WO2023071998A1

WO2023071998A1 - Novel pyrido or triazine-substituted pyrido heterocyclic compound

Info

Publication number: WO2023071998A1
Application number: PCT/CN2022/127094
Authority: WO
Inventors: 张龙; 牛张明
Original assignee: 杭州德睿智药科技有限公司
Priority date: 2021-10-26
Filing date: 2022-10-24
Publication date: 2023-05-04

Abstract

A substituted pyrido heterocyclic compound or a pharmaceutically acceptable salt thereof, a solvate thereof, a hydrate thereof, an isotope substitution thereof, or an isomer thereof. The structure of the compound is shown in formula (I). The compound of formula (I) has an affinity effect on an EGFR mutation target, especially has a strong proliferation inhibitory effect on EGFR19del/L858R-T790M-C797S triple mutant cancer cells, can be used for preparing drugs or molecular probes for preventing or treating diseases (such as cancer and immune diseases) related to the signal pathway of EGFR mutation (especially EGFR19del/L858R-T790M-C797S triple mutation).

Description

Novel pyrimidine or triazine substituted pyridoheterocyclic compounds

This application claims priority to the following earlier application:

Submitted to the State Intellectual Property Office of China on October 26, 2021, the patent application number is 202111250358.6, and the title is "Novel pyrimidine or triazine substituted pyridoheterocyclic compounds";

Submitted to the State Intellectual Property Office of China on June 16, 2022, the patent application number is 202210689115.0, and the name is "Novel pyrimidine or triazine substituted pyridoheterocyclic compound";

The entirety of said prior application is incorporated by reference into this application.

field of invention

The invention belongs to the field of medicinal chemistry and discloses a novel pyrimidine or triazine substituted pyridoheterocyclic compound, which can be used as an EGFR mutation target inhibitor. Specifically disclosed are compounds represented by the structure of formula (I) or pharmaceutically acceptable salts, solvates, hydrates, isotope substitutions or isomers thereof. The compound of the formula (I) has a strong affinity for the EGFR mutation target, especially for the EGFR19del/L858R-T790M-C797S triple mutant protein, and can be used to prepare for the prevention or treatment of EGFR mutations (especially 19del/L858R-T790M-C797S). L858R-T790M-C797S triple mutation) signaling pathway-related diseases (such as cancer, immune diseases, etc.)

Background of the invention

Epidermal growth factor receptor (EGFR) is a member of the erbB receptor family, which includes four major transmembrane protein tyrosine kinase receptor members EGFR, erbB2, erbB3 and erbB4. By binding to ligands such as epidermal growth factor (EGF), EGFR can form homodimers on the cell membrane or form heterodimers with several other major members of the same family, such as erbB2, erbB3 or erbB4. The formation of these dimers can lead to phosphorylation of key tyrosine residues in EGFR-expressing cells, thereby activating many intracellular downstream signaling pathways, resulting in cell proliferation, survival and resistance to apoptosis. Disorders of EGFR signal transduction pathways, including increased expression of ligands and receptors, EGFR gene amplification and changes such as mutations and deletions, can promote malignant transformation of cells and play an important role in tumor cell proliferation, invasion, metastasis and angiogenesis .

Studies have found that changes such as EGFR gene mutation and deletion are one of the most important causes of non-small cell lung cancer. Several of the most common EGFR mutations found in NSCLC tumors are exon 19 (del 19) deletion, L858R mutation, and single missense mutation in exon 21. These several changes lead to ligand-independent EGFR activation, leading to the occurrence, development and progression of tumors. At present, a variety of EGFR inhibitors have been approved for marketing, such as erlotinib, gefitinib, afatinib, osimertinib, etc.

However, tumors quickly develop resistance to these small molecule inhibitors after first-generation drugs (such as erlotinib or gefitinib) and second-generation drugs (afatinib). The most prominent resistance mechanism to first- and second-generation EGFR-TKIs is due to secondary mutations in genes such as T790M mutations, which occur in about 50% to 70% of patients. This secondary mutation reduces the affinity of the first- and second-generation drugs for the target protein, resulting in drug resistance and leading to tumor recurrence or disease progression. The third-generation EGFR TKI—osimertinib

It has been developed for the treatment of primary EGFR mutation-positive NSCFC patients with tumors with or without the T790M mutation in the dell9 or L858R gene mutation. Although the third-generation EGFR TKI osimertinib has shown good efficacy in NSCLC, unfortunately, after an average of more than 10 months of treatment, most patients still develop resistance to the drug, leading to disease progression. One of the main reasons for drug resistance is the mutation of EGFR exon 20 C797 (C797S).

The EGFR dell9/L858R-T790M-C797S cis mutation commonly occurs in patients treated with osimertinib and is referred to as a “triple mutation” where first-, second-, or third-generation EGFR inhibitors are no longer effective. There are currently no effective therapeutics that can inhibit the triple mutant variant. Therefore, there is an urgent need to develop new EGFR inhibitors that can highly selectively inhibit the triple EGFR mutant (dell9/L858R-T790M-C797S) while having no or low activity against wild type.

technical effect

The inventors unexpectedly found that some of the novel compounds of the formula (I) of the present invention showed a very high affinity with triple EGFR mutant (dell9/L858R-T790M-C797S) protein affinity prediction, which is expected to be used for the detection of EGFR mutant tumors treat. Further research is still ongoing.

Contents of the invention

The object of the present invention is to provide new compounds shown in formula (I) or pharmaceutically acceptable salts, solvates, isomers and isotope substitutions thereof:

in,

A and B are 3-20-membered ring structures, and the ring structures can be arbitrarily monocyclic, bicyclic, tricyclic, bridging rings or spiro rings containing 0 to more unsaturated bonds; and the ring structures It can optionally contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;

X ₁ , X ₂ , X ₃ , X ₄ , X ₅ , X ₆ , X ₇ and X ₈ are each independently selected from C(R ₀ ) or N; or, X ₅ , X ₆ and their respective attached atoms form a hydrocarbon ring or heterocycle; or, X ₂ and X ₁ or X ₂ and X ₃ form a hydrocarbon ring or a heterocycle with their respective attached atoms;

Y ₀ is independently selected from a single bond, an acetylene bond, -O-, -S-, -N(R ₃ )-, -C(R ₆ R ₇ )O-, -OC(R ₆ R ₇ )- or - C(R ₆ R ₇ )-;

_Y1 and _Y2 are each independently selected from CH or N;

_R is randomly selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, amino, alkenyl , hydroxyl, cyano, nitro; and any two adjacent X ₁ , X ₂ and X ₃ or any two adjacent X ₅ , X ₆ , X ₇ and X ₈ together with the R ₀ connected thereto can constitute 3-10 membered ring structure, the ring structure can be any saturated, unsaturated or aromatic structure, and the ring structure can contain 0 to more heteroatoms, the heteroatoms can be selected from O , S or N;

_R is independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, Deuterated C1-6 alkoxy, cycloalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy; and the hydroxyl, amino, C1-6 alkyl, alkenyl, Hydrogen on alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy Can be optionally further substituted by 1 to more substituents, the substituents are arbitrarily selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 Alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, cycloalkoxy;

_R is arbitrarily selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, amino, alkenyl, cyano, Cyanoalkyl, nitro, acyl, sulfonyl, phosphono; and the C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocyclic, The hydrogen on the heterocycloalkyl, amino, alkenyl, cyano, cyanoalkyl, nitro, acyl, sulfonyl, phosphono can be optionally further substituted by 1 to more substituents, and the substituents are optionally The following groups selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, unsubstituted or optionally substituted by one, two or more R ₅ : C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, sulfone, sulfoxide , alkylsulfone group, alkylsulfoxide group, alkylaminosulfone group, iminosulfone group, acyl group, sulfonyl group, sulfinyl group, phosphono group, cycloalkoxy group, phosphonocycloalkoxy group,

Z is any independently O, NH or N(R ₃ );

_R is arbitrarily selected from H, deuterium, halogen, hydroxyl, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, amino, C1-6 alkylamino, alkenyl, alkynyl, nitro, cyano, cyanoalkyl, C1-6 alkyl acyl, halogenated C1-6 alkyl acyl, sulfonyl, phosphono;

_R is independently selected from H, deuterium, halogen, hydroxyl, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, Amino, C1-6 alkylamino, alkenyl, alkynyl, cyano, cyanoalkyl, C1-6 alkyl acyl, halogenated C1-6 alkyl acyl; and the hydrogen on _R can be the most optional Further substituted by 1 to more substituents, any of which are independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkane Oxygen, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, cycloalkoxy, alkylamino;

R _and _R are arbitrarily selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, amino, C1-6 Alkylamino, alkenyl, alkynyl, nitro, cyano, cyanoalkyl; or R ₇ and R ₆ form a 3-10-membered ring structure together with the carbon directly connected to it, and the ring structure can be any It is a monocyclic ring, a bicyclic ring, a bridged ring or a spiro ring containing 0 to more unsaturated bonds; and the ring structure can optionally contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;

The halogen is F, Cl, Br and iodine and their respective isotopes;

m, n and t are each independently 0, 1, 2, 3, 4 or 5.

In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotopic substitution or its isomer has a structure of formula (I'):

in,

X ₁ , X ₂ , X ₃ , X ₄ , X ₅ , X ₆ , X ₇ and X ₈ are each independently selected from C(R ₀ ) or N;

_R is arbitrarily selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, amino, alkenyl, cyano, Cyanoalkyl, nitro, acyl, sulfonyl, phosphono; and the C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocyclic, The hydrogen on the heterocycloalkyl, amino, alkenyl, cyano, cyanoalkyl, nitro, acyl, sulfonyl, phosphono can be optionally further substituted by 1 to more substituents, and the substituents are optionally From hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkane Oxygen, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, sulfone, sulfoxide, alkylsulfone, alkylsulfoxide, alkylaminosulfone, iminosulfone , acyl, sulfonyl, phosphonocycloalkoxy;

R and _R are arbitrarily selected from H, deuterium, halogen, C1-6 alkyl, _halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, amino, C1-6 Alkylamino, alkenyl, alkynyl, nitro, cyano, cyanoalkyl; or R ₇ and R ₆ form a 3-10-membered ring structure together with the carbon directly connected to it, and the ring structure can be any It is a monocyclic ring, a bicyclic ring, a bridged ring or a spiro ring containing 0 to more unsaturated bonds; and the ring structure can optionally contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;

The halogen is F, Cl, Br and iodine and their respective isotopes;

m, n and t are each independently 0, 1, 2, 3, 4 or 5.

In one aspect of the present invention, the compound or its pharmaceutically acceptable salt, isotope substitution or its isomer has the structure of formula (IA):

in,

A is a 3-20-membered ring structure, and the ring structure can be arbitrarily monocyclic, bicyclic, tricyclic, bridged or spiro ring containing 0 to more unsaturated bonds; and the ring structure can be any Contains 0 to more heteroatoms, the heteroatoms are arbitrarily selected from O, S or N;

Y ₀ is independently selected from a bond, an acetylene bond, -O-, -S-, -N(R ₃ )-, -C(R ₆ R ₇ )O-, -OC(R ₆ R ₇ )- or -C (R ₆ R ₇ )-;

Each _of R and _R is independently selected from H, deuterium, halogen, hydroxyl, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocyclyl Cycloalkyl, amino, C1-6 alkylamino, alkenyl, alkynyl, nitro, cyano, cyanoalkyl, C1-6 alkyl acyl, halogenated C1-6 alkyl acyl, sulfonyl, phosphine Acyl;

Each of R _and _R is independently selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, amino, C1-6 alkylamino group, alkenyl group, alkynyl group, nitro group, cyano group, cyanoalkyl group; or R ₇ and R ₆ form a 3-10 membered ring structure together with the directly connected carbon, and the ring The structure can be arbitrarily monocyclic, bicyclic, bridged or spiro ring containing 0 to more unsaturated bonds; and the ring structure can arbitrarily contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;

The halogen is F, Cl, Br and iodine and their respective isotopes;

m and t are each independently 0, 1, 2, 3, 4 or 5;

n is independently 1, 2, 3, 4 or 5;

In one aspect of the present invention, the compound or its pharmaceutically acceptable salt, isotopic substitution or its isomer has the structure of formula (IB):

in,

Z is any independently absent, O, NH or N(R ₅ );

_R is randomly selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, amino, alkenyl , hydroxyl, cyano, nitro; and two adjacent X ₁ and X ₂ or any two adjacent X ₅ , X ₆ , X ₇ and X ₈ together with the R ₀ connected thereto can form 3-10 members A ring structure, the ring structure can be any saturated, unsaturated or aromatic structure, and the ring structure can optionally contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N ;

The halogen is F, Cl, Br and iodine and their respective isotopes;

m and t are each independently 0, 1, 2, 3, 4 or 5;

n is independently 1, 2, 3, 4 or 5;

In one aspect of the present invention, the compound or its pharmaceutically acceptable salt, isotope substitution or its isomer has the structure of formula (IC):

in,

Any represents a single or double bond;

X ₀ is independently selected from -O-, -S-, -N(R ₅ )-, -S(O)-, -S(O) ₂ -, -C(R ₆ R ₇ )O-, -OC (R ₆ R ₇ )-or -C(R ₆ R ₇ )-;

The halogen is F, Cl, Br and iodine and their respective isotopes;

m and t are each independently 0, 1, 2, 3, 4 or 5;

n is independently 1, 2, 3, 4 or 5;

In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope substitution or its isomer has the structure of formula (ID):

in,

X ₃ , X ₄ , X ₅ , X ₆ , X ₇ , X ₈ , X ₉ , X ₁₀ , X ₁₁ are each independently selected from C(R ₀ ) or N;

Z is any independently absent, O, NH or N(R ₅ );

_R is randomly selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, amino, alkenyl , hydroxyl, cyano, nitro; any two adjacent X ₅ , X ₆ , X ₇ and X ₈ together with the R ₀ connected thereto can form a 3-10-membered ring structure, and the ring structure can be Any saturated, unsaturated or aromatic structure, and the ring structure can optionally contain 0 to more heteroatoms, and the heteroatoms are randomly selected from O, S or N;

The halogen is F, Cl, Br and iodine and their respective isotopes;

m and t are each independently 0, 1, 2, 3, 4 or 5;

n is independently 1, 2, 3, 4 or 5;

In one aspect of the present invention, the compound or its pharmaceutically acceptable salt, isotope substitution or its isomer has the formula

(IE)Structure:

in,

Any represents a single or double bond;

X ₁ , X ₄ , X ₅ , X ₆ , X ₇ , X ₈ , X ₉ , X ₁₀ , X ₁₁ , X ₁₂ are each independently selected from C(R ₀ ), C(R ₀ ) ₂ , N(R ₀ ) or N;

Z is any independently absent, O, NH or N(R ₅ );

The halogen is F, Cl, Br and iodine and their respective isotopes;

m and t are each independently 0, 1, 2, 3, 4 or 5;

n is independently 1, 2, 3, 4 or 5;

In one aspect of the present invention, the compound or its pharmaceutically acceptable salt, isotope substitution or its isomer has the structure of formula (IF):

in,

Any represents a single or double bond;

X ₁ , X ₄ , X ₂ , X ₃ , X ₇ , X ₈ , X ₉ , and X ₁₀ are each independently selected from C(R ₀ ), C(R ₀ ) ₂ , C(R ₀ ) ₂ C(R ₀ ) ₂ , N(R ₀ ), C(R ₀ ) ₂ N(R ₀ ) or N;

Z is any independently absent, O, NH or N(R ₅ );

_R is randomly selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, amino, alkenyl , hydroxyl, cyano, nitro; any two adjacent X ₁ , X ₂ or X ₃ together with the R ₀ attached to it can form a 3-10 membered ring structure, and the ring structure can be arbitrarily saturated , unsaturated or aromatic structure, and the ring structure can optionally contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;

The halogen is F, Cl, Br and iodine and their respective isotopes;

m and t are each independently 0, 1, 2, 3, 4 or 5;

n is independently 1, 2, 3, 4 or 5;

In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope substitution or its isomer has the structure of formula (II):

in,

Each _R can be the same or different, and is arbitrarily selected from H, deuterium, halogen, C1-6 alkyl, haloC1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, hetero Cycloalkyl, amino, alkenyl, hydroxyl, cyano, nitro; and any two adjacent X ₁ , X ₂ and X ₃ or any two adjacent X ₅ , X ₆ , X ₇ and X ₈ and above The connected R ₀ can form a 3-10 membered ring structure together, and the ring structure can be any saturated, unsaturated or aromatic structure, and the ring structure can contain 0 to more heteroatoms at will, so The heteroatoms mentioned above are arbitrarily selected from O, S or N;

Each _R can be the same or different, and any independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halo Substituted C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy and other groups; and the hydrogen on _R It can be optionally further substituted by 1 to more substituents, any of which are independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl , C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, cycloalkoxy, Alkylamino; or any two R ₁ can form a 3-10-membered ring structure together with the carbon directly connected to it, and the ring structure can be arbitrarily monocyclic, bicyclic, or bridged ring containing 0 to more unsaturated bonds or a spiro ring; and the ring structure can optionally contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;

Each _R can be the same or different, and any independently selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkane group, amino group, alkenyl group, cyano group, cyanoalkyl group, nitro group, acyl group, sulfonyl group, phosphono group, etc.; and the hydrogen on _R2 can be optionally further substituted by 1 to more substituents, The substituents are arbitrarily selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy , deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, sulfone, sulfoxide, alkylsulfone, alkylsulfoxide, alkylamino Sulfone group, iminosulfone group, acyl group, sulfonyl group, phosphonocycloalkoxy group;

_R is independently selected from H, deuterium, hydroxyl, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, amino, C1-6 alkylamino, alkenyl, alkynyl, cyano, cyanoalkyl, C1-6 alkyl acyl, halogenated C1-6 alkyl acyl, sulfonyl, phosphono;

The halogen is F, Cl, Br and iodine and their respective isotopes;

m and t are each independently 0, 1, 2, 3, 4 or 5;

n is independently 1, 2, 3, 4 or 5.

In one aspect of the present invention, the compound or its pharmaceutically acceptable salt, isotopic substitution or its isomer has the structure of formula (IIA):

in,

X ₃ , X ₆ , X ₇ and X ₈ are each independently selected from C(R ₀ ) or N;

The halogen is F, Cl, Br and iodine and their respective isotopes;

m and t are each independently 0, 1, 2, 3, 4 or 5;

n is independently 1, 2, 3, 4 or 5.

In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope substitution or its isomer has the structure of formula (IIB):

in,

Any represents a single or double bond;

X is any independently selected from C, C(R ₀ ) or N;

X ₃ , X ₇ and X ₈ are each independently selected from C(R ₀ ) or N;

X ₁₀ is independently selected from -O-, -S-, -SO-, -SO ₂ -, -N(R ₃ )-, -C(R ₆ R ₇ )O-, -OC(R ₆ R ₇ )- or -C(R ₆ R ₇ )-;

Each _R can be the same or different, and is arbitrarily selected from H, deuterium, halogen, C1-6 alkyl, haloC1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, hetero Cycloalkyl, amino, alkenyl, hydroxyl, cyano, nitro; and two adjacent X ₇ and X ₈ together with the connected R ₀ can form a 3-10-membered ring structure, the ring The structure can be any saturated, unsaturated or aromatic structure, and the ring structure can optionally contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;

The halogen is F, Cl, Br and iodine and their respective isotopes;

Each _of R and _R is independently selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, amino, C1-6 alkylamino group, alkenyl group, alkynyl group, nitro group, cyano group, cyanoalkyl group; or R ₇ and R ₆ form a 3-10 membered ring structure together with the directly connected carbon, and the ring The structure can be arbitrarily monocyclic, bicyclic, bridged or spiro ring containing 0 to more unsaturated bonds; and the ring structure can arbitrarily contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;

m and t are each independently 0, 1, 2, 3, 4 or 5;

n is independently 1, 2, 3, 4 or 5.

In one aspect of the present invention, the compound or its pharmaceutically acceptable salt, isotopic substitution or its isomer has the structure of formula (IIC):

in,

Each _R can be the same or different, and is arbitrarily selected from H, deuterium, halogen, C1-6 alkyl, haloC1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, hetero Cycloalkyl, amino, alkenyl, hydroxyl, cyano, nitro;

The halogen is F, Cl, Br and iodine and their respective isotopes;

m and t are each independently 0, 1, 2, 3, 4 or 5;

n is independently 1, 2, 3, 4 or 5.

In some aspects of the present invention, the compound or its pharmaceutically acceptable salt, isotopic substitution or its isomer has the structure of formula (IID):

in,

Any represents a single or double bond;

X is any independently selected from C, C(R ₀ ) or N;

Z is any independently O, NH or N(R ₃ );

X ₃ , X ₇ and X ₈ are each independently selected from C(R ₀ ) or N; and when X ₃ is CH, X is not N;

The halogen is F, Cl, Br and iodine and their respective isotopes;

m and t are each independently 0, 1, 2, 3, 4 or 5;

n is independently 1, 2, 3, 4 or 5.

In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotopic substitution or its isomer has a structure of formula (IIE):

Any represents a single or double bond;

Z is any independently O, NH or N(R ₃ );

X ₇ and X ₈ are each independently selected from C(R ₀ ) or N;

The halogen is F, Cl, Br and iodine and their respective isotopes;

m and t are each independently 0, 1, 2, 3, 4 or 5;

n is independently 1, 2, 3, 4 or 5.

In one aspect of the present invention, the compound or its pharmaceutically acceptable salt, isotopic substitution or its isomer has the structure of formula (IIF):

in,

Z is any independently O, NH or N(R ₃ );

X ₇ and X ₈ are each independently selected from C(R ₀ ) or N;

The halogen is F, Cl, Br and iodine and their respective isotopes;

m and t are each independently 0, 1, 2, 3, 4 or 5;

n is independently 1, 2, 3, 4 or 5.

According to an embodiment of the present invention, A or B is independently selected from a 3-10 membered heterocycle or a C3-10 hydrocarbon ring;

According to an embodiment of the present invention, A is selected from piperidine ring, tetrahydropyrrole ring,

According to an embodiment of the invention, B is selected from N-hetidine rings.

According to an embodiment of the present invention, X ₁ , X ₂ , and X ₃ are independently selected from N or CH, and are not N at the same time; or, X ₂ and X ₁ or X ₂ and X ₃ form a

According to an embodiment of the present invention, X ₄ and X ₅ are independently selected from N or CH;

According to an embodiment of the present invention, X ₆ is selected from C(R ₀ ); or, X ₅ , X ₆ and their respective attached atoms form

According to an embodiment of the present invention, X ₇ , X ₈ are independently selected from N or CH.

According to an embodiment of the invention, Y _is selected from NH;

According to an embodiment of the present invention, when Y ₁ is CH, it is linked to Y ₀ , and Y ₂ is N; or, when Y ₂ is CH, it is linked to Y ₀ , and Y ₁ is N.

According to an embodiment of the present invention, R _is selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, C3-8 cycloalkyl;

According to an embodiment of the invention, R _is selected from H, deuterium, Cl, methyl, isopropyl, cyclopropyl.

According to an embodiment of the present invention, R _is selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, hydroxy C1-6 alkyl, hydroxy C1-6 alkoxy, C3-8 cycloalkyl, C1-6 alkoxy-C1-6 alkoxy, C1-6 alkyl-amino -C1-6 alkoxy, (C1-6 alkyl) ₂ -amino-C1-6 alkoxy, C1-6 alkylamino, (C1-6 alkyl) ₂ -amino;

According to an embodiment of the present invention, R _is selected from H, deuterium, F, hydroxy, amino, methyl, methoxy, methylamino, hydroxymethyl, hydroxyethyl, hydroxyethoxy, deuteromethyl, deuterium Substituted methoxy, methoxy-ethoxy,

According to an embodiment of the present invention, R _is selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, C3-8 cycloalkyl,

According to an embodiment of the present invention, R _is selected from H, deuterium, F, hydroxyl, amino, methyl, methoxy;

According to an embodiment of the present invention, R _is selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1 -6 alkoxy, deuterated C1-6 alkoxy, C3-8 cycloalkyl, C3-8 cycloalkyloxy, C1-6 alkyl-amino-C1-6 alkyl, (C1-6 alk Base) ₂ -amino-C1-6 alkyl, C1-6 alkyl-3-8 membered heterocyclic group;

According to an embodiment of the present invention, R _is selected from methyl, ethyl, isopropyl, cyclopropyl, dimethylaminoethyl, difluoromethyl, trifluoromethyl, cyclopropyloxy,

According to an embodiment of the present invention, R _and _R are each independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkane Oxygen, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, C3-8 cycloalkyl, amino C1-6 alkyl;

According to an embodiment of the present invention, _R6 and _R7 are each independently selected from H, methyl, aminomethyl.

In some aspects of the present invention, the above-mentioned compounds or their pharmaceutically acceptable salts, or their isomers and isotope substitutions are selected from the compounds with the following structures in the examples: Compound 1 to Compound 308, Compound A1 to Compound A40.

The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the compound represented by formula (I), its pharmaceutically acceptable salt, solvate, enantiomer and isotopic substitution kind.

According to an embodiment of the invention, the pharmaceutical composition is formulated for administration by a route selected from the group consisting of: oral, injectable, rectal, nasal, pulmonary, topical, buccal and sublingual, vaginal, parenteral, subcutaneous, Intramuscular, intravenous, intradermal, intrathecal, and epidural.

According to an embodiment of the present invention, the pharmaceutical composition is preferably administered orally.

The oral dosage form is not particularly limited, and any oral dosage form known in the art can be used, preferably including tablets, capsules, suspensions or oral solutions and other oral dosage forms known in the art. As an oral dosage form, the dosage standard used is, for example, 500-1500 mg/day, preferably 700-1200 mg/day, preferably 800-1000 mg/day, most preferably 1000 mg/day.

The medication time of the pharmaceutical composition according to the present invention can be determined according to the severity of the disease, preferably at least 1 month, for example, 1, 2, 3, 4, 5 or 6 months, the longest may be taken for life due to the needs of the disease .

According to an embodiment of the present invention, the pharmaceutical composition may further comprise pharmaceutically acceptable excipients, which are selected from at least one of the following excipients including but not limited to: fillers, disintegrants, binders, lubricants , surfactants, flavoring agents, wetting agents, pH regulators, solubilizers or co-solvents, osmotic pressure regulators. Those skilled in the art can easily determine how to select the corresponding excipients and their corresponding dosages according to the needs of specific dosage forms.

According to an embodiment of the present invention, the pharmaceutical composition may further contain one or more additional therapeutic agents.

Another object of the present invention is to provide the application of the above-mentioned compound, its pharmaceutically acceptable salt, solvate or hydrate and its isotope or isomer in the preparation of medicines for preventing or treating diseases caused by EGFR mutation .

Another object of the present invention is to provide the above-mentioned compound, its pharmaceutically acceptable salt, solvate or hydrate and its isotope or isomer in the preparation for the prevention or treatment of EGFR mutation, especially triple EGFR mutant ( dell9/L858R-T790M-C797S) mutation-related diseases or diseases caused by EGFR mutation-related signaling pathways.

Another object of the present invention is to provide the above compounds, their pharmaceutically acceptable salts, solvates or hydrates and their isotopes or isomers used in the preparation of prevention or treatment of EGFR mutations or signaling pathways related to EGFR mutations such as ROS1, BRAF, c-MET, EGFR/HER2, KRAS/MEK, PIK3CA, FDFR, DDR2 and/or VEGFR, PI3K, CDKs, PARP and other inhibitors, or with cytotoxin, immune target modulator PD-1/PD -Application in combined therapeutic drugs such as L1. The combined therapeutic drug at least comprises one or more compounds of the present invention, their pharmaceutically acceptable salts, solvates or hydrates and their isotopes or isomers.

The present invention also provides the compounds represented by the formula (I), their pharmaceutically acceptable salts, solvates, enantiomers and isotope substitutions, and the pharmaceutical composition in the prevention or treatment of EGFR mutation-induced use in diseases. The diseases caused by EGFR mutations have the above definition.

The present invention also provides a method for preventing or treating diseases caused by EGFR mutations, comprising administering to patients a preventive or therapeutically effective amount of the compound represented by formula (I), its pharmaceutically acceptable salt, solvate, enantiomer At least one of the conformers and isotope substitutions, or give the patient a prophylactically or therapeutically effective amount of the above-mentioned pharmaceutical composition. The diseases caused by EGFR mutations have the above definition.

In some embodiments, the patient is a mammal, preferably a human.

Definitions and clarifications:

C1-6 is selected from a group consisting of C ₁ , C ₂ , C ₃ , C ₄ , C ₅ or C ₆ , and the number indicates the group with the number of carbon atoms.

C _1-6 alkyl, C _1-6 heteroalkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, C _1-6 alkyl replaced by C _3-6 cycloalkyl or C _{3- 6} heterocycloalkyl, and C _1-6 heteroalkyl is substituted by C _3-6 cycloalkyl or C _3-6 heterocycloalkyl, including but not _limited to: methyl, ethyl, n-propyl, iso Propyl, -CH ₂ C(CH ₃ )(CH ₃ )(OH), Cyclopropyl, Cyclobutyl, Propylmethylene, Cyclopropylacyl, Benzyloxy, Cyclopropenyl, Trifluoro Methyl, aminomethyl, hydroxymethyl, methoxy, methylacyl, methoxyl, methylsulfonyl, methylsulfinyl, ethoxyl, acetyl, ethylsulfonyl, ethoxyl, Dimethylamino, Diethylamino, Dimethylamino, and Diethylamino; N(CH ₃ ) ₂ ,NH(CH ₃ ),-CH ₂ CF ₃ ,-CH2CH ₂ CF ₃ ,-CH ₂ CH ₂ F, -CH ₂ CH ₂ S(=O) ₂ CH ₃ , -CH ₂ CH ₂ CN,

-CH ₂ CH(OH)(CH ₃ ) ₂ ,-CH ₂ CH(F)(CH ₃ ) ₂ ,-CH ₂ CH ₂ F,-CH ₂ CF ₃ ,-CH ₂ CH ₂ CF ₃ ,-CH ₂ CH ₂ NH ₂ , -CH ₂ CH ₂ OH, -CH ₂ CH ₂ OCH ₃ , -CH ₂ CH ₂ CH ₂ OCH ₃ , -CH ₂ CH ₂ N(CH ₃ ) ₂ , -S(=O) ₂ CH ₃ ,-CH ₂ CH ₂ S(=O) ₂ CH ₃ ,

The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and/or dosage forms, which are suitable for use in contact with human and animal tissues within the scope of sound medical judgment , without undue toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, which is prepared from a compound having a specific substituent found in the present invention and a relatively non-toxic acid or base. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base, either neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the acid, either neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts of inorganic acids including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, Hydrogen sulfate, hydriodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid and similar acids; also salts of amino acids such as arginine and the like , and salts of organic acids such as glucuronic acid (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977)). Certain specific compounds of the present invention contain basic and acidic functional groups and can thus be converted into either base or acid addition salts.

Preferably, the neutral form of the compound is regenerated by contacting the salt with a base or acid in the conventional manner followed by isolation of the parent compound. The parent form of the compound differs from its various salt forms by certain physical properties, such as solubility in polar solvents.

"Pharmaceutically acceptable salt" as used herein belongs to the derivatives of the compounds of the present invention, wherein the parent compound is modified by forming a salt with an acid or a salt with a base. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound, such as salts formed from non-toxic inorganic or organic acids. Conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, Benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, Hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionic acid, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, Pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturin, propionic acid, salicylic acid, stearic acid, acetic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannin, tartaric acid and p-toluenesulfonic acid.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing acid groups or bases by conventional chemical methods. In general, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.

In addition to salt forms, the compounds provided herein also exist in prodrug forms. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert them to the compounds of the present invention. In addition, prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo environment.

Certain compounds of the present invention can exist in unsolvated or solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are within the scope of the present invention. Certain compounds of the present invention may exist in polycrystalline or amorphous forms.

Certain compounds of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the present invention.

The graphic representation of racemic, ambiscalemic and scalemic or enantiomerically pure compounds herein is from Maehr, J. Chem. Ed. 1985, 62:114-120. 1985, 62:114-120. Unless otherwise stated, the absolute configuration of a stereocenter is indicated by wedge-shaped bonds and dashed-line bonds. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, they include E, Z geometric isomers. Likewise, all tautomeric forms are included within the scope of the invention.

The compounds of the invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.

Optically active (R)- and (S)-isomers as well as D and L-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as amino group) or an acidic functional group (such as carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then step by step known in the art Resolution of diastereomers by crystallization or chromatography followed by recovery of the pure enantiomers. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally in combination with chemical derivatization methods (e.g. amines to amino groups formate).

The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds. For example, compounds may be labeled with radioactive isotopes such as tritium ( ³ H), iodine-125 ( ¹²⁵ I) or C-14 ( ¹⁴ C). All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.

The term "pharmaceutically acceptable carrier" refers to any preparation or carrier medium capable of delivering an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient. Representative carriers include water, oil, Vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, viscosity builders, skin penetration enhancers and the like. Their formulations are well known to those skilled in the field of cosmetics or topical medicine. Additional information on carriers can be found in Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

The term "excipient" generally refers to a carrier, diluent and/or medium required to formulate an effective pharmaceutical composition.

For a drug or a pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a non-toxic but sufficient amount of the drug or agent to achieve the desired effect. For the oral dosage forms in the present invention, the "effective amount" of one active substance in the composition refers to the amount needed to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in each case can be determined by those skilled in the art according to routine experiments.

The terms "active ingredient", "therapeutic agent", "active substance" or "active agent" refer to a chemical entity that is effective in treating the disorder, disease or condition of interest.

The term "substituted" refers to the replacement of any one or more hydrogen atoms on a specified atom with a substituent, including deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable . When a substituent is keto (ie =0), it means that two hydrogen atoms are replaced. Keto substitution does not occur on aromatic groups. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically realizable basis.

When any variable (eg, R) occurs more than once in the composition or structure of a compound, its definition is independent at each occurrence. Thus, for example, if a group is substituted with 0-2 R, said group may optionally be substituted with up to two R, with independent options for each occurrence of R. Also, combinations of substituents and/or variations thereof are permissible only if such combinations result in stable compounds.

When a bond of a substituent can cross-link two atoms in a ring, the substituent can be bonded to any atom in the ring. When a substituent is listed without specifying the atom through which it is bonded to a compound included in a general chemical formula but not specifically mentioned, such a substituent may be bonded through any atom thereof. Combinations of substituents and/or variations thereof are permissible only if such combinations result in stable compounds.

Alkyl and heteroalkyl radicals (including those commonly referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl The substituents of those groups) are generally referred to as "alkyl substituents", which may be selected from, but not limited to, one or more of the following groups: -R', -OR', =O, =NR' , =N-OR', -NR'R", -SR', Halogen, -SiR'R"R"', OC(O)R', -C(O)R', -CO ₂ R', - CONR'R", -OC(O)NR'R", -NR"C(O)R', NR'C(O)NR"R"', -NR"C(O) ₂ R', -NR ""'-C(NR'R"R'")=NR"", NR""C(NR'R")=NR'", -S(O)R', -S(O) ₂ R' , -S(O) ₂ NR'R", NR"SO ₂ R', -CN, -NO ₂ , -N ₃ , -CH(Ph) ₂ and fluoro(C ₁ -C ₄ )alkyl, substituted The number of radicals is 0～(2m'+1), wherein m' is the total number of carbon atoms in this type of atomic group. R', R", R"', R"" and R""' are each independently preferably hydrogen, Substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl (for example, aryl substituted by 1 to 3 halogens), substituted or unsubstituted alkyl, alkoxy, thioalkane Oxy group or aralkyl group. When the compound of the present invention includes more than one R group, for example, each R group is independently selected, as when there are more than one R', R", R "', R"" and R""' groups. When R' and R" are attached to the same nitrogen atom, they can combine with the nitrogen atom to form a 5-, 6-, or 7- - Yuan ring. For example, -NR'R" is intended to include, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. Based on the above discussion of substituents, those skilled in the art will understand that the term "alkyl" is intended to include carbon A group consisting of an atom bonded to a non-hydrogen group, such as a haloalkyl group (eg -CF ₃ , -CH ₂ CF ₃ ) and an acyl group (eg -C(O)CH ₃ , -C(O)CF ₃ , - C(O) _CH2OCH3 _, etc.). Similar to the substituents described for alkyl radicals, aryl and heteroaryl substituents are generally collectively referred to as "aryl substituents" selected from, for example, -R', -OR', -NR'R", -SR', -Halogen, -SiR'R"R"', OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC( O)NR'R", -NR"C(O)R', NR'C(O)NR"R"', -NR"C(O)2R', -NR""'-C(NR'R "R'")=NR"", NR""C(NR'R")=NR'", -S(O)R', -S(O) ₂ R', -S(O) ₂ NR'R",NR"SO ₂ R', -CN, -NO ₂ , -N ₃ , -CH(Ph) ₂ , fluoro(C ₁ -C ₄ )alkoxy and fluoro(C ₁ -C ₄ )alkyl etc., the number of substituents is between 0 and the total number of open valencies on the aromatic ring; wherein R', R", R"', R"" and R""' are independently preferably selected from hydrogen, substituted or unsubstituted Alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When a compound of the invention includes more than one R group, for example, each R group is independently selected, as when more than one R', R", R"', R"" and R"" are present ' group when each of these groups.

Two substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be substituted with substituents of the general formula -TC(O)-(CRR')qU-, where T and U are independently selected from From -NR-, -O-, CRR'- or a single bond, q is an integer of 0 to 3. Alternatively, two substituents on adjacent atoms of an aryl or heteroaryl ring may optionally be substituted with substituents of the general formula -A(CH2)rB-, where A and B are independently selected from From –CRR'-, -O-, -NR-, -S-, -S(O)-, S(O) ₂ -, -S(O) ₂ NR'- or a single bond, r is 1 to 4 an integer of . Optionally, a single bond on the new ring thus formed can be replaced by a double bond. Alternatively, two substituents on adjacent atoms of an aryl or heteroaryl ring may optionally be substituted with substituents of the general formula -A(CH2)rB-, where s and d are independently An integer selected from 0 to 3, X is -O-, -NR', -S-, -S(O)-, -S(O) ₂ - or -S(O) ₂ NR'-. The substituents R, R', R" and R"' are each independently preferably selected from hydrogen and substituted or unsubstituted (C ₁ -C ₆ )alkyl groups.

Unless otherwise specified, the term "halogen" or "halogen" by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom. Furthermore, the term "haloalkyl" is intended to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(C ₁ -C ₄ )alkyl" is intended to include, but not be limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl and 3-bromopropyl, etc. wait.

Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. "Alkoxy" represents the above-mentioned alkyl group having the specified number of carbon atoms attached through an oxygen bridge. C _1-6 alkoxy includes C ₁ , C ₂ , C ₃ , C ₄ , C ₅ and C ₆ alkoxy. Examples of alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, and S- Pentyloxy. "Cycloalkyl" includes saturated ring groups such as cyclopropyl, cyclobutyl or cyclopentyl. 3-7 cycloalkyl includes C ₃ , C ₄ , C ₅ , C ₆ and C ₇ cycloalkyl. "Alkenyl" includes hydrocarbon chains in straight or branched configuration in which one or more carbon-carbon double bonds are present at any stable point on the chain, eg, ethenyl and propenyl.

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

The term "heteroatom" as used herein includes atoms other than carbon (C) and hydrogen (H), including, for example, oxygen (O), nitrogen (N), sulfur (S), silicon (Si), germanium (Ge), aluminum ( Al) and boron (B), etc.

Unless otherwise stated, the terms "hetero", "heteroatom" or "heteroradical" (i.e. radicals containing heteroatoms) include atoms other than carbon (C) and hydrogen (H) and also include those of the aforementioned heteroatoms free radicals. For example, including oxygen (O), nitrogen (N), sulfur (S), silicon (Si), germanium (Ge), aluminum (Al) and boron (B), etc., also including any substituted -C(=O)N (H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)-, or -S(=O)N(H)-.

"Ring" means a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. The so-called ring includes fused rings. The number of atoms on a ring is usually defined as the number of ring members, for example, "5-7 membered ring" refers to 5-7 atoms arranged around it. Unless otherwise specified, the ring optionally contains 1 to 3 heteroatoms. Thus, "5-7 membered ring" includes, for example, phenylpyridine and piperidinyl; on the other hand, the term "5-7 membered heterocycloalkyl ring" includes pyridyl and piperidinyl, but excludes phenyl. The term "ring" also includes ring systems comprising at least one ring, wherein each "ring" is independently defined above.

The term "heterocycle" or "heterocyclyl" means a stable monocyclic or bicyclic or bicyclic heterocyclic ring, which may be saturated, partially unsaturated or unsaturated (aromatic), comprising carbon atoms and 1 , 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles can be fused to a benzene ring to form a bicyclic ring. Nitrogen and sulfur heteroatoms can optionally be oxidized (ie NO and S(O)p). The nitrogen atom may be substituted or unsubstituted (ie, N or NR, where R is H or other substituents already defined herein). The heterocycle can be attached to any heteroatom or pendant carbon atom to form a stable structure. The heterocyclic rings described herein may be substituted at the carbon or nitrogen positions if the resulting compound is stable. The nitrogen atoms in the heterocycle are optionally quaternized. A preferred solution is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred solution is that the total number of S and O atoms in the heterocycle does not exceed 1. As used herein, the term "aromatic heterocyclic group" or "heteroaryl" means a stable aromatic ring of 5, 6, 7 membered monocyclic or bicyclic or 7, 8, 9 or 10 membered bicyclic heterocyclic groups, It contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S. The nitrogen atom may be substituted or unsubstituted (ie, N or NR, where R is H or other substituents already defined herein). Nitrogen and sulfur heteroatoms can optionally be oxidized (ie NO and S(O)p). It is worth noting that the total number of S and O atoms on the aromatic heterocycle does not exceed 1. Bridged rings are also included in the definition of heterocycle. A bridged ring is formed when one or more atoms (ie, C, O, N, or S) link two non-adjacent carbon or nitrogen atoms. Preferred bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a triple ring. In bridged rings, substituents on the ring may also be present on the bridge.

Examples of heterocyclic compounds include, but are not limited to: acridinyl, aziocinyl, benzimidazolyl, benzofuryl, benzomercaptofuranyl, benzomercaptophenyl, benzoxazolyl, benzoxazolyl Azolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, carbazolyl, 4aH-carbazolyl, Carbolinyl, chromanyl, chromene, cinnolinyl decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b] Tetrahydrofuryl, furyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizyl, indolyl, 3H-indole Indolyl, isatinoyl, isobenzofuryl, pyran, isoindolyl, isoindolinyl, isoindolyl, indolyl, isoquinolyl, isothiazolyl, isoxazolyl, Methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, isoxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrole Phenyl, phenazine, phenothiazine, benzoxanthyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidinonyl, 4-piperidinonyl, piperonyl, pteridine Base, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridoxazole, pyridimidazole, pyridothiazole, pyridyl, pyrimidinyl, Pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, pyrazolyl, quinazolinyl, quinolinyl, 4H-quinazinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydro Isoquinolyl, tetrahydroquinolyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthryl, thiazolyl, isothiazolylthienyl, thienyl, thienooxazolyl, thienothiazolyl, thiophene Imidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthyl. Also included are fused ring and spiro compounds.

Unless otherwise specified, the term "hydrocarbyl" or its subordinate concepts (such as alkyl, alkenyl, alkynyl, phenyl, etc.) by itself or as part of another substituent means straight-chain, branched-chain or cyclic Hydrocarbon radicals or combinations thereof, which may be fully saturated, mono- or polyunsaturated, may be mono-, di- or polysubstituted, may include divalent or polyvalent radicals, have a specified number of carbon atoms (e.g. C ₁ -C ₁₀ represents 1 to 10 carbons). "Hydrocarbon group" includes but not limited to aliphatic hydrocarbon group and aromatic hydrocarbon group, said aliphatic hydrocarbon group includes chain and ring, specifically includes but not limited to alkyl, alkenyl, alkynyl, said aromatic hydrocarbon group includes but not limited to 6-12 members Aromatic hydrocarbon groups such as benzene, naphthalene, etc. In some embodiments, the term "alkyl" refers to straight or branched chain radicals or combinations thereof, which may be fully saturated, mono or polyunsaturated, and may include divalent and multivalent radicals. Examples of saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl) Homologues or isomers of methyl, cyclopropylmethyl, and n-pentyl, n-hexyl, n-heptyl, n-octyl and other atomic groups. Unsaturated alkyl has one or more double or triple bonds, examples of which include, but are not limited to, vinyl, 2-propenyl, butenyl, crotyl, 2-isopentenyl, 2-(butadienyl ), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and iso Construct.

Unless otherwise specified, the term "heterohydrocarbyl" or its subordinate concepts (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.) by itself or in combination with another term represent stable straight-chain, branched or cyclic hydrocarbon radicals or combinations thereof, consisting of a certain number of carbon atoms and at least one heteroatom. In some embodiments, the term "heteroalkyl" by itself or in combination with another term means a stable straight-chain, branched-chain hydrocarbon radical or a combination thereof, consisting of a certain number of carbon atoms and at least one heteroatom. In a typical embodiment, the heteroatom is selected from B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. The heteroatoms B, O, N and S may be located at any internal position of the heterohydrocarbyl group (other than the position where the hydrocarbyl group is attached to the rest of the molecule). Examples include, but are not limited to _-CH2 - _CH2 -O- _CH3 , -CH2 _- CH2 _- NH- _CH3 , _-CH2- _CH2 -N( _CH3 )-CH3 _, -CH2 _- S -CH ₂ -CH ₃ , -CH ₂ -CH ₂ , -S(O)-CH ₃ , -CH ₂ -CH ₂ -S(O) ₂ -CH ₃ , -CH=CH-O-CH ₃ , - CH2 _- CH=N- _OCH3 and -CH=CH-N( _CH3 ) _-CH3 . Up to two heteroatoms can be consecutive, eg _-CH2 -NH- _OCH3 .

The terms "alkoxy", "alkylamino" and "alkylthio" (or thioalkoxy) are conventional expressions referring to those alkyl groups attached to the rest of the molecule through an oxygen, amino or sulfur atom, respectively. base group.

Unless otherwise specified, the terms "cycloalkyl", "heterocycloalkyl", "cyclohydrocarbyl" or their subordinate concepts (such as aryl, heteroaryl, heteroaryl, cycloalkyl, heterocycloalkyl, cyclo Alkyl, cycloalkenyl, heterocycloalkenyl, cycloalkenyl, cycloalkynyl, heterocycloalkynyl, cycloalkynyl, etc.) by themselves or in combination with other terms represent respectively cyclized "hydrocarbyl", " Heterohydrocarbyl" or "heterohydrocarbyl". Furthermore, in the case of heteroalkyl or heterocycloalkyl (e.g., heteroalkyl, heterocycloalkyl), a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Non-limiting examples of heterocyclyl include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofurindol-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.

Unless otherwise specified, the term "aryl" denotes a polyunsaturated aromatic hydrocarbon substituent, which may be monosubstituted, disubstituted or polysubstituted, which may be monocyclic or polycyclic (preferably 1 to 3 rings), They are fused together or covalently linked. The term "heteroaryl" refers to an aryl group (or ring) containing one to four heteroatoms. In an illustrative example, the heteroatom is selected from B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. A heteroaryl can be attached to the rest of the molecule through a heteroatom. Non-limiting examples of aryl or heteroaryl include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrrolyl Azolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isox Azolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thiophene Base, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolinyl and 6-quinolinyl. Substituents for any of the above aryl and heteroaryl ring systems are selected from the acceptable substituents described below.

For convenience, aryl when used in conjunction with other terms (eg, aryloxy, arylthio, aralkyl) includes both aryl and heteroaryl rings as defined above. Thus, the term "aralkyl" is intended to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, etc.), including wherein a carbon atom (e.g., methylene) has been replaced by, e.g., oxygen Those alkyl groups in which atoms are substituted, such as phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl and the like.

The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (eg, an affinity substitution reaction). For example, representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, brosylate, tosylate esters, etc.; acyloxy groups such as acetoxy, trifluoroacetoxy, and the like.

General formula preparation embodiment:

In some embodiments, compounds of formula (I) can be prepared according to the synthetic methods described in the following schemes:

Another object of the present invention is to provide a method for preparing the above-mentioned compound, and its preparation route is as follows:

1) A coupling reaction between the starting material halogenated heterocycle and substituted or unsubstituted heterocycle A under the action of a catalyst or a substitution reaction with active hydrogen, and deprotection to obtain intermediate 1:

Wherein Z represents boronic acid or borate ester group or active hydrogen, G represents a protecting group, and other substituents are as described in claims 1-7.

2) The intermediate 2 is obtained from the coupling reaction between the starting material halogenated heterocycle and the substituted or unsubstituted heterocycle B under the action of a catalyst or the substitution reaction with active hydrogen:

Wherein Z represents boronic acid or borate ester group or active hydrogen, and other substituents are as described in claims 1-7.

3), the active hydrogen of intermediate 1 is substituted with the halogen of intermediate 2 to obtain the compound of formula (I):

Each functional group is as described in claims 1-7.

The invention is now further described by way of examples. The examples given below are for illustrative purposes only and do not limit the scope of this invention. The compounds of the present invention can be prepared by a number of methods known in the art of organic synthesis. Embodiments of the present invention may be synthesized using the methods described below, as well as synthetic methods known in the art of synthetic organic chemistry, or by modifications thereof. Preferred methods include, but are not limited to, the methods described below.

The present invention adopts the following abbreviations: aq represents water; DCM represents dichloromethane; PE represents petroleum ether; DMF represents N,N-dimethylformamide; DMSO represents dimethyl sulfoxide; EtOAc represents ethyl acetate; EtOH stands for ethanol; MeOH stands for methanol; Cbz stands for benzyloxycarbonyl, an amine protecting group; Boc stands for tert-butyloxycarbonyl, an amine protecting group; _HOAc stands for acetic acid; Sodium; rt stands for room temperature; THF stands for tetrahydrofuran; Boc ₂ O stands for di-tert-butyl dicarbonate; _TFA stands for trifluoroacetic acid; DIPEA stands for diisopropylethylamine; Pd(dppf)Cl stands for [1,1'- Bis(diphenylphosphino)ferrocene]palladium(II) dichloride; _POCl ₃ represents phosphorus oxychloride; NaH represents sodium hydride; LAH represents lithium aluminum hydride; Pd ₂ (dba) ₃ stands for tris(dibenzylideneacetone)dipalladium; Pd(PPh ₃ ) ₄ stands for tetrakis(triphenylphosphine)palladium; Et ₃ SiH stands for triethylsilane; PPh ₃ stands for tris Phenylphosphine; Xantphos stands for 4,5-bis(diphenylphosphino)-9,9-dimethyl; MeSO ₃ H stands for methanesulfonic acid; Xphos stands for 2-dicyclohexylphosphino-2',4' , 6'-triisopropylbiphenyl;Lawson's reagent represents 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphane-2,4- Disulfide; NBS stands for N-bromosuccinimide; t-BuOK stands for potassium tert-butoxide; DIPEA is diisopropylethylamine; _SOCl2 is thionyl chloride; CS2 is carbon disulfide; TsOH is 4-toluenesulfonate acid; MTBE is tert-butyl methyl ether; i-PrOH is 2-propanol.

Compounds can be named manually, or using

For naming, the supplier's catalog name may also be used if purchased commercially. Usually TLC or LC-MS is used to judge the completion of the reaction.

Detailed ways

In order to illustrate the present invention in more detail, the following examples are given, but the scope of the present invention is not limited thereto.

Example 1, N-(2-((3R,4S)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-(3- Synthesis of ((methylsulfoxide)methyl)azetidin-1-yl)isoquinolin-3-amine (Compound 1):

1), the synthesis of 3-(methylsulfinyl) methyl-azetidine-1-carboxylic acid tert-butyl ester:

3-(Iodomethyl)azetidine-l-carboxylic acid tert-butyl ester (10.1g, 34mmol) and NaSMe (7.2g, 51mmol) were mixed uniformly in a mixed solution of acetonitrile (60mL) and water (20mL) , heated to 60 ° C and stirred for 18 h. After cooling to room temperature, it was concentrated under reduced pressure and the residue was diluted with EA (50ml). The organic phase was back extracted 3 times with water (100ml) and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give a yellow oil (7.5 g). It was directly used in the next reaction without purification. LC-MS m/z:240[M+Na] ⁺ .

The yellow oil was dissolved in 100ml of 95% ethanol, sodium periodate and Al ₂ O ₃ were added at room temperature, and the reaction was stirred overnight. Suction filtration, the filter cake was washed several times with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by wet flash silica gel column chromatography to obtain 3-(methylsulfinyl)methyl-nitrogen tert-butyl heterocyclobutane-1-carboxylate (6.4 g). LC-MS m/z:234[M+H] ⁺ .

2), the synthesis of 3-chloro-5-nitroisoquinoline:

3-Chloroisoquinoline (50.0 g, 305.6 mmol) was dissolved in concentrated sulfuric acid (400 mL), cooled to 0° C. in an ice-water bath, and a solution of potassium nitrate (32.8 g, 324.4 mmol) in concentrated sulfuric acid (100 mL) was added dropwise. After the dropwise addition was completed, the reaction solution was kept at 0°C and stirred for 2 hours, then raised to 20°C and continued to stir for 16 hours. The reaction solution was poured into ice water (1000mL), a large number of yellow solids were precipitated, filtered, the filter cake was washed with pure water (400mL), and dried to obtain 3-chloro-5-nitroisoquinoline (35g, yellow solid, yield : 55.1%). LC-MS m/z:209[M+H] ⁺ .

3), the synthesis of 3-chloro-5-aminoisoquinoline:

Dissolve 3-chloro-5-nitroisoquinoline (35g, 168.0mmol) in methanol (350mL), add ammonia (28%-30%, 70mL), then slowly add sodium dithionite (87.7g, 504mmol) . The reaction solution was stirred at 25°C for 1 hour. The reaction solution was poured into pure water (500 mL), extracted three times with ethyl acetate (500 mL), the organic phases were combined, washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a crude product. 3-Chloro-5-aminoisoquinoline (10 g, white solid, yield: 27%) was separated by flash separation column (dichloromethane:methanol=10:1). LC-MS m/z:179[M+H] ⁺ .

4), the synthesis of 3-chloro-5-hydroxyisoquinoline:

3-Chloro-5-aminoisoquinoline (10 g, 56.0 mmol) was dissolved in 6N aqueous hydrochloric acid (50 mL), cooled to 0°C, sodium nitrite (11.59 g, 168.0 mmol) was added and stirred for 30 minutes. The reaction liquid was poured into 50% sulfuric acid aqueous solution (100 mL) at 100°C, and stirred at 100°C for 3 hours. The reaction solution was poured into ice water (200mL), a large amount of white solids were precipitated, filtered, the filter cake was washed with pure water (100mL), and dried to obtain 3-chloro-5-hydroxyisoquinoline (6.0g, white solid, harvested rate: 59.8%). LC-MS m/z:180[M+H] ⁺ .

5), the synthesis of 3-chloro-5-methoxyisoquinoline:

Under ice bath, 3-chloro-5-hydroxyisoquinoline (12g, 66.8mmol) was dissolved in N,N-dimethylformamide (150mL), sodium hydrogen (60% mineral oil) was added (10.68 g, 267.3mmol), the reaction solution was stirred at 0°C for 30 minutes, added methyl iodide (19g, 133.6mmol), and stirred at 25°C for 1 hour. The reaction solution was poured into ice water (300mL), a large amount of solid was precipitated, filtered, the filter cake was washed with pure water (100mL), and dried to obtain 3-chloro-5-methoxyisoquinoline (10g, yellow solid, yield : 77.5%). LC-MS m/z:194[M+H] ⁺ .

6), the synthesis of 8-bromo-3-chloro-5-methoxyisoquinoline:

3-Chloro-5-methoxyisoquinoline (8 g, 41.3 mmol) was dissolved in acetic acid (100 mL), bromine (13.2 g, 82.6 mmol) was added and stirred at 25° C. for 3 hours. The reaction solution was poured into pure water (200 mL), extracted three times with dichloromethane (150 mL), the organic phases were combined, washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a crude product. 8-Bromo-3-chloro-5-methoxyisoquinoline (8 g, white solid, yield: 71.2%) was obtained by flash separation column (petroleum ether: ethyl acetate = 8:1). LC-MS m/z:272[M+H] ⁺ .

7), the synthesis of 8-bromo-3-chloro-5-hydroxyisoquinoline:

Dissolve 8-bromo-3-chloro-5-methoxyisoquinoline (4.9g, 18.1mmol) in dichloromethane (60mL), add boron tribromide (1N solution in tetrahydrofuran) and heat to 45°C and Stir for 48 hours. The reaction solution was poured into ice water (100mL), a large amount of solids were precipitated, filtered, the filter cake was washed with pure water (50mL), and dried to obtain 8-bromo-3-chloro-5-hydroxyisoquinoline (3g, white solid, harvested rate: 64.2%). LC-MS m/z:258[M+H] ⁺ .

8), the synthesis of 8-bromo-3-chloroisoquinolin-5-yl trifluoromethanesulfonate:

8-Bromo-3-chloro-5-hydroxyisoquinoline (3g, 11.6mmol) was dissolved in dichloromethane (30mL), then triethylamine (3.52g, 34.8mmol) was added, and the temperature was lowered in a dry ice acetone bath to -70°C, trifluoromethanesulfonic anhydride (4.9 g, 17.4 mmol) was added dropwise. After the dropwise addition was completed, the temperature was raised to 25° C. and stirred for 2 hours. The reaction solution was poured into pure water (100mL), extracted three times with ethyl acetate (100mL), the organic phases were combined, washed with saturated brine (100mL), dried with anhydrous sodium sulfate, filtered and rotary evaporated to obtain a crude product, passed 8-Bromo-3-chloroisoquinolin-5-yl trifluoromethanesulfonate (3 g, yield: 66%) was separated by a flash separation column (petroleum ether: ethyl acetate = 5:1). LC-MS m/z:390[M+H] ⁺ .

9), the synthesis of 8-bromo-3-chloro-5-(prop-1-en-2-yl)isoquinoline:

Dissolve 8-bromo-3-chloroisoquinolin-5-yl trifluoromethanesulfonate (3 g, 7.69 mmol) in tetrahydrofuran (40 mL) and pure water (10 mL), and then add isopropenylboronic acid pinaac Alcohol ester (3.88g, 23.07mmol), sodium carbonate (1.63g, 15.38mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (563mg, 0.77mmol). Under a nitrogen atmosphere, the mixture was replaced three times, and stirred at room temperature for 16 hours. Pour the reaction solution into pure water (50 mL), extract three times with ethyl acetate (50 mL), combine the organic phases, wash the organic phase with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product , purified by flash column (petroleum ether: ethyl acetate = 10:1) to obtain 8-bromo-3-chloro-5-(prop-1-en-2-yl)isoquinoline (2g, yield: 92 %). LC-MS m/z:282[M+H] ⁺ .

10), the synthesis of 8-bromo-3-chloro-5-isopropylisoquinoline:

8-Bromo-3-chloro-5-(prop-1-en-2-yl)isoquinoline (Intermediate 8) (2 g, 7.09 mmol) was dissolved in ethyl acetate (2000 mL) and platinum dioxide was added (200 mg, 10% w/w%), replaced three times with a hydrogen balloon, and stirred at 25°C for 2 hours. The reaction solution was filtered with diatomaceous earth, the filter cake was washed with ethyl acetate (500 mL), the filtrate was concentrated under reduced pressure to obtain a crude product, and the 8-bromo-3 -Chloro-5-isopropylisoquinoline (Intermediate 9) (1.5 g, yield: 74%). LC-MS m/z:284[M+H] ⁺ .

11), the synthesis of 3-chloro-5-isopropyl-8-(3-((methylsulfoxide) methyl)azetidin-1-yl)isoquinoline:

3-(Methylsulfinyl)methyl-azetidine-1-carboxylic acid tert-butyl ester (6.4g) was dissolved in 16ml of dichloromethane, 4ml of TFA was added, and the reaction was stirred at room temperature for 4h. After concentration in vacuo, crude 3-((methylsulfinyl)methyl)azetidine trifluoroacetic acid salt (7.7 g) was obtained.

Under the protection of N ₂ , 8-bromo-3-chloro-5-isopropylisoquinoline (100mg, 0.35mmol) was dissolved in 1,4-dioxane (5mL), and 3-((methyl (sulfinyl)methyl)azetidine (Intermediate 3) (47mg, 0.35mmol, 1.0eq) and cesium carbonate (228mg, 0.7mmol, 2.0eq), and finally Xantphos Pd G4 (57mg, 0.035mmol , 0.1eq), heated to 100 ° C and stirred for 16 hours. The reaction solution was filtered and concentrated under reduced pressure to obtain a crude product, which was purified by a silica gel flash separation column (dichloromethane:methanol=20:1) to obtain 3-chloro-5-isopropyl-8-(3-(methylsulfinic acid) Acylmethyl)azetidin-1-yl)isoquinoline (90 mg, yield: 76.5%). LC-MS m/z:337[M+H] ⁺ .

12), Synthesis of (3R,4S)-3-fluoro-4-methoxypiperidine-1-carboxylic acid tert-butyl ester:

Dissolve tert-butyl (3R,4S)-3-fluoro-4-hydroxypiperidine-1-carboxylate (starting material 1) (500 mg, 2.28 mmol) in N,N-dimethylformamide (5 mL) and dissolve in Sodium hydride (60% in mineral oil) (365mg, 9.12mmol) was added under ice-cooling, and after stirring for 20 minutes, iodomethane (320mg, 2.28mmol) was added under ice-cooling, heated to 25°C and stirred for 3 hours. Add water (10 mL) to the reaction solution to dilute, extract three times with ethyl acetate (30 mL), combine the organic phases, wash three times with saturated brine (30 mL), dry with anhydrous sodium sulfate solid, filter, and concentrate the filtrate under reduced pressure The crude product was purified by flash silica gel separation column (petroleum ether:ethyl acetate=5:1) to obtain (3R,4S)-3-fluoro-4-methoxypiperidine-1-carboxylic acid tert-butyl ester (200mg, yield : 37%). LC-MS m/z:256[M+Na] ⁺ .

13), the synthesis of (3R,4S)-3-fluoro-4-methoxypiperidine:

Dissolve (3R,4S)-3-fluoro-4-methoxypiperidine-1-carboxylic acid tert-butyl ester (200mg, 0.85mmol) in dichloromethane (6mL), add trifluoroacetic acid (2mL), and heat up Stir at 25°C for 2 hours. The reaction solution was spin-dried to obtain trifluoroacetic acid salt of (3R,4S)-3-fluoro-4-methoxypiperidine (180 mg, crude product, yield: 100%), which was directly used in the next step without purification . LC-MS m/z:134[M+H] ⁺ .

14), the synthesis of 2-((3R,4S)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine:

Dissolve (3R,4S)-3-fluoro-4-methoxypiperidine (180 mg, 1.35 mmol) in isopropanol (12 mL), add 2-chloropyrimidin-4-amine (raw material 2) (157 mg, 1.2 mmol) and triethylamine (1 mL), heated to 100°C and stirred for 1 hour. The crude product obtained after concentrating the reaction solution under reduced pressure was purified by a flash silica gel separation column (ethyl acetate:methanol=20:1) to obtain 2-((3R,4S)-3-fluoro-4-methoxypiperidine-1 -yl)pyrimidin-4-amine (Intermediate 3) (150 mg, yield: 49%). LC-MS m/z:227[M+H] ⁺ .

15), N-(2-((3R, 4S)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-(3-( Synthesis of Methylsulfinylmethyl)azetidin-1-yl)isoquinolin-3-amine (Compound 1):

Under _N2 protection, 3-chloro-5-isopropyl-8-(3-(methylsulfinylmethyl)azetidin-1-yl)isoquinoline (34mg, 0.1mmol) was dissolved To dioxane (2 mL), add 2-((3R,4S)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine (23 mg, 0.1 mmol) and carbonic acid Cesium (65mg, 0.2mmol), finally Brettphos Pd G3 (9mg, 0.01mmol) was added, heated to 100°C and stirred for 16 hours. The reaction solution was filtered with celite, and the crude product obtained after the filtrate was concentrated under reduced pressure was separated and purified by a flash silica gel column (dichloromethane:methanol=10:1) to obtain a yellow solid (10 mg). The resulting solid was prepared by reverse-phase liquid phase (preparation instrument model: Gilson 281, column model: Welch Prep C18 10 μm 21.2 × 250mm, A: water (0.2% of FA), B: acetonitrile, 35%-65% B in 8min, stop at 16min) to obtain the racemic product, and then through chiral resolution (instrument: SFC-80 (Waters), column: AS 20*250mm, 10um (Daicel), column temperature: 35 ° C, mobile phase : CO ₂ /MeOH[0.2%NH ₃ (7M in MeOH)]=50/50, flow rate: 80g/min, pressure: 100bar, detection wavelength: 214nm, cycle time: 11min, sample dissolution: 12mg is dissolved in 3ml methanol , injection volume: 1ml) to obtain N-(2-((3R, 4S)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8 -2 isomers of -(3-(methylsulfinylmethyl)azetidin-1-yl)isoquinolin-3-amine (Compound 1): Compound 1A (2.1 mg, Yield: 7.8 %) and compound 1B (2.1 mg, yield: 7.8%).

Compound 1A: LC-MS m/z:527[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d6): δppm J=8.0Hz, 1H), 6.49(d, J=5.6Hz, 1H), 6.42(d, J=8.0Hz, 1H), 4.95(d, J=50.8Hz, 1H), 4.73(s, 1H) ,4.49(d,J=13.2Hz,1H),4.39(t,J=7.2Hz,2H),4.03–3.93(m,2H),3.69–3.40(m,4H),3.37(s,3H), 3.23(d,J=8.0Hz,2H),3.10(dd,J=16.0,10.0Hz,1H),2.60(s,3H),1.78(m,2H),1.30(m,6H).

Compound 1B: LC-MS m/z:527[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d6): δppm J=8.0Hz, 1H), 6.49(d, J=5.6Hz, 1H), 6.42(d, J=8.0Hz, 1H), 4.95(d, J=51.2Hz, 1H), 4.73(s, 1H) ,4.49(d,J=12.8Hz,1H),4.39(t,J=7.2Hz,2H),3.97(t,J=6.0Hz,2H),3.67–3.40(m,4H),3.37(s, 3H), 3.23(d, J＝8.0Hz, 2H), 3.14–3.07(m, 1H), 2.60(s, 3H), 1.90–1.65(m, 2H), 1.30(m, 6H).

Example 2, N-(4-((3R,4S)-3-fluoro-4-methoxypiperidin-1-yl)-1,3,5-triazin-2-yl)-5-iso Synthesis of Propyl-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-3-amine (Compound 2):

1), 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)isoquinoline Synthesis:

Dissolve 8-bromo-3-chloro-5-isopropylisoquinoline (100mg, 0.35mmol) in 1,4-dioxane (5mL), and add (2R,3S)-2-methyl -3-(Methylsulfonylmethyl)azetidine (57mg, 0.35mmol) and cesium carbonate (228mg, 0.7mmol), finally add Xantphos Pd G4 (57mg, 0.035mmol), heat to 100°C and stir React for 4 hours. The reaction solution was filtered, concentrated under reduced pressure to obtain a crude product, and then purified by a flash silica gel separation column (dichloromethane:methanol=10:1) to obtain 3-chloro-5-isopropyl-8-((2R,3S)-2 -Methyl-3-(methylsulfonylmethyl)azetidin-1-yl)isoquinoline (100 mg, yield: 78.1%). LC-MS m/z:367[M+H] ⁺ .

2), Synthesis of 4-((3R,4S)-3-fluoro-4-methoxypiperidin-1-yl)-1,3,5-triazin-2-amine:

Dissolve (3R,4S)-3-fluoro-4-methoxypiperidine (230 mg, 1.7 mmol) in isopropanol (10 mL), add 4-chloro-1,3,5-triazine-2- Amine (224mg, 1.7mmol) and triethylamine (1mL) were heated to 100°C and stirred for 1 hour. The crude product obtained after concentrating the reaction solution under reduced pressure was purified by a flash silica gel separation column (ethyl acetate:methanol from 1:0 to 10:1) to obtain 4-((3R,4S)-3-fluoro-4-methoxy Piperidin-1-yl)-1,3,5-triazin-2-amine (370 mg, yield: 95%). LC-MS m/z:228[M+H] ⁺ .

3), N-(4-((3R,4S)-3-fluoro-4-methoxypiperidin-1-yl)-1,3,5-triazin-2-yl)-5-isopropyl Synthesis of yl-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-3-amine (Compound 2):

3-Chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)isoquinoline (36mg , 0.1 mmol) was dissolved in dioxane (2 mL), and 4-((3R,4S)-3-fluoro-4-methoxypiperidin-1-yl)-1,3,5-tris Oxazin-2-amine (23mg, 0.1mmol) and cesium carbonate (65mg, 0.2mmol), and finally Brettphos Pd G3 (9mg, 0.01mmol, 0.1eq) was added, the temperature was raised to 100°C and the reaction was stirred for 5 hours. The reaction solution was filtered with celite, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated by a flash silica gel separation column (dichloromethane:methanol=10:1) to obtain a yellow solid (20 mg), and the obtained solid was prepared by reverse phase preparation. Phase (preparation instrument model: Gilson 281, chromatographic column model: Welch Prep C18 10 μ m 21.2 × 250mm, A: water (0.2% of FA), B: acetonitrile, 40%-70% B in 8min, stop at16min) purification to obtain N -(4-((3R,4S)-3-fluoro-4-methoxypiperidin-1-yl)-1,3,5-triazin-2-yl)-5-isopropyl-8- ((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-3-amine (compound 2) (8.3 mg, yield: 14.9 %). LC-MS m/z:558[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d6): δppm 1H), 6.60(d, J=8.1Hz, 1H), 5.01(d, J=49.6Hz, 1H), 4.80(s, 1H), 4.62(dd, J=48.8, 41.3Hz, 2H), 4.20( t,J=6.2Hz,1H), 3.62(d,J=24.8Hz,2H), 3.53(td,J=14.0,7.5Hz,4H), 3.34–3.30(m,4H), 2.99(s,3H ),2.89(dd,J=14.5,7.3Hz,1H),1.87(s,1H),1.70(s,1H),1.43(d,J=6.0Hz,3H),1.31(s,6H).

Example 3, N-(4-((3R,4S)-3-fluoro-4-methoxypiperidin-1-yl)-1,3,5-triazin-2-yl)-5-iso Synthesis of Propyl-8-(3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-3-amine (Compound 3):

1), the synthesis of 3-chloro-5-isopropyl-8-(3-(methylsulfonylmethyl)azetidin-1-yl)isoquinoline:

Dissolve 8-bromo-3-chloro-5-isopropylisoquinoline (Intermediate 1) (100mg, 0.35mmol, 1.0eq) in 1,4-dioxane (5mL), and add 3- (Methylsulfonylmethyl)azetidine (Intermediate 2, synthesized from ZLMR-E30) (57mg, 0.35mmol, 1.0eq) and cesium carbonate (228mg, 0.7mmol, 2.0eq), and finally Xantphos Pd G4 (57mg, 0.035mmol, 0.1eq), heated to 100°C and stirred for 4 hours, LCMS showed that the reaction was complete. The reaction solution was filtered and rotary evaporated to obtain the crude product, which was passed through a flash separation column (dichloromethane:methanol=20:1) to obtain 3-chloro-5-isopropyl-8-(3-(methylsulfonylmethyl)azepine Cyclobutan-1-yl)isoquinoline (Intermediate 11) (90 mg, yellow solid, yield: 73.5%). LC-MS m/z:353[M+H] ⁺ .

2), N-(4-((3R,4S)-3-fluoro-4-methoxypiperidin-1-yl)-1,3,5-triazin-2-yl)-5-isopropyl Synthesis of yl-8-(3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-3-amine (Compound 3):

Under nitrogen protection, 3-chloro-5-isopropyl-8-(3-(methylsulfonylmethyl)azetidin-1-yl)isoquinoline (20mg, 0.056mmol) was dissolved in dioxo Hexacyclic (2mL), sequentially added 4-((3R,4S)-3-fluoro-4-methoxypiperidin-1-yl)-1,3,5-triazin-2-amine (11mg, 0.051mmol) and cesium carbonate (36mg, 0.112mmol), and finally Brettphos Pd G3 (8mg, 0.008mmol, 0.15eq), heated to 100°C and stirred for 12 hours. The reaction solution was filtered with diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by a flash silica gel separation column (dichloromethane:methanol=10:1) to obtain a crude product, and the obtained crude product was prepared by reverse phase preparation (Preparation Instrument model: Gilson 281, chromatographic column model: Welch Prep C18 10 μ m 21.2 * 250mm, A: water (0.2% of FA), B: acetonitrile, 35%-65% B in 8min) Purification obtains N-(4-(( 3R, 4S)-3-fluoro-4-methoxypiperidin-1-yl)-1,3,5-triazin-2-yl)-5-isopropyl-8-(3-(methylsulfonyl Acylmethyl)azetidin-1-yl)isoquinolin-3-amine (Compound 3) (2.1 mg, yield: 6%). LC-MS m/z:544[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d6): δppm 1H), 6.44(d, J=8.0Hz, 1H), 5.01(d, J=50.6Hz, 1H), 4.81(s, 1H), 4.54(d, J=63.6Hz, 1H), 4.39(t, J＝7.6Hz, 2H), 3.96(t, J＝6.8Hz, 2H), 3.63(s, 1H), 3.58(d, J＝7.6Hz, 3H), 3.39(s, 2H), 3.36(s, 4H), 3.01(s,3H), 1.86(s,1H), 1.71(s,1H), 1.31(s,6H).

Example 4, N-(2-((3R,4S)-3-fluoro-4-methoxypiperidin-1-yl)-7-methyl-7H-pyrrole[2,3-d]pyrimidine- 4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-3-amine (Compound 4) Synthesis:

1), the synthesis of 2-chloro-7-methyl-7H-pyrrole [2,3-d] pyrimidin-4-amine:

Dissolve (2,4-dichloro-7-methyl-7H-pyrrole[2,3-d]pyrimidine (starting material 1) (5 g, 24.8 mmol) in dioxane (1 mL) and add (25% ~30%) ammonia water (60mL), heated to 50°C and stirred for 16 hours. Cooled to room temperature, a large amount of solid precipitated and filtered, the solid was washed with pure water (20mL), dried to obtain 2-chloro-7-methyl-7H- Pyrrolo[2,3-d]pyrimidin-4-amine (3.7g, yield: 82%).LC-MS m/z:256[M+H] ⁺ .

2), 2-((3R, 4S)-3-fluoro-4-methoxypiperidin-1-yl)-7-methyl-7H-pyrrole[2,3-d]pyrimidin-4-amine synthesis:

Dissolve 2-chloro-7-methyl-7H-pyrrole[2,3-d]pyrimidin-4-amine (220mg, 1.21mmol) in n-butanol (5mL), add (3R,4S)-3- Fluoro-4-methoxypiperidine (161mg, 1.21mmol) and triethylamine (611mg, 6.05mmol) were heated up to 150°C and stirred for 8 hours. The crude product obtained after concentrating the reaction solution under reduced pressure was purified by a flash silica gel separation column (dichloromethane:methanol=10:1) to obtain 2-((3R,4S)-3-fluoro-4-methoxypiperidine-1 -yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (160 mg, yield: 47.4%). LC-MS m/z:280[M+H] ⁺ .

3), N-(2-((3R,4S)-3-fluoro-4-methoxypiperidin-1-yl)-7-methyl-7H-pyrrole[2,3-d]pyrimidine-4 -yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-3-amine ( Compound 4) Synthesis:

Under nitrogen protection, 2-((3R,4S)-3-fluoro-4-methoxypiperidin-1-yl)-7-methyl-7H-pyrrole[2,3-d]pyrimidine-4- Amine (56mg, 0.2mmol) was dissolved in dioxane (2mL), and 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-(methylsulfonyl Acylmethyl) azetidin-1-yl) isoquinoline (73mg, 0.2mmol) and cesium carbonate (130mg, 0.4mmol), finally add Brettphos Pd G3 (18mg, 0.02mmol), heat to 100°C and The reaction was stirred for 3 hours. The reaction solution was filtered with diatomaceous earth, the filtrate was concentrated under reduced pressure and then separated by a flash silica gel separation column (dichloromethane:methanol=10:1) to obtain a crude product (30mg), and the obtained crude product was prepared by reverse phase (preparative instrument Model: Gilson 281, column model: Welch Prep C18 10μm 21.2×250mm, A: water (0.2% of FA), B: acetonitrile, 40%-70% B in 8min, stop at 16min) to obtain N-(2 -((3R,4S)-3-fluoro-4-methoxypiperidin-1-yl)-7-methyl-7H-pyrrole[2,3-d]pyrimidin-4-yl)-5-iso Propyl-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-3-amine (compound 4) (8.9mg, Yield: 7.3%). LC-MS m/z:610[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d6): δppm J=3.6Hz, 2H), 6.59(d, J=8.0Hz, 1H), 4.95(d, J=50.0Hz, 1H), 4.76(s, 1H), 4.65(t, J=7.2Hz, 1H) ,4.53(d,J＝13.2Hz,1H),4.25–4.13(m,1H),3.71–3.47(m,9H),3.38(s,3H),3.31(s,1H),3.00(s,3H ),2.91(m,1H),1.83(d,J=4.0Hz,2H),1.44(d,J=6.0Hz,3H),1.31(m,6H).

Example 5, N-(2-((3R,4S)-3-fluoro-4-methoxypiperidin-1-yl)-7-methyl-7H-pyrrole[2,3-d]pyrimidine- Synthesis of 4-yl)-5-isopropyl-8-(3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-3-amine (compound 5):

Under nitrogen protection, 2-((3R,4S)-3-fluoro-4-methoxypiperidin-1-yl)-7-methyl-7H-pyrrole[2,3-d]pyrimidine-4- Amine (56 mg, 0.2 mmol) was dissolved in dioxane (2 mL), and 3-chloro-5-isopropyl-8-(3-(methylsulfonylmethyl)azetidine-1- Base) isoquinoline (70mg, 0.2mmol) and cesium carbonate (130mg, 0.4mmol), finally added Brettphos Pd G3 (18mg, 0.02mmol), heated to 100°C and stirred for 3 hours. The reaction solution was filtered with diatomaceous earth, the filtrate was concentrated under reduced pressure and separated by a flash silica gel separation column (dichloromethane:methanol=10:1) to obtain the crude product (30mg), and the crude product was prepared by reverse phase (preparation instrument model : Gilson 281, chromatographic column model: Welch Prep C18 10 μ m 21.2 * 250mm, A: water (0.2% of FA), B: acetonitrile, 40%-70% B in 8min) purification obtains N-(2-((3R, 4S)-3-fluoro-4-methoxypiperidin-1-yl)-7-methyl-7H-pyrrole[2,3-d]pyrimidin-4-yl)-5-isopropyl-8- (3-(Methanesulfonylmethyl)azetidin-1-yl)isoquinolin-3-amine (Compound 5) (10.1 mg, yield: 8.5%). LC-MS m/z:596[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d6): δppm 2H), 6.44(d, J=8.0Hz, 1H), 4.95(d, J=49.6Hz, 1H), 4.76(s, 1H), 4.53(d, J=14.0Hz, 1H), 4.39(t, J＝7.6 Hz, 2H), 3.97(t, J＝6.8Hz, 2H), 3.68–3.48(m, 8H), 3.38(s, 3H), 3.32–3.24(m, 2H), 3.02(s, 3H ), 1.83(d, J=4.4Hz, 2H), 1.31(t, J=6.4Hz, 6H).

Example 6, N-(2-((3S,4R)-3-fluoro-4-(methoxy-d3)piperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8 Synthesis of -(3-(methylsulfinylmethyl)azetidin-1-yl)isoquinolin-3-amine (compound 6):

1), Synthesis of (3S,4R)-3-fluoro-4-(methoxyl-d3)piperidine-1-carboxylic acid tert-butyl ester:

Dissolve tert-butyl (3S,4R)-3-fluoro-4-hydroxypiperidine-1-carboxylate (starting material 1) (500 mg, 2.28 mmol) in N,N-dimethylformamide (10 mL) and dissolve in Under ice bath, sodium hydride (60% in mineral oil) (365 mg, 9.12 mmol) was added, and after stirring for 20 minutes, deuteroiodomethane (330 mg, 2.28 mmol) was added under ice bath, and the temperature was raised to 25° C. and stirred for reaction 3 Hour. Add water (10mL) to the reaction solution for dilution, extract three times with ethyl acetate (10mL), combine the organic phases, wash with saturated brine (20mL), dry over anhydrous sodium sulfate, filter, and the filtrate is concentrated under reduced pressure and passed through flash silica gel Separation column (petroleum ether: ethyl acetate = 5:1) was purified to obtain (3S,4R)-3-fluoro-4-(methoxy-d3)piperidine-1-carboxylic acid tert-butyl ester (260mg, yield: 48.3%). LC-MS m/z:259[M+Na] ⁺ .

2), the synthesis of (3S,4R)-3-fluoro-4-(methoxyl-d3)piperidine:

Dissolve (3S,4R)-3-fluoro-4-(methoxy-d3)piperidine-1-carboxylic acid tert-butyl ester (260mg, 1.1mmol) in dioxane (3mL), add 4N hydrochloric acid di Hexane solution (3 mL), and the reaction solution was stirred and reacted at 25°C for 2 hours. The reaction solution was concentrated to dryness under reduced pressure to obtain (3S,4R)-3-fluoro-4-(methoxy-d3)piperidine (200 mg, crude product), which was directly used in the next step without purification. LC-MS m/z:134[M+H] ⁺ .

3), Synthesis of 2-((3S,4R)-3-fluoro-4-(methoxy-d3)piperidin-1-yl)pyrimidin-4-amine:

Dissolve (3S,4R)-3-fluoro-4-(methoxy-d3)piperidine (200mg, 1.47mmol) in isopropanol (10mL), add 2-chloropyrimidin-4-amine (190mg, 1.47mmol) and triethylamine (2mL), heated to 100°C and stirred for 2 hours. After the reaction solution was concentrated under reduced pressure, it was purified by a flash silica gel separation column (dichloromethane:methanol=15:1) to obtain 2-((3S,4R)-3-fluoro-4-(methoxy-d3)piperidine- 1-yl)pyrimidin-4-amine (120 mg, yield: 49%). LC-MS m/z:230[M+H] ⁺ .

4), N-(2-((3S,4R)-3-fluoro-4-(methoxy-d3)piperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8- Synthesis of (3-(methylsulfinylmethyl)azetidin-1-yl)isoquinolin-3-amine (compound 6):

Under nitrogen protection, 3-chloro-5-isopropyl-8-(3-(methylsulfinylmethyl)azetidin-1-yl)isoquinoline (60mg, 0.18mmol) was dissolved in To dioxane (4mL), add 2-((3S,4R)-3-fluoro-4(methoxy-d3)piperidin-1-yl)pyrimidin-4-amine (41mg, 0.18mmol) successively and cesium carbonate (117mg, 0.36mmol), finally added Brettphos Pd G3 (18mg, 0.02mmol), heated to 100°C and stirred for 16 hours. The reaction solution was filtered with diatomaceous earth, the filtrate was concentrated under reduced pressure and separated by a flash silica gel separation column (dichloromethane:methanol=10:1) to obtain a crude product (30 mg), and the obtained crude product was separated by chiral preparative liquid phase ( Instrument: SFC-150 (Waters), column: AS 20*250mm, 10um (Daicel), column temperature: 35°C, mobile phase: CO2/MeOH [0.2% NH3 (7M in MeOH)] = 45/55, flow rate: 120g/min, pressure: 100bar, detection wavelength: 214nm, cycle time: 5min, sample dissolution: 30mg dissolved in 30ml methanol, injection volume: 3ml) purified to obtain N-(2-((3S, 4R)-3- Fluoro-4-(methoxy-d3)piperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-(3-(methylsulfinylmethyl)azetidin- 2 isomers of 1-yl)isoquinolin-3-amine (compound 6): compound 6A (4.9 mg, yield: 5.2%) and compound 6B (7.5 mg, yield: 6.2%).

Compound 6A: LC-MS m/z:530[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d6): δppm 9.92(s, 1H), 9.06(s, 1H), 8.62(s, 1H), 8.00(d, J=5.6Hz, 1H), 7.42(d, J =8.0Hz,1H),6.48(d,J=5.6Hz,1H),6.41(d,J=8.0Hz,1H),4.94(d,J=51.6Hz,1H),4.73(s,1H), 4.49(d, J=13.6Hz, 1H), 4.38(t, J=7.2Hz, 2H), 3.97(t, J=6.0Hz, 2H), 3.67–3.41(m, 3H), 3.25(m, 3H ),3.10(q,J＝10.0Hz,1H),2.60(s,3H),1.90–1.65(m,2H),1.30(m,6H).

Compound 6B: LC-MS m/z:530[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d6): δppm 9.93(s, 1H), 9.06(s, 1H), 8.62(s, 1H), 8.00(d, J=5.6Hz, 1H), 7.42(d, J =8.0Hz,1H),6.49(s,1H),6.42(d,J=8.0Hz,1H),4.94(d,J=52.0Hz,1H),4.73(s,1H),4.48(d,J =12.8Hz,1H),4.39(t,J=7.2Hz,2H),4.03–3.91(m,2H),3.67–3.42(m,3H),3.27–3.15(m,3H),3.10(q, J=10.0Hz, 1H), 2.60(s, 3H), 1.88–1.67(m, 2H), 1.30(m, 6H).

Example 7, N-(2-((3R,4S)-3-fluoro-4-(methoxy-d3)piperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8 Synthesis of -(3-(methylsulfinylmethyl)azetidin-1-yl)isoquinolin-3-amine (compound 7):

1), Synthesis of 2-((3R,4S)-3-fluoro-4-(methoxyl-d3)piperidin-1-yl)pyrimidin-4-amine:

Similar to the synthetic steps of 2-((3S,4R)-3-fluoro-4-(methoxyl-d3)piperidin-1-yl)pyrimidin-4-amine in Example 6 with (3R,4S)- Starting from tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate, 2-((3R,4S)-3-fluoro-4-(methoxy-d3)piperidin-1-yl) can be obtained pyrimidin-4-amine.

2), N-(2-((3R,4S)-3-fluoro-4-(methoxy-d3)piperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8- Synthesis of (3-(methylsulfinylmethyl)azetidin-1-yl)isoquinolin-3-amine (compound 7):

Under nitrogen protection, 3-chloro-5-isopropyl-8-(3-(methylsulfinylmethyl)azetidin-1-yl)isoquinoline (102mg, 0.3mmol) was dissolved in To dioxane (6mL), add 2-((3R,4S)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine (69mg, 0.3mmol) and cesium carbonate (195mg, 0.6mmol), and finally Brettphos Pd G3 (27mg, 0.03mmol) was added, the temperature was raised to 100°C and the reaction was stirred for 16 hours. The reaction solution was filtered with diatomaceous earth, the filtrate was concentrated under reduced pressure and separated by a flash silica gel separation column (dichloromethane:methanol=10:1) to obtain a crude product (36.3mg), and the resulting crude product was separated by chiral liquid phase ( Instrument: SFC-150 (Waters), column: AS 20*250mm, 10um (Daicel), column temperature: 35°C, mobile phase: CO2/MeOH [0.2% NH3 (7M in MeOH)] = 45/55, flow rate: 120g/min, pressure: 100bar, detection wavelength: 214nm, cycle time: 5min, sample dissolution: 30mg was dissolved in 30ml methanol, injection volume: 3ml) purified to obtain N-(2-((3R, 4S)-3- Fluoro-4-(methoxy-d3)piperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-(3-(methylsulfinylmethyl)azetidin- 2 isomers of 1-yl)isoquinolin-3-amine (compound 7): compound 7A (4.2 mg, yield: 5.2%) and compound 7B (4.9 mg, yield: 6.2%).

Compound 7A: LC-MS m/z:530[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d6): δppm 9.92(s, 1H), 9.06(s, 1H), 8.62(s, 1H), 8.00(d, J=5.6Hz, 1H), 7.42(d, J =8.0Hz, 1H), 6.48(d, J=5.6Hz, 1H), 6.41(d, J=8.0Hz, 1H), 4.94(d, J=51.0Hz, 1H), 4.75(d, J=14.4 Hz, 1H), 4.49(d, J=13.6Hz, 1H), 4.38(t, J=7.2Hz, 2H), 4.04–3.91(m, 2H), 3.66–3.41(m, 3H), 3.25(m ,3H),3.15–3.05(m,1H),2.60(s,3H),1.91–1.66(m,2H),1.30(m,6H).

Compound 7B: LC-MS m/z:530[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d6): δppm J＝8.0Hz, 1H), 6.48(d, J＝5.6Hz, 1H), 6.41(d, J＝8.0Hz, 1H), 4.94(d, J＝51.4Hz, 1H), 4.80–4.67(m, 1H), 4.49(d, J=13.2Hz, 1H), 4.38(t, J=7.2Hz, 2H), 3.97(t, J=6.0Hz, 2H), 3.67–3.40(m, 3H), 3.25( m,3H),3.10(m,1H),2.60(s,3H),1.80(m,2H),1.30(m,6H).

Example 8, (3S, 4S)-3-fluoro-1-(4-((5-isopropyl-8-(3-((methylsulfonyl)methyl)azetidine-1- Base) isoquinolin-3-yl)amino)-1,3,5-triazin-2-yl)-3-methylpiperidin-4-ol (compound 8):

Under nitrogen protection, mixed with ((3S, 4S)-1-(4-amino-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidin-4-ol ( 20mg, 0.09mmol), 3-chloro-5-isopropyl-8-(3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline (32mg, 0.09mmol) Add Brettphos Pd G3 (9 mg, 0.01 mmol) to a solution of cesium carbonate (59 mg, 0.18 mmol) in dioxane (7 mL), heat up to 100 ° C and stir for 5 hours. The reaction solution is directly concentrated under reduced pressure, and sequentially prepared Grade thin layer chromatography (dichloromethane/methanol=15/1) and preparative grade high performance liquid chromatography (chromatographic conditions are as follows: Waters 2767/2545/2489; Column: SunFire Prep C18 OBD 10um 19*250mm Column; Mobile phase 0.1% FA in H2O/CAN; detection wavelength: 254nm&214nm; flow rate: 20ml/min) was purified to obtain (3S, 4S)-3-fluoro-1-(4-((5-isopropyl-8-(3-((form Sulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)-1,3,5-triazin-2-yl)-3-methylpiperidine-4 -alcohol (compound 8) (13.93mg, 0.026mmol, yield: 28.9%).LC-MS m/z:544[M+H] ⁺ .

¹ H NMR (400MHz,DMSO-d ₆ )δ9.95-9.91(m,1H),9.08(s,1H),8.70-8.63(m,1H),8.33(s,1H),7.44(d,J =8.0Hz,1H),6.45(d,J=8.0Hz,1H),5.46(s,1H),4.40(t,J=7.6Hz,2H),4.25-4.23(m,1H),3.99-3.90 (m,3H),3.76-3.65(m,2H),3.60-3.44(m,4H),3.33-3.21(m,1H),3.01(s,3H),1.93-1.91(m,1H),1.64 -1.61(m,1H),1.35-1.29(m,9H).

Example 9, N-(4-(3S,4S)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)-1,3,5-triazin-2-yl) -5-isopropyl-8-(2R,3S)-2-methyl-3-(methylsulfonyl)methyl)azetidin-1-yl)-2,7-naphthyridine-3- Synthesis of amine (compound 9):

Under nitrogen protection, 4-(3S, 4S)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)-1,3,5-triazin-2-amine ( 20mg, 0.08mmol), 6-chloro-4-isopropyl-1-(2R,3S)-2-methyl-3-(methylsulfonyl)methyl)azetidin-1-yl) -2,7-Naphthyridine (29mg, 0.08mmol) and cesium carbonate (52mg, 0.16mmol) in dioxane (7mL) were added Brettphos Pd G3 (9mg, 0.01mmol), heated to 100°C and stirred for reaction 5 Hour. The reaction solution was directly concentrated under reduced pressure, and was subjected to preparative thin-layer chromatography (dichloromethane/methanol=15/1) and preparative high-performance liquid chromatography (chromatographic conditions as follows: Waters 2767/2545/2489; column: SunFire Prep C18 OBD 10um 19*250mm Column; mobile phase 0.1% FA in H2O/CAN; detection wavelength: 254nm&214nm; flow rate: 20ml/min) to obtain N-(4-(3S,4S)-3-fluoro-4-methoxy -3-methylpiperidin-1-yl)-1,3,5-triazin-2-yl)-5-isopropyl-8-(2R,3S)-2-methyl-3-(methyl sulfonyl)methyl)azetidin-1-yl)-2,7-naphthyridin-3-amine (compound 9) (12.98 mg, 0.025 mmol, 27.3% yield). LC-MS m/z:573[M+H] ⁺ .

¹ H NMR (400MHz,DMSO-d ₆ )δ10.22-10.21(m,1H),9.06(s,1H),8.59-8.54(m,1H),8.37(s,1H),8.04(s,1H ),4.87(t,J=8.0Hz,1H),4.55(t,J=6.4Hz,1H),4.05-3.97(m,3H),3.83-3.80(m,2H),3.54-3.52(m, 3H),3.48-3.21(m,4H),2.98(s,3H),2.92-2.87(m,1H),1.93-1.90(m,1H),1.84-1.75(m,1H),1.50(d, J＝6.0Hz,3H),1.37-1.31(m,9H),

Example 10, N-(4-(3R,4R)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)-1,3,5-triazin-2-yl) -5-isopropyl-8-(2R,3S)-2-methyl-3-(methylsulfonyl)methyl)azetidin-1-yl)-2,7-naphthyridine-3- Synthesis of Amine (Compound 10):

Under nitrogen protection, 4-(3R, 4R)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)-1,3,5-triazin-2-amine ( 20mg, 0.08mmol), 6-chloro-4-isopropyl-1-(2R,3S)-2-methyl-3-(methylsulfonyl)methyl)azetidin-1-yl) Add Brettphos Pd G3 (9 mg, 0.01 mmol) to a solution of -2,7-naphthyridine (29 mg, 0.08 mmol) and cesium carbonate (52 mg, 0.16 mmol) in dioxane (7 mL), heat up to 100 ° C for 5 hours . After the reaction was completed, the reaction solution was concentrated under reduced pressure and then used preparative thin-layer chromatography (dichloromethane/methanol=15/1) and preparative high-performance liquid chromatography (chromatographic conditions are as follows: Waters 2767/2545/2489; column: N-(4-(3R,4R)-3-fluoro-4- Methoxy-3-methylpiperidin-1-yl)-1,3,5-triazin-2-yl)-5-isopropyl-8-(2R,3S)-2-methyl-3 -(methylsulfonyl)methyl)azetidin-1-yl)-2,7-naphthyridin-3-amine (compound 10) (12.13 mg, 0.021 mmol, yield: 26%).LC- MS m/z:573[M+H] ⁺ .

¹ H NMR (400MHz,DMSO-d ₆ )δ10.21(s,1H),9.06(s,1H),8.59-8.54(m,1H),8.37(s,1H),8.04(s,1H), 4.87(t, J=8.0Hz, 1H), 4.55(t, J=6.0Hz, 1H), 4.07-3.78(m, 5H), 3.53(d, J=7.2Hz, 3H), 3.48-3.26(m ,4H),2.98(s,3H),2.92-2.87(m,1H),1.93-1.92(m,1H),1.84-1.75(m,1H),1.50(d,J＝6.0Hz,3H), 1.37-1.31(m,9H).

Example 11, (4R,5S)-5-fluoro-1-(4-(5-isopropyl-8-(3-(methylsulfonyl)methyl)azetidin-1-yl) Synthesis of isoquinolin-3-yl)amino)-1,3,5-triazin-2-yl)-3,3-dimethylpiperidin-4-ol (compound 11):

Under nitrogen protection, (4R, 5S)-1-(4-amino-1,3,5-triazin-2-yl)-5-fluoro-3,3-dimethylpiperidine-4- Alcohol (20mg, 0.083mmol) and 3-chloro-5-isopropyl-8-(3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline (29mg, 0.083 mmol) in dioxane (4 mL), cesium carbonate (108 mg, 0.332 mmol) and Brettphos Pd G3 (8 mg, 0.008 mmol) were added sequentially. The temperature was raised to 100°C, and the reaction was stirred for 5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and then subjected to silica gel column chromatography (dichloromethane/methanol=15/1) and preparative high-performance liquid chromatography (chromatographic conditions are as follows: Waters 2767/2545/2489; column: SunFire Prep C18 OBD 10um 19*250mm Column; mobile phase 0.1% FA in H2O/CAN; detection wavelength: 254nm&214nm; flow rate: 20ml/min) to obtain (4R,5S)-5-fluoro-1-(4-(5-isopropyl) Base-8-(3-(methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)-1,3,5-triazin-2-yl) -3,3-Dimethylpiperidin-4-ol (Compound 11) (3.58 mg, Yield: 7.7%). LC-MS m/z:558[M+H] ⁺ .

¹ H NMR (400MHz,DMSO-d ₆ )δ9.88-9.80(m,1H),9.07(s,1H),8.69-8.57(m,1H),8.32(s,1H),7.44(d,J =7.6Hz,1H),6.45(d,J=8.0Hz,1H),5.22(s,1H),4.86-4.74(m,1H),4.42-4.34(m,3H),3.99–3.84(m, 4H),3.59-3.40(m,4H),3.31-3.01(m,2H),3.01(s,3H),1.30(t,J＝6.8Hz,6H),0.93(s,6H).

Example 12, (4S, 5R)-5-fluoro-1-(4-(5-isopropyl-8-(3-(methylsulfonyl)methyl)azetidin-1-yl) Synthesis of isoquinolin-3-yl)amino)-1,3,5-triazin-2-yl)-3,3-dimethylpiperidin-4-ol (compound 12):

Under nitrogen protection, (4S, 5R)-1-(4-amino-1,3,5-triazin-2-yl)-5-fluoro-3,3-dimethylpiperidine-4- Alcohol (20mg, 0.083mmol) and 3-chloro-5-isopropyl-8-(3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline (29mg, 0.083 mmol) in dioxane (4 mL), cesium carbonate (108 mg, 0.332 mmol) and Brettphos Pd G3 (8 mg, 0.008 mmol) were added sequentially. The temperature was raised to 100° C., and the reaction was carried out for 5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and then subjected to silica gel column chromatography (dichloromethane/methanol=15/1) and preparative high-performance liquid chromatography (chromatographic conditions are as follows: Waters 2767/2545/2489; column: SunFire Prep (4S, 5R)-5-fluoro-1-(4-(5-iso Propyl-8-(3-(methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)-1,3,5-triazin-2-yl )-3,3-dimethylpiperidin-4-ol (7.65 mg, yield: 16.5%). LC-MS m/z:558[M+H] ⁺ .

¹ H NMR (400MHz,DMSO-d ₆ )δ9.88-9.80(m,1H),9.07(s,1H),8.69-8.57(m,1H),8.32(s,1H),7.44(d,J ＝8.0Hz,1H),6.45(d,J＝8.0Hz,1H),5.22(s,1H),4.86-4.73(m,1H),4.42-4.34(m,3H),3.98–3.86(m, 4H),3.59-3.40(m,4H),3.31-3.18(m,2H),3.01(s,3H),1.32-1.26(m,6H),0.89(s,6H).

Example 13, (3R, 4S)-1-(4-((8-((2R, 3S)-3-((ethylsulfonyl)methyl)-2-methylazetidine-1 -yl)-5-isopropyl-2,7-naphthyridin-3-yl)amino)-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidine-4 - Synthesis of Alcohol (Compound 13):

Under nitrogen protection, (3R,4S)-1-(4-amino-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (30mg , 0.13mmol) in dioxane solution (7mL), add 6-chloro-1-((2R,3S)-3-((ethylsulfonyl)methyl)-2-methylazacyclocycline successively Butan-1-yl)-4-isopropyl-2,7-naphthyridine (50mg, 0.13mmol), cesium carbonate (85mg, 0.26mmol) and Brettphos Pd G3 (12mg, 0.013mmol), warming to 100°C , reacted for 5 hours. After concentration under reduced pressure, the crude product was successively passed through preparative thin-layer chromatography (dichloromethane/methanol=15/1) and reversed-phase medium and low pressure liquid phase (chromatographic conditions: column: spherical C18, 20-40um, 80g; mobile phase A : water (containing 0.1% formic acid); mobile phase B: acetonitrile; flow rate: 80 mL/min; gradient: 5% B-30% B in 20 minutes; detector: 254 nm) to obtain (3R, 4S)-1 -(4-((8-((2R,3S)-3-((ethylsulfonyl)methyl)-2-methylazetidin-1-yl)-5-isopropyl-2 ,7-naphthyridin-3-yl)amino)-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (compound 13) (33.96mg, yield Yield: 45.4%). LC-MS m/z: 573[M+H] ⁺ .

¹ H NMR (400MHz,DMSO-d ₆ )δ10.26-10.18(m,1H),9.08(s,1H),8.60-8.52(m,1H),8.37(d,J=5.2Hz,1H), 8.04(s,1H),5.15(s,1H),4.87(t,J=8.0Hz,1H),4.81-4.53(m,3H),3.99(t,J=7.2Hz,1H),3.54(d ,J=4.8Hz,2H),3.47-3.29(m,2H),3.25-3.13(m,2H),3.07(t,J=7.2Hz,2H),2.94-2.85(m,1H),1.78- 1.62(m,2H),1.50(d,J=6.4Hz,3H),1.40-1.26(m,9H),1.22(t,J=7.2Hz,3H).

Example 14, (3S, 4R)-1-(4-((8-((2R, 3S)-3-((ethylsulfonyl)methyl)-2-methylazetidine-1 -yl)-5-isopropyl-2,7-naphthyridin-3-yl)amino)-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidine-4 - Synthesis of Alcohol (Compound 14):

Under nitrogen protection, (3S, 4R)-1-(4-amino-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (30mg , 0.13mmol) in dioxane solution (7mL), successively add 6-chloro-1-((2R, 3S)-3-((ethylsulfonyl)methyl)-2-methylazacyclic Butan-1-yl)-4-isopropyl-2,7-naphthyridine (50mg, 0.13mmol), cesium carbonate (85mg, 0.26mmol) and Brettphos Pd G3 (12mg, 0.013mmol), warming to 100°C , reacted for 5 hours. After the reaction solution was decompressed, the crude product was successively passed through preparative thin-layer chromatography (dichloromethane/methanol=15/1) and reversed-phase medium and low pressure liquid phase (chromatographic conditions: column: spherical C18, 20-40um, 80g; flow Phase A: water (contains 0.1% formic acid); mobile phase B: acetonitrile; flow rate: 80 mL/min; gradient: 5% B-30% B in 20 minutes; detector: 254 nm.) Purification gave (3S, 4R )-1-(4-((8-((2R,3S)-3-((ethylsulfonyl)methyl)-2-methylazetidin-1-yl)-5-isopropyl Base-2,7-naphthyridin-3-yl)amino)-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (compound 14) (12.37 mg, yield: 16.9%). LC-MS m/z:573[M+H] ⁺ .

¹ H NMR (400MHz,DMSO-d ₆ )δ10.21-10.15(m,1H),9.06(s,1H),8.60-8.51(m,1H),8.36(d,J=5.6Hz,1H), 8.04(s,1H),5.12(s,1H),4.86(t,J=8.0Hz,1H),4.80-4.53(m,3H),3.98(t,J=7.6Hz,1H),3.51(d ,J=7.2Hz,2H),3.46-3.45(m,2H),3.33–3.13(m,2H),3.09(q,J=7.2Hz,2H),2.92-2.87(m,1H),1.78- 1.63(m,2H),1.50(d,J=6.4Hz,3H),1.40-1.28(m,9H),1.22(t,J=7.2Hz,3H).

Example 15, (3S, 4S)-1-(4-((8-((2R, 3S)-3-((ethylsulfonyl)methyl)-2-methylazetidine-1 -yl)-5-isopropyl-2,7-naphthyridin-3-yl)amino)-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidine-4 - Synthesis of Alcohol (Compound 15):

Under nitrogen protection, (3S, 4S)-1-(4-amino-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (30mg , 0.13mmol) in dioxane solution (7mL), sequentially add 6-chloro-1-((2R,3S)-3-((ethylsulfonyl)methyl)-2-methylazepine Cyclobutan-1-yl)-4-isopropyl-2,7-naphthyridine (50 mg, 0.13 mmol), cesium carbonate (85 mg, 0.26 mmol) and Brettphos Pd G3 (12 mg, 0.013 mmol), warming to 100 °C, react for 5 hours. After the reaction solution was concentrated under reduced pressure, the crude product was sequentially passed through preparative thin-layer chromatography (dichloromethane/methanol=15/1) and reversed-phase medium and low pressure liquid phase (chromatographic conditions: column: spherical C18, 20-40um, 80g; flow Phase A: water (contains 0.1% formic acid); mobile phase B: acetonitrile; flow rate: 80 mL/min; gradient: 5% B-30% B in 20 minutes; detector: 254 nm) to obtain (3S, 4S) -1-(4-((8-((2R,3S)-3-((ethylsulfonyl)methyl)-2-methylazetidin-1-yl)-5-isopropyl Formic acid of -2,7-naphthyridin-3-yl)amino)-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (compound 15) Salt (6.38mg, Yield: 7.7%).LC-MS m/z:573[M+H] ⁺ .

¹ H NMR (400MHz,DMSO-d ₆ )δ10.18(s,1H),9.05(s,1H),8.61-8.54(m,1H),8.35(s,1H),8.29(s,1H), 8.04(s,1H),5.47(s,1H),4.86(t,J=8.0Hz,1H),4.55(t,J=6.0Hz,1H),4.28-4.22(m,1H),4.06-3.93 (m,2H),3.83-3.57(m,4H),3.51(d,J=7.6Hz,2H),3.08(q,J=6.8Hz,2H),2.92-2.86(m,1H),1.95- 1.64(m,1H),1.63-1.60(m,1H),1.50(d,J=6.0Hz,3H),1.36-1.30(m,9H),1.22(t,J=7.2Hz,3H).

Example 16, (3R, 4R)-1-(4-((8-((2R, 3S)-3-((ethylsulfonyl)methyl)-2-methylazetidine-1 -yl)-5-isopropyl-2,7-naphthyridin-3-yl)amino)-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidine-4 -Synthesis of Alcohol (Compound 16):

Under nitrogen protection, (3R,4R)-1-(4-amino-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (30mg , 0.13mmol) in dioxane solution (7mL), successively add 6-chloro-1-((2R, 3S)-3-((ethylsulfonyl)methyl)-2-methylazacyclic Butan-1-yl)-4-isopropyl-2,7-naphthyridine (50mg, 0.13mmol), cesium carbonate (85mg, 0.26mmol) and Brettphos Pd G3 were heated to 100°C and reacted for 5 hours. After the reaction solution was concentrated under reduced pressure, the crude product was sequentially passed through preparative thin-layer chromatography (dichloromethane/methanol=15/1) and reversed-phase medium and low pressure liquid phase (chromatographic conditions: column: spherical C18, 20-40um, 80g; flow Phase A: water (contains 0.1% formic acid); mobile phase B: acetonitrile; flow rate: 80 mL/min; gradient: 5% B-30% B in 20 minutes; detector: 254 nm) to obtain (3R, 4R) -1-(4-((8-((2R,3S)-3-((ethylsulfonyl)methyl)-2-methylazetidin-1-yl)-5-isopropyl -2,7-naphthyridin-3-yl)amino)-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (compound 16) (3.27mg , Yield: 4.6%). LC-MS m/z: 573[M+H] ⁺ .

¹ H NMR (400MHz,DMSO-d ₆ )δ10.20(s,1H),9.06(s,1H),8.61-8.54(m,1H),8.36(s,1H),8.04(s,1H), 5.51(s,1H),4.86(t,J=8.0Hz,1H),4.55(t,J=6.0Hz,1H),4.10-3.97(m,1H),3.98(t,J=7.4Hz,2H ),3.76-3.65(m,4H),3.51(d,J=7.6Hz,2H),3.08(q,J=7.2Hz,2H),2.92-2.86(m,1H),1.95-1.64(m, 1H), 1.63-1.60(m, 1H), 1.50(d, J=6.0Hz, 3H), 1.36–1.30(m, 9H), 1.22(t, J=7.2Hz, 3H).

Example 17, (3R, 4S)-3-fluoro-1-(4-((5-isopropyl-8-((2R, 3S)-2-methyl-3-((methylsulfonyl) Methyl) azetidin-1-yl)-2,7-naphthyridin-3-yl)amino)-1,3,5-triazin-2-yl)-3-methylpiperidine-4 - Synthesis of Alcohol (Compound 17):

Under nitrogen protection, (3R,4S)-1-(4-amino-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (30mg ,0.13mmol) in dioxane solution (7mL), add 6-chloro-4-isopropyl-1-((2R,3S)-2-methyl-3-((methylsulfonyl) Methyl)azetidin-1-yl)-2,7-naphthyridine (48mg, 0.13mmol), cesium carbonate (85mg, 0.26mmol) and Brettphos Pd G3 (12mg, 0.013mmol), warming to 100°C , reacted for 5 hours. After the reaction solution was concentrated under reduced pressure, the crude product was sequentially passed through preparative thin-layer chromatography (dichloromethane/methanol=15/1) and reversed-phase medium and low pressure liquid phase (chromatographic conditions: column: spherical C18, 20-40um, 80g; flow Phase A: water (contains 0.1% formic acid); mobile phase B: acetonitrile; flow rate: 80 mL/min; gradient: 5% B-30% B in 20 minutes; detector: 254 nm) to obtain (3R, 4S) -3-fluoro-1-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidine- 1-yl)-2,7-naphthyridin-3-yl)amino)-1,3,5-triazin-2-yl)-3-methylpiperidin-4-ol (compound 17) formic acid Salt (30.75 mg, yield: 39.2%). LC-MS m/z:559[M+H] ⁺ .

¹ H NMR (400MHz,DMSO-d ₆ )δ10.23-10.17(m,1H),9.07(s,1H),8.60-8.52(m,1H),8.36(d,J=6.0Hz,1H), 8.24(s,1H),8.04(s,1H),5.12(s,1H),4.87(t,J=8.0Hz,1H),4.80–4.52(m,3H),4.00(t,J=6.8Hz ,1H),3.64-3.56(m,2H),3.54-3.37(m,2H),3.35–3.10(m,2H),2.99(s,3H),2.95-2.67(m,1H),1.78–1.65 (m,2H),1.50(d,J=6.4Hz,3H),1.42–1.27(m,9H).

Example 18, (3S, 4R)-3-fluoro-1-(4-((5-isopropyl-8-((2R, 3S)-2-methyl-3-((methylsulfonyl) Methyl) azetidin-1-yl)-2,7-naphthyridin-3-yl)amino)-1,3,5-triazin-2-yl)-3-methylpiperidine-4 - Synthesis of Alcohol (Compound 18):

Under nitrogen protection, (3S, 4R)-1-(4-amino-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (30mg ,0.13mmol) in dioxane solution (7mL), add 6-chloro-4-isopropyl-1-((2R,3S)-2-methyl-3-((methylsulfonyl) Methyl)azetidin-1-yl)-2,7-naphthyridine (48mg, 0.13mmol), cesium carbonate (85mg, 0.26mmol) and Brettphos Pd G3 (12mg, 0.013mmol), warming to 100°C °C, react for 5 hours. After the reaction solution was concentrated under reduced pressure, the crude product was sequentially passed through preparative thin-layer chromatography (dichloromethane/methanol=15/1) and reversed-phase medium and low pressure liquid phase (chromatographic conditions: column: spherical C18, 20-40um, 80g; flow Phase A: water (containing 0.1% formic acid); mobile phase B: acetonitrile; flow rate: 80 mL/min; gradient: 5% B-30% B in 20 minutes; detector: 254 nm) purified to obtain (3S, 4R) -3-fluoro-1-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidine- 1-yl)-2,7-naphthyridin-3-yl)amino)-1,3,5-triazin-2-yl)-3-methylpiperidin-4-ol (compound 18) (6.60mg , 0.012 mmol, yield: 9.2%). LC-MS m/z:559[M+H] ⁺ .

¹ H NMR (400MHz,DMSO-d ₆ )δ10.18-10.12(m,1H),9.05(s,1H),8.60-8.51(m,1H),8.36(d,J=6.0Hz,1H), 8.04(s,1H),5.14-5.10(m,1H),4.86(t,J＝8.0Hz,1H),4.75-4.69(m,3H),4.58-4.53(m,1H),3.98(t, J＝7.6Hz, 2H), 3.62-3.37(m, 2H), 3.32-3.26(m, 2H), 3.12-3.09(m, 2H), 2.95(s, 3H), 2.92-2.67(m, 1H) ,1.78–1.65(m,2H),1.49(d,J＝6.0Hz,3H),1.40–1.21(m,9H).

Example 19, (3S, 4S)-3-fluoro-1-(4-((5-isopropyl-8-((2R, 3S)-2-methyl-3-((methylsulfonyl) Methyl) azetidin-1-yl)-2,7-naphthyridin-3-yl)amino)-1,3,5-triazin-2-yl)-3-methylpiperidine-4 - Synthesis of Alcohol (Compound 19):

Under nitrogen protection, (3S, 4S)-1-(4-amino-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (30mg ,0.13mmol) in dioxane solution (7mL), add 6-chloro-4-isopropyl-1-((2R,3S)-2-methyl-3-((methylsulfonyl) Methyl)azetidin-1-yl)-2,7-naphthyridine (48mg, 0.13mmol), cesium carbonate (85mg, 0.26mmol) and Brettphos Pd G3 (12mg, 0.013mmol), warming to 100°C , reacted for 5 hours. After the reaction solution was concentrated under reduced pressure, the crude product was sequentially passed through preparative thin-layer chromatography (dichloromethane/methanol=15/1) and reversed-phase medium and low pressure liquid phase (chromatographic conditions: column: spherical C18, 20-40um, 80g; flow Phase A: water (contains 0.1% formic acid); mobile phase B: acetonitrile; flow rate: 80 mL/min; gradient: 5% B-30% B in 20 minutes; detector: 254 nm) to obtain (3S, 4S) -3-fluoro-1-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidine- 1-yl)-2,7-naphthyridin-3-yl)amino)-1,3,5-triazin-2-yl)-3-methylpiperidin-4-ol (compound 19) (10.28mg , Yield: 13.8%). LC-MS m/z:559[M+H] ⁺ .

¹ H NMR (400MHz,DMSO-d ₆ )δ10.18(s,1H),9.06(s,1H),8.61-8.54(m,1H),8.35(s,1H),8.04(s,1H), 5.47(s,1H),4.87(t,J=8.0Hz,1H),4.56(t,J=6.4Hz,1H),4.53-4.19(m,1H),4.30-4.21(m,2H),4.05 -3.77(m,4H),3.53(d,J＝7.6Hz,2H),3.00(s,3H),2.91–2.87(m,1H),1.95-1.87(m,1H),1.65-1.55(m ,1H),1.49(d,J＝8.4Hz,3H),1.36–1.30(m,9H).

Example 20, (3R, 4R)-3-fluoro-1-(4-((5-isopropyl-8-((2R, 3S)-2-methyl-3-((methylsulfonyl) Methyl) azetidin-1-yl)-2,7-naphthyridin-3-yl)amino)-1,3,5-triazin-2-yl)-3-methylpiperidine-4 - Synthesis of Alcohol (Compound 20):

Under nitrogen protection, (3R,4R)-1-(4-amino-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (30mg ,0.13mmol) in dioxane solution (7mL), add 6-chloro-4-isopropyl-1-((2R,3S)-2-methyl-3-((methylsulfonyl) Methyl)azetidin-1-yl)-2,7-naphthyridine (48mg, 0.13mmol), cesium carbonate (85mg, 0.26mmol) and Brettphos Pd G3 (12mg, 0.013mmol), warming to 100°C , reacted for 5 hours. After the reaction solution was concentrated under reduced pressure, the crude product was sequentially passed through preparative thin-layer chromatography (dichloromethane/methanol=15/1) and reversed-phase medium and low pressure liquid phase (chromatographic conditions: column: spherical C18, 20-40um, 80g; flow Phase A: water (contains 0.1% formic acid); mobile phase B: acetonitrile; flow rate: 80 mL/min; gradient: 5% B-30% B in 20 minutes; detector: 254 nm) to obtain (3R, 4R) -3-fluoro-1-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidine- 1-yl)-2,7-naphthyridin-3-yl)amino)-1,3,5-triazin-2-yl)-3-methylpiperidin-4-ol (compound 20) formic acid Salt (9.87mg, yield: 13.6%) LC-MS m/z: 559[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.18 (d, J=11.6Hz, 1H), 9.06 (s, 1H), 8.61-8.54 (m, 1H), 8.36 (s, 1H), 8.33 ( s,1H),8.04(s,1H),5.44(s,1H),4.87(t,J=8.0Hz,1H),4.55(t,J=6.0Hz,1H),4.26-4.21(m,1H ),4.00-3.76(m,2H),3.68-3.52(m,4H),3.47(d,J＝7.6Hz,2H),3.01(s,3H),2.98-2.87(m,1H),1.94- 1.90(m,1H),1.89-1.64(m,1H),1.49(d,J=6.0Hz,3H),1.38-1.30(m,9H).

Example 21, (3R,4S)-3-fluoro-1-(4-((5-isopropyl-8-(3-((methylsulfonyl)methyl)azetidine-1- Synthesis of -2,6-naphthyridin-3-yl)amino)-1,3,5-triazin-2-yl)-3-methylpiperidin-4-ol (compound 21):

1), Synthesis of 1-isopropyl-7-chloro-4-(3-((methylsulfonyl)methyl)azetidin-1-yl)-2,6-naphthyridine:

Under nitrogen protection, 4-bromo-7-chloro-1-isopropyl-2,6-naphthyridine (200mg, 0.70mmol) and 3-((methylsulfonyl)methyl)azetidine were dissolved in Cesium carbonate (685 mg, 2.10 mmol) and Xantphos Pd G4 (65 mg, 0.07 mmol) were added successively to a dioxane solution (10 mL) of alkanes (209 mg, 1.40 mmol). The temperature was raised to 100° C., and the reaction was carried out for 3 hours. After the reaction was completed, water (40 mL) was added to the reaction solution to quench it, extracted with ethyl acetate (20 mL×3), and the organic phases were combined, washed with saturated brine (20 mL×3), dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the crude product was purified by reverse phase medium and low pressure liquid phase (column: spherical C18, 20-40um, 120g; mobile phase A: water (containing 0.1% ammonia water); mobile phase B: acetonitrile; flow rate: 80mL/ min; gradient: 14% B to 100% B in 40 minutes; detector: 254 nm) to give 1-isopropyl-7-chloro-4-(3-((methylsulfonyl)methyl)azacycle Butan-1-yl)-2,6-naphthyridine (120 mg, yield: 48.6%). LC-MS m/z:354[M+H] ⁺ .

2), (3R, 4S)-3-fluoro-1-(4-((5-isopropyl-8-(3-((methylsulfonyl)methyl)azetidin-1-yl Synthesis of )-2,6-naphthyridin-3-yl)amino)-1,3,5-triazin-2-yl)-3-methylpiperidin-4-ol (compound 21):

Under nitrogen protection, 1-isopropyl-7-chloro-4-(3-((methylsulfonyl)methyl)azetidin-1-yl)-2,6-naphthyridine ( 30mg, 0.08mmol) and (3R, 4S)-1-(4-amino-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (36mg, 0.16 mmol) in dioxane (4 mL), cesium carbonate (78 mg, 0.24 mmol) and Brettphos Pd G3 (9 mg, 0.01 mmol) were added in sequence. The temperature was raised to 100° C., and the reaction was carried out for 3 hours. After the reaction was completed, water (10 mL) was added to the reaction solution to quench the reaction, extracted with ethyl acetate (10 mL×2), the organic phases were combined, washed with saturated brine (20 mL×3), dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the crude product was subjected to preparative high-performance liquid chromatography (chromatographic conditions are as follows: Waters 2767/2545/2489; column: SunFire Prep C18 OBD 10um 19*250mm Column; mobile phase 0.1% FA in H2O/CAN; detection Wavelength: 254nm&214nm; flow rate: 20ml/min) to obtain (3R,4S)-3-fluoro-1-(4-((5-isopropyl-8-(3-((methylsulfonyl)methyl)) Azetidin-1-yl)-2,6-naphthyridin-3-yl)amino)-1,3,5-triazin-2-yl)-3-methylpiperidin-4-ol ( Compound 21) (2.18 mg, yield 5.0%). LC-MS m/z:545[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ10.23(d, J=22.4Hz, 1H), 9.15(s, 1H), 8.73(d, J=40.0Hz, 1H), 8.35(s, 1H ),7.63(s,1H),4.79-4.63(m,2H),4.49(t,J＝7.6Hz,2H),4.08(t,J＝6.8Hz,2H),3.62-3.60(m,4H) ,3.39-3.32(m,2H),3.21-3.12(m,2H),3.02(s,3H),1.79-1.63(m,2H),1.41-1.31(m,9H).

Example 22, (3S,4R)-3-fluoro-1-(4-((5-isopropyl-8-(3-((methylsulfonyl)methyl)azetidine-1- Synthesis of -2,6-naphthyridin-3-yl)amino)-1,3,5-triazin-2-yl)-3-methylpiperidin-4-ol (compound 22):

Under nitrogen protection, 1-isopropyl-7-chloro-4-(3-((methylsulfonyl)methyl)azetidin-1-yl)-2,6-naphthyridine ( 30mg, 0.08mmol) and (3S, 4R)-1-(4-amino-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (36mg, 0.16 mmol) in dioxane (4 mL), cesium carbonate (78 mg, 0.24 mmol) and Brettphos Pd G3 (9 mg, 0.01 mmol) were added in sequence. The temperature was raised to 100° C., and the reaction was carried out for 3 hours. After the reaction was completed, water (10 mL) was added to the reaction solution to quench the reaction, extracted with ethyl acetate (10 mL×2), the organic phases were combined, washed with saturated brine (20 mL×3), dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the crude product was subjected to preparative high-performance liquid chromatography (chromatographic conditions are as follows: Waters 2767/2545/2489; column: SunFire Prep C18 OBD 10um 19*250mm Column; mobile phase 0.1% FA in H2O/CAN; detection Wavelength: 254nm&214nm; flow rate: 20ml/min) to obtain (3S,4R)-3-fluoro-1-(4-((5-isopropyl-8-(3-((methylsulfonyl)methyl)) Azetidin-1-yl)-2,6-naphthyridin-3-yl)amino)-1,3,5-triazin-2-yl)-3-methylpiperidin-4-ol ( Compound 22) (3.51 mg, yield: 8.1%). LC-MS m/z:545[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ ):δ10.27-10.18(m,1H),9.16(s,1H),8.73(d,J＝39.6Hz,1H),8.35(s,2H),7.63 (s,1H),4.79-4.61(m,2H),4.49(t,J=7.6Hz,2H),4.08(t,J=6.0Hz,2H),3.74-3.60(m,4H),3.36- 3.34(m,2H),3.22-3.10(m,2H),3.02(s,3H),1.80-1.60(m,2H),1.41-1.31(m,9H).

Example 23, (3S,4S)-3-fluoro-1-(4-((5-isopropyl-8-(3-((methylsulfonyl)methyl)azetidine-1- Synthesis of -2,6-naphthyridin-3-yl)amino)-1,3,5-triazin-2-yl)-3-methylpiperidin-4-ol (compound 23):

Under nitrogen protection, 1-isopropyl-7-chloro-4-(3-((methylsulfonyl)methyl)azetidin-1-yl)-2,6-naphthyridine ( 30mg, 0.08mmol) and (3S, 4S)-1-(4-amino-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (36mg, 0.16 mmol) in dioxane (4 mL), cesium carbonate (78 mg, 0.24 mmol) and Brettphos Pd G3 (9 mg, 0.01 mmol) were added in sequence. The temperature was raised to 100° C., and the reaction was carried out for 3 hours. After the reaction was completed, water (10 mL) was added to the reaction solution to quench the reaction, extracted with ethyl acetate (10 mL×2), the organic phases were combined, washed with saturated brine (20 mL×3), dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the crude product was subjected to preparative high-performance liquid chromatography (chromatographic conditions are as follows: Waters 2767/2545/2489; column: SunFire Prep C18 OBD 10um 19*250mm Column; mobile phase 0.1% FA in H2O/CAN; detection Wavelength: 254nm&214nm; flow rate: 20ml/min) to obtain (3S,4S)-3-fluoro-1-(4-((5-isopropyl-8-(3-((methylsulfonyl)methyl)) Azetidin-1-yl)-2,6-naphthyridin-3-yl)amino)-1,3,5-triazin-2-yl)-3-methylpiperidin-4-ol ( Compound 23) (8.47 mg, 19.4%). LC-MS m/z:545[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ10.20(d, J=13.2Hz, 1H), 9.14(s, 1H), 8.75(d, J=26.0Hz, 1H), 8.36(d, J =10.4Hz,1H),7.63(s,1H),5.47(s,1H),4.49(t,J=8.0Hz,2H),4.27-4.25(m,1H),4.07(t,J=6.4Hz ,2H),3.79-3.75(m,1H),3.72-3.65(m,3H),3.61-3.59(m,2H),3.37-3.35(m,2H),3.02(s,3H),1.98-1.84 (m,1H),1.65-1.55(m,1H),1.36-1.30(m,9H).

Example 24, (3R, 4S)-1-(4-((8-((2R, 3S)-3-((ethylsulfonyl)methyl)-2-methylazetidine-1 -yl)-5-isopropyl-2,7-naphthyridin-3-yl)amino)-1,3,5-triazin-2-yl)-3-fluoro-4-methylpiperidine-4 - Synthesis of Alcohol (Compound 24):

Under nitrogen protection, (3R,4S)-1-(4-amino-1,3,5-triazin-2-yl)-3-fluoro-4-methylpiperidin-4-ol (30mg , 0.13mmol) and 6-chloro-1-((2R,3S)-3-((ethylsulfonyl)methyl)-2-methylazetidin-1-yl)-4-isopropyl To a dioxane solution (5 mL) of 2,7-naphthyridine (48 mg, 0.13 mmol), cesium carbonate (87 mg, 0.26 mmol) and Brettphos Pd G3 (24 mg, 0.026 mmol) were sequentially added. The temperature was raised to 100° C., and the reaction was carried out for 5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the crude product was successively subjected to silica gel column chromatography (dichloromethane/methanol=15/1) and preparative high-performance liquid chromatography (chromatographic conditions are as follows: Waters 2767/2545/2489; column : SunFire Prep C18 OBD10um 19*250mm Column; mobile phase 0.1% FA in H2O/CAN; detection wavelength: 254nm&214nm; flow rate: 20ml/min) to obtain (3R, 4S)-1-(4-((8-(( 2R,3S)-3-((ethylsulfonyl)methyl)-2-methylazetidin-1-yl)-5-isopropyl-2,7-naphthyridin-3-yl) Amino)-1,3,5-triazin-2-yl)-3-fluoro-4-methylpiperidin-4-ol (Compound 24) (6.92 mg, yield: 9.2%). LC-MS m/z:573[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ ):δ10.22(s,1H),9.06(s,1H),8.60(s,1H),8.37(s,1H),8.03(s,1H),4.95 (s,1H),4.86(t,J=8.0Hz,1H),4.55(t,J=6.0Hz,1H),4.48-4.32(m,2H),4.20-4.08(m,1H),3.98( t,J=7.2Hz,1H),3.73-3.65(m,2H),3.53(d,J=12.0Hz,3H),3.11-3.05(m,2H),2.92-2.83(m,1H),1.78 -1.65(m,2H),1.50(d,J=6.0Hz,3H),1.42-1.36(m,6H),1.33-1.20(m,6H).

Example 25, (3S,4R)-1-(4-((8-((2R,3S)-3-((ethylsulfonyl)methyl)-2-methylazetidine-1 -yl)-5-isopropyl-2,7-naphthyridin-3-yl)amino)-1,3,5-triazin-2-yl)-3-fluoro-4-methylpiperidine-4 -Synthesis of Alcohol (Compound 25):

Under nitrogen protection, (3S, 4R)-1-(4-amino-1,3,5-triazin-2-yl)-3-fluoro-4-methylpiperidin-4-ol (30mg , 0.13mmol) and 6-chloro-1-((2R,3S)-3-((ethylsulfonyl)methyl)-2-methylazetidin-1-yl)-4-isopropyl To a dioxane solution (5 mL) of 2,7-naphthyridine (48 mg, 0.13 mmol), cesium carbonate (87 mg, 0.26 mmol) and Brettphos Pd G3 (24 mg, 0.026 mmol) were sequentially added. The temperature was raised to 100° C., and the reaction was carried out for 5 hours. After the reaction was completed and the reaction solution was concentrated under reduced pressure, the crude product was successively subjected to silica gel column chromatography (dichloromethane/methanol=15/1) and preparative high-performance liquid chromatography (chromatographic conditions are as follows: Waters 2767/2545/2489; column: (3S, 4R)-1-(4-((8-((2R , 3S)-3-((ethylsulfonyl)methyl)-2-methylazetidin-1-yl)-5-isopropyl-2,7-naphthyridin-3-yl)amino )-1,3,5-triazin-2-yl)-3-fluoro-4-methylpiperidin-4-ol (Compound 25) (28.39 mg, 38.5%). LC-MS m/z:573[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ ):δ10.21(s,1H),9.06(s,1H),8.61(s,1H),8.37(s,1H),8.03(s,1H),4.97 (s,1H),4.86(t,J=8.4Hz,1H),4.56(t,J=6.4Hz,1H),4.50-4.32(m,2H),4.24-4.10(m,1H),3.98( t,J=7.6Hz,1H),3.83-3.66(m,2H),3.51(d,J=7.2Hz,3H),3.10-3.05(m,2H),2.94-2.82(m,1H),1.81 -1.77(m,1H),1.70-1.64(m,1H),1.54-1.49(m,3H),1.36-1.30(m,6H),1.26-1.14(m,6H).

Example 26, (3R, 4S)-3-fluoro-1-(4-((5-isopropyl-8-((2R, 3S)-2-methyl-3-((methylsulfonyl) Methyl) azetidin-1-yl)-2,6-naphthyridin-3-yl)amino)-1,3,5-triazin-2-yl)-4-methylpiperidine-4 -Synthesis of Alcohol (Compound 26):

1), 7-chloro-1-isopropyl-4-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)- Synthesis of 2,6-naphthyridine:

Under nitrogen protection, 4-bromo-7-chloro-1-isopropyl-2,6-naphthyridine (200mg, 0.70mmol) and (2R,3S)-2-methyl-3-((methyl Sulfonyl)methyl)azetidine (342mg, 2.10mmol) in dioxane solution (10mL), cesium carbonate (685mg, 2.10mmol) and methanesulfonic acid (4,5-bisbis Phenylphosphine-9,9-dimethylxanthene)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (65 mg, 0.07 mmol). The temperature was raised to 100°C, and the reaction was carried out for 3 hours. After the reaction solution was concentrated under reduced pressure, the crude product was purified by silica gel column chromatography (dichloromethane/sodium methoxide=20/1) and preparative thin-layer chromatography (dichloromethane/sodium methoxide=20/1) to obtain 7-chloro -1-isopropyl-4-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-2,6-naphthyridine (120 mg, yield: 47.1%). LC-MS m/z:368[M+H] ⁺ .

2), (3R, 4S)-3-fluoro-1-(4-((5-isopropyl-8-((2R, 3S)-2-methyl-3-((methylsulfonyl)methyl Base) azetidin-1-yl)-2,6-naphthyridin-3-yl)amino)-1,3,5-triazin-2-yl)-4-methylpiperidin-4- Synthesis of Alcohol (Compound 26):

Under nitrogen protection, 7-chloro-1-isopropyl-4-((2R, 3S)-2-methyl-3-((methylsulfonyl)methyl)azetidine-1 -yl)-2,6-naphthyridine (50mg, 0.14mmol) and (3R,4S)-1-(4-amino-1,3,5-triazin-2-yl)-3-fluoro-4- To a solution of methylpiperidin-4-ol (32 mg, 0.14 mmol) in dioxane (2 mL), cesium carbonate (137 mg, 0.42 mmol) and Brettphos Pd G3 (13 mg, 0.014 mmol) were added sequentially. The temperature was raised to 100° C., and the reaction was carried out for 5 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the crude product was successively passed through preparative thin-layer chromatography (dichloromethane/methanol=40/1) and preparative high-performance liquid chromatography (chromatographic conditions are as follows: Waters 2767/2545/2489; column : SunFire Prep C18 OBD10um 19*250mm Column; mobile phase 0.1% FA in H2O/CAN; detection wavelength: 254nm&214nm; flow rate: 20ml/min) to obtain (3R, 4S)-3-fluoro-1-(4-(( 5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-2,6-naphthyridine- 3-yl)amino)-1,3,5-triazin-2-yl)-4-methylpiperidin-4-ol (16.64 mg, yield: 21.3%). LC-MS m/z:559[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ ):δ10.25(s,1H),9.14(s,1H),8.78(s,1H),8.36(s,1H),7.76(s,1H),4.96 (s,1H),4.74(t,J＝7.6Hz,1H),4.49-4.44(m,1H),4.35-4.30(m,2H),4.18-4.15(m,1H),3.79-3.69(m ,3H),3.59-3.50(m,3H),3.00(s,3H),2.95-2.92(m,1H),1.75-1.63(m,2H),1.48(d,J＝6.0Hz,3H), 1.32-1.26(m,9H).

Example 27, (3S, 4R)-3-fluoro-1-(4-((5-isopropyl-8-((2R, 3S)-2-methyl-3-((methylsulfonyl) Methyl) azetidin-1-yl)-2,6-naphthyridin-3-yl)amino)-1,3,5-triazin-2-yl)-4-methylpiperidine-4 -Synthesis of Alcohol (Compound 27):

Under nitrogen protection, 7-chloro-1-isopropyl-4-((2R, 3S)-2-methyl-3-((methylsulfonyl)methyl)azetidine-1 -yl)-2,6-naphthyridine (50mg, 0.14mmol) and (3S,4R)-1-(4-amino-1,3,5-triazin-2-yl)-3-fluoro-4- To a solution of methylpiperidin-4-ol (32 mg, 0.14 mmol) in dioxane (2 mL), cesium carbonate (137 mg, 0.42 mmol) and Brettphos Pd G3 (13 mg, 0.014 mmol) were added sequentially. The temperature was raised to 100° C., and the reaction was carried out for 5 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the crude product was successively passed through preparative thin-layer chromatography (dichloromethane/methanol=40/1) and preparative high-performance liquid chromatography (chromatographic conditions are as follows: Waters 2767/2545/2489; column : SunFire Prep C18 OBD10um 19*250mm Column; mobile phase 0.1% FA in H2O/CAN; detection wavelength: 254nm&214nm; flow rate: 20ml/min) to obtain (3S, 4R)-3-fluoro-1-(4-(( 5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)-2,6-naphthyridine- 3-yl)amino)-1,3,5-triazin-2-yl)-4-methylpiperidin-4-ol (compound 27) (27.59 mg, 0.049 mmol, yield: 35.3%). LC-MS m/z:559[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ ):δ10.28(s,1H),9.15(1,1H),8.79(1,1H),8.37-8.33(m,1H),7.76(s,1H) ,4.97(s,1H),4.74(t,J=7.6Hz,1H),4.51-4.49(m,1H),4.35-4.29(m,2H),4.16(s,1H),3.80-3.71(m ,3H),3.61-3.48(m,3H),3.00(s,3H),2.96-2.90(m,1H),1.76-1.60(m,2H),1.49(d,J＝6.0Hz,3H), 1.33-1.27(m,9H).

Example 28, (3R,4S)-3-fluoro-1-(4-((5-isopropyl-8-(3-((methylsulfinyl)methyl)azetidine-1 Synthesis of -yl)isoquinolin-3-yl)amino)-1,3,5-triazin-2-yl)-3-methylpiperidin-4-ol (compound 28):

Under nitrogen protection, (3R, 4S)-1-(4-amino-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (60mg ,0.26mmol) in dioxane (7mL) solution, add 3-chloro-5-isopropyl-8-(3-((methylsulfinyl)methyl)azetidine-1 -yl) isoquinoline (87mg, 0.26mmol), cesium carbonate (170mg, 0.52mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6 '-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (24 mg, 0.026 mmol). The temperature of the reaction liquid was raised to 100° C., and the reaction was carried out for 5 hours. The reaction solution was concentrated under reduced pressure to remove the solvent and purified by silica gel column chromatography (dichloromethane/methanol=15/1) to obtain (3R,4S)-3-fluoro-1-(4-((5-isopropyl-8-( 3-((Methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)-1,3,5-triazin-2-yl)-3- Methylpiperidin-4-ol (Compound 28) (90 mg, yield: 65.3%). LC-MS: [M+H]+528.

(3R, 4S)-3-fluoro-1-(4-((5-isopropyl-8-(3-((methylsulfinyl)methyl)azetidin-1-yl) Isoquinolin-3-yl)amino)-1,3,5-triazin-2-yl)-3-methylpiperidin-4-ol (compound 28) (90 mg) was passed through supercritical fluid chromatography (chromatography Conditions: Waters SFC 150 system;

250*25mm 10μm column; Supercritical CO ₂ /MeOH (+0.1% 7.0mol/L Ammonia in MeOH)x elution; detection wavelength 214nM; column temperature: room temperature; flow rate: 70-80ml/min; Back up pressure 100bar) preparation Two isomers were isolated: compound 28A and compound 28B:

Compound 28A (29.64 mg, 0.06 mmol, yield: 32.9%) retention time: 0.976 min. LC-MS: [M+H] ⁺ 528.

¹ H NMR (400MHz, DMSO-d ₆ ): δ9.89(m, 1H), 9.08(s, 1H), 8.68-8.59(m, 1H), 8.31(s, 1H), 7.44(d, J= 7.6Hz, 1H), 6.44(d, J=8.0Hz, 1H), 5.10(s, 1H), 4.77-4.56(m, 2H), 4.39(t, J=6.8Hz, 2H), 3.99-3.97( m,2H),3.63-3.44(m,2H),3.24-3.06(m,5H),2.59(s,3H),1.77-1.63(m,2H),1.47-1.15(m,9H).

Compound 28B (27.81 mg, 0.053 mmol, yield: 30.9%). Retention time: 0.979min. LC-MS: [M+H] ⁺ 528.

¹ H NMR(400MHz,DMSO-d ₆ ):δ9.97-9.90(m,1H),9.10(s,1H),8.69-8.60(m,1H),8.33(s,1H),7.44(d, J＝8.0Hz, 1H), 6.44(d, J＝8.0Hz, 1H), 5.11-5.09(m, 1H), 4.78-4.57(m, 2H), 4.40(t, J＝6.4Hz, 2H), 3.98(s,2H),3.63-3.46(m,2H),3.31-3.06(m,5H),2.59(s,3H),1.78-1.67(m,2H),1.44-1.23(m,9H).

Example 29, (3S,4R)-3-fluoro-1-(4-(5-isopropyl-8-(3-(methylsulfinyl)methyl)azetidin-1-yl ) isoquinolin-3-yl)amino)-1,3,5-triazin-2-yl)-3-methylpiperidin-4-ol (compound 29):

Under nitrogen protection, (3S, 4R)-1-(4-amino-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidin-4-ol ( 60mg, 0.26mmol) in dioxane (7mL) solution, sequentially added 3-chloro-5-isopropyl-8-(3-((methylsulfinyl)methyl)azetidine- 1-yl)isoquinoline (87mg, 0.26mmol), cesium carbonate (170mg, 0.52mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4', 6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (24 mg, 0.026 mmol). The resulting reaction solution was heated up to 100° C. and reacted for 5 hours. The reaction solution was concentrated under reduced pressure to remove the solvent and purified by silica gel column chromatography (dichloromethane/methanol=15/1) to obtain (3S,4R)-3-fluoro-1-(4-((5-isopropyl-8-( 3-((Methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)-1,3,5-triazin-2-yl)-3- Methylpiperidin-4-ol (Compound 29) (35 mg, yield: 25.1%). LC-MS: [M+H] ⁺ 528.

(3S, 4R)-3-fluoro-1-(4-((5-isopropyl-8-(3-((methylsulfinyl)methyl)azetidin-1-yl) Isoquinolin-3-yl)amino)-1,3,5-triazin-2-yl)-3-methylpiperidin-4-ol (compound 29) (35 mg) was passed through supercritical fluid chromatography (chromatography Conditions: Waters SFC 150 system;

250*25mm 10μm column; Supercritical CO2/MeOH (+0.1% 7.0mol/L Ammonia in MeOH) x elution; detection wavelength 214nM; column temperature: room temperature; flow rate: 70-80ml/min; Back up pressure 100bar) preparative separation Two isomers were obtained: compound 29A and compound 29B:

Compound 29A (10.62 mg, yield: 30.3%), retention time: 0.985 min. LC-MS: [M+H] ⁺ 528.

¹ H NMR(400MHz,DMSO-d ₆ ):δ9.88-9.81(m,1H),9.07(s,1H),8.68-8.59(m,1H),8.31(s,1H),7.44(d, J＝8.0Hz, 1H), 6.44(d, J＝8.0Hz, 1H), 5.10-5.09(m, 1H), 4.77-4.56(m, 2H), 4.39(t, J＝7.2Hz, 2H), 4.00-3.97(m,2H),3.62-3.49(m,2H),3.25-3.08(m,5H),2.59(s,3H),1.77-1.69(m,2H),1.40-1.21(m,9H ).

Compound 29B (3.32mg, yield: 9.4%) retention time: 1.727min.LC-MS: [M+H] ⁺ 528.

¹ H NMR (400MHz,DMSO-d ₆ ):δ9.90-9.84(m,1H),9.08(s,1H),8.68-8.59(m,1H),8.31(s,1H),7.44(d, J＝7.6Hz, 1H), 6.44(d, J＝8.0Hz, 1H), 5.11(s, 1H), 4.80-4.58(m, 2H), 4.41-4.38(m, 2H), 4.03-3.98(m ,2H),3.64-3.43(m,2H),3.27-3.06(m,5H),2.59(s,3H),1.77-1.59(m,2H),1.46-1.17(m,9H).

Example 30, (3R,4S)-3-fluoro-1-(4-((5-isopropyl-8-(3-((methylsulfinyl)methyl)azetidine-1 Synthesis of -yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-ol (compound 30):

Under nitrogen protection, at room temperature, (3R, 4S)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (20mg, 0.09 mmol) was dissolved in Add 3-chloro-5-isopropyl-8-(3-((methylsulfinyl)methyl)azetidin-1-yl)isoquine to the dioxane solution (7mL) successively phenoline (30mg, 0.09mmol), cesium carbonate (59mg, 0.18mmol) and (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl methanesulfonate yl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (9 mg, 0.01 mmol). The resulting reaction solution was heated up to 100° C. and reacted for 5 hours. After the reaction solution was concentrated under reduced pressure, the crude product was sequentially subjected to silica gel column chromatography (dichloromethane/methanol=15/1) and reversed-phase liquid chromatography (chromatographic conditions: column: spherical C18, 20-40um, 80g; mobile phase A: Water (containing 0.1% ammonia water); Mobile phase B: acetonitrile; Flow rate: 80mL/min; Gradient: 20%B-50%B in 20 minutes; Detector: 254nm) purification gives (3R, 4S)-3- Fluoro-1-(4-((5-isopropyl-8-(3-((methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino )pyrimidin-2-yl)-3-methylpiperidin-4-ol (4.68 mg, yield: 10.1%). LC-MS: [M+H] ⁺⁵²⁷ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.84(s, 1H), 9.06(s, 1H), 8.59(s, 1H), 7.98(d, J=5.6Hz, 1H), 7.41(d, J＝8.0Hz, 1H), 6.47–6.40(m, 2H), 5.03(d, J＝6.4Hz, 1H), 4.75–4.72(m, 2H), 4.38(t, J＝6.4Hz, 2H), 3.98(s,2H),3.78-3.72(m,2H),3.26–3.09(m,5H),2.67(s,3H),1.74(s,2H),1.40–1.23(m,9H).

Example 31, (3S,4R)-3-fluoro-1-(4-((5-isopropyl-8-(3-((methylsulfinyl)methyl)azetidine-1 Synthesis of -yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-ol (compound 31):

Under nitrogen protection, at room temperature, (3S, 4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (20mg, 0.09mmol) was dissolved in Add 3-chloro-5-isopropyl-8-(3-((methylsulfinyl)methyl)azetidin-1-yl)isoquine to the dioxane solution (7mL) successively phenoline (30mg, 0.09mmol), cesium carbonate (59mg, 0.18mmol) and (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl methanesulfonate yl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (9 mg, 0.01 mmol). The resulting reaction solution was heated up to 100° C. and reacted for 5 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product is subjected to silica gel column chromatography (dichloromethane/methanol=15/1) and reverse phase liquid chromatography (chromatographic conditions: column: spherical C18, 20-40um, 80g; mobile phase A: water (containing 0.1% ammoniacal liquor) ); Mobile phase B: acetonitrile; Flow rate: 80mL/min; Gradient: 20% B-50% B in 20 minutes; ((5-isopropyl-8-(3-((methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl) -3-Methylpiperidin-4-ol (3.02 mg, yield: 6.5%). LC-MS: [M+H] ⁺⁵²⁷ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.86(s, 1H), 9.06(s, 1H), 8.60(s, 1H), 7.98(d, J=5.6Hz, 1H), 7.41(d, J＝8.0Hz, 1H), 6.47-6.40(m, 2H), 5.03(d, J＝6.4Hz, 1H), 4.75-4.70(m, 2H), 4.38(t, J＝6.4Hz, 2H), 3.97(s,2H),3.53-3.48(m,2H),3.25-3.09(m,5H),2.67(s,3H),1.74(s,2H),1.40-1.24(m,9H).

Example 32, (3R,4R)-3-fluoro-1-(4-((5-isopropyl-8-(3-((methylsulfinyl)methyl)azetidine-1 Synthesis of -yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-ol (compound 32):

Under nitrogen protection, at room temperature, (3R,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (20mg, 0.09mmol) was dissolved in 3-Chloro-5-isopropyl-8-(3-((methylsulfinyl)methyl)azetidin-1-yl)isoquine was added successively to the dioxane solution (7mL) phenoline (30mg, 0.09mmol), cesium carbonate (59mg, 0.18mmol) and (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl methanesulfonate yl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (9 mg, 0.01 mmol). The resulting reaction solution was heated up to 100° C. and reacted for 5 hours. After the reaction solution was concentrated under reduced pressure, the crude product was sequentially subjected to silica gel column chromatography (dichloromethane/methanol=15/1) and reversed-phase liquid chromatography (chromatographic conditions: column: spherical C18, 20-40um, 80g; mobile phase A: Water (containing 0.1% ammonia); mobile phase B: acetonitrile; flow rate: 80mL/min; gradient: 20%B-50%B in 20 minutes; detector: 254nm) was purified to obtain (3R, 4R)-3- Fluoro-1-(4-((5-isopropyl-8-(3-((methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino )pyrimidin-2-yl)-3-methylpiperidin-4-ol (4.82 mg, 10.4%). LC-MS: [M+H] ⁺⁵²⁷ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.87(s, 1H), 9.06(s, 1H), 8.62(s, 1H), 7.99(d, J=5.6Hz, 1H), 7.41(d, J＝8.0Hz, 1H), 6.47-6.40(m, 2H), 5.34(d, J＝4.4Hz, 1H), 4.38(t, J＝6.8Hz, 2H), 3.99-3.87(m, 6H), 3.76-3.74(m,1H),3.52-3.49(m,1H),3.30-3.13(m,2H),3.10-3.09(m,1H),2.60(s,3H),1.90-1.88(m,1H ),1.54-1.45(m,1H),1.33-1.23(m,9H).

Example 33, (3R, 4S)-3-fluoro-1-(4-((5-isopropyl-8-((2R, 3S)-2-methyl-3-((methylsulfonyl) Methyl) azetidin-1-yl) isoquinolin-3-yl) amino)-1,3,5-triazin-2-yl)-3-methylpiperidin-4-ol (compound 33) Synthesis of:

Under nitrogen protection, at room temperature, (3R, 4S)-1-(4-amino-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidine-4 -alcohol (20mg, 0.09mmol) in dioxane solution (7mL) was successively added 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methyl Sulfonyl)methyl)azetidin-1-yl)isoquinoline (33 mg, 0.09 mmol), cesium carbonate (59 mg, 0.18 mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6 -Dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (9 mg, 0.01 mmol). The resulting reaction solution was heated up to 100° C. and reacted for 5 hours. After the reaction solution was concentrated under reduced pressure, the crude product was sequentially subjected to silica gel column chromatography (dichloromethane/methanol=15/1) and reversed-phase liquid chromatography (chromatographic conditions: column: spherical C18, 20-40um, 80g; mobile phase A: Water (containing 0.1% formic acid); mobile phase B: acetonitrile; flow rate: 80 mL/min; gradient: 30% B-60% B in 20 minutes; detector: 254 nm) was purified to obtain (3R, 4S)-3- Fluoro-1-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl )isoquinolin-3-yl)amino)-1,3,5-triazin-2-yl)-3-methylpiperidin-4-ol (3.53 mg, yield: 7.2%).LC-MS :[M+H] ⁺⁵⁵⁸ .

¹ H NMR (400MHz,DMSO-d ₆ )δ9.92-9.86(m,1H),9.07(s,1H),8.69-8.60(m,1H),8.31(s,1H),7.45(d,J =8.0Hz,1H),6.60(d,J=8.0Hz,1H),5.10(d,J=6.8Hz,1H),4.80-4.65(m,3H),4.21-4.18(m,1H),3.67 -3.47(m,5H),3.20-3.09(m,2H),2.99(s,3H),2.92-2.87(m,1H),1.77-1.71(m,2H),1.44-1.15(m,12H) .

Example 34, (3S, 4R)-3-fluoro-1-(4-((5-isopropyl-8-((2R, 3S)-2-methyl-3-((methylsulfonyl) Methyl) azetidin-1-yl) isoquinolin-3-yl) amino)-1,3,5-triazin-2-yl)-3-methylpiperidin-4-ol (compound 34) Synthesis of:

Under nitrogen protection, at room temperature, (3S, 4R)-1-(4-amino-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidine-4 -alcohol (20mg, 0.09mmol) in dioxane solution (7mL) was successively added 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methyl Sulfonyl)methyl)azetidin-1-yl)isoquinoline (33 mg, 0.09 mmol), cesium carbonate (59 mg, 0.18 mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6 -Dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (9 mg, 0.01 mmol). The resulting reaction solution was heated up to 100° C. and reacted for 5 hours. After the reaction solution was concentrated under reduced pressure, the crude product was sequentially subjected to silica gel column chromatography (dichloromethane/methanol=15/1) and reversed-phase liquid chromatography (chromatographic conditions: column: spherical C18, 20-40um, 80g; mobile phase A: Water (containing 0.1% formic acid); mobile phase B: acetonitrile; flow rate: 80 mL/min; gradient: 30% B-60% B in 20 minutes; detector: 254 nm) was purified to obtain (3S, 4R)-3- Fluoro-1-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl (4.35 mg, yield : 8.2%). LC-MS: [M+H] ⁺⁵⁵⁸ .

¹ H NMR (400MHz,DMSO-d ₆ )δ9.93-9.85(m,1H),9.07(s,1H),8.69-8.61(m,1H),8.39(s,1H),8.31(s,1H ),7.45(d,J＝8.0Hz,1H),6.60(d,J＝8.0Hz,1H),5.12-5.10(m,1H),4.81–4.58(m,3H),4.21–4.17(m, 1H),3.66-3.60(m,2H),3.59-3.48(m,3H),3.22-3.08(m,2H),2.99(s,3H),2.93-2.86(m,1H),1.78-1.70( m,2H),1.44–1.14(m,12H).

Example 35, (3S,4S)-3-fluoro-1-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl) Methyl) azetidin-1-yl) isoquinolin-3-yl) amino)-1,3,5-triazin-2-yl)-3-methylpiperidin-4-ol (compound 35) Synthesis of:

Under nitrogen protection, at room temperature, (3S, 4S)-1-(4-amino-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidine-4 -alcohol (20mg, 0.09mmol) in dioxane solution (7mL) was successively added 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methyl Sulfonyl)methyl)azetidin-1-yl)isoquinoline (33 mg, 0.09 mmol), cesium carbonate (59 mg, 0.18 mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6 -Dimethoxy-2',4',6'-triisopropyl-,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)( 9 mg, 0.01 mmol). The resulting reaction solution was heated up to 100° C. and reacted for 5 hours. After the reaction solution was concentrated under reduced pressure, the crude product was sequentially subjected to silica gel column chromatography (dichloromethane/methanol=15/1) and reversed-phase liquid chromatography (chromatographic conditions: column: spherical C18, 20-40um, 80g; mobile phase A: Water (containing 0.1% formic acid); Mobile phase B: acetonitrile; Flow rate: 80mL/min; Gradient: 30% B-60% B in 20 minutes; Detector: 254nm.When containing 45% B in mobile phase, The mobile phase containing the product was collected) and purified to give (3S,4S)-3-fluoro-1-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-(( Methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)-1,3,5-triazin-2-yl)-3-methylpiperidine- 4-alcohol (compound 35) (13.36 mg, yield: 27.2%). LC-MS: [M+H] ⁺ 558.

¹ H NMR (400MHz,DMSO-d ₆ )δ9.95-9.91(m,1H),9.08(s,1H),8.70-8.64(m,1H),8.32(s,1H),7.45(d,J =8.0Hz,1H),6.60(d,J=8.4Hz,1H),5.44(s,1H),4.67(t,J=7.6Hz,1H),4.27-4.18(m,2H),3.76-3.63 (m,3H),3.59-3.54(m,2H),3.52-3.48(m,3H),2.99(s,3H),2.92-2.87(m,1H),1.94-1.92(m,1H),1.59 -1.50(m,1H),1.43(d,J＝6.0Hz,3H),1.36-1.30(m,9H).

Example 36, (3R,4R)-3-fluoro-1-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl) Methyl) azetidin-1-yl) isoquinolin-3-yl) amino)-1,3,5-triazin-2-yl)-3-methylpiperidin-4-ol (compound 36) Synthesis of:

Under nitrogen protection, at room temperature, (3R, 4R)-1-(4-amino-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidine-4 -alcohol (20mg, 0.09mmol) in dioxane solution (7mL) was successively added 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methyl Sulfonyl)methyl)azetidin-1-yl)isoquinoline (33 mg, 0.09 mmol), cesium carbonate (59 mg, 0.18 mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6 -Dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (9 mg, 0.01 mmol). The resulting reaction liquid was heated up to 100° C. and reacted for 5 hours. The reaction solution was concentrated by rotary evaporation to obtain a crude product. The crude product is successively subjected to silica gel column chromatography (dichloromethane/methanol=15/1) and reversed-phase liquid chromatography (chromatographic conditions: column: spherical C18, 20-40um, 80g; mobile phase A: water (containing 0.1% formic acid ); Mobile phase B: acetonitrile; Flow rate: 80mL/min; Gradient: 30%B-60%B in 20 minutes; ((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline-3- Base)amino)-1,3,5-triazin-2-yl)-3-methylpiperidin-4-ol (compound 36) (11.78mg, yield: 24.0%).LC-MS: [M +H] ⁺ :558

¹ H NMR (400MHz,DMSO-d ₆ )δ9.94-9.91(m,1H),9.07(s,1H),8.70-8.64(m,1H),8.32(s,1H),7.45(d,J =8.0Hz,1H),6.60(d,J=8.4Hz,1H),5.46(s,1H),4.67(t,J=7.6Hz,1H),4.29-4.20(m,2H),4.18-3.76 (m,3H),3.72-3.67(m,2H),3.65-3.48(m,3H),2.99(s,3H),2.92-2.87(m,1H),1.93-1.90(m,1H),1.60 -1.57 (m, 1H), 1.43 (d, J=6.0Hz, 3H), 1.35-1.30 (m, 9H).

Example 37, (3R,4S)-3-fluoro-1-(4-((5-isopropyl-8-(3-((methylsulfonyl)methyl)azetidine-1- Base) isoquinolin-3-yl)amino)-1,3,5-triazin-2-yl)-3-methylpiperidin-4-ol (compound 37):

Under nitrogen protection, at room temperature, to (3R, 4S)-1-(4-amino-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (20mg, 0.09mmol) in dioxane solution (7mL) was added successively 3-chloro-5-isopropyl-8-(3-((methylsulfonyl)methyl)azetidine-1 -yl)isoquinoline (32mg, 0.09mmol), cesium carbonate (59mg, 0.18mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6 '-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (9 mg, 0.01 mmol). The resulting reaction solution was heated up to 100° C. and reacted for 5 hours. After the reaction solution was concentrated under reduced pressure, the crude product was sequentially subjected to silica gel column chromatography (dichloromethane/methanol=15/1) and reversed-phase liquid chromatography (chromatographic conditions: column: spherical C18, 20-40um, 80g; mobile phase A: Water (containing 0.1% ammonia water); Mobile phase B: acetonitrile; Flow rate: 80mL/min; Gradient: 20%B-50%B in 20 minutes; Detector: 254nm) purification gives (3R, 4S)-3- Fluoro-1-(4-((5-isopropyl-8-(3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino) -1,3,5-triazin-2-yl)-3-methylpiperidin-4-ol (compound 37) (11.39 mg, yield: 23.7%).LC-MS: [M+H] ⁺ 544.

¹ H NMR (400MHz,DMSO-d ₆ )δ9.96-9.88(m,1H),9.08(s,1H),8.69-8.60(m,1H),8.32(s,1H),7.44(d,J =8.0Hz, 1H), 6.45(d, J=8.0Hz, 1H), 5.12(s, 1H), 4.81-4.59(m, 2H), 4.40(t, J=7.6Hz, 2H), 3.97(t ,J=6.4Hz,2H),3.64–3.61(m,3H),3.60–3.55(m,1H),3.49-3.48(m,1H),3.18-3.09(m,2H),3.01(s,3H ),1.78-1.71(m,2H),1.40-1.15(m,9H).

Example 38. (3S,4R)-3-fluoro-1-(4-((5-isopropyl-8-(3-((methylsulfonyl)methyl)azetidine-1- Base) isoquinolin-3-yl)amino)-1,3,5-triazin-2-yl)-3-methylpiperidin-4-ol (compound 38):

Under nitrogen protection, at room temperature, to (3S, 4R)-1-(4-amino-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (20mg, 0.09mmol) in dioxane solution (7mL) was added successively 3-chloro-5-isopropyl-8-(3-((methylsulfonyl)methyl)azetidine-1 -yl)isoquinoline (32mg, 0.09mmol), cesium carbonate (59mg, 0.18mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6 '-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (9 mg, 0.01 mmol). The resulting reaction solution was heated up to 100° C. and reacted for 5 hours. After the reaction solution was concentrated under reduced pressure, the crude product was sequentially subjected to silica gel column chromatography (dichloromethane/methanol=15/1) and reversed-phase liquid chromatography (chromatographic conditions: column: spherical C18, 20-40um, 80g; mobile phase A: Water (containing 0.1% ammonia); mobile phase B: acetonitrile; flow rate: 80mL/min; gradient: 20%B-50%B in 20 minutes; detector: 254nm) was purified to obtain (3S, 4R)-3- Fluoro-1-(4-((5-isopropyl-8-(3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino) Formate salt of -1,3,5-triazin-2-yl)-3-methylpiperidin-4-ol (compound 38) (17.31 mg, 33.3%).LC-MS: [M+H] ⁺ 544.

¹ H NMR (400MHz,DMSO-d ₆ )δ9.94-9.84(m,1H),9.08(s,1H),8.69-8.60(m,1H),8.39(s,1H),8.31(s,1H ), 7.44(d, J=8.0Hz, 1H), 6.45(d, J=8.0Hz, 1H), 5.15(s, 1H), 4.77-4.59(m, 2H), 4.40(t, J=7.6Hz ,2H),3.97(t,J＝6.8Hz,2H),3.66-3.59(m,3H),3.55-3.46(m,1H),3.34-3.29(m,1H),3.27-3.05(m,2H ),3.01(s,3H),1.78-1.64(m,2H),1.40-1.15(m,9H).

Example 39, (3R,4R)-3-fluoro-1-(4-((5-isopropyl-8-(3-((methylsulfonyl)methyl)azetidine-1- Base) isoquinolin-3-yl)amino)-1,3,5-triazin-2-yl)-3-methylpiperidin-4-ol (compound 39):

Under nitrogen protection, at room temperature, to (3R, 4R)-1-(4-amino-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (30mg, 0.13mmol) in dioxane solution (7mL) was added successively 3-chloro-5-isopropyl-8-(3-((methylsulfonyl)methyl)azetidine-1 -yl) isoquinoline (46mg, 0.13mmol), cesium carbonate (85mg, 0.26mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6 '-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (9 mg, 0.01 mmol). The resulting reaction solution was heated up to 100° C. and reacted for 5 hours. After the reaction solution was concentrated under reduced pressure, the crude product was purified by silica gel column chromatography (dichloromethane/methanol=15/1) and preparative high performance liquid chromatography (chromatographic conditions are as follows: Waters 2767/2545/2489; column: SunFire Prep C18 OBD 10um 19*250mm Column; mobile phase 0.1% FA in H2O/CAN; detection wavelength: 254nm&214nm; flow rate: 20ml/min) to get (3R, 4R)-3-fluoro-1-(4-((5-isopropyl Base-8-(3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)-1,3,5-triazin-2-yl )-3-methylpiperidin-4-ol (compound 39) (12.06 mg, yield: 16.9%). LC-MS: [M+H] ⁺ 544.

¹ H NMR (400MHz,DMSO-d ₆ )δ9.86-9.82(m,1H),9.06(s,1H),8.69-8.62(m,1H),8.31(s,1H),7.44(d,J =8.0Hz,1H),6.45(d,J=8.0Hz,1H),5.44-5.43(m,1H),4.40(t,J=7.6Hz,2H),4.26-4.22(m,1H),4.06 -3.90(m,3H),3.79-3.63(m,2H),3.58(d,J＝7.2Hz,4H),3.20-2.99(m,1H),3.01(s,3H),1.93-1.78(m ,1H),1.65-1.48(m,1H),1.35-1.29(m,9H).

Example 40, N-(4-((3R,4S)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)-1,3,5-triazin-2-yl )-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline-3- Synthesis of amine (compound 40):

Under nitrogen protection, at room temperature, to 4-((3R, 4S)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)-1,3,5-triazine-2 -Amine (20mg, 0.08mmol) in dioxane solution (7mL) was added successively 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methyl Sulfonyl)methyl)azetidin-1-yl)isoquinoline (29 mg, 0.08 mmol), cesium carbonate (52 mg, 0.16 mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6 -Dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (9 mg, 0.01 mmol). The resulting reaction solution was heated up to 100° C. and reacted for 5 hours. After the reaction solution was concentrated under reduced pressure, the crude product was sequentially subjected to silica gel column chromatography (dichloromethane/methanol=15/1) and reversed-phase liquid chromatography (chromatographic conditions: column: spherical C18, 20-40um, 80g; mobile phase A: Water (containing 0.1% formic acid); Mobile phase B: acetonitrile; Flow rate: 80mL/min; Gradient: 20%B-50%B in 20 minutes; Detector: 254nm) purification affords isomer N-(4-(( 3R, 4S)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)-1,3,5-triazin-2-yl)-5-isopropyl-8-( (2R,3S)-2-Methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine (compound 40) (20.96 mg, yield : 44.2%). LC-MS: [M+H] ⁺⁵⁷³ .

¹ H NMR (400MHz,DMSO-d ₆ )δ10.26-10.21(m,1H),9.08(s,1H),8.59-8.51(m,1H),8.37(d,J=6.8Hz,1H), 8.04(s,1H),4.87(t,J=8.0Hz,1H),4.77-4.54(m,3H),4.00(t,J=6.8Hz,1H),3.53(d,J=7.6Hz,2H ),3.49-3.48(m,1H),3.38(s,3H),3.36-3.32(m,1H),3.28-3.17(m,2H),2.99(s,3H),2.93-2.87(m,1H ),2.05-2.03(m,1H),1.59-1.57(m,1H),1.50(d,J=6.0Hz,3H),1.44-1.31(m,9H).

Example 41, N-(4-((3S,4R)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)-1,3,5-triazin-2-yl )-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline-3- Synthesis of amine (compound 41):

Under nitrogen protection, at room temperature, to 4-((3S, 4R)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)-1,3,5-triazine-2 -Amine (20mg, 0.08mmol) in dioxane solution (7mL) was added successively 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methyl Sulfonyl)methyl)azetidin-1-yl)isoquinoline (29 mg, 0.08 mmol), cesium carbonate (52 mg, 0.16 mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6 -Dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (9 mg, 0.01 mmol). The resulting reaction solution was heated up to 100° C. and reacted for 5 hours. After the reaction solution was concentrated under reduced pressure, the crude product was sequentially subjected to silica gel column chromatography (dichloromethane/methanol=15/1) and reversed-phase liquid chromatography (chromatographic conditions: column: spherical C18, 20-40um, 80g; mobile phase A: Water (containing 0.1% formic acid); Mobile phase B: acetonitrile; Flow rate: 80mL/min; Gradient: 20%B-50%B in 20 minutes; Detector: 254nm) purified to give N-(4-((3S , 4R)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)-1,3,5-triazin-2-yl)-5-isopropyl-8-(( 2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine (compound 41) (17.31 mg, yield: 36.5%). LC-MS: [M+H] ⁺⁵⁷³ .

¹ H NMR (400MHz,DMSO-d ₆ )δ10.24-10.19(m,1H),9.07(s,1H),8.59-8.51(m,1H),8.37(d,J=6.8Hz,1H), 8.04(s,1H),4.87(t,J=8.0Hz,1H),4.75-4.54(m,3H),3.99(t,J=7.6Hz,1H),3.53(d,J=7.6Hz,2H ),3.49-3.45(m,1H),3.38(s,3H),3.36-3.30(m,1H),3.27-3.20(m,2H),2.99(s,3H),2.93-2.87(m,1H ),2.05-2.03(m,1H),1.59-1.57(m,1H),1.50(d,J=6.0Hz,3H),1.44-1.33(m,9H).

Example 42, (4R, 5S)-5-fluoro-1-(4-(5-isopropyl-8-(2R, 3s)-2-methyl-3-(methylsulfonyl)methyl) Azetidin-1-yl)isoquinolin-3-yl)amino)-1,3,5-triazin-2-yl)-3,3-dimethylpiperidin-4-ol (compound 42) Synthesis of:

Under nitrogen protection, at room temperature, to (4R, 5S)-1-(4-amino-1,3,5-triazin-2-yl)-5-fluoro-3,3-dimethylpiperidine- To a solution of 4-alcohol (20mg, 0.08mmol) in dioxane (7mL) was successively added 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-((form sulfonyl)methyl)azetidin-1-yl)isoquinoline (29mg, 0.08mmol), cesium carbonate (52mg, 0.16mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3, 6-Dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II ) (9 mg, 0.01 mmol). The resulting reaction solution was heated up to 100° C. and reacted for 5 hours. After the reaction solution was concentrated under reduced pressure, the crude product was sequentially subjected to silica gel column chromatography (dichloromethane/methanol=15/1) and reversed-phase liquid chromatography (chromatographic conditions: column: spherical C18, 20-40um, 80g; mobile phase A: Water (containing 0.1% formic acid); mobile phase B: acetonitrile; flow rate: 80 mL/min; gradient: 40% B-60% B in 20 minutes; detector: 254 nm) was purified to obtain (4R, 5S)-5- Fluoro-1-(4-(5-isopropyl-8-(2R,3S)-2-methyl-3-(methylsulfonyl)methyl)azetidin-1-yl)isoquine Lin-3-yl)amino)-1,3,5-triazin-2-yl)-3,3-dimethylpiperidin-4-ol (compound 42) (6.38 mg, yield: 13.5%) .LC-MS: [M+H] ⁺ 572.

¹ H NMR (400MHz,DMSO-d ₆ )δ9.94-9.86(m,1H),9.08(s,1H),8.70-8.57(m,1H),8.32(s,1H),7.45(d,J =8.0Hz,1H),6.60(d,J=8.4Hz,1H),5.23(d,J=5.2Hz,1H),4.85-4.65(m,2H),4.34-4.18(m,2H),4.06 -3.84(m,2H),3.67-3.64(m,1H),3.57-3.52(m,4H),3.48-3.41(m,1H),2.99(s,3H),2.92-2.87(m,1H) ,1.43(d,J=6.0Hz,3H),1.31(d,J=6.4Hz,6H),0.93(s,6H).

Example 43, (4S,5R)-5-fluoro-1-(4-(5-isopropyl-8-(2R,3S)-2-methyl-3-(methylsulfonyl)methyl) Azetidin-1-yl)isoquinolin-3-yl)amino)-1,3,5-triazin-2-yl)-3,3-dimethylpiperidin-4-ol (compound 43) Synthesis of:

Under nitrogen protection, at room temperature, to (4S, 5R)-1-(4-amino-1,3,5-triazin-2-yl)-5-fluoro-3,3-dimethylpiperidine- To a solution of 4-alcohol (20mg, 0.08mmol) in dioxane (7mL) was successively added 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-((form sulfonyl)methyl)azetidin-1-yl)isoquinoline (29mg, 0.08mmol), cesium carbonate (52mg, 0.16mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3, 6-Dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II ) (9 mg, 0.01 mmol). The resulting reaction solution was heated up to 100° C. and reacted for 5 hours. After the reaction solution was concentrated under reduced pressure, the crude product was sequentially subjected to silica gel column chromatography (dichloromethane/methanol=15/1) and reversed-phase liquid chromatography (chromatographic conditions: column: spherical C18, 20-40um, 80g; mobile phase A: Water (containing 0.1% formic acid); mobile phase B: acetonitrile; flow rate: 80 mL/min; gradient: 40% B-60% B in 20 minutes; detector: 254 nm) was purified to obtain (4S, 5R)-5- Fluoro-1-(4-(5-isopropyl-8-(2R,3s)-2-methyl-3-(methylsulfonyl)methyl)azetidin-1-yl)isoquine Lin-3-yl)amino)-1,3,5-triazin-2-yl)-3,3-dimethylpiperidin-4-ol (Compound 43) (8.36mg Yield: 17.7%). LC-MS: [M+H] ⁺ : 572.

¹ H NMR (400MHz,DMSO-d ₆ )δ9.96-9.94(m,1H),9.07(s,1H),8.68-8.55(m,1H),8.32(s,1H),7.45(d,J =7.6,1H),6.60(d,J=8.0Hz,1H),5.23(s,J=5.2Hz,1H),4.74-4.65(d,2H),4.36-4.32(m,1H),4.22( t,J=5.2,1H),4.00-3.87(m,2H),3.64(t,J=7.2Hz,1H),3.59-3.53(m,4H),3.48-3.47(m,1H),2.99( s,3H),2.92-2.87(m,1H),1.43(d,J=6.0Hz,3H),1.37-1.27(m,6H),0.93(s,6H).

Example 44, (1-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidine- Synthesis of 1-yl)isoquinolin-3-yl)amino)-1,3,5-triazin-2-yl)-4-methoxypiperidin-4-yl)methanol (compound 44):

Under nitrogen protection, at room temperature, to (1-(4-amino-1,3,5-triazin-2-yl)-4-methoxypiperidin-4-yl)methanol (20mg, 0.08mmol) Add 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azepine to the dioxane solution (7mL) successively Cyclobutan-1-yl)isoquinoline (29 mg, 0.08 mmol), cesium carbonate (52 mg, 0.16 mmol) and (2-dicyclohexylphosphine)-3,6-dimethoxy-2' methanesulfonate , 4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (9 mg, 0.01 mmol). The resulting reaction solution was heated up to 100° C. and reacted for 5 hours. After the reaction solution was concentrated under reduced pressure, the crude product was sequentially subjected to silica gel column chromatography (dichloromethane/methanol=15/1) and reversed-phase liquid chromatography (chromatographic conditions: column: spherical C18, 20-40um, 80g; mobile phase A: Water (containing 0.1% formic acid); mobile phase B: acetonitrile; flow rate: 80 mL/min; gradient: 5% B-30% B in 20 minutes; detector: 254nm) was purified to obtain (1-(4-( (5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl )amino)-1,3,5-triazin-2-yl)-4-methoxypiperidin-4-yl)methanol (compound 44) (6.23mg, yield: 13.2%).LC-MS: [M+H] ⁺ 570.

¹ H NMR (400MHz, DMSO-d ₆ )δ9.85(s,1H),9.06(s,1H),8.72(s,1H),8.30(s,1H),7.44(d,J＝8.0Hz, 1H), 6.59(d, J=8.0Hz, 1H), 4.67-4.65(m, 2H), 4.58-4.45(m, 2H), 4.20-4.18(m, 1H), 3.64(t, J=7.2Hz ,1H),3.55-3.48(m,3H),3.40(s,2H),3.28-3.26(m,5H),2.99(s,3H),2.92-2.84(m,1H),1.79-1.76(m ,2H),1.57(s,2H),1.43(d,J=6.0Hz,3H),1.30(d,J=6.4Hz,6H).

Example 45, N-(4-((3R,4S)-4-(2-(dimethylamino)ethoxy)-3-fluoropiperidin-1-yl)-1,3,5-triazine -2-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquine Synthesis of olin-3-amine (compound 45):

Under nitrogen protection, at room temperature, to 4-((3R,4S)-4-(2-(dimethylamino)ethoxy)-3-fluoropiperidin-1-yl)-1,3,5- To a solution of triazin-2-amine (20 mg, 0.07 mmol) in dioxane (7 mL) was successively added 3-chloro-5-isopropyl-8-((2R, 3S)-2-methyl-3- ((Methylsulfonyl)methyl)azetidin-1-yl)isoquinoline (26 mg, 0.07 mmol), cesium carbonate (46 mg, 0.14 mmol) and methanesulfonic acid (2-dicyclohexylphosphine) -3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) Palladium(II) (9 mg, 0.01 mmol). The resulting reaction solution was heated up to 100° C. and reacted for 5 hours. After the reaction solution was concentrated under reduced pressure, the crude product was sequentially subjected to silica gel column chromatography (dichloromethane/methanol=15/1) and reversed-phase liquid chromatography (chromatographic conditions: column: spherical C18, 20-40um, 80g; mobile phase A: Water (containing 0.1% formic acid); mobile phase B: acetonitrile; flow rate: 80 mL/min; gradient: 5% B-30% B in 20 minutes; detector: 254 nm) was purified to give N-(4-((3R , 4S)-4-(2-(Dimethylamino)ethoxy)-3-fluoropiperidin-1-yl)-1,3,5-triazin-2-yl)-5-isopropyl- 8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine (compound 45) (8.23mg Yield: 19.1%). LC-MS: [M+H] ⁺⁶¹⁵ .

¹ H NMR (400MHz,DMSO-d ₆ )δ9.94(s,1H),9.07(s,1H),8.67(s,1H),8.33(s,1H),7.45(d,J＝8.0Hz, 1H), 6.60(d, J=8.0Hz, 1H), 5.04(s, 1H), 4.78(s, 1H), 4.67(t, J=7.6Hz, 2H), 4.20(t, J=6.0Hz, 1H),3.66-3.55(m,4H),3.53-3.41(m,4H),3.40(s,1H),2.99(s,3H),2.92-2.87(m,1H),2.44(d,J= 6.0Hz, 2H), 2.22(s, 6H), 1.87-1.83(m, 2H), 1.43(d, J=6.0Hz, 3H), 1.31(d, J=6.4Hz, 6H).

Example 46, N-(4-((3S,4R)-4-(2-(dimethylamino)ethoxy)-3-fluoropiperidin-1-yl)-1,3,5-triazine -2-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquine Synthesis of olin-3-amine (compound 46):

Under nitrogen protection, at room temperature, to 4-((3S,4R)-4-(2-(dimethylamino)ethoxy)-3-fluoropiperidin-1-yl)-1,3,5- To a solution of triazin-2-amine (20 mg, 0.07 mmol) in dioxane (7 mL) was successively added 3-chloro-5-isopropyl-8-((2R, 3S)-2-methyl-3- ((Methylsulfonyl)methyl)azetidin-1-yl)isoquinoline (26 mg, 0.07 mmol), cesium carbonate (46 mg, 0.14 mmol) and methanesulfonic acid (2-dicyclohexylphosphine) -3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) Palladium(II) (9 mg, 0.01 mmol). The resulting reaction solution was heated up to 100° C. and reacted for 5 hours. After the reaction solution was concentrated under reduced pressure, the crude product was sequentially subjected to silica gel column chromatography (dichloromethane/methanol=15/1) and reversed-phase liquid chromatography (chromatographic conditions: column: spherical C18, 20-40um, 80g; mobile phase A: Water (containing 0.1% formic acid); mobile phase B: acetonitrile; flow rate: 80 mL/min; gradient: 5% B-30% B in 20 minutes; detector: 254 nm) was purified to give N-(4-((3S , 4R)-4-(2-(dimethylamino)ethoxy)-3-fluoropiperidin-1-yl)-1,3,5-triazin-2-yl)-5-isopropyl- 8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine (compound 46) (7.29mg , Yield: 16.9%). LC-MS: [M+H] ⁺⁶¹⁵ .

¹ H NMR (400MHz,DMSO-d ₆ )δ9.94(s,1H),9.07(s,1H),8.67(s,1H),8.33(s,1H),7.45(d,J＝8.0Hz, 1H), 6.60(d, J=8.0Hz, 1H), 5.02(s, 1H), 4.78(s, 1H), 4.67-4.65(m, 2H), 4.19(t, J=6.4, 1H), 3.68 –3.57(m,4H),3.53-48(m,4H),3.37(s,1H),2.99(s,3H),2.90–2.88(m,1H),2.44(d,J＝6.0Hz,2H ),2.18(s,6H),1.85-1.42(m,2H),1.43(d,J＝6.0Hz,3H),1.31(s,6H).

Example 47, N-(4-((3R,4S)-3-fluoro-4-methoxypiperidin-1-yl)-1,3,5-triazin-2-yl)-5-iso Synthesis of Propyl-8-(3-(methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-amine (Compound 47):

Under nitrogen protection, at room temperature, 4-((3R,4S)-3-fluoro-4-methoxypiperidin-1-yl)-1,3,5-triazin-2-amine (80mg, 0.35mmol) of dioxane solution (7mL) was added successively 3-chloro-5-isopropyl-8-(3-((methylsulfinyl)methyl)azetidin-1-yl ) isoquinoline (118mg, 0.35mmol), cesium carbonate (230mg, 0.70mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'- Triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (36 mg, 0.04 mmol). The resulting reaction liquid was heated up to 100° C. and reacted for 5 hours. After the reaction solution was concentrated under reduced pressure, the crude product was sequentially subjected to silica gel column chromatography (dichloromethane/methanol=15/1) and reversed-phase liquid chromatography (chromatographic conditions: column: spherical C18, 20-40um, 80g; mobile phase A: Water (containing 0.1% ammonia); Mobile phase B: acetonitrile; Flow rate: 80mL/min; Gradient: 5%B-30%B in 20 minutes; Detector: 254nm) Purification gives N-(4-((3R , 4S)-3-fluoro-4-methoxypiperidin-1-yl)-1,3,5-triazin-2-yl)-5-isopropyl-8-(3-((methyl Sulfinyl)methyl)azetidin-1-yl)isoquinolin-3-amine (Compound 47) (80 mg, yield: 43.0%). The compound was prepared and separated by supercritical fluid chromatography (chromatographic conditions as shown in the table below) to obtain two isomers compound 47A (26.59 mg, yield: 33.2%) and compound 47B (23.52 mg, yield: 29.4%).

Supercritical fluid chromatography conditions:

Compound 47A: retention time: 1.447 min. LC-MS: [M+H] ⁺ 528.

¹ H NMR (400MHz,DMSO-d ₆ )δ9.98(s,1H),9.09(s,1H),8.67(s,1H),8.34(s,1H),7.44(d,J＝8.0Hz, 1H), 6.45(d, J=8.0Hz, 1H), 5.07-5.06(m, 1H), 4.95-4.93(m, 1H), 4.81(s, 1H), 4.79-4.41(m, 1H), 4.38 (t,J=6.8Hz,2H),3.98(t,J=6.0Hz,2H),3.66–3.45(m,3H),3.36(s,3H),3.27-3.24(m,2H),3.21– 3.09(m,1H),2.59(s,3H),1.87(s,1H),1.68(s,1H),1.34-1.26(m,6H),1.23(s,1H).

Compound 47B: retention time: 1.378 min. LCMS: [M+H] ⁺ 528.

¹ H NMR (400MHz,DMSO-d ₆ )δ9.95(s,1H),9.08(s,1H),8.66(s,1H),8.33(s,1H),7.44(d,J＝8.4Hz, 1H), 6.45(d, J＝8.0Hz, 1H), 5.07-5.05(m, 1H), 4.95-4.93(m, 1H), 4.81-4.79(m, 1H), 4.65-4.43(m, 1H) ,4.39(t,J=7.2Hz,2H),3.98(t,J=5.6Hz,2H),3.65–3.42(m,3H),3.36(s,3H),3.27-3.24(m,2H), 3.21-3.06(m,1H),2.59(s,3H),1.87(s,1H),1.65(s,1H),1.31-1.26(m,6H),1.21(s,1H).

Example 48, (3S,4S)-3-fluoro-1-(4-((5-isopropyl-8-(3-((methylsulfinyl)methyl)azetidine-1 Synthesis of -yl)isoquinolin-3-yl)amino)-1,3,5-triazin-2-yl)-3-methylpiperidin-4-ol (compound 48):

Under nitrogen protection, at room temperature, to (3S, 4S)-1-(4-amino-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (30mg, 0.13mmol) in dioxane solution (7mL) was added successively 3-chloro-5-isopropyl-8-(3-((methylsulfinyl)methyl)azetidine- 1-yl)isoquinoline (44mg, 0.13mmol), cesium carbonate (85mg, 0.26mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4', 6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (9 mg, 0.01 mmol). The resulting reaction solution was heated up to 100° C. and reacted for 5 hours. After the reaction solution was concentrated under reduced pressure, the crude product was sequentially subjected to silica gel column chromatography (dichloromethane/methanol=15/1) and reversed-phase liquid chromatography (chromatographic conditions: column: spherical C18, 20-40um, 80g; mobile phase A: Water (containing 0.1% ammonia); mobile phase B: acetonitrile; flow rate: 80mL/min; gradient: 5%B-30%B in 20 minutes; detector: 254nm) was purified to obtain (3S, 4S)-3- Fluoro-1-(4-((5-isopropyl-8-(3-((methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino )-1,3,5-triazin-2-yl)-3-methylpiperidin-4-ol (compound 48) (36 mg, yield: 51.6%). The compound was prepared and isolated by supercritical fluid chromatography (chromatographic conditions as shown in the table below) to obtain compound 48A (4.22 mg, yield: 11.7%) and compound 48B (4.72 mg, yield: 13.1%).

Supercritical fluid chromatography conditions:

Compound 48A: retention time: 1.373 min. LC-MS: [M+H] ⁺ : 528.

¹ H NMR (400MHz,DMSO-d ₆ )δ9.94-9.89(m,1H),9.08(s,1H),8.69-8.62(m,1H),8.32(s,1H),7.44(d,J ＝8.0Hz, 1H), 6.45(d, J＝8.0Hz, 1H), 5.46(s, 1H), 4.39(t, J＝6.4Hz, 2H), 4.26(s, 1H), 4.23–3.96(m ,3H),3.92–3.47(m,4H),3.24-3.20(m,2H),3.13–3.10(m,1H),2.59(s,3H),1.94-1.89(m,1H),1.62-1.50 (m,1H),1.35–1.24(m,9H).

Compound 48B: retention time: 1.378 min. LC-MS: [M+H] ⁺ 528.

¹ H NMR (400MHz,DMSO-d ₆ )δ9.93-9.89(m,1H),9.08(s,1H),8.69-8.63(m,1H),8.32(s,1H),7.44(d,J ＝8.0Hz, 1H), 6.45(d, J＝8.0Hz, 1H), 5.46(s, 1H), 4.39(t, J＝6.8Hz, 2H), 4.23(s, 1H), 4.08–3.91(m ,3H),3.73-3.46(m,4H),3.27-3.20(m,2H),3.13–3.09(m,1H),2.59(s,3H),1.94-1.90(m,1H),1.63-1.61 (m,1H),1.35-1.23(m,9H).

Example 49, (3R,4R)-3-fluoro-1-(4-((5-isopropyl-8-(3-((methylsulfinyl)methyl)azetidine-1 Synthesis of -yl)isoquinolin-3-yl)amino)-1,3,5-triazin-2-yl)-3-methylpiperidin-4-ol (compound 49):

Under nitrogen protection, at room temperature, to (3R, 4R)-1-(4-amino-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (30mg, 0.13mmol) in dioxane solution (7mL) was added successively 3-chloro-5-isopropyl-8-(3-((methylsulfinyl)methyl)azetidine- 1-yl)isoquinoline (44mg, 0.13mmol), cesium carbonate (85mg, 0.26mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4', 6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (9 mg, 0.01 mmol). The resulting reaction solution was heated up to 100° C. and reacted for 5 hours. After the reaction solution was concentrated under reduced pressure, the crude product was sequentially subjected to silica gel column chromatography (dichloromethane/methanol=15/1) and reversed-phase liquid chromatography (chromatographic conditions: column: spherical C18, 20-40um, 80g; mobile phase A: Water (containing 0.1% ammonia); Mobile phase B: acetonitrile; Flow rate: 80mL/min; Gradient: 5%B-30%B in 20 minutes; Detector: 254nm) Purification gives (3R, 4R)-3- Fluoro-1-(4-((5-isopropyl-8-(3-((methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino )-1,3,5-triazin-2-yl)-3-methylpiperidin-4-ol (36 mg, yield: 51.6%). The compound was prepared and separated by supercritical fluid chromatography (chromatographic conditions as shown in the table below) to obtain two isomers: compound 49A (4.05 mg, yield: 11.2%) and compound 49B (2.07 mg, yield: 5.8%).

Supercritical fluid chromatography conditions:

Compound 49A: retention time: 1.374min.LCMS: [M+H] ⁺ :528.3

¹ H NMR (400MHz,DMSO-d ₆ )δ9.92-9.89(m,1H),9.08(s,1H),8.69-8.63(m,1H),8.32(s,1H),7.44(d,J =8.0Hz, 1H), 6.45(d, J=8.0Hz, 1H), 5.46(s, 1H), 4.39(t, J=6.4Hz, 2H), 4.26(s, 1H), 3.99-3.97(m ,3H),3.73–3.42(m,4H),3.24-3.20(m,2H),3.13-3.09(m,1H),2.59(s,3H),1.93-1.88(m,1H),1.88-1.62 (m,1H),1.35-1.24(m,9H).

Compound 49B: retention time: 1.375min.LCMS: [M+H] ⁺ 528.3

¹ H NMR (400MHz,DMSO-d ₆ )δ9.93-9.89(m,1H),9.08(s,1H),8.69-8.62(m,1H),8.32(s,1H),7.44(d,J =8.0Hz, 1H), 6.44(d, J=8.0Hz, 1H), 5.46(s, 1H), 4.39(t, J=7.4Hz, 2H), 4.26(s, 1H), 4.23-4.00(m ,3H),3.76-3.47(m,4H),3.30-3.20(m,2H),3.19-3.09(m,1H),2.59(s,3H),1.91-1.86(m,1H),1.62-1.50 (m,1H),1.35-1.29(m,9H).

Example 50, (3R, 4S)-3-fluoro-1-(4-((5-isopropyl-8-((2R, 3S)-2-methyl-3-((methylsulfonyl) Synthesis of Methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-ol (Compound 50)

At room temperature, to dioxane dissolved in (3R,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (20mg, 0.09mmol) Ring solution (7mL) was added successively with 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidine- 1-yl)isoquinoline (33mg, 0.09mmol) cesium carbonate (59mg, 0.18mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6 '-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (9 mg, 0.01 mmol). The resulting reaction solution was heated to 100° C. under the protection of nitrogen and reacted for 5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product is successively subjected to silica gel column chromatography (dichloromethane/methanol=15/1) and reverse phase column chromatography (chromatographic conditions: column: spherical C18, 20-40um, 80g; mobile phase A: water (containing 0.1% formic acid) ; Mobile phase B: acetonitrile; Flow rate: 80mL/min; Gradient: 5% B-30% B in 20 minutes; Detector: 254nm. When containing 20% B in mobile phase, collect the mobile phase containing product) Purification (3R,4S)-3-fluoro-1-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methanol) was obtained as a yellow solid Base) azetidin-1-yl) isoquinolin-3-yl) amino) pyrimidin-2-yl)-3-methylpiperidin-4-ol (4.23mg, 7.6umol, yield: 8.6 %), LC-MS m/z:557[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.88(s, 1H), 9.06(s, 1H), 8.61(s, 1H), 7.98(d, J=5.6Hz, 1H), 7.42(d, J＝7.6Hz, 1H), 6.56(d, J＝8.0Hz, 1H), 6.45(d, J＝5.6Hz, 1H), 5.05-5.02(m, 1H), 4.77-4.64(m, 3H), 4.22-4.16(m,1H),3.64(t,J＝7.2Hz,1H),3.61-3.48(m,4H),3.20-3.06(m,2H),2.99(s,3H),2.93-2.67( m,1H),1.73(s,2H),1.43-1.30(m,12H).

Example 51, (3S,4R)-3-fluoro-1-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl) Synthesis of methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-ol formate (compound 51)

At room temperature, (3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (20 mg, 0.09 mmol) was dissolved in dioxy Add 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidine- 1-yl)isoquinoline (33mg, 0.09mmol), cesium carbonate (59mg, 0.18mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4', 6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (9 mg, 0.01 mmol). After the addition was complete, the resulting reaction liquid was heated up to 100° C. and stirred for 5 hours under the protection of nitrogen. The reaction was concentrated under reduced pressure to obtain the crude product. The crude product was subjected to silica gel column chromatography (dichloromethane/methanol=15/1) and reverse phase column chromatography (chromatographic conditions: column: spherical C18, 20-40um, 80g; mobile phase A: water (containing 0.1% formic acid); Mobile phase B: acetonitrile; Flow rate: 80mL/min; Gradient: 5% B-30% B in 20 minutes; Detector: 254nm. When containing 22% B in the mobile phase, collect the mobile phase containing the product) to purify Yellow solid (3S,4R)-3-fluoro-1-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl )azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-ol formate (6.38mg, 0.011mmol, yield : 12.9%), LCMS m/z: 557[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.89(s,1H),9.05(s,1H),8.62(s,1H),8.29(s,1H),7.98(d,J＝5.6Hz, 1H), 7.43(d, J=8.0Hz, 1H), 6.56(d, J=8.0Hz, 1H), 6.45(d, J=5.6Hz, 1H), 5.05(s, 1H), 4.76-4.64( m,3H),4.19(t,J=6.4Hz,1H),3.63(t,J=7.2Hz,1H),3.59-3.49(m,4H),3.25-3.10(m,2H),2.99(s ,3H),2.90-2.50(m,1H),1.74-1.73(m,2H),1.43-1.29(m,12H).

Example 52, (3S,4S)-3-fluoro-1-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl) Synthesis of methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-ol formate (compound 52)

Solution of (3S, 4S)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (20mg, 0.09mmol) in dioxane at room temperature 3-Chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidine-1- base) isoquinoline (33mg, 0.09mmol) cesium carbonate (59mg, 0.18mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'- Triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (9 mg, 0.01 mmol). The resulting reaction solution was heated to 100° C. under the protection of nitrogen and reacted for 5 hours. The reaction solution was concentrated by rotary evaporation to obtain a crude product. The crude product is successively subjected to silica gel column chromatography (dichloromethane/methanol=15/1) and reverse phase column chromatography (chromatographic conditions: column: spherical C18, 20-40um, 80g; mobile phase A: water (containing 0.1% formic acid) ; Mobile phase B: acetonitrile; Flow rate: 80mL/min; Gradient: 5% B-30% B in 20 minutes; Detector: 254nm. When containing 22% B in mobile phase, collect the mobile phase containing product) Purification (3S,4S)-3-Fluoro-1-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methanol) was obtained as a yellow solid yl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-ol formate (6.02mg, 0.01mmol, yield Yield: 11.3%), LCMS m/z: 557[M+H] ⁺ .

¹ H NMR (400MHz,DMSO-d ₆ )δ9.91(s,1H),9.05(s,1H),8.64(s,1H),8.42(s,1H),7.99(d,J＝5.6Hz, 1H), 7.42(d, J=8.0Hz, 1H), 6.56(d, J=8.0Hz, 1H), 6.45(d, J=5.2Hz, 1H), 5.35(s, 1H), 4.66(t, J＝7.2Hz, 1H), 4.21-4.18(m, 1H), 3.91-3.88(m, 4H), 3.75(s, 1H), 3.63(t, J＝6.8Hz, 1H), 3.59-3.48(m ,3H),2.99(s,3H),2.91-2.86(m,1H),1.91(s,1H),1.56-1.52(m,1H),1.42(d,J=5.6Hz,3H),1.33- 1.24(m,9H).

Example 53, (3R,4R)-3-fluoro-1-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl) Synthesis of Methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-ol (Compound 53)

(3R, 4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (20mg, 0.09mmol), 3-chloro-5-iso Propyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline (33mg, 0.09mmol), carbonic acid Cesium (59 mg, 0.18 mmol) and (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl methanesulfonate )(2'-Amino-1,1'-biphenyl-2-yl)palladium(II) (9 mg, 0.01 mmol) in dioxane (7 mL) was reacted at 100°C for 5 hours under nitrogen protection. After the reaction was completed, the reaction solution was directly spin-dried and was successively subjected to preparative thin-layer chromatography (dichloromethane/methanol=15/1) and preparative high-performance liquid chromatography (chromatographic conditions: Waters 2767/2545/2489; column: SunFire Prep C18 OBD 10um 19*250mm Column; mobile phase 0.1% FA in H ₂ O/CAN; detection wavelength: 254nm&214nm; flow rate: 20mL/min) to obtain (3R,4R)-3-fluoro-1-(4-((5 -Isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino )pyrimidin-2-yl)-3-methylpiperidin-4-ol (14.82 mg, 0.027 mmol, yield: 30%). LCMS m/z:557[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.91(s, 1H), 9.06(s, 1H), 8.63(s, 1H), 7.99(d, J=6.0Hz, 1H), 7.42(d, J=8.0Hz, 1H), 6.56(d, J=8.0Hz, 1H), 6.45(d, J=5.6Hz, 1H), 5.34(s, 1H), 4.66(t, J=7.6Hz, 1H) ,4.19(t,J=6.4Hz,1H),3.97-3.87(m,4H),3.75(s,1H),3.64(t,J=6.8Hz,1H),3.56-3.48(m,3H), 2.99(s,3H),2.90-2.88(m,1H),1.92(s,1H),1.53(s,1H),1.42(d,J＝6.0Hz,3H),1.33-1.27(m,9H) .

Example 54, 8-(3-((ethylsulfinyl)methyl)azetidin-1-yl)-N-(2-((3R,4S)-3-fluoro-4-methyl Synthesis of Oxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropylisoquinolin-3-amine (Compound 54)

1), the synthesis of 3-chloro-8-(3-((ethylsulfinyl) methyl) azetidin-1-yl)-5-isopropylisoquinoline

At room temperature, 3-((ethylsulfinyl )methyl)azetidine trifluoroacetate (84mg, 0.32mmol), cesium carbonate (522mg, 1.60mmol) and methanesulfonic acid (4,5-bisdiphenylphosphine-9,9-dimethyl oxanthene)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (49 mg, 0.03 mmol). The resulting reaction solution was heated to 100° C. and reacted under nitrogen protection for 3 hours. After the reaction solution was completed, the reaction solution was concentrated to obtain a residue after removing the solvent. The residue was purified by silica gel column chromatography (dichloromethane/methanol=15/1) as a yellow solid compound (55 mg, 0.16 mmol, yield: 49.6%), LCMS m/z: 351 [M+H] ⁺ .

2), 8-(3-((ethylsulfinyl)methyl)azetidin-1-yl)-N-(2-((3R,4S)-3-fluoro-4-methoxy Synthesis of 1-piperidin-1-yl)pyrimidin-4-yl)-5-isopropylisoquinolin-3-amine (Compound 54)

At room temperature, 2-((3R,4S)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine (55 mg, 0.24 mmol) was dissolved in dioxane (7 mL ) solution was added successively 3-chloro-8-(3-((ethylsulfinyl)methyl)azetidin-1-yl)-5-isopropylisoquinoline (84mg, 0.24mmol) , cesium carbonate (156mg, 0.48mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'- Biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)((21mg, 0.024mmol), under the protection of the obtained reaction liquid nitrogen, the temperature was raised to 100°C for 5 hours. The reaction was completed, The reaction solution was concentrated to remove the solvent to obtain a residue.The residue was passed through silica gel column chromatography (dichloromethane/methanol=15/1) and reverse phase column chromatography (chromatographic conditions: column: chromatographic conditions: column: spherical C18, 20-40um, 80g Mobile phase A: water (containing 0.1% ammoniacal liquor); Mobile phase B: acetonitrile; Flow velocity: 80mL/min; Gradient: 5% B-30% B in 20 minutes; Detector: 254nm.Contain in mobile phase At 21% B, the mobile phase containing the product was collected) to purify 8-(3-((ethylsulfinyl)methyl)azetidin-1-yl)-N-(2-((3R,4S )-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropylisoquinolin-3-amine (compound 54) (40mg, 0.074mmol, yield: 30.8%)

8-(3-((ethylsulfinyl)methyl)azetidin-1-yl)-N-(2-((3R,4S)-3-fluoro-4-methoxypiper Pyridin-1-yl)pyrimidin-4-yl)-5-isopropylisoquinolin-3-amine (40mg) was passed through supercritical fluid chromatography (chromatographic conditions: Waters SFC 150 system;

250*25mm 10μm column; Supercritical CO ₂ /MeOH (+0.1% 7.0mol/L Ammonia in MeOH)x elution; detection wavelength 214nM; column temperature: room temperature; flow rate: 80mL/min; Back up pressure 100bar) prepared and separated 2 isomers: Compound 54A and Compound 54B:

Compound 54A (7.38 mg, 0.014 mmol, yield: 18.5%) Peak 1: 1.235 min. LCMS m/z: 541 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.89(s, 1H), 9.06(s, 1H), 8.62(s, 1H), 8.00(d, J=5.6Hz, 1H), 7.41(d, J＝8.0Hz, 1H), 6.48(d, J＝5.6Hz, 1H), 6.41(d, J＝8.0Hz, 1H), 5.00-4.87(m, 1H), 4.73-4.50(m, 1H), 4.47-4.45(m,1H),4.38(t,J=7.2Hz,2H),3.97(t,J=6.0Hz,2H),3.51–3.46(m,3H),3.37(s,3H),3.32 -3.15(m,3H),3.10-3.07(m,1H),2.86-2.80(m,1H),2.72-2.67(m,1H),1.81-1.75(m,2H),1.31-1.30(m, 6H), 1.21(t, J=7.6Hz, 3H).

Compound 54B (7.52 mg, 0.014 mmol, yield: 18.8%). Peak 2: 1.985 min. LCMS m/z: 541 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.89(s, 1H), 9.06(s, 1H), 8.62(s, 1H), 8.00(d, J=5.6Hz, 1H), 7.41(d, J＝8.0Hz, 1H), 6.48(d, J＝6.0Hz, 1H), 6.41(d, J＝8.4Hz, 1H), 5.00-4.88(m, 1H), 4.73-4.53(m, 1H), 4.47-4.45(m,1H),4.38(t,J=7.2Hz,2H),3.97(t,J=6.8Hz,,2H),3.51-3.45(m,3H),3.37(s,3H), 3.32-3.15(m,3H),3.10-3.07(m,1H),2.86-2.80(m,1H),2.72-2.67(m,1H),1.81-1.75(m,2H),1.31-1.29(m ,6H),1.21(t,J=7.2Hz,3H).

Example 55, (3R,4S)-1-(4-((8-(3-((ethylsulfinyl)methyl)azetidin-1-yl)-5-isopropyliso Synthesis of quinolin-3-yl)amino)pyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (compound 55)

At room temperature, (3R,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (30mg, 0.13mmol) was dissolved in dioxane Add 3-chloro-8-(3-((ethylsulfinyl)methyl)azetidin-1-yl)-5-isopropylisoquinoline (46mg, 0.13mmol), cesium carbonate (85mg, 0.26mmol) and methanesulfonate (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1, 1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (11.7 mg, 0.013 mmol). Under the protection of nitrogen, the obtained reaction liquid was heated to 100° C. for 5 hours. After the reaction was completed, the reaction solution was concentrated to remove the solvent to obtain a residue. The residue is passed through silica gel column chromatography (dichloromethane/methanol=15/1) and reverse phase column chromatography (chromatographic conditions: column: chromatographic conditions: column: spherical C18, 20-40um, 80g; Mobile phase A: water (containing 0.1 % ammonia water); Mobile phase B: acetonitrile; Flow rate: 80mL/min; Gradient: 5% B-30% B in 20 minutes; Detector: 254nm.When containing 21% B in mobile phase, collect containing product mobile phase) to obtain (3R,4S)-1-(4-((8-(3-((ethylsulfinyl)methyl)azetidin-1-yl)-5-isopropyl Isoquinolin-3-yl)amino)pyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (Compound 55) (38 mg, 0.070 mmol, yield: 52.8%).

3R, 4S)-1-(4-((8-(3-((ethylsulfinyl)methyl)azetidin-1-yl)-5-isopropylisoquinoline-3 -yl)amino)pyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (compound 55) (38 mg) by supercritical fluid chromatography (chromatographic conditions: Waters SFC150 system;

250*25mm 10μm column; Supercritical CO2/MeOH (+0.1% 7.0mol/L Ammonia in MeOH) x elution; detection wavelength 214nM; column temperature: room temperature; flow rate: 80ml/min; Back up pressure 100bar) to obtain 2 isomers: Compound 55A and Compound 55B:

Compound 55A (2.64 mg, 0.0049 mmol, yield: 6.9%) Peak 1: 1.691 min. LCMS m/z: 541 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.86(s, 1H), 9.06(s, 1H), 8.60(s, 1H), 7.98(d, J=6.0Hz, 1H), 7.41(d, J＝8.0Hz, 1H), 6.46(d, J＝5.6Hz, 1H), 6.41(d, J＝8.4Hz, 1H), 5.03(d, J＝6.4Hz, 1H), 4.74–4.72(m, 2H),4.40-4.36(m,2H),3.97(t,J＝6.0Hz,2H),3.51-3.48(m,2H),3.21–3.07(m,5H),2.86–2.80(m,1H) ,2.72-2.67(m,1H),1.75-1.73(m,2H),1.39–1.28(m,9H),1.21(t,J＝6.8Hz,3H).

Compound 55B (4.56mg, 0.0084mmol, Yield: 12.0%) Peak 2: 2.602min. LCMS m/z: 541[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.86(s, 1H), 9.06(s, 1H), 8.60(s, 1H), 7.98(d, J=5.6Hz, 1H), 7.41(d, J＝8.0Hz, 1H), 6.46(d, J＝5.6Hz, 1H), 6.41(d, J＝8.0Hz, 1H), 5.03(d, J＝6.4Hz, 1H), 4.74-4.72(m, 2H), 4.38(t, J=7.2Hz, 2H), 3.99-3.95(m, 2H), 3.53-3.48(m, 2H), 3.21-3.07(m, 5H), 2.86-2.80(m, 1H) ,2.72-2.67(m,1H),1.75-1.73(m,2H),1.39–1.28(m,9H),1.21(t,J＝6.8Hz,3H).

Example 56, (3S,4R)-1-(4-((8-(3-((ethylsulfinyl)methyl)azetidin-1-yl)-5-isopropyliso Synthesis of quinolin-3-yl)amino)pyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (compound 56)

At room temperature, 3-((ethylsulfinyl ) methyl) azetidine 2,2,2-trifluoroacetate (73mg, 0.28mmol), cesium carbonate (456mg, 1.40mmol), methanesulfonic acid (4,5-bisdiphenylphosphine- 9,9-Dimethylxanthene)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (23 mg, 0.014 mmol). The resulting reaction solution was heated to 100° C. and stirred for 3 hours under the protection of nitrogen. After the reaction was completed, the reaction solution was concentrated to remove the solvent. The residue was purified by silica gel column chromatography (dichloromethane/methanol=15/1) to obtain yellow solid compound 3-chloro-8-(3-((ethylsulfinyl)methyl)azetidine-1- Base)-5-isopropylisoquinoline (70mg, 0.20mmol, yield: 71.1%) Retention time: 1.793min. LCMS m/z: 351[M+H] ⁺ .

2), (3S,4R)-1-(4-((8-(3-((ethylsulfinyl)methyl)azetidin-1-yl)-5-isopropylisoquinol Synthesis of Lin-3-yl)amino)pyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (Compound 56)

At room temperature, 3-chloro-8-(3-((ethylsulfinyl)methyl)azetidin-1-yl)-5-isopropylisoquinoline (70mg, 0.20 mmol) in dioxane solution was sequentially added (3S, 4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (45mg, 0.20mmol) , cesium carbonate (130mg, 0.40mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'- Biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (18 mg, 0.020 mmol). The resulting reaction solution was reacted at 100° C. for 16 hours under the protection of nitrogen. After the reaction was completed, the reaction solution was concentrated to remove the solvent to obtain a residue. The residue was purified by silica gel column chromatography (dichloromethane/methanol=15/1) to obtain yellow solid compound (3S,4R)-1-(4-((8-(3-((ethylsulfinyl)methyl) ) azetidin-1-yl)-5-isopropylisoquinolin-3-yl) amino) pyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-alcohol (100mg , 0.18mmol, yield: 92.7%) retention time: 0.890min.LCMS: [M+H] ⁺ : 541.6.

(3S,4R)-1-(4-((8-(3-((Ethylsulfinyl)methyl)azetidin-1-yl)-5-isopropylisoquinoline- 3-yl)amino)pyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (100mg, 0.18mmol) was purified by supercritical fluid chromatography (chromatographic conditions: Waters SFC 150 system ;

250*25mm 10μm column; Supercritical CO2/MeOH (+0.1% 7.0mol/L Ammonia in MeOH) x elution; detection wavelength 214nM; column temperature: room temperature; flow rate: 70mL/min; Back up pressure 100bar) preparation, separation and preparation Two isomers were isolated: compound 56A and compound 56B:

Compound 56A (4.48 mg, 0.008 mmol, yield: 9.0%) Peak 1: 1.604 min. LCMS m/z: 541 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ9.87(d, J=2.0Hz, 1H), 9.06(s, 1H), 8.59(s, 1H), 7.98(d, J=5.6Hz, 1H ),7.41(d,J=8.0Hz,1H),6.47(d,J=5.6Hz,1H),6.41(d,J=8.0Hz,1H),5.03(d,J=6.4Hz,1H), 4.77-4.66(m,2H),4.38(t,J＝6.8Hz,2H),3.99-3.95(m,2H),3.63-3.48(m,2H),3.23-3.07(m,5H),2.89- 2.80 (m, 1H), 2.72-2.60 (m, 1H), 1.76-1.73 (m, 2H), 1.39-1.28 (m, 9H), 1.23-1.19 (m, 3H).

Compound 56B (3.97 mg, 0.007 mmol, yield: 7.9%) Peak 2: 2.293 min. LCMS m/z: 541 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ9.86(s, 1H), 9.06(s, 1H), 8.60(s, 1H), 7.99(d, J=5.6Hz, 1H), 7.42(d ,J=8.0Hz,1H),6.47(d,J=5.2Hz,1H),6.41(d,J=7.6Hz,1H),5.04(d,J=6.4Hz,1H),4.76-4.68(m ,2H),4.40-4.37(m,2H),3.99-3.96(m,2H),3.60-3.48(m,2H),3.20-3.08(m,5H),2.83-2.81(m,1H),2.73 -2.71(m,1H),1.74-1.73(m,2H),1.40-1.29(m,9H),1.23-1.20(m,3H).

Example 57, N-(2-((3R,4S)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-(3- Synthesis of ((isopropylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-amine (Compound 57)

At room temperature, 3-chloro-5-isopropyl-8-(3-((isopropylsulfinyl)methyl)azetidin-1-yl)isoquinoline (100mg, 0.27mmol) in dioxane (2mL) was added 2-((3R,4S)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine (61mg, 0.27mmol) , cesium carbonate ((880mg, 2.70mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (24 mg, 0.027 mmol). The obtained reaction liquid was reacted at 100° C. for 5 hours under the protection of nitrogen. After the reaction was completed, the reaction solution was concentrated to remove the solvent to obtain a residue. The residue was purified by silica gel column chromatography (dichloromethane/methanol=15/1) to give yellow solid compound N-(2-((3R,4S)-3-fluoro-4-methoxypiperidin-1-yl) Pyrimidin-4-yl)-5-isopropyl-8-(3-((isopropylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-amine (70mg, 0.126mmol, yield: 46.1%), LCMS m/z: 555.3[M+H] ⁺ .

N-(2-((3R,4S)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-(3-((iso Propylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-amine (70mg, 0.126mmol) was purified by supercritical fluid chromatography (chromatographic conditions: chromatographic conditions: Waters SFC 150 system;

250*25mm 10μm column; Supercritical CO2/MeOH (+0.1% 7.0mol/L Ammonia in MeOH) x elution; detection wavelength 214nM; column temperature: room temperature; flow rate: 70mL/min; Back up pressure 100bar) preparation, separation and preparation Two isomers were isolated: Compound 57A and Compound 57B

Compound 57A (65 mg, 0.021 mmol, yield: 16.6%), peak 1: 5.507 min. LCMS m/z: 555[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ9.88(s, 1H), 9.06(s, 1H), 8.61(s, 1H), 8.00(d, J=5.6Hz, 1H), 7.41(d ,J=8.0Hz,1H),6.48(d,J=6.0Hz,1H),6.41(d,J=8.4Hz,1H),5.01-4.87(m,1H),4.75-4.69(m,1H) ,4.50-4.47(m,1H),4.38(t,J＝7.6Hz,2H),3.98(t,J＝6.8Hz,2H),3.65-3.35(m,3H),3.34(s,3H), 3.26-3.10(m,3H),3.02-2.97(m,1H),2.90-2.85(m,1H),1.84-1.73(m,2H),1.31-1.28(m,6H),1.19(d,J =6.8Hz,6H).

Compound 57B (11.83 mg, 0.021 mmol, yield: 16.9%), peak 2: 6.174 min. LCMS m/z: 555[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ9.88(s, 1H), 9.06(s, 1H), 8.61(s, 1H), 8.00(d, J=5.6Hz, 1H), 7.41(d ,J=8.0Hz,1H),6.48(d,J=6.0Hz,1H),6.41(d,J=8.0Hz,1H),5.00-4.87(m,1H),4.77-4.69(m,1H) ,4.50-4.46(m,1H),4.38(t,J=7.6Hz,2H),3.98(t,J=6.8Hz,2H),3.64-3.46(m,3H),3.37(s,3H), 3.22-3.10(m,3H),3.02-2.97(m,1H),2.88-2.85(m,1H),1.86-1.70(m,2H),1.31-1.28(m,6H),1.19(d,J =6.8Hz,6H).

Example 58, N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-(3- Synthesis of ((isopropylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-amine (Compound 58)

1), the synthesis of 3-((isopropylthio) methyl) azetidine-1-carboxylic acid tert-butyl ester

2- Potassium carbonate (3.55g, 25.71mmol) of iodopropane ((2.91g, 17.14mmol). After the addition, the resulting reaction solution was heated to 70°C and reacted for 16 hours. After the reaction, the reaction solution was poured into saturated ammonium chloride (100mL) solution The reaction was quenched in the middle, and extracted with ethyl acetate (100mL * 2).The combined organic phase was concentrated to remove the solvent to obtain the residue. The residue was passed through reverse phase flash column chromatography (chromatographic conditions: column: spherical C18, 20-40um, 330g; Mobile phase A: pure water containing 0.1% formic acid; Mobile phase B: acetonitrile; Flow velocity: 150mL/min; Gradient: 5% B-95% B in 30 minutes; Detection wavelength: 214nm.) Purification, when mobile phase B When reaching 73%, the fraction containing product was collected and concentrated to remove solvent to obtain yellow oily compound 3-((isopropylthio)methyl)azetidine-1-carboxylic acid tert-butyl ester (1.40g, 5.71mmol, Yield: 66.7%), LCMS m/z: 190[M+H-56] ⁺ .

2), 3-((isopropylsulfinyl) methyl) azetidine-1-carboxylate tert-butyl ester synthesis

At 0°C, in a solution of tert-butyl 3-((isopropylthio)methyl)azetidine-1-carboxylate (1.40g, 5.71mmol) in dichloromethane (30mL) After the addition of m-chloroperoxybenzoic acid (1.16 g, 5.71 mmol, content 85%), the reaction was continued at 0°C for 2 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium carbonate (50 mL), and extracted with dichloromethane (50 mL×2). The combined organic phases were concentrated to remove the solvent to obtain a residue. The residue is passed through a reverse-phase flash silica gel column (chromatographic conditions: column: spherical C18, 20-40um, 330g; mobile phase A: pure water containing 0.1% formic acid; mobile phase B: acetonitrile; flow rate: 150mL/min; gradient: 5%B-95%B within 30 minutes; detection wavelength: 214nm.) Purification, when the mobile phase B reached 50%, the fraction containing the product was collected and concentrated to remove the solvent to obtain a colorless oily compound 3-((isopropyl Sulfinyl)methyl)azetidine-1-carboxylate tert-butyl ester (0.99g g, 3.80mmol, 66.7%) Retention time: 1.339min. LCMS m/z: 262[M+H] ⁺ .

3) Synthesis of 3-((isopropylsulfinyl)methyl)azetidine 2,2,2-trifluoroacetate

At 0°C, add 3-(isopropylsulfoxide)methyl)azetidine-1-carboxylic acid tert-butyl ester (0.99g g, 3.80mmol) to dichloromethane (10mL) To the solution, 2,2,2-trifluoroacetic acid (2 mL) was added dropwise. The resulting reaction solution was reacted at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated to remove the solvent to obtain a yellow oily compound 3-((isopropylsulfinyl)methyl)azetidine 2,2,2-trifluoroacetate (1.0g, crude product), which was directly for the next step. LCMS m/z: 162 [M+H] ⁺ .

4), the synthesis of 3-chloro-5-isopropyl-8-(3-((isopropylsulfinyl) methyl) azetidin-1-yl) isoquinoline

At room temperature, to a solution of 8-bromo-3-chloro-5-isopropylisoquinoline (200mg, 0.70mmol) in dioxane (4mL) was successively added Acyl)methyl)azetidine trifluoroacetate (231mg, 0.84mmol, 1.2eq), cesium carbonate (2.28g, 7.00mmol) and methanesulfonic acid (4,5-bisdiphenylphosphine-9 ,9-Dimethylxanthene)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (113 mg, 0.07 mmol). Under the protection of nitrogen, the obtained reaction liquid was heated to 100° C. for 2 hours. After the reaction was completed, the reaction solution was concentrated to remove the solvent to obtain a residue. The residue was purified by silica gel column chromatography (dichloromethane/methanol=15/1) to give yellow solid compound 3-chloro-5-isopropyl-8-(3-((isopropylsulfinyl)methyl)nitrogen Heterobutan-1-yl)isoquinoline (170mg, 0.47mmol, yield: 66.4%).LCMS m/z:365[M+H] ⁺ .

5), N-(2-((3S, 4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-(3-( Synthesis of (isopropylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-amine (Compound 58)

At room temperature, 3-chloro-5-isopropyl-8-(3-((isopropylsulfinyl)methyl)azetidin-1-yl)isoquinoline (50mg, 0.14mmol) dioxane (2mL) solution was added 2-((3S, 4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine (32mg, 0.14mmol), Cesium carbonate (456mg, 1.40mmol) and methanesulfonate (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-bis Benzene)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (13mg, 0.014mmol), the resulting reaction solution was heated at 100°C for 5 hours under the protection of nitrogen. After the reaction was completed, the reaction solution was concentrated to remove the solvent to obtain a residue. The residue was purified by silica gel column chromatography (dichloromethane/methanol=15/1) to give yellow solid compound N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl) Pyrimidin-4-yl)-5-isopropyl-8-(3-((isopropylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-amine (compound 58 ) (40mg, 0.072mmol, yield: 52.6%), LCMS m/z: 555[M+H] ⁺ .

N-(2-((3S, 4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-(3-((iso Propylsulfinyl) methyl) azetidin-1-yl) isoquinolin-3-amine (70mg, 0.126mmol) by supercritical fluid chromatography (chromatographic conditions: Waters SFC 150 system;

250*25mm 10μm column; Supercritical CO ₂ /MeOH (+0.1% 7.0mol/L Ammonia in MeOH)x elution; detection wavelength 214nM; column temperature: room temperature; flow rate: 70-80ml/min; Back up pressure 100bar) preparation Two isomers were isolated: compound 58A and compound 58B:

Compound 58A (24.36mg, 0.044mmol, yield: 34.8%), peak 1: 1.389min. LCMS m/z: 555[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ9.88(s, 1H), 9.06(s, 1H), 8.61(s, 1H), 8.00(d, J=5.6Hz, 1H), 7.41(d ,J=8.0Hz,1H),6.48(d,J=5.6Hz,1H),6.41(d,J=8.0Hz,1H),5.00-4.88(m,1H),4.79-4.70(m,1H) ,4.50-4.46(m,1H),4.38(t,J＝7.6Hz,2H),3.98(t,J＝6.8Hz,2H),3.51-3.46(m,3H),3.37(s,3H), 3.29(s,1H),3.21-3.19(m,1H),3.15-3.10(m,1H),3.02-2.97(m,1H),2.88-2.85(m,1H),1.81-1.71(m,2H ),1.31-1.28(m,6H),1.19(d,J＝6.8Hz,6H).

Compound 58B (7.08mg, 0.013mmol, yield: 10.1%), peak 2: 1.972min. LCMS m/z: 555[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ9.89(s, 1H), 9.06(s, 1H), 8.62(s, 1H), 8.00(d, J=6.0Hz, 1H), 7.41(d ,J=8.0Hz,1H),6.47(d,J=5.6Hz,1H),6.41(d,J=8.0Hz,1H),5.01-4.87(m,1H),4.77-4.69(m,1H) ,4.51-4.47(m,1H),4.38(t,J=7.2Hz,2H),3.98(t,J=6.8Hz,2H),3.62-3.42(m,3H),3.37(s,3H), 3.22-3.19(m,1H),3.15-3.10(m,1H),3.02-2.99(m,1H),2.88-2.85(m,1H),1.81-1.80(m,2H),1.31-1.26(m ,6H),1.19(d,J=6.8Hz,6H).

Example 59, N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-(3- Synthesis of ((methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-amine (Compound 59)

At room temperature, to dioxane ( 7mL), sequentially added 3-chloro-5-isopropyl-8-(3-((methylsulfinyl)methyl)azetidin-1-yl)isoquinoline (87mg, 0.26mmol ), cesium carbonate (170mg, 0.52mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (18 mg, 0.026 mmol). After the addition was completed, the temperature of the obtained mixed reaction liquid was raised to 100° C. for 5 hours under the protection of nitrogen. After the reaction was completed, the reaction solution was concentrated to remove the solvent to obtain a residue. The residue was purified by silica gel column chromatography (dichloromethane/methanol=15/1) to obtain a crude product. The crude product was subjected to reverse-phase column chromatography (chromatographic conditions: column: spherical C18, 20-40um, 80g; mobile phase A: pure water containing 0.1% NH ₄ OH; mobile phase B: acetonitrile; flow rate: 80mL/min; gradient : 40% B-95% B detection wavelength: 254nm) purification within 20 minutes. When the mobile phase B reached 47%, the fractions containing the product were collected and then concentrated under reduced pressure to obtain N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidine- 4-yl)-5-isopropyl-8-(3-((methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-amine (compound 59) (60mg , 0.11 mmol, yield: 42.8%).

N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-(3-((methyl Sulfinyl) methyl) azetidin-1-yl) isoquinolin-3-amine (60mg) by supercritical fluid chromatography (chromatographic conditions: system: Waters SFC 150; column:

250*25mm 10μm; mobile phase A: Supercritical CO ₂ ; mobile phase B: methanol containing 0.1% ammonia methanol (7M); flow rate: 80ml/min; detection wavelength: 214nm) preparation, separation and purification to obtain 2 iso Conforms: Compound 59A and Compound 58B:

Compound 59A (6.74 mg, 0.013 mmol, yield: 11.2%), peak 1: 2.121 min. LCMS m/z: 525[MH] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.89(s, 1H), 9.06(s, 1H), 8.62(s, 1H), 8.00(d, J=5.6Hz, 1H), 7.41(d, J＝8.0Hz, 1H), 6.48(d, J＝5.6Hz, 1H), 6.41(d, J＝8.0Hz, 1H), 5.00-4.87(m, 1H), 4.77-4.70(m, 1H), 4.50-4.47(m,1H),4.38(t,J＝7.2Hz,2H),3.99-3.96(m,2H),3.64-3.42(m,3H),3.37(s,3H),3.29-3.19( m,3H),3.13-3.06(m,1H),2.60(s,3H),1.85-1.72(m,2H),1.31-1.28(m,6H).

Compound B (4.43mg, 0.0084mmol, yield: 7.3%), peak 2: 3.653min. LCMS: [M+H] ⁺ : 527

¹ H NMR (400MHz, DMSO-d ₆ )δ9.88(s, 1H), 9.06(s, 1H), 8.61(s, 1H), 8.00(d, J=5.6Hz, 1H), 7.41(d, J＝8.0Hz, 1H), 6.48(d, J＝5.6Hz, 1H), 6.41(d, J＝8.0Hz, 1H), 5.00-4.88(m, 1H), 4.77-4.70(m, 1H), 4.50-4.47(m,1H),4.38(t,J＝7.2Hz,2H),3.99-3.96(m,2H),3.64-3.42(m,3H),3.37(s,3H),3.25-3.20( m,3H),3.13-3.06(m,1H),2.60(s,3H),1.85-1.72(m,2H),1.31-1.29(m,6H).

Example 60, 8-(3-(((cyclopropyl-2-en-1-ylmethyl)sulfinyl)methyl)azetidin-1-yl)-N-(2-( Synthesis of (3R,4S)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropylisoquinolin-3-amine (Compound 60)

At room temperature, 3-chloro-8-(3-(((cyclopropylmethyl)sulfinyl)methyl)azetidin-1-yl)-5-isopropylisoquinol 2-((3R,4S)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine ( 36mg, 0.16mmol), cesium carbonate (157mg, 0.48mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl- 1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (15 mg, 0.016 mmol). After the addition was complete, the obtained reaction liquid was heated to 100° C. for 5 hours under the protection of nitrogen. After the reaction was completed, the reaction solution was concentrated to remove the solvent to obtain a residue. The residue was purified by silica gel column chromatography (dichloromethane/methanol=15/1) to purify the crude product. The crude product was passed through flash reverse phase column chromatography (chromatographic conditions: column: spherical C18, 20-40um, 80g; flow A: pure water containing 0.1% NH ₃ .H ₂ O; mobile phase B: acetonitrile; flow rate: 80mL/ min; gradient: 40%B-95%B in 20 minutes; detector: 254nm) purification. When the mobile phase B reached 47%, the fractions containing the product were collected and then concentrated under reduced pressure to obtain 8-(3-(((cyclopropyl-2-en-1-ylmethyl)sulfinyl)methyl)nitrogen Heterocyclobutan-1-yl)-N-(2-((3R,4S)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl Isoquinolin-3-amine (compound 60) (64 mg, 0.11 mmol, yield: 70.9%).

8-(3-(((cyclopropyl-2-en-1-ylmethyl)sulfinyl)methyl)azetidin-1-yl)-N-(2-((3R, 4S)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropylisoquinolin-3-amine (compound 60) by supercritical fluid chromatography (chromatographic conditions : System: Waters SFC 150; Column:

250*25mm 10μm; mobile phase A: Supercritical CO _2' ; mobile phase B: containing 0.1% NH ₃ /MeOH (7.0M) MeOH (; detection wavelength: 214nm; flow rate: 80mL/min) separation and purification to prepare and separate to obtain 2 isomers: Compound 60A and Compound 60B:

Compound 60A (6.89 mg, 0.012 mmol, yield: 10.7%), peak 1: 1.627 min. LCMS m/z: 567[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.88(s, 1H), 9.06(s, 1H), 8.61(s, 1H), 8.00(d, J=5.2Hz, 1H), 7.41(d, J＝8.0Hz, 1H), 6.48(d, J＝5.2Hz, 1H), 6.41(d, J＝7.6, 1H), 5.00-4.87(m, 1H), 4.73-4.72(m, 1H), 4.50 -4.47(m,1H),4.40-4.37(m,2H),3.98(s,2H),3.53-3.42(m,3H),3.37(s,3H),3.26-3.18(m,3H),3.14 -3.09(m,1H),2.82-2.77(m,1H),2.70-2.65(m,1H),1.81-1.73(m,2H),1.30(s,6H),1.05(s,1H),0.62 -0.59(m,2H),0.38-0.32(m,2H).

Compound B (5.94 mg, 0.010 mmol, yield: 9.2%), peak 2: 2.441 min. LCMS m/z: 567[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.88(s, 1H), 9.06(s, 1H), 8.61(s, 1H), 8.00(d, J=5.6Hz, 1H), 7.41(d, J＝8.0Hz, 1H), 6.48(d, J＝5.6Hz, 1H), 6.41(d, J＝8.4, 1H), 5.00-4.87(m, 1H), 4.73-4.72(m, 1H), 4.50 -4.47(m,1H),4.40-4.37(m,2H),3.98(s,2H),3.54-3.46(m,3H),3.37(s,3H),3.25-3.18(m,3H),3.14 -3.10(m,1H),2.82-2.77(m,1H),2.70-2.65(m,1H),1.81-1.75(m,2H),1.31-1.29(m,6H),1.07-1.03(m, 1H),0.65-0.57(m,2H),0.40-0.31(m,2H).

Example 61, 8-(3-(((cyclopropyl-2-en-1-ylmethyl)sulfinyl)methyl)azetidin-1-yl)-N-(2-( Synthesis of (3S, 4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropylisoquinolin-3-amine (Compound 61)

At room temperature, 3-chloro-8-(3-(((cyclopropylmethyl)sulfinyl)methyl)azetidin-1-yl)-5-isopropylisoquinol 2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine was added successively to a solution of morphine (60mg, 0.16mmol) in dioxane (7mL) (36mg, 0.16mmol), cesium carbonate (157mg, 0.48mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl -1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (15mg, 0.016mmol), the addition was completed, and the resulting reaction was heated under the protection of liquid nitrogen React at 100°C for 5 hours. After the reaction was completed, the reaction solution was concentrated to remove the solvent to obtain a residue. The residue was purified by silica gel column chromatography (dichloromethane/methanol=15/1) to obtain a crude product. This product passes through reversed-phase flash chromatography again (chromatographic condition: column: spherical C18,20-40um, 80g; Mobile phase A: the water that contains 0.1%NH ₃ .H ₂ O; Mobile phase B: acetonitrile; Flow velocity: 80mL/ min; Gradient: 40% B-95% B in 20 minutes; Detector: 254nm) purify, when mobile phase B reaches 47%, collect the cut that contains product, then concentrate under reduced pressure to obtain 8-(3-(( (Cyclopropyl-2-en-1-ylmethyl)sulfinyl)methyl)azetidin-1-yl)-N-(2-((3S,4R)-3-fluoro-4 -Methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropylisoquinolin-3-amine (Compound 61) (80 mg, 0.14 mmol, yield: 88.3%).

The 8-(3-(((cyclopropyl-2-en-1-ylmethyl)sulfinyl)methyl)azetidin-1-yl)-N-(2-((3S, 4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropylisoquinolin-3-amine (compound 61) by supercritical fluid chromatography (chromatographic conditions : System: Waters SFC 150; Column:

250*25mm 10μm; mobile phase A: Supercritical CO ₂ ; mobile phase B: methanol containing 0.1% ammonia/methanol (7M); wavelength: 214nm; flow rate: 80mL/min) prepared and separated to obtain 2 isomers : Compound 61A and Compound 61B:

Compound 61 (8.14 mg, 0.014 mmol, yield 10.1%), peak 1: 1.873 min. LCMS m/z: 567[M+H] ⁺ :

¹ H NMR (400MHz, DMSO-d ₆ )δ9.88(s, 1H), 9.06(s, 1H), 8.61(s, 1H), 8.00(d, J=6.0Hz, 1H), 7.41(d, J＝8.0Hz, 1H), 6.48(d, J＝5.6Hz, 1H), 6.41(d, J＝8.0Hz, 1H), 5.00-4.87(m, 1H), 4.75-4.71(m, 1H), 4.50-4.47(m,1H),4.38(t,J＝7.2Hz,2H),3.98(s,2H),3.64-3.42(m,3H),3.37(s,3H),3.25-3.18(m, 3H),3.14-3.10(m,1H),2.82-2.77(m,1H),2.70-2.65(m,1H),1.85-1.73(m,2H),1.31-1.28(m,6H),1.07- 1.03(m,1H),0.67-0.57(m,2H),0.40-0.30(m,2H).

Compound 61B (11.25mg, 0.019mmol, Yield: 14.0%) Peak 2: 2.466min. LCMS m/z: 567[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.88(s, 1H), 9.06(s, 1H), 8.61(s, 1H), 8.00(d, J=5.6Hz, 1H), 7.41(d, J＝8.0Hz, 1H), 6.48(d, J＝5.6Hz, 1H), 6.41(d, J＝8.4Hz, 1H), 5.00-4.87(m, 1H), 4.76-4.69(m, 1H), 4.50-4.47(m,1H),4.38(t,J＝7.2Hz,2H),3.99-3.96(m,2H),3.54-3.46(m,3H),3.37(s,3H),3.29-3.18( m,3H),3.14-3.10(m,1H),2.82-2.77(m,1H),2.70-2.65(m,1H),1.82-1.75(m,2H),1.31-1.28(m,6H), 1.07-1.03(m,1H),0.65-0.57(m,2H),0.40-0.31(m,2H).

Example 62, (3R,4S)-3-fluoro-1-(4-((5-isopropyl-8-(3-((((S)-methylsulfinyl)methyl)azepine Cyclobutan-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-ol or (3R,4S)-3-fluoro-1-(4 -((5-isopropyl-8-(3-((((R)-methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino) Synthesis of pyrimidin-2-yl)-3-methylpiperidin-4-ol (compound 62)

1), the synthesis of 3-(((methylsulfonyl)oxy)methyl)azetidine-1-carboxylic acid tert-butyl ester

At 0°C, to a solution of tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (25.00g, 133.69mmol) in dichloromethane (300mL), sequentially add triethyl After the addition of amine (27.01g, 267.38mmol) and methanesulfonyl chloride (30.75g, 267.38mmol), the resulting reaction solution continued to react at 0°C for 12 hours. After the reaction was completed, the reaction solution was quenched by adding saturated aqueous sodium bicarbonate solution (200 mL), and extracted with dichloromethane (300 mL×2). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/1) to obtain off-white oily compound 3-(((methylsulfonyl)oxy)methyl)azetidine-1 - tert-butyl carboxylate (21.00 g, 79.25 mmol, yield: 59.3%). LCMS m/z: 210 [M+H-56] ⁺ .

2), the synthesis of 3-((methylthio) methyl) azetidine-1-carboxylic acid tert-butyl ester

At room temperature, to dissolve tert-butyl 3-(((methylsulfonyl)oxy)methyl)azetidine-1-carboxylate (21.00g, 79.25mmol) in acetonitrile (250mL) and water Sodium methyl mercaptide (16.64 g, 237.75 mmol) was added into the mixed solution of (50 mL), and after the addition was completed, the temperature of the obtained reaction solution was raised to 70° C. for 16 hours. After the reaction was completed, the reaction solution was concentrated to remove the solvent to obtain a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=8/1) to obtain yellow oily compound 3-((methylthio)methyl)azetidine-1-carboxylic acid tert-butyl ester (180 g, crude product), LCMS m/z: 162.0 [M+H-56] ⁺ .

3), 3-((methylsulfinyl) methyl) azetidine-1-carboxylate tert-butyl ester synthesis

At 0°C, to a solution of tert-butyl 3-((methylthio)methyl)azetidine-1-carboxylate (18.00g, 82.95mmol) in dichloromethane (200mL) was added m-Chloroperoxybenzoic acid ((11.41g, 66.36mmol). After the addition, the resulting reaction solution continued to react at 0°C for 0.5 hours. After the reaction, the reaction solution was added to a saturated aqueous solution of sodium bisulfite (200mL), and washed with two Chloromethane (200mL * 2) extraction. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was passed through reversed-phase flash chromatography (chromatographic conditions: column: spherical C18, 20-40um, 330g; flow Phase A: water containing 0.1% formic acid; mobile phase B: acetonitrile; flow rate: 110mL/min; gradient: 20%B-50%B in 20 minutes; detector: 254nm) purification, when mobile phase B reached 37% , collect the fractions containing the product, then concentrate to remove the solvent to obtain yellow oily compound 3-((methylsulfinyl)methyl)azetidine-1-carboxylic acid tert-butyl ester (10.80g, 46.35mmol, yield Yield: 55.9%), LCMS m/z: 178[M+H-56] ⁺ .

4) Synthesis of 3-((methylsulfinyl)methyl)azetidine 2,2,2-trifluoroacetate

At room temperature, to a solution of tert-butyl 3-((methylsulfinyl)methyl)azetidine-1-carboxylate (10.80g, 46.35mmol) in dichloromethane (100mL) was added 2,2,2-Trifluoroacetic acid (10 mL). After the addition was complete, the resulting reaction solution was reacted at room temperature for 2 hours. After the reaction was completed, the reaction solution was directly concentrated to remove the solvent to obtain a brown oily compound 3-((methylsulfinyl)methyl)azetidine 2,2,2-trifluoroacetate (12.00g, crude product), LCMS m/z:134[M+H] ⁺ .

5), the synthesis of 3-chloro-5-isopropyl-8-(3-((methylsulfinyl) methyl) azetidin-1-yl) isoquinoline

At room temperature, to dioxane ( 20mL) solution was added successively cesium carbonate (6.87g, 21.06mmol) and methanesulfonic acid (4,5-bisdiphenylphosphine-9,9-dimethylxanthene) (2'-methylamino-1 , 1'-biphenyl-2-yl)palladium(II) (569 mg, 0.351 mmol). After the addition was complete, the obtained reaction liquid was heated to 100° C. for 2 hours under the protection of nitrogen. After the reaction was completed, the reaction solution was directly concentrated to remove the solvent to obtain a residue. The residue was subjected to silica gel column chromatography (dichloromethane/methanol=15/1) to obtain yellow solid compound 3-chloro-5-isopropyl-8-(3-((methylsulfinyl)methyl)azepine Cyclobutan-1-yl)isoquinoline (1.50g, 4.45mmol, yield: 63.4%), LCMS m/z: 337.0[M+H] ⁺ .

6), (S)-3-chloro-5-isopropyl-8-(3-((methylsulfinyl)methyl)azetidin-1-yl)isoquinoline and (R) Synthesis of -3-chloro-5-isopropyl-8-(3-((methylsulfinyl)methyl)azetidin-1-yl)isoquinoline

Compound 3-chloro-5-isopropyl-8-(3-((methylsulfinyl)methyl)azetidin-1-yl)isoquinoline (1.5g, 4.45mmol) was passed through supernatant Critical fluid chromatography (chromatographic conditions: system: Waters SFC 150; column:

250×25mm 10 μm; mobile phase A: Supercritical CO ₂ ; mobile phase B: methanol containing 0.1% ammonia/methanol (7M); wavelength: 214nm; flow rate: 90mL/min) prepared and separated to obtain two isomers:

Peak 1: 0.745min; (S)-3-chloro-5-isopropyl-8-(3-((methylsulfinyl)methyl)azetidin-1-yl)isoquinoline or (R)-3-Chloro-5-isopropyl-8-(3-((methylsulfinyl)methyl)azetidin-1-yl)isoquinoline (710mg, 2.11mmol, yield Rate: 47.3%);

Peak 2: 1.163min. (R)-3-chloro-5-isopropyl-8-(3-((methylsulfinyl)methyl)azetidin-1-yl)isoquinoline or (S)-3-Chloro-5-isopropyl-8-(3-((methylsulfinyl)methyl)azetidin-1-yl)isoquinoline (720mg, 2.14mmol, yield rate: 48.0%).

7), (3R, 4S)-3-fluoro-1-(4-((5-isopropyl-8-(3-((((S)-methylsulfinyl) methyl) azacyclic Butane-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-ol or (3R,4S)-3-fluoro-1-(4- ((5-isopropyl-8-(3-((((R)-methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidine -2-yl)-3-methylpiperidin-4-ol (compound 62) synthesis

At room temperature, (S)-3-chloro-5-isopropyl-8-(3-((methylsulfinyl)methyl)azetidin-1-yl)isoquinoline Or (R)-3-chloro-5-isopropyl-8-(3-((methylsulfinyl)methyl)azetidin-1-yl)isoquinoline (60mg, 0.17mmol) (3R, 4S)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (41mg, 0.18 mmol), cesium carbonate (176mg, 0.54mmol) and methanesulfonate (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1 '-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (16mg, 0.018mmol), after the addition was complete, the reaction solution was heated to 100°C under the protection of nitrogen for 16 Hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=15/1) to obtain a crude product. The crude product is passed through the reverse phase flash chromatography (chromatographic conditions: column: spherical C18, 20-40um, 80g; mobile phase A: water containing 0.1% NH ₃ H ₂ O; mobile phase B: acetonitrile; flow rate: 80mL/min Gradient: 40% B-95% B in 20 minutes; Detector: 254nm) purify, when mobile phase B content reaches 42%, collect the cut that contains product, then concentrate and remove solvent to obtain yellow solid compound (3R, 4S) -3-fluoro-1-(4-((5-isopropyl-8-(3-((((S)-methylsulfinyl)methyl)azetidin-1-yl)iso Quinolin-3-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-ol or (3R,4S)-3-fluoro-1-(4-((5-isopropyl- 8-(3-((((R)-methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-3- Methylpiperidin-4-ol (5.09 mg, 0.0097 mmol, yield: 5.4%), LCMS m/z: 527 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.86(s, 1H), 9.06(s, 1H), 8.60(s, 1H), 7.98(d, J=5.6Hz, 1H), 7.41(d, J＝8.0Hz, 1H), 6.46(d, J＝5.2Hz, 1H), 6.41(d, J＝8.0Hz, 1H), 5.03(d, J＝6.4Hz, 1H), 4.75-4.67(m, 2H), 4.39(t, J=5.6Hz, 2H), 3.97-3.96(m, 2H), 3.53-3.48(m, 2H), 3.26-3.09(m, 5H), 2.60(s, 3H), 1.73 -1.72(m,2H),1.39-1.28(m,9H).

Example 63, (3R,4S)-3-fluoro-1-(4-((5-isopropyl-8-(3-((((R)-methylsulfinyl)methyl)azepine Cyclobutan-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-ol or (3R,4S)-3-fluoro-1-(4 -((5-isopropyl-8-(3-((((S)-methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino) Synthesis of pyrimidin-2-yl)-3-methylpiperidin-4-ol (compound 63)

At room temperature, (R)-3-chloro-5-isopropyl-8-(3-((methylsulfinyl)methyl)azetidin-1-yl)isoquinoline or (S)-3-chloro-5-isopropyl-8-(3-((methylsulfinyl)methyl)azetidin-1-yl)isoquinoline (60mg, 0.17mmol) (3R, 4S)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (41mg, 0.18 mmol), cesium carbonate (176mg, 0.54mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1 '-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (16mg, 0.018mmol), after the addition was complete, the reaction solution was heated to 100°C under the protection of nitrogen for 16 Hour. After the reaction was completed, the reaction solution was concentrated to remove the solvent to obtain a residue. The residue was purified by silica gel column chromatography (dichloromethane/methanol=15/1) to obtain a crude product. The crude product was passed through reverse phase flash chromatography (chromatographic conditions: column: spherical C18, 20-40um, 80g; mobile phase A: pure water containing 0.1% NH ₃ H ₂ O; mobile phase B: acetonitrile; flow rate: 80mL/ min; Gradient: 40% B-95% B in 20 minutes; Detector: 254nm) purify, when mobile phase B content reaches 42%, collect the cut that contains product, then concentrating and compressing except (3R, 4S)-3 -Fluoro-1-(4-((5-isopropyl-8-(3-((((R)-methylsulfinyl)methyl)azetidin-1-yl)isoquinoline -3-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-ol or (3R,4S)-3-fluoro-1-(4-((5-isopropyl-8- (3-((((S)-methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-3-methyl Piperidin-4-ol (14.32 mg, 0.027 mmol, yield: 15.2%), LCMS m/z: 527[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.85(s, 1H), 9.06(s, 1H), 8.59(s, 1H), 7.98(d, J=5.6Hz, 1H), 7.41(d, J＝8.0Hz, 1H), 6.47(d, J＝5.2Hz, 1H), 6.41(d, J＝8.0Hz, 1H), 5.02(d, J＝6.4Hz, 1H), 4.78-4.67(m, 2H), 4.38(t, J=6.4Hz, 2H), 3.98(t, J=5.6Hz, 2H), 3.59-3.48(m, 2H), 3.25-3.06(m, 5H), 2.59(s, 3H ),1.74-1.73(m,2H),1.39-1.28(m,9H).

Example 64, (3S, 4R)-3-fluoro-1-(4-((5-isopropyl-8-((2R, 3S)-2-methyl-3-(((S)- Methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)piperidin-4-ol or 3S,4R)-3-fluoro -1-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-(((R)-methylsulfinyl)methyl)azetidine Synthesis of -1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)piperidin-4-ol (Compound 64)

1), the synthesis of (R, 3S)-1-benzhydryl-2-methylazetidin-3-yl methanesulfonate

At 0°C, to a solution of (2R,3S)-1-benzhydryl-2-methylazetidin-3-ol (5.00g, 19.76mmol) in dichloromethane (50mL) Triethylamine (3.99g, 39.52 g) and methanesulfonyl chloride (4.54 g, 39.52 mmol) were successively added to the mixture, and after the addition was complete, the resulting reaction solution continued to react at 0° C. for 1 hour. After the reaction was completed, the reaction solution was added into a saturated aqueous solution of sodium bicarbonate (80 mL) to quench the reaction, and extracted with dichloromethane (100 mL×2). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/1) to obtain yellow oily compound (2R,3S)-1-benzhydryl-2-methylazetidin-3-yl Mesylate (4.70g, 14.20mmol, yield: 71.8%), LCMS m/z: 332[M+H] ⁺

2), the synthesis of (2R, 3S)-1-benzhydryl-2-methylazetidine-3-carbonitrile

At room temperature, to N,N-bis(2R,3S)-1-benzhydryl-2-methylazetidin-3-yl methanesulfonate (4.70g, 14.20mmol) Sodium cyanide (3.48 g, 71.00 mmol) was added to the solution of methylformamide (50 mL). After the addition was completed, the temperature of the obtained reaction solution was raised to 100° C. for 16 hours. After the reaction was completed, the reaction solution was diluted with water (100 mL), and extracted with dichloromethane (100 mL×2). The combined organic phases were successively washed with saturated brine (60 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=4/1) to obtain yellow oily compound (2R,3S)-1-benzhydryl-2-methylazetidine-3-carbonitrile ( 2.10g, 8.02mmol, yield: 56.4%), LCMS m/z: 263[M+H] ⁺ .

3), the synthesis of (2R, 3S)-1-benzhydryl-2-methylazetidine-3-carboxylic acid

At room temperature, to dissolve (2R,3S)-1-benzhydryl-2-methylazetidine-3-carbonitrile (2.00g, 7.63mmol) in ethanol (30mL) and water (10mL) Potassium hydroxide (1.28g, 22.89mmol) was added to the mixed solution. After the addition was completed, the temperature of the obtained reaction solution was raised to 80° C. for 16 hours. After the reaction was completed, the pH of the reaction solution was adjusted to 5-6 with hydrochloric acid (30%) aqueous solution. After adjusting the pH, the resulting reaction solution was directly concentrated to remove the solvent to obtain (2R, 3S)-1-benzhydryl-2-methylazetidine-3-carboxylic acid (2.50 g, crude product) as yellow oil, LCMS m/z:282[M+H] ⁺ .

4), the synthesis of ((2R, 3S)-1-benzhydryl-2-methylazetidin-3-yl)methanol

At room temperature, tetrahydrofuran (30 mL) in which (2R, 3S)-1-benzhydryl-2-methylazetidine-3-carboxylic acid (2.50 g, 8.90 mmol) was dissolved was added tetrahydro Lithium aluminum (1.69 g, 44.50 mmol). After the addition was complete, the resulting reaction solution was reacted at room temperature for 16 hours. After the reaction was completed, methanol (50 mL) was added to the reaction solution to quench the reaction, and then concentrated to remove the solvent to obtain a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=4/1) to obtain a white solid compound ((2R,3S)-1-benzhydryl-2-methylazetidin-3-yl ) methanol (1.60 g, 5.99 mmol, yield: 67.3%), LCMS m/z: 268 [M+H] ⁺ .

5) Synthesis of ((2R, 3S)-2-methylazetidin-3-yl)methanol 2,2,2-trifluoroacetate

At room temperature, into a solution of (2R,3S)-1-benzhydryl-2-methylazetidin-3-yl)methanol (1.60g, 5.99mmol) in methanol (20mL) , palladium on carbon (800 mg, purity 10%, water content 55%) and 2,2,2-trifluoroacetic acid (2 mL) were added. After the addition was complete, the resulting reaction liquid was replaced by hydrogen three times, and then reacted under a hydrogen atmosphere for 16 hours. After the reaction was completed, the reaction solution was filtered through diatomaceous earth, the filter cake was washed with methanol (50 mL×3), and the filtrate was collected. The filtrate was concentrated to remove the solvent to obtain a residue. The residue is passed through reverse phase flash chromatography (chromatographic conditions: column: spherical C18, 20-40um, 120g; Mobile phase A: water containing 0.1% formic acid; Mobile phase B: acetonitrile; Flow velocity: 80mL/min; Gradient: at 20 0%B-15%B in minutes; detector: 214nm) purification, when the mobile phase B reached 5%, the fractions containing the product were collected, then concentrated to remove the solvent to obtain a brown oily compound ((2R, 3S)-2-formazan (3-ylazetidin-3-yl)methanol 2,2,2-trifluoroacetate (1.40 g, crude product), LCMS m/z: 102 [M+H] ⁺ .

6) Synthesis of ((2R, 3S)-1-(3-chloro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)methanol

At room temperature, to dioxane dissolved in (2R,3S)-2-methylazetidin-3-yl)methanol 2,2,2-trifluoroacetate (1.35g, 6.28mmol) Ring (20mL) solution, sequentially added cesium carbonate (6.14g, 18.84mmol), methanesulfonic acid (4,5-bisdiphenylphosphine-9,9-dimethylxanthene) (2'-methylamine (1,1'-biphenyl-2-yl)palladium(II) (502 mg, 0.31 mmol) and 8-bromo-3-chloro-5-isopropylisoquinoline (1.79 g, 6.28 mmol). After the addition was complete, the temperature of the reaction solution was raised to 100° C. under the protection of nitrogen, and stirred for 2 hours. After the reaction was completed, the reaction solution was concentrated to remove the solvent to obtain a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to obtain yellow oily compound ((2R,3S)-1-(3-chloro-5-isopropylisoquinolin-8-yl) -2-methylazetidin-3-yl)methanol (800 mg, 2.62 mmol, yield: 41.7%), LCMS m/z: 305[M+H] ⁺ .

7), ((2R,3S)-1-(3-chloro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)methylsulfonate

At 0°C, (2R,3S)-1-(3-chloro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl) To methanol (800 mg, 2.62 mmol) in dichloromethane (10 mL), triethylamine (529 mg, 5.24 mmol) and methanesulfonyl chloride (603 mg, 5.24 mmol) were added. After the addition was complete, the resulting reaction was continued at 0°C for 1 hour. After the reaction was completed, the reaction solution was poured into saturated aqueous sodium bicarbonate (50 mL), and extracted with dichloromethane (100 mL×2). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to obtain yellow oily compound ((2R,3S)-1-(3-chloro-5-isopropylisoquinolin-8-yl) -Methyl 2-methylazetidin-3-yl)methanesulfonate (800 mg, 2.09 mmol, yield: 79.6%), LCMS m/z: 383[M+H] ⁺ .

8), 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylthio)methyl)azetidin-1-yl)isoquine Synthesis of morphine

At room temperature, ((2R,3S)-1-(3-chloro-5-isopropylisoquinolin-8-yl)-2-methylazetidin-3-yl)methanol To a mixed solution of methyl sulfonate (800 mg, 2.09 mmol) in acetonitrile (10 mL) and water (20 mL), was added sodium methylthiolate (585 mg, 4.18 mmol). After the addition was completed, the temperature of the obtained reaction solution was raised to 70° C. for 16 hours. After the reaction was completed, the reaction solution was concentrated to remove the solvent to obtain a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/1) to obtain yellow oily compound 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-( (Methylthio)methyl)azetidin-1-yl)isoquinoline (650 mg, 1.94 mmol, yield: 92.8%), LCMS m/z: 335 [M+H] ⁺ .

9), 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfinyl)methyl)azetidin-1-yl) Synthesis of isoquinoline

At 0°C, 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylthio)methyl)azetidine- To a solution of 1-yl)isoquinoline (600mg, 1.79mmol) in dichloromethane (10mL), m-chloroperoxybenzoic acid (279mg, 1.61mmol) was added. After the addition was complete, the reaction was continued at 0°C for 1 hour. After the reaction was completed, the reaction solution was added to a saturated aqueous solution of sodium bisulfite (20 mL), the reaction was quenched, and extracted with dichloromethane (20 mL×3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain The residue. The residue was purified by silica gel column chromatography (dichloromethane/methanol=12/1) to obtain yellow oily compound 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-(( Methylsulfinyl)methyl)azetidin-1-yl)isoquinoline (500mg, 1.42mmol, yield: 79.5%), LCMS: m/z: 351[M+H] ⁺ .

10), 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-(((S)-methylsulfinyl)methyl)azetidine- 1-yl)isoquinoline and 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-(((R)-methylsulfinyl)methyl)nitrogen Synthesis of Heterocyclobutan-1-yl)isoquinoline

Compound 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfinyl)methyl)azetidin-1-yl)iso Quinoline (500mg, 1.42mmol) is passed through supercritical fluid chromatography (chromatographic conditions: system: Waters SFC 80; Column:

250*25mm 10μm; mobile phase A: Supercritical CO2; mobile phase B: methanol containing 0.1% ammonia/methanol (7M); detection wavelength: 214nm; flow rate: 70mL/min) preparation, separation and purification to obtain two isomers:

Peak 1: 2.995min; 3-Chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-(((S)-methylsulfinyl)methyl)azacycle Butane-1-yl)isoquinoline or 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-(((R)-methylsulfinyl)methyl yl)azetidin-1-yl)isoquinoline (240mg, 0.68mmol, yield: 48.0%).

Peak 2: 3.739min; 3-Chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-(((R)-methylsulfinyl)methyl)azacycle Butane-1-yl)isoquinoline or 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-(((S)-methylsulfinyl)methyl yl)azetidin-1-yl)isoquinoline (240mg, 0.68mmol, yield: 48.0%)

11), (3S, 4R)-3-fluoro-1-(4-((5-isopropyl-8-((2R, 3S)-2-methyl-3-(((S)-methyl Sulfinyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)piperidin-4-ol or 3S,4R)-3-fluoro-1 -(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-(((R)-methylsulfinyl)methyl)azetidine-1 Synthesis of -yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)piperidin-4-ol (compound 64)

At room temperature, 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-(((S)-methylsulfinyl)methyl)azepine was dissolved in Cyclobutan-1-yl)isoquinoline or 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-(((R)-methylsulfinyl) To a solution of methyl)azetidin-1-yl)isoquinoline (40mg, 0.11mmol) in dioxane (5mL), sequentially add (3S, 4R)-1-(4-aminopyrimidine-2 -yl)-3-fluoropiperidin-4-ol (23mg, 0.11mmol), cesium carbonate (108mg, 0.33mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy- 2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)(5mg,0.0055mmol) . After the addition was complete, the reaction solution was heated up to 100° C. and reacted for 16 hours under the protection of nitrogen. After the reaction was completed, the reaction solution was concentrated to remove the solvent to obtain a residue. The residue was subjected to silica gel column chromatography (dichloromethane/methanol=12/1) to obtain a crude product. The crude product was passed through reaction flash chromatography (chromatographic conditions: column: spherical C18, 20-40um, 40g; mobile phase A: water containing 0.1% NH ₃ .H ₂ O; mobile phase B: acetonitrile; flow rate: 40mL/min ; Gradient: 35% B-50% B in 15 minutes; Detector: 254 nm.) Purification. When the mobile phase B reached 37%, the fractions containing the product were collected and then concentrated under reduced pressure to obtain (3S, 4R)-3-fluoro-1-(4-((5-isopropyl-8-((2R, 3S )-2-methyl-3-(((S)-methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl) Piperidin-4-ol or 3S, 4R)-3-fluoro-1-(4-((5-isopropyl-8-((2R, 3S)-2-methyl-3-(((R) -Methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)piperidin-4-ol (14.57mg, 0.028mmol, Yield: 24.2%), LCMS m/z: 527[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.91(s, 1H), 9.06(s, 1H), 8.66(s, 1H), 7.99(d, J=5.6Hz, 1H), 7.42(d, J＝8.0Hz, 1H), 6.57(d, J＝8.0Hz, 1H), 6.45(d, J＝5.6Hz, 1H), 5.14(d, J＝5.2Hz, 1H), 4.76-4.58(m, 3H),4.40-4.37(m,1H),4.23-4.20(m,1H),3.91-3.83(m,1H),3.64-3.49(m,3H),3.39-3.36(m,1H),3.18- 3.12(m,1H),3.01-2.96(m,1H),2.90-2.85(m,1H),2.56(s,3H),1.76-1.72(m,2H),1.42(d,J＝6.0Hz, 3H), 1.30(d, J＝6.4Hz, 6H).

Example 65, (3S, 4R)-3-fluoro-1-(4-((5-isopropyl-8-((2R, 3S)-2-methyl-3-(((R)-methyl Sulfinyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)piperidin-4-ol or 3S,4R)-3-fluoro- 1-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-(((S)-methylsulfinyl)methyl)azetidine- Synthesis of 1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)piperidin-4-ol (Compound 65)

At room temperature, 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-(((R)-methylsulfinyl)methyl)azepine was dissolved in Cyclobutan-1-yl)isoquinoline or 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-(((S)-methylsulfinyl) To a solution of methyl)azetidin-1-yl)isoquinoline (40mg, 0.11mmol) in dioxane (5mL), sequentially add (3S, 4R)-1-(4-aminopyrimidine-2 -yl)-3-fluoropiperidin-4-ol (23mg, 0.11mmol), cesium carbonate (108mg, 0.33mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy- 2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)(5mg,0.0055mmol) . After the addition was complete, the reaction solution was heated up to 100° C. and reacted for 16 hours under the protection of nitrogen. After the reaction was completed, the reaction solution was concentrated to remove the solvent to obtain a residue. The residue was subjected to silica gel column chromatography (dichloromethane/methanol=12/1) to obtain a crude product. The crude product was passed through reaction flash chromatography (chromatographic conditions: column: spherical C18, 20-40um, 40g; mobile phase A: water containing 0.1% NH ₃ .H ₂ O; mobile phase B: acetonitrile; flow rate: 40mL/min ; Gradient: 35% B-50% B in 15 minutes; Detector: 254 nm.) Purification. When the mobile phase B reached 35%, the fractions containing the product were collected and then concentrated under reduced pressure to obtain (3S, 4R)-3-fluoro-1-(4-((5-isopropyl-8-((2R, 3S )-2-methyl-3-(((R)-methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl) Piperidin-4-ol or (3S, 4R)-3-fluoro-1-(4-((5-isopropyl-8-((2R, 3S)-2-methyl-3-(((S )-methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)piperidin-4-ol (compound 65) (26.80mg , 0.051 mmol, yield: 44.6%). LCMS m/z: 527[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.92(s, 1H), 9.06(s, 1H), 8.66(s, 1H), 7.98(d, J=5.6Hz, 1H), 7.42(d, J＝8.0Hz, 1H), 6.56(d, J＝8.0Hz, 1H), 6.44(d, J＝5.6Hz, 1H), 5.14(d, J＝4.8Hz, 1H), 4.76-4.58(m, 3H),4.40-4.36(m,1H),4.23-4.20(m,1H),3.91-3.83(m,1H),3.64-3.49(m,3H),3.39-3.35(m,1H),3.14- 3.03(m,2H),2.84-2.79(m,1H),2.57(s,3H),1.73-1.72(m,2H),1.41(d,J＝6.0Hz,3H),1.30(d,J＝ 6.0Hz,6H).

Example 66, (3S,4R)-3-fluoro-1-(4-(5-isopropyl-8-(3-(S)-methylsulfinyl)methyl)azetidine- 1-yl) isoquinolin-3-yl) amino) pyrimidin-2-yl) piperidin-4-ol or (3S, 4R)-3-fluoro-1-(4-(5-isopropyl-8 -(3-(R)-methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)piperidin-4-ol ( Compound 66) Synthesis

At room temperature, (S)-3-chloro-5-isopropyl-8-(3-((methylsulfinyl)methyl)azetidin-1-yl)isoquinoline Or (R)-3-chloro-5-isopropyl-8-(3-((methylsulfinyl)methyl)azetidin-1-yl)isoquinoline (60mg, 0.17mmol) (3S, 4R)-1-(4-aminopyrimidin-2-yl)-3-fluoropiperidin-4-ol (36mg, 0.17mmol), cesium carbonate (167mg, 0.51mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-Amino-1,1'-biphenyl-2-yl)palladium(II) (16mg, 0.017mmol), the addition was completed, and the reaction solution was heated at 100°C for 16 hours under the protection of nitrogen. After the reaction was completed, the reaction solution was concentrated to remove the solvent to obtain a residue. The residue was purified by silica gel column chromatography (dichloromethane/methanol=15/1) to obtain a crude product. The crude product was passed through the reverse phase flash chromatography (chromatographic conditions: column: spherical C18, 20-40um, 80g; mobile phase A: pure water containing 0.1% NH ₃ H ₂ O; mobile phase B: acetonitrile; flow rate: 80mL/ min; Gradient: 5% B-30% B in 20 minutes; Detector: 254nm) purify, when mobile phase B content reaches 20%, collect the cut that contains product, then concentrate and remove solvent to obtain yellow solid compound (3S, 4R)-3-fluoro-1-(4-(5-isopropyl-8-(3-(S)-methylsulfinyl)methyl)azetidin-1-yl)isoquinoline -3-yl)amino)pyrimidin-2-yl)piperidin-4-ol or (3S,4R)-3-fluoro-1-(4-(5-isopropyl-8-(3-(R) -Methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)piperidin-4-ol (31.77mg, 0.062mmol, Yield: 36.4%), LCMS m/z: 513[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.89(s, 1H), 9.05(s, 1H), 8.64(s, 1H), 7.99(d, J=5.6Hz, 1H), 7.41(d, J＝8.4Hz, 1H), 6.46(d, J＝5.6Hz, 1H), 6.41(d, J＝8.0Hz, 1H), 5.14(d, J＝5.2Hz, 1H), 4.74-4.59(m, 2H), 4.38(t, J=7.2Hz, 3H), 3.97(t, J=6.4Hz, 2H), 3.91-3.83(m, 1H), 3.61-3.48(m, 2H), 3.38-3.35(m ,1H),3.25-3.20(m,2H),3.13-3.09(m,1H),2.60(s,3H),1.73-1.72(m,2H),1.31-1.28(m,6H).

Example 67, (3S,4R)-3-fluoro-1-(4-(5-isopropyl-8-(3-(R)-methylsulfinyl)methyl)azetidine- 1-yl) isoquinolin-3-yl) amino) pyrimidin-2-yl) piperidin-4-ol or (3S, 4R)-3-fluoro-1-(4-(5-isopropyl-8 -(3-(S)-methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)piperidin-4-ol ( Compound 67) Synthesis

At room temperature, (R)-3-chloro-5-isopropyl-8-(3-((methylsulfinyl)methyl)azetidin-1-yl)isoquinoline Or (S)-3-chloro-5-isopropyl-8-(3-((methylsulfinyl)methyl)azetidin-1-yl)isoquinoline (60mg, 0.17mmol) (3S, 4R)-1-(4-aminopyrimidin-2-yl)-3-fluoropiperidin-4-ol (36mg, 0.17mmol), cesium carbonate (167mg, 0.51mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-Amino-1,1'-biphenyl-2-yl)palladium(II) (16 mg, 0.017 mmol). After the addition was complete, the reaction liquid was heated up to 100° C. for 16 hours under the protection of nitrogen. The reaction is over. The reaction solution was concentrated to remove the solvent to obtain a residue. The residue was first purified by silica gel column chromatography (dichloromethane/methanol=15/1) to obtain a crude product. The crude product was passed through reverse phase flash chromatography again (chromatographic conditions: column: spherical C18, 20-40um, 80g; mobile phase A: water containing 0.1% NH ₃ .H ₂ O); mobile phase B: acetonitrile; flow rate: 80mL /min; Gradient: 5% B-30% B in 20 minutes; Detector: 254nm) purify, when mobile phase B reaches 20%, collect the cut that contains product, then concentrate and remove solvent to obtain yellow solid compound (3S, 4R)-3-fluoro-1-(4-(5-isopropyl-8-(3-(R)-methylsulfinyl)methyl)azetidin-1-yl)isoquinoline -3-yl)amino)pyrimidin-2-yl)piperidin-4-ol or (3S,4R)-3-fluoro-1-(4-(5-isopropyl-8-(3-(S) -Methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)piperidin-4-ol (19.60mg, 0.038mmol, Efficiency: 22.4%).LCMS m/z: 513[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ )δ9.89(s, 1H), 9.06(s, 1H), 8.64(s, 1H), 7.99(d, J=5.6Hz, 1H), 7.41(d, J＝8.0Hz, 1H), 6.46(d, J＝5.6Hz, 1H), 6.41(d, J＝8.0Hz, 1H), 5.14(d, J＝4.8Hz, 1H), 4.75-4.57(m, 2H), 4.38(t, J=7.2Hz, 3H), 3.97(t, J=5.2Hz, 2H), 3.90-3.83(m, 1H), 3.61-3.46(m, 2H), 3.39-3.36(s ,1H),3.26-3.17(m,2H),3.13-3.06(m,1H),2.60(s,3H),1.73-1.72(m,2H),1.31-1.28(m,6H).

Example 68, (3R,4S)-3-fluoro-1-(4-((5-isopropyl-8-(3-((((S)-methylsulfinyl)methyl)azepine Cyclobutan-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)piperidin-4-ol or (3R,4S)-3-fluoro-1-(4-((5- Isopropyl-8-(3-((((R)-methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl ) Synthesis of piperidin-4-ol (compound 68)

At room temperature, (S)-3-chloro-5-isopropyl-8-(3-((methylsulfinyl)methyl)azetidin-1-yl)isoquinoline or (R)-3-chloro-5-isopropyl-8-(3-((methylsulfinyl)methyl)azetidin-1-yl)isoquinoline (60mg, 0.17mmol) (3R, 4S)-1-(4-aminopyrimidin-2-yl)-3-fluoropiperidin-4-ol ( 36mg, 0.17mmol), cesium carbonate (167mg, 0.51mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl- 1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (16 mg, 0.017 mmol). After the addition was complete, the reaction solution was heated to 100° C. and stirred for 16 hours under the protection of nitrogen. After the reaction was completed, the reaction solution was concentrated to remove the solvent to obtain a residue. The residue was subjected to silica gel column chromatography (dichloromethane/methanol=15/1) to obtain a crude product. The crude product was passed through reaction flash chromatography (chromatographic conditions: column: spherical C18, 20-40um, 80g; mobile phase A: water containing 0.1% NH ₃ .H ₂ O; mobile phase B: acetonitrile; flow rate: 80mL/min ; Gradient: 5% B-30% B in 20 minutes; Detector: 254 nm.) Purification. When the mobile phase B reached 35%, the fractions containing the product were collected and then concentrated under reduced pressure to obtain (3R, 4S)-3-fluoro-1-(4-((5-isopropyl-8-(3-(( ((S)-methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)piperidin-4-ol or (3R, 4S)-3-fluoro-1-(4-((5-isopropyl-8-(3-((((R)-methylsulfinyl)methyl)azetidin-1-yl )isoquinolin-3-yl)amino)pyrimidin-2-yl)piperidin-4-ol (29.13 mg, 0.057 mmol, yield: 33.4%), LCMS m/z: 513[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.88(s, 1H), 9.06(s, 1H), 8.64(s, 1H), 7.99(d, J=5.6Hz, 1H), 7.41(d, J＝8.0Hz, 1H), 6.46(d, J＝5.6Hz, 1H), 6.41(d, J＝8.0Hz, 1H), 5.14(d, J＝5.2Hz, 1H), 4.76-4.57(m, 2H), 4.38(t, J=7.2Hz, 3H), 3.98(t, J=5.6Hz, 2H), 3.93-3.82(m, 1H), 3.62-3.46(m, 2H), 3.39-3.36(m ,1H),3.25-3.19(m,2H),3.13-3.06(m,1H),2.60(s,3H),1.78-1.68(m,2H),1.31-1.28(m,6H).

Example 69, (3R,4S)-3-fluoro-1-(4-((5-isopropyl-8-(3-((((R)-methylsulfinyl)methyl)azepine Cyclobutan-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)piperidin-4-ol or (3R,4S)-3-fluoro-1-(4-((5- Isopropyl-8-(3-((((S)-methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl ) Synthesis of piperidin-4-ol (compound 69)

At room temperature, (R)-3-chloro-5-isopropyl-8-(3-((methylsulfinyl)methyl)azetidin-1-yl)isoquinoline or (S)-3-chloro-5-isopropyl-8-(3-((methylsulfinyl)methyl)azetidin-1-yl)isoquinoline (60mg, 0.17mmol) (3R, 4S)-1-(4-aminopyrimidin-2-yl)-3-fluoropiperidin-4-ol ( 36mg, 0.17mmol), cesium carbonate (167mg, 0.51mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl- 1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (16 mg, 0.017 mmol). After the addition was complete, the reaction solution was heated up to 100° C. and reacted for 16 hours under the protection of nitrogen. After the reaction was completed, the reaction solution was concentrated to remove the solvent to obtain a residue. The residue was subjected to silica gel column chromatography (dichloromethane/methanol=15/1) to obtain a crude product. The crude product was passed through reaction flash chromatography (chromatographic conditions: column: spherical C18, 20-40um, 80g; mobile phase A: water containing 0.1% NH ₃ .H ₂ O; mobile phase B: acetonitrile; flow rate: 80mL/min ; Gradient: 5% B-30% B in 20 minutes; Detector: 254 nm.) Purification. When the mobile phase B reached 20%, the fractions containing the product were collected, then concentrated to remove the solvent to obtain a yellow solid compound (3R, 4S)-3-fluoro-1-(4-((5-isopropyl-8-(3 -((((R)-methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)piperidin-4-ol or (3R,4S)-3-fluoro-1-(4-((5-isopropyl-8-(3-((((S)-methylsulfinyl)methyl)azetidine- 1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)piperidin-4-ol (34.95mg, 0.068mmol, yield: 40.0%), LCMS m/z: 513 [M+H ] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.89(s, 1H), 9.06(s, 1H), 8.64(s, 1H), 7.99(d, J=5.6Hz, 1H), 7.41(d, J＝8.0Hz, 1H), 6.46(d, J＝5.6Hz, 1H), 6.41(d, J＝8.0Hz, 1H), 5.14(d, J＝5.2Hz, 1H), 4.76-4.57(m, 2H), 4.38(t, J=7.6Hz, 3H), 3.97(t, J=5.6Hz, 2H), 3.93-3.82(m, 1H), 3.62-3.46(m, 2H), 3.39-3.35(m ,1H),3.25-3.19(m,2H),3.13-3.06(m,1H),2.60(s,3H),1.76-1.72(m,2H),1.31-1.28(m,6H).

Example 70, N-(2-((3S,4R)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl- 8-((2R,3S)-2-methyl-3-((S)-methylsulfinyl)methyl)azacyclo-1-ylisoquinolin-3-amine or N-(2- ((3S, 4R)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)- Synthesis of 2-methyl-3-((R)-methylsulfinyl)methyl)azacyclo-1-ylisoquinolin-3-amine (compound 70)

At room temperature, (3S,4R)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-amine (26mg, 0.11mmol,) was dissolved in dioxane Cyclo(10mL) solution, add 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-((((S)-methylsulfinyl)methyl) Azacyclo-1-ylisoquinoline or 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-((((R)-methylsulfinyl) Methyl)azacyclo-1-ylisoquinoline (40mg, 0.11mmol), cesium carbonate (108mg, 0.33mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy- 2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (5mg, 0.006mmol) After the addition, the resulting mixture was heated to 100° C. under nitrogen protection and stirred for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane/methanol=15/1) to obtain a crude product. Thick product is passed through reverse phase flash chromatography (chromatographic condition: column: spherical C18, 20-40um, 40g; Mobile phase A: the water that contains 0.1% ammoniacal liquor; Mobile phase B: acetonitrile; Flow rate: 40mL/min; Gradient: at 20 40% B-95% B in minutes; detection wavelength: 254nm) further purification, when the content of mobile phase B reaches 67%, the fraction containing the product is collected and concentrated under reduced pressure to obtain N-(2-((3S, 4R)- 3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3- ((S)-Methylsulfinyl)methyl)azacyclo-1-ylisoquinolin-3-amine or N-(2-((3S,4R)-3-fluoro-4-methoxy -3-methylpiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((R)-methylsulfinic acid Acyl)methyl)azacyclo-1-ylisoquinolin-3-amine (2.15 mg, 0.0039 mmol, yield: 3.5%), LCMS m/z: 555 [M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ9.11(s, 1H), 8.60(s, 1H), 7.95(d, J=5.6Hz, 1H), 7.47(d, J=8.0Hz, 1H), 6.65(d,J=8.0Hz,1H),6.37(d,J=6.0Hz,1H),4.67-4.56(m,3H),4.32-4.28(m,1H),3.63-3.59(m,2H) ,3.49(s,3H),3.44-3.38(m,2H),3.37-3.36(m,1H),3.15(d,J=7.6Hz,2H),2.95-2.92(m,1H),2.69(s ,3H),2.03-1.99(m,1H),1.84-1.82(m,1H),1.47-1.35(m,12H).

Example 71, N-(2-((3S,4R)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl- 8-((2R,3S)-2-methyl-3-((R)-methylsulfinyl)methyl)azacyclo-1-ylisoquinolin-3-amine or N-(2- ((3S, 4R)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)- Synthesis of 2-methyl-3-((S)-methylsulfinyl)methyl)azacyclo-1-ylisoquinolin-3-amine (Compound 71)

At room temperature, (3S,4R)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-amine (26mg, 0.11mmol, 1.0mmol) was dissolved in di Oxycycline (10mL) solution, add 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-((((R)-methylsulfinyl)methanol base) azacyclo-1-ylisoquinoline or 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-((((S)-methylsulfin Acyl)methyl)azacyclo-1-ylisoquinoline (40 mg, 0.011 mmol), cesium carbonate (108 mg, 0.33 mmol) and (2-dicyclohexylphosphine)-3,6-dimethoxymethanesulfonate Diphenyl-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (5mg, 0.006 mmol). After the addition, the resulting mixture was heated to 100° C. under nitrogen protection and stirred for 16 hours. The reaction was completed, and the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane/methanol=15/1) to obtain crude Product. Thick product is passed through reverse phase flash chromatography (chromatographic condition: column: spherical C18, 20-40um, 40g; Mobile phase A: the water that contains 0.1% ammoniacal liquor; Mobile phase B: acetonitrile; Flow rate: 40mL/min; Gradient: Within 20 minutes, 40% B-95% B; detection wavelength: 254nm) was further purified, and when the mobile phase B content reached 63%, the fraction containing the product was collected and concentrated under reduced pressure to obtain N-(2-((3S, 4R )-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl- 3-((R)-methylsulfinyl)methyl)azacyclo-1-ylisoquinolin-3-amine or N-(2-((3S,4R)-3-fluoro-4-methyl Oxy-3-methylpiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((S)-methyl Sulfinyl)methyl)azacyclo-1-ylisoquinolin-3-amine (12.96 mg, 0.023 mmol, yield: 21.6%), LCMS m/z: 555[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.89(s, 1H), 9.06(s, 1H), 8.58(s, 1H), 7.99(d, J=5.6Hz, 1H), 7.42(d, J＝8.0Hz, 1H), 6.56(d, J＝8.0Hz, 1H), 6.47(d, J＝5.6Hz, 1H), 4.71-4.63(m, 3H), 4.24-4.21(m, 1H), 3.62(t,J=6.8Hz,1H),3.52-3.49(m,1H),3.42-3.34(m,4H),3.29-3.22(m,2H),3.19-3.03(m,2H),2.85- 2.81(m,1H),2.57(s,3H),1.99-1.95(m,1H),1.65-1.62(m,1H),1.42-1.29(m,12H).

Example 72, (3S,4R)-3-fluoro-1-(4-((5-isopropyl-8-(3-(((R)-isopropylsulfinyl)methyl)azepine Cyclobutan-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-ol or (3S,4R)-3-fluoro-1-(4 -((5-isopropyl-8-(3-(((S)-isopropylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino) Synthesis of pyrimidin-2-yl)-3-methylpiperidin-4-ol (compound 72)

At room temperature, the solution of (R)-3-chloro-5-isopropyl-8-(3-((isopropylsulfoxide)methyl)azetidin-1-yl)iso Quinoline or (S)-3-chloro-5-isopropyl-8-(3-((isopropylsulfoxide)methyl)azetidin-1-yl)isoquinoline (70mg, 0.19mmol) dioxane solution (10mL), add (3S, 4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (43mg , 0.19mmol), cesium carbonate (186mg, 0.57mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1 ,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (8mg, 0.009mmol), the addition was completed, and the resulting reaction solution was heated to 100°C under nitrogen protection , stirred for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to the residue. The residue was purified by silica gel column chromatography (dichloromethane/methanol=15/1) to obtain a crude product. Thick product is passed through reverse phase flash chromatography (chromatographic condition: column: spherical C18, 20-40um, 40g; Mobile phase A: the water that contains 0.1% ammoniacal liquor; Mobile phase B: acetonitrile; Flow rate: 40mL/min; Gradient: 20 minutes 40%B-95%B; detector: 254nm) for further purification, when the content of the mobile phase reached 45%B, the fractions containing the product were collected and concentrated under reduced pressure to obtain (3S, 4R)-3-fluoro-1-(4 -((5-isopropyl-8-(3-(((R)-isopropylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino) Pyrimidin-2-yl)-3-methylpiperidin-4-ol or (3S,4R)-3-fluoro-1-(4-((5-isopropyl-8-(3-(((S )-isopropylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-ol ( Compound 72) (9.63 mg, 0.017 mmol, yield: 9.0%), LCMS m/z: 555[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.85(s, 1H), 9.06(s, 1H), 8.60(s, 1H), 7.98(d, J=5.6Hz, 1H), 7.41(d, J＝8.0Hz, 1H), 6.47(d, J＝5.6Hz, 1H), 6.40(d, J＝8.0Hz, 1H), 5.02(d, J＝6.4Hz, 1H), 4.75-4.72(m, 2H), 4.38(t, J=7.2Hz, 2H), 3.98(t, J=5.6Hz, 2H), 3.53-3.48(m, 2H), 3.21-3.10(m, 4H), 3.02-2.99(m ,1H),2.88-2.85(m,1H),1.74-1.73(m,2H),1.39-1.28(m,9H),1.19(d,J＝6.8Hz,6H).

Example 73, (3S,4R)-3-fluoro-1-(4-((5-isopropyl-8-(3-(((S)-isopropylsulfinyl)methyl)azepine Cyclobutan-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-ol or (3S,4R)-3-fluoro-1-(4 -((5-isopropyl-8-(3-(((R)-isopropylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino) Synthesis of pyrimidin-2-yl)-3-methylpiperidin-4-ol (compound 74)

At room temperature, to the solution of (S)-3-chloro-5-isopropyl-8-(3-((isopropylsulfoxide)methyl)azetidin-1-yl)iso Quinoline or (R)-3-chloro-5-isopropyl-8-(3-((isopropylsulfoxide)methyl)azetidin-1-yl)isoquinoline (70mg, 0.19mmol) dioxane solution (10mL), add (3S, 4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (43mg , 0.19mmol), cesium carbonate (186mg, 0.57mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1 ,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (8 mg, 0.009 mmol). After the addition was complete, the resulting reaction solution was heated up to 100° C. and stirred for 16 hours under the protection of nitrogen. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=15/1) to obtain a crude product. Thick product is passed through reverse phase flash chromatography (chromatographic condition: column: spherical C18, 20-40um, 40g; Mobile phase A: the water that contains 0.1% ammoniacal liquor; Mobile phase B: acetonitrile; Flow rate: 40mL/min; Gradient: 20 minutes 30%B-80%B; detection wavelength: 254nm) for further purification, when the content of the mobile phase reached 40%B, the fraction containing the product was collected and concentrated under reduced pressure to obtain (3S, 4R)-3-fluoro-1-(4 -((5-isopropyl-8-(3-(((S)-isopropylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino) Pyrimidin-2-yl)-3-methylpiperidin-4-ol or (3S,4R)-3-fluoro-1-(4-((5-isopropyl-8-(3-(((R )-isopropylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-ol ( 4.15 mg, 0.007 mmol, yield: 3.8%), LCMS m/z: 555 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.85(s, 1H), 9.06(s, 1H), 8.59(s, 1H), 7.98(d, J=5.6Hz, 1H), 7.41(d, J＝8.0Hz, 1H), 6.46(d, J＝6.0Hz, 1H), 6.41(d, J＝8.4Hz, 1H), 5.02(d, J＝6.4Hz, 1H), 4.75-4.72(m, 2H), 4.40-3.36(m, 2H), 3.98(t, J=5.6Hz, 2H), 3.53-3.48(m, 2H), 3.23-3.19(m, 1H), 3.17-3.10(m, 3H) ,3.02-2.97(m,1H),2.88-2.85(m,1H),1.75-1.73(m,2H),1.39-1.28(m,9H),1.19(d,J＝6.8Hz,6H).

Example 74, (3R,4S)-3-fluoro-1-(4-((5-isopropyl-8-(3-((((R)-isopropylsulfoxide)methyl)nitrogen Heterobutan-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-ol or (3R,4S)-3-fluoro-1-( 4-((5-isopropyl-8-(3-((((S)-isopropylsulfoxide)methyl)azetidin-1-yl)isoquinolin-3-yl) Synthesis of Amino)pyrimidin-2-yl)-3-methylpiperidin-4-ol (Compound 74)

At room temperature, (3R,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol) (30mg, 0.13mmol) was dissolved in Ring (10mL) solution, followed by (R)-3-chloro-5-isopropyl-8-(3-(((isopropylsulfonylsulfoxide)methyl)azacyclo-1-yl)isopropyl Quinoline or (S)-3-chloro-5-isopropyl-8-(3-(((isopropylsulfonylsulfoxide)methyl)azacyclo-1-yl)isoquinoline (47mg, 0.13mmol), cesium carbonate (127mg, 0.39mmol), and (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1 methanesulfonate ,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium (II) (6mg, 0.007mmol). After the addition, the resulting reaction solution was heated to 100°C under nitrogen protection Down, stirred for 16 hours.Reaction finished, reaction solution was reduced and concentrated and purified by silica gel column chromatography (methylene chloride/methanol=15/1) to obtain crude product, and crude product was passed through reverse phase flash chromatography (chromatographic condition: column: spherical C18, 20-40um, 40g; mobile phase A: water containing 0.1% ammonia; mobile phase B: acetonitrile; flow rate: 40mL/min; gradient: 40% B-95% B within 20 minutes; detector: 254nm) For further purification, when the mobile phase B content reached 45% B, the fractions containing the product were collected and concentrated under reduced pressure to obtain (3R, 4S)-3-fluoro-1-(4-((5-isopropyl-8-( 3-((((R)-isopropylsulfoxide)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-3-methyl Piperidin-4-ol or (3R,4S)-3-fluoro-1-(4-((5-isopropyl-8-(3-((((S)-isopropylsulfoxide)methanol Base) azetidin-1-yl) isoquinolin-3-yl) amino) pyrimidin-2-yl)-3-methylpiperidin-4-ol (23.81mg, 0.043mmol, yield: 32.6 %), LCMS m/z: 555. [M+H] ⁺ :

¹ H NMR (400MHz, DMSO-d ₆ )δ9.84(s, 1H), 9.06(s, 1H), 8.59(s, 1H), 7.98(d, J=5.6Hz, 1H), 7.41(d, J＝8.0Hz, 1H), 6.47(d, J＝5.6Hz, 1H), 6.40(d, J＝8.0Hz, 1H), 5.01(d, J＝6.4Hz, 1H), 4.75-4.67(m, 2H), 4.40-4.36(m, 2H), 3.98(t, J=5.6Hz, 2H), 3.53-3.48(m, 2H), 3.22-3.10(m, 4H), 3.02-2.97(m, 1H) , 2.88-2.85 (m, 1H), 1.74-1.73 (m, 2H), 1.39-1.29 (m, 9H), 1.19 (d, J=6.8Hz, 6H).

Example 75, (3R,4S)-3-fluoro-1-(4-((5-isopropyl-8-(3-((((S)-isopropylsulfoxide)methyl)nitrogen Heterobutan-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-ol or (3R,4S)-3-fluoro-1-( 4-((5-isopropyl-8-(3-((((R)-isopropylsulfoxide)methyl)azetidin-1-yl)isoquinolin-3-yl) Synthesis of Amino)pyrimidin-2-yl)-3-methylpiperidin-4-ol (Compound 75)

At room temperature, (3R,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol) (40mg, 0.18mmol) was dissolved in Ring (10mL) solution, followed by (S)-3-chloro-5-isopropyl-8-(3-(((isopropylsulfonylsulfoxide)methyl)azetidin-1-yl ) isoquinoline or (S)-3-chloro-5-isopropyl-8-(3-(((isopropylsulfonyl sulfoxide) methyl) azetidin-1-yl) isoquine phenoline (66 mg, 0.18 mmol), cesium carbonate (176 mg, 0.54 mmol), and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triiso Propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium (II) (8mg, 0.009mmol). After addition, the resulting reaction solution was under nitrogen protection , warming up to 100 ° C, stirred for 16 hours. The reaction was completed, and the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane/methanol=15/1) to obtain the crude product, and the crude product was passed through reverse phase flash chromatography (chromatographic conditions : Column: spherical C18, 20-40um, 40g; mobile phase A: water containing 0.1% ammonia; mobile phase B: acetonitrile; flow rate: 40mL/min; gradient: 40%B-95%B in 20 minutes; detector : 254nm) for further purification, when the content of mobile phase B reached 45% B, the fractions containing the product were collected and concentrated under reduced pressure to obtain (3R, 4S)-3-fluoro-1-(4-((5-isopropyl- 8-(3-((((S)-isopropylsulfoxide)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-3 -Methylpiperidin-4-ol or (3R,4S)-3-fluoro-1-(4-((5-isopropyl-8-(3-((((R)-isopropylsulfoxide yl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-ol (7.02mg, 0.013mmol, yield Efficiency: 7.1%), LCMS m/z: 555[M+H] ⁺ :

¹ H NMR (400MHz, DMSO-d ₆ )δ9.85(s, 1H), 9.06(s, 1H), 8.59(s, 1H), 7.98(d, J=5.6Hz, 1H), 7.41(d, J＝8.0Hz, 1H), 6.46(d, J＝5.6Hz, 1H), 6.41(d, J＝8.0Hz, 1H), 5.02(d, J＝6.4Hz, 1H), 4.75-4.67(m, 2H), 4.40-4.36(m, 2H), 3.98(t, J=5.6Hz, 2H), 3.53-3.48(m, 2H), 3.23-3.10(m, 4H), 3.02-2.97(m, 1H) ,2.88-2.85(m,1H),1.76-1.73(m,2H),1.39-1.28(m,9H),1.19(d,J＝6.8Hz,6H).

Example 76, (3S,4R)-1-(4-((8-(3-((((S)-(cyclopropylmethyl)sulfoxide)methyl)azetidine-1 -yl)-5-isopropylisoquinolin-3-yl)amino)pyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol or (3S,4R)-1-( 4-((8-(3-((((R)-(cyclopropylmethyl)sulfoxide)methyl)azetidin-1-yl)-5-isopropylisoquinoline- Synthesis of 3-yl)amino)pyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (Compound 76)

At room temperature, (S)-3-chloro-8-(3-(((cyclopropylmethyl)sulfoxide)methyl)azetidin-1-yl)-5-iso Propylisoquinoline or (R)-3-chloro-8-(3-(((cyclopropylmethyl)sulfoxide)methyl)azetidin-1-yl)-5 - To a solution of isopropylisoquinoline (50 mg, 0.13 mmol) in dioxane (7 mL) was added (3S, 4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3- Methylpiperidin-4-ol (29 mg, 0.13 mmol), cesium carbonate (127 mg, 0.39 mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium (II) (12mg, 0.013mmol), after addition, the obtained Under the protection of reaction liquid nitrogen, the temperature was raised to 100°C and stirred for 5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane/methanol=15/1) to obtain a crude product. The crude product was passed through reaction flash chromatography (chromatographic conditions: column: spherical C18, 20-40um, 80g; and mobile phase A: water containing 0.1% NH ₃ ·H ₂ O; mobile phase B: acetonitrile; flow rate: 80mL/ min; gradient: 5% B-30% B, within 20 minutes; detection wavelength: 254nm) purification, when the mobile phase B content reaches 20%, collect the fraction containing the product, then concentrate under reduced pressure to obtain (3S, 4R)- 1-(4-((8-(3-((((S)-(cyclopropylmethyl)sulfoxide)methyl)azetidin-1-yl)-5-isopropyliso Quinolin-3-yl)amino)pyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol or (3S,4R)-1-(4-((8-(3-( (((R)-(cyclopropylmethyl)sulfoxide)methyl)azetidin-1-yl)-5-isopropylisoquinolin-3-yl)amino)pyrimidine-2- yl)-3-fluoro-3-methylpiperidin-4-ol (18.51 mg, 0.033 mmol, yield: 24.6%), LCMS m/z: 567[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.85(s, 1H), 9.06(s, 1H), 8.60(s, 1H), 7.98(d, J=5.6Hz, 1H), 7.41(d, J＝8.0Hz, 1H), 6.46(d, J＝5.6Hz, 1H), 6.41(d, J＝8.0Hz, 1H), 5.03(d, J＝6.4Hz, 1H), 4.78-4.67(m, 2H),4.40-4.37(m,2H),3.99-3.96(m,2H),3.51-3.48(m,2H),3.23-3.10(m,5H),2.82-2.77(m,1H),2.70- 2.65(m,1H),1.75-1.73(m,2H),1.39-1.34(m,3H),1.30-1.28(m,6H),1.09-1.01(m,1H),0.65-0.58(m,2H ),0.39-0.31(m,2H).

Example 77, 1. (3S, 4R)-1-(4-((8-(3-((((R)-(cyclopropylmethyl)sulfoxide)methyl)azetidine -1-yl)-5-isopropylisoquinolin-3-yl)amino)pyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol or (3S,4R)-1 -(4-((8-(3-((((S)-(cyclopropylmethyl)sulfoxide)methyl)azetidin-1-yl)-5-isopropylisoquine Synthesis of Lin-3-yl)amino)pyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (Compound 77)

At room temperature, (R)-3-chloro-8-(3-(((cyclopropylmethyl)sulfoxide)methyl)azetidin-1-yl)-5-iso Propylisoquinoline or (S)-3-chloro-8-(3-(((cyclopropylmethyl)sulfoxide)methyl)azetidin-1-yl)-5 - To a solution of isopropylisoquinoline (50 mg, 0.13 mmol) in dioxane (7 mL) was added (3S, 4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3- Methylpiperidin-4-ol (29 mg, 0.13 mmol), cesium carbonate (127 mg, 0.39 mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium (II) (12mg, 0.013mmol), after addition, the obtained Under the protection of reaction liquid nitrogen, the temperature was raised to 100° C. and stirred for 5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane/methanol=15/1) to obtain a crude product. The crude product was passed through reaction flash chromatography (chromatographic conditions: column: spherical C18, 20-40um, 80g; and mobile phase A: water containing 0.1% NH ₃ ·H ₂ O; mobile phase B: acetonitrile; flow rate: 80mL/ min; gradient: 5% B-30% B, within 20 minutes; detection wavelength: 254nm) purification, when the mobile phase B content reached 20%, the fractions containing the product were collected and concentrated under reduced pressure to obtain (3S, 4R)- 1-(4-((8-(3-((((R)-(cyclopropylmethyl)sulfoxide)methyl)azetidin-1-yl)-5-isopropyliso Quinolin-3-yl)amino)pyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol or (3S,4R)-1-(4-((8-(3-( (((S)-(cyclopropylmethyl)sulfoxide)methyl)azetidin-1-yl)-5-isopropylisoquinolin-3-yl)amino)pyrimidine-2- yl)-3-fluoro-3-methylpiperidin-4-ol (19.90 mg, 0.035 mmol, yield: 26.5%), LCMS m/z: 567 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.85(s, 1H), 9.06(s, 1H), 8.59(s, 1H), 7.98(d, J=6.0Hz, 1H), 7.41(d, J＝8.0Hz, 1H), 6.46(d, J＝5.6Hz, 1H), 6.41(d, J＝8.0Hz, 1H), 5.02(d, J＝6.4Hz, 1H), 4.78-4.67(m, 2H),4.40-4.37(m,2H),4.00-3.95(m,2H),3.59-3.48(m,2H),3.25-3.08(m,5H),2.82-2.77(m,1H),2.70- 2.65(m,1H),1.75-1.70(m,2H),1.39-1.34(m,3H),1.31-1.28(m,6H),1.07-1.03(m,1H),0.65-0.57(m,2H ),0.40-0.30(m,2H).

Example 78, 1. N-(2-((3R,4S)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl Base-8-(3-(((S)-methylsulfinyl)methyl)azacyclo-1-yl]isoquinolin-3-amine or N-(2-((3R,4S)- 3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-(3-(((R)-methylsulfinyl ) methyl) azacyclo-1-yl] isoquinolin-3-amine (compound 78) synthesis

At room temperature, 2-((3R,4S)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-amine (50 mg, 0.21 mmol) was dissolved in di Oxycycline (10mL) was dissolved in medium, and (S)-3-chloro-5-isopropyl-8-(3-(((methylsulfoxide)methyl)azacyclo-1-yl )isoquinoline or (R)-3-chloro-5-isopropyl-8-(3-(((methylsulfoxide)methyl)azacyclo-1-yl)isoquinoline (71mg , 0.21mmol), cesium carbonate (205mg, 0.63mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1 ,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)(10mg, 0.01mmol), after the addition was completed, the resulting reaction liquid was stirred at 100°C under the protection of nitrogen 16 hours.Reaction finished, reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane/methanol=15/1) to obtain crude product.Crude product was passed through reverse phase flash chromatography again (chromatographic condition: column: spherical C18 , 20-40um, 40g; mobile phase A: water containing 0.1% NH ₃ ·H ₂ O; mobile phase B: acetonitrile; flow rate: 40mL/min; gradient: 40% B-95% B, within 20 minutes; detection Wavelength: 254nm) purification. When the content of mobile phase B reached 53%, the fraction containing the product was collected, then concentrated under reduced pressure to obtain N-(2-((3R, 4S)-3-fluoro-4-methoxyl- 3-methylpiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-(3-((((S)-methylsulfinyl)methyl)azepine-1 -- Base) isoquinolin-3-amine or N-(2-((3R, 4S)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-yl )-5-isopropyl-8-(3-((((R)-methylsulfinyl)methyl)azidine-1--yl)isoquinolin-3-amine (19.47mg, 0.036 mmol, yield: 17.3%), LCMS m/z: 541 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.85(s, 1H), 9.06(s, 1H), 8.56(s, 1H), 7.99(d, J=5.6Hz, 1H), 7.41(d, J＝7.6Hz, 1H), 6.49(d, J＝5.6Hz, 1H), 6.41(d, J＝8.0Hz, 1H), 4.71-4.66(m, 2H), 4.38(t, J＝6.4Hz, 2H),3.98-3.96(m,2H),3.51-3.48(m,1H),3.42-3.36(m,4H),3.25-3.16(m,4H),3.13-3.09(m,1H),2.59( s,3H),1.99-1.95(m,1H),1.65-1.62(m,1H),1.42-1.37(m,3H),1.33-1.24(m,6H).

Example 79, N-(2-((3R,4S)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl- 8-(3-(((R)-methylsulfinyl)methyl)azacyclo-1-yl]isoquinolin-3-amine or N-(2-((3R,4S)-3- Fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-(3-(((S)-methylsulfinyl)methyl base) azacyclo-1-yl] isoquinolin-3-amine (compound 79) synthesis

At room temperature, 2-((3R,4S)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-amine (50 mg, 0.21 mmol) was dissolved in di Oxyhexane (10mL) was dissolved in medium, and (R)-3-chloro-5-isopropyl-8-(3-(((methylsulfoxide)methyl)azacyclo-1-yl )isoquinoline or (S)-3-chloro-5-isopropyl-8-(3-(((methylsulfoxide)methyl)azacyclo-1-yl)isoquinoline (71mg , 0.21mmol), cesium carbonate (205mg, 0.63mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1 ,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)(10mg, 0.01mmol), after the addition was completed, the resulting reaction liquid was stirred at 100°C under the protection of nitrogen 16 hours.Reaction finished, reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane/methanol=15/1) to obtain crude product.Crude product was passed through reverse phase flash chromatography again (chromatographic condition: column: spherical C18 , 20-40um, 40g; mobile phase A: water containing 0.1% NH ₃ ·H ₂ O; mobile phase B: acetonitrile; flow rate: 40mL/min; gradient: 40% B-95% B, within 20 minutes; detection Wavelength: 254nm) purification. When the content of mobile phase B reached 56%, the fraction containing the product was collected, then concentrated under reduced pressure to obtain N-(2-((3R, 4S)-3-fluoro-4-methoxyl- 3-Methylpiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-(3-((((R)-methylsulfinyl)methyl)azepine-1 -- Base) isoquinolin-3-amine or N-(2-((3R, 4S)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-yl )-5-isopropyl-8-(3-((((S)-methylsulfinyl)methyl)azidine-1--yl)isoquinolin-3-amine (27.41mg, 0.051 mmol, yield: 24.4%), LCMS m/z: 541 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.86(s, 1H), 9.06(s, 1H), 8.57(s, 1H), 7.99(d, J=5.6Hz, 1H), 7.41(d, J＝8.0Hz, 1H), 6.49(d, J＝5.6Hz, 1H), 6.41(d, J＝8.0Hz, 1H), 4.71-4.66(m, 2H), 4.38(t, J＝6.4Hz, 2H), 3.98(t, J=5.2Hz, 2H), 3.53-3.46(m, 1H), 3.41-3.38(m, 4H), 3.24-3.16(m, 4H), 3.13-3.06(m, 1H) ,2.59(s,3H),1.99-1.96(m,1H),1.67-1.59(m,1H),1.42-1.37(m,3H),1.33-1.29(m,6H).

Example 80. (3S,4R)-3-fluoro-1-(4-((5-isopropyl-8-(3-(((S)-methylsulfinyl)azacyclo-1- Base) isoquinolin-3-yl) amino) pyrimidin-2-yl) piperidin-4-ol or (3S, 4R)-3-fluoro-1-(4-((5-isopropyl-8- (3-(((R)-methylsulfinyl) azacyclo-1-yl) isoquinolin-3-yl) amino) pyrimidin-2-yl) piperidin-4-ol (compound 80) synthesis

At room temperature, to dioxane dissolved in (3S, 4R)-1-(4-aminopyrimidin-2-yl)-3-fluoropropiperidin-4-ol (50mg, 0.24mmol, 0.24mmol) (10mL), add (S)-3-chloro-5-isopropyl-8-(3-(methylsulfinylmethylsulfoxide) aza-1-yl)isoquinoline or (( R)-3-chloro-5-isopropyl-8-(3-(methylsulfinylmethylsulfoxide)aza-1-yl)isoquinoline (78mg, 0.24mmol), cesium carbonate ( 235mg, 0.72mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)( 2'-Amino-1,1'-biphenyl-2-yl)palladium(II) (11 mg, 0.012 mmol). After the addition was complete, the temperature of the obtained reaction liquid was raised to 100° C. under the protection of nitrogen, and stirred for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane/methanol=15/1) to obtain a crude product. The crude product was passed through reverse phase flash chromatography again (chromatographic conditions: column: spherical C18, 20-40um, 40g; mobile phase A: water containing 0.1% NH ₃ H ₂ O; mobile phase B: acetonitrile; flow rate: 40mL/min ; Gradient: 30% B-80% B, within 20 minutes; Detection wavelength: 254nm) purify, when mobile phase B content reaches 44%, collect the cut that contains product, then concentrate under reduced pressure to obtain (3S, 4R)-3 -Fluoro-1-(4-((5-isopropyl-8-(3-(((S)-methylsulfinyl)azacyclo-1-yl)isoquinolin-3-yl)amino )pyrimidin-2-yl)piperidin-4-ol or (3S,4R)-3-fluoro-1-(4-((5-isopropyl-8-(3-(((R)-methyl Sulfinyl)azacyclo-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)piperidin-4-ol (22.03 mg, 0.044 mmol, yield: 18.3%), LCMS m /z:499[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ9.06(s, 1H), 8.56(s, 1H), 8.07(d, J=5.6Hz, 1H), 7.54(s, 1H), 7.42(d, J= 8.0Hz, 1H), 6.51(d, J=8.0Hz, 1H), 6.23(d, J=4.8Hz, 1H), 4.82-4.69(m, 1H), 4.64-4.61(m, 1H), 4.48- 4.38(m,3H),4.29-4.19(m,2H),4.11-3.95(m,2H),3.85-3.75(m,2H),3.59-3.52(m,1H),2.56(s,3H), 2.17-2.11(m,1H),2.03-1.88(m,2H),1.36-1.34(m,6H).

Example 81. (3S,4R)-3-fluoro-1-(4-((5-isopropyl-8-(3-(((R)-methylsulfinyl)azacyclo-1- Base) isoquinolin-3-yl) amino) pyrimidin-2-yl) piperidin-4-ol or (3S, 4R)-3-fluoro-1-(4-((5-isopropyl-8- (3-(((S)-methylsulfinyl) azacyclo-1-yl) isoquinolin-3-yl) amino) pyrimidin-2-yl) piperidin-4-ol (compound 81) synthesis

At room temperature, to dioxane dissolved in (3S, 4R)-1-(4-aminopyrimidin-2-yl)-3-fluoropropiperidin-4-ol (50mg, 0.24mmol, 0.24mmol) (10mL), add (S)-3-chloro-5-isopropyl-8-(3-(methylsulfinylmethylsulfoxide) aza-1-yl)isoquinoline or (( R)-3-chloro-5-isopropyl-8-(3-(methylsulfinylmethylsulfoxide)aza-1-yl)isoquinoline (78mg, 0.24mmol), cesium carbonate ( 235mg, 0.72mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)( 2'-Amino-1,1'-biphenyl-2-yl)palladium(II) (11 mg, 0.012 mmol). After the addition was complete, the temperature of the obtained reaction liquid was raised to 100° C. under the protection of nitrogen, and stirred for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane/methanol=15/1) to obtain a crude product. The crude product was passed through reverse phase flash chromatography again (chromatographic conditions: column: spherical C18, 20-40um, 40g; mobile phase A: water containing 0.1% NH ₃ H ₂ O; mobile phase B: acetonitrile; flow rate: 40mL/min ; Gradient: 30% B-80% B, within 20 minutes; Detection wavelength: 254nm) purify, when mobile phase B content reaches 47%, collect the cut that contains product, then concentrate under reduced pressure to obtain (3S, 4R)-3 -Fluoro-1-(4-((5-isopropyl-8-(3-(((R)-methylsulfinyl)azacyclo-1-yl)isoquinolin-3-yl)amino )pyrimidin-2-yl)piperidin-4-ol or (3S,4R)-3-fluoro-1-(4-((5-isopropyl-8-(3-(((S)-methyl Sulfinyl)azacyclo-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)piperidin-4-ol (17.64 mg, 0.035 mmol, yield: 14.7%), LCMS m /z:499[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ9.06(s, 1H), 8.57(s, 1H), 8.07(d, J=5.6Hz, 1H), 7.50(s, 1H), 7.42(d, J= 8.0Hz, 1H), 6.51(d, J=8.0Hz, 1H), 6.21(d, J=5.6Hz, 1H), 4.82-4.68(m, 1H), 4.64-4.60(m, 1H), 4.47- 4.38(m,3H),4.28-4.17(m,2H),4.12-3.94(m,2H),3.84-3.73(m,2H),3.58-3.54(m,1H),2.56(s,3H), 2.22-2.12(m,1H),2.02-1.88(m,2H),1.36-1.34(m,6H

Example 82, N-(2-((3S,4R)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl- 8-(3-(((S)-methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-amine or N-(2-((3S,4R)- 3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-(3-(((R)-methylsulfinyl ) methyl) azetidin-1-yl) isoquinolin-3-amine synthesis

At room temperature, 2-((3S,4R)-3-fluoro-4-methoxy-3-methylpiperidine-1-(2-((3S,4R)-3-fluoro-4 -Methoxy-3-methylpiperidin-1-yl)pyrimidin-4-amine (50 mg, 0.21 mmol) in dioxane (10 mL) was added ((S)-3-chloro-5- Isopropyl-8-(3-((methylsulfinylmethyl)methyl)azetidin-1-yl)isoquinoline or ((R)-3-chloro-5-isopropyl- 8-(3-((Methylsulfinylmethyl)methyl)azetidin-1-yl)isoquinoline (71 mg, 0.21 mmol), cesium carbonate (205 mg, 0.63 mmol) and methanesulfonic acid ( 2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'- Biphenyl-2-yl) palladium (II) (9mg, 0.01mmol), the addition was completed, and the resulting reaction was heated to 100°C under nitrogen protection, and stirred for 16 hours. After the reaction was completed, the reaction was concentrated under reduced pressure and passed through silica gel column chromatography (dichloromethane/methanol=15/1) purified to obtain the crude product, the crude product was passed through reverse phase flash chromatography (chromatographic conditions: column: spherical C18, 20-40 μm, 40g; Mobile phase A: water containing 0.1% ammoniacal liquor; Mobile phase B: acetonitrile; Flow rate: 40mL/min; Gradient: 40%B-95%B in 20 minutes; Detection wavelength: 254nm) purify further, when mobile phase B content reaches 45%, collect the cut that contains product, then Concentration under reduced pressure gave N-(2-((3S,4R)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl- 8-(3-(((S)-methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-amine or N-(2-((3S,4R)- 3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-(3-(((R)-methylsulfinyl )methyl)azetidin-1-yl)isoquinolin-3-amine (49.04 mg, 0.091 mmol, yield: 43.5%), LCMS m/z: 541 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.86(s, 1H), 9.06(s, 1H), 8.57(s, 1H), 7.99(d, J=5.6Hz, 1H), 7.41(d, J＝8.0Hz, 1H), 6.49(d, J＝5.2Hz, 1H), 6.41(d, J＝8.0Hz, 1H), 4.71-4.66(m, 2H), 4.40-4.37(m, 2H), 3.99-3.96(m,2H),3.51-3.48(m,1H),3.41-3.36(m,4H),3.25-3.16(m,4H),3.13-3.09(m,1H),2.60(s,3H ),1.99-1.95(m,1H),1.64-1.62(m,1H),1.42-1.37(m,3H),1.30(t,J＝6.4Hz,6H).

Example 83, N-(2-((3S,4R)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl- 8-(3-(((R)-methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-amine or N-(2-((3S,4R)- 3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-(3-(((S)-methylsulfinyl ) methyl) azetidin-1-yl) isoquinolin-3-amine (compound 83) synthesis

At room temperature, 2-((3S,4R)-3-fluoro-4-methoxy-3-methylpiperidine-1-(2-((3S,4R)-3-fluoro-4 -Methoxy-3-methylpiperidin-1-yl)pyrimidin-4-amine (50 mg, 0.21 mmol) in dioxane (10 mL) was added ((R)-3-chloro-5- Isopropyl-8-(3-((methylsulfinylmethyl)methyl)azetidin-1-yl)isoquinoline or ((S)-3-chloro-5-isopropyl- 8-(3-((Methylsulfinylmethyl)methyl)azetidin-1-yl)isoquinoline (71 mg, 0.21 mmol), cesium carbonate (205 mg, 0.63 mmol) and methanesulfonic acid ( 2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'- Biphenyl-2-yl) palladium (II) (9mg, 0.01mmol), the addition was completed, and the resulting reaction was heated to 100°C under nitrogen protection, and stirred for 16 hours. After the reaction was completed, the reaction was concentrated under reduced pressure and passed through silica gel column chromatography (dichloromethane/methanol=15/1) purified to obtain the crude product, the crude product was passed through reverse phase flash chromatography (chromatographic conditions: column: spherical C18, 20-40 μm, 40g; Mobile phase A: water containing 0.1% ammoniacal liquor; Mobile phase B: acetonitrile; Flow rate: 40mL/min; Gradient: 40%B-95%B in 20 minutes; Detection wavelength: 254nm) purify further, when mobile phase B content reaches 45%, collect the cut that contains product, then Concentration under reduced pressure gave N-(2-((3S,4R)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl- 8-(3-(((R)-methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-amine or N-(2-((3S,4R)- 3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-(3-(((S)-methylsulfinyl )methyl)azetidin-1-yl)isoquinolin-3-amine (48.47 mg, 0.090 mmol, yield: 43.0%), LCMS m/z: 541 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.85(s, 1H), 9.06(s, 1H), 8.56(s, 1H), 7.99(d, J=5.6Hz, 1H), 7.41(d, J＝8.0Hz, 1H), 6.49(d, J＝5.6Hz, 1H), 6.41(d, J＝8.0Hz, 1H), 4.71-4.66(m, 2H), 4.40-4.37(m, 2H), 3.97(s,2H),3.51-3.48(m,1H),3.41-3.35(m,4H),3.25-3.16(m,4H),3.13-3.09(m,1H),2.59(s,3H), 1.99-1.95(m,1H),1.65-1.62(m,1H),1.42-1.37(m,3H),1.30(t,J=6.0Hz,6H).

Example 84, (3S,4R)-3-fluoro-1-(4-(5-isopropyl-8-(2R,3S)-3-(S)-isopropylsulfinyl)methyl) -2-methylazetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-ol or (3S,4R)-3 -Fluoro-1-(4-(5-isopropyl-8-(2R,3S)-3-(R)-isopropylsulfinyl)methyl)-2-methylazetidine- Synthesis of 1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-ol (Compound 84)

1), 3-chloro-5-isopropyl-8-((2R,3S)-3-((isopropylthio)methyl)-2-methylazetidin-1-yl)iso Synthesis of Quinoline

At room temperature, S-(((2R,3S)-1-(3-chloro-5-isopropylisoquinolin-8-yl)-2-methylazetidine-3- Base) methyl) ethyl acetate (240mg, 0.66mmol) in methanol (10mL) solution, add potassium carbonate (273mg, 1.98mmol) and 2-iodopropane (337mg, 1.98mmol), after the addition is complete, the resulting reaction solution is heated 80°C, stirring for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=6/1) to obtain compound 3-chloro-5-isopropyl-8-((2R,3S)-3-((isopropylthio) )methyl)-2-methylazetidin-1-yl)isoquinoline (130 mg, 0.36 mmol, yield: 54.1%), LCMS m/z: 363 [M+H] ⁺ .

2), 3-chloro-5-isopropyl-8-((2R,3S)-3-((isopropylsulfinyl)methyl)-2-methylazetidin-1-yl ) Synthesis of isoquinoline

At 0°C, to 3-chloro-5-isopropyl-8-((2R,3S)-3-((isopropylthio)methyl)-2-methylazetidine-1 To a solution of -yl)isoquinoline (130mg, 0.36mmol) in dichloromethane (10mL) was added m-chloroperoxybenzoic acid (81mg, 0.47mmol). After the addition was complete, the resulting reaction solution was stirred at 0°C for 4 hours. After the reaction was completed, saturated sodium bisulfite (20 mL) was added to the reaction liquid to quench the mixture, and then extracted with dichloromethane (20 mL×2). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol=20/1) to obtain compound 3-chloro-5-isopropyl-8-((2R,3S)-3-((isopropylsulfinyl ))methyl)-2-methylazetidin-1-yl)isoquinoline (100 mg, 0.26 mmol, yield: 74.0%), LCMS m/z: 379 [M+H] ⁺ .

3), 3-chloro-5-isopropyl-8-((2R,3S)-3-(((R)-isopropylsulfinyl)methyl)-2-methylazetidine -1-yl)isoquinoline and 3-chloro-5-isopropyl-8-((2R,3S)-3-(((S)-isopropylsulfinyl)methyl)-2-methyl Synthesis of 1-azetidin-1-yl)isoquinoline

3-Chloro-5-isopropyl-8-((2R,3S)-3-((isopropylsulfinyl)methyl)-2-methylazetidin-1-yl)iso Quinoline) (100mg, 0.26mmol) by supercritical fluid chromatography (chromatographic conditions: system: Waters SFC 150; column:

250*25mm 10μm; mobile phase A: Supercritical CO ₂ ; mobile phase B: methanol containing 0.1% ammonia/methanol (7M); flow rate: 70mL/min; detection wavelength: 214nm) separation and purification to obtain two isomers:

Peak 1: 2.166min; 3-Chloro-5-isopropyl-8-((2R,3S)-3-(((R)-isopropylsulfinyl)methyl)-2-methylazepine Cyclobutan-1-yl)isoquinoline or 3-chloro-5-isopropyl-8-((2R,3S)-3-(((S)-isopropylsulfinyl)methyl)- 2-methylazetidin-1-yl)isoquinoline (35 mg, 0.09 mmol, yield: 35.0%).

Peak 2: 2.907min.; 3-Chloro-5-isopropyl-8-((2R,3S)-3-(((S)-isopropylsulfinyl)methyl)-2-methylnitrogen Heterobutan-1-yl)isoquinoline or 3-chloro-5-isopropyl-8-((2R,3S)-3-(((R)-isopropylsulfinyl)methyl) -2-methylazetidin-1-yl)isoquinoline (50 mg, 0.13 mmol, yield: 50.0%).

4), (3S, 4R)-3-fluoro-1-(4-(5-isopropyl-8-(2R, 3S)-3-(S)-isopropylsulfinyl)methyl)- 2-Methylazetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-ol or (3S,4R)-3- Fluoro-1-(4-(5-isopropyl-8-(2R,3S)-3-(R)-isopropylsulfinyl)methyl)-2-methylazetidine-1 Synthesis of -yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-ol (compound 84)

At room temperature, (3S, 4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-fluoro-3-methylpiperidin-4-ol (16mg, 0.07mmo) was dissolved in To a solution of dioxane (5 mL), add 3-chloro-5-isopropyl-8-((2R,3S)-3-(((S)-isopropylsulfinyl)methyl)- 2-Methylazacyclo-1-yl)isoquinoline or -3-chloro-5-isopropyl-8-((2R,3S)-3-(((R)-isopropylsulfinyl )methyl)-2-methylazacyclo-1-yl)isoquinoline (27mg, 0.07mmol), cesium carbonate (68mg, 0.21mmmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3, 6-Dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II ) (6 mg, 0.007 mmol). After the addition was complete, the temperature of the obtained reaction liquid was raised to 100° C. under the protection of nitrogen, and stirred for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane/methanol=15/1) to obtain a crude product. Crude product is passed through reverse phase flash chromatography (chromatographic condition: column: spherical C18,20-40 μ m, 40 grams; Mobile phase A: the water that contains 0.1% ammoniacal liquor; Mobile phase B: acetonitrile; Flow velocity: 40mL/min; Gradient: 20 30% B-80% B within minutes; detection wavelength: 254nm) for further purification, when the content of mobile phase B reached 42%, the fraction containing the product was collected and then concentrated under reduced pressure to obtain (3S, 4R)-3-fluoro-1 -(4-((5-isopropyl-8-((2R,3S)-3-(((S)-isopropylsulfinyl)methyl)-2-methylazetidine- 1-yl) isoquinolin-3-yl) amino) pyrimidin-2-yl)-3-methylpiperidin-4-ol or 3S, 4R)-3-fluoro-1-(4-((5- Isopropyl-8-((2R,3S)-3-(((R)-isopropylsulfinyl)methyl)-2-methylazetidin-1-yl)isoquinoline- 3-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-ol (12.05 mg, 0.021 mmol, yield: 30.1%), LCMS m/z: 569[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.88(s, 1H), 9.06(s, 1H), 8.61(s, 1H), 7.98(d, J=5.6Hz, 1H), 7.42(d, J＝8.0Hz, 1H), 6.55(d, J＝8.0Hz, 1H), 6.45(d, J＝5.6Hz, 1H), 5.02(d, J＝6.4Hz, 1H), 4.78-4.64(m, 3H),4.24-4.21(m,1H),3.65-3.49(m,3H),3.16-3.10(m,2H),3.04-2.99(m,1H),2.96-2.91(m,1H),2.86- 2.79(m,2H),1.75-1.73(m,2H),1.43-1.29(m,12H),1.17(d,J=6.8Hz,6H).

Example 85, 8-((2R,3S)-3-(((S)-ethylsulfinyl)methyl)-2-methylazetidin-1-yl)-N-(2 -((3S, 4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropylisoquinolin-3-amine or 8-((2R, 3S)-3-(((R)-ethylsulfinyl)methyl)-2-methylazetidin-1-yl)-N-(2-((3S,4R)-3- Synthesis of Fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropylisoquinolin-3-amine (Compound 85)

At room temperature, 2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine (25 mg, 0.11 mmol) was dissolved in dioxane (5 mL ) solution, add 3-chloro-8-((2R,3S)-3-(((S))-ethylsulfinyl)methyl)-2-methylazetidin-1-yl )-5-isopropylisoquinoline or -chloro-8-((2R,3S)-3-(((R))-ethylsulfinyl)methyl)-2-methylazetidine Alk-1-yl)-5-isopropylisoquinoline (40 mg, 0.11 mmol), cesium carbonate (108 mg, 0.33 mmol) and (2-dicyclohexylphosphine)-3,6-dimethoxymethanesulfonate Diphenyl-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (9mg, 0.011 mmol) at room temperature. After the addition was complete, the temperature of the obtained reaction liquid was raised to 100° C. under the protection of nitrogen, and stirred for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane/methanol=15/1) to obtain a crude product. Crude product is passed through reverse phase flash chromatography (chromatographic condition: column: spherical C18,20-40 μ m, 40g; Mobile phase A: the water that contains 0.1% ammoniacal liquor; Mobile phase B: acetonitrile; Flow rate: 40mL/min; Gradient: 20 minutes 40%B-95%B; detector: 254nm) purification, when the mobile phase B content reached 47%, the fraction containing the product was collected, then concentrated under reduced pressure to obtain 8-((2R, 3S)-3-(( (S)-Ethylsulfinyl)methyl)-2-methylazetidin-1-yl)-N-(2-((3S,4R)-3-fluoro-4-methoxy Piperidin-1-yl)pyrimidin-4-yl)-5-isopropylisoquinolin-3-amine or 8-((2R,3S)-3-(((R)-ethylsulfinyl) Methyl)-2-methylazetidin-1-yl)-N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidine-4 -yl)-5-isopropylisoquinolin-3-amine (6.35 mg, 0.011 mmol, yield: 10.4%), LCMS m/z: 555[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.92(s, 1H), 9.06(s, 1H), 8.63(s, 1H), 8.00(d, J=5.6Hz, 1H), 7.42(d, J＝8.0Hz, 1H), 6.57(d, J＝8.0Hz, 1H), 6.47(d, J＝5.6Hz, 1H), 5.01-4.87(m, 1H), 4.73-4.70(m, 1H), 4.65(t,J＝7.6Hz,1H),4.50-4.47(m,1H),4.24-4.21(m,1H),3.63-3.47(m,4H),3.37(s,3H),3.29-3.24( m,1H),3.13-3.07(m,1H),3.00-2.94(m,1H),2.89-2.77(m,2H),2.68-2.63(m,1H),1.82-1.75(m,2H), 1.42(d, J=6.0Hz, 3H), 1.30(d, J=6.0Hz, 6H), 1.19(t, J=7.6Hz, 3H).

Example 86, 8-((2R,3S)-3-(((R)-ethylsulfinyl)methyl)-2-methylazetidin-1-yl)-N-(2 -((3S, 4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropylisoquinolin-3-amine or 8-((2R, 3S)-3-(((S)-ethylsulfinyl)methyl)-2-methylazetidin-1-yl)-N-(2-((3S,4R)-3- Synthesis of Fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropylisoquinolin-3-amine (Compound 86)

At room temperature, 2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine (25 mg, 0.11 mmol) was dissolved in dioxane (5 mL ) solution, add 3-chloro-8-((2R,3S)-3-(((R))-ethylsulfinyl)methyl)-2-methylazetidin-1-yl )-5-isopropylisoquinoline or -chloro-8-((2R,3S)-3-(((S))-ethylsulfinyl)methyl)-2-methylazetidine Alk-1-yl)-5-isopropylisoquinoline (40 mg, 0.11 mmol), cesium carbonate (108 mg, 0.33 mmol) and (2-dicyclohexylphosphine)-3,6-dimethoxymethanesulfonate Diphenyl-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (9mg, 0.011 mmol) at room temperature. After the addition was complete, the temperature of the obtained reaction liquid was raised to 100° C. under the protection of nitrogen, and stirred for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane/methanol=15/1) to obtain a crude product. Crude product is passed through reverse phase flash chromatography (chromatographic condition: column: spherical C18,20-40 μ m, 40g; Mobile phase A: the water that contains 0.1% ammoniacal liquor; Mobile phase B: acetonitrile; Flow rate: 40mL/min; Gradient: 20 minutes 40%B-95%B; detector: 254nm) purification, when the mobile phase B content reached 40%, the fraction containing the product was collected, then concentrated under reduced pressure to obtain 8-((2R, 3S)-3-(( (R)-Ethylsulfinyl)methyl)-2-methylazetidin-1-yl)-N-(2-((3S,4R)-3-fluoro-4-methoxy Piperidin-1-yl)pyrimidin-4-yl)-5-isopropylisoquinolin-3-amine or 8-((2R,3S)-3-(((S)-ethylsulfinyl) Methyl)-2-methylazetidin-1-yl)-N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidine-4 -yl)-5-isopropylisoquinolin-3-amine (2.97 mg, 0.005 mmol, yield: 4.8%), LCMS m/z: 555.3 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.92(s, 1H), 9.06(s, 1H), 8.63(s, 1H), 8.00(d, J=5.6Hz, 1H), 7.42(d, J＝8.0Hz, 1H), 6.56(d, J＝8.0Hz, 1H), 6.46(d, J＝5.6Hz, 1H), 5.01-4.87(m, 1H), 4.73-4.64(m, 2H), 4.50-4.47(m,1H),4.23-4.20(m,1H),3.64-3.47(m,4H),3.37(s,3H),3.29-3.26(m,1H),3.06-3.03(m,2H ),2.84-2.75(m,2H),2.69-2.64(m,1H),1.83-1.75(m,2H),1.41(d,J＝6.0Hz,3H),1.31-1.29(m,6H), 1.19 (t, J=7.6Hz, 3H).

Example 87, (3R,4S)-1-(4-((8-(3-((S)-(cyclopropylmethyl)sulfinyl)methyl)azetidin-1-yl )-5-isopropylisoquinolin-3-yl)amino)pyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol or (3R, 4S)-1-(4- ((8-(3-((R)-(cyclopropylmethyl)sulfinyl)methyl)azetidin-1-yl)-5-isopropylisoquinolin-3-yl) Synthesis of amino)pyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (compound 87)

1), the synthesis of 3-(hydroxymethyl) azetidine-1-carboxylic acid tert-butyl ester

At 0°C, into a solution of 1-(tert-butyl) 3-methylazetidine-1,3-dicarboxylate (44.00g, 204.65mmol) in tetrahydrofuran (500mL), Lithium aluminum hydride (9.33 g, 245.58 mmol) was added. After the addition was complete, the resulting reaction solution was stirred at 0° C. for 1 hour. After the reaction was complete, the reaction solution was quenched with water (200 mL), and extracted with ethyl acetate (400 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=4/1) to obtain tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (35.00 g, 187.16 mmol, yield : 91.4%), LCMS m/z: 132[M+H-56] ⁺ .

2), the synthesis of 3-(((methylsulfonyl)oxy)methyl)azetidine-1-carboxylic acid tert-butyl ester

At 0°C, triethylamine ( 21.60 g, 213.90 mmol) and methanesulfonyl chloride (24.60 g, 213.90 mmol). After the addition was complete, the resulting reaction solution was stirred at 0°C for 1 hour. After the reaction was completed, saturated sodium bicarbonate (200 mL) was added to the phase reaction liquid to quench the mixture, and extracted with dichloromethane (300 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/1) to obtain tert-butyl 3-(((methylsulfonyl)oxy)methyl)azetidine-1-carboxylate (24.00 g, 90.57 mmol, yield 84.6%) LCMS m/z: 210[M+H-56] ⁺ .

3), the synthesis of 3-((acetylthio) methyl) azetidine-1-carboxylic acid tert-butyl ester

At room temperature, N, N-dimethyl To a solution of methyl formamide (250 mL), potassium ethsulfate (12.39 g, 108.68 mmol) was added. After the addition was complete, the resulting reaction was heated to 80°C and stirred for 4 hours. After the reaction was completed, the reaction solution was quenched with water (200 mL), and extracted with ethyl acetate (400 mL×2). The combined organics were washed with saturated brine (200 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated to give tert-butyl 3-((acetylthio)methyl)azetidine-1-carboxylate ( 22.00 g, 89.80 mmol, yield: 99.1%), LCMS m/z: 190[M+H-56] ⁺ .

4), the synthesis of 3-(((cyclopropylmethyl) thio) methyl) azetidine-1-carboxylic acid tert-butyl ester

At room temperature, add potassium carbonate (17.74g, 128.58mmol), potassium iodide (7.11g, 42.86mmol) and (bromomethyl)cyclopropane (17.36g, 108.68mmol). After the addition was complete, the resulting reaction solution was heated to 80° C. in a sealed tube and stirred for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=4/1) tert-butyl 3-(((cyclopropylmethyl)thio)methyl)azetidine-1-carboxylate (11.00g, 42.80mmol, Yield: 99.9%), LCMS m/z: 258[M+H] ⁺

5), Synthesis of 3-(((cyclopropylmethyl)sulfinyl)methyl)azetidine-1-carboxylic acid tert-butyl ester

At 0°C, dissolve tert-butyl 3-(((cyclopropylmethyl)thio)methyl)azetidine-1-carboxylate (11.00 g, 42.80 mmol) in tetrahydrofuran (200 mL ) solution, hydrogen peroxide (40 mL) was added, and after the addition was complete, the resulting reaction solution was stirred at 0° C. for 4 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. Residue is by reverse phase flash chromatography (chromatographic conditions: column: spherical C18,20-40 μ m, 330g; Mobile phase: water containing 0.1% formic acid; Mobile phase B: acetonitrile; Flow rate: 80mL/min; Gradient: within 20 minutes 20% B-50% B; Detector: 214nm) purify, when mobile phase B content reaches 45% B, collect and contain product all fractions, then concentrate under reduced pressure 3-(((cyclopropylmethyl)sulfinic acid Acyl)methyl)azetidine-1-carboxylic acid tert-butyl ester (6.00g, 21.98mmol, yield: 51.3%), LCMS m/z: 274[M+H] ⁺ .

6), Synthesis of 3-((cyclopropylmethyl)sulfinyl)methyl)azetidine 2,2,2-trifluoroacetate

Under room temperature conditions, to the dichloromethane ( 60 mL) solution, was added 2,2,2-trifluoroacetic acid (10 mL), after the addition was complete, the resulting reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain 3-((cyclopropylmethyl)sulfinyl)methyl)azetidine 2,2,2-trifluoroacetate (12.00g, crude product) , LCMS m/z:174[M+H] ⁺

7), the synthesis of 3-chloro-8-(3-(((cyclopropylmethyl)sulfinyl)methyl)azetidin-1-yl)-5-isopropylisoquinoline

At room temperature, to a solution of 3-(((cyclopropylmethyl)sulfinyl)methyl)azetidine 2,2,2-trifluoroacetate (3.02g, 10.53mmol) in di Cesium carbonate (11.44g, 35.10mmol) and XantPhos Pd G4 (285mg, 0.174mmol) and 8-bromo-3-chloro-5-isopropylisoquinoline (1.00g, 3.51 mmol). After the addition was complete, the temperature of the obtained reaction liquid was raised to 100° C. under the protection of nitrogen, and stirred for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=15/1) to purify 3-chloro-8-(3-(((cyclopropylmethyl)sulfinyl)methyl)azetidine- 1-yl)-5-isopropylisoquinoline (770mg, 2.04mmol, yield: 52.9%), LCMS m/z: 377[M+H] ⁺ .

8), (S)-3-chloro-8-(3-(((cyclopropylmethyl)sulfinyl)methyl)azetidin-1-yl)-5-isopropylisoquinol Line and (R)-3-chloro-8-(3-(((cyclopropylmethyl)sulfinyl)methyl)azetidin-1-yl)-5-isopropylisoquinoline Synthesis

3-Chloro-8-(3-(((cyclopropylmethyl)sulfinyl)methyl)azetidin-1-yl)-5-isopropylisoquinoline (260mg, 0.69mmol ) by supercritical fluid chromatography (chromatographic conditions: system: Waters SFC 150; column:

250×20mm 10μm; mobile phase A: Supercritical CO ₂ ,; mobile phase B: methanol (containing 0.1% 7.0mol/L ammonia/methanol (7M); flow rate: 70mL/min; detection wavelength: 214nm). isomers:

Peak 1: 0.764min; (S)-3-Chloro-8-(3-(((cyclopropylmethyl)sulfinyl)methyl)azetidin-1-yl)-5-isopropyl Isoquinoline or (R)-3-chloro-8-(3-(((cyclopropylmethyl)sulfinyl)methyl)azetidin-1-yl)-5-isopropyl Isoquinoline (88mg, 0.23mmol, yield: 33.8%)

Peak 2: 0.889min; (R)-3-Chloro-8-(3-(((cyclopropylmethyl)sulfinyl)methyl)azetidin-1-yl)-5-isopropyl Isoquinoline or (S)-3-chloro-8-(3-(((cyclopropylmethyl)sulfinyl)methyl)azetidin-1-yl)-5-isopropyl Isoquinoline (102mg, 0.27mmol, yield: 39.2%)

9), (3R, 4S)-1-(4-((8-(3-((S)-(cyclopropylmethyl)sulfinyl)methyl)azetidin-1-yl) -5-isopropylisoquinolin-3-yl)amino)pyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol or (3R,4S)-1-(4-( (8-(3-((R)-(cyclopropylmethyl)sulfinyl)methyl)azetidin-1-yl)-5-isopropylisoquinolin-3-yl)amino ) Synthesis of pyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (compound 96)

At room temperature, to dioxane dissolved in (3R,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-yl (40mg, 0.18mmol) Cyclo(10mL) solution, add (S)-3-chloro-8-(3-(((cyclopropylmethylmethyl)sulfinyl)methyl)azetidin-1-yl)-5- Isopropylisoquinoline or (R)-3-chloro-8-(3-(((cyclopropylmethylmethyl)sulfinyl)methyl)azetidin-1-yl)-5-iso Propylisoquinoline (68mg, 0.18mmol), cesium carbonate (176mg, 0.54mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-Triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (8mg, 0.009mmol), after addition, the resulting reaction solution, Under nitrogen protection, the temperature was raised to 100°C and stirred for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified to a crude product by silica gel column chromatography (dichloromethane/methanol=15/1), and the crude product was purified by reverse phase flash chromatography (chromatographic conditions: column: spherical C18,20- 40μm, 40g; mobile phase A: water with 0.1% ammonia; mobile phase B: acetonitrile; flow rate: 40mL/min; gradient: 40%B-95%B in 20 minutes; detector: 254nm) in further purification, when flow When the content of phase B reached 45%, the fractions containing the product were collected and then concentrated under reduced pressure to obtain the compound (3R, 4S)-1-(4-((8-(3-((S)-(cyclopropylmethyl )sulfinyl)methyl)azetidin-1-yl)-5-isopropylisoquinolin-3-yl)amino)pyrimidin-2-yl)-3-fluoro-3-methylpiper Pyridin-4-ol or (3R,4S)-1-(4-((8-(3-((R)-(cyclopropylmethyl)sulfinyl)methyl)azetidine-1 -yl)-5-isopropylisoquinolin-3-yl)amino)pyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (7.34mg, 0.013mmol, yield: 7.3%), LCMS m/z: 567.3 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.84(s, 1H), 9.06(s, 1H), 8.59(s, 1H), 7.98(d, J=5.6Hz, 1H), 7.41(d, J＝8.0Hz, 1H), 6.47(d, J＝6.0Hz, 1H), 6.41(d, J＝8.0Hz, 1H), 5.02(d, J＝6.4Hz, 1H), 4.75-4.66(m, 2H), 4.39(t, J=6.0Hz, 2H), 4.00-3.95(m, 2H), 3.53-3.48(m, 2H), 3.23-3.09(m, 5H), 2.82-2.77(m, 1H) ,2.70-2.65(m,1H),1.75-1.73(m,2H),1.39-1.28(m,9H),1.07-1.03(m,1H),0.65-0.57(m,2H),0.40-0.31( m,2H).

Example 88. (3R,4S)-1-(4-((8-(3-((S)-(cyclopropylmethyl)sulfinyl)methyl)azetidin-1-yl )-5-isopropylisoquinolin-3-yl)amino)pyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol or (3R, 4S)-1-(4- ((8-(3-((R)-(cyclopropylmethyl)sulfinyl)methyl)azetidin-1-yl)-5-isopropylisoquinolin-3-yl) Synthesis of amino)pyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (compound 88)

At room temperature, to dioxane dissolved in (3R,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-yl (40mg, 0.18mmol) Cyclo(10mL) solution, add (R)-3-chloro-8-(3-(((cyclopropylmethylmethyl)sulfinyl)methyl)azetidin-1-yl)-5- Isopropylisoquinoline or (S)-3-chloro-8-(3-(((cyclopropylmethylmethyl)sulfinyl)methyl)azetidin-1-yl)-5-iso Propylisoquinoline (68mg, 0.18mmol), cesium carbonate (176mg, 0.54mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-Triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (8mg, 0.009mmol), after addition, the resulting reaction solution, Under nitrogen protection, the temperature was raised to 100°C and stirred for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified to a crude product by silica gel column chromatography (dichloromethane/methanol=15/1), and the crude product was purified by reverse phase flash chromatography (chromatographic conditions: column: spherical C18,20- 40μm, 40g; mobile phase A: water with 0.1% ammonia; mobile phase B: acetonitrile; flow rate: 40mL/min; gradient: 40%B-95%B in 20 minutes; detector: 254nm) in further purification, when flow When the phase B content reached 45%, the product-containing fractions were collected and concentrated under reduced pressure to obtain (3R,4S)-1-(4-((8-(3-((R)-(cyclopropylmethyl) Sulfinyl)methyl)azetidin-1-yl)-5-isopropylisoquinolin-3-yl)amino)pyrimidin-2-yl)-3-fluoro-3-methylpiperidine -4-alcohol or (3R,4S)-1-(4-((8-(3-((S)-(cyclopropylmethyl)sulfinyl)methyl)azetidine-1- Base)-5-isopropylisoquinolin-3-yl)amino)pyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (8.60mg, 0.015mmol, yield: 8.6 %), LCMS m/z: 567 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.85(s, 1H), 9.06(s, 1H), 8.59(s, 1H), 7.98(d, J=5.6Hz, 1H), 7.41(d, J＝8.0Hz, 1H), 6.47(d, J＝5.6Hz, 1H), 6.41(d, J＝8.4Hz, 1H), 5.02(d, J＝6.4Hz, 1H), 4.78-4.67(m, 2H), 4.38(t, J=6.8Hz, 2H), 3.98(t, J=6.0Hz, 2H), 3.57-3.48(m, 2H), 3.25-3.08(m, 5H), 2.82-2.77(m ,1H),2.70-2.65(m,1H),1.74-1.73(m,2H),1.39-1.28(m,9H),1.07-1.03(m,1H),0.65-0.57(m,2H),0.40 -0.31(m,2H)

Example 89, (3R, 4S)-3-fluoro-1-(4-((5-isopropyl-8-((2R, 3S)-2-methyl-3-(((S)-methyl Sulfinyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-ol or (3R,4S )-3-fluoro-1-(4-((5-isopropyl-8-((2R, 3S)-2-methyl-3-(((R)-methylsulfinyl)methyl) Synthesis of Azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-ol (Compound 89)

At room temperature, (3R,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (30mg, 0.13mmol) was dissolved in dioxane Cyclo(10 mL) solution was added 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-(((S)-methylsulfinyl)methyl)nitrogen Heterocyclobutan-1-yl)isoquinoline or 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-(((R)-methylsulfinyl )methyl)azetidin-1-yl)isoquinoline (46mg, 0.13mmol), cesium carbonate (127mg, 0.39mmol) and (2-dicyclohexylphosphine)-3,6-bis Methoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (6mg , 0.007mmol) at room temperature. After the addition was complete, the temperature of the obtained reaction liquid was raised to 100° C. under the protection of nitrogen, and stirred for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane/methanol=15/1) to obtain a crude product. Crude product is passed through reverse phase flash chromatography (chromatographic condition: column: spherical C18,20-40 μ m, 40g; Mobile phase A: the water that contains 0.1% ammoniacal liquor; Mobile phase B: acetonitrile; Flow rate: 40mL/min; Gradient: 20 minutes 30% B-80% B; detector: 254nm) purification, when the mobile phase B content reached 40%, the fraction containing the product was collected, then concentrated under reduced pressure to obtain (3R, 4S)-3-fluoro-1-( 4-((5-isopropyl-8-((2R,3S)-2-methyl-3-(((S)-methylsulfinyl)methyl)azetidin-1-yl ) isoquinolin-3-yl) amino) pyrimidin-2-yl)-3-methylpiperidin-4-ol or (3R, 4S)-3-fluoro-1-(4-((5-isopropanol Base-8-((2R,3S)-2-methyl-3-(((R)-methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-yl )amino)pyrimidin-2-yl)-3-methylpiperidin-4-ol (3.23 mg, 0.006 mmol, yield: 4.5%), LCMS m/z: 541 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.89(s, 1H), 9.07(s, 1H), 8.61(s, 1H), 7.98(d, J=5.6Hz, 1H), 7.42(d, J＝8.0Hz, 1H), 6.57(d, J＝8.0Hz, 1H), 6.45(d, J＝5.6Hz, 1H), 5.03(d, J＝6.4Hz, 1H), 4.75-4.64(m, 3H),4.23-4.20(m,1H),3.64-3.49(m,3H),3.17-3.12(m,3H),3.01-2.96(m,1H),2.90-2.87(m,1H),2.56( s,3H),1.73-1.72(m,2H),1.43-1.29(m,12H).

Example 90, (3R, 4S)-3-fluoro-1-(4-((5-isopropyl-8-((2R, 3S)-2-methyl-3-(((R)-methyl Sulfinyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-ol or (3R,4S )-3-fluoro-1-(4-((5-isopropyl-8-((2R, 3S)-2-methyl-3-(((S)-methylsulfinyl)methyl) Synthesis of Azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-ol (Compound 90)

At room temperature, (3R,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (30mg, 0.13mmol) was dissolved in dioxane Cyclo(10 mL) solution, add 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-(((R)-methylsulfinyl)methyl)nitrogen Heterobutan-1-yl)isoquinoline or 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-(((S)-methylsulfinyl )methyl)azetidin-1-yl)isoquinoline (46mg, 0.13mmol), cesium carbonate (127mg, 0.39mmol) and (2-dicyclohexylphosphine)-3,6-bis Methoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (6mg , 0.007mmol) at room temperature. After the addition was complete, the temperature of the obtained reaction liquid was raised to 100° C. under the protection of nitrogen, and stirred for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane/methanol=15/1) to obtain a crude product. Crude product is passed through reverse phase flash chromatography (chromatographic condition: column: spherical C18,20-40 μ m, 40g; Mobile phase A: the water that contains 0.1% ammoniacal liquor; Mobile phase B: acetonitrile; Flow velocity: 40mL/min; Gradient: 20 minutes 30% B-80% B; detector: 254nm) purification, when the content of mobile phase B reached 40%, the fraction containing the product was collected, then concentrated under reduced pressure to obtain (3R, 4S)-3-fluoro-1-( 4-((5-isopropyl-8-((2R,3S)-2-methyl-3-(((R)-methylsulfinyl)methyl)azetidin-1-yl ) isoquinolin-3-yl) amino) pyrimidin-2-yl)-3-methylpiperidin-4-ol or (3R, 4S)-3-fluoro-1-(4-((5-isopropanol Base-8-((2R,3S)-2-methyl-3-(((S)-methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-yl )amino)pyrimidin-2-yl)-3-methylpiperidin-4-ol (6.40 mg, 0.012 mmol, yield: 9.0%), LCMS m/z: 541 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.89(s, 1H), 9.06(s, 1H), 8.61(s, 1H), 7.98(d, J=5.6Hz, 1H), 7.42(d, J＝8.0Hz, 1H), 6.56(d, J＝8.0Hz, 1H), 6.45(d, J＝5.6Hz, 1H), 5.03(d, J＝6.4Hz, 1H), 4.75-4.64(m, 3H),4.23-4.20(m,1H),3.64-3.49(m,3H),3.16-3.06(m,3H),3.01-2.96(m,1H),2.83-2.81(m,1H),2.57( s,3H),1.74-1.71(m,2H),1.42-1.29(m,12H).

Example 91. (3R,4S)-1-(4-((8-((2S,3R)-3-(((S)-ethylsulfinyl)methyl)-2-methylazepine Cyclobutan-1-yl)-5-isopropylisoquinolin-3-yl)amino)pyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol or (3R, 4S )-1-(4-((8-((2S,3R)-3-(((R)-ethylsulfinyl)methyl)-2-methylazetidin-1-yl) Synthesis of -5-isopropylisoquinolin-3-yl)amino)pyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (Compound 91)

At room temperature, ((3R,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (40mg, 0.18mmol) dissolved in dioxygen Hexacyclic (7mL) solution, add 3-chloro-8-((2S,3R)-3-(((S)-ethylsulfinyl)methyl)-2-methylazetidine- 1-yl)-5-isopropylisoquinoline or 3-chloro-8-((2S,3R)-3-(((R)-ethylsulfinyl)methyl)-2-methylnitrogen Heterobutan-1-yl)-5-isopropylisoquinoline (66 mg, 0.18 mmol), cesium carbonate (176 mg, 0.54 mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6- Dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)( 16 mg, 0.018 mmol). After the addition was complete, the resulting reaction solution was heated up to 100° C. and stirred for 16 hours under the protection of nitrogen. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane/methanol=15/1) to obtain a crude product. Crude product is passed through reverse phase flash chromatography (chromatographic condition: column: spherical C18,20-40 μ m, 40g; Mobile phase A: the water that contains 0.1% ammoniacal liquor; Mobile phase B: acetonitrile; Flow rate: 40mL/min; Gradient: 20 minutes 40%B-95%B; detector: 254nm) purification, when the mobile phase B content reached 40%, the fraction containing the product was collected, then concentrated under reduced pressure to obtain (3R, 4S)-1-(4-(( 8-((2S,3R)-3-(((S)-ethylsulfinyl)methyl)-2-methylazetidin-1-yl)-5-isopropylisoquinoline -3-yl)amino)pyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol or (3R, 4S)-1-(4-((8-((2S, 3R) -3-(((R)-ethylsulfinyl)methyl)-2-methylazetidin-1-yl)-5-isopropylisoquinolin-3-yl)amino)pyrimidine -2-yl)-3-fluoro-3-methylpiperidin-4-ol (7.50 mg, 0.014 mmol, yield: 7.6%), LCMS m/z: 555[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.87(s, 1H), 9.06(s, 1H), 8.61(s, 1H), 7.98(d, J=5.6Hz, 1H), 7.42(d, J＝8.0Hz, 1H), 6.56(d, J＝8.0Hz, 1H), 6.45(d, J＝5.6Hz, 1H), 5.02(d, J＝6.4Hz, 1H), 4.77-4.63(m, 3H), 4.22(t, J=5.6Hz, 1H), 3.64-3.49(m, 3H), 3.20-3.07(m, 3H), 3.00-2.95(m, 1H), 2.89-2.77(m, 2H) ,2.68-2.63(m,1H),1.75-1.73(m,2H),1.43-1.29(m,12H),1.19(t,J=7.6Hz,3H).

Example 92, (3R,4S)-1-(4-((8-((2S,3R)-3-(((R)-ethylsulfinyl)methyl)-2-methylazepine Cyclobutan-1-yl)-5-isopropylisoquinolin-3-yl)amino)pyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol or (3R, 4S )-1-(4-((8-((2S,3R)-3-(((S)-ethylsulfinyl)methyl)-2-methylazetidin-1-yl) Synthesis of -5-isopropylisoquinolin-3-yl)amino)pyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (compound 92)

At room temperature, ((3R,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (40mg, 0.18mmol) dissolved in dioxygen Hexacyclic (7mL) solution, add 3-chloro-8-((2S,3R)-3-(((R)-ethylsulfinyl)methyl)-2-methylazetidine- 1-yl)-5-isopropylisoquinoline or 3-chloro-8-((2S,3R)-3-(((S)-ethylsulfinyl)methyl)-2-methylnitrogen Heterobutan-1-yl)-5-isopropylisoquinoline (66 mg, 0.18 mmol), cesium carbonate (176 mg, 0.54 mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6- Dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)( 16 mg, 0.018 mmol). After the addition was complete, the resulting reaction solution was heated up to 100° C. and stirred for 16 hours under the protection of nitrogen. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane/methanol=15/1) to obtain a crude product. Crude product is passed through reverse phase flash chromatography (chromatographic condition: column: spherical C18,20-40 μ m, 40g; Mobile phase A: the water that contains 0.1% ammoniacal liquor; Mobile phase B: acetonitrile; Flow rate: 40mL/min; Gradient: 20 minutes 40%B-95%B; detector: 254nm) purification, when the mobile phase B content reached 40%, the fraction containing the product was collected, then concentrated under reduced pressure to obtain (3R, 4S)-1-(4-(( 8-((2S,3R)-3-(((R)-ethylsulfinyl)methyl)-2-methylazetidin-1-yl)-5-isopropylisoquinoline -3-yl)amino)pyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol or (3R, 4S)-1-(4-((8-((2S, 3R) -3-(((S)-ethylsulfinyl)methyl)-2-methylazetidin-1-yl)-5-isopropylisoquinolin-3-yl)amino)pyrimidine -2-yl)-3-fluoro-3-methylpiperidin-4-ol (2.35 mg, 0.004 mmol, yield: 2.3%), LCMS m/z: 555 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.87(s, 1H), 9.06(s, 1H), 8.61(s, 1H), 7.98(d, J=5.6Hz, 1H), 7.42(d, J＝8.0Hz, 1H), 6.55(d, J＝8.4Hz, 1H), 6.45(d, J＝5.6Hz, 1H), 5.02(d, J＝6.4Hz, 1H), 4.77-4.63(m, 3H), 4.22(t, J=6.0Hz, 1H), 3.64-3.49(m, 3H), 3.16-3.03(m, 4H), 2.84-2.77(m, 2H), 2.69-2.64(m, 1H) , 1.75-1.73 (m, 2H), 1.42-1.29 (m, 12H), 1.19 (t, J=7.2Hz, 3H).

Example 93, N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R , 3S)-2-methyl-3-(((S)-methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-amine or N-(2-( (3S, 4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3 Synthesis of -(((R)-methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-amine (Compound 93)

At room temperature, 2-(3S, 4R)-3-fluoro-4-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine (40mg, 0.18mol) dioxane (7 mL) solution, add 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-(((S)-methylsulfinyl)methyl)azepine Cyclobut-1-yl)isoquinoline or 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-(((R)-methylsulfinyl)methyl base) azetidin-1-yl) isoquinoline (63 mg, 0.18 mmol), cesium carbonate (176 mg, 0.54 mmol, 0.54 mmol) and (2-dicyclohexylphosphine)-3,6-bis Methoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (16mg , 0.018mmol). After the addition was complete, the resulting reaction solution was heated up to 100° C. and stirred for 16 hours under the protection of nitrogen. After the reaction was completed, the reaction was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane/methanol=15/1) to obtain a crude product. Thick product is passed through reverse phase flash chromatography again (chromatographic condition: column: spherical C18,20-40 μ m, 80g; Mobile phase A: the water that contains 0.1% ammoniacal liquor; Mobile phase B: acetonitrile; Flow velocity: 80mL/min; Gradient: 20 40%B-95%B in minutes; detector: 254nm) purification, when mobile phase B content reaches 45%B, collects the fraction containing product, then concentrates under reduced pressure to obtain N-(2-((3S, 4R) -3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-(((S )-methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-amine or N-(2-((3S,4R)-3-fluoro-4-methoxy Piperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-(((R)-methylsulfinyl)methyl )azetidin-1-yl)isoquinolin-3-amine (15.47 mg, 0.029 mmol, yield: 16.2%), LCMS m/z: 541 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.92(s, 1H), 9.07(s, 1H), 8.63(s, 1H), 8.00(d, J=5.6Hz, 1H), 7.42(d, J＝8.0Hz, 1H), 6.57(d, J＝8.0Hz, 1H), 6.47(d, J＝5.6Hz, 1H), 5.01-4.87(m, 1H), 4.75-4.64(m, 2H), 4.50-4.47(m,1H),4.23-4.20(m,1H),3.64-3.43(m,4H),3.37(s,3H),3.29-3.26(m,1H),3.17-3.12(m,1H ),3.01-2.96(m,1H),2.90-2.85(m,1H),2.56(s,3H),1.85-1.73(m,2H),1.42(d,J＝6.0Hz,3H),1.30( d,J=6.8Hz,6H)

Example 94, N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R , 3S)-2-methyl-3-(((R)-methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-amine or N-(2-( (3S, 4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3 Synthesis of -(((S)-methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-amine (Compound 94)

At room temperature, 2-(3S, 4R)-3-fluoro-4-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine (40mg, 0.18mol) dioxane (7 mL) solution, add 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-(((S)-methylsulfinyl)methyl)azepine Cyclobut-1-yl)isoquinoline or 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-(((R)-methylsulfinyl)methyl base) azetidin-1-yl) isoquinoline (63 mg, 0.18 mmol), cesium carbonate (176 mg, 0.54 mmol, 0.54 mmol) and (2-dicyclohexylphosphine)-3,6-bis Methoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (16mg , 0.018mmol). After the addition was complete, the resulting reaction solution was heated up to 100° C. and stirred for 16 hours under the protection of nitrogen. After the reaction was completed, the reaction was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane/methanol=15/1) to obtain a crude product. Thick product is passed through reverse phase flash chromatography again (chromatographic condition: column: spherical C18,20-40 μ m, 80g; Mobile phase A: the water that contains 0.1% ammoniacal liquor; Mobile phase B: acetonitrile; Flow velocity: 80mL/min; Gradient: 20 40%B-95%B in minutes; detector: 254nm) purification, when mobile phase B content reaches 45%B, collects the fraction containing product, then concentrates under reduced pressure to obtain N-(2-((3S, 4R) -3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-(((R )-methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-amine or N-(2-((3S,4R)-3-fluoro-4-methoxy Piperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-(((S)-methylsulfinyl)methyl )azetidin-1-yl)isoquinolin-3-amine (10.44 mg, 0.019 mmol, yield: 10.9%), LCMS m/z: 541 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.92(s, 1H), 9.06(s, 1H), 8.63(s, 1H), 8.00(d, J=5.6Hz, 1H), 7.42(d, J＝8.0Hz, 1H), 6.56(d, J＝8.4Hz, 1H), 6.47(d, J＝5.6Hz, 1H), 5.01-4.87(m, 1H), 4.77-4.63(m, 2H), 4.50-4.47(m,1H),4.25-4.19(m,1H),3.64-3.41(m,4H),3.37(s,3H),3.29-3.19(m,1H),3.14-3.03(m,2H ),2.86-2.77(m,1H),2.57(s,3H),1.85-1.71(m,2H),1.41(d,J＝6.0Hz,3H),1.30(d,J＝6.4Hz,6H) .

Example 95, N-(5-chloro-2-((3R,4S)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8 -((2R,3S)-2-methyl-3-(((S)-methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-amine or N- (5-Chloro-2-((3R, 4S)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R, 3S Synthesis of )-2-methyl-3-(((R)-methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-amine (compound 95)

At room temperature, 5-chloro-2-((3R,4S)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine (40 mg, 0.15 mmol) was dissolved in dioxy Hexacyclic solution (5 mL), add 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-(((S)-methylsulfinyl)methyl) Azetidin-1-yl)isoquinoline or 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-(((R)-methylsulfinic Acyl)methyl)azetidin-1-yl)isoquinoline (53mg, 0.15mmol), cesium carbonate (147mg, 0.45mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6- Dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)( 7 mg, 0.008 mmol). After the addition was complete, the resulting reaction solution was heated up to 100° C. and stirred for 16 hours under the protection of nitrogen. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=15/1) to obtain a crude product. Crude product is passed through reverse phase flash chromatography (column: spherical C18,20-40 μ m, 40g; Mobile phase A: the aqueous solution containing 0.1% ammoniacal liquor; Mobile phase B: acetonitrile; Flow velocity: 40mL/min; Gradient: 40% in 20 minutes B-95% B; detector: 254nm) purification, when the content of mobile phase B reached 46%, the fraction containing the product was collected and then concentrated under reduced pressure to obtain N-(5-chloro-2-((3R, 4S)-3 -Fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-(((S)- Methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-amine or N-(5-chloro-2-((3R,4S)-3-fluoro-4-methyl Oxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-(((R)-methylsulfinyl) Methyl)azetidin-1-yl)isoquinolin-3-amine (2.65 mg, 0.005 mmol, yield: 3.0%), LCMS m/z: 575 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.11(s,1H),8.62(s,1H),8.31(s,1H),8.19(s,1H),7.49(d,J＝7.6Hz, 1H),6.65(d,J＝8.0Hz,1H),5.02-4.89(m,1H),4.69-4.65(m,2H),4.46-4.43(m,1H),4.25-4.22(m,1H) ,3.66-3.50(m,4H),3.36(s,3H),3.27(s,1H),3.18-3.13(m,1H),3.02-2.97(m,1H),2.92-2.88(m,1H) , 2.67 (s, 3H), 1.84-1.72 (m, 2H), 1.43 (d, J=6.0Hz, 3H), 1.33-1.29 (m, 6H).

Example 96, N-(5-chloro-2-((3R,4S)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8 -((2R,3S)-2-methyl-3-(((R)-methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-amine or N- (5-Chloro-2-((3R, 4S)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R, 3S Synthesis of )-2-methyl-3-(((S)-methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-amine (Compound 96)

At room temperature, 5-chloro-2-((3R,4S)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine (40 mg, 0.15 mmol) was dissolved in dioxy Hexacyclic solution (5 mL), add 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-(((S)-methylsulfinyl)methyl) Azetidin-1-yl)isoquinoline or 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-(((R)-methylsulfinic Acyl)methyl)azetidin-1-yl)isoquinoline (53mg, 0.15mmol), cesium carbonate (147mg, 0.45mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6- Dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)( 7 mg, 0.008 mmol). After the addition was complete, the resulting reaction solution was heated up to 100° C. and stirred for 16 hours under the protection of nitrogen. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=15/1) to obtain a crude product. Crude product is passed through reverse phase flash chromatography (column: spherical C18,20-40 μ m, 40g; Mobile phase A: the aqueous solution containing 0.1% ammoniacal liquor; Mobile phase B: acetonitrile; Flow rate: 40mL/min; Gradient: 40% in 20 minutes B-95% B; detector: 254nm) purification, when the content of mobile phase B reached 48%, the fraction containing the product was collected, then concentrated under reduced pressure to obtain N-(5-chloro-2-((3R, 4S)- 3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-(((R) -Methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-amine or N-(5-chloro-2-((3R,4S)-3-fluoro-4- Methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-(((S)-methylsulfinyl )methyl)azetidin-1-yl)isoquinolin-3-amine (2.59 mg, 0.005 mmol, yield: 2.9%), LCMS m/z: 575[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.10(s,1H),8.62(s,1H),8.32(s,1H),8.19(s,1H),7.49(d,J＝8.0Hz, 1H),6.64(d,J＝8.0Hz,1H),5.02-4.89(m,1H),4.70-4.65(m,2H),4.46-4.43(m,1H),4.25-4.22(m,1H) ,3.66-3.49(m,4H),3.36(s,3H),3.30-3.26(m,1H),3.15-3.04(m,2H),2.86-2.82(m,1H),2.57(s,3H) ,1.84-1.71(m,2H),1.41(d,J＝6.0Hz,3H),1.33-1.29(m,6H).、

Example 97, (3R, 4S)-3-fluoro-1-(4-((5-isopropyl-8-((2R, 3S)-2-methyl-3-(((S)-methyl Sulfinyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)piperidin-4-ol or (3R,4S)-3-fluoro -1-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-(((R)-methylsulfinyl)methyl)azetidine Synthesis of -1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)piperidin-4-ol (Compound 97)

At room temperature, a solution of (3R,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoropiperidin-4-ol (30mg, 0.14mmol) in dioxane (5mL) In, add 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-(((S)-methylsulfinyl)methyl)azetidine- 1-yl)isoquinoline or 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-(((R)-methylsulfinyl)methyl)nitrogen Heterobutan-1-yl)isoquinoline (49 mg, 0.14 mmol), cesium carbonate (137 mg, 0.42 mmol) and (2-dicyclohexylphosphine)-3,6-dimethoxy-2 methanesulfonate ',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (6 mg, 0.007 mmol). After the addition was complete, the resulting reaction solution was heated up to 100° C. and stirred for 16 hours under the protection of nitrogen. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=15/1) to obtain a crude product. Crude product is passed through reverse phase flash chromatography (column: spherical C18,20-40 μ m, 40g; Mobile phase A: the aqueous solution containing 0.1% ammoniacal liquor; Mobile phase B: acetonitrile; Flow rate: 40mL/min; Gradient: 30% in 20 minutes B-80% B; Detector: 254nm) purification, when mobile phase B content reaches 43%, collects the cut that contains product and then concentrates under reduced pressure to obtain (3R, 4S)-3-fluoro-1-(4-(( 5-isopropyl-8-((2R,3S)-2-methyl-3-(((S)-methylsulfinyl)methyl)azetidin-1-yl)isoquinoline -3-yl)amino)pyrimidin-2-yl)piperidin-4-ol or (3R,4S)-3-fluoro-1-(4-((5-isopropyl-8-((2R,3S )-2-methyl-3-(((R)-methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl) Piperidin-4-ol (9.14 mg, 0.017 mmol, yield: 12.3%), LCMS m/z: 527 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.93(s, 1H), 9.07(s, 1H), 8.66(s, 1H), 8.00(d, J=5.6Hz, 1H), 7.42(d, J＝8.0Hz, 1H), 6.57(d, J＝8.0Hz, 1H), 6.45(d, J＝5.6Hz, 1H), 5.15(s, 1H), 4.75-4.63(m, 3H), 4.40- 4.37(m,1H),4.23-4.20(m,1H),3.91-3.84(m,1H),3.64-3.49(m,3H),3.36(s,1H),3.17-3.12(m,1H), 3.01-2.85 (m, 2H), 2.56 (s, 3H), 1.73-1.72 (m, 2H), 1.42 (d, J=5.6Hz, 3H), 1.30 (t, J=6.8Hz, 6H).

Example 98. (3R, 4S)-3-fluoro-1-(4-((5-isopropyl-8-((2R, 3S)-2-methyl-3-(((R)-methyl Sulfinyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)piperidin-4-ol or (3R,4S)-3-fluoro -1-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-(((S)-methylsulfinyl)methyl)azetidine Synthesis of -1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)piperidin-4-ol (compound 98)

At room temperature, a solution of (3R,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoropiperidin-4-ol (30mg, 0.14mmol) in dioxane (5mL) In, add 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-(((R)-methylsulfinyl)methyl)azetidine- 1-yl)isoquinoline or 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-(((S)-methylsulfinyl)methyl)nitrogen Heterobutan-1-yl)isoquinoline (49 mg, 0.14 mmol), cesium carbonate (137 mg, 0.42 mmol) and (2-dicyclohexylphosphine)-3,6-dimethoxy-2 methanesulfonate ',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (6 mg, 0.007 mmol). After the addition was complete, the resulting reaction solution was heated up to 100° C. and stirred for 16 hours under the protection of nitrogen. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=15/1) to obtain a crude product. Crude product is passed through reverse phase flash chromatography (column: spherical C18,20-40 μ m, 40g; Mobile phase A: the aqueous solution containing 0.1% ammoniacal liquor; Mobile phase B: acetonitrile; Flow rate: 40mL/min; Gradient: 30% in 20 minutes B-80% B; Detector: 254nm) purification, when mobile phase B content reaches 45%, collects the cut that contains product and then concentrates under reduced pressure to obtain (3R, 4S)-3-fluoro-1-(4-(( 5-isopropyl-8-((2R,3S)-2-methyl-3-(((R)-methylsulfinyl)methyl)azetidin-1-yl)isoquinoline -3-yl)amino)pyrimidin-2-yl)piperidin-4-ol or (3R,4S)-3-fluoro-1-(4-((5-isopropyl-8-((2R,3S )-2-methyl-3-(((S)-methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl) Piperidin-4-ol (15.37 mg, 0.029 mmol, yield: 20.7%), LCMS m/z: 527[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.92(s, 1H), 9.06(s, 1H), 8.66(s, 1H), 7.99(d, J=5.6Hz, 1H), 7.42(d, J＝8.0Hz, 1H), 6.56(d, J＝8.0Hz, 1H), 6.44(d, J＝5.6Hz, 1H), 5.14(d, J＝5.2Hz, 1H), 4.76-4.59(m, 3H),4.40-4.37(m,1H),4.23-4.20(m,1H),3.91-3.83(m,1H),3.64-3.47(m,3H),3.38-3.36(m,1H),3.14- 3.03(m,2H),2.85-2.79(m,1H),2.58(s,3H),1.73-1.72(m,2H),1.41(d,J＝6.4Hz,3H),1.30(t,J＝ 7.2Hz,6H).

Example 99, N-(2-((3R,4S)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl- 8-((2R,3S)-2-methyl-3-(((S)-methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-amine or N -(2-((3R,4S)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R , Synthesis of 3S)-2-methyl-3-(((R)-methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-amine (Compound 99)

At room temperature, 2-((3R,4S)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-amine (40mg, 0.17mmol) was dissolved in dioxygen To hexacyclone (10 mL), add 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-(((S)-methylsulfinyl)methyl)nitrogen Heterocyclobutan-1-yl)isoquinoline or 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-(((R)-methylsulfinyl )methyl)azetidin-1-yl)isoquinoline (60mg, 0.17mmol), cesium carbonate (166mg, 0.51mmol) and (2-dicyclohexylphosphine)-3,6-bis Methoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (15mg , 0.017mmol). After the addition was complete, the resulting reaction liquid was heated up to 100° C. and stirred for 16 hours under the protection of nitrogen. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane/methanol=15/1) to obtain a crude product. Crude product is passed through reverse phase flash chromatography (chromatographic condition: column: spherical C18,20-40 μ m, 40g mobile phase A: the water that contains 0.1% ammoniacal liquor; Mobile phase B: acetonitrile; Flow velocity: 40mL/min; Gradient: within 20 minutes 40% B-95% B; Detector: 254nm) purify, when mobile phase B content reaches 53% B, collect the fraction containing product, then concentrate under reduced pressure to obtain compound N-(2-((3R, 4S)- 3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3- (((S)-methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-amine or N-(2-((3R,4S)-3-fluoro-4 -Methoxy-3-methylpiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-(((R) -Methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-amine (3.08 mg, 0.006 mmol, yield: 3.3%) LCMS m/z: 555 [M+H ] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.88(s, 1H), 9.07(s, 1H), 8.58(s, 1H), 7.99(d, J=5.6Hz, 1H), 7.42(d, J＝8.0Hz, 1H), 6.57(d, J＝8.0Hz, 1H), 6.48(d, J＝5.6Hz, 1H), 4.71-4.64(m, 2H), 4.23-4.20(m, 2H), 3.62(t,J=7.2Hz,1H),3.53-3.49(m,1H),3.42-3.35(m,4H),3.26-3.12(m,3H),3.01-2.96(m,1H),2.90- 2.85 (m, 1H), 2.56 (s, 3H), 1.99-1.95 (m, 1H), 1.64-1.61 (m, 1H), 1.43-1.30 (m, 12H).

Example 100, N-(2-((3R,4S)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl- 8-((2R,3S)-2-methyl-3-(((R)-methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-amine or N -(2-((3R,4S)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R , Synthesis of 3S)-2-methyl-3-(((S)-methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-amine (Compound 100)

At room temperature, 2-((3R,4S)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-amine (40mg, 0.17mmol) was dissolved in dioxygen To hexacyclo (10 mL), add 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-(((R)-methylsulfinyl)methyl)nitrogen Heterobutan-1-yl)isoquinoline or 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-(((S)-methylsulfinyl )methyl)azetidin-1-yl)isoquinoline (60mg, 0.17mmol), cesium carbonate (166mg, 0.51mmol) and (2-dicyclohexylphosphine)-3,6-bis Methoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (15mg , 0.017mmol). After the addition was complete, the resulting reaction liquid was heated up to 100° C. and stirred for 16 hours under the protection of nitrogen. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane/methanol=15/1) to obtain a crude product. Crude product is passed through reverse phase flash chromatography (chromatographic condition: column: spherical C18,20-40 μ m, 40g mobile phase A: the water that contains 0.1% ammoniacal liquor; Mobile phase B: acetonitrile; Flow velocity: 40mL/min; Gradient: within 20 minutes 40% B-95% B; Detector: 254nm) purify, when mobile phase B content reaches 50% B, collect the fraction containing product, then concentrate under reduced pressure to obtain compound N-(2-((3R, 4S)- 3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3- (((R)-methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-amine or N-(2-((3R,4S)-3-fluoro-4 -Methoxy-3-methylpiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-(((S) -Methylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-amine (9.03 mg, 0.016 mmol, yield: 9.7%) LCMS m/z: 555 [M+H ] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.88(s, 1H), 9.06(s, 1H), 8.58(s, 1H), 7.99(d, J=5.6Hz, 1H), 7.42(d, J＝8.0Hz, 1H), 6.56(d, J＝8.0Hz, 1H), 6.48(d, J＝5.6Hz, 1H), 4.71-4.63(m, 3H), 4.22(t, J＝6.0Hz, 1H), 3.62(t, J=6.8Hz, 1H), 3.52-3.49(m, 1H), 3.41-3.35(m, 4H), 3.26-3.03(m, 4H), 2.84-2.81(m, 1H) ,2.57(s,3H),1.99-1.95(m,1H),1.65-1.62(m,1H),1.42-1.30(m,12H).

Example 101, (3R,4S)-1-(4-((8-((2R,3S)-3-(((S)-(cyclopropylmethyl)sulfinyl)methyl)-2 -Methylazetidin-1-yl)-5-isopropylisoquinolin-3-yl)amino)pyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol or (3R, 4S)-1-(4-((8-((2R, 3S)-3-(((R)-(cyclopropylmethyl)sulfinyl)methyl)-2-methyl Azetidin-1-yl)-5-isopropylisoquinolin-3-yl)amino)pyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (compound 101 )Synthesis

At room temperature, to dioxane dissolved in (3R,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (20mg, 0.09mmol) Cyclo(7mL) solution was added 3-chloro-8-((2R,3S)-3-(((S)-(cyclopropylmethyl)sulfinyl)methyl)-2-methylazepine Cyclobutan-1-yl)-5-isopropylisoquinoline or 3-chloro-8-((2R,3S)-3-(((R)-(cyclopropylmethyl)sulfinyl) Methyl)-2-methylazetidin-1-yl)-5-isopropylisoquinoline (35mg, 0.09mmol), cesium carbonate (88mg, 0.27mmol) and methanesulfonic acid (2-di Cyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl- 2-yl)palladium(II) (8mg, 0.009mmol). After the addition was complete, the resulting reaction solution was heated up to 100° C. and stirred for 16 hours under the protection of nitrogen. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane/methanol=15/1) to obtain a crude product. Crude product is passed through reverse phase flash chromatography (chromatographic condition: column: spherical C18,20-40 μ m, 40g; Mobile phase A: the water that contains 0.1% ammoniacal liquor; Mobile phase B: acetonitrile; Flow rate: 40mL/min; Gradient: 20 minutes 40%B-95%B; detector: 254nm) purification, when the mobile phase B content reached 47%, the fraction containing the product was collected, then concentrated under reduced pressure to obtain (3R, 4S)-1-(4-(( 8-((2R,3S)-3-(((S)-(cyclopropylmethyl)sulfinyl)methyl)-2-methylazetidin-1-yl)-5-iso Propylisoquinolin-3-yl)amino)pyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol or (3R,4S)-1-(4-((8-( (2R,3S)-3-(((R)-(cyclopropylmethyl)sulfinyl)methyl)-2-methylazetidin-1-yl)-5-isopropyliso Quinolin-3-yl)amino)pyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (2.34 mg, 0.004 mmol, yield: 4.5%), LCMS m/z: 581 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.89(s, 1H), 9.06(s, 1H), 8.61(s, 1H), 7.98(d, J=6.0Hz, 1H), 7.42(d, J＝8.0Hz, 1H), 6.56(d, J＝8.4Hz, 1H), 6.45(d, J＝5.6Hz, 1H), 5.04-5.03(m, 1H), 4.77-4.64(m, 3H), 4.24-4.21(m,1H),3.64-3.49(m,3H),3.20-3.03(m,4H),2.86-2.75(m,2H),2.67-2.61(m,1H),1.75-1.73(m ,2H), 1.42-1.29(m,12H), 1.05-1.01(m,1H), 0.63-0.56(m,2H), 0.39-0.28(m,2H).

Embodiment 102, compound 102 to compound 308, and the synthesis of A1-A40:

Similar to the synthesis steps of Compound 1 to Compound 101 in Example 1-101, the following Compound 102 to Compound 308, Compound A1 to Compound A40 can be obtained:

Biological test: biochemical analysis of EGFR enzyme activity inhibitory activity:

The EGFR inhibitory effect of the compounds of the invention was determined in a biochemical assay: EGFR enzyme phosphorylation of 2.5 micromolar 5-FAMEEPLYWSFPAKKK-CONFh was measured in the presence of adenosine-5'-triphosphate (ATP) and different concentrations of the test compound Activity of peptide substrate (FL-Peptide 22, PerkinElmer, 760366). Mix EGFR enzyme, fluorescently labeled substrate peptide, ATP, and test compound in 100 mM 2-[4-(2-hydroxyethyl)piperazin-l-yl]ethanesulfonic acid (HEPES), pH 7.5, 10 mM MgCl ₂ , 0.015% Brij-35, 1 mM dithiothreitol (DTT) and 1.0% dimethyl sulfoxide (DMSO), the kinase reaction was initiated. Assays were performed at 1.0 mM ATP or ATP Km for EGFR enzyme. The reaction was continued until 10% to 20% of the total peptides were phosphorylated at room temperature (25°C) with 35 mM 2,2',2'',2'"-(ethane-l,2-diacyldi The reaction was terminated with nitro)tetraacetic acid (EDTA). EGFR enzyme activity was monitored using the Perkin-Elmer electrophoretic mobility shift technology platform (caliper shift detection method), where phosphorylated peptide (product) and substrate were separated and measured by electrophoresis. According to the compound The logarithm of concentration and dot plot activity percentage.The enzyme phenotype of the EGFR of detection analysis is as follows: EGFRWT; EGFR (L858R T790M C797S); EGFR (d746-750) T790M C797S; D770_N77 IinsNPG T790M); EGFR (D770_N771 insNPG).

Reagents and consumables:

White 384-well MicroPlate(Cat#264706,Nunc);HTRF kinEASE TK kit(Cat#62TKOPEC,Cisbio);TK-biotin substrate;Streptavidin-XL665;TK Antibody-Cryptate;5x Enzymatic buffer;SEB;HTRF Detection buffer; EGFR -L858R/T790M/C797S (Cat#A33502, Invitrogen); EGFR-DEL19/T790M/C797S (Cat#E10-122UG-10, Signalchem); EGFR-WT (Invitrogen/PV3872); ATP 10mM (Cat#PV3227, Invitrogen ); DTT 1M (Cat#D5545, Sigma); MgCl2 1M (Cat#M8266, Sigma); MnCl2 1M (Cat#244589, Sigma);

equipment:

SpectraMax i3x Multi-Mode Reader(Molecular Devices)

Test operation:

1) The compound to be tested is diluted with 2.5% DMSO 1×enzyme buffer, starting from 1uM (the concentration used for EDFR-wt screening is from 100uM), diluted 4 times, and 10 concentration gradients.

2) Dilute with sterile water to configure 1× enzyme buffer, add DTT, MgCl2 and MnCl2.

3) Dilute with 1× enzyme buffer to prepare 10× working solution of TK-biotin substrate, ATP and enzyme. Dilute with sterile water to prepare Streptavidin-XL665 working solution.

4) Add 2 μL TK-biotin substrate (0.33uM), 2 μL ATP (1 μM), 2 μL Kinase (0.6ng/well) and 4 μL test compound to the 384-well plate in sequence. Mix well, seal the plate, and incubate at room temperature for 30 minutes.

5) Add 10μL Streptavidin-XL665 (41.25nM) and TK Antibody-Cryptate (1:100). Mix well, seal the plate, and incubate at room temperature for 60 minutes.

6) Read the plate with a microplate reader, the excitation light is 320nm, and the emission light is 615nm and 665nm.

Data processing and analysis:

Emission Ratio(ER)＝Em665/Em615

The ER of the compound well is marked as ER _compound , the ER of the Vehicle control well is marked as ER _vehicle , and the ER of the blank control well is marked as ER _blank .

Inhibition rate was calculated with the following formula:

Inhibition rate = (ER _vehicle -ER _compound )/(ER _vehicle -ER _blank )×100%

The inhibition rate was analyzed by GraphPad Prism 6 (version 6.01), and the IC50 was calculated.

Results and discussion:

The inhibitory activity of some representative compounds on various mutants of EGFR and EGFR-wt kinase is as follows:

The reference compound Blu-945 was purchased from Shanghai Pansuo Pharmaceutical Technology Co., Ltd.

As can be seen from the results in the table: most of the compounds of the present invention have a strong inhibitory effect on the protein activity of triple EGFR mutants (Dell9-T790M-C797S and L858R-T790M-C797S), and have extremely high selectivity to EGFR-wt .

The implementation manners of the technical solutions of the present invention are described above as examples. It should be understood that the protection scope of the present invention is not limited to the above-mentioned embodiments. Any modifications, equivalent replacements, improvements, etc. made by those skilled in the art within the spirit and principles of the present invention shall be included within the protection scope of the claims of the present application.

Claims

Compound shown in formula (I), its pharmaceutically acceptable salt, solvate or hydrate and its isotope or isomer:

in,

A and B are 3-20-membered ring structures, and the ring structures can be arbitrarily monocyclic, bicyclic, tricyclic, bridging rings or spiro rings containing 0 to more unsaturated bonds; and the ring structures It can optionally contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;

X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 and X 8 are each independently selected from C(R 0 ) or N; or, X 5 , X 6 and their respective attached atoms form a hydrocarbon ring or heterocycle; or, X 2 and X 1 or X 2 and X 3 form a hydrocarbon ring or a heterocycle with their respective attached atoms;

Y 0 is independently selected from a single bond, an acetylene bond, -O-, -S-, -N(R 3 )-, -C(R 6 R 7 )O-, -OC(R 6 R 7 )- or - C(R 6 R 7 )-;

Y1 and Y2 are each independently selected from CH or N;

R is randomly selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, amino, alkenyl , hydroxyl, cyano, nitro; and any two adjacent X 1 , X 2 and X 3 or any two adjacent X 5 , X 6 , X 7 and X 8 together with the R 0 connected thereto can constitute 3-10 membered ring structure, the ring structure can be any saturated, unsaturated or aromatic structure, and the ring structure can contain 0 to more heteroatoms, the heteroatoms can be selected from O , S or N;

R is independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, Deuterated C1-6 alkoxy, cycloalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy; and the hydroxyl, amino, C1-6 alkyl, alkenyl, Hydrogen on alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy Can be optionally further substituted by 1 to more substituents, the substituents are arbitrarily selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 Alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, cycloalkoxy;

R is arbitrarily selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, amino, alkenyl, cyano, Cyanoalkyl, nitro, acyl, sulfonyl, phosphono; and the C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocyclic, The hydrogen on the heterocycloalkyl, amino, alkenyl, cyano, cyanoalkyl, nitro, acyl, sulfonyl, phosphono can be optionally further substituted by 1 to more substituents, and the substituents are optionally The following groups selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, unsubstituted or optionally substituted by one, two or more R 5 : C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, sulfone, sulfoxide , alkylsulfone group, alkylsulfoxide group, alkylaminosulfone group, iminosulfone group, acyl group, sulfonyl group, sulfinyl group, phosphono group, cycloalkoxy group, phosphonocycloalkoxy group,

Z is any independently O, NH or N(R 3 );

R is arbitrarily selected from H, deuterium, halogen, hydroxyl, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, amino, C1-6 alkylamino, alkenyl, alkynyl, nitro, cyano, cyanoalkyl, C1-6 alkyl acyl, halogenated C1-6 alkyl acyl, sulfonyl, phosphono;

R is independently selected from H, deuterium, halogen, hydroxyl, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, Amino, C1-6 alkylamino, alkenyl, alkynyl, cyano, cyanoalkyl, C1-6 alkyl acyl, halogenated C1-6 alkyl acyl; and the hydrogen on R can be the most optional Further substituted by 1 to more substituents, any of which are independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkane Oxygen, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, cycloalkoxy, alkylamino;

R and R are arbitrarily selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, amino, C1-6 Alkylamino, alkenyl, alkynyl, nitro, cyano, cyanoalkyl; or R 7 and R 6 form a 3-10-membered ring structure together with the carbon directly connected to it, and the ring structure can be any It is a monocyclic ring, a bicyclic ring, a bridged ring or a spiro ring containing 0 to more unsaturated bonds; and the ring structure can optionally contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;

The halogen is F, Cl, Br and iodine and their respective isotopes;

m, n and t are each independently 0, 1, 2, 3, 4 or 5.
According to the compound described in claim 1, its pharmaceutically acceptable salt, solvate or hydrate and its isotope or isomer, it has formula (I') structure:

in,

A and B are 3-20-membered ring structures, and the ring structures can be arbitrarily monocyclic, bicyclic, tricyclic, bridging rings or spiro rings containing 0 to more unsaturated bonds; and the ring structures It can optionally contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;

X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 and X 8 are each independently selected from C(R 0 ) or N;

Y 0 is independently selected from a single bond, an acetylene bond, -O-, -S-, -N(R 3 )-, -C(R 6 R 7 )O-, -OC(R 6 R 7 )- or - C(R 6 R 7 )-;

R is randomly selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, amino, alkenyl , hydroxyl, cyano, nitro; and any two adjacent X 1 , X 2 and X 3 or any two adjacent X 5 , X 6 , X 7 and X 8 together with the R 0 connected thereto can constitute 3-10 membered ring structure, the ring structure can be any saturated, unsaturated or aromatic structure, and the ring structure can contain 0 to more heteroatoms, the heteroatoms can be selected from O , S or N;

R is independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, Deuterated C1-6 alkoxy, cycloalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy; and the hydroxyl, amino, C1-6 alkyl, alkenyl, Hydrogen on alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy Can be optionally further substituted by 1 to more substituents, the substituents are arbitrarily selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 Alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, cycloalkoxy;

R is arbitrarily selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, amino, alkenyl, cyano, Cyanoalkyl, nitro, acyl, sulfonyl, phosphono; and the C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocyclic, The hydrogen on the heterocycloalkyl, amino, alkenyl, cyano, cyanoalkyl, nitro, acyl, sulfonyl, phosphono can be optionally further substituted by 1 to more substituents, and the substituents are optionally From hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkane Oxygen, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, sulfone, sulfoxide, alkylsulfone, alkylsulfoxide, alkylaminosulfone, iminosulfone , acyl, sulfonyl, phosphonocycloalkoxy;

R is arbitrarily selected from H, deuterium, halogen, hydroxyl, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, amino, C1-6 alkylamino, alkenyl, alkynyl, nitro, cyano, cyanoalkyl, C1-6 alkyl acyl, halogenated C1-6 alkyl acyl, sulfonyl, phosphono;

R and R are arbitrarily selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, amino, C1-6 Alkylamino, alkenyl, alkynyl, nitro, cyano, cyanoalkyl; or R 7 and R 6 form a 3-10-membered ring structure together with the carbon directly connected to it, and the ring structure can be any It is a monocyclic ring, a bicyclic ring, a bridged ring or a spiro ring containing 0 to more unsaturated bonds; and the ring structure can optionally contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;

The halogen is F, Cl, Br and iodine and their respective isotopes;

m, n and t are each independently 0, 1, 2, 3, 4 or 5;

Preferably, the compound, its pharmaceutically acceptable salt, solvate or hydrate and its isotopes or isomers have the structure of formula (IA):

in,

A is a 3-20-membered ring structure, and the ring structure can be arbitrarily monocyclic, bicyclic, tricyclic, bridged or spiro ring containing 0 to more unsaturated bonds; and the ring structure can be any Contains 0 to more heteroatoms, the heteroatoms are arbitrarily selected from O, S or N;

X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 and X 8 are each independently selected from C(R 0 ) or N;

Y 0 is independently selected from a bond, an acetylene bond, -O-, -S-, -N(R 3 )-, -C(R 6 R 7 )O-, -OC(R 6 R 7 )- or -C (R 6 R 7 )-;

R is randomly selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, amino, alkenyl , hydroxyl, cyano, nitro; and any two adjacent X 1 , X 2 and X 3 or any two adjacent X 5 , X 6 , X 7 and X 8 together with the R 0 connected thereto can constitute 3-10 membered ring structure, the ring structure can be any saturated, unsaturated or aromatic structure, and the ring structure can contain 0 to more heteroatoms, the heteroatoms can be selected from O , S or N;

R is independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, Deuterated C1-6 alkoxy, cycloalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy; and the hydroxyl, amino, C1-6 alkyl, alkenyl, Hydrogen on alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy Can be optionally further substituted by 1 to more substituents, the substituents are arbitrarily selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 Alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, cycloalkoxy;

R is arbitrarily selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, amino, alkenyl, cyano, Cyanoalkyl, nitro, acyl, sulfonyl, phosphono; and the C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocyclic, The hydrogen on the heterocycloalkyl, amino, alkenyl, cyano, cyanoalkyl, nitro, acyl, sulfonyl, phosphono can be optionally further substituted by 1 to more substituents, and the substituents are optionally From hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkane Oxygen, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, sulfone, sulfoxide, alkylsulfone, alkylsulfoxide, alkylaminosulfone, iminosulfone , acyl, sulfonyl, phosphonocycloalkoxy;

Each of R and R is independently selected from H, deuterium, halogen, hydroxyl, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocyclyl Cycloalkyl, amino, C1-6 alkylamino, alkenyl, alkynyl, nitro, cyano, cyanoalkyl, C1-6 alkyl acyl, halogenated C1-6 alkyl acyl, sulfonyl, phosphine Acyl;

Each of R and R is independently selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, amino, C1-6 alkylamino group, alkenyl group, alkynyl group, nitro group, cyano group, cyanoalkyl group; or R 7 and R 6 form a 3-10 membered ring structure together with the directly connected carbon, and the ring The structure can be arbitrarily monocyclic, bicyclic, bridged or spiro ring containing 0 to more unsaturated bonds; and the ring structure can arbitrarily contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;

The halogen is F, Cl, Br and iodine and their respective isotopes;

m and t are each independently 0, 1, 2, 3, 4 or 5;

n is independently 1, 2, 3, 4 or 5.
According to the compound described in claim 1 or 2, its pharmaceutically acceptable salt, solvate or hydrate and its isotope or isomer, it has formula (IB) structure:

in,

A is a 3-20-membered ring structure, and the ring structure can be arbitrarily monocyclic, bicyclic, tricyclic, bridged or spiro ring containing 0 to more unsaturated bonds; and the ring structure can be any Contains 0 to more heteroatoms, the heteroatoms are arbitrarily selected from O, S or N;

X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 and X 8 are each independently selected from C(R 0 ) or N;

Y 0 is independently selected from a bond, an acetylene bond, -O-, -S-, -N(R 3 )-, -C(R 6 R 7 )O-, -OC(R 6 R 7 )- or -C (R 6 R 7 )-;

Z is any independently absent, O, NH or N(R 5 );

R is randomly selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, amino, alkenyl , hydroxyl, cyano, nitro; and two adjacent X 1 and X 2 or any two adjacent X 5 , X 6 , X 7 and X 8 together with the R 0 connected thereto can form 3-10 members A ring structure, the ring structure can be any saturated, unsaturated or aromatic structure, and the ring structure can optionally contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N ;

R is independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, Deuterated C1-6 alkoxy, cycloalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy; and the hydroxyl, amino, C1-6 alkyl, alkenyl, Hydrogen on alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy Can be optionally further substituted by 1 to more substituents, the substituents are arbitrarily selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 Alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, cycloalkoxy;

R is arbitrarily selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, amino, alkenyl, cyano, Cyanoalkyl, nitro, acyl, sulfonyl, phosphono; and the C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocyclic, The hydrogen on the heterocycloalkyl, amino, alkenyl, cyano, cyanoalkyl, nitro, acyl, sulfonyl, phosphono can be optionally further substituted by 1 to more substituents, and the substituents are optionally From hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkane Oxygen, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, sulfone, sulfoxide, alkylsulfone, alkylsulfoxide, alkylaminosulfone, iminosulfone , acyl, sulfonyl, phosphonocycloalkoxy;

Each of R and R is independently selected from H, deuterium, halogen, hydroxyl, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocyclyl Cycloalkyl, amino, C1-6 alkylamino, alkenyl, alkynyl, nitro, cyano, cyanoalkyl, C1-6 alkyl acyl, halogenated C1-6 alkyl acyl, sulfonyl, phosphine Acyl;

Each of R and R is independently selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, amino, C1-6 alkylamino group, alkenyl group, alkynyl group, nitro group, cyano group, cyanoalkyl group; or R 7 and R 6 form a 3-10 membered ring structure together with the directly connected carbon, and the ring The structure can be arbitrarily monocyclic, bicyclic, bridged or spiro ring containing 0 to more unsaturated bonds; and the ring structure can arbitrarily contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;

The halogen is F, Cl, Br and iodine and their respective isotopes;

m and t are each independently 0, 1, 2, 3, 4 or 5;

n is independently 1, 2, 3, 4 or 5.
According to the compound described in any one of claims 1-3, its pharmaceutically acceptable salt, solvate or hydrate and its isotope or isomer, it has formula (IC) structure:

in,

Any represents a single or double bond;

X 0 is independently selected from -O-, -S-, -N(R 5 )-, -S(O)-, -S(O) 2 -, -C(R 6 R 7 )O-, -OC (R 6 R 7 )-or -C(R 6 R 7 )-;

X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 and X 8 are each independently selected from C(R 0 ) or N;

Y 0 is independently selected from a bond, an acetylene bond, -O-, -S-, -N(R 3 )-, -C(R 6 R 7 )O-, -OC(R 6 R 7 )- or -C (R 6 R 7 )-;

R is randomly selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, amino, alkenyl , hydroxyl, cyano, nitro; and any two adjacent X 1 , X 2 and X 3 or any two adjacent X 5 , X 6 , X 7 and X 8 together with the R 0 connected thereto can constitute 3-10 membered ring structure, the ring structure can be any saturated, unsaturated or aromatic structure, and the ring structure can contain 0 to more heteroatoms, the heteroatoms can be selected from O , S or N;

R is independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, Deuterated C1-6 alkoxy, cycloalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy; and the hydroxyl, amino, C1-6 alkyl, alkenyl, Hydrogen on alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy Can be optionally further substituted by 1 to more substituents, the substituents are arbitrarily selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 Alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, cycloalkoxy;

R is arbitrarily selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, amino, alkenyl, cyano, Cyanoalkyl, nitro, acyl, sulfonyl, phosphono; and the C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocyclic, The hydrogen on the heterocycloalkyl, amino, alkenyl, cyano, cyanoalkyl, nitro, acyl, sulfonyl, phosphono can be optionally further substituted by 1 to more substituents, and the substituents are optionally From hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkane Oxygen, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, sulfone, sulfoxide, alkylsulfone, alkylsulfoxide, alkylaminosulfone, iminosulfone , acyl, sulfonyl, phosphonocycloalkoxy;

Each of R and R is independently selected from H, deuterium, halogen, hydroxyl, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocyclyl Cycloalkyl, amino, C1-6 alkylamino, alkenyl, alkynyl, nitro, cyano, cyanoalkyl, C1-6 alkyl acyl, halogenated C1-6 alkyl acyl, sulfonyl, phosphine Acyl;

Each of R and R is independently selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, amino, C1-6 alkylamino group, alkenyl group, alkynyl group, nitro group, cyano group, cyanoalkyl group; or R 7 and R 6 form a 3-10 membered ring structure together with the directly connected carbon, and the ring The structure can be arbitrarily monocyclic, bicyclic, bridged or spiro ring containing 0 to more unsaturated bonds; and the ring structure can arbitrarily contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;

The halogen is F, Cl, Br and iodine and their respective isotopes;

m and t are each independently 0, 1, 2, 3, 4 or 5;

n is independently 1, 2, 3, 4 or 5.
According to the compound described in any one of claims 1-4, its pharmaceutically acceptable salt, solvate or hydrate and its isotope or isomer, it has formula (ID) structure:

in,

A is a 3-20-membered ring structure, and the ring structure can be arbitrarily monocyclic, bicyclic, tricyclic, bridged or spiro ring containing 0 to more unsaturated bonds; and the ring structure can be any Contains 0 to more heteroatoms, the heteroatoms are arbitrarily selected from O, S or N;

X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 are each independently selected from C(R 0 ) or N;

Y 0 is independently selected from a bond, an acetylene bond, -O-, -S-, -N(R 3 )-, -C(R 6 R 7 )O-, -OC(R 6 R 7 )- or -C (R 6 R 7 )-;

Z is any independently absent, O, NH or N(R 5 );

R is randomly selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, amino, alkenyl , hydroxyl, cyano, nitro; any two adjacent X 5 , X 6 , X 7 and X 8 together with the R 0 connected thereto can form a 3-10-membered ring structure, and the ring structure can be Any saturated, unsaturated or aromatic structure, and the ring structure can optionally contain 0 to more heteroatoms, and the heteroatoms are randomly selected from O, S or N;

R is independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, Deuterated C1-6 alkoxy, cycloalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy; and the hydroxyl, amino, C1-6 alkyl, alkenyl, Hydrogen on alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy Can be optionally further substituted by 1 to more substituents, the substituents are arbitrarily selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 Alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, cycloalkoxy;

R is arbitrarily selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, amino, alkenyl, cyano, Cyanoalkyl, nitro, acyl, sulfonyl, phosphono; and the C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocyclic, The hydrogen on the heterocycloalkyl, amino, alkenyl, cyano, cyanoalkyl, nitro, acyl, sulfonyl, phosphono can be optionally further substituted by 1 to more substituents, and the substituents are optionally From hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkane Oxygen, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, sulfone, sulfoxide, alkylsulfone, alkylsulfoxide, alkylaminosulfone, iminosulfone , acyl, sulfonyl, phosphonocycloalkoxy;

Each of R and R is independently selected from H, deuterium, halogen, hydroxyl, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocyclyl Cycloalkyl, amino, C1-6 alkylamino, alkenyl, alkynyl, nitro, cyano, cyanoalkyl, C1-6 alkyl acyl, halogenated C1-6 alkyl acyl, sulfonyl, phosphine Acyl;

Each of R and R is independently selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, amino, C1-6 alkylamino group, alkenyl group, alkynyl group, nitro group, cyano group, cyanoalkyl group; or R 7 and R 6 form a 3-10 membered ring structure together with the directly connected carbon, and the ring The structure can be arbitrarily monocyclic, bicyclic, bridged or spiro ring containing 0 to more unsaturated bonds; and the ring structure can arbitrarily contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;

The halogen is F, Cl, Br and iodine and their respective isotopes;

m and t are each independently 0, 1, 2, 3, 4 or 5;

n is independently 1, 2, 3, 4 or 5;

Preferably, the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has a structure of formula (IE):

in,

Any represents a single or double bond;

A is a 3-20-membered ring structure, and the ring structure can be arbitrarily monocyclic, bicyclic, tricyclic, bridged or spiro ring containing 0 to more unsaturated bonds; and the ring structure can be any Contains 0 to more heteroatoms, the heteroatoms are arbitrarily selected from O, S or N;

X 1 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 are each independently selected from C(R 0 ), C(R 0 ) 2 , N(R 0 ) or N;

Y 0 is independently selected from a bond, an acetylene bond, -O-, -S-, -N(R 3 )-, -C(R 6 R 7 )O-, -OC(R 6 R 7 )- or -C (R 6 R 7 )-;

Z is any independently absent, O, NH or N(R 5 );

R is randomly selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, amino, alkenyl , hydroxyl, cyano, nitro; any two adjacent X 5 , X 6 , X 7 and X 8 together with the R 0 connected thereto can form a 3-10-membered ring structure, and the ring structure can be Any saturated, unsaturated or aromatic structure, and the ring structure can optionally contain 0 to more heteroatoms, and the heteroatoms are randomly selected from O, S or N;

R is independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, Deuterated C1-6 alkoxy, cycloalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy; and the hydroxyl, amino, C1-6 alkyl, alkenyl, Hydrogen on alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy Can be optionally further substituted by 1 to more substituents, the substituents are arbitrarily selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 Alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, cycloalkoxy;

R is arbitrarily selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, amino, alkenyl, cyano, Cyanoalkyl, nitro, acyl, sulfonyl, phosphono; and the C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocyclic, The hydrogen on the heterocycloalkyl, amino, alkenyl, cyano, cyanoalkyl, nitro, acyl, sulfonyl, phosphono can be optionally further substituted by 1 to more substituents, and the substituents are optionally From hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkane Oxygen, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, sulfone, sulfoxide, alkylsulfone, alkylsulfoxide, alkylaminosulfone, iminosulfone , acyl, sulfonyl, phosphonocycloalkoxy;

Each of R and R is independently selected from H, deuterium, halogen, hydroxyl, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocyclyl Cycloalkyl, amino, C1-6 alkylamino, alkenyl, alkynyl, nitro, cyano, cyanoalkyl, C1-6 alkyl acyl, halogenated C1-6 alkyl acyl, sulfonyl, phosphine Acyl;

Each of R and R is independently selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, amino, C1-6 alkylamino group, alkenyl group, alkynyl group, nitro group, cyano group, cyanoalkyl group; or R 7 and R 6 form a 3-10 membered ring structure together with the directly connected carbon, and the ring The structure can be arbitrarily monocyclic, bicyclic, bridged or spiro ring containing 0 to more unsaturated bonds; and the ring structure can arbitrarily contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;

The halogen is F, Cl, Br and iodine and their respective isotopes;

m and t are each independently 0, 1, 2, 3, 4 or 5;

n is independently 1, 2, 3, 4 or 5;

Preferably, the compound or a pharmaceutically acceptable salt, isotope substitution or isomer thereof has a structure of formula (IF):

in,

Any represents a single or double bond;

A is a 3-20-membered ring structure, and the ring structure can be arbitrarily monocyclic, bicyclic, tricyclic, bridged or spiro ring containing 0 to more unsaturated bonds; and the ring structure can be any Contains 0 to more heteroatoms, the heteroatoms are arbitrarily selected from O, S or N;

X 1 , X 4 , X 2 , X 3 , X 7 , X 8 , X 9 , and X 10 are each independently selected from C(R 0 ), C(R 0 ) 2 , C(R 0 ) 2 C(R 0 ) 2 , N(R 0 ), C(R 0 ) 2 N(R 0 ) or N;

Y 0 is independently selected from a bond, an acetylene bond, -O-, -S-, -N(R 3 )-, -C(R 6 R 7 )O-, -OC(R 6 R 7 )- or -C (R 6 R 7 )-;

Z is any independently absent, O, NH or N(R 5 );

R is randomly selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, amino, alkenyl , hydroxyl, cyano, nitro; any two adjacent X 1 , X 2 or X 3 together with the R 0 attached to it can form a 3-10 membered ring structure, and the ring structure can be arbitrarily saturated , unsaturated or aromatic structure, and the ring structure can optionally contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;

R is independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, Deuterated C1-6 alkoxy, cycloalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy; and the hydroxyl, amino, C1-6 alkyl, alkenyl, Hydrogen on alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy Can be optionally further substituted by 1 to more substituents, the substituents are arbitrarily selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 Alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, cycloalkoxy;

R is arbitrarily selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, amino, alkenyl, cyano, Cyanoalkyl, nitro, acyl, sulfonyl, phosphono; and the C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocyclic, The hydrogen on the heterocycloalkyl, amino, alkenyl, cyano, cyanoalkyl, nitro, acyl, sulfonyl, phosphono can be optionally further substituted by 1 to more substituents, and the substituents are optionally From hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkane Oxygen, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, sulfone, sulfoxide, alkylsulfone, alkylsulfoxide, alkylaminosulfone, iminosulfone , acyl, sulfonyl, phosphonocycloalkoxy;

Each of R and R is independently selected from H, deuterium, halogen, hydroxyl, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocyclyl Cycloalkyl, amino, C1-6 alkylamino, alkenyl, alkynyl, nitro, cyano, cyanoalkyl, C1-6 alkyl acyl, halogenated C1-6 alkyl acyl, sulfonyl, phosphine Acyl;

Each of R and R is independently selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, amino, C1-6 alkylamino group, alkenyl group, alkynyl group, nitro group, cyano group, cyanoalkyl group; or R 7 and R 6 form a 3-10 membered ring structure together with the directly connected carbon, and the ring The structure can be arbitrarily monocyclic, bicyclic, bridged or spiro ring containing 0 to more unsaturated bonds; and the ring structure can arbitrarily contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;

The halogen is F, Cl, Br and iodine and their respective isotopes;

m and t are each independently 0, 1, 2, 3, 4 or 5;

n is independently 1, 2, 3, 4 or 5.
According to any one of claims 1-5, the compound or its pharmaceutically acceptable salt, isotopic substitution or its isomer, which has the structure of formula (II):

in,

A is a 3-20-membered ring structure, and the ring structure can be arbitrarily monocyclic, bicyclic, tricyclic, bridged or spiro ring containing 0 to more unsaturated bonds; and the ring structure can be any Contains 0 to more heteroatoms, the heteroatoms are arbitrarily selected from O, S or N;

X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 and X 8 are each independently selected from C(R 0 ) or N;

Y 0 is independently selected from a bond, an acetylene bond, -O-, -S-, -N(R 3 )-, -C(R 6 R 7 )O-, -OC(R 6 R 7 )- or -C (R 6 R 7 )-;

Each R can be the same or different, and is arbitrarily selected from H, deuterium, halogen, C1-6 alkyl, haloC1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, hetero Cycloalkyl, amino, alkenyl, hydroxyl, cyano, nitro; and any two adjacent X 1 , X 2 and X 3 or any two adjacent X 5 , X 6 , X 7 and X 8 and above The connected R 0 can form a 3-10 membered ring structure together, and the ring structure can be any saturated, unsaturated or aromatic structure, and the ring structure can contain 0 to more heteroatoms at will, so The heteroatoms mentioned above are arbitrarily selected from O, S or N;

Each R can be the same or different, and any independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halo Substituted C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy and other groups; and the hydrogen on R It can be optionally further substituted by 1 to more substituents, any of which are independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl , C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, cycloalkoxy, Alkylamino; or any two R 1 can form a 3-10-membered ring structure together with the carbon directly connected to it, and the ring structure can be arbitrarily monocyclic, bicyclic, or bridged ring containing 0 to more unsaturated bonds or a spiro ring; and the ring structure can optionally contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;

Each R can be the same or different, and any independently selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkane group, amino group, alkenyl group, cyano group, cyanoalkyl group, nitro group, acyl group, sulfonyl group, phosphono group, etc.; and the hydrogen on R2 can be optionally further substituted by 1 to more substituents, The substituents are arbitrarily selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy , deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, sulfone, sulfoxide, alkylsulfone, alkylsulfoxide, alkylamino Sulfone group, iminosulfone group, acyl group, sulfonyl group, phosphonocycloalkoxy group;

R is independently selected from H, deuterium, hydroxyl, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, amino, C1-6 alkylamino, alkenyl, alkynyl, cyano, cyanoalkyl, C1-6 alkyl acyl, halogenated C1-6 alkyl acyl, sulfonyl, phosphono;

R is independently selected from H, deuterium, halogen, hydroxyl, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, Amino, C1-6 alkylamino, alkenyl, alkynyl, cyano, cyanoalkyl, C1-6 alkyl acyl, halogenated C1-6 alkyl acyl; and the hydrogen on R can be the most optional Further substituted by 1 to more substituents, any of which are independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkane Oxygen, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, cycloalkoxy, alkylamino;

Each of R and R is independently selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, amino, C1-6 alkylamino group, alkenyl group, alkynyl group, nitro group, cyano group, cyanoalkyl group; or R 7 and R 6 form a 3-10 membered ring structure together with the directly connected carbon, and the ring The structure can be arbitrarily monocyclic, bicyclic, bridged or spiro ring containing 0 to more unsaturated bonds; and the ring structure can arbitrarily contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;

The halogen is F, Cl, Br and iodine and their respective isotopes;

m and t are each independently 0, 1, 2, 3, 4 or 5;

n is independently 1, 2, 3, 4 or 5;

Preferably, the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has a structure of formula (IIA):

in,

A is a 3-20-membered ring structure, and the ring structure can be arbitrarily monocyclic, bicyclic, tricyclic, bridged or spiro ring containing 0 to more unsaturated bonds; and the ring structure can be any Contains 0 to more heteroatoms, the heteroatoms are arbitrarily selected from O, S or N;

X 3 , X 6 , X 7 and X 8 are each independently selected from C(R 0 ) or N;

Each R can be the same or different, and is arbitrarily selected from H, deuterium, halogen, C1-6 alkyl, haloC1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, hetero Cycloalkyl, amino, alkenyl, hydroxyl, cyano, nitro; and any two adjacent X 1 , X 2 and X 3 or any two adjacent X 5 , X 6 , X 7 and X 8 and above The connected R 0 can form a 3-10 membered ring structure together, and the ring structure can be any saturated, unsaturated or aromatic structure, and the ring structure can contain 0 to more heteroatoms at will, so The heteroatoms mentioned above are arbitrarily selected from O, S or N;

Each R can be the same or different, and any independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halo Substituted C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy and other groups; and the hydrogen on R It can be optionally further substituted by 1 to more substituents, any of which are independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl , C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, cycloalkoxy, Alkylamino; or any two R 1 can form a 3-10-membered ring structure together with the carbon directly connected to it, and the ring structure can be arbitrarily monocyclic, bicyclic, or bridged ring containing 0 to more unsaturated bonds or a spiro ring; and the ring structure can optionally contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;

Each R can be the same or different, and any independently selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkane group, amino group, alkenyl group, cyano group, cyanoalkyl group, nitro group, acyl group, sulfonyl group, phosphono group, etc.; and the hydrogen on R2 can be optionally further substituted by 1 to more substituents, The substituents are arbitrarily selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy , deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, sulfone, sulfoxide, alkylsulfone, alkylsulfoxide, alkylamino Sulfone group, iminosulfone group, acyl group, sulfonyl group, phosphonocycloalkoxy group;

R is independently selected from H, deuterium, halogen, hydroxyl, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, Amino, C1-6 alkylamino, alkenyl, alkynyl, cyano, cyanoalkyl, C1-6 alkyl acyl, halogenated C1-6 alkyl acyl; and the hydrogen on R can be the most optional Further substituted by 1 to more substituents, any of which are independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkane Oxygen, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, cycloalkoxy, alkylamino;

The halogen is F, Cl, Br and iodine and their respective isotopes;

m and t are each independently 0, 1, 2, 3, 4 or 5;

n is independently 1, 2, 3, 4 or 5;

Preferably, the compound or a pharmaceutically acceptable salt, isotope substitution or isomer thereof has a structure of formula (IIB):

in,

Any represents a single or double bond;

X is any independently selected from C, C(R 0 ) or N;

X 3 , X 7 and X 8 are each independently selected from C(R 0 ) or N;

X 10 is independently selected from -O-, -S-, -SO-, -SO 2 -, -N(R 3 )-, -C(R 6 R 7 )O-, -OC(R 6 R 7 )- or -C(R 6 R 7 )-;

Each R can be the same or different, and is arbitrarily selected from H, deuterium, halogen, C1-6 alkyl, haloC1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, hetero Cycloalkyl, amino, alkenyl, hydroxyl, cyano, nitro; and two adjacent X 7 and X 8 together with the connected R 0 can form a 3-10-membered ring structure, the ring The structure can be any saturated, unsaturated or aromatic structure, and the ring structure can optionally contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;

Each R can be the same or different, and any independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halo Substituted C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy and other groups; and the hydrogen on R It can be optionally further substituted by 1 to more substituents, any of which are independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl , C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, cycloalkoxy, Alkylamino; or any two R 1 can form a 3-10-membered ring structure together with the carbon directly connected to it, and the ring structure can be arbitrarily monocyclic, bicyclic, or bridged ring containing 0 to more unsaturated bonds or a spiro ring; and the ring structure can optionally contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;

Each R can be the same or different, and any independently selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkane group, amino group, alkenyl group, cyano group, cyanoalkyl group, nitro group, acyl group, sulfonyl group, phosphono group, etc.; and the hydrogen on R2 can be optionally further substituted by 1 to more substituents, The substituents are arbitrarily selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy , deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, sulfone, sulfoxide, alkylsulfone, alkylsulfoxide, alkylamino Sulfone group, iminosulfone group, acyl group, sulfonyl group, phosphonocycloalkoxy group;

R is independently selected from H, deuterium, hydroxyl, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, amino, C1-6 alkylamino, alkenyl, alkynyl, cyano, cyanoalkyl, C1-6 alkyl acyl, halogenated C1-6 alkyl acyl, sulfonyl, phosphono;

R is independently selected from H, deuterium, halogen, hydroxyl, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, Amino, C1-6 alkylamino, alkenyl, alkynyl, cyano, cyanoalkyl, C1-6 alkyl acyl, halogenated C1-6 alkyl acyl; and the hydrogen on R can be the most optional Further substituted by 1 to more substituents, any of which are independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkane Oxygen, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, cycloalkoxy, alkylamino;

The halogen is F, Cl, Br and iodine and their respective isotopes;

Each of R and R is independently selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, amino, C1-6 alkylamino group, alkenyl group, alkynyl group, nitro group, cyano group, cyanoalkyl group; or R 7 and R 6 form a 3-10 membered ring structure together with the directly connected carbon, and the ring The structure can be arbitrarily monocyclic, bicyclic, bridged or spiro ring containing 0 to more unsaturated bonds; and the ring structure can arbitrarily contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;

m and t are each independently 0, 1, 2, 3, 4 or 5;

n is independently 1, 2, 3, 4 or 5;

Preferably, the compound or a pharmaceutically acceptable salt, isotope substitution or isomer thereof has a structure of formula (IIC):

in,

X 10 is independently selected from -O-, -S-, -SO-, -SO 2 -, -N(R 3 )-, -C(R 6 R 7 )O-, -OC(R 6 R 7 )- or -C(R 6 R 7 )-;

Each R can be the same or different, and is arbitrarily selected from H, deuterium, halogen, C1-6 alkyl, haloC1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, hetero Cycloalkyl, amino, alkenyl, hydroxyl, cyano, nitro;

Each R can be the same or different, and any independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halo Substituted C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy and other groups; and the hydrogen on R It can be optionally further substituted by 1 to more substituents, any of which are independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl , C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, cycloalkoxy, Alkylamino; or any two R 1 can form a 3-10-membered ring structure together with the carbon directly connected to it, and the ring structure can be arbitrarily monocyclic, bicyclic, or bridged ring containing 0 to more unsaturated bonds or a spiro ring; and the ring structure can optionally contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;

Each R can be the same or different, and any independently selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkane group, amino group, alkenyl group, cyano group, cyanoalkyl group, nitro group, acyl group, sulfonyl group, phosphono group, etc.; and the hydrogen on R2 can be optionally further substituted by 1 to more substituents, The substituents are arbitrarily selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy , deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, sulfone, sulfoxide, alkylsulfone, alkylsulfoxide, alkylamino Sulfone group, iminosulfone group, acyl group, sulfonyl group, phosphonocycloalkoxy group;

R is independently selected from H, deuterium, hydroxyl, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, amino, C1-6 alkylamino, alkenyl, alkynyl, cyano, cyanoalkyl, C1-6 alkyl acyl, halogenated C1-6 alkyl acyl, sulfonyl, phosphono;

R is independently selected from H, deuterium, halogen, hydroxyl, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, Amino, C1-6 alkylamino, alkenyl, alkynyl, cyano, cyanoalkyl, C1-6 alkyl acyl, halogenated C1-6 alkyl acyl; and the hydrogen on R can be the most optional Further substituted by 1 to more substituents, any of which are independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkane Oxygen, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, cycloalkoxy, alkylamino;

The halogen is F, Cl, Br and iodine and their respective isotopes;

Each of R and R is independently selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, amino, C1-6 alkylamino group, alkenyl group, alkynyl group, nitro group, cyano group, cyanoalkyl group; or R 7 and R 6 form a 3-10 membered ring structure together with the directly connected carbon, and the ring The structure can be arbitrarily monocyclic, bicyclic, bridged or spiro ring containing 0 to more unsaturated bonds; and the ring structure can arbitrarily contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;

m and t are each independently 0, 1, 2, 3, 4 or 5;

n is independently 1, 2, 3, 4 or 5.

Preferably, the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has a structure of formula (IID):

in,

Any represents a single or double bond;

X is any independently selected from C, C(R 0 ) or N;

Z is any independently O, NH or N(R 3 );

X 3 , X 7 and X 8 are each independently selected from C(R 0 ) or N; and when X 3 is CH, X is not N;

X 10 is independently selected from -O-, -S-, -SO-, -SO 2 -, -N(R 3 )-, -C(R 6 R 7 )O-, -OC(R 6 R 7 )- or -C(R 6 R 7 )-;

Each R can be the same or different, and is arbitrarily selected from H, deuterium, halogen, C1-6 alkyl, haloC1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, hetero Cycloalkyl, amino, alkenyl, hydroxyl, cyano, nitro; and two adjacent X 7 and X 8 together with the connected R 0 can form a 3-10-membered ring structure, the ring The structure can be any saturated, unsaturated or aromatic structure, and the ring structure can optionally contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;

Each R can be the same or different, and any independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halo Substituted C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy and other groups; and the hydrogen on R It can be optionally further substituted by 1 to more substituents, any of which are independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl , C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, cycloalkoxy, Alkylamino; or any two R 1 can form a 3-10-membered ring structure together with the carbon directly connected to it, and the ring structure can be arbitrarily monocyclic, bicyclic, or bridged ring containing 0 to more unsaturated bonds or a spiro ring; and the ring structure can optionally contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;

Each R can be the same or different, and any independently selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkane group, amino group, alkenyl group, cyano group, cyanoalkyl group, nitro group, acyl group, sulfonyl group, phosphono group, etc.; and the hydrogen on R2 can be optionally further substituted by 1 to more substituents, The substituents are arbitrarily selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy , deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, sulfone, sulfoxide, alkylsulfone, alkylsulfoxide, alkylamino Sulfone group, iminosulfone group, acyl group, sulfonyl group, phosphonocycloalkoxy group;

R is independently selected from H, deuterium, hydroxyl, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, amino, C1-6 alkylamino, alkenyl, alkynyl, cyano, cyanoalkyl, C1-6 alkyl acyl, halogenated C1-6 alkyl acyl, sulfonyl, phosphono;

R is independently selected from H, deuterium, halogen, hydroxyl, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, Amino, C1-6 alkylamino, alkenyl, alkynyl, cyano, cyanoalkyl, C1-6 alkyl acyl, halogenated C1-6 alkyl acyl; and the hydrogen on R can be the most optional Further substituted by 1 to more substituents, any of which are independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkane Oxygen, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, cycloalkoxy, alkylamino;

The halogen is F, Cl, Br and iodine and their respective isotopes;

Each of R and R is independently selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, amino, C1-6 alkylamino group, alkenyl group, alkynyl group, nitro group, cyano group, cyanoalkyl group; or R 7 and R 6 form a 3-10 membered ring structure together with the directly connected carbon, and the ring The structure can be arbitrarily monocyclic, bicyclic, bridged or spiro ring containing 0 to more unsaturated bonds; and the ring structure can arbitrarily contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;

m and t are each independently 0, 1, 2, 3, 4 or 5;

n is independently 1, 2, 3, 4 or 5;

Preferably, the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has a structure of formula (IIE):

Any represents a single or double bond;

Z is any independently O, NH or N(R 3 );

X 7 and X 8 are each independently selected from C(R 0 ) or N;

X 10 is independently selected from -O-, -S-, -SO-, -SO 2 -, -N(R 3 )-, -C(R 6 R 7 )O-, -OC(R 6 R 7 )- or -C(R 6 R 7 )-;

Each R can be the same or different, and is arbitrarily selected from H, deuterium, halogen, C1-6 alkyl, haloC1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, hetero Cycloalkyl, amino, alkenyl, hydroxyl, cyano, nitro; and two adjacent X 7 and X 8 together with the connected R 0 can form a 3-10-membered ring structure, the ring The structure can be any saturated, unsaturated or aromatic structure, and the ring structure can optionally contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;

Each R can be the same or different, and any independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halo Substituted C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy and other groups; and the hydrogen on R It can be optionally further substituted by 1 to more substituents, any of which are independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl , C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, cycloalkoxy, Alkylamino; or any two R 1 can form a 3-10-membered ring structure together with the carbon directly connected to it, and the ring structure can be arbitrarily monocyclic, bicyclic, or bridged ring containing 0 to more unsaturated bonds or a spiro ring; and the ring structure can optionally contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;

Each R can be the same or different, and any independently selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkane group, amino group, alkenyl group, cyano group, cyanoalkyl group, nitro group, acyl group, sulfonyl group, phosphono group, etc.; and the hydrogen on R2 can be optionally further substituted by 1 to more substituents, The substituents are arbitrarily selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy , deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, sulfone, sulfoxide, alkylsulfone, alkylsulfoxide, alkylamino Sulfone group, iminosulfone group, acyl group, sulfonyl group, phosphonocycloalkoxy group;

R is independently selected from H, deuterium, hydroxyl, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, amino, C1-6 alkylamino, alkenyl, alkynyl, cyano, cyanoalkyl, C1-6 alkyl acyl, halogenated C1-6 alkyl acyl, sulfonyl, phosphono;

R is independently selected from H, deuterium, halogen, hydroxyl, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, Amino, C1-6 alkylamino, alkenyl, alkynyl, cyano, cyanoalkyl, C1-6 alkyl acyl, halogenated C1-6 alkyl acyl; and the hydrogen on R can be the most optional Further substituted by 1 to more substituents, any of which are independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkane Oxygen, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, cycloalkoxy, alkylamino;

The halogen is F, Cl, Br and iodine and their respective isotopes;

Each of R and R is independently selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, amino, C1-6 alkylamino group, alkenyl group, alkynyl group, nitro group, cyano group, cyanoalkyl group; or R 7 and R 6 form a 3-10 membered ring structure together with the directly connected carbon, and the ring The structure can be arbitrarily monocyclic, bicyclic, bridged or spiro ring containing 0 to more unsaturated bonds; and the ring structure can arbitrarily contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;

m and t are each independently 0, 1, 2, 3, 4 or 5;

n is independently 1, 2, 3, 4 or 5;

Preferably, the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has a structure of formula (IIF):

in,

Z is any independently O, NH or N(R 3 );

X 7 and X 8 are each independently selected from C(R 0 ) or N;

X 10 is independently selected from -O-, -S-, -SO-, -SO 2 -, -N(R 3 )-, -C(R 6 R 7 )O-, -OC(R 6 R 7 )- or -C(R 6 R 7 )-;

Each R can be the same or different, and is arbitrarily selected from H, deuterium, halogen, C1-6 alkyl, haloC1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, hetero Cycloalkyl, amino, alkenyl, hydroxyl, cyano, nitro; and two adjacent X 7 and X 8 together with the connected R 0 can form a 3-10-membered ring structure, the ring The structure can be any saturated, unsaturated or aromatic structure, and the ring structure can optionally contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;

Each R can be the same or different, and any independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halo Substituted C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy and other groups; and the hydrogen on R It can be optionally further substituted by 1 to more substituents, any of which are independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl , C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, cycloalkoxy, Alkylamino; or any two R 1 can form a 3-10-membered ring structure together with the carbon directly connected to it, and the ring structure can be arbitrarily monocyclic, bicyclic, or bridged ring containing 0 to more unsaturated bonds or a spiro ring; and the ring structure can optionally contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;

Each R can be the same or different, and any independently selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkane group, amino group, alkenyl group, cyano group, cyanoalkyl group, nitro group, acyl group, sulfonyl group, phosphono group, etc.; and the hydrogen on R2 can be optionally further substituted by 1 to more substituents, The substituents are arbitrarily selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy , deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, sulfone, sulfoxide, alkylsulfone, alkylsulfoxide, alkylamino Sulfone group, iminosulfone group, acyl group, sulfonyl group, phosphonocycloalkoxy group;

R is independently selected from H, deuterium, hydroxyl, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, amino, C1-6 alkylamino, alkenyl, alkynyl, cyano, cyanoalkyl, C1-6 alkyl acyl, halogenated C1-6 alkyl acyl, sulfonyl, phosphono;

R is independently selected from H, deuterium, halogen, hydroxyl, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, Amino, C1-6 alkylamino, alkenyl, alkynyl, cyano, cyanoalkyl, C1-6 alkyl acyl, halogenated C1-6 alkyl acyl; and the hydrogen on R can be the most optional Further substituted by 1 to more substituents, any of which are independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkane Oxygen, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, cycloalkoxy, alkylamino;

The halogen is F, Cl, Br and iodine and their respective isotopes;

Each of R and R is independently selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, amino, C1-6 alkylamino group, alkenyl group, alkynyl group, nitro group, cyano group, cyanoalkyl group; or R 7 and R 6 form a 3-10 membered ring structure together with the directly connected carbon, and the ring The structure can be arbitrarily monocyclic, bicyclic, bridged or spiro ring containing 0 to more unsaturated bonds; and the ring structure can arbitrarily contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;

m and t are each independently 0, 1, 2, 3, 4 or 5;

n is independently 1, 2, 3, 4 or 5.
According to any one of claims 1-6, the compound, its pharmaceutically acceptable salt, solvate or hydrate and its isotope or isomer, is characterized in that, A or B are independently selected from 3-10 Heterocycle or C3-10 hydrocarbon ring;

Preferably, A is selected from piperidine ring, tetrahydropyrrole ring,

Preferably, B is selected from N-hetidine rings;

Preferably, X 1 , X 2 , and X 3 are independently selected from N or CH, and are not N at the same time; or, X 2 forms with X 1 or X 2 and X 3 and their respective connected atoms

Preferably, X 4 and X 5 are independently selected from N or CH;

Preferably, X 6 is selected from C(R 0 ); or, X 5 , X 6 and their respective connected atoms form

Preferably, X 7 and X 8 are independently selected from N or CH;

Preferably, Y is selected from NH;

Preferably, when Y 1 is CH, it is connected to Y 0 , and Y 2 is N; or, when Y 2 is CH, it is connected to Y 0 , and Y 1 is N;

Preferably, R is selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, C3-8 cycloalkyl;

Preferably, R is selected from H, deuterium, Cl, methyl, isopropyl, cyclopropyl;

Preferably, R is selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkane Oxygen, hydroxy C1-6 alkyl, hydroxy C1-6 alkoxy, C3-8 cycloalkyl, C1-6 alkoxy-C1-6 alkoxy, C1-6 alkyl-amino-C1-6 Alkoxy, (C1-6 alkyl) 2 -amino-C1-6 alkoxy, C1-6 alkylamino, (C1-6 alkyl) 2 -amino;

Preferably, R is selected from H, deuterium, F, hydroxy, amino, methyl, methoxy, methylamino, hydroxymethyl, hydroxyethyl, hydroxyethoxy, deuteromethyl, deuteromethoxy , Methoxy-Ethoxy,

Preferably, R is selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkane Oxygen, C3-8 cycloalkyl,

Preferably, R is selected from H, deuterium, F, hydroxyl, amino, methyl, methoxy;

Preferably, R is selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy group, deuterated C1-6 alkoxy, C3-8 cycloalkyl, C3-8 cycloalkyloxy, C1-6 alkyl-amino-C1-6 alkyl, (C1-6 alkyl) 2 - Amino-C1-6 alkyl, C1-6 alkyl-3-8 membered heterocyclic group;

Preferably, R is selected from methyl, ethyl, isopropyl, cyclopropyl, dimethylaminoethyl, difluoromethyl, trifluoromethyl, cyclopropyloxy,

Preferably, R6 and R7 are each independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halo Substituted C1-6 alkoxy, deuterated C1-6 alkoxy, C3-8 cycloalkyl, amino C1-6 alkyl;

Preferably, R6 and R7 are each independently selected from H, methyl, aminomethyl.
The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, which is the compound of selected examples or its corresponding isomer and various salts thereof:

Compound 1 to Compound 308;

Compound Al to Compound A40.
A pharmaceutical composition comprising a therapeutically effective amount of at least one of the compounds described in any one of claims 1 to 8, pharmaceutically acceptable salts, solvates, enantiomers and isotopic substitutions thereof .
The compound according to any one of claims 1 to 8, its pharmaceutically acceptable salt, solvate or hydrate and its isotope or isomer are used for preventing, diagnosing or treating related diseases caused by EGFR mutation or in combination with Application in drugs for diseases caused by EGFR mutation-related signaling pathways;

Preferably, the compound described in any one of claims 1 to 8, its pharmaceutically acceptable salt, solvate or hydrate and its isotope or isomer are used for the prevention, diagnosis or treatment of EGFR mutation or in combination with EGFR Mutation-related signaling pathways such as ROS1, BRAF, c-MET, EGFR/HER2, KRAS/MEK, PIK3CA, FDFR, DDR2 and/or VEGFR, PI3K, CDKs, PARP and other inhibitors, or with cytotoxins, immune target regulators The application of combination therapy drugs such as PD-1/PD-L1; the combination therapy drugs at least contain one or more compounds of the present invention, their pharmaceutically acceptable salts, solvates or hydrates and their isotopes or isomer.