Compound acting as cbl-b inhibitor

Abstract

Disclosed are a compound having a Cbl-b inhibiting effect or a pharmaceutically acceptable salt thereof, and a use thereof in the preparation of a drug for diseases related to abnormal Cbl-b expression. Specifically disclosed is a compound represented by formula I or a pharmaceutically acceptable salt thereof.

Description

Compounds as Cbl-b inhibitors Technical Field

[0001] This invention relates to compounds that inhibit Cbl-b activity, or their pharmaceutically acceptable salts, esters, stereoisomers, tautomers, solvates, metabolites, isotopically labeled compounds or prodrugs, methods for their preparation, and pharmaceutical compositions comprising the same, for the use of said compounds and pharmaceutical compositions in the prevention or treatment of Cbl-b-mediated diseases, conditions, or disorders. Background Technology

[0002] Ubiquitin-mediated immune cell activation is a complex mechanism. Casitas B-lineage lymphoma b (Cbl-b) is a member of the RING E3 ubiquitin ligase Cbl family, mainly expressed on immune cells (such as CD8+ T cells, monocytes, and NK cells), negatively regulating immune function, and is considered a potential intracellular immune checkpoint.

[0003] Cbl-b, as a master regulator of effector cell (T cell and NK cell) immunity, can significantly enhance anti-tumor immunity by eliminating its endogenous negative regulatory function through inactivation. Human exome sequencing results indicate that loss-of-function mutations in Cbl-b lead to autoimmune diseases such as T1D, SLE, and MS, as well as myeloid hematologic malignancies. In vitro and in vivo mouse studies have demonstrated that Cbl-b knockout or loss of function promotes T cell and NK cell proliferation and anti-tumor effects, while inhibiting the immunosuppressive effects of Treg cells. Genetic or pharmacological inhibition of Cbl-b has shown significant tumor-suppressive effects in multiple mouse tumor models. Therefore, developing novel, highly active, and highly selective Cbl-b inhibitors to enhance anti-tumor immunity could bring significant benefits to cancer patients. Summary of the Invention

[0004] In some embodiments, the present invention provides compounds of formula (I) as described below, or pharmaceutically acceptable salts thereof:

[0005] in:

[0006] u is selected from 0, 1, or 2;

[0007] X1, X2, X3 and X4 are each independently selected from CR6 or N;

[0008] R1 and R2 are independently selected from H, halogens, CN, NH2, and NH(C). 1～6 Alkyl), N(C) 1～6 Alkyl)2, C 1～6 Alkyl, C 1～6 Alkoxy, C 3～10Cycloalkyl or 4-10 membered heterocyclic group, wherein the C 1～6 Alkyl, C 1～6 Alkoxy, C 3～10 Cycloalkyl or 4-10 membered heterocyclic groups are optionally R x replace;

[0009] Or R1, R2, and the atoms they are connected to together form C. 3～10 Cycloalkyl or 4-10 membered heterocyclic groups, wherein the C 3～10 Cycloalkyl or 4-10 membered heterocyclic groups are optionally R x replace;

[0010] Alternatively, R1, R2, and their respective connected atoms and bonds can together form C. 3～6 Cycloalkenyl or 4-7 membered heterocyclic groups, wherein the C 3～6 The cycloalkenyl or 4-7 membered heterocyclic group is optionally replaced by R v replace;

[0011] R3 is selected from L2-W;

[0012] L2 is selected from single bond, -CR d R e -;

[0013] W is selected from 5-10-membered heteroaryl or 4-10-membered heterocyclic group, wherein the 5-10-membered heteroaryl or 4-10-membered heterocyclic group is optionally replaced by R. w replace;

[0014] R d and R e Independently selected from H, halogens, OH, C 1～6 Alkyl or C 1～6 Alkoxy, the C 1～6 Alkyl or C 1～6 The alkoxy group may optionally be further substituted by a halogen 1 to 3 times;

[0015] R1 can be arbitrarily chosen with R, provided that the valence allows. d or R e Together with their respective atoms and bonds, they form C 3～6 cycloalkyl or 4-7 membered heterocyclic groups, wherein the C 3～6 Cycloalkyl or 4-7-membered heterocyclic groups are optionally R v replace;

[0016] Ring A is selected from phenyl, 5-6-membered heteroaryl, or 5-7-membered heterocyclic group, wherein the phenyl, 5-6-membered heteroaryl, or 5-7-membered heterocyclic group is... Structural units It can be arbitrarily replaced by R4 n times;

[0017] L1 is selected from single bonds, -(CRa R b ) p -、-NR c -, -O-, -C(=O)-, -C(=O)NH-, -CR a R b -NR c - where p is selected from 1, 2, or 3;

[0018] R a R b R c Each element is independently selected from H, halogen, OH, and C. 1～6 Alkyl or C 1～6 Alkoxy, the C 1～6 Alkyl or C 1～6 Alkoxy groups are optionally replaced by R x Replace 1 to 3 times;

[0019] n is independently selected from 0, 1, 2, 3, or 4;

[0020] Any R a and R b Under conditions where the valence allows, it can form 3-5 membered cycloalkyl groups or 3-5 membered heterocyclic groups;

[0021] R4 is selected from halogens, ⁵O, OH, NH₂, NO₂, CN, and C. 1～6 Alkyl, C 2～4 alkenyl, C 2～4 alkynyl group, C 1～6 Alkoxy, C 3～6 cycloalkyl, C 3～6 Cycloalkyloxy group, 4-7 membered heterocyclic group, 4-7 membered heterocyclic oxy group, wherein NH2, C 1～6 Alkyl, C 2～4 alkenyl, C 2～4 alkynyl group, C 1～6 Alkoxy, C 3～6 cycloalkyl, C 3～6 Cycloalkyloxy, 4-7 membered heterocyclic group, and 4-7 membered heterocyclic oxy group are optionally R y replace;

[0022] When u is 0, n is greater than 2 and two adjacent R4s form a 3- to 6-membered carbon ring or heterocycle. The heterocycle may optionally contain 1 to 3 heteroatoms independently selected from N, O, and S, which can be combined with structural units. Forming 7- to 12-member saturated spiral rings, bridged rings, or fused rings;

[0023] When u is not 0, any two adjacent R4s can optionally form a 3- to 6-membered carbon ring or heterocycle, wherein the heterocycle can optionally contain 1 to 3 heteroatoms independently selected from N, O, and S, which, together with the structural unit Forming 7- to 12-member saturated spiral rings, bridged rings, or parallel ring structures;

[0024] R5 is selected from halogens, CN, OH, COOH, CONH2, C 1～6 Alkyl, C 1～6 Alkoxy, 4-10 nitrogen-containing heterocyclic group, 5-10 nitrogen-containing heteroaryl, 4-10 sulfur-containing heterocyclic group, 5-10 sulfur-containing heteroaryl, C 3～10 cycloalkyl, 4-10 membered heterocyclic, phenyl, 5-10 membered heteroaryl, wherein the C 1～6 Alkyl or C 1～6 Alkoxy groups are optionally replaced by R y Substitution, wherein the 4-10 nucleotide nitrogen-containing heterocyclic group, 5-10 nucleotide nitrogen-containing heteroaryl group, 4-10 nucleotide sulfur-containing heterocyclic group, 5-10 nucleotide sulfur-containing heteroaryl group, C 3～10 Cycloalkyl, 4-10 heterocyclic, phenyl, and 5-10 heteroaryl groups are optionally enclosed by R. z replace;

[0025] R6 is independently selected from H, halogen, OH, CN, C 1～6 Alkyl, C 1～6 Alkoxy, NH2, NH(C) 1～6 Alkyl), N(C) 1～6 Alkyl)2, C 3～6 cycloalkyl, C 3～6 cycloalkyl-O-, C 3～6 Cycloalkyl-NH-, 4-7 membered heterocyclic group, 4-7 membered heterocyclic group oxy group, 4-7 membered heterocyclic group -NH-, C 6～10 Aryl, C 6～10 aryloxy group, C 6～10 aryl-NH-, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy or 5-10-membered heteroaryl-NH-, wherein the C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 cycloalkyl, 4-7 membered heterocyclic, C 6～10 Aryl or 5-10 heteroaryl groups are optionally occupied by R y replace;

[0026] Alternatively, two R6 atoms and their attached C atoms can together form C. 3～6 Cycloalkenyl, phenyl, 4-7 membered heterocyclic or 5-6 membered heteroaryl, wherein C 3～6 Cycloalkenyl, phenyl, 4-7-membered heterocyclic or 5-6-membered heteroaryl groups are optionally R y replace;

[0027] R v Independently selected from halogens, OH, CN, C 1～6 Alkyl, (C1～6 Alkyl)-CN or C 1～6 Alkoxy, the C 1～6 Alkyl or C 1～6 Alkoxy groups are optionally replaced by halogens, C 1～3 Alkyl, OH, or CN are substituted 1 to 3 times;

[0028] R w Independently selected from halogens, OH, NH2, NH(C) 1～6 Alkyl), N(C) 1～6 Alkyl)2, C 1～6 Alkyl, C 3～10 cycloalkyl or 4-7 membered heterocyclic group, wherein the C 1～6 Alkyl, C 3～10 Cycloalkyl or 4-7-membered heterocyclic groups are optionally surrounded by halogen, =O, OH, CN or C. 1～6 Alkyl substitution 1 to 3 times;

[0029] R x Independently selected from halogens, OH, CN, (C 1～6 Alkyl)-CN, =O,C 1～6 Alkyl, NH2, NH(C) 1～6 Alkyl), N(C) 1～6 Alkyl)2, COOH or C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally substituted 1 to 3 times with a halogen, cyano, hydroxyl or amino group;

[0030] R y Independently selected from halogens, OH, =O, NH2, NH(C) 1～6 Alkyl), N(C) 1～6 Alkyl)2, C 1～6 Alkyl, C 1～6 Alkoxy, wherein the C 1～6 Alkyl, C 1～6 Alkyl or C 1～6 The alkoxy group is further optionally substituted by a halogen or a hydroxyl group 1 to 3 times;

[0031] R z Independently selected from halogens, CN, =O, OH, NO2, C 1～6 Alkyl, OR n 、N(R n 2. S(O)2R n S(O)2N(R) n 2. S(O)R n 、S(O)N(R n 2. C(O)R n C(O)ORn C(O)N(R) n 2. C(O)N(R) n OR n OC(O)R n OC(O)N(R) n )2、N(R n )C(O)OR n 、N(R n )C(O)R n 、N(R n )C(O)N(R n )2、N(R n )C(NR n )N(R n )2、N(R n )S(O)2N(R n )2、N(R n )S(O)2R n C 3～10 Cycloalkyl, 4-7-membered heterocyclic, 6-10-membered aryl, or 5-10-membered heteroaryl, wherein the C 1～6 Alkyl, C 3～10 cycloalkyl, 4-7 membered heterocyclic, C 6～10 Selectively further R-type aryl or 5-10 heteroaryl groups. x replace;

[0032] R n Independently selected from H and C 1～6 Alkyl, phenyl, 4-7 membered heterocyclic or 5-6 membered heteroaryl, wherein C 1～6 Alkyl, phenyl, 4-7-membered heterocyclic or 5-6-membered heteroaryl groups are optionally further R x Substitution, or two R atoms on a N atom. n Together with the N group attached thereto, a 4-7 membered heterocyclic group or a 5-6 membered heteroaryl group is formed, wherein the 4-7 membered heterocyclic group or the 5-6 membered heteroaryl group is optionally further reacted with R. x replace.

[0033] In some embodiments, the present invention provides compounds of formula (I) as described below, or pharmaceutically acceptable salts thereof:

[0034] in,

[0035] u is selected from 0, 1, or 2;

[0036] X1, X2, X3 and X4 are each independently selected from CR6 or N;

[0037] R1 and R2 are independently selected from H, halogens, CN, NH2, and NH(C). 1～6 Alkyl), N(C)1～6 Alkyl)2, C 1～6 Alkyl, C 1～6 Alkoxy, C 3～10 Cycloalkyl or 4-10 membered heterocyclic group, wherein the C 1～6 Alkyl, C 1～6 Alkoxy, C 3～10 Cycloalkyl or 4-10 membered heterocyclic groups are optionally R x replace;

[0038] Or R1, R2, and the atoms they are connected to together form C. 3～10 Cycloalkyl or 4-10 membered heterocyclic groups, wherein the C 3～10 Cycloalkyl or 4-10 membered heterocyclic groups are optionally R x replace;

[0039] Alternatively, R1, R2, and their respective connected atoms and bonds can together form C. 3～6 Cycloalkenyl or 4-7 membered heterocyclic groups, wherein the C 3～6 The cycloalkenyl or 4-7 membered heterocyclic group is optionally replaced by R v replace;

[0040] R3 is selected from L2-W;

[0041] L2 is selected from single bond, -CR d R e -;

[0042] W is selected from 5-10-membered heteroaryl or 4-10-membered heterocyclic group, wherein the 5-10-membered heteroaryl or 4-10-membered heterocyclic group is optionally replaced by R. w replace;

[0043] R d and R e Independently selected from H, halogens, OH, C 1～6 Alkyl or C 1～6 Alkoxy, the C 1～6 Alkyl or C 1～6 The alkoxy group may optionally be further substituted by a halogen 1 to 3 times;

[0044] R1 can be arbitrarily chosen with R, provided that the valence allows. d or R e Together with their respective atoms and bonds, they form C 3～6 cycloalkyl or 4-7 membered heterocyclic groups, wherein the C 3～6 Cycloalkyl or 4-7-membered heterocyclic groups are optionally R v replace;

[0045] Ring A is selected from phenyl, 5-6-membered heteroaryl, or 5-7-membered heterocyclic group, wherein the phenyl, 5-6-membered heteroaryl, or 5-7-membered heterocyclic group is... Structural units It can be arbitrarily replaced by R4 n times;

[0046] L1 is selected from single bonds, -(CR a R b ) p -、-NR c -, -O-, -C(=O)-, -C(=O)NH-, -(CR a R b ) p -NR c - where p is independently selected from 1, 2, or 3;

[0047] R a R b R c Each element is independently selected from H, halogen, OH, and C. 1～6 Alkyl or C 1～6 Alkoxy, the C 1～6 Alkyl or C 1～6 Alkoxy groups are optionally replaced by R x Replace 1 to 3 times;

[0048] n is independently selected from 0, 1, 2, 3, or 4;

[0049] Any R a and R b Under conditions where the valence allows, it can form 3-5 membered cycloalkyl groups or 3-5 membered heterocyclic groups;

[0050] R4 is selected from halogens, ⁵O, OH, NH₂, NO₂, CN, and C. 1～6 Alkyl, C 2～4 alkenyl, C 2～4 alkynyl group, C 1～6 Alkoxy, C 3～6 cycloalkyl, C 3～6 Cycloalkyloxy group, 4-7 membered heterocyclic group, 4-7 membered heterocyclic oxy group, wherein NH2, C 1～6 Alkyl, C 2～4 alkenyl, C 2～4 alkynyl group, C 1～6 Alkoxy, C 3～6 cycloalkyl, C 3～6 Cycloalkyloxy, 4-7 membered heterocyclic group, and 4-7 membered heterocyclic oxy group are optionally R y replace;

[0051] When u is 0, n is greater than 2 and two adjacent R4s form a 3- to 6-membered carbon ring or heterocycle. The heterocycle may optionally contain 1 to 3 heteroatoms independently selected from N, O, and S, which can be combined with structural units. Forming 7- to 12-element saturated helical rings, bridged rings, or parallel rings, wherein the 7- to 12-element saturated helical rings, bridged rings, or parallel rings can be R v Replace 1 to 3 times;

[0052] When u is not 0, any two adjacent R4s can optionally form a 3- to 6-membered carbon ring or heterocycle, wherein the heterocycle can optionally contain 1 to 3 heteroatoms independently selected from N, O, and S, which, together with the structural unit This forms a 7- to 12-element saturated helical ring, bridged ring, or parallel ring structure, wherein the 7- to 12-element saturated helical ring, bridged ring, or parallel ring can be R v Replace 1 to 3 times;

[0053] R5 is selected from halogens, NH2, CN, OH, COOH, CONH2, C 1～6 Alkyl, C 1～6 Alkoxy, 4-10 nitrogen-containing heterocyclic group, 5-10 nitrogen-containing heteroaryl, 4-10 sulfur-containing heterocyclic group, 5-10 sulfur-containing heteroaryl, C 3～10 Cycloalkyl, 4-10 membered heterocyclic, phenyl, 5-10 membered heteroaryl, wherein the NH2, CONH2, C 1～6 Alkyl or C 1～6 Alkoxy groups are optionally replaced by R y Substitution 1 to 3 times, wherein the 4-10 member nitrogen-containing heterocyclic group, 5-10 member nitrogen-containing heteroaryl group, 4-10 member sulfur-containing heterocyclic group, 5-10 member sulfur-containing heteroaryl group, C 3～10 Cycloalkyl, 4-10 heterocyclic, phenyl, and 5-10 heteroaryl groups are optionally enclosed by R. z Replace 1 to 3 times;

[0054] m is selected from 0, 1, or 2;

[0055] R6 is independently selected from H, halogen, OH, CN, C 1～6 Alkyl, C 1～6 Alkoxy, NH2, NH(C) 1～6 Alkyl), N(C) 1～6 Alkyl)2, C 3～6 cycloalkyl, C 3～6 cycloalkyl-O-, C 3～6 Cycloalkyl-NH-, 4-7 membered heterocyclic group, 4-7 membered heterocyclic group oxy group, 4-7 membered heterocyclic group -NH-, C 6～10 Aryl, C 6～10 aryloxy group, C 6～10 aryl-NH-, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy or 5-10-membered heteroaryl-NH-, wherein the C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 cycloalkyl, 4-7 membered heterocyclic, C6～10 Aryl or 5-10 heteroaryl groups are optionally occupied by R y replace;

[0056] Alternatively, two R6 atoms and their attached C atoms can together form C. 3～6 Cycloalkenyl, phenyl, 4-7 membered heterocyclic or 5-6 membered heteroaryl, wherein C 3～6 Cycloalkenyl, phenyl, 4-7-membered heterocyclic or 5-6-membered heteroaryl groups are optionally R y replace;

[0057] R v Independently selected from halogens, OH, CN, C 1～6 Alkyl, (C 1～6 Alkyl)-CN or C 1～6 Alkoxy, the C 1～6 Alkyl or C 1～6 Alkoxy groups are optionally replaced by halogens, C 1～3 Alkyl, OH, or CN are substituted 1 to 3 times;

[0058] R w Independently selected from halogens, OH, NH2, NH(C) 1～6 Alkyl), N(C) 1～6 Alkyl)2, C 1～6 Alkyl, C 3～10 cycloalkyl or 4-7 membered heterocyclic group, wherein the C 1～6 Alkyl, C 3～10 Cycloalkyl or 4-7-membered heterocyclic groups are optionally surrounded by halogen, =O, OH, CN or C. 1～6 Alkyl substitution 1 to 3 times;

[0059] R x Independently selected from halogens, OH, CN, (C 1～6 Alkyl)-CN, =O,C 1～6 Alkyl, NH2, NH(C) 1～6 Alkyl), N(C) 1～6 Alkyl)2, COOH or C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally substituted 1 to 3 times with a halogen, cyano, hydroxyl or amino group;

[0060] R y Independently selected from halogens, OH, =O, NH2, NH(C) 1～6 Alkyl), N(C) 1～6 Alkyl)2, C 1～6 Alkyl, C 1～6 Alkoxy, wherein the C 1～6 Alkyl, C 1～6 Alkyl or C1～6 The alkoxy group is further optionally substituted by a halogen or a hydroxyl group 1 to 3 times;

[0061] R z Independently selected from halogens, CN, =O, OH, NO2, C 1～6 Alkyl, C 1～6 Alkoxy, OR n 、N(R n 2. S(O)2R n S(O)2N(R) n 2. S(O)R n 、S(O)N(R n 2. C(O)R n C(O)OR n C(O)N(R) n 2. C(O)N(R) n OR n OC(O)R n OC(O)N(R) n )2、N(R n )C(O)OR n 、N(R n )C(O)R n 、N(R n )C(O)N(R n )2、N(R n )C(NR n )N(R n )2、N(R n )S(O)2N(R n )2、N(R n )S(O)2R n C 3～10 Cycloalkyl, 4-7-membered heterocyclic, 6-10-membered aryl, or 5-10-membered heteroaryl, wherein the C 1～6 Alkyl, C 3～10 cycloalkyl, 4-7 membered heterocyclic, C 6～10 Selectively further R-type aryl or 5-10 heteroaryl groups. x replace;

[0062] R n Independently selected from H and C 1～6 Alkyl, phenyl, 4-7 membered heterocyclic or 5-6 membered heteroaryl, wherein C 1～6 Alkyl, phenyl, 4-7-membered heterocyclic or 5-6-membered heteroaryl groups are optionally further R x Substitution, or two R atoms on a N atom. n Together with the N group attached thereto, a 4-7 membered heterocyclic group or a 5-6 membered heteroaryl group is formed, wherein the 4-7 membered heterocyclic group or the 5-6 membered heteroaryl group is optionally further reacted with R.x replace.

[0063] In some embodiments, ring A is selected from phenyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazoleyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, or 5-7 membered heterocyclic groups, wherein the 5-7 membered heterocyclic group contains one or two N or S atoms as heteroatoms, and ring A may optionally be substituted by R4 1 to 3 times.

[0064] In some embodiments, ring A is a pyrrole group optionally substituted with R4 1 to 3 times.

[0065] In some implementations, ring A is selected from... The ring A can be optionally replaced by R4 1 to 3 times.

[0066] In some implementation schemes, structural units Selected from The structural unit It can be arbitrarily replaced by R4 n times.

[0067] In some implementations, R4 is selected from halogens, =O, OH, NH2, NO2, CN, C. 1～6 Alkyl, C 2～4 alkenyl, C 2～4 alkynyl group, C 1～6 Alkoxy, C 3～6 cycloalkyl, C 3～6 Cycloalkyloxy group, 4-7 membered heterocyclic group, 4-7 membered heterocyclic oxy group, wherein NH2, C 1～6 Alkyl, C 2～4 alkenyl, C 2～4 alkynyl group, C 1～6 Alkoxy, C 3～6 cycloalkyl, C 3～6 Cycloalkyloxy, 4-7 membered heterocyclic group, and 4-7 membered heterocyclic oxy group are optionally R y replace.

[0068] In some implementations, R4 is selected from halogens, =O, OH, NH2, CN, C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 cycloalkyl, C 3～6 Cycloalkyloxy groups, wherein NH2, C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 cycloalkyl, C 3～6 cycloalkyloxy groups are optionally R y replace.

[0069] In some implementations, R4 is selected from halogens, O, NH2, CN, C. 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 cycloalkyl, wherein NH2, C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 cycloalkyl groups are optionally R y replace.

[0070] In some embodiments, R4 is selected from halogens, or C4 optionally substituted with halogens. 1～6 Alkyl groups, C groups optionally substituted with halogens 1～6 Alkyl groups, C groups optionally substituted with halogens 3～6 Cycloalkyl.

[0071] In some implementations, R4 is selected from halogens, CN, OH, C. 1～6 Alkyl, Halogenated C 1～6 alkyl.

[0072] In some embodiments, R4 is selected from =O, F, Cl, Br, CN, OH, methyl, ethyl, ethynyl, CF3, CHF2, CH2F, methoxy, N(CH3)2, NHCH3, cyclopropyl.

[0073] In some embodiments, R4 is selected from =O, methyl, CF3, F, Cl, methoxy, and cyclopropyl.

[0074] In some implementations, R4 is selected from O, methyl, and CF3.

[0075] In some implementations, R4 is methyl or CF3.

[0076] In other embodiments, in the compound according to formula (I) described above, n is 2, 3 or 4, preferably 2 or 3;

[0077] u is not 0, and

[0078] Any two adjacent R4 atoms form a 3- to 6-membered carbon ring or heterocycle, wherein the heterocycle may optionally contain 1 to 3 heteroatoms independently selected from N, O, and S, which, together with the structural unit This forms a 7- to 12-element saturated helical ring, bridged ring, or parallel ring structure, wherein the 7- to 12-element saturated helical ring, bridged ring, or parallel ring can be R v Replace 1 to 3 times.

[0079] In some embodiments, any two adjacent R4 atoms form a 3- to 6-membered carbon ring, wherein the 3- to 6-membered carbon ring is selected from...

[0080] In some embodiments, any two adjacent R4 atoms form a 3- to 6-membered carbon ring, wherein the 3- to 6-membered carbon ring is selected from...

[0081] In some embodiments, any two adjacent R4 atoms form a 3- to 6-membered heterocycle, which optionally contains 1 to 3 heteroatoms independently selected from N, O, and S.

[0082] In some embodiments, any two adjacent R4 atoms form a 3- to 6-membered heterocycle, which optionally contains 1 to 3 heteroatoms independently selected from N, O, and S. More

[0083] In some implementations, any two adjacent R4s form a 3- to 6-membered carbon ring, which, along with the structural unit... The heterocyclic rings formed are 7- to 12-membered saturated nitrogen-containing spirocyclic rings, bridged rings, or fused rings, wherein the 7- to 12-membered saturated nitrogen-containing spirocyclic rings, bridged rings, or fused rings are selected from... Preferably, the 7- to 12-membered saturated nitrogen-containing spirocyclic, bridged, or fused heterocyclic rings are selected from...

[0084] In some implementations, any two adjacent R4s form a 3- to 6-membered carbon ring, which, along with the structural unit... The heterocyclic rings that form 7- to 12-membered saturated spirocyclic rings, bridged rings, or fused rings are selected from... The 7-12 member saturated spirocyclic, bridged, or fused heterocyclic rings may be substituted 1-3 times with halogens or methyl groups. Preferably, the 7-12 member saturated spirocyclic, bridged, or fused heterocyclic rings are selected from... It can be substituted by halogens or methyl groups 1 to 3 times.

[0085] In some implementations, any two adjacent R4s form a 3- to 6-membered carbon ring, which, along with the structural unit... The heterocyclic rings that form 7- to 12-membered saturated spirocyclic rings, bridged rings, or fused rings are selected from...

[0086] In some implementations, any two adjacent R4s form a 3- to 6-membered carbon ring, which, along with the structural unit... The heterocyclic rings that form 7- to 12-membered saturated spirocyclic rings, bridged rings, or fused rings are selected from...

[0087] In some embodiments, any two adjacent R4 atoms form a 3- to 6-membered heterocycle, which may optionally contain 1 to 3 heteroatoms independently selected from N, O, and S, which, together with the structural unit The formation of 7- to 12-membered saturated spirocyclic heterocycles, bridged heterocycles, or fused heterocycles, wherein the 7- to 12-membered saturated spirocyclic heterocycles, bridged heterocycles, or fused heterocycles are selected from...

[0088] In some embodiments, any two adjacent R4 atoms form a 3- to 6-membered heterocycle, which may optionally contain 1 to 3 heteroatoms independently selected from N, O, and S, which, together with the structural unit The formation of 7- to 12-membered saturated spirocyclic heterocycles, bridged heterocycles, or fused heterocycles, wherein the 7- to 12-membered saturated spirocyclic heterocycles, bridged heterocycles, or fused heterocycles are selected from... The 7- to 12-membered saturated spiroheterocycles, bridged heterocycles, or fused heterocycles may be substituted 1 to 3 times with halogens or methyl groups.

[0089] In some embodiments, any two adjacent R4 atoms form a 3- to 6-membered heterocycle, which may optionally contain 1 to 3 heteroatoms independently selected from N, O, and S, which, together with the structural unit The formation of 7- to 12-membered saturated spirocyclic heterocycles, bridged heterocycles, or fused heterocycles, wherein the 7- to 12-membered saturated spirocyclic heterocycles, bridged heterocycles, or fused heterocycles are selected from...

[0090] In some implementations, L1 is selected from single bonds, -(CR a R b ) p -、-NR c -、-O-、-C(=O-、-(CR) a R b ) p -NR c -

[0091] In some implementations, L1 is selected from single bonds, -(CR a R b ) p -、-NR c -、-O-、-C(=O-、-CR a R b NR c -

[0092] In some implementations, p is 1.

[0093] In some implementation schemes, Ra and R b Each of the C atoms is H, a halogen, or optionally substituted 1 to 3 times by a halogen or OH. 1～3 Alkyl group, preferably H. In some embodiments, any R a and R b Under conditions where the oxidation state allows, it can form C. 3- 5-Cycloalkyl.

[0094] In some implementation schemes, R c Selected from H and C 1～3 alkyl.

[0095] In some implementations, L1 is selected from single bonds, -CH2-, -NH-, -NHCH2-, -NHCH(CH3)-, -CH2CH2-, -CH(CH2OH)-, -CH(CH3)-, -C(CH3)2-, -CH(CF3)-, -CHF-, -CF2-, -C(=O)-.

[0096] In some implementations, L1 is selected from single bonds, -CH2-, -CHF-, -CF2-, -CH2NH-, and -CH2CH2-.

[0097] In some implementations, L1 is selected from -CH2- or -CH2-NH-. Alternatively or additionally, L1 is selected from -CH2-N(C 1～3 Alkyl)-, more preferably -CH2-N(CH3)- or -CH2-N(CH2CH3)-.

[0098] In some implementations, R5 is selected from halogens, CN, OH, COOH, CONH2, C 1～6 Alkyl, C 1～6 alkoxy group, wherein the C 1～6 Alkyl or C 1～6 Alkoxy groups are optionally replaced by R y replace.

[0099] In some embodiments, R5 is selected from 4-10 nitrogen-containing heterocyclic groups, 5-10 nitrogen-containing heteroaryl groups, 4-10 sulfur-containing heterocyclic groups, 5-10 sulfur-containing heteroaryl groups, and C. 3～10 Cycloalkyl, 4-10 membered heterocyclic, phenyl, 5-10 membered heteroaryl, wherein the 4-10 membered nitrogen-containing heterocyclic, 5-10 membered nitrogen-containing heteroaryl, 4-10 membered sulfur-containing heterocyclic, 5-10 membered sulfur-containing heteroaryl, C 3～10 Cycloalkyl, 4-10 heterocyclic, phenyl, and 5-10 heteroaryl groups are optionally enclosed by R. z replace.

[0100] In some embodiments, R5 is selected from halogens, CN, OH, and optionally R y Replacement C 1～6 alkyl.

[0101] In some embodiments, R5 is selected from halogens, CN, OH, and optionally R y Replaces C 1 to 3 times 1～6 Alkyl groups and NH2.

[0102] In some implementations, R5 is selected from C. 1～6 alkyl.

[0103] In some implementations, R5 is selected from F, Cl, CN, OH, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, NH2, NHCH3, N(CH3)2, N(CH3)CH2CH3, CH2OH, CH2CH2OH, CH2CN.

[0104] In some implementations, R5 is selected from CH3, CH2CH3, CH2CH2CH3, and CH(CH3)2.

[0105] Alternatively or additionally, in some implementations, R5 is selected from... The R5 is optionally R z Replace 1 to 6 times.

[0106] In some implementations, R5 is selected from... The R5 is optionally R z Replace 1 to 6 times.

[0107] In some implementations, R5 is selected from... The R5 is optionally R z Replace 1 to 6 times.

[0108] In some implementation schemes, R z Selected from halogens, CN, =O, OH, NO2, C 1～6 Alkyl, OR n 、N(R n 2. S(O)2R n S(O)2N(R) n 2. S(O)R n 、S(O)N(R n 2. C(O)R n C(O)OR n C(O)N(R) n2. C(O)N(R) n OR n OC(O)R n OC(O)N(R) n )2、N(R n )C(O)OR n 、N(R n )C(O)R n 、N(R n )C(O)N(R n )2、N(R n )C(NR n )N(R n )2、N(R n )S(O)2N(R n )2、N(R n )S(O)2R n C 3～10 Cycloalkyl, 4-7-membered heterocyclic, 6-10-membered aryl, or 5-10-membered heteroaryl, wherein the C 1～6 Alkyl, C 3～10 cycloalkyl, 4-7 membered heterocyclic, C 6～10 Selectively further R-type aryl or 5-10 heteroaryl groups. x replace;

[0109] In some implementation schemes, R z Selected from halogens, CN, =O, C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 cycloalkyl, 6-10 aryl, 5-10 heteroaryl, said R z Optionally R x replace.

[0110] In some implementation schemes, R z Selected from halogens, CN, =O, C 1～3 Alkyl, C 1～3 Alkoxy, C 3～6 cycloalkyl, phenyl, the R z Optionally R x replace.

[0111] In some implementation schemes, R z Independently selected from halogens, =O, CN, C 1～3 Alkyl or C 3～6 cycloalkyl, wherein the C 1～6 Alkyl or C 3～6 cycloalkyl groups may optionally be further subjected to R x Replace; and R x Selected from halogens, OH and C 1～3 Alkyl group.

[0112] In some implementation schemes, R z Independently selected from halogens, =O or C 1～3 Alkyl, wherein the C 1～3 Alkyl groups may optionally be further subjected to R x Replace, R x Selected from halogens, OH and C 1～3 Alkyl group.

[0113] In some implementations, R5 is selected from... Alternatively or additionally, R5 is selected from Alternatively or additionally, R5 is selected from Alternatively or additionally, R5 is selected from

[0114] In some implementations, R5 is selected from...

[0115] In some implementations, m is selected from 0, 1, or 2.

[0116] In some implementations, m is selected from 1 or 2.

[0117] In some implementations, m is 1.

[0118] In some implementations, R6 is selected from H, halogens, OH, CN, C. 1～6 Alkyl, C 1～6 Alkoxy, NH2, NH(C) 1～6 Alkyl), N(C) 1～6 Alkyl)2, C 3～6 cycloalkyl, C 3～6 cycloalkyl-O-, C 3～6 Cycloalkyl-NH-, 4-7 membered heterocyclic group, 4-7 membered heterocyclic group oxy group, 4-7 membered heterocyclic group -NH-, C 6～10 Aryl, C 6～10 aryloxy group, C 6～10 aryl-NH-, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy or 5-10-membered heteroaryl-NH-, wherein the C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 cycloalkyl, 4-7 membered heterocyclic, C 6～10 Aryl or 5-10 heteroaryl groups are optionally occupied by R y replace.

[0119] In some implementations, any two R6 atoms together with their attached C atoms form C. 3～6 Cycloalkenyl, phenyl, 4-7 membered heterocyclic or 5-6 membered heteroaryl, wherein C 3～6 Cycloalkenyl, phenyl, 4-7-membered heterocyclic or 5-6-membered heteroaryl groups are optionally R y replace.

[0120] In some implementations, R6 is selected from H, halogens, OH, CN, C. 1～6 Alkyl, C 1～6 Alkoxy, NH2, NH2, NH(C) 1～6 Alkyl), N(C) 1～6 Alkyl)2, C 3～6 cycloalkyl, C 3～6 cycloalkyl-O-, C 3～6 Cycloalkyl-NH-, 4-7-membered heterocyclic group, 4-7-membered heterocyclic oxy group, 4-7-membered heterocyclic-NH-, 5-10-membered heteroaryl or phenyl, wherein the C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, 4-7-membered heterocyclic, phenyl, or 5-10-membered heteroaryl groups are optionally R y replace.

[0121] In some implementations, R6 is selected from H, C 1～6 Alkoxy, NH(C) 1～6 Alkyl), N(C) 1～6 Alkyl)2 or C 3～6 Cycloalkyl group. Preferably, R6 is selected from H, C. 1～3 Alkoxy, NH(C) 1～3 Alkyl), N(C) 1～3 Alkyl)2 or C 3～6 Cycloalkyl, more preferably H, methoxy, ethoxy, NHCH3, NHCH2CH3, NHCH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0122] In some embodiments, R6 is selected from H, halogen, OH, CN, methyl, ethoxy, NHCH3, NHCH2CH3, NHCH(CH3)2, pyrazolyl, cyclopropyl, NH-cyclopropyl, O-cyclopropyl, and O-oxacyclobutyl, wherein the methyl, ethoxy, NHCH3, NHCH2CH3, NHCH(CH3)2, pyrazolyl, cyclopropyl, NH-cyclopropyl, O-cyclopropyl, and O-oxacyclobutyl groups are optionally replaced by R. y Substitution. Preferably, R6 is selected from H, methoxy, ethoxy, NHCH3, NHCH2CH3, NHCH(CH3)2, and cyclopropyl.

[0123] In some implementations, X1, X2, X3, and X4 are independently selected from CR6.

[0124] In some implementations, X2, X3, and X4 are independently selected from CR6 or N, and X1 is selected from CR6.

[0125] In some implementations, X2 and X4 are independently selected from CR6 or N, and X1 and X3 are independently selected from CR6.

[0126] In some implementations, X2 and X4 are N, and X1 and X3 are independently selected from CR6.

[0127] In some implementations, X2 is N, and X1, X3, and X4 are independently selected from CR6.

[0128] In some implementations, X1, X2, and X4 are independently selected from CR6, and X3 is N.

[0129] In some implementations, X1, X2, and X4 are CH, and X3 is CR6.

[0130] In some implementations, X2 is N, X1 and X4 are CH, and X3 is CR6.

[0131] In some implementations, X1, X2, and X4 are CH, and X3 is N.

[0132] In some implementations, n is selected from 0, 1, 2, or 3.

[0133] In some implementations, n is selected from 0, 1, or 2.

[0134] In some implementations, L1-R5 are selected from... Alternatively or additionally, L1-R5 are selected from Alternatively or additionally, L1-R5 are selected from Alternatively or additionally, L1-R5 are selected from Alternatively or additionally, L1-R5 are selected from

[0135] In some implementations, R1 and R2 are independently selected from H, halogens, CN, NH2, NH(C) 1～6 Alkyl), N(C) 1～6 Alkyl)2, C 1～6 Alkyl, C 1～6 Alkoxy, C 3～10 Cycloalkyl or 4-10 membered heterocyclic group, wherein the C 1～6 Alkyl, C 1～6Alkoxy, C 3～10 Cycloalkyl or 4-10 membered heterocyclic groups are optionally R x replace.

[0136] In some implementations, R1 and R2 are independently selected from H, halogens, CN, NH2, and C. 1～3 Alkyl, C 1～3 Alkoxy, C 3～6 cycloalkyl, wherein the C 1～3 Alkyl, C 1～3 Alkoxy, C 3～6 cycloalkyl groups are optionally R x Replace 1 to 3 times.

[0137] In some embodiments, R1 and R2 are independently selected from H, F, Cl, CH3, CH2CH3, CF3, cyclopropyl, cyclobutyl, and fluorocyclopropyl.

[0138] In some implementations, R1 is H or C 1～3 Alkyl group, and R2 is optionally replaced by R x Replaces C 1 to 3 times 3～6 Cycloalkyl. In some embodiments, R1 is selected from H, CH3 or CH2CH3, and R2 is selected from cyclopropyl, cyclobutyl, or fluorocyclopropyl.

[0139] In some implementations, R1 is H, and R2 is optionally R x Replaces C 1 to 3 times 3～6 Cycloalkyl. In some embodiments, R1 is H, and R2 is selected from cyclopropyl, cyclobutyl, and fluorocyclopropyl.

[0140] In some implementations, R1 is H, and R2 is cyclopropyl or cyclobutyl.

[0141] In some implementations, R1, R2, and the atoms they are bonded to together form C. 3～10 Cycloalkyl or 4-10 membered heterocyclic groups, wherein the C 3～10 Cycloalkyl or 4-10 membered heterocyclic groups are optionally R x replace.

[0142] In some implementations, R1, R2, and the atoms they are bonded to together form C. 3～6 cycloalkyl or 4-6 membered heterocyclic groups, wherein the C 3～6 cycloalkyl or 4-6 membered heterocyclic groups are optionally R x replace.

[0143] In some implementation schemes, R x Selected from halogens, OH, CN, -(C 1～3 Alkyl)-CN, C 1～3 Alkoxy or C1～3 Alkyl group, preferably F, Cl, OH, CN, -CH2-CN, or methyl. In some embodiments, R x Selected independently from C 1～6 Alkyl, preferably C 1～3 Alkyl group, more preferably CH3 or CH2CH3.

[0144] In some implementations, R1, R2, and their respective attached atoms and bonds together form C. 3～6 Cycloalkenyl or 4-7 membered heterocyclic groups, wherein the C 3～6 The cycloalkenyl or 4-7 membered heterocyclic group is optionally replaced by R v replace.

[0145] In some implementations, R1, R2, and the atoms they are bonded to together form

[0146] In some implementations, R1, R2, and the atoms they are bonded to together form

[0147] In some implementations, L2 is selected from single bonds, -CH2-, -CHF-, -CF2-, -CH(CH3)-, -C(CH3)2-, and -CH(CF3)-.

[0148] In some implementations, L2 is a single bond.

[0149] In some embodiments, W is selected from 5-10-membered heteroaryl or 4-10-membered heterocyclic groups, wherein the 5-10-membered heteroaryl and 4-10-membered heterocyclic groups are optionally replaced by R. w replace;

[0150] In some embodiments, W is selected from pyrrole, thiophene, furanyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, oxazolyl, isoxazolyl, and oxadiazolyl, each optionally being R w replace.

[0151] In some implementation schemes, R w Selected from halogens, OH, CN, C 1～3 Alkyl or C 3～6 cycloalkyl, the C 1～3 Alkyl and C 1～3 The alkoxy group can be substituted by halogens 1 to 3 times.

[0152] In some implementation schemes, W is selected from

[0153] In some implementation schemes, W is

[0154] In some embodiments, the compound of formula (I) of the present invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compound may be labeled with radioactive isotopes, such as tritium. 3 H), Iodine-125 125 I) or C-14 14 C).

[0155] As one specific implementation method, the isotope atom described in this invention is deuterium (… 3 H).

[0156] In some embodiments, the present invention provides compounds of formula (I) as described above, and pharmaceutically acceptable salts or isomers thereof, wherein said compounds have the structure of formula (I-1): Where: v is selected from 1, 2, 3 or 4, and the rest are defined as before, where n is preferably selected from 0, 1 or 2.

[0157] In some embodiments, the present invention provides compounds of formula (I) as described above and pharmaceutically acceptable salts or isomers thereof, wherein said compounds have the structure of formula (I-2): The rest of the definitions are the same as before.

[0158] In some embodiments, the present invention provides compounds of formula (I) as described above, and pharmaceutically acceptable salts or isomers thereof, wherein said compounds have the structure of formula (II):

[0159] in:

[0160] R1, R2, and the atoms they are connected to together form C. 3～10 Cycloalkyl or 4-10 membered heterocyclic groups, wherein the C 3～10 Cycloalkyl or 4-10 membered heterocyclic groups are optionally R x replace;

[0161] Structural unit Selected from The structural unit may optionally be substituted with halogen or methyl group 1 to 3 times.

[0162] The definitions of X1, X2, X3, X4, u, v, n, ring A, L1, R4, and R5 are the same as before, where n is preferably selected from 0, 1, or 2.

[0163] In some implementations, m is 1.

[0164] In some implementation schemes, structural units Selected from The structural unit may optionally be substituted with halogen or methyl group 1 to 3 times.

[0165] In some implementation schemes, structural units Selected from The structural unit may optionally be substituted with halogen or methyl group 1 to 3 times.

[0166] In some implementations, R1, R2, and the atoms they are bonded to together form

[0167] In some embodiments, the present invention provides compounds of formula (II) as described above, and pharmaceutically acceptable salts or isomers thereof, wherein said compounds are compounds of formula (III):

[0168] in:

[0169] R1, R2, X1, X2, X3, X4, u, v, L1, R4, R5 are as defined above, and

[0170] n is 0, 1, or 2.

[0171] In some embodiments, the present invention provides compounds of formula (II) as described above, and pharmaceutically acceptable salts or isomers thereof, wherein said compounds are compounds of formula (IV):

[0172] in:

[0173] R1, R2, u, v, L1, R4, R5, and R6 are as defined above, and

[0174] n is 0, 1, or 2.

[0175] In some embodiments, the present invention provides compounds of formula (I) as described above, and pharmaceutically acceptable salts or isomers thereof, wherein the compounds of formula (I) are compounds of formula (V):

[0176] R1, R2, X1, X2, X3, X4, L1, R4, and R5 are as defined above, and

[0177] u is 1 or 2.

[0178] In some embodiments, the present invention provides compounds of formula (V) as described above, and pharmaceutically acceptable salts or isomers thereof, wherein the compounds of formula (V) are compounds of formula (VI):

[0179] R1, R2, L1, R4, R5, and R6 are as defined above, and

[0180] u is 1 or 2.

[0181] In a preferred embodiment, n is 0 in the compounds of formula (II), (III), or (IV). In other embodiments, n is 1. In still other embodiments, n is 2.

[0182] In a preferred embodiment, u is 0 in the compounds of formula (II), (III), or (IV). In other embodiments, u is 1. In still other embodiments, u is 2.

[0183] In a preferred embodiment, u is 1 in the compound of formula (V) or formula (VI). In other embodiments, u is 2.

[0184] In a preferred embodiment, v is 1 in the compounds of formula (II), (III), or (IV). In other embodiments, v is 2. In other embodiments, v is 3. In other embodiments, v is 4.

[0185] In a preferred embodiment, in the compounds of formula (II), formula (III), formula (IV), formula (V) or formula (VI), L1 is selected from -CH2-, -CH2-NH-, or -CH2-N(C 1～3 Alkyl group (preferably -CH2-N(CH3)- or -CH2-N(CH2CH3)-).

[0186] In a preferred embodiment, in the compounds of formula (II), (III), (IV), (V), or (VI), R5 is selected from C. 1～6 Alkyl, C 3～6 Cycloalkyl or 4-10 nitrogen-containing heterocyclic groups, wherein the C 3～6 Cycloalkyl or 4-10 nitrogen-containing heterocyclic groups are optionally R z replace.

[0187] In a preferred embodiment, in the compounds of formula (II), (III), (IV), (V), or (VI), L1 is selected from -CH2-, and R5 is selected from 4- to 10-membered nitrogen-containing heterocyclic groups, wherein the 4- to 10-membered nitrogen-containing heterocyclic groups are optionally replaced by R z replace.

[0188] In a preferred embodiment, in the compounds of formula (II), formula (III), formula (IV), formula (V) or formula (VI), L1 is selected from -CH2-NH- or -CH2-N(C 1～3 Alkyl group (preferably -CH2-N(CH3)- or -CH2-N(CH2CH3)-), and R5 is selected from C 1～6 Alkyl or C 3～6 cycloalkyl, wherein the C 3～6 cycloalkyl groups are optionally R z replace.

[0189] In the preferred embodiment, R z Independently selected from halogen or C 1～3 Alkyl, wherein the C 1～3 Alkyl groups may optionally be further subjected to R x Replace, R x Independently selected from halogens, OH and C 1～3 Alkyl group. More preferably, R z It is independently selected from F, Cl, CH3, -CH2CH3, -CH2-OH, CHF3, CHF2, CH2F, -CH2OCH3, and -CH2OCH2CH3.

[0190] In a preferred embodiment, -L1-(R5) in formula (II) m (where m is 1), or -L1-R5 in compounds of formula (III), (IV), (V), or (VI) is selected from:

[0191] In a preferred embodiment, in the compound of formula (IV) or (VI), R6 is selected from H, C 1～6 Alkoxy, NH(C) 1～6 alkyl) or C 3～6 Cycloalkyl groups, preferably H and C 1～3 Alkoxy, NH(C) 1～3 alkyl) or C 3～6 Cycloalkyl, more preferably H, methoxy, ethoxy, NHCH3, NHCH2CH3, NHCH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0192] In a preferred embodiment, in the compounds of formula (II), (III), (IV), (V), or (VI), R1 is H, and R2 is optionally replaced by R x Replaces C 1 to 3 times 3～6 Cycloalkyl; or R1, R2 together with the atoms they are attached to form cyclobutyl, cyclopentyl, or cyclohexyl. In a preferred embodiment, the structural unit... Selected from:

[0193] In a preferred embodiment, in the compounds of formula (II), (III), or (IV), R4 is a halogenated C. 1～3 Alkyl group, preferably CF3.

[0194] In a preferred embodiment, in the compound of formula (V) or formula (VI), R4 is independently C. 1～6 Alkyl, preferably C 1～3 Alkyl, more preferably methyl, ethyl, and even more preferably methyl.

[0195] Some solutions in this invention are derived from arbitrary combinations of the above-mentioned variables.

[0196] This invention provides the following compounds and their pharmaceutically acceptable salts or isomers:

[0197] This invention provides the following compounds and their pharmaceutically acceptable salts or isomers:

[0198] This invention provides the following compounds and their pharmaceutically acceptable salts or isomers:

[0199] This invention provides the following compounds and their pharmaceutically acceptable salts or isomers:

[0200] The present invention also provides the use of the above-described compounds or pharmaceutically acceptable salts thereof in the preparation of Cbl-b inhibitor-related drugs.

[0201] The present invention also provides the above-described compounds or pharmaceutically acceptable salts thereof for use in the preparation of Cbl-b inhibitor-related drugs.

[0202] In some implementations, the Cbl-b inhibitor-related drug also comprises at least one other therapeutic agent.

[0203] The compounds provided by this invention are Cbl-b inhibitors, wherein the compounds of formula I and their pharmaceutically acceptable salts possess excellent Cbl-b receptor inhibitory activity. These Cbl-b inhibitor compounds are capable of treating and / or preventing Cbl-b-mediated diseases or conditions and related diseases or conditions.

[0204] The compounds of Formula I provided by this invention and their pharmaceutically acceptable salts can be used alone or in combination with at least one other therapeutic agent in treatment.

[0205] The pharmaceutically acceptable salts described in this article include acid addition salts and base salts.

[0206] The pharmaceutically acceptable salts described in this article can exist in both non-solvated and solvated forms.

[0207] The present invention also provides pharmaceutical compositions comprising a compound of formula I as described above and a pharmaceutically acceptable salt or isomer thereof, and a pharmaceutically acceptable excipient. In some embodiments, the excipient may be a pharmaceutically acceptable solvent or a pharmaceutically acceptable carrier.

[0208] The compounds and / or compositions provided by this invention may be administered in any suitable form and through any suitable route to provide sufficient levels of the compounds for the treatment of diseases or conditions.

[0209] The present invention also provides the use of compounds of Formula I as described above and pharmaceutically acceptable salts thereof in the preparation of medicaments for treating and / or preventing Cbl-b-mediated diseases or conditions and related diseases or conditions. In some embodiments, the medicaments further comprise at least one other therapeutic agent.

[0210] The present invention also provides compounds of formula I as described above and pharmaceutically acceptable salts thereof for the treatment and / or prevention of Cbl-b mediated diseases or conditions and related diseases or conditions.

[0211] The present invention also provides a method for treating diseases or conditions, the method comprising administering to a patient in need a therapeutically effective amount of a compound of formula I as described above and a pharmaceutically acceptable salt thereof, wherein the disease or condition is a Cbl-b mediated disease or condition and related diseases or conditions. In some embodiments, the method further comprises administering a therapeutically effective amount of at least one other therapeutic agent.

[0212] In some embodiments of the present invention, the disease or symptom is selected from tumors and / or cancer.

[0213] In some embodiments of the present invention, the tumor and / or cancer is selected from hematologic malignancies and solid tumors.

[0214] In some implementations, the Cbl-b-mediated tumors and / or cancers include, but are not limited to: melanoma, thyroid adenoma, head and neck cancer, endometrial cancer, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial carcinoma, bladder cancer, lung cancer, small cell lung cancer, colorectal adenoma, sarcoma, intestinal stromal tumor, gastric cancer, esophageal cancer, colorectal cancer, pancreatic cancer, small bowel cancer, kidney cancer, liver cancer, hepatocellular carcinoma, cholangiocarcinoma, mesothelioma, lymphoma, leukemia, myelodysplastic syndrome, multiple myeloma, plasmacytoma, neuroblastoma, retinoblastoma, and germ cell tumor.

[0215] The present invention also provides the use of the above-described compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of Cbl-b inhibitor-related medicaments.

[0216] In some implementations, the Cbl-b inhibitor-related drug also comprises at least one other therapeutic agent.

[0217] In some embodiments, at least one of the other therapeutic agents described above is an antitumor agent or an anticancer agent. In a further embodiment, the antitumor agent or anticancer agent is an immune checkpoint inhibitor.

[0218] The term "immune checkpoint" refers to a signaling pathway that inhibits the activation of immune cells, while the term "immune checkpoint inhibitor" refers to a compound that blocks immune checkpoints to release the brakes on immune cell activation. In some embodiments, the immune checkpoint inhibitor is an antagonist of at least one inhibitory checkpoint molecule. In some embodiments, the inhibitory checkpoint molecule is selected from: PD-1 (CD279), PD-L1 (CD274), CTLA-4 (CD125), LAG3 (CD223), PVR (CD155), PVRL2 (CD112), PVRL3 (CD113), TIGIT, TIM3 (CD366), and VISTA. In some embodiments, the immune checkpoint inhibitor is an antagonist of at least one inhibitory checkpoint molecule selected from PD-1 (CD279), PD-L1 (CD274), and CTLA-4 (CD152).

[0219] In some embodiments, the at least one inhibitory checkpoint molecule is PD-1. PD-1 antagonists suitable for the treatments, pharmaceuticals, and uses of the present invention include any chemical compound or biomolecule that blocks the binding of PD-L1 expressed on cancer cells or antigen-presenting cells to PD-1 expressed on lymphocytes (T cells, B cells, and / or NK cells). In some embodiments, the immune checkpoint inhibitor is an anti-PD-1 antibody.

[0220] In some embodiments, the at least one inhibitory checkpoint molecule is PD-L1. In some embodiments involving human subjects, the PD-1 antagonist blocks the binding of human PD-L1 to human PD-1. In some embodiments, the immune checkpoint inhibitor is an anti-PD-L1 antibody.

[0221] In some embodiments, the at least one inhibitory checkpoint molecule is CTLA-4. CTLA-4 antagonists suitable for the treatments, pharmaceuticals, and uses of the present invention comprise any chemical compound or biomolecule that blocks the binding of CTLA-4 expressed on lymphocytes (T cells, B cells, and / or NK cells) to ligands (CD80 and / or CD86) expressed on antigen-presenting cells. In some embodiments for treating human subjects, the CTLA-4 antagonist blocks the binding of human CTLA-4 to human ligands. In some embodiments, the immune checkpoint inhibitor is an anti-CTLA4 antibody.

[0222] In some embodiments, the antitumor agent is selected from cytotoxic antibiotics, plant alkaloids, antimetabolites, alkylating agents, and other antitumor agents. In some embodiments, the antitumor agent or anticancer agent is a small molecule drug (e.g., a cancer chemotherapy agent).

[0223] In some embodiments, the cytotoxic antibiotic is selected from: ixabepilone, mitomycin, plicamycin, bleomycin, pixantrone, amrubicin, valrubicin, pirarubicin, mitoxantrone, idarubicin, zorubicin, aclarubicin, epirubicin, daunorubicin, doxorubicin, and dactinomycin.

[0224] In some embodiments, the plant alkaloids are selected from: trabectedin, cabazitaxel, paclitaxel poliglumex, docetaxel, paclitaxel, demecolcine, teniposide, etoposide, vintafolide, vinflunine, vinorelbine, vindesine, vincristine, and vinblastine.

[0225] In some embodiments, the antimetabolite is a pyrimidine analog, a purine analog, or a folic acid analog. In some embodiments, the antimetabolite is selected from: fluxuridine, trifluridine, tegafur, fluorouracil, decitabine, azacitidine, capecitabine, gemcitabine, carmofur, tegafur, fluorouracil, cytarabine, nelarabine, clofarabine, fludarabine, cladribine, tioguanine, mercaptopurine, pralatrexate, pemetrexed, raltitrexed, and methotrexate.

[0226] In some embodiments, the alkylating agent is selected from: dacarbazine, temozolomide, pipebromide, mitobronitol, etoglucid, uracilmustard, ranimustine, nimustine, fotemustine, streptozocin, semustine, lomustine, carmustine, etc. Carboquone, triaziquone, thiotepa, mannosulfan, treosulfan, busulfan, bendamustine, prednimustine, trofosfamide, ifosfamide, mechlorethamine, melphalan, chlorambucil, and cyclophosphamide.

[0227] In other embodiments, the antitumor agent is selected from platinum compounds, methylhydrazine, sensitizers, protein kinase inhibitors, and other antitumor agents. In some embodiments, the platinum compound is selected from cisplatin, carboplatin, oxaliplatin, saxaplatin, and polyplatin.

[0228] Definitions and Explanations

[0229] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0230] The term “pharmaceutically acceptable” as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0231] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of this invention, prepared by reacting a compound with a relatively non-toxic acid or base, as discovered in this invention, with a specific substituent. When the compounds of this invention contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, or similar salts. When the compounds of this invention contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; salts of amino acids (such as arginine); and salts of organic acids such as glucuronic acid. Certain compounds of the present invention contain both basic and acidic functional groups, and thus can be converted into either a base or an acid addition salt.

[0232] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof.

[0233] Unless otherwise stated, the term "isomer" is intended to include geometric isomers, cis-trans isomers, stereo isomers, enantiomers, optical isomers, diastereomers and tautomers.

[0234] The compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this invention.

[0235] Unless otherwise stated, the terms "enantiomer" or "optical isomer" refer to stereoisomers that are mirror images of each other.

[0236] Unless otherwise stated, the terms "cis-trans isomers" or "geometric isomers" arise because the single bonds of double bonds or cyclic carbon atoms cannot rotate freely.

[0237] Unless otherwise stated, the term "diastereomer" refers to a stereoisomer of a molecule having two or more chiral centers and being in a non-mirror relationship with each other.

[0238] Unless otherwise stated, "(+)" indicates right-handed rotation, "(-)" indicates left-handed rotation, and "(±)" indicates racemic rotation.

[0239] Unless otherwise specified, use wedge-shaped solid line keys. and wedge-shaped dashed key The absolute configuration of the center of a solid is represented by a straight solid line key. and straight dashed key The relative configuration of the center of a solid is indicated by a wavy line. Indicates wedge-shaped solid line key or wedge-shaped dashed key Or use wavy lines Indicates a straight solid line key Or straight dashed key

[0240] Unless otherwise stated, the terms "rich in one isomer," "isomer enrichment," "rich in one enantiomer," or "enantiomer enrichment" mean that the content of one isomer or enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

[0241] Unless otherwise stated, the terms "isomer excess" or "enantiomer excess" refer to the difference between the relative percentages of two isomers or two enantiomers. For example, if one isomer or enantiomer is 90% and the other isomer or enantiomer is 10%, then the isomer or enantiomer excess (ee value) is 80%.

[0242] Optically active (R)- and (S)- isomers, as well as D- and L- isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. To obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated, and the auxiliary group is cleaved to provide the desired enantiomer in pure form. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a salt of the diastereomeric isomer is formed with a suitable optically active acid or base, followed by diastereomeric resolution using conventional methods known in the art, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished by using chromatography employing a chiral stationary phase, optionally combined with chemical derivatization (e.g., from amines to carbamates).

[0243] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium. 3 H), Iodine-125 125 I) or C-14 14 C). For example, deuterium can be used to replace hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds of this invention, regardless of radioactivity, are included within the scope of this invention.

[0244] The terms “optional” or “optionally” refer to events or conditions that may occur but are not required to occur as described below, and the description includes both cases where said events or conditions occur and cases where said events or conditions do not occur.

[0245] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which can include deuterium and hydrogen variants, provided that the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may or may not be substituted, unless otherwise specified, and the type and number of substituents can be arbitrary on a chemically feasible basis.

[0246] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and / or their variants are permissible only if such combinations result in stable compounds.

[0247] When the number of a linking group is 0, such as -(CRR)0-, it indicates that the linking group is a single bond. In some embodiments of the present invention, in the structural unit When u is 0, the linking group is a single bond, that is, the structural unit is...

[0248] When the number of a substituent is 0, it means that the substituent does not exist. For example, -A-(R)0 means that the structure is actually -A.

[0249] When a substituent is vacant, it means that the substituent does not exist. For example, if X is vacant in AX, it means that the structure is actually A.

[0250] When one of the variables is selected as a single bond, it means that the two groups it connects to are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0251] When a substituent can be cross-bonded to two or more atoms on a ring, this substituent can bond with any atom on that ring, for example, structural units. This indicates that the substituent R4 can be substituted at any position on ring A or piperidinone. When the listed substituents do not specify which atom they are attached to the substituted group, such substituents can be bonded to any of their atoms. For example, trifluoromethyl as a substituent can be attached to the substituted group through any carbon atom on the pyridine ring.

[0252] When the linking groups listed do not specify their linking direction, the linking direction is arbitrary.

[0253] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of that group can be connected to other groups by chemical bonds. When the chemical bond connection is non-directional and the connectable site contains H atoms, the number of H atoms at that site will decrease accordingly with the number of chemical bonds connected, resulting in a group with a corresponding valence. The chemical bonds connecting the site to other groups can be straight solid line bonds. Straight dashed key or wavy line express.

[0254] Unless otherwise specified, the number of atoms in a ring is usually defined as the elemental number of the ring. For example, a “5-7 elemental ring” refers to a “ring” with 5-7 atoms arranged around it.

[0255] In this invention, the terms "halogenated," "halogen," and "halogen atom" refer to fluorine atoms, chlorine atoms, bromine atoms, iodine atoms, etc. Preferably, the halogen atoms used as substituents for the aryl groups in this invention are fluorine atoms and chlorine atoms.

[0256] The term "C" in this invention 1～6 "Alkyl" refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1-methylpropyl, n-pentyl, isopentyl, 2-methylbutyl, 1,1-dimethylpropyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, and 2-ethylbutyl. The term "C"... 1～3 "Alkyl" refers to a straight-chain or branched alkyl group having 1 to 3 carbon atoms, including but not limited to methyl, ethyl, n-propyl and isopropyl.

[0257] The term "C" in this invention 1～6 "Alkoxy" refers to the carbon group. 1-6 Alkyl-O-, including but not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, 1-methylpropoxy, n-pentyloxy, isopentyloxy, 2-methylbutoxy, 1,1-dimethylpropoxy, 1-ethylpropoxy, n-hexyloxy, 4-methylpentyloxy, and 2-ethylbutoxy. The term "C" 1～3 "Alkoxy" refers to the carbon group. 1-3 Alkyl-O-, including but not limited to methoxy, ethoxy, n-propoxy and isopropoxy.

[0258] In this invention, the term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably a 6- to 10-membered ring, such as phenyl and naphthyl, more preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, including benzo3- to 8-membered cycloalkyl and benzo3- to 8-membered heterocyclic groups, wherein the heterocyclic group is a heterocyclic group containing 1-3 heterocyclic atoms independently selected from N, O, and S; or may further comprise a three-membered nitrogen-containing fused ring containing a benzene ring.

[0259] The term "heteroaryl" or "heteroaryl ring" in this invention refers to a heteroaryl system having 5 to 14 ring atoms, wherein the heteroaryl group has 1 to 4 heterocyclic atoms independently selected from N, O, and S. The heteroaryl group is preferably 5 to 10-membered, more preferably 5- or 6-membered, such as imidazolyl, furanyl, thiophene, thiazolyl, pyrazolyl, oxazolyl, pyrroleyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc.

[0260] Unless otherwise specified, the terms "5-6 membered heteroaryl" and "5-6 membered heteroaryl" in this invention are used interchangeably. The term "5-6 membered heteroaryl" refers to a monocyclic group with a conjugated π-electron system consisting of 5 to 6 ring atoms, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)). p (where p is 1 or 2). 5-6-membered heteroaryl groups can be attached to the rest of the molecule via heteroatoms or carbon atoms. The 5-6-membered heteroaryl groups include both 5-membered and 6-membered heteroaryl groups.

[0261] The term "3- to 6-membered heterocyclic group" in this invention refers to a non-aromatic cyclic group having 3 to 6 ring atoms, comprising one or more heterocyclic atoms independently selected from N, O, and S, and may be fully saturated (i.e., 3- to 6-membered heterocyclic alkyl) or partially unsaturated. The heterocycle may be a 3- to 6-membered monocyclic, bicyclic, or spirocyclic ring. The heterocyclic ring may be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclic group.

[0262] The term "cycloalkyl" refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups, including monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups, including fused cycloalkyl, bridged cycloalkyl, or spirocycloalkyl.

[0263] The term "spirocycloalkyl" refers to a cyclic structure containing a carbon atom and consisting of at least two rings sharing a common atom. For example, a 7- to 12-membered spirocycloalkyl refers to a cyclic structure containing 7 to 12 carbon atoms and consisting of at least two rings sharing a common atom.

[0264] The term "fused cycloalkyl" refers to a fused ring containing carbon atoms and formed by two or more rings sharing two adjacent atoms. For example, a 4- to 10-membered fused cycloalkyl refers to a fused ring containing 4 to 10 ring carbon atoms and formed by two or more rings sharing two adjacent atoms.

[0265] The term "bridged cycloalkyl" refers to a cyclic structure containing carbon atoms and formed by two rings sharing two non-adjacent atoms. For example, 7- to 12-membered bridged cycloalkyl refers to a cyclic structure containing 7 to 12 carbon atoms and formed by two rings sharing two non-adjacent atoms.

[0266] The term "spiroheterocycle" refers to a 5- to 20-membered polycyclic heterocyclic group having rings linked by a shared carbon atom (called a spiro atom), comprising one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon. One or more rings of the spiroheterocyclic group may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, the spiroheterocyclic group is 6- to 14-membered, and more preferably 7- to 12-membered. Depending on the number of shared spiro atoms, spiroheterocyclic groups are classified as monospirocyclic, dispirocyclic, or polyspirocyclic, and preferably refer to monospirocyclic or dispirocyclic groups, and more preferably 3 / 6, 3 / 7, 4 / 4, 3 / 5, 4 / 5, 4 / 6, 5 / 5, or 5 / 6 monospirocyclic groups.

[0267] The term "fused heterocyclic" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms (carbon and carbon or carbon and nitrogen) with another ring, containing one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon. One or more rings of a fused heterocyclic group may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, the fused heterocyclic group is 6- to 14-membered, more preferably 7- to 12-membered, and even more preferably 7- to 10-membered.

[0268] The term "bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic group in which every two rings share two unconnected atoms, comprising one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon. One or more rings of the bridging heterocyclic group may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, the bridging heterocyclic group is 6- to 14-membered, and more preferably 7- to 10-membered.

[0269] The term "C" in this invention 3～6 "Cycloalkyl" or "3- to 6-membered cycloalkyl" refers to a monovalent group obtained by removing any single hydrogen atom from a cyclic hydrocarbon having 3 to 6 carbons. It can be fully saturated (i.e., a 3 to 6-carbon cycloalkyl) or partially unsaturated.

[0270] The term "halogenated alkyl" in this invention refers to an alkyl group that has been substituted with one or more halogens.

[0271] In this invention, the term "alkenyl" refers to a straight-chain or branched monovalent aliphatic hydrocarbon group containing one or more double bonds.

[0272] In this invention, the term "alkynyl" refers to a straight-chain or branched monovalent aliphatic hydrocarbon group containing one or more triple bonds.

[0273] The term "excipient" in this invention includes pharmaceutically acceptable excipients, carriers, mediators, or stabilizers that are non-toxic to cells or mammals exposed thereto at the doses and concentrations used. Physiologically acceptable excipients are typically pH buffers or aqueous solutions. References to compounds described in a pharmaceutical composition, or compounds claimed in a pharmaceutical composition claim, refer to the compound described by the general formula as described in the pharmaceutical composition, excluding other elements of the pharmaceutical composition, i.e., excluding carriers, excipients, etc.

[0274] The compounds of the present invention can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, 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 of the present invention.

[0275] The compounds described in this invention are named according to their chemical structural formulas. If the name of a compound representing the same compound does not match its chemical structural formula, the chemical structural formula shall prevail.

[0276] The structures of the compounds of the present invention can be confirmed by conventional methods known to those skilled in the art. If the present invention relates to the absolute configuration of a compound, the absolute configuration can be confirmed by conventional techniques in the art.

[0277] The solvent used in this invention is commercially available.

[0278] Compounds are named according to conventional naming principles in the field or using Software naming conventions are used; commercially available compounds use supplier catalog names. Beneficial effects

[0279] As novel Cbl-b inhibitors, the compounds of this invention exhibit excellent inhibitory activity against Cbl-b and can be used for the prevention and / or treatment of Cbl-b-mediated diseases or conditions. The compounds of this invention possess excellent properties such as improved pharmacokinetic properties (e.g., improved metabolic stability, suitable half-life, and duration of action) and improved pharmacodynamic properties (e.g., improved antitumor activity, and antitumor activity when used in combination with another therapeutic agent).

[0280] Compared with existing Cbl-b inhibitors (such as those disclosed by Nurix WO2020 / 264398A1 and Arcus WO2024 / 020034A1), the compounds of this invention have excellent metabolic stability and in vivo pharmacological activity. Detailed Implementation

[0281] The present invention will be described in detail below with reference to embodiments, but this does not imply any adverse limitation on the invention. The present invention has been described in detail, and specific embodiments thereof have been disclosed. 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 invention without departing from the spirit and scope thereof.

[0282] intermediate int1

[0283] (1) Int1-1 (45 g, 196.4 mmol) and 1,3-dibromo-2-methylpropane (42 g, 196.4 mmol) were dissolved in N,N-dimethylformamide (600 ml) solution. Sodium hydride (26.2 g, 656 mmol) was added under nitrogen protection at 0 °C and stirred for 2 hours. After the reaction was complete, the mixture was extracted with ethyl acetate, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by silica gel column chromatography to obtain compound Int1-2 (32 g, 57%). 1 H NMR (400MHz, CDCl3) δ7.54(t,J=1.8Hz,1H),7.40–7.30(m,2H),7.17(ddd,J=9.2,4.8,3.3Hz,1H),3.69–3.59(m,3H),3.02–2.9 5(m,1H),2.64(ddd,J=8.2,5.4,2.1Hz,1H),2.45–2.37(m,1H),2.25(d,J=6.6Hz,1H),2.02(d,J=2.8Hz,1H),1.12–1.00(m,3H).

[0284] (2) Int1-2 (32 g, 113.46 mmol) and hydrazine hydrate (115.2 mL) were dissolved in ethanol (410 mL) and stirred at 80 °C for 18 hours under nitrogen protection. After the reaction was complete, the mixture was directly concentrated to obtain compound int1-3 (32 g). LC-MS: 283.0 [M+H] + .

[0285] (3) Dissolve int1-3 (32 g, 113.46 mmol) in tetrahydrofuran (832 mL), add methyl isothiocyanate (24.85 g, 340.38 mmol), and stir at 80 °C for 2 hours. After the reaction is complete, concentrate the reaction solution, purge with ethyl acetate, filter, and concentrate the filtrate to obtain int1-4 (28 g). LC-MS: 356.0 [M+H] + .

[0286] (4) Dissolve int1-4 (20 g, 56.3 mmol) in tetrahydrofuran (200 mL), then add 1.0 M sodium hydroxide solution (500 mL) and stir at 25 °C for 16 hours. After the reaction is complete, adjust the pH of the reaction solution to 3 with dilute hydrochloric acid. Dissolve in ethyl acetate, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, and filter. Concentrate the filtrate to obtain int1-5 (15 g, 79%). LC-MS: 338.0 [M+H] + .

[0287] (5) Dissolve int1-5 (15 g, 44.5 mmol) and acetic acid (60 mL) in dichloromethane (300 mL), then add 30% hydrogen peroxide solution (8 mL) and stir at 25 °C for 16 hours. After the reaction is complete, pour the reaction solution into water, adjust the pH to 10 with 2 M sodium hydroxide solution, extract with dichloromethane, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate. The crude product is purified by silica gel column chromatography and reversed-phase separation to obtain int1 (4 g). LC-MS: 306.0 [M+H] + .

[0288] (6) Compound int1 was separated by SFC (chromatographic column: 10 μm, 0.5 cm id x 25 cm L; mobile phase: A (CO2) and B (isopropanol, isopropanol solution containing 0.1% 7.0 mol / L ammonia); gradient: B% = 25%; flow rate: 140 mL / min; column temperature: 25 °C; wavelength: 214 nm; pressure: 100 bar) to obtain compounds int1A (retention time = 2.968 min) and int1B (retention time = 3.390 min).

[0289] intermediate int2:

[0290] (1) Dissolve int2-1 (10 g, 73.73 mmol), potassium (bromomethyl)trifluoroborate (17.77 g, 88.48 mmol), potassium carbonate (11.21 g, 81.103 mmol), and potassium iodide (1.23 g, 7.373 mmol) in tetrahydrofuran (200 mL). After purging with nitrogen three times, the mixture was heated to 80 °C and reacted for 8 hours. The reaction solution was filtered with acetone, and the filter cake was washed again with acetone. The filtrate was collected and concentrated to obtain compound int2 (7.3 g). LC-MS: 162.2 [M-KF+H] + .

[0291] intermediate int3:

[0292] (1) Int3-1 (45.0 g, 197.37 mmol) was dissolved in N,N-dimethylformamide (450.0 mL), and potassium tert-butoxide (28.89 g, 257.44 mmol) was added at 0 °C. The reaction mixture was reacted at 0 °C for half an hour. Cyclobutyl bromide (31.71 g, 234.86 mmol) was added to the reaction mixture at 0 °C, and the mixture was stirred at 25 °C for 16 hours. The reaction was quenched with ice water, extracted with ethyl acetate, and the organic phases were combined, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give compound int3-2 (34.20 g). LC-MS: 283.0 [M+H] + .

[0293] (2) Compound int3-2 (34.20 g, 120.85 mmol) was dissolved in ethanol (250.0 mL), and hydrazine hydrate (50.0 mL) was added. The mixture was reacted at 80 °C for 16 hours under nitrogen protection, and the solution was concentrated to obtain compound int3-3 (31.10 g). LC-MS: 283.0 [M+H] + .

[0294] (3) Under nitrogen protection, compound int3-3 (31.10 g, 109.89 mmol) was dissolved in tetrahydrofuran (300.0 mL), and methyl isothiocyanate (10.45 g, 142.86 mmol) was added at 25 °C. The reaction was carried out at 70 °C for 2 hours. The mixture was then cooled to 0 °C and filtered to give compound int3-4 (31.70 g). LC-MS: 356.0 [M+H] + .

[0295] (4) Under nitrogen protection, compound int3-4 (31.70 g, 89.04 mmol) was dissolved in tetrahydrofuran (300.0 mL), and 3N sodium hydroxide aqueous solution (100.0 mL) was added at 25 °C. The reaction was carried out at 25 °C for 24 hours. The mixture was cooled to 0 °C and neutralized with 3N hydrochloric acid aqueous solution (100.0 mL). The reaction solution was concentrated, and the residue was extracted with ethyl acetate (200.0 mL). The ethyl acetate phases were combined, dried over sodium sulfate, and evaporated to dryness. The residue was purified by silica gel column chromatography to give int3-5 (27.60 g). LC-MS: 337.0 [M+H] + .

[0296] (5) Under nitrogen protection, int3-5 (27.60 g, 82.14 mmol) was dissolved in dichloromethane (300.0 mL) and glacial acetic acid (100.0 mL). 30% hydrogen peroxide (60.0 mL) was slowly added dropwise at 0 °C. After the addition was complete, the temperature was slowly restored to 25 °C, and stirring was continued for 3 hours. The mixture was cooled to 0 °C, and a saturated sodium carbonate aqueous solution was added. The reaction solution was extracted with dichloromethane, dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was purified by silica gel column chromatography to obtain compound int3 (20.20 g). LC-MS: 306.0 [M+H] + .

[0297] intermediate int4

[0298] (1) Dissolve int4-1 (5 g, 23.36 mmol) in N,N-dimethylformamide (50 ml), add 4-methylaminothiourea hydrochloride (2.8 g, 26.4 mmol) and N,N-diisopropylethylamine (4.3 g, 33 mmol). Cool to 5 °C in an ice-water bath, add (7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (8.88 g, 23.36 mmol), and stir at room temperature for 2 hours under nitrogen protection. Quench the reaction solution with water, extract with ethyl acetate, dry to anhydrous sodium sulfate, and purify the crude product by silica gel column chromatography to obtain int4-2 (7.0 g). LC-MS: 302.0 [M+H] + .

[0299] (2) Dissolve int4-2 (7.0 g, 23.25 mmol) in tetrahydrofuran (50 mL), add 2N sodium hydroxide (20 mL), and react at room temperature for 1 hour under nitrogen protection. Adjust the pH of the reaction solution to weakly acidic with 1N hydrochloric acid aqueous solution. Extract three times with ethyl acetate, concentrate and dry to obtain int4-3 (5.0 g). LC-MS: 284.0 [M+H] + .

[0300] (3) Dissolve int4-3 (5.0 g, 17.67 mmol) in dichloromethane (50 mL), add hydrogen peroxide (10 mL) at 0 °C, and add 3 drops of acetic acid. React at room temperature for 3 hours under nitrogen protection. Pour the reaction solution into water, adjust the pH to 10 with sodium hydroxide aqueous solution, extract, separate the layers, and continue extraction with dichloromethane on the aqueous phase. Combine the organic phases, dry over anhydrous sodium sulfate, and concentrate. Purify the crude product using silica gel column chromatography to obtain int4-4 (2.2 g). LC-MS: 252.0 [M+H] + .

[0301] (4) Dissolve int4-4 (2.2 g, 8.76 mmol) in N,N-dimethylformamide (25 mL), add sodium hydride (770 mg, 19.27 mmol) at 0 °C, and react at 0 °C for 0.5 h under nitrogen protection. Add 1,3-dibromo-2,2-dimethylpropane (1.99 g, 8.76 mmol), and continue the reaction at 0 °C for 2 h. Pour the reaction solution into water, extract the aqueous phase with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate. Purify the crude product by silica gel column chromatography to obtain int4-5 (500 mg). LC-MS: 320.0 [M+H] + .

[0302] (5) Dissolve int4-5 (120 mg, 0.374 mmol) and diboron pinacol ester (190 mg, 0.749 mmol) in 1,4-dioxane (5 mL), add potassium acetate (73 mg, 0.749 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (30 mg, 0.037 mmol), displace nitrogen, and react at 100 °C for 16 hours. Quench the reaction solution in water, extract with ethyl acetate, dry to anhydrous sodium sulfate, and evaporate to dryness to obtain int4-6 (120 mg). LC-MS: 368.2 [M+H] + .

[0303] (6) Dissolve int4-6 (120 mg, 0.327 mmol) in 6 N concentrated hydrochloric acid (10 mL) and react at 25 °C for 16 hours. The reaction solution was evaporated to dryness, and the crude product was purified by reversed-phase column chromatography to obtain compound int4 (80 mg). LC-MS: 286.2 [M+H] + .

[0304] intermediate int5

[0305] (1) Dissolve int5-1 (100 g, 1.78 mol) and silver carbonate (55 g, 0.2 mol) in dioxane (1000 mL), purging three times with nitrogen. Add ethyl isocyanate (134 g, 1.18 mol) at 80 °C, stir at 80 °C for 4 hours, quench the reaction solution with water, filter, extract the filtrate with ethyl acetate, combine the organic phases and dry with sodium sulfate, concentrate the organic phase under reduced pressure to obtain the crude product. Purify the crude product by silica gel column chromatography to obtain int5-2 (78 g). LC-MS: 152.0 [M+H] + .

[0306] (2) Dissolve int5-2 (78 g, 0.46 mol) in chloroform (1000 mL), add manganese dioxide (400 g) at 25 °C, stir overnight at 70 °C, filter the reaction solution, wash the filter cake three times with methanol (1000 mL), and concentrate the filtrate to obtain compound int5-3 (60.6 g). LC-MS: 168.0 [M+H] + .

[0307] (3) Dissolve int5-3 (60.6 g, 0.36 mol) in N,N-dimethylformamide (1000 mL), add sodium hydride (21.7 g, 0.54 mol) in portions under ice bath conditions, and stir at 25 °C for 2 hours. Quench the reaction solution with ice-cold saturated ammonium chloride solution, extract three times with ethyl acetate, wash the organic phase with saturated sodium chloride solution, dry the organic phase with sodium sulfate, concentrate, and purify by column chromatography to obtain product int5-4 (45.5 g). LC-MS: 270.0 [M+H] + .

[0308] (4) Dissolve p-methylsulfonylmethylisocyanate (32.9 g, 0.17 mol) in tetrahydrofuran (500 mL), add potassium tert-butoxide tetrahydrofuran solution (340 mL, 1 M) at -65 °C, stir at -65 °C for 1 hour, then add int5-4 (45.5 g, 0.15 mol), stir at -65 °C for 1 hour, then add ethanol (100 mL), stir at 25 °C for 30 minutes, and then reflux for 2 hours. Quench the reaction solution with saturated ammonium chloride solution, extract with ethyl acetate, wash the organic phase with saturated sodium chloride solution, dry the organic phase with sodium sulfate, concentrate, and purify by column chromatography to obtain product int5 (19.6 g). LC-MS: 309.2 [M+H] + .

[0309] intermediate int6

[0310] (1) Sodium hydride (12.0 g, 60%, 300.0 mol) was dissolved in 1-methylpyrrolidone-2-one (500 mL), and ethyl cyanoacetate (33.9 g, 300.0 mol) was slowly added at 0 °C. After reacting at 0 °C for 30 minutes, int6-1 (30.0 g, 100.0 mmol) was added, and the mixture was stirred at 115 °C for 12 hours. The reaction solution was cooled to room temperature, poured into a saturated ammonium chloride aqueous solution, and extracted with ethyl acetate. The organic phases were combined and dried over sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound int6-2 (19.6 g). 1H NMR (400MHz, DMSO-d6) δ8.05(s,1H),7.80(s,1H),7.66(s,1H),5.72(s,1H),4.23-4.18(m,2H),1.20(t,J=7.2Hz,3H).

[0311] (2) Dissolve int6-2 (19.6 g, 49.87 mmol) in N,N-dimethylformamide (200 mL), add lithium chloride (10.47 g, 249.36 mmol) at 25 °C, and stir at 150 °C for 1 hour under nitrogen protection. Add saturated sodium chloride aqueous solution to the reaction solution, extract with ethyl acetate, combine the organic phases and dry with sodium sulfate, concentrate the organic phase under reduced pressure to obtain crude product. Purify the crude product by silica gel column chromatography to obtain compound int6-3 (12.30 g). 1 H NMR (400MHz, DMSO-d6) δ7.94(s,1H),7.76(s,1H),7.60(s,1H),4.04(s,2H).

[0312] (3) Dissolve int6-3 (12.30 g, 38.32 mmol) in 4N hydrochloric acid methanol (120 mL) and react at 60 °C for 16 hours. The reaction solution was evaporated to dryness to obtain compound int6-4 (12.10 g). 1 H NMR (400MHz, DMSO-d6) δ7.85(s,1H),7.69(s,1H),7.54(s,1H),3.71(s,2H),3.62(s,3H).

[0313] (4) Dissolve int6-4 (12.10 g, 34.18 mmol) and 1,3-dibromo-2-methylpropane (7.3 g, 34.18 mmol) in N,N-dimethylformamide (150 mL), add potassium tert-butoxide (11.50 g, 102.54 mmol) under ice bath, and stir overnight at 25 °C. Add saturated ammonium chloride aqueous solution to the reaction solution, extract with ethyl acetate, combine the organic phases and dry with sodium sulfate, concentrate the organic phase under reduced pressure to obtain crude product. Purify the crude product by silica gel column chromatography to obtain compound int6-5 (7.10 g). 1 H NMR (400MHz, DMSO-d6) δ7.90(s,1H),7.69(s,1H),7.54(s,1H),3.66(s,3H),2.83-2.81(m,4H),1.55-1.54(m,1H),1.11-1.03(m,3H).

[0314] (5) Dissolve int6-5 (7.10 g, 17.40 mmol) in tetrahydrofuran (40 mL), add 4N sodium hydroxide aqueous solution (40 mL) at 25 °C, and stir overnight. Add saturated ammonium chloride aqueous solution to the reaction solution, extract with ethyl acetate, combine the organic phases and dry with sodium sulfate, concentrate the organic phase under reduced pressure to obtain crude product. Purify the crude product by silica gel column chromatography to obtain compound int6-6 (6.20 g). 1 H NMR(400MHz,DMSO-d6)δ12.59(s,1H),7.85(s,1H),7.65(s,1H),7.51(s,1H),3.66( s,3H),2.87-2.82(m,2H),2.31-2.29(m,2H),2.16-2.13(m,1H),1.05-1.03(m,3H).

[0315] (6) Dissolve int6-6 (6.20 g, 15.74 mmol) in N,N-dimethylformamide (60 mL), add 4-methylaminothiourea (2.48 g, 23.60 mmol) and N,N-diisopropylethylamine (6.08 g, 47.22 mmol) at 25 °C, stir for 10 minutes, then add 2-(7-azobenzotriazole)-tetramethylurea hexafluorophosphate (7.16 g, 18.88 mmol), and stir overnight at 25 °C. Adjust the pH of the reaction solution to approximately 7 with 2N hydrochloric acid aqueous solution, extract with ethyl acetate, combine the organic phases and dry with sodium sulfate, concentrate the organic phase under reduced pressure to obtain the crude product. Purify the crude product by silica gel column chromatography to obtain compound int6-7 (3.62 g). LC-MS: 484.0 [M+H] + .

[0316] (7) Dissolve int6-7 (3.62 g, 7.48 mmol) in tetrahydrofuran (30 mL), add 3N sodium hydroxide aqueous solution (30 mL) at 25 °C, and stir overnight. Adjust the pH of the reaction solution to approximately 7 with 2N hydrochloric acid aqueous solution, extract with ethyl acetate, combine the organic phases and dry with sodium sulfate. Concentrate the organic phase under reduced pressure to obtain the crude product. Purify the crude product by silica gel column chromatography to obtain compound int6-8 (3.20 g). LC-MS: 464.0 [M+H] + .

[0317] (8) Dissolve int6-8 (3.20 g, 7.08 mmol) in dichloromethane (45 mL), add glacial acetic acid (10 mL) at 25 °C, and slowly add hydrogen peroxide (5 mL) dropwise under ice bath, stirring for 1 hour. Add saturated sodium bicarbonate aqueous solution to the reaction solution, extract with dichloromethane, combine the organic phases and dry with sodium sulfate, concentrate the organic phase under reduced pressure to obtain the crude product. Purify the crude product by silica gel column chromatography to obtain compound int6-9 (2.40 g). LC-MS: 432.0 [M+H] + .

[0318] (9) Dissolve int6-9 (2.40 g, 5.57 mmol) in dioxane (40 mL), then add cyclopropylboronic acid (1.44 g, 16.71 mmol), potassium phosphate (3.54 g, 16.71 mmol), and 1,1'-bis(di-phenylphosphino)ferrocene palladium chloride (0.61 g, 0.83 mmol) sequentially. Stir at 95 °C for 10 hours. Add saturated sodium chloride aqueous solution to the reaction mixture, extract with ethyl acetate, combine the organic phases and dry with sodium sulfate. Concentrate the organic phase under reduced pressure to obtain the crude product. Purify the crude product by silica gel column chromatography to obtain compound int6 (250 mg). LC-MS: 346.0 [M+H] + .

[0319] intermediate int7

[0320] (1) Dissolve int7-1 (50.0 g, 268.8 mmol) in N,N-dimethylformamide (500 mL), and add iodoethane (41.9 g, 268.8 mmol) and potassium carbonate (37.09 g, 268.8 mmol). Stir overnight at 70 °C under nitrogen protection. Add saturated ammonium chloride aqueous solution to the reaction mixture, extract with ethyl acetate, combine the organic phases and dry with sodium sulfate. Concentrate the organic phase under reduced pressure to obtain the crude product. Purify the crude product by silica gel column chromatography to obtain int7-2 (45.0 g). 1 H NMR (400MHz, DMSO-d6) δ6.94(s,1H),6.91(s,1H),6.75(s,1H),4.03-3.98(q,J=7.2Hz,2H),1.31-1.28(t,J=7.2Hz,3H).

[0321] (2) Dissolve int7-2 (45.0 g, 210.28 mmol) in carbon tetrachloride (500 mL), add N-bromosuccinimide (56.14 g, 315.42 mmol) and azobisisobutyronitrile (3.44 g, 21.03 mmol), and stir at 80 °C for 16 hours under nitrogen protection. Cool the reaction solution to room temperature and evaporate to dryness. Add saturated sodium chloride aqueous solution, extract with ethyl acetate, combine the organic phases and dry with sodium sulfate. Concentrate the organic phase under reduced pressure to obtain the crude product. Purify the crude product by silica gel column chromatography to obtain int7-3 (30.40 g). 1 H NMR(400MHz,DMSO-d6)δ7.22-7.21(m,1H),7.08-7.07(m,1H),7.03-7.02(m ,1H),4.64(s,2H),4.07-4.01(q,J=6.8Hz,2H),1.34-1.29(t,J=7.2Hz,3H).

[0322] (3) Dissolve int7-3 (30.40 g, 104.11 mmol) in tetrahydrofuran (300 mL), add trimethylcyanosilane (12.39 g, 124.93 mmol) and tetrabutylammonium fluoride (in 1N tetrahydrofuran, 125 mL, 125 mmol) at 25 °C, and stir overnight at 25 °C. Add saturated sodium chloride aqueous solution to the reaction solution, extract with ethyl acetate, combine the organic phases and dry with sodium sulfate, concentrate the organic phase under reduced pressure to obtain crude product. Purify the crude product by silica gel column chromatography to obtain int7-4 (13.20 g). 1 H NMR (400MHz, DMSO-d6) δ7.12-7.10(m,2H),6.92(s,1H),4.07-4.02(q,J=6.8Hz,2H),4.01(s,2H),1.33-1.30(t,J=6.8Hz,3H).

[0323] (4) Dissolve int7-4 (13.20 g, 55.23 mmol) in ethanol (150 mL), add 4N sodium hydroxide aqueous solution (150 mL), and stir at 80 °C for 12 hours. Add 4N hydrochloric acid aqueous solution (150 mL) to the reaction solution, add water, and filter to obtain int7-5 (8.92 g). 1 H NMR (400MHz, DMSO-d6) δ7.02-7.00(m,2H),6.83(s,1H),4.04-3.99(q,J=6.8Hz,2H),3.55(s,2H),1.32-1.28(t,J=6.8Hz,3H).

[0324] (5) Dissolve int7-5 (8.92 g, 34.57 mmol) in acetonitrile (140 mL), add potassium carbonate (14.31 g, 103.72 mmol) and methyl iodide (6.38 g, 44.94 mmol). Stir the mixture at 70 °C for 3 hours. Reduce the acetonitrile to dryness. Add a saturated aqueous sodium chloride solution to the mixture. Extract with ethyl acetate. Combine the organic layers, dry and concentrate to dryness. Purify the crude product by silica gel column chromatography to give int7-6 (7.86 g). 1 H NMR (400MHz, DMSO-d6) δ7.04-7.02(m,2H),6.84(s,1H),4.04-4.01(q,J=6.8Hz,2H),3.85(s,2H),3.63(s,2H),1.33-1.29(t,J=6.8Hz,3H).

[0325] (6) Dissolve int7-6 (7.86 g, 28.89 mmol) and 1,3-dibromo-2-methylpropane (6.57 g, 30.42 mmol) in N,N-dimethylformamide (100 mL), and add sodium hydroxide (3.47 g, 86.67 mmol) under ice bath conditions. Stir the mixture at 0 °C for 20 min, then at 25 °C for 4 h, and quench with a saturated aqueous solution of ammonium chloride. Extract with ethyl acetate. Combine the organic layers, dry and concentrate to dryness. Purify the crude product by silica gel column chromatography to give int7-7 (2.95 g). 1 H NMR(400MHz,DMSO-d6)δ7.05-7.03(m,2H),6.87-6.84(m,1H),4.06-4.01(m,2H),3.57(s,2H),2.62-2.6 0(m,2H),2.59-2.57(m,2H),2.31-2.27(m,2H),2.01-1.98(m,1H),1.32-1.29(m,3H),1.02-0.98(m,4H).

[0326] (7) Dissolve int7-7 (2.95 g, 9.05 mmol) in ethanol (40 mL), add hydrazine hydrate (8 mL), and react at 80 °C for 16 hours. Concentrate to dryness and wash with dichloromethane. Filter to obtain int7-8 (2.52 g). LC-MS: 327.0 [M+H] + .

[0327] (8) Dissolve int7-8 (2.52 g, 7.73 mmol) in tetrahydrofuran (30 mL), add methyl isothiocyanate (846 mg, 11.59 mmol), and stir at 70 °C for 4 hours under nitrogen protection. Cool the reaction solution to room temperature, wash with petroleum ether, filter, and collect the product to obtain int7-9 (1.84 g). LC-MS: 400.0 [M+H] + .

[0328] (9) Dissolve int7-9 (1.84 g, 4.61 mmol) in tetrahydrofuran (30 mL), add 4N sodium hydroxide aqueous solution (30 mL) at 25 °C, and stir overnight. Add saturated ammonium chloride aqueous solution to the reaction solution, extract with ethyl acetate, combine the organic phases and dry with sodium sulfate. Concentrate the organic phase under reduced pressure to obtain the crude product. Purify the crude product by silica gel column chromatography to obtain compound int7-10 (1.52 g). LC-MS: 384.0 [M+H] + .

[0329] (10) Dissolve int7-10 (1.52 g, 3.98 mmol) in dichloromethane (30 mL), add glacial acetic acid (5 mL) at 25 °C, and slowly add hydrogen peroxide (5 mL) dropwise under ice bath, stirring for 1 hour. Add saturated sodium bicarbonate aqueous solution to the reaction solution, extract with dichloromethane, combine the organic phases and dry with sodium sulfate, concentrate the organic phase under reduced pressure to obtain crude product. Purify the crude product by silica gel column chromatography to obtain int7 (1.02 g). LC-MS: 350.1 [M+H] + .

[0330] (11) Compound int7 was separated by SFC (column: CHIRALPAK ID (ID00CE-PB019), 0.46 cm id x 25 cm L; mobile phase: A (carbon dioxide) and B (n-hexane / isopropanol = 80 / 20); flow rate: 1 mL / min; column temperature: 35℃; wavelength: 214 nm) to obtain compounds int7A (retention time = 11.436 min) and int7B (retention time = 10.164 min).

[0331] intermediate int8

[0332] (1) Dissolve int8-1 (30.0 g, 98.04 mmol) in ethanol (200 mL), and add hydrazine hydrate (50 mL). Stir overnight at 85 °C under nitrogen protection. Cool the reaction mixture to 25 °C and concentrate under reduced pressure to obtain compound int8-2 (25.0 g). LC-MS: 308 [M+H] + .

[0333] (2) Compound int8-2 (25.0 g, 81.17 mmol) was dissolved in tetrahydrofuran (300 mL), and methyl isothiocyanate (8.91 g, 121.75 mmol) was added. The mixture was stirred at 70 °C for 4 hours under nitrogen protection. The reaction solution was cooled to 25 °C, petroleum ether was added, the mixture was filtered, and the solid was collected to obtain compound int8-3 (19.50 g). 1 H NMR (400MHz, DMSO-d6) δ9.95(s,1H),9.22(s,1H),8.10(s,1H),7.71(s,1H),7.54-7.42(m,2H),3.50(s,2H),2.88-2.87(d,J=4.4Hz,3H).

[0334] (3) Dissolve int8-3 (19.50 g, 51.45 mmol) in tetrahydrofuran (200 mL), add 4N sodium hydroxide aqueous solution at 25 °C, and stir overnight at 25 °C. Add saturated ammonium chloride aqueous solution to the reaction solution, extract three times with ethyl acetate, combine the organic phases and dry them with sodium sulfate. Concentrate the organic phase under reduced pressure to obtain the crude product. Purify the crude product by silica gel column chromatography to obtain compound int8-4 (17.42 g). LC-MS: 363.8 [M+H] + .

[0335] (4) Dissolve int8-4 (17.42 g, 47.86 mmol) in dichloromethane (200 mL), add glacial acetic acid (50 mL) at 25 °C, and slowly add hydrogen peroxide (30 mL) dropwise under ice bath, stirring for 1 hour. Add saturated sodium bicarbonate aqueous solution to the reaction solution, extract three times with dichloromethane, combine the organic phases and dry with sodium sulfate, concentrate the organic phase under reduced pressure to obtain crude product. Purify the crude product by silica gel column chromatography to obtain compound int8-5 (10.01 g, 63.0%). 1 H NMR (400MHz, DMSO-d6) δ8.40(s,1H),7.74-7.73(m,1H),7.49-7.48(m,1H),4.17(s,2H),3.54(s,3H).

[0336] (5) At -40°C, lithium bis(trimethylsilylaminolithium) (1M in tetrahydrofuran, 91.3mL, 91.26mmol) was added to a solution of int8-5 (10.01g, 30.42mmol) and 1,3-dibromo-2-methylpropane (6.57g, 30.42mmol) in 200mL of tetrahydrofuran. The mixture was stirred at -40°C for 20 minutes, then at 0°C for 1 hour, and quenched with 200mL of saturated ammonium chloride aqueous solution. Extraction was performed with ethyl acetate. The organic layers were combined, dried, and concentrated to dryness. Purification by silica gel chromatography gave compound int8-6 (4.22g, 36.1%). LC-MS: 386.0 [M+H] + .

[0337] (6) Compound int8-6 (4.22 g, 11.02 mmol), bis(tert-butyloxycarbonyl)amine (2.39 g, 11.02 mmol), cesium carbonate (7.18 g, 22.04 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (0.635 g, 1.10 mmol), and tris(dibenzylacetone)palladium (0.910 g, 1.10 mmol) were dissolved in dioxane (100 mL). The mixture was purged with nitrogen three times. The mixture was stirred at 100 °C for 16 hours, and then quenched with a saturated aqueous sodium chloride solution. Extraction was performed with ethyl acetate. The organic layers were combined, dried, and concentrated to dryness. Purification was performed by silica gel chromatography to give int8-7 (0.82 g). LC-MS: 423.0 [M+H] + .

[0338] (7) Dissolve int8-7 (0.82 g, 1.95 mmol) in N,N-dimethylformamide (10 mL), add sodium hydrogen (94 mg, 2.34 mmol) at 0 °C, and react at 0 °C for 20 minutes. Add iodoethane (365 mg, 2.34 mmol), and continue the reaction at 25 °C for 1 hour. Quench with saturated sodium chloride aqueous solution (200 mL). Extract with ethyl acetate. Combine the organic layers, dry and concentrate to dryness. Purify by silica gel chromatography to obtain int8 (0.32 g).

[0339] (8) Compound int8 was separated by SFC (column: CHIRALPAK ID (ID00CE-PB019), 0.46 cm id x 25 cm L; mobile phase: A (carbon dioxide) and B (n-hexane / isopropanol = 70 / 30); flow rate: 1 mL / min; column temperature: 35℃; wavelength: 214 nm) to obtain compounds int8A (retention time = 9.1 min) and int8B (retention time = 8.335 min).

[0340] intermediate int9

[0341] (1) Int5 (30 g, 0.097 mol) and diphenyl(vinyl)sulfonium trifluoromethanesulfonate (52.6 g, 0.14 mol) were dissolved in dimethyl sulfoxide (200 mL). 1,8-diazobisspirocyclic [5,4,0]undecyl-7-ene (44.2 g, 0.29 mol) was slowly added dropwise under ice bath conditions. The mixture was stirred at 25 °C for 2 hours. The reaction solution was quenched with water, extracted with ethyl acetate, dried over sodium sulfate, concentrated, and purified by column chromatography to obtain compound int9-1 (17 g). LC-MS: 307.2 [M+H] + .

[0342] (2) Dissolve 17 g (0.05 mol) of int9-1 in ethanol, add Raney nickel and ammonia, and stir under hydrogen atmosphere for 16 hours. Filter the reaction solution, dry the filtrate, and concentrate to obtain crude product int9-2 (14 g). LC-MS: 303.2 [M+H] + .

[0343] (3) Dissolve int9-2 (4 g, 13.6 mmol) in N,N-dimethylformamide, and slowly add N-bromosuccinimide (1.9 g, 10.9 mmol) under ice bath conditions. Stir at 25°C for 2 hours. Quench the reaction solution with water, extract three times with ethyl acetate, dry the organic phase, concentrate, and purify by column chromatography to obtain product int9-3 (3.4 g). LC-MS: 371.0 [M+H] + .

[0344] (4) Int9-3 (3 g, 8.1 mmol), tributyltin methanol (7.8 g, 24.3 mmol), and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (682 mg, 0.8 mmol) were dissolved in dioxane (20 mL). The mixture was stirred at 80 °C for 3 hours under nitrogen. The reaction solution was quenched with water, extracted three times with ethyl acetate, dried over the organic phase, concentrated, and purified by column chromatography to obtain product int9 (1.2 g). LC-MS: 323.0 [M+H] + .

[0345] Example 1

[0346] Synthesis route:

[0347] (1) Compound 1-1 (9.0 g, 58.754 mmol) was dissolved in N,N-dimethylformamide (150 mL), and the solution was purged with nitrogen three times. Sodium hydride (5.87 g, 146.886 mmol, 60% in mineral oil) was added in portions at 0 °C, and the mixture was stirred at 25 °C for 1 hour. p-Toluenesulfonyl chloride (16.80 g, 88.131 mmol) was added in portions, and the mixture was stirred at 25 °C for 4 hours. The reaction mixture was poured into a saturated ammonium chloride aqueous solution (200 mL), and extracted three times with ethyl acetate (50 mL). The organic phases were combined and dried over sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 1-2 (13 g). 1 H NMR (400MHz, DMSO-d6) δ7.83(d,J=8.4Hz,2H),7.68(d,J=3.2Hz,1H),7.45(d,J=8.2Hz,2H),6 .35(d,J=3.2Hz,1H),4.15(q,J=8.0Hz,2H),2.40(s,3H),2.18(s,3H),1.17(t,J=8.0Hz,3H).

[0348] (2) Compounds 1-2 (21.6 g, 70.267 mmol) were dissolved in carbon tetrachloride (500 mL). Azobisisobutyronitrile (1.14 g, 7.027 mmol) and N-bromosuccinimide (15.0 g, 84.32 mmol) were added at 25 °C, and the mixture was stirred at 80 °C for 8 hours under nitrogen protection. The reaction solution was then extracted three times with saturated sodium bicarbonate aqueous solution (200 mL) and dichloromethane (200 mL). The organic phases were combined and dried over sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 1-3 (8.0 g). 1 H NMR (400MHz, DMSO-d6) δ7.89(d,J=8.4Hz,2H),7.77(d,J=3.2Hz,1H),7.48(d,J=8.4Hz,2H),6 .57(d,J=3.6Hz,1H),4.65(s,2H),4.23(q,J=8.0Hz,2H),2.41(s,3H),1.23(t,J=8.0Hz,3H).

[0349] (3) Compounds 1-3 (8.0 g, 20.725 mmol) were dissolved in methanol (60 mL) and water (20 mL), and sodium cyanide (2.0 g, 41.45 mmol) was added. The reaction mixture was reacted at 25 °C for 16 hours. The reaction solution was diluted with ethyl acetate (200 mL) and quenched at 0 °C with saturated sodium hypochlorite aqueous solution (20 mL). The mixture was extracted three times with ethyl acetate (200 mL), and the organic phases were combined, dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compounds 1-4 (3.3 g).

[0350] (4) Compounds 1-4 (1.9 g, 5.723 mmol) were dissolved in dimethyl sulfoxide (20 mL), and diphenyl(vinyl)sulfonium trifluoromethanesulfonate (3.1 g, 8.584 mmol) was added at 25 °C. 1,8-diazobisspirocyclic [5.4.0]undec-7-ene (2.61 g, 17.149 mmol) was added dropwise. The reaction was carried out at 25 °C for 8 hours. The reaction solution was poured into water, and the mixture was extracted three times with ethyl acetate (100 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography to obtain compounds 1-5 (1.6 g). 1 H NMR (400MHz, DMSO-d6) δ7.92(d,J=8.4Hz,2H),7.75(d,J=3.2Hz,1H),7.49(d,J=8.4Hz,2H),6.50(d,J=3. 4Hz, 1H), 4.18 (q, J = 7.2Hz, 2H), 2.41 (s, 3H), 1.63–1.57 (m, 2H), 1.38–1.33 (m, 2H), 1.17 (t, J = 7.2Hz, 3H).

[0351] (5) Compounds 1-5 (1.9 g, 4.469 mmol) were dissolved in ethanol (20 mL), and Raney nickel (190 mg) and ammonia (1 mL) were added at 25 °C. The mixture was purged with hydrogen three times and reacted at 25 °C for 12 hours. The reaction solution was filtered, extracted three times with ethyl acetate (50 mL), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography to obtain compounds 1-6 (0.76 g). 1 H NMR (400MHz, DMSO-d6) δ7.92(d,J=8.4Hz,2H),7.61(d,J=3.2Hz,1H),7.41(d,J=8.4Hz ,2H),7.32(s,1H),6.12(d,J=3.2Hz,1H),3.16(s,2H),2.39(s,3H),0.91–0.86(m,4H).

[0352] (6) Compounds 1-6 (600 mg, 1.892 mmol) were dissolved in tetrahydrofuran (15 mL). Diisopropylaminolithium (1.4 mL, 2.84 mmol, 2 mol / L) was added dropwise at -78 °C under a nitrogen atmosphere. After the addition was complete, the reaction continued for 2 hours. Anhydrous N,N-dimethylformamide (1 mL) was added dropwise to the above reaction solution at -78 °C. After the addition was complete, the temperature was naturally raised to 25 °C, and the mixture was stirred for 8 hours. After the reaction was complete, the solution was quenched with saturated ammonium chloride aqueous solution (5 mL) and extracted with ethyl acetate (3 × 20 mL). The organic phases were combined and dried over sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain crude product 1-7 (250 mg), which was used directly in the next step. LC-MS: 345.1 [M+H] + .

[0353] (7) Compounds 1-7 (250 mg, 0.218 mmol) were dissolved in 1,2-dichloroethane (8 mL), and (S)-3-methylpiperidine hydrochloride (43 mg, 0.436 mmol) was added. The mixture was reacted at 25 °C for half an hour, and sodium triacetoxyborohydride (277 mg, 1.31 mmol) was added. The reaction mixture was then reacted at 25 °C for another hour. The reaction solution was quenched with water (20 mL), and extracted three times with dichloromethane (30 mL). The organic phases were combined, dried over sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography to obtain 1-8 (80 mg). LC-MS: 428.3 [M+H] + .

[0354] (8) Compounds 1-8 (42 mg, 0.098 mmol), int1 (60 mg, 0.196 mmol), cuprous iodide (2 mg, 0.01 mmol), trans-N,N,N'-trimethyl-1,2-cyclohexanediamine (7 mg, 0.05 mmol), and cesium carbonate (98 mg, 0.902 mmol) were dissolved in N,N-dimethylformamide (6 mL). The mixture was reacted at 120 °C for 2 hours under nitrogen protection. The mixture was extracted three times with saturated brine and ethyl acetate (20 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to obtain crude product 1-9 (42 mg), which was directly used in the next reaction. LC-MS: 653.4 [M+H] + .

[0355] (9) Under nitrogen protection, compounds 1-9 (42 mg, 0.095 mmol) were dissolved in tetrahydrofuran (2 mL), and tetrabutylammonium fluoride tetrahydrofuran solution (0.2 mL, 1.0 M tetrahydrofuran solution) was added at 25 °C. The mixture was reacted at 80 °C for 2 hours, diluted with ethyl acetate (50 mL), washed three times with saturated brine (5 mL), dried with sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to obtain 001A (2.02 mg) and 001B (0.56 mg).

[0356] Example 2

[0357] Synthesis route:

[0358] Synthesis route:

[0359] (1) Under nitrogen protection, compound 2-1 (15.0 g, 70.6 mmol) was dissolved in acetonitrile (250.0 mL), and ethyl 3-aminopropionate (12.47 g, 81.20 mmol) and triethylamine (9.29 g, 91.79 mmol, 1.3 eq) were added. The reaction mixture was reacted at 25 °C for 48 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane, washed with 0.5 N hydrochloric acid aqueous solution (100.0 mL) and saturated brine (100.0 mL), and the organic phase was dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound 2-2 (13.8 g). The crude product was used directly in the next reaction. LC-MS: 211.2 [M+H] +

[0360] (2) Under nitrogen protection, compound 2-2 (13.8 g, 65.6 mmol) was dissolved in a mixed solvent of methanol (1.4 L) and tetrahydrofuran (700.0 mL), and N-bromosuccinimide (11.68 g, 65.6 mmol) was added. The reaction mixture was then reacted at 25 °C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give compound 2-3 (15.9 g). LC-MS: 289.1 [M+H] + .

[0361] (3) Compound 2-3 (15.9 g, 55.0 mmol) was dissolved in 1N sodium hydroxide aqueous solution (105 mL). The mixture was stirred at 25 °C for 18 hours. Concentrated hydrochloric acid was added to adjust the pH to 2. After stirring for 20 minutes, the mixture was filtered and dried to obtain compound 2-4 (12.8 g). The crude product was used directly in the next reaction. LC-MS: 261.0 [M+H] + .

[0362] (4) Under nitrogen protection, phosphorus pentoxide (5.55 g, 39.07 mmol) was dissolved in methanesulfonic anhydride (50.0 mL), and compound 2-4 (8.5 g, 32.56 mmol) was added at 80 °C. The reaction mixture was reacted at 80 °C for 16 hours. The reaction solution was poured into ice water (200.0 mL), extracted with ethyl acetate (200.0 mL), washed with saturated brine (200.0 mL), dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 2-5 (4.9 g). LC-MS: 243.0 [M+H]+ .

[0363] (5) Under nitrogen protection, compound 2-5 (2.8 g, 11.52 mmol) was dissolved in N,N-dimethylformamide (40.0 mL), and cesium carbonate (11.26 g, 34.56 mmol) was added. The reaction was carried out at 50 °C for 16 hours. After cooling to room temperature, the reaction solution was poured into water (100.0 mL), extracted with ethyl acetate (100.0 mL), washed with saturated brine (100.0 mL), and dried over sodium sulfate. The mixture was filtered and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 2-6 (1.8 g). LC-MS: 483.1 [M+H] + .

[0364] (6) Under nitrogen protection, methyltriphenylphosphine bromide (3.99 g, 11.17 mmol) was dissolved in tetrahydrofuran (30.0 mL), and potassium tert-butoxide (11.17 mL, 11.17 mmol) was added. The reaction was carried out at 25 °C for half an hour, then compound 2-6 was added, and the reaction was continued at 25 °C for 1 hour. The reaction solution was extracted with water (100.0 mL), ethyl acetate (80.0 mL), washed with saturated brine (80.0 mL), and the organic phase was dried over sodium sulfate. The mixture was filtered and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 2-7 (1.7 g). LC-MS: 483.2 [M+H] + .

[0365] (7) Under nitrogen protection, diethylzinc (18.70 mL, 18.70 mmol, 6.0 eq) was added to dichloromethane (180 mL) at 0 °C and stirred for 10 minutes at 0 °C. Diiodomethane (5.0 g, 18.70 mmol) was added, and stirring continued for 20 minutes at 0 °C. Compound 2-7 (1.5 g, 3.12 mmol) was added, and stirring continued for 20 minutes at 0 °C. The mixture was then raised to 25 °C and reacted for 3 hours. Water (100.0 mL) was added to the reaction mixture, and extraction was performed with dichloromethane (80.0 mL). The mixture was washed with saturated brine (80.0 mL), dried over sodium sulfate, and the organic phase was filtered and concentrated to obtain compound 2-8 (1.5 g). The crude product was used directly in the next step. LC-MS: 497.2 [M+H] + .

[0366] (8) Compound 2-8 (1.5 g, 3.03 mmol, 1.0 eq) was dissolved in trifluoroacetic acid (12.0 mL) and reacted at 80 °C for 5 hours. The reaction solution was evaporated to dryness, dissolved in dichloromethane (100.0 mL), washed with saturated sodium bicarbonate solution (80.0 mL), washed with saturated brine (80.0 mL), and the organic phase was dried over sodium sulfate. The mixture was filtered and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 2-9 (280 mg). LC-MS: 296.1 [M+H] + .

[0367] (9) Under nitrogen protection, compound 2-9 (230.0 mg, 0.90 mmol) was dissolved in N,N-dimethylformamide (10.0 mL), potassium tert-butoxide (121.40 mg, 1.08 mmol) was added at 0 °C, and the mixture was stirred at 0 °C for 0.5 hours. Then, 2-(trimethylsilyl)ethoxymethyl chloride (165.34 mg, 0.99 mmol) was added, and the reaction was continued at 0 °C for 1 hour. The reaction solution was poured into an ice-cold ammonium chloride solution, extracted with ethyl acetate (60.0 mL), washed with saturated brine (60 mL), dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 2-10 (160 mg). LC-MS: 387.2 [M+H] + .

[0368] (10) Compound 2-10 (160 mg, 0.42 mmol) was dissolved in dioxane (4 mL) and water (2 mL). Int2 (181.93 mg, 0.83 mmol), potassium carbonate (172.14 mg, 1.25 mmol), XPhos (39.59 mg, 0.083 mmol), and XPhos-Pd-G3 (34.14 mg, 0.042 mmol) were added, and the mixture was reacted at 100 °C for 2 hours. The reaction solution was evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 2-11 (110 mg). LC-MS: 418.3 [M+H] + .

[0369] (11) Compound 2-11 (120.0 mg, 0.29 mmol), int1A (175.95 mg, 0.57 mmol), cuprous iodide (5.5 mg, 0.029 mmol), trans-N,N,N'-trimethyl-1,2-cyclohexanediamine (8.17 mg, 0.057 mmol), and cesium carbonate (280.83 mg, 0.86 mmol) were dissolved in N,N-dimethylformamide (4 mL). The mixture was reacted at 110 °C for 16 hours under nitrogen protection. After cooling to room temperature, saturated brine (40.0 mL) was added, and the mixture was extracted with ethyl acetate (30.0 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 2-12 (24 mg). LC-MS: 643.4 [M+H] + .

[0370] (12) Compound 2-12 (22.0 mg, 0.034 mmol) was dissolved in trifluoroacetic acid (2 ml) and reacted at 25 °C for 1 hour. The reaction solution was concentrated, dissolved in acetonitrile (2.0 mL), and then ammonia (1.0 mL) was added. The reaction was carried out at room temperature for 1 hour, and the reaction solution was concentrated. The crude product was purified by preparative liquid chromatography to obtain compound 002 (4.0 mg).

[0371] Example 3

[0372] Synthesis route:

[0373] (1) Under nitrogen protection, lithium aluminum hydride (209.0 mL, 522.26 mmol) was added dropwise to a tetrahydrofuran (800 mL) solution of compound 3-1 (40.0 g, 261.13 mmol) at -15 °C. After the addition was complete, the mixture was stirred at 45 °C for 12 hours. After the reaction was completed, water (20.0 mL), 15% sodium hydroxide aqueous solution (20.0 mL), and water (60.0 mL) were added dropwise to the reaction solution at -15 °C. The mixture was filtered through a diatomaceous earth mat, washed with ethyl acetate, dried over anhydrous sodium sulfate, and the filtrate was concentrated to obtain compound 3-2 (30.0 g). The crude product was used directly in the next reaction.

[0374] (2) Under nitrogen protection, di-tert-butyl dicarbonate (57.0 g, 260.47 mmol) was added to a dichloromethane (1700.0 mL) solution of compound 3-2 (30.0 g, 260.47 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 40 hours, and then quenched by adding saturated ammonium chloride aqueous solution (800 mL). The reaction mixture was extracted with dichloromethane. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 3-3 (36.0 g). 1 H NMR (400MHz, CDCl3) δ5.16 (s, 1H), 3.81–3.66 (m, 1H), 3.49 (d, J = 6.4Hz, 2H) ,3.24(d,J=6.4Hz,2H),1.96–1.83(m,2H),1.81–1.63(m,4H),1.44(s,9H).

[0375] (3) Under nitrogen protection, oxaloyl chloride (28.3 mL, 334.43 mmol) was added dropwise to a solution of dimethyl sulfoxide (52.3 g, 668.86 mmol) in dichloromethane (800.0 mL) at -70 °C. The mixture was stirred at -70 °C for 0.5 h. Then, a solution of compound 3-3 (36.0 g, 167.21 mmol) in dichloromethane (200.0 mL) was added dropwise. The mixture was stirred at -70 °C for another 1 h. Triethylamine (139.5 mL) was then added dropwise to the reaction mixture. The reaction mixture was slowly heated to 25 °C and stirred for 0.5 h. The reaction mixture was quenched in water and extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 3-4 (35.6 g). The crude product was used directly in the next reaction step.

[0376] (4) Under nitrogen protection, potassium carbonate (46.1 g, 333.84 mmol) and dimethyl 1-diazo-2-oxopropyl)phosphonate (32 g, 166.92 mmol) were added to a methanol (500.0 mL) solution of compound 3-4 (35.6 g, 166.92 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 12 hours. The reaction mixture was quenched in water (800 mL) and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 3-5 (35.5 g). The crude product was used directly in the next reaction.

[0377] (5) Under nitrogen protection, silver carbonate (5.9 g, 21.22 mmol) and compound 3-5 (35.5 g, 159.13 mmol) were added to a solution of ethyl isocyanate (12.0 g, 106.09 mmol) and 1,4-dioxane (400.0 mL) at 25 °C. The reaction mixture was stirred at 85 °C for 12 hours. The reaction mixture was evaporated to dryness, and the crude product was subjected to silica gel column chromatography to obtain compound 3-6 (2.3 g). LC-MS: 323.3 [M+H] + .

[0378] (6) Compound 3-6 (2 g, 6.20 mmol) was dissolved in hydrochloric acid-ethanol solution (15.0 mL, 6 N) at 25 °C, and the mixture was stirred for 1 hour. The reaction solution was evaporated to dryness to give compound 3-7 (1.38 g), and the crude product was used directly in the next reaction. LC-MS: 223.3 [M+H] + .

[0379] (7) Compound 3-7 (1.38 g, 6.21 mmol) was dissolved in ammonia-methanol (20.0 mL) at 25 °C, and the mixture was stirred for 12 hours. The reaction solution was evaporated to dryness to obtain the crude product, which was then slurried with methanol to obtain compound 3-8 (800 mg). LC-MS: 177.3 [M+H] + .

[0380] (8) Under nitrogen protection, N-bromosuccinimide (404.0 mg, 2.27 mmol) was added to a methanol / tetrahydrofuran (2:1, 234 mL) solution of compound 3-8 at 0 °C. The reaction mixture was reacted at 25 °C for 1 hour, and the reaction solution was evaporated to dryness. The crude product was purified by reversed-phase column chromatography to give compound 3-9 (375 mg). LC-MS: 257.2 [M+H] + .

[0381] (9) Under nitrogen protection, potassium tert-butoxide (198 mg, 1.76 mmol) was added to a solution of compound 3-9 (375.0 mg, 1.47 mmol) in N,N-dimethylformamide (5.0 mL) at 0 °C. After stirring the reaction mixture at 0 °C for 15 minutes, 2-(trimethylsilyl)ethoxymethyl chloride (294.0 mg, 1.76 mmol) was added, and the reaction was stirred at room temperature for 12 hours. The reaction mixture was quenched at 0 °C with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography to give compound 3-10 (387.0 mg). LC-MS: 385.1 [M+H] + .

[0382] (10) Under nitrogen protection, at 25°C, int2 (264 mg, 1.20 mmol), potassium carbonate (415.7 mg, 3.01 mmol), X-Phos (95.3 mg, 0.2 mmol), and XPos-Pd-G3 (84.6 mg, 0.1 mmol) were added to a solution of compound 3-10 (387 mg, 1.00 mmol) in 1,4-dioxane (14.0 mL) and water (7.0 mL). The reaction solution was stirred at 100°C for 12 hours, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 3-11 (150 mg).

[0383] (11) Under nitrogen protection, trans-N,N,N'-trimethyl-1,2-cyclohexanediamine (20.4 mg, 0.14 mmol), int1A (177.6 mg, 0.58 mmol), cesium carbonate (283.5 mg, 0.87 mmol), and cuprous iodide (5.7 mg, 0.03 mmol) were added to a solution of compound 3-11 (120.0 mg, 0.29 mmol) in N,N-dimethylformamide (5 mL) at 25 °C. The reaction mixture was stirred at 110 °C for 12 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 3-12 (130 mg), which was used directly in the next reaction. LC-MS: 643.5 [M+H] + .

[0384] (12) Compound 3-12 (77.0 mg, 0.12 mmol) was dissolved in trifluoroacetic acid (3.0 mL) at 25 °C and reacted for 1 hour. The reaction solution was evaporated to dryness and then dissolved in acetonitrile (3.0 mL), followed by the addition of ammonia (2.0 mL) and reacted for 1 hour. The reaction solution was evaporated to dryness, and the crude product was purified by preparative liquid chromatography to obtain compound 003 (18 mg).

[0385] Example 4

[0386] Synthesis route:

[0387] (1) Compound 1-7 (500 mg, 1.45 mmol) was dissolved in methanol (5.0 mL), and sodium borohydride (165.7 mg, 4.36 mmol) was added. The reaction mixture was reacted at 25 °C for half an hour. The reaction solution was quenched with water, extracted with dichloromethane, and the organic phases were combined, dried over sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography to obtain compound 4-1 (170 mg). LC-MS: 347.1 [M+H] + .

[0388] (2) Compound 4-1 (170 mg, 0.49 mmol) was dissolved in dichloromethane (5.0 mL), and thionyl chloride (0.5 mL) was added. The mixture was reacted at 25 °C for half an hour. The solution was evaporated to dryness to obtain crude compound 4-2 (150 mg), which was used directly in the next step. LC-MS: 365.0 [M+H] + .

[0389] (3) Compound 4-2 (250.0 mg, 0.687 mmol) was dissolved in N,N-dimethylformamide (5.0 mL), and 2-azabicyclo[2.1.1]hexane hydrochloride (123.1 mg, 1.030 mmol) and N,N-diisopropylethylamine (266.0 mg, 2.06 mmol) were added. The mixture was reacted at 80 °C for 2 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, extracted with brine, and the organic phases were combined, dried over sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography to obtain compound 4-3 (100.1 mg). LC-MS: 412.2 [M+H] + .

[0390] (4) Compound 4-3 (100.0 mg, 0.243 mmol), int1A (112.0 mg, 0.364 mmol), cuprous iodide (4.0 mg, 0.02 mmol), trans-N,N,N'-trimethyl-1,2-cyclohexanediamine (6.1 mg, 0.04 mmol), and cesium carbonate (237.1 mg, 0.729 mmol) were dissolved in N,N-dimethylformamide (6.0 mL). The reaction mixture was reacted at 110 °C for 2 hours under nitrogen protection. The reaction solution was cooled to room temperature, extracted with saturated brine and ethyl acetate, dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give compound 4-4 (50.1 mg). LC-MS: 637.4 [M+H] + .

[0391] (5) Under nitrogen protection, compound 4-4 (50.1 mg, 0.078 mmol) was dissolved in tetrahydrofuran (2 mL), and a tetrahydrofuran solution of tetrabutylammonium fluoride (0.2 mL, 1.0 M) was added at 25 °C. The mixture was reacted at 80 °C for 2 hours, diluted with ethyl acetate, washed with saturated brine, dried with sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 004 (5.0 mg).

[0392] Example 5

[0393] Synthesis route:

[0394] (1) Compound 4-2 (700.0 mg, 1.923 mmol) was dissolved in N,N-dimethylformamide (10.0 mL), and (3-methylazacyclobutane-3-yl)methanol hydrochloride (397.1 mg, 2.884 mmol) and N,N-diisopropylethylamine (744.0 mg, 5.769 mmol) were added. The mixture was reacted at 80 °C for 2 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with brine, and the organic phases were combined, dried over sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography to give compound 5-1 (130.1 mg). LC-MS: 430.3 [M+H] + .

[0395] (2) Compound 5-1 (110.1 mg, 0.256 mmol), int1A (53.0 mg, 0.384 mmol), cuprous iodide (6.0 mg, 0.03 mmol), trans-N,N,N'-trimethyl-1,2-cyclohexanediamine (9.0 mg, 0.06 mmol), and cesium carbonate (251.1 mg, 0.768 mmol) were dissolved in N,N-dimethylformamide (10.0 mL). The reaction mixture was carried out at 110 °C for 2 hours under nitrogen protection, and the reaction solution was cooled to room temperature. The mixture was extracted with saturated brine and ethyl acetate. The organic phase was dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 5-2 (60.1 mg). LC-MS: 665.4 [M+H] + .

[0396] (3) Under nitrogen protection, compound 5-2 (60.0 mg, 0.092 mmol) was dissolved in tetrahydrofuran (2.0 mL), and a tetrahydrofuran solution of tetrabutylammonium fluoride (0.2 mL, 1.0 M tetrahydrofuran solution) was added at 25 °C. The reaction was carried out at 80 °C for 2 hours. The mixture was diluted with ethyl acetate, washed with saturated brine, dried with sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to obtain compound 005 (5.0 mg).

[0397] Example 6

[0398] Synthesis route:

[0399] (1) Compound int3 (110.0 mg, 0.360 mmol), compounds 1-8 (120.1 mg, 0.281 mmol), cuprous iodide (5.7 mg, 0.03 mmol), trans-N,N,N'-trimethyl-1,2-cyclohexanediamine (4.0 mg, 0.03 mmol), and cesium carbonate (275.0 mg, 0.843 mmol) were dissolved in N,N-dimethylformamide (4.0 mL). The mixture was reacted at 110 °C for 6 hours under nitrogen protection. After cooling to room temperature, saturated brine was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain compound 6-1 (100.0 mg). LC-MS: 653.4 [M+H] + .

[0400] (2) Under nitrogen protection, compound 6-1 (100.0 mg, 0.153 mmol) was dissolved in tetrahydrofuran (3.0 mL), and a tetrabutylammonium fluoride tetrahydrofuran solution (0.5 mL, 1.0 M tetrahydrofuran solution) was added at 25 °C. The reaction was carried out at 80 °C for 2 hours. The reaction solution was cooled to 25 °C, diluted with ethyl acetate, washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to obtain a mixture (23 mg). The mixture was chirally prepared to obtain compounds 006A (5.43 mg) and 006B (5.00 mg).

[0401] Example 7

[0402] Synthesis route:

[0403] (1) Compound 4-2 (150.0 mg, 0.27 mmol) was dissolved in N,N-dimethylformamide (15.0 mL), and N,N-diisopropylethylamine (0.2 mL) and 3,3-dimethylazacyclobutane hydrochloride (42.07 mg, 0.49 mmol) were added at 25 °C. The mixture was stirred at 80 °C for 8 hours under nitrogen protection. The reaction solution was cooled to room temperature, quenched in water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography to obtain the target compound 7-1 (100.0 mg). LC-MS: 414.2 [M+H] + .

[0404] (2) Compound 7-1 (100.0 mg, 0.24 mmol), int1A (74.04 mg, 0.24 mmol), Brettphos-Pd-G3 (21.9 mg, 0.02 mmol), and cesium carbonate (236.37 mg, 0.73 mmol) were dissolved in N,N-dimethylformamide (10.0 mL) and reacted at 100 °C for 16 hours under nitrogen protection. The reaction solution was cooled to room temperature, quenched in water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography to obtain the target compound 7-2 (90.0 mg). LC-MS: 639.4 [M+H] + .

[0405] (3) Under nitrogen protection, compound 7-2 (90.0 mg, 0.14 mmol) was dissolved in tetrahydrofuran (5.0 mL), and a tetrabutylammonium fluoride tetrahydrofuran solution (0.5 mL, 1.0 M tetrahydrofuran solution) was added at 25 °C. The reaction was carried out at 50 °C for 2 hours. The reaction solution was cooled to room temperature, quenched in water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and the residue was purified by reverse-phase column chromatography to obtain the target compound 007 (12.18 mg).

[0406] Example 8

[0407] Synthesis route:

[0408] (1) Compound 4-2 (130.0 mg, 0.35 mmol) was dissolved in dimethyl sulfoxide (15.0 mL), and N,N-diisopropylethylamine (0.2 mL) and 2-methylmorpholine (43.25 mg, 0.42 mmol) were added at 25 °C. The mixture was stirred at 80 °C for 8 hours under nitrogen protection. The reaction solution was cooled to 25 °C, quenched in water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography to give compound 8-1 (88.0 mg). LC-MS: 430.2 [M+H] + .

[0409] (2) Compound 8-1 (100.0 mg, 0.24 mmol), int1A (74.04 mg, 0.24 mmol), Brettphos-Pd-G3 (21.9 mg, 0.02 mmol), and cesium carbonate (236.37 mg, 0.73 mmol) were dissolved in N,N-dimethylformamide (10.0 mL) and reacted at 100 °C for 16 hours under nitrogen protection. The reaction solution was cooled to room temperature, quenched in water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography to give compound 8-2 (90.0 mg). LC-MS: 639.4 [M+H] + .

[0410] (3) Under nitrogen protection, compound 8-2 (90.0 mg, 0.14 mmol) was dissolved in tetrahydrofuran (5.0 mL), and tetrabutylammonium fluoride in tetrahydrofuran solution (0.5 mL, 1.0 M) was added at 25 °C. The reaction was carried out at 50 °C for 2 hours. The reaction solution was cooled to room temperature, quenched in water, extracted with ethyl acetate, and the organic phases were combined, dried with anhydrous sodium sulfate, filtered, evaporated to dryness, and the residue was purified by reverse-phase column chromatography to obtain compound 008 (12.18 mg).

[0411] Example 9

[0412] Synthesis route:

[0413] (1) Compound 4-2 (130.0 mg, 0.35 mmol) was dissolved in dimethyl sulfoxide (15.0 mL), and N,N-diisopropylethylamine (0.2 mL) and (2R)-2-ethylpyrrolidine (42.41 mg, 0.42 mmol) were added at 25 °C. The mixture was stirred at 80 °C for 8 hours under nitrogen protection. The reaction solution was cooled to room temperature, quenched in water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography to give compound 9-1 (85.0 mg). LC-MS: 428.0 [M+H] + .

[0414] (2) Compound 9-1 (85.0 mg, 0.19 mmol), int1A (60.87 mg, 0.19 mmol), trans-N,N,N'-trimethyl-1,2-cyclohexanediamine (26.9 mg, 0.19 mmol), cuprous iodide (18.93 mg, 0.1 mmol), and cesium carbonate (194.32 mg, 0.59 mmol) were dissolved in N,N-dimethylformamide (10.0 mL) and reacted at 100 °C for 16 hours under nitrogen protection. The reaction solution was cooled to room temperature, quenched in water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography to obtain the target compound 9-2 (95.0 mg). MS: 653.2 [M+H] + .

[0415] (3) Under nitrogen protection, compound 9-2 (95.0 mg, 0.14 mmol) was dissolved in tetrahydrofuran (5 mL), and a tetrahydrofuran solution of tetrabutylammonium fluoride (0.5 mL, 1.0 M) was added at 25 °C. The reaction was carried out at 50 °C for 2 hours. The reaction solution was cooled to room temperature, quenched in water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by reverse-phase column chromatography to obtain the target compound 009 (25.0 mg).

[0416] Example 10

[0417] Synthesis route:

[0418] (1) Compound 1-7 (300.0 mg, 0.87 mmol) was dissolved in tetrahydrofuran (30.0 mL), and 1-methoxymethyl-cyclobutylamine (150.50 mg, 1.31 mmol) and glacial acetic acid (0.05 mL) were added at 25 °C. The mixture was stirred at room temperature for 0.5 h under nitrogen protection, followed by the addition of sodium borohydride acetate (82.39 mg, 2.18 mmol), and the reaction was continued for 2 h. The reaction solution was quenched in ice water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography to give the target compound 10-1 (57.0 mg). LC-MS: 444.2 [M+H] + .

[0419] (2) Compound 10-1 (57.0 mg, 0.13 mmol), int1A (39.35 mg, 0.13 mmol), trans-N,N,N'-trimethyl-1,2-cyclohexanediamine (18.29 mg, 0.13 mmol), cuprous iodide (12.24 mg, 0.06 mmol), and cesium carbonate (125.61 mg, 0.38 mmol) were dissolved in N,N-dimethylformamide (10.0 mL). The reaction mixture was reacted at 100 °C for 16 hours under nitrogen protection. The reaction solution was cooled to room temperature, quenched in water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography to obtain the target compound 10-2 (60.0 mg). LC-MS: 669.4 [M+H] + .

[0420] (3) Under nitrogen protection, compound 10-2 (60.0 mg, 0.089 mmol) was dissolved in tetrahydrofuran (5 mL), and a tetrabutylammonium fluoride tetrahydrofuran solution (0.5 mL, 1.0 M) was added at 25 °C. The reaction was carried out at 50 °C for 2 hours. The reaction solution was quenched in water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and the residue was purified by reverse-phase column chromatography to obtain the target compound 010 (9.36 mg).

[0421] Example 11

[0422] Synthesis route:

[0423] (1) Compound 4-2 (120.0 mg, 0.330 mmol) was dissolved in N,N-dimethylformamide (8.0 mL), and 1-methyl-1-cyclobutylamine hydrochloride (60.0 mg, 0.495 mmol) and N,N-diisopropylethylamine (128.1 mg, 0.99 mmol) were added. The mixture was reacted at 80 °C for 2 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, and washed three times with brine (10.0 mL). The organic phases were combined, dried over sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography to give compound 11-1 (35.0 mg). LC-MS: 414.2 [M+H] + .

[0424] (2) Compound 11-1 (35.0 mg, 0.085 mmol), int1A (39.0 mg, 0.127 mmol), cuprous iodide (2.0 mg, 0.01 mmol), trans-N,N,N'-trimethyl-1,2-cyclohexanediamine (5.0 mg, 0.02 mmol), and cesium carbonate (83.1 mg, 0.255 mmol) were dissolved in N,N-dimethylformamide (10.0 mL). The reaction mixture was reacted at 110 °C for 2 hours under nitrogen protection. The reaction solution was cooled to room temperature, extracted with saturated brine and ethyl acetate, dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give compound 11-2 (30.1 mg). LC-MS: 639.2 [M+H] + .

[0425] (3) Under nitrogen protection, compound 11-2 (30.0 mg, 0.047 mmol) was dissolved in tetrahydrofuran (2.0 mL), and a tetrabutylammonium fluoride tetrahydrofuran solution (0.2 mL, 1.0 M) was added at room temperature. The reaction was carried out at 80 °C for 2 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to obtain compound 011 (6.1 mg).

[0426] Example 12

[0427] Synthesis route:

[0428] (1) Compound 4-2 (120.0 mg, 0.330 mmol) was dissolved in N,N-dimethylformamide (8.0 mL), and N-ethylmethylamine (29 mg, 0.495 mmol) and N,N-diisopropylethylamine (128 mg, 0.99 mmol) were added. The mixture was reacted at 80 °C for 2 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed three times with brine, and the organic phases were combined, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to give compound 12-1 (90 mg). LC-MS: 388.2 [M+H] + .

[0429] (2) Compound 12-1 (90.0 mg, 0.147 mmol), int1A (41.6 mg, 0.135 mmol), cuprous iodide (1.9 mg, 0.01 mmol), trans-N,N,N'-trimethyl-1,2-cyclohexanediamine (2.8 mg, 0.02 mmol), and cesium carbonate (88.0 mg, 0.270 mmol) were dissolved in N,N-dimethylformamide (10.0 mL). The reaction mixture was reacted at 110 °C for 2 hours under nitrogen protection. The reaction solution was cooled to room temperature, extracted with saturated brine and ethyl acetate, dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 12-2 (30.0 mg). LC-MS: 613.3 [M+H] + .

[0430] (3) Under nitrogen protection, compound 12-2 (30 mg, 0.049 mmol) was dissolved in tetrahydrofuran (2 mL), and a tetrahydrofuran solution of tetrabutylammonium fluoride (0.2 mL, 1.0 M) was added at 25 °C. The reaction was carried out at 80 °C for 2 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to obtain 012 (1.90 mg).

[0431] Example 13

[0432] Synthesis route:

[0433] (1) Compounds 1-7 (170.0 mg, 0.247 mmol) were dissolved in 1,2-dichloroethane (8.0 mL), and (S)-2-aminobutane (27.1 mg, 0.371 mmol) was added. The reaction was carried out at 25 °C for half an hour, followed by the addition of sodium triacetoxyborohydride (157.1 mg, 0.741 mmol), and the reaction was continued at 25 °C for 1 hour. The reaction solution was quenched with water, extracted with dichloromethane, and the organic phases were combined, dried over sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography to give 13-1 (75 mg). LC-MS: 402.2 [M+H] + .

[0434] (2) Compound 13-1 (75.0 mg, 0.187 mmol), int1A (86.0 mg, 0.280 mmol), cuprous iodide (4.0 mg, 0.02 mmol), trans-N,N,N'-trimethyl-1,2-cyclohexanediamine (10.0 mg, 0.04 mmol), and cesium carbonate (182.9 mg, 0.561 mmol) were dissolved in N,N-dimethylformamide (10.0 mL). The mixture was reacted at 110 °C for 2 hours under nitrogen protection. After cooling to room temperature, saturated brine was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 13-2 (50.0 mg). LC-MS: 627.2 [M+H] + .

[0435] (3) Under nitrogen protection, compound 13-2 (50.0 mg, 0.080 mmol) was dissolved in tetrahydrofuran (2.0 mL), and a tetrabutylammonium fluoride tetrahydrofuran solution (0.2 mL, 1.0 M) was added at 25 °C. The reaction was carried out at 80 °C for 2 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to obtain 013 (10.48 mg).

[0436] Example 14

[0437] Synthesis route:

[0438] (1) Compound 4-2 (100.0 mg, 0.275 mmol) was dissolved in N,N-dimethylformamide (10.0 mL), and piperidine hydrochloride (50.1 mg, 0.412 mmol) and N,N-diisopropylethylamine (106.4 mg, 0.825 mmol) were added. The mixture was reacted at 80 °C for 2 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with brine, and the organic phases were combined, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to give compound 14-1 (90.0 mg). LC-MS: 414.0 [M+H] + .

[0439] (2) Compound 14-1 (90 mg, 0.218 mmol), int1A (100.2 mg, 0.326 mmol), cuprous iodide (3.8 mg, 0.02 mmol), trans-N,N,N'-trimethyl-1,2-cyclohexanediamine (5.7 mg, 0.04 mmol), and cesium carbonate (213.2 mg, 0.654 mmol) were dissolved in N,N-dimethylformamide (10.0 mL). The reaction mixture was reacted at 110 °C for 2 hours under nitrogen protection. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 14-2 (80.0 mg). LC-MS: 639.4 [M+H] + .

[0440] (3) Under nitrogen protection, compound 14-2 (80.0 mg, 0.125 mmol) was dissolved in tetrahydrofuran (2.0 mL), and a tetrabutylammonium fluoride tetrahydrofuran solution (0.2 mL, 1.0 M) was added at 25 °C. The reaction was carried out at 80 °C for 2 hours, and the reaction solution was cooled to room temperature. The solution was diluted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to obtain compound 014 (16.47 mg).

[0441] Example 15

[0442] Synthesis route:

[0443] (1) Compound 4-2 (120.0 mg, 0.330 mmol) was dissolved in N,N-dimethylformamide (10.0 mL), and morpholine hydrochloride (61.1 mg, 0.495 mmol) and N,N-diisopropylethylamine (128.1 mg, 0.990 mmol) were added. The mixture was reacted at 80 °C for 2 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with brine, and the organic phases were combined, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to give compound 15-1 (85.0 mg). LC-MS: 416.2 [M+H] + .

[0444] (2) Compound 15-1 (85.0 mg, 0.204 mmol), int1A (94.2 mg, 0.307 mmol), cuprous iodide (3.8 mg, 0.020 mmol), trans-N,N,N'-trimethyl-1,2-cyclohexanediamine (5.7 mg, 0.040 mmol), and cesium carbonate (199.5 mg, 0.6512 mmol) were dissolved in N,N-dimethylformamide (10.0 mL). The reaction mixture was reacted at 110 °C for 2 hours under nitrogen protection. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 15-2 (80.0 mg). LC-MS: 641.4 [M+H] + .

[0445] (3) Under nitrogen protection, compound 15-2 (80.0 mg, 0.124 mmol) was dissolved in tetrahydrofuran (2.0 mL), and a tetrabutylammonium fluoride tetrahydrofuran solution (0.2 mL, 1.0 M) was added at 25 °C. The reaction was carried out at 80 °C for 2 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by liquid chromatography to obtain 015 (19.68 mg).

[0446] Example 16

[0447] Synthesis route:

[0448] (1) Compound 1-7 (150.0 mg, 0.174 mmol) was dissolved in 1,2-dichloroethane (8.0 mL), and (3R)-4-difluoro-3-methylpiperidine hydrochloride (46.2 mg, 0.262 mmol) was added. The reaction was carried out at 25 °C for half an hour, followed by the addition of sodium triacetoxyborohydride (110.7 mg, 0.522 mmol), and the reaction was continued for 1 hour. The reaction solution was quenched with water, extracted with dichloromethane, and the organic phases were combined, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to obtain compound 16-1. LC-MS: 464.2 [M+H] + .

[0449] (2) Compound 16-1 (50.0 mg, 0.108 mmol), int1A (49.7 mg, 0.162 mmol), cuprous iodide (1.9 mg, 0.01 mmol), trans-N,N,N'-trimethyl-1,2-cyclohexanediamine (2.9 mg, 0.02 mmol), and cesium carbonate (105.6 mg, 0.324 mmol) were dissolved in N,N-dimethylformamide (10.0 mL). The reaction mixture was reacted at 110 °C for 2 hours under nitrogen protection. The reaction solution was cooled to room temperature, extracted with saturated brine and ethyl acetate, dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give compound 16-2 (32.0 mg). LC-MS: 689.5 [M+H] + .

[0450] (3) Under nitrogen protection, compound 16-2 (32.0 mg, 0.046 mmol) was dissolved in tetrahydrofuran (2.0 mL), and a tetrabutylammonium fluoride tetrahydrofuran solution (0.2 mL, 1.0 M) was added at 25 °C. The reaction was carried out at 80 °C for 2 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to obtain 016 (5.00 mg).

[0451] Example 17

[0452] Synthesis route:

[0453] (1) Compound 4-2 (40.0 mg, 0.11 mmol) was dissolved in dimethyl sulfoxide (2.0 mL), and (3S,5R)-3,5-dimethylpiperidine (13.65 mg, 0.12 mmol) and N,N-diisopropylethylamine (42.51 mg, 0.33 mmol) were added. The reaction mixture was stirred at 80 °C for 1 hour. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phases were combined and washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 17-1 (50.0 mg). LC-MS: 442.3 [M+H] + .

[0454] (2) Compound 17-1 (40.0 mg, 0.091 mmol), int1A (6.44 mg, 0.045 mmol), trans-N,N,N'-trimethyl-1,2-cyclohexanediamine (55.47 mg, 0.18 mmol), cesium carbonate (88.54 mg, 0.27 mmol), and cuprous iodide (1.73 mg, 0.009 mmol) were dissolved in N,N-dimethylformamide (3 mL). The reaction was carried out at 110 °C for 2 hours under nitrogen protection. After cooling to room temperature, saturated brine was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative liquid chromatography to obtain compound 17-2 (100 mg). LC-MS: 667.3 [M+H] + .

[0455] (3) Under nitrogen protection, compound 17-2 (90 mg, 0.13 mmol) was dissolved in tetrahydrofuran, and a tetrahydrofuran solution of tetrabutylammonium fluoride (0.6 mL, 1.0 M) was added at room temperature. The reaction was carried out at 80 °C for 16 hours. The mixture was diluted with ethyl acetate, washed with saturated brine, dried with sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to obtain compound 017 (7.5 mg).

[0456] Example 18

[0457] Synthesis route:

[0458] (1) Compound 4-2 (90.0 mg, 0.247 mmol) was dissolved in N,N-dimethylformamide (10.0 mL), and 2-azabicyclo[2.2.2]octane hydrochloride (54.7 mg, 0.371 mmol) and N,N-diisopropylethylamine (95.9 mg, 0.741 mmol) were added. The mixture was reacted at 80 °C for 2 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, back-extracted with brine, and the organic phases were combined, dried over sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography to give compound 18-1 (70.0 mg). LC-MS: 440.4 [M+H] + .

[0459] (2) Compound 18-1 (70.0 mg, 0.159 mmol), int1A (73.4 mg, 0.239 mmol), cuprous iodide (3.0 mg, 0.016 mmol), trans-N,N,N'-trimethyl-1,2-cyclohexanediamine (4.5 mg, 0.032 mmol), and cesium carbonate (155.5 mg, 0.477 mmol) were dissolved in N,N-dimethylformamide (10.0 mL). The reaction mixture was reacted at 110 °C for 2 hours under nitrogen protection. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to obtain compound 18-2 (45.0 mg). LC-MS: 665.4 [M+H] + .

[0460] (3) Under nitrogen protection, compound 18-2 (45.0 mg, 0.068 mmol) was dissolved in tetrahydrofuran (2 mL), and a tetrabutylammonium fluoride tetrahydrofuran solution (0.2 mL, 1.0 M) was added at room temperature. The reaction was carried out at 80 °C for 2 hours, and the reaction solution was cooled to room temperature. The solution was diluted with ethyl acetate, washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to obtain compound 018 (3.2 mg).

[0461] Example 19

[0462] Synthesis route:

[0463] (1) Compound 4-2 (70.0 mg, 0.19 mmol) was dissolved in dimethyl sulfoxide (5.0 mL), and 4,4-dimethylpiperidine hydrochloride (86.14 mg, 0.57 mmol) and N,N-diisopropylethylamine (247.68 mg, 1.92 mmol) were added. The reaction mixture was stirred at 80 °C for 1 hour. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic phases were washed twice with brine, dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 19-1 (60 mg). LC-MS: 442.0 [M+H] + .

[0464] (2) Compound 19-1 (40 mg, 0.091 mmol), int1A (55.47 mg, 0.18 mmol), trans-N,N,N'-trimethyl-1,2-cyclohexanediamine (1.29 mg, 0.009 mmol), cesium carbonate (88.54 mg, 0.27 mmol), and cuprous iodide (1.73 mg, 0.009 mmol) were dissolved in N,N-dimethylformamide (3.0 mL). The reaction mixture was subjected to nitrogen protection and reacted at 110 °C for 24 hours. The reaction solution was cooled to room temperature, extracted with ethyl acetate using saturated brine, and the combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative liquid chromatography to obtain compound 19-2 (30.0 mg). LC-MS: 667.5 [M+H] + .

[0465] (3) Under nitrogen protection, compound 19-2 (25 mg, 0.034 mmol) was dissolved in tetrahydrofuran (2 mL), and a tetrahydrofuran solution of tetrabutylammonium fluoride (0.3 mL, 1.0 M) was added at 25 °C. The reaction was carried out at 80 °C for 16 hours. The mixture was diluted with ethyl acetate, washed with saturated brine, dried with sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to obtain 019 (3.0 mg).

[0466] Example 20

[0467] Synthesis route:

[0468] (1) Compound 4-2 (80.0 mg, 0.219 mmol) was dissolved in dimethyl sulfoxide (4.0 mL), and (S)-3-ethylpiperidine hydrochloride (80.1 mg, 0.540 mmol) was added. The reaction mixture was reacted at 80°C for half an hour. The reaction solution was quenched with water, extracted with ethyl acetate, and the organic phases were combined, dried over sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography to give compound 20-1 (80.0 mg). LC-MS: 442.2 [M+H] + .

[0469] (2) Compound 20-1 (80.0 mg, 0.181 mmol), int1A (83.1 mg, 0.272 mmol), cuprous iodide (2.0 mg, 0.01 mmol), trans-N,N,N'-trimethyl-1,2-cyclohexanediamine (7.0 mg, 0.05 mmol), and cesium carbonate (177.1 mg, 0.543 mmol) were dissolved in N,N-dimethylformamide (4.0 mL). The mixture was reacted at 120 °C for 2 hours under nitrogen protection. After cooling to room temperature, saturated brine was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give compound 20-2 (50.1 mg). LC-MS: 667.5 [M+H] + .

[0470] (3) Under nitrogen protection, compound 20-2 (50.0 mg, 0.075 mmol) was dissolved in tetrahydrofuran (2 mL), and a tetrahydrofuran solution of potassium tert-butoxide (0.5 mL, 1.0 M) was added at 0 °C. The reaction was carried out for 2 hours. The solution was diluted with ethyl acetate, washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography to obtain compound 020 (3.2 mg).

[0471] Example 21

[0472] Synthesis route:

[0473] (1) Compounds 1-8 (100 mg, 0.233 mmol), int4 (111.5 mg, 0.349 mmol), cuprous iodide (3.8 mg, 0.02 mmol), trans-N,N,N'-trimethyl-1,2-cyclohexanediamine (5.7 mg, 0.04 mmol), and cesium carbonate (227.8 mg, 0.699 mmol) were dissolved in N,N-dimethylformamide (10.0 mL) and reacted at 110 °C for 2 hours under nitrogen protection. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to obtain compound 21-1 (35.0 mg). LC-MS: 667.4 [M+H] + .

[0474] (2) Under nitrogen protection, compound 21-1 (35.0 mg, 0.052 mmol) was dissolved in tetrahydrofuran (2 mL), and a tetrabutylammonium fluoride tetrahydrofuran solution (0.2 mL, 1.0 M) was added at 25 °C. The reaction was carried out at 80 °C for 2 hours, and the reaction solution was cooled to room temperature. The solution was diluted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to obtain compound 021 (5.00 mg).

[0475] Example 22

[0476] Synthesis route:

[0477] (1) Under nitrogen protection, trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (22.1 mg, 0.16 mmol), int4 (150 mg, 0.47 mmol), cesium carbonate (304.2 mg, 0.93 mmol), and cuprous iodide (6.0 mg, 0.03 mmol) were added to a solution of N,N-dimethylformamide (5.0 mL) containing 3-11 (130.0 mg, 0.31 mmol) at 25 °C. The reaction mixture was stirred at 110 °C for 12 hours. The reaction mixture was cooled to room temperature, quenched with water, and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 22-1 (58.0 mg). The crude product was used directly in the next reaction. LC-MS: 527.4 [M+H] + .

[0478] (2) Compound 22-1 (53.0 mg, 0.08 mmol) was dissolved in trifluoroacetic acid at 25 °C and reacted for 1 hour. The reaction solution was evaporated to dryness, and the residue was dissolved in acetonitrile (3.0 mL). Ammonia water (2.0 mL) was added and reacted for 1 hour. The reaction solution was evaporated to dryness, and the crude product was purified by silica gel column chromatography to obtain 022 (5.0 mg).

[0479] Example 23

[0480] Synthesis route:

[0481] (1) Dissolve int5 (12 g, 38.90 mmol) in tetrahydrofuran (240 mL) under nitrogen protection. Add bis(trimethylsilylaminolithium) (116.71 mL, 116.71 mmol) at -65 °C. Stir the mixture at -65 °C for 0.5 h. Add 2-bromobutane (25.20 g, 116.71 mmol). Stir the reaction mixture at 25 °C for 1 h. Pour the mixture into an ice-cold ammonium chloride solution and extract with ethyl acetate. Combine the organic phases, wash with saturated brine, and dry over anhydrous sodium sulfate. Filter the resulting mixture and concentrate the filtrate under reduced pressure to obtain the crude product. Purify the crude product by silica gel column chromatography to give compound 23-1 (11.5 g). LC-MS: 385.2 [M+H] + .

[0482] (2) Compound 23-1 (11.5 g, 31.72 mmol) was dissolved in methanol (120 mL) and ammonia (12 mL), and Raney nickel (2.2 g) was added. The reaction mixture was stirred at 25 °C under a hydrogen atmosphere for 16 hours. The reaction mixture was filtered and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 23-2 (9.4 g). LC-MS: 321.2 [M+H] + .

[0483] (3) Compound 23-2 (7.2 g, 22.46 mmol) was dissolved in N,N-dimethylformamide (200 mL), and N-bromosuccinimide (4 g, 22.46 mmol) was added at 0 °C. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 23-3 (8 g). LC-MS: 401.1 [M+H] + .

[0484] (4) Compound 23-3 (150 mg, 0.38 mmol) was dissolved in dioxane (6 mL) and water (3 mL), and (S)-3-methylpiperazine (329.14 mg, 1.5 mmol), potassium carbonate (155.71 mg, 1.13 mmol), X-Phos (35.81 mg, 0.075 mmol), and X-Phos-Pd-G3 (31.79 mg, 0.038 mmol) were added. The reaction mixture was reacted at 100 °C for 16 hours. The reaction solution was evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 23-4 (70 mg). LC-MS: 432.3 [M+H] + .

[0485] (5) Compound 23-4 (70 mg, 0.16 mmol), int1A (99.3 mg, 0.32 mmol), cesium carbonate (158.50 mg, 0.47 mmol), and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (32.43 mg, 0.032 mmol) were dissolved in dioxane (6 mL). The reaction was carried out under nitrogen protection at 110 °C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 23-5 (100 mg). LC-MS: 657.4 [M+H] + .

[0486] (6) Under nitrogen protection, compound 23-5 (100 mg, 0.15 mmol) was dissolved in trifluoroacetic acid (6 mL), and the reaction solution was stirred at 25 °C for 1 hour. The reaction solution was evaporated to dryness, dissolved in acetonitrile, and ammonia was added. The reaction solution was stirred at 25 °C for 1 hour, and the reaction solution was evaporated to dryness. The residue was purified by preparative liquid chromatography to obtain compound 023 (36.65 mg).

[0487] Example 24

[0488] Synthesis route:

[0489] (1) Compound 4-2 (80 mg, 0.22 mmol) was dissolved in dimethyl sulfoxide (6 mL), and (S)-3-(difluoromethyl)piperidine (88.91 mg, 0.66 mmol) and N,N-diisopropylethylamine (170.04 mg, 1.32 mmol) were added. The reaction mixture was stirred at 80 °C for 1 hour. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic phases were washed twice with brine, dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 24-1 (100 mg). LC-MS: 464.2 [M+H] + .

[0490] (2) Compound 24-1 (100 mg, 0.22 mmol), int1A (132.12 mg, 0.43 mmol), trans-N,N,N'-trimethyl-1,2-cyclohexanediamine (15.34 mg, 0.11 mmol), cesium carbonate (210.87 mg, 0.65 mmol), and cuprous iodide (4.11 mg, 0.02 mmol) were dissolved in N,N-dimethylformamide (6 mL). The reaction was carried out under nitrogen protection at 110 °C for 16 hours. Saturated brine was added, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 24-2 (140 mg). LC-MS: 689.2 [M+H] + .

[0491] (3) Under nitrogen protection, compound 24-2 (140 mg, 0.20 mmol) was dissolved in tetrahydrofuran (4 mL), and a tetrahydrofuran solution of tetrabutylammonium fluoride (1.0 mL, 1.0 M) was added at 25 °C. The mixture was reacted at 80 °C for 16 hours, diluted with ethyl acetate, washed with saturated brine, dried with sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to obtain compound 024 (40 mg).

[0492] Example 25

[0493] Synthesis route:

[0494] (1) Under nitrogen protection, (tributyltin)methanol (470 mg, 1.46 mmol) and X-Phos-Pd-G3 (103 mg, 0.12 mmol) were added to a 30 mL solution of dioxane (30 mL) containing compound 3-10 (470 mg, 1.22 mmol) at 25 °C. The mixture was stirred at 90 °C for 12 hours. The reaction solution was evaporated to dryness, and the residue was purified by silica gel column chromatography to give compound 25-1 (100 mg). LC-MS: 337.4 [M+H] + .

[0495] (2) Thionyl chloride (170 mg, 1.43 mmol) was added to a solution of compound 25-1 (80 mg, 0.24 mmol) in dichloromethane (5 mL) at 25 °C. The mixture was stirred at 25 °C for 1 hour. The reaction solution was evaporated to dryness to obtain crude product 25-2 (84 mg), which was used directly in the next step of the reaction.

[0496] (3) Under nitrogen protection, (3S,5R)-3,5-dimethylpiperidine (54 mg, 0.47 mmol) was added to a dichloromethane (5 mL) solution of compound 25-2 (84 mg, 0.24 mmol) at 25 °C. The mixture was stirred at 25 °C for 2 hours. The reaction solution was evaporated to dryness, and the residue was purified by silica gel column chromatography to give compound 25-3 (60 mg). LC-MS: 432.4 [M+H] + .

[0497] (4) Under nitrogen protection, int1A (71 mg, 0.23 mmol), cesium carbonate (113 mg, 0.35 mmol), and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (21 mg, 0.02 mmol) were added to a 5 mL solution of 1,4-dioxane (50 mg, 0.12 mmol) of compound 25-3 at 25 °C. The mixture was stirred at 110 °C for 12 hours. The reaction solution was evaporated to dryness, and the residue was purified by silica gel column chromatography to give 25-4 (55 mg). LC-MS: 657.4 [M+H] + .

[0498] (5) The mixture of (55mg, 0.08mmol) solution was added to trifluoroacetic acid (4mL) at 25℃. The mixture was stirred at 25℃ for 1 hour. After the reaction solution was dried by rotary evaporation, it was dissolved in acetonitrile (3mL) and ammonia water (2mL) was added. The mixture was stirred at 25℃ for 1 hour. The reaction solution was dried by rotary evaporation. The crude product was purified by preparative liquid chromatography to obtain compound 025 (18mg).

[0499] Example 26

[0500] Synthesis route:

[0501] (1) Compound 25-2 (150 mg, 0.42 mmol) was dissolved in dimethyl sulfoxide (8 mL), and (S)-3-(difluoromethyl)piperidine (171.71 mg, 1.27 mmol) and N,N-diisopropylethylamine (327.71 mg, 2.54 mmol) were added. The reaction mixture was stirred at 80 °C for 1 hour. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic phases were washed twice with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 26-1 (50 mg). LC-MS: 454.2 [M+H] + .

[0502] (2) Compound 26-1 (40 mg, 0.088 mmol), int1A (54 mg, 0.176 mmol), cesium carbonate (186.19 mg, 0.26 mmol), and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (15.99 mg, 0.018 mmol) were dissolved in dioxane (4 mL). The reaction was carried out under nitrogen protection at 110 °C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 26-2 (60 mg). LC-MS: 679.3 [M+H] + .

[0503] (3) Under nitrogen protection, compound 26-2 (50 mg, 0.074 mmol) was dissolved in trifluoroacetic acid (3 mL), and the reaction solution was stirred at 25 °C for 1 hour. The reaction solution was evaporated to dryness, dissolved in acetonitrile (2 mL), and ammonia water (2 mL) was added. The reaction solution was stirred at 25 °C for 1 hour, and the reaction solution was evaporated to dryness. The residue was purified by preparative liquid chromatography to obtain compound 026 (28.99 mg).

[0504] Example 27

[0505] Synthesis route:

[0506] (1) Compound 23-3 (700 mg, 1.75 mmol) was dissolved in dioxane (35 mL), and (tributyltin)methanol (675.30 mg, 2.1 mmol) and X-Phos-Pd-G3 (148.35 mg, 0.17 mmol) were added. Under nitrogen protection, the reaction mixture was stirred at 80 °C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 27-1 (210 mg). LC-MS: 351.2 [M+H] + .

[0507] (2) Compound 27-1 (100 mg, 0.27 mmol) was dissolved in dimethyl sulfoxide (8 mL), and (S)-3-ethylpiperidine (92.04 mg, 0.81 mmol) and N,N-diisopropylethylamine (210.17 mg, 1.63 mmol) were added. The reaction mixture was stirred at 80 °C for 1 hour. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 27-2 (90 mg). LC-MS: 365.2 [M+H] + .

[0508] (3) Compound 27-2 (100 mg, 0.27 mmol) was dissolved in dimethyl sulfoxide (8 mL), and (S)-3-ethylpiperidine (92.04 mg, 0.81 mmol) and N,N-diisopropylethylamine (210.17 mg, 1.63 mmol) were added. The reaction mixture was stirred at 80 °C for 1 hour. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic phases were washed twice with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 27-3 (90 mg). LC-MS: 446.4 [M+H] + .

[0509] (4) Compound 27-3 (70 mg, 0.16 mmol), int1A (96.18 mg, 0.31 mmol), cesium carbonate (153.51 mg, 0.67 mmol), and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (28.47 mg, 0.031 mmol) were dissolved in dioxane (6 mL). The reaction was carried out under nitrogen protection at 110 °C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 27-4 (70 mg). LC-MS: 671.4 [M+H] + .

[0510] (5) Under nitrogen protection, compound 27-4 (60 mg, 0.089 mmol) was dissolved in trifluoroacetic acid (4 mL), and the reaction solution was stirred at 25 °C for 1 hour. The reaction solution was evaporated to dryness, dissolved in acetonitrile (2 mL), and ammonia water (2 mL) was added. The reaction solution was stirred at 25 °C for 1 hour, and the reaction solution was evaporated to dryness. The residue was purified by preparative liquid chromatography to obtain compound 027 (6.7 mg).

[0511] Example 28

[0512] Synthesis route:

[0513] (1) Compound 27-2 (90 mg, 0.24 mmol) was dissolved in dimethyl sulfoxide (6 mL), and (S)-3-(difluoromethyl)piperidine (98.90 mg, 0.73 mmol) and N,N-diisopropylethylamine (189.15 mg, 1.46 mmol) were added. The reaction mixture was stirred at 80 °C for 1 hour. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 28-1 (100 mg). LC-MS: 468.3 [M+H] + .

[0514] (2) Compound 28-1 (90 mg, 0.19 mmol), int1A (117.85 mg, 0.38 mmol), cesium carbonate (188.10 mg, 0.58 mmol), and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (34.89 mg, 0.038 mmol) were dissolved in dioxane (8 mL). The reaction was carried out under nitrogen protection at 110 °C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 28-2 (140 mg). LC-MS: 693.3 [M+H] + .

[0515] (3) Under nitrogen protection, compound 28-2 (140 mg, 0.14 mmol) was dissolved in trifluoroacetic acid (4 mL), and the reaction solution was stirred at 25 °C for 1 hour. The reaction solution was evaporated to dryness, dissolved in acetonitrile (2 mL), ammonia water (2 mL), and the reaction solution was stirred at 25 °C for 1 hour. The reaction solution was evaporated to dryness, and the residue was purified by preparative liquid chromatography to obtain compound 028 (47 mg).

[0516] Example 29

[0517] Synthesis route:

[0518] (1) Under nitrogen protection, manganese dioxide (517 mg, 5.94 mmol) was added to dichloromethane (30 mL) containing compound 25-1 (200 mg, 0.59 mmol) at 25 °C. The mixture was stirred at 50 °C for 16 hours. The reaction solution was filtered and evaporated to dryness to obtain compound 29-1 (200 mg), which was used directly in the next step.

[0519] (2) Under nitrogen protection, int1A (275 mg, 0.897 mmol), cesium carbonate (487 mg, 1.49 mmol), and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (54 mg, 0.06 mmol) were added to a 5 mL solution of 1,4-dioxane (200 mg, 0.60 mmol) at 25 °C. The mixture was stirred at 110 °C for 12 hours. The reaction mixture was extracted with ethyl acetate, washed with saturated sodium chloride aqueous solution, dried, and evaporated to dryness to give compound 29-2 (270 mg). LC-MS: 560.9 [M+H] + .

[0520] (3) Under nitrogen protection, 1-methylcyclobutane-1-amine hydrochloride (234 mg, 1.93 mmol) was added to a methanol (5 mL) solution of compound 29-2 (270 mg, 0.48 mmol) at 25 °C, followed by the addition of sodium triacetoxyborohydride (409 mg, 1.93 mmol) in portions. The mixture was stirred at 25 °C for 16 hours. Sodium borohydride (18 mg, 0.24 mmol) was added in portions, followed by stirring for 2 hours. The reaction mixture was evaporated to dryness, and the residue was subjected to silica gel column chromatography to give compound 29-3 (100 mg). LC-MS: 629.5 [M+H] + .

[0521] (4) Compound 29-3 (100 mg, 0.159 mmol) was dissolved in trifluoroacetic acid (4 mL) at 25 °C and stirred for 1 hour. The reaction solution was evaporated to dryness, dissolved in acetonitrile (3 mL), and ammonia (3 mL) was added. The mixture was stirred at room temperature for 3 hours, and the reaction solution was evaporated to dryness. The crude product was purified by preparative liquid chromatography to obtain compound 029 (10 mg).

[0522] Example 30

[0523] Synthesis route:

[0524] (1) Int6 (60.0 mg, 0.144 mmol), compound 3-11 (60.0 mg, 0.173 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (13.0 mg, 0.014 mmol), and cesium carbonate (140.0 mg, 0.432 mmol) were dissolved in 1,4-dioxane (5.0 mL). The reaction mixture was subjected to nitrogen protection and reacted at 110 °C for 2 hours. The reaction solution was diluted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give compound 30-1 (50.0 mg). LC-MS: 683.4 [M+H] + .

[0525] (2) Under nitrogen protection, compound 30-1 (50.0 mg, 0.073 mmol) was dissolved in trifluoroacetic acid (2.0 mL), reacted at 25 °C for 1 hour, concentrated under reduced pressure, and the residue was dissolved in acetonitrile (5.0 mL). Ammonia water (1.0 mL) was added, reacted for 2 hours, concentrated under reduced pressure, and the residue was purified to obtain compound 030 (12.46 mg).

[0526] Example 31

[0527] Synthesis route:

[0528] (1) Compound 3-11 (50 mg, 0.12 mmol), int7A (41.9 mg, 0.12 mmol), cesium carbonate (117.0 mg, 0.36 mmol), and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (21.7 mg, 0.024 mmol) were dissolved in dioxane (4 mL). The reaction was carried out under argon protection at 110 °C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 31-1 (50 mg). LC-MS: 687.4 [M+H] + .

[0529] (2) Under nitrogen protection, compound 31-1 (50 mg, 0.073 mmol) was dissolved in trifluoroacetic acid (3 mL), and the reaction solution was stirred at 25 °C for 1 hour. The reaction solution was evaporated to dryness, dissolved in acetonitrile (2 mL), and ammonia water (2 mL) was added. The reaction solution was stirred for 1 hour, and the reaction solution was evaporated to dryness. The residue was purified by preparative liquid chromatography to obtain compound 031 (20 mg).

[0530] Example 32

[0531] Synthesis route:

[0532] (1) At 0 °C, hexamethyldisilamide lithium (1N in tetrahydrofuran, 19.48 mL, 19.48 mmol) was added to a solution of int5 (2.0 g, 6.493 mmol) in tetrahydrofuran (20 mL). The mixture was stirred at 0 °C for 30 min, then iodomethane (2.76 g, 19.48 mmol) was added and stirred at 0 °C for 1 h, followed by quenching with a saturated aqueous solution of ammonium chloride. Extraction was performed with ethyl acetate. The organic layers were combined, dried, and concentrated to dryness. Purification by silica gel column chromatography gave compound 32-1 (1.95 g). 1 H NMR (400MHz, DMSO-d6) δ7.33(d,J=2.4Hz,1H),6.32(d,J=2.8Hz,1H),5.65(s,2H),4.42–4.33(m,2 H),3.49(t,J=7.6Hz,2H),1.79(s,6H),1.43(t,J=7.2Hz,3H),0.86(t,J=7.7Hz,2H),-0.00(s,9H).

[0533] (2) Compound 32-1 (1.95 g, 5.80 mmol) was dissolved in ethanol (20 mL), and Raney nickel (190 mg) and ammonia (1 mL) were added at 25 °C. The mixture was purged with hydrogen three times and reacted at 25 °C for 12 hours. The reaction solution was filtered, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography to give compound 32-2 (1.52 g). LC-MS: 295.7 [M+H] + .

[0534] (3) Under nitrogen protection, compound 32-2 (1.52 g, 5.16 mmol) was dissolved in trifluoroacetic acid (20.0 mL), reacted at 25 °C for 1 hour, concentrated under reduced pressure, and the residue was dissolved in acetonitrile (50.0 mL). Ammonia water (1.0 mL) was added, and the reaction was carried out for 2 hours. The mixture was filtered and concentrated under reduced pressure to obtain compound 32-3 (600 mg). LC-MS: 165.1 [M+H] + .

[0535] (4) Compound 32-3 (600.0 mg, 3.65 mmol) was dissolved in tetrahydrofuran (60.0 mL) and methanol (120.0 mL), and N-bromosuccinimide (521.0 mg, 2.93 mmol) was added. The mixture was reacted at 25 °C for 1 hour. The reaction solution was filtered, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography to give compound 32-4 (340 mg). LC-MS: 243.0 [M+H] + .

[0536] (5) Compound 32-4 (340.0 mg, 1.40 mmol) and potassium tert-butoxide (188.3 mg, 1.68 mmol) were dissolved in N,N-dimethylformamide (5.0 mL), and 2-(trimethylsilyl)ethoxymethyl chloride (308.0 mg, 1.85 mmol) was added. The mixture was reacted at 25 °C for 1 hour, diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography to give compound 32-5 (420 mg). LC-MS: 373.1 [M+H] + .

[0537] (6) Compound 32-5 (800.0 mg, 2.15 mmol), tributyltin methanol (2.08 g, 6.45 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (180 mg, 0.215 mmol) were dissolved in 1,4-dioxane (20.0 mL) and reacted at 110 °C for 2 hours under nitrogen protection. The reaction solution was diluted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give compound 32-6 (600.0 mg). LC-MS: 325.2 [M+H] + .

[0538] (7) Compound 32-6 (500 mg, 1.613 mmol) was dissolved in dichloromethane (10 mL), and N,N-dimethylformamide (0.1 mL) and thionyl chloride (960 mg, 8.06 mmol) were added under ice-water bath conditions. The mixture was stirred at 25 °C for 2 hours. The reaction mixture was evaporated to dryness to give compound 32-7 (510 mg). LC-MS: 420.2 [M+H] + .

[0539] (8) Compound 32-8 (120.0 mg, 0.286 mmol), int1A (88.0 mg, 0.286 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (17.0 mg, 0.019 mmol), and cesium carbonate (187.0 mg, 0.575 mmol) were dissolved in 1,4-dioxane (5.0 mL). The reaction mixture was subjected to nitrogen protection and reacted at 110 °C for 2 hours. The reaction solution was diluted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 32-9 (65.0 mg). LC-MS: 645.4 [M+H] + .

[0540] (9) Under nitrogen protection, compound 32-9 (65 mg, 0.10 mmol) was dissolved in trifluoroacetic acid (2.0 mL), reacted at 25 °C for 1 hour, concentrated under reduced pressure, and the residue was dissolved in acetonitrile (5.0 mL). Ammonia water (1.0 mL) was added, reacted for 2 hours, concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography to obtain compound 032 (28.08 mg).

[0541] Example 33

[0542] Synthesis route:

[0543] (1) Compound 32-7 (150 mg, 0.438 mmol) was dissolved in dimethyl sulfoxide (5 mL), and (S)-3-difluoromethylpiperidine (88.8 mg, 0.657 mmol) and N,N-diisopropylethylamine (118 mg, 0.876 mmol) were added. The mixture was stirred at 80 °C for 2 hours. The reaction solution was quenched with water, extracted with ethyl acetate, and the organic phases were combined. The organic phase was dried over sodium sulfate, evaporated to dryness, and the crude product was purified by silica gel column chromatography to obtain compound 33-1 (90 mg). LC-MS: 442.2 [M+H] + .

[0544] (2) Compound 33-1 (90 mg, 0.20 mmol) was dissolved in dioxane (4 mL), and cesium carbonate (130 mg, 0.40 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) and int1A (91.5 mg, 0.30 mmol) were added. The mixture was purged with nitrogen and stirred overnight at 110 °C. The reaction solution was then diluted with water and extracted with ethyl acetate. The organic phases were combined, concentrated, and purified by column chromatography to obtain compound 33-2 (120 mg). LC-MS: 334.4 [M+H] + .

[0545] (3) Compound 33-2 (120 mg, 0.18 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (2 mL) was added. The mixture was stirred at 25 °C for 1 hour. The reaction solution was evaporated to dryness, and the residue was dissolved in tetrahydrofuran (5 mL). Ammonia water (2 mL) was added and the mixture was stirred overnight. The reaction solution was evaporated to dryness and purified by preparative liquid chromatography to obtain compound 033 (37 mg).

[0546] Example 34

[0547] Synthesis route:

[0548] (1) Compound int8A (54 mg, 0.12 mmol), cesium carbonate (78.2 mg, 0.24 mmol), and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (10.9 mg, 0.012 mmol) were added to a 2 mL solution of 1,4-dioxane (50 mg, 0.12 mmol) at 25 °C under nitrogen purging protection. The mixture was stirred at 110 °C for 12 hours. The reaction solution was evaporated to dryness, and the residue was purified by silica gel column chromatography to give compound 34-1 (70 mg). LC-MS: 786.5 [M+H] + .

[0549] (2) Compound 34-2 (70 mg, 0.089 mmol) was dissolved in trifluoroacetic acid (1 mL) at 25 °C. The mixture was stirred at 30 °C for 1 hour. After the reaction solution was evaporated to dryness, it was dissolved in acetonitrile (1 mL) and ammonia (1 mL) was added. The mixture was stirred at 30 °C for 12 hours. The reaction solution was evaporated to dryness, and the crude product was purified by preparative liquid chromatography to obtain compound 034 (10.5 mg).

[0550] Example 35

[0551] Synthesis route:

[0552] (1) Compound 25-2 (150 mg, 0.42 mmol) was added to a solution of (S)-3-ethylpiperidine (143.51 mg, 1.27 mmol) and N,N-diisopropylethylamine (327.70 mg, 2.54 mmol) in dimethyl sulfoxide (3 mL) at 25 °C. The mixture was stirred at 80 °C for 1 hour. The reaction solution was diluted with water, extracted twice with ethyl acetate, and the organic phases were combined and washed twice with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the reaction solution was evaporated to dryness. The residue was purified by silica gel column chromatography to give compound 35-1 (130 mg). LC-MS: 432.3 [M+H] + .

[0553] (2) At 25 °C, int1A (184.42 mg, 0.602 mmol), cesium carbonate (294.36 mg, 0.903 mmol), and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (27.30 mg, 0.030 mmol) were added to a 1,4-dioxane (4 mL) solution of compound 35-1 (130 mg, 0.301 mmol). Under nitrogen purging protection, the mixture was stirred at 110 °C for 12 hours. The reaction solution was evaporated to dryness, and the residue was purified by silica gel column chromatography to give compound 35-2 (90 mg).

[0554] (3) Compound 35-3 (90 mg, 0.14 mmol) was dissolved in trifluoroacetic acid (2 mL) at 25 °C. The mixture was stirred at 30 °C for 1 hour. After the reaction solution was evaporated to dryness, it was dissolved in acetonitrile (2 mL) and ammonia water (1 mL) was added. The mixture was stirred at 30 °C for 12 hours. The reaction solution was evaporated to dryness, and the crude product was purified by preparative liquid chromatography to obtain compound 035 (36 mg).

[0555] Example 36

[0556] Synthesis route:

[0557] (1) Compound 23-4 (40 mg, 0.093 mmol), int6 (40 mg, 0.12 mmol), cesium carbonate (90.57 mg, 0.28 mmol), and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (16.80 mg, 0.018 mmol) were dissolved in dioxane (4 mL). The reaction was carried out under nitrogen protection at 130 °C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 36-1 (30 mg). LC-MS: 697.5 [M+H] + .

[0558] (2) Under nitrogen protection, compound 36-2 (25 mg, 0.036 mmol) was dissolved in trifluoroacetic acid (3 mL), and the reaction solution was stirred at 25 °C for 1 hour. The reaction solution was evaporated to dryness, dissolved in acetonitrile (1.5 mL), and ammonia water (1.5 mL) was added. The reaction solution was stirred for 1 hour, and the reaction solution was evaporated to dryness. The residue was purified by preparative liquid chromatography to obtain compound 036 (20 mg).

[0559] Example 37

[0560] Synthesis route:

[0561] (1) Compound 27-2 (100 mg, 0.27 mmol) was dissolved in dimethyl sulfoxide (6 mL), and 3-azabicyclo[3.1.1]heptane hydrochloride (108.6 mg, 0.73 mmol) and N,N-diisopropylethylamine (210.2 mg, 1.63 mmol) were added. The reaction mixture was stirred at 80 °C for 1 hour. The reaction mixture was quenched with water and extracted three times with ethyl acetate. The combined organic phases were washed twice with brine, dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 37-1 (70.0 mg). LC-MS: 430.4 [M+H] + .

[0562] (2) Compound 37-1 (70.0 mg, 0.16 mmol), int1A (99.8 mg, 0.32 mmol), cesium carbonate (159.24 mg, 0.48 mmol), and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (29.54 mg, 0.032 mmol) were dissolved in dioxane (8 mL). The reaction was carried out under nitrogen protection at 110 °C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 37-2 (50 mg). LC-MS: 655.4 [M+H] + .

[0563] (3) Compound 37-2 (40 mg, 0.067 mmol) was dissolved in trifluoroacetic acid (2 mL), and the reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was evaporated to dryness, dissolved in acetonitrile (2 mL), and ammonia water (2 mL) was added. The reaction mixture was stirred at 25 °C for 1 hour, and then evaporated to dryness. The residue was purified by preparative liquid chromatography to obtain compound 037 (8.0 mg). LC-MS: 525.5 [M+H] + .

[0564] Example 38

[0565] Synthesis route:

[0566] (1) Thionyl chloride (368.9 mg, 3.10 mmol) was added to a solution of compound 38-1 (200 mg, 0.62 mmol) in dichloromethane (8 mL) at 25 °C, and the mixture was stirred for 1 hour. The reaction solution was evaporated to dryness to obtain compound 38-2 (200 mg), and the crude product was used directly in the next step of the reaction.

[0567] (2) Compound 38-2 (200 mg, 0.59 mmol) was added to a solution of (S)-3-(fluoromethyl)piperidine hydrochloride (108.1 mg, 0.704 mmol) and N,N-diisopropylethylamine (303.3 mg, 2.35 mmol) in dimethyl sulfoxide (6 mL) at 25 °C. The mixture was stirred at 80 °C for 1 hour. The reaction solution was quenched with water and extracted three times with ethyl acetate. The combined organic phases were washed twice with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 38-3 (80.0 mg). LC-MS: 422.3 [M+H] + .

[0568] (3) At 25 °C, int1A (69.7 mg, 0.23 mmol), cesium carbonate (154.6 mg, 0.474 mmol), and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (34.4 mg, 0.038 mmol) were added to a 1,4-dioxane (4 mL) solution of compound 38-3 (80 mg, 0.19 mmol). The mixture was stirred at 110 °C for 12 hours under nitrogen purging protection. The reaction mixture was evaporated to dryness, and the residue was purified by silica gel column chromatography to give compound 38-4 (60 mg). LC-MS: 647.5 [M+H] + .

[0569] (4) Compound 38-4 (60 mg, 0.093 mmol) was dissolved in trifluoroacetic acid (2 mL) at 25 °C. The mixture was stirred at 30 °C for 1 hour. After the reaction solution was evaporated to dryness, it was dissolved in acetonitrile (2 mL) and ammonia water (2 mL) was added. The mixture was stirred for 12 hours. The reaction solution was evaporated to dryness, and the crude product was purified by preparative liquid chromatography to obtain compound 038 (20 mg).

[0570] Example 39

[0571] Synthesis route:

[0572] (1) 25-2 (211 mg, 0.595 mmol) was added to a solution of (S)-3-(fluoromethyl)piperidine hydrochloride (92 mg, 0.595 mmol) and N,N-diisopropylethylamine (461 mg, 3.57 mmol) in dimethyl sulfoxide (6 mL) at 25 °C. The mixture was stirred at 70 °C for 12 hours. The reaction solution was diluted with water, extracted with ethyl acetate, and the combined organic phases were washed twice with saturated brine, dried over anhydrous sodium sulfate, and the reaction solution was evaporated to dryness. The residue was purified by silica gel column chromatography to give compound 39-1 (80 mg). LC-MS: 436.3 [M+H] + .

[0573] (2) Compound int1A (56 mg, 0.184 mmol), cesium carbonate (120 mg, 0.368 mmol), and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (16.7 mg, 0.018 mmol) were added to a 4 mL solution of 1,4-dioxane (80 mg, 0.184 mmol) of compound 39-1 at 25 °C under nitrogen protection. The mixture was stirred at 110 °C for 12 hours. The reaction solution was evaporated to dryness, and the residue was purified by silica gel column chromatography to give compound 39-2 (80 mg). LC-MS: 661.5 [M+H] + .

[0574] (3) Compound 39-2 (70 mg, 0.106 mmol) was dissolved in trifluoroacetic acid (1 mL) at 25 °C and stirred for 1 hour. After the reaction solution was evaporated to dryness, it was dissolved in acetonitrile (2 mL) and ammonia water (1 mL) was added. The reaction solution was stirred for 12 hours. After the reaction solution was evaporated to dryness, the crude product was purified by preparative liquid chromatography to obtain compound 039 (25 mg).

[0575] Example 40

[0576] Synthesis route:

[0577] (1) Thionyl chloride (254.5 mg, 254.5 mmol) was added to a dichloromethane (8 mL) solution of compound 27-2 (150 mg, 0.428 mmol) at 25 °C, and the mixture was stirred at 25 °C for 1 hour. The reaction solution was evaporated to dryness to give compound 40-1 (150 mg), and the crude product was used directly in the next step of the reaction.

[0578] (2) Compound 40-1 (150 mg, 0.406 mmol) was added to a solution of (S)-3-(fluoromethyl)piperidine hydrochloride (68.7 mg, 0.447 mmol) and N,N-diisopropylethylamine (262.7 mg, 2.03 mmol) in dimethyl sulfoxide (6 mL) at 25 °C. The mixture was stirred at 80 °C for 1 hour. The reaction solution was quenched with water and extracted three times with ethyl acetate. The combined organic phases were washed twice with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 40-2 (60 mg). LC-MS: 450.4 [M+H] + .

[0579] (3) At 25 °C, int1A (49.03 mg, 0.16 mmol), cesium carbonate (108.7 mg, 0.334 mmol), and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (12.1 mg, 0.013 mmol) were added to a 1,4-dioxane (4 mL) solution of compound 40-2 (60 mg, 0.133 mmol). Under nitrogen purging protection, the mixture was stirred at 110 °C for 12 hours. The reaction solution was evaporated to dryness, and the residue was purified by silica gel column chromatography to give compound 40-3 (30 mg).

[0580] (4) Compound 40-3 (30 mg, 0.044 mmol) was dissolved in trifluoroacetic acid (2 mL) at 25 °C. The mixture was stirred at 30 °C for 1 hour. After the reaction solution was evaporated to dryness, it was dissolved in acetonitrile (2 mL) and ammonia water (2 mL). The mixture was stirred at 30 °C for 12 hours. The reaction solution was evaporated to dryness, and the crude product was purified by preparative liquid chromatography to obtain compound 040 (10 mg).

[0581] Example 41

[0582] Synthesis route:

[0583] (1) 25-2 (1.22 g, 3.6 mmol), 3,5-dimethylpiperidine (489 mg, 4.3 mmol) and N,N-diisopropylethylamine (1.39 g, 10.8 mmol) were dissolved in N,N-dimethylformamide (15 mL), stirred at 70 °C for 1 hour under nitrogen, the reaction solution was quenched with water, extracted three times with ethyl acetate, the organic phase was dried, concentrated, and purified by column chromatography to obtain compound 41-1 (0.85 g).

[0584] (2) Compound 41-1 (100.0 mg, 0.286 mmol), int7A (119.0 mg, 0.286 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (17.0 mg, 0.019 mmol), and cesium carbonate (279.0 mg, 0.858 mmol) were dissolved in 1,4-dioxane (5.0 mL). The reaction mixture was subjected to nitrogen protection and reacted at 110 °C for 2 hours. The reaction solution was diluted with ethyl acetate, washed three times with saturated brine, dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 41-2 (80.0 mg). LC-MS: 344.2 [M+2H / 2] + .

[0585] (3) Under nitrogen protection, 41-2 (80.0 mg, 0.116 mmol) was dissolved in trifluoroacetic acid (2.0 mL), reacted at 25 °C for 1 hour, concentrated under reduced pressure, and the residue was dissolved in acetonitrile (5.0 mL). Ammonia water (1.0 mL) was added, reacted at 25 °C for 18 hours, concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography to obtain 041 (14.16 mg).

[0586] Example 42

[0587] Synthesis route:

[0588] (1) Compound 41-1 (100.0 mg, 0.227 mmol), int8A (93.0 mg, 0.192 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (17.0 mg, 0.019 mmol), and cesium carbonate (187.0 mg, 0.575 mmol) were dissolved in 1,4-dioxane (5.0 ml) and reacted at 110 °C for 2 hours under nitrogen protection. The reaction solution was diluted with ethyl acetate, washed three times with saturated brine, dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 42-1 (50.0 mg).

[0589] (2) Under nitrogen protection, compound 42-1 (50.0 mg, 0.064 mmol) was dissolved in trifluoroacetic acid (2.0 mL), reacted at room temperature for 1 hour, concentrated under reduced pressure, and the residue was dissolved in acetonitrile (5.0 mL). Ammonia water (1.0 mL) was added, reacted for 18 hours, concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography to obtain compound 042 (14.37 mg).

[0590] Various embodiments 1 The H NMR and MS data are shown in the table below.

[0591] Table 1: 1 H NMR and MS data

[0592] Biological testing

[0593] Experimental Example 1: Evaluation of the effect of the test compound on Cbl-b activity

[0594] 1. Cbl-b binding activity assay

[0595] Experimental Methods: Cbl-b binding assays were performed in 384-well plates (Greiner), with a total reaction volume of 15 μL. 150 nL of a 3-fold serially diluted compound (final concentration 1 μL - 0.05 nM, starting at 1 μL, 3-fold dilutions, 10 spots, the 10th spot being 0.05 nM) was incubated with 5 μL of 8 nM Cbl-b (in-house, Bioduro) protein at room temperature (25°C) for 1 hour. The reaction buffer consisted of 20 mM HEPES pH 7.5 (Gibco), 1 μL 50 mM NaCl (Sigma), 0.01% Triton X-100 (Sigma), and 0.01% BSA. And 0.5 mM TCEP (Thermo). Add 5 μL of 346.5 nM ligand PRJ1 / 3-1022 mixture (in-house, Bioduro) and 5 μL of 1 nM streptavidin-Terbium cryptate assay reagent (Cisbio) to the reaction plate and incubate at room temperature for 1 hour. Read the HTRF signal (520 / 615) on an EnVision (Perkin Elmer) instrument. Calculate the IC50 using IDBS XLfit. 50 .

[0596] Experimental results

[0597] Table 2: Results of in vitro activity tests

[0598] Conclusion: The compounds of this invention have strong inhibitory activity against Cbl-b.

[0599] Experimental Example 2: Evaluation of the effect of the test compound on IFN-γ release activation in PanT cells

[0600] Experimental reagents: RPMI medium 1640 (Gibco, A10491-01), human PBMCs (Sailybio, XFB-HP050B), FBS (Gibco, 10091-148), Pan T cell isolation kit (Miltenyi Biotech, 130-096-535), penicillin and streptomycin (Gibco, 15140-122), Trypan Blue (Invitrogen, T10282), DMSO (Solarbio, D8371), DPBS (Gibco, 14190-144), anti-huCD3 (eBioscience, 16-0037-38), Ancillary kit 2 (R&D Systems, DY008), 2-mercaptoethanol (Gibco, 21985023), human IFNγ Duoset ELISA kit (R&D Systems, DY285B).

[0601] Experimental materials: Cell counting slides (Invitrogen, C10283), 96-well culture plates (Corning, 3603), 384-well plates (Labcyte, LP-0200), centrifuge tubes 15ml / 50ml (BD, 352096 / 352070), Reagent Reserviors (JET BIOFIL, LTT001050), pipette tips 10μl / 200μl / 1ml (Axygen, T-300-RS / T-200-YRS / T-1000-BRS), pipettes 5ml / 10ml / 25ml / 50ml (ExCell / JET, CS017-0003 / CS017-0004 / GSP110025 / GSP110050).

[0602] Experimental instruments: Biosafety cabinet (Thermo Scientific, 1389), centrifuge (Eppendorf, 5702), CO2 incubator (Thermo Scientific, 371), cell counter (Invitrogen, C10281), dispenser (BIOHIT, Easypet), microplate (Olympus, CKX41), pipette (BIOHIT, Proline Plus), Echo (Labcyte, 655T), Microplate reader (BMG LABTECH, PHERAstar FSX).

[0603] Experimental methods:

[0604] 1. Day 0, PanT cell isolation and plating

[0605] 1) Remove human PBMC cells from the liquid nitrogen tank.

[0606] 2) Add 9 mL of preheated culture medium to a 15 mL centrifuge tube, thaw the cells in a 37 °C water bath, aspirate the cells into a pre-prepared centrifuge tube, take out 10 μL of cells for counting, and centrifuge the remaining cells at 1000 rpm for 5 min.

[0607] 3) Aspirate the centrifuged culture medium, every 10 7 The cells were resuspended in 40 μL of buffer and mixed with 10 μL of Pan T Cell Biotin-Antibody Cocktail, then incubated at 4°C for 5 minutes.

[0608] 4) Every 10 7 Add 30 μL of buffer and 20 μL of Pan T Cell MicroBead Cocktail to the cells, mix, and incubate at 4°C for 10 minutes. Shake well once after 5 minutes.

[0609] 5) Prepare the MACS separator, place the LS column in the separator, take 3 mL of buffer to rinse the LS column, aspirate 1 mL of cells into the LS column, take 1 mL of buffer to rinse the centrifuge tube and add it to the LS column, take another 2 mL of buffer to rinse the centrifuge tube and add it to the LS column, then rinse the centrifuge tube twice and add 3 mL of buffer each time.

[0610] 6) Centrifuge the collected cells at 1900 rpm for 5 min, remove the culture medium, add fresh culture medium (RPMI 1640 medium with 10% FBS and 1% PS, 0.1% of 2-mercaptoethanol) to resuspend the cells, and calculate the cell yield.

[0611] 7) Add 200 nL of the compound in a three-fold serial dilution (final concentration 10 μM-1.52 nM, starting concentration 10 μM, three-fold dilution, 9 spots, the 9th spot is 1.52 nM) and 0.1% DMSO to a cell culture plate (Corning, 3603).

[0612] 8) Prepare 5x10 5 PanT cell suspension was diluted with 1 mL of mercaptoethanol at a ratio of 1:1000. A portion of the suspension was taken as unstim, and CD3 antibody (1 μg / mL) was added to the remaining suspension. The mixture was thoroughly mixed, and 200 μL of the cell suspension was transferred to a 96-well cell plate containing the added compound. The plate was then incubated at 37°C in a 5% CO2 incubator for 48 hours.

[0613] 2. On the second day, collect the supernatant sample.

[0614] 1) Centrifuge the ELISA plate at 1000 rpm for 1 minute, then collect 150 μL of supernatant into a 96-well plate, attach the membrane, and place it in a -80°C freezer overnight.

[0615] 2) Add 100 μL of capture antibody (dilution factor: 1:120) to each well of the ELISA plate and coat the ELISA plate. Incubate overnight at room temperature.

[0616] 3. Day 3, IFNγ ELISA detection

[0617] 1) Discard the capture antibody in the plate, add 300 μL of washing buffer to wash the plate, and wash 3 times.

[0618] 2) Add 300 μL of blocking solution to each well to seal the plate, attach the sealing film, and incubate at room temperature for 1 hour.

[0619] 3) Discard the blocking solution, add 300 μL of washing buffer to each well to wash the plate, and wash 3 times.

[0620] 4) Discard the washing buffer, add 100 μL of diluted sample (dilution factor: 1:50) and standard to the plate, seal the plate with the film, and incubate at room temperature for 2 hours.

[0621] 5) Discard the samples and add 300 μL of washing buffer to each well to wash the plate three times.

[0622] 6) Discard the washing buffer, add 100 μL of detection antibody (dilution factor: 1:60) to each well, seal the plate, and incubate at room temperature for 2 hours.

[0623] 7) Discard the detection antibody, add 300 μL of washing buffer to each well to wash the plate, and wash 3 times.

[0624] 8) Discard the washing buffer, add 100 μL of Streptavidin-HRP B (dilution factor: 1:40) to each well, seal the plate with the membrane, and incubate at room temperature in the dark for 20 minutes.

[0625] 9) Discard Streptavidin-HRP B, add 300 μL of washing buffer to each well to wash the plate 3 times.

[0626] 10) Discard the washing buffer, add 100 μL of substrate solution to each well, and incubate at room temperature in the dark for 20 minutes.

[0627] 11) Add 50 μL of stop solution to each well and read the absorbance at 450 nm using a Pherastar FSX multi-microplate reader (BMG).

[0628] 12) Use IDBS XLfit to perform standard curve fitting and determine the IFN-γ content of the samples. Plot the dose-response curve using the original IFN-γ concentration of the samples and calculate EC. 50 .

[0629] Experimental conclusion: The compound of this invention has a good IFN-γ release activation effect on PanT cells.

[0630] Table 3: Results of in vitro activity tests

[0631] Experimental Example 3: Evaluation of the effect of the test compound on the activation of IFN-γ release from NK cells

[0632] Experimental reagents: RPMI medium 1640 (Gibco, A10491-01), human PBMCs (Sailybio, XFB-HP100B), FBS (Gibco, 10091-148), NK cell isolation kit (Miltenyi Biotech, 130-092-657), penicillin and streptomycin (Gibco, 15140-122), Trypan Blue (Invitrogen, T10282), DMSO (Solarbio, D8371), DPBS (Gibco, 14190-144), NKG2D (eBioscience, 16-5878-82), IL-2 (R&D, 202-IL-050), Ancillary kit 2 (R&D Systems, DY008), 2-mercaptoethanol (Gibco, 21985023), human IFNγ Duoset ELISA kit (R&D... Systems, DY285B).

[0633] Experimental methods:

[0634] 1. Day 0, NK cell isolation

[0635] 1) Remove human PBMC cells from the liquid nitrogen tank.

[0636] 2) Add 9 mL of preheated culture medium to a 15 mL centrifuge tube, thaw the cells in a 37 °C water bath, aspirate the cells into a pre-prepared centrifuge tube, take out 10 μL of cells for counting, and centrifuge the remaining cells at 1000 rpm for 5 min.

[0637] 3) Aspirate the centrifuged culture medium, every 10 7 The cells were resuspended in 40 μL of buffer and mixed with 10 μL of NK Cell Biotin-Antibody Cocktail, then incubated at 4°C for 5 minutes.

[0638] 4) Every 10 7 Add 30 μL of buffer and 20 μL of NK Cell MicroBead Cocktail to the cells, mix, and incubate at 4°C for 10 minutes. Shake well once after 5 minutes.

[0639] 5) Prepare the MACS separator, place the LS column in the separator, take 3 mL of buffer to rinse the LS column, aspirate 1 mL of cells into the LS column, take 1 mL of buffer to rinse the centrifuge tube and add it to the LS column, take another 2 mL of buffer to rinse the centrifuge tube and add it to the LS column, then rinse the centrifuge tube twice and add 3 mL of buffer each time.

[0640] 6) Centrifuge the collected cells at 1900 rpm for 5 min, remove the culture medium, add fresh culture medium to resuspend the cells, and calculate the cell yield.

[0641] 7) Resuspend the isolated NK cells in RPMI 1640 medium (with 10% FBS and 1% PS, 25 ng / ml IL-2, and 0.1% 2-mercaptoethanol) and incubate overnight at 37°C in a 5% CO2 incubator.

[0642] 2. Day 1, NK cell plating

[0643] 1) Add 200 nL of a three-fold serially diluted compound (final concentration 10 μM-1.52 nM, starting concentration 10 μM, three-fold dilution, 9 spots, the 9th spot is 1.52 nM) and 0.1% DMSO to a cell culture plate (Corning, 3603).

[0644] 2) Prepare 1.026 x 10 5 Mix 195 μL of NK cell suspension with 1 mL of the compound, transfer 195 μL of the cell suspension to a 96-well cell plate containing the compound, add 5 μL of NKG2D (1 μg / ml) and none (as non-stimulation), and incubate at 37°C in a 5% CO2 incubator for 24 hours.

[0645] 3. On the second day, collect the supernatant sample.

[0646] 1) Centrifuge the ELISA plate at 1000 rpm for 1 minute, then collect 150 μL of supernatant into a 96-well plate, attach the membrane, and place it in a -80°C freezer overnight.

[0647] 2) Add 100 μL of capture antibody (dilution factor: 1:120) to each well of the ELISA plate, coat the ELISA plate, and incubate overnight at room temperature.

[0648] 4. Day 3, IFNγ ELISA detection

[0649] 1) Discard the capture antibody in the plate, add 300 μL of washing buffer to wash the plate, and wash 3 times.

[0650] 2) Add 300 μL of blocking solution to each well to seal the plate, attach the sealing film, and incubate at room temperature for 1 hour.

[0651] 3) Discard the blocking solution, add 300 μL of washing buffer to each well to wash the plate, and wash 3 times.

[0652] 4) Discard the washing buffer, add 100 μL of diluted sample (dilution factor: 1:5) and standard to the plate, seal the plate with the film, and incubate at room temperature for 2 hours.

[0653] 5) Discard the samples and add 300 μL of washing buffer to each well to wash the plate three times.

[0654] 6) Discard the washing buffer, add 100 μL of detection antibody (dilution factor: 1:60) to each well, seal the plate, and incubate at room temperature for 2 hours.

[0655] 7) Discard the detection antibody, add 300 μL of washing buffer to each well to wash the plate, and wash 3 times.

[0656] 8) Discard the washing buffer, add 100 μL of Streptavidin-HRP B (dilution factor: 1:40) to each well, seal the plate with the membrane, and incubate at room temperature in the dark for 20 minutes.

[0657] 9) Discard Streptavidin-HRP B, add 300 μL of washing buffer to each well to wash the plate 3 times.

[0658] 10) Discard the washing buffer, add 100 μL of substrate solution to each well, and incubate at room temperature in the dark for 20 minutes.

[0659] 11) Add 50 μL of stop solution to each well and read the absorbance at 450 nm using a Pherastar FSX multi-microplate reader (BMG).

[0660] 12) Use IDBS XLfit to perform standard curve fitting and determine the IFNγ content of the samples. Plot the dose-response curve using the original IFNγ concentration of the samples and calculate EC. 50 .

[0661] Table 4: Results of in vitro activity tests

[0662] Experimental conclusion: The compound of this invention has a good activating effect on the release of IFN-γ from NK cells.

[0663] Experimental Example 4: Mouse Pharmacokinetic Experiment

[0664] Male C57BL / 6N mice (weighing 18-22g) were fasted overnight before the experiment. The test compound was dissolved in a solvent, with intravenous (iv) administration at 2 mg / kg (n=3) and oral (po) administration at 10 mg / kg (n=3). Blood samples were collected via the orbital venous plexus at 15 minutes, 30 minutes, and 1, 2, 4, 6, 8, and 24 hours post-administration, approximately 0.08 mL at each time point. Blood samples were placed in 1.5 mL centrifuge tubes containing EDTA-2K and centrifuged (3200g, 10 minutes, 4°C) over 2 hours to obtain plasma samples. Plasma samples were cryopreserved at -70°C to -80°C before processing. Before sample processing, plasma samples were removed from the refrigerator and thawed at room temperature. 20 μL of plasma sample was added to each well of a 96-well plate, followed by 120 μL of acetonitrile containing an internal standard to precipitate proteins. After vortexing, the samples were centrifuged at 4950 g for 15 minutes at 4 °C. The supernatant was then mixed with an equal volume of 0.1% formic acid water for LC-MS / MS analysis.

[0665] Table 5: Mouse pK Results

[0666] Experimental conclusion: The compounds of this invention exhibit excellent pharmacokinetic results.

[0667] Experimental Example 5: Study on the metabolic stability of compounds in hepatocytes of different species

[0668] 1. Purpose

[0669] The in vitro metabolic stability of the test compound in hepatocytes of different species was investigated. The concentration of the parent drug in the incubation system was determined using LC / MS / MS, and the intrinsic clearance of the test compound in the hepatocyte system was calculated to assess its stability. The concentration of the test compound was 1 μM.

[0670] 2. Materials and Reagents

[0671] The hepatocytes were preserved in liquid nitrogen; details are shown in the table below.

[0672] 3. Experimental Design

[0673] 3.1 Preparation of the compound working solution

[0674] The test compound and verapamil powder were prepared into a high-concentration stock solution using DMSO. Before use, the stock solution was diluted with DMSO to a working solution of 100 μM. The final concentration of the test compound and verapamil was 1 μM.

[0675] 3.2 Preparation of hepatocytes

[0676] 1) Specific preparation information for hepatocyte resuscitation solution is shown in the table below. Mix 49.5 mL Williams' E Medium and 0.5 mL glutaMAX as incubation solution. Preheat the hepatocyte resuscitation solution and incubation solution in a 37°C water bath for at least 15 minutes before use.

[0677] 2) Take a tube of cryopreserved hepatocytes, ensuring that the hepatocytes remain frozen before thawing. Quickly place the hepatocytes in a 37°C water bath and gently shake until all ice crystals are dispersed. Spray with 70% ethanol and transfer to a biosafety cabinet.

[0678] 3) Pour the contents of the hepatocyte tubules into a centrifuge tube containing 50 mL of resuscitation solution and centrifuge at 100 g for 10 minutes. After centrifugation, aspirate the resuscitation solution and add sufficient incubation solution to obtain a cell suspension with a cell density of approximately 1.0 × 10⁶ cells / mL.

[0679] 4) Use AO / PI staining to count cells and determine viable cell density. Hepatocyte viability must be greater than 75%. Dilute cells with culture medium to a working cell density of 0.5 × 10⁶ viable cells / mL.

[0680] 3.3 Test Methods

[0681] 1) Transfer 247.5 μL of live cell suspension to a 96-well deep-well plate. Place the deep-well plate on a vortex and preheat in an incubator for 10 minutes. Perform double-parallel incubation.

[0682] 2) Add 2.5 μL of 100 μM test compound or verapamil to each well to initiate the reaction, and place the deep well plate back onto the incubator vortex.

[0683] 3) Place the incubation plate in an incubator. At 0, 15, 30, 60, 90, and 120 minutes, transfer 25 μL of the suspension to a new 96-well plate. Add 12 times the volume (300 μL) of acetonitrile containing internal standards (100 nM alprazolam, 200 nM caffeine, and 100 nM tolbutamide) as a quencher to terminate the reaction. Vortex the plate for 5 minutes, then centrifuge at 3220 rpm for 45 minutes at 4°C to precipitate the protein. Transfer 100 μL of the supernatant to a sample plate, add 100 μL of pure water, mix well, and proceed with UPLC-MS / MS analysis. All incubations should be performed in duplicate.

[0684] 4. Data Analysis

[0685] All calculations were performed using Microsoft Excel software. Peak areas were detected by extracting ion spectra. The in vitro half-life (t) of the parent drug was determined by linearly fitting the natural logarithm of the elimination percentage of the parent drug to time.1 / 2 ).

[0686] Proportional factors for predicting clearance in vivo in humans, monkeys, dogs, mice, and rats. a Proportion factor = (Hepatocyte content) × (Liver weight)

[0687] Table 6: Results of metabolic stability of compounds in hepatocytes

[0688] Experimental conclusion: The test compound according to the present invention exhibits good metabolic stability in hepatocytes.

[0689] Experimental Example 6: Antitumor effect of the test compound in a mouse CT-26 colorectal cancer allogeneic xenograft model

[0690] 1. Experimental Methods

[0691] 1.1. Cell Culture and Inoculation

[0692] Mouse colon cancer CT26 cells (source: BNCC; catalog number: 287983) were cultured adherently under the following conditions: RPMI 1640 medium supplemented with 10% fetal bovine serum and 1% Antibiotic-Antimycotic, at 37°C and 5% CO2. 2 Cultured under controlled conditions. Digested with trypsin weekly, passaged twice routinely. Harvested and counted cells when they maintained exponential growth and viability greater than 95%. 0.1 mL of a well-mixed cell suspension (containing 3 x 10⁻⁶ cells / mL) was inoculated into the right nape of each Balb / C mouse (female, 18–22 g, 6–8 weeks old, Zhejiang Vital River Laboratory Technology Co., Ltd.). 5 CT26 cells).

[0693] 1.2. Animal grouping

[0694] The average tumor volume reached 92 mm on the 10th day after inoculation. 3 At the designated time, all animals were weighed (BW) and tumor volume was measured. They were then randomly grouped according to tumor volume and body weight to ensure all groups had the same baseline. Numerical ear tags were used for labeling. The day of grouping was designated D0.

[0695] 1.3. Dosing regimen and requirements

[0696] Anti-Mo PD-1 (also known as Anti-Mouse PD-1, RMP1-14) is a commercially available IgG-like immunoglobulin antibody against mouse PD-1 that blocks PD-1 / PD-L1 signaling. Anti-Mo PD-1 is administered via intraperitoneal injection (IP).

[0697] Each test compound was administered at body weight (10 μL / g) to the mice. The test compounds and control solvents were administered orally (PO).

[0698] Discontinuation criteria: For animal welfare reasons, if the mouse's body weight drops by more than 15% (compared to D0), discontinue administration and resume administration once the weight loss returns to within 10%.

[0699] The dosage and frequency of administration of the test compounds are shown in Table 10.

[0700] 1.4. Tumor Measurement and Weighing

[0701] The experimental parameters were mouse body weight, tumor volume, and tumor weight. Animal body weight was recorded twice a week at a fixed time, and tumor diameter was measured twice a week using calipers.

[0702] The tumor volume is calculated using the following formula: V = 0.5a × b 2 ,

[0703] Where: a and b represent the major diameter (mm) and minor diameter (mm) of the tumor, respectively.

[0704] 1.5. Efficacy Indicators

[0705] Evaluation of the antitumor efficacy of a drug (TGI) (%) or relative tumor proliferation rate (T / C) (%): TGI (%) = [(1-(Mean(Ti) / Mean(T0) / Mean(Ci) / Mean(C0))] × 100%

[0706] in:

[0707] Mean(Ti) represents the mean tumor volume in the treatment group on day i after drug administration;

[0708] Mean(T0) represents the mean tumor volume in the treatment group on day 0 after drug administration;

[0709] Mean(Ci) represents the mean tumor volume in the solvent control group on day i after drug administration;

[0710] Mean(C0) represents the mean tumor volume in the solvent control group on day 0 after drug administration. T / C (%) = T / C × 100%

[0711] in:

[0712] T represents the relative average tumor volume in the treatment group;

[0713] C represents the relative average tumor volume of the solvent control group.

[0714] 1.6. Statistical Analysis

[0715] Experimental data are expressed as mean ± standard error (Mean ± SEM). Statistical analysis was performed based on the data obtained at the end of the experiment to assess differences between groups. One-way analysis of variance (ANOVA) was used to compare differences among multiple groups, with p < 0.05 considered statistically significant. T-test analysis was used to analyze differences between two groups, with p < 0.05 considered statistically significant.

[0716] 2. Experimental Results

[0717] Table 10. Evaluation of the antitumor efficacy of the test compounds in a mouse CT-26 colorectal cancer allogeneic xenograft model

[0718] Experimental conclusion: The test compound according to the present invention exhibits good antitumor activity, and its antitumor effect is significant when used in combination with PD-1 monoclonal antibody.

[0719] This document uses examples to illustrate the principles and implementation methods of the present invention. These examples are merely illustrative and not intended to limit the scope of the invention. It should be noted that those skilled in the art can make various improvements and modifications to the invention without departing from its principles, and these improvements and modifications also fall within the scope of the claims.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, or an isomer thereof, in: u is selected from 0, 1, or 2; X1, X2, X3 and X4 are each independently selected from CR6 or N; R1 and R2 are independently selected from H, halogens, CN, NH2, and NH(C). 1～6 alkyl), N(C) 1～6 Alkyl)2, C 1～6 Alkyl, C 1～6 Alkoxy, C 3～10 Cycloalkyl or 4-10 membered heterocyclic group, wherein the C 1～6 Alkyl, C 1～6 Alkoxy, C 3～10 Cycloalkyl or 4-10 membered heterocyclic groups are optionally R x replace; Or R1, R2, and the atoms they are connected to together form C. 3～10 Cycloalkyl or 4-10 membered heterocyclic groups, wherein the C 3～10 Cycloalkyl or 4-10 membered heterocyclic groups are optionally R x replace; Alternatively, R1, R2, and their respective connected atoms and bonds can together form C. 3～6 Cycloalkenyl or 4-7 membered heterocyclic groups, wherein the C 3～6 The cycloalkenyl or 4-7 membered heterocyclic group is optionally replaced by R v replace; R3 is selected from L2-W; L2 is selected from single bond, -CR d R e -; W is selected from 5-10-membered heteroaryl or 4-10-membered heterocyclic group, wherein the 5-10-membered heteroaryl or 4-10-membered heterocyclic group is optionally replaced by R. w replace; R d and R e Independently selected from H, halogens, OH, C 1～6 Alkyl or C 1～6 Alkoxy, the C 1～6 Alkyl or C 1～6 The alkoxy group may optionally be further substituted by a halogen 1 to 3 times; R1 can be arbitrarily chosen with R, provided that the valence allows. d Or R e Together with their respective atoms and bonds, they form C 3～6 cycloalkyl or 4-7 membered heterocyclic groups, wherein the C 3～6 Cycloalkyl or 4-7-membered heterocyclic groups are optionally R v replace; Ring A is selected from phenyl, 5-6-membered heteroaryl, or 5-7-membered heterocyclic group, wherein the phenyl, 5-6-membered heteroaryl, or 5-7-membered heterocyclic group is... Structural units It can be arbitrarily replaced by R4 n times; L1 is selected from single bonds, -(CR a R b ) p -、-NR c -, -O-, -C(=O)-, -C(=O)NH-, -CR a R b -NR c - where p is selected from 1, 2, or 3; R a R b R c Each element is independently selected from H, halogen, OH, and C. 1～6 Alkyl or C 1～6 Alkoxy, the C 1～6 Alkyl or C 1～6 Alkoxy groups are optionally replaced by R x Replace 1 to 3 times; n is independently selected from 0, 1, 2, 3, or 4; Any R a and R b Under conditions where the valence allows, it can form 3-5 membered cycloalkyl groups or 3-5 membered heterocyclic groups; R4 is selected from halogens, ⁵O, OH, NH₂, NO₂, CN, and C. 1～6 Alkyl, C 2～4 alkenyl, C 2～4 alkynyl group, C 1～6 Alkoxy, C 3～6 cycloalkyl, C 3～6 Cycloalkyloxy group, 4-7 membered heterocyclic group, 4-7 membered heterocyclic oxy group, wherein NH2, C 1～6 Alkyl, C 2～4 alkenyl, C 2～4 alkynyl group, C 1～6 Alkoxy, C 3～6 cycloalkyl, C 3～6 Cycloalkyloxy, 4-7 membered heterocyclic group, and 4-7 membered heterocyclic oxy group are optionally R y replace; When u is 0, n is greater than 2 and two adjacent R4s form a 3- to 6-membered carbon ring or heterocycle. The heterocycle may optionally contain 1 to 3 heteroatoms independently selected from N, O, and S, which can be combined with structural units. Forming 7- to 12-member saturated spiral rings, bridged rings, or fused rings; When u is not 0, any two adjacent R4s can optionally form a 3- to 6-membered carbon ring or heterocycle, wherein the heterocycle can optionally contain 1 to 3 heteroatoms independently selected from N, O, and S, which, together with the structural unit Forming 7- to 12-member saturated spiral rings, bridged rings, or parallel ring structures; R5 is selected from halogens, CN, OH, COOH, CONH2, C 1～6 Alkyl, C 1～6 Alkoxy, 4-10 nitrogen-containing heterocyclic group, 5-10 nitrogen-containing heteroaryl, 4-10 sulfur-containing heterocyclic group, 5-10 sulfur-containing heteroaryl, C 3～10 cycloalkyl, 4-10 membered heterocyclic, phenyl, 5-10 membered heteroaryl, wherein the C 1～6 Alkyl or C 1～6 Alkoxy groups are optionally replaced by R y Substitution, wherein the 4-10 nucleotide nitrogen-containing heterocyclic group, 5-10 nucleotide nitrogen-containing heteroaryl group, 4-10 nucleotide sulfur-containing heterocyclic group, 5-10 nucleotide sulfur-containing heteroaryl group, C 3～10 Cycloalkyl, 4-10 heterocyclic, phenyl, and 5-10 heteroaryl groups are optionally enclosed by R. z replace; R6 is independently selected from H, halogen, OH, CN, C 1～6 Alkyl, C 1～6 Alkoxy, NH2, NH(C) 1～6 alkyl), N(C) 1～6 Alkyl)2, C 3～6 cycloalkyl, C 3～6 cycloalkyl-O-, C 3～6 Cycloalkyl-NH-, 4-7 membered heterocyclic group, 4-7 membered heterocyclic group oxy group, 4-7 membered heterocyclic group -NH-, C 6～10 Aryl, C 6～10 aryloxy group, C 6～10 aryl-NH-, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy or 5-10-membered heteroaryl-NH-, wherein the C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 cycloalkyl, 4-7 membered heterocyclic, C 6～10 Aryl or 5-10 heteroaryl groups are optionally occupied by R y replace; Alternatively, two R6 atoms and their attached C atoms can together form C. 3～6 Cycloalkenyl, phenyl, 4-7 membered heterocyclic or 5-6 membered heteroaryl, wherein C 3～6 Cycloalkenyl, phenyl, 4-7-membered heterocyclic or 5-6-membered heteroaryl groups are optionally R y replace; R v Independently selected from halogens, OH, CN, C 1～6 Alkyl, (C 1～6 Alkyl)-CN or C 1～6 Alkoxy, the C 1～6 Alkyl or C 1～6 Alkoxy groups are optionally replaced by halogens, C 1～3 Alkyl, OH, or CN are substituted 1 to 3 times; R w Independently selected from halogens, OH, NH2, NH(C) 1～6 alkyl), N(C) 1～6 Alkyl)2, C 1～6 Alkyl, C 3～10 cycloalkyl or 4-7 membered heterocyclic group, wherein the C 1～6 Alkyl, C 3～10 Cycloalkyl or 4-7-membered heterocyclic groups are optionally surrounded by halogen, =O, OH, CN or C. 1～6 Alkyl substitution 1 to 3 times; R x Independently selected from halogens, OH, CN, (C 1～6 Alkyl)-CN, =O,C 1～6 Alkyl, NH2, NH(C) 1～6 alkyl), N(C) 1～6 Alkyl)2, COOH or C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally substituted 1 to 3 times with a halogen, cyano, hydroxyl or amino group; R y Independently selected from halogens, OH, =O, NH2, NH(C) 1～6 alkyl), N(C) 1～6 Alkyl)2, C 1～6 Alkyl, C 1～6 Alkoxy, wherein the C 1～6 Alkyl, C 1～6 Alkyl or C 1～6 The alkoxy group is further optionally substituted by a halogen or a hydroxyl group 1 to 3 times; R z Independently selected from halogens, CN, =O, OH, NO2, C 1～6 Alkyl, OR n 、N(R n 2. S(O)2R n S(O)2N(R) n 2. S(O)R n 、S(O)N(R n 2. C(O)R n C(O)OR n C(O)N(R) n 2. C(O)N(R) n OR n OC(O)R n OC(O)N(R) n )2、N(R n )C(O)OR n 、N(R n )C(O)R n 、N(R n )C(O)N(R n )2、N(R n )C(NR n )N(R n )2、N(R n )S(O)2N(R n )2、N(R n )S(O)2R n C 3～10 Cycloalkyl, 4-7-membered heterocyclic, 6-10-membered aryl, or 5-10-membered heteroaryl, wherein the C 1～6 Alkyl, C 3～10 cycloalkyl, 4-7 membered heterocyclic, C 6～10 Selectively further R-type aryl or 5-10 heteroaryl groups. x replace; R n Independently selected from H and C 1～6 Alkyl, phenyl, 4-7 membered heterocyclic or 5-6 membered heteroaryl, wherein C 1～6 Alkyl, phenyl, 4-7-membered heterocyclic or 5-6-membered heteroaryl groups are optionally further R x Substitution, or two R atoms on a N atom n Together with the N group attached thereto, a 4-7 membered heterocyclic group or a 5-6 membered heteroaryl group is formed, wherein the 4-7 membered heterocyclic group or the 5-6 membered heteroaryl group is optionally further reacted with R. x replace.

2. A compound of formula (I), or a pharmaceutically acceptable salt thereof, or an isomer thereof: in: u is selected from 0, 1, or 2; X1, X2, X3 and X4 are each independently selected from CR6 or N; R1 and R2 are independently selected from H, halogens, CN, NH2, and NH(C). 1～6 alkyl), N(C) 1～6 Alkyl)2, C 1～6 Alkyl, C 1～6 Alkoxy, C 3～10 Cycloalkyl or 4-10 membered heterocyclic group, wherein the C 1～6 Alkyl, C 1～6 Alkoxy, C 3～10 Cycloalkyl or 4-10 membered heterocyclic groups are optionally R x replace; Or R1, R2, and the atoms they are connected to together form C. 3～10 Cycloalkyl or 4-10 membered heterocyclic groups, wherein the C 3～10 Cycloalkyl or 4-10 membered heterocyclic groups are optionally R x replace; Alternatively, R1, R2, and their respective connected atoms and bonds can together form C. 3～6 Cycloalkenyl or 4-7 membered heterocyclic groups, wherein the C 3～6 The cycloalkenyl or 4-7 membered heterocyclic group is optionally replaced by R v replace; R3 is selected from L2-W; L2 is selected from single bond, -CR d R e -; W is selected from 5-10-membered heteroaryl or 4-10-membered heterocyclic group, wherein the 5-10-membered heteroaryl or 4-10-membered heterocyclic group is optionally replaced by R. w replace; R d and R e Independently selected from H, halogens, OH, C 1～6 Alkyl or C 1～6 Alkoxy, the C 1～6 Alkyl or C 1～6 The alkoxy group may optionally be further substituted by a halogen 1 to 3 times; R1 can be arbitrarily chosen with R, provided that the valence allows. d Or R e Together with their respective atoms and bonds, they form C 3～6 cycloalkyl or 4-7 membered heterocyclic groups, wherein the C 3～6 Cycloalkyl or 4-7-membered heterocyclic groups are optionally R v replace; Ring A is selected from phenyl, 5-6-membered heteroaryl, or 5-7-membered heterocyclic group, wherein the phenyl, 5-6-membered heteroaryl, or 5-7-membered heterocyclic group is... Structural units It can be arbitrarily replaced by R4 n times; n is independently selected from 0, 1, 2, 3, or 4; L1 is selected from single bonds, -(CR a R b ) p -、-NR c -, -O-, -C(=O)-, -C(=O)NH-, -C(R a R b ) p -NR c - where p is independently selected from 1, 2, or 3; R a R b R c Each element is independently selected from H, halogen, OH, and C. 1～6 Alkyl or C 1～6 Alkoxy, the C 1～6 Alkyl or C 1～6 Alkoxy groups are optionally replaced by R x Replace 1 to 3 times; Any R a and R b Under conditions where the valence allows, it can form 3-5 membered cycloalkyl groups or 3-5 membered heterocyclic groups; R4 is selected from halogens, ⁵O, OH, NH₂, NO₂, CN, and C. 1～6 Alkyl, C 2～4 alkenyl, C 2～4 alkynyl group, C 1～6 Alkoxy, C 3～6 cycloalkyl, C 3～6 Cycloalkyloxy group, 4-7 membered heterocyclic group, 4-7 membered heterocyclic oxy group, wherein NH2, C 1～6 Alkyl, C 2～4 alkenyl, C 2～4 alkynyl group, C 1～6 Alkoxy, C 3～6 cycloalkyl, C 3～6 Cycloalkyloxy, 4-7 membered heterocyclic group, and 4-7 membered heterocyclic oxy group are optionally R y replace; When u is 0, n is greater than 2 and two adjacent R4s form a 3- to 6-membered carbon ring or heterocycle. The heterocycle may optionally contain 1 to 3 heteroatoms independently selected from N, O, and S, which can be combined with structural units. Forming 7- to 12-element saturated helical rings, bridged rings, or parallel rings, wherein the 7- to 12-element saturated helical rings, bridged rings, or parallel rings can be R v Replace 1 to 3 times; When u is not 0, any two adjacent R4s can optionally form a 3- to 6-membered carbon ring or heterocycle, wherein the heterocycle can optionally contain 1 to 3 heteroatoms independently selected from N, O, and S, which, together with the structural unit This forms a 7- to 12-element saturated helical ring, bridged ring, or parallel ring structure, wherein the 7- to 12-element saturated helical ring, bridged ring, or parallel ring can be R v Replace 1 to 3 times; R5 is selected from halogens, NH2, CN, OH, COOH, CONH2, C 1～6 Alkyl, C 1～6 Alkoxy, 4-10 nitrogen-containing heterocyclic group, 5-10 nitrogen-containing heteroaryl, 4-10 sulfur-containing heterocyclic group, 5-10 sulfur-containing heteroaryl, C 3～10 cycloalkyl, 4-10 membered heterocyclic, phenyl, 5-10 membered heteroaryl, wherein the NH2, CONH2, C 1～6 Alkyl or C 1～6 Alkoxy groups are optionally replaced by R y Substitution 1 to 3 times, wherein the 4-10 member nitrogen-containing heterocyclic group, 5-10 member nitrogen-containing heteroaryl group, 4-10 member sulfur-containing heterocyclic group, 5-10 member sulfur-containing heteroaryl group, C 3～10 Cycloalkyl, 4-10 heterocyclic, phenyl, and 5-10 heteroaryl groups are optionally enclosed by R. z Replace 1 to 3 times; m is selected from 0, 1, or 2; R6 is independently selected from H, halogen, OH, CN, C 1～6 Alkyl, C 1～6 Alkoxy, NH2, NH(C) 1～6 alkyl), N(C) 1～6 Alkyl)2, C 3～6 cycloalkyl, C 3～6 cycloalkyl-O-, C 3～6 Cycloalkyl-NH-, 4-7 membered heterocyclic group, 4-7 membered heterocyclic group oxy group, 4-7 membered heterocyclic group -NH-, C 6～10 Aryl, C 6～10 aryloxy group, C 6～10 aryl-NH-, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy or 5-10-membered heteroaryl-NH-, wherein the C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 cycloalkyl, 4-7 membered heterocyclic, C 6～10 Aryl or 5-10 heteroaryl groups are optionally occupied by R y replace; Alternatively, two R6 atoms and their attached C atoms can together form C. 3～6 Cycloalkenyl, phenyl, 4-7 membered heterocyclic or 5-6 membered heteroaryl, wherein C 3～6 Cycloalkenyl, phenyl, 4-7-membered heterocyclic or 5-6-membered heteroaryl groups are optionally R y replace; R v Independently selected from halogens, OH, CN, C 1～6 Alkyl, (C 1～6 Alkyl)-CN or C 1～6 Alkoxy, the C 1～6 Alkyl or C 1～6 Alkoxy groups are optionally replaced by halogens, C 1～3 Alkyl, OH, or CN are substituted 1 to 3 times; R w Independently selected from halogens, OH, NH2, NH(C) 1～6 alkyl), N(C) 1～6 Alkyl)2, C 1～6 Alkyl, C 3～10 cycloalkyl or 4-7 membered heterocyclic group, wherein the C 1～6 Alkyl, C 3～10 Cycloalkyl or 4-7-membered heterocyclic groups are optionally surrounded by halogen, =O, OH, CN or C. 1～6 Alkyl substitution 1 to 3 times; R x Independently selected from halogens, OH, CN, (C 1～6 Alkyl)-CN, =O,C 1～6 Alkyl, NH2, NH(C) 1～6 alkyl), N(C) 1～6 Alkyl)2, COOH or C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally substituted 1 to 3 times with a halogen, cyano, hydroxyl or amino group; R y Independently selected from halogens, OH, =O, NH2, NH(C) 1～6 alkyl), N(C) 1～6 Alkyl)2, C 1～6 Alkyl, C 1～6 Alkoxy, wherein the C 1～6 Alkyl, C 1～6 Alkyl or C 1～6 The alkoxy group is further optionally substituted by a halogen or a hydroxyl group 1 to 3 times; R z Independently selected from halogens, CN, =O, OH, NO2, C 1～6 Alkyl, C 1～6 Alkoxy, OR n 、N(R n 2. S(O)2R n S(O)2N(R) n 2. S(O)R n 、S(O)N(R n 2. C(O)R n C(O)OR n C(O)N(R) n 2. C(O)N(R) n OR n OC(O)R n OC(O)N(R) n )2、N(R n )C(O)OR n 、N(R n )C(O)R n 、N(R n )C(O)N(R n )2、N(R n )C(NR n )N(R n )2、N(R n )S(O)2N(R n )2、N(R n )S(O)2R n C 3～10 Cycloalkyl, 4-7-membered heterocyclic, 6-10-membered aryl, or 5-10-membered heteroaryl, wherein the C 1～6 Alkyl, C 3～10 cycloalkyl, 4-7 membered heterocyclic, C 6～10 Selectively further R-type aryl or 5-10 heteroaryl groups. x replace; R n Independently selected from H and C 1～6 Alkyl, phenyl, 4-7 membered heterocyclic or 5-6 membered heteroaryl, wherein C 1～6 Alkyl, phenyl, 4-7-membered heterocyclic or 5-6-membered heteroaryl groups are optionally further R x Substitution, or two R atoms on a N atom n Together with the N group attached thereto, a 4-7 membered heterocyclic group or a 5-6 membered heteroaryl group is formed, wherein the 4-7 membered heterocyclic group or the 5-6 membered heteroaryl group is optionally further reacted with R. x replace.

3. The compound of formula (I) as described in claim 1 or 2, or a pharmaceutically acceptable salt thereof or an isomer thereof, wherein: The ring A is selected from phenyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazoleyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, or 5-7 membered heterocyclic groups, wherein the 5-7 membered heterocyclic group contains one or two N or S atoms as heteroatoms, and the ring A may optionally be substituted by R4 1 to 3 times; and / or The ring A is selected from The ring A may optionally be replaced by R4 1 to 3 times; and / or The structural unit Selected from The structural unit It can be arbitrarily replaced by R4 n times.

4. The compound of formula (I) as claimed in any one of claims 1-3, or a pharmaceutically acceptable salt thereof or an isomer thereof, wherein: The R4 is selected from halogens, =O, OH, NH2, NO2, CN, and C. 1～6 Alkyl, C 2～4 alkenyl, C 2～4 alkynyl group, C 1～6 Alkoxy, C 3～6 cycloalkyl, C 3～6 Cycloalkyloxy group, 4-7 membered heterocyclic group, 4-7 membered heterocyclic oxy group, wherein NH2, C 1～6 Alkyl, C 2～4 alkenyl, C 2～4 alkynyl group, C 1～6 Alkoxy, C 3～6 cycloalkyl, C 3～6 Cycloalkyloxy, 4-7 membered heterocyclic group, and 4-7 membered heterocyclic oxy group are optionally R y replace; Preferably, R4 is selected from halogens, =O, OH, NH2, CN, C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 cycloalkyl, C 3～6 Cycloalkyloxy groups, wherein NH2, C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 cycloalkyl, C 3～6 cycloalkyloxy groups are optionally R y replace; More preferably, R4 is selected from halogens, =O, NH2, CN, and C. 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 cycloalkyl, wherein NH2, C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 cycloalkyl groups are optionally R y replace; More preferably, the R4 is selected from halogens, or optionally C substituted with halogens. 1～6 Alkyl groups, C groups optionally substituted with halogens 1～6 Alkyl groups, C groups optionally substituted with halogens 3～6 cycloalkyl; More preferably, R4 is selected from halogens, CN, OH, and C. 1～6 Alkyl, Halogenated C 1～6 Alkyl groups; and / or More preferably, the R4 is selected from =O, F, Cl, Br, CN, OH, methyl, ethyl, ethynyl, CF3, CHF2, CH2F, methoxy, N(CH3)2, NHCH3, cyclopropyl; More preferably, R4 is selected from =O, methyl, CF3, F, Cl, methoxy, cyclopropyl, preferably O, methyl, CF3, more preferably methyl, CF3; and / or n is 2, 3, or 4, preferably 2 or 3; u is not 0, and any two adjacent R4s form a 3- to 6-membered carbon ring or heterocycle, wherein the heterocycle may optionally contain 1 to 3 heteroatoms independently selected from N, O, and S, which, together with the structural unit This forms a 7- to 12-element saturated helical ring, bridged ring, or parallel ring structure, wherein the 7- to 12-element saturated helical ring, bridged ring, or parallel ring can be R v Replace 1 to 3 times; Preferably, any two adjacent R4 atoms form a 3- to 6-membered carbon ring, wherein the 3- to 6-membered carbon ring is selected from... Preferred or Any two adjacent R4 atoms form a 3- to 6-membered heterocycle, wherein the heterocycle may optionally contain 1 to 3 heteroatoms independently selected from N, O, and S. Preferred More preferably, any two adjacent R4s form a 3- to 6-membered carbon ring, which, together with the structural unit The heterocyclic rings, consisting of 7- to 12-membered saturated spirocyclic rings, bridged rings, or fused rings, are selected from... Preferred The 7- to 12-membered saturated spirocyclic, bridged, or fused heterocyclic rings are optionally substituted with halogens or methyl groups 1 to 3 times. More preferably, any two adjacent R4s form a 3- to 6-membered carbon ring, which, together with the structural unit The heterocyclic rings, consisting of 7- to 12-membered saturated spirocyclic rings, bridged rings, or fused rings, are selected from... or Any two adjacent R4 atoms form a 3- to 6-membered heterocycle, wherein the heterocycle may optionally contain 1 to 3 heteroatoms independently selected from N, O, and S, which, together with the structural unit The formation of 7- to 12-membered saturated spirocyclic heterocycles, bridged heterocycles, or fused heterocycles, wherein the 7- to 12-membered saturated spirocyclic heterocycles, bridged heterocycles, or fused heterocycles are selected from... The 7- to 12-membered saturated spiroheterocycles, bridged heterocycles, or fused heterocycles may optionally be substituted with halogens or methyl groups 1 to 3 times. More preferably, the 7- to 12-membered saturated spirocyclic heterocycle, bridged heterocycle, or fused heterocycle is selected from...

5. The compound of formula (I) as claimed in any one of claims 1-4, or a pharmaceutically acceptable salt thereof or an isomer thereof, wherein: L1 is selected from single bonds, -(CR) a R b ) p -、-NR c -、-O-、-C(=O-、-(CR) a R b ) p -NR c - wherein preferably, p is independently selected from 1 or 2, more preferably 1; and / or, preferably, R a and R b Each of the C atoms is H, a halogen, or optionally substituted 1 to 3 times by a halogen or OH. 1～3 Alkyl, or any R a and R b C forms under conditions where valence allows. 3- 5-cycloalkyl; and / or, preferably, R c Selected from H and C 1～3 alkyl; More preferably, L1 is selected from single bonds, -CH2-, -NH-, -NHCH2-, -CH2-N(C 1～3 Alkyl group, -NHCH(CH3)-, -CH2CH2-, -CH(CH2OH)-, -CH(CH3)-, -C(CH3)2-, -CH(CF3)-, -CHF-, -CF2-, -C(=O)-; More preferably, L1 is selected from single bonds, -CH2-, -NH-, -NHCH2-, -CH2-N(CH3)-, -CH2-N(CH2CH3)-, -NHCH(CH3)-, -CH2CH2-, -CH(CH2OH)-, -CH(CH3)-, -C(CH3)2-, -CH(CF3)-, -CHF-, -CF2-, -C(=O)-; More preferably, L1 is selected from single bonds, -CH2-, -CHF-, -CF2-, -CH2NH-, -CH2-N(CH3)-, and -CH2CH2-; More preferably, the L1 is selected from -CH2-, -CH2-NH-, -CH2-N(CH3)-; and / or The n is selected from 1, 2, 3, or 4; and / or R5 is selected from halogens, CN, OH, COOH, CONH2, C 1～6 Alkyl, C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 Alkoxy groups are optionally replaced by R y replace; Preferably, R5 is selected from 4-10 nucleotide nitrogen-containing heterocyclic groups, 5-10 nucleotide nitrogen-containing heteroaryl groups, 4-10 nucleotide sulfur-containing heterocyclic groups, 5-10 nucleotide sulfur-containing heteroaryl groups, and C. 3～10 Cycloalkyl, 4-10 membered heterocyclic, phenyl, 5-10 membered heteroaryl, wherein the 4-10 membered nitrogen-containing heterocyclic, 5-10 membered nitrogen-containing heteroaryl, 4-10 membered sulfur-containing heterocyclic, 5-10 membered sulfur-containing heteroaryl, C 3～10 Cycloalkyl, 4-10 heterocyclic, phenyl, and 5-10 heteroaryl groups are optionally enclosed by R. z replace; More preferably, R5 is selected from halogens, CN, OH, and optionally R y Replaces C 1 to 3 times 1～6 Alkyl or NH2; More preferably, R5 is selected from F, Cl, CN, OH, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, NH2, NHCH3, N(CH3)2, N(CH3)CH2CH3, CH2OH, CH2CH2OH, CH2CN; or R5 is selected from The R5 is optionally R z Replaced 1 to 6 times; Preferably, R5 is selected from... The R5 is optionally R z Replaced 1 to 6 times; More preferably, R5 is selected from... More and / or m is selected from 1 or 2, preferably 1; and / or The R6 is selected from H, halogens, OH, CN, and C. 1～6 Alkyl, C 1～6 Alkoxy, NH2, NH(C) 1～6 alkyl), N(C) 1～6 Alkyl)2, C 3～6 cycloalkyl, C 3～6 cycloalkyl-O-, C 3～6 Cycloalkyl-NH-, 4-7 membered heterocyclic group, 4-7 membered heterocyclic group oxy group, 4-7 membered heterocyclic group -NH-, C 6～10 Aryl, C 6～10 aryloxy group, C 6～10 aryl-NH-, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy or 5-10-membered heteroaryl-NH-, wherein the C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 cycloalkyl, 4-7 membered heterocyclic, C 6～10 Aryl or 5-10 heteroaryl groups are optionally occupied by R y replace; Preferably, R6 is selected from H, halogen, OH, CN, methyl, ethoxy, NHCH3, NHCH2CH3, NHCH(CH3)2, pyrazolyl, cyclopropyl, NH-cyclopropyl, O-cyclopropyl, and O-oxacyclobutyl, wherein the methyl, ethoxy, NHCH3, NHCH2CH3, NHCH(CH3)2, pyrazolyl, cyclopropyl, NH-cyclopropyl, O-cyclopropyl, and O-oxacyclobutyl groups are optionally replaced by R. y replace; More preferably, R6 is selected from H, methoxy, ethoxy, NHCH3, NHCH2CH3, NHCH(CH3)2, cyclopropyl; and / or Any two R6 atoms and their attached C atoms together form C 3～6 Cycloalkenyl, phenyl, 4-7 membered heterocyclic or 5-6 membered heteroaryl, wherein C 3～6 Cycloalkenyl, phenyl, 4-7-membered heterocyclic or 5-6-membered heteroaryl groups are optionally R y Substitution; and / or, R6 is selected from H, halogen, OH, CN, C 1～6 Alkyl, C 1～6 Alkoxy, NH2, NH2, NH(C) 1～6 alkyl), N(C) 1～6 Alkyl)2, C 3～6 cycloalkyl, C 3～6 cycloalkyl-O-, C 3～6 Cycloalkyl-NH-, 4-7-membered heterocyclic group, 4-7-membered heterocyclic oxy group, 4-7-membered heterocyclic-NH-, 5-10-membered heteroaryl or phenyl, wherein the C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, 4-7-membered heterocyclic, phenyl, or 5-10-membered heteroaryl groups are optionally R y replace.

6. The compound of formula (I) as claimed in any one of claims 1-5, or a pharmaceutically acceptable salt thereof or an isomer thereof, wherein: X1, X2, X3, and X4 are independently selected from CR6; or, X2, X3, and X4 are independently selected from CR6 or N, and X1 is selected from CR6; or, X2 and X4 are independently selected from CR6 or N, and X1 and X3 are independently selected from CR6; or, X2 and X4 are N, and X1 and X3 are independently selected from CR6; / or, X2 is N, and X1, X3, and X4 are independently selected from CR6; or, X1, X2, and X4 are independently selected from CR6, and X3 is N; or, X1, X2, and X4 are CH, and X3 is CR6; or, X2 is N, X1 and X4 are CH, and X3 is CR6; or, X1, X2, and X4 are CH, and X3 is N; and / or R z Selected from halogens, CN, =O, OH, NO2, C 1～6 Alkyl, OR n 、N(R n 2. S(O)2R n S(O)2N(R) n 2. S(O)R n 、S(O)N(R n 2. C(O)R n C(O)OR n C(O)N(R) n 2. C(O)N(R) n OR n OC(O)R n OC(O)N(R) n )2、N(R n )C(O)OR n 、N(R n )C(O)R n 、N(R n )C(O)N(R n )2、N(R n )C(NR n )N(R n )2、N(R n )S(O)2N(R n )2、N(R n )S(O)2R n C 3～10 Cycloalkyl, 4-7-membered heterocyclic, 6-10-membered aryl, or 5-10-membered heteroaryl, wherein the C 1～6 Alkyl, C 3～10 cycloalkyl, 4-7 membered heterocyclic, C 6～10 5-10 aryl groups may be further subjected to R x replace; Preferably, R z Selected from halogens, CN, =O, C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 cycloalkyl, 6-10 aryl, 5-10 heteroaryl, wherein R z Optionally R x replace; More preferably, R z Selected from halogens, CN, =O, C 1～3 Alkyl, C 1～3 Alkoxy, C 3～6 cycloalkyl, phenyl, the R z Optionally R x replace; More preferably, R z Selected from halogens, =O, CN, C 1～3 Alkyl or C 3～6 cycloalkyl, wherein the C 1～3 Alkyl or C 3～6 cycloalkyl groups may optionally be further R x Replace; and R x Selected from halogens, OH and C 1～3 Alkoxy; More preferably, R z Selected from halogens, =O or C 1～3 Alkyl, wherein the C 1～3 Alkyl groups may optionally be further subjected to R x Replace, and R x Selected from halogens, OH and C 1～3 Alkyl group.

7. The compound of formula (I) as claimed in any one of claims 1-6, or a pharmaceutically acceptable salt thereof or an isomer thereof, wherein: The L1-R5 are selected from and / or R1 and R2 are independently selected from H, halogens, CN, NH2, and NH(C). 1～6 alkyl), N(C) 1～6 Alkyl)2, C 1～6 Alkyl, C 1～6 Alkoxy, C 3～10 Cycloalkyl or 4-10 membered heterocyclic group, wherein the C 1～6 Alkyl, C 1～6 Alkoxy, C 3～10 Cycloalkyl or 4-10 membered heterocyclic groups are optionally R x replace; Preferably, R1 and R2 are independently selected from H, halogens, CN, NH2, and C. 1～3 Alkyl, C 1～3 Alkoxy, C 3～6 cycloalkyl, wherein the C 1～3 Alkyl, C 1～3 Alkoxy, C 3～6 cycloalkyl groups are optionally R x Replace 1 to 3 times; More preferably, R1 and R2 are independently selected from H, F, Cl, CH3, CH2CH3, CF3, cyclopropyl, cyclobutyl, and fluorocyclopropyl; More preferably, R1 is H or C 1～3 Alkyl group, and R2 is optionally replaced by R x Replaces C 1 to 3 times 3～6 cycloalkyl; More preferably, R1 is selected from H, CH3 or CH2CH3, and R2 is selected from cyclopropyl, cyclobutyl, or fluorocyclopropyl. More preferably, R1 is H, and R2 is optionally R x Replaces C 1 to 3 times 3～6 cycloalkyl; More preferably, R1 is H, and R2 is selected from cyclopropyl, cyclobutyl, and fluorocyclopropyl; More preferably, R1 is H, and R2 is cyclopropyl or cyclobutyl; and / or R1, R2, and the atoms they are connected to together form C. 3～10 Cycloalkyl or 4-10 membered heterocyclic groups, wherein the C 3～10 Cycloalkyl or 4-10 membered heterocyclic groups are optionally R x replace; Preferably, R1, R2, and the atoms they are bonded to together form C. 3～6 cycloalkyl or 4-6 membered heterocyclic groups, wherein the C 3～6 cycloalkyl or 4-6 membered heterocyclic groups are optionally R x Replacement, wherein preferably, R x Selected from halogens, OH, CN, -(C 1～3 Alkyl)-CN, C 1～3 Alkoxy or C 1～3 Alkyl groups, preferably F, Cl, OH, CN, -CH2-CN, methoxy, or methyl; More preferably, R1, R2 and the atoms they are connected to together form or R1, R2, and their respective bonds together form C 3～6 Cycloalkenyl or 4-7 membered heterocyclic groups, wherein the C 3～6 The cycloalkenyl or 4-7 membered heterocyclic group is optionally replaced by R v Replace; and / or The L2 is selected from single bonds, -CH2-, -CHF-, -CF2-, -CH(CH3)-, -C(CH3)2-, -CH(CF3)-, preferably single bonds; and / or The W is selected from 5-10-membered heteroaryl or 4-10-membered heterocyclic group, and the 5-10-membered heteroaryl and 4-10-membered heterocyclic group are optionally replaced by R. w replace; Preferably, W is selected from pyrroleyl, thiophenyl, furanyl, pyrazolyl, imidazoleyl, thiazolyl, isothiazolyl, thiadiazolyl, triazoleyl, oxazolyl, isoxazolyl, and oxadiazolyl, each of which is optionally R w replace; The R w Selected from halogens, OH, CN, C 1～3 Alkyl or C 3～6 cycloalkyl, the C 1～3 Alkyl and C 1～3 The alkoxy group can be substituted by a halogen 1 to 3 times; More preferably, the W is selected from More 8. The compound of formula (I) as described in claims 1-7, or a pharmaceutically acceptable salt thereof or an isomer thereof, wherein: The compound of formula (I) has the structure of formula (I-1): Wherein, v is selected from 1, 2, 3, or 4, and the remaining definitions are as defined in any one of claims 1 to 7, wherein n is preferably selected from 0, 1, or 2; or The compound of formula (I) has the structure of formula (I-2): The remaining definitions are as defined in any one of claims 1 to 7.

9. The compound of formula (I) as claimed in any one of claims 1-8, or a pharmaceutically acceptable salt thereof or an isomer thereof, wherein the compound has the structure of formula (II): in: R1, R2, and the atoms they are connected to together form C. 3～10 Cycloalkyl or 4-10 membered heterocyclic groups, wherein the C 3～10 Cycloalkyl or 4-10 membered heterocyclic groups are optionally R x replace; Structural unit Selected from The structural unit may optionally be substituted with halogen or methyl group 1 to 3 times; The definitions of X1, X2, X3, X4, u, v, n, ring A, L1, R4, and R5 are as defined in any one of claims 1 to 8, wherein n is preferably selected from 0, 1, or 2; and / or m is preferably 1.

10. The compound of claim 8 or 9, or a pharmaceutically acceptable salt thereof or an isomer thereof, wherein: In equation (I-1) or equation (II), the structural unit Selected from The structural unit may optionally be substituted with halogen or methyl group 1 to 3 times; Preferably, the structural unit Selected from The structural units may optionally be substituted with halogens or methyl groups 1 to 3 times; and / or R1, R2, and the atoms they are connected to together form Preferred 11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof or an isomer thereof, wherein: The compound is a compound of formula (III): in: R1, R2, X1, X2, X3, X4, u, v, L1, R4, R5 as defined in any one of claims 1-10, and n is 0, 1, or 2; or The compound is a compound of formula (IV): in: R1, R2, u, v, L1, R4, R5, R6 are as defined in any one of claims 1-10, and n is 0, 1, or 2; or The compound is a compound of formula (V): Wherein R1, R2, X1, X2, X3, X4, L1, R4, and R5 are as defined in any one of claims 1-10, and u is 1 or 2; Or the compound is a compound of formula (VI): Wherein R1, R2, L1, R4, R5, and R6 are as defined in any one of claims 1-10, and u is 1 or 2.

12. The compound of claim 9 or 11, or a pharmaceutically acceptable salt thereof or an isomer thereof, wherein: In the compounds of formula (II), formula (III) or formula (IV), n is 0; Alternatively, n is 1; Alternatively, n is 2; and / or In the compounds of formula (II), formula (III) or formula (IV), u is 0; or u is 1; or u is 2; In compounds of formula (V) or formula (VI), u is 1; or u is 2; and / or In the compounds of formula (II), formula (III) or formula (IV), v is 1; or v is 2; or v is 3; or v is 4; and / or In compounds of formula (II), (III), (IV), (V), or (VI), L1 is selected from -CH2-, -CH2-NH-, or -CH2-N(C 1～3 Alkyl group (preferably -CH2-N(CH3)-, -CH2-N(CH2CH3)-); and / or In compounds of formula (II), (III), (IV), (V), or (VI), R5 is selected from C. 1～6 Alkyl, C 3～6 Cycloalkyl or 4-10 nitrogen-containing heterocyclic groups, wherein the C 3～6 Cycloalkyl or 4-10 nitrogen-containing heterocyclic groups are optionally R z Replace; and / or In compounds of formula (II), (III), (IV), (V), or (VI), L1 is selected from -CH2-, and R5 is selected from 4- to 10-membered nitrogen-containing heterocyclic groups, wherein the 4- to 10-membered nitrogen-containing heterocyclic group is optionally replaced by R z Replace; and / or In compounds of formula (II), (III), (IV), (V), or (VI), L1 is selected from -CH2-NH- or -CH2-N(C 1～3 Alkyl group (preferably -CH2-N(CH3)- or -CH2-N(CH2CH3)-), and R5 is selected from C 1～6 Alkyl or C 3～6 cycloalkyl, wherein the C 3～6 cycloalkyl groups are optionally R z Replace; and / or R z Independently selected from halogen or C 1～3 Alkyl, wherein the C 1～3 Alkyl groups may optionally be further subjected to R x Replace, R x Independently selected from halogens, OH and C 1～3 Alkoxy; Preferably, R z Independently selected from F, Cl, CH3, -CH2CH3, -CH2-OH, CHF3, CHF2, CH2F, -CH2OCH3, -CH2OCH2CH3; and / or In formula (II), -L1-(R5) m (where m is 1), or -L1-R5 in compounds of formula (III), (IV), (V), or (VI) is selected from: and / or In compounds of formula (IV) or (VI), R6 is selected from H, C. 1～6 Alkoxy, NH(C) 1～6 alkyl) or C 3～6 Cycloalkyl groups, preferably H and C 1～3 Alkoxy, NH(C) 1～3 alkyl) or C 3～6 Cycloalkyl, more preferably H, methoxy, ethoxy, NHCH3, NHCH2CH3, NHCH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; and / or In compounds of formula (II), (III), (IV), (V), or (VI), R1 is H, and R2 is optionally replaced by R x Replaces C 1 to 3 times 3～6 Cycloalkyl; or R1, R2 and the atoms they are attached to together form cyclobutyl, cyclopentyl or cyclohexyl; Preferably, structural unit Selected from: and / or In the compounds of formula (II), (III), or (IV), R4 is a halogenated C. 1～3 Alkyl groups, preferably CF3; In compounds of formula (V) or (VI), R4 is independently C. 1～6 Alkyl, preferably C 1～3 Alkyl, more preferably methyl, ethyl, and even more preferably methyl.

13. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof or an isomer thereof, wherein the compound is:

14. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof or an isomer thereof, wherein the compound is:

15. The compound of formula (I), formula (I-1), formula (I-2), formula (II), formula (III), formula (IV), formula (V), or formula (VI) as described in any one of claims 1 to 14, or a pharmaceutically acceptable salt or isomer thereof, may contain an atomic isotope in a non-natural proportion on one or more atoms constituting the compound or its pharmaceutically acceptable salt or isomer, wherein the non-natural proportion of the atomic isotope may be a radioactive isotope selected from... 3 H, 125 I or 14 C, preferably 3 H.

16. A method for preventing or treating a disease or condition mediated by Cbl-b, comprising administering to an individual in need a compound as described in any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof or an isomer thereof, the method optionally further comprising administering at least one other therapeutic agent.

17. Use of the compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof or an isomer thereof, in the preparation of a medicament for the treatment and / or prevention of Cbl-b-mediated diseases or conditions and related diseases or conditions, wherein the medicament optionally further comprises at least one other therapeutic agent.

18. The method according to claim 16 or the use according to claim 17, wherein: The Cbl-b-mediated diseases or conditions and related diseases or conditions are tumors and / or cancers, wherein the tumors and / or cancers are preferably selected from melanoma, thyroid adenoma, head and neck cancer, endometrial cancer, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial carcinoma, bladder cancer, lung cancer, small cell lung cancer, colorectal adenoma, sarcoma, intestinal stromal tumor, gastric cancer, esophageal cancer, colorectal cancer, pancreatic cancer, small bowel cancer, kidney cancer, liver cancer, hepatocellular carcinoma, cholangiocarcinoma, mesothelioma, lymphoma, leukemia, myelodysplastic syndrome, multiple myeloma, plasmacytoma, neuroblastoma, retinoblastoma, and germ cell tumor; and / or The at least one other therapeutic agent is an antitumor agent or an anticancer agent, wherein: The antitumor or anticancer agent is preferably an immune checkpoint inhibitor, more preferably an antagonist of PD-1, PD-L1, CTLA-4, LAG3, PVR, PVRL2, PVRL3, TIGIT, TIM3, or VISTA, and even more preferably an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody; or The antitumor or anticancer agent is preferably a cytotoxic antibiotic, plant alkaloid, antimetabolite, alkylating agent, or other antitumor agent.

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