WO2025021181A1 - Substituted pyrrolinone compounds - Google Patents

Abstract

Substituted pyrrolinone compounds. The present disclosure specifically relates to compounds represented by formula (I), stereoisomers or pharmaceutically acceptable salts thereof, a preparation method therefor, a pharmaceutical composition containing the compounds, and the use thereof in treating diseases.

Description

Substituted pyrrolidone compounds

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the priority and rights of Chinese Patent Application No. 202310930174.7 filed with the State Intellectual Property Office of China on July 26, 2023, Chinese Patent Application No. 202311071166.8 filed with the State Intellectual Property Office of China on August 23, 2023, and Chinese Patent Application No. 202410971598.2 filed with the State Intellectual Property Office of China on July 18, 2024, and the contents disclosed in said applications are incorporated herein by reference in their entirety.

Technical Field

The present disclosure relates to substituted pyrrolidone compounds, methods for preparing the same, pharmaceutical compositions containing the same, and uses thereof in treating diseases.

Background Art

Hematopoietic progenitor kinase 1 (HPK1), also known as mitogen-activated protein kinase 1 (MAP4K1), is a mammalian Ste20-related serine/threonine protein kinase, a microtubule-associated protein, and a member of the mitogen-activated protein kinase (MAP4K) family, which also includes five subtypes: GCK/MAP4K2, GLK/MAP4K3, HGK/MAP4K4, KHS1/MAP4K5 and MINK1/MAP4K6. Unlike the other five MAP4K subtypes that are widely expressed in tissue cells, HPK1 is only expressed in hematopoietic tissue cells. It can participate in the regulation of signal transduction of the hematopoietic system including lymphocytes by mediating multiple cell signaling pathways (including MAPK signaling, antigen receptor signaling and cytokine signaling).

Studies have found that HPK1 mainly acts through the c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) signaling pathways to inhibit immune cell responses. In T cells, after T cell receptor (TCR) protein activation, HPK1 interacts with a large number of TCRs and is phosphorylated by tyrosine kinases Lck and Zap70. The activated HPK1 further phosphorylates the T cell receptor adaptor protein SLP-76, establishing a docking site for the negative regulator 14-3-3, ultimately destroying the stability of the TCR signaling complex (lato-gads-SLP76) and hindering the transmission of downstream mitogen-activated protein (MAP) kinase signals, negatively regulating TCR signal transduction and then inhibiting T cell proliferation. In B cells, there is also a similar negative feedback mechanism. The B cell receptor (BCR) signal is phosphorylated and activated by HPK1, thereby blocking downstream signal transmission and inhibiting B cell proliferation. In addition, HPK1 also has a negative feedback regulatory effect on NK cells (Natural killer) and dendritic cells (DC).

Currently, there is no drug on the market targeting HPK1, and there is still a need to develop compounds with selective inhibitory activity, or better pharmacodynamics, or better pharmacokinetics in this field.

Summary of the invention

The present disclosure relates to a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

in,

X ¹ is selected from N or CR ^x ;

X ² is selected from N or CR ^z ;

^Rx and ^Rz are each independently selected from hydrogen, deuterium, _-NH2 , -NH( _C1-4 alkyl), -N( _C1-4 alkyl) ₂ , -OH, _-OC1-4 alkyl, -CN, halogen, _C1-4 alkyl, C3-6 cycloalkyl, or _3-6 membered heterocycloalkyl, wherein said -NH( _C1-4 alkyl), -N( _C1-4 alkyl) ₂ , _-OC1-4 alkyl, _C1-4 alkyl, _C3-6 cycloalkyl, and 3-6 membered heterocycloalkyl are optionally substituted with one or more deuterium, halogen, or Substituent substitution;

Y is selected from the group consisting of bonds, -O-, -S-, -NR ^a -, -C(R ^a ) ₂ -, -C(R ^a ) ₂ N(R ^a )-, -S(O) ₂ -, - S(O)-, -C(O)-, -C(O)O-, -C(O)NR ^a -, -C(O)N(R ^a )O-, -OC(O)-, -OC(O)NR ^a -, -N(R ^a )C(O)O- or -N(R ^a )C(O)-;

Ring A is selected from a 3-10 membered heterocyclyl, a C _6-10 aryl or a 5-10 membered heteroaryl;

Each R ¹ is independently selected from the group consisting of -NH ₂ , -NO ₂ , -NHR ^d , -N(R ^d ) ₂ , -OH , -OR ^d , -SR ^d , -CN , halogen , -COOR ^d , -OCOR ^d , -N(R ^d )C(O)(R ^d ), -CONH(R ^d ), -CON(R ^d ) ₂ , -NHSO ₂ (R ^d ), -SO ₂ (R ^d ), -SO ₂ NH(R ^d ), -SO ₂ N(R ^d ) ₂ , -PO(R ^d ) ₂ , -P(O)(R ^d )NR ^d , -P(O)(R ^d )OR ^d , -C _1-6 alkylene-PO(R ^d ) ₂ , -C _1-6 alkylene-P(O)(R ^d )NR ^d , -C _1-6 alkylene-P(O)(R ^d )OR ^d , -NR ^d -C _1-6 alkylene-PO(R ^d ) ₂ , -NR ^d -C _1-6 alkylene-P(O)(R ^d )NR ^d , -NR ^d -C _1-6 alkylene-P(O)(R ^d )OR ^d , -OC _1-6 alkylene-PO(R ^d ) ₂ , -OC _1-6 alkylene-P(O)(R ^d )NR ^d , -OC _1-6 alkylene-P(O)(R ^d )OR ^d , C _1-6 alkyl, C _6-10 aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclic group, wherein the -C _1-6 alkylene-PO(R ^d ) ₂ , -C _1-6 alkylene-P(O)(R ^d )NR ^d , -C _1-6 alkylene _- P(O)(R ^d )OR ^d , -NR ^d -C _1-6 alkylene-PO(R ^d ) ₂ , -NR ^d -C _1-6 alkylene-P(O)(R ^d )NR ^d , -NR ^d -C _1-6 alkylene-P(O)(R ^d )OR ^d , -OC _1-6 alkylene-PO(R ^d ) ₂ , -OC _1-6 alkylene-P(O)(R ^d )NR ^d , -OC _1-6 alkylene-P(O)(R ^d )OR ^d , C _1-6 alkyl, C _6-10 aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl is optionally substituted with one or more R ^b ;

Each ^Rd is independently selected from hydrogen, _C1-6 alkyl, _C3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein said _C1-6 alkyl, _C3-6 cycloalkyl and 3-6 membered heterocycloalkyl are optionally substituted with one or more deuterium, halogen or Substituent substitution;

R ² is selected from 8-12 membered saturated, partially saturated or aromatic bicyclic groups, 9-14 membered saturated, partially saturated or aromatic tricyclic groups, wherein the bicyclic group or tricyclic group contains 0-6 heteroatoms independently selected from N, O or S, and the R ² is optionally substituted by one or more R ^c ;

Provided that when ^R2 is a bicyclic group, ^X2 is N, and at least one ^R1 is selected from the group consisting of -PO( ^Rd ) ₂ , -P(O)( ^Rd ) ^NRd , -P(O)( ^Rd ) ^ORd , _{-C1-6alkylene} -PO( ^Rd ) ₂ , _{-C1-6alkylene} -P(O)(Rd ^{) NRd} , _{-C1-6alkylene} -P(O)( ^Rd ) ^ORd , -NRd ^- _C1-6alkylene -PO( ^Rd ) ₂ , -NRd ^- _C1-6alkylene -P(O)( ^Rd ) ^NRd , -NRd ^- _C1-6alkylene -P(O)( ^Rd ) ^ORd , _{-OC1-6alkylene} -PO( ^Rd ) ₂ , -OC1-6alkylene _{-C 1-6} alkylene-P(O)(R ^d )NR ^d , -OC _1-6 alkylene-P(O)(R ^d )OR ^d , or a 3-10 membered heterocyclic group containing a phosphorus ring heteroatom, wherein the -C _1-6 alkylene-PO(R ^d ) ₂ , -C _1-6 alkylene-P(O)(R ^d )NR ^d , -C _1-6 alkylene-P(O)(R ^d )OR ^d , -NR ^d -C _1-6 alkylene-PO(R ^d ) ₂ , -NR ^d -C _1-6 alkylene-P(O)(R ^d )NR ^d , -NR ^d -C _1-6 alkylene-P(O)(R ^d )OR ^d , -OC _1-6 alkylene-PO(R ^d ) ₂ , -OC _1-6 alkylene-P(O)(R ^d )NR ^d , -OC _1-6 alkylene-P(O)(R ^d )OR ^d , or a 3-10 membered heterocyclic group containing a phosphorus ring heteroatom is optionally substituted by one or more R ^b ;

Each R ³ is independently selected from deuterium, -NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , -OH, -OC _1-4 alkyl, -CN, halogen, C _1-4 alkyl, C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein said -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , -OC _1-4 alkyl, C _1-4 alkyl, C _3-6 cycloalkyl and 3-6 membered heterocycloalkyl are optionally substituted with one or more deuterium, halogen or Substituent substitution;

^R4 is selected from hydrogen, deuterium, _C1-4 alkyl, _C3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein the _C1-4 alkyl, _C3-6 cycloalkyl and 3-6 membered heterocycloalkyl are optionally substituted with one or more deuterium, halogen or Substituent substitution;

Each ^Ra is independently selected _from hydrogen, deuterium, halogen, -CN, _C1-4 alkyl, _C3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein said _C1-4 alkyl, _C3-6 cycloalkyl and 3-6 membered heterocycloalkyl are optionally substituted with one or more deuterium, halogen or -CN. Substituent substitution;

Each R ^b is independently selected from deuterium, -NH ₂ , -NO ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , -OH, -OC _1-4 alkyl, -SC _1-4 alkyl, -CN _, halogen, C _1-4 alkyl, -C _1-4 alkylene-N(C _1-4 alkyl) ₂ , -CH(C _1-4 alkyl) ₂ , -C _1-4 alkylene-OC _1-4 alkyl, C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein said -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , -OC _1-4 alkyl, -SC _1-4 alkyl, C _1-4 alkyl, -C _1-4 alkylene-N(C _1-4 alkyl) ₂ , -CH(C _1-4 alkyl) ₂ , -C _1-4 alkylene-OC _1-4 alkyl, C _3-6 cycloalkyl and 3-6 membered heterocycloalkyl are optionally substituted with one or more deuterium, -OH, halogen or Substituent substitution;

Each R ^c is independently selected from deuterium, -NH ₂ , -NO ₂ , -CN, -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , -OH, -SC _1-4 alkyl, -OC _1-4 alkyl, halogen, or C _1-4 alkyl, C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein said -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , -SC _1-4 alkyl, -OC _1-4 alkyl, C _1-4 alkyl, C _3-6 cycloalkyl and 3-6 membered heterocycloalkyl are optionally substituted with one or more deuterium, halogen or Substituent substitution;

n is selected from 1, 2, 3 or 4;

m is selected from 0, 1 or 2;

Optionally, each R ^x , R ^z , R ³ , R ⁴ , Ra , R ^b , R ^c or ^{R d is} each independently optionally substituted with one or more additional substituents.

In some embodiments of the present disclosure, each R ^x , R ^z , R ³ , R ⁴ , ^Ra , R ^b , R ^c or R ^d is each independently optionally substituted with 1 , 2 or 3 additional substituents.

In some embodiments of the present disclosure, each of R ^x , R ^z , R ³ , R ⁴ , ^Ra , R ^b , R ^c or R ^d is independently substituted with one or more other substituents selected from the group consisting of deuterium, -OH, -SH, halogen, -NH ₂ , nitro, nitroso, -CN, an azide group, a sulfoxide group, a sulfone group, a sulfone group, a sulfonamide group, a carboxyl group, a carboxaldehyde group, an imine group, an alkyl group, a halo-alkyl group, a cycloalkyl group, a halo-cycloalkyl group, an alkenyl group, a halo-alkenyl group, a cycloalkenyl group, a halo-cycloalkenyl group, an alkynyl group, a halo-alkynyl group, a cycloalkynyl group, a halo-cycloalkynyl group, a heteroalkyl group, a halo-heteroalkyl group, an alkoxy group, an alkylthio group, an aryl group, an aryloxy group, an arylthio group, an aralkyl group, an arylalkoxy group, an arylalkylthio group, a heteroaryl group, a heteroaryloxy group, a heteroarylthio group, a heteroaralkyl group, a heteroarylalkoxy group, a heteroarylalkylthio group, a heterocyclyl group, a heterocyclyloxy group, a heterocyclylthio group, a heterocyclylalkyl group, a heterocyclylalkoxy group, a heterocyclylalkylthio group, an acyl group, an acyloxy group, a carbamate group, an amide group, a urea group, an epoxy group, and an ester group, etc.

In some embodiments of the present disclosure, the "one or more" is selected from 1, 2, 3, 4, 5, 6, 7, 8, or 9. In some embodiments of the present disclosure, the "one or more" is selected from 1, 2, 3, 4, 5, or 6. In some embodiments of the present disclosure, the "one or more" is selected from 1, 2, or 3. In some embodiments of the present disclosure, the "one or more" is selected from 1 or 2.

In some embodiments of the present disclosure, the pharmaceutically acceptable salt described in the present disclosure is a hydrochloride (eg, monohydrochloride).

In some embodiments of the present disclosure, the pharmaceutically acceptable salt of the compound of formula (I) is the hydrochloride salt of the compound of formula (I).

In some embodiments of the present disclosure, the pharmaceutically acceptable salt of the compound of formula (I) is the monohydrochloride salt of the compound of formula (I).

In some embodiments of the present disclosure, the heteroaryl, heterocyclyl and heterocycloalkyl each independently include 1, 2, 3 or 4 heteroatoms selected from N, O, S or P, and the remaining ring atoms are carbon. In some embodiments of the present disclosure, the heteroaryl, heterocyclyl and heterocycloalkyl each independently include 1, 2 or 3 heteroatoms selected from N, O or S, and the remaining ring atoms are carbon. In some embodiments of the present disclosure, the heteroaryl, heterocyclyl and heterocycloalkyl each independently include 1, 2 or 3 heteroatoms selected from N or O, and the remaining ring atoms are carbon. In some embodiments of the present disclosure, the heteroaryl, heterocyclyl and heterocycloalkyl each independently include 1 or 2 heteroatoms selected from N or O, and the remaining ring atoms are carbon. In some embodiments of the present disclosure, the heterocyclyl and heterocycloalkyl each independently include 1 or 2 heteroatoms selected from N or P, and the remaining ring atoms are carbon.

In some embodiments of the present disclosure, X ¹ is selected from CR ^x , and X ² is N.

In some embodiments of the present disclosure, X ¹ is N, and X ² is selected from CR ^z .

In some embodiments of the present disclosure, X ¹ is selected from CR ^x , and X ² is selected from CR ^z .

In some embodiments of the present disclosure, ^X1 and ^X2 are both CH.

In some embodiments of the present disclosure, X ¹ is CH and X ² is N.

In some embodiments of the present disclosure, X ¹ is N, and X ² is CH.

In some embodiments of the present disclosure, R ⁴ is selected from hydrogen or C _1-3 alkyl.

In some embodiments of the present disclosure, R ⁴ is selected from hydrogen or methyl.

In some embodiments of the present disclosure, R ⁴ is hydrogen.

In some embodiments of the present disclosure, ^Rx and ^Rz are each independently selected from hydrogen, deuterium, _-NH2 , -NH( _C1-3 alkyl), -N( _C1-3 alkyl) ₂ , -OH, _-OC1-3 alkyl, -CN, halogen, _C1-3 alkyl, _C3-5 cycloalkyl, or 3-5 membered heterocycloalkyl.

In some embodiments of the present disclosure, R ^x and R ^z are each independently selected from hydrogen or C _1-3 alkyl.

In some embodiments of the present disclosure, R ^x is selected from hydrogen or C _1-3 alkyl.

In some embodiments of the present disclosure, R ^z is selected from hydrogen or C _1-3 alkyl.

In some embodiments of the present disclosure, R ^x and R ^z are each independently hydrogen.

In some embodiments of the present disclosure, each ^Ra is independently selected from hydrogen or _C1-3 alkyl.

In some embodiments of the present disclosure, each ^Ra is independently selected from hydrogen or methyl.

In some embodiments of the present disclosure, ^Ra is hydrogen.

In some embodiments of the present disclosure, Y is selected from a bond, -O-, -S-, or -NR ^a -.

In some embodiments of the present disclosure, Y is -NR ^a -. In some embodiments of the present disclosure, Y is -NH-.

In some embodiments of the present disclosure, Ring A is selected from C _6-10 aryl or 5-10 membered heteroaryl.

In some embodiments of the present disclosure, Ring A is selected from C _6-8 aryl or 5-8 membered heteroaryl.

In some embodiments of the present disclosure, Ring A is selected from phenyl or 5-6 membered heteroaryl.

In some embodiments of the present disclosure, Ring A is selected from a 5-8 membered heterocyclyl.

In some embodiments of the present disclosure, Ring A is selected from a 5-6 membered heterocyclyl.

In some embodiments of the present disclosure, ring A is selected from phenyl or a 5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from N, O or S.

In some embodiments of the present disclosure, ring A is selected from phenyl or a 5-membered or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N or S.

In some embodiments of the present disclosure, Ring A is selected from phenyl or a 6-membered heteroaryl containing 1 or 2 N heteroatoms.

In some embodiments of the present disclosure, Ring A is selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, imidazolyl, or oxazolyl.

In some embodiments of the present disclosure, Ring A is selected from phenyl, pyridyl, or thiazolyl.

In some embodiments of the present disclosure, Ring A is selected from pyridyl or thiazolyl.

In some embodiments of the present disclosure, each R ¹ is independently selected from -NH ₂ , -NH(R ^d ), -N(R ^d ) ₂ , halogen, -N(R ^d )C(O)(R ^d ), -NHSO ₂ (R ^d ), -SO ₂ NH(R ^d ), PO(R ^d ) ₂ , C _1-6 alkyl, -OC _1-6 alkyl, 5-8 membered heteroaryl, or 3-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, S or P, wherein the C _1-6 alkyl, 5-8 membered heteroaryl, or 3-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, S or P is optionally substituted by one or more R ^b .

In some embodiments of the present disclosure, each R ¹ is independently selected from -NH ₂ , -NH(R ^d ), -N(R ^d ) ₂ , -OR ^d , halogen, - N(R ^d )C(O)(R ^d )、-NHSO ₂ (R ^d )、-SO ₂ NH(R ^d )、PO(R ^d ) ₂ , C _1-6 alkyl, 3-10 membered heterocycloalkyl, 5-6 membered heteroaryl or 5-10 membered heterocycloalkenyl, wherein the C _1-6 alkyl, 3-10 membered heterocycloalkyl, 5-6 membered heteroaryl or 5-10 membered heterocycloalkenyl is optionally substituted by one or more R ^b .

In some embodiments of the present disclosure, each R ¹ is independently selected from the group consisting of -NH ₂ , -NO ₂ , -NHR ^d , -N(R ^d ) ₂ , -OH, -OR ^d , -SR ^d , -CN, halogen, -COOR ^d , -OCOR ^d , -N(R ^d )C(O)(R ^d ), -CONH(R ^d ), -CON(R ^d ) ₂ , -NHSO ₂ (R ^d ), -SO ₂ (R ^d ), -SO ₂ NH(R ^d ), -SO ₂ N(R ^d ) ₂ , -PO(R ^d ) ₂ , -P(O)(R ^d )NR ^d , -P(O)(R ^d )OR ^d , -C _1-4 alkylene-PO(R ^d ) ₂ , -C _1-4 alkylene-P(O)(R ^d )NR ^d , -C _1-4 alkylene-P(O)(R ^d )OR ^d , -NR ^d -C _1-4 alkylene-PO(R ^d ) ₂ , -NR ^d -C _1-4 alkylene-P(O)(R ^d )NR ^d , -NR ^d -C _1-4 alkylene-P(O)(R ^d )OR ^d , -OC _1-4 alkylene-PO(R ^d ) ₂ , -OC _1-4 alkylene-P(O)(R ^d )NR ^d , -OC _1-4 alkylene-P(O)(R ^d )OR ^d , C _1-4 alkylene-PO(R ^d ) ₂ , -C _1-4 alkylene-P(O)(R ^{d )NR d , -C 1-4 alkylene-P(O)(R d} _{) OR} ^{d ,} -NR ^d -C _1-4 alkylene-PO(R ^d ) ₂ , -NR ^d -C _1-4 alkylene-P(O)(R d )NR ^d , -NR d -C _1-4 alkylene-P(O)(R ^d )OR ^d , -OC _1-4 alkylene-PO(R ^d ) 2 , -OC 1-4 alkylene-P(O)(R d )NR ^d , -OC 1-4 alkylene-P(O)(R d )OR ^d , C _1-4 alkylene-PO(R ^d ) ₂ , -OC _1-4 alkylene-P(O)(R ^d )NR ^d , -OC _1-4 alkylene-P(O)(R ^d )OR ^d , C The _1-4 alkyl, C _6-10 aryl, 5-10 membered heteroaryl or 5-9 membered heterocyclyl is optionally substituted with one or more R ^b .

In some embodiments of the present disclosure, when R ¹ is selected from a group containing an “alkylene” group, and is substituted by R ^b , the R ^b replaces a hydrogen atom on the “alkylene” group.

In some embodiments of the present disclosure, each R ¹ is independently selected from -NH ₂ , -NH(R ^d ), -N(R ^d ) ₂ , halogen, -N(R ^d )C(O)(R ^d ), -NHSO ₂ (R ^d ), -SO ₂ NH(R ^d ), -PO(R ^d ) ₂ , C _1-4 alkyl, -OC _1-4 alkyl, 5-9 membered heterocycloalkyl or 5-6 membered heterocycloalkenyl, wherein the C _1-4 alkyl, 5-9 membered heterocycloalkyl or 5-6 membered heterocycloalkenyl is optionally substituted by one or more R ^b .

In some embodiments of the present disclosure, the heteroatom in the heterocyclyl, heterocycloalkyl or heterocycloalkenyl in R ¹ is selected from N, O, S or P; or, is selected from N, O or S; or, is selected from N or P.

In some embodiments of the present disclosure, each R ¹ is independently selected from -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , F, Cl, Br, -OCH ₃ , -OCH ₂ CH ₃ , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, tetrahydropyrrolyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophenyl, morpholinyl, piperidinyl, piperazinyl, tetrahydroimidazolyl, azacycloheptanyl, azacycloheptanyl, azacycloheptanyl, azacycloheptanyl, azacycloheptanyl, -N(CH ₃ )C(O)CH ₃ , -NHSO ₂ (CH ₃ ), -SO ₂ NH(CH ₃ ), -PO(CH ₃ ) ₂ , Rb is substituted with 1 or more Rb, and the 1 or more Rb is substituted with 1 or more ^Rb .

In some embodiments of the present disclosure, each R ¹ is independently selected from halogen, -NH ₂ , -NH(R ^d ), -N(R ^d ) ₂ , -OR ^d , C _1-6 alkyl, 5-9 membered heterocyclyl, wherein the C _1-6 alkyl or 5-9 membered heterocyclyl is optionally substituted with one or more R ^b .

In some embodiments of the present disclosure, each R ¹ is independently selected from halogen, -NH ₂ , -NH(R ^d ), -N(R ^d ) ₂ , C _1-6 alkyl, -OC _1-6 alkyl, or 5-9 membered heterocyclyl, wherein the C _1-6 alkyl or 5-9 membered heterocyclyl is optionally substituted with one or more R ^b .

In some embodiments of the present disclosure, each R ¹ is independently selected from halogen, -NH ₂ , -NH(R ^d ), -N(R ^d ) ₂ , C _1-4 alkyl, -OC _1-4 alkyl, 5-9 membered heterocycloalkyl, or 5-6 membered heterocycloalkenyl, wherein the C _1-4 alkyl, 5-9 membered heterocycloalkyl, or 5-6 membered heterocycloalkenyl is optionally substituted with one or more R ^b .

In some embodiments of the present disclosure, each R ¹ is independently selected from halogen, -NH ₂ , -NH(R ^d ), -N(R ^d ) ₂ , C _1-4 alkyl, -OC _1-3 alkyl, or 5-, 6-, or 9-membered heterocycloalkyl, wherein the C _1-4 alkyl, or 5-, 6-, or 9-membered heterocycloalkyl is optionally substituted with one or more R ^b .

In some embodiments of the present disclosure, each R ¹ is independently selected from halogen, C _1-4 alkyl, -OC _1-3 alkyl, or 5-6 membered heterocycloalkyl, wherein the C _1-4 alkyl or 5-6 membered heterocycloalkyl is optionally substituted with one or more R ^b .

In some embodiments of the present disclosure, each R ¹ is independently selected from -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , F, Cl, Br, -OCH ₃ , -OCH ₂ CH ₃ , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, azophosphorus biheterocyclohexyl, or a 9-membered heterocycloalkyl containing 3 heteroatoms selected from N or O, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, azophosphorus biheterocyclohexyl, or a 9-membered heterocycloalkyl containing 3 heteroatoms selected from N or O is optionally substituted with one or more R ^b .

In some embodiments of the present disclosure, each R ¹ is independently selected from -NH ₂ , F, methyl, -OCH ₃ , tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, The methyl, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, Optionally substituted with 1, 2 or 3 R ^b .

In some embodiments of the present disclosure, each R ¹ is independently selected from F, methyl, -OCH ₃ , tetrahydrofuranyl, tetrahydropyranyl, or The methyl, tetrahydrofuranyl, tetrahydropyranyl or Optionally substituted with 1, 2 or 3 R ^b .

In some embodiments of the present disclosure, each R ¹ is independently selected from F, methyl, -OCH ₃ , The methyl group, -OCH ₃ , Optionally substituted with 1, 2 or 3 R ^b .

In some embodiments of the present disclosure, each R ¹ is independently selected from F, methyl, -OCH ₃ , The methyl group, Optionally substituted with 1, 2 or 3 R ^b .

In some embodiments of the present disclosure, each R ¹ is independently selected from F, methyl, -OCH ₃ , -CHF ₂ ,

In some embodiments of the present disclosure, each R ¹ is independently selected from F, -OCH ₃ , -CHF ₂ ,

In some embodiments of the present disclosure, each R ¹ is independently selected from F, methyl, -OCH ₃ , -CHF ₂ ,

In some embodiments of the present disclosure, each ^Rd is independently selected from _C1-6 alkyl, _C3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein the _C1-6 alkyl, _C3-6 cycloalkyl and 3-6 membered heterocycloalkyl are optionally substituted with one or more deuterium, halogen or Substituent substitution.

In some embodiments of the present disclosure, each ^Rd is independently selected from _{C1-4 alkyl} or _C3-6 cycloalkyl, wherein the _C1-4 alkyl or _C3-6 cycloalkyl is optionally substituted by one or more deuterium, halogen or Substituent substitution.

In some embodiments of the present disclosure, each R ^d is independently selected from C _1-4 alkyl or C _3-6 cycloalkyl.

In some embodiments of the present disclosure, each R ^d is each independently selected from C _1-3 alkyl. In some embodiments of the present disclosure, each R ^d is each independently selected from C _3-5 cycloalkyl.

In some embodiments of the present disclosure, each R ^d is independently selected from methyl, ethyl, n-propyl, or isopropyl.

In some embodiments of the present disclosure, each R ^d is independently methyl.

In some embodiments of the present disclosure, each R ^b is independently selected from deuterium, -OH, halogen, C _1-4 alkyl, -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , -OC _1-4 alkyl, -C _1-4 alkylene-N(C 1-4 alkyl) ₂ , _-CH (C _1-4 alkyl) ₂ , -C _1-4 alkylene-OC _1-4 alkyl, or 3-6 membered heterocycloalkyl, wherein the C _1-4 alkyl, -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , -OC _1-4 alkyl, -C _1-4 alkylene-N(C _1-4 alkyl) ₂ , -CH(C _1-4 alkyl) ₂ , -C _1-4 alkylene-OC _1-4 alkyl, or 3-6 membered heterocycloalkyl is optionally substituted with one or more deuterium, -OH, halogen or Substituent substitution.

In some embodiments of the present disclosure, each R ^b is independently selected from deuterium, -OH, halogen, C _1-4 alkyl, -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , -C _1-4 alkylene-N(C _1-4 alkyl) ₂ , -CH(C _1-4 alkyl) ₂ , -C _1-4 alkylene-OC _1-4 alkyl, or 3-6 membered heterocycloalkyl, wherein the C _1-4 alkyl, -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , -C _1-4 alkylene-N(C _1-4 alkyl) ₂ , -CH(C _1-4 alkyl) ₂ , -C _1-4 alkylene-OC _1-4 alkyl, or 3-6 membered heterocycloalkyl is optionally substituted with one or more deuterium, -OH, halogen or Substituent substitution.

In some embodiments of the present disclosure, each R ^b is independently selected from deuterium, halogen, C _1-4 alkyl, -NH(C _1-4 alkyl) or -N(C _1-4 alkyl) ₂ , wherein the C _1-4 alkyl, -NH(C _1-4 alkyl) or -N(C _1-4 alkyl) ₂ is optionally substituted with one or more deuterium.

In some embodiments of the present disclosure, each R ^b is independently selected from -OH, deuterium, F, Cl, Br, C _1-4 alkyl, -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , -C _1-4 alkylene-N(C _1-4 alkyl) ₂ , _-CH (C _1-4 alkyl) ₂ , -C _1-4 alkylene-OC _1-4 alkyl, or 5-membered heterocycloalkyl, wherein the C _1-4 alkyl, -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , -C _1-4 alkylene-N(C _1-4 alkyl) ₂ , -CH(C _1-4 alkyl) ₂ , -C _1-4 alkylene-OC _1-4 alkyl, or 5-membered heterocycloalkyl is optionally substituted with one or more deuterium, -OH, halogen or Substituent substitution.

In some embodiments of the present disclosure, each R ^b is independently selected from deuterium, -OH, F, C _1-3 alkyl, -NH(C _1-3 alkyl), -N(C _1-3 alkyl) ₂ , -C _1-3 alkylene-N(C _1-3 alkyl) ₂ , -CH(C _1-3 alkyl) ₂ or -C _1-3 alkylene-OC _1-3 alkyl, wherein the C _1-3 alkyl, -NH(C _1-3 alkyl), -N(C _1-3 alkyl) ₂ , -C _1-3 alkylene-N(C _1-3 alkyl) ₂ , -CH(C _1-3 alkyl) ₂ or -C _1-3 alkylene-OC _1-3 alkyl is optionally substituted with one or more deuterium or -OH.

In some embodiments of the present disclosure, each R ^b is independently selected from deuterium, -OH, F, -CH ₃ , -NH(CH ₃ ), -N(CH ₃ ) ₂ , -N(CD ₃ ) ₂ , -CH ₂ N(CH ₃ ) ₂ , -C(OH)(CH ₃ ) ₂ or -CH ₂ OCH ₃ .

In some embodiments of the present disclosure, n is selected from 1, 2 or 3.

In some embodiments of the present disclosure, n is selected from 1 or 2.

In some embodiments of the present disclosure, n is 2.

In some embodiments of the present disclosure, m is selected from 0, 1 or 2.

In some embodiments of the present disclosure, m is selected from 0 or 1.

In some embodiments of the present disclosure, m is 0.

In some embodiments of the present disclosure, Selected from

In some embodiments of the present disclosure, Selected from

In some embodiments of the present disclosure, Selected from

In some embodiments of the present disclosure, each R ³ is independently selected from halogen or C _1-4 alkyl, wherein the C _1-4 alkyl is optionally substituted with one or more deuterium or halogen substituents.

In some embodiments of the present disclosure, each R ³ is independently selected from halogen, C _1-3 alkyl or halogenated C _1-3 alkyl.

In some embodiments of the present disclosure, each R ³ is independently selected from F, Cl, Br or C _1-3 alkyl.

In some embodiments of the present disclosure, each R ³ is independently selected from F or methyl.

In some embodiments of the present disclosure, one or both rings in the bicyclic group are aromatic.

In some embodiments of the present disclosure, one, two or three rings in the tricyclic group are aromatic rings.

In some embodiments of the present disclosure, two or three rings in the tricyclic group are aromatic rings.

In some embodiments of the present disclosure, the bicyclic or tricyclic group is Some of the linked monocyclic rings are aromatic rings.

In some embodiments of the present disclosure, the bicyclic or tricyclic group is Some of the connected monocyclic rings are aromatic rings containing a nitrogen atom, or are 5-6 membered heteroaromatic rings containing 1 or 2 nitrogen atoms.

In some embodiments of the present disclosure, any two adjacent rings in the tricyclic group are optionally fused rings, bridged rings or spiro rings.

In some embodiments of the present disclosure, the bicyclic or tricyclic group is A partially connected single ring and its adjacent ring are a fused ring.

In some embodiments of the present disclosure, R ² is selected from a 9-14 membered saturated, partially saturated or aromatic tricyclic group, wherein the tricyclic group contains 1-6 heteroatoms independently selected from N, O or S, and the R ² is optionally substituted with one or more R ^c .

In some embodiments of the present disclosure, ^R is selected from a 9-, 10-, 11-, 12-, 13- or 14-membered partially saturated or aromatic tricyclic group, wherein the tricyclic group contains 2, 3 or 4 heteroatoms independently selected from N or O, and the ^R is optionally substituted with one or more ^R.

In some embodiments of the present disclosure, R ² is selected from a 12-membered aromatic tricyclic group, wherein the tricyclic group contains 2, 3 or 4 heteroatoms independently selected from N or O, and the R ² is optionally substituted with one or more R ^c .

In some embodiments of the present disclosure, R ² is selected from a 12-membered aromatic tricyclic group, wherein the tricyclic group contains 3 or 4 heteroatoms independently selected from N or O.

In some embodiments of the present disclosure, R ² is selected from a 9-, 10-, 11-, 12-membered partially saturated or aromatic bicyclic group.

In some embodiments of the present disclosure, R ² is selected from a 9-10 membered aromatic bicyclic group containing 1-3 heteroatoms independently selected from N, O or S.

In some embodiments of the present disclosure, R ² is selected from a 9-10 membered aromatic bicyclic group containing 1-3 N heteroatoms.

In some embodiments of the present disclosure, when R ² is a bicyclic group, X ² is N, and at least one R ¹ is selected from -PO(R ^d ) ₂ , -P(O)(R ^d )NR ^d , -P(O)(R ^d )OR ^d , -C _1-4 alkylene-PO(R ^d ) ₂ , -C _1-4 alkylene-P(O)(R ^d )NR ^d , -C _1-4 alkylene-P(O)(R ^d )OR ^d , -NR ^d -C _1-4 alkylene-PO(R ^d ) ₂ , -NR ^d -C _1-4 alkylene-P(O)(R ^d )NR ^d , -NR ^d -C _1-4 alkylene-P(O)(R ^d )OR ^d , -OC _1-4 alkylene-PO(R ^d ) ₂ , -OC _1-4 alkylene _-C 1-4 alkylene-P(O)(R ^d )NR ^d , -OC _1-4 alkylene-P(O)(R ^d )OR ^d , or a 3-10 membered heterocyclic group containing a phosphorus ring heteroatom, wherein the -C _1-4 alkylene-PO(R ^d ) ₂ , -C _1-4 alkylene-P(O)(R ^d )NR ^d , -C _1-4 alkylene-P(O)(R ^d )OR ^d , -NR ^d -C _1-4 alkylene-PO(R ^d ) ₂ , -NR ^d -C _1-4 alkylene-P(O)(R ^d )NR ^d , -NR ^d -C _1-4 alkylene-P(O)(R ^d )OR ^d , -OC _1-4 alkylene-PO(R ^d ) ₂ , -OC _1-4 alkylene-P(O)(R ^d )NR ^d , -OC _1-4 alkylene-P(O)(R ^d )OR ^d , 3-10 membered heterocyclic group containing a phosphorus ring heteroatom is optionally substituted by one or more R ^b .

In some embodiments of the present disclosure, when R ² is a bicyclic group, X ² is N, and at least one R ¹ is selected from -PO(R ^d ) ₂ , -P(O)(R ^d )NR ^d , -P(O)(R ^d )OR ^d , or a 3-10 membered heterocyclic group containing a phosphorus ring heteroatom, wherein the 3-10 membered heterocyclic group containing a phosphorus ring heteroatom is optionally substituted by one or more R ^b .

In some embodiments of the present disclosure, R ² is selected from an 8-12 membered partially saturated or aromatic bicyclic group, X ² is N, and at least one R ¹ is selected from -PO(R ^d ) ₂ , -P(O)(R ^d )NR ^d , -P(O)(R ^d )OR ^d , or a 5-8 membered heterocyclic group containing a phosphorus ring heteroatom, wherein the bicyclic group contains 1-6 heteroatoms independently selected from N, O or S, and the R ² is optionally substituted by one or more R ^c , and the 5-8 membered heterocyclic group containing a phosphorus ring heteroatom is The heterocyclyl group is optionally substituted with one or more R ^b .

In some embodiments of the present disclosure, when R ² is a bicyclic group, X ² is N, and at least one R ¹ is selected from a 5-8 membered heterocycloalkyl group containing a phosphorus ring heteroatom, wherein the R ² is optionally substituted by one or more R ^c , and the 5-8 membered heterocycloalkyl group containing a phosphorus ring heteroatom is optionally substituted by one or more halogen, or C _1-3 alkyl substituted.

In some embodiments of the present disclosure, when R ² is a bicyclic group, X ² is N, and one R ¹ is selected from a nitrogen phosphorus bis-heterocyclohexyl group, the nitrogen phosphorus bis-heterocyclohexyl group is optionally substituted by one or more halogens, or C _1-3 alkyl substituted.

In some embodiments of the present disclosure, when R ² is a bicyclic group, X ² is N, and one R ¹ is selected from Said Optionally, one or more halogens, or C _1-3 alkyl. In some embodiments of the present disclosure, when R ² is a bicyclic group, X ² is N, and at least one R ¹ is

In some embodiments of the present disclosure, R ² is selected from a 9-, 10-, 11-, 12-, 13-, or 14-membered partially saturated or aromatic tricyclic group, wherein the tricyclic group contains 1-4 heteroatoms independently selected from N, O, or S, and the R ² is optionally substituted with one or more R ^c .

In some embodiments of the present disclosure, the heteroatom in the bicyclic or tricyclic group described in R ² is selected from N, O or S.

In some embodiments of the present disclosure, the heteroatom in the bicyclic or tricyclic group described in R ² is selected from N or S.

In some embodiments of the present disclosure, the heteroatom in the bicyclic or tricyclic group described in R ² is selected from N or O.

In some embodiments of the present disclosure, the heteroatom in the bicyclic or tricyclic group described in R ² is N.

In some embodiments of the present disclosure, R ² is selected from a 9-, 10-, 11-, 12-, 13-membered partially saturated or aromatic tricyclic group, wherein the tricyclic group contains 1-3 heteroatoms independently selected from N, O or S, and the R ² is optionally substituted by one or more R ^c .

In some embodiments of the present disclosure, R ² is selected from a 9-, 10-, 11-, 12-membered partially saturated or aromatic bicyclic group, the bicyclic group contains 1-3 heteroatoms independently selected from N, O or S, and X ² is N, and at least 1 R ¹ is selected from -PO(CH ₃ ) ₂ , -P(O)(CH ₃ )NCH ₃ , -P(O)(CH ₃ )OCH ₃ , or a 5-8 membered heterocycloalkyl containing a phosphorus ring heteroatom, wherein the R ² is optionally substituted by one or more R ^c , and the 5-8 membered heterocycloalkyl containing a phosphorus ring heteroatom is optionally substituted by one or more R ^b .

In some embodiments of the present disclosure, R ² is selected from a 10-membered or 12-membered partially saturated or aromatic tricyclic group, wherein the tricyclic group contains 1-3 heteroatoms independently selected from N, O or S, and the R ² is optionally substituted with one or more R ^c .

In some embodiments of the present disclosure, R ² is selected from a 10-membered or 12-membered partially saturated or aromatic tricyclic group, wherein the tricyclic group contains 2, 3 or 4 heteroatoms independently selected from N or O, and the R ² is optionally substituted with one or more R ^c .

In some embodiments of the present disclosure, R ² is selected from a 9-10 membered aromatic bicyclic group containing 1-3 heteroatoms independently selected from N, O or S, and X ² is N, and at least one R ¹ is selected from a 5-8 membered heterocycloalkyl group containing a phosphorus ring heteroatom, wherein said R ² is optionally substituted by one or more R ^c , and said 5-8 membered heterocycloalkyl group containing a phosphorus ring heteroatom is optionally substituted by one or more halogen, or C _1-3 alkyl substituted.

In some embodiments of the present disclosure, R ² is selected from a 10-membered or 12-membered partially saturated or aromatic tricyclic group, wherein the tricyclic group contains 2 or 3 heteroatoms independently selected from N or O, and the R ² is optionally substituted with one or more R ^c .

In some embodiments of the present disclosure, R ² is selected from a 9-12 membered partially saturated or aromatic bicyclic group, X ² is N, and at least one R ¹ is selected from a 5-6 membered heterocycloalkyl group containing a phosphorus ring heteroatom, wherein the 5-6 membered heterocycloalkyl group containing a phosphorus ring heteroatom is optionally substituted with one or more halogens, or C _1-3 alkyl substituted.

In some embodiments of the present disclosure, R ² is selected from a 9-10 membered aromatic bicyclic group, X ² is N, and at least one R ¹ is a 5-6 membered heterocycloalkyl group containing nitrogen and phosphorus heteroatoms, wherein the R ² is optionally substituted with one or more halogens, and the 5-6 membered heterocycloalkyl group containing nitrogen and phosphorus heteroatoms is optionally substituted with one or more or C _1-3 alkyl substituted.

In some embodiments of the present disclosure, ^R2 is selected from a 9-10 membered aromatic bicyclic group containing 1-3 heteroatoms selected from N or O, ^X2 is N, n is 2, and one ^R1 is selected from a 6 membered heterocycloalkyl group containing nitrogen and phosphorus ring heteroatoms, the 6 membered heterocycloalkyl group containing nitrogen and phosphorus ring heteroatoms is optionally replaced by one or more or C _1-3 alkyl, said R ² is optionally substituted by one or more R ^c .

In some embodiments of the present disclosure, R ² is selected from a 9-10 membered aromatic bicyclic group containing 2 N atoms, X ² is N, n is 2, and one R ¹ is a 6 membered heterocycloalkyl group containing nitrogen and phosphorus heteroatoms, and the other R ¹ is -CH ₂ N(CH ₃ ) ₂ , wherein the 6 membered heterocycloalkyl group containing nitrogen and phosphorus heteroatoms is optionally replaced by one or more or C _1-3 alkyl, said R ² is optionally substituted by one or more halogens.

In some embodiments of the present disclosure, ^R2 is ^X2 is N, n is 2, and one ^R1 is a 6-membered heterocycloalkyl group containing nitrogen and phosphorus heteroatoms, and the other ^R1 is _-CH2N ( _CH3 ) ₂ , wherein the 6-membered heterocycloalkyl group containing nitrogen and phosphorus heteroatoms is optionally replaced by one or more or methyl, said R ² is optionally substituted by one or more F.

In some embodiments of the present disclosure, ^R2 is ^X2 is N, n is 2, and one of R1 ^is Another R ¹ is -CH ₂ N(CH ₃ ) ₂ , the Optionally one or more or methyl substituted.

In some embodiments of the present disclosure, ^R is selected from wherein said R ² is optionally substituted by one or more R ^c .

In some embodiments of the present disclosure, ^R is selected from wherein said R ² is optionally substituted by one or more R ^c .

In some embodiments of the present disclosure, ^R is selected from wherein said R ² is optionally substituted by one or more R ^c .

In some embodiments of the present disclosure, ^R is selected from wherein said R ² is optionally substituted by one or more R ^c .

In some embodiments of the present disclosure, ^R is selected from

In some embodiments of the present disclosure, ^R is selected from

In some embodiments of the present disclosure, ^R is selected from

In some embodiments of the present disclosure, R ^c is each independently selected from halogen, or a C _1-6 alkyl group optionally substituted by one or more deuterium groups.

In some embodiments of the present disclosure, R ^c is each independently selected from or a C _1-6 alkyl group optionally substituted by one or more deuterium groups.

In some embodiments of the present disclosure, R ^c is each independently selected from or a C _1-4 alkyl group optionally substituted by one or more deuteriums.

In some embodiments of the present disclosure, R ^c is each independently selected from halogen, or a C _1-4 alkyl group optionally substituted by one or more deuteriums.

In some embodiments of the present disclosure, R ^c is each independently selected from or the following substituents optionally substituted with one or more deuterium: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

In some embodiments of the present disclosure, R ^c is each independently selected from F, Cl, Br, or the following optionally substituted by one or more deuterium Substituents: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

In some embodiments of the present disclosure, R ^c is each independently selected from or methyl optionally substituted by one or more deuterium.

In some embodiments of the present disclosure, R ^c is each independently selected from F, Methyl or -CD ₃ .

In some embodiments of the present disclosure, R ^c is each independently selected from Methyl or -CD ₃ .

In some embodiments of the present disclosure, each R ^c is independently F.

In some embodiments of the present disclosure, the compound of formula (I) of the present disclosure, its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the following compounds of formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie) or formula (If), its stereoisomer or a pharmaceutically acceptable salt thereof:

wherein X ¹ , X ² , ring A, Y, R ¹ , R ² and n are as described in the present disclosure.

In some embodiments of the present disclosure, the compound of formula (I) of the present disclosure, its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the compound of formula (II), its stereoisomer or a pharmaceutically acceptable salt thereof:

in,

^X2 is selected from N or CH;

Each R ¹ is independently selected from halogen, C _1-4 alkyl, -OC _1-3 alkyl or 5-6 membered heterocycloalkyl, wherein the C _1-4 alkyl or 5-6 membered heterocycloalkyl is optionally substituted by one or more R ^b , and the 5-6 membered heterocycloalkyl contains 1 or 2 heteroatoms selected from N or O, or contains 1 P=O heteroatom group;

^R2 is selected from a 12-membered aromatic tricyclic group, wherein the aromatic tricyclic group contains 2, 3 or 4 heteroatoms independently selected from N or O;

Each R ^b is independently selected from deuterium, halogen, C _1-4 alkyl, -NH(C _1-4 alkyl) or -N(C _1-4 alkyl) ₂ , wherein said C _1-4 alkyl, -NH(C _1-4 alkyl) or -N(C _1-4 alkyl) ₂ is optionally substituted with one or more deuterium;

n is selected from 1, 2 or 3;

Provided that the compound of formula (II), its stereoisomer or a pharmaceutically acceptable salt thereof is not the following compound, its stereoisomer or a pharmaceutically acceptable salt thereof:

In some embodiments of the present disclosure, each R ¹ is independently selected from C _1-4 alkyl, or 6-membered heterocycloalkyl, wherein the C _1-4 alkyl or 6-membered heterocycloalkyl is optionally substituted by one or more R ^b , and the 6-membered heterocycloalkyl contains 1 or 2 heteroatoms selected from N or O, or contains 1 P＝O heteroatom group.

In some embodiments of the present disclosure, each R ¹ is independently selected from C _1-3 alkyl, or 6-membered heterocycloalkyl, wherein the 6-membered heterocycloalkyl contains 1 or 2 heteroatoms independently selected from N or O, and the C _1-3 alkyl or 6-membered heterocycloalkyl is optionally substituted with one or more R ^b .

In some embodiments of the present disclosure, each R ¹ is independently selected from methyl or The methyl or Optionally substituted with one or more R ^b .

In some embodiments of the present disclosure, each R ^b is independently selected from deuterium, F, C _1-3 alkyl, -NH(C _1-3 alkyl) or -N(C _1-3 alkyl) ₂ , wherein said -NH(C _1-3 alkyl) or -N(C _1-3 alkyl) ₂ is optionally substituted with one or more deuterium.

In some embodiments of the present disclosure, each R ^b is independently selected from deuterium, F, methyl, -NH(CH ₃ ) _or -N(CH ₃ ) ₂ , _which is optionally substituted with one or more deuterium.

In some embodiments of the present disclosure, the present disclosure comprises the above-defined variables and embodiments thereof, and any combination thereof.

It is understood that any embodiment of the compounds of the present disclosure as described above and any specific substituents described herein for specific X ¹ , X ² , Y, ring A, R ¹ , R ² , R ³ , R ⁴ substituents in the compounds of the present disclosure as described above can be independently combined with other embodiments of the present disclosure and/or substituents of the compounds to form embodiments of the present invention not specifically described above. In addition, where a substituent range is disclosed in a specific embodiment and/or claim for any specific X ¹ , X ² , Y, ring A, R ¹ , R ² , R ³ , R ⁴ substituent, it is understood that one or more substituents can be deleted from the range and the remaining substituent range should also be considered an embodiment of the present disclosure.

In some embodiments of the present disclosure, the heteroatoms in the heterocycloalkenyl, heterocycloalkyl, heterocyclyl or heteroaryl are selected from N, O, S or P, and the number of heteroatoms is selected from 1, 2, 3, 4 or 5; or, the number of heteroatoms is selected from 1, 2, 3 or 4; or, the number of heteroatoms is selected from 1, 2 or 3; or, the number of heteroatoms is selected from 1 or 2.

In some embodiments of the present disclosure, the compound of formula (I) of the present disclosure, its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the following compounds, its stereoisomer or a pharmaceutically acceptable salt thereof:

In some embodiments of the present disclosure, the pharmaceutically acceptable salt of the above compound is a hydrochloride (eg, monohydrochloride).

In some embodiments of the present disclosure, the compound of the present disclosure is not the following compound, or a stereoisomeric form thereof:

In some embodiments of the present disclosure, when Selected from And R ² is selected from When the compound of the present disclosure is not the following compound, or its stereoisomeric form:

In some embodiments of the present disclosure, when ring A is a benzene ring, the compound of the present disclosure is not the following compound, or its stereoisomer form:

On the other hand, the present disclosure provides a pharmaceutical composition comprising the above-mentioned compound of the present disclosure, its stereoisomer or a pharmaceutically acceptable salt thereof. In some embodiments of the present disclosure, the pharmaceutical composition of the present disclosure further comprises a pharmaceutically acceptable excipient.

In another aspect, the present disclosure provides a method for treating a disease in a mammal, comprising administering a therapeutically effective amount of the above compound, its stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.

In another aspect, the present disclosure provides use of the above-mentioned compound, its stereoisomer or pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of a drug for treating a disease.

In another aspect, the present disclosure provides use of the above-mentioned compound, its stereoisomer or pharmaceutically acceptable salt, or its pharmaceutical composition in treating a disease.

In another aspect, the present disclosure provides the above-mentioned compound, its stereoisomer or pharmaceutically acceptable salt, or pharmaceutical composition thereof for treating a disease.

In some embodiments of the present disclosure, the disease is selected from a disease associated with HPK1 kinase.

In some embodiments of the present disclosure, the disease associated with HPK1 kinase is cancer. Preferably, the cancer is leukemia or colon cancer.

The compounds disclosed herein have at least one of the following effects: improved or excellent HPK1 kinase inhibitory activity and Jurkat cell p-SLP76 phosphorylation inhibitory activity, improved or excellent in vivo efficacy, and good in vitro and in vivo pharmacokinetic properties, such as stable metabolism in mouse and human liver microsomes.

definition

Unless otherwise indicated, the following terms used in this disclosure have the following meanings. A particular term should not be considered as indefinite or unclear in the absence of a special definition, but should be understood according to the common meaning in the art. When a trade name appears in this article, it is intended to refer to the corresponding commodity or its active ingredient.

The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced, and oxo will not occur on an aromatic group.

The "substituent" described herein includes all substituents mentioned herein, for example, the terms "halogen", "deuterium", " _-NH2 ", "-NH( _C1-4 alkyl)", "-N( _C1-4 alkyl) ₂ ", "-OH", " _-OC1-4 alkyl", "-CN", " _C1-4 alkyl", "3-6 membered heterocycloalkyl", etc., and corresponding non-limiting or exemplary groups, wherein some non-limiting examples of the "substituent" include thiol, nitro, nitroso, cyano, azido, sulfoxide, sulfone, sulfonamide, carboxyl, aldehyde, imine, alkyl, halo-alkyl, cycloalkyl, halo-cycloalkyl, alkenyl, halo-alkenyl, cycloalkenyl, halo-cycloalkenyl, alkynyl, halo-alkynyl, cycloalkynyl, halo-cycloalkynyl, heteroalkyl, halo-heteroalkyl, alkoxy , alkylthio, aryl, aryloxy, arylthio, aryl alkylene, arylalkoxy, arylalkylthio, heteroaryl, heteroaryloxy, heteroarylthio, heteroaryl alkylene, heteroarylalkoxy, heteroarylalkylthio, heterocyclyl, heterocyclyloxy, heterocyclylthio, heterocyclylalkylene, heterocyclylalkoxy, heterocyclylalkylthio, acyl, acyloxy, carbamate group, amide group, urea group, epoxy group, ester group and oxo, etc., wherein the substituent is optionally substituted by one or more substituents selected from the following: oxygen alkyl)2, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl) ₂ , -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O) ₂ -alkyl, -S(O) _2NH2 , -S(O) _2NH -alkyl, -S(O) _2N (alkyl) ₂ , cycloalkyl, cycloalkylalkylene, cycloalkyloxy _, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocyclylalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, _heteroaryl , heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.

In some embodiments herein, the substituent is selected from deuterium, tritium, hydroxyl, thiol, halogen, amino, nitro, nitroso, cyano, azido, sulfoxide, sulfone, sulfonamide, carboxyl, aldehyde, imine, C _1-12 alkyl, halo-C 1-12 alkyl, 3-12 membered cycloalkyl, halo-3-12 membered cycloalkyl, C _2-12 alkenyl, halo-C _2-12 alkenyl, 3-12 membered cycloalkenyl, halo-3-12 _{membered cycloalkenyl, C 2-12 alkynyl} , halo-C _2-12 alkynyl, 8-12 membered cycloalkynyl, halo-8-12 membered cycloalkynyl, C _1-12 heteroalkyl, halo-C _1-12 heteroalkyl, C _1-12 alkoxy, C 1-12 _1-12- membered alkylthio, 6-10-membered aryl, 6-10-membered aryloxy, 6-10-membered arylthio, _6-10 -membered arylC 1-12 alkylene, 6-10-membered arylC _1-12 alkoxy, 6-10-membered arylC _1-12 alkylthio, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy, 5-10-membered heteroarylthio, 5-10-membered heteroarylalkylene, 5-10-membered heteroarylalkoxy, 5-10-membered heteroarylalkylthio, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, 3-12-membered heterocyclylthio, 3-12-membered heterocyclylC _1-12 alkylene, 3-12-membered heterocyclylC _1-12 alkoxy, 3-12-membered heterocyclylC _1-12 alkylthio, C _1-12 acyl, C The substituents are optionally substituted by one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, C _1-12 alkoxy, halogenated C 1-12 alkoxy, C _1-12 alkylamino, di-C _1-12 alkylamino, _{halogenated C 1-12 alkylamino, halogenated di-C 1-12 alkylamino, carboxyl, -C(O)OC 1-12 alkyl , -OC} (O)-C _1-12 alkyl, -C(O)NH ₂ , _-C (O)NH-C _1-12 alkyl, _-C (O)N(C _1-12 alkyl) ₂ , -NHC(O)-C _{1-12 1-12} alkyl, -C(O)-C _1-12 alkyl, -S(O)-C _1-12 alkyl, -S(O) ₂ -C _1-12 alkyl, -S(O) ₂ NH ₂ , -S(O) ₂ NH-C _1-12 alkyl, -S(O) ₂ N(C _1-12 alkyl) ₂ , 3-12-membered cycloalkyl, 3-12-membered cycloalkylC _1-12 alkylene, 3-12-membered cycloalkyloxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclylC 1-12 alkylene, 3-12-membered heterocyclyloxy, 3-12-membered heterocyclylalkyl, 3-12-membered heterocyclylC _1-12 alkylene, 3-12-membered heterocyclyloxy, 3-12-membered heterocycloalkyl, 3-12-membered heterocycloalkylC _1-12 alkylene, 3-12-membered heterocycloalkyloxy, 5-10-membered heteroaryl, 5-10-membered heteroarylC C _1-12 alkylene, 5-10 membered heteroaryloxy, 6-10 membered aryl, 6-10 membered arylC _1-12 alkylene or 6-10 membered aryloxy.

The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes both the occurrence of the event or circumstance and the non-occurrence of the event or circumstance. For example, an ethyl group is "optionally" substituted with a halogen, which means that the ethyl group may be unsubstituted ( _{-CH2CH3 )} , monosubstituted (such as _-CH2CH2F ), polysubstituted (such as _-CHFCH2F , _{-CH2CHF2 , etc.} ) or fully substituted ( _{-CF2CF3 ) .} It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible and/or cannot be synthesized will be introduced.

C _mn herein means that the moiety has an integer number of carbon atoms in a given range. For example, "C _1-6 " means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms; "C _1-3 " means that the group may have 1 carbon atom, 2 carbon atoms or 3 carbon atoms.

As used herein, "one or more" refers to an integer from one to ten. For example, "one or more" refers to one, two, three, four, five, six, seven, eight, nine or ten; or, "one or more" refers to one, two, three, four, five or six; or, "one or more" refers to one, two or three; or, "one or more" refers to one, two, three or six.

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 2 R's, each R has an independent choice.

When a substituent's bond crosses between two atoms on a ring, the substituent may be bonded to any atom on the ring. It means that it can be substituted at any position on the cyclohexyl group or cyclohexadiene.

The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

The term "hydroxy" refers to an -OH group.

The term "amino" refers to a _-NH2 group.

The term "nitro" refers to the _-NO2 group.

The term "cyano" refers to a -CN group.

The term "alkyl" refers to a hydrocarbon group of the general formula _{CnH2n +1} . The alkyl group may be straight or branched. For example, the term " _C1-6 alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio has the same definition as above.

The term "alkoxy" refers to an -O-alkyl group.

The term "monocyclic" refers to a cyclic group containing one ring, which may be fully saturated, partially saturated or aromatic. The monocyclic ring may be composed entirely of C atoms and may contain one or more heteroatoms selected from, for example, N, O, S or P.

The term "bicyclic" or "bicyclic radical" refers to a cyclic group containing two rings, which may be fully saturated, partially saturated or aromatic (fully unsaturated). The bicyclic ring may consist entirely of C atoms and may contain one or more heteroatoms selected from, for example, N, O, S or P. The bicyclic ring may be a fused ring, a bridged ring or a spiro ring.

The term "tricyclic" or "tricyclic radical" refers to a cyclic group containing three rings, which may be fully saturated, partially saturated or aromatic (fully unsaturated). The tricyclic ring may consist entirely of C atoms and may contain one or more heteroatoms selected from, for example, N, O, S or P. Any two adjacent monocyclic rings in the tricyclic ring may be fused rings, bridged rings or spiro rings.

The term "cycloalkyl" refers to a fully saturated carbocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 3 to 10 membered ring. Unless otherwise indicated, the cycloalkyl may be a monocyclic, bicyclic or tricyclic ring. Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, and the like.

The term "heterocyclyl" refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic) and can exist as a monocyclic, bridged, fused or spirocyclic ring. Unless otherwise indicated, the heterocyclic ring is typically a 3-20-membered _ring , a 3-15-membered ring, a 3-12-membered ring, or a 3-10-membered _ring (e.g., a 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered or 10-membered ring), a 4-8-membered ring, a 5-8-membered ring or a 5-6-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from S(O)n (where n is 0, 1 or 2), O, N, P(O)n (where n is 0, 1 or 2), Si and/or B. In some embodiments, the heterocyclyl is directly attached to the parent structure as a non-aromatic ring. Non-limiting examples of heterocyclyl groups include, but are not limited to, oxiranyl, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, tetrahydrothiophenyl, and the like.

The term "cycloalkenyl" refers to a non-aromatic carbocyclic ring that is not fully saturated and can exist as a monocyclic, bicyclic bridged ring or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically 4 to 16 rings, 4 to 12 rings, 4 to 10 rings or 4 to 8 rings (specifically, for example, 5, 6, 7, 8, 9, 10 or 11 rings). Non-limiting examples of cycloalkenyl include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, etc.

The term "monocycloalkyl" refers to a cycloalkyl group existing as a single ring.

The term "spirocycle" refers to a fully saturated or partially unsaturated polycyclic system in which the monocyclic rings share a carbon atom (called a spiro atom), including carbocycles and heterocycles. Unless otherwise indicated, the spirocycle is 5 to 20 members, preferably 6 to 14 members, and more preferably 9 to 14 members. When the spirocycle is a heterocycle, one or more ring atoms in the polycyclic ring are selected from heteroatoms (preferably 1 or 2 heteroatoms) selected from N, O, S(O) _n , P(O) _n (wherein n is 0, 1 or 2), and the remaining ring atoms are carbon atoms.

The term "spirocycloalkyl" refers to a fully saturated, all-carbon polycyclic ring that shares a carbon atom (called a spiro atom) between monocyclic rings. Unless otherwise indicated, the spirocycloalkyl is 5 to 20 yuan, preferably 6 to 14 yuan, and more preferably 9 to 14 yuan. According to the number of spiro atoms shared between rings, the spirocycloalkyl is divided into a single spirocycloalkyl, a double spirocycloalkyl, or a multi-spirocycloalkyl, preferably a single spirocycloalkyl and a double spirocycloalkyl, more preferably a 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan, or a 5 yuan/6 yuan single spirocycloalkyl. Non-limiting examples of spirocycloalkyl include

The term "spiroheterocycloalkyl" refers to a fully saturated polycyclic ring in which one carbon atom (called spiro atom) is shared between monocyclic rings, and one or more ring atoms in the polycyclic ring are selected from heteroatoms (preferably 1 or 2 heteroatoms) of N, O, S(O) _n , P(O) _n (wherein n is 0, 1 or 2), and the remaining ring atoms are carbon atoms. Unless otherwise indicated, the spiroheterocycloalkyl is 5 to 20 members, preferably 6 to 14 members, and more preferably 6 to 10 members. According to the number of spiro atoms shared between rings, the spiroheterocycle is divided into a monospiroheterocycle, a bispiroheterocycle or a polyspiroheterocycle, preferably a monospiroheterocycle or a bispiroheterocycle, and more preferably a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocycle. Non-limiting examples of spiroheterocycloalkyl include wait.

The term "bridged ring" refers to a fully saturated or partially unsaturated polycyclic system in which two rings share three or more atoms, including carbocyclic and heterocyclic rings. Unless otherwise indicated, the bridged ring is 5 to 14 members, preferably 6 to 14 members, and more preferably 6 to 10 members. According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged rings, preferably bicyclic or tricyclic, more preferably bicyclic. When the bridged ring is a heterocyclic ring, one or more ring atoms in the polycyclic ring are selected from heteroatoms (preferably 1 or 2 heteroatoms) of N, O, S(O) _n , P(O) _n (wherein n is 0, 1 or 2), and the remaining ring atoms are carbon atoms.

The term "bridged cycloalkyl" refers to a fully saturated all-carbon polycyclic ring in which two rings share three or more atoms. Unless otherwise indicated, the bridged cycloalkyl is 5 to 14 members, preferably 6 to 14 members, and more preferably 6 to 10 members. According to the number of rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic bridged ring, preferably a bicyclic or tricyclic, and more preferably a bicyclic. Non-limiting examples of bridged cycloalkyl include: wait.

The term "bridged heterocycloalkyl" is a fully saturated polycyclic ring in which two rings share three or more atoms, and one or more ring atoms are selected from heteroatoms such as N, O, S(O) _n , P(O) _n (wherein n is 0, 1 or 2), and the remaining ring atoms are carbon atoms. Unless otherwise indicated, the bridged heterocycloalkyl is 5 to 14 members, preferably 6 to 14 members, and more preferably 6 to 10 members. According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged rings, preferably bicyclic or tricyclic, and more preferably bicyclic. Non-limiting examples of bridged heterocycloalkyl include: wait.

The term "heterocycloalkyl" refers to a fully saturated cyclic group containing heteroatoms. Unless otherwise indicated, the heterocycloalkyl is typically a ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from N, O, S(O) _n , P(O) _n (wherein n is 0, 1 or 2). Unless otherwise indicated, the heterocycloalkyl may be a monocyclic, bicyclic or tricyclic ring. Unless otherwise indicated, the heterocycloalkyl includes, but is not limited to, 3 to 12-membered rings, 3 to 8-membered rings, or 5 to 8-membered rings. Examples of 3-membered heterocycloalkyls include, but are not limited to, oxirane, thiothrene, Cycloazine, non-limiting examples of 4-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxadiazolyl, thiadyl, examples of 5-membered heterocycloalkyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, tetrahydropyrazolyl, examples of 6-membered heterocycloalkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxane, thiomorpholinyl, 1,3-dithianyl or 1,4-dithianyl, examples of 7-membered heterocycloalkyl include, but are not limited to, azepanyl, oxacycloheptanyl, thiacycloheptanyl. Preferably, it is a monocyclic heterocycloalkyl with 5 or 6 ring atoms. The term "monoheterocycloalkyl" refers to a heterocycloalkyl existing in a single ring.

The term "heterocycloalkenyl" includes cycloalkenyl groups in which one or more carbon atoms are replaced by heteroatoms, for example, cycloalkenyl groups in which up to 3 carbon atoms, up to 2 carbon atoms, and in one embodiment, 1 carbon atom are independently replaced by N, O or S(O) _n (where n is 0, 1 or 2), provided that at least one cycloalkenyl carbon-carbon double bond is retained. Heterocycloalkenyl groups can be cyclic groups that exist as monocyclic, bridged or spirocyclic rings, and can be 3 to 16-membered rings (e.g., 3 to 12-membered, 5 to 8-membered rings, specifically 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered or 11-membered rings). Examples of heterocycloalkenyl groups include, but are not limited to, dihydropyridyl, dihydropyrrolyl, tetrahydropyridyl, tetrahydroazepine or azaspirocyclooctenes. The term "fused ring" refers to a polycyclic compound formed by two or more carbocyclic or heterocyclic rings with two common atoms, including fully saturated, partially saturated and aromatic. Unless otherwise indicated, the fused ring is 5 to 20 members, preferably 6 to 14 members, and more preferably 9 to 14 members. Non-limiting examples of fused rings include, but are not limited to, naphthalene, anthracene, phenanthrene, wait.

As described in this disclosure, For example, "the bicyclic group or tricyclic group and the In the "partially connected monocyclic ring is an aromatic ring", the "monocyclic ring" refers to a tricyclic ring The pyrazolyl group in For example, "the bicyclic group or tricyclic group and the In the "partially connected monocyclic ring is an aromatic ring", the "monocyclic ring" refers to a tricyclic ring The pyridyl group in

As described in this disclosure, For example, the "bicyclic or tricyclic group with formula (I) The partially connected single ring and the adjacent ring are fused rings" refers to a tricyclic group The pyridyl and pyrazolyl groups in the And For example, the "bicyclic or tricyclic group with formula (I) The partially connected single ring and the adjacent ring are fused rings" refers to a tricyclic group The pyridyl and pyrrolyl groups in the

The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π electron system. Unless otherwise indicated, an aryl group may have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and 1,2,3,4-tetrahydronaphthalene, etc.

The term "heteroaryl" refers to a monocyclic or polycyclic system containing at least one ring atom selected from N, O, S(O) _n , P(O) _n (wherein n is 0, 1 or 2), the remaining ring atoms being C, and having at least one aromatic ring. Unless otherwise indicated, the heteroaryl may be a monocyclic, bicyclic or tricyclic group. Unless otherwise indicated, the heteroaryl may have a single 5 to 8-membered ring, or a plurality of fused rings comprising 6 to 14 (e.g., 9, 10, 11, 12) ring atoms, particularly a plurality of fused rings of 6 to 10 ring atoms. Non-limiting examples of heteroaryl include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, etc. In some embodiments, the heteroaryl group is fully unsaturated, ie, has aromatic character overall.

The term "treatment" means administering the compounds or formulations described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

(i) inhibiting a disease or disease state, i.e. arresting its development;

(ii) ameliorating a disease or condition, even if causing regression of the disease or condition.

The term "therapeutically effective amount" means an amount of a compound of the present disclosure that (i) treats a specific disease, condition, or disorder described herein, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder described herein, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of a compound of the present disclosure that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and the present disclosure.

The term "pharmaceutically acceptable" 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 human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit/risk ratio.

As the pharmaceutically acceptable salt, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids (such as hydrochlorides), salts with organic acids, salts with basic or acidic amino acids and the like can be mentioned.

The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or their salts and a pharmaceutically acceptable excipient. The purpose of a pharmaceutical composition is to facilitate administration of a compound of the present disclosure to an organism. The pharmaceutical composition can be a pharmaceutical composition with a single dose of 0.001 to 2000 mg.

The term "pharmaceutically acceptable excipients" refers to those excipients that have no significant irritation to the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

The word "comprise" or "comprises" and its English variations such as comprises or comprising should be construed in an open and non-exclusive sense, ie, "including but not limited to".

Unless otherwise specifically stated, singular terms encompass plural terms and plural terms encompass singular terms. Unless otherwise specifically stated, the words "a" or "an" mean "at least one" or "at least one". Unless otherwise stated, the use of "or" means "and/or".

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.

Unless otherwise indicated, "(D)" or "(+)" indicates dextrorotatory, "(L)" or "(-)" indicates levorotatory, and "(DL)" or "(±)" indicates racemic.

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 Indicates the relative configuration of a stereocenter.

Optically active (R)- and (S)-isomers, as well as 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 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), diastereomeric salts are formed with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, separation of enantiomers and diastereomers is usually accomplished by using chromatography, which employs a chiral stationary phase and is optionally combined with chemical derivatization (e.g., carbamate formation from an amine).

The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but in which one or more atoms are replaced by atoms having an atomic mass or mass number different from that normally found in nature. Examples of isotopes that may be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N, 15 N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ¹²³ I, ¹²⁵ I, and ³⁶ Cl, etc., ^respectively .

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

Further, substitution with heavier isotopes such as deuterium (i.e., ² H or D) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances, wherein deuterium substitution may be partial or full, partial deuterium substitution refers to replacement of at least one hydrogen with at least one deuterium, full deuterium substitution refers to replacement of all hydrogens on a group with deuterium, for example, complete replacement of a methyl group ( _-CH3 ) with deuterium yields _-CD3 .

The compounds of the present disclosure may exist in their tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer can be an imidazole moiety, in which a proton can migrate between two ring nitrogens.

The pharmaceutical compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients.

Typical routes of administration of the disclosed compounds or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, topical, inhalation, parenteral, intranasal, intraocular, intramuscular, subcutaneous, intravenous administration.

The pharmaceutical compositions disclosed herein can be manufactured using methods well known in the art.

In all methods of administration of the compounds of formula (I) described herein, the dosage administered per day is 0.001 to 2000 mg/kg body weight, in the form of single or divided doses.

The compounds disclosed herein 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 the embodiments with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples disclosed herein.

The chemical reactions of the specific embodiments of the present disclosure are carried out in a suitable solvent, which must be suitable for the chemical changes of the present disclosure and the reagents and materials required. In order to obtain the compounds of the present disclosure, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction processes based on the existing embodiments.

An important consideration in synthetic route planning in the art is to select a suitable protecting group for a reactive functional group (such as the amino group in the present disclosure). For example, reference may be made to Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc. All references cited in the present disclosure are hereby incorporated into the present disclosure in their entirety.

In some embodiments of the present disclosure, the compound of formula (I) of the present disclosure can be prepared by a person skilled in the art of organic synthesis with reference to the following route: (1) when R ⁴ is selected from H, the preparation route is as follows:

Preparation route 1:

Preparation route 2:

(2) When R ⁴ is selected from C _1-4 alkyl, C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl, the preparation route is as follows:

Preparation route 3:

wherein Z is selected from halogen, OH, NH ₂ or NH(C _1-6 alkyl) and the like; R ^e is selected from halogen, NH ₂ , boric acid or boric ester and the like;

^Rf is selected from halogen, boronic acid or boronic ester groups;

Q is selected from halogen, OTf, trimethyltin, tri-n-butyltin, boric acid or boric acid ester;

M is selected from halogen, OTf, OTs, OH, OMs and the like;

wherein ring A, R ¹ , X ¹ , X ² , Y, R ² , R ³ , R ⁴ , m and n are as defined in the present disclosure.

For the purpose of description and disclosure, all patents, patent applications and other identified publications are expressly incorporated herein by reference. These publications are provided only because their disclosure precedes the filing date of the present disclosure. All statements regarding the dates of these documents or the representations of the contents of these documents are based on the information available to the applicant and do not constitute any admission as to the correctness of the dates of these documents or the contents of these documents. Furthermore, any reference to these publications herein does not constitute an admission that the publications are part of the common general knowledge in the art in any country.

This disclosure uses the following abbreviations:

DMSO stands for dimethyl sulfoxide; THF stands for tetrahydrofuran; NCS stands for N-chlorosuccinimide; NBS stands for N-bromosuccinimide; CCl ₄ stands for carbon tetrachloride; DMF stands for N,N-dimethylformamide; HOVEYDA-GRUBBS stands for (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o-isopropoxybenzylidene)ruthenium; Boc stands for tert-butyloxycarbonyl; Ms stands for methanesulfonyl; Ts stands for p-toluenesulfonyl; Cbz stands for benzyloxycarbonyl; and Tf stands for trifluoromethanesulfonyl.

DETAILED DESCRIPTION

For the sake of clarity, the present invention is further described with examples, but the examples are not intended to limit the scope of the present disclosure. It will be apparent to those skilled in the art that various changes and modifications will be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention. All reagents used in the present disclosure are commercially available and can be used without further purification.

The compounds of the present invention can be obtained by similar preparation methods of the embodiments, including but not limited to adjusting raw materials, reagents or process parameters with similar structures. The compounds of the present invention can obtain their structural confirmation information by MS or ¹ H NMR. The compounds of the present invention can also obtain results by the same effect test method.

Preparation of intermediates

Intermediate Example 1: Preparation of Intermediate 1A

Step A: Preparation of Intermediate 1A-1

Compound 6-amino-3-bromopicolinic acid methyl ester (100 g), N,N-dimethylpyridin-4-amine (10.6 g), di-tert-butyl dicarbonate (170 g) and tetrahydrofuran (600 mL) were added to the reaction flask in sequence. After the addition, the mixture was stirred at room temperature for reaction. After the reaction was complete, the reaction solution was quenched by adding 10% citric acid aqueous solution (200 mL, w/w), extracted with dichloromethane, washed with saturated brine, dried and concentrated to obtain intermediate 1A-1 (120.1 g).

MS (ESI, [M+H] ⁺ )m/z: 331.1.

Step B: Preparation of Intermediate 1A-2

Add intermediate 1A-1 (85 g), tetrahydrofuran (300 mL) and lithium borohydride (6.2 g) to the reaction flask in sequence. After the addition, stir at room temperature to react. After the reaction is complete, add saturated ammonium chloride solution to the reaction solution to quench, extract with dichloromethane, wash with saturated brine, dry, and concentrate to obtain intermediate 1A-2 (60.0 g).

MS (ESI, [M+H] ⁺ )m/z: 303.1.

Step C: Preparation of Intermediate 1A-3

Add intermediate 1A-2 (54.2 g), N,N-diisopropylethylamine, dichloromethane (200 mL) and methanesulfonic anhydride (78 g) to the reaction flask in sequence. After the addition, stir and react at -15°C. The reaction is complete and the reaction solution is used directly in the next step without treatment.

Step D: Preparation of Intermediate 1A-4

Add dimethylamine tetrahydrofuran solution (446 mL, 2M), dichloromethane (200 mL) and the reaction solution of intermediate 1A-3 to the reaction flask in sequence, and stir at room temperature to react. After the reaction is complete, extract with dichloromethane, wash with saturated brine, dry, and concentrate. Column chromatography (dichloromethane/methanol = 5/1) gives intermediate 1A-4 (38.2 g).

MS (ESI, [M+H] ⁺ )m/z: 330.1.

Step E: Preparation of Intermediate 1A-5

Add intermediate 1A-4 (38.2 g), potassium carbonate (36.0 g), tetrakis(triphenylphosphine)palladium (15.0 g), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (23.7 g), water (80 mL) and 1,4-dioxane (400 mL) to the reaction flask in sequence. After the addition, replace nitrogen and stir at 100°C to react. After the reaction is complete, filter and concentrate. Column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain intermediate 1A-5 (24.5 g).

MS (ESI, [M+H] ⁺ )m/z: 334.0.

Step F: Preparation of Intermediate 1A-6

Add intermediate 1A-5 (24.5 g), 10 wt% palladium hydroxide on carbon (24.5 g) and methanol (100 mL) to the reaction flask in sequence. After the addition, stir and react at 35°C under hydrogen. After the reaction is complete, filter and concentrate to obtain intermediate 1A-6 (22.0 g).

MS (ESI, [M+H] ⁺ )m/z: 336.0.

Step G: Preparation of Intermediate 1A-7

Add intermediate 1A-6 (22.0 g) and hydrochloric acid 1,4-dioxane solution (164 mL, 4 M) to the reaction flask in sequence. After the addition, stir at room temperature to react. After the reaction is complete, add saturated sodium bicarbonate solution to adjust the reaction solution to alkalinity (pH about 10), extract with dichloromethane, and concentrate to obtain intermediate 1A-7. (13.0g).

MS (ESI, [M+H] ⁺ )m/z: 236.3.

Step H: Preparation of Intermediate 1A-8

Add compound 5-bromo-2-chloro-3-methylpyridine-4-carboxylic acid (50.0 g), potassium carbonate (54.2 g), iodomethane (14.0 mL) and N,N-dimethylformamide (500 mL) to the reaction flask in sequence. After the addition, stir at room temperature to react. After the reaction is complete, add water (1000 mL) to the reaction solution, extract with ethyl acetate, and concentrate to obtain intermediate 1A-8 (41.2 g).

MS (ESI, [M+H] ⁺ )m/z: 264.2.

Step I: Preparation of Intermediate 1A-9

Add intermediate 1A-8 (41.2 g), N-bromosuccinimide (42.0 g), dibenzoyl peroxide (0.6 g) and 1,2-dichloroethane (500 mL) to the reaction flask in sequence. After the addition, stir and react at 90°C. After the reaction is complete, add saturated sodium sulfite solution (100 mL) to quench the reaction solution, extract with dichloromethane, wash with saturated brine, dry and concentrate to obtain intermediate 1A-9 (54.5 g).

¹ H NMR (500MHz, CDCl ₃ ) δ 8.51 (s, 1H), 4.53 (s, 2H), 4.05 (s, 3H).

Step J: Preparation of Intermediate 1A-10

Add intermediate 1A-9 (54.5 g), methanol solution of ammonia (60 mL, 7 M) and methanol (500 mL) to the reaction flask in sequence. After the addition, stir and react at 75°C. After the reaction is complete, filter the reaction solution and dry to obtain intermediate 1A-10 (29.2 g).

¹ H NMR (500MHz, DMSO-d ₆ ) δ 9.30 (s, 1H), 8.67 (d, J = 2.7Hz, 1H), 4.41 (s, 2H).

Step K: Preparation of Intermediate 1A-11

Add intermediate 1A-10 (29.2 g), N,N-dimethylpyridin-4-amine (1.5 g), di-tert-butyl dicarbonate (28.0 g) and 1,4-dioxane (200 mL) to the reaction flask in sequence. After the addition, stir at room temperature to react. After the reaction is complete, the reaction solution is concentrated and column chromatography (petroleum ether/ethyl acetate = 10/1) is performed to obtain intermediate 1A-11 (35.3 g).

¹ H NMR (500MHz, DMSO-d ₆ ) δ 8.75 (s, 1H), 4.73 (s, 2H), 1.54 (s, 9H).

Step L: Preparation of Intermediate 1A

Add intermediate 1A-7 (1.2 g), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (244.6 mg), tris(dibenzylideneacetone)dipalladium (258.3 mg), cesium carbonate (1.8 g), intermediate 1A-11 (1.1 g) and 1,4-dioxane (100 mL) to the reaction flask in sequence. After the addition, replace nitrogen and stir at 100°C to react. After the reaction is complete, filter and concentrate to obtain a crude product. Column chromatography (dichloromethane/methanol = 20/1) is performed to obtain intermediate 1A (1.2 g).

MS(ESI,[M+H] ⁺ )m/z:502.3.

Intermediate Example 2: Preparation of Intermediate 2A

Step A: Preparation of Intermediate 2A-1

To the reaction flask, add intermediate 1A-2 (112.2 g), dichloromethane (450 mL), N,N-diisopropylethylamine (162.0 mL) and methanesulfonate. Acid anhydride (162.0 g). After addition, stir at -15 °C to react. After the reaction is complete, add 3,3-difluoropyrrolidine (118.5 g) to the reaction solution in portions, after addition, stir at room temperature to react. After the reaction is complete, extract with dichloromethane, wash with saturated brine, dry, and concentrate. Column chromatography (dichloromethane/methanol = 30/1) to obtain intermediate 2A-1 (95.0 g).

MS (ESI, [M+H] ⁺ )m/z: 392.3.

Step B: Preparation of Intermediate 2A-2

Add intermediate 2A-1 (30.0 g), potassium carbonate (31.5 g), tetrakis(triphenylphosphine)palladium (10.5 g), 2,5-dihydrofuran-3-pinacol borate (19.5 g), water (100 mL) and 1,4-dioxane (500 mL) to the reaction flask in sequence. After the addition, replace nitrogen and stir at 100 ° C. After the reaction is complete, filter and concentrate. Column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain intermediate 2A-2 (23.2 g).

MS (ESI, [M+H] ⁺ )m/z: 382.5.

Step C: Preparation of Intermediate 2A-3

Add intermediate 2A-2 (15.0 g), 10 wt% palladium hydroxide on carbon (15.0 g) and methanol (225 mL) to the reaction flask in sequence. After the addition, stir and react at 35°C under hydrogen. After the reaction is complete, filter and concentrate to obtain intermediate 2A-3 (14.5 g).

MS (ESI, [M+H] ⁺ )m/z: 384.8.

Step D: Preparation of Intermediate 2A-4

Add intermediate 2A-3 (14.5 g) and hydrochloric acid 1,4-dioxane solution (122.4 mL, 4 M) to the reaction flask in sequence. After the addition, stir at room temperature to react. After the reaction is complete, add saturated sodium bicarbonate solution to adjust the reaction solution to alkalinity (pH about 10), extract with dichloromethane, and concentrate to obtain intermediate 2A-4 (7.5 g).

MS (ESI, [M+H] ⁺ )m/z: 284.1.

Step E: Preparation of Intermediate 2A

Add intermediate 2A-4 (1.0 g), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (244.6 mg), tris(dibenzylideneacetone)dipalladium (258.3 mg), cesium carbonate (1.8 g), intermediate 1A-11 (1.1 g) and 1,4-dioxane (100 mL) to the reaction flask in sequence. After the addition, replace the nitrogen atmosphere and stir at 100°C to react. After the reaction is complete, filter and concentrate to obtain a crude product. Column chromatography (dichloromethane/methanol = 20/1) is performed to obtain intermediate 2A (1.0 g).

MS (ESI, [M+H] ⁺ )m/z: 550.3.

Intermediate Example 3: Preparation of Intermediate 3A

Step A: Preparation of Intermediate 3A-1

At -10°C, add 7-amino-4-chloroisoindol-1-one (10 g) and 48% hydrogen bromide methanol solution (90 mL, w/w) to the reaction bottle in sequence. After the addition, slowly drop an aqueous solution (7.6 g, 65 mL) containing sodium nitrite into the reaction solution. After the addition, stir the reaction for 1 h. Slowly drop a 48% hydrogen bromide aqueous solution (8.6 g, 90 mL) containing cuprous bromide into the reaction solution. After the addition, stir the reaction at 80°C. After the reaction is complete, pour the reaction solution into ice water, stir well, filter, wash the filter cake, and dry the filter cake to obtain intermediate 3A-1 (8.5 g).

MS (ESI, [M+H] ⁺ )m/z: 245.9.

Step B: Preparation of Intermediate 3A-2

To the reaction flask, add intermediate 3A-1 (8.5 g), tetrahydrofuran (150 mL), 4-dimethylaminopyridine (1.0 g) and di-tert-butyl dicarbonate. Ester (11.2 g). After the addition, the reaction was stirred at room temperature. After the reaction was complete, the reaction solution was quenched by adding 10% citric acid aqueous solution (200 mL, w/w), extracted with dichloromethane, washed with saturated brine, dried, and concentrated to obtain intermediate 3A-2 (9.6 g).

MS (ESI, [M+H] ⁺ )m/z: 345.9.

Step C: Preparation of Intermediate 3A-3

Add intermediate 3A-2 (2.5 g), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (612 mg), tris(dibenzylideneacetone)dipalladium (645.3 mg), cesium carbonate (5.8 g), intermediate 2A-4 (4.6 g) and 1,4-dioxane (100 mL) to the reaction flask in sequence. After the addition, replace nitrogen and stir at 100°C to react. After the reaction is complete, filter and concentrate to obtain a crude product. Column chromatography (dichloromethane/methanol = 20/1) is performed to obtain intermediate 3A-3 (4.2 g).

MS (ESI, [M+H] ⁺ )m/z: 549.3.

Step D: Preparation of Intermediate 3A

Add intermediate 3A-3 (2.0 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (573.0 mg), biboric acid pinacol ester (1.9 g), potassium carbonate (1.0 g) and 1,4-dioxane (60 mL) into a microwave tube in sequence. After the addition, replace nitrogen and react with microwave at 90°C. After the reaction is complete, filter and concentrate. Column chromatography (dichloromethane/methanol=20/1) gives intermediate 3A (2.4 g).

MS (ESI, [M+H] ⁺ )m/z: 641.5.

Intermediate Example 4: Preparation of Intermediate 4A

Step A: Preparation of Intermediate 4A-1

Add intermediate 1A-4 (25.2 g), potassium carbonate (31.5 g), tetrakis(triphenylphosphine)palladium (10.5 g), 2,5-dihydrofuran-3-pinacol borate (19.6 g), water (100 mL) and 1,4-dioxane (500 mL) to the reaction flask in sequence. After the addition, replace the nitrogen and stir at 100°C to react. After the reaction is complete, filter and concentrate. Column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain intermediate 4A-1 (20.8 g).

MS (ESI, [M+H] ⁺ )m/z: 320.5.

Step B: Preparation of Intermediate 4A-2

Add intermediate 4A-1 (15.0 g), 10 wt% palladium hydroxide on carbon (15.0 g) and methanol (225 mL) to the reaction flask in sequence. After the addition, stir and react at 35°C under hydrogen. After the reaction is complete, filter and concentrate to obtain intermediate 4A-2 (14.8 g).

MS (ESI, [M+H] ⁺ )m/z: 322.8.

Step C: Preparation of Intermediate 4A-3

Add intermediate 4A-2 (14.8 g) and hydrochloric acid 1,4-dioxane solution (122.4 mL, 4 M) to the reaction flask in sequence. After the addition, stir at room temperature to react. After the reaction is complete, add saturated sodium bicarbonate solution to the reaction solution to adjust to alkalinity (pH about 10), extract with dichloromethane, and concentrate to obtain intermediate 4A-3 (8.2 g).

MS (ESI, [M+H] ⁺ )m/z: 222.1.

Step D: Preparation of Intermediate 4A-4

Add intermediate 3A-2 (2.5 g), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (612 mg), tris(dibenzylideneacetone)dipalladium (645.3 mg), cesium carbonate (5.8 g), intermediate 4A-3 (3.6 g) and 1,4-dioxane (100 mL) to the reaction flask in sequence. After the addition, replace nitrogen and stir at 100°C to react. After the reaction is complete, filter and concentrate to obtain a crude product. Column chromatography (dichloromethane/methanol = 20/1) to obtain intermediate 4A-4 (4.0 g).

MS (ESI, [M+H] ⁺ )m/z: 487.4.

Step E: Preparation of Intermediate 4A

Add intermediate 4A-4 (2.0 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (585.0 mg), biboric acid pinacol ester (2.1 g), potassium carbonate (1.2 g) and 1,4-dioxane (60 mL) into a microwave tube in sequence. After the addition, replace nitrogen and react with microwave at 90°C. After the reaction is complete, filter and concentrate. Column chromatography (dichloromethane/methanol=20/1) gives intermediate 4A (2.6 g).

MS (ESI, [M+H] ⁺ )m/z: 579.5.

Intermediate Example 5: Preparation of Intermediate 5A

Step A: Preparation of Intermediate 5A-1

Add intermediate 3A-2 (2.5 g), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (612 mg), tris(dibenzylideneacetone)dipalladium (645.3 mg), cesium carbonate (5.8 g), intermediate 1A-7 (3.8 g) and 1,4-dioxane (100 mL) to the reaction flask in sequence. After the addition, replace nitrogen and stir at 100°C to react. After the reaction is complete, filter and concentrate to obtain a crude product. Column chromatography (dichloromethane/methanol = 20/1) is performed to obtain intermediate 5A-1 (4.4 g).

MS (ESI, [M+H] ⁺ )m/z: 501.3.

Step B: Preparation of Intermediate 5A

Add intermediate 5A-1 (2.1 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (585.0 mg), biboric acid pinacol ester (2.1 g), potassium carbonate (1.2 g) and 1,4-dioxane (60 mL) into a microwave tube in sequence. After the addition, replace nitrogen and react with microwave at 90°C. After the reaction is complete, filter and concentrate. Column chromatography (dichloromethane/methanol=20/1) gives intermediate 5A (2.8 g).

MS (ESI, [M+H] ⁺ )m/z: 593.3.

Intermediate Example 6: Preparation of Intermediate 6A

Step A: Preparation of Intermediate 6A-1

Compound 5-chlorofuran[3,2-B]pyridine (9.5 g), toluene (150.0 mL), benzophenone imine (13.5 g), sodium tert-butoxide (11.9 g), tris(dibenzylideneacetone)dipalladium (2.8 g), 1,1-binaphthyl-2,2-bisdiphenylphosphine (1.9 g) were added to the reaction flask in sequence. After the addition, the reaction was stirred at 100°C. After the reaction was complete, dichloromethane was added to the reaction solution for extraction, and the organic phase was washed with saturated brine, dried, and concentrated. Column chromatography (dichloromethane/methanol = 30/1) gave intermediate 6A-1 (15.2 g).

MS (ESI, [M+H] ⁺ )m/z: 299.12.

Step B: Preparation of Intermediate 6A-2

Add intermediate 6A-1 (15.2 g), dichloromethane (20.0 mL), and hydrochloric acid 1,4-dioxane solution (4 M, 191.0 mL) to the reaction flask in sequence. After the addition, stir at 100°C to react. After the reaction is complete, filter the reaction solution and concentrate. Column chromatography (petroleum ether/ethyl acetate = 5/1) is performed to obtain intermediate 6A-2 (5.1 g).

MS (ESI, [M+H] ⁺ )m/z: 135.2.

Step C: Preparation of Intermediate 6A-3

Add intermediate 6A-2 (5.1 g), bromoacetaldehyde diacetaldehyde (36.7 g), methanol (10.0 mL), and hydrochloric acid (3M, 12.2 mL) to the reaction flask in sequence. After the addition, stir at 35°C to react. After the reaction is complete, filter the reaction solution, concentrate, and perform column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain intermediate 6A-3 (5.3 g).

MS (ESI, [M+H] ⁺ )m/z: 159.1.

Step D: Preparation of Intermediate 6A

Add intermediate 6A-3 (5.3 g), dimethyl sulfoxide (30.0 mL), 2,5-dibromo-4,4-dimethylcyclopentane-1,3-dione (3.8 g), and sodium carbonate (2.8 g) to the reaction flask in sequence. After the addition, stir at room temperature under nitrogen protection. After the reaction is complete, add water and dichloromethane to the reaction solution for extraction. After the organic phase is separated and concentrated, column chromatography (petroleum ether/ethyl acetate = 5/1) is performed to obtain intermediate 6A (4.3 g).

MS (ESI, [M+H] ⁺ )m/z: 237.4.

Intermediate Example 7: Preparation of Intermediate 7A

Step A: Preparation of Intermediate 7A-1

Compound 4-chlorofuranylpyridine (10 g), acetic acid (130 mL), and zinc powder (10.0 g) were added to the reaction flask in sequence, and the mixture was stirred at 100° C. After the reaction was complete, a saturated sodium bicarbonate solution was added to the reaction solution to adjust the pH to about 10, and the mixture was extracted with ethyl acetate. The organic phase was separated, washed, dried, concentrated, and column chromatography (petroleum ether/ethyl acetate = 9/1) was performed to obtain intermediate 7A-1 (5.2 g).

MS (ESI, [M+H] ⁺ )m/z: 120.0.

Step B: Preparation of Intermediate 7A-2

Add intermediate 7A-1 (5 g), acetonitrile (50.0 mL), and 2,4-dinitrophenylhydroxylamine (8.5 g) to the reaction flask in sequence, and stir the mixture at 40° C. After the reaction is complete, filter the reaction solution, wash it, and dry the residue to obtain intermediate 7A-2 (9.8 g), which is directly used in the next step.

Step C: Preparation of Intermediate 7A-3

Add intermediate 7A-2 (5 g), potassium carbonate (3 g), ethyl propiolate (3.2 g), and N,N-dimethylformamide (60 mL) to the reaction flask in sequence, and stir at room temperature to react after the addition is complete. After the reaction is complete, water is added to the reaction solution to quench the reaction, and the mixture is extracted with ethyl acetate. The organic phase is separated, dried, filtered, concentrated, and column chromatography (petroleum ether/ethyl acetate = 6/1) is performed to obtain intermediate 7A-3 (3.4 g).

MS (ESI, [M+H] ⁺ )m/z: 231.0.

Step D: Preparation of Intermediate 7A-4

To the reaction flask, add intermediate 7A-3 (3.4 g), lithium hydroxide monohydrate (6 g), methanol (60 mL) and water (6 mL) in sequence. After the addition, stir the reaction at 60°C. After the reaction is complete, add 1M dilute hydrochloric acid to the reaction solution to adjust it to acidity (pH is about 5), extract with ethyl acetate, separate the organic phase, dry, filter, concentrate, and obtain intermediate 7A-4 (2.9 g) by column chromatography (petroleum ether/ethyl acetate = 3/1).

MS (ESI, [M+H] ⁺ )m/z: 203.2.

Step E: Preparation of Intermediate 7A

To the reaction flask, add intermediate 7A-4 (2.9 g), N-bromosuccinimide (2.56 g), sodium bicarbonate (3.6 g), and N,N-dimethylformamide (40 mL) in sequence. After the addition, react at room temperature. After the reaction is complete, add water and ethyl acetate to the reaction solution for extraction. The organic phase is separated, dried, filtered, concentrated, and column chromatography (petroleum ether/ethyl acetate = 6/1) is used to obtain intermediate 7A (3.08 g).

MS (ESI, [M+H] ⁺ )m/z: 237.0.

Intermediate Example 8: Preparation of Intermediate 8A

Step A: Preparation of Intermediate 8A-1

4-methoxybenzylamine (10.00 g), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (6.60 g), potassium carbonate (20.15 g), chloroacetonitrile (6.05 g) and acetonitrile (100 mL) were added to the reaction flask in sequence. After the addition, the reaction was stirred at 60°C. After the reaction was complete, the reaction solution was concentrated and column chromatography (petroleum ether/ethyl acetate = 10/1) was performed to obtain intermediate 8A-1 (10.72 g).

MS (ESI, [M+H] ⁺ )m/z: 177.1.

Step B: Preparation of Intermediate 8A-2

Add intermediate 8A-1 (10.00 g), hydrochloric acid 1,4-dioxane solution (4M, 20 mL) and dichloromethane (100 mL) to the reaction flask in sequence, stir at room temperature for reaction. After the reaction is complete, filter the reaction solution and dry it to obtain intermediate 8A-2 (11.53 g).

MS (ESI, [M+H] ⁺ )m/z: 177.1.

Step C: Preparation of Intermediate 8A-3

At 0°C, add intermediate 8A-2 (10.00 g), chlorobenzene (75 mL) and oxalyl chloride (17.90 g) to the reaction flask in sequence. After addition, react at room temperature for 0.5 h. Continue to add triethylamine hydrochloride (32.40 g) to the reaction solution, after addition, stir and react at room temperature. After the reaction is complete, concentrate the reaction solution, add water and dichloromethane to extract, separate the organic phase, dry, filter, concentrate, and column chromatography (petroleum ether/ethyl acetate = 4/1) to obtain intermediate 8A-3 (10.60 g).

MS (ESI, [M+H] ⁺ )m/z: 285.2.

Step D: Preparation of Intermediate 8A-4

To the reaction flask, add intermediate 8A-3 (8.4 g), cuprous iodide (0.56 g), bistriphenylphosphine palladium dichloride (2.07 g), trimethylsilyl acetylene (5.50 g), triethylamine (24 mL) and N, N-dimethylformamide (24 mL) in sequence, replace nitrogen after addition, and stir to react at 80° C. After the reaction is complete, add saturated ammonium chloride solution to the reaction solution to quench, extract with dichloromethane, separate the organic phase, dry, filter, concentrate, and column chromatography (petroleum ether/ethyl acetate=5/1) to obtain intermediate 8A-4 (9.10 g).

MS (ESI, [M+H] ⁺ )m/z: 347.1.

Step E: Preparation of Intermediate 8A-5

Add intermediate 8A-4 (9.10 g), dichloromethane (150 mL), silver trifluoromethanesulfonate (0.40 g) and trifluoroacetic acid (9.75 mL) to the reaction flask in sequence. After the addition, stir at room temperature to react. After the reaction is complete, concentrate the reaction solution and perform column chromatography (petroleum ether/ethyl acetate = 10/1) to obtain intermediate 8A-5 (4.26 g).

MS (ESI, [M+H] ⁺ )m/z: 227.4.

Step F: Preparation of Intermediate 8A-6

At -78°C, add intermediate 8A-5 (1.42 g), tetrahydrofuran (25 mL) and tetrabutylammonium fluoride tetrahydrofuran solution (1 M, 7.52 mL) to the reaction flask in sequence. After the addition, stir at -78°C to react. After the reaction is complete, add saturated ammonium chloride solution to the reaction solution to quench, extract with dichloromethane, separate the organic phase, dry, filter, concentrate, and perform column chromatography (petroleum ether/ethyl acetate = 10/1) to obtain intermediate 8A-6 (0.89 g).

MS (ESI, [M+H] ⁺ )m/z: 155.1.

Step G: Preparation of Intermediate 8A-7

Add intermediate 8A-6 (0.57 g), benzophenone imine (0.80 g), sodium tert-butoxide (0.71 g), tris(dibenzylideneacetone)dipalladium (0.17 g), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (0.11 g) and 1,4-dioxane (30 mL) to the reaction flask in sequence. After the addition, replace the nitrogen and stir at 80°C to react. After the reaction is complete, filter the reaction solution and concentrate. Obtain intermediate 8A-7 (0.46 g) by column chromatography (petroleum ether/ethyl acetate = 5/1).

MS (ESI, [M+H] ⁺ )m/z: 300.1.

Step H: Preparation of Intermediate 8A-8

Add intermediate 8A-7 (0.46 g), hydrochloric acid 1,4-dioxane solution (4M, 5.76 mL) and dichloromethane (10 mL) to the reaction flask in sequence, stir at room temperature for reaction. After the reaction is complete, concentrate the reaction solution and perform column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain intermediate 8A-8 (0.17 g).

MS (ESI, [M+H] ⁺ )m/z: 136.0.

Step I: Preparation of Intermediate 8A-9

Add bromoacetaldehyde diethyl acetal (2.47 g), methanol (2 mL) and hydrochloric acid (3 M, 4 mL) to the reaction flask in sequence. After addition, react at 80 ° C for 1 h. Then add saturated sodium bicarbonate solution to adjust the pH of the reaction solution to 8, continue to add intermediate 8A-8 (0.11 g) to the reaction solution, and stir at room temperature to react. After the reaction is complete, the reaction solution is concentrated and column chromatography (dichloromethane/methanol = 20/1) is performed to obtain intermediate 8A-9 (0.12 g).

MS (ESI, [M+H] ⁺ )m/z: 160.2.

Step J: Preparation of Intermediate 8A

Add dibromohydantoin (108 mg), dimethyl sulfoxide (2 mL), sodium carbonate (160 mg) and intermediate 8A-9 (120 mg) to the reaction bottle in sequence. After the addition, stir and react at 60°C. After the reaction is complete, add water and dichloromethane to the reaction solution for extraction, separate the organic phase, dry, filter, concentrate, and perform column chromatography (dichloromethane/methanol=20/1) to obtain intermediate 8A (178 mg).

MS (ESI, [M+H] ⁺ )m/z: 238.0.

Intermediate Example 9: Preparation of Intermediate 9A

Step A: Preparation of Intermediate 9A-1

Pyrazole (10.0 g), 60 wt% sodium hydride (11 g), and N,N-dimethylformamide (120 mL) were added to the reaction bottle. 1,1-bis-bromomethylcyclopropane (10.0 g) was slowly added at 0°C. After the addition was completed, the reaction was allowed to react at room temperature. After the reaction was complete, 1 M dilute hydrochloric acid was added to the reaction solution to adjust it to neutral (pH was about 7). Ethyl acetate was added for extraction, and the organic phase was separated. After drying, filtration, concentration, and column chromatography (petroleum ether/ethyl acetate = 6/1), intermediate 9A-1 (8.6 g) was obtained.

MS (ESI, [M+H] ⁺ )m/z: 215.1.

Step B: Preparation of Intermediate 9A-2

At -78 ° C, to a reaction bottle containing intermediate 9A-1 (8.6 g) and tetrahydrofuran (100 mL), slowly add diisopropyllithium amide tetrahydrofuran solution (2M, 41 mL) dropwise. After the addition is completed, react at room temperature. After the reaction is complete, quench the reaction, add ethyl acetate for extraction, separate the organic phase, dry, filter, concentrate, and column chromatography (petroleum ether/ethyl acetate = 9/1) to obtain intermediate 9A-2 (2.6 g).

MS (ESI, [M+H] ⁺ )m/z: 135.1.

Step C: Preparation of Intermediate 9A

Under an ice-water bath, intermediate 9A-2 (2.6 g), N-bromosuccinimide (4 g) and dichloromethane (40 mL) were added to the reaction bottle. After the addition was completed, the reaction was quenched and ethyl acetate was added for extraction. The organic phase was separated, dried, filtered, concentrated, and column chromatography (petroleum ether/ethyl acetate = 9/1) was used to obtain intermediate 9A (2.5 g).

MS (ESI, [M+H] ⁺ )m/z: 213.1.

Intermediate Example 10: Preparation of Compound 14d

Step A: Preparation of compound 14a

Add intermediate 1A-2 (5 g), N,N-diisopropylethylamine (4 g), dichloromethane (30 mL) and methanesulfonic anhydride (7.2 g) to the reaction flask in sequence. After the addition, stir and react at -15 °C. After the reaction is complete, slowly add dimethyl-D6-amine (10 g) to the reaction flask, add and react at room temperature. After the reaction is complete, add dichloromethane for extraction, wash the organic phase with saturated sodium chloride aqueous solution, dry, concentrate, and column chromatography (dichloromethane/methanol = 5/1) to obtain compound 14a (3.8 g).

MS (ESI, [M+H] ⁺ )m/z: 336.1.

Step B: Preparation of compound 14b

Compound 14a (3.8 g), potassium carbonate (3.6 g), tetrakis(triphenylphosphine)palladium (1.5 g), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (2.3 g), water (8 mL) and 1,4-dioxane (40 mL) were added to the reaction bottle in sequence. After the addition, nitrogen was replaced and the reaction was stirred at 100°C. After the reaction was complete, the reaction solution was filtered, concentrated, and column chromatography (petroleum ether/ethyl acetate = 5/1) was performed to obtain compound 14b (2.6 g).

MS (ESI, [M+H] ⁺ )m/z: 340.0.

Step C: Preparation of Compound 14c

Compound 14b (2.6 g), 10 wt% palladium hydroxide on carbon (2.6 g) and methanol (12 mL) were added to the reaction flask in sequence. After the addition, the mixture was stirred at room temperature under hydrogen. After the reaction was complete, the reaction solution was filtered and concentrated to obtain compound 14c (2.2 g).

MS (ESI, [M+H] ⁺ )m/z: 342.0.

Step D: Preparation of compound 14d

Compound 14c (2.2 g) and hydrochloric acid 1,4-dioxane solution (16.4 mL, 4 M) were added to the reaction flask in sequence. After the addition, the mixture was stirred at room temperature for reaction. After the reaction was complete, saturated sodium bicarbonate solution was added to the reaction solution to adjust the pH to about 10, and the mixture was extracted with dichloromethane. The organic phase was dried, filtered, and concentrated to obtain compound 14d (1.4 g).

MS (ESI, [M+H] ⁺ )m/z: 242.3.

Intermediate Example 11: Preparation of Compound 16f

Step A: Preparation of compound 16a

Under nitrogen protection, intermediate 1A-1 (8.00 g), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (6.60 g), potassium carbonate (10.02 g), tetrakistriphenylphosphine palladium (5.58 g), 1,4-dioxane (100 mL) and water (15 mL) were added to the reaction bottle in sequence. After the addition, the reaction was stirred at 100°C. After the reaction was complete, the reaction solution was concentrated and column chromatography (petroleum ether/ethyl acetate = 5/1) was performed to obtain compound 16a (7.06 g).

MS (ESI, [M+H] ⁺ )m/z: 335.11.

Step B: Preparation of compound 16b

Compound 16a (7.06 g), methanol (50 mL), and 10 wt% palladium hydroxide on carbon (7.41 g) were added to the reaction flask in sequence, and the mixture was stirred at room temperature under hydrogen protection. After the reaction was complete, the reaction solution was filtered and concentrated to obtain compound 16b (5.19 g).

MS (ESI, [M+H] ⁺ )m/z: 337.12.

Step C: Preparation of compound 16c

At 0°C, compound 16b (5.14 g), tetrahydrofuran (100 mL) and deuterated lithium aluminum hydride (1.60 g) were added to the reaction bottle in sequence. After the addition, the reaction was stirred at room temperature. After the reaction was complete, water was added to quench the reaction, the mixture was filtered, and ethyl acetate was added for extraction. The organic phase was dried, filtered, and concentrated to obtain compound 16c (2.76 g).

MS (ESI, [M+H] ⁺ )m/z: 311.17.

Step D: Preparation of compound 16d

At -10°C, compound 16c (2.76 g), dichloromethane (60 mL), triethylamine (1.80 g), and methanesulfonic anhydride (3.10 g) were added to the reaction flask in sequence. After the addition, the mixture was stirred at 0°C for reaction. After the reaction was completed, the reaction solution was added dropwise to 40% dimethylamine aqueous solution (20.04 g) at -10°C. After the addition, the mixture was stirred at room temperature for reaction. After the reaction was complete, the reaction solution was concentrated, and the crude product was purified by column chromatography (dichloromethane: methanol = 20:1) to obtain compound 16d (1.17 g).

MS (ESI, [M+H] ⁺ )m/z: 336.26.

Step E: Preparation of compound 16e

Compound 16d (1.17 g), dichloromethane (10 mL) and a 1,4-dioxane solution of hydrochloric acid (4 M, 20 mL) were added to the reaction flask in sequence, and the mixture was stirred at room temperature for reaction. After the reaction was complete, the reaction solution was concentrated, and a saturated sodium bicarbonate solution was added to adjust the mixture to alkalinity (pH about 10), and the mixture was extracted with dichloromethane. The organic phase was dried, filtered, and the solvent was removed by drying under reduced pressure to obtain compound 16e (1.13 g).

MS (ESI, [M+H] ⁺ )m/z: 238.25.

Step F: Preparation of compound 16f

Under nitrogen protection, compound 16e (1.00 g), intermediate 1A-11 (0.86 g), tris(dibenzylideneacetone)dipalladium (0.26 g), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.20 g), cesium carbonate (2.82 g), 1,4-dioxane (30 mL) were added to the reaction bottle in sequence, and stirred at 110° C. After the reaction was complete, the reaction solution was filtered and concentrated. Column chromatography (dichloromethane/methanol=20/1) gave compound 16f (0.85 g).

MS (ESI, [M+H] ⁺ )m/z: 503.33.

Intermediate Example 12: Preparation of Compound 53a

Step A: Preparation of compound 53a

Compound 16f (0.85 g), pinacol diboron (0.86 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.27 g), potassium acetate (0.50 g) and 1,4-dioxane (20 mL) were added to a microwave tube in sequence. After the addition was complete, nitrogen was added. The reaction was stirred at 90°C in a microwave oven. After the reaction was complete, the reaction solution was filtered and concentrated. Column chromatography (dichloromethane/methanol = 20/1) gave compound 53a (0.54 g).

MS (ESI, [M+H] ⁺ )m/z: 595.43.

Intermediate Example 13: Preparation of Compound 79d

Step A: Preparation of intermediate 79a

Compound 6-amino-3-bromopicolinic acid methyl ester (20 g), triethylamine (26.3 g), cyclopropylcarbonyl chloride (36.2 g) and dichloromethane (200 mL) were added to the reaction flask in sequence. After the addition, the mixture was stirred at room temperature for reaction. After the reaction was complete, saturated sodium bicarbonate aqueous solution and dichloromethane were added to the reaction solution for extraction. The organic phase was dried, filtered and concentrated to obtain compound 79a (25.1 g).

MS (ESI, [M+H] ⁺ )m/z: 299.0.

Step B: Preparation of compound 79b

Compound 79a (10.0 g), tetrahydrofuran (100.0 mL), and lithium borohydride (0.88 g) were added to the reaction bottle in sequence at 0°C. After the addition, the atmosphere was replaced with nitrogen and the reaction was stirred at 0°C. After the reaction was complete, water was added to the reaction solution to quench the reaction, and the mixture was extracted with dichloromethane. The organic phase was separated, dried, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain compound 79b (7.0 g).

MS (ESI, [M+H] ⁺ )m/z: 271.0.

Step C: Preparation of Compound 79c

At 0°C, compound 79b (7.0 g), dichloromethane (50.0 mL), N,N-diisopropylethylamine (8.34 mL), and methanesulfonic anhydride (11.24 g) were added to the reaction bottle in sequence, and the mixture was stirred at 0°C for reaction. After the reaction was complete, an aqueous solution of methylamine (7M, 10 mL) was slowly added to the reaction solution at 0°C, and the mixture was stirred at 0°C for reaction. After the reaction was complete, the reaction solution was concentrated and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain compound 79c (2.8 g).

MS (ESI, [M+H] ⁺ )m/z: 283.9.

Step D: Preparation of compound 79d

Compound 79c (2.8 g), N,N-dimethylpyridin-4-amine (0.24 g), di-tert-butyl dicarbonate (2.58 g) and tetrahydrofuran (20 mL) were added to the reaction flask in sequence. After the addition, the mixture was stirred at room temperature for reaction. After the reaction was complete, 10% citric acid aqueous solution (80 mL, w/w) and dichloromethane were added to the reaction solution for extraction. The organic phase was separated, washed, dried and concentrated to obtain compound 79d (3.1 g).

MS (ESI, [M+H] ⁺ )m/z: 384.3.

Intermediate Example 14: Preparation of Compound 82c

Step A: Preparation of compound 82a

4-Chloro-3-iodopyridin-2-ylamine (5.00 g), 5-chloropent-1-yne (2.22 g), cuprous iodide (0.37 g), bistriphenylphosphine palladium dichloride (0.69 g), and triethylamine (30 mL) were added to the reaction flask in sequence. After the addition was completed, nitrogen was protected and the reaction was stirred at 80°C. After the reaction was complete, the reaction solution was filtered and concentrated. Compound 82a (3.0 g) was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain.

MS (ESI, [M+Na] ⁺ )m/z: 229.07.

Step B: Preparation of compound 82b

At 0°C, compound 82a (3.00 g), acetonitrile (30 mL) and trifluoroacetic acid (5.50 g) were added to the reaction bottle in sequence. After the addition, the mixture was stirred at 0°C. After 2 hours of reaction, the solvent was concentrated under reduced pressure, and acetonitrile (30 mL) and palladium dichloride (0.35 g) were added to the residue in sequence. After the addition, the mixture was protected by nitrogen and heated and stirred at 80°C for reaction. After the reaction was complete, the reaction solution was filtered and concentrated. Compound 82b (1.50 g) was obtained by purification by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1).

MS (ESI, [M+H] ⁺ )m/z: 229.05.

Step C: Preparation of Compound 82c

At 0°C, compound 82b (3.00 g), tetrahydrofuran (30 mL), 60 wt% sodium hydride (1.05 g), and potassium iodide (1.36 g) were added to the reaction bottle in sequence. After the addition, the mixture was stirred at room temperature. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution, extracted with dichloromethane, and the organic phase was dried, filtered, and concentrated. Compound 82c (0.80 g) was obtained by purification by silica gel column chromatography (petroleum ether/ethyl acetate = 4/1).

MS (ESI, [M+H] ⁺ )m/z: 193.27.

Intermediate Example 15: Preparation of Compound 85k

Step A: Preparation of Compound 85j

Compound tert-butyl-7-amino-4-chloro-1-oxoisoindoline-2-carboxylate (3.1 g), ethanol (50.0 mL), ethylene glycol (2.0 g), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (1.1 g), tetrahydroxydiboron (3.0 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.8 g), and potassium phosphate (7.1 g) were added to the reaction flask in sequence. After the addition, the reaction was stirred at 100°C. After the reaction was complete, the reaction solution was concentrated and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 2/1) to obtain compound 85j (1.7 g).

MS (ESI, [M+H] ⁺ )m/z: 293.2.

Step B: Preparation of compound 85k

Compound 85j (1.7 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.1 g), potassium phosphate (0.9 g), intermediate 7A (0.07 g), water (4.0 mL) and 1,4-dioxane (16.0 mL) were added to the reaction flask in sequence. After the addition was completed, the reaction mixture was stirred at 85°C. After the reaction was complete, the reaction solution was concentrated and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain compound 85k (0.3 g).

MS (ESI, [M+H] ⁺ )m/z: 405.2.

Intermediate Example 16: Preparation of Compound 97d

Step A: Preparation of compound 97d

To the reaction bottle, 3-bromo-7-fluoroimidazo[1,2-A]pyridine (3.5 g) and tetrahydrofuran (50 mL) were added in sequence. After the addition, under nitrogen protection, a tetrahydrofuran solution of isopropylmagnesium chloride (15 mL, 1.3 M) was slowly added dropwise at -15°C. After the addition, the reaction was stirred for 0.5 h at -15°C. Then, isopropyl alcohol pinacol borate (4.5 g) was slowly added dropwise. After the addition, the temperature was slowly raised to room temperature and stirred for the reaction. TLC was monitored until the reaction was complete. A saturated ammonium chloride solution was added to the reaction solution to quench the reaction, and the reaction was filtered, washed, and dried to obtain compound 97d (2.2 g).

MS (ESI, [M+H] ⁺ )m/z: 181.2.

Example 1: Preparation of Compound I-86

Step A: Preparation of compound 86a

Compound 85a (36.0 g), 2,5-dihydrofuran-3-naphthoyl borate (33.0 g), 1,1-bis(diphenylphosphino)diferropalladium dichloride (8.72 g), sodium carbonate (22.6 g), water (100.0 mL) and 1,4-dioxane (400.0 mL) were added to the reaction flask in sequence. After the addition, the reaction was stirred at 90°C. The reaction was monitored by TLC until the reaction was complete, and the reaction solution was filtered, concentrated, and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain compound 86a (15.0 g).

MS (ESI, [M+H] ⁺ )m/z: 327.3.

Step B: Preparation of compound 86b

Compound 86a (15.0 g), 10 wt% palladium hydroxide on carbon (15.0 g), and methanol (50.0 mL) were added to the reaction flask in sequence. After the addition, the mixture was stirred at 90° C. The reaction was monitored by TLC until the reaction was complete. The reaction solution was filtered, concentrated, and purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/1) to obtain compound 86b (14.5 g).

MS (ESI, [M+H] ⁺ )m/z: 329.1.

Step C: Preparation of Compound 86c

Compound 86b (10.0 g), dichloromethane (10.0 mL), and trifluoroacetic acid (33.8 mL) were added to the reaction flask in sequence. After the addition, the mixture was stirred at room temperature for reaction. TLC was used to monitor the reaction until it was complete. Saturated sodium bicarbonate solution was added to the reaction solution to adjust the pH to about 10, and the mixture was extracted with dichloromethane. The organic phase was dried, filtered, concentrated, and purified by silica gel column chromatography (dichloromethane/methanol = 5/1) to obtain compound 86c (6.50 g).

MS (ESI, [M+H] ⁺ )m/z: 229.0.

Step D: Preparation of compound 86d

Compound 86c (6.50 g), acetonitrile (50.0 mL), tert-butyl nitrite (2.0 g), and copper bromide (5.68 g) were added to the reaction flask in sequence. After the addition, the mixture was stirred at 60°C for reaction. TLC was used to monitor the reaction until the reaction was complete. Saturated sodium bicarbonate solution was added to the reaction solution to adjust the pH to about 10, and the mixture was extracted with ethyl acetate. The organic phase was dried, filtered, concentrated, and purified by silica gel column chromatography (dichloromethane/methanol = 2/1) to obtain compound 86d (3.8 g).

MS (ESI, [M+H] ⁺ )m/z: 292.1.

Step E: Preparation of compound 86e

Compound 86d (3.7 g), tetrahydrofuran (50.0 mL), and lithium borohydride (0.6 g) were added to the reaction bottle in sequence at 0°C. After the addition, the atmosphere was replaced with nitrogen and the reaction was stirred at 0°C. TLC was monitored until the reaction was complete, and a saturated ammonium chloride solution was added to the reaction solution to quench the reaction, and the mixture was extracted with dichloromethane. The organic phase was separated, dried, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain compound 86e (3.4 g).

MS (ESI, [M+H] ⁺ )m/z: 264.2.

Step F: Preparation of compound 86f

Compound 86e (3.4 g), dichloromethane (100.0 mL), and Dess-Martin reagent (6.4 g) were added to the reaction flask in sequence at 0°C. After addition, the atmosphere was replaced with nitrogen and the reaction was stirred at 0°C. TLC was used to monitor the reaction until the reaction was complete. Saturated sodium bicarbonate solution was added to the reaction solution to adjust the pH to about 10, and the reaction solution was extracted with ethyl acetate. The organic phase was dried, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain compound 86f (1.3 g).

MS (ESI, [M+H] ⁺ )m/z: 262.0.

Step G: Preparation of Compound 86g

At 0°C, compound 86f (1.3 g), acetonitrile (100.0 mL), sodium triacetoxyborohydride (2.0 g), and methylamine hydrochloride (1.6 g) were added to the reaction bottle in sequence. After the addition, the atmosphere was replaced with nitrogen and the reaction was stirred at 0°C. TLC was used to monitor the reaction until it was complete. Saturated sodium bicarbonate solution was added to the reaction solution to adjust it to alkaline (pH about 10), and the mixture was extracted with ethyl acetate. The organic phase was dried, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain compound 86g (1.3 g).

MS (ESI, [M+H] ⁺ )m/z: 277.2.

Step H: Preparation of Compound 86h

Compound 86g (1.3 g), dichloromethane (100.0 mL), triethylamine (0.7 g), and di-tert-butyl dicarbonate (1.3 g) were added to the reaction flask in sequence. After the addition, the mixture was stirred at room temperature for reaction. TLC was monitored until the reaction was complete, and the reaction solution was concentrated and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1) to obtain compound 86h (1.5 g).

MS (ESI, [M+H] ⁺ )m/z: 377.3.

Step I: Preparation of compound 86i

Compound 85k (0.3 g), compound 86h (0.3 g), 1,4-dioxane (20.0 mL), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.1 g), cesium carbonate (0.9 g), tris(dibenzylideneacetone)dipalladium (0.1 g) were added to the reaction flask in sequence. After the addition, the reaction was stirred at 110°C. TLC was monitored until the reaction was complete, and the reaction solution was filtered and concentrated. Compound 86i (0.4 g) was purified by silica gel column chromatography (dichloromethane/methanol=30/1).

MS(ESI,[M+H] ⁺ )m/z:701.1.

Step J: Preparation of Compound I-86

Compound 86i (0.4 g), methanesulfonic acid (0.7 mL), and dichloromethane (10 mL) were added to the reaction flask in sequence. After the addition was completed, the reaction was allowed to react at room temperature and monitored by TLC until the reaction was complete. Saturated aqueous sodium bicarbonate solution was added to the reaction solution to adjust it to alkaline (pH was about 9), and the solution was extracted with dichloromethane. The organic phase was dried, filtered, concentrated, and purified by silica gel column chromatography (dichloromethane/methanol = 5/1) to obtain compound I-86 (0.07 g).

MS(ESI,[M+H] ⁺ )m/z:501.2.

¹ H NMR (500MHz, CDCl ₃ )δ8.40(d,J＝7.6Hz,1H),8.32(d,J＝8.4Hz,1H),8.01(s,1H),7.72–7.62(m,2H),7.13(d,J＝7.5 Hz,1H),6.73(d,J＝2.2Hz,1H),4.40(s,2H),4 .09(td,J＝8.1,5.0Hz,2H),3.92(q,J＝7.8Hz,1H),3.78–3.65(m,4H),2.45(s,3H),2.41(dt,J＝8.0 ,4.1Hz,1H),1.96(dq,J＝12.7,7.6Hz,1H).

Example 2: Preparation of Compound I-87

Step A: Preparation of compound 87a

To the reaction bottle, add 6-bromo-3-methoxy-2-pyridinecarboxylic acid ethyl ester (1.5 g) and tetrahydrofuran (50 mL) in sequence. After the addition, under nitrogen protection, slowly add a tetrahydrofuran solution of lithium borohydride (8 mL, 2 M) dropwise at -15 °C. After the addition, slowly warm the temperature to room temperature and stir to react. Monitor by TLC until the reaction is complete. Add saturated ammonium chloride solution to the reaction solution to quench the reaction, filter, wash, and dry to obtain compound 87a (1.28 g).

MS (ESI, [M+H] ⁺ )m/z: 218.1.

Step B: Preparation of compound 87b

Compound 87a (1.2 g), methanesulfonic anhydride (1 g), triethylamine (3.57 g), and dichloromethane (30 mL) were added to the reaction flask in sequence. After addition, the mixture was reacted at -15°C for 1 h. After TLC monitoring, a tetrahydrofuran solution of dimethylamine (30 mL, 2 M) was slowly added dropwise, and the mixture was stirred and reacted at -15°C. After TLC monitoring, the mixture was extracted with ethyl acetate, and the organic phase was separated, dried, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1) to obtain compound 87b (1.02 g).

MS (ESI, [M+H] ⁺ )m/z: 245.1.

Step C: Preparation of Compound 87c

Compound 87b (0.18 g), compound 85k (0.32 g), potassium carbonate (0.3 g), tris(dibenzylideneacetone)dipalladium (0.07 g), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.08 g), water (1 mL), and dioxane (10 mL) were added to the reaction flask in sequence. The mixture was stirred and heated at 90°C under nitrogen protection. The reaction was monitored by TLC until the reaction was complete, and the reaction solution was filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol=50/1) to obtain compound 87c (0.3 g).

MS (ESI, [M+H] ⁺ )m/z: 569.6.

Step D: Preparation of Compound I-87

Compound 87c (0.3 g), methanesulfonic acid (1.2 mL), and dichloromethane (10 mL) were added to the reaction flask in sequence. After the addition was completed, the reaction was allowed to react at room temperature and monitored by TLC until the reaction was complete. Saturated aqueous sodium bicarbonate solution was added to the reaction solution to adjust it to alkaline (pH about 9), and extracted with dichloromethane. The organic phase was dried, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 5/1) to obtain compound I-87 (0.15 g).

MS (ESI, [M+H] ⁺ )m/z: 469.2.

¹ H NMR (500MHz, CDCl ₃ : CD ₃ OD＝10:1)δ9.65(s,1H),8.71(d,J＝8.5Hz,1H),8.38(d,J＝7.6Hz,1H),7.99(s,1H),7.65–7.58( m,2H),7.23(d,J=8.8Hz,1H),7. 08(d,J＝7.4Hz,1H),6.86(d,J＝8.8Hz,1H),6.75–6.71(m,1H),6.39(s,1H),4.37(s,2H),3.85(s ,3H),3.74(s,2H),2.46(s,6H).

Example 3: Preparation of Compound I-88

Step A: Preparation of intermediate 88a

Compound 79d (2.5 g), 1,4-dioxane (20.0 mL), water (5.0 mL), potassium phosphate (4.14 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.51 g), 3,6-dihydro-2H-pyran-4-boronic acid were added to the reaction flask in sequence. After the addition of acetyl alcohol ester (1.36 g), the mixture was stirred at 110° C. The reaction was monitored by TLC until completion, the reaction solution was filtered and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=30/1) to obtain compound 88a (2.01 g).

MS (ESI, [M+H] ⁺ )m/z: 388.3.

Step B: Preparation of compound 88b

Compound 88a (2.0 g), tetrahydrofuran (15.0 mL), methanol (15.0 mL), and 10% palladium hydroxide on carbon (2.0 g) were added to the reaction flask in sequence. After the addition, the atmosphere was replaced with hydrogen and stirred at room temperature for reaction. The reaction was monitored by TLC until the reaction was complete, and the reaction solution was filtered and concentrated to obtain compound 88b (1.75 g).

MS (ESI, [M+H] ⁺ )m/z: 390.5.

Step C: Preparation of Compound 88c

Compound 88b (1.75 g), water (32.0 mL), methanol (4.0 mL) and sodium hydroxide (3.2 g) were added to the reaction flask in sequence. After the addition, the mixture was stirred at 70°C and monitored by TLC until the reaction was complete. The mixture was diluted with water and extracted with dichloromethane. The organic phase was dried, filtered and concentrated to obtain compound 88c (1.2 g).

MS (ESI, [M+H] ⁺ )m/z: 322.4.

Step D: Preparation of compound 88d

Compound 3A-2 (0.54 g), compound 88c (0.51 g), 1,4-dioxane (10.0 mL), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.15 g), cesium carbonate (1.27 g), tris(dibenzylideneacetone)dipalladium (0.18 g) were added to the reaction flask in sequence. After the addition, the atmosphere was replaced with nitrogen and the reaction was stirred at 110°C. The reaction was monitored by TLC until the reaction was complete, and the reaction solution was filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol=50/1) to obtain compound 88d (0.65 g).

MS (ESI, [M+H] ⁺ )m/z: 587.1.

Step E: Preparation of compound 88e

Compound 88d (0.65 g), potassium acetate (0.20 g), biboronic acid pinacol ester (0.31 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.10 g), and 1,4-dioxane (20.0 mL) were added to the reaction flask in sequence. After the addition, the atmosphere was replaced with nitrogen and the reaction was stirred at 90°C. The reaction was monitored by TLC until the reaction was complete, the reaction solution was filtered and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=50/1) to obtain compound 88e (250 mg).

MS (ESI, [M+H] ⁺ )m/z: 679.1.

Step F: Preparation of Compound 88f

Compound 88e (250 mg), potassium phosphate (235 mg), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (29 mg), intermediate 7A (87 mg), water (3.0 mL) and 1,4-dioxane (12.0 mL) were added to the reaction flask in sequence. After the addition, the reaction was stirred at 110°C. The reaction was monitored by TLC until the reaction was complete, the reaction solution was filtered and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=50/1) to obtain compound 88f (150 mg).

MS(ESI,[M+H] ⁺ )m/z:709.1.

Step G: Preparation of Compound I-88

Compound 88f (150 mg), a solution of hydrogen chloride in 1,4-dioxane (4M, 2.1 mL), and dichloromethane (3 mL) were added to the reaction flask in sequence. After the addition was completed, the reaction was allowed to react at room temperature and monitored by TLC until the reaction was complete. Saturated aqueous sodium bicarbonate solution was added to the reaction solution to adjust it to alkaline (pH about 9), and the mixture was extracted with dichloromethane. The organic phase was dried, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 10/1) to obtain compound I-88 (50 mg).

MS (ESI, [M+H] ⁺ )m/z: 509.2.

1H NMR (500MHz, CDCl ₃ )δ9.74(s,1H),8.69(d,J＝8.5Hz,1H),8.38(d,J＝7.5Hz,1H),8.00(s,1H),7.68–7.58(m,2H) ,7.48(d,J＝8.4Hz,1H),7.09(d,J＝7.6Hz,1H),6.82(d,J＝8.4Hz,1H),6.72(d,J＝2.0Hz,1H), 6.45(s,1H),4.38(s,2H),4.10(dd,J＝11.5,4.1Hz,2H),3.93(s,2H),3.57(t,J＝11.6Hz,2H) ,2.98(tt,J＝12.2,3.7Hz,1H),2.57(s,3H),2.12–1.92(m,3H),1.80(qd,J＝12.3,4.2Hz,2H).

Example 4: Preparation of Compound I-89

Step A: Preparation of compound 89a

To the reaction flask, intermediate 5A (180 mg), compound 82c (56 mg), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (23 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (14 mg), tripotassium phosphate (123 mg), 1,4-dioxane (7.0 mL) and water (1.0 mL) were added in sequence, and the mixture was stirred at 85°C under nitrogen protection. The reaction solution was concentrated after TLC monitoring until the reaction was complete. Compound 89a (90 mg) was obtained by purification by silica gel column chromatography (dichloromethane/methanol=20/1).

MS (ESI, [M+H] ⁺ )m/z: 623.4.

Step B: Preparation of Compound I-89

Compound 89a (90 mg), 1,4-dioxane solution of hydrochloric acid (4M, 1.0 mL), and dichloromethane (4 mL) were added to the reaction flask in sequence. After the addition was completed, the reaction was allowed to react at room temperature and monitored by TLC until the reaction was complete. Saturated aqueous sodium bicarbonate solution was added to the reaction solution to adjust it to alkaline (pH about 9), and the mixture was extracted with dichloromethane. The organic phase was dried, filtered, concentrated, and purified by silica gel column chromatography (dichloromethane/methanol = 5/1) to obtain compound I-89 (25 mg).

MS (ESI, [M+H] ⁺ )m/z: 523.2.

¹ H NMR (500MHz, CDCl ₃ )δ8.79–8.68(m,1H),8.13(t,J＝4.6Hz,1H),7.66(dd,J＝8.6,4.2Hz,1H),7.55–7.46(m,1H) ,7.44–7.34(m,2H),7.01(t,J＝4.6Hz,1H),6.88–6.76(m,1H),6.08(s,1H),4.39(s,2H),4. 23–4.19(m,2H),4.06(d,J＝11.1Hz,2H),3.57(dd,J＝27.8,16.1Hz,4H),3.18–3.08(m,1H), 3.04(t,J＝7.3Hz,2H),2.65(dd,J＝14.3,7.2Hz,2H),2.36–2.27(m,6H),1.83–1.63(m,4H).

Example 5: Preparation of Compound I-90

Step A: Preparation of compound 90a

At 0°C, sodium borohydride (0.28 g) was added in batches to a reaction bottle containing 6-bromo-3-fluoro-2-pyridinecarboxaldehyde (1.0 g) and methanol (15 mL). After the addition was completed, the mixture was moved to room temperature for reaction. TLC was monitored until the reaction was complete, saturated aqueous ammonium chloride solution was added to quench the reaction, ethyl acetate was added for extraction, the organic phase was separated, dried, filtered, and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=8/2) to obtain compound 90a (0.65 g).

MS (ESI, [M+H] ⁺ )m/z: 205.9.

Step B: Preparation of compound 90b

Compound 90a (0.31 g), compound 85k (0.50 g), 1,4-dioxane (20.0 mL), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.15 g), cesium carbonate (1.2 g), tris(dibenzylideneacetone)dipalladium (0.11 g) were added to the reaction flask in sequence. After the addition, the reaction was stirred at 100°C. The reaction was monitored by TLC until the reaction was complete, and the reaction solution was filtered and concentrated. Compound 90b (0.7 g) was obtained by purification by silica gel column chromatography (dichloromethane/methanol=30/1).

MS (ESI, [M+H] ⁺ )m/z: 530.2.

Step C: Preparation of Compound 90c

In an ice-water bath, compound 90b (0.2 g), dichloromethane (5 mL), N,N-diisopropylethylamine (0.15 mL), and methanesulfonic anhydride (0.16 g) were added to the reaction bottle in sequence, and the mixture was reacted in an ice-water bath. TLC was monitored until the reaction was complete, and a tetrahydrofuran solution of dimethylamine (2 M, 5 mL) was slowly added, and the mixture was reacted at room temperature. TLC was monitored until the reaction was complete, and the reaction solution was concentrated and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain compound 90c (0.14 g).

MS (ESI, [M+H] ⁺ )m/z: 557.3.

Step D: Preparation of Compound I-90

Compound 90c (0.1 g), methanesulfonic acid (1.2 mL), and dichloromethane (10 mL) were added to the reaction flask in sequence. After the addition was completed, the reaction was allowed to react at room temperature and monitored by TLC until the reaction was complete. Saturated aqueous sodium bicarbonate solution was added to the reaction solution to adjust it to alkaline (pH about 9), and the mixture was extracted with dichloromethane. The organic phase was dried, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 5/1) to obtain compound I-90 (30 mg).

MS (ESI, [M+H] ⁺ )m/z: 457.2.

¹ H NMR (500MHz, CDCl ₃ )δ9.85(s,1H),8.81(d,J＝8.5Hz,1H),8.39(d,J＝7.6Hz,1H),8.00(s,1H),7.63(d,J＝8.4Hz, 2H),7.33(t,J＝8.8Hz,1H),7.09(d, J＝7.6Hz,1H),6.82(dd,J＝8.8,2.8Hz,1H),6.72(d,J＝1.3Hz,1H),6.13(s,1H),4.38(s,2H),3.70( d,J＝2.3Hz,2H),2.41(s,6H).

Example 6: Preparation of Compound I-91

Step A: Preparation of compound 91a

6-Chloro-3-formyl-2-methylpyridine (2.0 g) and dichloromethane (60 mL) were added to the reaction flask in sequence. After the addition was completed, diethylamino trifluoride (3.11 g) was slowly added dropwise at 0°C. After the addition was completed, the temperature was slowly raised to room temperature and stirred for reaction. TLC was monitored until the reaction was complete. Water was added to the reaction solution to quench the reaction, and dichloromethane was used for extraction. The organic phase was separated, dried, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1) to obtain compound 91a (2.2 g).

MS (ESI, [M+H] ⁺ )m/z: 178.0.

Step B: Preparation of compound 91b

Compound 91a (2.0 g), N-bromosuccinimide (2.3 g), dibenzoyl peroxide (0.27 g), and 1,2-dichloroethane (60 mL) were added to the reaction flask in sequence. After the addition was completed, nitrogen was protected and the reaction was stirred and heated at 90° C. TLC was monitored until the reaction was complete. Saturated sodium thiosulfate solution was added to the reaction solution to quench the reaction, and the reaction was extracted with dichloromethane. The organic phase was separated, dried, filtered, and concentrated to obtain compound 91b (2.3 g).

MS (ESI, [M+H] ⁺ )m/z: 256.1.

Step C: Preparation of Compound 91c

Compound 91b (2.3 g), sodium carbonate (0.32 g), dichloromethane (0.3 g) and dimethylamine ethanol solution (1 mL, 4 M) were added to the reaction flask in sequence. After the addition was completed, the mixture was stirred at room temperature for reaction. TLC was used to monitor the reaction until it was complete. Water and dichloromethane were added to the reaction solution for extraction. The organic phase was separated, dried, filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 10/1) to obtain compound 91c (1.6 g).

MS (ESI, [M+H] ⁺ )m/z: 221.4.

Step D: Preparation of compound 91d

Compound 91c (0.05 g), compound 85k (0.08 g), cesium carbonate (0.2 g), tris(dibenzylideneacetone)dipalladium (0.02 g), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.03 g) and dioxane (40 mL) were added to the reaction flask in sequence. The mixture was stirred and heated at 110°C under nitrogen protection. The reaction was monitored by TLC until the reaction was complete, and the reaction solution was filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol=50/1) to obtain compound 91d (0.1 g).

MS (ESI, [M+H] ⁺ )m/z: 589.2.

Step E: Preparation of Compound I-91

Compound 91d (0.1 g), methanesulfonic acid (0.7 mL), and dichloromethane (10 mL) were added to the reaction flask in sequence. After the addition was completed, the reaction was allowed to react at room temperature and monitored by TLC until the reaction was complete. Saturated aqueous sodium bicarbonate solution was added to the reaction solution to adjust it to alkaline (pH was about 9), and the solution was extracted with dichloromethane. The organic phase was dried, filtered, concentrated, and purified by silica gel column chromatography (dichloromethane/methanol = 5/1) to obtain compound I-91 (0.04 g).

MS (ESI, [M+H] ⁺ )m/z: 489.1.

¹ H NMR(500MHz,Chloroform-d)δ10.03(s,1H),8.93(d,J＝8.5Hz,1H),8.40(d,J＝7.5Hz,1H),8.01(s,1H),7.84( d,J＝8.5Hz,1H),7.67(d,J＝8.5Hz,1H),7.63 (d,J＝2.1Hz,1H),7.37(s,1H),7.15–7.08(m,1H),6.86(d,J＝8.5Hz,1H),6.7 3(dd,J=2.1,0.9Hz,1H),6.27(s,1H),4.40(s,2H),3.71(s,2H),2.30(s,6H).

Example 7: Preparation of Compound I-92

Step A: Preparation of Compound 92a

To the reaction flask, intermediate 3A-2 (948 mg), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (264 mg), tris(dibenzylideneacetone)dipalladium (313 mg), cesium carbonate (2.23 g), compound 14d (550 mg) and 1,4-dioxane (20 mL) were added in sequence, and after the addition, nitrogen was replaced, and the reaction was stirred at 100° C. TLC was monitored until the reaction was complete, filtered, concentrated, and the residue was purified by column chromatography (dichloromethane/methanol=20/1) to obtain compound 92a (1.0 g).

MS (ESI, [M+H] ⁺ )m/z: 507.3.

Step B: Preparation of compound 92b

Compound 92a (1.0 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino- After the addition, the mixture was stirred at 90°C under nitrogen protection. The reaction was monitored by TLC until the reaction was complete, filtered, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=20/1) to obtain compound 92b (0.82 g).

MS (ESI, [M+H] ⁺ )m/z: 599.3.

Step C: Preparation of Compound 92c

Compound 92b (0.25 g), intermediate 8A (0.11 g), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (20 mg), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (33 mg), tripotassium phosphate (0.18 g), 1,4-dioxane (12 mL) and water (3 mL) were added to the reaction bottle in sequence. After the addition was completed, the mixture was stirred at 85° C. under nitrogen protection. The reaction was monitored by TLC until completion, filtered, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=20/1) to obtain compound 92c (0.11 g).

MS (ESI, [M+H] ⁺ )m/z: 630.3.

Step D: Preparation of compound 92d

Compound 92c (0.11 g), dichloromethane (10 mL) and 1,4-dioxane hydrochloride solution (2 mL, 4 M) were added to the reaction flask in sequence and stirred at room temperature. TLC was used to monitor the reaction until it was complete. The reaction solution was adjusted to alkaline (pH about 9) by adding saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol = 20/1) to obtain compound 92d (50 mg).

HRMS(ESI, [M+H] ⁺ )m/z:530.2793.

Step E: Preparation of Compound I-92

Compound 92d (38 mg), dichloromethane (10 mL) and 1,4-dioxane hydrochloride solution (0.15 mL, 0.5 M) were added to the reaction flask in sequence and stirred at room temperature. The reaction was monitored by TLC until completion and concentrated to obtain compound I-92 (40 mg).

MS (ESI, [M+H] ⁺ )m/z: 530.2.

¹ H NMR (500 MHz, DMSO-d ₆ )δ10.06(s,1H),9.82(s,1H),8.86(d,J＝2.6Hz,2H),8.52(d,J＝8.1Hz,1H),8 .17–8.07(m,2H),7.80(d,J＝8.6Hz,1H),7.75(d,J＝8.5Hz,1H),7.19(d,J＝8. 5Hz, 1H), 6.62 (d, J = 2.4Hz, 1H), 4.45 (d, J = 45.5Hz, 4H), 3.98 (dd, J = 10.8, 2. 9Hz,2H),3.51(t,J＝10.7Hz,2H),3.03(t,J＝11.2Hz,1H),1.75–1.60(m,4H).

Example 8: Preparation of Compound I-93

Step A: Preparation of compound 93a

At -10°C, compound 16c (0.43 g), dichloromethane (30 mL), triethylamine (0.358 g), and methylsulfonic anhydride (0.603 g) were added to the reaction flask in sequence. After the addition, the mixture was stirred at 0°C. After TLC monitoring, the reaction was completed. At -10°C, the reaction solution was added dropwise to deuterated dimethylamine hydrochloride. The mixture was added with 1% paraformaldehyde (0.358 g) and sodium hydroxide (0.554 g) in dichloromethane (30 mL), and the mixture was stirred at room temperature until the reaction was complete. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (dichloromethane/methanol=20/1) to obtain compound 93a (0.4 g).

MS (ESI, [M+H] ⁺ )m/z: 344.2.

Step B: Preparation of compound 93b

Compound 93a (0.4 g), dichloromethane (10 mL) and a 1,4-dioxane solution of hydrochloric acid (4 M, 20 mL) were added to the reaction flask in sequence. After the addition was completed, the mixture was stirred at room temperature for reaction. TLC was used to monitor the reaction until it was complete. The reaction solution was concentrated and adjusted to alkalinity (pH about 9) by adding a saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane. The organic phase was dried, filtered, and the solvent was removed by drying under reduced pressure to obtain compound 93b (0.33 g).

MS (ESI, [M+H] ⁺ )m/z: 244.2.

Step C: Preparation of Compound 93c

To the reaction flask, add intermediate 3A-2 (564 mg), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (157 mg), tris(dibenzylideneacetone)dipalladium (186 mg), cesium carbonate (1.33 g), compound 93b (0.33 g) and 1,4-dioxane (10 mL) in sequence. After the addition, stir at 100°C under nitrogen protection. Monitor by TLC until the reaction is complete, filter the reaction solution and concentrate. The residue is purified by silica gel column chromatography (dichloromethane/methanol=10/1) to obtain compound 93c (0.55 g).

MS (ESI, [M+H] ⁺ )m/z: 509.3.

Step D: Preparation of compound 93d

Compound 93c (0.55 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.17 g), biboric acid pinacol ester (0.41 g), potassium carbonate (0.32 g) and 1,4-dioxane (10 mL) were added to the reaction bottle in sequence. After the addition was completed, nitrogen was protected and the reaction was stirred at 90°C. TLC was monitored until the reaction was complete, and the reaction solution was filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol=20/1) to obtain compound 93d (0.28 g).

MS (ESI, [M+H] ⁺ )m/z: 601.4.

Step E: Preparation of compound 93e

Compound 93d (0.25 g), intermediate 8A (0.11 g), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (20 mg), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (33 mg), tripotassium phosphate (0.18 g), 1,4-dioxane (12 mL) and water (3 mL) were added to the reaction flask in sequence. After the addition was completed, nitrogen was protected and the reaction was stirred at 85°C. TLC was monitored until the reaction was complete, and the reaction solution was filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol=20/1) to obtain compound 93e (0.12 g).

MS (ESI, [M+H] ⁺ )m/z: 632.4.

Step F: Preparation of compound 93f

Compound 93e (0.10 g), dichloromethane (10 mL) and 1,4-dioxane hydrochloride solution (2 mL, 4 M) were added to the reaction flask in sequence and stirred at room temperature. TLC was used to monitor the reaction until it was complete. The reaction solution was adjusted to alkaline (pH about 9) by adding saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol = 20/1) to obtain compound 93f (30 mg).

MS (ESI, [M+H] ⁺ )m/z: 532.3.

Step G: Preparation of Compound I-93

Compound 93f (28 mg), dichloromethane (10 mL) and 1,4-dioxane hydrochloride solution (0.11 mL, 0.5 M) were added to the reaction flask in sequence and stirred at room temperature. The reaction was monitored by TLC until completion and concentrated to obtain compound I-93 (30 mg).

MS (ESI, [M+H] ⁺ )m/z: 532.3.

¹ H NMR (500 MHz, DMSO-d ₆ )δ10.06(s,1H),9.78(s,1H),8.86(d,J＝3.1Hz,2H),8.50(d,J＝8.4Hz,1H),8.1 7–8.08(m,2H),7.81(d,J＝8.6Hz,1H),7.75(d,J＝8.5Hz,1H),7.21(d,J＝8.6Hz,1 H),6.62(d,J＝2.5Hz,1H),4.41(s,2H),3.98(dd,J＝10.7,3.4Hz,2H),3.51(dd,J ＝11.5,9.7Hz,2H),3.01(t,J＝11.4Hz,1H),1.69(ddd,J＝31.4,15.7,7.7Hz,4H).

Example 9: Preparation of Compound I-94

Step A: Preparation of compound 94a

To the reaction flask, 4-methyl-1,4-azaphosphane 4-oxide (2.0 g), 2-chloro-5-fluoropyridine-6-carboxaldehyde (2.1 g), potassium carbonate (4.6 g), N,N-dimethylformamide (20 mL) were added in sequence. After the addition, the mixture was stirred at 80°C for reaction. TLC was used to monitor the reaction until it was complete. The reaction solution was filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 20/1) to obtain compound 94a (2.0 g).

MS (ESI, [M+H] ⁺ )m/z: 273.0.

Step B: Preparation of compound 94b

To the reaction flask, add 94a (2.0 g), THF (20 mL), and a tetrahydrofuran solution of dimethylamine (5.5 mL 2M) in sequence. After addition, stir at room temperature for 1 hour. The reaction solution was cooled to 0°C, and sodium cyanoborohydride (1.2 g) was added in batches. After addition, the mixture was moved to room temperature for reaction. TLC was monitored until the reaction was complete, and a saturated ammonium chloride solution was added dropwise to quench the reaction. The reaction solution was concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 5/1) to obtain compound 94b (1.5 g).

MS (ESI, [M+H] ⁺ )m/z: 302.1.

Step C: Preparation of Compound 94c

Compound 85k (291 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2-yl) palladium (II) (62 mg), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (69 mg), cesium carbonate (725 mg), compound 94b (300 mg) and 1,4-dioxane (10 mL) were added to the reaction bottle in sequence. After the addition was completed, the mixture was stirred at 100°C under nitrogen protection. The reaction solution was filtered and concentrated after TLC monitoring until the reaction was complete. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 20/1) to obtain compound 94c (85 mg).

MS (ESI, [M+H] ⁺ )m/z: 670.4.

Step D: Preparation of compound 94d

Compound 94c (85 mg), dichloromethane (10 mL) and 1,4-dioxane hydrochloride solution (2 mL, 4 M) were added to the reaction flask in sequence and stirred at room temperature. The reaction was monitored by TLC until it was complete. The reaction solution was adjusted to alkaline (pH about 9) by adding saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=20/1) to obtain compound 94d (18 mg).

MS (ESI, [M+H] ⁺ )m/z: 570.2.

Step E: Preparation of Compound I-94

Compound 94d (18 mg), dichloromethane (5 mL) and 1,4-dioxane hydrochloride solution (0.66 mL, 0.05 M) were added to the reaction flask in sequence and stirred at room temperature. The reaction was monitored by TLC until completion and concentrated to obtain compound I-94 (19 mg).

MS (ESI, [M+H] ⁺ )m/z: 570.2.

Example 10: Preparation of Compound I-95

Step A: Preparation of compound 95a

Compound 53a (200 mg), intermediate 8A (88 mg), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (26 mg), tripotassium phosphate (143 mg), 1,4-dioxane (6.0 mL) and water (1.0 mL) were added to the reaction flask in sequence. After the addition was completed, nitrogen was protected and the reaction was stirred at 85°C. TLC was monitored until the reaction was complete and concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol=30/1) to obtain compound 95a (84 mg).

MS (ESI, [M+H] ⁺ )m/z: 626.39.

Step B: Preparation of compound 95b

Compound 95a (84 mg), methanesulfonic acid (1.2 mL) and dichloromethane (10 mL) were added to the reaction flask in sequence. After the addition was completed, the mixture was reacted at room temperature and monitored by TLC until the reaction was complete. Saturated aqueous sodium bicarbonate solution was added to the reaction solution to adjust the solution to alkalinity (pH about 9), and the solution was extracted with dichloromethane. The organic phase was dried, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 5/1) to obtain compound 95b (23 mg).

HRMS(ESI,[M+H] ⁺ )m/z:526.2537.

Step C: Preparation of Compound I-95

Compound 95b (23 mg), dichloromethane (2.00 mL) and 1,4-dioxane hydrochloride solution (0.09 mL, 0.5 M) (2 mg) were added to the reaction flask in sequence, and the mixture was reacted at room temperature. The reaction was monitored by TLC until completion, and the mixture was concentrated to obtain compound I-95 (24 mg).

MS (ESI, [M+H] ⁺ )m/z: 526.2.

¹ H NMR (500MHz, DMSO-d ₆ )δ10.13(s,1H),10.05–9.93(m,1H),8.94(d,J＝5.6Hz,2H),8.57(d,J＝8.5Hz,1H),8.25 (s,1H),8.18(d,J＝2.5Hz,1H),7.88(d,J＝8.6Hz,1H),7.81(d,J＝8.5Hz,1H),7.28(d,J＝8 .6Hz,1H),6.68(d,J＝2.5Hz,1H),4.47(s,2H),4.03(dd,J＝10.5,3.9Hz,2H),3.60(d,J＝2 .4Hz,2H),3.07(ddt,J＝11.6,8.0,4.0Hz,1H),2.99(d,J＝4.9Hz,6H),1.81–1.69(m,4H).

Example 11: Preparation of Compound I-96

Step A: Preparation of compound 96a

4-Bromo-7-chloro-1,2-dihydro-3H-pyrrolo[3,4-C]pyridin-3-one (9 g), N,N-dimethylpyridin-4-amine (0.3 g), di-tert-butyl dicarbonate (8.6 g), and 1,4-dioxane (60 mL) were added to the reaction flask in sequence. After the addition, the reaction was stirred at room temperature. The reaction was monitored by TLC until complete and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1) to obtain compound 96a (10 g).

MS (ESI, [M+H] ⁺ )m/z: 347.39.

Step B: Preparation of compound 96b

To the reaction flask, add intermediate 1A-7 (1.3 g), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (244.6 mg), tris(dibenzylideneacetone)dipalladium (258.3 mg), cesium carbonate (1.8 g), compound 96a (1.1 g) and 1,4-dioxane (100 mL) in sequence. After the addition, replace nitrogen and stir at 100°C to react. Monitor by TLC until the reaction is complete and concentrate. The residue is purified by silica gel column chromatography (dichloromethane/methanol=20/1) to obtain compound 96b (1.1 g).

MS(ESI,[M+H] ⁺ )m/z:502.2.

Step C: Preparation of Compound 96c

Compound 96b (1.1 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (306.4 mg), biboronic acid pinacol ester (1.1 g), potassium carbonate (0.62 g) and 1,4-dioxane (50 mL) were added to the reaction bottle in sequence. After the addition was completed, nitrogen was replaced and the reaction was stirred at 90°C. The reaction was monitored by TLC until completion and concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol=20/1) to obtain compound 96c (1.3 g).

MS (ESI, [M+H] ⁺ )m/z: 594.3.

Step D: Preparation of compound 96d

Compound 96c (200 mg), intermediate 8A (90 mg), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (26 mg), tripotassium phosphate (143 mg), 1,4-dioxane (6.0 mL) and water (1.0 mL) were added to the reaction flask in sequence. After the addition was completed, nitrogen was protected and the reaction was stirred at 85°C. TLC was monitored until the reaction was complete and concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol=30/1) to obtain compound 96d (90 mg).

MS (ESI, [M+H] ⁺ )m/z: 625.4.

Step E: Preparation of Compound I-96

Compound 96d (90 mg), methanesulfonic acid (1.2 mL), and dichloromethane (10 mL) were added to the reaction bottle in sequence. After addition, the mixture was reacted at room temperature. TLC Monitor until the reaction is complete, add saturated sodium bicarbonate aqueous solution to the reaction solution to adjust to alkalinity (pH about 9), extract with dichloromethane, dry the organic phase, filter and concentrate, and purify the residue by silica gel column chromatography (dichloromethane/methanol=5/1) to obtain compound I-96 (30 mg).

MS (ESI, [M+H] ⁺ )m/z: 525.3.

Example 12: Preparation of Compound I-97

Step A: Preparation of compound 97a

Compound 94b (1.1 g), benzophenone imine (0.83 g), sodium tert-butoxide (0.72 g), tris(dibenzylideneacetone)dipalladium (0.17 g), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (0.12 g) and 1,4-dioxane (30 mL) were added to the reaction bottle in sequence. After the addition was completed, nitrogen was replaced and the reaction was stirred at 80°C. The reaction was monitored by TLC until completion, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain compound 97a (0.98 g).

MS (ESI, [M+H] ⁺ )m/z: 447.2.

Step B: Preparation of intermediate 97b

Compound 97a (0.98 g), 4M hydrogen chloride in 1,4-dioxane solution (10.9 mL) and dichloromethane (10 mL) were added to the reaction flask in sequence. After the addition was completed, the mixture was stirred at room temperature for reaction. TLC was used to monitor the reaction until it was complete. Saturated sodium bicarbonate aqueous solution was added to the reaction solution to adjust the pH to about 9. The mixture was extracted with dichloromethane. The organic phase was dried, filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 5/1) to obtain compound 97b (0.53 g).

MS (ESI, [M+H] ⁺ )m/z: 283.3.

Step C: Preparation of Compound 97c

Compound 97b (0.5 g), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (81.5 mg), tris(dibenzylideneacetone)dipalladium (86.1 mg), cesium carbonate (0.6 g), compound 96a (0.37 g) and 1,4-dioxane (100 mL) were added to the reaction flask in sequence. After the addition was completed, nitrogen was replaced and the reaction was stirred at 100° C. The reaction was monitored by TLC until completion and concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol=20/1) to obtain compound 97c (0.4 g).

MS (ESI, [M+H] ⁺ )m/z: 549.2.

Step D: Preparation of compound 97e

Compound 97c (0.4 g), compound 97d (0.2 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.06 g), tripotassium phosphate (0.47 mg), 1,4-dioxane (12.0 mL) and water (2.5 mL) were added to the reaction flask in sequence, and the mixture was stirred at 85°C under nitrogen protection. The reaction was monitored by TLC until completion and concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 20/1). Compound 97e (0.44 g) was obtained.

MS (ESI, [M+H] ⁺ )m/z: 649.3.

Step E: Preparation of Compound I-97

Compound 97e (100 mg), methanesulfonic acid (1.2 mL), and dichloromethane (10 mL) were added to the reaction flask in sequence. After the addition was completed, the reaction was allowed to react at room temperature and monitored by TLC until the reaction was complete. Saturated aqueous sodium bicarbonate solution was added to the reaction solution to adjust it to alkaline (pH about 9), and extracted with dichloromethane. The organic phase was dried, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 5/1) to obtain compound I-97 (42 mg).

MS (ESI, [M+H] ⁺ )m/z: 549.2.

Experimental Example 1 HPK1 in vitro kinase inhibitory activity assay

Enzymatic buffer was diluted 5× to 1×, and 10mM MgCl ₂ , 1mM DTT and 0.005% Tween 20 were added. 100ng/μL HPK1 (Life technology) stock solution was prepared into 1.67× 1.67ng/μL working solution (final concentration was 1ng/μL) with kinase buffer, and 6μL was plated in each well (384-well plate). Different compounds dissolved in DMSO were added to the wells using a nanoliter pipette, so that the final concentration of the compound was 1000nM-0.244nM, 4-fold gradient, a total of 7 concentrations, and blank control wells (without enzyme) and negative control wells (with enzyme, solvent DMSO) were set up, and 2 duplicate wells were set up. After the enzyme and compound were incubated at room temperature for 1 hour, 5× 5mM ATP (final concentration of 1mM) and 5× 2.5μM substrate (Cisbio, STK Substrate 1-biotin, final concentration of 500nM) diluted with kinase buffer were mixed in equal volumes, 4μL was added to each well, the plate was sealed with a sealing film, and incubated at room temperature for 2 hours. The detection antibody was prepared by mixing equal volumes of antibody STK Antibody-cryptate (Cisbio, 5μl/test) and 4× 500nM Streptavidin-XL665 (Cisbio, final concentration of 125nM), 10μL was added to each well, and incubated at room temperature for 1 hour. The PE Envision multi-function plate reader was used to detect the signal value (excitation 665nm, emission 620nm), and the IC ₅₀ was calculated by four-parameter fitting. The results are shown in Table 1 below:

Table 1 In vitro enzyme inhibition activity results of each compound

The results show that the compounds of the present disclosure have improved or superior inhibitory effects on HPK1 kinase.

Experimental Example 2 In vitro cell inhibitory activity assay

2.1 Detection of p-SLP76 phosphorylation inhibitory activity in Jurkat cells

Jurkat cells in good growth state were collected into centrifuge tubes, resuspended after centrifugation, and the cell density was adjusted to 6.25×10 ⁶ cells/mL, and inoculated into 384-well small volume white plates (8 μL/well); different compounds dissolved in DMSO were added to the wells using a nanoliter pipette to make the final concentration of the compound 2500nM-10.29nM, 2 replicates, and a control was set at the same time. After cell culture for 1 hour, stimulator CD3CD28 (manufacturer: stemcell, 4 μL) was added and incubated at 37°C for 30 minutes; 3 μL of lysis solution (manufacturer: BioAuxilium) was added to each well, and the cells were shaken and lysed at room temperature for 30 minutes. After lysis and mixing, 5 μL of pre-mixed antibodies (manufacturer: BioAuxilium) prepared in detection buffer were added, incubated at room temperature overnight, and detected by PerkinElmer Envision multi-function microplate reader (excitation 320nm, emission 615nm/665nm), and IC ₅₀ was calculated using four-parameter fitting. The experimental results are shown in Table 2.

Table 2 In vitro cell inhibition activity results of each compound

Wherein A means IC ₅₀ ＜50nM; B means 50nM≤IC ₅₀ ＜100nM.

According to the above results, the compounds disclosed herein have improved or excellent Jurkat cell p-SLP76 phosphorylation inhibitory activity.

Experimental Example 3 In vitro metabolic stability of liver microsomes

The sample for incubation of liver microsomes was prepared by mixing PBS buffer (pH 7.4), liver microsome solution (0.5 mg/mL), test compound and NADPH+ _MgCl2 solution at 37°C and 300 rpm for 1 hour. The sample for 0 hours was prepared by mixing PBS buffer (pH 7.4), liver microsome solution (0.5 mg/mL) and test compound. The sample was added with acetonitrile solution containing internal standard to prepare supernatant by protein precipitation, and diluted for LC/MS/MS determination. The test results of some compounds are shown in Table 3.

Table 3 In vitro liver microsome stability results

The experimental results show that the in vitro metabolism of the disclosed compounds is relatively stable.

Experimental Example 4 In vivo pharmacokinetics

4.1 In vivo pharmacokinetic study in mice

ICR mice, weighing 21-23 g, were adapted for 3-5 days and randomly divided into groups, 9 mice in each group. They were intragastrically administered with a solution of the compound of the present invention at a dose of 10 mg/kg. The solvent for the intragastrically administered group was: DMSO: HS15: 0.5 mg/mL citrate glucose solution = 5:20:75; the solution of the compound of the present invention was intravenously injected at a dose of 1 mg/kg. The solvent for the intravenously injected group was: DMSO: Ethanol: EL: D5W = 1.5:2:4:92.5.

The time points for intravenous blood collection were 0.083 (5 min), 0.167 (10 min), 0.5 (30 min), 1, 2, 6, 8, 10, and 24 h. The time points for intragastric blood collection were 0.25 (15 min), 0.5 (30 min), 1, 2, 4, 6, 8, 10, and 24 h. Blood was collected from the eye sockets to prepare the plasma samples to be tested.

30 μL of the plasma sample to be tested and the standard curve sample were taken, and acetonitrile solution containing the internal standard was added to obtain the supernatant after protein precipitation, which was diluted for LC/MS/MS determination.

The experimental results show that the compounds disclosed in the present invention have good in vivo pharmacokinetic properties.

Experimental Example 5 In vivo efficacy evaluation

5.1 Pharmacodynamic evaluation of the compound in the CT26 murine colon cancer subcutaneous transplant tumor model of BALB/c mice

CT26 cells were subcutaneously inoculated in the right axilla of SPF female BALB/c mice (source: Shanghai Lingchang Biotechnology Co., Ltd.), 3×10 ⁵ cells/mouse. When the average tumor volume reached about 150 mm ³ , the animals were divided into groups.

The day of grouping was day 0. Starting from day 0, the compound of the present disclosure was administered orally once a day. The tumor volume was measured twice a week, and the mice were weighed and the data were recorded. The general performance of the mice was observed and recorded daily. After the experiment, the tumor was removed, weighed, and photographed.

The detection indicators and calculation formula are as follows:

Tumor volume, TV (mm ³ ) = 1/2 × (a × b ² ); where a is the long diameter of the tumor, and b is the short diameter of the tumor.

Relative tumor volume, RTV=TV _t /TV ₀ ; wherein TV ₀ is the tumor volume on day 0, and TV _t is the tumor volume at each measurement.

Relative tumor proliferation rate, T/C (%) = _TRTV / _CRTV × 100%; _TRTV is the RTV of the treatment group; _CRTV is the RTV of the vehicle control group.

Tumor growth inhibition rate, TGI (%) = (1-TW/TW ₀ ) × 100%; wherein, TW is the tumor weight of the treatment group, and TW ₀ is the tumor weight of the vehicle control group.

Body weight change rate, WCR (%) = (Wt _t - Wt ₀ )/Wt ₀ × 100%; wherein Wt ₀ is the body weight of mice on day 0, and Wt _t is the body weight of mice at each measurement.

The compounds disclosed in the present invention have good in vivo efficacy (for example, the tumor weight inhibition rate of mice can be greater than 30% after 14 days of administration of the compounds disclosed in the present invention at a dosage of 37.5 mpk).

Claims (15)

A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
in, X ¹ is selected from N or CR ^x ; X ² is selected from N or CR ^z ; ^Rx and ^Rz are each independently selected from hydrogen, deuterium, _-NH2 , -NH( _C1-4 alkyl), -N( _C1-4 alkyl) ₂ , -OH, _-OC1-4 alkyl, -CN, halogen, _C1-4 alkyl, C3-6 cycloalkyl, or _3-6 membered heterocycloalkyl, wherein said -NH( _C1-4 alkyl), -N( _C1-4 alkyl) ₂ , _-OC1-4 alkyl, _C1-4 alkyl, _C3-6 cycloalkyl, and 3-6 membered heterocycloalkyl are optionally substituted with one or more deuterium, halogen, or Substituent substitution; Y is selected from the group consisting of bonds, -O-, -S-, -NR ^a -, -C(R ^a ) ₂ -, -C(R ^a ) ₂ N(R ^a )-, -S(O) ₂ -, - S(O)-, -C(O)-, -C(O)O-, -C(O)NR ^a -, -C(O)N(R ^a )O-, -OC(O)-, -OC(O)NR ^a -, -N(R ^a )C(O)O- or -N(R ^a )C(O)-; Ring A is selected from a 3-10 membered heterocyclyl, a C _6-10 aryl or a 5-10 membered heteroaryl; Each R ¹ is independently selected from the group consisting of -NH ₂ , -NO ₂ , -NHR ^d , -N(R ^d ) ₂ , -OH , -OR ^d , -SR ^d , -CN , halogen , -COOR ^d , -OCOR ^d , -N(R ^d )C(O)(R ^d ), -CONH(R ^d ), -CON(R ^d ) ₂ , -NHSO ₂ (R ^d ), -SO ₂ (R ^d ), -SO ₂ NH(R ^d ), -SO ₂ N(R ^d ) ₂ , -PO(R ^d ) ₂ , -P(O)(R ^d )NR ^d , -P(O)(R ^d )OR ^d , -C _1-6 alkylene-PO(R ^d ) ₂ , -C _1-6 alkylene-P(O)(R ^d )NR ^d , -C _1-6 alkylene-P(O)(R ^d )OR ^d , -NR ^d -C _1-6 alkylene-PO(R ^d ) ₂ , -NR ^d -C _1-6 alkylene-P(O)(R ^d )NR ^d , -NR ^d -C _1-6 alkylene-P(O)(R ^d )OR ^d , -OC _1-6 alkylene-PO(R ^d ) ₂ , -OC _1-6 alkylene-P(O)(R ^d )NR ^d , -OC _1-6 alkylene-P(O)(R ^d )OR ^d , C _1-6 alkyl, C _6-10 aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclic group, wherein the -C _1-6 alkylene-PO(R ^d ) ₂ , -C _1-6 alkylene-P(O)(R ^d )NR ^d , -C _1-6 alkylene _- P(O)(R ^d )OR ^d , -NR ^d -C _1-6 alkylene-PO(R ^d ) ₂ , -NR ^d -C _1-6 alkylene-P(O)(R ^d )NR ^d , -NR ^d -C _1-6 alkylene-P(O)(R ^d )OR ^d , -OC _1-6 alkylene-PO(R ^d ) ₂ , -OC _1-6 alkylene-P(O)(R ^d )NR ^d , -OC _1-6 alkylene-P(O)(R ^d )OR ^d , C _1-6 alkyl, C _6-10 aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl is optionally substituted with one or more R ^b ; Each ^Rd is independently selected from hydrogen, _C1-6 alkyl, _C3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein said _C1-6 alkyl, _C3-6 cycloalkyl and 3-6 membered heterocycloalkyl are optionally substituted with one or more deuterium, halogen or Substituent substitution; R ² is selected from 8-12 membered saturated, partially saturated or aromatic bicyclic groups, 9-14 membered saturated, partially saturated or aromatic tricyclic groups, wherein the bicyclic group or tricyclic group contains 0-6 heteroatoms independently selected from N, O or S, and the R ² is optionally substituted by one or more R ^c ; Provided that when ^R2 is a bicyclic group, ^X2 is N, and at least one ^R1 is selected from the group consisting of -PO( ^Rd ) ₂ , -P(O)( ^Rd ) ^NRd , -P(O)( ^Rd ) ^ORd , _{-C1-6alkylene} -PO( ^Rd ) ₂ , _{-C1-6alkylene} -P(O)(Rd ^{) NRd} , _{-C1-6alkylene} -P(O)( ^Rd ) ^ORd , -NRd ^- _C1-6alkylene -PO( ^Rd ) ₂ , -NRd ^- _C1-6alkylene -P(O)( ^Rd ) ^NRd , -NRd ^- _C1-6alkylene -P(O)( ^Rd ) ^ORd , _{-OC1-6alkylene} -PO( ^Rd ) ₂ , -OC1-6alkylene _{-C 1-6} alkylene-P(O)(R ^d )NR ^d , -OC _1-6 alkylene-P(O)(R ^d )OR ^d , or a 3-10 membered heterocyclic group containing a phosphorus ring heteroatom, wherein said -C _1-6 alkylene-PO(R ^d ) ₂ , -C _1-6 alkylene-P(O)(R ^d )NR ^d , -C _1-6 alkylene-P(O)(R ^d )OR ^d , -NR ^d -C _1-6 alkylene-PO(R ^d ) ₂ , -NR ^d -C _1-6 alkylene-P(O)(R ^d )NR ^d , -NR ^d -C _1-6 alkylene-P(O)(R ^d )OR ^d , -OC _1-6 alkylene-PO(R ^d ) ₂ , -OC _1-6 alkylene-P(O)(R ^d )NR ^d , -OC _1-6 alkylene-P(O)(R ^d )OR ^d , or a 3-10 membered heterocyclyl containing a phosphorus ring heteroatom is optionally substituted with one or more R ^b ; Each R ³ is independently selected from deuterium, -NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , -OH, -OC _1-4 alkyl, -CN, halogen, C _1-4 alkyl, C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein said -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , -OC _1-4 alkyl, C _1-4 alkyl, C _3-6 cycloalkyl and 3-6 membered heterocycloalkyl are optionally substituted with one or more deuterium, halogen or Substituent substitution; ^R4 is selected from hydrogen, deuterium, _C1-4 alkyl, _C3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein the _C1-4 alkyl, _C3-6 cycloalkyl and 3-6 membered heterocycloalkyl are optionally substituted with one or more deuterium, halogen or Substituent substitution; Each ^Ra is independently selected _from hydrogen, deuterium, halogen, -CN, _C1-4 alkyl, _C3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein said _C1-4 alkyl, _C3-6 cycloalkyl and 3-6 membered heterocycloalkyl are optionally substituted with one or more deuterium, halogen or -CN. Substituent substitution; Each R ^b is independently selected from deuterium, -NH ₂ , -NO ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , -OH, -OC _1-4 alkyl, -SC _1-4 alkyl, -CN _, halogen, C _1-4 alkyl, -C _1-4 alkylene-N(C _1-4 alkyl) ₂ , -CH(C _1-4 alkyl) ₂ , -C _1-4 alkylene-OC _1-4 alkyl, C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein said -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , -OC _1-4 alkyl, -SC _1-4 alkyl, C _1-4 alkyl, -C _1-4 alkylene-N(C _1-4 alkyl) ₂ , -CH(C _1-4 alkyl) ₂ , -C _1-4 alkylene-OC _1-4 alkyl, C _3-6 cycloalkyl and 3-6 membered heterocycloalkyl are optionally substituted with one or more deuterium, -OH, halogen or Substituent substitution; Each R ^c is independently selected from deuterium, -NH ₂ , -NO ₂ , -CN, -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , -OH, -SC _1-4 alkyl, -OC _1-4 alkyl, halogen, or C _1-4 alkyl, C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein said -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , -SC _1-4 alkyl, -OC _1-4 alkyl, C _1-4 alkyl, C _3-6 cycloalkyl and 3-6 membered heterocycloalkyl are optionally substituted with one or more deuterium, halogen or Substituent substitution; n is selected from 1, 2, 3 or 4; m is selected from 0, 1 or 2; Optionally, each R ^x , R ^z , R ³ , R ⁴ , Ra , R ^b , R ^c or R ^d is each independently optionally substituted with one or more other substituents ^; Optionally, the pharmaceutically acceptable salt is a hydrochloride salt. The compound according to claim 1, its stereoisomer or pharmaceutically acceptable salt thereof, wherein X ¹ is selected from CR ^x , and X ² is N; Alternatively, X ¹ is N, and X ² is selected from CR ^z ; Alternatively, ^X1 is selected from ^CRx , and ^X2 is selected from ^CRz ; Alternatively, ^X1 and ^X2 are both CH; Alternatively, ^X1 is CH, and ^X2 is N; Alternatively, ^X1 is N, and ^X2 is CH; Optionally, R ^x and R ^z are each independently selected from hydrogen, deuterium, -NH ₂ , -NH(C _1-3 alkyl), -N(C _1-3 alkyl) ₂ , -OH, -OC _1-3 alkyl, -CN, halogen, C _1-3 alkyl, C _3-5 cycloalkyl, or 3-5 membered heterocycloalkyl; Alternatively, R ^x and R ^z are each independently selected from hydrogen or C _1-3 alkyl; Alternatively, R ^x and R ^z are each independently hydrogen. The compound according to claim 1 or 2, its stereoisomer or pharmaceutically acceptable salt thereof, wherein Y is selected from a bond, -O-, -S- or -NR ^a -; or, Y is -NR ^a -; or, Y is -NH-; optionally, each ^Ra is independently selected from hydrogen or C _1-3 alkyl; or, each ^Ra is independently selected from hydrogen or methyl; or, ^Ra is hydrogen. The compound according to any one of claims 1 to 3, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein ring A is selected from C _6-10 aryl or 5-10 membered heteroaryl; or, ring A is selected from phenyl or a 5-membered or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N or S; Alternatively, ring A is selected from phenyl or 5-6 membered heteroaryl; Alternatively, Ring A is selected from a 5-8 membered heterocyclic group; Alternatively, ring A is selected from phenyl or a 5-6 membered heteroaryl group containing 1 or 2 heteroatoms selected from N, O or S; Alternatively, ring A is selected from phenyl or a 6-membered heteroaryl group containing 1 or 2 N atoms; Alternatively, ring A is selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, imidazolyl or oxazolyl; Alternatively, Ring A is selected from phenyl, pyridyl or thiazolyl; Alternatively, Ring A is selected from pyridyl or thiazolyl. The compound according to any one of claims 1 to 4, its stereoisomer or pharmaceutically acceptable salt thereof, wherein each R ¹ is independently selected from -NH ₂ , -NH(R ^d ), -N(R ^d ) ₂ , halogen, -N(R ^d )C(O)(R ^d ), -NHSO ₂ (R ^d ), -SO ₂ NH(R ^d ), PO(R ^d ) ₂ , C _1-6 alkyl, -OC _1-6 alkyl, 5-8 membered heteroaryl, or 3-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, S or P, wherein the C _1-6 alkyl, 5-8 membered heteroaryl, or 3-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, S or P is optionally substituted with one or more R ^b ; Alternatively, each R ¹ is independently selected from -NH ₂ , -NH(R ^d ), -N(R ^d ) ₂ , -OR ^d , halogen, -N(R ^d )C(O)(R ^d ), -NHSO ₂ (R ^d ), -SO ₂ NH(R ^d ), PO(R ^d ) ₂ , C _1-6 alkyl, 3-10 membered heterocycloalkyl, 5-6 membered heteroaryl or 5-10 membered heterocycloalkenyl, wherein the C _1-6 alkyl, 3-10 membered heterocycloalkyl, 5-6 membered heteroaryl or 5-10 membered heterocycloalkenyl is optionally substituted with one or more R ^b ; Alternatively, each R ¹ is independently selected from halogen, C _1-4 alkyl, -OC _1-3 alkyl or 5-6 membered heterocycloalkyl, wherein the C _1-4 alkyl or 5-6 membered heterocycloalkyl is optionally substituted with one or more R ^b ; Alternatively, each R ¹ is independently selected from halogen, -NH ₂ , -NH(R ^d ), -N(R ^d ) ₂ , -OR ^d , C _1-6 alkyl, 5-9 membered heterocyclyl, wherein the C _1-6 alkyl or 5-9 membered heterocyclyl is optionally substituted with one or more R ^b ; or, each R ¹ is independently selected from -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , F, Cl, Br, -OCH ₃ , -OCH ₂ CH ₃ , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phosphanidinyl, or a 9-membered heterocyclohexyl group containing 3 heteroatoms selected from N or O, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phosphanidinyl, or a 9-membered heterocyclohexyl group containing 3 heteroatoms selected from N or O is optionally substituted with one or more R ^b ; Alternatively, each R ¹ is independently selected from -NH ₂ , F, methyl, -OCH ₃ , tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, The methyl, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, Optionally substituted with 1, 2 or 3 R ^b ; Alternatively, each R ¹ is independently selected from F, methyl, -OCH ₃ , tetrahydrofuranyl, tetrahydropyranyl, or The methyl, tetrahydrofuranyl, tetrahydropyranyl or Optionally substituted with 1, 2 or 3 R ^b ; Alternatively, each R ¹ is independently selected from F, methyl, -OCH ₃ , -CHF ₂ , Optionally, n is selected from 1, 2 or 3; Alternatively, n is selected from 1 or 2; Alternatively, n is 2. The compound according to any one of claims 1 to 5, its stereoisomer or pharmaceutically acceptable salt thereof, wherein each R ^d is independently selected from C _1-6 alkyl, C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C _1-6 alkyl, C _3-6 cycloalkyl and 3-6 membered heterocycloalkyl are optionally substituted by one or more deuterium, halogen or Substituent substitution; Alternatively, each ^Rd is independently selected from _C1-4 alkyl or _C3-6 cycloalkyl, wherein the _C1-4 alkyl or _C3-6 cycloalkyl is optionally substituted by one or more deuterium, halogen or Substituent substitution; Alternatively, each R ^d is independently selected from C _1-4 alkyl or C _3-6 cycloalkyl; Alternatively, each R ^d is independently selected from methyl, ethyl, n-propyl or isopropyl. The compound according to any one of claims 1 to 6, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R ² is selected from a 9-14 membered saturated, partially saturated or aromatic tricyclic group, wherein the tricyclic group contains 1-6 heteroatoms independently selected from N, O or S, and the R ² is optionally substituted by one or more R ^c ; Alternatively, R ² is selected from a 9-, 10-, 11-, or 12-membered partially saturated or aromatic bicyclic group; Alternatively, R ² is selected from a 8-12 membered partially saturated or aromatic bicyclic group, X ² is N, and at least one R ¹ is selected from -PO(R ^d ) ₂ , -P(O)(R ^d )NR ^d , -P(O)(R ^d )OR ^d , or a 5-8 membered heterocyclic group containing a phosphorus ring heteroatom, wherein the bicyclic group contains 1-6 heteroatoms independently selected from N, O or S, and the R ² is optionally substituted by one or more R ^c , and the 5-8 membered heterocyclic group containing a phosphorus ring heteroatom is optionally substituted by one or more R ^b ; Alternatively, R ² is selected from a 9-, 10-, 11-, 12-, 13-, 14-membered partially saturated or aromatic tricyclic group, wherein the tricyclic group contains 1-4 heteroatoms independently selected from N, O or S, and the R ² is optionally substituted by one or more R ^c ; Alternatively, R 2 is selected from a 9-, 10-, 11-, 12-membered partially saturated or aromatic tricyclic group, wherein the tricyclic group contains 1-4 heteroatoms independently selected from N, O or S, and the R ² is optionally substituted by one or more R c; a saturated or aromatic bicyclic group, the bicyclic group containing 1-3 heteroatoms independently selected from N, O or S, and X ² is N, and at least one R ¹ is selected from -PO(CH ₃ ) ₂ , -P(O)(CH ₃ )NCH ₃ , -P(O)(CH ₃ )OCH ₃ , or a 5-8 membered heterocycloalkyl group containing a phosphorus ring heteroatom, wherein the R ² is optionally substituted by one or more R ^c , and the 5-8 membered heterocycloalkyl group containing a phosphorus ring heteroatom is optionally substituted by one or more R ^b ; Alternatively, R ² is selected from a 10-membered or 12-membered partially saturated or aromatic tricyclic group, wherein the tricyclic group contains 1-3 heteroatoms independently selected from N, O or S, and the R ² is optionally substituted by one or more R ^c ; Alternatively, R ² is selected from a 12-membered aromatic tricyclic group, wherein the tricyclic group contains 2, 3 or 4 heteroatoms independently selected from N or O, and the R ² is optionally substituted by one or more R ^c ; Alternatively, R ² is selected from a 9-10 membered aromatic bicyclic group containing 1-3 heteroatoms independently selected from N, O or S, X ² is N, and at least one R ¹ is selected from a 5-8 membered heterocycloalkyl group containing a phosphorus ring heteroatom, wherein said R ² is optionally substituted by one or more R ^c , and said 5-8 membered heterocycloalkyl group containing a phosphorus ring heteroatom is optionally substituted by one or more halogen, or C _1-3 alkyl substituted; Alternatively, R ² is selected from a 9-12 membered partially saturated or aromatic bicyclic group, X ² is N, and at least one R ¹ is selected from a 5-6 membered heterocycloalkyl group containing a phosphorus ring heteroatom, wherein the 5-6 membered heterocycloalkyl group containing a phosphorus ring heteroatom is optionally substituted with one or more halogens, or C _1-3 alkyl substituted; Alternatively, ^R2 is ^X2 is N, n is 2, and one ^R1 is a 6-membered heterocycloalkyl group containing nitrogen and phosphorus heteroatoms, and the other ^R1 is _-CH2N ( _CH3 ) ₂ , wherein the 6-membered heterocycloalkyl group containing nitrogen and phosphorus heteroatoms is optionally replaced by one or more or methyl, said R ² is optionally substituted with one or more F; Alternatively, ^R2 is selected from Alternatively, ^R2 is selected from Optionally, Each R ^c is independently selected from halogen, or C _1-6 alkyl optionally substituted by one or more deuterium; Alternatively, each R ^c is independently selected from halogen, or C _1-4 alkyl optionally substituted by one or more deuterium; Alternatively, each R ^c is independently selected from F, Cl, Br, or the following substituents optionally substituted with one or more deuterium: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl; Alternatively, each R ^c is independently selected from or methyl optionally substituted by one or more deuterium; Alternatively, each R ^c is independently selected from F, Methyl or -CD ₃ . The compound according to any one of claims 1 to 7, its stereoisomer or pharmaceutically acceptable salt thereof, wherein each R ³ is independently selected from halogen or C _1-4 alkyl, wherein the C _1-4 alkyl is optionally substituted with one or more deuterium or halogen substituents; Alternatively, each R ³ is independently selected from halogen, C _1-3 alkyl or halogenated C _1-3 alkyl; Alternatively, each R ³ is independently selected from F, Cl, Br or C _1-3 alkyl; Alternatively, each R ³ is independently selected from F or methyl; Optionally, m is selected from 0, 1 or 2; Alternatively, m is selected from 0 or 1; Or, m is 0; and/or, R ⁴ is selected from hydrogen or C _1-3 alkyl; Alternatively, R ⁴ is selected from hydrogen or methyl; Alternatively ^R4 is hydrogen. The compound according to any one of claims 1 to 8, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein each R ^b is independently selected from deuterium, -OH, halogen, C _1-4 alkyl, -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , -OC _1-4 alkyl, -C _1-4 alkylene-N(C 1-4 alkyl) ₂ , _-CH (C _1-4 alkyl) ₂ , -C _1-4 alkylene-OC _1-4 alkyl or 3-6 membered heterocycloalkyl, wherein the C _1-4 alkyl, -NH(C _1-4 alkyl), -N(C _{1-4 alkyl} ) ₂ , -OC _1-4 alkyl, -C _1-4 alkylene-N(C _1-4 alkyl) ₂ , -CH(C _1-4 alkyl) ₂ , -C _1-4 alkylene-OC _1-4 alkyl and 3-6 membered heterocycloalkyl are optionally substituted with one or more deuterium, -OH, halogen or Substituent substitution; Alternatively, each R ^b is independently selected from deuterium, halogen, C _1-4 alkyl, -NH(C _1-4 alkyl) or -N(C _1-4 alkyl) ₂ , wherein said C _1-4 alkyl, -NH(C _1-4 alkyl) or -N(C _1-4 alkyl) ₂ is optionally substituted with one or more deuterium; Alternatively, each R ^b is independently selected from deuterium, -OH, F, C _1-3 alkyl, -NH(C _1-3 alkyl), -N(C _1-3 alkyl) ₂ , -C _1-3 alkylene-N(C _1-3 alkyl) ₂ , -CH(C _1-3 alkyl) ₂ , or -C _1-3 alkylene-OC _1-3 alkyl, wherein the C _1-3 alkyl, -NH(C _1-3 alkyl), -N(C _1-3 alkyl) ₂ , -C _1-3 alkylene-N(C _1-3 alkyl) ₂ , -CH(C _1-3 alkyl) ₂ , or -C _1-3 alkylene-OC _1-3 alkyl is optionally substituted with one or more deuterium or -OH _; Alternatively, each R ^b is independently selected from deuterium, -OH, F, -CH ₃ , -NH(CH ₃ ), -N(CH ₃ ) ₂ , -N(CD ₃ ) ₂ , -CH ₂ N(CH ₃ ) ₂ , -C(OH)(CH ₃ ) ₂ or -CH ₂ OCH ₃ . The compound according to any one of claims 1 to 9, its stereoisomer or a pharmaceutically acceptable salt thereof, which is selected from the following compounds of formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie) or formula (If), its stereoisomer or a pharmaceutically acceptable salt thereof:
wherein X ¹ , X ² , ring A, Y, R ¹ , R ² and n are as described in any one of claims 1-9. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, which is selected from the compound of formula (II), its stereoisomer or a pharmaceutically acceptable salt thereof:
in, ^X2 is selected from N or CH; Each R ¹ is independently selected from halogen, C _1-4 alkyl, -OC _1-3 alkyl or 5-6 membered heterocycloalkyl, wherein the C _1-4 alkyl or 5-6 membered heterocycloalkyl is optionally substituted by one or more R ^b , and the 5-6 membered heterocycloalkyl contains 1 or 2 heteroatoms selected from N or O, or contains 1 P=O heteroatom group; ^R2 is selected from a 12-membered aromatic tricyclic group, wherein the tricyclic group contains 2, 3 or 4 heteroatoms independently selected from N or O; Each R ^b is independently selected from deuterium, halogen, C _1-4 alkyl, -NH(C _1-4 alkyl) or -N(C _1-4 alkyl) ₂ , wherein said C _1-4 alkyl, -NH(C _1-4 alkyl) or -N(C _1-4 alkyl) ₂ is optionally substituted with one or more deuterium; n is selected from 1, 2 or 3; Provided that the compound of formula (II), its stereoisomer or a pharmaceutically acceptable salt thereof is not the following compound, its stereoisomer or a pharmaceutically acceptable salt thereof:

The compound according to claim 11, its stereoisomer or pharmaceutically acceptable salt thereof, wherein each R ¹ is independently selected from C _1-4 alkyl, or 6-membered heterocycloalkyl, wherein the C _1-4 alkyl or 6-membered heterocycloalkyl is optionally substituted by one or more R ^b , and the 6-membered heterocycloalkyl contains 1 or 2 heteroatoms selected from N or O, or contains 1 P＝O heteroatom group; Optionally, each R ^b is independently selected from deuterium, F, C _1-3 alkyl, -NH(C _1-3 alkyl) or -N(C _1-3 alkyl) ₂ , wherein said -NH(C _1-3 alkyl) or -N(C _1-3 alkyl) ₂ is optionally substituted with one or more deuterium; Alternatively, each R ^b is independently selected from deuterium, F, methyl, -NH(CH ₃ ) or -N(CH ₃ ) ₂ , wherein -N(CH ₃ ) ₂ is optionally substituted with one or more deuterium. The compound according to any one of claims 1 to 12, its stereoisomer or a pharmaceutically acceptable salt thereof, which is selected from the following compounds, their stereoisomers or pharmaceutically acceptable salts thereof:


A pharmaceutical composition comprising the compound according to any one of claims 1 to 13, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. Use of the compound according to any one of claims 1 to 13, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 14 in the preparation of a medicament for treating a disease; optionally, the disease is cancer; optionally, the cancer is leukemia or colon cancer.