Compounds that inhibit and degrade IRAK4, pharmaceutical compositions thereof, and pharmaceutical applications thereof

Abstract

The present invention relates to compounds according to general formula (I) or their stereoisomers, deuterated forms, solvates, prodrugs, metabolites, pharma- ceutically acceptable salts or co-crystals, and intermediates thereof, and their uses in IRAK4-associated diseases, such as autoimmune diseases, inflammatory diseases or cancer.

Description

[Technical field]

[0001] The present invention relates to compounds of general formula (I) or their stereoisomers, deuterated forms, solvates, prodrugs, metabolites, pharma-ceutically acceptable salts or co-crystals, and intermediates and processes for the preparation thereof, and their use in IRAK4-related diseases, such as tumors or autoimmune diseases. [Background technology]

[0002] Kinases catalyze the phosphorylation of proteins, lipids, sugars, nucleosides and other cellular metabolites, and play important roles in various aspects of eukaryotic cell physiology. In particular, protein kinases and lipid kinases are involved in the response of cells to extracellular media or stimuli, such as signal events, growth factors, cytokines or chemokines, that control their activation, growth, differentiation and survival. In general, protein kinases are divided into two classes: those that preferentially phosphorylate tyrosine residues and those that preferentially phosphorylate serine and / or threonine residues.

[0003] Interleukin 1 receptor kinase 4 (IRAK4) is a serine / threonine-specific protein kinase and a member of the tyrosine-like kinase (TLK) family, which is a key player in the innate immune response involving interleukin-1, 18, 33 receptors and Toll-like receptors. After binding to interleukin receptors or Toll-like receptors, extracellular signaling molecules are recruited to form the MyD88:IRAK4:IRAKl / 2 polyprotein complex, which causes phosphorylation of IRAK1 / 2 and mediates a series of downstream signaling events, activating p38, JNK and NF-kB signaling pathways, ultimately resulting in the expression of proinflammatory cytokines. Clinicopathological studies have shown that individuals with IRAK4 mutations have a protective effect against chronic lung disease and inflammatory bowel disease. IRAK4 deficiency itself is not lethal, and individuals can live to adulthood and have a reduced risk of infection as they age. Therefore, IRAK4 has become an important therapeutic target and has attracted extensive development interest.

[0004] PROTAC (proteolysis targeting chimera) molecules are a type of bifunctional compound that can simultaneously bind to a target protein and E3 ubiquitin ligase, and such compounds can be recognized by cellular proteasomes, causing the degradation of the target protein, and effectively reducing the content of the target protein in cells. By introducing ligands that can bind to different target proteins into PROTAC molecules, it becomes possible to apply PROTAC technology to the treatment of various diseases, and in recent years, the technology has also attracted widespread attention.

[0005] Therefore, the development of novel IRAK4 inhibitors and E3 ubiquitin ligase PROTAC drugs is necessary to treat IRAK4-related diseases. Summary of the Invention

[0006] The object of the present invention is to provide a compound that has a novel structure, excellent efficacy, high bioavailability, and is safer, and can inhibit or degrade IRAK4, for treating IRAK4-related diseases, such as autoimmune diseases, inflammatory diseases, or cancer.

[0007] The present invention provides a compound or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharma- ceutically acceptable salt or co-crystal thereof, wherein the compound has the general formula (I): BLK (I) The compound is selected from the compounds shown in In some embodiments, B is [ka] is selected from In some embodiments, B1, B3 are each independently C 6-10 an aryl group, a 5- to 10-membered heteroaryl group, or a 4- to 10-membered heterocyclic group, the heteroaryl group or the heterocyclic group containing 1 to 4 heteroatoms selected from O, S, and N; In some embodiments, B1 and B3 are each independently a pyrazolyl group, an oxazolyl group, a dioxazolyl group, an oxadiazolyl group, a triazolyl group, an imidazolyl group, a tetrazolyl group, a pyrrolyl group, a thienyl group, a thiazolyl group, a thiadiazolyl group, a pyridyl group, a phenyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, a thienopyrazinyl group, a benzimidazolyl group, a pyridotriazolyl group, a pyrimidopyrazolyl group, an imidazopyridazinyl group, a pyridopyrazolyl group, a pyrrolopyridazinyl group, or [ka] is selected from In some embodiments, B1, B3 are [ka] is selected from In some embodiments, R b1 , R b7 are each independently H, F, Cl, Br, I, =O, OH, NH2, CN, CF3, C(=O)OH, CHF2, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, -(CH2) n -R b21 , -OR b21 , -N(R b21 )2, C 6-10 aryl group, 5-10 membered heteroaryl group, or 4-10 membered heterocyclic group, wherein the alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group, or heteroaryl group is optionally selected from H, F, Cl, Br, I, OH, ═O, —N(R b21 )2, CN, CF3, C(=O)OH, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl group, 5- to 10-membered heteroaryl group, 4- to 10-membered heterocyclic group, or R b7a and the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S and N; In some embodiments, R b1 , R b7 are each independently H, F, Cl, Br, I, =O, OH, NH2, CN, CF3, CHF2, CH2F, a methyl group, an ethyl group, a methoxy group, an ethoxy group, a phenyl group, a pyrrolyl group, a pyridyl group, a morpholinyl group, [ka] wherein the methyl, ethyl, methoxy, ethoxy, phenyl, pyrrolyl, pyridyl, and morpholinyl groups are optionally selected from H, F, Cl, Br, I, OH, CN, CF3, NH2, NHC 1-4 Alkyl group, N(C 1-4 Alkyl)2, NHCH2C 3-6 Cycloalkyl groups, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl group or R b7a is further substituted with 0 to 4 substituents selected from In some embodiments, R b1 , R b7 are each independently selected from an azetidinyl group, an azacyclopentyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, and a 2-oxa-5-azabicyclo[2.2.1]heptyl group; b1 , R b7 is optionally F, Cl, Br, I, OH, =O, CN, CF3, NH2, NHC 1-4 Alkyl group, N(C 1-4 Alkyl)2, NHCH2C 3-6 Cycloalkyl groups, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl group or R b7a and the heterocyclic group contains 1 to 4 heteroatoms selected from O, S and N; In some embodiments, R b1 , R b7are each independently selected from an azetidinyl group, an azacyclopentyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, and a 2-oxa-5-azabicyclo[2.2.1]heptyl group; b1 , R b7 is optionally F, Cl, Br, I, OH, =O, CN, CF3, NH2, NHC 1-4 Alkyl group, N(C 1-4 Alkyl)2, NHCH2C 3-6 Cycloalkyl groups, halogen-substituted C 1-4 C substituted with alkyl or cyano groups 1-4 Alkyl group, -C 1-4 Alkylene-OH, C 1-4 Alkyl group, C 1-4 Alkoxy group, -CH2-OC 1-4 Alkyl group, -CH2-C 3-6 Cycloalkyl groups, -OC 3-6 Cycloalkyl groups, -NH-C 3-6 Cycloalkyl groups, C 3-6 substituted with 1 to 4 substituents selected from a cycloalkyl group, a -CH2-4 to 7-membered heterocycloalkyl group, a -O-4 to 7-membered heterocycloalkyl group, a -NH-4 to 7-membered heterocycloalkyl group, and a 4 to 7-membered heterocycloalkyl group, the heterocyclic group containing 1 to 4 heteroatoms selected from O, S, and N; In some embodiments, R b1 , R b7 each independently represents an azetidinyl group, an azacyclopentyl group, a phenyl group, a pyrrolyl group, a pyridyl group, a morpholinyl group, [ka] is selected from In some embodiments, R b1 , R b7 are each independently [ka] is selected from In some embodiments, R b1 , R b7is optionally F, Cl, Br, I, OH, ═O, CN or R b7a is substituted with 1 to 4 substituents selected from In some embodiments, R b7a is C 1-4 Alkyl group, -C 3-6 Cycloalkyl group, 4-10 membered heterocyclic group, -C 1-4 Alkylene-C 3-6 Cycloalkyl groups, -C 1-4 Alkylene-4 to 10 membered heterocyclic group, -OC 3-6 Cycloalkyl group, -O-4 to 10 membered heterocyclic group, -NH-C 3-6 Cycloalkyl group, -NH-4 to 10-membered heterocyclic group, -N(C 1-4 Alkyl)-C 3-6 Cycloalkyl groups, -N(C 1-4 alkyl)-4 to 10-membered heterocyclic group, b7a is optionally H, F, Cl, Br, I, OH, ═O, -N(R b21 )2, CN, CF3, C(=O)OH, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 It is substituted with 1 to 4 substituents selected from a cycloalkyl group and a 4- to 10-membered heterocyclic group, and the heterocyclic group contains 1 to 4 heteroatoms selected from O, S and N, In some embodiments, R b7ais a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, an azetidinyl group, an azacyclopentyl group, an azacyclohexyl group, a piperazinyl group, a morpholinyl group, an oxetanyl group, an oxacyclopentyl group, an oxacyclohexyl group, -CH2-cyclopropyl group, -CH2-cyclobutyl group, -CH2-cyclopentyl group, -CH2-cyclohexyl group, -CH2-azetidinyl group, -CH2-azacyclopentyl group, -CH2-azacyclohexyl group, -CH2-piperazinyl group, -CH2-morpholinyl group, -CH2-oxetanyl group, -CH2-oxacyclopentyl group, -CH2-oxacyclohexyl group, -O- is selected from the group consisting of a cyclopropyl group, an -O-cyclobutyl group, an -O-cyclopentyl group, an -O-cyclohexyl group, an -O-azetidinyl group, an -O-azacyclopentyl group, an -O-azacyclohexyl group, an -O-piperazinyl group, an -O-morpholinyl group, an -O-oxetanyl group, an -O-oxacyclopentyl group, an -O-oxacyclohexyl group, an -NH-cyclopropyl group, an -NH-cyclobutyl group, an -NH-cyclopentyl group, an -NH-cyclohexyl group, an -NH-azetidinyl group, an -NH-azacyclopentyl group, an -NH-azacyclohexyl group, an -NH-piperazinyl group, an -NH-morpholinyl group, an -NH-oxetanyl group, an -NH-oxacyclopentyl group, and an -NH-oxacyclohexyl group; b7a is optionally F, Cl, Br, I, OH, =O, CN, CF3, C(=O)OH, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 It is substituted with 1 to 4 substituents selected from a cycloalkyl group and a 4- to 10-membered heterocyclic group, and the heterocyclic group contains 1 to 4 heteroatoms selected from O, S and N, In some embodiments, R b7ais CF3, CHF2, CH2F, CH2CN, CH2OH, CH2OCH3, methyl group, ethyl group, -CH2-cyclopropyl group, -CH2-azetidinyl group, -CH2-oxetanyl group, -O-cyclopropyl group, -O-azetidinyl group, -O-oxetanyl group, -NH-cyclopropyl group, -NH-azetidinyl group, -NH-oxetanyl group, [ka] is selected from In some embodiments, R b2 , R b6 are each independently H, F, Cl, Br, I, =O, OH, -C(=O)N(R b21 )2, -N(R b21 ) 2、 CN, CF3, C(=O)OH, CHF2, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, -(CH2) n -R b21 , -OR b21 , C 6-10 aryl group, a 5-10 membered heteroaryl group, or a 4-10 membered heterocyclic group, wherein the alkyl group, alkoxy group, cycloalkyl group, aryl group, heteroaryl group, or heterocyclic group is optionally selected from H, F, Cl, Br, I, OH, =O, NH2, CN, CF3, C(=O)OH, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 It is further substituted with 0 to 4 substituents selected from a cycloalkyl group, a 5-10 membered heteroaryl group, or a 4-10 membered heterocyclic group, and the heteroaryl group or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N; In some embodiments, R b2 , R b6are each independently selected from H, F, Cl, Br, I, =O, CF3, CHF2, OH, NH2, NH(methyl), NH(ethyl), NH(propyl), NH(isopropyl), N(methyl)2, N(ethyl), CN, methyl, ethyl, methoxy, ethoxy, propoxy, isopropyloxy, morpholinyl, piperazinyl, pyrrolidinyl, piperidinyl, or oxazolidinyl, and the methyl, ethyl, methoxy, ethoxy, propoxy, isopropyloxy, morpholinyl, piperazinyl, pyrrolidinyl, piperidinyl, or oxazolidinyl groups are optionally selected from H, F, Cl, Br, I, OH, CN, CF3, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 is further substituted with 0 to 4 substituents selected from a cycloalkyl group; In some embodiments, R b21 are independently H, C 1-6 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 6-10 aryl group, a 5-10 membered heteroaryl group, or a 4-10 membered heterocyclic group, wherein the alkyl group, alkoxy group, cycloalkyl group, aryl group, heteroaryl group, or heterocyclic group is optionally selected from H, F, Cl, Br, I, OH, =O, NH2, CN, CF3, C(=O)OH, C 1-4 Alkyl group, C 3-6 Cycloalkyl groups, C 1-4 The heteroaryl or heterocyclic group is further substituted with 0 to 4 substituents selected from an alkoxy group, and the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N; In some embodiments, B is [ka] [ka] [ka] is selected from In some embodiments, L is selected from -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-; In some embodiments, L is a bond, -Cy1-, -Cy1-Ak2-, -Cy1-Ak2-Ak3-, -Cy1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-, -Cy1-Ak2-Cy2-, -Cy1-Cy2-Ak3-, -Cy1-Cy2-Ak3-Cy4-, -Cy1-Ak2-Cy2-Ak3-, -Cy1-Ak2-Cy2-Ak3-Ak4-, -Cy1-Ak2-Cy2-Cy3-Ak4-, -Cy1-Cy2-Ak3-Ak4-, -Cy1-Cy2-Ak3-Ak4-, -Cy1-Cy2-Ak3-Ak4-, -Cy1-Cy2-Ak3-Ak4-Ak5-, -Cy1- Ak2-Cy2-Ak3-Ak4-Ak5-, -Cy1-Ak2-Ak3-Cy3-Ak4-, -Cy1-Ak2-Ak3-Cy3 -Ak4-Ak5-, -Cy1-Ak2-Ak3-Ak4-Cy4-Ak5-, -Cy1-Cy2-Cy3-, -Cy1-Ak2- Cy2-Cy3-, -Cy1-Cy2-Cy3-Ak4-, -Cy1-Ak2-Cy2-Cy3-Ak4-, -Cy1-Ak2-C y2-Ak3-Cy3-, -Cy1-Ak2-Cy2-Cy3-Ak4-Ak5, -Cy1-Ak2-Cy2-Ak3-Cy3-A k4-Ak5-, -Cy1-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak3-Cy3-Cy4-, -Cy1-Cy2-Cy 3-Ak4-Cy4-, -Ak1-Cy1-Ak2-Cy2-, -Ak1-Cy1-Ak2-Cy2-Ak3-, -Ak1-Ak2 -Cy2-Ak3-, -Ak1-Ak2-Cy2-, -Ak1-Ak2-Cy2-Cy3-Ak4-, -Ak1-Ak2-Ak3- Cy3-Ak4-, -Ak1-Cy1-Ak2-, -Ak1-Cy1-Cy2-Ak3-Ak4-, -Ak1-Cy1-Cy2-A k3-, -Ak1-Cy1-Ak2-Ak3-Ak4-, -Ak1-Cy1-, -Ak1-Cy1-Ak2-Ak3-, -Ak1-Ak2-Cy2-Ak3-Ak4-, -Ak1-Cy1-Ak2-Cy2-Ak3-Ak4-, -Cy1-Ak2-Ak3-Cy3-Cy4-Ak5-, -Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-, -Ak1-Cy1-Cy2-, -Ak1-Ak2-Ak3-Ak4-, -Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-; In some embodiments, Ak1, Ak2, Ak3, Ak4 and Ak5 are each independently -(CH2) q -, O, -(CH2) q NR L -, NR L C=O, C=ONR L , C=O, -R L C=CR L -, C≡C or a bond; In some embodiments, Ak1, Ak2, Ak3, Ak4, and Ak5 are each independently selected from O, C≡C, CH2, CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2N(CH3), CH2CH2N(CH3), N(CH3), NH, C(=O), C(=O)N(CH3), N(CH3)C(=O), C(=O)NH, or NHC(=O); In some embodiments, R L is H or C 1-6 alkyl groups, In some embodiments, R L is selected from H, a methyl group or an ethyl group, In some embodiments, Cy1, Cy2, Cy3, and Cy4 are each independently selected from a bond, a 4- to 7-membered heteromonocyclic ring, a 4- to 10-membered heterofused ring, a 5- to 12-membered heterospirocyclic ring, a 7- to 10-membered heterobridged ring, a 3- to 7-membered monocycloalkyl group, a 4- to 10-membered fused cycloalkyl group, a 5- to 12-membered spirocycloalkyl group, a 7- to 10-membered bridged cycloalkyl group, a 5- to 10-membered heteroaryl group, or a 6- to 10-membered aryl group, and the aryl group, heteroaryl group, cycloalkyl group, heteromonocyclic ring, heterofused ring, heterospirocyclic ring, or heterobridged ring is optionally selected from H, F, Cl, Br, I, OH, C(═O)OH, CN, NH2, ═O, C 1-4 Alkyl, halogen-substituted C 1-4 C substituted with alkyl or hydroxy groups 1-4 Alkyl group or C 1-4 and the heteroaryl group, the heteromonocyclic ring, the heterocondensed ring, the heterospirocyclic ring or the heterobridged ring contains 1 to 4 heteroatoms selected from O, S and N; In some embodiments, Cy1, Cy2, Cy3, and Cy4 are each independently selected from a bond, a 4- to 7-membered nitrogen-containing heteromonocycle, a 4- to 10-membered nitrogen-containing heterofused ring, a 5- to 12-membered nitrogen-containing heterospirocycle, a 7- to 10-membered nitrogen-containing heterobridged ring, a 3- to 7-membered monocycloalkyl group, a 4- to 10-membered fused cycloalkyl group, a 5- to 12-membered spirocycloalkyl group, a 7- to 10-membered bridged cycloalkyl group, a 5- to 10-membered heteroaryl group, or a 6- to 10-membered aryl group, and the heteromonocycle, heterofused ring, heterobridged ring, heterospirocycle, cycloalkyl group, aryl group, or heteroaryl group is optionally selected from H, F, Cl, Br, I, OH, C(═O)OH, CN, NH, ═O ... 1-4 Alkyl, halogen-substituted C 1-4 C substituted with alkyl or hydroxy groups 1-4 Alkyl group or C 1-4 and the heteromonocyclic ring, heterocondensed ring, heterobridged ring, heterospirocyclic ring, or heteroaryl group contains 1 to 4 heteroatoms selected from O, S, and N; In some embodiments, Cy1, Cy2, Cy3, and Cy4 are each independently a bond or a substituted or unsubstituted group selected from the following: a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, an azetidinyl group, an azacyclopentyl group, a piperidinyl group, a morpholinyl group, a piperazinyl group, a phenyl group, a cyclopropyl-fused cyclopropyl group, a cyclopropyl-fused cyclobutyl group, a cyclopropyl-fused cyclopentyl group, a cyclopropyl-fused cyclohexyl group, a cyclobutyl-fused cyclobutyl group, a cyclobutyl-fused cyclopentyl ... fused cyclohexyl, cyclopentyl-fused cyclopentyl, cyclopentyl-fused cyclohexyl, cyclohexyl-fused cyclohexyl, cyclopropyl-spiro-cyclopropyl, cyclopropyl-spiro-cyclobutyl, cyclopropyl-spiro-cyclopentyl, cyclopropyl-spiro-cyclohexyl, cyclobutyl-spiro-cyclobutyl, cyclobutyl-spiro-cyclopentyl, cyclobutyl-spiro-cyclohexyl, cyclopentyl-spiro-cyclopentyl, cyclopentyl-spiro-cyclohexyl, cyclohexyl-spiro-cyclopentyl, cyclopentyl-spiro-cyclohexyl, cyclohexyl-spiro-cyclohexyl cyclohexyl, cyclopropyl-fused azetidinyl, cyclopropyl-fused azacyclopentyl, cyclopropyl-fused azacyclohexyl, cyclobutyl-fused azetidinyl, cyclobutyl-fused azacyclopentyl, cyclobutyl-fused azacyclohexyl, cyclopentyl-fused azetidinyl, cyclopentyl-fused azacyclopentyl, cyclopentyl-fused azacyclohexyl, cyclohexyl-fused azetidinyl, cyclohexyl-fused azacyclopentyl, cyclohexyl-fused azacyclohexyl, azetidinyl-fused azetidinyl, azetidinyl-fused azacyclopentyl butyl, azetidinyl-fused azacyclohexyl, azacyclopentyl-fused azacyclopentyl, azacyclopentyl-fused azacyclohexyl, azacyclohexyl-fused azacyclohexyl, cyclobutyl-spiro-azetidinyl, cyclobutyl-spiro-azacyclopentyl, cyclobutyl-spiro-azacyclohexyl, cyclopentyl-spiro-azetidinyl, cyclopentyl-spiro-azacyclopentyl, cyclopentyl-spiro-azacyclohexyl, cyclopentyl-spiro-azacyclohexyl, cyclohexyl-spiro-azetidinyl, cyclohexyl-spiro-azacyclopentyl,cyclohexyl-spiro-azacyclohexyl, azetidinyl-spiro-azetidinyl, azetidinyl-spiro-azacyclopentyl, azetidinyl-spiro-azacyclohexyl, azacyclopentyl-spiro-azacyclopentyl, azacyclopentyl-spiro-azacyclohexyl, azacyclohexyl-spiro-azacyclohexyl, [ka] and optionally, when substituted, H, F, Cl, Br, I, OH, NH2, C(=O)OH, CN, =O, C 1-4 Alkyl, halogen-substituted C 1-4 C substituted with alkyl or hydroxy groups 1-4 Alkyl group or C 1-4 is further substituted with 0 to 4 substituents selected from an alkoxy group; In some embodiments, Cy1, Cy2, Cy3, and Cy4 are each independently a bond or a substituted or unsubstituted group: [ka] and, if substituted, optionally further substituted with 0-4 substituents selected from H, F, CF3, methyl, =O, hydroxymethyl, C(=O)OH, CN, or NH2;

[0008] In some embodiments, L is [ka] [ka] is selected from In some embodiments, each J is independently [ka] is selected from In some embodiments, each J2 is independently [ka] is selected from In some embodiments, each J3 is independently [ka] is selected from In some embodiments, each J4 is independently [ka] is selected from In some embodiments, each J5 is independently [ka] is selected from In some embodiments, L is [ka] , R d is selected from H or D, and at least one R d is selected from D, d1 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, and d2 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9; In some embodiments, L is selected from the groups shown in Table L-1, where the left side of the group is linked to B.

[0009] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] In some embodiments, L is [ka] , R L1a are each independently halogen, CN, OH, C 1-4 Alkyl group, C 1-4 alkoxy groups, preferably F, Cl, Br, CN, OH, methyl, ethyl, hydroxymethyl, methoxy or ethoxy groups, and m is selected from 0, 1, 2, 3 or 4; In some embodiments, L is [ka] [ka] is selected from In some embodiments, K is [ka] is selected from In some embodiments, R k1 are independently H, C 1-4 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-6 cycloalkyl group, and 3- to 6-membered heterocycloalkyl group, wherein the alkyl group, cycloalkyl group, and heterocycloalkyl group are optionally selected from H, F, Cl, Br, I, OH, NH2, CN, CF3, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-6 is further substituted with 0 to 4 substituents selected from a cycloalkyl group; In some embodiments, R k1 are each independently selected from H, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclopentyl, piperidinyl, oxetanyl, oxacyclopentyl, and oxacyclohexyl, and the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclopentyl, piperidinyl, oxetanyl, oxacyclopentyl, and oxacyclohexyl groups are optionally selected from H, F, Cl, Br, I, OH, CN, CF3, C 1-4 Alkyl group, C 1-4 Alkoxy group, vinyl group, propenyl group, allyl group, ethynyl group, propynyl group, propargyl group, C 3-6 is further substituted with 0 to 4 substituents selected from a cycloalkyl group; R k1are each independently selected from H, methyl, ethyl, isopropyl, cyclopropyl, oxetanyl, oxacyclohexyl, -CHCF, -CH(CH)CF, -CH(CH)-cyclopropyl, -CH-cyclopropyl, -CH-vinyl, -CH-ethynyl, -CHCH-methoxy, and -CD; In some embodiments, R k2 , R k3 are each independently H, F, Cl, Br, I, OH, =O, NH2, CF3, CN, C(=O)OH, C(=O)NH2, C 1-4 Alkyl group or C 1-4 an alkoxy group, wherein the alkyl or alkoxy group is optionally further substituted with 0-4 substituents selected from H, F, Cl, Br, I, OH, and NH; Or two R k3 form a 3- to 6-membered carbocyclic ring or a 3- to 7-membered heterocyclic ring together with the carbon atom or ring skeleton directly bonded to both, and the carbocyclic ring or heterocyclic ring may optionally be H, F, Cl, Br, I, OH, ═O, NH2, CN, C(═O)OH, C(═O)NH2, C 1-4 Alkyl group or C 1-4 is further substituted with 0 to 4 substituents selected from an alkoxy group, and the heterocycle contains 1 to 4 heteroatoms selected from O, S, and N; In some embodiments, R k2 , R k3 are each independently selected from H, F, Cl, Br, I, OH, =O, NH2, CF3, CN, C(=O)OH, C(=O)NH2, methyl, ethyl, methoxy or ethoxy, and the methyl, ethyl, methoxy or ethoxy groups are optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH and NH2; In some embodiments, R k2 , R k3 are each independently selected from H or F; In some embodiments, K is [ka] is selected from In some embodiments, K is [ka] [ka] [ka] is selected from In some embodiments, 0-50 H in the compound represented by formula (I) are optionally replaced with 0-50 D; In some embodiments, 0-30 H in the compound represented by formula (I) are optionally replaced with 0-30 D; In some embodiments, 0-20 H in the compound represented by formula (I) are optionally replaced with 0-20 D; In some embodiments, 0-20 H in L are optionally replaced with 0-20 D; In some embodiments, 0-10 H in the compound represented by formula (I) are optionally replaced with 0-10 D; In some embodiments, 0-10 H in -LK are optionally replaced with 0-10 D; In some embodiments, 0-10 H in L are optionally replaced with 0-10 D; In some embodiments, 0-10 H in K are optionally replaced with 0-10 D; In some embodiments, 0-20 H in L are optionally replaced with 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 D; In some embodiments, 0-10 H in L are optionally replaced with 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 D; In some embodiments, 0-10 H in K are optionally replaced with 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 D; In some embodiments, 0-10 H in -LK are optionally replaced with 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 D; In some embodiments, n is selected from 0, 1, 2, 3, or 4; In some embodiments, q is selected from 0, 1, 2, 3, or 4; In some embodiments, n1, n2, and n6 are each independently selected from 0, 1, 2, or 3; In some embodiments, p2, p3 are each independently selected from 0, 1, 2, 3, or 4; In some embodiments, p2 or p3 is each independently selected from 0, 1, or 2.

[0010] As a first embodiment of the present invention, there is provided a compound represented by the above-mentioned general formula (I) or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharma- ceutically acceptable salt or cocrystal thereof, L is selected from: -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-; Ak1, Ak2, Ak3, Ak4 and Ak5 each independently represent -(CH2) q -, O, -(CH2) q NR L -, NR L C=O, C=ONR L , C=O, -R L C=CR L -, C≡C or a bond; R L is H or C 1-6 alkyl groups, Cy1, Cy2, Cy3, and Cy4 are each independently selected from a bond, a 4- to 7-membered heteromonocyclic ring, a 4- to 10-membered heterocondensed ring, a 5- to 12-membered heterospirocyclic ring, a 7- to 10-membered heterobridged ring, a 3- to 7-membered monocycloalkyl group, a 4- to 10-membered condensed cycloalkyl group, a 5- to 12-membered spirocycloalkyl group, a 7- to 10-membered bridged cycloalkyl group, a 5- to 10-membered heteroaryl group, and a 6- to 10-membered aryl group, and the aryl group, heteroaryl group, cycloalkyl group, heteromonocyclic ring, heterocondensed ring, heterospirocyclic ring, and heterobridged ring are optionally selected from H, F, Cl, Br, I, OH, C(=O)OH, CN, NH2, =O, C 1-4 Alkyl, halogen-substituted C 1-4 C substituted with alkyl or hydroxy groups 1-4 Alkyl group or C 1-4 and the heteroaryl group, the heteromonocyclic ring, the heterocondensed ring, the heterospirocyclic ring or the heterobridged ring contains 1 to 4 heteroatoms selected from O, S and N; B is, [ka] is selected from B1 and B3 are each independently C 6-10 an aryl group, a 5- to 10-membered heteroaryl group, or a 4- to 10-membered heterocyclic group, the heteroaryl group or the heterocyclic group containing 1 to 4 heteroatoms selected from O, S, and N; R b1 , R b7 are each independently H, F, Cl, Br, I, =O, OH, NH2, CN, CF3, C(=O)OH, CHF2, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, -(CH2) n -R b21 , -OR b21 , -N(R b21 )2, C 6-10aryl group, 5-10 membered heteroaryl group, or 4-10 membered heterocyclic group, wherein the alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group, or heteroaryl group is optionally selected from H, F, Cl, Br, I, OH, ═O, —N(R b21 )2, CN, CF3, C(=O)OH, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl group, 5- to 10-membered heteroaryl group, 4- to 10-membered heterocyclic group, or R b7a and the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S and N; R b7a is C 1-4 Alkyl group, -C 3-6 Cycloalkyl group, 4-10 membered heterocyclic group, -C 1-4 Alkylene-C 3-6 Cycloalkyl groups, -C 1-4 Alkylene-4 to 10 membered heterocyclic group, -OC 3-6 Cycloalkyl group, -O-4 to 10 membered heterocyclic group, -NH-C 3-6 Cycloalkyl group, -NH-4 to 10-membered heterocyclic group, -N(C 1-4 Alkyl)-C 3-6 Cycloalkyl groups, -N(C 1-4 alkyl)-4 to 10-membered heterocyclic group, b7a is optionally H, F, Cl, Br, I, OH, ═O, -N(R b21 )2, CN, CF3, C(=O)OH, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 It is substituted with 1 to 4 substituents selected from a cycloalkyl group and a 4- to 10-membered heterocyclic group, and the heterocyclic group contains 1 to 4 heteroatoms selected from O, S and N, R b2 , R b6 are each independently H, F, Cl, Br, I, =O, OH, -C(=O)N(R b21 ) 2、 -N(R b21 ) 2、 CN, CF3, C(=O)OH, CHF2, C1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, -(CH2) n -R b21 , -OR b21 , C 6-10 aryl group, a 5-10 membered heteroaryl group, or a 4-10 membered heterocyclic group, wherein the alkyl group, alkoxy group, cycloalkyl group, aryl group, heteroaryl group, or heterocyclic group is optionally selected from H, F, Cl, Br, I, OH, =O, NH2, CN, CF3, C(=O)OH, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 It is further substituted with 0 to 4 substituents selected from a cycloalkyl group, a 5-10 membered heteroaryl group, or a 4-10 membered heterocyclic group, and the heteroaryl group or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N; R b21 are independently H, C 1-6 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 6-10 aryl group, a 5-10 membered heteroaryl group, or a 4-10 membered heterocyclic group, wherein the alkyl group, alkoxy group, cycloalkyl group, aryl group, heteroaryl group, or heterocyclic group is optionally selected from H, F, Cl, Br, I, OH, =O, NH2, CN, CF3, C(=O)OH, C 1-4 Alkyl group, C 3-6 Cycloalkyl groups, C 1-4 The heteroaryl or heterocyclic group is further substituted with 0 to 4 substituents selected from an alkoxy group, and the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N; n is selected from 0, 1, 2, 3 or 4; K is [ka] is selected from R k1 are independently H, C 1-4 Alkyl group, C 2-6 Alkenyl group, C 2-6Alkynyl group, C 3-6 cycloalkyl group, and 3- to 6-membered heterocycloalkyl group, wherein the alkyl group, cycloalkyl group, and heterocycloalkyl group are optionally selected from H, F, Cl, Br, I, OH, NH2, CN, CF3, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-6 is further substituted with 0 to 4 substituents selected from a cycloalkyl group; R k2 , R k3 are each independently H, F, Cl, Br, I, OH, =O, NH2, CF3, CN, C(=O)OH, C(=O)NH2, C 1-4 Alkyl group or C 1-4 an alkoxy group, wherein the alkyl or alkoxy group is optionally further substituted with 0-4 substituents selected from H, F, Cl, Br, I, OH, and NH; Or two R k3 form a 3- to 6-membered carbocyclic ring or a 3- to 7-membered heterocyclic ring together with the carbon atom or ring skeleton directly bonded to both, and the carbocyclic ring or heterocyclic ring may optionally be H, F, Cl, Br, I, OH, ═O, NH2, CN, C(═O)OH, C(═O)NH2, C 1-4 Alkyl group or C 1-4 is further substituted with 0 to 4 substituents selected from an alkoxy group, and the heterocycle contains 1 to 4 heteroatoms selected from O, S, and N; q is selected from 0, 1, 2, 3 or 4; n1, n2, and n6 are each independently selected from 0, 1, 2, or 3; p2 and p3 are each independently selected from 0, 1, 2, 3, or 4; Optionally, 0-50 H in the compound represented by general formula (I) are replaced with 0-50 D.

[0011] As a second embodiment of the present invention, there is provided a compound represented by the above general formula (I) or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharma- ceutically acceptable salt or cocrystal thereof, Cy1, Cy2, Cy3 and Cy4 are each independently selected from a bond, a 4- to 7-membered nitrogen-containing heteromonocycle, a 4- to 10-membered nitrogen-containing heterocondensed ring, a 5- to 12-membered nitrogen-containing heterospirocycle, a 7- to 10-membered nitrogen-containing heterobridged ring, a 3- to 7-membered monocycloalkyl group, a 4- to 10-membered condensed cycloalkyl group, a 5- to 12-membered spirocycloalkyl group, a 7- to 10-membered bridged cycloalkyl group, a 5- to 10-membered heteroaryl group or a 6- to 10-membered aryl group, and the heteromonocycle, heterocondensed ring, heterobridged ring, heterospirocycle, cycloalkyl group, aryl group or heteroaryl group is optionally selected from H, F, Cl, Br, I, OH, C(=O)OH, CN, NH2, =O, C 1-4 Alkyl, halogen-substituted C 1-4 C substituted with alkyl or hydroxy groups 1-4 Alkyl group or C 1-4 and the heteromonocyclic ring, heterocondensed ring, heterobridged ring, heterospirocyclic ring, or heteroaryl group contains 1 to 4 heteroatoms selected from O, S, and N; Other definitions are the same as those in the first embodiment of the present invention.

[0012] As a third embodiment of the present invention, there is provided a compound represented by the above general formula (I) or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharma- ceutically acceptable salt or cocrystal thereof, R L is selected from H, a methyl group or an ethyl group, Cy1, Cy2, Cy3, and Cy4 each independently represent a bond or the following substituted or unsubstituted groups: a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, an azetidinyl group, an azacyclopentyl group, a piperidinyl group, a morpholinyl group, a piperazinyl group, a phenyl group, a cyclopropyl-fused cyclopropyl group, a cyclopropyl-fused cyclobutyl group, a cyclopropyl-fused cyclopentyl group, a cyclopropyl-fused cyclohexyl group, a cyclobutyl-fused cyclobutyl group, a cyclobutyl-fused cyclopentyl group, a cyclobutyl-fused cyclohexyl group, a cyclopropyl ... cyclopentyl-fused cyclopentyl, cyclopentyl-fused cyclohexyl, cyclohexyl-fused cyclohexyl, cyclopropyl-spiro-cyclopropyl, cyclopropyl-spiro-cyclobutyl, cyclopropyl-spiro-cyclopentyl, cyclopropyl-spiro-cyclohexyl, cyclobutyl-spiro-cyclobutyl, cyclobutyl-spiro-cyclopentyl, cyclobutyl-spiro-cyclohexyl, cyclopentyl-spiro-cyclopentyl, cyclopentyl-spiro-cyclohexyl, cyclohexyl-spiro-cyclohexyl, Cyclopropyl-fused azetidinyl, cyclopropyl-fused azacyclopentyl, cyclopropyl-fused azacyclohexyl, cyclobutyl-fused azetidinyl, cyclobutyl-fused azacyclopentyl, cyclobutyl-fused azacyclohexyl, cyclopentyl-fused azetidinyl, cyclopentyl-fused azacyclopentyl, cyclopentyl-fused azacyclohexyl, cyclohexyl-fused azetidinyl, cyclohexyl-fused azacyclopentyl, cyclohexyl-fused azacyclohexyl, azetidinyl-fused azetidinyl, azetidinyl-fused azacyclopentyl , azetidinyl-fused azacyclohexyl, azacyclopentyl-fused azacyclopentyl, azacyclopentyl-fused azacyclohexyl, azacyclohexyl-fused azacyclohexyl, cyclobutyl-spiro-azetidinyl, cyclobutyl-spiro-azacyclopentyl, cyclobutyl-spiro-azacyclohexyl, cyclopentyl-spiro-azetidinyl, cyclopentyl-spiro-azacyclopentyl, cyclopentyl-spiro-azacyclohexyl, cyclopentyl-spiro-azacyclohexyl, cyclohexyl-spiro-azetidinyl, cyclohexyl-spiro-azacyclopentyl, cyclohexyl-spiro-azacyclopentyl,cyclohexyl-spiro-azacyclohexyl, azetidinyl-spiro-azetidinyl, azetidinyl-spiro-azacyclopentyl, azetidinyl-spiro-azacyclohexyl, azacyclopentyl-spiro-azacyclopentyl, azacyclopentyl-spiro-azacyclohexyl, azacyclohexyl-spiro-azacyclohexyl, [ka] and optionally, when substituted, H, F, Cl, Br, I, OH, NH2, C(=O)OH, CN, =O, C 1-4 Alkyl, halogen-substituted C 1-4 C substituted with alkyl or hydroxy groups 1-4 Alkyl group or C 1-4 is further substituted with 0 to 4 substituents selected from an alkoxy group; B1 and B3 each independently represent a pyrazolyl group, an oxazolyl group, a dioxazolyl group, an oxadiazolyl group, a triazolyl group, an imidazolyl group, a tetrazolyl group, a pyrrolyl group, a thienyl group, a thiazolyl group, a thiadiazolyl group, a pyridyl group, a phenyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, a thienopyrazinyl group, a benzimidazolyl group, a pyridotriazolyl group, a pyrimidopyrazolyl group, an imidazopyridazinyl group, a pyridopyrazolyl group, a pyrrolopyridazinyl group, or [ka] is selected from R b1 , R b7 are each independently H, F, Cl, Br, I, =O, OH, NH2, CN, CF3, CHF2, CH2F, a methyl group, an ethyl group, a methoxy group, an ethoxy group, a phenyl group, a pyrrolyl group, a pyridyl group, a morpholinyl group, [ka] wherein the methyl, ethyl, methoxy, ethoxy, phenyl, pyrrolyl, pyridyl, and morpholinyl groups are optionally selected from H, F, Cl, Br, I, OH, CN, CF3, NH2, NHC 1-4 Alkyl group, N(C 1-4 Alkyl)2, NHCH2C 3-6 Cycloalkyl groups, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl group or R b7a is further substituted with 0 to 4 substituents selected from or R b1 , R b7 are each independently selected from an azetidinyl group, an azacyclopentyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, and a 2-oxa-5-azabicyclo[2.2.1]heptyl group; b1 , R b7 is optionally F, Cl, Br, I, OH, =O, CN, CF3, NH2, NHC 1-4 Alkyl group, N(C 1-4 Alkyl)2, NHCH2C 3-6 Cycloalkyl groups, halogen-substituted C 1-4 C substituted with alkyl or cyano groups 1-4 Alkyl group, -C 1-4 Alkylene-OH, C 1-4 Alkyl group, C 1-4 Alkoxy group, -CH2-OC 1-4 Alkyl group, -CH2-C 3-6 Cycloalkyl groups, -OC 3-6 Cycloalkyl groups, -NH-C 3-6 Cycloalkyl groups, C 3-6 substituted with 1 to 4 substituents selected from a cycloalkyl group, a -CH2-4 to 7-membered heterocycloalkyl group, a -O-4 to 7-membered heterocycloalkyl group, a -NH-4 to 7-membered heterocycloalkyl group, and a 4 to 7-membered heterocycloalkyl group, the heterocyclic group containing 1 to 4 heteroatoms selected from O, S, and N; R b2 , R b6are each independently selected from H, F, Cl, Br, I, =O, CF3, CHF2, OH, NH2, NH(methyl), NH(ethyl), NH(propyl), NH(isopropyl), N(methyl)2, N(ethyl), CN, methyl, ethyl, methoxy, ethoxy, propoxy, isopropyloxy, morpholinyl, piperazinyl, pyrrolidinyl, piperidinyl, or oxazolidinyl, and the methyl, ethyl, methoxy, ethoxy, propoxy, isopropyloxy, morpholinyl, piperazinyl, pyrrolidinyl, piperidinyl, or oxazolidinyl groups are optionally selected from H, F, Cl, Br, I, OH, CN, CF3, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 is further substituted with 0 to 4 substituents selected from a cycloalkyl group; R k1 are each independently selected from H, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclopentyl, piperidinyl, oxetanyl, oxacyclopentyl, and oxacyclohexyl, and the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclopentyl, piperidinyl, oxetanyl, oxacyclopentyl, and oxacyclohexyl groups are optionally selected from H, F, Cl, Br, I, OH, CN, CF3, C 1-4 Alkyl group, C 1-4 Alkoxy group, vinyl group, propenyl group, allyl group, ethynyl group, propynyl group, propargyl group, C 3-6 is further substituted with 0 to 4 substituents selected from a cycloalkyl group; R k2 , R k3are each independently selected from H, F, Cl, Br, I, OH, =O, NH2, CF3, CN, C(=O)OH, C(=O)NH2, methyl, ethyl, methoxy or ethoxy, and the methyl, ethyl, methoxy or ethoxy groups are optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH and NH2; p2 or p3 is independently selected from 0, 1 or 2; Other definitions are the same as those in the first or second embodiment of the present invention.

[0013] As a fourth embodiment of the present invention, there is provided a compound represented by the above general formula (I) or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharma- ceutically acceptable salt or cocrystal thereof, Cy1, Cy2, Cy3, and Cy4 each independently represent a bond or a substituted or unsubstituted group as follows: [ka] and, if substituted, optionally further substituted with 0-4 substituents selected from H, F, CF3, methyl, =O, hydroxymethyl, C(=O)OH, CN, or NH2; B is, [ka] [ka] [ka] is selected from Other definitions are the same as in the first, second or third embodiment of the present invention.

[0014] As a fifth embodiment of the present invention, there is provided a compound represented by the above general formula (I) or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharma- ceutically acceptable salt or cocrystal thereof, L is a bond, -Cy1-, -Cy1-Ak2-, -Cy1-Ak2-Ak3-, -Cy1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-, -Cy1-Ak2-Cy2-, -Cy1-Cy2-Ak3-, -Cy1-Cy2-Ak3-Cy4-, -C y1-Ak2-Cy2-Ak3-, -Cy1-Ak2-Cy2-Ak3-Ak4-, -Cy1-Ak2-Cy2-Cy3-Ak4 -, -Cy1-Cy2-Ak3-Ak4-, -Cy1-Cy2-Ak3-Ak4-Ak5-, -Cy1-Ak2-Cy2-Ak3 -Ak4-Ak5-, -Cy1-Ak2-Ak3-Cy3-Ak4-, -Cy1-Ak2-Ak3-Cy3-Ak4-Ak5-, -Cy1-Ak2-Ak3-Ak4-Cy4-Ak5-, -Cy1-Cy2-Cy3-, -Cy1-Ak2-Cy2-Cy3-, -Cy1-Cy2-Cy3-Ak4-, -Cy1-Ak2-Cy2-Cy3-Ak4-, -Cy1-Ak2-Cy2-Ak3-Cy3-, -Cy1-Ak2-Cy2-Cy3-Ak4-Ak5, -Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Ak5- , -Cy1-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak3-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak4- Cy4-, -Ak1-Cy1-Ak2-Cy2-, -Ak1-Cy1-Ak2-Cy2-Ak3-, -Ak1-Ak2-Cy2- Ak3-, -Ak1-Ak2-Cy2-, -Ak1-Ak2-Cy2-Cy3-Ak4-, -Ak1-Ak2-Ak3-Cy3-Ak4-, -Ak1-Cy1-Ak2-, -Ak1-Cy1-Cy2-Ak3-Ak4-, -Ak1-Cy1-Cy2-Ak3- , -Ak1-Cy1-Ak2-Ak3-Ak4-, -Ak1-Cy1-, -Ak1-Cy1-Ak2-Ak3-, -Ak1-Ak2-Cy2-Ak3-Ak4-, -Ak1-Cy1-Ak2-Cy2-Ak3-Ak4-, -Cy1-Ak2-Ak3-Cy3-Cy4-Ak5-, -Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-, -Ak1-Cy1-Cy2-, -Ak1-Ak2-Ak3-Ak4-, -Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-, Ak1, Ak2, Ak3, Ak4, Ak5 are each independently selected from O, C≡C, CH2, CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2N(CH3), CH2CH2N(CH3), N(CH3), NH, C(=O), C(=O)N(CH3), N(CH3)C(=O), C(=O)NH or NHC(=O); Other definitions are the same as in the first, second, third or fourth embodiment of the present invention.

[0015] As a sixth embodiment of the present invention, there is provided a compound represented by the above general formula (I) or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharma- ceutically acceptable salt or cocrystal thereof, comprising: L is [ka] [ka] is selected from J1 is independently [ka] is selected from J2 is independent of each other. [ka] is selected from J3 is independent of each other. [ka] is selected from J4 is independent of each other. [ka] is selected from J5 is independent of each other. [ka] is selected from Or, L is [ka] is selected from R d is selected from H or D, and at least one R d is selected from D, d1 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; d2 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9; Other definitions are the same as in the first, second, third, fourth or fifth embodiment of the present invention.

[0016] As a seventh embodiment of the present invention, there is provided a compound represented by the above general formula (I) or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharma- ceutically acceptable salt or cocrystal thereof, comprising: L is a group shown in Table L-1, where the left side of the group is connected to B, Other definitions are the same as in the first, second, third, fourth, fifth or sixth embodiment of the present invention.

[0017] As an eighth embodiment of the present invention, there is provided a compound represented by the above general formula (I) or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharma- ceutically acceptable salt or cocrystal thereof, comprising: K is [ka] [ka] [ka] is selected from Other definitions are the same as in the first, second, third, fourth, fifth, sixth or seventh embodiment of the present invention.

[0018] The present invention relates to the following compound or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharma- ceutically acceptable salt, or co-crystal thereof, wherein the compound is selected from one of the structures in Table P-1 below.

[0019] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10] [Table 2-11] [Table 2-12] [Table 2-13] [Table 2-14] [Table 2-15] [Table 2-16] [Table 2-17] [Table 2-18] [Table 2-19] [Table 2-20] [Table 2-21] [Table 2-22] [Table 2-23] [Table 2-24]

[0020] The present invention relates to a pharmaceutical composition, comprising the above-mentioned compound of the present invention or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharma- ceutically acceptable salt or co-crystal thereof, and a pharma- ceutically acceptable carrier.

[0021] The present invention relates to the application of the above-mentioned compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharma- ceutically acceptable salt or cocrystal, or pharmaceutical composition in the manufacture of a medicament for treating a disease associated with IRAK4 activity or expression level.

[0022] The present invention relates to the application of the above-mentioned compounds of the present invention or their stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharma- ceutically acceptable salts or cocrystals, or pharmaceutical compositions in the manufacture of medicaments for treating diseases associated with the inhibition or degradation of IRAK4.

[0023] The present invention relates to the application of the above-mentioned compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharma- ceutically acceptable salt or cocrystal, wherein the disease is selected from autoimmune diseases, inflammatory diseases or cancer.

[0024] The present invention relates to a pharmaceutical composition or formulation, comprising a therapeutically effective amount of a compound according to the present invention or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharma- ceutically acceptable salt or co-crystal thereof and a pharmaceutical excipient. The pharmaceutical composition may be in the form of a unit dosage form (the amount of active ingredient in a unit dosage form is also referred to as the "formulation specification").

[0025] The present invention further provides a method for treating a disease in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound according to the present invention or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharma- ceutically acceptable salt or co-crystal thereof, or a pharmaceutical composition. In some embodiments, the mammal according to the present invention comprises a human.

[0026] An "effective amount" or "therapeutically effective amount" as used herein includes the administration of a sufficient amount of a compound disclosed herein that relieves to some extent one or more symptoms of the disease or condition being treated (e.g., an autoimmune disease, an inflammatory disease, or cancer). In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound disclosed herein that is required to provide a clinically significant reduction in a disease symptom.Examples of therapeutically effective amounts include 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, 3-500 mg, 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, 90~500m g, 100~500mg, 125~500mg, 150~500mg, 200~500mg, 250~500mg, 300~500mg, 400~500mg, 5~400mg, 10~400mg, 20~400mg, 25~400mg, 30~400mg, 40~400 mg, 50~400mg, 60~400mg, 70~400mg, 75~400mg, 80~400mg, 90~400mg, 100~400mg, 125~400mg, 150~400mg, 200~400mg, 250~400mg, 300~400mg, 1~30 0mg, 2~300mg, 5~300mg, 10~300mg, 20~300mg, 25~300mg, 30~300mg, 40~300mg, 50~300mg, 60~300mg, 70~300mg, 75~300mg, 80~300mg, 90~300mg, 10 Including, but not limited to, 0-300mg, 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. In some embodiments, the pharmaceutical composition contains 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 mg, 130 mg, Including, but not limited to, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 300 mg, 320 mg, 400 mg, 480 mg, 500 mg, 600 mg, 640 mg, 840 mg, 1000 mg of a compound of the present invention or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharma- ceutically acceptable salt, or co-crystal thereof.

[0027] A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of a compound of the present invention or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharma- ceutically acceptable salt, or cocrystal thereof, wherein the therapeutically effective amount is preferably 1-1500 mg, and the disease is preferably an autoimmune disease, an inflammatory disease, or a cancer.

[0028] A method for treating a disease in a mammal, the method comprising administering to a subject a pharmaceutical compound of the present invention or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharma- ceutically acceptable salt, or cocrystal thereof in a daily dose of 1-1500 mg / day, the daily dose may be a single dose or a divided dose, and in some embodiments, the daily dose is 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, 300-350 mg / day, 400-400 mg / day, 500-600 mg / day, 600-700 mg / day, 700-800 mg / day, 800-900 mg / day, 900-1000 mg / day, ... In some embodiments, the daily dose includes, but is 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, and 1500 mg / day.

[0029] The present invention relates to a kit, which may comprise a composition in the form of a single dose or multiple doses, comprising a compound of the present invention or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharma- ceutically acceptable salt or co-crystal thereof, wherein the amount of the compound of the present invention or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharma- ceutically acceptable salt or co-crystal thereof is the same as that amount in the pharmaceutical composition.

[0030] In the present invention, the amounts of the compounds of the invention or their stereoisomers, deuterated forms, solvates, prodrugs, metabolites, pharma- ceutically acceptable salts or cocrystals are in each case calculated in the form of the free base.

[0031] Unless otherwise stated, terms used in the specification and claims have the following meanings.

[0032] Carbon, hydrogen, oxygen, sulfur, nitrogen, or F, Cl, Br, I in the groups and compounds described herein include their isotopic contexts, and carbon, hydrogen, oxygen, sulfur, or nitrogen in the groups and compounds described herein are optionally further replaced with one or more isotopes corresponding thereto, where the isotope of carbon is: 12 C and 13 C and 14 C; isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), and tritium (T, also called tritium); isotopes of oxygen include 16 O and 17 O and 18 The isotopes of sulfur include 32 S and 33 S and 34 S and 36 S and the nitrogen isotopes are 14 N and 15 N and the fluorine isotope is 17 F and 19 F and the chlorine isotope is 35 Cl and 37 The isotopes of bromine include Cl and 79 Br and 81 Includes Br.

[0033] "CN" refers to a cyano group.

[0034] “Halogen” refers to F, Cl, Br or I.

[0035] "Halogen substitution" refers to F, Cl, Br or I substitution, 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, substitution with 1 to 4 substituents selected from F, Cl, Br or I. "Halogen substitution" is abbreviated as "halogenation".

[0036] "Alkyl group" 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, and the definition of alkyl group described herein is consistent with this definition. The alkyl group may be monovalent, divalent, trivalent, or tetravalent.

[0037] An "alkylene group" is a substituted or unsubstituted straight-chain or branched-chain divalent saturated hydrocarbon group, -(CH2) v - (where v is an integer from 1 to 10), and examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene groups.

[0038] "Cycloalkyl group" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, typically having 3 to 10 carbon atoms, non-limiting examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. The definition of cycloalkyl group as described herein is as described above. Cycloalkyl group may be monovalent, divalent, trivalent, or tetravalent.

[0039] "Heterocycloalkyl group" refers to a substituted or unsubstituted saturated heteroatom-containing cyclic hydrocarbon group, containing 3-10 atoms, 3-8 atoms, but not limited to, 1-3 heteroatoms selected from N, O, or S, and optionally substituted N, S in the ring of the heterocycloalkyl group can be oxidized to various oxidation states. Heterocycloalkyl groups can be linked to heteroatoms or carbon atoms, heterocycloalkyl groups can be linked to aromatic or non-aromatic rings, and heterocycloalkyl groups can be linked to bridged or spiro rings, non-limiting examples of which include oxiranyl, azacyclopropyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolanyl, dioxanyl, pyrrole alkyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazinanyl, morpholinyl, hexahydropyrimidinyl, and piperazinyl groups. The heterocycloalkyl group may be monovalent, divalent, trivalent or tetravalent.

[0040] An "alkenyl group" is a substituted or unsubstituted straight and branched chain unsaturated hydrocarbon group that has at least one, and typically one, two or three, carbon-carbon double bonds and a backbone that contains 2 to 10, 2 to 6 or 2 to 4 carbon atoms, but is not limited to such examples of alkenyl groups include 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-3-butenyl, and the like. The definition of alkenyl as described herein is consistent with this definition, including, but not limited to, 1-pentenyl, 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. The alkenyl group may be monovalent, divalent, trivalent, or tetravalent.

[0041] "Alkynyl group" refers to a substituted or unsubstituted straight and branched chain unsaturated hydrocarbon group that has at least one, and typically one, two or three, carbon-carbon triple bonds and a main chain containing from 2 to 10 carbon atoms, from 2 to 6 carbon atoms in the main chain, and from 2 to 4 carbon atoms in the main chain, including, but not limited to, ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1- Alkynyl groups may be monovalent, divalent, trivalent or tetravalent, including, but not limited to, 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.

[0042] "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-pentyloxy, n-hexyloxy, cyclopropoxy, and cyclobutoxy. "Carbocyclic group" or "carbocycle" refers to a substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic ring, which may be a 3- to 8-membered monocyclic, 4- to 12-membered bicyclic, or 10- to 15-membered tricyclic system, and the carbocyclic group may be linked to an aromatic or non-aromatic ring, which may optionally be a monocyclic, bridged, or spirocyclic ring. 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, benzene ring, naphthalene ring, [ka] A "carbocyclic group" or "carbocycle" may be monovalent, divalent, trivalent or tetravalent.

[0043] A "heterocyclic group" or "heterocycle" refers to a substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic ring, which may be a 3- to 8-membered monocyclic, 4- to 12-membered bicyclic, or 10- to 15-membered tricyclic system, containing one or more (including but not limited to 2, 3, 4, or 5) heteroatoms selected from N, O, or S, and the optionally substituted N, S in the ring of the heterocyclic group may be oxidized to various oxidation states. Heterocyclic groups may be linked to heteroatoms or carbon atoms, heterocyclic groups may be linked to aromatic or non-aromatic rings, and heterocyclic groups may be linked to bridged or spiro rings, non-limiting examples of which are oxiranyl, aziridinyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azepanyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dihydrofuryl, dihydropyranyl, dithiolanyl, tetrahydrofuran ... tetrahydropyrrolyl group, tetrahydroimidazolyl group, tetrahydrothiazolyl group, tetrahydropyranyl group, benzopyridyl group, pyrrolopyridyl group, benzodihydrofuryl group, pyrrolyl group, pyrazolyl group, thiazolyl group, oxazolyl group, pyrazinyl group, indazolyl group, benzothienyl group, benzofuryl group, benzopyrrolyl group, benzimidazolyl group, benzothiazolyl group, benzoxazolyl group, benzopyridyl group, benzopyrimidinyl group, benzopyrazinyl group, piperazinyl group, azabicyclo[3.2.1]octyl group, azabicyclo[5.2.0]nonyl group, oxatricyclo[5.3.1.1]dodecyl group, azaadamantyl group, oxaspiro[3.3]heptyl group, [ka] The "heterocyclic group" or "heterocycle" may be monovalent, divalent, trivalent or tetravalent.

[0044] "Spiro ring" or "spirocyclic group" refers to a polycyclic group that shares one atom (called a spiro atom) between substituted or unsubstituted monocyclic rings, where the number of ring atoms in the spiro ring system can be, but is not limited to, 5-20, 6-14, 6-12, or 6-10, and where one or more of the rings can contain zero or more (including but not limited to 1, 2, 3, or 4) double bonds and optionally N, O, or S(=O) n (n is 0, 1 or 2). Non-limiting examples include: [ka] A "spiro ring" or "spiro ring group" may be monovalent, divalent, trivalent or tetravalent.

[0045] "Fused ring" or "fused ring group" refers to a polycyclic group in which each ring in the system shares an adjacent pair of atoms with another ring in the system, where one or more of the rings may contain zero or more (including but not limited to 1, 2, 3 or 4) double bonds, may be substituted or unsubstituted, and each ring in the fused ring system may contain zero to five heteroatoms or groups containing heteroatoms (N, S(=O) n or O, where n is 0, 1 or 2. The number of ring atoms in the fused ring system may include, but is not limited to, 5 to 20, 5 to 14, 5 to 12, 5 to 10. Non-limiting examples include: [ka] The "fused ring" or "fused ring group" may be monovalent, divalent, trivalent, or tetravalent.

[0046] A "bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing two atoms that are not directly linked, which may contain zero or more double bonds, and any ring in the fused ring system may contain zero to five groups selected from or containing heteroatoms, including but not limited to N, S(=O)n, or O, where n is 0, 1, or 2. The number of ring atoms includes, but is not limited to, 5-20, 5-14, 5-12, or 5-10. Non-limiting examples include: [ka] cubane, adamantane. A "bridged ring" or "bridged ring group" may be monovalent, divalent, trivalent, or tetravalent.

[0047] "Carbospirocycle", "spirocyclic carbocyclic group", "spirocarbocyclic group" or "carbospirocyclic group" refers to a "spirocycle" whose ring system consists only of carbon atoms. The definition of "carbospirocycle", "spirocyclic carbocyclic group", "spirocarbocyclic group" or "carbospirocyclic group" as used herein is consistent with spirocycle.

[0048] "Carbocyclic ring", "fused ring carbocyclic group", "fused carbocyclic group" or "carbocyclic fused ring group" refers to a "fused ring" whose ring system consists only of carbon atoms. The definition of "carbocyclic ring", "fused ring carbocyclic group", "fused carbocyclic group" or "carbocyclic fused ring group" as used herein is consistent with fused ring.

[0049] A "carbon bridged ring", "bridged ring carbocyclic group", "bridged carbocyclic group" or "carbon bridged ring group" refers to a "bridged ring" whose ring system consists only of carbon atoms. The definition of "carbon bridged ring", "bridged ring carbocyclic group", "bridged carbocyclic group" or "carbon bridged ring group" as described herein is consistent with a bridged ring.

[0050] The terms "heteromonocycle", "monocyclic heterocycle" or "heteromonocycle" refer to a monocyclic "heterocycle" or "heterocycle", and the definitions of heterocycle, "monocyclic heterocycle" or "heteromonocycle" described herein are consistent with the definition of heterocycle.

[0051] A "heterofused ring", "heterofused ring group", "fused cyclic heterocyclic group" or "heterofused ring group" refers to a "fused ring" containing a heteroatom. The definition of a heterofused ring, a "heterofused ring group", a "fused cyclic heterocyclic group" or a "heterofused ring group" described herein is consistent with the fused ring.

[0052] A "heterospirocycle", "heterospiro ring group", "spirocyclic heterocyclic group" or "heterospiro ring group" refers to a "spiro ring" containing a heteroatom. The definitions of heterospirocycle, "heterospiro ring group", "spirocyclic heterocyclic group" or "heterospiro ring group" described herein are consistent with spirocycle.

[0053] A "hetero bridged ring", "hetero bridged ring group", "bridged cyclic heterocyclic group" or "hetero bridged ring group" refers to a "bridged ring" containing a heteroatom. The definitions of hetero bridged ring, "hetero bridged ring group", "bridged cyclic heterocyclic group" or "hetero bridged ring group" described herein are consistent with the bridged ring.

[0054] "Aryl group" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a single ring or fused rings, the number of ring atoms in the aromatic ring including, but not limited to, 6 to 18, 6 to 12, or 6 to 10 carbon atoms. The aryl ring can be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, where the ring connected to the base skeleton is an aryl ring, non-limiting examples of which include a benzene ring, a naphthalene ring, [ka] The "aryl group" or "aromatic ring" may be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the linking site is on the aryl ring.

[0055] A "heteroaryl group" or "heteroaromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group containing 1-5 groups selected from or containing heteroatoms, including but not limited to N, O, or S(=O)n, where n is 0, 1, or 2, and the number of ring atoms in the heteroaromatic ring includes, but is not limited to, 5-15, 5-10, or 5-6. Non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazole, benzimidazole, benzopyridine, pyrrolopyridine, and the like. The heteroaryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, where the ring connected to the base skeleton is a heteroaryl ring, and non-limiting examples include [ka] The definition of the heteroaryl group described herein is consistent with this definition. The heteroaryl group may be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the linking site is on the heteroaryl ring.

[0056] "Substituted" or "unsubstituted" refers to substitution with one or more (including but not limited to 2, 3, 4, or 5) substituents, which may be any of the following: H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, halogenated alkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic, bridged ring, spiro ring, fused ring, 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 group-R a , OR d or -(CH2) m -Alkynyl group-R a (wherein m and n are 0, 1 or 2), an arylthio group, a thiocarbonyl group, a silyl group or -NR b R c and the like, where R b and R c are independently selected from H, a hydroxy group, an amino group, a carbonyl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a sulfonyl group, and a trifluoromethanesulfonyl group; b and R c can form a 5- or 6-membered cycloalkyl or heterocyclic group; R a and R d are each independently selected from an aryl group, a heteroaryl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro ring group, or a fused ring group.

[0057] "Containing 1 to 4 heteroatoms selected from O, S and N" refers to containing 1, 2, 3 or 4 heteroatoms selected from O, S and N.

[0058] "Substituted with 0 to X substituents" refers to substitution with 0, 1, 2, 3....X substituents, where X is selected from any integer from 1 to 10. For example, "substituted with 0 to 4 substituents" refers to substitution with 0, 1, 2, 3, or 4 substituents. For example, "substituted with 0 to 5 substituents" refers to substitution with 0, 1, 2, 3, 4, or 5 substituents. For example, "the heterobridged ring is optionally further substituted with 0 to 4 substituents selected from H or F" refers to the heterobridged ring being optionally further substituted with 0, 1, 2, 3, or 4 substituents selected from H or F.

[0059] The X-Y membered ring (X is selected from an integer of 3 or more and less than Y, and Y is selected from any integer of 4 to 12) includes X, X+1, X+2, X+3, X+4....Y membered rings. The ring includes a heterocycle, a carbocycle, an aromatic ring, an aryl group, a heteroaryl group, a cycloalkyl group, a heteromonocycle, a heterocondensed ring, a heterospirocycle, or a heterobridged ring. For example, a "4- to 7-membered heteromonocycle" refers to a 4-, 5-, 6-, or 7-membered heteromonocycle, and a "5- to 10-membered heterocondensed ring" refers to a 5-, 6-, 7-, 8-, 9-, or 10-membered heterocondensed ring.

[0060] "Optionally" or "optionally" means that the subsequently described event or circumstance may, but does not necessarily, occur, and the description includes both cases where the event or circumstance occurs and cases where it does not occur. For example, "an alkyl group optionally substituted with F" means that the alkyl group may, but does not necessarily, be substituted with F, and indicates that the alkyl group is substituted with F and the alkyl group is not substituted with F.

[0061] "Pharmaceutically acceptable salts" or "a pharma-ceutically acceptable salt thereof" refers to salts in which the compounds of the present invention retain the biological effectiveness and properties of the free acids or free bases and which are obtained by reaction of said free acids with non-toxic inorganic or organic bases, or by reaction of said free bases with non-toxic inorganic or organic acids.

[0062] "Pharmaceutical composition" refers to a mixture of one or more compounds according to the present invention, or a stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharma- ceutically acceptable salt, or co-crystal thereof, and other chemical components, where "other chemical components" refers to a pharma- ceutically acceptable carrier, excipient, and / or one or more other therapeutic agents.

[0063] "Formulation specifications" refers to the weight of the active ingredient contained in one unit dosage form, one tablet unit dosage form, or each other unit dosage form.

[0064] A "carrier" refers to a material that does not cause significant irritation to an organism and does not destroy the biological activity and properties of the administered compound.

[0065] "Prodrug" refers to a compound that can be converted to a biologically active compound of the present invention through metabolism in vivo. The prodrug of the present invention is prepared by modifying an amino or carboxyl group in the compound of the present invention, which can be removed by conventional manipulation or in vivo to yield the parent compound. When a prodrug of the present invention is administered to a mammalian individual, the prodrug splits to form a free amino or carboxyl group.

[0066] "Cocrystal" refers to a crystalline body formed by the association of an active pharmaceutical ingredient (API) and a cocrystal former (CCF) through the action of hydrogen bonds or other non-covalent bonds, where the API and CCF are both solids in their pure state at room temperature, and there is a fixed stoichiometric ratio between each component. Cocrystals are multi-component crystalline bodies, and include not only binary cocrystals formed between two neutral solids, but also multi-component cocrystals formed between a neutral solid and a salt or solvate.

[0067] "Animal" includes mammals such as humans, companion animals, zoo animals, and farm animals, and is preferably a human, horse, or dog.

[0068] "Stereoisomer" refers to isomers that result from different ways in which atoms are arranged in molecules, and includes cis-trans isomers, enantiomers and conformational isomers.

[0069] "Tautomer" refers to a functional isomer produced when an atom in a molecule rapidly shifts between two positions, for example, keto-enol isomers and amide-imido alcohol isomers.

[0070] "I C 50" is the concentration of a drug or inhibitor needed to inhibit a specified biological process (or some component in that process, e.g., enzyme, receptor, cell, etc.) by half. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0071] The technical solutions of the present invention are described in detail below in conjunction with the embodiments, the protection scope of the present invention includes but is not limited to them.

[0072] The compounds used in the reactions described herein are prepared by 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" are those obtained from legitimate commercial sources, including companies such as Taitan Technology, Ananji Chemical, Shanghai Demo, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, Yaoming Kangde and Bailingwei Technology.

[0073] The structures of the compounds were confirmed by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR displacements (δ) are 10 -6 The NMR data were given in ppm. Bruker Avance III 400 and Bruker Avance 300 nuclear magnetometers were used, the solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and the internal standard was tetramethylsilane (TMS). The MS measurements were performed using Agilent 6120B (ESI) and Agilent 6120B (APCI). HPLC measurements were performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100×4.6 mm, 3.5 μM). The silica gel plate used for thin layer chromatography is Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate specifications used for thin layer chromatography (TLC) are 0.15mm~0.20mm, and the specifications used for separation and purification of finished products by thin layer chromatography are 0.4mm~0.5mm. In column chromatography, Yantai Yellow Sea silica gel 200-300 mesh silica gel was generally used as the carrier.

[0074] Reagent and solvent abbreviations: Dess-Martin oxidant, (1,1,1-triacetoxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (CAS number: 87413-09-0), TBSOTf, tert-butyldimethylsilyl trifluoromethanesulfonate, rac-BINAP, 1,1'-binaphthyl-2,2'-diphenylphosphino (CAS number: 98327-87-8), Pd2(dba)3: tri(dibenzylideneacetone)dipalladium (CAS number: 51364-51-3), DMA: N,N-dimethylacetamide, DMF: N,N-dimethylcarboxamide, DCM: dichloromethane, MeOH: methanol, NMI: N-methylimidazole, TCFH: N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate.

[0075] Preparation of Intermediate 1 [ka]

[0076] Step 1: Preparation of 1-B 1-A (7.5g, 32.4mmol) was dissolved in THF (120mL), cooled to 0°C, and 1mol / L borane tetrahydrofuran solution (60mL, 60mmol) was slowly added under nitrogen gas atmosphere, and the reaction was carried out at room temperature for 16h. The reaction system was cooled to 0°C, 30mL of a mixed solution of methanol and acetic acid (v / v) = 9:1 was added, concentrated under reduced pressure, 130mL of water and 150mL of ethyl acetate were added, the liquids were separated, the aqueous phase was extracted with ethyl acetate (100mL x 2), the organic phase was combined, the organic phase was washed with saturated saline (190mL x 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by a silica gel chromatography column (petroleum ether / ethyl acetate (v / v) = 23:77) to obtain 1-B (5.5g, yield: 78%).

[0077] LCMS m / z=218.1[M+1] + .

[0078] Step 2: Preparation of 1-C 1-B (5.5g, 25.3mmol) was added to a 250mL one-neck flask, dichloromethane (80mL) was added, trifluoroacetic acid (20mL) was added, and the mixture was reacted at room temperature for 4h. The reaction system was concentrated under reduced pressure, acetonitrile (100mL) was added to the residue, N,N-diisopropylethylamine (9.8g, 75.8mmol) and 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate ethyl (5.3g, 23.49mmol) were added, and the mixture was reacted at 60°C for 12h. The reaction system was cooled to room temperature, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate (v / v)=41:59) to obtain 1-C (4.6g, yield: 59%).

[0079] LCMS m / z=307.1[M+1] + .

[0080] Step 3: 1-D Fabrication 1-C (2.4g, 7.8mmol) was added to a 100mL one-neck flask, dried DMF (30mL) was added, potassium carbonate (3.2g, 23.15mmol) was added, the mixture was cooled to 0℃, iodomethane (2.2g, 15.5mmol) was added, and the mixture was reacted at room temperature for 16h. Water (300mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (60mL×3), the organic phase was washed with saturated aqueous sodium chloride solution (80mL×2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel chromatography column (petroleum ether:ethyl acetate (v / v)=22:78) to obtain 1-D (1.3g, yield: 52%).

[0081] LCMS m / z=321.1[M+1] + .

[0082] Step 4: Preparation of Intermediate 1 1-D (1.2g, 3.75mmol) was added to a 100mL one-neck flask, methanol (15mL), water (5mL), and sodium hydroxide (760mg, 19mmol) were added, and the mixture was reacted at 50°C for 16h. The reaction system was cooled to room temperature, the pH was adjusted to 5 with 1mol / L hydrochloric acid solution, and the mixture was extracted with a mixed solvent of dichloromethane and methanol (v / v) = 10:1 (60mL x 3), and the organic phase was washed with a saturated aqueous sodium chloride solution (80mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude intermediate 1 (1.0g).

[0083] LCMS m / z=293.1[M+1] + .

[0084] Preparation of intermediate 2 [ka]

[0085] Step 1: Manufacturing 2-B The hydrochloride salt of 2-A (1.8 g, 9.4 mmol) was added to a 100 mL single-neck flask, acetonitrile (30 mL) was added, N,N-diisopropylethylamine (3.6 g, 27.9 mmol) and ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (2.1 g, 9.31 mmol) were added, and the mixture was reacted at 60° C. for 12 h. The reaction system was cooled to room temperature and concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate (v / v)=68:32) to obtain 2-B (2.3 g, yield: 71%).

[0086] LCMS m / z=345.1[M+1] + .

[0087] Step 2: Preparation of intermediate 2 2-B (2.3g, 6.68mmol) was added to a 250mL one-neck flask, methanol (30mL), water (10mL) and sodium hydroxide (1.3g, 32.5mmol) were added, and the mixture was reacted at 50°C for 16h. The reaction system was cooled to room temperature, the pH was adjusted to 5 with 1mol / L aqueous hydrochloric acid, and the mixture was extracted with a mixed solvent of dichloromethane and methanol (v / v) = 10:1 (80mL x 3), and the organic phase was washed with a saturated aqueous sodium chloride solution (80mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude intermediate 2 (1.8g).

[0088] LCMS m / z=317.1[M+1] + .

[0089] Preparation of intermediate 3 [ka]

[0090] Step 1: Manufacturing 3-A 1-C (2.3 g, 7.51 mmol) was dissolved in 20 mL of dichloromethane, triethylamine (2.28 g, 22.53 mmol) was added, the mixture was cooled to 0° C., TBSCl (1.70 g, 11.28 mmol) was added, and the mixture was reacted at room temperature for 16 h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether / ethyl acetate (v / v)=65:35) to obtain 3-A (1.4 g, yield: 44%).

[0091] Step 2: Preparation of intermediate 3

[0092] 3-A (1.4g, 3.33mmol) was dissolved in a mixed solvent of tetrahydrofuran / water (v / v) = 4:1, lithium hydroxide monohydrate (699mg, 16.66mmol) was added, and the mixture was reacted at room temperature for 16h. The pH of the reaction system was adjusted to 5 with 0.5mol / L aqueous hydrochloric acid, and the mixture was extracted with a mixed solvent of dichloromethane / methanol (v / v) = 10:1 (50mL x 3). The organic phase was washed with saturated saline (30mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude intermediate 3 (0.57g).

[0093] Preparation of intermediate 4 [ka]

[0094] Step 1: Preparation of 4-B 4-A (10 g, 85.4 mmol), ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (10.49 g, 46.49 mmol) and DIPEA (36.04 g, 278.8 mmol) were dissolved in 100 mL of acetonitrile and reacted at 60° C. for 12 h. The reaction system was cooled to room temperature and concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v / v) = 2:3) to obtain 4-B (10 g, yield: 70%).

[0095] LCMS m / z=307.1[M+1]+ .

[0096] Step 2: Preparation of 4-C 4-B (6g, 19.59mmol) was dissolved in DMF (60mL), 0.95g of 60% NaH was added at 0℃, and the mixture was stirred at room temperature for 1h. After that, iodomethane (4.2g, 29.59mmol) was added at 0℃, and the mixture was reacted at room temperature for 16h. Water (50mL) was added to the reaction system, and the mixture was extracted with dichloromethane (100mL×3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was separated and purified by a silica gel chromatography column (petroleum ether:ethyl acetate (v / v)=1:4) to obtain 4-C (2g, yield: 32%).

[0097] LCMS m / z=321.1[M+1] + .

[0098] Step 3: Preparation of intermediate 4 4-C (2g, 6.25mmol) and lithium hydroxide (0.47g, 19.62mmol) were added to a 100mL one-neck flask, methanol (10mL) and water (5mL) were added, and the mixture was reacted at 60°C for 4h. The reaction system was cooled to room temperature, added to 50mL of water, adjusted to pH 2 with 6mol / L aqueous hydrochloric acid, extracted with ethyl acetate (60mL x 3), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude intermediate 4 (2g).

[0099] Preparation of Intermediate 5 [ka]

[0100] Step 1: Fabrication of 5-A 4-B (4g, 13.06mmol) and triethylamine (5.29g, 52.28mmol) were dissolved in 50mL of dichloromethane, TBSCl (3.94g, 26.14mmol) was added, and the mixture was reacted at room temperature for 16h. 50mL of water was added to the reaction system, the liquids were separated, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether / ethyl acetate (v / v)=65:35) to obtain 5-A (2g, yield: 36%).

[0101] Step 2: Preparation of Intermediate 5

[0102] 5-A (1.8g, 4.28mmol) and lithium hydroxide (0.32g, 13.36mmol) were added to a 100mL one-neck flask, 20mL of methanol and 10mL of water were added, and the mixture was reacted at 60°C for 4h. The reaction system was cooled to room temperature, 50mL of water was added, the pH was adjusted to 2 with 1mol / L aqueous hydrochloric acid, and the mixture was extracted with ethyl acetate (50mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude intermediate 5 (2g).

[0103] Preparation of the hydrochloride salt of intermediate 6 (trans) [ka]

[0104] Step 1: Preparation of 6-B The trifluoroacetate salt (5.57g) of crude product 10d was dissolved in 40mL of DMA, sodium bicarbonate (1.49g, 17.74mmol) was added, and the mixture was stirred at room temperature for 15min. Then, 6-A (3.66g, 10.66mmol) (see WO 2021158634 for the synthesis method) was added with 1.2mL of acetic acid and 4 Å molecular sieves (5g), and the mixture was stirred at room temperature for 2h. After that, sodium triacetoxyborohydride (3.77g, 17.79mmol) was added and the mixture was reacted at room temperature for 16h. 150mL of saturated aqueous sodium bicarbonate solution was added to the reaction system, and the mixture was extracted with 100mL of dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was separated and purified by a silica gel chromatography column (dichloromethane / ethyl acetate (v / v)=1:1) to obtain 6-B (3.1g, yield: 40%).

[0105] Step 2: Synthesis of the hydrochloride salt of intermediate 6

[0106] 6-B (600 mg, 0.83 mmol) was dissolved in 10 mL of 1,4-dioxane, and 10 mL of 4 mol / L hydrochloric acid in 1,4-dioxane was added and reacted at room temperature for 2 h. The reaction system was concentrated under reduced pressure to obtain the crude product, intermediate 6 hydrochloride (0.65 g).

[0107] LCMS m / z=626.3[M+1] + .

[0108] Preparation of intermediate 7 (trans) [ka]

[0109] Step 1: Preparation of 7-B The trifluoroacetate salt (5.0 g) of crude product 11d was dissolved in 60 mL of DMA, sodium bicarbonate (1.68 g, 20.0 mmol) was added, and the mixture was stirred at room temperature for 15 min., followed by 7-A (3.29 g, 9.58 mmol) (see WO 2021158634 for the synthesis method), 1 mL of acetic acid and 4 Å molecular sieves (5 g), and the mixture was stirred at room temperature for 2 h. Then, sodium triacetoxyborohydride (3.38 g, 15.95 mmol) was added and the mixture was reacted at room temperature for 16 h. 150 mL of saturated aqueous sodium bicarbonate was added to the reaction system, and the mixture was extracted with 100 mL of dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was separated and purified by a silica gel chromatography column (dichloromethane / ethyl acetate (v / v) = 1:1) to obtain 7-B (1.0 g, yield: 14%).

[0110] Step 2: Preparation of intermediate 7

[0111] 7-B (1.1 g, 1.52 mmol) was added to 30 mL of acetonitrile, p-toluenesulfonic acid monohydrate (0.86 g, 4.52 mmol) was added, and the mixture was reacted at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure, 100 mL of ethyl acetate was added, and the pH was adjusted to 9 with saturated sodium bicarbonate solution. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude intermediate 7 (0.9 g).

[0112] Example 1: Preparation of Compound 1 (trans) [ka]

[0113] Step 1: Manufacturing 1A 2,6-Bis(benzyloxy)-3-bromopyridine (5.0 g, 13.50 mmol), bis(pinacolato)diboron (5.14 g, 20.24 mmol) and potassium acetate (2.65 g, 27.0 mmol) were added to dry 1,4-dioxane (20 mL), Pd(dppf)Cl2.DCM (1.10 g, 1.35 mmol) was added and reacted overnight at 100° C. under nitrogen gas protection. The reaction solution was cooled to room temperature, suction filtered through diatomaceous earth, extracted with ethyl acetate (50 mL×3), dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V)=1 / 20) to obtain 1A (4 g, yield: 71%).

[0114] LCMS m / z=418.2[M+H] + .

[0115] Step 2: Manufacturing 1C Under nitrogen gas protection, 1B (1.5g, 4.75mmol) (synthesized with reference to patent CN113512025), 1A (2.97g, 7.12mmol), Pd(dppf)Cl2.DCM (CAS: 95464-05-4) (0.78g, 0.96mmol), cesium carbonate (3.10g, 9.5mmol) were added to 1,4-dioxane (45mL) and water (10mL), and reacted at 105℃ for 3h. After the reaction was completed, the mixture was cooled to room temperature, water (50mL) was added, extracted with ethyl acetate (30mL×3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V)=1 / 5) to obtain 1C (1.06g, yield: 46.5%).

[0116] LCMS m / z=480.1[M+H] + .

[0117] Step 3: 1D Fabrication 1C (700 mg, 1.46 mmol) was dissolved in anhydrous THF (20 mL), lithium aluminum tetrahydride (166 mg, 4.37 mmol) was added, and the mixture was allowed to react at room temperature for 1 h. After the reaction was completed, water (2 mL) was added to quench the reaction, and the mixture was filtered by suction through diatomaceous earth, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 1) to give 1D (580 mg, yield: 88%).

[0118] LCMS m / z=452.2[M+H] + .

[0119] Step 4: Fabrication of 1E 1D (600 mg, 1.33 mmol) was dissolved in THF (30 mL), triethylamine (673 mg, 6.65 mmol) was added, and the mixture was stirred at room temperature for 10 min. TBSOTf (879 mg, 3.33 mmol) was added, and the mixture was reacted at room temperature for 1 h. After the reaction was completed, the mixture was concentrated and purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5) to obtain 1E (630 mg, yield: 84%).

[0120] 1 H NMR (400MHz,CDCl3) δ 7.89 (d,1H),7.66 - 7.61 (m,1H),7.48 - 7.42 (m,2H),7.41 - 7.34 (m,2H),7.34 - 7.29 (m,3H),7.27 - 7.21 (m,4H),6.96 (dd,1H),6.53 (d,1H),5.45 (s,2H),5.41 (s,2H),5.07 (s,2H),4.43 (s,3H),0.90 (s,9H),0.06 (s,6H).

[0121] Step 5: Fabrication of 1F 1E (630 mg, 1.11 mmol) was dissolved in ethanol (30 mL), palladium carbon (10%) (1 g) was added, the mixture was purged with hydrogen gas three times, and the mixture was reacted at room temperature overnight. The mixture was then suction filtered through diatomaceous earth, concentrated, and purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 1) to obtain 1F (197 mg, yield: 46%).

[0122] LCMS m / z=388.2[M+H] + .

[0123] Step 6: Manufacturing 1G 1F (197 mg, 0.51 mmol) was dissolved in THF (5 mL), and a solution of tetrabutylammonium fluoride in THF (2.55 mL, 1 mol / L) was added and reacted at room temperature for 1 h. After the reaction was completed, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 1G.

[0124] LCMS m / z=274.1[M+H] + .

[0125] Step 7: Fabrication of 1H 1G obtained in the previous step was dissolved in dichloromethane (5 mL), Dess-Martin oxidant (432 mg, 1.02 mmol) was added, and the mixture was reacted at room temperature for 1 h. The mixture was filtered through diatomaceous earth, concentrated, and purified by silica gel column chromatography (methanol / dichloromethane (V / V) = 1 / 20) to give 1H (100 mg, 2-step yield: 72%).

[0126] LCMS m / z=272.1[M+H] + .

[0127] Step 8: Fabrication of 1I 1H (50 mg, 0.18 mmol), tert-butyl methyl(piperidin-4-yl)aminocarboxylate (77 mg, 0.36 mmol) and glacial acetic acid (11 mg, 0.18 mmol) were dissolved in anhydrous dichloroethane (5 mL), 4 Å molecular sieves (1 g) were added and reacted at room temperature for 2 h, sodium triacetoxyborohydride (76 mg, 0.36 mmol) was added and reacted at room temperature overnight, and after the reaction was completed, the mixture was suction filtered through diatomaceous earth, concentrated and purified by a preparative silica gel plate (methanol / dichloromethane (V / V) = 1 / 20) to obtain 1I (54 mg, yield: 64%).

[0128] LCMS m / z=470.3[M+H] + .

[0129] Step 9: Fabrication of 1J 1I (52 mg, 0.11 mmol) was dissolved in hydrogen chloride-dioxane (5 mL, 4 mol / L) and reacted at room temperature for 1 h. After the reaction was completed, the mixture was concentrated, and the residue was redissolved in 5 mL of dioxane. Triethylamine (0.5 mL) was added, and the mixture was concentrated to obtain crude 1J.

[0130] Step 10: Preparation of Compound 1 1K (54 mg, 0.11 mmol) (synthesized with reference to patent WO 2020113233), 1J crude and glacial acetic acid (7 mg, 0.11 mmol) were dissolved in anhydrous DMA (5 mL), 4 Å molecular sieves (1 g) were added, and the mixture was reacted at room temperature for 2 h, and sodium triacetoxyborohydride (35 mg, 0.17 mmol) was added, and the mixture was reacted at room temperature overnight. The mixture was filtered, and the filtrate was purified by preparative HPLC (instrument: waters 2767 preparative liquid chromatography, chromatography column: XBridge@Prep C18 (30 mm × 150 mm), mobile phase composition: mobile phase A is acetonitrile, and mobile phase B is water (containing 0.1% trifluoroacetic acid)) and lyophilized. The resulting solid was redissolved in dichloromethane (10 mL), water (5 mL) and saturated sodium bicarbonate solution (1 mL) were added, the organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated to give compound 1 (20 mg, yield: 22%).

[0131] 1 H NMR (400MHz,DMSO-d6) δ 10.87 (s,1H),9.49(d,1H),8.78(d,1H),8.37(d,1H),8.25(d,1H),7.67 - 7.60 (m,1H),7.25 - 6.94 (m,3H),6.89 - 6.40 (m,1H),5.30 - 5.02 (m,1H),4.83 - 4.71 (m,1H),4.41 - 4.33 (m,1H),4.30 (s,3H),4.20 - 4.04 (m,2H),3.86 - 3.66 (m,4H),3.67 - 3.40 (m,3H),3.17(d,2H),2.94 - 2.83 (m,2H),2.70 - 2.61 (m,2H),.2.37 - 2.28 (m,2H),2.21 - 2.16 (m,3H),2.07 - 1.81 (m,8H),1.75 - 1.56 (m,4H),1.41 - 1.32 (m,2H),1.08 - 0.91 (m,2H).

[0132] LCMS m / z=839.4[M+H] + .

[0133] Example 2: Preparation of Compound 2 (trans) [ka]

[0134] Step 1: Manufacturing 2A Under nitrogen gas protection, 3-bromo-1-methyl-7-nitro-1H-indazole (3g, 11.72mmol), 1A (7.3g, 17.5mmol), dioxane (80mL), water (20mL), Pd(dppf)Cl2.DCM (1.4g, 1.71mmol) and cesium carbonate (11.5g, 35.3mmol) were added to a 50mL one-neck flask in sequence, purged with nitrogen gas three times, and reacted at 100°C for 12h. After the reaction was completed, it was cooled to room temperature, the reaction solution was poured into water, and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 2A (3.3g, yield 60%).

[0135] LCMS m / z=467.1[M+H] + .

[0136] Step 2: Fabrication of 2B 2A (1.6 g, 3.43 mmol), 10% palladium carbon (0.9 g), and 10% palladium hydroxide / carbon (1.2 g) were dissolved in 20 mL of tetrahydrofuran and 20 mL of methanol, purged with hydrogen gas three times, and reacted overnight at 30° C. The mixture was cooled to room temperature, filtered through diatomaceous earth, and the filter cake was washed three times with methanol. The organic phases were combined, dried over anhydrous sodium sulfate, and spin-dried under reduced pressure to obtain 2B (650 mg, 73% yield).

[0137] LCMS m / z=259.2[M+H] + .

[0138] Step 3: Manufacturing 2C 2B (250 mg, 0.97 mmol), KI (242 mg, 1.46 mmol), and iodine (371 mg, 1.46 mmol) were dissolved in acetonitrile (5 mL) and cooled to 0°C. Then, isoamyl nitrite (171 mg, 1.46 mmol) was slowly added, and the mixture was reacted at 30°C for 8 h under nitrogen gas protection. 10 mL of saturated ammonium chloride solution was added, and the mixture was extracted with dichloromethane. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 2C (130 mg, yield: 36%).

[0139] LCMS m / z=370.0[M+H] + .

[0140] Step 4: 2D Fabrication 2C (130 mg, 0.35 mmol), tert-butyl 4-(propan-2-yn-1-yloxy)piperidine-1-carboxylate (101 mg, 0.42 mmol), CuI (13 mg, 0.07 mmol), PdCl2(PPh3)2 (25 mg, 0.036 mmol), and triethylamine (1 mL) were dissolved in DMF (4 mL), purged with nitrogen gas three times, and reacted at 60 ° C for 6 h. The mixture was cooled to room temperature, diluted with 5 mL of aqueous solution, extracted with dichloromethane, the organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 2D (91 mg, yield: 54%).

[0141] LCMS m / z=381.2[M-Boc+H] + .

[0142] Step 5: Fabrication of 2E 2D (91 mg, 0.19 mmol) was dissolved in methanol (1 mL), and a 4N solution of hydrochloric acid in dioxane (3 mL) was added. The mixture was reacted at room temperature for 1 h, concentrated under reduced pressure, and redissolved by adding 5 mL of dichloromethane and 1 mL of methanol. 2 mL of triethylamine was added, and the mixture was concentrated under reduced pressure to obtain crude 2E.

[0143] Step 6: Preparation of Compound 2 The crude product of 2E from the previous step, 1K (102 mg, 0.21 mmol), and acetic acid (12.6 mg, 0.21 mmol) were dissolved in DMA (5 mL) and 4 Å molecular sieves (2 g) were added. After stirring at room temperature for 30 minutes, sodium triacetoxyborohydride (57 mg, 0.27 mmol) was added and reacted at room temperature overnight. 20 mL of saturated aqueous sodium bicarbonate and 20 mL of dichloromethane were added for extraction, the organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: DCM / MeOH (V / V) = 100 / 1-20 / 1) to obtain compound 2 (30 mg, 2-step yield: 19%).

[0144] LCMS m / z = 850.4 [M+H] + .

[0145] 1 H NMR (400MHz,DMSO-d6) δ10.90 (s,1H),9.56 - 9.42 (m,1H),8.77 (d,1H),8.42 - 8.35 (m,1H),8.28 - 8.22 (m,1H),7.78 (d,1H),7.51 (d,1H),7.27 - 6.94 (m,2H),6.89 - 6.42 (m,1H),5.31 - 5.03 (m,1H),4.82 - 4.70 (m,1H),4.54 (s,2H),4.41 (dd,1H),4.29 (s,3H),4.23 - 4.11 (m,1H),3.87 - 3.40 (m,5H),2.80 - 2.56 (m,4H),2.43 - 2.31 (m,1H),2.27 - 1.82 (m,13H),1.80 - 1.66 (m,2H),1.66 - 1.41 (m,3H),1.14 - 0.96 (m,2H).

[0146] Example 3: Preparation of Compound 3 (trans) [ka]

[0147] Step 1: Manufacturing 3A 2-(4-(hydroxymethyl)cyclohexyl)-6-morpholinyl-5-nitrosoisoindolin-1-one (500 mg, 1.33 mmol) (see patent WO 2020264499 for synthesis steps), triethylamine (540 mg, 5.34 mmol) were dissolved in anhydrous tetrahydrofuran (10 mL), cooled to 0 ° C, TBSOTf (700 mg, 2.65 mmol) was slowly added dropwise, and the reaction was carried out at room temperature for 2 h under nitrogen gas protection. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 3A (521 mg, yield: 80%).

[0148] LCMS m / z=490.2[M+H] + .

[0149] Step 2: Manufacturing 3B 3A (521 mg, 1.06 mmol) was dissolved in ethanol (10 mL) and water (2 mL), and the temperature was raised to 80° C., and a mixture of ammonium chloride (280 mg, 5.23 mmol) and iron powder (300 mg, 5.37 mmol) was added, and the mixture was stirred at 80° C. for 1 h. The mixture was cooled to room temperature and filtered. The filter cake was washed with 50 mL of dichloromethane, and 10 mL of saturated saline was added to the filtrate. The layers were separated, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude 3B (440 mg).

[0150] LCMS m / z = 460.3 [M+H] + .

[0151] Step 3: 3C Manufacturing 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (1.0 g, 3.84 mmol) was dissolved in thionyl chloride (30 mL) and stirred at 70° C. for 2 h. The mixture was cooled to room temperature and concentrated under reduced pressure to give crude 3C (1.1 g).

[0152] Step 4: 3D Fabrication Under a nitrogen gas atmosphere, 3B (440 mg, 0.96 mmol) and pyridine (150 mg, 1.9 mmol) were dissolved in anhydrous dichloromethane (10 mL) and cooled to 0°C. Crude 3C (500 mg) was dissolved in anhydrous dichloromethane (4 mL) and slowly added dropwise to the system, and reacted at room temperature for 2 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 3D (600 mg, yield: 89%).

[0153] LCMS m / z=702.3[M+H] + .

[0154] Step 5: Manufacturing 3E 3D (600 mg, 0.85 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to 0° C., and TBAF (1 M, 1.71 mL) was slowly added and reacted at room temperature for 4 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 3E (372 mg, yield: 74%).

[0155] LCMS m / z=588.2[M+H] + .

[0156] Step 6: Fabrication of 3F 3E (370 mg, 0.63 mmol) and Dess-Martin periodinane (530 mg, 1.25 mmol) were added to tetrahydrofuran (10 mL) and stirred at room temperature for 1 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 3F (350 mg, yield: 95%).

[0157] LCMS m / z=586.3[M+H] + .

[0158] Step 7: Preparation of Compound 3 2D (100mg, 0.21mmol) was dissolved in dichloromethane (4mL), trifluoroacetic acid (4mL) was added, and the mixture was reacted at room temperature for 1h, concentrated under reduced pressure, 10mL of dichloromethane was added to redissolve, 3mL of triethylamine was added to adjust the pH to alkaline, and the mixture was concentrated under reduced pressure to obtain the compound. The residue was dissolved in DMA (6mL), 3F (120mg, 0.20mmol), 4Å molecular sieves (2g) were added, and the mixture was stirred at room temperature for 30min, and sodium triacetoxyborohydride (58mg, 0.27mmol) was added and the mixture was reacted at room temperature overnight. 20mL of saturated aqueous sodium bicarbonate solution and 20mL of dichloromethane were added to extract the mixture, the organic layer was concentrated under reduced pressure, and the residue was purified by silica gel plate for thin layer chromatography (mobile phase: DCM / MeOH (V / V) = 20 / 1) to obtain compound 3 (93mg, yield: 49%).

[0159] LCMS m / z = 950.4 [M+H] + .

[0160] Example 4: Preparation of trifluoroacetate (trans) of compound 4 [ka]

[0161] 1I (131 mg, 0.28 mmol) was dissolved in hydrogen chloride-dioxane (5 mL, 4 mol / L) and reacted at room temperature for 1 h. After the reaction was completed, the mixture was concentrated, and the residue was added to 5 mL of dioxane and redissolved, and triethylamine (0.5 mL) was added and concentrated under vacuum. 3F, glacial acetic acid (17 mg, 0.28 mmol), anhydrous DMA (5 mL), and molecular sieves (2 g) were added to the concentrate. After reacting at room temperature for 2 h, sodium triacetoxyborohydride (119 mg, 0.56 mmol) was added and reacted at room temperature overnight. The reaction was quenched by adding saturated sodium bicarbonate solution (30 mL), extracted with ethyl acetate (3×30 mL), washed with saturated saline (2×20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, purified by preparative silica gel plate (DCM:MeOH=10:1), and the crude was continued to be purified by preparative HPLC (instrument: waters 2767 preparative liquid chromatography, chromatography column: XBridge@PrepC18 (30 mm×150 mm), mobile phase composition: mobile phase A is acetonitrile, mobile phase B is water (containing 0.1% trifluoroacetic acid)), and lyophilized to obtain the trifluoroacetate salt of compound 4 (17 mg).

[0162] LCMS m / z=470.4[(M+2H) / 2] + .

[0163] Example 6: Preparation of Compound 6 (trans) [ka]

[0164] Step 1: Fabrication of 6b 6a (6g, 24.79mmol) was dissolved in 30mL of acetone, potassium hydroxide (2.09g, 37.25mmol) was added at 0°C, the mixture was stirred at 0°C for 15min, iodoethane (3.87g, 24.81mmol) was added dropwise, and the mixture was reacted at 20°C for 16h. The reaction system was concentrated under reduced pressure, 50mL of ethyl acetate and 100mL of water were added, the liquids were separated, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by a silica gel chromatography column (ethyl acetate / petroleum ether (v / v)=1:20) to obtain 6b (1.40g, yield: 21%).

[0165] LCMS m / z=270.0[M+1] + .

[0166] Step 2: Fabrication of 6c Under nitrogen gas protection, 6b (1.3 g, 4.81 mmol), 1A (3.01 g, 7.21 mmol), 1,4-dioxane (60 mL), water (20 mL), Pd(dppf)Cl2.DCM (0.39 g, 0.48 mmol) and cesium carbonate (4.70 g, 14.43 mmol) were added to a 50 mL single-neck flask in this order, and the nitrogen gas was replaced three times, and the reaction was carried out at 100 ° C for 12 h. The reaction solution was cooled to room temperature, added to 30 mL of water, extracted three times with 200 mL of ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel chromatography column (ethyl acetate / petroleum ether (v / v) = 1: 5) to obtain 6c (1.5 g, yield: 65%).

[0167] LCMS m / z=481.1[M+1] + .

[0168] Step 3: Fabrication of 6d 6c (1.5g, 3.12mmol), 10% palladium carbon (0.8g) and 10% palladium hydroxide / carbon (1.0g) were dissolved in 30mL of tetrahydrofuran and 30mL of methanol, purged with hydrogen gas three times, and reacted under a hydrogen gas balloon atmosphere at 30°C for 16h. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, and the filter cake was washed three times with 50mL of methanol. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 6d (800mg).

[0169] LCMS m / z=273.2[M+1] + .

[0170] Step 4: Fabrication of 6e The crude product 6d (400 mg), KI (0.37 g, 2.23 mmol), CuI (0.406 g, 2.13 mmol), and iodine (560 mg, 2.21 mmol) were dissolved in acetonitrile (5 mL), cooled to 0 ° C., and isoamyl nitrite (260 mg, 2.21 mmol) was slowly added, and the mixture was reacted at 30 ° C. for 6 h under nitrogen gas protection. 10 mL of saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted with 50 mL of dichloromethane, separated, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by a silica gel chromatography column (petroleum ether / ethyl acetate (v / v) = 2: 1 to 1: 1) to obtain 6e (200 mg, 2-step yield from 6c: 33%).

[0171] LCMS m / z=384.1[M+1] + .

[0172] Step 5: Fabrication of 6f 6e (100 mg, 0.26 mmol), tert-butyl 4-(propan-2-yn-1-yloxy)piperidine-1-carboxylate (see WO 2021247899 for synthesis method) (75 mg, 0.313 mmol), CuI (10 mg, 0.0525 mmol), PdCl2(PPh3)2 (26 mg, 0.037 mmol) and triethylamine (0.13 g, 1.28 mmol) were dissolved in DMF (5 mL), substituted with nitrogen gas three times, and reacted at 60 ° C for 6 h. The reaction mixture was cooled to room temperature, 5 mL of water was added, and the mixture was extracted with 50 mL of dichloromethane. The organic phase was concentrated under reduced pressure, and the crude product was purified by a silica gel chromatography column (petroleum ether / ethyl acetate (v / v)=2:1-1:1) to obtain 6f (90 mg, yield: 70%).

[0173] Step 6: 6g of trifluoroacetate

[0174] 6f (90 mg, 0.18 mmol) was dissolved in 5 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, and the mixture was reacted at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain the crude product 6g as trifluoroacetate (0.1 g).

[0175] LCMS m / z=395.2[M+1] + .

[0176] Step 7: Preparation of compound 6 The trifluoroacetate salt (100mg) of the crude product 6g was dissolved in 5mL of DMA, sodium bicarbonate (30mg, 0.36mmol) was added, and the mixture was stirred at room temperature for 15min, followed by addition of 6h (100mg, 0.21mmol), 0.04mL of acetic acid and 4 Å molecular sieves (2g), and the mixture was stirred at room temperature for 30min, followed by addition of sodium triacetoxyborohydride (76mg, 0.36mmol), and the mixture was reacted at room temperature for 16h. 20mL of saturated aqueous sodium bicarbonate solution and 20mL of dichloromethane were added, and the organic phase was concentrated under reduced pressure. The crude product was separated and purified by a silica gel chromatography column (dichloromethane / methanol (v / v) = 100:1 to 20:1), and the obtained crude product was further subjected to chiral separation and freeze-dried to obtain compound 6 (78.5mg, yield: 43%).

[0177] Chiral Separation Methods: Instrument and preparative column: Waters 150 SFC preparative liquid chromatography was used, the model number of the preparative column was Chiralpak Column, Mobile phase system: sCO2 (supercritical CO2) / mixed solvent of isopropyl alcohol and acetonitrile, isocratic elution: sCO2 / mixed solvent of isopropyl alcohol and acetonitrile = 2:3, flow rate: 100 mL / min.

[0178] Chiral analysis method for target compound: Instrument: SHIMADZU LC-30AD sf, Chromatography column: Chiralpak AD-3, Specifications: 50×4.6 mm ID, 3 μm, Mobile phase A: sCO2 (supercritical CO2), Mobile phase B: Mixture of isopropyl alcohol and acetonitrile (containing 0.05% diethylamine), Column temperature: 35°C, Flow rate: 3 mL / min, Wavelength: 220 nm, Elution procedure: Isocratic elution: Mobile phase A:B=2:3, Retention time of target compound: 0.875 min.

[0179] 1H NMR (400MHz,DMSO-d6) δ 10.90 (s,1H),9.55 - 9.45 (m,1H),8.78 (d,1H),8.42 - 8.34 (m,1H),8.29 - 8.21 (m,1H),7.84 - 7.73 (m,1H),7.57 - 7.46 (m,1H),7.30 - 6.93 (m,2H),6.92 - 6.40 (m,1H),5.35 - 5.00 (m,1H),4.84 - 4.66 (m,3H),4.53 (s,2H),4.46 - 4.37 (m,1H),4.25 - 4.08 (m,1H),3.90 - 3.38 (m,5H),2.80 - 2.56 (m,4H),2.45 - 2.30 (m,1H),2.25 - 1.83 (m,13H),1.83 - 1.65 (m,2H),1.64 - 1.44 (m,3H),1.40 (t,3H),1.13 - 0.94 (m,2H).

[0180] LCMS m / z=864.3[M+1] + .

[0181] Example 7: Preparation of Compound 7 (Trans) Trans-5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)-1-(4-((4-((3-(3-(2,6-dioxopiperidin-3-yl)-1-(methyl -d3)-1H-indazol-7-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide [ka]

[0182] Compound 7 was obtained by using deuterated iodomethane as a starting material and following the synthesis method of Example 6.

[0183] Step 1: Fabrication of 7b 7a (6.00g, 24.79mmol) was dissolved in 30mL of acetone, potassium hydroxide (2.09g, 37.25mmol) was added at 0°C, the mixture was stirred at 0°C for 15min, deuterated iodomethane (3.60g, 24.83mmol) was added dropwise, and the mixture was reacted at 20°C for 16h. The reaction system was concentrated under reduced pressure, 50mL of ethyl acetate and 100mL of water were added, the liquids were separated, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by a silica gel chromatography column (ethyl acetate / petroleum ether (v / v)=1:20) to obtain 7b (4.90g, yield: 76%).

[0184] Step 2: Fabrication of 7c

[0185] Under nitrogen gas protection, 7b (1.5g, 5.79mmol), 1A (3.62g, 8.67mmol), 1,4-dioxane (60mL), water (20mL), Pd(dppf)Cl2.DCM (0.47g, 0.578mmol) and cesium carbonate (5.66g, 17.37mmol) were added to a 50mL one-neck flask in sequence, and nitrogen gas was replaced three times, and the reaction was carried out at 100°C for 12h. The reaction solution was cooled to room temperature, the reaction solution was added to 30mL of water, and extracted three times with 200mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel chromatography column (ethyl acetate / petroleum ether (v / v)=1:10) to obtain 7c (1.6g, yield: 59%).

[0186] LCMS m / z=470.2[M+1] + .

[0187] Step 3: Manufacturing 7d 7c (1.6 g, 3.41 mmol), 10% palladium carbon (0.8 g) and 10% palladium hydroxide / carbon (1.0 g) were dissolved in 30 mL of tetrahydrofuran and 30 mL of methanol, and the hydrogen gas was replaced three times. The mixture was reacted under a hydrogen gas balloon atmosphere at 30° C. for 16 h. The reaction solution was cooled to room temperature, 50 mL of dichloromethane was added, and the mixture was stirred for 5 min. The mixture was filtered through diatomaceous earth, and the filter cake was washed three times with 50 mL of methanol. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 7d (850 mg).

[0188] LCMS m / z=262.1[M+1] + .

[0189] Step 4: Manufacturing 7e The crude product 7d (380 mg), KI (0.37 g, 2.23 mmol), CuI (0.406 g, 2.13 mmol), and iodine (560 mg, 2.21 mmol) were dissolved in acetonitrile (5 mL), cooled to 0 ° C., and isoamyl nitrite (260 mg, 2.21 mmol) was slowly added, and the mixture was reacted at 30 ° C. for 6 h under nitrogen gas protection. 10 mL of saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted with 50 mL of dichloromethane, separated, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by a silica gel chromatography column (petroleum ether / ethyl acetate (v / v) = 2: 1 to 1: 1) to obtain 7e (220 mg, 2-step yield from 7c: 39%).

[0190] Step 5: Fabrication of 7f

[0191] 7e (100mg, 0.27mmol), tert-butyl 4-(propan-2-yn-1-yloxy)piperidine-1-carboxylate (78mg, 0.326mmol), CuI (10mg, 0.0525mmol), PdCl2(PPh3)2 (20mg, 0.0285mmol) and triethylamine (0.14g, 1.38mmol) were dissolved in DMF (5mL), substituted with nitrogen gas three times, and reacted at 60°C for 6h. The reaction solution was cooled to room temperature, 5mL of water was added, extracted with 50mL of dichloromethane, separated, the organic phase was concentrated under reduced pressure, and the crude product was separated and purified by a silica gel chromatography column (petroleum ether / ethyl acetate (v / v) = 2:1 to 1:1) to obtain 7f (110mg, yield: 84%).

[0192] Preparation of 7g Trifluoroacetate Salt of Step 6 7f (110 mg, 0.23 mmol) was dissolved in 5 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, and the mixture was reacted at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain the crude product 7g as trifluoroacetate (0.12 g).

[0193] Step 7: Preparation of Compound 7 The trifluoroacetate salt (120 mg) of the crude product 7g was dissolved in 5 mL of DMA, sodium bicarbonate (37 mg, 0.44 mmol) was added, and the mixture was stirred at room temperature for 15 min., followed by 6h (130 mg, 0.273 mmol), 0.04 mL of acetic acid and 4 Å molecular sieves (2 g), and the mixture was stirred at room temperature for 30 min., followed by addition of sodium triacetoxyborohydride (97 mg, 0.458 mmol), and the mixture was reacted at room temperature for 16 h. 20 mL of saturated aqueous sodium bicarbonate solution and 20 mL of dichloromethane were added to the reaction solution, and the mixture was separated. The organic phase was concentrated under reduced pressure, and the crude product was separated and purified by a silica gel chromatography column (dichloromethane / methanol (v / v) = 100:1 to 20:1), and the obtained crude product was subjected to chiral separation and freeze-dried to obtain compound 7 (57.1 mg, yield: 25%).

[0194] Chiral Separation Methods: Instrument and preparative column: Waters 150 SFC preparative liquid chromatography was used, the model number of the preparative column was Chiralpak Column, Mobile phase system: sCO2 (supercritical CO2) / mixed solvent of isopropyl alcohol and acetonitrile, isocratic elution: sCO2 / mixed solvent of isopropyl alcohol and acetonitrile = 2:3, flow rate: 100 mL / min.

[0195] Chiral analysis method for compound 7: Instrument: SHIMADZU LC-30AD sf, Chromatography column: Chiralpak AD-3, Specifications: 50×4.6 mm ID, 3 μm, Mobile phase A: sCO2 (supercritical CO2), Mobile phase B: Mixture of isopropyl alcohol and acetonitrile (containing 0.05% diethylamine), Column temperature: 35°C, Flow rate: 3 mL / min, Wavelength: 220 nm, Elution procedure: Isocratic elution: Mobile phase A:B=2:3, Compound 7 retention time: 0.989 min.

[0196] 1 H NMR (400MHz,DMSO-d6) δ 10.90 (s,1H),9.56 - 9.42 (m,1H),8.77 (d,1H),8.42 - 8.35 (m,1H),8.29 - 8.22 (m,1H),7.78 (d,1H),7.51 (d,1H),7.29 - 6.93 (m,2H),6.90 - 6.40 (m,1H),5.33 - 5.02 (m,1H),4.84 - 4.70 (m,1H),4.53 (s,2H),4.41 (dd,1H),4.24 - 4.10 (m,1H),3.97 - 3.40 (m,5H),2.80 - 2.56 (m,4H),2.43 - 2.31 (m,1H),2.27 - 1.82 (m,13H),1.80 - 1.66 (m,2H),1.66 - 1.41 (m,3H),1.14 - 0.96 (m,2H).

[0197] LCMS m / z=853.4[M+1] + .

[0198] Example 8: Preparation of Compound 8 (Trans) [ka]

[0199] Compound 8 was obtained by using 8a+ iodoisopropane as a starting material and following the synthesis method of Example 6.

[0200] Purification method of crude compound 8: The crude product was subjected to chiral separation, followed by conventional separation, and freeze-dried to obtain chiral isomer 1 (6.3 mg, yield: 4%) and chiral isomer 2 (9.6 mg, yield: 6%) of compound 8.

[0201] Chiral Separation Methods: Instrument and preparative column: Waters 150 SFC preparative liquid chromatography was used, the model number of the preparative column was Chiralpak Column, Mobile phase system: sCO2 (supercritical CO2) / mixed solvent of isopropyl alcohol and acetonitrile, isocratic elution: sCO2 / mixed solvent of isopropyl alcohol and acetonitrile = 65:35, flow rate: 140 mL / min.

[0202] Analytical method for target compounds: Instrument: SHIMADZU LC-30AD sf, Chromatographic column: Chiralpak AD-3, Specifications: 50×4.6 mm ID, 3 μm, Mobile phase A: sCO2 (supercritical CO2), Mobile phase B: Mixture of isopropyl alcohol and acetonitrile (containing 0.05% diethylamine), Column temperature: 35°C, Flow rate: 3 mL / min, Wavelength: 220 nm, Elution procedure: Isocratic elution: Mobile phase A:B=3:2, Retention time of compound 8 chiral isomer 1: 2.086 min. Retention time of compound 8 chiral isomer 2: 2.687 min.

[0203] Traditional separation methods: Instrument and preparative column: SHIMADZU LC-20AP preparative liquid chromatography was used, and the model number of the preparative column was C18 packing material. Preparative method: The crude product was dissolved in acetonitrile and water to prepare a sample solution. Mobile phase: Acetonitrile / water (containing 0.225% formic acid). Gradient elution method: Acetonitrile was eluted with a gradient of 30% to 60% (elution time 15 min).

[0204] Nuclear magnetic resonance of compound 8 chiral isomer 1: 1 H NMR (400MHz,DMSO-d6) δ 10.88 (s,1H),9.56 - 9.42 (m,1H),8.78 (d,1H),8.42 - 8.35 (m,1H),8.28 - 8.22 (m,1H),7.78 (d,1H),7.51 (d,1H),7.27 - 6.94 (m,2H),6.89 - 6.42 (m,1H),5.80 - 5.63 (m,1H),5.33 - 5.01 (m,1H),4.83 - 4.70 (m,1H),4.66 - 4.48 (m,2H),4.42 (dd,1H),4.30 - 4.10 (m,1H),3.96 - 3.40 (m,5H),2.80 - 2.56 (m,3H),2.45 - 1.65 (m,17H),1.65 - 1.41 (m,9H),1.15 - 0.95 (m,2H).

[0205] LCMS m / z of chiral isomer 1 of compound 8 = 878.4 [M+1] + It is.

[0206] Nuclear magnetic resonance of compound 8 chiral isomer 2: 1H NMR (400MHz,DMSO-d6) δ 10.88 (s,1H),9.56 - 9.42 (m,1H),8.77 (d,1H),8.42 - 8.35 (m,1H),8.28 - 8.22 (m,1H),7.78 (d,1H),7.50 (d,1H),7.28 - 6.94 (m,2H),6.89 - 6.40 (m,1H),5.80 - 5.63 (m,1H),5.33 - 5.01 (m,1H),4.83 - 4.70 (m,1H),4.66 - 4.48 (m,2H),4.42 (dd,1H),4.30 - 4.10 (m,1H),3.96 - 3.40 (m,5H),2.80 - 2.56 (m,3H),2.45 - 1.65 (m,17H),1.65 - 1.41 (m,9H),1.15 - 0.95 (m,2H).

[0207] LCMS m / z of chiral isomer 2 of compound 8 = 878.4 [M+1] + It is.

[0208] Example 10: Preparation of Compound 10 (Trans) [ka]

[0209] Compound 10 was obtained using tert-butyl (3S,4R)-3-fluoro-4-hydroxypiperidine-1-carboxylate (10a) as a starting material and following the synthesis method of Example 12 to obtain compound 10 (20.5 mg, yield: 11%).

[0210] Chiral Separation Methods: Instrument and preparative column: Waters 150 SFC preparative liquid chromatography was used, the preparative column model number was Chiralpak OD Column, Mobile phase system: sCO2 (supercritical CO2) / mixed solvent of isopropyl alcohol and acetonitrile (containing 0.1% aqueous ammonia), isocratic elution: sCO2 / mixed solvent of isopropyl alcohol and acetonitrile (containing 0.1% aqueous ammonia) = 3:7, flow rate: 100 mL / min.

[0211] Analytical method for target compounds: Instrument: SHIMADZU LC-30AD sf, Chromatography column: Chiralpak OD-3, Specifications: 50×4.6mm ID, 3μm, Mobile phase A: sCO2 (supercritical CO2), Mobile phase B: Mixture of isopropyl alcohol and acetonitrile (containing 0.05% diethylamine), Column temperature: 35℃, Flow rate: 3mL / min, Wavelength: 220nm, Elution procedure: Isocratic elution: Mobile phase A:B=2:3, Retention time of target compound: 2.329min.

[0212] Traditional separation methods: Instrument and preparative column: SHIMADZU LC-20AP preparative liquid chromatography was used, and the model number of the preparative column was Phenomenex C18. Preparation method: The crude product was dissolved in acetonitrile and water to prepare a sample solution. Mobile phase system: acetonitrile / water (containing 10 mmol / L ammonium bicarbonate). Gradient elution method: Acetonitrile was eluted with a gradient of 50% to 80% (elution time 10 min).

[0213] 1H NMR (400MHz,DMSO-d6) δ 10.90 (s,1H),9.56 - 9.42 (m,1H),8.78 (d,1H),8.42 - 8.35 (m,1H),8.28 - 8.22 (m,1H),7.79 (d,1H),7.52 (d,1H),7.27 - 6.94 (m,2H),6.89 - 6.42 (m,1H),5.33 - 5.01 (m,1H),4.95 - 4.70 (m,2H),4.61 (s,2H),4.46 - 4.36 (m,1H),4.29 (s,3H),4.24 - 4.10 (m,1H),3.88 - 3.40 (m,5H),2.95 - 2.55 (m,4H),2.45 - 1.65 (m,16H),1.65 - 1.45 (m,1H),1.11 - 0.95 (m,2H).

[0214] LCMS m / z=868.3[M+1] + .

[0215] Example 11: Preparation of Compound 11 (Trans) [ka]

[0216] Using 11a and 3-bromoprop-1-yne as starting materials, compound 11 (25.7 mg) was obtained according to the synthesis method of Example 12.

[0217] Chiral Separation Methods: Instrument and preparative column: Waters 150 SFC preparative liquid chromatography was used, the model number of the preparative column was Chiralpak Column, Mobile phase system: sCO2 (supercritical CO2) / mixed solvent of isopropyl alcohol and acetonitrile (containing 0.1% aqueous ammonia), isocratic elution: sCO2 / mixed solvent of isopropyl alcohol and acetonitrile (containing 0.1% aqueous ammonia) = 3:7, flow rate: 100 mL / min.

[0218] Analytical method for target compounds: Instrument: SHIMADZU LC-30AD sf, Chromatography column: Chiralpak OD-3, Specifications: 50×4.6 mm ID, 3 μm, Mobile phase A: sCO2 (supercritical CO2), Mobile phase B: Mixture of isopropyl alcohol and acetonitrile (containing 0.05% diethylamine), Column temperature: 35°C, Flow rate: 3 mL / min, Wavelength: 220 nm, Elution procedure: Isocratic elution: Mobile phase A:B=2:3, Retention time of target compound: 2.263 min.

[0219] Traditional separation methods: Instrument and preparative column: SHIMADZU LC-20AP preparative liquid chromatography was used, and the model number of the preparative column was Phenomenex C18. Preparation method: The crude product was dissolved in acetonitrile and water to prepare a sample solution. Mobile phase system: acetonitrile / water (containing 10 mmol / L ammonium bicarbonate). Gradient elution method: Acetonitrile was eluted with a gradient of 40% to 70% (elution time 10 min).

[0220] 1 H NMR (400MHz,DMSO-d6) δ 10.90 (s,1H),9.56 - 9.42 (m,1H),8.78 (d,1H),8.42 - 8.35 (m,1H),8.28 - 8.22 (m,1H),7.79 (d,1H),7.52 (d,1H),7.27 - 6.94 (m,2H),6.89 - 6.42 (m,1H),5.33 - 5.01 (m,1H),4.95 - 4.70 (m,2H),4.61 (s,2H),4.46 - 4.36 (m,1H),4.29 (s,3H),4.24 - 4.10 (m,1H),3.88 - 3.40 (m,5H),2.95 - 2.55 (m,4H),2.45 - 1.65 (m,16H),1.65 - 1.45 (m,1H),1.11 - 0.95 (m,2H).

[0221] LCMS m / z=868.3[M+1] + .

[0222] Example 12: Preparation of Compound 12 (Trans) [ka]

[0223] Step 1: Fabrication of 12b 12a (1.3g, 5.93mmol) was added to 50mL of tetrahydrofuran, cooled to 0℃, and 0.22g of sodium hydride was added. After stirring for 30min at 0℃, 3-bromoprop-1-yne (0.77g, 6.48mmol) was added and reacted at room temperature for 12h. 100mL of saturated ammonium chloride solution was added to the reaction system, and the mixture was extracted with 100mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was separated and purified by silica gel chromatography column (petroleum ether / ethyl acetate (v / v)=4:1) to obtain 12b (1.1g, yield: 72%).

[0224] Step 2: Manufacturing 12c

[0225] 12b (0.07g, 0.27mmol) and 3-(7-iodo-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (2C) (0.1g, 0.27mmol) were added to 5mL of DMF, 1mL of triethylamine, CuI (0.02g, 0.1mmol) and PdCl2(PPh3)2 (0.035g, 0.05mmol) were added, and the mixture was purged with nitrogen gas three times and reacted at 60°C for 4h under nitrogen gas protection. The reaction solution was cooled to room temperature, 30mL of ethyl acetate was added, the organic phase was washed with 50mL of purified water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel chromatography column (petroleum ether / ethyl acetate (v / v) = 2:1 to 1:1) to obtain 12c (0.09g, yield: 67%).

[0226] Step 3: Preparation of the trifluoroacetate salt of 12d

[0227] 12c (0.09 g, 0.18 mmol) was added to 3 mL of dichloromethane, 1 mL of trifluoroacetic acid was added, and the mixture was reacted at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain crude trifluoroacetate salt of 12d (0.1 g).

[0228] LCMS m / z=399.1[M+1] + .

[0229] Step 4: Preparation of compound 12 2mL of triethylamine was added to the trifluoroacetate salt (0.1g) of the crude product 12d, 5mL of DMA solution was added, 6h (0.087g, 0.18mmol) was added, and the mixture was stirred at room temperature for 3h, after which sodium triacetoxyborohydride (0.042g, 0.2mmol) was added and reacted at room temperature for 16h. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the resulting crude product was subjected to chiral separation, followed by conventional separation, and then freeze-dried to obtain compound 12 (22mg, yield: 14%).

[0230] Chiral Separation Methods: Instrument and preparative column: Waters 150 SFC preparative liquid chromatography was used, the model number of the preparative column was Chiralpak Column, Mobile phase system: sCO2 (supercritical CO2) / mixed solvent of isopropyl alcohol and acetonitrile, isocratic elution, sCO2 / mixed solvent of isopropyl alcohol and acetonitrile = 2:3, flow rate: 100 mL / min.

[0231] Analytical method for target compounds: Instrument: SHIMADZU LC-30AD sf, Chromatography column: Chiralpak AD-3, Specifications: 50×4.6 mm ID, 3 μm, Mobile phase A: sCO2 (supercritical CO2), Mobile phase B: Mixture of isopropyl alcohol and acetonitrile (containing 0.05% diethylamine), Column temperature: 35°C, Flow rate: 3 mL / min, Wavelength: 220 nm, Elution procedure: Isocratic elution: Mobile phase A:B=2:3, Retention time of target compound: 1.16 min.

[0232] Traditional separation methods: Instrument and preparative column: SHIMADZU LC-20AP preparative liquid chromatography was used, and the model number of the preparative column was Phenomenex C18. Preparation method: The crude product was dissolved in acetonitrile and water to prepare a sample solution. Mobile phase system: acetonitrile / water (containing 0.05% ammonium bicarbonate). Gradient elution method: Acetonitrile was eluted with a gradient of 45% to 75% (elution time 15 min).

[0233] 1 H NMR (400MHz,DMSO-d6) δ 10.90 (s,1H),9.56 - 9.42 (m,1H),8.77 (d,1H),8.42 - 8.35 (m,1H),8.28 - 8.22 (m,1H),7.79 (d,1H),7.52 (d,1H),7.27 - 6.94 (m,2H),6.89 - 6.42 (m,1H),5.33 - 5.01 (m,1H),4.85 - 4.70 (m,1H),4.63 (s,2H),4.59 - 4.35 (m,2H),4.29 (s,3H),4.24 - 4.08 (m,1H),3.88 - 3.40 (m,5H),3.10 - 2.95 (m,1H),2.78 - 2.55 (m,3H),2.45 - 1.37 (m,17H),1.11 - 0.95 (m,2H).

[0234] LCMS m / z=434.8[M / 2+1] + .

[0235] Example 13: Preparation of Compound 13 (Trans) [ka]

[0236] 13a+3-Bromoprop-1-yne was used as the starting material, and the synthesis method of Example 12 was followed to obtain compound 13 (10.6 mg).

[0237] Chiral Separation Methods: Instrument and preparative column: Waters 150 SFC preparative liquid chromatography was used, the model number of the preparative column was Chiralpak AD Column, Mobile phase system: sCO2 (supercritical CO2) / mixed solvent of isopropyl alcohol and acetonitrile (containing 0.1% aqueous ammonia), isocratic elution: sCO2 / mixed solvent of isopropyl alcohol and acetonitrile (containing 0.1% aqueous ammonia) = 2:3, flow rate: 100 mL / min.

[0238] Analytical method for target compounds: Instrument: SHIMADZU LC-30AD sf, Chromatography column: Chiralpak AD-3, Specifications: 50×4.6 mm ID, 3 μm, Mobile phase A: sCO2 (supercritical CO2), Mobile phase B: Mixture of isopropyl alcohol and acetonitrile (containing 0.05% diethylamine), Column temperature: 35°C, Flow rate: 3 mL / min, Wavelength: 220 nm, Elution procedure: Isocratic elution: Mobile phase A:B=1:1, Retention time of target compound: 2.345 min.

[0239] Traditional separation methods: Instrument and preparative column: SHIMADZU LC-20AP preparative liquid chromatography was used, and the model number of the preparative column was Phenomenex C18. Preparation method: The crude product was dissolved in acetonitrile and water to prepare a sample solution. Mobile phase system: acetonitrile / water (containing 10 mmol / L ammonium bicarbonate). Gradient elution method: Acetonitrile was eluted with a gradient of 40% to 70% (elution time 15 min).

[0240] 1H NMR (400MHz,DMSO-d6) δ 10.90 (s,1H),9.56 - 9.42 (m,1H),8.78 (d,1H),8.42 - 8.35 (m,1H),8.28 - 8.22 (m,1H),7.79 (d,1H),7.52 (d,1H),7.27 - 6.94 (m,2H),6.89 - 6.42 (m,1H),5.33 - 5.01 (m,1H),4.85 - 4.70 (m,1H),4.63 (s,2H),4.59 - 4.35 (m,2H),4.29 (s,3H),4.24 - 4.08 (m,1H),3.88 - 3.40 (m,5H),3.10 - 2.95 (m,1H),2.78 - 2.55 (m,3H),2.45 - 1.37 (m,17H),1.11 - 0.95 (m,2H).

[0241] LCMS m / z=868.3[M+1] + .

[0242] Example 14: Preparation of trifluoroacetate salt of compound 14 (Trans) [ka]

[0243] Step 1: Fabrication of 14b 14a (1.1g, 4.09mmol), (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane (0.49g, 4.94mmol), rac-BINAP (0.25g, 0.40mmol), cesium carbonate (4.0g, 12.3mmol) and Pd2(dba)3 (0.75g, 0.82mmol) were dissolved in 30mL of dioxane, substituted with nitrogen gas three times, and reacted at 100°C for 20h. The reaction solution was cooled to room temperature, 50mL of water was slowly added, extracted with ethyl acetate (50mL), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0:1 to 7:3) to obtain 14b (0.40g, yield: 34%).

[0244] LCMS m / z=288.1[M+1] + .

[0245] Step 2: Fabrication of 14c 14b (400 mg, 1.39 mmol) and lithium hydroxide monohydrate (290 mg, 6.91 mmol) were dissolved in methanol (10 mL) and water (20 mL) and reacted at 70° C. for 20 h. The reaction solution was cooled to room temperature, concentrated under reduced pressure, 20 mL of water was added, the pH was adjusted to 5 with 1 mol / L aqueous hydrochloric acid solution, and extracted with 50 mL of dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product (200 mg). The above crude product (170 mg), trans-(4-(4-amino-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)methanol (see WO 2021247897 for synthesis method) (160 mg, 0.65 mmol) and N-methylimidazole (190 mg, 2.31 mmol) were dissolved in acetonitrile (5 mL), and then TCFH (270 mg, 0.96 mmol) was added and reacted at room temperature for 20 h. The reaction solution was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (methanol / dichloromethane (v / v) = 0:1 to 1:9) to obtain 14c (150 mg, yield: 47%).

[0246] LCMS m / z=487.2[M+1] + .

[0247] Step 3: Preparation of the trifluoroacetate salt of compound 14 14c (200mg, 0.41mmol) was dissolved in dichloromethane (3mL), Dess-Martin oxidant (340mg, 0.80mmol) was added, and the mixture was reacted at room temperature for 2h. The reaction solution was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (methanol / dichloromethane (v / v) = 0:1 to 1:9) to obtain intermediate 14A (100mg). The above crude product 2E (46mg) was dissolved in DMA (3mL), and intermediate 14A (60mg) and 0.1mL acetic acid were added. After stirring at room temperature for 30min, sodium triacetoxyborohydride (31mg, 0.146mmol) was added, and the mixture was reacted at room temperature for 16h. 10 mL of saturated aqueous sodium bicarbonate solution was slowly added to the reaction solution, and the mixture was extracted twice with 20 mL of ethyl acetate. The organic phases were combined, washed with 30 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (methanol / dichloromethane (v / v)=0:1-1:9). The crude product thus obtained was subjected to conventional separation and freeze-dried to obtain the trifluoroacetate salt of compound 14 (9 mg).

[0248] Traditional separation methods: Instrument and preparative column: SHIMADZU LC-20AP preparative liquid chromatography was used, and the model number of the preparative column was Phenomenex C18. Preparative method: The crude product was dissolved in acetonitrile and water to prepare a sample solution. Mobile phase system: acetonitrile / water (containing 0.1% trifluoroacetic acid). Gradient elution method: Acetonitrile was eluted with a gradient of 25% to 40% (elution time 16 min).

[0249] 1H NMR (400MHz,DMSO-d6) δ 10.90 (s,1H),9.34 (s,1H),8.58 - 8.42 (m,2H),8.11 (s,1H),7.80 (d,1H),7.52 (d,1H),7.33 - 6.93 (m,3H),6.78 - 6.66 (m,1H),4.82 - 4.66 (m,2H),4.60 (s,2H),4.42 (dd,1H),4.35 - 4.27 (m,3H),4.27 - 4.15 (m,1H),4.05 - 3.76 (m,2H),3.74 - 3.65 (m,1H),3.65 - 3.33 (m,3H),3.18 - 2.93 (m,5H),2.77 - 2.57 (m,2H),2.45 - 1.60 (m,15H),1.30 - 1.09 (m,2H). LCMS m / z=849.2[M+1] + .

[0250] Example 15: Preparation of trifluoroacetate (Trans) of compound 15 [ka]

[0251] 15a+(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane was used as the starting material, and the trifluoroacetate salt of compound 15 (10 mg) was obtained according to the synthesis method of Example 14.

[0252] Purification method: The crude product was separated and purified by silica gel column chromatography (methanol / dichloromethane (v / v)=0:1 to 1:9), and the obtained crude product was subjected to conventional separation. The separated solution was then acidified with trifluoroacetic acid and lyophilized to obtain the trifluoroacetate salt of compound 15 (10 mg).

[0253] Traditional separation methods: Instrument and preparative column: SHIMADZU LC-20AP preparative liquid chromatography was used, and the model number of the preparative column was Phenomenex C18. Preparative method: The crude product was dissolved in acetonitrile and water to prepare a sample solution. Mobile phase system: acetonitrile / water (containing 10 mmol / L ammonium bicarbonate). Gradient elution method: Acetonitrile was eluted with a gradient of 30% to 60% (elution time 10 min).

[0254] 1 H NMR (400MHz,DMSO-d6) δ 10.90 (s,1H),9.35 - 9.17 (m,2H),8.40 (s,1H),8.29 (s,1H),7.80 (d,1H),7.53 (d,1H),7.30 - 6.93 (m,2H),5.33 - 5.12 (m,1H),4.77 - 4.70 (m,1H),4.60 (s,2H),4.47 - 4.37 (m,1H),4.35 - 4.15 (m,4H),4.07 - 3.65 (m,5H),3.63 - 3.32 (m,2H),3.15 - 2.92 (m,4H),2.78 - 2.55 (m,2H),2.46 - 1.65 (m,15H),1.28 - 1.10 (m,2H). LCMS m / z=868.3[M+1] + .

[0255] Example 16: Preparation of Compound 16 (Trans) [ka]

[0256] Step 1: Fabrication of 16b 16a (4.0g, 16.53mmol), cyclopropylboronic acid (4.28g, 49.83mmol), sodium carbonate (5.28g, 49.82mmol), Cu(OAc)2 (3.00g, 16.52mmol) and 2,2'-bipyridine (2.60g, 16.65mmol) were dissolved in 60mL of DCE, and the mixture was purged with nitrogen gas three times and reacted at 80°C under nitrogen gas protection for 6h. The reaction system was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate (v / v)=5:1) to give 16b (1.7g, yield: 36%).

[0257] Step 2: Fabrication of 16c

[0258] Under nitrogen gas protection, 16b (1.5g, 5.32mmol), 1A (3.33g, 7.98mmol), dioxane (60mL), water (20mL), Pd(dppf)Cl2·CH2Cl2 (CAS:95464-05-4) (0.43g, 0.53mmol) and cesium carbonate (5.20g, 15.96mmol) were added to a 100mL single-neck flask in this order, and the nitrogen gas was replaced three times. The reaction was carried out at 100℃ for 12h under nitrogen gas protection. The reaction system was cooled to room temperature, added to 50mL of water, extracted with ethyl acetate (100mL×3), the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel chromatography column (petroleum ether:ethyl acetate (v / v) =5:1) to obtain 16c (1.8g, yield: 69%).

[0259] LCMS m / z=493.1[M+1] + .

[0260] Step 3: Fabrication of 16d 16c (1.7 g, 3.45 mmol) and 10% Pd / C (0.8 g) were dissolved in 30 mL of tetrahydrofuran and 30 mL of methanol, and the mixture was reacted for 16 h at 30° C. after replacing hydrogen gas three times. The reaction system was filtered through diatomaceous earth, and the filter cake was washed with methanol (30 mL×3). The filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product 16d (850 mg).

[0261] LCMS m / z=285.1[M+1] + .

[0262] Step 4: Fabrication of 16e The crude product 16d (400 mg), KI (0.35 g, 2.11 mmol), CuI (0.40 g, 2.10 mmol), and I2 (0.54 g, 2.13 mmol) were dissolved in 10 mL of acetonitrile, cooled to 0 ° C., and isoamyl nitrite (250 mg, 2.13 mmol) was slowly added, and the reaction was carried out at 30 ° C. for 6 h under nitrogen gas protection. 10 mL of saturated aqueous ammonium chloride was added to the reaction system, and the mixture was extracted with 50 mL of dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was separated and purified by a silica gel chromatography column (petroleum ether: ethyl acetate (v / v) = 2: 1 to 1: 1) to obtain 16e (220 mg, 2-step yield from compound 16c: 34%).

[0263] LCMS m / z=396.0[M+1] + .

[0264] Step 5: Fabrication of 16f 16e (150mg, 0.38mmol), tert-butyl 4-(propan-2-yn-1-yloxy)piperidine-1-carboxylate (0.11g, 0.46mmol), CuI (14mg, 0.074mmol), PdCl2(PPh3)2 (27mg, 0.0385mmol) and TEA (0.19g, 1.88mmol) were dissolved in 5mL of DMF, purged with nitrogen gas three times, and reacted at 60°C for 6h. The reaction system was cooled to room temperature, 5mL of water was added, extracted with 30mL of dichloromethane, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by a silica gel chromatography column (petroleum ether:ethyl acetate (v / v) = 2:1 to 1:1) to obtain 16f (130mg, yield: 68%).

[0265] Step 6: Preparation of 16 g of trifluoroacetate salt

[0266] 16f (120 mg, 0.24 mmol) was dissolved in 5 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, and the mixture was reacted at room temperature for 2 h. The reaction system was concentrated under reduced pressure to obtain the crude product 16g as trifluoroacetate (0.13 g).

[0267] LCMS m / z=407.2[M+1] + .

[0268] Step 7: Preparation of Compound 16 The trifluoroacetate salt (130mg) of the crude product 16g was dissolved in 5mL of DMA, sodium bicarbonate (40mg, 0.48mmol) was added, and the mixture was stirred at room temperature for 15min, followed by 6h (140mg, 0.29mmol), 0.04mL of acetic acid and 4 Å molecular sieves (2g) were added, and the mixture was stirred at room temperature for 30min, followed by sodium triacetoxyborohydride (102mg, 0.48mmol) and reacted at room temperature for 16h. 20mL of saturated aqueous sodium bicarbonate solution and 20mL of dichloromethane were added to the reaction solution, and the organic phase was concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (dichloromethane / methanol (v / v) = 100:1 to 20:1), and the obtained crude product was purified by HPLC to obtain compound 16 (50.4mg, yield: 20%).

[0269] 1 H NMR (400MHz,DMSO-d6) δ 10.89 (s,1H),9.55 - 9.45 (m,1H),8.78 (d,1H),8.38 (d,1H),8.25 (d,1H),7.75 (d,1H),7.52 (d,1H),7.27 - 6.92 (m,2H),6.90 - 6.40 (m,1H),5.33 - 5.02 (m,1H),4.83 - 4.70 (m,1H),4.51 (s,2H),4.43 - 4.32 (m,1H),4.23 - 4.01 (m,2H),3.88 - 3.40 (m,5H),2.78 - 2.55 (m,4H),2.44 - 1.40 (m,19H),1.30 - 0.94 (m,6H).

[0270] LCMS m / z=876.3[M+1] + .

[0271] Example 17: Preparation of Compound 17 (Trans) [ka]

[0272] The hydrochloride salt (130 mg) of the crude intermediate 6 was dissolved in 5 mL of acetonitrile, the crude intermediate 2 (61 mg) and TCFH (67 mg, 0.24 mmol) were added, and NMI (0.11 g, 1.34 mmol) was added, and the mixture was reacted at room temperature for 16 h. The reaction system was concentrated under reduced pressure, 10 mL of water was added to the residue, filtered, the filter cake was washed with 5 mL of water, dissolved in 10 mL of DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by a silica gel chromatography column (dichloromethane / methanol (v / v) = 12:1), and the obtained crude product was subjected to chiral separation to obtain chiral isomer 1 (37.5 mg, 2-step yield from compound 2-B: 18%) and chiral isomer 2 (18.4 mg, 2-step yield from compound 2-B: 9%) of compound 17, respectively.

[0273] Chiral Separation Methods: Instrument and preparative column: Shimadzu LC-A HPLC preparative liquid chromatography was used, the preparative column model was Chiralpak IE, 250×30 mm, 10 μm, mobile phase system: acetonitrile / methanol, isocratic elution: acetonitrile / methanol=1:1, flow rate: 80 mL / min.

[0274] Analytical method for target compounds: Instrument: Shimadzu LC-20AB with PDA detector Chromatography column: Chiralpak IE-3, specifications: 150×4.6 mm ID, 3 μm, mobile phase A: acetonitrile, mobile phase B: methanol, column temperature: 35°C, flow rate: 1 mL / min, wavelength: 220 nm, Elution procedure: Isocratic elution: mobile phase A:B=3:7; Retention time for chiral isomer 1: 3.368 min.

[0275] 1H NMR (400MHz, DMSO-d6) δ 10.89 (s,1H),9.28 (s,1H),8.88 (d,1H),8.38 - 8.29 (m,2H),7.79 (d,1H),7.52 (d,1H),7.26 - 6.90 (m,3H),4.94 - 4.72 (m,1H),4.61 (s,2H),4.58 - 4.48 (m,1H),4.48 - 4.34 (m,3H),4.29 (s,3H),4.24 - 4.04 (m,2H),3.85 - 3.71 (m,2H),3.30 - 3.22 (m,2H),2.95 - 2.76 (m,1H),2.76 - 2.55 (m,3H),2.46 - 2.26 (m,2H),2.24 - 2.10 (m,4H),2.10 - 1.95 (m,2H),1.95 - 1.65 (m,6H),1.65 - 1.49 (m,1H),1.13 - 0.94 (m,2H).

[0276] LCMS m / z=924.4[M+1] + .

[0277] Kirara heterosexual body 2 retention time: 4.029min.

[0278] 1H NMR (400MHz, DMSO-d6) δ 10.89 (s,1H),9.28 (s,1H),8.88 (d,1H),8.38 - 8.29 (m,2H),7.79 (d,1H),7.52 (d,1H),7.26 - 6.90 (m,3H),4.94 - 4.72 (m,1H),4.60 (s,2H),4.58 - 4.48 (m,1H),4.48 - 4.34 (m,3H),4.29 (s,3H),4.24 - 4.04 (m,2H),3.85 - 3.71 (m,2H),3.30 - 3.22 (m,2H),2.95 - 2.76 (m,1H),2.76 - 2.55 (m,3H),2.46 - 2.26 (m,2H),2.24 - 2.10 (m,4H),2.10 - 1.95 (m,2H),1.95 - 1.65 (m,6H),1.65 - 1.49 (m,1H),1.13 - 0.94 (m,2H).

[0279] LCMS m / z=924.4[M+1] + .

[0280] Example 18: Production of Compound 18 (Trans)

change

[0281] The hydrochloride salt (130 mg) of the crude intermediate 6 was dissolved in 5 mL of acetonitrile, the crude intermediate 1 (56 mg) and TCFH (67 mg, 0.24 mmol) were added, and NMI (0.11 g, 1.34 mmol) was added, and the mixture was reacted at room temperature for 16 h. The reaction system was concentrated under reduced pressure, 10 mL of water was added to the residue, filtered, the filter cake was washed with 5 mL of water, dissolved in 10 mL of DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by a silica gel chromatography column (dichloromethane / methanol (v / v) = 12:1), and the obtained crude product was subjected to chiral separation to obtain chiral isomer 1 (17.8 mg, 2-step yield from compound 1-D: 9%) and chiral isomer 2 (16.2 mg, 2-step yield from compound 1-D: 9%) of compound 18, respectively.

[0282] Chiral Separation Methods: Instrument and preparative column: Shimadzu LC-A HPLC preparative liquid chromatography was used, the preparative column model was Chiralpak IE, 250×30 mm, 10 μm, mobile phase system: acetonitrile / methanol, isocratic elution: acetonitrile / methanol=1:1, flow rate: 80 mL / min.

[0283] Analytical method for target compounds: Instrument: Shimadzu LC-20AB with PDA detector, Chromatography column: Chiralpak IE-3, Specifications: 150×4.6mm ID, 3μm, Mobile phase A: Acetonitrile, Mobile phase B: Methanol, Column temperature: 35℃, Flow rate: 1mL / min, Wavelength: 220nm, Elution procedure: Isocratic elution: Mobile phase A:B=3:7, Retention time for chiral isomer 1: 6.469 min.

[0284] 1H NMR (400MHz, DMSO-d6) δ 10.89 (s,1H),9.32 (s,1H),8.81 (d,1H),8.37 (s,1H),8.29 (s,1H),7.84 - 7.73 (m,1H),7.56 - 7.48 (m,1H),7.28 - 6.96 (m,2H),6.91 (d,1H),4.94 - 4.71 (m,1H),4.60 (s,2H),4.46 - 4.24 (m,6H),4.24 - 4.10 (m,1H),4.00 - 3.91 (m,1H),3.87 - 3.53 (m,3H),3.50 - 3.42 (m,2H),3.29 (s,3H),3.21 - 3.07 (m,1H),3.06 - 2.93 (m,1H),2.93 - 2.76 (m,1H),2.76 - 2.55 (m,3H),2.45 - 2.25 (m,2H),2.25 - 2.10 (m,4H),2.10 - 1.95 (m,2H),1.95 - 1.65 (m,6H),1.65 - 1.49 (m,1H),1.12 - 0.95 (m,2H).

[0285] LCMS m / z=900.5[M+1] + .

[0286] Kirara heterosexual body 2 retention time: 7.967min.

[0287] 1H NMR (400MHz, DMSO-d6) δ 10.89 (s,1H),9.32 (s,1H),8.81 (d,1H),8.37 (s,1H),8.29 (s,1H),7.84 - 7.73 (m,1H),7.56 - 7.48 (m,1H),7.28 - 6.96 (m,2H),6.91 (d,1H),4.94 - 4.71 (m,1H),4.60 (s,2H),4.46 - 4.24 (m,6H),4.24 - 4.10 (m,1H),4.00 - 3.91 (m,1H),3.87 - 3.53 (m,3H),3.50 - 3.42 (m,2H),3.29 (s,3H),3.21 - 3.07 (m,1H),3.06 - 2.93 (m,1H),2.93 - 2.76 (m,1H),2.76 - 2.55 (m,3H),2.45 - 2.25 (m,2H),2.25 - 2.10 (m,4H),2.10 - 1.95 (m,2H),1.95 - 1.65 (m,6H),1.65 - 1.49 (m,1H),1.12 - 0.95 (m,2H).

[0288] LCMS m / z=900.4[M+1] + .

[0289] Example 19: Production of Compound 19 (Trans)

change

[0290] The hydrochloride salt (130 mg) of the crude intermediate 6 was dissolved in 5 mL of acetonitrile, the crude intermediate 3 (53 mg) and TCFH (67 mg, 0.24 mmol) were added, and NMI (0.11 g, 1.34 mmol) was added, and the mixture was reacted at room temperature for 16 h. The reaction system was concentrated under reduced pressure, 10 mL of water was added to the residue, filtered, the filter cake was washed with 5 mL of water, dissolved in 10 mL of DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by a silica gel chromatography column (dichloromethane / methanol (v / v) = 12:1), and the obtained crude product was subjected to chiral separation to obtain chiral isomer 1 (18.2 mg, 2-step yield from compound 3-A: 7%) and chiral isomer 2 (12.5 mg, 2-step yield from compound 3-A: 5%) of compound 19, respectively.

[0291] Chiral Separation Methods: Instrument and preparative column: Shimadzu LC-A HPLC preparative liquid chromatography was used, the preparative column model was Chiralpak IE, 250×30 mm, 10 μm, mobile phase system: acetonitrile / methanol, isocratic elution: acetonitrile / methanol=1:1, flow rate: 80 mL / min.

[0292] Analytical method for target compounds: Instrument: Shimadzu LC-20AB with PDA detector Chromatography column: Chiralpak IE-3, specifications: 150×4.6 mm ID, 3 μm, mobile phase A: acetonitrile, mobile phase B: methanol, column temperature: 35°C, flow rate: 1 mL / min, wavelength: 220 nm, elution procedure: isocratic elution: mobile phase A:B=3:7, Retention time for chiral isomer 1: 5.313 min.

[0293] 1H NMR (400MHz, DMSO-d6) δ 10.90 (s,1H),9.34 (s,1H),8.81 (d,1H),8.36 (s,1H),8.29 (s,1H),7.79 (d,1H),7.52 (d,1H),7.27 - 6.94 (m,2H),6.90 (d,1H),4.93 - 4.72 (m,2H),4.61 (s,2H),4.52 - 4.10 (m,7H),4.03 - 3.92 (m,1H),3.87 - 3.70 (m,1H),3.67 - 3.46 (m,4H),3.20 - 3.06 (m,1H),3.05 - 2.93 (m,1H),2.93 - 2.76 (m,1H),2.75 - 2.56 (m,3H),2.44 - 2.30 (m,2H),2.25 - 2.10 (m,4H),2.09 - 1.95 (m,2H),1.95 - 1.66 (m,6H),1.65 - 1.50 (m,1H),1.12 - 0.95 (m,2H).

[0294] LCMS m / z=886.4[M+1] + .

[0295] Kirara heterosexual body 2 retention time: 6.457min.

[0296] 1H NMR (400MHz,DMSO-d6) δ 10.89 (s,1H),9.34 (s,1H),8.81 (d,1H),8.36 (s,1H),8.29 (s,1H),7.79 (d,1H),7.52 (d,1H),7.27 - 6.94 (m,2H),6.90 (d,1H),4.93 - 4.72 (m,2H),4.60 (s,2H),4.52 - 4.10 (m,7H),4.03 - 3.92 (m,1H),3.87 - 3.70 (m,1H),3.67 - 3.46 (m,4H),3.20 - 3.06 (m,1H),3.05 - 2.93 (m,1H),2.93 - 2.76 (m,1H),2.75 - 2.56 (m,3H),2.44 - 2.30 (m,2H),2.25 - 2.10 (m,4H),2.09 - 1.95 (m,2H),1.95 - 1.66 (m,6H),1.65 - 1.50 (m,1H),1.12 - 0.95 (m,2H).

[0297] LCMS m / z=886.4[M+1] + .

[0298] The obtained chiral isomer 2 was subjected to acidic fractionation to obtain a trifluoroacetate salt of chiral isomer 2.

[0299] Acidic preparative method: Instrument and preparative column: Shimadzu LC-20AP preparative liquid is used, the model number of the preparative column is Welch Xtimate C18, mobile phase system: water (containing 0.1% trifluoroacetic acid) / acetonitrile, gradient elution: water (containing 0.1% trifluoroacetic acid) / acetonitrile = 18:82 ~ 48:52, flow rate: 25mL / min.

[0300] Nuclear magnetic resonance data for the trifluoroacetate salt of chiral isomer 2: 1H NMR (400MHz,DMSO-d6) δ 10.91 (s,1H),9.35 (s,1H),8.82 (d,1H),8.38 (s,1H),8.29 (s,1H),7.81 (d,1H),7.53 (d,1H),7.27 - 7.07 (m,2H),6.91 (d,1H),4.90 - 4.56 (m,3H),4.53 - 3.82 (m,10H),3.65 - 3.46 (m,4H),3.20 - 3.08 (m,2H),3.07 - 2.90 (m,2H),2.76 - 2.56 (m,2H),2.45 - 1.68 (m,14H),1.60 - 1.46 (m,1H), 1.34 - 1.10 (m,2H).

[0301] Example 20: Preparation of Compound 20 (Trans) [ka]

[0302] The hydrochloride salt (130 mg) of the crude intermediate 6 was dissolved in 5 mL of acetonitrile, and the crude intermediate 5 (53 mg) and TCFH (67 mg, 0.24 mmol) were added, and NMI (0.11 g, 1.34 mmol) was added, and the mixture was reacted at room temperature for 16 h. The reaction system was concentrated under reduced pressure, and 10 mL of water was added to the residue, filtered, and the filter cake was washed with 5 mL of water, dissolved in 10 mL of DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by a silica gel chromatography column (dichloromethane / methanol (v / v) = 12:1). The obtained crude product was subjected to chiral separation, and chiral isomer 1 (10.3 mg, 2-step yield from compound 5-A: 4%) and chiral isomer 2 (9.8 mg, 2-step yield from compound 5-A: 4%) of compound 20 were obtained, respectively.

[0303] Chiral Separation Methods: Instrument and preparative column: Shimadzu LC-A HPLC preparative liquid chromatography was used, the preparative column model was Chiralpak IE, 250×30 mm, 10 μm, mobile phase system: acetonitrile / methanol, isocratic elution: acetonitrile / methanol=1:1, flow rate: 80 mL / min.

[0304] Analytical method for target compounds: Instrument: Shimadzu LC-20AB with PDA detector Chromatography column: Chiralpak IE-3, specifications: 150×4.6 mm ID, 3 μm, mobile phase A: acetonitrile, mobile phase B: methanol, column temperature: 35°C, flow rate: 1 mL / min, wavelength: 220 nm, elution procedure: isocratic elution: mobile phase A:B=3:7, Retention time for chiral isomer 1: 5.229 min.

[0305] 1 H NMR (400MHz,DMSO-d6) δ 10.89 (s,1H),9.34 (s,1H),8.81 (d,1H),8.36 (s,1H),8.29 (s,1H),7.79 (d,1H),7.52 (d,1H),7.27 - 6.94 (m,2H),6.89 (d,1H),4.93 - 4.72 (m,2H),4.61 (s,2H),4.52 - 4.10 (m,7H),4.03 - 3.92 (m,1H),3.87 - 3.70 (m,1H),3.67 - 3.46 (m,4H),3.20 - 3.06 (m,1H),3.05 - 2.93 (m,1H),2.93 - 2.76 (m,1H),2.75 - 2.56 (m,3H),2.44 - 2.30 (m,2H),2.25 - 2.10 (m,4H),2.09 - 1.95 (m,2H),1.95 - 1.66 (m,6H),1.65 - 1.50 (m,1H),1.12 - 0.94 (m,2H).

[0306] LCMS m / z=886.4[M+1] + .

[0307] Kirara heterosexual body 2 retention time: 6.378min.

[0308] 1 H NMR (400MHz, DMSO-d6) δ 10.89 (s,1H),9.34 (s,1H),8.81 (d,1H),8.36 (s,1H),8.29 (s,1H),7.79 (d,1H),7.52 (d,1H),7.27 - 6.94 (m,2H),6.90 (d,1H),4.93 - 4.72 (m,2H),4.60 (s,2H),4.52 - 4.10 (m,7H),4.03 - 3.92 (m,1H),3.87 - 3.70 (m,1H),3.67 - 3.46 (m,4H),3.20 - 3.06 (m,1H),3.05 - 2.93 (m,1H),2.93 - 2.76 (m,1H),2.75 - 2.56 (m,3H),2.44 - 2.30 (m,2H),2.25 - 2.10 (m,4H),2.09 - 1.95 (m,2H),1.95 - 1.66 (m,6H),1.65 - 1.50 (m,1H),1.12 - 0.94 (m,2H).

[0309] LCMS m / z=886.4[M+1] + .

[0310] Example 21: Production of Compound 21 (Trans)

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[0311] The hydrochloride salt (130 mg) of the crude intermediate 6 was dissolved in 5 mL of acetonitrile, the crude intermediate 4 (56 mg) and TCFH (67 mg, 0.24 mmol) were added, and NMI (0.11 g, 1.34 mmol) was added, and the mixture was reacted at room temperature for 16 h. The reaction system was concentrated under reduced pressure, 10 mL of water was added to the residue, filtered, the filter cake was washed with 5 mL of water, dissolved in 10 mL of DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by a silica gel chromatography column (dichloromethane / methanol (v / v) = 12:1), and the obtained crude product was subjected to chiral separation to obtain chiral isomer 1 (18.3 mg, 2-step yield from compound 4-C: 5%) and chiral isomer 2 (20.3 mg, 2-step yield from compound 4-C: 6%) of compound 21, respectively.

[0312] Chiral Separation Methods: Instrument and preparative column: Shimadzu LC-A HPLC preparative liquid chromatography was used, the preparative column model was Chiralpak IE, 250×30 mm, 10 μm, mobile phase system: acetonitrile / methanol, isocratic elution: acetonitrile / methanol=1:1, flow rate: 80 mL / min.

[0313] Analytical method for target compounds: Instrument: Shimadzu LC-20AB with PDA detector Chromatography column: Chiralpak IE-3, specifications: 150×4.6 mm ID, 3 μm, mobile phase A: acetonitrile, mobile phase B: methanol, column temperature: 35°C, flow rate: 1 mL / min, wavelength: 220 nm, Elution procedure: Isocratic elution: mobile phase A:B=3:7; Retention time for chiral isomer 1: 6.563 min.

[0314] 1H NMR (400MHz, DMSO-d6) δ 10.90 (s,1H),9.33 (s,1H),8.81 (d,1H),8.37 (s,1H),8.29 (s,1H),7.84 - 7.73 (m,1H),7.56 - 7.48 (m,1H),7.28 - 6.96 (m,2H),6.91 (d,1H),4.94 - 4.71 (m,1H),4.61 (s,2H),4.46 - 4.24 (m,6H),4.24 - 4.10 (m,1H),4.00 - 3.91 (m,1H),3.87 - 3.53 (m,3H),3.50 - 3.42 (m,2H),3.30 (s,3H),3.21 - 3.07 (m,1H),3.06 - 2.93 (m,1H),2.93 - 2.76 (m,1H),2.76 - 2.55 (m,3H),2.45 - 2.25 (m,2H),2.25 - 2.10 (m,4H),2.10 - 1.95 (m,2H),1.95 - 1.65 (m,6H),1.65 - 1.49 (m,1H),1.12 - 0.95 (m,2H).

[0315] LCMS m / z=900.4[M+1] + .

[0316] Kirara heterosexual body 2 retention time: 8.07min.

[0317] 1H NMR (400MHz,DMSO-d6) δ 10.90 (s,1H),9.33 (s,1H),8.81 (d,1H),8.37 (s,1H),8.29 (s,1H),7.84 - 7.73 (m,1H),7.56 - 7.48 (m,1H),7.28 - 6.96 (m,2H),6.91 (d,1H),4.94 - 4.71 (m,1H),4.61 (s,2H),4.46 - 4.24 (m,6H),4.24 - 4.10 (m,1H),4.00 - 3.91 (m,1H),3.87 - 3.53 (m,3H),3.50 - 3.42 (m,2H),3.30 (s,3H),3.21 - 3.07 (m,1H),3.06 - 2.93 (m,1H),2.93 - 2.76 (m,1H),2.76 - 2.55 (m,3H),2.45 - 2.25 (m,2H),2.25 - 2.10 (m,4H),2.10 - 1.95 (m,2H),1.95 - 1.65 (m,6H),1.65 - 1.49 (m,1H),1.12 - 0.95 (m,2H).

[0318] LCMS m / z=900.4[M+1] + .

[0319] Example 22: Preparation of Compound 22 (Trans) [ka]

[0320] The above crude intermediate 7 (0.12 g) was added to 5 mL of acetonitrile, the above crude intermediate 2 (0.08 g) and TCFH (0.084 g, 0.3 mmol) were added, NMI (0.08 g, 0.97 mmol) was added at 0° C., and the reaction was carried out at room temperature for 16 h. The reaction system was concentrated under reduced pressure, and the residue was subjected to chiral separation to obtain chiral isomer 1 (21.6 mg, yield: 8%) and chiral isomer 2 (22.7 mg, yield: 8%) of compound 22, respectively.

[0321] Chiral Separation Methods: Instrument and preparative column: Shimadzu LC-A HPLC preparative liquid chromatography was used, the preparative column model was Chiralpak IE, 250×30 mm, 10 μm, mobile phase system: acetonitrile / methanol, isocratic elution: acetonitrile / methanol=1:1, flow rate: 80 mL / min.

[0322] Analytical method for target compounds: Instrument: Shimadzu LC-20AB with PDA detector, Chromatography column: Chiralpak IE-3, Specifications: 150×4.6 mm ID, 3 μm, Mobile phase A: acetonitrile, Mobile phase B: methanol, Column temperature: 35°C, Flow rate: 1 mL / min, Wavelength: 220 nm, Elution procedure: Isocratic elution: mobile phase A:B=3:7; Retention time for chiral isomer 1: 3.449 min.

[0323] 1 H NMR (400MHz,DMSO-d6) δ 10.90 (s,1H),9.28 (s,1H),8.88 (d,1H),8.38 - 8.29 (m,2H),7.78 (d,1H),7.52 (d,1H),7.26 - 6.90 (m,3H),4.94 - 4.72 (m,1H),4.61 (s,2H),4.58 - 4.48 (m,1H),4.48 - 4.34 (m,3H),4.29 (s,3H),4.24 - 4.04 (m,2H),3.85 - 3.71 (m,2H),3.30 - 3.22 (m,2H),2.95 - 2.76 (m,1H),2.76 - 2.55 (m,3H),2.46 - 2.26 (m,2H),2.24 - 2.10 (m,4H),2.10 - 1.95 (m,2H),1.95 - 1.65 (m,6H),1.65 - 1.49 (m,1H),1.13 - 0.94 (m,2H).

[0324] LCMS m / z=924.4[M+1] + .

[0325] Retention time for chiral isomer 2: 4.165 min.

[0326] 1 H NMR (400MHz,DMSO-d6) δ 10.90 (s,1H),9.28 (s,1H),8.88 (d,1H),8.38 - 8.29 (m,2H),7.79 (d,1H),7.52 (d,1H),7.26 - 6.90 (m,3H),4.94 - 4.72 (m,1H),4.61 (s,2H),4.58 - 4.48 (m,1H),4.48 - 4.34 (m,3H),4.29 (s,3H),4.24 - 4.04 (m,2H),3.85 - 3.71 (m,2H),3.30 - 3.22 (m,2H),2.95 - 2.76 (m,1H),2.76 - 2.55 (m,3H),2.46 - 2.26 (m,2H),2.24 - 2.10 (m,4H),2.10 - 1.95 (m,2H),1.95 - 1.65 (m,6H),1.65 - 1.49 (m,1H),1.13 - 0.94 (m,2H).

[0327] LCMS m / z=924.4[M+1] + .

[0328] Example 23: Preparation of Compound 23 (Trans) [ka]

[0329] The above crude intermediate 7 (0.12 g) was added to 5 mL of acetonitrile, the above crude intermediate 1 (0.073 g) and TCFH (0.084 g, 0.3 mmol) were added, NMI (0.08 g, 0.97 mmol) was added at 0° C., and the reaction was carried out at room temperature for 16 h. The reaction system was concentrated under reduced pressure, and the residue was subjected to chiral separation to obtain chiral isomer 1 (20.5 mg, 2-step yield from compound 1-D: 8%) and chiral isomer 2 (17.8 mg, 2-step yield from compound 1-D: 7%) of compound 23, respectively.

[0330] Chiral Separation Methods: Instrument and preparative column: Shimadzu LC-A HPLC preparative liquid chromatography was used, the preparative column model was Chiralpak IE, 250×30 mm, 10 μm, mobile phase system: acetonitrile / methanol, isocratic elution: acetonitrile / methanol=1:1, flow rate: 80 mL / min.

[0331] Analytical method for target compounds: Instrument: Shimadzu LC-20AB with PDA detector, Chromatography column: Chiralpak IE-3, Specifications: 150×4.6mm ID, 3μm, Mobile phase A: acetonitrile, Mobile phase B: methanol, Column temperature: 35℃, Flow rate: 1mL / min, Wavelength: 220nm, Elution procedure: Isocratic elution: Mobile phase A:B=3:7, Retention time for chiral isomer 1: 6.645 min.

[0332] 1 H NMR (400MHz,DMSO-d6) δ 10.90 (s,1H),9.33 (s,1H),8.81 (d,1H),8.37 (s,1H),8.29 (s,1H),7.84 - 7.73 (m,1H),7.56 - 7.48 (m,1H),7.28 - 6.96 (m,2H),6.92 (d,1H),4.94 - 4.71 (m,1H),4.61 (s,2H),4.46 - 4.24 (m,6H),4.24 - 4.10 (m,1H),4.00 - 3.91 (m,1H),3.87 - 3.53 (m,3H),3.50 - 3.42 (m,2H),3.29 (s,3H),3.21 - 3.07 (m,1H),3.06 - 2.93 (m,1H),2.93 - 2.76 (m,1H),2.76 - 2.55 (m,3H),2.45 - 2.25 (m,2H),2.25 - 2.10 (m,4H),2.10 - 1.95 (m,2H),1.95 - 1.65 (m,6H),1.65 - 1.49 (m,1H),1.12 - 0.95 (m,2H).

[0333] LCMS m / z=900.5[M+1] + .

[0334] Kirara heterosexual body 2 retention time: 8.228min.

[0335] 1 H NMR (400MHz, DMSO-d6) δ 10.90 (s,1H),9.32 (s,1H),8.80 (d,1H),8.36 (s,1H),8.28 (s,1H),7.84 - 7.73 (m,1H),7.56 - 7.48 (m,1H),7.28 - 6.96 (m,2H),6.91 (d,1H),4.94 - 4.71 (m,1H),4.60 (s,2H),4.46 - 4.24 (m,6H),4.24 - 4.10 (m,1H),4.00 - 3.91 (m,1H),3.87 - 3.53 (m,3H),3.50 - 3.42 (m,2H),3.29 (s,3H),3.21 - 3.07 (m,1H),3.06 - 2.93 (m,1H),2.93 - 2.76 (m,1H),2.76 - 2.55 (m,3H),2.45 - 2.25 (m,2H),2.25 - 2.10 (m,4H),2.10 - 1.95 (m,2H),1.95 - 1.65 (m,6H),1.65 - 1.49 (m,1H),1.12 - 0.95 (m,2H).

[0336] LCMS m / z=900.4[M+1] + .

[0337] Example 24: Production of Compound 24 (Trans)

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[0338] The above crude intermediate 7 (0.12 g) was added to 5 mL of acetonitrile, the above crude intermediate 3 (0.07 g) and TCFH (0.084 g, 0.3 mmol) were added, NMI (0.08 g, 0.97 mmol) was added at 0° C., and the reaction was carried out at room temperature for 16 h. The reaction system was concentrated under reduced pressure, and the residue was subjected to chiral separation to obtain chiral isomer 1 (30.5 mg, 2-step yield from compound 3-A: 8%) and chiral isomer 2 (28 mg, 2-step yield from compound 3-A: 8%) of compound 24, respectively.

[0339] Chiral Separation Methods: Instrument and preparative column: Shimadzu LC-A HPLC preparative liquid chromatography was used, the preparative column model was Chiralpak IE, 250×30 mm, 10 μm, mobile phase system: acetonitrile / methanol, isocratic elution: acetonitrile / methanol=1:1, flow rate: 80 mL / min.

[0340] Analytical method for target compounds: Instrument: Shimadzu LC-20AB with PDA detector, Chromatography column: Chiralpak IE-3, Specifications: 150×4.6 mm ID, 3 μm, Mobile phase A: acetonitrile, Mobile phase B: methanol, Column temperature: 35°C, Flow rate: 1 mL / min, Wavelength: 220 nm, Elution procedure: Isocratic elution: mobile phase A:B=3:7; Retention time for chiral isomer 1: 5.434 min.

[0341] 1H NMR (400MHz, DMSO-d6) δ 10.89 (s,1H),9.34 (s,1H),8.81 (d,1H),8.36 (s,1H),8.29 (s,1H),7.79 (d,1H),7.52 (d,1H),7.27 - 6.94 (m,2H),6.89 (d,1H),4.93 - 4.72 (m,2H),4.61 (s,2H),4.52 - 4.10 (m,7H),4.03 - 3.92 (m,1H),3.87 - 3.70 (m,1H),3.67 - 3.46 (m,4H),3.20 - 3.06 (m,1H),3.05 - 2.93 (m,1H),2.93 - 2.76 (m,1H),2.75 - 2.56 (m,3H),2.44 - 2.30 (m,2H),2.25 - 2.10 (m,4H),2.09 - 1.95 (m,2H),1.95 - 1.66 (m,6H),1.65 - 1.50 (m,1H),1.12 - 0.95 (m,2H).

[0342] LCMS m / z=886.4[M+1] + .

[0343] Kirara heterosexual body 2 retention time: 6.706min.

[0344] 1H NMR (400MHz,DMSO-d6) δ 10.89 (s,1H),9.34 (s,1H),8.81 (d,1H),8.36 (s,1H),8.29 (s,1H),7.79 (d,1H),7.52 (d,1H),7.27 - 6.94 (m,2H),6.90 (d,1H),4.93 - 4.72 (m,2H),4.61 (s,2H),4.52 - 4.10 (m,7H),4.03 - 3.92 (m,1H),3.87 - 3.70 (m,1H),3.67 - 3.46 (m,4H),3.20 - 3.06 (m,1H),3.05 - 2.93 (m,1H),2.93 - 2.76 (m,1H),2.75 - 2.56 (m,3H),2.44 - 2.30 (m,2H),2.25 - 2.10 (m,4H),2.09 - 1.95 (m,2H),1.95 - 1.66 (m,6H),1.65 - 1.50 (m,1H),1.12 - 0.95 (m,2H).

[0345] LCMS m / z=886.4[M+1] + .

[0346] Example 25: Preparation of Compound 25 (Trans) [ka]

[0347] The above crude intermediate 7 (0.12 g) was added to 5 mL of acetonitrile, the above crude intermediate 5 (0.07 g) and TCFH (0.084 g, 0.3 mmol) were added, NMI (0.08 g, 0.97 mmol) was added at 0° C., and the reaction was carried out at room temperature for 16 h. The reaction system was concentrated under reduced pressure, and the residue was subjected to chiral separation to obtain chiral isomer 1 (25 mg, 2-step yield from compound 5-A: 19%) and chiral isomer 2 (26.4 mg, 2-step yield from compound 5-A: 20%) of compound 25, respectively.

[0348] Chiral Separation Methods: Instrument and preparative column: Shimadzu LC-A HPLC preparative liquid chromatography was used, the preparative column model was Chiralpak IE, 250×30 mm, 10 μm, mobile phase system: acetonitrile / methanol, isocratic elution: acetonitrile / methanol=1:1, flow rate: 80 mL / min.

[0349] Analytical method for target compounds: Instrument: Shimadzu LC-20AB with PDA detector, Chromatography column: Chiralpak IE-3, Specifications: 150×4.6 mm ID, 3 μm, Mobile phase A: acetonitrile, Mobile phase B: methanol, Column temperature: 35°C, Flow rate: 1 mL / min, Wavelength: 220 nm, Elution procedure: Isocratic elution: mobile phase A:B=3:7; Retention time for chiral isomer 1: 5.364 min.

[0350] 1 H NMR (400MHz,DMSO-d6) δ 10.89 (s,1H),9.34 (s,1H),8.81 (d,1H),8.36 (s,1H),8.28 (s,1H),7.79 (d,1H),7.52 (d,1H),7.27 - 6.94 (m,2H),6.90 (d,1H),4.93 - 4.72 (m,2H),4.61 (s,2H),4.52 - 4.10 (m,7H),4.03 - 3.92 (m,1H),3.87 - 3.70 (m,1H),3.67 - 3.46 (m,4H),3.20 - 3.06 (m,1H),3.05 - 2.93 (m,1H),2.93 - 2.76 (m,1H),2.75 - 2.56 (m,3H),2.44 - 2.30 (m,2H),2.25 - 2.10 (m,4H),2.09 - 1.95 (m,2H),1.95 - 1.66 (m,6H),1.65 - 1.50 (m,1H),1.12 - 0.94 (m,2H).

[0351] LCMS m / z=886.4[M+1] + .

[0352] Kirara heterosexual body 2 retention time: 6.619min.

[0353] 1 H NMR (400MHz, DMSO-d6) δ 10.89 (s,1H),9.34 (s,1H),8.81 (d,1H),8.36 (s,1H),8.29 (s,1H),7.79 (d,1H),7.52 (d,1H),7.27 - 6.94 (m,2H),6.90 (d,1H),4.93 - 4.72 (m,2H),4.60 (s,2H),4.52 - 4.10 (m,7H),4.03 - 3.92 (m,1H),3.87 - 3.70 (m,1H),3.67 - 3.46 (m,4H),3.20 - 3.06 (m,1H),3.05 - 2.93 (m,1H),2.93 - 2.76 (m,1H),2.75 - 2.56 (m,3H),2.44 - 2.30 (m,2H),2.25 - 2.10 (m,4H),2.09 - 1.95 (m,2H),1.95 - 1.66 (m,6H),1.65 - 1.50 (m,1H),1.12 - 0.94 (m,2H).

[0354] LCMS m / z=886.4[M+1] + .

[0355] Example 26: Synthesis of Compound 26 (Trans)

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[0356] The above crude intermediate 7 (0.12 g) was added to 5 mL of acetonitrile, the above crude intermediate 4 (0.073 g) and TCFH (0.084 g, 0.3 mmol) were added, NMI (0.08 g, 0.97 mmol) was added at 0° C., and the reaction was carried out at room temperature for 16 h. The reaction system was concentrated under reduced pressure, and the residue was subjected to chiral separation to obtain chiral isomer 1 (25.2 mg, 2-step yield from compound 4-C: 12%) and chiral isomer 2 (18.9 mg, 2-step yield from compound 4-C: 9%) of compound 26, respectively.

[0357] Chiral Separation Methods: Instrument and preparative column: Shimadzu LC-A HPLC preparative liquid chromatography was used, the preparative column model was Chiralpak IE, 250×30 mm, 10 μm, mobile phase system: acetonitrile / methanol, isocratic elution: acetonitrile / methanol=1:1, flow rate: 80 mL / min.

[0358] Analytical method for target compounds: Instrument: Shimadzu LC-20AB with PDA detector, Chromatography column: Chiralpak IE-3, Specifications: 150×4.6mm ID, 3μm, Mobile phase A: acetonitrile, Mobile phase B: methanol, Column temperature: 35℃, Flow rate: 1mL / min, Wavelength: 220nm, Elution procedure: Isocratic elution: Mobile phase A:B=3:7, Retention time for chiral isomer 1: 6.733 min.

[0359] 1H NMR (400MHz, DMSO-d6) δ 10.90 (s,1H),9.33 (s,1H),8.81 (d,1H),8.37 (s,1H),8.29 (s,1H),7.84 - 7.73 (m,1H),7.56 - 7.48 (m,1H),7.28 - 6.96 (m,2H),6.92 (d,1H),4.94 - 4.71 (m,1H),4.61 (s,2H),4.46 - 4.24 (m,6H),4.24 - 4.10 (m,1H),4.00 - 3.91 (m,1H),3.87 - 3.53 (m,3H),3.50 - 3.42 (m,2H),3.29 (s,3H),3.21 - 3.07 (m,1H),3.06 - 2.93 (m,1H),2.93 - 2.76 (m,1H),2.76 - 2.55 (m,3H),2.45 - 2.25 (m,2H),2.25 - 2.10 (m,4H),2.10 - 1.95 (m,2H),1.95 - 1.65 (m,6H),1.65 - 1.49 (m,1H),1.12 - 0.95 (m,2H).

[0360] LCMS m / z=900.4[M+1] + .

[0361] Kirara heterosexual body 2 retention time: 8.385min.

[0362] 1H NMR (400MHz, DMSO-d6) δ 10.89 (s,1H),9.32 (s,1H),8.81 (d,1H),8.37 (s,1H),8.29 (s,1H),7.84 - 7.73 (m,1H),7.56 - 7.48 (m,1H),7.28 - 6.96 (m,2H),6.91 (d,1H),4.94 - 4.71 (m,1H),4.60 (s,2H),4.46 - 4.24 (m,6H),4.24 - 4.10 (m,1H),4.00 - 3.91 (m,1H),3.87 - 3.53 (m,3H),3.50 - 3.42 (m,2H),3.30 (s,3H),3.21 - 3.07 (m,1H),3.06 - 2.93 (m,1H),2.93 - 2.76 (m,1H),2.76 - 2.55 (m,3H),2.45 - 2.25 (m,2H),2.25 - 2.10 (m,4H),2.10 - 1.95 (m,2H),1.95 - 1.65 (m,6H),1.65 - 1.49 (m,1H),1.12 - 0.95 (m,2H).

[0363] LCMS m / z=900.5[M+1] + .

[0364] Example 27: Production of Compound 27 (Trans)

change

[0365] Made by ステップ1:27a 16e (600mg, 1.52mmol), 10b (470mg, 1.83mmol), CuI (58mg, 0.30mmol), PdCl2(PPh3)2 (110mg, 0.157mmol) and TEA (0.77g, 7.61mmol) were dissolved in 20mL of DMF, purged with nitrogen gas three times, and reacted at 60℃ for 5h. The reaction system was cooled to room temperature, 80mL of water was added, extracted with 100mL of ethyl acetate, the organic phase was washed with 50mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel chromatography column (dichloromethane / ethyl acetate (v / v)=1:1) to obtain 27a (550mg, yield: 69%).

[0366] Step 2: Preparation of the trifluoroacetate salt of 27b

[0367] 27a (500 mg, 0.95 mmol) was dissolved in 10 mL of dichloromethane, 4 mL of trifluoroacetic acid was added, and the mixture was reacted at room temperature for 2 h. The reaction system was concentrated under reduced pressure to give crude trifluoroacetate salt of 27b (0.65 g).

[0368] LCMS m / z=425.2[M+1] + .

[0369] Step 3: Synthesis of compound 27 The trifluoroacetate salt (650 mg) of the crude product 27b was dissolved in 20 mL of DMA, and sodium bicarbonate (160 mg, 1.90 mmol) was added. After stirring at room temperature for 15 min, 6H (560 mg, 1.16 mmol), 0.15 mL of acetic acid, and 4 Å molecular sieves (2 g) were added. After stirring at room temperature for 2 h, sodium triacetoxyborohydride (410 mg, 1.93 mmol) was added and the mixture was allowed to react at room temperature for 16 h. To the reaction system, 40 mL of saturated aqueous sodium hydrogen carbonate solution and 20 mL of dichloromethane were added, the liquids were separated, the organic phase was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (dichloromethane / methanol (v / v) = 100:1 to 20:1). The obtained crude product was subjected to chiral separation to obtain chiral isomer 1 (270 mg, yield: 26%) and chiral isomer 2 (200 mg, yield: 19%) of compound 27, respectively.

[0370] Chiral Separation Methods: Instrument and preparative column: Shimadzu LC-A HPLC preparative liquid chromatography was used, the preparative column model was Chiralpak IE, 250×30 mm, 10 μm, mobile phase system: acetonitrile / methanol, isocratic elution: acetonitrile / methanol=1:1, flow rate: 80 mL / min.

[0371] Analytical method for target compounds: Instrument: Shimadzu LC-20AB with PDA detector, Chromatography column: Chiralpak IE-3, Specifications: 150×4.6 mm ID, 3 μm, Mobile phase A: acetonitrile, Mobile phase B: methanol, Column temperature: 35°C, Flow rate: 1 mL / min, Wavelength: 220 nm, Elution procedure: Isocratic elution: mobile phase A:B=3:7; Retention time for chiral isomer 1: 5.139 min.

[0372] 1H NMR (400MHz, DMSO-d6) δ 10.88 (s,1H),9.49 (d,1H),8.77 (d,1H),8.38 (d,1H),8.25 (d,1H),7.76 (d,1H),7.53 (d,1H),7.28 - 6.93 (m,2H),6.90 - 6.40 (m,1H),5.35 - 5.02 (m,1H),4.95 - 4.70 (m,2H),4.59 (s,2H),4.43 - 4.32 (m,1H),4.24 - 4.02 (m,2H),3.88 - 3.40 (m,5H),2.95 - 2.54 (m,4H),2.45 - 1.45 (m,17H),1.27 - 0.94 (m,6H).

[0373] LCMS m / z=894.5[M+1] + .

[0374] Kirara heterosexual body 2 retention time: 5.982min.

[0375] 1 H NMR (400MHz, DMSO-d6) δ 10.88 (s,1H),9.49 (d,1H),8.77 (d,1H),8.38 (d,1H),8.25 (d,1H),7.76 (d,1H),7.53 (d,1H),7.28 - 6.93 (m,2H),6.90 - 6.40 (m,1H),5.35 - 5.02 (m,1H),4.95 - 4.70 (m,2H),4.59 (s,2H),4.43 - 4.32 (m,1H),4.24 - 4.02 (m,2H),3.88 - 3.40 (m,5H),2.95 - 2.54 (m,4H),2.45 - 1.45 (m,17H),1.27 - 0.94 (m,6H).

[0376] LCMS m / z=894.5[M+1] + .

[0377] Example 28: Production of Compound 28 (Trans)

change

[0378] Using (3R,4S)-tert-butyl 3-fluoro-4-(propan-2-yn-1-yloxy)piperidine-1-carboxylate + 16e as a starting material, compound 28 was obtained according to the synthesis method of Example 27.

[0379] Purification method: The crude product was separated and purified using a silica gel chromatography column (dichloromethane / methanol (v / v) = 100:1 to 20:1), and the obtained crude product was subjected to chiral separation to obtain chiral isomer 1 (290 mg, yield: 24%) and chiral isomer 2 (250 mg, yield: 21%) of compound 28, respectively.

[0380] Chiral Separation Methods: Instrument and preparative column: Shimadzu LC-A HPLC preparative liquid chromatography was used, the preparative column model was Chiralpak IE, 250×30 mm, 10 μm, mobile phase system: acetonitrile / methanol, isocratic elution: acetonitrile / methanol=1:1, flow rate: 80 mL / min.

[0381] Analytical method for target compounds: Instrument: Shimadzu LC-20AB with PDA detector, Chromatography column: Chiralpak IE-3, Specifications: 150×4.6 mm ID, 3 μm, Mobile phase A: acetonitrile, Mobile phase B: methanol, Column temperature: 35°C, Flow rate: 1 mL / min, Wavelength: 220 nm, Elution procedure: Isocratic elution: mobile phase A:B=3:7; Retention time for chiral isomer 1: 5.277 min.

[0382] 1H NMR (400MHz, DMSO-d6) δ 10.88 (s,1H),9.49 (d,1H),8.77 (d,1H),8.38 (d,1H),8.25 (d,1H),7.76 (d,1H),7.53 (d,1H),7.28 - 6.93 (m,2H),6.90 - 6.40 (m,1H),5.35 - 5.02 (m,1H),4.95 - 4.70 (m,2H),4.59 (s,2H),4.43 - 4.32 (m,1H),4.24 - 4.02 (m,2H),3.88 - 3.40 (m,5H),2.95 - 2.54 (m,4H),2.45 - 1.45 (m,17H),1.27 - 0.94 (m,6H).

[0383] LCMS m / z=447.9[M / 2 +1] + .

[0384] Kirara heterosexual body 2 retention time: 6.017min.

[0385] 1 H NMR (400MHz, DMSO-d6) δ 10.89 (s,1H),9.50 (d,1H),8.78 (d,1H),8.38 (d,1H),8.26 (d,1H),7.76 (d,1H),7.53 (d,1H),7.28 - 6.93 (m,2H),6.90 - 6.40 (m,1H),5.35 - 5.02 (m,1H),4.95 - 4.70 (m,2H),4.59 (s,2H),4.43 - 4.32 (m,1H),4.24 - 4.02 (m,2H),3.88 - 3.40 (m,5H),2.95 - 2.54 (m,4H),2.45 - 1.45 (m,17H),1.27 - 0.94 (m,6H).

[0386] LCMS m / z=894.5[M+1] + .

[0387] Biological Experiments Test Example 1: Study on the decomposition activity of IRAK4 in hPBMC cells (24 hours) hPBMC cells are human peripheral blood mononuclear cells. Peripheral venous blood was collected from healthy volunteers, and hPBMCs were isolated using Ficoll density gradient centrifugation (Ficoll-PaqueTM PLUS 1.077, GE, Cat. 17-1140-02). Culture conditions: RPMI-1640 + 10% FBS + 1% double antibody were cultured in an incubator at 37°C and 5% CO2. Cells were cultured at 1 × 10 6 The cells were seeded in a 24-well plate at 1000 / well. After seeding, different concentrations of compounds were added and cultured in an incubator at 37°C and 5% CO2 for 24 hours. After the culture was completed, the cells were collected, RIPA lysis solution (beyotime, Cat. P0013B) was added, and the cells were lysed on ice for 20 minutes, then centrifuged at 12000 rpm and 4°C for 10 minutes. The supernatant protein sample was collected, and protein quantification was performed with a BCA kit (Beyotime, Cat. P0009), after which the protein was diluted to 1 mg / mL. The expression of IRAK4 (CST, Cat. 4363S) and the internal standard cofilin (CST, Cat. 5175S) was detected using a fully automated Western blot quantitative analyzer (Proteinsimple). The expression amount of IRAK4 relative to the internal standard was calculated using compass software. The remaining amount of IRAK4 protein IRAK4% at different doses relative to the vehicle control group was calculated according to formula (1), and the degradation amount of IRAK4 protein at different doses relative to the vehicle control group was calculated according to formula (2), where IRAK4 投与 is the expression level of IRAK4 in the different dose groups, and IRAK4 ビヒクル The IRAK4 degradation-drug concentration curve was fitted using Graphpad Prism 8 software, and DC 50 was calculated.

number

number

[0388] [Table 3]

[0389] [Table 4]

[0390] Conclusion: The compounds of the present invention have a certain degrading effect on IRAK4 protein in hPBMC cells at 24 h.

[0391] Test Example 2: Pharmacokinetics test in mice Test animals: male ICR mice, ~25g, 6 mice / compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0392] Experimental design: On the day of the experiment, six ICR mice were randomly divided into groups according to weight. One day before administration, they were fasted for 12-14 h without water prohibition, and fed 4 h after administration.

[0393] [Table 5]

[0394] Vehicle for intravenous administration: 5% DMA + 5% Solutol + 90% Saline, Vehicle for intragastric administration: 5% DMSO + 30% PEG400 + 65% (20% SBE-CD), (DMSO: dimethyl sulfoxide, DMA: dimethylacetamide, Solutol: polyethylene glycol-15-hydroxyhydroxystearate, PEG400: polyethylene glycol 400, SBE-β-CD: sulfobutyl-β-cyclodextrin, Saline: physiological saline,)

[0395] Before and after administration, 0.15 mL of blood was collected from the orbit under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, and centrifuged at 5000 rpm at 4°C for 10 min to collect plasma. Blood was collected at 0, 5, 15, 30 min, 1, 2, 4, 7, and 24 h for intravenous and intragastric administration. All samples were stored at -60°C before analytical detection. Quantitative analysis of the samples was performed using LC-MS / MS.

[0396] [Table 6]

[0397] Conclusion: The compounds of the present invention have good oral absorbability in mice.

[0398] Test Example 3. hERG potassium ion channel activity test Experimental platform: electrophysiological manual patch clamp system Cell line: Chinese hamster ovary (CHO) cell line stably expressing the hERG potassium ion channel Experimental Method: hERG potassium channel currents were recorded using the whole-cell patch clamp technique at room temperature in CHO (Chinese Hamster Ovary) cells stably expressing the hERG potassium channel. Glass microelectrodes were prepared by pulling glass electrode blanks with a (BF150-86-10, Sutter) puller. The tip resistance after filling with the electrode internal solution was approximately 2-5 MΩ, and the glass microelectrode was inserted into the amplifier probe to be connected to a patch clamp amplifier. Clamping voltage and data recording were recorded under computer control with pClamp 10 software, the sampling frequency was 10 kHz, and the filter frequency was 2 kHz. After obtaining whole-cell recordings, the cells were clamped to -80 mV, and the hERG potassium current (I hERGFor the step voltage to induce hERG, the depolarizing voltage was applied from -80 mV to +20 mV for 2 s, then repolarized to -50 mV and sustained for 1 s before returning to -80 mV. This voltage was applied every 10 s, and the hERG potassium current was confirmed to be stable (for at least 1 min) before starting the dosing process. Compounds were applied for at least 1 min per test concentration, and at least two cells were tested for each concentration (n ≥ 2).

[0399] Data processing: Data analysis and processing were carried out using pClamp 10, GraphPad Prism 5 and Excel software. The inhibition degree of different compound concentrations on hERG potassium current (hERG tail current peak evoked at -50 mV) was calculated by the following formula:

[0400] Inhibition %=[1-(I / Io)]×100% Here, Inhibition% represents the percentage of inhibition of the hERG potassium current by the compound, and I and Io represent the amplitude of the hERG potassium current after administration and before administration, respectively.

[0401] Compound IC 50 was calculated by fitting the following equation using GraphPad Prism 5 software:

[0402] Y=Bottom +(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope)) where X is the Log value of the detected concentration of the analyte, Y is the percentage inhibition at the corresponding concentration, and Bottom and Top are the minimum and maximum percentage inhibition, respectively.

[0403] [Table 7]

[0404] Conclusion: The compounds of the present invention have no obvious inhibitory effect on the hERG potassium channel.

[0405] The structure of control compound 1 is as follows, and its synthesis is described in patent WO 2020113233A1. [ka]

[0406] Test Example 4: Pharmacokinetics test in rats Test animals: male SD rats, approximately 200 g, 6-8 weeks old, 6 rats / compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0407] Experimental design: On the day of the experiment, six SD rats were randomly divided into groups according to their weight. They were fasted for 12-14 h without water restriction one day before administration, and fed 4 h after administration.

[0408] [Table 8]

[0409] Vehicle for intravenous administration: 5% DMA + 5% Solutol + 90% Saline, Vehicle for intragastric administration: 5% DMSO + 30% PEG400 + 65% (20% SBE-CD), (DMSO: dimethyl sulfoxide, DMA: dimethylacetamide, Solutol: polyethylene glycol-15-hydroxyhydroxystearate, PEG400: polyethylene glycol 400, SBE-β-CD: sulfobutyl-β-cyclodextrin, Saline: physiological saline,)

[0410] Before and after administration, 0.15 mL of blood was collected from the orbit under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, and centrifuged at 6000 rpm at 4°C for 5 min to collect plasma. Blood was collected at 0, 5, 15, 30 min, 1, 2, 4, 6, 8, and 24 h after intravenous and intragastric administration. All samples were stored at -60°C before analytical detection. Quantitative analysis of the samples was performed using LC-MS / MS.

[0411] Conclusion: The compound of the present invention has good oral absorbability in rats.

[0412] Test Example 5: Pharmacokinetic study in beagle dogs Test animals: male beagle dogs, approximately 8-11 kg, 6 animals / compound, purchased from Beijing Masu Biotechnology Co., Ltd.

[0413] Test method: On the day of the test, six beagle dogs were randomly divided into groups according to weight. They were fasted for 14-18 hours without water restriction one day before administration, and were fed 4 hours after administration.

[0414] [Table 9]

[0415] Vehicle for intravenous administration: 10% DMA + 5% Solutol + 85% Saline, Vehicle for intragastric administration: 5% DMSO + 30% PEG400 + 65% (20% SBE-CD),

[0416] Before and after administration, 1 mL of blood was collected from the jugular vein or limb vein, placed in an EDTAK2 centrifuge tube, and centrifuged at 5000 rpm at 4°C for 10 min to collect plasma. Blood was collected at 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, and 24 h for intravenous and intragastric administration. All samples were stored at -60°C before analytical detection. Quantitative analysis of the samples was performed by LC-MS / MS.

[0417] Conclusion: The compound of the present invention has good oral absorbability in dogs.

[0418] Test Example 6: Pharmacokinetic study in monkeys Test animals: male cynomolgus monkeys, approximately 3-5 kg, 3-6 years old, 6 animals / compound. Purchased from Suzhou Xishan Biotechnology Co., Ltd.

[0419] Test method: On the day of the test, six monkeys were randomly divided into groups according to their weight. They were fasted for 14 to 18 hours without water restriction one day before administration, and were fed 4 hours after administration.

[0420] [Table 10]

[0421] Vehicle for intravenous administration: 10% DMA + 5% Solutol + 85% Saline, Vehicle for intragastric administration: 5% DMSO + 30% PEG400 + 65% (20% SBE-CD),

[0422] Before and after administration, 1 mL of blood was collected from the vein of each limb, placed in an EDTAK2 centrifuge tube, and centrifuged at 5000 rpm at 4°C for 10 min to collect plasma. Blood was collected at 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, and 24 h for intravenous and intragastric administration. All samples were stored at -60°C before analytical detection. Quantitative analysis of the samples was performed using LC-MS / MS.

[0423] Conclusion: The compound of the present invention has good oral absorbability in monkeys.

[0424] Test Example 7: Liver microsome stability test This study used liver microsomes from five genera, namely human, monkey, dog, rat and mouse, as an in vitro model to evaluate the metabolic stability of the test substance.

[0425] Under the condition of 37℃, 1μM of the test substance was incubated with microsomal protein and coenzyme NADPH, and reacted for a certain time (5, 10, 20, 30, 60 min). The reaction was stopped by adding cold acetonitrile containing an internal standard. The concentration of the test substance in the sample was detected by LC-MS / MS method, and T was calculated from the ln value of the drug residual rate in the incubation system and the incubation time. 1 / 2 The hepatic microsomal specific clearance CL was calculated. int(mic) and liver specific clearance CL int(Liver) was further calculated.

[0426] Conclusion: The compounds of the present invention have good liver microsomal stability.

[0427] Test Example 8: CYP450 Enzyme Inhibition Test The purpose of this study is to evaluate the effects of test substances on the activity of five types of cytochrome P450 (CYP) isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) in human liver microsomes using an in vitro test system. Specific probe substrates for CYP450 isoenzymes were incubated with human liver microsomes and different concentrations of test substances, and reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to start the reaction. After the reaction was completed, the metabolites generated by the specific substrates were quantitatively detected by treating the samples and using liquid chromatography-tandem mass spectrometry (LC-MS / MS) to measure the changes in the activity of CYP enzymes and obtain IC. 50 Values ​​were calculated to assess the potential inhibitory potential of the test substances against each CYP enzyme subtype.

[0428] Conclusion: The compounds of the present invention have no obvious inhibitory effects on CYP450 enzyme subtypes.

[0429] Test Example 9: Caco2 permeability test The test was carried out with monolayers of Caco-2 cells incubated in triplicate in a 96-well Transwell plate. Transport buffer solution (HBSS, 10 mM HEPES, pH 7.4±0.05) containing the compounds of the invention (2 μM) or the control compounds digoxin (10 μM), nadolol (2 μM) and metoprolol (2 μM) was placed in the apical or basal dosing wells. The corresponding receiving wells were filled with transport buffer solution containing DMSO. After 2 hours of incubation at 37±1° C., the cell plate was removed and appropriate samples were taken from the apical and basal wells and placed in a new 96-well plate. Then, acetonitrile containing an internal standard was added to precipitate the proteins. The samples were analyzed by LC MS / MS to measure the concentrations of the compounds of the invention and the control compounds. The concentration data were used to calculate the efflux rates by calculating the apparent permeability coefficients of transport from the apical to the basal side and from the basal to the apical side of the monolayer cells. The integrity of the cell monolayer after 2 h of incubation was assessed by leakage of fluorescein.

[0430] Conclusion: The compounds of the present invention have good CaCO2 permeability.

[0431] Test Example 10: Study of the degradative activity of Ikaros in hPBMC cells (24 hours) hPBMC cells are human peripheral blood mononuclear cells. Peripheral venous blood was collected from healthy volunteers, and hPBMCs were isolated using Ficoll density gradient centrifugation (Ficoll-PaqueTM PLUS 1.077, GE, Cat. 17-1140-02). Culture conditions: RPMI-1640 + 10% FBS + 1% double antibody were cultured in an incubator at 37°C and 5% CO2. Cells were cultured at 1 × 10 6The cells were seeded in a 24-well plate at 1000 cells / well. After seeding, different concentrations of compounds were added and the cells were cultured in an incubator at 37°C and 5% CO2 for 24 hours. After the culture was completed, the cells were collected, RIPA lysis solution (beyotime, Cat. P0013B) was added, and the cells were lysed on ice for 20 minutes, then centrifuged at 12000 rpm and 4°C for 10 minutes. The supernatant protein sample was collected, and protein quantification was performed with a BCA kit (Beyotime, Cat. P0009), after which the protein was diluted to 1 mg / mL. The expression of Ikaros (CST, Cat. #14859S) and the internal standard β-actin (CST, Cat. #4970S) was detected using a fully automated Western blot quantitative analyzer (Proteinsimple). The expression amount of Ikaros relative to the internal standard was calculated using compass software. The remaining amount of Ikaros protein relative to the vehicle control group at different doses was calculated using equation (3), and the amount of Ikaros protein decomposition relative to the vehicle control group at different doses was calculated using equation (4), and the maximum degradation rate (Dmax) of the drug relative to the Ikaros protein was obtained.

number

number

[0432] Conclusion: The compounds of the present invention have no obvious degradative effect on Ikaros protein in hPBMC cells.

[0433] Test Example 11: Study of the decomposition activity of Aiolos in hPBMC cells (24 hours) hPBMC cells are human peripheral blood mononuclear cells. Peripheral venous blood was collected from healthy volunteers, and hPBMCs were isolated using Ficoll density gradient centrifugation (Ficoll-PaqueTM PLUS 1.077, GE, Cat. 17-1140-02). Culture conditions: RPMI-1640 + 10% FBS + 1% double antibody were cultured in an incubator at 37°C and 5% CO2. Cells were cultured at 1 × 10 6The cells were seeded in a 24-well plate at 1000 / well. After seeding, different concentrations of compounds were added and the cells were cultured in an incubator at 37°C and 5% CO2 for 24 hours. After the culture was completed, the cells were collected, RIPA lysis solution (beyotime, Cat. P0013B) was added, and the cells were lysed on ice for 20 minutes, then centrifuged at 12000 rpm and 4°C for 10 minutes. The supernatant protein sample was collected, and protein quantification was performed with a BCA kit (Beyotime, Cat. P0009), after which the protein was diluted to 1 mg / mL. The expression of Aiolos (CST, Cat. #15103) and the internal standard β-actin (CST, Cat. 5175S) was detected using a fully automated Western blot quantitative analyzer (Proteinsimple). The expression amount of Aiolos relative to the internal standard was calculated using compass software. The remaining amount of Aiolos protein relative to the vehicle control group at different doses was calculated using equation (5), and the amount of Aiolos protein decomposition relative to the vehicle control group at different doses was calculated using equation (6), and the maximum degradation rate (Dmax) of the drug relative to Aiolos protein was obtained.

number

number

[0434] Conclusion: The compounds of the present invention have no obvious degradative effect on Aiolos protein in hPBMC cells.

[0435] Test Example 12: Study of IRAK4 decomposition activity in hPBMC cells (4 hours) hPBMC cells are human peripheral blood mononuclear cells. Peripheral venous blood was collected from healthy volunteers, and hPBMCs were isolated using Ficoll density gradient centrifugation (Ficoll-PaqueTM PLUS 1.077, GE, Cat. 17-1140-02). Culture conditions: RPMI-1640 + 10% FBS + 1% double antibody were cultured in an incubator at 37°C and 5% CO2. Cells were cultured at 1 × 10 6The cells were seeded in a 24-well plate at 1000 / well. After seeding, different concentrations of compounds were added and cultured in an incubator at 37°C and 5% CO2 for 4 hours. After the culture was completed, the cells were collected, RIPA lysis solution (beyotime, Cat. P0013B) was added, and the cells were lysed on ice for 20 minutes, then centrifuged at 12000 rpm and 4°C for 10 minutes. The supernatant protein sample was collected, and protein quantification was performed with a BCA kit (Beyotime, Cat. P0009), after which the protein was diluted to 1 mg / mL. The expression of IRAK4 (CST, Cat. 4363S) and the internal standard cofilin (CST, Cat. 5175S) was detected using a fully automated Western blot quantitative analyzer (Proteinsimple). The expression amount of IRAK4 relative to the internal standard was calculated using compass software. The remaining amount of IRAK4 protein at different doses relative to the vehicle control group was calculated according to formula (7), and the decomposition amount of IRAK4 protein at different doses relative to the vehicle control group was calculated according to formula (8), where IRAK4 化合物 is the expression level of IRAK4 in the different dose groups, and IRAK4 ビヒクル The IRAK4 degradation-drug concentration curve was fitted using Graphpad Prism 8 software, and DC 50 was calculated.

number

number

[0436] Conclusion: The compounds of the present invention have a certain degrading effect on IRAK4 protein in hPBMC cells at 4 h.

Claims

1. A compound or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharma- ceutically acceptable salt or co-crystal thereof, the compound having the general formula (I): B-L-K (I) The compound is selected from the compounds shown in L is selected from: -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-; Ak1, Ak2, Ak3, Ak4 and Ak5 each independently represent -(CH ２ ) ｑ -, O, -(CH ２ ) ｑ N.R. Ｌ -, N.R. Ｌ C=O, C=ONR Ｌ , C=O, -R Ｌ C=CR Ｌ -, C≡C or a bond; R Ｌ is H or C １－６ alkyl groups, Cy1, Cy2, Cy3, and Cy4 are each independently selected from a bond, a 4- to 7-membered heteromonocyclic ring, a 4- to 10-membered heterofused ring, a 5- to 12-membered heterospirocyclic ring, a 7- to 10-membered heterobridged ring, a 3- to 7-membered monocycloalkyl group, a 4- to 10-membered fused cycloalkyl group, a 5- to 12-membered spirocycloalkyl group, a 7- to 10-membered bridged cycloalkyl group, a 5- to 10-membered heteroaryl group, or a 6- to 10-membered aryl group, and the aryl group, heteroaryl group, cycloalkyl group, heteromonocyclic ring, heterofused ring, heterospirocyclic ring, or heterobridged ring is optionally selected from H, F, Cl, Br, I, OH, C(═O)OH, CN, NH ２ , =O, C １－４ Alkyl group, halogen-substituted C １－４ C substituted with alkyl or hydroxyl groups １－４ Alkyl group or C １－４ wherein the heteroaryl group, the heteromonocyclic ring, the heterofused ring, the heterospirocyclic ring or the heterobridged ring contains 1 to 4 heteroatoms selected from O, S or N; B is, 【Chemistry 1】 is selected from B1 and B3 are each independently C ６－１０ an aryl group, a 5- to 10-membered heteroaryl group, or a 4- to 10-membered heterocyclic group, said heteroaryl group or heterocyclic group containing 1 to 4 heteroatoms selected from O, S or N; R ｂ１ , R ｂ７ are each independently H, F, Cl, Br, I, ═O, OH, or NH ２ , C.N., C.F. ３ , C(=O)OH, CHF ２ , C １－４ Alkyl group, C １－４ Alkoxy group, C ３－６ Cycloalkyl groups, -(CH ２ ) ｎ -R ｂ２１ , -OR ｂ２１ , -N(R ｂ２１ ) ２ , C ６－１０ aryl group, a 5- to 10-membered heteroaryl group, or a 4- to 10-membered heterocyclic group, wherein the alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group, or heteroaryl group is optionally selected from H, F, Cl, Br, I, OH, ═O, —N(R ｂ２１ ) ２ , C.N., C.F. ３ ,C(=O)OH,C １－４ Alkyl group, C １－４ Alkoxy group, C ３－６ A cycloalkyl group, a 5- to 10-membered heteroaryl group, a 4- to 10-membered heterocyclic group, or R ｂ７ａ wherein the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S or N; R ｂ７ａ is C １－４ Alkyl group, -C ３－６ Cycloalkyl group, 4- to 10-membered heterocyclic group, -C １－４ Alkylene-C ３－６ Cycloalkyl group, -C １－４ alkylene-4 to 10 membered heterocyclic group, —O—C ３－６ Cycloalkyl group, -O-4 to 10 membered heterocyclic group, -NH-C ３－６ Cycloalkyl group, -NH-4 to 10 membered heterocyclic group, -N(C １－４ Alkyl)-C ３－６ Cycloalkyl group or -N(C １－４ alkyl)-4 to 10 membered heterocyclic group, ｂ７ａ is optionally H, F, Cl, Br, I, OH, ═O, —N(R ｂ２１ ) ２ , C.N., C.F. ３ ,C(=O)OH,C １－４ Alkyl group, C １－４ Alkoxy group, C ３－６ substituted with 1 to 4 substituents selected from a cycloalkyl group or a 4- to 10-membered heterocyclic group, said heterocyclic group containing 1 to 4 heteroatoms selected from O, S or N; R ｂ２ , R ｂ６ are each independently H, F, Cl, Br, I, ═O, OH, or —C(═O)N(R ｂ２１ ) ２、 -N(R ｂ２１ ) ２、 C.N., C.F. ３ , C(=O)OH, CHF ２ , C １－４ Alkyl group, C １－４ Alkoxy group, C ３－６ Cycloalkyl groups, -(CH ２ ) ｎ -R ｂ２１ , -OR ｂ２１ , C ６－１０ aryl, 5- to 10-membered heteroaryl or 4- to 10-membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl, aryl, heteroaryl or heterocyclic group is optionally selected from H, F, Cl, Br, I, OH, ═O, NH ２ , C.N., C.F. ３ ,C(=O)OH,C １－４ Alkyl group, C １－４ Alkoxy group, C ３－６ is further substituted with 0-4 substituents selected from a cycloalkyl group, a 5-10 membered heteroaryl group, or a 4-10 membered heterocyclic group, said heteroaryl group or heterocyclic group containing 1-4 heteroatoms selected from O, S or N; R ｂ２１ are each independently H, C １－６ Alkyl group, C １－４ Alkoxy group, C ３－６ Cycloalkyl group, C ６－１０ aryl, 5- to 10-membered heteroaryl or 4- to 10-membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl, aryl, heteroaryl or heterocyclic group is optionally selected from H, F, Cl, Br, I, OH, ═O, NH ２ , C.N., C.F. ３ ,C(=O)OH,C １－４ Alkyl group, C ３－６ Cycloalkyl group or C １－４ and wherein the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S or N; n is selected from 0, 1, 2, 3 or 4; K. 【Chemistry 2】 is selected from R ｋ１ are each independently H, C １－４ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－６ cycloalkyl group or 3-6 membered heterocycloalkyl group, said alkyl group, cycloalkyl group or heterocycloalkyl group being optionally selected from H, F, Cl, Br, I, OH, NH ２ , C.N., C.F. ３ , C １－６ Alkyl group, C １－６ Alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group or C ３－６ is further substituted with 0 to 4 substituents selected from cycloalkyl groups; R ｋ２ , R ｋ３ are each independently H, F, Cl, Br, I, OH, ═O, or NH ２ , C.F. ３ , CN, C(=O)OH, C(=O)NH ２ , C １－４ Alkyl group or C １－４ alkoxy groups, said alkyl or alkoxy groups being optionally selected from H, F, Cl, Br, I, OH, NH ２ is further substituted with 0 to 4 substituents selected from Or two R ｋ３ together with the carbon atoms or ring skeleton directly connected thereto, form a 3- to 6-membered carbocyclic ring or a 3- to 7-membered heterocyclic ring, said carbocyclic ring or heterocyclic ring optionally being selected from the group consisting of H, F, Cl, Br, I, OH, ═O, NH ２ , CN, C(=O)OH, C(=O)NH ２ , C １－４ Alkyl group or C １－４ and wherein the heterocycle contains 1 to 4 heteroatoms selected from O, S, or N; q is selected from 0, 1, 2, 3 or 4; n1, n2, and n6 are each independently selected from 0, 1, 2, or 3; p2 and p3 are each independently selected from 0, 1, 2, 3, or 4; Optionally, 0-50 H in the compound represented by general formula (I) are replaced with 0-50 D, or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharma- ceutically acceptable salt, or co-crystal thereof.

2. Cy1, Cy2, Cy3 and Cy4 are each independently selected from a bond, a 4-7 membered nitrogen-containing heteromonocycle, a 4-10 membered nitrogen-containing heterofused ring, a 5-12 membered nitrogen-containing heterospirocycle, a 7-10 membered nitrogen-containing heterobridged ring, a 3-7 membered monocycloalkyl group, a 4-10 membered fused cycloalkyl group, a 5-12 membered spirocycloalkyl group, a 7-10 membered bridged cycloalkyl group, a 5-10 membered heteroaryl group or a 6-10 membered aryl group, wherein the heteromonocycle, heterofused ring, heterobridged ring, heterospirocycle, cycloalkyl group, aryl group or heteroaryl group is optionally selected from H, F, Cl, Br, I, OH, C(═O)OH, CN, NH ２ , =O, C １－４ Alkyl group, halogen-substituted C １－４ C substituted with alkyl or hydroxyl groups １－４ Alkyl group or C １－４ 2. The compound of claim 1, or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharma- ceutically acceptable salt, or co-crystal thereof, wherein the monocyclic, fused, bridged, spiro, or heteroaryl group contains 1 to 4 heteroatoms selected from O, S, or N, and is further substituted with 0-4 substituents selected from alkoxy groups.

3. R Ｌ is selected from H, a methyl group or an ethyl group, Cy1, Cy2, Cy3, and Cy4 each independently represent a bond or the following substituted or unsubstituted groups: a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, an azetidinyl group, an azacyclopentyl group, a piperidinyl group, a morpholinyl group, a piperazinyl group, a phenyl group, a cyclopropyl-fused cyclopropyl group, a cyclopropyl-fused cyclobutyl group, a cyclopropyl-fused cyclopentyl group, a cyclopropyl-fused cyclohexyl group, a cyclobutyl-fused cyclobutyl group, a cyclobutyl-fused cyclopentyl group, a cyclobutyl-fused cyclohexyl group, a cyclopropyl ... cyclopentyl-fused cyclopentyl, cyclopentyl-fused cyclohexyl, cyclohexyl-fused cyclohexyl, cyclopropyl-spiro-cyclopropyl, cyclopropyl-spiro-cyclobutyl, cyclopropyl-spiro-cyclopentyl, cyclopropyl-spiro-cyclohexyl, cyclobutyl-spiro-cyclobutyl, cyclobutyl-spiro-cyclopentyl, cyclobutyl-spiro-cyclohexyl, cyclopentyl-spiro-cyclopentyl, cyclopentyl-spiro-cyclohexyl, cyclohexyl-spiro-cyclohexyl, Cyclopropyl-fused azetidinyl, cyclopropyl-fused azacyclopentyl, cyclopropyl-fused azacyclohexyl, cyclobutyl-fused azetidinyl, cyclobutyl-fused azacyclopentyl, cyclobutyl-fused azacyclohexyl, cyclopentyl-fused azetidinyl, cyclopentyl-fused azacyclopentyl, cyclopentyl-fused azacyclohexyl, cyclohexyl-fused azetidinyl, cyclohexyl-fused azacyclopentyl, cyclohexyl-fused azacyclohexyl, azetidinyl-fused azetidinyl, azetidinyl-fused azacyclopentyl , azetidinyl-fused azacyclohexyl, azacyclopentyl-fused azacyclopentyl, azacyclopentyl-fused azacyclohexyl, azacyclohexyl-fused azacyclohexyl, cyclobutyl-spiro-azetidinyl, cyclobutyl-spiro-azacyclopentyl, cyclobutyl-spiro-azacyclohexyl, cyclopentyl-spiro-azetidinyl, cyclopentyl-spiro-azacyclopentyl, cyclopentyl-spiro-azacyclohexyl, cyclohexyl-spiro-azetidinyl, cyclopentyl-spiro-azacyclopentyl, cyclopentyl-spiro-azacyclohexyl, cyclohexyl-spiro-azetidinyl, cyclohexyl-spiro-azacyclopentyl,cyclohexyl-spiro-azacyclohexyl, azetidinyl-spiro-azetidinyl, azetidinyl-spiro-azacyclopentyl, azetidinyl-spiro-azacyclohexyl, azacyclopentyl-spiro-azacyclopentyl, azacyclopentyl-spiro-azacyclohexyl, azacyclohexyl-spiro-azacyclohexyl, 【Chemistry 3】 and optionally, when substituted, H, F, Cl, Br, I, OH, NH ２ ,C(=O)OH,CN,=O,C １－４ Alkyl group, halogen-substituted C １－４ C substituted with alkyl or hydroxyl groups １－４ Alkyl group or C １－４ is further substituted with 0 to 4 substituents selected from an alkoxy group; B1 and B3 each independently represent a pyrazolyl group, an oxazolyl group, a dioxazolyl group, an oxadiazolyl group, a triazolyl group, an imidazolyl group, a tetrazolyl group, a pyrrolyl group, a thienyl group, a thiazolyl group, a thiadiazolyl group, a pyridyl group, a phenyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, a thienopyrazinyl group, a benzimidazolyl group, a pyridotriazolyl group, a pyrimidopyrazolyl group, an imidazopyridazinyl group, a pyridopyrazolyl group, a pyrrolopyridazinyl group, or 【Chemistry 4】 is selected from R ｂ１ , R ｂ７ are each independently H, F, Cl, Br, I, ═O, OH, or NH ２ , C.N., C.F. ３ , C.H.F. ２ , C.H. ２ F, a methyl group, an ethyl group, a methoxy group, an ethoxy group, a phenyl group, a pyrrolyl group, a pyridyl group, a morpholinyl group, 【Chemistry 5】 wherein the methyl, ethyl, methoxy, ethoxy, phenyl, pyrrolyl, pyridyl or morpholinyl group is optionally selected from H, F, Cl, Br, I, OH, CN, CF ３ , N.H. ２ , N.H.C. １－４ Alkyl group, N(C １－４ Alkyl) ２ , N.H.H. ２ C ３－６ Cycloalkyl group, C １－４ Alkyl group, C １－４ Alkoxy group, C ３－６ Cycloalkyl group or R ｂ７ａ is further substituted with 0 to 4 substituents selected from Or R ｂ１ , R ｂ７ are each independently selected from an azetidinyl group, an azacyclopentyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, or a 2-oxa-5-azabicyclo[2.2.1]heptyl group; ｂ１ , R ｂ７ is optionally F, Cl, Br, I, OH, ═O, CN, CF ３ , N.H. ２ , N.H.C. １－４ Alkyl group, N(C １－４ Alkyl) ２ , N.H.H. ２ C ３－６ Cycloalkyl groups, halogen-substituted C １－４ C substituted with alkyl or cyano groups １－４ Alkyl group, -C １－４ Alkylene-OH,C １－４ Alkyl group, C １－４ Alkoxy group, -CH ２ -O-C １－４ Alkyl group, -CH ２ -C ３－６ Cycloalkyl group, —O—C ３－６ Cycloalkyl group, -NH-C ３－６ Cycloalkyl group, C ３－６ Cycloalkyl group, -CH ２ -4- to 7-membered heterocycloalkyl group, -O-4- to 7-membered heterocycloalkyl group, -NH-4- to 7-membered heterocycloalkyl group4- to 7-membered heterocycloalkyl group, said heterocyclic group containing 1-4 heteroatoms selected from O, S or N; R ｂ２ , R ｂ６ are each independently H, F, Cl, Br, I, ═O, or CF ３ , C.H.F. ２ , O.H., N.H. ２ , NH(methyl), NH(ethyl), NH(propyl), NH(isopropyl), N(methyl) ２ , N(ethyl) ２ , CN, methyl, ethyl, methoxy, ethoxy, propoxy, isopropyloxy, morpholinyl, piperazinyl, pyrrolidinyl, piperidinyl or oxazolidinyl, wherein the methyl, ethyl, methoxy, ethoxy, propoxy, isopropyloxy, morpholinyl, piperazinyl, pyrrolidinyl, piperidinyl or oxazolidinyl group is optionally selected from H, F, Cl, Br, I, OH, CN, CF ３ , C １－４ Alkyl group, C １－４ Alkoxy group or C ３－６ is further substituted with 0 to 4 substituents selected from cycloalkyl groups; R ｋ１ are each independently selected from H, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclopentyl, piperidinyl, oxetanyl, oxacyclopentyl, and oxacyclohexyl, and the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclopentyl, piperidinyl, oxetanyl, oxacyclopentyl, and oxacyclohexyl groups are optionally selected from H, F, Cl, Br, I, OH, CN, CF ３ , C １－４ Alkyl group, C １－４ An alkoxy group, a vinyl group, a propenyl group, an allyl group, an ethynyl group, a propynyl group, a propargyl group, or C ３－６ is further substituted with 0 to 4 substituents selected from cycloalkyl groups; R ｋ２ , R ｋ３ are each independently H, F, Cl, Br, I, OH, ═O, or NH ２ , C.F. ３ , CN, C(=O)OH, C(=O)NH ２ , a methyl group, an ethyl group, a methoxy group or an ethoxy group, the methyl group, the ethyl group, the methoxy group or the ethoxy group being optionally selected from H, F, Cl, Br, I, OH or NH ２ is further substituted with 0 to 4 substituents selected from The compound of claim 2, or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharma- ceutically acceptable salt or cocrystal thereof, wherein p2 or p3 is independently selected from 0, 1 or 2.

4. Cy1, Cy2, Cy3, and Cy4 each independently represent a bond or a substituted or unsubstituted group as follows: 【Chemistry 6】 and optionally, when substituted, H, F, CF ３ , methyl group, ═O, hydroxymethyl group, C(═O)OH, CN, or NH ２ is further substituted with 0 to 4 substituents selected from B is, 【Chemistry 7】 【Chemistry 8】 【Chemistry 9】 4. The compound of claim 3, or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharma- ceutically acceptable salt, or co-crystal thereof, selected from:

5. L is a bond, -Cy1-, -Cy1-Ak2-, -Cy1-Ak2-Ak3-, -Cy1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-, -Cy1-Ak2-Cy2-, -Cy1-Cy2-Ak3-, -Cy1-Cy2-Ak3-Cy4-, -C y1-Ak2-Cy2-Ak3-, -Cy1-Ak2-Cy2-Ak3-Ak4-, -Cy1-Ak2-Cy2-Cy3-Ak4 -, -Cy1-Cy2-Ak3-Ak4-, -Cy1-Cy2-Ak3-Ak4-Ak5-, -Cy1-Ak2-Cy2-Ak3 -Ak4-Ak5-, -Cy1-Ak2-Ak3-Cy3-Ak4-, -Cy1-Ak2-Ak3-Cy3-Ak4-Ak5-, -Cy1-Ak2-Ak3-Ak4-Cy4-Ak5-, -Cy1-Cy2-Cy3-, -Cy1-Ak2-Cy2-Cy3-, -Cy1-Cy2-Cy3-Ak4-, -Cy1-Ak2-Cy2-Cy3-Ak4-, -Cy1-Ak2-Cy2-Ak3-C y3-, -Cy1-Ak2-Cy2-Cy3-Ak4-Ak5, -Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak3-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak4-C y4-, -Ak1-Cy1-Ak2-Cy2-, -Ak1-Cy1-Ak2-Cy2-Ak3-, -Ak1-Ak2-Cy2-A k3-, -Ak1-Ak2-Cy2-, -Ak1-Ak2-Cy2-Cy3-Ak4-, -Ak1-Ak2-Ak3-Cy3-A k4-, -Ak1-Cy1-Ak2-, -Ak1-Cy1-Cy2-Ak3-Ak4-, -Ak1-Cy1-Cy2-Ak3-, -Ak1-Cy1-Ak2-Ak3-Ak4-, -Ak1-Cy1-, -Ak1-Cy1-Ak2-Ak3-, -Ak1-Ak2-Cy2-Ak3-Ak4-, -Ak1-Cy1-Ak2-Cy2-Ak3-Ak4-, -Cy1-Ak2-Ak3-Cy3-Cy4-Ak5-, -Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-, -Ak1-Cy1-Cy2-, -Ak1-Ak2-Ak3-Ak4- or -Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-; Ak1, Ak2, Ak3, Ak4, and Ak5 each independently represent O, C≡C, or CH ２ , C.H. ２ CH ２ , C.H. ２ CH ２ CH ２ , C.H. ２ CH ２ CH ２ CH ２ , C.H. ２ N (CH ３ ), C.H. ２ CH ２ N (CH ３ ), N(CH ３ ), NH, C(=O), C(=O)N(CH ３ ), N(CH ３ 5. The compound of claim 4, wherein the compound is selected from: C(=O), C(=O)NH, or NHC(=O); or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharma- ceutically acceptable salt, or co-crystal thereof.

6. L is, 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 is selected from J １ are each independently 【Chemistry 13】 is selected from J ２ are each independently 【Chemistry 14】 is selected from J ３ are each independently 【Chemistry 15】 is selected from J ４ are each independently 【Chemistry 16】 is selected from J ５ are each independently 【Chemistry 17】 is selected from Or, L is 【Chemistry 18】 is selected from R ｄ is selected from H or D, and at least one R ｄ is selected from D; d1 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; 5. The compound of claim 4, or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharma- ceutically acceptable salt or co-crystal thereof, wherein d2 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9.

7. The compound of claim 4, or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharma- ceutically acceptable salt, or co-crystal thereof, wherein L is selected from the groups shown in Table L-1, where the left side of the group is linked to B.

8. K. 【Chemistry 19】 【Chemistry 20】 8. The compound according to claim 5 to 7, or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharma- ceutically acceptable salt or co-crystal thereof, selected from:

9. The compound of claim 1, wherein the compound is selected from one of the structures in Table P-1, or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharma- ceutically acceptable salt, or co-crystal thereof.

10. 10. A pharmaceutical composition comprising the compound of any one of claims 1 to 9 or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharma- ceutically acceptable salt or co-crystal thereof, and a pharma- ceutically acceptable carrier, preferably wherein the pharmaceutical composition contains 1 to 1500 mg of the compound of any one of claims 1 to 9 or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharma- ceutically acceptable salt or co-crystal thereof.

11. Use of a compound according to any one of claims 1 to 9 or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharma- ceutically acceptable salt or cocrystal thereof, or a pharmaceutical composition according to claim 10, in the manufacture of a medicament for treating a disease associated with IRAK4 activity or expression level.

12. Use of a compound according to any one of claims 1 to 9 or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharma- ceutically acceptable salt or cocrystal thereof, or a pharmaceutical composition according to claim 10, in the manufacture of a medicament for treating a disease associated with the inhibition or degradation of IRAK4.

13. The application according to claim 12, wherein the disease is selected from an autoimmune disease, an inflammatory disease or cancer.

14. 10. A method for treating a disease in a mammal, said method comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 9 or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharma- ceutically acceptable salt or co-crystal thereof, or a pharmaceutical composition according to claim 10, wherein the therapeutically effective amount is preferably 1 to 1500 mg, and wherein the disease is preferably an autoimmune disease, an inflammatory disease or cancer.

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