" can contain 1, 2, or 3 heteroatoms independently selected from N, O, or S.

[0153] The term "aryl" refers to an all-carbon monocyclic or fused ring polycyclic ring system that has a conjugated pi-electron system. The aryl group can have from 6 to 20 carbon atoms, from 6 to 14 carbon atoms, or from 6 to 12 carbon atoms. In particular, a ring having 6 carbon atoms ("C6 aryl"), such as a phenyl group; or a ring having 9 carbon atoms ("C9 aryl"), such as an indane or indenyl group; or a ring having 10 carbon atoms ("C10 aryl"), such as a tetrahydronaphthyl, dihydronaphthyl, or naphthyl group. 10 The term "aryl" refers to an all-carbon monocyclic or fused ring polycyclic ring system that has a conjugated pi-electron system. The aryl group can have from 6 to 20 carbon atoms, from 6 to 14 carbon atoms, or from 6 to 12 carbon atoms. In particular, a ring having 6 carbon atoms ("C6 aryl"), such as a phenyl group; or a ring having 9 carbon atoms ("C9 aryl"), such as an indane or indenyl group; or a ring having 10 carbon atoms ("C10 aryl"), such as a tetrahydronaphthyl, dihydronaphthyl, or naphthyl group.

[0154] The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system having aromaticity, which contains at least one ring atom selected from N, O, S, the remaining ring atoms being C. The term "5-12 membered heteroaryl" is to be understood as including a monovalent monocyclic or bicyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, in particular 5 or 6 or 9 or 10 ring atoms, and which contains 1-5, preferably 1-3 heteroatoms independently selected from N, O and S. In particular, the heteroaryl group is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiadiazolyl and the like as well as their benzo derivatives, such as, for example, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzoisoxazolyl, benzoimidazolyl, benzotriazolyl, indazolyl, indolyl or isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or pyridazinyl and the like as well as their benzo derivatives, such as, for example, quinolinyl, quinazolinyl or isoquinolinyl and the like; or azocinyl, indolizinyl, purinyl and the like as well as their benzo derivatives; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenoxazinyl, phenothiazinyl or phenoxazinyl and the like. The "5-12 membered heteroaryl" can include the range of "5-10 membered heteroaryl", "5-6 membered heteroaryl" and the like. The term "5-10 membered heteroaryl" refers to an aromatic ring system having 5 or 10 ring atoms, and which contains 1-5, preferably 1-3 heteroatoms independently selected from N, O and S. The term "5-6 membered heteroaryl" refers to an aromatic ring system having 5 or 6 ring atoms, and which contains 1-3, preferably 1-2 heteroatoms independently selected from N, O and S. The term "heteroarylene" refers to a divalent heteroaryl group. The "heteroaryl" or "heteroarylene" can contain 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0155] Any of the above terms can be modified with the prefix "hetero" to describe the divalent form of the moiety. For example, a divalent heteroaromatic ring is "heteroarylene", a divalent benzene ring is "phenylene", a divalent heterocyclic ring is "heterocyclene".

[0156] The term "halo" or "halogen" refers to fluoro, chloro, bromo or iodo.

[0157] The term "therapeutically effective amount" means an amount of a compound of the present disclosure that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein. The amount of a compound of the present disclosure that will constitute a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the manner of administration, and the age of the mammal to be treated, but can be determined routinely by the skilled practitioner as an initial consideration by dosing in the range of 0.01 to 100 mg / kg, preferably 0.1 to 50 mg / kg, and more preferably 0.1 to 10 mg / kg, of the mammal's weight per day.

[0158] 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.

[0159] The term "pharmaceutically acceptable salt" refers to a salt of an acid or a base which is pharmaceutically acceptable, including salts of compounds with inorganic acids or organic acids, and salts of compounds with inorganic or organic bases.

[0160] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or salts thereof with a pharmaceutically acceptable excipient. The purpose of a pharmaceutical composition is to facilitate administration of a compound of the present disclosure to an organism.

[0161] The term "pharmaceutically acceptable excipient" refers to an excipient that is not biologically or otherwise undesirable, i.e., the excipient can be administered to an organism without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained. The presence of an excipient in a composition does not imply that the excipient is intended to be part of the dosage form in a sense of being a pharmacologically active compound.

[0162] The words "comprise" or "comprising" and variations such as "comprises" or "comprising", when used in this document, are to be interpreted as specifying the presence of the stated features or components and are not to be interpreted as precluding the presence of one or more other features or components.

[0163] The present disclosure also includes isotopically-labeled compounds of the present disclosure which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be present in compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I, and 36 Cl, and the like.

[0164] Certain isotopically-labeled compounds of the present disclosure (e.g., with 3 H and 14 C) are useful in compound and / or substrate tissue distribution analysis. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Positron emitting isotopes such as 15 O, 13 N, 11 C and 18 F are useful in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically-labeled compounds of the present disclosure can generally be prepared by substituting a readily available isotopically-labeled reagent for a non-isotopically labeled reagent in a procedure similar to those disclosed in the schemes and / or examples below.

[0165] The pharmaceutical compositions of the present disclosure can be prepared by combining a compound of the present disclosure with a suitable pharmaceutically acceptable excipient, such as can be formulated into solid, semi-solid, liquid, or gaseous dosage forms, such as tablets, pills, capsules, powders, granules, ointments, creams, lotions, suppositories, injectables, inhalables, gels, microspheres, aerosols, and the like.

[0166] Typical routes of administering a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, include, but are not limited to, oral, rectal, topical, inhalant, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.

[0167] The pharmaceutical compositions of the present disclosure can be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, emulsifying, lyophilizing or

[0168] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by combining the active compound with a pharmaceutically acceptable excipient well known in the art. These excipients enable the compounds of the present disclosure to be formulated as tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, and the like, for oral administration to a patient.

[0169] Solid oral compositions can be prepared by conventional mixing or compaction methods. For example, the active compound can be mixed with a solid excipient, optionally ground, and then compacted to create a solid dosage form, if desired with additional excipients. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, or flavoring agents.

[0170] The pharmaceutical compositions can also be in unit dosage form in ampules or disposable syringes. The pharmaceutical compositions can also be adapted for parenteral administration, such as sterile solutions, suspensions, or lyophilized products in suitable unit dosage form.

[0171] In all methods of administration of the compounds of general formula (A) described herein, the daily dose is from 0.01 mg / kg to 200 mg / kg of body weight, preferably from 0.05 mg / kg to 50 mg / kg of body weight, more preferably from 0.1 mg / kg to 30 mg / kg of body weight, in single or divided doses.

[0172] The compounds of the present disclosure can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed using combinations of the other chemical synthetic methods well known in the art, and equivalents thereof as appreciated by those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present disclosure.

[0173] The chemical reactions of the specific embodiments of the present disclosure are performed in solvents appropriate to the reagents and materials employed and suitable for the chemical changes being effected. In the synthetic schemes and examples that follow, all substituents unless otherwise indicated, are as previously defined. The chemical reactions described in the preceding disclosure, including the reactions described in the specific embodiments, are preferably performed at temperatures from about 0°C to about 40°C, more preferably at about 20°C to about 25°C. The reagents are preferably mixed at room temperature, and the reaction is maintained at that temperature unless otherwise stated.

[0174] The following abbreviations are used herein:

[0175] DMP: Dess-Martin periodinane; DCM: dichloromethane; THF: tetrahydrofuran; DMF: N,N-dimethylformamide; Pd(Amphos)2Cl2: dichlorobis[bis-tert-butyl-(4-dimethylaminophenyl)phosphine] palladium(II); t-BuOK: potassium tert-butoxide; KOAc: potassium acetate; t-BuONa: sodium tert-butoxide; EtOH: ethanol; t-AmOH: tert-amyl alcohol; Pd(OAc)2: palladium acetate; PivOK: potassium pivalate; cataCXium A: n-butylbis(l-adamantyl)phosphine; EtBr: ethyl bromide; TES: triethylsilane; TFA: trifluoroacetic acid; MeOH: methanol; NH2Boc: tert-butyl carbamate; t-Bu XPhos Pd G3: [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'- biphenyl)]palladium(II) methanesulfonate; MeI: methyl iodide; Cy3P: tricyclohexylphosphine; Pd2dba3: tris(dibenzylideneacetone)dipalladium; Tebbe's reagent: μ-chloro(dicyclopentadienyl)(dimethylaluminumyl)-μ-methylene titanium; toluene: toluene; Raney-Ni: Raney nickel; dioxane: 1,4-dioxane; water: water; xylene: xylene; PE: petroleum ether; EA: ethyl acetate; PPh3: triphenylphosphine; DBAD: di-tert-butyl azodicarboxylate; LDA: lithium diisopropylamide; NMP: N-methyl pyrrolidone; PMBCI: 4-methoxychlorobenzyl; DIPEA: N,N-diisopropylethylamine; P(t-Bu)3Pd G2: chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II); NIS: N-iodosuccinimide; B2pin2,: pinacolatoboronate; DME: 1,2-dimethoxyethane; TES: triethylsilane; PMB: p-methoxybenzyl; DIAD: diisopropyl azodicarboxylate; PCC: pyridinium chlorochromate; MTBE: methyl tert-butyl ether; HMT: hexamethylenetetramine; TPMP: methyltriphenylphosphonium bromide; GPhos Pd G6: [2-(dicyclohexylphosphino)-3-tert-butoxy-6-methoxy-2',6'-diisopropyl-1,1'- biphenyl](4-((2-(trimethylsilyl)ethoxy)carbonyl)phenyl-1-yl) bromopalladium; cataCXium A Pd G3: [(bis(1-adamantyl)butylphosphino)-2-(2'-amino-1,1'-biphenyl)]palladium(II) mesylate; i-PrMgBr: isopropylmagnesium bromide; PCy3: tricyclohexylphosphine; TBSCl: tert-butyldimethylsilyl chloride; DMAP: 4-dimethylaminopyridine; BAST: bis(2-methoxyethyl)amino sulfur trifluoride; Copper(II) acetate: copper acetate; TBME: methyl tert-butyl ether; LAH: lithium aluminum hydride;BEHT Triflate: (1,2-bis(ethoxycarbonyl)hydrazino)triphenylphosphine trifluoromethane sulfonate; NBS: N-bromosuccinimide; Pd-PEPPSI-IHept; Cl (SP-4-1)-[1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylylene]dichloro(3-chloropyridine-κN)palladium; (dppf)PdCl2: 1,1-bis(diphenylphosphine)ferrocene palladium chloride; Pd(PPh3)4: tetrakis(triphenylphosphine)palladium; n BuLi: n-Butyllithium; Bu3SnCl: Tri-n-Butyltin chloride. Detailed Implementation

[0176] The disclosure is described in detail below with reference to examples, but this does not imply any adverse limitation of the disclosure. The disclosure has been described in detail herein, including specific embodiments thereof. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the disclosure without departing from the spirit and scope thereof. All reagents used in this disclosure are commercially available and can be used without further purification.

[0177] Unless otherwise stated, proportions expressed for mixed solvents are volume-based. Unless otherwise stated, % refers to wt%.

[0178] Compounds are processed manually or Software naming conventions are used; commercially available compounds use supplier catalog names.

[0179] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts are measured in units of 10⁻⁶. -6 (ppm). The solvents used for NMR determination were deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., with tetramethylsilane (TMS) as the internal standard; "IC 50 "Half-inhibition concentration" refers to the concentration at which half of the maximum inhibitory effect is achieved.

[0180] The eluent described below may be a mixture of two or more solvents, with the ratio being the volume ratio of each solvent. For example, "0-40% tetrahydrofuran / petroleum ether" indicates that in the gradient elution process, the volume ratio of tetrahydrofuran to petroleum ether in the mixed eluent is 0:100 to 40:60.

[0181] Example 1: Synthesis of Compound 1

[0182] Step 1: Synthesis of (3-chloro-1-ethyl-1H-pyrazol-4-yl)(3-iodo-1-methyl-1H-pyrazol-4-yl) methyl ketone (intermediates 1-2)

[0183] Intermediate 1-1 (2 g) was dissolved in dichloromethane (20 mL), and Dess-Martin Oxidizing Reagent (4.63 g) was added. The reaction solution was stirred at 25 °C for 16 h. Then the reaction solution was diluted with dichloromethane (20 mL) and washed with water (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (eluent: 0-40% tetrahydrofuran / petroleum ether at a flow rate of 40 mL / min) to give the title compound, intermediate 1-2 (900 mg). 12g The residue was purified by flash column chromatography on silica gel (eluent: 0-40% tetrahydrofuran / petroleum ether at a flow rate of 40 mL / min) to give the title compound, intermediate 1-2 (900 mg).

[0184] MS m / z (ESI): 365.0 [M+H] +

[0185] Step 2: Synthesis of 3-chloro-l-ethyl-4-(l-(3-iodo-l-methyl-lH-pyrazol-4-yl)vinyl)-lH- pyrazole (intermediate 1-3)

[0186] Intermediate 1-2 (800 mg) was dissolved in tetrahydrofuran (0.3 mL), and Tebbe reagent (0.5 M, 5.27 mL) was added at 0 °C under a nitrogen atmosphere. The reaction solution was stirred at room temperature for 1 h. Then the reaction solution was diluted with ethyl acetate (30 mL) and washed with water (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (eluent: 0-40% tetrahydrofuran / petroleum ether at a flow rate of 50 mL / min) to give the title compound, intermediate 1-3 (350 mg). 12g The residue was purified by flash column chromatography on silica gel (eluent: 0-40% tetrahydrofuran / petroleum ether at a flow rate of 40 mL / min) to give the title compound, intermediate 1-2 (900 mg).

[0187] MS m / z (ESI): 365.0 [M+H] +

[0188] Step 3: Synthesis of (R)-l-(2-(4-(l-(3-chloro-l-ethyl-lH-pyrazol-4-yl)vinyl)-l-methyl- lH-pyrazol-3-yl)-5-fluorophenyl)ethan-l-ol (intermediate 1-5)

[0189] Intermediate 1-3 (100 mg) and intermediate 1-4 (50.35 mg) were dissolved in DMF (1 mL) and water (0.2 mL), and Pd(Amphos)2Cl2 (19.53 mg) and potassium carbonate (152.46 mg) were added under a nitrogen atmosphere. The reaction solution was stirred at 70 °C for 3 h. Then the reaction solution was directly concentrated under reduced pressure, and the crude product was purified by flash column chromatography on silica gel (eluent: 0-40% tetrahydrofuran / petroleum ether at a flow rate of 50 mL / min) to give the title compound, intermediate 1-5 (50 mg). 12g The title compound intermediate 1-5 (80 mg) was purified by flash column chromatography (silica gel, eluent of 0-60% tetrahydrofuran / petroleum ether at a flow rate of 40 mL / min) to give the title compound intermediate 1-5 (80 mg).

[0190] MS m / z (ESI): 375.2 [M+H] + .

[0191] Step 4: Synthesis of (1R)-1-(2-(4-(1-(3-chloro-1-ethyl-1H-pyrazol-4-yl)ethyl)-1- methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethan-1-ol (intermediate 1-6)

[0192] Intermediate 1-5 (80 mg) was dissolved in ethanol (2 mL), and platinum dioxide (24.23 mg) was added. The reaction solution was stirred at room temperature for 16 hours under a hydrogen atmosphere. The reaction solution was then filtered, and the filtrate was concentrated under reduced pressure to give the title compound intermediate 1-6 (80 mg).

[0193] MS m / z (ESI): 377.1 [M+H] +

[0194] Step 5: Synthesis of 5-bromo-3-((1R)-1-(2-(4-(1-(3-chloro-1-ethyl-1H-pyrazol-4-yl)ethyl)- 1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine (intermediate 1-7)

[0195] Intermediate 1-6 (80 mg) and 5-bromo-3-fluoro-2-nitropyridine (56.29 mg) were dissolved in toluene (1 mL), and t-BuOK (1 M, 318.43 μL) was slowly added dropwise at 0 °C under a nitrogen atmosphere. The reaction solution was stirred at 0 °C for 1 hour. Saturated aqueous ammonium chloride solution (2 mL) was then slowly added to the reaction solution, and the reaction solution was stirred at 15 °C for 0.25 hours. The reaction solution was diluted with ethyl acetate (20 mL) and washed with water (20 mL x 2), and the organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, eluent of 0-60% tetrahydrofuran / petroleum ether at a flow rate of 40 mL / min) to give the title compound intermediate 1-7 (80 mg). 4g The title compound intermediate 1-5 (80 mg) was purified by flash column chromatography (silica gel, eluent of 0-60% tetrahydrofuran / petroleum ether at a flow rate of 40 mL / min) to give the title compound intermediate 1-5 (80 mg).

[0196] MS m / z (ESI): 579.0 [M+H] +

[0197] Step 6: Synthesis of 5-bromo-3-((lR)-l-(2-(4-(l-(3-chloro-l-ethyl-lH- pyrazol-4-yl)ethyl)-l-methyl-lH-pyrazol-3-yl)-5-fluorophenyl)ethoxy)pyridin-2- amine (Intermediate 1-8)

[0198] Intermediate 1-7 (80 mg) was dissolved in a mixture solution of ethanol (2 mL) and water (0.5 mL), and then ammonium chloride (44.43 mg) and iron powder (46.39 mg) were added into the reaction. The reaction was stirred at 80 °C for 3 h. After that, the reaction was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (eluent: 0-60% tetrahydrofuran / petroleum ether, gradient elution, flow rate 40 mL / min) to give the title compound, Intermediate 1-8 (55 mg). 4g The residue was purified by flash silica gel column chromatography (eluent: 0-60% tetrahydrofuran / petroleum ether, gradient elution, flow rate 40 mL / min) to give the title compound, Intermediate 1-8 (55 mg).

[0199] MS m / z (ESI): 549.2 [M+H] +

[0200] Step 7: Synthesis of Compound 1 and Compound 2

[0201] Intermediate 1-8 (50 mg) was dissolved in t-AmOH (1 mL), and then Pd(OAc)2 (4.10 mg), PivOK (38.39 mg) and cataCXium A (13.09 mg) were added into the reaction under nitrogen atmosphere. The reaction was stirred at 100 °C for 16 h. After that, the reaction was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (column: C18, 150 x 40 mm; mobile phase: [A: water (0.05% ammonia water + 10 mM ammonium bicarbonate), B: acetonitrile]; B%: 25%-65%, 9 min) to give Compound 1 (5 mg) and Compound 2 (2.2 mg).

[0202] Compound 1:

[0203] LC-MS: m / z (ESI): 467.1 [M+H] + .

[0204] 1H NMR (400 MHz, DMSO-d6) d = 7.75-7.71 (m, 1H), 7.64 (s, 1H), 7.50-7.48 (m, 1H), 7.19-7.10 (m, 2H), 6.28 (s, 1H), 6.23 (s, 2H), 5.34-5.25 (m, 1H), 3.97-3.93 (m, 2H), 3.87 (s, 3H), 3.11-3.07 (m, 1H), 1.68 (d, J = 6.2 Hz, 3H), 1.62 (d, J = 7.5 Hz, 3H), 1.24 (t, J = 7.2 Hz, 3H).

[0205] Compound 2:

[0206] LC-MS: m / z (ESI): 465.1 [M+H] + .

[0207] 1 H NMR (400 MHz, DMSO-d6) d = 7.70-7.64 (m, 2H), 7.55-7.48 (m, 2H), 7.17-7.10 (m, 1H), 6.43 (s, 1H), 6.22 (s, 2H), 5.41-5.39 (m, 1H), 5.16-5.09 (m, 1H), 4.83-4.81 (m, 1H), 4.12-4.04 (m, 2H), 3.89 (s, 3H), 1.61 (d, J = 6.2 Hz, 3H), 1.32 (t, J = 7.2 Hz, 3H).

[0208] Example 2: Synthesis of compound 2

[0209] Step 1: Synthesis of (R)-5-bromo-3-(1-(2-(4-(1-(3-chloro-1-ethyl-1H-pyrazol-4-yl)vinyl)-1- methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine (Intermediate 2-1)

[0210] Intermediate 1-5 (1.0 g, 2.7 mmol) and 5-bromo-3-fluoro-2-nitropyridine (707.5 mg, 3.2 mmol) were dissolved in toluene (10.0 mL), and potassium tert-butoxide (4.0 mL, 1M, 4.0 mmol) was slowly added dropwise under nitrogen atmosphere at 0 °C. The reaction solution was stirred at 0 °C for 1 hour. After the reaction solution was quenched with water (20.0 mL), it was extracted with ethyl acetate (20 mL x 3), and the organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 4: 1) to obtain intermediate 2-1 (1.4 g).

[0211] LCMS: m / z (ESI): 575.1 / 577.1 [M+H] +

[0212] Step 2: Synthesis of (R)-5-bromo-3-(l-(2-(4-(l-(3-chloro-l-ethyl-lH-pyrazol-4-yl)vinyl)-l- methyl-lH-pyrazol-3-yl)-5-fluorophenyl)ethoxy)pyridin-2-amine (Intermediate 2-2)

[0213] Intermediate 2-1 (1.4 g, 2.4 mmol) was dissolved in ethanol (10.0 mL) / water (2.0 mL) with anhydrous ammonium chloride (641.0 mg, 11.4 mmol), and iron powder (669.0 mg, 11.4 mmol) was added, and the resulting mixture was heated to 80 °C for 1 hour. The reaction was filtered, extracted with ethyl acetate (10.0 mL), and the organic phases were combined and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 1: 1) to give Intermediate 2-2 (1.0 g).

[0214] LCMS: m / z (ESI): 545.1.1 / 547.1 [M+H] +

[0215] Step 3: Synthesis of Compound 2

[0216] Intermediate 2-2 (1.0 g, 1.8 mmol), palladium acetate (82.3 mg, 0.36 mmol), potassium pinacolate (769.81 mg, 5.49 mmol), and n-butyl bis(l-adamantyl)phosphine (262.5 mg, 0.72 mmol) were dissolved in tert-amyl alcohol (4.0 mL). The reaction was stirred at 100 °C under an argon atmosphere for 16 hours. Subsequently, the reaction was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative chromatography (column: YMC TA-C18, 30*150 mm, 5 μm; mobile phase A: 7 mmol / L aqueous NH4HCO3, mobile phase B: acetonitrile; flow rate: 30 mL / min; acetonitrile ratio 45-75%, elution for 10 minutes) to give Compound 2 (44.0 mg).

[0217] LCMS: m / z (ESI): 465.2 [M+H] + .

[0218] 1H NMR (400 MHz, DMSO-d6) δ 7.71-7.63 (m, 2H), 7.58-7.50 (m, 2H), 7.19-7.12 (m, 1H), 6.51 (s, 1H), 5.41 (d, J = 1.9 Hz, 1H), 5.17 (d, J = 6.0 Hz, 1H), 4.82 (d, J = 1.8 Hz, 1H), 4.08 (q, J = 7.2 Hz, 2H), 3.89 (s, 3H), 1.62 (d, J = 6.2 Hz, 3H), 1.31 (t, J = 7.2 Hz, 3H).

[0219] Example 3: Synthesis of compound 3

[0220] Step 1: Synthesis of 3-bromo-l-methyl-lH-pyrazole-4-carbonyl chloride (intermediate 3-2)

[0221] Intermediate 3-1 (100 mg) was dissolved in dichloromethane (2 mL), and the resulting solution was cooled to 0 °C after dropwise addition of DMF (0.2 mL), then oxalyl chloride (123.82 mg) was added dropwise to the solution. The resulting reaction solution was stirred at room temperature for 3 h, and then concentrated to dryness under reduced pressure. The obtained crude intermediate 3-2 was used directly in the next reaction.

[0222] Step 2: Synthesis of (3-bromo-l-methyl-lH-pyrazol-4-yl)(lH-pyrrolo[2,3-b]pyridin-3- yl)methanone (intermediate 3-3)

[0223] Intermediate 3-2 (109 mg) was dissolved in dichloromethane (2 mL), then aluminum chloride (195.13 mg) was added to the resulting solution, and the reaction solution was cooled to 0 °C under a nitrogen atmosphere, then a solution of lH-pyrrolo[2,3-b]pyridine (57.63 mg) in dichloromethane (1 mL) was added dropwise to the solution, and the resulting reaction solution was stirred at room temperature for 12 h. Subsequently, the reaction solution was concentrated to dryness under reduced pressure, and the residue was purified and isolated by preparative thin layer chromatography (PE / EA = 1 / 1) to obtain intermediate 3-3 (134 mg).

[0224] LCMS: m / z (ESI): 305.0 [M+H] +

[0225] Step 3: Synthesis of (3-bromo-l-methyl-lH-pyrazol-4-yl)(l-ethyl-lH-pyrrolo[2,3-b]pyridin- 3-yl)methanone (intermediate 3-4)

[0226] Intermediate 3-3 (387 mg) was dissolved in DMF (5 mL), the resulting solution was cooled to 0 °C, NaH (60.9 mg, 60% active content) was added to the resulting solution, the reaction was stirred at room temperature for 2 h. Subsequently, the reaction was diluted with ethyl acetate (100 mL), the organic phase was washed with saturated brine twice, then the organic phase was concentrated to dryness under reduced pressure, the residue was purified by column chromatography (EA / PE = 0-70%), to obtain intermediate 3-4 (284 mg).

[0227] LCMS: m / z (ESI): 333.0 [M+H] +

[0228] Step 4: Synthesis of (3-bromo-l-methyl-lH-pyrazol-4-yl)(l-ethyl-lH-pyrrolo[2,3- b]pyridin-3-yl)methanol (intermediate 3-5)

[0229] Intermediate 3-4 (171 mg) was dissolved in THF (10 mL), then LiBH4(33.53 mg) was added to the solution in batches, the reaction was stirred at 80 °C for 1 h. Subsequently, saturated aqueous NH4Cl solution (20 mL) was added to the reaction, and DCM (50 mL*3 times) was added for extraction, then the organic phase was separated, and the organic phase was concentrated under reduced pressure to obtain intermediate 3-5.

[0230] LCMS: m / z (ESI): 335.0 [M+H] +

[0231] Step 5: Synthesis of 3-((3-bromo-l-methyl-lH-pyrazol-4-yl)methyl)-l-ethyl-lH- pyrrolo[2,3-b]pyridine (intermediate 3-6)

[0232] Intermediate 3-5 (172.03 mg) was dissolved in dichloromethane (5 mL), then TES (179.03 mg) and TFA (175.56 mg) were added to the solution in sequence, the resulting mixture was stirred at room temperature for 1 h. Subsequently, saturated aqueous sodium bicarbonate solution (20 mL) was added to the reaction, and DCM (50 mL*3 times) was added for extraction, then the organic phase was separated, and the organic phase was concentrated under reduced pressure, the residue was purified by column chromatography (EA / PE = 0-50%), to obtain intermediate 3-6 (139.7 mg).

[0233] LCMS: m / z (ESI): 319.0 [M+H] +

[0234] Step 6: Synthesis of (R)-1-(2-(4-((1-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-1- methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethan-1-ol (Intermediate 3-7)

[0235] Intermediate 3-6 (136 mg), Intermediate 1-4 (84.85 mg), Pd(AmPhos)2Cl2 (15.13 mg) and potassium carbonate (117.77 mg) were dissolved in DMF (6 mL) and water (1 mL), the reaction was heated to 80 °C under argon atmosphere and stirred for 16 h. Then, the reaction was concentrated under reduced pressure, the residue was purified by column chromatography (EA / PE = 0-50%) to give Intermediate 3-7 (45.6 mg).

[0236] LCMS: m / z (ESI): 379.1 [M+H] +

[0237] Step 7: Synthesis of (R)-3-((3-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4- fluorophenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-1-ethyl-1H-pyrrolo[2,3-b]pyridine (Intermediate 3-8)

[0238] Intermediate 3-7 (40 mg) and 5-bromo-3-fluoro-2-nitropyridine (28.03 mg) were dissolved in THF (5 mL), the resulting mixture was cooled to 0 °C, then a THF solution (1 mL) of t-BuOK (14.23 mg) was added dropwise to the mixture, the resulting reaction was reacted at 0 °C for 16 h, then, saturated aqueous NH4Cl solution (10 mL) was added to the reaction, and DCM (30 mL*3 times) was added for extraction, the organic phase was separated, and the organic phase was concentrated under reduced pressure, the residue was purified by thin layer preparative chromatography (PE / EA = 1 / 1) to give Intermediate 3-8 (28.3 mg).

[0239] LCMS: m / z (ESI): 579.1 [M+H] +

[0240] Step 8: Synthesis of (R)-5-bromo-3-(1-(2-(4-((1-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)- 1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethoxy)pyridin-2-amine (Intermediate 3-9)

[0241] Intermediate 3-8 (23 mg) was dissolved in THF (2 mL) and MeOH (4 mL), then Raney nickel (120 mg) was added. The reaction was stirred at room temperature under hydrogen atmosphere for 6 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by thin layer preparative chromatography (PE / EA = 1 / 3) to give intermediate 3-9 (7.7 mg).

[0242] LCMS: m / z (ESI): 549.1 [M+H] +

[0243] Step 9: Synthesis of compound 3

[0244] Intermediate 3-9 (5.5 mg), Pd(OAc)2(674.21 μg), PivOK (4.21 mg) and CataCXium A (2.15 mg) were dissolved in t-AmOH (1 mL). The reaction was heated to 105 °C under argon atmosphere and stirred for 16 h. Then, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (column: YMC TA-C18, 30*150 mm, 5 μm; mobile phase A: 7 mmol / L NH4HCO3, mobile phase B: acetonitrile; flow rate: 30 mL / min; acetonitrile ratio 45-75%, elution 10-11 min) to give compound 3 (0.25 mg).

[0245] LCMS: m / z (ESI): 469.2 [M+H] +

[0246] 1 H NMR (400 MHz, CDC13) δ 8.37 (d, J = 4.5 Hz, 1H), 8.01 (d, J = 7.7 Hz, 1H), 7.68 (s, 1H), 7.35-7.32 (m, 1H), 7.20-7.14 (m, 2H), 7.06-6.99 (m, 2H), 6.71 (s, 1H), 5.45-5.41 (m, 1H), 4.80 (s, 2H), 4.39-4.31 (m, 2H), 3.90 (d, J = 15.8 Hz, 1H), 3.86 (s, 3H), 3.18 (d, J = 15.8 Hz, 1H), 1.80 (d, J = 6.3 Hz, 3H), 1.31 (s, 3H).

[0247] Example 4: Synthesis of compound 4

[0248] Step 1: Synthesis of tert-butyl (3-chloro-l-ethyl-lH-pyrazol-4-yl)carbamate (intermediate 4-2)

[0249] Intermediate 4-1 (3.03 g), NH2Boc (1.55 g), Cul (225.00 mg), K3PO4 (5.02 g) and (1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (3.36 g) were dissolved in 1,4-dioxane (30 mL), the reaction was heated to 110 °C under argon atmosphere and stirred for 16 h. Then, the reaction was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (EA / PE = 0-60%) to give intermediate 4-2 (1.29 g).

[0250] LCMS: m / z (ESI): 246.1 [M+H] +

[0251] Step 2: Synthesis of 3-chloro-1-ethyl-1H-pyrazol-4-amine (Intermediate 4-3)

[0252] Intermediate 4-2 (211 mg) was dissolved in DCM (5 mL) and TFA (1 mL), the reaction was stirred at room temperature for 4 h, then saturated aqueous sodium bicarbonate solution (20 mL) was added to the reaction, followed by extraction with DCM (100 mL*3 times), the organic phase was separated, concentrated under reduced pressure, and the residue was purified by column chromatography (EA / PE = 0-50%) to give intermediate 4-3 (108.9 mg).

[0253] LCMS: m / z (ESI): 146.1 [M+H] +

[0254] Step 3: Synthesis of 3-bromo-N-(3-chloro-1-ethyl-1H-pyrazol-4-yl)-1-methyl-1H-pyrazol-4- amine (Intermediate 4-4)

[0255] Intermediate 4-3 (298 mg), 3-bromo-4-iodo-1-methylpyrazole (763.40 mg), t-BuONa (590.12 mg) and tBuXPhos Pd G3 (162.80 mg) were dissolved in xylene (4 mL), the reaction was heated to 140 °C under argon atmosphere and stirred for 3 h. Then, the reaction was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer preparative chromatography (PE / EA = 1 / 1) to give intermediate 4-4 (185 mg).

[0256] LCMS: m / z (ESI): 304.0 [M+H] +

[0257] Step 4: Synthesis of 3-bromo-N-(3-chloro-1-ethyl-1H-pyrazol-4-yl)-N,1-dimethyl-1H-pyrazol-4- amine (Intermediate 4-5)

[0258] Intermediate 4-4 (128.8 mg) was dissolved in DMF (5 mL), the resulting solution was cooled to 0 °C, then NaH (25.37 mg, 60% effective content) was added, the resulting mixture was stirred at 0 °C for 10 min, then MeI (120.05 mg) was added dropwise, the reaction was allowed to warm to room temperature and reacted for 2 h. Subsequently, the reaction was diluted with EA (50 mL), washed with saturated brine (25 mL*2 times) twice, then the organic phase was separated and concentrated to dryness under reduced pressure, and the resulting crude product of intermediate 4-5 was directly used in the next reaction.

[0259] LCMS: m / z (ESI): 318.0 [M+H] +

[0260] Step 5: Synthesis of (R)-1-(2-(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)(methyl)amino)-1- methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethan-1-ol (Intermediate 4-6)

[0261] Intermediate 4-5 (121.8 mg), intermediate 1-4 (253.78 mg), Pd2dba3 (35.01 mg), Cy3P (21.44 mg) and KF (66.63 mg) were dissolved in 1,4-dioxane (10 mL) and water (1 mL), the reaction was heated to 100 °C under argon atmosphere and stirred for 2 h. The reaction was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (EA / PE = 0-70%) to give intermediate 4-6 (110.8 mg).

[0262] LCMS: m / z (ESI): 378.1 [M+H] +

[0263] Step 6: Synthesis of (R)-3-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-N-(3- chloro-1-ethyl-1H-pyrazol-4-yl)-N,1-dimethyl-1H-pyrazol-4-amine (Intermediate 4-7)

[0264] Intermediate 4-6 (110.8 mg) and 5-bromo-3-fluoro-2-nitropyridine (129.60 mg) were dissolved in THF (10 mL), the resulting mixture was cooled to 0 °C, then a solution of t-BuOK (98.72 mg) in THF (0.9 mL) was added dropwise. The reaction was stirred at room temperature for 16 h. Subsequently, saturated aqueous NH4Cl (10 mL) was added to the reaction, and extracted with dichloromethane (50 mL*3 times), then the organic phase was separated and concentrated under reduced pressure, the residue was purified by column chromatography (EA / PE = 0-70%) to give intermediate 4-7 (134 mg).

[0265] LCMS: m / z (ESI): 578.0 [M+H] +

[0266] Step 7: Synthesis of (R)-5-bromo-3-(1-(2-(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)(methyl)amino)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethoxy)pyridin-2-amine (Intermediate 4-8)

[0267] Intermediate 4-7 (153.5 mg) and NH4Cl (141.86 mg) were dissolved in ethanol (10 mL) and water (2 mL), then iron powder (148.10 mg) was added to the resulting solution, the resulting mixture was stirred at 85 °C for 3 h. Subsequently, the reaction was filtered, extracted with DCM (50 mL*3 times), the organic phase was separated and concentrated to dryness under reduced pressure, the resulting crude product of intermediate 4-8 was used directly in the next reaction.

[0268] LCMS: m / z (ESI): 548.1 [M+H] +

[0269] Step 8: Synthesis of compound 4

[0270] Intermediate 4-8 (72.5 mg), Pd(OAc)2 (3.56 mg), CataXium A (11.37 mg) and t-BuOK (55.57 mg) were dissolved in t-AmOH (5 mL), the reaction was heated to 105 °C under argon atmosphere and stirred for 16 h. Subsequently, the reaction was filtered, the filtrate was concentrated under reduced pressure, the residue was purified by preparative chromatography (column: YMC TA-C18, 30*150 mm, 5 μm; mobile phase A: 7 mmol / L NH4HCO3, mobile phase B: acetonitrile; flow rate: 30 mL / min; acetonitrile ratio 40-70%, elution 10 min) to give compound 4 (8.08 mg)

[0271] LCMS: m / z (ESI): 468.1 [M+H]+

[0272] 1 H NMR (400 MHz, CDC13) δ 7.55 (d, J = 1.8 Hz, 1H), 7.46 (s, 1H), 7.37 - 7.30 (m, 1H), 7.29 - 7.26 (m, 1H), 7.04 - 6.98 (m, 1H), 6.93 (d, J = 1.8 Hz, 1H), 5.42 - 5.31 (m, 1H), 4.86 (s, 2H), 4.11 (q, J = 7.2 Hz, 2H), 3.88 (s, 3H), 2.98 (s, 3H), 1.72 (d, J = 6.3 Hz, 3H), 1.42 (t, J = 7.2 Hz, 3H).

[0273] Example 5: Synthesis of compound 5

[0274] Step 1: Synthesis of tert-butyl 3-cyclopropoxy-lH-pyrazole-l-carboxylate (Intermediate 5-2)

[0275] Intermediate 5-1 (950.0 mg, 5.2 mmol), PPh3 (2.0 g, 7.7 mmol), DBAD (1.8 g, 7.7 mmol) and cyclopropyl-l-ol (449.0 mg, 7.7 mmol) were dissolved in toluene (20.0 mL), the mixture was stirred at 25 °C for 30 min under argon atmosphere, then heated to 110 °C for 12 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and purified by column chromatography (PE:EA = 1: 1) to give intermediate 5-2 (800.0 mg).

[0276] LCMS: m / z (ESI): 169.0 [M+H- t Bu] +

[0277] Step 2: Synthesis of 3-cyclopropoxy-lH-pyrazole (Intermediate 5-3)

[0278] Intermediate 5-2 (2.1 g, 9.2 mmol) was dissolved in a mixture of DCM (20.0 mL) and TFA (7.0 mL), and reacted at 25 °C for 1.5 h. The reaction solution was concentrated, the residue was dissolved in ethyl acetate (20.0 mL), washed with saturated aqueous sodium bicarbonate solution (20.0 mL), and the organic phase was concentrated under reduced pressure to give intermediate 5-3 (491.0 mg).

[0279] LCMS: m / z (ESI): 125.1 [M+H] +

[0280] Step 3: Synthesis of 3-cyclopropoxy-l-ethyl-lH-pyrazole (Intermediate 5-4)

[0281] Intermediate 5-3 (475.0 mg, 3.8 mmol) was dissolved in DMF (5.0 mL), cesium carbonate (1.9 g, 5.7 mmol) and iodoethane (3.0 g, 19.1 mmol) were added, and the mixture was reacted at 25 °C for 3 hours. After the reaction was completed, water (10.0 mL) was added for quenching, and extraction was performed with ethyl acetate (20 mL x 3). The organic phase was concentrated under reduced pressure and then purified by column chromatography (PE:EA = 1:1) to obtain intermediate 5-4 (260.0 mg).

[0282] LCMS: m / z (ESI): 153.1 [M+H] +

[0283] Step 4: Synthesis of 3-cyclopropoxy-l-ethyl-lH-pyrazole-4-carbaldehyde (Intermediate 5-5)

[0284] Phosphorus oxychloride (1.0 g, 6.6 mmol) was added to DMF (7.0 mL) at 0 °C, and the mixture was reacted at 25 °C for 30 minutes. Intermediate 5-4 (250.0 mg, 1.6 mmol) was added, and the temperature was increased to 70 °C for reaction for 12 hours. After the reaction was completed, water (10.0 mL) was added for quenching, and extraction was performed with ethyl acetate (20 mL x 3). The organic phase was concentrated under reduced pressure and then purified by column chromatography (PE:EA = 1:1) to obtain intermediate 5-5 (93.0 mg).

[0285] LCMS: m / z (ESI): 181.1 [M+H] +

[0286] Step 5: Synthesis of (3-bromo-l-methyl-lH-pyrazol-4-yl)(3-cyclopropoxy-l-ethyl-lH-pyrazol-4-yl)methanol (Intermediate 5-6)

[0287] Isopropyl magnesium bromide (448.0 μL, 1M, 448.0 μmol,) was added to a solution of 3-bromo-4-iodo-l-methyl-lH-pyrazole (116.9 mg, 407.3 μmol) in tetrahydrofuran (2.0 mL) at 0 °C, and the mixture was stirred for 1 hour. Intermediate 5-5 (73.4 mg, 407.3 μmol) was added, and the temperature was slowly increased to 25 °C for reaction for 2 hours. After the reaction was completed, water (2.0 mL) was added for quenching, and extraction was performed with ethyl acetate (2.0 mL x 3). The organic phase was concentrated under reduced pressure and then purified by column chromatography (PE:EA = 1:1) to obtain intermediate 5-6 (96.0 mg).

[0288] LCMS: m / z (ESI): 341.0 / 343.0 [M+H] +

[0289] Step 6: Synthesis of 3-bromo-4-((3-cyclopropoxy-l-ethyl-lH-pyrazol-4-yl)methyl)-l- methyl-lH-pyrazole (Intermediate 5-7)

[0290] Intermediate 5-6 (96.0 mg, 281.4 μmol) was dissolved in dichloromethane (5.0 mL), trifluoroacetic acid (160.4 mg, 1.4 mmol) and triethylsilane (98.1 mg, 844.1 μmol) were added, and the resulting mixture was reacted at 25 °C for 2 hours. After the reaction was completed, the reaction solution was concentrated, the residue was dissolved in ethyl acetate (10.0 mL), washed with saturated aqueous sodium bicarbonate solution (10.0 mL), and the organic phase was concentrated under reduced pressure to give Intermediate 5-7 (90.0 mg).

[0291] LCMS: m / z (ESI): 325.0 / 327.0 [M+H] +

[0292] Step 7: Synthesis of (R)-l-(2-(4-((3-cyclopropoxy-l-ethyl-lH-pyrazol-4-yl)methyl)-l- methyl-lH-pyrazol-3-yl)-5-fluorophenyl)ethan-l-ol (Intermediate 5-8)

[0293] Intermediate 5-7 (89.9 mg, 276.4 μmol), Intermediate 1-4 (68.8 mg, 414.7 μmol), Pd(Amphos)2Cl2(19.6 mg, 27.6 μmol) and potassium carbonate (114.6 mg, 829.3 μmol) were added to a mixed solvent of 1,4-dioxane (6.0 mL) / water (1.0 mL), and the mixture was reacted at 100 °C for 12 hours. After the reaction was completed, the temperature was lowered to 25 °C, water (10.0 mL) was added to quench the reaction, and then ethyl acetate (20.0 mL x 3) was added to extract the organic phase. The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 1:1) to give Intermediate 5-8 (85.0 mg).

[0294] LCMS: m / z (ESI): 385.2 [M+H] +

[0295] Step 8: Synthesis of (R)-5-bromo-3-(l-(2-(4-((3-cyclopropoxy-l-ethyl-lH-pyrazol-4- yl)methyl)-l-methyl-lH-pyrazol-3-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine (Intermediate 5-9)

[0296] Intermediate 5-8 (80.0 mg, 208.1 μmol) was dissolved in tetrahydrofuran (5.0 mL), sodium hydride (12.5 mg, 312.1 μmol, 60% active content) was added at 0 °C, stirred for 30 minutes, then 5-bromo-3-fluoro-2-nitropyridine (69.0 mg, 312.1 μmol) was added, and the mixture was immediately moved to 25 °C and reacted for 1 hour. After the reaction was completed, water (5.0 mL) was added to quench the reaction, and ethyl acetate (20.0 mL x 3) was added to extract the organic phase. The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 1:1) to obtain intermediate 5-9 (100.0 mg).

[0297] LCMS: m / z (ESI): 585.1 / 587.1 [M+H] +

[0298] Step 9: Synthesis of (R)-5-bromo-3-(1-(2-(4-((3-cyclopropoxy-1-ethyl-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethoxy)pyridin-2-amine (Intermediate 5-10)

[0299] Intermediate 5-9 (100.0 mg, 170.8 μmol), iron powder (57.2 mg, 1.0 mmol), and ammonium chloride (54.8 mg, 1.0 mmol) were stirred in a mixture of ethanol (2.0 mL) / water (0.4 mL) at 80 °C for 1 hour. After the reaction was completed, the mixture was filtered, and the filtrate was extracted with ethyl acetate (5.0 mL x 3) and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 4:1) to obtain intermediate 5-10 (91.7 mg).

[0300] LCMS: m / z (ESI): 555.1 / 557.1 [M+H] +

[0301] Step 10: Synthesis of compound 5

[0302] Intermediate 5-10 (43.0 mg, 77.4 μmol), Pd(OAc)2(3.5 mg, 15.5 μmol), PivOK (43.4 mg, 309.7 μmol) and cataCXium A (11.1 mg, 31.0 μmol) were dissolved in t-AmOH (2.0 mL). The reaction was heated to 105 °C under argon atmosphere and stirred for 16 h. Then, the reaction was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (column: YMC TA-C18, 30*150 mm, 5 μm; mobile phase A: 7 mmol / L NH4HCO3 in water, mobile phase B: acetonitrile; flow rate: 30 mL / min; acetonitrile gradient 45-75% over 10-11 min) to give compound 5 (5.8 mg).

[0303] LCMS: m / z (ESI): 475.2 [M+H] +

[0304] 1 H NMR (400 MHz, DMSO-d6) δ 7.72-7.65 (m, 1H), 7.45-7.39 (m, 2H), 7.16-7.08 (m, 2H), 6.26 (d, J = 1.9 Hz, 1H), 6.09 (s, 2H), 5.33-5.26 (m, 1H), 4.22-4.13 (m, 1H), 3.93-3.87 (m, 2H), 3.86 (s, 3H), 3.42-3.36 (m, 2H), 1.70 (d, J = 6.3 Hz, 3H), 1.24 (t, J = 7.1 Hz, 3H), 0.89-0.81 (m, 1H), 0.78-0.68 (m, 3H).

[0305] Example 6: Synthesis of compound 6

[0306] Step 1: Synthesis of 3-bromo-l-methyl-4-(trimethylstannyl)-lH-pyrazole (Intermediate 6-2)

[0307] Intermediate 6-1 (2.0 g, 6.8 mmol), hexamethylditin (3.4 g, 10.4 mmol) and Pd(PPh3)4(805.2 mg, 0.7 mmol) were dissolved in 1,4-dioxane (30.0 mL). The reaction was stirred at 100 °C under argon atmosphere for 3 h. After cooling, the reaction was filtered and the filtrate was concentrated under reduced pressure to remove the solvent to give Intermediate 6-2 (1.8 g).

[0308] LCMS: m / z (ESI): 325.0 / 327.0 [M+H] +

[0309] Step 2: Synthesis of 2,2-difluoro-l-(tributylstannyl)vinyl 4-methylbenzenesulfonate (Intermediate 6-4)

[0310] After intermediate 6-3 (9.7 g, 38.2 mmol) was dissolved in tetrahydrofuran (40.0 mL), it was protected by nitrogen and cooled to -78 °C, and LDA (42.0 mL, 2 M, 83.9 mmol) was added dropwise into the reaction solution. After the addition was completed, it was incubated for 30 minutes, and then tributyltin chloride (12.4 g, 38.2 mmol) was added dropwise into the reaction. After the addition was completed, it was naturally increased to 25 °C. After the reaction was completed, saturated aqueous ammonium chloride solution (5.0 mL) was added for quenching, and ethyl acetate (20.0 mL x 3) was used for extraction. The organic phase was concentrated under reduced pressure, and the residue was further purified by column chromatography (PE:EA = 95:5) to obtain intermediate 6-4 (12.0 g).

[0311] 1 H NMR (400 MHz, Chloroform-d) δ 7.78 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 2.45 (s, 3H), 1.69-1.49 (m, 6H), 1.35 (m, 6H), 1.22-1.11 (m, 6H), 0.92 (t, J = 7.3 Hz, 9H).

[0312] Step 3: Synthesis of l-(3-chloro-l-ethyl-lH-pyrazol-4-yl)-2,2-difluoroethenyl 4- methylbenzenesulfonate (Intermediate 6-5)

[0313] 3-chloro-l-ethyl-4-iodo-lH-pyrazole (2.0 g, 7.8 mmol), intermediate 6-4 (3.5 g, 6.6 mmol), Pd(PPh3)4 (900.7 mg, 779.8 μmol), CuI (148.5 mg, 779.8 μmol) were dissolved in DMF (20.0 mL), heated to 100 °C under argon atmosphere for 12 hours. After the reaction was completed, water (5.0 mL) was added for quenching, and ethyl acetate (10.0 mL x 3) was used for extraction. The organic phase was concentrated under reduced pressure, and the residue was further purified by column chromatography (PE:EA = 9:1) to obtain intermediate 6-5 (2.4 g).

[0314] LCMS: m / z (ESI): 363.2 [M+H] +

[0315] Step 4: Synthesis of 3-bromo-4-(l-(3-chloro-l-methyl-lH-pyrazol-4-yl)-2,2- difluoroethenyl)-l-methyl-lH-pyrazole (Intermediate 6-6)

[0316] Intermediate 6-5 (600.0 mg, 1.7 mmol), intermediate 6-2 (910.4 mg, 2.8 mmol), Pd(PPh3)4 (191.0 mg, 165.4 μmol), CuI (31.5 mg, 165.4 μmol) were dissolved with DMF (10.0 mL) and heated to 100 °C for 12 hours under nitrogen atmosphere. The reaction was cooled down and quenched with water (5.0 mL), extracted with ethyl acetate (10.0 mL x 3), the organic phase was concentrated under reduced pressure, the residue was purified by preparative liquid chromatography (column: YMC TA-C18, 30*150 mm, 5 μm; mobile phase A: 7 mmol / L NH4HCO3 aqueous solution, mobile phase B: acetonitrile; flow rate: 30 mL / min; acetonitrile ratio 45-75%, elution 10-11 min) to give intermediate 6-6 (190.0 mg).

[0317] LCMS: m / z (ESI): 337.0 / 339.0 [M+H] +

[0318] Step 5: Synthesis of (R)-1-(2-(4-(1-(3-chloro-1-ethyl-1H-pyrazol-4-yl)-2,2- difluorovinyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethan-1-ol (Intermediate 6-7)

[0319] Intermediate 6-6 (103.0 mg, 307.2 μmol), intermediate 1-4 (51.0 mg, 307.2 μmol), Pd(Amphos)2Cl2 (21.8 mg, 30.7 μmol) and K2CO3 (127.2 mg, 921.6 μmol) were added to a mixture of 1,4-dioxane (5.0 mL) / water (1.2 mL) and heated to 100 °C for 12 hours. The reaction was cooled down to 25 °C and quenched with water (5.0 mL), extracted with ethyl acetate (10.0 mL x 3), the organic phase was concentrated under reduced pressure, the residue was purified by column chromatography (PE:EA = 7:3) to give intermediate 6-7 (78.0 mg).

[0320] LCMS: m / z (ESI): 411.1 [M+H] +

[0321] Step 6: Synthesis of (R)-5-bromo-3-(1-(2-(4-(1-(3-chloro-1-ethyl-1H-pyrazol-4-yl)-2,2- difluorovinyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine (Intermediate 6-8)

[0322] Intermediate 6-7 (34.0 mg, 82.8 μmol) was dissolved in tetrahydrofuran (5.0 mL), sodium hydride (5.0 mg, 124.1 μmol, 60%) was added at 0 °C, stirred for 30 min, 5-bromo-3-fluoro-2-nitropyridine (27.3 mg, 124.1 μmol) was added and then moved to 25 °C for 1 h. After the reaction was completed, water (5.0 mL) was added to quench the reaction, and then extracted with ethyl acetate (10.0 mL x 3). The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 9:1) to give intermediate 6-8 (18.0 mg).

[0323] LCMS: m / z (ESI): 611.1 / 613.0 [M+H] +

[0324] Step 7: Synthesis of (R)-5-bromo-3-(l-(2-(4-(l-(3-chloro-l-ethyl-lH-pyrazol-4-yl)-2,2- difluorovinyl)-l-methyl-lH-pyrazol-3-yl)-5-fluorophenyl)ethoxy)pyridin-2-amine (Intermediate 6-9)

[0325] Intermediate 6-8 (18.0 mg, 29.4 μmol), iron powder (16.4 mg, 294.0 μmol) and ammonium chloride (15.7 mg, 294.0 μmol) were heated to 80 °C in a mixture of ethanol (2.0 mL) / water (0.4 mL) and stirred for 1 h. After the reaction was completed, the reaction was filtered, extracted with ethyl acetate (5.0 mL x 3) and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 4:1) to give intermediate 6-9 (12.5 mg).

[0326] LCMS: m / z (ESI): 581.1 / 583.1 [M+H] +

[0327] Step 8: Synthesis of compound 6

[0328] Intermediate 6-9 (12.0 mg, 20.6 μmol), Pd(OAc)2(1.4 mg, 6.2 μmol), PivOK (8.7 mg, 61.9 μmol) and cataCXium A (4.4 mg, 12.4 μmol) were dissolved in t-AmOH (3.0 mL). The reaction was heated to 105 °C under argon atmosphere and stirred for 16 h. Then, the reaction was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (column: YMC TA-C18, 30*150 mm, 5 μm; mobile phase A: 7 mmol / L NH4HCO3, mobile phase B: acetonitrile; flow rate: 30 mL / min; acetonitrile ratio 45-75%, elution 10-11 min) to give compound 6 (1.3 mg).

[0329] LCMS: m / z (ESI): 501.1 [M+H] +

[0330] 1 H NMR (400 MHz, DMSO-d6) δ 7.81 (s, 1H), 7.72-7.70 (m, 1H), 7.53 (s, 1H), 7.36-7.26 (m, 1H), 7.21-7.11 (m, 1H), 6.37 (s, 1H), 6.31 (s, 2H), 5.26 (d, J = 6.8 Hz, 1H), 4.06 (q, J = 7.3 Hz, 2H), 3.91 (s, 3H), 1.65 (d, J = 6.2 Hz, 3H), 1.29 (t, J = 7.2 Hz, 3H).

[0331] Example 7: Synthesis of compound 7

[0332] Step 1: Synthesis of (R)-1-(2-(3-chloro-1H-pyrazol-1-yl)-5-fluorophenyl)ethan-1-ol (Intermediate 7-2)

[0333] Intermediate 7-1 (5.0 g, 18.8 mmol) was dissolved in NMP (30.0 mL), then 3-chloro-1H-pyrazole (2.1 g, 20.7 mmol), cuprous iodide (357.9 mg, 1.9 mmol), potassium carbonate (5.2 g, 37.6 mmol) were added, and the reaction was heated to 120 °C under argon atmosphere for 12 h. The reaction was cooled to 25 °C, quenched with water (5.0 mL), and extracted with ethyl acetate (20.0 mL x 3). The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 9:1) to give intermediate 7-2 (4.0 g).

[0334] LCMS: m / z (ESI): 241.2 [M+H]+

[0335] Step 2: Synthesis of (R)-3-chloro-l-(4-fluoro-2-(l-((4-methoxybenzyl)oxy)ethyl)phenyl)- lH-pyrazole (Intermediate 7-3)

[0336] Intermediate 7-2 (2.0 g, 8.3 mmol), PMBC1 (1.4 g, 9.1 mmol) and DIPEA (2.2 g, 16.6 mmol) were added to a reaction flask and heated to 150 °C for 1 h. The reaction was cooled to 25 °C and quenched with water (5.0 mL). The reaction mixture was extracted with ethyl acetate (20.0 mL x 3). The organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 9: 1) to give Intermediate 7-3 (2.6 g).

[0337] LCMS: m / z (ESI): 361.2 [M+H] +

[0338] Step 3: Synthesis of (R)-3-chloro-l-(4-fluoro-2-(l-((4-methoxybenzyl)oxy)ethyl)phenyl)- 5-iodo-lH-pyrazole (Intermediate 7-4)

[0339] Intermediate 7-3 (2.0 g, 5.5 mmol) was dissolved in tetrahydrofuran (20.0 mL) and cooled to -78 °C under argon atmosphere. n-BuLi (2.5 mL, 2.5 M, 6.1 mmol) was added dropwise to the reaction. After 30 min, iodine (1.5 g, 6.1 mmol) in tetrahydrofuran (5.0 mL) was added dropwise to the reaction. The reaction was allowed to warm to 25 °C and stirred for 1 h. The reaction was quenched with saturated aqueous ammonium chloride solution (5.0 mL) and extracted with ethyl acetate (20.0 mL x 3). The organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 95:5) to give Intermediate 7-4 (2.5 g).

[0340] LCMS: m / z (ESI): 487.2 [M+H] +

[0341] Step 4: Synthesis of (R)-3-chloro-5-(l-ethoxyvinyl)-l-(4-fluoro-2-(l-((4- methoxybenzyl)oxy)ethyl)phenyl)-lH-pyrazole (Intermediate 7-5)

[0342] Intermediate 7-4 (1.8 g, 3.7 mmol) was dissolved in 1,4-dioxane (20.0 mL), and under the condition of nitrogen atmosphere, triethylamine (935.6 mg, 9.3 mmol), tributyl(1-ethoxyvinyl)tin (2.0 g, 5.6 mmol) were added into the reaction bottle and stirred for 10 minutes, then dichlorobis(triphenylphosphine)palladium (259.3 mg, 369.8 μmol) was added into the reaction and raised to 100 °C for 12 hours. After the reaction was completed, it was lowered to 25 °C, water (5.0 mL) was added for quenching, and then extracted with ethyl acetate (10.0 mL x 3), the organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 9:1) to obtain intermediate 7-5 (1.3 g).

[0343] LCMS: m / z (ESI): 431.2 [M+H] +

[0344] Step 5: Synthesis of (R)-1-(3-chloro-1-(4-fluoro-2-(1-((4-methoxybenzyl)oxy)ethyl)phenyl)-1H-pyrazol-5-yl)ethan-1-one (Intermediate 7-6)

[0345] Intermediate 7-5 (1.0 g, 2.3 mmol) was dissolved in tetrahydrofuran (10.0 mL) at 0 °C, and hydrochloric acid (2.3 mL, 3M, 7.0 mmol) was added dropwise into the reaction, and then it was raised to 25 °C for 2 hours after the dropwise addition was completed. After the reaction was completed, water (5.0 mL) was added for quenching, and then extracted with ethyl acetate (10.0 mL x 3), the organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 8:2) to obtain intermediate 7-6 (870.0 mg).

[0346] LCMS: m / z (ESI): 403.2 [M+H] +

[0347] Step 6: Synthesis of (R)-1-(3-chloro-1-(4-fluoro-2-(1-((4-methoxybenzyl)oxy)ethyl)phenyl)-1H-pyrazol-5-yl)vinyl trifluoromethanesulfonate (Intermediate 7-7)

[0348] Intermediate 7-6 (500.0 mg, 1.2 mmol) was dissolved in dichloromethane (10.0 mL), the reaction was cooled to -78 °C under nitrogen atmosphere, LDA (6.3 mL, 1 M, 6.2 mmol) was added dropwise to the reaction, the reaction was stirred for 30 min, triflic anhydride (1.8 g, 6.2 mmol) was added dropwise to the reaction, after the addition was completed, the reaction was warmed to 25 °C for 1 h. The reaction was quenched by water (5.0 mL), extracted with ethyl acetate (10.0 mL x 3), the organic phase was concentrated under reduced pressure, the residue was purified by column chromatography (PE:EA = 9:1) to give intermediate 7-7 (180.0 mg).

[0349] 1 H NMR (400 MHz, Chloroform-d) δ 7.47 (m, 1H), 7.26-7.07 (m, 4H), 6.91-6.82 (m, 2H), 6.59 (s, 1H), 5.30 (d, J = 4.5 Hz, 1H), 4.79 (d, J = 4.6 Hz, 1H), 4.36-4.18 (m, 3H), 3.80 (s, 3H), 1.36 (d, J = 7.0 Hz, 3H).

[0350] Step 7: Synthesis of 3-chloro-l-ethyl-4-(trimethylstannyl)-lH-pyrazole (Intermediate 7-9)

[0351] Intermediate 7-8 (0.8 g, 3.1 mmol), hexamethylditin (1.3 g, 4.0 mmol) and Pd(PPh3)4(360.0 mg, 0.3 mmol) were dissolved in 1,4-dioxane (15.0 mL), the reaction was stirred at 100 °C under argon atmosphere for 3 h. The reaction was cooled to 25 °C, filtered, the filtrate was concentrated under reduced pressure to give intermediate 7-9 (0.75 g).

[0352] LCMS: m / z (ESI): 295.0 [M+H] +

[0353] Step 8: Synthesis of (R)-3-chloro-4-(l-(3-chloro-l-(4-fluoro-2-(l-((4- methoxybenzyl)oxy)ethyl)phenyl)-lH-pyrazol-5-yl)vinyl)-l-ethyl-lH-pyrazole (Intermediate 7-10)

[0354] Intermediate 7-7 (150.0 mg, 280.4 μmol), Intermediate 7-9 (148.1 mg, 504.8 μmol), Pd(PPh3)4 (32.4 mg, 28.0 μmol), Copper(I) iodide (5.4 mg, 28.0 μmol) were dissolved in DMF (5.0 mL) and heated to 100 °C for 12 h under nitrogen atmosphere. The reaction was cooled to 25 °C and quenched with water (5.0 mL). The mixture was extracted with ethyl acetate (10.0 mL x 3). The organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 9:1) to give intermediate 7-10 (80.0 mg).

[0355] LCMS: m / z (ESI): 515.2 [M+H] +

[0356] Step 9: Synthesis of (R)-1-(2-(3-chloro-5-(1-(3-chloro-1-ethyl-1H-pyrazol-4-yl)vinyl)-1H-pyrazol-1-yl)-5-fluorophenyl)ethan-1-ol (Intermediate 7-11)

[0357] Intermediate 7-10 (80.0 mg, 155.2 μmol) was dissolved in dichloromethane (3.0 mL) and trifluoroacetic acid (0.6 mL) was added at 25 °C for 2 h. The reaction was quenched with water (5.0 mL). The mixture was extracted with ethyl acetate (10.0 mL x 3). The organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 8:2) to give intermediate 7-11 (30.0 mg).

[0358] LCMS: m / z (ESI): 395.2 [M+H] +

[0359] Step 10: Synthesis of (R)-5-bromo-3-(1-(2-(3-chloro-5-(1-(3-chloro-1-ethyl-1H-pyrazol-4-yl)vinyl)-1H-pyrazol-1-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine (Intermediate 7-12)

[0360] Intermediate 7-11 (25.0 mg, 63.3 μmol) was dissolved in tetrahydrofuran (5.0 mL) and sodium hydride (3.8 mg, 94.9 μmol, 60% active content) was added at 0 °C. The mixture was stirred for 30 min and 5-bromo-3-fluoro-2-nitropyridine (25.0 mg, 113.9 μmol) was added. The mixture was stirred at 25 °C for 1 h. The reaction was quenched with water (5.0 mL). The mixture was extracted with ethyl acetate (10.0 mL x 3). The organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 8:2) to give intermediate 7-12 (12.0 mg).

[0361] LCMS: m / z (ESI): 595.0 / 597.0 [M+H] +

[0362] Step 11: Synthesis of (R)-5-bromo-3-(l-(2-(3-chloro-5-(l-(3-chloro-l- ethyl-lH-pyrazol-4-yl)vinyl)-lH-pyrazol-l-yl)-5-fluorophenyl)ethoxy)pyridin-2- amine (Intermediate 7-13)

[0363] Intermediate 7-12 (12.0 mg, 20.1 μmol), iron powder (11.2 mg, 201.3 μmol) and ammonium chloride (10.7 mg, 201.3 μmol) were stirred in a mixture solvent of ethanol (2.0 mL) / water (0.4 mL) at 80 °C for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by thin layer preparative chromatography (PE:EA = 3: 1) to give intermediate 7-13 (11.0 mg).

[0364] LCMS: m / z (ESI): 565.0 / 567.0 [M+H] +

[0365] Step 12: Synthesis of compound 7

[0366] Intermediate 7-13 (11.0 mg, 19.4 μmol), Pd(OAc)2(1.3 mg, 5.8 μmol), PivOK (8.2 mg, 58.3 μmol) and cataCXium A (4.2 mg, 11.7 μmol) were dissolved in t-AmOH (3.0 mL). The reaction solution was heated to 105 °C under argon atmosphere and stirred for 16 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (column: YMC TA-C18, 30*150 mm, 5 μm; mobile phase A: 7 mmol / L NH4HCO3 aqueous solution, mobile phase B: acetonitrile; flow rate: 30 mL / min; acetonitrile ratio 45-75%, elution 10-11 min) to give compound 7 (1.6 mg).

[0367] LCMS: m / z (ESI): 485.1 [M+H] +

[0368] 1H NMR (400 MHz, DMSO-d6) δ 7.98 - 7.92 (m, 1H), 7.83 (dd, J = 9.7, 3.0 Hz, 1H), 7.56 (d, J = 1.7 Hz, 1H), 7.35 - 7.24 (m, 1H), 6.42 - 6.34 (m, 3H), 5.84 (s, 1H), 5.28 (s, 1H), 5.02 - 4.88 (m, 1H), 4.22 - 4.08 (m, 2H), 1.60 (d, J = 6.2 Hz, 3H), 1.34 (t, J = 7.2 Hz, 3H).

[0369] Example 8: Synthesis of compound 8

[0370] Step 1: Synthesis of (R)-5-bromo-3-(l-(2-(4-(l-(3-chloro-l-ethyl-lH-pyrazol-4-yl)vinyl)-l- methyl-lH-pyrazol-3-yl)-5-fluorophenyl)ethoxy)pyrazin-2-amine (Intermediate 8-1)

[0371] Intermediate 1-5 (64.0 mg, 170.7 mmol) was added to tetrahydrofuran (5.0 mL) under argon atmosphere, sodium hydride (20.5 mg, 60%, 512.2 mmol) was added at 0 °C, after addition, the reaction was stirred for 0.5 h. 3,5-dibromo-2-nitropyridine (86.4 mg, 341.5 mmol) was added to the reaction solution. After addition, the reaction was heated to 70 °C and stirred for 16 h. The reaction solution was quenched with water (5.0 mL) and extracted with ethyl acetate (5.0 mL x 3). The organic phase was concentrated and purified by column chromatography (PE:EA = 1:4) to give Intermediate 8-1 (70.0 mg).

[0372] LCMS: m / z (ESI): 546.1 [M+H] +

[0373] Step 2: Synthesis of compound 8

[0374] Intermediate 8-1 (60.0 mg, 109.72 μmol), Pd(OAc)2(4.9 mg, 21.9 μmol), PivOK (46.8 mg, 329.2 μmol) and cataCXium A 15.7 mg, 43.9 μmol) were dissolved in t-AmOH (2.0 mL). The reaction was heated to 105 °C under argon atmosphere and stirred for 16 h. Then, the reaction was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (column: YMC TA-C18, 30*150 mm, 5 μm; mobile phase A: 7 mmol / L NH4HCO3 in water, mobile phase B: acetonitrile; flow rate: 30 mL / min; acetonitrile ratio 45-75%, elution 10-11 min) to give compound 8 (6.0 mg).

[0375] LCMS: m / z (ESI): 466.2 [M+H] +

[0376] 1 H NMR (400 MHz, DMSO-d6) δ 7.65 (dd, J = 10.3, 2.8 Hz, 1H), 7.62 (s, 1H), 7.54 (s, 1H), 7.48 (dd, J = 8.5, 5.8 Hz, 1H), 7.17-7.12 (m, 1H), 6.83 (s, 2H), 5.69 (dd, J = 6.6, 1.9 Hz, 1H), 4.98 (d, J = 2.1 Hz, 1H), 4.56 (d, J = 2.0 Hz, 1H), 4.13 (q, J = 7.2 Hz, 2H), 3.84 (s, 3H), 1.47 (d, J = 6.6 Hz, 3H), 1.35 (t, J = 7.2 Hz, 3H).

[0377] Example 9: Synthesis of compound 9

[0378] Step 1: Synthesis of 3-(1-(3-bromo-1-methyl-1H-pyrazol-4-yl)vinyl)-1- ethyl-1H-pyrrolo[2,3-b]pyridine (Intermediate 9-1)

[0379] Intermediate 3-4 (400.0 mg, 1.2 mmol) was added to tetrahydrofuran (0.4 mL) under argon atmosphere, and Tebbe reagent (3.6 mL, 1.8 mmol, 0.5 M) was added dropwise at 0 °C. After addition, the reaction was allowed to warm to room temperature and stirred for 16 h. The reaction was then added dropwise to sodium hydroxide (10.0 mL, 1 M) and stirred well. The mixture was filtered, the filter cake was rinsed with n-hexane (5.0 mL x 3), and the filtrate was extracted with ethyl acetate (10.0 mL x 3). The combined organic phase was washed with saturated brine, and the organic phase was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE:EA = 5:3) to give intermediate 9-1 (180 mg).

[0380] LCMS: m / z (ESI): 331.1 / 333.1 [M+H] +

[0381] Step 2: Synthesis of (R)-1-(2-(4-(1-(1-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)vinyl)-1- methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethan-1-ol (Intermediate 9-2)

[0382] Intermediate 9-1 (105.0 mg, 317.0 µmol), intermediate 1-4 (78.9 mg, 475.5 µmol), tris(dibenzylideneacetone)dipalladium (29.0 mg, 31.7 µmol), tricyclohexylphosphine (17.8 mg, 63.4 µmol) and potassium fluoride (55.3 mg, 951.1 µmol) were added to a mixture of 1,4-dioxane (5.0 mL) / water (1.2 mL) and the reaction was stirred at 100 °C for 12 h. The reaction was cooled to 25 °C and quenched with water (5.0 mL). The mixture was extracted with ethyl acetate (10.0 mL x 3), and the organic phase was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE:EA = 7:3) to give intermediate 9-2 (90.0 mg).

[0383] LCMS: m / z (ESI): 391.1 [M+H] +

[0384] Step 3: Synthesis of (R)-3-(1-(3-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4- fluorophenyl)-1-methyl-1H-pyrazol-4-yl)vinyl)-1-ethyl-1H-pyrrolo[2,3-b]pyridine (Intermediate 9-3)

[0385] Intermediate 9-2 (90.0 mg, 230.5 μmol) was dissolved in tetrahydrofuran (5.0 mL), sodium hydride (13.8 mg, 345.8 μmol, 60% active content) was added at 0 °C, stirred for 30 minutes, 5-bromo-3-fluoro-2-nitropyridine (91.3 mg, 414.9 μmol) was added, and then the reaction was moved to 25 °C for 1 hour. After the reaction was completed, water (5.0 mL) was added to quench the reaction, and then the reaction was extracted with ethyl acetate (10.0 mL x 3). The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 9:1) to give intermediate 9-3 (110.0 mg).

[0386] LCMS: m / z (ESI): 591.1 / 593.1 [M+H] +

[0387] Step 4: Synthesis of (R)-5-bromo-3-(l-(2-(4-(l-(l-ethyl-lH-pyrrolo[2,3-b]pyridin-3-yl)vinyl)-l- methyl-lH-pyrazol-3-yl)-5-fluorophenyl)ethoxy)pyridin-2-amine (Intermediate 9-4)

[0388] Intermediate 9-3 (110.0 mg, 186.0 μmol), iron powder (103.9 mg, 1.9 mmol), and ammonium chloride (104.2 mg, 1.9 mmol) were heated to 80 °C in a mixture solvent of ethanol (2.0 mL) / water (0.4 mL) and stirred for 1 hour. After the reaction was completed, the reaction was concentrated under reduced pressure, and the residue was purified by thin layer preparative chromatography (PE:EA = 3:1) to give intermediate 9-4 (77.0 mg).

[0389] LCMS: m / z (ESI): 561.1 / 563.1 [M+H] +

[0390] Step 5: Synthesis of compound 9

[0391] A mixture of intermediate 9-4 (77.0 mg, 137.2 μmol), palladium acetate (9.2 mg, 41.1 μmol), potassium tert-butoxide (58.0 mg, 411.4 μmol) and n-butyl bis(1-adamantyl)phosphine (29.5 mg, 82.3 μmol) was dissolved in t-AmOH (3.0 mL). The reaction was heated to 120 °C under an argon atmosphere and stirred for 16 h. Subsequently, the reaction was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (column: YMC TA-C18, 30*150 mm, 5 μm; mobile phase A: 7 mmol / L NH4HCO3 in water, mobile phase B: acetonitrile; flow rate: 30 mL / min; acetonitrile gradient 45-75% over 10-11 min) to give compound 9 (1.3 mg).

[0392] LCMS: m / z (ESI): 481.1 [M+H] +

[0393] 1 H NMR (400 MHz, DMSO-d6) δ 8.30 (dd, J = 4.7, 1.6 Hz, 1H), 7.93 (dd, J = 7.8, 1.5 Hz, 1H), 7.73 (dd, J = 10.4, 2.8 Hz, 1H), 7.61 (d, J = 1.7 Hz, 1H), 7.58 - 7.51 (m, 2H), 7.27 - 7.12 (m, 2H), 6.69 (s, 1H), 6.18 (s, 2H), 5.39 (d, J = 2.3 Hz, 1H), 5.16 (d, J = 6.5 Hz, 1H), 4.77 (d, J = 2.1 Hz, 1H), 4.39 - 4.26 (m, 2H), 3.82 (s, 3H), 1.61 (d, J = 6.2 Hz, 3H), 1.23 (t, J = 7.0 Hz, 3H).

[0394] Example 10: Synthesis of compound 10

[0395] Step 1: Synthesis of 3-ethyl-l-methyl-lH-pyrazol-5-amine (intermediate 10-2)

[0396] A mixture of compound 10-1 (5 g, 51.5 mmol), methyl hydrazine sulfate (11.13 g, 77.24 mmol), triethylamine (26.05 g, 257.45 mmol), ethanol (50 mL) was heated to 80 °C under argon atmosphere for 4 h. After that, the mixture was concentrated under reduced pressure to remove the solvent and purified by column chromatography (THF / PE, 0-100%) to give intermediate 10-2 (3.5 g).

[0397] LC-MS: m / z (ESI): 126.4 [M+H] +

[0398] Step 2: Synthesis of 3-bromo-N-(3-ethyl-l-methyl-lH-pyrazol-5-yl)-l-methyl- lH-pyrazol-4-amine (Intermediate 10-3)

[0399] A mixture of Intermediate 10-2 (625 mg, 5 mmol), 3-bromo-4-iodo-l-methyl- lH-pyrazole (4.3 g, 15 mmol), t-Bu Brettphos Pd G3 (426 mg, 0.5 mmol), sodium tert-butoxide (1.44 g, 15 mmol) and mesitylene (20 mL) was heated to 120 °C under argon atmosphere for 16 h. The mixture was then purified by column chromatography (THF / PE, 0-100%) to give Intermediate 10-3 (142 mg). o C for 16 h. The mixture was then purified by column chromatography (THF / PE, 0-100%) to give Intermediate 10-3 (142 mg).

[0400] LC-MS: m / z (ESI): 284.3 / 286.3 [M+H] +

[0401] Step 3: Synthesis of 3-bromo-N-(3-ethyl-l-methyl-lH-pyrazol-5-yl)-N,l- dimethyl-lH-pyrazol-4-amine (Intermediate 10-4)

[0402] A mixture of Intermediate 10-3 (142 mg, 0.5 mmol), methyl p-toluenesulfonate (465 mg, 2.5 mmol), cesium carbonate (488 mg, 1.5 mmol) and acetonitrile (5 mL) was heated to 45 °C under argon atmosphere for 2 h. The mixture was then concentrated under reduced pressure to remove the solvent and the residue was purified by column chromatography (THF / PE, 0-100%) to give Intermediate 10-4 (89 mg).

[0403] LC-MS: m / z (ESI): 284.3 / 286.3 [M+H] +

[0404] Step 4: Synthesis of (R)-l-(2-(4-((3-ethyl-l-methyl-lH-pyrazol-5-yl)(methyl)amino)- 1-methyl-lH-pyrazol-3-yl)-5-fluorophenyl)ethan-l-ol (Intermediate 10-5)

[0405] A mixture of Intermediate 10-4 (89 mg, 0.3 mmol), Intermediate 1-4 (148.6 mg, 895.43 μmol), P(t-Bu)3Pd (9.6 mg, 8.95 μmol) and potassium phosphate tribasic (K3P04) (1.44 g, 6.95 mmol) in dioxane (5 mL) was heated to 90 °C under argon atmosphere for 16 h. The mixture was then purified by column chromatography (THF / PE, 0-100%) to give Intermediate 10-5 (30 mg).

[0406] G2 (30.6 mg, 59.7 μmol), cesium carbonate (486 mg, 1.5 mmol), a mixture of 1,4-dioxane (8 mL) and water (1 mL) was heated to 110 °C for 2 h. The mixture was then concentrated under reduced pressure to remove the solvents, and the residue was purified by column chromatography (THF / PE, 0-100%) to give intermediate 10-5 (100 mg). o C for 2 h. The mixture was then concentrated under reduced pressure to remove the solvents, and the residue was purified by column chromatography (THF / PE, 0-100%) to give intermediate 10-5 (100 mg).

[0407] LC-MS: m / z (ESI): 358.5 [M+H] +

[0408] Step 5: Synthesis of (R)-3-(2-(l-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4- fluorophenyl)-N-(3-ethyl-l-methyl-lH-pyrazol-5-yl)-N,l-dimethyl-lH-pyrazol-4- amine (Intermediate 10-6)

[0409] To a mixture of intermediate 10-5 (100 mg, 280 μmol), 5-bromo-3-fluoro-2- nitropyridine (185 mg, 839 μmol) and toluene (1 mL) was added tert-butyllithium (2.2 M in THF, 0.25 mL, 0.55 mmol) at 0 °C under argon atmosphere, and the resulting mixture was allowed to warm to room temperature and stirred for 0.5 h. The mixture was then concentrated under reduced pressure to remove the solvents, and the residue was purified by column chromatography (THF / PE, 0-100%) to give intermediate 10-6 (97 mg).

[0410] LC-MS: m / z (ESI): 558.5 / 560.5 [M+H] +

[0411] Step 6: Synthesis of (R)-3-(2-(l-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4- fluorophenyl)-N-(3-ethyl-4-iodo-l-methyl-lH-pyrazol-5-yl)-N,l-dimethyl-lH-pyrazol-4- amine (Intermediate 10-7)

[0412] To a solution of intermediate 10-6 (77 mg, 138 μmol) in MeCN (2 mL) was added dropwise a solution of NIS (31 mg, 138 μmol) in MeCN (1 mL) at 0 °C under argon atmosphere, and the resulting mixture was stirred at 0 °C for 15 min. To the mixture was then added saturated aqueous sodium thiosulfate solution (0.2 mL), and the mixture was concentrated under reduced pressure to remove the solvents. The residue was purified by column chromatography (THF / PE, 0-100%) to give intermediate 10-7 (94 mg).

[0413] LC-MS: m / z (ESI): 684.2 / 686.2 [M+H]+

[0414] Step 7: Synthesis of (R)-3-(2-(l-((5-bromo-2-aminopyridin-3-yl)oxy)ethyl)-4- fluorophenyl)-N-(3-ethyl-4-iodo-l-methyl-lH-pyrazol-5-yl)-N,l-dimethyl-lH-pyrazol-4- amine (Intermediate 10-8)

[0415] A mixture of Intermediate 10-7 (94 mg, 138 μmol), iron powder (7.7 mg, 138 μmol), ammonium chloride (7.4 mg, 138 μmol), EtOH (1.5 mL) and water (0.5 mL) was heated to 80 °C under argon atmosphere and stirred for 1 h. The mixture was then directly purified by column chromatography (THF / PE, 0-100%) to give Intermediate 10-8 (88 mg).

[0416] LC-MS: m / z (ESI): 654.2 / 656.2 [M+H] +

[0417] Step 8: Synthesis of compound 10

[0418] A mixture of Intermediate 10-8 (60 mg, 92 μmol), Pd(OAc)2(4.12 mg, 18.34 μmol), catacXium A (13.15 mg, 36.68 μmol), B2pin2(70 mg, 275 μmol), CsF (41.8 mg, 275 μmol), MeOH (4 mL) and water (0.1 mL) was heated to 80 °C under argon atmosphere and stirred for 4 h. The mixture was then concentrated under reduced pressure to remove the solvent and purified by preparative liquid chromatography (column: waters Xbridge OBD 19*150mm*5μm; mobile phase: [A: water (with 0.0125% NH3), B: acetonitrile]; B%: 25%-60%, 10 min) to give compound 10 (0.3 mg).

[0419] LC-MS: m / z (ESI): 448.5 [M+H] +

[0420] Example 11: Synthesis of compound 11

[0421] Compound 9 (28.0 mg, 58.2 μmol), p-toluenesulfonylhydrazide (173.4 mg, 932.3 μmol), sodium acetate (28.7 mg, 349.6 μmol) were dissolved with dry DME (4.0 mL) at 25 °C, heated to 85 °C for 12 h. The reaction was cooled to room temperature, concentrated to dryness under reduced pressure, and the residue was purified by preparative liquid chromatography (column: YMC TA-C18, 30 x 150 mm, 5 μm; mobile phase A: 7 mmol / L ammonium bicarbonate in water, mobile phase B: acetonitrile; flow rate: 30 mL / min; acetonitrile ratio 45-75%, elution 10-11 min) to give compound 11 (1.7 mg).

[0422] LCMS: m / z (ESI): 483.2 [M+H]+

[0423] 1H NMR (400 MHz, Methanol-d4) δ 8.35-8.17 (m, 2H), 7.62-7.59 (m, 1H), 7.56-7.49 (m, 1H), 7.46-7.35 (m, 2H), 7.31-7.23 (m, 1H), 7.06 (m, 1H), 6.91 (d, J = 1.8 Hz, 1H), 5.61-5.50 (m, 1H), 4.88-4.84 (m, 1H), 4.42-4.21 (m, 2H), 3.84 (s, 3H), 1.78 (d, J = 6.2 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H), 0.85 (d, J = 7.7 Hz, 3H).

[0424] Example 12: Synthesis of compound 12

[0425] Step 1: Synthesis of 1-ethyl-4-nitro-3-(trifluoromethyl)-1H-pyrazole (Intermediate 12-2)

[0426] A mixture of compound 12-1 (500 mg, 2.76 mmol), iodoethane (430 mg, 2.76 mmol), potassium carbonate (572 mg, 4.14 mmol) in DMF (10 mL) was stirred at room temperature for 3 h under argon atmosphere. The mixture was then concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography (THF / PE, 0-100%) to give intermediate 12-2 (505 mg).

[0427] LC-MS: m / z (ESI): 210.1 [M+H] +

[0428] Step 2: Synthesis of 1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-amine (Intermediate 12-3)

[0429] A mixture of intermediate 12-2 (505 mg, 2.41 mmol), palladium on carbon (10%) (25 mg, 0.24 mmol), and methanol (5 mL) was stirred at room temperature under hydrogen atmosphere for 16 h. After filtration, the mixture was concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography (THF / PE, 0-100%) to give intermediate 12-3 (275 mg).

[0430] LC-MS: m / z (ESI): 180.1 [M+H] +

[0431] Step 3: Synthesis of 3-bromo-N-(l-ethyl-3-(trifluoromethyl)-lH-pyrazol-4-yl)-l- methyl-lH-pyrazol-4-amine (intermediate 12-4)

[0432] A mixture of intermediate 12-3 (255 mg, 1.42 mmol), 3-bromo-4-iodo-l-methyl- lH-pyrazole (1.23 g, 4.27 mmol), t-Bu Xphos Pd G3 (226 mg, 0.28 mmol), sodium tert- butoxide (410 mg, 4.27 mmol), and mesitylene (10 mL) was heated to 120 °C under argon atmosphere for 16 h. The mixture was then purified by column chromatography (THF / PE, 0-100%) to give intermediate 12-4 (100 mg).

[0433] LC-MS: m / z (ESI): 338.2 / 340.2 [M+H] +

[0434] Step 4: Synthesis of 3-bromo-N-(l-ethyl-3-(trifluoromethyl)-lH-pyrazol-4-yl)-N,l- dimethyl-lH-pyrazol-4-amine (intermediate 12-5)

[0435] A mixture of intermediate 12-4 (100 mg, 0.3 mmol), iodomethane (46 mg, 0.33 mmol), cesium carbonate (145 mg, 0.44 mmol), and acetonitrile (5 mL) was heated to 45 °C under argon atmosphere for 16 h. The mixture was then concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography (THF / PE, 0-100%) to give intermediate 12-5 (65 mg).

[0436] LC-MS: m / z (ESI): 352.2 / 354.2 [M+H] +

[0437] Step 5: Synthesis of (R)-1-(2-(4-((1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)(methyl)amino)-1- methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethan-1-ol (Intermediate 12-6)

[0438] A mixture of Intermediate 12-5 (200 mg, 0.57 mmol), Intermediate 1-4 (283 mg, 1.7 mmol), Pd(Amphos)2Cl2(80 mg, 0.11 mmol), potassium carbonate (235 mg, 1.7 mmol), 1,4-dioxane (10 mL) and water (0.5 mL) was heated to 110 °C for 3 h under argon atmosphere. The mixture was then concentrated under reduced pressure to remove the solvent and the residue was purified by column chromatography (THF / PE, 0-100%) to give Intermediate 12-6 (228 mg).

[0439] LC-MS: m / z (ESI): 412.4 [M+H] +

[0440] Step 6: Synthesis of (R)-3-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-N-(1- ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-N,1-dimethyl-1H-pyrazol-4-amine (Intermediate 12-7)

[0441] To a mixture of Intermediate 12-6 (208 mg, 505 μmol), 5-bromo-3-fluoro-2-nitropyridine (335 mg, 1.52 mmol) and toluene (1 mL) was added tert-butoxy lithium (2.2 M in THF, 0.46 mL, 1.01 mmol) at 0 °C under argon atmosphere and the resulting mixture was allowed to warm to room temperature for 0.5 h. The mixture was then concentrated under reduced pressure to remove the solvent and the residue was purified by column chromatography (THF / PE, 0-100%) to give Intermediate 12-7 (128 mg).

[0442] LC-MS: m / z (ESI): 612.4 / 614.4 [M+H] +

[0443] Step 7: Synthesis of (R)-5-bromo-3-(1-(2-(4-((1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)(methyl)amino)-1- methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethoxy)pyridin-2-amine (Intermediate 12-8)

[0444] A mixture of intermediate 12-7 (108 mg, 176 μmol), iron powder (79 mg, 1.41 mmol), ammonium chloride (47 mg, 881 μmol), EtOH (2.5 mL) and water (0.5 mL) was heated to 80 °C under argon atmosphere and stirred for 1 h. The mixture was then directly purified by column chromatography (THF / PE, 0-100%) to give intermediate 12-8 (84 mg).

[0445] LC-MS: m / z (ESI): 582.4 / 584.4 [M+H] +

[0446] Step 8: Synthesis of compound 12

[0447] A mixture of intermediate 12-8 (74 mg, 121 μmol), Pd(OAc)2(8 mg, 36 μmol), catacXium A (26 mg, 72 μmol), PivOK (34 mg, 242 μmol), t-AmOH (1 mL) was heated to 110 °C under argon atmosphere and stirred for 16 h. The mixture was then concentrated under reduced pressure to remove the solvent and purified by preparative liquid chromatography (column: waters Xbridge OBD 19*150mm*5μm; mobile phase: [A: water (0.0125% NH3), B: acetonitrile]; B%: 25%-60%, 10 min) to give compound 12 (7 mg).

[0448] LC-MS: m / z (ESI): 502.4 [M+H] +

[0449] 1 H NMR (400 MHz, DMSO-d6) δ 7.74 - 7.63 (m, 1H), 7.54 (d, J = 1.6 Hz, 1H), 7.48 (dd, J = 8.6, 6.0 Hz, 1H), 7.42 (s, 1H), 7.20 - 7.06 (m, 1H), 6.68 (s, 1H), 6.26 (s, 2H), 5.33 - 5.18 (m, 1H), 4.26 - 4.10 (m, 2H), 3.80 (s, 3H), 2.79 (s, 3H), 1.62 (d, J = 6.4 Hz, 3H), 1.32 (t, J = 7.2 Hz, 3H).

[0450] Example 13: Synthesis of compound 13

[0451] Step 1: Synthesis of 3-bromo-l-methyl-lH-pyrazole-4-carboxylic acid chloride (intermediate 13-2)

[0452] Intermediate 13-1 (2.0 g, 9.8 mmol) was dissolved in dichloromethane (10.0 mL), and the mixture was cooled to 0 °C. Oxalyl chloride (2.48 g, 19.5 mmol) was added dropwise. The mixture was stirred at 25 °C for 3 h. Then, the reaction was concentrated to dryness under reduced pressure to give crude intermediate 13-2, which was used directly in the next step without purification.

[0453] Step 2: Synthesis of (3-bromo-l-methyl-lH-pyrazol-4-yl)(lH-pyrrolo[2,3- c]pyridin-3-yl)methanone (Intermediate 13-3)

[0454] Intermediate 13-2 (2.2 g, 9.8 mmol) was dissolved in dichloromethane (10.0 mL), and aluminum chloride (3.9 g, 29.3 mmol) was added. The mixture was cooled to 0 °C under argon atmosphere, and a solution of 6-azaindole (1.27 g, 10.7 mmol) in dichloromethane (10.0 mL) was added dropwise. The resulting mixture was stirred at room temperature for 12 h. Then, the reaction was quenched with water (50.0 mL), and the pH was adjusted to 8.0 with 1 M HC1 solution. The mixture was extracted with dichloromethane (100 mL x 3), and the organic phases were combined and concentrated under reduced pressure to give intermediate 13-3 (520.0 mg).

[0455] LCMS: m / z (ESI): 305.0 / 307.0 [M+H] +

[0456] Step 3: Synthesis of (3-bromo-l-methyl-lH-pyrazol-4-yl)(l-ethyl-lH-pyrrolo[2,3- c]pyridin-3-yl)methanone (Intermediate 13-4)

[0457] Intermediate 13-3 (100.0 mg, 327.7 μmol) and iodoethane (102.3 mg, 655.5 μmol) were dissolved in DMF (2.0 mL), and the resulting solution was cooled to 0 °C. Sodium hydride (26.2 mg, 655.5 μmol, 60%) was added, and the mixture was stirred at 25 °C for 2 h. After the reaction was completed, ethyl acetate (50.0 mL) was added, and the mixture was washed twice with saturated brine. The organic phase was concentrated under reduced pressure to give intermediate 13-4 (54.4 mg).

[0458] LCMS: m / z (ESI): 333.0 / 335.0 [M+H] +

[0459] Step 4: Synthesis of (3-bromo-l-methyl-lH-pyrazol-4-yl)(l-ethyl-lH-pyrrolo[2,3- c]pyridin-3-yl)methanol (Intermediate 13-5)

[0460] Intermediate 13-4 (54.5 mg, 163.6 μmol) was dissolved in tetrahydrofuran (1.0 mL) and ethanol (1.0 mL), to the resulting solution was added sodium borohydride (18.6 mg, 490.7 μmol), then the resulting mixture was heated to 50 °C, and stirred at this temperature for 12 hours. Subsequently, the reaction was quenched with saturated aqueous ammonium chloride solution (15 mL), and dichloromethane was added to the mixture to extract (30 mL x 3), the organic phases were combined, concentrated under reduced pressure, and the residue was separated by preparative thin layer chromatography (dichloromethane:methanol = 10:1) to obtain intermediate 13-5 (20.0 mg).

[0461] LCMS: m / z (ESI): 335.0 / 337.0 [M+H] +

[0462] Step 5: Synthesis of 3-((3-bromo-l-methyl-lH-pyrazol-4-yl)methyl)-l-ethyl-lH- pyrrolo[2,3-c]pyridine (Intermediate 13-6)

[0463] Intermediate 13-5 (20 mg, 59.7 μmol) was dissolved in dichloromethane (2 mL), then triethylsilane (20.8 mg, 179.0 μmol) and trifluoroacetic acid (20.4 mg, 179.0 μmol) were added to the solution successively, and the resulting mixture was stirred at 25 °C for 1 hour. Subsequently, the reaction was quenched with saturated aqueous sodium bicarbonate solution, and dichloromethane was added to the mixture to extract (30 mL x 3), the organic phases were combined, concentrated under reduced pressure to obtain intermediate 13-6 (19.1 mg).

[0464] LCMS: m / z (ESI): 319.0 / 321.0 [M+H] +

[0465] Step 6: Synthesis of (R)-l-(2-(4-((l-ethyl-lH-pyrrolo[2,3-c]pyridin-3-yl)methyl)-l- methyl-lH-pyrazol-3-yl)-5-fluorophenyl)ethan-l-ol (Intermediate 13-7)

[0466] Intermediate 13-6 (19.1 mg, 59.7 μmol), intermediate 1-4 (39.6 mg, 238.7 μmol), tris(dibenzylideneacetone)dipalladium (5.5 mg, 6.0 μmol), tricyclohexylphosphine (3.4 mg, 11.9 μmol) and potassium fluoride (10.4 mg, 179.0 μmol) were dissolved in 1,4-dioxane (1.0 mL) and water (0.1 mL), the resulting mixture was heated to 110 °C under argon atmosphere and stirred at this temperature for 6 h. Then, the reaction was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer preparative chromatography (dichloromethane:methanol = 10:1) to give intermediate 13-7 (22.6 mg).

[0467] LCMS: m / z (ESI): 379.1 [M+H] +

[0468] Step 7: Synthesis of (R)-3-((3-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4- fluorophenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-1-ethyl-1H-pyrrolo[2,3-c]pyridine (intermediate 13-8)

[0469] Intermediate 13-7 (22.6 mg, 59.7 μmol) and 5-bromo-3-fluoro-2-nitropyridine (26.4 mg, 119.4 μmol) were dissolved in tetrahydrofuran (1.0 mL), the resulting mixture was cooled to 0 °C, then a solution of potassium tert-butoxide in tetrahydrofuran (1.0 mol / L, 180.0 μL) was added dropwise, the resulting reaction was allowed to warm to room temperature and stirred for 3 h. Then, the reaction was quenched with saturated aqueous ammonium chloride solution and extracted with dichloromethane (30 mL x 3), the organic phases were combined and concentrated under reduced pressure to give intermediate 13-8 (34.6 mg).

[0470] LCMS: m / z (ESI): 579.1 / 581.1 [M+H] +

[0471] Step 8: Synthesis of (R)-5-bromo-3-(1-(2-(4-((1-ethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)methyl)-1- methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethoxy)pyridin-2-amine (intermediate 13-9)

[0472] Intermediate 13-8 (34.6 mg, 59.7 μmol) was dissolved in ethanol (1.0 mL) and water (0.2 mL), then iron powder (33.4 mg, 597.2 μmol) and ammonium chloride (31.9 mg, 597.2 μmol) were added. The resulting mixture was heated to 80 °C and stirred at this temperature for 3 hours. Subsequently, the reaction solution was filtered, the filtrate was extracted with dichloromethane (30 mL x 3), the combined organic phase was concentrated under reduced pressure, and the residue was separated by thin layer preparative chromatography (dichloromethane:methanol = 5:1) to give intermediate 13-9 (20 mg).

[0473] LCMS: m / z (ESI): 549.1 / 551.1 [M+H] +

[0474] Step 9: Synthesis of compound 13

[0475] Intermediate 13-9 (20 mg, 36.4 μmol), palladium acetate (2.5 mg, 10.9 μmol), potassium tert- butoxide (15.3 mg, 109.2 μmol) and n-butyl bis(1-adamantyl)phosphine (7.8 mg, 21.8 μmol) were dissolved in t-AmOH (1.0 mL), the resulting mixture was heated to 120 °C under argon atmosphere and stirred at this temperature for 12 hours. Subsequently, the reaction solution was filtered, concentrated under reduced pressure and purified by preparative chromatography (column: YMC TA-C18, 30 x 150 mm, 5 μm; mobile phase A: 7 mmol / L ammonium bicarbonate, mobile phase B: acetonitrile; flow rate: 30 mL / min; acetonitrile ratio 95-60%, elution for 6 minutes) to give compound 13 (1.6 mg).

[0476] LCMS: m / z (ESI): 469.2 [M+H] +

[0477] 1 H NMR (400 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.24 (d, J = 5.4 Hz, 1H), 7.80-7.71 (m, 2H), 7.56 (d, J = 1.8 Hz, 1H), 7.39 (s, 1H), 7.23-7.14 (m, 2H), 6.47 (d, J = 1.9 Hz, 1H), 6.21 (s, 2H), 5.36-5.30 (m, 1H), 4.31-4.15 (m, 2H), 3.91 (d, J = 15.6 Hz, 1H), 3.80 (s, 3H), 2.91 (d, J = 15.5 Hz, 1H), 1.71 (d, J = 6.2 Hz, 3H), 1.23-1.18 (m, 3H).

[0478] Example 14: Synthesis of compound 14

[0479] Step 1: Synthesis of (3-bromo-l-methyl-lH-pyrazol-4-yl)(3-cyclopropoxy-l- ethyl-lH-pyrazol-4-yl)methanone (Intermediate 14-1)

[0480] Intermediate 5-6 (1.2 g, 3.4 mmol) was dissolved in dichloromethane (10.0 mL), manganese dioxide (3.0 g, 34.3 mmol) was added, and the resulting mixture was reacted at 40 °C for 12 hours. The reaction liquid was filtered, and the filtrate was concentrated under reduced pressure to obtain Intermediate 14-1 (1.0 g).

[0481] LCMS: m / z (ESI): 339.0 / 341.0 [M+H] +

[0482] Step 2: Synthesis of 3-bromo-4-(l-(3-cyclopropoxy-l-ethyl-lH-pyrazol-4-yl)vinyl)-l- methyl-lH-pyrazole (Intermediate 14-2)

[0483] Intermediate 14-1 (1.0 g, 3.0 mmol) was added to tetrahydrofuran (15.0 mL) under an argon atmosphere, and Tebbe reagent (9.2 mL, 0.5 M, 4.6 mmol) was added dropwise at 0 °C. After the addition was completed, the reaction was stirred at room temperature for 16 hours. Water (20.0 mL) was added for quenching, and extraction was performed with ethyl acetate (20.0 mL x 3). After the organic phase was concentrated under reduced pressure, the residue was purified by column chromatography (petroleum ether: ethyl acetate = 1: 1) to obtain Intermediate 14-2 (809.9 mg).

[0484] LCMS: m / z (ESI): 336.9 / 338.9 [M+H] +

[0485] Step 3: Synthesis of (R)-l-(2-(4-(l-(3-cyclopropoxy-l-ethyl-lH-pyrazol-4-yl)vinyl)-l- methyl-lH-pyrazol-3-yl)-5-fluorophenyl)ethan-l-ol (Intermediate 14-3)

[0486] Intermediate 14-2 (809.9 mg, 2.4 mmol), intermediate 1-4 (597.9 mg, 3.6 mmol), tris(dibenzylideneacetone)dipalladium (219.9 mg, 240.2 μmol), tricyclohexylphosphine (134.7 mg, 480.4 μmol) and potassium fluoride (418.6 mg, 7.2 mmol) were added into a mixed solvent of 1,4-dioxane (15.0 mL) and water (3.0 mL) under argon atmosphere, and the mixture was stirred at 100 °C for 2 h. The reaction was quenched by adding water (20.0 mL), and extracted with ethyl acetate (20.0 mL x 3). The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to give intermediate 14-3 (712.5 mg).

[0487] LCMS: m / z (ESI): 397.0 [M+H] +

[0488] Step 4: Synthesis of (R)-5-bromo-3-(1-(2-(4-(1-(3-cyclopropoxy-1-ethyl-1H-pyrazol-4-yl)vinyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine (intermediate 14-4)

[0489] Sodium hydride (86.3 mg, 2.2 mmol, 60%) was added into a solution of intermediate 14-3 (712.5 mg, 1.8 mmol) in tetrahydrofuran (10.0 mL) at 0 °C, and the mixture was stirred for 30 min. 5-bromo-3-fluoro-2-nitropyridine (476.6 mg, 2.2 mmol) was added, and the mixture was stirred at 25 °C for 12 h. The reaction was quenched by adding saturated aqueous ammonium chloride solution (10.0 mL), and extracted with ethyl acetate (10.0 mL x 3). The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to give intermediate 14-4 (912.3 mg).

[0490] LCMS: m / z (ESI): 596.9 / 598.9 [M+H] +

[0491] Step 5: Synthesis of (R)-5-bromo-3-(1-(2-(4-(1-(3-cyclopropoxy-1-ethyl-1H-pyrazol-4-yl)vinyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethoxy)pyridin-2-amine (intermediate 14-5)

[0492] Intermediate 14-4 (912.3 mg, 1.5 mmol) was dissolved in ethanol (15.0 mL) / water (3.0 mL) with anhydrous ammonium chloride (490.1 mg, 9.2 mmol), and iron powder (511.7 mg, 9.2 mmol) was added, and the resulting mixture was heated to 80 °C for 1 hour. The reaction was filtered, extracted with ethyl acetate (20.0 mL), and the organic phases were combined and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to give intermediate 14-5 (719.0 mg).

[0493] LCMS: m / z (ESI): 566.9 / 568.9 [M+H] +

[0494] Step 6: Synthesis of compound 14

[0495] Intermediate 14-5 (500.0 mg, 881.2 μmol), palladium acetate (39.6 mg, 176.3 μmol), n-butyl bis(1-adamantyl)phosphine (126.4 mg, 352.5 μmol), and potassium pivalate (494.2 mg, 3.5 mmol) were dissolved in t-AmOH (10.0 mL), and the reaction was stirred at 115 °C under an argon atmosphere for 6 hours. It was filtered, concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to give compound 14 (140.0 mg).

[0496] LCMS: m / z (ESI): 487.0 [M+H] +

[0497] 1 H NMR (400 MHz, DMSO-d6) δ 7.70-7.62 (m, 1H), 7.52 (s, 1H), 7.50-7.44 (m, 2H), 7.13 (m, 1H), 6.49-6.42 (m, 1H), 5.23 (d, J = 2.3 Hz, 1H), 5.16-5.08 (m, 1H), 4.69 (d, J = 2.2 Hz, 1H), 4.21-4.13 (m, 1H), 4.03-3.91 (m, 2H), 3.88 (s, 3H), 1.60 (d, J = 6.2 Hz, 3H), 1.28 (t, J = 7.2 Hz, 3H), 0.85-0.76 (m, 1H), 0.75-0.62 (m, 3H).

[0498] Example 15: Synthesis of compound 15

[0499] Compound 14 (95.0 mg, 195.3 μmol), sodium acetate (98.4 mg, 1.2 mmol) and p-toluenesulfonylhydrazide (577.3 mg, 3.1 mmol) were dissolved in DME (10.0 mL), the resulting mixture was heated to 85 °C and reacted for 12 hours. The reaction solution was filtered, and the filtrate was concentrated and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 15 (91.0 mg).

[0500] LCMS: m / z (ESI): 489.0 [M+H] +

[0501] Example 16: Synthesis of compound 16

[0502] Step 1: Synthesis of (3-bromo-l-methyl-lH-pyrazol-4-yl)(6-methyl-lH-pyrrolo[2,3- b]pyridin-3-yl)methanone (Intermediate 16-1)

[0503] Intermediate 3-1 (1.5 g, 7.3 mmol) was dissolved in dichloromethane (10.0 mL) at 25 °C, and oxalyl chloride (1.9 g, 14.6 mmol) and DMF (109.6 mg, 1.5 mmol) were added under argon atmosphere, and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, then dissolved in dichloromethane (10.0 mL), and aluminum chloride (2.9 g, 21.9 mmol) was added at 0 °C, and stirred for 10 minutes. A solution of 6-methyl-lH-pyrrolo[2,3-b]pyridine (867.7 mg, 6.6 mmol) in dichloromethane (5.0 mL) was added, and the reaction was reacted at 25 °C for 12 hours. The reaction solution was poured into water (20.0 mL), and the pH was adjusted to >7.0 with aqueous sodium bicarbonate solution, and extracted with ethyl acetate (30 mL x 3), and the organic phase was concentrated under reduced pressure to obtain intermediate 16-1 (2.0 g).

[0504] LCMS: m / z (ESI): 319.0 / 321.0 [M+H] +

[0505] Step 2: Synthesis of (3-bromo-l-methyl-lH-pyrazol-4-yl)(l-ethyl-6-methyl-lH-pyrrolo[2,3- b]pyridin-3-yl)methanone (Intermediate 16-2)

[0506] Intermediate 16-1 (2.0 g, 6.3 mmol) was dissolved in DMF (30.0 mL), NaH (300.8 mg, 7.5 mmol, 60% active content) and iodoethane (1.3 g, 8.2 mmol) were added, and the mixture was reacted at 25 °C for 1 h. Water (30.0 mL) was added for quenching, extracted with ethyl acetate (30 mL x 3), the organic phases were combined, concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to give intermediate 16-2 (1.7 g).

[0507] LCMS: m / z (ESI): 347.1 / 349.1 [M+H] +

[0508] Step 3: Synthesis of (3-bromo-l-methyl-lH-pyrazol-4-yl)(l-ethyl-6-methyl-lH- pyrrolo[2,3-b]pyridin-3-yl)methanol (Intermediate 16-3)

[0509] Intermediate 16-2 (400 mg, 1.2 mmol) was dissolved in tetrahydrofuran (10.0 mL), lithium borohydride (75.3 mg, 3.5 mmol) was added, and the mixture was reacted at 80 °C for 2 h. Saturated aqueous ammonium chloride solution (10.0 mL) was added for quenching, extracted with ethyl acetate (10 mL x 3), the organic phases were combined, concentrated under reduced pressure to give intermediate 16-3 (400.0 mg).

[0510] LCMS: m / z (ESI): 348.9 / 350.9 [M+H] +

[0511] Step 4: Synthesis of 3-((3-bromo-l-methyl-lH-pyrazol-4-yl)methyl)-l-ethyl-6- methyl-lH-pyrrolo[2,3-b]pyridine (Intermediate 16-4)

[0512] Intermediate 16-3 (400.0 mg, 1.1 mmol) was dissolved in dichloromethane (5.0 mL), trifluoroacetic acid (391.8 mg, 3.4 mmol) and triethylsilane (399.6 mg, 3.4 mmol) were added, and the mixture was stirred for 2 h. Saturated aqueous sodium bicarbonate solution (20.0 mL) was added for quenching, extracted with ethyl acetate (15 mL x 3), the organic phases were combined, concentrated to dryness under reduced pressure to give intermediate 16-4 (309.0 mg).

[0513] LCMS: m / z (ESI): 332.9 / 334.9 [M+H] +

[0514] Step 5: Synthesis of (R)-1-(2-(4-((1-ethyl-6-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-1- methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethan-1-ol (Intermediate 16-5)

[0515] Intermediate 16-4 (309.0 mg, 927.3 pmol), Intermediate 1-4 (230.8 mg, 1.4 mmol), tris(dibenzylideneacetone)dipalladium (84.9 mg, 92.7 pmol), tricyclohexylphosphine (52.0 mg, 185.5 pmol) and potassium fluoride (161.6 mg, 2.8 mmol) were added into a mixed solvent of 1,4-dioxane (10.0 mL) and water (2.0 mL) under argon atmosphere, and the reaction was carried out at 100 °C for 2 h. The reaction was cooled down to 25 °C and quenched by water (10.0 mL), and extracted with ethyl acetate (10.0 mL x 3). The organic phase was combined and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 1: 1) to give Intermediate 16-5 (286.4 mg).

[0516] LCMS: m / z (ESI): 393.0 [M+H] +

[0517] Step 6: Synthesis of (R)-3-((3-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1- methyl-1H-pyrazol-4-yl)methyl)-1-ethyl-6-methyl-1H-pyrrolo[2,3-b]pyridine (Intermediate 16-6)

[0518] Sodium hydride (35.0 mg, 875.7 pmol, 60% active content) was added to a solution of Intermediate 16-5 (286.4 mg, 729.7 pmol) in tetrahydrofuran (7.0 mL) at 0 °C, and the reaction was stirred for 30 min. 5-Bromo-3-fluoro-2-nitro-pyridine (193.5 mg, 875.7 pmol) was added, and the reaction was carried out at 25 °C for 12 h. The reaction was quenched by water (10.0 mL) and extracted with ethyl acetate (10.0 mL x 3). The organic phase was combined and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 1: 1) to give Intermediate 16-6 (403.8 mg).

[0519] LCMS: m / z (ESI): 592.9 / 594.9 [M+H] +

[0520] Step 7: Synthesis of (R)-5-bromo-3-(l-(2-(4-((l-ethyl-6-methyl-lH-pyrrolo[2,3- b]pyridin-3-yl)methyl)-l-methyl-lH-pyrazol-3-yl)-5-fluorophenyl)ethoxy)pyridin-2- amine (Intermediate 16-7)

[0521] Intermediate 16-6 (403.8 mg, 680.4 μmol) was dissolved in ethanol (6.0 mL) / water (1.2 mL) with anhydrous ammonium chloride (218.4 mg, 4.1 mmol), and iron powder (228.0 mg, 4.1 mmol) was added. The resulting mixture was heated to 80 °C for 1 h. The reaction was filtered, extracted with ethyl acetate (10.0 mL), and the organic phases were combined and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 1: 1) to give Intermediate 16-7 (356.2 mg).

[0522] LCMS: m / z (ESI): 562.9 / 564.9 [M+H] +

[0523] Step 8: Synthesis of Compound 16

[0524] Intermediate 16-7 (356.2 mg, 632.2 μmol), palladium acetate (28.4 mg, 126.4 μmol), n- butyldi(l-adamantyl)phosphine (90.7 mg, 252.9 μmol), and potassium pivalate (350.6 mg, 2.5 mmol) were dissolved in t-AmOH (8.0 mL), and the reaction was stirred at 120 °C under an argon atmosphere for 6 h. The reaction was filtered, and the filtrate was concentrated and purified by preparative liquid chromatography (column: YMC TA-C18, 30 x 150 mm, 5 μm; mobile phase A: 7 mmol / L NH4HCO3 in water, mobile phase B: acetonitrile; flow rate: 30 mL / min; acetonitrile ratio 48-78%, elution for 10 min) to give Compound 16 (10.1 mg).

[0525] LCMS: m / z (ESI): 483.0 [M+H] +

[0526] 1H NMR (400 MHz, DMSO-d6) δ 8.02 (d, J = 7.9 Hz, 1H), 7.78 - 7.70 (m, 1H), 7.56 (d, J = 1.8 Hz, 1H), 7.39 (s, 1H), 7.21 - 7.15 (m, 2H), 7.06 (d, J = 7.9 Hz, 1H), 6.47 (d, J = 1.8 Hz, 1H), 6.11 (s, 2H), 5.36 - 5.28 (m, 1H), 4.31 - 4.22 (m, 1H), 4.20 - 4.12 (m, 1H), 3.87 (d, J = 15.6 Hz, 1H), 3.79 (s, 3H), 2.91 (d, J = 15.5 Hz, 1H), 2.58 (s, 3H), 1.70 (d, J = 6.3 Hz, 3H), 1.12 (t, J = 7.1 Hz, 3H).

[0527] Example 17: Synthesis of compound 17

[0528] Step 1: Synthesis of tert-butyl 3-cyclopropoxy-lH-pyrazole-l-carboxylate (Intermediate 17-2)

[0529] Intermediate 17-1 (10.0 g, 54.3 mmol), PPh3 (21.4 g, 81.4 mmol), DBAD (18.8 g, 81.4 mmol) and cyclopropyl-l-ol (4.73 g, 81.4 mmol) were dissolved in toluene (120.0 mL) and the resulting mixture was stirred at 25 °C for 30 min under argon atmosphere, then heated to 110 °C for 12 h. Subsequently, the reaction was concentrated under reduced pressure and purified by column chromatography (THF / PE, 0-100%) to give Intermediate 17-2 (8.50 g).

[0530] LCMS: m / z (ESI): 169.0 [M+H- t Bu] +

[0531] Step 2: Synthesis of 3-cyclopropoxy-lH-pyrazole (Intermediate 17-3)

[0532] Intermediate 17-2 (8.5 g, 37.9 mmol) was dissolved in a mixture of DCM (100 mL) and TFA (20.0 mL) and the reaction was stirred at 25 °C for 1.5 h. The reaction was concentrated, the residue was dissolved in ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate solution (100 mL). The organic phase was concentrated to dryness under reduced pressure to give Intermediate 17-3 (4.50 g).

[0533] LCMS: m / z (ESI): 125.1 [M+H] +

[0534] Step 3: Synthesis of 3-cyclopropoxy-l-ethyl-lH-pyrazole (Intermediate 17-4)

[0535] Intermediate 17-3 (475.0 mg, 3.8 mmol) was dissolved in DMF (5.0 mL), cesium carbonate (1.9 g, 5.7 mmol) and iodoethane (3.0 g, 19.1 mmol) were added, and the mixture was reacted at 25 °C for 3 h. Subsequently, water (10.0 mL) was added to quench, and extraction was performed with ethyl acetate (20 mL x 3). After the organic phase was concentrated under reduced pressure, column chromatography purification (THF / PE, 0-100%) was performed to obtain intermediate 17-4 (260 mg).

[0536] LCMS: m / z (ESI): 153.1 [M+H] +

[0537] Step 4: Synthesis of 3-cyclopropoxy-l-ethyl-lH-pyrazole-4-carbaldehyde (Intermediate 17-5)

[0538] Phosphorus oxychloride (1.0 g, 6.6 mmol) was added to DMF (7.0 mL) at 0 °C, and the mixture was reacted at 25 °C for 1 h. Intermediate 17-4 (250.0 mg, 1.6 mmol) was added, and the temperature was increased to 70 °C for reaction for 12 h. Subsequently, water (10.0 mL) was added to quench, and extraction was performed with ethyl acetate (20 mL x 3). After the organic phase was concentrated under reduced pressure, column chromatography purification (THF / PE, 0-100%) was performed to obtain intermediate 17-5 (93.0 mg).

[0539] LCMS: m / z (ESI): 181.1 [M+H] +

[0540] Step 5: Synthesis of (4-bromo-2-methylthiazol-5-yl)(3-cyclopropoxy-l-ethyl-lH-pyrazol-4-yl)methanol (Intermediate 17-6)

[0541] Under an argon atmosphere, 4-bromo-2-methylthiazole (513 mg, 2.89 mmol) was added to tetrahydrofuran (5 mL), and LDA (231 mg, 2.16 mmol) was added at -78 °C. The mixture was reacted at -78 °C for 1 h. Intermediate 17-5 (260 mg, 1.44 mmol) was dissolved in 1 mL of tetrahydrofuran, and the solution was slowly added to the reaction solution at -78 °C for reaction for 1 h. Water (0.5 mL) was added to quench the reaction solution, and column chromatography purification (THF / PE, 0-100%) was directly performed to obtain intermediate 17-6 (228 mg).

[0542] LC-MS: m / z (ESI): 358.1 [M+H] +

[0543] Step 6: Synthesis of (4-bromo-2-methylthiazol-5-yl)(3-cyclopropoxy-l- ethyl-lH-pyrazol-4-yl)methanone (Intermediate 17-7)

[0544] Under argon atmosphere, Intermediate 17-6 (140 mg, 390 μmol), manganese dioxide (509 mg, 5.86 mmol) were added into dichloromethane (5 mL) and reacted at 45 °C for 16 h. After that, the reaction was filtered under reduced pressure and concentrated, then purified by column chromatography (THF / PE, 0-100%) to give Intermediate 17-7 (114 mg).

[0545] LC-MS: m / z (ESI): 356.2 [M+H] +

[0546] Step 7: Synthesis of 4-bromo-5-(l-(3-cyclopropoxy-l-ethyl-lH-pyrazol-4- yl)vinyl)-2-methylthiazole (Intermediate 17-8)

[0547] Under argon atmosphere, Intermediate 17-7 (108 mg, 303 μmol) was added into tetrahydrofuran (0.5 mL) and Tebbe reagent (143 mg, 505 μmol) was added dropwise at 0 °C, then the reaction was allowed to warm to room temperature and reacted for 16 h. The reaction was directly purified by column chromatography (THF / PE, 0-100%) to give Intermediate 17-8 (50 mg).

[0548] LC-MS: m / z (ESI): 354.3 [M+H] +

[0549] Step 8: Synthesis of (R)-l-(2-(5-(l-(3-cyclopropoxy-l-ethyl-lH-pyrazol-4- yl)vinyl)-2-methylthiazol-4-yl)-5-fluorophenyl)ethanol-l-ol (Intermediate 17-9)

[0550] Under argon atmosphere, Intermediate 17-8 (40 mg, 113 μmol), Intermediate 1-4 (56 mg, 339 μmol), Pd(Amphos)2Cl2(8.0 mg, 11.3 μmol), potassium carbonate (47 mg, 338 μmol), a mixture of 1,4-dioxane (1 mL) and water (0.1 mL) were heated to 110 °C and reacted for 3 h. After that, the mixture was concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography (THF / PE, 0-100%) to give Intermediate 17-9 (44 mg).

[0551] LC-MS: m / z (ESI): 414.2 [M+H] +

[0552] Step 9: Synthesis of (R)-4-(2-(l-(5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4- fluorophenyl)-5-(l-(3-cyclopropoxy-l-ethyl-lH-pyrazol-4-yl)vinyl)-2- methylthiazole (Intermediate 17-10)

[0553] To a mixture of Intermediate 17-9 (64 mg, 155 μmol), 5-bromo-3-fluoro-2- nitropyridine (102 mg, 464 μmol) and toluene (1 mL) was added tert-butyllithium (2.2 M in THF, 0.14 mL, 309 μmol) at 0 °C under argon atmosphere. The resulting mixture was allowed to warm to room temperature and stirred for 0.5 h. The mixture was then concentrated under reduced pressure to remove the solvent and the residue was purified by column chromatography (THF / PE, 0-100%) to give Intermediate 17-10 (72 mg).

[0554] LC-MS: m / z (ESI): 614.5 [M+H] +

[0555] Step 10: Synthesis of (R)-5-bromo-3-(l-(2-(5-(l-(3-cyclopropoxy-l-ethyl-lH- pyrazol-4-yl)vinyl)-2-methylthiazol-4-yl)-5-fluorophenyl)ethoxy)pyridin-2- amine (Intermediate 17-11)

[0556] A mixture of Intermediate 17-10 (72 mg, 117 μmol), iron powder (33 mg, 586 μmol), ammonium chloride (33 mg, 586 μmol), EtOH (2.5 mL) and water (0.5 mL) was heated to 80 °C under argon atmosphere and stirred for 1 h. The mixture was then directly purified by column chromatography (THF / PE, 0-100%) to give Intermediate 17-11 (52 mg).

[0557] LC-MS: m / z (ESI): 584.5 [M+H] +

[0558] Step 11: Synthesis of Compound 17

[0559] A mixture of intermediate 17-11 (52 mg, 89 μmol), Pd(OAc)2(6 mg, 27 μmol), catacXium A (19 mg, 53 μmol), potassium pivalate (25 mg, 178 μmol) and tert-amyl alcohol (1 mL) was heated to 110 °C under an argon atmosphere and stirred for 16 h. The mixture was then concentrated under reduced pressure to remove the solvent and purified by preparative liquid chromatography (column: waters Xbridge OBD 19*150mm*5μm; mobile phase: [A: water (with 0.0125% NH3), B: acetonitrile]; B%: 25%-60%, 10 min) to give compound 17 (10.1 mg).

[0560] LC-MS: m / z (ESI): 504.3 [M+H] +

[0561] 1 H NMR (400 MHz, DMSO-d6) δ 7.67 (dd, J = 10.4, 2.8 Hz, 1H), 7.52 (dd, J = 8.4, 6.0 Hz, 1H), 7.47 (d, J = 1.6 Hz, 1H), 7.12 (td, J = 8.4, 2.8 Hz, 1H), 6.37 (d, J = 1.6 Hz, 1H), 6.18 (s, 1H), 5.64 (d, J = 1.6 Hz, 1H), 4.98 (dd, J = 6.0, 3.6 Hz, 2H), 4.23 - 4.13 (m, 1H), 3.96 (dt, J = 13.6, 6.8 Hz, 2H), 2.64 (s, 3H), 1.61 (d, J = 6.0 Hz, 3H), 1.28 (t, J = 7.2 Hz, 3H), 1.23 (s, 1H), 0.72 (d, J = 5.6 Hz, 4H).

[0562] Example 18: Synthesis of compound 18

[0563] Step 1: Synthesis of 3-(3,3-difluorocyclobutoxy)-1-ethyl-1H-pyrazole (intermediate 18-2)

[0564] Intermediate 18-1 (2.9 g, 25.9 mmol), triphenylphosphine (20.3 g, 77.6 mmol) and 3,3-difluorocyclobutanol (5.0 g, 46.6 mmol) were dissolved in xylene (40.0 mL), the reaction was placed at 0 °C, and then diisopropyl azodicarboxylate (15.7 g, 77.6 mmol) was added dropwise into the reaction, after the addition was completed, it was heated to 110 °C for 12 hours. After the reaction was completed, the reaction was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 4:1) to give intermediate 18-2 (0.98 g).

[0565] LCMS: m / z (ESI): 203.2 [M+H] +

[0566] Step 2: Synthesis of 3-(3,3-difluorocyclobutoxy)-1-ethyl-1H-pyrazole-4-carbaldehyde (Intermediate 18-3)

[0567] Phosphorus oxychloride (3.6 g, 23.7 mmol) was added to DMF (1.74 g, 23.7 mmol) at 0 °C, and reacted at 25 °C for 30 minutes, then a DMF solution (1.0 mL) of intermediate 18-2 (960.0 mg, 4.8 mmol) was added, and the temperature was raised to 70 °C for 12 hours. After the reaction was completed, it was quenched with an aqueous sodium hydroxide solution (10.0 mL, 3M), extracted with ethyl acetate (20 mL x 3), and the organic phase was concentrated under reduced pressure and then purified by column chromatography (petroleum ether: ethyl acetate = 4:1) to give intermediate 18-3 (0.38 g).

[0568] LCMS: m / z (ESI): 231.2 [M+H] +

[0569] Step 3: Synthesis of (3-bromo-1-methyl-1H-pyrazol-4-yl)(3-(3,3-difluorocyclobutoxy)-1- ethyl-1H-pyrazol-4-yl)methanol (Intermediate 18-4)

[0570] Isopropylmagnesium bromide (1.7 mL, 1M, 1.7 mmol) was added to a solution of 3-bromo-4-iodo-1-methyl-1H-pyrazole (436.0 mg, 1.5 mmol) in tetrahydrofuran (10.0 mL) at 0 °C, and the reaction was stirred for 1 hour, then intermediate 18-3 (350.0 mg, 1.5 mmol) was added, and the temperature was slowly raised to 25 °C for 2 hours. After the reaction was completed, it was quenched with water (5.0 mL), extracted with ethyl acetate (10.0 mL x 3), and the organic phase was concentrated under reduced pressure and then purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to give intermediate 18-4 (380.0 mg).

[0571] LCMS: m / z (ESI): 391.2 / 393.2 [M+H] +

[0572] Step 4: Synthesis of (3-bromo-l-methyl-lH-pyrazol-4-yl)(3-(3,3- difluorocyclobutoxy)-l-ethyl-lH-pyrazol-4-yl)methanone (Intermediate 18-5)

[0573] Intermediate 18-4 (0.38 g, 971.3 μmol) was dissolved in dichloromethane (20.0 mL), manganese dioxide (0.84 g, 9.7 mmol) was added, and the resulting mixture was reacted at 25 °C for 2 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain Intermediate 18-5 (317.0 mg).

[0574] LCMS: m / z (ESI): 389.2 / 391.2 [M+H] +

[0575] Step 5: Synthesis of 3-bromo-4-(l-(3-(3,3-difluorocyclobutoxy)-l-ethyl-lH- pyrazol-4-yl)vinyl)-l-methyl-lH-pyrazole (Intermediate 18-6)

[0576] Intermediate 18-5 (317.0 mg, 814.5 μmol) was added to tetrahydrofuran (0.5 mL) under an argon atmosphere, and Tebbe reagent (2.4 mL, 0.5 M, 1.2 mmol) was added dropwise at 0 °C. After the addition was completed, the reaction solution was allowed to warm to room temperature and was stirred for 16 hours. Subsequently, the reaction solution was poured into an aqueous sodium hydroxide solution (10.0 mL, 3 M) and stirred well, and extracted with ethyl acetate (10.0 mL x 3). The combined organic phase was washed with saturated brine, and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1: 1) to obtain Intermediate 18-6 (210.0 mg).

[0577] LCMS: m / z (ESI): 387.2 / 389.2 [M+H] +

[0578] Step 6: Synthesis of (R)-l-(2-(4-(l-(3-(3,3-difluorocyclobutoxy)-l-ethyl-lH- pyrazol-4-yl)vinyl)-l-methyl-lH-pyrazol-3-yl)-5-fluorophenyl)ethan-l-ol (Intermediate 18-7)

[0579] Intermediate 18-6 (200.0 mg, 516.5 μmol), intermediate 1-4 (154.3 mg, 929.7 μmol), tris(dibenzylideneacetone)dipalladium (47.3 mg, 51.7 μmol), tricyclohexylphosphine (28.9 mg, 103.3 μmol) and potassium fluoride (90.0 mg, 1.6 mmol) were added into a mixed solvent of 1,4-dioxane (10.0 mL) and water (5.0 mL) and reacted at 100 °C for 12 h. The reaction was cooled to 25 °C and quenched with water (5.0 mL), and extracted with ethyl acetate (10.0 mL x 3). The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:2) to give intermediate 18-7 (187.0 mg).

[0580] LCMS: m / z (ESI): 447.1 [M+H] +

[0581] Step 7: Synthesis of (R)-5-bromo-3-(1-(2-(4-(1-(3-(3,3-difluorocyclobutyloxy)-1- ethyl-1H-pyrazol-4-yl)vinyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethoxy)-2- nitropyridine (intermediate 18-8)

[0582] Intermediate 18-7 (87.0 mg, 194.9 μmol) was dissolved in tetrahydrofuran (5.0 mL), and sodium hydride (17.5 mg, 729 μmol, 60%) was added at 0 °C. After stirring for 30 min, 5-bromo-3-fluoro-2-nitropyridine (77.5 mg, 350.8 μmol) was added, and the mixture was stirred at 25 °C for 12 h. After the reaction was completed, the mixture was quenched with water (5.0 mL) and extracted with ethyl acetate (10.0 mL x 3). The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:2) to give intermediate 18-8 (67.0 mg).

[0583] LCMS: m / z (ESI): 647.1 / 649.1 [M+H] +

[0584] Step 8: Synthesis of (R)-5-bromo-3-(1-(2-(4-(1-(3-(3,3-difluorocyclobutyloxy)-1- ethyl-1H-pyrazol-4-yl)vinyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethoxy)pyridin-2- amine (intermediate 18-9)

[0585] Intermediate 18-8 (67.0 mg, 103.5 μmol), iron powder (57.8 mg, 1.0 mmol) and ammonium chloride (58.0 mg, 1.0 mmol) were stirred in a mixture solvent of ethanol (5.0 mL) and water (1.0 mL) at 80 °C for 1 h. After the reaction was completed, the reaction solution was filtered, extracted with ethyl acetate (5.0 mL x 3) and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:2) to give intermediate 18-9 (54.0 mg).

[0586] LCMS: m / z (ESI): 617.2 / 619.2 [M+H] +

[0587] Step 9: Synthesis of compound 18

[0588] Intermediate 18-9 (54.0 mg, 87.5 μmol), palladium acetate (5.9 mg, 26.2 μmol), n- butyldi(1-adamantyl)phosphine (18.8 mg, 52.5 μmol) and potassium pivalate (37.0 mg, 0.26 mmol) were dissolved in t-AmOH (2.0 mL). The reaction solution was heated to 125 °C under argon atmosphere and stirred for 6 h. Subsequently, the reaction solution was filtered, the filtrate was concentrated under reduced pressure and the residue was purified by preparative liquid chromatography (column: YMC TA-C18, 30 x 150 mm, 5 μm; mobile phase A: 7 mmol / L NH4HCO3 in water, mobile phase B: acetonitrile; flow rate: 30 mL / min; acetonitrile ratio 48-78%, elution 10 min) to give compound 18 (18.0 mg).

[0589] LCMS: m / z (ESI): 537.2 [M+H] +

[0590] 1 H NMR (400 MHz, DMSO-d6) δ 7.68-7.65 (m, 1H), 7.60 (s, 1H), 7.52-7.41 (m, 2H), 7.16-7.11 (m, 1H), 6.43 (d, J = 1.9 Hz, 1H), 6.14 (s, 2H), 5.26 (d, J = 2.2 Hz, 1H), 5.14-5.06 (m, 1H), 5.02-4.94 (m, 1H), 4.73 (d, J = 2.1 Hz, 1H), 3.98-3.89 (m, 2H), 3.88 (s, 3H), 3.18-3.07 (m, 2H), 2.91-2.84 (m, 1H), 2.78-2.64 (m, 1H), 1.59 (d, J = 6.2 Hz, 3H), 1.27 (t, J = 7.1 Hz, 3H).

[0591] Example 19: Synthesis of compound 19

[0592] Step 1: Synthesis of 3-bromo-l-ethyl-lH-pyrazole (Intermediate 19-2)

[0593] Intermediate 19-1 (25.0 g, 170 mmol), iodoethane (29.2 g, 187 mmol) and cesium carbonate (61.0 g, 187 mmol) were dissolved in acetonitrile (100 mL), the mixture was stirred at 25 °C for 5 h under argon atmosphere, the filtrate was concentrated after filtration, the residue was purified by column chromatography (THF / PE, 0-25%) to give intermediate 19-2 (29.0 g).

[0594] LCMS: m / z (ESI): 175.0 [M+H] +

[0595] Step 2: Synthesis of benzyl 4-(l-ethyl-lH-pyrazol-3-yl)piperazine-l-carboxylate (Intermediate 19-3)

[0596] Intermediate 19-2 (29.0 g, 166 mmol), benzyl piperazine-l-carboxylate (43.8 g, 199 mmol), Pd2(dba)3 (7.59 g, 8.28 mmol), RuPhos (7.73 g, 16.6 mmol) and tBuONa (31.9 g, 331 mmol) were dissolved in 1,4-dioxane (300 mL), the reaction was carried out at 110 °C for 16 h, water (300 mL) was added, then extracted with ethyl acetate (200 mL x 3), the organic phase was concentrated under reduced pressure, the residue was purified by column chromatography (THF / PE, 0-30%) to give intermediate 19-3 (17.3 g).

[0597] LCMS: m / z (ESI): 315.2 [M+H] +

[0598] Step 3: Synthesis of benzyl 4-(l-ethyl-4-formyl-lH-pyrazol-3-yl)piperazine-l- carboxylate (Intermediate 19-4)

[0599] Phosphorus oxychloride (6.34 g, 41 mmol) was added dropwise into DMF (3.2 mL) at 0 °C, then the reaction was stirred at room temperature for 1 h, intermediate 19-3 (6.5 g, 20.7 mmol) was added, the mixture was reacted at 25 °C for 1 h. Then, aqueous sodium bicarbonate solution (30.0 mL) was added to quench, extracted with ethyl acetate (20 mL x 3), the organic phase was concentrated under reduced pressure and purified by column chromatography (THF / PE, 0-70%) to give intermediate 19-4 (3.9 g).

[0600] LCMS: m / z (ESI): 343.1 [M+H] +

[0601] Step 4: Synthesis of benzyl 4-(4-((3-bromo-l-methyl-lH-pyrazol-4-yl)(hydroxy)methyl)-l- ethyl-lH-pyrazol-3-yl)piperazine-l-carboxylate (Intermediate 19-5)

[0602] Isopropyl magnesium chloride (13.1 mL, 1.3 M, 17.9 mmol) was added to a solution of 3-bromo-4-iodo-l-methyl-lH-pyrazole (4.9 g, 17.1 mmol) in tetrahydrofuran (50.0 mL) at 0 °C, stirred for 1 h, then intermediate 19-4 (3.9 g, 11.4 mmol) was added, slowly warmed to 25 °C for 2 h. Then quenched with water (20 mL), extracted with ethyl acetate (50 mL x 3), the organic phase was concentrated under reduced pressure and purified by column chromatography (THF / PE, 0-78%) to give intermediate 19-5 (5.4 g).

[0603] LCMS: m / z (ESI): 503.4 [M+H] +

[0604] Step 5: Synthesis of benzyl 4-(4-(3-bromo-l-methyl-lH-pyrazole-4-carbonyl)-l-ethyl- lH-pyrazol-3-yl)piperazine-l-carboxylate (Intermediate 19-6)

[0605] Under argon atmosphere, intermediate 19-5 (5.4 g, 10.7 mmol), PCC (3.01 g, 14.0 mmol) were added to dichloromethane (80 mL), stirred at room temperature for 8 h. Then the reaction was filtered under reduced pressure, concentrated and purified by column chromatography (THF / DCM, 0-37%) to give intermediate 19-6 (3.0 g).

[0606] LC-MS: m / z (ESI): 501.4 [M+H] +

[0607] Step 6: Synthesis of benzyl 4-(4-(l-(3-bromo-l-methyl-lH-pyrazol-4-yl)vinyl)-l-ethyl- lH-pyrazol-3-yl)piperazine-l-carboxylate (Intermediate 19-7)

[0608] Under argon atmosphere, intermediate 19-6 (1.4 g, 2.79 mmol) was added to tetrahydrofuran (2 mL), Tebbe reagent (1.59 g, 5.58 mmol) was added dropwise at 0 °C, stirred at this temperature for 1 h, then the reaction was filtered under reduced pressure, concentrated and purified by column chromatography (THF / PE, 0-60%) to give intermediate 19-7 (528 mg).

[0609] LC-MS: m / z (ESI): 499.4 [M+H] +

[0610] Step 7: Synthesis of (R)-benzyl 4-(l-ethyl-4-(l-(3-(4-fluoro-2-(l- hydroxyethyl)phenyl)-l-methyl-lH-pyrazol-4-yl)vinyl)-lH-pyrazol-3-yl)piperazine-l- carboxylate (Intermediate 19-8)

[0611] A mixture of Intermediate 19-7 (56.4 mg, 113 μmol), Intermediate 1-4 (56 mg, 339 μmol), Pd(Amphos)2Cl2(8.0 mg, 11.3 μmol), potassium carbonate (47 mg, 338 μmol), 1,4-dioxane (1 mL) and water (0.1 mL) was heated to 110 °C under argon atmosphere for 3 h. The mixture was then concentrated under reduced pressure to remove the solvents and the residue was purified by column chromatography (THF / PE, 0-100%) to give Intermediate 19-8 (44 mg).

[0612] LC-MS: m / z (ESI): 559.6 [M+H] +

[0613] Step 8: Synthesis of (R)-benzyl 4-(4-(l-(3-(2-(l-((5-bromo-2-nitropyridin-3- yl)oxy)ethyl)-4-fluorophenyl)-l-methyl-lH-pyrazol-4-yl)vinyl)-l-ethyl-lH-pyrazol-3- yl)piperazine-l-carboxylate (Intermediate 19-9)

[0614] To a mixture of Intermediate 19-8 (578 mg, 1.03 mmol), 5-bromo-3-fluoro-2- nitropyridine (686 mg, 3.10 mmol) and toluene (10 mL) was added tert-butoxy lithium (2.2 M in THF, 0.94 mL, 2.07 mmol) at 0 °C under argon atmosphere and the resulting mixture was allowed to warm to room temperature for 0.5 h. The mixture was then concentrated under reduced pressure to remove the solvents and the residue was purified by column chromatography (THF / PE, 0-60%) to give Intermediate 19-9 (778 mg).

[0615] LC-MS: m / z (ESI): 759.6 [M+H] +

[0616] Step 9: Synthesis of (R)-benzyl 4-(4-(l-(3-(2-(l-((2-amino-5-bromopyridin-3- yl)oxy)ethyl)-4-fluorophenyl)-lH-pyrazol-4-yl)vinyl)-lH-pyrazol-3-yl)piperazin- 1 - ylate (Intermediate 19-10)

[0617] A mixture of Intermediate 19-9 (995 mg, 1.31 mmol), iron powder (366 mg, 6.56 mmol), ammonium chloride (351 mg, 6.56 mmol), EtOH (10.0 mL) and water (2.0 mL) was heated to 80 °C under argon and stirred for 1 h. The mixture was then purified directly by column chromatography (THF / PE, 0-46%) to give Intermediate 19-10 (600 mg).

[0618] LC-MS: m / z (ESI): 729.6 [M+H] +

[0619] Step 10: Synthesis of Intermediate 19-11

[0620] A mixture of Intermediate 19-10 (335 mg, 459 pmol), Pd(OAc)2(41 mg, 183 pmol), catacXium A (132 mg, 367 pmol), potassium pivalate (193 mg, 1.38 mmol) and tert- amyl alcohol (16.7 mL) was heated to 150 °C under microwave for 1 h. The mixture was then purified directly by column chromatography (THF / PE, 0-60%) to give Intermediate 19-11 (244 mg).

[0621] LC-MS: m / z (ESI): 649.7 [M+H] +

[0622] Step 11: Synthesis of Intermediate 19-12

[0623] A mixture of Intermediate 19-11 (189 mg, 291.4 pmol) was added to TFA (1 mL) and the reaction was heated to 50 °C and stirred for 5 h. The mixture was then purified directly by column chromatography (THF / PE, 0-100%) to give Intermediate 19-12 (64 mg).

[0624] LC-MS: m / z (ESI): 515.6 [M+H] +

[0625] Step 12: Synthesis of Compound 19

[0626] A mixture of intermediate 19-12 (40 mg, 77 μmol), paraformaldehyde (15 mg), sodium cyanoborohydride (6.8 mg, 108 μmol), dichloromethane (1 mL) was heated to 50 °C and stirred for 5 h under argon atmosphere. The mixture was then concentrated under reduced pressure to remove the solvent and purified by preparative liquid chromatography (column: waters Xbridge OBD 19*150mm*5μm; mobile phase: [A: water (0.0125% NH3), B: acetonitrile]; B%: 25%-60%, 10 min) to give compound 19 (15.1 mg).

[0627] LC-MS: m / z (ESI): 529.5 [M+H] +

[0628] 1 H NMR (400 MHz, DMSO-d6) δ 7.74 (s, 1H), 7.68 (dd, J = 10.4, 2.8 Hz, 1H), 7.49 (dd, J = 8.4, 5.6 Hz, 1H), 7.40 (d, J = 1.6 Hz, 1H), 7.16 - 7.06 (m, 1H), 6.43 (d, J = 1.6 Hz, 1H), 6.06 (s, 2H), 5.15 (d, J = 2.4 Hz, 1H), 5.12 - 5.08 (m, 1H), 4.63 (d, J = 2.4 Hz, 1H), 3.95 - 3.85 (m, 5H), 3.27 - 3.15 (m, 4H), 2.45 - 2.42 (m, 4H), 2.22 (s, 3H), 1.57 (d, J = 6.4 Hz, 3H), 1.24 (t, 3H).

[0629] Example 20: Synthesis of compound 20

[0630] Step 1: Synthesis of (3-bromo-l-ethyl-lH-pyrazol-4-yl)(3-iodo-l-methyl-lH- pyrazol-4-yl)methanone (intermediate 20-2)

[0631] Intermediate 20-1 (0.86 g, 2.1 mmol) was dissolved in DCM (40 mL) and activated manganese dioxide (5 g, 57 mmol) was added. The reaction was stirred at room temperature for 2 h. After the solvent was removed by concentration under reduced pressure, the residue was purified by column chromatography to give intermediate 20-2 (0.85 g).

[0632] MS m / z (ESI): 409.0 / 411.0 [M+H] +

[0633] Step 2: Synthesis of 3-bromo-l-ethyl-4-(l-(3-iodo-l-methyl-lH-pyrazol-4- yl)vinyl)-lH-pyrazole (Intermediate 20-3)

[0634] To Intermediate 20-2 (0.75 g, 1.8 mmol) was added Tebbe reagent (0.5 M in toluene, 6 mL) at room temperature under argon atmosphere. The reaction was stirred at room temperature overnight. The mixture was poured into 1 M NaOH solution (40 mL), extracted with ethyl acetate (30 mL x 3), the organic phases were combined and concentrated under reduced pressure. The residue was purified by column chromatography (0-50% THF / DCM) to give Intermediate 20-3 (356 mg).

[0635] MS m / z (ESI): 407.1 / 409.1 [M+H] +

[0636] Step 3: Synthesis of (R)-l-(2-(4-(l-(3-bromo-l-ethyl-lH-pyrazol-4-yl)vinyl)-l- methyl-lH-pyrazol-3-yl)-5-fluorophenyl)ethan-l-ol (Intermediate 20-4)

[0637] A mixture of Intermediate 20-3 (280 mg, 688 μmol), potassium phosphate (438 mg, 2.06 mmol), Pd(Amphos)2Cl2(14.6 mg, 20.6 μmol), Intermediate 1-4 (171 mg, 1.03 mmol), MTBE (2 mL) and water (2 mL) was reacted at 65 °C for 3 h under argon atmosphere. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (0-90% tetrahydrofuran / petroleum ether) to give Intermediate 20-4 (219 mg).

[0638] MS m / z (ESI): 419.3 / 421.3 [M+H] +

[0639] Step 4: Synthesis of (R)-5-bromo-3-(l-(2-(4-(l-(3-bromo-l-ethyl-lH-pyrazol-4- yl)vinyl)-l-methyl-lH-pyrazol-3-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine (Intermediate 20-5)

[0640] To a mixture of intermediate 20-4 (100 mg, 238 μmol), 5-bromo-3-fluoro-2- nitropyridine (158 mg, 716 μmol), toluene (2.5 mL) was added slowly lithium tert-butoxide (2.2 M in THF, 325 μL, 716 μmol) at room temperature and the reaction was stirred at room temperature for 1 h. Purification by column chromatography (0-95% tetrahydrofuran / petroleum ether) gave intermediate 20-5 (140 mg).

[0641] MS m / z (ESI): 619.2 / 621.2 / 623.2 [M+H] +

[0642] Step 5: Synthesis of (R)-5-bromo-3-(l-(2-(4-(l-(3-bromo-l-ethyl-lH-pyrazol-4-yl)vinyl)-l- methyl-lH-pyrazol-3-yl)-5-fluorophenyl)ethoxy)pyridin-2-amine (Intermediate 20-6)

[0643] To a mixture of intermediate 20-5 (152 mg, 245 μmol), iron powder (152 mg, 2.72 mmol), ammonium chloride (152 mg, 2.84 mmol), water (1 mL) and ethanol (1 mL) was stirred at 85 °C for 1 h under argon atmosphere. Purification by column chromatography (0-95% tetrahydrofuran / petroleum ether) gave intermediate 20-6 (144 mg).

[0644] MS m / z (ESI): 589.2 / 591.2 / 593.2 [M+H] +

[0645] Step 6: Synthesis of compound 20

[0646] To a mixture of intermediate 20-6 (600 mg, 1.02 mmol), palladium acetate (45.6 mg, 203 μmol), cataCXium A (146 mg, 407 μmol), potassium pivalate (1.43 g, 10.2 mmol), 3-methyl-3- pentanol (20 mL) was stirred at 130 °C for 6 h under argon atmosphere. Purification by reverse phase column chromatography (25 g C18 column, 0-80% acetonitrile / 0.025% ammonia water, 15 mL / min) gave compound 20 (126 mg).

[0647] MS m / z (ESI): 509.3 / 511.3 [M+H] +

[0648] 1H NMR (400 MHz, DMSO-d6) δ 7.70-7.63 (m, 2H), 7.56-7.47 (m, 2H), 7.16-7.09 (m, 1H), 6.43 (d, J = 1.8 Hz, 1H), 6.21 (s, 2H), 5.41 (d, J = 2.0 Hz, 1H), 5.15-5.08 (m, 1H), 4.79 (d, J = 1.9 Hz, 1H), 4.12-4.04 (m, 2H), 3.89 (s, 3H), 1.60 (d, J = 6.2 Hz, 3H), 1.32 (t, J = 7.2 Hz, 3H).

[0649] Example 21: Synthesis of compound 21

[0650] Step 1: Synthesis of 1-ethyl-3-methoxy-1H-pyrazole (intermediate 21-2)

[0651] Intermediate 21-1 (1.5 g, 13.4 mmol) was dissolved in N,N-dimethylformamide (15.0 mL), potassium carbonate (3.7 g, 26.8 mmol) and iodomethane (3.8 g, 26.8 mmol) were added, and the reaction liquid was reacted at 25 °C for 16 hours. Water (30.0 mL) was added for quenching, extracted with ethyl acetate (30 mL x 3), and the organic phase was concentrated under reduced pressure to obtain intermediate 21-2 (1.7 g).

[0652] LCMS: m / z (ESI): 127.1 [M+H] +

[0653] Step 2: Synthesis of 1-ethyl-4-iodo-3-methoxy-1H-pyrazole (intermediate 21-3)

[0654] Intermediate 21-2 (1.7 g, 13.5 mmol) was dissolved in acetonitrile (20.0 mL), N-iodosuccinimide (3.6 g, 16.2 mmol) was added, and the reaction liquid was reacted at 25 °C for 6 hours. Saturated aqueous sodium thiosulfate solution (20.0 mL) was added for quenching, extracted with ethyl acetate (30 mL x 3), and the organic phase was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain intermediate 21-3 (1.0 g).

[0655] LCMS: m / z (ESI): 253.0 [M+H] +

[0656] Step 3: Synthesis of (1-ethyl-3-methoxy-1H-pyrazol-4-yl)(3-iodo-1-methyl-1H-pyrazol-4- yl)methanol (intermediate 21-4)

[0657] Isopropylmagnesium bromide (3.9 mL, 1 M, 3.9 mmol) was added to a solution of intermediate 21-3 (900 mg, 3.6 mmol) in tetrahydrofuran (10.0 mL) at 0 °C, stirred for 1 h, then 3-iodo-l-methyl-lH-pyrazole-4-carbaldehyde (842.7 mg, 3.6 mmol) was added, slowly warmed to 25 °C and stirred for 2 h. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (20.0 mL), extracted with ethyl acetate (20.0 mL x 3), the organic phases were combined and concentrated to dryness under reduced pressure, the residue was purified by column chromatography (petroleum ether: ethyl acetate = 1: 1) to give intermediate 21-4 (1.0 g).

[0658] LCMS: m / z (ESI): 362.9 [M+H] +

[0659] Step 4: Synthesis of (l-ethyl-3-methoxy-lH-pyrazol-4-yl)(3-iodo-l-methyl-lH-pyrazol-4- yl)methanone (intermediate 21-5)

[0660] Intermediate 21-4 (950 mg, 2.6 mmol) was dissolved in dichloromethane (20.0 mL), manganese dioxide (2.3 g, 26.2 mmol) was added, the resulting mixture was stirred at 40 °C for 12 h. The reaction was filtered, the filtrate was concentrated to dryness under reduced pressure, the residue was purified by column chromatography (petroleum ether: ethyl acetate = 1: 1) to give intermediate 21-5 (430.0 mg).

[0661] LCMS: m / z (ESI): 361.0 [M+H] +

[0662] Step 5: Synthesis of l-ethyl-4-(l-(3-iodo-l-methyl-lH-pyrazol-4-yl)vinyl)-3-methoxy-lH- pyrazole (intermediate 21-6)

[0663] Intermediate 21-5 (400.0 mg, 1.11 mmol) was added to tetrahydrofuran (4.0 mL) under argon, Tebbe’s reagent (3.3 mL, 0.5 M, 1.7 mmol) was added dropwise at 0 °C, the reaction was stirred at room temperature for 16 h. The reaction was quenched by the addition of water (20.0 mL), extracted with ethyl acetate (20.0 mL x 3), the organic phases were combined and concentrated to dryness under reduced pressure, the residue was purified by column chromatography (petroleum ether: ethyl acetate = 1: 1) to give intermediate 21-6 (280.0 mg).

[0664] LCMS: m / z (ESI): 359.1 [M+H] +

[0665] Step 6: Synthesis of (R)-1-(2-(4-(1-(1-ethyl-3-methoxy-1H-pyrazol-4-yl)vinyl)-1- methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethan-1-ol (Intermediate 21-7)

[0666] Under argon atmosphere, intermediate 21-6 (260.0 mg, 725.9 umol), intermediate 1-4 (132.5 mg, 798.5 umol), tris(dibenzylideneacetone)dipalladium (66.5 mg, 72.6 umol), tricyclohexylphosphine (40.7 mg, 145.2 umol) and potassium fluoride (126.5 mg, 2.2 mmol) were added into a mixture solvent of 1,4-dioxane (5.0 mL) / water (1.0 mL) and reacted at 100 °C for 2 h. The reaction was quenched by water (20.0 mL) and extracted with ethyl acetate (20.0 mL x 3). The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to give intermediate 21-7 (150.0 mg).

[0667] LCMS: m / z (ESI): 371.2 [M+H] +

[0668] Step 7: Synthesis of (R)-5-bromo-3-(1-(2-(4-(1-(1-ethyl-3-methoxy-1H-pyrazol-4-yl)vinyl)-1- methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine (Intermediate 21-8)

[0669] Under argon atmosphere, intermediate 21-7 (140.0 mg, 378.0 umol), 5-bromo-3-fluoro-2- nitropyridine (250.6 mg, 1.1 mmol) were added into tetrahydrofuran (2.0 mL) solution, and potassium tert-butoxide (1.1 mL, 1M, 1.1 mmol) was added dropwise at 0 °C and reacted at 0 °C for 2 h. The reaction was quenched by saturated aqueous ammonium chloride solution (10.0 mL) and extracted with ethyl acetate (10.0 mL x 3). The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to give intermediate 21-8 (140.0 mg).

[0670] LCMS: m / z (ESI): 571.1 / 573.1 [M+H] +

[0671] Step 8: Synthesis of (R)-5-bromo-3-(1-(2-(4-(1-(1-ethyl-3-methoxy-1H-pyrazol-4-yl)vinyl)-1- methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethoxy)pyridin-2-amine (Intermediate 21-9)

[0672] Intermediate 21-8 (120.0 mg, 210.0 μmol) was dissolved in a mixture of ethanol (5.0 mL) and water (1.0 mL) with anhydrous ammonium chloride (56.2 mg, 1.1 mmol), and iron powder (58.7 mg, 1.1 mmol) was added. The mixture was heated to 80 °C for 1 hour. The reaction was filtered, extracted with ethyl acetate (10.0 mL), and the organic phases were combined and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 1: 1) to give intermediate 21-9 (110.0 mg).

[0673] LCMS: m / z (ESI): 541.1 / 543.1 [M+H] +

[0674] Step 9: Synthesis of compound 21

[0675] Intermediate 21-9 (100 mg, 184.7 μmol), palladium acetate (8.3 mg, 37.0 μmol), n- butyldi(1-adamantyl)phosphine (53.0 mg, 147.8 μmol), and potassium pivalate (77.7 mg, 554.1 μmol) were dissolved in tert-amyl alcohol (3.0 mL). The reaction was stirred at 120 °C under an argon atmosphere for 6 hours. The reaction was filtered and concentrated. The residue was purified by preparative liquid chromatography (column: YMC TA-C18, 30 x 150 mm, 5 μm; mobile phase A: 7 mmol / L ammonium bicarbonate in water, mobile phase B: acetonitrile; flow rate: 30 mL / min; acetonitrile ratio 50-80%, 8 min) to give compound 21 (35.0 mg).

[0676] LCMS: m / z (ESI): 461.2 [M+H] +

[0677] 1 H NMR (400 MHz, DMSO-d6) δ 7.66 (dd, J = 10.4, 2.8 Hz, 1H), 7.60 (s, 1H), 7.50 - 7.41 (m, 2H), 7.12 (td, J = 8.5, 2.8 Hz, 1H), 6.42 (s, 1H), 6.12 (s, 2H), 5.24 (s, 1H), 5.14 - 5.08 (m, 1H), 4.72 (d, J = 2.2 Hz, 1H), 3.97 - 3.90 (m, 2H), 3.89 (s, 3H), 3.88 (s, 3H), 1.59 (d, J = 6.2 Hz, 3H), 1.27 (t, J = 7.1 Hz, 3H).

[0678] Example 22: Synthesis of compound 22

[0679] Step 1: Synthesis of 1-ethyl-3-(fluoromethoxy)-1H-pyrazole (Intermediate 22-2)

[0680] Intermediate 22-1 (2.4 g, 21.4 mmol) was dissolved in N,N-dimethylformamide with bromofluoromethane (4.8 g, 42.8 mmol), and anhydrous potassium carbonate (8.9 g, 64.2 mmol) was added to the resulting solution. The resulting mixture was stirred at 25 °C overnight. After the reaction was completed, the reaction solution was diluted with ethyl acetate (100.0 mL), washed with water (50 mL x 2 times), and the organic phase was concentrated under reduced pressure. The resulting 22-2 crude product was directly used in the next reaction.

[0681] Step 2: Synthesis of 1-ethyl-3-(fluoromethoxy)-1H-pyrazole-4-carbaldehyde (Intermediate 22-3)

[0682] Phosphorus oxychloride (14.25 g, 92.96 mmol) was added dropwise to N,N-dimethylformamide (7.20 mL, 92.96 mmol) at 0 °C, and the resulting mixture was stirred at 0 °C for 30 minutes. Intermediate 22-2 (2.68 g, 18.59 mmol) was added to the mixture, and the resulting mixture was heated to 70 °C for 16 hours. After the reaction was completed, the reaction solution was quenched with saturated aqueous sodium bicarbonate solution (100 mL), and extracted with ethyl acetate (100 mL x 3 times). The resulting organic phases were combined and concentrated under reduced pressure. Column chromatography (petroleum ether: ethyl acetate = 1:1) was used to separate the product, yielding Intermediate 22-3 (1.9 g). o C and stirred at this temperature for 16 hours. After the reaction was completed, the reaction solution was quenched with saturated aqueous sodium bicarbonate solution (100 mL), and extracted with ethyl acetate (100 mL x 3 times). The resulting organic phases were combined and concentrated under reduced pressure. Column chromatography (petroleum ether: ethyl acetate = 1:1) was used to separate the product, yielding Intermediate 22-3 (1.9 g).

[0683] LCMS: m / z (ESI): 173.1 [M+H] +

[0684] Step 3: Synthesis of (3-bromo-1-methyl-1H-pyrazol-4-yl)(1-ethyl-3- (fluoromethoxy)-1H-pyrazol-4-yl)methanol (Intermediate 22-4)

[0685] Isopropylmagnesium bromide (16.6 mL, 1M, 16.6 mmol) was added to a solution of 3-bromo-4-iodo-1-methyl-1H-pyrazole (4.8 g, 16.6 mmol) in tetrahydrofuran (20 mL) at 0 °C, and the reaction was stirred for 30 minutes. Intermediate 22-3 (1.9 g, 11.4 mmol) was added, and stirring was continued at 0 °C for 1 hour. After the reaction was completed, the reaction was quenched with saturated aqueous ammonium chloride solution (10 mL), extracted with dichloromethane (50 mL x 3), and the organic phases were combined and concentrated under reduced pressure. The resulting 22-4 crude product was directly used in the next reaction.

[0686] LCMS: m / z (ESI): 333.0 / 335.0 [M+H] +

[0687] Step 4: Synthesis of (3-bromo-l-methyl-lH-pyrazol-4-yl)(l-ethyl-3- (fluoromethoxy)-lH-pyrazol-4-yl)methanone (Intermediate 22-5)

[0688] Intermediate 22-4 (3.7 g, 11.1 mmol) was dissolved in dichloromethane (20.0 mL), and manganese dioxide (19.2 g, 220.9 mmol) was added. The resulting mixture was stirred at 25 °C for 16 h. The reaction was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1:2) to give Intermediate 22-5 (2.1 g).

[0689] LCMS: m / z (ESI): 333.0 / 335.0 [M+H] +

[0690] Step 5: Synthesis of 3-bromo-4-(l-(l-ethyl-3-(fluoromethoxy)-lH-pyrazol-4- yl)vinyl)-l-methyl-lH-pyrazole (Intermediate 22-6)

[0691] Intermediate 22-5 (2.06 g, 6.2 mmol) was dissolved in tetrahydrofuran (30 mL), and potassium fluoride (3.61 g, 62.2 mmol) was added to the resulting solution. The resulting mixture was cooled to 0 °C, and Tebbe reagent (18.6 mL, 0.5 M, 9.3 mmol) was added dropwise under an argon atmosphere. The resulting mixture was stirred at room temperature for 16 h. The reaction was quenched with water (20.0 mL) and extracted with ethyl acetate (50.0 mL x 3). The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1:1) to give Intermediate 22-6 (595.6 mg).

[0692] LCMS: m / z (ESI): 333.0 / 335.0 [M+H] +

[0693] Step 6: Synthesis of (R)-l-(2-(4-(l-(l-ethyl-3-(fluoromethoxy)-lH-pyrazol-4- yl)vinyl)-l-methyl-lH-pyrazol-3-yl)-5-fluorophenyl)ethan-l-ol (Intermediate 22-7)

[0694] Intermediate 22-6 (595.6 mg, 1.8 mmol), intermediate 1-4 (600.6 mg, 3.6 mmol), tris(dibenzylideneacetone)dipalladium (165.7 mg, 180.9 μmol), tricyclohexylphosphine (101.5 mg, 361.9 μmol) and potassium fluoride (315.4 mg, 5.4 mmol) were added into a mixed solvent of 1,4-dioxane (20.0 mL) and water (2.0 mL) under argon atmosphere, and the mixture was stirred at 100 °C for 16 h. The reaction was quenched by adding water (20.0 mL), and extracted with dichloromethane (50.0 mL x 3). The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to give intermediate 22-7 (702.3 mg).

[0695] LCMS: m / z (ESI): 389.2 [M+H] +

[0696] Step 7: Synthesis of (R)-5-bromo-3-(1-(2-(4-(1-(1-ethyl-3-(fluoromethoxy)-1H-pyrazol-4-yl)vinyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine (Intermediate 22-8)

[0697] Intermediate 22-7 (610.8 mg, 1.6 mmol) and 5-bromo-3-fluoro-2-nitropyridine (1.0 g, 4.7 mmol) were dissolved in tetrahydrofuran (15.0 mL), and the resulting mixture was cooled to 0 °C. Then, a solution of potassium tert-butoxide in tetrahydrofuran (1.0 M, 4.7 mL) was added dropwise, and the resulting mixture was stirred at 0 °C for 1 h. After the reaction was completed, the reaction was quenched by adding saturated aqueous ammonium chloride solution (10.0 mL), and extracted with dichloromethane (50.0 mL x 3). The combined organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:2) to give intermediate 22-8 (803.5 mg).

[0698] LCMS: m / z (ESI): 589.1 / 591.1 [M+H] +

[0699] Step 8: Synthesis of (R)-5-bromo-3-(1-(2-(4-(1-(1-ethyl-3-(fluoromethoxy)-1H-pyrazol-4-yl)vinyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethoxy)pyridin-2-amine (Intermediate 9)

[0700] Intermediate 22-8 (821.0 mg, 1.4 mmol) was dissolved in ethanol (15.0 mL) and water (3.0 mL), then iron powder (466.7 mg, 8.4 mmol) and ammonium chloride (447.1 mg, 8.4 mmol) were added thereto. The resulting mixture was heated to 80°C and stirred at the temperature for 1 hour. After completion of the reaction, the reaction solution was filtered, the filtrate was extracted with dichloromethane (50 mL x 3 times), the combined organic phase was concentrated under reduced pressure, and then purified by column chromatography (petroleum ether: ethyl acetate = 1:3) to obtain intermediate 22-9 (625.0 mg).

[0701] LCMS: m / z (ESI): 559.1 / 561.1 [M+H] +

[0702] Step 9: Synthesis of compound 22

[0703] Intermediate 22-9 (161.5 mg, 288.7 µmol), palladium acetate (19.4 mg, 86.6 µmol), potassium pivalate (121.4 mg, 866.1 µmol) and n-butyl bis(1-adamantyl)phosphine (62.1 mg, 173.2 µmol) were dissolved in tert-amyl alcohol (3 mL), and the resulting mixture was heated to 120°C under an argon atmosphere and stirred at the temperature for 16 hours. After completion of the reaction, the reaction solution was filtered, concentrated under reduced pressure, and then purified by column chromatography (petroleum ether: ethyl acetate = 1:1.5) and reverse-phase medium-pressure preparative chromatography (column: YMC TA-C18, 30*150mm, 5µm; mobile phase A: water, mobile phase B: acetonitrile; flow rate: 60 mL / min; acetonitrile ratio 10-95%, elution 10 min) to obtain compound 22 (62 mg).

[0704] LCMS: m / z (ESI): 479.2 [M+H] +

[0705] 1 H NMR (400 MHz, DMSO-d6) δ 7.69-7.64 (m, 1H), 7.59 (s, 1H), 7.50-7.44 (m, 2H), 7.16-7.09 (m, 1H), 6.43 (d, J = 1.9 Hz, 1H), 6.17 (s, 2H), 6.03-5.98 (m, 1H), 5.90-5.85 (m, 1H), 5.30 (d, J = 2.2 Hz, 1H), 5.15-5.09 (m, 1H), 4.77 (d, J = 2.1 Hz, 1H), 4.02-3.94 (m, 2H), 3.88 (s, 3H), 1.60 (d, J = 6.2 Hz, 3H), 1.29 (t, J = 7.2 Hz, 3H).

[0706] Example 23: Synthesis of compound 23

[0707] Step 1: Synthesis of ethyl 3-(difluoromethyl)-l-ethyl-lH-pyrazole-4-carboxylate (Intermediate 23-2)

[0708] Ethylhydrazine oxalate (3.0 g, 20.3 mmol) was dissolved in dry tetrahydrofuran (30.0 mL) at 25 °C, triethylamine (4.1 g, 40.5 mmol) was added, then intermediate 23-1 (4.5 g, 20.3 mmol) was added to the reaction, stirred for 12 hours. After the reaction was completed, aqueous sodium bicarbonate solution (20.0 mL) was added to quench, and extracted with dichloromethane (20 mL*3 times), the organic phase was separated, and the organic phase was concentrated under reduced pressure, and then purified by column chromatography (petroleum ether: ethyl acetate = 9: 1) to give intermediate 23-2 (2.4 g).

[0709] LCMS: m / z (ESI): 219.1 [M+H] +

[0710] Step 2: Synthesis of (3-(difluoromethyl)-l-ethyl-lH-pyrazol-4-yl)methanol (Intermediate 23-3)

[0711] Intermediate 23-2 (0.5 g, 2.3 mmol) was dissolved in dry tetrahydrofuran (10.0 mL) at 0 °C, lithium aluminum hydride (2.8 mL, 1M, 2.8 mmol) was added dropwise to the reaction and incubated for 2 hours. After the reaction was completed, methanol (5.0 mL) was added dropwise to quench the reaction, and the reaction was poured into water and extracted with ethyl acetate (20 mL*3 times), the organic phase was separated, and the organic phase was concentrated under reduced pressure, and then purified by column chromatography (petroleum ether: ethyl acetate = 8:2) to give intermediate 23-3 (0.33 g).

[0712] LCMS: m / z (ESI): 177.1 [M+H] +

[0713] Step 3: Synthesis of 3-(difluoromethyl)-l-ethyl-lH-pyrazole-4-carbaldehyde (Intermediate 23-4)

[0714] Intermediate 23-3 (0.3 g, 1.7 mmol) was dissolved in dichloromethane (10.0 mL), manganese dioxide (1.5 g, 17.0 mmol) was added, and the resulting mixture was reacted at 25 °C for 2 hours. The reaction was filtered, and the filtrate was concentrated under reduced pressure to give intermediate 23-4 (0.24 g).

[0715] LCMS: m / z (ESI): 175.1 [M+H] +

[0716] Step 4: Synthesis of (3-bromo-l-methyl-lH-pyrazol-4-yl)(3-(difluoromethyl)-l- ethyl-lH-pyrazol-4-yl)methanol (Intermediate 23-5)

[0717] Isopropyl magnesium bromide (2.8 mL, 1 M, 2.8 mmol) was added to a solution of 3-bromo-4-iodo-l-methyl-lH-pyrazole (790.8 mg, 2.8 mmol) in tetrahydrofuran (10.0 mL) at 0 °C, stirred for 1 h, then Intermediate 23-4 (240.0 mg, 1.4 mmol) was added, slowly warmed to 25 °C for 2 h. After completion of the reaction, quenched with water (5.0 mL), extracted with ethyl acetate (10.0 mL x 3), the organic phase was concentrated under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate = 1: 1) to give Intermediate 23-5 (360.0 mg).

[0718] LCMS: m / z (ESI): 335.2 / 337.2 [M+H] +

[0719] Step 5: Synthesis of (3-bromo-l-methyl-lH-pyrazol-4-yl)(3-(difluoromethyl)-l- ethyl-lH-pyrazol-4-yl)methanone (Intermediate 23-6)

[0720] Intermediate 23-5 (0.3 g, 895.1 pmol) was dissolved in dichloromethane (10.0 mL), manganese dioxide (0.8 g, 9.0 mmol) was added, the resulting mixture was stirred at 25 °C for 2 h. The reaction was filtered, the filtrate was concentrated under reduced pressure to give Intermediate 23-6 (280.0 mg).

[0721] LCMS: m / z (ESI): 333.1 / 335.2 [M+H] +

[0722] Step 6: Synthesis of 3-bromo-4-(l-(3-(difluoromethyl)-l-ethyl-lH-pyrazol-4- yl)vinyl)-l-methyl-lH-pyrazole (Intermediate 23-7)

[0723] Intermediate 23-6 (280.0 mg, 840.5 μmol) was added into dichloromethane (10.0 mL) under argon atmosphere, and Tebbe reagent (3.4 mL, 0.5 M, 1.7 mmol) was added dropwise at 0 °C. After addition, the reaction was allowed to warm to room temperature and stirred for 16 h. The reaction was then poured into water and stirred well, and extracted with ethyl acetate (10.0 mL x 3). The combined organic phase was washed with saturated brine, and the organic phase was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1:1) to give intermediate 23-7 (230.0 mg).

[0724] LCMS: m / z (ESI): 331.1 / 333.1 [M+H] +

[0725] Step 7: Synthesis of (R)-1-(2-(4-(1-(3-(difluoromethyl)-1-ethyl-1H-pyrazol-4-yl)vinyl)-1- methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethan-1-ol (Intermediate 23-8)

[0726] Intermediate 23-7 (230.0 mg, 694.5 μmol), intermediate 1-4 (115.3 mg, 694.5 μmol), tris(dibenzylideneacetone)dipalladium (63.6 mg, 69.5 μmol), tricyclohexylphosphine (38.9 mg, 138.9 μmol) and potassium fluoride (121.1 mg, 2.1 mmol) were added into a mixture of 1,4-dioxane (10.0 mL) and water (5.0 mL) and reacted at 100 °C for 12 h. The reaction was cooled to 25 °C and quenched by adding water (5.0 mL), and extracted with ethyl acetate (10.0 mL x 3). The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1:2) to give intermediate 23-8 (230.0 mg).

[0727] LCMS: m / z (ESI): 391.2 [M+H] +

[0728] Step 8: Synthesis of (R)-5-bromo-3-(1-(2-(4-(1-(3-(difluoromethyl)-1-ethyl-1H-pyrazol-4-yl)vinyl)-1- methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine (Intermediate 23-9)

[0729] Intermediate 23-8 (200.0 mg, 512.3 μmol) was dissolved in tetrahydrofuran (5.0 mL), sodium hydride (36.9 mg, 922.1 μmol, 60%) was added at 0 °C, stirred for 30 min, 5-bromo-3-fluoro-2-nitropyridine (203.8 mg, 922.13 μmol) was added and then moved to 70 °C for 12 h. After the reaction was completed, water (5.0 mL) was added to quench the reaction, and then extracted with ethyl acetate (10.0 mL x 3). The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:2) to give intermediate 23-9 (190.0 mg).

[0730] LCMS: m / z (ESI): 591.1 / 593.1 [M+H] +

[0731] Step 9: Synthesis of (R)-5-bromo-3-(l-(2-(4-(l-(3-(difluoromethyl)-l-ethyl-lH- pyrazol-4-yl)vinyl)-l-methyl-lH-pyrazol-3-yl)-5-fluorophenyl)ethoxy)pyridin-2-amine (Intermediate 23-10)

[0732] Intermediate 23-9 (190.0 mg, 321.3 μmol), iron powder (179.4 mg, 3.2 mmol) and ammonium chloride (179.9 mg, 3.2 mmol) were stirred in a mixture of ethanol (10.0 mL) and water (2.0 mL) at 80 °C for 1 h. After the reaction was completed, the reaction solution was filtered, extracted with ethyl acetate (5.0 mL x 3) and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:2) to give intermediate 23-10 (135.0 mg).

[0733] LCMS: m / z (ESI): 561.2 / 563.2 [M+H] +

[0734] Step 10: Synthesis of compound 23

[0735] Intermediate 23-9 (135.0 mg, 240.4 μmol), palladium acetate (10.8 mg, 48.0 μmol), n-butyl bis(l-adamantyl)phosphine (34.4 mg, 96.2 μmol) and potassium pivalate (101.7 mg, 0.72 mmol) were dissolved in t-AmOH (3.0 mL). The reaction solution was heated to 125 °C under an argon atmosphere and stirred for 6 h. Subsequently, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to give compound 23 (67.0 mg).

[0736] LCMS: m / z (ESI): 481.2 [M+H] +

[0737] 1 H NMR (400 MHz, DMSO-d6) δ 7.68 (dd, J = 10.4, 2.8 Hz, 1H), 7.57 (s, 1H), 7.55-7.50 (m, 1H), 7.49 (d, J = 1.8 Hz, 1H), 7.22-6.79 (m, 2H), 6.46 (d, J = 1.4 Hz, 1H), 6.20 (s, 2H), 5.40 (d, J = 1.9 Hz, 1H), 5.23-5.12 (m, 1H), 4.81 (d, J = 1.7 Hz, 1H), 4.14 (q, J = 7.2 Hz, 2H), 3.88 (s, 3H), 1.61 (d, J = 6.2 Hz, 3H), 1.34 (t, J = 7.2 Hz, 3H).

[0738] Example 24: Synthesis of compound 24

[0739] Step 1: Synthesis of 3-fluoro-4-iodo-1H-pyrazole (Intermediate 24-1)

[0740] A mixture of 3-fluoro-1H-pyrazole (100 mg, 1.16 mmol), NIS (392 mg, 1.74 mmol) and MeCN (1 mL) was reacted at 60 °C for 16 h. The reaction was then quenched by adding 1 mL of 30% sodium thiosulfate aqueous solution, and the reaction was concentrated under reduced pressure. The residue was purified by column chromatography (0-50% tetrahydrofuran / petroleum ether) to give 24-1 (173 mg).

[0741] 1 H NMR (400 MHz, DMSO-d6) δ 12.81 (s, 1H), 7.85 (t, J = 1.9 Hz, 1H).

[0742] Step 2: Synthesis of 1-ethyl-3-fluoro-4-iodo-1H-pyrazole (Intermediate 24-2)

[0743] To a mixture of intermediate 24-1 (1.38 g, 6.51 mmol), cesium carbonate (4.24 g, 13.0 mmol) and DMF (9 mL) was added dropwise bromoethane (780 mg, 7.16 mmol) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was directly purified by column chromatography (0-20% tetrahydrofuran / petroleum ether) to give 24-2 (1.15 g).

[0744] 1H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J = 2.2 Hz, 1H), 4.01 (qd, J = 7.3, 1.2 Hz, 2H), 1.31 (t, J = 7.2 Hz, 3H).

[0745] 19F NMR (376 MHz, DMSO) δ -132.23.

[0746] Step 3: Synthesis of (l-ethyl-3-fluoro-lH-pyrazol-4-yl)(3-iodo-l-methyl-lH- pyrazol-4-yl)methanol (Intermediate 24-3)

[0747] Under argon atmosphere, Intermediate 24-2 (1.15 g, 4.79 mmol) was dissolved in THF (6 mL), and isopropylmagnesium chloride lithium chloride complex (1.3 M, 4.79 mL) was added at 0 °C. The reaction was stirred for 1 h. Then 3-iodo-l-methyl-lH-pyrazole-4- carboxaldehyde (1 g, 4.24 mmol) was added, and the reaction was allowed to warm to room temperature for 1 h. Then saturated aqueous ammonium chloride solution (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was concentrated and purified by column (0-100% tetrahydrofuran / petroleum ether) to give 24-3 (1.55 g).

[0748] MS m / z (ESI): 351.2 [M+H] +

[0749] Step 4: Synthesis of compound 24

[0750] In a similar manner as described in the synthesis of Example 19, compound 24 (7 mg) was synthesized using Intermediate 24-3 (240 mg, 0.685 mmol) as starting material instead of compound 20-1 in Example 20.

[0751] MS m / z (ESI): 449.3 [M+H] +

[0752] 1 H NMR (400 MHz, DMSO-d6) δ 7.76 - 7.63 (m, 2H), 7.55 - 7.46 (m, 2H), 7.18 - 7.08 (m, 1H), 6.42 (d, J = 1.9 Hz, 1H), 6.24 (s, 2H), 5.39 (d, J = 2.0 Hz, 1H), 5.17 - 5.10 (m, 1H), 4.89 (d, J = 1.9 Hz, 1H), 3.99 (q, J = 7.2 Hz, 2H), 3.88 (s, 3H), 1.61 (d, J = 6.2 Hz, 3H), 1.29 (t, J = 7.2 Hz, 3H).

[0753] Example 25: Synthesis of compound 25

[0754] Step 1: Synthesis of 3-iodo-l-methyl-lH-pyrazole-4-carbaldehyde (Intermediate 25-2)

[0755] Compound 25-1 (2.08 g, 10.00 mmol), urotropine (2.10 g, 15.00 mmol) and trifluoroacetic acid (10 mL) were added to a reaction flask, stirred at 90 °C for 12 h. The reaction solution was cooled to room temperature, adjusted to pH 7 with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane (15 mL x 3), and the combined organic layers were concentrated under reduced pressure and purified by column chromatography (THF / PE, 0-100%) to give intermediate 25-2 (1.7 g).

[0756] LC-MS: m / z (ESI): 237.0 [M+H] +

[0757] Step 2: Synthesis of 5-(hydroxy(3-iodo-l-methyl-lH-pyrazol-4-yl)methyl)-l- methyl-lH-pyrazole-3-carbonitrile (Intermediate 25-4)

[0758] Intermediate 25-3 (300 mg, 2.80 mmol) and tetrahydrofuran (3 mL) were added to a reaction flask. Lithium diisopropylamide (2 M in THF, 2.10 mL, 4.20 mmol) was added to the reaction flask under an argon atmosphere at -78 °C and stirred for 1 h. A solution of intermediate 25-2 (991.52 mg, 4.20 mmol) in tetrahydrofuran (10 mL) was added while maintaining the temperature at -78 °C and stirred for 2 h. The reaction was quenched by adding saturated aqueous ammonium chloride solution (15 mL), extracted with dichloromethane (10 mL x 3), and the combined organic layers were concentrated under reduced pressure and purified by column chromatography (THF / PE, 0-100%) to give intermediate 25-4 (940 mg).

[0759] LC-MS: m / z (ESI): 344.0 [M+H] +

[0760] Step 3: Synthesis of 5-(3-iodo-l-methyl-lH-pyrazole-4-carbonyl)-l-methyl-lH- pyrazole-3-carbonitrile (Intermediate 25-5)

[0761] A mixture of intermediate 25-4 (880 mg, 2.56 mmol), manganese dioxide (6.69 g, 76.94 mmol), and dichloromethane (5 mL) was reacted at room temperature for 1 h. After filtration, the mixture was concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography (THF / PE, 0-100%) to give intermediate 25-5 (577 mg).

[0762] LC-MS: m / z (ESI): 342.1 [M+H] +

[0763] Step 4: Synthesis of 5-(1-(3-iodo-1-methyl-1H-pyrazol-4-yl)vinyl)-1-methyl-1H- pyrazole-3-carbonitrile (intermediate 25-6)

[0764] A reaction flask was charged with TPMP (689.4 mg, 1.93 mmol) and n-butyllithium (0.5 M in Hexane, 3.86 mL, 1.93 mmol) under an argon atmosphere at 0 °C and stirred for 30 min, maintaining the argon atmosphere at 0 °C, a solution of intermediate 25-5 (330 mg, 967.44 μmol) in tetrahydrofuran (3 mL) was added, followed by increasing the temperature to 50 °C and stirring for 1 h. The reaction was quenched by adding saturated aqueous ammonium chloride solution (10 mL), and the combined organic layers were extracted with dichloromethane (10 mL x 3), and the mixture was concentrated under reduced pressure and purified by column chromatography (THF / PE, 0-100%) to give intermediate 25-6 (160 mg).

[0765] LC-MS: m / z (ESI): 340.1 [M+H] +

[0766] Step 5: Synthesis of (R)-5-(1-(3-(4-fluoro-2-(1-hydroxyethyl)phenyl)-1-methyl-1H- pyrazol-4-yl)vinyl)-1-methyl-1H-pyrazole-3-carbonitrile (intermediate 25-7)

[0767] A mixture of intermediate 25-6 (190 mg, 560.25 μmol), intermediate 1-4 (185.95 mg, 1.12 mmol), Pd(Amphos)2Cl2(79.34 mg, 112.05 μmol), potassium phosphate (356.77 mg, 1.68 mmol), methyl tert-butyl ether (4 mL), and water (2 mL) was heated to 60 °C and reacted for 1 h. The mixture was then concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography (THF / PE, 0-100%) to give intermediate 25-7 (190 mg).

[0768] LC-MS: m / z (ESI): 352.3 [M+H]+

[0769] Step 6: Synthesis of (R)-5-(l-(3-(2-(l-((5-bromo-2-nitropyridin-3- yl)oxy)ethyl)-4-fluorophenyl)-l-methyl-lH-pyrazol-4-yl)vinyl)-l-methyl- lH-pyrazole-3-carbonitrile (Intermediate 25-8)

[0770] To a mixture of Intermediate 25-7 (220 mg, 626.11 μmol), 5-bromo-3- fluoro-2-nitropyridine (179.87 mg, 813.94 μmol) and toluene (3 mL) was added tert-butyllithium (2.2 M in THF, 569.19 μL, 1.25 mmol) at 0 °C under argon atmosphere. The resulting mixture was allowed to warm to room temperature for 0.5 h. The mixture was then concentrated under reduced pressure to remove the solvent and the residue was purified by column chromatography (THF / PE, 0-100%) to give Intermediate 25-8 (240 mg).

[0771] LC-MS: m / z (ESI): 552.2 [M+H] +

[0772] Step 7: Synthesis of (R)-5-(l-(3-(2-(l-((2-amino-5-bromopyridin-3- yl)oxy)ethyl)-4-fluorophenyl)-l-methyl-lH-pyrazol-4-yl)vinyl)-l-methyl- lH-pyrazole-3-carbonitrile (Intermediate 25-9)

[0773] A mixture of Intermediate 25-8 (120 mg, 217.25 μmol), iron powder (121.32 mg, 2.17 mmol), ammonium chloride (116.21 mg, 2.17 mmol), EtOH (3 mL) and water (3 mL) was heated to 80 °C under argon atmosphere and stirred for 1 h. The mixture was then directly purified by column chromatography (THF / PE, 0-100%) to give Intermediate 25-9 (100 mg).

[0774] LC-MS: m / z (ESI): 522.3 [M+H] +

[0775] Step 8: Synthesis of Compound 25

[0776] A mixture of intermediate 25-11 (210 mg, 402.01 μmol), Pd(OAc)2(63.18 mg, 281.41 μmol), catacXium A (201.79 mg, 562.82 μmol), potassium pivalate (563.70 mg, 4.02 mmol) and tert-amyl alcohol (5 mL) was heated to 120 °C under argon atmosphere with stirring for 4 h. After that the mixture was concentrated under reduced pressure to remove the solvent and purified by preparative liquid chromatography (column: waters Xbridge OBD 19*150mm*5μm; mobile phase: [A: water(containing 0.0125% NH3), B: acetonitrile]; B%: 25%-60%, 10 min) to give compound 25 (35 mg).

[0777] LC-MS: m / z (ESI): 442.3 [M+H] +

[0778] 1 H NMR (400 MHz, DMSO-d6) δ 7.99 (s, 1H), 7.66-7.50 (m, 3H), 7.18 (m, 1H), 6.42 (d, J = 1.9 Hz, 1H), 6.04 (s, 2H), 5.79 (d, J = 1.2 Hz, 1H), 5.21 (s, 1H), 5.09-4.96 (m, 1H), 4.02 (s, 3H), 3.89 (s, 3H), 1.62 (d, J = 6.2 Hz, 3H).

[0779] Example 26: Synthesis of compound 26

[0780] Step 1: Synthesis of 3-chloro-l-ethyl-lH-pyrazole (intermediate 26-2)

[0781] Intermediate 26-1 (3.0 g, 29.2 mmol) was dissolved in MeCN (5.0 mL), cesium carbonate (10.5 g, 32.1 mmol) and iodoethane (5.02 g, 32.1 mmol) were added and the mixture was allowed to react at 25 °C for 3 hours. Subsequently, the mixture was filtered and the organic phase was concentrated under reduced pressure and purified by column chromatography (THF / PE, 0-25%) to give intermediate 26-2 (2.99 g).

[0782] LCMS: m / z (ESI): 131.6 [M+H] +

[0783] Step 2: Synthesis of 3-chloro-l-ethyl-lH-pyrazole-4-carbaldehyde (intermediate 26-3)

[0784] Phosphorous oxychloride (4.0 mL) was added to DMF (4.0 mL) at 0 °C, and the mixture was stirred at 25 °C for 1 h. Then, intermediate 26-2 (2.99 g, 22.7 mmol) was added, and the mixture was stirred at room temperature for 1 h. Subsequently, the reaction was quenched with saturated aqueous NaHC03solution (100 mL), and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was concentrated under reduced pressure and purified by column chromatography (THF / PE, 0-35%) to give intermediate 26-3 (2.29 g).

[0785] LCMS: m / z (ESI): 159.5 [M+H] +

[0786] Step 3: Synthesis of (4-bromo-2-methylthiazol-5-yl)(3-chloro-l-ethyl-lH- pyrazol-4-yl)methanol (intermediate 26-4)

[0787] Under argon atmosphere, 4-bromo-2-methylthiazole (1.35 g, 7.57 mmol) was added to tetrahydrofuran (10 mL), and LDA (810 mg, 7.57 mmol) was added at -78 °C. The mixture was stirred at -78 °C for 1 h, and intermediate 26-3 (1 g, 6.31 mmol) was dissolved in 1 mL of tetrahydrofuran and added slowly to the reaction mixture at -78 °C. The mixture was stirred at -78 °C for 1 h. The reaction was quenched by adding water (0.5 mL), and the mixture was directly purified by column chromatography (THF / PE, 0-38%) to give intermediate 26-4 (1.2 g).

[0788] LCMS: m / z (ESI): 336.1 [M+H] +

[0789] Step 4: Synthesis of (4-bromo-2-methylthiazol-5-yl)(3-chloro-l-ethyl-lH- pyrazol-4-yl)methanone (intermediate 26-5)

[0790] Under argon atmosphere, intermediate 26-4 (1.80 g, 5.35 mmol) and manganese dioxide (4.65 g, 53.5 mmol) were added to dichloromethane (5 mL), and the mixture was stirred at 40 °C for 16 h. The reaction was filtered under reduced pressure, and the filtrate was concentrated and purified by column chromatography (THF / PE, 0-30%) to give intermediate 26-5 (1.50 g).

[0791] LCMS: m / z (ESI): 334.1 [M+H] +

[0792] Step 5: Synthesis of 4-bromo-5-(l-(3-chloro-l-ethyl-lH-pyrazol-4-yl)vinyl)-2- methylthiazole (intermediate 26-6)

[0793] Under argon atmosphere, intermediate 26-5 (1 g, 2.99 mmol) was added into tetrahydrofuran (2 mL), Tebbe reagent (1.7 g, 5.98 mmol) was added dropwise at 0 °C, the reaction was allowed to warm to room temperature and stirred for 3 h. The reaction was directly purified by column chromatography (THF / PE, 0-28%) to give intermediate 26-6 (625 mg).

[0794] LC-MS: m / z (ESI): 332.1 [M+H] +

[0795] Step 6: Synthesis of (R)-1-(2-(5-(1-(3-chloro-1-ethyl-1H-pyrazol-4-yl)vinyl)-2- methylthiazol-4-yl)-5-fluorophenyl)ethanol-1-ol (intermediate 26-7)

[0796] Under argon atmosphere, a mixture of intermediate 26-6 (625 mg, 1.88 mmol), intermediate 1-4 (624 mg, 3.76 mmol), Pd(Amphos)2Cl2(66 mg, 94 μmol), potassium carbonate (780 mg, 5.64 mmol), 1,4-dioxane (10 mL) and water (1 mL) was heated to 100 °C for 3 h. The mixture was then concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography (THF / PE, 0-35%) to give intermediate 26-7 (709 mg).

[0797] LC-MS: m / z (ESI): 392.2 [M+H] +

[0798] Step 7: Synthesis of (R)-4-(2-(1-(5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4- fluorophenyl)-5-(1-(3-chloro-1-ethyl-1H-pyrazol-4-yl)vinyl)-2-methylthiazole (intermediate 26-8)

[0799] Under argon atmosphere, to a mixture of intermediate 26-7 (709 mg, 1.81 mmol), 5-bromo-3-fluoro-2-nitropyridine (1.2 g, 5.43 mol) and toluene (5 mL) was added tert-butoxy lithium (2.2 M in THF, 1.64 mL, 3.62 mmol) at 0 °C, the resulting mixture was allowed to warm to room temperature and stirred for 0.5 h. The mixture was then concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography (THF / PE, 0-45%) to give intermediate 26-8 (716 mg).

[0800] LC-MS: m / z (ESI): 592.1 [M+H] +

[0801] Step 8: Synthesis of (R)-5-bromo-3-(l-(2-(5-(l-(3-chloro-l-ethyl-lH- pyrazol-4-yl)ethenyl)-2-methylthiazol-4-yl)-5-fluorophenyl)ethoxy)pyridin-2-amine (Intermediate 26-9)

[0802] A mixture of Intermediate 26-8 (716 mg, 1.21 mmol), iron powder (337 mg, 6.04 mmol), ammonium chloride (323 mg, 6.04 mmol), EtOH (10.0 mL) and water (2.0 mL) was heated to 80 °C under argon and stirred for 1 h. The mixture was directly purified by column chromatography (THF / PE, 0-46%) to give Intermediate 26-9 (630 mg).

[0803] LC-MS: m / z (ESI): 562.1 [M+H] +

[0804] Step 9: Synthesis of compound 26

[0805] A mixture of Intermediate 26-9 (300 mg, 533 μmol), Pd(OAc)2(36 mg, 160 μmol), cataCXium A (115 mg, 320 μmol), potassium pivalate (152 mg, 1.07 mmol), tert- amyl alcohol (10 mL) was heated to 130 °C under microwave for 1 h. The mixture was then concentrated under reduced pressure to remove the solvent and purified by preparative liquid chromatography (column: waters Xbridge OBD 19*150mm*5μm; mobile phase: [A: water(containing 0.0125% NH3), B: acetonitrile]; B%: 25%-60%, 10 min) to give compound 26 (34.5 mg).

[0806] LC-MS: m / z (ESI): 482.2 [M+H] +

[0807] 1H NMR (400 MHz, DMSO-d6) δ 7.68 (dd, J = 10.4, 2.8 Hz, 1H), 7.58 (dd, J = 8.4, 5.6 Hz, 1H), 7.51 (d, J = 1.6 Hz, 1H), 7.13 (td, J = 8.4, 2.8 Hz, 1H), 6.38 (d, J = 2.0 Hz, 1H), 6.27 (s, 2H), 5.83 (d, J = 1.6 Hz, 1H), 5.11 (d, J = 1.6 Hz, 1H), 5.06 - 4.97 (m, 1H), 4.15 - 4.04 (m, 2H), 2.66 (s, 3H), 1.62 (d, J = 6.4 Hz, 3H), 1.31 (t, J = 7.2 Hz, 3H).

[0808] Example 27: Synthesis of compound 27

[0809] Compound 20 (10 mg, 19.63 μmol), tetrahydro pyrrole (17.1 mg, 240 μmol), GPhos Pd G6 (5.6 mg, 5.9 μmol) and sodium tert-butoxide (37.7 mg, 393 μmol) were dissolved in 1,4-dioxane (1 mL) and stirred at 115 °C for 4 h under argon atmosphere. Purification by reverse phase column chromatography (C18 column, 25 g, 0-80% acetonitrile / water with 0.025% NH3, 15 mL / min) gave compound 27 (0.92 mg).

[0810] MS m / z (ESI): 500.3 [M+H] +

[0811] 1 H NMR (400 MHz, DMSO-d6) δ 7.68 (dd, J = 10.4, 2.8 Hz, 1H), 7.58 (dd, J = 8.4, 5.6 Hz, 1H), 7.51 (d, J = 1.6 Hz, 1H), 7.13 (td, J = 8.4, 2.8 Hz, 1H), 6.38 (d, J = 2.0 Hz, 1H), 6.27 (s, 2H), 5.83 (d, J = 1.6 Hz, 1H), 5.11 (d, J = 1.6 Hz, 1H), 5.06 - 4.97 (m, 1H), 4.15 - 4.04 (m, 2H), 2.66 (s, 3H), 1.62 (d, J = 6.4 Hz, 3H), 1.31 (t, J = 7.2 Hz, 3H).

[0812] Example 28: Synthesis of compound 28

[0813] Compound 20 (5 mg, 9.8 μmol), 1 -methyl- 1 H-pyrazole-4-boronic acid (12.4 mg, 98.2 μmol), cataCXium A Pd G3 (2.1 mg, 2.9 μmol) and cesium carbonate (32 mg, 98 μmol) were dissolved in 1,4-dioxane (0.5 mL) and water (0.05 mL) and stirred at 115 °C for 2 h. Purification by reverse phase column chromatography (C18 column, 25 g, 0-80% acetonitrile / water with 0.025% NH3, 15 mL / min) afforded compound 28 (2.08 mg).

[0814] MS m / z (ESI): 511.3 [M+H] +

[0815] 1 H NMR (400 MHz, DMSO-d6) δ 7.98 (s, 1H), 7.78 (s, 1H), 7.72-7.65 (m, 1H), 7.58-7.52 (m, 1H), 7.47 (d, J = 1.8 Hz, 1H), 7.43 (s, 1H), 7.20-7.10 (m, 1H), 6.48 (d, J = 1.8 Hz, 1H), 6.11 (s, 2H), 5.39 (d, J = 2.3 Hz, 1H), 5.17-5.08 (m, 1H), 4.78 (d, J = 2.1 Hz, 1H), 4.13-4.02 (m, 2H), 3.87 (s, 3H), 3.84 (s, 3H), 1.60 (d, J = 6.2 Hz, 3H), 1.34 (t, J = 7.2 Hz, 3H).

[0816] Example 29: Synthesis of compound 29

[0817] Compound 20 (10 mg, 19.6 μmol), cyclopropylboronic acid (16.8 mg, 196 μmol), cataCXium A Pd G3 (4.3 mg, 5.9 μmol) and cesium carbonate (64 mg, 196 μmol) were dissolved in 1,4-dioxane (1 mL) and water (0.1 mL) and stirred at 115 °C for 2 h. Purification by reverse phase column chromatography (C18 column, 25 g, 0-80% acetonitrile / water with 0.025% NH3, 15 mL / min) afforded compound 29 (4.6 mg).

[0818] MS m / z (ESI): 471.3 [M+H] +

[0819] 1H NMR (400 MHz, DMSO-d6) δ 7.70-7.64 (m, 1H), 7.63 (s, 1H), 7.54-7.48 (m, 1H), 7.41 (d, J = 1.8 Hz, 1H), 7.18-7.08 (m, 1H), 6.45 (d, J = 1.8 Hz, 1H), 6.07 (s, 2H), 5.35 (d, J = 2.3 Hz, 1H), 5.19-5.05 (m, 1H), 4.77 (d, J = 2.2 Hz, 1H), 4.03-3.92 (m, 2H), 3.89 (s, 3H), 1.97-1.87 (m, 1H), 1.60 (d, J = 6.2 Hz, 3H), 1.26 (t, J = 7.2 Hz, 3H), 0.97-0.77 (m, 4H).

[0820] Example 30: Synthesis of compound 30

[0821] Step 1: Synthesis of 1-ethyl-4-iodo-1H-pyrazole-3-carbonitrile (Intermediate 30-2)

[0822] Intermediate 30-1 (3.0 g, 13.7 mmol) was dissolved in MeCN (30 mL), cesium carbonate (11.6 g, 35.5 mmol) and iodoethane (5.53 g, 35.5 mmol) were added, and the mixture was reacted at 25 °C for 3 hours. Then it was filtered, and the organic phase was concentrated under reduced pressure and purified by column chromatography (THF / PE, 0-40%) to give Intermediate 30-2 (3.01 g).

[0823] LCMS: m / z (ESI): 248.1 [M+H] +

[0824] Step 2: Synthesis of 1-ethyl-4-(hydroxy(3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1H- pyrazole-3-carbonitrile (Intermediate 30-3)

[0825] Isopropyl magnesium chloride (1.35 mL, 1.3 M, 1.75 mmol) was added to a solution of Intermediate 30-2 (433 mg, 1.75 mmol) in tetrahydrofuran (10 mL) at 0 °C, and the reaction was stirred for 1 hour, 3-iodo-1-methyl-1H-pyrazole-4-carbaldehyde (496 mg, 2.10 mmol) was added, and the reaction was slowly raised to 25 °C and reacted for 2 hours. Then it was quenched with water (20 mL), extracted with ethyl acetate (50 mL x 3), and the organic phase was concentrated under reduced pressure and purified by column chromatography (THF / PE, 0-78%) to give Intermediate 30-3 (286 mg).

[0826] LCMS: m / z (ESI): 358.0 [M+H]+

[0827] Step 3: Synthesis of l-ethyl-4-(3-iodo-l-methyl-lH-pyrazole-4-carbonyl)-lH- pyrazole-3-carbonitrile (Intermediate 30-4)

[0828] Under argon atmosphere, Intermediate 30-3 (286 mg, 0.8 mmol), manganese dioxide (696 mg, 8.0 mmol) were added into dichloromethane (5 mL) and reacted at 45 °C for 3 h. After that, the reaction was filtered under reduced pressure and concentrated, then purified by column chromatography (MeOH / DCM, 0-12%) to give Intermediate 30-4 (56 mg).

[0829] LCMS: m / z (ESI): 356.1 [M+H] +

[0830] Step 4: Synthesis of l-ethyl-4-(l-(3-iodo-l-methyl-lH-pyrazol-4-yl)vinyl)-lH- pyrazole-3-carbonitrile (Intermediate 30-5)

[0831] Under argon atmosphere, Intermediate 30-4 (46 mg, 129 μmol) was added into tetrahydrofuran (0.5 mL) and Tebbe reagent (85 mg, 299 μmol) was added dropwise at 0 °C, then the reaction was allowed to warm to room temperature and reacted for 3 h. The reaction was directly purified by column chromatography (THF / PE, 0-50%) to give Intermediate 30-5 (22 mg).

[0832] LCMS: m / z (ESI): 354.1 [M+H] +

[0833] Step 5: Synthesis of (R)-l-ethyl-4-(l-(3-(4-fluoro-2-(l-hydroxyethyl)phenyl)-l- methyl-lH-pyrazol-4-yl)vinyl)-lH-pyrazole-3-carbonitrile (Intermediate 30-6)

[0834] Under argon atmosphere, a mixture of Intermediate 30-5 (22 mg, 62 μmol), Intermediate 1-4 (31 mg, 187 μmol), Pd(Amphos)2Cl2(4.4 mg, 6.2 μmol), potassium carbonate (25.8 mg, 187 μmol), 1,4-dioxane (1 mL) and water (0.1 mL) was heated to 100 °C for 1 h. After that, the mixture was concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography (THF / PE, 0-40%) to give Intermediate 30-6 (20 mg).

[0835] LC-MS: m / z (ESI): 366.4 [M+H] +

[0836] Step 6: Synthesis of (R)-4-(l-(3-(2-(l-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4- fluorophenyl)-l-methyl-lH-pyrazol-4-yl)vinyl)-l-ethyl-lH-pyrazole-3-carbonitrile (Intermediate 30-7)

[0837] To a mixture of Intermediate 30-6 (20 mg, 54 μmol), 5-bromo-3-fluoro-2- nitropyridine (36 mg, 164 μmol) and toluene (1 mL) was added tert-butyllithium (2.2 M in THF, 25.62 μL, 54 μmol) at 0 °C under argon atmosphere. The resulting mixture was allowed to warm to room temperature and stirred for 1 h. The mixture was then concentrated under reduced pressure to remove the solvent and the residue was purified by column chromatography (THF / PE, 0-30%) to give Intermediate 30-7 (20 mg).

[0838] LC-MS: m / z (ESI): 566.4 [M+H] +

[0839] Step 7: Synthesis of (R)-4-(l-(3-(2-(l-((2-amino-5-bromopyridin-3-yl)oxy)ethyl)-4- fluorophenyl)-l-methyl-lH-pyrazol-4-yl)vinyl)-l-ethyl-lH-pyrazole-3-carbonitrile (Intermediate 30-8)

[0840] A mixture of Intermediate 30-7 (20 mg, 35 μmol), iron powder (10.0 mg, 176 μmol), ammonium chloride (9.5 mg, 177.6 μmol), EtOH (1 mL) and water (0.1 mL) was heated to 80 °C under argon atmosphere and stirred for 1 h. The mixture was directly purified by column chromatography (THF / PE, 0-46%) to give Intermediate 30-8 (11 mg).

[0841] LC-MS: m / z (ESI): 536.4 [M+H] +

[0842] Step 8: Synthesis of Compound 30

[0843] A mixture of intermediate 30-8 (11 mg, 20.5 μmol), Pd(OAc)2(1.8 mg, 8.2 μmol), cataCXium A (5.9 mg, 16.4 μmol), potassium pivalate (8.6 mg, 61.5 mmol), tert- amyl alcohol (1 mL) was heated to 130 °C under microwave for 1 h. After that the mixture was concentrated under reduced pressure to remove the solvent, purified by preparative liquid chromatography (column: waters Xbridge OBD 19*150mm*5μm; mobile phase: [A: water(containing 0.0125% NH3), B: acetonitrile]; B%: 25%-60%, 10 min) to give compound 30 (3.6 mg).

[0844] LC-MS: m / z (ESI): 456.4 [M+H] +

[0845] 1 H NMR (400 MHz, DMSO-d6) δ 7.74 (s, 1H), 7.71-7.66 (m, 1H), 7.59-7.50 (m, 2H), 7.21-7.10 (m, 1H), 6.40 (d, J = 1.7 Hz, 1H), 6.32 (s, 2H), 5.51 (s, 1H), 5.18-5.10 (m, 1H), 4.96 (s, 1H), 4.22 (q, J = 7.3 Hz, 2H), 3.89 (s, 3H), 1.61 (d, J = 6.2 Hz, 3H), 1.35 (t, J = 7.2 Hz, 3H).

[0846] Example 31: Synthesis of compound 31

[0847] Step 1: Synthesis of 1-ethyl-3-(2-fluoroethoxy)-1H-pyrazole (intermediate 31-2)

[0848] Intermediate 31-1 (1.5 g, 13.4 mmol) was dissolved in N,N-dimethylformamide (15.0 mL), potassium carbonate (3.7 g, 26.8 mmol) and 2-fluoroethyl-4-methylbenzenesulfonate (5 g, 22.9 mmol) were added, and the mixture was reacted at 25 °C for 16 hours. Water (30.0 mL) was added for quenching, and extracted with ethyl acetate (30 mL x 3), and the organic phase was concentrated under reduced pressure to give intermediate 31-2 (2.1 g).

[0849] LCMS: m / z (ESI): 159.1 [M+H] +.

[0850] Step 2: Synthesis of 1-ethyl-3-(2-fluoroethoxy)-4-iodo-1H-pyrazole (Intermediate 31-3)

[0851] Intermediate 31-2 (2.1 g, 13.3 mmol) was dissolved in acetonitrile (20.0 mL), N- iodosuccinimide (3.6 g, 15.9 mmol) was added, and the mixture was reacted at 25 °C for 6 hours. Saturated aqueous sodium thiosulfate solution (20.0 mL) was added for quenching, and the reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 2:1) to give Intermediate 31-3 (2.0 g).

[0852] LCMS: m / z (ESI): 285.0 [M+H] +

[0853] Step 3: Synthesis of (1-ethyl-3-(2-fluoroethoxy)-1H-pyrazol-4-yl)(3-iodo-1-methyl-1H- pyrazol-4-yl)methanol (Intermediate 31-4)

[0854] Isopropylmagnesium bromide (5.4 mL, 1M, 5.4 mmol) was added to a solution of Intermediate 31-3 (1.4 g, 4.9 mmol) in tetrahydrofuran (20.0 mL) at 0 °C, and the reaction was stirred for 1 hour. 3-Iodo-1-methyl-1H-pyrazole-4-carbaldehyde (1.2 g, 4.9 mmol) was added, and the reaction was slowly warmed to 25 °C and reacted for 2 hours. Saturated aqueous ammonium chloride solution (20.0 mL) was added for quenching, and the reaction mixture was extracted with ethyl acetate (20.0 mL x 3). The combined organic phase was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to give Intermediate 31-4 (1.9 g).

[0855] LCMS: m / z (ESI): 395.0 [M+H] +

[0856] Step 4: Synthesis of (1-ethyl-3-(2-fluoroethoxy)-1H-pyrazol-4-yl)(3-iodo-1-methyl-1H- pyrazol-4-yl)methanone (Intermediate 31-5)

[0857] Intermediate 31-4 (1.9 g, 4.8 mmol) was dissolved in dichloromethane (30.0 mL), and manganese dioxide (4.3 g, 48.2 mmol) was added. The resulting mixture was reacted at 40 °C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to give Intermediate 31-5 (960.0 mg).

[0858] LCMS: m / z (ESI): 393.0 [M+H] +

[0859] Step 5: Synthesis of l-ethyl-3-(2-fluoroethoxy)-4-(l-(3-iodo-l-methyl-lH- pyrazol-4-yl)vinyl)-lH-pyrazole (Intermediate 31-6)

[0860] Under argon atmosphere, Intermediate 31-5 (900.0 mg, 2.3 mmol) was added into tetrahydrofuran (5.0 mL), and Tebbe’s reagent (6.9 mL, 0.5 M, 3.4 mmol) was added dropwise at 0 °C. After addition, the reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction was quenched by the addition of water (20.0 mL) and extracted with ethyl acetate (20.0 mL x 3). The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 1: 1) to give Intermediate 31-6 (620.0 mg).

[0861] LCMS: m / z (ESI): 391.1 [M+H] +

[0862] Step 6: Synthesis of (R)-l-(2-(4-(l-(l-ethyl-3-(2-fluoroethoxy)-lH-pyrazol-4-yl)vinyl)- 1 -methyl- 1 H-pyrazol-3 -yl)-5 -fluorophenyl)ethan- 1 -ol (Intermediate 31-7)

[0863] Under argon atmosphere, Intermediate 31-6 (600.0 mg, 1.5 mmol), Intermediate 1-4 (280.7 mg, 1.7 mmol), tris(dibenzylideneacetone)dipalladium (140.8 mg, 153.7 μmol), tricyclohexylphosphine (86.2 mg, 307.5 μmol) and potassium fluoride (268.0 mg, 4.6 mmol) were added into a mixture of 1,4-dioxane (10.0 mL) / water (2.0 mL), and the reaction mixture was stirred at 100 °C for 2 h. The reaction was quenched by the addition of water (20.0 mL) and extracted with ethyl acetate (20.0 mL x 3). The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 1: 1) to give Intermediate 31-7 (400.2 mg).

[0864] LCMS: m / z (ESI): 403.2 [M+H] +

[0865] Step 7: Synthesis of (R)-5-bromo-3-(l-(2-(4-(l-(l-ethyl-3-(2-fluoroethoxy)-lH-pyrazol-4- yl)vinyl)- 1 -methyl- 1 H-pyrazol-3 -yl)-5 -fluorophenyl)ethoxy)-2-nitropyridine (Intermediate 31-8)

[0866] Intermediate 31-7 (340.0 mg, 844.9 μmol), 5-bromo-3-fluoro-2-nitropyridine 373.4 mg, 1.7 mmol) were added to a solution of tetrahydrofuran (4.0 mL) at 0 °C, potassium tert-butoxide (1.7 mL, 1 M, 1.7 mmol) was added dropwise at 0 °C and reacted for 2 hours at 0 °C. Saturated ammonium chloride solution (10.0 mL) was added to quench, extracted with ethyl acetate (10.0 mL x 3), the organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to give intermediate 31-8 (400.0 mg).

[0867] LCMS: m / z (ESI): 603.1 / 605.1 [M+H] +

[0868] Step 8: Synthesis of (R)-5-bromo-3-(l-(2-(4-(l-(l-ethyl-3-(2- fluoroethoxy)-lH-pyrazol-4-yl)ethenyl)-l-methyl-lH-pyrazol-3-yl)-5- fluorophenyl)ethoxy)pyridin-2-amine (Intermediate 31-9)

[0869] Intermediate 31-8 (350.0 mg, 580.0 μmol) and anhydrous ammonium chloride (155.1 mg, 2.9 mmol) were dissolved in ethanol (5.0 mL) / water (1.0 mL), iron powder (162.0 mg, 2.9 mmol) was added, and the resulting mixture was heated to 80 °C for 1 hour. The reaction was filtered, extracted with ethyl acetate (10.0 mL), and the combined organic phases were concentrated to dryness under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to give intermediate 31-9 (300.0 mg).

[0870] LCMS: m / z (ESI): 573.1.1 / 575.1 [M+H] +

[0871] Step 9: Synthesis of compound 31

[0872] Intermediate 31-9 (140 mg, 244.1 μmol), palladium acetate (11.0 mg, 48.8 μmol), n-butyl bis(1-adamantyl)phosphine (70.0 mg, 195.3 μmol) and potassium pivalate (102.7 mg, 732.4 μmol) were dissolved in tert-amyl alcohol (3.0 mL) and stirred at 120 °C for 6 hours under argon atmosphere. After filtration, the filtrate was concentrated and the residue was purified by preparative liquid chromatography (column: YMC TA-C18, 30 x 150 mm, 5 μm; mobile phase A: 7 mmol / L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; flow rate: 30 mL / min; acetonitrile ratio 50-80%, elution for 8 minutes) to give compound 31 (60.0 mg).

[0873] LCMS: m / z (ESI): 493.2 [M+H] +

[0874] 1 H NMR (400 MHz, DMSO-d6) δ 7.66 (dd, J = 10.4, 2.8 Hz, 1H), 7.58 (s, 1H), 7.51 - 7.43 (m, 2H), 7.18 - 7.09 (m, 1H), 6.43 (d, J = 1.8 Hz, 1H), 6.14 (s, 2H), 5.24 (d, J = 2.3 Hz, 1H), 5.14 - 5.08 (m, 1H), 4.88 - 4.78 (m, 1H), 4.74 - 4.70 (m, 2H), 4.55 - 4.37 (m, 2H), 3.93 (q, J = 7.0 Hz, 2H), 3.87 (s, 3H), 1.59 (d, J = 6.2 Hz, 3H), 1.27 (t, J = 7.2 Hz, 3H).

[0875] Example 32: Synthesis of compound 32

[0876] Step 1: Synthesis of 1-ethyl-4-iodo-1H-pyrazol-3-ol (Intermediate 32-1)

[0877] 21-1 (5.0 g, 44.6 mmol) was dissolved in dry acetonitrile (40.0 mL) at 25 °C, and NIS (10.1 g, 45.6 mmol) was added. The reaction was allowed to proceed for 2 hours. The reaction was quenched with water (10.0 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated aqueous sodium sulfite solution and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 9: 1) to give intermediate 32-1 (9.5 g).

[0878] LCMS: m / z (ESI): 239.2 [M+H] +

[0879] Step 2: Synthesis of 1-ethyl-4-iodo-3-((4-methoxybenzyl)oxy)-1H-pyrazole (Intermediate 32-2)

[0880] Intermediate 32-1 (9.0 g, 37.8 mmol) was dissolved in DMF (30.0 mL), potassium carbonate (10.4 g, 75.6 mmol) was added and PMBCl (11.8 g, 75.6 mmol) was added dropwise into the reaction, which was stirred at 25 °C for 3 h. After the reaction was completed, the reaction was quenched by water (10.0 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 9: 1) to give Intermediate 32-2 (7.0 g).

[0881] LCMS: m / z (ESI): 359.2 [M+H] +

[0882] Step 3: Synthesis of (1-ethyl-3-((4-methoxybenzyl)oxy)-1H-pyrazol-4-yl)(3-iodo-1- methyl-1H-pyrazol-4-yl)methanol (Intermediate 32-3)

[0883] Isopropyl magnesium bromide (19.0 mL, 1M, 19.0 mmol) was added to a solution of 43-iodo-1-methyl-1H-pyrazole-4-carbaldehyde (4.1 g, 17.2 mmol) in tetrahydrofuran (20.0 mL) at 0 °C, and the reaction was stirred for 1 h. A solution of Intermediate 32-2 (6.15 g, 17.2 mmol) in tetrahydrofuran (5.0 mL) was added, and the reaction was stirred at 0 °C for 1 h. After the reaction was completed, the reaction was quenched by water (10.0 mL) and extracted with ethyl acetate (20.0 mL x 3). The organic phase was concentrated under reduced pressure to give crude Intermediate 32-3 (6.2 g), which was used directly in the next step.

[0884] LCMS: m / z (ESI): 469.2 [M+H] +

[0885] Step 4: Synthesis of (1-ethyl-3-((4-methoxybenzyl)oxy)-1H-pyrazol-4-yl)(3-iodo-1- methyl-1H-pyrazol-4-yl)methanol (Intermediate 32-3)

[0886] Intermediate 32-3 (1.2 g, 2.6 mmol) was dissolved in dichloromethane (10.0 mL), and manganese dioxide (661.0 mg, 7.8 mmol) was added. The mixture was stirred at 25 °C for 12 h. The reaction was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 1: 1) to give Intermediate 32-4 (850 mg).

[0887] LCMS: m / z (ESI): 467.2 [M+H] +

[0888] Step 5: Synthesis of 1-ethyl-4-(1-(3-iodo-1-methyl-1H-pyrazol-4-yl)vinyl)-3-((4- methoxybenzyl)oxy)-1H-pyrazole (Intermediate 32-5)

[0889] n-Butyllithium (1.29 mL, 2.5 M, 3.2 mmol) was added dropwise to a solution of TPMP (1.2 g, 3.2 mmol) in tetrahydrofuran (10.0 mL) at 0 °C, then the reaction was raised to 25 °C and stirred for 30 min. A solution of Intermediate 32-4 (600.0 mg, 1.3 mmol) in tetrahydrofuran (2.0 mL) was added dropwise to the reaction solution and the reaction was continued for 1 h. The reaction was quenched with aqueous ammonium chloride solution and extracted with ethyl acetate (10 mL x 3). The organic phase was concentrated under reduced pressure and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 9: 1) to give Intermediate 32-5 (510 mg).

[0890] LCMS: m / z (ESI): 465.2 [M+H] +

[0891] Step 6: Synthesis of (R)-1-(2-(4-(1-(1-ethyl-3-((4-methoxybenzyl)oxy)-1H-pyrazol-4-yl)vinyl)-1- methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethan-1-ol (Intermediate 32-6)

[0892] Intermediate 32-5 (500.0 mg, 1.1 mmol), 1-4 (321.7 mg, 1.9 mmol), tetrakis(triphenylphosphine)palladium (98.5 mg, 107.7 μmol), PCy3 (60.3 mg, 215.4 μmol) and potassium fluoride (187.7 mg, 3.2 mmol) were dissolved in 1,4-dioxane (20 mL) and water (2 mL) under argon atmosphere. The reaction was heated to 100 °C and stirred for 12 h. The reaction was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 1: 1) to give Intermediate 32-6 (420.0 mg).

[0893] LCMS: m / z (ESI): 477.1 [M+H] +

[0894] Step 7: Synthesis of (R)-5-bromo-3-(l-(2-(4-(l-(l-ethyl-3-((4- methoxybenzyl)oxy)-lH-pyrazol-4-yl)vinyl)-l-methyl-lH-pyrazol-3-yl)-5- fluorophenyl)ethoxy)-2-nitropyridine (Intermediate 32-7)

[0895] Intermediate 32-6 (400.0 mg, 839.4 pmol) and 5-bromo-3-fluoro-2-nitropyridine (556.5 mg, 2.5 mmol) were dissolved in tetrahydrofuran (25.0 mL), the resulting mixture was cooled to 0 °C, then potassium tert-butoxide (2.5 mL, 1.0 M, 2.5 mmol) was added dropwise and reacted for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride solution (10 mL), extracted with dichloromethane (10.0 mL x 3), and the organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 1 : 1) to give Intermediate 32-7 (360.0 mg).

[0896] LCMS: m / z (ESI): 677.2 / 679.2 [M+H] +

[0897] Step 8: Synthesis of (R)-5-bromo-3-(l-(2-(4-(l-(l-ethyl-3-((4- methoxybenzyl)oxy)-lH-pyrazol-4-yl)vinyl)-l-methyl-lH-pyrazol-3-yl)-5- fluorophenyl)ethoxy)pyridin-2-amine (Intermediate 32-8)

[0898] Intermediate 32-7 (300.0 mg, 442.8 pmol) and ammonium chloride (248.0 mg, 4.4 mmol) were dissolved in ethanol (10.0 mL) and water (2.0 mL), then iron powder (248.0 mg, 4.4 mmol) was added, and the resulting mixture was stirred at 85 °C for 3 hours. The reaction was filtered, extracted with dichloromethane (10.0 mL x 3), and the organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 1 : 1) to give Intermediate 32-8 (210.0 mg).

[0899] LCMS: m / z (ESI): 647.1 / 649.1 [M+H] +

[0900] Step 9: Synthesis of Intermediate 32-9

[0901] Intermediate 32-8 (200.0 mg, 308.8 μmol), Pd(OAc)2(13.8 mg, 61.8 μmol), PivOK (130.6 mg, 926.4 μmol) and cataCXium A (44.2 mg, 123.6 μmol) were dissolved in tert-amyl alcohol (4.0 mL). The reaction was heated to 110 °C under argon atmosphere and stirred for 16 h. Then, the reaction was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (column: YMC TA-C18, 30*150 mm, 5 μm; mobile phase A: 7 mmol / L NH4HCO3, mobile phase B: acetonitrile; flow rate: 30 mL / min; acetonitrile ratio 45-75%, elution 10-11 min) to give intermediate 32-9 (30 mg).

[0902] LCMS: m / z (ESI): 567.2 [M+H] +

[0903] Step 10: Synthesis of intermediate 32-10

[0904] Intermediate 32-9 (100.0 mg, 176.4 μmol) was dissolved in dichloromethane (5.0 mL) at 25 °C, and trifluoroacetic acid (24.2 mg, 211.8 μmol) was added dropwise to the reaction. After 30 min, the reaction was poured into water, and the product was extracted with ethyl acetate (10.0 mL x 3). The organic phase was concentrated under reduced pressure to give intermediate 32-10 (62.0 mg) as a crude product, which was used directly in the next step.

[0905] LCMS: m / z (ESI): 447.2 [M+H] +

[0906] Step 11: Synthesis of compound 32

[0907] Intermediate 32-10 (60.0 mg, 134.4 μmol), PPh3(105.6 mg, 403.2 μmol), DIAD (81.4 mg, 403.2 μmol) and 1-methyl-4-piperidinol (46.8 mg, 403.2 μmol) were dissolved in xylene (2.5 mL). The reaction was stirred at 110 °C under argon atmosphere for 12 h. The reaction was purified by preparative liquid chromatography (column: YMC TA-C18, 30*150 mm, 5 μm; mobile phase A: 7 mmol / L NH4HCO3, mobile phase B: acetonitrile; flow rate: 30 mL / min; acetonitrile ratio 45-75%, elution 10-11 min) to give compound 32 (34.0 mg).

[0908] LCMS: m / z (ESI): 544.3 [M+H]+

[0909] 1 H NMR (400 MHz, DMSO-d6) δ 7.69-7.60 (m, 1H), 7.54 (s, 1H), 7.52-7.41 (m, 2H), 7.17-7.08 (m, 1H), 6.43 (d, J = 1.8 Hz, 1H), 6.09 (s, 2H), 5.23 (d, J = 2.4 Hz, 1H), 5.15-5.06 (m, 1H), 4.70 (d, J = 2.2 Hz, 1H), 4.63-4.53 (m, 1H), 3.99-3.82 (m, 5H), 2.69-2.60 (m, 2H), 2.21-2.08 (m, 5H), 2.04-1.94 (m, 1H), 1.87-1.64 (m, 3H), 1.59 (d, J = 6.2 Hz, 3H), 1.24 (t, J = 7.1 Hz, 3H).

[0910] Example 33: Synthesis of compound 33

[0911] Step 1: Synthesis of (1-ethyl-1H-pyrazol-3-yl)methanol (intermediate 33-2)

[0912] Intermediate 33-1 (5.0 g, 40.3 mmol) was dissolved in methanol (20.0 mL), sodium borohydride (2.3 g, 60.4 mmol) was added, and the mixture was reacted at 25 °C for 1 hour. Water (20.0 mL) was added for quenching, and extraction was performed with ethyl acetate (20.0 mL x 3). After the organic phase was concentrated under reduced pressure, intermediate 33-2 (5.0 g) was obtained.

[0913] LCMS: m / z (ESI): 127.1 [M+H] +

[0914] Step 2: Synthesis of 3-(((tert-butyldimethylsilyl)oxy)methyl)-1-ethyl-1H-pyrazole (intermediate 33-3)

[0915] Intermediate 33-2 (1.5 g, 11.9 mmol) was dissolved in DMF (10.0 mL), TBSCl (2.7 g, 17.8 mmol), triethylamine (2.4 g, 23.8 mmol) and 4-dimethylaminopyridine (145.3 mg, 1.2 mmol) were added, and the mixture was reacted at 25 °C for 1 hour. Water (30.0 mL) was added for quenching, and extraction was performed with ethyl acetate (30.0 mL x 3). After the organic phase was concentrated under reduced pressure, the residue was purified by column chromatography (petroleum ether: ethyl acetate = 8: 1) to obtain intermediate 33-3 (2.5 g).

[0916] LCMS: m / z (ESI): 241.2 [M+H] +

[0917] Step 3: Synthesis of 3-(((tert-butyldimethylsilyl)oxy)methyl)-l-ethyl-4-iodo-lH- pyrazole (Intermediate 33-4)

[0918] Intermediate 33-3 (1.5 g, 6.2 mmol) was dissolved in acetonitrile (15.0 mL), NIS (1.5 g, 6.8 mmol) was added, and the mixture was reacted at 70 °C for 4 hours. Saturated aqueous sodium sulfite solution (20.0 mL) was added for quenching, and extraction was performed with ethyl acetate (20.0 mL x 3). After the organic phase was concentrated under reduced pressure, the residue was purified by column chromatography (petroleum ether: ethyl acetate = 9: 1) to obtain intermediate 33-4 (1.8 g).

[0919] LCMS: m / z (ESI): 367.0 [M+H] +

[0920] Step 4: Synthesis of 3-(((tert-butyldimethylsilyl)oxy)methyl)-l-ethyl-lH-pyrazole-4- carboxaldehyde (Intermediate 33-5)

[0921] Isopropyl magnesium bromide (6.0 mL, 1M, 6.0 mmol) was added to a solution of intermediate 33-4 (1.8 g, 5.0 mmol) in tetrahydrofuran (25.0 mL) at 0 °C, and the reaction was stirred for 1 hour. DMF (730.3 mg, 9.9 mmol) was added, and the reaction was stirred for 2 hours. Saturated aqueous ammonium chloride solution (20.0 mL) was added for quenching, extraction was performed with ethyl acetate (20.0 mL x 3), the combined organic phases were concentrated to dryness under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 4: 1) to obtain intermediate 33-5 (1.2 g).

[0922] LCMS: m / z (ESI): 269.1 [M+H] +

[0923] Step 5: Synthesis of (3-bromo-l-methyl-lH-pyrazol-4-yl)(3-(((tert-butyldimethylsilyl)oxy)methyl)-l-ethyl-lH-pyrazol-4-yl)methanol (Intermediate 33-6)

[0924] Isopropyl magnesium bromide (2.2 mL, 1 M, 2.2 mmol) was added to a solution of intermediate 33-5 (500.0 mg, 1.8 mmol) in tetrahydrofuran (10.0 mL) at 0 °C, and stirred for 30 min. Intermediate 33-6 (600.0 mg, 1.4 mmol) was added, and stirred for 1.5 h. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (10.0 mL), and extracted with ethyl acetate (10.0 mL x 3). The combined organic phase was concentrated under reduced pressure to dryness, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to give intermediate 33-7 (501.9 mg).

[0925] LCMS: m / z (ESI): 429.1 / 431.1 [M+H] +

[0926] Step 6: Synthesis of (3-bromo-l-methyl-lH-pyrazol-4-yl)(3-(((tert- butyldimethylsilyl)oxy)methyl)-l-ethyl-lH-pyrazol-4-yl)methanone (intermediate 33-7)

[0927] Intermediate 33-6 (600.0 mg, 1.4 mmol) was dissolved in dichloromethane (10.0 mL), and manganese dioxide (1.6 g, 18.6 mmol) was added. The resulting mixture was stirred at 40 °C for 12 h. The reaction was filtered, and the filtrate was concentrated under reduced pressure to dryness. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to give intermediate 33-7 (501.9 mg).

[0928] LCMS: m / z (ESI): 427.1 / 429.1 [M+H] +

[0929] Step 7: Synthesis of 3-bromo-4-(l-(3-(((tert-butyldimethylsilyl)oxy)methyl)-l- ethyl-lH-pyrazol-4-yl)vinyl)-l-methyl-lH-pyrazole (intermediate 33-8)

[0930] Intermediate 33-7 (450.0 mg, 1.0 mmol) was added to tetrahydrofuran (5.0 mL) under argon atmosphere, and Tebbe’s reagent (3.2 mL, 0.5 M, 1.6 mmol) was added dropwise at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The reaction was quenched by the addition of water (5.0 mL), and extracted with ethyl acetate (5.0 mL x 3). The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to give intermediate 33-8 (295.9 mg).

[0931] LCMS: m / z (ESI): 425.1 / 427.1 [M+H] +

[0932] Step 8: Synthesis of (R)-1-(2-(4-(1-(3-(((tert-butyldimethylsilyl)oxy)methyl)-1- ethyl-1H-pyrazol-4-yl)vinyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethan-1-ol (Intermediate 33-9)

[0933] Intermediate 33-8 (275.9 mg, 648.5 μmol), 1-4 (161.4 mg, 972.7 μmol), Pd2dba3 (59.4 mg, 64.8 μmol), PCy3 (36.4 mg, 129.7 μmol) and potassium carbonate (268.8 mg, 1.9 mmol) were added into a mixture solvent of 1,4-dioxane (6.0 mL) / water (1.2 mL) under argon atmosphere, and the reaction was carried out at 100 °C for 4 h. The reaction was quenched by adding water (5.0 mL), and extracted with ethyl acetate (5.0 mL x 3). The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to give Intermediate 33-9 (303.8 mg).

[0934] LCMS: m / z (ESI): 485.2 [M+H] +

[0935] Step 9: Synthesis of (R)-5-bromo-3-(1-(2-(4-(1-(3-(((tert-butyldimethylsilyl)oxy)methyl)-1- ethyl-1H-pyrazol-4-yl)vinyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethoxy)-2- nitropyridine (Intermediate 33-10)

[0936] Sodium hydride (75.2 mg, 1.9 mmol, 60%) was added to a solution of Intermediate 33-9 (303.8 mg, 626.8 μmol) in tetrahydrofuran (6.0 mL) at 0 °C, and the reaction was stirred for 1 h. 5-Bromo-3-fluoro-2-nitropyridine (415.5 mg, 1.9 mmol) was added, and the reaction was carried out at 70 °C for 12 h. The reaction was quenched by adding saturated aqueous ammonium chloride solution (5.0 mL), and extracted with ethyl acetate (5.0 mL x 3). The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to give Intermediate 33-10 (304.0 mg).

[0937] LCMS: m / z (ESI): 685.1 / 687.1 [M+H] +

[0938] Step 10: Synthesis of (R)-5-bromo-3-(l-(2-(4-(l-(3-(((tert- butyldimethylsilyl)oxy)methyl)-l-ethyl-lH-pyrazol-4-yl)vinyl)-l-methyl- lH-pyrazol-3-yl)-5-fluorophenyl)ethoxy)pyridin-2-amine (Intermediate 33-11)

[0939] Intermediate 33-10 (304.0 mg, 443.4 μmol) was dissolved in ethanol (5.0 mL) / water (1.0 mL) with anhydrous ammonium chloride (142.3 mg, 2.7 mmol), and iron powder (148.5 mg, 2.7 mmol) was added. The resulting mixture was heated to 80 °C for 1 h. The reaction was filtered, extracted with ethyl acetate (10.0 mL), and the organic phases were combined and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 1 : 1) to give Intermediate 33-11 (257.8 mg).

[0940] LCMS: m / z (ESI): 655.1 / 657.1 [M+H] +

[0941] Step 11: Synthesis of Intermediate 33-12

[0942] Intermediate 33-11 (257.8 mg, 393.2 μmol), Pd(OAc)2(17.6 mg, 78.6 μmol), cataCXium A (56.4 mg, 157.3 μmol), and PivOK (220.5 mg, 1.6 mmol) were dissolved in t-AmOH (4.0 mL). The reaction was stirred at 150 °C under an argon atmosphere for 12 h. The reaction was filtered and concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 1 : 1) to give 33-12 (12.3 mg).

[0943] LCMS: m / z (ESI): 575.3 [M+H] +

[0944] Step 12: Synthesis of Intermediate 33-13

[0945] Intermediate 33-12 (12.3 mg, 21.4 μmol) was dissolved in methanol (2.0 mL), and hydrochloric acid (17.83 μL, 12 M, 214.0 μmol) was added. The reaction was stirred at 25 °C for 1 h. The reaction was concentrated under reduced pressure to give 33-13 (7.0 mg).

[0946] LCMS: m / z (ESI): 461.2 [M+H] +

[0947] Step 13: Synthesis of Compound 33

[0948] Intermediate 33-13 (7.0 mg, 15.2 μmol) was dissolved in dichloromethane (1.0 mL), and BAST (5.0 mg, 22.8 μmol) was added. The reaction solution was stirred at 25 °C for 2 h. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution (10.0 mL), and extracted with ethyl acetate (5.0 mL x 3). The organic phase was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (column: YMC TA-C18, 30 x 150 mm, 5 μm; mobile phase A: 7 mmol / L ammonium bicarbonate, mobile phase B: acetonitrile; flow rate: 30 mL / min; acetonitrile ratio 45-75%, elution 10-11 min) to give compound 33 (0.07 mg).

[0949] LC-MS: m / z (ESI): 463.3 [M+H] +

[0950] Example 34: Synthesis of compound 34

[0951] Compound 20 (15.0 mg, 29.4 μmol), 2-(tri-n-butylstannyl)thiazole (55.1 mg, 147 μmol) and tetrakis(triphenylphosphine)palladium (6.8 mg, 5.9 μmol) were dissolved in 1,4-dioxane (1.0 mL) under argon atmosphere, and the reaction was stirred at 150 °C for 6 h in a microwave. The mixture was then concentrated under reduced pressure to remove the solvent, and the residue was purified by preparative liquid chromatography (column: waters Xbridge OBD 19*150mm*5μm; mobile phase: [A: water (0.0125% NH3), B: acetonitrile]; B%: 25%-60%, 10 min) to give compound 34 (5.0 mg).

[0952] LC-MS: m / z (ESI): 514.3 [M+H] +

[0953] 1 H NMR (400 MHz, DMSO-d6) δ 7.90 (d, J = 3.4 Hz, 1H), 7.71 (d, J = 3.1 Hz, 1H), 7.68 (d, J = 6.2 Hz, 2H), 7.57-7.53 (m, 2H), 7.17-7.05 (m, 1H), 6.54 (s, 1H), 6.20 (s, 2H), 5.24 (d, J = 1.9 Hz, 1H), 5.16 (d, J = 6.7 Hz, 1H), 4.65 (s, 1H), 4.18 (m, 2H), 3.84 (s, 3H), 1.61 (d, J = 6.2 Hz, 3H), 1.36 (t, J = 7.2 Hz, 3H).

[0954] Example 35: Synthesis of compound 35

[0955] Compound 20 (5 mg, 9.8 pmol), morpholine (8.5 mg, 98 pmol), GPhos Pd G6 (2.8 mg, 2.9 pmol) and potassium tert-butoxide (22.0 mg, 196 pmol) were dissolved in 1,4-dioxane (0.5 mL) under argon atmosphere, and stirred at 130 °C for 4 h. The reaction solution was purified by preparative liquid chromatography (column: waters Xbridge OBD 19*150mm*5pm; mobile phase: [A: water (0.0125% NH3), B: acetonitrile]; B%: 25%-60%, 10 min) to give compound 35 (0.44 mg).

[0956] MS m / z (ESI): 516.4 [M+H] +

[0957] 1 H NMR (400 MHz, DMSO-d6) d 7.80 (s, 1H), 7.74-7.66 (m, 1H), 7.54-7.46 (m, 1H), 7.45-7.39 (m, 1H), 7.17-7.08 (m, 1H), 6.43 (s, 1H), 6.10 (s, 2H), 5.17 (s, 1H), 5.13-5.02 (m, 2H), 4.65 (s, 1H), 3.91 (s, 3H), 3.77-3.68 (m, 2H), 3.21-3.12 (m, 1H), 1.57 (d, J = 6.1 Hz, 3H), 1.29-1.20 (m, 3H).

[0958] Example 36: Synthesis of compound 36

[0959] Compound 20 (25 mg, 49.1 pmol), Gphos Pd G6 (13.9 mg, 14.7 pmol), potassium tert-butoxide (82.6 mg, 736 pmol), 2-methyl-2,6-diazaspiro[3.3]heptane dihydrochloride (45.4 mg, 245 pmol) were added to 1,4-dioxane (1 mL) under argon atmosphere, and stirred at 125 °C for 4 h. The reaction solution was then filtered and purified by preparative liquid chromatography (column: waters Xbridge OBD 19*150mm*5pm; mobile phase: [A: water (0.0125% NH3), B: acetonitrile]; B%: 25%-60%, 10 min) to give compound 36 (1.29 mg).

[0960] LC-MS: m / z (ESI): 541.5 [M+H] +

[0961] 1 H NMR (400 MHz, DMSO-d6) δ 7.72 (s, 1H), 7.70-7.64 (m, 1H), 7.49-7.42 (m, 1H), 7.37 (d, J = 1.8 Hz, 1H), 7.17-7.10 (m, 1H), 6.40 (s, 1H), 6.09 (s, 2H), 5.28-5.20 (m, 1H), 5.13-5.05 (m, 1H), 4.73 (d, J = 2.2 Hz, 1H), 4.07-3.95 (m, 4H), 3.93-3.84 (m, 4H), 3.83-3.69 (m, 3H), 1.58 (d, J = 6.2 Hz, 3H), 1.24 (t, J = 7.1 Hz, 3H).

[0962] Example 37: Synthesis of compound 37

[0963] Compound 20 (30 mg, 59 μmol), (2R)-1,2-dimethylpiperazine (67.3 mg, 588 μmol), GPhos Pd G6 (16.7 mg, 17.7 μmol) and potassium tert-butoxide (66.1 mg, 589 μmol) were dissolved in 1,4-dioxane (1.8 mL) under argon atmosphere and stirred at 100 °C for 2 h in a microwave reactor. The mixture was then concentrated under reduced pressure to remove the solvent and the residue was purified by preparative liquid chromatography (column: waters Xbridge OBD 19*150mm*5μm; mobile phase: [A: water (0.0125% NH3), B: acetonitrile]; B%: 25%-60%, 10 min) to give the title compound 37 (0.69 mg).

[0964] LC-MS: m / z (ESI): 543.6 [M+H] +

[0965] Example 38: Synthesis of compound 38

[0966] Step 1: Synthesis of 1-cyclopropyl-1H-pyrazole-3-carbonitrile (Intermediate 38-2)

[0967] Into a reaction vial was placed 38-1 (1.0 g, 11 mmol), cyclopropylboronic acid (1.85 g, 21.5 mmol), copper acetate (1.95 g, 10.7 mmol), 2,2’-bipyridine (1.68 g, 10.7 mmol) and DCE (20 mL), the mixture was stirred at 70 °C for 4 h. The mixture was concentrated under reduced pressure, then ethyl acetate (15 mL) was added, extracted with saturated aqueous ammonium chloride solution (5 mL x 3), the organic layer was concentrated under reduced pressure, then purified by column chromatography (THF / PE, 0-100%) to give intermediate 38-2 (0.69 g).

[0968] LC-MS: m / z (ESI): 134.2 [M+H] +

[0969] Step 2: Synthesis of 1-cyclopropyl-5-(hydroxy(3-iodo-1-methyl-1H-pyrazol-4- yl)methyl)-1H-pyrazole-3-carbonitrile (Intermediate 38-3)

[0970] Into a reaction vial was placed intermediate 38-2 (200 mg, 1.50 mmol), tetrahydrofuran (4 mL). Under argon atmosphere, LDA (2 Min THF, 1.13 mL, 2.25 mmol) was added to the reaction vial and stirred for 1 h at -78 °C. A solution of 3-iodo-1-methyl-1H-pyrazole-4- carbaldehyde (531 mg, 2.25 mmol) in tetrahydrofuran (10 mL) was added to the reaction vial and stirred for 2 h at -78 °C. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (15 mL), extracted with dichloromethane (10 mL x 3), the organic layers were combined and the mixture was concentrated under reduced pressure, then purified by column chromatography (THF / PE, 0-100%) to give intermediate 38-3 (258 mg).

[0971] LC-MS: m / z (ESI): 370.3 [M+H] +

[0972] Step 3: Synthesis of 1-cyclopropyl-5-(3-iodo-1-methyl-1H-pyrazole-4-carbonyl)-1H- pyrazole-3-carbonitrile (Intermediate 38-4)

[0973] Into a reaction vial was placed intermediate 38-3 (419 mg, 1.14 mmol), manganese dioxide (2.47 g, 28.4 mmol), and dichloromethane (20 mL), the mixture was stirred at room temperature for 1 h. The mixture was filtered and concentrated under reduced pressure to remove the solvent, the residue was purified by column chromatography (THF / PE, 0-100%) to give intermediate 38-4 (251 mg).

[0974] LC-MS: m / z (ESI): 368.3 [M+H] +

[0975] Step 4: Synthesis of l-cyclopropyl-5-(l-(3-iodo-l-methyl-lH-pyrazol-4-yl)vinyl)- lH-pyrazole-3-carbonitrile (Intermediate 38-5)

[0976] To the reaction flask was added TPMP (486 mg, 1.36 mmol) under argon atmosphere at 0 °C, n-butyllithium (1.6 M in Hexane, 0.851 mL, 1.36 mmol) was stirred for 30 min, kept under argon atmosphere at 0 °C, a solution of Intermediate 38-4 (250 mg, 681 μmol) in tetrahydrofuran (4 mL) was added, followed by increasing the temperature to 50 °C and stirring for 1 h. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (10 mL), the organic layer was extracted with dichloromethane (10 mL x 3) and the combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography (THF / PE, 0-100%) to give Intermediate 38-5 (184 mg).

[0977] LC-MS: m / z (ESI): 366.1 [M+H] +

[0978] Step 5: Synthesis of (R)-l-cyclopropyl-5-(l-(3-(4-fluoro-2-(l-hydroxyethyl)phenyl)-l- methyl-lH-pyrazol-4-yl)vinyl)-lH-pyrazole-3-carbonitrile (Intermediate 38-6)

[0979] A mixture of Intermediate 38-5 (184 mg, 504 μmol), Intermediate 1-4 (167 mg, 1.01 mmol), Pd(Amphos)2Cl2(53.5 mg, 75.6 μmol), potassium phosphate (320 mg, 1.51 mmol), TBME (2 mL) and water (2 mL) was heated to 60 °C for 1 h under argon atmosphere. The mixture was then concentrated under reduced pressure to remove the solvent and the residue was purified by column chromatography (THF / PE, 0-100%) to give Intermediate 38-6 (185 mg).

[0980] LC-MS: m / z (ESI): 378.3 [M+H] +

[0981] Step 6: Synthesis of (R)-5-(l-(3-(2-(l-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4- fluoro phenyl)-l-methyl-lH-pyrazol-4-yl)vinyl)-l-cyclopropyl-lH-pyrazole-3-carbonitrile (Intermediate 38-7)

[0982] To a mixture of intermediate 38-6 (185 mg, 490 pmol), 5-bromo-3-fluoro-2- nitropyridine (216 mg, 980 pmol) and toluene (2 mL) was added tert-butoxy lithium (2.2 M in THF, 668 pL, 1.47 mmol) at 0 °C under argon atmosphere. The resulting mixture was allowed to warm to rt for 0.5 h. The mixture was then concentrated under reduced pressure to remove the solvent and the residue was purified by column chromatography (THF / PE, 0-100%) to give intermediate 38-7 (205 mg).

[0983] LC-MS: m / z (ESI): 578.4 / 580.4 [M+H] +

[0984] Step 7: Synthesis of (R)-5-(l-(3-(2-(l-((2-amino-5-bromopyridin-3-yl)oxy)ethyl)-4- fluorophenyl)-lH-pyrazol-4-yl)vinyl)-l-cyclopropyl-lH-pyrazole-3-carbonitrile (Intermediate 38-8)

[0985] A mixture of intermediate 38-7 (205 mg, 354 pmol), iron powder (198 mg, 3.54 mmol), ammonium chloride (190 mg, 3.54 mmol), EtOH (2 mL) and water (2 mL) was heated to 80 °C under argon atmosphere and stirred for 1 h. The mixture was then directly purified by column chromatography (THF / PE, 0-100%) to give intermediate 38-8 (191 mg).

[0986] LC-MS: m / z (ESI): 548.4 / 550.4 [M+H] +

[0987] Step 8: Synthesis of compound 38

[0988] A mixture of intermediate 38-8 (95.0 mg, 174 pmol), Pd(OAc)2(27.2 mg, 121 pmol), cataCXium A (93.2 mg, 260 pmol), potassium pivalate (72.9 mg, 520 mmol) and t-AmOH (5 mL) was heated to 120 °C under argon atmosphere and stirred for 4 h. The mixture was then concentrated under reduced pressure to remove the solvent and the residue was purified by preparative liquid chromatography (column: waters Xbridge OBD 19*150mm*5pm; mobile phase: [A: water (0.0125% NH3), B: acetonitrile]; B%: 25%-60%, 10 min) to give the title compound (5.6 mg).

[0989] LC-MS: m / z (ESI): 468.4 [M+H]+

[0990] 1 H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.66-7.56 (m, 3H), 7.18 (td, J = 8.4, 2.8 Hz, 1H), 6.44 (d, J = 1.9 Hz, 1H), 6.03 (s, 2H), 5.82 (d, J = 1.2 Hz, 1H), 5.25 (d, J = 1.1 Hz, 1H), 5.10-4.96 (m, 1H), 3.91 (s, 3H), 2.33 (p, J = 1.9 Hz, 1H), 1.62 (d, J = 6.2 Hz, 3H), 1.35-1.22 (m, 2H), 1.21-1.01 (m, 2H).

[0991] Example 39: Synthesis of compound 39

[0992] Compound 20 (30 mg, 59 μmol), 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (131 mg, 588 μmol), cataCXium A Pd G3 (12.9 mg, 17.7 μmol) and cesium carbonate (192 mg, 589.3 μmol) were dissolved in 1,4-dioxane (4 mL) and water (0.4 mL) under argon atmosphere and stirred at 115 °C for 4 h. The reaction mixture was then purified by reverse phase column chromatography (acetonitrile / 0.0125% ammonia water, 40-80%) to give compound 39 (4.1 mg).

[0993] MS m / z (ESI): 526.5 [M+H] +

[0994] 1 H NMR (400 MHz, DMSO-d6) δ 7.73-7.66 (m, 1H), 7.57-7.51 (m, 2H), 7.45 (d, J = 1.8 Hz, 1H), 7.17-7.09 (m, 1H), 6.48-6.39 (m, 2H), 6.09 (s, 2H), 5.25 (d, J = 2.2 Hz, 1H), 5.11 (d, J = 6.7 Hz, 1H), 4.66 (d, J = 2.1 Hz, 1H), 4.11-3.99 (m, 2H), 3.88 (s, 3H), 3.09-2.91 (m, 3H), 2.66-2.60 (m, 3H), 2.29 (s, 3H), 1.59 (d, J = 6.2 Hz, 3H), 1.30 (t, J = 7.2 Hz, 3H).

[0995] Example 40: Synthesis of compound 40

[0996] Under an argon atmosphere, 19-12 (30 mg, 58.3 μmol), K2CO3 (8.06 mg, 58.3 μmol), and 1-fluoro-2-iodoethane (10.1 mg, 58.3 μmol) were added to acetonitrile (1 mL), and the reaction was carried out at room temperature for 2 h. The reaction solution was then filtered and purified by preparative liquid chromatography (column: Waters Xbridge OBD 19*150 mm*5 μm; mobile phase: [A: water (0.0125% NH3), B: acetonitrile]; B%: 25%-60%, 10 min) to give compound 40 (6.4 mg).

[0997] LC-MS: m / z (ESI): 561.4 [M+H] +

[0998] 1 H NMR(400MHz, DMSO-d6)δ7.76(s,1H),7.69(dd,J=10.4,2.8Hz,1H),7.49(dd,J=8.4,6.0Hz,1H), 7.40(d,J=1.6Hz,1H),7.12(td,J=8.4,2.8Hz,1H),6.43(s,1H),6.08(s,2H),5.16(d,J=2.4Hz,1 H),5.10(d,J=6.4Hz,1H),4.66-4.59(m,2H),4.50(t,J=4.8Hz,1H),3.96-3.84(m,6H),3.38-3.3 5(m,2H),2.62(t,J=4.8Hz,2H),2.58-2.55(m,4H),1.57(d,J=6.4Hz,3H),1.25(t,J=7.2Hz,3H).

[0999] Example 41: Synthesis of Compound 41

[1000] Under an argon atmosphere, intermediate 19-12 (50 mg, 97.2 μmol), cyclopropylboronic acid (9.1 mg, 107 μmol), copper acetate (17.6 mg, 97 μmol), sodium carbonate (20.6 mg, 194 μmol), and 2,2'-bipyridine (15.2 mg, 97 μmol) were added to 1,2-dichloroethane (1 mL), purged with nitrogen, and reacted at 60 °C for 5 h. The reaction solution was then filtered and purified by preparative liquid chromatography (column: Waters Xbridge OBD 19*150 mm*5 μm; mobile phase: [A: water (0.0125% NH3), B: acetonitrile]; B%: 25%-60%, 10 min) to obtain compound 41 (4.1 mg).

[1001] LC-MS: m / z (ESI): 555.47 [M+H] +

[1002] 1 H NMR(400MHz, DMSO-d6)δ7.75(s,1H),7.68(dd,J=10.4,2.8Hz,1H),7.49(dd,J=8.5,5.8Hz,1H),7.4 1(s,1H),7.12(td,J=8.4,2.9Hz,1H),6.43(s,1H),6.06(s,2H),5.16(d,J=2.3Hz,1H),5.10(d,J=7 .1Hz,1H),4.63(d,J=2.1Hz,1H),3.94-3.85(m,5H),3.17(d,J=11.9Hz,2H),2.70-2.56(m,6H),1.7 2-1.62(m,1H),1.57(d,J=6.2Hz,3H),1.24(t,J=7.1Hz,3H),0.47-0.40(m,2H),0.36-0.31(m,2H).

[1003] Example 42: Synthesis of Compound 42

[1004] Compound 39 (6 mg, 11 μmol), a mixture of 5% palladium / carbon (5 mg) and methanol (2 mL) was stirred at room temperature for 7 h under a hydrogen atmosphere. The reaction solution was purified by reversed-phase column chromatography (acetonitrile / 0.0125% ammonia, 40-80%) to give compound 42 (1.38 mg).

[1005] MS m / z (ESI): 528.4 [M+H] +

[1006] 1H NMR(400MHz,DMSO-d6)δ7.62-7.56(m,1H),7.51-7.43(m,2H),7.38-7.32(m,1H),7.10-7.01(m ,1H),6.37(d,J=1.8Hz,1H),5.98(s,2H),5.28(d,J=2.3Hz,1H),5.09-4.97(m,1H),4.65(d,J= 2.2Hz,1H),4.02-3.89(m,2H),3.82(s,3H),2.94-2.72(m,2H),2.65-2.61(m,1H),2.21-2.10( m,3H),2.03-1.98(m,3H),1.97-1.57(m,3H),1.53(d,J=6.2Hz,3H),1.22(t,J=8.2,7.7Hz,3H).

[1007] Example 43: Synthesis of Compound 43

[1008] Step 1: Synthesis of (5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)methanol (intermediate 43-1)

[1009] Methyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate (1.2 g, 7.2 mmol) was dissolved in tetrahydrofuran (30.0 mL). The reaction solution was cooled to 0 °C, and LAH (10.8 mL, 1.0 M, 10.8 mmol) was added dropwise to the reaction mixture, which was reacted for 1 hour. After the reaction was completed, methanol (5.0 mL) was added dropwise to quench the reaction. The reaction solution was extracted with water / ethyl acetate, the organic phase was dried under reduced pressure, and then purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain intermediate 43-1 (890 mg).

[1010] LCMS: m / z (ESI): 139.2 [M+H] +

[1011] Step 2: Synthesis of 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxaldehyde (intermediate 43-2)

[1012] Intermediate 43-1 (700.0 g, 5.1 mmol) was dissolved in dichloromethane (10.0 mL), and manganese dioxide (2.2 g, 25.3 mmol) was added. The resulting mixture was reacted at 25 °C for 12 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give intermediate 43-2 (600 mg).

[1013] LCMS: m / z (ESI): 137.2 [M+H] +

[1014] Step 3: Synthesis of (3-bromo-1-methyl-1H-pyrazol-4-yl)(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl) methyl ketone (intermediate 43-3)

[1015] Isopropyl magnesium bromide (4.0 mL, 1 M, 4.0 mmol) was added to a tetrahydrofuran (10.0 mL) solution of 3-bromo-4-iodo-1-methyl-1H-pyrazole (1.1 g, 3.7 mmol) at 0 °C, and the mixture was stirred for 1 hour. Then, a tetrahydrofuran (2.0 mL) solution of intermediate 43-2 (500.0 mg, 3.7 mmol) was added, and the mixture was reacted at 0 °C for 1 hour. After the reaction was complete, the mixture was quenched with water (10.0 mL), extracted with ethyl acetate (10.0 mL × 3), and the organic phase was concentrated under reduced pressure. The concentrate was dissolved in dichloromethane (10.0 mL), and manganese dioxide (2.2 g, 25.3 mmol) was added. The resulting mixture was reacted at 25 °C for 12 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain intermediate 43-3 (450 mg).

[1016] LCMS: m / z(ESI): 295.3 / 297.3[M]

[1017] Step 4: Synthesis of 2-(1-(3-bromo-1-methyl-1H-pyrazol-4-yl)vinyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (intermediate 43-4)

[1018] At 0°C, 1.1 mL (2.5 M, 2.6 mmol) of n-butyllithium was added dropwise to a 10.0 mL solution of tetrahydrofuran containing 940.5 mg (2.6 mmol) of TPMP. After the addition was complete, the temperature was raised to 25°C and the reaction was carried out for 1 hour. Then, a 1.0 mL solution of tetrahydrofuran containing 310 mg (1.1 mmol) of intermediate 43-3 was added dropwise to the reaction and the mixture was stirred for 1 hour. After the reaction was completed, the mixture was quenched with 5.0 mL of ammonium chloride solution, extracted with ethyl acetate (10.0 mL × 3), concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain intermediate 43-4 (289 mg).

[1019] LCMS: m / z(ESI): 293.3 / 295.3[M]

[1020] Step 5: Synthesis of (R)-1-(2-(4-(1-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)vinyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethyl-1-ol (intermediate 43-5)

[1021] Intermediate 43-4 (250.0 mg, 0.85 mmol), 1-4 (254.5 mg, 1.5 mmol), tris(dibenzylacetone)palladium (78.0 mg, 85.3 μmol), tricyclohexylphosphine (47.8 mg, 170.0 μmol), and potassium fluoride (148.7 mg, 2.6 mmol) were dissolved in 1,4-dioxane (10 mL) and water (1 mL). The reaction mixture was heated to 100 °C and stirred for 12 hours under an argon atmosphere. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain intermediate 43-5 (240.0 mg).

[1022] LCMS:m / z(ESI):353.1[M+H] +

[1023] Step 6: Synthesis of (R)-2-(1-(3-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1-methyl-1H-pyrazole-4-yl)vinyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (intermediate 43-6)

[1024] Intermediate 43-5 (200.0 mg, 567.5 μmol) and 5-bromo-3-fluoro-2-nitropyridine (376.0 mg, 1.7 mmol) were dissolved in tetrahydrofuran (10.0 mL). The resulting mixture was cooled to 0 °C, and then potassium tert-butoxide (1.7 mL, 1.0 M, 1.7 mmol) was added dropwise, and the reaction was carried out for 1 hour. After the reaction was completed, it was quenched with saturated ammonium chloride aqueous solution (10 mL), extracted with dichloromethane (10.0 mL × 3), concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain intermediate 43-6 (260.0 mg).

[1025] LCMS:m / z(ESI):553.2 / 555.2[M]

[1026] Step 7: Synthesis of (R)-5-bromo-3-(1-(2-(4-(1-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)vinyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethoxy)pyridine-2-amine (intermediate 43-7)

[1027] Intermediate 43-6 (250.0 mg, 450.0 μmol) was dissolved in ammonium chloride (253.0 mg, 4.5 mmol) in ethanol (10.0 mL) and water (2.0 mL), followed by the addition of iron powder (253.0 mg, 4.5 mmol). The resulting mixture was stirred at 85 °C for 3 hours. The reaction solution was filtered, extracted with dichloromethane (10.0 mL × 3), and the organic phase was concentrated under reduced pressure. The residue was then purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain intermediate 43-7 (200.0 mg).

[1028] LCMS:m / z(ESI):523.1 / 525.1[M]

[1029] Step 8: Synthesis of Compound 43

[1030] Intermediate 43-7 (40.0 mg, 76.4 μmol), Pd(OAc)2 (3.4 mg, 15.3 μmol), PivOK (107.8 mg, 764.2 μmol), and CataCXium A (10.9 mg, 30.6 μmol) were dissolved in t-AmOH (2.0 mL). The reaction mixture was heated to 110 °C and stirred for 16 hours under an argon atmosphere. Subsequently, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (column: YMC TA-C18, 30*150 mm, 5 μm; mobile phase A: 7 mmol / L NH4HCO3, mobile phase B: acetonitrile; flow rate: 30 mL / min; acetonitrile ratio 45-75%, elution 10-11 min) to give compound 43 (3.2 mg).

[1031] LCMS: m / z (ESI): 443.2 [M+H] +

[1032] 1 H NMR (400MHz, DMSO-d6) δ7.63 (s, 1H), 7.62-7.58 (m, 1H), 7.54 (dd, J = 10.3, 2.8Hz, 1 H),7.39(d,J=1.8Hz,1H),7.18(td,J=8.5,2.9Hz,1H),6.53(d,J=1.8Hz,1H),5.60 (s,2H),5.41(d,J=2.2Hz,1H),4.92(h,J=2.3,1.9Hz,2H),4.08(q,J=7.5Hz,2H),3 .86(s,3H),3.08(dt,J=15.3,7.6Hz,2H),2.83-2.70(m,2H),1.60(d,J=6.2Hz,3H).

[1033] Example 44: Synthesis of Compound 44

[1034] Step 1: Synthesis of 4-(4-((4-bromo-2-methylthiazolyl)(hydroxy)methyl)-1-ethyl-1H-pyrazol-3-yl)piperazine-1-carboxylic acid benzyl ester (intermediate 44-1)

[1035] Under an argon atmosphere, 4-bromo-2-methylthiazole (780 mg, 4.38 mmol) was added to tetrahydrofuran (10 mL), and LDA (469 mg, 4.38 mmol) was added at -78 °C. The reaction was continued at -78 °C for 1 h. Intermediate 19-4 (1 g, 2.92 mmol) was dissolved in 3 mL of tetrahydrofuran and slowly added to the reaction solution at -78 °C for 1 h. The reaction solution was quenched with water (0.5 mL), and the solution was directly purified by column chromatography (THF / PE, 0-38%) to obtain intermediate 44-1 (1.17 g).

[1036] LCMS:m / z(ESI):520.4[M+H] +

[1037] Step 2: Synthesis of 4-(4-(4-bromo-2-methylthiazolyl-5-carbonyl)-1-ethyl-1H-pyrazol-3-yl)piperazine-1-carboxylic acid benzyl ester (intermediate 44-2)

[1038] Under an argon atmosphere, intermediate 44-1 (1.12 g, 2.15 mmol) and PCC (603 mg, 2.8 mmol) were added to dichloromethane (20 mL) and reacted at 25 °C for 3 h. The reaction solution was then filtered under reduced pressure, concentrated, and purified by column chromatography (THF / PE, 0-50%) to obtain intermediate 44-2 (1.12 g).

[1039] LC-MS: m / z (ESI): 518.4 [M+H] +

[1040] Step 3: Synthesis of 4-(4-(1-(4-bromo-2-methylthiazolyl-5-yl)vinyl)-1-ethyl-1H-pyrazole-3-yl)piperazine-1-carboxylic acid benzyl ester (intermediate 44-3)

[1041] Under an argon atmosphere, TPMP (617 mg, 1.73 mmol) was added to tetrahydrofuran (10 mL), and n-butyllithium (110 mg, 1.73 mmol) was added at 0 °C and reacted for 30 min. Then, intermediate 44-2 was dissolved in 5 mL of tetrahydrofuran and slowly added dropwise to the reaction solution, continuing the reaction for another 30 min. The reaction was quenched with water (0.5 mL), concentrated, and purified by column chromatography (THF / PE, 0-40%) to obtain intermediate 44-3 (283 mg).

[1042] LC-MS: m / z (ESI): 516.4 [M+H] +

[1043] Step 4: Synthesis of (R)-4-(1-ethyl-4-(1-(4-(4-fluoro-2-(1-hydroxyethyl)phenyl)-2-methylthiazolyl-5-yl)vinyl)-1H-pyrazole-3-yl)piperazine-1-carboxylic acid benzyl ester (intermediate 44-4)

[1044] Under an argon atmosphere, a mixture of intermediate 44-3 (283 mg, 548 μmol), intermediate 1-4 (273 mg, 1.64 mmol), Pd(Amphos)₂Cl₂ (38.8 mg, 54.8 μmol), potassium carbonate (227 mg, 1.64 mmol), 1,4-dioxane (5 mL), and water (1 mL) was heated to 110 °C and reacted for 1 h. The mixture was then concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography (THF / PE, 0-100%) to give intermediate 44-4 (281 mg).

[1045] LC-MS: m / z (ESI): 576.4 [M+H] +

[1046] Step 5: Synthesis of (R)-4-(4-(4-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-2-methylthiazolyl-5-yl)vinyl)-1-ethyl-1H-pyrazole-3-yl)piperazine-1-carboxylic acid benzyl ester (intermediate 44-5)

[1047] Under an argon atmosphere, lithium tert-butoxide (2.2 M in THF, 78.1 mg, 976 μmol) was added to a mixture of intermediate 44-4 (281 mg, 488 μmol), 5-bromo-3-fluoro-2-nitropyridine (323 mg, 1.46 mmol), and toluene (5 mL). The resulting mixture was then reacted at room temperature for 0.5 h. The mixture was then concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography (THF / PE, 0-50%) to give intermediate 44-5 (320 mg).

[1048] LC-MS: m / z (ESI): 776.3 [M+H] +

[1049] Step 6: Synthesis of (R)-4-(4-(4-(2-(1-((2-amino-5-bromopyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-2-methylthiazolyl-5-yl)vinyl)-1-ethyl-1H-pyrazol-3-yl)piperazine-1-carboxylic acid benzyl ester (intermediate 44-6)

[1050] Under an argon atmosphere, a mixture of intermediate 44-5 (320 mg, 412 μmol), iron powder (115 mg, 2.06 mmol), ammonium chloride (110 mg, 2.06 mmol), EtOH (5 mL), and water (1 mL) was heated to 80 °C and stirred for 1 h. The mixture was then directly purified by column chromatography (THF / PE, 0-100%) to obtain intermediate 44-6 (300 mg).

[1051] LC-MS: m / z (ESI): 746.3 [M+H] +

[1052] Step 7: Synthesis of intermediate 44-7

[1053] Under an argon atmosphere, a mixture of intermediate 44-6 (240 mg, 321 μmol), Pd(OAc)2 (57 mg, 257 μmol), cataCXium A (184 mg, 514 μmol), PivOK (135 mg, 964 μmol), and t-AmOH (5 mL) was heated to 150 °C and reacted under microwave for 1 h. The mixture was then directly purified by column chromatography (THF / PE, 0-90%) to obtain intermediate 44-7 (100 mg).

[1054] LC-MS: m / z (ESI): 666.5 [M+H] +

[1055] Step 8: Synthesis of intermediate 44-8

[1056] Under an argon atmosphere, intermediate 44-7 (80 mg, 120 μmol) was added to TFA (1 mL), and the reaction solution was heated to 50 °C and stirred for 5 h. The mixture was then directly purified by column chromatography (THF / PE, 0-100%) to obtain intermediate 44-8 (60 mg).

[1057] LC-MS: m / z (ESI): 532.6 [M+H] +

[1058] Step 9: Synthesis of Compound 44

[1059] Under an argon atmosphere, a mixture of intermediate 44-8 (60 mg, 112.8 μmol), paraformaldehyde (10.6 mg), sodium cyanoborohydride (10.6 mg, 169 μmol), and dichloromethane (1 mL) was stirred at 25 °C for 3 h. The mixture was then concentrated under reduced pressure to remove the solvent. The residue was purified by preparative liquid chromatography (column: Waters Xbridge OBD 19*150 mm*5 μm; mobile phase: [A: water (0.0125% NH3), B: acetonitrile]; B%: 25%-60%, 10 min) to give compound 44 (6.53 mg).

[1060] LC-MS: m / z (ESI): 546.9 [M+H] +

[1061] 1 H NMR (400MHz, DMSO-d6) δ7.69(dd,J=10.4,2.8Hz,1H),7.55(dd,J=8.5,5.8Hz,1H),7.42(d,J=1.8Hz,1 H),7.11(td,J=8.4,2.8Hz,1H),6.36(d,J=1.8Hz,1H),6.12(s,2H),5.59(d,J=1.8Hz,1H),4.98(d,J= 6.0Hz,1H),4.93(d,J=1.7Hz,1H),3.90(dt,J=11.7,6.9Hz,2H),3.43-3.38(m,2H),3.30-3.24(m,2H) ,3.21-3.10(m,2H),2.65(s,3H),2.47-2.40(m,2H),2.22(s,3H),1.59(d,J=6.2Hz,3H),1.23(t,3H).

[1062] Example 45: Synthesis of Compound 45

[1063] Compound 20 (21.2 mg, 41.6 μmol), Pd(OAc)2 (2.8 mg, 12.5 μmol), PivOK (17.5 mg, 124.9 μmol), and cataCXium A (9.0 mg, 25.0 μmol) were dissolved in 1,4-dioxane (2.0 mL) and water (0.2 mL). The resulting mixture was heated to 110 °C under an argon atmosphere and stirred at this temperature for 16 hours. After the reaction was complete, the reaction solution was filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane:methanol = 20:1), followed by preparative chromatography to obtain compound 45 (4.0 mg).

[1064] LCMS: m / z (ESI): 511.4 [M+H] +

[1065] 1 H NMR (400MHz, DMSO-d6) δ7.72(d,J=2.2Hz,1H),7.70-7.66(m,1H),7.64(s,1H),7.60-7.56(m,2H),7.21-7.16(m,1H),6.78(s,1H),6.56(d,J=2 .2Hz,1H),5.32–5.26(m,2H),4.68(d,J=2.0Hz,1H),4.16-4.11(m,2H), 3.88(s,3H),3.85(s,3H),1.65(d,J=6.2Hz,3H),1.33(t,J=7.2Hz,3H).

[1066] Example 46: Synthesis of Compound 46

[1067] Under an argon atmosphere, compound 20 (10 mg, 19.6 μmol), Gphos Pd G6 (5.6 mg, 5.89 μmol), potassium tert-butoxide (11 mg, 98 μmol), and 2-methyl-2,6-diazaspiro[3,4]octane (12.4 mg, 98 μmol) were added to 1,4-dioxane (1 mL), purged with nitrogen, and reacted at 125 °C for 4 h. The reaction solution was then filtered and purified by preparative liquid chromatography (column: Waters Xbridge OBD 19*150 mm*5 μm; mobile phase: [A: water (0.0125% NH3), B: acetonitrile]; B%: 25%-60%, 10 min) to obtain compound 46 (1.5 mg).

[1068] LC-MS: m / z (ESI): 555.5 [M+H] +

[1069] 1H NMR (400MHz, DMSO-d6) δ7.71-7.66(m,2H),7.55-7.48(m,1H),7.37(d,J=1.8Hz,1H),7.17-7. 07(m,1H),6.44(d,J=1.7Hz,1H),6.07(s,2H),5.22(d,J=2.4Hz,1H),5.14-5.06(m,1H),4.66( d,J=2.2Hz,1H),3.91-3.85(m,5H),3.57(d,J=9.9Hz,2H),3.43(d,J=10.0Hz,2H),3.25-3.04( m,5H),2.30-2.26(m,2H),2.03(t,J=7.0Hz,2H),1.57(d,J=6.1Hz,3H),1.25(t,J=7.2Hz,3H).

[1070] Example 47: Synthesis of Compound 47

[1071] Under an argon atmosphere, compound 20 (5 mg, 9.8 μmol), Gphos Pd G6 (2.8 mg, 2.9 μmol), potassium tert-butoxide (5.5 mg, 49 μmol), and 6-methyl-2,6-diazaspiro[3,4]octane (6.2 mg, 49 μmol) were added to 1,4-dioxane (1 mL), purged with nitrogen, and reacted at 125 °C for 4 h. The reaction solution was then filtered and purified by preparative liquid chromatography (column: Waters Xbridge OBD 19*150 mm*5 μm; mobile phase: [A: water (0.0125% NH3), B: acetonitrile]; B%: 25%-60%, 10 min) to obtain compound 47 (1.29 mg).

[1072] LC-MS: m / z (ESI): 555.5 [M+H] +

[1073] 1H NMR (400MHz, DMSO-d6) δ7.72(s,1H),7.66(dd,J=10.3,2.9Hz,1H),7.45(dd,J=8.5,5.9Hz,1H),7.38 (d,J=1.7Hz,1H),7.12(td,J=8.4,2.8Hz,1H),6.41(d,J=1.9Hz,1H),6.06(s,2H),5.21(d,J=2.4Hz,1 H),5.09(q,J=6.7Hz,1H),4.73(d,J=2.3Hz,1H),3.93-3.87(m,5H),3.83-3.72(m,4H),2.68-2.65(m, 2H),2.34-2.31(m,2H),2.23(s,3H),2.03-1.99(m,2H),1.58(d,J=6.2Hz,3H),1.23(t,J=3.3Hz,3H).

[1074] Example 48: Synthesis of Compound 48

[1075] Step 1: Synthesis of Compound 48-1

[1076] Compound 20 (50 mg, 98 μmol), Gphos Pd G6 (27.8 mg, 29.4 μmol), potassium tert-butoxide (55 mg, 490 μmol), and (R)-1-methyl-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (104 mg, 490 μmol) were added to 1,4-dioxane (2 mL) under an argon atmosphere, purged with nitrogen, and reacted at 125 °C for 4 h. After the reaction was complete, the mixture was filtered, and the organic phase was concentrated under reduced pressure and purified by column chromatography (THF / PE, 0-80%) to give compound 48-1 (50 mg).

[1077] LC-MS: m / z (ESI): 641.5 [M+H] +

[1078] Step 2: Synthesis of compound 48-2

[1079] Under an argon atmosphere, a mixture of intermediate 48-1 (50 mg, 78 μmol), trifluoroacetic acid (0.1 mL), and dichloromethane (3.0 mL) was stirred at room temperature for 1 h. The mixture was then directly purified by reversed-phase column chromatography (MeCN / water, 0-56%) to give compound 48-2 (30 mg).

[1080] LC-MS: m / z (ESI): 541.5 [M+H] +

[1081] Step 3: Synthesis of Compound 48

[1082] Under an argon atmosphere, a mixture of intermediate 48-2 (11 mg, 20.5 μmol), (1,2-bis(ethoxycarbonyl)hydrazino)triphenylphosphine trifluoromethane sulfonate (23.9 mg, 40.6 μmol), DIPEA (26.3 mg, 203 μmol), methanol (6.5 mg, 203 μmol), and acetonitrile (1 mL) was reacted at room temperature for 1 h. The mixture was then concentrated under reduced pressure to remove the solvent, and purified by preparative liquid chromatography (column: Waters Xbridge OBD 19*150 mm*5 μm; mobile phase: [A: water (0.0125% NH3), B: acetonitrile]; B%: 25%-60%, 10 min) to give compound 48 (0.4 mg).

[1083] LC-MS: m / z (ESI): 555.6 [M+H] +

[1084] Example 49: Synthesis of Compound 49

[1085] Under an argon atmosphere, compound 20 (5 mg, 9.8 μmol), Gphos Pd G6 (2.8 mg, 2.9 μmol), potassium tert-butoxide (16.5 mg, 147 μmol), and 7-methyl-2,7-diazaspiro[3.5]nonane dihydrochloride (10.5 mg, 49 μmol) were added to 1,4-dioxane (1 mL), purged with nitrogen, and reacted at 125 °C for 4 h. The reaction solution was then filtered and purified by preparative liquid chromatography (column: Waters Xbridge OBD 19*150 mm*5 μm; mobile phase: [A: water (0.0125% NH3), B: acetonitrile]; B%: 25%-60%, 10 min) to obtain compound 49 (1.12 mg).

[1086] LC-MS: m / z (ESI): 569.6 [M+H] +

[1087] 1H NMR (400MHz, DMSO-d6) δ7.66 (dd, J=10.5, 2.8Hz, 1H), 7.47 (dd, J=8.5, 5.9Hz, 1H), 7.39 (d, J=1. 7Hz,1H),7.16-7.08(m,1H),6.41(s,1H),6.06(s,2H),5.22(d,J=2.4Hz,1H),5.09(d,J=6.4Hz, 1H),4.72(s,1H),3.90(s,3H),3.65(d,J=7.0Hz,2H),3.57(d,J=7.0Hz,2H),2.28-2.16(m,5H), 2.12(s,3H),1.80-1.72(m,4H),1.72-1.62(m,2H),1.58(d,J=6.2Hz,3H),1.23(d,J=3.5Hz,3H).

[1088] Example 50: Synthesis of Compound 50

[1089] Under an argon atmosphere, compound 20 (10.0 mg, 19.6 μmol), 4-methyl-4,7-diazaspiro[2.5]octane hydrochloride (31.9 mg, 196 μmol), GPhos Pd G6 (5.6 mg, 5.9 μmol), and potassium tert-butoxide (22.0 mg, 196 μmol) were dissolved in 1,4-dioxane (1.2 mL) and reacted with microwave stirring at 100 °C for 2 h. The mixture was then concentrated under reduced pressure to remove the solvent, and the residue was purified by preparative liquid chromatography (column: Waters Xbridge OBD 19*150 mm*5 μm; mobile phase: [A: water (0.0125% NH3), B: acetonitrile]; B%: 25%-60%, 10 min) to give compound 50 (0.60 mg).

[1090] LC-MS: m / z (ESI): 555.6 [M+H] +

[1091] Example 51: Synthesis of Compound 51

[1092] Under an argon atmosphere, compound 20 (22.0 mg, 43.2 μmol), 1-cyclopropylpyrazole-4-boronic acid pinacol ester (70.8 mg, 302 μmol), cacXium A Pd G3 (9.44 mg, 13.0 μmol), and cesium carbonate (28.1 mg, 86.4 μmol) were dissolved in 1,4-dioxane (1 mL) and water (0.05 mL), and the mixture was stirred at 120 °C for 2 h. The mixture was then concentrated under reduced pressure to remove the solvent. The residue was purified by preparative liquid chromatography (column: Waters Xbridge OBD 19*150 mm*5 μm; mobile phase: [A: water (0.0125% NH3), B: acetonitrile]; B%: 25%-60%, 10 min) to give compound 51 (9.5 mg).

[1093] LC-MS: m / z (ESI): 537.6 [M+H] +

[1094] 1 H NMR(400MHz,DMSO-d6)δ8.02(s,1H),7.86(s,1H),7.77(d,J=0.7Hz,1H),7.69(s,2H),7 .58(dd,J=8.5,5.9Hz,1H),7.47(d,J=1.8Hz,1H),7.45(s,1H),6.10(s,2H),5.40(d,J=2 .2Hz,1H),5.13(d,J=6.8Hz,1H),4.78(d,J=2.0Hz,1H),4.07(dq,J=13.9,6.9Hz,2H),3. 85(s,3H),2.05-1.94(m,1H),1.60(d,J=6.2Hz,3H),1.33(t,J=7.2Hz,3H),1.24(s,4H).

[1095] Example 52: Synthesis of Compound 52

[1096] Step 1: Synthesis of methyl 3-cyclopropoxy-1-methyl-1H-pyrazole-5-carboxylate (intermediate 52-2)

[1097] Intermediate 52-1 (3.0 g, 19.2 mmol), cyclopropanol (3.4 g, 57.6 mmol), and PPh3 (15.1 g, 57.6 mmol) were dissolved in toluene (20.0 mL). The resulting solution was cooled to 0 °C, and then DIAD (11.66 g, 57.64 mmol) was added dropwise. The resulting mixture was heated to 105 °C and stirred at this temperature for 24 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 6:1) to give intermediate 52-2 (2.8 g).

[1098] LCMS: m / z (ESI): 197.1 [M+H] +

[1099] Step 2: Synthesis of (3-cyclopropoxy-1-methyl-1H-pyrazole-5-yl)methanol (intermediate 52-3)

[1100] Intermediate 52-2 (2.8 g, 14.2 mmol) was dissolved in tetrahydrofuran (10.0 mL). The resulting solution was cooled to 0 °C, and then a tetrahydrofuran solution of lithium aluminum hydride (1.0 M, 14.2 mL) was added dropwise. The mixture was stirred at 0 °C for 1 hour. After the reaction was complete, the reaction solution was quenched with methanol and extracted with dichloromethane (100 mL × 3 times). The organic phases were combined and concentrated under reduced pressure. The crude product was used directly in the next reaction step.

[1101] LCMS: m / z (ESI): 169.1 [M+H] +

[1102] Step 3: Synthesis of 3-cyclopropoxy-1-methyl-1H-pyrazole-5-carboxaldehyde (intermediate 52-4)

[1103] Intermediate 52-3 (2.4 g, 14.2 mmol) was dissolved in dichloromethane (20.0 mL), and manganese dioxide (24.7 g, 284.2 mmol) was added to the resulting solution. The mixture was stirred at room temperature for 24 hours. After the reaction was complete, the mixture was filtered, and the reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to give intermediate 52-4 (1.2 g).

[1104] LCMS: m / z (ESI): 167.1 [M+H] +

[1105] Step 4: Synthesis of (3-bromo-1-methyl-1H-pyrazol-4-yl)(3-cyclopropoxy-1-methyl-1H-pyrazol-5-yl)methanol (intermediate 52-5)

[1106] Isopropyl magnesium bromide (1.0 M, 9.5 mmol) was added to a tetrahydrofuran (20.0 mL) solution of 3-bromo-4-iodo-1-methyl-1H-pyrazole (2.5 g, 8.7 mmol) at 0 °C. The mixture was stirred for 30 minutes, and intermediate 52-4 (1.2 g, 7.3 mmol) was added. The mixture was stirred for another hour at 0 °C. After the reaction was complete, the mixture was quenched with saturated ammonium chloride aqueous solution (10 mL), extracted with dichloromethane (50 mL × 3), and the organic phases were combined and concentrated under reduced pressure. The crude intermediate 52-5 was used directly in the next step of the reaction.

[1107] LCMS: m / z(ESI): 327.0 / 329.0[M+H] +

[1108] Step 5: Synthesis of (3-bromo-1-methyl-1H-pyrazol-4-yl)(3-cyclopropoxy-1-methyl-1H-pyrazol-5-yl) methyl ketone (intermediate 52-6)

[1109] Intermediate 52-5 (2.4 g, 7.3 mmol) was dissolved in dichloromethane (20.0 mL), and manganese dioxide (12.7 g, 145.5 mmol) was added to the resulting solution. The mixture was stirred at room temperature for 24 hours. After the reaction was complete, the mixture was filtered, and the reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:3) to give intermediate 52-6 (2.1 g).

[1110] LCMS: m / z(ESI): 325.0 / 327.0[M+H] +

[1111] Step 6: Synthesis of (R)-(3-cyclopropoxy-1-methyl-1H-pyrazol-5-yl)(3-(4-fluoro-2-(1-hydroxyethyl)phenyl)-1-methyl-1H-pyrazol-4-yl) methyl ketone (intermediate 52-7)

[1112] Intermediate 52-6 (400.0 mg, 1.2 mmol), 1-4 (408.3 mg, 2.5 mmol), Pd2dba3 (112.7 mg, 123.0 μmol), PCy3 (69.0 mg, 246.0 μmol), and potassium fluoride (214.4 mg, 3.7 mmol) were added to a mixed solvent of 1,4-dioxane (10.0 mL) and water (1.0 mL) under an argon atmosphere, and reacted at 100 °C for 16 hours. The reaction was quenched with water (20.0 mL), and then extracted with dichloromethane (50.0 mL × 3). After concentration of the organic phase under reduced pressure, the residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:3) to obtain intermediate 52-7 (436.4 mg).

[1113] LCMS: m / z (ESI): 385.1 [M+H] +

[1114] Step 7: Synthesis of (R)-(3-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)(3-cyclopropoxy-1-methyl-1H-pyrazol-5-yl) methyl ketone (intermediate 52-8)

[1115] Intermediate 52-7 (441.5 mg, 1.2 mmol) and 5-bromo-3-fluoro-2-nitropyridine (507.6 mg, 2.3 mmol) were dissolved in tetrahydrofuran (10.0 mL). The resulting mixture was cooled to 0 °C, and then a tetrahydrofuran solution of potassium tert-butoxide (1.0 M, 2.3 mL) was added dropwise. The mixture was stirred at 0 °C for 1 hour. After the reaction was completed, the reaction was quenched with a saturated ammonium chloride aqueous solution (10.0 mL), and the mixture was extracted with dichloromethane (50.0 mL × 3 times). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:2) to give intermediate 52-8 (633.3 mg).

[1116] LCMS: m / z(ESI): 585.1 / 587.1[M+H] +

[1117] Step 8: Synthesis of (R)-(3-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)(4-bromo-3-cyclopropoxy-1-methyl-1H-pyrazol-5-yl) methyl ketone (intermediate 52-9)

[1118] Intermediate 52-8 (317 mg, 541.5 μmol) was dissolved in acetonitrile (10.0 mL), and NBS (106.0 mg, 595.7 μmol) was added. The resulting mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was diluted with dichloromethane and washed with water. The organic phase was concentrated under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to give intermediate 52-9 (359.7 mg).

[1119] LCMS: m / z(ESI): 663.1 / 665.1 / 667.1[M+H] +

[1120] Step 9: Synthesis of (R)-5-bromo-3-(1-(2-(4-(1-(4-bromo-3-cyclopropoxy-1-methyl-1H-pyrazol-5-yl)vinyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine (intermediate 52-10)

[1121] At 0°C, 1.0 mL (2.5 M, 2.5 mmol) of n-butyllithium was added dropwise to a solution of 10.0 mL of tetrahydrofuran containing 1.01 g (2.5 mmol) of TPMP. After the addition was complete, the temperature was raised to 25°C and the reaction was allowed to proceed for 0.5 hours. Then, a solution of 10.0 mL of tetrahydrofuran containing 414 mg (623 μmol) of intermediate 52-9 was added dropwise to the reaction mixture and stirred for 1 hour. After the reaction was completed, the mixture was quenched with 5.0 mL of saturated ammonium chloride aqueous solution, extracted with dichloromethane (20.0 mL × 3), concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain intermediate 52-10 (200 mg).

[1122] LCMS: m / z(ESI): 661.0 / 663.0 / 665.0[M+H] +

[1123] Step 10: Synthesis of (R)-5-bromo-3-(1-(2-(4-(1-(4-bromo-3-cyclopropoxy-1-methyl-1H-pyrazol-5-yl)vinyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethoxy)pyridine-2-amine (intermediate 52-11)

[1124] Intermediate 52-10 (200.0 mg, 302.0 μmol) was dissolved in ammonium chloride (161.5 mg, 3.0 mmol) in ethanol (10.0 mL) and water (2.0 mL), followed by the addition of iron powder (168.6 mg, 3.0 mmol). The resulting mixture was stirred at 80 °C for 3 hours. The reaction solution was filtered, extracted with dichloromethane (20.0 mL × 3), and the organic phase was concentrated under reduced pressure. The residue was then purified by column chromatography (petroleum ether: ethyl acetate = 1:3) to obtain intermediate 52-11 (109.7 mg).

[1125] LCMS: m / z(ESI): 631.0 / 633.0 / 635.0[M+H] +

[1126] Step 11: Synthesis of Compound 52

[1127] Intermediate 52-11 (109.7 mg, 173.5 μmol), Pd(OAc)2 (11.7 mg, 52.1 μmol), Sn2Me6 (85.3 mg, 260.2 μmol), and CataCXium A (37.3 mg, 104.1 μmol) were dissolved in 1,4-dioxane (10.0 mL) under an argon atmosphere. The resulting mixture was reacted at 110 °C for 16 hours. The reaction solution was filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane:methanol = 20:1), followed by preparative chromatography (column: Waters Xbridge OBD 19*150 mm*5 μm; mobile phase: [A: water (0.0125% NH3), B: acetonitrile]; B%: 25%-60%, 10 min) to give compound 52 (7.5 mg).

[1128] LCMS: m / z (ESI): 473.4 [M+H] +

[1129] 1 H NMR (400MHz, DMSO-d6) δ7.91(s,1H),7.72-7.51(m,3H),7.46-7.42(m,1H),7.24(d,J=1.7Hz,1H),7.21-7.16(m,1H),6.62(d,J=1.7Hz,1H),5.66( s,1H),5.07(s,1H),4.97-4.92(m,1H),4.07-4.02(m,1H),3.83(s,3H),3 .75(s,3H),1.58(d,J=6.2Hz,3H),0.67-0.60(m,3H),0.59-0.52(m,1H).

[1130] Example 53: Synthesis of Compound 53

[1131] Under an argon atmosphere, compound 20 (30 mg, 59 μmol), (S)-1,2-dimethylpiperazine (33.6 mg, 294 μmol), GPhos Pd G6 (16.7 mg, 17.6 μmol), and potassium tert-butoxide (66.1 mg, 589 μmol) were dissolved in 1,4-dioxane (1.8 mL) and reacted with microwave at 100 °C for 2 h. The mixture was then concentrated under reduced pressure to remove the solvent. The residue was purified by preparative liquid chromatography (column: Waters Xbridge OBD 19*150 mm*5 μm; mobile phase: [A: water (0.0125% NH3), B: acetonitrile]; B%: 25%-60%, 10 min) to give compound 53 (2.33 mg).

[1132] LC-MS: m / z (ESI): 543.6 [M+H] +

[1133] 1 H NMR (400MHz, DMSO-d6) δ7.75(s,1H),7.70(dd,J=10.4,2.8Hz,1H),7.47(dd,J=8.6,5.9Hz,1H ),7.43(s,1H),7.19-7.11(m,1H),6.43(s,1H),6.20(s,1H),5.33(t,J=4.8Hz,1H),5.23(s,1 H),5.11(d,J=6.7Hz,1H),4.71(s,1H),3.92(d,J=15.6Hz,5H),2.87(s,2H),2.67(d,J=2.2Hz ,1H),2.37-2.27(m,1H),2.03-1.93(m,2H),1.59(d,J=5.9Hz,3H),1.46(s,1H),1.24(s,9H).

[1134] Example 54: Synthesis of Compound 54

[1135] Step 1: Synthesis of (R)-3-bromo-4-(1-(3-(2-(1-((tert-butyldimethylsilyl)oxy)ethyl)-4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)vinyl)-1-ethyl-1H-pyrazol (compound 54-1)

[1136] Intermediate 20-4 (543 mg, 1.30 mmol), TBSCl (390 mg, 2.59 mmol), imidazole (352 mg, 5.18 mmol), and DCM (20 mL) were added sequentially to a reaction flask and stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure and purified by column chromatography (THF / PE, 0-100%) to give compound 54-1 (558 mg).

[1137] LC-MS:m / z(ESI):533.2 / 535.2[M+H] +

[1138] Step 2: Synthesis of (R)-1-(2-(4-(1-(3-((R)-2,4-dimethylpiperazin-1-yl)-1-ethyl-1H-pyrazol-4-yl)vinyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethane-1-ol (compound 54-2)

[1139] Under an argon atmosphere, compounds 54-1 (300 mg, 562 μmol), (3R)-1,3-dimethylpiperazine (321 mg, 2.81 mmol), and Pd-PEPPSI-IHept were detected. Cl (27.4 mg, 28.1 μmol) was dissolved in 1,4-dioxane (1.5 mL) with potassium tert-butoxide (315 mg, 2.81 mmol) and stirred at 100 °C for 2 h. The mixture was then concentrated under reduced pressure to remove the solvent, and the residue was purified by preparative liquid chromatography (column: Waters Xbridge OBD 19*150 mm*5 μm; mobile phase: [A: water (0.0125% NH3), B: acetonitrile]; B%: 25%-60%, 10 min) to give compound 54-2 (154 mg).

[1140] LC-MS: m / z (ESI): 453.4 [M+H] +

[1141] Step 3: Synthesis of (R)-1-(4-(1-(3-(2-((R)-1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)vinyl)-1-ethyl-1H-pyrazol-3-yl)-2,4-dimethylpiperazine (intermediate 54-3)

[1142] Under an argon atmosphere, lithium tert-butoxide (2.2 M in THF, 773 μL, 1.70 mmol) was added to a mixture of intermediate 54-2 (154 mg, 340 μmol), 5-bromo-3-fluoro-2-nitropyridine (150 mg, 680 μmol), and toluene (2 mL). The resulting mixture was then reacted at room temperature for 0.5 h. The mixture was then concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography (THF / PE, 0-100%) to give intermediate 54-3 (135 mg).

[1143] LC-MS:m / z(ESI):653.4 / 655.4[M+H] +

[1144] Step 4: Synthesis of 5-bromo-3-((R)-1-(2-(4-(1-(3-((R)-2,4-dimethylpiperazin-1-yl)-1-ethyl-1H-pyrazol-4-yl)vinyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethoxy)pyridine-2-amine (intermediate 54-4)

[1145] Under an argon atmosphere, a mixture of intermediate 54-3 (130 mg, 199 μmol), iron powder (111 mg, 1.99 mmol), ammonium chloride (106 mg, 1.99 mmol), EtOH (4 mL), and water (2 mL) was heated to 80 °C and stirred for 1 h. The mixture was then directly purified by column chromatography (THF / PE, 0-100%) to obtain intermediate 54-4 (107 mg).

[1146] LC-MS:m / z(ESI):623.4 / 625.4[M+H] +

[1147] Step 5: Synthesis of Compound 54

[1148] Under an argon atmosphere, a mixture of intermediate 54-4 (67.0 mg, 107 μmol), Pd(OAc)2 (7.24 mg, 32.2 μmol), cacXium A (23.1 mg, 64.5 μmol), PivOK (30.1 mg, 215 μmol), and 2-methyl-2-butanol (8 mL) was heated to 120 °C and stirred for 4 h. The mixture was then concentrated under reduced pressure to remove the solvent. The residue was purified by preparative liquid chromatography (column: Waters Xbridge OBD 19*150 mm*5 μm; mobile phase: [A: water (0.0125% NH3), B: acetonitrile]; B%: 25%-60%, 10 min) to give compound 54 (16 mg).

[1149] LC-MS: m / z (ESI): 543.6 [M+H] +

[1150] 1 H NMR(400MHz, DMSO-d6)δ7.69(d,J=7.3Hz,2H),7.50-7.47(m,1H),7.46(d,J=1.5Hz,1H),7.11(td,J= 8.4,2.8Hz,1H),6.44(d,J=1.8Hz,1H),6.08(s,2H),5.10(d,J=2.0Hz,1H),5.07(d,J=2.3Hz,1H),4. 59(d,J=2.2Hz,1H),4.00-3.81(m,6H),3.26(s,1H),3.19-3.10(m,1H),2.65(dd,J=14.3,6.5Hz,2H) ,2.46-2.30(m,2H),2.19(s,3H),1.56(d,J=6.2Hz,3H),1.20(t,J=7.1Hz,3H),1.07(d,J=6.4Hz,3H).

[1151] Example 55: Synthesis of Compound 55

[1152] Step 1: Synthesis of (R)-1-(2-(4-(1-(3-((S)-2,4-dimethylpiperazin-1-yl)-1-ethyl-1H-pyrazol-4-yl)vinyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethane-1-ol (intermediate 55-1)

[1153] Under an argon atmosphere, compounds 54-1 (300 mg, 562 μmol), (3S)-1,3-dimethylpiperazine (632 mg, 5.54 mmol), and Pd-PEPPSI-IHept were analyzed. Cl (98.1 mg, 104 μmol) was dissolved in 1,4-dioxane (8 mL) with potassium tert-butoxide (777 mg, 6.92 mmol) and stirred at 100 °C for 2 h. The mixture was then concentrated under reduced pressure to remove the solvent, and the residue was purified by preparative liquid chromatography (column: Waters Xbridge OBD 19*150 mm*5 μm; mobile phase: [A: water (0.0125% NH3), B: acetonitrile]; B%: 25%-60%, 10 min) to give intermediate 55-1 (230 mg).

[1154] LC-MS: m / z (ESI): 453.5 [M+H] +

[1155] Step 2: Synthesis of (S)-1-(4-(1-(3-(2-((R)-1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)vinyl)-1-ethyl-1H-pyrazol-3-yl)-2,4-dimethylpiperazine (intermediate 55-2)

[1156] Under an argon atmosphere, lithium tert-butoxide (2.2 M in THF, 402 μL, 884 μmol) was added to a mixture of intermediate 55-1 (100 mg, 221 μmol), 5-bromo-3-fluoro-2-nitropyridine (97.7 mg, 442 μmol), and toluene (2 mL). The resulting mixture was then reacted at room temperature for 0.5 h. The mixture was then concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography (THF / PE, 0-100%) to give intermediate 55-2 (85 mg).

[1157] LC-MS: m / z (ESI): 653.3 [M+H] +

[1158] Step 3: Synthesis of 5-bromo-3-((R)-1-(2-(4-(1-(3-((S)-2,4-dimethylpiperazin-1-yl)-1-ethyl-1H-pyrazol-4-yl)vinyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethoxy)pyridine-2-amine (intermediate 55-3)

[1159] Under an argon atmosphere, a mixture of intermediate 55-2 (85 mg, 130 μmol), iron powder (36.3 mg, 650 μmol), ammonium chloride (34.8 mg, 650 μmol), EtOH (2 mL), and water (2 mL) was heated to 80 °C and stirred for 1 h. The mixture was then directly purified by column chromatography (THF / PE, 0-100%) to obtain intermediate 55-3 (55 mg).

[1160] LC-MS:m / z(ESI):623.3 / 625.3[M+H] +

[1161] Step 4: Synthesis of Compound 55

[1162] Under an argon atmosphere, a mixture of intermediate 55-3 (50.0 mg, 80.2 μmol), Pd(OAc)2 (5.40 mg, 24.1 μmol), cataCXium A (17.2 mg, 48.1 μmol), PivOK (56.2 mg, 401 μmol), and 2-methyl-2-butanol t-AmOH (5 mL) was heated to 120 °C and stirred for 4 h. The mixture was then concentrated under reduced pressure to remove the solvent. The residue was purified by preparative liquid chromatography (column: Waters Xbridge OBD 19*150 mm*5 μm; mobile phase: [A: water (0.0125% NH3), B: acetonitrile]; B%: 25%-60%, 10 min) to give compound 55 (6.7 mg).

[1163] LC-MS: m / z (ESI): 543.5 [M+H] +

[1164] 1H NMR (400MHz, DMSO-d6) δ7.68(d,J=4.5Hz,2H),7.60-7.46(m,3H),7.19(d,J=8.9Hz,1H),6.64(d,J=9.9Hz,1H),5.27-5.16(m,2H),4.70(s ,1H),4.60(s,1H),3.91(d,J=7.5Hz,5H),2.92-2.82(m,4H),2.05-1.93(m,2H),1.61(d,J=6.2Hz,3H),1.37(d,J=6.9Hz,2H),1.23(s,8H).

[1165] Example 56: Synthesis of Compound 56

[1166] Step 1: Synthesis of 3-bromo-1-cyclopropyl-1H-pyrazole (intermediate 56-2)

[1167] Intermediate 56-1 (5.0 g, 34.0 mmol) and cyclopropylboronic acid (3.5 g, 40.8 mmol) were dissolved in 1,2-dioxane (60.0 mL), and copper acetate (4.3 g, 23.8 mmol), 2,2'-bipyridine (3.7 g, 23.8 mmol), and sodium carbonate (4.3 g, 40.8 mmol) were added. The mixture was reacted at 25 °C for 16 hours. The reaction was quenched with water (60.0 mL), extracted with ethyl acetate (50.0 mL × 3), and the organic phase was concentrated under reduced pressure to give intermediate 56-2 (6.0 g).

[1168] LCMS: m / z(ESI): 187.0 / 189.0[M+H] +

[1169] Step 2: Synthesis of 3-bromo-1-cyclopropyl-4-iodo-1H-pyrazole (intermediate 56-3)

[1170] Intermediate 56-2 (5.9 g, 31.5 mmol) and NIS (7.8 g, 34.7 mmol) were dissolved in acetonitrile (60.0 mL), and the mixture was reacted at 80 °C for 12 hours. The reaction was quenched with saturated sodium sulfite aqueous solution (30.0 mL), extracted with ethyl acetate (30.0 mL × 3), concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 4:1) to give intermediate 56-3 (3.6 g).

[1171] LCMS: m / z(ESI): 312.8 / 314.8[M+H] +

[1172] Step 3: Synthesis of 3-bromo-1-cyclopropyl-1H-pyrazole-4-carboxaldehyde (intermediate 56-4)

[1173] Isopropyl magnesium bromide (2.0 mL, 1 M, 2.0 mmol) was added to a tetrahydrofuran (10.0 mL) solution of intermediate 56-3 (511.0 mg, 1.6 mmol) at 0 °C, and the mixture was stirred for 1 hour. DMF (238.7 mg, 3.3 mmol) was then added, and the mixture was stirred for another 1 hour. The reaction was quenched with saturated ammonium chloride aqueous solution (10.0 mL), and the mixture was extracted with ethyl acetate (10.0 mL × 3). The organic phases were combined, concentrated to dryness under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 4:1) to give intermediate 56-4 (237.1 mg).

[1174] LCMS: m / z(ESI): 214.9 / 216.9[M+H] +

[1175] Step 4: Synthesis of (3-bromo-1-cyclopropyl-1H-pyrazol-4-yl)(1-ethyl-3-methoxy-1H-pyrazol-4-yl)methanol (intermediate 56-5)

[1176] Isopropyl magnesium bromide (1.1 mL, 1 M, 1.1 mmol) was added to a tetrahydrofuran (6.0 mL) solution of 1-ethyl-4-iodo-3-methoxy-1H-pyrazole (263.6 mg, 1.0 mmol) at 0 °C. The mixture was stirred for 30 minutes. Intermediate 56-4 (204.5 mg, 950.9 μmol) was added, and the mixture was stirred for 1.5 hours. The reaction was quenched with saturated ammonium chloride aqueous solution (5.0 mL), extracted with ethyl acetate (5.0 mL × 3), and the organic phases were combined and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to give intermediate 56-5 (260.3 mg).

[1177] LCMS: m / z(ESI): 341.1 / 343.1[M+H] +

[1178] Step 5: Synthesis of (3-bromo-1-cyclopropyl-1H-pyrazol-4-yl)(1-ethyl-3-methoxy-1H-pyrazol-4-yl) methyl ketone (intermediate 56-6)

[1179] Intermediate 56-5 (260.3 mg, 762.9 μmol) was dissolved in dichloromethane (5.0 mL), and manganese dioxide (663.2 mg, 7.6 mmol) was added. The resulting mixture was reacted at 40 °C for 12 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to give intermediate 56-6 (193.7 mg).

[1180] LCMS: m / z(ESI): 339.0 / 341.0[M+H] +

[1181] Step 6: Synthesis of 3-bromo-1-cyclopropyl-4-(1-(1-ethyl-3-methoxy-1H-pyrazol-4-yl)vinyl)-1H-pyrazol (intermediate 56-7)

[1182] Intermediate 56-6 (193.7 mg, 571.1 μmol) was added to tetrahydrofuran (3.0 mL) under an argon atmosphere. Tebbe reagent (1.7 mL, 0.5 M, 856.6 μmol) was added dropwise at 0 °C. After the addition was complete, the mixture was brought to room temperature and stirred for 16 hours. The reaction was quenched with water (5.0 mL), extracted with ethyl acetate (5.0 mL × 3), concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to give intermediate 56-7 (122.4 mg).

[1183] LCMS: m / z(ESI): 337.1 / 339.1[M+H] +

[1184] Step 7: Synthesis of (R)-1-(2-(1-cyclopropyl-4-(1-(1-ethyl-3-methoxy-1H-pyrazol-4-yl)vinyl)-1H-pyrazol-3-yl)-5-fluorophenyl)ethyl-1-ol (intermediate 56-8)

[1185] Intermediate 56-7 (122.4 mg, 362.9 μmol), 1-4 (90.3 mg, 544.4 μmol), Pd2dba3 (33.2 mg, 36.3 μmol), PCy3 (20.3 mg, 72.6 μmol), and potassium fluoride (63.2 mg, 1.1 mmol) were added to a mixed solvent of 1,4-dioxane (5.0 mL) and water (1.0 mL) under an argon atmosphere and reacted at 100 °C for 12 hours. The reaction was quenched with water (5.0 mL), and then extracted with ethyl acetate (5.0 mL × 3). After concentration of the organic phase under reduced pressure, the residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain intermediate 56-8 (130.0 mg).

[1186] LCMS: m / z (ESI): 397.2 [M+H] +

[1187] Step 8: Synthesis of (R)-5-bromo-3-(1-(2-(1-cyclopropyl-4-(1-(1-ethyl-3-methoxy-1H-pyrazol-4-yl)vinyl)-1H-pyrazol-3-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine (intermediate 56-9)

[1188] Potassium tert-butoxide (1.4 mL, 1.0 M, 1.4 mmol) was added to a tetrahydrofuran (5.0 mL) solution of intermediate 56-8 (130.0 mg, 327.9 μmol) and 5-bromo-3-fluoro-2-nitropyridine (309.3 mg, 1.4 mmol) at 0 °C, and the reaction was stirred for 2 hours. The reaction was quenched with saturated ammonium chloride aqueous solution (5.0 mL), extracted with ethyl acetate (5.0 mL × 3), concentrated the organic phase under reduced pressure, and purified the residue by column chromatography (petroleum ether: ethyl acetate = 1:1) to give intermediate 56-9 (144.8 mg).

[1189] LCMS: m / z(ESI): 597.1 / 599.1[M+H] +

[1190] Step 9: Synthesis of (R)-5-bromo-3-(1-(2-(1-cyclopropyl-4-(1-(1-ethyl-3-methoxy-1H-pyrazol-4-yl)vinyl)-1H-pyrazol-3-yl)-5-fluorophenyl)ethoxy)pyridine-2-amine (intermediate 56-10)

[1191] Intermediate 56-9 (144.8 mg, 242.3 μmol) and anhydrous ammonium chloride (77.8 mg, 1.4 mmol) were dissolved in ethanol (5.0 mL) / water (1.0 mL), and iron powder (81.2 mg, 1.4 mmol) was added. The resulting mixture was heated to 80 °C and reacted for 1 hour. The reaction solution was filtered, extracted with ethyl acetate (10.0 mL), and the organic phases were combined and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to give intermediate 56-10 (121.6 mg).

[1192] LCMS: m / z(ESI):567.1 / 569.1[M+H] +

[1193] Step 9: Synthesis of Compound 56

[1194] Intermediate 56-10 (113.0 mg, 199.1 μmol), palladium acetate (13.4 mg, 59.7 μmol), n-butyldi(1-adamantyl)phosphine (42.8 mg, 119.5 μmol), and potassium pentovalinate (279.2 mg, 2.0 mmol) were dissolved in t-AmOH (3.0 mL). The reaction mixture was stirred at 140 °C for 2 hours under an argon atmosphere. After filtration, the filtrate was concentrated, and the residue was purified by preparative liquid chromatography (column: YMC TA-C18, 30 × 150 mm, 5 μm; mobile phase A: 7 mmol / L ammonium bicarbonate, mobile phase B: acetonitrile; flow rate: 30 mL / min; acetonitrile ratio 45-75%, elution for 10-11 min) to give compound 56 (23.9 mg).

[1195] LCMS: m / z (ESI): 487.2 [M+H] +

[1196] 1 H NMR (400MHz, DMSO-d6) δ7.71-7.62(m,2H),7.53-7.46(m,2H),7.14(m,1H),6.94(m,2H),6.50(m,1H),5.28(m,1H),5.15-5.07( m,1H),4.77(m,1H),3.99-3.92(m,2H),3.90(s,3H),3.83(m,1H),1.61(d,J=6.2Hz,3H),1.26(m,3H),1.08(m,2H),0.95(m,2H).

[1197] Example 57: Synthesis of Compound 57

[1198] Under an argon atmosphere, compound 20 (10 mg, 20 μmol), pinacol ester of pyridine-3-boronate (43.8 mg, 214 μmol), cacXium A Pd G3 (2.9 mg, 3.9 μmol), and cesium carbonate (64 mg, 195 μmol) were dissolved in 1,4-dioxane (1 mL) and water (0.1 mL), and the mixture was stirred at 110 °C for 1 h. The reaction solution was purified by reverse-phase column chromatography (acetonitrile / 0.0125% ammonia, 25-65%) to give the title compound (5.5 mg).

[1199] MS m / z (ESI): 508.5 [M+H] +

[1200] 1H NMR (400MHz, DMSO-d6) δ9.25-8.99(m,1H),8.62-8.37(m,1H),8.23(d,J=7.9Hz,1H ),7.70-7.59(m,1H),7.58-7.50(m,1H),7.50-7.29(m,3H),7.13-7.01(m,1H),6.4 4(s,1H),6.10(s,2H),5.33(d,J=2.0Hz,1H),5.16-4.99(m,1H),4.73(d,J=1.8Hz, 1H), 4.19-4.03 (m, 2H), 3.76 (s, 3H), 1.53 (d, J = 6.2Hz, 3H), 1.33 (t, J = 7.2Hz, 3H).

[1201] Example 58: Synthesis of Compound 58

[1202] Compound 20 (15 mg, 29.4 μmol), cataXium A Pd G3 (2.1 mg, 2.9 μmol), cesium carbonate (28.8 mg, 88.3 μmol), and pinacol 4-pyridineborate (60.4 mg, 294 μmol) were added to a mixed solvent of 1,4-dioxane (0.5 mL) and water (0.1 mL) under an argon atmosphere and reacted at 100 °C for 1 h. The reaction solution was then filtered and purified by preparative liquid chromatography (column: Waters Xbridge OBD 19*150 mm*5 μm; mobile phase: [A: water (0.0125% NH3), B: acetonitrile]; B%: 25%-60%, 10 min) to give the title compound (4.69 mg).

[1203] LC-MS: m / z (ESI): 508.6 [M+H] +

[1204] 1H NMR(400MHz,DMSO-d6)δ8.62-8.56(m,2H),7.97-7.91(m,2H),7.75-7.67(m,1H) ,7.63-7.55(m,1H),7.51(d,J=1.8Hz,1H),7.49(s,1H),7.20-7.10(m,1H),6.50( s,1H),6.17(s,2H),5.40(d,J=2.0Hz,1H),5.17-5.09(m,1H),4.78(d,J=1.8Hz,1 H),4.24-4.13(m,2H),3.83(s,3H),1.60(d,J=6.1Hz,3H),1.39(t,J=7.2Hz,3H).

[1205] Example 59: Synthesis of Compound 59

[1206] Under an argon atmosphere, compound 20 (10 mg, 20 μmol), 1-(difluoromethyl)pyrazole-4-boronic acid pinacol ester (47.9 mg, 196 μmol), cacXium A Pd G3 (2.9 mg, 3.9 μmol), and cesium carbonate (64 mg, 195 μmol) were dissolved in 1,4-dioxane (1 mL) and water (0.1 mL), and the mixture was stirred at 110 °C for 1 h. The reaction solution was purified by reverse-phase column chromatography (acetonitrile / 0.0125% ammonia, 25-65%) to give the title compound (4.7 mg).

[1207] MS m / z (ESI): 547.6 [M+H] +

[1208] 1 H NMR (400MHz, DMSO-d6) δ8.43 (s, 1H), 8.14 (s, 1H), 7.87 (t, J = 58.9Hz, 1H), 7.71-7.65(m,1H),7.61-7.44(m,3H),7.21-7.11(m,1H),6.49(s,1H),6.15 (s,2H),5.44(d,J=2.1Hz,1H),5.21-5.07(m,1H),4.83(d,J=2.0Hz,1H),4. 19-4.05(m,2H),3.85(s,3H),1.61(d,J=6.2Hz,3H),1.36(t,J=7.2Hz,3H).

[1209] Example 60: Synthesis of Compound 60

[1210] Under an argon atmosphere, compound 20 (10 mg, 20 μmol), 1-(trifluoromethyl)pyrazole-4-boronic acid pinacol ester (51.4 mg, 196 μmol), cacXium A Pd G3 (2.9 mg, 3.9 μmol), and cesium carbonate (64 mg, 195 μmol) were dissolved in 1,4-dioxane (1 mL) and water (0.1 mL), and the mixture was stirred at 110 °C for 1 h. The reaction solution was purified by reverse-phase column chromatography (acetonitrile / 0.0125% ammonia, 25-65%) to give the title compound (2.8 mg).

[1211] MS m / z (ESI): 565.6 [M+H] +

[1212] 1 H NMR(400MHz,DMSO-d6)δ8.53(s,1H),8.28(s,1H),7.74-7.64(m,1H),7.63-7.56 (m,1H),7.54(s,1H),7.49(d,J=1.8Hz,1H),7.20-7.09(m,1H),6.48(d,J=1.8Hz ,1H),6.15(s,2H),5.46(d,J=2.1Hz,1H),5.21-5.09(m,1H),4.86(d,J=1.9Hz,1 H),4.23-4.04(m,2H),3.84(s,3H),1.61(d,J=6.2Hz,3H),1.36(t,J=7.2Hz,3H).

[1213] Example 61: Synthesis of Compound 61

[1214] Step 1: Synthesis of intermediate 61-1

[1215] A mixture of 4-bromo-5-fluoro-1-methylpyrazole (200 mg, 1.12 mmol), (dppf)PdCl2 (81.8 mg, 112 μmol), pinacol diboronate (340 mg, 1.34 mmol), potassium acetate (329 mg, 3.35 mmol), and 1,4-dioxane (4 mL) was stirred at 110 °C for 1.5 h under an argon atmosphere. The resulting mixture was concentrated under reduced pressure to remove the solvent and purified by column chromatography (tetrahydrofuran / petroleum ether, 0-50%) to give the title compound (70 mg).

[1216] MS m / z (ESI): 227.3 [M+H] +

[1217] Step 2: Synthesis of Compound 61

[1218] Under an argon atmosphere, compound 20 (10 mg, 20 μmol), intermediate 61-1 (35.5 mg, 157 μmol), catalyst Xium A Pd G3 (2.9 mg, 3.9 μmol), and cesium carbonate (64 mg, 195 μmol) were dissolved in 1,4-dioxane (1 mL) and water (0.1 mL), and the mixture was stirred at 110 °C for 1 h. The reaction solution was purified by reverse-phase column chromatography (acetonitrile / 0.0125% ammonia, 25-65%) to give the title compound (5 mg).

[1219] MS m / z (ESI): 529.6 [M+H] +

[1220] 1 H NMR (400MHz, DMSO-d6) δ7.72-7.65(m,2H),7.59-7.52(m,1H),7.47(d,J=1.7Hz,2H),7.18-7.09(m,1H),6.48(s,1H),6.13(s,2H),5.36(d,J=2.2Hz ,1H),5.18-5.06(m,1H),4.77(d,J=2.1Hz,1H),4.16-4.04(m,2H),3.85(s ,3H),3.76(d,J=1.1Hz,3H),1.60(d,J=6.2Hz,3H),1.34(t,J=7.2Hz,3H).

[1221] Example 62: Synthesis of Compound 62

[1222] Step 1: Synthesis of intermediate 62-1

[1223] Under an argon atmosphere, a mixture of 4-bromo-5-chloro-1-methylpyrazole (150 mg, 76.8 mmol), (dppf)PdCl2 (56.2 mg, 76.8 μmol), pinacol diboronate (234 mg, 921 μmol), potassium acetate (226 mg, 2.30 mmol), and 1,4-dioxane (3 mL) was stirred at 110 °C for 1 h. The resulting mixture was concentrated under reduced pressure to remove the solvent, and purified by column chromatography (tetrahydrofuran / petroleum ether, 0-50%) to give the title compound (72 mg).

[1224] MS m / z(ESI): 243.2 [M+H] +

[1225] Step 2: Synthesis of Compound 62

[1226] Under an argon atmosphere, compound 20 (10 mg, 20 μmol), intermediate 62-1 (23.8 mg, 98.2 μmol), catalyst Xium A Pd G3 (2.9 mg, 3.9 μmol), and cesium carbonate (64 mg, 195 μmol) were dissolved in 1,4-dioxane (1 mL) and water (0.1 mL), and the mixture was stirred at 100 °C for 1 h. The reaction solution was purified by reversed-phase column chromatography (acetonitrile / 0.0125% ammonia, 25-65%) to give the title compound (5 mg).

[1227] MS m / z (ESI): 545.6 [M+H] +

[1228] Example 63: Synthesis of Compound 63

[1229] Step 1: Synthesis of intermediate 63-1

[1230] A mixture of 4-bromo-3-fluoro-1-methylpyrazole (220 mg, 1.23 mmol), (dppf)PdCl2 (89.9 mg, 123 μmol), pinacol diboronate (375 mg, 1.47 mmol), potassium acetate (362 mg, 3.69 mmol), and 1,4-dioxane (4 mL) was stirred at 110 °C for 1.5 h under an argon atmosphere. The resulting mixture was concentrated under reduced pressure to remove the solvent and purified by column chromatography (tetrahydrofuran / petroleum ether, 0-50%) to give the title compound (124 mg).

[1231] MS m / z (ESI): 227.3 [M+H] +

[1232] Step 2: Synthesis of Compound 63

[1233] Under an argon atmosphere, compound 20 (10 mg, 20 μmol), intermediate 63-1 (22.2 mg, 98.2 μmol), catalyst Xium A Pd G3 (2.9 mg, 3.9 μmol), and cesium carbonate (64 mg, 195 μmol) were dissolved in 1,4-dioxane (1 mL) and water (0.1 mL), and the mixture was stirred at 100 °C for 1 h. The reaction solution was purified by reversed-phase column chromatography (acetonitrile / 0.0125% ammonia, 25-65%) to give the title compound (9.1 mg).

[1234] MS m / z (ESI): 529.6 [M+H] +

[1235] 1H NMR (400MHz, DMSO-d6) δ7.87(d,J=2.1Hz,1H),7.72-7.63(m,1H),7.55-7.41(m,3H),7.19-7.11(m,1H),6.47(s,1H),6.11(s,2H),5.36(d,J=2 .1Hz,1H),5.19-5.08(m,1H),4.77(d,J=2.1Hz,1H),4.16-4.04(m,2H), 3.85(s,3H),3.76(s,3H),1.60(d,J=6.2Hz,3H),1.33(t,J=7.2Hz,3H).

[1236] Example 64: Synthesis of Compound 64

[1237] Step 1: Synthesis of intermediate 64-1

[1238] A mixture of 4-bromo-3-chloro-1-methylpyrazole (218 mg, 1.12 mmol), (dppf)PdCl2 (81.6 mg, 112 μmol), pinacol diboronate (425 mg, 1.67 mmol), potassium acetate (328 mg, 3.35 mmol), and 1,4-dioxane (4 mL) was stirred at 110 °C for 1.5 h under an argon atmosphere. The resulting mixture was concentrated under reduced pressure to remove the solvent and purified by column chromatography (tetrahydrofuran / petroleum ether, 0-50%) to give the title compound (107 mg).

[1239] MS m / z(ESI): 243.2 [M+H] +

[1240] Step 2: Synthesis of Compound 64

[1241] Under an argon atmosphere, compound 20 (10 mg, 20 μmol), intermediate 64-1 (23.8 mg, 98.2 μmol), catalyst Xium A Pd G3 (2.9 mg, 3.9 μmol), and cesium carbonate (64 mg, 195 μmol) were dissolved in 1,4-dioxane (1 mL) and water (0.1 mL), and the mixture was stirred at 100 °C for 1 h. The reaction solution was purified by reversed-phase column chromatography (acetonitrile / 0.0125% ammonia, 25-65%) to give the title compound (5.9 mg).

[1242] MS m / z (ESI): 545.6 [M+H] +

[1243] Example 65: Synthesis of Compound 65

[1244] Under an argon atmosphere, compound 20 (8 mg, 16 μmol), 1-isopropylpyrazole-4-boronic acid (24.2 mg, 157 μmol), catacXium A Pd G3 (2.3 mg, 3.1 μmol), and cesium carbonate (51.2 mg, 157 μmol) were dissolved in 1,4-dioxane (0.8 mL) and water (0.08 mL), and the mixture was stirred at 110 °C for 1 h. The reaction solution was purified by reversed-phase column chromatography (acetonitrile / 0.0125% ammonia, 25-65%) to give the title compound (3.7 mg).

[1245] MS m / z (ESI): 539.6 [M+H] +

[1246] 1 H NMR(400MHz,DMSO-d6)δ8.02(s,1H),7.80(s,1H),7.72-7.65(m,1H),7.61-7.54(m,1 H),7.49-7.42(m,2H),7.19-7.11(m,1H),6.49(d,J=1.8Hz,1H),6.10(s,2H),5.39(d, J=2.2Hz,1H),5.19-5.07(m,1H),4.78(d,J=2.1Hz,1H),4.60-4.47(m,1H),4.17-3.99 (m,2H),3.84(s,3H),1.60(d,J=6.2Hz,3H),1.49-1.41(m,6H),1.34(t,J=7.2Hz,3H).

[1247] Example 66: Synthesis of Compound 66

[1248] Compound 20 (8 mg, 15.7 μmol), cataXium A Pd G3 (1.1 mg, 1.6 μmol), cesium carbonate (15.4 mg, 47.3 μmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-5,6-dihydro-4H-pyrrolo(1,2-b)pyrazole (36.8 mg, 157 μmol) were added to a mixed solvent of 1,4-dioxane (0.5 mL) and water (0.1 mL) under an argon atmosphere and reacted at 100 °C for 1 h. The reaction solution was then filtered and purified by preparative liquid chromatography (column: Waters Xbridge OBD 19*150mm*5μm; mobile phase: [A: water (0.0125% NH3), B: acetonitrile]; B%: 25%-60%, 10min) to obtain the title compound (2.25mg).

[1249] LC-MS: m / z (ESI): 537.5 [M+H] +

[1250] 1 H NMR(400MHz, DMSO-d6)δ7.79(s,1H),7.68(dd,J=10.4,2.8Hz,1H),7.57(dd,J=8.5,5.9Hz,1H) ,7.46(d,J=1.8Hz,1H),7.44(s,1H),7.14(td,J=8.5,2.8Hz,1H),6.48(d,J=1.8Hz,1H),6.10(s ,2H),5.37(d,J=2.2Hz,1H),5.16-5.05(m,1H),4.75(d,J=2.1Hz,1H),4.15-4.03(m,4H),3.84 (s,3H),3.03(t,J=7.3Hz,2H),2.62-2.56(m,2H),1.60(d,J=6.1Hz,3H),1.34(t,J=7.2Hz,3H).

[1251] Example 67: Synthesis of Compound 67

[1252] Compound 20 (8 mg, 15.7 μmol), cataXium A Pd G3 (1.1 mg, 1.6 μmol), cesium carbonate (15.4 mg, 47.3 μmol), and N-cyclobutyl-pyrazole-4-pinacol diboronic acid ester (38.9 mg, 157 μmol) were added to a mixed solvent of 1,4-dioxane (0.5 mL) and water (0.1 mL) under an argon atmosphere and reacted at 100 °C for 1 h. The reaction solution was then filtered and purified by preparative liquid chromatography (column: Waters Xbridge OBD 19*150 mm*5 μm; mobile phase: [A: water (0.0125% NH3), B: acetonitrile]; B%: 25%-60%, 10 min) to give the title compound (3.7 mg).

[1253] LC-MS: m / z (ESI): 551.5 [M+H] + ...

Claims

1. A compound represented by Formula (A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, X1, X2, X3are independently selected from CH or N; Ring A is selected from phenylene or 5-6 membered heteroarylene; Ring B is selected from 5-membered heteroarylene comprising at least one N atom; Ring C is selected from 5-15 membered heterocyclene or 5-12 membered heteroarylene; Y 1 selected from O, NR 6 or CR 7 R 7b ; Y 2 selected from O, NR 8 or CR 9 R 9b ; R 1 and R 2 is independently selected from H or C1-C6 alkyl; Each R 3 Independently selected from CN, halogen, OH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 4-7-membered heterocyclic, 5-6-membered heteroaryl, or phenyl, wherein the OH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 4-7-membered heterocyclic, 5-6-membered heteroaryl, or phenyl is optionally converted by R. 3a replace; or R 1 , R 3 together with the atom to which they are attached form a C5-C 10 unsaturated carbocyclic or 5-10 membered heterocyclyl; Each R 3a Independently selected from CN, halogen, OH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 4-7-membered heterocyclic, 5-6-membered heteroaryl, or phenyl, wherein the OH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 4-7-membered heterocyclic, 5-6-membered heteroaryl, or phenyl is optionally converted by R. 3b replace; Each R 3b Independently selected from CN, halogen, OH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclic group, wherein the OH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclic group is optionally replaced by R. 3c replace; Each R 3c Independently selected from CN, OH, NH2, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 alkylamino; Each R 4 Independently selected from CN, halogen, OH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, C3-C 12 Cycloalkyl, 4-12 membered heterocyclic, 5-6 membered heteroaryl or phenyl, wherein the OH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, C3-C 12 Cycloalkyl, 4-12-membered heterocyclic, 5-6-membered heteroaryl, or phenyl groups optionally marked with R 4a replace; or R 3 , R 4 together with the atom to which they are attached form a C5-C 10 unsaturated carbocyclic or 5-10 membered heterocyclyl; Each R 4a Independently selected from CN, halogen, OH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 4-7-membered heterocyclic, 5-6-membered heteroaryl, or phenyl, wherein the OH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 4-7-membered heterocyclic, 5-6-membered heteroaryl, or phenyl is optionally converted by R. 4b replace; Each R 4b Independently selected from CN, halogen, OH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclic group, wherein the OH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclic group is optionally replaced by R. 4c replace; Each R 4c Independently selected from CN, OH, NH2, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 alkylamino; Each R 5 Independently selected from CN, halogen, OH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 4-12-membered heterocyclic, 5-6-membered heteroaryl, or phenyl, wherein the OH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 4-12-membered heterocyclic, 5-6-membered heteroaryl, or phenyl is optionally R 5a replace; Each R 5a Independently selected from CN, halogen, OH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 4-7-membered heterocyclic, 5-6-membered heteroaryl, or phenyl, wherein the OH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 4-7-membered heterocyclic, 5-6-membered heteroaryl, or phenyl is optionally converted by R. 5b replace; Each R 5b Independently selected from CN, halogen, OH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclic group, wherein the OH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclic group is optionally replaced by R. 5c replace; Each R 5c Independently selected from CN, OH, NH2, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 alkylamino; R 6 and R 8 are independently selected from H or C1-C6alkyl optionally substituted with R 8a ; Each R 8a Independently selected from halogens, C3-C6 cycloalkyl groups, or 4-7 membered heterocyclic groups; R 7 , R 7b , R 9 , R 9b is independently selected from H, halogen or Ci-C6alkyl optionally substituted with halogen; or, R 9 , R 9b together with the atom to which they are attached form a or C3-C6cycloalkyl, said or C3-C6cycloalkyl optionally substituted with halogen or C1-C6alkyl; or, R 5 , R 9 with the atom to which it is attached forms a C5-C 10 unsaturated carbocyclic or 5-10 membered heterocyclyl; m, n and p are independently selected from an integer from 0 to 3.

2. The compound of formula (A), stereoisomers thereof, or pharmaceutically acceptable salts thereof, according to claim 1, wherein, said ring A is selected from phenylene, thiazolylene or thiophenylene; or ring A is selected from 3. The compound of formula (A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein, said ring B is selected from a pyrazolylene, imidazolylene or thiazolylene; or ring B is selected from a pyrazolylene or thiazolylene; or, ring B is selected from a pyrazolylene; or ring B is selected from 4. The compound of formula (A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein, said ring C is selected from a 5-12 membered heterocyclyl ene or a 5-10 membered heteroarylene; or ring C is selected from or ring C is selected from wherein c represents the position of attachment to Y 2 or ring C is selected from wherein c represents the position of attachment to Y 2 or ring C is selected from wherein c represents the position of attachment to Y 2 or ring C is selected from 5. The compound of formula (A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein, X1is N, X2, X3are CH; or X1, X3are N, X2is CH; or, X1is N, X2, X3are CH.

6. The compound of formula (A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein said R 1 is selected from C1-C3 alkyl; or R 1 is methyl; and / or, R 2 is H; or R 1 is methyl and R 2 is H.

7. The compound of formula (A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein said R 3 is independently selected from halogen or Ci-C6alkyl; or R 3 is selected from halogen or Ci-C3alkyl; or R 3 is selected from F or methyl.

8. The compound of formula (A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein, said R 4 is selected from halogen, Ci-C6-alkyl or C3-C6-cycloalkyl; or R 4 is selected from CI, methyl or cyclopropyl.

9. The compound of formula (A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein, The R 9 R 9b Independently selected from H or C1-C3 alkyl; or, R 9 R 9b The atoms connected to it form together Or cyclopropyl, the Alternatively, the cyclopropyl group may be substituted with a halogen or a C1-C6 alkyl group; or, R 5 R 9 The atoms bonded to it together form a C5-C6 unsaturated carbon ring or a 5-6 membered heterocyclic group; or R 9 R 9b Independently selected from H or methyl; or, R 9 R 9b The atoms connected to it form together Or, R 5 R 9 The atoms bonded to it together form cyclopentenyl, cyclohexenyl, or... Or, Y 2 Selected from -CH(CH3)-, -CH2-, -N(CH3)-, -NH-, -N(CH2CF3)-, Or, Y 2 -CH(CH3)-, -CH2-, -N(CH3)- or Or Y 2 for 10. The compound of formula (A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein, Each R 5 Independently selected from CN, halogen, OH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 4-9 membered heterocyclic, 5-6 membered heteroaryl, or phenyl, wherein the OH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 4-9 membered heterocyclic, 5-6 membered heteroaryl, or phenyl is optionally converted by R. 5a Replace; and / or, each R 5a It is independently selected from halogens, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, or 4-7 membered heterocyclic groups; or each R is independently selected from the group consisting of CN, halogen, OH, NH2, Ci-C6alkyl, 5 independently selected from the group consisting of CN, halogen, OH, NH2, Ci-C6alkyl, said OH, NH2, C1-C6 alkyl, optionally substituted with R 5a substituted; and / or, Each R 5a Independently selected from halogens, OH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 4-7-membered heterocyclic or 5-6-membered heteroaryl, wherein the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7-membered heterocyclic or 5-6-membered heteroaryl are optionally R 5b Replace; and / or, each R is independently selected from the group consisting of H, halogen, C1-C6alkyl, or 4-7 membered heterocyclyl, said H, halogen, C1-C6alkyl, or 4-7 membered heterocyclyl optionally substituted with R 5b independently selected from the group consisting of H, halogen, C1-C6alkyl, or 4-7 membered heterocyclyl, said H, halogen, C1-C6alkyl, or 4-7 membered heterocyclyl optionally substituted with R 5c substituted; and / or, Each R 5c It is independently selected from C1-C6 alkyl groups.

11. The compound of formula (A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein, n is 1, m is 1, and / or p is 0, 1 or 2.

12. The compound of formula (A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein, the compound of formula (A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein ring A, ring B, ring C, Y 1 , Y 2 , R 1 , R 2 , R 3 , R 4 , R 5 , m, n and p are as defined in any one of claims 1-11. or the compound of formula (A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from a compound of formula (A-l), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 7c and R 7d are independently selected from H, halogen or Ci-C6alkyl; ring A, ring B, ring C, X3, Y 1 , R 1 , R 2 , R 3 , R 4 , R 5 , m, n and p are as defined in any one of claims 1-11; or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from a compound of Formula (A-2), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 7c and R 7d are independently selected from H, halogen or Ci-C6alkyl; ring B, ring C, X3, R 3 , R 4 , R 5 , m, n and p are as defined in any one of claims 1-11; or a stereoisomer or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (A) is selected from the group consisting of a compound of Formula (III), a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R 7c and R 7d are independently selected from H, halogen or Ci-C6alkyl; ring A, ring B, ring C, Y 1 , R 1 , R 2 , R 3 , R 4 , R 5 , m, n and p are as defined in any one of claims 1-11.

13. The compound of formula (A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 12, selected from the group consisting of the following compounds, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, 14. A pharmaceutical composition comprising a compound of formula (A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13 and a pharmaceutically acceptable adjuvant.

15. A method for treating a disease associated with ALK in a mammal, comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a compound of formula (A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, or a pharmaceutical composition according to claim 14.

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