Macrocyclic derivative as ras inhibitor and use thereof

Abstract

Provided is a compound of formula (I) as an RAS inhibitor or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing same, and the use thereof in the prevention or treatment of RAS-mediated diseases.

Description

Macrocyclic derivatives as ras inhibitors and uses thereof

[0001] Cross-reference to Related Applications

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

[0003] Chinese Patent Application No. 202410648606.X, filed May 23, 2024, with the

[0004] Chinese Patent Application No. 202411057037.8, filed August 02, 2024, with the

[0005] Chinese Patent Application No. 202411352594.2, filed September 26, 2024, with the

[0006] Chinese Patent Application No. 202411494908.2, filed October 24, 2024, with the

[0007] Chinese Patent Application No. 202510493709.8, filed April 18, 2025, with the TECHNICAL FIELD

[0008] The present disclosure belongs to the technical field of medicine, and specifically relates to macrocyclic compounds or stereoisomers thereof or pharmaceutically acceptable salts thereof as RAS inhibitors, pharmaceutical compositions containing them, and the use thereof as RAS inhibitors in the prevention or treatment of diseases related to RAS. BACKGROUND

[0009] The KRAS gene (Kirsten Rat Sarcoma Viral Oncogene Homolog) belongs to the RAS family of genes (RAS is the first human oncogene discovered, among the KRAS family of genes, there are also NRAS (Neuroblastoma-RAS) and HRAS (Harvey-RAS)), located on chromosome 12, involved in intracellular signal transduction. The KRAS protein encoded by the KRAS gene is a small GTPase, belonging to the RAS superfamily of proteins, the KRAS protein has 188 amino acids, and the molecular weight is 21.6 kD. KRAS is in an activated state when bound to GTP, and in a closed state when bound to GDP. KRAS protein is regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) to be in an activated and inactivated state. The activated KRAS protein mainly activates downstream signaling pathways such as the PI3K-AKT-mTOR signaling pathway that controls cell generation, and the RAS-RAF-MEK-ERK signaling pathway that controls cell proliferation. Most small molecule drugs work by binding to functionally important pockets on target proteins, thereby modulating the activity of the protein. For example, cholesterol-lowering drugs called statins bind to the enzyme active site of HMG-CoA reductase, thereby preventing the enzyme from binding to its substrate. In fact, the knowledge of many such drug / target pairs can mislead one into believing that small molecule modulators can be found for most, if not all, proteins, and thus provide a reasonable amount of time, effort, and resources. This is not the case, and currently, it is estimated that only about 10% of all human proteins are available as small molecule targets. The remaining 90% are currently considered to be small molecule drug discovery intractable or difficult to deal with as mentioned above. Such targets are often referred to as “undruggable”. A large portion of these undruggable targets or medically important human proteins have not yet been studied with a compound library. Therefore, there is a great interest in finding novel molecules that can modulate the function of such undruggable targets. Given the importance of the RAS signaling pathway in tumor therapy, targeted therapy against the RAS signaling pathway has become a research hotspot in the field of tumor therapy in recent years. SUMMARY

[0010] The present disclosure relates to a compound of Formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

[0011] wherein,

[0012] X 1 is selected from CH2and NH;

[0013] n is selected from 0, 1, 2 and 3.

[0014] A is selected from C3-C 12 cycloalkylene, 4-10 membered heterocyclylene, C6-C 10 arylene, and 5-12 membered heteroarylene, said C3-C 12 cycloalkylene, 4-10 membered heterocyclylene, C6-C 10 arylene, and 5-12 membered heteroarylene are optionally substituted with 1 or more R a ;

[0015] R 1 is selected from C(O)R 11 , C2-C 10 alkenylene, C2-C 10 alkynylene, C1-C 10 alkyl, C4-C 12 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5-10 membered heteroaryl, said C2-C 10 alkenylene, C2-C 10 alkynylene, C1-C 10 alkyl, C4-C 12 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5-10 membered heteroaryl are optionally substituted with 1 or more R 1a ;

[0016] R 2 , R 3 , R 4 , R 7 , R 8 , and R 9 are independently selected from hydrogen, halogen, hydroxyl, thiol, amino, cyano, C1-C 10 alkyl, C1-C 10 alkoxy, C1-C 10 hydroxyalkyl, C1-C 10 haloalkyl, and C3-C7cycloalkyl, said hydroxyl, thiol, amino, C1-C 10 alkyl, C1-C 10 alkoxy, C1-C 10 hydroxyalkyl, C1-C 10 haloalkyl, and C3-C7cycloalkyl are optionally substituted with 1 or more R 2a ;

[0017] Alternatively, R 4 and R 7 , and the atom to which they are attached, together form a 4-10 membered heterocyclic ring, said 4-10 membered heterocyclic ring is optionally substituted with 1 or more R b ;

[0018] R 5 Selected from C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl and 5-10 heteroaryl, the C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl and 5-10 heteroaryl groups are optionally bounded by one or more R groups. 5a replace;

[0019] R 6 Selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic groups and C1-C4 alkoxy groups, wherein the hydroxyl, mercapto, amino, C1-C4 alkyl, C1-C4 haloalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic groups and C1-C4 alkoxy groups are optionally surrounded by one or more R groups. 6a replace;

[0020] R 11 Selected from amino, C2-C 10 alkenyl, C2-C 10 alkynyl group, C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl and 5-10 heteroaryl groups, wherein the amino group, C2-C 10 alkenyl, C2-C 10 alkynyl group, C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl and 5-10 heteroaryl groups are optionally bounded by one or more R groups. 11a replace;

[0021] Each R a and R 10 Independently selected from halogens, amino groups, hydroxyl groups, mercapto groups, cyano groups, and C1-C4 alkyl groups;

[0022] Each R 1a and R 11a Independently selected from halogen, amino, hydroxyl, mercapto, cyano, C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 aryl and 5-10 heteroaryl groups, wherein the amino, hydroxyl, mercapto, C1-C 10 Alkyl, C3-C12 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Aryl and 5-10 membered heteroaryl are optionally substituted with 1 or more R 1aa substituents;

[0023] Each R 2a is independently selected from the group consisting of halogen, cyano, hydroxyl, amino, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl, C3-C7cycloalkyl, and 4-6 membered heterocyclyl, which hydroxyl, amino, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl, C3-C7cycloalkyl, and 4-6 membered heterocyclyl is optionally substituted with 1 or more R 1aa substituents;

[0024] Each R 1aa is independently selected from the group consisting of halogen, amino, hydroxyl, thiol, cyano, C1-C7alkyl, C1-C7haloalkyl, and C1-C7alkoxy;

[0025] Each R 5a is independently selected from the group consisting of halogen, cyano, C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 alkoxy, C3-C 12 cycloalkyl, 4-14 membered heterocyclyl, C6-C 10 aryl and 5-10 membered heteroaryl, which C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 alkoxy, C3-C 12 cycloalkyl, 4-14 membered heterocyclyl, C6-C 10 aryl and 5-10 membered heteroaryl are optionally substituted with 1 or more R c substituents;

[0026] Each R 6a is independently selected from the group consisting of halogen, cyano, hydroxyl, amino, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl, C3-C7cycloalkyl, and 4-6 membered heterocyclyl;

[0027] Each R c is independently selected from the group consisting of halogen, amino, hydroxyl, thiol, cyano, C1-C7alkyl, C1-C7alkoxy, C3-C 10 cycloalkyl, and 4-12 membered heterocyclyl, which amino, hydroxyl, thiol, C1-C7alkyl, C1-C7alkoxy, C3-C 10 cycloalkyl, and 4-12 membered heterocyclyl is optionally substituted with 1 or more Rh substituted;

[0028] R 5b and R 5b’ are independently selected from the group consisting of C1-C7alkyl, C3-C 12 cycloalkyl, 4-12 membered heterocyclyl, C6-C 10 aryl and 5-10 membered heteroaryl, said C1-C7alkyl, C3-C 12 cycloalkyl, 4-12 membered heterocyclyl, C6-C 10 aryl and 5-10 membered heteroaryl are optionally substituted with 1 or more R d substituted;

[0029] or, R 5b and R 5b’ and the atom to which they are attached collectively form a 4-12 membered heterocyclyl, said 4-12 membered heterocyclyl is optionally substituted with 1 or more R e substituted;

[0030] each R d and R e are independently selected from the group consisting of halogen, hydroxyl, amino, C1-C7alkyl, C1-C4alkoxy, C3-C6cycloalkyl, 4-10 membered heterocyclyl, said amino, C1-C7alkyl, C1-C4alkoxy, C3-C6cycloalkyl, 4-10 membered heterocyclyl is optionally substituted with 1 or more R f substituted;

[0031] each R f is independently selected from the group consisting of C1-C4alkyl, C1-C4alkoxy, C3-C6cycloalkyl, 4-10 membered heterocyclyl, said C1-C4alkyl, C1-C4alkoxy, C3-C6cycloalkyl, 4-10 membered heterocyclyl is optionally substituted with 1 or more R g substituted;

[0032] each R b , R g and R h are independently selected from the group consisting of halogen, hydroxyl, thiol, amino, =O, =CR j R j , C1-C4alkyl, cyano, C3-C6cycloalkyl, 3-6 membered heterocycloalkyl, C1-C4hydroxyalkyl, C1-C4aminoalkyl, C1-C4haloalkyl, (C1-C4alkylene)OC1-C4alkyl, C(O)R k , S(O)2R kand C1-C4alkoxy, optionally substituted with one or more substituents selected from the group consisting of =0, halogen, hydroxyl, cyano, C1-C4haloalkyl, and C1-C4alkyl;

[0033] R j and R k are independently selected from the group consisting of H, halogen, hydroxyl, thiol, cyano, amino, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C6cycloalkyl, 3- to 6-membered heterocycloalkyl, C1-C4hydroxyalkyl, C1-C4aminoalkyl, C1-C4haloalkyl, (C1-C4alkylene)OC1-C4alkyl, C(O)Ra, S(O)2Ra, and C1-C4alkoxy, said hydroxyl, thiol, amino, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C6cycloalkyl, 3- to 6-membered heterocycloalkyl, C1-C4hydroxyalkyl, C1-C4aminoalkyl, C1-C4haloalkyl, (C1-C4alkylene)OC1-C4alkyl, and C1-C4alkoxy optionally substituted with halogen, hydroxyl, cyano, and C1-C4alkyl. 10 and C1-C4alkoxy, optionally substituted with one or more substituents selected from the group consisting of =0, halogen, hydroxyl, cyano, C1-C4haloalkyl, and C1-C4alkyl. 10 and C1-C4alkoxy, optionally substituted with one or more substituents selected from the group consisting of =0, halogen, hydroxyl, cyano, C1-C4haloalkyl, and C1-C4alkyl. 10 and C1-C4alkoxy, optionally substituted with one or more substituents selected from the group consisting of =0, halogen, hydroxyl, cyano, C1-C4haloalkyl, and C1-C4alkyl. 10 and C1-C4alkoxy, optionally substituted with one or more substituents selected from the group consisting of =0, halogen, hydroxyl, cyano, C1-C4haloalkyl, and C1-C4alkyl. 10 and C1-C4alkoxy, optionally substituted with one or more substituents selected from the group consisting of =0, halogen, hydroxyl, cyano, C1-C4haloalkyl, and C1-C4alkyl. 10 and C1-C4alkoxy, optionally substituted with one or more substituents selected from the group consisting of =0, halogen, hydroxyl, cyano, C1-C4haloalkyl, and C1-C4alkyl.

[0034] one or more hydrogen atoms of the compound are optionally deuterium atoms.

[0035] In some embodiments, each R b , R g , and R h are independently selected from the group consisting of halogen, hydroxyl, thiol, amino, =0, =CR j R j , C1-C4alkyl, cyano, C3-C6cycloalkyl, 3- to 6-membered heterocycloalkyl, C1-C4hydroxyalkyl, C1-C4aminoalkyl, C1-C4haloalkyl, (C1-C4alkylene)OC1-C4alkyl, C(O)Ra, S(O)2Ra, and C1-C4alkoxy, said hydroxyl, thiol, amino, C1-C4alkyl, C3-C6cycloalkyl, 3- to 6-membered heterocycloalkyl, C1-C4hydroxyalkyl, C1-C4aminoalkyl, C1-C4haloalkyl, (C1-C4alkylene)OC1-C4alkyl, and C1-C4alkoxy optionally substituted with halogen, hydroxyl, cyano, and C1-C4alkyl. k , S(O)2Ra, and C1-C4alkoxy, said hydroxyl, thiol, amino, C1-C4alkyl, C3-C6cycloalkyl, 3- to 6-membered heterocycloalkyl, C1-C4hydroxyalkyl, C1-C4aminoalkyl, C1-C4haloalkyl, (C1-C4alkylene)OC1-C4alkyl, and C1-C4alkoxy optionally substituted with halogen, hydroxyl, cyano, and C1-C4alkyl. k

[0036] In some embodiments, R 2 , R 3 , R 4 , R 7 , R​8 and R 9 is independently selected from hydrogen, halogen, hydroxyl, thiol, amino, cyano, C1-C4alkyl, C1-C4haloalkyl, and C1-C4alkoxy. 10 C1-C4alkyl, C1-C4haloalkyl, and C1-C4alkoxy. 10 C1-C4alkyl, C1-C4haloalkyl, and C1-C4alkoxy. 10 C1-C4alkyl, C1-C4haloalkyl, and C1-C4alkoxy.

[0037] In some embodiments, each R b , R g , and R h is independently selected from halogen, hydroxyl, thiol, amino, =0, C1-C4alkyl, cyano, C3-C6cycloalkyl, 3-6 membered heterocycloalkyl, C1-C4hydroxyalkyl, C1-C4haloalkyl, (C1-C4alkylene)OC1-C4alkyl, and C1-C4alkoxy.

[0038] In some embodiments, R 6 is selected from hydrogen, halogen, hydroxyl, thiol, amino, cyano, C1-C4alkyl, C1-C4haloalkyl, and C1-C4alkoxy.

[0039] In some embodiments, X 1 is NH.

[0040] In some embodiments, n is 0.

[0041] In some embodiments, A is selected from C6-C 10 arylene and 5-12 membered heteroarylene, said C6-C 10 arylene and 5-12 membered heteroarylene being optionally substituted with 1 or more R a groups.

[0042] In some embodiments, A is selected from 5-12 membered heteroarylene, said 5-12 membered heteroarylene being optionally substituted with 1 or more R a groups.

[0043] In some embodiments, A is selected from 5-6 membered heteroarylene, said 5-6 membered heteroarylene being optionally substituted with 1 or more R a groups.

[0044] In some embodiments, A is selected from 5-6 membered heterocyclene or 5-6 membered heteroarylene, wherein said 5-6 membered heterocyclene or 5-6 membered heteroarylene is optionally substituted with 1 or more R a groups. In some embodiments, A is selected from 6 membered heterocyclene or 5 membered heteroarylene, wherein said 6 membered heterocyclene or 5 membered heteroarylene is optionally substituted with 1 or more R aReplacement. In some embodiments, A is selected from a 6-membered heterocyclic group having 1 N atom and 1 O atom, a 5-membered heteroaryl group having 1 N atom and 1 O atom, or a 5-membered heteroaryl group having 1 N atom and 1 S atom, wherein the 6-membered heterocyclic group or the 5-membered heteroaryl group is optionally replaced by one or more R atoms. a replace.

[0045] In some embodiments, A is selected from imomorpholino, imidazolyl, and imoxazolyl, wherein the imomorpholino, imidazolyl, and imoxazolyl groups are optionally surrounded by one or more R groups. a Replacement. In some embodiments, A is selected from imidazolyl and imidazolyl, said imidazolyl and imidazolyl are optionally replaced by R. a replace.

[0046] In some embodiments, A is selected from an imidazolyl group, wherein the imidazolyl group is optionally replaced by R. a replace.

[0047] In some implementation schemes, A is selected from The Optional by one or more R a Replacement. In some implementations, A is selected from... The Optional R a replace.

[0048] In some implementation schemes, A is selected from The Optional by one or more R a replace.

[0049] In some implementation schemes, R a It is independently selected from halogen, amino, hydroxyl, mercapto and cyano groups.

[0050] In some implementation schemes, A is In some implementation schemes, A is

[0051] In some implementation schemes, R 1 Selected from C(O)R 11 C1-C 10 Alkyl, C4-C 12 Cycloalkyl and 4-10 membered heterocyclic groups, the C1-C 10 Alkyl, C4-C 12 Cycloalkyl groups and 4-10-membered heterocyclic groups are optionally surrounded by one or more R groups. 1a replace.

[0052] In some implementation schemes, R 1 Selected from C(O)R11 C1-C 10 Alkyl, C4-C 12 Cycloalkyl and 4-10 membered heterocyclic groups, the C1-C 10 Alkyl, C4-C 12 Cycloalkyl groups and 4-10-membered heterocyclic groups are optionally surrounded by one or more R groups. 1a Substitution, and the 4-10 membered heterocyclic group contains at least one N atom.

[0053] In some implementation schemes, R 1 Selected from C(O)R 11 C1-C5 alkyl, C4-C6 cycloalkyl, and 4, 5, or 6-membered heterocyclic groups, wherein the C1-C5 alkyl, C4-C6 cycloalkyl, and 4, 5, or 6-membered heterocyclic groups are optionally surrounded by one or more R groups. 1a replace.

[0054] In some implementation schemes, R 1 Selected from C(O)R 11 C1-C5 alkyl groups, C4-C6 cycloalkyl groups, and 4, 5, or 6-membered heterocyclic groups containing at least one nitrogen atom, wherein the C1-C5 alkyl groups and the 4, 5, or 6-membered heterocyclic groups containing at least one nitrogen atom are optionally surrounded by one or more R atoms. 1a replace.

[0055] In some implementation schemes, R 1 Selected from C(O)R 11 C1-C 10 Alkyl groups and 4-10 membered heterocyclic groups, the C1-C 10 Alkyl groups and 4-10 membered heterocyclic groups are optionally surrounded by one or more R groups. 1a replace.

[0056] In some implementation schemes, R 1 Selected from C(O)R 11 C4-C 12 cycloalkyl and C1-C 10 Alkyl, the C4-C 12 cycloalkyl and C1-C 10 Alkyl groups are optionally surrounded by one or more R 1a replace.

[0057] In some implementation schemes, R 1 Selected from C(O)R 11 C4-C6 cycloalkyl and C1-C 10 Alkyl groups, the C4-C6 cycloalkyl groups and C1-C 10 Alkyl groups are optionally surrounded by one or more R 1a replace.

[0058] In some implementation schemes, R1 C(O)R 11 and C1-C5alkyl optionally substituted with 1 or more R 10 alkyl, said C1-C5alkyl optionally substituted with 1 or more R 10 substituted with 1 or more R 1a substituted with 1 or more R

[0059] In some embodiments, R 1 C(O)R 11 and C1-C5alkyl optionally substituted with 1 or more R 1a substituted with 1 or more R

[0060] In some embodiments, R 1 C(O)R 11 , C1-C5alkyl and 4, 5 or 6 membered heterocyclyl, said C1-C5alkyl and 4, 5 or 6 membered heterocyclyl optionally substituted with 1 or more R 1a substituted with 1 or more R

[0061] In some embodiments, R 1 C(O)R 11 and C1-C5alkyl optionally substituted with 1 or more R 1a substituted with 1 or more R

[0062] In some embodiments, R 1 C(O)R 11 , methyl, pentyl, tetrahydropyrrolyl and cyclopentyl, said methyl, pentyl, tetrahydropyrrolyl and cyclopentyl optionally substituted with 1 or more R 1a substituted with 1 or more R

[0063] In some embodiments, R 1 C(O)R 11 , pentyl and cyclopentyl, said pentyl and cyclopentyl optionally substituted with 1 or more R 1a substituted with 1 or more R

[0064] In some embodiments, R 1 C(O)R 11 , methyl, pentyl and tetrahydropyrrolyl, said methyl, pentyl and tetrahydropyrrolyl optionally substituted with 1 or more R 1a substituted with 1 or more R

[0065] In some embodiments, R 1 C(O)R 11 , methyl and pentyl, said methyl and pentyl optionally substituted with 1 or more R 1a substituted with 1 or more R

[0066] In some embodiments, R 1 C(O)R 11, methyl, cyclopentyl and pentyl, said methyl, cyclopentyl and pentyl being optionally substituted with 1 or more R 1a substituents.

[0067] In some embodiments, each R 1a is independently selected from the group consisting of halogen, C1-C4alkyl and C3-C4cycloalkyl, said C1-C4alkyl and C3-C4cycloalkyl being optionally substituted with 1 or more R 10 substituents. 12 In some embodiments, each R 10 is independently selected from the group consisting of halogen, C1-C4alkyl and C3-C4cycloalkyl, said C1-C4alkyl and C3-C4cycloalkyl being optionally substituted with 1 or more R 12 substituents. 1aa substituents.

[0068] In some embodiments, each R 1a is independently selected from the group consisting of halogen, C1-C4alkyl and C3-C4cycloalkyl, said C1-C4alkyl and C3-C4cycloalkyl being optionally substituted with 1 or more R 1aa substituents.

[0069] In some embodiments, each R 1a is independently selected from the group consisting of halogen, C1-C4alkyl and C3-C4cycloalkyl, said C1-C4alkyl and C3-C4cycloalkyl being optionally substituted with 1 or more R 1aa substituents.

[0070] In some embodiments, each R 1a is independently selected from the group consisting of halogen, C1-C4alkyl and C3-C4cycloalkyl, said C1-C4alkyl and C3-C4cycloalkyl being optionally substituted with 1 or more R

[0071] In some embodiments, R 11 is selected from the group consisting of 4-10 membered heterocyclyl, said 4-10 membered heterocyclyl being optionally substituted with 1 or more R 11a substituents.

[0072] In some embodiments, R 11 is selected from the group consisting of 4-6 membered heterocyclyl, said 4-6 membered heterocyclyl being optionally substituted with 1 or more R 11a substituents.

[0073] In some embodiments, R 11 is selected from the group consisting of 4, 5 or 6 membered heterocycloalkyl, said 4, 5 or 6 membered heterocycloalkyl optionally containing 1 N atom, and being optionally substituted with 1 or more R 11a substituents.

[0074] In some embodiments, R 11 is selected from the group consisting of tetrahydropyrrolyl, said tetrahydropyrrolyl being optionally substituted with 1 or more R 11a substituents.

[0075] In some embodiments, each R 11a is independently selected from the group consisting of halogen, amino, hydroxyl, thiol, cyano and C1-C4alkyl, said amino, hydroxyl, thiol and C1-C4alkyl being optionally substituted with 1 or more R 10 substituents.10 alkyl is optionally substituted with 1 or more R 1aa substituents.

[0076] In some embodiments, each R 11a is independently selected from C1-C4 alkyl optionally substituted with 1 or more R 10 substituents. 10 alkyl is optionally substituted with 1 or more R 1aa substituents.

[0077] In some embodiments, each R 11a is independently selected from C1-C4 alkyl optionally substituted with 1 or more R 1aa substituents.

[0078] In some embodiments, each R 11a is independently selected from methyl optionally substituted with 1 or more R 1aa substituents.

[0079] In some embodiments, each R 1aa is independently selected from halogen, C1-C7 alkyl, C1-C7 haloalkyl, and C1-C7 alkoxy.

[0080] In some embodiments, each R 1aa is independently selected from halogen and C1-C4 alkyl.

[0081] In some embodiments, each R 1aa is independently selected from methyl, chloro, and fluoro.

[0082] In some embodiments, R 1 is selected from cyclopentyl,

[0083] In some embodiments, R 1 is selected from cyclopentyl,

[0084] In some embodiments, R 1 is selected from cyclopentyl,

[0085] In some embodiments, R 2 , R 3 is independently selected from hydrogen, halogen, hydroxyl, cyano, and C1-C4 alkyl. 10 alkyl.

[0086] In some embodiments, R 2 , R 3 is independently selected from C1-C4 alkyl, such as methyl.

[0087] In some embodiments, R 2 , R 3 are each methyl.

[0088] In some embodiments, R 4 is selected from C1-C 10 alkyl, C1-C 10 hydroxyalkyl, C1-C 10 haloalkyl, and C3-C7cycloalkyl, said C1-C 10 alkyl, C1-C 10 hydroxyalkyl, C1-C 10 haloalkyl, and C3-C7cycloalkyl being optionally substituted with one or more R 2a .

[0089] In some embodiments, R 4 is selected from C1-C4alkyl, C1-C4hydroxyalkyl, C1-C4haloalkyl, and C3-C6cycloalkyl, said C1-C4alkyl, C1-C4hydroxyalkyl, C1-C4haloalkyl, and C3-C6cycloalkyl being optionally substituted with one or more R 2a .

[0090] In some embodiments, R 4 is selected from hydrogen, halogen, hydroxyl, cyano, C1-C 10 alkyl, and C1-C 10 haloalkyl.

[0091] In some embodiments, R 4 is selected from C1-C2alkyl, C1-C2hydroxyalkyl, C1-C2haloalkyl, and C4cycloalkyl, said C1-C2alkyl, C1-C2hydroxyalkyl, and C4cycloalkyl being optionally substituted with one or more R 2a .

[0092] In some embodiments, R 4 is selected from C1-C4alkyl, C1-C4haloalkyl, and C3-C6cycloalkyl, said C1-C4alkyl, C1-C4haloalkyl, and C3-C6cycloalkyl being optionally substituted with one or more R 2a .

[0093] In some embodiments, R 4 is selected from C1-C4alkyl and C3-C6cycloalkyl, said C1-C4alkyl and C3-C6cycloalkyl being optionally substituted with one or more R 2a .

[0094] In some embodiments, R 4 is selected from C1-C4alkyl and C1-C4haloalkyl.

[0095] In some embodiments, R 4 is ethyl optionally substituted with halo.

[0096] In some embodiments, R 4 is ethyl optionally substituted with fluoro, such as ethyl and trifluoroethyl.

[0097] In some embodiments, each R 2a is independently selected from cyano, C3-C7cycloalkyl, and 4-6 membered heterocyclyl, said C3-C7cycloalkyl and 4-6 membered heterocyclyl optionally substituted with 1 or more R 1aa In some embodiments, each R 2a is independently selected from cyano, C3-C4cycloalkyl, and 5-6 membered heterocyclyl, said C3-C4cycloalkyl and 5-6 membered heterocyclyl optionally substituted with 1 or more R 1aa , and / or said 5-6 membered heterocyclyl contains one O atom.

[0098] In some embodiments, each R 2a is independently selected from cyano, cyclopropyl, and tetrahydropyranyl, said cyclopropyl and tetrahydropyranyl optionally substituted with 1 or more R 1aa In some embodiments, R 1aa is C1-C4alkyl, or C1-C2alkyl, or methyl.

[0099] In some embodiments, R 4 is selected from ethyl, trifluoroethyl, cyclopropylmethyl,

[0100] In some embodiments, R 4 is selected from ethyl, trifluoroethyl, cyclopropylmethyl, and

[0101] In some embodiments, R 4 is selected from ethyl and In some embodiments, R 4 is ethyl.

[0102] In some embodiments, R 5 is selected from C6-C 10 aryl and 5-10 membered heteroaryl, said C6-C 10 aryl and 5-10 membered heteroaryl optionally substituted with 1 or more R 5a .

[0103] In some embodiments, R 5 is selected from 6-10 membered heteroaryl, said 6-10 membered heteroaryl optionally substituted with 1 or more R 5a .

[0104] In some embodiments, R 5 is selected from 6-10 membered heteroaryl, said 6-10 membered heteroaryl containing at least one N atom and optionally substituted with 1 or more R 5a substituents.

[0105] In some embodiments, R 5 is selected from 5-6 membered heteroaryl, said 5-6 membered heteroaryl optionally substituted with 1 or more R 5a substituents.

[0106] In some embodiments, R 5 is selected from pyridyl, said N in the pyridyl optionally oxidized ( + N-O - ), said pyridyl optionally substituted with 1 or more R 5a substituents.

[0107] In some embodiments, R 5 is selected from pyridyl, said pyridyl optionally substituted with 1 or more R 5a substituents.

[0108] In some embodiments, R 5 is selected from phenyl, quinolinyl and pyrazolopyridinyl, said phenyl, quinolinyl and pyrazolopyridinyl optionally substituted with 1 or more R 5a substituents.

[0109] In some embodiments, R 5 is selected from quinolinyl and pyrazolopyridinyl, said quinolinyl and pyrazolopyridinyl optionally substituted with 1 or more R 5a substituents.

[0110] In some embodiments, R 5 is said optionally substituted with 1 or more R 5a substituents.

[0111] In some embodiments, R 5 is wherein N can be oxidized to form said optionally substituted with 1 or more R 5a substituents.

[0112] In some embodiments, each R 5a is independently selected from C1-C 10 alkyl, C2-C10 alkenyl, C2-C 10 alkynyl, C1-C 10 alkoxy, C3-C 12 cycloalkyl, 4-14 membered heterocyclyl, C6-C 10 aryl and 5-10 membered heteroaryl, said C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 alkoxy, C3-C 12 cycloalkyl, 4-14 membered heterocyclyl, C6-C 10 aryl and 5-10 membered heteroaryl optionally substituted with 1 or more R c substituents.

[0113] In some embodiments, each R 5a is independently selected from halogen, cyano, C1-C 10 alkyl, C2-C 10 alkynyl, C1-C 10 alkoxy, 4-14 membered heterocyclyl and 5-10 membered heteroaryl, said C1-C 10 alkyl, C2-C 10 alkynyl, C1-C 10 alkoxy, 4-14 membered heterocyclyl and 5-10 membered heteroaryl optionally substituted with 1 or more R c substituents.

[0114] In some embodiments, each R 5a is independently selected from C1-C 10 alkyl, C2-C 10 alkynyl, C1-C 10 alkoxy, 4-14 membered heterocyclyl and 5-10 membered heteroaryl, said C1-C 10 alkyl, C2-C 10 alkynyl, C1-C 10 alkoxy, 4-14 membered heterocyclyl and 5-10 membered heteroaryl optionally substituted with 1 or more R c substituents.

[0115] In some embodiments, each R 5a is independently selected from C1-C 10 alkyl, C2-C 10 alkynyl, C1-C 10 alkoxy and 4-14 membered heterocyclyl, said C1-C 10 alkyl, C2-C 10 alkynyl, C1-C 10alkoxy and 4-14 membered heterocyclyl are optionally substituted with 1 or more R c substituted.

[0116] In some embodiments, each R 5a is independently selected from halogen, cyano, C1-C4 alkyl, C2-C4 alkynyl, C1-C4 alkoxy, 4-13 membered heterocyclyl and 5-6 membered heteroaryl, said C1-C4 alkyl, C2-C4 alkynyl, C1-C4 alkoxy, 4-13 membered heterocyclyl and 5-6 membered heteroaryl groups are optionally substituted with 1 or more R c substituted.

[0117] In some embodiments, each R 5a is independently selected from halogen, cyano, C1-C3 alkyl, C2-C3 alkynyl, C1-C2 alkoxy, 4-13 membered heterocyclyl containing at least one N atom and 6 membered heteroaryl containing two N atoms, said C1-C3 alkyl, C2-C3 alkynyl, C1-C2 alkoxy, 4-13 membered heterocyclyl and 6 membered heteroaryl groups are optionally substituted with 1 or more R c substituted.

[0118] In some embodiments, each R 5a is independently selected from C1-C4 alkyl, C2-C4 alkynyl, C1-C4 alkoxy, 4-10 membered heterocyclyl and 5-6 membered heteroaryl, said C1-C4 alkyl, C2-C4 alkynyl, C1-C4 alkoxy, 4-10 membered heterocyclyl and 5-6 membered heteroaryl groups are optionally substituted with 1 or more R c substituted.

[0119] In some embodiments, each R 5a is independently selected from C1-C4 alkyl, C2-C4 alkynyl, C1-C4 alkoxy and 4-10 membered heterocyclyl, said C1-C4 alkyl, C2-C4 alkynyl, C1-C4 alkoxy and 4-10 membered heterocyclyl groups are optionally substituted with 1 or more R c substituted.

[0120] In some embodiments, each R 5a is independently selected from halogen, cyano, piperazinyl, piperidinyl, pyrimidinyl, propynyl, pentynyl, ethynyl, methoxy, ethyl, ethoxy, isopropyl, pyrrolidinyl, azetidinyl, piperazinyl, piperidinyl, pyrimidinyl, propynyl, pentynyl, ethynyl, methoxy, ethyl, ethoxy, isopropyl, pyrrolidinyl, azetidinyl, optionally substituted with 1 or more R c substituents.

[0121] In some embodiments, each R 5a is independently selected from piperazinyl, piperidinyl, propynyl, methoxy, ethyl, piperazinyl, piperidinyl, propynyl, methoxy, ethyl, optionally substituted with 1 or more R c substituents.

[0122] In some embodiments, each R 5a is independently selected from piperazinyl, piperidinyl, propynyl, methoxy, ethyl, piperazinyl, piperidinyl, propynyl, methoxy, ethyl, optionally substituted with 1 or more R c substituents.

[0123] In some embodiments, each R 5a is independently selected from isopropyl, fluoro, cyano, piperazinyl, piperidinyl, pyrimidinyl, propynyl, and ethyl, optionally substituted with 1 or more R c substituents.

[0124] In some embodiments, each R 5a is independently selected from ethoxy and isopropyl, optionally substituted with 1 or more R c substituents.

[0125] In some embodiments, each R c is independently selected from amino, C1-C7alkyl, C1-C7alkoxy, C3-C8cycloalkyl, and 4-12 membered heterocyclyl, optionally substituted with 1 or more R 10 substituents. 10 is independently selected from amino, C1-C7alkyl, C1-C7alkoxy, C3-C8cycloalkyl, and 4-12 membered heterocyclyl, optionally substituted with 1 or more R h substituents.

[0126] In some embodiments, each R c is independently selected from amino, C1-C4alkyl, C1-C4alkoxy, C3-C8cycloalkyl, and 4-8 membered heterocyclyl, optionally substituted with 1 or more R h substituents.

[0127] In some embodiments, each R c is independently selected from amino, Ci-C4alkyl, Ci-C4alkoxy, C3-C6cycloalkyl, and 4-6 membered heterocyclyl, which amino, Ci-C4alkyl, Ci-C4alkoxy, C3-C6cycloalkyl, and 4-6 membered heterocyclyl is optionally substituted with 1 or more R h substituents.

[0128] In some embodiments, each R c is independently selected from amino, Ci-C4alkyl, Ci-C4alkoxy, C3-C6cycloalkyl, and 4-12 membered heterocyclyl containing 1, 2, or 3 heteroatoms or groups of heteroatoms independently selected from N, O, S, -S(=0)2-, S(=0)2-NH-, -P(=0)-, -PH(=0)-, -S(=0)(=NH)-, -C(=0)-, or -C(=0)NH-, which amino, Ci-C4alkyl, Ci-C4alkoxy, C3-C6cycloalkyl, and 4-12 membered heterocyclyl is optionally substituted with 1 or more R h substituents.

[0129] In some embodiments, each R c is independently selected from amino, methyl, ethyl, methoxy, cyclopropyl, morpholinyl, thiomorpholinyl, azetidinyl, oxetanyl, piperazinyl, and piperidinyl, which amino, methyl, ethyl, methoxy, cyclopropyl, morpholinyl, thiomorpholinyl, azetidinyl, oxetanyl, piperazinyl, and piperidinyl is optionally substituted with 1 or more R h substituents.

[0130] In some embodiments, each R c is independently selected from amino, methyl, ethyl, methoxy, cyclopropyl, morpholinyl, azetidinyl, oxetanyl, piperazinyl, and piperidinyl, which amino, methyl, ethyl, methoxy, cyclopropyl, morpholinyl, azetidinyl, oxetanyl, piperazinyl, and piperidinyl is optionally substituted with 1 or more R h substituents.

[0131] In some embodiments, each R c is independently selected from amino, methyl, ethyl, methoxy, cyclopropyl, morpholinyl, and piperidinyl, which amino, methyl, ethyl, methoxy, cyclopropyl, morpholinyl, and piperidinyl is optionally substituted with 1 or more R hsubstituted.

[0132] In some embodiments, each R c is independently selected from azetidinyl, oxetanyl, the azetidinyl, oxetanyl, is optionally substituted with one or more R h substituted.

[0133] In some embodiments, each R c is independently selected from amino, methyl, methoxy, cyclopropyl, morpholinyl, oxetanyl, and piperidinyl, the amino, methyl, methoxy, cyclopropyl, morpholinyl, oxetanyl, and piperidinyl is optionally substituted with one or more R h substituted.

[0134] In some embodiments, each R g and R h is independently selected from halogen, hydroxyl, thiol, amino, =0, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, (C1-C4 alkylene)OC1-C4 alkyl, C1-C4 alkoxy, and 4-6 membered heterocycloalkyl.

[0135] In some embodiments, each R g and R h is independently selected from halogen, hydroxyl, thiol, amino, =0, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, (C1-C4 alkylene)OC1-C4 alkyl, and C1-C4 alkoxy.

[0136] In some embodiments, each R g and R h is independently selected from halogen, hydroxyl, thiol, amino, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, and C1-C4 alkoxy.

[0137] In some embodiments, each R h is independently selected from halogen, hydroxyl, cyano, =0, C(O)R k , S(O)2R k , =CR j R jC1-C4alkyl, C1-C4haloalkyl, C3-C6cycloalkyl, (C1-C4alkylene)OC1-C4alkyl, C1-C4hydroxyalkyl, C1-C4aminoalkyl, and 3- to 6-membered heterocycloalkyl, optionally substituted with one or more substituents selected from =0, halogen, hydroxyl, cyano, C1-C4haloalkyl, and C1-C4alkyl.

[0138] In some embodiments, each R h is independently selected from halogen, hydroxyl, cyano, =0, C(O)R k , S(O)2R k , =CR j R j , C1-C4alkyl, C1-C4haloalkyl, C3-C6cycloalkyl, (C1-C4alkylene)OC1-C4alkyl, C1-C4hydroxyalkyl, C1-C4aminoalkyl, and 3- to 6-membered heterocycloalkyl, optionally substituted with halogen, hydroxyl, cyano, and C1-C4alkyl.

[0139] In some embodiments, R k is selected from C1-C4alkyl, optionally substituted with one or more hydroxyl, N(C1-C4alkyl)2, C1-C4alkoxy, and 3- to 6-membered heterocycloalkyl.

[0140] In some embodiments, R j is selected from H, halogen, and C1-C4alkyl.

[0141] In some embodiments, each R h is independently selected from halogen, hydroxyl, =0, C1-C4alkyl, C3-C6cycloalkyl, (C1-C4alkylene)OC1-C4alkyl, C1-C4hydroxyalkyl, and 6-membered heterocycloalkyl.

[0142] In some embodiments, each R h is independently selected from halogen, hydroxyl, =0, C1-C4alkyl, C3-C6cycloalkyl, (C1-C4alkylene)OC1-C4alkyl, and C1-C4hydroxyalkyl.

[0143] In some embodiments, each R hindependently selected from the group consisting of halogen, hydroxyl, =0, C1-C4alkyl, (C1-C4alkylene)OC1-C4alkyl, and C1-C4hydroxyalkyl.

[0144] In some embodiments, each R h is independently selected from the group consisting of halogen, hydroxyl, C1-C4alkyl, and C1-C4hydroxyalkyl.

[0145] In some embodiments, each R h is independently selected from the group consisting of fluorine, hydroxyl, =0, hydroxymethyl, ethyl, methoxyethyl, cyclopropyl, morpholinyl, cyano, trifluoromethyl, acetyl, =CF2, =CH2, aminomethyl, methylaminomethyl, S(O)2CH3, and methyl.

[0146] In some embodiments, each R h is independently selected from the group consisting of fluorine, hydroxyl, =0, hydroxymethyl, ethyl, methoxyethyl, cyclopropyl, morpholinyl, cyano, trifluoromethyl, acetyl, =CF2, =CH2, aminomethyl, methylaminomethyl, S(O)2CH3, and methyl.

[0147] In some embodiments, each R h is independently selected from the group consisting of fluorine, hydroxyl, =0, hydroxymethyl, methoxyethyl, cyclopropyl, morpholinyl, and methyl.

[0148] In some embodiments, each R h is independently selected from the group consisting of hydroxymethyl, cyclopropyl, morpholinyl, cyano, and methyl.

[0149] In some embodiments, each R h is independently selected from the group consisting of fluorine, hydroxyl, =0, hydroxymethyl, methoxyethyl, and methyl.

[0150] In some embodiments, each R h is independently selected from the group consisting of fluorine, hydroxyl, hydroxymethyl, and methyl.

[0151] In some embodiments, each R h is independently selected from the group consisting of =0 and methoxyethyl.

[0152] In some embodiments, R 5b and R 5b’ together with the atom to which they are attached form a 4-6 membered heterocyclyl, which is optionally substituted with 1 or more R e .

[0153] In some embodiments, R5b and the atom to which they are attached collectively form a thietanyl and thiomorpholinyl, which are optionally substituted with 1 or more R 5b’ and the atom to which they are attached collectively form a thietanyl and thiomorpholinyl, which are optionally substituted with 1 or more R e substituents.

[0154] In some embodiments, is selected from the is optionally substituted with 1 or more R e substituents.

[0155] In some embodiments, each R e is independently selected from halogen, hydroxyl, amino, C1-C7alkyl, and 4-10 membered heterocyclyl, which are optionally substituted with 1 or more R f substituents.

[0156] In some embodiments, each R e is independently selected from C1-C4alkyl and 4-6 membered heterocyclyl, which are optionally substituted with 1 or more R f substituents. In some embodiments, each R e is independently selected from C1-C4alkyl and 6 membered heterocyclyl, which are optionally substituted with 1 or more R f substituents.

[0157] In some embodiments, each R e is independently selected from ethyl and morpholinyl, which are optionally substituted with 1 or more R f substituents.

[0158] In some embodiments, each R f is independently selected from C1-C4alkoxy.

[0159] In some embodiments, R f is methoxy.

[0160] In some embodiments, each R 5a is independently selected from isopropyl, fluoro, cyano,

[0161] In some embodiments, each R 5a is independently selected from isopropyl,

[0162] In some embodiments, each R5a is independently selected from isopropyl,

[0163] In some embodiments, R 1 is C1-C4alkyl-substituted cyclopropyl, and R 5a is independently selected from isopropyl,

[0164] In some embodiments, each R 5a is independently selected from isopropyl, fluoro, cyano,

[0165] In some embodiments, R 1 is C1-C4alkyl-substituted cyclopropyl, and R 5a is independently selected from isopropyl,

[0166] In some embodiments, R 6 is selected from hydrogen, halogen, hydroxyl, thiol, C1-C4alkyl, C1-C4alkoxy, and 4-10 membered heterocyclyl, the hydroxyl, thiol, C1-C4alkyl, C1-C4alkoxy, and 4-10 membered heterocyclyl being optionally substituted with 1 or more R 6a .

[0167] In some embodiments, R 6 is selected from hydrogen, C1-C4alkoxy, and 4-10 membered heterocyclyl, the C1-C4alkoxy and 4-10 membered heterocyclyl being optionally substituted with 1 or more R 6a . In some embodiments, R 6 is selected from hydrogen, C1-C2alkoxy, and 4, 5, 6, 7, or 8 membered heterocyclyl containing 1 N atom, 2 N atoms, or 1 N atom and 1 O atom, the C1-C2alkoxy and the heterocyclyl being optionally substituted with 1 or more R 6a .

[0168] In some embodiments, R 6 is selected from hydrogen, halogen, hydroxyl, thiol, C1-C4alkyl, and C1-C4alkoxy.

[0169] In some embodiments, R 6 is selected from hydrogen and C1-C4alkoxy.

[0170] In some embodiments, R 6 is selected from hydrogen, ethoxy, morpholinyl, azetidinyl, pyrrolidinyl, and the ethoxy, morpholinyl, azetidinyl, pyrrolidinyl and optionally substituted with 1 or more R 6a substituents.

[0171] In some embodiments, each R 6a is independently selected from halogen, C1-C4alkoxy, cyano, and C1-C4alkyl. In some embodiments, each R 6a is independently selected from halogen, C1-C2alkoxy, cyano, and C1-C2alkyl.

[0172] In some embodiments, each R 6a is independently selected from fluorine, cyano, methoxy, and methyl.

[0173] In some embodiments, R 6 is selected from hydrogen, ethoxy, morpholinyl, pyrrolidinyl and

[0174] In some embodiments, R 6 is hydrogen and ethoxy.

[0175] In some embodiments, R 6 is hydrogen.

[0176] In some embodiments, R 7 is selected from hydrogen, halogen, hydroxyl, and cyano.

[0177] In some embodiments, R 7 is hydrogen.

[0178] In some embodiments, R 4 and R 7 and the atoms to which they are attached collectively form a 6-7 membered heterocycloalkyl optionally substituted with 1 or more R b substituents. In some embodiments, R 4 and R 7 and the atoms to which they are attached collectively form a 6-7 membered heterocycloalkyl optionally substituted with 1 or more R b substituents. In some embodiments, R 4 and R 7 and the atoms to which they are attached collectively form a 6-7 membered heterocycloalkyl having 1 N atom and optionally 1 O atom, the 6-7 membered heterocycloalkyl optionally substituted with 1 or more R b substituents.

[0179] In some embodiments, each R b is independently selected from halogen, amino, hydroxyl, thiol, and cyano.

[0180] In some embodiments, each R b is independently selected from halogen, such as fluorine.

[0181] In some embodiments, is selected from said t is selected from 0, 1, 2, and 3.

[0182] In some embodiments, is selected from said t is selected from 0, 1, 2, and 3.

[0183] In some embodiments, R 8 is selected from hydrogen, halogen, hydroxyl, cyano, C1-C 10 alkyl, and C3-C7cycloalkyl.

[0184] In some embodiments, R 8 is selected from hydrogen, cyano, C1-C4alkyl, and C3-C7cycloalkyl.

[0185] In some embodiments, R 8 is hydrogen.

[0186] In some embodiments, R 9 is selected from hydrogen, halogen, and hydroxyl.

[0187] In some embodiments, R 9 is selected from hydrogen and halogen.

[0188] In some embodiments, R 9 is selected from hydrogen and fluorine.

[0189] In some embodiments, R 9 is hydrogen.

[0190] In some embodiments, the compound of Formula (I) of the present disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is selected from a compound of Formula (II), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0191] wherein A, R 1 , R 2 , R 3 , R 4 , R 5a , R 6 , R 7 , R 8 , and R 9 are as defined above.

[0192] In some embodiments of the compound of Formula (II), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, A is thiazolylene; R 1selected from C(O)R 11 , C1-C5 alkyl or C4-C6 cycloalkyl, said C1-C5 alkyl or C4-C6 cycloalkyl being optionally substituted with 1 or more R 1a , R 1a is independently selected from halogen (e.g., fluorine) or C1-C4 alkyl (e.g., methyl), R 11 is selected from 4-6 membered heterocyclyl, said 4-6 membered heterocyclyl being optionally substituted with 1 or more R 11a , R 11a is independently selected from C1-C4 alkyl (e.g., methyl); R 2 and R 3 are each methyl; R 4 is selected from ethyl, trifluoroethyl, cyclopropylmethyl, is preferably ethyl and is more preferably ethyl; R 5a is R 5a is selected from C2 alkynyl, C3 alkynyl, C4 alkynyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered heteroaryl and 6-membered heteroaryl, each of said alkynyl, heterocyclyl and heteroaryl being optionally substituted with 1 or more R c , each R c is independently selected from amino, C1-C4 alkyl, C3-C6 cycloalkyl and 4-7 membered heterocyclyl, said amino, C1-C4 alkyl, C3-C6 cycloalkyl and 4-7 membered heterocyclyl being optionally substituted with 1 or more R h , each R h is independently selected from cyano, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 hydroxyalkyl, 3-6 membered heterocycloalkyl and (C1-C4 alkylene)OC1-C4 alkyl optionally substituted with one or more substituents selected from =O and C1-C4 haloalkyl; and R 6 , R 7 , R 8 and R 9 are each hydrogen.

[0193] In some embodiments of the compound of Formula (II), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, A is thiazolylene; R 1 is selected from C(O)R 11 , C5 alkyl or C4 or C5 cycloalkyl, said C5 alkyl or C4 or C5 cycloalkyl being optionally substituted with 1 or more R 1a , R 1a is independently selected from fluorine or methyl, R 11 is selected from 4-, 5- or 6-membered heterocycloalkyl, said 4-, 5- or 6-membered heterocycloalkyl containing 1 N atom and being optionally substituted with 1 or more R11a substituted, R 11a is independently selected from the group consisting of methyl; R 2 and R 3 are each methyl; R 4 is selected from the group consisting of ethyl, trifluoroethyl, cyclopropylmethyl, preferably ethyl and more preferably ethyl; R 5a is R 5a is selected from the group consisting of propynyl, 6-membered heterocycloalkyl and 6-membered heteroaryl, said 6-membered heterocycloalkyl and 6-membered heteroaryl containing at least one N atom, and said propynyl, 6-membered heterocycloalkyl and 6-membered heteroaryl each being optionally substituted with one or more R c each R c is independently selected from the group consisting of amino, methyl, C3 cycloalkyl and 4-7 membered heterocycloalkyl, optionally said 4-7 membered heterocycloalkyl containing one or two heteroatoms or heteroatom groups independently selected from N, O and -SO2-; said amino, methyl, C3 cycloalkyl and 4-7 membered heterocycloalkyl being optionally substituted with one or more R h each R h is independently selected from the group consisting of cyano, methyl, cyclopropyl, hydroxymethyl, 6-membered heterocycloalkyl and (C2-C4 alkylene)O C1-C2 alkyl optionally substituted with one =O and one C1-C2 haloalkyl; and R 6 , R 7 , R 8 and R 9 are each hydrogen.

[0194] In some embodiments of the compound of formula (II), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, A is R 1 is selected from the group consisting of C(O)R 11 , and cyclopentyl, said and cyclopentyl being optionally substituted with one or more R 1a each R 1a is independently selected from the group consisting of fluoro or methyl, R 11 is tetrahydropyrrolyl and optionally substituted with one or more R 11a each R 11a is independently selected from the group consisting of methyl; R 2 and R 3 are each methyl; R 4 is selected from the group consisting of ethyl, trifluoroethyl, cyclopropylmethyl, preferably ethyl and more preferably ethyl; R 5a is R located meta to the N atom in the pyridine 5a selected from propynyl, 6-membered heterocycloalkyl containing 1 or 2 N atoms, and 6-membered heteroaryl containing 2 N atoms, each of said propynyl, 6-membered heterocycloalkyl and 6-membered heteroaryl being optionally substituted with 1 or more R c each R c is independently selected from amino, methyl, cyclopropyl, piperidinyl and said amino, methyl, cyclopropyl, piperidinyl and optionally substituted with 1 or more R h each R h is independently selected from cyano, methyl, cyclopropyl, hydroxymethyl, and R 6 , R 7 , R 8 and R 9 are each hydrogen.

[0195] In some embodiments of the compound of formula (II), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, A is R 1 is selected from cyclopentyl, R 2 and R 3 are each methyl; R 4 is selected from ethyl, trifluoroethyl, cyclopropylmethyl, is preferably ethyl and is more preferably ethyl; R 5a is R located meta to the N atom in the pyridine 5a is selected from propynyl, piperazinyl, piperidinyl and pyrimidinyl, each of said propynyl, piperazinyl, piperidinyl and pyrimidinyl being optionally substituted with 1 or more R c each R c is independently selected from amino, methyl, cyclopropyl, piperidinyl and said amino, methyl, cyclopropyl, piperidinyl and optionally substituted with 1 or more R h each R h is independently selected from cyano, methyl, cyclopropyl, hydroxymethyl, and R 6 , R 7 , R 8 and R 9 are each hydrogen.

[0196] In some embodiments of the compound of Formula (II), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, A is R 1 selected from cyclopentyl, R 2 and R 3 are each methyl; R 4 is selected from ethyl, trifluoroethyl, cyclopropylmethyl, preferably ethyl and more preferably ethyl; R 5a is R 5a is selected from propynyl, piperazinyl, piperidinyl and pyrimidinyl, each of which is optionally substituted with one or more R c each R c is independently selected from methyl, methyl substituted with cyclopropyl, methyl substituted with cyclopropyl, methyl, -N(CH3)2, and morpholinyl substituted with methyl; and R 6 , R 7 , R 8 and R 9 are each hydrogen.

[0197] In some embodiments of the compound of Formula (II), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, A is R 1 selected from cyclopentyl, R 2 and R 3 are each methyl; R 4 is selected from ethyl, trifluoroethyl, cyclopropylmethyl, preferably ethyl and more preferably ethyl; R 5a is R 5a is selected from and R 6 , R 7 , R 8 and R 9 are each hydrogen.

[0198] In some embodiments, the compound of Formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, of the present disclosure, A is thiazolylene; R 1selected from C1-C5 alkyl, said C1-C5 alkyl optionally substituted with 1 or more R 1a substituted, R 1a is independently selected from halogen (e.g., fluorine), R 2 and R 3 are each methyl; R 4 is ethyl; R 5 is selected from quinolinyl and pyrazolopyridinyl, said quinolinyl and pyrazolopyridinyl substituted with multiple R 5a ; R 5 is at the ortho position to the site of attachment of the remainder of the molecule; R 5a the remaining R 5a is selected from halogen, cyano, C2 alkynyl, C3 alkynyl, C4 alkynyl, 4-, 5-, or 6-membered heterocyclyl, said alkynyl and heterocyclyl each optionally substituted with 1 or more R c , each R c is independently selected from C1-C4 alkyl and 4-7 membered heterocyclyl; and R 6 , R 7 , R 8 , and R 9 are each hydrogen.

[0199] In some embodiments, in the compounds of Formula (I) of the present disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, A is thiazolylene; R 1 is selected from C5 alkyl, said C5 alkyl optionally substituted with 1 or more R 1a substituted, R 1a is independently selected from halogen (e.g., fluorine); R 2 and R 3 are each methyl; R 4 is ethyl; R 5 is selected from quinolinyl and pyrazolopyridinyl, said quinolinyl and pyrazolopyridinyl substituted with multiple R 5a ; R 5 is at the ortho position to the site of attachment of the remainder of the molecule; R 5a the remaining R 5a is selected from halogen (e.g., fluorine), cyano, C3 alkynyl, or 6-membered heterocyclyl, said alkynyl and heterocyclyl each optionally substituted with 1 or more R c , each R c is independently selected from C1-C4 alkyl and 4-7 membered heterocyclyl; and R 6 , R 7 , R 8 , and R 9 are each hydrogen.

[0200] ​​In some embodiments, in the compounds of Formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, of the present disclosure, A is thiazolyl; R 1 is selected from the R 1a is independently selected from fluoro; R 1a is independently selected from fluoro; R 2 and R 3 are each methyl; R 4 is ethyl; R 5 is selected from quinolinyl and pyrazolopyridinyl, said quinolinyl and pyrazolopyridinyl being substituted with multiple R 5a ; at the ortho position to the site of attachment of R 5 to the remainder of the molecule is R 5a the remaining R 5a is selected from fluoro, cyano, C3 alkynyl, or 6-membered heterocyclyl containing 1 or 2 N atoms, each of said alkynyl and heterocyclyl being optionally substituted with 1 or more R c , each R c is independently selected from methyl and 7-membered heterocyclyl containing 1 O atom and 1 N atom; and R 6 , R 7 , R 8 , and R 9 are each hydrogen.

[0201] In some embodiments, in the compounds of Formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, of the present disclosure, A is R 1 is selected from R 2 and R 3 are each methyl; R 4 is ethyl; R 5 is selected from quinolinyl and pyrazolopyridinyl, said quinolinyl and pyrazolopyridinyl being substituted with multiple R 5a ; at the ortho position to the site of attachment of R 5 to the remainder of the molecule is R 5a the remaining R 5a is selected from fluoro, cyano, C3 alkynyl, piperazinyl, and piperidinyl, each of said C3 alkynyl, piperazinyl, and piperidinyl being optionally substituted with 1 or more R c , each R c is independently selected from methyl and , R 6 , R 7 , R 8 , and R 9 are each hydrogen.

[0202] ​​In some embodiments, the compound of Formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, of the present disclosure is R 1 is selected from R 2 and R 3 are each methyl; R 4 is ethyl; R 5 is selected from quinolinyl and pyrazolopyridinyl, said quinolinyl and pyrazolopyridinyl being substituted with multiple R 5a substituents; R 5 is at the ortho position to the site of attachment of R 5a to the remainder of the molecule is the remaining R 5a is selected from fluoro, cyano, and R 6 , R 7 , R 8 and R 9 are each hydrogen.

[0203] In some embodiments, the compound of Formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, of the present disclosure is selected from a compound of Formula (III), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0204] wherein R 1 , R 4 , R 5 and R 6 are as defined above.

[0205] In some embodiments, the compound of the present disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is selected from the following compounds, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0206] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (I) or Formula (II) or Formula (III) or the specific compounds described above, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, of the present disclosure and a pharmaceutically acceptable excipient.

[0207] In another aspect, the present disclosure provides a method of treating a disease mediated by RAS in a subject (e.g., a mammal), comprising administering to a subject (e.g., a mammal, preferably a human) in need of such treatment a therapeutically effective amount of a compound of Formula (I) or Formula (II) or Formula (III) or the specific compounds described above or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0208] In another aspect, the present disclosure provides use of a compound of Formula (I) or Formula (II) or Formula (III) or the specific compounds described above or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the manufacture of a medicament for preventing or treating a disease mediated by RAS.

[0209] In another aspect, the present disclosure provides use of a compound of Formula (I) or Formula (II) or Formula (III) or the specific compounds described above or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in preventing or treating a disease mediated by RAS.

[0210] In another aspect, the present disclosure provides a compound of Formula (I) or Formula (II) or Formula (III) or the specific compounds described above or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in preventing or treating a disease mediated by RAS.

[0211] In some embodiments, the disease mediated by RAS is a tumor.

[0212] The compound of Formula (I) or Formula (II) or Formula (III) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof of the present disclosure can selectively inhibit RAS, can prevent or treat a disease mediated by RAS, has a good killing effect on tumor cells associated with RAS, in particular on different RAS mutations and RAS protein-dependent tumors, and can treat tumors mediated by RAS mutations.

[0213] The compound of Formula (I) or Formula (II) or Formula (III) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof of the present disclosure can achieve at least one of the following advantages: (1) good, even excellent, inhibitory effect on RAS-mediated tumor cell proliferation; (2) good, even excellent, safety and metabolic stability; and (3) good, even excellent, bioavailability.

[0214] Definitions and explanations

[0215] Unless otherwise indicated, the terms used in the present disclosure have the following meanings, the definitions of groups and terms recited in the present disclosure, including the definitions as examples, exemplary definitions, preferred definitions, definitions recited in tables, definitions of specific compounds in examples, etc., can be combined and integrated with each other arbitrarily. A particular term should not be considered as indefinite or unclear without a special 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.

[0216] Herein represents a point of attachment.

[0217] Certain compounds of the present disclosure can exist in atropisomeric forms, which are conformational isomers that occur when rotation about a single bond in a molecule is prevented or greatly slowed due to steric interactions with other parts of the molecule. Compounds of the present disclosure include all atropisomers, either as pure individual atropisomers, or as atropisomers enriched in one, or as non-specific mixtures of each. If the potential energy for rotation about a single bond is sufficiently high, and the interconversion between conformations is sufficiently slow, then separation of isomers can be allowed. For example, (or ) and (or ) are a pair of atropisomers, wherein the represents the side stereo orientation as outward, represents the side stereo orientation as inward.

[0218] The graphical representation of racemates or enantiomerically pure compounds herein is from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated, a wedge solid bond and a wedge dashed bond represents the absolute configuration of a stereocenter, with a straight solid bond and a straight dashed bond represents the relative configuration of a stereocenter (e.g., the syn or anti configuration of an alicyclic compound).

[0219] When one of the variables is selected from a bond or nothing, it means that the two groups to which it is attached are directly connected, such as L represents a bond in A-L-Z means that the structure is actually A-Z.

[0220] When a linking group referred to herein is not indicated for its connection direction, its connection direction is arbitrary. For example, when L in a structural unit 1 is selected from “C1-C3 alkylene-O”, then L 1 can be connected to ring Q and R either in the direction from left to right 1"ring Q-C1-C3alkylene-O-R 1 ", or in the reverse direction, connecting ring Q and R 1 "ring Q-O-C1-C3alkylene-R 1 ".

[0221] When a bond of a substituent crosslinks to two atoms on a ring, the substituent can be bonded to any atom on the ring. For example, the structural unit represents that R 10 may be substituted at any position on the ring.

[0222] 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 specific geometric or stereoisomeric forms. The specific 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 contain an excess of one enantiomer or diastereomer, all of which are within the scope of the compounds of the present disclosure. Additional asymmetric carbon, sulfur, nitrogen, or phosphorus atoms or

[0223] The term "substituted" means that any one or more hydrogen atoms on a particular atom is / are replaced with a substituent group, provided that the valence of the particular atom is not exceeded, and that the substituted compound is stable. When the substituent is oxo (i.e., =0), it means that two hydrogen atoms are replaced by the oxo group. The oxo group cannot be on an aromatic group.

[0224] The terms “optional,” “optional,” “optionally,” or “optionally” mean that the event or condition described below may or may not occur, including both the occurrence and non-occurrence of said event or condition. For example, the phrase “optionally” substituted with one or more halogens means that the ethyl group can be unsubstituted (CH2CH3), monosubstituted (CH2CH2F, CH2CH2Cl, etc.), polysubstituted (CHFCH2F, CH2CHF2, CHFCH2Cl, CH2CHCl2, etc.), or fully substituted (CF2CF3, CF2CCl3, CCl2CCl3, etc.). Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern that is spatially impossible and / or cannot be synthesized is introduced.

[0225] When any variable (e.g., R) a R b When a group appears more than once in the composition or structure of a compound, its definition is independent in each case. For example, if a group is surrounded by two R... b Replaced, then each R b Each has its own independent options.

[0226] C in this article m -C n It refers to having an integer number of carbon atoms in the range mn. For example, "C1-C 10 "" means that the group can have 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms.

[0227] The term "alkyl" refers to a compound with the general formula C10. n H 2n+1 The alkyl group can be straight-chain or branched. The term "C1-C" refers to a hydrocarbon group. 10"Alkyl" can be understood as representing a straight-chain or branched saturated hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Specific examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1 The term "C1-C7 alkyl" can be understood as referring to alkyl groups having 1 to 7 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc. The term "C1-C5 alkyl" can be understood as referring to straight-chain or branched saturated alkyl groups having 1 to 5 carbon atoms. The term "C1-C4 alkyl" can be understood as referring to straight-chain or branched saturated alkyl groups having 1 to 4 carbon atoms. The term "C1-C3 alkyl" can be understood as referring to straight-chain or branched saturated alkyl groups having 1 to 3 carbon atoms. The term "C5-C6 alkyl" can also be understood as referring to straight-chain or branched saturated alkyl groups having 1 to 3 carbon atoms. 10 "Alkyl" can be understood as referring to a straight-chain or branched saturated alkyl group having 5 to 10 carbon atoms. The "C1-C" 10 "alkyl" can include "C1-C6 alkyl", "C1-C4 alkyl", "C1-C3 alkyl" or "C5-C6 alkyl". 10 The term "alkyl" is used within the range of "C1-C6 alkyl," which may further include "C1-C4 alkyl" or "C1-C3 alkyl." The term "halogenated alkyl" is intended to include both monohalogenated and polyhalogenated alkyl groups. For example, the term "C1-C6 alkyl" may include "C1-C4 alkyl" or "C1-C3 alkyl." 10 "Haloalkyl" refers to a C1-C alkyl group as defined above that has been substituted with one or more halogens. 10 Alkyl groups include, but are not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. The term "hydroxyalkyl" is intended to include both monohydroxy-substituted and polyhydroxy-substituted alkyl groups. For example, the term "C1-C4 hydroxyalkyl" refers to a C1-C4 alkyl group as defined above, substituted with one or more hydroxyl groups. The term "C1-C4 aminoalkyl" refers to a C1-C4 alkyl group as defined above, substituted with one or more amino groups.

[0228] The term "alkoxy" refers to a group formed by the loss of a hydrogen atom from a hydroxyl group in straight-chain or branched alcohols, and can be understood as "alkyloxy" or "alkyl-O-", where alkyl is as defined above. The term "C1-C" refers to a group formed by the loss of a hydrogen atom from a hydroxyl group in straight-chain or branched alcohols. 10"Alkoxy" can be understood as "C1-C" 10 "alkyloxy" or "C1-C" 10 Alkyl-O-"; the term "C1-C7 alkoxy" can be understood as "C1-C7 alkyloxy" or "C1-C7 alkyl-O-". The "C1-C" 10 "Alkoxy" can include the range of "C1-C7 alkoxy" and "C1-C3 alkoxy", and the "C1-C7 alkoxy" can further include "C1-C3 alkoxy".

[0229] The term "alkenyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms and having at least one double bond. The term "C2-C"... 10 "Alkenyl" can be understood as referring to a straight-chain or branched unsaturated hydrocarbon group that contains one or more double bonds and has 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The term "C6-C" is used to describe this type of unsaturated hydrocarbon group. 10 "Alkenyl" can be understood as representing a straight-chain or branched unsaturated hydrocarbon group that contains one or more double bonds and has 6, 7, 8, 9, or 10 carbon atoms, "C2-C". 10 "Alkenyl" can include "C2-C6 alkenyl", "C2-C4 alkenyl", "C6-C6 alkenyl", "C2-C4 ... 10 "Alkenyl", C2 or C3 alkenyl. It is understood that when the alkenyl group contains more than one double bond, the double bonds may be separable or conjugated with each other. Specific examples of alkenyl groups include, but are not limited to, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl or (Z)-1-methylprop-1-enyl, etc.

[0230] The term "alkynyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms and having at least one triple bond. The term "C2-C"... 10 "Alkyne" can be understood as representing a straight-chain or branched unsaturated hydrocarbon group containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. "C2-C" 10 Examples of "alkynyl" include, but are not limited to, ethynyl (-C≡CH) and propynyl (-C≡CCH). 3、 -CH2C≡CH), but-1-ynyl, but-2-ynyl, or but-3-ynyl. "C2-C 10"Alkynyl" can include "C2-C3alkynyl", examples of which include ethynyl (-C≡CH), prop-1-ynyl (-C≡CCH3), prop-2-ynyl (-CH2C≡CH).

[0231] The term "cycloalkyl" refers to a carbocyclic radical which is completely saturated and which exists in a single ring, fused ring, bridged ring, or spiro ring form, among others. Unless otherwise indicated, the carbocyclic ring is typically a 3- to 20-membered ring. The term "C3-C12cycloalkyl" refers to a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ring carbon atoms. The term "C3-C6cycloalkyl" refers to a cycloalkyl group having 3, 4, 5, or 6 ring carbon atoms. The term "cycloalkyl" also includes "cycloalkylalkyl" groups, which are radicals derived from a cycloalkyl group by the removal of one hydrogen. 12 The term "cycloalkyl" refers to a carbocyclic radical which is completely saturated and which exists in a single ring, fused ring, bridged ring, or spiro ring form, among others. Unless otherwise indicated, the carbocyclic ring is typically a 3- to 20-membered ring. The term "C3-C12cycloalkyl" refers to a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ring carbon atoms. The term "C3-C6cycloalkyl" refers to a cycloalkyl group having 3, 4, 5, or 6 ring carbon atoms. The term "cycloalkyl" also includes "cycloalkylalkyl" groups, which are radicals derived from a cycloalkyl group by the removal of one hydrogen.

[0232] The term "heterocyclyl" or "heterocycle" refers to a monocyclic, fused ring, spiro, or bridged ring radical which is completely saturated or partially saturated (not an aromatic heteroaromatic overall) having 1, 2, 3, 4, or 5 (e.g., 1, 2, or 3, or 1-2) heteroatoms or heteroatom groups (i.e., groups of atoms containing heteroatoms) in the ring atom count, including but not limited to nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), boron (B), -S(=0)2-, -S(=0)-, -P(=0)2-, -P(=0)-, -PH(=0)-, -NH-, -S(=0)(=NH)-, -C(=0)NH-, or -NHC(=0)NH-, and the like, in the ring atom count. The term "4-10 membered heterocyclyl" refers to a heterocyclyl having a ring atom count of 4, 5, 6, 7, 8, 9, or 10, and having 1, 2, 3, 4, or 5 heteroatoms or heteroatom groups independently selected from those described above. A "4-10 membered heterocyclyl" can include a "4-7 membered heterocyclyl." The term "4-7 membered heterocyclyl" refers to a heterocyclyl having a ring atom count of 4, 5, 6, or 7, and having 1, 2, 3, 4, or 5 heteroatoms or heteroatom groups independently selected from those described above. Specific examples of 4-membered heterocyclyls include, but are not limited to, azetidinyl or oxetanyl; specific examples of 5-membered heterocyclyls 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 heterocyclyls 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 heterocyclyls include, but are not limited to, diazepanyl. The heterocyclyl can also be a bicyclic radical, where specific examples of 5,5 membered bicyclic radicals include, but are not limited to, hexahydrocyclopenta[c]pyrrol-2(lH)-yl; specific examples of 5,6 membered bicyclic radicals 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 can be a benzo-fused ring of the aforementioned 4-7 membered heterocyclyls, specific examples include, but are not limited to, dihydroisoquinolinyl, and the like. A "4-10 membered heterocyclyl" can include a "5-10 membered heterocyclyl," a "4-7 membered heterocyclyl," a "5-6 membered heterocyclyl," a "6-8 membered heterocyclyl," a "4-10 membered heterocycloalkyl," a "5-10 membered heterocycloalkyl," a "4-7 membered heterocycloalkyl," a "5-6 membered heterocycloalkyl," a "6-8 membered heterocycloalkyl," and the like. A "4-7 membered heterocyclyl" can further include a "4-6 membered heterocyclyl," a "5-6 membered heterocyclyl," a "4-7 membered heterocycloalkyl," a "4-6 membered heterocycloalkyl," a "5-6 membered heterocycloalkyl," and the like.Although some bicyclic heterocyclic groups in this disclosure partially contain a benzene ring or a heteroaromatic ring, the heterocyclic group as a whole remains non-aromatic. The term "subheterocyclic group" refers to a residue derived by further removing a hydrogen atom from a heterocyclic group.

[0233] The term "heterocyclic alkyl" refers to a fully saturated cyclic group existing in the form of a monocyclic, fused, bridged, or spirocyclic ring, wherein the ring atoms contain 1, 2, 3, 4, or 5 heteroatoms or heteroatom groups (i.e., groups containing heteroatoms). These "heteroatoms or heteroatom groups" include, but are not limited to, nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), boron (B), -S(=O)2-, -S(=O)-, -NH-, -S(=O)(=NH)-, -C(=O)NH-, or -NHC(=O)NH-. The term "4-10 membered heterocyclic alkyl" refers to a heterocyclic alkyl group with 4, 5, 6, 7, 8, 9, or 10 ring atoms, and its ring atoms contain 1, 2, 3, 4, or 5 independently selected heteroatoms or heteroatom groups as described above. The term "5-10 membered heterocyclic alkyl" refers to a heterocyclic alkyl group having 5, 6, 7, 8, 9 or 10 ring atoms, and containing 1, 2, 3, 4 or 5 heteroatoms or heterogroups independently selected from those described above. "4-10-membered heterocyclic alkyl" and "5-10-membered heterocyclic alkyl" include "4-7-membered heterocyclic alkyl", wherein specific examples of 4-membered heterocyclic alkyl include, but are not limited to, acridine, oxadiazolyl, or thiobutylcycloyl; specific examples of 5-membered heterocyclic alkyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, imidazolyl, or tetrahydropyrazolyl; specific examples of 6-membered heterocyclic alkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, morpholinyl, piperazine, 1,4-thiaoxalyl, 1,4-dioxane, thiomorpholinyl, 1,3-dithiaalkyl, or 1,4-dithiaalkyl; and specific examples of 7-membered heterocyclic alkyl include, but are not limited to, azirheptanyl, oxaheptanyl, or thioheptanyl.

[0234] The term "aryl" refers to an aromatic ring group consisting of an all-carbon monocyclic or fused polycyclic aromatic cyclic group with a conjugated π-electron system. Aryl groups can have 6-20, 6-14, or 6-12 carbon atoms. The term "C6-C"... 10 "Aryl" can be understood as an aryl group having 6 to 10 carbon atoms. The term "C6-C7 aryl" can be understood as an aryl group having 6 to 7 carbon atoms. For example, a ring with 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring with 9 carbon atoms ("C9 aryl"), such as indenyl or indenyl; or a ring with 10 carbon atoms ("C9 aryl"). 10 Aryl), such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl. The term "aryl" refers to a residue derived from an aryl group by further removing a hydrogen atom.

[0235] The term "heteroaryl" refers to a monocyclic or fused polycyclic system having overall 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 understood to include monocyclic or bicyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, e.g. 5 or 6 or 9 or 10 or 11 or 12 ring atoms, and which contain 1, 2, 3, 4 or 5, e.g. 1, 2 or 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, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl or 1,2,5-thiadiazolyl and the like and their benzo derivatives, e.g. benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzoisoxazolyl, benzoimidazolyl, benzotriazolyl, indazolyl, indolyl or isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or pyrazinyl and the like and their benzo derivatives, e.g. quinolinyl, quinazolinyl or isoquinolinyl and the like; or azocinyl, indolizinyl, purinyl and the like and their benzo derivatives; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenoxazinyl, phenothiazinyl or phenoxazinyl and the like. The term "6-10 membered heteroaryl" is understood to include monocyclic or bicyclic aromatic ring systems having 6, 7, 8, 9 or 10 ring atoms, e.g. 6 or 9 or 10 ring atoms, and which contain 1, 2, 3, 4 or 5, e.g. 1, 2 or 3, heteroatoms independently selected from N, O and S. The term "5-6 membered heteroaryl" refers to aromatic ring systems having 5 or 6 ring atoms, and which contain 1, 2 or 3, e.g. 1 -2, heteroatoms independently selected from N, O and S. The term "heteroarylene" is a residue derived from heteroaryl by further removal of one hydrogen

[0236] The term "halo" or "halogen" refers to fluoro, chloro, bromo or iodo.

[0237] The term "hydroxy" refers to an -OH group.

[0238] The term "cyano" refers to a -CN group.

[0239] The term "amino" refers to an -NH2 group.

[0240] The term "nitro" refers to an -NO2 group.

[0241] The term "treatment" means the administration of a compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0242] (i) inhibiting the disease or condition, i.e., arresting its development;

[0243] (ii) relieving the disease or condition, i.e., causing regression of the disease or condition.

[0244] The term "therapeutically effective amount" means an amount of a compound of the present disclosure that (i) treats a particular disease, condition, or disorder, (ii) delays or reduces the onset of one or more symptoms of a particular disease, condition, or disorder. The amount of a compound of the present disclosure that constitutes 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 a matter of routine application of his own knowledge and the disclosure presented herein.

[0245] The term "prevention" means the administration of a compound or formulation described herein to prevent a disease or one or more symptoms associated with the disease, and includes preventing the disease or condition from occurring in an individual (e.g., a mammal), particularly when such individual (e.g., a mammal) is predisposed to having the disease or condition, but has not yet been diagnosed as having it.

[0246] The term "individual" includes mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. Examples of non-human mammals include, but are not limited to, birds and fish, and the like. In one embodiment of the methods and compositions provided herein, the mammal is a human. The terms "patient" and "individual" are used interchangeably.

[0247] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that 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.

[0248] The term "pharmaceutically acceptable salt" refers to pharmaceutically acceptable acid or base salts of the compounds of the present disclosure, including salts of the compounds of the present disclosure with inorganic or organic acids, and salts of the compounds of the present disclosure with inorganic or organic bases.

[0249] The term "pharmaceutical composition" means a mixture of one or more compounds of the disclosure or salts thereof with a pharmaceutically acceptable excipient. The purpose of a pharmaceutical composition is to facilitate administration of a compound of the disclosure to an organism.

[0250] The term "pharmaceutically acceptable excipient" means an excipient that is not

[0251] The words "comprise" or "comprising" and variations thereof such as "comprises" or "comprising", when used in this document, can be understood to encompass the terms "consisting of" or "consisting of".

[0252] 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 incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, 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.

[0253] Certain isotopically-labeled compounds of the disclosure (for example, those 3 H, and 14 C) can be used 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 18F can be used 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 synthesis route such as those disclosed in the schemes and / or examples below.

[0254] The pharmaceutical composition of the present disclosure can be prepared by combining a compound of the present disclosure with suitable pharmaceutically acceptable excipients, for example, can be formulated into solid, semi-solid, liquid, or gaseous dosage forms, such as tablets, pills, capsules, powders, granules, creams, emulsions, suspensions, suppositories, injections, inhalers, gels, microspheres, aerosols, and the like.

[0255] 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, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.

[0256] The pharmaceutical composition of the present disclosure can be manufactured by methods well known in the art, such as the conventional mixing, dissolving, granulating, emulsifying, dr ying, lyophilizing, encapsulating, entrapping or lyophilizing processes.

[0257] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by combining the active compounds with pharmaceutically acceptable excipients 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.

[0258] Solid oral compositions can be prepared by conventional mixing, encapsulating, or dissolving processes. For example, the active compounds can be mixed with a solid excipient, optionally ground using, if necessary, a suitable mill, and the resulting mixture tabletted or filled into capsules. Suitable excipients include, but are not limited to, binders, diluents, disintegrating agents, lubricants, glidants, or flavoring agents.

[0259] The pharmaceutical composition can also be adapted for parenteral administration, such as sterile solutions, suspensions, or lyophilized products in suitable unit dosage forms.

[0260] The dosage administered will depend on factors such as the particular compound, the disease condition and its severity, the identity of the subject or host to be treated (e.g., body weight, sex), and the particular formulation to be used, the route of administration, the condition being treated, and the subject or host being treated.

[0261] In all methods of administration of the compounds of general formula (I) described herein, the daily dose is from 0.001 mg / kg to 5000 mg / kg of body weight, preferably from 0.01 mg / kg to 100 mg / kg of body weight, in single or divided doses. The daily dose and unit dose vary depending on a number of variables, including but not limited to the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

[0262] 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 by a combination of the specific embodiments with other chemical synthetic methods, and equivalents thereof as appreciated by those skilled in the art, preferred embodiments including but not limited to the examples of the present disclosure.

[0263] The chemical reactions of the present disclosure are performed in suitable solvents, which can vary and depend on the reactants and reagents used in the chemical transformations of the present disclosure. Modifications to the synthetic procedures or reaction sequences can sometimes be necessary in order to obtain the compounds of the present disclosure, as appreciated by those skilled in the art.

[0264] Abbreviations:

[0265] EA stands for ethyl acetate; TBDPS stands for tert-butyldiphenylsilyl; TBDPSCl stands for tert-butyldiphenylchlorosilane; DCM stands for dichloromethane; DMF stands for N,N-dimethylformamide; THF stands for tetrahydrofuran; diludine stands for dihydro-4-methyl-2H-pyridine; Piperidine stands for piperidine; MeOH stands for methanol; TsOH-H20 stands for p-toluenesulfonic acid monohydrate; TsCl stands for p-toluenesulfonyl chloride; n-BuLi stands for n-butyllithium; Boc20 stands for di-tert-butyl dicarbonate; TFA: trifluoroacetic acid; DIEA or DIPEA stands for N,N-diisopropylethylamine; Pd(dppf)Cl2 stands for [l,l'-bis(diphenylphosphino) ferrocene]dichloropalladium(II); Pd(dtbpf)Cl2 stands for 1,1'-bis(di-tert-butylphosphino) ferrocene dichloropalladium; HATU stands for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate or 2-(7-azobenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate; Et3N or TEA stands for triethylamine; PPh3: triphenylphosphine; Ru-L(S,S) stands for (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethane diamine(p-cymene)chloro ruthenium; [Ir(cod)Cl]2 stands for 1,5-cyclooctadiene iridium chloride dimer; B2Pin2 stands for bis(pinacolato)diboron or 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane); COMU stands for (2-hydroxymethyl-cyanoacetic acid ethyl ester)-N,N-dimethyl-morpholino urea hexafluorophosphate; ACN stands for acetonitrile; NIS stands for N-iodosuccinimide; KOAc stands for potassium acetate; DME stands for ethylene glycol dimethyl ether; EtI stands for ethyl iodide; EDCI stands for 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride; HOBT stands for 1-hydroxybenzotriazole; AcOH stands for acetic acid; Boc stands for tert-butoxycarbonyl; Cbz stands for benzyloxycarbonyl; toluene stands for methylbenzene; dioxane stands for 1,4-dioxane; TMSCHN2 stands for trimethylsilyldiazomethane; Pd(PPh3)2Cl2 stands for bis(triphenylphosphine)palladium dichloride; Ac20 stands for acetic anhydride; TCFH stands for N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate; NMI stands for N-methylimidazole; Pd2(dba)3 stands for tris(dibenzylideneacetone)dipalladium; SPhos stands for 2-dicyclohexylphosphino-2',6'-dimethoxy-biphenyl; IPA / i-PrOH stands for isopropyl alcohol; DMAP stands for 4-dimethylaminopyridine; NMP stands for N-methylpyrrolidone; LDA stands for lithium diisopropylamide; DTBA stands for di-tert-butyl azodicarboxylate; DMPU stands for N,N-dimethylpropylene urea; TBAF stands for tetrabutylammonium fluoride; DMSO stands for dimethyl sulfoxide;NMM stands for N-methylmorpholine; (CH2O); n The symbols dtbpy, tBuXPhosPdG3, and tBuOH represent tert-butanol, mCPBA, TMSCN, trimethylcyanosilane, FA, formic acid, Pyridine, Tf2O, (Ms)2O, and Bpin represent pinacolborane, CDI, 1,1'-carbonyldiimidazole, LC-MS, and MS represent mass spectrometry. 1 1H NMR stands for 1H nuclear magnetic resonance spectroscopy; ESI stands for electrospray ionization; HPLC stands for high-performance liquid chromatography; TLC stands for thin-layer chromatography; ABPR stands for back pressure regulator; DTT stands for dithiothreitol; HEPES stands for 4-hydroxyethylpiperazine ethanesulfonic acid; PBS stands for phosphate buffered saline; BSA stands for bovine serum albumin; NADPH stands for reduced coenzyme II; IC50 50 The half-maximum inhibitory concentration (WMC) refers to the concentration at which half of the maximum inhibitory effect is achieved; SolutolHS-15 represents polyethylene glycol-15 hydroxystearate. Example

[0266] The compounds disclosed herein can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed herein, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments disclosed herein.

[0267] The present disclosure is described in detail below with reference to embodiments, but this does not imply any adverse limitation thereof. The present 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 present 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.

[0268] Unless otherwise stated, the proportions expressed for mixed solvents are volume-based.

[0269] Unless otherwise stated, % refers to weight percentage (wt%).

[0270] Compounds are processed manually or Software nomenclature, commercially available compounds use the supplier catalog name.

[0271] The structure of the compound is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The unit of NMR shift is 10 -6 (ppm). The solvent for NMR determination is deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS);

[0272] The eluent or mobile phase can be a mixed eluent or mobile phase composed of two or more solvents, and the ratio is the volume ratio of each solvent.

[0273] Preparation Example

[0274] Synthesis of intermediate compound Int-1 in Preparation Example 1

[0275] Synthesis of 3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropanoic acid (compound A2) in the first step

[0276] Tert-butyldiphenylchlorosilane (76.82 g, 279.35 mmol), imidazole (19.02 g, 279.35 mmol) and compound A1 (30 g, 253.96 mmol) were added to dichloromethane (1000 mL). The reaction solution was stirred at 25°C for 2 hours. After the reaction was completed, the reaction solution was acidified to pH = 5 with 2N HCl. The solution was extracted with dichloromethane (100 mL) three times. The obtained organic phase was combined, washed with saturated brine (100 mL) twice, dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary evaporated to obtain compound A2 (88 g, 246.82 mmol, yield: 97.19%), which was used directly in the next step without purification.

[0277] Synthesis of 3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropanoyl chloride (compound A3) in the second step

[0278] Compound A2 (88 g, 246.82 mmol) was dissolved in dichloromethane (1000 mL) at 0°C, and N,N-dimethylformamide (1.80 g, 24.68 mmol, 1.91 mL) was added to the solution under nitrogen protection, followed by dropwise addition of oxalyl chloride (62.69 g, 493.65 mmol, 42.13 mL) into the reaction solution. It was stirred at 0°C for 2 hours. The reaction was monitored by LC-MS. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound A3 (80 g, 213.35 mmol, yield: 86.44%) which was used directly in the next step without purification.

[0279] Step 3 Synthesis of 1-(5-bromo-1H-indol-3-yl)-3-((tert-butyldiphenylsilyl)oxy)- 2,2-dimethylpropan-1-one (Compound A4)

[0280] Compound A3 (80 g, 213.35 mmol) was dissolved in dichloromethane (1.5 L) at 0 °C, tin tetrachloride solution (1 M, 213.35 mL) and 5-bromo-1H-indole (41.83 g, 213.35 mmol) were added under nitrogen protection. The reaction was stirred at 0 °C for 10 hours. LC-MS showed that the starting material was consumed and the product was detected. The reaction was diluted with ethyl acetate (600 mL) and washed with saturated brine (100 mL) for four times. The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate / tetrahydrofuran = 5 / 1 to 3 / 1) to give Compound A4 (8 g, 14.97 mmol, yield: 7.01 %). MS (ESI + m / z = 534.0 [M+H] + .

[0281] Step 4 Synthesis of 1-(5-bromo-1H-indol-3-yl)-3-((tert-butyldiphenylsilyl)oxy)- 2,2-dimethylpropan-1-ol (Compound A5)

[0282] Compound A4 (8 g, 14.97 mmol) was dissolved in tetrahydrofuran (71.30 mL) at 0 °C, 2M lithium borohydride tetrahydrofuran solution (2 M, 18.71 mL) was added slowly dropwise into the reaction under nitrogen protection, then the reaction was heated to 60 °C and stirred for 16 hours. LC-MS showed that the starting material was consumed and the desired compound was detected. The reaction was quenched with methanol (20 mL) and extracted with ethyl acetate (50 mL) for three times. The organic layers were combined and washed with saturated brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give Compound A5 (8 g, 14.91 mmol, yield: 99.62 %). No further purification was performed and it was used directly in the next step.

[0283] Step 5 Synthesis of 5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)- 1H-indole (Compound A6)

[0284] Compound A5 (8 g, 14.91 mmol), dihydro pyridine (4.37 g, 17.25 mmol), p-toluenesulfonic acid monohydrate (2.84 g, 14.91 mmol) were dissolved in dichloromethane (150 mL) and stirred at 0 °C for 2 hours under nitrogen protection. LC-MS showed that the reactants were consumed completely and the desired compound was detected. After the reaction was completed, water (50 mL) was added to quench the reaction, and the organic phase was washed with dichloromethane (50 mL) three times, then washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary evaporated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound A6 (7 g, 13.45 mmol, yield: 90.19%).

[0285] MS (ESI + )m / z = 520.0 [M+H] + .

[0286] Synthesis of 5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-2-iodo-1H-indole (compound Int-1)

[0287] Compound A6 (3 g, 5.76 mmol) was dissolved in tetrahydrofuran (10 mL), and I2 (1.46 g, 5.76 mmol) and silver trifluoromethanesulfonate (1.78 g, 6.92 mmol) were added. The reaction solution was stirred at room temperature for 2 hours. LC-MS showed that the reactants were consumed completely and the desired compound was detected. The reaction solution was diluted with ethyl acetate (50 mL) and washed with saturated Na2S2O3 aqueous solution (50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 10 / 1) to obtain compound Int-1 (973 mg, 1.51 mmol, yield: 26.12%). + )m / z = 646.1 [M+H] + .

[0288] Synthesis of intermediate compound Int-2 in Preparation Example 2

[0289] Synthesis of (4-bromothiazol-2-yl)methanol (compound B2)

[0290] Compound B1 (10 g, 52 mmol) was taken in methanol (15 mL) and sodium borohydride (2.95 g, 78.11 mmol) was added and stirred for 0.5 h at 0 °C. TLC showed compound B1 was completely reacted. The reaction was quenched by adding 10 mL of dilute hydrochloric acid. The reaction mixture was concentrated under reduced pressure to remove the solvent to get compound B2 (9 g, 46.38 mmol, 89.07 % yield).

[0291] MS (ESI + )m / z = 194.3 [M+H] + .

[0292] Synthesis of 4-bromo-2-(bromoethyl)thiazole (compound B3) in second step

[0293] Carbon tetrabromide (23.07 g, 69.57 mmol), compound B2 (9 g, 46.38 mmol) and triphenylphosphine (18.25 g, 69.57 mmol) were added in dichloromethane (120 mL) at 0 °C. After stirring for 1 h at 25 °C. LC-MS monitoring showed the reaction was complete. The mixture was filtered and the filtrate was concentrated under vacuum. The crude was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0-10%) to get compound B3 (9.0 g, 35.20 mmol, 75.9 % yield).

[0294] MS (ESI + )m / z = 255.7 [M+H] + .

[0295] Synthesis of 4-bromo-2-[[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5- dihydropyrazin-2-yl]methyl]thiazole (compound B5) in third step

[0296] (R)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine (compound B4, 7.10 g, 38.53 mmol) was taken in tetrahydrofuran (100 mL) and n-butyllithium (16.81 mL, 42.03 mmol, 2.5 M) was added slowly at -78 °C. After addition, it was stirred for 0.5 h at -78 °C. Compound B3 (9.0 g, 35.20 mmol) was added to the above mixture and stirred for 1 h at -78 °C. LC-MS monitoring showed the reaction was complete. It was quenched with saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (100 mL x 2) and the organic layer was dried and purified by silica gel column (0-15% petroleum ether / ethyl acetate) to get compound B5 (10.5 g, 29.14 mmol, 83 % yield).

[0297] MS (ESI + )m / z = 360.2 [M+H]+ .

[0298] Fourth Step Synthesis of (S)-methyl 2-amino-3-(4-bromothiazol-2-yl)propanoate (B6)

[0299] To a solution of compound B5 (10.5 g, 29.14 mmol) in acetonitrile (60 mL) was added hydrochloric acid (195 mL, 0.3 M). Stirring at 25 °C for 2 h. LC-MS monitoring reaction complete. The mixture was basified to pH = 8 with saturated aqueous sodium bicarbonate solution. Then extracted with ethyl acetate (100 mL x 6), the organic phase was dried over anhydrous sodium sulfate, after filtration, the filtrate was concentrated in vacuo to give compound B6 (6.8 g, 25.65 mmol, yield: 88%).

[0300] MS (ESI + )m / z = 264.9 [M+H] + .

[0301] Fifth Step Synthesis of (S)-methyl 3-(4-bromothiazol-2-yl)-2-((tert- butoxycarbonyl)amino)propanoate (compound B7)

[0302] Triethylamine (8.94 mL, 64.12 mmol) and di-tert-butyl dicarbonate (8.4 g, 38.47 mmol) were added to a solution of compound B6 (6.8 g, 25.65 mmol) in dichloromethane (80 mL) respectively. Stirring at 25 °C for 16 h. LC-MS monitoring reaction complete. Quenched with water (75 mL) and extracted with dichloromethane (75 mL x 2). The organic layer was rotary evaporated and purified by silica gel column (petroleum ether / ethyl acetate = 0-30%) to give compound B7 (6.5 g, yield: 68%).

[0303] MS (ESI + )m / z = 364.9 [M+H] + .

[0304] Sixth Step Synthesis of (S)-3-(4-bromothiazol-2-yl)-2-((tert- butoxycarbonyl)amino)propanoic acid (compound B8)

[0305] To a mixture solvent of tetrahydrofuran (60 mL), methanol (5 mL) and water (20 mL) was added compound B7 (6.5 g, 17.44 mmol) and lithium hydroxide monohydrate (2.93 g, 69.76 mmol). Stirring at 25 °C for 1 h. LC-MS monitoring reaction complete. The mixture was acidified to pH = 5 with 1 M aqueous hydrochloric acid solution. Extracted with ethyl acetate (100 mL x 2), the organic phase was dried over anhydrous sodium sulfate, after filtration, concentrated in vacuo to give compound B8 (6 g, 17.08 mmol, yield: 98%).

[0306] MS (ESI + m / z = 351.2 [M+H] + .

[0307] Step 7: Synthesis of methyl (S)-2-((S)-3-(4-bromothiazol-2-yl)-2- ((tert-butoxycarbonyl)amino)propanoyl)-2,3-diazabicyclo[3.1.1]octane-4- carboxylate (Compound Int-2)

[0308] Compound Int-5 (309 mg, 1.98 mmol) and N,N-diisopropylethylamine (3.45 mL, 19.8 mmol) were added to a solution of Compound B8 (695.4 mg, 1.98 mmol) and 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (896.3 mg, 2.38 mmol) in N,N-dimethylformamide (7.0 mL) at room temperature and stirred for 2 hours. Purification by reverse phase silica gel column (water:acetonitrile, gradient: 95 / 5 to 5 / 95) gave Compound Int-2 (600.0 mg, yield: 61.9%).

[0309] MS m / z (ESI): 489.2 [M+H] + .

[0310] Synthesis of intermediate compound Int-3 in Preparation Example 3

[0311] Step 1: Synthesis of (S)-1-(3-bromopyridin-2-yl)ethan-1-ol (Compound C2)

[0312] A solution of formic acid (6.63 g, 143.98 mmol, 5.43 mL) in triethylamine (72.84 g, 719.88 mmol, 100.41 mL) was cooled to 0 °C under N2protection, then (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene) ruthenium chloride (379 mg, 599.90 µmol) was added, the reaction was heated to 40 °C and stirred for 15 minutes, then cooled to room temperature, Compound C1 (12 g, 59.99 mmol) was added, then the reaction was heated to 40 °C and stirred for 2 hours. After the reaction was cooled to room temperature, the reaction was concentrated under reduced pressure, and column chromatography was used for purification to give Compound C2 (12 g, 59.41 mmol, yield: 99%). MS (ESI + m / z = 202.1 [M+H] + .

[0313] Step 2: Synthesis of (S)-3-bromo-2-(1-methoxyethyl)pyridine (Compound C3)

[0314] A solution of compound C2 (12.00 g, 59.41 mmol) in N,N-dimethylformamide (75 mL) was cooled to 0 °C under N2protection, sodium hydride (2.85 g, 71.27 mmol, 60% purity) was added, the mixture was stirred at 0 °C for 15 min, then iodomethane (16.86 g, 118.78 mmol) was added, and it was allowed to naturally rise to room temperature, and the reaction was stirred for 2 h. The reaction solution was slowly added to ice water (750 mL), extracted with ethyl acetate (100 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated, and the residue was purified by column chromatography to obtain compound C3 (11 g, 50.9 mmol, yield: 86%). MS (ESI + )m / z = 216.1 [M+H] + .

[0315] Synthesis of 5-bromo-6-[(1S)-1-methoxyethyl]pyridin-3-yl boronic acid (compound C4) in the third step

[0316] 4,4'-Di-tert-butyl-2,2'-bipyridine (931.61 mg, 3.47 mmol) and 1,5-cyclooctadiene iridium dimer chloride (466.30 mg, 694.20 mmol) were added to a solution of compound C3 (5.0 g, 23.14 mmol) and bis(pinacolato)diboron (8.81 g, 34.71 mmol) in tetrahydrofuran (50 mL) under N2atmosphere. The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 16 h. The reaction was monitored by LC-MS, and no starting material was left. The mixture was concentrated under reduced pressure. The resulting mixture was dissolved in ethyl acetate (30 mL), and the mixture was adjusted to pH = 10 with a solution of sodium carbonate (40 g) and sodium hydroxide (10 g) (mass ratio 4:1) in water (600 mL). Extraction was performed with ethyl acetate (100 mL). The aqueous phase was acidified with hydrochloric acid (6 M) to pH = 6 to obtain compound C4 (4.5 g, 17.3 mmol, yield: 75%).

[0317] MS (ESI + )m / z = 260.0 [M+H] + .

[0318] Synthesis of (S)-3-bromo-5-iodo-2-(1-methoxyethyl)pyridine (compound C5) in the fourth step

[0319] Compound C4 (4.5 g, 17.3 mmol) and N-iodosuccinimide (36.70 g, 163.14 mmol) were added in acetonitrile (50 mL) under N2protection. The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 16 h. The reaction was monitored by LC-MS. The resulting mixture was dissolved in dichloromethane (80 mL) and washed with saturated aqueous sodium thiosulfate (80 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column (petroleum ether / ethyl acetate: 0-15%) to give compound C5 (4.3 g, 12.6 mmol, yield: 73%).

[0320] MS (ESI + )m / z = 341.8 [M+H] + .

[0321] Synthesis of (S)-4-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester (Compound C7)

[0322] Compound C5 (4.3 g, 12.6 mmol), compound C6 (2.77 g, 12.57 mmol), (R)-(+)-2,2-bis(diphenylphosphino)-1,1-binaphthyl (BINAP) (156.59 mg, 251.48 μmol), palladium acetate (141.15 mg, 628.71 μmol), Cs2CO3 (10.24 g, 31.44 mmol), toluene (50 mL) were mixed in a sealed tube under N2protection. The resulting solution was stirred at 100 °C under nitrogen atmosphere for 16 h. The reaction was monitored by LC-MS. After completion of the reaction, the reaction mixture was cooled to 25 °C. The mixture was extracted with ethyl acetate (80 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column (petroleum ether / ethyl acetate: 0-45%) to give compound C7 (3.6 g, 8.29 mmol, yield: 65.92%).

[0323] MS (ESI + )m / z = 434.2 [M+H] + .

[0324] Synthesis of (S)-4-(6-(1-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester (Compound Int-3)

[0325] Compound C7 (9.6 g, 22.10 mmol), B2Pin2 (28.06 g, 110.52 mmol), potassium acetate (6.51 g, 66.31 mmol) were dissolved in dioxane (100 mL), Pd(dppf)Cl2(1.62 g, 2.21 mmol) was added into the reaction solution under nitrogen protection and replaced with nitrogen for 5 times, stirred at 100 °C for 16 hours, the reaction was monitored to be completed. Filtration, concentrated under reduced pressure, added ethyl acetate (100 mL) and 6N HCl (100 mL) and stirred for 16 hours, filtered, concentrated under reduced pressure, purified by reversed-phase silica gel column (water / acetonitrile = 1 / 0~1 / 1) to obtain compound Int-3 (4.6 g, 9.52 mmol, yield: 43.06 %). MS (ESI + )m / z = 482.2 [M+H] +

[0326] Synthesis of intermediate compound Int-4 in Preparation Example 4

[0327] Synthesis of (S)-4-(5-(5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-1H- indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)benzyl piperazine-1-carboxylate (compound D1)

[0328] Compound Int-1 (4 g, 6.19 mmol), compound Int-3 (4.47 g, 9.28 mmol), potassium carbonate (2.57 g, 18.56 mmol) were dissolved in a solution of ethylene glycol dimethyl ether (40 mL) and water (8 mL), Pd(dppf)Cl2(452.74 mg, 618.74 µmol) was added into the reaction solution under nitrogen protection and replaced with nitrogen for 5 times, stirred at 100 °C for 16 hours, the reaction was monitored to be completed by LC-MS. Diluted with water (100 mL), extracted with ethyl acetate (100 mL x 3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, purified by normal-phase silica gel column (petroleum ether / ethyl acetate = 1 / 0~1 / 5) to obtain compound D1 (2.3 g, 2.63 mmol, yield: 42.49 %).

[0329] MS (ESI + )m / z = 873.3 [M+H] +

[0330] Synthesis of (S)-4-(5-(5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-1- ethyl-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)benzyl piperazine-1-carboxylate (compound D2)​​

[0331] Compound D1 (2.3 g, 2.63 mmol) was dissolved in DMF (30 mL), cesium carbonate (2.57 g, 7.89 mmol) was added in portions, iodoethane (820.88 mg, 5.26 mmol), stirred at 25 °C for 16 hours. LC-MS monitoring reaction complete. Diluted with water (100 mL), extracted with ethyl acetate (100 mL x 3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to give compound D2 (2.0 g, crude). Directly used in next step.

[0332] MS (ESI + )m / z = 901.3 [M+H] + .

[0333] Synthesis of (S)-4-(5-(5-bromo-l-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-lH- indol-2-yl)-6-(l-methoxyethyl)pyridin-3-yl)piperazine-l-carboxylic acid benzyl ester (Compound D3)

[0334] Compound D2 (2.0 g, crude) was dissolved in tetrahydrofuran (30 mL), TBAF (1 M, 22.17 mL) was added, stirred at 25 °C for 16 hours. LC-MS monitoring reaction complete. The mixture was concentrated under reduced pressure, purified with normal phase silica gel column (petroleum ether / ethyl acetate = 1 / 0 ~ 0 / 1) to give less polar isomer (reference to WO2022060836 Al), to give compound D3 (0.5 g, 753.42 pmol, yield: 33.4%).

[0335] MS (ESI + )m / z = 663.3 [M+H] + .

[0336] Synthesis of (S)-4-(5-(l-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-lH-indol-2-yl)-6-(l-methoxyethyl)pyridin-3-yl)piperazine-l- carboxylic acid benzyl ester (Compound D4)

[0337] Compound D3 (0.5 g, 753.42 μmol), bis(pinacolato)diboron (573.96 mg, 2.26 mmol), potassium acetate (184.86 mg, 1.88 mmol) were dissolved in toluene (10 mL), Pd(dppf)Cl2(55.13 mg, 75.34 μmol) was added into the reaction solution under nitrogen atmosphere and replaced with nitrogen for 5 times, stirred at 100 ℃ for 16 hours, LC-MS was used to monitor the completion of the reaction. Filtration, concentrated under reduced pressure, diluted with water (50 mL), extracted with ethyl acetate (100 mL x 3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, purified by normal phase silica gel column (petroleum ether / ethyl acetate = 1 / 0 ~ 1 / 3) to give compound D4 (0.4 g, 562.82 μmol, yield: 74.7%).

[0338] MS (ESI + )m / z = 711.4 [M+H] + .

[0339] Step 5 Synthesis of (S)-2-((S)-3-(4-(2-(5-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2- ((S)-1-methoxyethyl)pyridin-3-yl)-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-5-yl)thiazol- 2-yl)-2-((tert-butoxycarbonyl)amino)propanoyl)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid methyl ester (Compound D5)

[0340] Compound D4 (117.6 mg, 165.5 μmol), compound Int-2 (89 mg, 182.05 μmol) and potassium phosphate (232.96 mg, 1.10 mmol) were dissolved in a mixed solution of dioxane (1 mL), toluene (3 mL) and water (1 mL), Pd(dtbpf)Cl2(23.84 mg, 36.58 μmol) was added into the reaction solution under nitrogen atmosphere and replaced with nitrogen for 5 times, stirred at 100 ℃ for 16 hours, LC-MS was used to monitor the completion of the reaction. Diluted with water (50 mL), extracted with ethyl acetate (10 mL x 3), washed with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, purified by normal phase silica gel column (petroleum ether / ethyl acetate = 1 / 0 ~ 1 / 3) to give compound D5 (142.2 mg, 143.16 μmol, yield: 86.5%).

[0341] MS (ESI + )m / z = 993.4 [M+H] + .

[0342] Step 6. Synthesis of (S)-2-((S)-3-(4-(2-(5-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2- ((S)-1-methoxyethyl)pyridin-3-yl)-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-5-yl)thiazol- 2-yl)-2-((tert-butoxycarbonyl)amino)propanoyl)-2,3-diazabicyclo[3.1.1]octane-4-carboxylic acid (Compound D6)

[0343] Compound D5 (142.2 mg, 143.16 μmol) was dissolved in a mixture solution of tetrahydrofuran (5 mL) and water (5 mL), lithium hydroxide (32.95 mg, 1.37 mmol) was added into the reaction solution, stirred at 25 °C for 16 hours, LC-MS was used to monitor the reaction completion. Diluted with ethyl acetate (30 mL) and water (30 mL), the aqueous phase was adjusted to pH about 6 with 1M aqueous hydrochloric acid solution, extracted with ethyl acetate (30 mL), the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Compound D6 (120 mg, 122.83 μmol, yield: 85.8%) as a yellow solid.

[0344] MS (ESI + )m / z = 979.5 [M+H] + .

[0345] Step 7. Synthesis of Compound D7

[0346] Compound D6 (120 mg, 122.83 μmol), DIEA (1.12 g, 8.69 mmol, 1.51 mL), EDCI (1.25 g, 6.51 mmol) and HOBt (293.39 mg, 2.17 mmol) were dissolved in acetonitrile (5 mL), stirred at 25 °C for 16 hours, LC-MS was used to monitor the reaction completion. Diluted with water (20 mL), extracted with ethyl acetate (50 mL x 3), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, purified by normal phase silica gel column (petroleum ether / ethyl acetate = 1 / 0 ~ 1 / 4) to obtain Compound D7 (35.4 mg, 36.85 μmol, yield: 30.4%).

[0347] MS (ESI + )m / z = 961.1 [M+H] + .

[0348] Step 8. Synthesis of Compound D8

[0349] Compound D7 (35.4 mg, 36.85 μmol) was dissolved in methanol (10 mL), Pd(OH)2 / C (64.11 mg, 273.92 μmol, 60% purity) was added to the reaction solution under nitrogen protection, then replaced with hydrogen for 5 times, stirred at 25 °C for 16 hours under one atmosphere of hydrogen, LC-MS was used to monitor the completion of the reaction. Filtration, the filtrate was concentrated under reduced pressure to obtain compound D8 (28 mg, 33.9 μmol, yield: 92%).

[0350] MS (ESI + )m / z = 827.2 [M+H] + .

[0351] Step 9 Synthesis of compound D9

[0352] Compound D8 (28 mg, 33.9 μmol) and acetic acid (22.10 mg, 368.08 μmol) were dissolved in methanol (5 mL), stirred at 25 °C for 1 hour, then paraformaldehyde (36.85 mg, 1.23 mmol) and NaBH3CN (23.13 mg, 368.08 μmol) were added to the reaction solution, stirred at 25 °C for 16 hours, LC-MS was used to monitor the completion of the reaction. Filtration and concentration under reduced pressure to obtain compound D9 (24 mg, 28.53 μmol, yield: 84.16%).

[0353] MS (ESI + )m / z = 841.2 [M+H] + .

[0354] Step 10 Synthesis of compound Int-4

[0355] Compound D9 (14 mg, 16.7 μmol) was dissolved in methanol (10 mL), 4N hydrogen chloride dioxane (5 mL) was added to the reaction solution under nitrogen protection, stirred at 25 °C for 5 hours, LC-MS was used to monitor the completion of the reaction, rotary evaporation and concentration to obtain compound Int-4 (10 mg, 13.54 μmol, yield: 81.1%).

[0356] MS (ESI + )m / z = 741.1 [M+H] + .

[0357] Synthesis of intermediate compound Int-5 in Preparation Example 5

[0358] Step 1 Synthesis of 3-(2-diazoacetyl)cyclobutan-1-one (compound E2)

[0359] Dichlorosulfoxide (89.12 mL, 1.23 mol) was added dropwise to a solution of compound E1 (70.0 g, 613.5 mmol) in ethyl acetate (700.0 mL) under ice-bath. The mixture was heated to 60 °C and stirred for 4 h. After the reaction was completed, the reaction was concentrated to dryness and azeotroped with toluene. The obtained crude was dissolved in a mixture of tetrahydrofuran (250.0 mL) and acetonitrile (250.0 mL). 2.0 M trimethylsilyldiazomethane in hexane (460.1 mL, 920.2 mmol) was added dropwise to the solution of crude at 0 °C, slowly warmed to room temperature and stirred for 12 h. After the reaction was completed, the reaction was cooled to 0 °C and quenched by the addition of acetic acid (50.0 mL) and water (200.0 mL), then concentrated to give a residue, which was diluted with saturated aqueous sodium bicarbonate solution (200.0 mL). The obtained mixture was extracted with ethyl acetate (300 mL) three times. The combined organic layers were washed with saturated aqueous sodium chloride solution (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1:1) to give compound E2 (45.0 g, 325.77 mmol, yield: 53.1%).

[0360] MS m / z (ESI): 139.0 [M+H] + .

[0361] Preparation of the second step 2-(3-oxocyclobutyl)acetic acid (compound E3)

[0362] Silver nitrate (59.0 g, 347.5 mmol) was added portionwise to a mixture of compound E2 (40.0 g, 289.6 mmol) in water (360.0 mL) and tetrahydrofuran (720.0 mL) and stirred at room temperature for 12 h. After the reaction was completed, the reaction was concentrated to give a residue, to which was added water (1000.0 mL) and the pH was adjusted to 1-2 with dilute hydrochloric acid (1.0 M). The obtained mixture was extracted with ethyl acetate (300 mL) five times. The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound E3 (36.0 g, 280.91 mmol, yield: 97.0%), which was used in the next step without further purification.

[0363] MS m / z (ESI): 127.0 [M-H] - .

[0364] Preparation of the third step (S)-4-benzyl-3-(2-(3-oxocyclobutyl)acetyl)oxazolidin-2-one (compound E4)

[0365] Compound E3 (36 g, 280.91 mmol), (S)-4-benzyl oxazolidin-2-one (49.8 g, 281.0 mmol), 4-dimethylaminopyridine (3.8 g, 31.2 mmol) and triethylamine (130.6 mL, 936.6 mmol) were added into dichloromethane (800.0 mL) in turn, then 2-chloro-1-methylpyridinium iodide (87.7 g, 343.4 mmol) was added portionwise. Stirring at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with water, and the organic phase was washed with water (1000.0 mL) twice, the organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain compound E4 (49.43 g, 171.64 mmol, yield: 61.1%).

[0366] MS m / z (ESI): 288.1 [M+H] + .

[0367] Preparation of (S)-4-benzyl-3-(2-(3-hydroxycyclobutyl)acetyl)oxazolidin-2-one (compound E5)

[0368] Compound E4 (49.43 g, 171.64 mmol) and acetic acid (22.9 g, 381.4 mmol) were added into tetrahydrofuran (550.0 mL) in turn, cooled to 0°C, and sodium borohydride (5.77 g, 152.6 mmol) was added portionwise, and stirred for 2 hours after the addition was completed. After the reaction was completed, saturated aqueous ammonium chloride solution (150.0 mL) was slowly added dropwise to quench the reaction, and concentrated under reduced pressure to a residue, which was extracted with ethyl acetate (300.0 mL) three times, and the organic phase was washed with saturated aqueous sodium bicarbonate solution, and the pH was adjusted to 8, and the organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain compound E5 (48.68 g, 167.86 mmol, yield: 97.8%), which was used directly in the next step without further purification.

[0369] MS m / z (ESI): 290.2 [M+H] + .

[0370] Preparation of (S)-3-(2-(4-benzyl-2-oxooxazolidin-3-yl)-2-oxoethyl)cyclobutyl-4-methyl benzenesulfonate (compound E6)

[0371] Compound E5 (48.68 g, 167.86 mmol), 4-dimethylaminopyridine (18.2 g, 149.3 mmol) and N,N-diisopropylethylamine (48.8 mL, 280.0 mmol) were added to anhydrous dichloromethane (500.0 mL), cooled to 0°C, and p-toluenesulfonyl chloride (39.1 g, 205.3 mmol) was added portionwise. After the addition was completed, the reaction solution was slowly warmed to room temperature and stirred overnight. After the reaction was completed, the mixture was washed with water (500.0 mL) and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain compound E6 (49.8 g, 112.14 mmol, yield: 66.8%).

[0372] MS m / z (ESI): 444.1 [M+H] + .

[0373] Preparation of (S)-4-benzyl-3-(2-(3-bromocyclobutyl)acetyl)oxazolidin-2-one (Compound E7)

[0374] Compound E6 (49.8 g, 112.14 mmol) and lithium bromide (19.0 g, 219.2 mmol) were added to N-methylpyrrolidone (500.0 mL), and the reaction solution was heated to 90°C and stirred for 12 hours. After the reaction was completed, it was diluted with saturated aqueous sodium chloride solution (1.0 L) and extracted with ethyl acetate (300.0 mL) three times. The organic phase was washed once more with saturated sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound E7 (34.74 g, 98.68 mmol, yield: 88.0%).

[0375] MS m / z (ESI): 352.2 [M+H] + .

[0376] Preparation of (S)-2,3-bis(tert-butoxycarbonyl)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid (Compound E8)

[0377] Compound E7 (10.0 g, 28.4 mmol) was dissolved in tetrahydrofuran (100.0 mL) under argon atmosphere, cooled to -78 °C, then lithium diisopropylamide tetrahydrofuran n-heptane mixed solution (18.5 mL, 2.0 M) was added dropwise slowly, stirred for 0.5 h. Then di-tert-butyl azodicarboxylate (7.84 g, 34.0 mmol) in anhydrous dichloromethane (20.0 mL) was added to the above solution, continued to stir for 0.5 h. Then N,N-dimethylpropenylurea (109.2 g, 851.7 mmol) was added slowly to the above reaction solution, slowly warmed to room temperature and continued to stir for 13 h. After the reaction was completed, the reaction was quenched by adding water (100.0 mL), then lithium hydroxide monohydrate (3.58 g, 85.1 mmol) was added, stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated, then saturated aqueous sodium chloride solution (200.0 mL) was added to dilute, extracted with ethyl acetate (200.0 mL) three times, the organic phase was discarded, the aqueous phase was adjusted to pH 5 with dilute hydrochloric acid (1.0 M), then extracted with ethyl acetate (200.0 mL) three times, the organic phase was washed with saturated aqueous sodium chloride solution once, the organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain compound E8 (1.0 g, 2.91 mmol, yield: 10.2%).

[0378] MS m / z (ESI): 343.1 [M+H] + .

[0379] Eighth Step Preparation of 2,3-di-tert-butyl-4-methyl (S)-2,3-diazabicyclo[3.1.1]heptane-2,3,4-tricarboxylate (Compound E9)

[0380] To a solution of compound E8 (1.0 g, 2.91 mmol) in methanol (10.0 mL) was added dropwise slowly trimethylsilyldiazomethane in n-hexane (7.3 mL, 2.0 M) at room temperature, the mixture was stirred at room temperature for 30 min. After the reaction was completed, a few drops of acetic acid were added to quench the reaction. The reaction solution was concentrated to obtain the title compound E9 (1.0 g, 2.8 mmol, yield: 96.2%).

[0381] MS m / z (ESI): 343.1 [M+H] + .

[0382] Ninth Step Preparation of (S)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid methyl ester (Compound Int-5)

[0383] To a solution of compound E9 (706.0 mg, 1.98 mmol) in dichloromethane (6.0 mL) was added trifluoroacetic acid (2.0 mL) dropwise at room temperature, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated to obtain the title compound Int-5 (312 mg, 1.98 mmol, yield: 100.0%).

[0384] MS m / z (ESI): 157.0 [M+H] + .

[0385] Synthesis of intermediate compound Int-6 in Preparation Example 6

[0386] Synthesis of (S)-4-(3-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)prop-2-yn-1-yl)morpholine (compound Int-6) in the first step

[0387] Compound C5 (3.4 g, 10.0 mmol) was dissolved in tetrahydrofuran (20 mL), and cuprous iodide (190 mg, 1.0 mmol), triethylamine (2.02 g, 20.0 mmol), bis(triphenylphosphine)palladium dichloride (702 mg, 1.0 mmol), and 4-propyn-1-morpholine (1.88 g, 15.0 mmol) were sequentially added, and the reaction mixture was reacted at room temperature for 5 hours under argon protection. After the reaction was completed, the organic solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:3) to obtain compound Int-6 (2.5 g, 7.3 mmol, yield: 73%).

[0388] MS m / z (ESI): 339.1 [M+H] + .

[0389] Synthesis of intermediate compound Int-7 in Preparation Example 7

[0390] Synthesis of compound F2 in the first step

[0391] Under nitrogen protection, 3-bromo-2-iodopyridine F1 (7.00 g, 24.66 mmol), isopropenyl potassium trifluoroborate (4.23 g, 28.60 mmol), bis(triphenylphosphine)palladium dichloride (347.1 mg, 493.15 µmol) and cesium carbonate (24.10 g, 73.97 mmol) were added to a mixture solution of tert-butyl alcohol (54 mL) and water (20 mL), and the mixture was reacted at 90 °C overnight. After the reaction solution was cooled to room temperature, most of the organic solvent was removed by distillation under reduced pressure, and the residue was poured into water (80 mL) and extracted with ethyl acetate (100 mL*3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:3) to obtain compound F2 (4.60 g, 23.23 mmol, yield: 94%).

[0392] MS m / z (ESI): 198.0 [M+H] + .

[0393] Second Step: Synthesis of compound F3

[0394] Under hydrogen atmosphere, platinum dioxide (1.51 g, 6.66 mmol) was added to a solution of compound F2 (4.40 g, 22.22 mmol) in ethyl acetate (30 mL), and the mixture was stirred at room temperature overnight. After the reaction was completed by LC-MS monitoring, the mixture was filtered under suction with diatomite, and the filter residue was washed with ethyl acetate. The combined organic phase was concentrated to obtain compound F3 (3.60 g, 18 mmol, yield: 81%).

[0395] MS m / z (ESI): 200.0 [M+H] + .

[0396] Third Step: Synthesis of compound F4

[0397] Under nitrogen protection, bis(pinacolato)diboron (6.66 g, 26.24 mmol), iridium (III) chloride dimer (587.5 mg, 874.67 µmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (563.4 mg, 2.10 mmol) were added to a solution of compound F3 (3.50 g, 17.49 mmol) in tetrahydrofuran (30 mL), and the mixture was reacted at 75 °C overnight. After the reaction was completed by LC-MS monitoring, most of the organic solvent was removed by distillation under reduced pressure, and the residue was poured into ethyl acetate (100 mL) and washed with saturated brine (50 mL*3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:2) to obtain compound F4 (1.88 g, 5.8 mmol, yield: 33%).

[0398] MS m / z (ESI): 326.1 [M+H] + .

[0399] Fourth Step Synthesis of compound F5

[0400] Sodium periodate (2.36 g, 11.04 mmol) and hydrochloric acid (3 M, 5.52 mL) were added to a solution of compound F4 (1.80 g, 5.52 mmol) in ethyl acetate (15 mL) sequentially, and the mixture was allowed to react at room temperature overnight. After LC-MS monitoring showed that the reaction was complete, the ethyl acetate was removed by distillation under reduced pressure, and an aqueous sodium hydroxide solution (1 M) was added to the residue to adjust the pH to 6. After the solid was completely precipitated, it was suction filtered, the filter residue was washed with water, and the filter residue was dissolved in a mixed solvent of methanol and acetonitrile (1:1) (40 mL), filtered, and concentrated to obtain compound F5 (1.24 g, 5.08 mmol, yield: 92%), which was directly used in the next step.

[0401] MS m / z (ESI): 244.0 [M+H] + .

[0402] Fifth Step Synthesis of compound Int-7

[0403] N-iodosuccinimide (4.29 g, 19.08 mmol) was added to a solution of compound F5 (1.55 g, 6.36 mmol) in acetonitrile (10 mL) in batches at room temperature, and the mixture was stirred at 75°C under nitrogen protection overnight. After LC-MS monitoring showed that the reaction was complete, the solvent was removed by distillation under reduced pressure, ethyl acetate (50 mL) was added, and the mixture was washed with saturated aqueous sodium thiosulfate solution (50 mL*3). The organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:3) to obtain compound Int-7 (1.50 g, 4.58 mmol, yield: 72%).

[0404] MS m / z (ESI): 325.9 [M+H] + .

[0405] Synthesis of intermediate compound Int-8 in Preparation Example 8

[0406] First Step Synthesis of compound G2

[0407] To a solution of compound H1 (100.0 mg, 0.28 mmol) in N,N- dimethylformamide (2 mL) was added 3-bromopropynyl acetate (0.1 mL, 0.84 mmol) and potassium carbonate (95.0 mg, 0.69 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into ethyl acetate (50 mL) and washed with saturated brine (20 mL*3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1: 2) to give compound H2 (100.0 mg, 0.27 mmol, yield: 97%).

[0408] MS m / z (ESI): 140.1 [M+H] + .

[0409] Second Step Synthesis of compound Int-8

[0410] To a solution of compound G2 (307.5 mg, 2.21 mmol), bis(triphenylphosphine) palladium dichloride (129.6 mg, 184.07 μmol), cuprous iodide (70.1 mg, 368.13 μmol) and N,N-diisopropylethylamine (475.8 mg, 3.68 mmol, 641.20 μL) in acetonitrile (5 mL) was added compound Int-7 (600.0 mg, 1.84 mmol) under nitrogen protection at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ethyl acetate (50 mL) and washed with saturated brine (20 mL*3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1: 3) to give compound Int-8 (613.0 mg, 1.82 mmol, yield: 99%).

[0411] MS m / z (ESI): 337.1 [M+H] + .

[0412] Synthesis of intermediate compound Int-9 in Preparation 9

[0413] First Step Synthesis of compound H1

[0414] Compound A4 (20.0 g, 37.41 mmol) was added into tetrahydrofuran (40.0 mL), trifluoroacetic acid (40.0 mL) was added slowly at 0 °C, then sodium borodeuteride (4.70 g, 112.24 mmol) was added slowly at 0 °C under nitrogen protection, the mixture was stirred at 80 °C for 10 hours. The mixture was quenched with water (40 mL) at 0 °C, then extracted with ethyl acetate (40 mL), washed with saturated brine (40 mL) to get the crude product. The crude product was purified by column chromatography (dichloromethane / petroleum ether = 0~20%) to get compound H1 (8.5 g, 16.27 mmol, yield: 43.47%).

[0415] MS (ESI+) m / z = 522.3 [M+H] + .

[0416] Synthesis of compound Int-9

[0417] Compound H1 (8.5 g, 16.27 mmol) was dissolved in tetrahydrofuran (130.0 mL), then iodine (4.13 g, 16.27 mmol) and silver trifluoromethanesulfonate (4.60 g, 17.89 mmol) were added, stirred at 25 °C for 2 hours. The mixture was filtered, the filtrate was added into saturated aqueous sodium sulfite solution (50 mL), extracted with ethyl acetate (50 mL), concentrated to get the crude product. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 0~10%) to get compound Int-9 (8 g, 12.36 mmol, yield: 75.9%).

[0418] MS (ESI+) m / z = 648.1 [M+H] + .

[0419] Synthesis of intermediate compound Int-10 in Preparation Example 10

[0420] Using the same synthetic route as compound Int-4, using intermediate compound Int-9 to replace compound Int-1 in the synthetic route, compound Int-10 was obtained.

[0421] MS (ESI + )m / z = 743.4 [M+H] + .

[0422] Synthesis of intermediate compound Int-11 in Preparation Example 11

[0423] First step: synthesis of (5-bromopyrimidin-2-yl)methyl methanesulfonate (compound I2)

[0424] Compound II (0.50 g, 2.7 mmol) was dissolved in dichloromethane (5 mL), N,N- diisopropylethylamine (0.51 g, 4.0 mmol) and methanesulfonic anhydride (0.55 g, 3.2 mmol) were added successively under ice-bath. The reaction mixture was stirred at room temperature for 1 h. After the reaction was completed, water (20 mL) was added to the reaction system, extracted with dichloromethane (20 mL) twice, combined the organic phase, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give compound I2 (0.69 g, 2.6 mmol, 97% yield).

[0425] MS (ESI + )m / z = 267.2 [M+H] + .

[0426] Second Step: Synthesis of 4-((5-bromopyrimidin-2-yl)methyl)morpholine (Compound I3)

[0427] Compound I2 (0.69 g, 2.6 mmol) was dissolved in tetrahydrofuran (10 mL), N,N- diisopropylethylamine (1.0 g, 7.7 mmol) and morpholine (0.34 g, 3.9 mmol) were added under ice-bath. The reaction mixture was stirred at 60 °C for 2 h. After the reaction was completed, water (20 mL) was added to the reaction system, extracted with dichloromethane (20 mL) twice, combined the organic phase, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give compound I3 (0.47 g, 1.82 mmol, 71% yield).

[0428] MS (ESI + )m / z = 258.1 [M+H] + .

[0429] Third Step: Synthesis of 4-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2- yl)methyl)morpholine (Compound I4)

[0430] Compound I3 (0.42 g, 1.6 mmol) was dissolved in dioxane (5 mL), bis(pinacolato)diboron (0.50 g, 2 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.12 g, 0.16 mmol) and potassium acetate (403 mg, 4.11 mmol) were added successively. The reaction mixture was stirred at 100 °C under nitrogen protection overnight, LC-MS monitoring showed that the starting material was completely reacted, filtered with diatomite, the filtrate was concentrated to give the crude product of compound I4, which was directly used in the next step.

[0431] ESI-MS MS (ESI +m / z = 306.2 [M+H] + .

[0432] Fourth Step: Synthesis of (S)-4-((5-(5-bromo-6-(1-methoxyethyl)pyridin-3- yl)pyrimidin-2-yl)methyl)morpholine (Compound Int-11)

[0433] The above obtained compound I4 crude was dissolved in a mixture solution of dioxane (5 mL) and water (0.5 mL), and compound C5 (0.56 g, 1.64 mmol), potassium carbonate (0.68 g, 4.9 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (120 mg, 0.16 mmol) were added successively. The reaction was carried out at 50 °C for 1 hour under nitrogen protection. LC-MS monitoring showed that the raw material was completely reacted. The diatomite was filtered, the filtrate was concentrated, and the residue was purified by normal silica gel column (dichloromethane / methanol = 30:1) to obtain compound Int-11 (0.61 g, 1.55 mmol, yield 97%).

[0434] MS (ESI + )m / z = 393.3 [M+H] + .

[0435] Synthesis of intermediate compound Int-12 in Preparation Example 12

[0436] First Step: Synthesis of compound J3

[0437] Compound J1 (40 g, 184.95 mmol) was dissolved in N,N-dimethylformamide (800 mL) and cooled to 0 °C. Sodium hydride (18.49 g, 462.38 mmol, 60% purity) was slowly added under nitrogen protection and stirred at 0 °C for 0.5 hours. Then compound J2 (58.70 g, 462.38 mmol) was added dropwise into the reaction solution at 0 °C, and then stirred at 25 °C for 16 hours under nitrogen protection. LC-MS monitoring showed that the reaction was complete. The reaction mixture was quenched by adding saturated aqueous ammonium chloride solution (100 mL), and extracted with ethyl acetate (500 mL*3). The combined organic layer was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound J3 (45 g, 145.54 mmol, yield: 78.69%).

[0438] MS (ESI + )m / z = 309.2 [M+H] + .

[0439] Second Step: Synthesis of compound J4

[0440] Compound J3 (45 g, 145.54 mmol) was dissolved in a solution of trifluoroacetic acid (120 mL) and dichloromethane (480 mL) and stirred at 25 °C for 16 hours. The reaction was monitored by LC-MS until completion. The mixture was filtered and concentrated under reduced pressure to obtain compound J4 (14.8 g, 75.09 mmol, yield: 51.59%).

[0441] MS (ESI + )m / z = 197.1 [M+H] + .

[0442] Step 3. Synthesis of compound Int-12

[0443] Compound J4 (14.8 g, 75.09 mmol) was dissolved in tetrahydrofuran (200 mL), and 1,1'-carbonyldiimidazole (13.46 g, 83.00 mmol) was added portionwise, and stirred at 25 °C for 16 hours. Then sodium hydroxide aqueous solution (5 M, 45.27 mL) was added, and stirred at 25 °C for 16 hours. The reaction was monitored by LC-MS until completion. The mixture was adjusted to pH = 1 with 6 N hydrochloric acid, extracted with ethyl acetate (100 mL*2) and dichloromethane (100 mL*2), washed with saturated brine (100 mL*2) respectively, and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound Int-12 (10.6 g, 69.24 mmol, yield: 92.21%).

[0444] MS (ESI + )m / z = 153.1 [M+H] + .

[0445] Synthesis of intermediate compound Int-13 in Preparation Example 13

[0446] Compound K2 (450 mg, 2.6 mmol), bis(triphenylphosphine)palladium dichloride (129.6 mg, 184.07 μmol), cuprous iodide (70.1 mg, 368.13 μmol) and N,N-diisopropylethylamine (475.8 mg, 3.68 mmol, 641.20 μL) were added to a solution of compound C5 (600.0 mg, 1.75 mmol) in acetonitrile (5 mL) under nitrogen protection, and the reaction was carried out at room temperature for 2 hours. The reaction solution was poured into ethyl acetate (50 mL), washed with saturated brine (20 mL*3), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:3) to obtain compound Int-13 (561.4 mg, 1.45 mmol, yield: 83%).

[0447] MS (ESI + m / z = 387.2 [M+H] + .

[0448] Synthesis of intermediate compound Int-14 in Preparation 14

[0449] Compound 3-9 (50.0 mg, 70.8 μmol), compound C7 (61.5 mg, 141.6 μmol) and potassium carbonate (14.7 mg, 106.2 μmol) were added to a mixture solution of 1,4-dioxane (4 mL) and water (1 mL) and replaced by argon. [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (5.2 mg, 7.1 μmol) was added under argon atmosphere, the resulting mixture was heated to 80 °C under argon protection and stirred for 15 hours. After the reaction was completed, the reaction solution was filtered with diatomite, the filtrate was washed with saturated sodium chloride aqueous solution and extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, the obtained crude product was purified by reverse phase column chromatography (water: acetonitrile, gradient: 95 / 5 to 5 / 95) to obtain the title compound Int-14 (42.7 mg, 45.7 μmol, yield: 64.5%).

[0450] MS m / z (ESI): 933.4 [M+H] + .

[0451] Synthesis of intermediate compound Int-15 in Preparation 15

[0452] First step: Synthesis of compound L2

[0453] Compound L1 (1.1 g, 10.0 mmol) was dissolved in acetonitrile (10 mL), then potassium carbonate (2.4 g, 17.50 mmol) and 3-bromopropyne (1.77 g, 15.0 mmol) were added, and the mixture was reacted at 25 °C for 4 hours. The reaction solution was filtered, water (50 mL) was added to the filtrate, and ethyl acetate (50 mL*3) was extracted, the combined organic phase was dried over anhydrous sodium sulfate, filtered and rotary evaporated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 100:0-30:70) to obtain compound L2 (940.0 mg, 6.3 mmol, yield: 63.0%).

[0454] MS (ESI + m / z = 149.2 [M+H] + .

[0455] Second step: Synthesis of compound Int-15

[0456] Compound L2 (388.0 mg, 2.6 mmol), bis(triphenylphosphine)palladium dichloride (129.6 mg, 184.07 μmol), cuprous iodide (70.1 mg, 368.13 μmol) and N,N-diisopropylethylamine (475.8 mg, 3.68 mmol, 641.20 μL) were added to a solution of compound C5 (600.0 mg, 1.75 mmol) in acetonitrile (5 mL) under nitrogen protection, and the mixture was reacted at room temperature for 2 hours. The reaction solution was poured into ethyl acetate (50 mL), washed with saturated brine (20 mL*3), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:3) to obtain compound Int-15 (450.0 mg, 1.24 mmol, yield: 71.0%).

[0457] MS (ESI + )m / z = 362.2 [M+H] + .

[0458] Synthesis of intermediate compound Int-16 in Preparation Example 16

[0459] First step: Synthesis of compound M1

[0460] Under nitrogen protection, 2-(2-propargyloxy)tetrahydropyran (2.05 g, 14.62 mmol), compound C5 (5.00 g, 14.62 mmol), bis(triphenylphosphine)palladium dichloride (1.03 g, 1.46 mmol), cuprous iodide (278.4 mg, 1.46 mmol) and triethylamine (2.96 g, 29.24 mmol) were dissolved in tetrahydrofuran (20 mL), and the mixture was reacted at room temperature for 3 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, the residue was poured into water (100 mL), extracted with dichloromethane (80 mL*3), the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 100:0-35:65) to obtain compound M1 (4.50 g, 12.7 mmol, yield: 87%).

[0461] MS (ESI + )m / z = 354.0 [M+H] + .

[0462] Second step: Synthesis of compound M2

[0463] Compound Ml (4.50 g, 12.7 mmol) was dissolved in methanol (100 mL), then p-toluenesulfonic acid (4.38 g, 25.41 mmol) was added, the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, the residue was poured into water (80 mL), extracted with dichloromethane (60 mL*3), the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 100:0-34:66) to give compound M2 (2.80 g, 10.37 mmol, yield: 82%).

[0464] MS (ESI + )m / z = 270.0 [M+H] + .

[0465] Step 3 Synthesis of compound M3

[0466] Methylsulfonic anhydride (1.77 g, 10.18 mmol) was added to a solution of compound M2 (550.0 mg, 2.04 mmol) and N,N-diisopropylethylamine (2.11 g, 16.29 mmol) in dichloromethane (20 mL) at 0 °C, and the mixture was slowly warmed to room temperature and reacted for 2 hours. The reaction solution was poured into water (60 mL), extracted with dichloromethane (60 mL*3), the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give compound M3 (680.0 mg, 1.95 mmol, yield: 96%).

[0467] MS (ESI + )m / z = 347.9 [M+H] + .

[0468] Step 4 Synthesis of compound Int-16

[0469] Compound M3 (500.0 mg, 1.44 mmol), (R)-3-hydroxymethylmorpholine (218.6 mg, 1.87 mmol) and N,N-diisopropylethylamine (371.1 mg, 2.87 mmol, 501.6 μL) were added to dichloromethane (10 mL) at room temperature, and the mixture was reacted at room temperature for 4 hours. After the reaction was completed, water (30 mL) was added to the reaction solution, extracted with dichloromethane (30 mL*3), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (dichloromethane:methanol = 100:0-95:5) to give compound Int-16 (400.0 mg, 1.08 mmol, yield: 75%).

[0470] MS (ESI + )m / z = 369.0 [M+H] + .

[0471] Synthesis of intermediate compound Int-17 in Preparation Example 17

[0472] First Step: Synthesis of compound N2

[0473] Oxalyl chloride monoethyl ester (1.60 g, 11.74 mmol) was added dropwise to a solution of compound N1 (1.00 g, 11.74 mmol) and N,N-diisopropylethylamine (4.50 g, 35.23 mmol) in tetrahydrofuran (10.0 mL) at 0 °C, and the mixture was allowed to react at room temperature for 2 hours. The reaction was concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 100:0-70:30) to obtain compound N2 (1.00 g, 5.4 mmol, yield: 46.0%).

[0474] MS (ESI + )m / z = 186.1 [M+H] + .

[0475] Second Step: Synthesis of compound Int-17

[0476] Lithium hydroxide monohydrate (453.1 mg, 10.80 mmol) was added to a mixture of compound N2 (500.0 mg, 2.70 mmol) in water (2 mL) and tetrahydrofuran (6 mL) at room temperature, and the mixture was allowed to react at room temperature for 1 hour. After the reaction was completed, the reaction solution was adjusted to weakly acidic pH with dilute hydrochloric acid (1M), extracted with ethyl acetate (50 mL*3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound Int-17 (300.0 mg, 1.91 mmol, yield: 70.7%).

[0477] MS (ESI + )m / z = 158.1 [M+H] + .

[0478] Synthesis of intermediate compound Int-18 in Preparation Example 18

[0479] Compound M3 (680.0 mg, 1.95 mmol) was dissolved in dichloromethane (10 mL), then N,N-diisopropylethylamine (504.7 mg, 3.91 mmol) and (S)-3-hydroxymethylmorpholine (274.5 mg, 2.34 mmol) were added, and the mixture was reacted at room temperature for 4 hours. Water (30 mL) was added to the reaction solution, and dichloromethane (30 mL*3) was extracted. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (dichloromethane:methanol = 100:0-90:10) to obtain compound Int-18 (500.0 mg, 1.35 mmol, yield: 69.3%).

[0480] MS (ESI + )m / z = 369.0 [M+H] + .

[0481] Synthesis of intermediate compound Int-19 of Preparation Example 19

[0482] First step: Synthesis of compound P2

[0483] 2-amino-5-bromobenzaldehyde (5.0 g, 25.0 mmol) and ethyl nitroacetate (6.65 g, 49.99 mmol) were added to a mixed solution of acetic acid (20.0 mL) and water (20.0 mL), then piperidine (1.23 mL, 12.5 mmol) was added, and stirred at 100°C for 16 hours. After the reaction was completed, the mixture was added dropwise to ice water, and the precipitated solid was filtered, washed with pure water, and dried to obtain compound P2 (6.0 g, 22.3 mmol, yield: 89.2%).

[0484] MS (ESI + )m / z = 269.0 [M-H] - .

[0485] Second step: Synthesis of compound P3

[0486] Compound P2 (2.0 g, 7.43 mmol) and benzyl piperazine-1-carboxylate (2.46 g, 11.15 mmol) were added into tert-butyl alcohol (20.0 mL), then added methane sulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) palladium(II) (2'-amino-1,1'-biphenyl-2-yl) (590.2 mg, 743.3 μmol) and potassium tert-butoxide (2.5 g, 22.3 mmol), stirred at 90 °C for 16 hours under argon protection, the reaction was monitored by LC-MS. The mixture was filtered, the filtrate was added into water (50 mL), extracted with ethyl acetate (50 mL), concentrated to get the crude product. The crude product was purified by reverse phase (Water / NH4OH (0.5%):MeCN = 95:5 to 5:95) to get compound P3 (1.2 g, 2.94 mmol, yield: 39.5%).

[0487] MS (ESI + )m / z = 409.1 [M+H] + .

[0488] Step 3 Synthesis of compound P4

[0489] Compound P3 (1.2 g, 2.94 mmol) was added into phosphorus oxychloride (20.0 mL), stirred at 90 °C for 3 hours. After the reaction was completed, the mixture was added into ice water dropwise to quench the reaction, then extracted with ethyl acetate, the organic phase was concentrated to get the crude product. The crude product was purified by column chromatography (PE:EA = 1:1) to get compound P4 (500.0 mg, 1.17 mmol, yield: 39.8%).

[0490] MS (ESI + )m / z = 427.1 [M+H] + .

[0491] Step 4 Synthesis of compound P5

[0492] Compound P4 (500.0 mg, 1.17 mmol) was added into N,N-dimethylformamide (10.0 mL), then bis(triphenylphosphine)palladium dichloride (82.1 mg, 117.1 μmol), (1-ethoxyvinyl)trimethylstannane (846.0 mg, 3.58 mmol) were added, and the mixture was stirred at 110 °C under nitrogen protection for 1 hour. After the reaction was completed, hydrochloric acid 1,4-dioxane solution (10.0 mL, 4.0 M) was added into the reaction solution, and the mixture was stirred for 30 minutes. After the reaction was completed, the pH value of the reaction solution was adjusted to 7-8 with saturated sodium bicarbonate aqueous solution, and then the mixture was extracted with ethyl acetate. The obtained crude product was concentrated, and then purified by column chromatography (PE:EA = 3:1) to obtain compound P5 (380.0 mg, 874.7 μmol, yield: 74.7%).

[0493] MS (ESI + )m / z = 435.1 [M+H] + .

[0494] Step 5 Synthesis of compound P6

[0495] Compound P5 (330.0 mg, 759.5 μmol) and iron powder (849.4 mg, 15.19 mmol) were added into acetic acid (10.0 mL), and the mixture was stirred at 60 °C for 1 hour. After the reaction was completed, the residue was filtered off, and the filtrate was washed with saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The obtained crude product was concentrated, and then purified by reversed-phase silica gel column (Water / NH4OH (0.5%):MeCN = 95:5 to 5:95) to obtain compound P6 (280.0 mg, 692.2 μmol, yield: 91.1%).

[0496] MS (ESI + )m / z = 405.1 [M+H] + .

[0497] Step 6 Synthesis of compound P7

[0498] In an argon atmosphere and ice bath condition, triethylamine (744.5 mg, 7.36 mmol) and (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene) ruthenium chloride (39.0 mg, 61.3 μmol) were added to formic acid (67.7 mg, 1.47 mmol), heated to 40°C and stirred for 15 minutes. The reaction was cooled to room temperature and compound P6 (248.0 mg, 613.1 μmol) was added, then heated to 40°C and stirred for 2 hours. After the reaction was completed, the reaction was concentrated to obtain the crude product which was purified by reverse phase (Water / NH4OH (0.5%):MeCN = 95:5 to 5:95) to obtain compound P7 (196.0 mg, 482.1 μmol, yield: 78.6%).

[0499] MS (ESI + )m / z = 407.1 [M+H] + .

[0500] Seventh step Synthesis of compound P8

[0501] In an ice bath condition, p-toluenesulfonic acid (360.0 mg, 2.09 mmol) and compound P7 (170.0 mg, 418.23 μmol) were added to acetonitrile (10.0 mL), then an aqueous solution of sodium nitrite (144.3 mg, 2.09 mmol) and potassium iodide (347.1 mg, 2.09 mmol) was added dropwise to the system, stirred for 10 minutes in an ice bath, then transferred to room temperature and stirred for 1 hour. After the reaction was completed, saturated aqueous sodium sulfite was added to quench the reaction, and extracted with ethyl acetate, and the organic phase was concentrated to obtain the crude product which was purified by column chromatography (PE:EA = 3:1) to obtain compound P8 (132.0 mg, 255.1 μmol, yield: 61.0%).

[0502] MS (ESI + )m / z = 518.0 [M+H] + .

[0503] Eighth step Synthesis of compound Int-19

[0504] Compound P8 (150.0 mg, 289.9 µmol) was added to sodium hydride (23.2 mg, 579.9 µmol, 60% dispersion in paraffin liquid) in N,N-dimethylformamide (5.0 mL) under an argon atmosphere with ice-bath cooling, stirred for 10 minutes, then iodomethane (82.3 mg, 579.9 µmol) was added, then the mixture was allowed to warm to room temperature and stirring was continued for 1 hour. After the reaction was completed, the reaction solution was added dropwise to 0.5 M dilute hydrochloric acid, then extracted with ethyl acetate, and the crude product obtained by concentrating the organic phase was purified by column chromatography (PE:EA = 3:1) to obtain compound Int-19 (132.0 mg, 248.1 µmol, yield: 85.6%).

[0505] MS (ESI + )m / z = 532.0 [M+H] + .

[0506] Synthesis of intermediate compound Int-20 in Preparation Example 20

[0507] First step: Synthesis of compound Q2

[0508] Compound Q1 (6.00 g, 30.30 mmol) was dissolved in anhydrous ethyl acetate (80 mL), then m-chloroperoxybenzoic acid (10.46 g, 60.60 mmol) was added, and the reaction was carried out at room temperature for 30 minutes and then at 50°C for 5 hours. The reaction solution was filtered, the filter cake was washed with a small amount of ethyl acetate, and the filter cake was dried to obtain compound Q2 (5.60 g, 26.17 mmol, yield: 86.4%).

[0509] MS (ESI + )m / z = 213.9 [M+H] + .

[0510] Second step: Synthesis of compound Q3

[0511] Compound Q2 (5.40 g, 25.23 mmol) was dissolved in acetonitrile (100 mL), then trimethylsilyl cyanide (5.01 g, 50.46 mmol) and triethylamine (7.66 g, 75.69 mmol, 10.55 mL) were added, and the mixture was heated to 80°C and reacted for 12 hours. The reaction solution was concentrated, the residue was slurried with ethyl acetate (20 mL), the reaction solution was filtered, the filter cake was washed with a small amount of ethyl acetate, and the filter cake was dried to obtain compound Q3 (4.10 g, 18.39 mmol, yield: 73%).

[0512] MS (ESI + )m / z = 222.9 [M+H] + .

[0513] Step 3 Synthesis of compound Q4

[0514] Methylmagnesium bromide (3M, 18 mL) was added dropwise to a solution of compound Q3 (4.00 g, 17.93 mmol) in tetrahydrofuran (20 mL) at 0 °C, the mixture was warmed to room temperature and stirred for 3 hours, the reaction was poured into dilute hydrochloric acid (6M, 20 mL), the tetrahydrofuran was removed by reduced pressure concentration, water (60 mL) was added to the residue, dichloromethane (80 mL*3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and rotary evaporated, the residue was purified by column chromatography (dichloromethane:methanol = 100:0-90:10) to give compound Q4 (2.80 g, 11.66 mmol, yield: 65%).

[0515] MS (ESI + )m / z = 240.2 [M+H] + .

[0516] Step 4 Synthesis of compound Q5

[0517] Compound Q4 (1.4 g, 5.83 mmol) was dissolved in N,N-dimethylformamide (20 mL), then potassium carbonate (2.4 g, 17.50 mmol) and 4-((methylsulfonyl)oxy)piperidine-1-carboxylic acid benzyl ester (2.92 g, 9.33 mmol) were added, the mixture was reacted at 100 °C for 8 hours, the reaction was filtered, water (100 mL) was added to the filtrate, ethyl acetate (80 mL*3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and rotary evaporated, the residue was purified by column chromatography (petroleum ether: ethyl acetate = 100:0-50:50) to give compound Q5 (640.0 mg, 1.40 mmol, yield: 24%).

[0518] MS (ESI + )m / z = 457.0 [M+H] + .

[0519] Step 5 Synthesis of compound Q6

[0520] Formic acid (130.2 mg, 2.83 mmol) was added to triethylamine (1.43 g, 14.17 mmol, 1.97 mL) at 0 °C, and the mixture was exchanged with nitrogen three times, then (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanedi- amine (p-cymene) chlororuthenium (7.5 mg, 11.81 μmol) was added, and the mixture was stirred at 40 °C for 30 min, cooled to room temperature, then compound Q5 (540.0 mg, 1.18 mmol) was added, and the mixture was stirred at 40 °C for 2 h. The reaction mixture was concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 80:20-50:50) to give compound Q6 (480.0 mg, 1.04 mmol, yield: 89%).

[0521] MS (ESI + )m / z = 459.2 [M+H] + .

[0522] Seventh step Synthesis of compound Q8

[0523] Sodium hydride (51.5 mg, 1.25 mmol, 60% dispersion in paraffin liquid) was added to a solution of compound Q6 (480.0 mg, 1.04 mmol) in N,N-dimethylformamide (5 mL) at 0 °C, and the mixture was stirred at 0 °C for 1 h, then iodomethane (296.7 mg, 2.09 mmol) was added, and the mixture was stirred at 0 °C for 1 h. The reaction mixture was poured into saturated aqueous ammonium chloride solution (10 mL), then water (10 mL) was added, and the mixture was extracted with ethyl acetate (100 mL*3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to give compound Q7 (480.0 mg, 1.01 mmol, yield: 97%).

[0524] MS (ESI + )m / z = 473.0 [M+H] + .

[0525] Seventh step Synthesis of compound Q8

[0526] Compound Q7 (1.5 g, 3.17 mmol) in dichloromethane (5 mL) at room temperature, the mixture was warmed to 40 °C and stirred for 4 hours. When the reaction was completed, the reaction was dropped into saturated sodium bicarbonate solution (20 mL), then water (20 mL) was added, and the mixture was extracted with ethyl acetate (100 mL*3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 100:00-70:30) to give compound Q8 (1.40 g, 2.34 mmol, yield: 74%).

[0527] MS (ESI + )m / z = 599.0 [M+H] + .

[0528] Second Step Synthesis of compound Int-20

[0529] Copper(I) cyanide (56.2 mg, 627.51 μmol) was added to a solution of compound Q8 (300.0 mg, 500.62 μmol) in pyridine (2 mL) at room temperature, and the mixture was warmed to 100 °C and stirred for 8 hours. After the reaction was completed, the reaction was directly rotary evaporated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 80:20-50:50) to give compound Int-20 (180.0 mg, 361.18 μmol, yield: 72%).

[0530] MS (ESI + )m / z = 498.0 [M+H] + .

[0531] Synthesis of intermediate compound Int-21 in Preparation Example 21

[0532] First Step Synthesis of compound R2

[0533] Compound R1 (5.0 g, 21.37 mmol) was added to borane tetrahydrofuran complex (12.55 mL, 126.2 mmol, 1.0 M in THF) in batches under ice bath condition, and after the addition was completed, it was transferred to room temperature and stirred for 16.0 hours. After the reaction was completed, methanol was added dropwise to the reaction, which was quenched with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give compound R2 (4.2 g, 19.09 mmol, yield: 89.3%).

[0534] MS (ESI +m / z = 220.0 [M+H] + .

[0535] Step 2 - Synthesis of compound Int-21

[0536] Manganese dioxide (9.96 g, 114.53 mmol) was added to a solution of compound R2 (4.2 g, 19.09 mmol) in dichloromethane (180.0 mL) in batches under ice bath condition, and transferred to room temperature to stir for 16.0 hours after the addition was completed. After the reaction was completed, the reaction liquid was filtered to remove the residue through kieselguhr, and the organic phase was concentrated to obtain compound Int-21 (4.0 g, 18.35 mmol, yield: 96.1%).

[0537] MS (ESI + )m / z = 218.0 [M+H] + .

[0538] Synthesis of intermediate compound Int-22 in Preparation Example 22

[0539] Compound Int-22 was synthesized by using the similar synthetic route and procedure of Preparation Example 19, by replacing the raw material P1 with intermediate Int-21.

[0540] MS (ESI+) m / z = 550.0 [M+H]+.

[0541] Synthesis of intermediate compound Int-23 in Preparation Example 23

[0542] Step 1 - Synthesis of compound S1

[0543] Compound P2 (11.2 g, 41.6 mmol) was added to dichloromethane (300 mL) at room temperature, followed by the addition of triflic anhydride (17.6 g, 62.6 mmol), and the mixture was stirred at 25°C for 10 minutes. Then N,N-diisopropylethylamine (16.1 g, 128.9 mmol) was added dropwise at room temperature, and stirred at room temperature for 1 hour. After the reaction was completed, the reaction liquid was poured into water, extracted with dichloromethane (100 mL*3), and the combined organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 90:10) to obtain compound S1 (8.2 g, 20.3 mmol, yield: 48.8%).

[0544] MS (ESI + )m / z = 400.8 [M+H] + .

[0545] Step 2 - Synthesis of compound S2

[0546] Under argon atmosphere, bis(triphenylphosphine) palladium dichloride (1.4 g, 2.0 mmol) and (1-ethoxyvinyl)trimethylstannane (4.6 g, 19.3 mmol) were added to a solution of compound S1 (8.2 g, 20.3 mmol) in N,N-dimethylformamide (80.0 mL), then the mixture was stirred at 60 °C for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, hydrochloric acid ethanol solution (10.0 mL, 10.0 M) was added, and the mixture was stirred at 25 °C for 1 hour. Filtration was performed through diatomite, the filter cake was washed with ethyl acetate, the organic phases were combined, washed twice with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 85:15) to obtain compound S2 (2.0 g, 6.8 mmol, yield: 33.4%).

[0547] MS (ESI + )m / z = 295.2 [M+H] + .

[0548] Third step Synthesis of compound S3

[0549] Under argon atmosphere protection and ice bath conditions, triethylamine (24.7 g, 244.0 mmol) and (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene) ruthenium chloride (97.0 mg, 152.5 μmol) were added to formic acid (4.9 g, 101.7 mmol), the mixture was warmed to 50 °C and stirred for 0.5 hours. The reaction solution was cooled to room temperature and compound S2 (1.5 g, 5.1 mmol) was added, then the reaction solution was heated to 40 °C again and stirred for 2.0 hours. After the reaction was completed, the reaction solution was concentrated, ethyl acetate and aqueous sodium chloride solution were layered, the aqueous phase was extracted with ethyl acetate (200 mL*3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 100:0-60:40) to obtain compound S3 (293.0 mg, 1.1 mmol, yield: 21.6%).

[0550] MS (ESI + )m / z = 267.0 [M+H] + .

[0551] Fourth step Synthesis of compound S4

[0552] Compound S3 (293.0 mg, 1.1 mmol), 4-dimethylaminopyridine (13.4 mg, 109.7 μmol) and di-tert-butyl dicarbonate (287.3 mg, 1.3 mmol) were dissolved in anhydrous tetrahydrofuran (5 mL) and reacted at room temperature for 1 hour. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (50 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound S4 (402.0 mg, 1.1 mmol, yield: 99.8%).

[0553] MS (ESI + )m / z = 367.0 [M+H] + .

[0554] Fifth step Synthesis of compound S5

[0555] Compound S4 (165.0 mg, 449.3 μmol), potassium carbonate (155.2 mg, 1.1 mmol), cuprous iodide (8.6 mg, 44.9 μmol), triphenylphosphine (11.8 mg, 44.9 μmol) and palladium on carbon (27.3 mg, 10% loading) were dissolved in ethylene glycol dimethyl ether (3 mL) and water (3 mL) under argon protection. The mixture was stirred at room temperature for 0.5 hour under argon atmosphere, followed by the addition of 4-(prop-2-yn-1-yl)-1,4-oxazepane (156.4 mg, 1.1 mmol). The mixture was stirred at 100°C for 18 hours under argon protection. Water and ethyl acetate were added to the reaction solution, and the aqueous phase was discarded after separation. Water was added to the organic phase, and the pH was adjusted to 3 using dilute hydrochloric acid (2N). The aqueous phase was obtained after separation, and the pH was adjusted to 8 using saturated sodium bicarbonate. The organic phase was extracted with ethyl acetate (20 mL*3), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude compound S5 (113.0 mg), which was directly used in the next step.

[0556] MS (ESI + )m / z = 326.2 [M+H] + .

[0557] Sixth step Synthesis of compound S6

[0558] To a solution of compound S5 (113.0 mg, 347.3 μmol) in acetonitrile (5.0 mL) was added p-toluenesulfonic acid (330.3 mg, 1.7 mmol) at 0 °C, then a solution of sodium nitrite (119.8 mg, 1.7 mmol) and potassium iodide (288.2 mg, 1.7 mmol) in water (5 mL) was added dropwise. The mixture was stirred at 0 °C for 10 min, then was allowed to warm to room temperature and stirred for another 1.0 h. After the reaction was completed, the reaction was quenched by the addition of aqueous sodium sulfite solution, extracted with ethyl acetate (30 mL*3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the crude compound S6 (406.0 mg), which was used directly in the next step.

[0559] MS (ESI + )m / z = 437.0 [M+H] + .

[0560] Step 7 Synthesis of compound Int-23

[0561] To a solution of compound S6 (406.0 mg, 930.6 μmol) in anhydrous N,N- dimethylformamide (5.0 mL) was added sodium hydride (48.4 mg, 1.2 mmol, 60%) portion- wise at 0 °C. The mixture was stirred at 0 °C for 15 min, then iodomethane (158.5 mg, 1.1 mmol) was added. The mixture was allowed to warm to room temperature and stirred for another 1.0 h. After the reaction was completed, the reaction was quenched by the addition of saturated aqueous ammonium chloride solution, extracted with ethyl acetate (20 mL*2), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by reverse phase column chromatography (Water / NH4OH (0.5%):MeCN = 95:5 to 5:95) to give compound Int-23 (90.0 mg, 200.0 μmol, yield: 21.5%).

[0562] MS (ESI + )m / z = 451.0 [M+H] + .

[0563] Example 1 Synthesis of compound 1

[0564] To a solution of compound Int-4 (10 mg, 13.54 μmol), N,N- diisopropylethylamine (23.5 μL, 135.0 μmol) was added to a solution of 2- ethylbutanoic acid 1A (3.1 mg, 27.0 μmol) and (2-oximino-cyanoacetic acid ethyl ester)-N,N-dimethyl-morpholinyl urea hexafluorophosphate (11.5 mg, 27.0 μmol) in N,N-dimethylformamide (1.0 mL) at room temperature and stirred for 1 h. Ethyl acetate (5 mL) and water (5 mL) were added to extract, the organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase column (column: Boston Prime C18; 150*30 mm*5 μm; mobile phase A: H2O-(NH3H2O-NH4HCO3), NH3H2O concentration: 0.05%, NH4HCO3 concentration: 2 mM; mobile phase B: MeCN; MeCN ratio: 40%-60%) to give compound 1 (8.5 mg, 10.16 μmol, 75% yield).

[0565] MS (ESI + m / z = 839.5 [M+H] + .

[0566] 1 H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J = 2.8 Hz, 1H), 8.42 (s, 1H), 8.34 (d, J = 8.6 Hz, 1H), 7.83 (s, 1H), 7.74 (d, J = 8.6 Hz, 1H), 7.56 (d, J = 8.7 Hz, 1H), 7.23 (s, 1H), 5.92 (d, J = 11.1 Hz, 1H), 5.36-5.32 (m, 2H), 4.74 (d, J = 11.0 Hz, 1H), 4.53-4.49 (m, 1H), 4.33-4.28 (m, 1H), 4.21-4.12 (m, 2H), 3.58-3.53 (m, 2H), 3.30-3.27 (m, 3H), 3.26-3.24 (m, 1H), 3.22 (s, 3H), 2.95 (d, J = 14.3 Hz, 1H), 2.69-2.65 (m, 2H), 2.37-2.32 (m, 1H), 2.25 (s, 3H), 2.18-2.13 (m, 2H), 2.06-2.01 (m, 3H), 1.64-1.58 (m, 1H), 1.47-1.40 (m, 6H), 1.34 (d, J = 6.0 Hz, 3H), 0.96-0.91 (m, 9H), 0.90-0.84 (m, 7H).

[0567] Synthesis of compound 2 of example 2

[0568] Synthesis of the first step ethyl 2-((2S,5S)-2,5-dimethylpyrrolidin-1-yl)-2- oxoacetate (compound 2-2)

[0569] Compound 2-1 (1 g, 10.1 mmol), triethylamine (1.42 g, 14.06 mmol, 1.96 mL) were dissolved in dichloromethane (20 mL) and stirred, compound 2A (1.5 g, 11 mmol) was added dropwise to the reaction solution at 0 °C, then stirred at 25 °C for 2 hours, LC-MS monitoring reaction complete. Added ethyl acetate (100 mL) and water (100 mL) extraction, the organic phase was washed with saturated brine (100 mL), added anhydrous sodium sulfate drying, filtration, the filtrate was concentrated under reduced pressure, to obtain compound 2-2 (0.86 g, 4.3 mmol, yield: 42.57%).

[0570] MS (ESI + )m / z = 200.2 [M+H] + .

[0571] Synthesis of the second step 2-((2S,5S)-2,5-dimethylpyrrolidin-1-yl)-2-oxoacetic acid (compound 2-3)

[0572] Compound 2-2 (0.86 g, 4.3 mmol) was dissolved in tetrahydrofuran (5 mL) solution, LiOH.H2O (629.51 mg, 15 mmol) was dissolved in water (5 mL) and added to the reaction solution, stirred at 25 °C for 1 hour, LC-MS monitoring reaction complete. Added ethyl acetate (30 mL) and water (30 mL) extraction, the aqueous phase was adjusted to about pH 2 with 6M hydrochloric acid, added ethyl acetate (30 mL) extraction, the organic phase was washed with saturated brine (30 mL), added anhydrous sodium sulfate drying, filtration, the filtrate was concentrated under reduced pressure, to obtain compound 2-3 (460 mg, 2.68 mmol, yield: 62.3%).

[0573] MS (ESI + )m / z = 172.0 [M+H] + .

[0574] Synthesis of the third step compound 2

[0575] Compound 2-3 (5.68 mg, 32.92 umol), compound Int-4 (10 mg, 13.54 umol) were dissolved in DMF (1 mL), DIEA (21.28 mg, 164.62 umol, 28.67 uL), COMU (28.20 mg, 65.85 umol) were added portionwise, stirred at 25 °C for 2 hours. The reaction was monitored to completion. Ethyl acetate (5 mL) and water (5 mL) were added to extract, the organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the residue was purified by reverse phase column (column: Boston Prime C18; 150*30mm*5um; mobile phase A: H2O-(NH3H2O-NH4HCO3), NH3H2O concentration was 0.05%, NH4HCO3 concentration was 2mM; mobile phase B: MeCN; MeCN ratio 40%-60%) to obtain compound 2 (4.2 mg, 4.69 umol, yield: 34.63%).

[0576] MS (ESI + )m / z = 894.3 [M+H] + .

[0577] 1 H NMR (400 MHz, DMSO-d6) d 9.07 (d, J = 8.3 Hz, 1H), 8.44 (s, 1H), 8.41 (s, 1H), 7.84 (s, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.56 (d, J = 8.5 Hz, 1H), 7.22 (s, 1H), 6.06 (d, J = 11.6 Hz, 1H), 4.72 (d, J = 11.1 Hz, 1H), 4.54-4.50 (m, 2H), 4.38-4.23 (m, 1H), 4.21-4.08 (m, 3H), 3.60-3.50 (m, 2H), 3.48-3.42 (m, 2H), 3.21 (s, 3H), 2.92 (d, J = 14.3 Hz, 1H), 2.69-2.64 (m, 1H), 2.37-2.31 (m, 1H), 2.21 (s, 3H), 2.03-1.95 (m, 6H), 1.65-1.61 (m, 1H), 1.56-1.51 (m, 1H), 1.48-1.43 (m, 6H), 1.33 (d, J = 6.0 Hz, 3H), 1.16 (d, J = 6.4 Hz, 3H), 1.08 (d, J = 6.5 Hz, 3H), 0.93-0.87 (m, 6H), 0.86-0.81 (m, 6H).

[0578] Synthesis of compound 3 of example 3

[0579] First Step: Synthesis of 3-(5-bromo-lH-indol-3-yl)-2,2-dimethyl-l- propanol (Compound A6-1)

[0580] Compound A6 (10.4 g, 20.0 mmol) was dissolved in tetrahydrofuran (20 mL) at room temperature, and a solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 M, 50.0 mL) was added. The mixed solution was stirred at 60 °C for 16 hours. After the reaction was completed, the reaction solution was added dropwise to water to quench the reaction, and extracted with dichloromethane, and the organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:3) to obtain the title compound A6-1 (4.67 g, 16.6 mmol, yield: 83.0%).

[0581] MS m / z (ESI): 282.1 [M+H] + .

[0582] Second Step: Synthesis of 3-(5-bromo-lH-indol-3-yl)-2,2-dimethylpropyl acetate (Compound 3-1)

[0583] Acetic anhydride (1.28 mL, 13.11 mmol) was slowly added dropwise to a solution of compound A6-1 (3.7 g, 13.11 mmol), 4-dimethylaminopyridine (80.1 mg, 655.6 μmol), and triethylamine (3.98 g, 39.34 mmol) in dichloromethane (40.0 mL) under ice bath. The mixture was slowly warmed to room temperature and stirred for 6 hours. After the reaction was completed, the reaction solution was added dropwise to ice water to quench the reaction, and extracted with dichloromethane, and the organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain the title compound 3-1 (4.0 g, 12.34 mmol, yield: 94.0%).

[0584] MS m / z (ESI): 324.1 [M+H] + .

[0585] Third Step: Preparation of 2,2-dimethyl-3-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indol-3-yl)propyl acetate (Compound 3-2)

[0586] Compound 3-1 (4.6 g, 14.19 mmol), potassium acetate (3.48 g, 35.47 mmol) and bis(pinacolato)diboron (9.0 g, 35.47 mmol) were added to 1,4-dioxane (46.0 mL), then [1,1'-bis(diphenylphosphino)ferrocene] palladium(II) dichloride (1.04 g, 1.42 mmol) was added, and the mixture was purged with argon three times. The resulting mixture was heated to 90 °C under argon protection and stirred for 3 hours. After the reaction was completed, the reaction solution was filtered with diatomite, washed with ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain the title compound 3-2 (4.5 g, 12.12 mmol, yield: 85.4%).

[0587] MS m / z (ESI): 372.1 [M-H] + .

[0588] Fourth step: Preparation of (S)-3-(4-(3-(3-acetyloxy-2,2-dimethylpropyl)-1H-indol-5-yl)thiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propanoic acid methyl ester (compound 3-3)

[0589] Compound 3-2 (2.6 g, 7.0 mmol), compound B7 (2.81 g, 7.7 mmol) and potassium phosphate (3.71 g, 17.5 mmol) were dissolved in a mixed solution of dioxane (30.0 mL) and water (3.0 mL), and [1,1'-bis(diphenylphosphino)ferrocene] palladium(II) dichloride (452.2 mg, 618 μmol) was added to the reaction solution under nitrogen protection and purged with argon five times, and stirred at 90 °C for 12 hours. The reaction was monitored by LC-MS. After dilution with water (50 mL), extraction was performed with ethyl acetate (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase column chromatography (water: acetonitrile, gradient: 95 / 5 to 5 / 95) to obtain compound 3-3 (3.0 g, 5.66 mmol, yield: 80.9%).

[0590] MS m / z (ESI): 530.1 [M+H] + .

[0591] Fifth step: Preparation of (S)-3-(4-(3-(3-acetyloxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)thiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propanoic acid methyl ester (compound 3-4)

[0592] Compound 3-3 (3.7 g, 6.98 mmol) and N-iodosuccinimide (1.57 g, 6.99 mmol) were added to N,N-dimethylformamide (40.0 mL), warmed to 50 °C, and stirred for 2 hours. After the reaction was completed, the reaction solution was poured into water (400.0 mL) and extracted with ethyl acetate (50.0 mL) three times. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by reverse phase column chromatography (water: acetonitrile, gradient: 95 / 5 to 5 / 95) to obtain the title compound 3-4 (2.6 g, 3.97 mmol, yield: 56.77%).

[0593] MS m / z (ESI): 656.5 [M-H] + .

[0594] Sixth step: Preparation of (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(3-(3- hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)thiazol-2-yl)propanoic acid (Compound 3-5)

[0595] Compound 3-4 (2.6 g, 3.97 mmol) was dissolved in a mixed solution of tetrahydrofuran (30 mL) and water (5 mL), and lithium hydroxide (474.9 mg, 19.8 mmol) was added to the reaction solution. The mixture was stirred at 25 °C for 16 hours, and the reaction was completed by LC-MS monitoring. The organic solvent was removed by distillation under reduced pressure, and the solution was diluted with ethyl acetate and water. The aqueous phase was adjusted to a pH of about 6 with 1M aqueous HC1 solution, and extracted with ethyl acetate (30.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 3-5 (2.3 g, 3.84 mmol, yield: 96.7%).

[0596] MS m / z (ESI): 600.0 [M+H] + .

[0597] Seventh step: Preparation of (S)-2-((S)-2-(tert-butoxycarbonyl)amino)-3-(4-(3-(3- hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)thiazol-2-yl)propanoyl)-2,3- diazabicyclo[3.1.1]heptane-4-carboxylic acid methyl ester (Compound 3-6)

[0598] Compound 3-5 (393.0 mg, 655.2 μmol), compound Int-5 (265.0 mg, 1.7 mmol), N,N-diisopropylethylamine (1.69 g, 13.11 mmol) and 2-(7-azabenzotriazol-1- yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (370.8 mg, 975.3 μmol) were added to a solution of N,N-dimethylformamide (8.0 mL) and stirred at room temperature for 2 hours. After the reaction was completed, the crude product was purified by reverse phase column chromatography (water:acetonitrile, gradient: 95 / 5 to 5 / 95) to obtain the title compound 3-6 (290.0 mg, 393.1 μmol, yield: 60.0%).

[0599] MS m / z (ESI): 738.1 [M+H] + .

[0600] Eighth step: Preparation of (S)-2-((S)-2-((tert-butoxycarbonyl)amino)-3-(4-(3-(3- hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)thiazol-2-yl)propanoyl)-2,3- diazabicyclo[3.1.1]octane-4-carboxylic acid (Compound 3-7)

[0601] Compound 3-6 (290 mg, 393.1 μmol) was dissolved in a mixed solution of tetrahydrofuran (2.0 mL) and water (2.0 mL), and lithium hydroxide (94.1 mg, 3.93 mmol) was added to the reaction solution, which was stirred at 25°C for 2 hours. The reaction was monitored by LC-MS, and after the reaction was completed, the reaction solution was diluted with ethyl acetate and water, and the aqueous phase was adjusted to a pH of about 6 with 1M aqueous HC1 solution. Ethyl acetate was added to the reaction solution, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 3-7 (200.0 mg, 276.4 μmol, yield: 70.3%).

[0602] MS m / z (ESI): 724.1 [M+H] + .

[0603] Ninth step: Preparation of compound 3-8

[0604] Compound 3-7 (140.0 mg, 193.4 μmol), N-methylimidazole (794.2 mg, 9.67 mmol) and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (298.5 mg, 1.06 mmol) were added to a mixture solution of N,N-dimethylformamide (1.2 mL) and acetonitrile (12.0 mL) and stirred at room temperature for 2 hours. After the reaction was completed, the crude product was purified by reverse phase column chromatography (water: acetonitrile, gradient: 95 / 5 to 5 / 95) to obtain the title compound 3-8 (44.0 mg, 62.3 μmol, yield: 32.2%).

[0605] MS m / z (ESI): 706.2 [M+H] + .

[0606] Tenth step: Preparation of compound 3-9

[0607] Compound 3-8 (98.0 mg, 138.0 μmol), potassium acetate (19.47 mg, 198.4 μmol), 2-dicyclohexylphosphino-2',6'-dimethoxy-biphenyl (11.6 mg, 28.3 μmol) and tris(dibenzylideneacetone)dipalladium (10.3 mg, 11.3 μmol) were added to 1,4-dioxane (4.0 mL) and replaced with argon three times. The mixture was cooled to 0°C in an ice bath and a solution of pinacolborane (58.0 mg, 453.5 μmol) in 1,4-dioxane (4.0 mL) was added dropwise to the mixture under an argon atmosphere, and then the reaction solution was heated to 50°C and stirred for 3 hours. After the reaction was completed, the reaction solution was filtered with celite, the filtrate was washed with saturated aqueous sodium chloride solution and extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a crude product which was purified by reverse phase column chromatography (water: acetonitrile, gradient: 95 / 5 to 5 / 95) to obtain the title compound 3-9 (25.0 mg, 35.4 μmol, yield: 25.6%).

[0608] MS m / z (ESI): 706.1 [M+H] + .

[0609] Eleventh step: Preparation of compound 3-10

[0610] Compound 3-9 (25.0 mg, 35.4 μmol), compound Int-6 (18.0 mg, 53.1 μmol) and potassium carbonate (14.7 mg, 106.2 μmol) were added to a mixture solution of 1,4-dioxane (3.6 mL) and water (0.9 mL) and replaced by argon. Under argon atmosphere, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (5.2 mg, 7.1 μmol) was added and the resulting mixture was heated to 70 °C under argon atmosphere and stirred for 16 hours. After the end of the reaction, the reaction mixture was filtered on celite, the filtrate was washed with saturated aqueous sodium chloride solution and extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude obtained was purified by reverse phase column chromatography (water: acetonitrile, gradient: 95 / 5 to 5 / 95) to give the title compound 3-10 (21.0 mg, 25.0 μmol, yield: 70.7%).

[0611] MS m / z (ESI): 838.2 [M+H] + .

[0612] Twelfth step: Preparation of compound 3-11

[0613] Compound 3-10 (25.0 mg, 29.8 μmol) and cesium carbonate (24.5 mg, 75.2 μmol) were added to N,N-dimethylformamide (2.0 mL) and replaced by argon. Under argon atmosphere, iodoe thane (5.8 mg, 37.5 μmol) was added dropwise to the reaction mixture and the resulting mixture was stirred at room temperature for 3 hours. After the end of the reaction, the organic phase was dried and concentrated. The crude obtained was purified by reverse phase column chromatography (water: acetonitrile, gradient: 95 / 5 to 5 / 95) to give the title compound 3-11 (16.0 mg, 18.4 μmol, yield: 61.7%).

[0614] MS m / z (ESI): 866.3 [M+H] + .

[0615] Thirteenth step: Preparation of compound 3-12

[0616] To a solution of compound 3-11 (16.0 mg, 18.4 μmol) in dichloromethane (2.0 mL) was added slowly and dropwise trifluoroacetic acid (0.7 mL) at room temperature and the mixture was stirred at room temperature for 1 hour. After the end of the reaction, the reaction mixture was concentrated to dryness and washed with aqueous sodium bicarbonate solution and extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound 3-12 (14.0 mg, 18.2 μmol, yield: 98.9%).

[0617] MS m / z (ESI): 766.2 [M+H]+ .

[0618] Fourteenth step: preparation of compounds 3-P1 and 3-P2

[0619] Compound 3-12 (14.0 mg, 18.2 μmol) and N,N-diisopropylethylamine (23.6 μL, 135.0 μmol) were added successively to a solution of 2-ethylbutanoic acid (6.3 mg, 54.8 μmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (8.2 mg, 21.9 μmol) in N,N-dimethylformamide (1.0 mL) and stirred at room temperature for 1 hour. After the reaction was completed, compounds 3-P1 (3.5 mg, 4.0 μmol, yield: 22.1%, retention time: 8.5 min) and 3-P2 (3.0 mg, 3.4 μmol, yield: 19.0%, retention time: 9.07 min) were obtained after purification by reverse phase column (chromatography column: Boston Prime C18; 150*30 mm*5 μm; mobile phase A: H2O-(NH3H2O), NH3H2O concentration: 0.05%; mobile phase B: MeCN; MeCN ratio: 50%-75%).

[0620] Compound 3-P1 MS (ESI + )m / z = 864.3 [M+H] + .

[0621] 1H NMR (400 MHz, CDC13) δ 8.84 (d, J = 2.0 Hz, 1H), 8.41 (d, J = 1.5 Hz, 1H), 7.69 (d, J = 2.1 Hz, 1H), 7.61 (dd, J = 8.6, 1.6 Hz, 1H), 7.37 - 7.30 (m, 2H), 6.70 (d, J = 8.4 Hz, 1H), 5.52 (m, 1H), 5.29 (d, J = 10.7 Hz, 1H), 4.90 (d, J = 10.7 Hz, 1H), 4.73 (q, J = 4.9 Hz, 1H), 4.10 (q, J = 6.3 Hz, 1H), 3.99 (m, 1H), 3.78 (t, J = 4.7 Hz, 4H), 3.75 - 3.70 (m, 1H), 3.69 (d, J = 3.4 Hz, 2H), 3.54 (s, 2H), 3.46 (m, 1H), 3.26 (s, 3H), 3.21 (d, J = 14.4 Hz, 1H), 3.10 (m, 1H), 2.78 (q, J = 5.9 Hz, 1H), 2.65 (t, J = 4.6 Hz, 4H), 2.58 (m, 1H), 2.42 (m, 1H), 2.31 (d, J = 14.3 Hz, 1H), 2.05 (m, 3H), 1.79 - 1.62 (m, 7H), 1.60 - 1.48 (m, 3H), 1.28 (s, 3H), 1.23 (d, J = 6.3 Hz, 3H), 1.01 (t, J = 7.4 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H).

[0622] Compound 3-P2 MS (ESI + m / z = 864.3 [M+H] +

[0623] 1H NMR (400 MHz, CDC13) δ 8.81 (d, J = 2.1 Hz, 1H), 8.41 (d, J = 1.6 Hz, 1H), 7.67 (d, J = 2.2 Hz, 1H), 7.61 (m, 1H), 7.36 (d, J = 8.6 Hz, 1H), 7.31 (s, 1H), 6.61 (d, J = 8.6 Hz, 1H), 5.59 (m, 1H), 5.31 (d, J = 10.7 Hz, 1H), 4.86 (d, J = 10.8 Hz, 1H), 4.73 (q, J = 4.9 Hz, 1H), 4.34 (q, J = 6.0 Hz, 1H), 4.19 (m, 2H), 3.78 (t, J = 4.6 Hz, 4H), 3.71 (d, J = 10.9 Hz, 1H), 3.62 (d, J = 10.9 Hz, 1H), 3.54 (s, 2H), 3.46 (m, 1H), 3.18-3.09 (m, 2H), 2.75 (q, J = 5.9 Hz, 1H), 2.66 (t, J = 4.7 Hz, 4H), 2.58 (m, 1H), 2.42 (m, 2H), 2.11 (m, 1H), 2.04 (m, 1H), 1.78-1.63 (m, 8H), 1.62-1.49 (m, 8H), 1.43 (d, J = 6.1 Hz, 3H), 1.01 (t, J = 7.4 Hz, 3H), 0.95-0.91 (m, 4H).

[0624] Synthesis of compound 4 of Example 4

[0625] Compound 3-12 (20.0 mg, 26 μmol) and N,N-diisopropylethylamine (23.6 μL, 135.0 μmol) were added to a solution of compound 2-3 (9.0 mg, 52 μmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (20.0 mg, 52 μmol) in N,N-dimethylformamide (1.0 mL) successively, and stirred at room temperature for 3 hours. After the reaction was completed, compound 4 (3.0 mg, 3.2 μmol, yield: 15%) was obtained after purification by a reverse phase column (chromatography column: Boston Prime C18; 150*30 mm*5 μm; mobile phase A: H2O-(NH3H2O), NH3H2O concentration: 0.05%; mobile phase B: MeCN; MeCN ratio: 50%-80%).

[0626] MS m / z (ESI): 919.4 [M+H] + .

[0627] 1H NMR (400 MHz, CDC13) δ 8.81 (d, J = 2.1 Hz, 1H), 8.43 (d, J = 1.6 Hz, 1H), 8.20 (d, J = 9.3 Hz, 1H), 7.67 (d, J = 2.1 Hz, 1H), 7.62 (dd, J = 8.6, 1.6 Hz, 1H), 7.36 (d, J = 8.6 Hz, 1H), 7.33 (s, 1H), 5.65 - 5.58 (m, 1H), 5.33 (d, J = 10.7 Hz, 1H), 5.10 - 5.04 (m, 1H), 4.89 - 4.84 (m, 1H), 4.77 - 4.71 (m, 1H), 4.41 - 4.30 (m, 2H), 4.25 - 4.15 (m, 2H), 3.82 - 3.76 (m, 4H), 3.74 - 3.70 (m, 1H), 3.62 (d, J = 10.9 Hz, 1H), 3.54 (s, 2H), 3.52 - 3.45 (m, 1H), 3.39 (s, 3H), 3.29 - 3.21 (m, 1H), 3.18 - 3.11 (m, 1H), 2.77 - 2.72 (m, 1H), 2.71 - 2.62 (m, 4H), 2.60 - 2.54 (m, 1H), 2.49 - 2.39 (m, 2H), 2.25 - 2.17 (m, 1H), 2.15 - 2.06 (m, 2H), 1.71 - 1.69 (m, 1H), 1.56 - 1.53 (m, 1H), 1.44 (d, J = 6.1 Hz, 3H), 1.26 - 1.23 (m, 3H), 1.12 (d, J = 6.4 Hz, 3H), 1.00 - 0.90 (m, 6H), 0.40 (s, 3H).

[0628] Synthesis of compound 5 of example 5

[0629] To a solution of compound Int-4 (23.0 mg, 31.04 μmol), N,N- diisopropylethylamine (23.5 μL, 135.0 μmol) in compound 4-fluoro-2-(2- fluoroethyl)butanoic acid (6.2 mg, 40.6 μmol) and (2-oximino-cyanoacetic acid ethyl ester)-N,N-dimethyl-morpholinyl urea hexafluorophosphate (23 mg, 54.0 μmol) in N,N-dimethylformamide (1.0 mL) was stirred at room temperature for 1 hour. Added ethyl acetate (5 mL) and water (5 mL) to extract, the organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the residue was purified by reverse phase column (column: Boston Prime C18; 150*30mm*5μm; mobile phase A: H2O-(NH3H2O-NH4HCO3), NH3H2O concentration was 0.05%, NH4HCO3 concentration was 2mM; mobile phase B: MeCN; MeCN ratio 40%-80%) to give compound 5 (6 mg, 6.8 μmol, yield: 22%).

[0630] MS m / z (ESI): 875.4 [M+H] + .

[0631] 1H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J = 8.4 Hz, 1H), 8.44 (d, J = 2.9 Hz, 1H), 8.41 (d, J = 1.6 Hz, 1H), 7.85 (s, 1H), 7.74 (dd, J = 8.9, 1.8 Hz, 1H), 7.56 (d, J = 8.7 Hz, 1H), 7.22 (d, J = 2.9 Hz, 1H), 5.95 (d, J = 11.1 Hz, 1H), 5.27 (t, J = 7.8 Hz, 1H), 4.73 (d, J = 11.0 Hz, 1H), 4.57 - 4.47 (m, 3H), 4.42 (s, 1H), 4.33 - 4.26 (m, 1H), 4.20 - 4.11 (m, 2H), 3.61 - 3.49 (m, 2H), 3.28 - 3.25 (m, 4H), 3.22 (s, 3H), 2.95 (d, J = 14.4 Hz, 1H), 2.71 - 2.63 (m, 2H), 2.48 - 2.44 (m, 4H), 2.38 - 2.31 (m, 1H), 2.22 (s, 3H), 2.19 - 2.13 (m, 1H), 2.06 - 1.94 (m, 1H), 1.92 - 1.80 (m, 3H), 1.66 - 1.59 (m, 1H), 1.40 - 1.32 (m, 5H), 1.28 - 1.18 (m, 3H), 0.94 - 0.86 (m, 6H), 0.32 (s, 2H).

[0632] Synthesis of compound 6 of Example 6

[0633] First Step: Synthesis of compound 6-1

[0634] Compound D8 (40.0 mg, 48.37 μmol), (1-ethoxycyclopropyl)trimethylsilane (16.9 mg, 96.73 μmol), sodium cyanoborohydride (9.1 mg, 145.10 μmol) and acetic acid (5.8 mg, 96.73 μmol) were added into isopropanol (1 mL), the mixture was stirred at 50 °C overnight, after the reaction was completed, the reaction solution was spin dried, the residue was purified by silica gel column chromatography (dichloromethane:methanol = 30:1) to give compound 6-1 (20.0 mg, 23.07 μmol, 47.5% yield).

[0635] MS: m / z (ESI): 867.5 [M+H] + .

[0636] Second Step: Synthesis of compound 6-2

[0637] Compound 6-1 (20.0 mg, 23.07 μmol) was dissolved in hydrochloric acid dioxane solution (4 M, 2 mL), the mixture was stirred at room temperature for 2 hours, the reaction conversion was monitored by LC-MS. The reaction solution was directly spin-dried to obtain compound 6-2 (15.0 mg, 19.5 μmol, yield 84.5%).

[0638] MS: m / z (ESI): 767.4 [M+H] + .

[0639] Step 3: synthesis of compound 6

[0640] Compound 6-2 (12.0 mg, 15.65 μmol), N,N-diisopropylethylamine (10.1 mg, 78.23 μmol, 13.6 μL) were added to a solution of 2-ethylbutyric acid 1A (3.6 mg, 31.29 μmol) and (2-oximino-cyanoacetic acid ethyl ester)-N,N-dimethyl-morpholinyl urea hexafluorophosphate (20.1 mg, 46.94 μmol) in N,N-dimethylformamide (1.0 mL) successively, and stirred at room temperature for 1 hour. Ethyl acetate (5 mL) and water (5 mL) were added for extraction, the organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by reversed-phase column (chromatography column: Boston Prime C18; 150*30 mm*5 μm; mobile phase A: H2O-(NH3H2O-NH4HCO3), NH3H2O concentration was 0.05%, NH4HCO3 concentration was 2 mM; mobile phase B: MeCN; MeCN ratio 30%-70%) to obtain compound 6 (6 mg, 6.89 μmol, yield: 44%).

[0641] MS (ESI + )m / z = 865.4 [M+H] + .

[0642] 1H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J = 2.9 Hz, 1H), 8.41 (d, J = 1.5 Hz, 1H), 8.33 (d, J = 8.7 Hz, 1H), 7.83 (s, 1H), 7.73 (dd, J = 8.6, 1.6 Hz, 1H), 7.56 (d, J = 8.7 Hz, 1H), 7.21 (d, J = 2.9 Hz, 1H), 5.92 (d, J = 11.1 Hz, 1H), 5.37 - 5.29 (m, 2H), 4.73 (d, J = 11.1 Hz, 1H), 4.56 - 4.44 (m, 1H), 4.34 - 4.23 (m, 1H), 4.23 - 4.10 (m, 2H), 3.55 - 3.52 (m, 2H), 3.22 - 3.21 (m, 3H), 2.94 (d, J = 14.4 Hz, 1H), 2.69 - 2.66 (m, 4H), 2.36 - 2.31 (m, 1H), 2.20 - 2.10 (m, 2H), 2.03 - 1.94 (m, 1H), 1.70 - 1.59 (m, 2H), 1.56 - 1.35 (m, 6H), 1.33 (d, J = 6.1 Hz, 4H), 0.96 - 0.81 (m, 15H), 0.47 - 0.40 (m, 2H), 0.37 - 0.27 (m, 5H).

[0643] Synthesis of compound 7 of example 7

[0644] Compound 6-2 (10.0 mg, 12.45 μmol), N,N-diisopropylethylamine (8.0 mg, 62.23 μmol, 10.84 μL) were added into a solution of 2,3-dimethylbutanoic acid (2.9 mg, 24.89 μmol) and (2-hydroxyimino-cyanoacetic acid ethyl ester)-N,N-dimethyl-morpholinyl urea hexafluorophosphate (16.0 mg, 37.34 μmol) in N,N-dimethylformamide (1.0 mL) successively, stirred at room temperature for 2 hours. Ethyl acetate (5 mL) and water (5 mL) were added to extract, the organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase column (Boston Prime C18; 150*30 millimeter*5 microns; mobile phase A: H2O-(NH3H2O-NH4HCO3), NH3H2O concentration was 0.05%, NH4HCO3 concentration was 2 mM; mobile phase B: MeCN; MeCN ratio 30%-80%) to obtain compound 7 (1.6 mg, 1.87 μmol, yield: 15%).

[0645] MS (ESI + )m / z = 865.4 [M+H]+ .

[0646] 1 H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J = 2.9 Hz, 1H), 8.41 (d, J = 5.8 Hz, 1H), 8.30 - 8.23 (m, 1H), 7.83 (d, J = 5.2 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 8.7 Hz, 1H), 7.21 (d, J = 2.8 Hz, 1H), 5.99 - 5.89 (m, 1H), 5.36 - 5.27 (m, 1H), 4.72 (d, J = 10.9 Hz, 1H), 4.53 - 4.47 (m, 1H), 4.22 - 4.10 (m, 2H), 3.56 - 3.51 (m, 2H), 3.22 - 3.20 (m, 8H), 2.98 - 2.89 (m, 1H), 2.74 - 2.61 (m, 6H), 2.35 - 2.29 (m, 1H), 1.69 - 1.60 (m, 1H), 1.33 (d, J = 6.1 Hz, 3H), 1.28 - 1.21 (m, 5H), 1.07 (d, J = 7.0 Hz, 2H), 1.01 - 0.94 (m, 3H), 0.93 - 0.81 (m, 12H), 0.48 - 0.40 (m, 2H), 0.36 - 0.28 (m, 5H).

[0647] Synthesis of compound 8 of example 8

[0648] Compound 6-2 (47.7 mg, 62.23 μmol), N,N-diisopropylethylamine (40.2 mg, 311.16 μmol, 54.2 μL) were added into a solution of compound 4-fluoro-2-(2-fluoroethyl)butanoic acid (18.9 mg, 124.46 μmol) and (2-oximino-cyanoacetic acid ethyl ester)-N,N-dimethyl-morpholinyl urea hexafluorophosphate (COMU) (80.0 mg, 186.69 μmol) in N,N-dimethylformamide (1.0 mL) successively, stirred at room temperature for 4 hours. Ethyl acetate (5 mL) and water (5 mL) were added to extract, the organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase column (Boston Prime C18; 150*30 millimeter*5 microns; mobile phase A: H2O-(NH3H2O-NH4HCO3), NH3H2O concentration was 0.05%, NH4HCO3 concentration was 2 mM; mobile phase B: MeCN; MeCN ratio 35%-85%) to obtain compound 8 (14 mg, 15.53 μmol, yield: 25%).

[0649] MS m / z (ESI): 901.4 [M+H] + .

[0650] 1 H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J = 8.5 Hz, 1H), 8.44 (d, J = 2.9 Hz, 1H), 8.41 (d, J = 1.6 Hz, 1H), 7.84 (s, 1H), 7.73 (dd, J = 8.7, 1.7 Hz, 1H), 7.56 (d, J = 8.7 Hz, 1H), 7.21 (d, J = 2.9 Hz, 1H), 5.95 (d, J = 11.1 Hz, 1H), 5.27 (t, J = 7.7 Hz, 1H), 4.72 (d, J = 11.0 Hz, 1H), 4.57 - 4.48 (m, 3H), 4.44 - 4.39 (m, 1H), 4.33 - 4.24 (m, 1H), 4.19 - 4.10 (m, 2H), 3.59 - 3.50 (m, 2H), 3.24 - 3.20 (m, 7H), 2.98 - 2.90 (m, 1H), 2.73 - 2.61 (m, 7H), 2.38 - 2.29 (m, 1H), 2.21 - 2.12 (m, 1H), 2.05 - 1.94 (m, 1H), 1.94 - 1.78 (m, 4H), 1.69 - 1.58 (m, 2H), 1.38 - 1.30 (m, 4H), 1.27 - 1.19 (m, 2H), 0.93 - 0.85 (m, 6H), 0.47 - 0.40 (m, 2H), 0.34 - 0.30 (m, 4H).

[0651] Synthesis of compound 9

[0652] First step: synthesis of compound 9-1

[0653] Compound D8 (40.0 mg, 48.37 μmol), 3-oxetanone (7.0 mg, 97 μmol), sodium cyanoborohydride (6.0 mg, 97 μmol) and acetic acid (9.0 mg, 145 μmol) were added into isopropanol (3 mL), the mixture was reacted at room temperature for 2 hours, after the reaction was completed, the reaction solution was spin dried, the residue was purified by silica gel column chromatography (dichloromethane:methanol = 30:1) to obtain compound 9-1 (38.0 mg, 43 μmol, yield 89%).

[0654] MS: m / z (ESI): 883.4 [M+H] + .

[0655] Second step: synthesis of compound 9-2

[0656] Compound 9-1 (38.0 mg, 43 μmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added dropwise to the solution at 0 °C, the mixture was stirred at room temperature for 2 hours, the reaction solution was concentrated under reduced pressure, the residue was poured into saturated sodium bicarbonate solution (20 mL), extracted with dichloromethane (10 ml x 3), the combined organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated to obtain compound 9-2 (32.0 mg, 40.85 μmol, yield 95%).

[0657] MS: m / z (ESI): 783.4 [M+H] + .

[0658] Step 3: synthesis of compound 9

[0659] Compound 9-2 (40.0 mg, 51 μmol), 2-ethylbutyric acid (9.0 mg, 76 μmol), triethylamine (10.0 mg, 98.8 μmol) and 2-(7-azobenzo triazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (39.0 mg, 102 μmol) were dissolved in N,N-dimethylformamide (2 mL), the mixture was reacted at room temperature overnight, the reaction solution was poured into water (10 mL), extracted with ethyl acetate (10 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated, and the residue was purified by reversed-phase column (the chromatographic column was Boston Prime C18; 150*30 mm*5 μm; mobile phase A: H2O-(NH3H2O-NH4HCO3), NH3H2O concentration was 0.05%, NH4HCO3 concentration was 2 mM; mobile phase B: MeCN; MeCN ratio 30%-80%) to obtain compound 9 (10.0 mg, 11.22 μmol, yield: 22%).

[0660] MS (ESI + )m / z = 881.5 [M+H] + .

[0661] 1H NMR (400 MHz, CDC13) δ 8.49 (d, J = 2.9 Hz, 1H), 8.39 (d, J = 1.6 Hz, 1H), 7.60 (dd, J = 8.6, 1.6 Hz, 1H), 7.35 (d, J = 8.6 Hz, 1H), 7.30 (s, 1H), 7.08 (d, J = 3.0 Hz, 1H), 6.62 (d, J = 8.6 Hz, 1H), 5.64 - 5.56 (m, 1H), 5.32 (d, J = 10.8 Hz, 1H), 4.84 (d, J = 10.7 Hz, 1H), 4.76 - 4.73 (m, 1H), 4.73 - 4.68 (m, 2H), 4.65 (t, J = 6.2 Hz, 2H), 4.32 - 4.23 (m, 2H), 4.20 - 4.12 (m, 1H), 3.72 (d, 1H), 3.62 (d, J = 10.7 Hz, 1H), 3.60 - 3.55 (m, 1H), 3.48 - 3.43 (m, 1H), 3.35 (s, 3H), 3.34 - 3.28 (m, 4H), 3.16 - 3.12 (m, 1H), 3.12 - 3.08 (m, 1H), 2.78 - 2.71 (m, 1H), 2.58 - 2.52 (m, 4H), 2.49 - 2.38 (m, 2H), 2.16 - 2.09 (m, 1H), 2.08 - 2.02 (m, 1H), 2.01 - 1.94 (m, 1H), 1.62 - 1.59 (m, 1H), 1.56 - 1.50 (m, 2H), 1.43 (d, J = 6.1 Hz, 3H), 1.01 (t, J = 7.4 Hz, 3H), 0.98 - 0.96 (m, 2H), 0.96 - 0.94 (m, 5H), 0.94 - 0.93 (m, 2H), 0.93 - 0.91 (m, 1H), 0.41 (s, 3H).

[0662] Synthesis of compound 10 of example 10

[0663] First step: synthesis of compound 10-1

[0664] Compound D8 (50.0 mg, 60.46 μmol), N-methyl-4-piperidone (13.7 mg, 120.91 μmol), sodium cyanoborohydride (11.4 mg, 181.37 μmol), acetic acid (7.3 mg, 120.91 μmol, 7.0 μL) were added into isopropanol (2 mL). The reaction was stirred at 50 °C overnight. After monitoring the reaction was finished by LC-MS, the reaction was spin dried, the residue was purified by silica gel column chromatography (dichloromethane:methanol = 30:1) to give compound 10-1 (29.0 mg, 31.38 μmol, 52% yield).

[0665] MS: m / z (ESI): 924.5 [M+H] + .

[0666] Second Step: Synthesis of compound 10-2

[0667] Compound 10-1 (29.0 mg, 31.38 µmol) was added to a solution of hydrochloric acid dioxane (4 M, 5 mL). The reaction was stirred at room temperature. After the reaction was monitored to be completed by LC-MS, the reaction was directly spin dried to get compound 10-2 (25.0 mg, 30.34 µmol, yield 97%).

[0668] MS: m / z (ESI): 824.4 [M+H] + .

[0669] Third Step: Synthesis of compound 10

[0670] Compound 10-2 (25.0 mg, 30.34 µmol), 2-ethylbutyric acid (7.1 mg, 60.67 µmol), 2-(7-azobenzo-triazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (33.1 mg, 87.15 µmol) and N,N-diisopropylethylamine (18.8 mg, 145.26 µmol, 25.30 µL) were added to N,N-dimethylformamide (2 mL). The reaction was stirred at room temperature for 2 hours. The reaction was poured into water (10 mL), extracted with ethyl acetate (10 mL x 3), the organic phase was combined, dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated, and the residue was purified by reverse phase column (the chromatographic column was Boston Prime C18; 150*30 millimeters*5 microns; mobile phase A: H2O-(NH3H2O-NH4HCO3), NH3H2O concentration was 0.05%, NH4HCO3 concentration was 2 mM; mobile phase B: MeCN; MeCN ratio 30%-70%) to obtain compound 10 (5.3 mg, 5.76 µmol, yield: 19%).

[0671] MS: m / z (ESI): 922.5 [M+H] + .

[0672] 1H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J = 2.9 Hz, 1H), 8.41 (d, J = 1.6 Hz, 1H), 8.32 (d, J = 8.7 Hz, 1H), 7.82 (s, 1H), 7.72 (dd, J = 9.0, 1.3 Hz, 1H), 7.55 (d, J = 8.7 Hz, 1H), 7.19 (d, J = 2.9 Hz, 1H), 5.91 (d, J = 11.1 Hz, 1H), 5.33 (t, J = 7.8 Hz, 1H), 4.73 (d, J = 11.1 Hz, 1H), 4.54 - 4.47 (m, 1H), 4.35 - 4.23 (m, 1H), 4.20 - 4.11 (m, 2H), 3.56 - 3.52 (m, 2H), 3.25 - 3.23 (m, 4H), 3.21 (s, 3H), 2.97 - 2.91 (m, 1H), 2.86 - 2.80 (m, 2H), 2.69 - 2.65 (m, 1H), 2.65 - 2.59 (m, 5H), 2.48 - 2.45 (m, 1H), 2.36 - 2.32 (m, 1H), 2.20 - 2.12 (m, 6H), 1.97 - 1.86 (m, 2H), 1.77 - 1.72 (m, 2H), 1.63 - 1.57 (m, 1H), 1.52 - 1.36 (m, 6H), 1.33 (d, J = 6.1 Hz, 3H), 0.95 - 0.91 (m, 3H), 0.91 - 0.89 (m, 5H), 0.89 - 0.87 (m, 2H), 0.87 - 0.83 (m, 3H), 0.31 (s, 3H).

[0673] Synthesis of compound 11

[0674] First step: synthesis of compound 11-1

[0675] Compound D8 (17.0 mg, 20.56 μmol) and acetic acid (3.7 mg, 61.67 μmol) were added into isopropanol (1 mL), the mixture was stirred at room temperature for 15 minutes, to the mixture was added cyclopropanecarboxaldehyde (2.9 mg, 41.11 μmol) and sodium cyanoborohydride (2.6 mg, 41.11 μmol), the mixture was reacted at room temperature for 2 hours. The mixture was poured into water (20 mL), extracted with ethyl acetate (3*30 mL), the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure, the residue was purified by column chromatography (dichloromethane:methanol = 95:5) to obtain compound 11-1 (16.0 mg, 18.15 μmol, yield 88%).

[0676] MS m / z (ESI) = 881.4 [M+H] +.

[0677] Step 2: Synthesis of compound 11-2

[0678] Dioxane hydrochloride solution (4 M, 1 mL) was slowly added to a solution of compound 11-1 (13.0 mg, 14.75 μmol) in dichloromethane (1 mL), and the mixture was allowed to react at room temperature for 2 hours. Concentration under reduced pressure gave a crude product of compound 11-2 (10.9 mg, 14.0 μmol, yield 95%), which was directly used in the next step.

[0679] MS m / z (ESI) = 781.4 [M+H] + .

[0680] Step 3: Synthesis of compound 11

[0681] Compound 11-2 (20.0 mg, 25.61 μmol), 2-ethylbutyric acid (6.0 mg, 51.22 μmol), N,N- diisopropylethylamine (16.6 mg, 128.04 μmol, 22.30 μL) and (2-hydroxylamino- cyanoacetic acid ethyl ester)-N,N-dimethyl-morpholino urea hexafluorophosphate (32.9 mg, 76.82 μmol) were added to N,N-dimethylformamide (1 mL), and the mixture was allowed to react at room temperature for 2 hours. The reaction solution was poured into water (10 mL), extracted with ethyl acetate (10 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated, and the residue was purified by reverse phase column (the chromatographic column was Boston Prime C18; 150*30 millimeters*5 microns; mobile phase A: H2O-(NH3H2O-NH4HCO3), NH3H2O concentration was 0.05%, NH4HCO3 concentration was 2 mM; mobile phase B: MeCN; MeCN ratio 30%-75%) to give compound 11 (0.7 mg, 0.77 μmol, yield: 3%).

[0682] MS m / z (ESI) = 879.4 [M+H] + .

[0683] 1H NMR (400 MHz, CDC13) δ 8.49 (d, J = 2.9 Hz, 1H), 8.40 (d, J = 1.6 Hz, 1H), 7.60 (dd, J = 8.6, 1.6 Hz, 1H), 7.35 (d, J = 8.6 Hz, 1H), 7.30 (s, 1H), 7.07 (d, J = 2.9 Hz, 1H), 6.60 (d, J = 8.6 Hz, 1H), 5.64 - 5.57 (m, 1H), 5.39 - 5.29 (m, 3H), 4.89 - 4.81 (m, 1H), 4.78 - 4.71 (m, 1H), 4.33 - 4.21 (m, 2H), 4.21 - 4.12 (m, 1H), 3.72 (d, J = 10.9 Hz, 1H), 3.61 (d, J = 10.8 Hz, 1H), 3.46 (dd, J = 15.2, 2.9 Hz, 1H), 3.36 (s, 2H), 3.35 - 3.28 (m, 2H), 3.16 - 3.07 (m, 2H), 2.81 - 2.65 (m, 4H), 2.61 - 2.53 (m, 1H), 2.50 - 2.37 (m, 2H), 2.37 - 2.26 (m, 2H), 2.22 (t, J = 7.6 Hz, 2H), 2.15 - 2.08 (m, 1H), 2.08 - 1.96 (m, 4H), 1.44 - 1.40 (m, 2H), 1.34 - 1.29 (m, 6H), 1.01 (t, J = 7.4 Hz, 2H), 0.98 - 0.91 (m, 5H), 0.91 - 0.84 (m, 3H), 0.61 - 0.49 (m, 2H), 0.41 (s, 2H), 0.20 - 0.09 (m, 2H).

[0684] Synthesis of compound 12 of example 12

[0685] Compound 6-2 (90 mg, 117.34 μmol), N,N-diisopropylethylamine (72.4 mg, 560.08 μmol, 97.6 μL) were added into a solution of compound 2-3 (38.4 mg, 224.03 μmol) and COMU (143.9 mg, 336.05 μmol) in N,N-dimethylformamide (2.0 mL) successively, stirred at room temperature for 4 hours. Ethyl acetate (5 mL) and water (5 mL) were added to extract, the organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase column (Boston Prime C18; 150*30 millimeters*5 microns; mobile phase A: H2O-(NH3H2O-NH4HCO3), NH3H2O concentration was 0.05%, NH4HCO3 concentration was 2 mM; mobile phase B: MeCN; MeCN ratio 35%-80%) to obtain compound 12 (31 mg, 34.03 μmol, yield: 29%).

[0686] MS m / z (ESI) = 920.4 [M+H] + .

[0687] 1H NMR (400 MHz, DMSO-d6) δ 9.06 (d, J = 8.2 Hz, 1H), 8.43 (d, J = 2.8 Hz, 1H), 8.42 - 8.38 (m, 1H), 7.83 (s, 1H), 7.73 (dd, J = 8.6, 1.6 Hz, 1H), 7.55 (d, J = 8.6 Hz, 1H), 7.21 (d, J = 2.9 Hz, 1H), 6.05 (d, J = 11.0 Hz, 1H), 5.31 (t, J = 7.7 Hz, 1H), 4.72 (d, 1H), 4.59 - 4.46 (m, 2H), 4.32 - 4.24 (m, 1H), 4.22 - 4.10 (m, 3H), 3.60 - 3.52 (m, 2H), 3.51 - 3.48 (m, 1H), 3.45 (s, 1H), 3.31 - 3.29 (m, 1H), 3.28 - 3.25 (m, 1H), 3.24 - 3.21 (m, 3H), 3.20 (s, 4H), 2.92 (d, J = 14.5 Hz, 1H), 2.70 - 2.63 (m, 5H), 2.38 - 2.29 (m, 1H), 2.23 - 2.13 (m, 2H), 2.10 - 2.01 (m, 1H), 1.70 - 1.61 (m, 2H), 1.59 - 1.48 (m, 2H), 1.33 (d, J = 6.0 Hz, 3H), 1.16 (d, J = 6.4 Hz, 3H), 1.07 (d, J = 6.4 Hz, 3H), 0.94 - 0.85 (m, 6H), 0.46 - 0.41 (m, 2H), 0.35 - 0.31 (m, 4H).

[0688] Synthesis of compound 13 of example 13

[0689] Compound 9-2 (55.0 mg, 70.24 μmol), 4-fluoro-2-(2-fluoroethyl)butanoic acid (21.3 mg, 140.49 μmol), N,N-diisopropylethylamine (45.3 mg, 351.22 μmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (53.4 mg, 140.49 μmol) were dissolved in N,N-dimethylformamide (2 mL), the mixture was reacted at room temperature for 2 hours, the reaction solution was poured into water (10 mL), extracted with ethyl acetate (10 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated, the residue was purified by reversed-phase column (the chromatographic column was Boston Prime C18; 150*30 millimeters*5 microns; mobile phase A: H2O-(NH3H2O-NH4HCO3), NH3H2O concentration was 0.05%, NH4HCO3 concentration was 2 mM; mobile phase B: MeCN; MeCN ratio 30%-70%) to obtain compound 13 (29 mg, 31.6 μmol, yield: 45%).

[0690] MS (ESI + )m / z = 917.3 [M+H] + .

[0691] 1H NMR (400 MHz, DMSO-d6) δ 8.64 (d, J = 8.5 Hz, 1H), 8.45 (d, J = 2.8 Hz, 1H), 8.42 (d, J = 1.6 Hz, 1H), 7.86 (s, 1H), 7.74 (dd, J = 8.7, 1.6 Hz, 1H), 7.57 (d, J = 8.7 Hz, 1H), 7.25 (d, J = 2.9 Hz, 1H), 5.96 (d, J = 11.0 Hz, 1H), 5.31 - 5.24 (m, 1H), 4.73 (d, J = 11.0 Hz, 1H), 4.64 - 4.49 (m, 5H), 4.49 - 4.38 (m, 4H), 4.34 - 4.24 (m, 1H), 4.23 - 4.11 (m, 2H), 3.59 - 3.49 (m, 2H), 3.47 - 3.42 (m, 2H), 3.30 (s, 4H), 3.27 - 3.24 (m, 1H), 3.24 - 3.20 (m, 3H), 2.95 (d, J = 14.3 Hz, 1H), 2.73 - 2.62 (m, 2H), 2.48 (d, J = 6.1 Hz, 1H), 2.45 - 2.38 (m, 4H), 2.38 - 2.31 (m, 1H), 2.17 (t, J = 9.8 Hz, 1H), 2.04 - 1.78 (m, 4H), 1.63 (t, J = 9.3 Hz, 1H), 1.34 (d, J = 6.1 Hz, 3H), 0.98 - 0.82 (m, 6H), 0.31 (s, 3H).

[0692] Synthesis of compound 14

[0693] Compound 14 was prepared according to the procedure described in Example 1.4. 4-Fluoro-2-(2-fluoroethyl)butanoic acid (18.0 mg, 118.31 μmol), triethylamine (28.7 mg, 283.95 μmol, 39.58 μL) and 2-(7-azabenzotriazol-1- yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (54.0 mg, 141.98 μmol) were dissolved in N,N-dimethylformamide (3 mL), the mixture was stirred at room temperature for 20 minutes, then compound 10-2 (78 mg, 94.65 μmol) was added, the mixture was reacted at room temperature for 1 hour. The reaction solution was poured into water (10 mL), extracted with ethyl acetate (10 mL*3), the combined organic phase was dried over anhydrous sodium sulfate and filtered, the residue after concentration of the filtrate was purified by reverse phase column (the chromatographic column was Boston Prime C18; 150*30 millimeters*5 microns; mobile phase A: H2O-(NH3H2O-NH4HCO3), NH3H2O concentration was 0.05%, NH4HCO3 concentration was 2 mM; mobile phase B: MeCN; MeCN ratio 30%-70%) to obtain compound 14 (19 mg, 19.88 μmol, yield: 21%).

[0694] MS m / z (ESI) = 958.5 [M+H] + .

[0695] 1H NMR (400 MHz, CDC13) δ 8.48 (d, J = 2.9 Hz, 1H), 8.41 (d, J = 1.6 Hz, 1H), 7.60 (dd, J = 8.6, 1.6 Hz, 1H), 7.35 (d, J = 8.5 Hz, 1H), 7.31 (s, 1H), 7.07 (d, J = 3.0 Hz, 1H), 6.71 (d, J = 8.7 Hz, 1H), 5.62 - 5.55 (m, 1H), 5.33 (d, J = 10.8 Hz, 1H), 4.85 (d, J = 10.8 Hz, 1H), 4.77 - 4.72 (m, 1H), 4.71 - 4.63 (m, 1H), 4.63 - 4.58 (m, 1H), 4.57 - 4.51 (m, 1H), 4.51 - 4.46 (m, 1H), 4.32 - 4.27 (m, 1H), 4.27 - 4.22 (m, 1H), 4.20 - 4.12 (m, 1H), 3.72 (d, J = 10.9 Hz, 1H), 3.62 (d, J = 10.9 Hz, 1H), 3.46 (d, J = 15.8 Hz, 1H), 3.37 (s, 3H), 3.33 - 3.20 (m, 4H), 3.18 - 3.13 (m, 1H), 3.12 - 3.09 (m, 1H), 3.00 - 2.91 (m, 2H), 2.81 - 2.71 (m, 5H), 2.62 - 2.55 (m, 1H), 2.50 - 2.38 (m, 2H), 2.37 - 2.25 (m, 4H), 2.24 - 2.16 (m, 1H), 2.16 - 2.07 (m, 2H), 2.07 - 1.89 (m, 5H), 1.88 - 1.79 (m, 2H), 1.71 - 1.66 (m, 3H), 1.43 (d, J = 6.1 Hz, 3H), 0.98 - 0.91 (m, 5H), 0.40 (s, 3H).

[0696] Synthesis of compounds 15-P1 and 15-P2

[0697] First step: synthesis of compound 15-1

[0698] Compound [1,1'-bis(ditert-butylphosphino)ferrocene]dichloropalladium(II) (14.5 mg, 22.24 μmol) and potassium carbonate (14.5 mg, 104.9 μmol) were added to a mixed solution of compound Int-8 (90.0 mg, 266.86 μmol) and compound 3-9 (156.9 mg, 222.38 μmol) in tetrahydrofuran (2 mL) and water (0.5 mL) under nitrogen protection, and the reaction liquid was heated to 70℃. After reacting for 2 hours, the reaction liquid was poured into water (15 mL), extracted with ethyl acetate (20 mL*3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 30:1) to obtain compound 15-1 (110.0 mg, 131.2 μmol, yield: 59%).

[0699] MS m / z (ESI): 836.5 [M+H] + .

[0700] Second Step: Synthesis of compound 15-2

[0701] Cesium carbonate (204.7 mg, 627.95 μmol) and iodoethane (195.9 mg, 1.26 mmol) were sequentially added to a solution of compound 15-1 (105.0 mg, 125.59 μmol) in N,N-dimethylformamide (2 mL), and the mixture was reacted at room temperature for 1 hour. The mixture was poured into ethyl acetate (20 mL), washed with saturated brine (10 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain compound 15-2 (50.0 mg, 57.8 μmol, yield: 46%).

[0702] MS m / z (ESI): 864.4 [M+H] + .

[0703] Third Step: Synthesis of compound 15-3

[0704] Hydrogen chloride ethyl acetate solution (4 M, 1 mL) was added dropwise to a solution of compound 15-2 (45.0 mg, 52.08 μmol) in dichloromethane (2 mL), and the mixture was reacted at room temperature for 1 hour. The solvent was removed by distillation under reduced pressure to obtain compound 15-3 (35.83 mg, 46.87 μmol, yield: 90%).

[0705] MS m / z (ESI): 764.4 [M+H] + .

[0706] Third Step: Synthesis of compound 15-P1 and 15-P2

[0707] Compound 15-3 (50.0 mg, 65.45 μmol) and N,N-diisopropylethylamine (42.3 mg, 327.23 μmol, 57.00 μL) were added to a solution of compound 2-3 (22.4 mg, 130.89 μmol) and 2-(7-azobenzo-triazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (49.8 mg, 130.89 μmol) in N,N-dimethylformamide (3.0 mL) successively, and stirred at room temperature for 2 hours. After the reaction was completed, purification by reverse phase column (the chromatographic column was Waters XBridge C18; 150*19 mm*5 μm; mobile phase A: H2O-(NH3H2O), NH3H2O concentration was 0.05%; mobile phase B: MeCN; MeCN ratio 65%-85%; flow rate: 15 mL / min; 13 min) gave compound 15-P1 (5.5 mg, 6.0 μmol, yield: 9.2%, retention time: 8.63 min) and 15-P2 (11.5 mg, 12.5 μmol, yield: 19.0%, retention time: 9.32 min).

[0708] Compound 15-P1 MS (ESI + )m / z = 917.5 [M+H] + .

[0709] 1H NMR (400 MHz, CDC13) δ 8.76 (d, J = 2.1 Hz, 1H), 8.44 (d, J = 1.6 Hz, 1H), 8.17 (d, J = 9.2 Hz, 1H), 7.60 (dd, J = 8.6, 1.6 Hz, 1H), 7.58 (d, J = 2.1 Hz, 1H), 7.34 (d, J = 8.6 Hz, 1H), 7.31 (s, 1H), 5.72 - 5.64 (m, 1H), 5.35 (d, J = 10.8 Hz, 1H), 5.12 - 5.02 (m, 1H), 4.78 (d, J = 10.7 Hz, 1H), 4.75 - 4.70 (m, 1H), 4.41 - 4.32 (m, 1H), 4.19 - 4.07 (m, 1H), 3.88 - 3.80 (m, 3H), 3.80 - 3.74 (m, 3H), 3.68 - 3.61 (m, 3H), 3.49 (dd, J = 15.3, 3.3 Hz, 1H), 3.28 (dd, J = 15.2, 5.9 Hz, 1H), 3.10 - 2.97 (m, 2H), 2.89 - 2.83 (m, 4H), 2.74 - 2.67 (m, 1H), 2.59 - 2.50 (m, 2H), 2.44 - 2.36 (m, 1H), 2.27 - 2.18 (m, 1H), 2.17 - 2.10 (m, 1H), 2.10 - 2.03 (m, 1H), 2.01 - 1.93 (m, 2H), 1.56 - 1.49 (m, 2H), 1.36 (d, J = 6.6 Hz, 3H), 1.24 (d, J = 6.5 Hz, 3H), 1.18 (d, J = 6.5 Hz, 3H), 1.12 (d, J = 6.3 Hz, 3H), 1.09 - 1.03 (m, 3H), 0.92 (s, 3H), 0.55 (s, 3H).

[0710] Compound 15-P2 MS (ESI + m / z = 917.5 [M+H] + .

[0711] 1H NMR (400 MHz, CD3OD) δ 8.72 (d, J = 2.1 Hz, 1H), 8.42 (d, J = 1.6 Hz, 1H), 7.89 (d, J = 2.1 Hz, 1H), 7.70 (dd, J = 8.7, 1.7 Hz, 1H), 7.58 (s, 1H), 7.48 (d, J = 8.6 Hz, 1H), 5.98 (d, J = 11.0 Hz, 1H), 5.52-5.46 (m, 1H), 4.79-4.64 (m, 2H), 4.58 (s, 2H), 4.36-4.27 (m, 1H), 4.11-4.02 (m, 1H), 3.85-3.75 (m, 5H), 3.73-3.65 (m, 4H), 3.47-3.41 (m, 2H), 3.20 (d, J = 14.4 Hz, 1H), 2.92-2.86 (m, 4H), 2.83-2.74 (m, 2H), 2.68-2.60 (m, 1H), 2.52-2.44 (m, 1H), 2.24-2.11 (m, 4H), 2.00-1.93 (m, 2H), 1.76-1.56 (m, 4H), 1.29-1.27 (m, 3H), 1.25 (d, J = 6.4 Hz, 3H), 1.18 (d, J = 6.4 Hz, 3H), 1.05 (d, J = 6.7 Hz, 3H), 1.00 (s, 3H), 0.56 (s, 3H).

[0712] Synthesis of compound 16

[0713] First step: synthesis of compound 16-2

[0714] Benzyl-N-succinimidyl carbonate (12.79 g, 51.33 mmol) was added to a solution of compound 16-1 (11.00 g, 51.33 mmol) and sodium bicarbonate (8.62 g, 102.33 mmol) in acetonitrile (100 mL) and water (50 mL), and the mixture was stirred at room temperature for 3 hours. Most of the organic solvent was removed by distillation under reduced pressure, the residue was poured into water (50 mL), extracted with ethyl acetate (60 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated to give compound 16-2 (14.88 g, 42.6 mmol, yield: 83%).

[0715] MS m / z (ESI): 349.2 [M+H] + .

[0716] Second step: synthesis of compound 16-3

[0717] To a solution of compound 16-2 (14.88 g, 42.6 mmol) in ethyl acetate (30 mL) was added hydrochloric acid ethyl acetate solution (80 mL, 2M) slowly dropwise at 0 °C, the mixture was reacted at room temperature for 4 hours. The reaction was concentrated under reduced pressure, the residue was added with saturated sodium bicarbonate solution (50 mL) and water (50 mL), extracted with dichloromethane / isopropanol (3:1) (70 mL x 5), the combined organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated to give compound 16-3 (10.00 g, 40.0 mmol, yield: 94%).

[0718] MS m / z (ESI): 249.2 [M+H] + .

[0719] Step 3: Synthesis of compound 16-4

[0720] Compound 16-3 (7.26 g, 29.24 mmol), (S)-3-bromo-5-iodo-2-(1-methoxyethyl)pyridine (C5, 10.00 g, 29.24 mmol), palladium acetate (328.3 mg, 1.46 mmol), S-(-)-1,1'-binaphthalene-2,2'-diphenylphosphine (910.4 mg, 1.46 mmol) and cesium carbonate (23.82 g, 73.11 mmol) were dissolved in toluene (100 mL) under the protection of nitrogen, the mixture was reacted at 100 °C for 12 hours. The reaction was concentrated, the residue was purified by column chromatography (ethyl acetate: petroleum ether = 1:4) to give compound 16-4 (11.00 g, 23.68 mmol, yield: 81%).

[0721] MS m / z (ESI): 462.1 [M+H] + .

[0722] Step 4: Synthesis of compound 16-5

[0723] Bis(pinacolato)diboron (2.20 g, 8.66 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (316.2 mg, 432.55 μmol) and potassium acetate (1.27 g, 12.98 mmol) were added to a solution of compound 16-4 (2.00 g, 4.32 mmol) in 1,4-dioxane (20 mL) under the protection of nitrogen, the mixture was reacted at 90 °C for 12 hours. The reaction was filtered, the filtrate was concentrated under reduced pressure, the residue was purified by column chromatography (methanol:dichloromethane = 1:10) to give compound 16-5 (1.20 g, 2.33 mmol, yield: 54%).

[0724] MS m / z (ESI): 510.3 [M+H] + .

[0725] Step 5: Synthesis of compound 16-6

[0726] PdCl2[PPh3]2(137.2 mg, 187.66 pmol) and potassium phosphate (796.7 mg, 3.75 mmol) were added to a mixture of compound 16-5 (800 mg, 1.57 mmol) and compound Int-1 (1.21 g, 1.88 mmol) in dioxane (10 mL) and water (2 mL) under nitrogen protection. The mixture was stirred at 70 °C for 12 h. The reaction was concentrated, the residue was poured into water (50 mL), extracted with ethyl acetate (50 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated and purified by column chromatography (petroleum ether: ethyl acetate = 1:4) to give compound 16-6 (1.20 g, 1.33 mmol, 85% yield).

[0727] MS m / z (ESI): 901.4 [M+H] + .

[0728] Step 6: Synthesis of compound 16-7

[0729] Tetrabutylammonium fluoride (2 M, 5.00 mL) was added dropwise to a solution of compound 16-6 (1.20 g, 1.33 mmol) in tetrahydrofuran (18 mL), and the mixture was reacted at 60 °C for 12 h. The reaction was concentrated, the residue was poured into water (50 mL), extracted with ethyl acetate (50 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated and purified by column chromatography (ethyl acetate: petroleum ether = 1:4) to give compound 16-7 (530.6 mg, 0.8 mmol, 60% yield).

[0730] MS m / z (ESI): 663.2 [M+H] + .

[0731] Step 7: Synthesis of compound 16-8

[0732] Cesium carbonate (638.4 mg, 1.95 mmol) and iodoethane (317.3 mg, 2.04 mmol) were added to a solution of compound 16-7 (450.0 mg, 0.68 mmol) in N,N-dimethylformamide (5 mL) sequentially, and the mixture was allowed to react at room temperature for 5 hours. The reaction solution was filtered, and the filtrate was concentrated and purified by column chromatography (petroleum ether: ethyl acetate = 2: 1) to obtain a less polar isomer (LC-MS, time: 3 min, mobile phase A: H2O-(NH3H2O), NH3H2O concentration was 0.05%; mobile phase B: MeCN; MeCN ratio 45%-95%, retention time: 1.36 min, ) as compound 16-8 (180 mg, 0.26 mmol, yield: 38%), MS m / z (ESI): 691.3 [M+H] + ; another isomer (LC-MS, time: 3 min, mobile phase A: H2O-(NH3H2O), NH3H2O concentration was 0.05%; mobile phase B: MeCN; MeCN ratio 45%-95%, retention time: 1.27 min, ) as compound 16-8-1 (193.5 mg, 0.28 mmol, yield: 41%).

[0733] Eighth step: synthesis of compound 16-9

[0734] Acetic anhydride (47.8 mg, 468.41 μmol) was added dropwise to a solution of compound 16-8 (360.0 mg, 520.46 μmol), 4-dimethylaminopyridine (6.4 mg, 52.05 μmol) and triethylamine (158.0 mg, 1.56 mmol) in dichloromethane (10 mL) at 0°C, and the mixture was allowed to react at room temperature for 3 hours. The reaction solution was poured into water (10 mL), extracted with dichloromethane (20 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated and purified by column chromatography (ethyl acetate: petroleum ether = 1: 1) to obtain compound 16-9 (316.7 mg, 432 μmol, yield: 83%).

[0735] MS m / z (ESI): 733.2 [M+H] + .

[0736] Ninth step: synthesis of compound 16-10

[0737] Palladium (II) chloride [1,1'-bis(diphenylphosphino)ferrocene] (31.9 mg, 43.61 µmol) and potassium acetate (128.2 mg, 1.31 mmol) were added to a solution of compound 16-9 (320.0 mg, 436.13 µmol) and bis(pinacolato)diboron (221.5 mg, 872.25 µmol) in toluene (1 mL) under nitrogen, and the mixture was reacted at 90 °C for 12 hours. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain compound 16-10 (228.0 mg, 292.21 µmol, yield: 67%).

[0738] MS m / z (ESI): 781.5 [M+H] + .

[0739] Step 10: Synthesis of compound 16-11

[0740] Palladium (II) chloride [1,1'-bis(diphenylphosphino)ferrocene] (18.7 mg, 25.61 µmol) and potassium phosphate (108.7 mg, 512.30 µmol) were added to a mixed solution of compound 16-10 (200.0 mg, 256.15 µmol) and compound Int-2 (125.3 mg, 256.15 µmol) in dioxane (5 mL) and water (0.5 mL) under nitrogen, and the mixture was reacted at 80 °C for 12 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (ethyl acetate: petroleum ether = 1:2) to obtain compound 16-11 (128.0 mg, 120.39 µmol, yield: 47%).

[0741] MS m / z (ESI): 1063.4 [M+H] + .

[0742] Step 11: Synthesis of compound 16-12

[0743] Lithium hydroxide monohydrate (23.7 mg, 564.28 µmol) was added to a solution of compound 16-11 (120.0 mg, 112.86 µmol) in tetrahydrofuran (6 mL) and water (2 mL) at room temperature, and the mixture was warmed to 40 °C and stirred for 2 hours. Most of the organic solvent was removed by concentration under reduced pressure, the residue was adjusted to pH 3 with hydrochloric acid (2N), and the aqueous phase was extracted with dichloromethane / isopropyl alcohol (3:1) (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 16-12 (102.3 mg, 101.57 µmol, yield: 90%).

[0744] MS m / z (ESI): 1007.5 [M+H]+ .

[0745] Twelfth step: synthesis of compound 16-13

[0746] N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (139.3 mg, 496.40 μmol) was added to a mixture solution of compound 16-12 (100.0 mg, 99.28 μmol) and N-methylimidazole (407.6 mg, 4.96 mmol) in N,N-dimethylformamide (1 mL) and acetonitrile (5 mL), and the mixture was stirred at 80 °C for 2 h. The reaction was concentrated, the residue was poured into water (10 mL), extracted with ethyl acetate (10 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (ethyl acetate: petroleum ether = 9: 1) to give compound 16-13 (56.0 mg, 56.59 μmol, yield: 57%).

[0747] MS m / z (ESI): 989.5 [M+H] + .

[0748] Thirteenth step: synthesis of compound 16-14

[0749] Under a hydrogen atmosphere, 10% palladium on carbon (14.0 mg) was added to a solution of compound 16-13 (130.0 mg, 131.42 μmol) in methanol (5 mL), and the mixture was reacted under a hydrogen atmosphere for 12 h. The reaction was filtered, and the filtrate was concentrated to give compound 16-14 (109.0 mg, 127.48 μmol, yield: 97%).

[0750] MS m / z (ESI): 855.4 [M+H] + .

[0751] Fourteenth step: synthesis of compound 16-15

[0752] Paraformaldehyde (6.9 mg, 230.12 μmol), acetic acid (20.7 mg, 345.18 μmol) and sodium cyanoborohydride (14.5 mg, 230.12 μmol) were sequentially added to a solution of compound 16-14 (100.0 mg, 117.03 μmol) in methanol (5 mL), and the mixture was reacted at room temperature for 2 h. The reaction was concentrated, the residue was poured into water (10 mL), extracted with dichloromethane (10 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated to give compound 16-15 (65.0 mg, 74.79 μmol, yield: 65%).

[0753] MS m / z (ESI): 869.5 [M+H] +.

[0754] Step 15: Synthesis of compound 16-16

[0755] Compound 16-15 (60.0 mg, 69.04 μmol) was dissolved in hydrochloric acid dioxane (4 M, 5 mL) and stirred at room temperature for 3 hours. Concentration under reduced pressure gave compound 16-16 (44.6 mg, 58.0 μmol, yield: 84%).

[0756] MS m / z (ESI): 769.5 [M+H] + .

[0757] Step 16: Synthesis of compound 16

[0758] Compound 16-16 (25.0 mg, 32.51 μmol) was dissolved in N,N-dimethylformamide (3 mL), and 2,3-dimethylbutyric acid (3.8 mg, 32.51 μmol), triethylamine (9.9 mg, 97.53 μmol) and 2-(7-azobenzo-triazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (24.7 mg, 65.02 μmol) were added successively, and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into water (10 mL), extracted with ethyl acetate (10 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by reverse phase column (chromatography column: Boston Prime C18; 150*30 millimeters*5 microns; mobile phase A: H2O-(NH3H2O-NH4HCO3), NH3H2O concentration was 0.05%, NH4HCO3 concentration was 2 mM; mobile phase B: MeCN; MeCN ratio 40%-70%), to give compound 16 (5.0 mg, 5.76 μmol, yield: 17.7%).

[0759] MS m / z (ESI): 867.5 [M+H] + .

[0760] 1H NMR (400 MHz, CDC13) δ 8.48 (d, J = 3.0 Hz, 1H), 8.40 (s, 1H), 7.61-7.58 (m, 1H), 7.35 (d, J = 8.5 Hz, 1H), 7.30 (s, 1H), 7.08 (d, J = 3.0 Hz, 1H), 6.58 (d, J = 9.6 Hz, 1H), 5.36-5.29 (m, 3H), 4.84 (d, J = 10.7 Hz, 1H), 4.75-4.71 (m, 1H), 4.29-4.14 (m, 3H), 4.07-3.97 (m, 2H), 3.82-3.77 (m, 2H), 3.74-3.70 (m, 1H), 3.64-3.60 (m, 1H), 3.48-3.43 (m, 1H), 3.36 (s, 3H), 3.15-3.09 (m, 2H), 2.88-2.83 (m, 2H), 2.44-2.41 (m, 1H), 2.37-2.32 (m, 6H), 2.22 (t, J = 7.6 Hz, 3H), 2.03-1.96 (m, 6H), 1.44-1.41 (m, 2H), 1.18-1.15 (m, 2H), 1.07-1.03 (m, 2H), 1.00-0.94 (m, 8H), 0.89-0.87 (m, 3H), 0.42 (s, 3H).

[0761] Synthesis of compound 17

[0762] To a solution of compound Int-10 (21.0 mg, 28.2 μmol), N,N- diisopropylethylamine (14.8 μL, 84.8 μmol) in a solution of compound 4-fluoro-2-(2-fluoroethyl)butanoic acid (4.3 mg, 28.2 μmol) and 2-(7-azobenzotriazol-1- yl)-1,1,3,3-hexafluoro-phosphonic 6-hydroxyhexane-1,2,3,4-tetramide (16.1 mg, 42.4 μmol) in N,N-dimethylformamide (2.0 mL) was added at room temperature for 1 h. Compound 17 (12.0 mg, 13.6 μmol, 48.2% yield) was obtained after purification by reverse phase column (column: Boston Prime C18; 150*30 mm*5 μm; mobile phase A: H2O-(NH3H2O-NH4HCO3), NH3H2O concentration: 0.05%, NH4HCO3 concentration: 2 mM; mobile phase B: MeCN; MeCN ratio: 50%-80%).

[0763] MS (ESI + )m / z = 877.4 [M+H] + .

[0764] 1 H NMR (400 MHz, CD3OD) δ 8.45 (d, J = 1.6 Hz, 1H), 8.40 (d, J = 2.9 Hz, 1H), 7.69 (dd, J = 8.7, 1.6 Hz, 1H), 7.57 (s, 1H), 7.48 (d, J = 8.7 Hz, 1H), 7.33 (d, J = 3.0 Hz, 1H), 5.50 (d, J = 6.7 Hz, 1H), 4.71 - 4.64 (m, 2H), 4.57 (s, 4H), 4.47 (dt, J = 19.5, 5.5 Hz, 2H), 4.31 - 4.24 (m, 2H), 4.23 - 4.14 (m, 1H), 3.67 (q, J = 10.9 Hz, 2H), 3.42 (dd, J = 15.1, 2.8 Hz, 2H), 3.35 (t, J = 5.2 Hz, 6H), 2.84 (dq, J = 9.8, 5.0 Hz, 1H), 2.72 (q, J = 5.8 Hz, 1H), 2.65 (t, J = 5.0 Hz, 4H), 2.62 - 2.55 (m, 1H), 2.47 (dd, J = 10.8, 5.2 Hz, 1H), 2.37 (s, 3H), 2.21 (t, J = 9.8 Hz, 1H), 2.13 - 1.98 (m, 2H), 1.97 - 1.87 (m, 2H), 1.61 (t, J = 9.5 Hz, 1H), 1.42 (d, J = 6.2 Hz, 3H), 1.02 - 0.87 (m, 7H), 0.45 (s, 3H).

[0765] Synthesis of compound 18

[0766] First step Synthesis of compound 18-1

[0767] Compound 3-8 (0.10 g, 0.14 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added, stirred at room temperature for 1 hour, the reaction solution was rotary dried, dichloromethane (5 mL) was added again, the pH was adjusted to 8 with saturated sodium bicarbonate solution, extracted with dichloromethane (10 mL) for three times, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain compound 18-1 crude which was directly used in the next step.

[0768] MS (ESI + )m / z = 606.5 [M+H] + .

[0769] Second step Synthesis of compound 18-2

[0770] The crude compound 18-1 from previous step and 2-ethylbutyric acid (16 mg, 0.14 mmol) were dissolved in acetonitrile (5 mL), N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (60 mg, 0.21 mmol), N-methylimidazole (30 mg, 0.36 mmol) were added into the solution under ice-bath, and the reaction was allowed to proceed for 1 h under ice-bath. The reaction was diluted with dichloromethane (15 mL), poured into water (20 mL), and extracted with dichloromethane (20 mL) for three times. The organic phase was combined and concentrated. The residue was purified by HPLC column (column: Welch Xtimate C18 column length 150 mm, inner diameter 30 mm, particle size 5 μm; mobile phase A: water (0.225% NH3), mobile phase B: acetonitrile; gradient: mobile phase B from 5% to 95% for 10 column volumes) to give compound 18-2 (87 mg, 0.12 mmol, yield: 88%).

[0771] MS (ESI + )m / z = 704.6 [M+H] + .

[0772] Step 3 Synthesis of compound 18-3

[0773] Compound 18-2 (35 mg, 50 μmol), 2-dicyclohexylphosphino-2',6'-dimethoxy- biphenyl (4.0 mg, 10 μmol), tris(dibenzylideneacetone)dipalladium (9.1 mg, 10 μmol), potassium acetate (17 mg, 0.17 mmol) were dissolved in tetrahydrofuran (4 mL), and the air in the flask was replaced with argon for three times. The reaction was stirred under ice-bath for 5 min. Pinacolborane (51 mg, 0.40 mmol) was added dropwise into the reaction. After the addition was completed, the reaction was moved to 50 °C for 3 h. After the reaction was monitored to be complete by LC-MS, the reaction was filtered and purified by normal silica gel column (ethyl acetate / petroleum ether: 0% to 40%) to give compound 18-3 (22 mg, 31 μmol, yield: 63%).

[0774] MS (ESI + )m / z = 704.7 [M+H] + .

[0775] Step 4 Synthesis of compound 18-4

[0776] Compound 18-3 (22 mg, 31 μmol), Int-11 (18 mg, 47 μmol), potassium phosphate (16 mg, 74 μmol), [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (2.1 mg, 3.0 μmol) were dissolved in dioxane / water (3 mL / 1 mL), replaced with argon three times, and reacted at 80°C for 4 hours. The reaction solution was filtered, dried, and purified by column chromatography (Welch Xtimate C18 column length 150 mm, inner diameter 30 mm, particle size 5 μm; mobile phase A: water (0.225% NH3), mobile phase B: acetonitrile; gradient: mobile phase B from 5% to 95%, elution of 10 column volumes) to obtain compound 18-4 (27 mg, 30 μmol, yield: 97%).

[0777] MS (ESI + )m / z = 890.7 [M+H] + .

[0778] Fifth step Synthesis of compound 18

[0779] Compound 18-4 (27 mg, 30 μmol) was dissolved in N,N-dimethylformamide (3 mL), and cesium carbonate (20 mg, 61 μmol) and iodoethane (7.0 mg, 46 μmol) were added, and the mixture was reacted at room temperature for 12 hours. The reaction solution was directly purified by column chromatography (Welch Xtimate C18 column length 150 mm, inner diameter 30 mm, particle size 5 μm; mobile phase A: water (0.225% NH3), mobile phase B: acetonitrile; gradient: mobile phase B from 5% to 95%, elution of 10 column volumes) to obtain compound 18 (4 mg, 4.3 μmol, yield: 14%).

[0780] MS (ESI + )m / z = 918.9 [M+H] + .

[0781] 1H NMR (400 MHz, Methanol-d4) δ 9.16 (d, J = 13.8 Hz, 2H), 9.10 (d, J = 2.3 Hz, 1H), 8.49 (s, 1H), 8.33 (dd, J = 44.0, 2.4 Hz, 1H), 7.77 - 7.68 (m, 1H), 7.61 - 7.55 (m, 1H), 7.51 (t, J = 8.4 Hz, 1H), 5.93 (d, J = 11.0 Hz, 1H), 5.61 - 5.51 (m, 1H), 5.48 - 5.40 (m, 1H), 5.37 - 5.29 (m, 1H), 4.74 - 4.52 (m, 2H), 3.94 - 3.82 (m, 3H), 3.81 - 3.63 (m, 7H), 3.50 - 3.36 (m, 4H), 3.28 - 3.22 (m, 1H), 2.83 - 2.69 (m, 1H), 2.70 - 2.55 (m, 5H), 2.54 - 2.37 (m, 2H), 2.30 - 2.12 (m, 3H), 2.10 - 1.96 (m, 1H), 1.77 - 1.42 (m, 8H), 1.10 - 0.86 (m, 14H).

[0782] Synthesis of compounds 19-P1 and 19-P2 of Example 19

[0783] First Step Synthesis of compound 19-1

[0784] Compound C5 (200.0 mg, 584.8 μmol) and 4-(4-piperidinyl)morpholine (99.6 mg, 584.8 μmol) were added into 1,4-dioxane (2.0 mL), then palladium acetate (13.1 mg, 58.4 μmol), S-(-)-l,l'-binaphthalene-2,2'-bisphosphine (36.4 mg, 58.4 μmol), cesium carbonate (476.6 mg, 1.46 mmol) and water, stirred at 100 °C under nitrogen protection for 16.0 hours, LC-MS monitored the reaction was complete. The mixture was filtered, the filtrate was added into water (50 mL), extracted with ethyl acetate (50 mL), concentrated to get the crude product. Purified by liquid chromatography column (column: Welch Xtimate C18 column long 150 mm, inner diameter 30 mm, particle size 5 μm; mobile phase A: water (0.225% NH3), mobile phase B: acetonitrile; gradient: mobile phase B from 5% to 95%, eluted 8 column volumes) to get compound 19-1 (150.0 mg, 390.3 μmol, yield: 66.7%).

[0785] MS (ESI+) m / z = 384.2 [M+H] + .

[0786] Second Step Synthesis of compound 19-2

[0787] Compound 19-1 (26.1 mg, 68.1 μmol) was added to a mixture solution of 1,4-dioxane (1.0 mL) and water (0.2 mL), then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (2.8 mg, 3.4 μmol), compound 3-9 (24.0 mg, 34.0 μmol), potassium carbonate (9.4 mg, 68.1 μmol) and water (0.25 mL) were added, and the mixture was stirred at 65 °C for 2.0 hours under nitrogen protection. After the reaction was completed, compound 19-2 (25.0 mg, 28.3 μmol, yield: 83.0%) was obtained by purification through a liquid chromatography column (column: Welch Xtimate C18 column long 150 mm, inner diameter 30 mm, particle size 5 μm; mobile phase A: water (0.225% NH3), mobile phase B: acetonitrile; gradient: mobile phase B from 5% to 95%, elution of 10 column volumes).

[0788] MS (ESI+) m / z = 883.4 [M+H] + .

[0789] Third Step Synthesis of compound 19-3

[0790] Compound 19-2 (25.0 mg, 28.3 μmol) and cesium carbonate (13.8 mg, 42.4 μmol) were added to N,N-dimethylformamide (0.3 mL) and argon was replaced. Iodoethane (4.9 mg, 31.4 μmol) was added dropwise to the reaction solution under argon atmosphere, and the mixture was stirred at room temperature for 1.0 hour. After the reaction was completed, the reaction solution was slowly poured into ice water and stirred, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure to obtain compound 19-3 (25.0 mg, 27.44 μmol, yield: 96.9%).

[0791] MS (ESI+) m / z = 911.4 [M+H] + .

[0792] Fourth Step Synthesis of compound 19-4

[0793] Compound 19-3 (25.0 mg, 27.4 μmol) was dissolved in dichloromethane (1.0 mL), and 4M hydrochloric acid dioxane solution (2.0 mL) was added to the reaction solution under nitrogen protection, and stirred at 25 °C for 0.5 hours, and concentrated under reduced pressure to obtain compound 19-4 (22.0 mg, 27.13 μmol, yield: 99%).

[0794] MS (ESI +m / z = 811.4 [M+H] + .

[0795] Fifth step Synthesis of compounds 19-P1 and 19-P2

[0796] To a solution of compound 19-4 (22.0 mg, 27.1 μmol), N,N- diisopropylethylamine (14.1 μL, 81.3 μmol), compound 4-fluoro-2-(2- fluoroethyl)butanoic acid (4.1 mg, 27.1 μmol) and O-(7-azabenzotriazol- 1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (12.4 mg, 32.5 μmol) in N,N-dimethylformamide (3.0 mL) was added successively and stirred at room temperature for 1 hour. The crude was purified by supercritical fluid chromatography (column: DAICEL CHIRALPAK AD column length 250 mm, inner diameter 30 mm, particle size 10 μm; mobile phase A: supercritical carbon dioxide, mobile phase B: ethanol (containing 0.1% ammonia water); gradient: mobile phase B: 60% isocratic; flow rate: 80 mL / min;). Two title compounds (10.36 mg, 10.3 μmol, yield: 38.1%) were obtained. Both title compounds were further analyzed by the following chiral HPLC analytical method respectively.

[0797] Chiral HPLC analytical method:

[0798] Column: (Chiralcel OD-3 column length 50 mm, inner diameter 4.6 mm, particle size 3 μm; mobile phase: A: supercritical carbon dioxide B: ethanol (containing 0.2% methylamine); gradient: mobile phase B 40% isocratic for 2 minutes; flow rate 3.5 mL / min; column temperature: 35 °C; ABPR: 1500 psi), compound 19-P1 retention time: 0.533 min; compound 19-P2 retention time: 1.229 min.

[0799] Compound 19-P1 MS (ESI + m / z = 945.6 [M+H] +

[0800] 1H NMR (400 MHz, Methanol-d4) δ 8.45 (s, 1H), 8.42 (d, J = 2.8 Hz, 1H), 7.70 (dd, J = 8.6, 1.6 Hz, 1H), 7.58 (s, 1H), 7.47 (d, J = 8.6 Hz, 1H), 7.44 (d, J = 2.9 Hz, 1H), 5.43 - 5.37 (m, 1H), 4.80 (d, J = 4.4 Hz, 1H), 4.70 - 4.44 (m, 9H), 4.13 - 3.99 (m, 2H), 3.95 - 3.85 (m, 2H), 3.83 - 3.74 (m, 1H), 3.71 (t, J = 4.7 Hz, 4H), 3.68 (d, J = 5.0 Hz, 2H), 3.23 (s, 3H), 2.93 - 2.82 (m, 3H), 2.81 - 2.73 (m, 1H), 2.61 (d, J = 5.3 Hz, 5H), 2.53 - 2.36 (m, 3H), 2.25 - 2.16 (m, 1H), 2.12 - 1.85 (m, 7H), 1.74 - 1.66 (m, 1H), 1.65 - 1.57 (m, 2H), 1.26 (d, J = 7.1 Hz, 2H), 1.21 (d, J = 6.3 Hz, 3H), 0.99 (s, 3H), 0.93 - 0.87 (m, 1H), 0.61 (s, 3H).

[0801] Compound 19-P2 MS (ESI + m / z = 945.6 [M+H] +

[0802] 1H NMR (400 MHz, Methanol-d4) δ 8.45 (d, J = 1.4 Hz, 1H), 8.40 (d, J = 2.9 Hz, 1H), 7.73 - 7.68 (m, 1H), 7.58 (s, 1H), 7.49 (d, J = 8.6 Hz, 1H), 7.32 (d, J = 2.8 Hz, 1H), 5.55 - 5.43 (m, 1H), 4.69 (s, 1H), 4.67 - 4.65 (m, 1H), 4.59 - 4.52 (m, 1H), 4.45 (t, J = 6.1 Hz, 1H), 4.33 - 4.16 (m, 3H), 3.98 - 3.89 (m, 2H), 3.76 - 3.70 (m, 4H), 3.70 - 3.63 (m, 2H), 3.50 - 3.34 (m, 2H), 3.15 - 3.07 (m, 1H), 2.92 - 2.80 (m, 3H), 2.75 - 2.69 (m, 1H), 2.62 (d, J = 17.8 Hz, 6H), 2.51 - 2.40 (m, 2H), 2.20 (q, J = 8.6, 7.0 Hz, 2H), 2.12 - 1.86 (m, 8H), 1.70 - 1.55 (m, 4H), 1.42 (d, J = 6.2 Hz, 3H), 1.00 - 0.82 (m, 9H), 0.46 (s, 3H).

[0803] Synthesis of compound 20

[0804] First step Synthesis of compound 20-1

[0805] Tert-butyldimethyl(prop-2-yn-1-yloxy)silane (0.21 g, 1.2 mmol), compound C5 (0.40 g, 1.2 mmol) were dissolved in acetonitrile (3 mL), N,N-diisopropylethylamine (0.30 g, 2.3 mmol) was added, followed by palladium dichloride bis(triphenylphosphine) (40 mg, 56 μmol), cuprous iodide (22 mg, 0.12 mmol), and the mixture was replaced with argon three times. The reaction was carried out at room temperature for 16 hours. Ethyl acetate (10 mL) was added to dilute and filter, and the residue was purified by normal silica gel column (petroleum ether: ethyl acetate = 0% - 10%) to obtain compound 20-1 (0.43 g, 1.1 mmol, yield: 95%).

[0806] MS (ESI + )m / z = 384.1 [M+H] + .

[0807] Second step Synthesis of compound 20-2

[0808] Compound 3-9 (40 mg, 57 μmol) and compound 20-1 (26 mg, 68 μmol), potassium phosphate (36 mg, 0.17 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (8.1 mg, 11 μmol,) were dissolved in dioxane / water (2 mL / 0.5 mL), replaced with argon three times, and reacted at 70°C for 3 hours. The reaction solution was diluted with ethyl acetate (10 mL), washed with saturated brine (10 mL) twice, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and purified by normal silica gel column (petroleum ether: ethyl acetate = 0% - 70%) to obtain compound 20-2 (35 mg, 40 μmol, yield: 70%).

[0809] MS (ESI + )m / z = 883.2 [M+H] + .

[0810] Step 3 Synthesis of compound 20-3

[0811] Compound 20-2 (35 mg, 40 μmol) was dissolved in N,N-dimethylformamide (3 mL), cesium carbonate (0.14 g, 0.44 mmol,) and iodoethane (61 mg, 0.40 mmol) were added, and the reaction was performed at room temperature for 1 hour. The reaction solution was poured into saturated brine (10 mL), extracted with ethyl acetate (15 mL) three times, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain crude compound 20-3 (30 mg, 33 μmol, yield: 83%) which was directly used in the next step.

[0812] MS (ESI + )m / z = 911.3 [M+H] + .

[0813] Step 4 Synthesis of compound 20-4

[0814] Compound 20-3 (30 mg, 33 μmol) was dissolved in tetrahydrofuran (3 mL), tetrabutylammonium fluoride (0.1 mL, 1M tetrahydrofuran solution) was added under ice bath, and the reaction was performed at ice bath for 2 hours. After the reaction was completed by LC-MS monitoring, the reaction solution was diluted with ethyl acetate (10 mL), washed with saturated brine (10 mL) twice, dried, and concentrated to obtain compound 20-4 (22 mg, 28 μmol, yield: 83%) which was purified by normal silica gel column (petroleum ether: ethyl acetate = 0% - 90%).

[0815] MS (ESI + )m / z = 797.4 [M+H] + .

[0816] Step 5 Synthesis of compound 20-5

[0817] Compound 20-4 (22 mg, 28 pmol) was dissolved in dichloromethane (3 mL), N,N- diisopropylethylamine (18 mg, 0.14 mmol), methanesulfonic anhydride (7 mg, 41 pmol) were added under ice-bath, and the reaction was allowed to proceed at room temperature for 1 hour. After dilution with ethyl acetate (10 mL), it was washed with saturated brine (10 mL) twice, dried and concentrated. Purification by normal silica gel column (petroleum ether: ethyl acetate = 0% - 90%) gave compound 20-5 (18 mg, 21 pmol, yield: 75%).

[0818] MS (ESI + )m / z = 875.1 [M+H] + .

[0819] Step 6 Synthesis of compound 20-6

[0820] Compound 20-5 (18 mg, 21 pmol) was dissolved in N.N-dimethylformamide (3 mL), N,N- diisopropylethylamine (8 mg, 60 pmol), homomorpholine (3.0 mg, 30 pmol) were added, and the reaction was allowed to proceed at 50°C for 3 hours. After dilution with ethyl acetate (10 mL), it was washed with saturated brine (10 mL) twice, concentrated and dried. Purification by normal silica gel column (petroleum ether: ethyl acetate = 0% - 90%) gave compound 20-6 (16.6 mg, 18.9 pmol, yield: 90%).

[0821] MS (ESI + )m / z = 880.4 [M+H] + .

[0822] Step 7 Synthesis of compound 20-7

[0823] Compound 20-6 (16.6 mg, 18.9 pmol) was dissolved in 4M hydrochloric acid in dioxane (3 mL), and the reaction was allowed to proceed at room temperature for 1 hour. Compound 20-7 (14.0 mg, 18.0 pmol, yield: 95%) was obtained by distillation under reduced pressure.

[0824] MS (ESI + )m / z = 780.3 [M+H] + .

[0825] Step 8 Synthesis of compound 20-P1 and 20-P2

[0826] Compound 20-7 (14.0 mg, 18.0 μmol) was dissolved in N,N-dimethylformamide (3 mL), compound 2-3 (4.0 mg, 23 μmol), N,N-diisopropyl ethylamine (15 mg, 0.12 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (22 mg, 58 μmol) were added, and the reaction was allowed to proceed at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (10 mL), washed twice with saturated brine (10 mL), dried and concentrated, and purified by reverse phase column (column: Boston Prime C18; 150*30 mm*5 μm; mobile phase A: H2O-(NH3H2O-NH4HCO3), NH3H2O concentration 0.05%, NH4HCO3 concentration 2 mM; mobile phase B: MeCN; MeCN ratio 50%-75%, flow rate: 15 mL / min) to give compound 20-P1 (2.0 mg, 2.1 μmol, yield: 11.7%, retention time: 8.60 min) and 20-P2 (1.5 mg, 1.6 μmol, yield: 8.9%, retention time: 9.48 min).

[0827] Compound 20-P1 MS (ESI + m / z = 933.5 [M+H] + .

[0828] 1H NMR (400 MHz, Methanol-d4) δ 8.83-8.66 (m, 1H), 8.52-8.35 (m, 1H), 8.10-7.90 (m, 1H), 7.81-7.67 (m, 1H), 7.60 (s, 1H), 7.55-7.42 (m, 1H), 5.57-5.44 (m, 1H), 5.42-5.28 (m, 1H), 4.74-4.64 (m, 2H), 4.61 (s, 3H), 4.37-4.27 (m, 1H), 4.18-4.02 (m, 2H), 3.85-3.74 (m, 2H), 3.74-3.61 (m, 4H), 3.46-3.40 (m, 1H), 3.26 (s, 2H), 3.25-3.18 (m, 1H), 2.92-2.87 (m, 3H), 2.83-2.74 (m, 1H), 2.69-2.59 (m, 1H), 2.53-2.43 (m, 1H), 2.38-2.31 (m, 1H), 2.30-2.11 (m, 4H), 2.07-1.91 (m, 3H), 1.76-1.56 (m, 4H), 1.24 (q, J=6.9, 6.5 Hz, 8H), 1.20-1.15 (m, 3H), 0.99 (s, 3H), 0.94-0.84 (m, 2H), 0.56 (s, 3H).

[0829] Compound 20-P2 MS (ESI + m / z = 933.5 [M+H] + .

[0830] 1H NMR (400 MHz, Methanol-d4) δ 8.82-8.72 (m, 1H), 8.53-8.42 (m, 1H), 7.93-7.84 (m, 1H), 7.76-7.68 (m, 1H), 7.64-7.56 (m, 1H), 7.55-7.47 (m, 1H), 5.67-5.55 (m, 1H), 5.37-5.31 (m, 1H), 4.72-4.65 (m, 2H), 4.62-4.58 (m, 3H), 4.39-4.27 (m, 3H), 4.19-4.06 (m, 1H), 3.84-3.75 (m, 4H), 3.74-3.62 (m, 4H), 3.53-3.39 (m, 2H), 2.95-2.86 (m, 3H), 2.77-2.69 (m, 1H), 2.64-2.53 (m, 4H), 2.51-2.42 (m, 1H), 2.29-2.11 (m, 4H), 2.07-1.93 (m, 4H), 1.71-1.53 (m, 4H), 1.49-1.41 (m, 3H), 1.26-1.21 (m, 3H), 1.20-1.12 (m, 3H), 1.00-0.82 (m, 3H), 0.52-0.40 (m, 3H).

[0831] Synthesis of compounds 21-P1 and 21-P2

[0832] First step Synthesis of compounds 21-P1 and 21-P2

[0833] Compound 20-7 (11.7 mg, 15.0 μmol) was dissolved in N,N-dimethylformamide (3 mL), compound 4-fluoro-2-(2-fluoroethyl)butanoic acid (4.6 mg, 30 μmol), N,N-diisopropyl ethylamine (15 mg, 0.12 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (22 mg, 58 μmol) were added, and the reaction was allowed to proceed at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (10 mL), washed twice with saturated brine (10 mL), dried and concentrated, and purified by reverse phase column (column: Boston Prime C18; 150*30 mm*5 μm; mobile phase A: H2O-(NH3H2O-NH4HCO3), NH3H2O concentration: 0.05%, NH4HCO3 concentration: 2 mM; mobile phase B: MeCN; MeCN ratio: 50%-75%, flow rate: 15 mL / min) to obtain compound 21-P1 (2.5 mg, 2.7 μmol, yield: 18.2%, retention time: 7.43 min) and 21-P2 (1.6 mg, 1.7 μmol, yield: 11.3%, retention time: 8.17 min).

[0834] Compound 21-P1 MS (ESI + m / z = 914.6 [M+H] + .

[0835] 1H NMR (400 MHz, Methanol-d4) δ 8.79-8.77 (m, 1H), 8.49-8.45 (m, 1H), 8.00-7.97 (m, 1H), 7.75-7.70 (m, 1H), 7.62-7.58 (m, 1H), 7.51-7.47 (m, 1H), 5.96-5.90 (m, 1H), 5.42-5.36 (m, 1H), 4.83-4.78 (m, 1H), 4.69-4.63 (m, 2H), 4.61-4.57 (m, 3H), 4.55-4.44 (m, 2H), 4.18-4.03 (m, 2H), 3.85-3.76 (m, 4H), 3.75-3.62 (m, 4H), 3.50-3.33 (m, 2H), 3.27-3.25 (m, 3H), 3.25-3.18 (m, 1H), 2.93-2.82 (m, 5H), 2.81-2.75 (m, 1H), 2.67-2.60 (m, 1H), 2.52-2.45 (m, 1H), 2.37-2.31 (m, 1H), 2.25-2.17 (m, 1H), 2.15-1.86 (m, 4H), 1.73-1.66 (m, 1H), 1.30-1.21 (m, 7H), 1.02-0.97 (m, 3H), 0.58-0.54 (m, 3H).

[0836] Compound 21-P2 MS (ESI + m / z = 914.6 [M+H] + .

[0837] 1H NMR (400 MHz, Methanol-d4) δ 8.81-8.73 (m, 1H), 8.50-8.45 (m, 1H), 7.89-7.85 (m, 1H), 7.76-7.69 (m, 1H), 7.61-7.57 (m, 1H), 7.54-7.48 (m, 1H), 5.54-5.46 (m, 1H), 4.72-4.69 (m, 1H), 4.69-4.54 (m, 5H), 4.53-4.43 (m, 2H), 4.40-4.34 (m, 1H), 4.34-4.27 (m, 1H), 4.20-4.10 (m, 1H), 3.84-3.76 (m, 4H), 3.73-3.70 (m, 2H), 3.70-3.63 (m, 2H), 3.50-3.38 (m, 2H), 3.37-3.35 (m, 3H), 3.15-3.09 (m, 1H), 2.93-2.88 (m, 4H), 2.88-2.81 (m, 1H), 2.76-2.71 (m, 1H), 2.64-2.52 (m, 2H), 2.50-2.44 (m, 1H), 2.25-2.18 (m, 1H), 2.13-1.84 (m, 5H), 1.66-1.57 (m, 1H), 1.48-1.42 (m, 3H), 0.97-0.92 (m, 6H), 0.47-0.42 (m, 3H).

[0838] Synthesis of compounds 22-P1 and 22-P2

[0839] First step Synthesis of compounds 22-P1 and 22-P2

[0840] Compound 20-7 (11.7 mg, 15.0 μmol) was dissolved in N,N-dimethylformamide (2 mL), compound (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid (3.4 mg, 30 μmol), N,N-diisopropyl ethylamine (13 mg, 0.1 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (22 mg, 58 μmol) were added, and the reaction was allowed to proceed at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (10 mL), washed twice with saturated brine (10 mL), dried and concentrated, and purified by reverse phase column (column: Boston Prime C18; 150*30 mm*5 μm; mobile phase A: H2O-(NH3H2O-NH4HCO3), NH3H2O concentration: 0.05%, NH4HCO3 concentration: 2 mM; mobile phase B: MeCN; MeCN ratio: 50%-75%, flow rate: 15 mL / min) to obtain compound 22-P1 (3.7 mg, 4.2 μmol, yield: 28.0%, retention time: 8.42 min) and 22-P2 (2.0 mg, 2.3 μmol, yield: 15.6%, retention time: 8.97 min).

[0841] Compound 22-P1 MS (ESI + m / z = 876.4 [M+H] + .

[0842] 1H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J = 2.1 Hz, 1H), 8.46 - 8.41 (m, 2H), 8.00 (d, J = 2.1 Hz, 1H), 7.82 (s, 1H), 7.76 - 7.72 (m, 1H), 7.54 (d, J = 8.7 Hz, 1H), 5.93 - 5.86 (m, 1H), 5.34 - 5.27 (m, 1H), 4.76 - 4.71 (m, 1H), 4.52 - 4.46 (m, 1H), 3.99 - 3.90 (m, 2H), 3.86 - 3.77 (m, 1H), 3.71 - 3.66 (m, 3H), 3.66 - 3.57 (m, 3H), 3.54 - 3.49 (m, 1H), 3.44 - 3.38 (m, 2H), 3.31 - 3.25 (m, 2H), 3.24 - 3.19 (m, 1H), 3.18 - 3.13 (m, 1H), 3.10 - 3.07 (m, 2H), 3.06 - 3.01 (m, 1H), 2.80 - 2.72 (m, 4H), 2.69 - 2.63 (m, 1H), 2.38 - 2.30 (m, 2H), 2.18 - 2.12 (m, 1H), 1.88 - 1.81 (m, 2H), 1.65 - 1.58 (m, 1H), 1.29 - 1.22 (m, 2H), 1.21 - 1.16 (m, 4H), 1.13 - 1.10 (m, 3H), 1.10 - 1.03 (m, 5H), 0.95 - 0.89 (m, 3H), 0.47 (s, 3H).

[0843] Compound 22-P2 MS (ESI + m / z = 876.4 [M+H] + .

[0844] 1H NMR (400 MHz, DMSO-d6) δ 8.80 (d, J = 2.1 Hz, 1H), 8.45 - 8.39 (m, 2H), 7.86 (d, J = 2.1 Hz, 1H), 7.82 (s, 1H), 7.78 - 7.73 (m, 1H), 7.58 (d, J = 8.7 Hz, 1H), 5.95 - 5.91 (m, 1H), 5.41 - 5.33 (m, 1H), 4.69 - 4.63 (m, 1H), 4.51 - 4.45 (m, 1H), 4.36 - 4.23 (m, 2H), 4.11 - 4.03 (m, 1H), 3.70 - 3.66 (m, 3H), 3.66 - 3.61 (m, 2H), 3.60 - 3.53 (m, 2H), 3.41 - 3.38 (m, 3H), 3.31 - 3.26 (m, 2H), 3.25 - 3.21 (m, 3H), 3.17 - 3.10 (m, 1H), 2.96 - 2.89 (m, 1H), 2.77 - 2.73 (m, 3H), 2.65 - 2.60 (m, 1H), 2.35 - 2.29 (m, 1H), 2.19 - 2.12 (m, 1H), 1.89 - 1.81 (m, 2H), 1.61 - 1.53 (m, 1H), 1.39 - 1.32 (m, 3H), 1.28 - 1.21 (m, 3H), 1.19 - 1.14 (m, 2H), 1.11 - 1.04 (m, 5H), 0.91 - 0.85 (m, 5H), 0.33 (s, 3H).

[0845] Synthesis of compound 23

[0846] First step: synthesis of compound 23

[0847] To a solution of compound 9-2 (35.0 mg, 44.70 μmol), compound 2-3 (15.3 mg, 89.40 μmol) and N,N-diisopropylethylamine (57.8 mg, 447.00 μmol, 77.86 μL) in N,N-dimethylformamide (2 mL) was added 2-(7-azobenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (51.0 mg, 134.10 μmol). The mixture was stirred at room temperature for 2 hours. After filtration, the reaction solution was purified by reverse phase column (column: Boston Prime C18; 150*30mm*5μm; mobile phase A: H2O-(NH3H2O-NH4HCO3), NH3H2O concentration: 0.05%, NH4HCO3 concentration: 2mM; mobile phase B: MeCN; MeCN ratio: 50%-75%, flow rate: 15 mL / min) to give compound 23 (9.2 mg, 9.8 μmol, yield: 22%).

[0848] MS (ESI + m / z = 936.5 [M+H] + .

[0849] 1 H NMR (400 MHz, DMSO-d6) δ 9.09 (d, J = 8.2 Hz, 1H), 8.45 (d, J = 2.8 Hz, 1H), 8.41 (s, 1H), 7.85 (s, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.57 (d, J = 8.6 Hz, 1H), 7.25 (d, J = 2.8 Hz, 1H), 6.07 (d, J = 11.0 Hz, 1H), 5.35 - 5.25 (m, 1H), 4.72 (d, J = 11.1 Hz, 1H), 4.60 - 4.54 (m, 2H), 4.54 - 4.49 (m, 2H), 4.49 - 4.42 (m, 2H), 4.32 - 4.25 (m, 1H), 4.21 - 4.10 (m, 3H), 3.59 - 3.51 (m, 2H), 3.48 - 3.43 (m, 2H), 3.42 - 3.40 (m, 2H), 3.32 - 3.27 (m, 4H), 3.21 (s, 2H), 2.98 - 2.88 (m, 1H), 2.70 - 2.62 (m, 1H), 2.47 - 2.38 (m, 4H), 2.35 - 2.31 (m, 1H), 2.23 - 2.14 (m, 2H), 2.13 - 2.05 (m, 1H), 2.05 - 1.96 (m, 1H), 1.66 - 1.60 (m, 1H), 1.59 - 1.46 (m, 2H), 1.34 (d, J = 6.0 Hz, 3H), 1.16 (d, J = 6.4 Hz, 3H), 1.08 (d, J = 6.5 Hz, 3H), 0.95 - 0.82 (m, 6H), 0.33 (s, 3H).

[0850] Synthesis of compound 24 of example 24

[0851] Compound 9-2 (55.0 mg, 70.2 μmol), cyclopentanoic acid (22.8 mg, 200.0 μmol), N,N-diisopropylamine (45.3 mg, 351.2 μmol) and 2-(7-azobenzo-triazol-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (53.4 mg, 140.5 μmol) were dissolved in N,N-dimethylformamide (2 mL), the mixture was reacted at room temperature for 2 hours, the reaction solution was poured into water (10 mL), extracted with ethyl acetate (10 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated, and the residue was purified by reversed-phase column (the chromatographic column was Boston Prime C18; 150*30 millimeters*5 microns; mobile phase A: H2O-(NH3H2O-NH4HCO3), NH3H2O concentration was 0.05%, NH4HCO3 concentration was 2 mM; mobile phase B: MeCN; MeCN ratio 45%-70%) to obtain compound 24 (32.7 mg, 37.2 μmol, yield: 53%).

[0852] MS (ESI + )m / z = 879.4 [M+H] + .

[0853] 1 H NMR (400 MHz, CDCl3) δ 8.49 (d, J = 2.8 Hz, 1H), 8.39 (s, 1H), 7.60 (d, J = 8.6 Hz, 1H), 7.35 (d, J = 8.6 Hz, 1H), 7.31 (s, 1H), 7.12 (s, 1H), 6.67-6.56 (m, 1H), 5.55 (s, 1H), 5.28 (d, J = 10.8 Hz, 1H), 4.91-4.67 (m, 5H), 4.33-4.22 (m, 2H), 4.22-4.13 (m, 1H), 3.71 (d, J = 10.9 Hz, 1H), 3.61 (d, J = 10.9 Hz, 1H), 3.50-3.41 (m, 2H), 3.37 (s, 3H), 3.19-3.08 (m, 2H), 2.78-2.64 (m, 3H), 2.63-2.53 (m, 2H), 2.47-2.37 (m, 2H), 2.15-2.06 (m, 1H), 2.02-1.84 (m, 4H), 1.82-1.73 (m, 2H), 1.68-1.54 (m, 6H), 1.45 (d, J = 6.1 Hz, 3H), 1.36-1.27 (m, 2H), 1.00-0.92 (m, 5H), 0.91-0.79 (m, 2H), 0.41 (s, 3H).

[0854] Synthesis of compounds 25-P1 and 25-P2 of Example 25

[0855] First Step Synthesis of compound 25-2

[0856] To a solution of (1R,3R)-3-hydroxycyclobutan-1-carbonitrile (225.0 mg, 2.32 mmol) and 4-dimethylaminopyridine (424.5 mg, 3.48 mmol) in dichloromethane (2.5 mL) was added p-toluenesulfonyl chloride (530.0 mg, 2.78 mmol) at 25 °C, and the mixture was stirred for 16.0 h. The reaction was monitored by LC-MS until the starting material was consumed. The mixture was added dropwise into ice water (10 mL) to quench the reaction, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 10:1) to give compound 25-2 (470.0 mg, 1.87 mmol, 80.7% yield).

[0857] MS (ESI + )m / z = 252.0 [M+H] + .

[0858] Second Step Synthesis of compound 25-3

[0859] To a solution of compound Int-14 (70.0 mg, 75.0 μmol) and cesium carbonate (73.3 mg, 225.0 μmol) in N,N-dimethylformamide (5.0 mL) was bubbled with argon. To the reaction was added compound 25-2 (22.6 mg, 90.0 μmol), and the resulting mixture was stirred at 60 °C for 49.0 h. After the reaction was completed, the mixture was purified by reverse phase column (Water / NH4OH (0.5%):MeCN = 95:5 to 5:95) to give compound 25-3 (61.0 mg, 60.3 μmol, 80.3% yield).

[0860] MS (ESI + )m / z = 1012.4 [M+H] + .

[0861] Third Step Synthesis of compound 25-4

[0862] Compound 25-3 (61.0 mg, 60.3 μmol) was dissolved in isopropanol (3.0 mL), Pd(OH)2 / C (67.7 mg, 482.1 μmol, 20% content) was added to the reaction solution, and then hydrogen was replaced for 5 times, stirred at 25 °C for 6.0 hours under one atmosphere, and LC-MS was used to monitor the completion of the reaction. After the crude product was filtered to remove the residue, concentration was performed to obtain compound 25-4 (43.0 mg, 49.0 μmol, yield: 81.2%).

[0863] MS (ESI + )m / z = 878.4 [M+H] + .

[0864] Step 4 Synthesis of compound 25-5

[0865] Compound 25-4 (55.0 mg, 62.6 μmol), 3-oxetanone (9.0 mg, 125.3 μmol), one drop of acetic acid and sodium cyanoborohydride (7.87 mg, 125.3 μmol) were added to isopropanol (3.0 mL) at room temperature, and stirred at room temperature for 4.0 hours. LC-MS was used to monitor the completion of the reaction, saturated aqueous ammonium chloride solution was added to the reaction solution to quench the reaction, the residue after concentration was washed with saturated aqueous sodium chloride solution, extracted with dichloromethane (10 mL x 3) for three times, the organic phase was dried, filtered and concentrated, and then the obtained crude product was purified by a reversed-phase column (Water / NH4OH (0.5%):MeCN = 95:5 to 5:95) to obtain compound 25-5 (34.0 mg, 36.4 μmol, yield: 58.1%).

[0866] MS (ESI + )m / z = 934.4 [M+H] + .

[0867] Step 4 Synthesis of compound 25-6

[0868] Compound 25-5 (110.0 mg, 117.8 μmol) was dissolved in dichloromethane (3.0 mL), trifluoroacetic acid (1.0 mL) was added to the reaction solution, stirred at 25 °C for 0.5 hours, LC-MS was used to monitor the completion of the reaction, and concentration was performed under reduced pressure to obtain compound 25-6 (98.0 mg, 117.5 μmol, yield: 99.8%).

[0869] MS (ESI + )m / z = 834.4 [M+H] + .

[0870] Step 5 Synthesis of compounds 25-P1 and 25-P2

[0871] A solution of compound 25-6 (98.0 mg, 117.5 mΐΐ) and N,N- diisopropylethylamine (61.4 pL, 352.5 mΐΐ) in N,N-dimethylformamide (3.0 mL) was added to a solution of compound 4-fluoro-2-(2-fluoroethyl)butanoic acid (Int-12, 35.7 mg, 235 mΐΐ) and 2-(7-azabenzotriazol-1- yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (67.0 mg, 176.2 mΐΐ) in N,N- dimethylformamide (1.0 mL). Stirred at room temperature for 0.5 hours. LC-MS monitored the reaction was complete, purified by reverse phase column (column: XBridge Prep C18; 150 mm * 19 mm * 5 pm; mobile phase A: H20-(NH3H20), NH3H20 concentration was 0.05%; mobile phase B: MeCN; MeCN ratio 35%-65%, time: 13 min, flow rate: 15 mL / min) to give compound 25-P1 (14.19 mg, 14.4 mΐΐ, yield: 12.3%, retention time: 6.72 min) and 25-P2 (20.4 mg, 20.6 mΐΐ, yield: 17.5%, retention time: 7.38 min).

[0872] Compound 25-P1 MS (ESI + m / z = 968.5 [M+H] + .

[0873] 1H NMR (400 MHz, Methanol-d4) δ 8.47-8.44 (m, 2H), 7.78 (d, J = 8.8 Hz, 1H), 7.75-7.70 (m, 1H), 7.62 (s, 1H), 7.45 (d, J = 2.8 Hz, 1H), 5.42-5.37 (m, 1H), 4.78-4.75 (m, 1H), 4.75-4.71 (m, 2H), 4.68-4.61 (m, 4H), 4.60-4.56 (m, 2H), 4.54-4.43 (m, 2H), 4.06 (q, J = 6.4 Hz, 1H), 3.72-3.60 (m, 2H), 3.57 (t, J = 6.3 Hz, 1H), 3.50-3.46 (m, 2H), 3.44-3.35 (m, 6H), 3.24 (s, 3H), 3.17 (d, J = 14.4 Hz, 1H), 3.14-3.11 (m, 1H), 2.91-2.81 (m, 1H), 2.80-2.73 (m, 2H), 2.67-2.59 (m, 1H), 2.58-2.52 (m, 4H), 2.52-2.45 (m, 2H), 2.37-2.30 (m, 1H), 2.23-2.15 (m, 2H), 2.06-1.88 (m, 5H), 1.69 (t, J = 9.5 Hz, 1H), 1.64-1.56 (m, 1H), 1.18 (d, J = 6.4 Hz, 3H), 0.98 (s, 3H), 0.93-0.88 (m, 2H).

[0874] Compound 25-P2 MS (ESI + m / z = 968.4 [M+H] + .

[0875] 1H NMR (400 MHz, Methanol-d4) δ 8.48 (d, J = 1.5 Hz, 1H), 8.43 (d, J = 2.9 Hz, 1H), 7.84 (d, J = 8.7 Hz, 1H), 7.80-7.76 (m, 1H), 7.65 (s, 1H), 7.42 (d, J = 2.9 Hz, 1H), 5.42-5.36 (m, 1H), 4.78-4.69 (m, 2H), 4.69-4.64 (m, 2H), 4.64-4.57 (m, 4H), 4.57-4.49 (m, 1H), 4.48-4.44 (m, 1H), 4.05 (q, J = 6.3 Hz, 1H), 3.66 (q, J = 11.0 Hz, 2H), 3.59-3.54 (m, 1H), 3.44-3.39 (m, 1H), 3.39-3.32 (m, 6H), 3.29-3.25 (m, 3H), 3.24-3.22 (m, 3H), 3.17 (d, J = 14.3 Hz, 1H), 3.12-3.04 (m, 1H), 2.92-2.82 (m, 2H), 2.79-2.73 (m, 1H), 2.69-2.60 (m, 2H), 2.58-2.51 (m, 4H), 2.51-2.45 (m, 1H), 2.33 (d, J = 14.4 Hz, 1H), 2.24-2.18 (m, 1H), 2.18-1.81 (m, 5H), 1.69 (t, J = 9.6 Hz, 1H), 1.33-1.32 (m, 1H), 1.17 (d, J = 6.4 Hz, 3H), 0.98 (s, 3H), 0.93-0.80 (m, 2H).

[0876] The compounds in the following table were synthesized by adapting the procedures of the above examples by changing some of the starting materials, preparation and purification conditions: reverse phase column (chromatography column was XBridge Prep C18; 150 mm * 19 mm * 5 μm; mobile phase A: H20-(NH3H20), NH3H20 concentration was 0.05%; mobile phase B: MeCN)

[0877] Synthesis of compounds 38-P1 and 38-P2 of Example 38

[0878] Synthesis of compound 38-1 of the first step

[0879] Compound Int-22 (101.0 mg, 183.9 µmol) was added to 1,4-dioxane (10.0 mL), then [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (13.5 mg, 18.4 µmol), compound 3-9 (181.6 mg, 257.4 µmol), potassium phosphate (78.0 mg, 367.7 µmol) and water (2.0 mL) were added, stirred at 65 °C for 2.0 hours under nitrogen protection. After the reaction was completed, the crude product was purified by reverse phase (Water / NH4OH (0.5%):MeCN = 95:5 to 5:95) to give compound 38-1 (174.0 mg, 173.8 µmol, yield: 94.5%).

[0880] MS (ESI+) m / z = 1001.4 [M+H] + .

[0881] Second Step, Synthesis of compound 38-2

[0882] Compound 38-1 (170.0 mg, 169.8 µmol) and cesium carbonate (276.6 mg, 849.0 µmol) were added to N,N-dimethylformamide (10.0 mL) and replaced with argon. To the reaction solution, iodoethane (264.8 mg, 1.7 mmol) was added dropwise under argon atmosphere, and the resulting mixture was stirred at 25 °C for 3.0 hours. After the reaction was completed, the reaction solution was slowly poured into ice water and stirred, extracted with ethyl acetate, and the organic phase was concentrated to give the crude product. The crude product was purified by reverse phase (Water / NH4OH (0.5%):MeCN = 95:5 to 5:95) to give compound 38-2 (158.0 mg, 153.5 µmol, yield: 90.4%).

[0883] MS (ESI+) m / z = 1029.4 [M+H] + .

[0884] Third Step, Synthesis of compound 38-3

[0885] Compound 38-2 (43.0 mg, 41.8 µmol) was dissolved in methanol (5.0 mL), Pd(OH)2 / C (20% loading, 45.6 mg) and paraformaldehyde (24.0 mg, 801 µmol) were added to the reaction solution, then replaced with hydrogen 5 times, stirred at 25 °C for 5 hours under one atmosphere, and the reaction was monitored by LC-MS. The crude product was purified by reverse phase column chromatography (Water / NH4OH (0.5%):MeCN = 95:5 to 5:95) to give compound 38-3 (35.4 mg, 38.9 µmol, yield: 93.2%).

[0886] MS (ESI + m / z = 909.4 [M+H] + .

[0887] Step 4 Synthesis of compound 38-4

[0888] Compound 38-3 (12.0 mg, 13.2 μmol) was dissolved in dichloromethane (0.3 mL), 4M hydrogen chloride solution in dioxane (1.5 mL) was added to the reaction solution under the condition of nitrogen protection, stirred at 25°C for 0.5 hours, LC-MS monitoring showed that the reaction was complete, rotary evaporation to concentrate to obtain compound 38-4 (10.6 mg, 13.2 μmol, yield: 100.0%).

[0889] MS (ESI + m / z = 809.3 [M+H] + .

[0890] Step 5 Synthesis of compounds 38-P1 and 38-P2

[0891] Compound 38-4 (10.0 mg, 12.4 μmol) and N,N-diisopropylethylamine (13.8 μL, 79.2 μmol) were added to a solution of 2-ethylbutyric acid (6.0 mg, 51.7 μmol) and 2-(7-azobenzenetriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (15.1 mg, 39.6 μmol) in N,N-dimethylformamide (1.5 mL) in sequence, stirred at room temperature for 1.0 hours. After the reaction was completed, reversed-phase column purification (the chromatographic column was XBridge Prep C18; 150 millimeters * 19 millimeters * 5 microns; mobile phase A: H2O-(NH3H2O), NH3H2O concentration was 0.05%; mobile phase B: MeCN; MeCN ratio 65%-90%, time: 20 min, flow rate: 20 mL / min) to obtain compound 38-P1 (4.0 mg, 4.41 μmol, yield: 35.6%, retention time: 12.85 min) and 38-P2 (2.5 mg, 2.76 μmol, yield: 22.2%, retention time: 17.42 min).

[0892] Compound 38-P1 MS (ESI + m / z = 907.4 [M+H] + .

[0893] 1H NMR (400 MHz, Methanol-d4) δ 8.55-8.48 (m, 2H), 8.02 (d, J = 9.3 Hz, 1H), 7.78-7.70 (m, 2H), 7.60 (s, 1H), 7.51 (d, J = 8.7 Hz, 1H), 5.50-5.44 (m, 1H), 4.67 (q, J = 4.9 Hz, 1H), 4.27 (q, J = 6.3 Hz, 1H), 4.20-4.09 (m, 1H), 3.79-3.67 (m, 3H), 3.45-3.38 (m, 5H), 3.28 (s, 3H), 3.26-3.19 (m, 1H), 2.83-2.72 (m, 5H), 2.67-2.60 (m, 1H), 2.51-2.46 (m, 1H), 2.32 (d, J = 14.3 Hz, 1H), 2.29-2.22 (m, 1H), 2.22-2.18 (m, 1H), 1.73-1.66 (m, 2H), 1.65-1.47 (m, 4H), 1.39-1.35 (m, 3H), 1.32 (d, J = 6.8 Hz, 8H), 1.28 (s, 2H), 1.05 (t, J = 7.4 Hz, 3H), 1.00-0.94 (m, 6H), 0.93-0.83 (m, 2H).

[0894] Compound 38-P2 MS (ESI + m / z = 907.4 [M+H] + .

[0895] 1H NMR (400 MHz, Methanol-d4) δ 8.50 (d, J = 1.6 Hz, 1H), 8.38 (s, 1H), 7.99 (d, J = 9.2 Hz, 1H), 7.76-7.69 (m, 2H), 7.58 (s, 1H), 7.53 (d, J = 8.6 Hz, 1H), 5.56 (d, J = 6.7 Hz, 1H), 5.34 (dd, J = 5.4, 4.2 Hz, 1H), 4.66 (q, J = 4.8 Hz, 1H), 4.51 (q, J = 6.1 Hz, 1H), 4.41-4.27 (m, 1H), 4.19-4.10 (m, 1H), 3.75-3.70 (m, 1H), 3.65 (d, J = 10.8 Hz, 1H), 3.47-3.39 (m, 5H), 3.37 (s, 3H), 3.26-3.19 (m, 1H), 3.14-3.10 (m, 1H), 2.88 (s, 3H), 2.72 (q, J = 5.9 Hz, 1H), 2.68-2.57 (m, 2H), 2.53 (s, 3H), 2.49-2.43 (m, 1H), 2.24-2.16 (m, 3H), 2.06-1.99 (m, 2H), 1.66-1.58 (m, 3H), 1.55 (d, J = 6.1 Hz, 3H), 1.39-1.35 (m, 3H), 1.02 (t, J = 7.4 Hz, 3H), 0.95 (t, J = 7.3 Hz, 6H), 0.90-0.88 (m, 5H).

[0896] Synthesis of compounds 39-P1 and 39-P2

[0897] Following the procedures in Example 38, replacing Int-22 with compound Int-20, compounds 39-P1 and 39-P2 were prepared. Purification on a reverse phase column (XBridge Prep C18; 150 mm * 19 mm * 5 µm; mobile phase A: H2O-(NH3H2O), NH3H2O concentration 0.05%; mobile phase B: MeCN; MeCN ratio 55%-75%, time: 20 min, flow rate: 20 mL / min) gave compound 39-P1 (retention time: 10.55 min) and 39-P2 (retention time: 13.67 min).

[0898] Compound 39-P1 MS (ESI + )m / z = 903.4 [M+H] + .

[0899] 1H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.45 (s, 1H), 8.37 (d, J = 8.6 Hz, 1H), 7.86 (s, 1H), 7.76 (dd, J = 8.8, 1.6 Hz, 1H), 7.57 (d, J = 8.6 Hz, 1H), 5.92 (d, J = 11.0 Hz, 1H), 5.36 - 5.27 (m, 2H), 5.22 - 5.11 (m, 1H), 4.78 (d, J = 11.1 Hz, 1H), 4.55 - 4.48 (m, 1H), 4.08 - 3.97 (m, 1H), 3.95 - 3.88 (m, 1H), 3.79 - 3.64 (m, 3H), 3.63 - 3.57 (m, 2H), 3.22 - 3.16 (m, 2H), 3.10 - 3.01 (m, 4H), 2.91 - 2.85 (m, 2H), 2.67 - 2.64 (m, 1H), 2.36 - 2.33 (m, 1H), 2.30 - 2.25 (m, 1H), 2.20 - 2.13 (m, 2H), 2.03 - 1.95 (m, 2H), 1.66 - 1.60 (m, 1H), 1.58 - 1.51 (m, 1H), 1.48 - 1.38 (m, 4H), 1.31 - 1.23 (m, 8H), 1.16 - 1.08 (m, 3H), 0.96 - 0.91 (m, 3H), 0.89 - 0.82 (m, 4H), 0.81 - 0.75 (m, 1H), 0.63 - 0.55 (m, 2H).

[0900] Compound 39-P2 MS (ESI + m / z = 903.4 [M+H] + .

[0901] 1H NMR (400 MHz, DMSO-d6) δ 8.46 (s, 1H), 8.39-8.32 (m, 1H), 7.86 (s, 1H), 7.80-7.76 (m, 1H), 7.64-7.55 (m, 1H), 7.25-7.16 (m, 1H), 6.73-6.59 (m, 1H), 6.00-5.86 (m, 1H), 5.39-5.28 (m, 3H), 4.79-4.68 (m, 1H), 4.55-4.46 (m, 1H), 4.41-4.31 (m, 1H), 3.96 (s, 1H), 3.65-3.57 (m, 1H), 3.56-3.51 (m, 1H), 3.29-3.27 (m, 2H), 3.26-3.23 (m, 4H), 3.07-3.02 (m, 1H), 2.99-2.93 (m, 1H), 2.83-2.78 (m, 1H), 2.66-2.62 (m, 1H), 2.37-2.34 (m, 1H), 2.21-2.13 (m, 2H), 2.04-1.94 (m, 6H), 1.48-1.41 (m, 5H), 1.32-1.27 (m, 5H), 1.15-1.06 (m, 1H), 0.96-0.90 (m, 3H), 0.89-0.83 (m, 10H), 0.29 (s, 2H).

[0902] Biological tests

[0903] Compound A122 in WO2022060836 and compound 6A in WO2024067857 are introduced into the present disclosure as reference compounds.

[0904] Test Example 1, Effect of compounds on the proliferation activity of tumor cells

[0905] Experimental materials and instruments:

[0906] The materials required for the experiment include: cell culture medium RPMI-1640 (Basal Media #L240KJ); DMEM (Basal Media #L110KJ); IMDM (Basal Media #L610KJ); fetal bovine serum (FBS) (Excell #FSP500); PBS phosphate buffer (Basal Media #B320KJ); 0.25% trypsin (Basal Media #S310KJ); 100% DMSO (Sigma #D2650); 96-well sterile transwell culture plate (Corning #3599); 96-well plate (Xinyou Biotec Co., Ltd #062096); Cell Viability Detection cell viability detection kit (VKEY-BIO #A2010005N); 25 mL pipette (Corning); 5 mL pipette (Corning); P1000 pipette tip, P200 pipette tip and P10 pipette tip (Axygen).

[0907] The instruments and equipment required for the experiment include: Eppendorf pipette; Eppendorf pipette gun; Eppendorf centrifuge; constant temperature carbon dioxide incubator (ThermoFisher); automatic cell counter Vi-cell XR (Beckman Coulter); Envision enzyme labeler (Perkin Elmer).

[0908] The cells required for the experiment include: KRAS G12D mutant cell strain AsPC-1 (ATCC, #CRL-1682 TM ), and the complete culture medium is RPMI-1640 medium containing 10% FBS.

[0909] Experimental method:

[0910] AsPC-1 cells were digested from culture flasks using 0.25% trypsin and resuspended with corresponding fresh complete medium. After counting, AsPC-1 was adjusted to a cell density of 2000 cells / 90 μL / well, and 90 μL was added to a 96-well plate, which was incubated in a 37°C, 5% CO2 cell incubator overnight. Compound stock solution was 10 mM, diluted to 1 mM using DMSO 10-fold, then diluted to 10 μM using complete medium 100-fold, and then diluted 3-fold gradient using complete medium containing 1% DMSO, with 9 concentration gradients in sequence; 10 μL / well of the gradient-diluted compound was added to the cell culture well, so that the final DMSO content in each well was 1 / 1000. The positive control group was the medium well without cell planting; the negative control group was the cell- planted well without compound treatment. The cell plate was incubated in a 37°C, 5% CO2 incubator for 5 days. An equal volume of Cell Counting-Lite 2.0 detection reagent was added to each well of the cell plate, and the cells were fully lysed by shaking for 2-5 min, and the luminescence signal was stabilized by placing the plate at room temperature for 10 min. The luminescence value was read using an Envision microplate reader. The inhibition rate was calculated according to the following formula: Inhibition % = (Signal negative control - Signal sample ) / (Signal negative control - Signal positive control) * 100. The IC 50 values were calculated using 4-parameter fitting of IDBS XLfit. The measured IC 50 values are shown in Table 1.

[0911] Table 1

[0912] Test Example 2: Inhibition of cytochrome P450 enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 by the compounds of the present disclosure

[0913] I. Test materials and test equipment

[0914] 1. Reagents

[0915] 2. Liver microsomes

[0916] 3. Test equipment

[0917] II. Experimental procedures

[0918] 1. Prepare the test compound as a 10 mM stock solution in DMSO. Dilute the stock solution with DMSO to obtain the following concentrations of the test compound in DMSO: 0, 4, 20, 100, 400, 2000 and 10000 μM. The final concentration of the test compound in the incubation system is 0, 0.02, 0.1, 0.5, 2, 10 and 50 μM. The volume ratio of the organic solvent introduced into the test system with the test compound is 0.5%. The final concentration of the positive inhibitor in the reaction system is shown in the following table.

[0919] Working solution concentration of the positive inhibitor

[0920] Final concentration of the positive inhibitor in the reaction system

[0921] 2. Preparation of the substrate stock solution

[0922] The preparation of the substrate stock solution is shown in the following table. The stock solution is stored at -20 °C. Before use, it is thawed at room temperature.

[0923] Information of the substrate stock solution

[0924] 3. Preparation of the phosphate buffer (100 mM, pH 7.4)

[0925] Weigh 7.098 g of disodium hydrogen phosphate and add 500 mL of purified water. Dissolve by ultrasonic and use as solution A. Weigh 3.400 g of potassium dihydrogen phosphate and add 250 mL of purified water. Dissolve by ultrasonic and use as solution B. Place solution A on a stirrer and slowly add solution B until the pH value reaches 7.4. Store the phosphate buffer at 4 °C.

[0926] 4. Preparation of 10 mM NADPH

[0927] Before the test, weigh an appropriate amount of NADPH and prepare a working solution with a concentration of 10 mM in phosphate buffer. The final concentration of NADPH in the test system is 1 mM.

[0928] 5. Preparation of the incubation system

[0929] The preparation of the incubation system is shown in the following table. Before use, preheat in a water bath at 37 °C for 15 minutes.

[0930] 6. Test method

[0931] The whole incubation process was carried out in a 96-well deep well plate. First, 179 μL of the incubation system was added to the deep well plate, then 1 μL of the compound solution or solvent (DMSO) was added, and then 20 μL of 10 mM NADPH solution was added. Before starting the reaction, the incubation system was preheated at 37°C for 15 minutes. After adding NADPH to start the reaction, it was incubated at 37°C for 45 minutes. The test samples were prepared in duplicate.

[0932] After incubation for 45 min, the reaction was terminated by adding 400 μL of ice methanol (containing internal standard, 10 ng / mL gliclazide and 10 ng / mL propranolol). After vortex mixing, the deep well plate was centrifuged at 4000 rpm, 4°C for 10 min. 100 μL of supernatant was transferred to a new 96-well plate, 100 μL of pure water was added and mixed, and then subjected to LC-MS / MS analysis.

[0933] III. Data analysis

[0934] The generated metabolites were analyzed by LC-MS / MS. The decrease in metabolite production in the drug-treated group compared to the blank solvent control group was compared by the ratio of sample to internal standard peak area, and the IC value was calculated based on the percentage of residual activity using GraphPad Prism 8.0. 50

[0935] The percentage of residual activity was calculated using the following formula:

[0936] Percentage of residual activity (%) = ratio of metabolite peak area to internal standard peak area 受试物 / ratio of metabolite peak area to internal standard peak area 空白溶剂 x 100%.

[0937] The test results are shown in Table 2.

[0938] Table 2 Inhibition of cytochrome P450 enzymes by compounds

[0939] Test Example 3: Rat hepatocyte stability test

[0940] Purpose of the experiment: to study the metabolic stability of the compound in frozen SD rat hepatocytes

[0941] Experimental materials: suspended hepatocytes of SD rats (Milecell Biological Science & Technology Co., Ltd.), control compound ethoxy coumarin (commercially available);

[0942] ​Experimental procedure: The cryopreserved rat hepatocytes were taken out from the liquid nitrogen tank and thawed, and the cell viability was calculated by trypan blue staining method. The hepatocyte suspension was added to the preheated incubation plate, and then the test sample and control compound working solution (preparation method: 1 mM test compound ACN solution was diluted to 100 μM, 3 mM control compound was diluted to 300 μM with ACN) were added, mixed well and immediately placed in the shaking plate machine in the incubator, and the timer was started to start the reaction. The reaction was set at 0, 15, 30, 60 and 90 minutes incubation time points, and the incubation conditions were 37°C, saturated humidity, containing 5% CO2. In the reaction system, the final concentration of the test sample was 1 μM, the final concentration of the control sample was 3 μM, and the final concentration of rat hepatocytes was 0.5 x 10 6 cells / mL. At the corresponding time point, the incubation plate was taken out, and an appropriate amount of cell suspension was taken into a sample plate containing a certain volume of stop solution (250 nM tolbutamide and labetalol in acetonitrile solution). After all the sample plates were sealed and shaken on the shaking plate machine at 600 rpm for 10 minutes, they were centrifuged at 3220 x g for 20 minutes. The supernatant of the test sample and control sample was diluted with ultrapure water at a ratio of 1:3. After all the samples were mixed, they were analyzed by LC / MS / MS method, and the elimination rate constant and clearance rate of the test compound in rat hepatocytes were calculated using the following formula.

[0943] Data analysis: The in vitro elimination rate constant k of the test sample and control compound was obtained by converting the ratio of the peak area of the compound to the internal standard in the following formula to the remaining percentage. e

[0944] When

[0945] The in vitro intrinsic clearance (CL e ) was obtained by the elimination rate k int(liver) , and the formula was as follows:

[0946] CL int(hep) = k e / per million cells (million cells / mL)

[0947] CL int(liver) = CL int(hep) x liver weight / body weight x liver cell number per gram of liver

[0948] The experimental results showed that the compound of the present disclosure had excellent stability in rat hepatocytes.

[0949] The test results are shown in Table 3.

[0950] ​Table 3 Stability of compounds in rat hepatocytes

[0951] Test Example 4: Assessment of the effect of compounds of the disclosure on hERG potassium ion channel current using automated patch clamp technique

[0952] I. Materials and Instruments

[0953] II. Test Method

[0954] 1. Cell line and cell culture

[0955] CHO cell line stably expressing hERG ion channel was purchased from B'SYS GmbH, Switzerland. The cell line was cultured in F-12 (HAM) medium with 10% FBS, 100 U / mL penicillin-streptomycin, 100 μg / mL hygromycin and 100 μg / mL Geneticin TM When the cell density reached 40% to 80% of the bottom area of the culture dish, the cells were digested and subcultured with TrypLE Express cell digestion solution, and subcultured three times a week. TM (Notes: The cell number for safety evaluation test was less than 55 generations).

[0956] 2. Solution preparation

[0957] 1) NMDG 60 extracellular solution (in mM): 80 sodium chloride, 60 NMDG, 4 potassium chloride, 2 calcium chloride, 1 magnesium chloride, 5 glucose, 10 HEPES (pH 7.4 adjusted with hydrochloric acid, osmotic pressure 289 mOsm / kg).

[0958] 2) NMDG 60 cell seal solution (in mM): 80 sodium chloride, 60 NMDG, 4 potassium chloride, 10 calcium chloride, 1 magnesium chloride, 5 glucose, 10 HEPES (pH 7.4 adjusted with hydrochloric acid, osmotic pressure 313 mOsm / kg).

[0959] 3) Chip filling solution (in mM): 140 sodium chloride, 4 potassium chloride, 5 glucose, 10 HEPES (pH 7.4 adjusted with sodium hydroxide, osmotic pressure 289 mOsm / kg).

[0960] 4) Standard external solution (in mM): 140 sodium chloride, 4 potassium chloride, 2 calcium chloride, 1 magnesium chloride, 5 glucose, 10 HEPES (pH 7.4 adjusted with sodium hydroxide, osmotic pressure 298 mOsm / kg).

[0961] 5) KF110 intracellular solution (in mM): 10 EGTA, 10 HEPES, 10 KCl, 10 NaCl, 110 KF (pH adjusted to 7.2 with KOH, osmolality 280-300 mOsm / kg).

[0962] 3. Preparation of test compound solutions

[0963] 1) Dissolve test compound in DMSO and prepare a stock solution with a final concentration of 10 mM.

[0964] 2) Dilute the stock solution with DMSO to three other intermediate concentration solutions with a ratio of 1:3, the concentrations are 3.33 mM, 1.11 mM and 0.37 mM, respectively. The dilution is done by NMS Apricot Personal Pipettor Pipetting Station.

[0965] 3) Before the start of the experiment, dilute the test compound stock solution and intermediate solutions with NMDG 60 extracellular solution to obtain working solutions with concentrations of 20 μΜ, 6.66 μΜ, 2.22 μΜ and 0.74 μΜ, respectively. Meanwhile, dilute the 10 mM stock solution with NMDG 60 extracellular solution to obtain a working solution with a concentration of 60 μΜ. The content of DMSO in the working solution is 0.2%-0.6% (volume ratio). (Note: when dosing, the working solution will be added to the chip well containing the same volume of NMDG 60 extracellular solution with a volume ratio of 1:1, so the actual dosing concentration should be 30 μΜ, 10 μΜ, 3.33 μΜ, 1.11 μΜ, 0.37 μΜ, and the final DMSO content is 0.1%-0.3%).

[0966] 4) After the preparation of the working solution, observe whether there is precipitation or turbidity in the working solution with the naked eye. If so, it may be due to poor solubility of the compound in physiological solution, which can be further sonicated in water bath for 30 minutes to improve the clarity of the solution.

[0967] 5) Determine the potential inhibition of hERG channel by the test substance at 30 μΜ, 10 μΜ, 3.33 μΜ, 1.11 μΜ and 0.37 μΜ, fit the dose-effect curve and calculate the corresponding IC 50 .

[0968] 4. Experimental operation

[0969] 4.1 Preparation before the experiment

[0970] 1) Run "Home All Axes" on the SyncroPatch 384i system to calibrate the mechanical arm.

[0971] 2) Run the "LH_Startup" method to clean the instrument and fill the lines with intracellular solution before starting the experiment.

[0972] 3) Place the prepared NMDG 60 extracellular solution and compound working solutions in the corresponding plate positions in the instrument and the experiment is ready to start.

[0973] 4.2 Cell processing

[0974] 1) Take the adherent cells from two T175 flasks and discard the supernatant.

[0975] 2) Rinse twice with 8 mL of phosphate buffered saline with 2 mM EDTA using a 10 mL pipette at room temperature to wash away excess media.

[0976] 3) Add 3 mL of TrypLE Express to the flasks and gently rock to ensure the solution covers the entire cell plane. TM

[0977] 4) Remove half of the volume of the digestion solution so that it only covers the cells with a thin layer.

[0978] 5) Incubate the cells at 37 °C for 8-10 minutes, gently rock under the microscope and observe the cells for complete detachment. Stop the incubation when the cells are completely detached.

[0979] 6) Prepare 10 mL of F-12 (HAM) media with 15 mM HEPES and 10 mL of Standard extracellular solution in a 50 mL centrifuge tube to obtain a 1 : 1 mixture. Add 3 mL of the mixture to each flask and incubate at 4-8 °C for 5 minutes to stop the digestion.

[0980] 7) Gently pipette the cells 3-5 times to detach them and transfer them to a 10 cm cell culture dish.

[0981] 8) Count the cells using a Countess cell counter and dilute the cells with cold Standard extracellular solution to ensure a final density of 5-7.5 * 10 5 cells / mL.

[0982] 9) Transfer the diluted cell suspension to a 10 cm low attachment cell culture dish and incubate at 4-10 °C for 10 minutes.

[0983] 10) Gently mix the cells and transfer them to a Teflon plate for the SyncroPatch 384i system and place them in the cell incubation chamber of the automated patch clamp system. Incubate at 15 °C at 200 rpm for 30 minutes before starting the experiment.

[0984] ​4.3 Recording electrophysiological signals using the SyncroPatch 384i system

[0985] 1) Fill the chip with chip filling solution, fill the bottom with KF110 intracellular solution containing 15 μΜ Aescin as a perforating agent, form the initial internal and external solution environment on both sides of the chip, and compensate the junction potential.

[0986] 2) Add cell suspension to the chip, and set the cell grabbing pressure to -150 mBar, so that the cells are adsorbed on the microwells on the bottom of the chip, and each microwell contains only a single cell. At this time, the bottom of the cell is exposed to the intracellular solution on the other side of the chip. The pressure should be maintained at -50 mBar during the test to prevent the cells from falling off the microwells.

[0987] 3) Add NMDG 60 cell sealing solution, set the clamping potential to -90 mV, and compensate the slow capacitive current C slow and the cell membrane capacitance under this condition.

[0988] 4) Set the clamping voltage to 500 ms and -90 mV; the current sampling frequency is 500 Hz, and the filtering frequency is 3 kHz. The detection condition of the leakage current is -90 mV, and the time course is 500 ms.

[0989] 5) hERG current test method:

[0990] Apply a 4.8-second depolarization to depolarize the membrane potential from -90 mV to +30 mV, then instantaneously apply a repolarization voltage to reduce the membrane potential to -50 mV, and maintain for 5.2 seconds to remove channel inactivation, so as to observe the hERG tail current, and the peak of the tail current is the size of the hERG current. The sampling interval of this stimulation mode is 15 seconds.

[0991] 6) The hERG current of the test compound is continuously recorded for 120 seconds before administration to evaluate the stability of the hERG current generated by the test cell. Only stable cells within the evaluation standard acceptance range can be trusted for subsequent test results.

[0992] 7) Test of the inhibitory effect of the test compound on hERG current: First, the cells are perfused with NMDG 60 extracellular solution containing 0.1% DMSO for 6 times to determine the stable hERG current as the detection baseline, and the baseline current value is the average of 5 stable sampling points. After the hERG current is stable, the solution containing the test compound is perfused around the cells, and 10 minutes are waited for the compound to fully act on the cells and record the hERG current synchronously. After the current tends to be stable, 5 stable hERG current values are read, and their average is taken as the final current value at a specific concentration. If it does not reach a stable state within 10 minutes, the last 5 current peaks recorded are taken as the reading value. Cisapride is used as a positive drug in the test for synchronous determination of 6 concentration points to verify the stability of the test cells and the accuracy of the test results. After testing the compound, 450 nM dofetilide is added to all test cells to completely inhibit the current as a complete positive control of the cells.

[0993] For all test compounds including positive drugs, the test detects the inhibitory effect of multiple different concentration samples on hERG current in at least 2 independent test wells (n>=2) to fit the IC 50 curve.

[0994] 4.4 Data quality control standards

[0995] Only data meeting the following standards can be analyzed subsequently:

[0996] 1) The initial seal resistance is greater than 100 MΩ;

[0997] 2) The series resistance is less than 25 MΩ;

[0998] 3) The leakage current at the detection voltage is less than 50% of the current value under the condition;

[0999] 4) The tail current is greater than the platform current size of the pre-pulse, and the initial tail current value is greater than 150 pA;

[1000] 5) The decay rate of the tail current is less than 30%.

[1001] III. Data analysis

[1002] The data is output by the Data control 384 software, and only data meeting the above standards can be analyzed according to the following steps:

[1003] 1) After perfusing the blank solvent or compound or positive drug gradient solution, 5 consecutive current values stably obtained are averaged to be taken as the "tail current size 空白 ", "tail current size 化合物 ", and "tail current size 阳性对照 ", respectively;

[1004] 2) The percentage of current inhibition was calculated by the following formula:

[1005] The dose-effect curve was fitted and the IC50value was calculated by Graphpad Prism 8.0 software. The results are shown in Table 4. 50

[1006] Table 4. Effects of compounds on hERG potassium ion channel current

[1007] Test Example 5, Effects of Compounds on Proliferative Activity of Multiple Tumor Cells

[1008] Experimental materials and instruments:

[1009] The materials required for this experiment include: cell culture medium RPMI-1640 (BasalMedia #L240KJ); DMEM (BasalMedia #L110KJ); IMDM (BasalMedia #L610KJ); fetal bovine serum (FBS) (Excell #FSP500); PBS phosphate buffer (BasalMedia #B320KJ); 0.25% trypsin (BasalMedia #S310KJ); 100% DMSO (Sigma #D2650); 96-well transparent sterile culture plate (Corning #3599); 96-well plate (Xinyou Biotec Co., Ltd #062096); Cell Viability Detection cell viability detection kit (VKEY-BIO #A2010005N); MRTX1133 (MCE #HY-134813); 25 mL pipette (Corning); 5 mL pipette (Corning); P1000 pipette tip, P200 pipette tip and P10 pipette tip (Axygen).

[1010] ​The instruments and equipment required in the experiment include: Eppendorf pipette; Eppendorf pipette gun; Eppendorf centrifuge; constant temperature carbon dioxide incubator (ThermoFisher); automatic cell counter Vi-cell XR (Beckman Coulter); Envision enzyme label instrument (Perkin Elmer). The cells required in the experiment: HPAC (COBIOER); GP2D (COBIOER); H441 (ATCC); SW480 (COBIOER); Capan-1 (COBIOER); MKN-1 (COBIOER); HS766T (COBIOER); H929 (COBIOER); H727 (ATCC); Capan-2 (COBIOER); SW620 (ATCC); SW403 (COBIOER); PSN1 (COBIOER); A549 (ATCC); SKGT4 (COBIOER); HCT116 (ATCC); THP-1 (ATCC); AN3 CA (ATCC); H1650 (ATCC); H1975 (ATCC); H1944 (COBIOER); MRTX1133-resistant HPAC: HPAC cells were induced with 2000nM MRTX1133, and after 6 months of continuous induction, drug-resistant polyclonal cells were successfully obtained (verified that the 5-day anti-proliferation IC 50 value of the drug-resistant cells was greater than 10μM).

[1011] Experimental method:

[1012] Cells were digested from culture flasks using 0.25% trypsin, collected and resuspended with corresponding fresh complete medium. After counting, the density was adjusted to ensure the detection read value was in the linear response interval, and the negative control group cells could grow uniformly and did not reach contact inhibition. Each 90 μL was added to a 96-well plate, which was placed in a 37°C, 5% carbon dioxide cell incubator overnight. 10 μL of culture solution containing the compound was added to each well, and the compound was diluted by 3 times gradient, with 9 concentration gradients. The positive control group was the medium well without planting cells; the negative control group was the cell planting well without compound treatment. The cell plate was incubated in a 37°C, 5% carbon dioxide condition for 7 days. The cell plate was taken out, and an equal volume of Cell Viability Detection detection reagent was added to each well. The cells were fully lysed by shaking for 2-5 min, and the luminescence signal was stabilized by placing at room temperature for 10 min. The Envision enzyme label instrument was used to read the luminescence value. The inhibition rate was calculated according to the following formula: Inhibition% = (Signal negative control- Signal sample ) / (Signal negative control- Signal positive control)*100. The IC 50 value was calculated by 4-parameter fitting using IDBS XLfit.

[1013] Table 5

[1014] Test Example 6: Rat in vivo pharmacokinetic test (PK)

[1015] Purpose of the experiment: using rats as test animals, using LC / MS / MS method to determine the drug concentration in whole blood at different time after injection or oral administration of the test compound. Study the pharmacokinetics of the compound in rats, and evaluate its pharmacokinetic characteristics.

[1016] Experimental method: 6 healthy male SD rats were randomly divided into 2 dose groups, 3 rats in each dose group, of which 1 group was a tail vein administration group, and the administration dose was 2 mg / kg; the other group was an oral administration group, and the administration dose was 5 mg / kg; the tail vein administration group used a total solvent of 5% DMSO + 10% Solutol HS-15 + 85% H2O or 5% NMP + 15% PEG400 + 80% (20% HP-β-CD), and the oral administration group used a total solvent of 5% DMSO + 10% solutol + 85% H2O or 5% NMP + 15% PEG400 + 80% (20% HP-β-CD). The individual administration amount was calculated according to the body weight of the rats. The tail vein administration group was subjected to jugular vein puncture for blood collection at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 h after administration, and the oral administration group was subjected to jugular vein puncture for blood collection at 0.25, 0.5, 1, 2, 4, 6, 8 and 24 h after administration, about 50 μL of whole blood was taken at each time point, 3 times the volume of ultrapure water was added to the whole blood to obtain a whole blood and water mixed matrix (hereinafter referred to as rat whole blood) of whole blood: ultrapure water (v / v = 1:3), and stored at -80°C. The following is referred to as rat whole blood.

[1017] Take 40 μL of rat whole blood sample, add 600 μL of acetonitrile / methanol (50 / 50, v / v) solvent (containing 10 ng / mL internal standard compound verapamil (purchased from Sigma) to precipitate protein, shake for 5 min, centrifuge for 5 min (14000 rpm), take 70 μL of supernatant, add 70 μL of 0.1% formic acid ultrapure water solution, mix for 5 min at 600 rpm, then centrifuge for 5 min (4000 rpm), and perform quantitative detection on the LC-MS / MS system (AB Sciex Triple Quad 6500+). The beagle dog whole blood standard curve and quality control samples were run along with the determination of sample concentration. For 10x diluted samples, take 2 μL of sample and add 18 μL of blank whole blood, shake for 5 min, then add 300 μL of acetonitrile / methanol (50 / 50, v / v) solvent (containing internal standard compound verapamil) to precipitate protein, and the rest of the processing steps are the same as for the undiluted sample. The drug concentration in the whole blood sample was determined by the LC-MS / MS method, and the lower limit of detection of the method was 1.2 ng / mL, and then the main PK parameters were calculated by the non-compartment model method of WinNonlin software (Phoenix 8.3 version).

[1018] The experimental results are shown in Table 6.

[1019] Table 6

[1020] Test Example 7: In vivo pharmacokinetic test (PK) of beagle dogs

[1021] Purpose of the experiment: Using LC / MS / MS method, the drug concentration in whole blood of beagle dogs at different time points after injection or oral administration of the test compound was determined. The pharmacokinetics of the compound in beagle dogs was studied, and the pharmacokinetic characteristics were evaluated.

[1022] Experimental method: Four healthy male beagle dogs were randomly divided into two dose groups, two in each dose group. One group was the hind limb saphenous vein administration group, and the dose was 1 mg / kg. The other group was the oral administration group, and the dose was 2 mg / kg. The fully dissolved solvent for the intravenous administration group was 5% NMP + 95% (20% HP-β-CD), and the fully dissolved solvent for the oral administration group was 5% NMP + 95% (20% HP-β-CD). The individual dose was calculated according to the body weight of the beagle dogs. For the intravenous administration group, blood was taken at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 h after administration, and for the oral administration group, blood was taken at 0.25, 0.5, 1, 2, 4, 6, 8 and 24 h after administration. About 50 μL of whole blood was taken at each time point, and 3 times the volume of ultrapure water was added to obtain a whole blood and water mixture (v / v = 1:3) of whole blood: ultrapure water (hereinafter referred to as beagle dog whole blood), which was stored at -80°C. The following is referred to as beagle dog whole blood.

[1023] 40 μL of beagle dog whole blood sample was taken, 600 μL of acetonitrile / methanol (50 / 50, v / v) solvent (containing 10 ng / mL of internal standard compound verapamil (from Sigma) to precipitate protein) was added, shaken for 5 min, then centrifuged for 5 min (14000 rpm), 70 μL of supernatant was taken, 70 μL of ultrapure water solution containing 0.1% formic acid was added, mixed for 5 min at 600 rpm, then centrifuged for 5 min (4000 rpm), and quantitatively detected on the LC-MS / MS system (AB Sciex Triple Quad 6500+). The beagle dog whole blood standard curve and quality control samples were run along with the sample concentration determination. For the 10x diluted sample, 2 μL of sample was added to 18 μL of blank whole blood, shaken for 5 min, then 300 μL of acetonitrile / methanol (50 / 50, v / v) solvent (containing internal standard compound verapamil) was added to precipitate protein, and the rest of the processing steps were the same as for the undiluted sample. The drug concentration in the whole blood sample was determined by LC-MS / MS method, and the lower limit of detection of this method was 1.2 ng / mL. Then the main PK parameters were calculated by non-compartment model method of WinNonlin software (Phoenix 8.3 version).

[1024] The experimental results are shown in Table 7.

[1025] Table 7

[1026] Test Example 8: In vivo pharmacokinetic test (PK) in cynomolgus monkeys

[1027] Purpose of the experiment: To determine the drug concentration in whole blood at different time points after injection or oral administration of the test compound in cynomolgus monkeys using LC / MS / MS method. To study the pharmacokinetics of the compound in beagle dogs and evaluate its pharmacokinetic characteristics.

[1028] Experimental method: Five healthy male cynomolgus monkeys were selected and randomly divided into two groups, three in the intravenous injection group and two in the oral gavage group. The dose for the intravenous injection group was 1 mg / kg, and the dose for the oral gavage group was 10 mg / kg. The intravenous injection used a fully dissolved solvent of 5% NMP + 95% (20% HP-β-CD), and the oral gavage group used a solvent (20% HP-β-CD). The individual dose was calculated according to the body weight of the cynomolgus monkeys. The intravenous injection group was taken blood from the limbs at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration, and the oral gavage group was taken blood at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. About 500 μL of whole blood was taken at each time point, and 2 times the volume of ultrapure water was added to obtain 1500 μL of whole blood and water mixed matrix (v / v = 1:2) at -80°C. The following is referred to as cynomolgus monkey whole blood.

[1029] Take 40 μL of cynomolgus monkey whole blood sample, add 600 μL of acetonitrile / methanol (50 / 50, v / v) solvent (containing 10 ng / mL internal standard compound verapamil (from Sigma) to precipitate protein), shake for 5 min, centrifuge for 5 min (14000 rpm), take 70 μL of supernatant, add 70 μL of ultrapure water containing 0.1% formic acid, mix for 5 min at 600 rpm, and then centrifuge for 5 min (4000 rpm). Quantitative detection was performed on the LC-MS / MS system (AB Sciex Triple Quad 6500+). The cynomolgus monkey whole blood standard curve and quality control samples were run along with the sample concentration determination. For the 10x diluted sample, take 2 μL of sample and add 18 μL of blank whole blood, shake for 5 min, add 300 μL of acetonitrile / methanol (50 / 50, v / v) solvent (containing internal standard compound verapamil) to precipitate protein, and follow the same processing steps as the undiluted sample. The drug concentration in the whole blood sample was determined by LC-MS / MS method, and the lower limit of detection of this method was 1.2 ng / mL. Then the main PK parameters were calculated by non-compartment model method of WinNonlin software (Phoenix 8.3 version).

[1030] The experimental results are shown in Table 8.

[1031] Table 8

Claims

a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein X 1 is selected from CH2and NH; n is selected from 0, 1, 2 and 3; A is selected from C3-C 12 Cycloalkylene, 4-10 membered heterocyclic alkylene, C6-C 10 arylene and 5-12-membered heteroarylene, the C3-C 12 Cycloalkylene, 4-10 membered heterocyclic alkylene, C6-C 10 arylene and 5-12 heteroarylene are optionally enclosed by one or more R a replace; R 1 is selected from C(O)R 11 , C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 alkyl, C4-C 12 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl and 5-10 membered heteroaryl, said C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 alkyl, C4-C 12 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl and 5-10 membered heteroaryl are optionally substituted with 1 or more R 1a ; R 2 , R 3 , R 4 , R 7 , R 8 and R 9 are independently selected from hydrogen, halogen, hydroxy, thiol, amino, cyano, C1-C 10 alkyl, C1-C 10 alkoxy, C1-C 10 hydroxyalkyl, C1-C 10 haloalkyl and C3-C7cycloalkyl, which hydroxy, thiol, amino, C1-C 10 alkyl, C1-C 10 alkoxy, C1-C 10 hydroxyalkyl, C1-C 10 haloalkyl and C3-C7cycloalkyl are optionally substituted with one or more R 2a ; or R 4 and the atom to which they are attached together form a 4-10 membered heterocyclyl ring, which is optionally substituted with 1 or more R 7 and the atom to which they are attached together form a 4-10 membered heterocyclyl ring, which is optionally substituted with 1 or more R b substituents; R 5 selected from the group consisting of C1-C 10 alkyl, C3-C 12 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl and 5-10 membered heteroaryl, said C1-C 10 alkyl, C3-C 12 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl and 5-10 membered heteroaryl are optionally substituted with 1 or more R 5a ; R 6 Selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic groups and C1-C4 alkoxy groups, wherein the hydroxyl, mercapto, amino, C1-C4 alkyl, C1-C4 haloalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic groups and C1-C4 alkoxy groups are optionally surrounded by one or more R groups. 6a replace; R 11 selected from amino, C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 alkyl, C3-C 12 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5-10 membered heteroaryl, said amino, C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 alkyl, C3-C 12 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5-10 membered heteroaryl are optionally substituted with 1 or more R 11a ; Each R a and R 10 Independently selected from halogens, amino groups, hydroxyl groups, mercapto groups, cyano groups, and C1-C4 alkyl groups; each R 1a and R 11a is independently selected from the group consisting of halogen, amino, hydroxyl, thiol, cyano, C1-C 10 alkyl, C3-C 12 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5-10 membered heteroaryl, said amino, hydroxyl, thiol, C1-C 10 alkyl, C3-C 12 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5-10 membered heteroaryl is optionally substituted with 1 or more R 1aa ; Each R 2a The radical is independently selected from halogen, cyano, hydroxyl, amino, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C3-C7 cycloalkyl, and 4-6 membered heterocyclic groups, wherein the hydroxyl, amino, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C3-C7 cycloalkyl, and 4-6 membered heterocyclic groups are optionally surrounded by one or more R groups. 1aa replace; Each R 1aa Independently selected from halogen, amino, hydroxyl, mercapto, cyano, C1-C7 alkyl, C1-C7 haloalkyl and C1-C7 alkoxy; each R is independently selected from the group consisting of halogen, cyano, 5a independently selected from the group consisting of halogen, cyano, C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 alkoxy, C3-C 12 cycloalkyl, 4-14 membered heterocyclyl, C6-C 10 aryl and 5-10 membered heteroaryl, said C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 alkoxy, C3-C 12 cycloalkyl, 4-14 membered heterocyclyl, C6-C 10 aryl and 5-10 membered heteroaryl are optionally substituted with 1 or more R c ; Each R 6a Independently selected from halogen, cyano, hydroxyl, amino, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C3-C7 cycloalkyl and 4-6 membered heterocyclic groups; Each R c Independently selected from halogen, amino, hydroxyl, mercapto, cyano, C1-C7 alkyl, C1-C7 alkoxy, C3-C 10 Cycloalkyl and 4-12 membered heterocyclic groups, wherein the amino, hydroxyl, mercapto, C1-C7 alkyl, C1-C7 alkoxy, C3-C 10 Cycloalkyl groups and 4-12 membered heterocyclic groups are optionally surrounded by one or more R groups. h replace; R 5b and R 5b’ are independently selected from the group consisting of C1-C7alkyl, C3-C 12 cycloalkyl, 4-12 membered heterocyclyl, C6-C 10 aryl, and 5-10 membered heteroaryl, said C1-C7alkyl, C3-C 12 cycloalkyl, 4-12 membered heterocyclyl, C6-C 10 aryl, and 5-10 membered heteroaryl are optionally substituted with 1 or more R d ; or R 5b and the atom to which they are attached together form a 4-12 membered heterocyclyl group optionally substituted with 1 or more R 5b’ and the atom to which they are attached together form a 4-12 membered heterocyclyl group optionally substituted with 1 or more R e substituents; each R is independently selected from the group consisting of halogen, hydroxyl, amino, C1-C7alkyl, C1-C4alkoxy, C3-C6cycloalkyl, 4-10 membered heterocyclyl, said amino, C1-C7alkyl, C1-C4alkoxy, C3-C6cycloalkyl, 4-10 membered heterocyclyl optionally substituted with 1 or more R d and R e is independently selected from the group consisting of halogen, hydroxyl, amino, C1-C7alkyl, C1-C4alkoxy, C3-C6cycloalkyl, 4-10 membered heterocyclyl, said amino, C1-C7alkyl, C1-C4alkoxy, C3-C6cycloalkyl, 4-10 membered heterocyclyl optionally substituted with 1 or more R f substituents; Each R f Independently selected from C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, and 4-10 membered heterocyclic groups, wherein the C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, and 4-10 membered heterocyclic groups are optionally surrounded by one or more R... g replace; each R b , R g and R h are independently selected from the group consisting of halogen, hydroxyl, thiol, amino, =0, =CR j R j , C1-C4alkyl, cyano, C3-C6cycloalkyl, 3-6 membered heterocycloalkyl, C1-C4hydroxyalkyl, C1-C4aminoalkyl, C1-C4halogenoalkyl, (C1-C4alkylene)OC1-C4alkyl, C(O)R k , S(O)2R k and C1-C4alkoxy, said hydroxyl, thiol, amino, C1-C4alkyl, C3-C6cycloalkyl, 3-6 membered heterocycloalkyl, C1-C4hydroxyalkyl, C1-C4aminoalkyl, C1-C4halogenoalkyl, (C1-C4alkylene)OC1-C4alkyl and C1-C4alkoxy being optionally substituted by one or more substituents selected from the group consisting of =0, halogen, hydroxyl, cyano, C1-C4halogenoalkyl and C1-C4alkyl; R j and R k Independently selected from H, halogen, hydroxyl, mercapto, cyano, amino, C1-C4 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl and C1-C 10 Alkoxy, hydroxyl, mercapto, amino, C1-C4 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl and C1-C 10 The alkoxy group may be optionally substituted with halogen, hydroxyl, mercapto, amino, =O, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclic alkyl, N(C1-C4 alkyl)2 and NH(C1-C4 alkyl); one or more hydrogen atoms of the compound are optionally deuterium atoms. The compound of claim 1, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein X 1 is NH; or, X 1 is NH and n is 0. The compound of Formula (I) as claimed in any one of claims 1-2, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, A is selected from a 5-6 membered heterocyclyl ene or a 5-6 membered heteroarylene, wherein the 5-6 membered heterocyclyl ene or 5-6 membered heteroarylene is optionally substituted with 1 or more R a substituents; or, A is selected from a 6 membered heterocyclyl ene having 1 N atom and 1 O atom, a 5 membered heteroarylene having 1 N atom and 1 O atom, or a 5 membered heteroarylene having 1 N atom and 1 S atom, wherein the 6 membered heterocyclyl ene or 5 membered heteroarylene is optionally substituted with 1 or more R a substituents; or, A is selected from a morpholene, thiazolene, and oxazolene, which are optionally substituted with 1 or more R a substituents; or, A is selected from a thiazolene and oxazolene, which are optionally substituted with R a substituents; or, A is selected from The optionally substituted with one or more R a substituted; alternatively, A is selected from The optionally substituted with R a substituted; or, A is selected from The optionally substituted by 1 or more R a substituted; or, A is or A is The compound of Formula (I) as described in any one of claims 1-3, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 1 Selected from C(O)R 11 C1-C 10 Alkyl, C4-C 12 Cycloalkyl and 4-10 membered heterocyclic groups, the C1-C 10 Alkyl, C4-C 12 Cycloalkyl groups and 4-10-membered heterocyclic groups are optionally surrounded by one or more R groups. 1a Replace; or, R 1 Selected from C(O)R 11 C1-C5 alkyl, C4-C6 cycloalkyl, and 4, 5, or 6-membered heterocyclic groups, wherein the C1-C5 alkyl, C4-C6 cycloalkyl, and 4, 5, or 6-membered heterocyclic groups are optionally surrounded by one or more R groups. 1a Replace; or, R 1 Selected from C(O)R 11 C1-C5 alkyl groups, C4-C6 cycloalkyl groups, and 4, 5, or 6-membered heterocyclic groups containing at least one nitrogen atom, wherein the C1-C5 alkyl groups and the 4, 5, or 6-membered heterocyclic groups containing at least one nitrogen atom are optionally surrounded by one or more R atoms. 1a Replace; or, R 1 Selected from C(O)R 11 C4-C6 cycloalkyl and C1-C 10 Alkyl groups, the C4-C6 cycloalkyl groups and C1-C 10 Alkyl groups are optionally surrounded by one or more R 1a Replace; or, R 1 Selected from C(O)R 11 C1-C5 alkyl groups and 4, 5, or 6-membered heterocyclic groups, wherein the C1-C5 alkyl groups and 4, 5, or 6-membered heterocyclic groups are optionally surrounded by one or more R groups. 1a Replace; or, R 1 Selected from C(O)R 11 methyl, pentyl, tetrahydropyrrolyl, and cyclopentyl, wherein the methyl, pentyl, tetrahydropyrrolyl, and cyclopentyl groups are optionally separated by one or more R groups. 1a Replace; or R 1 Selected from C(O)R 11 methyl, pentyl, and tetrahydropyrrolyl, wherein the methyl, pentyl, and tetrahydropyrrolyl groups are optionally surrounded by one or more R groups. 1a Replace; or R 1 Selected from C(O)R 11 methyl and pentyl, wherein the methyl and pentyl groups are optionally separated by one or more R groups. 1a Replace; or R 1 Selected from C(O)R 11 methyl, cyclopentyl, and pentyl, wherein the methyl, cyclopentyl, and pentyl groups are optionally separated by one or more R groups. 1a Replace; or, R 1 selected from C(O)R 11 , pentyl and cyclopentyl, said pentyl and cyclopentyl being optionally substituted with 1 or more R 1a ; alternatively, R 1 is selected from cyclopentyl, or R is selected from the group consisting of cyclopentyl, 1 selected from the group consisting of cyclopentyl, The compound of Formula (I) as described in any one of claims 1-4, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, each R 1a is independently selected from the group consisting of halogen, C1-C4alkyl, and C3-C4cycloalkyl, said C1-C4alkyl and C3-C4cycloalkyl being optionally substituted with 1 or more R 1aa ; or each R 1a is independently selected from the group consisting of fluorine, methyl, and cyclopropyl, said methyl and cyclopropyl being optionally substituted with 1 or more R 1aa ; or each R 1a is independently selected from the group consisting of halogen, for example fluorine; and / or R 11 is selected from the group consisting of 4-10 membered heterocyclyl, said 4-10 membered heterocyclyl being optionally substituted with 1 or more R 11a ; or R 11 is selected from the group consisting of 4-6 membered heterocyclyl, said 4-6 membered heterocyclyl being optionally substituted with 1 or more R 11a ; or R 11 is selected from the group consisting of 4, 5, or 6 membered heterocycloalkyl, said 4, 5, or 6 membered heterocycloalkyl optionally containing 1 N atom, and being optionally substituted with 1 or more R 11a ; or R 11 is selected from the group consisting of tetrahydropyrrolyl, said tetrahydropyrrolyl being optionally substituted with 1 or more R 11a ; and / or each R 11a is independently selected from the group consisting of halogen, amino, hydroxyl, thiol, cyano, and C1-C 10 alkyl, said amino, hydroxyl, thiol, and C1-C 10 alkyl being optionally substituted with 1 or more R 1aa ; or each R 11a is independently selected from the group consisting of C1-C4alkyl, said C1-C4alkyl being optionally substituted with 1 or more R 1aa ; or each R 11a is independently selected from the group consisting of methyl, said methyl being optionally substituted with 1 or more R 1aa ; and / or each R 1aa is independently selected from the group consisting of halogen, C1-C7alkyl, C1-C7haloalkyl, and C1-C7alkoxy; or each R 1aa is independently selected from the group consisting of halogen and C1-C4alkyl; or each R 1aa is independently selected from the group consisting of methyl, chloro, and fluoro. The compound of formula (I) as claimed in any one of claims 1 to 5, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 4 selected from C1-C4alkyl, C1-C4hydroxyalkyl, C1-C4haloalkyl, and C3-C6cycloalkyl, said C1-C4alkyl, C1-C4hydroxyalkyl, C1-C4haloalkyl, and C3-C6cycloalkyl being optionally substituted with 1 or more R 2a ; or, R 4 selected from C1-C2alkyl, C1-C2hydroxyalkyl, C1-C2haloalkyl, and C4cycloalkyl, said C1-C2alkyl, C1-C2hydroxyalkyl, and C4cycloalkyl being optionally substituted with 1 or more R 2a ; or, R 4 selected from C1-C4alkyl, C1-C4haloalkyl, and C3-C6cycloalkyl, said C1-C4alkyl, C1-C4haloalkyl, and C3-C6cycloalkyl being optionally substituted with 1 or more R 2a ; or, R 4 selected from C1-C4alkyl and C3-C6cycloalkyl, said C1-C4alkyl and C3-C6cycloalkyl being optionally substituted with 1 or more R 2a ; or, R 4 selected from ethyl optionally substituted with halo; or, R 4 is ethyl optionally substituted with fluoro, such as ethyl and trifluoroethyl; or, R 4 is selected from ethyl, trifluoroethyl, cyclopropylmethyl, or R is selected from the group consisting of ethyl, trifluoroethyl, cyclopropylmethyl and 4 or R is selected from the group consisting of ethyl, trifluoroethyl, cyclopropylmethyl and or R is selected from the group consisting of ethyl and 4 selected from the group consisting of ethyl and or R is H, or R 4 is ethyl. The compound of formula (I) as claimed in any one of claims 1 to 6, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, Each R 2a Independently selected from cyano, C3-C7 cycloalkyl, and 4-6 membered heterocyclic groups, wherein the C3-C7 cycloalkyl and 4-6 membered heterocyclic groups are optionally surrounded by one or more R groups. 1aa Replace; or, each R 2a Independently selected from cyano, C3-C4 cycloalkyl, and 5-6 membered heterocyclic groups, wherein the C3-C4 cycloalkyl and 5-6 membered heterocyclic groups are optionally surrounded by one or more R groups. 1aa Substitution, and / or, the 5-6 membered heterocyclic group contains an O atom; or, each R 2a The groups are independently selected from cyano, cyclopropyl, and tetrahydropyrano, wherein the cyclopropyl and tetrahydropyrano groups are optionally surrounded by one or more R groups. 1aa Replace; and / or, R 1aa It is a C1-C4 alkyl, or a C1-C2 alkyl, or a methyl. The compound of formula (I) as claimed in any one of claims 1 to 7, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 5 Selected from C6-C 10 Aryl and 5-10 heteroaryl, the C6-C 10 Aryl and 5-10 heteroaryl groups are optionally bounded by one or more R groups. 5a Replace; or, R 5 Selected from 6-10 heteroaryl groups, wherein the 6-10 heteroaryl group is optionally surrounded by one or more R groups. 5a Replace; or, R 5 Selected from 6-10-membered heteroaryl groups, wherein the 6-10-membered heteroaryl group contains at least one N atom and is optionally surrounded by one or more R atoms. 5a Replace; or, R 5 Selected from 5-6-membered heteroaryl groups, wherein the 5-6-membered heteroaryl group is optionally surrounded by one or more R groups. 5a Replace; or, R 5 Selected from phenyl, quinolinyl and pyrazolopyridinyl, which are substituted by one or more radicals Rq; phenyl, quinolinyl, and pyrazolopyridinyl are optionally substituted with 1 or more R 5a substituted; or, R 5 is The optionally substituted by 1 or more R 5a ; or, R 5 is wherein N can be oxidized to form The optionally substituted by 1 or more R 5a substituted. The compound of formula (I) as claimed in any one of claims 1 to 8, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, each R is independently selected from the group consisting of halogen, cyano, 5a independently selected from the group consisting of halogen, cyano, C1-C 10 alkyl, C2-C 10 alkenyl, C1-C 10 alkoxy, 4-14 membered heterocyclyl, and 5-10 membered heteroaryl, said C1-C 10 alkyl, C2-C 10 alkenyl, C1-C 10 alkoxy, 4-14 membered heterocyclyl, and 5-10 membered heteroaryl are optionally substituted with 1 or more R c each R 5a is independently selected from halogen, cyano, C1-C4alkyl, C2-C4alkynyl, C1-C4alkoxy, 4- to 13-membered heterocyclyl, and 5- to 6-membered heteroaryl, optionally substituted with 1 or more R c substituents; or each R 5a independently selected from fluoro, cyano, C1-C3 alkyl, C2-C3 alkynyl, C1-C2 alkoxy, 4-13 membered heterocyclyl containing at least one N atom and 6 membered heteroaryl containing two N atoms, said C1-C3 alkyl, C2-C3 alkynyl, C1-C2 alkoxy, 4-13 membered heterocyclyl and 6 membered heteroaryl groups are optionally substituted with 1 or more R c each R 5a independently selected from fluoro, cyano, piperazinyl, piperidinyl, pyrimidinyl, propynyl, pentynyl, ethynyl, methoxy, ethyl, ethoxy, isopropyl, pyrrolidinyl, azetidinyl, said piperazinyl, piperidinyl, pyrimidinyl, propynyl, pentynyl, ethynyl, methoxy, ethyl, ethoxy, isopropyl, pyrrolidinyl, azetidinyl, optionally substituted with 1 or more R c ; or each R 5a is independently selected from isopropyl, fluoro, cyano, piperazinyl, piperidinyl, pyrimidinyl, propynyl, and ethyl, said isopropyl, piperazinyl, piperidinyl, pyrimidinyl, propynyl, and ethyl optionally substituted with 1 or more R c ; or each R 5a is independently selected from each R 5a is independently selected from isopropyl, fluoro, cyano, or each R is independently selected from the group consisting of isopropyl, fluoro, cyano, 5a is independently selected from the group consisting of isopropyl, fluoro, cyano, The compound of formula (I) as claimed in any one of claims 1 to 9, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, Each R c The amino group, C1-C4 alkyl group, C1-C4 alkoxy group, C3-C8 cycloalkyl group, and 4-8 membered heterocyclic group are independently selected from amino, C1-C4 alkyl, C1-C4 alkoxy, C3-C8 cycloalkyl, and 4-8 membered heterocyclic groups, which are optionally surrounded by one or more R groups. h Replace; or, each R c The heterocyclic group is selected independently from amino, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, and contains 1, 2, or 3 heteroatoms or heterogroups independently selected from N, O, S, -S(=O)2-, S(=O)2-NH-, -P(=O)-, -PH(=O)-, -S(=O)(=NH)-, -C(=O)-, or -C(=O)NH-, wherein the amino, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, and 4-12 heterocyclic group are optionally separated by one or more R h Replace; or, each R c Independently selected from amino, methyl, ethyl, butyl, methoxy, cyclopropyl, morpholino, thiomorpholino, azacyclic butyl, oxacyclic butyl, piperazine, And piperidinyl, wherein the amino, methyl, ethyl, butyl, methoxy, cyclopropyl, morpholinyl, thiomorpholinyl, azacyclic butyl, oxacyclic butyl, piperazine, and piperidinyl is optionally substituted with 1 or more R h ; or, each R c is independently selected from the group consisting of amino, methyl, methoxy, cyclopropyl, morpholinyl, oxetanyl, and piperidinyl, said amino, methyl, methoxy, cyclopropyl, morpholinyl, oxetanyl, and piperidinyl is optionally substituted with 1 or more R h substituents. The compound of formula (I) as claimed in any one of claims 1 to 10, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, each R g and R h are independently selected from the group consisting of halogen, hydroxyl, thiol, amino, =0, C1-C4alkyl, C1-C4hydroxyalkyl, C1-C4haloalkyl, (C1-C4alkylene)OC1-C4alkyl, C1-C4alkoxy, and 4- to 6-membered heterocycloalkyl; or each R g and R h are independently selected from the group consisting of halogen, hydroxyl, thiol, amino, =0, C1-C4alkyl, C1-C4hydroxyalkyl, C1-C4haloalkyl, (C1-C4alkylene)OC1-C4alkyl, and C1-C4alkoxy; or each R g and R h are independently selected from the group consisting of halogen, hydroxyl, thiol, amino, C1-C4alkyl, C1-C4hydroxyalkyl, C1-C4haloalkyl, and C1-C4alkoxy. The compound of formula (I) as claimed in any one of claims 1 to 11, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, Each R h Independently selected from halogens, hydroxyl groups, cyano groups, =O, C(O)R k S(O)2R k =CR j R j C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, (C1-C4 alkylene)O C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl and 3-6 membered heterocyclic alkyl, wherein the hydroxyl, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, (C1-C4 alkylene)O C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl and 3-6 membered heterocyclic alkyl are optionally substituted by one or more substituents selected from =O, halogen, hydroxyl, cyano, C1-C4 haloalkyl and C1-C4 alkyl; or, each R h Independently selected from halogens, hydroxyl groups, =O, C1-C4 alkyl groups, C3-C6 cycloalkyl groups, (C1-C4 alkylene)O C1-C4 alkyl groups, C1-C4 hydroxyalkyl groups, and 6-membered heterocyclic alkyl groups; or, each R h Independently selected from fluorine, hydroxyl, =O, hydroxymethyl, ethyl, methoxyethyl, methoxymethyl, cyclopropyl, morpholino, cyano, trifluoromethyl, acetyl, =CF2, =CH2, aminomethyl, methylaminomethyl, S(O)2CH3, and methyl; or each R h independently selected from fluoro, hydroxy, =0, hydroxymethyl, methoxyethyl, cyclopropyl, morpholinyl, and methyl; or each R h independently selected from fluoro, hydroxy, =0, hydroxymethyl, ethyl, methoxyethyl, cyclopropyl, morpholinyl, cyano, trifluoromethyl, acetyl, =CF2, =CH2, aminomethyl, methylaminomethyl, S(O)2CH3, and methyl; or, each R h independently selected from hydroxymethyl, cyclopropyl, morpholinyl, cyano, and methyl; and / or, R k selected from the group consisting of C1-C4alkyl optionally substituted with 1 or more hydroxyl, N(C1-C4alkyl)2, C1-C4alkoxy, and 3-6 membered heterocycloalkyl; and / or, R j selected from the group consisting of H, halogen, and C1-C4alkyl. The compound of formula (I) as claimed in any one of claims 1 to 12, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 5b and the atom to which they are attached together form a 4-6 membered heterocyclyl group optionally substituted with 1 or more R 5b’ and the atom to which they are attached together form a 4-6 membered heterocyclyl group optionally substituted with 1 or more R e or R 5b and the atom to which they are attached together form a 4-6 membered heterocyclyl group optionally substituted with 1 or more R 5b’ or R e and the atom to which they are attached together form a 4-6 membered heterocyclyl group optionally substituted with 1 or more R selected from the group consisting of The optionally substituted by 1 or more R e substituted. The compound of Formula (I) as described in any of claims 1-13, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, Each R e The radical is independently selected from halogen, hydroxyl, amino, C1-C7 alkyl, and 4-10 membered heterocyclic groups, wherein the hydroxyl, amino, C1-C7 alkyl, and 4-10 membered heterocyclic groups are optionally surrounded by one or more R... f Replace; or, each R e Independently selected from C1-C4 alkyl groups and 4-6 membered heterocyclic groups, wherein the C1-C4 alkyl groups and 4-6 membered heterocyclic groups are optionally surrounded by one or more R... f Replace; or, each R e Independently selected from C1-C4 alkyl and 6-membered heterocyclic groups, wherein the C1-C4 alkyl and 6-membered heterocyclic groups are optionally surrounded by one or more R... f Replace; or, each R e Independently selected from ethyl and morpholino groups, wherein the ethyl and morpholino groups are optionally surrounded by one or more R groups. f Replace, and / or, each R f Independently selected from C1-C4 alkoxy groups; or, R f It is a methoxy group. The compound of formula (I) as claimed in any one of claims 1 to 14, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 6 Selected from hydrogen, C1-C4 alkoxy groups and 4-10 membered heterocyclic groups, wherein the C1-C4 alkoxy groups and 4-10 membered heterocyclic groups are optionally surrounded by one or more R groups. 6a Replace; or, R 6 Selected from hydrogen, C1-C2 alkoxy groups and 4, 5, 6, 7 or 8-membered heterocyclic groups containing 1 N atom, 2 N atoms, or 1 N atom and 1 O atom, wherein the C1-C2 alkoxy group and the heterocyclic group are optionally surrounded by one or more R atoms. 6a Replace; or, R 6 Selected from hydrogen, halogen, hydroxyl, mercapto, C1-C4 alkyl, and C1-C4 alkoxy; or, R 6 Selected from hydrogen and C1-C4 alkoxy groups; or, R 6 For hydrogen and ethoxy; or, R 6 Selected from hydrogen, ethoxy, morpholinyl, azetidinyl, pyrrolidinyl and said ethoxyl group, morpholinyl, azetidinyl, pyrrolidinyl and optionally substituted by 1 or more R 6a ; or, R 6 is selected from hydrogen, ethoxy, morpholinyl, pyrrolidinyl and or R 6 is hydrogen and ethoxy; or, R 6 is hydrogen; and / or each R 6a is independently selected from halogen, C1-C4alkoxy, cyano and C1-C4alkyl, or each R 6a is independently selected from halogen, C1-C2alkoxy, cyano and C1-C2alkyl, or each R 6a is independently selected from fluorine, cyano, methoxy and methyl. The compound of formula (I) as claimed in any one of claims 1 to 15, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 7 selected from hydrogen, halogen, hydroxyl, and cyano; or, R 7 is hydrogen. The compound of formula (I) as claimed in any one of claims 1 to 16, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 4 and R 7 The atoms connected to it together form a 6-7 membered heterocycle, which is optionally bounded by one or more R atoms. b Replace; or, R 4 and R 7 Together with the atoms they are attached to, they form a 6-7 membered heterocyclic alkyl group, which is optionally bound by one or more R atoms. b Replace; or, R 4 and R 7 Together with the atoms they are connected to, they form a 6-7 membered heterocyclic alkyl group having one N atom and optionally one O atom, wherein the 6-7 membered heterocyclic alkyl group is optionally separated by one or more R atoms. b Replace; or, selected from the group consisting of said t is selected from 0, 1, 2, and 3; or selected from the group consisting of said t is selected from 0, 1, 2, and 3; and / or, each R b is independently selected from halogen, amino, hydroxy, thiol, and cyano, or each R b is independently selected from halogen, such as fluorine. The compound of formula (I) as claimed in any one of claims 1 to 17, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 2 and R 3 Independently selected from hydrogen, halogen, hydroxyl, cyano and C1-C 10 Alkyl; or, R 2 and R 3 Independently selected from C1-C4 alkyl groups, such as methyl; or, R 2 and R 3 All are methyl; and / or, R 8 Selected from hydrogen, halogen, hydroxyl, cyano, C1-C 10 Alkyl and C3-C7 cycloalkyl; or, R 8 Selected from hydrogen, cyano, C1-C4 alkyl and C3-C7 cycloalkyl; or, R 8 For hydrogen, and / or, R 9 Selected from hydrogen, halogens, and hydroxyl groups; or, R 9 Selected from hydrogen and halogens; or, R 9 Selected from hydrogen and fluorine. The compound of claim 1, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein The compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of formula (II) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof: wherein R 1 , R 2 , R 3 , R 4 , R 5a , R 6 , R 7 , R 8 and R 9 are as defined in claim 1. The compound of formula (I) or its stereoisomers or its pharmaceutically acceptable salts as claimed in claim 19, wherein, A is thiazolylene; R 1 selected from C(O)R 11 , C1-C5 alkyl or C4-C6 cycloalkyl, said C1-C5 alkyl or C4-C6 cycloalkyl being optionally substituted by one or more R 1a , R 1a are independently selected from halogen (e.g. fluorine) or C1-C4 alkyl (e.g. methyl), R 11 selected from 4-6 membered heterocyclyl, said 4-6 membered heterocyclyl being optionally substituted by one or more R 11a , R 11a are independently selected from C1-C4 alkyl (e.g. methyl); R 2 and R 3 are both methyl; R 4 selected from ethyl, trifluoroethyl, cyclopropylmethyl, preferably ethyl and more preferably ethyl; R located at the ortho position to the N atom in the pyridine 5a is R located at the meta position of the N atom in pyridine 5a The group is selected from C2-alkynyl, C3-alkynyl, C4-alkynyl, 4-membered heterocyclic, 5-membered heterocyclic, 6-membered heterocyclic, 5-membered heteroaryl, and 6-membered heteroaryl, wherein each of the alkynyl, heterocyclic, and heteroaryl groups is optionally surrounded by one or more R groups. c Replace, each R c The amino group, C1-C4 alkyl group, C3-C6 cycloalkyl group, and 4-7 membered heterocyclic group are independently selected from amino, C1-C4 alkyl, C3-C6 cycloalkyl, and 4-7 membered heterocyclic groups, which are optionally surrounded by one or more R groups. h Replace, each R h Independently selected from cyano, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 hydroxyalkyl, 3-6 membered heterocyclic alkyl, and (C1-C4 alkylene)O-C1-C4 alkyl groups optionally substituted with substituents selected from =O and C1-C4 haloalkyl groups; and R 6 R 7 R 8 and R 9 All are hydrogen; or, A is R 1 selected from C(O)R 11 、 and cyclopentyl, said and cyclopentyl is optionally substituted with 1 or more R 1a substituents, R 1a is independently selected from fluoro or methyl, R 11 is tetrahydropyrrolyl and is optionally substituted with 1 or more R 11a substituents, R 11a is independently selected from methyl; R 2 and R 3 are each methyl; R 4 is selected from ethyl, trifluoroethyl, cyclopropylmethyl, preferably ethyl and more preferably ethyl; R located at the ortho position to the N atom in the pyridine 5a is R located meta to the N atom in the pyridine 5a selected from propynyl, 6-membered heterocycloalkyl containing 1 or 2 N atoms, and 6-membered heteroaryl containing 2 N atoms, each of said propynyl, 6-membered heterocycloalkyl and 6-membered heteroaryl being optionally substituted with 1 or more R c substituents, each R c is independently selected from amino, methyl, cyclopropyl, piperidinyl and said amino group, methyl group, cyclopropyl group, piperidinyl and optionally substituted with 1 or more R h each R h is independently selected from the group consisting of cyano, methyl, cyclopropyl, hydroxymethyl, and R 6 , R 7 , R 8 and R 9 are each hydrogen; or, A is R 1 selected from cyclopentyl, R 2 and R 3 are each methyl; R 4 is selected from ethyl, trifluoroethyl, cyclopropylmethyl, preferably ethyl and more preferably ethyl; R located at the ortho position to the N atom in the pyridine 5a is R located meta to the N atom in the pyridine 5a selected from propynyl, piperazinyl, piperidinyl, and pyrimidinyl, each optionally substituted with 1 or more R c substituents, each R c is independently selected from methyl, methyl substituted with cyclopropyl, methyl substituted with substituted methyl, cyclopropyl, -N(CH3)2, is substituted morpholinyl; and R 6 , R 7 , R 8 and R 9 are each hydrogen; or, A is R 1 selected from cyclopentyl, R 2 and R 3 are each methyl; R 4 is selected from ethyl, trifluoroethyl, cyclopropylmethyl, preferably ethyl and more preferably ethyl; R located at the ortho position to the N atom in the pyridine 5a is R located meta to the N atom in the pyridine 5a selected from and R 6 , R 7 , R 8 and R 9 are each hydrogen. The compound of formula (I) as claimed in claim 1 or its stereoisomers or its pharmaceutically acceptable salts, wherein, A is a thiazolylene group; R 1 selected from C1-C5 alkyl, said C1-C5 alkyl being optionally substituted with 1 or more R 1a substituted, R 1a independently selected from halogen (e.g. fluorine), R 2 and R 3 are both methyl; R 4 is ethyl; R 5 selected from quinolinyl and pyrazolopyridinyl, said quinolinyl and pyrazolopyridinyl being substituted with multiple R 5a ; at the ortho position to the site of attachment of R 5 to the remainder of the molecule is R 5a ​ the remaining R 5a selected from halogen, cyano, C2alkynyl, C3alkynyl, C4alkynyl, 4- to 7-membered heterocyclyl, 5- to 6-membered heteroaryl, said alkynyl and heterocyclyl and heteroaryl each being optionally substituted with 1 or more R c each R c is independently selected from C1-C4alkyl and 4- to 7-membered heterocyclyl; and R 6 , R 7 , R 8 and R 9 are each hydrogen; or, A is a thiazolylene group; R 1 selected from The optionally substituted with 1 or more R 1a substituted, R 1a is independently selected from fluoro; R 2 and R 3 are both methyl; R 4 is ethyl; R 5 is selected from quinolinyl and pyrazolopyridinyl, said quinolinyl and pyrazolopyridinyl being substituted with multiple R 5a substituted; at the ortho position to the site of attachment of R 5 to the remainder of the molecule is R 5a ​ the remaining R 5a selected from fluoro, cyano, C3alkynyl, or 6-membered heterocyclyl containing 1 or 2 N atoms, each of said alkynyl and heterocyclyl optionally substituted with 1 or more R c each R c is independently selected from methyl and 7-membered heterocyclyl containing 1 O atom and 1 N atom; and R 6 , R 7 , R 8 , and R 9 are each hydrogen; or, A is R 1 selected from R 2 and R 3 are each methyl; R 4 is ethyl; R 5 is selected from quinolinyl and pyrazolopyridinyl, said quinolinyl and pyrazolopyridinyl being substituted with multiple R 5a ; R 5 is at the ortho position to the site of attachment of R 5a to the remainder of the molecule. the remainder of R 5a selected from fluoro, cyano, C3alkynyl, piperazinyl, and piperidinyl, each of which is optionally substituted with 1 or more R c each R c is independently selected from methyl and and R 6 , R 7 , R 8 and R 9 are each hydrogen; or, A is R 1 selected from R 2 and R 3 are each methyl; R 4 is ethyl; R 5 is selected from quinolinyl and pyrazolopyridinyl, said quinolinyl and pyrazolopyridinyl being substituted with multiple R 5a ; R 5 is at the ortho position to the site of attachment of R 5a to the remainder of the molecule. the remaining R 5a selected from fluoro, cyano, and R 6 , R 7 , R 8 , and R 9 are each hydrogen. The compound of claim 1 of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, selected from the following compounds or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, A pharmaceutical composition comprising a compound of Formula (I) as described in any one of claims 1-22, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. A compound of Formula (I) as described in any one of claims 1-22, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 23, for use in the prevention or treatment of a RAS-mediated disease.

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