CN117247395A

CN117247395A - PDE4B inhibitors

Info

Publication number: CN117247395A
Application number: CN202310724689.1A
Authority: CN
Inventors: 张学军; 贾一民; 李金平; 刘勇; 杨俊�; 李莉娥
Original assignee: Humanwell Healthcare Group Co ltd; Wuhan Humanwell Innovative Drug Research and Development Center Ltd Co
Current assignee: Humanwell Healthcare Group Co ltd; Wuhan Humanwell Innovative Drug Research and Development Center Ltd Co
Priority date: 2022-06-16
Filing date: 2023-06-16
Publication date: 2023-12-19
Also published as: WO2023241684A1; TW202408518A

Abstract

The invention provides a compound shown in a formula II, or a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof; the compound has better PDE4B inhibition effect,

Description

PDE4B inhibitors

Technical Field

The invention belongs to the field of medicines, and particularly relates to a PDE4B inhibitor.

Background

PDE4 is a cyclic nucleotide phosphodiesterase, which is abundantly expressed in most cells and hydrolyzes cAMP at micromolar Km values. PDE4 molecules are involved in a variety of physiological processes including brain function, activation of mononuclear macrophages, neutrophil infiltration, vascular smooth muscle proliferation, and myocardial contraction. PDE4 is reported to be a target for various inflammatory diseases, such as asthma, chronic Obstructive Pulmonary Disease (COPD) and rheumatoid arthritis. PDE4 consists of four isoforms of PDE4A, PDE4B, PDE4C and PDE4D, located on the 19p13.2, 1p31, 19p13.11 and 5q12 chromosomes, respectively. PDE4 molecules exist in long, short, and ultrashort forms depending on their molecular size. The X-ray structure of PDE4 molecules suggests that the active center can be divided into three sub-pockets: a divalent metal pocket that interacts with the phosphate moiety of cAMP; two Q pockets forming hydrogen bonds and hydrophobic interactions with the inhibitor; and a solvation pocket (S pocket). PDE4 inhibitors occupy active sites through a variety of interactions, including hydrophobic interactions with conserved phenylalanine and isoleucine, and hydrogen bonding with unchanged 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 believed to be caused by inhibition of the PDE4D subtype. Likewise, side effects limit the therapeutic index of the second generation PDE4 inhibitors cilomilast and roflumilast. Selective inhibition of PDE4B isoforms may provide a method of achieving therapeutic efficacy while potentially alleviating these adverse events.

There is currently no pharmaceutical market for PDE4B inhibitor inhibition pathways to treat a number of conditions including fibrosis. Thus, the development of novel compounds which inhibit PDE4B activity has positive implications for the treatment of diseases.

Disclosure of Invention

It is an object of the present invention to provide a novel compound useful as an inhibitor of PDE 4B.

In a first aspect of the invention, the invention provides a compound which is a compound of formula II or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of a compound of formula II:

wherein,

ring A is a 5-10 membered aromatic or heteroaromatic ring;

b is selected from 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl or 3-10 membered cycloalkyl;

R ^a and R is ^b Each independently selected from H, halogen, hydroxy, 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 Halogenated cycloalkyl, C _1-6 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, 3-10 membered heterocycloalkyl; the C is _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 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy and C _1-6 Haloalkoxy groups are optionally substituted with one or more R ^c Substitution; the R is ^c A substituent selected from the group consisting of: halogen, hydroxy, 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 hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups; when the substituent R ^c When there are a plurality of R ^c 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 Selected from H, C _1-10 Alkyl, C _2-6 Alkenyl group, the C _1-10 Alkyl, C _2-6 Alkenyl is optionally substituted with one or more R ^d Substitution; the R is ^d A substituent selected from the group consisting of: 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 bicyclo-C _5-8- Cycloalkyl; wherein the R is ^f Is hydrogen, C _1-6 An alkyl group; the het is ¹ Represents a 5-to 8-membered monocyclic or bicyclic, saturated or unsaturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms selected independently of one another from N, S, O;

q is selected from the following groups:or Q ¹ ；

M is cyano;

R ² and R is ³ To, R ⁵ And R is ⁶ Each of the pairs may independently form a saturated or partially saturated 3-, 4-, 5-, 6-membered monocyclic ring with the carbon atoms to which they are attached; wherein the 3-membered, 4-memberedA 5-, 2-, or 6-membered monocyclic ring containing 0, 1, 2, or 3N atoms and 0, 1, or 2 atoms selected from O and S, and further wherein the 3-, 4-, 5-, or 6-membered monocyclic ring is selected from 0, 1, 2, or 3R ²³ Substitution, said R ²³ Selected from at least one of the following: halogen, hydroxy, 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 hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -COO-C _1-6 Alkyl, -C (O) NR ^f R ^f The method comprises the steps of carrying out a first treatment on the surface of the Wherein the R is ^f Is hydrogen, C _1-6 An alkyl group;

alternatively, R ⁵ And R is ⁶ Each independently selected from H, C _1-10 Alkyl, C _2-6 Alkenyl group, the C _1-10 Alkyl, C _2-6 Alkenyl is optionally substituted with one or more R ^d Substitution; the R is ^d A substituent selected from the group consisting of: 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 ² Mono-or bicyclo-C _5-8- Cycloalkyl; wherein the R is ^f Is hydrogen, C _1-6 An alkyl group; the het is ² Represents a 5-to 8-membered monocyclic or bicyclic, saturated or unsaturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms selected independently of one another from N, S, O;

R ⁴ selected from halogen, hydroxy, 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 Halogenated cycloalkyl, C _1-6 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, 3-10 membered heterocycloalkyl; the C is _1-6 Alkyl, C _3-8 Cycloalkyl, C _1-6 Deuterated alkyl, C _2-6 Alkynyl, C _1-6 HaloalkanesRadical, C _3-8 Halogenated cycloalkyl, C _1-6 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups are optionally substituted with one or more R ^g Substitution; the R is ^g A substituent selected from at least one of: halogen, hydroxy, 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 hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups; when the substituent R ^g When there are a plurality of R ^g The same or different;

Q ¹ to optionally be covered by one or more R ⁷ Substituted 4-6 membered heterocycloalkyl, said R ⁷ A substituent selected from at least one of: H. halogen, hydroxy, 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 hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups; when the substituent R ⁷ When there are a plurality of R ⁷ The same or different.

In a preferred embodiment of the invention, a compound of formula II, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof:

wherein,

ring A is a 5-10 membered aromatic or heteroaromatic ring;

R ^a and R is ^b Each independently selected from H, halogen, hydroxy, amino, nitro, cyano, carbonyl, oxo, carboxyl, C _1-6 Alkyl, C _3-8 Cycloalkyl, C _1-6 Deuterated alkaneRadical, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _3-8 Halogenated cycloalkyl, C _1-6 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, 3-10 membered heterocycloalkyl; the C is _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 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups are optionally substituted with one or more R ^c Substitution; the R is ^c A substituent selected from the group consisting of: halogen, hydroxy, 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 hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups; when the substituent R ^c When there are a plurality of R ^c 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 ；

q is selected from the following groups:or Q ¹ ；

M is cyano;

R ² and R is ³ To, R ⁵ And R is ⁶ Each of the pairs may independently form a saturated or partially saturated 3-, 4-, 5-, 6-membered monocyclic ring with the carbon atoms to which they are attached; wherein the 3-, 4-, 5-, 6-, membered monocyclic ring contains 0, 1, 2 or 3N atoms and 0, 1 or 2 atoms selected from O and S, and further wherein the 3-, 4-, 5-, 6-, membered monocyclic ring is substituted with 0, 1, 2 or 3 groups selected from: halogen, hydroxy, 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 hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -COO-C _1-6 Alkyl, -C (O) NR ^f R ^f The method comprises the steps of carrying out a first treatment on the surface of the Wherein the R is ^f Is hydrogen, C _1-6 An alkyl group;

R ⁴ selected from halogen, hydroxy, 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 Halogenated cycloalkyl, C _1-6 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, 3-10 membered heterocycloalkyl; the C is _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 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups are optionally substituted with one or more R ^g Substitution; the R is ^g A substituent selected from the group consisting of: halogen, hydroxy, 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 hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups; when the substituent R ^g When there are a plurality of R ^g The same or different;

Q ¹ to optionally be covered by one or more R ⁷ Substituted 4-6 membered heterocycloalkyl, said R ⁷ A substituent selected from the group consisting of: halogen, hydroxy, 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 hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups; when the substituent R ⁷ When there are a plurality of R ⁷ The same or different.

wherein,

ring A is a 5-10 membered aromatic or heteroaromatic ring;

R ^a And R is ^b Each independently selected from H, halogen, hydroxy, 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 Halogenated cycloalkyl, C _1-6 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, 3-10 membered heterocycloalkyl; the C is _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 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups are optionally substituted with one or more R ^c Substitution; the R is ^c A substituent selected from the group consisting of: halogen, hydroxy, 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 hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups; when the substituents are plural, the R ^c 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 Selected from H, C _1-10 Alkyl, C _2-6 Alkenyl group, the C _1-10 Alkyl, C _2-6 Alkenyl is optionally substituted with one or more R ^d Substitution; the R is ^d A substituent selected from the group consisting of: 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 bicyclo-C _5-8- Cycloalkyl; wherein the R is ^f Is hydrogen, C _1-6 An alkyl group; the het represents a 5-8 membered monocyclic or bicyclic, saturated or unsaturated ringA heterocycle containing 1, 2, 3 or 4 heteroatoms selected independently of each other from N, S, O;

q is selected from the following groups:

m is cyano;

alternatively, R ⁵ And R is ⁶ Each independently selected from H, C _1-10 Alkyl, C _2-6 Alkenyl group, the C _1-10 Alkyl, C _2-6 Alkenyl is optionally substituted with one or more R ^d Substitution; the R is ^d A substituent selected from the group consisting of: 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 bicyclo-C _5-8- Cycloalkyl; wherein the R is ^f Is hydrogen, C _1-6 An alkyl group; said het represents a 5-8 membered monocyclic or bicyclic, saturated or unsaturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms selected independently of each other from N, S, O;

R ⁴ selected from halogen, hydroxy, 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 Halogenated cycloalkyl, C _1-6 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, 3-10 membered heterocycloalkyl; the C is _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 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups are optionally substituted with one or more R ^g Substitution; the R is ^g A substituent selected from the group consisting of: halogen, hydroxy, 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 hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups; when the substituents are plural, the R ^g The same or different.

wherein,

ring A is a 5-10 membered aromatic or heteroaromatic ring;

b is selected from 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl;

R ^a and R is ^b Each independently selected from H, halogen, hydroxy, 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 Halogenated compoundsCycloalkyl, C _1-6 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, 3-10 membered heterocycloalkyl; the C is _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 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups are optionally substituted with one or more R ^c Substitution; the R is ^c A substituent selected from the group consisting of: halogen, hydroxy, 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 hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups; when the substituents are plural, the R ^c 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 Selected from H, C _1-10 Alkyl, C _2-6 Alkenyl group, the C _1-10 Alkyl, C _2-6 Alkenyl is optionally substituted with one or more R ^d Substitution; the R is ^d A substituent selected from the group consisting of: 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 bicyclo-C _5-8- Cycloalkyl; wherein the R is ^f Is hydrogen, C _1-6 An alkyl group; said het represents a 5-8 membered monocyclic or bicyclic, saturated or unsaturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms selected independently of each other from N, S, O;

q is selected from the following groups:

m is cyano;

R ⁴ selected from halogen, hydroxy, 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 Halogenated cycloalkyl, C _1-6 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, 3-10 membered heterocycloalkyl; the C is _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 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups are optionally substituted with one or more R ^g Substitution; the R is ^g A substituent selected from the group consisting of: halogen, hydroxy, 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 hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups; when the substituents are plural, the R ^g The same or different.

In a preferred embodiment of the invention, there is provided a compound of formula II, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof:

wherein,

ring A is a 5-10 membered aromatic or heteroaromatic ring;

b is selected from 3-10 membered heterocycloalkyl;

m and n are 0, 1, 2 or 3 respectively;

y is selected from NR ¹ O, S or CHR ¹ ；

q is selected from the following groups:

m is cyano;

R ² and R is ³ To, R ⁵ And R is ⁶ Each of the pairs may independently form a saturated or partially saturated 3-, 4-, 5-, 6-membered monocyclic ring with the carbon atoms to which they are attached; wherein the 3-, 4-, 5-, 6-, or 6-membered monocyclic ring contains 0, 1, 2, or 3N atoms and 0, 1, or 2 atoms selected from O and S, and further wherein the 3-, 4-, 5-, 6-, or 6-membered monocyclic ring is taken by 0, 1, 2, or 3 groups selected from And (3) substitution: halogen, hydroxy, 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 hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -COO-C _1-6 Alkyl, -C (O) NR ^f R ^f The method comprises the steps of carrying out a first treatment on the surface of the Wherein the R is ^f Is hydrogen, C _1-6 An alkyl group;

R ⁴ selected from halogen, hydroxy, 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 Halogenated cycloalkyl, C _1-6 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, 3-10 membered heterocycloalkyl; the C is _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 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups are optionally substituted with one or more R ^g Substitution; the R is ^g A substituent selected from the group consisting of: halogen, hydroxy, 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 hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups; when the substituents are plural, the R ^g The same or different.

wherein,

ring A is a 5-10 membered aromatic or heteroaromatic ring;

b is selected from 3-10 membered heterocyclenyl;

m and n are 0, 1, 2 or 3 respectively;

y is selected from NR ¹ O, S or CHR ¹ ；

q is selected from the following groups:

m is cyano;

R ² and R is ³ To, R ⁵ And R is ⁶ Each of the pairs may independently form a saturated or partially saturated 3-, 4-, 5-, 6-membered monocyclic ring with the carbon atoms to which they are attached; wherein the 3-, 4-, 5-, 6-, membered monocyclic ring contains 0, 1, 2 or 3N atoms and 0, 1 or 2 atoms selected from O and S, and further wherein the 3-, 4-, 5-, 6-, membered monocyclic ring is substituted with 0, 1, 2 or 3 groups selected from: halogen, hydroxy, 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 hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -COO-C _1-6 Alkyl, -C (O) NR ^f R ^f The method comprises the steps of carrying out a first treatment on the surface of the Wherein said at least one ofThe R is ^f Is hydrogen, C _1-6 An alkyl group;

In a preferred embodiment of the invention, it is a compound of formula II-A or formula II-B or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of a compound of formula II-A or formula II-B,

in the present invention, the definition of certain substituents in the compounds of formula I, II-A or II-B may be as follows, and the definitions of the substituents not mentioned are as described in any of the schemes above.

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

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

In a preferred embodiment of the invention, the heteroatom is selected from N or O.

In a preferred embodiment of the 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, pyrimidine ring, pyrazine ring, pyridazine ring or benzoxazolyl group.

In a preferred embodiment of the invention, the ring A is selected from

In a preferred embodiment of the invention, the building blocksSelected from->

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

In a preferred embodiment of the present invention, the R ^a Is F, cl, CH ₃ Or CH substituted by halogen ₃ 。

In a preferred embodiment of the present invention, the R ^a F, cl or CHF ₂ 。

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

In a preferred embodiment of the invention, said Y is selected from NR ¹ Or CHR (CHR) ¹ When R is ¹ Selected from H or C _1-6 An alkyl group.

In a preferred embodiment of the invention, said Y is selected from the group consisting of-NH-.

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

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

in a preferred embodiment of the invention, Q is selected from the following groups:

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

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

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

In a preferred embodiment of the invention, the 3-10 membered heterocycloalkyl is monocyclic, fused bicyclic, bicyclic including bridged or spiro bicyclic.

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

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

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

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

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

In a preferred embodiment of the invention, said B is selected from the group consisting of:/> Z ¹ 、Z ² 、Z ³ 、Z ⁴ 、Z ⁵ 、Z ⁶ 、Z ⁷ 、Z ⁸ and Z ⁹ Each independently is N, NH, CH ₂ 、CH、C、-NH-CH ₂ -or-CH ₂ -CH ₂ -。

In a preferred embodiment of the invention, said B is selected from the group consisting of: Z ¹ 、Z ² 、Z ³ 、Z ⁴ 、Z ⁵ 、Z ⁶ 、Z ⁷ and Z ⁸ Each independently represents a ring atom; z is Z ¹ 、Z ² 、Z ³ 、Z ⁴ 、Z ⁵ 、Z ⁶ 、Z ⁷ And Z ⁸ Each independently is 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 invention, when p is 0,is->

In a preferred embodiment of the invention, said B is selected from the group consisting of: Z ¹ 、Z ² 、Z ³ 、Z ⁴ 、Z ⁵ 、Z ⁶ 、Z ⁷ And Z ⁸ Each independently represents a ring atom; z is Z ¹ 、Z ² 、Z ³ 、Z ⁴ 、Z ⁵ 、Z ⁶ 、Z ⁷ And Z ⁸ Each independently is N or C; p is 0, 1 or 2.

In a preferred embodiment of the present invention,is->

In a preferred embodiment of the invention, said B is selected from the group consisting of: Z ¹ 、Z ² 、Z ³ 、Z ⁴ 、Z ⁵ and Z ⁶ Each independently represents a ring atom; z is Z ¹ 、Z ² 、Z ³ 、Z ⁴ 、Z ⁵ And Z ⁶ Each independently is N, NH, CH ₂ CH or C.

In a preferred embodiment of the invention, said B is selected from the group consisting of: Z ¹ 、Z ² 、Z ³ 、Z ⁴ 、Z ⁵ and Z ⁶ Each independently represents a ring atom; z is Z ¹ 、Z ² 、Z ³ 、Z ⁴ 、Z ⁵ And Z ⁶ Each independently is N or C.

In a preferred embodiment of the present invention,is->

In a preferred embodiment of the present invention,is->/>

In a preferred embodiment of the present invention, the R ^b Selected from C _1-6 Alkyl, halogen, C _3-8 Cycloalkyl or oxo.

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

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

In a preferred embodiment of the present invention, the R ^c Selected from halogen, oxo, C _1-6 Alkyl or C _1-6 A haloalkyl group.

In a preferred embodiment of the present invention, the R ^g Selected from 0, 1, 2 or 3.

In a preferred embodiment of the present invention, the R ^g Selected from halogen, hydroxy, cyano, C _1-6 Alkyl or C _1-6 A haloalkyl group.

As will be appreciated by those skilled in the art, in accordance with the conventions used in the art, in the structural formulae of the present application,for depicting chemical bonds, which are points where a moiety or substituent is attached to a core structure or a backbone structure.

In a preferred embodiment of the invention, the fragmentsSelected from the group consisting of

In a preferred embodiment of the invention, the fragmentsSelected from the group consisting of/>

In a preferred embodiment of the invention, the fragmentsSelected from the group consisting of />

In a preferred embodiment of the present invention, the R ¹ Selected from H, C _1-6 An alkyl group.

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

In a preferred embodiment of the invention, said Q is selected from the group consisting of: r is 0, 1, 2 or 3; m, R ⁴ And R is ⁷ Is as defined in the first aspect of the invention.

In a preferred embodiment of the invention, said Q is selected from the group consisting of:R ⁴ and R is ⁷ Is as defined in the first aspect of the invention.

In a preferred embodiment of the invention, said Q is selected from the group consisting of:R ⁴ is as defined in the first aspect of the invention.

In a preferred embodiment of the invention, R ⁷ Selected from 1, 2 or 3.

In a preferred embodiment of the present invention, the R ²³ Selected from F.

In a preferred embodiment of the present invention, the R ⁷ Selected from H, hydroxy, cyano or CH ₃ 。

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

In a preferred embodiment of the invention, said Q is selected from the group consisting of:

in a preferred embodiment of the invention, said Q is selected from the group consisting of: in a preferred embodiment of the invention, the compound has the following structure:

/>

wherein B' is selected fromZ ¹ 、Z ⁴ Each independently selected from N or CH, and Z ¹ 、Z ⁴ At least 1 is N;

the Z is ¹ And (3) withConnected with the Z ⁴ Is connected with the ring A;

R ^b selected from halogen, hydroxy, 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 Halogenated cycloalkyl, C _1-6 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, 3-10 membered heterocycloalkyl; the C is _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 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups optionally being substituted with oneOr a plurality of R ^c Substitution; the R is ^c A substituent selected from the group consisting of: halogen, hydroxy, 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 hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups; when the substituent R ^c When there are a plurality of R ^c The same or different;

m, n are each independently 0,1,2 or 3;

when B' is selected fromZ ₁ Is N, Z ₄ In the case of CH, Q is not +.>n is 0,1,2,3; or Q isWhen n is 1,2,3; r is R ⁴ Is as defined in the first aspect of the invention.

In a preferred embodiment of the invention, the compound is selected from the following structures:wherein Y, Q, ring A, B, R ^a And R is ^b As defined herein; m and n are defined in the invention.

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

In a preferred embodiment of the invention, the compound is selected from the following structures:

wherein,

R ^b selected from halogen, hydroxy, 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 Halogenated cycloalkyl, C _1-6 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, 3-10 membered heterocycloalkyl; the C is _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 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups are optionally substituted with one or more R ^c Substitution; the R is ^c A substituent selected from the group consisting of: halogen, hydroxy, 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 hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups; when the substituent R ^c When there are a plurality of R ^c The same or different;

m is 0, 1, 2 or 3;

n is 1, 2 or 3 respectively;

Z ¹ 、Z ⁴ each independently selected from N, CH or C;

y, Q, ring A and R ^a Is as defined in the first aspect of the invention.

In a preferred embodiment of the invention, the compound is selected from the following structures:wherein the ring A, B, R ^a And R is ^b Is as defined in the first aspect of the invention; m, n are as defined in the first aspect of the invention.

In a preferred embodiment of the invention, the compound is selected from the following structures:wherein the ring A, B, R ²³ 、R ^a And R is ^b Is as defined in the first aspect of the invention; r, m, n are as defined in the first aspect of the invention.

In a preferred embodiment of the invention, the compound is selected from the following structures: Wherein the ring A, B, R ^a And R is ^b As defined herein; m and n are defined in the invention.

In a preferred embodiment of the invention, the compound is selected from the following structures: wherein the ring A, B,R ^a And R is ^b As defined herein; m and n are defined in the invention.

In a preferred embodiment of the invention, the compound is selected from the following structures: wherein the ring A, B, R ^a And R is ^b As described in the first aspect of the invention; m, n are as described in the first aspect of the invention.

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

In a preferred embodiment of the invention, the compound is selected from the following structures: wherein the ring A, B, R ^a And R is ^b As defined herein; m and n are defined in the invention. />

In a preferred embodiment of the invention, the compound is selected from the following structures: wherein the ring A, B, R ²³ 、R ^a And R is ^b Is as defined in the first aspect of the invention; r, m, n are as defined in the first aspect of the invention.

In a preferred embodiment of the invention, the compound is selected from the following structures:wherein B is a 4-to 9-membered heterocycloalkyl having 1 to 3 heteroatoms selected from N, O, S; the 4-9 membered heterocycloalkyl is monocyclic, fused bicyclic, bicyclic including bridged or spiro; r is R ^b Selected from halogen, hydroxy, 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 hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups; n is 0, 1, 2 or 3.

In a preferred embodiment of the invention, the compound is selected from the following structures:wherein B is a compound having 1 to 3 options6-8 membered heterocycloalkyl from a heteroatom of N, O, S; the 6-8 membered heterocycloalkyl is monocyclic, fused bicyclic, bicyclic including bridged or spiro; r is R ^b Selected from halogen, hydroxy, 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 hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups; n is 0, 1, 2 or 3.

In a preferred embodiment of the invention, the compound is selected from the following structures:wherein B is a 6-8 membered heterocycloalkyl having 1 to 3 heteroatoms selected from N, O, S; the 6-8 membered heterocycloalkyl is monocyclic, fused bicyclic, bicyclic including bridged or spiro; r is R ^b Selected from halogen, hydroxy, 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 hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups; n is 0, 1, 2 or 3.

In the present inventionIn a preferred embodiment, the compound is selected from the following structures:wherein B is a 4-to 9-membered heterocycloalkyl having 1 to 3 heteroatoms selected from N, O, S; the 4-9 membered heterocycloalkyl is monocyclic, fused bicyclic, bicyclic including bridged or spiro; r is R ^b Selected from halogen, hydroxy, 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 hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups; n is 0, 1, 2 or 3.

In a preferred embodiment of the invention, the compound is selected from the following structures: Wherein B is a 4-to 9-membered heterocycloalkyl having 1 to 3 heteroatoms selected from N, O, S; the 4-9 membered heterocycloalkyl is monocyclic, fused bicyclic, bicyclic including bridged or spiro; r is R ^b Selected from halogen, hydroxy, 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 hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups; n is 0, 1, 2 or 3.

In a preferred embodiment of the invention, the compound is selected from the following structures:wherein B is a 6-8 membered heterocycloalkyl having 1 to 3 heteroatoms selected from N, O, S; the 6-8 membered heterocycloalkyl is a singleCyclic, fused bicyclic, bicyclic including bridged or spiro bicyclic; r is R ^b Selected from halogen, hydroxy, 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 hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups; n is 0, 1, 2 or 3.

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

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

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

In a preferred embodiment of the inventionWherein the compound is selected from the following structures:wherein Z is ¹ Each independently N, CH or C; ring A, R ^a And R is ^b Is as defined in the first aspect of the invention; m, n are as defined in the first aspect of the invention. / >

In a preferred embodiment of the invention, the compound is selected from the following structures:wherein Z is ¹ And Z ⁴ Each independently N, CH or C; ring A, R ^a Is as defined in the first aspect of the invention; m is as defined in the first aspect of the invention.

In a preferred embodiment of the invention, the compound is selected from the following structures:wherein Z is ¹ And Z ⁴ Each independently is N, CH or C ring a; r is R ^a Is as defined in the first aspect of the invention; m is as defined in the first aspect of the invention.

In a preferred embodiment of the invention, the compound is selected from the following structures:wherein Z is ¹ And Z ⁴ Each independently N, CH or C; ring A, R ^a Is as defined in the first aspect of the invention; m is defined as the first aspect of the inventionAs described in the above.

In a preferred embodiment of the invention, the compound is selected from the following structures:wherein Z is ¹ And Z ⁴ Each independently N, CH or C; ring A、R ^a Is as defined in the first aspect of the invention; m is as defined in the first aspect of the invention.

In a preferred embodiment of the invention, the compound is selected from the following structures: Wherein Z is ¹ And Z ⁴ Each independently N, CH or C; ring A, R ^a And R is ^b Is as defined in the first aspect of the invention; m, n are as defined in the first aspect of the invention.

At the bookIn a preferred embodiment of the invention, the compound is selected from the following structures: Wherein Z is ¹ And Z ⁴ Each independently N, CH or C; ring A, R ^a Is as defined in the first aspect of the invention; m is as defined in the first aspect of the invention.

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

In a preferred embodiment of the invention, the compound is selected from the following structures:wherein Z is ¹ Each independently N, CH or C; ring A, R ^a And R is ^b Is as defined in the first aspect of the invention; m, nThe definition is as described in the first aspect of the invention.

In a preferred embodiment of the invention, the compound is selected from the following structures:wherein Z is ¹ Each independently N, CH or C; ring A, R ^a Is as defined in the first aspect of the invention; m is as defined in the first aspect of the invention.

In a preferred embodiment of the invention, the compound is selected from the following structures:wherein Z is ¹ And Z ⁴ Each independently N, CH or C; r is R ^b Selected from H, halogen, hydroxy, 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 Halogenated cycloalkyl, C _1-6 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, 3-10 membered heterocycloalkyl; the C is _1-6 Alkyl, C ₃ -C ₈ Cycloalkyl, C _1-6 Deuterated alkyl, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _3-8 Halogenated cycloalkyl, C _1-6 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups are optionally substituted with one or more R ^c Substitution; the R is ^c A substituent selected from the group consisting of: halogen, hydroxy, amino, nitroCyano, carbonyl, oxo, carboxyl, C _1-6 Alkyl, C _1-6 Deuterated alkyl, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _1-6 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups; when the substituents are plural, the R ^c The same or different; n is 0, 1, 2 or 3.

In a preferred embodiment of the invention, the compound is selected from the following structures:wherein Z is ¹ And Z ⁴ Each independently is N or C; r is R ^b Selected from H, halogen, hydroxy, 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 Halogenated cycloalkyl, C _1-6 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, 3-10 membered heterocycloalkyl; the C is _1-6 Alkyl, C ₃ -C ₈ Cycloalkyl, C _1-6 Deuterated alkyl, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _3-8 Halogenated cycloalkyl, C _1-6 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups are optionally substituted with one or more R ^c Substitution; the R is ^c A substituent selected from the group consisting of: halogen, hydroxy, 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 hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups; when the substituents are plural, the R ^c The same or different; n is 0, 1, 2 or 3.

In a preferred embodiment of the invention, the compound is selected from the following structures:wherein Z is ¹ And Z ⁴ Each independently N, CH or C; r is R ^b Selected from H, halogen, hydroxy, 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 Halogenated cycloalkyl, C _1-6 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, 3-10 membered heterocycloalkyl; the C is _1-6 Alkyl, C ₃ -C ₈ Cycloalkyl, C _1-6 Deuterated alkyl, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _3-8 Halogenated cycloalkyl, C _1-6 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups are optionally substituted with one or more R ^c Substitution; the R is ^c A substituent selected from the group consisting of: halogen, hydroxy, 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 hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups; when the substituents are plural, the R ^c The same or different; n is 0, 1, 2 or 3.

In a preferred embodiment of the invention, the compound is selected from the following structures:wherein Z is ¹ N, CH or C; r is R ^b Selected from H, halogen, hydroxy, 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 Halogenated cycloalkyl, C _1-6 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, 3-10 membered heterocycloalkyl; the C is _1-6 Alkyl, C ₃ -C ₈ Cycloalkyl, C _1-6 Deuterated alkyl, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _3-8 Halogenated cycloalkyl, C _1-6 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups are optionally substituted with one or more R ^c Substitution; the R is ^c A substituent selected from the group consisting of: halogen, hydroxy, 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 hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups; when the substituents are plural, the R ^c The same or different; n is 0, 1, 2 or 3.

In a preferred embodiment of the invention, the compound is selected from the following structures:wherein Z is ¹ Is N or C; r is R ^b Selected from H, halogen, hydroxy, 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 Halogenated cycloalkyl, C _1-6 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, 3-10 membered heterocycloalkyl; the C is _1-6 Alkyl, C ₃ -C ₈ Cycloalkyl, C _1-6 Deuterated alkyl, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _3-8 Halogenated cycloalkyl, C _1-6 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups are optionally substituted with one or more R ^c Substitution; the R is ^c A substituent selected from the group consisting of: halogen, hydroxy, 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 hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups; when the substituents are plural, the R ^c The same or different; n is 0, 1, 2 or 3.

In a preferred embodiment of the invention, the compound is selected from the following structures:wherein Z is ¹ N, CH or C;R ^b selected from H, halogen, hydroxy, 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 Halogenated cycloalkyl, C _1-6 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, 3-10 membered heterocycloalkyl; the C is _1-6 Alkyl, C ₃ -C ₈ Cycloalkyl, C _1-6 Deuterated alkyl, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _3-8 Halogenated cycloalkyl, C _1-6 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups are optionally substituted with one or more R ^c Substitution; the R is ^c A substituent selected from the group consisting of: halogen, hydroxy, 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 hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups; when the substituents are plural, the R ^c The same or different; n is 0, 1, 2 or 3.

In a preferred embodiment of the invention, the compound is selected from the following structures:wherein Z is ¹ And Z ⁴ Each independently N, CH or C; r is R ^b Selected from H, halogen, hydroxy, amino, nitro, cyano, carbonyl, oxygenSubstituted, 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 Halogenated cycloalkyl, C _1-6 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, 3-10 membered heterocycloalkyl; the C is _1-6 Alkyl, C ₃ -C ₈ Cycloalkyl, C _1-6 Deuterated alkyl, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _3-8 Halogenated cycloalkyl, C _1-6 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups are optionally substituted with one or more R ^c Substitution; the R is ^c A substituent selected from the group consisting of: halogen, hydroxy, 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 hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups; when the substituents are plural, the R ^c The same or different; n is 0, 1, 2 or 3.

In a preferred embodiment of the invention, the compound is selected from the following structures:wherein Z is ¹ And Z ⁴ Each independently is N or C; r is R ^b Selected from H, halogen, hydroxy, 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 Halogenated cycloalkyl, C _1-6 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, 3-10 membered heterocycloalkyl; the C is _1-6 Alkyl, C ₃ -C ₈ Cycloalkyl, C _1-6 Deuterated alkyl, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _3-8 Halogenated ringAlkyl, C _1-6 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups are optionally substituted with one or more R ^c Substitution; the R is ^c A substituent selected from the group consisting of: halogen, hydroxy, 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 hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups; when the substituents are plural, the R ^c The same or different; n is 0, 1, 2 or 3.

In a preferred embodiment of the invention, the compound is selected from the following structures:wherein Z is ¹ N, CH or C; r is R ^b Selected from H, halogen, hydroxy, 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 Halogenated cycloalkyl, C _1-6 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, 3-10 membered heterocycloalkyl; the C is _1-6 Alkyl, C ₃ -C ₈ Cycloalkyl, C _1-6 Deuterated alkyl, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _3-8 Halogenated cycloalkyl, C _1-6 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups are optionally substituted with one or more R ^c Substitution; the R is ^c A substituent selected from the group consisting of: halogen, hydroxy, 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 hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups; when the substituents are plural, theR ^c The same or different; n is 0, 1, 2 or 3.

In a preferred embodiment of the invention, the compound is selected from the following structures:wherein Z is ¹ Is N or C; r is R ^b Selected from H, halogen, hydroxy, 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 Halogenated cycloalkyl, C _1-6 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, 3-10 membered heterocycloalkyl; the C is _1-6 Alkyl, C ₃ -C ₈ Cycloalkyl, C _1-6 Deuterated alkyl, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _3-8 Halogenated cycloalkyl, C _1-6 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups are optionally substituted with one or more R ^c Substitution;the R is ^c A substituent selected from the group consisting of: halogen, hydroxy, 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 hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups; when the substituents are plural, the R ^c The same or different; n is 0, 1, 2 or 3.

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

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

In a preferred embodiment of the inventionIn an embodiment, the compound is selected from the following structures:wherein Z is ¹ And Z ⁴ Each independently is N or C.

In a preferred embodiment of the invention, the compound is selected from the following structures: Wherein Z is ¹ And Z ⁴ Each independently is N or C.

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

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

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

In a preferred embodiment of the invention, the compound is selected from the following structures:wherein Z is ¹ 、Z ⁴ N, CH or C, respectively; r is R ^b Is as defined in the first aspect of the invention; n is nThe definition is as described in the first aspect of the invention.

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

In a preferred embodiment of the invention, the compound is selected from the following structures:wherein Z is ¹ 、Z ⁴ N, CH or C, respectively.

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

In a preferred embodiment of the invention, the compound is selected from the following structures:wherein Z is ¹ 、Z ⁴ N, CH or C, respectively; r is R ^b Is as defined in the first aspect of the invention; n is as defined in the first aspect of the invention.

In a preferred embodiment of the invention, the compounds are selected from the group consisting ofThe following structure:wherein Z is ¹ And Z ⁴ Each independently N, CH or C.

In a preferred embodiment of the invention, the compound is selected from the following structures: Wherein Z is ¹ And Z ⁴ Each independently N, CH or C.

In a preferred embodiment of the invention, theThe compound is selected from the following structures:wherein Z is ¹ Is N or C; r is R ^b Selected from H, halogen, hydroxy, 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 Halogenated cycloalkyl, C _1-6 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, 3-10 membered heterocycloalkyl; the C is _1-6 Alkyl, C ₃ -C ₈ Cycloalkyl, C _1-6 Deuterated alkyl, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _3-8 Halogenated cycloalkyl, C _1-6 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups are optionally substituted with one or more R ^c Substitution; the R is ^c A substituent selected from the group consisting of: halogen, hydroxy, 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 hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups; when the substituents are plural, the R ^c The same or different; n is 0, 1, 2 or 3.

In a preferred embodiment of the invention, the compound is selected from the following structures:wherein Z is ⁴ N, CH or C; r is R ^b Selected from H, halogen, hydroxy, 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 Halogenated cycloalkyl, C _1-6 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, 3-10 membered heterocycloalkyl; the C is _1-6 Alkyl, C ₃ -C ₈ Cycloalkyl, C _1-6 Deuterated alkyl, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _3-8 Halogenated cycloalkyl, C _1-6 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups are optionally substituted with one or more R ^c Substitution; the R is ^c A substituent selected from the group consisting of: halogen, hydroxy, 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 hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups; when the substituents are plural, the R ^c The same or different; n is 0, 1, 2 or 3.

In a preferred embodiment of the invention, the compound is selected from the following structures:wherein Z is ⁴ Is N or C; r is R ^b Selected from H, halogen, hydroxy, 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 Halogenated cycloalkyl, C _1-6 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, 3-10 membered heterocycloalkyl; the C is _1-6 Alkyl, C ₃ -C ₈ Cycloalkyl, C _1-6 Deuterated alkyl, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _3-8 Halogenated cycloalkyl, C _1-6 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups are optionally substituted with one or more R ^c Substitution; the R is ^c A substituent selected from the group consisting of: halogen, hydroxy, 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 hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups; when the substituents are plural, the R ^c The same or different; n is 0, 1, 2 or 3.

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

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

In a preferred embodiment of the invention, the compound is selected from the following structures:said fragment->Selected from the group consisting of/>

In a preferred embodiment of the invention, the compound is selected from the following structures:said fragment->Selected from the group consisting of

In a preferred embodiment of the invention, the building blocksSelected from->

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

/>

1)(representation)) Wherein chiral separation is performed by normal phase high performance liquid chromatography, the separation method is (column: DAICEL CHIRALPAK AD (250 mm. Times.30 mm,10 μm); solvent: a=carbon dioxide, b=aqueous ammonia (0.1%) + isopropanol; gradient (B): 40% -40%,4.7 min), the retention time is 0.835min;

2)(representation)) Wherein chiral separation is performed by normal phase high performance liquid chromatography, the separation method is (column: DAICEL CHIRALPAK AD (250 mm. Times.30 mm,10 μm); solvent: a=carbon dioxide, b=aqueous ammonia (0.1%) + isopropanol; gradient (B): 40% -40%,4.7 min), the retention time is 1.084min;

3)(representation->) Wherein chiral separation is performed by normal phase high performance liquid chromatography, the separation method is (column: DAICEL CHIRALPAK AD (250 mm. Times.30 mm,10 μm); solvent: a=carbon dioxide, b=aqueous ammonia (0.1%) + ethanol; gradient: 50% -50%,7 min), retention time 1.387min;

4)(representation)) Wherein chiral separation is performed by normal phase high performance liquid chromatography, the separation method is (column: DAICEL CHIRALPAK AD (250 mm. Times.30 mm,10 μm); solvent: a=carbon dioxide, b=aqueous ammonia (0.1%) + ethanol; gradient: 50% -50%,7 min), retention time 1.572min;

5)(representation->) Wherein chiral separation is performed by normal phase high performance liquid chromatography, the separation method is (column: DAICEL CHIRALPAK AD (250 mm. Times.30 mm,10 μm); solvent: a=carbon dioxide, b=aqueous ammonia (0.1%) + ethanol; gradient: 50% -50%,7 min), retention time 1.657min;

6)(representation)) Wherein chiral separation is performed by normal phase high performance liquid chromatography, the separation method is (column: DAICELCHIRALPAK AD (250 mm. Times.30 mm,10 μm); solvent: a=carbon dioxide, b=aqueous ammonia (0.1%) + ethanol; gradient: 50% -50%,7 min), retention time 1.742min;

7)(representation->) Wherein chiral separation is performed by normal phase high performance liquid chromatography, the separation method is (column: DAICEL CHIRALPAK AD (250 mm. Times.30 mm,10 μm); solvent: a=carbon dioxide, b=aqueous ammonia (0.1%) + ethanol; gradient: 50% -50%,7 min), retention time 1.852min;

8)(representation)) Wherein chiral separation is performed by normal phase high performance liquid chromatography, the separation method is (column: DAICEL CHIRALPAK AD (250 mm. Times.30 mm,10 μm); solvent: a=carbon dioxide, b=aqueous ammonia (0.1%) + ethanol; gradient: 50% -50%,7 min), retention time 1.477min;

9)(representation->) Wherein chiral separation is performed by normal phase high performance liquid chromatography, the separation method is (column: DAICEL CHIRALPAK AD (250 mm. Times.30 mm,10 μm; solvent: A=carbon dioxide+acetonitrile, B=)Ammonia (0.1%) + isopropanol; gradient: 45% -45%,20 min), retention time 1.899min;

10)(representation)) Wherein chiral separation is performed by normal phase high performance liquid chromatography, the separation method is (column: DAICEL CHIRALPAK AD (250 mm. Times.30 mm,10 μm; solvent: A=carbon dioxide+acetonitrile, B=ammonia (0.1%) +isopropanol; gradient: 45% -45%,20 min), retention time 1.586min;

11)(representation->) Wherein chiral separation is performed by normal phase high performance liquid chromatography, the separation method is (column: DAICEL CHIRALPAK IG (250 mm. Times.30 mm,10 μm); the method comprises the steps of carrying out a first treatment on the surface of the Solvent: a=carbon dioxide, b=aqueous ammonia (0.1%) + ethanol; gradient: 50% -50%,20 min), retention time 1.507min;

12)(representation)) Wherein chiral separation is performed by normal phase high performance liquid chromatography, the separation method is (column: DAICEL CHIRALPAK IG (250 mm. Times.30 mm,10 μm); the method comprises the steps of carrying out a first treatment on the surface of the Solvent: a=carbon dioxide, b=aqueous ammonia (0.1%) + ethanol; gradient: 50% -50%,20 min), retention time 1.964min;

13)(representation->) Wherein chiral separation is performed by normal phase high performance liquid chromatography, the separation method is (column: DAICEL CHIRALPAK IG (250 mm. Times.30 mm,10 μm); the method comprises the steps of carrying out a first treatment on the surface of the Solvent: a=carbon dioxide, b=aqueous ammonia (0.1%) + ethanol; gradient: 50% -50%,20 min), retention time 1.507min; or (b)

14)(representation)) Wherein chiral separation is performed by normal phase high performance liquid chromatography, the separation method is (column: DAICEL CHIRALPAK IG (250 mm. Times.30 mm,10 μm); the method comprises the steps of carrying out a first treatment on the surface of the Solvent: a=carbon dioxide, b=aqueous ammonia (0.1%) + ethanol; gradient: 50% -50%,20 min), retention time 1.625min.

In a second aspect of the present invention, there is provided a pharmaceutical composition comprising: a compound as described in the first aspect of the invention, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof.

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

In a second aspect of the present invention, there is provided a pharmaceutical composition comprising: a compound of formula I as described in the first aspect of the invention, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof; and a pharmaceutically acceptable carrier.

In a third aspect of the invention there is provided the use of a compound according to the first aspect of the invention, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition according to the second aspect, for the inhibition of PDE 4B.

In a fourth aspect of the invention there is provided the use of a compound according to the first aspect of the invention, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition according to the second aspect, in the manufacture of a medicament or formulation for inhibiting PDE4B, and/or for the prophylaxis and/or treatment of a PDE 4B-related disease.

In a fifth aspect of the present invention there is provided the use of a compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, as described in the first aspect of the invention, or the use of a pharmaceutical composition according to the second aspect of the invention, the use comprising: inhibition of PDE4B; and/or, preventing and/or treating PDE 4B-related diseases; and/or preparing a medicament, pharmaceutical composition or formulation for inhibiting PDE4B, and/or preventing and/or treating PDE 4B-related diseases.

Preferably, the PDE 4B-related disease comprises: respiratory diseases, gastrointestinal diseases, inflammatory diseases of the 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 xerosis), graft rejection, and diseases associated with smooth muscle contractility.

Preferably, the respiratory disease is selected from respiratory or pulmonary diseases accompanied by increased mucus production, respiratory inflammation and/or obstructive diseases.

Preferably, the respiratory disease is selected from COPD, idiopathic pulmonary fibrosis, alpha 1-antitrypsin deficiency, chronic sinusitis, asthma, and chronic bronchitis.

Preferably, the gastrointestinal disease is selected from Crohn's disease, ulcerative colitis or Crohn's disease.

Preferably, the inflammatory disease of the joint, skin or eye is selected from 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 parenchymal cancer, ovarian cancer, cervical cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, bladder cancer, testicular cancer, breast cancer, urinary carcinoma, melanoma, brain tumor, lymphoma, head and neck cancer, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, acute myeloid leukemia, chronic granulocytic leukemia, hepatocellular carcinoma, gall bladder cancer, bronchogenic carcinoma, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal sarcoma, teratoma, retinoblastoma, choriocarcinoma, seminoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, myoma, liposarcoma, fibrosarcoma, ewing sarcoma, and plasmacytoma.

Preferably, the peripheral or central nervous system disorder 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.

In a sixth aspect of the invention there is provided a method of inhibiting PDE4B, or preventing and/or treating a PDE 4B-related disease, comprising the steps of: administering to a subject in need thereof a compound of formula II, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to the first aspect of the invention.

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.

Terminology and definitions

Unless otherwise indicated, the radical and term definitions recited in the specification and claims of this application, including as examples, exemplary definitions, preferred definitions, definitions recited in tables, definitions of specific compounds in the examples, and the like, may be arbitrarily combined and coupled with each other. Such combinations and combined group definitions and structures of compounds should fall within the scope of the description herein.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety unless otherwise indicated. If there are multiple definitions of terms herein, the definitions of this chapter shall control.

The articles "a," "an," and "the" are intended to include "at least one" or "one or more" unless the context clearly dictates otherwise or otherwise. Thus, as used herein, these articles refer to one or to more than one (i.e., to at least one) object. For example, "a component" refers to one or more components, i.e., more than one component is contemplated as being employed or used in embodiments of the described embodiments.

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the inventive subject matter. In this application, the singular is used to include the plural unless specifically stated otherwise. It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the use of "or" means "and/or" unless stated otherwise. Furthermore, the terms "include," as well as other forms, such as "comprising," "including," and "containing," are not limiting.

The definition of standard chemical terms can be found in references (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4 speed." vols. A (2000) and B (2001), plenum Press, new York). Conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV/VIS spectroscopy, and pharmacological methods are employed unless otherwise indicated. Unless specifically defined otherwise, the terms used herein in the description of analytical chemistry, organic synthetic chemistry, and pharmaceutical chemistry are known in the art. Standard techniques may be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, the reaction and purification can be carried out using the manufacturer's instructions for the kit, or in a manner well known in the art or in accordance with the teachings of the present invention. The techniques and methods described above may generally be practiced according to conventional methods well known in the art, based on a number of general and more specific descriptions in the literature cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by one skilled in the art to provide stable moieties and compounds.

In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a specific substituent. Unless otherwise indicated, a substituted group may have a substituent substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, then the substituents may be the same or different substituted at each substitutable position.

The term "unsubstituted" means that the specified group does not carry a substituent.

The compounds of the invention may be optionally substituted with one or more substituents, as described herein, for example, for compounds of the general formula above, or as specific examples within the examples, subclasses, and classes of compounds encompassed by the invention. It is to be understood that the term "optionally substituted" may be used interchangeably with the term "substituted or unsubstituted". In general, the term "optionally" whether or not preceding the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a particular substituent. An optional substituent group may have a substituent substituted at each substitutable position of the group unless otherwise indicated. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, then the substituents may be the same or different at each position.

In addition, unless explicitly indicated otherwise, the descriptions used in this disclosure of the manner in which each … is independently "and" … is independently "and" … is independently "are to be construed broadly as meaning that particular items expressed between the same symbols in different groups do not affect each other, or that particular items expressed between the same symbols in the same groups do not affect each other.

When substituents are described by conventional formulas written from left to right, the substituents also include chemically equivalent substituents obtained when writing formulas from right to left. For example, CH ₂ O is equal to OCH ₂ . As used herein, representing the attachment site of the group. As used herein, "R ₁ "," R1 "and" R ¹ "has the same meaning and can be replaced with each other. For R ₂ And the like, and the meanings of like definitions are the same.

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

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

Where a range of values recited in the specification and claims is understood to be an "integer," it is understood that both endpoints of the range and each integer within the range are recited. For example, an "integer of 1 to 6" should be understood to describe each integer of 0, 1, 2, 3, 4, 5, and 6. When a numerical range is understood as a "number," it is understood that both endpoints of the range are noted, as well as each integer within the range, and each fraction within the range. For example, a "number of 1 to 10" should be understood to describe not only each integer of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, but also at least the sum of each integer with 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 substituents that are saturated, substituents that are fully unsaturated with hydrogen, and substituents that are partially saturated with hydrogen.

In the present application, the term "halogen" means fluorine, chlorine, bromine, iodine, alone or as part of other substituents; fluorine or chlorine is preferred.

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

As used herein, the term "amino" means-NH, alone or as part of another substituent ₂ 。

In this application, the term "hydroxy" means-OH, alone or as part of another substituent.

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

Unless otherwise indicated, with solid wedge bondsAnd wedge-shaped dotted bond->Representing the absolute configuration of a solid centre, using straight solid keys +.>And straight dotted bond->Representing the relative configuration of the stereogenic centers, for example:denoted as->One of the configurations of->Then another configuration is indicated as being left; />Denoted as->One of the configurations of->Then this is indicated as the remaining alternative configuration.

The term "alkyl" denotes a saturated straight or branched chain 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 may be independently and optionally substituted with one or more substituents described herein, including but not limited to deuterium, amino, hydroxyl, cyano, F, cl, br, I, mercapto, nitro, oxo (=o), and the like. 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 ) Sec-butyl (s-Bu, -CH (CH) ₃ )CH ₂ CH ₃ ) Tert-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 "alkane" are used herein to encompass both straight and branched saturated carbon chains.

The term "alkylene" when used alone or as part of another substituent is understood to mean a straight or branched chain saturated, unsaturated or partially saturated divalent hydrocarbon radical. For example "C _1-6 Alkylene "or" C _1- C ₆ Alkylene "means a straight or branched chain divalent hydrocarbon radical having 1 to 6 carbon atoms including, but not limited to, methylene, ethylene, propylene, 1-methylpropylene, butylene.

"benzo group", alone or in combination, means a divalent group C ₄ H ₄ =, wherein one representation is-ch=ch-, forming a benzene-like ring when ortho-attached to another ring, e.g. tetrahydronaphthalene, indole, etc.

The term "C", alone or as part of another substituent _α-β Haloalkyl "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 with fluorine, chlorine, bromine or iodine.

The term "cycloalkyl" alone or as part of another substituent means a cyclic alkyl group. The term "m-n membered cycloalkyl" or "C _m-n 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, which may contain 1 to 4 rings. "3-to 10-membered cycloalkyl" contains 3 to 10 carbon atoms. Including monocyclic, bicyclic, tricyclic, spiro, or bridged rings. Examples of unsubstituted cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl, or a bicyclic hydrocarbon group such as a decalin ring. Cycloalkyl groups may be substituted with one or more substituents. In some embodiments, cycloalkyl groups may be cycloalkyl groups fused to aryl or heteroaryl ring groups. The term "cycloalkyl" may be used interchangeably with the term "carbocyclyl".

The term "heterocycloalkyl" when used alone or as part of another substituent refers to cycloalkyl groups in which one or more (in some embodiments 1 to 3) carbon atoms are replaced with heteroatoms such as, but not limited to N, O, S and P. The term "m-n membered heterocycloalkyl" or "C _m-n 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 from N, O or S. For example, the term "4-8 membered heterocycloalkyl" or "C ₄ -C ₈ Heterocycloalkyl "is understood to mean a saturated, unsaturated or partially saturated ring having from 4 to 8 atoms, wherein 1, 2, 3 or 4 ring atoms are selected from N, O, S, P, preferably from N, O or S. "4-10 membered heterocyclyl" is intended to mean a saturated, unsaturated or partially saturated ring having 4 to 10 atoms. In some embodiments, the heterocycloalkyl group can be a heterocycloalkyl group fused with an aromatic or heteroaromatic ring group. When a prefix such as 4-8 or 4-10 membered is used to represent a heterocycloalkyl group, the number of carbons is also meant to include heteroatoms. Including monocyclic, bicyclic, tricyclic, spiro, or bridged rings. Examples of heterocycloalkyl groups are: pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridinyl, azetidinyl, thiazolidinyl, oxazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, diazepinyl, oxazepanyl, and the like. The term "heterocycloalkyl" may be used interchangeably with the term "heteroalkyl" ring.

The term "alkenyl", alone or as part of another substituent, refers to a straight or branched chain monovalent hydrocarbon radical of two to forty carbon atoms having at least one carbon-carbon sp2 double bond (e.g., C ₂ -C ₆ Alkenyl radicals, also e.g. C ₂ -C ₄ Alkenyl) and includes groups having "cis" and "trans" orientations or "E" and "Z" orientations. Examples of alkenyl groups include, but are not limited to, vinylAnd allyl.

The term "alkynyl", alone or as part of another substituent, refers to a straight or branched chain monovalent hydrocarbon radical of two to forty carbon atoms having at least one carbon-carbon sp triple bond (e.g., C ₂ -C ₆ Alkynyl radicals, also e.g. 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 means a group-O-R ^Q Wherein R is ^Q Is an "alkyl" group as defined above.

The term "oxo" when used alone or as part of another substituent means that the two hydrogens on the methylene group are replaced with oxygen, i.e., the methylene group is replaced with a carbonyl group, representing =o.

The term "thio" when used alone or as part of another substituent means that two hydrogens on the methylene group are replaced with sulfur, representing =s.

The term "aromatic ring" when used alone or as part of another substituent means a monocyclic or polycyclic carbocycle having 6 to 20 carbon atoms, wherein at least one ring is an aromatic ring. When one of the rings is a non-aromatic ring, the groups may be linked through an aromatic ring or through a non-aromatic ring. Examples of aryl groups include, but are not limited to: phenyl, naphthyl, tetrahydronaphthyl, 2, 3-indanyl, biphenyl, phenanthryl, anthracyl and acenaphthylenyl. The term "aromatic ring" may be used interchangeably with the term "aryl".

The term "heteroaryl ring", alone or as part of another substituent, 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, the remaining ring atoms being C, wherein at least one ring is an aromatic ring. The group may be a carbon group or a heteroatom group (i.e., it may be C-linked or N-linked, as long as it is possible). When one of the rings is a non-aromatic ring, the groups may be linked through an aromatic ring or through a non-aromatic ring. Examples of heteroaryl groups include, but are not limited to: imidazolyl, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazole, furanyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, N-methylpyrrolidinyl, and tetrahydroquinolinyl. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic", "heteroaryl" or "heteroaryl ring radical".

The term "bicyclic" refers to a group having two connecting rings, alone or as part of another substituent. A bicyclic ring may be a carbocycle (all ring atoms being carbon atoms) or a heterocycle (ring atoms include, in addition to carbon atoms, for example, 1, 2 or 3 heteroatoms, such as N, O or S). Both rings may be aliphatic (e.g., decalin and norbornane), or may be aromatic (e.g., naphthalene), or a combination of aliphatic and aromatic (e.g., tetrahydronaphthalene).

Bicyclic rings include (a) spiro compounds in which two rings share only one single atom (the spiro atom, which is typically a quaternary carbon). Examples of spiro compounds include, but are not limited to:

spirocycloalkyl groups also containing a spiro atom common to both the monocyclocycloalkyl and heterocycloalkyl groups, non-limiting examples include:

(b) Fused rings, i.e., fused bicyclic compounds in which two rings share two adjacent atoms. In other words, the rings share a covalent bond, i.e. the bridgehead atoms are directly linked (e.g. αthujaene and decalin). Examples of fused bicyclic rings include, but are not limited to:

and (c) a bridged bicyclic compound, wherein the two rings share three or more atoms and the two bridgehead atoms are separated by a bridge comprising at least one atom. For example, norbornane, also known as bicyclo [2.2.1] heptane, can be considered a pair of cyclopentane rings, each sharing three of their five carbon atoms. Examples of bridged bicyclic rings include, but are not limited to:

NR, alone or as part of other substituents ^f R ^f The groups may beIn the form of (C) or may also include two of R ^f The groups together form a ring, which optionally contains N, O or S atoms, and may also include groups such as: />

The radicals N (C _α-β Alkyl) C _α-β Alkyl (wherein alpha and beta are as defined above) includes two of these C' s _α-β The alkyl groups together form a substituent of a ring (optionally containing N, O or S atoms) and include, for example:

compounds provided herein, including intermediates useful in the preparation of compounds provided herein, contain reactive functional groups (such as, but not limited to, carboxyl, hydroxyl, and amino 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 referred to as protecting groups). Suitable protecting groups for the carboxyl moiety include benzyl, t-butyl, and the like, as well as isotopes and the like. Suitable amino and amido protecting groups include acetyl, trifluoroacetyl, t-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.

In this application, "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both substituted aryl groups and unsubstituted aryl groups.

In the present application, the term "salt" or "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. The term "pharmaceutically acceptable" is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

By "pharmaceutically acceptable acid addition salt" is meant a salt with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects. By "pharmaceutically acceptable base addition salt" is meant a salt formed with an inorganic or organic base that is capable of maintaining the bioavailability 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 of neutralizing an alkyl primary, secondary or tertiary amine with an acid. The acid includes inorganic or organic acids as described herein.

The term "stereoisomer" refers to an isomer produced by the spatial arrangement of atoms in a molecule, and includes cis-trans isomers, enantiomers, non-corresponding isomers and conformational isomers.

Depending on the choice of starting materials and methods, the compounds according to the invention may be present in the form of one of the possible isomers or mixtures thereof, for example as pure optical isomers or as isomer mixtures, for example as racemic and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. When describing optically active compounds, the prefix D and L or R and S are used to denote the absolute configuration of the molecule in terms of chiral center (or chiral centers) in the molecule. The prefixes D and L or (+) and (-) are symbols for designating the rotation of plane polarized light by a compound, where (-) or L represents that the compound is left-handed. The compound prefixed with (+) or D is dextrorotatory.

When the bonds to chiral carbons in the formulae of the present invention are depicted in straight lines, it is understood that both the (R) and (S) configurations of the chiral carbons and the enantiomerically pure compounds and mixtures thereof resulting therefrom are included within the general formula. The graphic representation of racemates or enantiomerically pure compounds herein is from Maehr, J.chem. Ed.1985, 62:114-120. The absolute configuration of a solid center is represented by wedge-shaped keys and dashed keys.

The term "tautomer" refers to a functional group isomer that results from the rapid movement of an atom in a molecule at two positions. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Proton-mobile tautomers result from the migration of a hydrogen atom covalently bonded between two atoms. Tautomers generally exist in equilibrium and attempts to isolate individual tautomers often result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The location of the equilibrium depends on the chemical nature of the molecule. For example, among many aliphatic aldehydes and ketones such as acetaldehyde, the ketone type predominates; whereas, among phenols, the enol form is dominant. The present invention encompasses all tautomeric forms of the compounds.

The term "solvate" refers to a compound of the invention or a salt thereof that includes a stoichiometric or non-stoichiometric solvent that binds with non-covalent intermolecular forces, and when the solvent is water, 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. Prodrugs of the invention are prepared by modifying functional groups in the compounds, which modifications may be removed by conventional procedures or in vivo to give the parent compound. Prodrugs include compounds wherein a hydroxyl group or amino group of a compound of the invention is attached to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl group, free amino group, respectively.

In this application, "pharmaceutical composition" refers to a formulation of a compound of the invention with a medium commonly accepted in the art for delivery of biologically active compounds to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote the administration of organisms, facilitate the absorption of active ingredients and further 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, dispersing agent, suspending agent, stabilizer, isotonizing agent, solvent, or emulsifying agent that is approved by the relevant government regulatory agency as acceptable for human or livestock use.

The term "adjuvant" refers to a pharmaceutically acceptable inert ingredient. Examples of the category of the term "excipient" include, without limitation, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients can enhance the handling characteristics of the pharmaceutical formulation, i.e., by increasing flowability and/or tackiness, making the formulation more suitable for direct compression.

The term "treatment" refers to therapeutic therapy. When specific conditions are involved, treatment refers to: (1) alleviating a disease or one or more biological manifestations of a disorder, (2) interfering with (a) one or more points in a biological cascade that results in or causes a disorder or (b) one or more biological manifestations of a disorder, (3) ameliorating one or more symptoms, effects, or side effects associated with a disorder, or one or more symptoms, effects, or side effects associated with a disorder or treatment thereof, or (4) slowing the progression of a disorder or one or more biological manifestations of a disorder.

The term "preventing" refers to a reduced risk of acquiring or developing a disease or disorder.

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

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 disorder described herein. The "therapeutically effective amount" will vary depending on the compound, the condition and severity thereof, and the age of the patient to be treated, and can be adjusted as desired by those skilled in the art.

The reaction temperature of each step may be appropriately selected depending on the solvent, starting material, reagent, etc., and the reaction time may be appropriately selected depending on the reaction temperature, solvent, starting material, reagent, etc. After the reaction of each step is finished, the target compound can be separated and purified from the reaction system according to a common method, such as filtration, extraction, recrystallization, washing, silica gel column chromatography and the like. Under the condition of not influencing the next reaction, the target compound can also directly enter the next reaction without separation and purification.

The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.

Advantageous effects

The present inventors have studied extensively and intensively, and have unexpectedly developed a compound or a pharmaceutically acceptable salt thereof, and a preparation method and use thereof. The invention provides a compound shown in a formula I and a formula II, or a tautomer, a stereoisomer, a hydrate, a solvate and pharmaceutically acceptable salt or prodrug thereof, wherein the compound shown in the formula I and the formula II has obvious inhibition effect on PDE4B, can be used as a selective inhibitor of PDE4B, and has higher safety and pharmaceutical properties; the compound has excellent inhibition activity of secreting TNFα by human PBMC, can better inhibit 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.

Detailed Description

The invention will be further illustrated with reference to specific examples. It is to be understood that the following description is only of the most preferred embodiments of the present invention and should not be taken as limiting the scope of the invention. Upon a complete understanding of the present invention, experimental methods without specific references in the following examples, generally according to conventional conditions or according to conditions suggested by the manufacturer, may make insubstantial changes to the technical solutions of the present invention, and such changes should be considered as included in the scope of the present invention.

The application has the following definitions:

symbol or unit:

IC ₅₀ : half inhibition concentration, meaning the concentration at which half of the maximum inhibition effect is achieved

M: mol/L, for example n-butyllithium (14.56 mL,29.1mmol,2.5M in n-hexane) means an n-hexane solution of n-butyllithium at a molar concentration of 2.5mol/L

N: equivalent concentration, e.g. 2N hydrochloric acid means 2mol/L hydrochloric acid solution

Reagent:

DCM: dichloromethane (dichloromethane)

DIPEA: n, N-diisopropylethylamine

DMF: n, N-dimethylformamide

TFA: trifluoroacetic acid

THF: tetrahydrofuran (THF)

S- (-) -BINOL: s-1,1' -bi-2-naphthol

Ti (OiPr) 4: titanium tetraisopropoxide

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

the first step: synthesis of (1-aminocyclobutyl) methanol (intermediate A1-2)

1 amino ring Ding Jiasuan (15 g,130.3 mmol) was dissolved in tetrahydrofuran (300 ml) at room temperature, and lithium aluminum hydride (2.5M tetrahydrofuran solution, 104mL,260 mmol) was added dropwise under argon at 0℃and with stirring. After the completion of the dropwise addition, the reaction solution was slowly warmed to room temperature and stirred under argon for 16 hours. The reaction was quenched with sodium sulfate decahydrate solid in ice bath, dried over anhydrous sodium sulfate, and filtered. The filter cake was rinsed with ethyl acetate. The combined filtrates were concentrated at room temperature to give (1-aminocyclobutyl) methanol (intermediate A1-2) (12 g, yield 90%).

And a second step of: synthesis of (1- ((2-chloro-6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl) amino) cyclobutyl) methanol (intermediate A1-4)

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 stirred at 75deg.C for 12h. 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 give (1- ((2-chloro-6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl) amino) cyclobutyl) methanol (intermediate A1-4) (3.5 g, yield 43%).

And a third step of: synthesis of (5R) -2-chloro-4- ((1- (hydroxymethyl) cyclobutyl) amino) -5-oxo-6, 7-dihydrothieno [3,2-d ] pyrimidine (intermediate A1)

Nitrogen at 21 °cUnder air, 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 the flask and stirred for 1h. Tert-butanol peroxide (70% in water, 1.5mL,11mmo 1) was added at 21℃and stirred at room temperature for 1.5h, the reaction mixture was concentrated, and purified by column chromatography on silica gel (dichloromethane: methanol (V/V) =10:1, gradient elution) to give (5R) -2-chloro-4- ((1- (hydroxymethyl) cyclobutyl) amino) -5-oxo-6, 7-dihydrothieno [3, 2-d)]Pyrimidine (intermediate A1) (2.5 g, 87% yield).

Preparation of intermediate A2:5-chloro-2- (piperazin-1-yl) pyrimidine

The synthetic route for intermediate A2 is as follows:

the first step: synthesis of tert-butyl 4- (5-chloropyrimidin-2-yl) piperazine-1-carboxylate (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 stirred at 80℃for 8h. The reaction mixture was diluted with water (50 mL), then extracted twice with ethyl acetate, 50mL each time, the organic layers were combined, the organic phases were washed with saturated brine (50 mL), dried over sodium sulfate, concentrated to give a crude product, which was purified by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =2:1-10:1, gradient elution) to give tert-butyl 4- (5-chloropyrimidin-2-yl) piperazine-1-carboxylate (intermediate A2-3) (0.5 g, yield 83%).

And a second step of: synthesis of 5-chloro-2- (piperazin-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 stirred at 75deg.C for 12h. 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 give 5-chloro-2- (piperazin-1-yl) pyrimidine (intermediate A2) (3.5 g, yield 43%). Preparation of intermediate A3 and intermediate A4 with reference to the synthetic route for intermediate A2

Preparation of intermediate A5:5-chloro-2- (piperidin-4-yl) pyrimidine

The synthetic route for intermediate A5 is as follows:

the first step: synthesis of piperidine-4-carboxamidine (intermediate A5-2)

1, 4-Dioxahexacyclic ring (45 ml,3eq,180mmo 1) in 4M HCl was added to the flask. The solution was cooled to 0 ℃ and 4-cyanopiperidine (6.6 g,60 mmol) was added over about 30 minutes followed by methanol (6 ml,180mmol,3 eq) while maintaining the temperature below 10 ℃ (exothermic reaction). The above mixture was stirred at room temperature for 6 to 8 hours, the mixture was cooled to 5℃and added to a methanol solution (32 g,100mmol,2 eq) containing 25wt% NaOMe while maintaining the temperature below 15℃and then the reaction solution was stirred for 1 hour. Aqueous ammonia (13 ml,1.5eq,90 mmol) of 7 n in methanol was added to the mixture and stirred at standard room temperature for 8 hours. The mixture was concentrated under reduced pressure to a volume of about 50ml to give a solution of crude intermediate A5-2, which was used without isolation.

And a second step of: synthesis of 5-chloro-2- (piperidin-4-yl) pyrimidine (intermediate A5)

The above solution of intermediate A5-2 was cooled to about 20℃and a methanol solution (33 g,150 mmol) containing 25wt% NaOMe was added. The compound was then stirred for 30 minutes. Compound D (= (Z) -N- (2-chloro-3- (dimethylamino) allylidene) -N-methyl-methane-hexafluorophosphate (17 g,51 mmol) was added to the above mixture in two portions over about 30 min at standard room temperature, and stirred at room temperature for 3 hours the mixture was concentrated under reduced pressure, the reaction mixture was diluted with water, then extracted with ethyl acetate, the organic layers were combined, the organic phase was washed with saturated brine, dried over sodium sulfate, concentrated to give crude product, and purified (dichloromethane: methanol (V/V) =20:1-10:1, gradient elution) was separated with a silica gel column to give tert-butyl 4- (5-chloropyrimidin-2-yl) piperazine-1-carboxylate (intermediate A5) (9 g, 75% yield).

Preparation of intermediate A6:6- (5-chloropyrimidin-2-yl) -3-azabicyclo [4.1.0] heptane

The synthetic route for intermediate A6 is as follows:

the first step: synthesis of tert-butyl 4- (5-chloropyrimidin-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate (intermediate A6-2)

Intermediate A6-1 (1.5 g,5 mmol), A2-2 (2.4 g,5 mmol), (dppf) ₂ PdCl ₂ (0.5mmol)、K ₂ CO ₃ (10 mmol) was added to 1, 4-dioxane (30 ml), reacted at 80℃for 8 hours, the reaction mixture was concentrated, and purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) =20:1-10:1, gradient elution) to give tert-butyl 4- (5-chloropyrimidin-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate (intermediate A6-2) (1.8 g, yield 60%).

And a second step of: synthesis of tert-butyl 6- (5-chloropyrimidin-2-yl) -3-azabicyclo [4.1.0] heptane-3-carboxylate (intermediate A6-3)

Diiodomethane (2.3 g,8.5 mmol) was added to 20mL of DCM containing diethyl zinc (8.5 mL,1m in n-hexane) at-20 ℃ and the temperature was maintained under stirring for 30min, after which tert-butyl 4- (5-chloropyrimidin-2-yl) -3, 6-dihydropyridin-1 (2H) -carboxylate (0.5 g,1.7 mmol) was added to the reaction system, the reaction was continued for 2H at-20 ℃, the reaction mixture was concentrated, and purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) =20:1-10:1, gradient elution) to give tert-butyl 6- (5-chloropyrimidin-2-yl) -3-azabicyclo [4.1.0] heptane-3-carboxylate (intermediate A6-3) (0.3 g, 60% yield).

And a third step of: 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, stirred at room temperature for 6h, concentrated to give the crude product, which was purified by column chromatography on silica gel (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, 75% yield).

Preparation of intermediate A7:5-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 6h, concentrated to give crude product, which was purified by column chromatography on silica gel (dichloromethane: methanol (V/V) =2:1-10:1, gradient elution) to give 5-chloro-2- (1, 2,3, 6-tetrahydropyridin-4-yl) pyrimidine (intermediate A7) (0.4 g, 100% yield).

Preparation of intermediate A8 5-chloro-2- ((2S) -2-methylpiperidin-4-yl) pyrimidine

The synthetic route for intermediate A8 is as follows:

the first step: synthesis of (2S) -4-hydroxy-2-methylpiperidine-1-carboxylic acid tert-butyl ester (intermediate A8-2)

To a solution of Compound A8-1 (4 g,18.8 mmol) in MeOH (100 mL) at 0deg.C was added NaBH ₄ (1.4 g,37.6 mmol) the mixture was stirred at room temperature overnight, quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated to give crude intermediate A8-2.

And a second step of: synthesis of (2S) -4-iodo-2-methylpiperidine-1-carboxylic acid tert-butyl ester (intermediate A8-3)

Will I ₂ (1.2 eq) dissolved in CH ₂ Cl ₂ In (150 mL), the solution was cooled to 0deg.C. PPh is treated with ₃ (1.2 eq) was added to the reaction mixture in portions, 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 hours. By NaHSO ₃ The reaction was quenched with water, the aqueous layer extracted with DCM and the solvent evaporated. Purification by silica gel column (petroleum ether: ethyl acetate (V/V) =50:1-10:1, gradient elution) afforded (2S) -4-iodo-2-methylpiperidine-1-carboxylic acid tert-butyl ester (intermediate A8-3) (4.2 g, 70% yield).

And a third step of: 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 at reflux for 1 hour. After cooling to room temperature, the reaction mixture was treated with trisilyl 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 ℃ 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℃for about 8 hours. The reaction was filtered through celite, the filtrate was concentrated, and purified by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =50:1-10:1, gradient elution) to give (2S) -4- (5-chloropyrimidin-2-yl) -2-methylpiperidine-1-carboxylic acid tert-butyl ester (intermediate A8-4) (0.3 g, yield 10%).

Fourth step: 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 6h, concentrated to give crude product, which was purified by column chromatography on silica gel (dichloromethane: methanol (V/V) =2:1-10:1, gradient elution) to give 5-chloro-2- ((2S) -2-methylpiperidin-4-yl) pyrimidine (intermediate A8) (0.15 g, 80% yield).

Preparation of intermediate A9:2- (azapyridin-3-yl) -5-chloropyrimidine

The synthetic route for intermediate A9 is as follows:

the first step: synthesis of tert-butyl 3- (5-chloropyridin-2-yl) azetidine-1-carboxylate (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 hour. After cooling to room temperature, the reaction mixture was treated with trisilyl 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 ℃ 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℃for about 8 hours. The reaction was filtered through celite, the filtrate was concentrated, and purified by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =50:1-10:1, gradient elution) to give tert-butyl 3- (5-chloropyridin-2-yl) azetidine-1-carboxylate (intermediate A9-2) (1.0 g, 42% yield).

And a second step of: synthesis of 2- (azapyridin-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, stirred at room temperature for 6h, concentrated to give crude product, which was purified by column chromatography on silica gel (dichloromethane: methanol (V/V) =2:1-10:1, gradient elution) to give 2- (azapyridin-3-yl) -5-chloropyrimidine (intermediate A9) (0.4 g, 80% yield).

Intermediate A10 (R) -1- (2-chloro-5-oxo-6, 7-dihydrothiophen [3,2-d ] pyrimidin-4-yl) amino) cyclopropane-1-carbonitrile the synthetic route for the preparation of intermediate A10 is as follows:

the first step: 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) and 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℃for 12 h. 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 give 1- ((2-chloro-6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl) amino) cyclopropane-1-carbonitrile (intermediate a 10-3) (2 g, yield 53%).

And a third step of: synthesis of (R) -1- (2-chloro-5-oxo-6, 7-dihydrothiophen [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) were reacted under nitrogen at 20 ℃ ₄ (0.7 mL,0.25 mmol) and water (0.1 mL,5 mmol) were added to the flask and stirred for 1 hour. Tert-butanol peroxide (70% in water, 0.7ml,0.6mmo 1) was added at 21℃and stirred at room temperature for 1.5 hours, the reaction mixture was concentrated, and purified by column chromatography on silica gel (dichloromethane: methanol (V/V) =10:1, gradient elution) to give (R) -1- (2-chloro-5-oxo-6, 7-dihydrothiophene [3, 2-d)]Pyrimidin-4-yl) amino) cyclopropane-1-carbonitrile (intermediate a 10) (1 g, 71% yield).

Synthesis of intermediate A11 (R) -2-chloro-4- ((tetrahydro-2-hydro-pyran-4-yl) amino) -6, 7-dihydrothieno [3,2-d ] pyrimidine 5-oxide

The synthetic route for intermediate a11 is as follows:

the first step: 2-chloro-nitrogen- (tetrahydro-2-hydro-pyran-4-yl) -6, 7-dihydrothieno [3,2-d ] pyrimidin-4-amine (intermediate A11-3)

Compounds 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℃for 12 h. After the completion of the reaction, the reaction solution was concentrated, and purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) =1:1 to methylene chloride: methanol (V/V) =10:1 gradient elution) to finally obtain 2-chloro-nitrogen- (tetrahydro-2-hydro-pyran-4-yl) -6, 7-dihydrothieno [3,2-d ] pyrimidin-4-amine (intermediate a 11-3) (8.06 g).

And a second step of: (R) -2-chloro-4- ((tetrahydro-2-hydro-pyran-4-yl) amino) -6, 7-dihydrothieno [3,2-d ] pyrimidine 5-oxide (intermediate A11)

Intermediate A11-3 (3.0 g,1 eq), S- (-) -BINOL (0.30, 0.1 eq), dichloromethane (80 mL), ti (OiPr) were reacted under nitrogen at 21 ℃ ₄ (156.88 mg,0.05 eq) and water (198.87 mg,1 eq) were added to the flask and stirred for 1 hour. T-butanol peroxide (70% in water, 1.56ml,1.1 eq) was added at 21℃and the reaction stirred at room temperature for 1.5 hours. After the reaction was completed, the reaction solution was concentrated, and purified by silica gel column separation (dichloromethane: methanol (V/V) =10:1, gradient elution) to give the product (R) -2-chloro-4- ((tetrahydro-2-hydro-pyran-4-yl) amino) -6, 7-dihydrothieno [3,2-d]Pyrimidine 5-oxide (intermediate a 11) (2.5 g, 78.7% yield).

Synthesis of intermediate A12:2- (5-chloropyrimidin-2-yl) -1,2,3,4,5, 6-hexahydropyrrolo [3,4-c ] pyrrole

The synthetic route for intermediate a12 is as follows:

the first step: 3,4,5, 6-Tetrahydropyrrolo [3,4-c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester (intermediate A12-2)

1,2,3,4,5, 6-hexahydropyrrolo [3,4-C]Pyrrole (intermediate A12-1) (1.0 g,9.08 mmol) was added to H ₂ To O (10 mL) was then added sodium bicarbonate (1.98 g,23.60 mmol) and the mixture stirred for half an hour. Boc is then added ₂ A solution of O (990 mg,4.54 mmol) in methanol (2 mL) was stirred at room temperature for 4 hours. After the reaction is completed, the filter cake is obtained as a crude product (3, 4,5, 6-tetrahydropyrrolo [3, 4-c)]Pyrrole-2 (1 hydrogen) -carboxylic acid tert-butyl ester) (intermediate a 12-2) (1 g, 52% yield).

And a second step of: 5- (5-Chloropyrimidin-2-yl) -3,4,5, 6-tetrahydropyrrolo [3,4-c ] pyrrole-2 (1H) -carboxylic acid tert-butyl 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℃for 12 hours after completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted twice with ethyl acetate, 20mL ethyl acetate each time was used, the organic layers were combined, washed twice with saturated brine, dried over sodium sulfate and concentrated to give the crude product, which was isolated and purified by column on silica gel (petroleum ether: ethyl acetate (V/V) =10:1-5:1, gradient elution) to give 5- (5-chloropyrimidin-2-yl) -3,4,5, 6-tetrahydropyrrolo [3,4-c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester (intermediate A12-3) (500 mg, yield 74%).

And a third step of: 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 solution of DCM (6 mL), TFA (2 mL) was added and stirred at room temperature for 3 hours. After the reaction is completed, the crude product is obtained by concentration. The crude product was purified by column chromatography on silica gel (dichloromethane: methanol (V/V) =1:0-10:1, gradient elution) to give 2- (5-chloropyrimidin-2-yl) -1,2,3,4,5, 6-hexahydropyrrolo [3,4-c ] pyrrole (intermediate a 12) (320 mg, 93% yield).

Example 1: preparation of (R) -2- (6- (5-chloropyrimidin-2-yl) -3-azabicyclo [4.1.0] heptan-3-yl) -5-oxo- (6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl) aminocyclobutyl-methanol (compound 1-A) the synthetic route for the 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), and after microwave reaction at 120 ℃ for 30min, the concentrated crude product was isolated by reverse phase high performance liquid chromatography (column: phenomenex Luna C, 150×25mm×10 μm; mobile phase: a=water+0.01 vol% trifluoroacetic acid (99%), b=acetonitrile; gradient 35% -65% B,10 min), to give (R) -2- (6- (5-chloropyrimidin-2-yl) -3-azabicyclo [4.1.0] heptan-3-yl) -5-oxo- (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(400MHz,CDCl ₃ ):δ8.59(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: the synthetic route for the preparation of the target compound 11-a of (R) -2- (6- (5-chloropyrimidin-2-yl) -2, 6-diazaspiro [3.3] heptan-2-yl) -5-oxo- (6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl) amino-cyclobutyl-methanol (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 after microwave reaction at 120 ℃ for 30min, the concentrated crude product was isolated by reverse phase high performance liquid chromatography (column: phenomenex Luna C, 150×25mm×10 μm; mobile phase: a=water+0.01 vol% trifluoroacetic acid (99%), b=acetonitrile; gradient 35% -65% B,10 min), to give (R) -2- (6- (5-chloropyrimidin-2-yl) -2, 6-diazaspiro [3.3] heptan-2-yl) -5-oxo- (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(400MHz,CDCl ₃ ):δ8.63(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: the synthetic route for the preparation of the target compound 13-a of (R) -2- (6- (5-chloropyrimidin-2-yl) -3-azabicyclo [4.1.0] heptan-3-yl) -5-oxo- (6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl) amino-cyclobutyl-methanol (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), and after microwave reaction at 120 ℃ for 30min, the crude product was isolated by reverse phase high performance liquid chromatography (column: phenomenex Luna C, 150×25mm×10 μm; mobile phase: a=water+0.01 vol% trifluoroacetic acid (99%), b=acetonitrile; gradient 35% -65% B,10 min), to give (R) -2- (5- (5-chloropyrimidin-2-yl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) -5-oxo- (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(400MHz,cdcl ₃ ):δ8.23(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: preparation of (R) -2- (4- (5-chloropyrimidin-2-yl) -3, 6-dihydropyridin-1 (2H) -yl) -5-oxo- (6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl) amino-cyclobutyl-methanol (compound 20-a) the synthetic route for 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), and after microwave reaction at 120 ℃ for 30min, the concentrated crude product was isolated by reverse phase high performance liquid chromatography (column: phenomenex Luna C, 150×25mm×10 μm; mobile phase: a=water+0.01 vol% trifluoroacetic acid (99%), b=acetonitrile; gradient 35% -65% B,10 min), to give (R) -2- (4- (5-chloropyrimidin-2-yl) -3, 6-dihydropyridin-1 (2H) -yl) -5-oxo- (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(400MHz,DMSO-d ₆ ):δ8.85(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: the synthetic route for the preparation of the target compound 26-a of (R) -2- (3- (5-chloropyrimidin-2-yl) azetidin-1-yl) -5-oxo- (6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl) amino-cyclobutyl-methanol (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), and after concentration the crude product was isolated by reverse phase high performance liquid chromatography (column: phenomenex Luna C, 150×25mm×10 μm; mobile phase: a=water+0.01 vol% trifluoroacetic acid (99%), b=acetonitrile; gradient 35% -65% B,10 min) by microwave reaction at 120 ℃ for 30min to give (R) -2- (3- (5-chloropyrimidin-2-yl) azetidin-1-yl) -5-oxo- (6, 7-dihydrothieno [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(400MHz,cdcl ₃ ):δ8.67(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: the synthetic route for the preparation of the target compound 27-a of (R) -2- ((2S) -4- (5-chloropyrimidin-2-yl) -2-methylpiperidin-1-yl) -5-oxo- (6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl) amino-cyclobutyl-methanol (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 after microwave reaction at 120 ℃ for 30min, the concentrated crude product was isolated by reverse phase high performance liquid chromatography (column: phenomenex Luna C, 150×25mm×10 μm; mobile phase: a=water+0.01 vol% trifluoroacetic acid (99%), b=acetonitrile; gradient 35% -65% B,10 min) to give (R) -2- ((2S) -4- (5-chloropyrimidin-2-yl) -2-methylpiperidin-1-yl) -5-oxo- (6, 7-dihydrothieno [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(400MHz,cdcl ₃ ):δ8.62(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: the synthetic route for the preparation of the target compound 28-a of (R) -1- (2- (4- (5-chloropyrimidin-2-yl) piperidin-1-yl) -5-oxo-6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl) amino) cyclopropane-1-carbonitrile (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 after microwave reaction at 120 ℃ for 30min, the crude product was isolated by reverse phase high performance liquid chromatography (column: phenomenex Luna C18150×25mm×10 μm; mobile phase: a=water+0.01 vol% trifluoroacetic acid (99%), b=acetonitrile; gradient 35% -65% B,10 min) to give (R) -1- (2- (4- (5-chloropyrimidin-2-yl) piperidin-1-yl) -5-oxo-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(400MHz,CDCl ₃ ):δ8.63(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) hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) -5-oxo- (6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl) amino-cyclobutyl-methanol (target compound 12-A)

The synthetic route for the target compound 12-A is as follows:

the first step: synthesis of tert-butyl-5- (((trifluoromethyl) sulfonyl) oxo) -3,3a,6 a-tetrahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylate (Compound 12-2)

Tert-butyl 5-oxocyclopenta [ c ] pyrrole-2 (1H) -carboxylate (compound 12-1) (10.0 g,44.4 mmol) was dissolved in tetrahydrofuran (200 mL), replaced with nitrogen, cooled to-65℃and 1M lithium bis (trimethylsilyl) amide tetrahydrofuran solution (1M, 11.1g,66.6 mL) was slowly added dropwise and reacted for 30 minutes after the completion of the dropwise addition. N, N-bis (trifluoromethanesulfonyl) aniline (19.0 g,53.3 mmol) was dissolved in tetrahydrofuran (100 mL), and the mixture was slowly added dropwise to the reaction mixture, followed by reaction at 25℃for 4 hours after completion of the dropwise addition. The reaction mixture was poured into a saturated ammonium chloride solution (300 mL), quenched, extracted 3 times with ethyl acetate (300 mL), dried over anhydrous sodium sulfate, and concentrated to mix. Purification by silica gel column (petroleum ether: ethyl acetate (V/V) =1/0-10/1) afforded the product tert-butyl 5- (((trifluoromethyl) sulfonyl) oxo) -3,3a,6 a-tetrahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylate (compound 12-2) as a yellow oil (15.9 g, 63.0% yield).

¹ H NMR(400MHz,CDCl ₃ )δ＝5.55(d,1H),3.69(br t,1H),3.46-3.56(m,1H),3.37(br t,2H),3.13(br s,1H),2.90-2.97(m,1H),2.81-2.90(m,1H),2.37(br d,1H),1.43(s,9H)

And a second step of: synthesis of tert-butyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3,3a,6 a-tetrahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylate (Compound 12-3)

Tert-butyl-5- (((trifluoromethyl) sulfonyl) oxo) -3,3a,6 a-tetrahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylate (compound 12-2) (10.0 g,28.0 mmol) and bis (pinacolato) diboron (7.82 g,30.8 mmol) were dissolved in 1, 4-dioxane (200 mL), and 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, and after the addition, nitrogen was replaced, and the reaction was slowly raised to 90℃for 6 hours. The reaction solution was filtered through celite and concentrated to give tert-butyl 5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3,3a,6 a-tetrahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylate (compound 12-3) (9.38 g, crude). LC-MS, M/Z280.1 (M-56+H).

And a third step of: synthesis of tert-butyl-5- (5-chloropyrimidin-2-yl) -3,3a,6 a-tetrahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylate (compound 12-4)

Tert-butyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3,3a,6 a-tetrahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylate (compound 12-3) crude (9.38 g) and 5-chloro-2-iodopyrimidine (compound A2-2) (7.40 g,30.8 mmol) were dissolved in 1, 4-dioxan (200 mL) and water (30 mL), and potassium carbonate (11.6 g,84.0 mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (II) (1.02 g,1.40 mmol) were added to the reaction solution. Slowly heating to 90 ℃, and reacting for 6 hours. The reaction solution was concentrated, water (270 mL) was then added thereto, extracted 3 times with ethyl acetate (300 mL), dried over sodium sulfate, concentrated, and purified by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =1/0-5/1) to give the product tert-butyl 5- (5-chloropyrimidin-2-yl) -3,3a,6 a-tetrahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylate (compound 12-4) (7.00 g, yield 77.7%). LC-MS, M/Z266.3 (M-56+H).

¹ H NMR(400MHz,CDCl ₃ )δ＝8.63(s,2H),6.82(br s,1H),3.71(br s,1H),3.57(br s,3H),2.95-3.17(m,3H),2.76(br d,1H),1.44(s,9H)

Fourth step: synthesis of tert-butyl-5- (5-chloropyrimidin-2-yl) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylate (compound 12-5)

Tert-butyl-5- (5-chloropyrimidin-2-yl) -3,3a,6 a-tetrahydrocyclopenta [ c ] ]Pyrrole-2 (1H) -carboxylate (compound 12-4) (7.00 g,21.8 mmol) was dissolved in methanol (100 mL), tris (triphenylphosphine) rhodium (I) chloride (805 mg, 870. Mu. Mol) was added, replaced with argon, and hydrogen was introduced to react at 50℃under 50Psi for 24 hours. The reaction solution is concentrated, and a sample is stirred and separated by a silica gel column to purify (petroleum ether: ethyl acetate (V/V) =1/0-5/1) to obtain a brown oily product tert-butyl 5- (5-chloropyrimidine-2-yl) hexahydrocyclopenta [ c)]Pyrrole-2 (1H) -carboxylic acid ester (compound 12-5) (6.50 g, 92.3% yield). LC-MS, M/Z268.3 (M-56+H). ¹ H NMR(400MHz,CHLOROFORM-d)δ＝8.58(s,2H),3.40-3.65(m,3H),3.33(br d,2H),2.68-2.92(m,2H),2.10-2.39(m,2H),1.93-2.01(m,1H),1.76-1.87(m,1H),1.42-1.46(m,9H)

Fifth step: synthesis of 5- (5-chloropyrimidin-2-yl) octahydrocyclopenta [ 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 hydrogen chloride methanol (4M, 100 mL) and reacted at 25℃for 2 hours. Concentrating the reaction liquid to obtain 5- (5-chloropyrimidin-2-yl) octahydrocyclopenta [ c ]]Pyrrole (Compound 12-6) (4.50 g, 93.4% yield). LC-MS, M/Z224.3 (M+H) ⁺ 。

Sixth step: synthesis of (5R) -2- (5- (5-chloropyrimidin-2-yl) hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) -5-oxo- (6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl) amino-cyclobutyl-methanol (compound 12-A)

To 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-oxide (intermediate A1) (1.50 g,5.21 mmol) was dissolved in 1, 4-dioxane (40 mL), N-diisopropylethylamine (4.04 g,31.3 mmol) was added and then slowly warmed to 80℃for 4 hours. The reaction mixture was poured into saturated sodium bicarbonate solution (100 mL), extracted 4 times with ethyl acetate (240 mL) and methanol (20 mL), dried over sodium sulfate, concentrated, and separated by normal phase hplc (column: welch Ultimate XB-CN 250 x 70 x 10 μm; solvent: a=n-hexane, b=ethanol; gradient (ethanol): 1% -40%,25 min) to give (5R) -2- (5- (5-chloropyrimidin-2-yl) hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) -5-oxo- (6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl) amino-cyclobutyl-methanol (compound 12-a) (1.50 g, 60.5% yield). LC-MS, M/Z475.2 (M+H).

¹ H NMR(400MHz,DMSO-d ₆ )δ＝8.85(s,2H),7.26(s,1H),4.86(t,1H),3.71-3.80(m,4H),3.37-3.46(m,4H),3.15-3.29(m,2H),2.82-2.97(m,4H),2.39(br d,1H),2.12-2.20(m,4H),1.92-2.01(m,2H),1.71-1.84(m,2H)

Seventh step: synthesis of (R) -2- ((3 aR,5 (R) & (S), 6 aS) -5- (5-chloropyrimidin-2-yl) hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) -5-oxo-6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl) amino) cyclobutyl-methanol (target compounds 12-A-P1 and 12-A-P2).

The racemate compound (5R) -2- (5- (5-chloropyrimidin-2-yl) hexahydrocyclopenta [ c ]]Pyrrol-2 (1H) -yl) -5-oxo-6, 7-dihydrothieno [3,2-d]Pyrimidin-4-yl) amino) cyclobutyl) -methanol (compound 12-a) (1.50 g,3.16 mmol) was isolated by normal phase high performance liquid chromatography by (column: DAICEL CHIRALPAK AD (2)50mm 30mm,10 μm); solvent: a=carbon dioxide, b=aqueous ammonia (0.1%) + isopropanol; gradient (B): 40% -40%,4.7 min) to give compound (R) -2- ((3 aR,5 (R)&(S), 6 aS) -5- (5-chloropyrimidin-2-yl) hexahydrocyclopenta [ c]Pyrrol-2 (1H) -yl) -5-oxo-6, 7-dihydrothieno [3,2-d]Pyrimidin-4-yl) amino) cyclobutyl-methanol (target compound 12-A-P1, retention time 0.835 min) (862 mg, 57.5% yield), LC-MS, M/Z (ESI): 475.3 (M+H). ¹ H NMR(400MHz,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), 6 aS) -5- (5-chloropyrimidin-2-yl) hexahydrocyclopenta [ c]Pyrrol-2 (1H) -yl) -5-oxo-6, 7-dihydrothieno [3,2-d]Pyrimidin-4-yl) amino) cyclobutyl-methanol (target compound 12-A-P2, retention time 1.084 min) (457 mg, 30.5% yield). LC-MS, M/Z (ESI): 475.4 (M+H). ¹ H NMR(400MHz,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: preparation of (5R) -1- ((2- (4- (5-chloropyrimidin-2-yl) piperidin-1-yl) -5-oxo-6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl) amino) cyclobutane-1-carbonitrile (compound 15-A)

The first step: synthesis of 1- ((2-chloro-6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl) amino) cyclobutane-1-carbonitrile (compound 15-2)

The starting material 2, 4-dichloro-6, 7-dihydrothieno [3,2-d ] pyrimidine (intermediate A1-3) (1.27 g,6.14 mmol), 1-aminocyclobutane-1-carbonitrile 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℃and stirred for 12 hours. Water (10 mL) was added to dilute, extraction was performed with ethyl acetate (10 mL. Times.3), 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 (petroleum ether: ethyl acetate (V/V) =3:1-1:2) to give the title compound 15-2 (0.34 g, yield 36%). LC-MS, M/Z (ESI): 267.1 (M+1)

And a second step of: 1- ((2-chloro-5-oxo-6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl) amino) cyclobutane-1-carbonitrile (compound 15-3)

Raw material 1- ((2-chloro-6, 7-dihydrothieno [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 dichloromethane (3 mL), nitrogen was replaced, the temperature was kept at 20℃and the reaction was stirred for 1h, and then tert-butanol hydrogen peroxide (111.5 mg,1.24 mmol) was added to the reaction system to continue the reaction for 2h. After the reaction, the reaction mixture was diluted with methylene chloride and purified by chromatography on silica gel (methylene chloride: methanol=50:1-10:1), and the column-passing solution was concentrated to give the title compound 15-3 (0.2 g, yield 67%) as LC-MS, M/Z (ESI): 283.4 (M+1)

And a third step of: (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-carbonitrile (compound 15-A)

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) were dissolved in dioxane (3.0 mL) and placed in a microwave tube and reacted at 120℃for 0.5h. After the completion of the reaction, the reaction mixture was diluted with methylene chloride and purified by chromatography on a column (methylene chloride: methanol=50:1-10:1), the column-passing solution was concentrated, and then the title compound 15-A (20 mg, yield 7%) was obtained by preparative purification through high performance liquid chromatography, LC-MS, M/Z (ESI): 444.2 (M+1).

¹ H NMR(400MHz,DMSO-d ₆ )δ8.85(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-oxo- (6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl) amino-cyclobutyl-methanol (target compound 16-A)

The synthetic route for the target compound 16-A is as follows:

the first step: synthesis of tert-butyl 6- (((trifluoromethyl) sulfonyl) oxo) -2-azaspiro [3.3] hept-5-ene-2-carboxylate (Compound 16-2)

Tert-butyl 6-oxy-2-azaspiro [3.3] heptane-2-carboxylate (compound 16-1) (5.00 g,23.7 mmol) was dissolved in tetrahydrofuran (80 mL), then lithium bis (trimethylsilyl) amide (4.75 g,28.4 mmol) was added dropwise at-70 ℃,

n-phenyl bis (trifluoromethanesulfonyl) imide (9.30 g,26.0 mmol) was dissolved in tetrahydrofuran (10 mL) and the reaction mixture was added dropwise at-78deg.C, followed by mixing and reaction at 25deg.C for 2 hours. The reaction solution was quenched with ammonium chloride (100 mL), 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 purified by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =1:0-20:1) to give the compound tert-butyl 6- (((trifluoromethyl) sulfonyl) oxo) -2-azaspiro [3.3] hept-5-ene-2-carboxylate (compound 16-2) (4.20 g, yield 43.1%).

And a second step of: synthesis of tert-butyl 6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2-azaspiro [3.3] hept-5-ene-2-carboxylate (Compound 16-3)

Tert-butyl 6- (((trifluoromethyl) sulfonyl) oxo) -2-azaspiro [3.3] hept-5-ene-2-carboxylate (compound 16-2) (700 mg,2.04 mmol), bis-pinacolato borate (569 mg,2.24 mmol), 1-bis (diphenylphosphorus) ferrocene palladium chloride (47.6 mg,102 umol), potassium acetate (600 mg,6.12 mmol) were dissolved in 1,4 dioxane (10 mL) and then reacted under nitrogen at 100℃for 10 hours. The reaction solution was filtered through celite, and concentrated to give a tan compound of tert-butyl 6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2-azaspiro [3.3] hept-5-ene-2-carboxylate (compound 16-3) (1.00 g, crude).

LC-MS,M/Z(ESI):266.2[M-56+H]

And a third step of: synthesis of tert-butyl 6- (5-chloropyrimidin-2-yl) -2-azaspiro [3.3] hept-5-ene-2-carboxylate (compound 16-4)

Tert-butyl 6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2-azaspiro [3.3] hept-5-ene-2-carboxylate (Compound 16-3) (800 mg,2.49 mmol), 5-chloro-2-iodopyrimidine (7198 mg,2.99 mmol) was dissolved in 1,4 dioxane

To (20 mL) and water (4 mL) were added potassium carbonate (860 mg,6.23 mmol) and 1, 1-bis (diphenylphosphorus) ferrocene palladium chloride (182 mg,249 umol), and the mixture was reacted at 90℃for 5 hours under nitrogen. 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 over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =1:0-5:1) to give tert-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(400MHz,CDCl ₃ )δ＝8.65(s,2H),6.92(s,1H),4.15(d,4H),3.07(s,2H),1.46(s,9H)

Fourth step: synthesis of tert-butyl 6- (5-chloropyrimidin-2-yl) -2-azaspiro [3.3] heptane-2-carboxylic acid ester (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), rhodium tris (triphenylphosphine) chloride (120 mg,130 umol) was added under nitrogen, the suspension was replaced 3 times with nitrogen and hydrogen, respectively, and then reacted at 50℃under a hydrogen pressure of 50psi for 16 hours. The reaction solution was filtered, concentrated, and purified by silica gel column separation and purification (petroleum ether: ethyl acetate (V/V) =10:0-5:1) to give tert-butyl 6- (5-chloropyrimidin-2-yl) -2-azaspiro [3.3 ]Heptane-2-carboxylic acid ester (compound 16-5) (360 mg, 94.0%). LC-MS, M/Z (ESI): 209.2[ M-100 ]] ⁺

Fifth step: synthesis of 6- (5-chloropyrimidin-2-yl) -2-azaspiro [3.3] heptane (compound 16-6)

Tert-butyl-6- (5-chloropyrimidin-2-yl) -2-azaspiro [3.3]Heptane-2-carboxylate (16-5) (360 mg,1.16 mmol) was dissolved in methanol (10 mL) and reacted at 25℃for 5 hours with the addition of a hydrochloric acid gas/methanol solution (4M, 5 mL). The reaction solution was concentrated to give a white solid compound 6- (5-chloro)Pyrimidin-2-yl) -2-azaspiro [3.3]Heptane (compound 16-6) (172 mg, yield 54.1%). LC-MS, M/Z (ESI) 210.2[ M+H ]] ⁺

Sixth step: synthesis of (R) -2- (6- (5-chloropyrimidin-2-yl) spiro [3.3] heptan-2-yl) -5-oxo- (6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl) amino-cyclobutyl-methanol (compound 16-A)

6- (5-Chloropyrimidin-2-yl) -2-azaspiro [3.3]Heptane (16-6) (60.0 mg,219 umol) and diisopropylethylamine (141 mg,1.10 mmol) were added to (R) -2-chloro-4- ((1- (hydroxymethyl) cyclobutyl) amino) -6, 7-dihydrothieno [3,2-d]Pyrimidine 5-oxide (64.4 mg,219 umol) in 1,4 dioxane (10 mL) was slowly warmed to 100deg.C and reacted for 3 hours. Extraction with dichloromethane (60 mL) three times, drying over sodium sulfate, concentrating, and purifying the crude product by reverse phase high performance liquid chromatography (column: waters Xbridge 150X 25mm X5 μm; solvent: A=water+0.05% ammonia, B=acetonitrile; gradient (acetonitrile): 18% -48%,9 min) to give compound (R) -2- (6- (5-chloropyrimidin-2-yl) spiro [ 3.3) ]Heptan-2-yl) -5-oxo- (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(400MHz,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 for the target compound 29-A is as follows:

the first step: 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]]To a solution of decylcarbon-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) in dioxane (20 mL) and water (4 mL) was added potassium carbonate (6.49 g,47.0 mmol) and 1, 1-bis (diphenylphosphorus) ferrocene palladium chloride (1.37 g,1.88 mmol) and stirred at 90℃for 10 hours under nitrogen. The reaction solution was diluted with water (50 mL), extracted three times with ethyl acetate (150 mL), the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =15:1-5:1) to give 5-chloro-2- (1, 4-dioxaspiro [ 4.5: ]Dec-7-en-8-yl) pyrimidine (compound 29-2) (3.90 g, 82.2% yield). LC-MS, M/Z (ESI): 253.1[ M+H ]] ⁺ 。

And a second step of: 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]]Decane-8-yl) pyrimidine (compound 29-2) (3.90 g,15.4 mmol) was dissolved in methanol (20 mL), rhodium tris (triphenylphosphine) chloride (1.43 g,1.54 mmol) was added under nitrogen, and the suspension was replaced 3 times with nitrogen and hydrogen, respectively. Stirred at 50℃and 50psi for 16 hours. The reaction solution was filtered, concentrated, and purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) =15:1-5:1) to give a yellow liquid compound 5-chloro-2- (1, 4-dioxaspiro [ 4.5)]Decan-8-yl) pyrimidine (compound 29-3) (3.70 g, 94.1% yield). LC-MS, M/Z (ESI) 255.2[ M+H ]] ⁺

And a third step of: synthesis of 4- (5-chloropyrimidin-2-yl) cyclohexanone (compound 29-4)

The 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 trifluoroacetic acid (3.13 g,27.5mmol,2.03 mL) was added and stirred at 25℃for 5 hours. The reaction solution was neutralized with saturated sodium bicarbonate solution (30 mL), extracted three times with dichloromethane (90 mL), the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =15:1-3:1) to give 4- (5-chloropyrimidin-2-yl) cyclohexanone (compound 29-4) (2.80 g, yield 96.7%). LC-MS, M/Z (ESI): 211.0[ M+H ] ] ⁺

Fourth step: synthesis of 4- (5-chloropyridin-2-yl) Cyclomethyl-1-en-1-yl triflate (Compound 29-5)

4- (5-Chloropyrimidin-2-yl) cyclohexanone (Compound 29-4) (2.80 g,13.3 mmol) and N-phenyl bis (trifluoromethanesulfonyl) imide (5.22 g,14.62 mmol) were dissolved in tetrahydrofuran (15 mL), then cooled to-78℃and then lithium bis (trimethylsilyl) amide (1.00M, 4.45g,26.6 mL) was slowly added dropwise, stirred at-78℃for 30 minutes, then warmed to 25℃and stirred for 16 hours. The reaction solution was quenched with saturated ammonium chloride solution (30 mL), 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 high performance liquid chromatography (column: welch Ultimate XB-SiOH 250 x 70 x 10um; solvent: a=n-hexane, b=ethanol; gradient: 1% -30%,15 minutes) to give 4- (5-chloropyridin-2-yl) cycloprop-1-en-1-yl triflate (compound 29-5) (890 mg, yield 31.8%).

LC-MS,M/Z(ESI):343.1[M+H] ⁺

Fifth step: synthesis of 5-chloro-2- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclohexatrien-3-en-1-yl) pyrimidine (Compound 29-6)

4- (5-Chloropyridin 2-yl) Cyclomethyl-1-en-1-yl triflate (Compound 29-5) (400 mg,1.19 mmol), bis-pinacolato-borate (326 mg,1.28 mmol), 1-bis (diphenylphosphorus) ferrocene palladium chloride (42.8 mg, 58.4. Mu. Mol) and potassium acetate (34 mg,3.50 mmol) were dissolved in dioxane (10 mL) and stirred under nitrogen at 90℃for 10 hours. The reaction solution was quenched with water (10 mL), extracted with ethyl acetate (30 mL), the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =1:0-20:1) to give the compound 5-chloro-2- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclohexen-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)

Sixth step: synthesis of (5R) -2- (4- (5-chloropyrimidin-2-yl) cyclohexen-1-en-1-yl) -5-oxo-6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl) amino) cyclobutyl-methanol (compound 29-7A)

5-chloro-2- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclohexen-3-en-1-yl) pyrimidine (compound 29-6) (200 mg, 561. Mu. Mol) and (R) -2-chloro-4- ((1- (hydroxymethyl) cyclobutyl) amino) -6, 7-dihydrothieno [3,2-d]Pyrimidine 5-oxide (75.0 mg, 255. Mu. Mol) was dissolved in dioxane (5 mL) and water (0.5 mL), followed by sodium carbonate (81.1 mg, 766. Mu. Mol) and tetrakis triphenylphosphine palladium (30.0 mg,25.5. Mu. Mol) and then stirred under nitrogen at 85℃for 16 hours. The reaction solution was diluted with water (10 mL), extracted three times with ethyl acetate (30 mL), the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel plate separation (dichloromethane: methanol (V/V) =10/1) to give (5R) -2- (4- (5-chloropyrimidin-2-yl) cyclohexen-1-yl) -5-oxo-6, 7-dihydrothieno [3, 2-d)]Pyrimidin-4-yl) amino) cyclobutyl-methanol (compound 29-7A) (130 mg, 65.0% yield). LC-MS, M/Z (ESI): 466.3[ M+1 ]] ⁺

Seventh step: synthesis of (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)

(5R) -2- (4- (5-Chloropyrimidin-2-yl) cyclohexatrien-1-en-1-yl) -5-oxo-6, 7-dihydrothieno [3,2-d]Pyrimidin-4-yl) amino) cyclobutyl) -methanol (compound 29-7A) (100 mg, 224. Mu. Mol) was dissolved in methanol (10 mL). Rhodium tris (triphenylphosphine) chloride (20.8 mg, 22.4. Mu. Mol) was added under nitrogen, the suspension was replaced 3 times with nitrogen and hydrogen, respectively, and then reacted at 50psi at 50℃for 16 hours. The reaction solution was filtered, concentrated, and the crude product was purified by reverse phase high performance liquid chromatography (column: phenomenex luna C18:150:25 mm x 10um; solvent: a=water+0.05% formic acid, b=acetonitrile; gradient (acetonitrile): 18% -48%,9 min) to give (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, 49.3% yield) LC-MS, M/Z (ESI): 448.3[ M+H ]] ⁺ 。 ¹ H NMR(400MHz,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-oxo-6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl) amino) cyclobutyl-methanol (target compound 30-A)

The synthetic route for the target compound 30-A is shown below:

the first step: synthesis of tert-butyl 2- (((trifluoromethyl) sulfonyl) oxo) -7-azaspiro [3.5] non-1-ene-7-carboxylate (Compound 30-2)

Tert-butyl 2-oxaspiro [3.5] nonane-7-carboxylate (compound 30-1) (5.00 g,20.8 mmol) was dissolved in tetrahydrofuran (100 mL), replaced with nitrogen, cooled to-65℃and a solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran (1M, 4.54g,27.1mmol,27.1 mL) was slowly added dropwise and reacted for 30 minutes after the addition was completed. N, N-bis (trifluoromethanesulfonyl) aniline (8.96 g,25.1 mmol) was dissolved in tetrahydrofuran (30 mL), and the mixture was slowly added dropwise to the reaction mixture, followed by reaction at 25℃for 3 hours. The reaction mixture was poured into a saturated ammonium chloride solution (200 mL) and quenched, and then extracted 3 times with ethyl acetate (600 mL), dried over anhydrous sodium sulfate, and concentrated to give a sample. Isolation and purification using silica gel column (Petroleum ether: ethyl acetate (V/V) =1/0-10/1) afforded the product tert-butyl-2- (((trifluoromethyl) sulfonyl) oxo) -7-azaspiro [3.5] non-1-ene-7-carboxylate (Compound 30-2) as a yellow oil (4.00 g, 51.6% yield)

And a second step of: synthesis of tert-butyl-2- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -7-azaspiro [3.5] non-1-ene-7-carboxylate (Compound 30-3)

Tert-butyl 2- (((trifluoromethyl) sulfonyl) oxo) -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, 256 umol) were added to the reaction solution, nitrogen was replaced after the addition, and the reaction was slowly raised to 90℃for 6 hours. The reaction solution was filtered through celite and concentrated to give tert-butyl-2- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -7-azaspiro [3.5] non-1-ene-7-carboxylate (compound 30-3) (1.08 g, crude). LC-MS, M/Z294.2 (M-56+H).

And a third step of: synthesis of tert-butyl-2- (5-chloropyrimidin-2-yl) -7-azaspiro [3.5] non-1-ene-7-carboxylate (compound 30-4)

Tert-butyl 2- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-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. Slowly heating to 90 ℃, and reacting for 6 hours. The reaction solution was concentrated, water (30 mL) was then added thereto, extracted 3 times with ethyl acetate (90 mL), dried over sodium sulfate, concentrated, and purified by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =1/0-5/1) to give 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/Z280.3 (M-56+H).

Fourth step: synthesis of tert-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) (303 mg,328 umol) was added, and the mixture was replaced with argon, and reacted at 50℃under 50Psi for 24 hours by introducing hydrogen. Concentrating the reaction solution, mixing, and separating and purifying (petroleum ether: ethyl acetate (V/V) =1/0-5/1) by a silica gel column to obtain a product tert-butyl 2- (5-chloropyrimidine-2-yl) -7-azaspiro [3.5] ]Nonane-7-carboxylate (compound 30-5) (303 mg, 92.3% yield) 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)

Fifth step: synthesis of 2- (5-chloropyrimidin-2-yl) -7-azaspiro [3.5] nonane (compound 30-6)

Tert-butyl 2- (5-chloropyrimidin-2-yl) -7-azaspiro [3.5] nonane-7-carboxylate (compound 30-5) (600 mg,1.78 mmol) was dissolved in methanol hydrogen chloride (20 mL) and reacted at 25℃for 2 hours. The reaction liquid was concentrated to give 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) ⁺ 。

Sixth step: synthesis of (R) -2- (2- (5-chloropyrimidin-2-yl) -7-azaspiro [3.5] nonan-7-yl) -5-oxo-6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl) amino) cyclobutyl-methanol (end product 30-A)

To 2- (5-chloropyrimidin-2-yl) -7-azaspiro [3.5]Nonane (Compound 30-6) hydrochloride (100 mg, 365. Mu. Mol) and (R) -2-chloro-4- ((1- (hydroxymethyl) cyclobutyl) amino) -6, 7-dihydrothieno [3,2-d]Pyrimidine 5-oxide (intermediate A1) (105 mg, 365. Mu. Mol) was dissolvedSolution to 1, 4-Dioxohexanaphthene (20 mL) N, N-diisopropylethylamine (236 mg,1.82 mmol) was added, followed by a slow reaction at 80℃for 4 hours. The reaction mixture was poured into saturated sodium bicarbonate solution (30 mL), extracted 4 times with ethyl acetate (80 mL) and methanol (8 mL), dried over sodium sulfate, concentrated, and separated by reverse phase hplc (column: waters Xbridge 150 x 25mm x 5 μm; solvent: a=water+aqueous ammonia (0.5%), b=acetonitrile; gradient: 28% -58%,7 min) to give (R) -2- (2- (5-chloropyrimidin-2-yl) -7-azaspiro [ 3.5: ]Nonan-7-yl) -5-oxo-6, 7-dihydrothieno [3,2-d]Pyrimidin-4-yl) amino) cyclobutyl-methanol (final product 30-A) (100 mg, 56.1% yield). LC-MS, M/Z489.3 (M+H). ¹ H NMR(400MHz,DMSO-d ₆ )δ＝8.86(s,2H),7.29(s,1H),4.74-4.91(m,1H),3.62-3.78(m,7H),3.36-3.42(m,1H),3.15-3.23(m,1H),2.81-2.95(m,2H),2.22-2.33(m,4H),2.09-2.16(m,4H),1.72-1.81(m,2H),1.68(br t,2H)1.50(br t,2H)

Example 13: preparation of Compound 31-A

(R) -2- (3- (benzo [ d ] oxazol-2-yl) azetidin-1-yl) -5-oxo- (6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl) amino-cyclobutyl-methanol (compound 31-A)

The first step: 3- (benzo [ d ] oxazol-2-yl) azetidine-1-carboxylic acid tert-butyl ester (Compound 31-2)

The starting 3-iodoazetidine-1-carboxylic acid tert-butyl ester (1.85 g,6.51 mmol) and zinc powder (0.5 g,7.81 mmol) were dissolved in tetrahydrofuran (10 mL) and stirred for 15 minutes at 70℃with nitrogen replaced. Tetratriphenylphosphine palladium (0.7 g,0.65 mmol) and 2-chlorobenzo [ d ] oxazole (1.0 g,6.51 mmol) were dissolved in tetrahydrofuran (5 mL), and the mixture was stirred uniformly and poured into the reaction system, followed by further reaction for 2 hours. After the reaction was completed, 20mL of water was added to quench the reaction, followed by extraction with ethyl acetate three times, 10mL of ethyl acetate each time, 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 (petroleum ether: ethyl acetate (V/V) =3:1-1:2) to give the title compound 31-2 (0.74 g, yield 38%). LC-MS, M/Z (ESI): 275.1 (M+1).

And a second step of: 2- (azetidin-3-yl) benzo [ d ] oxazole (Compound 31-3)

The starting material 3- (benzo [ d ] oxazol-2-yl) azetidine-1-carboxylic acid tert-butyl ester (compound 31-2) (0.6 g,2.19 mmol) was dissolved in dioxane (5.0 mL), 3mL of dioxane hydrochloride solution (4M) was added thereto, and the reaction was stirred for 2h. After the reaction, the mixture was concentrated to dryness to give Compound 31-3 (0.3 g, yield: 78.9%). LC-MS, M/Z (ESI): 175.1 (M+1).

And a third step of: (R) -2- (3- (benzo [ d ] oxazol-2-yl) azetidin-1-yl) -5-oxo- (6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl) amino-cyclobutyl-methanol (compound 31-A)

The starting 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) were dissolved in dioxane (4.0 mL) and placed in a microwave tube and reacted at 120℃for 0.5h. After the completion of the reaction, the reaction mixture was diluted with methylene chloride and purified by chromatography on a column (methylene chloride: methanol=50:1-10:1), the column-passing solution was concentrated, and then the title compound 31-a (20 mg, yield 4.5%) was obtained by purification through high performance liquid chromatography, LC-MS, M/Z (ESI): 426.1 (m+1).

¹ H NMR(400MHz,DMSO-d ₆ )δ7.72(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 the target Compound 8-A:

(R) -2- (1- (5-Chloropyrimidin-2-yl) piperidin-4-yl) -5-oxo- (6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl) amino-cyclobutyl-methanol (target compound 8-A)

The first step: 4- (4- (1- (hydroxymethyl) cyclobutyl) amino) -5-oxo-6, 7-dihydrothieno [3,2-d ] pyrimidin-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (compound 8-1)

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, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (compound A6-1) (0.63 g,2.02 mmol), tetrakis triphenylphosphine palladium (0.2 g,0.18 mmol) dissolved in dioxane (10.0 mL) and water (2 mL) were substituted for nitrogen and warmed to 85 ℃ and stirred overnight. After completion of the reaction, water (30 mL) was added thereto for dilution, extraction with ethyl acetate (30 mL. Times.3), 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 (petroleum ether: ethyl acetate (V/V) =3:1-1:2) to give the title compound 8-1 (0.6 g, yield 86%). LC-MS, M/Z (ESI): 363.1 (M+1).

And a second step of: 4- (4- ((1- (hydroxymethyl) cyclobutyl) amino) -5-oxo-6, 7-dihydrothieno [3,2-d ] pyrimidin-2-yl) -piperidine-1-carboxylic acid tert-butyl ester (compound 8-2)

Compound 8-1 (320 mg,0.736 mmol), rh (PPh ₃ ) ₃ Cl (102 mg,0.110 mmol) was dissolved in methanol (10 mL), hydrogen was replaced and the temperature was raised to 50℃and the reaction was stirred for 12 hours. After the completion of the reaction, the reaction mixture was concentrated to give a crude product, which was purified by chromatography (dichloromethane: methanol (V/V) =10:1) to give the title compound 8-2 (200 mg, yield 62%). LC-MS, M/Z (ESI): 437.41 (M+1).

And a third step of: (1- ((2- (piperidin-4-yl) -5-oxo-6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl ] amino) cyclobutyl) methanol (compound 8-3)

Compound 8-2 (200 mg,0.458 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added, and the reaction was stirred at room temperature for 2 hours. After the reaction, the crude product was concentrated and dried by spin-drying, and purified by column chromatography (dichloromethane: methanol (V/V) =10:1) to give the title compound 8-3 (150 mg. Yield 97%). LC-MS, M/Z (ESI): 337.45 (M+1).

Fourth step: (R) -2- (1- (5-Chloropyrimidin-2-yl) piperidin-4-yl) -5-oxo- (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 and reacted at 120℃for 0.5 h. After the reaction was completed, the reaction mixture was diluted with methylene chloride and purified by separation with a column chromatography (methylene chloride: methanol (V/V) =10:1), the column-passed solution was concentrated, and then purified by reverse phase high performance liquid chromatography (column: sunFileTM Prep C18 OBDTM (5 μm 30mm×150 mm); solvent: a=acetonitrile, b=water; gradient: 1% -38.7%,10 minutes) to give (R) -2- (1- (5-chloropyrimidin-2-yl) piperidin-4-yl) -5-oxo- (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(400MHz,CDCl ₃ )δ8.21(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: preparation of (5R) -2- (5- (5-chloropyrimidin-2-yl) hexahydrocyclopentyl [ c ] pyrrol-2 (1H) -yl) -5-oxo-6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl-) amino) -tetrahydro-2H-pyran (target compound 32-A) the synthetic routes for the target compounds 32-A, 32-A-P1 and 32-A-P2 are as follows:

the first step: compound 32-1 was prepared by the method of preparation of reference compound 30-6.

And a second step of: synthesis of (5R) -2- (5- (5-chloropyrimidin-2-yl) hexahydrocyclopentyl [ c ] pyrrol-2 (1H) -yl) -5-oxo-6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl-) amino) -tetrahydro-2H-pyran (compound 32-A)

Intermediate 32-1 (100 mg, 447.02. Mu. Mol), intermediate A11 (128.64 mg, 447.02. Mu. Mol) and DIPEA (172 mg,1.34 mmol) were added to a microwave tube containing 1, 4-dioxane (2 mL) and reacted at 120℃for 30min. After the completion of the reaction, the reaction mixture was concentrated to give a crude product, which was separated by reverse phase high performance liquid chromatography (column: sunFileTM Prep C18 OBDTM (5 μm 30 mm. Times.150 mm), solvent: A=acetonitrile, B=water; gradient: 1% -65%,10 minutes) to give (5R) -2- (5- (5-chloropyrimidin-2-yl) hexahydrocyclopentyl [ C ] pyrrol-2 (1H) -yl) -5-oxo-6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl-) amino) -tetrahydro-2H-pyran (compound 32-A) (27 mg, yield 13%).

And a third step of: synthesis of (5R) -2- ((3 aR,5 (R) & (S), 6 aS) -5- (5-chloropyrimidin-2-yl) hexahydrocyclopentyl [ c ] pyrrol-2 (1H) -yl) -5-oxo-6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl-) amino) -tetrahydro-2H-pyran (target compounds 32-A-P1 and 32-A-P2).

/>

The racemate compound (5R) -2- (5- (5-chloropyrimidin-2-yl) hexahydrocyclopentyl [ c ]]Pyrrol-2 (1H) -yl) -5-oxo-6, 7-dihydrothieno [3,2-d]Pyrimidine-4-yl-amino) -tetrahydro-2H-pyran (Compound 32-A) (27 mg, 56. Mu. Mol) is chiral isolated by normal phase high performance liquid chromatography, by (column: DAICEL CHIRALPAK AD (250 mm. Times.30 mm,10 μm); solvent: a=carbon dioxide, b=aqueous ammonia (0.1%) + ethanol; gradient: 50% -50%,7 min), (5R) -2- ((3 aR,5 (R)&(S), 6 aS) -5- (5-chloropyrimidin-2-yl) hexahydrocyclopentyl [ c]Pyrrol-2 (1H) -yl) -5-oxo-6, 7-dihydrothieno [3,2-d]Pyrimidin-4-yl-) amino) -tetrahydro-2H-pyran (target compound 32-A-P1) retention time 1.387min (10.0 mg, 37% yield), LCMS, M/Z (ESI): 475.07 (M+1), ¹ H NMR(400MHz,cdcl3)δ8.60(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), 6 aS) -5- (5-chloropyrimidin-2-yl) hexahydrocyclopentyl [ c]Pyrrol-2 (1H) -yl) -5-oxo-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, 37% yield), LCMS, M/Z (ESI): 475.07 (M+1), ¹ H NMR(400MHz,CDCl ₃ )δ8.59(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: preparation of (5R) -2- (5- (5-chloropyrimidin-2-yl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) -5-oxo-6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl-) amino) -tetrahydro-2H-pyran (compound 33-A)

The synthetic route for the target compound 33-A is as follows:

intermediate A4 (100 mg, 445.05. Mu. Mol), intermediate A11 (128 mg, 445.05. Mu. Mol) and DIPEA (172 mg,1.34 mmol) were added to a microwave tube containing 1, 4-dioxane (2 mL) and reacted at 120℃for 30min. After the reaction is completed, the reaction solution is concentrated to obtain a crude product, and the crude product is separated and purified by a silica gel column (dichloromethane: methanol (V/V) =10:1 gradient elution) to obtain a compound (5R) -2- (5- (5-chloropyrimidine-2-yl) hexahydropyrrole [3, 4-c)]Pyrrol-2 (1H) -yl) -5-oxo-6, 7-dihydrothieno [3,2-d]Pyrimidin-4-yl-) amino) -tetrahydro-2H-pyran (target compound 33-A) (80 mg, 95% purity). LCMS, M/Z (ESI): 476.1 (M+1), ¹ H NMR(400MHz,CDCl ₃ )δ8.24(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 ] pyrrol-2 (1H) -yl) -5-oxo- (6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl) amino-cyclobutyl-methanol (target compound 34-A)

The synthetic route for the target compound 34-A is as follows:

intermediate A12 (100 mg, 347.51. Mu. Mol), intermediate A1 (77.38 mg, 347.51. Mu. Mol) and DIPEA (134.74 mg,1.04 mmol) were added to a microwave tube containing 1, 4-dioxane (15 mL) and reacted at 120℃for 30min. After the reaction, the reaction mixture was concentrated to give a crude product, which was separated by reverse phase high performance liquid chromatography (column: sunFileTM Prep C18 OBDTM (5 μm 30 mm. Times.150 mm), solvent: A=acetonitrile, B=water, gradient: 1% -49%,10 minutes) to give (R) -2- (5- (5-chloropyrimidin-2-yl) -3,4,5, 6-tetrahydropyrrole [3, 4-C) ]Pyrrol-2 (1H) -yl) -5-oxo-67-Dihydrothieno [3,2-d ]]Pyrimidin-4-yl) amino) cyclobutyl) -methanol (target compound 34-a) (10 mg, 6% yield). LCMS, M/Z (ESI): 474.21 (M+1), ¹ H NMR(400MHz,cdcl3)δ8.28(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-oxo-6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl-) amino) -tetrahydro-2H-pyran (compound 35-A) the synthetic routes for the target compounds 35-A, 35-A-P1 and 35-A-P2 are as follows:

the first step: synthesis of Compound (5R) -2- ((2S) -4- (5-chloropyrimidin-2-yl) -2-methylpiperidin-1-yl) -5-oxo-6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl-) amino) -tetrahydro-2H-pyran (Compound 35-A)

Intermediate A8 (100 mg, 472.38. Mu. Mol), intermediate A11 (95.15 mg, 330.67. Mu. Mol) and DIPEA (183.16 mg,1.42 mmol) were added to a microwave tube containing 1, 4-dioxane (15 mL) and reacted at 120℃for 30min. After the reaction was completed, the reaction mixture was concentrated to give a crude product, which was separated by reverse phase high performance liquid chromatography (column: sunFileTM Prep C18 OBDTM (5 μm 30 mm. Times.150 mm), solvent: A=acetonitrile, B=water; gradient: 1% -58%,10 minutes) to give (5R) -2- ((2S) -4- (5-chloropyrimidin-2-yl) -2-methylpiperidin-1-yl) -5-oxo-6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl-) amino) -tetrahydro-2H-pyran (compound 35-A) (50 mg, yield 23%).

And a second step of: synthesis of Compound (5R) -2- ((2S, 4S &2S, 4R) - (5-Chloropyrimidin-2-yl) -2-methylpiperidin-1-yl) -5-oxo-6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl-) amino) -tetrahydro-2H-pyran (target Compounds 35-A-P1 and 35-A-P2)

(5R) -2- ((2S) -4- (5-Chloropyrimidin-2-yl) -2-methylpiperidin-1-yl) -5-oxo-6, 7-dihydrothieno [3,2-d]Pyrimidine-4-yl-) amino) -tetrahydro-2H-pyran (50 mg) is chiral isolated by normal phase high performance liquid chromatography (column: DAICEL CHIRALPAK AD (250 mm. Times.30 mm,10 μm); solvent: a=carbon dioxide, b=aqueous ammonia (0.1%) + ethanol; gradient: 50% -50%,7 min), compound (5R) -2- ((2 s,4 s)&2S, 4R) - (5-Chloropyrimidin-2-yl) -2-methylpiperidin-1-yl) -5-oxo-6, 7-dihydrothieno [3,2-d]Pyrimidin-4-yl-) amino) -tetrahydro-2H-pyran (target compound 35-A- -P1) retention time 1.657min (20.0 mg, 40% yield), LCMS, M/Z (ESI): 463.50 (M+1), ¹ H NMR(600MHz,CDCl ₃ )δ8.62(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-oxo-6, 7-dihydrothieno [3,2-d]Pyrimidin-4-yl-) amino) -tetrahydro-2H-pyran (target compound 35-A-P2), retention time 1.742min (15.0 mg, 30% yield), LCMS, M/Z (ESI): 463.50 (M+1), ¹ H NMR(600MHz,CDCl ₃ )δ8.63(s,2H),5.56(d,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-oxo-6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl) amino) cyclobutyl) -methanol (Compounds 27-A-P1 and 27-A-P2)

The synthetic routes for 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-oxo-6, 7-dihydrothieno [3,2-d]Pyrimidin-4-yl) amino) cyclobutyl) -methanol (compound 27-a) (100 mg) was chiral separated by normal phase high performance liquid chromatography (column: DAICEL CHIRALPAK AD (250 mm. Times.30 mm,10 μm); solvent: a=carbon dioxide, b=aqueous ammonia (0.1%) + ethanol; gradient: 50% -50%,7 min), compound (5R) -2- ((2 s,4 s)&2S, 4R) -2- ((2S) -4- (5-chloropyrimidin-2-yl) -2-methylpiperidin-1-yl) -5-oxo-6, 7-dihydrothieno [3,2-d]Pyrimidin-4-yl) amino) cyclobutyl) -methanol (compound 27-A-P1), retention time 1.852min (40.0 mg, 80% yield), LC-MS, M/Z (ESI): 463.1 (M+1). ¹ H NMR(400MHz,D-DMSO):δ8.86(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-oxo-6, 7-dihydrothieno [3,2-d]Pyrimidin-4-yl) amino) cyclobutyl) -methanol (compound 27-A-P2), 1.477min (35.0 mg, 70% yield), LC-MS, M/Z (ESI): 463.1 (M+1). ¹ H NMR(400MHz,D-DMSO):δ8.89(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 Compound 27-B-P1&27-B-P2

(R) -2- ((2R, 4ror 4S) -4- (5-Chloropyrimidin-2-yl) -2-methylpiperidin-1-yl) -5-oxo- (6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl) amino-cyclobutyl-methanol (the title compound 27-B- -P1& 27-B-P2)

The synthetic route for the target compound 27-B- -P1&27-B-P2 is shown below:

the first step: synthesis of tert-butyl (R) -2-methyl-4- (((trifluoromethyl) sulfonyl) oxo) -3, 6-dihydropyridine-1 (2H) -carboxylate (Compound 27-2)

Tert-butyl (2R) -2-methyl-4-oxo-piperidine-1-carboxylate (16.0 g,75.0 mmol) was dissolved in tetrahydrofuran (300 mL), replaced with nitrogen, cooled to-65℃and 1M lithium bis (trimethylsilyl) amide tetrahydrofuran solution (1M, 16.3g,97.5mmol,97.5 mL) was slowly added dropwise and reacted for 30 minutes after the completion of the dropwise addition. N, N-bis (trifluoromethanesulfonyl) aniline (29.4 g,82.5 mmol) was dissolved in tetrahydrofuran (100 mL), and the mixture was slowly added dropwise to the reaction mixture, followed by reaction at 25℃for 4 hours. The reaction mixture was quenched by pouring it into a saturated ammonium chloride solution (1000 mL), extracted 3 times with ethyl acetate, each time with 1500mL of ethyl acetate, washed with saturated brine (1000 mL), dried over anhydrous sodium sulfate, and concentrated to mix. Purification by silica gel column (petroleum ether: ethyl acetate (V/V) =1/0-10/1) afforded the product tert-butyl (R) -2-methyl-4- (((trifluoromethyl) sulfonyl) oxo) -3, 6-dihydropyridine-1 (2H) -carboxylic acid ester (compound 27-2) (24.2 g, 93.4% yield) as a yellow oil

And a second step of: synthesis of tert-butyl (R) -2-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate (Compound 27-3)

Tert-butyl (R) -2-methyl-4- (((trifluoromethyl) sulfonyl) oxo) -3, 6-dihydropyridine-1 (2H) -carboxylate (compound 27-2) (10 g,28.9 mmol) and bis (pinacolato) diboron (7.35 g,28.9 mmol) were dissolved in 1, 4-dioxane (100 mL), and potassium acetate (7.10 g,72.3 mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (II) (1.06 g,1.45 mmol) were added to the reaction solution, and after the addition, nitrogen was replaced, the reaction was slowly raised to 90℃for 3 hours. The reaction solution was filtered through celite, concentrated and stirred, and purified by silica gel column (petroleum ether: ethyl acetate (V/V) =1/0-10/1) to give tert-butyl (R) -2-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid ester (compound 27-3) (8.00 g, yield 90%) as a yellow oily compound.

And a third step of: synthesis of tert-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, 5-tetramethyl-1, 3, 2-dioxaborolan-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), and 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, nitrogen was replaced three times, and the temperature was slowly raised to 90℃for 2 hours. The reaction solution was filtered through celite, concentrated, and purified by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =1/0-5/1) to give the product tert-butyl (R) -4- (5-chloropyrimidin-2-yl) -2-methyl-3, 6-dihydropyridine-1 (2H) -carboxylic acid ester (compound 27-4) (8.00 g, yield 66.6%).

Fourth step: synthesis of tert-butyl (2R) -4- (5-chloropyrimidin-2-yl) -2-methylpiperidine-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) (1.79 g,1.94 mmol) was added, replaced with argon, and hydrogen was introduced to react at 50℃under 50Psi for 48 hours. The reaction solution was concentrated and stirred, and the mixture was purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) =1/0-5/1) to give tert-butyl (2R) -4- (5-chloropyrimidin-2-yl) -2-methylpiperidine-1-carboxylate (compound 27-5) (3.50 g, yield 57.0%)

Fifth step: synthesis of 5-chloro-2- ((2R) -2-methylpiperidin-4-yl) pyrimidine (Compound 27-6)

Tert-butyl (2R) -4- (5-chloropyrimidin-2-yl) -2-methylpiperidine-1-carboxylate (compound 27-5) (3.00 g,9.40 mmol) was dissolved in hydrogen chloride methanol (4M, 10 mL) and methanol (10 mL) and reacted at 25℃for 1 hour. The reaction liquid was concentrated to give 5-chloro-2- ((2R) -2-methylpiperidin-4-yl) pyrimidine hydrochloride (compound 27-6) (2.40 g, 92.6% yield). LC-MS, M/Z212.2 (M+H) ⁺ 。

Sixth step: synthesis of (R) -2- ((2R, 4ror 4S) -4- (5-Chloropyrimidin-2-yl) -2-methylpiperidin-1-yl) -5-oxo- (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-diisopropylethylamine (5.40 g,41.7mmol,7.26 mL) was added, and then slowly warmed to 120℃for 10 hours. The reaction solution was poured into saturated sodium hydrogencarbonate solution (100 mL), extracted 3 times with ethyl acetate (300 mL), washed with saturated brine (200 mL), dried over sodium sulfate, concentrated and purified by column chromatography on silica gel (dichloromethane: methanol (V/V) =1/0-10/1), and separated by normal phase hplc (column: welch Ultimate XB-NH2250 x 50 μm; solvent: a=n-hexane, b=ethanol; gradient: 1% -40%,25 minutes) to give (R) -2- ((2R, 4ror4 s) -4- (5-chloropyrimidin-2-yl) -2-methylpiperidin-1-yl) -5-oxo- (6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl) amino-cyclobutyl-methanol (compound 27-B) (2.00 g, 72.0% yield). LC-MS, M/Z463.2 (M+H).

Seventh step: synthesis of (R) -2- ((2R, 4ror 4S) -4- (5-Chloropyrimidin-2-yl) -2-methylpiperidin-1-yl) -5-oxo- (6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl) amino-cyclobutyl-methanol (target compound 27-B-P1& 27-B-P2)

The racemate compound (R) -2- ((2R, 4ror 4S) -4- (5-chloropyrimidin-2-yl) -2-methylpiperidin-1-yl) -5-oxo- (6, 7-dihydrothieno [3, 2-d)]Pyrimidin-4-yl) amino-cyclobutyl-methanol (compound 27-B) (1.60 g,3.43 mmol) was isolated by chiral separation by normal phase high performance liquid chromatography (column: DAICEL CHIRALPAK AD (250 mm. Times.30 mm,10 μm; solvent: A=carbon dioxide+acetonitrile, B=aqueous ammonia (0.1%) +isopropanol; gradient: 45% -45%,20 min), gives the compound (R) -2- ((2R, 4ror 4S) -4- (5-chloropyrimidin-2-yl) -2-methylpiperidin-1-yl) -5-oxo- (6, 7-dihydrothieno [3, 2-d)]Pyrimidin-4-yl) amino-cyclobutyl-methanol (target compound 27-B- -P1) retention time 1.899min (400 mg, 24.7% yield), LC-MS, M/Z (ESI): 463.2 (M+H). ¹ H NMR(400MHz,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, 4ror 4S) -4- (5-Chloropyrimidin-2-yl) -2-methylpiperidin-1-yl) -5-oxo- (6, 7-dihydrothieno [3, 2-d)]Pyrimidin-4-yl) amino-cyclobutyl-methanol (target compound 27-B- -P2) retention time 1.586min (900 mg, 56.1% yield). LC-MS, M/Z (ESI): 463.2 (M+H). ¹ H NMR(400MHz,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 the target Compound 4-A- -P1&4-A-P2&4-A-P3&4-A-P4

(5R) -2- (5- (5-Chloropyrimidin-2-yl) -2-azabicyclo [2.2.1] heptan-2-yl) -5-oxo- (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 for the target compound 4-A- -P1&4-A-P2&4-A-P3&4-A-P4 is shown below:

the first step: synthesis of tert-butyl-5- (5-chloropyrimidin-2-yl) -5-hydroxy-2-azabicyclo [2.2.1] heptane-2-carboxylic acid ester (compound 4-2)

5-chloro-2-iodopyrimidine (12.5 g,52.0 mmol) was dissolved in dry ice ethanol in dry toluene (400 mL), cooled to-70℃in an ice bath, and a tetrahydrofuran solution of n-butyllithium (2.5 mol/L,20.8 mL) was slowly added dropwise thereto and reacted for 1 hour. The tert-butyl 5-oxy-2-azabicyclo [2.2.1] heptane-2-carboxylic acid ester (1) was dissolved in anhydrous toluene (50 ml) and added dropwise to the reaction mixture, followed by reaction at 25℃for 3 hours. After the completion of the reaction, the reaction mixture was slowly poured into a saturated aqueous ammonium chloride solution (300 ml) to quench the reaction mixture, and the mixture was separated. The aqueous phase was extracted 2 times with ethyl acetate, washed with 300mL each of ethyl acetate, saturated sodium chloride (200 mL) solution, dried over anhydrous sodium sulfate and concentrated. Mix silica gel column purification (petroleum ether: ethyl acetate (V/V) =1:0-3:1). To give tert-butyl 5- (5-chloropyrimidin-2-yl) -5-hydroxy-2-azabicyclo [2.2.1] heptane-2-carboxylic acid ester (compound 4-2) (5.00 g, 32.4% yield) LC-MS, M/Z (ESI): 270.2 (M-56.06+H)

And a second step of: synthesis of tert-butyl-5-chloro-5- (5-chloropyrimidin-2-yl) -2-azabicyclo [2.2.1] heptane-2-carboxylic acid ester (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,11.5mmol, 929. Mu.L) were dissolved in dichloromethane (30 mL), cooled to 0 ℃, and thionyl chloride (1.10 g,9.21mmol, 668. Mu.L) was diluted with dichloromethane (10 mL) and added dropwise to the reaction solution, followed by reaction at 25℃for 2 hours. After the completion of the reaction, the reaction mixture was poured into a saturated aqueous sodium hydrogencarbonate solution (40 ml), the solution was separated, the aqueous phase was extracted 2 times with 40ml of methylene chloride each time, and washed 2 times with 40ml of saturated brine each time. Adding excessive anhydrous sodium sulfate for drying, concentrating and mixing. Purification on a silica gel column (petroleum ether: ethyl acetate (V/V) =1:0-5:1) afforded the product tert-butyl-5-chloro-5- (5-chloropyrimidin-2-yl) -2-azabicyclo [2.2.1] heptane-2-carboxylic acid ester (compound 4-3) (1.3 g, yield 55.04%).

And a third step of: synthesis of tert-butyl-5- (5-chloropyrimidin-2-yl) -2-azabicyclo [2.2.1] heptane-2-carboxylic acid ester (compound 4-4)

Tert-butyl-5-chloro-5- (5-chloropyrimidin-2-yl) -2-azabicyclo [2.2.1] heptane-2-carboxylic acid ester (compound 4-3) (1.20 g,3.49 mmol) was dissolved in anhydrous methanol (10 mL), zinc powder (683 mg,10.4 mmol) and ammonium chloride (559 mg,10.4 mmol) were added, and the mixture was heated to 65℃and reacted for 8 hours. After the reaction is finished, zinc powder is filtered out, and the filtrate is concentrated and stirred. Purification on a silica gel column (petroleum ether: ethyl acetate (V/V) =1:0-5:1) afforded the brown product tert-butyl 5- (5-chloropyrimidin-2-yl) -2-azabicyclo [2.2.1] heptane-2-carboxylic acid ester (compound 4-4) (1.00 g, 92.6% yield).

Fourth step: synthesis of 5- (5-chloropyrimidin-2-yl) -2-azabicyclo [2.2.1] heptane (compound 4-5)

Tert-butyl-5- (5-chloropyrimidin-2-yl) -2-azabicyclo [2.2.1] heptane-2-carboxylic acid ester (compound 4-4) (800 mg,1.29 mmol) was dissolved in dioxane hydrogen chloride (20 mL), and reacted at 25℃for 2 hours. The reaction liquid was concentrated to give 25- (5-chloropyrimidin-2-yl) -2-azabicyclo [2.2.1] heptane (compound 4-5) hydrochloride (635 mg, yield 99.8%).

Fifth step: synthesis of (5R) -2- (5- (5-chloropyrimidin-2-yl) -2-azabicyclo [2.2.1] heptan-2-yl) -5-oxo- (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-diisopropylethylamine (2.24 g,17.3 mmol) was added, and then reacted to 80℃for 4 hours. The reaction solution was poured into saturated sodium bicarbonate solution (20 mL), extracted 4 times with ethyl acetate (30 mL) and methanol (3.00 mL), dried over sodium sulfate, concentrated, and purified by reverse phase hplc (column: waters Xbridge 150 x 25mm x 5 μm); mobile phase: a=water+ammonia (0.1%), b=acetonitrile; b=18-48%, for 20 min), concentrating to give (5R) -2- (5- (5-chloropyrimidin-2-yl) -2-azabicyclo [2.2.1] heptan-2-yl) -5-oxo- (6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl) amino-cyclobutyl-methanol (compound 4-a).

Sixth step: synthesis of (5R) -2- (5- (5-chloropyrimidin-2-yl) -2-azabicyclo [2.2.1] heptan-2-yl) -4- ((1- (hydroxymethyl) cyclobutyl) amino) -6, 7-dihydrothieno [3,2-d ] pyrimidine 5-oxidation (target compound 4-A-P1&4-A-P2&4-A-P3& 4-A-P4)

The racemate compound (5R) -2- (5- (5-chloropyrimidin-2-yl) -2-azabicyclo [2.2.1]Heptan-2-yl) -5-oxo- (6, 7-dihydrothieno [3, 2-d)]Pyrimidin-4-yl) amino-cyclobutyl-methanol (compound 4-a) (1.00 g,2.17 mmol) was isolated by chiral separation by normal phase high performance liquid chromatography (column: daicel ChiralPak IG (250×30mm,10 μm); mobile phase: a=carbon dioxide-acetonitrile, b=methanol+ammonia (0.1%); b=75% isocratic elution, 3.9 min) to give the compound (5R) -2- (5- (5-chloropyrimidin-2-yl) -2-azabicyclo [ 2.2.1)]Heptan-2-yl) -5-oxo- (6, 7-dihydrothieno [3, 2-d)]Pyrimidin-4-yl) amino-cyclobutyl-methanol (compound 4-A-P1) retention time 1.447min (400 mg, 80.0% yield, yield), LC-MS, M/Z (ESI): 461.2 (M+H). ¹ H NMR(400MHz,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]Heptan-2-yl) -5-oxo- (6, 7-dihydrothieno [3, 2-d)]Pyrimidin-4-yl) amino-cyclobutyl-methanol (compound 4-a-P2) retention time 1.400min (400 mg, 80.0% yield). LC-MS, M/Z (ESI): 461.2 (M+H). ¹ H NMR(400MHz,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]Heptan-2-yl) -5-oxo- (6, 7-dihydrothieno [3, 2-d)]Pyrimidin-4-yl) amino-cyclobutyl-methanol (compound 4-a) (200 mg,433.86 μmol) was chiral separated by normal phase high performance liquid chromatography (column: daicel ChiralPak IG (250×30mm,10 um); mobile phase: a=carbon dioxide-acetonitrile, b=isopropanol+aqueous ammonia (0.1%); b=66% isocratic elution, 3.4 min), lyophilization to give compound (5R) -2- (5- (5-chloropyrimidin-2-yl) -2-azabicyclo [ 2.2.1)]Heptan-2-yl) -5-oxo- (6, 7-dihydrothieno [3, 2-d)]Pyrimidin-4-yl) amino-cyclobutyl-methanol (compound 4-A-P3) retention time 1.683min (60 mg, 60.0% yield, yield), LC-MS, M/Z (ESI): 461.2 (M+H). ¹ H NMR(400MHz,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]Heptan-2-yl) -5-oxo- (6, 7-dihydrothieno [3, 2-d)]Pyrimidin-4-yl) amino-cyclobutyl-methanol (compound 4-a-P4) retention time 1.603min (60 mg, 60.0% yield). LC-MS, M/Z (ESI): 461.2 (M+H). ¹ H NMR(400MHz,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-oxo-6, 7-dihydrothieno [3,2-d ] pyrimidin-5-yl) amino) cyclobutyl) -methanol (target compound 36-A)

Synthetic route to target compound 36-A:

the first step: synthesis of 3- (5-chloropyrimidin-2-yl) -2, 5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (compound 36-3)

The starting material 1-tert-butoxycarbonyl-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, 0.336 mmol) were dissolved in 1, 4-dioxane (10 mL) and water (1 mL), nitrogen was replaced and the temperature was raised to 100℃and the reaction was stirred overnight. After the reaction was completed, water (30 mL) was added to dilute, extraction was performed three times with ethyl acetate, 30mL of ethyl acetate was used each time, 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 (petroleum ether: ethyl acetate (V/V) =10:1-5:1) to give the title compound 36-3 (0.75 g, yield 78.6%). LC-MS, M/Z (ESI): 181.9 (M-100).

And a second step of: synthesis of tert-butyl 3- (5-chloropyrimidin-2-yl) pyrrolidine-1-carboxylate (compound 36-4)

Compound 36-3 (400 mg,1.42 mmol), rh (PPh ₃ ) ₃ Cl (113.76 mg,0.283 mmol) was dissolved in methanol (5 mL), hydrogen was replaced and the temperature was raised to 50℃and the reaction was stirred for 12 hours. After the completion of the reaction, the reaction mixture was concentrated to give a crude product, which was purified by column chromatography (dichloromethane: methanol (V/V) =10:1) to give the title compound 36-4 (300 mg, yield 74.5%). LC-MS, M/Z (ESI): 283.7 (M+1).

And a third step of: 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, the crude product was concentrated and dried by spin-drying, and purified by column chromatography (dichloromethane: methanol (V/V) =10:1) to give the title compound 36-5 (190 mg. Yield 98%). LC-MS, M/Z (ESI): 183.9 (M+1).

Fourth step: synthesis of (5R) -2- (3- (5-chloropyrimidin-2-yl) pyrrolidin-1-yl) -5-oxo- (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), N, N-diisopropylethylamine (422.3 mg,3.27 mmol) was dissolved in 1, 4-dioxane (3 mL) and placed in a microwave tube and reacted at 120℃for 0.5 h. After the reaction, the reaction mixture was diluted with methylene chloride and purified by chromatography (methylene chloride: methanol (V/V) =10:1), the column-passing solution was concentrated, and then purified by reversed-phase high performance liquid chromatography (column: sunFileTM Prep C18 OBDTM 5 μm30mm×150 mm); solvent: a=0.1% fa, b=acetonitrile; gradient: 1% -33.8%,7.2 min) to give the title compound (5R) -2- (3- (5-chloropyrimidin-2-yl) pyrrolidin-1-yl) -5-oxo- (6, 7-dihydrothieno [3, 2-d) ]Pyrimidin-5-yl) amino) cyclobutyl) -methanol (compound 36-a) (200 mg, 42.2% yield). LC-MS, M/Z (ESI): 435.0 (M+1). ¹ HNMR (400 mhz, cdcl 3) delta 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: target Compound 37-A-P1&Preparation of 37-A-P2:

(R) -2- ((2S, 4S or 4R) -4- (5-Chloropyrimidin-2-yl) -2-methylpiperidin-1-yl) -5-oxo- (6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl) amino) cyclobutane-1-carbonitrile (target compound 37-A-P1& 37-A-P2)

The synthetic route of the target compound 37-A- -P1 is as follows:

intermediate 4-P1 (50 mg,0.236 mmol), intermediate A1 (53.4 mg,0.189 mmol) and DIPEA (92 mg,0.708 mmol) were added to a microwave tube of 1, 4-dioxane (2 mL), and after microwave reaction at 120deg.C for 30min, the concentrated crude product was separated by reverse phase HPLC (column: phenomenex Luna C18150X 25 mm. Times.10 μm; mobile phase: A=water+0.01% by volume trifluoroacetic acid (99%), B=acetonitrile; gradient 35% -65% B,8 min) to give (R) -2- ((2S, 4S or 4R) -4- (5-chloropyrimidin-2-yl) -2-methylpiperidin-1-yl) -5-oxo- (6, 7-dihydrothieno [3,2-d ] ]Pyrimidin-4-yl) amino) cyclobutane-1-carbonitrile (retention time: 1.387 min) (Compound 37-A-P1,31.1mg, yield 28.7%). LC-MS, M/Z (ESI): 458.3 (M+1). ¹ H NMR(400MHz,cdcl3)δ8.62(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:

intermediate 4-P2 (50 mg,0.236 mmol), intermediate A1 (53.4 mg,0.189 mmol) and DIPEA (92 mg,0.708 mmol) were added to a microwave tube of 1, 4-dioxane (2 mL), and after microwave reaction at 120deg.C for 30min, the concentrated crude product was separated by reverse phase HPLC (column: phenomenex Luna C18150X 25 mm. Times.10 μm; mobile phase: A=water+0.01% by volume trifluoroacetic acid (99%), B=acetonitrile; gradient 35% -65% B,8 min) to give (R) -2- ((2S, 4S or 4R) -4- (5-chloropyrimidin-2-yl) -2-methylpiperidin-1-yl) -5-oxo-6, 7-dihydrothieno [3,2-d ]]Pyrimidin-4-yl) amino) cyclobutane-1-carbonitrile (retention time: 1.465 min) (Compound 37-A-P2, 54mg, yield 49.9%). LC-MS, M/Z (ESI): 458.3 (M+1). ¹ H NMR(400MHz,cdcl3)δ8.62(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 the target Compound 38-A:

(R) -2- (6- (5-Chloropyrimidin-2-yl) -2-azaspiro [3.3] heptan-2-yl) -5-oxo- (6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl) amino) -3, 3-difluorocyclobutyl) -methanol (target compound 38-A)

Synthetic route to the target compound 38-A:

starting 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 preparation reference 41-A synthesis), 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 ℃ for 2 hours. After the completion of the reaction, the reaction mixture was diluted with methylene chloride and purified by chromatography on a column (methylene chloride: methanol=50:1-10:1), the column-passing solution was concentrated and then purified by reverse phase high performance liquid chromatography (column: sunFileTM Prep C18 OBDTM (5 μm 30 mm. Times.150 mm); solvent: A=0.1% FA, B=acetonitrile; gradient: 1% -39%,6.8 minutes) to give the title compound 38-A (24.7 mg, yield 32.2%). LC-MS, M/Z (ESI): 497.12 (M+1). ¹ H NMR(600MHz,cdcl3)δ8.62(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-oxo- (6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl) amino-cyclobutyl-methanol (target compound 39-A)

Synthetic route to the target compound 39-A:

the first step: synthesis of tert-butyl 7- (((trifluoromethyl) sulfonyl) oxy) -2-azaspiro [3.5] non-6-ene-2-carboxylate (Compound 39-2)

The starting 7-oxo-2-azaspiro [3.5] nonane-2-carboxylic acid tert-butyl ester (800 mg,3.34 mmol) was dissolved in tetrahydrofuran (10 mL), liHMDs (2.51 mL, 2M) was slowly added dropwise at-78deg.C, and the reaction was stirred at-78deg.C for 1 hour. Then, a tetrahydrofuran solution (2.39g,6.69mmol in THF 10mL) of N-phenylbis (trifluoromethanesulfonyl) imide was added thereto at-78℃and the reaction was slowly warmed to room temperature to react for 10 hours. After completion of the reaction, water (10 mL) was added for dilution, extraction with ethyl acetate was performed three times, 20mL of ethyl acetate was used each time, and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by chromatography (petroleum ether: ethyl acetate (V/V) =50:1-5:1) to give the title compound 39-2 as a yellow oil (1.2 g, yield 96%).

And a second step of: synthesis of tert-butyl 7- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2-azaspiro [3.5] non-6-ene-2-carboxylate (Compound 39-3)

Starting material 7- (((trifluoromethyl) sulfonyl) oxyRadical) -2-azaspiro [3.5]Tert-butyl non-6-ene-2-carboxylate (1.2 g,3.23 mmol), pinacol biborate (984.6 mg,3.88 mmol), potassium acetate (951.37 mg,9.69 mmol) and Pd (dppf) Cl ₂ (234 mg,0.323 mmol) was dissolved in 1, 4-dioxane (15 mL), nitrogen was replaced and the temperature was raised to 80℃for 2 hours. After the reaction was completed, water (10 mL) was added to dilute, extraction was performed three times with ethyl acetate, 20mL of ethyl acetate was used each time, and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by chromatography (petroleum ether: ethyl acetate (V/V) =50:1-5:1) to give the title compound 39-3 as a pale yellow solid (1.0 g, yield 88.6%). LC-MS, M/Z (ESI): 294.0 (M-55).

And a third step of: synthesis of 7- (5-chloropyrimidin-2-yl) -2-azaspiro [3.5] non-6-ene-2-carboxylic acid tert-butyl ester (compound 39-5)

5-chloro-2-iodopyrimidine (450 mg,1.87 mmol), 7- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2-azaspiro [3.5] non-6-ene-2-carboxylic acid tert-butyl ester (719.1 mg,2.06 mmol), potassium carbonate (776 mg,5.61 mmol) and Pd (dppf) Cl2 (136 mg, 0.87 mmol) were dissolved in 1, 4-dioxane (10 mL) and water (1 mL), nitrogen was replaced and the temperature was raised to 80℃for 10 hours. After the reaction was completed, water (10 mL) was added to dilute, extraction was performed three times with ethyl acetate, 20mL of ethyl acetate was used each time, 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 (petroleum ether: ethyl acetate (V/V) =50:1-5:1) to give the title compound 39-5 (200 mg, yield 31.8%). LC-MS, M/Z (ESI): 280.0 (M-55).

Fourth step: synthesis of 7- (5-chloropyrimidin-2-yl) -2-azaspiro [3.5] non-2-carboxylic acid tert-butyl ester (compound 39-6)

Starting material 7- (5-chloropyrimidin-2-yl) -2-azaspiro [3.5]Non-6-ene-2-carboxylic acidTert-butyl ester (100 mg,0.297 mmol), rh (PPh ₃ ) ₃ Cl (23.8 mg,0.059 mmol) was dissolved in methanol (2 mL), hydrogen was replaced and the reaction was stirred for 12 hours at 50 ℃. After the completion of the reaction, the reaction mixture was concentrated to give a crude product, which was purified by column chromatography (dichloromethane: methanol (V/V) =10:1) to give the title compound 39-6 (80 mg, yield 79.5%). LC-MS, M/Z (ESI): 282.1 (M-55).

Fifth step: synthesis of 7- (5-chloropyrimidin-2-yl) -2-azaspiro [3.5] nonane (compound 39-7)

The starting material, tert-butyl 7- (5-chloropyrimidin-2-yl) -2-azaspiro [3.5] non-2-carboxylate (0.1 g, 0.298 mmol), was dissolved in dichloromethane (2 mL), then trifluoroacetic acid (0.5 mL) was added and the reaction stirred for 2h. After the completion of the reaction, the mixture was concentrated directly to dryness and purified by column chromatography (dichloromethane: methanol (V/V) =10:1) to give the title compound 39-7 (50 mg, yield 71.0%). LC-MS, M/Z (ESI): 237.9 (M+1).

Sixth step: synthesis of 2- (7- (5-chloropyrimidin-2-yl) -2-azaspiro [3.5] non-2-yl) -5-oxo- (6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl) amino-cyclobutyl-methanol (compound 39-A)

Starting 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)]Pyrimidine-4-yl) amino-cyclobutyl) methanol (29 mg,0.1 mmol) and N, N-diisopropylethylamine (49 mg,0.378 mmol) were dissolved in dioxane (2.0 mL) and placed in a microwave tube and reacted at 120℃for 0.5h. After the reaction, the reaction mixture was diluted with methylene chloride and purified by chromatography with silica gel (methylene chloride: methanol=50:1-10:1, concentrated to pass through the column, and then purified by reversed-phase high performance liquid chromatography (column: sunFileTM Prep C18 OBDTM (5 μm 30 mm. Times.150 mm); solvent: A=0.1% FA, B=acetonitrile; gradient: 1% -45.0%,9 minutes) to give 2- (7- (5-17-fold)Chloropyrimidin-2-yl) -2-azaspiro [3.5]Non-2-yl) -5-oxo- (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(400MHz,cdcl3)δ8.61(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 Compound 40-A-P1&40-A-P2

(R) -2- ((2S, 4S or 4R) -4- (5- (difluoromethyl) pyrimidin-2-yl) -2-methylpiperidin-1-yl) -5-oxo- (6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl) amino-cyclobutyl-methanol (target compound 40-A-P1& 40-A-P2)

The synthetic route for the target compound 40-A-P1&40-A-P2 is shown below:

the first step: synthesis of tert-butyl- (S) -2-methyl-4- (((trifluoromethyl) sulfonyl) oxo) -3, 6-dihydropyridine-1 (2H) -carboxylate (Compound 40-2)

Tert-butyl- (2S) -2-methyl-4-oxo-piperidine-1-carboxylic acid ester (20.0 g,93.7 mmol) was dissolved in tetrahydrofuran (300 mL), replaced with nitrogen, cooled to-65℃and 1M lithium bis (trimethylsilyl) amide tetrahydrofuran solution (1M, 20.4g,121mmol,121 mL) was slowly added dropwise and reacted for 30 minutes after the completion of the dropwise addition. Trifluoromethanesulfonic anhydride (31.7 g,112mmol,18.5 mL) was slowly added dropwise to the reaction mixture, and the mixture was allowed to react at 25℃for 3 hours after the completion of the dropwise addition. The reaction mixture was quenched by pouring it into a saturated ammonium chloride solution (1000 mL), extracted 3 times with ethyl acetate, 1500mL each time, and finally washed with saturated brine (1000 mL), dried over anhydrous sodium sulfate, and concentrated. Purification by silica gel column (petroleum ether: ethyl acetate (V/V) =1/0-10/1) gave (S) -2-methyl-4- (((trifluoromethyl) sulfonyl) oxo) -3, 6-dihydropyridine-1 (2H) -carboxylic acid ester (compound 40-2) (10.0 g, 30.9% yield) as a yellow oil

And a second step of: synthesis of tert-butyl- (S) -2-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate (Compound 40-3)

Tert-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 (pinacolato) diboron (1.76 g,6.95 mmol) were dissolved in 1, 4-dioxane (30 mL), and potassium acetate (1.14 g,11.5 mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (II) (423 mg, 579. Mu. Mol) were added to the reaction solution, and after the addition, nitrogen was replaced, the reaction was slowly raised to 90℃for 10 hours. The reaction solution was filtered through celite, concentrated and stirred, and purified by silica gel column (petroleum ether: ethyl acetate (V/V) =1/0-10/1) to give tert-butyl (S) -2-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid ester (compound 40-3) (1.50 g, yield 80.1%) as a yellow oily compound.

And a third step of: synthesis of tert-butyl- (S) -4- (5- (difluoromethyl) pyrimidin-2-yl) -2-methyl-3, 6-dihydropyridine-1 (2H) -carboxylic acid ester (compound 40-4)

Tert-butyl- (S) -2-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate (compound 40-3) (1.4 g,4.33 mmol) and 2-chloro-5- (difluoromethyl) pyrimidine (714 mg,4.33 mmol) were dissolved in 1, 4-dioxan (20 mL) and water (4 mL), and then potassium carbonate (1.20 g,8.66 mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (II) (316 mg, 433. Mu. Mol) were added to the reaction mixture, nitrogen was replaced three times, and the temperature was slowly raised to 90℃for 10 hours. The reaction solution was filtered through celite, and after concentration, the silica gel column was separated and purified (petroleum ether: ethyl acetate (V/V) =1/0-5/1) to give tert-butyl (S) -4- (5- (difluoromethyl) pyrimidin-2-yl) -2-methyl-3, 6-dihydropyridine-1 (2H) -carboxylic acid ester (compound 40-4) as a yellow solid (620 mg, yield 44.0%).

Fourth step: synthesis of tert-butyl (2S) -4- (5- (difluoromethyl) pyrimidin-2-yl) -2-methylpiperidine-1-carboxylate (compound 40-5)

Tert-butyl- (S) -4- (5- (difluoromethyl) pyrimidin-2-yl) -2-methyl-3, 6-dihydropyridine-1 (2H) -carboxylic acid ester (compound 40-4) (300 mg, 922. Mu. Mol) was dissolved in methanol (5 mL), tris (triphenylphosphine) rhodium (I) chloride (85.3 mg, 92.2. Mu. Mol) was added, and the mixture was replaced with argon, and then reacted at 50℃under 50Psi for 16 hours by introducing hydrogen. The reaction solution was concentrated and stirred, and purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) =1/0-5/1) to give tert-butyl- (2S) -4- (5- (difluoromethyl) pyrimidin-2-yl) -2-methylpiperidine-1-carbazate (compound 40-5) (280 mg, yield 93.3%)

Fifth step: 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-carboxylic acid ester (compound 40-5) (400 mg, 879. Mu. Mol) was dissolved in hydrogen chloride-dioxane (4M, 5 mL) and dioxane (5 mL) and reacted at 25℃for 1 hour. The reaction liquid was concentrated to give 5- (difluoromethyl) -2- ((2S) -2-methylpiperidin-4-yl) pyrimidine hydrochloride (compound 40-6) (232 mg, yield 98.6%).

Sixth step: synthesis of (R) -2- ((2S, 4S or 4R) -4- (5- (difluoromethyl) pyrimidin-2-yl) -2-methylpiperidin-1-yl) -5-oxo- (6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl) amino-cyclobutyl-methanol (40-A)

To 5- (difluoromethyl) -2- ((2S) -2-methylpiperidin-4-yl) pyrimidine hydrochloride (compound 40-6) (230 mg, 872. Mu. Mol) and (R) -2-chloro-4- ((1- (hydroxymethyl) cyclobutyl) amino) -6, 7-dihydrothieno [3,2-d ] pyrimidine 5-oxide (25.8 mg, 784. Mu. Mol) were dissolved in 1, 4-dioxane (10 mL), N-diisopropylethylamine (563 mg,4.36mmol, 759. Mu. L) was added, and then slowly warmed to 110℃for 10 hours. The reaction solution was poured into saturated sodium bicarbonate solution (20 mL), extracted 3 times with ethyl acetate (30 mL), washed with 30mL of ethyl acetate each time, saturated brine (30 mL), dried over sodium sulfate, concentrated, and purified by column chromatography on silica gel (dichloromethane: methanol (V/V) =1/0-10/1), followed by reversed phase high performance liquid chromatography (column: waters Xbridge 150 x 25 μm; solvent: a=water+aqueous ammonia (0.1%), b=acetonitrile; gradient: 30% -50%,10 minutes) to give (R) -2- ((2 s,4s or 4R) -4- (5- (difluoromethyl) pyrimidin-2-yl) -2-methylpiperidin-1-yl) - -5-oxo- (6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl) amino-cyclobutyl-methanol (compound 40-a) (150 mg, yield 33.8%). LC-MS, M/Z479.2 (M+H).

Seventh step: synthesis of (R) -2- ((2S, 4S or 4R) -4- (5- (difluoromethyl) pyrimidin-2-yl) -2-methylpiperidin-1-yl) -5-oxo- (6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl) amino-cyclobutyl-methanol (target compound 40-A-P1&40-A P2)

The racemate compound (R) -2- ((2S, 4S or 4R) -4- (5- (difluoromethyl) pyrimidin-2-yl) -2-methylpiperidin-1-yl) -5-oxide- (6, 7-dihydrothieno [3, 2-d)]Pyrimidin-4-yl) amino-cyclobutyl-methanol (compound 40-a) (80.0 mg,167 μmol) was chiral separated by normal phase high performance liquid chromatography (column: DAICEL CHIRALPAK IG (250 mm. Times.30 mm,10 μm); the method comprises the steps of carrying out a first treatment on the surface of the Solvent: a=carbon dioxide, b=aqueous ammonia (0.1%) + ethanol; gradient: 50% -50%,20 min) to give the compound (R) -2- ((2S, 4S or 4R) -4- (5- (difluoromethyl) pyrimidin-2-yl) -2-methylpiperidin-1-yl) -5-oxo- (6, 7-dihydrothieno [3, 2-d)]Pyrimidin-4-yl) amino-cyclobutyl-methanol (target compound 40-A-P1) retention time 1.507min (20.0 mg, 25.0% yield), LC-MS, M/Z (ESI): 479.2 (M+H). ¹ H NMR(400MHz,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-oxo- (6, 7-dihydrothieno [3, 2-d)]Pyrimidin-4-yl) amino-cyclobutyl-methanol (target compound 40-a-P2) retention time 1.964min (40.0 mg, yield 50.0%). LC-MS, M/Z (ESI): 479.2 (M+H). ¹ H NMR(400MHz,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-methylpiperidin-1-yl) -5-oxo-6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl) amino) -3, 3-difluorocyclobutyl) -methanol (compound 41-A-P1& 41-A-P2)

The synthetic route for the target compound 41-A- -P1&41-A-P2 is shown below:

the first step: synthesis of tert-butyl- (S) -2-methyl-4- (((trifluoromethyl) sulfonyl) oxo) -3, 6-dihydropyridine-1 (2H) -carboxylate (Compound 41-2)

Tert-butyl- (S) -2-methyl-4-oxopiperidine-1-carboxylate (20.0 g,93.7 mmol) was dissolved in tetrahydrofuran (400 mL), replaced with nitrogen, cooled to-70℃and a solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran (1M, 112 mL) was slowly added dropwise to the reaction mixture, and the reaction was continued for 30 minutes after the completion of the dropwise addition. N, N-bis (trifluoromethanesulfonyl) aniline (31.8 g,89.0 mmol) was dissolved in tetrahydrofuran (80 mL), and the mixture was slowly added dropwise to the reaction mixture, followed by reaction at 25℃for 3 hours after 30 minutes after completion of the dropwise addition. The reaction solution was poured into a saturated ammonium chloride solution (400 mL), quenched, extracted 3 times with ethyl acetate, washed 2 times with 1.2L of ethyl acetate each time, and with 800mL of sodium chloride each time, dried over anhydrous sodium sulfate, and concentrated. Purification by silica gel column (petroleum ether: ethyl acetate (V/V) =1/0-20/1) afforded the product tert-butyl (S) -2-methyl-4- (((trifluoromethyl) sulfonyl) oxo) -3, 6-dihydropyridine-1 (2H) -carboxylic acid ester (compound 41-2) as a yellow oil (23.0 g, 71.0% yield).

And a second step of: synthesis of tert-butyl- (S) -2-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate (Compound 41-3)

Tert-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 (pinacolato) diboron (7.35 g,28.9 mmol) were dissolved in 1, 4-dioxane (120 mL), and 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, and after the addition, nitrogen was replaced, the reaction was slowly raised to 90℃for 6 hours. The reaction solution was filtered through celite, concentrated and purified by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =1/0-20/1) to give tert-butyl- (S) -2-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate (compound 41-3) (8.00 g, crude product) as a colorless oily product.

And a third step of: synthesis of tert-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, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridin-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-dioxan (50 mL) and water (5 mL), and then potassium carbonate (4.17 g,30.1 mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (II) (367 mg, 502. Mu. Mol) were added to the reaction solution. The temperature was raised to 90℃and the reaction was carried out for 6 hours. The reaction solution was concentrated, diluted with 50mL of water, extracted 3 times with ethyl acetate, each time with 150mL of ethyl acetate, dried over sodium sulfate, concentrated, and purified by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =1/0-5/1) to give tert-butyl (S) -4- (5-chloropyrimidin-2-yl) -2-methyl-3, 6-dihydropyridine-1 (2H) -carboxylate (compound 41-4) (2.00 g, yield 80.0%).

Fourth step: synthesis of tert-butyl- (2S) -4- (5-chloropyrimidin-2-yl) -2-methylpiperidine-1-carboxylic acid ester (Compound 41-5)

Tert-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 methyl (50 mL), tris (triphenylphosphine) rhodium (I) chloride (593 mg, 641. Mu. Mol) was added, replaced with argon, and hydrogen was introduced to react at 50℃for 48 hours at 50 Psi. The reaction solution was concentrated and stirred after celite filtration, and purified by silica gel column (petroleum ether: ethyl acetate (V/V) =1/0-5/1) to give tert-butyl (2S) -4- (5-chloropyrimidin-2-yl) -2-methylpiperidine-1-carboxylate (compound 41-5) (1.8 g,5.77mmol, yield 90.4%) as a brown oily product

Fifth step: synthesis of 5-chloro-2- ((2S) -2-methylpiperidin-4-yl) pyrimidine hydrochloride (Compound 41-6)

Tert-butyl- (2S) -4- (5-chloropyrimidin-2-yl) -2-methylpiperidine-1-carboxylate (compound 41-5) (1.00 g,2.89 mmol) was dissolved in anhydrous dichloromethane (10 mL), and dioxane hydrochloride (4M, 3 mL) was slowly added dropwise to the reaction solution at 25℃for 1 hour. The reaction liquid was concentrated to give 5-chloro-2- ((2S) -2-methylpiperidin-4-yl) pyrimidine hydrochloride (compound 41-6) (700 mg, yield 92.3%).

Sixth step: 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. Mu. Mol) 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. Mu. Mol) were dissolved in 1, 4-dioxane (30 mL), N-diisopropylethylamine (454 mg,3.52 mmol) was added, and then slowly warmed to 120℃for 48 hours. The reaction solution was poured into saturated sodium hydrogencarbonate solution (30 mL), extracted 4 times with ethyl acetate (20 mL) and methanol (2.00 mL), dried over excess anhydrous sodium sulfate, and concentrated. Silica gel plate separation and purification (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).

Seventh step: synthesis of (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-P1& 41-A-P2)

The racemate (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) (120 mg,240.4 μmol) was chiral separated by normal phase high performance liquid chromatography (column: DAICEL CHIRALCEL OJ (250 mm. Times.30 mm,10 μm); mobile phase: a=carbon dioxide-methanolic ammonia (0.1%), b=ammonia (0.1%); b=25% isocratic elution, 5.6 min) to give (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-P1) retention time 1.291min (30.0 mg, 25.0%). LC-MS, M/Z (ESI): 449.2 (M+H). 1H NMR (400 MHz, DMSO-d 6) delta: 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) had a retention time of 1.625min (50.0 mg, yield 41.7%). LC-MS, M/Z (ESI): 449.3 (M+H). 1H NMR (400 MHz, DMSO-d 6) delta: 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 analogously to the synthetic method of reference compound 1-A.

/>

Test example 1: PDE4B and PDE4D enzyme Activity assays

The inhibitory activity of the compounds of the invention on PDE4B and PDE4D can be detected using PDE-Glo Phosphodiesterase Assay Kit (promega, V1361). Firstly, preparing a concentrated solution of a compound to be detected into 10mM in DMSO solvent, and then diluting the concentrated solution into 10X working solution by using a Reaction buffer provided by a kit. PDE4B enzyme (Enzo Life Sciences, BML-SE 522-0020) was diluted to a concentration of 1 ng/. Mu.L and PDE4D enzyme (Enzo Life Sciences, BML-SE 523-0020) to a concentration of 4 ng/. Mu.L with a Reaction buffer, operating on ice. 1.5ul of PDE4B or PDE4D working solution and 1. Mu.L of compound working solution were added to wells of 384 well plates (Corning, CLS 3707) and incubated at room temperature with shaking for 5 minutes, followed by addition of 2.5. Mu.L/well cAMP (2. Mu. M in Reaction Buffer), followed by incubation at room temperature with shaking for 20 minutes, followed by addition of 2.5. Mu.L/well 1X Termination Buffer, followed by addition of 2.5. Mu.L/well 1X Detection Buffer, and followed by shaking at room temperature for 20 minutes. Finally, 10. Mu.L/well 1 XKinase-Glo was added, incubated for 10 minutes with shaking at room temperature, and bioluminescence was detected with a PheraStar instrument. Inputting experimental results into GraphPad Prism software, and performing fitting calculation to obtain IC of each compound ₅₀ 。

TABLE 1 IC of Compounds ₅₀ Value of

/>

Experimental results show that the compounds of the invention can be used as selective inhibitors of PDE 4B. When the composition is used for treating diseases related to PED4, side effects such as vomiting can be effectively improved.

Test column 2: LPS-induced human PBMC secretion TNFα model assay

PBMC extraction process: fresh human peripheral concentrated blood was obtained, 1 unit of human peripheral concentrated blood (concentrated from 200cc of peripheral blood) was aspirated, and 0.9% physiological saline was quantitatively added to a total volume of 120ml, and mixed well. A50 ml centrifuge tube was added with 15ml LymphoprepTM, and the tube was held by hand, at about 45℃to draw 30ml of diluted concentrated blood, and carefully and slowly attached to the tube to allow the diluted blood to overlap the separate liquid and avoid mixing the diluted blood into the separate liquid or bursting the separate liquid surface. The ratio of LymphoprepTM to diluted blood was 1:2. The tube was trimmed and placed in a horizontal centrifuge (eppendorf, 5810R), centrifuged at 800g for 20min at 20℃with an up-speed of 1 and a down-speed of 0. Carefully remove the centrifuge tube. The Pasteur pipette is directly penetrated into the tunica albuginea layer to suck the PBMC. Adding 3 times of 0.9% physiological saline or PBS (without calcium and magnesium), and gently stirring. After homogenization, the cells were centrifuged at 20℃and 250g for 10min, the platelets remaining in the cell suspension were removed, the supernatant was removed, the cell pellet was suspended in 20ml PBS and trypan blue staining counted.

PBMC screening procedure: PBMCs obtained in step 1 were centrifuged, PBS was removed, and then counted in complete medium (RPMI 1640+10% fbs+1% p/S) for resuspension. According to 5X 10 ⁴ Well, 100. Mu.L/well into cells. The compounds to be screened were formulated to a final concentration of 4×. Added to the cells at 50. Mu.L/well. Preincubation was performed for 30min in advance. Control wells were also set without compound. The final stimulation concentration of LPS was 10ng/ml, diluted to 4-fold solution and added to the cells at 50. Mu.l/well. Control wells were also set without LPS wells. Cells were continued to be incubated and 10% of the supernatant was collected at 24h for detection. The collected supernatants were assayed according to the Invitrogen Human TNFα kit (REF: 88-7346-88). According to the upper partThe method is used for measuring the inhibitory activity of the compound provided by the invention on LPS induced human secretion of TNF alpha.

TABLE 2 results of test Compounds for inhibitory Activity of LPS-induced human PBMC to secrete TNFa

Numbering of compounds	TNFalpha 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 has excellent human PBMC secretion TNFα inhibition activity, can better inhibit the secretion of inflammatory factor TNFα in human PBMC, and has good anti-inflammatory effect.

Test example 3: pharmacokinetic test in mice

Mouse pharmacokinetic experiments Male ICR mice, 20-25g, were used, fasted overnight. 3 mice were taken and orally administered with 10mg/kg by intragastric administration. Blood was collected before and 15, 30 minutes and 1, 2, 4, 8, 24 hours after administration, respectively. Blood samples 6800g were centrifuged at 2-8deg.C for 6 minutes, and plasma was collected and stored at-20deg.C. Plasma at each time point is taken, 3-5 times of acetonitrile solution containing an internal standard is added, vortex mixing is carried out for 1 minute, 13000 r/min and centrifugation are carried out at 4 ℃ for 10 minutes, 3 times of water is added into the supernatant for mixing, and a proper amount of mixed solution is taken for LC-MS/MS analysis. The principal pharmacokinetic parameters were analyzed using the WinNonlin 7.0 software non-compartmental model.

TABLE 3 pharmacokinetic test results in mice

Experimental results show that the compounds of the invention exhibit excellent plasma exposure and have excellent pharmacokinetic properties.

Test example 4: rat pharmacokinetic test

Rat pharmacokinetic experiments Male SD mice were used, weighing 200-250 g/mouse, and fasted overnight. 3 rats were given 10mg/kg orally administered by intragastric administration using the compounds of the invention. Blood was collected 5, 15, 30 minutes and 1, 2, 4, 8, 24 hours before and after administration, respectively. Blood was collected in 0.2mL place in EDTA-2K anticoagulant tubes containing the label. After thoroughly mixing the anticoagulant (EDTA-2K) with blood by gentle inversion, the mixture was immediately placed in wet ice and the plasma was centrifuged at 6800 Xg for 6 minutes at 4℃within 1 hour after blood collection. The plasma obtained after centrifugation is placed in a labeled EP tube and stored in an ultra-low temperature refrigerator as soon as possible until the sample is analyzed. The principal pharmacokinetic parameters were analyzed using the WinNonlin 7.0 software non-compartmental model and the results are shown in table 4.

TABLE 4 pharmacokinetic test results in rats

Test example 5: beagle dog pharmacokinetic test

Beagle dogs were used for pharmacokinetic testing with male Beagle dogs weighing 7-12 kg/dog, and fasted overnight. 3 Beagle dogs were taken and administered 3 or 10mg/kg orally by gavage with the compounds of the present invention. Blood was collected 5, 15, 30 minutes and 1, 2, 4, 8, 24 hours before and after administration, respectively. Blood samples were centrifuged at 2200 Xg at 2-8deg.C for 6 minutes, and plasma was collected and stored at-20deg.C. The principal pharmacokinetic parameters were analyzed using the WinNonlin 7.0 software non-compartmental model and the results are shown in table 5.

TABLE 5 pharmacokinetic test results for Beagle dogs

While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.

Claims

1. A compound which is a compound of formula II or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of a compound of formula II:

wherein,

ring A is a 5-10 membered aromatic or heteroaromatic ring;

m and n are 0, 1, 2 or 3 respectively;

y is selected from NR ¹ O, S or CHR ¹ ；

q is selected from the following groups:or Q ¹ ；

M is cyano;

R ² and R is ³ To, R ⁵ And R is ⁶ Each of the pairs may independently form a saturated or partially saturated 3-, 4-, 5-, 6-membered monocyclic ring with the carbon atoms to which they are attached; wherein the 3-, 4-, 5-, 6-, or 6-membered monocyclic ring contains 0, 1, 2, or 3N atoms and 0, 1, or 2 atoms selected from O and S, and further wherein the 3-, 4-, 5-, or 6-membered monocyclic ring is selected from 0, 1, 2, or 3R ²³ Substitution, said R ²³ Selected from at least one of the following: halogen, hydroxy, amino, cyano, carbonyl, oxo, carboxyl, C _1-6 Alkyl, C _2-6 Alkenyl group,C _2-6 Alkynyl, C _1-6 Deuterated alkyl, C _1-4 Haloalkyl, C _1-6 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -COO-C _1-6 Alkyl, -C (O) NR ^f R ^f The method comprises the steps of carrying out a first treatment on the surface of the Wherein the R is ^f Is hydrogen, C _1-6 An alkyl group;

R ⁴ selected from halogen, hydroxy, 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 Halogenated cycloalkyl, C _1-6 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, 3-10 membered heterocycloalkyl; the C is _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 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups are optionally substituted with one or more R ^g Substitution; the R is ^g A substituent selected from at least one of: halogen, hydroxy, 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 hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups; when the substituent R ^g When there are a plurality of R ^g The same or different;

2. The compound of claim 1, wherein the compound has a structure of formula II-A or formula II-B,

3. the compound of claim 1, wherein ring a is selected from 5-9 membered heteroaryl rings;

optionally, the heteroaryl ring has 1 or 2 heteroatoms;

Optionally, the heteroatom is selected from N or O;

optionally, the ring a is selected from a pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, or benzoxazolyl;

optionally, the ring A is selected from

Optionally, the structural unitSelected from->

Optionally, the R ^a Selected from F, cl, CH ₃ Or CH substituted by halogen ₃ ；

Optionally, the R ^a Selected from F, cl or CHF ₂ ；

Optionally, said Y is selected from NR ¹ Or CHR (CHR) ¹ When R is ¹ Selected from H or C _1-6 An alkyl group;

optionally, the Y is selected from-NH-.

4. The compound of claim 1, wherein the compound has a structure of formula III or formula IV,

5. a compound according to any one of claims 1 to 4 wherein Q is selected from the group consisting of:

optionally, B is selected from 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl;

optionally, B is selected from 3-10 membered heterocycloalkyl;

optionally, the 3-10 membered heterocycloalkyl is selected from monocyclic, fused bicyclic, bridged or spiro bicyclic;

optionally, the 3-10 membered heterocycloalkyl further has 1 to 3 heteroatoms selected from N, O, S;

optionally, B is selected from 3-10 membered heterocycloalkenyl;

optionally, the 3-10 membered heterocycloalkenyl is selected from monocyclic or fused bicyclic;

Optionally, the 3-10 membered heterocycloalkenyl further has 1 to 3 heteroatoms selected from N, O, S.

6. A compound according to any one of claims 1 to 5, wherein B is selected from the group consisting of:

Z ¹ 、Z ² 、Z ³ 、Z ⁴ 、Z ⁵ 、Z ⁶ 、Z ⁷ 、Z ⁸ and Z ⁹ Each independently is N, NH, CH ₂ 、CH、C、-NH-CH ₂ -or-CH ₂ -CH ₂ -；

p is 0, 1 or 2, wherein when p is 0,is->Preferably, the +>Is that

Preferably, the method comprises the steps of,is->

7. The compound of claims 1-6, wherein R ^b Selected from C _1-6 Alkyl, halogen, C _3-8 Cycloalkyl or oxo;

optionally, the R ^b Selected from methyl, F, cyclic ethyl or oxo;

optionally, the R ^c Selected from 0, 1, 2 or 3;

optionally, the R ^c Selected from halogen, oxo, C _1-6 Alkyl or C _1-6 A haloalkyl group;

optionally, the R ^g Selected from 0, 1, 2 or 3;

optionally, the R ^g Selected from halogen, hydroxy, cyano, C _1-6 Alkyl or C _1-6 A haloalkyl group.

8. The compound of any one of claims 1-4, wherein the fragment Selected from the group consisting of

9. A compound according to claim 1, wherein the compound is selected from the following structures:

wherein Z is ¹ 、Z ⁴ Each independently selected from N, CH or C.

10. A compound according to claim 1, wherein the compound is selected from the following structures:

wherein,

m is 0, 1, 2 or 3;

n is 1, 2 or 3;

Z ¹ 、Z ⁴ each independently selected from N, CH or C.

11. The compound according to claims 1-10, wherein Q is selected from the group consisting of:

r is 0, 1, 2 or 3;

optionally R ²³ Selected from at least one of the following: halogen, hydroxy, 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 hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -COO-C _1-6 Alkyl or-C (O) NR ^f R ^f The method comprises the steps of carrying out a first treatment on the surface of the Wherein the R is ^f Is hydrogen, C _1-6 An alkyl group;

optionally R ⁴ Selected from at least one of the following: halogen, hydroxy, 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 Halogenated cycloalkyl, C _1-6 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, 3-10 membered heterocycloalkyl; the C is _1-6 Alkyl, C ₃ -C ₈ Cycloalkyl, C _1-6 Deuterated alkyl, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _3-8 Halogenated cycloalkyl, C _1-6 Alkyl hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups are optionally substituted with one or more R ^g Substitution; the R is ^g A substituent selected from the group consisting of: halogen, hydroxy, 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 hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups; when the substituent R ^g When there are a plurality of R ^g The same or different;

optionally R ⁷ Selected from 1, 2 or 3;

optionally R ⁷ Selected from at least one of the following: H. halogen, hydroxy, 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 hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups;

optionally, said M is selected from cyano;

optionally, the R ⁴ Selected from hydroxyl or cyano;

optionally, the R ²³ Selected from F;

optionally, the R ⁷ Selected from H, hydroxy, cyano or CH ₃ ；

Optionally, Q is selected from the group consisting of:

12. the compound of claim 1, wherein the compound has the structure:

the Z is ¹ And (3) withConnected with the Z ⁴ Is connected with the ring A;

m, n are each independently 0,1,2 or 3;

when B' is selected fromZ ₁ Is N, Z ₄ In the case of CH, Q is not +.>n is 0,1,2,3;

or Q isWhen n is 1,2,3.

13. A compound according to claim 1, wherein the compound is selected from the following structures:

wherein r is 0,1,2 or 3.

14. A compound according to claim 1, wherein the compound is selected from the following structures:

/>

wherein B is a 4-to 9-membered heterocycloalkyl having 1 to 3 heteroatoms selected from N, O, S; the 4-9 membered heterocycloalkyl is monocyclic, fused bicyclic, bicyclic including bridged or spiro;

R ^b Selected from halogen, hydroxy, 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 hydroxy, C _1-6 Alkylcarbonyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups;

n is 0, 1, 2 or 3.

15. A compound according to claim 1, wherein the compound is selected from the following structures:

preferably, the compound is selected from the following structures:

wherein Z is ¹ And Z ⁴ Each independently N, CH or C.

16. A compound according to claim 1, wherein the compound is selected from the following structures:

preferably, the compound is selected from the following structures:

wherein Z is ¹ And Z ⁴ Each independently N, CH or C.

17. A compound according to claim 1, wherein the compound is selected from the following structures:

preferably, the compound is selected from the following structures:

wherein Z is ¹ And Z ⁴ Each independently N, CH or C.

18. A compound according to claim 1, wherein the compound is selected from the following structures:

preferably, the compound is selected from the following structures:

wherein Z is ¹ And Z ⁴ Each independently N, CH or C.

19. A compound according to claim 1, wherein the compound is selected from the following structures:

Preferably, the compound is selected from the following structures:

wherein Z is ¹ And Z ⁴ Each independently N, CH or C.

20. A compound according to claim 1, wherein the compound is selected from the following structures:

preferably, the compound is selected from the following structures:

wherein Z is ¹ And Z ⁴ Each independently N, CH or C.

21. A compound according to claim 1, wherein the compound is selected from the following structures:

preferably, the compound is selected from the following structures:

wherein Z is ¹ And Z ⁴ Each independently N, CH or C.

22. A compound according to claim 1, wherein the compound is selected from the following structures:

wherein the fragmentSelected from->

Ring A, R ^a And m is as defined in claim 1.

23. A compound according to claim 1, wherein the compound is selected from the following structures:

wherein the fragmentSelected from->Ring A, R ^a And m is as defined in claim 1.

24. A compound according to claim 22 or 23, wherein the structural unitSelected from the group consisting of

25. A compound according to claim 1, wherein the compound is selected from the following structures:

/>

26. the compound of claim 1, wherein the compound is selected from the following structures:

/>

27. A compound according to claim 1, wherein the compound is selected from the following structures:

/>

28. a pharmaceutical composition, the pharmaceutical composition comprising: the compound of any one of claims 1-27, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof;

optionally, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or adjuvant.

29. Use of a compound of any one of claims 1-27, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition of claim 28, for inhibiting PDE 4B.

30. Use of a compound according to any one of claims 1 to 27, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition according to claim 28, for the manufacture of a medicament or formulation for inhibiting PDE4B, and/or for the prophylaxis and/or treatment of a PDE 4B-related disease.

31. The use according to claim 30, wherein the PDE 4B-related disease comprises: respiratory diseases, gastrointestinal diseases, inflammatory diseases of the joints, skin or eyes, cancer, peripheral or central nervous system diseases, autoimmune diseases, graft rejection reactions or diseases associated with smooth muscle contractility;

Optionally, the respiratory disease is selected from respiratory or pulmonary diseases accompanied by increased mucus production, airway inflammation, and/or obstructive diseases;

optionally, the respiratory disease is selected from COPD, idiopathic pulmonary fibrosis, alpha 1-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 xerosis;

optionally, the gastrointestinal disease is selected from the group consisting of Crohn's disease, ulcerative colitis, and Crohn's disease;

optionally, the inflammatory disease of the joint, skin or eye 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, renal parenchymal carcinoma, ovarian cancer, cervical cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, bladder cancer, testicular cancer, breast cancer, urinary carcinoma, melanoma, brain tumor, lymphoma, head and neck cancer, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, acute myeloid leukemia, chronic granulocytic leukemia, hepatocellular carcinoma, gall bladder cancer, bronchogenic cancer, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal sarcoma, teratoma, retinoblastoma, choriocarcinoma, seminoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, myoma, liposarcoma, fibrosarcoma, ewing sarcoma, and plasmacytoma;

Optionally, the peripheral or central nervous system disorder 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.