Compound with cbl-b inhibiting effect and application thereof

Abstract

The invention relates to a compound with a cbl-b inhibiting effect and application of the compound, in particular to a compound shown in a formula (I) or pharmaceutically acceptable salt of the compound and application of the compound or the pharmaceutically acceptable salt to preparation of medicine for treating and / or preventing diseases related to abnormal expression of cbl-b. # imgabs0 #

Description

Technical Field

[0001] The present application relates to a compound having a Cbl-b inhibitory effect and its use. The compound or a pharmaceutically acceptable salt thereof can be used to treat and / or prevent diseases related to abnormal expression of Cbl-b. The present application relates to a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof. Background Art

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

[0003] Cbl-b is a master regulator of effector cell (T cell and NK cell) immunity. Its inactivation eliminates its endogenous negative regulatory function and can significantly enhance anti-tumor immunity. Human exome sequencing results show that Cbl-b loss-of-function mutations can lead to autoimmune diseases such as T1D, SLE, MS, and myeloid hematological tumors. In vivo and in vitro studies in mice have shown that Cbl-b knockout or functional loss can promote T cell and NK cell proliferation and anti-tumor effects, while inhibiting the immunosuppressive effect of Treg cells. Genetic or pharmacological inhibition of Cbl-b has shown significant tumor inhibitory effects in multiple mouse tumor models. Therefore, the development of novel, highly active, and highly selective Cbl-b inhibitors to enhance anti-tumor immunity can bring good benefits to cancer patients. Summary of the invention

[0004] The present application provides novel cbl-b inhibitor compounds or pharmaceutically acceptable salts thereof. The present application also provides pharmaceutical compositions comprising such compounds or pharmaceutically acceptable salts thereof.

[0005] The compounds of the present invention have excellent inhibitory activity against cbl-b. Therefore, the present application also provides the use of the compounds for preventing and / or treating cbl-b-mediated diseases or conditions. The present application also provides the use of the compounds for treating and / or preventing diseases related to abnormal expression of cbl-b. The present application further provides methods for treating and / or preventing the above-mentioned diseases or conditions using the compounds and pharmaceutical compositions.

[0006] 1. Compounds

[0007] 1.1. First aspect

[0008] In a first aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0009]

[0010] in,

[0011] X1, X2, X3 and X4 are independently selected from CR6 or N;

[0012] R1 and R2 are independently selected from H, halogen, 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 1～6 Alkoxy, C 3～10 Cycloalkyl or 4-10 membered heterocyclic group is optionally substituted by R x replace;

[0013] Or R1, R2 and the atoms they are connected to together form C 3～10 Cycloalkyl or 4-10 membered heterocyclic group, wherein the C 3～10 Cycloalkyl or 4-10 membered heterocyclic group is optionally substituted by R x replace;

[0014] Or R1, R2 and their respective atoms and bonds together form C 3～6 Cycloalkenyl or 4-7 membered heterocyclic group, wherein the C 3～6 The cycloalkenyl or 4-7 membered heterocyclic group is optionally substituted by R v replace;

[0015] R3 is selected from L2-W;

[0016] L2 is selected from a single bond, -CR d R e -;

[0017] W is selected from hydrogen, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, wherein the 5-10 membered heteroaryl, 4-10 membered heterocyclyl is optionally replaced by R w replace;

[0018] R d and R e independently selected from H, halogen, OH, C 1～6 Alkyl or C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally further substituted 1 to 3 times by halogen;

[0019] R1 can be optionally combined with R d or Re and their respective atoms and bonds together form C 3～6 Cycloalkyl or 4-7 membered heterocyclic group, wherein the C 3～6 Cycloalkyl or 4-7 membered heterocyclic group is optionally replaced by R v replace;

[0020] 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 The structural unit may be optionally substituted n times by R4;

[0021] n is independently selected from 0, 1, 2 or 3;

[0022] L1 is selected from a single bond, -(CR a R b ) p -、-NR c -, -O-, -C(=O)-, -C(=O)NH-, -CR a R b -NR c -;

[0023] R a , R b , R c are independently selected from H, halogen, OH, C 1～6 Alkyl or C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally replaced by R x Replace 1 to 3 times;

[0024] p is selected from 1, 2 or 3;

[0025] Any R a and R b Under the conditions of chemical valence permitting, it can form a 3-5 membered cycloalkyl or a 3-5 membered heterocyclic group;

[0026] R4 is selected from halogen, =O, OH, NH2, NO2, CN, C 1～6 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, C 3～6 Cycloalkyloxy, 4-7 membered heterocyclyl, 4-7 membered heterocyclyloxy, wherein the NH2, C 1～6 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, C 1～6 Alkoxy, C 3～6Cycloalkyl, C 3～6 Cycloalkyloxy, 4-7 membered heterocyclyl, 4-7 membered heterocyclyloxy are optionally substituted by R y replace;

[0027] R5 is selected from halogen, CN, OH, COOH, CONH2, C 1～6 Alkyl, C 1～6 alkoxy, 4-10 membered nitrogen-containing heterocyclic group, 5-10 membered nitrogen-containing heteroaryl group, 4-10 membered sulfur-containing heterocyclic group, 5-10 membered sulfur-containing heteroaryl group, C 3～10 Cycloalkyl, 4-10 membered heterocyclyl, phenyl, 5-10 membered heteroaryl, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally replaced by R y substituted, and wherein the 4-10 membered nitrogen-containing heterocyclic group, the 5-10 membered nitrogen-containing heteroaryl group, the 4-10 membered sulfur-containing heterocyclic group, the 5-10 membered sulfur-containing heteroaryl group, C 3～10 Cycloalkyl, 4-10 membered heterocyclyl, phenyl, 5-10 membered heteroaryl are optionally substituted by R z replace;

[0028] 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 heterocyclyl, 4-7 membered heterocyclyloxy, 4-7 membered heterocyclyl-NH-, C 6～10 Aryl, C 6～10 Aryloxy, 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 group, C 6～10 Aryl or 5-10 membered heteroaryl is optionally substituted by R y replace;

[0029] Or two R6 and the C atom to which they are connected together form a C 3～6 Cycloalkenyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl, wherein the C 3～6 Cycloalkenyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl are optionally replaced by R y replace;

[0030] R vindependently selected from halogen, =O, OH, CN, (C 1～6 Alkyl)-CN, C 1～6 Alkyl or C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally substituted with halogen, C 1～3 Alkyl, OH or CN substituted 1 to 3 times;

[0031] R w independently selected from halogen, 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 group is optionally substituted by halogen, =O, OH, CN or C 1～6 Alkyl substituted 1 to 3 times;

[0032] R x independently selected from halogen, OH, CN, ═O, C 1～6 Alkyl, (C 1～6 Alkyl)-CN, 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 further optionally substituted 1 to 3 times by halogen, cyano, hydroxyl or amine;

[0033] R y independently selected from halogen, 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 1 to 3 times by halogen or hydroxy;

[0034] R z are independently selected from halogen, CN, (C 1～6 alkyl)-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)Rn 、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 heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl, wherein the C 1～6 Alkyl, C 3～10 Cycloalkyl, 4-7 membered heterocyclic group, C 6～10 The 5- to 10-membered aryl or heteroaryl group is optionally further substituted by R x replace;

[0035] R n Independently selected from H, C 1～6 alkyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl, wherein the C 1～6 Alkyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl are optionally further substituted by R x Substitution, or 2 R on a N atom n The N to which it is attached forms a 4-7 membered heterocyclic group or a 5-6 membered heteroaryl group, wherein the 4-7 membered heterocyclic group or the 5-6 membered heteroaryl group is optionally further substituted by R x replace;

[0036] The conditions are:

[0037] (1) When the ring A is a 5-membered heteroaryl or a 5-7-membered heterocyclic group, R4 is not CN or C 3～6 cycloalkyl; and

[0038] (2) The compound of formula (I) is not any one or more compounds selected from the compounds in Table A below, or an isomer or isomer mixture of any one compound:

[0039] Table A

[0040]

[0041]

[0042] In some embodiments, W is selected from 5-10 membered heteroaryl or 4-10 membered heterocyclyl, wherein the 5-10 membered heteroaryl and 4-10 membered heterocyclyl are optionally replaced by R w Replace, and R v are independently selected from halogen, OH, CN, (C 1～6 Alkyl)-CN, C 1～6 Alkyl or C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally substituted with halogen, C 1～3 Alkyl, OH or CN substituted 1 to 3 times.

[0043] In some embodiments, W is selected from 5-10 membered heteroaryl or 4-10 membered heterocyclyl, wherein the 5-10 membered heteroaryl and the 4-10 membered heterocyclyl are optionally replaced by R w Replace, and R v are independently selected from halogen, OH, CN, (C 1～6 Alkyl)-CN, C 1～6 Alkyl or C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally substituted with halogen, C 1～3 Alkyl, OH or CN substituted 1 to 3 times.

[0044] In some embodiments, W is selected from hydrogen, pyrrolyl, thiophenyl, furanyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl.

[0045] In some embodiments, R w Selected from halogen, OH, CN, C 1～3 Alkyl or C 3～6 Cycloalkyl, wherein the C 1～3 Alkyl and C 1～3 The alkoxy group is optionally substituted 1 to 3 times by halogen.

[0046] In some preferred embodiments, R w Selected from C 1～3 Alkyl, more preferably methyl.

[0047] In some embodiments, W is selected from hydrogen,

[0048] In other embodiments, W is selected from 5-10 membered heteroaryl or 4-10 membered heterocyclyl, wherein the 5-10 membered heteroaryl and 4-10 membered heterocyclyl are optionally replaced by R w replace;

[0049] R v independently selected from halogen, OH, CN, C 1～6 Alkyl or C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally substituted with halogen, C 1～3 Alkyl, OH or CN substituted 1 to 3 times;

[0050] R x independently selected from halogen, OH, 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 further optionally substituted 1 to 3 times by halogen, cyano, hydroxyl or amine; and

[0051] R z independently selected from halogen, 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(Rn )S(O)2R n , C 3～10 Cycloalkyl, 4-7 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein C 1～6 Alkyl, C 3～10 Cycloalkyl, 4-7 membered heterocyclic group, C 6～10 The 5- to 10-membered aryl or heteroaryl group is optionally further substituted by R x replace.

[0052] In some embodiments, W is selected from 5-10 membered heteroaryl or 4-10 membered heterocyclyl, wherein the 5-10 membered heteroaryl and 4-10 membered heterocyclyl are optionally replaced by R w replace;

[0053] p is selected from 1 or 2;

[0054] R v independently selected from halogen, OH, CN, C 1～6 Alkyl or C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally substituted with halogen, C 1～3 Alkyl, OH or CN substituted 1 to 3 times;

[0055] R x independently selected from halogen, OH, 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 further optionally substituted 1 to 3 times by halogen, cyano, hydroxyl or amine;

[0056] R y independently selected from halogen, OH, =O, NH2, NH(C 1～6 Alkyl), N(C 1～6 Alkyl)2, C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is further optionally substituted 1 to 3 times by halogen; and

[0057] R z independently selected from halogen, 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 heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein C 1～6 Alkyl, C 3～10 Cycloalkyl, 4-7 membered heterocyclic group, C 6～10 The 5- to 10-membered aryl or heteroaryl group is optionally further substituted by R x replace.

[0058] In some further embodiments, W is selected from pyrrolyl, thienyl, furanyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl.

[0059] In some such embodiments, R w Selected from halogen, OH, CN, C 1～3 Alkyl or C 3～6 Cycloalkyl, the C 1～3 Alkyl and C 1～3 The alkoxy group is optionally substituted 1 to 3 times by halogen.

[0060] In some preferred embodiments, R w Selected from C 1～3 Alkyl, more preferably methyl.

[0061] In some embodiments, W is selected from

[0062] In some embodiments, L2 is selected from a single bond, -CH2-, -CHF-, -CF2-, -CH(CH3)-, -C(CH3)2-, -CH(CF3)-.

[0063] In some preferred embodiments, L2 is a single bond.

[0064] In some embodiments, the compound of formula (I) is selected from the structure shown in formula (I-1):

[0065]

[0066] In some embodiments, ring A is selected from phenyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl or 5-7 membered heterocyclyl, wherein the 5-7 membered heterocyclyl contains 1 or 2 N or S as heteroatoms, and the ring A can be optionally substituted n times by R4.

[0067] In some embodiments, Ring A is selected from The ring A may be optionally substituted n times by R4.

[0068] In some embodiments, Ring A is selected from The ring A may be optionally substituted n times by R4.

[0069] In some embodiments, the structural unit Selected from The structural unit Optionally substituted n times by R4.

[0070] In some embodiments, the structural unit Selected from The structural unit Optionally substituted n times by R4.

[0071] In some embodiments, the structural unit Selected from

[0072] In some embodiments, the structural unit Selected from

[0073] In some embodiments, the compound of formula (I) is selected from the structures shown in formula (I-2), formula (I-3), formula (I-4), and formula (I-5):

[0074]

[0075] 1.2. Second Aspect

[0076] In a second aspect, the present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof:

[0077]

[0078] in,

[0079] X1, X2, X3 and X4 are independently selected from CR6 or N;

[0080] R1 and R2 are independently selected from H, halogen, 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 1～6 Alkoxy, C 3～10 Cycloalkyl or 4-10 membered heterocyclic group is optionally substituted by R x replace;

[0081] Or R1, R2 and the atoms they are connected to together form C 3～10 Cycloalkyl or 4-10 membered heterocyclic group, wherein the C 3～10 Cycloalkyl or 4-10 membered heterocyclic group is optionally substituted by R x replace;

[0082] Or R1, R2 and their respective atoms and bonds together form C 3～6 Cycloalkenyl or 4-7 membered heterocyclic group, wherein the C 3～6 The cycloalkenyl or 4-7 membered heterocyclic group is optionally substituted by R v replace;

[0083] R3 is selected from L2-W;

[0084] L2 is selected from a single bond, -CR d R e -;

[0085] W is selected from hydrogen, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, wherein the 5-10 membered heteroaryl, 4-10 membered heterocyclyl is optionally replaced by R w replace;

[0086] R d and R e independently selected from H, halogen, OH, C 1～6 Alkyl or C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6The alkoxy group is optionally further substituted 1 to 3 times by halogen;

[0087] R1 can be optionally combined with R d or R e and their respective atoms and bonds together form C 3～6 Cycloalkyl or 4-7 membered heterocyclic group, wherein the C 3～6 Cycloalkyl or 4-7 membered heterocyclic group is optionally replaced by R v replace;

[0088] Ring A is selected from phenyl or 6-membered heteroaryl, wherein the phenyl or 6-membered heteroaryl is The structural unit may be optionally substituted n times by R4;

[0089] n is independently selected from 0, 1, 2 or 3;

[0090] L1 is selected from a single bond, -(CR a R b ) p -、-NR c -, -O-, -C(=O)-, -C(=O)NH-, -CR a R b -NR c -;

[0091] R a , R b , R c are independently selected from H, halogen, OH, C 1～6 Alkyl or C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally replaced by R x Replace 1 to 3 times;

[0092] p is selected from 1, 2 or 3;

[0093] Any R a and R b Under the conditions of chemical valence permitting, it can form a 3-5 membered cycloalkyl or a 3-5 membered heterocyclic group;

[0094] R4 is selected from halogen, =O, OH, NH2, NO2, CN, C 1～6 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, C 3～6 Cycloalkyloxy, 4-7 membered heterocyclyl, 4-7 membered heterocyclyloxy, wherein the NH2, C 1～6 Alkyl, C2～4 Alkenyl, C 2～4 Alkynyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, C 3～6 Cycloalkyloxy, 4-7 membered heterocyclyl, 4-7 membered heterocyclyloxy are optionally substituted by R y replace;

[0095] R5 is selected from halogen, CN, OH, COOH, CONH2, C 1～6 Alkyl, C 1～6 alkoxy, 4-10 membered nitrogen-containing heterocyclic group, 5-10 membered nitrogen-containing heteroaryl group, 4-10 membered sulfur-containing heterocyclic group, 5-10 membered sulfur-containing heteroaryl group, C 3～10 Cycloalkyl, 4-10 membered heterocyclyl, phenyl, 5-10 membered heteroaryl, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally replaced by R y substituted, and wherein the 4-10 membered nitrogen-containing heterocyclic group, the 5-10 membered nitrogen-containing heteroaryl group, the 4-10 membered sulfur-containing heterocyclic group, the 5-10 membered sulfur-containing heteroaryl group, C 3～10 Cycloalkyl, 4-10 membered heterocyclyl, phenyl, 5-10 membered heteroaryl are optionally substituted by R z replace;

[0096] 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 heterocyclyl, 4-7 membered heterocyclyloxy, 4-7 membered heterocyclyl-NH-, C 6～10 Aryl, C 6～10 Aryloxy, 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 group, C 6～10 Aryl or 5-10 membered heteroaryl is optionally substituted by R y replace;

[0097] Or two R6 and the C atom to which they are connected together form a C 3～6 Cycloalkenyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl, wherein the C 3～6Cycloalkenyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl are optionally replaced by R y replace;

[0098] R v independently selected from halogen, =O, OH, CN, (C 1～6 Alkyl)-CN, C 1～6 Alkyl or C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally substituted with halogen, C 1～3 Alkyl, OH or CN substituted 1 to 3 times;

[0099] R w independently selected from halogen, 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 group is optionally substituted by halogen, =O, OH, CN or C 1～6 Alkyl substituted 1 to 3 times;

[0100] R x independently selected from halogen, OH, CN, ═O, C 1～6 Alkyl, (C 1～6 Alkyl)-CN, 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 further optionally substituted 1 to 3 times by halogen, cyano, hydroxyl or amine;

[0101] R y independently selected from halogen, 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 1 to 3 times by halogen or hydroxy;

[0102] R z are independently selected from halogen, CN, (C 1～6 alkyl)-CN, =O, OH, NO2, C 1～6 Alkyl, ORn 、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 heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl, wherein the C 1～6 Alkyl, C 3～10 Cycloalkyl, 4-7 membered heterocyclic group, C 6～10 The 5- to 10-membered aryl or heteroaryl group is optionally further substituted by R x replace;

[0103] R n Independently selected from H, C 1～6 alkyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl, wherein the C 1～6 Alkyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl are optionally further substituted by R x Substitution, or 2 R on a N atom n The N to which it is attached forms a 4-7 membered heterocyclic group or a 5-6 membered heteroaryl group, wherein the 4-7 membered heterocyclic group or the 5-6 membered heteroaryl group is optionally further substituted by R x replace.

[0104] In some embodiments, W is selected from 5-10 membered heteroaryl or 4-10 membered heterocyclyl, wherein the 5-10 membered heteroaryl and 4-10 membered heterocyclyl are optionally replaced by R w Replace, and R vare independently selected from halogen, OH, CN, (C 1～6 Alkyl)-CN, C 1～6 Alkyl or C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally substituted with halogen, C 1～3 Alkyl, OH or CN substituted 1 to 3 times.

[0105] In some embodiments, W is selected from hydrogen, pyrrolyl, thiophenyl, furanyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl;

[0106] In some embodiments, R w Selected from halogen, OH, CN, C 1～3 Alkyl or C 3～6 Cycloalkyl, wherein the C 1～3 Alkyl and C 1～3 The alkoxy group is optionally substituted 1 to 3 times by halogen;

[0107] In some preferred embodiments, R w Selected from C 1～3 Alkyl, more preferably methyl;

[0108] In some embodiments, W is selected from hydrogen,

[0109] In other embodiments, W is selected from 5-10 membered heteroaryl or 4-10 membered heterocyclyl, wherein the 5-10 membered heteroaryl and 4-10 membered heterocyclyl are optionally replaced by R w replace;

[0110] R v independently selected from halogen, OH, CN, C 1～6 Alkyl or C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally substituted with halogen, C 1～3 Alkyl, OH or CN substituted 1 to 3 times;

[0111] R x independently selected from halogen, OH, 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 further optionally substituted 1 to 3 times by halogen, cyano, hydroxyl or amine; and

[0112] R z independently selected from halogen, 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 heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein C 1～6 Alkyl, C 3～10 Cycloalkyl, 4-7 membered heterocyclic group, C 6～10 The 5- to 10-membered aryl or heteroaryl group is optionally further substituted by R x replace.

[0113] In some embodiments, W is selected from 5-10 membered heteroaryl or 4-10 membered heterocyclyl, wherein the 5-10 membered heteroaryl and 4-10 membered heterocyclyl are optionally replaced by R w replace;

[0114] p is selected from 1 or 2;

[0115] R v independently selected from halogen, OH, CN, C 1～6 Alkyl or C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally substituted with halogen, C 1～3Alkyl, OH or CN substituted 1 to 3 times;

[0116] R x independently selected from halogen, OH, 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 further optionally substituted 1 to 3 times by halogen, cyano, hydroxyl or amine;

[0117] R y independently selected from halogen, OH, =O, NH2, NH(C 1～6 Alkyl), N(C 1～6 Alkyl)2, C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is further optionally substituted 1 to 3 times by halogen; and

[0118] R z independently selected from halogen, 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 3～10Cycloalkyl, 4-7 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein C 1～6 Alkyl, C 3～10 Cycloalkyl, 4-7 membered heterocyclic group, C 6～10 The 5- to 10-membered aryl or heteroaryl group is optionally further substituted by R x replace.

[0119] In some further embodiments, W is selected from pyrrolyl, thienyl, furanyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl.

[0120] In some such embodiments, R w Selected from halogen, OH, CN, C 1～3 Alkyl or C 3～6 Cycloalkyl, the C 1～3 Alkyl and C 1～3 The alkoxy group is optionally substituted 1 to 3 times by halogen.

[0121] In some preferred embodiments, R w Selected from C 1～3 Alkyl, more preferably methyl.

[0122] In some embodiments, W is selected from

[0123] In some embodiments, L2 is selected from a single bond, -CH2-, -CHF-, -CF2-, -CH(CH3)-, -C(CH3)2-, -CH(CF3)-.

[0124] In some preferred embodiments, L2 is a single bond.

[0125] In some embodiments, the compound of formula (I) is selected from the structure shown in formula (I-1):

[0126]

[0127] In some embodiments, ring A is selected from phenyl, pyridyl, pyrimidinyl or 5-7 membered heterocyclyl, wherein the 5-7 membered heterocyclyl contains 1 or 2 N or S as heteroatoms, and the ring A may be optionally substituted n times by R4.

[0128] In some embodiments, Ring A is selected from The ring A may be optionally substituted n times by R4.

[0129] In some embodiments, Ring A is selected from The ring A may be optionally substituted n times by R4.

[0130] In some embodiments, the structural unit Selected from The structural unit Optionally substituted n times by R4.

[0131] In some embodiments, the structural unit Selected from The structural unit Optionally substituted n times by R4.

[0132] In some embodiments, the structural unit Selected from

[0133] In some embodiments, the structural unit Selected from

[0134] In some embodiments, the compound of formula (I) is selected from the structure shown in formula (I-2) or formula (I-3):

[0135]

[0136] 1.3. Aspect 1 and / or Aspect 2

[0137] In the embodiment according to the first aspect and / or the second aspect described above, R4 is selected from halogen, =O, OH, NH2, NO2, CN, C 1～6 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, C 3～6 Cycloalkyloxy, 4-7 membered heterocyclyl, 4-7 membered heterocyclyloxy, wherein the NH2, C 1～6 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, C 3～6 Cycloalkyloxy, 4-7 membered heterocyclyl, 4-7 membered heterocyclyloxy are optionally substituted by R y replace.

[0138] In some embodiments, R4 is selected from halogen, =O, OH, NH2, CN, C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, C 3～6 Cycloalkyloxy, wherein the NH2, C 1～6 Alkyl, C 1～6 Alkoxy, C3～6 Cycloalkyl, C 3～6 The cycloalkyloxy group is optionally substituted by R y replace.

[0139] In some embodiments, R4 is selected from halogen, =O, NH2, CN, C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, wherein the NH2, C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 The cycloalkyl group is optionally substituted by R y replace.

[0140] In some embodiments, R4 is selected from halogen, C optionally substituted by halogen 1～6 Alkyl, optionally substituted by halogen, C 1～6 Alkoxy, optionally substituted by halogen, C 3～6 Cycloalkyl.

[0141] In some embodiments, R4 is selected from halogen, CN, OH, C 1～6 Alkyl, halogenated C 1～6 alkyl.

[0142] 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.

[0143] In some embodiments, R4 is selected from =0, methyl, CF3, F, Cl, methoxy, cyclopropyl.

[0144] 1.4. The third aspect

[0145] In a third aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0146]

[0147] in,

[0148] X1, X2, X3 and X4 are independently selected from CR6 or N;

[0149] R1 and R2 are independently selected from H, halogen, 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, C1～6 Alkoxy, C 3～10 Cycloalkyl or 4-10 membered heterocyclic group is optionally substituted by R x replace;

[0150] Or R1, R2 and the atoms they are connected to together form C 3～10 Cycloalkyl or 4-10 membered heterocyclic group, wherein the C 3～10 Cycloalkyl or 4-10 membered heterocyclic group is optionally substituted by R x replace;

[0151] Or R1, R2 and their respective atoms and bonds together form C 3～6 Cycloalkenyl or 4-7 membered heterocyclic group, wherein the C 3～6 The cycloalkenyl or 4-7 membered heterocyclic group is optionally substituted by R v replace;

[0152] R3 is selected from L2-W;

[0153] L2 is selected from a single bond, -CR d R e -;

[0154] W is selected from hydrogen, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, wherein the 5-10 membered heteroaryl, 4-10 membered heterocyclyl is optionally replaced by R w replace;

[0155] R d and R e independently selected from H, halogen, OH, C 1～6 Alkyl or C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally further substituted 1 to 3 times by halogen;

[0156] R1 can be optionally combined with R d or R e and their respective atoms and bonds together form C 3～6 Cycloalkyl or 4-7 membered heterocyclic group, wherein the C 3～6 Cycloalkyl or 4-7 membered heterocyclic group is optionally replaced by R v replace;

[0157] Ring A is selected from a 5-membered heteroaryl or a 5-7-membered heterocyclic group, wherein the 5-membered heteroaryl is The structural unit may be optionally substituted n times by R4;

[0158] n is independently selected from 0, 1, 2 or 3;

[0159] L1 is selected from a single bond, -(CRa R b ) p -、-NR c -, -O-, -C(=O)-, -C(=O)NH-, -CR a R b -NR c -;

[0160] R a , R b , R c are independently selected from H, halogen, OH, C 1～6 Alkyl or C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally replaced by R x Replace 1 to 3 times;

[0161] p is selected from 1, 2 or 3;

[0162] Any R a and R b Under the conditions of chemical valence permitting, it can form a 3-5 membered cycloalkyl or a 3-5 membered heterocyclic group;

[0163] R4 is selected from halogen, =O, OH, NH2, NO2, C 1～6 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, C 1～6 Alkoxy, C 3～6 Cycloalkyloxy, 4-7 membered heterocyclyl, 4-7 membered heterocyclyloxy, wherein the NH2, C 1～6 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, C 1～6 Alkoxy, C 3～6 Cycloalkyloxy, 4-7 membered heterocyclyl, 4-7 membered heterocyclyloxy are optionally substituted by R y replace;

[0164] R5 is selected from halogen, CN, OH, COOH, CONH2, C 1～6 Alkyl, C 1～6 alkoxy, 4-10 membered nitrogen-containing heterocyclic group, 5-10 membered nitrogen-containing heteroaryl group, 4-10 membered sulfur-containing heterocyclic group, 5-10 membered sulfur-containing heteroaryl group, C 3～10 Cycloalkyl, 4-10 membered heterocyclyl, phenyl, 5-10 membered heteroaryl, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally replaced by R y substituted, and wherein the 4-10 membered nitrogen-containing heterocyclic group, the 5-10 membered nitrogen-containing heteroaryl group, the 4-10 membered sulfur-containing heterocyclic group, the 5-10 membered sulfur-containing heteroaryl group, C3～10 Cycloalkyl, 4-10 membered heterocyclyl, phenyl, 5-10 membered heteroaryl are optionally substituted by R z replace;

[0165] 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 heterocyclyl, 4-7 membered heterocyclyloxy, 4-7 membered heterocyclyl-NH-, C 6～10 Aryl, C 6～10 Aryloxy, 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 group, C 6～10 Aryl or 5-10 membered heteroaryl is optionally substituted by R y replace;

[0166] Or two R6 and the C atom to which they are connected together form a C 3～6 Cycloalkenyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl, wherein the C 3～6 Cycloalkenyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl are optionally replaced by R y replace;

[0167] R v independently selected from halogen, =O, OH, CN, (C 1～6 Alkyl)-CN, C 1～6 Alkyl or C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally substituted with halogen, C 1～3 Alkyl, OH or CN substituted 1 to 3 times;

[0168] R w independently selected from halogen, 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 3～10Cycloalkyl or 4-7 membered heterocyclic group is optionally substituted by halogen, =O, OH, CN or C 1～6 Alkyl substituted 1 to 3 times;

[0169] R x independently selected from halogen, OH, CN, ═O, C 1～6 Alkyl, (C 1～6 Alkyl)-CN, 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 further optionally substituted 1 to 3 times by halogen, cyano, hydroxyl or amine;

[0170] R y independently selected from halogen, 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 1 to 3 times by halogen or hydroxy;

[0171] R z are independently selected from halogen, CN, (C 1～6 alkyl)-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 heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl, wherein the C 1～6 Alkyl, C 3～10 Cycloalkyl, 4-7 membered heterocyclic group, C 6～10 The 5- to 10-membered aryl or heteroaryl group is optionally further substituted by R x replace;

[0172] R n Independently selected from H, C 1～6 alkyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl, wherein the C 1～6 Alkyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl are optionally further substituted by R x Substitution, or 2 R on a N atom n The N to which it is attached forms a 4-7 membered heterocyclic group or a 5-6 membered heteroaryl group, wherein the 4-7 membered heterocyclic group or the 5-6 membered heteroaryl group is optionally further substituted by R x replace;

[0173] Provided that the compound of formula (I) is not any compound selected from the compounds in Table A described in claim 1, or a mixture of any two or more compounds, or an isomer or isomer mixture of any compound.

[0174] In some embodiments, W is selected from 5-10 membered heteroaryl or 4-10 membered heterocyclyl, wherein the 5-10 membered heteroaryl and 4-10 membered heterocyclyl are optionally replaced by R w Replace, and R v are independently selected from halogen, OH, CN, (C 1～6 Alkyl)-CN, C 1～6 Alkyl or C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally substituted with halogen, C 1～3 Alkyl, OH or CN substituted 1 to 3 times.

[0175] In some embodiments, W is selected from 5-10 membered heteroaryl or 4-10 membered heterocyclyl, wherein the 5-10 membered heteroaryl and 4-10 membered heterocyclyl are optionally replaced by R w Replace, and R v are independently selected from halogen, OH, CN, (C 1～6 Alkyl)-CN, C 1～6Alkyl or C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally substituted with halogen, C 1～3 Alkyl, OH or CN substituted 1 to 3 times.

[0176] In some embodiments, W is selected from hydrogen, pyrrolyl, thiophenyl, furanyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl.

[0177] In some embodiments, R w Selected from halogen, OH, CN, C 1～3 Alkyl or C 3～6 Cycloalkyl, wherein the C 1～3 Alkyl and C 1～3 The alkoxy group is optionally substituted 1 to 3 times by halogen.

[0178] In some embodiments, R w Selected from C 1～3 Alkyl, more preferably methyl.

[0179] In some embodiments, W is selected from hydrogen,

[0180] In some embodiments, W is selected from

[0181] In other embodiments, W is selected from 5-10 membered heteroaryl or 4-10 membered heterocyclyl, wherein the 5-10 membered heteroaryl and 4-10 membered heterocyclyl are optionally replaced by R w replace;

[0182] R v independently selected from halogen, OH, CN, C 1～6 Alkyl or C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally substituted with halogen, C 1～3 Alkyl, OH or CN substituted 1 to 3 times;

[0183] R x independently selected from halogen, OH, 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 further optionally substituted 1 to 3 times by halogen, cyano, hydroxyl or amine; and

[0184] R z independently selected from halogen, 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 heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein C 1～6 Alkyl, C 3～10 Cycloalkyl, 4-7 membered heterocyclic group, C 6～10 The 5- to 10-membered aryl or heteroaryl group is optionally further substituted by R x replace.

[0185] In some embodiments, W is selected from 5-10 membered heteroaryl or 4-10 membered heterocyclyl, wherein the 5-10 membered heteroaryl and 4-10 membered heterocyclyl are optionally replaced by R w replace;

[0186] p is selected from 1 or 2;

[0187] R v independently selected from halogen, OH, CN, C 1～6 Alkyl or C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally substituted with halogen, C 1～3Alkyl, OH or CN substituted 1 to 3 times;

[0188] R x independently selected from halogen, OH, 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 further optionally substituted 1 to 3 times by halogen, cyano, hydroxyl or amine;

[0189] R y independently selected from halogen, OH, =O, NH2, NH(C 1～6 Alkyl), N(C 1～6 Alkyl)2, C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is further optionally substituted 1 to 3 times by halogen; and

[0190] R z independently selected from halogen, 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 3～10Cycloalkyl, 4-7 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein C 1～6 Alkyl, C 3～10 Cycloalkyl, 4-7 membered heterocyclic group, C 6～10 The 5- to 10-membered aryl or heteroaryl group is optionally further substituted by R x replace.

[0191] In some further embodiments, W is selected from pyrrolyl, thienyl, furanyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl.

[0192] In some such embodiments, R w Selected from halogen, OH, CN, C 1～3 Alkyl or C 3～6 Cycloalkyl, wherein the C 1～3 Alkyl and C 1～3 The alkoxy group is optionally substituted 1 to 3 times by halogen.

[0193] In some embodiments, R w Selected from C 1～3 Alkyl, more preferably methyl.

[0194] In some embodiments, W is selected from

[0195] In some embodiments, L2 is selected from a single bond, -CH2-, -CHF-, -CF2-, -CH(CH3)-, -C(CH3)2-, -CH(CF3)-.

[0196] In some preferred embodiments, L2 is a single bond.

[0197] In some embodiments, the compound of formula (I) is selected from the structure shown in formula (I-1):

[0198]

[0199] In some embodiments, ring A is selected from pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl or 5-7 membered heterocyclyl, wherein the 5-7 membered heterocyclyl contains 1 or 2 N or S as heteroatoms, and the ring A can be optionally substituted n times by R4.

[0200] In some embodiments, Ring A is selected from The ring A may be optionally substituted n times by R4.

[0201] In some embodiments, Ring A is selected from The ring A may be optionally substituted n times by R4.

[0202] In some embodiments, the structural unit Selected from The structural unit Optionally substituted n times by R4.

[0203] In some embodiments, the structural unit Selected from

[0204] In some embodiments, the compound of formula (I) is selected from the structure shown in formula (I-4) or formula (I-5):

[0205]

[0206] In some embodiments, R4 is selected from halogen, =O, OH, NH2, NO2, C 1～6 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, C 1～6 Alkoxy, C 3～6 Cycloalkyloxy, 4-7 membered heterocyclyl, 4-7 membered heterocyclyloxy, wherein the NH2, C 1～6 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, C 1～6 Alkoxy, C 3～6 Cycloalkyloxy, 4-7 membered heterocyclyl, 4-7 membered heterocyclyloxy are optionally substituted by R y replace.

[0207] In some embodiments, R4 is selected from halogen, =O, OH, NH2, C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 Cycloalkyloxy, wherein the NH2, C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 The cycloalkyloxy group is optionally substituted by R y replace.

[0208] In some embodiments, R4 is selected from halogen, =O, NH2, C 1～6 Alkyl, C 1～6 Alkoxy, wherein the NH2, C 1～6 Alkyl, C 1～6 The alkoxy group is optionally replaced by R y replace.

[0209] In some embodiments, R4 is selected from halogen, C optionally substituted by halogen 1～6 Alkyl, optionally substituted by halogen, C 1～6 Alkoxy.

[0210] In some embodiments, R4 is selected from halogen, OH, C 1～6 Alkyl, halogenated C 1～6 alkyl.

[0211] In some embodiments, R4 is selected from =O, F, Cl, Br, OH, methyl, ethyl, ethynyl, CF3, CHF2, CH2F, methoxy, N(CH3)2, NHCH3.

[0212] In some embodiments, R4 is selected from =0, methyl, CF3, F, Cl, methoxy.

[0213] 1.5. The first aspect and / or the second aspect and / or the third aspect

[0214] In an embodiment according to any one of the first, second and / or third aspects described above, R4 is selected from =0, methyl, CF3.

[0215] In some embodiments, L1 is selected from a single bond, -(CR a R b ) p -、-NR c -, -O-, -C(=O)-, -CR a R b NR c -.

[0216] In some embodiments, R a , R b Each is independently selected from H, halogen, and OH.

[0217] In some embodiments, R a , R b are each independently H.

[0218] In some embodiments, R c For H.

[0219] In some embodiments, L1 is selected from a single bond, -CH2-, -NH-, -NHCH2-, -NHCH(CH3)-, -CH2CH2-, -CH(CH2OH)-, -CH(CH3)-, -C(CH3)2-, -CH(CF3)-, -CHF-, -CF2-, -C(=O)-.

[0220] In some embodiments, L1 is selected from a single bond, -CH2-, -CHF-, -CF2-, -CH2NH-, -CH2CH2-.

[0221] In some embodiments, L1 is selected from a single bond, -CH2-, -CHF-, -CF2.

[0222] In some embodiments, L1 is selected from -CH2-, -CH2NH-.

[0223] In some embodiments, p is selected from 1 or 2.

[0224] In some embodiments, R5 is selected from halogen, CN, OH, COOH, CONH2, C 1～6 Alkyl, C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally replaced by R y replace.

[0225] In some embodiments, R5 is selected from halogen, CN, OH, optionally substituted by R y Substituted C 1～6 alkyl.

[0226] In some embodiments, R5 is selected from 4-10 membered nitrogen-containing heterocyclyl, 5-10 membered nitrogen-containing heteroaryl, 4-10 membered sulfur-containing heterocyclyl, 5-10 membered sulfur-containing heteroaryl, C 3～10 Cycloalkyl, 4-10 membered heterocyclic group, phenyl, 5-10 membered heteroaryl, wherein the 4-10 membered nitrogen-containing heterocyclic group, 5-10 membered nitrogen-containing heteroaryl, 4-10 membered sulfur-containing heterocyclic group, 5-10 membered sulfur-containing heteroaryl, C 3～10 Cycloalkyl, 4-10 membered heterocyclyl, phenyl, 5-10 membered heteroaryl are optionally substituted by R z replace.

[0227] In some embodiments, R5 is selected from

[0228]

[0229] The R5 is optionally replaced by R z Replace 1 to 6 times.

[0230] In some embodiments, R5 is selected from The R5 is optionally replaced by R z Replace 1 to 4 times.

[0231] In some embodiments, R5 is selected from

[0232] The R5 is optionally replaced by R z Replace 1 to 6 times.

[0233] In some embodiments, R5 is selected from

[0234] The R5 is optionally replaced by R z Replace 1 to 6 times.

[0235] In some embodiments, R5 is selected from The R5 is optionally replaced by R z Replace 1 to 4 times.

[0236] In some embodiments, R6 is 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 heterocyclyl, 4-7 membered heterocyclyloxy, 4-7 membered heterocyclyl-NH-, C 6～10 Aryl, C 6～10 Aryloxy, 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 group, C 6～10 Aryl or 5-10 membered heteroaryl is optionally substituted by R y replace.

[0237] In some embodiments, any two R6 and the C atoms to which they are attached together form a C 3～6 Cycloalkenyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl, wherein the C 3～6 Cycloalkenyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl are optionally replaced by R y replace.

[0238] In some embodiments, R6 is 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 3～6Cycloalkyl-NH-, 4-7 membered heterocyclyl, 4-7 membered heterocyclyloxy, 4-7 membered heterocyclyl-NH-, 5-10 membered heteroaryl or phenyl, wherein the C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-10 membered heteroaryl are optionally replaced by R y replace.

[0239] In some embodiments, R6 is selected from H, halogen, OH, CN, methyl, ethoxy, NHCH3, NHCH2CH3, NHCH(CH3)2, pyrazolyl, cyclopropyl, NH-cyclopropyl, O-cyclopropyl, O-oxetanyl, wherein the methyl, ethoxy, NHCH3, NHCH2CH3, NHCH(CH3)2, pyrazolyl, cyclopropyl, NH-cyclopropyl, O-cyclopropyl, and O-oxetanyl are optionally replaced by R y replace.

[0240] In some embodiments, n is selected from 0, 1 or 2.

[0241] In some embodiments X1, X2, X3 and X4 are independently selected from CR6.

[0242] In some embodiments, X2, X3 and X4 are independently selected from CR6 or N, and X1 is selected from CR6.

[0243] In some embodiments, X2 and X4 are independently selected from CR6 or N, and X1 and X3 are independently selected from CR6.

[0244] In some embodiments, X2 and X4 are N, and X1 and X3 are independently selected from CR6.

[0245] In some embodiments, X2 is N, and X1, X3 and X4 are independently selected from CR6.

[0246] In some embodiments, X1, X2 and X4 are independently selected from CR6, and X3 is N.

[0247] In some embodiments, X1, X2 and X4 are CH, and X3 is CR6.

[0248] In some embodiments, X2 is N, X1 and X4 are CH, and X3 is CR6.

[0249] In some embodiments, X1, X2 and X4 are CH, and X3 is N.

[0250] In some embodiments, R z Selected from halogen, 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 heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl, wherein the C 1～6 Alkyl, C 3～10 Cycloalkyl, 4-7 membered heterocyclic group, C 6～10 The 5- to 10-membered aryl or heteroaryl group may be further substituted with R x replace.

[0251] In some embodiments, R z Selected from halogen, CN, =O, C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, said R z Optionally R x replace.

[0252] In some embodiments, R z Selected from halogen, CN, =O, C 1～3 Alkyl, C 1～3 Alkoxy, C 3～6 Cycloalkyl, phenyl, said R z Optionally R x replace.

[0253] In some embodiments, R zis selected from halogen, optionally further R x Substituted C 1～3 alkyl.

[0254] In some embodiments, R5 is selected from

[0255] In some embodiments, L1-R5 is selected from

[0256] In some embodiments, L1-R5 is selected from

[0257]

[0258] In some embodiments, L1-R5 is selected from

[0259] In some embodiments, R1 and R2 are independently selected from H, halogen, 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 1～6 Alkoxy, C 3～10 Cycloalkyl or 4-10 membered heterocyclic group is optionally substituted by R x Substituted; and / or, R1 and R2 are independently selected from H, halogen, CN, NH2, C 1～3 Alkyl, C 1～3 Alkoxy, C 3～6 Cycloalkyl, and wherein the C 1～3 Alkyl, C 1～3 Alkoxy, C 3～6 The cycloalkyl group is optionally substituted by R x Replace 1 to 3 times.

[0260] In some embodiments, R1, R2 and the atoms to which they are attached together form C 3～10 Cycloalkyl or 4-10 membered heterocyclic group, wherein the C 3～10 Cycloalkyl or 4-10 membered heterocyclic group is optionally substituted by R x replace.

[0261] In some embodiments, R1, R2 and the atoms and bonds to which they are attached together form C 3～6 Cycloalkenyl or 4-7 membered heterocyclic group, wherein the C 3～6The cycloalkenyl or 4-7 membered heterocyclic group is optionally substituted by R v replace.

[0262] In some embodiments, R1 and R2 are independently selected from H, F, Cl, CH3, CH2CH3, CF3, cyclopropyl, cyclobutyl, fluorocyclopropyl.

[0263] In some embodiments, R1 and R2 are independently selected from H, F, Cl, CH3, CF3, cyclopropyl, cyclobutyl, fluorocyclopropyl.

[0264] In some embodiments, R1, R2 and the atoms to which they are attached together form

[0265] In some embodiments, R1, R2 and the atoms to which they are attached together form

[0266] In some embodiments, R1, R2 and the atoms to which they are attached together form

[0267] In some embodiments, R1, R2 and the atoms to which they are attached together form

[0268] In some preferred embodiments, R1, R2 and the atoms to which they are attached together form

[0269] In some embodiments, R x independently selected from halogen, OH, CN, C 1～6 Alkyl, NH2, wherein the C 1～6 The alkyl group is further optionally substituted 1 to 3 times by halogen, cyano, hydroxyl or amine.

[0270] 1.6. The fourth aspect

[0271] In a fourth aspect, the present invention provides a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof:

[0272]

[0273] in,

[0274] X1, X2, X3 and X4 are independently selected from CR6 or N;

[0275] R1 and R2 are independently selected from H, halogen, CN, NH2, NH(C 1～6 Alkyl), N(C 1～6 Alkyl)2, C1～6 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 group is optionally substituted by R x replace;

[0276] Or R1, R2 and the atoms they are connected to together form C 3～10 Cycloalkyl or 4-10 membered heterocyclic group, wherein the C 3～10 Cycloalkyl or 4-10 membered heterocyclic group is optionally substituted by R x replace;

[0277] Or R1, R2 and their respective atoms and bonds together form C 3～6 Cycloalkenyl or 4-7 membered heterocyclic group, wherein the C 3～6 The cycloalkenyl or 4-7 membered heterocyclic group is optionally substituted by R v replace;

[0278] R3 is selected from L2-W;

[0279] L2 is selected from a single bond, -CR d R e -;

[0280] W is selected from hydrogen, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, wherein the 5-10 membered heteroaryl, 4-10 membered heterocyclyl is optionally replaced by R w replace;

[0281] R d and R e independently selected from H, halogen, OH, C 1～6 Alkyl or C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally further substituted 1 to 3 times by halogen;

[0282] R1 can be optionally combined with R d or R e and their respective atoms and bonds together form C 3～6 Cycloalkyl or 4-7 membered heterocyclic group, wherein the C 3～6 Cycloalkyl or 4-7 membered heterocyclic group is optionally replaced by R v replace;

[0283] 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 The structural unit may be optionally substituted n times by R4;

[0284] n is independently selected from 0, 1, 2 or 3;

[0285] L1 is selected from a single bond, -(CR a R b ) p -、-NR c -, -O-, -C(=O)-, -C(=O)NH-, -CR a R b -NR c -;

[0286] R a , R b , R c are independently selected from H, halogen, OH, C 1～6 Alkyl or C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally replaced by R x Replace 1 to 3 times;

[0287] p is independently selected from 0, 1, 2 or 3;

[0288] Any R a and R b Under the conditions of chemical valence permitting, it can form a 3-5 membered cycloalkyl or a 3-5 membered heterocyclic group;

[0289] R4 is selected from halogen, =O, OH, NH2, NO2, CN, C 1～6 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, C 3～6 Cycloalkyloxy, 4-7 membered heterocyclyl, 4-7 membered heterocyclyloxy, wherein the NH2, C 1～6 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, C 3～6 Cycloalkyloxy, 4-7 membered heterocyclyl, 4-7 membered heterocyclyloxy are optionally substituted by R y replace;

[0290] R5 is selected from halogen, CN, OH, COOH, CONH2, C 1～6 Alkyl, C 1～6 alkoxy, 4-10 membered nitrogen-containing heterocyclic group, 5-10 membered nitrogen-containing heteroaryl group, 4-10 membered sulfur-containing heterocyclic group, 5-10 membered sulfur-containing heteroaryl group, C3～10 Cycloalkyl, 4-10 membered heterocyclyl, phenyl, 5-10 membered heteroaryl; wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally replaced by R y wherein the 4-10 membered nitrogen-containing heterocyclic group, the 5-10 membered nitrogen-containing heteroaryl group, the 4-10 membered sulfur-containing heterocyclic group, the 5-10 membered sulfur-containing heteroaryl group, 3～10 Cycloalkyl, 4-10 membered heterocyclyl, phenyl, 5-10 membered heteroaryl are optionally substituted by R z replace;

[0291] 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 heterocyclyl, 4-7 membered heterocyclyloxy, 4-7 membered heterocyclyl-NH-, C 6～10 Aryl, C 6～10 Aryloxy, 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 group, C 6～10 Aryl or 5-10 membered heteroaryl is optionally substituted by R y replace;

[0292] Or two R6 and the C atom to which they are connected together form a C 3～6 Cycloalkenyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl, wherein the C 3～6 Cycloalkenyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl are optionally replaced by R y replace;

[0293] R v independently selected from halogen, =O, OH, CN, C 1～6 Alkyl, (C 1～6 Alkyl)-CN or C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally substituted with halogen, C 1～3 Alkyl, OH or CN substituted 1 to 3 times;

[0294] R windependently selected from halogen, 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 group is optionally substituted by halogen, =O, OH, CN or C 1～6 Alkyl substituted 1 to 3 times;

[0295] R x are independently selected from halogen, 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 further optionally substituted 1 to 3 times by halogen, cyano, hydroxyl or amine;

[0296] R y independently selected from halogen, 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 1 to 3 times by halogen or hydroxy;

[0297] R z independently selected from halogen, 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)ORn 、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 heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein C 1～6 Alkyl, C 3～10 Cycloalkyl, 4-7 membered heterocyclic group, C 6～10 The 5- to 10-membered aryl or heteroaryl group is optionally further substituted by R x replace;

[0298] R n Independently selected from H, C 1～6 alkyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl, wherein the C 1～6 Alkyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl are optionally further substituted by R x Substitution, or 2 R on a N atom n The N to which it is attached forms a 4-7 membered heterocyclic group or a 5-6 membered heteroaryl group, wherein the 4-7 membered heterocyclic group or the 5-6 membered heteroaryl group is optionally further substituted by R x replace.

[0299] In some embodiments, both the following conditions (1) and (2) apply:

[0300] (1) When the ring A is a 5-membered heteroaryl group or a 5-7-membered heterocyclic group, R 4 Not CN or C 3～6 cycloalkyl; and

[0301] (2) The compound of formula (I) is not any one or more compounds selected from the compounds in Table A described above, or an isomer or isomer mixture of any one compound.

[0302] In some embodiments, ring A is selected from phenyl or 6-membered heteroaryl, wherein the phenyl or 6-membered heteroaryl is The structural unit Optionally substituted n times by R4.

[0303] In some embodiments, Ring A is selected from a 5-membered heteroaryl or a 5-7-membered heterocyclyl, wherein the 5-membered heteroaryl is The structural unit may be optionally substituted n times by R4; and R4 is selected from halogen, =O, OH, NH2, NO2, C 1～6 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, C 1～6 Alkoxy, C 3～6 Cycloalkyloxy, 4-7 membered heterocyclyl, 4-7 membered heterocyclyloxy, wherein the NH2, C 1～6 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, C 1～6 Alkoxy, C 3～6 Cycloalkyloxy, 4-7 membered heterocyclyl, 4-7 membered heterocyclyloxy are optionally substituted by R y The compound of formula (I) according to such embodiments is not any one compound, or a mixture of any two or more compounds, or an isomer or mixture of isomers of any one compound selected from the compounds in Table A described above.

[0304] In some embodiments, ring A is selected from phenyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl or 5-7 membered heterocyclyl, wherein the 5-7 membered heterocyclyl contains 1 or 2 N or S as heteroatoms, and the ring A can be optionally substituted n times by R4.

[0305] In some embodiments, Ring A is selected from The ring A may be optionally substituted n times by R4.

[0306] In some embodiments, Ring A is selected from The ring A may be optionally substituted n times by R4.

[0307] In some embodiments, Ring A is selected from The ring A may be optionally substituted n times by R4.

[0308] In some embodiments, Ring A is selected from The ring A may be optionally substituted n times by R4.

[0309] In some embodiments, Ring A is selected from The ring A may be optionally substituted n times by R4.

[0310] In some embodiments, Ring A is selected from The ring A may be optionally substituted n times by R4.

[0311] In some embodiments, the structural unit Selected from The structural unit Optionally substituted n times by R4.

[0312] In some embodiments, the structural unit Selected from The structural unit Optionally substituted n times by R4.

[0313] In some embodiments, the structural unit Selected from The structural unit Optionally substituted n times by R4.

[0314] In some embodiments, the structural unit Selected from The structural unit Optionally substituted n times by R4.

[0315] In some embodiments, the structural unit Selected from The structural unit Optionally substituted n times by R4.

[0316] In some embodiments, the structural unit Selected from The structural unit Optionally substituted n times by R4.

[0317] In some embodiments, the structural unit Selected from

[0318] In some embodiments, the structural unit Selected from

[0319] In some embodiments, the structural unit Selected from

[0320] In some embodiments, the structural unit Selected from

[0321] In some embodiments, the structural unit Selected from

[0322] In some embodiments, the structural unit Selected from

[0323] In some embodiments, R4 is selected from halogen, =O, OH, NH2, NO2, CN, C 1～6 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, C 3～6 Cycloalkyloxy, 4-7 membered heterocyclyl, 4-7 membered heterocyclyloxy, wherein the NH2, C 1～6 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, C 3～6 Cycloalkyloxy, 4-7 membered heterocyclyl, 4-7 membered heterocyclyloxy are optionally substituted by R y replace.

[0324] In some embodiments, R4 is selected from halogen, =O, OH, NH2, CN, C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, C 3～6 Cycloalkyloxy, wherein the NH2, C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, C 3～6 The cycloalkyloxy group is optionally substituted by R y replace.

[0325] In some embodiments, R4 is selected from halogen, =O, NH2, CN, C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, wherein the NH2, C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 The cycloalkyl group is optionally substituted by R y replace.

[0326] In some embodiments, R4 is selected from halogen, C optionally substituted by halogen 1～6 Alkyl, optionally substituted by halogen, C 1～6 Alkoxy, optionally substituted by halogen, C 3～6 Cycloalkyl.

[0327] In some embodiments, R4 is selected from halogen, CN, OH, C 1～6 Alkyl, halogenated C1～6 alkyl.

[0328] 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.

[0329] In some embodiments, R4 is selected from =0, methyl, CF3, F, Cl, methoxy, cyclopropyl.

[0330] In some embodiments, R4 is selected from =0, methyl, CF3.

[0331] In some embodiments, L1 is selected from a single bond, -(CR a R b ) p -、-NR c -, -O-, -C(=O)-, -CR a R b NR c -.

[0332] In some embodiments, R a , R b Each is independently selected from H, halogen, and OH.

[0333] In some embodiments, R a , R b are each independently H.

[0334] In some embodiments, R c For H.

[0335] In some embodiments, L1 is selected from a single bond, -CH2-, -NH-, -NHCH2-, -NHCH(CH3)-, -CH2CH2-, -CH(CH2OH)-, -CH(CH3)-, -C(CH3)2-, -CH(CF3)-, -CHF-, -CF2-, -C(=O)-.

[0336] In some embodiments, L1 is selected from a single bond, -CH2-, -CHF-, -CF2-, -CH2NH-, -CH2CH2-.

[0337] In some embodiments, L1 is selected from a single bond, -CH2-, -CHF-, -CF2-.

[0338] In some preferred embodiments, L1 is selected from -CH2-, -CH2NH-.

[0339] In some embodiments, p is selected from 1 or 2.

[0340] In some embodiments, R5 is selected from halogen, CN, OH, COOH, CONH2, C 1～6 Alkyl, C 1～6 Alkoxy; wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally replaced by R y replace.

[0341] In some embodiments, R5 is selected from 4-10 membered nitrogen-containing heterocyclyl, 5-10 membered nitrogen-containing heteroaryl, 4-10 membered sulfur-containing heterocyclyl, 5-10 membered sulfur-containing heteroaryl, C 3～10 Cycloalkyl, 4-10 membered heterocyclic group, phenyl, 5-10 membered heteroaryl; wherein the 4-10 membered nitrogen-containing heterocyclic group, 5-10 membered nitrogen-containing heteroaryl, 4-10 membered sulfur-containing heterocyclic group, 5-10 membered sulfur-containing heteroaryl, C 3～10 Cycloalkyl, 4-10 membered heterocyclyl, phenyl, 5-10 membered heteroaryl are optionally substituted by R z replace.

[0342] In some embodiments, R5 is selected from halogen, CN, OH, optionally substituted by R y Substituted C 1～6 alkyl.

[0343] In some embodiments, R5 is selected from

[0344] The R5 is optionally replaced by R z Replace 1 to 6 times.

[0345] In some embodiments, R5 is selected from The R5 is optionally replaced by R z Replace 1 to 6 times.

[0346] In some embodiments, R5 is selected from

[0347] The R5 is optionally replaced by R z Replace 1 to 6 times.

[0348] In some embodiments, R5 is selected from

[0349] The R5 is optionally replaced by R z Replace 1 to 6 times.

[0350] In some embodiments, R5 is selected from The R5 is optionally replaced by Rz Replace 1 to 4 times.

[0351] In some embodiments, R5 is selected from

[0352] In some embodiments, R6 is 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 heterocyclyl, 4-7 membered heterocyclyloxy, 4-7 membered heterocyclyl-NH-, C 6～10 Aryl, C 6～10 Aryloxy, 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 group, C 6～10 Aryl or 5-10 membered heteroaryl is optionally substituted by R y replace.

[0353] In some embodiments, any two R6 and the C atoms to which they are attached together form a C 3～6 Cycloalkenyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl, wherein the C 3～6 Cycloalkenyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl are optionally replaced by R y replace.

[0354] In some embodiments, R6 is 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 heterocyclyl, 4-7 membered heterocyclyloxy, 4-7 membered heterocyclyl-NH-, 5-10 membered heteroaryl or phenyl, wherein the C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-10 membered heteroaryl are optionally replaced by R y replace.

[0355] In some embodiments, R6 is selected from H, halogen, OH, CN, methyl, ethoxy, NHCH3, NHCH2CH3, NHCH(CH3)2, pyrazolyl, cyclopropyl, NH-cyclopropyl, O-cyclopropyl, O-oxetanyl, wherein the methyl, ethoxy, NHCH3, NHCH2CH3, NHCH(CH3)2, pyrazolyl, cyclopropyl, NH-cyclopropyl, O-cyclopropyl, and O-oxetanyl are optionally replaced by R y replace.

[0356] In some embodiments, X1, X2, X3 and X4 are independently selected from CR6.

[0357] In some embodiments, X2, X3 and X4 are independently selected from CR6 or N, and X1 is selected from CR6.

[0358] In some embodiments, X2 and X4 are independently selected from CR6 or N, and X1 and X3 are independently selected from CR6.

[0359] In some embodiments, X2 and X4 are N, and X1 and X3 are independently selected from CR6.

[0360] In some embodiments, X2 is N, and X1, X3 and X4 are independently selected from CR6.

[0361] In some embodiments, X1, X2 and X4 are independently selected from CR6, and X3 is N.

[0362] In some embodiments, X1, X2 and X4 are CH, and X3 is CR6.

[0363] In some embodiments, X2 is N, X1 and X4 are CH, and X3 is CR6.

[0364] In some embodiments, X1, X2 and X4 are CH, and X3 is N.

[0365] In some embodiments, R z Selected from halogen, 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 heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein C 1～6 Alkyl, C 3～10 Cycloalkyl, 4-7 membered heterocyclic group, C 6～10 The 5- to 10-membered aryl or heteroaryl group is optionally further substituted by R x replace;

[0366] In some embodiments, R z Selected from halogen, CN, =O, C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, wherein R z Optionally R x replace.

[0367] In some embodiments, R z Selected from halogen, CN, =O, C 1～3 Alkyl, C 1～3 Alkoxy, C 3～6 Cycloalkyl, phenyl, said R z Optionally R x replace.

[0368] In some embodiments, R z is selected from halogen, optionally further R x Substituted C 1～3 alkyl.

[0369] In some embodiments, n is selected from 0, 1, 2, or 3.

[0370] In some embodiments, n is selected from 0, 1 or 2.

[0371] In some embodiments, L1-R5 is selected from

[0372] In some embodiments, L1-R5 is selected from

[0373] In some embodiments, L1-R5 is selected from

[0374] In some embodiments, R1 and R2 are independently selected from H, halogen, 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 1～6 Alkoxy, C 3～10 Cycloalkyl or 4-10 membered heterocyclic group is optionally substituted by R x replace.

[0375] In some embodiments, R1 and R2 are independently selected from H, halogen, CN, NH2, 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 The cycloalkyl group is optionally substituted by R x Replace 1 to 3 times.

[0376] In some embodiments, R1, R2 and the atoms to which they are attached together form C 3～10 Cycloalkyl or 4-10 membered heterocyclic group, wherein the C 3～10 Cycloalkyl or 4-10 membered heterocyclic group is optionally substituted by R x replace.

[0377] In some embodiments, R1, R2 and the atoms and bonds to which they are attached together form C 3～6 Cycloalkenyl or 4-7 membered heterocyclic group, wherein the C 3～6 The cycloalkenyl or 4-7 membered heterocyclic group is optionally substituted by R v replace.

[0378] In some embodiments, R1 and R2 are independently selected from H, F, Cl, CH3, CH2CH3, CF3, cyclopropyl, cyclobutyl, fluorocyclopropyl.

[0379] In some embodiments, R1 and R2 are independently selected from H, F, Cl, CH3, CF3, cyclopropyl, cyclobutyl, fluorocyclopropyl.

[0380] In some embodiments, R1, R2 and the atoms to which they are attached together form

[0381] In some embodiments, R1, R2 and the atoms to which they are attached together form

[0382] In some embodiments, R1, R2 and the atoms to which they are attached together form

[0383] In some embodiments, R1, R2 and the atoms to which they are attached together form

[0384] In some preferred embodiments, R1, R2 and the atoms to which they are attached together form

[0385] In some embodiments, R x independently selected from halogen, OH, CN, C 1～6 Alkyl, NH2, wherein the C 1～6 The alkyl group is further optionally substituted 1 to 3 times by halogen, cyano, hydroxyl or amine.

[0386] In some embodiments, L2 is selected from a single bond, -CH2-, -CHF-, -CF2-, -CH(CH3)-, -C(CH3)2-, -CH(CF3)-.

[0387] In some preferred embodiments, L2 is a single bond.

[0388] In some embodiments, W is selected from 5-10 membered heteroaryl or 4-10 membered heterocyclyl, wherein the 5-10 membered heteroaryl and 4-10 membered heterocyclyl are optionally replaced by R w Replace, and R v are independently selected from halogen, OH, CN, (C 1～6 Alkyl)-CN, C 1～6 Alkyl or C 1～6 Alkoxy, the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally substituted with halogen, C 1～3 Alkyl, OH or CN substituted 1 to 3 times.

[0389] In some embodiments, W is selected from hydrogen, pyrrolyl, thiophenyl, furanyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl.

[0390] In some embodiments, R w Selected from halogen, OH, CN, C 1～3 Alkyl or C 3～6 Cycloalkyl, wherein the C 1～3 Alkyl and C 1～3 The alkoxy group is optionally substituted 1 to 3 times by halogen.

[0391] In some preferred embodiments, R w Selected from C 1～3 Alkyl, more preferably methyl.

[0392] In some embodiments, W is selected from hydrogen.

[0393] In some embodiments, W is selected from

[0394] In other embodiments, W is selected from 5-10 membered heteroaryl or 4-10 membered heterocyclyl, wherein the 5-10 membered heteroaryl and 4-10 membered heterocyclyl are optionally replaced by R w replace;

[0395] R v independently selected from halogen, OH, CN, C 1～6 Alkyl or C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally substituted with halogen, C 1～3 Alkyl, OH or CN substituted 1 to 3 times;

[0396] R x independently selected from halogen, OH, 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 further optionally substituted 1 to 3 times by halogen, cyano, hydroxyl or amine; and

[0397] R z independently selected from halogen, 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 heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein C 1～6 Alkyl, C 3～10 Cycloalkyl, 4-7 membered heterocyclic group, C 6～10 The 5- to 10-membered aryl or heteroaryl group is optionally further substituted by R x replace.

[0398] In some embodiments, W is selected from 5-10 membered heteroaryl or 4-10 membered heterocyclyl, wherein the 5-10 membered heteroaryl and 4-10 membered heterocyclyl are optionally replaced by R w replace;

[0399] p is selected from 1 or 2;

[0400] R v independently selected from halogen, OH, CN, C 1～6 Alkyl or C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally substituted with halogen, C 1～3 Alkyl, OH or CN substituted 1 to 3 times;

[0401] R x independently selected from halogen, OH, 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 further optionally substituted 1 to 3 times by halogen, cyano, hydroxyl or amine;

[0402] R y independently selected from halogen, OH, =O, NH2, NH(C 1～6 Alkyl), N(C 1～6 Alkyl)2, C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is further optionally substituted 1 to 3 times by halogen; and

[0403] R z independently selected from halogen, 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 heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein C 1～6 Alkyl, C 3～10 Cycloalkyl, 4-7 membered heterocyclic group, C 6～10 The 5- to 10-membered aryl or heteroaryl group is optionally further substituted by R x replace.

[0404] In some further embodiments, W is selected from pyrrolyl, thienyl, furanyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl.

[0405] In some such embodiments, R w Selected from halogen, OH, CN, C 1～3 Alkyl or C 3～6 Cycloalkyl, the C 1～3 Alkyl and C 1～3 The alkoxy group is optionally substituted 1 to 3 times by halogen.

[0406] In some preferred embodiments, R w Selected from C 1～3 Alkyl, more preferably methyl.

[0407] In some embodiments, W is selected from

[0408] In some embodiments, the compounds of formula (I) of the present invention may contain unnatural ratios of atomic isotopes on one or more of the atoms constituting the compound. For example, radioactive isotope-labeled compounds, such as tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C).

[0409] As a specific embodiment, the isotope atom described in the present invention is deuterium ( 3 H).

[0410] The compound of formula I or a pharmaceutically acceptable salt thereof according to the present invention may be further selected from the structure shown in formula (I-1): The rest of the definitions are the same as before.

[0411] The compound of formula I or a pharmaceutically acceptable salt thereof according to the present invention may be further selected from the structures shown in formula (I-2), formula (I-3), formula (I-4), and formula (I-5): The rest of the definitions are the same as before.

[0412] Some other solutions of the present invention are obtained by arbitrarily combining the above variables.

[0413] 1.7. Fifth Aspect

[0414] The present invention also provides the following compounds or pharmaceutically acceptable salts thereof:

[0415]

[0416]

[0417]

[0418] The present invention also provides the following compounds or pharmaceutically acceptable salts thereof:

[0419]

[0420]

[0421] The present invention also provides the following compounds or pharmaceutically acceptable salts thereof:

[0422] 2. Pharmaceutical compositions and uses

[0423] The present invention also provides the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof in the preparation of Cbl-b inhibitor-related drugs.

[0424] The compounds provided by the present invention are Cbl-b inhibitors, wherein the compounds of formula (I) and pharmaceutically acceptable salts thereof have excellent Cbl-b receptor inhibitory activity. These Cbl-b inhibitor compounds can treat and / or prevent Cbl-b-mediated diseases or conditions and related diseases or conditions.

[0425] The compound of formula (I) and its pharmaceutically acceptable salt provided by the present invention can be used alone or in combination with at least one other therapeutic agent in treatment.

[0426] The present invention also provides a pharmaceutical composition, which contains the compound of formula (I) as described above or a pharmaceutically acceptable salt thereof, and one or more other therapeutically active ingredients.

[0427] The present invention also provides a pharmaceutical composition comprising a compound of formula (I) as described above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or diluent.

[0428] The pharmaceutically acceptable salts described herein include acid addition salts and base salts.

[0429] The pharmaceutically acceptable salts described herein can exist in unsolvated as well as solvated forms.

[0430] The present invention also provides the use of the compound of formula (I) as described above and its pharmaceutically acceptable salt in the preparation of a medicament for treating and / or preventing diseases or conditions mediated by Cbl-B and related diseases or conditions.

[0431] The present invention also provides a method for treating a disease or condition, comprising administering a therapeutically effective amount of a compound of formula (I) as described above and a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the disease or condition is a Cbl-B-mediated disease or condition and related diseases or conditions.

[0432] In some embodiments of the present invention, the disease or disorder is selected from tumors and / or cancer.

[0433] In some embodiments, the Cbl-B mediated tumors and / or cancers include, but are not limited to, melanoma, thyroid tumor, head and neck cancer, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial carcinoma, bladder cancer, non-small cell lung cancer, small cell lung cancer, colorectal adenoma, sarcoma, intestinal stromal tumor, gastric cancer, esophageal cancer, colorectal cancer, pancreatic cancer, small intestine cancer, kidney cancer, liver cancer, hepatocellular carcinoma, cholangiocarcinoma, mesothelioma, lymphoma, leukemia, myelodysplastic syndrome, multiple myeloma, plasmacytoma, neuroblastoma, retinoblastoma and germ cell tumor.

[0434] The present invention also provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of drugs related to Cbl-b inhibitors.

[0435] Definition and Description

[0436] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commercial product or its active ingredient.

[0437] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0438] The term "pharmaceutically acceptable salt" refers to salts of compounds of the invention, prepared from compounds of the invention having specific substituents with relatively nontoxic acids or bases. When the compounds of the 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 the 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, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid, and salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic functional groups, and thus can be converted into any base or acid addition salt.

[0439] Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, the preparation method of such salts is: in water or an organic solvent or a mixture of the two, these compounds in free acid or base form are reacted with a stoichiometric amount of an appropriate base or acid to prepare.

[0440] Unless otherwise stated, the term "isomer" is intended to include geometric isomers, cis-trans isomers, stereoisomers, enantiomers, optical isomers, diastereomers and tautomers.

[0441] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present invention.

[0442] Unless otherwise indicated, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of one another.

[0443] Unless otherwise indicated, the term "cis-trans isomers" or "geometric isomers" arises from the inability of a ring carbon atom to rotate freely about double bonds or single bonds forming a ring.

[0444] Unless otherwise indicated, the term "diastereomer" refers to stereoisomers that have two or more chiral centers and that are not mirror images of each other.

[0445] Unless otherwise indicated, "(+)" indicates dextrorotatory, "(-)" indicates levorotatory, and "(±)" indicates racemic.

[0446] Unless otherwise specified, the key is a solid wedge. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond. and straight dashed key To indicate the relative configuration of a stereocenter, use a wavy line Denotes a solid wedge bond or dotted wedge key Or use a wavy line Represents a straight solid bond or straight dashed key

[0447] Unless otherwise indicated, the terms "enriched in one isomer", "isomerically enriched", "enriched in one enantiomer" or "enantiomerically enriched" 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%.

[0448] Unless otherwise indicated, the term "isomer excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80%.

[0449] Optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, 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 pure desired enantiomer. 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 diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is usually accomplished by using chromatography, which uses a chiral stationary phase and is optionally combined with a chemical derivatization method (for example, a carbamate is generated from an amine).

[0450] The compounds of the invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up 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 another example, deuterium can be used to replace hydrogen to form a deuterated drug. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing efficacy, and extending the biological half-life of drugs. All isotopic composition changes of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.

[0451] The terms "optional" or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0452] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as 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 be substituted or not substituted, and unless otherwise specified, the type and number of the substituents may be arbitrary on the basis of chemical achievable.

[0453] 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, and each occurrence of R is an independent choice. In addition, combinations of substituents and / or variants thereof are permitted only if such combinations result in stable compounds.

[0454] When the number of a linking group is 0, such as -(CRR)0-, it means that the linking group is a single bond.

[0455] 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.

[0456] When a substituent is vacant, it means that the substituent does not exist. For example, when X in AX is vacant, it means that the structure is actually A.

[0457] When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0458] When a substituent has bonds that cross-link to two or more atoms in a ring, the substituent may be bonded to any atom in the ring, e.g. It means that the substituent R4 can be substituted at any position on the ring A or the piperidone. When the listed substituent does not specify which atom it is connected to the substituted group through, the substituent can be bonded through any atom thereof. For example, the pyridyl group as a substituent can be connected to the substituted group through any carbon atom on the pyridine ring.

[0459] When the listed linking group does not indicate its linking direction, the linking direction is arbitrary.

[0460] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection mode is non-positional and there are H atoms at the connectable sites, when the chemical bonds are connected, the number of H atoms at the site will decrease with the number of connected chemical bonds to become a group with the corresponding valence. The chemical bond connecting the site to other groups can be a straight solid bond. Straight dotted key or wavy line express.

[0461] Unless otherwise specified, the number of atoms in a ring is generally defined as the ring member number, for example, a "5-7 membered ring" refers to a "ring" having 5-7 atoms arranged around it.

[0462] The terms "halo", "halogen" and "halogen atom" in the present invention mean fluorine atom, chlorine atom, bromine atom, iodine atom, etc. Preferred halogen atoms as substituents of the aryl group in the present invention are fluorine atom and chlorine atom.

[0463] The term "C 1～6 "Alkyl" refers to a straight or branched chain 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 or branched chain alkyl group having 1 to 3 carbons, including but not limited to methyl, ethyl, n-propyl and isopropyl.

[0464] The term "C 1～6 "Alkoxy" means a group C 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" means a group C 1-3 Alkyl-O-, includes but is not limited to methoxy, ethoxy, n-propoxy and isopropoxy.

[0465] The term "aryl" in the present invention 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 a benzo 3- to 8-membered cycloalkyl, a benzo 3- to 8-membered heterocyclic group, wherein the heterocyclic group is a heterocyclic group containing 1-3 heteroatoms independently selected from N, O and S; or further comprising a three-membered nitrogen-containing fused ring containing a benzene ring.

[0466] The term "heteroaryl" or "heteroaryl ring" of the present invention refers to a heteroaromatic system having 5 to 14 ring atoms, which has 1 to 4 heteroatoms independently selected from N, O and S. The heteroaryl group is preferably 5 to 10 members, more preferably 5 or 6 members, such as imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl and the like.

[0467] Unless otherwise specified, the terms "5-6 membered heteroaromatic ring" and "5-6 membered heteroaryl" in the present invention can be 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, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). The 5-6 membered heteroaryl group may be attached to the rest of the molecule via a heteroatom or a carbon atom. The 5-6 membered heteroaryl group includes 5-membered and 6-membered heteroaryl groups.

[0468] The term "3-6 membered heterocyclyl" in the present invention means a non-aromatic cyclic group having 3 to 6 ring atoms, which contains 1 or more heterocyclic atoms independently selected from N, O and S, and which may be fully saturated (i.e., 3-6 membered heterocycloalkyl) or partially unsaturated. The heterocycle may be a 3-6 membered monocyclic, bicyclic or spirocyclic ring. The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclyl.

[0469] The term "C 3～6 "Cycloalkyl" or "3-6 membered cycloalkyl" means a monovalent group derived from a cyclic hydrocarbon having 3 to 6 carbons by removing any single hydrogen atom, which may be fully saturated (ie, 3 to 6 carbon cycloalkyl) or partially unsaturated.

[0470] The term "haloalkyl" of the present invention refers to an alkyl group substituted by one or more halogens.

[0471] The term "alkenyl" of the present invention means a linear or branched monovalent aliphatic hydrocarbon group containing one or more double bonds.

[0472] The term "alkynyl" of the present invention means a linear or branched monovalent aliphatic hydrocarbon group containing one or more triple bonds.

[0473] The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the embodiments of the present invention.

[0474] The compounds described in the present invention are named according to the chemical structural formula. If the compound name and the chemical structural formula representing the same compound do not match, the chemical structural formula shall prevail.

[0475] The structure of the compound 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 the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction (SXRD) is used to collect diffraction intensity data of the cultured single crystal using a Bruker D8 venture diffractometer, the light source is CuKα radiation, and the scanning mode is: After scanning and collecting relevant data, the crystal structure is further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0476] The solvent used in the present invention is commercially available.

[0477] Compounds are named according to the conventional nomenclature in the art or using The software names were used, and commercially available compounds were named using the supplier's catalog names.

[0478] Beneficial Effects

[0479] As novel Cbl-B inhibitors, the compounds of the present invention have excellent inhibitory activity against Cbl-B and can be used to prevent and / or treat Cbl-B-mediated diseases or conditions. In particular, the compounds of the present invention have improved pharmacokinetic properties (e.g., improved bioavailability, improved metabolic stability, suitable half-life and duration of action). The compounds of the present invention may also have improved safety (lower toxicity (e.g., reduced cardiac toxicity) and / or fewer side effects), less prone to drug resistance, and other more excellent properties. DETAILED DESCRIPTION

[0480] The present invention is described in detail below by way of examples, but it is not intended to impose any adverse limitations on the present invention. The present invention has been described in detail herein, and specific embodiments thereof are also disclosed therein. It will be apparent to those skilled in the art that various changes and modifications may be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0481] Example

[0482] Intermediate int1:

[0483]

[0484] (1) Int1-1 (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) were dissolved in tetrahydrofuran (200 mL), replaced with nitrogen three times, and then heated to 80°C for 8 hours. The reaction solution was filtered with acetone, the filter cake was washed with acetone again, the filtrate was collected, and concentrated to obtain compound int1 (7.3 g). LC-MS: 162.2 [M-KF+H] + .

[0485] Intermediate int2

[0486]

[0487] (1) Int2-1 (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 completed, the mixture was extracted with ethyl acetate, and the organic phase was washed three times with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation. The crude product was purified by silica gel column to obtain compound Int-2-2 (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).

[0488] (2) Dissolve int2-2 (32 g, 113.46 mmol) and hydrazine hydrate (115.2 mL) in ethanol (410 mL) and stir at 80 °C for 18 hours under nitrogen protection. After the reaction is complete, concentrate directly to obtain compound int2-3 (32 g). LC-MS: 283.0 [M+H] + .

[0489] (3) Int2-3 (32 g, 113.46 mmol) was dissolved in tetrahydrofuran (832 mL), methyl isothiocyanate (24.85 g, 340.38 mmol) was added, and then stirred at 80°C for 2 hours. After the reaction was completed, the reaction solution was concentrated, slurried with ethyl acetate, filtered, and the filtrate was concentrated to obtain int2-4 (28 g) LC-MS: 356.0 [M+H] + .

[0490] (4) Dissolve int2-4 (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. Add ethyl acetate to dissolve, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, and filter. Concentrate the filtrate to obtain int2-5 (15 g, 79%) LC-MS: 338.0 [M+H] + .

[0491] (5) Int2-5 (15 g, 44.5 mmol) and acetic acid (60 mL) were dissolved in dichloromethane (300 mL), and then 30% hydrogen peroxide solution (8 mL) was added and stirred at 25°C for 16 hours. After the reaction, the reaction solution was poured into water, and the pH value was adjusted to 10 with 2M sodium hydroxide solution. The mixture was extracted with dichloromethane, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column and reverse phase separation to obtain int2 (4 g). LC-MS: 306.0 [M+H] + .

[0492] Intermediate int3

[0493] (1) Compound int2 (300 mg, 0.98 mmol), potassium acetate (192 mg, 1.96 mmol), and biboronic acid pinacol ester (498 mg, 1.96 mmol) were dissolved in 1,4-dioxane (15 mL), and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (90 mg, 0.098 mmol) was added. The mixture was protected by nitrogen and heated to 100°C for 5 hours. Subsequently, water was added to dilute the mixture, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried, and concentrated to obtain int3-1. LC-MS: 354.2 [M+H] + .

[0494] (2) Dissolve int3-1 (300 mg, 0.847 mmol) and sodium periodate (906 mg, 4.236 mmol) in tetrahydrofuran / water (15 mL / 3 mL) and stir at 25°C for 16 hours. The reaction solution was filtered and concentrated to obtain a crude product. The crude product was separated by reverse phase to obtain compound int3 (140 mg). LC-MS: 272.1 [M+H] + .

[0495] Intermediate int4

[0496]

[0497] (1) Dissolve int4-1 (5 g, 23.36 mmol) in N,N-dimethylformamide (50 ml), add 4-methylthiosemicarbazide 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'-tetramethyluronium 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 over anhydrous sodium sulfate, spin dry, and purify the crude product by silica gel column chromatography to obtain int4-2 (7.0 g). LC-MS: 302.0 [M+H] + .

[0498] (2) Dissolve int4-2 (7.0 g, 23.25 mmol) in tetrahydrofuran (50 mL), add 2N sodium hydroxide (20 mL), react at room temperature for 1 hour under nitrogen protection, and adjust the pH of the reaction solution to weak acidity with 1N hydrochloric acid aqueous solution. Extract with ethyl acetate three times, concentrate and dry to obtain int4-3 (5.0 g). LC-MS: 284.0 [M+H] + .

[0499] (3) Dissolve int4-3 (5.0 g, 17.67 mmol) in dichloromethane (50 mL), add hydrogen peroxide (10 mL) at 0°C, add 3 drops of acetic acid, and 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, extract the aqueous phase with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate. The crude product is purified by silica gel column to obtain int4-4 (2.2 g). LC-MS: 252.0 [M+H] + .

[0500] (4) Dissolve int4-4 (2.2 g, 8.76 mmol) in N,N-dimethylformamide (25 mL), add sodium hydrogen sulfide (770 mg, 19.27 mmol) at 0°C, react at 0°C for 0.5 hours under nitrogen protection, add 1,3-dibromo-2,2-dimethylpropane (1.99 g, 8.76 mmol), and continue to react at 0°C for 2 hours. Pour the reaction solution into water, extract the aqueous phase with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate. The crude product is purified by silica gel column to obtain int4-5 (500 mg). LC-MS: 320.0 [M+H] + .

[0501] (5) Int4-5 (120 mg, 0.374 mmol) and bis(boron pinacol) ester (190 mg, 0.749 mmol) were dissolved in 1,4-dioxane (5 mL), potassium acetate (73 mg, 0.749 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (30 mg, 0.037 mmol) were added, nitrogen was replaced, and the mixture was reacted at 100°C for 16 hours. The reaction solution was poured into water to quench, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and dried to obtain int4-6 (120 mg). LC-MS: 368.2 [M+H] + .

[0502] (6) Int4-6 (120 mg, 0.327 mmol) was dissolved in 6N concentrated hydrochloric acid (10 mL) and reacted at 25°C for 16 hours. The reaction solution was spin-dried and the crude product was purified by reverse phase column chromatography to obtain compound int4 (80 mg). LC-MS: 286.2 [M+H] + .

[0503] Intermediate int5

[0504]

[0505] (1) Int4-1 (10 g, 46.5 mmol) was dissolved in tetrahydrofuran (100 mL), isopropylmagnesium chloride (2.0 M tetrahydrofuran, 50.1 ml, 102.3 mmol) was added, and the mixture was stirred at 20°C for 1 hour, and then 2-(chloromethyl)oxirane (7.3 ml, 93.0 mmol) was added. The resulting mixture was stirred at 0°C for 1.5 hours, and another portion of isopropylmagnesium chloride (2.0 M tetrahydrofuran, 50.1 ml, 102.3 mmol) was added. The mixture was stirred at 20°C for another 16 hours. Aqueous hydrochloric acid solution (1.0 M) was added to adjust the pH to 4. The solution was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography to give int5-1 (3 g). LC-MS: 293.0 [M+H] + .

[0506] (2) Dissolve int5-1 (3 g, 11 mmol) in DMF (50 ml), add N-methylhydrazine methylsulfamide hydrochloride (1.4 g, 13.2 mmol) and N,N-dimethylformamide (4.3 g, 33 mmol). Cool to 5°C with an ice-water bath, add (7-azobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (4.2 g, 11 mmol), and stir at room temperature for 2 hours under nitrogen protection. Concentrate the reaction solution, purify the residue by reverse phase column chromatography, and lyophilize to obtain compound int5-2 (3.2 g). LC-MS: 358.0 [M+H] + .

[0507] (3) Dissolve int5-2 (3.2 g, 9 mmol) in tetrahydrofuran (20 mL), add 2N sodium hydroxide solution (20 mL), react at room temperature for 1 hour under nitrogen protection, adjust the pH of the reaction solution to weak acidity with 1N hydrochloric acid aqueous solution, extract three times with ethyl acetate, and concentrate and dry to obtain int5-3 (2.8 g). LC-MS: 342.0 [M+H] + .

[0508] (4) Dissolve int5-3 (2.8 g, 8.3 mmol) in DCM (40 mL), add hydrogen peroxide (10 mL) at 0°C, add 3 drops of acetic acid, and 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 liquids, extract the aqueous phase with dichloromethane, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate. The crude product is purified by reverse phase column chromatography and freeze-dried to obtain int5-4 (2 g). LC-MS: 308.0 [M+H] + .

[0509] (5) Dissolve int5-4 (1 g, 3.26 mmol) and p-toluenesulfonyl chloride (621 mg, 3.26 mmol) in dichloromethane (20 mL), add triethylamine (988 mg, 9.78 mmol), and stir at 25°C for 4 hours. The reaction solution was diluted with dichloromethane and washed twice with water. The organic phase after separation was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The residue was purified by silica gel column chromatography to obtain the product int5-5 (950 mg). LC-MS: 462.0 [M+H] + .

[0510] (6) Int5-5 (950 mg, 2.06 mmol) and sodium cyanide (202 mg, 4.12 mmol) were dissolved in N,N-dimethylformamide (15 mL), cesium carbonate (1.34 g, 4.12 mmol) was added, and the mixture was stirred at 105°C for 24 hours. The reaction solution was diluted with ethyl acetate and washed with water twice. The organic phase after separation was washed with saturated brine twice, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The residue was purified by silica gel column chromatography to obtain the product int5 (300 mg). LC-MS: 317.0 [M+H] + .

[0511] Intermediate int6

[0512]

[0513] (1) Int6-1 (4.0 g, 17.391 mmol) and 1,3-dibromo-2-methylpropane (4.5 g, 20.833 mmol) were dissolved in N,N-dimethylformamide (70 ml). Sodium hydride (2.8 g, 70.0 mmol) was added in batches at 0°C and reacted at 25°C for 4 hours. The reaction solution was poured into a saturated aqueous ammonium chloride solution, extracted three times with ethyl acetate, the organic phases were combined and dried over sodium sulfate, and the organic phases were concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in 50 mL of methanol, 20 mL of an aqueous sodium hydroxide solution (2 mol / L) was added, the reaction solution was stirred for 2 hours, and then neutralized with 4 mol / L hydrochloric acid to a pH of about 6. Ethyl acetate was added and extracted three times, the organic phases were combined and dried over sodium sulfate, and the organic phases were concentrated under reduced pressure. The residue was purified by reverse phase column chromatography and freeze-dried to obtain int6-2 (3.0 g). LC-MS: 272.0 [M+H] + .

[0514] (2) Dissolve int6-2 (3.0 g, 11.029 mmol) in N,N-dimethylformamide (50 mL), and add 4-methylthiosemicarbazide (1.4 g, 13.333 mmol) and N,N-diisopropylethylamine (4.3 g, 33.333 mmol). Cool to 0°C with an ice-water bath, add 2-(7-azobenzotriazole)-N,N,N,N'-tetramethyluronium hexafluorophosphate (4.2 g, 11.05 mmol), and stir at room temperature for 2 hours under nitrogen protection. Concentrate the reaction solution, purify the residue by reverse phase column chromatography, and lyophilize to obtain int6-3 (3.2 g). LC-MS: 357.0 [M+H] + .

[0515] (3) Dissolve int6-3 (3.2 g, 8.913 mmol) in tetrahydrofuran (10 mL), add 2N sodium hydroxide aqueous solution (10 mL), react at 25°C for 1 hour under nitrogen protection, and adjust the pH of the reaction solution to weak acidity with 1N dilute hydrochloric acid. Extract with ethyl acetate three times, combine the organic phases, dry with sodium sulfate, and filter and concentrate the organic phase to obtain int6-4 (2.8 g). LC-MS: 341.0 [M+H] + .

[0516] (4) Dissolve int6-4 (2.8 g, 8.211 mmol) in dichloromethane (40 ml), add hydrogen peroxide (10 mL) at 0°C, add 3 drops of acetic acid, react at 25°C for 3 hours under nitrogen protection, pour the reaction solution into water, adjust the pH to about 10 with sodium hydroxide aqueous solution, extract with dichloromethane, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate. The crude product is purified by reverse phase column chromatography and freeze-dried to obtain int6 (2.0 g). LC-MS: 307.0 [M+H] + .

[0517] Example 1: Preparation of Compound 1

[0518]

[0519] Synthesis route:

[0520]

[0521] (1) 1-1 (10 g, 40.97 mmol) and 1,3,5-triazine (3.66 g, 45.067 mmol) were dissolved in dimethyl sulfoxide (100 mL) and reacted at 25°C for 0.5 hour. Potassium tert-butoxide (5.52 g, 49.164 mmol) was added, heated to 80°C, and reacted for 2 hours. After completion, the reaction solution was filtered and concentrated to obtain compound 1-2 (7.3 g). 1H NMR (400MHz, DMSO-d6) δ11.74(s,1H),9.01(d,J=2.4Hz,1H),8.60(d,J=2.4Hz,1H),7.50(d,J=3.4Hz,1H),6.63(d,J=7.4Hz,1H).

[0522] (2) Compound 1-2 (6.3 g, 28 mmol) and N-iodosuccinimide (12.6 g, 56 mmol) were dissolved in a mixed solution of trifluoroacetic acid (70 mL) and concentrated sulfuric acid (549.3 mg, 5.6 mmol), heated to 70°C, and reacted for 16 hours. The reaction solution was concentrated and filtered with water to obtain compound 1-3 (6.5 g). 1 H NMR (400MHz, DMSO-d6) δ11.96(s,1H),9.09(d,J=2.4Hz,1H),8.58(d,J=2.4Hz,1H),7.94(d,J=5.8Hz,1H).

[0523] (3) 1-3 (6.5 g, 16.97 mmol) was dissolved in N,N-dimethylformamide (70 mL), cesium carbonate (11.06 g, 33.94 mmol) and benzyl bromide (5.23 g, 30.546 mmol) were added, and the mixture was heated to 90°C and reacted for 3 hours. The reaction solution was then filtered, and the filter cake was washed with petroleum ether and dried to obtain compound 1-4 (6.3 g). 1 H NMR (400MHz, DMSO-d6) δ9.10(d,J=2.4Hz,1H),8.64(d,J=2.4Hz,1H),8.47(s,1H),7.37–7.28(m,5H),5.21(s,2H).

[0524] (4) 1-4 (6.3 g, 14.3 mmol), methyl fluorosulfonyl difluoroacetate (27.5 g, 143 mmol) and cuprous iodide (27.3 g, 143 mmol) were dissolved in N,N-dimethylformamide (70 mL), tris(dibenzylideneacetone)dipalladium (1.31 g, 1.43 mmol) was added, nitrogen was replaced, and the mixture was heated to 100°C for 2 hours. The reaction solution was filtered, water was added, and the mixture was extracted three times with ethyl acetate. The organic phase was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain compound 1-5 (5 g). 1 H NMR (400MHz, CDCl3) δ9.03 (d, J = 2.4Hz, 1H), 8.85 (d, J = 2.4Hz, 1H), 7.80 (s, 1H), 7.39–7.32 (m, 5H), 5.23 (s, 2H).

[0525] (5) 1-5 (5 g, 13.1 mmol), int1 (3.45 g, 15.72 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (624.5 mg, 1.31 mmol), potassium carbonate (5.43 g, 39.3 mmol) were dissolved in a mixture of 1,4-dioxane and water (100 mL, 4:1), followed by the addition of chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (1.03 g, 1.31 mmol) and replacement of nitrogen. The reaction mixture was reacted at 100°C for 4 hours. After the reaction was completed, the mixture was filtered, water was added, and the mixture was extracted three times with ethyl acetate. The organic phase was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain compound 1-6 (4.1 g).

[0526] 1 H NMR(400MHz, CDCl3)δ8.94(d,J=2.0Hz,1H),8.56(s,1H),7.70(s,1H),7.32–7.25(m,5H),5.17(s,2H) ,3.57(s,2H),2.68(d,J=7.2Hz,2H),1.91(d,J=13.8Hz,1H),1.68–1.59(m,5H),0.77(t,J=7.0Hz,4H).

[0527] (6) 1-6 (2.7 g, 6.5 mmol) was dissolved in a mixed solution of tetrahydrofuran and ethyl acetate (70 mL, 1:1), palladium carbon (1.35 g) was added, and the mixture was reacted at 25° C. for 16 hours. The reaction solution was filtered and purified by reverse phase separation to obtain compound 1-7 (70 mg). 1 H NMR (400MHz, CDCl3) δ10.58(s,1H),9.09(d,J=2.0Hz,1H),8.67(s,1H),7.80(s,1H),3.83(s,2 H),3.01(dd,J=31.2,8.6Hz,2H),2.16–2.09(m,1H),1.86–1.70(m,5H),0.89(d,J=5.6Hz,4H).

[0528] (7) 1-7 (40 mg, 0.123 mmol), int-3 (66.7 mg, 0.246 mmol), N,N-diisopropylethylamine (64 mg, 0.492 mmol), pyridine (39 mg, 0.492 mmol) were dissolved in dichloromethane (10 mL), anhydrous copper acetate (6 mg, 0.03075 mmol) was added, oxygen was replaced, and the mixture was reacted at 25°C for 16 hours. After the reaction was completed, the mixture was filtered, water was added, and the mixture was extracted three times with ethyl acetate. The organic phase was concentrated to obtain a crude product. The crude product was separated by preparative liquid phase to obtain compound 1 (12.07 mg).

[0529] Example 2: Preparation of Compound 3

[0530]

[0531] Synthesis route:

[0532]

[0533] (1) Compound 3-1 (5.0 g, 22.3 mmol) was dissolved in trifluoroacetic acid (50 mL), and N-iodosuccinimide (10 g, 44.6 mmol) and concentrated sulfuric acid (440 mg, 4.46 mmol) were added. Under nitrogen protection, the temperature was raised to 70°C for 16 hours. Ice water was added to the reaction solution, and it was extracted three times with ethyl acetate. The organic phases were combined and dried, and the residue was purified by silica gel column chromatography to obtain compound 3-2 (3 g). 1 H NMR (400MHz, DMSO-d6) δ11.79(s,1H),7.83(s,1H),7.55(s,1H).

[0534] (2) 3-2 (3.0 g, 8.43 mmol) was dissolved in 1,4-dioxane (30 mL), and silver carbonate (2.83 g, 16.86 mmol) and benzyl bromide (1.73 g, 10.12 mmol) were added. The temperature was raised to 100°C under nitrogen protection and the reaction was continued for 1 hour. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate three times. The organic phases were combined, dried and filtered, and the filtrate was dried by rotary evaporation. The residue was purified by silica gel column chromatography to obtain 3-3 (2.0 g). 1 H NMR (400MHz, CDCl3) δ8.16 (s, 1H), 7.73 (s, 1H), 7.48 (d, J = 7.1Hz, 2H), 7.42–7.35 (m, 3H).

[0535] (3) 3-3 (1.7 g, 3.81 mmol), cuprous iodide (885 mg, 4.61 mmol) and 2,2-difluoro-2-(fluorosulfonyl)acetic acid trifluoromethyl ester (2.81 g, 11.43 mmol) were placed in N,N-dimethylformamide (20 mL). Under nitrogen protection, the reaction was carried out at 100°C for 2 hours. The reaction solution was cooled to room temperature, water was added, and extracted with ethyl acetate three times. The organic phases were combined, dried and filtered, and the filtrate was spin-dried. The residue was purified by silica gel column chromatography to obtain 3-4 (500 mg). LC-MS: 387.7, 389.7 [M+H] + .

[0536] (4) 3-4 (480 mg, 1.24 mmol), int-1 (326 mg, 1.48 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (60 mg, 0.124 mmol), potassium carbonate (378 mg, 3.72 mmol) were dissolved in 1,4-dioxane / water (8 mL / 2 mL), and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium (98 mg, 0.124 mmol) was added. The reaction solution was replaced with nitrogen three times and reacted at 100° C. for 4 hours. The reaction solution was cooled to room temperature, water was added, and extracted with ethyl acetate three times. The organic phases were combined, dried and filtered, the filtrate was spin-dried, and the residue was purified by silica gel column chromatography to obtain 3-5 (160 mg). LC-MS:421.1[M+H] + .

[0537] (5) 3-5 (160 mg, 0.38 mmol) was dissolved in methanol (10 mL), palladium carbon (16 mg) was added, and the reaction solution was reacted at 25°C for 12 hours under a hydrogen atmosphere. The reaction solution was filtered through diatomaceous earth, and the filtrate was dried to obtain 3-6 (120 mg). LC-MS: 329.1 [M+H] + .

[0538] (6) 3-6 (50 mg, 0.152 mmol), int3 (80 mg, 0.3 mmol), copper acetate (7.5 mg, 0.038 mmol), pyridine (47.5 mg, 0.6 mmol) and N,N-diisopropylethylamine (77.5 mg, 0.6 mmol) were dissolved in dichloromethane (10 mL), replaced with oxygen three times, and reacted for 16 hours. Water was added, extracted with ethyl acetate three times, the organic phases were combined, dried and filtered, the filtrate was spin-dried, and the residue was purified by silica gel column chromatography to obtain 3 (4 mg).

[0539] Example 3: Preparation of Compound 4

[0540]

[0541] Synthesis route:

[0542]

[0543] (1) 4-1 (1 g, 4.4 mmol) was dissolved in tetrahydrofuran (15 mL), and n-butyl lithium (6.05 mL, 9.68 mmol) was added dropwise at -78 °C under a nitrogen atmosphere. After the addition was complete, the reaction was continued for 2 hours. Subsequently, anhydrous N,N-dimethylformamide (2 mL) was added dropwise. After the addition was complete, the temperature was naturally raised to room temperature and stirring was continued for 16 hours. After the reaction was completed, saturated ammonium chloride was used to quench the reaction and the mixture was extracted with ethyl acetate. The organic phases were combined, dried, filtered, and the filtrate was spin-dried. The residue was subjected to silica gel column chromatography to obtain compound 4-2 (400 mg).

[0544] 1 H NMR (400MHz, DMSO-d6) δ11.73(s,1H),10.01(s,1H),8.40(d,J=0.6Hz,1H),7.47(dd,J=6.4,5.8Hz,1H),6.94(d,J=7.0Hz,1H).

[0545] (2) 4-2 (300 mg, 1.7 mmol) and (S)-3-methylpiperidine (253 mg, 2.55 mmol) were dissolved in 1,2-dichloroethane (20 mL) and stirred at 0°C for 1 hour under a nitrogen atmosphere. Sodium triacetylborohydride (1.08 g, 5.1 mmol) was added and the reaction was continued at 25°C for 16 hours. The reaction solution was concentrated and the residue was purified by silica gel column chromatography to obtain compound 4-3 (286 mg).

[0546] 1 H NMR (400MHz, CDCl3) δ11.12(s,1H),7.43(s,1H),7.14(d,J=7.0Hz,1H),6.75(d,J=7.0Hz,1H),3.77(s,2 H),2.87(dd,J=19.8,9.0Hz,2H),2.01(dd,J=12.8,9.0Hz,1H),1.72–1.62(m,6H),0.85(d,J=5.8Hz,3H).

[0547] (3) 4-3 (100 mg, 0.37 mmol), int3 (49 mg, 0.185 mmol), N,N-diisopropylethylamine (96 mg, 0.74 mmol), and pyridine (59 mg, 0.74 mmol) were dissolved in dichloromethane (10 mL) at 25°C, and then acetic acid (8.4 mg, 0.04625 mmol) was added. The gas was replaced three times under an oxygen atmosphere, and the reaction was stirred for 16 hours under an oxygen atmosphere. The reactants were filtered, water was added, and extracted with dichloromethane. The organic phases were combined and dried by rotation, and the residue was purified by preparative liquid chromatography (chromatographic column: Sunfire C1819*250 mm, 10 μm; mobile phase A: 0.1% formic acid / water B: acetonitrile; flow rate: 20 mL / min; gradient: 16-25%) to obtain compound 4 (11.43 mg).

[0548] Example 4: Preparation of Compound 5

[0549]

[0550] Synthesis route:

[0551]

[0552] (1) At 25°C, 5-1 (4 g, 16.4 mmol) and s-triazine (1.462 g, 18.04 mmol) were dissolved in dimethyl sulfoxide (40 mL) and stirred for half an hour. Potassium tert-butoxide (2.21 g, 19.68 mmol) was added to the above solution and the temperature was raised to 80°C and stirred for 2 hours. Water was added and extracted with ethyl acetate. The organic phases were combined and dried, and the residue was purified by silica gel column chromatography to obtain compound 5-2 (3.5 g). 1 HNMR (400MHz, DMSO-d6) δ11.73(s,1H),9.01(d,J=2.4Hz,1H),8.60(d,J=2.0Hz,1H),7.50(d,J=6.8Hz,1H),6.63(d,J=7.4Hz,1H).

[0553] (2) At 25°C, 5-2 (2 g, 8.9 mmol), int1 (2.4 g, 10.68 mmol), X-Phos (424.3 mg, 0.89 mmol), potassium carbonate (3.69 g, 26.7 mmol) were placed in dioxane / water (100 mL, 4:1), Xphos-Pd-G2 (700 mg, 0.89 mmol) was added, and the gas was replaced three times under nitrogen atmosphere. The reaction solution was heated to 100°C and stirred for 4 hours. The reaction solution was cooled to room temperature, water was added and extracted with ethyl acetate, the organic phases were combined and dried, and the residue was purified by silica gel column chromatography to obtain compound 5-3 (1.9 g). 1H NMR (400MHz, CDCl3) δ10.47(s,1H),8.88(dd,J=9.2,2.0Hz,1H),8.49(d,J=1.6Hz,1H),7.26(d,J=7.0Hz,1H),6.76(d,J=7.4Hz,1H),3.54(d,J=1 4.2Hz,2H),2.71(dd,J=19.4,9.2Hz,2H),1.88(td,J=11.2,3.4Hz,1H),1.64(s,1H),1.53(dd,J=21.8,10.0Hz,4H),0.78(dd,J=13.6,6.6Hz,4H).

[0554] (3) 5-3 (50 mg, 0.195 mmol), int3 (105.8 mg, 0.39 mmol), N,N-diisopropylethylamine (101 mg, 0.78 mmol), pyridine (62 mg, 0.78 mmol) were dissolved in dichloromethane (10 mL) at 25°C, and copper acetate (9 mg, 0.04875 mmol) was added. The gas was replaced three times under an oxygen atmosphere. The reaction was continued under an oxygen atmosphere at room temperature with stirring for 16 hours. Water was added and the mixture was extracted with ethyl acetate. The organic phases were combined and dried by spin drying, and the residue was purified by preparative liquid separation (Waters 2767 / Qda, column: Pursuit XRs C18 21.2*250mm, 10μm; mobile phase A: 0.1% formic acid / water B: acetonitrile; flow rate: 20mL / min; gradient: 17-24%; Retention Time: 7.7–9.4min of 16min) to obtain compound 5 (4.32mg).

[0555] Example 5: Preparation of Compound 6

[0556]

[0557] Synthesis route:

[0558]

[0559] (1) 6-1 (10 g, 48.98 mmol) was dissolved in 60 mL of N,N-dimethylformamide, and iodomethane (4.52 ml) and potassium carbonate (20 g, 144.71 mmol) were added at 0°C. The mixture was reacted at 25°C for 18 hours under nitrogen protection. Saturated brine was added to the reaction solution and extracted with ethyl acetate. The organic phases were combined and dried, and the residue was purified by silica gel column chromatography to obtain compound 6-2 (9 g). 1HNMR (400MHz, DMSO-d6) δ7.96 (d, J = 7.8Hz, 1H), 7.90 (d, J = 7.8Hz, 1H), 7.53 (t, J = 7.8Hz, 1H), 3.88 (s, 3H), 2.53 (d, J = 7.9Hz, 3H).

[0560] (2) 6-2 (9 g, 41.25 mmol) was dissolved in 3 mL of acetic acid, and nitric acid (40.68 mL), silver nitrate (9.09 g), and liquid bromine (1.8 mL) were added at 0°C. The mixture was reacted at 25°C for 18 hours under nitrogen protection. Ice water was added to the reaction solution, and the mixture was neutralized with saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, the organic phases were combined and dried, and the residue was purified by silica gel column chromatography to obtain product 6-3 (5 g). 1 HNMR (400MHz, DMSO-d6) δ8.13 (s, 1H), 8.05 (d, J = 1.6Hz, 1H), 3.88 (s, 3H), 2.48 (s, 3H).

[0561] (3) Compound 6-3 (5 g, 16.83 mmol) was dissolved in 18.5 mL of N,N-dimethylformamide solution, and N,N-dimethylformamide dimethyl acetal (6.5 mL) was slowly added dropwise at 0°C. Under nitrogen protection, the reaction was carried out at 110°C for 8 hours. The reaction was cooled to 25°C, saturated brine was added to the reaction solution and extracted with ethyl acetate, the organic phases were combined and dried, and the residue was subjected to silica gel column chromatography to obtain 6-4 (896 mg). 1 HNMR (400MHz, DMSO-d6) δ8.53 (s, 1H), 8.41 (s, 1H), 7.77 (d, J = 6.0 Hz, 1H), 6.78 (d, J = 4.2 Hz, 1H).

[0562] (4) 6-4 (896 mg, 3.07 mmol) was dissolved in 9 mL of ammonia / methanol (7.0 M) solution and reacted at 60°C for 4 hours in a sealed tube. The reaction solution was spin-dried and the residue was purified by column chromatography to obtain compound 6-5 (180 mg). LC-MS: 291.8 [M+H] + .

[0563] (5) 6-5 (180 mg, 0.62 mmol) was dissolved in 1,4-dioxane solution (4 mL), and int1 (162 mg, 0.74 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (49 mg, 0.062 mmol) and XPhos (30 mg, 0.062 mmol) were added. Potassium carbonate (257 mg, 1.86 mmol) was then dissolved in water (1 mL) and added to the reaction solution. The gas was replaced three times under nitrogen atmosphere, and the temperature was raised to 100°C for reaction for 4 hours. Water was added to the reaction solution and extracted with ethyl acetate, dried and spun off. The residue was purified by silica gel column chromatography to obtain compound 6-6 (150 mg, 75%). LC-MS: 325.1 [M+H] + .

[0564] (6) 6-6 (100 mg, 0.279 mmol) was dissolved in N,N-dimethylformamide solution (4 mL), and then int2 (102 mg, 0.33 mmol), trans-N,N,N'-trimethyl-1,2-cyclohexanediamine (21 mg, 0.141 mmol), cuprous iodide (12 mg, 0.057 mmol) and potassium carbonate (78 mg, 0.558 mmol) were added, and the gas was replaced three times under nitrogen atmosphere. The reaction solution was stirred at 100°C for 2 hours. Water was added to the reaction solution, and extracted with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. The residue was purified by silica gel column chromatography to obtain compound 6-7 (90 mg).

[0565] Example 6: Preparation of Compound 7

[0566]

[0567] Synthesis route:

[0568]

[0569] (1) Compound 7-1 (9.5 g, 42.4 mmol) was dissolved in trifluoroacetic acid (100 mL), iodosuccinimide (19.1 g, 84.8 mmol) and concentrated sulfuric acid (832 mg, 8.48 mmol) were added, and the temperature was raised to 70°C under nitrogen protection for 16 hours. The reaction solution was cooled to room temperature, water was added, and extracted with ethyl acetate three times. The organic phases were combined, dried and filtered, the filtrate was spin-dried, and the residue was purified by silica gel column chromatography to obtain compound 7-2 (3 g). 1HNMR (400MHz, DMSO-d6) δ11.71(s,1H),8.25(t,J=13.7Hz,1H),7.98(dd,J=8.7,2.0Hz,1H),7.67(d,J=5.7Hz,1H),7.61(d,J=8.7Hz,1H).

[0570] (2) Compound 7-2 (3 g, 8.57 mmol) was dissolved in 1,4-dioxane (30 mL), and silver carbonate (5.54 g, 20.08 mmol) and benzyl bromide (2.74 g, 16.15 mmol) were added. The temperature was raised to 100°C under nitrogen protection and the reaction was continued for 1 hour. The reaction solution was cooled to room temperature, water was added, and extracted with ethyl acetate three times. The organic phases were combined, dried and filtered, and the filtrate was spin-dried. The residue was purified by silica gel column chromatography to obtain compound 7-3 (1.8 g). LC-MS: 439.5 [M+H] + .

[0571] (3) 7-3 (1.8 g, 4.07 mmol), cuprous iodide (955 mg, 4.95 mmol) and 2,2-difluoro-2-(fluorosulfonyl)acetic acid trifluoromethyl ester (2.35 g, 12.323 mmol) were dissolved in N,N-dimethylformamide (20 mL). Under nitrogen protection, the reaction was carried out at 100° C. for 2 hours. The reaction solution was cooled to room temperature, water was added, and it was extracted three times with ethyl acetate. The organic phases were combined, dried and filtered, and the filtrate was spin-dried. The residue was purified by silica gel column chromatography to obtain compound 7-4 (900 mg). 1 H NMR (400MHz, CDCl3) δ8.51(d,J=1.8Hz,1H),8.40(s,1H),7.94–7.82(m,2H),7.53(d,J=6.9Hz,2H),7.40(m,3H),5.62(s,2H).

[0572] (4) Compound 7-4 (900 mg, 2.36 mmol), potassium carbonate (977 mg, 7.08 mmol), int1 (620 mg, 2.83 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (112 mg, 0.236 mmol) were dissolved in 1,4-dioxane / water (10 mL / 2.5 mL), and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (186 mg, 0.236 mmol) was added to the above solution, and the gas was replaced three times under nitrogen. The reaction was stirred at 100°C under nitrogen for 4 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried and filtered, and the filtrate was spin-dried. The residue was purified by silica gel column chromatography to obtain compound 7-5 (200 mg). LC-MS: 325.1 [M+H] + .

[0573] (5) Compound 7-5 (240 mg, 0.74 mmol) was dissolved in N,N-dimethylformamide (4 mL), and 3-(1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (273 mg, 0.89 mmol), trans-N,N,N'-trimethyl-1,2-cyclohexanediamine (325 mg, 0.37 mmol), cuprous iodide (21 mg, 0.148 mmol) and potassium carbonate (211 mg, 1.11 mmol) were added, and the mixed reaction solution was reacted at 100°C for 2 hours. The reaction solution was cooled to room temperature, water was added, and extracted with ethyl acetate three times. The organic phases were combined, dried and filtered, and the filtrate was spin-dried. The residue was purified by silica gel column chromatography to obtain compound 7 (130 mg).

[0574] Example 7: Preparation of Compound 8

[0575]

[0576] Synthesis route:

[0577]

[0578] (1) Compound 2-7 (1.2 g, 3.015 mmol) was dissolved in 1,2-dichloroethane (10 mL), N-methylcyclobutylamine (510 mg, 6.0 mmol) was added, and the mixture was reacted at 25°C for half an hour. Sodium triacetoxyborohydride (763 mg, 3.6 mmol) was added, and the mixture was reacted at 25°C for 1 hour. The reaction solution was quenched by adding water, extracted three times with dichloromethane, the organic phases were combined, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain 8-1 (800 mg). LC-MS: 468.1 [M+H]+ .

[0579] (2) 8-1 (800.0 mg, 1.701 mmol) was dissolved in 1,4-dioxane (10 mL), and under nitrogen protection, hydrochloric acid / dioxane solution (5 mL) was added. After reacting at 50°C for 1 hour, the mixture was concentrated under reduced pressure to obtain 8-2 (750 mg). LC-MS: 454.0 [M+H] + .

[0580] (3) 8-2 (100.1 mg, 0.220 mmol), int3 (81.0 mg, 0.299 mmol), copper acetate (7.0 mg, 0.039 mmol), pyridine (63.0 mg, 0.797 mmol), N,N-diisopropylethylamine (103.1 mg, 0.798 mmol) were dissolved in dichloromethane (5 mL), reacted at 25 ° C for 16 hours under an oxygen atmosphere, added water, extracted with ethyl acetate three times, combined the organic phases, dried and concentrated to obtain a crude product 8-3 (120 mg), which was directly used in the next step. LC-MS: 679.2 [M+H] + .

[0581] (4) 8-3 (120.1 mg, 0.177 mmol) was dissolved in tetrahydrofuran / isopropanol (2 mL:2 mL), potassium tert-butoxide (2 mL, 1.0 M tetrahydrofuran solution) was added at 0°C, and the mixture was reacted at 25°C for 1 hour under nitrogen protection. Water and ethyl acetate were added for extraction three times, and the organic phases were combined, dried and concentrated to obtain a crude product. The crude product was purified by reverse phase preparative method to obtain compound 8 (2.1 mg).

[0582] Example 8: Preparation of Compound 9

[0583]

[0584] Synthesis route:

[0585]

[0586] (1) Compound 2-7 (500 mg, 1.26 mmol) was dissolved in tetrahydrofuran (10 mL), 1-methylcyclopropane-1-amine (134 mg, 1.88 mmol) and sodium cyanoborohydride (229 mg, 3.77 mmol) were added, and the nitrogen atmosphere was replaced, and the mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched with water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The residue was purified by silica gel column chromatography to obtain product 9-1 (240 mg). LC-MS: 454.0 [M+H] + .

[0587] (2) Compound 9-1 (220 mg, 0.485 mmol) was dissolved in dioxane (10 mL), 4.0 M hydrogen chloride / dioxane solution (5 mL) was added, and the mixture was stirred at 50° C. for 1 hour. The reaction solution was concentrated under reduced pressure to obtain compound 9-2 (200 mg). LC-MS: 440.0 [M+H] + .

[0588] (3) Compound 9-2 (180 mg, 0.409 mmol) and int3 (167 mg, 0.614 mmol) were dissolved in dichloromethane (5 mL), pyridine (130 mg, 1.64 mmol), N,N-diisopropylethylamine (212 mg, 1.64 mmol), and copper acetate (37 mg, 0.205 mmol) were added, and the oxygen was replaced, and stirred at 35°C for 16 hours. The reaction solution was diluted with dichloromethane and washed twice with water. The organic phase after separation was washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The residue was purified by silica gel column chromatography to obtain compound 9-3 (140 mg). LC-MS: 665.2 [M+H] + .

[0589] (4) Compound 9-3 (140 mg, 0.211 mmol) was dissolved in tetrahydrofuran (2 mL) and isopropanol (2 mL), and potassium tert-butoxide (0.632 mL, 1 M tetrahydrofuran, 0.632 mmol) was added and stirred at 30°C for 2 hours. The reaction solution was diluted with ethyl acetate and washed twice with water. The organic phase after separation was washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and dried by rotation. The residue was prepared by reverse phase to obtain compound 9 (12 mg).

[0590] Example 9: Preparation of Compound 10

[0591]

[0592] Synthesis route:

[0593]

[0594] (1) Compound 10-1 (1.0 g, 4.651 mmol) was dissolved in dichloromethane (15 mL) and Dess-Martin reagent (2.7 g, 6.368 mmol) was added at 0°C. After stirring at 0°C for 30 minutes, the temperature was raised to 25°C and the reaction was continued for 1.5 hours. The mixture was quenched with a 1.0 mol / L aqueous sodium thiosulfate solution, extracted with dichloromethane, and the organic phase was washed with a saturated aqueous sodium bicarbonate solution, dried with anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography to obtain compound 10-2 (0.4 g). LC-MS: 236.0 [M+H] + .

[0595] (2) 10-2 (0.4 g, 1.878 mmol) was dissolved in dichloromethane (10 mL), and diethylaminosulfur trifluoride (677 mg, 4.205 mmol) was added dropwise at -20°C. After the addition was completed, the mixture was heated to room temperature and stirred for 2 hours. At 0°C, the mixture was quenched with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 10-3 (150 mg,). LC-MS: 180.0 [M+H] + .

[0596] (3) 10-3 (150.0 mg, 0.636 mmol) was dissolved in a hydrochloric acid / 1,4-dioxane solution (2 mL, 4.0 M / dioxane), and reacted at 25°C for 1 hour under nitrogen protection. The reaction solution was concentrated under reduced pressure to obtain 10-4 (70.0 mg). The crude product was directly used in the next step. LC-MS: 136.2 [M+H] + .

[0597] (4) 10-4 (70.0 mg, 0.515 mmol) was dissolved in N,N-dimethylformamide (5 mL), 18-2 (315.0 mg, 0.50 mmol) and N,N-diisopropylethylamine (194 mg, 1.504 mmol) were added, and the mixture was reacted at 80°C for 1 hour under nitrogen protection. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added for extraction. The organic phase was concentrated and dried to obtain compound 10-5 (80.1 mg), which was directly used in the next step. LC-MS: 729.2 [M+H] + .

[0598] (5) 10-5 (80 mg, 0.11 mmol) was dissolved in tetrahydrofuran / isopropanol (2 mL / 2 mL) under nitrogen protection, and potassium tert-butoxide (2 mL) was added at 0°C. After reacting at 25°C for 1 hour, saturated brine was added, extracted with ethyl acetate, and the organic phases were combined, dried, and concentrated. The residue was subjected to reverse phase reaction to obtain compound 10 (10.0 mg).

[0599] Example 10: Preparation of Compound 11

[0600]

[0601] Synthesis route:

[0602]

[0603] (1) Compound 2-7 (430 mg, 1.08 mmol) was dissolved in 1,2-dichloroethane (10 mL), 4,4-difluoropiperidine hydrochloride (340 mg, 2.16 mmol) and sodium triacetylborohydride (687 mg, 3.24 mmol) were added, and the nitrogen atmosphere was replaced, and the mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched with water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The residue was purified by silica gel column chromatography to obtain compound 11-1 (220 mg). LC-MS: 504.2 [M+H] + .

[0604] (2) Dissolve 11-1 (220 mg, 0.405 mmol) in 1,4-dioxane (10 mL), and add a solution of hydrogen chloride in dioxane (5 mL). Stir at 50°C for 1 hour. Concentrate the reaction solution under reduced pressure to obtain the product compound 11-2 (200 mg, 93%). LC-MS: 490.2 [M+H] + .

[0605] (3) Compound 11-2 (200 mg, 0.409 mmol) and int3 (222 mg, 0.818 mmol) were dissolved in dichloromethane (5 mL), and pyridine (129 mg, 1.636 mmol), N,N-diisopropylethylamine (211 mg, 1.636 mmol), and copper acetate (74 mg, 0.409 mmol) were added to replace oxygen and stirred at 35°C for 16 hours. The reaction solution was diluted with dichloromethane and washed with water twice. The organic phase after separation was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The residue was purified by silica gel column chromatography to obtain compound 11-3 (100 mg). LC-MS: 715.2 [M+H] + .

[0606] (4) Compound 11-3 (100 mg, 0.14 mmol) was dissolved in tetrahydrofuran (2 mL) and isopropanol (2 mL), and potassium tert-butoxide (0.420 mL, 1 M tetrahydrofuran, 0.420 mmol) was added and stirred at 30°C for 2 hours. The reaction solution was diluted with ethyl acetate and washed twice with water. The organic phase after separation was washed twice with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and dried by rotation. The residue was subjected to reverse phase preparation to obtain compound 11 (12.47 mg).

[0607] Example 11: Preparation of Compound 12

[0608]

[0609] Synthesis route:

[0610]

[0611] (1) Compound 2-7 (500 mg, 1.26 mmol) was dissolved in tetrahydrofuran (10 mL), (3S, 5R)-3,5-dimethylpiperidine (284 mg, 2.51 mmol) and sodium cyanoborohydride (237 mg, 3.77 mmol) were added, and the nitrogen atmosphere was replaced, and the mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched with water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The residue was purified by silica gel column chromatography to obtain compound 12-1 (280 mg, 45%). LC-MS: 496.0 [M+H] + .

[0612] (2) Compound 12-1 (260 mg, 0.525 mmol) was dissolved in dioxane (10 mL) and hydrogen chloride / dioxane (5 mL). Stirred at 50°C for 1 hour. The reaction solution was concentrated in vacuo to obtain compound 12-2 (220 mg). LC-MS: 482.0 [M+H] + .

[0613] (3) Compound 12-2 (200 mg, 0.470 mmol) and int3 (201 mg, 0.705 mmol) were dissolved in dichloromethane (5 mL), and pyridine (149 mg, 1.88 mmol), N,N-diisopropylethylamine (243 mg, 1.88 mmol), and copper acetate (21 mg, 0.117 mmol) were added to replace oxygen and stirred at 35°C for 16 hours. The reaction solution was diluted with dichloromethane and washed with water twice. The organic phase after separation was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. Compound 12-3 (160 mg) was obtained by column chromatography purification. LC-MS: 708.2 [M+H] + .

[0614] (4) Compound 12-3 (140 mg, 0.198 mmol) was dissolved in tetrahydrofuran (2 mL) and isopropanol (2 mL), and potassium tert-butoxide (0.594 mL, 1 M tetrahydrofuran, 0.594 mmol) was added and stirred at 30°C for 2 hours. The reaction solution was diluted with ethyl acetate and washed twice with water. The organic phase after separation was washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and dried by rotation. The residue was subjected to reverse phase preparation to obtain compound 12 (12 mg).

[0615] Example 12: Preparation of Compounds 13A and 13B

[0616]

[0617] Synthesis route:

[0618]

[0619] (1) Dissolve 2-7 (1.4 g, 3.51 mmol) in 1,4-dioxane (20.0 mL), add a solution of hydrogen chloride in 1,4-dioxane (40.0 mmol, 10 mL), and stir at 50°C for 1 hour. Concentrate the reaction solution under reduced pressure to obtain the product 13-1 (1.3 g). LC-MS: 385.0 [M+H] + .

[0620] (2) 13-1 (390.0 mg, 1.01 mmol) and int3 (300.1 mg, 1.11 mmol) were dissolved in dichloromethane (10 mL), and pyridine (320.0 mg, 4.04 mmol), N,N-diisopropylethylamine (521.1 mg, 4.04 mmol), and copper acetate (192.0 mg, 1.01 mmol) were added to replace oxygen and stirred at 35°C for 16 hours. The reaction solution was diluted with dichloromethane and washed twice with water. The organic phase after separation was washed twice with 30 mL of saturated saline solution, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product 13-2 (500.1 mg) which was directly used in the next step. LC-MS: 610.2 [M+H] + .

[0621] (3) Compound 13-2 (120 mg, 0.197 mmol) was dissolved in methanol (10 mL), (3R)-4-difluoro-3-methyl-piperidine hydrochloride (53 mg, 0.394 mmol) and sodium cyanoborohydride (37 mg, 0.591 mmol) were added, and the nitrogen atmosphere was replaced and stirred at 25°C for 2 hours. The reaction mixture was quenched with water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The residue was purified by silica gel column chromatography to obtain compound 13-1 (30 mg). LC-MS: 729.2 [M+H] + .

[0622] (4) Compound 13-1 (30 mg, 0.04 mmol) was dissolved in tetrahydrofuran (2 mL) and isopropanol (2 mL), and potassium tert-butoxide solution (0.120 mL, 1 M tetrahydrofuran, 0.120 mmol) was added and stirred at 30°C for 2 hours. The reaction solution was diluted with ethyl acetate and washed twice with water. The organic phase after separation was washed twice with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation. The residue was prepared by reverse phase to obtain 13A (3.21 mg) and 13B (1.0 mg).

[0623] Example 13: Preparation of Compound 14

[0624]

[0625] Synthesis route:

[0626]

[0627] (1) Compound 2-9 (50 mg, 0.106 mmol) and int4 (46 mg, 0.16 mmol) were dissolved in dichloromethane (5 mL), pyridine (34 mg, 0.428 mmol), N,N-diisopropylethylamine (57 mg, 0.428 mmol), and copper acetate (5 mg, 0.027 mmol) were added, and the oxygen was replaced, and stirred at 35°C for 16 hours. The reaction solution was diluted with dichloromethane and washed twice with water. The organic phase after separation was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried to obtain compound 14-1 (50 mg). LC-MS: 707.2 [M+H] + .

[0628] (2) Compound 14-1 (50 mg, 0.07 mmol) was dissolved in tetrahydrofuran (2 mL) and isopropanol (2 mL), and potassium tert-butoxide (0.212 mL, 1 M tetrahydrofuran, 0.212 mmol) was added and stirred at 30°C for 2 hours. The reaction solution was diluted with ethyl acetate and washed twice with water. The organic phase after separation was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation. The residue was subjected to reverse phase preparation to obtain 14 (12 mg).

[0629] Example 14: Preparation of Compound 15

[0630]

[0631] Synthesis route:

[0632]

[0633] (1) Int5 (200 mg, 0.63 mmol), compound 2-9 (294 mg, 0.63 mmol), cuprous iodide (12 mg, 0.063 mmol), trans-N,N,N'-trimethyl-1,2-cyclohexanediamine (10 mg, 0.063 mmol) and potassium carbonate (260 mg, 1.89 mmol) were dissolved in N,N-dimethylformamide (5 mL) and stirred at 110°C for 2 hours under nitrogen protection. The reaction solution was diluted with ethyl acetate and washed twice with water. The organic phase after separation was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried. The residue was purified by reverse phase column chromatography to obtain compound 15-1 (87 mg). LC-MS: 704.2 [M+H] + .

[0634] (2) Compound 15-1 (87 mg, 0.12 mmol) was dissolved in tetrahydrofuran (2 mL) and isopropanol (2 mL), and potassium tert-butoxide (0.212 mL, 1 M in tetrahydrofuran, 0.212 mmol) was added and stirred at 25°C for 1 hour. The reaction solution was diluted with ethyl acetate and washed twice with water. The organic phase after separation was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation. The residue was subjected to reverse phase preparation to obtain compound 15 (4 mg).

[0635] Example 15: Preparation of Compounds 16A and 16B

[0636]

[0637] Synthesis route:

[0638]

[0639] (1) Int6 (100 mg, 0.324 mmol), compound 2-9 (187 mg, 0.40 mmol), cuprous iodide (11 mg, 0.06 mmol), trans-N,N,N'-trimethyl-1,2-cyclohexanediamine (21 mg, 0.15 mmol), cesium carbonate (293 mg, 0.902 mmol) were dissolved in N,N-dimethylformamide (6 ml), reacted at 120°C for 2 hours under nitrogen protection, extracted three times with saturated brine and ethyl acetate, the organic phase was dried with sulfuric acid, and concentrated under reduced pressure to obtain the crude compound 16-1 (120 mg), which was directly used in the next step. LC-MS: 694.2 [M+H] + .

[0640] (2) Under nitrogen protection, int6 (120 mg, 0.173 mmol) was dissolved in tetrahydrofuran / isopropanol (2 mL:2 mL), potassium tert-butoxide (2 mL, 1.0 M tetrahydrofuran solution) was added at 0°C, reacted at 25°C for 2 hours, quenched with ice water, extracted three times with ethyl acetate, the organic phases were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was prepared by reverse phase to give compounds 16A (4.0 mg) and 16B (1.0 mg).

[0641] Example 16: Preparation of Compounds 17A and 17B

[0642]

[0643] Synthesis route:

[0644]

[0645] (1) Compound 2-7 (1.0 g, 2.7 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), replaced with nitrogen three times, and lithium diisopropylamide solution (2.03 ml, 2.0 M, 4.05 mmol) was added in batches at -78 ° C. The mixture was stirred at -78 ° C for 1 hour, and deuterated-N,N-dimethylformamide (648 mg, 8.1 mmol) was added dropwise, and stirring was continued for half an hour. The reaction mixture was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The product 17-1 (900 mg) was purified by column chromatography. LC-MS: 400.0 [M+H] + .

[0646] (2) 17-1 (900 mg, 2.256 mmol) was dissolved in deuterated methanol (12 mL), sodium deuterated borohydride (189 mg, 4.512 mmol) was added in batches under an ice-water bath, and stirred at 25°C for 2 hours. The reaction mixture was quenched with water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The residue was purified by silica gel column chromatography to obtain the product 17-2 (700 mg). LC-MS: 403.0 [M+H] + .

[0647] (3) Compound 17-2 (400 mg, 0.994 mmol) was dissolved in dichloromethane (10 mL), and N,N-dimethylformamide (0.1 mL) and thionyl chloride (592 mg, 4.974 mmol) were added under ice-water bath, and stirred at 25°C for 2 hours. The reaction mixture was dried to obtain product 17-3 (380 mg). LC-MS: 421.1 [M+H] + .

[0648] (4) Compound 17-3 (380 mg, 0.904 mmol), (S)-3-methylpiperidine hydrochloride (179 mg, 1.81 mmol), N,N-diisopropylethylamine (350 mg, 2.712 mmol) were dissolved in N,N-dimethylformamide (10 mL) and stirred at 80°C for 2 hours. The reaction mixture was purified by reverse phase column chromatography to obtain compound 17-4 (360 mg). LC-MS: 484.2 [M+H] + .

[0649] (5) Compound 17-4 (360 mg, 0.745 mmol) was dissolved in 1,4-dioxane (10 mL), and then a hydrogen chloride / dioxane solution (5 mL) was added. The mixture was stirred at 50°C for 1 hour, and the reaction solution was concentrated in vacuo to obtain product 17-5 (350 mg). LC-MS: 470.2 [M+H] + .

[0650] (6) Compound 17-5 (150 mg, 0.320 mmol) and int3 (130 mg, 0.479 mmol) were dissolved in dichloromethane (5 mL), pyridine (101 mg, 1.279 mmol), N,N-diisopropylethylamine (165 mg, 1.279 mmol), and copper acetate (58 mg, 0.320 mmol) were added, and the oxygen was replaced, and stirred at 35°C for 16 hours. The reaction solution was diluted with dichloromethane and washed with water twice. The organic phase after separation was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. Compound 17-6 (60 mg) was obtained by column chromatography purification. LC-MS: 695.3 [M+H] + .

[0651] (7) Compound 17-6 (60 mg, 0.086 mmol) was dissolved in tetrahydrofuran (2 mL) and isopropanol (2 mL), and potassium tert-butoxide (0.260 mL, 1 M tetrahydrofuran, 0.260 mmol) was added and stirred at 30°C for 2 hours. The reaction solution was diluted with ethyl acetate and washed twice with water. The organic phase after separation was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation. The residue was prepared by reverse phase liquid chromatography to obtain 17A (4.29 mg) and 17B (1.25 mg).

[0652] Example 17: Preparation of Compounds 18A and 18B

[0653]

[0654] Synthesis route:

[0655]

[0656] (1) Compound 13-2 (700 mg, 1.149 mmol) was dissolved in methanol (12 mL), sodium borohydride (87 mg, 2.298 mmol) was added in batches under an ice-water bath, and stirred at 25°C for 2 hours. The reaction mixture was quenched with water, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation. The residue was purified by reverse phase column chromatography to obtain product 18-1 (180 mg). LC-MS: 612.2 [M+H] + .

[0657] (2) Compound 18-1 (180 mg, 0.294 mmol) was dissolved in dichloromethane (10 mL), and thionyl chloride (175 mg, 1.472 mmol) and N,N-dimethylformamide (0.1 mL) were added under ice-water bath, and stirred at 25°C for 2 hours. The reaction mixture was dried by rotary evaporation to obtain product 18-2 (160 mg). LC-MS: 630.1 [M+H] + .

[0658] (3) Compound 18-2 (160 mg, 0.239 mmol), (3-methylazetidin-3-yl)methanol hydrochloride (29 mg, 0.287 mmol), and N,N-diisopropylethylamine (148 mg, 1.147 mmol) were dissolved in N,N-dimethylformamide (10 mL) and stirred at 80°C for 2 hours. The reaction mixture was purified by reverse phase chromatography to obtain product 18-3 (60 mg). LC-MS: 695.2 [M+H] + .

[0659] (4) 18-3 (60 mg, 0.086 mmol) was dissolved in tetrahydrofuran (2 mL) and isopropanol (2 mL), and potassium tert-butoxide (0.260 mL, 1 M tetrahydrofuran, 0.260 mmol) was added, and stirred at 30°C for 2 hours. The reaction solution was diluted with ethyl acetate and washed twice with water. The organic phase after separation was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation. The residue was purified by reverse phase liquid chromatography to obtain compounds 18A (7.75 mg) and 18B (1.35 mg).

[0660] Example 18: Preparation of Compounds 19 and 19A and 19B

[0661]

[0662] Synthesis route:

[0663]

[0664] (1) Compound 18-2 (40 mg, 0.06 mmol), 2-azabicyclo[2.1.1]hexane hydrochloride (10 mg, 0.12 mmol), and N,N-diisopropylethylamine (31 mg, 0.24 mmol) were dissolved in N,N-dimethylformamide (2 mL) and stirred at 80°C for 2 hours. The reaction mixture was purified by reverse phase column chromatography to obtain product 19-1 (40 mg). LC-MS: 677.3 [M+H] + .

[0665] (2) Compound 19-1 (40 mg, 0.059 mmol) was dissolved in tetrahydrofuran (2 mL) and isopropanol (2 mL), and potassium tert-butoxide (0.180 mL, 1 M tetrahydrofuran, 0.180 mmol) was added and stirred at 30°C for 2 hours. The reaction solution was diluted with ethyl acetate and washed twice with water. The organic phase after separation was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain compound 19 (2.92 mg) by reverse phase liquid separation. Compounds 19A and 19B were obtained by chiral preparative separation.

[0666] Comparative Example 1: Preparation of Compound 2

[0667]

[0668] Synthesis route:

[0669]

[0670] (1) Compound 2-1 (31.9 g, 189.71 mmol) and N-iodosuccinimide (85.4 g, 379.42 mmol) were dissolved in trifluoroacetic acid (340 mL), sulfuric acid (3.72 g, 37.942 mmol) was added at 0°C, and stirred at 25°C for 16 hours. After the reaction was completed, the reaction solution was concentrated, water was added, the pH was adjusted to 8, and extracted with ethyl acetate for 3 times. The organic phases were combined and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain compound 2-2 (51.7 g). 1 H NMR (400MHz, DMSO-d6) δ8.67(s,1H),3.95(s,3H),2.33(s,3H).

[0671] (2) 2-2 (20 g, 68.02 mmol), methyl fluorosulfonyl difluoroacetate (130.7 g, 680.2 mmol), and cuprous iodide (129.6 g, 680.2 mmol) were dissolved in N,N-dimethylformamide (500 mL), and tris(dibenzylideneacetone)dipalladium (6.23 g, 6.802 mmol) was added, replaced with nitrogen, heated to 100°C and stirred for 2 hours. After the reaction was completed, water was added, extracted with ethyl acetate, and the organic phases were combined and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain compound 2-3 (14.2 g). 1 H NMR (400MHz, DMSO-d6) δ8.74 (s, 1H), 4.06 (s, 3H), 2.37 (d, J = 1.2Hz, 3H).

[0672] (3) Compound 2-3 (14.2 g, 60.13 mmol) was dissolved in N,N-dimethylformamide (150 mL), heated to 80°C, and then N,N-dimethylformamide dimethyl acetal (63.9 mL) was added and reacted at 95°C for 3 hours. After the reaction, water was added, extracted with ethyl acetate, and the organic phases were combined and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain compound 2-4 (15.4 g). 1 H NMR (400MHz, DMSO-d6) δ8.37 (s, 1H), 6.85 (d, J = 13.4Hz, 1H), 4.81 (d, J = 13.4Hz, 1H), 3.96 (d, J = 5.0Hz, 3H), 2.89 (s, 6H).

[0673] (4) Compound 2-4 (15.4 g, 52.88 mmol) was dissolved in methanol (500 mL) and an aqueous solution (66 mL) containing ammonium chloride (15.4 g), and heated to 60°C. Subsequently, iron (15.4 g) was added, and the reaction solution was reacted at 90°C for 3 hours. After the reaction was completed, the solution was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain compound 2-5 (7.6 g). 1 H NMR (400MHz, CDCl3) δ8.79 (s, 1H), 8.08 (d, J = 1.0Hz, 1H), 7.37 (t, J = 2.8Hz, 1H), 6.68 (s, 1H), 4.14 (s, 3H).

[0674] (5) Compound 2-5 (7.6 g, 35.16 mmol) was dissolved in N,N-dimethylformamide (50 mL), and sodium hydride (2.11 g, 52.74 mmol) was added at 0°C under nitrogen protection. N,N-dimethylformamide (50 mL) containing p-toluenesulfonyl chloride (10.06 g, 52.74 mmol) was added, and the reaction solution was reacted at 25°C for 16 hours. After the reaction, water was added, extracted with ethyl acetate, and the organic phases were combined and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain compound 2-6 (12.3 g, 93.2%). 1 HNMR (400MHz, CDCl3) δ8.05(d,J=1.0Hz,1H),7.97(d,J=3.6Hz,1H),7.72(d,J=8.4H z,2H),7.24(d,J=8.2Hz,2H),6.71(dd,J=3.6,1.6Hz,1H),3.88(s,3H),2.35(s,3H).

[0675] (6) Compound 2-6 (5 g, 13.5 mmol) was dissolved in tetrahydrofuran (50 mL) at -78°C, and lithium diisopropylamide (2.21 g, 20.25 mmol) was slowly added, stirred for 0.5 hours, and then N,N-dimethylformamide (1.48 g, 20.25 mmol) was added at -78°C, and the temperature was slowly raised to 25°C and stirred for 2 hours. After the reaction was completed, saturated ammonium chloride solution was added to quench, and then extracted with ethyl acetate, the organic phases were combined and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain compound 2-7 (2.8 g). 1 HNMR (400MHz, CDCl3) δ10.39 (s, 1H), 8.14 (d, J = 1.0Hz, 1H), 7.84 (d, J = 8.4Hz ,2H),7.39(d,J=1.4Hz,1H),7.30(d,J=8.2Hz,2H),3.93(s,3H),2.39(s,3H).

[0676] (7) Compound 2-7 (2.8 g, 7.03 mmol) and (S)-3-methylpiperidine (1.43 g, 10.545 mmol) were dissolved in dichloroethane (170 mL), stirred at 0°C for 1 hour, sodium triacetoxyborohydride (2.98 g, 14.06 mmol) was added, and then the temperature was raised to 25°C for 16 hours. Subsequently, the reaction solution was concentrated, and the crude product was purified by silica gel column chromatography to obtain compound 2-8 (1.9 g, 56.1%).

[0677] 1 H NMR (400MHz, CDCl3) δ8.34(d,J=8.2Hz,2H),8.05(s,1H),7.24(d,J=8.4Hz,2H),6.59(s,1H),3.90(s,2H),3.82(s,3H ),2.85(t,J=9.8Hz,2H),2.37(s,3H),1.92(t,J=10.6Hz,1H),1.63(dt,J=39.6,15.0Hz,5H),0.81(t,J=11.6Hz,4H).

[0678] (8) Compound 2-8 (1.9 g, 3.95 mmol) was dissolved in dioxane (30 mL), 4M hydrochloric acid / 1,4- (15 mL) was added, and the mixture was reacted at 50°C for 2 hours. The reaction solution was concentrated and washed with ether to obtain compound 2-9 (1.4 g). 1 H NMR (400MHz, CDCl3) δ11.49(s,1H),8.47(d,J=8.2Hz,2H),7.29(d,J=9.8Hz,2H),6.53(s,1H),3.98–3.89(m ,2H),2.90(t,J=9.4Hz,2H),2.40(s,3H),1.98(t,J=10.4Hz,1H),1.79–1.63(m,5H),0.88(t,J=10.2Hz,4H).

[0679] (9) Compound 2-9 (50 mg, 0.107 mmol), int3 (58 mg, 0.214 mmol), N,N-diisopropylethylamine (55.3 mg, 0.428 mmol), and pyridine (33.9 mg, 0.428 mmol) were dissolved in dichloromethane (10 mL), and copper acetate (5 mg, 0.02675 mmol) was added to replace oxygen and reacted at 25°C for 16 hours. After the reaction, water was added, extracted with dichloromethane, and the organic phases were combined and concentrated to obtain a crude product. The crude product was separated by preparative liquid phase to obtain compound 2-10 (13 mg). LC-MS: 693.1 [M+H] + .

[0680] (10) Compound 2-10 (11 mg, 0.016 mmol) was dissolved in a tetrahydrofuran / isopropanol mixed solution (4 mL, 1:1), potassium tert-butoxide (11 mg, 0.096 mmol) was added at 0°C, and stirred at 25°C for 5 hours. After the reaction was completed, the reaction solution was concentrated, and the crude product was separated by preparative liquid phase to obtain compound 2 (4.4 mg).

[0681] Each compound 1 H NMR and MS data are shown in Table 1

[0682] Table 1: 1 H NMR and MS data

[0683]

[0684]

[0685]

[0686] Biological Testing

[0687] Experimental Example 1: Evaluation of the Effects of Test Compounds on Cbl-b Activity

[0688] 1. CBL-B binding activity test

[0689] Experimental method: CBLB binding assay was performed in 384-well plates (greiner), with a total reaction volume of 15 μL. 150 nL of 3-fold graded dilution of compound (final concentration 1 μL-0.05 nM, starting concentration 1 μL, 3-fold dilution, 10 points, the 10th point is 0.05 nM) was incubated with 5 μL of 8 nM CBLB (in-house, Bioduro) protein at room temperature (25°C) for 1 hour. The reaction buffer was 20 mM HEPES PH7.5 (Gibco), 1 μL 50 mM NaCl (Sigma), 0.01% Triton X-100 (Sigma), 0.01% BSA and 0.5 mM TCEP (Thermo). 5 μL of 346.5 nM ligand PRJ1 / 3-1022 mixture (in-house, Bioduro) and 5 μL of 1 nM streptavidin-Terbium cryptate detection reagent (Cisbio) were added to the reaction plate and incubated at room temperature for 1 hour. HTRF signals (520 / 615) were read on EnVision (PerkinElmer). IC was calculated using IDBS XLfit. 50 .

[0690] Experimental Results

[0691] Table 2: In vitro activity test results

[0692]

[0693]

[0694] *: Values ​​after test data review.

[0695] Conclusion: The compounds of the present invention have strong inhibitory activity against Cbl-b.

[0696] Experimental Example 2: Evaluation of the effect of the test compound on the activation of IFN-γ release in PanT cells Experimental reagents

[0697]

[0698] Experimental Materials

[0699]

[0700] Experimental instruments

[0701]

[0702]

[0703] Experimental methods:

[0704] 1. Day 0, PanT cell isolation and plating

[0705] 1) Take out human PBMC cells from the liquid nitrogen tank.

[0706] 2) Add 9 mL of preheated culture medium to a 15 mL centrifuge tube, thaw the cells in a 37°C water bath, pipette the cells into a prepared centrifuge tube, take out 10 μL of cells for counting, and centrifuge the remaining cells at 1000 rpm for 5 min.

[0707] 3) Aspirate the culture medium after centrifugation and 7 Add 40 μL of buffer to resuspend the cells and 10 μL of Pan TCell Biotin-Antibody Cocktail, mix and place in a 4°C refrigerator for incubation for 5 minutes.

[0708] 4) Every 10 7 Add 30 μL buffer and 20 μL Pan T Cell MicroBead Cocktail to the cells, mix and incubate in a 4°C refrigerator for 10 minutes, and shake once after 5 minutes.

[0709] 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, then take 2 mL of buffer to rinse the centrifuge tube and add it to the LS column, then rinse the centrifuge tube twice and add it to the LS column, adding 3 mL of buffer each time.

[0710] 6) The collected cells were centrifuged at 1900 rpm for 5 min, the culture medium was aspirated, and fresh culture medium (RPMI1640 culture medium supplemented with 10% FBS and 1% PS, 0.1% of 2-Mercaptoethanol) was added to resuspend the cells and calculate the cell yield.

[0711] 7) Add 200 nL of three-fold serial dilutions of the compound (final concentration 10 μM-1.52 nM, starting concentration 10 μM, 3-fold dilution, 9 points, the 9th point is 1.52 nM) and 0.1% DMSO to a cell culture plate (Corning, 3603).

[0712] 8) Prepare 5x10 5 / mL PanT cell suspension, add mercaptoethanol at a ratio of 1:1000, take out a part of the suspension as unstim, add CD3 antibody (1ug / ml) to the rest of the suspension, mix well, transfer 200μL of cell suspension to the 96-well cell plate to which the compound has been added, and incubate in a 37°C, 5% CO2 incubator for 48 hours.

[0713] 2. Day 2, collect supernatant samples

[0714] 1) Centrifuge the ELISA plate at 1000 rpm for 1 minute, then collect 150 μL of supernatant into a 96-well plate, apply film and place in a -80°C refrigerator overnight.

[0715] 2) Add 100 μL of Capture Antibody (dilution factor: 1:120) to each well of the ELISA plate to coat the ELISA plate and incubate at room temperature overnight.

[0716] 3. Day 3, IFNγ ELISA detection

[0717] 1) Discard the capture antibody in the plate, add 300 μL of washing buffer to wash the plate, and wash 3 times.

[0718] 2) Add 300 μL of blocking solution to each well to block the plate, apply sealing film, and incubate at room temperature for 1 hour.

[0719] 3) Discard the blocking solution, add 300 μL of washing buffer to each well to wash the plate, and wash three times.

[0720] 4) Discard the washing buffer, add 100 μL of diluted sample (dilution factor: 1:50) and standard to the plate, apply sealing film, and incubate at room temperature for 2 hours.

[0721] 5) Discard the sample, add 300 μL of washing buffer to each well to wash the plate, and wash three times.

[0722] 6) Discard the washing buffer, add 100 μL of Detection Antibody (dilution factor: 1:60) to each well, apply sealing film, and incubate at room temperature for 2 hours.

[0723] 7) Discard the Detection Antibody, add 300 μL of washing buffer to each well, and wash the plate three times.

[0724] 8) Discard the washing buffer, add 100 μL of Streptavidin-HRP B (dilution factor: 1:40) to each well, apply the sealing film, and incubate at room temperature for 20 minutes in the dark.

[0725] 9) Discard Streptavidin-HRP B, add 300 μL of washing buffer to each well to wash the plate, and wash three times.

[0726] 10) Discard the washing buffer, add 100 μL of Substrate Solution to each well, and incubate at room temperature for 20 minutes in the dark.

[0727] 11) Add 50 μL of Stop Solution to each well and measure the absorbance at 450 nm using a PHERAstar FSX multifunctional microplate reader (BMG).

[0728] 12) Use IDBS XLfit to fit the standard curve and determine the IFN-γ content of the sample, draw the dose-response curve based on the original IFN-γ concentration of the sample and calculate the EC 50 .

[0729] Experimental Results

[0730] Table 3: In vitro activity test results

[0731] Compound No. <![CDATA[EC 50 (nM)]]> 1 45.3 3 54.2 6 56.5 7 109.3 18A 56.4 19A 51.1

[0732] Conclusion: The compounds of the present invention have a good IFN-γ release and activation effect on PanT cells.

[0733] Experimental Example 3: Evaluation of the effect of the test compound on the activation of NK cell IFN-γ release

[0734] Experimental reagents

[0735]

[0736] Experimental Materials

[0737]

[0738] Experimental instruments

[0739]

[0740] Experimental methods:

[0741] 1. Day 0, NK cell isolation

[0742] 1) Take out human PBMC cells from the liquid nitrogen tank.

[0743] 2) Add 9 mL of preheated culture medium to a 15 mL centrifuge tube, thaw the cells in a 37°C water bath, pipette the cells into a prepared centrifuge tube, take out 10 μL of cells for counting, and centrifuge the remaining cells at 1000 rpm for 5 min.

[0744] 3) Aspirate the culture medium after centrifugation and 7 Add 40 μL of buffer to resuspend the cells and 10 μL of NKCell Biotin-Antibody Cocktail, mix and place in a 4°C refrigerator for incubation for 5 minutes.

[0745] 4) Every 10 7 Add 30 μL buffer and 20 μL NK Cell MicroBead Cocktail to the cells, mix and incubate in a 4°C refrigerator for 10 minutes, and shake once after 5 minutes.

[0746] 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, then take 2 mL of buffer to rinse the centrifuge tube and add it to the LS column, then rinse the centrifuge tube twice and add it to the LS column, adding 3 mL of buffer each time.

[0747] 6) The collected cells were centrifuged at 1900 rpm for 5 min, the culture medium was aspirated, fresh culture medium was added to resuspend the cells, and the cell yield was calculated.

[0748] 7) The separated NK cells were resuspended in RPMI1640 medium (supplemented with 10% FBS and 1% PS, 25 ng / ml IL-2, and 0.1% of 2-Mercaptoethanol) and placed in a 37° C., 5% CO 2 incubator to recover overnight.

[0749] 2. Day 1, NK cell plating

[0750] 1) Add 200 nL of three-fold serial dilutions of the compound (final concentration 10 μM-1.52 nM, starting concentration 10 μM, 3-fold dilution, 9 points, the 9th point is 1.52 nM) and 0.1% DMSO to a cell culture plate (Corning, 3603).

[0751] 2) Prepare 1.026x 10 5 / mL NK cell suspension, mix well, transfer 195 μL of cell suspension to a 96-well cell plate to which compounds have been added, add 5 μL of NKG2D (1 ug / ml) and none (as non-stimulation), and incubate in a 37°C, 5% CO2 incubator for 24 hours.

[0752] 3. Day 2, collect supernatant samples

[0753] 1) Centrifuge the ELISA plate at 1000 rpm for 1 minute, then collect 150 μL of supernatant into a 96-well plate, apply film and place in a -80°C refrigerator overnight.

[0754] 2) Add 100 μL of Capture Antibody (dilution factor: 1:120) to each well of the ELISA plate, coat the ELISA plate, and incubate at room temperature overnight.

[0755] 4. Day 3, IFNγ ELISA detection

[0756] 1) Discard the Capture Antibody in the plate, add 300 μL of washing buffer to wash the plate, and wash 3 times.

[0757] 2) Add 300 μL of blocking solution to each well to block the plate, apply sealing film, and incubate at room temperature for 1 hour.

[0758] 3) Discard the blocking solution, add 300 μL of washing buffer to each well to wash the plate, and wash three times.

[0759] 4) Discard the washing buffer, add 100 μL of diluted sample (dilution factor: 1:5) and standard to the plate, apply sealing film, and incubate at room temperature for 2 hours.

[0760] 5) Discard the sample, add 300 μL of washing buffer to each well to wash the plate, and wash three times.

[0761] 6) Discard the washing buffer, add 100 μL of Detection Antibody (dilution factor: 1:60) to each well, apply sealing film, and incubate at room temperature for 2 hours.

[0762] 7) Discard the Detection Antibody, add 300 μL of washing buffer to each well, and wash the plate three times.

[0763] 8) Discard the washing buffer, add 100 μL of Streptavidin-HRP B (dilution factor: 1:40) to each well, apply the sealing film, and incubate at room temperature for 20 minutes in the dark.

[0764] 9) Discard Streptavidin-HRP B, add 300 μL of washing buffer to each well to wash the plate, and wash three times.

[0765] 10) Discard the washing buffer, add 100 μL of Substrate Solution to each well, and incubate at room temperature for 20 minutes in the dark.

[0766] 11) Add 50 μL of Stop Solution to each well and measure the absorbance at 450 nm using a PHERAstar FSX multifunctional microplate reader (BMG).

[0767] 12) Use IDBS XLfit to fit the standard curve and determine the IFNγ content of the sample, draw the dose-response curve based on the original IFNγ concentration of the sample and calculate the EC 50 .

[0768] Experimental Example 4: (Human / Mouse) Liver Microsome Metabolic Stability

[0769] 1. Experimental design: assay concentration: 1 μM; control compound: testosterone; incubation conditions: incubation at 37°C for 0, 5, 15, 30, 45 min; assay method: LC-MS / MS; calculation method: T 1 / 2 = 0.693 / K (K is the rate constant of the ln [concentration] relative to the incubation time graph), Cl int = (0.693 / T 1 / 2) × (1 / (microsomal protein concentration (0.5 mg / mL))) × proportional factor.

[0770] The following table shows the scaling factors for the prediction of intrinsic clearance in human microsomes:

[0771]

[0772] 2. Experimental methods:

[0773] 1. Preheat 0.1M K-buffer, 5nM MgCl2, pH = 7.4; 2. Experimental solution of test compound and reference compound, 500μM Addition solution: add 5μL 10mM stock solution to 95μL 1.5 μM spike solution in microsomes (0.75 mg / mL) in ACN: 1.5 μL of 500 μM spike solution and 18.75 μL of 20 Mg / mL liver microsomes were added to 479.75 μL of K / Mg buffer; 3.3× NADPH stock solution (6 mM, 5 mg / mL) was NADPH dissolved in buffer; 4. 30 μL of 1.5 μM spike solution containing 0.75 mg / mL microsomal solution was distributed to the assay plates designated for different time points (0, 5, 15, 30, 45 minutes); 5. At 0 minutes, 150 μL of ACN containing IS was added to the wells of the plate, followed by 15 μL of NADPH stock solution (6 mM, step 3); 6. All other plates were pre-incubated at 37°C for 5 minutes; 7. 15 μL of NADPH stock solution to start the reaction and timing; 8. At 5 minutes, 15 minutes, 30 minutes and 45 minutes, add 150 μL of ACN containing IS to the wells of the corresponding plate to terminate the reaction; 9. After quenching, shake the plate on a shaker for 10 minutes (600 rpm / min), and then centrifuge at 6000 rpm for 15 minutes; 10. Transfer 80 μL of supernatant from each well to a 96-well sample plate containing 140 μL of water for LC / MS analysis.

[0774] 3. Analytical methods:

[0775] Detection method: LC-MS / MS-11 (8050), internal standard: tolbutamide, MS conditions: testosterone and the test compound positive ion ESI; tolbutamide negative ion ESI; mobile phase: mobile phase A is 0.1% FA in water, mobile phase B is 0.1% FA in ACN; column and specifications: ACQUITY UPLC HSS T3 1.8um 2.1*50mm.

[0776] LC conditions:

[0777]

[0778] 4. Experimental results:

[0779] Table 4: Human / rat liver microsome stability results

[0780] Compound No. <![CDATA[Human liver microsomes (t 1 / 2 min)]]> <![CDATA[Mouse liver microsomes (t 1 / 2 min)]]> 2 5.7 11.1 18A 167.9 36.4 19A >216.8 96.8

[0781] Conclusion: The compounds of the present invention have good stability in human or mouse liver microsomes.

[0782] The principles and implementation methods of the present invention are described herein using examples, and the above examples are only used to help understand the present invention rather than to limit it. It should be noted that for those of ordinary skill in the art, several improvements and modifications may be made to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the scope of the claims of the present invention.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: in, X1, X2, X3 and X4 are independently selected from CR6 or N; R1 and R2 are independently selected from H, halogen, 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 1～6 Alkoxy, C 3～10 Cycloalkyl or 4-10 membered heterocyclic group is optionally substituted by R x replace; Or R1, R2 and the atoms they are connected to together form C 3～10 Cycloalkyl or 4-10 membered heterocyclic group, wherein the C 3～10 Cycloalkyl or 4-10 membered heterocyclic group is optionally substituted by R x replace; Or R1, R2 and their respective atoms and bonds together form C 3～6 Cycloalkenyl or 4-7 membered heterocyclic group, wherein the C 3～6 The cycloalkenyl or 4-7 membered heterocyclic group is optionally substituted by R v replace; R3 is selected from L2-W; L2 is selected from a single bond, -CR d R e -; W is selected from hydrogen, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, wherein the 5-10 membered heteroaryl, 4-10 membered heterocyclyl is optionally replaced by R w replace; R d and R e independently selected from H, halogen, OH, C 1～6 Alkyl or C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally further substituted 1 to 3 times by halogen; R1 can be optionally combined with R d or R e and their respective atoms and bonds together form C 3～6 Cycloalkyl or 4-7 membered heterocyclic group, wherein the C 3～6 Cycloalkyl or 4-7 membered heterocyclic group is optionally replaced by 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 The structural unit may be optionally substituted n times by R4; n is independently selected from 0, 1, 2 or 3; L1 is selected from a single bond, -(CR a R b ) p -、-NR c -, -O-, -C(=O)-, -C(=O)NH-, -CR a R b -NR c -; R a , R b , R c are independently selected from H, halogen, OH, C 1～6 Alkyl or C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally replaced by R x Replace 1 to 3 times; p is selected from 1, 2 or 3; Any R a and R b Under the conditions of chemical valence permitting, it can form a 3-5 membered cycloalkyl or a 3-5 membered heterocyclic group; R4 is selected from halogen, =O, OH, NH2, NO2, CN, C 1～6 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, C 3～6 Cycloalkyloxy, 4-7 membered heterocyclyl, 4-7 membered heterocyclyloxy, wherein the NH2, C 1～6 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, C 3～6 Cycloalkyloxy, 4-7 membered heterocyclyl, 4-7 membered heterocyclyloxy are optionally substituted by R y replace; R5 is selected from halogen, CN, OH, COOH, CONH2, C 1～6 Alkyl, C 1～6 alkoxy, 4-10 membered nitrogen-containing heterocyclic group, 5-10 membered nitrogen-containing heteroaryl group, 4-10 membered sulfur-containing heterocyclic group, 5-10 membered sulfur-containing heteroaryl group, C 3～10 Cycloalkyl, 4-10 membered heterocyclyl, phenyl, 5-10 membered heteroaryl, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally replaced by R y substituted, and wherein the 4-10 membered nitrogen-containing heterocyclic group, the 5-10 membered nitrogen-containing heteroaryl group, the 4-10 membered sulfur-containing heterocyclic group, the 5-10 membered sulfur-containing heteroaryl group, C 3～10 Cycloalkyl, 4-10 membered heterocyclyl, phenyl, 5-10 membered heteroaryl are optionally substituted 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 heterocyclyl, 4-7 membered heterocyclyloxy, 4-7 membered heterocyclyl-NH-, C 6～10 Aryl, C 6～10 Aryloxy, 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 group, C 6～10 Aryl or 5-10 membered heteroaryl is optionally substituted by R y replace; Or two R6 and the C atom to which they are connected together form a C 3～6 Cycloalkenyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl, wherein the C 3～6 Cycloalkenyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl are optionally replaced by R y replace; R v independently selected from halogen, =O, OH, CN, (C 1～6 Alkyl)-CN, C 1～6 Alkyl or C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally substituted with halogen, C 1～3 Alkyl, OH or CN substituted 1 to 3 times; R w independently selected from halogen, 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 group is optionally substituted by halogen, =O, OH, CN or C 1～6 Alkyl substitution 1 to 3 times; R x independently selected from halogen, OH, CN, ═O, C 1～6 Alkyl, (C 1～6 Alkyl)-CN, 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 further optionally substituted 1 to 3 times by halogen, cyano, hydroxyl or amine; R y independently selected from halogen, 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 1 to 3 times by halogen or hydroxy; R z are independently selected from halogen, CN, (C 1～6 alkyl)-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 heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl, wherein the C 1～6 Alkyl, C 3～10 Cycloalkyl, 4-7 membered heterocyclic group, C 6～10 The 5- to 10-membered aryl or heteroaryl group is optionally further substituted by R x replace; R n Independently selected from H, C 1～6 alkyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl, wherein the C 1～6 Alkyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl are optionally further substituted by R x Substitution, or 2 R on a N atom n The N to which it is attached forms a 4-7 membered heterocyclic group or a 5-6 membered heteroaryl group, wherein the 4-7 membered heterocyclic group or the 5-6 membered heteroaryl group is optionally further substituted by R x replace; The conditions are: (1) When the ring A is a 5-membered heteroaryl group or a 5-7-membered heterocyclic group, R 4 Not CN or C 3～6 cycloalkyl; and (2) The compound of formula (I) is not any one or more compounds selected from the compounds in Table A below, or an isomer or isomer mixture of any one compound: Table A 2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: W is selected from 5-10 membered heteroaryl or 4-10 membered heterocyclyl, wherein the 5-10 membered heteroaryl and 4-10 membered heterocyclyl are optionally replaced by R w Replace, and R v are independently selected from halogen, OH, CN, (C 1～6 Alkyl)-CN, C 1～6 Alkyl or C 1～6 Alkoxy, the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally substituted with halogen, C 1～3 Alkyl, OH or CN substituted 1 to 3 times; and / or, W is selected from hydrogen, pyrrolyl, thienyl, furanyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl; and / or, R w Selected from halogen, OH, CN, C 1～3 Alkyl or C 3～6 Cycloalkyl, wherein the C 1～3 Alkyl and C 1～3 The alkoxy group is optionally substituted 1 to 3 times by halogen; and / or, R w Selected from C 1～3 alkyl; and / or, R w is methyl; and / or, W is selected from hydrogen, and / or, W is selected from 3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: W is selected from 5-10 membered heteroaryl or 4-10 membered heterocyclyl, wherein the 5-10 membered heteroaryl and 4-10 membered heterocyclyl are optionally replaced by R w replace; R v independently selected from halogen, OH, CN, C 1～6 Alkyl or C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally substituted with halogen, C 1～3 Alkyl, OH or CN substituted 1 to 3 times; R x independently selected from halogen, OH, 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 further optionally substituted 1 to 3 times by halogen, cyano, hydroxyl or amine; and R z independently selected from halogen, 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 heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein C 1～6 Alkyl, C 3～10 Cycloalkyl, 4-7 membered heterocyclic group, C 6～10 The 5- to 10-membered aryl or heteroaryl group is optionally further substituted by R x replace.

4. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 3, wherein: p is selected from 1 or 2; and R y independently selected from halogen, OH, =O, NH2, NH(C 1～6 Alkyl), N(C 1～6 Alkyl)2, C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is further optionally substituted 1 to 3 times by halogen.

5. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 3 or 4, wherein: W is selected from pyrrolyl, thienyl, furanyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl; and / or, R w Selected from halogen, OH, CN, C 1～3 Alkyl or C 3～6 Cycloalkyl, the C 1～3 Alkyl and C 1～3 The alkoxy group is optionally substituted 1 to 3 times by halogen; and / or, R w Selected from C 1～3 alkyl; and / or, R w is methyl; and / or, W is selected from 6. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 5, wherein: L2 is selected from a single bond, -CH2-, -CHF-, -CF2-, -CH(CH3)-, -C(CH3)2-, -CH(CF3)-; And / or, L2 is a single bond.

7. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein the compound of formula (I) is selected from the structure shown in formula (I-1):

8. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 7, wherein: (1) Ring A is selected from phenyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl or 5-7 membered heterocyclyl, wherein the 5-7 membered heterocyclyl contains 1 or 2 N or S as heteroatoms, and the ring A may be optionally substituted by R4 n times; or (2) Ring A is selected from The ring A may be optionally substituted n times by R4; or (3) Ring A is selected from The ring A may be optionally substituted n times by R4; or (4) Structural unit Selected from The structural unit may be optionally substituted n times by R4, Preferably, the structural unit Selected from or Structural unit Selected from The structural unit may be optionally substituted n times by R4, Preferably, the structural unit Selected from 9. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 8, wherein the compound of formula (I) is selected from the structures shown in formula (I-2), formula (I-3), formula (I-4) and formula (I-5):

10. A compound of formula (I) or a pharmaceutically acceptable salt thereof: in, X1, X2, X3 and X4 are independently selected from CR6 or N; R1 and R2 are independently selected from H, halogen, 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 1～6 Alkoxy, C 3～10 Cycloalkyl or 4-10 membered heterocyclic group is optionally substituted by R x replace; Or R1, R2 and the atoms they are connected to together form C 3～10 Cycloalkyl or 4-10 membered heterocyclic group, wherein the C 3～10 Cycloalkyl or 4-10 membered heterocyclic group is optionally substituted by R x replace; Or R1, R2 and their respective atoms and bonds together form C 3～6 Cycloalkenyl or 4-7 membered heterocyclic group, wherein the C 3～6 The cycloalkenyl or 4-7 membered heterocyclic group is optionally substituted by R v replace; R3 is selected from L2-W; L2 is selected from a single bond, -CR d R e -; W is selected from hydrogen, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, wherein the 5-10 membered heteroaryl, 4-10 membered heterocyclyl is optionally replaced by R w replace; R d and R e are independently selected from H, halogen, OH, C 1～6 Alkyl or C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally further substituted 1 to 3 times by halogen; R1 can be optionally combined with R d or R e and their respective atoms and bonds together form C 3～6 Cycloalkyl or 4-7 membered heterocyclic group, wherein the C 3～6 Cycloalkyl or 4-7 membered heterocyclic group is optionally replaced by R v replace; Ring A is selected from phenyl or 6-membered heteroaryl, wherein the phenyl or 6-membered heteroaryl is The structural unit may be optionally substituted n times by R4; n is independently selected from 0, 1, 2 or 3; L1 is selected from a single bond, -(CR a R b ) p -、-NR c -, -O-, -C(=O)-, -C(=O)NH-, -CR a R b -NR c -; R a , R b , R c are independently selected from H, halogen, OH, C 1～6 Alkyl or C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally replaced by R x Replace 1 to 3 times; p is selected from 1, 2 or 3; Any R a and R b Under the conditions of chemical valence permitting, it can form a 3-5 membered cycloalkyl or a 3-5 membered heterocyclic group; R4 is selected from halogen, =O, OH, NH2, NO2, CN, C 1～6 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, C 3～6 Cycloalkyloxy, 4-7 membered heterocyclyl, 4-7 membered heterocyclyloxy, wherein the NH2, C 1～6 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, C 3～6 Cycloalkyloxy, 4-7 membered heterocyclyl, 4-7 membered heterocyclyloxy are optionally substituted by R y replace; R5 is selected from halogen, CN, OH, COOH, CONH2, C 1～6 Alkyl, C 1～6 alkoxy, 4-10 membered nitrogen-containing heterocyclic group, 5-10 membered nitrogen-containing heteroaryl group, 4-10 membered sulfur-containing heterocyclic group, 5-10 membered sulfur-containing heteroaryl group, C 3～10 Cycloalkyl, 4-10 membered heterocyclyl, phenyl, 5-10 membered heteroaryl, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally replaced by R y substituted, and wherein the 4-10 membered nitrogen-containing heterocyclic group, the 5-10 membered nitrogen-containing heteroaryl group, the 4-10 membered sulfur-containing heterocyclic group, the 5-10 membered sulfur-containing heteroaryl group, C 3～10 Cycloalkyl, 4-10 membered heterocyclyl, phenyl, 5-10 membered heteroaryl are optionally substituted 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 heterocyclyl, 4-7 membered heterocyclyloxy, 4-7 membered heterocyclyl-NH-, C 6～10 Aryl, C 6～10 Aryloxy, 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 group, C 6～10 Aryl or 5-10 membered heteroaryl is optionally substituted by R y replace; Or two R6 and the C atom to which they are connected together form a C 3～6 Cycloalkenyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl, wherein the C 3～6 Cycloalkenyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl are optionally replaced by R y replace; R v independently selected from halogen, =O, OH, CN, (C 1～6 Alkyl)-CN, C 1～6 Alkyl or C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally substituted with halogen, C 1～3 Alkyl, OH or CN substituted 1 to 3 times; R w independently selected from halogen, 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 group is optionally substituted by halogen, =O, OH, CN or C 1～6 Alkyl substitution 1 to 3 times; R x independently selected from halogen, OH, CN, ═O, C 1～6 Alkyl, (C 1～6 Alkyl)-CN, 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 further optionally substituted 1 to 3 times by halogen, cyano, hydroxyl or amine; R y independently selected from halogen, 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 1 to 3 times by halogen or hydroxy; R z are independently selected from halogen, CN, (C 1～6 alkyl)-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 heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl, wherein the C 1～6 Alkyl, C 3～10 Cycloalkyl, 4-7 membered heterocyclic group, C 6～10 The 5- to 10-membered aryl or heteroaryl group is optionally further substituted by R x replace; R n Independently selected from H, C 1～6 alkyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl, wherein the C 1～6 Alkyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl are optionally further substituted by R x Substitution, or 2 R on a N atom n The N to which it is attached forms a 4-7 membered heterocyclic group or a 5-6 membered heteroaryl group, wherein the 4-7 membered heterocyclic group or the 5-6 membered heteroaryl group is optionally further substituted by R x replace.

11. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 10, wherein: W is selected from 5-10 membered heteroaryl or 4-10 membered heterocyclyl, wherein the 5-10 membered heteroaryl and 4-10 membered heterocyclyl are optionally replaced by R w Replace, and R v are independently selected from halogen, OH, CN, (C 1～6 Alkyl)-CN, C 1～6 Alkyl or C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally substituted with halogen, C 1～3 Alkyl, OH or CN substituted 1 to 3 times; and / or, W is selected from hydrogen, pyrrolyl, thienyl, furanyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl; and / or, R w Selected from halogen, OH, CN, C 1～3 Alkyl or C 3～6 Cycloalkyl, wherein the C 1～3 Alkyl and C 1～3 The alkoxy group is optionally substituted 1 to 3 times by halogen; and / or, R w Selected from C 1～3 alkyl; and / or, R w is methyl; and / or, W is selected from hydrogen, and / or, W is selected from 12. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 10, wherein: W is selected from 5-10 membered heteroaryl or 4-10 membered heterocyclyl, wherein the 5-10 membered heteroaryl and 4-10 membered heterocyclyl are optionally replaced by R w replace; R v independently selected from halogen, OH, CN, C 1～6 Alkyl or C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally substituted with halogen, C 1～3 Alkyl, OH or CN substituted 1 to 3 times; R x independently selected from halogen, OH, 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 further optionally substituted 1 to 3 times by halogen, cyano, hydroxyl or amine; and R z independently selected from halogen, 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 heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein C 1～6 Alkyl, C 3～10 Cycloalkyl, 4-7 membered heterocyclic group, C 6～10 The 5- to 10-membered aryl or heteroaryl group is optionally further substituted by R x replace.

13. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 12, wherein: p is selected from 1 or 2; and R y independently selected from halogen, OH, =O, NH2, NH(C 1～6 Alkyl), N(C 1～6 Alkyl)2, C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is further optionally substituted 1 to 3 times by halogen.

14. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 12 or 13, wherein: W is selected from pyrrolyl, thienyl, furanyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl; and / or, R w Selected from halogen, OH, CN, C 1～3 Alkyl or C 3～6 Cycloalkyl, the C 1～3 Alkyl and C 1～3 The alkoxy group is optionally substituted 1 to 3 times by halogen; and / or, R w Selected from C 1～3 alkyl; and / or, R w is methyl; and / or, W is selected from 15. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 10 to 14, wherein: L2 is selected from a single bond, -CH2-, -CHF-, -CF2-, -CH(CH3)-, -C(CH3)2-, -CH(CF3)-; And / or, L2 is a single bond.

16. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 10 to 15, wherein the compound of formula (I) is selected from the structure shown in formula (I-1):

17. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 10 to 16, wherein: (1) Ring A is selected from phenyl, pyridyl, pyrimidinyl or 5-7 membered heterocyclic group, wherein the 5-7 membered heterocyclic group contains 1 or 2 N or S as heteroatoms, and the ring A may be optionally substituted by R4 n times; or (2) Ring A is selected from The ring A may be optionally substituted n times by R4; or (3) Ring A is selected from The ring A may be optionally substituted n times by R4; or (4) Structural unit Selected from The structural unit may be optionally substituted n times by R4, Preferably, the structural unit Selected from or Structural unit Selected from The structural unit may be optionally substituted n times by R4, Preferably, the structural unit Selected from 18. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 10 to 17, wherein the compound of formula (I) is selected from the structure shown in formula (I-2) or formula (I-3):

19. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, wherein: R4 is selected from halogen, =O, OH, NH2, NO2, CN, C 1～6 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, C 3～6 Cycloalkyloxy, 4-7 membered heterocyclyl, 4-7 membered heterocyclyloxy, wherein the NH2, C 1～6 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, C 3～6 Cycloalkyloxy, 4-7 membered heterocyclyl, 4-7 membered heterocyclyloxy are optionally substituted by R y replace; and / or, R4 is selected from halogen, =O, OH, NH2, CN, C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, C 3～6 Cycloalkyloxy, wherein the NH2, C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, C 3～6 The cycloalkyloxy group is optionally substituted by R y replace; and / or, R4 is selected from halogen, =O, NH2, CN, C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, wherein the NH2, C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 The cycloalkyl group is optionally substituted by R y replace; and / or, R4 is selected from halogen, C optionally substituted by halogen 1～6 Alkyl, optionally substituted by halogen, C 1～6 Alkoxy, optionally substituted by halogen, C 3～6 Cycloalkyl; and / or, R4 is selected from halogen, CN, OH, C 1～6 Alkyl, halogenated C 1～6 alkyl; and / or, R4 is selected from =O, F, Cl, Br, CN, OH, methyl, ethyl, ethynyl, CF3, CHF2, CH2F, methoxy, N(CH3)2, NHCH3, cyclopropyl; And / or, R4 is selected from =O, methyl, CF3, F, Cl, methoxy, cyclopropyl.

20. A compound of formula (I) or a pharmaceutically acceptable salt thereof: in, X1, X2, X3 and X4 are independently selected from CR6 or N; R1 and R2 are independently selected from H, halogen, 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 1～6 Alkoxy, C 3～10 Cycloalkyl or 4-10 membered heterocyclic group is optionally substituted by R x replace; Or R1, R2 and the atoms they are connected to together form C 3～10 Cycloalkyl or 4-10 membered heterocyclic group, wherein the C 3～10 Cycloalkyl or 4-10 membered heterocyclic group is optionally substituted by R x replace; Or R1, R2 and their respective atoms and bonds together form C 3～6 Cycloalkenyl or 4-7 membered heterocyclic group, wherein the C 3～6 The cycloalkenyl or 4-7 membered heterocyclic group is optionally substituted by R v replace; R3 is selected from L2-W; L2 is selected from a single bond, -CR d R e -; W is selected from hydrogen, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, wherein the 5-10 membered heteroaryl, 4-10 membered heterocyclyl is optionally replaced by R w replace; R d and R e are independently selected from H, halogen, OH, C 1～6 Alkyl or C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally further substituted 1 to 3 times by halogen; R1 can be optionally combined with R d or R e and their respective atoms and bonds together form C 3～6 Cycloalkyl or 4-7 membered heterocyclic group, wherein the C 3～6 Cycloalkyl or 4-7 membered heterocyclic group is optionally replaced by R v replace; Ring A is selected from a 5-membered heteroaryl or a 5-7-membered heterocyclic group, wherein the 5-membered heteroaryl is The structural unit may be optionally substituted n times by R4; n is independently selected from 0, 1, 2 or 3; L1 is selected from a single bond, -(CR a R b ) p -、-NR c -, -O-, -C(=O)-, -C(=O)NH-, -CR a R b -NR c -; R a , R b , R c are independently selected from H, halogen, OH, C 1～6 Alkyl or C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally replaced by R x Replace 1 to 3 times; p is selected from 1, 2 or 3; Any R a and R b Under the conditions of chemical valence permitting, it can form a 3-5 membered cycloalkyl or a 3-5 membered heterocyclic group; R4 is selected from halogen, =O, OH, NH2, NO2, C 1～6 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, C 1～6 Alkoxy, C 3～6 Cycloalkyloxy, 4-7 membered heterocyclyl, 4-7 membered heterocyclyloxy, wherein the NH2, C 1～6 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, C 1～6 Alkoxy, C 3～6 Cycloalkyloxy, 4-7 membered heterocyclyl, 4-7 membered heterocyclyloxy are optionally substituted by R y replace; R5 is selected from halogen, CN, OH, COOH, CONH2, C 1～6 Alkyl, C 1～6 alkoxy, 4-10 membered nitrogen-containing heterocyclic group, 5-10 membered nitrogen-containing heteroaryl group, 4-10 membered sulfur-containing heterocyclic group, 5-10 membered sulfur-containing heteroaryl group, C 3～10 Cycloalkyl, 4-10 membered heterocyclyl, phenyl, 5-10 membered heteroaryl, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally replaced by R y substituted, and wherein the 4-10 membered nitrogen-containing heterocyclic group, the 5-10 membered nitrogen-containing heteroaryl group, the 4-10 membered sulfur-containing heterocyclic group, the 5-10 membered sulfur-containing heteroaryl group, C 3～10 Cycloalkyl, 4-10 membered heterocyclyl, phenyl, 5-10 membered heteroaryl are optionally substituted 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 heterocyclyl, 4-7 membered heterocyclyloxy, 4-7 membered heterocyclyl-NH-, C 6～10 Aryl, C 6～10 Aryloxy, 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 group, C 6～10 Aryl or 5-10 membered heteroaryl is optionally substituted by R y replace; Or two R6 and the C atom to which they are connected together form a C 3～6 Cycloalkenyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl, wherein the C 3～6 Cycloalkenyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl are optionally replaced by R y replace; R v independently selected from halogen, =O, OH, CN, (C 1～6 Alkyl)-CN, C 1～6 Alkyl or C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally substituted with halogen, C 1～3 Alkyl, OH or CN substituted 1 to 3 times; R w independently selected from halogen, 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 group is optionally substituted by halogen, =O, OH, CN or C 1～6 Alkyl substitution 1 to 3 times; R x independently selected from halogen, OH, CN, ═O, C 1～6 Alkyl, (C 1～6 Alkyl)-CN, 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 further optionally substituted 1 to 3 times by halogen, cyano, hydroxyl or amine; R y independently selected from halogen, 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 1 to 3 times by halogen or hydroxy; R z are independently selected from halogen, CN, (C 1～6 alkyl)-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 heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl, wherein the C 1～6 Alkyl, C 3～10 Cycloalkyl, 4-7 membered heterocyclic group, C 6～10 The 5- to 10-membered aryl or heteroaryl group is optionally further substituted by R x replace; R n Independently selected from H, C 1～6 alkyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl, wherein the C 1～6 Alkyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl are optionally further substituted by R x Substitution, or 2 R on a N atom n The N to which it is attached forms a 4-7 membered heterocyclic group or a 5-6 membered heteroaryl group, wherein the 4-7 membered heterocyclic group or the 5-6 membered heteroaryl group is optionally further substituted by R x replace; Provided that the compound of formula (I) is not any compound selected from the compounds in Table A described in claim 1, or a mixture of any two or more compounds, or an isomer or isomer mixture of any compound.

21. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 20, wherein: W is selected from 5-10 membered heteroaryl or 4-10 membered heterocyclyl, wherein the 5-10 membered heteroaryl and 4-10 membered heterocyclyl are optionally replaced by R w Replace, and R v are independently selected from halogen, OH, CN, (C 1～6 Alkyl)-CN, C 1～6 Alkyl or C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally substituted with halogen, C 1～3 Alkyl, OH or CN substituted 1 to 3 times; and / or, W is selected from hydrogen, pyrrolyl, thienyl, furanyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl; and / or, R w Selected from halogen, OH, CN, C 1～3 Alkyl or C 3～6 Cycloalkyl, wherein the C 1～3 Alkyl and C 1～3 The alkoxy group is optionally substituted 1 to 3 times by halogen; and / or, R w Selected from C 1～3 alkyl; and / or, R w is methyl; and / or, W is selected from hydrogen, and / or, W is selected from 22. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 21, wherein: W is selected from 5-10 membered heteroaryl or 4-10 membered heterocyclyl, wherein the 5-10 membered heteroaryl and 4-10 membered heterocyclyl are optionally replaced by R w replace; R v independently selected from halogen, OH, CN, C 1～6 Alkyl or C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally substituted with halogen, C 1～3 Alkyl, OH or CN substituted 1 to 3 times; R x independently selected from halogen, OH, 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 further optionally substituted 1 to 3 times by halogen, cyano, hydroxyl or amine; and R z independently selected from halogen, 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 heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein C 1～6 Alkyl, C 3～10 Cycloalkyl, 4-7 membered heterocyclic group, C 6～10 The 5- to 10-membered aryl or heteroaryl group is optionally further substituted by R x replace.

23. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 22, wherein: p is selected from 1 or 2; and R y independently selected from halogen, OH, =O, NH2, NH(C 1～6 Alkyl), N(C 1～6 Alkyl)2, C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is further optionally substituted 1 to 3 times by halogen.

24. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 22 or 23, wherein: W is selected from pyrrolyl, thienyl, furanyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl; and / or, R w Selected from halogen, OH, CN, C 1～3 Alkyl or C 3～6 Cycloalkyl, the C 1～3 Alkyl and C 1～3 The alkoxy group is optionally substituted 1 to 3 times by halogen; and / or, R w Selected from C 1～3 alkyl; and / or, R w is methyl; and / or, W is selected from 25. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 20 to 24, wherein: L2 is selected from a single bond, -CH2-, -CHF-, -CF2-, -CH(CH3)-, -C(CH3)2-, -CH(CF3)-; And / or, L2 is a single bond.

26. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 20 to 25, wherein the compound of formula (I) is selected from the structure shown in formula (I-1):

27. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 20 to 26, wherein: (1) Ring A is selected from pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl or 5-7 membered heterocyclyl, wherein the 5-7 membered heterocyclyl contains 1 or 2 N or S as heteroatoms, and the ring A may be optionally substituted by R4 n times; or (2) Ring A is selected from The ring A may be optionally substituted n times by R4; or (3) Ring A is selected from The ring A may be optionally substituted n times by R4; or (4) Structural unit Selected from The structural unit may be optionally substituted n times by R4, Preferably, the structural unit Selected from 28. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 20 to 27, wherein the compound of formula (I) is selected from the structure shown in formula (I-4) or formula (I-5):

29. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 20 to 28, wherein: R4 is selected from halogen, =O, OH, NH2, NO2, C 1～6 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, C 1～6 Alkoxy, C 3～6 Cycloalkyloxy, 4-7 membered heterocyclyl, 4-7 membered heterocyclyloxy, wherein the NH2, C 1～6 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, C 1～6 Alkoxy, C 3～6 Cycloalkyloxy, 4-7 membered heterocyclyl, 4-7 membered heterocyclyloxy are optionally substituted by R y replace; and / or, R4 is selected from halogen, =O, OH, NH2, C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 Cycloalkyloxy, wherein the NH2, C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 The cycloalkyloxy group is optionally substituted by R y replace; and / or, R4 is selected from halogen, =O, NH2, C 1～6 Alkyl, C 1～6 Alkoxy, wherein the NH2, C 1～6 Alkyl, C 1～6 The alkoxy group is optionally replaced by R y replace; and / or, R4 is selected from halogen, C optionally substituted by halogen 1～6 Alkyl, optionally substituted by halogen, C 1～6 Alkoxy; and / or, R4 is selected from halogen, OH, C 1～6 Alkyl, halogenated C 1～6 alkyl; and / or, R4 is selected from =O, F, Cl, Br, OH, methyl, ethyl, ethynyl, CF3, CHF2, CH2F, methoxy, N(CH3)2, NHCH3; And / or, R4 is selected from =O, methyl, CF3, F, Cl, methoxy.

30. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 29, wherein: R4 is selected from =O, methyl, CF3.

31. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 30, wherein: (1) L1 is selected from a single bond, -(CR a R b ) p -、-NR c -, -O-, -C(=O)-, -CR a R b NR c -; Among them, preferably, R a , R b are independently selected from H, halogen, OH, more preferably H; and / or, preferably R c is H; Preferably, L1 is selected from a single bond, -CH2-, -NH-, -NHCH2-, -NHCH(CH3)-, -CH2CH2-, -CH(CH2OH)-, -CH(CH3)-, -C(CH3)2-, -CH(CF3)-, -CHF-, -CF2-, -C(=O)-; More preferably, L1 is selected from a single bond, -CH2-, -CHF-, -CF2-, -CH2NH-, -CH2CH2-; More preferably, L1 is selected from a single bond, -CH2-, -CHF-, -CF2; More preferably, L1 is selected from -CH2-, -CH2NH-; and / or (2) p is selected from 1 or 2; and / or (3) R5 is selected from halogen, CN, OH, COOH, CONH2, C 1～6 Alkyl, C 1～6 Alkoxy, wherein the C 1～6 Alkyl or C 1～6 The alkoxy group is optionally replaced by R y replace; Preferably, R5 is selected from halogen, CN, OH, optionally substituted by R y Substituted C 1～6 alkyl; or R5 is selected from 4-10 membered nitrogen-containing heterocyclic group, 5-10 membered nitrogen-containing heteroaryl group, 4-10 membered sulfur-containing heterocyclic group, 5-10 membered sulfur-containing heteroaryl group, C 3～10 Cycloalkyl, 4-10 membered heterocyclic group, phenyl, 5-10 membered heteroaryl, wherein the 4-10 membered nitrogen-containing heterocyclic group, 5-10 membered nitrogen-containing heteroaryl, 4-10 membered sulfur-containing heterocyclic group, 5-10 membered sulfur-containing heteroaryl, C 3～10 Cycloalkyl, 4-10 membered heterocyclyl, phenyl, 5-10 membered heteroaryl are optionally substituted by R z replace; Preferably, R5 is selected from The R5 is optionally replaced by R z Replace 1 to 6 times; More preferably, R5 is selected from The R5 is optionally replaced by R z Replace 1 to 4 times; or Preferably, R5 is selected from The R5 is optionally replaced by R z Replace 1 to 6 times; More preferably, R5 is selected from The R5 is optionally replaced by R z Replace 1 to 6 times; More preferably, R5 is selected from The R5 is optionally replaced by R z Replace 1 to 4 times.

32. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 31, wherein: R6 is 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 heterocyclyl, 4-7 membered heterocyclyloxy, 4-7 membered heterocyclyl-NH-, C 6～10 Aryl, C 6～10 Aryloxy, 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 group, C 6～10 Aryl or 5-10 membered heteroaryl is optionally substituted by R y replace; And / or, any two R6 and the C atoms to which they are connected together form a C 3～6 Cycloalkenyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl, wherein the C 3～6 Cycloalkenyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl are optionally replaced by R y replace; and / or, R6 is 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 heterocyclyl, 4-7 membered heterocyclyloxy, 4-7 membered heterocyclyl-NH-, 5-10 membered heteroaryl or phenyl, wherein the C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-10 membered heteroaryl are optionally replaced by R y replace; and / or, R6 is selected from H, halogen, OH, CN, methyl, ethoxy, NHCH3, NHCH2CH3, NHCH(CH3)2, pyrazolyl, cyclopropyl, NH-cyclopropyl, O-cyclopropyl, O-oxetanyl, wherein the methyl, ethoxy, NHCH3, NHCH2CH3, NHCH(CH3)2, pyrazolyl, cyclopropyl, NH-cyclopropyl, O-cyclopropyl and O-oxetanyl are optionally replaced by R y replace; And / or, n is selected from 0, 1 or 2.

33. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 32, wherein: X1, X2, X3 and X4 are independently selected from CR6; and / or, X2, X3 and X4 are independently selected from CR6 or N, and X1 is selected from CR6; and / or, X2 and X4 are independently selected from CR6 or N, and X1 and X3 are independently selected from CR6; and / or, X2 and X4 are N, X1 and X3 are independently selected from CR6; and / or, X2 is N, X1, X3 and X4 are independently selected from CR6; and / or, X1, X2 and X4 are independently selected from CR6, and X3 is N; and / or, X1, X2 and X4 are CH, and X3 is CR6; and / or, X2 is N, X1 and X4 are CH, and X3 is CR6; and / or, X1, X2 and X4 are CH, and X3 is N; and / or, R z Selected from halogen, 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 heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl, wherein the C 1～6 Alkyl, C 3～10 Cycloalkyl, 4-7 membered heterocyclic group, C 6～10 The 5- to 10-membered aryl or heteroaryl group may be further substituted with R x replace; and / or, R z Selected from halogen, CN, =O, C 1～6 Alkyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, said R z Optionally R x replace; and / or, R z Selected from halogen, CN, =O, C 1～3 Alkyl, C 1～3 Alkoxy, C 3～6 Cycloalkyl, phenyl, said R z Optionally R x replace; and / or, R z is selected from halogen, optionally further R x Substituted C 1～3 alkyl; and / or, R5 is selected from and / or, L1-R5 is selected from and / or, L1-R5 is selected from and / or, L1-R5 is selected from 34. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 33, wherein: R1 and R2 are independently selected from H, halogen, 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 1～6 Alkoxy, C 3～10 Cycloalkyl or 4-10 membered heterocyclic group is optionally substituted by R x replace; and / or, R1 and R2 are independently selected from H, halogen, CN, NH2, 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 The cycloalkyl group is optionally substituted by R x Replace 1 to 3 times; And / or, R1, R2 and the atoms to which they are connected together form C 3～10 Cycloalkyl or 4-10 membered heterocyclic group, wherein the C 3～10 Cycloalkyl or 4-10 membered heterocyclic group is optionally substituted by R x replace; And / or, R1, R2 and their respective atoms and bonds together form C 3～6 Cycloalkenyl or 4-7 membered heterocyclic group, wherein the C 3～6 The cycloalkenyl or 4-7 membered heterocyclic group is optionally substituted by R v replace; and / or, R1 and R2 are independently selected from H, F, Cl, CH3, CH2CH3, CF3, cyclopropyl, cyclobutyl, fluorocyclopropyl; and / or, R1 and R2 are independently selected from H, F, Cl, CH3, CF3, cyclopropyl, cyclobutyl, fluorocyclopropyl; And / or, R1, R2 and the atoms to which they are connected together form And / or, R1, R2 and the atoms to which they are connected together form And / or, R1, R2 and the atoms to which they are connected together form And / or, R1, R2 and the atoms to which they are connected together form And / or, R1, R2 and the atoms to which they are connected together form and / or, R x independently selected from halogen, OH, CN, C 1～6 Alkyl, NH2, wherein the C 1～6 The alkyl group is further optionally substituted 1 to 3 times by halogen, cyano, hydroxyl or amine.

35. A compound or a pharmaceutically acceptable salt thereof, which is:

36. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 34, or a compound or a pharmaceutically acceptable salt thereof as claimed in claim 35, which may contain an unnatural proportion of atomic isotopes on one or more atoms constituting the compound or its pharmaceutically acceptable salt, wherein the isotopes are selected from tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C), preferably tritium ( 3 H).

37. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 34, or a compound or a pharmaceutically acceptable salt thereof according to claim 23, or a compound or a pharmaceutically acceptable salt thereof according to claim 35 in the preparation of a Cbl-b inhibitor-related drug; and / or, Use of a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt thereof, or a compound according to claim 23 or a pharmaceutically acceptable salt thereof, or a compound according to claim 35 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing Cbl-b-mediated diseases or conditions and related diseases or conditions.

38. The use according to claim 37, wherein the Cbl-b mediated disease or condition and related diseases or conditions are tumors and / or cancers; wherein the tumors and / or cancers are preferably selected from: melanoma, thyroid tumor, head and neck cancer, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial carcinoma, bladder cancer, non-small cell lung cancer, small cell lung cancer, colorectal adenoma, sarcoma, intestinal stromal tumor, gastric cancer, esophageal cancer, colorectal cancer, pancreatic cancer, small intestine cancer, kidney cancer, liver cancer, hepatocellular carcinoma, cholangiocarcinoma, mesothelioma, lymphoma, leukemia, myelodysplastic syndrome, multiple myeloma, plasmacytoma, neuroblastoma, retinoblastoma and germ cell tumor.

Images