TW202408518A - Pde4b inhibitor - Google Patents

Abstract

The present invention provides a compound represented by formula II, tautomeric form, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof. The compound has better PDE4B inhibitory effect.

Description

PDE4B inhibitors

The present invention belongs to the field of medicine. Specifically, the present invention relates to a PDE4B inhibitor.

PDE4 is a cyclic nucleotide phosphodiesterase that is abundantly expressed in most cells and hydrolyzes cAMP with a micromolar Km value. PDE4 molecules are involved in a variety of physiological processes, including brain function, monocyte macrophage activation, neutrophil infiltration, vascular smooth muscle proliferation, and myocardial contraction. PDE4 has been reported to be a target of various inflammatory diseases, such as asthma, chronic obstructive pulmonary disease (COPD), and rheumatoid arthritis. PDE4 consists of four subtypes, PDE4A, PDE4B, PDE4C, and PDE4D, which are located on chromosomes 19p13.2, 1p31, 19p13.11, and 5q12, respectively. PDE4 molecules exist in long, short, and ultrashort forms according to their molecular size. The X-ray structure of the PDE4 molecule shows that the active site can be divided into three subpockets: a divalent metal pocket that interacts with the phosphate portion of cAMP; two Q pockets that form hydrogen bonds and hydrophobic interactions with inhibitors; and a solvation pocket (S pocket). PDE4 inhibitors occupy the active site through multiple interactions, including hydrophobic interactions with conserved phenylalanine and isoleucine, and hydrogen bonding with invariant glutamine. The high degree of conservation and structural homology of the PDE4 catalytic domain makes the discovery of PDE4 subtype-selective inhibitors challenging.

Clinical studies of PDE4 inhibitors have been limited by side effects, including nausea and vomiting, which are thought to be caused by inhibition of the PDE4D isoform. Similarly, side effects have limited the therapeutic index of the second-generation PDE4 inhibitors, cilomilast and roflumilast. Selective inhibition of the PDE4B isoform may offer a way to achieve therapeutic efficacy while potentially mitigating these adverse events.

There are currently no drugs on the market that inhibit the PDE4B inhibitor pathway to treat many conditions, including fibrosis. Therefore, the development of new compounds that can inhibit PDE4B activity is of positive significance for the treatment of diseases.

The object of the present invention is to provide a novel compound useful as a PDE4B inhibitor.

In the first aspect of the present invention, the present invention provides a compound, which is a compound represented by formula II or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula II: wherein Ring A is a 5-10 membered aromatic ring or a heteroaromatic ring; B is selected from a 3-10 membered heterocycloalkyl, a 3-10 membered heterocycloalkenyl or a 3-10 membered cycloalkyl; ^Ra and ^Rb are each independently selected from H, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C1-6 alkyl, C3-8 cycloalkyl, C1-6 deuterated alkyl, _C2-6 alkenyl, C2-6 alkynyl, C1-6 halogenated alkyl, C3-8 halogenated cycloalkyl, C1-6 alkylhydroxyl, _C1-6 alkylcarbonyl, _C1-6 alkoxy, C1-6 halogenated alkoxy, 3-10 membered heterocycloalkyl; the C1-6 alkyl, _C3-8 cycloalkyl, _C2-6 alkynyl, _C1-6 halogenated alkyl, _C3-8 halogenated cycloalkyl, _C1-6 alkylhydroxyl, _C1-6 alkylcarbonyl, _C1-6 alkoxy, C1-6 halogenated alkoxy, 3-10 membered heterocycloalkyl; the C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkynyl, C1-6 halogenated alkyl, _C3-8 halogenated cycloalkyl, C1-6 alkylhydroxyl, _C1-6 alkylcarbonyl, _C1-6 alkoxy, C1-6 halogenated alkoxy, 3-10 membered heterocycloalkyl, ... C _1-6 deuterated alkyl, C _2-6 alkynyl, C _1-6 halogenated alkyl, C _3-8 halogenated cycloalkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy and C _1-6 halogenated alkoxy are optionally substituted by one or more R ^c ; said R ^c is selected from the following substituents: halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C 2-6 alkynyl, C _1-6 halogenated alkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy; when the substituent R ^c is multiple, said R ^c are the same or different; m and n are 0, 1 _, 2 or 3 respectively; Y is selected from NR ¹ , O, S or CHR ¹ ; R ¹ is selected from Ｈ, C _1-10 alkyl, C _2-6 alkenyl, and the C _1-10 alkyl, C _2-6 alkenyl is optionally substituted by one or more R ^d ; the R ^d is selected from the following substituents: halogen, C _1-3 fluoroalkyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy, -COO-C _1-6 alkyl, -C(O)NR ^f R ^f , 5-8 membered aromatic ring, -het ¹ , mono- or bicyclic-C _5-8- cycloalkyl; wherein the R ^f is hydrogen, C _1-6 alkyl; the het ¹ represents a 5-8 membered monocyclic or bicyclic, saturated or unsaturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S and O; Q is selected from the following groups: , or Q ¹ ; M is cyano; each of the pairs of R ² and R ³ , R ⁵ and R ⁶ can independently form a saturated or partially saturated 3-membered, 4-membered, 5-membered, 6-membered monocyclic ring with the carbon atoms to which they are attached; wherein the 3-membered, 4-membered, 5-membered, 6-membered monocyclic ring contains 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, and further, wherein the 3-membered, 4-membered, 5-membered, 6-membered monocyclic ring is substituted with 0, 1, 2 or 3 R ²³ selected from the following, wherein R ²³ is selected from at least one of the following: halogen, hydroxyl, amine, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C 1-4 halogenated alkyl, C _1-4 wherein R ^f is hydrogen or C _1-6 alkyl; or, R 5 and ^R ₆ are each independently selected from H, C _1-10 alkyl, C _2-6 alkenyl, and the C _1-10 ^alkyl , C _2-6 alkenyl is optionally substituted with one or more R ^d ; wherein R ^d is selected from the following substituents: halogen, C _1-3 fluoroalkyl _, C _1-6 alkoxy, C _1-6 halogenated alkoxy, -COO-C ^1-6 alkyl ^, -C(O)NR ^f R ^f , _5-8 membered _aromatic ring, -het ₂ , mono- or bicyclic- ^C _{5-8- cycloalkyl} ; wherein, R ^f is hydrogen, C _1-6 alkyl; het ² represents a 5-8 membered monocyclic or bicyclic, saturated or unsaturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S and O; R ⁴ is selected from halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 deuterated alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenated alkyl, C _3-8 halogenated cycloalkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy, 3-10 membered heterocycloalkyl; the C _1-6 alkyl, C _3-8 C _1-6 cycloalkyl, C _1-6 deuterated alkyl, C _2-6 alkynyl, C _1-6 halogenated alkyl, C _3-8 halogenated cycloalkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy are optionally substituted by one or more R ^g ; said R ^g is selected from at least one of the following substituents: halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C 2-6 alkynyl, C _1-6 halogenated alkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, _{C 1-6 halogenated} alkoxy; when the substituent R ^g is multiple, said R ^g are the same or different; Q ¹ is optionally substituted by one or more R g The present invention relates to a 4-6 membered heterocycloalkyl group substituted by ^R7 , wherein ^R7 is selected from at least one of the following substituents: H, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, _C1-6 alkyl, _C1-6 deuterated alkyl, _C2-6 alkynyl, _C1-6 halogenated alkyl, _C1-6 alkylhydroxyl, _C1-6 alkylcarbonyl, _C1-6 alkoxy, _C1-6 halogenated alkoxy; when there are multiple substituents ^R7 , the ^R7 are the same or different.

In a preferred embodiment of the present invention, the compound represented by formula II, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug: wherein Ring A is a 5-10 membered aromatic ring or a heteroaromatic ring; B is selected from a 3-10 membered heterocycloalkyl, a 3-10 membered heterocycloalkenyl or a 3-10 membered cycloalkyl; ^Ra and ^Rb are each independently selected from H, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C1-6 alkyl, C3-8 cycloalkyl, C1-6 deuterated alkyl, _C2-6 alkenyl, C2-6 alkynyl, C1-6 halogenated alkyl, C3-8 halogenated cycloalkyl, C1-6 alkylhydroxyl, _C1-6 alkylcarbonyl, _C1-6 alkoxy, C1-6 halogenated alkoxy, 3-10 membered heterocycloalkyl; the C1-6 alkyl, _C3-8 cycloalkyl, _C2-6 alkynyl, _C1-6 halogenated alkyl, _C3-8 halogenated cycloalkyl, _C1-6 alkylhydroxyl, _C1-6 alkylcarbonyl, _C1-6 alkoxy, C1-6 halogenated alkoxy, 3-10 membered heterocycloalkyl; the C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkynyl, C1-6 halogenated alkyl, _C3-8 halogenated cycloalkyl, C1-6 alkylhydroxyl, _C1-6 alkylcarbonyl, _C1-6 alkoxy, C1-6 halogenated alkoxy, 3-10 membered heterocycloalkyl, ... C _1-6 deuterated alkyl, C _2-6 alkynyl, C _1-6 halogenated alkyl, C _3-8 halogenated cycloalkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy are optionally substituted by one or more R ^c ; said R ^c is selected from the following substituents: halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C 2-6 alkynyl, C _1-6 halogenated alkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy; when the substituent R ^c is multiple, said R ^c are the same or different; m and n are 0, 1 _, 2 or 3 respectively; Y is selected from NR ¹ , O, S or CHR ¹ ; R ¹ is selected from Ｈ, C _1-10 alkyl, C _2-6 alkenyl, and the C _1-10 alkyl, C _2-6 alkenyl is optionally substituted by one or more R ^d ; the R ^d is selected from the following substituents: halogen, C _1-3 fluoroalkyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy, -COO-C _1-6 alkyl, -C(O)NR ^f R ^f , 5-8 membered aromatic ring, -het ¹ , mono- or bicyclic-C _5-8- cycloalkyl; wherein the R ^f is hydrogen, C _1-6 alkyl; the het ¹ represents a 5-8 membered monocyclic or bicyclic, saturated or unsaturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S and O; Q is selected from the following groups: , or Q ¹ ; M is cyano; each of the pairs of R ² and R ³ , R ⁵ and R ⁶ can independently form a saturated or partially saturated 3-membered, 4-membered, 5-membered, 6-membered monocyclic ring with the carbon atoms to which they are attached; wherein the 3-membered, 4-membered, 5-membered, 6-membered monocyclic ring contains 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, and further, wherein the 3-membered, 4-membered, 5-membered, 6-membered monocyclic ring is substituted with 0, 1, 2 or 3 groups selected from the following: halogen, hydroxyl, amine, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-4 halogenated alkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C wherein R ^f is hydrogen or C _1-6 alkyl; or, R ⁵ and R ⁶ are each independently selected from H, C _1-10 alkyl, C _2-6 alkenyl, and ^the C _1-10 alkyl, C _2-6 alkenyl is optionally substituted with one or more R ^d ; wherein R ^d is selected from the following ^substituents : halogen, C _1-3 fluoroalkyl, _{C 1-6 alkoxy, C 1-6 halogenated alkoxy, -COO-C 1-6 alkyl , -C} (O)NR ^f R ^f , 5-8 membered _aromatic ring, -het ² , mono- or bicyclic-C _{5-8- cycloalkyl} ; wherein R ^f is hydrogen or C _1-6 alkyl; wherein het ^R2 represents a 5-8 membered monocyclic or bicyclic, saturated or unsaturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S and O; ^R4 is selected from halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C1-6 alkyl, C3-8 cycloalkyl, _{C1-6 deuterated alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 halogenated alkyl, C3-8 halogenated cycloalkyl, C1-6 alkylhydroxyl ,} C1-6 alkylcarbonyl, C1-6 alkoxy, _C1-6 halogenated alkoxy, 3-10 membered heterocycloalkyl; the C1-6 alkyl, C3-8 cycloalkyl, C1-6 deuterated alkyl, _C2-6 alkenyl, _C2-6 alkynyl, C1-6 halogenated alkyl, _C3-8 halogenated cycloalkyl, _C1-6 alkylhydroxyl, C1-6 alkylcarbonyl, C1-6 alkoxy, C1-6 halogenated alkoxy, 3-10 membered heterocycloalkyl; the _C1-6 alkyl, C3-8 cycloalkyl, _C1-6 deuterated alkyl, C2-6 alkenyl, C2-6 alkynyl, _C1-6 halogenated alkyl, _C3-8 halogenated cycloalkyl, _C1-6 alkylhydroxyl, _C1-6 alkylcarbonyl, _C1-6 alkoxy, C1-6 halogenated alkoxy, 3-10 membered heterocycloalkyl C _2-6 alkynyl, C _1-6 halogenated alkyl, C _3-8 halogenated cycloalkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy are optionally substituted by one or more R ^g ; said R ^g is selected from the following substituents: halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _2-6 alkynyl, C _1-6 halogenated alkyl _, C 1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy; when the substituent R ^g is multiple, said R ^g are the same or different; Q ¹ is a 4-6 membered heterocycloalkyl optionally substituted by one or more R ⁷ , said R ^{R 7} is a substituent selected from the following: halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _2-6 alkynyl, C _1-6 halogenated alkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy; when there are multiple substituents R ⁷ , the R ⁷ are the same or different.

In a preferred embodiment of the present invention, the compound represented by formula II, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug: wherein Ring A is a 5-10 membered aromatic ring or a heteroaromatic ring; B is selected from a 3-10 membered heterocycloalkyl, a 3-10 membered heterocycloalkenyl or a 3-10 membered cycloalkyl; ^Ra and ^Rb are each independently selected from H, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C1-6 alkyl, C3-8 cycloalkyl, C1-6 deuterated alkyl, _C2-6 alkenyl, C2-6 alkynyl, C1-6 halogenated alkyl, C3-8 halogenated cycloalkyl, C1-6 alkylhydroxyl, _C1-6 alkylcarbonyl, _C1-6 alkoxy, C1-6 halogenated alkoxy, 3-10 membered heterocycloalkyl; the C1-6 alkyl, _C3-8 cycloalkyl, _C2-6 alkynyl, _C1-6 halogenated alkyl, _C3-8 halogenated cycloalkyl, _C1-6 alkylhydroxyl, _C1-6 alkylcarbonyl, _C1-6 alkoxy, C1-6 halogenated alkoxy, 3-10 membered heterocycloalkyl; the C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkynyl, C1-6 halogenated alkyl, _C3-8 halogenated cycloalkyl, C1-6 alkylhydroxyl, _C1-6 alkylcarbonyl, _C1-6 alkoxy, C1-6 halogenated alkoxy, 3-10 membered heterocycloalkyl, ... C _1-6 deuterated alkyl, C _2-6 alkynyl, C _1-6 halogenated alkyl, C _3-8 halogenated cycloalkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy are optionally substituted by one or more R ^c ; said R ^c is selected from the following substituents: halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _{1-6 deuterated alkyl, C 2-6} alkynyl, C _1-6 halogenated alkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy; when there are multiple substituents, said R ^c are the same or different; m and n are 0, 1, ₂ or 3 respectively; Y is selected from NR ¹ , O, S or CHR ¹ ; R ¹ is selected from Ｈ, C _1-10 alkyl, C _2-6 alkenyl, and the C _1-10 alkyl, C _2-6 alkenyl is optionally substituted by one or more R ^d ; the R ^d is selected from the following substituents: halogen, C _1-3 fluoroalkyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy, -COO-C _1-6 alkyl, -C(O)NR ^f R ^f , 5-8 membered aromatic ring, -het, mono- or bicyclic-C _5-8 -cycloalkyl; wherein the R ^f is hydrogen, C _1-6 alkyl; the het represents a 5-8 membered monocyclic or bicyclic, saturated or unsaturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S and O; Q is selected from the following groups: or ; M is cyano; each of the pairs of R ² and R ³ , and R ⁵ and R ⁶ can independently form a saturated or partially saturated 3-membered, 4-membered, 5-membered, or 6-membered monocyclic ring with the carbon atoms to which they are attached; wherein the 3-membered, 4-membered, 5-membered, or 6-membered monocyclic ring contains 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S, and further, wherein the 3-membered, 4-membered, 5-membered, or 6-membered monocyclic ring is substituted with 0, 1, 2, or 3 groups selected from the following: halogen, hydroxyl, amine, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-4 halogenated alkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C wherein ^Rf is hydrogen, _C1-6 alkyl; or, ^R5 and ^R6 are each independently selected from H, _C1-10 alkyl, _C2-6 alkenyl, and the C1-10 alkyl, _C2-6 alkenyl is optionally substituted by one or more ^Rd ; wherein ^Rd is selected from the following substituents: halogen, C1-3 fluoroalkyl, _C1-6 alkoxy, C1-6 halogenated alkoxy, -COO- _C1-6 alkyl, -C(O)NRfRf, 5-8 membered aromatic ring, -het, mono- or bicyclic- _C5-8- cycloalkyl; wherein ^{Rf is} hydrogen, C1-6 alkyl; or, R5 and R6 are each independently selected from H, _C1-10 alkyl, _C2-6 alkenyl, and the _C1-10 alkyl, C2-6 alkenyl is optionally substituted by one or more Rd; wherein ^Rd is selected from the following substituents: halogen, C1-3 fluoroalkyl, C1-6 alkoxy, C1-6 halogenated ^alkoxy , -COO- _C1-6 alkyl, -C(O) ^NRfRf , 5-8 membered aromatic ring, -het, mono- or bicyclic- _C5-8- cycloalkyl; wherein wherein het represents a 5-8 membered monocyclic or bicyclic, saturated or unsaturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S and O; ^R4 is selected from halogen, hydroxyl, amine, nitro, cyano, carbonyl, _oxo , carboxyl, C1-6 alkyl, C3-8 cycloalkyl, C1-6 deuterated alkyl, _C2-6 alkenyl, C2-6 alkynyl, C1-6 halogenated alkyl, _C3-8 halogenated cycloalkyl, _C1-6 alkylhydroxyl, C1-6 alkylcarbonyl, C1-6 alkoxy, _C1-6 halogenated alkoxy, 3-10 membered heterocycloalkyl; the C1-6 alkyl, C3-8 cycloalkyl, _C2-6 alkynyl, _C1-6 halogenated alkyl, _C3-8 halogenated cycloalkyl, C1-6 alkylhydroxyl, _C1-6 alkylcarbonyl, _C1-6 alkoxy, _C1-6 halogenated alkoxy, 3-10 membered heterocycloalkyl; the C1-6 alkyl, C3-8 cycloalkyl, _C2-6 alkynyl, C1-6 halogenated alkyl, _C3-8 halogenated cycloalkyl, C1-6 alkylhydroxyl, C1-6 alkylcarbonyl, _C1-6 alkoxy, _C1-6 halogenated alkoxy, 3-10 membered heterocycloalkyl C _1-6 deuterated alkyl, C _2-6 alkynyl, C _1-6 halogenated alkyl, C _3-8 halogenated cycloalkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy are optionally substituted with one or more R ^g ; said R ^g is selected from the following substituents: halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _2-6 alkynyl, C 1-6 _{halogenated alkyl, C 1-6 alkylhydroxyl, C 1-6 alkylcarbonyl, C 1-6 alkoxy, C 1-6 halogenated alkoxy ; when} there are multiple substituents, said R ^g are the same or different.

In a preferred embodiment of the present invention, the compound represented by formula II, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug: , wherein, ring A is a 5-10 membered aromatic ring or heteroaromatic ring; B is selected from 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl; R ^a and R ^b are each independently selected from H, Halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 deuterated alkyl, C _2-6 alkenyl , C _2-6 alkynyl, C _1-6 haloalkyl, C _3-8 halocycloalkyl, C _1-6 alkylhydroxy, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 haloalkoxy, 3-10 membered heterocycloalkyl; the C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 deuterated alkyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-8 halocycloalkyl, C _1-6 alkylhydroxy, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 haloalkoxy optionally Substituted by one or more R ^c ; the R ^c is selected from the following substituents: halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _{1- 6} deuterated alkyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 alkylhydroxy, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 haloalkoxy group; when there are multiple substituents, the ^Rc is the same or different; m, n are 0, 1, 2 or 3 respectively; Y is selected from NR ¹ , O, S or CHR ¹ ; R ¹ is selected from H, C _1-10 alkyl and C _2-6 alkenyl, the C _1-10 alkyl and C _2-6 alkenyl are optionally substituted by one or more R ^d ; the R ^d is selected from the following substitutions Base: halogen, C _1-3 fluoroalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, -COO-C _1-6 alkyl, -C(O)NR ^f R ^f , 5 -8-membered aromatic ring, -het, mono- or bicyclic-C _5-8- cycloalkyl; wherein, the R ^f is hydrogen, C _1-6 alkyl; the het represents a 5-8-membered monocyclic ring or Bicyclic, saturated or unsaturated heterocycle, containing 1, 2, 3 or 4 heteroatoms independently selected from N, S, O; Q is selected from the following groups: or ; M is cyano; Each pair of R ² and R ³ , R ⁵ and R ⁶ can be independently combined with their respective attached carbon atoms to form a saturated or partially saturated 3-, 4-, 5-element 3-membered, 6-membered monocyclic ring; wherein the 3-membered, 4-membered, 5-membered, 6-membered monocyclic ring contains 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, and Further, wherein the 3-membered, 4-membered, 5-membered, 6-membered monocyclic ring is substituted with 0, 1, 2 or 3 groups selected from the following: halogen, hydroxyl, amino, cyano, carbonyl, oxo , carboxyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-4 haloalkyl, C _1-6 alkyl hydroxyl, C _{1 -6} alkylcarbonyl, C _1-6 alkoxy, C _1-6 haloalkoxy, -COO-C _1-6 alkyl, -C(O)NR ^f R ^f ; wherein, the R ^f is hydrogen , C _1-6 alkyl; or, R ⁵ and R ⁶ are each independently selected from H, C _1-10 alkyl, C _2-6 alkenyl, the C _1-10 alkyl, C _2-6 alkenyl The radical is optionally substituted by one or more R ^d ; the R ^d is selected from the following substituents: halogen, C _1-3 fluoroalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy , -COO-C _1-6 alkyl, -C(O)NR ^f R ^f , 5-8 membered aromatic ring, -het, mono- or bicyclic-C _5-8- cycloalkyl; wherein, the R ^f is hydrogen, C _1-6 alkyl; the het represents a 5-8 membered monocyclic or bicyclic, saturated or unsaturated heterocyclic ring, which contains 1, 2, 3 or 4 independently selected from N, Heteroatom in S, O; R ⁴ is selected from halogen, hydroxyl, amine, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _3-8 cycloalkyl, C _{1- 6} deuterated alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-8 halocycloalkyl, C _1-6 alkyl hydroxyl, C _1-6 alkyl Carbonyl group, C _1-6 alkoxy group, C _1-6 haloalkoxy group, _3-10 membered heterocycloalkyl group; the C _1-6 alkyl group, C _3-8 cycloalkyl group, C _1-6 deuterium group Alkyl group, C _2-6 alkynyl group, C _1-6 haloalkyl group, C _3-8 halocycloalkyl group, C _1-6 alkyl hydroxyl group, C _1-6 alkyl carbonyl group, C _1-6 alkoxy group The C _1-6 haloalkoxy group is optionally substituted by one or more ^Rg ; the ^Rg is selected from the following substituents: halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, Carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 alkylhydroxy, C _1-6 alkylcarbonyl, C _{1 -6} alkoxy group, C _1-6 haloalkoxy group; when there are multiple substituents, the ^Rg may be the same or different.

In a preferred embodiment of the present invention, there is provided a compound of formula II, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug: wherein Ring A is a 5-10 membered aromatic ring or a heteroaromatic ring; B is selected from a 3-10 membered heterocycloalkyl group; ^Ra and ^Rb are each independently selected from H, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, _C1-6 alkyl, _C3-8 cycloalkyl, _C1-6 deuterated alkyl, _C2-6 alkenyl, C2-6 alkynyl, _C1-6 halogenated alkyl, _C3-8 halogenated cycloalkyl, _C1-6 alkylhydroxyl, _C1-6 alkylcarbonyl, _C1-6 alkoxy, _C1-6 halogenated alkoxy _{, and a 3-10 membered heterocycloalkyl group; the C1-6 alkyl, C3-8 cycloalkyl, C1-6 deuterated alkyl , C2-6} alkynyl, C C _1-6 halogenated alkyl, C _3-8 halogenated cycloalkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy are optionally substituted by one or more R ^c ; said R ^c is selected from the following substituents: halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C 1-6 deuterated alkyl, C _2-6 alkynyl, C _1-6 halogenated alkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy; when there are multiple substituents, said R ^c are the same or different; m and n are 0, 1, 2 or 3 _respectively ; Y is selected from NR ¹ , O, S or CHR ¹ ; R ¹ is selected from Ｈ, C C _1-10 alkyl, C _2-6 alkenyl, the C _1-10 alkyl, C _2-6 alkenyl is optionally substituted by one or more R ^d ; the R ^d is selected from the following substituents: halogen, C _1-3 fluoroalkyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy, -COO-C _1-6 alkyl, -C(O)NR ^f R ^f , 5-8 membered aromatic ring, -het, mono- or bicyclic-C _5-8- cycloalkyl; wherein the R ^f is hydrogen, C _1-6 alkyl; the het represents a 5-8 membered monocyclic or bicyclic, saturated or unsaturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S and O; Q is selected from the following groups: or ; M is cyano; each of the pairs of R ² and R ³ , and R ⁵ and R ⁶ can independently form a saturated or partially saturated 3-membered, 4-membered, 5-membered, or 6-membered monocyclic ring with the carbon atoms to which they are attached; wherein the 3-membered, 4-membered, 5-membered, or 6-membered monocyclic ring contains 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S, and further, wherein the 3-membered, 4-membered, 5-membered, or 6-membered monocyclic ring is substituted with 0, 1, 2, or 3 groups selected from the following: halogen, hydroxyl, amine, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-4 halogenated alkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C wherein ^Rf is hydrogen, _C1-6 alkyl; or, ^R5 and ^R6 are each independently selected from H, _C1-10 alkyl, _C2-6 alkenyl, and the C1-10 alkyl, _C2-6 alkenyl is optionally substituted by one or more ^Rd ; wherein ^Rd is selected from the following substituents: halogen, C1-3 fluoroalkyl, _C1-6 alkoxy, C1-6 halogenated alkoxy, -COO- _C1-6 alkyl, -C(O)NRfRf, 5-8 membered aromatic ring, -het, mono- or bicyclic- _C5-8- cycloalkyl; wherein ^{Rf is} hydrogen, C1-6 alkyl; or, R5 and R6 are each independently selected from H, _C1-10 alkyl, _C2-6 alkenyl, and the _C1-10 alkyl, C2-6 alkenyl is optionally substituted by one or more Rd; wherein ^Rd is selected from the following substituents: halogen, C1-3 fluoroalkyl, C1-6 alkoxy, C1-6 halogenated ^alkoxy , -COO- _C1-6 alkyl, -C(O) ^NRfRf , 5-8 membered aromatic ring, -het, mono- or bicyclic- _C5-8- cycloalkyl; wherein wherein het represents a 5-8 membered monocyclic or bicyclic, saturated or unsaturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S and O; ^R4 is selected from halogen, hydroxyl, amine, nitro, cyano, carbonyl, _oxo , carboxyl, C1-6 alkyl, C3-8 cycloalkyl, C1-6 deuterated alkyl, _C2-6 alkenyl, C2-6 alkynyl, C1-6 halogenated alkyl, _C3-8 halogenated cycloalkyl, _C1-6 alkylhydroxyl, C1-6 alkylcarbonyl, C1-6 alkoxy, _C1-6 halogenated alkoxy, 3-10 membered heterocycloalkyl; the C1-6 alkyl, C3-8 cycloalkyl, _C2-6 alkynyl, _C1-6 halogenated alkyl, _C3-8 halogenated cycloalkyl, C1-6 alkylhydroxyl, _C1-6 alkylcarbonyl, _C1-6 alkoxy, _C1-6 halogenated alkoxy, 3-10 membered heterocycloalkyl; the C1-6 alkyl, C3-8 cycloalkyl, _C2-6 alkynyl, C1-6 halogenated alkyl, _C3-8 halogenated cycloalkyl, C1-6 alkylhydroxyl, C1-6 alkylcarbonyl, _C1-6 alkoxy, _C1-6 halogenated alkoxy, 3-10 membered heterocycloalkyl C _1-6 deuterated alkyl, C _2-6 alkynyl, C _1-6 halogenated alkyl, C _3-8 halogenated cycloalkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy are optionally substituted with one or more R ^g ; said R ^g is selected from the following substituents: halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _2-6 alkynyl, C 1-6 _{halogenated alkyl, C 1-6 alkylhydroxyl, C 1-6 alkylcarbonyl, C 1-6 alkoxy, C 1-6 halogenated alkoxy ; when} there are multiple substituents, said R ^g are the same or different.

In a preferred embodiment of the present invention, there is provided a compound represented by formula II, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug: Among them, ring A is a 5-10 membered aromatic ring or heteroaromatic ring; B is selected from 3-10 membered heterocyclic alkenyl; R ^a and R ^b are each independently selected from H, halogen, hydroxyl, amino group, nitro, Cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 deuterated alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{1 -6} haloalkyl, C _3-8 halocycloalkyl, C _1-6 alkylhydroxy, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 haloalkoxy, 3~10 Member heterocycloalkyl; the C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 deuterated alkyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-8 Halogenated cycloalkyl, C _1-6 alkylhydroxy, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 haloalkoxy are optionally substituted by one or more R ^c ; Said R ^c is selected from the following substituents: halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _2-6 Alkynyl, C _1-6 haloalkyl, C _1-6 alkylhydroxy, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 haloalkoxy; when there are multiple substituents, The R ^c is the same or different; m and n are 0, 1, 2 or 3 respectively; Y is selected from NR ¹ , O, S or CHR ¹ ; R ¹ is selected from H, C _1-10 alkyl, C _{2- 6} alkenyl, the C _1-10 alkyl and C _2-6 alkenyl are optionally substituted by one or more R ^d ; the R ^d is selected from the following substituents: halogen, C _1-3 fluoro Alkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, -COO-C _1-6 alkyl, -C(O)NR ^f R ^f , 5-8 membered aromatic ring, -het, single - or bicyclic-C _5-8- cycloalkyl; wherein, the R ^f is hydrogen, C _1-6 alkyl; the het represents a 5-8 membered monocyclic or bicyclic, saturated or unsaturated heterocycle , which contains 1, 2, 3 or 4 heteroatoms independently selected from N, S, O; Q is selected from the following groups: or ; M is cyano; Each pair of R ² and R ³ , R ⁵ and R ⁶ can be independently combined with their respective attached carbon atoms to form a saturated or partially saturated 3-, 4-, 5-element 3-membered, 6-membered monocyclic ring; wherein the 3-membered, 4-membered, 5-membered, 6-membered monocyclic ring contains 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, and Further, wherein the 3-membered, 4-membered, 5-membered, 6-membered monocyclic ring is substituted with 0, 1, 2 or 3 groups selected from the following: halogen, hydroxyl, amino, cyano, carbonyl, oxo , carboxyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-4 haloalkyl, C _1-6 alkyl hydroxyl, C _{1 -6} alkylcarbonyl, C _1-6 alkoxy, C _1-6 haloalkoxy, -COO-C _1-6 alkyl, -C(O)NR ^f R ^f ; wherein, the R ^f is hydrogen , C _1-6 alkyl; or, R ⁵ and R ⁶ are each independently selected from H, C _1-10 alkyl, C _2-6 alkenyl, the C _1-10 alkyl, C _2-6 alkenyl The radical is optionally substituted by one or more R ^d ; the R ^d is selected from the following substituents: halogen, C _1-3 fluoroalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy , -COO-C _1-6 alkyl, -C(O)NR ^f R ^f , 5-8 membered aromatic ring, -het, mono- or bicyclic-C _5-8- cycloalkyl; wherein, the R ^f is hydrogen, C _1-6 alkyl; the het represents a 5-8 membered monocyclic or bicyclic, saturated or unsaturated heterocyclic ring, which contains 1, 2, 3 or 4 independently selected from N, Heteroatom in S, O; R ⁴ is selected from halogen, hydroxyl, amine, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _3-8 cycloalkyl, C _{1- 6} deuterated alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-8 halocycloalkyl, C _1-6 alkyl hydroxyl, C _1-6 alkyl Carbonyl group, C _1-6 alkoxy group, C _1-6 haloalkoxy group, _3-10 membered heterocycloalkyl group; the C _1-6 alkyl group, C _3-8 cycloalkyl group, C _1-6 deuterium group Alkyl group, C _2-6 alkynyl group, C _1-6 haloalkyl group, C _3-8 halocycloalkyl group, C _1-6 alkyl hydroxyl group, C _1-6 alkyl carbonyl group, C _1-6 alkoxy group The C _1-6 haloalkoxy group is optionally substituted by one or more ^Rg ; the ^Rg is selected from the following substituents: halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, Carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 alkylhydroxy, C _1-6 alkylcarbonyl, C _{1 -6} alkoxy group, C _1-6 haloalkoxy group; when there are multiple substituents, the ^Rg may be the same or different.

In a preferred embodiment of the present invention, it is a compound represented by formula II-A or formula II-B or a tautomer, stereoisomer, hydrated compound of formula II-A or formula II-B. substances, solvates, pharmaceutically acceptable salts or prodrugs, or .

In the present invention, the definitions of certain substituents in the compounds shown in Formula II, II-A or II-B can be as described below, and the definitions of substituents not mentioned are as described in any of the above schemes.

In a preferred embodiment of the present invention, the ring A is a 5-9 membered heteroaryl ring.

In a preferred embodiment of the present invention, the heteroaromatic ring has 1 or 2 heteroatoms.

In a preferred embodiment of the present invention, the impurity atom is selected from N or O.

In a preferred embodiment of the present invention, the ring A is a 5-9 membered heteroaromatic ring having 1 or 2 heteroatoms which are N or O.

In a preferred embodiment of the present invention, the ring A is selected from a pyridine ring, a pyrimidine ring, a pyridine ring, a pyridine ring or a benzoxazolyl ring.

In a preferred embodiment of the present invention, the ring A is selected from the group consisting of or .

In a preferred embodiment of the present invention, the structural unit Selected from or .

In a preferred embodiment of the present invention, the ring A is a 5-6 membered heteroaromatic ring. Preferably, the heteroaromatic ring has 1 or 2 heteroatoms which are N; more preferably, the ring A is selected from a pyridine ring, a pyrimidine ring, a pyridine ring or a pyridine ring.

In a preferred embodiment of the present invention, the ^Ra is F, Cl, CH ₃ or CH ₃ substituted by a halogen.

In a preferred embodiment of the present invention, the ^Ra is F, Cl or CHF ₂ .

In a preferred embodiment of the present invention, the R ^a is F or Cl.

In a preferred embodiment of the present invention, when Y is selected from NR ¹ or CHR ¹ , R ¹ is selected from H or C _1-6 alkyl.

In a preferred embodiment of the present invention, the Y is selected from -NH-.

In a preferred embodiment of the present invention, it is a compound represented by formula III or formula IV, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of a compound represented by formula III or formula IV, , .

In a preferred embodiment of the present invention, it is a compound represented by formula III-A, III-B or formula IV-A, IV-B, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of a compound represented by formula III-A, III-B or formula IV-A, IV-B, , .

In a preferred embodiment of the invention, Q is selected from the following groups: or .

In a preferred embodiment of the present invention, B is selected from 3-10 membered heterocycloalkyl and 3-10 membered heterocycloalkenyl.

In a preferred embodiment of the present invention, B is selected from 3-10 membered heterocycloalkyl.

In a preferred embodiment of the present invention, the 3-10 membered heterocycloalkyl group is monocyclic, condensed and bicyclic, bridged or spiro bicyclic.

In a preferred embodiment of the present invention, the 3-10 membered heterocycloalkyl group is monocyclic, condensed and bicyclic, including bridged or spirocyclic bicyclic.

In a preferred embodiment of the present invention, the 3-10 membered heterocycloalkyl group further has 1 to 3 heteroatoms selected from N, O, and S.

In a preferred embodiment of the present invention, B is selected from 3-10 membered heterocyclic alkenyl.

In a preferred embodiment of the present invention, the 3-10 membered heterocycloalkenyl group is monocyclic or fused bicyclic.

In a preferred embodiment of the present invention, the 3-10 membered heterocyclenyl group is monocyclic.

In a preferred embodiment of the present invention, the 3-10 membered heterocyclic alkenyl group further has 1 to 3 heteroatoms selected from N, O, and S.

In a preferred embodiment of the present invention, the B is selected from the following groups: , , , , , , , , , , , , ; Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , Z ⁶ , Z ⁷ , Z ⁸ and Z ⁹ are each independently N, NH, CH ₂ , CH, C, -NH-CH ₂ - or -CH ₂ -CH ₂ -.

In a preferred embodiment of the present invention, the B is selected from the following groups: , , , or ; Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , Z ⁶ , Z ⁷ and Z ⁸ each independently represent a ring atom; Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , Z ⁶ , Z ⁷ and Z ⁸ each independently represent N, NH, CH ₂ , CH, C, -NH-CH ₂ - or -CH ₂ -CH ₂ -; p is 0, 1 or 2.

In a preferred embodiment of the present invention, said B is selected from the following groups: , , or ; Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , Z ⁶ , Z ⁷ and Z ⁸ each independently represent ring atoms; Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , Z ⁶ , Z ⁷ and Z ⁸ are each independently N, NH, CH ₂ , CH, C, -NH-CH ₂ - or -CH ₂ -CH ₂ -; p is 0, 1 or 2.

In a preferred embodiment of the present invention, when p is 0, for .

In a preferred embodiment of the present invention, the B is selected from the following groups: , , ; Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , Z ⁶ , Z ⁷ and Z ⁸ each independently represent a ring atom; Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , Z ⁶ , Z ⁷ and Z ⁸ each independently represent N or C; p is 0, 1 or 2.

In a preferred embodiment of the invention, for or .

In a preferred embodiment of the present invention, for , .

In a preferred embodiment of the present invention, for .

In a preferred embodiment of the present invention, for .

In a preferred embodiment of the present invention, for .

In a preferred embodiment of the invention, for , .

In a preferred embodiment of the invention, for , .

In a preferred embodiment of the invention, for or .

In a preferred embodiment of the invention, for .

In a preferred embodiment of the invention, for .

In a preferred embodiment of the present invention, for .

In a preferred embodiment of the present invention, said B is selected from the following groups: , , ; Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ and Z ⁶ each independently represent ring atoms; Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ and Z ⁶ each independently represent N, NH, CH ₂ , CH or C.

In a preferred embodiment of the present invention, said B is selected from the following groups: , , ; Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ and Z ⁶ each independently represent a ring atom; Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ and Z ⁶ each independently represent N or C.

In a preferred embodiment of the invention, for .

In a preferred embodiment of the invention, for .

In a preferred embodiment of the present invention, for .

In a preferred embodiment of the present invention, R ^b is selected from C _1-6 alkyl, halogen, C _3-8 cycloalkyl or oxo.

In a preferred embodiment of the present invention, said R ^b is selected from methyl, F, cycloethyl or oxo.

In a preferred embodiment of the present invention, the R ^c is selected from 0, 1, 2 or 3.

In a preferred embodiment of the present invention, R ^c is selected from halogen, oxo, C _1-6 alkyl or C _1-6 halogenated alkyl.

In a preferred embodiment of the present invention, the ^Rg is selected from 0, 1, 2 or 3.

In a preferred embodiment of the present invention, ^Rg is selected from halogen, hydroxyl, cyano, _C1-6 alkyl or _C1-6 halogenated alkyl.

A person skilled in the art to which the present invention belongs can understand that, according to the common practice used in the field, in the structural formula of the present application, Used to depict chemical bonds, which are the points at which a moiety or substituent is attached to a core or backbone structure.

In a preferred embodiment of the invention, the fragment Selected from , , , , , , , , , , , , , , , , , , , , , or .

In a preferred embodiment of the present invention, the fragment Selected from , , , , , , , , , , , , , , , , , , , , , or .

In a preferred embodiment of the present invention, the fragment Selected from , , , , , , , , , , , , , , , , , , , , .

In a preferred embodiment of the present invention, the fragment Selected from , , , , , , , , , , , , , , , , , , .

In a preferred embodiment _of the present invention, R ¹ is selected from H and C _1-6 alkyl.

In a preferred embodiment of the present invention, Y is -NH-.

In a preferred embodiment of the present invention, Q is selected from the following groups: , , , , or ; r is 0, 1, 2 or 3; M, R ⁴ and R ⁷ are as defined in the first aspect of the invention.

In a preferred embodiment of the present invention, Q is selected from the following groups: , , or ; R ⁴ and R ⁷ are as defined in the first aspect of the invention.

In a preferred embodiment of the present invention, Q is selected from the following groups: , , ; R ⁴ is as defined in the first aspect of the invention.

In a preferred embodiment of the present invention, ^R7 is selected from 1, 2 or 3.

In a preferred embodiment of the present invention, said R ²³ is selected from F.

In a preferred embodiment of the present invention, the R ⁷ is selected from H, hydroxyl, cyano or CH ₃ .

In a preferred embodiment of the present invention, R ⁴ is selected from hydroxyl or cyano.

In a preferred embodiment of the present invention, Q is selected from the following groups: , , , , , , or .

In a preferred embodiment of the present invention, Q is selected from the following groups: , , , , , or .

In a preferred embodiment of the present invention, the compound has the following structure: Wherein, the B' is selected from , , or , Z ¹ and Z ⁴ are each independently selected from N or CH, and at least one of Z ¹ and Z ⁴ is N; Z ¹ and Connected, the Z ⁴ is connected to ring A; R ^b is selected from halogen, hydroxyl, amine, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 deuterated alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-8 halocycloalkyl, C _1-6 alkyl hydroxyl, C _{1 -6} alkylcarbonyl, C _1-6 alkoxy, C _1-6 haloalkoxy, 3-10 membered heterocycloalkyl; the C _1-6 alkyl, C _3-8 cycloalkyl, C _{1 -6} deuterated alkyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-8 halocycloalkyl, C _1-6 alkylhydroxy, C _1-6 alkylcarbonyl, C _{1- 6} alkoxy and C _1-6 haloalkoxy are optionally substituted by one or more R ^c ; the R ^c is selected from the following substituents: halogen, hydroxyl, amino, nitro, cyano, carbonyl, Oxo, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 alkylhydroxy, C _1-6 alkylcarbonyl , C _1-6 alkoxy group, C _1-6 haloalkoxy group; when the substituent R ^c is multiple, the R ^c is the same or different; m and n are independently 0, 1, 2 or 3; When B' is selected from , when Z ₁ is N and Z ₄ is CH, Q is not , n is 0, 1, 2, 3; or Q is When, n is 1, 2, 3; R ⁴ is defined as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Y, Q, ring A, B, ^Ra and ^Rb are as defined in the present invention; m and n are as defined in the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Y, Q, ring A, B, ^Ra and ^Rb are as defined in the present invention; m and n are as defined in the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Y, Q, ring A, R ^a and R ^b are defined as described in the first aspect of the present invention; m and n are defined as described in the first aspect of the present invention, and Z ¹ and Z ⁴ are independently Selected from N, CH or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Y, Q, ring A, R ^a and R ^b are defined as described in the first aspect of the present invention; m and n are defined as described in the first aspect of the present invention, and Z ¹ is each independently selected from N , CH or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Y, Q, Ring A and ^Ra are defined as described in the first aspect of the present invention; m is defined as described in the first aspect of the present invention, and Z ¹ and Z ⁴ are each independently selected from N, CH or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Y, Q, ring A and R ^a are defined as described in the first aspect of the present invention; m is defined as described in the first aspect of the present invention, and Z ¹ and Z ⁴ are each independently selected from N, CH or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein, Y, Q, ring A, R ^a and R ^b are defined as described in the first aspect of the present invention; m and n are defined as described in the first aspect of the present invention, and Z ¹ and Z ⁴ are independently Selected from N, CH or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Y, Q, Ring A and ^Ra are defined as described in the first aspect of the present invention; m is defined as described in the first aspect of the present invention, and Z ¹ and Z ⁴ are each independently selected from N, CH or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Y, Q, Ring A and ^Ra are defined as described in the first aspect of the present invention; m is defined as described in the first aspect of the present invention, and Z ¹ and Z ⁴ are each independently selected from N, CH or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Y, Q, ring A and R ^a are defined as described in the first aspect of the present invention; m is defined as described in the first aspect of the present invention, and Z ¹ and Z ⁴ are each independently selected from N, CH or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Y, Q, ring A and R ^a are defined as described in the first aspect of the present invention; m is defined as described in the first aspect of the present invention, and Z ¹ and Z ⁴ are each independently selected from N, CH or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Y, Q, ring A and R ^a are defined as described in the first aspect of the present invention; m is defined as described in the first aspect of the present invention, and Z ¹ and Z ⁴ are each independently selected from N, CH or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Y, Q, ring A, ^Ra and ^Rb are as defined in the first aspect of the present invention; m and n are as defined in the first aspect of the present invention, and Z ¹ is independently selected from N, CH or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Y, Q, ring A, R ^a and R ^b are defined as described in the first aspect of the present invention; m and n are defined as described in the first aspect of the present invention, and Z ⁴ is each independently selected from N , CH or C.

In a preferred embodiment of the invention, the compound is selected from the following structures: , wherein Y, Q, ring A, R ^a and R ^b are defined as described in the first aspect of the present invention; m and n are defined as described in the first aspect of the present invention, and Z ¹ is each independently selected from N , CH or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Y, Q, ring A and R ^a are defined as described in the first aspect of the present invention; m is defined as described in the first aspect of the present invention, and Z ¹ and Z ⁴ are each independently selected from N, CH or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Y, Q, Ring A and ^Ra are defined as described in the first aspect of the present invention; m is defined as described in the first aspect of the present invention, and Z ¹ and Z ⁴ are each independently selected from N, CH or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein R ^b is selected from halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 deuterated alkyl, C _2-6 alkenyl, C 2-6 alkynyl, C _1-6 halogenated alkyl, C _3-8 halogenated cycloalkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy, 3-10 membered heterocycloalkyl; the C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 deuterated alkyl, C _2-6 alkynyl, C _1-6 halogenated alkyl _, C _3-8 halogenated cycloalkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C The _1-6 halogenated alkoxy group is optionally substituted by one or more R ^c ; the R ^c is selected from the following substituents: halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _2-6 alkynyl, C _1-6 halogenated alkyl, C 1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy; when the substituent R ^c is multiple, the R ^c are the same or different; m is 0, 1, ₂ or 3; n is 1, 2 or 3 respectively; Z ¹ and Z ⁴ are each independently selected from N, CH or C; Y, Q, ring A and ^Ra are defined as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein the definitions of rings A, B, ^Ra and R ^b are as described in the first aspect of the present invention; the definitions of m and n are as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein rings A, B, ^Ra and ^Rb are defined as described in the first aspect of the present invention; and m and n are defined as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein the definitions of rings A, B, ^Ra and R ^b are as described in the first aspect of the present invention; the definitions of m and n are as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein the definitions of rings A, B, ^Ra and R ^b are as described in the first aspect of the present invention; the definitions of m and n are as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein rings A, B, ^Ra and ^Rb are defined as described in the first aspect of the present invention; and m and n are defined as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein rings A, B, ^Ra and ^Rb are defined as described in the first aspect of the present invention; and m and n are defined as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein rings A, B, ^Ra and ^Rb are defined as described in the first aspect of the present invention; and m and n are defined as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: Wherein, the definitions of rings A, B, R ²³ , ^Ra and R ^b are as described in the first aspect of the present invention; the definitions of r, m and n are as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: or , wherein, rings A, B, R ^a and R ^b are as defined in the present invention; m and n are as defined in the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: or , wherein, rings A, B, R ^a and R ^b are as defined in the present invention; m and n are as defined in the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: or , wherein ring A, B, ^Ra and ^Rb are as described in the first aspect of the present invention; m and n are as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: or , wherein rings A, B, ^Ra and ^Rb are as defined in the present invention; and m and n are as defined in the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: or , wherein ring A, B, ^Ra and ^Rb are as defined in the present invention; m and n are as defined in the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: or , wherein, rings A, B, R ^a and R ^b are as defined in the present invention; m and n are as defined in the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: or , wherein, rings A, B, R ^a and R ^b are as defined in the present invention; m and n are as defined in the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: or Wherein, the definitions of rings A, B, R ²³ , ^Ra and R ^b are as described in the first aspect of the present invention; the definitions of r, m and n are as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein B is a 4- to 9-membered heterocycloalkyl group having 1 to 3 heteroatoms selected from N, O, and S; the 4- to 9-membered heterocycloalkyl group is a monocyclic, fused bicyclic, bicyclic including a bridged ring or a spirocyclic ring; ^R is selected from a halogen, a hydroxyl, an amine, a nitro, a cyano, a carbonyl, an oxo, a carboxyl, a C _1-6 alkyl, a C _1-6 deuterated alkyl, a C _2-6 alkynyl, a C 1-6 halogenated alkyl, a C _1-6 alkylhydroxyl, a C _1-6 alkylcarbonyl, a C _1-6 alkoxyl, a C _1-6 halogenated alkoxyl; and n is ₀ , 1, 2, or 3.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein B is a 6- to 8-membered heterocycloalkyl group having 1 to 3 heteroatoms selected from N, O, and S; the 6- to 8-membered heterocycloalkyl group is a monocyclic, fused bicyclic, bicyclic including a bridged ring or a spirocyclic ring; R ^b is selected from a halogen, a hydroxyl, an amine, a nitro, a cyano, a carbonyl, an oxo, a carboxyl, a C _1-6 alkyl, a C _1-6 deuterated alkyl, a C _2-6 alkynyl, a C 1-6 halogenated alkyl, a C _1-6 alkylhydroxyl, a C _1-6 alkylcarbonyl, a C _1-6 alkoxyl, a C _1-6 halogenated alkoxyl; and n is 0 _, 1, 2, or 3.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein B is a 4 to 9-membered heterocycloalkyl group with 1 to 3 heteroatoms selected from N, O, and S; the 4 to 9-membered heterocycloalkyl group is monocyclic, fused, and bicyclic. , bicyclic including bridged ring or spiro ring; R ^b is selected from halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl base, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 alkyl hydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 haloalkoxy; n is 0, 1, 2 or 3.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein B is a 6- to 8-membered heterocycloalkyl group with 1 to 3 heteroatoms selected from N, O, and S; the 6- to 8-membered heterocycloalkyl group is monocyclic, fused, and bicyclic. , bicyclic including bridged ring or spiro ring; R ^b is selected from halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl base, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 alkyl hydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 haloalkoxy; n is 0, 1, 2 or 3.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein B is a 4 to 9-membered heterocycloalkyl group with 1 to 3 heteroatoms selected from N, O, and S; the 4 to 9-membered heterocycloalkyl group is monocyclic, fused, and bicyclic. , bicyclic including bridged ring or spiro ring; R ^b is selected from halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl base, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 alkyl hydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 haloalkoxy; n is 0, 1, 2 or 3.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein B is a 6- to 8-membered heterocycloalkyl group with 1 to 3 heteroatoms selected from N, O, and S; the 6- to 8-membered heterocycloalkyl group is monocyclic, fused, and bicyclic. , bicyclic including bridged ring or spiro ring; R ^b is selected from halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl base, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 alkyl hydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 haloalkoxy; n is 0, 1, 2 or 3.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein B is a 4- to 9-membered heterocycloalkyl group having 1 to 3 heteroatoms selected from N, O, and S; the 4- to 9-membered heterocycloalkyl group is a monocyclic, fused bicyclic, bicyclic including a bridged ring or a spirocyclic ring; ^R is selected from a halogen, a hydroxyl, an amine, a nitro, a cyano, a carbonyl, an oxo, a carboxyl, a C _1-6 alkyl, a C _1-6 deuterated alkyl, a C _2-6 alkynyl, a C 1-6 halogenated alkyl, a C _1-6 alkylhydroxyl, a C _1-6 alkylcarbonyl, a C _1-6 alkoxyl, a C _1-6 halogenated alkoxyl; and n is ₀ , 1, 2, or 3.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein B is a 6- to 8-membered heterocycloalkyl group with 1 to 3 heteroatoms selected from N, O, and S; the 6- to 8-membered heterocycloalkyl group is monocyclic, fused, and bicyclic. , bicyclic including bridged ring or spiro ring; R ^b is selected from halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl base, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 alkyl hydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 haloalkoxy; n is 0, 1, 2 or 3.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein B is a 4 to 9-membered heterocycloalkyl group with 1 to 3 heteroatoms selected from N, O, and S; the 4 to 9-membered heterocycloalkyl group is monocyclic, fused, and bicyclic. , bicyclic including bridged ring or spiro ring; R ^b is selected from halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl base, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 alkyl hydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 haloalkoxy; n is 0, 1, 2 or 3.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein B is a 6- to 8-membered heterocycloalkyl group having 1 to 3 heteroatoms selected from N, O, and S; the 6- to 8-membered heterocycloalkyl group is a monocyclic, fused bicyclic, bicyclic including a bridged ring or a spirocyclic ring; R ^b is selected from a halogen, a hydroxyl, an amine, a nitro, a cyano, a carbonyl, an oxo, a carboxyl, a C _1-6 alkyl, a C _1-6 deuterated alkyl, a C _2-6 alkynyl, a C 1-6 halogenated alkyl, a C _1-6 alkylhydroxyl, a C _1-6 alkylcarbonyl, a C _1-6 alkoxyl, a C _1-6 halogenated alkoxyl; and n is 0 _, 1, 2, or 3.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein B is a 4 to 9-membered heterocycloalkyl group with 1 to 3 heteroatoms selected from N, O, and S; the 4 to 9-membered heterocycloalkyl group is monocyclic, fused, and bicyclic. , bicyclic including bridged ring or spiro ring; R ^b is selected from halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl base, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 alkyl hydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 haloalkoxy; n is 0, 1, 2 or 3.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein B is a 6- to 8-membered heterocycloalkyl group with 1 to 3 heteroatoms selected from N, O, and S; the 6- to 8-membered heterocycloalkyl group is monocyclic, fused, and bicyclic. , bicyclic including bridged ring or spiro ring; R ^b is selected from halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl base, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 alkyl hydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 haloalkoxy; n is 0, 1, 2 or 3.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein B is a 4- to 9-membered heterocycloalkyl group having 1 to 3 heteroatoms selected from N, O, and S; the 4- to 9-membered heterocycloalkyl group is a monocyclic, fused bicyclic, bicyclic including a bridged ring or a spirocyclic ring; ^R is selected from a halogen, a hydroxyl, an amine, a nitro, a cyano, a carbonyl, an oxo, a carboxyl, a C _1-6 alkyl, a C _1-6 deuterated alkyl, a C _2-6 alkynyl, a C 1-6 halogenated alkyl, a C _1-6 alkylhydroxyl, a C _1-6 alkylcarbonyl, a C _1-6 alkoxyl, a C _1-6 halogenated alkoxyl; and n is ₀ , 1, 2, or 3.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein B is a 4 to 9-membered heterocycloalkyl group with 1 to 3 heteroatoms selected from N, O, and S; the 4 to 9-membered heterocycloalkyl group is monocyclic, fused, and bicyclic. , bicyclic including bridged ring or spiro ring; R ^b is selected from halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl base, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 alkyl hydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 haloalkoxy; n is 0, 1, 2 or 3.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein, Z ¹ and Z ⁴ are each independently N, CH or C; Ring A, R ^a and R ^b are as defined in the first aspect of the present invention; m and n are as defined in the first aspect of the present invention. described.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are each independently N, CH or C; ring A, ^Ra and R ^b are defined as described in the first aspect of the present invention; m and n are defined as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ is independently N, CH or C; ring A, ^Ra and R ^b are defined as described in the first aspect of the present invention; m and n are defined as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ is independently N, CH or C; ring A, ^Ra and R ^b are defined as described in the first aspect of the present invention; m and n are defined as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are each independently N, CH or C; ring A, ^Ra and R ^b are defined as described in the first aspect of the present invention; m and n are defined as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein, Z ¹ and Z ⁴ are each independently N, CH or C; Ring A, R ^a and R ^b are as defined in the first aspect of the present invention; m and n are as defined in the first aspect of the present invention. described.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ is independently N, CH or C; ring A, ^Ra and R ^b are defined as described in the first aspect of the present invention; m and n are defined as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein, Z ¹ is each independently N, CH or C; Ring A, ^Ra and R ^b are defined as described in the first aspect of the present invention; m and n are defined as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are each independently N, CH or C; ring A and ^Ra are defined as described in the first aspect of the present invention; and m is defined as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are each independently N, CH or C; Ring A and R ^a are as defined in the first aspect of the present invention; m is defined as as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are each independently N, CH or C; Ring A and R ^a are as defined in the first aspect of the present invention; m is defined as as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are each independently N, CH or C; Ring A and R ^a are as defined in the first aspect of the present invention; m is defined as as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are each independently N, CH or C; ring A, ^Ra and R ^b are defined as described in the first aspect of the present invention; m and n are defined as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are each independently N, CH or C; Ring A and R ^a are as defined in the first aspect of the present invention; m is defined as as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are each independently N, CH or C; Ring A and R ^a are as defined in the first aspect of the present invention; m is defined as as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are each independently N, CH or C; Ring A and R ^a are as defined in the first aspect of the present invention; m is defined as as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein, Z ¹ and Z ⁴ are each independently N, CH or C; Ring A, R ^a and R ^b are as defined in the first aspect of the present invention; m and n are as defined in the first aspect of the present invention. described.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are each independently N, CH or C; ring A, ^Ra and R ^b are defined as described in the first aspect of the present invention; m and n are defined as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein, Z ¹ and Z ⁴ are each independently N, CH or C; Ring A, R ^a and R ^b are as defined in the first aspect of the present invention; m and n are as defined in the first aspect of the present invention. described.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are each independently N, CH or C; Ring A and R ^a are as defined in the first aspect of the present invention; m is defined as as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are each independently N, CH or C; Ring A and R ^a are as defined in the first aspect of the present invention; m is defined as as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are each independently N, CH or C; ring A and ^Ra are defined as described in the first aspect of the present invention; and m is defined as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are each independently N, CH or C; Ring A and R ^a are as defined in the first aspect of the present invention; m is defined as as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are each independently N, CH or C; ring A and ^Ra are defined as described in the first aspect of the present invention; and m is defined as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are each independently N, CH or C; Ring A and R ^a are as defined in the first aspect of the present invention; m is defined as as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are each independently N, CH or C; ring A and ^Ra are defined as described in the first aspect of the present invention; and m is defined as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are each independently N, CH or C; Ring A and R ^a are as defined in the first aspect of the present invention; m is defined as as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are each independently N, CH or C; Ring A and R ^a are as defined in the first aspect of the present invention; m is defined as as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are each independently N, CH or C; ring A and ^Ra are defined as described in the first aspect of the present invention; and m is defined as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are each independently N, CH or C; ring A and ^Ra are defined as described in the first aspect of the present invention; and m is defined as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are each independently N, CH or C; ring A and ^Ra are defined as described in the first aspect of the present invention; and m is defined as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are each independently N, CH or C; ring A and ^Ra are defined as described in the first aspect of the present invention; and m is defined as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ is independently N, CH or C; ring A, ^Ra and R ^b are defined as described in the first aspect of the present invention; m and n are defined as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ⁴ is each independently N, CH or C; Ring A, ^Ra and R ^b are defined as described in the first aspect of the present invention; m and n are defined as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ is independently N, CH or C; ring A, ^Ra and R ^b are defined as described in the first aspect of the present invention; m and n are defined as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ is each independently N, CH or C; Ring A and R ^a are as defined in the first aspect of the present invention; m is defined as as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are each independently N, CH or C; Ring A and R ^a are as defined in the first aspect of the present invention; m is defined as as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are each independently N, CH or C; R ^b is selected from H, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 deuterated alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenated alkyl, C _3-8 halogenated cycloalkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy, 3-10 membered heterocycloalkyl; the C _1-6 alkyl, C ₃ -C ₈ cycloalkyl, C _1-6 deuterated alkyl, C _2-6 alkynyl, C _1-6 halogenated alkyl, C _3-8 halogenated cycloalkyl, C C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy is optionally substituted by one or more R ^c ; said R ^c is selected from the following substituents: halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _{1-6 deuterated alkyl, C 2-6} alkynyl _, C _1-6 halogenated alkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy; when there are multiple substituents, said R ^c are the same or different; n is 0, 1, 2 or 3.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are each independently N or C; R ^b is selected from H, halogen, hydroxyl, amine, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 deuterated alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenated alkyl, C _3-8 halogenated cycloalkyl, C _{1-6 alkylhydroxyl, C 1-6 alkylcarbonyl} , C _1-6 alkoxy, C _1-6 halogenated alkoxy, 3-10 membered heterocycloalkyl; the C _1-6 alkyl, C ₃ -C ₈ cycloalkyl, C _1-6 deuterated alkyl, C _2-6 alkynyl, C _1-6 halogenated alkyl, C _3-8 halogenated cycloalkyl, C C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy is optionally substituted by one or more R ^c ; said R ^c is selected from the following substituents: halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _{1-6 deuterated alkyl, C 2-6} alkynyl _, C _1-6 halogenated alkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy; when there are multiple substituents, said R ^c are the same or different; n is 0, 1, 2 or 3.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are each independently N, CH or C; R ^b is selected from H, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 deuterated alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenated alkyl, C _3-8 halogenated cycloalkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy, 3-10 membered heterocycloalkyl; the C _1-6 alkyl, C ₃ -C ₈ cycloalkyl, C _1-6 deuterated alkyl, C _2-6 alkynyl, C _1-6 halogenated alkyl, C _3-8 halogenated cycloalkyl, C C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy is optionally substituted by one or more R ^c ; said R ^c is selected from the following substituents: halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _{1-6 deuterated alkyl, C 2-6} alkynyl _, C _1-6 halogenated alkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy; when there are multiple substituents, said R ^c are the same or different; n is 0, 1, 2 or 3.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are each independently N or C; R ^b is selected from H, halogen, hydroxyl, amine, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 deuterated alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenated alkyl, C _3-8 halogenated cycloalkyl, C _{1-6 alkylhydroxyl, C 1-6 alkylcarbonyl} , C _1-6 alkoxy, C _1-6 halogenated alkoxy, 3-10 membered heterocycloalkyl; the C _1-6 alkyl, C ₃ -C ₈ cycloalkyl, C _1-6 deuterated alkyl, C _2-6 alkynyl, C _1-6 halogenated alkyl, C _3-8 halogenated cycloalkyl, C C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy is optionally substituted by one or more R ^c ; said R ^c is selected from the following substituents: halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _{1-6 deuterated alkyl, C 2-6} alkynyl _, C _1-6 halogenated alkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy; when there are multiple substituents, said R ^c are the same or different; n is 0, 1, 2 or 3.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ is N, CH or C; R ^b is selected from H, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _3-8 cycloalkyl, C _{1-6 deuterated alkyl, C 2-6} alkenyl, C _2-6 alkynyl, C _1-6 halogenated alkyl, C _3-8 halogenated cycloalkyl, C 1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy, 3-10 membered heterocycloalkyl; the C _1-6 alkyl, C ₃ -C 8 cycloalkyl, C _1-6 deuterated alkyl, C _2-6 alkynyl, C _1-6 halogenated alkyl, C _3-8 halogenated cycloalkyl, C _1-6 alkylhydroxyl, C _{1-6 alkylcarbonyl, C 1-6} alkoxy, C _1-6 halogenated alkoxy, 3-10 _membered heterocycloalkyl C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy is optionally substituted by one or more R ^c ; said R ^c is selected from the following substituents: halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _2-6 alkynyl, _C 1-6 halogenated alkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy; when there are multiple substituents, said R ^c are the same or different; n is 0, 1, 2 or 3.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ is N or C; R ^b is selected from H, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 deuterated alkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenated alkyl, C _3-8 halogenated cycloalkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy, 3-10 membered heterocycloalkyl; the C _1-6 alkyl, C ₃ -C _{8 cycloalkyl, C 1-6 deuterated alkyl, C 2-6 alkynyl} , C _1-6 halogenated alkyl, C 3-8 halogenated cycloalkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C 1-6 alkoxy, C _1-6 halogenated alkoxy, _3-10 membered heterocycloalkyl C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy is optionally substituted by one or more R ^c ; said R ^c is selected from the following substituents: halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _2-6 alkynyl, _C 1-6 halogenated alkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy; when there are multiple substituents, said R ^c are the same or different; n is 0, 1, 2 or 3.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ is N, CH or C; R ^b is selected from H, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _3-8 cycloalkyl, C _{1-6 deuterated alkyl, C 2-6} alkenyl, C _2-6 alkynyl, C _1-6 halogenated alkyl, C _3-8 halogenated cycloalkyl, C 1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy, 3-10 membered heterocycloalkyl; the C _1-6 alkyl, C ₃ -C 8 cycloalkyl, C _1-6 deuterated alkyl, C _2-6 alkynyl, C _1-6 halogenated alkyl, C _3-8 halogenated cycloalkyl, C _1-6 alkylhydroxyl, C _{1-6 alkylcarbonyl, C 1-6} alkoxy, C _1-6 halogenated alkoxy, 3-10 _membered heterocycloalkyl C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy is optionally substituted by one or more R ^c ; said R ^c is selected from the following substituents: halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _2-6 alkynyl, _C 1-6 halogenated alkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy; when there are multiple substituents, said R ^c are the same or different; n is 0, 1, 2 or 3.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ is N or C; R ^b is selected from H, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 deuterated alkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenated alkyl, C _3-8 halogenated cycloalkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy, 3-10 membered heterocycloalkyl; the C _1-6 alkyl, C ₃ -C _{8 cycloalkyl, C 1-6 deuterated alkyl, C 2-6 alkynyl} , C _1-6 halogenated alkyl, C 3-8 halogenated cycloalkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C 1-6 alkoxy, C _1-6 halogenated alkoxy, _3-10 membered heterocycloalkyl C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy is optionally substituted by one or more R ^c ; said R ^c is selected from the following substituents: halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _2-6 alkynyl, _C 1-6 halogenated alkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy; when there are multiple substituents, said R ^c are the same or different; n is 0, 1, 2 or 3.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are each independently N, CH or C; R ^b is selected from H, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl , C _3-8 cycloalkyl, C _1-6 deuterated alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-8 halocycloalkyl, C _1-6 alkylhydroxy, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 haloalkoxy, 3 to 10-membered heterocycloalkyl; the C _1-6 alkyl, C ₃ -C ₈ cycloalkyl, C _1-6 deuterated alkyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-8 halocycloalkyl, C _1-6 alkyl hydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 haloalkoxy are optionally substituted by one or more R ^c ; the R ^c is selected from the following substituents: halogen, hydroxyl, amine Base, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 alkyl hydroxyl group, C _1-6 alkylcarbonyl group, C _1-6 alkoxy group, C _1-6 haloalkoxy group; when there are multiple substituents, the R ^c is the same or different; n is 0, 1, 2 or 3.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are each independently N or C; R ^b is selected from H, halogen, hydroxyl, amine, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 deuterated alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenated alkyl, C _3-8 halogenated cycloalkyl, C _{1-6 alkylhydroxyl, C 1-6 alkylcarbonyl} , C _1-6 alkoxy, C _1-6 halogenated alkoxy, 3-10 membered heterocycloalkyl; the C _1-6 alkyl, C ₃ -C ₈ cycloalkyl, C _1-6 deuterated alkyl, C _2-6 alkynyl, C _1-6 halogenated alkyl, C _3-8 halogenated cycloalkyl, C C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy is optionally substituted by one or more R ^c ; said R ^c is selected from the following substituents: halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _{1-6 deuterated alkyl, C 2-6} alkynyl _, C _1-6 halogenated alkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy; when there are multiple substituents, said R ^c are the same or different; n is 0, 1, 2 or 3.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are each independently N, CH or C; R ^b is selected from H, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 deuterated alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenated alkyl, C _3-8 halogenated cycloalkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy, 3-10 membered heterocycloalkyl; the C _1-6 alkyl, C ₃ -C ₈ cycloalkyl, C _1-6 deuterated alkyl, C _2-6 alkynyl, C _1-6 halogenated alkyl, C _3-8 halogenated cycloalkyl, C C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy is optionally substituted by one or more R ^c ; said R ^c is selected from the following substituents: halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _{1-6 deuterated alkyl, C 2-6} alkynyl _, C _1-6 halogenated alkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy; when there are multiple substituents, said R ^c are the same or different; n is 0, 1, 2 or 3.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are each independently N or C; R ^b is selected from H, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 deuterated alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-8 halocycloalkyl, C _{1- 6} alkyl hydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 haloalkoxy, 3 to 10 membered heterocycloalkyl; the C _1-6 alkyl, C ₃ - C ₈ cycloalkyl, C _1-6 deuterated alkyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-8 halocycloalkyl, C _1-6 alkyl hydroxyl, C _{1- 6} alkylcarbonyl, C _1-6 alkoxy, C _1-6 haloalkoxy are optionally substituted by one or more R ^c ; the R ^c is selected from the following substituents: halogen, hydroxyl, amino, Nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 alkyl hydroxyl , C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 haloalkoxy; when there are multiple substituents, the R ^c is the same or different; n is 0, 1, 2 or 3 .

In a preferred embodiment of the present invention, the compound is selected from the following structures: , where Z ¹ is N, CH or C; R ^b is selected from H, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _3-8 ring Alkyl, C _1-6 deuterated alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-8 halocycloalkyl, C _1-6 alkyl hydroxyl , C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 haloalkoxy, 3 to 10-membered heterocycloalkyl; the C _1-6 alkyl, C ₃ -C ₈ cycloalkyl Base, C _1-6 deuterated alkyl group, C _2-6 alkynyl group, C _1-6 haloalkyl group, C _3-8 halocycloalkyl group, C _1-6 alkyl hydroxyl group, C _1-6 alkyl carbonyl group , C _1-6 alkoxy, C _1-6 haloalkoxy are optionally substituted by one or more R ^c ; the R ^c is selected from the following substituents: halogen, hydroxyl, amino, nitro, cyanide Base, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl _, C 2-6 alkynyl, C _1-6 haloalkyl, C _1-6 alkyl hydroxyl, C _{1- 6} alkylcarbonyl, C _1-6 alkoxy, C _1-6 haloalkoxy; when there are multiple substituents, the R ^c is the same or different; n is 0, 1, 2 or 3.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ is N or C; R ^b is selected from H, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 deuterated alkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenated alkyl, C _3-8 halogenated cycloalkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy, 3-10 membered heterocycloalkyl; the C _1-6 alkyl, C ₃ -C _{8 cycloalkyl, C 1-6 deuterated alkyl, C 2-6 alkynyl} , C _1-6 halogenated alkyl, C 3-8 halogenated cycloalkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C 1-6 alkoxy, C _1-6 halogenated alkoxy, _3-10 membered heterocycloalkyl C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy is optionally substituted by one or more R ^c ; said R ^c is selected from the following substituents: halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _2-6 alkynyl, _C 1-6 halogenated alkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy; when there are multiple substituents, said R ^c are the same or different; n is 0, 1, 2 or 3.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ is N, CH or C; R ^b is selected from H, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _3-8 cycloalkyl, C _{1-6 deuterated alkyl, C 2-6} alkenyl, C _2-6 alkynyl, C _1-6 halogenated alkyl, C _3-8 halogenated cycloalkyl, C 1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy, 3-10 membered heterocycloalkyl; the C _1-6 alkyl, C ₃ -C 8 cycloalkyl, C _1-6 deuterated alkyl, C _2-6 alkynyl, C _1-6 halogenated alkyl, C _3-8 halogenated cycloalkyl, C _1-6 alkylhydroxyl, C _{1-6 alkylcarbonyl, C 1-6} alkoxy, C _1-6 halogenated alkoxy, 3-10 _membered heterocycloalkyl C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy is optionally substituted by one or more R ^c ; said R ^c is selected from the following substituents: halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _2-6 alkynyl, _C 1-6 halogenated alkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy; when there are multiple substituents, said R ^c are the same or different; n is 0, 1, 2 or 3.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , where Z ¹ is N or C; R ^b is selected from H, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _3-8 cycloalkyl , C _1-6 deuterated alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-8 halocycloalkyl, C _1-6 alkyl hydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 haloalkoxy, 3 to 10-membered heterocycloalkyl; the C _1-6 alkyl, C ₃ -C ₈ cycloalkyl, C _1-6 deuterated alkyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-8 halocycloalkyl, C _1-6 alkylhydroxy, C _1-6 alkylcarbonyl, C _1-6 alkoxy and C _1-6 haloalkoxy are optionally substituted by one or more R ^c ; the R ^c is selected from the following substituents: halogen, hydroxyl, amino, nitro, cyano, Carbonyl, oxo, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 alkylhydroxy, C _1-6 alkyl carbonyl group, C _1-6 alkoxy group, C _1-6 haloalkoxy group; when there are multiple substituents, the R ^c is the same or different; n is 0, 1, 2 or 3.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are each independently N, CH or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are each independently N or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , where Z ¹ and Z ⁴ are each independently N, CH or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , where Z ¹ and Z ⁴ are each independently N or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , where Z ¹ and Z ⁴ are each independently N, CH or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , where Z ¹ and Z ⁴ are each independently N or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are each independently N, CH or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are each independently N or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are each independently N, CH or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are each independently N or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , where Z ⁴ is N, CH or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , where Z ⁴ is N or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ⁴ is N, CH or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , where Z ⁴ is N or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ⁴ is N, CH or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , where Z ⁴ is N or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ⁴ is N, CH or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , where Z ⁴ is N or C.

In a preferred embodiment of the invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are independently N, CH or C; R ^b is defined as described in the first aspect of the present invention; n is defined as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are independently N or C; R ^b is defined as described in the first aspect of the present invention; and n is defined as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , where Z ¹ and Z ⁴ are independently N, CH or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , where Z ¹ and Z ⁴ are independently N or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are independently N, CH or C; R ^b is defined as described in the first aspect of the present invention; and n is defined as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are independently N or C; R ^b is defined as described in the first aspect of the present invention; n is defined as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are independently N, CH or C; R ^b is defined as described in the first aspect of the present invention; n is defined as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are independently N or C; R ^b is defined as described in the first aspect of the present invention; and n is defined as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are independently N, CH or C; R ^b is defined as described in the first aspect of the present invention; and n is defined as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are independently N or C; R ^b is defined as described in the first aspect of the present invention; and n is defined as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are each independently N, CH or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , where Z ¹ and Z ⁴ are each independently N or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , where Z ¹ and Z ⁴ are each independently N, CH or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are each independently N or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are each independently N, CH or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , where Z ¹ and Z ⁴ are each independently N or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , where Z ¹ and Z ⁴ are each independently N, CH or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , where Z ¹ and Z ⁴ are each independently N or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , where Z ¹ and Z ⁴ are each independently N, CH or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are each independently N, CH or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are each independently N, CH or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , where Z ¹ and Z ⁴ are each independently N, CH or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , where Z ¹ and Z ⁴ are each independently N or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , where Z ¹ and Z ⁴ are each independently N, CH or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are each independently N or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , where Z ¹ and Z ⁴ are each independently N, CH or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are each independently N or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , where Z ¹ and Z ⁴ are each independently N, CH or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , where Z ¹ and Z ⁴ are each independently N or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , where Z ¹ and Z ⁴ are each independently N, CH or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are each independently N or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are each independently N, CH or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are each independently N or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ is N, CH or C; R ^b is selected from H, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _3-8 cycloalkyl, C _{1-6 deuterated alkyl, C 2-6} alkenyl, C _2-6 alkynyl, C _1-6 halogenated alkyl, C _3-8 halogenated cycloalkyl, C 1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy, 3-10 membered heterocycloalkyl; the C _1-6 alkyl, C ₃ -C 8 cycloalkyl, C _1-6 deuterated alkyl, C _2-6 alkynyl, C _1-6 halogenated alkyl, C _3-8 halogenated cycloalkyl, C _1-6 alkylhydroxyl, C _{1-6 alkylcarbonyl, C 1-6} alkoxy, C _1-6 halogenated alkoxy, 3-10 _membered heterocycloalkyl C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy is optionally substituted by one or more R ^c ; said R ^c is selected from the following substituents: halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _2-6 alkynyl, _C 1-6 halogenated alkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy; when there are multiple substituents, said R ^c are the same or different; n is 0, 1, 2 or 3.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ is N or C; R ^b is selected from H, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 deuterated alkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenated alkyl, C _3-8 halogenated cycloalkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy, 3-10 membered heterocycloalkyl; the C _1-6 alkyl, C ₃ -C _{8 cycloalkyl, C 1-6 deuterated alkyl, C 2-6 alkynyl} , C _1-6 halogenated alkyl, C 3-8 halogenated cycloalkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C 1-6 alkoxy, C _1-6 halogenated alkoxy, _3-10 membered heterocycloalkyl C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy is optionally substituted by one or more R ^c ; said R ^c is selected from the following substituents: halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _2-6 alkynyl, _C 1-6 halogenated alkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy; when there are multiple substituents, said R ^c are the same or different; n is 0, 1, 2 or 3.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , where Z ⁴ is N, CH or C; R ^b is selected from H, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _3-8 ring Alkyl, C _1-6 deuterated alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-8 halocycloalkyl, C _1-6 alkyl hydroxyl , C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 haloalkoxy, 3 to 10-membered heterocycloalkyl; the C _1-6 alkyl, C ₃ -C ₈ cycloalkyl Base, C _1-6 deuterated alkyl group, C _2-6 alkynyl group, C _1-6 haloalkyl group, C _3-8 halocycloalkyl group, C _1-6 alkyl hydroxyl group, C _1-6 alkyl carbonyl group , C _1-6 alkoxy, C _1-6 haloalkoxy are optionally substituted by one or more R ^c ; the R ^c is selected from the following substituents: halogen, hydroxyl, amino, nitro, cyanide Base, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl _, C 2-6 alkynyl, C _1-6 haloalkyl, C _1-6 alkyl hydroxyl, C _{1- 6} alkylcarbonyl, C _1-6 alkoxy, C _1-6 haloalkoxy; when there are multiple substituents, the R ^c is the same or different; n is 0, 1, 2 or 3.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , where Z ⁴ is N or C; R ^b is selected from H, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _3-8 cycloalkyl , C _1-6 deuterated alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-8 halocycloalkyl, C _1-6 alkyl hydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 haloalkoxy, 3 to 10-membered heterocycloalkyl; the C _1-6 alkyl, C ₃ -C ₈ cycloalkyl, C _1-6 deuterated alkyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-8 halocycloalkyl, C _1-6 alkylhydroxy, C _1-6 alkylcarbonyl, C _1-6 alkoxy and C _1-6 haloalkoxy are optionally substituted by one or more R ^c ; the R ^c is selected from the following substituents: halogen, hydroxyl, amino, nitro, cyano, Carbonyl, oxo, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 alkylhydroxy, C _1-6 alkyl carbonyl group, C _1-6 alkoxy group, C _1-6 haloalkoxy group; when there are multiple substituents, the R ^c is the same or different; n is 0, 1, 2 or 3.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , where Z ¹ is N, CH or C; R ^b is selected from H, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _3-8 ring Alkyl, C _1-6 deuterated alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-8 halocycloalkyl, C _1-6 alkyl hydroxyl , C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 haloalkoxy, 3 to 10-membered heterocycloalkyl; the C _1-6 alkyl, C ₃ -C ₈ cycloalkyl Base, C _1-6 deuterated alkyl group, C _2-6 alkynyl group, C _1-6 haloalkyl group, C _3-8 halocycloalkyl group, C _1-6 alkyl hydroxyl group, C _1-6 alkyl carbonyl group , C _1-6 alkoxy, C _1-6 haloalkoxy are optionally substituted by one or more R ^c ; the R ^c is selected from the following substituents: halogen, hydroxyl, amino, nitro, cyanide Base, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl _, C 2-6 alkynyl, C _1-6 haloalkyl, C _1-6 alkyl hydroxyl, C _{1- 6} alkylcarbonyl, C _1-6 alkoxy, C _1-6 haloalkoxy; when there are multiple substituents, the R ^c is the same or different; n is 0, 1, 2 or 3.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ is N or C; R ^b is selected from H, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 deuterated alkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenated alkyl, C _3-8 halogenated cycloalkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy, 3-10 membered heterocycloalkyl; the C _1-6 alkyl, C ₃ -C _{8 cycloalkyl, C 1-6 deuterated alkyl, C 2-6 alkynyl} , C _1-6 halogenated alkyl, C 3-8 halogenated cycloalkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C 1-6 alkoxy, C _1-6 halogenated alkoxy, _3-10 membered heterocycloalkyl C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy is optionally substituted by one or more R ^c ; said R ^c is selected from the following substituents: halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _2-6 alkynyl, _C 1-6 halogenated alkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy; when there are multiple substituents, said R ^c are the same or different; n is 0, 1, 2 or 3.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ is N, CH or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ is N or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ is N, CH or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ is N or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are each independently N, CH or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , wherein Z ¹ and Z ⁴ are each independently N or C.

In a preferred embodiment of the present invention, the compound is selected from the following structures: ; said fragment Selected from , , , , , , , , , .

In a preferred embodiment of the present invention, the compound is selected from the following structures: ; said fragment Selected from , , .

In a preferred embodiment of the present invention, the structural unit Selected from .

In a preferred embodiment of the present invention, the compound is selected from any of the following compounds: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

In a preferred embodiment of the present invention, the compound is selected from any one of the following compounds: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

In a preferred embodiment of the present invention, the compound is selected from any one of the following compounds: , , , , , , , , , , , , , , , .

In a preferred embodiment of the present invention, the compound is selected from any one of the following compounds: 1) (express ), wherein chiral separation was performed by normal phase HPLC, the separation method was (column: DAICEL CHIRALPAK AD (250mm*30mm, 10μm); solvent: A = carbon dioxide, B = ammonia (0.1%) + isopropanol; gradient (B): 40% - 40%, 4.7 minutes), retention time was 0.835 min; 2) (express ), wherein chiral separation was performed by normal phase HPLC, the separation method was (column: DAICEL CHIRALPAK AD (250mm*30mm, 10μm); solvent: A = carbon dioxide, B = ammonia (0.1%) + isopropanol; gradient (B): 40% - 40%, 4.7 minutes), the retention time was 1.084 min; 3) (express ） Among them, chiral separation was performed by normal phase HPLC, the separation method was (column: DAICEL CHIRALPAK AD (250mm*30mm, 10μm); solvent: A = carbon dioxide, B = ammonia (0.1%) + ethanol; gradient: 50% - 50%, 7 minutes), retention time 1.387 min; 4) (express ), wherein chiral separation was performed by normal phase HPLC, the separation method was (column: DAICEL CHIRALPAK AD (250mm*30mm, 10μm); solvent: A = carbon dioxide, B = ammonia (0.1%) + ethanol; gradient: 50% - 50%, 7 minutes), retention time 1.572min; 5) (express ), wherein chiral separation was performed by normal phase HPLC, the separation method was (column: DAICEL CHIRALPAK AD (250mm*30mm, 10μm); solvent: A = carbon dioxide, B = ammonia (0.1%) + ethanol; gradient: 50% - 50%, 7 minutes), retention time 1.657 min; 6) (express ), wherein chiral separation was performed by normal phase HPLC, the separation method was (column: DAICEL CHIRALPAK AD (250mm*30mm, 10μm); solvent: A = carbon dioxide, B = ammonia (0.1%) + ethanol; gradient: 50% - 50%, 7 minutes), retention time 1.742 min; 7) (express ), wherein chiral separation was performed by normal phase HPLC, the separation method was (column: DAICEL CHIRALPAK AD (250mm*30mm, 10μm); solvent: A = carbon dioxide, B = ammonia (0.1%) + ethanol; gradient: 50% - 50%, 7 minutes), retention time 1.852 min; 8) (express ), wherein chiral separation was performed by normal phase HPLC (column: DAICEL CHIRALPAK AD (250mm*30mm, 10μm); solvent: A = carbon dioxide, B = ammonia (0.1%) + ethanol; gradient: 50% - 50%, 7 minutes), retention time 1.477 min; 9) (express or ), wherein chiral separation was performed by normal phase HPLC, the separation method was (column: DAICEL CHIRALPAK AD (250mm*30mm, 10μm; solvent: A = carbon dioxide + acetonitrile, B = ammonia water (0.1%) + isopropanol; gradient: 45% - 45%, 20 minutes), retention time 1.899 min; 10) (express or ), wherein chiral separation was performed by normal phase HPLC, the separation method was (column: DAICEL CHIRALPAK AD (250mm*30mm, 10μm; solvent: A = carbon dioxide + acetonitrile, B = ammonia water (0.1%) + isopropanol; gradient: 45% - 45%, 20 minutes), retention time 1.586 min; 11) (express or ), wherein chiral separation was performed by normal phase HPLC, the separation method was (column: DAICEL CHIRALPAK IG (250mm*30mm, 10μm); solvent: A = carbon dioxide, B = ammonia (0.1%) + ethanol; gradient: 50% - 50%, 20 minutes), retention time 1.507 min; 12) (express or ), wherein chiral separation was performed by normal phase HPLC, the separation method was (column: DAICEL CHIRALPAK IG (250mm*30mm, 10μm); solvent: A = carbon dioxide, B = ammonia (0.1%) + ethanol; gradient: 50% - 50%, 20 minutes), retention time 1.964 min; 13) (express or ), wherein chiral separation was performed by normal phase HPLC, the separation method was (column: DAICEL CHIRALPAK IG (250mm*30mm, 10μm); solvent: A = carbon dioxide, B = ammonia (0.1%) + ethanol; gradient: 50% - 50%, 20 minutes), retention time 1.507 min; or 14) (express or ), wherein chiral separation was performed by normal phase HPLC (column: DAICEL CHIRALPAK IG (250mm*30mm, 10μm); solvent: A = carbon dioxide, B = ammonia water (0.1%) + ethanol; gradient: 50% - 50%, 20 minutes), retention time 1.625 min.

In a second aspect, the present invention provides a pharmaceutical composition, which comprises: the compound as described in the first aspect of the present invention, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug.

In a preferred embodiment of the present invention, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.

In a second aspect of the present invention, a pharmaceutical composition is provided. The pharmaceutical composition includes: the compound represented by formula I as described in the first aspect of the present invention, its tautomers, stereoisomers, hydrates, Solvates, pharmaceutically acceptable salts or prodrugs; and pharmaceutically acceptable carriers.

The third aspect of the present invention provides use of the compound as described in the first aspect of the present invention, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the drug composition as described in the second aspect for inhibiting PDE4B.

The fourth aspect of the present invention provides the use of the compound as described in the first aspect of the present invention, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the drug composition as described in the second aspect in the preparation of a drug or preparation for inhibiting PDE4B, and/or preventing and/or treating PDE4B-related diseases.

The fifth aspect of the present invention provides the compound represented by formula I as described in the first aspect of the present invention, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs The use, or the use of the pharmaceutical composition according to the second aspect of the present invention, the use includes: inhibiting PDE4B; and/or, preventing and/or treating PDE4B-related diseases; and/or, preparing for inhibiting PDE4B, and/or drugs, pharmaceutical compositions or preparations for preventing and/or treating PDE4B-related diseases.

Preferably, the PDE4B-related diseases include: respiratory diseases, gastrointestinal diseases, inflammatory diseases of joints, skin or eyes, cancer and peripheral or central nervous system diseases, autoimmune diseases (such as systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, dermatomyositis, polymyositis, vasculitis, and diffuse connective tissue diseases such as Sjögren's disease), transplant rejection, and disorders related to smooth muscle contractility. Preferably, the respiratory disease is selected from respiratory or pulmonary diseases associated with increased mucus production, airway inflammation and/or obstructive diseases. Preferably, the respiratory disease is selected from the group consisting of COPD, idiopathic pulmonary fibrosis, α1-antitrypsin deficiency, chronic sinusitis, asthma and chronic bronchitis. Preferably, the gastrointestinal disease is selected from stage ileitis, ulcerative colitis or Crohn's disease. Preferably, the inflammatory disease of the joints, skin or eyes is selected from the group consisting of rheumatoid arthritis, sarcoidosis, dry eye syndrome and glaucoma. Preferably, the cancer is selected from mesothelioma, neuroblastoma, rectal cancer, colon cancer, familiar adenomatous polyposis and hereditary non-polyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, Hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, renal cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, uterine corpus cancer, endometrial cancer, choriocarcinoma , pancreatic cancer, prostate cancer, bladder cancer, testicular cancer, breast cancer, urinary cancer, melanoma, brain tumor, lymphoma, head and neck cancer, acute lymphoid leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myelogenous leukemia, liver Cell carcinoma, gallbladder cancer, bronchial cancer, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal sarcoma, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, osteosarcoma, Chondrosarcoma, fibroid, liposarcoma, fibrosarcoma, Ewing sarcoma, and plasmacytoma. Preferably, the peripheral or central nervous system disease is selected from the group consisting of depression, bipolar or manic depression, acute and chronic anxiety states, schizophrenia, Alzheimer's disease, Parkinson's disease, acute and chronic multiple sclerosis or acute and chronic pain and brain damage caused by stroke, hypoxia, or cranio-cerebral trauma.

In the sixth aspect of the present invention, there is provided a method for inhibiting PDE4B, or preventing and/or treating PDE4B-related diseases, including the steps of: administering to a subject in need the compound represented by formula II described in the first aspect of the present invention, its tautological variation Conforms, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs.

Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. Terms and definitions

Unless otherwise stated, the definitions of groups and terms recorded in the specification and patent scope of this application include their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific compounds in the examples. etc., can be arbitrarily combined and combined with each other. Such combinations and combined group definitions and compound structures should fall within the scope described in the specification of this application.

Unless otherwise defined, all technical and scientific terms herein have the same meanings as commonly understood by a person of ordinary skill in the technical field to which the subject matter of the claim belongs. Unless otherwise indicated, all patents, patent applications, and published materials cited in their entirety are hereby incorporated by reference in their entirety. If there are multiple definitions for a term herein, the definitions in this chapter shall prevail.

As used herein, the articles "a," "an," and "the" are intended to include "at least one" or "one or more" unless otherwise stated or there is an obvious conflict from the context. Therefore, as used in this article, these articles refer to one or more than one (i.e. at least one) object. For example, "a component" refers to one or more components, ie, more than one component may be contemplated for use or use in the implementation of the described embodiments.

It should be understood that the foregoing brief description and the following detailed description are exemplary and are for explanation only, and do not limit the subject matter of the present invention in any way. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, unless the context clearly dictates otherwise, the singular form used in this specification and claims includes the plural form of the referent. It should also be noted that the use of "or", "or" means "and/or" unless stated otherwise. Furthermore, the use of the term "includes" and other forms such as "includes," "includes" and "contains" is not limiting.

Definitions of standard chemical terms may be found in references including Carey and Sundberg, "ADVANCED ORGANIC CHEMISTRY 4THED." Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise stated, conventional methods within the skill in the art, such as mass spectrometry, NMR, IR and UV/VIS spectroscopy and pharmacological methods, were used. Unless specific definitions are given, the terminology employed herein in connection with the description of analytical chemistry, synthetic organic chemistry, and pharmaceutical and medicinal chemistry is known in the art. Standard techniques may be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and treatment of patients. For example, the manufacturer's instructions for using the kit can be used, or the reaction and purification can be carried out in accordance with methods known in the art or the instructions of the present invention. The above techniques and methods can generally be implemented in accordance with conventional methods well known in the art, as described in the various general and more specific documents cited and discussed in this specification. In this specification, groups and substituents thereof may be selected by one of ordinary skill in the art to provide stable moieties and compounds.

Generally speaking, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced by a specified substituent. Unless otherwise indicated, a substituted group may have a substituent at each substitutable position of the group. When more than one position in a given structural formula can be substituted by one or more substituents selected from a specific group, then the substituents may be identically or differently substituted at each substitutable position.

The term "unsubstituted" means that the designated group bears no substituents.

As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as the general formula compounds above, or as the specific examples in the examples, subclasses, and classes of compounds encompassed by the present invention. It should be understood that the term "optionally substituted" can be used interchangeably with the term "substituted or unsubstituted". In general, the term "optionally", whether or not it precedes the term "substituted", indicates that one or more hydrogen atoms in a given structure are replaced by a specific substituent. Unless otherwise indicated, an optional substituent group may have a substituent substituted at each substitutable position of the group. When more than one position in a given structural formula can be substituted by one or more substituents selected from a specific group, the substituents may be substituted at each position in the same or different manner.

In addition, it should be noted that, unless otherwise explicitly stated, the description methods used in the present invention, "each... independently is" and "... each independently is" and "... independently is" can be interchanged and should be understood in a broad sense. They can mean that in different groups, the specific options expressed by the same symbols do not affect each other, and can also mean that in the same group, the specific options expressed by the same symbols do not affect each other.

When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes substituents that are chemically equivalent when the structural formula is written from right to left. For example, CH ₂ O is equivalent to OCH ₂ . As used in this article, or Indicates the attachment site of the group. As used herein, “R ₁ ”, “R1” and “R ¹ ” have the same meaning and are interchangeable. For other symbols such as R ₂ , similar definitions have the same meaning.

The section headings used herein are for the purpose of organizing the article only and should not be construed as limiting the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and theses, are incorporated herein by reference in their entirety.

In addition to the foregoing, when used in the specification and scope of the patent application of this application, unless otherwise specifically indicated, the following terms have the meanings as shown below.

When the numerical range described in this application specification and the patent application is understood as an "integer", it should be understood as recording the two endpoints of the range and each integer in the range. For example, "integers from 1 to 6" should be understood as recording each integer of 0, 1, 2, 3, 4, 5 and 6. When the numerical range is understood as a "number", it should be understood as recording the two endpoints of the range and each integer in the range and each decimal in the range. For example, "numbers from 1 to 10" should be understood as not only recording each integer of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, but also recording at least the sum of each of these integers and 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 respectively.

In the present application, "saturated, partially saturated or unsaturated" includes saturated substituents, completely unsaturated substituents and partially saturated substituents.

In this application, the term "halogen", alone or as part of another substituent, means fluorine, chlorine, bromine, iodine; preferably fluorine or chlorine.

As used herein, the term "cyano", alone or as part of another substituent, means -CN.

As used herein, the term "amine", alone or as part of another substituent, means _-NH2 .

As used herein, the term "hydroxy" when used alone or as part of another substituent refers to -OH.

The term "alkyl" when used alone or as part of another substituent means a straight or branched chain consisting solely of carbon atoms and hydrogen atoms, having, for example, 1 to 6 carbon atoms, and connected to the rest of the molecule by a single bond. hydrocarbon chain group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, pentyl, isopentyl, neopentyl, and hexyl. Alkyl groups may be unsubstituted or substituted with one or more suitable substituents. The alkyl group may also be an isotopomer of the naturally abundant alkyl group that is rich in isotopes of carbon and/or hydrogen (ie, deuterium or tritium).

Unless otherwise stated, use wedge-shaped solid line keys ( ) and wedge-shaped dotted keys ( ) represents the absolute configuration of a stereocenter, using a straight solid line key ( ) and straight dotted keys ( ) represents the relative configuration of the stereocenter, for example: Expressed as , one of the configurations in It is expressed as the remaining other configuration; Expressed as , one of the configurations in It is expressed as the remaining configuration.

The term "alkyl" refers to a saturated linear or branched monovalent hydrocarbon group of 1 to 6 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms, wherein the alkyl group can be independently and optionally Substituted by one or more substituents described in the present invention, the substituents include, but are not limited to, deuterium, amine, hydroxyl, cyano, F, Cl, Br, I, thiol, nitro, oxo (=O) etc. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH ₃ ), ethyl (Et, -CH ₂ CH ₃ ), n-propyl (n-Pr, -CH ₂ CH ₂ CH ₃ ), Isopropyl (i-Pr, -CH(CH ₃ ) ₂ ), n-butyl (n-Bu, -CH ₂ CH ₂ CH ₂ CH ₃ ), isobutyl (i-Bu, -CH ₂ CH (CH ₃ ) ₂ ), secondary butyl (s-Bu, -CH(CH ₃ )CH ₂ CH ₃ ), tertiary butyl (t-Bu, -C(CH ₃ ) ₃ ), n-pentyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₃ ), 3-pentyl (-CH(CH ₂ CH ₃ ) ₂ ), etc. The term "alkyl" and its prefix "alkyl" as used herein include both straight and branched saturated carbon chains.

When used alone or as part of other substituents, the term "alkylene" should be understood to mean a straight or branched saturated, unsaturated or partially saturated divalent hydrocarbon group. For example, "C _1-6 alkylene" or "C _1- C ₆ alkylene" means a straight or branched divalent hydrocarbon group having 1 to 6 carbon atoms, including but not limited to methylene, ethylene, propylene, 1-methylpropylene, and butylene.

"Benzo group" alone or in combination refers to the divalent group C ₄ H ₄ =, one of which is -CH=CH-CH=CH-, which when ortho-attached to another ring forms a benzene-like ring , such as tetralin, indole, etc.

The term "C _α-β haloalkyl" when alone or as part of another substituent refers to an alkyl group as described above, wherein any number (at least one) of the hydrogen atoms attached to the alkyl chain are replaced by fluorine, chlorine, bromine or iodine.

The term "cycloalkyl" when used alone or as part of another substituent refers to a cyclic alkyl group. The term "mn-membered cycloalkyl" or "C _mn cycloalkyl" is understood to mean a saturated, unsaturated or partially saturated carbocyclic ring having m to n atoms. For example, "3-15-membered cycloalkyl" or "C ₃ -C ₁₅ cycloalkyl" refers to a cyclic alkyl group containing 3 to 15, 3 to 9, 3 to 6 or 3 to 5 carbon atoms. May contain 1 to 4 rings. "3-10 membered cycloalkyl" contains 3-10 carbon atoms. Including single ring, two rings, three rings, spiro rings or bridged rings. Examples of unsubstituted cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and adamantyl, or bicyclic hydrocarbon groups such as decalin rings. Cycloalkyl groups may be substituted by one or more substituents. In some embodiments, a cycloalkyl group can be a cycloalkyl group fused to an aryl or heteroaryl group. The term "cycloalkyl" may be used interchangeably with the term "carbocyclyl".

The term "heterocycloalkyl" when used alone or as part of other substituents refers to a cycloalkyl group in which one or more (in some embodiments, 1 to 3) carbon atoms are replaced by heteroatoms such as, but not limited to, N, O, S and P. The term "mn-membered heterocycloalkyl" or " _Cmn heterocycloalkyl" is understood to mean a saturated, unsaturated or partially saturated ring having m to n atoms, wherein the heterocyclic atoms are selected from N, O, S, P, preferably selected from N, O or S. For example, the term "4-8 membered heterocycloalkyl" or " _C4 - _C8 heterocycloalkyl" is understood to mean a saturated, unsaturated or partially saturated ring having 4 to 8 atoms, wherein 1, 2, 3, or 4 ring atoms are selected from N, O, S, P, preferably N, O or S. "4-10 membered heterocycloalkyl" means a saturated, unsaturated or partially saturated ring having 4 to 10 atoms. In some embodiments, the heterocycloalkyl can be a heterocycloalkyl fused to an aromatic ring or a heteroaromatic ring. When prefixes such as 4-8 or 4-10 membered are used to represent heterocycloalkyl, the number of carbons is also meant to include heteroatoms. Including monocyclic, bicyclic, tricyclic, spirocyclic or bridged ring. Examples of heterocycloalkyl are: pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridinyl, tetrahydropyrrolyl, azacyclobutanyl, thiazolidinyl, oxazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperidine, azacycloheptanyl, diazacycloheptanyl, oxazacycloheptanyl, etc. The term "heterocycloalkyl" can be used interchangeably with the term "heteroalkane ring".

The term "alkenyl" when used alone or as part of other substituents refers to a linear or branched monovalent hydrocarbon group of two to forty carbon atoms with at least one carbon-carbon sp2 double bond (e.g., _C2 - _C6 alkenyl, for example, _C2 - _C4 alkenyl), and includes groups with "cis" and "trans" orientations or "E" and "Z" orientations. Examples of alkenyl groups include, but are not limited to, vinyl and allyl.

The term "alkynyl" when used alone or as part of other substituents refers to a straight or branched chain monovalent hydrocarbon radical of two to forty carbon atoms (e.g., C ₂ -C _{6 )} having at least one carbon-carbon sp triple bond. Alkynyl, another example is C ₂ -C ₄ alkynyl). Examples of alkynyl groups include, but are not limited to, ethynyl and propynyl.

The term "alkoxy" when used alone or as part of another substituent refers to the group ^-ORQ , where ^RQ is "alkyl" as defined above.

The term "oxo" when used alone or as part of other substituents means that the two hydrogens on the methylene group are replaced by oxygen, that is, the methylene group is replaced by a carbonyl group, meaning =O.

The term "thio" when used alone or as part of another substituent refers to the replacement of two hydrogen atoms of a methylene group with sulfur, representing =S.

The term "aromatic ring" when used alone or as part of other substituents, refers to a monocyclic or polycyclic carbocyclic ring having from 6 to 20 carbon atoms, at least one of which is aromatic. When one of the rings is non-aromatic, the group can be attached through the aromatic ring or through the non-aromatic ring. Examples of aryl groups include, but are not limited to: phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthrenyl, anthracenyl, and acenaphthyl. The term "aromatic ring" may be used interchangeably with the term "aryl".

The term "heteroaryl ring" when used alone or as part of other substituents, refers to a monocyclic or polycyclic carbocyclic ring in which at least one ring atom is a heteroatom independently selected from oxygen, sulfur and nitrogen, and the remaining ring atoms are C, at least one of the rings is aromatic. The group may be a carbon group or a heteroatom group (ie it may be C-linked or N-linked, wherever possible). When one of the rings is non-aromatic, the group can be attached through the aromatic ring or through the non-aromatic ring. Examples of heteroaryl groups include, but are not limited to: imidazolyl, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furyl, thienyl, Benzothienyl, benzofuryl, quinolyl, isoquinolyl, oxazolyl, isoethazolyl, indolyl, pyridyl, pyrrolyl, pyridyl, pyrimidinyl, pyrrolyl, N -Methyl pyrrolyl and tetrahydroquinoline. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic," "heteroaryl," or "heteroaryl."

The term "bicyclo" when used alone or as part of other substituents refers to a group having two linked rings. Bicycles can be carbocyclic (all ring atoms are carbon atoms) or heterocyclic (in addition to carbon atoms, the ring atoms include, for example, 1, 2 or 3 heteroatoms, such as N, O or S). Both rings can be aliphatic (such as decalin and norbornane), or they can be aromatic (such as naphthalene), or a combination of aliphatic and aromatic (such as tetralin).

Bicycles include (a) spiro compounds in which the two rings share only a single atom (the spiro atom, which is usually a quaternary carbon). Examples of spiro compounds include, but are not limited to: , also includes a spirocycloalkyl group in which a single spirocycloalkyl group and a heterocycloalkyl group share a spiro atom. Non-limiting examples include: ; (b) Fused ring, that is, a fused bicyclic compound in which two rings share two adjacent atoms. In other words, the rings share a covalent bond, i.e. the bridgehead atoms are directly connected (e.g. α-thujane and decalin). Examples of fused bicyclic rings include, but are not limited to: ; and (c) bridged bicyclic compounds in which two rings share three or more atoms and the two bridgehead atoms are separated by a bridge containing at least one atom. For example, norbornane, also known as bicyclo[2.2.1]heptane, can be thought of as a pair of cyclopentane rings, each sharing three of their five carbon atoms. Examples of bridged dual rings include, but are not limited to: .

When alone or as part of another substituent, the NR ^f R ^f group can be In the form of, or may include two R ^f groups together to form a ring, the ring optionally contains N, O or S atoms, and may also include the following groups, for example: , , .

The group N(Cα _- βalkyl)Cα _-βalkyl (wherein α and β are as defined above) when alone or as part of other substituents includes substituents wherein two Cα _-βalkyl groups are taken together to form a ring (optionally containing N, O or S atoms), and includes groups such as: , , , , .

The compounds provided herein include intermediates useful in preparing the compounds provided herein, which contain reactive functional groups (such as, but not limited to, carboxyl, hydroxyl and amine moieties), and also include protected derivatives thereof. "Protected derivatives" are those compounds in which one or more reactive sites are blocked by one or more protecting groups (also called protecting groups). Suitable protecting groups for the carboxyl moiety include benzyl, tertiary butyl, etc., as well as isotopes and the like. Suitable amine and amide protecting groups include acetyl, trifluoroacetyl, tertiary butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable hydroxyl protecting groups include benzyl and the like. Other suitable protecting groups are well known to those of ordinary skill in the art to which this invention pertains.

In the present application, "optionally" or "optionally" means that the subsequently described event or situation may or may not occur, and the description includes both the event or situation occurring and the situation not occurring. For example, "optionally substituted aryl" means that aryl is substituted or unsubstituted, and the description includes both substituted aryl and unsubstituted aryl.

In this application, the term "salt" or "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue without undue toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.

"Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without other side effects. "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that can maintain the biological effectiveness of the free acid without other side effects. In addition to pharmaceutically acceptable salts, other salts are contemplated by the present invention. They may serve as intermediates in the purification of the compounds or in the preparation of other pharmaceutically acceptable salts or may be used in the identification, characterization or purification of the compounds of the invention.

The term "amine salt" refers to the product obtained by neutralizing an alkyl primary, secondary or tertiary amine with an acid. The acid includes an inorganic acid or an organic acid as described in this application.

The term "stereoisomers" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereoisomers, and conformational isomers.

Depending on the choice of starting materials and methods, the compounds of the invention may exist in the form of one of the possible isomers or a mixture thereof, for example as pure optical isomers, or as a mixture of isomers, for example as racemic and non-racemic isomers. A mixture of enantiomers, depending on the number of asymmetric carbon atoms. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to the chiral center (or centers) in the molecule. The prefixes D and L or (+) and (–) are symbols used to designate the rotation of plane-polarized light caused by a compound, where (–) or L indicates that the compound is levorotatory. Compounds prefixed with (+) or D are dextrorotatory.

When the bonds to the chiral carbon in the formula of the present invention are drawn as straight lines, it should be understood that both the (R) and (S) configurations of the chiral carbon and the enantiomerically pure compounds and mixtures thereof produced therefrom are included within the scope of the general formula. The diagrammatic representation of racemates or enantiomerically pure compounds herein is from Maehr, J. Chem. Ed. 1985, 62: 114-120. The absolute configuration of a stereocenter is represented by a wedge-shaped bond and a dashed bond.

The term "tautomer" refers to functional group isomers that arise from the rapid movement of an atom in a molecule between two positions. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Prototropic tautomers arise from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to separate a single tautomer usually produce a mixture whose physical and chemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form is predominant, while in phenols, the enol form is predominant. The present invention includes all tautomeric forms of the compounds.

The term "solvate" refers to a compound of the present invention or a salt thereof including a stoichiometric or non-stoichiometric solvent bound by intermolecular non-covalent forces. When the solvent is water, it is a hydrate.

The term "prodrug" refers to a compound of the invention that can be converted to a biologically active compound under physiological conditions or by solvolysis. The prodrugs of the present invention are prepared by modifying the functional groups in the compound, and the modifications can be removed by conventional procedures or in vivo to obtain the parent compound. Prodrugs include compounds in which a hydroxyl or amine group in the compound of the present invention is connected to any group. When the prodrug of the compound of the present invention is administered to a mammalian subject, the prodrug is cleaved to form free hydroxyl groups, Free amine group.

In this application, "pharmaceutical composition" refers to a preparation of the compound of the present invention and a medium generally accepted in the art for delivering biologically active compounds to mammals (such as humans). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote drug administration in an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

In this application, "pharmaceutically acceptable carrier" includes but is not limited to any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the relevant governmental regulatory authorities as acceptable for human or livestock use.

The term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples of the types of the term "excipient" include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, and diluents. Excipients can enhance the handling characteristics of a drug formulation, i.e., make the formulation more suitable for direct compression by increasing flowability and/or adhesion.

The term "treatment" refers to therapeutic treatment. With respect to a specific condition, treatment means: (1) alleviating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade leading to or causing the condition or (b) one or more biological manifestations of the condition, (3) ameliorating one or more symptoms, effects, or side effects associated with the condition or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of the condition or one or more biological manifestations of the condition.

The term "prevention" means reducing the risk of getting or developing a disease or disorder.

The term "patient" refers to any animal, preferably a mammal, that is about to or has been administered the compound or composition according to the embodiments of the present invention. The term "mammal" includes any mammal. Examples of mammals include but are not limited to cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., preferably humans.

The term "therapeutically effective amount" refers to an amount of a compound that, when administered to a patient, is sufficient to effectively treat a disease or condition described herein. The "therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, and can be adjusted as needed by a person skilled in the art to which the present invention belongs.

In the reaction of each step, the reaction temperature can be appropriately selected based on the solvent, starting materials, reagents, etc., and the reaction time can also be appropriately selected based on the reaction temperature, solvent, starting materials, reagents, etc. After the reaction of each step is completed, the target compound can be separated and purified from the reaction system according to common methods, such as filtration, extraction, recrystallization, washing, silica gel column chromatography and other methods. Without affecting the next step of the reaction, the target compound can also directly enter the next step of the reaction without separation and purification.

Without violating the common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain the best embodiments of the present invention. Beneficial effects

After extensive and in-depth research, the inventor unexpectedly developed a compound or a pharmaceutically acceptable salt thereof, as well as a preparation method and use. The invention provides compounds represented by formula I, or their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs. The compounds of formula I have significant inhibitory effects on PDE4B. , can be used as a selective inhibitor of PDE4B, with high safety and medicinal properties; the compound of the present invention has excellent inhibitory activity on human PBMC secretion of TNFα, can better inhibit the secretion of inflammatory factor TNFα in human PBMC, and has good Anti-inflammatory effect; the compounds of the present invention exhibit excellent plasma exposure and have excellent pharmacokinetic properties.

The present invention is further described below in conjunction with specific embodiments. It should be understood that the following description is only the most preferred embodiment of the present invention and should not be considered as limiting the scope of protection of the present invention. On the basis of a full understanding of the present invention, the experimental methods in the following embodiments that do not specify specific conditions are usually carried out under conventional conditions or under conditions recommended by the manufacturer. A person with ordinary knowledge in the technical field to which the present invention belongs may make non-essential changes to the technical solution of the present invention, and such changes should be deemed to be included in the scope of protection of the present invention.

This application has the following definitions: Symbol or unit: IC ₅₀ : half inhibitory concentration, refers to the concentration at which half of the maximum inhibitory effect is achieved M: mol/L, such as n-butyllithium (14.56 mL, 29.1 mmol, 2.5 M n-hexane solution ) represents a n-hexane solution of n-butyllithium with a molar concentration of 2.5 mol/L N: equivalent concentration, for example, 2N hydrochloric acid represents a 2 mol/L hydrochloric acid solution Reagents: DCM: dichloromethane DIPEA: N,N-diisopropyl Ethylamine DMF: N,N-dimethylformamide TFA: Trifluoroacetic acid THF: Tetrahydrofuran S-(-)-BINOL: S-1,1'-bis-2-naphthol Ti(OiPr)4: Tetrahydrofuran Titanium isopropoxide

Intermediate A1: (5R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d ] The synthesis route of pyrimidine preparation intermediate A1 is as follows:

Step 1: Synthesis of 1-aminocyclobutyl)methanol (intermediate A1-2) Dissolve 1-aminocyclobutanecarboxylic acid (15 g, 130.3 mmol) in tetrahydrofuran (300 ml) at room temperature, 0°C, under argon protection and add dropwise lithium aluminum hydride (2.5 M tetrahydrofuran solution, 104 mL) with stirring. , 260 mmol). After the dropwise addition, the reaction solution was slowly raised to room temperature and stirred for 16 h under argon protection. The reaction was quenched with sodium sulfate decahydrate solid in an ice bath, dried with anhydrous sodium sulfate, and filtered. The filter cake was rinsed with ethyl acetate. The combined filtrate was concentrated at room temperature to obtain (1-aminocyclobutyl)methanol (intermediate A1-2) (12 g, yield 90%).

Step 2: (1-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methanol (intermediate A1-4) synthesis Intermediates A1-2 (3 g, 29.7 mmol) and A1-3 (2.1 g, 29.7 mmol) and triethylamine (9 g, 100 mmol) were added to acetonitrile (100 mL), and the mixture was heated at 75 Stir for 12 h at ℃. The reaction solution was concentrated and separated and purified using a silica gel column (petroleum ether: ethyl acetate (V/V) = 5:1-1:1, gradient elution) to obtain (1-((2-chloro-6,7-dihydrogen) Thieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methanol (intermediate A1-4) (3.5 g, yield 43%).

Step 3: Synthesis of (5R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidine (Intermediate A1) At 21°C under nitrogen, intermediate A1-4 (2.7 g, 10 mmol), S-(-)-BINOL (0.28 g, 1 mmol), dichloromethane (80 mL), Ti(OiPr) ₄ (1.4 mL, 0.5 mmol) and water (0.18 mL, 10 mmol) were added to a flask and stirred for 1 h. Tributyl peroxide (70% in water, 1.5 mL, 11 mmol) was added at 21°C and stirred at room temperature for 1.5 h. The reaction solution was concentrated and purified by silica gel column separation (dichloromethane:methanol (V/V) = 10:1, gradient elution) to obtain (5R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidine (intermediate A1) (2.5 g, yield 87%).

Intermediate A2: Preparation of 5-chloro-2-(piperidine-1-yl)pyrimidine The synthetic route of intermediate A2 is as follows:

Step 1: Synthesis of 4-(5-chloropyrimidin-2-yl)piperidin-1-carboxylic acid tributyl ester (intermediate A2-3) Intermediate A2-1 (0.18 g, 2 mmol) and A2-2 (0.5 g, 2 mmol) and DIPEA (0.7 g, 6 mmol) were added to DMF (20 mL), and the mixture was stirred at 80°C for 8 h. The reaction mixture was diluted with water (50 mL), and then extracted twice with ethyl acetate, 50 mL each time, and the organic layers were combined and washed with saturated brine (50 mL), dried over sodium sulfate, and concentrated to obtain a crude product, which was separated and purified by silica gel column (petroleum ether: ethyl acetate (V/V) = 2:1-10:1, gradient elution) to obtain 4-(5-chloropyrimidin-2-yl)piperidin-1-carboxylic acid tributyl ester (intermediate A2-3) (0.5 g, yield 83%).

Step 2: Synthesis of 5-chloro-2-(piperidin-1-yl)pyrimidine (Intermediate A2) Intermediate A1-2 (3 g, 29.7 mmol) and A1-3 (2.1 g, 29.7 mmol) and triethylamine (9 g, 100 mmol) were added to acetonitrile (100 mL), and the mixture was stirred at 75 ° C for 12 h. The reaction solution was concentrated and separated and purified by silica gel column (petroleum ether: ethyl acetate (V/V) = 5:1-1:1, gradient elution) to obtain 5-chloro-2-(piperidin-1-yl)pyrimidine (intermediate A2) (3.5 g, yield 43%). Intermediates A3 and A4 were prepared according to the synthetic route of intermediate A2 .

Intermediate A5: Preparation of 5-chloro-2-(piperidin-4-yl)pyrimidine The synthetic route of intermediate A5 is as follows:

Step 1: Synthesis of piperidine-4-carboxamidine (intermediate A5-2) Add 1,4-dioxane (45 ml, 3 eq, 180 mmol) in 4M HCl to the flask. The solution was cooled to 0 °C and 4-cyanopiperidine (6.6 g, 60 mmol) was added over approximately 30 min, followed by methanol (6 mL, 180 mmol, 3 eq) while maintaining the temperature below 10 ℃ (exothermic reaction). The above mixture was stirred at room temperature for 6-8 hours. The mixture was cooled to 5°C and added to a methanol solution containing 25wt% NaOMe (32 g, 100 mmol, 2 eq) while keeping the temperature below 15°C, and then The reaction solution was stirred for 1 hour. 7 N ammonia in methanol (13 mL, 1.5 eq, 90 mmol) was added to the above mixture and stirred at standard room temperature for 8 hours. The mixture was concentrated under reduced pressure to a volume of about 50 ml to obtain a crude solution of intermediate A5-2, which could be used without isolation.

Step 2: Synthesis of 5-chloro-2-(piperidin-4-yl)pyrimidine (intermediate A5) The above solution of Intermediate A5-2 was cooled to approximately 20°C, and a methanolic solution containing 25 wt% NaOMe (33 g, 150 mmol) was added. The mixture was then stirred for 30 minutes. At standard room temperature, compound D (= (Z) -N- (2-chloro-3-(dimethylamino)allylene)-N-methylmethane-hexafluorocarbon was added in two batches over about 30 minutes. Ammonium phosphate (17 g, 51 mmol) was added to the above mixture and stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure, the reaction mixture was diluted with water, and then extracted with ethyl acetate. The organic layers were combined and washed with saturated brine. The organic phase was washed, dried over sodium sulfate, and concentrated to obtain a crude product, which was separated and purified using a silica gel column (dichloromethane: methanol (V/V) = 20:1-10:1, gradient elution) to obtain 4-(5-chloropyrimidine- 2-yl)piperidine-1-carboxylic acid tertiary butyl ester (intermediate A5) (9 g, yield 75%).

Intermediate A6: Preparation of 6-(5-chloropyrimidin-2-yl)-3-azabicyclo[4.1.0]heptane The synthetic route of intermediate A6 is as follows:

Step 1: Synthesis of 4-(5-chloropyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tributyl ester (intermediate A6-2) Intermediate A6-1 (1.5 g, 5 mmol), A2-2 (2.4 g, 5 mmol), (dppf) ₂ PdCl ₂ (0.5 mmol), and K ₂ CO ₃ (10 mmol) were added to 1,4-dioxane (30 ml), and the reaction was carried out at 80°C for 8 hours. The reaction solution was concentrated and purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) = 20:1-10:1, gradient elution) to obtain 4-(5-chloropyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tributyl ester (intermediate A6-2) (1.8 g, yield 60%).

Step 2: Synthesis of 6-(5-chloropyrimidin-2-yl)-3-azabicyclo[4.1.0]heptane-3-carboxylic acid tertiary butyl ester (intermediate A6-3) Add diiodomethane (2.3 g, 8.5 mmol) to 20 mL DCM containing diethylzinc (8.5 mL, 1M n-hexane solution) at -20°C, maintain this temperature and stir for 30 min, and then add it to the reaction system. Add 4-(5-chloropyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tertiary butyl ester (0.5 g, 1.7 mmol), continue the reaction at -20°C for 2 hours, and the reaction solution Concentrate, use silica gel column to separate and purify (petroleum ether: ethyl acetate (V/V) = 20:1-10:1, gradient elution) to obtain 6-(5-chloropyrimidin-2-yl)-3-aza Bicyclo[4.1.0]heptane-3-carboxylic acid tertiary butyl ester (intermediate A6-3) (0.3 g, yield 60%).

Step 3: Synthesis of 6-(5-chloropyrimidin-2-yl)-3-azabicyclo[4.1.0]heptane (Intermediate A6) Intermediate A6-3 (0.3 g, 1 mmol) was added to DCM (10 mL), TFA (2 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 6 h. The crude product was concentrated and purified by silica gel column separation (dichloromethane:methanol (V/V) = 2:1-10:1, gradient elution) to give 6-(5-chloropyrimidin-2-yl)-3-azabicyclo[4.1.0]heptane (intermediate A6) (0.15 g, yield 75%).

Intermediate A7: Preparation of 5-chloro-2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidine Intermediate A6-2 (0.6 g, 2 mmol) was added to DCM (10 mL), TFA (2 mL) was added to the reaction solution, stirred at room temperature for 6 h, concentrated to obtain a crude product, which was separated and purified with a silica gel column (dichloro Methane: methanol (V/V)=2:1-10:1, gradient elution) to obtain 5-chloro-2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidine (intermediate A7 ) (0.4 g, yield 100%).

Intermediate A8: Preparation of 5-chloro-2-((2S)-2-methylpiperidin-4-yl)pyrimidine The synthetic route of intermediate A8 is as follows:

The first step: Synthesis of 2S)-4-hydroxy-2-methylpiperidine-1-carboxylic acid tertiary butyl ester (intermediate A8-2) To a solution of compound A8-1 (4 g, 18.8 mmol) in MeOH (100 mL) was added NaBH ₄ (1.4 g, 37.6 mmol) at 0°C, the mixture was stirred at room temperature overnight, water was added to quench the reaction, and acetic acid was added Extract with ethyl ester, dry with anhydrous sodium sulfate, and concentrate to obtain crude intermediate A8-2.

Step 2: Synthesis of (2S)-4-iodo-2-methylpiperidine-1-carboxylic acid tert-butyl ester (intermediate A8-3) I ₂ (1.2 eq) was dissolved in CH ₂ Cl ₂ (150 mL), and the solution was cooled to 0°C. PPh ₃ (1.2 eq) was added to the reaction mixture in batches, and then imidazole (1.2 eq) was added to the reaction mixture. Finally, intermediate A8-2 (4 g) was added dropwise to the mixture, and the reaction solution was reacted at room temperature for 6 h. The reaction was quenched with aqueous NaHSO ₃ solution, the aqueous layer was extracted with DCM, and the solvent was evaporated. Separation and purification by silica gel column (petroleum ether: ethyl acetate (V/V) = 50:1-10:1, gradient elution) gave (2S)-4-iodo-2-methylpiperidine-1-carboxylic acid tributyl ester (intermediate A8-3) (4.2 g, yield 70%).

Step 3: Synthesis of (2S)-4-(5-chloropyrimidin-2-yl)-2-methylpiperidine-1-carboxylic acid tert-butyl ester (intermediate A8-4) 1,2-Dibromoethane (0.8 mL, 9.2 mmol) was added to a suspension of zinc powder (0.9 g, 13.8 mmol) in THF (50 mL), and the reaction mixture was heated under reflux for 1 hour. After cooling to room temperature, the reaction mixture was treated with trimethylsilyl chloride (0.1 mL, 0.9 mmol) and stirred for 1 hour. At this time, a solution of A8-3 (3.0 g, 9.2 mmol) in THF (15 mL) was added dropwise. The reaction solution was stirred at 60°C for 1 hour and cooled to room temperature. Compound A2-2 (2.6 g, 10.9 mmol) and tetrakis(triphenylphosphine)palladium (215.5 mg, 0.2 mmol) were added, and the mixture was heated under reflux for 1 hour, and then stirred at 60°C for about 8 hours. The reaction mixture was filtered through diatomaceous earth, the filtrate was concentrated, and purified by silica gel column separation (petroleum ether:ethyl acetate (V/V) = 50:1-10:1, gradient elution) to obtain (2S)-4-(5-chloropyrimidin-2-yl)-2-methylpiperidine-1-carboxylic acid tert-butyl ester (intermediate A8-4) (0.3 g, yield 10%).

Step 4: Synthesis of 5-chloro-2-((2S)-2-methylpiperidin-4-yl)pyrimidine (intermediate A8) Intermediate A8-4 (0.3 g, 1 mmol) was added to DCM (10 mL), TFA (2 mL) was added to the reaction solution, stirred at room temperature for 6 h, concentrated to obtain a crude product, which was separated and purified with a silica gel column (dichloro Methane: methanol (V/V)=2:1-10:1, gradient elution) to obtain 5-chloro-2-((2S)-2-methylpiperidin-4-yl)pyrimidine (intermediate A8 ) (0.15 g, yield 80%).

Intermediate A9: Preparation of 2-(Azapyridin-3-yl)-5-chloropyrimidine The synthetic route of Intermediate A9 is as follows:

Step 1: Synthesis of 3-(5-chloropyridin-2-yl)azetidine-1-carboxylic acid tertiary butyl ester (intermediate A9-2) 1,2-Dibromoethane (0.8 mL, 9.2 mmol) was added to a suspension of zinc powder (0.9 g, 13.8 mmol) in THF (50 mL) and the reaction mixture was heated at reflux for 1 h. After cooling to room temperature, the reaction mixture was treated with trimethylsilyl chloride (0.1 mL, 0.9 mmol) and stirred for 1 hour. At this time, a solution of compound A9-1 (2.6 g, 9.2 mmol) in THF (15 mL) was added dropwise. The reaction solution was stirred at 60°C for 1 hour and cooled to room temperature. Compound A2-2 (2.6 g, 10.9 mmol) and tetrakis(triphenylphosphine)palladium (215.5 mg, 0.2 mmol) were added and the mixture was heated at reflux for 1 hour and then stirred at 60°C for approximately 8 hours. The reaction was filtered through celite, the filtrate was concentrated, and separated and purified using a silica gel column (petroleum ether: ethyl acetate (V/V) = 50:1-10:1, gradient elution) to obtain 3-(5-chloropyridine-2) -Azetidine-1-carboxylic acid tertiary butyl ester (intermediate A9-2) (1.0 g, yield 42%).

Step 2: Synthesis of 2-(nitropyridin-3-yl)-5-chloropyrimidine (Intermediate A9) Intermediate A9-2 (0.8 g, 1 mmol) was added to DCM (10 mL), TFA (2 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 6 h. The crude product was concentrated and purified by silica gel column separation (dichloromethane: methanol (V/V) = 2:1-10:1, gradient elution) to obtain 2-(nitropyridin-3-yl)-5-chloropyrimidine (intermediate A9) (0.4 g, yield 80%).

Intermediate A10: Preparation of (R)-1-(2-chloro-5-oxido-6,7-dihydrothiophene[3,2-d]pyrimidin-4-yl)amino)cyclopropane-1-carbonitrile The synthetic route of intermediate A10 is as follows:

Step 1: Synthesis of 1-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclopropane-1-carbonitrile (intermediate A10-3) Intermediate A1-3 (1.5 g, 15 mmol), 1-aminocyclopropane-1-carbonitrile (1.2 g, 15 mmol) and triethylamine (4.5 g, 50 mmol) were added to acetonitrile (100 mL), and the mixture was stirred at 75°C for 12 hours. The reaction solution was concentrated and purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) = 5:1-1:1, gradient elution) to obtain 1-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclopropane-1-carbonitrile (intermediate A10-3) (2 g, yield 53%).

Step 3: Synthesis of (R)-1-(2-chloro-5-oxido-6,7-dihydrothiophene[3,2-d]pyrimidin-4-yl)amino)cyclopropane-1-carbonitrile (Intermediate A10) Compound A10-3 (1.3 g, 5 mmol), S-(-)-BINOL (0.14 g, 0.5 mmol), dichloromethane (30 mL), Ti(OiPr) ₄ (0.7 mL, 0.25 mmol) and water (0.1 mL, 5 mmol) were added to a flask at 20 °C under nitrogen and stirred for 1 hour. Tributyl peroxide (70% in water, 0.7 mL, 0.6 mmol) was added at 21°C and stirred at room temperature for 1.5 hours. The reaction solution was concentrated and purified by silica gel column separation (dichloromethane:methanol (V/V) = 10:1, gradient elution) to obtain (R)-1-(2-chloro-5-oxido-6,7-dihydrothiophene[3,2-d]pyrimidin-4-yl)amino)cyclopropane-1-carbonitrile (intermediate A10) (1 g, yield 71%).

Intermediate A11: (R)-2-chloro-4-((tetrahydro-2hydro-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5 - Synthesis of preparation of oxides The synthetic route of intermediate A11 is as follows:

Step 1: 2-Chloro-nitrogen-(tetrahydro-2-hydro-pyran-4-yl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-amine (Intermediate A11-3) Compound A11-1 (6.14 g, 88.98 mmol) and A11-2 (3.0 g, 29.66 mmol) and DIPEA were added to 1,4-dioxane (50 mL), and the mixture was stirred at 120 °C for 12 hours. After the reaction was completed, the reaction solution was concentrated and purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) = 1:1 to dichloromethane: methanol (V/V) = 10:1 gradient elution), and finally 2-chloro-nitrogen-(tetrahydro-2-hydro-pyran-4-yl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-amine (intermediate A11-3) (8.06 g) was obtained.

Step 2: (R)-2-chloro-4-((tetrahydro-2hydro-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5 -Oxide (intermediate A11) Under nitrogen protection at 21°C, combine intermediate A11-3 (3.0 g, 1 eq), S-(-)-BINOL (0.30, 0.1 eq), dichloromethane (80 mL), Ti(OiPr) ₄ (156.88 mg, 0.05 eq) and water (198.87 mg, 1 eq) were added to the flask and stirred for 1 hour. Add tertiary butanol peroxide (70% in water, 1.56 mL, 1.1 eq) at 21°C, and stir the reaction at room temperature for 1.5 hours. After the reaction is completed, the reaction solution is concentrated and separated and purified using a silica gel column (dichloromethane: methanol (V/V) = 10:1, gradient elution) to obtain the product (R)-2-chloro-4-((tetrahydrogen) -2Hydro-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (intermediate A11) (2.5 g, yield 78.7%).

Intermediate A12: Synthesis of 2-(5-chloropyrimidin-2-yl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole The synthetic route of intermediate A12 is as follows:

The first step: 3,4,5,6-tetrahydropyrro[3,4-c]pyrrole-2(1 hydrogen)-carboxylic acid tertiary butyl ester (intermediate A12-2) Add 1,2,3,4,5,6-hexahydropyrro[3,4-C]pyrrole (Intermediate A12-1) (1.0 g, 9.08 mmol) to H ₂ O (10 mL), Sodium bicarbonate (1.98 g, 23.60 mmol) was then added and the mixture was stirred for half an hour. A solution of Boc ₂ O (990 mg, 4.54 mmol) in methanol (2 mL) was then added, and the reaction was stirred at room temperature for 4 hours. After the reaction is completed, filter the filter cake to obtain a crude product (3,4,5,6-tetrahydropyrro[3,4-c]pyrrolo-2(1 hydrogen)-carboxylic acid tertiary butyl ester) (Intermediate A12 -2) (1 g, yield 52%).

Step 2: 5-(5-chloropyrimidin-2-yl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tributyl ester (intermediate A12-3) 5-Chloro-2-iodopyrimidine (500 mg, 2.08 mmol) and intermediate A12-2 (437 mg, 2.08 mmol) and DIPEA (800 mg, 6.24 mmol) were added to DMF (8 mL), and the mixture was stirred at 80 °C for 12 h. After the reaction was completed, the reaction mixture was diluted with water (10 mL) and then extracted twice with ethyl acetate, each time using 20 mL of ethyl acetate, the organic layers were combined, washed twice with saturated brine, dried over sodium sulfate, and concentrated to obtain a crude product, which was purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) = 10:1-5:1, gradient elution) to obtain 5-(5-chloropyrimidin-2-yl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tributyl ester (intermediate A12-3) (500 mg, yield 74%).

Step 3: 2-(5-chloropyrimidin-2-yl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole (Intermediate A12) Intermediate A12-3 (500 mg, 1.55 mmol) was added to a DCM (6 mL) solution, TFA (2 mL) was added, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the crude product was concentrated. The crude product was separated and purified by silica gel column (dichloromethane: methanol (V/V) = 1:0-10:1, gradient elution) to obtain 2-(5-chloropyrimidin-2-yl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole (intermediate A12) (320 mg, yield 93%).

Example 1: (R)-2-(6-(5-chloropyrimidin-2-yl)-3-azabicyclo[4.1.0]heptan-3-yl)-5-oxygen-(6,7 - Preparation of dihydrothio[3,2-d]pyrimidin-4-yl)aminocyclobutyl-methanol (compound 1-A). The synthetic route of target compound 1-A is as follows: Intermediate A1 (140 mg, 0.5 mmol), intermediate A6 (105 mg, 0.5 mmol) and DIPEA (200 mg, 0.5 mmol) were added to a microwave tube containing 1,4-dioxane (5 mL) , microwave reaction at 120°C for 30 minutes, and the crude product after concentration was separated by reversed-phase high performance liquid chromatography. The separation method was (chromatographic column: Phenomenex Luna C18 150×25mm×10μm; mobile phase: A=water+0.01 volume% trifluoroacetic acid (99%), B=acetonitrile; gradient 35%-65%B, 10 minutes), the obtained (R)-2-(6-(5-chloropyrimidin-2-yl)-3-azabicyclo [4.1 .0]heptan-3-yl)-5-oxy-(6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino-cyclobutyl-methanol (compound 1-A ) (70 mg, yield 31%). LC-MS, M/Z (ESI): 461.1 (M+1). ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.59 (s, 2H), 5.60 (s, 1H), 4.82 (s, 1H), 3.89 (s, 2H), 3.46 – 3.29 (m, 2H), 3.23 – 3.09 (m, 6H), 2.06 (d, 2H), 1.88 (ddd, 4H), 1.29 – 1.04 (m, 3H).

Example 2: Preparation of (R)-2-(6-(5-chloropyrimidin-2-yl)-2,6-diazaspiro[3.3]heptane-2-yl)-5-oxido-(6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino-cyclobutyl-methanol (Compound 11-A) The synthetic route of the target compound 11-A is as follows: Intermediate A1 (140 mg, 0.5 mmol), intermediate A3 (105 mg, 0.5 mmol) and DIPEA (200 mg, 0.5 mmol) were added to a microwave tube containing 1,4-dioxane (5 mL), and microwaved at 120°C for 30 min. The concentrated crude product was separated by reversed-phase high performance liquid chromatography (chromatographic column: Phenomenex Luna C18 150×25mm×10μm; mobile phase: A=water+0.01 volume % trifluoroacetic acid (99%), B=acetonitrile; gradient 35%-65% B, 10 min) to obtain (R)- 2-(6-(5-chloropyrimidin-2-yl)-2,6-diazaspiro[3.3]heptane-2-yl)-5-oxido-(6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino-cyclobutyl-methanol (Compound 11-A) (70 mg, yield 31%). LC-MS, M/Z (ESI): 462.1 (M+1). ¹ H NMR (400 MHz, CDCl ₃ ):δ 8.63 (s, 2H), 5.70 (s, 1H), 3.55 (s, 2H), 4.48 (s, 2H), 4.04 (s, 2H), 3.92 (dd, 2H), 3.65 – 3.49 (m, 2H), 3.49 – 3.32 (m, 2H), 3.15 – 2.90 (m, 2H), 2.77 (s, 2H), 2.43 – 2.13 (m, 4H), 1.95 (ddd, 2H).

Example 3: (R)-2-(6-(5-chloropyrimidin-2-yl)-3-azabicyclo[4.1.0]heptan-3-yl)-5-oxidation-(6,7 Preparation of -dihydrothio[3,2-d]pyrimidin-4-yl)amino-cyclobutyl-methanol (compound 13-A) The synthetic route of the target compound 13-A is as follows: Intermediate A1 (140 mg, 0.5 mmol), intermediate A4 (112 mg, 0.5 mmol) and DIPEA (200 mg, 0.5 mmol) were added to a microwave tube containing 1,4-dioxane (5 mL) , microwave reaction at 120°C for 30 minutes, and the crude product after concentration was separated by reversed-phase high performance liquid chromatography. The separation method was (chromatographic column: Phenomenex Luna C18 150×25mm×10μm; mobile phase: A=water+0.01 volume% trifluoroacetic acid (99%), B=acetonitrile; gradient 35%-65%B, 10 minutes), the obtained (R)-2-(5-(5-chloropyrimidin-2-yl)hexahydropyrrolo[3,4 -c]pyrrole-2(1H)-yl)-5-oxy-(6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino-cyclobutyl-methanol (compound 13 -A) (70 mg, yield 30%). LC-MS, M/Z (ESI): 476.1 (M+1). ¹ H NMR (400 MHz, cdcl ₃ ): δ 8.23 (s, 2H), 5.74 (s, 1H), 5.05 (s, 1H), 3.86 (dd, 4H), 3.67 – 3.34 (m, 6H), 3.26 – 2.85 (m, 4H), 2.24 (dt, 5H), 1.93 (ddd, 3H).

Example 4: (R)-2-(4-(5-chloropyrimidin-2-yl)-3,6-dihydropyridin-1(2H)-yl)-5-oxygen-(6,7-di Preparation of hydrothieno[3,2-d]pyrimidin-4-yl)amino-cyclobutyl-methanol (compound 20-A). The synthetic route of the target compound 20-A is as follows: Intermediate A1 (140 mg, 0.5 mmol), intermediate A7 (100 mg, 0.5 mmol) and DIPEA (200 mg, 0.5 mmol) were added to a microwave tube containing 1,4-dioxane (5 mL) , microwave reaction at 120°C for 30 minutes, and the crude product after concentration was separated by reversed-phase high performance liquid chromatography. The separation method was (chromatographic column: Phenomenex Luna C18 150×25mm×10μm; mobile phase: A=water+0.01 volume% trifluoroacetic acid (99%), B=acetonitrile; gradient 35%-65%B, 10 minutes), the obtained (R)-2-(4-(5-chloropyrimidin-2-yl)-3,6-dihydropyridine -1(2H)-yl)-5-oxy-(6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino-cyclobutyl-methanol (Compound 20-A)( 70 mg, yield 32%). LC-MS, M/Z (ESI): 447.1 (M+1). ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.85 (s, 2H), 7.34 (s, 1H), 7.30 – 7.20 (m, 1H), 4.43 (s, 1H), 3.74 (ddd, 2H) , 3.49 – 3.32 (m, 2H), 3.33 – 3.13 (m, 2H), 2.90 (ddd, 4H), 2.62 (s, 2H), 2.39 – 2.25 (m, 2H), 2.18 (dd, 2H), 1.90 – 1.69 (m, 2H).

Example 5: (R)-2-(3-(5-chloropyrimidin-2-yl)azetidin-1-yl)-5-oxy-(6,7-dihydrothieno[3,2- Preparation of d]pyrimidin-4-yl)amino-cyclobutyl-methanol (compound 26-A) The synthetic route of the target compound 26-A is as follows: Intermediate A1 (140 mg, 0.5 mmol), intermediate A9 (85 mg, 0.5 mmol) and DIPEA (280 mg, 0.7 mmol) were added to a microwave tube containing 1,4-dioxane (5 mL) , microwave reaction at 120°C for 30 minutes, and the crude product after concentration was separated by reversed-phase high performance liquid chromatography. The separation method was (chromatographic column: Phenomenex Luna C18 150×25mm×10μm; mobile phase: A=water+0.01 volume% trifluoroacetic acid (99%), B=acetonitrile; gradient 35%-65%B, 10 minutes), obtained (R)-2-(3-(5-chloropyrimidin-2-yl)azetidin-1-yl) - 5-Oxid-(6,7-dihydrothio[3,2-d]pyrimidin-4-yl)amino-cyclobutyl-methanol (compound 26-A) (20 mg, yield 10%) . LC-MS, M/Z (ESI): 421.1 (M+1). ¹ H NMR (400 MHz, cdcl ₃ ): δ 8.67 (s, 2H), 6.26 (s, 1H), 4.48 (d, 4H), 4.17 (ddd, 1H), 3.96 – 3.76 (m, 2H), 3.72 – 3.56 (m, 1H), 3.52 – 3.35 (m, 1H), 3.08 (ddd, 2H), 2.25 (tdd, 4H), 2.06 – 1.78 (m, 2H).

Example 6: Preparation of (R)-2-((2S)-4-(5-chloropyrimidin-2-yl)-2-methylpiperidin-1-yl)-5-oxido-(6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino-cyclobutyl-methanol (Compound 27-A) The synthetic route of the target compound 27-A is as follows: Intermediate A1 (140 mg, 0.5 mmol), intermediate A8 (150 mg, 0.7 mmol) and DIPEA (280 mg, 0.7 mmol) were added to a microwave tube containing 1,4-dioxane (5 mL) and subjected to microwave reaction at 120°C for 30 min. The concentrated crude product was separated by reverse phase high performance liquid chromatography (chromatographic column: Phenomenex Luna C18 150×25mm×10μm; mobile phase: A=water+0.01 volume % trifluoroacetic acid (99%), B=acetonitrile; gradient 35%-65% B, 10 min) to obtain (R)-2-((2S)-4-(5-chloropyrimidin-2-yl)-2-methylpiperidin-1-yl)-5-oxido-(6,7-dihydrothienyl)-[ 3,2-d]pyrimidin-4-yl)amino-cyclobutyl-methanol (Compound 27-A) (20 mg, yield 9%). LC-MS, M/Z (ESI): 463.1 (M+1). ¹ H NMR (400 MHz, cdcl ₃ ):δ 8.62 (s, 2H), 3.90 (s, 2H), 3.73 – 3.50 (m, 2H), 3.47 – 3.27 (m, 2H), 3.22 – 2.90 (m, 3H), 2.43 – 2.15 (m, 4H), 2.04 – 1.62 (m, 7H), 1.30 (d, 3H).

Example 7: Preparation of (R)-1-(2-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclopropane-1-carbonitrile (Compound 28-A) The synthetic route of the target compound 28-A is as follows: Intermediate A10 (135 mg, 0.5 mmol), intermediate A5 (100 mg, 0.5 mmol) and DIPEA (280 mg, 0.7 mmol) were added to a microwave tube containing 1,4-dioxane (5 mL) and subjected to microwave reaction at 120°C for 30 min. The concentrated crude product was separated by reversed-phase HPLC (chromatographic column: Phenomenex Luna C18 150×25mm×10μm; mobile phase: A=water+0.01 volume % trifluoroacetic acid (99%), B=acetonitrile; gradient 35%-65% B, 10 minutes) to obtain (R)-1-(2-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclopropane-1-carbonitrile (Compound 28-A) (22 mg, yield 11%). LC-MS, M/Z (ESI): 430.1 (M+1). ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.63 (s, 2H), 6.28 (s, 1H), 4.99 (s, 2H), 3.62 (dt, 1H), 3.46 – 3.34 (m, 1H), 3.25 – 2.97 (m, 5H), 2.10 (d, 2H), 1.89 (d, 2H), 1.30 (dd, 2H), 1.25 (s, 2H).

Example 8: Preparation of target compound 12-A (5R)-2-(5-(5-chloropyrimidin-2-yl)hexahydrocyclopentadienyl[c]pyrrole-2(1H)-yl)-5-oxido-(6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino-cyclobutyl-methanol (target compound 12-A) The synthetic route of the target compound 12-A is as follows:

Step 1: Synthesis of tert-butyl-5-(((trifluoromethyl)sulfonyl)oxy)-3,3a,6,6a-tetrahydrocyclopentadien[c]pyrrole-2(1H)-carboxylate (Compound 12-2) Dissolve tert-butyl 5-oxyylidene hexahydrocyclopentadienyl[c]pyrrole-2(1H)-carboxylate (Compound 12-1) (10.0 g, 44.4 mmol) in tetrahydrofuran (200 mL), replace nitrogen, cool to -65°C, slowly add 1M bis(trimethylsilyl)amide lithium tetrahydrofuran solution (1M, 11.1 g, 66.6 mL) dropwise, and react for 30 minutes. Dissolve N,N-bis(trifluoromethanesulfonyl)aniline (19.0 g, 53.3 mmol) in tetrahydrofuran (100 mL), slowly dropwise add to the reaction solution, and raise to 25°C after the addition is complete to react for 4 hours. The reaction solution was poured into a saturated ammonium chloride solution (300 mL) to quench, and then extracted with ethyl acetate (300 mL) for 3 times. After adding anhydrous sodium sulfate to dry, the sample was concentrated and stirred. The yellow oily product tert-butyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,3a,6,6a-tetrahydrocyclopentadien[c]pyrrole-2(1H)-carboxylate (Compound 12-2) (15.9 g, yield 63.0%) was obtained by separation and purification using a silica gel column (petroleum ether:ethyl acetate (V/V) = 1/0-10/1). ¹ H NMR (400 MHz, CDCl ₃ ) δ = 5.55 (d, 1 H), 3.69 (br t, 1 H), 3.46 - 3.56 (m, 1 H), 3.37 (br t, 2 H), 3.13 (br s, 1 H), 2.90 - 2.97 (m, 1 H), 2.81 - 2.90 (m, 1 H), 2.37 (br d, 1 H), 1.43 (s, 9 H)

Step 2: Tertiary butyl-5-(4,4,5,5-tetramethyl-1,3,2-dimethylborane-2-yl)-3,3a,6,6a-tetramethyl Synthesis of Hydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Compound 12-3) Tertiary butyl-5-(((trifluoromethyl)sulfonyl)oxo)-3,3a,6,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Compound 12-2) (10.0 g, 28.0 mmol) and bis(pinacol)diboron (7.82 g, 30.8 mmol) were dissolved in 1,4-dioxane (200 mL), and then potassium acetate (8.24 g, 84.0 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.02 g, 1.40 mmol) were added to the reaction solution. After the addition, nitrogen was replaced. Slowly raise to 90°C and react for 6 hours. The reaction solution was filtered through diatomaceous earth and concentrated to obtain tertiary-butyl 5-(4,4,5,5-tetramethyl-1,3,2-diboropentacyclo-2-yl)-3 ,3a,6,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (compound 12-3) (9.38 g, crude product). LC-MS, M/Z: 280.1 (M-56+H).

Step 3: Tertiary butyl-5-(5-chloropyrimidin-2-yl)-3,3a,6,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate Synthesis of (compound 12-4) Tertiary butyl-5-(4,4,5,5-tetramethyl-1,3,2-diboropentane-2-yl)-3,3a,6,6a-tetrahydrocyclopentadienyl Crude enzo[c]pyrrole-2(1H)-carboxylate (compound 12-3) (9.38 g) and 5-chloro-2-iodopyrimidine (compound A2-2) (7.40 g, 30.8 mmol) were dissolved in In 1,4-dioxane (200 mL) and water (30 mL), add potassium carbonate (11.6 g, 84.0 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] Palladium(II) dichloride (1.02 g, 1.40 mmol) was added to the reaction solution. Slowly raise the temperature to 90°C and react for 6 hours. After the reaction solution was concentrated, water (270 mL) was added, extracted three times with ethyl acetate (300 mL), dried over sodium sulfate, concentrated, and separated and purified on a silica gel column (petroleum ether: ethyl acetate (V/V) = 1 /0-5/1) to obtain the product tertiary-butyl 5-(5-chloropyrimidin-2-yl)-3,3a,6,6a-tetrahydrocyclopenta[c]pyrrole-2(1H )-formate (compound 12-4) (7.00 g, yield 77.7%). LC-MS, M/Z: 266.3 (M-56+H). ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.63 (s, 2 H), 6.82 (br s, 1 H), 3.71 (br s , 1 H), 3.57 (br s, 3 H), 2.95 - 3.17 (m, 3 H), 2.76 (br d, 1 H), 1.44 (s, 9 H)

Step 4: Synthesis of tert-butyl-5-(5-chloropyrimidin-2-yl)hexahydrocyclopentadienyl[c]pyrrole-2(1H)-carboxylate (Compound 12-5) Tert-butyl-5-(5-chloropyrimidin-2-yl)-3,3a,6,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Compound 12-4) (7.00 g, 21.8 mmol) was dissolved in methanol (100 mL), and tris(triphenylphosphine)rhodium(I) chloride (805 mg, 870 μmol) was added. The atmosphere was replaced with hydrogen, and hydrogen was introduced at 50°C, 50 Psi for 24 hours. The reaction solution was concentrated, mixed and purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) = 1/0-5/1) to obtain a brown oily product, tert-butyl 5-(5-chloropyrimidin-2-yl) hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Compound 12-5) (6.50 g, yield 92.3%). LC-MS, M/Z : 268.3 (M-56+H). ¹ H NMR (400 MHz, CHLOROFORM- d ) δ = 8.58 (s, 2 H), 3.40 - 3.65 (m, 3 H), 3.33 (br d, 2 H), 2.68 - 2.92 (m, 2 H), 2.10 - 2.39 (m, 2 H), 1.93 - 2.01 (m, 1 H), 1.76 - 1.87 (m, 1 H), 1.42 - 1.46 (m, 9 H)

Step 5: Synthesis of 5-(5-chloropyrimidin-2-yl)octahydrocyclopentadien[c]pyrrole (Compound 12-6) 3-(7,7-difluoro-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-4-fluoro-N-(4-methoxybenzyl)-N-methylbenzenesulfonamide (6.01 g, 18.5 mmol) was dissolved in methanolic chloride (4M, 100 mL) and reacted at 25 °C for 2 hours. The reaction liquid was concentrated to obtain 5-(5-chloropyrimidin-2-yl)octahydrocyclopenta[c]pyrrole (Compound 12-6) (4.50 g, yield 93.4 %). LC-MS, M/Z : 224.3 (M+H) ⁺ .

Step 6: (5R)-2-(5-(5-chloropyrimidin-2-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-5-oxygen-(6, Synthesis of 7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino-cyclobutyl-methanol (compound 12-A) 5-(5-Chloropyrimidin-2-yl)octahydrocyclopenta[c]pyrrole (compound 12-6) hydrochloride (1.76 g, 6.78 mmol) and (R)-2-chloro- 4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxidation (Intermediate A1) (1.50 g, 5.21 mmol) Dissolve in 1,4-dioxane (40 mL), add N,N-diisopropylethylamine (4.04 g, 31.3 mmol), then slowly raise to 80 °C and react for 4 hours. Pour the reaction solution into saturated sodium bicarbonate solution (100 ml), extract 4 times with ethyl acetate (240 mL) and methanol (20 mL), dry over sodium sulfate, concentrate, and separate using normal phase high performance liquid chromatography (column ：Welch Ultimate Chloropyrimidin-2-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-5-oxo-(6,7-dihydrothieno[3,2-d]pyrimidine-4 -yl)amino-cyclobutyl-methanol (compound 12-A) (1.50 g, yield 60.5%). LC-MS, M/Z: 475.2 (M+H). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.85 (s, 2 H), 7.26 (s, 1 H), 4.86 (t, 1 H), 3.71 - 3.80 (m, 4 H), 3.37 - 3.46 (m, 4 H), 3.15 - 3.29 (m, 2 H), 2.82 - 2.97 (m, 4 H), 2.39 (br d, 1 H ), 2.12 - 2.20 (m, 4 H), 1.92 - 2.01 (m, 2 H), 1.71 - 1.84 (m, 2 H)

Step 7: (R)-2-((3aR,5(R)&(S),6aS)-5-(5-chloropyrimidin-2-yl)hexahydrocyclopenta[c]pyrrole- 2(1H)-yl)-5-oxy-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amine) cyclobutyl-methanol (target compound 12-A-P1 and Synthesis of 12-A-P2). Racemic compound (5R)-2-(5-(5-chloropyrimidin-2-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-5-oxidation-6 ,7-Dihydrothio[3,2-d ]pyrimidin-4-yl)amino)cyclobutyl)-methanol (compound 12-A) (1.50 g, 3.16 mmol) by normal phase high performance liquid chromatography For chiral separation, the separation method is (column: DAICEL CHIRALPAK AD (250mm*30mm, 10μm); solvent: A=carbon dioxide, B=ammonia (0.1%) + isopropyl alcohol; gradient (B): 40% - 40% , 4.7 minutes) to obtain compound (R)-2-((3aR,5(R)&(S),6aS)-5-(5-chloropyrimidin-2-yl)hexahydrocyclopenta[c ]pyrrole-2(1H)-yl)-5-oxy-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amine) cyclobutyl-methanol (target compound 12-A -P1, retention time 0.835 min) (862 mg, yield 57.5%), LC-MS, M/Z (ESI): 475.3 (M+H). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.82 (s, 2H), 7.30 (br s, 1H), 4.85 (br m, 1H), 3.73 (br s, 2H), 3.37-3.61 (m, 6H), 3.16-3.22 (m, 1H), 2.80-2.97 (m, 4H), 2.29-2.38 (m, 4H), 2.09-2.19 (m, 2H), 1.66-1.82 (m, 4H). (R)-2-((3aR,5(R)&(S),6aS)-5-(5-chloropyrimidin-2-yl)hexahydrocyclopenta[c]pyrrole-2(1H) -yl)-5-oxy-6,7-dihydrothio[3,2-d]pyrimidin-4-yl)amino)cyclobutyl-methanol (target compound 12-A-P2, retention time is 1.084 min) (457 mg, yield 30.5%). LC-MS, M/Z (ESI): 475.4 (M+H). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.85 (s, 2H), 7.26 (s, 1H), 4.85 (m, 1H), 3.70-3.78 (m, 4H), 3.50-3.57 (m, 1H), 3.36-3.45 (m, 3H), 3.15-3.24 (m, 1H), 2.81-2.96 (m, 4H), 2.30-2.40 (m, 2H), 2.10-2.20 (m, 4H), 1.95 ( br m, 2H), 1.69-1.83 (m, 2H)

Example 9: (5R)-1-((2-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-5-oxo-6,7-dihydrothieno[3, Preparation of 2-d]pyrimidin-4-yl)amino)cyclobutane-1-nitrile (compound 15-A)

Step 1: Synthesis of 1-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutane-1-carbonitrile (Compound 15-2) The raw material 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine (intermediate A1-3) (1.27 g, 6.14 mmol), 1-aminocyclobutane-1-nitrile hydrochloride (0.74 g, 5.58 mmol) and N,N-diisopropylethylamine (2.16 g, 16.14 mmol) were dissolved in N,N-dimethylformamide (5 mL) and heated to 110°C and stirred for 12 hours. Water (10 mL) was added to dilute, and the mixture was extracted with ethyl acetate (10 mL×3), separated, and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by chromatography column (petroleum ether: ethyl acetate (V/V) = 3:1-1:2) to obtain the title compound 15-2 (0.34 g, yield 36 %). LC-MS, M/Z (ESI): 267.1 (M+1)

Step 2: 1-((2-chloro-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutane-1-carbonitrile (compound 15-3) The raw material 1-((2-chloro-6,7-dihydrothio[3,2-d]pyrimidin-4-yl)amino)cyclobutane-1-carbonitrile (compound 15-2) (0.3 g , 1.12 mmol), S-1,1'-bi-2-naphthol (0.03 g, 0.11 mmol), isopropyl titanate (0.16 mg, 0.056 mmol) and water (20.26 mg, 1.12 mmol) were dissolved in diacetate. In methyl chloride (3 mL), replace nitrogen, keep the temperature at 20°C and stir for 1 h, then add hydrogen peroxide tertiary butanol (111.5 mg, 1.24 mmol) to the reaction system and continue the reaction for 2 h. After the reaction is completed, the reaction solution is diluted with dichloromethane, mixed with silica gel, and separated and purified by a chromatography column (dichloromethane: methanol = 50:1-10:1). The title compound 15-3 (0.2 g, Yield 67%) LC-MS, M/Z (ESI): 283.4 (M+1)

Step 3: ( R ) -1-((2-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-5-oxo-6,7-dihydrothieno[3, 2-d]pyrimidin-4-yl)amino)cyclobutane-1-nitrile (compound 15-A) The raw material 1-((2-chloro-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutane-1-carbonitrile (15-3 ) (0.2 g, 0.7 mmol), 5-chloro-2-(piperidin-4-yl)pyrimidine (intermediate A5) (0.21 g, 1.05 mmol) and N,N-diisopropylethylamine (0.27 g , 2.1 mmol) was dissolved in dioxane (3.0 mL) and placed in a microwave tube, and microwaved at 120°C for 0.5 h. After the reaction is completed, the reaction solution is diluted with dichloromethane, mixed with silica gel, separated and purified with a chromatography column (dichloromethane: methanol = 50:1-10:1), concentrated through the column liquid, and then purified by high-performance liquid chromatography to obtain the title Compound 15-A (20 mg, yield 7%), LC-MS, M/Z (ESI): 444.2 (M+1). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.85 (s, 2H), 8.64 (s, 1H), 4.77 (d, 2H), 3.52 – 3.41 (m, 1H), 3.22 (ddd, 2H), 3.12 (t, 2H), 3.05 – 2.96 (m, 1H), 2.95 – 2.88 (m, 1H), 2.67 (dt, 2H), 2.58 – 2.51 (m, 1H), 2.44 (d, 1H), 2.06 ( ddd, 1H), 1.97 (dt, 3H), 1.66 (d, 2H).

Example 10: Preparation of target compound 16-A (R)-2-(6-(5-chloropyrimidin-2-yl)spiro[3.3]heptan-2-yl)-5-oxy-(6,7 -Dihydrothieno[3,2-d]pyrimidin-4-yl)amino-cyclobutyl-methanol (target compound 16-A) The synthetic route of target compound 16-A is as follows:

Step 1: Tertiary-butyl 6-(((trifluoromethyl)sulfonyl)oxo)-2-azaspiro[3.3]hept-5-en-2-carboxylate (compound 16-2 )Synthesis Dissolve tertiary-butyl 6-oxyylidene-2-azaspiro[3.3]heptane-2-carboxylate (compound 16-1) (5.00 g, 23.7 mmol) in tetrahydrofuran (80 mL) , then add lithium bis(trimethylsilyl)amide (4.75 g, 28.4 mmol) dropwise at -70°C, react at 25°C for 1 hour, and N-phenylbis(trifluoromethanesulfonyl)imine (9.30 g , 26.0 mmol) was dissolved in tetrahydrofuran (10 mL) and the reaction solution was added dropwise at -78°C, then the temperature was raised to 25°C and mixed for 2 hours. The reaction solution was quenched with ammonium chloride (100 mL), and then extracted three times with ethyl acetate (300 mL). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and used with a silica gel column. Separation and purification (petroleum ether: ethyl acetate (V/V) = 1:0-20:1) and purification yield compound tertiary-butyl 6-(((trifluoromethyl)sulfonyl)oxo)-2- Azaspiro[3.3]hept-5-en-2-carboxylate (compound 16-2) (4.20 g, yield 43.1%).

Step 2: Tertiary-butyl 6-(4,4,5,5-tetramethyl-1,3,2-diethylboropentane-2-yl)-2-azaspiro[3.3]heptane -Synthesis of 5-en-2-carboxylate (compound 16-3) Tertiary-butyl 6-(((trifluoromethyl)sulfonyl)oxo)-2-azaspiro[3.3]hept-5-ene-2-carboxylate (compound 16-2) (700 mg, 2.04 mmol), dipinopinacol boronate (569 mg, 2.24 mmol), 1,1-bis(diphenylphosphono)ferrocene palladium chloride (47.6 mg, 102 umol), potassium acetate ( 600 mg, 6.12 mmol) was dissolved in 1,4-dioxane (10 mL), and then reacted at 100°C under nitrogen protection for 10 hours. The reaction solution was filtered through diatomaceous earth and concentrated to obtain a tan compound tertiary-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dichloropentacyclo-2-yl)- 2-Azaspiro[3.3]hept-5-ene-2-carboxylate (compound 16-3) (1.00 g, crude product). LC-MS, M/Z (ESI): 266.2[M-56+H]

Step 3: Synthesis of tertiary butyl 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]hept-5-ene-2-carboxylate (Compound 16-4) Tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-diboryl-2-yl)-2-azaspiro[3.3]hept-5-ene-2-carboxylate (Compound 16-3) (800 mg, 2.49 mmol), 5-chloro-2-iodopyrimidine (718 mg, 2.99 mmol) were dissolved in 1,4-dioxane (20 mL) and water (4 mL), potassium carbonate (860 mg, 6.23 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (182 mg, 249 umol) were added, and the reaction was carried out at 90°C for 5 hours under nitrogen protection. The reaction solution was diluted with water (50 mL), then extracted three times with ethyl acetate (150 mL), the organic phase was washed with saturated brine (100 mL), dried with anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) = 1:0-5:1) to obtain the compound tri-butyl 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]hept-5-ene-2-carboxylate (compound 16-4) (312 mg, yield 41.7%). LC-MS, M/Z (ESI): 252.2 [M-55] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.65 (s, 2H), 6.92 (s, 1H), 4.15 (d, 4H), 3.07 (s, 2H), 1.46 (s, 9H)

Step 4: Synthesis of tertiary butyl 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Compound 16-5) Tert-butyl-6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]hept-5-ene-2-carboxylate (Compound 16-4) (400 mg, 1.30 mmol) was dissolved in methanol (10 mL), and tris(triphenylphosphine)rhodium chloride (120 mg, 130 umol) was added under nitrogen protection. The suspension was replaced with nitrogen and hydrogen three times respectively, and then reacted at 50°C under hydrogen pressure of 50 psi for 16 hours. The reaction solution was filtered, concentrated, and purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) = 10:0-5:1) to obtain the compound tri-butyl 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Compound 16-5) (360 mg, 94.0%). LC-MS, M/Z (ESI): 209.2 [M-100] ⁺

Step 5: Synthesis of 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]heptane (compound 16-6) Dissolve tertiary butyl-6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]heptane-2-carboxylate (16-5) (360 mg, 1.16 mmol) in methanol (10 mL), add hydrochloric acid gas/methanol solution (4M, 5 mL), and react at 25°C for 5 hours. The reaction solution was concentrated to obtain a white solid compound 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]heptane (compound 16-6) (172 mg, yield 54.1%). LC-MS, M/Z (ESI): 210.2 [M+H] ⁺

Step 6: (R)-2-(6-(5-chloropyrimidin-2-yl)spiro[3.3]heptan-2-yl)-5-oxy-(6,7-dihydrothieno[3 ,2-d]Synthesis of pyrimidin-4-yl)amino-cyclobutyl-methanol (compound 16-A) Combine 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]heptane (16-6) (60.0 mg, 219 umol) and diisopropylethylamine (141 mg, 1.10 mmol) Add to (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxidation (64.4 mg, 219 umol) in a solution of 1,4-dioxane (10 mL), slowly raise the temperature to 100°C and react for 3 hours. Extract three times with dichloromethane (60 mL), dry over sodium sulfate, and concentrate. The crude product is subjected to reversed-phase high-performance liquid chromatography (chromatographic column: Waters Xbridge 150*25mm* 5μm; solvent: A = water + 0.05% ammonia, B =acetonitrile; gradient (acetonitrile): 18% - 48%, 9 minutes) was purified to obtain compound (R)-2-(6-(5-chloropyrimidin-2-yl)spiro[3.3]heptan-2-yl )-5-oxy-(6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino-cyclobutyl-methanol (compound 16-A) (75.0 mg, yield 57.2% ). LC-MS, M/Z (ESI): 461.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO_ d ₆ ) δ = 8.87 (s, 2H), 7.33 (s, 1H), 4.87 (m, 1H), 4.12 (s, 2H), 3.95 (s, 2H), 3.64- 3.72 (m, 3H), 3.36-3.42 (m, 1H), 3.16-3.23 (m, 1H), 2.82-2.94 (m, 2H), 2.58-2.65 (m, 3H), 2.37 (br d, 2H) , 2.30 (br s, 1H), 2.10-2.15 (m, 2H), 1.71-1.82 (m, 2H)

Example 11: Synthesis of target compound 29-A (R)-2-(4-(5-chloropyrimidin-2-yl)cyclohexyl)-5-oxo-6,7-dihydrothieno[3,2 -d]pyrimidin-4-yl)amino)cyclobutyl-methanol (target compound 29-A) The synthetic route of target compound 29-A is as follows:

Step 1: Synthesis of 5-chloro-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyrimidine (Compound 29-2) 1,4-Dioxa-spiro[4,5]decan-7-ene-8-boronic acid pinacol ester (Compound 29-1) (5.00 g, 18.8 mmol) and 5-chloro-2-iodopyrimidine (Compound A2-2) (5.42 g, 22.5 mmol) were dissolved in a solution of dioxane (20 mL) and water (4 mL), potassium carbonate (6.49 g, 47.0 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (1.37 g, 1.88 mmol) were added, and the mixture was stirred at 90°C under nitrogen for 10 hours. The reaction solution was diluted with water (50 mL), extracted three times with ethyl acetate (150 mL), and the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) = 15:1-5:1) to obtain 5-chloro-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyrimidine (compound 29-2) (3.90 g, yield 82.2%). LC-MS, M/Z (ESI): 253.1 [M+H] ⁺ .

Step 2: Synthesis of 5-chloro-2-(1,4-dioxaspiro[4.5]decan-8-yl)pyrimidine (compound 29-3) 5-Chloro-2-(1,4-dioxaspiro[4.5]decan-8-yl)pyrimidine (compound 29-2) (3.90 g, 15.4 mmol) was dissolved in methanol (20 mL). Tris(triphenylphosphine)rhodium chloride (1.43 g, 1.54 mmol) was added under nitrogen, and the suspension was replaced three times with nitrogen and hydrogen respectively. Stir at 50°C, 50 psi for 16 hours. The reaction solution was filtered, concentrated, and separated and purified using a silica gel column (petroleum ether: ethyl acetate (V/V) = 15:1-5:1) to obtain a yellow liquid compound 5-chloro-2-(1,4-dioxy Heterospiro[4.5]decan-8-yl)pyrimidine (compound 29-3) (3.70 g, yield 94.1%). LC-MS, M/Z (ESI): 255.2 [M+H] ⁺

Step 3: Synthesis of 4-(5-chloropyrimidin-2-yl)cyclohexanone (Compound 29-4) Compound 5-chloro-2-(1,4-dioxaspiro[4.5]decane-8-yl)pyrimidine (Compound 29-3) (3.50 g, 13.7 mmol) was dissolved in dichloromethane (20 mL), and then trifluoroacetic acid (3.13 g, 27.5 mmol, 2.03 mL) was added and stirred at 25°C for 5 hours. The reaction solution was adjusted to neutral with saturated sodium bicarbonate solution (30 mL), extracted three times with dichloromethane (90 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) = 15:1-3:1) to obtain 4-(5-chloropyrimidin-2-yl)cyclohexanone (compound 29-4) (2.80 g, yield 96.7%). LC-MS, M/Z (ESI): 211.0 [M+H] ⁺

Step 4: Synthesis of 4-(5-chloropyridinyl)cyclomethan-1-ene-1-yl trifluoromethanesulfonate (Compound 29-5) 4-(5-Chloropyrimidin-2-yl)cyclohexanone (Compound 29-4) (2.80 g, 13.3 mmol) and N-phenylbis(trifluoromethanesulfonyl)imide (5.22 g, 14.62 mmol) were dissolved in tetrahydrofuran (15 mL), then cooled to -78°C, and then lithium bis(trimethylsilyl)amide (1.00 M, 4.45 g, 26.6 mL) was slowly added dropwise, stirred at -78°C for 30 minutes, and then heated to 25°C and stirred for 16 hours. The reaction solution was quenched with saturated ammonium chloride solution (30 mL), and then extracted three times with ethyl acetate (90 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative HPLC (column: Welch Ultimate XB-SiOH 250*70*10um; solvent: A = n-hexane, B = ethanol; gradient: 1% - 30%, 15 minutes) to obtain yellow solid 4-(5-chloropyridinyl)cyclomethan-1-ene-1-yl trifluoromethanesulfonate (Compound 29-5) (890 mg, yield 31.8%). LC-MS, M/Z (ESI): 343.1 [M+H] ⁺

Step 5: Synthesis of 5-chloro-2-(4-(4,4,5,5-tetramethyl-1,3,2-diborylpentyl-2-yl)cyclohexatriene-3-ene-1-yl)pyrimidine (Compound 29-6) 4-(5-Chloropyridin-2-yl)cyclomethan-1-en-1-yl trifluoromethanesulfonate (Compound 29-5) (400 mg, 1.19 mmol), bis-pinacol boronate (326 mg, 1.28 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (42.8 mg, 58.4 μmol) and potassium acetate (344 mg, 3.50 mmol) were dissolved in dioxane (10 mL) and then stirred at 90°C for 10 hours under nitrogen. The reaction solution was quenched with water (10 mL), extracted with ethyl acetate (30 mL), and the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) = 1:0-20:1) to obtain compound 5-chloro-2-(4-(4,4,5,5-tetramethyl-1,3,2-diboropentan-2-yl)cyclohexatriene-3-en-1-yl)pyrimidine (compound 29-6) (260 mg, yield 63.2%). LC-MS, M/Z (ESI): 321.2 [M+H] ⁺ . ¹ H NMR (CHLOROFORM-d) δ = 8.64 (s, 2H), 6.67 (br d, 1H), 3.05-3.20 (m, 1H), 2.45-2.60 (m, 2H), 2.21-2.40 (m, 2H), 2.06-2.16 (m, 1H), 1.70-1.83 (m, 1H), 1.28 (d, 12H)

Step 6: Synthesis of (5R)-2-(4-(5-chloropyrimidin-2-yl)cyclohexatriene-1-ene-1-yl)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl-methanol (Compound 29-7A) 5-Chloro-2-(4-(4,4,5,5-tetramethyl-1,3,2-diboropentan-2-yl)cyclohexatrien-3-en-1-yl)pyrimidine (Compound 29-6) (200 mg, 561 μmol) and (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (75.0 mg, 255 μmol) were dissolved in dioxane (5 mL) and water (0.5 mL), and then sodium carbonate (81.1 mg, 766 μmol) and tetrakistriphenylphosphine palladium (30.0 mg, 25.5 μmol) were added, and then stirred at 85°C for 16 hours under nitrogen. The reaction solution was diluted with water (10 mL), extracted three times with ethyl acetate (30 mL), and the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel separation (dichloromethane: methanol (V/V) = 10/1) to obtain (5R)-2-(4-(5-chloropyrimidin-2-yl)cyclohexatriene-1-ene-1-yl)-5-oxido-6,7-dihydrothienyl[3,2-d]pyrimidin-4-yl)amino)cyclobutyl-methanol (Compound 29-7A) (130 mg, yield 65.0%). LC-MS, M/Z (ESI): 466.3 [M+1] ⁺

Step 7: (R)-2-(4-(5-chloropyrimidin-2-yl)cyclohexyl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidine-4- Synthesis of cyclobutyl-methanol (target compound 29-A) (5R)-2-(4-(5-chloropyrimidin-2-yl)cyclohexatrien-1-en-1-yl)-5-oxy-6,7-dihydrothieno[3,2 -d ]pyrimidin-4-yl)amino)cyclobutyl)-methanol (compound 29-7A) (100 mg, 224 μmol) was dissolved in methanol (10 mL). Tris(triphenylphosphine)rhodium chloride (20.8 mg, 22.4 μmol) was added under nitrogen, the suspension was replaced three times with nitrogen and hydrogen respectively, and then reacted at 50 psi and 50°C for 16 hours. The reaction solution was filtered and concentrated, and the crude product was subjected to reversed-phase high-performance liquid chromatography (column: Phenomenex luna C18 150*25mm*10 um; solvent: A = water + 0.05% formic acid, B = acetonitrile; gradient (acetonitrile): 18% - 48%, 9 minutes) was purified to obtain (R)-2-(4-(5-chloropyrimidin-2-yl)cyclohexyl)-5-oxo-6,7-dihydrothieno[3,2- d ]pyrimidin-4-yl)amino) cyclobutyl-methanol (compound 29-A) (51.5 mg, yield 49.3%) LC-MS, M/Z (ESI): 448.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO_d ₆ ) δ = 8.85 (d, 2H), 7.71-7.87 (m, 1H), 4.76-4.92 (m, 1H), 3.72-3.82 (m, 1H), 3.62 (br d , 1H), 3.42-3.58 (m, 1H), 3.21-3.30 (m, 1H), 3.05-3.13 (m, 1H), 2.90-3.00 (m, 1H), 2.75-2.89 (m, 1H), 2.55 -2.65 (m, 1H), 2.15-2.34 (m, 3H), 1.98 (s, 5H), 1.73-1.84 (m, 2H), 1.59-1.72 (m, 4H).

Example 12: Preparation of target compound 30-A (R)-2-(2-(5-chloropyrimidin-2-yl)-7-azaspiro[3.5]nonan-7-yl)-5-oxidation -6,7-Dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl-methanol (target compound 30-A) The synthetic route of target compound 30-A is as follows:

Step 1: Tertiary-butyl 2-(((trifluoromethyl)sulfonyl)oxo)-7-azaspiro[3.5]non-1-en-7-carboxylate (compound 30-2 )Synthesis Tertiary-butyl 2-oxyylidene-7-azaspiro[3.5]nonane-7-carboxylate (compound 30-1) (5.00 g, 20.8 mmol) was dissolved in tetrahydrofuran (100 mL) and replaced Nitrogen, cool to - 65°C, slowly add tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (1 M, 4.54 g, 27.1 mmol, 27.1 mL) dropwise, and react for 30 minutes after the dropwise addition. Dissolve N,N-bis(trifluoromethanesulfonyl)aniline (8.96 g, 25.1 mmol) in tetrahydrofuran (30 mL) and slowly add it dropwise to the reaction solution. After the dropwise addition is completed, the temperature is raised to 25°C and reacted for 3 hours. The reaction solution was poured into saturated ammonium chloride solution (200 mL) to quench, and then extracted three times with ethyl acetate (600 mL). After drying by adding anhydrous sodium sulfate, concentrate and mix the sample. Use a silica gel column for separation and purification (petroleum ether: ethyl acetate (V/V) = 1/0-10/1) to obtain the yellow oily product tertiary butyl-2-((trifluoromethyl)sulfonyl)oxy Generation)-7-azaspiro[3.5]non-1-ene-7-carboxylate (compound 30-2) (4.00 g, yield 51.6 %)

Step 2: Synthesis of tert-butyl-2-(4,4,5,5-tetramethyl-1,3,2-diboryl-2-yl)-7-azaspiro[3.5]non-1-ene-7-carboxylate (Compound 30-3) Tributyl 2-(((trifluoromethyl)sulfonyl)oxy)-7-azaspiro[3.5]non-1-ene-7-carboxylate (Compound 30-2) (1.10 g, 2.96 mmol) and bis(pinacolato)diboron (977 mg, 3.85 mmol) were dissolved in 1,4-dioxane (30 mL), and potassium acetate (872 mg, 8.89 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (217 mg, 296 umol) were added to the reaction solution. After the addition, nitrogen was replaced and the temperature was slowly raised to 90 °C for 6 hours. The reaction solution was filtered through diatomaceous earth and concentrated to obtain tert-butyl-2-(4,4,5,5-tetramethyl-1,3,2-diboryl-2-yl)-7-azaspiro[3.5]non-1-ene-7-carboxylate (Compound 30-3) (1.08 g, crude product). LC-MS, M/Z: 294.2 (M-56+H).

Step 3: Synthesis of tertiary butyl-2-(5-chloropyrimidin-2-yl)-7-azaspiro[3.5]non-1-ene-7-carboxylate (Compound 30-4) Tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2-diboryl-2-yl)-7-azaspiro[3.5]non-1-ene-7-carboxylate (Compound 30-3) (1.08 g, crude) and 5-chloro-2-iodopyrimidine (851 mg, 3.54 mmol) were dissolved in 1,4-dioxane (30 mL) and water (5 mL), and potassium carbonate (1.22 g, 8.85 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (108 mg, 147 umol) were added to the reaction solution. The temperature was slowly raised to 90 °C and the reaction was carried out for 6 hours. The reaction solution was concentrated and water (30 mL) was added. The mixture was extracted three times with ethyl acetate (90 mL), dried over sodium sulfate, concentrated, and separated and purified on a silica gel column (petroleum ether:ethyl acetate (V/V) = 1/0-5/1) to obtain the product tert-butyl 2-(5-chloropyrimidin-2-yl)-7-azaspiro[3.5]non-1-ene-7-carboxylate (Compound 30-4) (690 mg, yield 69.7%). LC-MS, M/Z : 280.3 (M-56+H).

Step 4: Synthesis of tertiary butyl-2-(5-chloropyrimidin-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate (Compound 30-5) Tert-butyl 2-(5-chloropyrimidin-2-yl)-7-azaspiro[3.5]non-1-ene-7-carboxylate (Compound 30-4) (1.10 g, 3.28 mmol) was dissolved in methanol (30 mL), tris(triphenylphosphine)rhodium(I) chloride (303 mg, 328 umol) was added, the atmosphere was replaced with hydrogen, and hydrogen was introduced at 50 °C, 50 Psi for 24 hours. The reaction solution was concentrated and stirred, and then purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) = 1/0-5/1) to obtain the product tert-butyl 2-(5-chloropyrimidin-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate (Compound 30-5) (303 mg, yield 92.3%). LC-MS, M/Z: 268.3 (M-56.06+H). ¹ H NMR (CDCl ₃ ) δ = 8.63 (s, 2H), 3.76 (m, 1H), 3.39-3.48 (m, 2H), 3.24-3.36 (m, 2H), 2.25-2.34 (m, 2H), 2.11-2.23 (m, 2H), 1.68-1.72 (m, 2H), 1.55-1.59 (m, 2H), 1.46 (s, 9H)

Step 5: Synthesis of 2-(5-chloropyrimidin-2-yl)-7-azaspiro[3.5]nonane (compound 30-6) Tertiary-butyl 2-(5-chloropyrimidin-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate (compound 30-5) (600 mg, 1.78 mmol) dissolved in methanol In hydrogen chloride (20 mL), react at 25°C for 2 hours. The reaction liquid was concentrated to obtain 2-(5-chloropyrimidin-2-yl)-7-azaspiro[3.5]nonane (compound 30-6) hydrochloride (480 mg, yield 98.8%). LC-MS, M/Z: 238.2 (M+H) ⁺ .

Step 6: (R)-2-(2-(5-chloropyrimidin-2-yl)-7-azaspiro[3.5]nonan-7-yl)-5-oxy-6,7-dihydro Synthesis of thieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl-methanol (final product 30-A) 2-(5-Chloropyrimidin-2-yl)-7-azaspiro[3.5]nonane (compound 30-6) hydrochloride (100 mg, 365 μmol) and (R)-2-chloro- 4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxidation (Intermediate A1) (105 mg, 365 μmol) Dissolve in 1,4-dioxane (20 mL), add N,N-diisopropylethylamine (236 mg, 1.82 mmol), then slowly raise to 80°C and react for 4 hours. Pour the reaction solution into saturated sodium bicarbonate solution (30 mL), extract 4 times with ethyl acetate (80 mL) and methanol (8 mL), dry over sodium sulfate, concentrate, and separate using reverse-phase high-performance liquid chromatography (column ：Waters Pyrimidin-2-yl)-7-azaspiro[3.5]nonan-7-yl)-5-oxy-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amine ) cyclobutyl-methanol (final product 30-A) (100 mg, yield 56.1%). LC-MS, M/Z: 489.3 (M+H). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.86 (s, 2 H), 7.29 (s, 1 H), 4.74 - 4.91 (m , 1 H), 3.62 - 3.78 (m, 7 H), 3.36 - 3.42 (m, 1 H), 3.15 - 3.23 (m, 1 H), 2.81 - 2.95 (m, 2 H), 2.22 - 2.33 (m , 4 H), 2.09 - 2.16 (m, 4 H), 1.72 - 1.81 (m, 2 H), 1.68 (br t, 2 H) 1.50 (br t, 2 H)

Example 13: Preparation of Compound 31-A (R)-2-(3-(Benzo[d]oxazol-2-yl)azepanocyclobutane-1-yl)-5-oxido-(6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino-cyclobutyl-methanol (Compound 31-A)

Step 1: 3-(Benzo[d]oxazol-2-yl)azinecyclobutane-1-carboxylic acid tributyl ester (Compound 31-2) Dissolve the raw material 3-iodoazolocyclobutane-1-carboxylic acid tributyl ester (1.85 g, 6.51 mmol) and zinc powder (0.5 g, 7.81 mmol) in tetrahydrofuran (10 mL), replace the nitrogen, heat to 70 °C and stir for 15 minutes. Then dissolve tetrakistriphenylphosphine palladium (0.7 g, 0.65 mmol) and 2-chlorobenzo[d]oxazole (1.0 g, 6.51 mmol) in tetrahydrofuran (5 mL), shake evenly and then inject into the reaction system, and continue the reaction for 2 h. After the reaction is completed, add 20 mL of water to quench the reaction, then extract with ethyl acetate three times, using 10 mL of ethyl acetate each time, separate the liquids, and combine the organic phases. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by chromatography column separation (petroleum ether:ethyl acetate (V/V) = 3:1-1:2) to obtain the title compound 31-2 (0.74 g, yield 38 %). LC-MS, M/Z (ESI): 275.1 (M+1).

Step 2: 2-(azetidin-3-yl)benzo[d]oxazole (compound 31-3) The raw material 3-(benzo[d]oxazol-2-yl)azetidine-1-carboxylic acid tertiary butyl ester (compound 31-2) (0.6 g, 2.19 mmol) was dissolved in dioxane ( 5.0 mL), then add 3 mL of dioxane hydrochloride solution (4M), and stir for 2 h. After the reaction is completed, it is directly concentrated to dryness to obtain the product compound 31-3 (0.3 g, yield 78.9%). LC-MS, M/Z (ESI): 175.1 (M+1).

Step 3: (R) -2-(3-(benzo[d]oxazol-2-yl)azetidin-1-yl)-5-oxy-(6,7-dihydrothieno [3,2-d]pyrimidin-4-yl)amino-cyclobutyl-methanol (Compound 31-A) The raw material 2-(azetidin-3-yl)benzo[d]oxazole (compound 31-3) (0.3 g, 1.72 mmol), (S)-2-chloro-4-((1- (hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (intermediate A1) (0.55 g, 1.89 mmol) and N,N- Diisopropylethylamine (0.67 g, 5.17 mmol) was dissolved in dioxane (4.0 mL) and placed in a microwave tube, and microwaved at 120°C for 0.5 h. After the reaction is completed, the reaction solution is diluted with dichloromethane, mixed with silica gel, separated and purified with a chromatography column (dichloromethane: methanol = 50:1-10:1), concentrated through the column liquid, and then purified by high-performance liquid chromatography to obtain the title Compound 31-A (20 mg, yield 4.5%), LC-MS, M/Z (ESI): 426.1 (M+1). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.72 (ddd, 2H), 7.45 (s, 1H), 7.41 – 7.33 (m, 2H), 4.84 (t, 1H), 4.43 (d, 2H), 4.31 – 4.22 (m, 3H), 3.70 (d, 2H), 3.40 (dd, 1H), 3.24 – 3.17 (m, 1H), 2.98 – 2.83 (m, 2H), 2.32 (dt, 2H), 2.12 ( dd, 2H), 1.83 – 1.67 (m, 2H).

Example 14: Preparation of target compound 8-A: (R)-2-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)-5-oxy-(6,7-dihydro Thieno[3,2-d]pyrimidin-4-yl)amino-cyclobutyl-methanol (target compound 8-A)

Step 1: 4-(4-(1-(hydroxymethyl)cyclobutyl)amino)-5-oxy-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl) -3,6-Dihydropyridine-1(2H)-carboxylic acid tertiary butyl ester (compound 8-1) The raw material (1-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methanol (intermediate A1) (0.5 g, 1.84 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid Tertiary butyl ester (compound A6-1) (0.63 g, 2.02 mmol), tetrakis triphenylphosphorus palladium (0.2 g, 0.18 mmol) were dissolved in dioxane (10.0 mL) and water (2 mL) and replaced with nitrogen. The temperature was raised to 85°C and the reaction was stirred overnight. After the reaction is completed, add water (30 mL) to dilute, extract with ethyl acetate (30 mL×3), separate the liquids, and combine the organic phases. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified using a chromatography column (petroleum ether: ethyl acetate (V/V) = 3:1-1:2) to obtain the title compound 8-1 (0.6 g, yield 86%). LC-MS, M/Z (ESI): 363.1 (M+1).

Step 2: 4-(4-((1-(Hydroxymethyl)cyclobutyl)amino)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)-piperidine-1-carboxylic acid tributyl ester (Compound 8-2) Compound 8-1 (320 mg, 0.736 mmol) and Rh(PPh ₃ ) ₃ Cl (102 mg, 0.110 mmol) were dissolved in methanol (10 mL), the hydrogen was replaced and the temperature was raised to 50 ℃ for stirring and reaction for 12 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, which was separated and purified by chromatography column (dichloromethane: methanol (V/V) = 10:1) to obtain the title compound 8-2 (200 mg, yield 62%). LC-MS, M/Z (ESI): 437.41 (M+1).

Step 3: (1-((2-(piperidin-4-yl)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl]amino)cyclobutyl)methanol (Compound 8-3) Dissolve compound 8-2 (200 mg, 0.458 mmol) in dichloromethane (3 mL), add trifluoroacetic acid (1 mL), and stir the reaction solution at room temperature for 2 hours. After the reaction is completed, concentrate and vortex to obtain a crude product, which is purified by chromatography column separation (dichloromethane: methanol (V/V) = 10:1) to obtain the title compound 8-3 (150 mg. Yield 97%). LC-MS, M/Z (ESI): 337.45 (M+1).

Step 4: (R)-2-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)-5-oxy-(6,7-dihydrothieno[3,2-d ]pyrimidin-4-yl)amino-cyclobutyl-methanol (target compound 8-A) Compound 8-3 (150 mg, 0.445 mmol), 5-chloro-2-iodopyrimidine (123 mg, 0.512 mmol) and N,N-diisopropylethylamine (172 mg, 1.34 mmol) were dissolved in 1, 4-dioxane (3 mL) and placed in a microwave tube, microwave at 120°C for 0.5 hours. After the reaction is completed, the reaction solution is diluted with dichloromethane and separated and purified with a chromatography column (dichloromethane: methanol (V/V) = 10:1), concentrated through the column, and then purified by reversed-phase high-performance liquid chromatography, ( Column column: SunFileTM Prep C18 OBDTM (5μm 30mm×150mm); solvent: A = acetonitrile, B = water; gradient: 1% - 38.7%, 10 minutes) to obtain (R)-2-(1-(5-chloropyrimidine) -2-yl)piperidin-4-yl)-5-oxy-(6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino-cyclobutyl-methanol (target compound 8-A) (90 mg, yield 44.9%). LC-MS, M/Z (ESI): 449.1 (M+1). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.21 (s, 2H), 6.22 (s, 1H), 5.34 (s, 1H), 4.80 (d, 2H), 3.87 (d, 2H), 3.72 – 3.53 (m, 2H), 3.23 – 3.09 (m, 2H), 3.01 – 2.89 (m, 3H), 2.35 – 2.18 (m, 4H), 1.96 (ddd, 4H), 1.76 (ddd, 2H).

Example 15: (5R)-2-(5-(5-chloropyrimidin-2-yl)hexahydrocyclopentyl[c]pyrrole-2(1H)-yl)-5-oxy-6,7-di Preparation of Hydrothieno[3,2-d]pyrimidin-4-yl-)amino)-tetrahydro-2H-pyran (target compound 32-A) Target compounds 32-A, 32-A -P1 and 32 The synthesis route of -A-P2 is as follows:

Step 1: Compound 32-1 was prepared by referring to the preparation method of compound 30-6.

Step 2: Synthesis of (5R)-2-(5-(5-chloropyrimidin-2-yl)hexahydrocyclopentyl[ c ]pyrrole-2(1H)-yl)-5-oxido-6,7-dihydrothieno[3,2-d ]pyrimidin-4-yl-)amino)-tetrahydro-2H-pyran (Compound 32-A) Intermediate 32-1 (100 mg, 447.02 μmol), intermediate A11 (128.64 mg, 447.02 μmol) and DIPEA (172 mg, 1.34 mmol) were added to a microwave tube containing 1,4-dioxane (2 mL) and microwaved at 120°C for 30 min. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, which was separated by reverse phase high performance liquid chromatography (column: SunFileTM Prep C18 OBDTM (5μm 30mm×150mm); solvent: A = acetonitrile, B = water; gradient: 1% - 65%, 10 minutes) to obtain (5R)-2-(5-(5-chloropyrimidin-2-yl)hexahydrocyclopentyl[c]pyrrole-2(1H)-yl)-5-oxido-6,7-dihydrothienyl[3,2-d]pyrimidin-4-yl-)amino)-tetrahydro-2H-pyran (Compound 32-A) (27 mg, yield 13%).

Step 3: Synthesis of (5R)-2-((3aR,5(R)&(S),6aS)-5-(5-chloropyrimidin-2-yl)hexahydrocyclopentyl[ c ]pyrrol-2(1H)-yl)-5-oxido-6,7-dihydrothieno[3,2-d ]pyrimidin-4-yl-)amino)-tetrahydro-2H-pyran (target compounds 32-A-P1 and 32-A-P2). The racemic compound (5R)-2-(5-(5-chloropyrimidin-2-yl)hexahydrocyclopentyl[c]pyrrol-2(1H)-yl)-5-oxido-6,7-dihydrothieno[3,2-d ]pyrimidin-4-yl-)amino)-tetrahydro-2H-pyran (Compound 32-A) (27 mg, 56 μmol) was chirally separated by normal phase HPLC (column: DAICEL CHIRALPAK AD (250mm*30mm, 10μm); solvent: A = carbon dioxide, B = ammonia (0.1%) + ethanol; gradient: 50% - 50%, 7 minutes), (5R)-2-((3aR,5(R)&(S),6aS)-5-(5-chloropyrimidin-2-yl) Hexahydrocyclopentyl[c]pyrrol-2(1H)-yl)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl-)amino)-tetrahydro-2H-pyran (target compound 32-A-P1) retention time 1.387 min (10.0 mg, yield 37%), LCMS, M/Z (ESI): 475.07 (M+1), ¹ H NMR (400 MHz, cdcl3) δ 8.60 (d, 2H), 5.19 (d, 1H), 4.24 (ddd, 1H), 4.06 – 3.96 (d, 2H), 3.91 – 3.78 (m, 2H), 3.64 – 3.38 (m, 6H), 3.04 – 2.95 (m, 3H), 2.31– 2.20 (d, 2H), 2.11 – 1.99 (dd, 4H), 1.65 – 1.56 (m, 4H). (5R)-2-((3aR,5(R)&(S),6aS)-5-(5-chloropyrimidin-2-yl)hexahydrocyclopentyl[c]pyrrol-2(1H)-yl)-5-oxido-6,7-dihydrothieno[3,2-d ]pyrimidin-4-yl-)amino)-tetrahydro-2H-pyran (target compound 32-A-P2), retention time 1.572min (10.0 mg, yield 37%), LCMS, M/Z (ESI): 475.07 (M+1), ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.59 (d, 2H), 5.74 (s, 1H), 4.23 (d, 1H), 3.99 (d, 2H), 3.85 – 3.61 (m, 5H), 3.58 – 3.37 (m, 4H), 3.17 – 3.02 (m, 2H), 2.90 (d, 2H), 2.44 (dd, 2H), 2.05 – 1.84 (m, 4H), 1.71 – 1.54 (m, 2H).

Example 16: (5R)-2-(5-(5-chloropyrimidin-2-yl)hexahydropyrrole[3,4-c]pyrrole-2(1H)-yl)-5-oxygen-6,7 Preparation of -dihydrothieno[3,2-d]pyrimidin-4-yl-)amino)-tetrahydro-2H-pyran (compound 33-A) The synthetic route of target compound 33-A is as follows: Intermediate A4 (100 mg, 445.05 μmol), intermediate A11 (128 mg, 445.05 μmol) and DIPEA (172 mg, 1.34 mmol) were added to a microwave tube containing 1,4-dioxane (2 mL) , microwave reaction at 120°C for 30 minutes. After the reaction is completed, the reaction solution is concentrated to obtain a crude product, which is separated and purified using a silica gel column (dichloromethane: methanol (V/V) = 10:1 gradient elution) to obtain compound (5R)-2-(5-(5-chloropyrimidine) -2-yl)hexahydropyrrole[3,4-c]pyrrole-2(1H)-yl)-5-oxy-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl- )Amino)-tetrahydro-2H-pyran (target compound 33-A) (80 mg, purity 95%). LCMS, M/Z (ESI): 476.1 (M+1), ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.24 (s, 2H), 5.79 (s, 1H), 4.27 – 4.17 (m, 1H), 4.04 – 3.82 (m, 6H), 3.65 – 3.49 (m, 8H), 3.18 – 3.05 (m, 4H), 2.02 (s, 2H), 1.63 (dd, 2H).

Example 17: Preparation of (R)-2-(5-(5-chloropyrimidin-2-yl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)-5-oxido-(6,7-dihydrothienyl[3,2-d]pyrimidin-4-yl)amino-cyclobutyl-methanol (target compound 34-A) The synthetic route of the target compound 34-A is as follows: Intermediate A12 (100 mg, 347.51 μmol), intermediate A1 (77.38 mg, 347.51 μmol) and DIPEA (134.74 mg, 1.04 mmol) were added to a microwave tube containing 1,4-dioxane (15 mL) and microwaved at 120 °C for 30 min. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, which was separated by reverse phase high performance liquid chromatography (column: SunFileTM Prep C18 OBDTM (5μm 30mm×150mm); solvent: A = acetonitrile, B = water; gradient: 1% - 49%, 10 minutes) to obtain (R)-2-(5-(5-chloropyrimidin-2-yl)-3,4,5,6-tetrahydropyrrolo[3,4-c ]pyrrol-2(1H)-yl)-5-oxido-6,7-dihydrothieno[3,2-d ]pyrimidin-4-yl)amino)cyclobutyl)-methanol (target compound 34-A) (10 mg, yield 6%). LCMS, M/Z (ESI): 474.21 (M+1), ¹ H NMR (400 MHz, cdcl3) δ 8.28 (d, 2H), 6.53 (s, 1H), 4.50 – 4.33 (m, 9H), 3.92 (dd, 2H), 3.75 – 3.63 (m, 1H), 3.47 (s, 1H), 3.18 (dd, 2H), 2.70 – 2.48 (m, 2H), 2.32 (d, 2H), 2.01 – 1.86 (m, 2H).

Example 18: Preparation of (5R)-2-((2S)-4-(5-chloropyrimidin-2-yl)-2-methylpiperidin-1-yl)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl-)amino)-tetrahydro-2H-pyran (Compound 35-A) The synthetic routes of target compounds 35-A, 35-A-P1 and 35-A-P2 are as follows:

Step 1: Compound (5R)-2-((2S)-4-(5-chloropyrimidin-2-yl)-2-methylpiperidin-1-yl)-5-oxy-6,7-di Synthesis of hydrothieno[3,2-d]pyrimidin-4-yl-)amino)-tetrahydro-2H-pyran (compound 35-A) Intermediate A8 (100 mg, 472.38 μmol), intermediate A11 (95.15 mg, 330.67 μmol) and DIPEA (183.16 mg, 1.42 mmol) were added to a microwave tube containing 1,4-dioxane (15 mL) , microwave reaction at 120°C for 30 minutes. After the reaction is completed, the reaction solution is concentrated to obtain the crude product, which is separated by reversed-phase high performance liquid chromatography (column: SunFileTM Prep C18 OBDTM (5μm 30mm×150mm); solvent: A = acetonitrile, B = water; gradient: 1% - 58%, 10 minutes) to obtain (5R)-2-((2S)-4-(5-chloropyrimidin-2-yl)-2-methylpiperidin-1-yl)-5-oxy-6, 7-Dihydrothio[3,2-d]pyrimidin-4-yl-)amino)-tetrahydro-2H-pyran (compound 35-A) (50 mg, yield 23%).

Step 2: Synthesis of compound (5R)-2-((2S,4S&2S,4R)-(5-chloropyrimidin-2-yl)-2-methylpiperidin-1-yl)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl-)amino)-tetrahydro-2H-pyran (target compound 35-A-P1 and 35-A-P2) (5R)-2-((2S)-4-(5-chloropyrimidin-2-yl)-2-methylpiperidin-1-yl)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl-)amino)-tetrahydro-2H-pyran (50 mg) was chirally separated by normal phase HPLC (column: DAICEL CHIRALPAK AD (250mm*30mm, 10μm); solvent: A = carbon dioxide, B = ammonia (0.1%) + ethanol; gradient: 50%-50%, 7 minutes). Compound (5R)-2-((2S,4S&2S,4R)-(5-chloropyrimidin-2-yl)-2-methylpiperidin-1-yl)- 5-Oxidation-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl-)amino)-tetrahydro-2H-pyran (target compound 35-A--P1) retention time 1.657 min (20.0 mg, yield 40%), LCMS, M/Z (ESI): 463.50 (M+1), ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.62 (s, 2H), 5.28 (dd, 2H), 4.86 (s, 1H), 4.19 (d, 1H), 4.01 – 3.97 (m, 2H), 3.63 – 3.55 (m, 1H), 3.50 (dd, 2H), 3.42 – 3.30 (m, 2H), 3.11 (t, 1H), 3.07 – 2.91 (m, 2H), 2.04 (dd, 4H), 1.64 (s, 4H), 1.31 – 1.25 (d, 3H). Compound (5R)-2-((2S,4S&2S,4R)-(5-chloropyrimidin-2-yl)-2-methylpiperidin-1-yl)-5-oxido-6,7-dihydrothieno[3,2-d ]pyrimidin-4-yl-)amino)-tetrahydro-2H-pyran (target compound 35-A-P2), retention time 1.742 min (15.0 mg, yield 30%), LCMS, M/Z (ESI): 463.50 (M+1), ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.63 (s, 2H), 5.56 (d, 7-11 (m, 2H), 3.75-3.54 (m, 1H), 4.75-4.59 (m, 2H), 4.19 (d, 1H), 3.99 (t, 2H), 3.66 – 3.58 (m, 1H), 3.48 (dd, 2H), 3.43 – 3.31 (m, 2H), 3.17 (t, 1H), 3.12 – 2.98 (m, 2H), 2.24-2.08 (dd, 4H), 1.99 (d, 2H), 1.62 (dd, 2H), 1.31 – 1.25 (d, 3H).

Example 19: Preparation of (5R)-2-((2S,4S&2S,4R)-2-((2S)-4-(5-chloropyrimidin-2-yl)-2-methylpiperidin-1-yl)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)-methanol (Compounds 27-A-P1 and 27-A-P2) The synthetic routes of compounds 27-A-P1 and 27-A-P2 are as follows: (5R)-2-((2S,4S&2S,4R)-2-((2S)-4-(5-chloropyrimidin-2-yl)-2-methylpiperidin-1-yl)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)-methanol (Compound 27-A) (100 mg) was chirally separated by normal phase HPLC (column: DAICEL CHIRALPAK AD (250mm*30mm, 10μm); solvent: A = carbon dioxide, B = ammonia (0.1%) + ethanol; gradient: 50% - 50%, 7 minutes), compound (5R)-2-((2S,4S&2S,4R)-2-((2S)-4-(5-chloropyrimidin-2-yl)-2-methylpiperidin-1-yl)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)-methanol (compound 27-A-P1), retention time 1.852 min (40.0 mg, yield 80%), LC-MS, M/Z (ESI): 463.1 (M+1). ¹ H NMR (400 MHz, D-DMSO) :δ 8.86 (s, 2H), 7.30 (s, 1H), 5.25 – 5.07 (m, 1H), 4.84 – 4.66 (m, 2H), 3.72 – 3.70 (m, 2H), 3.40 – 3.31 (m, 2H), 3.31 – 3.18 (m, 2H), 2.88 – 2.84 (m, 2H), 2.33 – 2.31 (m, 2H), 2.16 – 2.13 (m, 2H), 1.79 – 1.73 (m, 5H), 1.58 – 1.56 (m, 1H), 1.24 (d, 3H). Compound (5R)-2-((2S,4S&2S,4R)-2-((2S)-4-(5-chloropyrimidin-2-yl)-2-methylpiperidin-1-yl)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)-methanol (Compound 27-A-P2), retention time 1.477 min (35.0 mg, yield 70%), LC-MS, M/Z (ESI): 463.1 (M+1). ¹ H NMR (400 MHz, D-DMSO) :δ 8.89 (s, 2H), 7.23 (s, 1H), 4.84 – 4.81 (m, 1H), 4.68 – 4.66 (m, 1H), 4.55 – 4.52 (m, 1H), 3.72 – 3.70 (m, 2H), 3.41 – 3.36 (m, 1H), 3.31 – 3.21 (m, 2H), 3.18 – 3.16 (m, 1H), 2.85 – 2.75 (m, 2H), 2.50 – 2.33 (m, 2H), 2.18 – 2.12 (m, 5H), 2.11 – 2.10 (m, 1H), 1.77 – 1.75 (m, 2H), 0.91 (d, 3H).

Example 20: Preparation of target compounds 27-B-P1 & 27-B-P2 (R)-2-((2R, 4R or 4S)-4-(5-chloropyrimidin-2-yl)-2-methylpiperidin-1-yl)-5-oxido-(6,7-dihydrothienyl[3,2-d]pyrimidin-4-yl)amino-cyclobutyl-methanol (target compounds 27-B--P1 & 27-B-P2) The synthetic routes of target compounds 27-B--P1 & 27-B-P2 are as follows:

The first step: tertiary-butyl(R)-2-methyl-4-(((trifluoromethyl)sulfonyl)oxo)-3,6-dihydropyridine-1(2H)-carboxylic acid group Synthesis of ester (compound 27-2) Dissolve tertiary-butyl(2R)-2-methyl-4-oxyylidene-piperidine-1-carboxylate (16.0 g, 75.0 mmol) in tetrahydrofuran (300 mL), replace with nitrogen, and cool to -65°C, slowly add 1 M lithium bis(trimethylsilyl)amine tetrahydrofuran solution (1 M, 16.3 g, 97.5 mmol, 97.5 mL) dropwise and wait for 30 minutes after the dropwise addition is completed. Dissolve N,N-bis(trifluoromethanesulfonyl)aniline (29.4 g, 82.5 mmol) in tetrahydrofuran (100 mL) and slowly add it dropwise to the reaction solution. After the dropwise addition is completed, raise the temperature to 25°C and react for 4 hours. Pour the reaction solution into saturated ammonium chloride solution (1000 mL) to quench, and then extract with ethyl acetate three times, using 1500 mL of ethyl acetate each time. Finally, wash with saturated brine (1000 mL), and add anhydrous sodium sulfate. After drying, concentrate and mix the sample. Use a silica gel column for separation and purification (petroleum ether:ethyl acetate (V/V)=1/0-10/1) to obtain the yellow oily product tertiary-butyl(R)-2-methyl-4-(((( Trifluoromethyl)sulfonyl)oxo)-3,6-dihydropyridine-1(2H)-carboxylate (compound 27-2) (24.2 g, yield 93.4 %)

Step 2: Tertiary-butyl(R)-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-diboropentane-2-yl)- Synthesis of 3,6-dihydropyridine-1(2H)-carboxylate (compound 27-3) Tertiary-butyltertiary-butyl(R)-2-methyl-4-(((trifluoromethyl)sulfonyl)oxo)-3,6-dihydropyridine-1(2H)- Formate (compound 27-2) (10 g, 28.9 mmol) and bis(pinacolate)diboron (7.35 g, 28.9 mmol) were dissolved in 1,4-dioxane (100 mL), and then Add potassium acetate (7.10 g, 72.3 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.06 g, 1.45 mmol) to the reaction solution. Replace the nitrogen and slowly raise the temperature to 90°C for 3 hours. The reaction solution was filtered through celite, concentrated and mixed, and separated and purified using a silica gel column (petroleum ether: ethyl acetate (V/V) = 1/0-10/1) to obtain a yellow oily compound tertiary-butyl ( R)-2-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-diboropentan-2-yl)-3,6-dihydropyridine-1( 2H)-formate (compound 27-3) (8.00 g, yield 90%).

Step 3: Synthesis of tertiary butyl (R)-4-(5-chloropyrimidin-2-yl)-2-methyl-3,6-dihydropyridine-1(2H)-carboxylate (Compound 27-4) Tert-butyl (R)-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-diboryl-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (Compound 27-3) (10 g, 30.9 mmol) and 5-chloro-2-iodopyrimidine (7.44 g, 30.9 mmol) were dissolved in 1,4-dioxane (100 mL) and water (20 mL). Potassium carbonate (12.8 g, 92.8 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (1.13 g, 1.55 mmol) were added to the reaction solution. The nitrogen atmosphere was replaced three times, the temperature was slowly raised to 90 °C, and the reaction was carried out for 2 hours. The reaction solution was filtered through diatomaceous earth, concentrated, and then separated and purified on a silica gel column (petroleum ether:ethyl acetate (V/V) = 1/0-5/1) to obtain the product tertiary-butyl (R)-4-(5-chloropyrimidin-2-yl)-2-methyl-3,6-dihydropyridine-1(2H)-carboxylate (Compound 27-4) (8.00 g, yield 66.6%).

Step 4: Synthesis of tertiary butyl (2R)-4-(5-chloropyrimidin-2-yl)-2-methylpiperidin-1-carboxylate (Compound 27-5) Tert-butyl (R)-4-(5-chloropyrimidin-2-yl)-2-methyl-3,6-dihydropyridine-1(2H)-carboxylate (Compound 27-4) (6.00 g, 19.3 mmol) was dissolved in methanol (100 mL), tris(triphenylphosphine)rhodium(I) chloride (1.79 g, 1.94 mmol) was added, the atmosphere was replaced with hydrogen, and hydrogen was introduced at 50 °C, 50 Psi for 48 hours. The reaction solution was concentrated and stirred, and then purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) = 1/0-5/1) to obtain the product tertiary-butyl (2R)-4-(5-chloropyrimidin-2-yl)-2-methylpiperidin-1-carboxylate (Compound 27-5) (3.50 g, yield 57.0%)

Step 5: Synthesis of 5-chloro-2-((2R)-2-methylpiperidin-4-yl)pyrimidine (Compound 27-6) Tert-butyl (2R)-4-(5-chloropyrimidin-2-yl)-2-methylpiperidin-1-carboxylate (Compound 27-5) (3.00 g, 9.40 mmol) was dissolved in methanolic hydrochloride (4M, 10 mL) and methanol (10 mL) and reacted at 25 °C for 1 hour. The reaction liquid was concentrated to obtain 5-chloro-2-((2R)-2-methylpiperidin-4-yl)pyrimidine hydrochloride (Compound 27-6) (2.40 g, yield 92.6 %). LC-MS, M/Z : 212.2 (M+H) ⁺ .

Step 6: Synthesis of (R)-2-((2R,4R or 4S)-4-(5-chloropyrimidin-2-yl)-2-methylpiperidin-1-yl)-5-oxido-(6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino-cyclobutyl-methanol (Compound 27-B) 5-Chloro-2-((2R)-2-methylpiperidin-4-yl)pyrimidine hydrochloride (Compound 27-6) (2.30 g, 8.34 mmol) and (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (2.42 g, 8.34 mmol) were dissolved in 1,4-dioxane (60 mL), N,N-diisopropylethylamine (5.40 g, 41.7 mmol, 7.26 mL) was added, and then the temperature was slowly raised to 120 °C and the reaction was carried out for 10 hours. The reaction solution was poured into saturated sodium bicarbonate solution (100 ml), extracted with ethyl acetate (300 mL) three times, washed with saturated brine (200 ml), dried over sodium sulfate, concentrated, and the reaction solution was concentrated and stirred, separated and purified by silica gel column (dichloromethane: methanol (V/V) = 1/0-10/1), and then separated by normal phase HPLC (column: Welch Ultimate XB-NH2 250*50*10μm; solvent: A = n-hexane, B = ethanol; gradient: 1% -40%, 25 minutes) to obtain (R)-2-((2R,4R or 4S)-4-(5-chloropyrimidin-2-yl)-2-methylpiperidin-1-yl)-5-oxido-(6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino-cyclobutyl-methanol (Compound 27-B) (2.00 g, yield 72.0 %). LC-MS, M/Z : 463.2 (M+H).

Step 7: (R)-2-((2R,4R or 4S)-4-(5-chloropyrimidin-2-yl)-2-methylpiperidin-1-yl)-5-oxidation-(6 ,Synthesis of 7-dihydrothio[3,2-d]pyrimidin-4-yl)amino-cyclobutyl-methanol (target compound 27-B-P1&27-B-P2) Oxidation of racemate compound (R)-2-((2R,4R or 4S)-4-(5-chloropyrimidin-2-yl)-2-methylpiperidin-1-yl)-5- (6,7-Dihydrothieno[3,2-d]pyrimidin-4-yl)amino-cyclobutyl-methanol (compound 27-B) (1.60 g, 3.43 mmol) by normal phase HPLC Method for chiral separation, the separation method is (column: DAICEL CHIRALPAK AD (250mm*30mm, 10μm; solvent: A = carbon dioxide + acetonitrile, B = ammonia (0.1%) + isopropyl alcohol; gradient: 45% - 45%, 20 minutes) to obtain compound (R)-2-((2R,4R or 4S)-4-(5-chloropyrimidin-2-yl)-2-methylpiperidin-1-yl)-5-oxid- (6,7-Dihydrothieno[3,2-d]pyrimidin-4-yl)amino-cyclobutyl-methanol (target compound 27-B--P1) retention time 1.899 min (400 mg, yield 24.7%), LC-MS, M/Z (ESI): 463.2 (M+H). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.89 (s, 2H), 7.25 (s, 1H), 4.84 (br s, 1H), 4.43-4.73 (m, 2H), 3.72 (s, 2H), 3.36-3.45 (m, 1H), 3.07-3.31 (m, 3H), 2.75-2.95 (m, 2H) , 2.27-2.41 (m, 2H), 1.97-2.24 (m, 6H), 1.66-1.85 (m, 2H), 0.91 (d, 3H) (R)-2-((2R,4R or 4S)-4 -(5-chloropyrimidin-2-yl)-2-methylpiperidin-1-yl)-5-oxy-(6,7-dihydrothieno[3,2-d]pyrimidin-4-yl) Amino-cyclobutyl-methanol (target compound 27-B--P2) retention time 1.586 min (900 mg, yield 56.1%). LC-MS, M/Z (ESI): 463.2 (M+H). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.87 (s, 2H), 7.32 (s, 1H), 4.98-5.31 (m, 1H), 4.84 (m, 1H), 4.56-4.81 (m, 1H), 3.72 (br d, 2H), 3.32-3.48 (m, 2H), 3.00-3.25 (m, 2H), 2.76-2.97 (m, 2H), 2.24-2.43 (m, 2H), 2.08-2.22 (m, 2H), 1.53-2.06 (m, 6H), 1.24 (br s, 3H)

Example 21: Preparation of target compound 4-A--P1&4-A-P2&4-A-P3&4-A-P4 (5R)-2-(5-(5-chloropyrimidin-2-yl)-2-aza Bicyclo[2.2.1]heptan-2-yl)-5-oxy-(6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino-cyclobutyl-methanol ( Compound 4-A- P1&4-A-P2&4-A-P3&4-A-P4) The synthetic route of the target compound 4-A--P1&4-A-P2&4-A-P3&4-A-P4 is as follows:

The first step: tertiary butyl-5-(5-chloropyrimidin-2-yl)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate (compound 4-2 )Synthesis 5-Chloro-2-iodopyrimidine (12.5 g, 52.0 mmol) was dissolved in anhydrous toluene (400 ml), cooled to -70°C in a dry ice ethanol ice bath, and n-butyllithium in tetrahydrofuran (2.5 mol/L, 2.5 mol/L, 20.8 mL) and then react for 1 hour. Then dissolve tertiary-butyl 5-oxyylidene-2-azabicyclo[2.2.1]heptane-2-carboxylate (1) in anhydrous toluene (50 ml) and add it dropwise to the reaction solution. Raise to 25°C and react for 3 hours. After the reaction is completed, the reaction solution is slowly poured into a saturated aqueous ammonium chloride solution (300 ml) to quench and separate the layers. The aqueous phase was extracted twice with ethyl acetate, washed with 300 ml of ethyl acetate each time and saturated sodium chloride (200 mL) solution, then dried by adding excess anhydrous sodium sulfate and concentrated. Stir the sample into silica gel column for purification (petroleum ether:ethyl acetate (V/V)=1:0-3:1). Obtained tertiary-butyl 5-(5-chloropyrimidin-2-yl)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylic acid ester (compound 4-2) (5.00 g, yield 32.4 %).LC-MS, M/Z (ESI): 270.2 (M-56.06+H)

Step 2: Synthesis of tertiary butyl-5-chloro-5-(5-chloropyrimidin-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (Compound 4-3) Tert-butyl-5-(5-chloropyrimidin-2-yl)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate (Compound 4-2) (2.50 g, 7.67 mmol) and pyridine (910 mg, 11.5 mmol, 929 μL) were dissolved in dichloromethane (30 mL), cooled to 0°C, dichlorosulfoxide (1.10 g, 9.21 mmol, 668 μL) was diluted with dichloromethane (10 ml) and added dropwise to the reaction solution, and then the temperature was raised to 25°C for reaction for 2 hours. After the reaction is completed, the reaction solution is poured into a saturated sodium bicarbonate aqueous solution (40 ml), separated, and the aqueous phase is extracted twice with dichloromethane, using 40 ml of dichloromethane each time, and washed twice with saturated brine, using 40 ml of saturated brine each time. Add an excess of anhydrous sodium sulfate to dry, concentrate and stir the sample. Purify on a silica gel column (petroleum ether: ethyl acetate (V/V) = 1:0-5:1) to obtain the product tertiary butyl-5-chloro-5-(5-chloropyrimidin-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (Compound 4-3) (1.3 g, yield 55.04%).

Step 3: Synthesis of tertiary butyl-5-(5-chloropyrimidin-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (Compound 4-4) Dissolve tert-butyl-5-chloro-5-(5-chloropyrimidin-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (Compound 4-3) (1.20 g, 3.49 mmol) in anhydrous methanol (10 mL), add zinc powder (683 mg, 10.4 mmol) and ammonium chloride (559 mg, 10.4 mmol), raise the temperature to 65 °C, and react for 8 hours. After the reaction, filter out the zinc powder, and concentrate the filtrate and stir. Silica gel column purification (petroleum ether: ethyl acetate (V/V) = 1:0-5:1) gave a brown product, tert-butyl 5-(5-chloropyrimidin-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (Compound 4-4) (1.00 g, yield 92.6%).

Step 4: Synthesis of 5-(5-chloropyrimidin-2-yl)-2-azabicyclo[2.2.1]heptane (compound 4-5) Tertiary butyl-5-(5-chloropyrimidin-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (compound 4-4) (800 mg, 1.29 mmol) Dissolve in dioxane hydrogen chloride (20 mL), react at 25°C for 2 hours. The reaction liquid was concentrated to obtain 25-(5-chloropyrimidin-2-yl)-2-azabicyclo[2.2.1]heptane (compound 4-5) hydrochloride (635 mg, yield 99.8%).

Step 5: Synthesis of (5R)-2-(5-(5-chloropyrimidin-2-yl)-2-azabicyclo[2.2.1]heptane-2-yl)-5-oxido-(6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino-cyclobutyl-methanol (Compound 4-A) 25-(5-chloropyrimidin-2-yl)-2-azabicyclo[2.2.1]heptane (Compound 4-5) hydrochloride (635 mg, 2.58 mmol) and (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound A1) (830 mg, 2.89 mmol) were dissolved in 1,4-dioxane (30 mL), N,N-diisopropylethylamine (2.24 g, 17.3 mmol) was added, and then the temperature was raised to 80°C and reacted for 4 hours. The reaction solution was poured into a saturated sodium bicarbonate solution (20 mL), extracted four times with ethyl acetate (30 mL) and methanol (3.00 mL), dried over sodium sulfate, concentrated, and separated and purified by reverse phase high performance liquid chromatography (column: Waters Xbridge 150*25mm* 5μm); mobile phase: A = water + ammonia water (0.1%), B = acetonitrile; B = 18-48%, 20 minutes), and concentrated to obtain (5R)-2-(5-(5-chloropyrimidin-2-yl)-2-azabicyclo[2.2.1]heptane-2-yl)-5-oxido-(6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino-cyclobutyl-methanol (compound 4-A).

Step 6: Synthesis of (5R)-2-(5-(5-chloropyrimidin-2-yl)-2-azabicyclo[2.2.1]heptane-2-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxidation (target compounds 4-A-P1 & 4-A-P2 & 4-A-P3 & 4-A-P4) The racemic compound (5R)-2-(5-(5-chloropyrimidin-2-yl)-2-azabicyclo[2.2.1]heptane-2-yl)-5-oxido-(6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino-cyclobutyl-methanol (Compound 4-A) (1.00 g, 2.17 mmol) was chirally separated by normal phase HPLC (column: Daicel ChiralPak IG (250*30mm, 10μm); mobile phase: A = carbon dioxide-acetonitrile, B = = methanol + ammonia water (0.1%); B = 75% isocratic elution, 3.9 minutes), to obtain compound (5R)-2-(5-(5-chloropyrimidin-2-yl)-2-azabicyclo[2.2.1]heptane-2-yl)-5-oxido-(6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino-cyclobutyl-methanol (compound 4-A-P1) with retention time of 1.447 min (400 mg, yield 80.0% yield), LC-MS, M/Z (ESI): 461.2 (M+H). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 8.85 (d, 2H), 7.11-7.31 (m, 1H), 4.74-4.94 (m, 1H), 4.54-4.71 (m, 1H), 3.64-3.82 (m, 2H), 3.56 (d, 1H), 3.37 (br m, 1H), 3.10-3.30 (m, 2H), 2.76-3.06 (m, 4H), 2.28-2.42 (m, 2H), 1.92-2.27 (m, 4H), 1.59-1.88 (m, 4H) Compound (5R)-2-(5-(5-chloropyrimidin-2-yl)-2-azabicyclo[2.2.1]heptane-2-yl)-5-oxido-(6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino-cyclobutyl-methanol (Compound 4-A-P2) Retention time 1.400 min (400 mg, yield 80.0%). LC-MS, M/Z (ESI): 461.2 (M+H). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 8.86 (d, 2H), 7.17 (d, 1H), 4.73-4.95 (m, 1H), 4.57-4.71 (m, 1H), 3.71 (qd, 2H), 3.55 (d, 1H), 3.33-3.49 (m, 1H), 3.10-3.28 (m, 2H), 2.74-3.07 (m, 4H), 2.26-2.44 (m, 2H), 1.96-2.22 (m, 4H), 1.59-1.88 (m, 4H). (5R)-2-(5-(5-chloropyrimidin-2-yl)-2-azabicyclo[2.2.1]heptane-2-yl)-5-oxido-(6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino-cyclobutyl-methanol (Compound 4-A) (200 mg, 433.86 μmol) was chirally separated by normal phase HPLC (column: Daicel ChiralPak IG (250*30mm, 10um); mobile phase: A = carbon dioxide-acetonitrile, B = 4-nitropropane-1,2-dihydro-1-nitropropane-2-yl) ... = isopropanol + ammonia water (0.1%); B = 66% isocratic elution, 3.4 minutes), and freeze-dried to obtain compound (5R)-2-(5-(5-chloropyrimidin-2-yl)-2-azabicyclo[2.2.1]heptane-2-yl)-5-oxido-(6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino-cyclobutyl-methanol (compound 4-A-P3) with retention time of 1.683 min (60 mg, yield 60.0% yield), LC-MS, M/Z (ESI): 461.2 (M+H). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 8.88 (s, 2H), 7.22 (br d, 1H), 4.80-4.92 (m, 1H), 4.55-4.77 (m, 1H), 3.73 (br d, 2H), 3.43-3.50 (m, 1H), 3.32-3.42 (m, 2H), 3.15-3.26 (m, 2H), 2.80-3.00 (m, 3H), 2.32-2.45 (m, 2H), 2.02-2.24 (m, 4H), 1.57-1.83 (m, 4H). Compound (5R)-2-(5-(5-chloropyrimidin-2-yl)-2-azabicyclo[2.2.1]heptane-2-yl)-5-oxido-(6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino-cyclobutyl-methanol (Compound 4-A-P4) Retention time 1.603 min (60 mg, yield 60.0%). LC-MS, M/Z (ESI): 461.2 (M+H). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 8.88 (d, 2H), 7.23 (br d, 1H), 4.86 (br d, 1H), 4.60-4.73 (m, 1H), 3.73 (br s, 2H), 3.35-3.50 (m, 3H), 3.16-3.26 (m, 2H), 2.81-2.96 (m, 3H), 2.28-2.44 (m, 2H), 2.02-2.24 (m, 4H), 1.56-1.86 (m, 4H)

Example 22: Preparation of target compound 36-A: (5R)-2-(3-(5-chloropyrimidin-2-yl)pyrrolidin-1-yl)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-5-yl)amino)cyclobutyl)-methanol (target compound 36-A) Synthesis route of target compound 36-A:

Step 1: Synthesis of 3-(5-chloropyrimidin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid tributyl ester (Compound 36-3) The raw materials 1-tert-butyloxycarbonyl-2,5-dihydro-1H-pyrrole-3-boronic acid pinacol ester (1.0 g, 3.39 mmol), 5-chloro-2-iodopyrimidine (814.5 mg, 3.39 mmol), potassium carbonate (1.4 g, 10.16 mmol), Pd(dppf)Cl2 (246 mg, 0.339 mmol) were dissolved in 1,4-dioxane (10 mL) and water (1 mL), replaced with nitrogen and heated to 100 degrees to stir overnight. After the reaction was completed, water (30 mL) was added to dilute, and extracted with ethyl acetate three times, using 30 mL of ethyl acetate each time, and the liquids were separated and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by chromatography column (petroleum ether: ethyl acetate (V/V) = 10:1-5:1) to obtain the title compound 36-3 (0.75 g, yield 78.6 %). LC-MS, M/Z (ESI): 181.9 (M-100).

Step 2: Synthesis of 3-(5-chloropyrimidin-2-yl)pyrrolidine-1-carboxylic acid tributyl ester (Compound 36-4) Compound 36-3 (400 mg, 1.42 mmol) and Rh(PPh ₃ ) ₃ Cl (113.76 mg, 0.283 mmol) were dissolved in methanol (5 mL), the hydrogen was replaced and the temperature was raised to 50 ℃ for stirring and reaction for 12 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, which was separated and purified by chromatography column (dichloromethane: methanol (V/V) = 10:1) to obtain the title compound 36-4 (300 mg, yield 74.5%). LC-MS, M/Z (ESI): 283.7 (M+1).

Step 3: 5-Chloro-2-(pyrrolidin-3-yl)pyrimidine (Compound 36-5) Compound 36-4 (300 mg, 1.06 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added, and the reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the crude product was concentrated and vortexed to obtain a crude product, which was purified by chromatography column separation (dichloromethane: methanol (V/V) = 10:1) to obtain the title compound 36-5 (190 mg. Yield 98%). LC-MS, M/Z (ESI): 183.9 (M+1).

Step 4: Synthesis of (5R)-2-(3-(5-chloropyrimidin-2-yl)pyrrolidin-1-yl)-5-oxido-(6,7-dihydrothieno[3,2-d]pyrimidin-5-yl)amino)cyclobutyl)-methanol (target compound 36-A) Compound 36-5 (200 mg, 1.09 mmol), (5R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (313.4 mg, 1.09 mmol), and N,N-diisopropylethylamine (422.3 mg, 3.27 mmol) were dissolved in 1,4-dioxane (3 mL) and placed in a microwave tube for reaction at 120 °C for 0.5 h. After the reaction, the reaction solution was diluted with dichloromethane and purified by chromatography column (dichloromethane: methanol (V/V) = 10:1), concentrated and passed through the column, and then purified by reverse phase high performance liquid chromatography (column: SunFileTM Prep C18 OBDTM 5μm 30mm×150mm); solvent: A = 0.1% FA, B = acetonitrile; gradient: 1% - 33.8%, 7.2 minutes) to obtain the title compound (5R)-2-(3-(5-chloropyrimidin-2-yl)pyrrolidin-1-yl)-5-oxido-(6,7-dihydrothieno[3,2-d]pyrimidin-5-yl)amino)cyclobutyl)-methanol (Compound 36-A) (200 mg, yield 42.2%). LC-MS, M/Z (ESI): 435.0 (M+1). ¹ H NMR (400 MHz, CDCl3) δ 8.63 (t, 2H), 6.06 (t, 1H), 4.16 – 4.07 (m, 1H), 3.93 (ddd, 3H), 3.79 (dd, 2H), 3.70 – 3.59 (m, 2H), 3.41 (dd, 2H), 3.12 – 3.05 (m, 2H), 2.46 – 2.25 (m, 6H), 1.91 (dd, 2H).

Example 23: Preparation of target compounds 37-A-P1 & 37-A-P2: (R)-2-((2S,4S or 4R)-4-(5-chloropyrimidin-2-yl)-2-methylpiperidin-1-yl)-5-oxido-(6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutane-1-carbonitrile (target compounds 37-A-P1 & 37-A-P2) The synthetic route of the target compound 37-A--P1 is as follows: The intermediate 4-P1 (50 mg, 0.236 mmol), the intermediate A1 (53.4 mg, 0.189 mmol) and DIPEA (92 mg, 0.708 mmol) were added to a microwave tube containing 1,4-dioxane (2 mL) and subjected to microwave reaction at 120 °C for 30 min. The concentrated crude product was separated by reversed-phase high performance liquid chromatography (chromatographic column: Phenomenex Luna C18 150×25mm×10μm; mobile phase: A=water+0.01 volume % trifluoroacetic acid (99%), B=acetonitrile; gradient 35%-65% B, 8 minutes) to obtain (R)-2-((2S,4S or 4R)-4-(5-chloropyrimidin-2-yl)-2-methylpiperidin-1-yl)-5-oxido-(6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutane-1-carbonitrile (retention time: 1.387 min) (Compound 37-A-P1, 31.1 mg, yield 28.7%). LC-MS, M/Z (ESI): 458.3 (M+1). ¹ H NMR (400 MHz, cdcl3) δ 8.62 (s, 2H), 6.73 (d, 1H), 5.34 (s, 1H), 4.91 (d, 1H), 3.68 – 3.55 (m, 1H), 3.39 (d, 2H), 3.22 – 2.98 (m, 3H), 2.78 (s, 2H), 2.46 (d, 2H), 2.10 (ddd, 6H), 1.33 (t, 3H). The synthetic route of the target compound 37-A--P2 is as follows: The intermediate 4-P2 (50 mg, 0.236 mmol), the intermediate A1 (53.4 mg, 0.189 mmol) and DIPEA (92 mg, 0.708 mmol) were added to a microwave tube containing 1,4-dioxane (2 mL) and subjected to microwave reaction at 120 °C for 30 min. The concentrated crude product was separated by reversed-phase high performance liquid chromatography (chromatographic column: Phenomenex Luna C18 150×25mm×10μm; mobile phase: A=water+0.01 volume % trifluoroacetic acid (99%), B=acetonitrile; gradient 35%-65% B, 8 minutes) to obtain (R)-2-((2S,4S or 4R)-4-(5-chloropyrimidin-2-yl)-2-methylpiperidin-1-yl)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutane-1-carbonitrile (retention time: 1.465 min) (compound 37-A-P2, 54 mg, yield 49.9%). LC-MS, M/Z (ESI): 458.3 (M+1). ¹ H NMR (400 MHz, cdcl3) δ 8.62 (d, 2H), 7.08 (s, 1H), 4.74 (ddd, 2H), 3.67 – 3.56 (m, 1H), 3.43 – 3.27 (m, 2H), 3.21 – 3.01 (m, 3H), 2.75 (ddd, 2H), 2.53 – 2.35 (m, 2H), 2.24 – 2.08 (m, 4H), 1.96 (ddd, 2H), 1.07 (t, 3H).

Example 24: Preparation of target compound 38-A: (R)-2-(6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]heptan-2-yl)-5- Oxidation-(6,7-dihydrothio[3,2-d]pyrimidin-4-yl)amine)-3,3-difluorocyclobutyl)-methanol (target compound 38-A) Synthetic route of target compound 38-A: The raw material (R)-2-chloro-4-((3,3-difluoro-1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d ]pyrimidine 5-oxide (50 mg, 0.154 mmol) ((R)-2-chloro-4-((3,3-difluoro-1-(hydroxymethyl)cyclobutyl)amino)-6, 7-Dihydrothieno[3,2-d]pyrimidine 5-oxide is prepared according to the synthesis of 41-A), 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]heptane (38.8 mg, 0.185 mmol) and N,N-diisopropylethylamine (59.8 mg, 0.463 mmol) were dissolved in dioxane (2.0 mL), and the reaction was heated to 100 °C for 2 hours. After the reaction is completed, the reaction solution is diluted with dichloromethane, mixed with silica gel, separated and purified by a chromatography column (dichloromethane: methanol = 50:1-10:1), concentrated through the column, and then purified by reversed-phase high-performance liquid chromatography. , (column: SunFileTM Prep C18 OBDTM (5μm 30mm×150mm); solvent: A=0.1% FA, B=acetonitrile; gradient: 1%-39%, 6.8 minutes) to obtain the title compound 38-A (24.7 mg, collected rate 32.2%). LC-MS, M/Z (ESI): 497.12 (M+1). ¹ H NMR (600 MHz, cdcl3) δ 8.62 (s, 2H), 7.03 (s, 1H), 4.19 (dd, 4H), 3.83 – 3.57 (m, 4H), 3.35 (dt, 1H), 3.16 – 2.98 (m, 4H), 2.80 – 2.56 (m, 6H).

Example 25: Preparation of target compound 39-A 2-(7-(5-chloropyrimidin-2-yl)-2-azaspiro[3.5]non-2-yl)--5-oxidation-(6, 7-Dihydrothieno[3,2-d]pyrimidin-4-yl)amino-cyclobutyl-methanol (target compound 39-A) Synthetic route of target compound 39-A:

Step 1: Synthesis of 7-(((trifluoromethyl)sulfonyl)oxy)-2-azaspiro[3.5]non-6-ene-2-carboxylic acid tributyl ester (Compound 39-2) The raw material 7-oxo-2-azaspiro[3.5]nonane-2-carboxylic acid tributyl ester (800 mg, 3.34 mmol) was dissolved in tetrahydrofuran (10 mL), and LiHMDs (2.51 mL, 2 M) was slowly added dropwise at -78 °C, and the reaction was stirred at -78 °C for 1 hour. Then, a tetrahydrofuran solution of N-phenylbis(trifluoromethanesulfonyl)imide (2.39 g, 6.69 mmol in THF 10 mL) was added at -78 °C, and the temperature was slowly raised to room temperature for 10 hours. After the reaction was completed, water (10 mL) was added to dilute, and extracted with ethyl acetate three times, using 20 mL of ethyl acetate each time, and the layers were separated and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by chromatography column (petroleum ether:ethyl acetate (V/V) = 50:1-5:1) to obtain the title compound 39-2 as a yellow oil (1.2 g, yield 96%).

Step 2: Synthesis of 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-2-azaspiro[3.5]non-6-ene-2-carboxylic acid tributyl ester (Compound 39-3) The raw material 7-(((trifluoromethyl)sulfonyl)oxy)-2-azaspiro[3.5]non-6-ene-2-carboxylic acid tributyl ester (1.2 g, 3.23 mmol), diboric acid pinacol ester (984.6 mg, 3.88 mmol), potassium acetate (951.37 mg, 9.69 mmol) and Pd(dppf)Cl ₂ (234 mg, 0.323 mmol) were dissolved in 1,4-dioxane (15 mL), replaced with nitrogen and heated to 80 °C for 2 hours. After the reaction was completed, water (10 mL) was added to dilute, and extracted with ethyl acetate three times, using 20 mL of ethyl acetate each time, and the layers were separated and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by chromatography column (petroleum ether: ethyl acetate (V/V) = 50:1-5:1) to obtain the title compound 39-3 as a light yellow solid (1.0 g, yield 88.6%). LC-MS, M/Z (ESI): 294.0 (M-55).

Step 3: Synthesis of 7-(5-chloropyrimidin-2-yl)-2-azaspiro[3.5]non-6-ene-2-carboxylic acid tertiary butyl ester (compound 39-5) 5-Chloro-2-iodopyrimidine (450 mg, 1.87 mmol), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-2 -Azaspiro[3.5]non-6-ene-2-carboxylic acid tertiary butyl ester (719.1 mg, 2.06 mmol), potassium carbonate (776 mg, 5.61 mmol) and Pd(dppf)Cl2 (136 mg, 0.187 mmol) ) was dissolved in 1,4-dioxane (10 mL) and water (1 mL), replaced with nitrogen and heated to 80°C for 10 hours. After the reaction is completed, add water (10 mL) to dilute, and extract with ethyl acetate three times, using 20 mL of ethyl acetate each time, separate the liquids, and combine the organic phases. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified using a chromatography column (petroleum ether: ethyl acetate (V/V) = 50:1-5:1) to obtain the title compound 39-5 (200 mg, yield 31.8%). LC-MS, M/Z (ESI): 280.0 (M-55).

Step 4: Synthesis of 7-(5-chloropyrimidin-2-yl)-2-azaspiro[3.5]nonane-2-carboxylic acid tributyl ester (Compound 39-6) The raw material 7-(5-chloropyrimidin-2-yl)-2-azaspiro[3.5]non-6-ene-2-carboxylic acid tributyl ester (100 mg, 0.297 mmol) and Rh(PPh ₃ ) ₃ Cl (23.8 mg, 0.059 mmol) were dissolved in methanol (2 mL), the hydrogen atmosphere was replaced and the temperature was raised to 50 ℃ for stirring and reaction for 12 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, which was purified by chromatography column separation (dichloromethane: methanol (V/V) = 10:1) to obtain the title compound 39-6 (80 mg, yield 79.5%). LC-MS, M/Z (ESI): 282.1 (M-55).

Step 5: Synthesis of 7-(5-chloropyrimidin-2-yl)-2-azaspiro[3.5]nonane (Compound 39-7) The raw material 7-(5-chloropyrimidin-2-yl)-2-azaspiro[3.5]nonane-2-carboxylic acid tributyl ester (0.1 g, 0.296 mmol) was dissolved in dichloromethane (2 mL), and then trifluoroacetic acid (0.5 mL) was added and stirred for 2 h. After the reaction was completed, it was directly concentrated and dried, and purified by chromatography column separation (dichloromethane: methanol (V/V) = 10:1) to obtain the title compound 39-7 (50 mg, yield 71.0%). LC-MS, M/Z (ESI): 237.9 (M+1).

Step 6: 2-(7-(5-chloropyrimidin-2-yl)-2-azaspiro[3.5]non-2-yl)--5-oxy-(6,7-dihydrothieno[ Synthesis of 3,2-d]pyrimidin-4-yl)amino-cyclobutyl-methanol (compound 39-A) The raw material 7-(5-chloropyrimidin-2-yl)-2-azaspiro[3.5]nonane (30 mg, 0.126 mmol), 1-((2-chloro-6,7-dihydrothieno[ 3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methanol (29 mg, 0.1 mmol) and N,N-diisopropylethylamine (49 mg, 0.378 mmol) were dissolved in dioxane Ring (2.0 mL) and placed in a microwave tube, microwave at 120°C for 0.5 h. After the reaction is completed, the reaction solution is diluted with methylene chloride, mixed with silica gel, and separated and purified by a chromatography column (methylene chloride: methanol = 50:1-10:1). Concentrate and pass through the column liquid, and then purify through reversed-phase high-performance liquid chromatography. (Column: SunFileTM Prep C18 OBDTM (5μm 30mm×150mm); Solvent: A=0.1% FA, B=acetonitrile; Gradient: 1%-45.0%, 9 minutes) Obtain 2-(7-(5-chloropyrimidine- 2-yl)-2-azaspiro[3.5]non-2-yl)--5-oxy-(6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino- Cyclobutyl-methanol (Compound 39-A) (6 mg, yield 9.7%). LC-MS, M/Z (ESI): 489.9 (M+1). ¹ H NMR (400 MHz, cdcl3) δ 8.61 (s, 2H), 5.88 (d, 1H), 5.32 (d, 1H), 3.83 (dd, 6H), 3.63 – 3.37 (m, 2H), 3.04 (dt, 2H), 2.85 (s, 1H), 2.32 (s, 2H), 2.18 (dd, 2H), 2.08 – 1.85 (m, 6H), 1.66 (d, 4H).

Example 26: Preparation of target compounds 40-A-P1&40-A-P2 (R)-2-((2S,4S or 4R)-4-(5-(difluoromethyl)pyrimidin-2-yl)- 2-methylpiperidin-1-yl)--5-oxy-(6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino-cyclobutyl-methanol (target compound 40-A-P1&40-A-P2) The synthetic route of the target compounds 40-A-P1&40-A-P2 is as follows:

Step 1: Synthesis of tertiary butyl-(S)-2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate (Compound 40-2) Dissolve tert-butyl-(2S)-2-methyl-4-oxygen-piperidin-1-carboxylate (20.0 g, 93.7 mmol) in tetrahydrofuran (300 mL), replace nitrogen, cool to -65°C, slowly add 1M bis(trimethylsilyl)amide lithium tetrahydrofuran solution (1 M, 20.4 g, 121 mmol, 121 mL) dropwise, and react for 30 minutes. Slowly add trifluoromethanesulfonic anhydride (31.7 g, 112 mmol, 18.5 mL) dropwise to the reaction solution, and raise the temperature to 25°C and react for 3 hours. The reaction solution was poured into a saturated ammonium chloride solution (1000 mL) for quenching, and then extracted with ethyl acetate for 3 times, 1500 mL of ethyl acetate each time, and finally washed with saturated brine (1000 mL), added with anhydrous sodium sulfate, dried, and concentrated. Separation and purification using a silica gel column (petroleum ether: ethyl acetate (V/V) = 1/0-10/1) gave a yellow oily product (S)-2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate (Compound 40-2) (10.0 g, yield 30.9 %)

Step 2: Tertiary butyl-(S)-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dichloropentanyl-2-yl)- Synthesis of 3,6-dihydropyridine-1(2H)-carboxylate (compound 40-3) Tertiary butyl-(S)-2-methyl-4-(((trifluoromethyl)sulfonyl)oxo)-3,6-dihydropyridine-1(2H)-carboxylate (compound 40 -2) (2.00 g, 5.79 mmol) and di(pinacolate) diboron (1.76 g, 6.95 mmol) were dissolved in 1,4-dioxane (30 mL), and then potassium acetate (1.14 g , 11.5 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (423 mg, 579 μmol) were added to the reaction solution. After the addition was completed, the nitrogen was replaced and slowly raised to React at 90°C for 10 hours. The reaction solution was filtered through celite, concentrated and mixed, and separated and purified using a silica gel column (petroleum ether: ethyl acetate (V/V) = 1/0-10/1) to obtain a yellow oily compound tertiary-butyl ( S)-2-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-diboropentacyclyl-2-yl)-3,6-dihydropyridine-1( 2H)-formate (compound 40-3) (1.50 g, yield 80.1%).

Step 3: Tertiary butyl-(S)-4-(5-(difluoromethyl)pyrimidin-2-yl)-2-methyl-3,6-dihydropyridine-1(2H)-carboxylic acid Synthesis of base ester (compound 40-4) The tertiary butyl-(S)-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dichloropentan-2-yl)-3,6 -Dihydropyridine-1(2H)-carboxylate (compound 40-3) (1.4 g, 4.33 mmol) and 2-chloro-5-(difluoromethyl)pyrimidine (712 mg, 4.33 mmol) were dissolved in 1 , 4-dioxane (20 mL) and water (4 mL), then potassium carbonate (1.20 g, 8.66 mmol,) and [1,1'-bis(diphenylphosphino)ferrocene] Palladium(II) dichloride (316 mg, 433 μmol) was added to the reaction solution, nitrogen was replaced three times, the temperature was slowly raised to 90°C, and the reaction was carried out for 10 hours. The reaction solution was filtered through diatomaceous earth, concentrated and then separated and purified on a silica gel column (petroleum ether: ethyl acetate (V/V) = 1/0-5/1) to obtain the yellow solid product tertiary-butyl (S)-4- (5-(difluoromethyl)pyrimidin-2-yl)-2-methyl-3,6-dihydropyridine-1(2H)-carboxylate (compound 40-4) (620 mg, yield 44.0 %).

Step 4: Synthesis of tertiary butyl (2S)-4-(5-(difluoromethyl)pyrimidin-2-yl)-2-methylpiperidin-1-carboxylate (Compound 40-5) Tert-butyl-(S)-4-(5-(difluoromethyl)pyrimidin-2-yl)-2-methyl-3,6-dihydropyridine-1(2H)-carboxylate (Compound 40-4) (300 mg, 922 μmol) was dissolved in methanol (5 mL), tris(triphenylphosphine)rhodium(I) chloride (85.3 mg, 92.2 μmol) was added, the atmosphere was replaced with hydrogen, and hydrogen was introduced at 50 °C, 50 Psi for 16 hours. The reaction solution was concentrated and stirred, and then purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) = 1/0-5/1) to obtain the product tertiary butyl-(2S)-4-(5-(difluoromethyl)pyrimidin-2-yl)-2-methylpiperidin-1-carboxylate (Compound 40-5) (280 mg, yield 93.3%)

Step 5: Synthesis of 5-(difluoromethyl)-2-((2S)-2-methylpiperidin-4-yl)pyrimidine (Compound 40-6) Tert-butyl-(2S)-4-(5-(difluoromethyl)pyrimidin-2-yl)-2-methylpiperidine-1-carboxylate (Compound 40-5) (400 mg, 879 μmol) was dissolved in hydrogen chloride-dioxane (4M, 5 mL) and dioxane (5 mL) and reacted at 25 °C for 1 hour. The reaction liquid was concentrated to obtain 5-(difluoromethyl)-2-((2S)-2-methylpiperidin-4-yl)pyrimidine hydrochloride (Compound 40-6) (232 mg, yield 98.6 %).

Step 6: Synthesis of (R)-2-((2S,4S or 4R)-4-(5-(difluoromethyl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)-5-oxido-(6,7-dihydrothienyl[3,2-d]pyrimidin-4-yl)amino-cyclobutyl-methanol (40-A) 5-(Difluoromethyl)-2-((2S)-2-methylpiperidin-4-yl)pyrimidine hydrochloride (Compound 40-6) (230 mg, 872 μmol) and (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (25.8 mg, 784 μmol) were dissolved in 1,4-dioxane (10 mL), N,N-diisopropylethylamine (563 mg, 4.36 mmol, 759 μL) was added, and then the temperature was slowly raised to 110 °C and the reaction was carried out for 10 hours. The reaction solution was poured into saturated sodium bicarbonate solution (20 ml), extracted with ethyl acetate (30 mL) three times, using 30 mL ethyl acetate each time, washed with saturated brine (30 ml), dried over sodium sulfate, concentrated, and the reaction solution was concentrated and stirred, separated and purified by silica gel column (dichloromethane: methanol (V/V) = 1/0-10/1), and then separated by reversed-phase high performance liquid chromatography (column: Waters Xbridge 150*25mm* 5μm; solvent: A = water + ammonia water (0.1%), B = acetonitrile; gradient: 30% -50%, 10 minutes) to obtain (R)-2-((2S,4S or 4R) -4-(5-(difluoromethyl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)--5-oxido-(6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino-cyclobutyl-methanol (Compound 40-A) (150 mg, yield 33.8 %). LC-MS, M/Z : 479.2 (M+H).

Step 7: Synthesis of (R)-2-((2S,4S or 4R)-4-(5-(difluoromethyl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)-5-oxido-(6,7-dihydrothienyl[3,2-d]pyrimidin-4-yl)amino-cyclobutyl-methanol (target compounds 40-A-P1 & 40-A-P2) The racemic compound (R)-2-((2S,4S or 4R)-4-(5-(difluoromethyl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)-5-oxido-(6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino-cyclobutyl-methanol (Compound 40-A) (80.0 mg, 167 μmol) was chirally separated by normal phase HPLC (column: DAICEL CHIRALPAK IG (250mm*30mm,10μm); solvent: A = carbon dioxide, B = ammonia (0.1%) + ethanol; gradient: 50% - 50%, 20 minutes) to obtain compound (R)-2-((2S,4S or 4R) -4-(5-(difluoromethyl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)--5-oxido-(6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino-cyclobutyl-methanol (target compound 40-A-P1) retention time 1.507 min (20.0 mg, yield 25.0%), LC-MS, M/Z (ESI): 479.2 (M+H). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 9.01 (s, 2H), 7.04-7.39 (m, 1H), 4.84 (br m, 1H), 4.63-4.77 (m, 1H), 4.55 (br m, 1H), 3.72 (br d, 2H), 3.36-3.45 (m, 2H), 3.13-3.30 (m, 3H), 2.77-3.01 (m, 2H), 2.28-2.42 (m, 2H), 2.08-2.27 (m, 5H), 1.97-2.07 (m, 1H), 1.69-1.84 (m, 2H), 0.86-0.96 (m, 3H). (R)-2-((2S,4S or 4R)-4-(5-(difluoromethyl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)-5-oxido-(6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino-cyclobutyl-methanol (target compound 40-A-P2) Retention time 1.964 min (40.0 mg, 50.0% yield). LC-MS, M/Z (ESI) : 479.2 (M+H). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.98 (s, 2H), 7.00-7.37 (m, 1H), 5.04-5.40 (m, 1H), 4.80-4.86 (m, 1H), 4.43-4.76 (m, 1H), 3.72 (br d, 2H), 3.41 (br m, 3H), 3.07-3.26 (m, 2H), 2.82-2.99 (m, 2H), 2.27-2.43 (m, 2H), 2.11-2.23 (m, 2H), 1.84-2.10 (m, 3H), 1.73-1.82 (m, 2H), 1.58-1.71 (m, 1H), 1.23-1.29 (m, 3H)

Example 27: Preparation of target compound 41-A-P1&41-A-P2 (R)-2-((2S,4(R&S))-4-(5-chloropyrimidin-2-yl)-2-methyl Piperidin-1-yl)-5-oxy-6,7-dihydrothio[3,2-d]pyrimidin-4-yl)amino)-3,3-difluorocyclobutyl)-methanol ( Compound 41-A-P1&41-A-P2) The synthetic route of target compounds 41-A--P1&41-A-P2 is as follows:

Step 1: Synthesis of tertiary butyl-(S)-2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate (Compound 41-2) Dissolve tert-butyl-(S)-2-methyl-4-oxygenated piperidine-1-carboxylate (20.0 g, 93.7 mmol) in tetrahydrofuran (400 mL), replace nitrogen, cool to -70°C, slowly add bis(trimethylsilyl)amide lithium tetrahydrofuran solution (1 M, 112 mL) dropwise to the reaction solution, and react for 30 minutes after the addition is completed. Dissolve N,N-bis(trifluoromethanesulfonyl)aniline (31.8 g, 89.0 mmol) in tetrahydrofuran (80 mL), slowly dropwise add to the reaction solution, and heat to 25°C 30 minutes after the addition is completed and react for 3 hours. The reaction solution was poured into a saturated ammonium chloride solution (400 mL) for quenching, and then extracted with ethyl acetate 3 times, using 1.2 L of ethyl acetate each time, washed with a saturated sodium chloride solution 2 times, using 800 mL of sodium chloride solution each time, and then concentrated after adding excess anhydrous sodium sulfate for drying. The product was separated and purified using a silica gel column (petroleum ether: ethyl acetate (V/V) = 1/0-20/1) to obtain a yellow oily product, tert-butyl (S)-2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate (Compound 41-2) (23.0 g, yield 71.0 %).

Step 2: Tertiary butyl-(S)-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-diboropentane-2-yl)- Synthesis of 3,6-dihydropyridine-1(2H)-carboxylate (compound 41-3) Tertiary butyl-(S)-2-methyl-4-(((trifluoromethyl)sulfonyl)oxo)-3,6-dihydropyridine-1(2H)-carboxylate (compound 41 -2) (10.0 g, 28.9 mmol) and di(pinacollate) diboron (7.35 g, 28.9 mmol) were dissolved in 1,4-dioxane (120 mL), and then potassium acetate (8.53 g , 86.8 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.06 g, 1.45 mmol) were added to the reaction solution. After the addition was completed, nitrogen was replaced and slowly raised to React at 90°C for 6 hours. The reaction solution was filtered through celite, concentrated and the sample was separated and purified using a silica gel column (petroleum ether: ethyl acetate (V/V) = 1/0-20/1) to obtain the colorless oily product tertiary butyl-( S)-2-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dichloropentan-2-yl)-3,6-dihydropyridine-1( 2H)-formate (compound 41-3) (8.00 g, crude product).

Step 3: Synthesis of tertiary butyl-(S)-4-(5-chloropyrimidin-2-yl)-2-methyl-3,6-dihydropyridine-1(2H)-carboxylate (Compound 41-4) Tert-butyl-(S)-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-diboryl-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (Compound 41-3) (5.00 g, 10.0 mmol) and 5-chloro-2-iodopyrimidine (2.42 g, 10.0 mmol) were dissolved in 1,4-dioxane (50 mL) and water (5 mL), and potassium carbonate (4.17 g, 30.1 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (367 mg, 502 μmol) were added to the reaction solution. The temperature was raised to 90 °C and the reaction was carried out for 6 hours. The reaction solution was concentrated and diluted with 50 mL of water, extracted with ethyl acetate three times, using 150 mL of ethyl acetate each time, dried over sodium sulfate, concentrated, and separated and purified on a silica gel column (petroleum ether:ethyl acetate (V/V) = 1/0-5/1) to obtain the product tertiary-butyl (S)-4-(5-chloropyrimidin-2-yl)-2-methyl-3,6-dihydropyridine-1(2H)-carboxylate (compound 41-4) (2.00 g, yield 80.0%).

Step 4: Synthesis of tertiary butyl-(2S)-4-(5-chloropyrimidin-2-yl)-2-methylpiperidine-1-carboxylate (compound 41-5) Tertiary butyl-(S)-4-(5-chloropyrimidin-2-yl)-2-methyl-3,6-dihydropyridine-1(2H)-carboxylate (compound 41-4) (2.00 g, 6.41 mmol) was dissolved in formaldehyde (50 mL), added tris(triphenylphosphine)rhodium(I) chloride (593 mg, 641 μmol), replaced with argon, and introduced hydrogen at 50 ℃, 50 React under Psi conditions for 48 hours. The reaction solution was filtered through diatomaceous earth, concentrated and mixed, and then separated and purified on a silica gel column (petroleum ether: ethyl acetate (V/V) = 1/0-5/1) to obtain the brown oily product tertiary-butyl (2S) -4-(5-chloropyrimidin-2-yl)-2-methylpiperidine-1-carboxylate (compound 41-5) (1.8 g, 5.77 mmol, yield 90.4 %)

Step 5: Synthesis of 5-chloro-2-((2S)-2-methylpiperidin-4-yl)pyrimidine hydrochloride (compound 41-6) Tertiary butyl-(2S)-4-(5-chloropyrimidin-2-yl)-2-methylpiperidine-1-carboxylate (compound 41-5) (1.00 g, 2.89 mmol) was dissolved in anhydrous In dichloromethane (10 mL), dioxane hydrochloric acid gas (4M, 3ml) was slowly added dropwise to the reaction solution at 25°C for 1 hour. The reaction liquid was concentrated to obtain 5-chloro-2-((2S)-2-methylpiperidin-4-yl)pyrimidine hydrochloride (compound 41-6) (700 mg, yield 92.3%).

Step 6: Synthesis of (5R)-2-((2S)-4-(5-chloropyrimidin-2-yl)-2-methylpiperidin-1-yl)-4-((3,3-difluoro-1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 41-A) 5-Chloro-2-((2S)-2-methylpiperidin-4-yl)pyrimidine hydrochloride (Compound 41-6) (168 mg, 644 μmol) and (R)-2-chloro-4-((3,3-difluoro-1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 41A) (200 mg, 586 μmol) were dissolved in 1,4-dioxane (30 mL), N,N-diisopropylethylamine (454 mg, 3.52 mmol) was added, and then the temperature was slowly raised to 120°C and the reaction was carried out for 48 hours. The reaction solution was poured into a saturated sodium bicarbonate solution (30 mL), extracted four times with ethyl acetate (20 mL) and methanol (2.00 mL), dried with excess anhydrous sodium sulfate, and concentrated. Purification by silica gel separation (dichloromethane: methanol (V/V) = 10/1) gave compound (R)-2-((2S,4(R&S))-4-(5-chloropyrimidin-2-yl)-2-methylpiperidin-1-yl)-4-((3,3-difluoro-1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 41-A) (130 mg, yield 41.6%). LC-MS, M/Z (ESI): 499.2 (M+H).

Step 7: (R)-2-((2S,4(R&S))-4-(5-chloropyrimidin-2-yl)-2-methylpiperidin-1-yl)-5-oxygen-6 ,Synthesis of 7-dihydrothio[3,2-d]pyrimidin-4-yl)amino)-3,3-difluorocyclobutyl)-methanol (compound 41-A-P1&41-A-P2) Racemate (R)-2-((2S,4(R&S))-4-(5-chloropyrimidin-2-yl)-2-methylpiperidin-1-yl)-5-oxidized- 6,7-Dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-3,3-difluorocyclobutyl)-methanol (Compound 41-A) (120 mg, 240.4 μmol) Chiral separation was carried out by normal phase high performance liquid chromatography. The separation method was (column: DAICEL CHIRALCEL OJ (250mm*30mm, 10μm); mobile phase: A = carbon dioxide-methanol ammonia water (0.1%), B = ammonia water (0.1% ); B=25% isocratic elution, 5.6 minutes) and concentrated to obtain (R)-2-((2S,4(R&S))-4-(5-chloropyrimidin-2-yl)-2-methyl Piperidin-1-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-3,3-difluorocyclobutyl)-methanol ( Compound 41-A-P1) retention time 1.291 min (30.0 mg, recovery 25.0%). LC-MS, M/Z (ESI): 449.2 (M+H). 1H NMR (400 MHz, DMSO-d6) δ: 8.90 (s, 2H), 7.84 (s, 1H), 5.06-5.36 (m, 1H), 4.58-4.71 (m, 1H), 4.44-4.56 (m, 1H), 3.64-3.75 (m, 2H), 3.37-3.45 (m, 1H), 3.08-3.21 (m, 2H), 2.84-2.98 (m, 6H), 2.00-2.18 (m, 3H), 1.60 ( br s, 1H), 1.23 (br s, 1H), 0.92 (br d, 3H) (R)-2-((2S,4(R&S))-4-(5-chloropyrimidin-2-yl)- 2-methylpiperidin-1-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-3,3-difluorocyclobutyl )-methanol (compound 41-A -P2) retention time 1.625 min (50.0 mg, yield 41.7%). LC-MS, M/Z (ESI): 449.3 (M+H). 1H NMR (400 MHz, DMSO-d6) δ: 8.87 (s, 2H), 7.89 (s, 1H), 4.89-5.42 (m, 2H), 4.78 (br m, 1H), 3.61-3.78 (m, 2H ), 3.39-3.47 (m, 1H), 3.04-3.22 (m, 2H), 2.82-3.01 (m, 6H), 1.99-2.08 (m, 1H), 1.75-1.98 (m, 2H), 1.57 (br s, 2H), 1.25 (br d, 3H).

The following target compounds were prepared similarly by referring to the synthetic method of compound 1-A. structure LC-MS LC-MS, M/Z (ESI): 461.1 (M+1) ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.59 (s, 2H), 5.60 (s, 1H), 4.82 (s, 1H), 3.89 (s, 2H), 3.46 – 3.29 (m, 2H), 3.23 – 3.09 (m, 6H), 1.88 –1.29 (m, 5H), 0.46 – 0.21 (m, 4H). LC-MS, M/Z (ESI): 447.1 (M+1) ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.59 (s, 2H), 5.62 (s, 1H), 4.92 (s, 1H), 3.89 (s, 2H), 3.46 – 3.29 (m, 4H), 3.23 – 2.89 (m, 4H), 1.98 –1.79 (m, 5H), 1.76 – 1.42 (m, 4H), 0.46 – 0.21 (m, 2H ). LC-MS, M/Z (ESI): 461.1 (M+1) ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.59 (s, 2H), 5.62 (s, 1H), 4.92 (s, 1H), 3.89 (s, 2H), 3.46 – 3.29 (m, 4H), 3.23 – 2.89 (m, 5H), 2.50 – 2.47 (m, 2H), 1.98 –1.83 (m, 2H), 1.76 – 1.66 (m, 4H ), 1.46 – 1.21 (m, 2H). LC-MS, M/Z (ESI): 463.1 (M+1) ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.59 (s, 2H), 5.62 (s, 1H), 4.92 (s, 1H), 3.89 (s, 2H), 3.46 – 3.29 (m, 4H), 3.23 – 2.89 (m, 5H), 2.50 – 2.47 (m, 3H), 2.08 –1.88 (m, 2H), 1.79 – 1.68 (m, 4H ), 0.93 (d, 3H). LC-MS, M/Z (ESI): 463.1 (M+1) ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.59 (s, 2H), 5.62 (s, 1H), 4.92 (s, 1H), 3.89 (s, 2H), 3.46 – 3.29 (m, 3H), 3.23 – 2.89 (m, 5H), 2.50 – 2.47 (m, 4H), 2.08 –1.88 (m, 2H), 1.79 – 1.68 (m, 4H ), 0.93 (d, 3H). LC-MS, M/Z (ESI): 476.1 (M+1) ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.59 (s, 2H), 5.62 (s, 1H), 4.92 (s, 1H), 3.89 (s, 2H), 3.46 – 3.29 (m, 6H), 3.23 – 2.89 (m, 4H), 1.98 –1.79 (m, 4H), 1.76 – 1.42 (m, 2H), 0.46 – 0.21 (m, 4H ). LC-MS, M/Z (ESI): 458.1 (M+1) ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.59 (s, 2H), 5.62 (s, 1H), 3.46 – 3.29 (m, 4H ), 3.23 – 2.89 (m, 5H), 2.69 (s, 2H), 2.50 – 2.47 (m, 2H), 2.28 –2.08 (m, 2H), 1.98 –1.79 (m, 4H), 1.76 – 1.42 (m , 2H). LC-MS, M/Z (ESI): 471.1 (M+1) ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.59 (s, 2H), 5.62 (s, 1H), 3.46 – 3.29 (m, 4H ), 3.23 – 2.89 (m, 4H), 2.69 (s, 2H), 2.50 – 2.47 (m, 4H), 1.98 –1.79 (m, 4H), 1.76 – 1.42 (m, 2H). LC-MS, M/Z (ESI): 484.1 (M+1) ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.69 (s, 2H), 5.72 (s, 1H), 3.46 – 3.29 (m, 4H ), 3.23 – 2.89 (m, 5H), 2.69 (s, 2H), 2.50 – 2.47 (m, 2H), 2.28 –2.08 (m, 2H), 1.98 –1.79 (m, 4H), 1.76 – 1.42 (m , 2H). LC-MS, M/Z (ESI): 485.1 (M+1) ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.69 (s, 2H), 5.72 (s, 1H), 3.46 – 3.29 (m, 4H ), 3.23 – 2.89 (m, 4H), 2.69 (s, 2H), 2.50 – 2.47 (m, 4H), 1.98 –1.79 (m, 4H), 1.76 – 1.42 (m, 2H). LC-MS, M/Z (ESI): 465.1 (M+1) ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.59 (s, 2H), 5.62 (s, 1H), 4.92 (s, 1H), 3.89 (s, 2H), 3.46 – 3.29 (m, 4H), 3.23 – 2.89 (m, 4H), 1.98 –1.79 (m, 6H), 1.76 – 1.42 (m, 2H). LC-MS, M/Z (ESI): 483.1 (M+1) ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.59 (s, 2H), 6.13(t, 1H), 5.62 (s, 1H), 4.92 (s, 1H), 3.89 (s, 2H), 3.46 – 3.29 (m, 4H), 3.23 – 2.89 (m, 4H), 1.98 –1.79 (m, 4H), 1.76 – 1.42 (m, 2H). LC-MS, M/Z (ESI): 459.1 (M+1) ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.59 (s, 2H), 6.15 (d, 1H), 5.68 (d, 1H), 5.57 (s, 1H), 5.62 (s, 1H), 4.92 (s, 1H), 3.89 (s, 2H), 3.46 – 3.29 (m, 4H), 1.98 –1.79 (m, 4H), 1.76 – 1.42 ( m, 2H). LC-MS, M/Z (ESI): 463.1 (M+1) ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.59 (s, 2H), 5.62 (s, 1H), 4.92 (s, 1H), 3.89 (s, 2H), 3.46 – 3.29 (m, 4H), 3.23 – 2.89 (m, 2H), 2.85 – 2.58 (m, 2H), 2.50 – 2.47 (m, 2H), 1.98 –1.79 (m, 4H ), 1.76 – 1.42 (m, 2H). LC-MS, M/Z (ESI): 485.1 (M+1) ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.59 (s, 2H), 5.62 (s, 1H), 4.92 (s, 1H), 3.89 (s, 2H), 3.46 – 3.29 (m, 5H), 3.23 – 2.89 (m, 4H), 2.50 – 2.47 (m, 2H), 1.98 –1.79 (m, 4H), 1.76 – 1.42 (m, 2H ).

Test Example 1: PDE4B and PDE4D enzyme activity test The inhibitory activity of the compounds of the present invention on PDE4B and PDE4D can be detected using PDE-Glo Phosphodiesterase Assay Kit (promega, V1361). First, prepare the compound to be detected in DMSO solvent to make a 10 mM concentrated stock solution, and then dilute it into a 10× working solution with the reaction buffer provided in the kit. Operating on ice, dilute PDE4B enzyme (Enzo Life Sciences, BML-SE522-0020) to a concentration of 1 ng/μL and PDE4D enzyme (Enzo Life Sciences, BML-SE523-0020) to a concentration of 4 ng/μL using Reaction buffer. μL. Add 1.5ul PDE4B or PDE4D working solution and 1μL compound working solution to the wells of a 384-well plate (Corning, CLS3707), incubate with shaking at room temperature for 5 minutes, then add 2.5μL/well cAMP (2μM in Reaction buffer), continue at room temperature Incubate with shaking for 20 minutes, add 2.5 μL/well 1×Termination Buffer, then add 2.5 μL/well 1×Detection Buffer, and continue shaking at room temperature for 20 minutes. Finally, add 10 μL/well 1×Kinase-Glo, incubate with shaking at room temperature for 10 minutes, and detect bioluminescence with a PheraStar instrument. The experimental results were input into GraphPad Prism software, and the IC ₅₀ of each compound was calculated through fitting. Table 1. IC ₅₀ values of compounds Compound number PDE4B IC ₅₀ (nM) PDE4D IC ₅₀ (nM) Compound 1-A 13.46 30.28 Compound 11-A 343.2 961.2 Compound 12-A-P1 12.24 30.92 Compound 12-A-P2 9.36 18.87 Compound 13-A 6.26 29.91 Compound 15-A 3.00 5.74 Compound 16-A 14.02 41.67 Compound 20-A 0.53 4.2 Compound 26-A 23.25 48.96 Compound 27-A 22.80 53.51 Compound 27-A-P1 13.96 24.52 Compound 27-A-P2 7.16 18.68 Compound 28-A 10.10 13.47 Compound 29-A 157.8 721.0 Compound 31-A 1.53 3.01 Compound 32-A-P1 9.85 24.80 Compound 32-A-P2 13.01 24.01 Compound 33-A 3.762 8.216 Compound 34-A 4.185 10.46 Compound 35-A-P1 11.31 29.96 Compound 35-A-P2 4.83 11.31 Compound 27-B-P1 54.88 123.30 Compound 27-B-P2 32.31 59.33 Compound 36-A 41.30 77.18 Compound 4-A-P4 12.31 34.42 Compound 37-A-P1 0.77 2.86 Compound 37-A-P2 1.14 1.70 Compound 39 29.24 45.24 Compound 40-A-P2 29.63 34.98 Compound 41-A-P2 45.68 67.76 Experimental results show that the compound of the present invention can be used as a selective inhibitor of PDE4B. When used in the treatment of PED4-related diseases, it can effectively improve the occurrence of side effects such as vomiting.

Test column 2: LPS-induced human PBMC secretion of TNFα model test PBMC extraction process: Obtain fresh human peripheral concentrated blood, draw 1 unit of human peripheral concentrated blood (concentrated from 200cc of peripheral blood), and quantitatively add 0.9% normal saline to a total volume of 120 ml. Mix well. Take a 50ml centrifuge tube, add 15ml LymphoprepTM respectively, hold the centrifuge tube at an angle of about 45°, draw 30ml of diluted concentrated blood, carefully and slowly add it to the wall, so that the diluted blood overlaps the layering solution to avoid mixing the diluted blood. The separation liquid may break through the separation liquid level. The ratio of LymphoprepTM to diluted blood is 1:2. Place the centrifuge tube into a horizontal centrifuge (eppendorf, 5810R), and centrifuge at 800g and 20°C for 20 minutes. The increasing speed is set to 1 and the decreasing speed is set to 0. Carefully remove the centrifuge tube. Directly insert the Pasteur pipette into the buffy coat layer to aspirate PBMC. Add 3 times the volume of 0.9% normal saline or PBS (without calcium and magnesium), and mix by gently pipetting. After mixing, centrifuge at 20°C and 250g for 10 minutes to remove the remaining platelets in the cell suspension, remove the supernatant, suspend the cell pellet in 20 ml of PBS, and stain with trypan blue for counting. PBMC screening process: Centrifuge the PBMC obtained in step 1, remove PBS, and then resuspend in complete culture medium (RPMI1640+10%FBS+1%P/S) for counting. Add cells at 5×10 ⁴ /well and 100μL/well. Compounds to be screened were formulated to 4× the final concentration. Add 50 μL/well to the cells. Pre-incubate for 30 minutes in advance. At the same time, set the control well without adding compound. The final stimulation concentration of LPS is 10ng/ml, dilute it into a 4-fold solution, and add it to the cells at 50μl/well. At the same time, control holes are set without adding LPS holes. Continue to incubate the cells, and collect 10% of the supernatant for detection at 24 hours. The collected supernatant was tested according to Invitrogen's Human TNFα kit (REF: 88-7346-88). The inhibitory activity of the compounds provided by the present invention on LPS-induced human secretion of TNFα is determined according to the above method. Table 2 Results of the inhibitory activity of test compounds on LPS-induced TNFα secretion from human PBMCs Compound number TNFα secretion IC ₅₀ (nM) Compound 12-A-P1 39.10 Compound 12-A-P2 35.41 Compound 13-A 12.76 Compound 15-A 5.99 Compound 16-A 42.96 Compound 20-A 8.12 Compound 26-A 32.36 Compound 28-A 24.97 Compound 31-A 3.71 Compound 32-A-P2 41.19 Compound 33-A 19.60 Experimental results show that the compound of the present invention has excellent inhibitory activity on the secretion of TNFα by human PBMC, can better inhibit the secretion of the inflammatory factor TNFα in human PBMC, and has good anti-inflammatory effect.

Test Example 3: Mouse Pharmacokinetic Test In the mouse pharmacokinetic test, male ICR mice, 20-25g, were fasted overnight. Take 3 mice and administer 10 mg/kg orally. Blood was collected before administration and at 15, 30 minutes and 1, 2, 4, 8, and 24 hours after administration. Blood samples were centrifuged at 6800 g for 6 minutes at 2-8°C, and plasma was collected and stored at -20°C. Take the plasma at each time point, add 3-5 times the amount of acetonitrile solution containing the internal standard, vortex and mix for 1 minute, centrifuge at 13000 rpm and 4°C for 10 minutes, take the supernatant and add 3 times the amount of water to mix, and take an appropriate amount of the mixture. Perform LC-MS/MS analysis. The main pharmacokinetic parameters were analyzed using WinNonlin 7.0 software non-compartmental model. Table 3 Pharmacokinetic test results in mice test compound Mouse pharmacokinetic parameters (oral administration) Cmax (ng/mL) Tmax(hr) AUC _ot (h*ng/mL) T _1/2 (h) Compound 13-A 1757 1 11146 3.93 Compound 15-A 3360 0.5 19186 10.70 Compound 16-A 3650 0.5 11114 5.72 Compound 20-A 3303 2 35219 6.59 Compound 33-A 2560 0.5 13772 7.44 Compound 27-A-P1 2817 0.25 10186 3.31 Compound 27-A-P2 3850 0.5 18186 3.27 Experimental results show that the compound of the present invention exhibits excellent plasma exposure and has excellent pharmacokinetic properties.

Test Example 4: Rat Pharmacokinetic Test In the rat pharmacokinetic test, male SD mice, weighing 200-250g/mouse, were fasted overnight. Take 3 rats and administer 10 mg/kg orally with the compound of the present invention. Blood was collected before administration and at 5, 15, 30 minutes, and 1, 2, 4, 8, and 24 hours after administration. Collect 0.2 mL of blood into labeled EDTA-2K anticoagulant tubes. Gently invert the anticoagulant (EDTA-2K) and blood thoroughly, then immediately place it in wet ice, and centrifuge to separate the plasma within 1 hour after blood collection. The centrifugation conditions are set to 4°C, 6800 × g, 6 minutes. . The separated plasma after centrifugation is placed in labeled EP tubes and stored in an ultra-low temperature refrigerator as soon as possible until sample analysis. The main pharmacokinetic parameters were analyzed using WinNonlin 7.0 software non-compartmental model. The results are shown in Table 4. Table 4 Pharmacokinetic test results in rats test compound Pharmacokinetic parameters in rats (oral administration) Cmax (ng/mL) Tmax(hr) AUC _ot (h*ng/mL) T _1/2 (h) Compound 13-A 1002 0.5 5893 2.33 Compound 15-A 2070 2 22894 11.9 Compound 16-A 1563 0.5 8046 3.38 Compound 20-A 1075 6 15256 7.69 Compound 27-A-P1 1537 0.5 8472 6.6 Compound 27-A-P2 1577 0.25 8293 3.43 Compound 27-B-P2 1890 0.5 10538 3.32 Experimental results show that the compound of the present invention exhibits excellent plasma exposure and has excellent pharmacokinetic properties.

Test Example 5: Beagle Dog Pharmacokinetic Test In the Beagle dog pharmacokinetic test, male Beagle dogs weighing 7-12kg/animal were fasted overnight. Three Beagle dogs were administered orally orally with 3 or 10 mg/kg of the compound of the present invention. Blood was collected before administration and at 5, 15, 30 minutes, and 1, 2, 4, 8, and 24 hours after administration. Blood samples were centrifuged at 2200 × g and 2-8°C for 6 minutes, and plasma was collected and stored at -20°C. The main pharmacokinetic parameters were analyzed using WinNonlin 7.0 software non-compartmental model. The results are shown in Table 5. Table 5 Pharmacokinetic test results in Beagle dogs test compound Beagle dog pharmacokinetic parameters (oral administration) Cmax (ng/mL) Tmax(hr) AUC _0-t (h*ng/mL) T _1/2 (h) Compound 13-A (10mpk) 831.0 2.7 6923 3.6 Compound 16-A (10mpk) 5529.7 0.7 27538 6.9 Compound 27-A-P1 (10mpk) 2787.7 0.6 18622 4.93 Compound 27-A-P2 (3mpk) 943.4 1.3 6717 7.33 Compound 27-B-P2 (10mpk) 1164.0 0.6 4169 4.5 Experimental results show that the compound of the present invention exhibits excellent plasma exposure and has excellent pharmacokinetic properties.

Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and cannot be understood as limitations of the present invention. A person having ordinary knowledge in the technical field to which the present invention belongs can change, modify, replace and modify the above embodiments within the scope of the present invention.

without

without

Claims (31)

A compound that is a compound represented by formula II or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of a compound represented by formula II: , wherein, ring A is a 5-10-membered aromatic ring or heteroaromatic ring; B is selected from 3-10-membered heterocycloalkyl, 3-10-membered heterocycloalkenyl or 3-10-membered cycloalkyl; R ^a and R ^b is each independently selected from H, halogen, hydroxyl, amine, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 deuterated alkyl Base, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-8 halocycloalkyl, C _1-6 alkyl hydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy group, C _1-6 haloalkoxy group, 3-10 membered heterocycloalkyl group; the C _1-6 alkyl group, C _3-8 cycloalkyl group, C _1-6 deuterated alkyl group, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-8 halocycloalkyl, C _1-6 alkylhydroxy, C _1-6 alkylcarbonyl, C _1-6 alkoxy and C _{1 -6} Haloalkoxy is optionally substituted by one or more R ^c ; the R ^c is selected from the following substituents: halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _{1 -6} alkyl, C _1-6 deuterated alkyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 alkylhydroxy, C _1-6 alkylcarbonyl, C _1-6 alkoxy group, C _1-6 haloalkoxy group; when the substituent R ^c is multiple, the R ^c is the same or different; m and n are 0, 1, 2 or 3 respectively; Y is selected from NR ¹ , O, S Or CHR ¹ ; R ¹ is selected from H, C _1-10 alkyl, C _2-6 alkenyl, the C _1-10 alkyl, C _2-6 alkenyl is optionally substituted by one or more R ^d ; The R ^d is selected from the following substituents: halogen, C _1-3 fluoroalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, -COO-C _1-6 alkyl, - C(O)NR ^f R ^f , 5-8 membered aromatic ring, -het ¹ , mono- or bicyclic-C _5-8- cycloalkyl; wherein, the R ^f is hydrogen, C _1-6 alkyl; The het ¹ represents a 5-8 membered monocyclic or bicyclic, saturated or unsaturated heterocyclic ring, which contains 1, 2, 3 or 4 heteroatoms independently selected from N, S, and O; Q is selected From the following groups: , Or Q ¹ ; M is cyano; Each pair of R ² and R ³ , R ⁵ and R ⁶ can be independently associated with their respective attached carbon atoms to form a saturated or partially saturated 3-membered, 4 3-, 5-, and 6-membered monocyclic rings; wherein the 3-, 4-, 5-, and 6-membered monocyclic rings contain 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S. atoms, and further, wherein the 3-membered, 4-membered, 5-membered, 6-membered monocyclic ring is replaced by 0, 1, 2 or 3 R ²³ selected from the following, and the R ²³ is selected from at least one of the following : Halogen, hydroxyl, amino, cyano, carbonyl _, oxo, carboxyl, C _1-6 alkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _{1 -4} haloalkyl, C _1-6 alkylhydroxy, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 haloalkoxy, -COO-C _1-6 alkyl, -C( O) NR ^f R ^f ; wherein, the R ^f is hydrogen, C _1-6 alkyl; or, R ⁵ and R ⁶ are each independently selected from H, C _1-10 alkyl, C _2-6 alkenyl , the C _1-10 alkyl and C _2-6 alkenyl are optionally substituted by one or more R ^d ; the R ^d is selected from the following substituents: halogen, C _1-3 fluoroalkyl, C _1-6 alkoxy group, C _1-6 haloalkoxy group, -COO-C _1-6 alkyl group, -C(O)NR ^f R ^f , 5-8 membered aromatic ring, -het ² , mono-or Bicyclic-C _5-8- cycloalkyl; wherein, the R ^f is hydrogen, C _1-6 alkyl; the het ² represents a 5-8 membered monocyclic or bicyclic, saturated or unsaturated heterocyclic ring, It contains 1, 2, 3 or 4 heteroatoms independently selected from N, S, O; R ⁴ is selected from halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 deuterated alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-8 halo Cycloalkyl, C _1-6 alkylhydroxy, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 haloalkoxy, 3 to 10-membered heterocycloalkyl; the C _{1- 6} alkyl, C _3-8 cycloalkyl _, C _1-6 deuterated alkyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-8 halocycloalkyl, C _1-6 alkyl Hydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 haloalkoxy are optionally substituted by one or more ^Rg ; the ^Rg is selected from the substitution of at least one of the following Group: halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _2-6 alkynyl, C _1-6 haloalkyl group, C _1-6 alkyl hydroxyl group, C _1-6 alkyl carbonyl group, C _1-6 alkoxy group, C _1-6 haloalkoxy group; when the substituent R ^g is multiple, the R ^g is the same or Different; Q ¹ is a 4-6 membered heterocycloalkyl group optionally substituted by one or more R ⁷ , ^which is selected from at least one of the following substituents: H, halogen, hydroxyl, amino, nitro group, cyano group, carbonyl group, oxo, carboxyl group, C _1-6 alkyl group, C _1-6 deuterated alkyl group, C _2-6 alkynyl group, C _1-6 haloalkyl group, C _1-6 alkyl hydroxyl group, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 haloalkoxy; when there are multiple substituents R ⁷ , the R ^7s may be the same or different. The compound as described in claim 1, wherein the compound has a structure shown in Formula II-A or Formula II-B, or . The compound of claim 1, wherein ring A is selected from a 5-9 membered heteroaromatic ring; optionally, the heteroaromatic ring has 1 or 2 heteroatoms; optionally, the heteroatoms are selected from N or O; optionally, the ring A is selected from a pyridine ring, a pyrimidine ring, a pyridine ring, a pyridine ring or a benzoxazolyl ring; optionally, the ring A is selected from or Optionally, the structural unit Selected from or ; Optionally, the ^Ra is selected from F, Cl, CH ₃ or CH ₃ substituted by halogen; Optionally, the ^Ra is selected from F, Cl or CHF ₂ ; Optionally, when the Y is selected from NR ¹ or CHR ¹ , R ¹ is selected from H or C _1-6 alkyl; Optionally, the Y is selected from -NH-. The compound as described in claim 1, wherein the compound has a structure shown in formula III or formula IV, , . The compound according to any one of claims 1-4, wherein Q is selected from the following groups: or ; Optionally, B is selected from 3-10-membered heterocycloalkyl, 3-10-membered heterocycloalkenyl; Optionally, B is selected from 3-10-membered heterocycloalkyl; Optionally, the 3- The 10-membered heterocycloalkyl group is selected from monocyclic, condensed and bicyclic, bridged or spiro-bicyclic rings; Optionally, the 3-10 membered heterocycloalkyl further has 1 to 3 selected from Heteroatoms of N, O and S; Optionally, B is selected from 3-10 membered heterocyclic alkenyl; Optionally, the 3-10 membered heterocyclic alkenyl is selected from monocyclic or fused bicyclic ; Optionally, the 3-10-membered heterocyclic alkenyl group further has 1 to 3 heteroatoms selected from N, O, and S. The compound according to any one of claims 1-5, wherein said B is selected from the following groups: , , , , , , , , , , , , ; Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , Z ⁶ , Z ⁷ , Z ⁸ and Z ⁹ are each independently N, NH, CH ₂ , CH, C, -NH-CH ₂ -or- CH ₂ -CH ₂ -; p is 0, 1 or 2, where, when p is 0, for ; Preferably, for or ; Preferably, for or ; Preferably, for ; Preferably, for ; Preferably, for ; Preferably, for or ; Preferably, for or ; Preferably, for or ; Preferably, for ; Preferably, for ; Preferably, for ; Preferably, for ; Preferably, for ; Preferably, for . A compound as described in claim 1-6, wherein the R ^b is selected from C _1-6 alkyl, halogen, C _3-8 cycloalkyl or oxo; optionally, the R ^b is selected from methyl, F, cycloethyl or oxo; optionally, the R ^c is selected from 0, 1, 2 or 3; optionally, the R ^c is selected from halogen, oxo, C _1-6 alkyl or C _1-6 halogenated alkyl; optionally, the R ^g is selected from 0, 1, 2 or 3; optionally, the R ^g is selected from halogen, hydroxyl, cyano, C _1-6 alkyl or C _1-6 halogenated alkyl. The compound according to any one of claims 1-4, wherein the fragment Selected from , , , , , , , , , , , , , , , , , , , , , , , or . The compound of claim 1, wherein the compound is selected from the following structures: , , , , , , , , , , , , , or ; Wherein, Z ¹ and Z ⁴ are each independently selected from N, CH or C. The compound as claimed in claim 1, wherein the compound is selected from the following structures: , wherein R ^b is selected from halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 deuterated alkyl, C _2-6 alkenyl, C 2-6 alkynyl, C _1-6 halogenated alkyl, C _3-8 halogenated cycloalkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy, 3-10 membered heterocycloalkyl; the C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 deuterated alkyl, C _2-6 alkynyl, C _1-6 halogenated alkyl _, C _3-8 halogenated cycloalkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C The _1-6 halogenated alkoxy group is optionally substituted by one or more R ^c ; the R ^c is selected from the following substituents: halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _2-6 alkynyl, C _1-6 halogenated alkyl, C 1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy; when the substituent R ^c is multiple, the R ^c are the same or different; m is 0, 1, ₂ or 3; n is 1, 2 or 3; Z ¹ and Z ⁴ are each independently selected from N, CH or C. The compound as described in claim 1-10, wherein the Q is selected from the following groups: , , , , or ; r is 0, 1, 2 or 3; Optionally, R ²³ is selected from at least one of the following: halogen, hydroxyl, amine, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-4 halogenated alkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy, -COO-C _1-6 alkyl or -C(O)NR ^f R ^f ; wherein R ^f is hydrogen, C _1-6 alkyl; Optionally, R ⁴ is selected from at least one of the following: halogen, hydroxyl, amine, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 deuterated alkyl, C C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenated alkyl, C _3-8 halogenated cycloalkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C 1-6 alkoxy, C 1-6 halogenated alkoxy, 3 to 10 membered heterocycloalkyl; the C _1-6 alkyl, C 3 -C ₈ cycloalkyl, C _1-6 deuterated alkyl, C _2-6 alkynyl, C _1-6 halogenated alkyl, C _3-8 halogenated cycloalkyl, C _1-6 alkylhydroxyl, C 1-6 alkylcarbonyl, C 1-6 alkoxy, C 1-6 halogenated alkoxy, 3 to 10 membered heterocycloalkyl; the C 1-6 alkyl, C 3 -C 8 cycloalkyl, C _1-6 deuterated alkyl, C _2-6 alkynyl, C _1-6 halogenated alkyl, C _3-8 halogenated cycloalkyl, C _{1-6 alkylhydroxyl, C 1-6} alkylcarbonyl, C 1-6 alkoxy, C _1-6 halogenated alkoxy is optionally substituted with one or more R ^g ; the R ^g is selected from the following substituents: halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C wherein the substituent Rg is _{a C1-6} alkyl, a _C1-6 deuterated alkyl, a _C2-6 alkynyl, a _C1-6 halogenated alkyl, a _C1-6 alkylhydroxyl, a _C1-6 alkylcarbonyl, a _C1-6 alkoxyl, a _C1-6 halogenated alkoxyl group; when the substituent ^Rg is multiple, the ^Rgs are the same or different; optionally, ^R7 is selected from 1, 2 or 3; optionally, ^R7 is selected from at least one of the following: H, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, _C1-6 alkyl, _C1-6 deuterated alkyl, _C2-6 alkynyl, _C1-6 halogenated alkyl, _C1-6 alkylhydroxyl, _C1-6 alkylcarbonyl, _C1-6 alkoxyl, _C1-6 halogenated alkoxyl group; optionally, the M is selected from cyano; optionally, the R Optionally, said ^{R 4} is selected from hydroxyl or cyano; Optionally, said R ²³ is selected from F; Optionally, said R ⁷ is selected from H, hydroxyl, cyano or CH _3. Optionally, said Q is selected from the following groups: , , , , , , or . The compound as claimed in claim 1, wherein the compound has the following structure: Wherein, said B' is selected from , , or , Z ¹ and Z ⁴ are ^each independently selected from N or CH, and at least one of Z ¹ and Z ⁴ is N; connected to ring A; said Z ⁴ is connected to ring A; R ^b is selected from halogen, hydroxyl, amine, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 deuterated alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenated alkyl, C _3-8 halogenated cycloalkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy, 3-10 membered heterocycloalkyl; said C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 deuterated alkyl, C _2-6 alkynyl, C _1-6 halogenated alkyl, C _3-8 halogenated cycloalkyl, C _1-6 alkylhydroxyl, C C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy is optionally substituted by one or more R ^c ; said R ^c is selected from the following substituents: halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _2-6 alkynyl, C 1-6 _halogenated alkyl, C _1-6 alkylhydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy; when the substituent R ^c is multiple, said R ^c is the same or different; m, n are independently 0, 1, 2 or 3; when B 'is selected from , Z ₁ is N, Z ₄ is CH, Q is not , n is 0, 1, 2, 3; or Q is When n is 1, 2, or 3. The compound of claim 1, wherein the compound is selected from the following structures: , , , , , , or , where r is 0, 1, 2 or 3. The compound as claimed in claim 1, wherein the compound is selected from the following structures: , , , , , , or ; wherein B is a 4- to 9-membered heterocycloalkyl group having 1 to 3 heteroatoms selected from N, O, and S; the 4- to 9-membered heterocycloalkyl group is a monocyclic, fused bicyclic, bicyclic including a bridged ring or a spirocyclic ring; R ^b is selected from a halogen, a hydroxyl, an amine, a nitro, a cyano, a carbonyl, an oxo, a carboxyl, a C _1-6 alkyl, a C _1-6 deuterated alkyl, a C _2-6 alkynyl, a C _{1-6 halogenated alkyl, a C 1-6} alkylhydroxyl, a C _1-6 alkylcarbonyl, a C _1-6 alkoxyl, a C _1-6 halogenated alkoxyl; n is ₀ , 1, 2, or 3. The compound as claimed in claim 1, wherein the compound is selected from the following structures: , , , , , , , ; Preferably, the compound is selected from the following structures: , , , , , , , ; wherein Z ¹ and Z ⁴ are each independently N, CH or C. The compound as claimed in claim 1, wherein the compound is selected from the following structures: , , , ; Preferably, the compound is selected from the following structures: , , , , ; wherein Z ¹ and Z ⁴ are each independently N, CH or C. The compound of claim 1, wherein the compound is selected from the following structures: , , , , , , ; Preferably, the compound is selected from the following structures: , , , , , , , , ; Wherein, Z ¹ and Z ⁴ are each independently N, CH or C. The compound as claimed in claim 1, wherein the compound is selected from the following structures: , , , , , , ; Preferably, the compound is selected from the following structures: , , , , , , ; wherein Z ¹ and Z ⁴ are each independently N, CH or C. The compound as claimed in claim 1, wherein the compound is selected from the following structures: , , , , , ; Preferably, the compound is selected from the following structures: , , , , , ; wherein Z ¹ and Z ⁴ are each independently N, CH or C. The compound of claim 1, wherein the compound is selected from the following structures: , , ; Preferably, the compound is selected from the following structures: , , ; Wherein, Z ¹ and Z ⁴ are each independently N, CH or C. The compound as claimed in claim 1, wherein the compound is selected from the following structures: , ; Preferably, the compound is selected from the following structures: , , ; wherein Z ¹ and Z ⁴ are each independently N, CH or C. The compound of claim 1, wherein the compound is selected from the following structures: ; Wherein, the fragment Selected from , , , , , , , , , ; Rings A, R ^a and m are as defined in weight 1. The compound as claimed in claim 1, wherein the compound is selected from the following structures: ; wherein the fragment Selected from , , ; Ring A, ^Ra and m are as defined in claim 1. The compound as claimed in claim 22 or 23, wherein the structural unit Selected from . The compound as claimed in claim 1, wherein the compound is selected from the following structures: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or . The compound of claim 1, wherein the compound is selected from the following structures: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or . The compound of claim 1, wherein the compound is selected from the following structures: , , , , , , , , , , , , , , or . A pharmaceutical composition, wherein the pharmaceutical composition includes: a compound as described in any one of claims 1-27, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug; Optionally, the pharmaceutical composition further includes a pharmaceutically acceptable carrier or excipient. A compound as described in any one of claims 1-27, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or a compound as described in claim 28 Use of a pharmaceutical composition for inhibiting PDE4B. Use of a compound as described in any one of claims 1 to 27, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition as described in claim 28 in the preparation of a medicament or preparation for inhibiting PDE4B, and/or preventing and/or treating a disease associated with PDE4B. The use as described in claim 30, wherein the PDE4B-related diseases include: respiratory diseases, gastrointestinal diseases, inflammatory diseases of joints, skin or eyes, cancer and peripheral or central nervous system diseases, autoimmune diseases, transplant rejection or diseases related to smooth muscle contractility; Optionally, the respiratory disease is selected from respiratory or lung diseases accompanied by increased mucus production, airway inflammation and/or obstructive diseases; Optionally, the respiratory disease is selected from COPD, idiopathic pulmonary fibrosis, α1-antitrypsin deficiency, chronic sinusitis, asthma or chronic bronchitis; Optionally, the autoimmune disease is selected from diffuse connective tissue diseases such as systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, dermatomyositis, polymyositis, vasculitis or sicca; Optionally, the gastrointestinal disease is selected from symptomatic ileitis, ulcerative colitis or Crohn's disease; Optionally, the inflammatory disease of the joints, skin or eyes is selected from rheumatoid arthritis, sarcoidosis, dry eye syndrome or glaucoma; Optionally, the cancer is selected from mesothelioma, neuroblastoma, rectal cancer, colon cancer, familiar adenomatous polyposis and hereditary non-polyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, uterine cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, bladder cancer, testicular cancer, breast cancer, urinary cancer, melanoma Pigmented tumor, brain tumor, lymphoma, head and neck cancer, acute lymphatic leukemia, chronic lymphatic leukemia, acute myeloid leukemia, chronic myeloid leukemia, hepatocellular carcinoma, gallbladder cancer, bronchial carcinoma, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal sarcoma, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, myoma, liposarcoma, fibrosarcoma, Ewing sarcoma and plasma cell tumor; Optionally, the peripheral or central nervous system disease is selected from depression, bipolar depression or manic depression, acute and chronic anxiety states, schizophrenia, Alzheimer's disease, Parkinson's disease, acute and chronic multiple sclerosis or acute and chronic pain and brain damage caused by stroke, hypoxia or craniocerebral trauma.