A hpk1 degradation agent and medical use thereof

Abstract

An HPK1 degrading agent and its pharmaceutical application, specifically relating to a compound of general formula (I) or its stereoisomers, racemates, tautomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and intermediates thereof, and their use in diseases related to the inhibition or degradation of HPK1, such as cancer. B-L-K(I)

Description

HPK1 degrader and its application in medicine Technical Field

[0001] The present invention relates to a compound of general formula (I) or its stereoisomers, racemates, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, as well as intermediates and preparation methods, and uses thereof in HPK1-related diseases such as tumors. Background Art

[0002] Kinases catalyze the phosphorylation of proteins, lipids, sugars, nucleosides, and other cellular metabolites, playing a key role in various aspects of eukaryotic cell physiology. In particular, protein kinases and lipid kinases are involved in controlling the activation of signaling events that drive cell growth, differentiation, and survival in response to extracellular mediators or stimuli such as growth factors, cytokines, or chemokines. In general, protein kinases are divided into two classes: one that preferentially phosphorylates tyrosine residues and the other that preferentially phosphorylates serine and / or threonine residues.

[0003] Hematopoietic progenitor kinase HPK1 (also known as Mitogen-Activated Protein Kinase Kinase Kinase Kinase 1, MAP4K1) is a serine / threonine protein kinase, a member of the MAP4K family, and a negative signaling regulator of the T cell receptor (TCR). TCR activation recruits and activates HPK1, which phosphorylates the Ser376 amino acid residue of the SLP76 protein, thereby destabilizing the TCR signaling complex and ultimately inhibiting T cell activation and proliferation. Compared with wild-type mice, mice lacking HPK1 kinase exhibited superior T cell proliferation activity and anti-tumor immunity under TCR stimulation. At the same time, mice lacking HPK1 kinase did not show a lethal inflammatory response. Therefore, HPK1 has become an important therapeutic target and has attracted widespread research and development interest.

[0004] PROTAC (proteolysis targeting chimera) molecules are a class of bifunctional compounds that can simultaneously bind to target proteins and E3 ubiquitin ligases. Such compounds can be recognized by the cell's proteasome, causing degradation of the target protein, and can effectively reduce the content of the target protein in the cell. By introducing ligands that can bind to different target proteins into PROTAC molecules, PROTAC technology has become possible for the treatment of various diseases. This technology has also received widespread attention in recent years. Compared with inhibitors, PROTAC can not only inhibit the kinase activity of the target, but also regulate its backbone function.

[0005] Therefore, it is necessary to develop novel HPK1 PROTAC drugs for the treatment of HPK1-related tumor diseases. Summary of the Invention

[0006] The object of the present invention is to provide a compound with novel structure, good efficacy, high bioavailability, greater safety, and the ability to inhibit or degrade HPK1, for treating HPK1-related diseases such as cancer.

[0007] The compounds of the present invention have a good inhibitory effect on the phosphorylation of SLP76 in Jurkat cells, good degradation and inhibitory activity on HPK1 kinase, good pharmacokinetic properties (good oral absorption, long half-life, high Cmax, and low clearance in animal pharmacokinetic tests), no obvious inhibitory effect on the hERG potassium ion channel, and a good activating effect on IL-2.

[0008] The present invention provides a compound or its stereoisomer, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from the compound represented by general formula (I),

[0009] BLK(I);

[0010] In some embodiments, the compound of formula (I) is selected from formula (Ia),

[0011] In some embodiments, Selected from

[0012] In some embodiments, Selected from

[0013] In some embodiments, J1 is selected from N or CH;

[0014] In some embodiments, Selected from single bonds or does not exist;

[0015] In some embodiments, L is selected from a bond or -C 1-50 Hydrocarbyl-, wherein 1 to 20 methylene units in the hydrocarbyl group are optionally replaced by -Ak- or -Cy-;

[0016] In some embodiments, L is selected from a bond or -C 1-20 Hydrocarbyl-, wherein 1 to 20 methylene units in the hydrocarbyl group are optionally replaced by -Ak- or -Cy-;

[0017] In some embodiments, each -Ak- is independently selected from -(CH2) q -、-(CH2) q -O-, -O-(CH2) q -、-(CH2) q -S-, -S-(CH2) q -、-(CH2) q -NR L -、-NR L -(CH2) q -、-(CH2) q -NR L C(=O)-、-NR L (CH2) q C(=O)-、-(CH2) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH2) q -NR L -、-(C≡C) q -、-CH=CH-、-Si(R L )2-、-Si(OH)(R L )-、-Si(OH)2-、-P(=O)(OR L )-、-P(=O)(R L )-, -S-, -S(=O)-, -S(=O)2- or a bond, wherein the CH, -CH2- is optionally replaced by 1 to 2 R z replace;

[0018] In some embodiments, q is each independently selected from 0, 1, 2, 3, 4, 5, or 6;

[0019] In some embodiments, R L Selected from H, C 1-4 Alkyl, C 3-7 Carbocyclic group, 4 to 10 membered heterocyclic group, said alkyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R z replace;

[0020] In some embodiments, each -Cy- is independently selected from a bond or optionally substituted by 1 to 4 R L2 One of the following substituted groups: 4-8 membered heteromonocyclic group, 4-12 membered heterocyclic group, 5-13 membered heterospirocyclic group, 7-12 membered heterobridged ring group, C 3-7 Monocyclic alkyl, C 4-7 Monocyclic alkenyl, C 4-12 Cycloalkyl, C 5-13 Spiroalkyl, C 5-12Bridged cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl;

[0021] In some embodiments, Ak is selected from Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, or Ak9;

[0022] In some embodiments, Ak is selected from Ak1, Ak2, Ak3, Ak4, or Ak5;

[0023] In some embodiments, -Cy- is selected from Cy1, Cy2, Cy3, Cy4, or Cy5;

[0024] In some embodiments, -Cy- is selected from Cy1, Cy2, Cy3, or Cy4;

[0025] In some embodiments, L is selected from -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-, -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, 5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak1-Ak2-Ak 3-Ak4-Ak5-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-, -Cy1 -Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-A k3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy 3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Ak2-Cy2-Cy3-Cy4-Ak3-Ak4- Ak5-, -Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1- Ak2-Cy4-Ak3-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-, - Cy1-Cy2-Ak1-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3 -Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Cy2-Cy3-Cy4-Ak5-, -Cy1-Cy2 -Ak1-Ak2-Ak3-Ak4-Cy3-Cy4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy 4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Ak5-Cy1-Cy2-Cy3-Cy4-, -Ak1-Cy1-Cy2-Cy 3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-,-Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-、-Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Cy1-Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Cy1-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Cy1-Cy2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Ak1-Ak2-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Ak3-Cy1-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-、-Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Ak5-Cy4-、-Ak1-、-Ak1-Ak2-、-Ak1-Ak2-Ak3-、-Ak1-Ak2-Ak3-Ak4-、-Ak1-Ak2-Ak3-Ak4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-、-Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-、-Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-、-Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-Ak9-;、

[0026] In certain embodiments, L is selected from a bond, -Ak1-, -Ak1-Ak2-, -Ak1-Ak2-Ak3-, -Ak1-Ak2-Ak3-Ak4-, -Ak1-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-, -Cy1-, -Cy1-Ak1-, -Cy1-Ak1-Ak2-, -Cy1-Ak1-Ak2-Ak3-, -Cy1-Ak1-Ak2-Ak3-Ak4-, -Cy1-Cy2-, -Cy1-Ak1-Cy2-, -Cy1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-Ak3-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Cy2-Ak2-Ak3-, -Cy1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Ak2-Cy3-, -Cy1-Ak1-Ak2-Cy3-Ak3-, -Cy1-Cy2-Cy3-, -Cy1-Ak1-Cy2-Cy3-, -Cy1-Cy2-Ak2-Cy3-, -Cy1-Cy2-Cy3-Ak3-, -Cy1-Ak1-Cy2-Cy3-Ak3-, -Cy1-Cy2-Ak2-Cy3-Ak3-, -Cy1-Ak1-Cy2-Ak2-Cy3-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-, -Cy1-Cy2-Cy3-Ak3-Ak4-, -Cy1-Cy2-Cy3-Ak3-Cy4-, -Cy1-Cy2-Cy3-Cy4-, -Cy1-Ak1-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak2-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak3-Cy4-, -Cy1-Cy2-Cy3-Cy4-Ak4-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Cy4-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-, -Ak1-Cy2-, -Ak1-Cy2-Cy3-, -Ak1-Ak2-Cy3-, -Ak1-Ak2-Cy3-Cy4-, -Ak!-Cy2-Ak2-Cy3-, -Ak1-Cy2-Cy3-Ak3-Cy4-, -Ak1-Cy2-Cy3-Cy4-Ak4-Cy5-, -Ak1-Cy2-Ak2-, -Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak2-Cy3-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5--Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-, -Ak1-Cy 2-Ak2-Ak3-Ak4-Ak5-, -Ak1-Cy2-Ak2-Ak3-Ak4-, -Ak1-Cy2-Ak2-Ak3-;,

[0027] In certain embodiments, L is selected from -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-;

[0028] In certain embodiments, L is selected from a bond, -Ak1-, -NHCH2-, -Cy1-, -Cy1-CH2-, -Cy1-C≡C-, -Cy1-Cy2-, -Cy1-CH2-Cy2-, -CH2-Cy2-, -Cy1-Cy2-Cy3-, -Cy1-CH2-Cy2-Cy3-, -Cy1-Cy2-CH2-Cy3-, -NH-Cy1-, -NH-Cy1-Cy2-, -NH-Cy1-CH2-Cy2, -Cy1-Ak2-, -Ak1-Cy1-, -Ak1-Cy1-Ak2-, -Ak1-Cy2-Ak2-Cy3-, -Ak1-Cy2-Cy3-;

[0029] In certain embodiments, L is selected from a bond, -Ak1-, -NHCH2-, -Cy1-, -Cy1-CH2-, -Cy1-C≡C-, -Cy1-Cy2-, -Cy1-CH2-Cy2-, -CH2-Cy2-, -Cy1-Cy2-Cy3-, -Cy1-CH2-Cy2-Cy3-, -Cy1-Cy2-CH2-Cy3-, -NH-Cy1-, -NH-Cy1-Cy2-, -NH-Cy1-CH2-Cy2, -Cy1-CH2-, -CH2-Cy1-, -CH2-Cy1-CH2-, -CH2-Cy2-CH2-Cy3-, -CH2-Cy2-Cy3-;

[0030] In certain embodiments, Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, and Ak9 are each independently selected from -(CH2) q -、-(CH2) q -O-, -O-(CH2) q -、-(CH2) q -S-, -S-(CH2) q -、-(CH2) q -NR L -、-NR L -(CH2) q -、-(CH2)q -NR L C(=O)-、-(CH2) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH2) q -NR L -、-(C≡C) q - or bond, wherein the -CH2- is optionally replaced by 1 to 2 R z replace;

[0031] In certain embodiments, Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, Ak9 are each independently selected from a bond, -O-, -S-, -OCH2-, -CH2O-, -OCH2CH2-, -CH2CH2O-, -C≡C-, -C(CH3)2-, -CH2-, -CH2CH2-, -CH2CH2CH2-, -N(CH3)-, -NH-, -CH2N(CH3)-, -CH2NH-, -NHCH2-, -CH2CH2N(CH3)-, -CH2CH2NH-, -NHCH2CH2-, -C(=O)-, -C(=O)CH2NH-, -CH2C(=O)NH-, -C(=O)NH-, or -NHC(=O)-;

[0032] In certain embodiments, R L Selected from H or C 1-4 alkyl;

[0033] In certain embodiments, R L Selected from H, methyl or ethyl;

[0034] In certain embodiments, Cy1, Cy2, Cy3, Cy4, or Cy5 are each independently selected from a bond or optionally substituted by 1 to 4 R L2 One of the following groups substituted: 4-7 membered nitrogen-containing heteromonocyclic group, 4-12 membered nitrogen-containing heterocyclic group, 5-13 membered nitrogen-containing heterospirocyclic group, 7-12 membered nitrogen-containing heterobridged ring group, C 3-7 Monocyclic alkyl, C 4-7 Monocyclic alkenyl, C 4-12 Cycloalkyl, C 5-13 Spiroalkyl, C 7-12 Bridged cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl;

[0035] In certain embodiments, Cy5 is defined the same as Cy1;

[0036] In certain embodiments, Cy1, Cy2, Cy3, and Cy4 are each independently selected from a bond or optionally substituted by 1 to 4 R L2One of the following substituted groups: phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, s1, s3, and s5 are each independently selected from 0, 1, or 2, s2 and s4 are each independently selected from 0 or 1, s6 is selected from 0, 1, 2, or 3, and s7 is selected from 1, 2, or 3;

[0037] In certain embodiments, Cy1, Cy2, Cy3, Cy4, and Cy5 are each independently selected from a bond or one of the following optionally substituted groups: When substituted, it is substituted with 1 to 4 substituents selected from deuterium, F, CF3, OH, methyl, =O, hydroxymethyl, methoxy, COOH, CN or NH2;

[0038] In certain embodiments, Cy1, Cy2, and Cy3 are each independently selected from one of the following optionally substituted groups: When substituted, it is substituted with 1 to 4 substituents selected from deuterium, F, CF3, OH, =O, COOH, CN, NH2, hydroxymethyl, methyl, methoxy, cyclopropyl;

[0039] In certain embodiments, Cy1 is selected from one of the following optionally substituted groups: a 4-7 membered nitrogen-containing heteromonocyclic group, a 4-12 membered nitrogen-containing heterocyclyl, a 5-13 membered nitrogen-containing heterospirocyclic group, a 7-12 membered nitrogen-containing heterobridged ring group, a C 3-7 Monocyclic alkyl, C 4-7 Monocyclic alkenyl, C 4-12 Cycloalkyl, C 5-13 Spiroalkyl, C 5-12 Bridged cycloalkyl, 5-10 membered heteroaryl or C 6-10 Aryl, preferably one of the following optionally substituted groups: When substituted, it is substituted with 1 to 4 substituents selected from deuterium, F, CF3, OH, =O, COOH, CN, NH2, hydroxymethyl, methyl, methoxy, cyclopropyl;

[0040] In certain embodiments, L is selected from the group shown in Table L-1, wherein the left side of the group is connected to B;

[0041] In certain embodiments, L is selected from a bond, a group shown in Table L-1 or Table L-2, wherein the left side of the group is connected to B;

[0042] Table L-1 L Group

[0043] Table L-2 L Group

[0044] In certain embodiments, B is selected from

[0045] In certain embodiments, B is selected from

[0046] In certain embodiments, B is selected from

[0047] In certain embodiments, B is selected from

[0048] In certain embodiments, Ba or Bb is selected from N or CR b ;

[0049] In certain embodiments, Ba or Bb is selected from N or CH;

[0050] In certain embodiments, R b Selected from H, deuterium, halogen, OH, CN, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -C 0-2 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy or cycloalkyl group is optionally substituted by 1 to 4 R z replace;

[0051] In certain embodiments, B1 is selected from C 6-10 Carbocyclic group, 5 to 10 membered heterocyclic group, said B1 is optionally substituted by 1 to 4 R b1 replace;

[0052] In certain embodiments, B1 is selected from phenyl, benzo 4-6 carbocyclyl, benzo 4 to 6 membered heterocyclyl, 5 to 6 membered heteroaryl, 8 to 10 membered heteroaryl, said B1 is optionally substituted by 1 to 4 R b1 replace;

[0053] In certain embodiments, B1 is selected from phenyl, thiazolyl, furanyl, thienyl, oxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, said B1 being optionally substituted with 1 to 4 R b1 replace;

[0054] In certain embodiments, R b2 Selected from C 6-10 Carbocyclic group, 5 to 10 membered heterocyclic group, said R b2 Optional 1 to 4 R b2a replace;

[0055] In certain embodiments, R b2 Selected from phenyl, benzo C 4-6 Carbocyclic group, benzo 4 to 6 membered heterocyclic group, 5 to 6 membered heteroaryl group, 8 to 10 membered heteroaryl group, said R b2 Optional 1 to 4 R b2a replace;

[0056] In certain embodiments, R b2 Selected from The R b2 Optional 1 to 4 R b2a Substitution; in certain embodiments, R b2 Selected from The R b2 Optional 1 to 4 R b2a replace;

[0057] In certain embodiments, R b2 Selected from

[0058] In certain embodiments, R b3 、R b4 are each independently selected from H, deuterium, halogen, C 1-4 Alkyl, wherein the alkyl is optionally substituted with 1 to 4 halogens;

[0059] In certain embodiments, R b1 、R b2a Each independently selected from deuterium, halogen, OH, CN, NH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C1-4 Alkoxy, -C 0-2 Alkylene-C 3-6 Cycloalkyl, -C 0-2 Alkylene-OC 3-6 Cycloalkyl, -C 0-2 Alkylene-4 to 7 membered heterocycloalkyl, -C 0-2 Alkylene-O-4 to 7 membered heterocycloalkyl, -C 0-2 Alkylene-NHC 1-4 Alkyl, -C 0-2 Alkylene-N(C 1-4 alkyl) 2, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R z replace;

[0060] In certain embodiments, R b1 、R b2a Each independently selected from deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2 or optionally substituted by 1 to 4 R z substituted one of the following groups: methyl, ethyl, propyl, isopropyl, ethynyl, -CH2-ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, -CH2NHCH3, -CH2N(CH3)2, tetrahydropyranyl, piperidinyl, -CH2-azetidinyl, -CH2-pyrrolidinyl, -CH2-piperidinyl;

[0061] In certain embodiments, R b2a Each is independently selected from deuterium, F, Cl, Br, OH, CN, NH2, NHCH3, N(CH3)2, methyl, ethyl, methoxy, CF3;

[0062] In certain embodiments, R b1 Each is independently selected from deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2, methyl, ethyl, -CH2NHCH3, -CH2N(CH3)2, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, -CH2-azetidinyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, said methyl, ethyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, azetidinyl, pyrrolidinyl, piperidinyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, CF3, OH, =O, COOH, CN, NH2;

[0063] In certain embodiments, R b1Each independently selected from deuterium, N(CH3)2, -CH2N(CH3)2,

[0064] In certain embodiments, K is selected from

[0065] In certain embodiments, Selected from

[0066] In certain embodiments, G is selected from N or CH;

[0067] In certain embodiments, each Q is independently selected from a bond, -O-, -S-, -CH2-, -NR q -, -C(=O)-, -NR q C(=O)-, -C(=O)NR q -;

[0068] In certain embodiments, Q is selected from a bond, CH2, NH, N(CH3), O, S, C(=O), NHC(=O), C(=O)NH, N(CH3)C(=O), C(=O)N(CH3);

[0069] In certain embodiments, Q is selected from a bond, C(=O)NH;

[0070] In certain embodiments, Q and G cannot directly form a nitrogen-nitrogen bond, a nitrogen-oxygen bond, or a nitrogen-sulfur bond;

[0071] In certain embodiments, R q Selected from H or C 1-4 alkyl;

[0072] In certain embodiments, F is selected from C 3-20 Carbocyclic group, C 6-20 aryl, 3-20 membered heterocyclyl or 5-20 membered heteroaryl;

[0073] In certain embodiments, F is selected from C 3-7 Monocyclic, C 4-10 Cyclic group, C 5-12 Spirocyclyl, C 5-10 bridged cyclic group, 4-7 membered heteromonocyclic group, 4-10 membered bicyclic heterocyclic group, 8-15 membered tricyclic heterocyclic group, 12-19 membered tetracyclic heterocyclic group, 5-17 membered heterospirocyclic group, 5-10 membered heterobridged cyclic group, C 6-14 Aryl, 5-10 membered heteroaryl;

[0074] In certain embodiments, F is selected from cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentanyl, 6,7-dihydro-5H-cyclopenta[c]pyridinyl, 2,3-dihydro-1H-indenyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furanyl, thienyl, thiazolyl, 2-pyridonyl,

[0075] The ring where the representative is located is an aromatic ring or a non-aromatic ring;

[0076] In certain embodiments, Fa is selected from N, CH, or CR k1 In certain embodiments, Fb is selected from N, CH or CR k1 ;

[0077] In certain embodiments, Fc is selected from O, S, NH, N(CH3) or NR k7a In certain embodiments, Fd is selected from N, CH or CR k1 ;

[0078] In certain embodiments, Fg is selected from N or C; in certain embodiments, Fh is selected from N or C; in certain embodiments, Faa is selected from a bond, O, CH2; in certain embodiments, Fab is selected from O, CH2;

[0079] In certain embodiments, H1 is selected from N, NH, CH, CH2, CHR k1 NR k1 , CR k1 、C(=O)、C(R k1 )2;

[0080] In certain embodiments, H2 is selected from a bond, O, N, NH, CH, CH2, CHR k1 NR k1 , CR k1 or C(R k1 )2;

[0081] In certain embodiments, H3 is selected from N or CH; in certain embodiments, H4 is selected from C, N or CH;

[0082] In certain embodiments, H5, H6, and H7 are each independently selected from N, C, CH, or CR k1 , and H5, H6, and H7 contain at most 2 Ns;

[0083] In certain embodiments, ring E is selected from phenyl or 5-6 membered heteroaryl, said ring E being optionally substituted with 1 to 3 R k1 replace;

[0084] In certain embodiments, each ring E is independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furanyl, thienyl or oxazolyl, and the ring E is optionally substituted by 1 to 3 R k1 replace;

[0085] In certain embodiments, ring F1, ring F2, ring F3, and ring F4 are each independently selected from phenyl or 5-6 membered heteroaryl, and the ring F1, ring F2, ring F3, and ring F4 are optionally substituted by 1 to 2 R k1 replace;

[0086] In certain embodiments, ring F1 and ring F2 are each independently selected from phenyl, pyridyl, thiazolyl, furyl, thienyl or oxazolyl, and the ring F1 and ring F2 are optionally substituted by 1 to 2 R k1 replace;

[0087] In certain embodiments, ring F3 and ring F4 are each independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furanyl, thienyl or oxazolyl, and the ring F3 and ring F4 are optionally substituted by 1 to 2 R k1 replace;

[0088] In certain embodiments, R k1 Each independently selected from H, deuterium, halogen, OH, =O, NH2, CN, COOH, CONH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 3 to 6 membered heterocycloalkyl, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl are optionally substituted by 1 to 4 R z replace;

[0089] In certain embodiments, R k2 Each independently selected from a bond, -C(=O)-, -S(=O)2-, -S(=O)- or -C(R k3 )2-;

[0090] In certain embodiments, R k3 Each independently selected from H, deuterium, halogen, OH, =O, NH2, CN, COOH, CONH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8Cycloalkyl or 3 to 8 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl or heterocyclic group is optionally substituted by 1 to 4 groups selected from R z replace;

[0091] In certain embodiments, R k1 、R k3 Each is independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH2, CF3, CN, COOH, CONH2, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, and cyclopropyl, wherein the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, and cyclopropyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, and NH2;

[0092] Alternatively, two R k3 Direct connection to form C 3-8 Carbocyclic or 4-8 membered heterocyclic, said carbocyclic or heterocyclic group is optionally substituted by 1 to 4 groups selected from R z replace;

[0093] In certain embodiments, R k1 Each independently selected from H, deuterium, F, Cl, Br, NH2, CF3, CN, methyl, ethyl;

[0094] In certain embodiments, R L2 、R z Each independently selected from deuterium, halogen, OH, =O, CF3, SF5, CN, NH2, NO2, COOH, CONH2, NHC 1-4 Alkyl, N(C 1-4 alkyl)2, COOH, CONH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -SC 1-4 Alkyl, -C 0-4 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkoxy, alkenyl, alkynyl, cycloalkyl is optionally substituted by 1 to 4 groups selected from deuterium, F, Cl, Br, I, OH, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0095] In certain embodiments, R L2 、R zEach independently selected from deuterium, F, Cl, Br, I, OH, =O, CF3, SF5, CN, NH2, NO2, COOH, CONH2, N(CH3)2, NHCH3, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl is optionally substituted by 1 to 4 selected from deuterium, F, Cl, Br, I, OH, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0096] In certain embodiments, R k5 Each independently selected from C(CH3)2, C(=O), CH2, CH2CH2, S(=O)2,

[0097] In certain embodiments, R k6 Each is independently selected from C(=O), CH, S(=O), S(=O)2, CH2 or N;

[0098] In certain embodiments, R k7 Each independently selected from C(CH3)2, CH2, O or NR k7a ;

[0099] In certain embodiments, R k7a is selected from H, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl is optionally substituted by 1 to 4 deuterium, F, Cl, Br, I, OH, CN, CF3, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 substituted by a cycloalkyl substituent;

[0100] In certain embodiments, R k9 are each independently selected from a bond, C(CH3)2, C(=O), CH2, CH2CH2 or S(=O)2;

[0101] In certain embodiments, n1 is selected from 0, 1, 2, or 3;

[0102] In certain embodiments, p1 or p2 are each independently selected from 0, 1, 2, 3, 4, or 5;

[0103] In certain embodiments, p2 is each independently selected from 0, 1, 2, or 3; in certain embodiments, p3 is selected from 0, 1, 2, or 3;

[0104] In certain embodiments, p4 is selected from 0, 1, 2, or 3; in certain embodiments, p5 is selected from 0 or 1; in certain embodiments, p6 is selected from 0 or 1;

[0105] In certain embodiments, K is selected from one of the structural fragments shown in Table K-1; in certain embodiments, K is selected from one of the structural fragments shown in Table K-2;

[0106] In certain embodiments, K is selected from

[0107] In certain embodiments, K is selected from In certain embodiments, K is selected from

[0108] Table K-1

[0109] Table K-2

[0110] As a first embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, racemate, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein,

[0111] L is selected from a bond or -C 1-50 Hydrocarbyl-, wherein 1 to 20 methylene units in the hydrocarbyl group are optionally replaced by -Ak- or -Cy-;

[0112] Each -Ak- is independently selected from -(CH2) q -、-(CH2) q -O-, -O-(CH2) q -、-(CH2) q -S-, -S-(CH2)q -、-(CH2) q -NR L -、-NR L -(CH2) q -、-(CH2) q -NR L C(=O)-、-NR L (CH2) q C(=O)-、-(CH2) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH2) q -NR L -、-(C≡C) q -、-CH=CH-、-Si(R L )2-、-Si(OH)(R L )-、-Si(OH)2-、-P(=O)(OR L )-、-P(=O)(R L )-, -S-, -S(=O)-, -S(=O)2- or a bond, wherein the CH, -CH2- is optionally replaced by 1 to 2 R z replace;

[0113] q is each independently selected from 0, 1, 2, 3, 4, 5 or 6;

[0114] R L Selected from H, C 1-4 Alkyl, C 3-7 Carbocyclic group, 4 to 10 membered heterocyclic group, said alkyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R z replace;

[0115] Each -Cy- is independently selected from a bond or optionally substituted by 1 to 4 R L2 One of the following substituted groups: 4-8 membered heteromonocyclic group, 4-12 membered heterocyclic group, 5-13 membered heterospirocyclic group, 7-12 membered heterobridged ring group, C 3-7 Monocyclic alkyl, C 4-7 Monocyclic alkenyl, C 4-12 Cycloalkyl, C 5-13 Spiroalkyl, C 5-12 Bridged cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl;

[0116] B is selected from

[0117] Ba or Bb is selected from N or CR b ;

[0118] R bSelected from H, deuterium, halogen, OH, CN, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -C 0-2 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy or cycloalkyl group is optionally substituted by 1 to 4 R z replace;

[0119] B1 is selected from C 6-10 Carbocyclic group, 5 to 10 membered heterocyclic group, said B1 is optionally substituted by 1 to 4 R b1 replace;

[0120] R b2 Selected from C 6-10 Carbocyclic group, 5 to 10 membered heterocyclic group, said R b2 Optional 1 to 4 R b2a replace;

[0121] R b3 、R b4 are each independently selected from H, deuterium, halogen, C 1-4 Alkyl, wherein the alkyl is optionally substituted with 1 to 4 halogens;

[0122] R b1 、R b2a Each independently selected from deuterium, halogen, OH, CN, NH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -C 0-2 Alkylene-C 3-6 Cycloalkyl, -C 0-2 Alkylene-OC 3-6 Cycloalkyl, -C 0-2 Alkylene-4 to 7 membered heterocycloalkyl, -C 0-2 Alkylene-O-4 to 7 membered heterocycloalkyl, -C 0-2 Alkylene-NHC 1-4 Alkyl, -C 0-2 Alkylene-N(C 1-4 alkyl) 2, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R z replace;

[0123] K is selected from

[0124] G is selected from N or CH;

[0125] Q is independently selected from a bond, -O-, -S-, -CH2-, -NR q -, -C(=O)-, -NR q C(=O)-, -C(=O)NR q -;

[0126] Q and G cannot directly form nitrogen-nitrogen bonds, nitrogen-oxygen bonds, or nitrogen-sulfur bonds;

[0127] R q Selected from H or C 1-4 alkyl;

[0128] F is selected from C 3-20 Carbocyclic group, C 6-20 aryl, 3-20 membered heterocyclyl or 5-20 membered heteroaryl;

[0129] R k1 Each independently selected from H, deuterium, halogen, OH, =O, NH2, CN, COOH, CONH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 3 to 6 membered heterocycloalkyl, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl are optionally substituted by 1 to 4 R z replace;

[0130] R k2 Each independently selected from a bond, -C(=O)-, -S(=O)2-, -S(=O)- or -C(R k3 )2-;

[0131] R k3 Each independently selected from H, deuterium, halogen, OH, =O, NH2, CN, COOH, CONH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl or 3 to 8 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl or heterocyclic group is optionally substituted by 1 to 4 groups selected from R z replace;

[0132] Alternatively, two R k3 Direct connection to form C 3-8 Carbocyclic or 4-8 membered heterocyclic, said carbocyclic or heterocyclic group is optionally substituted by 1 to 4 groups selected from R z replace;

[0133] R L2 、R zEach independently selected from deuterium, halogen, OH, =O, CF3, SF5, CN, NH2, NO2, COOH, CONH2, NHC 1-4 Alkyl, N(C 1-4 alkyl)2, COOH, CONH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -SC 1-4 Alkyl, -C 0-4 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkoxy, alkenyl, alkynyl, cycloalkyl is optionally substituted by 1 to 4 groups selected from deuterium, F, Cl, Br, I, OH, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0134] n1 is selected from 0, 1, 2 or 3;

[0135] p1 and p2 are each independently selected from 0, 1, 2, 3, 4 or 5.

[0136] As a second embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, racemate, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein,

[0137] L is selected from -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-;

[0138] Ak1, Ak2, Ak3, Ak4, Ak5 are each independently selected from -(CH2) q -、-(CH2) q -O-, -O-(CH2) q -、-(CH2) q -S-, -S-(CH2) q -、-(CH2) q -NR L -、-NR L -(CH2) q -、-(CH2) q -NR L C(=O)-、-(CH2) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH2) q -NR L -、-(C≡C) q - or bond, wherein the -CH2- is optionally replaced by 1 to 2 R zreplace;

[0139] R L Each independently selected from H or C 1-4 alkyl;

[0140] Cy1, Cy2, Cy3 or Cy4 are each independently selected from a bond or optionally substituted by 1 to 4 R L2 One of the following groups substituted: 4-7 membered nitrogen-containing heteromonocyclic group, 4-12 membered nitrogen-containing heterocyclic group, 5-13 membered nitrogen-containing heterospirocyclic group, 7-12 membered nitrogen-containing heterobridged ring group, C 3-7 Monocyclic alkyl, C 4-7 Monocyclic alkenyl, C 4-12 Cycloalkyl, C 5-13 Spiroalkyl, C 5-12 Bridged cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl;

[0141] F is selected from C 3-7 Monocyclic, C 4-10 Cyclic group, C 5-12 Spirocyclyl, C 5-10 bridged cyclic group, 4-7 membered heteromonocyclic group, 4-10 membered bicyclic heterocyclic group, 8-15 membered tricyclic heterocyclic group, 12-19 membered tetracyclic heterocyclic group, 5-17 membered heterospirocyclic group, 5-10 membered heterobridged cyclic group, C 6-14 Aryl, 5-10 membered heteroaryl;

[0142] B1 is selected from phenyl, benzo 4-6 carbocyclyl, benzo 4 to 6 membered heterocyclyl, 5 to 6 membered heteroaryl, 8 to 10 membered heteroaryl, said B1 is optionally substituted by 1 to 4 R b1 replace;

[0143] R b2 Selected from phenyl, benzo C 4-6 Carbocyclic group, benzo 4 to 6 membered heterocyclic group, 5 to 6 membered heteroaryl group, 8 to 10 membered heteroaryl group, said R b2 Optional 1 to 4 R b2a replace;

[0144] The remaining definitions are the same as those of the first embodiment of the present invention.

[0145] As a third embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, racemate, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein,

[0146] R L Selected from H, methyl or ethyl;

[0147] Cy1, Cy2, Cy3, and Cy4 are each independently selected from a bond or optionally substituted by 1 to 4 R L2 One of the following substituted groups: phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl,

[0148] s1, s3, and s5 are each independently selected from 0, 1, or 2;

[0149] s2 and s4 are each independently selected from 0 or 1;

[0150] s6 is selected from 0, 1, 2 or 3;

[0151] s7 is selected from 1, 2 or 3;

[0152] Selected from

[0153] F is selected from the group consisting of cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentanyl, 6,7-dihydro-5H-cyclopenta[c]pyridinyl, 2,3-dihydro-1H-indenyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furanyl, thienyl, thiazolyl, 2-pyridonyl,

[0154] The ring where the representative is located is an aromatic ring or a non-aromatic ring;

[0155] Fa is selected from N, CH or CR k1 ;

[0156] Fb is selected from N, CH or CR k1 ;

[0157] Fc is selected from O, S, NH, N(CH3) or NR k7a ;

[0158] Fd is selected from N, CH or CR k1 ;

[0159] Fg is selected from N or C;

[0160] Fh is selected from N or C;

[0161] Faa is selected from a bond, O, CH2;

[0162] Fab is selected from O, CH2;

[0163] H1 is selected from N, NH, CH, CH2, CHRk1 NR k1 , CR k1 、C(=O)、C(R k1 )2;

[0164] H2 is selected from a bond, O, N, NH, CH, CH2, CHR k1 NR k1 , CR k1 or C(R k1 )2;

[0165] H3 is selected from N or CH;

[0166] H4 is selected from C, N or CH;

[0167] H5, H6, H7 are each independently selected from N, C, CH or CR k1 , and H5, H6, and H7 contain at most 2 Ns;

[0168] Ring E is selected from phenyl or 5-6 membered heteroaryl, said ring E is optionally substituted by 1 to 3 R k1 replace;

[0169] Ring F1, ring F2, ring F3, ring F4 are each independently selected from phenyl or 5-6 membered heteroaryl, and the ring F1, ring F2, ring F3, ring F4 are optionally substituted by 1 to 2 R k1 replace;

[0170] Q is selected from a bond, CH2, NH, N(CH3), O, S, C(=O), NHC(=O), C(=O)NH, N(CH3)C(=O), C(=O)N(CH3);

[0171] R k1 、R k3 Each is independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH2, CF3, CN, COOH, CONH2, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, and cyclopropyl, wherein the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, and cyclopropyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, and NH2;

[0172] R k5 Each independently selected from C(CH3)2, C(=O), CH2, CH2CH2, S(=O)2,

[0173] R k6 Each is independently selected from C(=O), CH, S(=O), S(=O)2, CH2 or N;

[0174] R k7 Each independently selected from C(CH3)2, CH2, O or NR k7a ;

[0175] R k7a is selected from H, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl is optionally substituted by 1 to 4 deuterium, F, Cl, Br, I, OH, CN, CF3, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 substituted by a cycloalkyl substituent;

[0176] R k9 are each independently selected from a bond, C(CH3)2, C(=O), CH2, CH2CH2 or S(=O)2;

[0177] R L2 、R z Each independently selected from deuterium, F, Cl, Br, I, OH, =O, CF3, SF5, CN, NH2, NO2, COOH, CONH2, N(CH3)2, NHCH3, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl is optionally substituted by 1 to 4 selected from deuterium, F, Cl, Br, I, OH, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0178] p2 are each independently selected from 0, 1, 2 or 3;

[0179] The remaining definitions are the same as those of the first or second embodiment of the present invention.

[0180] As a fourth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, racemate, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein,

[0181] Ring E is independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furanyl, thienyl or oxazolyl, and the ring E is optionally substituted by 1 to 3 R k1 replace;

[0182] Ring F1 and Ring F2 are each independently selected from phenyl, pyridyl, thiazolyl, furyl, thienyl or oxazolyl, and the ring F1 and ring F2 are optionally substituted by 1 to 2 R k1 replace;

[0183] Ring F3 and Ring F4 are each independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furyl, thienyl or oxazolyl, and the ring F3 and ring F4 are optionally substituted by 1 to 2 R k1 replace;

[0184] B1 is selected from phenyl, thiazolyl, furyl, thienyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, said B1 is optionally substituted by 1 to 4 R b1 replace;

[0185] R b2 Selected from The R b2 Optional 1 to 4 R b2a replace;

[0186] R b1 、R b2a Each independently selected from deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2 or optionally substituted by 1 to 4 R z substituted one of the following groups: methyl, ethyl, propyl, isopropyl, ethynyl, -CH2-ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, -CH2NHCH3, -CH2N(CH3)2, tetrahydropyranyl, piperidinyl, -CH2-azetidinyl, -CH2-pyrrolidinyl, -CH2-piperidinyl;

[0187] Ak1, Ak2, Ak3, Ak4, Ak5 are each independently selected from a bond, -O-, -S-, -OCH2-, -CH2O-, -OCH2CH2-, -CH2CH2O-, -C≡C-, -C(CH3)2-, -CH2-, -C(CH3)2-, -CH2CH2-, -CH2CH2CH2-, -N(CH3)-, -NH-, -CH2N(CH3)-, -CH2NH-, -NHCH2-, -CH2CH2N(CH3)-, -CH2CH2NH-, -NHCH2CH2-, -C(=O)-, -C(=O)CH2NH-, -CH2C(=O)NH-, -C(=O)NH- or -NHC(=O)-;

[0188] Cy1, Cy2, Cy3, and Cy4 are each independently selected from a bond or one of the following optionally substituted groups: When substituted, it is substituted with 1 to 4 substituents selected from deuterium, F, CF3, OH, =O, COOH, CN, NH2, hydroxymethyl, methyl, methoxy, cyclopropyl;

[0189] The remaining definitions are the same as those of the first, second or third embodiment of the present invention.

[0190] As a fifth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, racemate, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein,

[0191] B is selected from

[0192] L is selected from the group consisting of bonds, -Ak1-, -NHCH2-, -Cy1-, -Cy1-CH2-, -Cy1-C≡C-, -Cy1-Cy2-, -Cy1-CH2-Cy2-, -CH2-Cy2-, -Cy1-Cy2-Cy3-, -Cy1-CH2-Cy2-Cy3-, -Cy1- Cy2-CH2-Cy3-, -NH-Cy1-, -NH-Cy1-Cy2-, -NH-Cy1-CH2-Cy2, -Cy1-Ak2-, -Ak1-Cy1-, -Ak1-Cy1-Ak2-, -Ak1-Cy2-Ak2-Cy3-, -Ak1-Cy2-Cy3-;

[0193] Cy1, Cy2, and Cy3 are each independently selected from one of the following optionally substituted groups: When substituted, it is substituted with 1 to 4 substituents selected from deuterium, F, CF3, OH, =O, COOH, CN, NH2, hydroxymethyl, methyl, methoxy, cyclopropyl;

[0194] The remaining definitions are the same as those of the first, second, third or fourth embodiment of the present invention.

[0195] As a sixth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, racemate, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein,

[0196] L is selected from one of the structures shown in Table L-1 or L-2;

[0197] K is selected from one of the structural fragments shown in Table K-1 or Table K-2;

[0198] The remaining definitions are the same as those of the first, second, third, fourth or fifth embodiment of the present invention.

[0199] As a seventh embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound represented by the general formula (I) is selected from the general formula (Ia),

[0200] Selected from single bonds or does not exist;

[0201] J1 is selected from N or CH;

[0202] Cy1 is selected from one of the following groups that are optionally substituted: a 4-7 membered nitrogen-containing heteromonocyclic group, a 4-12 membered nitrogen-containing heterocyclic group, a 5-13 membered nitrogen-containing heterospirocyclic group, a 7-12 membered nitrogen-containing heterobridged ring group, a C 3-7 Monocyclic alkyl, C 4-7 Monocyclic alkenyl, C 4-12 Cycloalkyl, C 5-13 Spiroalkyl, C 5-12 Bridged cycloalkyl, 5-10 membered heteroaryl or C 6-10 Aryl, preferably one of the following optionally substituted groups: When substituted, it is substituted with 1 to 4 substituents selected from deuterium, F, CF3, OH, =O, COOH, CN, NH2, hydroxymethyl, methyl, methoxy, cyclopropyl;

[0203] G is selected from N or CH;

[0204] Q is selected from C(=O)NH or a bond;

[0205] R b2 Selected from The R b2 Optional 1 to 4 R b2a replace;

[0206] R b2a Each is independently selected from deuterium, F, Cl, Br, OH, CN, NH2, NHCH3, N(CH3)2, methyl, ethyl, methoxy, CF3;

[0207] R b1 Each is independently selected from deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2, methyl, ethyl, -CH2NHCH3, -CH2N(CH3)2, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, -CH2-azetidinyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, said methyl, ethyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, azetidinyl, pyrrolidinyl, piperidinyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, CF3, OH, =O, COOH, CN, NH2;

[0208] R k1 Each independently selected from H, deuterium, F, Cl, Br, NH2, CF3, CN, methyl, ethyl;

[0209] p3 is selected from 0, 1, 2 or 3;

[0210] p4 is selected from 0, 1, 2 or 3;

[0211] p5 is selected from 0 or 1;

[0212] p6 is selected from 0 or 1.

[0213] The present invention relates to the following compound or its stereoisomer, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from one of the structures in Table E below:

[0214] Table E

[0215] The present invention relates to a pharmaceutical composition comprising the above-mentioned compound of the present invention or its stereoisomer, racemate, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and a pharmaceutically acceptable carrier.

[0216] The present invention relates to the use of the above-mentioned compound of the present invention or its stereoisomers, racemates, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals in the preparation of drugs for treating diseases related to HPK1 activity or expression.

[0217] The present invention relates to the use of the above-mentioned compound of the present invention or its stereoisomers, racemates, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals in the preparation of drugs for treating diseases related to the inhibition or degradation of HPK1.

[0218] In some embodiments, the disease associated with the inhibition or degradation of HPK1 is cancer, preferably a solid tumor.

[0219] The present invention relates to a pharmaceutical composition or pharmaceutical preparation comprising a therapeutically effective amount of a compound of the present invention, or a stereoisomer, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof, and a pharmaceutically acceptable excipient. The pharmaceutical composition may be in the form of a unit dosage form (the amount of the active ingredient in a unit dosage form is also referred to as the "drug strength").

[0220] The present invention also provides a method for treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of the present invention, or a stereoisomer, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, cocrystal, or pharmaceutical composition thereof. In some embodiments, the mammal of the present invention comprises a human.

[0221] As used herein, an "effective amount" or "therapeutically effective amount" refers to administering a sufficient amount of a compound disclosed herein to alleviate, to some extent, one or more symptoms of the disease or condition being treated (e.g., cancer). In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a compound disclosed herein required to provide a clinically significant reduction in disease symptoms.Examples of therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5-600 mg, 6-600 mg, 10-600 mg, 20-600 mg, 25-600 mg, 30-600 mg, 40-600 mg, 50-600 mg, 60-600 mg, 70-600 mg, 75-600 mg, 80-600 mg, 90-600 mg, 100-600 mg, 200-600 mg, 1-500 mg, 2-500 mg, 3 -500mg, 4-500mg, 5-500mg, 6-500mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40-500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg, 80-500mg , 90-500mg, 100-500mg, 125-500mg, 150-500mg, 200-500mg, 250-500mg, 300-500mg, 400-500mg, 5-400mg, 10-400mg, 20-400mg, 25-400mg, 30-400 mg, 40-400mg, 50-400mg, 60-400mg, 70-400mg, 75-400mg, 80-400mg, 90-400mg, 100-400mg, 125-400mg, 150-400mg, 200-400mg, 250-400mg, 300- 400mg, 1-300mg, 2-300mg, 5-300mg, 10-300mg, 20-300mg, 25-300mg, 30-300mg, 40-300mg, 50-300mg, 60-300mg, 70-300mg, 75-300mg, 80-300mg, 9 0-300mg, 100-300mg, 125-300mg, 150-300mg, 200-300mg, 250-300mg, 1-200mg, 2-200mg, 5-200mg, 10-200mg, 20-200mg, 25-200mg, 30-200mg, 40 -200mg, 50-200mg, 60-200mg, 70-200mg, 75-200mg, 80-200mg, 90-200mg, 100-200mg, 125-200mg, 150-200mg, 80-1500mg, 80-1000mg, 80-800mg;.

[0222] In some embodiments, the pharmaceutical composition includes but is not limited to 1-1500 mg, 1-1000 mg, 20-800 mg, 40-800 mg, 40-400 mg, 25-200 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 or 1000 mg of a compound of the present invention or a stereoisomer, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

[0223] A method for treating a disease in a mammal, comprising administering to a subject a therapeutically effective amount of a compound of the present invention or a stereoisomer, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof, wherein the therapeutically effective amount is preferably 1-1500 mg, and the disease is preferably cancer, more preferably a solid tumor.

[0224] A method for treating a disease in a mammal, comprising administering to a subject a compound of the present invention or a stereoisomer, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof at a daily dose of 1-1500 mg / day. The daily dose may be a single dose or divided doses. In some embodiments, the daily dose includes but is not limited to 10-1500 mg / day, 10-1000 mg / day, 10-800 mg / day, 25-800 mg / day, 50-800 mg / day, 100-800 mg / day, 200-800 mg / day. , 25-400 mg / day, 50-400 mg / day, 100-400 mg / day, 200-400 mg / day, in some embodiments, daily doses include but are not limited to 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 80 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 160 mg / day, 200 mg / day, 300 mg / day, 320 mg / day, 400 mg / day, 480 mg / day, 600 mg / day, 640 mg / day, 800 mg / day, 1000 mg / day, 1500 mg / day.

[0225] The present invention relates to a kit, which may include a composition in single-dose or multi-dose form, wherein the kit contains a compound of the present invention or a stereoisomer, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and the amount of the compound of the present invention or its stereoisomer, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is the same as the amount in the above-mentioned pharmaceutical composition.

[0226] The amount of the compound of the invention or its stereoisomer, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in the present invention is in each case calculated as the free base.

[0227] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0228] The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds of the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C. 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include 16 O. 17 O and 18 O, sulfur isotopes include 32 S. 33 S. 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Isotopes of Cl, bromine include 79 Br and 81 Br.

[0229] "CN" refers to cyano.

[0230] "Halogen" refers to F, Cl, Br or I.

[0231] "Halogen-substituted" refers to substitution with F, Cl, Br or I, including but not limited to substitution with 1 to 10 substituents selected from F, Cl, Br or I, substitution with 1 to 6 substituents selected from F, Cl, Br or I, and substitution with 1 to 4 substituents selected from F, Cl, Br or I. "Halogen-substituted" is abbreviated as "halo".

[0232] "Alkyl" refers to a substituted or unsubstituted straight or branched chain saturated aliphatic hydrocarbon group, including but not limited to alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, and alkyl groups of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched chain isomers thereof; alkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0233] "Alkylene" refers to substituted or unsubstituted straight-chain and branched divalent saturated hydrocarbon groups, including -(CH2) v -(v is an integer from 1 to 10), examples of alkylene include but are not limited to methylene, ethylene, propylene and butylene.

[0234] "Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon radical, typically having 3 to 12 carbon atoms. Cycloalkyl groups can be monocyclic, fused, bridged, or spirocyclic. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutyl-cyclobutyl, cyclobutyl-spirocyclobutyl, and adamantane. Cycloalkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0235] "Heterocycloalkyl" refers to a substituted or unsubstituted saturated cyclic hydrocarbon radical containing heteroatoms, including but not limited to 3 to 12 atoms, 3 to 8 atoms, comprising 1 to 3 heteroatoms selected from N, O or S, and the C, N, S on the ring of the heterocycloalkyl can be oxidized to various oxidation states. Heterocycloalkyl can be a monocyclic, cyclic, bridged and spirocyclic ring. Heterocycloalkyl can be connected to a heteroatom or carbon atom, and non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolane, dioxane, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl, The heterocycloalkyl group can be monovalent, divalent, trivalent, or tetravalent.

[0236] "Alkenyl" refers to substituted or unsubstituted straight and branched unsaturated hydrocarbon groups having at least one, typically one, two or three carbon-carbon double bonds, with a backbone of 2 to 10, 2 to 6 or 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-2-butenyl, 2-methyl-3-butenyl, 2-methyl-4-butenyl, 2-methyl-5-butenyl, 2-methyl-6-butenyl, 2-methyl-7-butenyl, 2-methyl-8-butenyl, 2-methyl-9-butenyl, 2-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-2-butenyl, 2-methyl-3 ... -methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene and 1,4-hexadiene, etc.; the alkenyl group can be monovalent, divalent, trivalent or tetravalent.

[0237] "Alkynyl" refers to substituted or unsubstituted straight and branched unsaturated hydrocarbon groups having at least one, typically one, two or three carbon-carbon triple bonds, with a backbone comprising 2 to 10 carbon atoms, including but not limited to 2 to 6 carbon atoms in the backbone, and 2 to 4 carbon atoms in the backbone. Examples of alkynyl groups include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 5-pentynyl, 6-pentynyl, 7-pentynyl, 8-pentynyl, 9-pentynyl, 10-pentynyl, 11-pentynyl, 12-pentynyl, 13-pentynyl, 14-pentynyl, 15-pentynyl, 16-pentynyl, 17-pentynyl, 18-pentynyl, 19-pentynyl, 20-pentynyl, 21-pentynyl, 22-pentynyl, 23-pentynyl, 24-pentynyl, 25-pentynyl, 26-pentynyl, 27-pentynyl, 28-pentynyl, 29-pentynyl, 30-pentynyl, 31-pentynyl, 32-pentynyl, 33-pentynyl, 34-pentynyl, 35-pentynyl, 36-pentynyl, 37-pentynyl, 38-pentynyl, 39-pentynyl, 40-pentynyl, 41-pentynyl, 42-pentynyl, 43-pentynyl, 44-pentynyl, 45-pentynyl, 46-pentynyl, 47-pentynyl, 48-pentyn Alkynyl, 1-methyl-1-butynyl, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl, and the like; an alkynyl group may be monovalent, divalent, trivalent, or tetravalent.

[0238] "Alkoxy" refers to a substituted or unsubstituted -O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropyloxy, and cyclobutyloxy.

[0239] "Carbocyclyl" or "carbocycle" refers to a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3-8 membered monocycle, a 4-12 membered bicycle, a 10-15 membered tricycle, or a 12-18 membered quaternary system. The carbocyclyl can be attached to the aromatic or non-aromatic ring, and the ring can be optionally a monocycle, a cyclic ring, a bridged ring, or a spirocycle. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, a benzene ring, a naphthalene ring, "Carbocyclyl" or "carbocycle" can be monovalent, divalent, trivalent, or tetravalent.

[0240] "Heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3-8 membered monocyclic ring, a 4-12 membered bicyclic ring, a 10-15 membered tricyclic ring, or a 12-18 membered quaternary system, and contains one or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O, S or Se. The C, N, S optionally substituted in the heterocyclyl ring can be oxidized to various oxidation states. The heterocyclic group can be attached to a heteroatom or a carbon atom, and can be attached to an aromatic ring or a non-aromatic ring. The heterocyclic group is optionally a monocyclic, bridged, fused or spirocyclic ring. Non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolane, 1,4-dioxolane, 1,3-dioxane, azepanyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithiazyl, dihydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothiophenyl, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptanyl, "Heterocyclyl" or "heterocycle" can be monovalent, divalent, trivalent or tetravalent.

[0241] "Spirocycle" or "spirocyclyl" refers to a polycyclic group in which substituted or unsubstituted monocyclic rings share one atom (called a spiro atom), and the number of ring atoms in the spirocycle system includes but is not limited to 5 to 20, 6 to 14, 6 to 12, 6 to 10, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds, and optionally may contain 0 to 5 atoms selected from N, O, S (=O) n OrSe(=O) n (n is 0, 1 or 2).

[0242] "Spirocycle" or "spirocyclyl" can be monovalent, divalent, trivalent or tetravalent.

[0243] "Parallel ring" or "parallel ring group" refers to a polycyclic group in which each ring in the system shares a pair of adjacent atoms with other rings in the system, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds and may be substituted or unsubstituted, and each ring in the parallel ring system may contain 0 to 5 heteroatoms or groups containing heteroatoms (including but not limited to N, S(=O) n 、Se(=O) n or O, n is 0, 1 or 2). The number of ring atoms in the cyclic system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, and 5 to 10. Non-limiting examples include:

[0244] "Bicyclic" or "bicyclic group" can be monovalent, divalent, trivalent or tetravalent.

[0245] "Bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two atoms that are not directly connected, and may contain zero or more double bonds. Any ring in the bridged ring system may contain zero to five heteroatoms or groups containing heteroatoms (including but not limited to N, S(=O)n, Se(=O) n or O, wherein n is 0, 1, 2). The number of ring atoms includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include cubane, adamantane, A "bridged ring" or "bridged ring group" may be monovalent, divalent, trivalent, or tetravalent.

[0246] "Carbospirocycle," "spirocarbocyclyl," "spirocarbocyclyl," or "carbospirocyclyl" refers to a "spirocycle" wherein the ring system consists of only carbon atoms.

[0247] "Carbocyclyl," "carbocyclyl," "carbocyclyl," or "carbocyclyl" refers to a "carbocyclyl" ring system consisting of only carbon atoms.

[0248] "Carbobridged ring," "bridged carbocyclic group," "bridged carbocyclic group," or "carbon-bridged cyclic group" refers to a "bridged ring" in which the ring system consists of only carbon atoms.

[0249] "Heteromonocycle", "monocyclic heterocyclyl" or "heteromonocyclyl" refers to a monocyclic ring system of "heterocyclyl" or "heterocycle",

[0250] "Heterocyclo", "heterocycloalkyl", "cycloheterocyclyl" or "cycloheterocyclyl" refers to a "cyclo" containing a heteroatom.

[0251] "Heterospirocycle," "heterospirocyclyl," "spiroheterocyclyl," or "spiroheterocyclyl" refers to a "spirocycle" containing a heteroatom.

[0252] "Heterobridged ring", "heterobridged cyclic group", "bridged ring heterocyclic group" or "bridged heterocyclic group" refers to a "bridged ring" containing a heteroatom.

[0253] "Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a single ring or a fused ring, wherein the number of ring atoms in the aromatic ring includes, but is not limited to, 6 to 18, 6 to 12, or 6 to 10 carbon atoms. The aryl ring may be fused to a saturated or unsaturated carbon ring, wherein the ring connected to the parent structure is the aryl ring, non-limiting examples of which include benzene ring, naphthalene ring, "Aryl" or "aromatic ring" can be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the point of attachment is on the aryl ring.

[0254] "Heteroaryl" or "heteroaromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 heteroatoms or groups containing heteroatoms (including but not limited to N, O, S(=O)n, Se(=O) n , n is 0, 1, 2), the number of ring atoms in the heteroaromatic ring includes but is not limited to 5 to 15, 5 to 10 or 5 to 6. The atoms C, N, S, and Se on the ring are optionally oxidized (i.e., C(=O), NO, S(=O)n, Se(=O)n, n is 1, 2). Non-limiting examples of heteroaryl include but are not limited to pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazolyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, pyridonyl, etc. The heteroaryl ring can be fused to a saturated or unsaturated carbocyclic ring or heterocyclic ring, wherein the ring connected to the parent structure is an aryl ring. Non-limiting examples include When heteroaryl appears in this document, its definition is consistent with this definition. Heteroaryl can be monovalent, divalent, trivalent or tetravalent. When it is divalent, trivalent or tetravalent, the attachment point is located on the ring with aromaticity.

[0255] "Substituted" or "substituted" refers to substitution by one or more (including but not limited to 2, 3, 4 or 5) substituents, including but not limited to H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic, bridged, spiro, cycloalkyl, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -(CH2), m -C(=O)-R a 、-O-(CH2) m -C(=O)-R a 、-(CH2) m -C(=O)-NR b R c 、-(CH2) m S(=O) n R a 、-(CH2) m -alkenyl-R a , OR d or -(CH2) m -alkynyl-R a (wherein m and n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or -NR b R c etc., where R b With R c R is independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, b With R c Can form five or six-membered cycloalkyl or heterocyclic group, R a With R d Each is independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spiro ring or paracyclic group.

[0256] "1 to X substituents selected from..." means substituted by 1, 2, 3, ..., X substituents selected from ..., where X is any integer from 1 to 10. For example, "1 to 4 R k "Substituted" means replaced by 1, 2, 3 or 4 R k Substitution. For example, "substituted by 1 to 5 substituents selected from..." means substituted by 1, 2, 3, 4, or 5 substituents selected from..." For example, "a heterobridged ring is optionally substituted by 1 to 4 substituents selected from H or F" means that the heterobridged ring is optionally substituted by 1, 2, 3, or 4 substituents selected from H or F.

[0257] An XY-membered ring (X and Y are integers, and 3≤X<Y, X<Y≤20 is selected from any integer between 4 and 20) includes rings with X, X+1, X+2, X+3, X+4, ..., Y members. Rings include heterocyclic rings, carbocyclic rings, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocyclic rings, heterocyclic rings, heterospirocyclic rings, or heterobridged rings. For example, "4-7 membered heteromonocyclic ring" refers to a 4-, 5-, 6-, or 7-membered heteromonocyclic ring, and "5-10 membered heterocyclic ring" refers to a 5-, 6-, 7-, 8-, 9-, or 10-membered heterocyclic ring.

[0258] C x-y Carbocycles (including aryl, cycloalkyl, monocyclic carbocycle, spirocyclic carbocycle, fused carbocycle or bridged carbocycle) include C x 、C x+1 、C x+2 、C x+3 、C x+4 ….C y A ring of 1-membered ring (x is an integer, and 3≤x<y, y is selected from any integer between 4 and 20), for example. 3-6 "Cycloalkyl" refers to C3, C4, C5 or C6 cycloalkyl;

[0259] When a group has one or more bondable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection mode is non-positional and there are hydrogen atoms at the bondable sites, when the chemical bond is connected, the number of H atoms at the site will decrease accordingly with the number of chemical bonds connected, and the group will become a group with the corresponding valence. For example Indicates that any linkable site on the piperidinyl group can be connected to other groups through a chemical bond, including at least These four connection methods, even if the H atom is drawn on -N-, Also included For example Indicates that the R group on the piperidinyl group can be located on C, can be located on N, and at least includes

[0260] When the listed linking groups do not specify their connection direction, their connection directions include connection from left to right and from right to left in the reading order, for example, when ALB, L is selected from -MW-, it includes AMWB and AWMB.

[0261] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs and instances where it does not. For example, "alkyl optionally substituted with F" means that the alkyl group may but need not be substituted with F, and the description includes instances where the alkyl group is substituted with F and instances where the alkyl group is not substituted with F.

[0262] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to a salt of the compound of the present invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, or the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

[0263] "Pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, or stereoisomers, racemates, tautomers, deuterated forms, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals thereof and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients and / or one or more other therapeutic agents.

[0264] Unless otherwise specified, use a solid wedge key. and dotted wedge key Indicates the absolute configuration of a stereocenter.

[0265] "Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.

[0266] "Carrier" refers to a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

[0267] "Prodrugs" refer to compounds of the present invention that can be converted into biologically active compounds through in vivo metabolism. Prodrugs of the present invention are prepared by modifying amino or carboxyl groups in compounds of the present invention. These modifications can be removed by conventional manipulation or in vivo to yield the parent compound. When the prodrugs of the present invention are administered to a mammalian subject, the prodrugs are cleaved to form free amino or carboxyl groups.

[0268] A "cocrystal" is a crystal formed by the active pharmaceutical ingredient (API) and cocrystal former (CCF) bound together by hydrogen bonds or other non-covalent bonds. Both the API and CCF are solid in their pure form at room temperature, and the components exist in a fixed stoichiometric ratio. A cocrystal is a multi-component crystal, encompassing both binary cocrystals formed between two neutral solids and multi-component cocrystals formed between a neutral solid and a salt or solvate.

[0269] "Animal" is meant to include mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.

[0270] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers, and conformational isomers.

[0271] "Tautomers" refer to functional group isomers produced by the rapid movement of an atom in a molecule between two positions, such as keto-enol isomers and amide-imino alcohol isomers.

[0272] “IC 50 "It is the concentration of a drug or inhibitor required to inhibit a specified biological process (or a component of the process such as an enzyme, receptor, cell, etc.) by half.

[0273] Synthesis method 1:

[0274] K is selected from

[0275] The definitions of the remaining groups are consistent with the specification;

[0276] The compound of general formula (D-1-1) or the compound of general formula (D-1-2) is subjected to a substitution reaction to obtain a compound of general formula (D-1-3);

[0277] The compound of general formula (D-1-3) is subjected to reduction reaction to obtain the compound of general formula (D-1-4);

[0278] The compound of the general formula (D-1-4) and the compound of the general formula (D-1-5) are reacted by coupling reaction to obtain the compound of the general formula (D-1-6);

[0279] The compound of general formula (D-1-6) is subjected to coupling reaction to obtain the compound of general formula (D-1-7);

[0280] The compound of general formula (D-1-7) is subjected to coupling reaction to obtain the compound of general formula (D-1-8);

[0281] The compound of the general formula (D-1-8) is subjected to a deprotection reaction to obtain a compound of the general formula (D-1-9);

[0282] The compound of general formula (D-1-9) is reacted with the compound of general formula (D-1-10) or the compound of general formula (D-1-11) to obtain the compound of general formula (I) through reductive amination or substitution reaction. DETAILED DESCRIPTION

[0283] The following examples illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited to them.

[0284] The compounds used in the reactions described herein were prepared using organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and / or compounds described in the chemical literature. "Commercially available chemicals" were obtained from reputable commercial sources, including suppliers such as Titan Technology, Anage Chemical, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec, and J&K Technology.

[0285] The structures of the compounds were determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The unit of (ppm) is given. NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0286] MS was determined using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0287] HPLC determination was performed using an Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100 × 4.6 mm, 3.5 μM);

[0288] Thin layer chromatography silica gel plates used were Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications of the silica gel plates used for thin layer chromatography (TLC) were 0.15 mm to 0.20 mm, and the specifications used for thin layer chromatography separation and purification products were 0.4 mm to 0.5 mm.

[0289] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier;

[0290] EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS: 7084-11-9);

[0291] XANT PHOS / Xant-Phos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (CAS: 161265-03-8);

[0292] HOBT: 1-hydroxybenzotriazole (CAS: 2592-95-2); DIPEA: N,N-diisopropylethylamine (CAS: 7087-68-5);

[0293] Boc: tert-butyloxycarbonyl; XPhos Pd G4: CAS: 1599466-81-5; Pd2(dba)3: CAS: 60748-47-2;

[0294] TFA: trifluoroacetic acid; XPHOS-Pd-G2: CAS: 1310584-14-5; X-PHOS: CAS: 564483-18-7;

[0295] TBAF: Tetrabutylammonium fluoride, CAS: 429-41-4.

[0296] Final product prep-HPLC acidic preparation method: instrument: Waters 2767 preparative liquid phase; chromatographic column: XBridge@Prep C18 (30mm×150mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)), the preparative solution was lyophilized.

[0297] Example 1: Preparation of Compound 1

[0298] Step 1: Preparation of 1B

[0299] Dissolve 1A (1.2 g, 4.77 mmol, CAS: 3011833-57-8, synthesis reference patent WO2023220640) and tert-butyl 7-bromo-4-chloro-1-oxoisoindoline-2-carboxylate (CAS: 2628351-94-8, 1.65 g, 4.77 mmol) in 1,4-dioxane (70 mL). Add tris(dibenzylideneindeneacetone)dipalladium (0.44 g, 0.48 mmol), Xant-phos (0.55 g, 0.95 mmol), and cesium carbonate (3.89 g, 11.92 mmol). After addition, react at 90°C under nitrogen for 3 h. The reaction mixture was cooled to room temperature, and 100 mL of ethyl acetate was added to dilute the reaction solution. The mixture was filtered through celite, and the filter cake was washed three times with ethyl acetate. The combined filtrates were washed once with water and once with saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to flash column chromatography (mobile phase: dichloromethane / methanol (v / v) = 20 / 1) to obtain 1B (1.8 g, yield: 73%).

[0300] LCMS m / z=517.4[M+H] +

[0301] 1 H NMR(400MHz, CDCl3)δ9.46(s,1H),8.60(d,1H),8.00(s,1H),7.41(d,1H),7.35-7.26(m,1H),6.77(d,1H),4.67(s,2H),4.09(d ,1H),3.64-3.51(m,2H),3.38(s,6H),2.77-2.57(m,2H),1.99-1.83(m,2H),1.80-1.70(m,1H),1.62(s,9H),1.57-1.47(m,2H).

[0302] Step 2: Preparation of 1C

[0303] 1B (1.8 g, 3.48 mmol), XPHOS-Pd-G2 (CAS: 1310584-14-5) (0.27 g, 0.35 mmol), 1B-1 (1.37 g, 5.22 mmol), X-PHOS (0.33 g, 0.7 mmol), and potassium phosphate (2.22 g, 10.44 mmol) were added to a mixture of dioxane (60 mL) and water (20 mL) under a nitrogen atmosphere at 100°C for 2 h. After cooling to room temperature, water (30 mL) was added and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 2 / 3) to afford 1C (2.05 g, 95% yield).

[0304] LCMS m / z=617.3[M+H] +

[0305] Step 3: 1D preparation

[0306] 1C (2.05 g, 3.32 mmol) was dissolved in tetrahydrofuran (20 mL), and hydrochloric acid (2N) (120 mL) was added dropwise at room temperature. The mixture was stirred at room temperature for 2 h. Saturated aqueous sodium bicarbonate was added to quench the reaction, and the mixture was extracted with ethyl acetate (110 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol v / v) = 100 / 3) to afford 1D (1.9 g).

[0307] LCMS m / z=571.2[M+H] +

[0308] Step 4: Preparation of 1E

[0309] 1D (0.15 g, 0.26 mmol) and 3-(2-fluoro-4-(piperazin-1-yl)phenyl)piperidine-2,6-dione (CAS: 2861233-27-2, 0.076 g, 0.26 mmol) were dissolved in dichloromethane (10 mL). Glacial acetic acid (0.031 g, 0.52 mmol) was added dropwise at room temperature. Sodium sulfate (0.088 g, 0.62 mmol) and sodium triacetoxyborohydride (0.11 g, 0.52 mmol) were also added. The mixture was stirred at room temperature for 16 h. The mixture was adjusted to alkalinity by adding 1N aqueous sodium hydroxide solution. The mixture was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 15 / 1) to afford 1E (0.1 g, yield: 45%).

[0310] LCMS m / z=846.5[M+H] +

[0311] Step 5: Preparation of compound 1

[0312] 1E (0.1 g, 0.12 mmol) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (3 mL) was added dropwise at room temperature and stirred for 1 h. The reaction mixture was concentrated under reduced pressure to remove the trifluoroacetic acid. The crude product was purified by prep-HPLC to obtain the trifluoroacetic acid salt of compound 1 (0.035 g).

[0313] LCMS m / z=746.2[M+H] +

[0314] 1 H NMR(400MHz,DMSO-d6)δ10.82(s,1H),9.90(s,1H),8.80(s,1H),8.67-8.51(m,2H),8.22(s,1H),8.05 (d,1H),7.94-7.84(m,1H),7.72(d,1H),7.50(dd,1H),7.41-7.30(m,1H),7.17(t,1H),7.01(d,1H),6 .93-6.74(m,2H),4.37(s,2H),3.96-3.84(m,3H),3.72-3.57(m,4H),3.26-3.03(m,6H),2.80-2.65(m ,3H),2.58-2.52(m,1H),2.23-2.10(m,1H),2.07-1.92(m,2H),1.92-1.83(m,2H),1.46-1.31(m,2H).

[0315] The trifluoroacetic acid salt of compound 1 (280 mg) was subjected to chiral separation and purification.

[0316] Preparation conditions: Instrument: SHIMADZU LC-20AP; Column: Chiral WHEIK column; Mobile phase: A for n-Hexane; B for 0.1% IPAm in ethanol and acetonitrile; Gradient: B for 100%; Flow rate: 80mL / min; Column temperature: room temperature; Wavelength: 220nm; Cycle time:20.0min;Sample preparation:Compound concentration was 10mg / ml,dissolved in acetonitrile.;Injection:3.0ml per injection.

[0317] Analysis conditions: Instrument: SHIMADZU LC-20AD; Column: Chiral WHEIK column; Mobile phase: A for n-Hexane; B for 0.1% IPAm in ethanol and acetonitrile; Gradient: B for 80%; Flow rate: 1mL / min; Column temperature: 35℃; Wavelength: 220nm

[0318] After preparative separation, fractions with the same retention time were combined and concentrated under reduced pressure to give compound 1-1 (87 mg) and compound 1-2 (92 mg).

[0319] One of compound 1-1 and compound 1-2 is 1-A, and the other is 1-B

[0320] Retention time of compound 1-1 under analytical conditions: 2.855 min, LCMS m / z=746.3[M+H] +

[0321] Retention time of compound 1-2 under analytical conditions: 4.270 min, LCMS m / z=746.3[M+H] +

[0322] Example 2: Preparation of Compound 2

[0323] Step 1: Preparation of 2B

[0324] 2A (2.87 g, 10 mmol) and N-BOC-piperazine (1.86 g, 10 mmol) were dissolved in toluene (50 mL). 2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (0.47 g, 1 mmol), RuPhos Pd G3 (CAS 1445085-77-7) (0.84 g, 1 mmol), and lithium bis(trimethylsilyl)amide (30 mL, 60 mmol) were added. The mixture was reacted at 80°C under nitrogen for 0.5 h. The reaction mixture was quenched with water and extracted three times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then flash column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 1) was performed to obtain compound 2B (1.6 g, yield: 41%).

[0325] Step 2: Preparation of 2C

[0326] 2B (1.6 g, 4.08 mmol) was dissolved in dichloromethane (15 mL). Trifluoroacetic acid (5 mL) was added dropwise at room temperature and stirred for 1 h. The reaction solution was concentrated under reduced pressure to remove the trifluoroacetic acid, and then redissolved in 100 mL of dichloromethane / methanol (V / V = 10 / 1). The solution was adjusted to alkaline with aqueous sodium hydroxide solution, and the mixture was separated and extracted. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 2C (0.8 g).

[0327] Step 3: 2D preparation

[0328] 1D (0.15 g, 0.26 mmol) and 2C (76 mg, 0.14 mmol) were dissolved in dichloromethane (10 mL). Glacial acetic acid (0.031 g, 0.52 mmol) was added dropwise at room temperature. Sodium sulfate (0.088 g, 0.62 mmol) and sodium triacetoxyborohydride (0.11 g, 0.52 mmol) were then added. The mixture was stirred at room temperature for 16 h. A 1N aqueous sodium hydroxide solution was added to make the solution alkaline. The mixture was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 15 / 1) to afford 2D (0.1 g, 45% yield).

[0329] Step 4: Preparation of compound 2

[0330] 2D (0.1 g, 0.12 mmol) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (3 mL) was added dropwise at room temperature and stirred for 1 h. The reaction mixture was directly concentrated under reduced pressure to remove the trifluoroacetic acid. The crude product was purified by prep-HPLC to obtain the trifluoroacetic acid salt of compound 2 (0.03 g).

[0331] LCMS m / z=747.6[M+H] +

[0332] 1 H NMR(400MHz,DMSO-d6)δ10.39(s,1H),9.91(s,1H),8.80(s,1H),8.70-8.61(m,1H),8.59-8.51(m,1 H),8.26(s,1H),8.08-7.99(m,1H),7.96-7.85(m,1H),7.73(d,1H),7.56-7.45(m,1H),7.43-7.34(m ,1H),7.29(t,1H),7.06-6.93(m,2H),6.87(dd,1H),4.37(s,2H),3.98-3.83(m,2H),3.70-3.54(m, 6H),3.24-3.03(m,6H),2.81-2.65(m,4H),2.12-1.95(m,1H),1.93-1.83(m,2H),1.49-1.32(m,2H).

[0333] Example 3: Preparation of Compound 3

[0334] Step 1: Preparation of compounds 3B-1 and 3B-2

[0335] Compound 3A (2.8 g, 13.58 mmol) (synthesis method, see Bioorganic & Medicinal Chemistry Letters, 2016, 26, 5877-5882) was dissolved in dichloromethane (50 mL), and di-tert-butyl dicarbonate (5.93 g, 27.17 mmol) and DMAP (3.32 g, 27.18 mmol) were added. The reaction was allowed to react at room temperature for 16 h. The reaction system was washed with 0.5 mol / L hydrochloric acid (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (ethyl acetate:petroleum ether (v / v) = 0:1-1:9) to obtain the racemate of compound 3B (3.4 g, yield: 82%).

[0336] The racemate of 3B was subjected to chiral separation as follows:

[0337] 1. Instrument: SFC Prep 150AP; Chromatographic column: Daicel IC-H (19 mm × 250 mm).

[0338] 2. Dissolve the sample in methanol and filter with a 0.45 μm filter to prepare a sample solution.

[0339] 3. Preparative chromatographic conditions: a. Mobile phases consisted of a system of A and B: mobile phase A: CO2; mobile phase B: methanol / isopropanol (v / v) = 1:1; b. Isocratic elution, mobile phase B content was 20%; c. Flow rate was 40 mL / min.

[0340] Peak time: chiral isomer 1 (compound 3B-1): 5.7 min, chiral isomer 2 (compound 3B-2): 6.47 min.

[0341] According to MicroED structure determination, compound 3B-1 has R configuration and compound 3B-2 has S configuration.

[0342] LCMS m / z=307.3[M+1] +

[0343] Step 2: Preparation of 3C

[0344] 3B-1 (0.45 g, 1.47 mmol) and NBS (0.31 g, 1.74 mmol) were added to acetonitrile (10 mL) and reacted at room temperature for 1 h. The mixture was then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate (v / v) = 0-50%) to afford 3C (0.50 g, yield: 88%).

[0345] LCMS m / z=329.1[M-55] +

[0346] Step 3: 3D preparation

[0347] 3C (0.5 g, 1.30 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.36 g, 3.26 mmol), Pd(dppf)Cl2·DCM (0.11 g, 0.13 mmol), and cesium carbonate (1.27 g, 3.90 mmol) were added to dioxane (15 mL) and water (3 mL) and reacted at 100°C overnight under a nitrogen atmosphere. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate (v / v) = 0-60%) to obtain 3D (0.34 g, yield: 44%).

[0348] Step 4: Preparation of 3E

[0349] 3D (0.34 g, 0.57 mmol) and palladium on carbon (10%, 0.49 g) were added to THF (10 mL) and reacted at 35°C overnight under a hydrogen atmosphere. The reaction was filtered through celite, and the filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (mobile phase: methanol / dichloromethane (v / v) = 0-10%) to afford 3E (0.22 g, yield: 92%).

[0350] LCMS m / z=418.2[M+1] +

[0351] Step 5: Preparation of 3F

[0352] 3E (0.22 g, 0.53 mmol) was dissolved in 3 mL of dichloromethane, and 3 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 30 min. The reaction solution was concentrated under reduced pressure, and a mixed solvent of dichloromethane / methanol (10:1) (30 mL x 5) and saturated sodium bicarbonate solution (30 mL) were added. The layers were stirred and separated. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 3F (160 mg).

[0353] Step 6: Preparation of 3G

[0354] Compound 1D (0.15 g, 0.26 mmol) and 3F (83 mg, 0.26 mmol) were dissolved in dichloromethane (10 mL). Glacial acetic acid (0.031 g, 0.52 mmol) was added dropwise at room temperature, followed by sodium sulfate (0.088 g, 0.62 mmol) and sodium triacetoxyborohydride (0.11 g, 0.52 mmol). The mixture was stirred at room temperature for 16 h. A 1N aqueous sodium hydroxide solution was added to make the solution alkaline. The mixture was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 15 / 1) to afford 3G (0.1 g, 44% yield).

[0355] Step 7: Preparation of compound 3

[0356] 3G (0.1 g, 0.121 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (3 mL) was added dropwise at room temperature. The mixture was stirred at room temperature for 1 h. The reaction mixture was directly concentrated under reduced pressure to remove the trifluoroacetic acid. The crude product was purified by prep-HPLC to obtain the trifluoroacetic acid salt of compound 3 (0.03 g).

[0357] LCMS m / z=772.6[M+H] +

[0358] 1H NMR(400MHz,DMSO-d6)δ10.78(s,1H),9.90(s,1H),8.79(s,1H),8.67-8.53(m,2H),8.22(s,1H),8.05(d,1 H),7.89(d,1H),7.72(d,1H),7.50(dd,1H),7.36(s,1H),7.01(d,1H),6.88(d,1H),6.80(d,1H),4.37(s,2 H),4.13-4.06(m,1H),3.89-3.82(m,1H),3.73-3.57(m,4H),3.43-3.31(m,1H),3.21-3.00(m,4H),2.94-2 .82(m,1H),2.80-2.51(m,6H),2.20-2.08(m,1H),2.07-1.83(m,5H),1.70-1.54(m,1H),1.46-1.32(m,2H).

[0359] Example 4: Preparation of Compound 4

[0360] Step 1: Preparation of 4C

[0361] 3B-2 (1.145 g, 3.74 mmol) and NBS (0.73 g, 4.11 mmol) were added to acetonitrile (30 mL) and allowed to react at room temperature for 1 h. The reaction solution was diluted with 200 mL of ethyl acetate, washed three times with water, and once with saturated sodium bicarbonate solution. The organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by flash column chromatography (mobile phase: ethyl acetate / petroleum ether (v / v) = 0-50%) to afford 4C (1.30 g, yield: 90%).

[0362] LCMS m / z=329.0[M-55] +

[0363] Step 2: 4D preparation

[0364] 4C (1.30 g, 3.37 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.11 g, 5.05 mmol), Pd(dppf)Cl2·DCM (0.28 g, 0.34 mmol), and cesium carbonate (3.29 g, 10.12 mmol) were added to dioxane (50 mL) and water (5 mL) and reacted at 80°C overnight under a nitrogen atmosphere. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (v / v) = 0-60%) to obtain 4D (1.75 g, yield: 87%).

[0365] Step 3: Preparation of 4E

[0366] 4D (1.75 g, 2.94 mmol) and palladium on carbon (10%, 1.75 g) were added to THF (20 mL) and reacted at 25°C overnight under a hydrogen atmosphere. The palladium on carbon was removed by filtration through celite, and the filter cake was washed with 200 mL of dichloromethane and concentrated under reduced pressure to give 4E (1.20 g).

[0367] LCMS m / z=362.1[M-55] +

[0368] Step 4: Preparation of 4F

[0369] 4E (0.50 g, 1.20 mmol) was dissolved in 15 mL of dichloromethane, and 15 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 30 min. The reaction solution was concentrated under reduced pressure, and a dichloromethane / methanol (10:1) mixed solvent (30 mL x 5) and saturated sodium bicarbonate aqueous solution (30 mL) were added. The layers were stirred and separated. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 4F (0.38 g).

[0370] LCMS m / z=318.2[M+H] +

[0371] Step 5: Preparation of 4G

[0372] To a reaction flask were added 4F (0.11 g, 0.35 mmol), 1D (0.20 g, 0.35 mmol), 1,2-dichloroethane (10 mL), sodium triacetoxyborohydride (0.15 g, 0.70 mmol), and glacial acetic acid (0.042 g, 0.70 mmol) and stirred at room temperature overnight. Dichloromethane and saturated aqueous sodium bicarbonate were added, and the layers were separated by stirring. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: DCM-CH3OH = 100-0 to 90-10) to afford 4G (0.17 g, yield: 51.50%).

[0373] Step 6: Preparation of compound 4

[0374] 4G (0.11 g, 0.13 mmol) and dichloromethane (5 mL) were added to the reaction flask, and trifluoroacetic acid (2 mL) was added with stirring. The reaction was stirred at room temperature for 2 hours, and the mixture was concentrated under reduced pressure to dryness. The crude product was lyophilized by prep-HPLC acid preparation to obtain trifluoroacetate salt of compound 4 (41 mg).

[0375] LCMS m / z=772.4[M+H] +

[0376] 1 H NMR (400MHz, DMSO-d6) δ10.91-10.56(m,1H),9.82(s,1H),8.73(s,1H),8.53(d,1H),8.46-8.33(m,1H),7.99(d,1H ),7.79(s,1H),7.67(d,1H),7.50(dd,1H),7.43(dd,1H),7.00-6.90(m,2H),6.82-6.72(m,1H),6.62(d,1H),4.36(s ,2H),3.86-3.77(m,1H),3.76-3.67(m,1H),3.65-3.52(m,3H),3.02-2.89(m,2H),2.78-2.56(m,7H),2.55-2.51(m ,1H),2.21(d,2H),2.16-2.00(m,2H),2.00-1.91(dd,1H),1.88-1.72(m,4H),1.63-1.55(m,1H),1.33-1.26(m,2H).

[0377] Example 5: Preparation of Compound 5

[0378] Step 1: Preparation of 5B

[0379] 4C (6.29 g, 16.32 mmol), benzophenone imine (4.14 g, 22.85 mmol), cesium carbonate (10.63 g, 32.64 mmol), palladium acetate (0.73 g, 3.26 mmol), and XANT PHOS (0.94 g, 1.63 mmol) were added to a dioxane solution (100 mL) and reacted at 105°C under a nitrogen atmosphere for 16 h. The reaction solution was cooled to room temperature, filtered through celite to remove the solid, and the filter cake was washed with dichloromethane. The organic phase was collected and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (v / v) = 1 / 5) to obtain 5B (6.94 g, yield: 87%).

[0380] LCMS m / z=486.2[M+H] +

[0381] Step 2: Preparation of 5C

[0382] 5B (6.94 g, 14.29 mmol) was added to methanol (200 mL), followed by palladium on carbon (6.92 g, wt% = 10%) and ammonium acetate (6.79 g, 88.03 mmol). The mixture was reacted under a hydrogen atmosphere (balloon pressure) at room temperature for 12 h. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (v / v) = 1 / 1) to obtain 5C (4.15 g, 90% yield).

[0383] LCMS m / z=322.2[M+H] +

[0384] Step 3: 5D preparation

[0385] 5C (4.15 g, 12.91 mmol), ethyl acrylate (3.88 g, 38.73 mmol), and N,N-diisopropylethylamine (5.01 g, 38.73 mmol) were added sequentially to ethanol (60 mL) and reacted at 100°C for 72 h. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1:20) to obtain 5D (3.91 g, yield: 71%).

[0386] LCMS m / z=422.3[M+H] +

[0387] Step 4: Preparation of 5E

[0388] 5D (0.50 g, 1.19 mmol) and N,N-diisopropylethylamine (0.46 g, 3.56 mmol) were added to tetrahydrofuran (20 mL), followed by the slow addition of triphosgene (0.39 g, 1.31 mmol) and the reaction was allowed to react at room temperature for 1 h. Aqueous ammonia (5 mL) was added, and the temperature was raised to 50°C and the reaction continued for 2 h. After cooling to room temperature, the reaction solution was diluted with 100 mL of ethyl acetate. The organic phase was washed three times with water and once with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1:15) to afford 5E (0.46 g, yield: 83%).

[0389] LCMS m / z=465.3[M+H] +

[0390] Step 5: Preparation of 5F

[0391] 5E (0.46 g, 1.00 mmol) was added to acetonitrile (10 mL), followed by a 40% methanolic solution of benzyltrimethylammonium hydroxide (1.2 mL). The temperature was raised to 60°C and the reaction mixture was allowed to react for 2 h. After cooling to room temperature, an appropriate amount of silica gel was added and the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) to afford 5F (0.21 g, 50% yield).

[0392] Step 6: 5G preparation

[0393] 5F (0.21 g, 0.50 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (5 mL) was added, and the mixture was stirred at room temperature for 1 h. The reaction solution was concentrated under reduced pressure to remove trifluoroacetic acid, and 10 mL of dichloromethane and 1 mL of isopropanol were added to dissolve the residue. The mixture was adjusted to alkaline with aqueous sodium bicarbonate solution, and extracted three times with dichloromethane / isopropanol (v / v) = 10 / 1. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 5G (0.158 g).

[0394] LCMS m / z=319.2[M+H] +

[0395] Step 7: Preparation of 5H

[0396] 5G (0.02 g, 0.28 mmol), 1D (0.16 g, 0.28 mmol), 1,2-dichloroethane (10 mL), sodium triacetoxyborohydride (0.12 g, 0.56 mmol) and glacial acetic acid (0.034 g, 0.56 mmol) were added to the reaction flask and stirred at room temperature overnight. Dichloromethane and saturated aqueous sodium bicarbonate solution were added and the layers were stirred. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated residue was purified by column chromatography (eluent: DCM-CH3OH = 100-0 to 90-10) to give 5H (0.12 g, yield: 49%).

[0397] Step 8: Preparation of compound 5

[0398] 5H (0.12 g, 0.14 mmol) and dichloromethane (5 mL) were added to the reaction flask, and trifluoroacetic acid (2 mL) was added with stirring. The reaction was carried out at room temperature for 2 h. After concentration under reduced pressure, compound 5 (37 mg, yield: 34%) was prepared by prep-HPLC acidification.

[0399] LCMS m / z=773.3[M+H] +

[0400] 1 H NMR(400MHz,DMSO-d6)δ10.45-10.15(m,1H),9.82(s,1H),8.73(s,1H),8.54(d,1H),8.46-8.35(m,1H ),8.00(d,1H),7.79(s,1H),7.67(d,1H),7.51(dd,1H),7.43(dd,1H),7.03-6.89(m,3H),6.75-6.68(m ,1H),4.36(s,2H),3.77-3.70(m,1H),3.66-3.53(m,4H),3.05-2.96(m,1H),2.95-2.85(m,2H),2.77- 2.58(m,7H),2.21(d,2H),2.11-1.98(m,1H),1.95-1.75(m,4H),1.73-1.55(m,2H),1.31-1.25(m,2H).

[0401] Example 6: Preparation of Compound 6

[0402] Step 1: Preparation of 6A

[0403] 3C (5.0 g, 12.98 mmol), benzophenone imine (3.05 mL, 3.29 g, 18.17 mmol), cesium carbonate (9.30 g, 28.56 mmol), palladium acetate (583 mg, 2.6 mmol), and XANT PHOS (751 mg, 1.3 mmol) were added to a dioxane solution (100 mL) and reacted at 100°C under a nitrogen atmosphere for 16 h. The reaction solution was cooled to room temperature, filtered through celite to remove the solid, and the filter cake was washed with dichloromethane. The organic phase was collected and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (v / v) = 1 / 5) to obtain 6A (5.6 g, yield: 89%).

[0404] LCMS m / z=486.3[M+H] +

[0405] Step 2: Preparation of 6B

[0406] 6A (5.6 g, 11.53 mmol) was added to methanol (200 mL), followed by palladium on carbon (3.0 g, wt% = 10%) and ammonium acetate (5.6 g, 72.6 mmol). The mixture was reacted under a hydrogen atmosphere (balloon pressure) at room temperature for 16 h. The product was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (v / v) = 1 / 1) to obtain 6B (3.6 g, 97% yield).

[0407] LCMS m / z=322.3[M+H] +

[0408] Step 3: Preparation of 6C

[0409] 6B (3.6 g, 11.2 mmol), ethyl acrylate (3.36 g, 33.60 mmol), and N,N-diisopropylethylamine (4.34 g, 33.60 mmol) were added sequentially to ethanol (100 mL) and the temperature was raised to 100°C for 72 h. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1:20) to afford 6C (3.0 g, yield: 64%).

[0410] LCMS m / z=422.3[M+H] +

[0411] Step 4: Preparation of 6D

[0412] 6C (1.0 g, 2.37 mmol) and N,N-diisopropylethylamine (0.92 g, 7.11 mmol) were added to tetrahydrofuran (30 mL), followed by the slow addition of triphosgene (0.77 g, 2.61 mmol) and the reaction was allowed to react at room temperature for 1 h. Aqueous ammonia (9 mL) was then added, and the temperature was raised to 50°C, where the reaction continued for 2 h. The reaction solution was diluted with 100 mL of ethyl acetate, and the organic phase was washed three times with water and once with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1:15) to afford 6D (1.0 g, yield: 91%).

[0413] LCMS m / z=465.3[M+H] +

[0414] Step 5: Preparation of 6E

[0415] 6D (1.0 g, 2.15 mmol) was added to acetonitrile (20 mL), followed by a 40% methanolic solution of benzyltrimethylammonium hydroxide (2.5 mL, 6.45 mmol). The mixture was heated to 60°C for 2 h. Silica gel was added, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) to afford 6E (0.69 g, yield: 77%).

[0416] LCMS m / z=363.2[M-55] +

[0417] Step 6: Preparation of 6F

[0418] 6E (0.5 g, 1.19 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (5 mL) was added, and the mixture was stirred at room temperature for 1 h. The reaction solution was concentrated under reduced pressure to remove trifluoroacetic acid, and 10 mL of dichloromethane and 1 mL of isopropanol were added to dissolve the residue. The mixture was adjusted to alkaline with aqueous sodium carbonate solution, and extracted three times with dichloromethane / isopropanol (v / v) = 10 / 1. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 6F (0.37 g).

[0419] Step 7: Preparation of Compound 6G

[0420] Compound 1D (0.15 g, 0.26 mmol) and 6F (83 mg, 0.26 mmol) were dissolved in dichloromethane (10 mL). Glacial acetic acid (0.031 g, 0.52 mmol) was added dropwise at room temperature, followed by sodium sulfate (0.088 g, 0.62 mmol) and sodium triacetoxyborohydride (0.11 g, 0.52 mmol). The mixture was stirred at room temperature for 16 h. A 1N aqueous sodium hydroxide solution was added to make the solution alkaline. The mixture was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 15 / 1) to obtain compound 6G (0.1 g, yield: 44%).

[0421] Step 8: Preparation of compound 6

[0422] Dissolve 6G (0.1 g, 0.11 mmol) in dichloromethane (10 mL) and add trifluoroacetic acid (3 mL) dropwise at room temperature. Stir at room temperature for 1 h. The reaction mixture is directly concentrated under reduced pressure to remove trifluoroacetic acid. The crude product is purified by prep-HPLC to obtain the trifluoroacetic acid salt of compound 6 (0.025 g).

[0423] LCMS m / z=387.3[(M+2H) / 2] +

[0424] 1 H NMR(400MHz,D2O)δ8.58(dd,1H),8.27-8.17(m,1H),8.16-8.00(m,3H),7.94-7.78(m,2H), 7.54(d,1H),7.49-7.40(m,1H),7.17(d,1H),6.92(d,1H),4.49(s,2H),4.23-4.09(m,1H),3 .94-3.79(m,5H),3.79-3.69(m,1H),3.62-3.49(m,1H),3.42-3.21(m,6H),3.16-3.02(m,1H ),2.96(t,2H),2.92-2.76(m,2H),2.49-2.32(m,1H),2.26-2.09(m,3H),1.93-1.65(m,3H).

[0425] Example 7: Preparation of Compound 7

[0426] Step 1: Preparation of 7A

[0427] Under a nitrogen atmosphere, a reaction flask was charged with 4C (7.00 g, 18.17 mmol) and 70 mL of tetrahydrofuran. The temperature was cooled to -78°C, and a 2.5 M n-butyllithium solution in n-hexane (14.50 mL, 36.34 mmol) was slowly added dropwise. The system was stirred at -78°C for 1.5 h, after which the carbon dioxide was replaced three times. The temperature was maintained below -40°C, and the reaction was carried out under a carbon dioxide balloon for 0.5 h. The system was returned to room temperature, and 20 mL of ethyl acetate was added. The pH was adjusted to 2 with 1 M dilute hydrochloric acid, and the reaction was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10:1 to 2:1) to afford 7A (2.4 g, 37% yield).

[0428] Step 2: Preparation of 7B

[0429] To a reaction flask were added 7A (0.15 g, 0.43 mmol), (S)-3-aminopiperidine-2,6-dione hydrochloride (0.071 g, 0.43 mmol), EDCI (0.16 g, 0.86 mmol), HOBT (0.087 g, 0.65 mmol) and DMF (5 mL). N-methylmorpholine (0.13 g, 1.29 mmol) was added with stirring and the mixture was reacted at room temperature for 3 h. Ethyl acetate and saturated aqueous sodium bicarbonate solution were added, stirred, and allowed to stand for stratification. The organic layer was washed once with saturated aqueous sodium bicarbonate solution and once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 7B (0.18 g).

[0430] Step 3: Preparation of 7C

[0431] 7B (0.18 g, 0.39 mmol) and dichloromethane (5 mL) were added to the reaction flask, and trifluoroacetic acid (2 mL) was added with stirring. The reaction was carried out at room temperature for 2 h, and the mixture was concentrated under reduced pressure. A mixed solution of dichloromethane / isopropanol (2 / 1) and a saturated aqueous sodium bicarbonate solution were added, and the layers were stirred and separated. The aqueous layer was extracted once with a mixed solution of dichloromethane / isopropanol (2 / 1). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 7C (0.13 g).

[0432] Step 4: Preparation of 7D

[0433] To a reaction flask were added 7C (0.13 g, 0.36 mmol), 1D (0.21 g, 0.36 mmol), 1,2-dichloroethane (10 mL), sodium triacetoxyborohydride (0.15 g, 0.72 mmol), and glacial acetic acid (0.043 g, 0.72 mmol). The mixture was stirred at room temperature overnight. Dichloromethane and saturated aqueous sodium bicarbonate solution were added, and the layers were stirred. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (eluent: DCM-CH3OH = 100-0 to 90-10) to give 7D (0.17 g, yield: 52%).

[0434] Step 5: Preparation of compound 7

[0435] 7D (0.17 g, 0.19 mmol) and dichloromethane (5 mL) were added to the reaction flask, and trifluoroacetic acid (2 mL) was added with stirring. The reaction was carried out at room temperature for 2 h, and the mixture was concentrated to dryness under reduced pressure. The crude product was purified by prep-HPLC to obtain trifluoroacetate salt of compound 7 (3 mg).

[0436] LCMS m / z=408.6[(M+2H) / 2] +

[0437] 1 H NMR (400MHz, CD3OD) δ8.62(dd,1H),8.47(d,1H),8.18(s,1H),8.14-8.05(m,1H),7.83(dd,1H),7.78-7. 63(m,2H),7.54(d,1H),7.48-7.37(m,1H),7.22-7.10(m,1H),6.75(d,1H),4.79(dd,1H),4.42(s,2H),4 .26-4.14(m,1H),3.84-3.66(m,4H),3.61-3.48(m,1H),3.30-3.12(m,4H),3.08-2.92(m,3H),2.90-2.6 6(m,4H),2.38-2.26(m,1H),2.25-2.09(m,3H),2.08-1.94(m,2H),1.86-1.72(m,1H),1.70-1.51(m,2H).

[0438] Example 8: Preparation of Compound 8

[0439] The trifluoroacetic acid salt of compound 8 (10 mg) was prepared by prep-HPLC acidification according to the synthesis method of compound 7.

[0440] LCMS m / z=408.2[(M+2H) / 2]+

[0441] Example 9: Preparation of Compound 9

[0442] Step 1: Preparation of 9A

[0443] Compound 2A (0.50 g, 1.74 mmol) and 4-(dimethoxymethyl)-piperidine (0.55 g, 3.48 mmol) were dissolved in toluene (10 mL). 2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (0.16 g, 0.35 mmol), RuPhos Pd G3 (0.29 g, 0.35 mmol), and lithium bistrimethylsilylamide (10.44 mL, 10.44 mmol, 1 M) were added. The mixture was stirred at 80°C under nitrogen for 0.5 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography (mobile phase: dichloromethane / methanol (v / v) = 10 / 1) to afford 9A (0.27 g, 42% yield).

[0444] LCMS m / z=366.2[M+H] +

[0445] Step 2: Preparation of 9B

[0446] 9A (0.27 g, 0.75 mmol) was dissolved in tetrahydrofuran (4 mL), and hydrochloric acid (3N) (4 mL) was added dropwise at room temperature. The mixture was stirred at 60°C for 2 h. Saturated aqueous sodium carbonate was added to quench the mixture, and the mixture was extracted with dichloromethane / methanol (v / v) = 10 / 1 (50 mL x 4). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 9B (0.23 g).

[0447] Step 3: Preparation of 9C

[0448] Methyl 6-aminopicolinate (10.00 g, 65.72 mmol) was dissolved in acetonitrile (300 mL), and NBS (12.28 g, 69.01 mmol) was added. The mixture was stirred at room temperature for 1 h. The reaction solution was diluted with 500 mL of ethyl acetate, washed three times with water, and once with saturated sodium bicarbonate. The organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by slurrying with petroleum ether / ethyl acetate (20 mL / 80 mL) to afford 9C (11.00 g, yield: 72%).

[0449] LCMS m / z=231.1[M+H] +

[0450] Step 4: Preparation of 9D

[0451] 9C (5.00 g, 65.72 mmol) was dissolved in acetic anhydride (20 mL) and stirred at 70°C for 1 h. The reaction mixture was cooled to room temperature and water was added to precipitate a yellow solid. The solid was filtered and the filter cake was washed three times with water. The solid was redissolved in 200 mL of dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 9D (5.90 g).

[0452] LCMS m / z=273.0[M+H] +

[0453] Step 5: Preparation of 9E

[0454] 9D (5.90 g, 21.61 mmol) was dissolved in methanol (300 mL), cooled to 0°C, and sodium borohydride (4.09 g, 108.05 mmol) was slowly added. The mixture was stirred at 80°C for 16 h. The reaction solution was cooled to room temperature and quenched with saturated aqueous ammonium chloride. 500 mL of ethyl acetate was added, and the layers were separated by stirring. The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography (mobile phase: petroleum ether / ethyl acetate (v / v) = 1 / 1) to obtain compound 9E (1.00 g, yield: 19%).

[0455] LCMS m / z=245.0[M+H] +

[0456] Step 6: Preparation of 9F

[0457] 9E (1.00 g, 4.08 mmol) was dissolved in DCM (30 mL). Triethylamine (1.24 g, 12.24 mmol) was added, and the temperature was lowered to 0°C. Methanesulfonic anhydride (1.07 g, 6.12 mmol) was slowly added, and the mixture was allowed to react at room temperature for 0.5 h. The reaction solution was washed three times with water, once with a saturated aqueous ammonium chloride solution, and once with a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 9F (1.11 g).

[0458] LCMS m / z=323.0[M+H] +

[0459] Step 7: Preparation of 9G

[0460] 9F (1.11 g, 3.43 mmol) was dissolved in acetonitrile (30 mL), and DIPEA (1.77 g, 13.72 mmol) and dimethylamine hydrochloride (0.56 g, 6.86 mmol) were added. The mixture was allowed to react at 80°C for 1 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography (mobile phase: dichloromethane / methanol (v / v) = 10 / 1) to obtain compound 9G (0.90 g, yield: 96%).

[0461] LCMS m / z=272.0[M+H] +

[0462] Step 8: Preparation of 9H

[0463] 9G (0.90 g, 3.31 mmol) and N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (CAS: 286961-14-6, 1.54 g, 4.96 mmol) were dissolved in 1,4-dioxane (40 mL). XPhos Pd G4 (0.28 g, 0.33 mmol), X-PHOS (0.32 g, 0.66 mmol), and a 10 mL aqueous solution of potassium phosphate (2.11 g, 9.93 mmol) were added. The mixture was reacted at 105°C under nitrogen for 16 h. The reaction solution was cooled to room temperature, diluted with 300 mL of dichloromethane, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (mobile phase: dichloromethane / methanol (v / v) = 10 / 1) to obtain compound 9H (0.72 g, yield: 58%).

[0464] LCMS m / z=375.3[M+H] +

[0465] Step 9: Preparation of 9I

[0466] 9H (0.72 g, 1.93 mmol) was added to a mixture of methanol (15 mL) and ethanol (15 mL), followed by palladium on carbon (0.72 g, wt% = 10%). The mixture was reacted under a hydrogen atmosphere (balloon pressure) at 40°C for 16 h. The reaction mixture was cooled to room temperature, filtered through celite, and the filter cake was washed with dichloromethane / methanol (v / v) = 10 / 1. The organic phases were combined and concentrated under reduced pressure to afford 9I (0.72 g).

[0467] LCMS m / z=377.2[M+H] +

[0468] Step 10: Preparation of 9J

[0469] 9I (0.74 g, 1.98 mmol) was dissolved in ethanol (15 mL), and water (15 mL) and sodium hydroxide (0.63 g, 15.84 mmol) were added. The mixture was reacted at 80°C for 16 h. The reaction solution was cooled to room temperature and extracted with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, and the residue was concentrated under reduced pressure to yield 9J (0.62 g).

[0470] LCMS m / z=335.2[M+H] +

[0471] Step 11: Preparation of 9K

[0472] 9J (0.52 g, 1.55 mmol) and tert-butyl 7-bromo-4-chloro-1-oxoisoindoline-2-carboxylate (CAS: 2628351-94-8, 0.54 g, 1.55 mmol) were dissolved in 1,4-dioxane (10 mL). Tris(dibenzylideneindeneacetone)dipalladium (0.14 g, 0.16 mmol), Xant-phos (0.18 g, 0.31 mmol), and potassium carbonate (0.64 g, 4.65 mmol) were added. The reaction was stirred at 100°C under nitrogen for 4 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography (mobile phase: dichloromethane / methanol (v / v) = 15 / 1) to afford 9K (0.38 g, 40% yield).

[0473] LCMS m / z=600.2[M+H] +

[0474] Step 12: Preparation of 9L

[0475] 9K (0.45 g, 0.75 mmol), 1B-1 (0.29 g, 1.13 mmol), X-PHOS (0.07 g, 0.15 mmol), XPHOS-Pd-G2 (0.06 g, 0.075 mmol), and potassium phosphate (0.48 g, 2.25 mmol) were added to a mixture of dioxane (20 mL) and water (5 mL). The atmosphere was replaced with nitrogen three times and the reaction was carried out at 100°C for 3 h. The reaction solution was diluted with 200 mL of dichloromethane, the layers separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (mobile phase: dichloromethane / methanol (v / v) = 15 / 1) to afford 9L (0.34 g, yield: 65%).

[0476] LCMS m / z=700.5[M+H] +

[0477] Step 13: Preparation of 9M

[0478] Compound 9L (0.34 g, 0.49 mmol) was dissolved in DCM (10 mL) and trifluoroacetic acid (10 mL) was added. The mixture was allowed to react at room temperature for 1 h. The reaction solution was concentrated under reduced pressure and redissolved in dichloromethane / methanol (15 / 1) (200 mL). Aqueous sodium carbonate solution was added to make the solution alkaline. After separation, the aqueous phase was extracted three times with DCM. The combined organic phases were dried over anhydrous sodium sulfate, and the residue was concentrated under reduced pressure to yield 9M (0.23 g).

[0479] LCMS m / z=500.0[M+H] +

[0480] Step 14: Preparation of Compound 9

[0481] 9M (0.12 g, 0.24 mmol) and 9B (0.08 g, 0.24 mmol) were dissolved in chloroform (10 mL). Glacial acetic acid (0.03 g, 0.48 mmol) was added at room temperature, followed by anhydrous sodium sulfate (0.07 g, 0.48 mmol). The mixture was reacted at 60°C for 16 h. Sodium triacetoxyborohydride (0.51 g, 2.40 mmol) was slowly added, and the reaction was continued at 60°C for 3 h. Saturated aqueous sodium bicarbonate solution was added to adjust the mixture to alkalinity. The mixture was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by prep-HPLC with acidic preparative HPLC to give the trifluoroacetate salt of compound 9 (38 mg).

[0482] LCMS m / z=803.0[M+H] +

[0483] 1 H NMR(400MHz,CD3OD)δ8.64-8.54(m,1H),8.38(d,1H),8.16(s,1H),7.85-7.74(m,3 H),7.45-7.35(m,1H),7.29(d,1H),7.22(t,1H),6.86-6.76(m,2H),4.66(s,2H),4 .43(s,2H),3.88-3.76(m,4H),3.73(t,2H),3.27-3.11(m,5H),3.09(s,6H),2.92- 2.82(m,2H),2.80(t,2H),2.27-2.00(m,5H),1.99-1.88(m,2H),1.57-1.41(m,2H).

[0484] Example 10: Preparation of Compound 10

[0485] The trifluoroacetic acid salt of compound 10 (10 mg) was obtained by prep-HPLC acidification according to the synthesis of the aforementioned compound.

[0486] LCMS m / z=830.3[M+H] +

[0487] 1H NMR(400MHz,DMSO-d6)δ10.37(s,1H),10.07(s,1H),8.88(s,1H),8.51(dd,1H),8.41(d,1H),8.10 (s,1H),7.87-7.67(m,3H),7.35-7.17(m,2H),7.03(d,1H),6.91(d,1H),4.54-4.45(m,2H),4.40(s ,2H),4.16-4.10(m,1H),3.73-3.56(m,4H),3.49-3.33(m,1H),3.22-3.04(m,4H),3.01-2.83(m,9 H),2.82-2.59(m,6H),2.11-1.97(m,2H),1.96-1.82(m,2H),1.74-1.59(m,1H),1.57-1.36(m,2H).

[0488] Example 11: Preparation of Compound 11

[0489] The trifluoroacetic acid salt of compound 11 (10 mg) was obtained by prep-HPLC according to the synthesis of the aforementioned compound.

[0490] LCMS m / z=830.4[M+H] +

[0491] 1 H NMR(400MHz,DMSO-d6)δ10.36(s,1H),10.06(s,1H),8.86(s,1H),8.54-8.34(m,2H),8.04(s,1H) ),7.83-7.68(m,3H),7.32-7.19(m,2H),7.03(d,1H),6.91(d,1H),4.53-4.46(m,2H),4.40(s,2H ),4.17-4.09(m,1H),3.68-3.59(m,4H),3.44-3.35(m,1H),3.21-3.04(m,4H),3.02-2.84(m,9H) ,2.83-2.61(m,6H),2.10-1.97(m,2H),1.97-1.81(m,2H),1.73-1.59(m,1H),1.55-1.38(m,2H).

[0492] Example 12: Preparation of Compound 12

[0493] The trifluoroacetic acid salt of compound 12 (12 mg) was prepared by prep-HPLC acidification according to the synthesis method of the fourth step of Example 1.

[0494] LCMS m / z=804.2[M+H] +

[0495] Example 13: Preparation of Compound 13

[0496] The trifluoroacetic acid salt of compound 13 (18 mg) was prepared by the synthetic method of the fourth step of Reference Example 1 via prep-HPLC acidification.

[0497] LCMS m / z=759.5[M+H] +

[0498] 1 H NMR(400MHz,CD3OD)δ8.65-8.51(m,2H),8.15(s,1H),8.07(d,1H),7.80(dd,1H),7.71(d,1H),7 .54(dd,1H),7.46-7.38(m,1H),7.12-7.00(m,2H),6.81(d,1H),4.40(s,2H),4.21-4.11(m,1H) ,3.89-3.80(m,2H),3.79-3.65(m,4H),3.50-3.32(m,4H),3.20-3.08(m,1H),3.08-2.99(m,1H) ,2.90-2.77(m,5H),2.38-2.26(m,2H),2.17-2.07(m,1H),2.03-1.89(m,2H),1.88-1.75(m,1H).

[0499] Example 14: Preparation of Compound 14

[0500] Step 1: Preparation of 14A

[0501] 5-Fluoro-2-nitropyridine (2.8 g, 19.71 mmol), 4-piperidone ethylene glycol acetal (2.82 g, 19.71 mmol), sodium bicarbonate (1.66 g, 19.71 mmol), and DMF (30 mL) were added to a reaction flask and reacted at 90°C for 4 h. After cooling to room temperature, water (100 mL) was added and stirred for 1 h to allow crystallization. The mixture was filtered, the filter cake was washed with water, and concentrated to dryness under reduced pressure to obtain 14A (4.82 g).

[0502] Step 2: Preparation of 14B

[0503] To a reaction flask, 14A (2 g, 7.54 mmol), tetrahydrofuran (30 mL), and water (7 mL) were added. Zinc powder (2.47 g, 37.7 mmol) and ammonium chloride (2.02 g, 37.7 mmol) were added with stirring and allowed to react at room temperature for 1 h. Dichloromethane and saturated aqueous sodium bicarbonate were added, stirred, and filtered. The filtrate was separated, and the organic layer was added with an appropriate amount of silica gel and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: DCM-CH3OH = 100-0 to 90-10) to afford 14B (1.2 g, yield: 68%).

[0504] 14D (0.5 g, yield: 52%) was obtained by referring to the first and second steps of the synthesis method in Example 1.

[0505] Step 5: Preparation of 14E

[0506] To a reaction flask, 14D (0.6 g, 1.0 mmol), tetrahydrofuran (6 mL), and 3 M hydrochloric acid (6 mL) were added and reacted at 60°C for 2 h. The mixture was cooled to room temperature, ethyl acetate was added, and the pH was adjusted to 8-9 with saturated aqueous sodium carbonate. The layers were separated, and an appropriate amount of silica gel was added to the organic layer, which was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: DCM-CH3OH = 100-0 to 90-10) to afford 14E (0.28 g, yield: 61%).

[0507] LCMS m / z=457.3[M+H] +

[0508] Step 6: Preparation of compound 14

[0509] The trifluoroacetic acid salt of compound 14 (27 mg) was prepared by prep-HPLC acidification according to the synthesis method of the fourth step of Example 1.

[0510] LCMS m / z=759.5[M+H] +

[0511] 1H NMR (400MHz, DMSO-d6) δ10.36(s,1H),9.92(s,1H),8.80(s,1H),8.67-8.61(m,1H),8.58(d,1H),8.23(s,1H),8.07( d,1H),7.91(dd,1H),7.73(d,1H),7.52(dd,1H),7.41-7.32(m,1H),7.02(dd,2H),6.91(d,1H),4.38(s,2H),4.20-4. 13(m,1H),3.87-3.78(m,2H),3.73-3.64(m,2H),3.60(d,2H),3.48-3.37(m,1H),3.35-3.26(m,1H),3.21-3.00(m,2H ),2.98-2.87(m,1H),2.82-2.60(m,6H),2.27-2.15(m,2H),2.09-1.97(m,1H),1.88-1.74(m,2H),1.73-1.60(m,1H).

[0512] Example 15: Preparation of Compound 15

[0513] Step 1: Preparation of 15B

[0514] 15A (4.0 g, 15.79 mmol), ethylene glycol (8 mL, 157.9 mmol), and 4-methylbenzenesulfonate pyridinium (0.4 g, 1.58 mmol) were added to toluene (20 mL) and reacted at 140°C for 5 h. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (v / v) = 1 / 5) to obtain 15B (3.86 g, yield: 82%).

[0515] Step 2: Preparation of 15C

[0516] 15B (1.5 g, 5.04 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (3 mL) was added dropwise at room temperature. The mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to remove trifluoroacetic acid. 5-Fluoro-2-nitropyridine (1.43 g, 10.08 mmol), triethylamine (2.55 g, 25.2 mmol), and DMF (30 mL) were added to the crude product. The reaction was allowed to proceed at 90°C for 4 h. After cooling to room temperature, water (100 mL) was added and the mixture was stirred for 1 h to allow crystallization. The mixture was filtered, the filter cake was washed with water, and concentrated under reduced pressure to dryness to obtain 15C (1.3 g).

[0517] Step 3: Preparation of compound 15D

[0518] Palladium on carbon (1.3 g) was added to a solution of compound 15C (1.3 g, 4.08 mmol) in methanol (30 mL). The mixture was stirred at room temperature overnight under a hydrogen atmosphere. The mixture was filtered through celite and eluted with methanol. The eluate was concentrated under reduced pressure to give 15D (1 g).

[0519] LCMS m / z=290.2[M+H] +

[0520] The synthesis method of steps 4 to 8 was similar to that of Example 1, and trifluoroacetate (0.2 g) of compound 15 was prepared by prep-HPLC acidification.

[0521] LCMS m / z=813.0[M+H] +

[0522] 1 H NMR(400MHz,CD3OD)δ8.61(dd,1H),8.55(d,1H),8.21(d,1H),8.17(s,1H),7.82(dd,1H),7.78-7.70(m,2H),7 .46-7.39(m,1H),7.15(d,1H),7.03(d,1H),6.79(d,1H),4.42(s,2H),4.16-4.06(m,1H),3.72(t,2H),3.67-3. 58(m,1H),3.58-3.49(m,1H),3.40-3.32(m,5H),3.28-3.23(m,2H),3.22-3.07(m,2H),3.01-2.90(m,1H),2.9 0-2.68(m,5H),2.33-2.21(m,2H),2.13-2.03(m,1H),2.03-1.95(m,2H),1.91-1.82(m,2H),1.82-1.71(m,3H).

[0523] Example 16: Preparation of Compound 16

[0524] Step 1: Preparation of 16A

[0525] To a reaction flask were added 15G (0.2 g, 0.39 mmol), 6F (0.12 g, 0.39 mmol), dichloromethane (10 mL), and glacial acetic acid (0.070 g, 1.17 mmol). The mixture was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (0.25 g, 1.17 mmol) was then added and the reaction continued at room temperature for 3 h. Water and dichloromethane were added, and the layers were separated by stirring. The organic layer was washed with saturated sodium bicarbonate solution and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: DCM-CH3OH = 100-0 to 90-10) to afford 16A (0.22 g, yield: 69%).

[0526] Step 2: Preparation of compound 16

[0527] To a reaction flask, 16A (0.22 g, 0.24 mmol) and dichloromethane (5 mL) were added dropwise, followed by stirring with trifluoroacetic acid (3.07 g, 26.93 mmol). The mixture was allowed to react at room temperature for 2 h. The mixture was concentrated under reduced pressure to dryness, and dichloromethane / methanol and saturated aqueous sodium bicarbonate were added. The mixture was stirred and separated into layers. An appropriate amount of silica gel was added to the organic phase, which was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: DCM-CH3OH = 100-0 to 90-10) to afford compound 16 (0.11 g, yield: 56%).

[0528] LCMS m / z=812.9[M+H] +

[0529] 1 H NMR(400MHz,DMSO-d6)δ10.32(s,1H),9.82(s,1H),8.72(s,1H),8.52(d,1H),8.44-8.33(m,1H),8.09- 7.89(m,1H),7.79(s,1H),7.67(d,1H),7.56-7.30(m,2H),7.04-6.83(m,3H),6.70(d,1H),4.36(s,2H) ,3.79-3.65(m,1H),3.59(t,2H),3.13-2.90(m,5H),2.90-2.78(m,2H),2.77-2.64(m,4H),2.64-2.53( m,1H),2.49-2.32(m,3H),2.13-1.82(m,4H),1.82-1.65(m,3H),1.64-1.50(m,3H),1.49-1.36(m,2H).

[0530] Example 17: Preparation of Compound 17

[0531] The trifluoroacetic acid salt of compound 17 (114 mg) was prepared by the synthetic method of steps 11 to 14 of reference example 9 via prep-HPLC acidification.

[0532] LCMS m / z=745.0[M+H] +

[0533] 1 H NMR(400MHz,CD3OD)δ8.72(d,1H),8.63(dd,1H),8.31-8.22(m,1H),8.19(s,1H),7.84( dd,1H),7.77(d,1H),7.71(dd,1H),7.48-7.39(m,1H),7.17(t,1H),7.07(d,1H),6.91- 6.76(m,2H),4.42(s,2H),3.93(dd,1H),3.85-3.68(m,4H),3.24-3.08(m,4H),3.03-2. 85(m,3H),2.81-2.60(m,2H),2.34-2.02(m,7H),2.02-1.90(m,2H),1.64-1.45(m,2H).

[0534] Example 18: Preparation of Compound 18

[0535] The trifluoroacetic acid salt of compound 18 (54 mg) was prepared by prep-HPLC under the reaction conditions of step 14 of reference example 9.

[0536] LCMS m / z=746.0[M+H] +

[0537] 1 H NMR(400MHz,CD3OD)δ8.75(d,1H),8.63(dd,1H),8.31-8.22(m,1H),8.19(s,1H), 7.84(dd,1H),7.76(d,1H),7.70(dd,1H),7.48-7.37(m,1H),7.23(t,1H),7.06(d, 1H),6.90-6.74(m,2H),4.42(s,2H),3.88-3.66(m,6H),3.23-3.08(m,4H),3.02-2 .83(m,3H),2.80(t,2H),2.29-2.01(m,5H),1.99-1.82(m,2H),1.58-1.38(m,2H).

[0538] Example 19: Preparation of Compound 19

[0539] Step 1: Preparation of 19A

[0540] To a reaction flask, 7-N-BOC-heterospiro[3.5]nonane-2-one ethylene acetal (CAS: 2761524-74-5, 4 g, 14.12 mmol) and dichloromethane (20 mL) were added. Trifluoroacetic acid (8 mL) was added with stirring and the mixture was allowed to react at room temperature for 1 h. The mixture was concentrated under reduced pressure to dryness, dichloromethane was added, and the pH was adjusted to 9-10 with saturated aqueous sodium carbonate. The layers were stirred and separated. The aqueous layer was extracted twice with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 19A (2 g).

[0541] Step 2: Preparation of 19B

[0542] 5-Fluoro-2-nitropyridine (1.1 g, 7.74 mmol), 19A (1.42 g, 7.74 mmol), sodium bicarbonate (1.30 g, 15.48 mmol), and DMF (15 mL) were added to a reaction flask and reacted at 90°C for 4 h. After cooling to room temperature, water (50 mL) was added and stirred for 1 h to precipitate a solid. The solid was filtered, the filter cake was washed with water, and concentrated under reduced pressure to afford 19B (2.1 g).

[0543] Step 3: Preparation of 19C

[0544] 19B (2.1 g, 6.88 mmol), palladium on carbon (0.4 g), and methanol (20 mL) were added to the reaction flask, purged with hydrogen three times, and hydrogenated under a hydrogen balloon. The reaction was stirred at room temperature overnight, covered with an appropriate amount of celite, filtered, and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure to dryness to give 19C (1.2 g).

[0545] Step 4: Preparation of 19D

[0546] To a reaction flask were added 19C (0.34 g, 1.23 mmol), tert-butyl 7-bromo-4-chloro-1-oxoisoindoline-2-carboxylate (CAS: 2628351-94-8, 0.47 g, 1.35 mmol), Pd2(dba)3 (0.11 g, 0.12 mmol), Xant-Phos (0.14 g, 0.25 mmol), potassium carbonate (0.51 g, 3.69 mmol), and 1,4-dioxane (10 mL). The mixture was purged with nitrogen three times and allowed to react overnight at 80°C under a nitrogen atmosphere. The mixture was cooled to room temperature, an appropriate amount of silica gel was added, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: DCM-CH3OH = 100-0 to 90-10) to afford 19D (0.6 g, 90% yield).

[0547] LCMS m / z=541.3[M+H] +

[0548] Step 5: Preparation of compound 19E

[0549] To a reaction flask were added 19D (0.5 g, 0.92 mmol), 1B-1 (0.36 g, 1.38 mmol), XPHOS-Pd-G2 (0.072 g, 0.092 mmol), X-PHOS (0.088 g, 0.18 mmol), potassium phosphate (0.59 g, 2.76 mmol), 1,4-dioxane (10 mL), and water (3 mL). The mixture was purged with nitrogen three times and reacted at 95°C for 5 h. The mixture was cooled to room temperature, and ethyl acetate and water were added. The layers were stirred and separated. The organic layer was added with an appropriate amount of silica gel and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: DCM-CH3OH = 100-0 to 90-10) to afford 19E (0.32 g, 54% yield).

[0550] LCMS m / z=641.4[M+H] +

[0551] Step 6: Preparation of 19F

[0552] To a reaction flask, 19E (0.32 g, 0.50 mmol), tetrahydrofuran (3 mL), and 3 M hydrochloric acid (3 mL) were added and reacted at 60°C for 2 h. The mixture was cooled to room temperature, ethyl acetate was added, and the pH was adjusted to 8-9 with saturated aqueous sodium carbonate. The layers were separated, and an appropriate amount of silica gel was added to the organic layer, which was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: DCM-CH3OH = 100-0 to 90-10) to afford 19F (0.15 g, yield: 60%).

[0553] Step 7: Preparation of compound 19

[0554] To a reaction flask were added 19F (0.15 g, 0.30 mmol), 6F (0.11 g, 0.36 mmol), acetic acid (0.054 g, 0.90 mmol), anhydrous sodium sulfate (0.43 g, 3.0 mmol), and chloroform (10 mL). The mixture was heated at 50°C overnight. Sodium triacetoxyborohydride (0.19 g, 0.90 mmol) was added, and the reaction was allowed to proceed for 3 h. An additional sodium triacetoxyborohydride (0.19 g, 0.90 mmol) was added, and the reaction was continued for 2 h. The mixture was cooled to room temperature, and water and dichloromethane were added. The layers were stirred and separated. The organic layer was washed with saturated sodium bicarbonate aqueous solution, and an appropriate amount of silica gel was added, and the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: DCM-CH3OH = 100-0 to 90-10). The resulting product was purified by acidic prep-HPLC to afford the trifluoroacetate salt of compound 19 (100 mg).

[0555] LCMS m / z=799.0[M+H] +

[0556] 1 H NMR(400MHz,D2O)δ8.57(dd,1H),8.35-8.28(m,1H),8.23-8.15(m,1H),8.12(s,1H),8.10-8.00(m,1H),7.91-7.77(m,2H) ,7.52-7.41(m,2H),7.16(d,1H),6.92(d,1H),4.48(s,2H),4.26-4.12(m,1H),3.98-3.82(m,3H),3.78-3.63(m,2H),3.64 -3.42(m,5H),3.32-3.17(m,1H),3.16-3.03(m,1H),2.96(t,2H),2.93-2.73(m, 3H),2.68-2.54(m,2H),2.35-2.21(m,2H),2.21-2.03(m,5H),1.92-1.76(m,1H).

[0557] Example 20: Preparation of Compound 20

[0558] The trifluoroacetic acid salt of compound 20 (150 mg) was prepared by the synthetic method of Reference Example 13 via prep-HPLC acidification.

[0559] LCMS m / z=799.2[M+H] +

[0560] 1 H NMR(400MHz,D2O)δ8.57(dd,1H),8.33-8.27(m,1H),8.23-8.15(m,1H),8.11(s,1H),8.10-8.00(m,1 H),7.90-7.79(m,2H),7.51-7.39(m,2H),7.16(d,1H),6.92(d,1H),4.48(s,2H),4.24-4.13(m,1H),3 .96-3.81(m,3H),3.79-3.63(m,2H),3.62-3.41(m,5H),3.32-3.18(m,1H),3.16-3.03(m,1H),2.96(t ,2H),2.93-2.75(m,3H),2.67-2.53(m,2H),2.33-2.20(m,2H),2.20-1.99(m,5H),1.91-1.76(m,1H).

[0561] Example 21: Preparation of Compound 21

[0562] Step 1: Preparation of 21B

[0563] 21A (2.0 g, 10.80 mmol), ethylene glycol (5.5 mL, 108.0 mmol), and 4-methylbenzenesulfonate pyridinium (0.27 g, 1.08 mmol) were added to toluene (20 mL) and the reaction temperature was raised to 140°C for 5 h. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (v / v) = 1 / 5) to afford 21B (0.63 g, yield: 25%).

[0564] Step 2: Preparation of 21C

[0565] 21B (0.63 g, 2.75 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (3 mL) was added dropwise at room temperature. The mixture was stirred at room temperature for 1 h. The reaction mixture was decompressed to obtain a crude trifluoroacetic acid product, which was redissolved in 10 mL of dichloromethane and 0.3 mL of N,N-diisopropylethylamine was added. The mixture was concentrated to obtain 21C.

[0566] Step 3: Preparation of 21D

[0567] 21C obtained in the previous step was dissolved in acetonitrile (15 mL), and 5-fluoro-2-nitropyridine (0.39 g, 2.75 mmol) and potassium carbonate (1.14 g, 8.25 mmol) were added. The reaction was carried out at 65°C for 3 h, cooled to room temperature, and the reaction solution was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (v / v) = 1 / 1) to obtain 21D (0.59 g, yield: 85%).

[0568] Step 4: Preparation of 21E

[0569] Palladium carbon (0.3 g) was added to a solution of 21D (0.59 g, 2.35 mmol) in methanol (30 mL), stirred at room temperature overnight under a hydrogen atmosphere, filtered through celite, the filter cake was washed with methanol, and the filtrate was concentrated under reduced pressure to give 21E (0.46 g).

[0570] LCMS m / z=222.1[M+H] +

[0571] Step 5: Preparation of 21F

[0572] 21E (0.4 g, 1.81 mmol) and tert-butyl 7-bromo-4-chloro-1-oxoisoindoline-2-carboxylate (CAS: 2628351-94-8, 0.63 g, 1.81 mmol) were dissolved in 1,4-dioxane (15 mL). Tris(dibenzylideneindeneacetone)dipalladium (0.17 g, 0.18 mmol), Xant-phos (0.21 g, 0.36 mmol), and potassium carbonate (0.63 g, 4.53 mmol) were added. The mixture was reacted at 90°C under nitrogen for 8 h. After cooling, the reaction mixture was filtered through celite. The filter cake was washed three times with ethyl acetate. The combined filtrates were concentrated under reduced pressure, and the residue was purified by flash column chromatography (mobile phase: dichloromethane / methanol (v / v) = 20 / 1) to afford 21F (0.65 g, yield: 74%).

[0573] Step 6: Preparation of 21G

[0574] 21F (0.65 g, 1.33 mmol), 1B-1 (0.52 g, 2.0 mmol), XPHOS-Pd-G2 (0.21 g, 0.27 mmol), X-PHOS (0.13 g, 0.27 mmol), and potassium phosphate (0.71 g, 3.33 mmol) were added to a mixture of dioxane (20 mL) and water (4 mL) and reacted overnight at 90°C under a nitrogen atmosphere. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 2 / 3) to afford 21G (0.7 g, 54% yield).

[0575] Step 7: Preparation of 21H

[0576] 21G (0.7 g, 1.19 mmol) was dissolved in tetrahydrofuran (5 mL), and sulfuric acid (3 M) (10 mL) was added dropwise at room temperature. The temperature was raised to 50°C and stirred for 2 h. The mixture was quenched by addition of saturated aqueous sodium carbonate solution, and extracted with dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was eluted through a reverse-phase C18 column (mobile phase: 0-30% acetonitrile / water (containing 0.1% trifluoroacetic acid)) to afford 21H (0.3 g, yield: 57%).

[0577] Step 8: Preparation of compound 21

[0578] 21H (0.15 g, 0.34 mmol) and 6F (108 mg, 0.34 mmol) were dissolved in chloroform (10 mL). Glacial acetic acid (61 mg, 1.0 mmol) was added dropwise at room temperature. The temperature was raised to 60°C and stirred overnight. Sodium triacetoxyborohydride (216 mg, 1.0 mmol) was then added in small portions. Stirring was continued for 2 h. A 1N aqueous sodium hydroxide solution was added to make the solution alkaline. The mixture was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by prep-HPLC to obtain the trifluoroacetate salt of compound 21 (12 mg).

[0579] LCMS m / z=745.0[M+H] +

[0580] 1 H NMR(400MHz,CD3OD)δ8.60(dd,1H),8.42(d,1H),8.14(s,1H),7.79(dd,1H),7.67(d,1H), 7.65(d,1H),7.45-7.36(m,1H),7.11-6.98(m,3H),6.81(d,1H),4.39(s,2H),4.23-4.08( m,3H),3.78-3.69(m,4H),3.69-3.55(m,4H),3.42-3.32(m,2H),3.28-3.21(m,1H),3.21- 3.08(m,1H),3.07-2.95(m,1H),2.93-2.69(m,4H),2.18-2.01(m,1H),1.87-1.72(m,1H).

[0581] Example 22: Preparation of Compound 22

[0582] The trifluoroacetic acid salt of compound 22 (10 mg) was prepared by the synthetic method of Reference Example 20 via prep-HPLC acidification.

[0583] LCMS m / z=745.0[M+H] +

[0584] 1H NMR(400MHz,CD3OD)δ8.58(dd,1H),8.42(d,1H),8.12(s,1H),7.78(dd,1H),7.69-7.63 (m,2H),7.43-7.34(m,1H),7.09-6.98(m,3H),6.81(d,1H),4.39(s,2H),4.23-4.03(m,3 H),3.78-3.69(m,4H),3.69-3.54(m,4H),3.43-3.32(m,2H),3.28-3.20(m,1H),3.19-3 .09(m,1H),3.07-2.97(m,1H),2.91-2.71(m,4H),2.15-2.04(m,1H),1.89-1.71(m,1H).

[0585] Example 23: Preparation of Compound 23

[0586] The trifluoroacetic acid salt of compound 23 (19 mg) was obtained by prep-HPLC acidification according to the synthesis of the aforementioned compound.

[0587] LCMS m / z=878.3[M+H] +

[0588] 1 H NMR(400MHz,CD3OD)δ8.60(dd,1H),8.32(d,1H),8.17(s,1H),7.86-7.75(m,3H),7.46-7.36(m,1 H),7.24(d,1H),7.04(d,1H),6.81(d,1H),4.90(t,4H),4.85(s,2H),4.43(s,2H),4.18-4.05(m,1 H),3.83-3.63(m,4H),3.52-3.38(m,1H),3.28-3.14(m,4H),3.14-3.04(m,2H),3.04-2.94(m,1H ),2.94-2.71(m,6H),2.21-2.06(m,2H),2.04-1.94(m,2H),1.87-1.73(m,1H),1.70-1.53(m,2H).

[0589] Example 24: Preparation of Compound 24

[0590] The trifluoroacetic acid salt of compound 24 (0.13 g) was obtained by prep-HPLC acidification according to the synthesis of the aforementioned compound.

[0591] LCMS m / z=439.9[(M+2H) / 2] +

[0592] 1 H NMR(400MHz,D2O)δ8.55(dd,1H),8.24(d,1H),8.09(s,1H),7.92-7.76(m,3H),7.50-7.41(m,1 H),7.34(d,1H),7.17(d,1H),6.93(d,1H),4.95(t,4H),4.89(s,2H),4.46(s,2H),4.24-4.09(m ,1H),3.94-3.71(m,4H),3.61-3.48(m,1H),3.41-3.23(m,4H),3.21-3.12(m,2H),3.07(t,1H), 3.02-2.74(m,6H),2.32-2.09(m,2H),2.09-1.96(m,2H),1.93-1.78(m,1H),1.73-1.55(m,2H).

[0593] Example 25: Preparation of Compound 25

[0594] The trifluoroacetic acid salt of compound 25 (0.28 g) was obtained by prep-HPLC acidification according to the synthesis of the aforementioned compound.

[0595] LCMS m / z=446.9[(M+2H) / 2] +

[0596] 1H NMR(400MHz,D2O)δ8.61-8.49(m,1H),8.30(d,1H),8.09(s,1H),7.91(d,1H),7.87-7.75(m,2H),7.49-7.40(m,1H) ,7.35(d,1H),7.16(d,1H),6.92(d,1H),4.79-4.63(m,2H),4.45(s,2H),4.22-4.12(m,1H),4.06(t,2H),3.94-3.81 (m,5H),3.79-3.70(m,1H),3.61-3.49(m,1H),3.39-3.25(m,4H),3.24-3.15(m,2H),3.14-2.98(m,3H),2.95(t,2H) ,2.92-2.72(m,4H),2.34-2.20(m,1H),2.19-2.10(m,1H),2.10-1.99(m,2H),1.93-1.79(m,1H),1.73-1.56(m,2H).

[0597] Example 26: Preparation of Compound 26

[0598] The trifluoroacetic acid salt of compound 26 (16 mg) was obtained by prep-HPLC acidification according to the synthesis of the aforementioned compound.

[0599] LCMS m / z=831.0[M+H] +

[0600] 1 H NMR(400MHz,CD3OD)δ8.57(dd,1H),8.36(d,1H),8.13(s,1H),7.93-7.71(m,3H),7 .44-7.22(m,3H),6.97-6.78(m,2H),4.65(s,2H),4.42(s,2H),4.17-4.05(m,2H), 4.00-3.80(m,3H),3.80-3.71(m,3H),3.68-3.32(m,9H),3.30-3.13(m,4H),2.80( t,2H),2.55-2.29(m,2H),2.26-2.12(m,2H),2.08-1.92(m,1H),1.91-1.66(m,2H).

[0601] Example 27: Preparation of Compound 27

[0602] The trifluoroacetic acid salt of compound 27 (56 mg) was obtained by prep-HPLC acidification according to the synthesis of the aforementioned compound.

[0603] LCMS m / z=817.0[M+H] +

[0604] 1 H NMR(400MHz,CD3OD)δ8.61(dd,1H),8.43(d,1H),8.18(s,1H),7.92-7.76(m,3 H),7.49-7.19(m,3H),6.96-6.78(m,2H),4.69(s,2H),4.43(s,2H),4.15-4.06 (m,2H),4.06-3.88(m,3H),3.80-3.70(m,3H),3.69-3.32(m,12H),2.80(t,2H ),2.63-2.51(m,2H),2.51-2.40(m,1H),2.40-2.23(m,2H),2.05-1.91(m,1H).

[0605] Example 28: Preparation of Compound 28

[0606] The trifluoroacetic acid salt of compound 28 (20 mg) was obtained by prep-HPLC acidification according to the synthesis of the aforementioned compound.

[0607] LCMS m / z=892.3[M+H] +

[0608] 1 H NMR(400MHz,CD3OD)δ8.56(dd,1H),8.46(d,1H),8.14(s,1H),7.84-7.71(m,3H),7.42- 7.34(m,1H),7.22(d,1H),7.04(d,1H),6.81(d,1H),4.70(s,2H),4.42(s,2H),4.18-3.9 4(m,3H),3.81(t,2H),3.78-3.62(m,4H),3.51-3.35(m,1H),3.28-3.06(m,6H),3.03-2 .63(m,9H),2.20-2.05(m,2H),2.05-1.93(m,2H),1.86-1.73(m,1H),1.67-1.52(m,2H).

[0609] Example 29: Preparation of Compound 29

[0610] Step 1: Preparation of 29A

[0611] 10B (1.90 g, 6.36 mmol) was dissolved in 50 mL of chloroform, and (3S)-3-fluoropyrrolidine hydrochloride (0.96 g, 7.63 mmol), acetic acid (0.36 mL, 6.36 mmol), and anhydrous sodium sulfate (1.81 g, 12.72 mmol) were added. The mixture was stirred at room temperature for 1 hour. Sodium triacetylborohydride (6.74 g, 31.80 mmol) was slowly added, and the mixture was stirred at room temperature for 1 hour. 50 mL of saturated aqueous sodium bicarbonate was added, and the layers were separated. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography (mobile phase: petroleum ether / ethyl acetate (v / v) = 4 / 1) to obtain compound 29A (0.70 g, yield: 30%).

[0612] LCMS m / z=372.1[M+H] +

[0613] Step 2: Preparation of 29B

[0614] 29A (0.77 g, 2.07 mmol) was dissolved in 1,4-dioxane (20 mL), and cyclopropaneamide (0.35 g, 4.14 mmol), cesium carbonate (2.02 g, 6.21 mmol), tris(dibenzylideneacetone)dipalladium (0.19 g, 0.21 mmol), and XantPhos (0.24 g, 0.41 mmol) were added. The atmosphere was purged with nitrogen three times, and the temperature was raised to 100°C for overnight reaction. After completion of the reaction, the reaction solution was diluted with 100 mL of ethyl acetate and filtered through celite. The filter cake was washed three times with ethyl acetate. The combined filtrates were washed once with water and once with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (mobile phase: dichloromethane / methanol (v / v) = 20 / 1) to obtain 29B (0.86 g).

[0615] LCMS m / z=421.1[M+H] +

[0616] Step 3: Preparation of 29C

[0617] 29B (0.86 g, 2.05 mmol) was dissolved in methanol (20 mL), and water (5 mL) and sodium hydroxide (1.64 g, 41.00 mmol) were added. The mixture was reacted at 80°C overnight. The methanol was removed by concentration, and 100 mL of dichloromethane and 20 mL of water were added, stirred, and the layers were separated. The aqueous layer was extracted twice with dichloromethane. The combined organic phases were washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 29C (0.67 g).

[0618] LCMS m / z=353.1[M+H] +

[0619] Step 4: Preparation of 29D

[0620] Dissolve 29C (0.67 g, 1.90 mmol) and tert-butyl 7-bromo-4-chloro-1-oxoisoindoline-2-carboxylate (CAS: 2628351-94-8, 0.66 g, 1.90 mmol) in 1,4-dioxane (20 mL). Add tris(dibenzylideneindeneacetone)dipalladium (0.17 g, 0.19 mmol), Xant-phos (0.22 g, 0.38 mmol), and potassium carbonate (0.79 g, 5.70 mmol). React at 100°C under nitrogen for 4 h. The reaction solution was diluted with 100 mL of ethyl acetate and filtered through celite. The filter cake was washed three times with ethyl acetate. The combined filtrates were washed once with water and once with a saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (mobile phase: dichloromethane / methanol (v / v) = 20 / 1) to obtain compound 29D (0.93 g, yield: 79%).

[0621] LCMS m / z=618.3[M+H] +

[0622] Step 5: Preparation of 29E

[0623] 29D (0.93 g, 1.50 mmol), 1B-1 (0.59 g, 2.25 mmol), X-PHOS (0.14 g, 0.30 mmol), XPHOS-Pd-G2 (0.12 g, 0.15 mmol), and potassium phosphate (0.96 g, 4.50 mmol) were added to a mixture of dioxane (20 mL) and water (5 mL). The atmosphere was replaced with nitrogen three times and the reaction was carried out at 100°C for 3 h. Water (30 mL) was added and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol = 15 / 1) to obtain 29E (0.67 g, yield: 62%).

[0624] LCMS m / z=718.4[M+H] +

[0625] Step 6: Preparation of 29F

[0626] 29E (0.67 g, 0.93 mmol) was dissolved in tetrahydrofuran (6 mL), and 2M aqueous sulfuric acid (13.3 mL) was added. The temperature was raised to 60°C and the reaction mixture was reacted for 2 h. The reaction mixture was cooled to room temperature, adjusted to alkalinity with aqueous sodium carbonate, and extracted with dichloromethane / isopropanol. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 29F (0.53 g).

[0627] LCMS m / z=572.1[M+H] +

[0628] Step 7: Preparation of compound 29

[0629] 29F (0.30 g, 0.31 mmol) and 6F (0.099 g, 0.31 mmol) were dissolved in chloroform (10 mL). Glacial acetic acid (0.037 g, 0.62 mmol) was added at room temperature, followed by anhydrous sodium sulfate (0.037 g, 0.26 mmol). The temperature was raised to 60°C for 16 h. Sodium triacetoxyborohydride (0.66 g, 3.10 mmol) was slowly added. After addition, the mixture was allowed to react at 60°C for 3 h. Saturated aqueous sodium bicarbonate was added to make the solution alkaline. The mixture was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the trifluoroacetate salt of compound 29 (27 mg).

[0630] LCMS m / z=874.4[M+H] +

[0631] 1 H NMR(400MHz,CD3OD)δ8.55(dd,1H),8.46(d,1H),8.13(s,1H),7.87-7.70(m,3H),7.43-7 .32(m,1H),7.22(d,1H),7.04(d,1H),6.81(d,1H),5.67-5.31(m,1H),4.77(s,2H),4.42( s,2H),4.18-4.07(m,1H),4.00-3.37(m,9H),3.28-3.14(m,4H),3.11-3.02(m,2H),3.01- 2.69(m,7H),2.62-2.31(m,2H),2.23-1.91(m,4H),1.85-1.71(m,1H),1.69-1.49(m,2H).

[0632] Example 30: Preparation of Compound 30

[0633] The trifluoroacetic acid salt of compound 30 (80 mg) was obtained by referring to the synthesis of compound 29 and prep-HPLC acidification.

[0634] LCMS m / z=874.4[M+H] +

[0635] 1 H NMR(400MHz,D2O)δ8.33(dd,1H),8.10(d,1H),7.87(s,1H),7.72-7.53(m,3H),7.28-7.18(m, 1H),7.12(d,1H),6.94(d,1H),6.70(d,1H),5.55-5.26(m,1H),4.57(s,2H),4.23(s,2H),3.9 8-3.90(m,1H),3.85-3.24(m,9H),3.18-3.01(m,4H),2.98-2.80(m,3H),2.78-2.54(m,6H),2 .44-2.20(m,2H),2.09-1.88(m,2H),1.87-1.73(m,2H),1.72-1.54(m,1H),1.50-1.30(m,2H).

[0636] Example 31: Preparation of Compound 31

[0637] The trifluoroacetic acid salt of compound 31 (44 mg) was prepared by the synthetic method of Reference Example 16 via prep-HPLC acidification.

[0638] LCMS m / z=780.3[M+H] +

[0639] 1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),9.93(s,1H),8.79(s,1H),8.58-8.50(m,2H),8.47(s,1H),8 .18(s,1H),8.07(d,1H),7.74(d,1H),7.53(dd,1H),7.25(dd,1H),7.03(d,2H),6.90(d,1H),4.40( s,2H),4.19-4.03(m,1H),3.76-3.55(m,6H),3.45-3.33(m,1H),3.22-3.04(m,4H),2.97-2.83(m,1 H),2.83-2.62(m,6H),2.13-1.99(m,2H),1.97-1.82(m,2H),1.72-1.57(m,1H),1.50-1.32(m,2H).

[0640] Example 32: Preparation of Compound 32

[0641] Step 1: Preparation of 32A

[0642] To a reaction flask, 35B (0.17 g, 0.28 mmol), 6F (0.106 g, 0.33 mmol), and dichloromethane (15 mL) were added. After stirring at room temperature for 1 h, sodium triacetoxyborohydride (0.19 g, 0.90 mmol) and glacial acetic acid (0.054 g, 0.90 mmol) were added. After reacting at room temperature for 3 h, saturated aqueous sodium bicarbonate and dichloromethane were added. The layers were separated by stirring, and the organic layer was concentrated under reduced pressure to dryness. The residue was purified by silica gel column chromatography (eluent: DCM-CH3OH = 100-0 to 90-10) to afford 32A (0.14 g, 54% yield).

[0643] Step 2: Preparation of compound 32

[0644] 32A (0.14 g, 0.16 mmol) and dichloromethane (5 mL) were added to the reaction flask, and trifluoroacetic acid (2 mL) was added with stirring. The reaction was carried out at room temperature for 3 h, and the mixture was concentrated to dryness under reduced pressure. The residue was subjected to acidic prep-HPLC to obtain the trifluoroacetate salt of compound 32 (90 mg).

[0645] LCMS m / z=385.3[(M+2H) / 2] +

[0646] 1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),9.98(s,1H),8.75(s,1H),8.50(d,1H),8.32(d,1H),8.07( d,1H),7.73(d,1H),7.62-7.48(m,2H),7.26(d,1H),7.03(dd,2H),6.91(d,1H),6.47(d,1H),4.4 5(s,2H),4.21-4.04(m,1H),3.87(s,3H),3.73-3.56(m,6H),3.45-3.33(m,1H),3.24-3.01(m,4H ),2.97-2.60(m,7H),2.16-1.98(m,2H),1.98-1.80(m,2H),1.72-1.57(m,1H),1.52-1.32(m,2H).

[0647] Example 33: Preparation of Compound 33

[0648] Step 1: Preparation of compound 33A

[0649] Compound 7B (100 mg, 0.17 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (3 mL) was added. The reaction mixture was allowed to react at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was stirred with triethylamine (3 mL). The mixture was then concentrated under reduced pressure. Chloroform (15 mL), 37D (94 mg, 0.20 mmol), and glacial acetic acid (10 mg, 0.17 mmol) were added, followed by anhydrous sodium sulfate (0.037 g, 0.26 mmol). The reaction mixture was allowed to react at 60°C for 16 h. Sodium triacetoxyborohydride (108 mg, 0.51 mmol) was slowly added, and the reaction was continued for 3 h after the addition was complete. Saturated aqueous sodium bicarbonate solution was added to make the mixture alkaline, and the mixture was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to flash column chromatography (mobile phase: dichloromethane / methanol (v / v) = 20 / 1) to obtain compound 33A (200 mg).

[0650] Step 2: Preparation of compound 33

[0651] 33A (0.16 g, 0.17 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (3 mL) was added dropwise at room temperature, and stirred at room temperature for 1 h. The reaction solution was directly concentrated under reduced pressure, and the residue was acidified by prep-HPLC to prepare the trifluoroacetic acid salt of compound 33 (30 mg).

[0652] LCMS m / z=421.2[(M+2H) / 2] +

[0653] 1 H NMR(400MHz,CD3OD)δ8.62(dd,1H),8.49(d,1H),8.18(s,1H),8.12(1H),7.82(dd,1H),7.74(d,1H),7.68(dd ,1H),7.54(d,1H),7.48-7.38(m,1H),7.14(d,1H),6.76(d,1H),4.81-4.74(m,1H),4.41(s,2H),4.31-4.15( m,1H),3.88-3.72(m,1H),3.69-3.53(m,2H),3.53-3.41(m,1H),3.30-3.17(m,5H),3.09-2.95(m,1H),2.91- 2.65(m,5H),2.52-2.38(m,2H),2.37-2.25(m,1H),2.22-2.07(m,4H),1.98-1.85(m,4H),1.84-1.71(m,1H).

[0654] Example 34: Preparation of Compound 34

[0655] The trifluoroacetic acid salt of compound 34 (45 mg) was prepared by prep-HPLC using the synthetic method of the first step of Reference Example 33.

[0656] LCMS m / z=428.4[(M+2H) / 2] +

[0657] 1 H NMR(400MHz,CD3OD)δ8.62(dd,1H),8.55(d,1H),8.24-8.13(m,2H),7.82(dd,1H),7.7 7-7.67(m,2H),7.54(d,1H),7.46-7.36(m,1H),7.13(d,1H),6.75(d,1H),4.81-4.74( m,1H),4.41(s,2H),4.28-4.11(m,1H),3.69-3.32(m,7H),3.27-3.09(m,4H),3.04-2. 61(m,6H),2.39-2.21(m,3H),2.21-2.05(m,2H),2.05-1.92(m,2H),1.91-1.69(m,5H).

[0658] Example 35: Preparation of Compound 35

[0659] Step 1: Preparation of 35A

[0660] Compound 1B (0.8 g, 1.55 mmol), XPHOS-Pd-G2 (0.12 g, 0.16 mmol), 1-methyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (0.48 g, 1.86 mmol), X-PHOS (0.15 g, 0.31 mmol), and potassium phosphate (0.99 g, 4.65 mmol) were added to a mixture of dioxane (60 mL) and water (20 mL) and reacted at 100°C for 2 h under a nitrogen atmosphere. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 2 / 3) to afford 35A (0.5 g, yield: 53%).

[0661] LCMS m / z=613.3[M+H] +

[0662] Step 2: Preparation of compound 35B

[0663] Compound 35A (0.5 g, 3.32 mmol) was dissolved in tetrahydrofuran (10 mL), and hydrochloric acid (2N) (60 mL) was added dropwise at room temperature. The mixture was stirred at room temperature for 2 h. Saturated aqueous sodium bicarbonate was added to quench the reaction, and the mixture was extracted with ethyl acetate (110 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 100 / 5) to provide compound 35B (0.5 g, yield: 71%).

[0664] LCMS m / z=567.3[M+H] +

[0665] Step 3: Preparation of compound 35C

[0666] Compound 35B (0.16 g, 0.28 mmol) and compound 5G (0.089 g, 0.28 mmol) were dissolved in dichloromethane (10 mL). Glacial acetic acid (0.034 g, 0.56 mmol) was added dropwise at room temperature, followed by sodium sulfate (0.088 g, 0.62 mmol) and sodium triacetoxyborohydride (0.12 g, 0.56 mmol). The mixture was stirred at room temperature for 16 h. A 1N aqueous sodium hydroxide solution was added to make the solution alkaline. The mixture was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 15 / 1) to afford compound 35C (0.2 g, yield: 82%).

[0667] LCMS m / z=869.5[M+H] +

[0668] Step 4: Preparation of compound 35

[0669] 35C (0.2 g, 0.23 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (3 mL) was added dropwise at room temperature. The mixture was stirred at room temperature for 1 h. The reaction mixture was directly concentrated under reduced pressure to remove the trifluoroacetic acid. The crude product was subjected to acidification by prep-HPLC to prepare the trifluoroacetic acid salt of compound 35 (0.08 g).

[0670] LCMS m / z=769.2[M+H] +

[0671] 1 H NMR(400MHz,D2O)δ8.44(d,1H),8.17-8.02(m,2H),8.00-7.88(m,2H),7.71-7.59(m,2H),7.4 9(d,1H),7.14(d,1H),6.90(d,1H),6.81(d,1H),4.57(s,2H),4.19-4.10(m,1H),4.06(s,3H) ,3.88-3.70(m,6H),3.59-3.48(m,1H),3.37-3.21(m,6H),3.12-3.01(m,1H),2.94(t,2H),2. 91-2.73(m,2H),2.45-2.29(m,1H),2.24-2.05(m,3H),1.90-1.79(m,1H),1.78-1.62(m,2H).

[0672] Example 36: Preparation of Compound 36

[0673] Step 1: Preparation of compound 36A

[0674] Compound 15F (0.27 g, 0.41 mmol) was dissolved in tetrahydrofuran (4 mL), and sulfuric acid (2N) (4 mL) was added dropwise at room temperature. The temperature was raised to 60°C and stirred for 2 h. The mixture was quenched by addition of saturated aqueous sodium carbonate solution, and extracted with dichloromethane / isopropanol (v / v) = 10 / 1 (50 mL x 4). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 36A (0.2 g).

[0675] Step 2: Preparation of compound 36

[0676] To a reaction flask, 8B (116 mg, 0.25 mmol) and dichloromethane (2 mL) were added, followed by trifluoroacetic acid (1 mL) with stirring and allowed to react at room temperature for 1 h. After concentration under reduced pressure, the mixture was redissolved in 3 mL of dichloromethane, stirred with 0.5 mL of triethylamine, and concentrated under reduced pressure. To the residue were added 36A (90 mg, 0.18 mmol), acetic acid (0.022 g, 0.36 mmol), anhydrous sodium sulfate (51 mg, 0.36 mmol), and chloroform (10 mL), and stirred at 60°C overnight. Sodium triacetoxyborohydride (0.11 g, 0.54 mmol) was added in small portions, and the reaction continued for 5 h. The mixture was adjusted to alkalinity by adding saturated aqueous sodium bicarbonate solution, extracted three times with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the trifluoroacetate salt of compound 36 (110 mg).

[0677] LCMS m / z=855.3[M+H] +

[0678] 1 H NMR(400MHz,D2O)δ8.47(dd,1H),8.32(d,1H),8.21(d,1H),8.01(s,1H),7.94(dd,1 H),7.82-7.69(m,2H),7.43(d,1H),7.38-7.25(m,2H),6.71(d,1H),4.87-4.78(m,1H ),4.37(s,2H),4.18-4.01(m,1H),3.73-3.39(m,7H),3.38-3.06(m,4H),3.02-2.63 (m,6H),2.35-2.17(m,4H),2.14-2.01(m,3H),1.99-1.88(m,2H),1.86-1.64(m,3H).

[0679] Example 37: Preparation of Compound 37

[0680] Step 1: Preparation of 37B

[0681] 37A (3 g, 11.48 mmol) was dissolved in 100 mL of methanol, and 2.0 g of palladium-carbon catalyst was added. The mixture was purged with hydrogen three times and hydrogenated under a hydrogen balloon with stirring at room temperature overnight. An appropriate amount of celite was applied, and the mixture was filtered. The filter cake was washed with methanol, and the filtrate was concentrated under reduced pressure to dryness to obtain 37B (2.3 g).

[0682] LCMS m / z=232.3[M+H] +

[0683] Step 2: Preparation of 37C

[0684] To a reaction flask were added 37B (0.32 g, 1.38 mmol), tert-butyl 7-bromo-4-chloro-1-oxoisoindoline-2-carboxylate (CAS: 2628351-94-8, 0.48 g, 1.38 mmol), Pd(dba) (0.25 g, 0.28 mmol), Xant-Phos (0.16 g, 0.28 mmol), potassium carbonate (0.57 g, 4.14 mmol), and 1,4-dioxane (25 mL). The mixture was purged with nitrogen three times and reacted at 100°C under nitrogen for 4 h. The reaction mixture was cooled to room temperature, added with an appropriate amount of silica gel, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: DCM-CHOH = 100-0 to 90-10) to afford 37C (0.49 g, 89% yield).

[0685] Step 3: Preparation of 37D

[0686] To a reaction flask were added 37C (0.49 g, 0.99 mmol), 1B-1 (0.26 g, 0.99 mmol), XPHOS-Pd-G2 (0.16 g, 0.2 mmol), X-PHOS (94 mg, 0.2 mmol), potassium phosphate (0.63 g, 2.97 mmol), 1,4-dioxane (20 mL), and water (4 mL). The mixture was purged with nitrogen three times and reacted at 90°C under nitrogen for 5 h. The mixture was cooled to room temperature, and ethyl acetate and water were added. The layers were stirred and separated. The organic layer was added with an appropriate amount of silica gel and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: DCM-CH3OH = 100-0 to 90-10) to afford 37D (0.24 g, yield: 41%).

[0687] Step 4: Preparation of 37E

[0688] 8B (129 mg, 0.28 mmol) and dichloromethane (2 mL) were added to a reaction flask, followed by trifluoroacetic acid (1 mL) with stirring and allowed to react at room temperature for 1 h. The mixture was concentrated to dryness under reduced pressure, redissolved in 3 mL of dichloromethane, stirred with 0.5 mL of triethylamine, and concentrated under reduced pressure. 37D (0.12 g, 0.20 mmol), acetic acid (0.024 g, 0.40 mmol), anhydrous sodium sulfate (85 mg, 0.6 mmol), and chloroform (10 mL) were added to the residue and stirred at 60°C overnight. Sodium triacetoxyborohydride (0.13 g, 0.60 mmol) was added in small portions and the reaction continued for 5 h. The mixture was cooled to room temperature, and water and dichloromethane were added, stirred, and the layers separated. The organic layer was washed with saturated aqueous sodium bicarbonate solution, and an appropriate amount of silica gel was added and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: DCM-CH3OH = 100-0 to 90-10) to give 37E (0.15 g, yield: 79%).

[0689] Step 5: Preparation of compound 37

[0690] 37E (0.15 g) was dissolved in 2 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 1 h and concentrated. The crude product was purified by prep-HPLC to give the trifluoroacetic acid salt of compound 37 (100 mg).

[0691] LCMS m / z=841.3[M+H] +

[0692] 1 H NMR(400MHz,D2O)δ8.54-8.40(m,1H),8.27-8.16(m,1H),8.09(d,1H),8.05-7.90(m,2H),7.80- 7.69(m,2H),7.48-7.30(m,3H),6.72(d,1H),4.89-4.78(m,1H),4.37(s,2H),4.22-4.06(m,1H) ,3.86-3.70(m,1H),3.68-3.53(m,2H),3.53-3.34(m,5H),3.29-3.16(m,1H),3.10-2.93(m,1H) ,2.90-2.68(m,5H),2.57-2.40(m,2H),2.29-2.12(m,4H),2.12-1.91(m,5H),1.80-1.64(m,1H).

[0693] Example 38: Preparation of Compound 38

[0694] Step 1: Preparation of 38A

[0695] 1-tert-Butyloxycarbonyl-4-fluoro-4-(hydroxymethyl)piperidine (5.00 g, 21.43 mmol) was added to a 250 mL round-bottom flask, followed by a 4 M hydrochloric acid solution in dioxane (60 mL). The mixture was allowed to react at room temperature for 2 h. The reaction mixture was cooled and concentrated under reduced pressure to afford the hydrochloride salt of 38A (3.63 g).

[0696] Step 2: Preparation of 38B

[0697] The hydrochloride of compound 38A (3.63 g), 1-bromo-2-fluoro-4-iodobenzene (5.85 g, 19.44 mmol), L-proline (0.90 g, 7.78 mmol), cuprous iodide (0.74 g, 3.89 mmol), and potassium carbonate (8.06 g, 58.32 mmol) were added to DMSO (100 mL). The atmosphere was purged with nitrogen three times and the reaction was continued at 90°C for 16 h. The reaction solution was cooled to room temperature and diluted with 300 mL of ethyl acetate. The organic phase was washed three times with water and once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate = 2 / 1) to obtain 38B (3.00 g, yield: 50%).

[0698] LCMS m / z=306.0[M+H] +

[0699] Step 3: Preparation of 38C

[0700] Compound 38B (3.00 g, 9.80 mmol) was dissolved in DMF (40 mL), and triethylamine (1.98 g, 19.60 mmol) was added. tert-Butyldimethylsilyl chloride (2.22 g, 14.70 mmol) was slowly added, and the mixture was allowed to react at room temperature for 4 h. The reaction solution was diluted with 200 mL of ethyl acetate, and the organic phase was washed three times with water and once with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1) to obtain 38C (3.66 g, yield: 88%).

[0701] Step 4: Preparation of 38D

[0702] 38C (2.96 g, 7.04 mmol), benzophenone imine (1.79 g, 9.86 mmol), cesium carbonate (4.59 g, 14.08 mmol), palladium acetate (0.32 g, 1.41 mmol), and XANT PHOS (0.41 g, 0.70 mmol) were added to a dioxane solution (50 mL) and reacted at 105°C under a nitrogen atmosphere for 16 h. The reaction solution was cooled to room temperature, filtered through celite to remove the solid, and the filter cake was washed with dichloromethane. The organic phase was collected and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate (v / v) = 10 / 1) to afford 38D (1.57 g, yield: 43%).

[0703] Step 5: Preparation of 38E

[0704] 38D (1.57 g, 3.01 mmol) was added to methanol (50 mL), followed by palladium on carbon (1.46 g, wt% = 10%) and ammonium acetate (1.43 g, 18.54 mmol). The mixture was reacted under a hydrogen atmosphere (balloon pressure) at room temperature for 16 h. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (v / v) = 1 / 1) to afford 38E (0.69 g, 64% yield).

[0705] LCMS m / z=357.2[M+H] +

[0706] Step 6: Preparation of 38F

[0707] 38E (1.04 g, 2.92 mmol), ethyl acrylate (0.88 g, 8.76 mmol), and N,N-diisopropylethylamine (1.13 g, 8.76 mmol) were added sequentially to ethanol (10 mL) and the mixture was heated to 100°C for 72 h. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate (v / v) = 6 / 1) to afford 38F (1.22 g, 91% yield).

[0708] LCMS m / z=457.2[M+H] +

[0709] Step 7: Preparation of 38G

[0710] 38F (1.22 g, 2.66 mmol) and N,N-diisopropylethylamine (1.03 g, 7.98 mmol) were added to tetrahydrofuran (40 mL), followed by the slow addition of triphosgene (0.87 g, 2.93 mmol) and the reaction was allowed to proceed at room temperature for 1 h. Aqueous ammonia (10 mL) was then added, and the temperature was raised to 50°C, where the reaction continued for 2 h. The reaction solution was diluted with 100 mL of ethyl acetate, and the organic phase was washed three times with water and once with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: dichloromethane / methanol (v / v) = 15 / 1) to afford 38G (1.24 g, yield: 93%).

[0711] LCMS m / z=500.3[M+H] +

[0712] Step 8: Preparation of 38H

[0713] 38G (1.24 g, 2.47 mmol) was added to acetonitrile (30 mL), followed by the addition of a 40% methanolic solution of benzyltrimethylammonium hydroxide (2.92 mL). The mixture was heated to 60°C and reacted for 0.5 h. Silica gel was added, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (mobile phase: dichloromethane / methanol (v / v) = 15 / 1) to afford 38H (0.29 g, yield: 26%).

[0714] LCMS m / z=454.3[M+H] +

[0715] Step 9: Preparation of 38I

[0716] 38H (0.27 g, 0.60 mmol) was added to tetrahydrofuran (10 mL), followed by TBAF (0.47 g, 1.80 mmol). The mixture was allowed to react at room temperature for 0.5 h. Silica gel was added, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (mobile phase: dichloromethane / methanol (v / v) = 10 / 1) to afford 38I (0.195 g, 97% yield).

[0717] Step 10: Preparation of 38J

[0718] 38I (0.20 g, 0.59 mmol) was added to pyridine (5 mL), followed by trifluoromethanesulfonic anhydride (0.25 g, 0.89 mmol), and the reaction was allowed to react at room temperature for 1 h. The reaction solution was diluted with 50 mL of ethyl acetate, and the organic phase was washed three times with water and once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: dichloromethane / methanol (v / v) = 15 / 1) to afford 38J (0.206 g, yield: 74%).

[0719] Step 11: Preparation of compound 38

[0720] Compound 38J (0.057 g, 0.12 mmol) and 9M (0.058 g, 0.12 mmol) were dissolved in acetonitrile (10 mL). Triethylamine (0.036 g, 0.36 mmol) was added at room temperature, and the temperature was raised to 50°C for 16 h. The reaction solution was diluted with 50 mL of ethyl acetate, and the organic phase was washed three times with water and once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by column chromatography (mobile phase: dichloromethane / methanol (v / v) = 15 / 1) to obtain compound 38 (46 mg).

[0721] LCMS m / z=821.2[M+H] +

[0722] 1H NMR (400MHz, CD3OD / CDCl3(v / v)=1 / 1)δ8.64(d,1H),8.21(dd,1H),7.73-7.60(m,3 H),7.30(dd,1H),7.16(t,1H),7.04(d,1H),6.95-6.81(m,1H),6.44-6.23(m,2H),4 .36(s,2H),4.01(s,2H),3.75(t,2H),3.62-3.43(m,4H),3.29-3.15(m,2H),3.02- 2.76(m,5H),2.64(s,6H),2.48-2.33(m,3H),2.30-2.11(m,3H),1.95-1.81(m,4H).

[0723] Example 39: Preparation of Compound 39

[0724] Step 1: Preparation of 39B

[0725] Under nitrogen, isopropylmagnesium chloride-lithium chloride (8 mL, 1.3 M in THF) was added dropwise to a solution of 39A (2 g, 7.43 mmol) and isopropyl pinacol borate (2.21 g, 11.89 mmol) in tetrahydrofuran (70 mL) at -15°C. After stirring at -15°C for 2 h, the reaction was quenched with saturated aqueous ammonium chloride (150 mL) and filtered. The resulting solid was slurried with ethyl acetate to afford compound 39B (1.6 g, 80% yield).

[0726] Step 2: Preparation of 39C

[0727] Compound 1B (0.8 g, 1.55 mmol), XPHOS-Pd-G2 (0.12 g, 0.16 mmol), compound 39B (0.5 g, 1.86 mmol), X-PHOS (0.15 g, 0.31 mmol), and potassium phosphate (0.99 g, 4.65 mmol) were added to a mixture of dioxane (60 mL) and water (20 mL) under a nitrogen atmosphere at 100°C for 2 h. After cooling to room temperature, water (30 mL) was added and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 2 / 3) to afford 39C (0.6 g, yield: 62%).

[0728] LCMS m / z=624.3[M+H] +

[0729] 1H NMR(400MHz,CD3OD)δ8.51(d,1H),8.45-8.37(m,1H),8.22-8.14(m,1H),8.04-7.95(m,2H),7.69(d,1H),7.44(dd,1H),7.15(dd,1H),6.98(d,1H), 4.70(s,2H),4.13(d,1H),3.68-3.60(m,2H),3.38(s,6H),2.74-2.61(m,2 H),1.90-1.83(m,2H),1.81-1.71(m,1H),1.55(s,9H),1.53-1.43(m,2H).

[0730] Step 3: Preparation of compound 39D

[0731] Compound 39C (0.6 g, 3.32 mmol) was dissolved in tetrahydrofuran (20 mL), and hydrochloric acid (2N) (120 mL) was added dropwise at room temperature. The mixture was stirred at room temperature for 2 h. Saturated aqueous sodium bicarbonate was added to quench the reaction, and the mixture was extracted with ethyl acetate (110 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 100 / 3) to provide compound 39D (0.6 g, yield: 90%).

[0732] LCMS m / z=578.3[M+H] +

[0733] Step 4: Preparation of compound 39E

[0734] Compound 39D (0.27 g, 0.47 mmol) and compound 5G (0.15 g, 0.47 mmol) were dissolved in dichloromethane (10 mL). Glacial acetic acid (0.056 g, 0.94 mmol) was added dropwise at room temperature, followed by sodium sulfate (0.088 g, 0.62 mmol) and sodium triacetoxyborohydride (0.2 g, 0.94 mmol). The mixture was stirred at room temperature for 16 h. A 1N aqueous sodium hydroxide solution was added to make the solution alkaline. The mixture was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 15 / 1) to afford compound 39E (0.22 g, 53% yield).

[0735] Step 5: Preparation of compound 39

[0736] 39E (0.22 g, 0.12 mmol) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (3 mL) was added dropwise at room temperature and stirred for 1 h. The reaction mixture was concentrated under reduced pressure to remove the trifluoroacetic acid. The crude product was purified by prep-HPLC to obtain the trifluoroacetic acid salt of compound 39 (0.11 g).

[0737] LCMS m / z=780.2[M+H] +

[0738] 1 H NMR(400MHz,D2O)δ8.71(d,1H),8.66(s,1H),8.40(s,1H),8.27-8.19(m,1H),8.17-8.04(m,2H ),7.90(d,1H),7.75(d,1H),7.56(d,1H),7.17(d,1H),6.93(d,1H),4.50(s,2H),4.23-4.12(m, 1H),3.93-3.81(m,5H),3.80-3.70(m,1H),3.62-3.50(m,1H),3.46-3.24(m,6H),3.16-3.05(m ,1H),2.96(t,2H),2.93-2.76(m,2H),2.50-2.34(m,1H),2.28-2.10(m,3H),1.94-1.68(m,3H).

[0739] Example 40: Preparation of Compound 40

[0740] The trifluoroacetic acid salt of compound 40 (25 mg) was obtained by prep-HPLC acidification according to the synthesis of the aforementioned compound.

[0741] LCMS m / z=393.3[(M+2H) / 2] +

[0742] 1H NMR (400MHz, CD3OD) δ8.53-8.44(m,1H),8.37(d,1H),8.11-8.03(m,1H),7.98(s,1H),7. 70(d,1H),7.64-7.53(m,1H),7.34-7.26(m,1H),7.17-6.97(m,3H),6.81(d,1H),4.41(s ,2H),4.20-4.03(m,4H),3.83-3.63(m,6H),3.46-3.38(m,1H),3.25-3.12(m,4H),3.04- 2.70(m,7H),2.21-2.05(m,2H),2.06-1.94(m,2H),1.86-1.73(m,1H),1.66-1.50(m,2H).

[0743] Example 41: Preparation of Compound 41

[0744] The trifluoroacetic acid salt of compound 41 (110 mg) was prepared by the synthetic method of Reference Example 12 via prep-HPLC acidification.

[0745] LCMS m / z=393.3[(M+2H) / 2] +

[0746] 1 H NMR(400MHz,DMSO-d6)δ10.37(s,1H),9.92(s,1H),9.86-9.61(m,1H),8.82(s,1H),8.58(d,1H),8.4 8(d,1H),8.23(s,1H),8.05(d,1H),7.74(d,1H),7.51(dd,1H),7.45-7.35(m,1H),7.12(dd,1H),7.02 (dd,2H),6.91(d,1H),4.40(s,2H),4.17-4.08(m,1H),4.03(s,3H),3.76-3.53(m,6H),3.47-3.33(m ,1H),3.26-2.99(m,4H),2.96-2.58(m,7H),2.15-1.79(m,4H),1.74-1.57(m,1H),1.51-1.30(m,2H).

[0747] Example 42: Preparation of Compound 42

[0748] 8B (0.12 g, 0.26 mmol) and dichloromethane (3 mL) were added to a reaction flask, followed by trifluoroacetic acid (2 mL) with stirring. The mixture was allowed to react at room temperature for 2 h, concentrated under reduced pressure, redissolved in 2 mL of dichloromethane, basified with 0.5 mL of triethylamine, and concentrated to dryness. Compound 14E (0.1 g, 0.22 mmol) was added to the resulting crude product, followed by trichloromethane (10 mL). Glacial acetic acid (40 mg, 0.66 mmol) was added dropwise at room temperature, followed by anhydrous sodium sulfate (0.2 g). The mixture was stirred at 60°C overnight, and sodium triacetoxyborohydride (0.19 g, 0.88 mmol) was slowly added in small portions. Stirring at 60°C for 24 h was continued. The mixture was adjusted to alkalinity with 1N aqueous sodium hydroxide solution, extracted three times with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by prep-HPLC to afford the trifluoroacetate salt of compound 42 (25 mg).

[0749] LCMS m / z=801.3[M+H] +

[0750] 1 H NMR(400MHz,D2O)δ8.55-8.43(m,1H),8.03(s,1H),7.97-7.80(m,3H),7.80-7.71(m,2H ),7.51-7.42(m,2H),7.41-7.30(m,1H),6.80-6.67(m,1H),4.90-4.79(m,1H),4.38(s,2 H),4.23-4.10(m,1H),3.89-3.64(m,4H),3.57-3.42(m,2H),3.35-3.15(m,2H),3.06-2 .70(m,7H),2.39-2.20(m,4H),2.18-2.04(m,1H),2.00-1.84(m,2H),1.81-1.67(m,1H).

[0751] Example 43: Preparation of Compound 43

[0752] Step 1: Preparation of 43A

[0753] To a reaction flask were added 37C (400 mg, 0.80 mmol), 39B (320 mg, 1.2 mmol), XPHOS-Pd-G2 (126 mg, 0.16 mmol), X-PHOS (76 mg, 0.16 mmol), potassium phosphate (509 mg, 2.4 mmol), 1,4-dioxane (20 mL), and water (4 mL). The mixture was purged with nitrogen three times and reacted at 90°C under nitrogen for 3 h. The mixture was cooled to room temperature, and ethyl acetate and water were added. The layers were stirred and separated. The organic layer was added with an appropriate amount of silica gel and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: DCM-CH3OH = 100-0 to 90-10) to afford 43A (380 mg, 78% yield).

[0754] Step 2: Preparation of 43B

[0755] 43A (380 mg, 0.63 mmol) and dichloromethane (4 mL) were added to a reaction flask, followed by the addition of trifluoroacetic acid (2 mL) with stirring. The mixture was allowed to react at room temperature for 1 h. The mixture was concentrated to dryness under reduced pressure, redissolved in 30 mL of dichloromethane, and adjusted to alkalinity with aqueous sodium carbonate. The mixture was stirred and separated into layers. The organic layer was washed once with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 43B (250 mg).

[0756] LCMS m / z=504.2[M+H] +

[0757] Step 3: Preparation of compound 43

[0758] To a reaction flask were added 43B (90 mg, 0.18 mmol), 5G (57 mg, 0.18 mmol), and chloroform (20 mL), followed by the dropwise addition of 0.1 mL of acetic acid. The reaction mixture was stirred at 70°C overnight and refluxed at 80°C for 5 h. Sodium triacetoxyborohydride (110 mg, 0.54 mmol) was added and the mixture was allowed to react at 80°C for 3 h. Saturated aqueous sodium carbonate and dichloromethane were then added, and the layers were separated by stirring. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by prep-HPLC to afford the trifluoroacetate salt of compound 43 (50 mg).

[0759] LCMS m / z=403.8[(M+2H) / 2] +

[0760] 1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),10.07-9.73(m,1H),8.77(s,1H),8.59-8.49(m,2H),8.46-8.42( m,1H),8.15(s,1H),8.03(d,1H),7.73(d,1H),7.48(dd,1H),7.22(dd,1H),7.10-6.86(m,3H),4.39(s,2 H),4.19-4.16(m,1H),3.82-3.77(m,1H),3.61(t,2H),3.55-3.44(m,2H),3.35-3.23(m,1H),3.19-2.97 (m,5H),2.97-2.84(m,1H),2.83-2.60(m,5H),2.31-2.17(m,2H),2.14-1.99(m,3H),1.83-1.57(m,5H).

[0761] Example 44: Preparation of Compound 44

[0762] The trifluoroacetic acid salt of compound 44 (20 mg) was obtained by prep-HPLC acidification according to the synthesis of the aforementioned compound.

[0763] LCMS m / z=827.3[M+H] +

[0764] 1 H NMR(400MHz,DMSO-d6)δ10.36(s,1H),9.89(s,1H),8.78(s,1H),8.65-8.51(m,2H),8.19(s, 1H),8.05(d,1H),7.87(dd,1H),7.72(d,1H),7.50(dd,1H),7.41-7.28(m,1H),7.07-6.97(m ,2H),6.90(d,1H),4.37(s,2H),4.20-4.08(m,1H),3.62-3.59(m,4H),3.33-2.99(m,8H),2. 95-2.83(m,1H),2.81-2.62(m,4H),2.11-1.80(m,5H),1.76-1.43(m,7H),1.28-1.12(m,2H).

[0765] Example 45: Preparation of Compound 45

[0766] The trifluoroacetic acid salt of compound 45 (10 mg) was prepared by the synthetic method of steps 4 to 6 of reference example 14 via prep-HPLC acidification.

[0767] LCMS m / z=766.3[M+H] +

[0768] 1 H NMR(400MHz,DMSO-d6)δ10.37(s,1H),9.91(s,1H),8.79(s,1H),8.57(d,1H),8.54-8.48(m,1H),8.4 7-8.40(m,1H),8.14(s,1H),8.07(d,1H),7.73(d,1H),7.51(dd,1H),7.22(dd,1H),7.07-6.99(m,2H ),6.92(d,1H),4.40(s,2H),4.22-4.10(m,1H),3.92-3.75(m,2H),3.74-3.56(m,4H),3.33-2.85(m, 5H),2.78-2.63(m,6H),2.28-2.13(m,2H),2.09-1.97(m,1H),1.88-1.76(m,2H),1.73-1.60(m,1H).

[0769] Example 46: Preparation of Compound 46

[0770] Step 1: Preparation of 46A

[0771] To a reaction flask were added 44C (600 mg, 1.14 mmol), 39B (0.46 g, 1.71 mmol), XPHOS-Pd-G2 (90 mg, 0.11 mmol), X-PHOS (54 mg, 0.11 mmol), potassium phosphate (726 mg, 3.42 mmol), 1,4-dioxane (25 mL), and water (5 mL). The mixture was purged with nitrogen three times and reacted at 90°C under nitrogen for 5 h. The mixture was cooled to room temperature, and ethyl acetate and water were added. The layers were stirred and separated. The organic layer was added with an appropriate amount of silica gel and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: DCM-CH3OH = 100-0 to 90-10) to afford 46A (0.41 g, yield: 57%).

[0772] LCMS m / z=632.3[M+H] +

[0773] Step 2: Preparation of 46B

[0774] To a reaction flask were added 46A (130 mg, 0.21 mmol), 6F (80 mg, 0.25 mmol), and chloroform (20 mL), followed by the dropwise addition of 0.1 mL of acetic acid. The reaction mixture was stirred at 70°C overnight and refluxed at 80°C for 5 h. Sodium triacetoxyborohydride (130 mg, 0.63 mmol) was added and the mixture was allowed to react at 80°C for 3 h. Saturated aqueous sodium carbonate and dichloromethane were then added. The layers were stirred and separated. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness. The residue was purified by silica gel column chromatography (eluent: DCM-CH3OH = 100-0 to 90-10) to afford 46B (100 mg, yield: 52%).

[0775] LCMS m / z=934.3[M+H] +

[0776] Step 3: Preparation of Compound 46

[0777] 46E (100 mg, 0.11 mmol) was dissolved in 2 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 1 h. The reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by prep-HPLC to obtain trifluoroacetate salt of compound 46 (20 mg).

[0778] LCMS m / z=834.4[M+H] +

[0779] 1 H NMR(400MHz,DMSO-d6)δ10.37(s,1H),9.89(s,1H),8.78(s,1H),8.59-8.48(m,2H),8 .45(s,1H),8.15(s,1H),8.10-7.98(m,1H),7.73(d,1H),7.55-7.42(m,1H),7.22(dd, 1H),7.06-6.85(m,3H),4.40(s,2H),4.21-4.06(m,1H),3.70-3.57(m,4H),3.34-2.9 8(m,8H),2.95-2.58(m,5H),2.09-1.81(m,5H),1.76-1.37(m,7H),1.29-1.10(m,2H).

[0780] Example 47: Preparation of Compound 47

[0781] The trifluoroacetic acid salt of compound 47 (30 mg) was prepared by referring to the synthesis method of step 6 of Example 44 via prep-HPLC acidification.

[0782] LCMS m / z=827.5[M+H]+

[0783] 1 H NMR(400MHz,DMSO-d6)δ10.37(s,1H),9.92(s,1H),8.81(s,1H),8.70-8.52(m,2H),8.2 5(s,1H),8.10-8.03(m,1H),7.99-7.88(m,1H),7.73(d,1H),7.60-7.49(m,1H),7.44-7. 34(m,1H),7.08-6.85(m,3H),4.38(s,2H),4.22-4.04(m,1H),3.71-3.53(m,4H),3.37-2 .98(m,8H),2.97-2.62(m,5H),2.15-1.79(m,5H),1.78-1.40(m,7H),1.31-1.07(m,2H).

[0784] Example 48: Preparation of Compound 48

[0785] To a reaction flask were added 43B (250 mg, 0.50 mmol), 6F (159 mg, 0.50 mmol), and chloroform (30 mL), followed by the dropwise addition of 0.1 mL of acetic acid. The reaction mixture was stirred at 70°C overnight and refluxed at 80°C for 5 h. Sodium triacetoxyborohydride (320 mg, 1.5 mmol) was added and the mixture was allowed to react at 80°C for 3 h. Saturated aqueous sodium carbonate and dichloromethane were then added, and the layers were separated by stirring. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (Waters 2767 preparative HPLC; XBridge@Prep C18 column (30 mm × 150 mm); mobile phase: acetonitrile, 5 mmol / L aqueous ammonium bicarbonate). The preparative solution was lyophilized to afford compound 48 (50 mg, 15% yield).

[0786] LCMS m / z=806.5[M+H] +

[0787] 1H NMR(400MHz,DMSO-d6)δ10.33(s,1H),9.85(s,1H),8.76(s,1H),8.59-8.49(m,2H),8.46-8.39( m,1H),8.13(s,1H),8.00(d,1H),7.72(d,1H),7.43(dd,1H),7.20(dd,1H),7.01-6.86(m,2H),6 .72(d,1H),4.39(s,2H),3.83-3.71(m,1H),3.59(t,2H),3.15-3.06(m,2H),3.05-2.92(m,3H), 2.92-2.81(m,2H),2.80-2.56(m,6H),2.06-1.94(m,2H),1.94-1.80(m,2H),1.76-1.50(m,8H).

[0788] Example 49: Preparation of Compound 49

[0789] The trifluoroacetic acid salt of compound 49 (60 mg) was prepared by the synthetic method from the fifth to sixth steps of Reference Example 44 via prep-HPLC acidification.

[0790] LCMS m / z=417.8[(M+2H) / 2] +

[0791] 1 H NMR(400MHz,DMSO-d6)δ10.37(s,1H),9.93(s,1H),8.80(s,1H),8.60-8.50(m,2H),8.4 8-8.42(m,1H),8.16(s,1H),8.13-8.04(m,1H),7.74(d,1H),7.62-7.46(m,1H),7.24-7. 20(m,1H),7.03-6.85(m,3H),4.40(s,2H),4.17-4.10(m,1H),3.68-3.50(m,4H),3.38-2 .98(m,8H),2.97-2.60(m,5H),2.10-1.80(m,5H),1.75-1.40(m,7H),1.30-1.09(m,2H).

[0792] Example 50: Preparation of Compound 50

[0793] Step 1: Preparation of 50B

[0794] 50A (5.00 g, 19.90 mmol) was dissolved in 1,4-dioxane hydrochloric acid solution (50 mL, 4N) and reacted at room temperature for 2 h. The reaction solution was directly concentrated under reduced pressure to obtain 50B (3.73 g).

[0795] LCMS m / z=152.2[M+H] +

[0796] Step 2: Preparation of 50C

[0797] 50B (3.73 g) and 5-fluoro-2-nitropyridine (2.82 g, 19.88 mmol) were dissolved in N,N-dimethylformamide (100 mL). Sodium bicarbonate (5.01 g, 59.64 mmol) was added at room temperature and reacted at 100°C for 2 h. The reaction solution was cooled to room temperature and diluted with 500 mL of ethyl acetate. The solution was washed three times with water and once with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Flash column chromatography (mobile phase: dichloromethane / methanol (v / v) = 20 / 1) afforded 50C (2.96 g, 54% yield).

[0798] LCMS m / z=274.0[M+H] +

[0799] Step 3: Preparation of 50D

[0800] 50C (2.96 g, 10.83 mmol), 3,4-dihydro-2H-pyran (2.92 g, 34.66 mmol), and 4-methylbenzenesulfonate pyridinium (0.33 g, 1.30 mmol) were added to a 500 mL reaction flask, followed by dichloromethane (100 mL). The temperature was raised to 45°C and the reaction was allowed to react for 1 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography (mobile phase: petroleum ether / ethyl acetate (v / v) = 1 / 1) to afford 50D (3.85 g).

[0801] LCMS m / z=358.1[M+H] +

[0802] Step 4: Preparation of 50E

[0803] 50D (0.50 g, 1.40 mmol) was dissolved in tetrahydrofuran (20 mL), and zinc powder (0.46 g, 7.00 mmol) and an aqueous solution of ammonium chloride (0.37 g, 7.00 mmol) (4 mL) were added. The reaction mixture was stirred at room temperature for 10 min. Dichloromethane was added to the reaction solution, and the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography (mobile phase: dichloromethane / methanol (v / v) = 15 / 1) to afford 50E (0.43 g, 94% yield).

[0804] LCMS m / z=328.2[M+H] +

[0805] Step 5: Preparation of 50F

[0806] 50E (0.43 g, 1.31 mmol) and tert-butyl 7-bromo-4-chloro-1-oxoisoindoline-2-carboxylate (0.45 g, 1.31 mmol) were dissolved in 1,4-dioxane (20 mL). Tris(dibenzylideneindeneacetone)dipalladium (0.12 g, 0.13 mmol), Xant-phos (0.15 g, 0.26 mmol), and potassium carbonate (0.54 g, 3.93 mmol) were added. The reaction was allowed to proceed at 95°C for 3 h under nitrogen. The reaction mixture was cooled to room temperature, diluted with 100 mL of dichloromethane, and filtered through Celite. The filter cake was washed three times with dichloromethane. The combined filtrates were concentrated under reduced pressure, and the residue was purified by flash column chromatography (mobile phase: dichloromethane / methanol (v / v) = 20 / 1) to afford 50F (0.58 g, yield: 74%).

[0807] LCMS m / z=593.2[M+H] +

[0808] Step 6: Preparation of 50G

[0809] 50F (0.70 g, 1.18 mmol), tetrahydroxydiboron (0.19 g, 2.12 mmol), XPHOS-Pd-G2 (0.093 g, 0.12 mmol), X-PHOS (0.056 g, 0.12 mmol), ethylene glycol (0.22 g, 3.54 mmol), and potassium acetate (0.35 g, 3.54 mmol) were added to a reaction flask, followed by anhydrous ethanol (20 mL) and the reaction was continued at 80°C under nitrogen for 1 h. The mixture was cooled to room temperature, and 5 mL of water, XPHOS-Pd-G2 (0.046 g, 0.06 mmol), X-PHOS (0.028 g, 0.06 mmol), potassium phosphate (0.75 g, 3.54 mmol), and 3-bromo-7-cyanoimidazolo[1,2-A]pyridine (0.26 g, 1.18 mmol) were added and the reaction was continued at 80°C under nitrogen for 2 h. The reaction solution was cooled to room temperature and water was added to precipitate a yellow solid which was filtered to obtain a solid. The solid was redissolved in dichloromethane and dried over anhydrous sodium sulfate. The solid was concentrated under reduced pressure and the residue was purified by flash column chromatography (mobile phase: petroleum ether / ethyl acetate (v / v) = 1 / 2) to obtain 50G (0.49 g, yield: 60%).

[0810] LCMS m / z=600.2[M-99] +

[0811] Step 7: Preparation of 50H

[0812] 50G (0.49 g, 0.71 mmol) was dissolved in dichloromethane (8 mL), and trifluoroacetic acid (8 mL) was added. The mixture was allowed to react at room temperature for 2 h. The reaction solution was directly concentrated under reduced pressure to remove the solvent, and then redissolved in dichloromethane / methanol ((v / v) = 10 / 1). The solution was adjusted to alkalinity with solid potassium carbonate, and the filtrate was filtered. The filtrate was concentrated under reduced pressure and then flash column chromatography (mobile phase: dichloromethane / methanol (v / v) = 15 / 1) was performed to obtain compound 50H (0.23 g, yield: 62%).

[0813] LCMS m / z=516.2[M+H] +

[0814] Step 8: Preparation of 50I

[0815] 50H (0.17 g, 0.33 mmol) was added to dichloromethane (20 mL), followed by triethylamine (0.2 g, 0.27 mL, 1.98 mmol). Methanesulfonic anhydride (0.345 g, 1.98 mmol) was added in three portions and allowed to react at room temperature for 1 h. The reaction solution was diluted with 20 mL of dichloromethane, and the organic phase was washed once with aqueous ammonium chloride and once with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 50I (0.19 g).

[0816] Step 9: Preparation of Compound 50

[0817] 50I (0.19 g, 0.32 mmol) and 5G (0.112 g, 0.35 mmol) were dissolved in N,N-dimethylformamide (3 mL). N,N-diisopropylethylamine (0.124 g, 0.16 mL, 0.96 mmol) was added at room temperature, and the mixture was heated to 80°C for 16 h. After the reaction mixture cooled, 10 mL of ice water was added to precipitate a yellow solid. The solid was filtered, and the filter cake was dried and purified by column chromatography (mobile phase: dichloromethane / methanol (v / v) = 15 / 1) to afford compound 50 (170 mg, 65% yield).

[0818] LCMS m / z=408.8[(M+2H) / 2] +

[0819] Compound 50 was purified by chiral separation.

[0820] Preparation conditions: Instrument: CAS-05-Prep-HPLC-C; Column: IA column; Mobile phase: A for DCM; B for IPA+ACN; Isocratic elution: 70% B in A; Column temperature: room temperature; Wavelength: 254nm.

[0821] Analytical conditions: Instrument: CAS-05-HPLC-AB (SHIMADZU LC-20AD); Mobile phase: IA-IPA + ACN (IPAm). Wavelength: 254 nm.

[0822] After preparative separation, fractions with the same retention time were combined and concentrated under reduced pressure to give compound 50-1 (67 mg) and compound 50-2 (66 mg).

[0823] One of compound 50-1 and compound 50-2 has a structure of 50-A and the other has a structure of 50-B.

[0824] Retention time of compound 50-1 under analytical conditions: 2.07 min, LCMS m / z=816.5[M+H] +

[0825] 1 H NMR(400MHz,DMSO-d6)δ10.32(s,1H),9.79(s,1H),8.75(s,1H),8.57-8.37(m,3H),8.12(s,1H),7.8 1-7.65(m,2H),7.19(dd,1H),7.14(dd,1H),7.01(d,1H),6.93(d,1H),6.73(d,1H),4.38(s,2H),3.9 3-3.74(m,3H),3.73-3.63(m,1H),3.59(t,2H),3.19-3.08(m,1H),3.07-2.90(m,3H),2.87-2.70(m, 3H),2.70-2.56(m,3H),2.48-2.37(m,2H),2.15-2.03(m,1H),1.97-1.77(m,3H),1.69-1.58(m,2H).

[0826] Retention time of compound 50-2 under analytical conditions: 2.94 min, LCMS m / z=816.5[M+H] +

[0827] 1 H NMR(400MHz,DMSO-d6)δ10.32(s,1H),9.79(s,1H),8.74(s,1H),8.55-8.39(m,3H),8.12(s,1H),7.8 1-7.64(m,2H),7.19(dd,1H),7.14(dd,1H),7.00(d,1H),6.93(d,1H),6.73(d,1H),4.38(s,2H),3.9 1-3.73(m,3H),3.73-3.63(m,1H),3.60(t,2H),3.17-3.07(m,1H),3.06-2.88(m,3H),2.87-2.70(m, 3H),2.70-2.54(m,3H),2.48-2.36(m,2H),2.15-2.04(m,1H),1.96-1.75(m,3H),1.73-1.54(m,2H).

[0828] Biological test cases

[0829] Test Example 1: Detection of SLP76 phosphorylation levels in Jurkat cells

[0830] Jurkat cells from ATCC were placed in RPMI-1640 complete medium (supplemented with 10% FBS and 1% double-antibody) and cultured at 37°C and 5% CO2. Cells in the logarithmic growth phase were collected and the cell density was adjusted to 5×10 51 mL / well was added to a 6-well cell culture plate. Test compounds were prepared to 3x the final concentration. 500 μL of each compound was added to the dosing wells, while control wells were treated with culture medium containing 0.3% DMSO. The cells were incubated at 37°C, 5% CO₂ for 4 hours. 500 μL of CD3 antibody (BD, Cat# 555329; final concentration 1 μg / mL) was added, and the cells were incubated at 37°C, 5% CO₂ for 10 minutes. After incubation, the cells were collected in a 1.5 mL centrifuge tube and washed twice with pre-chilled PBS. A protease inhibitor cocktail and phosphatase inhibitor cocktail were prepared at a ratio of 1:1:100 to lysis buffer. Each sample was resuspended in 10 μL of lysis buffer and incubated on ice for 15 minutes with repeated shaking until the cells were completely lysed. The cells were then centrifuged at 12,000 rpm at 4°C for 15 minutes. The supernatant was collected and protein content was determined using the BCA assay. The protein samples to be tested were diluted to 2 mg / mL and 0.8 mg / mL, and the phosphorylated SLP76 (p-SLP76) and total SLP76 protein levels were detected using a fully automated protein expression quantitative analyzer (ProteinSimple) (both antibodies were from CST). The raw data were processed using the software of the fully automated protein expression quantitative analyzer (Compass for SW), and the peak area A was calculated. [p-SLP76] / A [SLP76] The expression level of p-SLP76 relative to the total SLP76 protein was calculated and the expression level R was calculated as [1-(R 给药孔 -R 阴性 对照 ) / (R 阳性对照 -R 阴性对照 )]×100% to calculate the inhibition rate of p-SLP76, where R 阴性对照 For the control wells, only 0.3% DMSO medium was added. 阳性对照 The IC values ​​were calculated using a four-parameter nonlinear fitting model in Graphpad 8.3.0 software. 50 value.

[0831] Conclusion: The compounds of the present application, such as the compounds in the examples, have a good inhibitory effect on the phosphorylation of SLP76 in Jurkat cells.

[0832] Test Example 2: Detection of HPK1 protein expression level in Jurkat cells

[0833] Jurkat cells from ATCC were placed in RPMI-1640 complete medium (supplemented with 10% FBS and 1% double-antibody) and cultured at 37°C and 5% CO2. Cells in the logarithmic growth phase were collected and the cell density was adjusted to 5×10 5 / well, added to a 6-well cell culture plate at a volume of 1mL / well. Prepare the test compound to twice the final concentration, add 1mL of different concentrations of the compound to the dosing well, and add culture medium containing 0.2% DMSO to the control well, and incubate at 37°C, 5% CO2 for 48 hours. Collect the cells in a 1.5mL centrifuge tube, add 25μL RIPA lysis buffer (containing 1X protease inhibitor mixture), lyse on ice for 15 minutes, centrifuge at 12000 rpm, 4°C for 10 minutes, collect the supernatant, and determine the protein content by BCA method. The protein sample to be tested was diluted to 0.2mg / mL, and HPK1 was detected using a fully automatic protein expression quantitative analyzer (ProteinSimple). The internal reference protein was β-actin (all antibodies were from CST). The software of the fully automatic protein expression quantitative analyzer (Compass for SW) was used to process the raw data and calculate the peak area and HPK1 degradation rate relative to the control group. According to A 给药孔 / A 对照孔 ×100% to calculate the inhibition rate of HPK1, where A 给药孔 is the relative peak area of ​​the drug-treated group, A 对照孔 DC was calculated using a four-parameter nonlinear fitting model in Graphpad 8.3.0 software. 50 value.

[0834] Conclusion: The compounds of the present application, such as the compounds in the examples, have a degradation effect on HPK1 kinase.

[0835] Test Example 3: HPK1 Kinase Assay (Km Concentration ATP)

[0836] Kinase HPK1 (Carna, Cat. No. 07-410) was prepared into a 2× kinase solution using 1× kinase buffer. The substrates Fluorescein-PKC (Invitrogen, Cat. No. PV3506) and ATP (working concentration: 9 μM) (Sigma, Cat. No. 2383-5G) were prepared into a 2× substrate solution using 1× kinase buffer. The detection reagent was diluted to twice the final concentration using antibody diluent. 100 nL of compound at various concentrations and 5 μL of kinase solution were added to each well of a 384-well plate and incubated at room temperature for 10 minutes. After incubation, 5 μL of substrate solution was added to each well and the reaction was incubated at room temperature for 90 minutes. After the reaction was complete, 10 μL of detection reagent was added to each well to terminate the reaction and incubated at room temperature for 60 minutes. Fluorescence was measured using an Envision instrument with an excitation wavelength of 320 nm and emission wavelengths of 520 nm and 495 nm. IC was calculated using XLFit Excel add-in version 5.4.0.8 software.50 The inhibition rate calculation formula is shown in formula 3-1, where max is the DMSO control ratio, min is the negative control ratio without enzyme, and sample is the compound ratio. Ratio = RFU 520nm / RFU 495nm Inhibition%=(max-sample) / (max-min)×100% (Formula 3-1)

[0837] Table 3-1 Inhibitory activity of test compounds on HPK1 kinase Note: A in Table 3-1 is less than 0.01 μM

[0838] Conclusion: The compounds of the present invention, such as the compounds in the examples, have an inhibitory effect on HPK1 kinase. Specifically, compounds 1, 2, 3, 4, 5, and 6 have good inhibitory activity on HPK1 kinase.

[0839] Test Example 4: Detection of HPK1 protein expression level in Jurkat cells (24h)

[0840] Jurkat cells from ATCC were placed in RPMI-1640 complete medium (supplemented with 10% FBS and 1% double-antibody) and cultured at 37°C and 5% CO2. Cells in the logarithmic growth phase were collected and the cell density was adjusted to 5×10 5 1 mL / well was added to a 6-well cell culture plate. Test compounds were prepared to twice the final concentration. 1 mL of each compound was added to the dosing wells, while control wells were incubated with culture medium containing 0.2% DMSO. The cells were incubated at 37°C, 5% CO₂ for 24 hours. Cells were harvested in a 1.5 mL centrifuge tube and lysed on ice for 15 minutes using 30 μL of RIPA lysis buffer (containing a 1X protease inhibitor cocktail). The supernatant was collected and protein content was determined using the BCA assay. The test protein samples were diluted to 0.2 mg / mL and assayed for HPK1 using an automated protein expression quantitative analyzer (ProteinSimple). The internal reference protein was β-actin (antibodies from CST). Raw data were processed using the automated protein expression quantitative analyzer software (Compass for SW). Peak areas normalized to the internal reference protein and HPK1 degradation rates relative to the control group were calculated. The degradation rate of HPK1 was calculated according to formula 4-1, where A 给药孔 A is the relative peak area after normalization of the internal reference in the drug-treated group. 对照孔 The DC was calculated using a four-parameter nonlinear fitting model in Graphpad 8.3.0 software. 50HPK1 降解 % = 100-(A 给药孔 / A 对照孔 ×100%) Formula 4-1

[0841] Table 4-1 Degradation activity of test compounds on HPK1 protein in Jurkat cells (24h) Note: A in Table 4-1 is less than 20nM

[0842] Conclusion: The compounds of the present invention, such as the example compounds, have good degradation activity of HPK1 protein in Jurkat cells.

[0843] Test Example 5: HPK1 kinase assay (1 mM ATP)

[0844] The kinase HPK1 (Carna, Cat. No. 07-410) was prepared into a 2× kinase solution using 1× kinase buffer. The substrates Fluorescein-PKC (Invitrogen, Cat. No. PV3506) and ATP (working concentration: 1 mM) (Sigma, Cat. No. 2383-5G) were prepared into a 2× substrate solution using 1× kinase buffer. The detection reagent was diluted to twice the final concentration using antibody diluent. 100 nL of compound at various concentrations and 5 μL of kinase solution were added to each well of a 384-well plate and incubated at room temperature for 10 minutes. After incubation, 5 μL of substrate solution was added to each well and the reaction was incubated at room temperature for 90 minutes. After the reaction was complete, 10 μL of detection reagent was added to each well to terminate the reaction and incubated at room temperature for 60 minutes. Fluorescence was measured using an Envision instrument with an excitation wavelength of 320 nm and emission wavelengths of 520 nm and 495 nm. IC was calculated using XLFit Excel add-in version 5.4.0.8 software. 50 The inhibition rate calculation formula is shown in Formula 5-1, where max is the DMSO control ratio, min is the negative control ratio without enzyme, and sample is the compound ratio. Ratio = RFU 520nm / RFU 495nm Inhibition%=(max-sample) / (max-min)×100% (Formula 5-1)

[0845] Table 5-1 Inhibitory activity of test compounds on HPK1 kinase Note: A in Table 5-1 is less than 50nM

[0846] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good inhibitory activity against HPK1 kinase.

[0847] Test Example 6: Pharmacokinetic Test in Mice

[0848] Experimental purpose: This study administered the test substance to ICR mice by single-dose intravenous and oral gavage, measured the concentration of the test substance in mouse plasma, and evaluated the pharmacokinetic characteristics and bioavailability of the test substance in mice.

[0849] Experimental animals: Male ICR mice, 20-35 g, purchased from Chengdu Dashuo Experimental Animal Co., Ltd. (SCXK (Sichuan) 2020-030).

[0850] Experimental Methods: On the day of the experiment, ICR mice were randomly divided into groups according to body weight. They were fasted overnight before administration, but not water. Food was resumed 4 hours after administration. * Dosage is based on the free base;

[0851] Sampling: Blood was collected from the eye socket at designated time points and placed in EDTAK2 centrifuge tubes. The tubes were centrifuged at 5000 rpm and 4°C for 10 min to collect plasma.

[0852] Time points for plasma collection in G1 and G1-2 groups: 0, 5 min, 15 min, 30 min, 1, 2, 4, 7, and 24 h;

[0853] Time points for plasma collection in G2 and G2-2 groups: 0, 5 min, 15 min, 30 min, 1, 2, 4, 7, and 24 h;

[0854] All samples were stored below -60°C before analysis and quantitative analysis was performed using LC-MS / MS.

[0855] Table 6-1 PK data of test compound in mice *Note: Compounds were administered ig (orally).

[0856] Table 6-2 PK data of test compound in mice *Note: Compounds were administered IV (intravenously).

[0857] Conclusion: The compounds synthesized using the technology of the present invention, such as the example compounds, have good pharmacokinetic properties in mice (such as better oral absorption, longer half-life, higher Cmax, and lower clearance), which are superior to the control compound 1.

[0858] Test Example 7: Pharmacokinetic Test in Rat

[0859] Experimental animals: Male SD rats, 180–200 g, purchased from Chengdu Dashuo Experimental Animal Co., Ltd., Laboratory Animal Production License No.: SCXK(Chuan)2020-030.

[0860] Experimental Design: On the day of the experiment, SD rats were randomly divided into groups according to body weight. They were fasted overnight before administration, but not with water. Food was resumed 4 hours after administration. Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline or 10% DMA + 10% Solutol + 80% Saline;

[0861] Oral administration solvent: 5% Solutol + 5% TPGS + 30% PEG400 + 60% (20% SBE-β-CD)

[0862] Blood was collected from the eye socket at designated time points and placed in EDTAK2 centrifuge tubes. The tubes were centrifuged at 5000 rpm for 10 min to collect plasma.

[0863] Blood was collected from the venous group at 0, 5, 15, 30 minutes, 1, 2, 4, 6, 8, and 24 hours; from the oral gavage group at 0, 5, 15, 30 minutes, 1, 2, 4, 6, 8, and 24 hours. All samples were stored below -60°C before analysis. Quantitative analysis was performed using LC-MS / MS.

[0864] Table 7-1 PK data of test compound in rats *Note: Compounds were administered ig (orally).

[0865] Table 7-2 PK data of test compound in rats *Note: Compounds were administered IV (intravenously).

[0866] Conclusion: The compounds synthesized using the technology of the present invention, such as the example compounds, have good pharmacokinetic properties in rats (such as better oral absorption, longer half-life, higher Cmax, and lower clearance), which are superior to the control compound 1.

[0867] 8. hERG potassium channel effect test

[0868] Experimental platform: electrophysiology manual patch clamp system

[0869] Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channel

[0870] Experimental methods: CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channels were used to record hERG potassium channel currents using the whole-cell patch clamp technique at room temperature. Glass microelectrodes were pulled from glass electrode blanks (BF150-86-10, Sutter) using a puller. The tip resistance after perfusing the electrode liquid was about 2-5 MΩ. The glass microelectrode was inserted into the amplifier probe to connect to the patch clamp amplifier. The clamping voltage and data recording were controlled and recorded by a computer using pClamp 10 software, with a sampling frequency of 10 kHz and a filter frequency of 2 kHz. After obtaining the whole-cell recording, the cell was clamped at -80 mV to induce the hERG potassium current (I hERG ) was administered with a 2-second depolarization step from -80 mV to +20 mV, followed by repolarization to -50 mV for 1 second before returning to -80 mV. This voltage stimulus was administered every 10 seconds, and administration began after confirming that the hERG potassium current was stable (for at least 1 minute). Compounds were administered for at least 1 minute at each test concentration, and at least two cells (n ≥ 2) were tested for each concentration.

[0871] Data processing: Data analysis was performed using pClamp 10, GraphPad Prism 5, and Excel. The degree of inhibition of hERG potassium current (peak hERG tail current induced at -50 mV) by different compound concentrations was calculated using the following formula: Inhibition% = [1-(I / Io)] × 100%

[0872] Wherein, Inhibition% represents the inhibition percentage of the compound on hERG potassium current, and I and Io represent the amplitude of hERG potassium current before and after drug addition, respectively.

[0873] Compound IC 50 The results were calculated using GraphPad Prism 5 software by fitting the following equation: Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC 50 -X)*HillSlope))

[0874] Where X is the Log value of the test sample concentration, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively.

[0875] Conclusion: The compounds of the present invention, such as the compounds in the examples, have no significant inhibitory effect on hERG potassium ion channels.

[0876] 9. Cell Detection of IL-2 Experiment

[0877] The activating effect of the compound on T cell secretion of IL-2 was evaluated by ELISA. The frozen PBMCs were revived and pan T cells were isolated and purified using T cell sorting kit (Stemcell, 17951). The cells were resuspended in 1640 complete medium and incubated overnight in a 37°C & 5% CO2 incubator. A 96-well plate was coated with anti-human CD3 antibody (Thermo, 16-0037-38) at a final concentration of 5 μg / mL and incubated at 37°C for 2 hours. The cells cultured overnight were collected by centrifugation, the supernatant was removed, and the cells were resuspended in 1640 complete medium and cultured according to 10 5 Cells were seeded at a density of 100 cells / well in a 96-well plate coated with a CD3 antibody. Compounds were added at varying concentrations and incubated for 24 hours at 37°C in a 5% CO2 incubator. After incubation, the cells were centrifuged at 1000 rpm for 1 minute, and the supernatant was collected and assayed for IL-2 according to the ELISA instructions. DMSO without compound was used as a control group to calculate compound activation rates. Activation curves were fitted using Prism. Maximum activation fold = maximum activation rate / control group.

[0878] Table 9-1 Results of IL-2 activation by test compounds

[0879] Conclusion: Compared with the control compound, the compounds of the present invention, such as the example compounds, have a better activation effect on IL-2.

[0880] 10. Monkey Pharmacokinetic Test

[0881] Test animals: Male cynomolgus monkeys, 3-5 kg, 4-6 per compound.

[0882] Test method: On the day of the test, 4-6 monkeys / compound were randomly divided into groups according to body weight. The monkeys were fasted but not watered for 14-18 hours before administration and fed 4 hours after administration. Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 5% DMSO + 5% Solutol + 30% PEG400 + 60% (20% SBE-CD).

[0883] (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline.)

[0884] Before and after dosing, 1.0 mL of blood was collected from a limb vein and placed in an EDTAK2 centrifuge tube. The samples were centrifuged at 5000 rpm at 4°C for 10 minutes, and plasma was collected. Blood was collected from both the intravenous and oral administration groups at the following time points: 0, 5 minutes, 15 minutes, 30 minutes, and 1, 2, 4, 6, 8, 10, 12, and 24 hours. All samples were stored below -60°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0885] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic properties in monkeys.

[0886] 11. Pharmacokinetic testing in beagle dogs

[0887] Test animals: Male beagle dogs, approximately 8 to 10 kg.

[0888] Experimental method: On the day of the experiment, beagle dogs were randomly divided into groups according to body weight. They were fasted but not watered for 14-18 hours before administration and fed 4 hours after administration. Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 5% Solutol + 5% TPGS + 30% PEG400 + 60% (20% SBE-b-CD).

[0889] Before and after dosing, 1 ml of blood was collected from the jugular vein or limb vein into an EDTAK2 centrifuge tube. Plasma was collected by centrifugation at 5000 rpm at 4°C for 10 minutes. Blood was collected from the intravenous and oral gavage groups in groups G1, G2, and G3 at the following time points: 0, 5, 15, 30 minutes, and 1, 2, 4, 6, 8, 10, 12, 24, and 48 hours. All samples were stored below -60°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0890] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic properties in beagle dogs.

Claims

1. A compound or a stereoisomer, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein: The compound is selected from the compounds represented by the general formula (I), BLK(I); L is selected from a bond or -C 1-50 Hydrocarbyl-, wherein 1 to 20 methylene units in the hydrocarbyl are optionally replaced by -Ak-, -Cy-; Each -Ak- is independently selected from -(CH2) q -、-(CH2) q -O-, -O-(CH2) q -、-(CH2) q -S-, -S-(CH2) q -、-(CH2) q -NR L -、-NR L -(CH2) q -、-(CH2) q -NR L C(=O)-、-NR L (CH2) q C(=O)-、-(CH2) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH2) q -NR L -、-(C≡C) q -、-CH=CH-、-Si(R L )2-、-Si(OH)(R L )-、-Si(OH)2-、-P(=O)(OR L )-、-P(=O)(R L )-, -S-, -S(=O)-, -S(=O)2- or a bond, wherein the CH, -CH2- is optionally substituted by 1 to 2 R z replace; q is each independently selected from 0, 1, 2, 3, 4, 5 or 6; R L Selected from H, C 1-4 Alkyl, C 3-7 carbocyclic group, 4 to 10 membered heterocyclic group, the alkyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R z replace; Each -Cy- is independently selected from a bond or optionally substituted by 1 to 4 R L2 One of the following substituted groups: 4-8 membered heteromonocyclic group, 4-12 membered heterocyclic group, 5-13 membered heterospirocyclic group, 7-12 membered heterobridged ring group, C 3-7 Monocyclic alkyl, C 4-7 Monocyclic alkenyl, C 4-12 Cycloalkyl, C 5-13 Spirocycloalkyl, C 5-12 bridged cycloalkyl, 5-10 membered heteroaryl or C 6-10 Aryl; B is selected from Ba or Bb is selected from N or CR b ; R b Selected from H, deuterium, halogen, OH, CN, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -C 0-2 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy or cycloalkyl is optionally substituted by 1 to 4 R z replace; B1 is selected from C 6-10 carbocyclic group, 5 to 10 membered heterocyclic group, said B1 is optionally substituted by 1 to 4 R b1 replace; R b2 Selected from C 6-10 carbocyclic group, 5 to 10 membered heterocyclic group, said R b2 Optional 1 to 4 R b2a replace; R b3 , R b4 are each independently selected from H, deuterium, halogen, C 1-4 Alkyl, wherein the alkyl is optionally substituted by 1 to 4 halogens; R b1 , R b2a Each independently selected from deuterium, halogen, OH, CN, NH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -C 0-2 Alkylene-C 3-6 Cycloalkyl, -C 0-2 Alkylene-OC 3-6 Cycloalkyl, -C 0-2 Alkylene-4 to 7 membered heterocycloalkyl, -C 0-2 Alkylene-O-4 to 7 membered heterocycloalkyl, -C 0-2 Alkylene-NHC 1-4 Alkyl, -C 0-2 Alkylene-N(C 1-4 alkyl) 2, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R z replace; K is selected from G is selected from N or CH; Q is independently selected from a bond, -O-, -S-, -CH2-, -NR q -, -C(=O)-, -NR q C(=O)-, -C(=O)NR q -; Q and G cannot directly form a nitrogen-nitrogen bond, a nitrogen-oxygen bond, or a nitrogen-sulfur bond; R q Select from H or C 1-4 alkyl; F is selected from C 3-20 Carbocyclic group, C 6-20 Aryl, 3-20 membered heterocyclyl or 5-20 membered heteroaryl; R k1 Each independently selected from H, deuterium, halogen, OH, =O, NH2, CN, COOH, CONH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 3 to 6 membered heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl is optionally substituted by 1 to 4 R z replace; R k2 are each independently selected from a bond, -C(=O)-, -S(=O)2-, -S(=O)- or -C(R k3 )2-; R k3 Each independently selected from H, deuterium, halogen, OH, =O, NH2, CN, COOH, CONH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl or 3 to 8 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl or heterocyclic group is optionally substituted by 1 to 4 groups selected from R z replace; Alternatively, two R k3 Direct connection to form C 3-8 A carbocyclic group or a 4-8 membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 groups selected from R z replace; R L2 , R z Each independently selected from deuterium, halogen, OH, =O, CF3, SF5, CN, NH2, NO2, COOH, CONH2, NHC 1-4 Alkyl, N(C 1-4 alkyl)2, COOH, CONH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -SC 1-4 Alkyl, -C 0-4 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkoxy, alkenyl, alkynyl, cycloalkyl is optionally substituted by 1 to 4 deuterium, F, Cl, Br, I, OH, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; n1 is selected from 0, 1, 2 or 3; p1 and p2 are each independently selected from 0, 1, 2, 3, 4 or 5.

2. The compound according to claim 1 or its stereoisomer, racemate, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: L is selected from -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-; Ak1, Ak2, Ak3, Ak4, Ak5 are each independently selected from -(CH2) q -、-(CH2) q -O-, -O-(CH2) q -、-(CH2) q -S-, -S-(CH2) q -、-(CH2) q -NR L -、-NR L -(CH2) q -、-(CH2) q -NR L C(=O)-、-(CH2) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH2) q -NR L -、-(C≡C) q - or a bond, wherein the -CH2- is optionally replaced by 1 to 2 R z replace; R L Each independently selected from H or C 1-4 alkyl; Cy1, Cy2, Cy3 or Cy4 are each independently selected from a bond or optionally substituted by 1 to 4 R L2 One of the following substituted groups: 4-7 membered nitrogen-containing heteromonocyclic group, 4-12 membered nitrogen-containing heterocyclic group, 5-13 membered nitrogen-containing heterospirocyclic group, 7-12 membered nitrogen-containing heterobridged ring group, C 3-7 Monocyclic alkyl, C 4-7 Monocyclic alkenyl, C 4-12 Cycloalkyl, C 5-13 Spirocycloalkyl, C 5-12 bridged cycloalkyl, 5-10 membered heteroaryl or C 6-10 Aryl; F is selected from C 3-7 Monocyclic group, C 4-10 Cyclic group, C 5-12 Spirocyclyl, C 5-10 bridged cyclyl, 4-7 membered heteromonocyclic group, 4-10 membered bicyclic heterocyclic group, 8-15 membered tricyclic heterocyclic group, 12-19 membered tetracyclic heterocyclic group, 5-17 membered heterospirocyclic group, 5-10 membered heterobridged cyclyl, C 6-14 Aryl, 5-10 membered heteroaryl; B1 is selected from phenyl, benzo 4-6 carbocyclyl, benzo 4 to 6 membered heterocyclyl, 5 to 6 membered heteroaryl, 8 to 10 membered heteroaryl, said B1 is optionally substituted by 1 to 4 R b1 replace; R b2 Selected from phenyl, benzo C 4-6 carbocyclic group, benzo 4 to 6 membered heterocyclic group, 5 to 6 membered heteroaryl group, 8 to 10 membered heteroaryl group, said R b2 Optional 1 to 4 R b2a replace.

3. The compound according to claim 2 or its stereoisomer, racemate, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: R L is selected from H, methyl or ethyl; Cy1, Cy2, Cy3, and Cy4 are each independently selected from a bond or optionally substituted by 1 to 4 R L2 Substituted by one of the following groups: phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, s1, s3, s5 are each independently selected from 0, 1 or 2; s2 and s4 are each independently selected from 0 or 1; s6 is selected from 0, 1, 2 or 3; s7 is selected from 1, 2 or 3; Selected from F is selected from the group consisting of cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentanyl, 6,7-dihydro-5H-cyclopenta[c]pyridinyl, 2,3-dihydro-1H-indenyl, phenyl, naphthyl, anthracenyl, phenanthryl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazine, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furanyl, thienyl, thiazolyl, 2-pyridonyl, The ring where the representative is located is an aromatic ring or a non-aromatic ring; Fa is selected from N, CH or CR k1 ; Fb is selected from N, CH or CR k1 ; Fc is selected from O, S, NH, N(CH3) or NR k7a ; Fd is selected from N, CH or CR k1 ; Fg is selected from N or C; Fh is selected from N or C; Faa is selected from a bond, O, CH2; Fab is selected from O, CH2; H1 is selected from N, NH, CH, CH2, CHR k1 NR k1 , CR k1 , C(=O), C(R k1 )2; H2 is selected from a bond, O, N, NH, CH, CH2, CHR k1 NR k1 , CR k1 or C(R k1 )2; H3 is selected from N or CH; H4 is selected from C, N or CH; H5, H6, H7 are each independently selected from N, C, CH or CR k1 , and H5, H6, and H7 contain at most 2 Ns; Ring E is selected from phenyl or 5-6 membered heteroaryl, and the ring E is optionally substituted by 1 to 3 R k1 replace; Ring F1, ring F2, ring F3, ring F4 are each independently selected from phenyl or 5-6 membered heteroaryl, and the ring F1, ring F2, ring F3, ring F4 are optionally substituted by 1 to 2 R k1 replace; Q is selected from a bond, CH2, NH, N(CH3), O, S, C(=O), NHC(=O), C(=O)NH, N(CH3)C(=O), C(=O)N(CH3); R k1 , R k3 Each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH2, CF3, CN, COOH, CONH2, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, wherein the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH2; R k5 Each independently selected from C(CH3)2、C(=O)、CH2、CH2CH2、S(=O)2、 R k6 Each is independently selected from C(═O), CH, S(═O), S(═O)2, CH2 or N; R k7 Each independently selected from C(CH3)2, CH2, O or NR k7a ; R k7a is selected from H, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl is optionally substituted by 1 to 4 deuterium, F, Cl, Br, I, OH, CN, CF3, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Substituted by a cycloalkyl substituent; R k9 are each independently selected from a bond, C(CH3)2, C(=O), CH2, CH2CH2 or S(=O)2; R L2 , R z Each independently selected from deuterium, F, Cl, Br, I, OH, =O, CF3, SF5, CN, NH2, NO2, COOH, CONH2, N(CH3)2, NHCH3, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl is optionally substituted by 1 to 4 selected from deuterium, F, Cl, Br, I, OH, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; p2 is independently selected from 0, 1, 2 or 3.

4. The compound according to claim 3 or its stereoisomer, racemate, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: Ring E is independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furanyl, thienyl or oxazolyl, and the ring E is optionally substituted by 1 to 3 R k1 replace; Ring F1 and Ring F2 are each independently selected from phenyl, pyridyl, thiazolyl, furyl, thienyl or oxazolyl, and the ring F1 and ring F2 are optionally substituted by 1 to 2 R k1 replace; Ring F3 and Ring F4 are each independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furanyl, thienyl or oxazolyl, and the ring F3 and ring F4 are optionally substituted by 1 to 2 R k1 replace; B1 is selected from phenyl, thiazolyl, furanyl, thienyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, and B1 is optionally substituted by 1 to 4 R b1 replace; R b2 Selected from The R b2 Optional 1 to 4 R b2a replace; R b1 , R b2a Each independently selected from deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2 or optionally substituted by 1 to 4 R z substituted with one of the following groups: methyl, ethyl, propyl, isopropyl, ethynyl, -CH2-ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, -CH2NHCH3, -CH2N(CH3)2, tetrahydropyranyl, piperidinyl, -CH2-azetidinyl, -CH2-pyrrolidinyl, -CH2-piperidinyl; Ak1, Ak2, Ak3, Ak4, Ak5 are each independently selected from a bond, -O-, -S-, -OCH2-, -CH2O-, -OCH2CH2-, -CH2CH2O-, -C≡C-, -C(CH3)2-, -CH2-, -C(CH3)2-, -CH2CH2-, -CH2CH2CH2-, -N(CH3)-, -NH-, -CH2N(CH3)-, -CH2NH-, -NHCH2-, -CH2CH2N(CH3)-, -CH2CH2NH-, -NHCH2CH2-, -C(=O)-, -C(=O)CH2NH-, -CH2C(=O)NH-, -C(=O)NH- or -NHC(=O)-; Cy1, Cy2, Cy3, and Cy4 are each independently selected from a bond or one of the following groups which are optionally substituted: When substituted, it is substituted with 1 to 4 substituents selected from deuterium, F, CF3, OH, =O, COOH, CN, NH2, hydroxymethyl, methyl, methoxy, and cyclopropyl.

5. The compound according to claim 4 or its stereoisomer, racemate, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: B is selected from L is selected from the group consisting of bonds, -Ak1-, -NHCH2-, -Cy1-, -Cy1-CH2-, -Cy1-C≡C-, -Cy1-Cy2-, -Cy1-CH2-Cy2-, -CH2-Cy2-, -Cy1-Cy2-Cy3-, -Cy1-CH2-Cy2-Cy3-, -Cy1- Cy2-CH2-Cy3-, -NH-Cy1-, -NH-Cy1-Cy2-, -NH-Cy1-CH2-Cy2, -Cy1-Ak2-, -Ak1-Cy1-, -Ak1-Cy1-Ak2-, -Ak1-Cy2-Ak2-Cy3-, -Ak1-Cy2-Cy3-; Cy1, Cy2, and Cy3 are each independently selected from one of the following optionally substituted groups: When substituted, it is substituted with 1 to 4 substituents selected from deuterium, F, CF3, OH, =O, COOH, CN, NH2, hydroxymethyl, methyl, methoxy, and cyclopropyl.

6. The compound according to claim 1 or 5, or its stereoisomer, racemate, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: L is selected from one of the structures shown in Table L-1 or L-2; K is selected from one of the structural fragments shown in Table K-1 or Table K-2.

7. The compound according to claim 1 or its stereoisomer, racemate, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: The compound described in general formula (I) is selected from general formula (Ia), Select from single bond or does not exist; J1 is selected from N or CH; Cy1 is selected from one of the following optionally substituted groups: 4-7 membered nitrogen-containing heteromonocyclic group, 4-12 membered nitrogen-containing heterocyclic group, 5-13 membered nitrogen-containing heterospirocyclic group, 7-12 membered nitrogen-containing heterobridged ring group, C 3-7 Monocyclic alkyl, C 4-7 Monocyclic alkenyl, C 4-12 Cycloalkyl, C 5-13 Spirocycloalkyl, C 5-12 bridged cycloalkyl, 5-10 membered heteroaryl or C 6-10 Aryl, preferably one of the following groups which are optionally substituted: When substituted, it is substituted by 1 to 4 substituents selected from deuterium, F, CF3, OH, =O, COOH, CN, NH2, hydroxymethyl, methyl, methoxy, cyclopropyl; G is selected from N or CH; Q is selected from C(=O)NH or a bond; R b2 Selected from The R b2 Optional 1 to 4 R b2a replace; R b2a Each is independently selected from deuterium, F, Cl, Br, OH, CN, NH2, NHCH3, N(CH3)2, methyl, ethyl, methoxy, CF3; R b1 Each is independently selected from deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2, methyl, ethyl, -CH2NHCH3, -CH2N(CH3)2, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, -CH2-azetidinyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, wherein the methyl, ethyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, azetidinyl, pyrrolidinyl, piperidinyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, CF3, OH, =O, COOH, CN, NH2; R k1 Each independently selected from H, deuterium, F, Cl, Br, NH2, CF3, CN, methyl, ethyl; p3 is selected from 0, 1, 2 or 3; p4 is selected from 0, 1, 2 or 3; p5 is selected from 0 or 1; p6 is selected from 0 or 1.

8. The compound according to claim 1 or its stereoisomer, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from one of the structures shown in Table E.

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 or a stereoisomer, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition contains 1 to 1500 mg of a compound according to any one of claims 1 to 8 or a stereoisomer, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

10. Use of the compound according to any one of claims 1 to 8 or its stereoisomer, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal or the pharmaceutical composition according to claim 9 in the preparation of a medicament for treating a disease associated with HPK1 activity or expression.

11. Use of the compound according to any one of claims 1 to 8 or its stereoisomer, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal or the pharmaceutical composition according to claim 9 in the preparation of a drug for treating a disease associated with the inhibition or degradation of HPK1.

12. The use according to claim 11, characterized in that: The disease is selected from cancer, preferably solid tumor.

13. A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 8 or a stereoisomer, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, or a pharmaceutical composition according to claim 9, the therapeutically effective amount preferably being 1-1500 mg, the disease preferably being cancer, more preferably being a solid tumor.