Substituted pyrrolinone compounds

Abstract

The invention relates to a substituted pyrrolinone compound, in particular to a compound as shown in a formula (I), a stereoisomer or pharmaceutically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition containing the compound and application thereof in treating diseases.

Description

Substituted pyrrolidone compounds

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority and benefits 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

[0003] The present disclosure relates to substituted pyrrolidinone compounds, methods for preparing the same, pharmaceutical compositions containing the same, and uses thereof in treating diseases. Background Art

[0004] Hematopoietic progenitor kinase 1 (HPK1), also known as mitogen-activated protein kinase 1 (MAP4K1), is a mammalian Ste20-related serine / threonine protein kinase. It is a microtubule-associated protein and a member of the mitogen-activated protein kinase (MAP4K) family, which also includes five isoforms: GCK / MAP4K2, GLK / MAP4K3, HGK / MAP4K4, KHS1 / MAP4K5, and MINK1 / MAP4K6. Unlike the other five MAP4K isoforms that are widely expressed in tissue cells, HPK1 is exclusively expressed in hematopoietic tissue cells. It can regulate signal transduction in the hematopoietic system, including lymphocytes, by mediating multiple cell signaling pathways (including MAPK signaling, antigen receptor signaling, and cytokine signaling).

[0005] Studies have found that HPK1 primarily inhibits immune cell responses through the c-Jun N-terminal kinase (JNK) and extracellular signal-regulated protein kinases (ERK) signaling pathways. In T cells, upon T cell receptor (TCR) activation, HPK1 interacts with numerous TCRs and is phosphorylated by the tyrosine kinases Lck and Zap70. Activated HPK1 further phosphorylates the T cell receptor adaptor protein SLP-76, establishing a docking site for the negative regulator 14-3-3. This ultimately destabilizes the TCR signaling complex (lato-gads-SLP76) and hinders downstream mitogen-activated protein (MAP kinase) signaling, negatively regulating TCR signaling and subsequently inhibiting T cell proliferation. A similar negative feedback mechanism also exists in B cells. B cell receptor (BCR) signaling, through HPK1-mediated phosphorylation and activation of B-cell linker protein (BLNK), hinders downstream signaling and inhibits B cell proliferation. Furthermore, HPK1 also has a negative feedback regulatory effect on NK cells (natural killer cells) and dendritic cells (DCs).

[0006] Currently, there are no drugs targeting HPK1 on the market, and there is still a need to develop compounds with selective inhibitory activity, better pharmacodynamics, or better pharmacokinetics in this field.

[0007] Summary of the Invention

[0008] The present disclosure relates to compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof,

[0009] in,

[0010] X 1 Select N or CR x ;

[0011] X 2 Select N or CR z ;

[0012] R x and R z are each independently selected from hydrogen, deuterium, -NH2, -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, -OH, -OC 1-4 Alkyl, -CN, halogen, C1-4 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein the -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;

[0013] Y is selected from a bond, -O-, -S-, -NR a -、-C(R a )2-、-C(R a )2N(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)-;

[0014] Ring A is selected from 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0015] Every R 1 Each independently selected from -NH2, -NO2, -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、-NHSO2(R d )、-SO2(R d )、-SO2NH(R d )、-SO2N(R d )2、-PO(R d )2、-P(O)(R d )NR d 、-P(O)(R d )OR d 、-C 1-6 Alkylene-PO(Rd )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 、-OC1-6 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 is optionally substituted by one or more R b replace;

[0016] Every R d are each independently selected from hydrogen, 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 with one or more deuterium, halogen or Substituent substitution;

[0017] 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 or tricyclic groups contain 0-6 heteroatoms independently selected from N, O or S, and the R 2 Optionally, one or more R c replace;

[0018] The condition is that when R 2 When X is a bicyclic group, 2 is N, and has at least 1 R 1 Selected from -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 、-OC1-6 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, 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 replaced by one or more R b replace;

[0019] Every R 3 Each independently selected from deuterium, -NH2, -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 the -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, -OC 1-4 Alkyl, C 1-4 Alkyl, C 3-6Cycloalkyl and 3-6 membered heterocycloalkyl are optionally substituted with one or more deuterium, halogen or Substituent substitution;

[0020] R 4 Selected from hydrogen, deuterium, C 1-4 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein the 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;

[0021] Every R a are each independently selected from hydrogen, deuterium, halogen, -CN, C 1-4 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein the 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;

[0022] Every R b Each independently selected from deuterium, -NH2, -NO2, -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 the -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;

[0023] Every R c Each independently selected from deuterium, -NH2, -NO2, -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 the -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;

[0024] n is selected from 1, 2, 3 or 4;

[0025] m is selected from 0, 1 or 2;

[0026] Optionally, each R x 、R z 、R 3 、R 4 、R a 、R b 、R c or R d Each is independently optionally substituted with one or more additional substituents.

[0027] In some embodiments of the present disclosure, each R x 、R z 、R 3 、R 4 、R a 、R b 、R c or R d Each is independently optionally substituted with 1, 2 or 3 additional substituents.

[0028] In some embodiments of the present disclosure, each of the R x 、R z 、R 3 、R 4 、R a 、R b 、R c or R dEach is independently substituted with one or more other substituents selected from the group consisting of deuterium, -OH, -SH, halogen, -NH2, nitro, nitroso, -CN, an azide group, a sulfoxide 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 , halo-heteroalkyl, alkoxy, alkylthio, aryl, aryloxy, arylthio, aralkyl, arylalkoxy, arylalkylthio, heteroaryl, heteroaryloxy, heteroarylthio, heteroaralkyl, heteroarylalkoxy, heteroarylalkylthio, heterocyclyl, heterocyclyloxy, heterocyclylthio, heterocyclylalkyl, heterocyclylalkoxy, heterocyclylalkylthio, acyl, acyloxy, carbamate group, amide group, urea group, epoxy group and ester group, etc.

[0029] 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.

[0030] In some embodiments of the present disclosure, the pharmaceutically acceptable salt described herein is a hydrochloride (eg, monohydrochloride).

[0031] 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).

[0032] 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).

[0033] 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.

[0034] In some embodiments of the present disclosure, X 1 Selected from CR x , and X 2 is N.

[0035] In some embodiments of the present disclosure, X 1 is N, and X 2 Selected from CR z .

[0036] In some embodiments of the present disclosure, X 1 Selected from CR x , and X 2 Selected from CR z .

[0037] In some embodiments of the present disclosure, X 1 and X 2 All are CH.

[0038] In some embodiments of the present disclosure, X 1 CH, X 2 is N.

[0039] In some embodiments of the present disclosure, X 1 is N, and X 2 For CH.

[0040] In some embodiments of the present disclosure, R 4 Selected from hydrogen or C 1-3 alkyl.

[0041] In some embodiments of the present disclosure, R 4 is selected from hydrogen or methyl.

[0042] In some embodiments of the present disclosure, R 4 For hydrogen.

[0043] In some embodiments of the present disclosure, R x and R z are each independently selected from hydrogen, deuterium, -NH2, -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.

[0044] In some embodiments of the present disclosure, R x and R z are each independently selected from hydrogen or C 1-3 alkyl.

[0045] In some embodiments of the present disclosure, R x Selected from hydrogen or C 1-3 alkyl.

[0046] In some embodiments of the present disclosure, R z Selected from hydrogen or C 1-3 alkyl.

[0047] In some embodiments of the present disclosure, R x and R z are each independently hydrogen.

[0048] In some embodiments of the present disclosure, each R a are each independently selected from hydrogen or C 1-3 alkyl.

[0049] In some embodiments of the present disclosure, each R a are each independently selected from hydrogen or methyl.

[0050] In some embodiments of the present disclosure, R a For hydrogen.

[0051] In some embodiments of the present disclosure, Y is selected from a bond, -O-, -S-, or -NR a -.

[0052] In some embodiments of the present disclosure, Y is -NR a In some embodiments of the present disclosure, Y is -NH-.

[0053] In some embodiments of the present disclosure, Ring A is selected from C 6-10 aryl or 5-10 membered heteroaryl.

[0054] In some embodiments of the present disclosure, Ring A is selected from C 6-8 aryl or 5-8 membered heteroaryl.

[0055] In some embodiments of the present disclosure, Ring A is selected from phenyl or 5-6 membered heteroaryl.

[0056] In some embodiments of the present disclosure, Ring A is selected from a 5-8 membered heterocyclyl.

[0057] In some embodiments of the present disclosure, Ring A is selected from a 5-6 membered heterocyclyl.

[0058] In some embodiments of the present disclosure, ring A is selected from phenyl or a 5-6 membered heteroaryl group containing 1 or 2 heteroatoms selected from N, O or S.

[0059] In some embodiments of the present disclosure, ring A is selected from phenyl or a 5-membered or 6-membered heteroaryl group containing 1 or 2 heteroatoms selected from N or S.

[0060] In some embodiments of the present disclosure, Ring A is selected from phenyl or a 6-membered heteroaryl group containing 1 or 2 N heteroatoms.

[0061] In some embodiments of the present disclosure, Ring A is selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, imidazolyl, or oxazolyl.

[0062] In some embodiments of the present disclosure, Ring A is selected from phenyl, pyridyl, or thiazolyl.

[0063] In some embodiments of the present disclosure, Ring A is selected from pyridyl or thiazolyl.

[0064] In some embodiments of the present disclosure, each R 1 Each independently selected from -NH2, -NH(R d )、-N(R d )2、Halogen、-N(R d )C(O)(R d )、-NHSO2(R d )、-SO2NH(R d )、PO(R d )2. C 1-6 Alkyl, -OC 1-6 alkyl, 5-8 membered heteroaryl or 3-10 membered heterocyclic group 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 heterocyclic group containing 1-3 heteroatoms selected from N, O, S or P, optionally substituted by one or more R b replace.

[0065] In some embodiments of the present disclosure, each R 1 Each independently selected from -NH2, -NH(R d )、-N(R d )2、-OR d , halogen, - N(R d )C(O)(R d )、-NHSO2(R d )、-SO2NH(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 1-6Alkyl, 3-10 membered heterocycloalkyl, 5-6 membered heteroaryl or 5-10 membered heterocycloalkenyl is optionally substituted by one or more R b replace.

[0066] In some embodiments of the present disclosure, each R 1 Each independently selected from -NH2, -NO2, -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、-NHSO2(R d )、-SO2(R d )、-SO2NH(R d )、-SO2N(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 Alkyl, C 6-10 aryl, 5-10 membered heteroaryl or 5-9 membered heterocyclic group, 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 、C 1-4 Alkyl, C 6-10 Aryl, 5-10 membered heteroaryl or 5-9 membered heterocyclic group is optionally substituted by one or more R b replace.

[0067] In some embodiments of the present disclosure, when R 1 is selected from the group containing "alkylene" and is b When substituted, the R b Substitute the hydrogen atoms on the "alkylene" group.

[0068] In some embodiments of the present disclosure, each R 1 Each independently selected from -NH2, -NH(R d )、-N(R d )2、Halogen、-N(R d )C(O)(R d )、-NHSO2(R d )、-SO2NH(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 are optionally substituted with one or more R b replace.

[0069] In some embodiments of the present disclosure, the R 1 The heteroatom in the heterocyclyl, heterocycloalkyl or heterocycloalkenyl group is selected from N, O, S or P; or, is selected from N, O or S; or, is selected from N or P.

[0070] In some embodiments of the present disclosure, each R 1 Each is independently selected from -NH2, -NHCH3, -N(CH3)2, F, Cl, Br, -OCH3, -OCH2CH3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, tetrahydropyrrolyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophenyl, morpholinyl, piperidinyl, piperazinyl, tetrahydroimidazolyl, azacycloheptanyl, azacyclobispiranonanyl, azacyclobispiranonanyl, -N(CH3)C(O)CH3, -NHSO2(CH3), -SO2NH(CH3), -PO(CH3)2, Oxazolidinyl, phosphine oxygen bis heterocyclohexyl, nitrogen oxygen bis heterocyclohexyl, phosphazenium nitrogen bis heterocyclohexyl, dihydropyridinyl, furanyl or thiazinyl, the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, tetrahydropyrrolyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophenyl, morpholinyl, piperidinyl, piperazinyl, tetrahydroimidazolyl, nitrogen oxygen bicycloheptyl, nitrogen oxygen bihetero-nonane, nitrogen oxygen bihetero-spironanyl, oxazolidinyl, phosphine oxygen bis heterocyclohexyl, nitrogen oxygen bihetero- ... b replace.

[0071] In some embodiments of the present disclosure, each R 1 are each independently selected from halogen, -NH2, -NH(R d )、-N(R d )2、-OR d 、C 1-6 Alkyl, 5-9 membered heterocyclic group, wherein the C 1-6 The alkyl or 5-9 membered heterocyclic group is optionally substituted by one or more R b replace.

[0072] In some embodiments of the present disclosure, each R 1are each independently selected from halogen, -NH2, -NH(R d )、-N(R d )2、C 1-6 Alkyl, -OC 1-6 Alkyl or 5-9 membered heterocyclic group, wherein the C 1-6 The alkyl or 5-9 membered heterocyclic group is optionally substituted by one or more R b replace.

[0073] In some embodiments of the present disclosure, each R 1 are each independently selected from halogen, -NH2, -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 are optionally substituted with one or more R b replace.

[0074] In some embodiments of the present disclosure, each R 1 are each independently selected from halogen, -NH2, -NH(R d )、-N(R d )2、C 1-4 Alkyl, -OC 1-3 alkyl or 5-membered, 6-membered or 9-membered heterocycloalkyl, wherein the C 1-4 Alkyl, or 5-membered, 6-membered or 9-membered heterocycloalkyl is optionally substituted with one or more R b replace.

[0075] In some embodiments of the present disclosure, each R 1 are each 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 replace.

[0076] In some embodiments of the present disclosure, each R 1Each is independently selected from -NH2, -NHCH3, -N(CH3)2, F, Cl, Br, -OCH3, -OCH2CH3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phosphazenetriheterocyclohexyl 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, phosphazenetriheterocyclohexyl or a 9-membered heterocycloalkyl containing 3 heteroatoms selected from N or O is optionally replaced by one or more R b replace.

[0077] In some embodiments of the present disclosure, each R 1 Each independently selected from -NH2, F, methyl, -OCH3, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, The methyl, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, Optional 1, 2 or 3 R b replace.

[0078] In some embodiments of the present disclosure, each R 1 Each independently selected from F, methyl, -OCH3, tetrahydrofuranyl, tetrahydropyranyl, or The methyl, tetrahydrofuranyl, tetrahydropyranyl or Optional 1, 2 or 3 R b replace.

[0079] In some embodiments of the present disclosure, each R 1 Each independently selected from F, methyl, -OCH3, The methyl group, -OCH3, Optional 1, 2 or 3 R b replace.

[0080] In some embodiments of the present disclosure, each R 1 Each independently selected from F, methyl, -OCH3, The methyl group, Optional 1, 2 or 3 R b replace.

[0081] In some embodiments of the present disclosure, each R1 Each independently selected from F, methyl, -OCH3, -CHF2,

[0082] In some embodiments of the present disclosure, each R 1 Each independently selected from F, -OCH3, -CHF2,

[0083] In some embodiments of the present disclosure, each R 1 Each independently selected from F, methyl, -OCH3, -CHF2,

[0084] In some embodiments of the present disclosure, each R d Each 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 with one or more deuterium, halogen or Substituent substitution.

[0085] In some embodiments of the present disclosure, each R d Each independently selected from C 1-4 Alkyl or C 3-6 Cycloalkyl, the C 1-4 Alkyl or C 3- 6 cycloalkyl is optionally substituted with one or more deuterium, halogen or Substituent substitution.

[0086] In some embodiments of the present disclosure, each R d Each independently selected from C 1-4 Alkyl or C 3-6 Cycloalkyl.

[0087] In some embodiments of the present disclosure, each R d Each independently selected from C 1-3 In some embodiments of the present disclosure, each R d Each independently selected from C 3-5 Cycloalkyl.

[0088] In some embodiments of the present disclosure, each R d Each is independently selected from methyl, ethyl, n-propyl or isopropyl.

[0089] In some embodiments of the present disclosure, Rd are each independently methyl.

[0090] In some embodiments of the present disclosure, each R b Each 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.

[0091] In some embodiments of the present disclosure, each R b Each 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.

[0092] In some embodiments of the present disclosure, each R b are each 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.

[0093] In some embodiments of the present disclosure, each R b Each 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 The alkyl or 5-membered heterocycloalkyl group is optionally substituted with one or more deuterium, -OH, halogen or Substituent substitution.

[0094] In some embodiments of the present disclosure, each R b Each 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, the C 1-3 Alkyl, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2, -C 1-3Alkylene-N(C 1-3 Alkyl)2, -CH(C 1-3 Alkyl)2 or -C 1-3 Alkylene-OC 1-3 The alkyl group is optionally substituted with one or more deuterium or -OH.

[0095] In some embodiments of the present disclosure, each R b Each independently selected from deuterium, -OH, F, -CH3, -NH(CH3), -N(CH3)2, -N(CD3)2, -CH2N(CH3)2, -C(OH)(CH3)2 or -CH2OCH3.

[0096] In some embodiments of the present disclosure, n is selected from 1, 2 or 3.

[0097] In some embodiments of the present disclosure, n is selected from 1 or 2.

[0098] In some embodiments of the present disclosure, n is 2.

[0099] In some embodiments of the present disclosure, m is selected from 0, 1 or 2.

[0100] In some embodiments of the present disclosure, m is selected from 0 or 1.

[0101] In some embodiments of the present disclosure, m is 0.

[0102] In some embodiments of the present disclosure, Selected from

[0103] In some embodiments of the present disclosure, Selected from

[0104] In some embodiments of the present disclosure, Selected from

[0105] In some embodiments of the present disclosure, each R 3 are each independently selected from halogen or C 1-4 Alkyl, wherein the C 1-4 The alkyl group is optionally substituted with one or more deuterium or halogen substituents.

[0106] In some embodiments of the present disclosure, each R 3 are each independently selected from halogen, C 1-3 Alkyl or halogenated C 1-3 alkyl.

[0107] In some embodiments of the present disclosure, each R 3 Each independently selected from F, Cl, Br or C 1-3 alkyl.

[0108] In some embodiments of the present disclosure, each R 3 Each is independently selected from F or methyl.

[0109] In some embodiments of the present disclosure, one or both rings in the bicyclic group are aromatic.

[0110] In some embodiments of the present disclosure, one, two, or three rings in the tricyclic group are aromatic.

[0111] In some embodiments of the present disclosure, two or three rings in the tricyclic group are aromatic rings.

[0112] In some embodiments of the present disclosure, the bicyclic or tricyclic group is Some of the connected monocyclic rings are aromatic rings.

[0113] In some embodiments of the present disclosure, the bicyclic or tricyclic group is Part of the connected monocyclic rings is an aromatic ring containing a nitrogen atom, or a 5- to 6-membered heteroaromatic ring containing 1 or 2 nitrogen atoms.

[0114] In some embodiments of the present disclosure, any two adjacent rings in the tricyclic group are optionally fused, bridged, or spiro rings.

[0115] In some embodiments of the present disclosure, the bicyclic or tricyclic group is A partially connected monocyclic ring and its adjacent ring are a fused ring.

[0116] 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 Optionally, one or more R c replace.

[0117] 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 2, 3 or 4 heteroatoms independently selected from N or O, and the R 2 Optionally, one or more R c replace.

[0118] In some embodiments of the present disclosure, R 2 A tricyclic group selected from 12-membered aromatic groups, wherein the tricyclic group contains 2, 3 or 4 heteroatoms independently selected from N or O, and the R 2 Optionally, one or more R c replace.

[0119] In some embodiments of the present disclosure, R 2 A tricyclic group selected from 12-membered aromatic groups, wherein the tricyclic group contains 3 or 4 heteroatoms independently selected from N or O.

[0120] In some embodiments of the present disclosure, R 2 Selected from 9-, 10-, 11-, or 12-membered partially saturated or aromatic bicyclic groups.

[0121] 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.

[0122] In some embodiments of the present disclosure, R 2 is selected from 9-10 membered aromatic bicyclic groups containing 1-3 N heteroatoms.

[0123] In some embodiments of the present disclosure, when R 2 When X is a bicyclic group, 2 is N, and has at least 1 R 1 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 、-OC1-4 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 , 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 , a 3-10 membered heterocyclic group containing a phosphorus ring heteroatom is optionally replaced by one or more R b replace.

[0124] In some embodiments of the present disclosure, when R 2 When X is a bicyclic group, 2 is N, and has at least 1 R 1 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 replaced by one or more R b replace.

[0125] In some embodiments of the present disclosure, R 2 is selected from 8-12 membered partially saturated or aromatic bicyclic groups, X 2 is N, and has at least 1 R 1 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 Optionally, one or more R c Substituted, the 5-8 membered heterocyclic group containing a phosphorus ring heteroatom is optionally replaced by one or more R b replace.

[0126] In some embodiments of the present disclosure, when R 2 When X is a bicyclic group, 2 is N, and has at least 1 R 1 is selected from 5-8 membered heterocycloalkyl groups containing a phosphorus ring heteroatom, wherein said R 2 Optionally, one or more R c The 5-8 membered heterocycloalkyl containing a phosphorus ring heteroatom is optionally substituted by one or more halogens, or C 1-3 Alkyl substitution.

[0127] In some embodiments of the present disclosure, when R 2 When X is a bicyclic group, 2 is N, and one of them is R 1 is selected from nitrogen phosphorus bis heterocyclohexyl, the nitrogen phosphorus bis heterocyclohexyl is optionally substituted by one or more halogen, or C 1-3 Alkyl substitution.

[0128] In some embodiments of the present disclosure, when R 2 When X is a bicyclic group, 2 is N, and one of them is R 1 Selected from described optionally substituted by one or more halogens, or C 1-3 In some embodiments of the present disclosure, when R 2 When X is a bicyclic group, 2 is N, and has at least 1 R 1 for

[0129] In some embodiments of the present disclosure, R2 is selected from 9-, 10-, 11-, 12-, 13-, 14-membered partially saturated or aromatic tricyclic groups, wherein the tricyclic group contains 1-4 heteroatoms independently selected from N, O or S, and the R 2 Optionally, one or more R c replace.

[0130] In some embodiments of the present disclosure, R 2 The heteroatom in the bicyclic or tricyclic group is selected from N, O or S.

[0131] In some embodiments of the present disclosure, R 2 The heteroatom in the bicyclic or tricyclic group is selected from N or S.

[0132] In some embodiments of the present disclosure, R 2 The heteroatom in the bicyclic or tricyclic group is selected from N or O.

[0133] In some embodiments of the present disclosure, R 2 The heteroatom in the bicyclic or tricyclic group is N.

[0134] In some embodiments of the present disclosure, R 2 A 9-, 10-, 11-, 12-, or 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 Optionally, one or more R c replace.

[0135] In some embodiments of the present disclosure, R 2 is selected from a 9-, 10-, 11-, or 12-membered partially saturated or aromatic bicyclic group containing 1-3 heteroatoms independently selected from N, O, or S, and X 2 is N, and has at least 1 R 1 is selected from -PO(CH3)2, -P(O)(CH3)NCH3, -P(O)(CH3)OCH3, or a 5-8 membered heterocycloalkyl containing a phosphorus ring heteroatom, wherein R 2 Optionally, one or more R c Substituted, the 5-8 membered heterocycloalkyl containing a phosphorus ring heteroatom is optionally substituted by one or more R b replace.

[0136] 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 Optionally, one or more R c replace.

[0137] 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 Optionally, one or more R c replace.

[0138] 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 has at least 1 R 1 is selected from 5-8 membered heterocycloalkyl groups containing a phosphorus ring heteroatom, wherein said R 2 Optionally, one or more R c The 5-8 membered heterocycloalkyl containing a phosphorus ring heteroatom is optionally substituted by one or more halogens, or C 1-3 Alkyl substitution.

[0139] 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 Optionally, one or more R c replace.

[0140] 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 has at least 1 R 1 is selected from 5-6 membered heterocycloalkyl containing a phosphorus ring heteroatom, wherein the 5-6 membered heterocycloalkyl containing a phosphorus ring heteroatom is optionally substituted by one or more halogens, or C 1-3 Alkyl substitution.

[0141] In some embodiments of the present disclosure, R 2 is selected from a 9-10 membered aromatic bicyclic group, X 2 is N, and has at least 1 R 1 is a 5-6 membered heterocycloalkyl group containing nitrogen and phosphorus heteroatoms, wherein R 2 Optionally substituted with one or more halogens, the 5-6 membered heterocycloalkyl containing nitrogen and phosphorus heteroatoms is optionally substituted with one or more or C 1-3 Alkyl substitution.

[0142] 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, X 2 is N, n is 2, and one of them is R 1 Selected from 6-membered heterocycloalkyl containing nitrogen and phosphorus ring heteroatoms, the 6-membered heterocycloalkyl containing nitrogen and phosphorus ring heteroatoms is optionally replaced by one or more or C 1-3 Alkyl substituted, the R 2 Optionally, one or more R c replace.

[0143] 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 of them is R 1 is a 6-membered heterocycloalkyl group containing nitrogen and phosphorus heteroatoms, and another R 1 -CH2N(CH3)2, wherein the 6-membered heterocycloalkyl containing nitrogen and phosphorus heteroatoms is optionally replaced by one or more or C 1-3 Alkyl substituted, the R 2 Optionally substituted with one or more halogens.

[0144] In some embodiments of the present disclosure, R 2 for X 2 is N, n is 2, and one of them is R 1 is a 6-membered heterocycloalkyl group containing nitrogen and phosphorus heteroatoms, and another R 1 -CH2N(CH3)2, wherein the 6-membered heterocycloalkyl containing nitrogen and phosphorus heteroatoms is optionally replaced by one or more or methyl substituted, the R 2 Optionally substituted with one or more F.

[0145] In some embodiments of the present disclosure, R 2 for X 2 is N, n is 2, and one of them is R 1 for Another R 1 is -CH2N(CH3)2, Optionally one or more or methyl substituted.

[0146] In some embodiments of the present disclosure, R 2 Selected from wherein R 2 Optionally, one or more Rc replace.

[0147] In some embodiments of the present disclosure, R 2 Selected from wherein R 2 Optionally, one or more R c replace.

[0148] In some embodiments of the present disclosure, R 2 Selected from wherein R 2 Optionally, one or more R c replace.

[0149] In some embodiments of the present disclosure, R 2 Selected from wherein R 2 Optionally, one or more R c replace.

[0150] In some embodiments of the present disclosure, R 2 Selected from

[0151] In some embodiments of the present disclosure, R 2 Selected from

[0152] In some embodiments of the present disclosure, R 2 Selected from

[0153] In some embodiments of the present disclosure, R c are each independently selected from halogen, or C optionally substituted by one or more deuteriums 1-6 alkyl.

[0154] In some embodiments of the present disclosure, R c Each independently selected from or C optionally substituted by one or more deuteriums 1-6 alkyl.

[0155] In some embodiments of the present disclosure, R c Each independently selected from or C optionally substituted by one or more deuteriums 1-4 alkyl.

[0156] In some embodiments of the present disclosure, R care each independently selected from halogen, or C optionally substituted by one or more deuteriums 1-4 alkyl.

[0157] In some embodiments of the present disclosure, R c 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.

[0158] In some embodiments of the present disclosure, R c Each 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 or tert-butyl.

[0159] In some embodiments of the present disclosure, R c Each independently selected from or methyl optionally substituted by one or more deuterium groups.

[0160] In some embodiments of the present disclosure, R c Each independently selected from F, Methyl or -CD3.

[0161] In some embodiments of the present disclosure, R c Each independently selected from Methyl or -CD3.

[0162] In some embodiments of the present disclosure, R c Each is independently F.

[0163] In some embodiments of the present disclosure, the compound of formula (I) of the present disclosure, its stereoisomers, or pharmaceutically acceptable salts thereof are selected from the following compounds of formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie), or formula (If), its stereoisomers, or pharmaceutically acceptable salts thereof:

[0164] Among them, X 1 、X 2 , Ring A, Y, R 1 、R 2 and n are as described in this disclosure.

[0165] In some embodiments of the present disclosure, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof of the present disclosure is selected from the compound of formula (II), its stereoisomers, or pharmaceutically acceptable salts thereof:

[0166] in,

[0167] X 2 selected from N or CH;

[0168] Every R 1 are each 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 Substitution, the 5-6 membered heterocycloalkyl contains 1 or 2 heteroatoms selected from N or O, or contains 1 P=O heteroatom group;

[0169] R 2 A 12-membered aromatic tricyclic group, wherein the aromatic tricyclic group contains 2, 3 or 4 heteroatoms independently selected from N or O;

[0170] Every R b are each 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;

[0171] n is selected from 1, 2 or 3;

[0172] 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:

[0173] In some embodiments of the present disclosure, each R 1 Each 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 The 6-membered heterocycloalkyl group contains 1 or 2 heteroatoms selected from N or O, or contains 1 P=O heteroatom group.

[0174] In some embodiments of the present disclosure, each R 1 Each 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, the C 1-3 Alkyl or 6-membered heterocycloalkyl is optionally substituted by one or more R b replace.

[0175] In some embodiments of the present disclosure, each R 1 Each independently selected from methyl or The methyl group or Optionally, one or more R b replace.

[0176] In some embodiments of the present disclosure, each R b Each independently selected from deuterium, F, C 1-3 Alkyl, -NH(C 1-3 alkyl) or -N(C 1-3 alkyl) 2, wherein the -NH(C 1-3 alkyl) or -N(C 1-3 alkyl)2 is optionally substituted with one or more deuterium.

[0177] In some embodiments of the present disclosure, each R b Each is independently selected from deuterium, F, methyl, -NH(CH3) or -N(CH3)2, wherein -N(CH3)2 is optionally substituted with one or more deuterium.

[0178] In some embodiments of the present disclosure, the present disclosure comprises the above-defined variables and embodiments thereof, and any combination thereof.

[0179] It is to be understood that any of the embodiments of the compounds of the present disclosure as described above and the descriptions herein with respect to a particular X in the compounds of the present disclosure as described above 1 、X 2 , Y, Ring A, R 1 、R 2 、R 3 、R 4 Any specific substituent described herein can be independently combined with other embodiments and / or substituents of the present disclosure to form embodiments of the invention not specifically described above. 1 、X 2 , Y, Ring A, R 1 、R 2 、R 3 、R 4 Substituents Where a range of substituents is disclosed, it is understood that one or more substituents can be deleted from the range and the remaining range of substituents is also considered an embodiment of the disclosure.

[0180] 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.

[0181] In some embodiments of the present disclosure, the compound of formula (I) of the present disclosure, its stereoisomers or pharmaceutically acceptable salts thereof are selected from the following compounds, its stereoisomers or pharmaceutically acceptable salts thereof:

[0182] In some embodiments of the present disclosure, the pharmaceutically acceptable salt of the above compound is a hydrochloride (eg, monohydrochloride).

[0183] In some embodiments of the present disclosure, the compound of the present disclosure is not the following compound, or a stereoisomeric form thereof:

[0184] In some embodiments of the present disclosure, when Selected from And R 2 Selected from When the compound of the present disclosure is not the following compound, or its stereoisomeric form:

[0185] 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 stereoisomeric form:

[0186] In another aspect, 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.

[0187] 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-mentioned compound, its stereoisomer or pharmaceutically acceptable salt, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.

[0188] 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 medicament for treating a disease.

[0189] 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.

[0190] 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.

[0191] In some embodiments of the present disclosure, the disease is selected from diseases associated with HPK1 kinase.

[0192] In some embodiments of the present disclosure, the disease associated with HPK1 kinase is cancer. Preferably, the cancer is leukemia or colon cancer.

[0193] 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 metabolic stability in mouse and human liver microsomes.

[0194] definition

[0195] Unless otherwise indicated, the following terms used in this disclosure have the following meanings. A particular term should not be construed as undefined or unclear unless specifically defined, but rather should be understood according to its ordinary meaning in the art. When a trade name appears herein, it is intended to refer to the corresponding commercial product or its active ingredient.

[0196] The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom 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 an oxo (i.e., =O), it means that two hydrogen atoms are replaced. Oxo does not occur on aromatic groups.

[0197] The "substituent" mentioned herein includes all substituents mentioned herein, such as the terms "halogen", "deuterium", "-NH2", "-NH(C 1-4 Alkyl)", "-N(C 1-4 Alkyl)2", "-OH", "-OC 1-4 Alkyl", "-CN", "C 1-4alkyl", "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, azide, 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, arylalkylene, arylalkoxy, arylalkylthio, heteroaryl, heteroaryloxy, heteroarylthio, heteroarylalkylene, 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 group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC( -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, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

[0198] In some embodiments herein, the substituent is selected from deuterium, tritium, hydroxyl, sulfhydryl, halogen, amino, nitro, nitroso, cyano, azide, sulfoxide, sulfone, sulfone, sulfonamide, carboxyl, aldehyde, imine, C 1-12 Alkyl, halo-C 1-12 Alkyl, 3-12 membered cycloalkyl, halogenated 3-12 membered cycloalkyl, C 2-12 Alkenyl, halo-C 2-12 Alkenyl, 3-12 membered cycloalkenyl, halogenated 3-12 membered cycloalkenyl, C 2-12 Alkynyl, halo-C 2-12 Alkynyl, 8-12 membered cycloalkynyl, halogenated 8-12 membered cycloalkynyl, C 1-12 Heteroalkyl, halo-C 1-12 Heteroalkyl, C 1-12 Alkoxy, C 1-12Alkylthio, 6-10 membered aryl, 6-10 membered aryloxy, 6-10 membered arylthio, 6-10 membered arylC 1-12 Alkylene, 6-10 membered aryl C 1-12 Alkoxy, 6-10 membered aryl C 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 heterocyclic group C 1-12 Alkoxy, 3-12 membered heterocyclic group C 1-12 Alkylthio, C 1-12 Acyl, C 1-12 Acyloxy, carbamate group, C 1-12 Amide group, urea group, epoxy group, C 2-12 Ester group and oxo, said substituent being 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)NH2, -C(O)NH-C 1-12 Alkyl, -C(O)N(C 1-12 Alkyl)2, -NHC(O)-C 1-12 Alkyl, -C(O)-C 1-12 Alkyl, -S(O)-C 1-12 Alkyl, -S(O)2-C 1-12 Alkyl, -S(O)2NH2, -S(O)2NH-C 1-12 Alkyl, -S(O)2N(C 1-12 alkyl) 2, 3-12 membered cycloalkyl, 3-12 membered cycloalkyl C 1-12 Alkylene, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group C 1-12 Alkylene, 3-12 membered heterocyclyloxy, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkylC 1-12Alkylene, 3-12 membered heterocycloalkyloxy, 5-10 membered heteroaryl, 5-10 membered heteroarylC 1-12 Alkylene, 5-10 membered heteroaryloxy, 6-10 membered aryl, 6-10 membered arylC 1-12 an alkylene group or a 6- to 10-membered aryloxy group.

[0199] The term "optionally" or "optionally" means that the event or situation described subsequently may or may not occur, and the description includes both the occurrence of the event or situation and the non-occurrence of the event or situation. For example, an ethyl group is "optionally" substituted with a halogen, meaning that the ethyl group may be unsubstituted (-CH2CH3), monosubstituted (e.g., -CH2CH2F), polysubstituted (e.g., -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 would be sterically impossible and / or incomposable to synthesize will be introduced.

[0200] In this article, C m-n , 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 can have 1 carbon atom, 2 carbon atoms, or 3 carbon atoms.

[0201] 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, three, or six.

[0202] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition on each occurrence is independent. Thus, for example, if a group is substituted with two R's, each R has an independent alternative.

[0203] When a substituent's bond crosses between two atoms in a ring, the substituent may be bonded to any atom in the ring. It means that it can be substituted at any position on the cyclohexyl group or cyclohexadiene.

[0204] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0205] The term "hydroxy" refers to an -OH group.

[0206] The term "amino" refers to a -NH2 group.

[0207] The term "nitro" refers to a -NO2 group.

[0208] The term "cyano" refers to a -CN group.

[0209] The term "alkyl" refers to a group of the formula C n H 2n+1 The alkyl group may be straight chain or branched. For example, the term "C 1-6 The term "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.

[0210] The term "alkoxy" refers to an -O-alkyl group.

[0211] 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.

[0212] 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.

[0213] The term "tricyclic" or "tricyclyl" refers to a cyclic group containing three rings, which may be fully saturated, partially saturated, or aromatic (fully unsaturated). The tricyclic ring may be composed 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.

[0214] 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 group may be monocyclic, bicyclic, or tricyclic. Non-limiting examples of cycloalkyl groups 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.

[0215] 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 ring containing 1 to 3 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 heteroatoms (preferably 1 or 2 heteroatoms) 3 to 20-membered ring, 3 to 15-membered ring, 3 to 12-membered ring or 3 to 10-membered ring (e.g., 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered or 10-membered), 4 to 8-membered ring, 5 to 8-membered ring or 5 to 6-membered ring. In some embodiments, the heterocyclic group is directly attached to the parent structure is a non-aromatic ring. Non-limiting examples of heterocyclic groups include, but are not limited to, oxiranyl, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, etc.

[0216] The term "cycloalkenyl" refers to an incompletely saturated, non-aromatic carbocyclic ring that can exist as a monocycle, a bicyclic bridged ring or a spirocycle. 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.

[0217] The term "monocycloalkyl" refers to a cycloalkyl group existing as a single ring.

[0218] 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 N, O, S(O) n 、P(O) n (wherein n is 0, 1 or 2) heteroatoms (preferably 1 or 2 heteroatoms), and the remaining ring atoms are carbon atoms.

[0219] The term "spiroalkyl" 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 spiroalkyl 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, spiroalkyl is divided into single spiroalkyl, double spiroalkyl or multiple spiroalkyl, preferably single spiroalkyl and double spiroalkyl, more preferably 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiroalkyl. Non-limiting examples of spiroalkyl include

[0220] The term "spiroheterocycloalkyl" refers to a fully saturated polycyclic ring in which the monocyclic rings share a carbon atom (called a spiro atom), and one or more ring atoms in the polycyclic ring are selected from N, O, S(O) n 、P(O) n (wherein n is 0, 1 or 2) heteroatoms (preferably 1 or 2 heteroatoms), and the remaining ring atoms are carbon atoms. Unless otherwise indicated, the spiro heterocycloalkyl is 5 to 20 yuan, preferably 6 to 14 yuan, more preferably 6 to 10 yuan. According to the number of shared spiro atoms between the rings, the spiro heterocycle is divided into a monospiro heterocycle, a dispiro heterocycle or a polyspiro heterocycle, preferably a monospiro heterocycle or a dispiro heterocycle, 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 monospiro heterocycle. Non-limiting examples of spiro heterocycloalkyl include wait.

[0221] The term "bridged ring" refers to a fully saturated or partially unsaturated polycyclic ring 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, more preferably 6 to 10 members. Depending on 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 N, O, S(O) n 、P(O) n (wherein n is 0, 1 or 2) heteroatoms (preferably 1 or 2 heteroatoms), and the remaining ring atoms are carbon atoms.

[0222] 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 group is 5 to 14 members, preferably 6 to 14 members, and more preferably 6 to 10 members. Depending on the number of rings, the bridged cycloalkyl group can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged ring, preferably a bicyclic or tricyclic, and more preferably a bicyclic. Non-limiting examples of bridged cycloalkyl groups include: wait.

[0223] The term "bridged heterocycloalkyl" is a fully saturated polycyclic ring in which two rings share three or more atoms, and one or more of the ring atoms is selected from N, O, S(O), n 、P(O) n (where n is 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon atoms. Unless otherwise indicated, the bridged heterocycloalkyl group is 5 to 14 members, preferably 6 to 14 members, more preferably 6 to 10 members. Depending on the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged rings, preferably bicyclic or tricyclic, more preferably bicyclic. Non-limiting examples of bridged heterocycloalkyl groups include: wait.

[0224] The term "heterocycloalkyl" refers to a fully saturated cyclic group containing heteroatoms. Unless otherwise indicated, the heterocycloalkyl group is typically a cyclic group containing 1 to 3 atoms independently selected from N, O, S(O), n 、P(O) n (wherein n is 0, 1 or 2) a heteroatom (preferably 1 or 2 heteroatoms). Unless otherwise indicated, the heterocycloalkyl group may be a monocyclic, bicyclic or tricyclic group. Unless otherwise indicated, the heterocycloalkyl group includes but is not limited to a 3 to 12-membered ring, a 3 to 8-membered ring or a 5 to 8-membered ring. Examples of 3-membered heterocycloalkyl groups include, but are not limited to, oxiranyl, thioranyl, and nitroanilinyl. Non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, and tetrahydropyrazolyl. Examples of 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, or 1,4-dithianyl. Examples of 7-membered heterocycloalkyl groups include, but are not limited to, azepanyl, oxetanyl, and thiepanyl. Preferably, the heterocycloalkyl group is a monocyclic heterocycloalkyl group having 5 or 6 ring atoms. The term "monoheterocycloalkyl" refers to a heterocycloalkyl group that exists as a single ring.

[0225] The term "heterocycloalkenyl" includes cycloalkenyl groups in which one or more carbon atoms are replaced by heteroatoms, for example, up to 3 carbon atoms, up to 2 carbon atoms, and in one embodiment, 1 carbon atom are each independently replaced by N, O, or S(O). n(wherein n is 0, 1 or 2), provided that at least one cycloalkenyl carbon-carbon double bond is retained. The heterocycloalkenyl group may be a cyclic group existing as a monocyclic ring, a bridged ring or a spirocyclic ring, and may be a 3- to 16-membered ring (e.g., a 3- to 12-membered, a 5- to 8-membered ring, specifically a 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered or 11-membered ring). Examples of heterocycloalkenyl groups include, but are not limited to, dihydropyridyl, dihydropyrrolyl, tetrahydropyridyl, tetrahydroazepine or azaspirocyclooctenyl. The term "fused ring" refers to a polycyclic compound formed by two or more carbocyclic or heterocyclic rings with a common two atoms, including fully saturated, partially saturated and aromatic. Unless otherwise indicated, the fused ring is 5-20 members, preferably 6-14 members, and more preferably 9-14 members. Non-limiting examples of fused rings include, but are not limited to, naphthalene, anthracene, phenanthrene, wait.

[0226] As described in this disclosure, For example, "the bicyclic or tricyclic group and the In the case of "a partially connected monocyclic ring is an aromatic ring", the "monocyclic ring" refers to a tricyclic ring The pyrazolyl group in For example, "the bicyclic or tricyclic group and the In the case of "a partially connected monocyclic ring is an aromatic ring", the "monocyclic ring" refers to a tricyclic ring The pyridyl group in

[0227] As described in this disclosure, For example, the "bicyclic or tricyclic group with formula (I) The partially connected monocyclic ring and its 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 monocyclic ring and its adjacent ring are fused rings" refers to a tricyclic group The pyridyl and pyrrolyl groups in the

[0228] 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.

[0229] The term "heteroaryl" refers to a monocyclic or polycyclic ring system containing at least one ring selected from N, O, S(O) n 、P(O)n (wherein n is 0,1 or 2) ring atoms, and the remaining ring atoms are C, and have at least one aromatic ring.Unless otherwise indicated, the heteroaryl can be monocyclic, bicyclic or tricyclic.Unless otherwise indicated, the heteroaryl can have single 5 to 8 rings, or multiple fused rings comprising 6 to 14 (such as 9,10,11,12) ring atoms, especially multiple fused rings of 6 to 10 ring atoms. The limiting examples of heteroaryl include but are not limited to pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl etc. In some embodiments, heteroaryl is completely undersaturated, that is, the whole has aromaticity.

[0230] The term "treating" means administering a compound or formulation of the present disclosure to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0231] (i) inhibiting a disease or disease state, i.e., arresting its development;

[0232] (ii) ameliorating the disease or condition, i.e., causing regression of the disease or condition.

[0233] 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 one skilled in the art based on their own knowledge and this disclosure.

[0234] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are 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.

[0235] 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.

[0236] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or their salts with a pharmaceutically acceptable excipient. The purpose of a pharmaceutical composition is to facilitate administration of the compounds 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.

[0237] The term "pharmaceutically acceptable excipient" refers to an excipient that is non-irritating to organisms and does not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0238] The word "comprise" or "comprises" and its English variations such as comprises or comprising should be understood as having an open and non-exclusive meaning, ie, "including but not limited to".

[0239] Unless otherwise specifically stated, singular terms encompass plural terms and plural terms encompass the singular. Unless otherwise specifically stated, the words "a" or "an" mean "at least one" or "at least one." Unless otherwise specified, the use of "or" means "and / or."

[0240] 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 thereof and other mixtures, 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 groups. All such isomers and mixtures thereof are within the scope of the present invention.

[0241] Unless otherwise indicated, "(D)" or "(+)" indicates dextrorotatory, "(L)" or "(-)" indicates levorotatory, and "(DL)" or "(±)" indicates racemic.

[0242] Unless otherwise specified, use a solid wedge key. 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.

[0243] 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 the pure enantiomers are recovered. In addition, separation of enantiomers and diastereomers is typically accomplished by using chromatography using a chiral stationary phase, optionally combined with chemical derivatization (e.g., carbamate formation from an amine).

[0244] The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but where one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the 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 et al.

[0245] Certain isotopically labeled compounds of the present disclosure (e.g., 3 H and 14 C-labeled) can be used in compound and / or substrate tissue distribution assays. 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 18F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the disclosure can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0246] In addition, the use of heavier isotopes such as deuterium (i.e. 2 H or D)) substitution can provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and may therefore be preferred in certain circumstances, wherein deuterium substitution may be partial or complete, partial deuterium substitution means that at least one hydrogen is replaced by at least one deuterium, and complete deuterium substitution means that all hydrogens on the group are replaced by deuterium, for example, complete replacement of a methyl group (-CH3) by deuterium yields -CD3.

[0247] 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.

[0248] The pharmaceutical compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients.

[0249] 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, and intravenous administration.

[0250] The pharmaceutical compositions disclosed herein can be manufactured using methods well known in the art.

[0251] 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 single or divided doses.

[0252] 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 same with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples disclosed herein.

[0253] The chemical reactions of the embodiments of the present disclosure are carried out in a suitable solvent that is compatible with the chemical transformations 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 synthetic steps or reaction schemes based on existing embodiments.

[0254] An important consideration in synthetic route planning in the art is the selection of 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.

[0255] In some embodiments of the present disclosure, the compound of formula (I) of the present disclosure can be prepared by those skilled in the art of organic synthesis by referring to the following route: (1) when R 4 When selected from H, the preparation route is as follows:

[0256] Preparation route 1:

[0257] Preparation route 2:

[0258] (2) When R 4 Selected from C 1-4 Alkyl, C 3-6 When cycloalkyl or 3-6 membered heterocycloalkyl, the preparation route is as follows:

[0259] Preparation route 3:

[0260] Wherein, Z is selected from halogen, OH, NH2 or NH(C 1-6 alkyl) and other groups; R e A group selected from halogen, NH2, boronic acid or boric acid ester;

[0261] R f A group selected from halogen, boronic acid or boronic ester;

[0262] Q is selected from halogen, OTf, trimethyltin, tri-n-butyltin, boric acid or boric acid ester groups;

[0263] M is selected from halogen, OTf, OTs, OH, OMs and the like;

[0264] Among them, ring A, R 1 、X 1 、X 2 , Y, R 2 、R3 、R 4 The definitions of , m, and n are as described in this disclosure.

[0265] For the purposes of description and disclosure, all patents, patent applications, and other identified publications are expressly incorporated herein by reference. These publications are provided solely because their disclosure predates the filing date of the present disclosure. All statements regarding the dates of these documents or 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 citation of these publications herein does not constitute an admission that such publications are part of the common general knowledge in the art in any country.

[0266] This disclosure uses the following abbreviations:

[0267] DMSO stands for dimethyl sulfoxide; THF stands for tetrahydrofuran; NCS stands for N-chlorosuccinimide; NBS stands for N-bromosuccinimide; CCl4 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

[0268] For the sake of clarity, the present invention is further illustrated by 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 can 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 this disclosure are commercially available and can be used without further purification.

[0269] The compounds of the present invention can be obtained by similar preparation methods as in the examples, including but not limited to adjusting the raw materials, reagents or process parameters of similar structures. 1 The structure of the compound of the present invention can also be confirmed by the same test method.

[0270] Preparation of intermediates

[0271] Intermediate Example 1: Preparation of Intermediate 1A

[0272] Step A: Preparation of Intermediate 1A-1

[0273] To a reaction flask, methyl 6-amino-3-bromopicolinate (100 g), N,N-dimethylpyridin-4-amine (10.6 g), di-tert-butyl dicarbonate (170 g), and tetrahydrofuran (600 mL) were added sequentially. The mixture was stirred at room temperature. Upon completion, the reaction mixture was quenched with 10% aqueous citric acid (200 mL, w / w), extracted with dichloromethane, washed with saturated brine, dried, and concentrated to afford Intermediate 1A-1 (120.1 g).

[0274] MS (ESI, [M+H] + )m / z:331.1.

[0275] Step B: Preparation of Intermediate 1A-2

[0276] To a reaction flask, add Intermediate 1A-1 (85 g), tetrahydrofuran (300 mL), and lithium borohydride (6.2 g) in sequence. Stir the mixture at room temperature until complete. After completion, quench the reaction mixture with saturated ammonium chloride solution, extract with dichloromethane, wash with saturated brine, dry, and concentrate to afford Intermediate 1A-2 (60.0 g).

[0277] MS (ESI, [M+H] + )m / z:303.1.

[0278] Step C: Preparation of Intermediate 1A-3

[0279] To the reaction flask, add Intermediate 1A-2 (54.2 g), N,N-diisopropylethylamine, dichloromethane (200 mL), and methanesulfonic anhydride (78 g) in sequence. Stir the mixture at -15°C until complete. The reaction mixture was used directly in the next step without further treatment.

[0280] Step D: Preparation of Intermediate 1A-4

[0281] To the reaction flask, add dimethylamine tetrahydrofuran solution (446 mL, 2M), dichloromethane (200 mL), and the reaction mixture of Intermediate 1A-3 in sequence, and stir at room temperature. Once the reaction is complete, extract with dichloromethane, wash with saturated brine, dry, and concentrate. Column chromatography (dichloromethane / methanol = 5 / 1) affords Intermediate 1A-4 (38.2 g).

[0282] MS (ESI, [M+H] + )m / z:330.1.

[0283] Step E: Preparation of Intermediate 1A-5

[0284] To a reaction flask, 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). After addition, replace the atmosphere with nitrogen and stir at 100°C. After completion, filter and concentrate the reaction mixture. Column chromatography (petroleum ether / ethyl acetate = 5 / 1) affords Intermediate 1A-5 (24.5 g).

[0285] MS (ESI, [M+H] + )m / z:334.0.

[0286] Step F: Preparation of Intermediate 1A-6

[0287] To the reaction flask, add Intermediate 1A-5 (24.5 g), 10 wt% palladium hydroxide on carbon (24.5 g), and methanol (100 mL) in sequence. After addition, stir and react at 35°C under hydrogen atmosphere. After the reaction is complete, filter and concentrate to obtain Intermediate 1A-6 (22.0 g).

[0288] MS (ESI, [M+H] + )m / z:336.0.

[0289] Step G: Preparation of Intermediate 1A-7

[0290] To the reaction flask, add Intermediate 1A-6 (22.0 g) and 1,4-dioxane hydrochloride solution (164 mL, 4 M). Stir the mixture at room temperature until complete. After completion, adjust the reaction mixture to alkaline (pH approximately 10) by adding saturated sodium bicarbonate solution, extract with dichloromethane, and concentrate to afford Intermediate 1A-7 (13.0 g).

[0291] MS (ESI, [M+H] + )m / z:236.3.

[0292] Step H: Preparation of Intermediate 1A-8

[0293] To the reaction flask, add 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) in sequence. Stir the mixture at room temperature until complete. Add water (1000 mL) to the reaction mixture, extract with ethyl acetate, and concentrate to yield Intermediate 1A-8 (41.2 g).

[0294] MS (ESI, [M+H] + )m / z:264.2.

[0295] Step I: Preparation of Intermediate 1A-9

[0296] To the reaction flask, add Intermediate 1A-8 (41.2 g), N-bromosuccinimide (42.0 g), dibenzoylmethane peroxide (0.6 g), and 1,2-dichloroethane (500 mL) in sequence. After addition, stir at 90°C and react. Upon completion, quench the reaction mixture with saturated sodium sulfite solution (100 mL), extract with dichloromethane, wash with saturated brine, dry, and concentrate to afford Intermediate 1A-9 (54.5 g).

[0297] 1 H NMR (500MHz, CDCl3) δ8.51 (s, 1H), 4.53 (s, 2H), 4.05 (s, 3H).

[0298] Step J: Preparation of Intermediate 1A-10

[0299] To the reaction flask, add intermediate 1A-9 (54.5 g), ammonia in methanol solution (60 mL, 7 M), and methanol (500 mL) in sequence. After addition, stir at 75°C and react. After the reaction is complete, filter the reaction mixture and dry to obtain intermediate 1A-10 (29.2 g).

[0300] 1 H NMR (500MHz, DMSO-d6) δ9.30 (s, 1H), 8.67 (d, J = 2.7Hz, 1H), 4.41 (s, 2H).

[0301] Step K: Preparation of Intermediate 1A-11

[0302] To a reaction flask, 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) in sequence. Stir the mixture at room temperature. Upon completion, concentrate the reaction mixture and perform column chromatography (petroleum ether / ethyl acetate = 10 / 1) to afford Intermediate 1A-11 (35.3 g).

[0303] 1 H NMR (500MHz, DMSO-d6) δ8.75(s,1H),4.73(s,2H),1.54(s,9H).

[0304] Step L: Preparation of Intermediate 1A

[0305] To a reaction flask, 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) were added sequentially. After the addition, the atmosphere was replaced with nitrogen and the reaction was stirred at 100°C. After the reaction was complete, the product was filtered and concentrated to obtain the crude product. Column chromatography (dichloromethane / methanol = 20 / 1) afforded Intermediate 1A (1.2 g).

[0306] MS (ESI, [M+H] + )m / z:502.3.

[0307] Intermediate Example 2: Preparation of Intermediate 2A

[0308] Step A: Preparation of Intermediate 2A-1

[0309] To the reaction flask, add Intermediate 1A-2 (112.2 g), dichloromethane (450 mL), N,N-diisopropylethylamine (162.0 mL), and methanesulfonic anhydride (162.0 g) in sequence. Stir the reaction at -15°C. Once the reaction is complete, add 3,3-difluoropyrrolidine (118.5 g) in portions to the reaction mixture. Stir the reaction at room temperature. After the reaction is complete, extract with dichloromethane, wash with saturated brine, dry, and concentrate. Column chromatography (dichloromethane / methanol = 30 / 1) yields Intermediate 2A-1 (95.0 g).

[0310] MS (ESI, [M+H] + )m / z:392.3.

[0311] Step B: Preparation of Intermediate 2A-2

[0312] To a reaction flask, 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). After addition, replace the atmosphere with nitrogen and stir at 100°C. After completion, filter and concentrate the reaction mixture. Column chromatography (petroleum ether / ethyl acetate = 5 / 1) affords Intermediate 2A-2 (23.2 g).

[0313] MS (ESI, [M+H] + )m / z:382.5.

[0314] Step C: Preparation of Intermediate 2A-3

[0315] To the reaction flask, add Intermediate 2A-2 (15.0 g), 10 wt% palladium hydroxide on carbon (15.0 g), and methanol (225 mL) in sequence. After addition, stir and react at 35°C under hydrogen atmosphere. After the reaction is complete, filter and concentrate to obtain Intermediate 2A-3 (14.5 g).

[0316] MS (ESI, [M+H] + )m / z:384.8.

[0317] Step D: Preparation of Intermediate 2A-4

[0318] To the reaction flask, add Intermediate 2A-3 (14.5 g) and 1,4-dioxane hydrochloride solution (122.4 mL, 4 M). Stir the mixture at room temperature until complete. After completion, adjust the reaction mixture to alkaline (pH approximately 10) by adding saturated sodium bicarbonate solution. Extract with dichloromethane and concentrate to obtain Intermediate 2A-4 (7.5 g).

[0319] MS (ESI, [M+H] + )m / z:284.1.

[0320] Step E: Preparation of Intermediate 2A

[0321] To a reaction flask, 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) were added sequentially. After the addition, the atmosphere was replaced with nitrogen and the reaction was stirred at 100°C. After the reaction was complete, the product was filtered and concentrated to obtain the crude product. Column chromatography (dichloromethane / methanol = 20 / 1) afforded intermediate 2A (1.0 g).

[0322] MS (ESI, [M+H] + )m / z:550.3.

[0323] Intermediate Example 3: Preparation of Intermediate 3A

[0324] Step A: Preparation of Intermediate 3A-1

[0325] At -10°C, add 7-amino-4-chloroisoindole-1-one (10 g) and a 48% methanol solution of hydrogen bromide (90 mL, w / w) to the reaction flask in sequence. After the addition is complete, slowly add an aqueous solution of sodium nitrite (7.6 g, 65 mL) dropwise to the reaction solution. After the addition is complete, stir and react for 1 hour. Slowly add a 48% aqueous solution of hydrogen bromide (8.6 g, 90 mL) dissolved in cuprous bromide dropwise to the reaction solution. After the addition is complete, stir and react at 80°C. After the reaction is complete, pour the reaction solution into ice water, stir thoroughly, filter, wash the filter cake, and dry the filter cake to obtain intermediate 3A-1 (8.5 g).

[0326] MS (ESI, [M+H] + )m / z:245.9.

[0327] Step B: Preparation of Intermediate 3A-2

[0328] To a reaction flask, add Intermediate 3A-1 (8.5 g), tetrahydrofuran (150 mL), 4-dimethylaminopyridine (1.0 g), and di-tert-butyl dicarbonate (11.2 g) in sequence. After addition, stir at room temperature. Upon completion, quench the reaction mixture with 10% aqueous citric acid (200 mL, w / w), extract with dichloromethane, wash with saturated brine, dry, and concentrate to afford Intermediate 3A-2 (9.6 g).

[0329] MS (ESI, [M+H] + )m / z:345.9.

[0330] Step C: Preparation of Intermediate 3A-3

[0331] To a reaction flask, intermediate 3A-2 (2.5 g), 4,5-bis(diphenylphosphino)-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) were added sequentially. After the addition, the atmosphere was replaced with nitrogen and the reaction was stirred at 100°C. After the reaction was complete, the product was filtered and concentrated to obtain the crude product. Column chromatography (dichloromethane / methanol = 20 / 1) afforded intermediate 3A-3 (4.2 g).

[0332] MS (ESI, [M+H] + )m / z:549.3.

[0333] Step D: Preparation of Intermediate 3A

[0334] To a microwave tube, 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), pinacol diboron (1.9 g), potassium carbonate (1.0 g), and 1,4-dioxane (60 mL) were added sequentially. After addition, the atmosphere was replaced with nitrogen and microwave-treated at 90°C. The reaction was complete, filtered, and concentrated. Column chromatography (dichloromethane / methanol = 20 / 1) afforded intermediate 3A (2.4 g).

[0335] MS (ESI, [M+H] + )m / z:641.5.

[0336] Intermediate Example 4: Preparation of Intermediate 4A

[0337] Step A: Preparation of Intermediate 4A-1

[0338] To a reaction flask, 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). After addition, replace the atmosphere with nitrogen and stir at 100°C. After completion, filter and concentrate the reaction mixture. Column chromatography (petroleum ether / ethyl acetate = 5 / 1) yields Intermediate 4A-1 (20.8 g).

[0339] MS (ESI, [M+H] + )m / z:320.5.

[0340] Step B: Preparation of Intermediate 4A-2

[0341] To the reaction flask, add Intermediate 4A-1 (15.0 g), 10 wt% palladium hydroxide on carbon (15.0 g), and methanol (225 mL) in sequence. After addition, stir and react at 35°C under hydrogen atmosphere. After the reaction is complete, filter and concentrate to obtain Intermediate 4A-2 (14.8 g).

[0342] MS (ESI, [M+H] + )m / z:322.8.

[0343] Step C: Preparation of Intermediate 4A-3

[0344] To the reaction flask, add intermediate 4A-2 (14.8 g) and 1,4-dioxane hydrochloride solution (122.4 mL, 4 M). Stir the mixture at room temperature until complete. After completion, adjust the reaction mixture to alkaline (pH approximately 10) by adding saturated sodium bicarbonate solution. Extract with dichloromethane and concentrate to obtain intermediate 4A-3 (8.2 g).

[0345] MS (ESI, [M+H] + )m / z:222.1.

[0346] Step D: Preparation of Intermediate 4A-4

[0347] To a reaction flask, 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) were added sequentially. After the addition, the atmosphere was replaced with nitrogen and the reaction was stirred at 100°C. After the reaction was complete, the product was filtered and concentrated to obtain the crude product. Column chromatography (dichloromethane / methanol = 20 / 1) afforded intermediate 4A-4 (4.0 g).

[0348] MS (ESI, [M+H] + )m / z:487.4.

[0349] Step E: Preparation of Intermediate 4A

[0350] To a microwave tube, 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), pinacol diboron (2.1 g), potassium carbonate (1.2 g), and 1,4-dioxane (60 mL) were added sequentially. After addition, the atmosphere was replaced with nitrogen and microwave-treated at 90°C. The reaction was complete, filtered, and concentrated. Column chromatography (dichloromethane / methanol = 20 / 1) afforded intermediate 4A (2.6 g).

[0351] MS (ESI, [M+H] + )m / z:579.5.

[0352] Intermediate Example 5: Preparation of Intermediate 5A

[0353] Step A: Preparation of Intermediate 5A-1

[0354] To a reaction flask, 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) were added sequentially. After the addition, the atmosphere was replaced with nitrogen and the reaction was stirred at 100°C. After the reaction was complete, the product was filtered and concentrated to obtain the crude product. Column chromatography (dichloromethane / methanol = 20 / 1) afforded intermediate 5A-1 (4.4 g).

[0355] MS (ESI, [M+H] + )m / z:501.3.

[0356] Step B: Preparation of Intermediate 5A

[0357] To a microwave tube, 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), pinacol diboron (2.1 g), potassium carbonate (1.2 g), and 1,4-dioxane (60 mL). After addition, replace nitrogen atmosphere and microwave reaction at 90°C. After completion of the reaction, filter, concentrate, and obtain Intermediate 5A (2.8 g). Column chromatography (dichloromethane / methanol = 20 / 1) yields Intermediate 5A.

[0358] MS (ESI, [M+H] + )m / z:593.3.

[0359] Intermediate Example 6: Preparation of Intermediate 6A

[0360] Step A: Preparation of Intermediate 6A-1

[0361] To a reaction flask, 5-chlorofuro[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), and 1,1-binaphthyl-2,2-bisdiphenylphosphine (1.9 g) were added sequentially. After the addition, the reaction mixture was stirred at 100°C. Upon completion of the reaction, dichloromethane was added to extract the mixture. The organic phase was washed with saturated brine, dried, and concentrated. Column chromatography (dichloromethane / methanol = 30 / 1) afforded Intermediate 6A-1 (15.2 g).

[0362] MS (ESI, [M+H] + )m / z:299.12.

[0363] Step B: Preparation of Intermediate 6A-2

[0364] To the reaction flask, add Intermediate 6A-1 (15.2 g), dichloromethane (20.0 mL), and 1,4-dioxane hydrochloride solution (4 M, 191.0 mL) in sequence. Stir the mixture at 100°C. Upon completion, filter and concentrate the reaction mixture. Column chromatography (petroleum ether / ethyl acetate = 5 / 1) affords Intermediate 6A-2 (5.1 g).

[0365] MS (ESI, [M+H] + )m / z:135.2.

[0366] Step C: Preparation of Intermediate 6A-3

[0367] To the reaction flask, add Intermediate 6A-2 (5.1 g), bromoacetaldehyde diacetaldehyde (36.7 g), methanol (10.0 mL), and hydrochloric acid (3 M, 12.2 mL) in sequence. Stir the mixture at 35°C. Upon completion of the reaction, filter the reaction mixture, concentrate, and perform column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain Intermediate 6A-3 (5.3 g).

[0368] MS (ESI, [M+H] + )m / z:159.1.

[0369] Step D: Preparation of Intermediate 6A

[0370] To a reaction flask, 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). After addition, stir at room temperature under nitrogen. Upon completion of the reaction, extract with water and dichloromethane. The organic phase is separated, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to afford Intermediate 6A (4.3 g).

[0371] MS (ESI, [M+H] + )m / z:237.4.

[0372] Intermediate Example 7: Preparation of Intermediate 7A

[0373] Step A: Preparation of Intermediate 7A-1

[0374] To the reaction flask, 4-chlorofurylpyridine (10 g), acetic acid (130 mL), and zinc powder (10.0 g) were added sequentially. After the addition, the mixture was stirred at 100°C. After the reaction was complete, saturated sodium bicarbonate solution was added to adjust the reaction mixture to alkalinity (pH approximately 10). The mixture was extracted with ethyl acetate. The organic phase was separated, washed, dried, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 9 / 1) to afford Intermediate 7A-1 (5.2 g).

[0375] MS (ESI, [M+H] + )m / z:120.0.

[0376] Step B: Preparation of Intermediate 7A-2

[0377] To the reaction flask, add intermediate 7A-1 (5 g), acetonitrile (50.0 mL), and 2,4-dinitrophenylhydroxylamine (8.5 g) in sequence. After the addition, stir and react at 40°C. After the reaction is complete, filter the reaction solution, wash, and dry the residue to obtain intermediate 7A-2 (9.8 g), which is used directly in the next reaction.

[0378] Step C: Preparation of Intermediate 7A-3

[0379] To the reaction flask, add Intermediate 7A-2 (5 g), potassium carbonate (3 g), ethyl propiolate (3.2 g), and N,N-dimethylformamide (60 mL) in sequence. After addition, stir at room temperature. After completion of the reaction, the reaction solution is quenched by adding water, extracted with ethyl acetate, and the organic phase is separated, dried, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 6 / 1) to obtain Intermediate 7A-3 (3.4 g).

[0380] MS (ESI, [M+H] + )m / z:231.0.

[0381] Step D: Preparation of Intermediate 7A-4

[0382] To the reaction flask, intermediate 7A-3 (3.4 g), lithium hydroxide monohydrate (6 g), methanol (60 mL) and water (6 mL) were added in sequence. After the addition was complete, the reaction was stirred at 60°C. After the reaction was complete, 1 M dilute hydrochloric acid was added to the reaction solution to adjust the acidity (pH about 5), and the mixture was extracted with ethyl acetate. The organic phase was separated, dried, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain intermediate 7A-4 (2.9 g).

[0383] MS (ESI, [M+H] + )m / z:203.2.

[0384] Step E: Preparation of Intermediate 7A

[0385] To the reaction flask were added 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 was complete, the mixture was reacted at room temperature. After completion of the reaction, water and ethyl acetate were added to the reaction solution for extraction. The organic phase was separated, dried, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 6 / 1) to obtain intermediate 7A (3.08 g).

[0386] MS (ESI, [M+H] + )m / z:237.0.

[0387] Intermediate Example 8: Preparation of Intermediate 8A

[0388] Step A: Preparation of Intermediate 8A-1

[0389] To a reaction flask, add 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) in sequence. Stir the mixture at 60°C. Upon completion of the reaction, concentrate the reaction solution and perform column chromatography (petroleum ether / ethyl acetate = 10 / 1) to afford Intermediate 8A-1 (10.72 g).

[0390] MS (ESI, [M+H] + )m / z:177.1.

[0391] Step B: Preparation of Intermediate 8A-2

[0392] To the reaction flask, add Intermediate 8A-1 (10.00 g), a 1,4-dioxane solution of hydrochloric acid (4 M, 20 mL), and dichloromethane (100 mL) in sequence. After the addition, stir at room temperature and react. After the reaction is complete, filter the reaction solution and dry it to obtain Intermediate 8A-2 (11.53 g).

[0393] MS (ESI, [M+H] + )m / z:177.1.

[0394] Step C: Preparation of Intermediate 8A-3

[0395] At 0°C, intermediate 8A-2 (10.00 g), chlorobenzene (75 mL), and oxalyl chloride (17.90 g) were added sequentially to the reaction flask. The reaction mixture was allowed to react at room temperature for 0.5 h. Triethylamine hydrochloride (32.40 g) was then added to the reaction mixture. The mixture was stirred at room temperature until the reaction was complete. The reaction mixture was concentrated, extracted with water and dichloromethane, and the organic phase was separated, dried, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to afford intermediate 8A-3 (10.60 g).

[0396] MS (ESI, [M+H] + )m / z:285.2.

[0397] Step D: Preparation of Intermediate 8A-4

[0398] To a reaction flask, intermediate 8A-3 (8.4 g), cuprous iodide (0.56 g), bistriphenylphosphine palladium dichloride (2.07 g), trimethylsilylacetylene (5.50 g), triethylamine (24 mL), and N,N-dimethylformamide (24 mL) were added sequentially. After the addition, the atmosphere was replaced with nitrogen and the reaction was stirred at 80°C. After the reaction was complete, saturated ammonium chloride solution was added to quench the reaction solution, and the mixture was extracted with dichloromethane. The organic phase was separated, dried, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain intermediate 8A-4 (9.10 g).

[0399] MS (ESI, [M+H] + )m / z:347.1.

[0400] Step E: Preparation of Intermediate 8A-5

[0401] To the reaction flask, add Intermediate 8A-4 (9.10 g), dichloromethane (150 mL), silver trifluoromethanesulfonate (0.40 g), and trifluoroacetic acid (9.75 mL) in sequence. Stir the mixture at room temperature until complete. After completion, concentrate the reaction mixture and perform column chromatography (petroleum ether / ethyl acetate = 10 / 1) to afford Intermediate 8A-5 (4.26 g).

[0402] MS (ESI, [M+H] + )m / z:227.4.

[0403] Step F: Preparation of Intermediate 8A-6

[0404] To the reaction flask, intermediate 8A-5 (1.42 g), tetrahydrofuran (25 mL), and a tetrahydrofuran solution of tetrabutylammonium fluoride (1 M, 7.52 mL) were added sequentially at -78°C. The reaction was stirred at -78°C. After completion of the reaction, the reaction mixture was quenched by adding saturated ammonium chloride solution, extracted with dichloromethane, and the organic phase was separated, dried, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to afford intermediate 8A-6 (0.89 g).

[0405] MS (ESI, [M+H] + )m / z:155.1.

[0406] Step G: Preparation of Intermediate 8A-7

[0407] To a reaction flask, 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) were added sequentially. After the addition, the atmosphere was replaced with nitrogen and the reaction was stirred at 80°C. After the reaction was complete, the reaction solution was filtered and concentrated. Column chromatography (petroleum ether / ethyl acetate = 5 / 1) afforded intermediate 8A-7 (0.46 g).

[0408] MS (ESI, [M+H] + )m / z:300.1.

[0409] Step H: Preparation of Intermediate 8A-8

[0410] To the reaction flask, intermediate 8A-7 (0.46 g), a 1,4-dioxane solution of hydrochloric acid (4 M, 5.76 mL), and dichloromethane (10 mL) were added sequentially. The mixture was stirred at room temperature. After completion of the reaction, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to afford intermediate 8A-8 (0.17 g).

[0411] MS (ESI, [M+H] + )m / z:136.0.

[0412] Step I: Preparation of Intermediate 8A-9

[0413] Bromoacetaldehyde diethyl acetal (2.47 g), methanol (2 mL), and hydrochloric acid (3 M, 4 mL) were added to the reaction flask in sequence. The reaction was allowed to react at 80°C for 1 h. Saturated sodium bicarbonate solution was then added to adjust the pH of the reaction solution to 8. Intermediate 8A-8 (0.11 g) was then added to the reaction solution, and the reaction was stirred at room temperature. Upon completion of the reaction, the reaction solution was concentrated and purified by column chromatography (dichloromethane / methanol = 20 / 1) to afford Intermediate 8A-9 (0.12 g).

[0414] MS (ESI, [M+H] + )m / z:160.2.

[0415] Step J: Preparation of Intermediate 8A

[0416] To the reaction flask, dibromohydantoin (108 mg), dimethyl sulfoxide (2 mL), sodium carbonate (160 mg), and intermediate 8A-9 (120 mg) were added sequentially. The reaction was stirred at 60°C. After the reaction was complete, water and dichloromethane were added to the reaction solution for extraction. The organic phase was separated, dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 20 / 1) to afford intermediate 8A (178 mg).

[0417] MS (ESI, [M+H]+ )m / z:238.0.

[0418] Intermediate Example 9: Preparation of Intermediate 9A

[0419] Step A: Preparation of Intermediate 9A-1

[0420] Pyrazole (10.0 g), 60 wt% sodium hydride (11 g), and N,N-dimethylformamide (120 mL) were added to the reaction flask. 1,1-bis-bromomethylcyclopropane (10.0 g) was slowly added at 0°C. After the addition was complete, the reaction was allowed to react at room temperature. 1 M dilute hydrochloric acid was added to the reaction solution to adjust it to neutral (pH approximately 7). Ethyl acetate was added for extraction. The organic phase was separated, dried, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 6 / 1) to obtain intermediate 9A-1 (8.6 g).

[0421] MS (ESI, [M+H] + )m / z:215.1.

[0422] Step B: Preparation of Intermediate 9A-2

[0423] To a reaction flask containing intermediate 9A-1 (8.6 g) and tetrahydrofuran (100 mL) was slowly added dropwise a solution of lithium diisopropylamide in tetrahydrofuran (2 M, 41 mL) at -78°C. After the addition was complete, the reaction was allowed to react at room temperature. After completion, the reaction was quenched and extracted with ethyl acetate. The organic phase was separated, dried, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 9 / 1) to give intermediate 9A-2 (2.6 g).

[0424] MS (ESI, [M+H] + )m / z:135.1.

[0425] Step C: Preparation of Intermediate 9A

[0426] Under ice-water bath, intermediate 9A-2 (2.6 g), N-bromosuccinimide (4 g) and dichloromethane (40 mL) were added to the reaction flask. After the addition was complete, the reaction was allowed to react at room temperature. After completion of the reaction, the reaction was quenched and extracted with ethyl acetate. The organic phase was separated, dried, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 9 / 1) to obtain intermediate 9A (2.5 g).

[0427] MS (ESI, [M+H] + )m / z:213.1.

[0428] Intermediate Example 10: Preparation of Compound 14d

[0429] Step A: Preparation of compound 14a

[0430] To a reaction flask, intermediate 1A-2 (5 g), N,N-diisopropylethylamine (4 g), dichloromethane (30 mL), and methanesulfonic anhydride (7.2 g) were added sequentially. After addition, the reaction was stirred at -15°C. After the reaction was complete, dimethyl-D6-amine (10 g) was slowly added to the reaction flask. After addition, the reaction was stirred at room temperature. After the reaction was complete, dichloromethane was added for extraction. The organic phase was washed with saturated sodium chloride solution, dried, concentrated, and purified by column chromatography (dichloromethane / methanol = 5 / 1) to obtain compound 14a (3.8 g).

[0431] MS (ESI, [M+H] + )m / z:336.1.

[0432] Step B: Preparation of compound 14b

[0433] Compound 14a (3.8 g), potassium carbonate (3.6 g), tetrakistriphenylphosphine 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 a reaction flask in this order. After the addition, the atmosphere was replaced with nitrogen and the reaction was stirred at 100°C. After the reaction was complete, the reaction solution was filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to afford compound 14b (2.6 g).

[0434] MS (ESI, [M+H] + )m / z:340.0.

[0435] Step C: Preparation of compound 14c

[0436] Compound 14b (2.6 g), 10 wt% palladium hydroxide on carbon (2.6 g), and methanol (12 mL) were added sequentially to the reaction flask. After addition, the mixture was stirred at room temperature under hydrogen atmosphere. Upon completion of the reaction, the reaction solution was filtered and concentrated to afford compound 14c (2.2 g).

[0437] MS (ESI, [M+H] + )m / z:342.0.

[0438] Step D: Preparation of compound 14d

[0439] Compound 14c (2.2 g) and 1,4-dioxane hydrochloride solution (16.4 mL, 4 M) were added to the reaction flask in sequence. The mixture was stirred at room temperature. Upon completion of the reaction, the reaction mixture was adjusted to alkaline (pH approximately 10) by adding saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane, and the organic phase was dried, filtered, and concentrated to afford compound 14d (1.4 g).

[0440] MS (ESI, [M+H]+ )m / z:242.3.

[0441] Intermediate Example 11: Preparation of Compound 16f

[0442] Step A: Preparation of compound 16a

[0443] Under nitrogen, 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 sequentially to a reaction flask. After the addition, the mixture was stirred at 100°C. After the reaction was complete, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to afford compound 16a (7.06 g).

[0444] MS (ESI, [M+H] + )m / z:335.11.

[0445] Step B: Preparation of compound 16b

[0446] 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. After the addition was complete, 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).

[0447] MS (ESI, [M+H] + )m / z:337.12.

[0448] Step C: Preparation of compound 16c

[0449] Compound 16b (5.14 g), tetrahydrofuran (100 mL), and lithium aluminum hydride (1.60 g) were added sequentially to a reaction flask at 0°C. The mixture was stirred at room temperature. Upon completion, the reaction was quenched with water, filtered, and extracted with ethyl acetate. The organic phase was dried, filtered, and concentrated to afford compound 16c (2.76 g).

[0450] MS (ESI, [M+H] + )m / z:311.17.

[0451] Step D: Preparation of compound 16d

[0452] Compound 16c (2.76 g), dichloromethane (60 mL), triethylamine (1.80 g), and methanesulfonic anhydride (3.10 g) were added sequentially to a reaction flask at -10°C. The mixture was stirred at 0°C. After completion of the reaction, the reaction solution was added dropwise to a 40% aqueous dimethylamine solution (20.04 g) at -10°C. After completion of the addition, the mixture was stirred at room temperature. After completion of the reaction, 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).

[0453] MS (ESI, [M+H] + )m / z:336.26.

[0454] Step E: Preparation of compound 16e

[0455] Compound 16d (1.17 g), dichloromethane (10 mL), and a 4 M solution of hydrochloric acid in 1,4-dioxane (20 mL) were added sequentially to a reaction flask. The mixture was stirred at room temperature until complete. After completion, the reaction solution was concentrated and adjusted to alkaline (pH approximately 10) by adding saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane, and the organic phase was dried, filtered, and the solvent removed by vacuum drying to afford compound 16e (1.13 g).

[0456] MS (ESI, [M+H] + )m / z:238.25.

[0457] Step F: Preparation of compound 16f

[0458] Under nitrogen, 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), and 1,4-dioxane (30 mL) were added sequentially to a reaction flask and stirred at 110°C. After completion of the reaction, the reaction solution was filtered and concentrated. Column chromatography (dichloromethane / methanol = 20 / 1) afforded compound 16f (0.85 g).

[0459] MS (ESI, [M+H] + )m / z:503.33.

[0460] Intermediate Example 12: Preparation of Compound 53a

[0461] Step A: Preparation of compound 53a

[0462] Compound 16f (0.85 g), pinacol diboronate (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 sequentially to a microwave tube. After addition, the mixture was stirred in a microwave oven at 90°C under nitrogen atmosphere. After completion of the reaction, the reaction solution was filtered and concentrated. Column chromatography (dichloromethane / methanol = 20 / 1) afforded compound 53a (0.54 g).

[0463] MS (ESI, [M+H] + )m / z:595.43.

[0464] Intermediate Example 13: Preparation of Compound 79d

[0465] Step A: Preparation of intermediate 79a

[0466] To a reaction flask, methyl 6-amino-3-bromopicolinate (20 g), triethylamine (26.3 g), cyclopropylcarbonyl chloride (36.2 g), and dichloromethane (200 mL) were added sequentially. The reaction was stirred at room temperature. Upon completion of the reaction, the reaction mixture was extracted with saturated sodium bicarbonate solution and dichloromethane. The organic phase was dried, filtered, and concentrated to afford compound 79a (25.1 g).

[0467] MS (ESI, [M+H] + )m / z:299.0.

[0468] Step B: Preparation of compound 79b

[0469] Compound 79a (10.0 g), tetrahydrofuran (100.0 mL), and lithium borohydride (0.88 g) were added sequentially to a reaction flask at 0°C. After the addition, the atmosphere was replaced with nitrogen and the reaction was stirred at 0°C. Upon completion of the reaction, water was added to quench the reaction solution, 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 afford compound 79b (7.0 g).

[0470] MS (ESI, [M+H] + )m / z:271.0.

[0471] Step C: Preparation of compound 79c

[0472] Compound 79b (7.0 g), dichloromethane (50.0 mL), N,N-diisopropylethylamine (8.34 mL), and methanesulfonic anhydride (11.24 g) were added sequentially to a reaction flask at 0°C. After the addition was complete, the mixture was stirred at 0°C. After the reaction was complete, a 7 M aqueous solution of methylamine (10 mL) was slowly added to the reaction solution at 0°C. After the addition was complete, the mixture was stirred at 0°C. 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).

[0473] MS (ESI, [M+H] + )m / z:283.9.

[0474] Step D: Preparation of compound 79d

[0475] 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 sequentially to a reaction flask. The mixture was stirred at room temperature. Upon completion of the reaction, 10% aqueous citric acid (80 mL, w / w) and dichloromethane were added to the reaction mixture for extraction. The organic phase was separated, washed, dried, and concentrated to afford compound 79d (3.1 g).

[0476] MS (ESI, [M+H] + )m / z:384.3.

[0477] Intermediate Example 14: Preparation of Compound 82c

[0478] Step A: Preparation of compound 82a

[0479] To a reaction flask were added 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) in sequence. After addition, the mixture was stirred under nitrogen at 80°C. After completion of the reaction, 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 afford compound 82a.

[0480] MS (ESI, [M+Na] + )m / z:229.07.

[0481] Step B: Preparation of compound 82b

[0482] To a reaction flask at 0°C, compound 82a (3.00 g), acetonitrile (30 mL), and trifluoroacetic acid (5.50 g) were added sequentially. The reaction was stirred at 0°C. After 2 hours of reaction, the solvent was concentrated under reduced pressure. Acetonitrile (30 mL) and palladium dichloride (0.35 g) were added to the residue. After the addition was complete, the mixture was heated and stirred at 80°C under nitrogen. After the reaction was complete, the reaction solution was filtered and concentrated. Compound 82b (1.50 g) was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to afford compound 82b.

[0483] MS (ESI, [M+H] + )m / z:229.05.

[0484] Step C: Preparation of compound 82c

[0485] To a reaction flask 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 sequentially. The reaction was stirred at room temperature. Upon completion, the reaction was quenched with saturated ammonium chloride solution and extracted with dichloromethane. The organic phase was dried, filtered, and concentrated. Compound 82c (0.80 g) was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to afford compound 82c.

[0486] MS (ESI, [M+H] + )m / z:193.27.

[0487] Intermediate Example 15: Preparation of Compound 85k

[0488] Step A: Preparation of compound 85j

[0489] To a reaction flask, 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 sequentially. After the addition, the reaction mixture 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).

[0490] MS (ESI, [M+H] + )m / z:293.2.

[0491] Step B: Preparation of compound 85k

[0492] 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 sequentially to a reaction flask. The mixture was stirred at 85°C. After completion of the reaction, the reaction solution was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to afford compound 85k (0.3 g).

[0493] MS (ESI, [M+H] + )m / z:405.2.

[0494] Intermediate Example 16: Preparation of Compound 97d

[0495] Step A: Preparation of compound 97d

[0496] To a reaction flask, 3-bromo-7-fluoroimidazo[1,2-A]pyridine (3.5 g) and tetrahydrofuran (50 mL) were added sequentially. After addition, a solution of isopropylmagnesium chloride in tetrahydrofuran (15 mL, 1.3 M) was slowly added dropwise under nitrogen at -15°C. The reaction was stirred for 0.5 h at -15°C. Then, isopropyl pinacol borate (4.5 g) was slowly added dropwise. After addition, the temperature was slowly warmed to room temperature and stirred. The reaction was monitored by TLC until completion. Saturated ammonium chloride solution was added to quench the reaction, filtered, washed, and dried to yield compound 97d (2.2 g).

[0497] MS (ESI, [M+H] + )m / z:181.2.

[0498] Example 1: Preparation of Compound I-86

[0499] Step A: Preparation of compound 86a

[0500] Compound 85a (36.0 g), 2,5-dihydrofuran-3-naphthalene borate (33.0 g), 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (8.72 g), sodium carbonate (22.6 g), water (100.0 mL), and 1,4-dioxane (400.0 mL) were added sequentially to a reaction flask. After addition, the reaction was stirred at 90°C. TLC was monitored 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 afford compound 86a (15.0 g).

[0501] MS (ESI, [M+H]+ )m / z:327.3.

[0502] Step B: Preparation of compound 86b

[0503] Compound 86a (15.0 g), 10 wt% palladium hydroxide on carbon (15.0 g), and methanol (50.0 mL) were added sequentially to a reaction flask. The reaction was stirred at 90°C. TLC was monitored 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).

[0504] MS (ESI, [M+H] + )m / z:329.1.

[0505] Step C: Preparation of compound 86c

[0506] Compound 86b (10.0 g), dichloromethane (10.0 mL), and trifluoroacetic acid (33.8 mL) were added sequentially to the reaction flask. The reaction was stirred at room temperature. TLC was used to monitor the reaction until complete. Saturated sodium bicarbonate solution was added to the reaction solution to adjust the pH to approximately 10. 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 afford compound 86c (6.50 g).

[0507] MS (ESI, [M+H] + )m / z:229.0.

[0508] Step D: Preparation of compound 86d

[0509] Compound 86c (6.50 g), acetonitrile (50.0 mL), tert-butyl nitrite (2.0 g), and copper bromide (5.68 g) were added sequentially to a reaction flask. After addition, the reaction was stirred at 60°C. TLC was monitored until the reaction was complete. Saturated sodium bicarbonate solution was added to the reaction solution to adjust the pH to approximately 10. Extraction was performed with ethyl acetate. The organic phase was dried, filtered, concentrated, and purified by silica gel column chromatography (dichloromethane / methanol = 2 / 1) to afford compound 86d (3.8 g).

[0510] MS (ESI, [M+H] + )m / z:292.1.

[0511] Step E: Preparation of compound 86e

[0512] Compound 86d (3.7 g), tetrahydrofuran (50.0 mL), and lithium borohydride (0.6 g) were added sequentially to a reaction flask at 0°C. After addition, the atmosphere was replaced with nitrogen and the reaction was stirred at 0°C. TLC was performed to monitor the reaction until completion. Saturated ammonium chloride solution was added to the reaction solution to quench the reaction, followed by extraction with dichloromethane. The organic phase was separated, dried, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to afford compound 86e (3.4 g).

[0513] MS (ESI, [M+H] + )m / z:264.2.

[0514] Step F: Preparation of compound 86f

[0515] Compound 86e (3.4 g), dichloromethane (100.0 mL), and Dess-Martin reagent (6.4 g) were added sequentially to a reaction flask 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 completion. Saturated sodium bicarbonate solution was added to the reaction solution to adjust the pH to approximately 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 afford compound 86f (1.3 g).

[0516] MS (ESI, [M+H] + )m / z:262.0.

[0517] Step G: Preparation of compound 86g

[0518] To a reaction flask 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 sequentially. 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. Saturated sodium bicarbonate solution was added to the reaction solution to adjust the pH to approximately 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 afford compound 86f (1.3 g).

[0519] MS (ESI, [M+H] + )m / z:277.2.

[0520] Step H: Preparation of compound 86h

[0521] Compound 86g (1.3 g), dichloromethane (100.0 mL), triethylamine (0.7 g), and di-tert-butyl dicarbonate (1.3 g) were added sequentially to the reaction flask. The reaction mixture was stirred at room temperature. TLC was monitored until the reaction was complete. 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).

[0522] MS (ESI, [M+H] + )m / z:377.3.

[0523] Step I: Preparation of compound 86i

[0524] Compound 85k (0.3 g), compound 86h (0.3 g), 1,4-dioxane (20.0 mL), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.1 g), cesium carbonate (0.9 g), and tris(dibenzylideneacetone)dipalladium (0.1 g) were added sequentially to a reaction flask. The reaction was stirred at 110°C. TLC was used to monitor the reaction until completion. The reaction solution was filtered and concentrated. Purification by silica gel column chromatography (dichloromethane / methanol = 30 / 1) afforded compound 86i (0.4 g).

[0525] MS (ESI, [M+H] + )m / z:701.1.

[0526] Step J: Preparation of Compound I-86

[0527] 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, 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 it to alkaline (pH about 9), and 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).

[0528] MS (ESI, [M+H] + )m / z:501.2.

[0529] 1 H NMR (500MHz, CDCl3) 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=7.5Hz,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,4 H), 2.45 (s, 3H), 2.41 (dt, J = 8.0, 4.1Hz, 1H), 1.96 (dq, J = 12.7, 7.6Hz, 1H).

[0530] Example 2: Preparation of Compound I-87

[0531] Step A: Preparation of compound 87a

[0532] To a reaction flask, ethyl 6-bromo-3-methoxy-2-pyridinecarboxylate (1.5 g) and tetrahydrofuran (50 mL) were added sequentially. After addition, a 2 M solution of lithium borohydride in tetrahydrofuran (8 mL) was slowly added dropwise under nitrogen at -15°C. The temperature was slowly warmed to room temperature and stirred. The reaction was monitored by TLC until completion. Saturated ammonium chloride solution was added to quench the reaction, which was then filtered, washed, and dried to yield compound 87a (1.28 g).

[0533] MS (ESI, [M+H] + )m / z:218.1.

[0534] Step B: Preparation of compound 87b

[0535] To a reaction flask, compound 87a (1.2 g), methanesulfonic anhydride (1 g), triethylamine (3.57 g), and dichloromethane (30 mL) were added sequentially. The reaction was allowed to proceed at -15°C for 1 h. TLC was used to monitor the reaction until completion. A solution of dimethylamine in tetrahydrofuran (30 mL, 2 M) was then slowly added dropwise. The reaction was continued with stirring at -15°C. TLC was used to monitor the reaction until completion. The product was extracted with ethyl acetate. 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 afford compound 87b (1.02 g).

[0536] MS (ESI, [M+H] + )m / z:245.1.

[0537] Step C: Preparation of compound 87c

[0538] To a reaction flask, 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 sequentially. The reaction was stirred and heated at 90°C under nitrogen. TLC was used to monitor the reaction until completion. The reaction solution was filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 50 / 1) to afford compound 87c (0.3 g).

[0539] MS (ESI, [M+H] + )m / z:569.6.

[0540] Step D: Preparation of Compound I-87

[0541] 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, 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).

[0542] MS (ESI, [M+H] + )m / z:469.2.

[0543] 1 H NMR (500MHz, CDCl3:CD3OD=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).

[0544] Example 3: Preparation of Compound I-88

[0545] Step A: Preparation of intermediate 88a

[0546] 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), and 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (1.36 g) were added to a reaction flask in this order. After the addition, 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 give compound 88a (2.01 g).

[0547] MS (ESI, [M+H] + )m / z:388.3.

[0548] Step B: Preparation of compound 88b

[0549] Compound 88a (2.0 g), tetrahydrofuran (15.0 mL), methanol (15.0 mL), and 10% palladium hydroxide on carbon (2.0 g) were added sequentially to a reaction flask. After addition, the atmosphere was replaced with hydrogen and the reaction was stirred at room temperature. TLC was used to monitor the reaction until completion. The reaction mixture was filtered and concentrated to afford compound 88b (1.75 g).

[0550] MS (ESI, [M+H] + )m / z:390.5.

[0551] Step C: Preparation of compound 88c

[0552] 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 reaction 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).

[0553] MS (ESI, [M+H] + )m / z:322.4.

[0554] Step D: Preparation of compound 88d

[0555] To a reaction flask, compound 3A-2 (0.54 g), compound 88c (0.51 g), 1,4-dioxane (10.0 mL), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.15 g), cesium carbonate (1.27 g), and tris(dibenzylideneacetone)dipalladium (0.18 g) were added sequentially. After the addition, the atmosphere was purged with nitrogen and the reaction was stirred at 110°C. The reaction was monitored by TLC until completion. The reaction solution was filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 50 / 1) to afford compound 88d (0.65 g).

[0556] MS (ESI, [M+H] + )m / z:587.1.

[0557] Step E: Preparation of compound 88e

[0558] Compound 88d (0.65 g), potassium acetate (0.20 g), pinacol diboronate (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 a reaction flask in this order. After the addition, the atmosphere was purged with nitrogen and the reaction was stirred at 90°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 = 50 / 1) to afford compound 88e (250 mg).

[0559] MS (ESI, [M+H] + )m / z:679.1.

[0560] Step F: Preparation of compound 88f

[0561] 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 sequentially to a reaction flask. After the addition, the reaction was stirred at 110°C. TLC was monitored 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 afford compound 88f (150 mg).

[0562] MS (ESI, [M+H] + )m / z:709.1.

[0563] Step G: Preparation of compound I-88

[0564] Compound 88f (150 mg), a 1,4-dioxane solution of hydrogen chloride (4 M, 2.1 mL), and dichloromethane (3 mL) were added to the reaction flask in this order. After the addition was complete, the reaction was allowed to react at room temperature and monitored by TLC until the reaction was complete. The reaction solution was adjusted to alkaline (pH approximately 9) by adding saturated aqueous sodium bicarbonate solution, and 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).

[0565] MS (ESI, [M+H] + )m / z:509.2.

[0566] 1H NMR (500MHz, CDCl3) δ9.74(s,1H),8.69(d,J=8.5Hz,1H),8.38(d,J=7.5Hz,1H),8.00(s,1H),7.6 8–7.58(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).

[0567] Example 4: Preparation of Compound I-89

[0568] Step A: Preparation of compound 89a

[0569] To a 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 sequentially. The reaction was stirred at 85°C under nitrogen. The reaction was monitored by TLC until completion, and the reaction solution was concentrated. Compound 89a (90 mg) was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to afford compound 89a.

[0570] MS (ESI, [M+H] + )m / z:623.4.

[0571] Step B: Preparation of Compound I-89

[0572] To the reaction flask, compound 89a (90 mg), a 1,4-dioxane solution of hydrochloric acid (4 M, 1.0 mL), and dichloromethane (4 mL) were added in sequence. After the addition, the reaction was allowed to react at room temperature and monitored by TLC until the reaction was complete. The reaction solution was adjusted to alkaline (pH approximately 9) by adding saturated aqueous sodium bicarbonate solution, and 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).

[0573] MS (ESI, [M+H] + )m / z:523.2.

[0574] 1 H NMR (500MHz, CDCl3) δ8.79–8.68(m,1H),8.13(t,J=4.6Hz,1H),7.66(dd,J=8.6,4.2Hz,1H),7.5 5–7.46(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).

[0575] Example 5: Preparation of Compound I-90

[0576] Step A: Preparation of compound 90a

[0577] To a reaction flask containing 6-bromo-3-fluoro-2-pyridinecarboxaldehyde (1.0 g) and methanol (15 mL) was added sodium borohydride (0.28 g) portionwise at 0°C. After addition, the mixture was allowed to react at room temperature. TLC monitored the reaction until completion. Saturated aqueous ammonium chloride was added to quench the reaction, and ethyl acetate was added for extraction. The organic phase was separated, dried, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8 / 2) to afford compound 90a (0.65 g).

[0578] MS (ESI, [M+H] + )m / z:205.9.

[0579] Step B: Preparation of compound 90b

[0580] Compound 90a (0.31 g), compound 85k (0.50 g), 1,4-dioxane (20.0 mL), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.15 g), cesium carbonate (1.2 g), and tris(dibenzylideneacetone)dipalladium (0.11 g) were added sequentially to a reaction flask. After addition, the reaction was stirred at 100°C. TLC was monitored until the reaction was complete. The reaction solution was filtered and concentrated. Purification by silica gel column chromatography (dichloromethane / methanol = 30 / 1) afforded compound 90b (0.7 g).

[0581] MS (ESI, [M+H] + )m / z:530.2.

[0582] Step C: Preparation of compound 90c

[0583] Compound 90b (0.2 g), dichloromethane (5 mL), N,N-diisopropylethylamine (0.15 mL), and methanesulfonic anhydride (0.16 g) were added sequentially to the reaction flask under an ice-water bath. The reaction was allowed to react under an ice-water bath. TLC was used to monitor the reaction until completion. A 2 M solution of dimethylamine in tetrahydrofuran (5 mL) was then slowly added. The reaction was allowed to react at room temperature and monitored by TLC until completion. 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).

[0584] MS (ESI, [M+H] + )m / z:557.3.

[0585] Step D: Preparation of Compound I-90

[0586] Compound 90c (0.1 g), methanesulfonic acid (1.2 mL), and dichloromethane (10 mL) were added to the reaction flask in this order. After the addition, the mixture was reacted at room temperature and monitored by TLC until the reaction was complete. The reaction solution was adjusted to alkaline (pH approximately 9) by adding saturated aqueous sodium bicarbonate solution 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-90 (30 mg).

[0587] MS (ESI, [M+H] + )m / z:457.2.

[0588] 1 H NMR (500MHz, CDCl3) 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).

[0589] Example 6: Preparation of Compound I-91

[0590] Step A: Preparation of compound 91a

[0591] To the reaction flask, 6-chloro-3-formyl-2-methylpyridine (2.0 g) and dichloromethane (60 mL) were added sequentially. After addition, diethylaminotrifluoride (3.11 g) was slowly added dropwise at 0°C. After addition, the mixture was slowly warmed to room temperature and stirred. TLC was used to monitor the reaction until completion. Water was added to quench the reaction mixture, and the mixture was extracted with dichloromethane. 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).

[0592] MS (ESI, [M+H] + )m / z:178.0.

[0593] Step B: Preparation of compound 91b

[0594] To a reaction flask, compound 91a (2.0 g), N-bromosuccinimide (2.3 g), dibenzoyl peroxide (0.27 g), and 1,2-dichloroethane (60 mL) were added sequentially. After addition, the mixture was stirred under nitrogen at 90°C. TLC was used to monitor the reaction until completion. Saturated sodium thiosulfate solution was added to the reaction mixture to quench the reaction. The mixture was extracted with dichloromethane, and the organic phase was separated, dried, filtered, and concentrated to afford compound 91b (2.3 g).

[0595] MS (ESI, [M+H] + )m / z:256.1.

[0596] Step C: Preparation of compound 91c

[0597] Compound 91b (2.3 g), sodium carbonate (0.32 g), dichloromethane (0.3 g), and a 4 M dimethylamine ethanol solution (1 mL) were added sequentially to a reaction flask. The reaction mixture was stirred at room temperature. TLC was used to monitor the reaction until completion. 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).

[0598] MS (ESI, [M+H] + )m / z:221.4.

[0599] Step D: Preparation of compound 91d

[0600] To a reaction flask, 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 sequentially. Under nitrogen, the reaction was stirred and heated at 110°C. TLC was monitored until the reaction was complete. The reaction solution was filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 50 / 1) to afford compound 91d (0.1 g).

[0601] MS (ESI, [M+H] + )m / z:589.2.

[0602] Step E: Preparation of Compound I-91

[0603] 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, 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 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 give compound I-91 (0.04 g).

[0604] MS (ESI, [M+H] + )m / z:489.1.

[0605] 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).

[0606] Example 7: Preparation of Compound I-92

[0607] Step A: Preparation of compound 92a

[0608] To a 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 sequentially. After the addition, the atmosphere was replaced with nitrogen, and the reaction was stirred at 100°C. The reaction was monitored by TLC until completion, filtered, and concentrated. The residue was purified by column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound 92a (1.0 g).

[0609] MS (ESI, [M+H] + )m / z:507.3.

[0610] Step B: Preparation of compound 92b

[0611] To a reaction flask, compound 92a (1.0 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.31 g), pinacol diboron (0.75 g), potassium carbonate (0.58 g), and 1,4-dioxane (20 mL) were added sequentially. After addition, the mixture was stirred at 90°C under nitrogen atmosphere. The reaction was monitored by TLC until completion, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to afford compound 92b (0.82 g).

[0612] MS (ESI, [M+H] + )m / z:599.3.

[0613] Step C: Preparation of compound 92c

[0614] To a reaction flask, 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 sequentially. After addition, the mixture was stirred at 85°C under nitrogen atmosphere. The reaction was monitored by TLC until completion, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound 92c (0.11 g).

[0615] MS (ESI, [M+H] + )m / z:630.3.

[0616] Step D: Preparation of compound 92d

[0617] Compound 92c (0.11 g), dichloromethane (10 mL), and 1,4-dioxane hydrochloride solution (2 mL, 4 M) were added sequentially to a reaction flask and stirred at room temperature. TLC was used to monitor the reaction until completion. The reaction mixture was adjusted to alkaline (pH approximately 9) by adding saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to afford compound 92d (50 mg).

[0618] HRMS (ESI, [M+H] + )m / z:530.2793.

[0619] Step E: Preparation of Compound I-92

[0620] 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 the mixture was concentrated to afford compound I-92 (40 mg).

[0621] MS (ESI, [M+H] + )m / z:530.2.

[0622] 1 H NMR(500MHz,DMSO-d6)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).

[0623] Example 8: Preparation of Compound I-93

[0624] Step A: Preparation of compound 93a

[0625] Compound 16c (0.43 g), dichloromethane (30 mL), triethylamine (0.358 g), and methanesulfonic anhydride (0.603 g) were added sequentially to a reaction flask at -10°C. After addition, the reaction was stirred at 0°C. TLC was used to monitor the reaction until completion. The reaction solution was then added dropwise to a solution of deuterated dimethylamine hydrochloride (0.358 g) and sodium hydroxide (0.554 g) in dichloromethane (30 mL) at -10°C. After addition, the reaction was stirred at room temperature. TLC was used to monitor the reaction until completion. 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).

[0626] MS (ESI, [M+H] + )m / z:344.2.

[0627] Step B: Preparation of compound 93b

[0628] Compound 93a (0.4 g), dichloromethane (10 mL), and a 4 M solution of hydrochloric acid in 1,4-dioxane (20 mL) were added sequentially to a reaction flask. The reaction was stirred at room temperature. TLC was used to monitor the reaction until completion. The reaction solution was concentrated and adjusted to alkaline (pH approximately 9) by adding saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane. The organic phase was dried, filtered, and the solvent was removed by vacuum drying to afford compound 93b (0.33 g).

[0629] MS (ESI, [M+H] + )m / z:244.2.

[0630] Step C: Preparation of compound 93c

[0631] To a reaction flask, intermediate 3A-2 (564 mg), 4,5-bis(diphenylphosphino-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) were added sequentially. After addition, the mixture was stirred at 100°C under nitrogen atmosphere. The reaction was monitored by TLC until completion. The reaction solution was filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain compound 93c (0.55 g).

[0632] MS (ESI, [M+H] + )m / z:509.3.

[0633] Step D: Preparation of compound 93d

[0634] To a reaction flask, 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), pinacol diboron (0.41 g), potassium carbonate (0.32 g), and 1,4-dioxane (10 mL) were added sequentially. After addition, the mixture was stirred at 90°C under nitrogen atmosphere. The reaction was monitored by TLC until completion. The reaction solution was filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to afford compound 93d (0.28 g).

[0635] MS (ESI, [M+H] + )m / z:601.4.

[0636] Step E: Preparation of compound 93e

[0637] To a reaction flask, 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 sequentially. After addition, the mixture was stirred at 85°C under nitrogen atmosphere. The reaction was monitored by TLC until completion, and the reaction solution was filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to afford compound 93e (0.12 g).

[0638] MS (ESI, [M+H] + )m / z:632.4.

[0639] Step F: Preparation of compound 93f

[0640] Compound 93e (0.10 g), dichloromethane (10 mL), and 1,4-dioxane hydrochloride solution (2 mL, 4 M) were added sequentially to a reaction flask and stirred at room temperature. TLC was used to monitor the reaction until completion. The reaction mixture was adjusted to alkaline (pH approximately 9) by adding saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to afford compound 93f (30 mg).

[0641] MS (ESI, [M+H] + )m / z:532.3.

[0642] Step G: Preparation of Compound I-93

[0643] 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 the mixture was concentrated to afford compound I-93 (30 mg).

[0644] MS (ESI, [M+H] + )m / z:532.3.

[0645] 1 H NMR (500MHz, DMSO-d6) δ10.06(s,1H),9.78(s,1H),8.86(d,J=3.1Hz,2H),8.50(d,J= 8.4Hz,1H),8.17–8.08(m,2H),7.81(d,J=8.6Hz,1H),7.75(d,J=8.5Hz,1H),7.21(d, J=8.6Hz,1H),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).

[0646] Example 9: Preparation of Compound I-94

[0647] Step A: Preparation of compound 94a

[0648] To a reaction flask, 4-methyl-1,4-azaphosphane 4-oxide (2.0 g), 2-chloro-5-fluoropyridine-6-carbaldehyde (2.1 g), potassium carbonate (4.6 g), and N,N-dimethylformamide (20 mL) were added sequentially. After addition, the mixture was stirred at 80°C. The reaction was monitored by TLC until completion. The reaction solution was filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to afford compound 94a (2.0 g).

[0649] MS (ESI, [M+H] + )m / z:273.0.

[0650] Step B: Preparation of compound 94b

[0651] To a reaction flask, 94a (2.0 g), THF (20 mL), and a 2M solution of dimethylamine in tetrahydrofuran (5.5 mL) were added sequentially. After addition, the mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to 0°C, and sodium cyanoborohydride (1.2 g) was added portionwise. After addition, the mixture was brought to room temperature. TLC was monitored until the reaction was complete. Saturated ammonium chloride solution was added dropwise to quench the reaction, and the reaction mixture was concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 5 / 1) to afford compound 94b (1.5 g).

[0652] MS (ESI, [M+H] + )m / z:302.1.

[0653] Step C: Preparation of compound 94c

[0654] To a reaction flask, 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 sequentially. After addition, the mixture was stirred at 100°C under nitrogen atmosphere. The reaction was monitored by TLC until completion, and the reaction solution was filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound 94c (85 mg).

[0655] MS (ESI, [M+H] + )m / z:670.4.

[0656] Step D: Preparation of compound 94d

[0657] Compound 94c (85 mg), dichloromethane (10 mL), and 1,4-dioxane hydrochloride solution (2 mL, 4 M) were added sequentially to a reaction flask and stirred at room temperature. TLC was used to monitor the reaction until completion. The reaction mixture was adjusted to alkaline (pH approximately 9) by adding saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to afford compound 94d (18 mg).

[0658] MS (ESI, [M+H] + )m / z:570.2.

[0659] Step E: Preparation of Compound I-94

[0660] 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 the mixture was concentrated to afford compound I-94 (19 mg).

[0661] MS (ESI, [M+H] + )m / z:570.2.

[0662] Example 10: Preparation of Compound I-95

[0663] Step A: Preparation of compound 95a

[0664] 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 sequentially to a reaction flask. After addition, the mixture was stirred at 85°C under nitrogen atmosphere. The reaction was monitored by TLC until completion, and the mixture was concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to afford compound 95a (84 mg).

[0665] MS (ESI, [M+H] + )m / z:626.39.

[0666] Step B: Preparation of compound 95b

[0667] Compound 95a (84 mg), methanesulfonic acid (1.2 mL), and dichloromethane (10 mL) were added sequentially to a reaction flask. After the addition, 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 pH to approximately 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).

[0668] HRMS (ESI, [M+H] + )m / z:526.2537.

[0669] Step C: Preparation of Compound I-95

[0670] Compound 95b (23 mg), dichloromethane (2.00 mL), and 1,4-dioxane hydrochloride solution (0.09 mL, 0.5 M) (2 mg) were added sequentially to the reaction flask. The reaction was allowed to react at room temperature. TLC was used to monitor the reaction until completion. The mixture was concentrated to afford compound I-95 (24 mg).

[0671] MS (ESI, [M+H] + )m / z:526.2.

[0672] 1 H NMR(500MHz,DMSO-d6)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).

[0673] Example 11: Preparation of Compound I-96

[0674] Step A: Preparation of compound 96a

[0675] To the reaction flask, 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 sequentially. After addition, the reaction was stirred at room temperature. The reaction was monitored by TLC until completion, and the product was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to afford compound 96a (10 g).

[0676] MS (ESI, [M+H] + )m / z:347.39.

[0677] Step B: Preparation of compound 96b

[0678] To a reaction flask were added intermediate 1A-7 (1.3 g), 4,5-bis(diphenylphosphino)-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 addition, the atmosphere was replaced with nitrogen and the reaction was stirred at 100°C. The reaction was monitored by TLC until completion, and the product was concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to afford compound 96b (1.1 g).

[0679] MS (ESI, [M+H] + )m / z:502.2.

[0680] Step C: Preparation of compound 96c

[0681] 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 sequentially to a reaction flask. After the addition, the atmosphere was replaced with nitrogen and the reaction was stirred at 90°C. The reaction was monitored by TLC until completion, and the product was concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to afford compound 96c (1.3 g).

[0682] MS (ESI, [M+H] + )m / z:594.3.

[0683] Step D: Preparation of compound 96d

[0684] 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 sequentially to a reaction flask. After addition, the mixture was stirred at 85°C under nitrogen atmosphere. The reaction was monitored by TLC until completion, and the mixture was concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to afford compound 96d (90 mg).

[0685] MS (ESI, [M+H] + )m / z:625.4.

[0686] Step E: Preparation of Compound I-96

[0687] Compound 96d (90 mg), methanesulfonic acid (1.2 mL), and dichloromethane (10 mL) were added sequentially to a reaction flask. After addition, the mixture was reacted at room temperature and monitored by TLC until completion of the reaction. Saturated aqueous sodium bicarbonate solution was added to the reaction solution to adjust the pH to approximately 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-96 (30 mg).

[0688] MS (ESI, [M+H] + )m / z:525.3.

[0689] Example 12: Preparation of Compound I-97

[0690] Step A: Preparation of compound 97a

[0691] To a reaction flask, 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 sequentially. After the addition, the atmosphere was replaced with nitrogen 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 afford compound 97a (0.98 g).

[0692] MS (ESI, [M+H] + )m / z:447.2.

[0693] Step B: Preparation of Intermediate 97b

[0694] Compound 97a (0.98 g), a 4M solution of hydrogen chloride in 1,4-dioxane (10.9 mL), and dichloromethane (10 mL) were added sequentially to a reaction flask. The reaction was stirred at room temperature. TLC was used to monitor the reaction until completion. Saturated aqueous sodium bicarbonate was added to the reaction solution, which was adjusted to alkaline (pH approximately 9). 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 afford compound 97b (0.53 g).

[0695] MS (ESI, [M+H] + )m / z:283.3.

[0696] Step C: Preparation of compound 97c

[0697] To a reaction flask were added compound 97b (0.5 g), 4,5-bis(diphenylphosphino-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) in sequence. After addition, the atmosphere was replaced with nitrogen and the reaction was stirred at 100°C. The reaction was monitored by TLC until completion, and the product was concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to afford compound 97c (0.4 g).

[0698] MS (ESI, [M+H] + )m / z:549.2.

[0699] Step D: Preparation of compound 97e

[0700] 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 sequentially to a reaction flask. The reaction was stirred at 85°C under nitrogen. The reaction was monitored by TLC until completion, and the product was concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to afford compound 97e (0.44 g).

[0701] MS (ESI, [M+H] + )m / z:649.3.

[0702] Step E: Preparation of Compound I-97

[0703] Compound 97e (100 mg), methanesulfonic acid (1.2 mL), and dichloromethane (10 mL) were added to the reaction flask in sequence. After the addition, 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).

[0704] MS (ESI, [M+H] + )m / z:549.2.

[0705] Experimental Example 1 HPK1 in vitro kinase inhibitory activity assay

[0706] Kinase buffer was diluted 5× to 1× and supplemented with 10 mM MgCl2, 1 mM DTT, and 0.005% Tween 20. A 100 ng / μL stock solution of HPK1 (Life Technologies) was prepared in kinase buffer to a 1.67× working solution of 1.67 ng / μL (final concentration 1 ng / μL). 6 μL was plated per well in a 384-well plate. Compounds dissolved in DMSO were added to the wells using a nanoliter pipette to achieve a final concentration of 1000 nM to 0.244 nM in a 4-fold gradient, for a total of 7 concentrations. Blank control wells (without enzyme) and negative control wells (with enzyme and DMSO) were also established, with duplicate wells. 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 in 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 the 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 was calculated by four-parameter fitting. 50 The results are shown in Table 1 below:

[0707] Table 1 In vitro enzyme inhibition activity results of each compound

[0708] The results indicate that the compounds of the present disclosure have improved or superior inhibitory effects on HPK1 kinase.

[0709] Experimental Example 2 In vitro cell inhibitory activity assay

[0710] 2.1 Detection of p-SLP76 phosphorylation inhibitory activity in Jurkat cells

[0711] Take Jurkat cells that are in good growth condition, collect them into a centrifuge tube, centrifuge and resuspend them, and adjust the cell density to 6.25×10 6Cells were plated at 400 μg / mL in a 384-well small-volume white plate (8 μL / well). Different compounds dissolved in DMSO were added to the wells using a nanoliter pipette to a final concentration of 2500 nM to 10.29 nM. Two replicate wells were used, and a control was set up. After 1 hour of cell culture, the stimulator CD3CD28 (manufacturer: stemcell, 4 μL) was added and incubated at 37°C for 30 minutes. 3 μL of lysis buffer (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 prepared in detection buffer (manufacturer: BioAuxilium) were added and incubated at room temperature overnight. The cells were detected using a PerkinElmer Envision multi-function microplate reader (excitation 320 nm, emission 615 nm / 665 nm). Four-parameter fitting was used to calculate the IC 50 The experimental results are shown in Table 2.

[0712] Table 2 In vitro cell inhibition activity results of each compound

[0713] Where A represents IC 50 <50nM; B indicates 50nM≤IC 50 <100nM.

[0714] According to the above results, the compounds disclosed herein have improved or excellent Jurkat cell p-SLP76 phosphorylation inhibitory activity.

[0715] Experimental Example 3 In vitro metabolic stability of liver microsomes

[0716] Liver microsomal incubation samples were prepared by mixing PBS buffer (pH 7.4), liver microsomal solution (0.5 mg / mL), test compound, and NADPH+MgCl₂ solution at 37°C and 300 rpm for 1 hour. Hour 0 samples were prepared by mixing PBS buffer (pH 7.4), liver microsomal solution (0.5 mg / mL), and test compound. Protein precipitation was performed with acetonitrile containing an internal standard to prepare the supernatant, which was diluted and used for LC / MS / MS analysis. Results for selected compounds are shown in Table 3.

[0717] Table 3 In vitro liver microsome stability results

[0718] The experimental results show that the compounds disclosed herein are relatively stable in vitro.

[0719] Experimental Example 4 In vivo pharmacokinetics

[0720] 4.1 Pharmacokinetic study in mice

[0721] ICR mice weighing 21-23 g were acclimated for 3-5 days and randomly divided into groups of 9. Each group was orally administered with a solution of the compound of the present invention at a dose of 10 mg / kg. The solvent for the orally administered group was DMSO:HS15:0.5 mg / mL citrate glucose solution in a ratio of 5:20:75. The intravenous administration of a solution of the compound of the present invention at a dose of 1 mg / kg was performed. The solvent for the intravenous administration group was DMSO:Ethanol:EL:D5W in a ratio of 1.5:2:4:92.5.

[0722] 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, and the time points for gavage 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.

[0723] 30 μL of plasma sample to be tested and standard curve sample were taken, and acetonitrile solution containing internal standard was added to obtain protein precipitation to obtain supernatant, which was diluted and used for LC / MS / MS determination.

[0724] The experimental results show that the disclosed compounds have good pharmacokinetic properties in vivo.

[0725] Experimental Example 5 In vivo efficacy evaluation

[0726] 5.1 Pharmacodynamic evaluation of the compound in a CT26 murine colon cancer subcutaneous transplant tumor model in BALB / c mice

[0727] CT26 cells were inoculated subcutaneously in the right axilla of SPF female BALB / c mice (source: Shanghai Lingchang Biotechnology Co., Ltd.) at a rate of 3 × 10 5 When the average tumor volume reaches 150mm 3 When about 30 seconds, divide the animals into groups.

[0728] The day of grouping was designated Day 0. Starting from Day 0, the compounds of the present disclosure were administered orally once daily. Tumor volume was measured twice weekly, and mice were weighed and recorded. General performance of the mice was observed and recorded daily. At the end of the experiment, tumors were removed, weighed, and photographed.

[0729] The detection indicators and calculation formulas are as follows:

[0730] 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.

[0731] Relative tumor volume, RTV = TV t / TV0; TV0 is the tumor volume on day 0, TV tis the tumor volume at each measurement.

[0732] Relative tumor growth rate, T / C (%) = T RTV / C RTV ×100%; where T RTV RTV for the treatment group; C RTV The vehicle control group was RTV.

[0733] Tumor growth inhibition rate, TGI (%) = (1-TW / TW0) × 100%; wherein, TW is the tumor weight of the treatment group, and TW0 is the tumor weight of the vehicle control group.

[0734] Body weight change rate, WCR (%) = (Wt t -Wt0) / Wt0×100%; where Wt0 is the weight of mice on day 0, Wt t is the weight of the mice at each measurement.

[0735] The compounds disclosed herein have good in vivo efficacy (for example, the compounds disclosed herein can inhibit tumor weight in mice by more than 30% after 14 days at a dosage of 37.5 mpk).

Claims

1. A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, in, X 1 Select from N or CR x ; X 2 Select from N or CR z ; R x and R z are each independently selected from hydrogen, deuterium, -NH2, -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 the -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; Y is selected from a bond, -O-, -S-, -NR a -, -C(R a )2-, -C(R a )2N(R a )-, -S(O)2-, -S(O)-, -C(O)-, -C(O)O-, -C(O)NR a (R a )O-, -OC(O)-, -OC(O)NR a (R a )C(O)O- or -N(R a )C(O)-; Ring A is selected from 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; Every R 1 Each independently selected from -NH2, -NO2, -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、-NHSO2(R d )、-SO2(R d )、-SO2NH(R d )、-SO2N(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 heterocyclyl, 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 heterocyclic group is optionally substituted by one or more R b replace; Every R d are each independently selected from hydrogen, 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 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 Optionally one or more R c replace; The condition is that when R 2 When X is a bicyclic group, 2 is N, and has at least 1 R 1 Selected from -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 , 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 replaced by one or more R b replace; Every R 3 Each independently selected from deuterium, -NH2, -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 the -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; R 4 Selected from hydrogen, deuterium, C 1-4 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein the 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; Every R a are each independently selected from hydrogen, deuterium, halogen, -CN, C 1-4 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein the 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; Every R b Each independently selected from deuterium, -NH2, -NO2, -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, -OH, -OC 1-4 Alkyl, -SC 1- 4Alkyl, -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 the -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; Every R c Each independently selected from deuterium, -NH2, -NO2, -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 the -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 , R a , R b , R c or R d each independently optionally substituted with one or more other substituents; Optionally, the pharmaceutically acceptable salt is a hydrochloride salt.

2. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein X 1 Selected from CR x , and X 2 is N; Or, X 1 is N, and X 2 Selected from CR z ; Or, X 1 Selected from CR x , and X 2 Selected from CR z ; Or, X 1 and X 2 All are CH; Or, X 1 is CH, and X 2 is N; Or, X 1 is N, and X 2 for CH; Optionally, R x and R z are each independently selected from hydrogen, deuterium, -NH2, -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; Or, R x and R z are each independently selected from hydrogen or C 1-3 alkyl; Or, R x and R z are each independently hydrogen.

3. The compound according to claim 1 or 2, its stereoisomer or a 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 R a are each independently selected from hydrogen or C 1-3 Alkyl; or, each R a are each independently selected from hydrogen or methyl; or, R a For hydrogen.

4. 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.

5. The compound according to any one of claims 1 to 4, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein each R 1 Each independently selected from -NH2, -NH(R d )、-N(R d )2, halogen, -N(R d )C(O)(R d )、-NHSO2(R d )、-SO2NH(R d )、PO(R d )2. C 1-6 Alkyl, -OC 1-6 alkyl, 5-8 membered heteroaryl or 3-10 membered heterocyclic group 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 heterocyclic group containing 1-3 heteroatoms selected from N, O, S or P, optionally substituted by one or more R b replace; Or, each R 1 Each independently selected from -NH2, -NH(R d )、-N(R d )2.-OR d , halogen, -N(R d )C(O)(R d )、-NHSO2(R d )、-SO2NH(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 replace; Or, each R 1 are each independently selected from halogen, C 1-4 Alkyl, -OC 1-3 alkyl or 5-6 membered heterocycloalkyl, wherein the C 1-4 The alkyl or 5-6 membered heterocycloalkyl group is optionally substituted with one or more R b replace; Or, each R 1 are each independently selected from halogen, -NH2, -NH(R d )、-N(R d )2.-OR d , C 1-6 Alkyl, 5-9 membered heterocyclic group, wherein the C 1-6 The alkyl or 5-9 membered heterocyclic group is optionally substituted with one or more R b replace; Or, each R 1 Each is independently selected from -NH2, -NHCH3, -N(CH3)2, F, Cl, Br, -OCH3, -OCH2CH3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phosphanidic acid bis-heterocyclohexyl 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, tetrahydrothienyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phosphanidic acid bis-heterocyclohexyl or a 9-membered heterocycloalkyl containing 3 heteroatoms selected from N or O is optionally replaced by one or more R b replace; Or, each R 1 Each is independently selected from -NH2, F, methyl, -OCH3, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, The methyl, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, Optional 1, 2 or 3 R b replace; Or, each R 1 Each independently selected from F, methyl, -OCH3, tetrahydrofuranyl, tetrahydropyranyl, or The methyl, tetrahydrofuranyl, tetrahydropyranyl or Optional 1, 2 or 3 R b replace; Or, each R 1 Each independently selected from F, methyl, -OCH3, -CHF2, Optionally, n is selected from 1, 2 or 3; Alternatively, n is selected from 1 or 2; Alternatively, n is 2.

6. The compound according to any one of claims 1 to 5, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Every R d Each 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 with one or more deuterium, halogen or Substituent substitution; Or, each R d Each independently selected from C 1-4 Alkyl or C 3-6 Cycloalkyl, the C 1-4 Alkyl or C 3-6 The cycloalkyl group is optionally substituted with one or more deuterium, halogen or Substituent substitution; Or, each R d Each independently selected from C 1-4 Alkyl or C 3-6 Cycloalkyl; Or, each R d Each is independently selected from methyl, ethyl, n-propyl or isopropyl.

7. 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 Optionally one or more R c replace; Or, R 2 A 9-, 10-, 11-, or 12-membered partially saturated or aromatic bicyclic group; Or, R 2 is selected from 8-12 membered partially saturated or aromatic bicyclic groups, X 2 is N, and has at least 1 R 1 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 Optionally one or more R c The 5-8 membered heterocyclic group containing a phosphorus ring heteroatom is optionally substituted by one or more R b replace; Or, R 2 A 9-, 10-, 11-, 12-, 13-, or 14-membered partially saturated or aromatic tricyclic group, wherein the tricyclic group contains 1 to 4 heteroatoms independently selected from N, O, or S, and the R 2 Optionally one or more R c Replace; or, R 2 Selected from 9, 10, 11, 12 yuan A 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 has at least 1 R 1 is selected from -PO(CH3)2, -P(O)(CH3)NCH3, -P(O)(CH3)OCH3, or a 5-8 membered heterocycloalkyl containing a phosphorus ring heteroatom, wherein R 2 Optionally one or more R c The 5-8 membered heterocycloalkyl containing a phosphorus ring heteroatom is optionally substituted by one or more R b replace; Or, 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 Optionally one or more R c replace; Or, R 2 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 Optionally one or more R c replace; Or, 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 has at least 1 R 1 is selected from a 5-8 membered heterocycloalkyl group containing a phosphorus ring heteroatom, wherein said R 2 Optionally one or more R c The 5-8 membered heterocycloalkyl containing a phosphorus ring heteroatom is optionally substituted by one or more halogens, or C 1-3 Alkyl substitution; Or, R 2 is selected from a 9-12 membered partially saturated or aromatic bicyclic group, X 2 is N, and has at least 1 R 1 is selected from a 5-6 membered heterocycloalkyl containing a phosphorus ring heteroatom, wherein the 5-6 membered heterocycloalkyl containing a phosphorus ring heteroatom is optionally substituted by one or more halogens, or C 1-3 Alkyl substitution; Or, R 2 for X 2 is N, n is 2, and one of them is R 1 is a 6-membered heterocycloalkyl group containing nitrogen and phosphorus heteroatoms, and another R 1 is -CH2N(CH3)2, the 6-membered heterocycloalkyl containing nitrogen and phosphorus heteroatoms is optionally substituted by one or more or methyl substituted, the R 2 optionally substituted with one or more F; Or, R 2 Selected from Or, R 2 Selected from Optionally, Every R c Each independently selected from halogen, or C optionally substituted by one or more deuterium 1-6 alkyl; Or, each R c Each independently selected from halogen, or C optionally substituted by one or more deuterium 1-4 alkyl; Or, each R c Each 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; Or, each R c Each independently selected from or methyl optionally substituted by one or more deuterium; Or, each R c Each independently selected from F, Methyl or -CD3.

8. The compound according to any one of claims 1 to 7, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Every R 3 are each independently selected from halogen or C 1-4 Alkyl, wherein the C 1-4 The alkyl group is optionally substituted with one or more deuterium or halogen substituents; Or, each R 3 are each independently selected from halogen, C 1-3 Alkyl or halogenated C 1-3 alkyl; Or, each R 3 Each independently selected from F, Cl, Br or C 1-3 alkyl; Or, each R 3 Each 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 Selected from hydrogen or C 1-3 alkyl; Or, R 4 is selected from hydrogen or methyl; or R 4 For hydrogen.

9. The compound according to any one of claims 1 to 8, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein each R b Each 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 The alkyl and 3-6 membered heterocycloalkyl groups are optionally substituted with one or more deuterium, -OH, halogen or Substituent substitution; Or, each R b Each 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; Or, each R b Each 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, 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 The alkyl group is optionally substituted with one or more deuterium or -OH; Or, each R b Each independently selected from deuterium, -OH, F, -CH3, -NH(CH3), -N(CH3)2, -N(CD3)2, -CH2N(CH3)2, -C(OH)(CH3)2 or -CH2OCH3.

10. A compound according to any one of claims 1 to 9, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the following compounds of formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie) or formula (If), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: in, X 1 , X 2 , Ring A, Y, R 1 , R 2 and n as described in any one of claims 1-9.

11. 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, X 2 is selected from N or CH; Every R 1 are each independently selected from halogen, C 1-4 Alkyl, -OC 1-3 alkyl or 5-6 membered heterocycloalkyl, wherein the C 1-4 The alkyl or 5-6 membered heterocycloalkyl group is optionally substituted with one or more R b Substitution, the 5-6 membered heterocycloalkyl contains 1 or 2 heteroatoms selected from N or O, or contains 1 P=O heteroatom group; R 2 A tricyclic group selected from 12-membered aromatic groups, wherein the tricyclic group contains 2, 3 or 4 heteroatoms independently selected from N or O; Every R b are each 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; 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:

12. The compound according to claim 11, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Every R 1 Each independently selected from C 1-4 alkyl, or a 6-membered heterocycloalkyl, wherein the C 1-4 The alkyl or 6-membered heterocycloalkyl group is optionally substituted with one or more R b Substitution, 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 Each independently selected from deuterium, F, C 1-3 Alkyl, -NH(C 1-3 Alkyl) or -N(C 1-3 alkyl)2, wherein the -NH(C 1-3 Alkyl) or -N(C 1-3 alkyl)2 is optionally substituted with one or more deuterium; Or, each R b Each is independently selected from deuterium, F, methyl, -NH(CH3) or -N(CH3)2, wherein -N(CH3)2 is optionally substituted with one or more deuterium.

13. 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, its stereoisomer or a pharmaceutically acceptable salt thereof:

14. A pharmaceutical composition comprising the compound according to any one of claims 1 to 13, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

15. 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.

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