WO2023198199A1 - Myt1 kinase inhibitor - Google Patents

Abstract

Provided are a compound represented by formula (I) having an inhibitory activity against membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase (MYT1 kinase), a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof, and use of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof as an MYT1 kinase inhibitor in preventing or treating a disease mediated by MYT1 kinase, such as a tumor.

Description

membrane-associated tyrosine and threonine kinase inhibitor

Cross-references to related applications

This application claims the rights and priorities of the following two Chinese invention patent applications, and their entire contents are hereby incorporated into this article by reference:

Patent application No. 202210396376.3 submitted to the State Intellectual Property Office of China on April 15, 2022; and

Patent application No. 202211312187.X submitted to the State Intellectual Property Office of China on October 25, 2022.

Technical field

The present application relates to membrane-associated tyrosine and threonine kinase inhibitors, methods for their preparation, pharmaceutical compositions containing the compounds, and their use in the prevention or treatment of cancer.

Background technique

Continuous exposure of the genomic DNA of cells to a variety of harmful factors from inside or outside the body may cause DNA damage. Therefore, cells have evolved a series of complex DNA damage response mechanisms to deal with these harmful factors, thereby maintaining the integrity of the genome and avoiding the occurrence of diseases, including tumors, caused by genome instability. The activation of cell cycle checkpoint pathways is one of the important mechanisms. Cell cycle checkpoints include checkpoints in G1, S, G2 and M phases. Unlike normal cells, the survival of tumor cells often relies on misregulation of DNA damage repair. Many tumor cells have lost the G1 checkpoint due to the presence of p53 gene mutations, and thus rely more on the G2 checkpoint to repair DNA damage to maintain the survival of tumor cells.

Membrane-associated tyrosine and threonine kinase (Myt1 kinase, also known as PKMYT1) is encoded by the PKMYT1 gene. PKMYT1 inhibits the activity of cdc2 by phosphorylating cdc2Thr-14 and Tyr-15, thereby regulating the cell cycle, causing the cell cycle to stay at the G2-M checkpoint and repair DNA damage. Studies have shown that inhibiting PKMYT1 will lead to the activation of cdc2, forcing cells to enter the mitosis phase prematurely and unable to repair DNA damage, thereby killing rapidly proliferating tumor cells.

Therefore, PKMYT1 inhibitors have the potential to inhibit tumor proliferation, and the development of PKMYT1 inhibitors can provide a new strategy for tumor targeted therapy.

Summary of the invention

In one aspect, the application relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof,

Among them, ring A is selected from

Represents the bond to the carbonyl group, Represents the bond connected to ring B;

X is selected from N or CR ^X ;

^R _{_ _ _ _ _ _ _ _ _} C ₂ -C ₆ alkynyl or C(=O)H, the OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₂ aryl, C ₂ - C ₆ alkenyl, C ₂ -C ₆ alkynyl or C(=O)H are optionally substituted by R ^a ;

Ring B is selected from C ₆ -C ₁₂ aryl or 6-10 membered heteroaryl, and the C ₆ -C ₁₂ aryl or 6-10 membered heteroaryl is optionally substituted by R ^b ;

R ¹ is selected from hydrogen, halogen, CN, OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C ( =O)H, the OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C(=O) H is optionally substituted by R ^a ;

R ² and R ³ are independently selected from hydrogen, halogen, CN, OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₆ -C ₁₂ aryl, 5-10 membered heteroaryl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C(=O)H, the OH, NH ₂ , C ₁ -C ₆ Alkyl, C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₆ -C ₁₂ aryl, 5-10 membered heteroaryl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ Alkynyl or C(=O)H is optionally substituted by R ^a ;

Or ^{R 2} , ^R

R ⁴ is selected from hydrogen, halogen, CN, OH, SH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₆ -C ₁₂ aryl , 5-10 membered heteroaryl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C(=O)H, the OH, SH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₆ -C ₁₂ aryl, 5-10 membered heteroaryl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C (=O)H is optionally substituted by R ^a ;

R ⁵ is selected from hydrogen, halogen, CN, OH, SH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₆ -C ₁₂ aryl , 5-10 membered heteroaryl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C(=O)H, the OH, SH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₆ -C ₁₂ aryl, 5-10 membered heteroaryl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C (=O)H is optionally substituted by R ^a ;

R ⁶ is selected from O, S, CR ^6a R ^6b or NR ^6a ;

R ⁷ is selected from O, S, CR ^7a R ^7b or NR ^7a ;

R ^6a , R ^6b , R ^7a , R ^7b are independently selected from hydrogen, halogen, CN, OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl base, C ₆ -C ₁₂ aryl or 5-10 membered heteroaryl, the OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl , C ₆ -C ₁₂ aryl or 5-10 membered heteroaryl is optionally substituted by R ^a ;

Or R ^6a , R ⁵ and the atoms to which they are connected together form a 5-10-membered heterocyclyl group or a 5-10-membered heteroaryl group, and the 5-10-membered heterocyclyl group or 5-10-membered heteroaryl group is optionally replaced by R ^a replace;

Or R ^7a , R ⁵ and the atoms to which they are connected together form a 5-10-membered heterocyclyl group or a 5-10-membered heteroaryl group, and the 5-10-membered heterocyclyl group or 5-10-membered heteroaryl group is optionally replaced by R ^a replace;

R ^a and R ^b are independently selected from halogen, CN, =O, OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-7 membered heterocyclyl, C ₆ -C ₁₂ aryl or 5-10 membered heteroaryl, the OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-7 membered heterocyclyl, C ₆ -C ₁₂ aryl The base or 5-10 membered heteroaryl group is optionally substituted by R ^c ;

R ^c is selected from halogen, CN, =O, OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or 4-7 membered heterocyclyl, the OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or 4-7 membered heterocyclyl is optionally substituted by R ^d ;

R ^d is selected from halogen, CN, OH, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₆ ring Alkyl or 4-7 membered heterocyclyl.

On the other hand, the present application provides a pharmaceutical composition, which contains the compound of formula (I) of the present application or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients.

On the other hand, the present application provides a method for treating diseases mediated by PKMYT1 in mammals, including administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a mammal in need of the treatment, preferably a human. or pharmaceutical compositions thereof.

On the other hand, the present application provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for preventing or treating PKMYT1-mediated diseases.

On the other hand, the present application provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in preventing or treating PKMYT1-mediated diseases.

On the other hand, the present application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating PKMYT1-mediated diseases.

Detailed description of the invention

This application relates to compounds of formula (I) or pharmaceutically acceptable salts thereof,

Among them, ring A is selected from

Represents the bond to the carbonyl group, Represents the bond connected to ring B;

X is selected from N or CR ^X ;

^R _{_ _ _ _ _ _ _ _ _} C ₂ -C ₆ alkynyl or C(=O)H, the OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₂ aryl, C ₂ - C ₆ alkenyl, C ₂ -C ₆ alkynyl or C(=O)H are optionally substituted by R ^a ;

Ring B is selected from C ₆ -C ₁₂ aryl or 6-10 membered heteroaryl, and the C ₆ -C ₁₂ aryl or 6-10 membered heteroaryl is optionally substituted by R ^b ;

R ¹ is selected from hydrogen, halogen, CN, OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C ( =O)H, the OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C(=O) H is optionally substituted by R ^a ;

R ² and R ³ are independently selected from hydrogen, halogen, CN, OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₆ -C ₁₂ aryl, 5-10 membered heteroaryl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C(=O)H, the OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₆ -C ₁₂ aryl, 5-10 membered heteroaryl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C(=O)H is optionally substituted by R ^a ;

Or ^{R 2} , ^R

R ⁴ is selected from hydrogen, halogen, CN, OH, SH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₆ -C ₁₂ aryl , 5-10 membered heteroaryl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C(=O)H, the OH, SH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₆ -C ₁₂ aryl, 5-10 membered heteroaryl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C (=O)H is optionally substituted by R ^a ;

R ⁵ is selected from hydrogen, halogen, CN, OH, SH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₆ -C ₁₂ aryl , 5-10 membered heteroaryl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C(=O)H, the OH, SH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₆ -C ₁₂ aryl, 5-10 membered heteroaryl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C (=O)H is optionally substituted by R ^a ;

R ⁶ is selected from O, S, CR ^6a R ^6b or NR ^6a ;

R ⁷ is selected from O, S, CR ^7a R ^7b or NR ^7a ;

R ^6a , R ^6b , R ^7a , R ^7b are independently selected from hydrogen, halogen, CN, OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl base, C ₆ -C ₁₂ aryl or 5-10 membered heteroaryl, the OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl , C ₆ -C ₁₂ aryl or 5-10 membered heteroaryl is optionally substituted by R ^a ;

Or R ^6a , R ⁵ and the atoms to which they are connected together form a 5-10-membered heterocyclyl group or a 5-10-membered heteroaryl group, and the 5-10-membered heterocyclyl group or 5-10-membered heteroaryl group is optionally replaced by R ^a replace;

Or R ^7a , R ⁵ and the atoms to which they are connected together form a 5-10-membered heterocyclyl group or a 5-10-membered heteroaryl group, and the 5-10-membered heterocyclyl group or 5-10-membered heteroaryl group is optionally replaced by R ^a replace;

R ^a and R ^b are independently selected from halogen, CN, =O, OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-7 membered heterocyclyl, C ₆ -C ₁₂ aryl or 5-10 membered heteroaryl, the OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-7 membered heterocyclyl, C ₆ -C ₁₂ aryl The base or 5-10 membered heteroaryl group is optionally substituted by R ^c ;

R ^c is selected from halogen, CN, =O, OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or 4-7 membered heterocyclyl, the OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or 4-7 membered heterocyclyl is optionally substituted by R ^d ;

R ^d is selected from halogen, CN, OH, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₆ ring Alkyl or 4-7 membered heterocyclyl.

In some embodiments, Ring A is selected from

In some embodiments, Ring A is selected from

In some embodiments, Ring A is selected from

In some embodiments, X is selected from N.

In some embodiments, X is selected from ^CRx .

In some embodiments, X is selected from CH.

_{In some embodiments ,} ^R _{_ _ _ _} -C ₆ alkynyl or C(=O)H, the OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ Alkynyl or C(=O)H is optionally substituted by ^Ra .

_{In some embodiments ,} ^R _{_ _} C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl or C(=O)H are optionally substituted by R ^a .

_{In some embodiments ,} ^{R _}

_{In some embodiments ,} ^{R _}

In some embodiments, R ^X is selected from hydrogen or phenyl.

In some embodiments, ^R

In some embodiments, Ring B is selected from phenyl or 6-9 membered heteroaryl, which phenyl or 6-9 membered heteroaryl is optionally substituted with ^Rb .

In some embodiments, Ring B is selected from phenyl and The phenyl and are replaced by R ^b .

In some embodiments, Ring B is selected from phenyl, which is optionally substituted with ^Rb .

In some embodiments, Ring B is selected from described Optionally substituted by R ^b .

In some embodiments, R ¹ is selected from hydrogen, halogen, CN, OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, or C(=O)H, said OH, NH _2. C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl or C(=O)H are optionally substituted by R ^a .

In some embodiments, ^R1 is _{selected from hydrogen, halogen, NH2, or Ci-C6 alkyl optionally substituted with Ra} ^.

In some _embodiments , ^R1 is selected from _NH2 , which is optionally substituted with ^Ra .

In some embodiments, ^R1 is selected from _NH2 .

In some embodiments, R ² and R ³ are independently selected from hydrogen, halogen, CN, OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl base, C ₆ -C ₁₂ aryl, 5-10 membered heteroaryl or C(=O)H, the OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 4 -10-membered heterocycloalkyl, C ₆ -C ₁₂ aryl, 5-10 membered heteroaryl or C(=O)H is optionally substituted by R ^a .

In some embodiments, R ² , R ³ are independently selected from hydrogen, halogen, OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl or 4-10 membered heterocycloalkyl, The OH, NH ₂ , C ₁ -C ₆ alkyl group, C ₃ -C ₁₀ cycloalkyl group or 4-10 membered heterocycloalkyl group are optionally substituted by R ^a .

In some embodiments, R ² , R ³ are independently selected from hydrogen.

In some embodiments ^, R ² , ^R

In some embodiments ^, R ³ is selected from hydrogen, and R ² , ^R

In some embodiments, R ⁴ is selected from hydrogen, halogen, CN, OH, SH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₆ -C ₉ aryl, 5-10 membered heteroaryl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl, the OH, SH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₆ -C ₉ aryl, 5-10 membered heteroaryl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl is optionally R ^a replaced.

In some embodiments, R ⁴ is selected from hydrogen, halogen, OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, 5- 10-membered heteroaryl or C ₂ -C ₆ alkynyl, the OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, The 5-10 membered heteroaryl or C ₂ -C ₆ alkynyl group is optionally substituted by R ^a .

In some embodiments, R ⁴ is selected from hydrogen, halogen, OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, phenyl, C ₂ -C ₆ alkynyl, The OH, NH ₂ , C ₁ -C ₆ alkyl group, C ₃ -C ₁₀ cycloalkyl group, phenyl group, C ₂ -C ₆ alkynyl group, Optionally substituted by R ^a .

In some embodiments, R ⁴ is selected from hydrogen, OH substituted by ^Ra , NH ₂ substituted by ^Ra , C ₁ -C ₃ alkyl optionally substituted by halogen, C ₃ -C ₆ cycloalkyl, phenyl optionally substituted by halogen, C ₂ -C ₃ alkynyl optionally substituted by C ₃ -C ₆ cycloalkyl, described Optionally substituted by C ₁ -C ₃ alkyl.

In some embodiments, R ⁴ is selected from hydrogen, C ₁ -C ₆ alkyl, or C ₃ -C ₆ cycloalkyl.

In some embodiments, ^R5 is selected from hydrogen, halogen, CN, OH, SH, _NH2 , _C1 - _C6 alkyl, _C3 - _C10 cycloalkyl, 4-10 membered heterocycloalkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl, the OH, SH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl is optionally substituted by R ^a .

In some embodiments, R ⁵ is selected from hydrogen, halogen, OH, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, or 4-10 membered heterocycloalkyl, said OH, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl or 4-10 membered heterocycloalkyl is optionally substituted by R ^a .

In some embodiments, R ⁵ is _selected from hydrogen, _{C 1} -C ₆ alkyl _{, or C 3 -C 10} cycloalkyl, _optionally substituted by R ^a replaced.

In some embodiments, ^R5 is selected from hydrogen or _Ci - _C6 alkyl.

In some embodiments ^{, R6} is selected from O, ^CR6aR6b , or ^NR6a .

In some embodiments, ^R6 is selected from O or ^NR6a .

In some embodiments, R ⁶ is selected from O or NR ^6a , wherein R ^6a , R ⁵ and the atoms to which they are connected together form a 5-6 membered heterocyclyl group or a 5-6 membered heteroaryl group, and the 5-6 membered heterocyclic group The cyclic group or 5-6 membered heteroaryl group is optionally substituted by R ^a .

In some embodiments, ^R6 is selected from ^NR6a .

In some embodiments, R ^is selected from O.

In some embodiments ^{, R7} is selected from O, ^CR7aR7b , or ^NR7a .

In some embodiments, ^R7 is selected from O or ^NR7a .

In some embodiments, ^R7 is selected from ^NR7a .

In some embodiments, R ^is selected from O.

In some embodiments, R ^6a , R ^6b , R ^7a , R ^7b are independently selected from hydrogen, OH, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, or 4-10 membered heterocycloalkyl , the OH, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl or 4-10 membered heterocycloalkyl is optionally substituted by R ^a .

In some embodiments, R ^6a , R ^6b , R ^7a , R ^7b are independently selected from C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl or 4-10 membered heterocycloalkyl, the C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl or 4-10 membered heterocycloalkyl is optionally substituted by R ^a .

In some embodiments, R ^6a , R ⁵ and the atoms to which they are connected together form a 5-8-membered heterocyclyl group or a 5-8-membered heteroaryl group, and the 5-8-membered heterocyclyl group or 5-8-membered heteroaryl group Optionally substituted by R ^a .

In some embodiments, R ^6a , R ⁵ and the atoms to which they are connected together form a 5-6 membered heterocyclyl group or a 5-6 membered heteroaryl group, and the 5-6 membered heterocyclyl group or 5-6 membered heteroaryl group Optionally substituted by R ^a .

In some embodiments, R ^6a , R ⁵ and the atom to which they are connected together form a 5-membered heterocyclyl or 5-membered heteroaryl, and the 5-membered heterocyclyl or 5-membered heteroaryl is optionally substituted by ^Ra .

In some embodiments, R ^7a , R ⁵ and the atoms to which they are connected together form a 5-8 membered heterocyclyl group or a 5-8 membered heteroaryl group, and the 5-8 membered heterocyclyl group or 5-8 membered heteroaryl group Optionally substituted by R ^a .

In some embodiments, R ^7a , R ⁵ and the atoms to which they are connected together form a 5-6 membered heterocyclyl group or a 5-6 membered heteroaryl group, and the 5-6 membered heterocyclyl group or 5-6 membered heteroaryl group Optionally substituted by R ^a .

In some embodiments, R ^7a , R ⁵ and the atom to which they are connected together form a 5-membered heterocyclyl or 5-membered heteroaryl, and the 5-membered heterocyclyl or 5-membered heteroaryl is optionally substituted by ^Ra .

In some embodiments, R ^a , R ^b are independently selected from halogen, CN, =O, OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-7 membered heterocycle group or C ₆ -C ₁₂ aryl group, the OH, NH ₂ , C ₁ -C ₆ alkyl group, C ₃ -C ₁₀ cycloalkyl group, 4-7 membered heterocyclyl group or C ₆ -C ₁₂ aryl group is any The choice is replaced by R ^c .

In some embodiments, R ^a , R ^b are independently selected from halogen, =O, OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-7 membered heterocyclyl, or Phenyl, the OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-7 membered heterocyclyl or phenyl is optionally substituted by R ^c .

In some embodiments, R ^a , R ^b are independently selected from halogen, =O, OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, 4-7 membered heterocyclyl, Phenyl or 5-6 membered heteroaryl, the OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered Heteroaryl is optionally substituted with ^Rc .

In some embodiments, R ^a , R ^b are independently selected from halogen, =O, OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, 4-7 membered heterocyclyl, or Phenyl, the OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, 4-7 membered heterocyclyl or phenyl is optionally substituted by R ^c .

In some embodiments, ^Rc is selected from _{halogen, OH, NH2, or Ci-C3 alkyl optionally substituted with Rd} ^.

In some embodiments, R ^c is selected from halogen, =O, OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, or 4-7 membered heterocyclyl, said OH, NH _2. C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or 4-7 membered heterocyclyl is optionally substituted by R ^d .

In some embodiments, ^Rc is selected _{from OH, NH2, or Ci-C6 alkyl , which is optionally} substituted with ^Rd .

In some embodiments, R ^d is selected from halogen, CN, OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, or 4-7 membered heterocyclyl.

In some embodiments, R ^d is selected from halogen, OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, or 4-7 membered heterocyclyl.

In some embodiments, R ^d is selected from N(C ₁ -C ₆ alkyl) ₂ .

In some embodiments, Ra ^is selected from =O, halogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, phenyl, or 5-6 membered heteroaryl, said C ₁ -C ₆ Alkyl, C ₃ -C ₆ cycloalkyl, phenyl or 5-6 membered heteroaryl is optionally substituted by R ^c .

In some embodiments, Ra ^is selected from =O, halogen, C ₁ -C ₆ alkyl, CH ₂ N(CH ₃ ) ₂ , CH ₂ OCH ₃ , cyclopropyl, phenyl, or pyridyl.

In _some embodiments, R ^b is selected _from halogen, OH, or C ₁ -C ₆ alkyl optionally substituted with R ^c .

In some embodiments, R ^b is selected from OH or C ₁ -C ₆ alkyl.

In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of compounds of formula (II), or a pharmaceutically acceptable salt thereof,

Among them, ring B, X, R ¹ , R ² , R ³ and R ⁴ are as defined in formula (I).

In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of compounds of formula (IIa), or a pharmaceutically acceptable salt thereof,

Wherein, X ¹ is selected from CR ⁵ or N, and the R ⁵ , ring B, X, R ¹ , R ² , R ³ and R ⁴ are as defined in formula (I).

In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of compounds of formula (IIb), or a pharmaceutically acceptable salt thereof,

in, Represents a single bond or a double bond, X ¹ is selected from CR ⁵ or N, and the R ⁵ , ring B, R ¹ , R ⁴ and R ^a are as defined in formula (I).

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of compounds of formula (III) or a pharmaceutically acceptable salt thereof,

Among them, Ring B, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined in formula (I).

In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of compounds of formula (IIIa), or a pharmaceutically acceptable salt thereof,

Wherein, X ¹ is selected from CH or N, and the ring B, R ¹ , R ² , R ³ , R ⁴ and R ^a are as defined in formula (I).

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of compounds of formula (IV) or a pharmaceutically acceptable salt thereof,

Among them, ring B, X, R ¹ , R ² , R ³ , R ⁵ and R ⁷ are as defined in formula (I).

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof,

On the other hand, the present application provides a pharmaceutical composition, which contains the compound of formula (I) of the present application or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients.

On the other hand, the present application provides a method for treating diseases mediated by PKMYT1 in mammals, including administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a mammal in need of the treatment, preferably a human. or pharmaceutical compositions thereof.

On the other hand, the present application provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for preventing or treating PKMYT1-mediated diseases.

On the other hand, the present application provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in preventing or treating PKMYT1-mediated diseases.

On the other hand, the present application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating PKMYT1-mediated diseases.

In some embodiments, the PKMYT1-mediated disease is neoplasm, such as breast cancer.

Definitions and explanations of terms

Unless otherwise stated, the terms used in this application have the following meanings. The definitions of groups and terms recorded in this application include their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and examples. The definitions of specific compounds, etc., can be arbitrarily combined and combined with each other. A particular term should not be considered uncertain or unclear in the absence of a specific definition, but should be understood in accordance with its ordinary meaning in the art. Where a trade name appears herein, it is intended to refer to its corresponding trade name or its active ingredient.

In this article, Indicates the connection site.

In this article, bonds depicted by solid and dashed lines Represents a single or double bond.

In this article, the double arrows in the synthetic route Represents a multi-step reaction.

The term "tautomer" refers to a functional group isomer resulting from the rapid movement of an atom in a molecule between two positions. The compounds of the present application may exhibit tautomerism. Tautomeric compounds can exist in two or more interconvertible species. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer usually yield a mixture whose physical and chemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form is dominant; in phenols, the enol form is dominant. This application encompasses all tautomeric forms of the compounds.

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

The compounds of the present application may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds, so the compounds of the present application may exist in specific geometric or stereoisomer forms. Specific geometric or stereoisomeric forms may be cis and trans isomers, E and Z geometric isomers, (-)- and (+)-enantiomers, (R)- and (S) )-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic or other mixtures thereof, such as enantiomers or diastereomers Enriched mixtures, all of the above isomers and their mixtures are within the scope of the definition of compounds in this application. There may be additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms or Asymmetric phosphorus atoms, these isomers involved in all substituents, and their mixtures are also included in the definition of compounds in this application. The compounds containing asymmetric atoms of the present application can be isolated in an optically active pure form or a racemic form. The optically active pure form can be resolved from a racemic mixture or synthesized by using chiral starting materials or chiral reagents. .

The term "substituted" means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, as long as the valence state of the specific atom is normal and the substituted compound is stable. When the substituent is oxo (i.e. =O), it means that two hydrogen atoms are replaced, and oxo does not occur on aromatic groups.

The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes both the occurrence and absence of the stated event or circumstance. For example, the ethyl group is "optionally" substituted by halogen, which means that the ethyl group can be unsubstituted (CH ₂ CH ₃ ), monosubstituted (CH ₂ CH ₂ F, CH ₂ CH ₂ Cl, etc.), or polysubstituted. (CHFCH ₂ F, CH ₂ CHF ₂ , CHFCH ₂ Cl, CH ₂ CHCl _2, etc.) or completely substituted (CF ₂ CF ₃ , CF ₂ CCl ₃ , CCl ₂ CCl _3, etc.). It will be understood by those skilled in the art that any substitution or substitution pattern that is sterically impossible and/or cannot be synthesized will not be introduced for any group containing one or more substituents.

When any variable (eg, R ^a , R ^b ) occurs more than once in the composition or structure of a compound, its definition in each instance is independent. For example, if a group is replaced by 2 R ^b , there are separate options for each R ^b .

When a substituent's bond is cross-linked to two atoms on a ring, the substituent can be bonded to any atom on the ring. For example, structural unit Indicates that R ⁵ can be substituted at any position on the benzene ring.

_Cm - _Cn as used herein refers to having an integer number of carbon atoms in the range of mn. For example, "C ₁ -C ₁₀ " means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms or 10 carbon atoms.

The term "alkyl" refers to a hydrocarbon group of the general formula C _n H _2n+1 , which alkyl group may be straight or branched. The term "C ₁ -C ₁₀ alkyl" is understood to mean a straight-chain or branched saturated hydrocarbon radical having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Specific examples of the alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2- Methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-di Methylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc.; the term "C ₁ -C ₆ alkyl "can be understood to mean an alkyl group having 1 to 6 carbon atoms. Specific examples include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec. Butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc. The term "C ₁ -C ₃ alkyl" is understood to mean a straight-chain or branched saturated alkyl group having 1 to 3 carbon atoms. The "C ₁ -C ₁₀ alkyl" may include "C ₁ -C ₆ alkyl" or "C ₁ -C ₃ alkyl" and other ranges, and the "C ₁ -C ₆ alkyl" may further include " C ₁ -C ₃ alkyl”.

The term "alkenyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one double bond. The term "C ₂ -C ₁₀ alkenyl" is understood to mean a straight-chain or branched unsaturated hydrocarbon radical containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, "C ₂ -C ₁₀ alkenyl" is preferably "C ₂ -C ₆ alkenyl", more preferably "C ₂ -C ₄ alkenyl", and even more preferably C ₂ or C ₃ alkenyl. It will be appreciated that where the alkenyl group contains more than one double bond, the double bonds may be separated or conjugated to each other. Specific examples of the alkenyl group include, but are not limited to, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl , (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1 -Methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl or (Z)-1-methylprop-1-enyl wait.

The term "alkynyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one triple bond. The term "C ₂ -C ₁₀ alkynyl" is understood to mean a linear or branched unsaturated hydrocarbon radical containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Examples of "C ₂ -C ₁₀ alkynyl" include, but are not limited to, ethynyl (-C≡CH), propynyl (-C≡CCH _3, -CH ₂ C≡CH), but-1-ynyl, butyl -2-alkynyl or but-3-ynyl. "C ₂ -C ₁₀ alkynyl" may include "C ₂ -C ₃ alkynyl", and examples of "C ₂ -C ₃ alkynyl" include ethynyl (-C≡CH), prop-1-ynyl (-C ≡CCH ₃ ), prop-2-ynyl (-CH ₂ C≡CH).

The term "cycloalkyl" refers to a fully saturated carbocyclic ring that exists in the form of a single ring, a branched ring, a bridged ring or a spiro ring. Unless otherwise indicated, the carbocyclic ring is generally 3 to 10 membered. The term "C ₃ -C ₁₀ cycloalkyl" is understood to mean a saturated monocyclic, paracyclic, spirocyclic or bridged ring having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Specific examples of the cycloalkyl group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl (bicyclo[2.2 .1]heptyl), bicyclo[2.2.2]octyl, adamantyl, spiro[4.5]decyl, etc. The term "C ₃ -C ₁₀ cycloalkyl" may include "C ₃ -C ₆ cycloalkyl", and the term "C ₃ -C ₆ cycloalkyl" is understood to mean a saturated monocyclic or bicyclic hydrocarbon ring having 3, 4, 5 or 6 carbon atoms, specific examples include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, etc.

The term "heterocyclyl" refers to a fully saturated or partially saturated (not aromatic heteroaromatic as a whole) monocyclic, paracyclic, spirocyclic or bridged cyclic group whose ring atoms contain 1, 2, 3, 4 or 5 heteroatoms or heteroatom groups (i.e. atomic groups containing heteroatoms), the "heteroatoms or heteroatom groups" include but are not limited to nitrogen atoms (N), oxygen atoms (O), sulfur atoms (S) , phosphorus atom (P), boron atom (B), -S(=O) ₂ -, -S(=O)-, -P(=O) ₂ -, -P(=O)-, -NH- , -S(=O)(=NH)-, -C(=O)NH- or -NHC(=O)NH-, etc. The term "4-10 membered heterocyclyl" refers to a heterocyclyl with a number of ring atoms of 4, 5, 6, 7, 8, 9 or 10, and its ring atoms contain 1, 2, 3, 4 or 5 independent Selected from the heteroatoms or heteroatom groups described above. "4-10-membered heterocyclyl" includes "4-7-membered heterocyclyl", wherein specific examples of 4-membered heterocyclyl include but are not limited to azetidinyl, thietanyl or oxa cyclobutanyl; specific examples of 5-membered heterocyclyl include but are not limited to tetrahydrofuryl, dioxolyl, pyrrolidyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4,5-di Hydrooxazolyl or 2,5-dihydro-1H-pyrrolyl; specific examples of 6-membered heterocyclic groups include but are not limited to tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thio Morpholinyl, piperazinyl, trithialkyl, tetrahydropyridyl or 4H-[1,3,4]thiadiazinyl; specific examples of 7-membered heterocyclyl include but are not limited to diazepane base. The heterocyclic group may also be a bicyclic group, wherein specific examples of 5,5-membered bicyclic groups include but are not limited to hexahydrocyclopenta[c]pyrrole-2(1H)-yl; 5,6-membered bicyclic groups. Specific examples include, but are not limited to, hexahydropyrro[1,2-a]pyrazin-2(1H)-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4 ,3-a]pyrazinyl or 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinyl. Optionally, the heterocyclic group may be a benzo-fused cyclic group of the above-mentioned 4-7 membered heterocyclic group, and specific examples include but are not limited to dihydroisoquinolyl and the like. "4-10-membered heterocyclyl" may include "5-10-membered heterocyclyl", "4-7-membered heterocyclyl", "5-6-membered heterocyclyl", "6-8-membered heterocyclyl" , "4-10 membered heterocycloalkyl", "5-10 membered heterocycloalkyl", "4-7 membered heterocycloalkyl", "5-6 membered heterocycloalkyl", "6-8 membered "Heterocycloalkyl" and other scopes, "4-7 membered heterocyclyl" may further include "4-6 membered heterocyclyl", "5-6 membered heterocyclyl", "4-7 membered heterocyclyl" , "4-6 membered heterocycloalkyl", "5-6 membered heterocycloalkyl" and other ranges. Although some bicyclic heterocyclic groups in this application partially contain a benzene ring or a heteroaromatic ring, the heterocyclic groups are still non-aromatic as a whole.

The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and exists in the form of a single ring, a branched ring, a bridged ring or a spiro ring, and the ring atoms of its ring contain 1, 2, 3, 4 or 5 heteroatoms or heteroatom groups (that is, atomic groups containing heteroatoms). The "heteroatoms or heteroatom groups" include but are not limited to nitrogen atoms (N), oxygen atoms (O), sulfur atoms (S), phosphorus atoms (P ), boron atom (B), -S(=O) ₂ -, -S(=O)-, -NH-, -S(=O)(=NH)-, -C(=O)NH- or -NHC(=O)NH-etc. The term "4-10 membered heterocycloalkyl" refers to a heterocycloalkyl group with a number of ring atoms of 4, 5, 6, 7, 8, 9 or 10, and its ring atoms contain 1, 2, 3, 4 or 5 are independently selected from the heteroatoms or heteroatom groups described above. "4-10-membered heterocycloalkyl" includes "4-7-membered heterocycloalkyl", wherein specific examples of 4-membered heterocycloalkyl include but are not limited to azetidinyl, oxetanyl or thibutanyl; Specific examples of 5-membered heterocycloalkyl include, but are not limited to, tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl or tetrahydrofuranyl. Hydropyrazolyl; specific examples of 6-membered heterocycloalkyl include but are not limited to piperidyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl , 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl or 1,4-dithianyl; specific examples of 7-membered heterocycloalkyl include but are not limited to aza Cycloheptyl, oxeptanyl or thieptanyl.

The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π electron system. Aryl groups can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. The term "C ₆ -C ₂₀ aryl" is understood to mean an aryl group having 6 to 20 carbon atoms. In particular, a ring with 6 carbon atoms ("C ₆ aryl"), for example phenyl; or a ring with 9 carbon atoms ("C ₉ aryl"), for example indanyl or indenyl; or a ring with 10 or a ring of 13 carbon atoms ("C ₁₀ aryl"), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl; or a ring of 13 carbon atoms ("C ₁₃ aryl"), such as fluorenyl; or is a ring having 14 carbon atoms ("C ₁₄ aryl"), such as anthracenyl. The term "C ₆ -C ₁₀ aryl" is understood to mean an aryl group having 6 to 10 carbon atoms. In particular, rings with 6 carbon atoms ("C ₆ aryl"), e.g. phenyl; or rings with 9 carbon atoms ("C ₉ aryl"), e.g. Such as indanyl or indenyl; or a ring with 10 carbon atoms ("C ₁₀ aryl"), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl.

The term "heteroaryl" refers to an aromatic monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, and S, and the remaining ring atoms are C. The term "5-10 membered heteroaryl" is understood to include monocyclic or bicyclic aromatic ring systems having 5, 6, 7, 8, 9 or 10 ring atoms, in particular 5 or 6 or 9 or 10 ring atoms, and it contains 1, 2, 3, 4 or 5, preferably 1, 2 or 3 heteroatoms independently selected from N, O and S. In particular, the heteroaryl group is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiazolyl Diazolyl, etc. and their benzo derivatives, such as benzofuryl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazole base, indazolyl, indolyl or isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl, etc. and their benzo derivatives, such as quinolyl, quinazole Phyllinyl or isoquinolinyl, etc.; or azocinyl, indolizinyl, purinyl, etc. and their benzo derivatives; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyl, etc. Aldyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl or phenoxazinyl, etc. The term "5-6 membered heteroaryl" refers to an aromatic ring system having 5 or 6 ring atoms and containing 1, 2 or 3, preferably 1 or 2 heteroatoms independently selected from N, O and S .

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

The term "hydroxy" refers to the -OH group.

The term "cyano" refers to the -CN group.

The term "amino" refers to the -NH _group .

The term "therapeutically effective amount" means (i) treating a particular disease, condition, or disorder, (ii) alleviating, ameliorating, or eliminating one or more symptoms of a particular disease, condition, or disorder, or (iii) delaying the symptoms described herein An amount of a compound of the present application that is associated with the onset of one or more symptoms of a particular disease, condition or disorder. The amount of a compound of the present application that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art. based on its own knowledge and the contents of this disclosure.

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

The term "pharmaceutically acceptable salts" refers to salts of pharmaceutically acceptable acids or bases, including salts of compounds with inorganic or organic acids, and salts of compounds with inorganic or organic bases.

The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or salts thereof and pharmaceutically acceptable excipients. The purpose of pharmaceutical compositions is to facilitate administration to an organism of the compounds of the present application.

The term "pharmaceutically acceptable excipients" refers to those excipients that have no obvious irritating effect on the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

The words "comprise" or "comprise" and their English variations such as compris or comprising can be understood as having an open, non-exclusive meaning, that is, "including but not limited to".

The present application also includes compounds of the present application that are the same as those described herein, but are isotopically labeled in which one or more atoms are replaced by an atom having an atomic weight or mass number different from that typically found in nature. Examples of isotopes that may be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹³ respectively N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ¹²³ I, ¹²⁵ I and ³⁶ Cl, etc.

Certain isotopically labeled compounds of the present application (eg, labeled with ³ H and ¹⁴ C) can be used in compound and/or substrate tissue distribution analysis. Tritiated (ie ³ H) and carbon-14 (ie ¹⁴ C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron-emitting isotopes such as ¹⁵ O, ¹³ N, ¹¹ C, and ¹⁸ F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present application can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent by following procedures similar to those disclosed in the Schemes and/or Examples below.

The pharmaceutical compositions of the present application can be prepared by combining the compounds of the present application with appropriate pharmaceutically acceptable excipients. For example, they can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, and powders. , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.

Typical routes of administration of the compounds of the present application or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, and intravenous administration.

The pharmaceutical composition of the present application can be manufactured using methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, emulsification methods, freeze-drying methods, etc.

In some embodiments, the pharmaceutical composition is in an oral form. For oral administration, the pharmaceutical compositions may be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These excipients enable the compound of the present application to be formulated into tablets, pills, lozenges, sugar-coated agents, capsules, liquids, gels, slurries, suspensions, etc. for oral administration to patients.

Solid oral compositions may be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by the following method: mixing the active compound with solid excipients, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain tablets Or sugar-coated core. Suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants or flavoring agents, etc.

The pharmaceutical compositions may also be suitable for parenteral administration as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.

The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and methods well known to those skilled in the art. Equivalent alternatives and preferred implementations include but are not limited to the embodiments of this application.

The chemical reactions in the specific embodiments of the present application are completed in a suitable solvent. The solvent must be suitable for the chemical changes of the present application and the required reagents and materials. In order to obtain the compounds of the present application, those skilled in the art sometimes need to modify or select the synthesis steps or reaction procedures based on the existing embodiments.

An important consideration in the planning of synthetic routes in this field is the selection of appropriate protecting groups for reactive functional groups. For example, please refer to Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc. Referenced in this application All references to are incorporated into this application in their entirety.

Example

The present application is described in detail below through examples, but does not mean any adverse limitations to the present application. The present application has been described in detail, and specific embodiments thereof have also been disclosed. For those skilled in the art, various changes and improvements can be made to the specific embodiments of the present application without departing from the spirit and scope of the present application. It is obvious. All reagents used in this application are commercially available and used without further purification.

Compounds are manually or For software naming, commercially available compounds adopt supplier catalog names.

The structure of the compound is determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). The units of NMR shifts are 10 ^-6 (ppm). The solvents measured by NMR are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS); "IC ₅₀ " refers to the half inhibitory concentration, which refers to the concentration when half of the maximum inhibitory effect is achieved. concentration.

Explanation of terms or abbreviations:

TsOH·H ₂ O: p-toluenesulfonic acid monohydrate; NMP: N-methylpyrrolidone; dioxane: 1,4-dioxane; DME: ethylene glycol dimethyl ether; ^t BuONa: tert-butanol Sodium; ^t BuOLi: lithium tert-butoxide; Pd(dppf)Cl ₂ : [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride; Pd(dppf)Cl ₂ ·DCM: [1 ,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex; rt: room temperature; min: minutes; h: hours; DCM: dichloromethane; MeCN/ACN: acetonitrile; HOAc: acetic acid; 4A MS: Molecular sieve; TMPLiClMgCl ₂ : 2,2,6,6-tetramethylpiperidine lithium magnesium chloride; Me: methyl; MeOH: methanol; MeONa: sodium methoxide; EtOH: ethanol; LiHMDS: bis(trimethylsilyl) )Lithium amide; THF: tetrahydrofuran; DMF: N,N-dimethylformamide; TBSCl: tert-butyldimethylsilyl chloride; imidazol: imidazole; Pd(dba) ₂ : bis(dibenzylideneacetone)palladium ;Pd ₂ (dba) ₃ : tris(dibenzylideneacetone)dipalladium; xantphos: 4,5-bisdiphenylphosphine-9,9-dimethylxanthene; t-am-OH: tert-pentyl Alcohol; pyridine: pyridine; Pd(OAc) ₂ : palladium acetate; Sphos: 2-bicyclohexylphosphine-2',6'-dimethoxybiphenyl; Parkins catalyst: (dimethylphosphonic acid) platinum (II) Hydrogenated complex; NCS: N-chlorosuccinimide; MeB(OH) ₂ : methylboronic acid; Pd(PPh ₃ ) ₂ Cl ₂ : bistriphenylphosphine palladium dichloride; Et ₃ N: Triethylamine; TMS: trimethylsilyl; meCgPPh: 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphoryladamantane; DHP: 3,4-dihydro-2H-pyran; CyPF-tBu: (R)-(-)-1-[(S)-2-(dicyclohexylphosphine)ferrocene]ethyldi-tert-butylphosphine; ((PhMe) ₃ P) ₂ Pd: bis [Tris(2-tolyl)phosphine]palladium; t-BuXPhos: 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl; DMA: N,N-dimethylaniline ; 2,6-lutidine: 2,6-lutidine; formic acid: formic acid; Ti(iPrO) ₄ : tetraisopropyl titanate; DAST: diethylamine sulfur trifluoride; XantPhos Pd G ₄ : Methanesulfonic acid [9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene](2'-methylamino-1,1'-biphenyl-2-yl)palladium( II); Cy ₂ NMe: N-methyldicyclohexylamine; AgOTf: silver triflate; toluene: toluene.

Compounds can be obtained through the following routes:

Example 1: 8-amino-7-(3-hydroxy-2,6-dimethylphenyl)-7H-imidazo[1,2-c]pyrrolo[3,2-e]pyrimidine-9- Preparation of formamide (compound 1)

Step 1: 6-chloro-5-iodo-N-(3-methoxy-2,6-dimethylphenyl)pyrimidin-4-amine (1c)

Dissolve 4,6-dichloro-5-iodopyrimidine (0.50g, 1.8mmol) and 3-methoxy-2,6-dimethylaniline (0.28g, 1.8mmol) in N-methyl at room temperature. To pyrrolidone (1 mL), p-toluenesulfonic acid monohydrate (10 mg, 0.18 mmol) was added, and then stirred at 150°C for 1 h. After the reaction is cooled to room temperature, add water (10 mL) to the reaction solution to dilute, then extract with ethyl acetate (10 mL*3), combine the organic phases, wash the organic phases with saturated brine (10 mL), dry over anhydrous sodium sulfate, and filter. , the filtrate was concentrated, and the resulting residue was purified with a normal phase chromatography column (ethyl acetate: petroleum ether = 10:1-1:2) to obtain the target product 1c (0.11g, yield 16%) as a white solid. LC-MS: m/z(ESI):390.0[M+H] ⁺ .

Step 2: 5-iodo-N ⁴ -(3-methoxy-2,6-dimethylphenyl)pyrimidine-4,6-diamine (1d)

Compound 1c (0.11g, 0.28mmol) was dissolved in N-methylpyrrolidone (1mL), and ammonia water (0.20g, 5.7mmol) was added, followed by stirring at 140°C for 6 hours. After the reaction was cooled to room temperature, the reaction solution was concentrated, and the resulting residue was purified by reverse-phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1 ~ 1:20) to obtain the target compound 1d (80 mg, yield 77%). LC-MS: m/z(ESI):371.0[M+H] ⁺ .

Step 3: 8-iodo-N-(3-methoxy-2,6-dimethylphenyl)imidazo[1,2-c]pyrimidin-7-amine (1e)

Compound 1d (80 mg, 0.22 mmol) was dissolved in 1,4-dioxane (1 mL), then chloroacetaldehyde (85 mg, 1.1 mmol) was added, and the reaction was carried out at 90°C for 1 hour. After the reaction was cooled to room temperature, water (10 mL) was added to the reaction solution, and then extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with saturated brine, dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated. The resulting residue was purified by reverse phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1 ~ 1:20) to obtain The target product 1e (40 mg, yield 47%). m/z(ESI):395.0[M+H] ⁺ .

Step 4: 8-amino-7-(3-methoxy-2,6-dimethylphenyl)-7H-imidazo[1,2-c]pyrrolo[3,2-e]pyrimidine-9 -Carbonitrile(1f)

Dissolve malononitrile (27 mg, 0.41 mmol) in ethylene glycol dimethyl ether (1 mL) at room temperature, add sodium tert-butoxide (59 mg, 0.61 mmol), stir for 30 min until clear, and then add compound 1e (40 mg, 0.10 mol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (37 mg, 0.05 mmol). Replace the air with nitrogen three times, and then stir at 80°C for 12 hours under nitrogen protection. After the reaction was cooled to room temperature, the insoluble matter was removed by filtration, and the filtrate was spun to dryness. The resulting residue was purified by a reversed-phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1 ~ 1:20) to obtain the target compound 1f as a white solid (20 mg , yield 59%). m/z(ESI):333.1[M+H] ⁺ .

Step 5: 8-amino-7-(3-methoxy-2,6-dimethylphenyl)-7H-imidazo[1,2-c]pyrrolo[3,2-e]pyrimidine-9 -Formamide (1g)

Compound 1f (20 mg, 60 μmol) was dissolved in concentrated sulfuric acid (1 mL) at room temperature, and stirred at room temperature for 45 minutes. The reaction solution was cooled with ice water, neutralized with ammonia water, and the reaction solution was concentrated. The resulting residue was purified by a reversed-phase chromatography column (C18, 0.05% ammonia solution: acetonitrile = 20:1~1:20) to obtain 1g of the target compound as a white solid (10 mg, Yield 47%). m/z(ESI):351.1[M+H] ⁺ .

Step 6: 8-amino-7-(3-hydroxy-2,6-dimethylphenyl)-7H-imidazo[1,2-c]pyrrolo[3,2-e]pyrimidine-9-methyl Amide(1)

Dissolve 1 g (10 mg, 30 μmol) in dichloromethane (1 mL) at room temperature, add boron tribromide (1 mol/L, 0.14 mL) in dichloromethane, and stir for 30 minutes. The reaction solution was quenched with methanol (5 mL), and then the reaction solution was concentrated. The resulting residue was purified by reverse-phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1 ~ 1:20) to obtain compound 1 (3.9 mg, collected rate 41%).

m/z(ESI):337.1[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ10.2 (s, 1H), 8.56 (s, 1H), 7.63 (d, J = 1.2Hz, 1H), 7.58 (d, J = 1.2Hz, 1H), 7.14 (d,J＝8.4Hz,1H),6.92(d,J＝8.4Hz,1H),5.86(brs,2H),5.51(s,1H),1.95(s,3H),1.91(s,3H) .

Example 2: 7-amino-8-(3-hydroxy-2,6-dimethylphenyl)-8H-imidazo[1,2-a]pyrrolo[2,3-d]pyrimidine-6- Preparation of formamide (compound 2)

Step 1: 5-Bromo-N ⁴ -(3-methoxy-2,6-dimethylphenyl)pyrimidine-2,4-diamine (2b)

2-Amino-5-bromo-4-chloropyrimidine (0.16g, 0.77mmol), 3-methoxy-2,6-dimethylaniline (0.17g, 1.1mmol) and p-toluenesulfonic acid monohydrate (13 mg, 0.077 mmol) was dissolved in N-methylpyrrolidone (2 mL), and then the reaction system was placed in a 110°C oil bath to react for 3 hours. After the reaction was completed, it was cooled to room temperature. The reaction solution was purified by reverse-phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1~1:20) to obtain compound 2b (0.20g, yield 82%). m/z(ESI):323.0[M+H] ⁺ .

Compound 2 was prepared using a method similar to Example 1, substituting compound 2b for compound 1c in Example 1. m/z(ESI):337.1[M+H] ⁺ .

Example 3: 7-amino-8-(3-hydroxy-2,6-dimethylphenyl)-2,8-dihydro-3H-imidazo[1,2-a]pyrrolo[2,3 Preparation of -d]pyrimidine-6-carboxamide (compound 3)

Step 1: 5-bromo-2-chloro-N-(3-methoxy-2,6-dimethylphenyl)pyrimidin-4-amine (3b)

At room temperature, 5-bromo-2,4-dichloropyrimidine (0.30g, 1.3mmol), 3-methoxy-2,6-dimethylaniline (0.30g, 2.0mmol) and p-toluene sulfonate were mixed Acid monohydrate (6.9 mg, 0.13 mmol) was dissolved in N-methylpyrrolidone (5 mL), and the resulting solution was reacted at 90°C for 12 hours. After the reaction solution is cooled to room temperature, add water (10 mL) to the reaction solution to dilute, and then extract with ethyl acetate (10 mL*3). The organic phases are combined and washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and filtered. , the filtrate was concentrated, and the resulting residue was purified through a silica gel column (ethyl acetate: petroleum ether = 10:1 ~ 1:2) to obtain the target product 3b (0.20g, yield 44%) as a white solid. LC-MS: m/z(ESI):342.0[M+H] ⁺ .

Step 2: 2-[[5-bromo-4-(3-methoxy-2,6-dimethylaniline)pyrimidin-2-yl]amino]ethanol (3c)

Compound 3b (0.2g, 0.59mmol) and ethanolamine (53mg, 0.88mmol) were dissolved in N-methylpyrrolidone (3mL), and then heated to 120°C for 1 hour. After the reaction was cooled to room temperature, the reaction solution was reacted directly Phase chromatography column purification (C18, 0.05% ammonia water: acetonitrile = 20:1 ~ 1:20) gave the target product 3c (0.21g, yield 98%) as a white solid. LC-MS: m/z(ESI):367.1[M+H] ⁺ .

Step 3: 5-Bromo-N ² -(2-chloroethyl)-N ⁴ -(3-methoxy-2,6-dimethylphenyl)pyrimidine-2,4-diamine (3d)

At room temperature, compound 3c (0.21g, 0.57mmol) was added to thionyl chloride (5mL), and the temperature was raised to 85°C for 2 hours. After the reaction was cooled to room temperature, the solvent was evaporated under reduced pressure to obtain compound 3d (0.22g, Yield 99%). m/z(ESI):385.0[M+H] ⁺ .

Step 4: 6-bromo-N-(3-methoxy-2,6-dimethylphenyl)-2,3-dihydroimidazo[1,2-a]pyrimidin-7-amine (3e)

Compound 3d (0.22g, 0.57mmol) and potassium carbonate (0.39g, 2.9mmol) were dissolved in acetonitrile (5mL), and then the temperature was raised to 85°C for 3 hours. The solvent was distilled off under reduced pressure, and the obtained solid residue was purified by a reversed-phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1~1:20) to obtain the target product 3e (90 mg, yield 45%) as a white solid. m/z(ESI):349.1[M+H] ⁺ .

Step 5: 7-amino-8-(3-methoxy-2,6-dimethylphenyl)-2,8-dihydro-3H-imidazo[1,2-a]pyrrolo[2, 3-d]pyrimidine-6-carbonitrile (3f)

Dissolve malononitrile (68 mg, 1.0 mmol) in ethylene glycol dimethyl ether (5 mL), then add sodium tert-butoxide (0.15 g, 1.6 mmol), and stir at room temperature for 30 min until clear. Compound 3e (90 mg, 0.26 mol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (19 mg, 26 μmol) were then added. Replace the air with nitrogen three times, and then stir at 90°C for 5 hours under nitrogen protection. After the reaction was cooled to room temperature, the insoluble matter was removed by filtration, and the filtrate was spun to dryness. The resulting residue was purified through a reversed-phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1 ~ 1:20) to obtain the white solid target compound 3f (30 mg, yield 35%). m/z(ESI):335.2[M+H] ⁺ .

Step 6: 7-amino-8-(3-methoxy-2,6-dimethylphenyl)-2,8-dihydro-3H-imidazo[1,2-a]pyrrolo[2, 3-d]pyrimidine-6-carboxamide (3g)

Compound 3f (30 mg, 90 μmol) was dissolved in concentrated sulfuric acid (1 mL) at room temperature, and stirred at room temperature for 45 minutes. The reaction solution was cooled with ice water, neutralized with ammonia water, and the solvent was evaporated under reduced pressure. The obtained residue was purified by a reverse-phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1~1:20) to obtain 3g of the target compound (30 mg, yield 99%). m/z(ESI):352.2[M+H] ⁺ .

Step 7: 7-amino-8-(3-hydroxy-2,6-dimethylphenyl)-2,8-dihydro-3H-imidazo[1,2-a]pyrrolo[2,3- d]pyrimidine-6-carboxamide(3)

Dissolve compound 3g (30 mg, 85 μmol) in dichloromethane (1 mL) at room temperature, then add a dichloromethane solution of boron tribromide (1 mol/L, 0.85 mL), and stir at room temperature for 30 minutes. The reaction solution was then quenched with methanol (5 mL) and concentrated. The resulting residue was purified by a reversed-phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1 ~ 1:20) to obtain compound 3 (13.3 mg, yield 46 %). m/z(ESI):339.1[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.72 (s, 1H), 8.82 (s, 1H), 7.49 (brs, 2H), 7.09 (d, J = 8.0Hz, 1H), 6.97-6.94 ( m,3H),4.56(dd,J＝10.0,8.0Hz,2H),3.82(dd,J＝10.0,8.0Hz,2H),1.83(s,3H),1.75(s,3H).

Example 4: 8-amino-7-(3-hydroxy-2,6-dimethylphenyl)-2,7-dihydro-3H-imidazo[1,2-c]pyrrolo[3,2 Preparation of -e]pyrimidine-9-carboxamide (compound 4)

Compound 4 was prepared by using a method similar to Example 3, substituting 4,5,6-trichloropyrimidine for compound 3a in Example 3. m/z(ESI):339.1[M+H] ⁺ .

Example 5: 6-amino-7-(3-hydroxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (compound 5) Preparation

Step 1: 5-bromo-N-(3-methoxy-2,6-dimethylphenyl)-2-methylpyrimidin-4-amine (5b)

At room temperature, 5-bromo-4-chloro-2-methylpyrimidine (0.75g, 3.6mmol) and 3-methoxy-2,6-dimethylaniline (0.50g, 3.3mmol) were dissolved in N- Methylpyrrolidone (10 mL) was then added with acetic acid (20 mg, 0.33 mmol), and the reaction solution was heated to 140°C for 12 hours. After the reaction solution was cooled to room temperature, it was poured into water (20 mL), and then extracted with ethyl acetate (25 mL*3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was collected, the solvent was evaporated under reduced pressure, and the resulting residue was passed through a normal phase chromatography column (petroleum ether:ethyl acetate=10:1~2: 1) Purify to obtain the target compound 5b (0.70g, yield 66%) as a white solid. m/z(ESI):322.0[M+H] ⁺ .

Step 2: 6-amino-7-(3-methoxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile ( 5c)

Dissolve malononitrile (22 mg, 0.30 mmol) in ethylene glycol dimethyl ether (3 mL) at room temperature, and add lithium tert-butoxide (2.2 M, 0.18mL), stir at room temperature for 30 minutes until clear. Then compound 5b (50 mg, 0.16 mmol) and [1,1'-bis(diphenylphosphine)ferrocene] dichloride palladium dichloromethane complex (13 mg, 20 μmol) were added, and nitrogen was used to replace the air 3 times, and then stirred at 100°C for 16 hours under nitrogen protection. After the reaction was cooled to room temperature, the insoluble matter was removed by filtration, and the filtrate was spun to dryness. The resulting residue was purified by preparative chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1 ~ 1:20) to obtain the white solid target compound 5c (46 mg, Yield 46%). m/z(ESI):308.1[M+H] ⁺ .

Step 3: 6-amino-7-(3-hydroxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (5d)

Compound 5c (40 mg, 0.13 mmol) was dissolved in dichloromethane (2 mL) at room temperature, a dichloromethane solution of boron tribromide (1 mol/L, 2 mL) was added, and the mixture was stirred at room temperature for 30 minutes. Under ice bath conditions, the reaction solution was quenched with methanol (5 mL) and concentrated. The resulting residue was purified by a reversed-phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1 ~ 1:20) to obtain the white solid target product 5d. (38mg, yield 99%). m/z(ESI):294.1[M+H] ⁺ .

Step 4: 6-amino-7-(3-hydroxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (5)

Compound 5d (38 mg, 0.13 mmol) was dissolved in concentrated sulfuric acid (1 mL) and stirred at room temperature for 45 minutes. The reaction solution was cooled with ice water, neutralized with ammonia water, and concentrated under reduced pressure. The resulting residue was purified by preparative chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1 ~ 1:20) to obtain compound 5 (25 mg, yield 62 %). m/z(ESI):312.1[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.59 (s, 1H), 8.88 (s, 1H), 7.15-6.98 (m, 3H), 6.93 (d, J = 8.0Hz, 1H), 6.84 ( br s,2H),2.43(s,3H),1.75(s,3H),1.67(s,3H).

Example 6: 6-amino-7-(3-hydroxy-2,6-dimethylphenyl)-3-methyl-4-oxo-4,7-dihydro-3H-pyrrolo[2, Preparation of 3-d]pyrimidine-5-carboxamide (compound 6)

Step 1: 6-((3-methoxy-2,6-dimethylphenyl)amino)-3-methylpyrimidin-4(3H)-one (6b)

Combine 6-chloro-3-methyl-pyrimidin-4-one (0.10g, 0.69mmol), 3-methoxy-2,6-dimethylaniline (0.16g, 1.0mmol), tris(dibenzylidene) Acetone) dipalladium (32mg, 0.03mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (40mg, 0.07mmol) and cesium carbonate (0.68g, 2.1mmol) were dissolved in into tert-amyl alcohol (1 mL), and then use nitrogen to replace the air, and then heat to 100°C for 16 hours under nitrogen protection. After the reaction was cooled to room temperature, the insoluble matter was removed by filtration, and the filtrate was concentrated. The resulting residue was purified by preparative chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1 ~ 1:20) to obtain the white solid target product 6b (0.40g, collected rate 62%). m/z(ESI):260.1[M+H] ⁺ .

Step 2: 5-bromo-6-((3-methoxy-2,6-dimethylphenyl)amino)-3-methyl-pyrimidine-4(3H)-one (6c)

A solution of liquid bromine (0.37 g, 2.3 mmol) in dichloromethane (2 mL) was slowly added dropwise to a solution of compound 6b (0.40 g, 1.5 mmol) in pyridine (4 mL) at room temperature. After the dropwise addition is completed, continue the reaction at room temperature for 15 minutes. The solid was removed by filtration, and the filtrate was treated with 1M hydrochloric acid until neutral, and then extracted with dichloromethane (10 mL*3). The organic phases were combined and washed with 10% sodium carbonate aqueous solution, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was collected, the solvent was evaporated under reduced pressure, and the resulting residue was purified by a silica gel column (ethyl acetate:petroleum ether=10: 1-1:3) to obtain light yellow solid 6c (0.20g, yield 38%). m/z(ESI):338.0[M+H] ⁺ .

Step 3: 6-amino-7-(3-methoxy-2,6-dimethylphenyl)-3-methyl-4-oxo-4,7-dihydro-3H-pyrrolo[2 ,3-d]pyrimidine-5-carbonitrile (6d)

Dissolve malononitrile (41 mg, 0.62 mmol) into ethylene glycol dimethyl ether (2 mL) at room temperature, add lithium tert-butoxide (2.2 M, 0.34 mL), and stir for 30 minutes until clear. Compound 6c (0.10 g, 0.30 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]dichloride palladium dichloromethane complex (24 mg, 0.03 mmol) were then added. The air was purged three times with nitrogen, and then reacted at 100°C for 12 hours under nitrogen protection. After the reaction was cooled to room temperature, the insoluble matter was removed by filtration, and the filtrate was concentrated. The resulting residue was purified through a reversed-phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1 ~ 1:20) to obtain the white solid target compound 6d (40 mg, collected rate 42%). m/z(ESI):324.1[M+H] ⁺ .

Step 4: 6-amino-7-(3-hydroxy-2,6-dimethylphenyl)-3-methyl-4-oxo-4,7-dihydro-3H-pyrrolo[2,3 -d]pyrimidine-5-carbonitrile (6e)

Compound 6d (30 mg, 93 μmol) was dissolved in dichloromethane (2 mL) at room temperature, then a dichloromethane solution of boron tribromide (1M/L, 2 mL) was added, stirred at room temperature for 30 minutes, and the reaction solution was added with methanol ( 5 mL), then the reaction solution was concentrated, and the resulting residue was purified by a reversed-phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1 ~ 1:20) to obtain the white solid target product 6e (15 mg, yield 51% ). m/z(ESI):310.1[M+H] ⁺ .

Step 5: 6-amino-7-(3-hydroxy-2,6-dimethylphenyl)-3-methyl-4-oxo-4,7-dihydro-3H-pyrrolo[2,3 -d]pyrimidine-5-carboxamide(6)

Compound 6e (15 mg, 0.05 mmol) was dissolved in concentrated sulfuric acid (1 mL) at room temperature, and stirred at room temperature for 45 minutes. After the reaction is completed, the reaction solution is neutralized with ammonia water under ice bath conditions and concentrated. The resulting residue is purified by a reverse-phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1 ~ 1:20) to obtain a white solid. Target compound 6 (3.0 mg, yield 19%). m/z(ESI):328.1[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.57 (s, 1H), 9.49 (d, J = 2.0Hz, 1H), 8.04 (s, 1H), 7.06 (d, J = 8.0Hz, 1H) ,6.92(d,J＝8.0Hz,1H),6.81(br d,J＝2.0Hz,1H),6.56(s,2H),3.50(s,3H),1.79(s,3H),1.70(s ,3H).

Example 7: 8-amino-7-(3-hydroxy-2,6-dimethylphenyl)-2-methyl-7H-imidazo[1,2-c]pyrrolo[3,2-e Preparation of ]pyrimidine-9-carboxamide (compound 7)

Step 1: 8-iodo-N-(3-methoxy-2,6-dimethylphenyl)-2-methylimidazo[1,2-c]pyrimidin-7-amine (7e)

Under normal temperature conditions, compound 1d (50 mg, 0.14 mmol) was dissolved in acetonitrile (5 mL), sodium iodide (51 mg, 0.34 mmol) and chloroacetone (38 mg, 0.41 mmol) were added in sequence, and then the temperature was raised to 90°C for reaction 1 Hours, wait for the reaction to cool to room temperature, add water (10mL) to the reaction solution to dilute, then extract with ethyl acetate (10mL*3), combine the organic phases, wash the organic phases with saturated brine (10mL), and dry over anhydrous sodium sulfate , filtered, the filtrate was concentrated, and the resulting residue was purified by reverse-phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1 ~ 1:20) to obtain the target compound 7e (22 mg) as a white solid. LC-MS:m/z:409.0,[M+H] ⁺ .

Compound 7 was prepared by using a method similar to step 4 to step 6 in Example 1, substituting compound 7e for compound 1e in Example 1. m/z(ESI):351.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.65(s,1H),9.55(s,1H),8.76(s,1H),7.71(s,1H),7.06(t,J＝8.4,2H ),6.92(d,J＝8.4,1H),6.67(s,2H),2.36(s,3H),1.79(s,3H),1.70(s,3H).

Example 8: 8-amino-7-(3-hydroxy-2,6-dimethylphenyl)-2-cyclopropyl-7H-imidazo[1,2-c]pyrrolo[3,2- e] Preparation of pyrimidine-9-carboxamide (compound 8)

Compound 8 was prepared by using a method similar to Example 7, substituting compound 2-chloro-1-cyclopropylethan-1-one for chloroacetone in Example 7. m/z(ESI):377.4[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.59 (s, 1H), 9.54 (s, 1H), 8.70 (s, 1H), 7.74 (s, 1H), 7.06 (t, J = 8.4Hz, 1H),6.97(s,1H),6.92(d,J＝8.4Hz,1H),6.65(s,2H),2.07-2.00(m,1H),1.77(s,3H),1.68(s,3H ),0.96-0.92(m,2H),0.82-0.78(m,2H).

Example 9: 8-amino-7-(3-hydroxy-2,6-dimethylphenyl)-3-methyl-7H-imidazo[1,2-c]pyrrolo[3,2-e Preparation of ]pyrimidine-9-carboxamide (compound 9)

Compound 9 was prepared using a method similar to Example 7, using compound 2-bromo-1,1-dimethoxypropane instead of chloroacetone in Example 7. m/z(ESI):351.2[M+H] ⁺ .

Example 10: 8-amino-7-(3-hydroxy-2,6-dimethylphenyl)-5-methyl-7H-imidazo[1,2-c]pyrrolo[3,2-e Preparation of ]pyrimidine-9-carboxamide (compound 10)

Step 1: 6-chloro-5-iodo-N-(3-methoxy-2,6-dimethylphenyl)-2-methylpyrimidin-4-amine (10b)

At room temperature, 4,6-dichloro-5-iodo-2methylpyrimidine (5.8g, 20mmol) and 3-methoxy-2,6-dimethylaniline (6.0g, 40mmol) were dissolved in N- To methylpyrrolidone (10 mL), p-toluenesulfonic acid monohydrate (0.19 g, 1.0 mmol) was added, and then stirred at 100°C for 48 h. After the reaction is cooled to room temperature, add water (20 mL) to the reaction solution to dilute, then extract with ethyl acetate (20 mL*3), combine the organic phases, wash the organic phases with saturated brine (20 mL), dry over anhydrous sodium sulfate, and filter. , the filtrate was concentrated, and the resulting residue was purified with a normal phase chromatography column (petroleum ether: ethyl acetate = 10:1-2:1) to obtain the target product 10b (1.8g) as a white solid. LC-MS: m/z(ESI):404.1[M+H] ⁺ .

Step 2: 6-amino-4-chloro-7-(3-methoxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5 -Carbonitrile (10c)

Dissolve malononitrile (0.20g, 3.0mmol) into anhydrous glycol dimethyl ether (2mL), add sodium tert-butoxide (0.43g, 4.5mmol), stir at room temperature for 30 minutes, then add 10b (0.30g, 0.75 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (24 mg, 30 μmol). Replace the air with nitrogen three times, and then under nitrogen protection conditions React at 90°C for 3 hours. After the reaction was cooled to room temperature, the insoluble matter was removed by filtration, and the filtrate was spun to dryness. The resulting residue was purified through a reversed-phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1 to 1:20) to obtain compound 10c (0.2g). m/z(ESI):342.3[M+H] ⁺ .

Step 3: 4,6-diamino-7-(3-methoxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5- Carbonitrile(10d)

Compound 10c (0.2g, 0.58mmol) was dissolved in N-methylpyrrolidone (5mL), ammonia water (10mL) was added, and the reaction was carried out under sealed tube conditions at 130°C for 16 hours. After the reaction was cooled to room temperature, the reaction solution was concentrated, and the resulting residue was purified by reverse-phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1 to 1:20) to obtain the target compound 10d (0.14g). LC-MS: m/z(ESI):323.0[M+H] ⁺ .

Step 4: 8-amino-7-(3-methoxy-2,6-dimethylphenyl)-5-methyl-7H-imidazo[1,2-c]pyrrolo[3,2- e]pyrimidine-9-carbonitrile (10e)

Compound 10d (0.14g, 0.42mmol) was dissolved in 1,4-dioxane (10mL), then chloroacetaldehyde (4mL) and Molecular sieve (30 mg), the reaction was carried out at 100°C for 1 hour. After the reaction was cooled to room temperature, the molecular sieve was removed by filtration, and the reaction solution was concentrated. The resulting residue was purified by a reversed-phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1~1:20) to obtain the target compound 10e (0.13g). m/z(ESI):347.1[M+H] ⁺ .

Step 5: 8-amino-7-(3-hydroxy-2,6-dimethylphenyl)-5-methyl-7H-imidazo[1,2-c]pyrrolo[3,2-e] Pyrimidine-9-carboxamide (10f)

Dissolve 10e (0.13g, 0.37mmol) in concentrated sulfuric acid (5 mL) at room temperature, and stir at room temperature for 30 minutes. Under ice bath conditions, the reaction solution was neutralized with ammonia water until alkaline, the reaction solution was concentrated, and the resulting residue was purified by a reversed-phase chromatography column (C18, 0.05% ammonia solution: acetonitrile = 20:1~1:20) to obtain the target compound as a white solid 10f(0.11g). m/z(ESI):365.1[M+H] ⁺ .

Step 6: 8-amino-7-(3-hydroxy-2,6-dimethylphenyl)-5-methyl-7H-imidazo[1,2-c]pyrrolo[3,2-e] Pyrimidine-9-carboxamide(10)

Dissolve 10f (0.11g, 0.31mmol) in dichloromethane (5mL) at room temperature, add boron tribromide (1mol/L, 5mL) in dichloromethane, and stir for 30 minutes. The reaction solution was quenched with methanol (5 mL), and then the reaction solution was concentrated. The resulting residue was purified by reverse-phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1~1:20) to obtain compound 10 (98 mg).

m/z(ESI):351.1[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ9.70 (s, 1H), 9.56 (s, 1H), 7.90 (s, 1H), 7.61 (s, 1H), 7.09 (d, J = 8.0Hz ,1H),7.04(s,1H),6.94(d,J＝8.0Hz,1H),6.60(s,2H),2.67(s,3H),1.80(s,3H),1.71(s,3H) .

Example 11: 8-amino-7-(3-hydroxy-2,6-dimethylphenyl)-5-cyclopropyl-7H-imidazo[1,2-c]pyrrolo[3,2- e] Preparation of pyrimidine-9-carboxamide (compound 11)

Step 1: Synthesis of 4,6-dichloro-2-cyclopropyl-5-iodopyrimidine (11b)

4,6-Dichloro-2-cyclopropylpyrimidine (1.5g, 7.9mmol) was dissolved in anhydrous tetrahydrofuran, and then 2,2,6,6-tetramethyl was added dropwise under ice bath conditions. A solution of piperidine lithium chloride and magnesium chloride in tetrahydrofuran (10 mL, 1 mol/L) was added dropwise. After the addition was completed, the mixture was raised to room temperature and reacted for 1 hour. Then, iodine element (3.0 g, 12 mmol) was dissolved in tetrahydrofuran and added dropwise to the above solution. After the dropwise addition was completed, the reaction was continued for 1 hour. Slowly add saturated ammonium chloride solution to the solution to quench the reaction, then extract with ethyl acetate (50mL*3), combine the organic phases, wash the organic phases with saturated brine (50mL), dry over anhydrous sodium sulfate, filter, and remove the filtrate Concentrate, and the obtained residue is purified by column chromatography (petroleum ether: ethyl acetate = 1:0 to 10:1) to obtain product 11b (1.0 g). m/z:315.1[M+H] ⁺ .

Compound 11 was prepared using a method similar to Example 10, substituting Compound 11b for Compound 10a in Example 10.

m/z(ESI):377.4[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.70 (s, 1H), 9.53 (s, 1H), 8.19 (d, J = 1.6Hz, 1H), 7.62 (d, J＝1.6Hz,1H),7.07(d,J＝8.4Hz,1H),7.02(s,1H),6.92(d,J＝8.4Hz,1H),6.59(brs,2H),2.55-2.50( m,1H),1.77(s,3H),1.68(s,3H),1.04-1.01(m,2H),0.82-0.79(m,2H).

Example 12: 8-amino-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[4, Preparation of 3-c]pyrimidine-9-carboxamide (compound 12)

Step 1: 6-amino-4-chloro-7-(3-methoxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (12a )

Dissolve malononitrile (0.20g, 3.0mmol) into anhydrous glycol dimethyl ether (2mL), add sodium tert-butoxide (0.43g, 4.5mmol), stir at room temperature for 30 minutes, then add 1c (0.29g, 0.75 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (24 mg, 30 μmol). Replace the air with nitrogen three times, and then react at 90°C for 3 hours under nitrogen protection. After the reaction was cooled to room temperature, the insoluble matter was removed by filtration, and the filtrate was spun to dryness. The resulting residue was purified through a reversed-phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1 to 1:20) to obtain compound 12a (0.2g). m/z(ESI):328.1[M+H] ⁺ .

Step 2: (Z)-6-amino-4-hydrazino-7-(3-methoxy-2,6-dimethylphenyl)-4,7-dihydro-3H-pyrrolo[2 ,3-d]pyrimidine-5-carbonitrile (12b)

Compound 12a (0.2g, 0.61mmol) was dissolved in N-methylpyrrolidone (5mL), then hydrazine hydrate (5mL) was added, and the reaction was placed at 100°C for 1 hour, and the reaction was cooled to room temperature. The filtrate was spun to dryness, and the resulting residue was purified through a reversed-phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1~1:20) to obtain compound 12b (0.15g). m/z(ESI):324.1[M+H] ⁺ .

Step 3: 8-amino-7-(3-methoxy-2,6-dimethylphenyl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[4 ,3-c]pyrimidine-9-carbonitrile (12c)

Compound 12b (0.15g, 0.46mmol) was dissolved in trimethyl orthoformate (5mL), and the reaction was placed in a 100°C oil bath for 8 hours. After the reaction was cooled to room temperature, the filtrate was spun to dryness, and the resulting residue was purified through a reversed-phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1 to 1:20) to obtain compound 12c (96 mg). m/z(ESI):334.2[M+H] ⁺ .

Step 4: 8-amino-7-(3-methoxy-2,6-dimethylphenyl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[4 ,3-c]pyrimidine-9-carboxamide (12d)

Dissolve 12c (60 mg, 0.18 mmol) in concentrated sulfuric acid (3 mL) at room temperature, and stir at room temperature for 30 minutes. The reaction solution was cooled with ice water, neutralized with ammonia water, and the reaction solution was concentrated. The resulting residue was purified through a reversed-phase chromatography column (C18, 0.05% ammonia solution: acetonitrile = 20:1~1:20) to obtain the target compound 12d (32 mg) as a white solid. . m/z(ESI):352.2[M+H] ⁺ .

Step 5: 8-amino-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[4,3 -C] Synthesis of pyrimidine-9-carboxamide (12)

Dissolve 12d (32 mg, 0.09 mmol) in dichloromethane (5 mL) at room temperature, add boron tribromide (1 mol/L, 5 mL) in dichloromethane, and stir for 30 minutes. The reaction solution was quenched with methanol (5 mL), and then the reaction solution was concentrated. The resulting residue was purified by a reversed-phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1 ~ 1:20) to obtain compound 12 (18 mg).

m/z(ESI):338.2[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ9.43 (s, 1H), 8.96 (s, 1H), 8.35 (s, 1H), 7.17 (d, J＝8.0Hz, 1H), 6.97 (d, J＝ 8.0Hz,1H),5.98(s,2H),1.95(s,3H),1.90(s,2H).

Example 13: 1-amino-2-(3-hydroxy-2,6-dimethylphenyl)-2,6,7,8-tetrahydro-9H-2,3,8-triazabenzo [cd] Synthesis of Azulen-9-one (Compound 13)

Step 1: 2,3-Dibromoisonicotine aldehyde (13b)

Dissolve 2,3-dibromopyridine (5.0g, 21mmol) in anhydrous tetrahydrofuran, and add LiHMDS (63mL, 1mol/L) in THF dropwise at -78°C. After the dropwise addition is completed, gradually increase the temperature to React at 0°C for 30 minutes, then add DMF (2.3g, 31.7mmol) dropwise, and continue to react at this temperature for 1 hour. Then it was raised to room temperature and reacted for 12 hours. Slowly add a saturated solution of ammonium chloride to the reaction to quench the reaction, then extract with ethyl acetate (150mL*3), combine the organic phases, wash the organic phases with saturated brine (100mL), dry over anhydrous sodium sulfate, and filter. The filtrate was concentrated, and the crude product (13b) obtained could be directly used in the next reaction without purification.

Step 2: (2,3-dibromopyridin-4-yl)methanol (13c)

The crude product 13b (22g, 83mmol) obtained in the previous step was dissolved in anhydrous methanol, and then sodium cyanoborohydride (13g, 0.21mol) was slowly added, and the reaction system was stirred at 40°C for 12 hours. The solvent was evaporated under reduced pressure, then water was added to the reaction system, and then extracted with ethyl acetate (150mL*3). The organic phases were combined, washed with saturated brine (150mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. , the obtained crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1-2:1) to obtain yellow solid 13c (4.0g). MS(ESI)m/z:267.8[M+H] ⁺ .

Step 3: 2,3-Dibromo-4-(((tert-butyldimethylsilyl)oxy)methyl)pyridine (13d)

Under ice bath conditions, dissolve 13c (4.0g, 15mmol) in anhydrous N,N-dimethylformamide, then add imidazole (2.1g, 32mmol), continue stirring for 15 minutes, and then add tert-butyl dropwise After the dropwise addition of a solution of dimethylsilyl chloride (2.5g, 17mmol) in N,N-dimethylformamide, the solution was raised to room temperature and reacted for 3 hours. Then slowly add water to the reaction system to quench the reaction, then extract with ethyl acetate (100mL*3), combine the organic phases, wash the organic phase with saturated brine (150mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:0-5:1) to obtain yellow solid 13d (4.0g). MS(ESI)m/z:381.9[M+H] ⁺ .

Step 4: 3-Bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)-N-(3-methoxy-2,6-dimethylphenyl)pyridine -2-amine(13e)

Compound 13d (4.0g, 10.5mmol), 3-methoxy-2,6-dimethylaniline (1.6g, 10.5mmol), cesium carbonate (6.8g, 21mmol), 4,5-bisdiphenyl Phosphine-9,9-dimethylxanthene (0.64g, 1.1mmol) and bis(dibenzylideneacetone)palladium (0.61g, 1.1mmol) were dissolved in 1,4-dioxane, and then The air was purged with nitrogen, and then placed in a 100°C oil bath to react for 12 hours. After the reaction is completed, add water to the reaction to quench the reaction, then extract with ethyl acetate (100mL*3), combine the organic phases, wash the organic phases with saturated brine (100mL), dry over anhydrous sodium sulfate, filter, and remove the filtrate. After concentration, the obtained crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:0-5:1) to obtain yellow solid 13e (1.7g). MS(ESI)m/z:453.2 [M+H] ⁺ .

Step 5: 2-Amino-4-(((tert-butyldimethylsilyl)oxy)methyl)-1-(3-methoxy-2,6-dimethylphenyl)- 1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (13f)

Dissolve malononitrile (0.58g, 8.8mmol) in ethylene glycol dimethyl ether (5mL), then add sodium tert-butoxide (1.3g, 13mmol), stir at room temperature for 30 minutes, then add 13e (1.0g, 2.2 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (89 mg, 0.11 mmol), then replace the air with nitrogen, and then place it at 100 ℃ oil bath for 12 hours. After the reaction is completed, add water to the reaction to quench the reaction, then extract with ethyl acetate (100mL*3), combine the organic phases, wash the organic phases with saturated brine (100mL), dry over anhydrous sodium sulfate, filter, and remove the filtrate. After concentration, the obtained crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:0-1:1) to obtain yellow solid 13f (0.46g). MS(ESI)m/z:437.2[M+H] ⁺ .

Step 6: 2-amino-4-(hydroxymethyl)-1-(3-methoxy-2,6-dimethylphenyl)-1H-pyrrolo[2,3-b]pyridine-3- Methyl carboxylate (13g)

Compound 13f (0.22g, 0.68mmol) was dissolved in methanol (9mL), then concentrated hydrochloric acid (1mL) was added, and the reaction was carried out at 90°C for 16 hours. Wait for the reaction to cool to room temperature, add water (10mL) to the reaction solution, and then extract with ethyl acetate (10mL*3). Combine the organic phases, wash with saturated brine (10mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate , the obtained residue was purified by reverse phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1 ~ 1:20) to obtain 13g (90mg) of the target product. m/z(ESI):356.0[M+H] ⁺ .

Step 7: 2-amino-4-(chloromethyl)-1-(3-methoxy-2,6-dimethylphenyl)-1H-pyrrolo[2,3-b]pyridine-3- Methyl carboxylate (13h)

Dissolve 13g (90mg, 0.25mmol) in phosphorus oxychloride (3mL) at room temperature, and then stir at 80°C for 2h. Wait for the reaction to cool to room temperature, add water (5mL) to the reaction solution to dilute, then extract with ethyl acetate (5mL*3), combine the organic phases, and wash the organic layer with saturated sodium bicarbonate solution (5mL) and saturated brine ( 5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified with a normal phase chromatography column (ethyl acetate: petroleum ether = 10:1-1:2) to obtain the target product 13h (51 mg) as a white solid. LC-MS: m/z(ESI):374.8[M+H] ⁺ .

Step 8: 2-amino-4-(cyanomethyl)-1-(3-methoxy-2,6-dimethylphenyl)-1H-pyrrolo[2,3-b]pyridine-3 -Methyl carboxylate (13i)

Compound 13h (51 mg, 0.14 mmol) was dissolved in acetonitrile (0.5 mL), then trimethylcyanosilane (8 mg, 80.25 μmol) and tetrabutylammonium fluoride (1 M, 80.25 μL) were added successively, and the mixture was incubated at room temperature. Leave to react for 5 minutes. Water (2mL) was added to the reaction solution, and then extracted with ethyl acetate (10mL*3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by normal phase chromatography column (ethyl acetate: petroleum ether = 10:1-1:3) to obtain The target product 13i (30 mg) was a white solid. LC-MS: m/z(ESI):365.4[M+H] ⁺ .

Step 9: 1-amino-2-(3-methoxy-2,6-dimethylphenyl)-2,6,7,8-tetrahydro-9H-2,3,8-triazaphenyl And[cd]azulene-9-one(13j)

Compound 13i (26 mg, 0.071 mmol) was dissolved in methanol (1 mL), then nickel chloride (11 mg, 0.086 mmol) and sodium borohydride (19 mg, 0.50 mmol) were added in sequence, stirred at room temperature for 30 minutes, and then at 80°C The reaction was carried out under these conditions for 8 hours. After the reaction was cooled to room temperature, water (1mL) was added to the reaction solution, and then extracted with ethyl acetate (10mL*3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated. The resulting residue was purified by normal phase chromatography column (ethyl acetate: petroleum ether = 10:1-1:3) The target product 13j (6.0 mg) was obtained as a white solid. LC-MS: m/z(ESI):337.3[M+H] ⁺ .

Step 10: 1-amino-2-(3-hydroxy-2,6-dimethylphenyl)-2,6,7,8-tetrahydro-9H-2,3,8-triazabenzo[ cd]azulene-9-one(13)

Dissolve 13j (6.0 mg, 0.018 mmol) in anhydrous dichloromethane (1 mL) at room temperature, add boron tribromide (1 mol/L, 0.2 mL) in dichloromethane, and stir for 30 minutes. The reaction was quenched with methanol (1 mL), and then the reaction solution was concentrated. The resulting residue was purified by reversed-phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1 ~ 1:20) to obtain compound 13 (3.3 mg) as a white solid. . m/z(ESI):323.3[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ7.67 (s, 1H), 7.07 (d, J = 8.0Hz, 2H), 6.93-6.83 (m, 3H), 3.41 (s, 2H), 3.02 ( s,2H),1.74(s,3H),1.65(s,3H).

Example 14: 1-amino-2-(3-hydroxy-2,6-dimethylphenyl)-2,8-dihydro-9H-2,3,8-triazabenzo[cd]azulene Preparation of -9-one (compound 14)

Step 1: 3-Bromo-4-chloro-N-(3-methoxy-2,6-dimethylphenyl)pyridin-2-amine (14b)

The compound 3-bromo-2,4-dichloropyridine (2.3g, 10mmol), 3-methoxy-2,6-dimethylaniline (3.0g, 20mmol), cesium carbonate (9.8g, 30mmol), 4,5-Bisdiphenylphosphine-9,9-dimethylxanthene (0.12g, 2.0mmol) and bis(dibenzylideneacetone)palladium (0.91g, 1.0mmol) were dissolved in anhydrous 1, 4-Dioxane (10 mL), replace the air with nitrogen, and then place it in a 100°C oil bath for reaction for 8 hours. After the reaction is completed, add water to the reaction to quench the reaction, then extract with ethyl acetate (50mL*3), combine the organic phases, wash the organic phases with saturated brine (50mL), dry over anhydrous sodium sulfate, filter, and remove the filtrate. Concentrate, and the obtained residue is purified by reverse-phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1 ~ 1:20) to obtain the target compound 14b (836 mg) as a white solid. m/z:341.0,343.0[M+H] ⁺ .

Step 2: 2-Amino-4-chloro-1-(3-methoxy-2,6-dimethylphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (14c )

Dissolve malononitrile (0.66g, 10mmol) in ethylene glycol dimethyl ether (10mL), then add sodium tert-butoxide (1.4g, 15mmol), stir at room temperature for 30 minutes, then add 14b (0.84g, 2.5mmol) ) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (81mg, 0.1mmol), then replace the air with nitrogen, and then place it at 100℃ React in oil bath for 12 hours. After the reaction is completed, filter, and the filtrate is concentrated. The resulting residue is purified by a reverse-phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1 to 1:20) to obtain the target compound 14c (589 mg) as a white solid. m/z:327.0[M+H] ⁺ .

Step 3: (E)-2-amino-4-(2-ethoxyvinyl)-1-(3-methoxy-2,6-dimethylphenyl)-1H-pyrrolo[2, 3-b]pyridine-3-carbonitrile (14d)

Compound 14c (0.33g, 1mmol), (E)-1-ethoxyvinyl-2-boronic acid pinacol ester (0.60g, 3mmol), palladium acetate (22mg, 0.1mmol), 2-bicyclohexylphosphine- 2',6'-Dimethoxybiphenyl (0.11g, 0.25mmol) and potassium carbonate (0.50g, 3mmol) were dissolved in a mixed solution of acetonitrile/water (6mL/4mL), and the air was replaced with nitrogen. , and then placed in a 70°C oil bath to react for 8 hours. After the reaction is completed, filter, and the filtrate is concentrated. The resulting residue is purified by a reverse-phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1~1:20) to obtain the target compound 14d (0.15g) as a white solid. m/z:363.3[M+H] ⁺ .

Step 4: 1-Amino-2-(3-methoxy-2,6-dimethylphenyl)-2,8-dihydro-9H-2,3,8-triazabenzo[cd] Azulen-9-one(14e)

Dissolve 14d (0.13g, 0.4mmol) in a mixed solution of ethanol (3mL)/water (2mL) at room temperature, and add (dimethylphosphonate) platinum (II) hydrogenation complex (10mg, 0.02mmol) , and then reacted at 110°C for 16 hours. After the reaction was cooled to room temperature, the insoluble matter was removed by filtration, and the filtrate was spun to dryness. The resulting residue was purified through a reversed-phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1 to 1:20) to obtain product 14e (72 mg). m/z(ESI):335.1[M+H] ⁺ .

Step 5: 1-Amino-2-(3-hydroxy-2,6-dimethylphenyl)-2,8-dihydro-9H-2,3,8-triazabenzo[cd]azulene- 9-keto(14)

Dissolve 14e (20 mg, 0.06 mmol) in anhydrous dichloromethane (1 mL) at room temperature, add boron tribromide (1 mol/L, 0.5 mL) in dichloromethane, and stir for 10 minutes. The reaction was quenched with methanol (1 mL), and then the reaction solution was concentrated. The resulting residue was purified by reversed-phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1~1:20) to obtain solid compound 14 (9.6 mg). m/z(ESI):322.3[M+H] ⁺ .

Example 15: 1-amino-2-(3-hydroxy-2,6-dimethylphenyl)-2,8-dihydro-9H-2,3,5,8-tetraazabenzo[cd ] Azul-9-one (chemical Preparation of compound 15)

Step 1: 6-amino-4-chloro-7-(3-methoxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (15a )

Dissolve malononitrile (0.33g, 5.0mmol) into anhydrous glycol dimethyl ether (4mL), add sodium tert-butoxide (0.75g, 7.5mmol), stir at room temperature for 30 minutes, then add 1c (0.50g, 1.2 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (40 mg, 50 μmol). Replace the air with nitrogen three times, and then react at 90°C for 3 hours under nitrogen protection. After the reaction was cooled to room temperature, the insoluble matter was removed by filtration, and the filtrate was spun to dryness. The resulting residue was purified through a reversed-phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1 to 1:20) to obtain compound 15a (0.29g). m/z(ESI):328.1[M+H] ⁺ .

Step 2: (E)-6-amino-4-(2-ethoxyvinyl)-7-(3-methoxy-2,6-dimethylphenyl)-7H-pyrrolo[2, 3-d]pyrimidine-5-carbonitrile (15c)

At room temperature, compound 15a (0.20g, 0.6mmol) was dissolved in a mixed solution of 1,4-dioxane (1.5mL)/water (0.5mL), and [1,1'-bis(diphenyl) was added Phosphine)ferrocene]palladium dichloride dichloromethane complex (25mg, 31μmol), potassium carbonate (0.17g, 1.2mmol), replace the air with nitrogen three times, and then add (E)-1-ethyl Oxyethylene-2-boronic acid pinacol ester 15b (0.24g, 1.2mmol) was then reacted at 80°C for 8 hours. After the reaction was cooled to room temperature, the insoluble matter was removed by filtration, and the filtrate was spun to dryness. The resulting residue was purified through a reversed-phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1 to 1:20) to obtain product 15c (86 mg). m/z(ESI):364.2[M+H] ⁺ .

Step 3: 1-amino-2-(3-methoxy-2,6-dimethylphenyl)-2,8-dihydro-9H-2,3,5,8-tetraazabenzo[ cd]azulene-9-one(15d)

Dissolve 15c (40 mg, 0.1 mmol) in a mixed solution of ethanol (3 mL)/water (2 mL) at room temperature, and add (dimethylphosphonate) platinum (II) hydrogenation complex (10 mg, 0.02 mmol). Then react at 110°C for 8 hours. After the reaction was cooled to room temperature, the insoluble matter was removed by filtration, and the filtrate was spun to dryness. The resulting residue was purified through a reversed-phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1 to 1:20) to obtain product 15d (20 mg). m/z(ESI):336.2[M+H] ⁺ .

Step 4: 1-amino-2-(3-hydroxy-2,6-dimethylphenyl)-2,8-dihydro-9H-2,3,5,8-tetraazabenzo[cd] Azulen-9-one (compound 15)

Dissolve 15d (10 mg, 30 μmol) in dichloromethane (2 mL) at room temperature, then add boron tribromide (1 M/L, 0.5 mL) in dichloromethane and stir for 30 minutes. The reaction solution was quenched with methanol (1 mL), and the solvent was evaporated under reduced pressure. The resulting residue was purified by a reversed-phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1 ~ 1:20) to obtain the solid target product 15 (5.0 mg ).

m/z(ESI):322.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.60 (s, 1H), 8.72 (d, J = 7.4Hz, 1H), 8.03 (s, 1H), 7.11-7.03 (m, 1H), 6.98- 6.89(m,1H),6.73(s,2H),5.91(dd,J＝10.3,7.4Hz,1H),5.18(d,J＝10.3Hz,1H),1.76(s,3H),1.68(s ,3H).

Example 16: 1-amino-2-(3-hydroxy-2,6-dimethylphenyl)-2,6,7,8-tetrahydro-9H-2,3,5,8-tetraaza Preparation of benzo[cd]azulen-9-one (compound 16)

Step 1: 1-Amino-2-(3-methoxy-2,6-dimethylphenyl)-2,6,7,8-tetrahydro-9H-2,3,5,8-tetraazo Heterobenzo[cd]azulen-9-one(16a)

Dissolve 15d (10 mg) in ethanol (10 mL) at room temperature, add palladium/carbon (10 mg, 10% Pd, containing about 55% water), replace the air with hydrogen three times, and then react at room temperature under hydrogen for 4 hours. The reaction solution was filtered, the filtrate was spun to dryness, and the residue was purified through a reversed-phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1 to 1:20) to obtain compound 16a (9.0 mg). m/z(ESI):338.2[M+H] ⁺ .

Step 2: 1-amino-2-(3-hydroxy-2,6-dimethylphenyl)-2,6,7,8-tetrahydro-9H-2,3,5,8-tetraazabenzene And[cd]azulene-9-one (compound 16)

Dissolve 16a (9.0 mg, 30 μmol) in dichloromethane (2 mL) at room temperature, then add boron tribromide (1 mol/L, 0.5 mL) in dichloromethane and stir for 30 minutes. The reaction solution was quenched with methanol (1 mL), and the solvent was evaporated under reduced pressure. The resulting residue was purified through a reversed-phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1 ~ 1:20) to obtain the white solid target product 16 (7.1 mg). m/z(ESI):324.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.61 (s, 1H), 8.31 (s, 1H), 7.31 (t, J = 4.0Hz, 1H), 7.08 (d, J = 8.4Hz, 1H) ,7.04(s,2H),6.94(d,J＝8.4Hz,1H),3.49-3.46(m,2H),3.11-3.08(m,2H),1.78(s,3H),1.69(s,3H ).

Example 17: 1-amino-2-(3-hydroxy-2,6-dimethylphenyl)-4-methyl-2,8-dihydro-9H-2,3,5,8-tetraazo Preparation of heterobenzo[cd]azulen-9-one (compound 17)

Compound 17 was prepared using a method similar to Example 15, replacing compound 1c with compound 10b.

m/z(ESI):336.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.62 (s, 1H), 8.64 (d, J = 7.5Hz, 1H), 7.06 (d, J = 8.2Hz, 1H), 6.92 (d, J = 8.2Hz,1H),6.57(s,2H),5.88(dd,J＝10.3,7.4Hz,1H),5.14(d,J＝10.3Hz,1H),2.24(s,3H),1.77(s, 3H),1.68(s,3H).

Example 18: 1-amino-2-(3-hydroxy-2,6-dimethylphenyl)-4-methyl-2,6,7,8-tetrahydro-9H-2,3,5, Preparation of 8-tetraazabenzo[cd]azulen-9-one (compound 18)

Compound 18 was prepared by using a method similar to step 1 of Example 16, replacing compound 15d with compound 17.

m/z(ESI):338.3[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.62 (s, 1H), 7.28 (brs, 1H), 7.09 (d, J = 8.4Hz, 1H), 6.98 (brs, 2H), 6.94 (d, J＝8.4Hz,1H),3.48-3.45(m,2H),3.08-3.05(m,2H),2.44(s,3H),1.78(s,3H),1.69(s,3H).

Example 19: 1-amino-6-chloro-2-(3-hydroxy-2,6-dimethylphenyl)-4-methyl-2,8-dihydro-9H-2,3,5, Preparation of 8-tetraazabenzo[cd]azulen-9-one (compound 19)

Step 1: (E)-6-Amino-4-(2-ethoxyvinyl)-7-(3-methoxy-2,6-dimethylphenyl)-2-methyl-7H- Pyrro[2,3-d]pyrimidine-5-carbonitrile (19a)

Compound 10c (0.26g, 0.75mmol) and (E)-1-ethoxyvinyl-2-boronic acid pinacol ester 15b (0.30g, 1.5mmol) were dissolved in 1,4-dioxane at room temperature. (1.5mL)/water (0.5mL), add [1,1'-bis(diphenylphosphine)ferrocene]dichloride palladium dichloromethane complex (30mg, 50μmol), carbonic acid Potassium (0.21g, 1.5mmol), replace the air with nitrogen three times, and then react at 80°C for 4 hours. After the reaction was cooled to room temperature, the insoluble matter was removed by filtration, and the filtrate was concentrated. The resulting residue was purified through a reversed-phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1~1:20) to obtain product 19a (0.18g, yield 62 %). m/z(ESI):378.2[M+H] ⁺ .

Step 2: 1-amino-2-(3-methoxy-2,6-dimethylphenyl)-4-methyl-2,8-dihydro-9H-2,3,5,8-tetrahydrofuran Azabenzo[cd]azulen-9-one(19b)

Dissolve 19a (0.18g, 0.47mmol) in a mixed solution of ethanol (4.5mL)/water (3mL) at room temperature, and add (dimethylphosphonate) platinum (II) hydrogenation complex (34mg, 80μmol) , and then reacted at 110°C for 8 hours. After the reaction was cooled to room temperature, the insoluble matter was removed by filtration, and the filtrate was concentrated. The resulting residue was purified through a reversed-phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1 ~ 1:20) to obtain product 19b (30 mg, yield 19%) ). m/z(ESI):350.2[M+H] ⁺ .

Step 3: 1-amino-6-chloro-2-(3-methoxy-2,6-dimethylphenyl)-4-methyl-2,8-dihydro-9H-2,3,5 ,8-tetraazabenzo[cd]azulen-9-one (19c)

Compound 19b (35 mg, 0.10 mmol) was dissolved in anhydrous acetonitrile (2 mL) at room temperature, N-chlorosuccinimide (13 mg, 0.10 mmol) was added, and then the temperature was raised to 70°C for 6 hours. After the reaction was cooled to room temperature, the solvent was evaporated under reduced pressure, and the resulting residue was purified by reverse-phase chromatography (C18, 0.05% ammonia water: acetonitrile = 20:1~1:20) to obtain solid compound 19c (12 mg, yield 31%) ). m/z(ESI):384.1[M+H] ⁺ .

Step 4: 1-amino-6-chloro-2-(3-hydroxy-2,6-dimethylphenyl)-4-methyl-2,8-dihydro-9H-2,3,5,8 -Tetraazabenzo[cd]azulen-9-one(19)

Dissolve 19c (3.0 mg, 7.8 μmol) in anhydrous dichloromethane (2 mL) at room temperature, add boron tribromide (1 mol/L, 0.5 mL) in dichloromethane, and stir at this temperature. Continue the reaction for 30 minutes. The reaction was quenched with methanol (1 mL), and then the reaction solution was concentrated. The resulting residue was purified by reverse-phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1 ~ 1:20) to obtain solid compound 19 (2.7 mg, collected rate 93%). m/z(ESI):370.1[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.62 (s, 1H), 8.83 (d, J = 8.0Hz, 1H), 7.07 (d, J = 8.0Hz, 1H), 6.93 (d, J = 8.0Hz,1H),6.76(s,2H),6.33(d,J＝8.0Hz,1H),2.33(s,3H),1.76(s,3H),1.68(s,3H).

Example 20: 1-amino-2-(3-hydroxy-2,6-dimethylphenyl)-4,6-dimethyl-2,8-dihydro-9H-2,3,5,8 - Preparation of tetraazabenzo[cd]azulen-9-one (compound 20)

Step 1: 1-amino-2-(3-methoxy-2,6-dimethylphenyl)-4,6-dimethyl-2,8-dihydro-9H-2,3,5, 8-Tetraazabenzo[cd]azulen-9-one (20a)

Dissolve compound 19c (5.0 mg, 13 μmol) and methylboronic acid (4.7 mg, 1.5 mmol) in a mixed solution of 1,4-dioxane (2 mL)/water (0.2 mL) at room temperature, and add palladium acetate. (0.43mg, 2.6μmol), 2-bicyclohexylphosphine-2',6'-dimethoxybiphenyl (2.1mg, 5.2μmol), potassium phosphate (11mg, 52μmol), replace the air 3 with nitrogen times, and then reacted at 80°C for 8 hours. After the reaction was cooled to room temperature, the insoluble matter was removed by filtration, and the filtrate was spun to dryness. The resulting residue was purified through a reversed-phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1 ~ 1:20) to obtain product 20a (2.1 mg, yield 44%). m/z(ESI):364.2[M+H] ⁺ .

Step 2: 1-Amino-2-(3-hydroxy-2,6-dimethylphenyl)-4,6-dimethyl-2,8-dihydro-9H-2,3,5,8- Tetraazabenzo[cd]azulen-9-one(20)

Dissolve 20a (2.1 mg, 5.8 μmol) in anhydrous dichloromethane (1 mL) at room temperature, add boron tribromide (1 mol/L, 0.5 mL) in dichloromethane, and continue under this condition. React for 30 minutes. The reaction was quenched with methanol (1 mL), and then the reaction solution was concentrated. The resulting residue was purified by reverse-phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1 ~ 1:20) to obtain solid compound 20 (1.1 mg, collected rate 54%). m/z(ESI):350.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.58 (s, 1H), 8.53 (d, J = 8.0Hz, 1H), 7.06 (d, J = 8.0Hz, 1H), 6.92 (d, J = 8.0Hz,1H),6.54(s,2H),5.89(d,J＝8.0Hz,1H),2.30(s,3H),1.83(s,3H),1.76(s,3H),1.68(s, 3H).

Example 21: 1-amino-2-(3-hydroxy-2,6-dimethylphenyl)-4-methyl-6-(1-methyl-1,2,3,6-tetrahydropyridine Preparation of -4-yl)-2,8-dihydro-9H-2,3,5,8-tetraazabenzo[cd]azulen-9-one (compound 21)

Compound 21 was prepared using a similar method to Example 20, replacing methylboronic acid in step 1 with compound 21a.

m/z(ESI):431.4[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.60 (s, 1H), 8.57 (d, J = 8.0Hz, 1H), 7.06 (d, J = 8.0Hz, 1H), 6.58 (s, 2H) ,5.83(d,J＝8.0Hz,1H),5.51(s,1H),2,90-2.85(m,2H),2.68-2.66(m,1H),2.48-2.42(m,3H),2.35 -2.31(m,1H),2.25(s,3H),2.24(s,3H),1.76(s,3H),1.67(s,3H).

Example 22: 1-amino-2-(3-hydroxy-2,6-dimethylphenyl)-7-phenyl-2,8-dihydro-9H-2,3,5,8-tetraazo Preparation of heterobenzo[cd]azulen-9-one (compound 22)

Step 1: 6-amino-4-chloro-7-(3-methoxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (22a )

Compound 12a (0.33g, 1.0mmol) was dissolved in concentrated sulfuric acid (3mL) at room temperature, and then reacted at 60°C for 1 hour. Wait for the reaction solution to cool to room temperature, add ice water to quench the reaction, then adjust the pH to neutral with ammonia (25% ammonia aqueous solution), extract three times with ethyl acetate (15 mL), combine the organic phases, and wash with saturated sodium chloride aqueous solution. Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue is purified through a reversed-phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1~1:20) to obtain product 22a (0.31g, yield 88%) ). m/z(ESI):346.2[M+H] ⁺ .

Step 2: 6-amino-7-(3-methoxy-2,6-dimethylphenyl)-4-(phenylethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5 -Formamide (22c)

At room temperature, add 22a (0.10g, 0.30mmol), 22b (0.12g, 1.2mmol), copper iodide (17mg, 0.09mmol), and bistriphenylphosphine palladium dichloride (63mg, 0.09mmol) into 100mL. In the three-necked flask, replace the air with nitrogen three times, add anhydrous tetrahydrofuran (10 mL), and stir at room temperature for 5 minutes. Anhydrous triethylamine (0.30g, 3.0mmol) was then added, and then the reaction was moved to 60°C for 8 hours. After the reaction was cooled to room temperature, the insoluble matter was removed by filtration, and the filtrate was spun to dryness. The resulting residue was purified through a reversed-phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1~1:20) to obtain product 22c (85 mg, yield 71 %). m/z(ESI):412.0[M+H] ⁺ .

Step 3: 1-amino-2-(3-methoxy-2,6-dimethylphenyl)-7-phenyl-2,8-dihydro-9H-2,3,5,8-tetrahydrofuran Azabenzo[cd]azulen-9-one (22d)

Dissolve 22c (20 mg, 72 μmol) in water (1 mL) at room temperature, slowly add concentrated sulfuric acid (1 mL) dropwise until completely dissolved, and then move the reaction to 120°C for 2 hours. After the reaction solution is cooled to room temperature, add ice water to quench the reaction, then adjust the pH to neutral with ammonia (25% ammonia aqueous solution), extract three times with ethyl acetate (10mL*3), combine the organic phases, and add saturated sodium chloride. Wash with aqueous solution (10 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue obtained is purified by a reversed-phase chromatography column (C18, 0.05% ammonia: acetonitrile = 20:1~1:20) to obtain 22d (6.0 mg) , yield 30%). m/z(ESI):412.0[M+H] ⁺ .

Step 4: 1-amino-2-(3-hydroxy-2,6-dimethylphenyl)-7-phenyl-2,8-dihydro-9H-2,3,5,8-tetraaza Benzo[cd]azulene-9-one(22)

Dissolve 22d (6 mg, 15 μmol) in anhydrous dichloromethane (5 mL), and slowly add boron tribromide (1 mL, 1 mol/L dichloromethane solution) dropwise in an ice bath. Then it was raised to room temperature and reacted for 30 minutes. The reaction was quenched with methanol (5 mL), and the solvent was distilled off under reduced pressure. Use ammonia (25% ammonia aqueous solution) to adjust the pH to neutral, and purify through reversed phase chromatography column (C18, 0.05% ammonia: acetonitrile = 20:1 ~ 1:20) to obtain compound 22 (5.8 mg, yield 99%) . m/z(ESI):398.0[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.60 (s, 1H), 8.39 (s, 1H), 8.08 (d, J = 1.6Hz, 1H), 7.61-7.50 (m, 2H), 7.49- 7.36(m,3H),7.08(d,J＝8.3Hz,1H),6.94(d,J＝8.3Hz,1H),6.81(s,2H),5.41(s,1H),1.80(s,3H ),1.71(s,3H).

Example 23: 1-amino-2-(3-hydroxy-2,6-dimethylphenyl)-7-(1-methyl-1H-pyrazol-4-yl)-2,8-dihydro Preparation of -9H-2,3,5,8-tetraazabenzo[cd]azulen-9-one (compound 23)

Compound 23 was synthesized using a method similar to Example 22 by replacing 22b with N-methyl-4-ethynylpyrazole 23b.

m/z(ESI):402.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.62(s,1H),8.27(s,1H),8.14(brs,1H),8.09(s,1H),7.89(s,1H),7.08( d,J＝8.4Hz,1H),6.93(d,J＝8.4Hz,1H),6.85(brs,2H),5.71(d,J＝1.6Hz,1H),3.85(s,3H),1.79( s,3H),1.70(s,3H).

Example 24: 1-amino-2-(3-hydroxy-2,6-dimethylphenyl)-7-(pyridin-4-yl)-2,8-dihydro-9H-2,3,5 , Preparation of 8-tetraazabenzo[cd]azulen-9-one (compound 24)

Step 1: 6-Amino-7-(3-methoxy-2,6-dimethylphenyl)-4-(pyridin-4-ylethynyl)-7H-pyrrolo[2,3-d] Pyrimidine-5-carboxamide (24b)

At room temperature, add 22a (0.10g, 0.30mmol), 24a (0.12g, 1.2mmol), copper iodide (17mg, 0.09mmol), and bistriphenylphosphine palladium dichloride (63mg, 0.09mmol) into 100mL. In a three-necked flask, replace the air with nitrogen three times, then add anhydrous tetrahydrofuran (10mL), stir at room temperature for 5 minutes, then add anhydrous triethylamine (0.30g, 3.0mmol), and then move the reaction to 62 ℃ reaction for 8 hours. After the reaction was cooled to room temperature, the insoluble matter was removed by filtration, and the filtrate was spun to dryness. The resulting residue was purified by a reversed-phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1 ~ 1:20) to obtain product 24b (80 mg, yield 67 %). m/z(ESI):412.0[M+H] ⁺ .

Step 2: 6-Amino-7-(3-methoxy-2,6-dimethylphenyl)-4-(2-methoxy-2-(pyridin-4-yl)vinyl)-7H -pyrrolo[2,3-d]pyrimidine-5-carboxamide (24c)

Dissolve 24b (80 mg, 0.2 mmol) in methanol (10 mL) at room temperature, then add sodium methoxide (160 mg, 3.0 mmol), and move the reaction to 82°C and reflux for 30 minutes. After the reaction solution cooled to room temperature, the solvent was evaporated under reduced pressure. The pH of the resulting residue was adjusted to neutral with saturated ammonium chloride solution, and extracted three times with ethyl acetate (15 mL). The organic phases were combined and saturated aqueous sodium chloride solution (10 mL) was obtained. Wash, dry over anhydrous sodium sulfate, filter, and evaporate under reduced pressure to remove the solvent. The crude product 24c obtained is directly used in the next step.

Step 3: 1-amino-2-(3-methoxy-2,6-dimethylphenyl)-7-(pyridin-4-yl)-2,8-dihydro-9H-2,3, 5,8-tetraazabenzo[cd]azulen-9-one (24d)

At room temperature, crude product 24c (45 mg, 0.10 mmol) was added to water (3 mL), concentrated sulfuric acid (3 mL) was slowly added dropwise until completely dissolved, and then the reaction was moved to 120°C for 30 minutes. After the reaction solution is cooled to room temperature, add ice water to quench the reaction, then adjust the pH to neutral with ammonia (25% ammonia aqueous solution), extract three times with ethyl acetate (10mL*3), combine the organic phases, and add saturated sodium chloride. The aqueous solution (10 mL) was washed, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a reversed-phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1 ~ 1:20) to obtain 24d (15 mg, Yield 36%). m/z(ESI):412.0[M+H] ⁺ .

Step 4: 1-amino-2-(3-hydroxy-2,6-dimethylphenyl)-7-(pyridin-4-yl)-2,8-dihydro-9H-2,3,5, 8-tetraazabenzo[cd]azulen-9-one(24)

Under ice bath conditions, 24d (15 mg, 36 μmol) was dissolved in anhydrous dichloromethane (5 mL), and then boron tribromide (1 mL, 1 mol/L dichloromethane solution) was slowly added dropwise. The reaction was carried out at room temperature for 30 minutes, the reaction was quenched with methanol (5 mL), and the solvent was evaporated under reduced pressure. Use ammonia (25% ammonia aqueous solution) to adjust the pH to neutral, and purify through reversed phase chromatography column (C18, 0.05% ammonia: acetonitrile = 20:1 ~ 1:20) to obtain compound 24 (2.2 mg, yield 15%) . m/z(ESI):399.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.60 (s, 1H), 8.68-8.58 (m, 3H), 8.10 (s, 1H), 7.57-7.49 (m, 2H), 7.08 (d, J ＝8.3Hz,1H),6.93(d,J＝8.3Hz,1H),6.86(s,2H),5.50(d,J＝1.4Hz,1H),1.79(s,3H),1.71(s,3H ).

Example 25: 1-amino-2-(3-hydroxy-2,6-dimethylphenyl)-7-(pyridin-3-yl)-2,8-dihydro-9H-2,3,5 , Preparation of 8-tetraazabenzo[cd]azulen-9-one (compound 25)

Compound 24a was replaced with 3-ethynylpyridine 25a, and compound 25 was prepared using a method similar to Example 24.

m/z(ESI):399.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.61 (s, 1H), 8.78-8.70 (m, 2H), 8.60 (dd, J = 4.8, 1.6 Hz, 1H), 7.44 (dd, J = 7.8 ,5.0Hz,1H),7.08(d,J＝8.3Hz,1H),6.93(d,J＝8.3Hz,1H),6.84(s,2H),5.39(d,J＝1.4Hz,1H), 1.79(s,3H),1.71(s,3H).

Example 26: 1-amino-2-(3-hydroxy-2,6-dimethylphenyl)-4,7-dimethyl-2,8-dihydro-9H-2,3,5,8 - Preparation of tetraazabenzo[cd]azulen-9-one (compound 26)

Step 1: 6-Amino-4-chloro-7-(3-methoxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5 -Formamide (26a)

Compound 10c (0.34g, 1.0mmol) was dissolved in concentrated sulfuric acid (5mL) at room temperature, and then reacted at 60°C for 1 hour. Wait for the reaction solution to cool to room temperature, add ice water to quench the reaction, then adjust the pH to neutral with ammonia (25% ammonia aqueous solution), extract three times with ethyl acetate (15 mL), combine the organic phases, and wash with saturated sodium chloride aqueous solution. Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue obtained is purified by reverse phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1～1:20) to obtain product 26a (0.31g, yield 86%).

m/z(ESI):360.2[M+H] ⁺ .

Step 2: 6-amino-7-(3-methoxy-2,6-dimethylphenyl)-2-methyl-4-(3-(trimethylsilyl)propan-1-yne -1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (26c)

At room temperature, add 26a (60 mg, 0.17 mmol), 26b (47 mg, 0.33 mmol), copper iodide (3.2 mg, 17 μmol), and bistriphenylphosphine palladium dichloride (12 mg, 17 μmol) into a 100 mL three-neck flask. , replace the air with nitrogen three times, then add anhydrous tetrahydrofuran (10 mL), stir at room temperature for 5 minutes, then add anhydrous triethylamine (0.17g, 1.7mmol), and then move the reaction to 60°C for 8 hours. . After the reaction solution was cooled to room temperature, the insoluble matter was removed by filtration, and the filtrate was spun to dryness. The resulting residue was purified by a reversed-phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1 ~ 1:20) to obtain product 26c (40 mg, yield 67%).

m/z(ESI):436.2[M+H] ⁺ .

Step 3: 1-amino-2-(3-methoxy-2,6-dimethylphenyl)-4,7-dimethyl-2,8-dihydro-9H-2,3,5, 8-tetraazabenzo[cd]azulen-9-one (26d)

Compound 26c (80 mg, 0.18 mmol) was dissolved in water (3 mL) at room temperature, concentrated sulfuric acid (3 mL) was slowly added dropwise until completely dissolved, and then the reaction was moved to 120°C for 2 hours. After the reaction solution is cooled to room temperature, add ice water to quench the reaction, then adjust the pH to neutral with ammonia (25% ammonia aqueous solution), extract three times with ethyl acetate (10mL*3), combine the organic phases, and add saturated sodium chloride. The aqueous solution (10 mL) was washed, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1 ~ 1:20) to obtain 26d (17 mg, Yield 25%). m/z(ESI):364.2[M+H] ⁺ .

Step 4: 1-amino-2-(3-hydroxy-2,6-dimethylphenyl)-4,7-dimethyl-2,8-dihydro-9H-2,3,5,8- Tetraazabenzo[cd]azulen-9-one(26)

Under ice bath conditions, 26d (17 mg, 47 μmol) was dissolved in anhydrous dichloromethane (5 mL), and then boron tribromide (1 mL, 1 mol/L dichloromethane solution) was slowly added dropwise. Then it was raised to room temperature and reacted for 2 hours. The reaction was quenched with methanol (10 mL), and the solvent was distilled off under reduced pressure. Use ammonia (25% ammonia aqueous solution) to adjust the pH to neutral, and purify through reversed-phase chromatography column (C18, 0.05% ammonia: acetonitrile = 20:1 ~ 1:20) to obtain compound 26 (1 mg, yield 7%). m/z(ESI):350.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.64 (s, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 6.74 (s, 1H) ,6.56(s,2H),5.18(s,1H),2.24(s,3H),1.85(s,3H),1.77(s,3H),1.68(s,3H).

Example 28: 6-amino-7-(3-hydroxy-2,6-dimethylphenyl)-4-phenyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (compound 28) Preparation

Step 1: 6-amino-7-(3-methoxy-2,6-dimethylphenyl)-4-phenyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile ( 28b)

At room temperature, 12a (40mg, 0.12mmol), 28a (45mg, 0.37mmol), bis(dibenzylideneacetone)palladium (5.6mg, 6.1μmol), 1,3,5,7-tetramethyl-6 -Phenyl-2,4,8-trioxa-6-phosphoryladamantane (7.1 mg, 25 μmol) and cesium carbonate (0.12 g, 0.37 mmol) were dissolved in 1,4-dioxane/water (2 mL /0.2mL), replace the air with nitrogen three times. The reaction was then moved to 100°C for 4 hours. After the reaction was cooled to room temperature, the insoluble matter was removed by filtration, and the filtrate was spun to dryness. The resulting residue was purified through a reversed-phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1~1:20) to obtain product 28b (37 mg, yield 82 %).

m/z(ESI):370.2[M+H] ⁺ .

Step 2: 6-amino-7-(3-methoxy-2,6-dimethylphenyl)-4-phenyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide ( 28c)

Dissolve 28b (37 mg, 0.10 mmol) in concentrated sulfuric acid (8 mL) at room temperature, and then raise the temperature to 60°C for 1 hour. After the reaction solution is cooled to room temperature, add ice water, adjust the pH to neutral with ammonia water (25% ammonia aqueous solution), and distill under reduced pressure. The solvent was removed, and the crude product was purified by reverse-phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1~1:20) to obtain 28c (30 mg, yield 77%). m/z(ESI):388.2[M+H] ⁺ .

Step 3: 6-amino-7-(3-hydroxy-2,6-dimethylphenyl)-4-phenyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (28)

Dissolve 28c (30 mg, 77 μmol) in anhydrous dichloromethane (5 mL) at room temperature, add boron tribromide (1 mol/L, 5 mL) in dichloromethane, and stir for 30 minutes. The reaction was quenched with methanol (10 mL), and then the reaction solution was concentrated. The resulting residue was purified by reversed-phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1 ~ 1:20) to obtain solid compound 28 (25 mg, yield 54%). m/z(ESI):374.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.62(s,1H),8.49(s,1H),7.45-7.20(m,3H),7.52-7.49(m,3H),7.13(brs,2H ),7.11(d,J＝8.4Hz,1H),6.96(d,J＝8.4Hz,1H),1.81(s,3H),1.72(s,3H).

Example 29: 8-amino-7-(5-methyl-1H-indazol-4-yl)-7H-imidazo[1,2-c]pyrrolo[3,2-e]pyrimidine-9- Preparation of formamide (compound 29)

Step 1: 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (29b)

Dissolve 4-bromo-5-methyl-1H-indazole (4.5g, 21mmol) and 3,4-dihydro-2H-pyran (3.6g, 42mmol) in anhydrous dichloromethane solution at room temperature. , then add p-toluenesulfonic acid monohydrate (0.37g, 2.1mmol) and react at this temperature for 3 hours. The reaction was quenched with saturated aqueous ammonium chloride solution (20 mL), and then extracted with ethyl acetate (30 mL*3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel chromatography column (petroleum ether: ethyl acetate = 20:1 ~ 10:1) The target product 29b (11.2 g, yield 87%) was obtained. m/z(ESI):295.1[M+H] ⁺ .

Step 2: 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine (29c)

29b (6.0 g, 20 mmol) was dissolved in ammonia in 1,4-dioxane (0.4 M, 60 mL), and (R)-(-)-1-[(S)-2- was added (Dicyclohexylphosphine)ferrocene]ethyldi-tert-butylphosphine (0.11g, 0.2mmol), bis[tris(2-tolyl)phosphine]palladium (0.15g, 0.2mmol) and sodium tert-butoxide (5.8g.60mmol), the reaction was raised to 100°C for 16 hours, the reaction was quenched with water (20mL), and then extracted with ethyl acetate (30mL*3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel chromatography column (petroleum ether: ethyl acetate = 5:1 ~ 2:1) The target product 29c (4.4g, yield 93%) was obtained. m/z(ESI):232.2[M+H] ⁺ .

Step 3: N-(6-chloro-5-iodopyrimidin-4-yl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-amine ( 29d)

Dissolve 4,6-dichloro-5-iodopyrimidine (6.8g, 25mmol) and 29c (4.4g, 19mmol) in N,N-dimethylaniline (20mL), then add tris(dibenzylideneacetone) ) Dipalladium (1.3g, 19mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (0.80g, 19mmol) and cesium carbonate (15.6g, 48mmol), heat to React at 140°C for 5 hours. After the reaction is cooled to room temperature, gradually add saturated ammonium chloride (10 mL) aqueous solution to the reaction to quench, and then extract with ethyl acetate (20 mL*2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel chromatography column (petroleum ether: ethyl acetate = 20:1 ~ 5:1) The target product 29d (0.60g, yield 7%) was obtained.

m/z(ESI):470.2[M+H] ⁺ .

Step 4: 6-amino-4-chloro-7-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-7H-pyrrolo[ 2,3-d]pyrimidine-5-carbonitrile (29e)

Dissolve malononitrile (0.13g, 1.9mmol) in anhydrous glycol dimethyl ether (4mL), then add sodium tert-butoxide (0.49g, 5.0mmol), and react at room temperature for 30 minutes. Then 29d (0.6g, 1.3mmol) and [1,1'-bis(diphenylphosphine)ferrocene] dichloride palladium dichloromethane complex (0.19g, 0.26mmol) were added and the temperature was raised to 80°C Reaction takes 1 hour. After the reaction was cooled to room temperature, saturated aqueous ammonium chloride (20 mL) was gradually added to the reaction to quench, and then extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel chromatography column (petroleum ether: ethyl acetate = 3:1 ~ 2:1) The target product 29e (0.35g, yield 62%) was obtained.

MS(ESI)m/z:408.2[M+H] ⁺ .

Step 5: 4,6-diamino-7-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-7H-pyrrolo[2 ,3-d]pyrimidine-5-carbonitrile (29f)

At room temperature, compound 29e (90 mg, 0.22 mmol) was dissolved in N-methylpyrrolidone (3 mL), and ammonia water (0.27 g, 0.22 mmol) was added, and then the temperature was raised to 130°C and reacted for 16 hours. After the reaction was cooled to room temperature, water (10 mL) was gradually added to the reaction to dilute, and then extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel chromatography column (petroleum ether: ethyl acetate = 1:1 ~ 1:3) The target product 29f (45 mg, yield 49%) was obtained. MS(ESI)m/z:389.2[M+H] ⁺ .

Step 6: 8-amino-7-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-7H-imidazo[1,2- c]pyrrolo[3,2-e]pyrimidine-9-carbonitrile (29g)

Compound 29f (40 mg, 0.10 mmol) was dissolved in DMF at room temperature, and then 40% chloroacetaldehyde aqueous solution (20 mg, 0.10 mmol) was added dropwise, and then the temperature was raised to 60°C for 1 hour. Slowly add saturated sodium bicarbonate solution (10 mL) to the reaction system, and then extract with ethyl acetate (10 mL*3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel chromatography column (ethyl acetate: ethanol = 80:1 ~ 70:1) to obtain The target product was 29g (30mg, yield 67%). MS(ESI)m/z:413.2[M+H] ⁺ .

Step 7: 8-amino-7-(5-methyl-1H-indazol-4-yl)-7H-imidazo[1,2-c]pyrrolo[3,2-e]pyrimidine-9-methyl Nitrile(29h)

Under ice bath conditions, compound 29g (50mg, 0.12mmol) was dissolved in anhydrous dichloromethane (4mL), and trifluoroacetic acid (69mg, 0.61mmol) was added dropwise thereto, and then the temperature was raised to room temperature for 4 hours. Slowly add saturated sodium bicarbonate solution (15 mL) to the reaction system, and then extract with ethyl acetate (10 mL*3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated. The resulting residue was passed through a preparative chromatography column (C18, 0.05% ammonia: acetonitrile = 20:1 ~ 1:20) After purification, the target product 29h (25 mg, yield 62%) was obtained. MS(ESI)m/z:329.2[M+H] ⁺ .

Step 8: 8-Amino-7-(5-methyl-1H-indazol-4-yl)-7H-imidazo[1,2-c]pyrrolo[3,2-e]pyrimidine-9-methyl Amides(29)

Under ice bath conditions, compound 29h (10 mg, 30 μmol) was dissolved in anhydrous acetonitrile (1 mL), and concentrated sulfuric acid (1.0 mL) was added dropwise, and then raised to room temperature to react for 2 hours. Slowly added to the reaction system Saturated sodium bicarbonate solution (10mL), then extracted with ethyl acetate (20mL*3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated. The resulting residue was purified by preparative chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1 ~ 1:20 ) to obtain the target product 29 (1.5 mg, yield 13%). MS(ESI)m/z:347.2[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ -d) δ8.54 (s, 1H), 7.71 (d, J = 1.0Hz, 1H), 7.66 (s, 1H), 7.64 (t, J = 1.6Hz, 1H) ,7.60(d,J＝1.6Hz,1H),7.52(d,J＝5.2Hz,1H),7.49(s,1H),5.95(brs,2H),2.23(s,3H).

Example 30: 8-amino-7-(4-fluoro-3-hydroxy-2,6-dimethylphenyl)-5-methyl-7H-imidazo[1,2-c]pyrrolo[3 ,2-e]pyrimidine Preparation of -9-carboxamide (compound 30)

Step 1: 2,6-dibromo-4-fluoro-3-methoxyaniline (30b)

Under normal temperature conditions, dissolve 4-fluoro-3-methoxyaniline 30a (4g, 28mmol) in acetic acid, then add liquid bromine (11g, 71mmol) dropwise, react at room temperature for 2 hours, and add to the reaction system Slowly add saturated sodium bicarbonate solution (30mL), and then extract with ethyl acetate (100mL*3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified through a silica gel chromatography column (petroleum ether: ethyl acetate = 70:1 to 60:1) to obtain the target product. 30b (6.8g, yield 57%). MS(ESI)m/z:299.9[M+H] ⁺ .

Step 2: 2,6-dimethyl-4-fluoro-3-methoxyaniline (30c)

Under normal temperature conditions, dissolve 30b (4.0g, 13mmol) in 1,4-dioxane/water (40mL/4mL), and then add methylboronic acid (4.0g, 70mmol), [1,1'- Bis(diphenylphosphine)ferrocene]palladium dichloride (0.98g, 1.3mmol) and potassium carbonate (11g, 80mmol), replace the air with nitrogen three times, and then react at 100°C for 6 hours. Slowly add saturated ammonium chloride solution (20mL) to the reaction system, and then extract with ethyl acetate (100mL*3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography column (petroleum ether: ethyl acetate = 20:1 ~ 10:1) to obtain the target product. 30c (1.0g, yield 45%). MS(ESI)m/z:170.2[M+H] ⁺ .

Then, a similar method to Example 10 was used, replacing compound 1b with compound 30c, to prepare compound 30.

MS(ESI)m/z:369.2[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ -d) δ10.20 (brs, 1H), 7.59 (d, J = 1.2Hz, 1H), 7.48 (d, J = 1.2Hz, 1H), 7.00 (d, J = 2.4Hz,1H),5.77(br s,2H),5.57(s,1H),5.48(br s,1H),2.72(s,3H),1.94(s,3H),1.93(s,3H).

Example 31: 8-amino-3-((dimethylamino)methyl)-7-(3-hydroxy-2,6-dimethylphenyl)-7H-imidazo[1,2-c]pyrrole Preparation of [3,2-e]pyrimidine-9-carboxamide (compound 31)

Step 1: 4,6-diamino-7-(3-methoxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (31a)

Compound 12a (0.11g, 0.34mmol) was dissolved in N-methylpyrrolidone (2mL), and ammonia water (17mg, 1.01mmol) was added, and then the reaction was carried out under sealed tube conditions at 130°C for 16 hours. The reaction solution was cooled to room temperature, concentrated, and the residue was purified by reverse-phase chromatography (C18, 0.05% ammonia water: acetonitrile = 20:1-1:20) to obtain target compound 31a (60 mg, yield 58%). MS(ESI)m/z:309.2[M+H] ⁺ .

Step 2: 8-amino-3-formyl-7-(3-methoxy-2,6-dimethylphenyl)-7H-imidazo[1,2-c]pyrrolo[3,2- e]pyrimidine-9-carbonitrile (31b)

Compound 31a (60 mg, 0.19 mmol) was dissolved in anhydrous DMF (2 mL), and then 2,6-dimethylpyridine (0.13 g, 1.2 mmol), formic acid (0.27 g, 5.8 mmol), and 2-bromo were added in sequence. Malondialdehyde (0.18g, 1.2mmol) and molecular sieve, and then placed at 65°C for 2 hours. After the reaction was cooled to room temperature, the reaction solution was directly purified by reverse-phase chromatography (C18, 0.05% ammonia water: acetonitrile = 20:1-1:20) to obtain target compound 31b (26 mg, yield 37%). MS(ESI)m/z:360.2[M+H] ⁺ .

Step 3: 8-amino-3-formyl-7-(3-methoxy-2,6-dimethylphenyl)-7H-imidazo[1,2-c]pyrrolo[3,2- e]pyrimidine-9-carboxamide (31c)

Dissolve compound 31b (26 mg, 72 μmol) in concentrated sulfuric acid (1 mL) at room temperature, and react at room temperature for 1 hour. Add ice water to the reaction flask to quench the reaction, then use ammonia to adjust the pH of the solution to alkaline, and then extract with ethyl acetate (20 mL*3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified through a reversed-phase chromatography column (C18, 0.05% ammonia: acetonitrile = 20:1~1:20) The target compound 31c (18 mg, yield 66%) was obtained. MS(ESI)m/z:379.2[M+H] ⁺ .

Step 4: 8-amino-3-((dimethylamino)methyl)-7-(3-methoxy-2,6-dimethylphenyl)-7H-imidazo[1,2-c] Pyrro[3,2-e]pyrimidine-9-carboxamide (31d)

Compound 31c (18 mg, 48 μmol) and dimethylamine (4.3 mg, 95 μmol) were dissolved in anhydrous tetrahydrofuran, then tetraisopropyl titanate (27 mg, 95 μmol) was added, and stirring was continued for 30 minutes at room temperature before adding Sodium borohydride (3.6 mg, 95 mmol), and stirring was continued for 30 minutes. After the reaction is completed, add methanol (1 mL) to the reaction flask and stir for 30 minutes to quench the reaction. Then add water, filter to remove insoluble matter, and the filtrate is concentrated. The resulting residue is purified by a reverse-phase chromatography column (C18, 0.05% ammonia water: Acetonitrile=20:1～1:20) to obtain target compound 31d (10 mg, yield 52%). MS(ESI)m/z:407.2[M+H] ⁺ .

Step 5: 8-amino-3-((dimethylamino)methyl)-7-(3-hydroxy-2,6-dimethylphenyl)-7H-imidazo[1,2-c]pyrrolo [3,2-e]pyrimidine-9-carboxamide (31)

Dissolve 31d (10 mg, 25 μmol) in anhydrous dichloromethane (1 mL), and slowly add boron tribromide (1 mL, 1 mol/L dichloromethane solution) dropwise in an ice bath. The reaction was carried out at room temperature for 30 minutes, the reaction was quenched with methanol (1 mL), and the solvent was evaporated under reduced pressure. The pH was adjusted to neutral with ammonia (25% ammonia aqueous solution), and compound 31 (6 mg, yield 62%) was obtained through reverse-phase chromatography column purification (C18, 0.05% ammonia: acetonitrile = 20:1 ~ 1:20). m/z(ESI):394.4[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.68 (brs, 1H), 9.57 (s, 1H), 8.72 (s, 1H), 7.46 (s, 1H), 7.09 (d, J = 8.4Hz, 1H),7.08(s,1H),6.94(d,J＝8.4Hz,1H),6.72(s,2H),3.76(s,2H),2.18(s,6H),1.80(s,3H), 1.71(s,3H).

Example 32: 8-amino-7-(3-hydroxy-2,6-dimethylphenyl)-3-(methoxymethyl)-7H-imidazo[1,2-c]pyrrolo[ Preparation of 3,2-e]pyrimidine-9-carboxamide (compound 32)

Step 1: 8-amino-3-(hydroxymethyl)-7-(3-methoxy-2,6-dimethylphenyl)-7H-imidazo[1,2-c]pyrrolo[3 ,2-e]pyrimidine-9-carboxamide (32a)

Dissolve compound 31c (40 mg, 0.11 mmol) in anhydrous tetrahydrofuran at room temperature, then add sodium borohydride (8.0 mg, 0.21 mmol), and react at room temperature for 30 minutes. Methanol (2 mL) was added to quench the reaction, and the reaction solution was concentrated. The resulting residue was purified by reversed-phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1 ~ 1:20) to obtain target compound 32a (35 mg, yield 87%) ). m/z(ESI):381.2[M+H] ⁺ .

Step 2: 8-amino-7-(3-methoxy-2,6-dimethylphenyl)-3-(methoxymethyl)-7H-imidazo[1,2-c]pyrrolo [3,2-e] Pyrimidine-9-carboxamide (32b)

Dissolve compound 32a (27 mg, 71 μmol) in anhydrous dichloromethane at room temperature, then add diethylamine sulfur trifluoride and react under this condition for 5 minutes, then add anhydrous methanol (1 mL), The reaction was continued for another 30 minutes, the reaction solution was concentrated, and the resulting residue was purified by reverse-phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1~1:20) to obtain target compound 32b (35 mg, yield 87%). m/z(ESI):395.2[M+H] ⁺ .

Step 3: 8-amino-7-(3-hydroxy-2,6-dimethylphenyl)-3-(methoxymethyl)-7H-imidazo[1,2-c]pyrrolo[3 ,2-e]pyrimidine-9-carboxamide (32)

Compound 32b (12 mg, 30 μmol) was dissolved in anhydrous dichloromethane at room temperature, and boron tribromide (1 mL, 1 mol/L dichloromethane solution) was slowly added dropwise. The reaction was carried out at room temperature for 30 minutes, the reaction was quenched with methanol (1 mL), and the solvent was evaporated under reduced pressure. The pH was adjusted to neutral with ammonia (25% ammonia aqueous solution), and compound 32 (7 mg, yield 60%) was obtained through reversed-phase chromatography column purification (C18, 0.05% ammonia: acetonitrile = 20:1~1:20). m/z(ESI):381.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.65(s,1H),9.58(s,1H),8.68(s,1H),7.59(s,1H),7.11(s,1H),7.09( d,J＝8.4Hz,1H),6.94(d,J＝8.4Hz,1H),6.76(brs,2H),4.81(s,2H),3.27(s,3H),1.80(s,3H), 1.71(s,3H).

Example 33: 1-amino-2-(3-hydroxy-2,6-dimethylphenyl)-7-(pyridin-2-yl)-2,8-dihydro-9H-2,3,5 , Preparation of 8-tetraazabenzo[cd]azulen-9-one (compound 33)

Step 1: 6-Amino-7-(3-methoxy-2,6-dimethylphenyl)-4-(pyridin-2-ylethynyl)-7H-pyrrolo[2,3-d] Pyrimidine-5-carboxamide (33b)

At room temperature, compound 22a (0.20g, 0.58mmol), 2-ethynylpyridine 33a (0.12g, 1.2mmol), N-methyldicyclohexylamine (0.29g, 1.5mmol), methane sulfonic acid [9 ,9-dimethyl-4,5-bis(diphenylphosphino)xanthene](2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (17 mg, 58 μmol) was dissolved in anhydrous acetonitrile, the air was replaced with nitrogen three times, and then the reaction was moved to 90°C for 12 hours. After the reaction was cooled to room temperature, the insoluble matter was removed by filtration, and the filtrate was spun to dryness. The resulting residue was purified through a reversed-phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1~1:20) to obtain product 33b (42 mg, yield 18 %).

m/z(ESI):413.2[M+H] ⁺ .

Step 2: 1-amino-2-(3-methoxy-2,6-dimethylphenyl)-7-(pyridin-2-yl)-2,8-dihydro-9H-2,3, 5,8-tetraazabenzo[cd]azulen-9-one (33c)

Dissolve 33b (20 mg, 48 μmol) in toluene (2 mL) at room temperature, and then add silver triflate (2.5 mg, 9.7 μmol). The reaction was moved to 110°C for 2 hours. After the reaction solution was cooled to room temperature, the insoluble matter was removed by filtration, and the filtrate was spun to dryness. The resulting residue was purified by a reversed-phase chromatography column (C18, 0.05% ammonia water: acetonitrile = 20:1 ~ 1:20) to obtain 33c (12 mg, yield 60%).

m/z(ESI):413.2[M+H] ⁺ .

Step 3: 1-amino-2-(3-hydroxy-2,6-dimethylphenyl)-7-(pyridin-2-yl)-2,8-dihydro-9H-2,3,5, 8-tetraazabenzo[cd]azulen-9-one(33)

Dissolve 33c (12 mg, 29 μmol) in anhydrous dichloromethane (4 mL), and slowly add boron tribromide (1 mL, 1mol/L methylene chloride solution). The reaction was carried out at room temperature for 30 minutes, the reaction was quenched with methanol (5 mL), and the solvent was evaporated under reduced pressure. Use ammonia (25% ammonia aqueous solution) to adjust the pH to neutral, and purify through reversed phase chromatography column (C18, 0.05% ammonia: acetonitrile = 20:1 ~ 1:20) to obtain compound 33 (5.6 mg, yield 48%) . m/z(ESI):399.3[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )9.60(s,1H),8.92(d,J＝1.2Hz,1H),8.70(d,J＝4.8Hz,1H),8.25(d,J＝8.0Hz ,1H),8.17(s,1H),7.97(td,J＝8.0,1.2Hz,1H),7.54(dd,J＝8.0,4.8Hz,1H),7.08(d,J＝8.4Hz,1H) ,6.94(d,J＝8.4Hz,1H),6.87(s,2H),6.45(d,J＝1.2Hz,1H),1.80(s,3H),1.72(s,3H).

Example 34: 1-amino-7-(2-((dimethylamino)methyl)phenyl)-2-(3-hydroxy-2,6-dimethylphenyl)-2,8-dihydro Preparation of -9H-2,3,5,8-tetraazabenzo[cd]azulen-9-one (compound 34)

Step 1: 1-(3-ethynylphenyl)-N,N-dimethylmethylamine (34b)

Dissolve 3-ethynylbenzaldehyde 34a (0.50g, 3.8mmol) and dimethylamine (2.9mL, 2mol/L tetrahydrofuran solution) in anhydrous dichloromethane (10mL), then add glacial acetic acid (23mg, 0.38mmol) , stir at room temperature for 30 minutes. Then sodium triacetoxyborohydride (3.3g, 15mmol) was added, and the reaction was continued for 4 hours at room temperature. The reaction solution was then slowly added dropwise to water (30 mL), and washed twice with ethyl acetate (20 mL). The remaining aqueous phase was adjusted to pH 9 with saturated sodium bicarbonate aqueous solution, and then extracted three times with ethyl acetate (20 mL). The organic phases were combined, washed once with saturated brine (30 mL), and then filtered and dried over anhydrous sodium sulfate. Concentrate under reduced pressure to obtain yellow oily crude product 34b (0.20g, yield 33%).

Step 2: 6-amino-4-((3-((dimethylamino)methyl)phenyl)ethynyl)-7-(3-methoxy-2,6-dimethylphenyl)-7H -pyrrolo[2,3-d]pyrimidine-5-carboxamide (34c)

Dissolve 22a (0.16g, 0.46mmol) in ultra-dry tetrahydrofuran (2.9mL), then add 34b (0.15g, 0.93mmol), bistriphenylphosphine palladium dichloride (53mg, 46μmol), and copper iodide (4.4 mg, 23 μmol), triethylamine (94 mg, 0.93 mmol). After replacing the air with nitrogen three times, the reaction was moved to 60°C for 8 hours. When the reaction reaches room temperature, add the reaction solution to water (40mL), extract three times with ethyl acetate (10mL*3), combine the organic phases, wash with saturated aqueous sodium chloride solution (30mL), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. , the obtained residue was purified by normal phase silica gel chromatography column (petroleum ether: ethyl acetate = 100:1 ~ 0:1, and then dichloromethane: methanol = 10:1) to obtain yellow solid 34c (0.11g, yield 44 %).

m/z(ESI):469.3[M+H] ⁺ .

Then, a method similar to step 2 to step 3 of Example 33 was used, and compound 34c was used to replace compound 33b in Example 33 to prepare compound 34.

m/z(ESI):455.3[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.59 (s, 1H), 8.38 (d, J = 1.2Hz, 1H), 8.07 (s, 1H), 7.47-7.34 (m, 4H), 7.08 ( d,J＝8.4Hz,1H),6.93(d,J＝8.4Hz,1H),6.80(s,2H),5.42(d,J＝1.2Hz,1H),3.45(s,2H),2.20( s,6H),1.80(s,3H),1.71(s,3H).

Example 35: 1-amino-2-(3-hydroxy-2,6-dimethylphenyl)-7-(1-methyl-1H-imidazol-4-yl)-2,8-dihydro- Preparation of 9H-2,3,5,8-tetraazabenzo[cd]azulen-9-one (compound 35)

Compound 35 was prepared using a method similar to Example 34, substituting compound 35a for compound 34b in Example 34.

m/z(ESI):402.3[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.58 (s, 1H), 8.15 (s, 1H), 8.07 (s, 1H), 7.95 (d, J = 1.2Hz, 1H), 7.77 (s, 1H),7.07(d,J＝8.4Hz,1H),6.93(d,J＝8.4Hz,1H),6.78(s,2H),5.97(d,J＝1.2Hz,1H),3.72(s, 3H),1.79(s,3H),1.71(s,3H).

Example 36: 1-amino-2-(3-hydroxy-2,6-dimethylphenyl)-7-(2-methylphenyl)-2,8-dihydro-9H-2,3, Preparation of 5,8-tetraazabenzo[cd]azulen-9-one (compound 36)

Compound 36 was prepared using a method similar to Example 34, substituting compound 36a for compound 34b in Example 34.

m/z(ESI):412.3[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ )9.59(s,1H),8.47(s,1H),8.05(s,1H),7.31-7.23(m,4H),7.08(d,J＝8.0Hz, 1H),6.94(d,J＝8.0Hz,1H),6.77(s,2H),5.09(s,1H),2.43(s,3H),1.81(s,3H),1.72(s,3H).

Biological activity and related property test examples

Test Example 1: PKMYT1 enzyme activity inhibition experiment

Experimental principle: After incubation with compounds, PKMYT1 phosphorylates the substrate CDK1 under the action of ATP. Promega's ADP-Glo detection kit was used to quantify the ADP produced by the reaction to reflect the enzyme activity.

Experimental instruments: Echo550 pipetting system from Labcyte; Envision microplate reader from Perkin Elmer; 5810R centrifuge from Eppendorf.

Experimental Materials:

Experimental method: Use the Echo pipetting system to dilute the compound to be tested in dimethyl sulfoxide (DMSO) to different concentrations and transfer it to a 384-well plate so that the final concentration of the compound in the reaction system starts from 1 μM and is diluted 3 times in a gradient. , the final concentration of DMSO is 1%. Add 3 μL/well of PKMYT1, and after incubation for 15 minutes, add 2 μL/well of a reaction mixture solution composed of substrate CDK1 and ATP to start the enzyme reaction. The final concentration of enzyme PKMYT1 in the reaction is 4.5ng/μL, and the final concentration of ATP is 25 μM, and the final concentration of substrate CDK1 is 20 ng/μL. After reacting for 40 minutes, add 5 μL/well ADP-Glo reagent and incubate for 40 minutes. Then add 10 μL/well kinase reaction detection reagent, incubate for 30 minutes, and read the fluorescence signal with an Envision microplate reader.

data analysis:

Calculate the compound inhibition percentage and use XLfit software to fit to obtain the IC ₅₀ value of the compound.

The experiment set up the blank group and DMSO group: the reaction system of the blank group was 0.2% DMSO and reaction mixture solution, and the compound inhibition rate was considered to be 100% at this time; the reaction system of the DMSO group was 0.2% DMSO, PKMYT1 (100nM) and reaction mixture solution, and it was considered that At this time, the compound inhibition rate was 0.

Compound inhibition percentage = (100-100*(experimental well-blank well)/(DMSO group-blank well))%

Among them, the experimental well, blank well, and DMSO group refer to the fluorescence signals read by the experimental group, blank group, and DMSO group respectively.

The biological activity of the compound of the present application was measured through the above test, and the measured IC ₅₀ value is shown in Table 1.

Table 1 IC ₅₀ values of compounds inhibiting PKMYT1 kinase activity

Test Example 2: Experiment on the inhibition of tumor cell proliferation by compounds

Introduction to the experimental principle: After incubating the compound with tumor cells for 7 days, use Promega's CTG kit to quantify ATP in living cells to reflect the effect of the compound on tumor cell proliferation.

Experimental instruments: Perkin Elmer Envision microplate reader; Eppendorf 5810R centrifuge, Countstar automatic cell counter.

Experimental Materials:

Experimental method: Dilute 1000 cells/well of SKOV3 or 3000 cells/well of HCC1569 cells with McCoy's 5A or RPMI Medium 1640 medium containing 10% FBS and add them to a 96-well plate (90 μL/well), and place at 37°C. Incubate in a 5% _CO2 incubator for 24 hours. After the compound to be tested was diluted to different concentrations in dimethyl sulfoxide (DMSO), it was added to a 96-well plate so that the final concentration of the compound in the reaction system started from 25 μM, followed by 4-fold gradient dilution, with the final concentration of DMSO being 0.25%. After the compounds and cells were incubated for 7 days in a 37°C, 5% _CO2 incubator, 50 μL/well CTG was added to measure the growth inhibition of tumor cells by the compounds, and the inhibition rate and half inhibitory concentration (IC ₅₀ ) were calculated.

data analysis:

Calculate % compound inhibition (Compound inhibition), and use XLfit software to fit to obtain the IC ₅₀ of the compound.

The experiment set up blank wells and DMSO wells. The blank wells were 100 μL of RPMI Medium 1640 or McCoy's 5A medium containing 10% FBS. It was considered that the inhibitory rate of the compound on tumor cell growth at this time was 100%; the DMSO wells were 0.25% added to the cell wells. DMSO, it is believed that the inhibitory rate of the compound on tumor cell growth is 0 at this time.

Compound inhibition percentage = (100*(DMSO well-experimental well)/(DMSO well-blank well))%

The growth inhibition of tumor cells by the compound of the present application was measured through the above test. The measured IC ₅₀ value is shown in Table 2 below.

Table 2 IC ₅₀ of compounds in Examples inhibiting the growth of HCC1569 cells

Unless expressly excluded or otherwise limited, every document cited herein, including any cross-referenced patent or patent application, or any patent application or patent to which this application claims priority, is hereby incorporated by reference in its entirety and Enter this article. Furthermore, to the extent that any meaning or definition of a term herein conflicts with any meaning or definition of the same term in a document incorporated by reference, the meaning or definition assigned to that term herein shall govern.

Although specific embodiments of the present disclosure have been illustrated and described, those skilled in the art will appreciate that, where feasible, technical features described in one embodiment may be applied to, or combined with, another embodiment. The technical features described in the scheme are combined, therefore, those skilled in the art can make various changes and modifications to the embodiments of the present disclosure without departing from the essence and scope of the present disclosure.

Claims (24)

A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein,
in, Ring A is selected from Represents the bond to the carbonyl group, Represents the bond connected to ring B; X is selected from N or CR ^X ; ^R _{_ _ _ _ _ _ _ _ _} C ₂ -C ₆ alkynyl or C(=O)H, the OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₂ aryl, C ₂ - C ₆ alkenyl, C ₂ -C ₆ alkynyl or C(=O)H are optionally substituted by R ^a ; Ring B is selected from C ₆ -C ₁₂ aryl or 6-10 membered heteroaryl, and the C ₆ -C ₁₂ aryl or 6-10 membered heteroaryl is optionally substituted by R ^b ; R ¹ is selected from hydrogen, halogen, CN, OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C ( =O)H, the OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C(=O) H is optionally substituted by R ^a ; R ² and R ³ are independently selected from hydrogen, halogen, CN, OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₆ -C ₁₂ aryl, 5-10 membered heteroaryl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C(=O)H, the OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₆ -C ₁₂ aryl, 5-10 membered heteroaryl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C(=O)H is optionally substituted by R ^a ; Or ^{R 2} , ^R R ⁴ is selected from hydrogen, halogen, CN, OH, SH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₆ -C ₁₂ aryl , 5-10 membered heteroaryl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C(=O)H, the OH, SH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₆ -C ₁₂ aryl, 5-10 membered heteroaryl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C (=O)H is optionally substituted by R ^a ; R ⁵ is selected from hydrogen, halogen, CN, OH, SH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₆ -C ₁₂ aryl , 5-10 membered heteroaryl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C(=O)H, the OH, SH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₆ -C ₁₂ aryl, 5-10 membered heteroaryl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C (=O)H is optionally substituted by R ^a ; R ⁶ is selected from O, S, CR ^6a R ^6b or NR ^6a ; R ⁷ is selected from O, S, CR ^7a R ^7b or NR ^7a ; R ^6a , R ^6b , R ^7a , R ^7b are independently selected from hydrogen, halogen, CN, OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl base, C ₆ -C ₁₂ aryl or 5-10 membered heteroaryl, the OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl , C ₆ -C ₁₂ aryl or 5-10 membered heteroaryl is optionally substituted by R ^a ; Or R ^6a , R ⁵ and the atoms to which they are connected together form a 5-10-membered heterocyclyl group or a 5-10-membered heteroaryl group, and the 5-10-membered heterocyclyl group or 5-10-membered heteroaryl group is optionally replaced by R ^a replace; Or R ^7a , R ⁵ and the atoms to which they are connected together form a 5-10-membered heterocyclyl group or a 5-10-membered heteroaryl group, and the 5-10-membered heterocyclyl group or 5-10-membered heteroaryl group is optionally replaced by R ^a replace; R ^a and R ^b are independently selected from halogen, CN, =O, OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-7 membered heterocyclyl, C ₆ -C ₁₂ aryl or 5-10 membered heteroaryl, the OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-7 membered heterocyclyl, C ₆ -C ₁₂ aryl or 5-10 membered heteroaryl is optionally substituted by R ^c ; R ^c is selected from halogen, CN, =O, OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or 4-7 membered heterocyclyl, the OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or 4-7 membered heterocyclyl is optionally substituted by R ^d ; R ^d is selected from halogen, CN, OH, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₆ ring Alkyl or 4-7 membered heterocyclyl. The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is selected from Alternatively, Ring A is selected from The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein X is selected from ^CRX ; or X is selected from CH. The compound of formula (I) according to any one of claims 1-3 or _a pharmaceutically acceptable salt _thereof , wherein ^R The OH, C ₁ -C ₆ alkyl or phenyl group is optionally substituted by R ^a ; alternatively, R ^X is selected from hydrogen, halogen, OH or C ₁ -C ₆ alkyl, the OH or C ₁ -C ₆ Alkyl is optionally ^substituted with R; alternatively, ^R is selected from hydrogen or phenyl. The compound of formula (I) according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein ring B is selected from phenyl or 6-9 membered heteroaryl, said phenyl or 6- The 9-membered heteroaryl group is optionally substituted by R ^b ; or Ring B is selected from phenyl and The phenyl and are replaced by R ^b ; or Ring B is selected from phenyl, which is optionally substituted by R ^b ; or Ring B is selected from described Optionally substituted by R ^b . The compound of formula (I) according to any one of claims 1-5 or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from hydrogen, halogen, CN, OH, NH ₂ , C ₁ -C ₆ alkyl , C ₃ -C ₁₀ cycloalkyl or C(=O)H, the OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl or C(=O)H is optionally replaced by R ^a substitution; or R ¹ is selected from hydrogen, halogen, NH ₂ or C ₁ -C ₆ alkyl, which NH ₂ or C ₁ -C ₆ alkyl is optionally substituted by R ^a ; or ^R1 is selected from _{NH2 optionally} substituted by ^Ra . The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein R ² and R ³ are independently selected from hydrogen, halogen, CN, OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₆ -C ₁₂ aryl, 5-10 membered heteroaryl or C(=O)H, the OH , NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₆ -C ₁₂ aryl, 5-10 membered heteroaryl or C(=O )H optionally substituted by R ^a ; or R ² and R ³ are independently selected from hydrogen, halogen, OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl or 4-10 membered heterocycloalkyl, the OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl or 4-10 membered heterocycloalkyl are optionally substituted by R ^a ; or R ² and R ³ are independently selected from hydrogen; or ^{R 2} , ^R R ³ is selected from hydrogen, and R ² and ^R R ^a replaced. The compound of formula (I) according to any one of claims 1-7 or a pharmaceutically acceptable salt thereof, wherein R ⁴ is selected from hydrogen, halogen, CN, OH, SH, NH ₂ , C ₁ -C ₆ Alkyl, C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₆ -C ₉ aryl, 5-10 membered heteroaryl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ Alkynyl group, the OH, SH, NH ₂ , C ₁ -C ₆ alkyl group, C ₃ -C ₁₀ cycloalkyl group, 4-10 membered heterocycloalkyl group, C ₆ -C ₉ aryl group, 5-10 membered Heteroaryl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl is optionally substituted by R ^a ; or R ⁴ is selected from hydrogen, halogen, OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, 5-10 membered heteroaryl or C ₂ -C ₆ alkynyl, the OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, 5-10 membered heteroaryl or C ₂ -C ₆ alkynyl group optionally substituted by R ^a ; or R ⁴ is selected from hydrogen, halogen, OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, phenyl, C ₂ -C ₆ alkynyl, The OH, NH ₂ , C ₁ -C ₆ alkyl group, C ₃ -C ₁₀ cycloalkyl group, phenyl group, C ₂ -C ₆ alkynyl group, optionally substituted by R ^a ; or R ⁴ is selected from hydrogen, OH substituted by ^Ra , NH ₂ substituted by ^Ra , C ₁ -C ₃ alkyl optionally substituted by halogen, C ₃ -C ₆ cycloalkyl, optionally substituted by halogen Phenyl, C ₂ -C ₃ alkynyl optionally substituted by C ₃ -C ₆ cycloalkyl, described optionally substituted by C ₁ -C ₃ alkyl; or R ⁴ is selected from hydrogen, C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl. The compound of formula (I) according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, wherein R ⁵ is selected from hydrogen, halogen, CN, OH, SH, NH ₂ , C ₁ -C ₆ Alkyl, C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl, the OH, SH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl is optionally substituted by R ^a ; or R ⁵ is selected from hydrogen, halogen, OH, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl or 4-10 membered heterocycloalkyl, said OH, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl or 4-10 membered heterocycloalkyl is optionally substituted by R ^a ; or R ⁵ is selected from hydrogen, C ₁ -C ₆ alkyl or C ₃ -C ₁₀ cycloalkyl, which C ₁ -C ₆ alkyl or C ₃ -C ₁₀ cycloalkyl is optionally substituted by R ^a ; or R ⁵ is selected from hydrogen or C ₁ -C ₆ alkyl. The compound of formula (I) according to any one of claims 1-9 or a pharmaceutically acceptable salt thereof, wherein R ⁶ is selected from O, CR ^6a R ^6b or NR ^6a ; or R ⁶ is selected from O or NR ^6a ; or R ⁶ is selected from O or NR ^6a , wherein R ^6a , R ⁵ and the atoms to which they are connected together form a 5-6-membered heterocyclic group or a 5-6-membered heteroaryl group, and the 5-6-membered heterocyclic group or 5-6 A heteroaryl group is optionally substituted with ^Ra . The compound of formula (I) according to any one of claims 1-10 or a pharmaceutically acceptable salt thereof, wherein R ⁷ is selected from O, CR ^7a R ^7b or NR ^7a ; or R ⁷ is selected from O or NR ^7a . The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein R ^6a , R ^6b , R ^7a , R ^7b are independently selected from hydrogen, OH, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl or 4-10 membered heterocycloalkyl, the OH, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl or 4-10 membered heterocycloalkyl Cycloalkyl is optionally substituted by ^Ra ; or R ^6a , R ^6b , R ^7a , R ^7b are independently selected from C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl or 4-10 membered heterocycloalkyl, the C ₁ -C ₆ alkyl , C ₃ -C ₁₀ cycloalkyl or 4-10 membered heterocycloalkyl is optionally substituted by R ^a ; or R ^6a , R ⁵ and the atoms to which they are connected together form a 5-8-membered heterocyclyl group or a 5-8-membered heteroaryl group, and the 5-8-membered heterocyclyl group or 5-8-membered heteroaryl group is optionally substituted by R ^a ;or R ^7a , R ⁵ and the atoms to which they are connected together form a 5-8-membered heterocyclyl group or a 5-8-membered heteroaryl group, and the 5-8-membered heterocyclyl group or 5-8-membered heteroaryl group is optionally substituted by R ^a . The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-12, wherein R ^a and R ^b are independently selected from halogen, =O, OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-7 membered heterocyclyl or phenyl, the OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-7 membered heterocyclyl or phenyl is optionally substituted by R ^c ; or R ^a and R ^b are independently selected from halogen, =O, OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, 4-7 membered heterocyclyl or phenyl, the OH , NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, 4-7 membered heterocyclyl or phenyl are optionally substituted by R ^c ; or R ^a and R ^b are independently selected from halogen, =O, OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, 4-7-membered heterocyclyl, phenyl or 5-6-membered heteroaryl are optionally substituted by R ^c replaced. The compound of formula (I) according to any one of claims 1-13 or a pharmaceutically acceptable salt thereof, wherein R ^c is selected from halogen, =O, OH, NH ₂ , C ₁ -C ₆ alkyl , C ₃ -C ₆ cycloalkyl or 4-7 membered heterocyclyl, the OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or 4-7 membered heterocyclyl is any Select to be replaced by R ^d ; or R ^c is selected from OH, NH ₂ or C ₁ -C ₆ alkyl, which OH, NH ₂ or C ₁ -C ₆ alkyl is optionally substituted by R ^d . The compound of formula (I) according to any one of claims 1-14 or a pharmaceutically acceptable salt thereof, wherein R ^d is selected from halogen, OH, NH ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or 4-7 membered heterocyclyl. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from a compound of formula (II) or a pharmaceutically acceptable salt thereof of salt,
Wherein, ring B, X, R ¹ , R ² , R ³ and R ⁴ are as defined in claim 1. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from a compound of formula (III) or a pharmaceutically acceptable salt thereof of salt,
Wherein, ring B, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined in claim 1. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of compounds of formula (IV) or a pharmaceutically acceptable salt thereof of salt,
Wherein, ring B, X, R ¹ , R ² , R ³ , R ⁵ and R ⁷ are as defined in claim 1. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof,







A pharmaceutical composition comprising the compound of any one of claims 1-19 or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable auxiliary materials. A method for treating a disease mediated by PKMYT1 in a mammal, which includes administering a therapeutically effective amount of a compound according to any one of claims 1-19 or a pharmaceutically acceptable compound thereof to a mammal in need of the treatment, preferably a human. of salt, Or the pharmaceutical composition of claim 20, preferably, the disease mediated by PKMYT1 is a tumor, such as breast cancer. The use of the compound according to any one of claims 1-19 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 20 in the preparation of medicines for preventing or treating PKMYT1-mediated diseases, preferably , the PKMYT1-mediated disease is a tumor, such as breast cancer. The use of the compound of any one of claims 1-19 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 20 in preventing or treating PKMYT1-mediated diseases, preferably, PKMYT1-mediated diseases are tumors, such as breast cancer. The compound of any one of claims 1-19 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 20 for preventing or treating PKMYT1-mediated diseases, preferably, the PKMYT1-mediated disease Caused diseases are tumors, such as breast cancer.