Membrane association tyrosine and threonine kinase inhibitors

Abstract

Provided is a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, having membrane associated tyrosine and threonine kinase inhibitory activity, and the use of the compound of formula (I) or the pharmaceutically acceptable salt thereof as a membrane associated tyrosine and threonine kinase inhibitor for the prevention or treatment of diseases mediated by membrane associated tyrosine and threonine kinase, such as tumors. # imgabs0 #

Description

Membrane-associated tyrosine and threonine kinase inhibitors

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of and priority to the following two Chinese invention patent applications, the entire contents of which are hereby incorporated by reference into this application:

[0003] Patent application No. 202210396376.3 filed with the State Intellectual Property Office of China on April 15, 2022; and

[0004] Patent application No. 202211312187.X submitted to the State Intellectual Property Office of China on October 25, 2022. Technical Field

[0005] The present application relates to membrane-associated tyrosine and threonine kinase inhibitors, methods for preparing the same, pharmaceutical compositions containing the same, and uses thereof in preventing or treating cancer. Background Art

[0006] Continuous exposure of cellular genomic DNA to a variety of harmful factors from both inside and outside the body may cause DNA damage. Therefore, cells have evolved a series of complex DNA damage response mechanisms to cope with these harmful factors, thereby maintaining the integrity of the genome and avoiding the occurrence of diseases including tumors due to genomic instability. Activation of the cell cycle checkpoint pathway is one of the important mechanisms. Cell cycle checkpoints include checkpoints in the G1, S, G2, and M phases. Unlike normal cells, the survival of tumor cells often depends on the misregulation of DNA damage repair. Many tumor cells lose the G1 checkpoint due to the presence of p53 gene mutations, and are therefore more dependent on the G2 checkpoint to repair DNA damage and maintain tumor cell survival.

[0007] The membrane-associated tyrosine and threonine kinase (Myt1 kinase, also known as PKMYT1) is encoded by the PKMYT1 gene. PKMYT1 inhibits CDC2 activity by phosphorylating CDC2 at Thr-14 and Tyr-15, thereby regulating the cell cycle and arresting cells at the G2-M checkpoint to repair DNA damage. Studies have shown that inhibition of PKMYT1 leads to CDC2 activation, forcing cells to enter mitosis prematurely and unable to repair DNA damage, thereby killing rapidly proliferating tumor cells.

[0008] 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.

[0009] SUMMARY OF THE INVENTION

[0010] In one aspect, the present application relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0011] wherein ring A is selected from

[0012] represents the bond to the carbonyl group, represents the bond to ring B;

[0013] X is selected from N or CR X ;

[0014] R X independently selected from hydrogen, halogen, CN, OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, C6-C 12 Aryl, C2-C6 alkenyl, C2-C6 alkynyl or C(=O)H, the OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, C6-C 12 Aryl, C2-C6 alkenyl, C2-C6 alkynyl or C(=O)H is optionally replaced by R a replace;

[0015] Ring B is selected from C6-C 12 Aryl or 6-10 membered heteroaryl, the C6-C 12 Aryl or 6-10 membered heteroaryl is optionally replaced by R b replace;

[0016] R 1 Selected from hydrogen, halogen, CN, OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl or C(=O)H, the OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl or C(=O)H is optionally replaced by R a replace;

[0017] R 2 、R 3 independently selected from hydrogen, halogen, CN, OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 12 aryl, 5-10 membered heteroaryl, C2-C6 alkenyl, C2-C6 alkynyl or C(=O)H, said OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 12Aryl, 5-10 membered heteroaryl, C2-C6 alkenyl, C2-C6 alkynyl or C(=O)H is optionally replaced by R a replace;

[0018] or R 2 、R X The atoms to which it is attached together form a 6-10 membered heterocyclic group, wherein the 6-10 membered heterocyclic group is optionally replaced by R a replace;

[0019] R 4 Selected from hydrogen, halogen, CN, OH, SH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 12 aryl, 5-10 membered heteroaryl, C2-C6 alkenyl, C2-C6 alkynyl or C(=O)H, said OH, SH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 12 Aryl, 5-10 membered heteroaryl, C2-C6 alkenyl, C2-C6 alkynyl or C(=O)H is optionally replaced by R a replace;

[0020] R 5 Selected from hydrogen, halogen, CN, OH, SH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 12 aryl, 5-10 membered heteroaryl, C2-C6 alkenyl, C2-C6 alkynyl or C(=O)H, said OH, SH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 12 Aryl, 5-10 membered heteroaryl, C2-C6 alkenyl, C2-C6 alkynyl or C(=O)H is optionally replaced by R a replace;

[0021] R 6 Selected from O, S, CR 6a R 6b or NR 6a ;

[0022] R 7 Selected from O, S, CR 7a R 7b or NR 7a ;

[0023] R 6a 、R 6b 、R 7a 、R 7bindependently selected from hydrogen, halogen, CN, OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 12 Aryl or 5-10 membered heteroaryl, the OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 12 Aryl or 5-10 membered heteroaryl is optionally replaced by R a replace;

[0024] or R 6a 、R 5 The atoms to which it is attached together form a 5-10 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein the 5-10 membered heterocyclic group or the 5-10 membered heteroaryl group is optionally replaced by R a replace;

[0025] or R 7a 、R 5 The atoms to which it is attached together form a 5-10 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein the 5-10 membered heterocyclic group or the 5-10 membered heteroaryl group is optionally replaced by R a replace;

[0026] R a 、R b Independently selected from halogen, CN, =O, OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-7 membered heterocyclic group, C6-C 12 Aryl or 5-10 membered heteroaryl, the OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-7 membered heterocyclic group, C6-C 12 Aryl or 5-10 membered heteroaryl is optionally replaced by R c replace;

[0027] R c is selected from halogen, CN, =O, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclic group, wherein the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclic group is optionally replaced by R d replace;

[0028] R d Selected from halogen, CN, OH, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclyl.

[0029] On the other hand, the present application provides a pharmaceutical composition comprising the compound of formula (I) of the present application or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0030] On the other hand, the present application provides a method for treating a disease mediated by PKMYT1 in a mammal, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.

[0031] 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 a PKMYT1-mediated disease.

[0032] 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 a PKMYT1-mediated disease.

[0033] 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 a PKMYT1-mediated disease.

[0034] Detailed Description of the Invention

[0035] The present application relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0036] wherein ring A is selected from

[0037] represents the bond to the carbonyl group, represents the bond to ring B;

[0038] X is selected from N or CR X ;

[0039] R X independently selected from hydrogen, halogen, CN, OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, C6-C 12 Aryl, C2-C6 alkenyl, C2-C6 alkynyl or C(=O)H, the OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, C6-C 12 Aryl, C2-C6 alkenyl, C2-C6 alkynyl or C(=O)H is optionally replaced by R a replace;

[0040] Ring B is selected from C6-C 12 Aryl or 6-10 membered heteroaryl, the C6-C 12 Aryl or 6-10 membered heteroaryl is optionally replaced by R b replace;

[0041] R 1Selected from hydrogen, halogen, CN, OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl or C(=O)H, the OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl or C(=O)H is optionally replaced by R a replace;

[0042] R 2 、R 3 independently selected from hydrogen, halogen, CN, OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 12 Aryl, 5-10 membered heteroaryl, C2-C6 alkenyl, C2-C6 alkynyl or C(=O)H, the OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 12 Aryl, 5-10 membered heteroaryl, C2-C6 alkenyl, C2-C6 alkynyl or C(=O)H is optionally replaced by R a replace;

[0043] or R 2 、R X The atoms to which it is attached together form a 6-10 membered heterocyclic group, wherein the 6-10 membered heterocyclic group is optionally replaced by R a replace;

[0044] R 4 Selected from hydrogen, halogen, CN, OH, SH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 12 aryl, 5-10 membered heteroaryl, C2-C6 alkenyl, C2-C6 alkynyl or C(=O)H, said OH, SH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 12 Aryl, 5-10 membered heteroaryl, C2-C6 alkenyl, C2-C6 alkynyl or C(=O)H is optionally replaced by R a replace;

[0045] R 5 Selected from hydrogen, halogen, CN, OH, SH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 12 aryl, 5-10 membered heteroaryl, C2-C6 alkenyl, C2-C6 alkynyl or C(=O)H, said OH, SH, NH2, C1-C6 alkyl, C3-C 10Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 12 Aryl, 5-10 membered heteroaryl, C2-C6 alkenyl, C2-C6 alkynyl or C(=O)H is optionally replaced by R a replace;

[0046] R 6 Selected from O, S, CR 6a R 6b or NR 6a ;

[0047] R 7 Selected from O, S, CR 7a R 7b or NR 7a ;

[0048] R 6a 、R 6b 、R 7a 、R 7b independently selected from hydrogen, halogen, CN, OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 12 Aryl or 5-10 membered heteroaryl, the OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 12 Aryl or 5-10 membered heteroaryl is optionally replaced by R a replace;

[0049] or R 6a 、R 5 The atoms to which it is attached together form a 5-10 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein the 5-10 membered heterocyclic group or the 5-10 membered heteroaryl group is optionally replaced by R a replace;

[0050] or R 7a 、R 5 The atoms to which it is attached together form a 5-10 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein the 5-10 membered heterocyclic group or the 5-10 membered heteroaryl group is optionally replaced by R a replace;

[0051] R a 、R b Independently selected from halogen, CN, =O, OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-7 membered heterocyclic group, C6-C 12 Aryl or 5-10 membered heteroaryl, the OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-7 membered heterocyclic group, C6-C 12Aryl or 5-10 membered heteroaryl is optionally replaced by R c replace;

[0052] R c is selected from halogen, CN, =O, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclic group, wherein the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclic group is optionally replaced by R d replace;

[0053] R d Selected from halogen, CN, OH, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclyl.

[0054] In some embodiments, Ring A is selected from

[0055] In some embodiments, Ring A is selected from

[0056] In some embodiments, Ring A is selected from

[0057] In some embodiments, X is selected from N.

[0058] In some embodiments, X is selected from CR X .

[0059] In some embodiments, X is selected from CH.

[0060] In some embodiments, R X independently selected from hydrogen, halogen, CN, OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl or C(=O)H, the OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl or C(=O)H is optionally replaced by R a replace.

[0061] In some embodiments, R X Selected from hydrogen, halogen, OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl or C(=O)H, said OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl or C(=O)H is optionally replaced by R a replace.

[0062] In some embodiments, R Xis selected from hydrogen, halogen, OH, C1-C6 alkyl or phenyl, wherein the OH, C1-C6 alkyl or phenyl is optionally replaced by R a replace.

[0063] In some embodiments, R X is selected from hydrogen, halogen, OH or C1-C6 alkyl, wherein the OH or C1-C6 alkyl is optionally replaced by R a replace.

[0064] In some embodiments, R X is selected from hydrogen or phenyl.

[0065] In some embodiments, R X Selected from hydrogen.

[0066] In some embodiments, Ring B is selected from phenyl or 6-9 membered heteroaryl, wherein the phenyl or 6-9 membered heteroaryl is optionally replaced by R b replace.

[0067] In some embodiments, Ring B is selected from phenyl and The phenyl group and All were R b replace.

[0068] In some embodiments, Ring B is selected from phenyl, said phenyl being optionally replaced by R b replace.

[0069] In some embodiments, Ring B is selected from described Optional R b replace.

[0070] In some embodiments, R 1 Selected from hydrogen, halogen, CN, OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl or C(=O)H, said OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl or C(=O)H is optionally replaced by R a replace.

[0071] In some embodiments, R 1 is selected from hydrogen, halogen, NH2 or C1-C6 alkyl, wherein the NH2 or C1-C6 alkyl is optionally replaced by R a replace.

[0072] In some embodiments, R 1 is selected from NH2, wherein the NH2 is optionally replaced by R a replace.

[0073] In some embodiments, R 1 Selected from NH2.

[0074] In some embodiments, R 2 、R 3 independently selected from hydrogen, halogen, CN, OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 12 Aryl, 5-10 membered heteroaryl or C(=O)H, said OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 12 Aryl, 5-10 membered heteroaryl or C(=O)H is optionally replaced by R a replace.

[0075] In some embodiments, R 2 、R 3 independently selected from hydrogen, halogen, OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-10 membered heterocycloalkyl, the OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-10 membered heterocycloalkyl is optionally replaced by R a replace.

[0076] In some embodiments, R 2 、R 3 are independently selected from hydrogen.

[0077] In some embodiments, R 2 、R X The atoms to which it is attached together form a 6-7 membered heterocyclic group, wherein the 6-7 membered heterocyclic group is optionally replaced by R a replace.

[0078] In some embodiments, R 3 is selected from hydrogen, and R 2 、R X The atoms to which it is attached together form a 6-7 membered heterocyclic group, wherein the 6-7 membered heterocyclic group is optionally replaced by R a replace.

[0079] In some embodiments, R 4 Selected from hydrogen, halogen, CN, OH, SH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C9 aryl, 5-10 membered heteroaryl, C2-C6 alkenyl or C2-C6 alkynyl, the OH, SH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C9 aryl, 5-10 membered heteroaryl, C2-C6 alkenyl or C2-C6 alkynyl are optionally replaced by R areplace.

[0080] In some embodiments, R 4 Selected from hydrogen, halogen, OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, 5-10 membered heteroaryl or C2-C6 alkynyl, the OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, 5-10 membered heteroaryl or C2-C6 alkynyl is optionally replaced by R a replace.

[0081] In some embodiments, R 4 Selected from hydrogen, halogen, OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, phenyl, C2-C6 alkynyl, The OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, phenyl, C2-C6 alkynyl, Optional R a replace.

[0082] In some embodiments, R 4 Selected from hydrogen, R a OH substituted by R a substituted NH2, C1-C3 alkyl optionally substituted by halogen, C3-C6 cycloalkyl, phenyl optionally substituted by halogen, C2-C3 alkynyl optionally substituted by C3-C6 cycloalkyl, described Optionally substituted with C1-C3 alkyl.

[0083] In some embodiments, R 4 is selected from hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl.

[0084] In some embodiments, R 5 Selected from hydrogen, halogen, CN, OH, SH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C2-C6 alkenyl or C2-C6 alkynyl, the OH, SH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally replaced by R a replace.

[0085] In some embodiments, R 5 Selected from hydrogen, halogen, OH, C1-C6 alkyl, C3-C 10Cycloalkyl or 4-10 membered heterocycloalkyl, the OH, C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-10 membered heterocycloalkyl is optionally replaced by R a replace.

[0086] In some embodiments, R 5 Selected from hydrogen, C1-C6 alkyl or C3-C 10 Cycloalkyl, the C1-C6 alkyl or C3-C 10 The cycloalkyl group is optionally replaced by R a replace.

[0087] In some embodiments, R 5 Selected from hydrogen or C1-C6 alkyl.

[0088] In some embodiments, R 6 Selected from O, CR 6a R 6b or NR 6a .

[0089] In some embodiments, R 6 Selected from O or NR 6a .

[0090] In some embodiments, R 6 Selected from O or NR 6a , where R 6a 、R 5 The atoms to which it is attached together form a 5-6 membered heterocyclic group or a 5-6 membered heteroaryl group, wherein the 5-6 membered heterocyclic group or the 5-6 membered heteroaryl group is optionally replaced by R a replace.

[0091] In some embodiments, R 6 Selected from NR 6a .

[0092] In some embodiments, R 6 Selected from O.

[0093] In some embodiments, R 7 Selected from O, CR 7a R 7b or NR 7a .

[0094] In some embodiments, R 7 Selected from O or NR 7a .

[0095] In some embodiments, R 7 Selected from NR 7a .

[0096] In some embodiments, R7 Selected from O.

[0097] In some embodiments, R 6a 、R 6b 、R 7a 、R 7b Independently selected from hydrogen, OH, C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-10 membered heterocycloalkyl, the OH, C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-10 membered heterocycloalkyl is optionally replaced by R a replace.

[0098] In some embodiments, R 6a 、R 6b 、R 7a 、R 7b Independently selected from C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-10 membered heterocycloalkyl, the C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-10 membered heterocycloalkyl is optionally replaced by R a replace.

[0099] In some embodiments, R 6a 、R 5 The atoms to which it is attached together form a 5-8 membered heterocyclic group or a 5-8 membered heteroaryl group, wherein the 5-8 membered heterocyclic group or the 5-8 membered heteroaryl group is optionally replaced by R a replace.

[0100] In some embodiments, R 6a 、R 5 The atoms to which it is attached together form a 5-6 membered heterocyclic group or a 5-6 membered heteroaryl group, wherein the 5-6 membered heterocyclic group or the 5-6 membered heteroaryl group is optionally replaced by R a replace.

[0101] In some embodiments, R 6a 、R 5 The atoms to which it is attached together form a 5-membered heterocyclic group or a 5-membered heteroaryl group, wherein the 5-membered heterocyclic group or the 5-membered heteroaryl group is optionally replaced by R a replace.

[0102] In some embodiments, R 7a 、R 5 The atoms to which it is attached together form a 5-8 membered heterocyclic group or a 5-8 membered heteroaryl group, wherein the 5-8 membered heterocyclic group or the 5-8 membered heteroaryl group is optionally replaced by R a replace.

[0103] In some embodiments, R 7a 、R 5The atoms to which it is attached together form a 5-6 membered heterocyclic group or a 5-6 membered heteroaryl group, wherein the 5-6 membered heterocyclic group or the 5-6 membered heteroaryl group is optionally replaced by R a replace.

[0104] In some embodiments, R 7a 、R 5 The atoms to which it is attached together form a 5-membered heterocyclic group or a 5-membered heteroaryl group, wherein the 5-membered heterocyclic group or the 5-membered heteroaryl group is optionally replaced by R a replace.

[0105] In some embodiments, R a 、R b Independently selected from halogen, CN, =O, OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-7 membered heterocyclic group or C6-C 12 Aryl, the OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-7 membered heterocyclic group or C6-C 12 The aryl group is optionally replaced by R c replace.

[0106] In some embodiments, R a 、R b Independently selected from halogen, =O, OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-7 membered heterocyclic group or phenyl, the OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-7 membered heterocyclic group or phenyl group is optionally replaced by R c replace.

[0107] In some embodiments, R a 、R b independently selected from halogen, =O, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally replaced by R c replace.

[0108] In some embodiments, R a 、R b independently selected from halogen, =O, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl or phenyl, wherein the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl or phenyl is optionally replaced by R c replace.

[0109] In some embodiments, R cis selected from halogen, OH, NH2 or C1-C3 alkyl, wherein the OH, NH2 or C1-C3 alkyl is optionally replaced by R d replace.

[0110] In some embodiments, R c is selected from halogen, =O, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclic group, wherein the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclic group is optionally replaced by R d replace.

[0111] In some embodiments, R c is selected from OH, NH2 or C1-C6 alkyl, wherein the OH, NH2 or C1-C6 alkyl is optionally replaced by R d replace.

[0112] In some embodiments, R d Selected from halogen, CN, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclyl.

[0113] In some embodiments, R d Selected from halogen, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclyl.

[0114] In some embodiments, R d Selected from N(C1-C6 alkyl)2.

[0115] In some embodiments, R a is selected from =O, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl or 5-6 membered heteroaryl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, phenyl or 5-6 membered heteroaryl is optionally replaced by R c replace.

[0116] In some embodiments, R a Selected from =O, halogen, C1-C6 alkyl, CH2N(CH3)2, CH2OCH3, cyclopropyl, phenyl, or pyridyl.

[0117] In some embodiments, R b is selected from halogen, OH or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally replaced by R c replace.

[0118] In some embodiments, R b Selected from OH or C1-C6 alkyl.

[0119] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the compound of formula (II) or a pharmaceutically acceptable salt thereof,

[0120] Among them, ring B, X, R 1 、R 2 、R 3 、R 4 As defined in formula (I).

[0121] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the compound of formula (IIa) or a pharmaceutically acceptable salt thereof,

[0122] Among them, X 1 Selected from CR 5 or N, the R 5 , Ring B, X, R 1 、R 2 、R 3 、R 4 As defined in formula (I).

[0123] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the compound of formula (IIb) or a pharmaceutically acceptable salt thereof,

[0124] in, represents a single bond or a double bond, X 1 Selected from CR 5 or N, the R 5 , Ring B, R 1 、R 4 、R a As defined in formula (I).

[0125] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the compound of formula (III) or a pharmaceutically acceptable salt thereof,

[0126] Among them, ring B, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 As defined in formula (I).

[0127] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the compound of formula (IIIa) or a pharmaceutically acceptable salt thereof,

[0128] Among them, X1 is selected from CH or N, the ring B, R 1 、R 2 、R 3 、R 4 、R a As defined in formula (I).

[0129] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the compound of formula (IV) or a pharmaceutically acceptable salt thereof,

[0130] Among them, ring B, X, R 1 、R 2 、R 3 、R 5 、R 7 As defined in formula (I).

[0131] 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,

[0132] On the other hand, the present application provides a pharmaceutical composition comprising the compound of formula (I) of the present application or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0133] On the other hand, the present application provides a method for treating a disease mediated by PKMYT1 in a mammal, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.

[0134] 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 a PKMYT1-mediated disease.

[0135] 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 a PKMYT1-mediated disease.

[0136] 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 a PKMYT1-mediated disease.

[0137] In some embodiments, the PKMYT1-mediated disease is a tumor, such as breast cancer.

[0138] Definitions and Explanations of Terms

[0139] Unless otherwise indicated, the terms used in this application have the following meanings. The definitions of groups and terms described in this application, including their definitions as examples, exemplary definitions, preferred definitions, definitions described in tables, and definitions of specific compounds in the examples, may be combined and coupled with each other in any manner. A specific term should not be considered as undefined or unclear unless specifically defined, but should be understood according to its common meaning in the art. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0140] In this article, Indicates the junction site.

[0141] In this paper, the bonds depicted by solid and dashed lines Indicates a single bond or a double bond.

[0142] In this article, the double arrows in the synthetic routes Indicates a multi-step reaction.

[0143] The term "tautomer" refers to functional group isomers 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 may exist as two or more interconvertible species. Tautomers generally exist in equilibrium, and attempts to separate a single tautomer usually produce a mixture whose physical and chemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical characteristics within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; whereas in phenols, the enol form predominates. The present application encompasses all tautomeric forms of the compounds.

[0144] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and diastereomers.

[0145] The compounds of the present application may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds, and therefore the compounds of the present application may exist in specific geometric or stereoisomeric forms. Specific geometric or stereoisomeric forms may be cis and trans isomers, E-type and Z-type geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures or other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the definition of the compounds of the present application and mixtures thereof. Additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus atoms may be present in substituents such as alkyl groups, and all of these isomers and mixtures thereof involved in the substituents are also within the definition of the compounds of the present application. The compounds of the present invention containing an asymmetric atom can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.

[0146] The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is an oxo (i.e., =O), it means that two hydrogen atoms are replaced. Oxo does not occur on aromatic groups.

[0147] The term "optional" or "optionally" refers to that the event or situation described subsequently may or may not occur, and the description includes that the event or situation occurs and that the event or situation does not occur. For example, an ethyl group is "optionally" substituted with halogen, meaning that the ethyl group may be unsubstituted (CH2CH3), monosubstituted (CH2CH2F, CH2CH2Cl, etc.), polysubstituted (CHFCH2F, CH2CHF2, CHFCH2Cl, CH2CHCl2, etc.), or fully substituted (CF2CF3, CF2CCl3, CCl2CCl3, etc.). It will be appreciated by those skilled in the art that for any group comprising one or more substituents, any sterically impossible and / or incomposable replacement or substitution pattern will not be introduced.

[0148] When any variable (such as R a 、R b ) appears more than once in the composition or structure of a compound, its definition is independent in each case. For example, if a group is represented by two R b is replaced, then each R b There are independent options.

[0149] When a substituent's bond crosses two atoms in a ring, the substituent may be bonded to any atom in the ring. Represents R 5 Substitution can occur at any position on the benzene ring.

[0150] In this article, C m -C n It means having an integer number of carbon atoms in the range mn. For example, "C1-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.

[0151] The term "alkyl" refers to a group of the formula C n H 2n+1 The term "C1-C 10 The term "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 radical 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- dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc.; the term "C1-C6 alkyl" can be understood to mean an alkyl group having 1 to 6 carbon atoms, and 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 "C1-C3 alkyl" can be understood to mean a straight-chain or branched saturated alkyl group having 1 to 3 carbon atoms. The "C1-C 10 The term "alkyl" may include "C1-C6 alkyl" or "C1-C3 alkyl" and the like, and the "C1-C6 alkyl" may further include "C1-C3 alkyl".

[0152] The term "alkenyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond. 10 "Alkenyl" is understood to mean a linear 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, "C2-C10 "Alkenyl" is preferably "C2-C6 alkenyl", further preferably "C2-C4 alkenyl", and further preferably C2 or C3 alkenyl. It will be understood that when the alkenyl contains more than one double bond, the double bonds may be separated from each other or conjugated. Specific examples of the alkenyl 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, etc.

[0153] The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one triple bond. 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. "C2-C 10 Examples of "alkynyl" include, but are not limited to, ethynyl (-C≡CH), propynyl (-C≡CCH 3、 -CH2C≡CH), but-1-ynyl, but-2-ynyl or but-3-ynyl. "C2-C 10 The term "alkynyl" may include "C2-C3 alkynyl". Examples of "C2-C3 alkynyl" include ethynyl (-C≡CH), prop-1-ynyl (-C≡CCH3), and prop-2-ynyl (-CH2C≡CH).

[0154] The term "cycloalkyl" refers to a fully saturated carbon ring that exists in the form of a monocyclic, fused, bridged, or spirocyclic ring. Unless otherwise indicated, the carbon ring is typically a 3- to 10-membered ring. The term "C3-C 10 "Cycloalkyl" is understood to mean a saturated monocyclic, bicyclic, 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, and the like. The term "C3-C 10 "Cycloalkyl" may include "C3-C6 cycloalkyl". The term "C3-C6 cycloalkyl" may be 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.

[0155] The term "heterocyclyl" refers to a fully saturated or partially saturated (heteroaromatic as a whole that is not aromatic) monocyclic, fused, spirocyclic or bridged ring group, which contains 1, 2, 3, 4 or 5 heteroatoms or heteroatomic groups (i.e., heteroatom-containing atomic groups) in its ring atoms, wherein the "heteroatoms or heteroatomic groups" include, but are not limited to, nitrogen atom (N), oxygen atom (O), sulfur atom (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-. The term "4-10 membered heterocyclyl" refers to a heterocyclyl group having 4, 5, 6, 7, 8, 9 or 10 ring atoms, and containing 1, 2, 3, 4 or 5 heteroatoms or heteroatomic groups independently selected from the above-mentioned heteroatoms in its ring atoms. “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 oxetanyl; specific examples of 5 membered heterocyclyl include but are not limited to tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4,5-dihydrooxazolyl or 2,5-dihydro-1H-pyrrolyl; specific examples of 6 membered heterocyclyl include but are not limited to tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridinyl or 4H-[1,3,4]thiadiazinyl; specific examples of 7 membered heterocyclyl include but are not limited to diazepanyl. 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]pyrrol-2(1H)-yl; specific examples of 5,6-membered bicyclic groups include but are not limited to hexahydropyrrolo[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 ring group of the above-mentioned 4-7-membered heterocyclic groups, specific examples of which include but are not limited to dihydroisoquinolinyl 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", etc., and "4-7 membered heterocyclyl" may further include "4-6 membered heterocyclyl", "5-6 membered heterocyclyl", "4-7 membered heterocycloalkyl", "4-6 membered heterocycloalkyl", "5-6 membered heterocycloalkyl", etc. In the present application, although some bicyclic heterocyclyl groups partially contain a benzene ring or a heteroaromatic ring, the heterocyclyl group as a whole is still non-aromatic.

[0156] The term "heterocycloalkyl" refers to a fully saturated cyclic group in the form of a monocyclic, fused, bridged or spirocyclic ring, wherein the ring atoms of the ring contain 1, 2, 3, 4 or 5 heteroatoms or heteroatomic groups (i.e., heteroatomic groups containing heteroatoms), wherein the "heteroatoms or heteroatomic groups" include, but are not limited to, nitrogen atom (N), oxygen atom (O), sulfur atom (S), phosphorus atom (P), boron atom (B), -S(=O)2-, -S(=O)-, -NH-, -S(=O)(=NH)-, -C(=O)NH- or -NHC(=O)NH-. The term "4-10 membered heterocycloalkyl" refers to a heterocycloalkyl group having 4, 5, 6, 7, 8, 9 or 10 ring atoms, wherein the ring atoms contain 1, 2, 3, 4 or 5 heteroatoms or heteroatomic groups independently selected from the above-mentioned heteroatoms. “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 thietanyl; specific examples of 5 membered heterocycloalkyl include but are not limited to tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl or tetrahydropyrazolyl; specific examples of 6 membered heterocycloalkyl include but are not limited to piperidinyl, 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 azepanyl, oxetanyl or thiepanyl.

[0157] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π electron system. The aryl group may have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. The term "C6-C 20 "Aryl" is understood to be an aromatic radical having 6 to 20 carbon atoms. In particular, a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring having 9 carbon atoms ("C9 aryl"), such as indanyl or indenyl; or a ring having 10 carbon atoms ("C 10 or a ring having 13 carbon atoms ("C 13 aryl) such as fluorenyl; or a ring having 14 carbon atoms ("C 14 The term "C6-C 10 "Aryl" is understood to be an aromatic radical having 6 to 10 carbon atoms. In particular, a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring having 9 carbon atoms ("C9 aryl"), such as indanyl or indenyl; or a ring having 10 carbon atoms ("C 10 "aryl"), for example tetrahydronaphthyl, dihydronaphthyl or naphthyl.

[0158] The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system having aromatic character, which contains at least one ring atom selected from N, O, 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 containing 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 thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiadiazolyl, and the like, and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl or isoindolyl, and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl, and the like, and benzo derivatives thereof, such as quinolyl, quinazolinyl or isoquinolyl, and the like; or acinyl, indolizinyl, purinyl, and the like, and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl or phenoxazinyl, and the like. 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.

[0159] The term "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.

[0160] The term "hydroxy" refers to an -OH group.

[0161] The term "cyano" refers to a -CN group.

[0162] The term "amino" refers to a -NH2 group.

[0163] The term "therapeutically effective amount" means an amount of a compound of the present invention that (i) treats a specific disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder, or (iii) delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of a compound of the present invention that constitutes a "therapeutically effective amount" varies 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 those skilled in the art based on their own knowledge and this disclosure.

[0164] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0165] The term "pharmaceutically acceptable salt" refers to a salt of a pharmaceutically acceptable acid or base, including a salt formed between a compound and an inorganic acid or organic acid, and a salt formed between a compound and an inorganic base or an organic base.

[0166] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or their salts and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.

[0167] The term "pharmaceutically acceptable excipient" refers to an excipient that is non-irritating to organisms and does not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0168] The word "comprise" or "comprises" and its English variations such as comprises or comprising are to be understood as having an open and non-exclusive meaning, ie, "including but not limited to".

[0169] The present application also includes isotopically labeled compounds of the present application that are identical to those described herein, but in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can 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 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 123 I. 125 I and 36 Cl et al.

[0170] Certain isotope-labeled compounds of the present application (e.g. 3 H and 14 C-labeled) can be used in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14C) 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 following procedures analogous to those disclosed in the Schemes and / or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0171] The pharmaceutical compositions of the present application can be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, and can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.

[0172] Typical routes of administration of the compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0173] The pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, emulsification methods, freeze-drying methods, etc.

[0174] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, and the like for oral administration to a patient.

[0175] Solid oral compositions can be prepared by conventional mixing, filling, or tableting methods. For example, they can be prepared by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients as needed, and then granulating the mixture to obtain a tablet or dragee core. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, or flavoring agents.

[0176] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

[0177] 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 equivalent replacement methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.

[0178] The chemical reactions in the specific examples of this application are carried out in a suitable solvent that is compatible with the chemical transformations of this application and the reagents and materials required. In order to obtain the compounds of this application, it is sometimes necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing implementations.

[0179] An important consideration in synthetic route planning in this field is the selection of appropriate protecting groups for reactive functional groups. For example, reference may be made to Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc. All references cited in this application are incorporated herein in their entirety. Example

[0180] The present application is described in detail below by way of examples, but this is not intended to limit the present application in any way. While the present application has been described in detail herein, including specific examples thereof, it will be apparent to those skilled in the art that various changes and modifications can be made to the specific examples without departing from the spirit and scope of the present application. All reagents used herein are commercially available and can be used without further purification.

[0181] Compounds are manually or Software naming, commercially available compounds use supplier catalog names.

[0182] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The units of NMR shifts are 10 -6 (ppm). The solvents for NMR determination are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS); "IC 50 ” refers to the half-maximal inhibitory concentration, which is the concentration at which half of the maximum inhibitory effect is achieved.

[0183] Explanation of terms or abbreviations:

[0184] TsOH·H2O: p-toluenesulfonic acid monohydrate; NMP: N-methylpyrrolidone; dioxane: 1,4-dioxane; DME: ethylene glycol dimethyl ether; t BuONa: sodium tert-butoxide;t BuOLi: lithium tert-butoxide; Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride; Pd(dppf)Cl2·DCM: [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex; rt: room temperature; min: minute; h: hour; DCM: dichloromethane; MeCN / ACN: acetonitrile; HOAc: acetic acid; 4A MS: molecular sieves; TMPLiClMgCl2: 2,2,6,6-tetramethylpiperidinium lithium chloride magnesium chloride; Me: methyl; MeOH: methanol; MeONa: sodium methoxide; EtOH: ethanol; LiHMDS: lithium bis(trimethylsilyl)amide; THF: tetrahydrofuran; DMF: N,N-dimethylformamide; TBSCl: tert-butyldimethylchlorosilane; imidazol: imidazole; Pd(dba)2: bis(dibenzylideneacetone)palladium; Pd2(dba)3: tris(dibenzylideneacetone)dipalladium; xantphos: 4,5-bis(diphenylphosphino-9,9-dimethylxanthene); t-am-OH: tert-amyl alcohol; pyridine: pyridine; Pd(OAc)2: palladium acetate; Sphos: 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl; Parkins catalyst: (dimethylphosphonate) platinum(II) hydrogen complex; NCS: N-chlorosuccinimide; MeB(OH)2: methylboronic acid; Pd(PPh3)2Cl2: bistriphenylphosphine palladium dichloride; Et3N: 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-(dicyclohexylphosphino)ferrocene]ethyldi-tert-butylphosphine; ((PhMe)3P)2Pd: bis(tri(2-methylphenyl)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: diethylaminosulfur trifluoride; XantPhos Pd G4: methanesulfonate [9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene] (2'-methylamino-1,1'-biphenyl-2-yl) palladium(II); Cy2NMe: N-methyldicyclohexylamine; AgOTf: silver trifluoromethanesulfonate; toluene: toluene.

[0185] The compound can be obtained through the following routes:

[0186] Example 1: Preparation of 8-amino-7-(3-hydroxy-2,6-dimethylphenyl)-7H-imidazo[1,2-c]pyrrolo[3,2-e]pyrimidine-9-carboxamide (Compound 1)

[0187] Step 1: 6-Chloro-5-iodo-N-(3-methoxy-2,6-dimethylphenyl)pyrimidin-4-amine (1c)

[0188] At room temperature, 4,6-dichloro-5-iodopyrimidine (0.50 g, 1.8 mmol) and 3-methoxy-2,6-dimethylaniline (0.28 g, 1.8 mmol) were dissolved in N-methylpyrrolidone (1 mL). p-Toluenesulfonic acid monohydrate (10 mg, 0.18 mmol) was added, and the mixture was stirred at 150°C for 1 h. After cooling to room temperature, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. The resulting residue was purified by normal phase chromatography (ethyl acetate:petroleum ether = 10:1-1:2) to afford the desired product 1c as a white solid (0.11 g, 16% yield). LC-MS: m / z (ESI): 390.0 [M+H]. + .

[0189] Step 2: 5-Iodo-N 4 -(3-Methoxy-2,6-dimethylphenyl)pyrimidine-4,6-diamine (1d)

[0190] Compound 1c (0.11 g, 0.28 mmol) was dissolved in N-methylpyrrolidone (1 mL), and aqueous ammonia (0.20 g, 5.7 mmol) was added. The mixture was then stirred at 140°C for 6 hours. After cooling to room temperature, the reaction solution was concentrated, and the resulting residue was purified by reverse-phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to obtain the target compound 1d (80 mg, 77% yield). LC-MS: m / z (ESI): 371.0 [M+H] + .

[0191] Step 3: 8-iodo-N-(3-methoxy-2,6-dimethylphenyl)imidazo[1,2-c]pyrimidin-7-amine (1e)

[0192] Compound 1d (80 mg, 0.22 mmol) was dissolved in 1,4-dioxane (1 mL), followed by the addition of chloroacetaldehyde (85 mg, 1.1 mmol). The reaction was allowed to react at 90°C for 1 hour. After cooling to room temperature, water (10 mL) was added to the reaction solution, followed by extraction with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and the filtrate concentrated. The resulting residue was purified by reverse-phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to afford the desired product 1e (40 mg, 47% yield). m / z (ESI): 395.0 [M+H] + .

[0193] Step 4: 8-amino-7-(3-methoxy-2,6-dimethylphenyl)-7H-imidazo[1,2-c]pyrrolo[3,2-e]pyrimidine-9-carbonitrile (1f)

[0194] Malononitrile (27 mg, 0.41 mmol) was dissolved in ethylene glycol dimethyl ether (1 mL) at room temperature, and sodium tert-butoxide (59 mg, 0.61 mmol) was added. The mixture was stirred for 30 min until clear, followed by the addition of compound 1e (40 mg, 0.10 mol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (37 mg, 0.05 mmol). The atmosphere was replaced with nitrogen three times, and the mixture was stirred at 80°C for 12 hours under nitrogen. After the reaction mixture was cooled to room temperature, the insoluble material was removed by filtration, and the filtrate was dried by rotary evaporation. The resulting residue was purified by reverse phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to afford the target compound 1f (20 mg, 59% yield) as a white solid. m / z (ESI): 333.1 [M+H] + .

[0195] Step 5: 8-amino-7-(3-methoxy-2,6-dimethylphenyl)-7H-imidazo[1,2-c]pyrrolo[3,2-e]pyrimidine-9-carboxamide (1 g)

[0196] Compound 1f (20 mg, 60 μmol) was dissolved in concentrated sulfuric acid (1 mL) at room temperature and stirred for 45 minutes. The reaction mixture was cooled with ice water, neutralized with aqueous ammonia, and concentrated. The resulting residue was purified by reverse-phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to afford the title compound 1g (10 mg, 47% yield) as a white solid. m / z (ESI): 351.1 [M+H] + .

[0197] Step 6: 8-amino-7-(3-hydroxy-2,6-dimethylphenyl)-7H-imidazo[1,2-c]pyrrolo[3,2-e]pyrimidine-9-carboxamide (1)

[0198] At room temperature, 1 g (10 mg, 30 μmol) of the compound was dissolved in dichloromethane (1 mL). A dichloromethane solution of boron tribromide (1 mol / L, 0.14 mL) was added and stirred for 30 minutes. The reaction mixture was quenched with methanol (5 mL) and concentrated. The resulting residue was purified by reverse-phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to afford compound 1 (3.9 mg, 41% yield).

[0199] m / z(ESI):337.1[M+H] + .

[0200] 1 H NMR (400MHz, CDCl3) δ10.2(s,1H),8.56(s,1H),7.63(d,J=1.2Hz,1H),7.58(d,J=1.2Hz,1H),7.1 4(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).

[0201] Example 2: Preparation of 7-amino-8-(3-hydroxy-2,6-dimethylphenyl)-8H-imidazo[1,2-a]pyrrolo[2,3-d]pyrimidine-6-carboxamide (Compound 2)

[0202] Step 1: 5-Bromo-N 4 -(3-Methoxy-2,6-dimethylphenyl)pyrimidine-2,4-diamine (2b)

[0203] 2-Amino-5-bromo-4-chloropyrimidine (0.16 g, 0.77 mmol), 3-methoxy-2,6-dimethylaniline (0.17 g, 1.1 mmol), and p-toluenesulfonic acid monohydrate (13 mg, 0.077 mmol) were dissolved in N-methylpyrrolidone (2 mL). The reaction system was then placed in an oil bath at 110°C for 3 hours. After completion of the reaction, the mixture was cooled to room temperature. The reaction solution was purified by reverse-phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to obtain compound 2b (0.20 g, 82% yield). m / z (ESI): 323.0 [M+H] + .

[0204] A method similar to Example 1 was used, and Compound 2b was used instead of Compound 1c in Example 1 to prepare Compound 2. m / z (ESI): 337.1 [M+H] + .

[0205] Example 3: Preparation of 7-amino-8-(3-hydroxy-2,6-dimethylphenyl)-2,8-dihydro-3H-imidazo[1,2-a]pyrrolo[2,3-d]pyrimidine-6-carboxamide (Compound 3)

[0206] Step 1: 5-Bromo-2-chloro-N-(3-methoxy-2,6-dimethylphenyl)pyrimidin-4-amine (3b)

[0207] 5-Bromo-2,4-dichloropyrimidine (0.30 g, 1.3 mmol), 3-methoxy-2,6-dimethylaniline (0.30 g, 2.0 mmol), and p-toluenesulfonic acid monohydrate (6.9 mg, 0.13 mmol) were dissolved in N-methylpyrrolidone (5 mL) at room temperature and reacted at 90°C for 12 hours. After cooling to room temperature, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified on a silica gel column (ethyl acetate:petroleum ether = 10:1 to 1:2) to obtain the desired product 3b as a white solid (0.20 g, 44% yield). LC-MS: m / z (ESI): 342.0 [M+H] + .

[0208] Step 2: 2-[[5-Bromo-4-(3-methoxy-2,6-dimethylanilino)pyrimidin-2-yl]amino]ethanol (3c)

[0209] Compound 3b (0.2 g, 0.59 mmol) and ethanolamine (53 mg, 0.88 mmol) were dissolved in N-methylpyrrolidone (3 mL) and heated to 120°C for 1 hour. After cooling to room temperature, the reaction solution was directly purified by reverse phase chromatography (C18, 0.05% ammonia water:acetonitrile = 20:1 to 1:20) to obtain the desired product 3c as a white solid (0.21 g, yield 98%). LC-MS: m / z (ESI): 367.1 [M+H] + .

[0210] Step 3: 5-Bromo-N 2 -(2-chloroethyl)-N 4 -(3-Methoxy-2,6-dimethylphenyl)pyrimidine-2,4-diamine (3d)

[0211] Compound 3c (0.21 g, 0.57 mmol) was added to thionyl chloride (5 mL) at room temperature and heated to 85°C for 2 hours. After the reaction was cooled to room temperature, the solvent was removed by distillation under reduced pressure to obtain compound 3d (0.22 g, yield 99%). m / z (ESI): 385.0 [M+H] + .

[0212] Step 4: 6-Bromo-N-(3-methoxy-2,6-dimethylphenyl)-2,3-dihydroimidazo[1,2-a]pyrimidin-7-amine (3e)

[0213] Compound 3d (0.22 g, 0.57 mmol) and potassium carbonate (0.39 g, 2.9 mmol) were dissolved in acetonitrile (5 mL) and heated to 85°C for 3 hours. The solvent was removed by distillation under reduced pressure, and the resulting solid residue was purified by reverse phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to obtain the desired product 3e as a white solid (90 mg, 45% yield). m / z (ESI): 349.1 [M+H] + .

[0214] 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)

[0215] Malononitrile (68 mg, 1.0 mmol) was dissolved in ethylene glycol dimethyl ether (5 mL), followed by the addition of sodium tert-butoxide (0.15 g, 1.6 mmol). The mixture was stirred at room temperature for 30 min until clear. Compound 3e (90 mg, 0.26 mol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (19 mg, 26 μmol) were then added. The atmosphere was replaced with nitrogen three times, and the mixture was stirred at 90°C under nitrogen for 5 hours. After the reaction mixture was cooled to room temperature, the insoluble matter was removed by filtration, and the filtrate was dried by rotary evaporation. The resulting residue was purified by reverse phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to afford the target compound 3f (30 mg, 35% yield) as a white solid. m / z (ESI): 335.2 [M+H] + .

[0216] 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 (3 g)

[0217] Compound 3f (30 mg, 90 μmol) was dissolved in concentrated sulfuric acid (1 mL) at room temperature and stirred for 45 minutes. The reaction mixture was cooled with ice water, neutralized with aqueous ammonia, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by reverse phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to obtain the title compound 3g (30 mg, 99% yield). m / z (ESI): 352.2 [M+H] + .

[0218] 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)

[0219] Compound 3g (30 mg, 85 μmol) was dissolved in dichloromethane (1 mL) at room temperature, followed by the addition of a dichloromethane solution of boron tribromide (1 mol / L, 0.85 mL). The mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched with methanol (5 mL) and concentrated. The resulting residue was purified by reverse phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to afford compound 3 (13.3 mg, 46% yield). m / z (ESI): 339.1 [M+H] + .

[0220] 1 H NMR (400MHz, DMSO-d6) 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).

[0221] Example 4: Preparation of 8-amino-7-(3-hydroxy-2,6-dimethylphenyl)-2,7-dihydro-3H-imidazo[1,2-c]pyrrolo[3,2-e]pyrimidine-9-carboxamide (Compound 4)

[0222] A method similar to Example 3 was used, and compound 4 was prepared by substituting 4,5,6-trichloropyrimidine for compound 3a in Example 3. m / z (ESI): 339.1 [M+H] + .

[0223] Example 5: Preparation of 6-amino-7-(3-hydroxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (Compound 5)

[0224] Step 1: 5-Bromo-N-(3-methoxy-2,6-dimethylphenyl)-2-methylpyrimidin-4-amine (5b)

[0225] At room temperature, 5-bromo-4-chloro-2-methylpyrimidine (0.75 g, 3.6 mmol) and 3-methoxy-2,6-dimethylaniline (0.50 g, 3.3 mmol) were dissolved in N-methylpyrrolidone (10 mL). Acetic acid (20 mg, 0.33 mmol) was then added, and the reaction mixture was heated to 140°C for 12 hours. After cooling to room temperature, the mixture was poured into water (20 mL) and extracted with ethyl acetate (25 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by normal phase chromatography (petroleum ether:ethyl acetate = 10:1 to 2:1) to obtain the target compound 5b as a white solid (0.70 g, 66% yield). m / z (ESI): 322.0 [M+H] + .

[0226] Step 2: 6-amino-7-(3-methoxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (5c)

[0227] Malononitrile (22 mg, 0.30 mmol) was dissolved in ethylene glycol dimethyl ether (3 mL) at room temperature. Lithium tert-butoxide (2.2 M, 0.18 mL) was added and stirred at room temperature for 30 minutes until the solution became clear. Compound 5b (50 mg, 0.16 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (13 mg, 20 μmol) were then added. The atmosphere was purged with nitrogen three times and stirred at 100°C for 16 hours under nitrogen. The reaction mixture was cooled to room temperature, filtered to remove insoluble matter, and the filtrate was dried by rotary evacuation. The resulting residue was purified by preparative chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to afford the target compound 5c as a white solid (46 mg, 46% yield). m / z (ESI): 308.1 [M+H] + .

[0228] Step 3: 6-amino-7-(3-hydroxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (5d)

[0229] Compound 5c (40 mg, 0.13 mmol) was dissolved in dichloromethane (2 mL) at room temperature. A solution of boron tribromide (1 mol / L, 2 mL) in dichloromethane was added and stirred at room temperature for 30 minutes. The reaction mixture was quenched with methanol (5 mL) in an ice bath and concentrated. The resulting residue was purified by reverse-phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to afford the desired product 5d (38 mg, 99% yield) as a white solid. m / z (ESI): 294.1 [M+H] + .

[0230] Step 4: 6-amino-7-(3-hydroxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (5)

[0231] 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 mixture was cooled with ice water, neutralized with aqueous ammonia, and concentrated under reduced pressure. The resulting residue was purified by preparative column chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to obtain compound 5 (25 mg, yield 62%). m / z (ESI): 312.1 [M+H] + .

[0232] 1 H NMR (400MHz, DMSO-d6) 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).

[0233] Example 6: Preparation of 6-amino-7-(3-hydroxy-2,6-dimethylphenyl)-3-methyl-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (Compound 6)

[0234] Step 1: 6-((3-methoxy-2,6-dimethylphenyl)amino)-3-methylpyrimidin-4(3H)-one (6b)

[0235] 6-Chloro-3-methyl-pyrimidin-4-one (0.10 g, 0.69 mmol), 3-methoxy-2,6-dimethylaniline (0.16 g, 1.0 mmol), tris(dibenzylideneacetone)dipalladium (32 mg, 0.03 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (40 mg, 0.07 mmol), and cesium carbonate (0.68 g, 2.1 mmol) were dissolved in tert-amyl alcohol (1 mL). The atmosphere was purged with nitrogen and the mixture was heated to 100°C under nitrogen for 16 hours. The reaction mixture was cooled to room temperature, filtered to remove insoluble matter, and the filtrate was concentrated. The resulting residue was purified by preparative chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to afford the desired product 6b as a white solid (0.40 g, 62% yield). m / z(ESI):260.1[M+H] + .

[0236] Step 2: 5-Bromo-6-((3-methoxy-2,6-dimethylphenyl)amino)-3-methyl-pyrimidin-4(3H)-one (6c)

[0237] At room temperature, 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). After the addition was complete, the reaction was continued at room temperature for 15 min. The solid was removed by filtration, and the filtrate was treated with 1M hydrochloric acid until neutral, then extracted with dichloromethane (10 mL x 3). The organic phases were combined and washed with 10% aqueous sodium carbonate solution, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified on a silica gel column (ethyl acetate:petroleum ether = 10:1-1:3) to afford 6c (0.20 g, 38% yield) as a pale yellow solid. m / z (ESI): 338.0 [M+H] + .

[0238] 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)

[0239] Malononitrile (41 mg, 0.62 mmol) was dissolved in ethylene glycol dimethyl ether (2 mL) at room temperature. Lithium tert-butoxide (2.2 M, 0.34 mL) was added and stirred for 30 minutes until the solution became clear. Compound 6c (0.10 g, 0.30 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (24 mg, 0.03 mmol) were then added. The atmosphere was purged with nitrogen three times, and the reaction was continued at 100°C under nitrogen protection for 12 hours. The reaction mixture was cooled to room temperature, filtered to remove insoluble matter, and the filtrate was concentrated. The resulting residue was purified by reverse phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to afford the target compound 6d (40 mg, 42% yield) as a white solid. m / z (ESI): 324.1 [M+H] + .

[0240] 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)

[0241] Compound 6d (30 mg, 93 μmol) was dissolved in dichloromethane (2 mL) at room temperature, and a dichloromethane solution of boron tribromide (1 M / L, 2 mL) was added. The mixture was stirred at room temperature for 30 minutes. The reaction solution was quenched with methanol (5 mL) and then concentrated. The resulting residue was purified by reverse phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to obtain the desired product 6e (15 mg, 51% yield) as a white solid. m / z (ESI): 310.1 [M+H] + .

[0242] 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)

[0243] Compound 6e (15 mg, 0.05 mmol) was dissolved in concentrated sulfuric acid (1 mL) at room temperature and stirred for 45 minutes. After completion of the reaction, the reaction solution was neutralized with aqueous ammonia in an ice bath and concentrated. The resulting residue was purified by reverse-phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to afford the target compound 6 (3.0 mg, 19% yield) as a white solid. m / z (ESI): 328.1 [M+H] + .

[0244] 1H NMR (400MHz, DMSO-d6) 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).

[0245] Example 7: Preparation of 8-amino-7-(3-hydroxy-2,6-dimethylphenyl)-2-methyl-7H-imidazo[1,2-c]pyrrolo[3,2-e]pyrimidine-9-carboxamide (Compound 7)

[0246] Step 1: 8-iodo-N-(3-methoxy-2,6-dimethylphenyl)-2-methylimidazo[1,2-c]pyrimidin-7-amine (7e)

[0247] At room temperature, 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 sequentially. The mixture was then heated to 90°C for 1 hour. After cooling to room temperature, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. The resulting residue was purified by reverse-phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to obtain the target compound 7e (22 mg) as a white solid. LC-MS: m / z: 409.0, [M+H] + .

[0248] Compound 7 was prepared by a method similar to steps 4 to 6 of Example 1, using compound 7e instead of compound 1e in Example 1. m / z (ESI): 351.2 [M+H] + .

[0249] 1 H NMR(400MHz,DMSO-d6)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).

[0250] Example 8: Preparation of 8-amino-7-(3-hydroxy-2,6-dimethylphenyl)-2-cyclopropyl-7H-imidazo[1,2-c]pyrrolo[3,2-e]pyrimidine-9-carboxamide (Compound 8)

[0251] A method similar to that of Example 7 was used, and the chloroacetone in Example 7 was replaced with 2-chloro-1-cyclopropylethane-1-one to prepare Compound 8. m / z (ESI): 377.4 [M+H] + .

[0252] 1 H NMR (400MHz, DMSO-d6) 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),6.9 2(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).

[0253] Example 9: Preparation of 8-amino-7-(3-hydroxy-2,6-dimethylphenyl)-3-methyl-7H-imidazo[1,2-c]pyrrolo[3,2-e]pyrimidine-9-carboxamide (Compound 9)

[0254] A method similar to Example 7 was used, using 2-bromo-1,1-dimethoxypropane instead of chloroacetone in Example 7 to prepare compound 9. m / z (ESI): 351.2 [M+H] + .

[0255] Example 10: Preparation of 8-amino-7-(3-hydroxy-2,6-dimethylphenyl)-5-methyl-7H-imidazo[1,2-c]pyrrolo[3,2-e]pyrimidine-9-carboxamide (Compound 10)

[0256] Step 1: 6-Chloro-5-iodo-N-(3-methoxy-2,6-dimethylphenyl)-2-methylpyrimidin-4-amine (10b)

[0257] At room temperature, 4,6-dichloro-5-iodo-2-methylpyrimidine (5.8 g, 20 mmol) and 3-methoxy-2,6-dimethylaniline (6.0 g, 40 mmol) were dissolved in N-methylpyrrolidone (10 mL). p-Toluenesulfonic acid monohydrate (0.19 g, 1.0 mmol) was added, and the mixture was stirred at 100°C for 48 h. After cooling to room temperature, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. The resulting residue was purified by normal phase chromatography (petroleum ether:ethyl acetate = 10:1-2:1) to obtain the desired product 10b (1.8 g) as a white solid. LC-MS: m / z (ESI): 404.1 [M+H]. + .

[0258] Step 2: 6-amino-4-chloro-7-(3-methoxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (10c)

[0259] Malononitrile (0.20 g, 3.0 mmol) was dissolved in anhydrous ethylene glycol dimethyl ether (2 mL), and sodium tert-butoxide (0.43 g, 4.5 mmol) was added. After stirring at room temperature for 30 minutes, compound 10b (0.30 g, 0.75 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (24 mg, 30 μmol) were added. The atmosphere was replaced with nitrogen three times, and the reaction was continued 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 dried by rotary evaporation. The resulting residue was purified by reverse phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to obtain compound 10c (0.2 g). m / z (ESI): 342.3 [M+H] + .

[0260] Step 3: 4,6-Diamino-7-(3-methoxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (10d)

[0261] Compound 10c (0.2 g, 0.58 mmol) was dissolved in N-methylpyrrolidone (5 mL), and aqueous ammonia (10 mL) was added. The mixture was then reacted at 130°C under sealed conditions for 16 hours. After cooling to room temperature, the reaction solution was concentrated, and the resulting residue was purified by reverse-phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to obtain the target compound 10d (0.14 g). LC-MS: m / z (ESI): 323.0 [M+H] + .

[0262] 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)

[0263] Compound 10d (0.14 g, 0.42 mmol) was dissolved in 1,4-dioxane (10 mL), and then chloroacetaldehyde (4 mL) and Molecular sieves (30 mg) were added and the reaction was allowed to proceed at 100°C for 1 hour. After the reaction mixture was cooled to room temperature, the molecular sieves were removed by filtration, and the reaction solution was concentrated. The resulting residue was purified by reverse-phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to obtain the target compound 10e (0.13 g). m / z (ESI): 347.1 [M+H] + .

[0264] 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)

[0265] 10e (0.13 g, 0.37 mmol) was dissolved in concentrated sulfuric acid (5 mL) at room temperature and stirred for 30 minutes. The reaction mixture was neutralized with aqueous ammonia in an ice bath until alkaline. The reaction mixture was concentrated, and the resulting residue was purified by reverse-phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to afford the title compound 10f (0.11 g) as a white solid. m / z (ESI): 365.1 [M+H] + .

[0266] 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)

[0267] At room temperature, 10f (0.11 g, 0.31 mmol) was dissolved in dichloromethane (5 mL). A solution of boron tribromide (1 mol / L, 5 mL) in dichloromethane was added and stirred for 30 minutes. The reaction mixture was quenched with methanol (5 mL) and concentrated. The resulting residue was purified by reverse-phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to afford compound 10 (98 mg).

[0268] m / z(ESI):351.1[M+H] + .

[0269] 1H NMR (400MHz, DMSO-d6): 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).

[0270] Example 11: Preparation of 8-amino-7-(3-hydroxy-2,6-dimethylphenyl)-5-cyclopropyl-7H-imidazo[1,2-c]pyrrolo[3,2-e]pyrimidine-9-carboxamide (Compound 11)

[0271] Step 1: Synthesis of 4,6-dichloro-2-cyclopropyl-5-iodopyrimidine (11b)

[0272] 4,6-Dichloro-2-cyclopropylpyrimidine (1.5 g, 7.9 mmol) was dissolved in anhydrous tetrahydrofuran. A solution of 2,2,6,6-tetramethylpiperidinium chloride, lithium chloride, and magnesium chloride in tetrahydrofuran (10 mL, 1 mol / L) was then added dropwise under an ice bath. After the addition was complete, the mixture was allowed to react at room temperature for 1 hour. Elemental iodine (3.0 g, 12 mmol) was then dissolved in tetrahydrofuran and added dropwise to the solution. After the addition was complete, the reaction was continued for 1 hour. Saturated ammonium chloride solution was slowly added to the solution to quench the reaction. The mixture was then extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. The resulting residue was purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 10:1) to yield product 11b (1.0 g). m / z: 315.1 [M+H] + .

[0273] Compound 11 was prepared by a method similar to Example 10, with Compound 11b replacing Compound 10a in Example 10.

[0274] m / z(ESI):377.4[M+H] + .

[0275] 1H NMR (400MHz, DMSO-d6) 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).

[0276] Example 12: Preparation of 8-amino-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine-9-carboxamide (Compound 12)

[0277] Step 1: 6-amino-4-chloro-7-(3-methoxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (12a)

[0278] Malononitrile (0.20 g, 3.0 mmol) was dissolved in anhydrous ethylene glycol dimethyl ether (2 mL), and sodium tert-butoxide (0.43 g, 4.5 mmol) was added. After stirring at room temperature for 30 minutes, 1c (0.29 g, 0.75 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (24 mg, 30 μmol) were added. The atmosphere was replaced with nitrogen three times, and the reaction was continued at 90°C under nitrogen protection for 3 hours. After the reaction was cooled to room temperature, the insoluble matter was removed by filtration, and the filtrate was dried by rotary evaporation. The resulting residue was purified by reverse phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to obtain compound 12a (0.2 g). m / z (ESI): 328.1 [M+H] + .

[0279] Step 2: (Z)-6-amino-4-hydrazono-7-(3-methoxy-2,6-dimethylphenyl)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (12b)

[0280] Compound 12a (0.2 g, 0.61 mmol) was dissolved in N-methylpyrrolidone (5 mL), followed by the addition of hydrazine hydrate (5 mL). The reaction was allowed to proceed at 100°C for 1 hour. After cooling to room temperature, the filtrate was dried by rotary evaporation. The resulting residue was purified by reverse phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to obtain compound 12b (0.15 g). m / z (ESI): 324.1 [M+H]+ .

[0281] 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)

[0282] Compound 12b (0.15 g, 0.46 mmol) was dissolved in trimethyl orthoformate (5 mL) and the reaction was incubated in a 100°C oil bath for 8 hours. After cooling to room temperature, the filtrate was dried by rotary evaporation. The resulting residue was purified by reverse-phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to afford compound 12c (96 mg). m / z (ESI): 334.2 [M+H] + .

[0283] 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)

[0284] At room temperature, 12c (60 mg, 0.18 mmol) was dissolved in concentrated sulfuric acid (3 mL) and stirred at room temperature for 30 minutes. The reaction mixture was cooled with ice water, neutralized with aqueous ammonia, and concentrated. The resulting residue was purified by reverse-phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to afford the target compound 12d (32 mg) as a white solid. m / z (ESI): 352.2 [M+H] + .

[0285] Step 5: Synthesis of 8-amino-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine-9-carboxamide (12)

[0286] At room temperature, 12d (32 mg, 0.09 mmol) was dissolved in dichloromethane (5 mL). A solution of boron tribromide (1 mol / L, 5 mL) in dichloromethane was added and stirred for 30 minutes. The reaction solution was quenched with methanol (5 mL) and then concentrated. The resulting residue was purified by reverse-phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to afford compound 12 (18 mg).

[0287] m / z(ESI):338.2[M+H] + .

[0288] 1H NMR (400MHz, CDCl3) 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).

[0289] Example 13: Synthesis of 1-amino-2-(3-hydroxy-2,6-dimethylphenyl)-2,6,7,8-tetrahydro-9H-2,3,8-triazabenzo[cd]azulene-9-one (Compound 13)

[0290] Step 1: 2,3-Dibromoisonicotinaldehyde (13b)

[0291] 2,3-Dibromopyridine (5.0 g, 21 mmol) was dissolved in anhydrous tetrahydrofuran. A solution of LiHMDS (63 mL, 1 mol / L) in THF was added dropwise at -78°C. After the addition was complete, the temperature was gradually raised to 0°C for 30 minutes. DMF (2.3 g, 31.7 mmol) was then added dropwise and the reaction continued at this temperature for 1 hour. The temperature was then raised to room temperature for 12 hours. A saturated solution of ammonium chloride was slowly added to the reaction mixture to quench the reaction. The mixture was then extracted with ethyl acetate (150 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product (13b) was used directly in the next reaction without purification.

[0292] Step 2: (2,3-Dibromopyridin-4-yl)methanol (13c)

[0293] The crude product 13b (22 g, 83 mmol) obtained in the previous step was dissolved in anhydrous methanol, and sodium cyanoborohydride (13 g, 0.21 mol) was slowly added. The reaction system was stirred at 40°C for 12 hours. The solvent was removed by distillation under reduced pressure, and water was added to the reaction system. The mixture was then extracted with ethyl acetate (150 mL x 3). The organic phases were combined, washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1-2:1) to obtain 13c (4.0 g) as a yellow solid. MS (ESI) m / z: 267.8 [M+H] + .

[0294] Step 3: 2,3-Dibromo-4-(((tert-butyldimethylsilyl)oxy)methyl)pyridine (13d)

[0295] Under ice-cooling conditions, 13c (4.0 g, 15 mmol) was dissolved in anhydrous N,N-dimethylformamide. Imidazole (2.1 g, 32 mmol) was then added and stirred for 15 minutes. A solution of tert-butyldimethylsilyl chloride (2.5 g, 17 mmol) in N,N-dimethylformamide was then added dropwise. After the addition was complete, the mixture was allowed to warm to room temperature and allowed to react for 3 hours. Water was then slowly added to the reaction system to quench the reaction. The mixture was then extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:0-5:1) to afford 13d (4.0 g) as a yellow solid. MS (ESI) m / z: 381.9 [M+H] + .

[0296] Step 4: 3-Bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)-N-(3-methoxy-2,6-dimethylphenyl)pyridin-2-amine (13e)

[0297] Compound 13d (4.0 g, 10.5 mmol), 3-methoxy-2,6-dimethylaniline (1.6 g, 10.5 mmol), cesium carbonate (6.8 g, 21 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.64 g, 1.1 mmol), and bis(dibenzylideneacetone)palladium (0.61 g, 1.1 mmol) were dissolved in 1,4-dioxane. The atmosphere was purged with nitrogen and the mixture was reacted in an oil bath at 100°C for 12 hours. After completion of the reaction, water was added to quench the reaction, followed by extraction with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:0-5:1) to afford 13e (1.7 g) as a yellow solid. MS (ESI) m / z: 453.2 [M+H] + .

[0298] Step 5: 2-amino-4-(((tert-butyldimethylsilyl)oxy)methyl)-1-(3-methoxy-2,6-dimethylphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (13f)

[0299] Malononitrile (0.58 g, 8.8 mmol) was dissolved in ethylene glycol dimethyl ether (5 mL), followed by the addition of sodium tert-butoxide (1.3 g, 13 mmol). The mixture was stirred at room temperature for 30 minutes, followed by the addition of 13e (1.0 g, 2.2 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (89 mg, 0.11 mmol). The atmosphere was then purged with nitrogen, and the mixture was placed in an oil bath at 100°C for 12 hours. After completion of the reaction, water was added to quench the reaction, followed by extraction with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:0-1:1) to afford 13f (0.46 g) as a yellow solid. MS (ESI) m / z: 437.2 [M+H] + .

[0300] Step 6: 2-amino-4-(hydroxymethyl)-1-(3-methoxy-2,6-dimethylphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid methyl ester (13 g)

[0301] Compound 13f (0.22 g, 0.68 mmol) was dissolved in methanol (9 mL), followed by the addition of concentrated hydrochloric acid (1 mL). The reaction mixture was allowed to react at 90°C for 16 hours. After cooling to room temperature, water (10 mL) was added to the reaction solution, followed by extraction with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. The resulting residue was purified by reverse-phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to yield the desired product 13g (90 mg). m / z (ESI): 356.0 [M+H] + .

[0302] Step 7: 2-amino-4-(chloromethyl)-1-(3-methoxy-2,6-dimethylphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid methyl ester (13h)

[0303] At room temperature, 13g (90mg, 0.25mmol) was dissolved in phosphorus oxychloride (3mL) and stirred at 80°C for 2h. After the reaction mixture cooled to room temperature, water (5mL) was added to dilute the mixture, followed by extraction with ethyl acetate (5mL*3). The organic phases were combined and washed sequentially with saturated sodium bicarbonate solution (5mL) and saturated brine (5mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. The resulting residue was purified by normal phase chromatography (ethyl acetate:petroleum ether = 10:1-1:2) to obtain the desired product 13h (51mg) as a white solid. LC-MS: m / z (ESI): 374.8 [M+H] + .

[0304] Step 8: 2-amino-4-(cyanomethyl)-1-(3-methoxy-2,6-dimethylphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid methyl ester (13i)

[0305] Compound 13h (51 mg, 0.14 mmol) was dissolved in acetonitrile (0.5 mL), followed by the addition of trimethylsilyl cyanide (8 mg, 80.25 μmol) and tetrabutylammonium fluoride (1 M, 80.25 μL). The mixture was allowed to react at room temperature for 5 minutes. Water (2 mL) was added to the reaction solution, followed by extraction with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. The resulting residue was purified by normal phase chromatography (ethyl acetate:petroleum ether = 10:1-1:3) to afford the desired product 13i (30 mg) as a white solid. LC-MS: m / z (ESI): 365.4 [M+H] + .

[0306] Step 9: 1-amino-2-(3-methoxy-2,6-dimethylphenyl)-2,6,7,8-tetrahydro-9H-2,3,8-triazabenzo[cd]azulene-9-one (13j)

[0307] Compound 13i (26 mg, 0.071 mmol) was dissolved in methanol (1 mL), followed by the addition of nickel chloride (11 mg, 0.086 mmol) and sodium borohydride (19 mg, 0.50 mmol). The mixture was stirred at room temperature for 30 minutes and then reacted at 80°C for 8 hours. After cooling to room temperature, water (1 mL) was added to the reaction solution, followed by extraction with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate concentrated. The resulting residue was purified by normal phase chromatography (ethyl acetate:petroleum ether = 10:1-1:3) to afford the desired product 13j (6.0 mg) as a white solid. LC-MS: m / z (ESI): 337.3 [M+H] +.

[0308] 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)

[0309] At room temperature, 13j (6.0 mg, 0.018 mmol) was dissolved in anhydrous dichloromethane (1 mL). A dichloromethane solution of boron tribromide (1 mol / L, 0.2 mL) was added and stirred for 30 minutes. The reaction was quenched with methanol (1 mL), and the reaction solution was concentrated. The resulting residue was purified by reverse phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to afford compound 13 (3.3 mg) as a white solid. m / z (ESI): 323.3 [M+H] + .

[0310] 1 H NMR (400MHz, DMSO-d6) 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).

[0311] Example 14: Preparation of 1-amino-2-(3-hydroxy-2,6-dimethylphenyl)-2,8-dihydro-9H-2,3,8-triazabenzo[cd]azulene-9-one (Compound 14)

[0312] Step 1: 3-Bromo-4-chloro-N-(3-methoxy-2,6-dimethylphenyl)pyridin-2-amine (14b)

[0313] The compound 3-bromo-2,4-dichloropyridine (2.3 g, 10 mmol), 3-methoxy-2,6-dimethylaniline (3.0 g, 20 mmol), cesium carbonate (9.8 g, 30 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.12 g, 2.0 mmol) and bis(dibenzylideneacetone)palladium (0.91 g, 1.0 mmol) were dissolved in anhydrous 1,4-dioxane (10 mL), the air was replaced with nitrogen, and then placed in an oil bath at 100 ° C for 8 hours. After the reaction was complete, water was added to quench the reaction, followed by extraction with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. The resulting residue was purified by reverse-phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to afford the target compound 14b (836 mg) as a white solid. m / z: 341.0, 343.0 [M+H] + .

[0314] Step 2: 2-Amino-4-chloro-1-(3-methoxy-2,6-dimethylphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (14c)

[0315] Malononitrile (0.66 g, 10 mmol) was dissolved in ethylene glycol dimethyl ether (10 mL), followed by the addition of sodium tert-butoxide (1.4 g, 15 mmol). The mixture was stirred at room temperature for 30 minutes. 14b (0.84 g, 2.5 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (81 mg, 0.1 mmol) were then added. The atmosphere was purged with nitrogen, and the mixture was allowed to react in a 100°C oil bath for 12 hours. After completion of the reaction, the mixture was filtered, the filtrate was concentrated, and the resulting residue was purified by reverse-phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to afford the target compound 14c (589 mg) as a white solid. m / z: 327.0 [M+H] + .

[0316] Step 3: (E)-2-amino-4-(2-ethoxyvinyl)-1-(3-methoxy-2,6-dimethylphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (14d)

[0317] Compound 14c (0.33 g, 1 mmol), (E)-1-ethoxyvinyl-2-boronic acid pinacol ester (0.60 g, 3 mmol), palladium acetate (22 mg, 0.1 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0.11 g, 0.25 mmol), and potassium carbonate (0.50 g, 3 mmol) were dissolved in a mixture of acetonitrile and water (6 mL / 4 mL). The atmosphere was purged with nitrogen and the mixture was allowed to react in a 70°C oil bath for 8 hours. After completion of the reaction, the mixture was filtered, the filtrate was concentrated, and the resulting residue was purified by reverse phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to afford the target compound 14d (0.15 g) as a white solid. m / z: 363.3 [M+H] + .

[0318] Step 4: 1-amino-2-(3-methoxy-2,6-dimethylphenyl)-2,8-dihydro-9H-2,3,8-triazabenzo[cd]azulene-9-one (14e)

[0319] At room temperature, 14d (0.13 g, 0.4 mmol) was dissolved in a mixture of ethanol (3 mL) and water (2 mL). (Dimethylphosphonic acid) platinum(II) hydrogen complex (10 mg, 0.02 mmol) was added, and the mixture was reacted at 110°C for 16 hours. After cooling to room temperature, the insoluble matter was removed by filtration, and the filtrate was dried by rotary evaporation. The resulting residue was purified by reverse-phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to obtain product 14e (72 mg). m / z (ESI): 335.1 [M+H] + .

[0320] Step 5: 1-amino-2-(3-hydroxy-2,6-dimethylphenyl)-2,8-dihydro-9H-2,3,8-triazabenzo[cd]azulene-9-one (14)

[0321] At room temperature, 14e (20 mg, 0.06 mmol) was dissolved in anhydrous dichloromethane (1 mL). A dichloromethane solution of boron tribromide (1 mol / L, 0.5 mL) was added and stirred for 10 minutes. The reaction was quenched with methanol (1 mL), and the reaction solution was concentrated. The resulting residue was purified by reverse phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to afford solid compound 14 (9.6 mg). m / z (ESI): 322.3 [M+H] + .

[0322] Example 15: Preparation of 1-amino-2-(3-hydroxy-2,6-dimethylphenyl)-2,8-dihydro-9H-2,3,5,8-tetraazabenzo[cd]azulene-9-one (Compound 15)

[0323] Step 1: 6-amino-4-chloro-7-(3-methoxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (15a)

[0324] Malononitrile (0.33 g, 5.0 mmol) was dissolved in anhydrous ethylene glycol dimethyl ether (4 mL), and sodium tert-butoxide (0.75 g, 7.5 mmol) was added. After stirring at room temperature for 30 minutes, 1c (0.50 g, 1.2 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (40 mg, 50 μmol) were added. The atmosphere was replaced with nitrogen three times, and the reaction was continued at 90°C under nitrogen protection for 3 hours. After the reaction was cooled to room temperature, the insoluble matter was removed by filtration, and the filtrate was dried by rotary evaporation. The resulting residue was purified by reverse phase chromatography (C18, 0.05% ammonia water:acetonitrile = 20:1 to 1:20) to obtain compound 15a (0.29 g). m / z (ESI): 328.1 [M+H] + .

[0325] Step 2: (E)-6-amino-4-(2-ethoxyvinyl)-7-(3-methoxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (15c)

[0326] At room temperature, compound 15a (0.20 g, 0.6 mmol) was dissolved in a mixture of 1,4-dioxane (1.5 mL) and water (0.5 mL). [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (25 mg, 31 μmol) and potassium carbonate (0.17 g, 1.2 mmol) were added. The atmosphere was purged with nitrogen three times. (E)-1-ethoxyethylene-2-boronic acid pinacol ester 15b (0.24 g, 1.2 mmol) was then added. The mixture was then reacted at 80°C for 8 hours. After cooling to room temperature, the insoluble material was removed by filtration, and the filtrate was dried by rotary evaporation. The resulting residue was purified by reverse phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to afford product 15c (86 mg). m / z (ESI): 364.2 [M+H] + .

[0327] Step 3: 1-amino-2-(3-methoxy-2,6-dimethylphenyl)-2,8-dihydro-9H-2,3,5,8-tetraazabenzo[cd]azulene-9-one (15d)

[0328] At room temperature, 15c (40 mg, 0.1 mmol) was dissolved in a mixture of ethanol (3 mL) and water (2 mL). (Dimethylphosphonic acid) platinum(II) hydrogen complex (10 mg, 0.02 mmol) was added, and the mixture was reacted at 110°C for 8 hours. After cooling to room temperature, the insoluble matter was removed by filtration, and the filtrate was dried by rotary evaporation. The resulting residue was purified by reverse-phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to obtain product 15d (20 mg). m / z (ESI): 336.2 [M+H] + .

[0329] Step 4: 1-amino-2-(3-hydroxy-2,6-dimethylphenyl)-2,8-dihydro-9H-2,3,5,8-tetraazabenzo[cd]azulene-9-one (Compound 15)

[0330] At room temperature, 15d (10 mg, 30 μmol) was dissolved in dichloromethane (2 mL). A solution of boron tribromide (1 M / L, 0.5 mL) in dichloromethane was then added and stirred for 30 minutes. The reaction mixture was quenched with methanol (1 mL), and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by reverse-phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to afford the desired product 15 (5.0 mg) as a solid.

[0331] m / z(ESI):322.2[M+H] + .

[0332] 1 H NMR (400MHz, DMSO-d6) δ9.60 (s, 1H), 8.72 (d, J = 7.4Hz, 1H), 8.03 (s, 1H), 7.11-7.03 (m, 1H), 6.98-6.8 9(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).

[0333] Example 16: Preparation of 1-amino-2-(3-hydroxy-2,6-dimethylphenyl)-2,6,7,8-tetrahydro-9H-2,3,5,8-tetraazabenzo[cd]azulene-9-one (Compound 16)

[0334] Step 1: 1-amino-2-(3-methoxy-2,6-dimethylphenyl)-2,6,7,8-tetrahydro-9H-2,3,5,8-tetraazabenzo[cd]azulene-9-one (16a)

[0335] At room temperature, 15d (10 mg) was dissolved in ethanol (10 mL). Palladium / carbon (10 mg, 10% Pd, approximately 55% water content) was added, and the air was replaced with hydrogen three times. The mixture was then reacted at room temperature under hydrogen for 4 hours. The reaction solution was filtered, the filtrate was dried, and the resulting residue was purified by reverse phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to obtain compound 16a (9.0 mg). m / z (ESI): 338.2 [M+H] + .

[0336] Step 2: 1-amino-2-(3-hydroxy-2,6-dimethylphenyl)-2,6,7,8-tetrahydro-9H-2,3,5,8-tetraazabenzo[cd]azulene-9-one (Compound 16)

[0337] At room temperature, 16a (9.0 mg, 30 μmol) was dissolved in dichloromethane (2 mL). A dichloromethane solution of boron tribromide (1 mol / L, 0.5 mL) was then added and stirred for 30 minutes. The reaction mixture was quenched with methanol (1 mL), and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by reverse phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to afford the desired product 16 (7.1 mg) as a white solid. m / z (ESI): 324.2 [M+H] + .

[0338] 1 H NMR (400MHz, DMSO-d6) 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).

[0339] Example 17: Preparation of 1-amino-2-(3-hydroxy-2,6-dimethylphenyl)-4-methyl-2,8-dihydro-9H-2,3,5,8-tetraazabenzo[cd]azulene-9-one (Compound 17)

[0340] Compound 17 was prepared by a method similar to Example 15, replacing compound 1c with compound 10b.

[0341] m / z(ESI):336.2[M+H] + .

[0342] 1H NMR (400MHz, DMSO-d6) 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).

[0343] Example 18: Preparation of 1-amino-2-(3-hydroxy-2,6-dimethylphenyl)-4-methyl-2,6,7,8-tetrahydro-9H-2,3,5,8-tetraazabenzo[cd]azulene-9-one (Compound 18)

[0344] Compound 18 was prepared by a method similar to that in step 1 of Example 16, with compound 17 replacing compound 15d.

[0345] m / z(ESI):338.3[M+H] + .

[0346] 1 H NMR(400MHz,DMSO-d6)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).

[0347] Example 19: Preparation of 1-amino-6-chloro-2-(3-hydroxy-2,6-dimethylphenyl)-4-methyl-2,8-dihydro-9H-2,3,5,8-tetraazabenzo[cd]azulene-9-one (Compound 19)

[0348] Step 1: (E)-6-amino-4-(2-ethoxyvinyl)-7-(3-methoxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (19a)

[0349] At room temperature, compound 10c (0.26 g, 0.75 mmol) and (E)-1-ethoxyvinyl-2-boronic acid pinacol ester 15b (0.30 g, 1.5 mmol) were dissolved in a mixture of 1,4-dioxane (1.5 mL) and water (0.5 mL). [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (30 mg, 50 μmol) and potassium carbonate (0.21 g, 1.5 mmol) were added. The atmosphere was purged with nitrogen three times, and the mixture was allowed to react at 80°C for 4 hours. After cooling to room temperature, the insoluble material was removed by filtration, and the filtrate was concentrated. The resulting residue was purified by reverse phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to afford product 19a (0.18 g, 62% yield). m / z (ESI): 378.2 [M+H] + .

[0350] Step 2: 1-amino-2-(3-methoxy-2,6-dimethylphenyl)-4-methyl-2,8-dihydro-9H-2,3,5,8-tetraazabenzo[cd]azulene-9-one (19b)

[0351] At room temperature, 19a (0.18 g, 0.47 mmol) was dissolved in a mixture of ethanol (4.5 mL) and water (3 mL). (Dimethylphosphonic acid) platinum(II) hydrogen complex (34 mg, 80 μmol) was added, and the mixture was reacted at 110°C for 8 hours. After cooling to room temperature, the insoluble matter was removed by filtration, and the filtrate was concentrated. The resulting residue was purified by reverse-phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to obtain product 19b (30 mg, 19% yield). m / z (ESI): 350.2 [M+H] + .

[0352] Step 3: 1-Amino-6-chloro-2-(3-methoxy-2,6-dimethylphenyl)-4-methyl-2,8-dihydro-9H-2,3,5,8-tetraazabenzo[cd]azulene-9-one (19c)

[0353] At room temperature, compound 19b (35 mg, 0.10 mmol) was dissolved in anhydrous acetonitrile (2 mL), and N-chlorosuccinimide (13 mg, 0.10 mmol) was added. The reaction mixture was heated to 70°C for 6 hours. After cooling to room temperature, the solvent was removed by distillation under reduced pressure. The resulting residue was purified by reverse phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to obtain solid compound 19c (12 mg, 31% yield). m / z (ESI): 384.1 [M+H] + .

[0354] Step 4: 1-Amino-6-chloro-2-(3-hydroxy-2,6-dimethylphenyl)-4-methyl-2,8-dihydro-9H-2,3,5,8-tetraazabenzo[cd]azulene-9-one (19)

[0355] At room temperature, 19c (3.0 mg, 7.8 μmol) was dissolved in anhydrous dichloromethane (2 mL). A dichloromethane solution of boron tribromide (1 mol / L, 0.5 mL) was added and the reaction continued at this temperature for 30 minutes. The reaction was quenched with methanol (1 mL), and the reaction solution was concentrated. The resulting residue was purified by reverse phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to afford solid compound 19 (2.7 mg, 93% yield). m / z (ESI): 370.1 [M+H] + .

[0356] 1 H NMR (400MHz, DMSO-d6) 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).

[0357] Example 20: Preparation of 1-amino-2-(3-hydroxy-2,6-dimethylphenyl)-4,6-dimethyl-2,8-dihydro-9H-2,3,5,8-tetraazabenzo[cd]azulene-9-one (Compound 20)

[0358] Step 1: 1-amino-2-(3-methoxy-2,6-dimethylphenyl)-4,6-dimethyl-2,8-dihydro-9H-2,3,5,8-tetraazabenzo[cd]azulene-9-one (20a)

[0359] At room temperature, compound 19c (5.0 mg, 13 μmol) and methylboronic acid (4.7 mg, 1.5 mmol) were dissolved in a mixture of 1,4-dioxane (2 mL) and water (0.2 mL). Palladium acetate (0.43 mg, 2.6 μmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (2.1 mg, 5.2 μmol), and potassium phosphate (11 mg, 52 μmol) were added. The atmosphere was purged with nitrogen three times, and the mixture was allowed to react at 80°C for 8 hours. After cooling to room temperature, the insoluble material was removed by filtration, and the filtrate was dried by rotary evacuation. The resulting residue was purified by reverse-phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to afford product 20a (2.1 mg, 44% yield). m / z (ESI): 364.2 [M+H] + .

[0360] Step 2: 1-amino-2-(3-hydroxy-2,6-dimethylphenyl)-4,6-dimethyl-2,8-dihydro-9H-2,3,5,8-tetraazabenzo[cd]azulene-9-one (20)

[0361] At room temperature, 20a (2.1 mg, 5.8 μmol) was dissolved in anhydrous dichloromethane (1 mL). A dichloromethane solution of boron tribromide (1 mol / L, 0.5 mL) was added and the reaction continued for 30 minutes. The reaction was quenched with methanol (1 mL), and the reaction solution was concentrated. The resulting residue was purified by reverse phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to obtain solid compound 20 (1.1 mg, 54% yield). m / z (ESI): 350.2 [M+H] + .

[0362] 1 H NMR (400MHz, DMSO-d6) δ9.58(s,1H),8.53(d,J=8.0Hz,1H),7.06(d,J=8.0Hz,1H),6.92(d,J=8.0 Hz,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).

[0363] Example 21: Preparation of 1-amino-2-(3-hydroxy-2,6-dimethylphenyl)-4-methyl-6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2,8-dihydro-9H-2,3,5,8-tetraazabenzo[cd]azulene-9-one (Compound 21)

[0364] A similar method to Example 20 was used to replace the methylboronic acid in step 1 with compound 21a to prepare compound 21.

[0365] m / z(ESI):431.4[M+H] + .

[0366] 1 H NMR (400MHz, DMSO-d6) 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).

[0367] Example 22: Preparation of 1-amino-2-(3-hydroxy-2,6-dimethylphenyl)-7-phenyl-2,8-dihydro-9H-2,3,5,8-tetraazabenzo[cd]azulene-9-one (Compound 22)

[0368] Step 1: 6-amino-4-chloro-7-(3-methoxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (22a)

[0369] Compound 12a (0.33 g, 1.0 mmol) was dissolved in concentrated sulfuric acid (3 mL) at room temperature and reacted at 60°C for 1 hour. After the reaction mixture was cooled to room temperature, ice water was added to quench the reaction. The pH was then adjusted to neutral with ammonia (25% ammonia in water). The mixture was extracted three times with ethyl acetate (15 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to obtain product 22a (0.31 g, 88% yield). m / z (ESI): 346.2 [M+H] + .

[0370] Step 2: 6-amino-7-(3-methoxy-2,6-dimethylphenyl)-4-(phenylethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (22c)

[0371] At room temperature, 22a (0.10 g, 0.30 mmol), 22b (0.12 g, 1.2 mmol), cuprous iodide (17 mg, 0.09 mmol), and bistriphenylphosphine palladium dichloride (63 mg, 0.09 mmol) were added to a 100 mL three-necked flask. The atmosphere was replaced with nitrogen three times, and anhydrous tetrahydrofuran (10 mL) was added. The mixture was stirred at room temperature for 5 minutes. Anhydrous triethylamine (0.30 g, 3.0 mmol) was then added, and the reaction mixture was moved to 60°C for 8 hours. The reaction mixture was cooled to room temperature, filtered to remove insoluble matter, and the filtrate was dried. The resulting residue was purified by reverse phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to afford product 22c (85 mg, 71% yield). m / z (ESI): 412.0 [M+H] + .

[0372] Step 3: 1-amino-2-(3-methoxy-2,6-dimethylphenyl)-7-phenyl-2,8-dihydro-9H-2,3,5,8-tetraazabenzo[cd]azulene-9-one (22d)

[0373] At room temperature, 22c (20 mg, 72 μmol) was dissolved in water (1 mL). Concentrated sulfuric acid (1 mL) was slowly added dropwise until completely dissolved. The reaction was then moved to 120°C for 2 hours. After the reaction mixture cooled to room temperature, ice water was added to quench the reaction. The pH was then adjusted to neutral with ammonia (25% ammonia in water). The mixture was extracted three times with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse-phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to afford 22d (6.0 mg, 30% yield). m / z (ESI): 412.0 [M+H] + .

[0374] Step 4: 1-amino-2-(3-hydroxy-2,6-dimethylphenyl)-7-phenyl-2,8-dihydro-9H-2,3,5,8-tetraazabenzo[cd]azulene-9-one (22)

[0375] 22d (6 mg, 15 μmol) was dissolved in anhydrous dichloromethane (5 mL), and boron tribromide (1 mL, 1 mol / L dichloromethane solution) was slowly added dropwise under ice-cooling. The mixture was then allowed to react at room temperature for 30 minutes, quenched with methanol (5 mL), and the solvent was removed by distillation under reduced pressure. The pH was adjusted to neutral with ammonia (25% ammonia in water) and purified by reverse-phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to obtain compound 22 (5.8 mg, 99% yield). m / z (ESI): 398.0 [M+H] + .

[0376] 1 H NMR (400MHz, DMSO-d6) 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).

[0377] Example 23: Preparation of 1-amino-2-(3-hydroxy-2,6-dimethylphenyl)-7-(1-methyl-1H-pyrazol-4-yl)-2,8-dihydro-9H-2,3,5,8-tetraazabenzo[cd]azulene-9-one (Compound 23)

[0378] Compound 23 was synthesized by a method similar to Example 22, using N-methyl-4-ethynylpyrazole 23b instead of 22b.

[0379] m / z(ESI):402.2[M+H] + .

[0380] 1 H NMR(400MHz,DMSO-d6)δ9.62(s,1H),8.27(s,1H),8.14(brs,1H),8.09(s,1H),7.89(s,1H),7.08(d,J=8.4H z,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).

[0381] Example 24: Preparation of 1-amino-2-(3-hydroxy-2,6-dimethylphenyl)-7-(pyridin-4-yl)-2,8-dihydro-9H-2,3,5,8-tetraazabenzo[cd]azulene-9-one (Compound 24)

[0382] Step 1: 6-amino-7-(3-methoxy-2,6-dimethylphenyl)-4-(pyridin-4-ylethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (24b)

[0383] At room temperature, 22a (0.10 g, 0.30 mmol), 24a (0.12 g, 1.2 mmol), cuprous iodide (17 mg, 0.09 mmol), and bistriphenylphosphine palladium dichloride (63 mg, 0.09 mmol) were added to a 100 mL three-necked flask. The atmosphere was replaced with nitrogen three times, and then anhydrous tetrahydrofuran (10 mL) was added. The mixture was stirred at room temperature for 5 minutes, and then anhydrous triethylamine (0.30 g, 3.0 mmol) was added. The reaction mixture was then heated to 62°C for 8 hours. The reaction mixture was cooled to room temperature, filtered to remove insoluble matter, and the filtrate was dried. The resulting residue was purified by reverse phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to obtain product 24b (80 mg, 67% yield). m / z (ESI): 412.0 [M+H] + .

[0384] 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)

[0385] 24b (80 mg, 0.2 mmol) was dissolved in methanol (10 mL) at room temperature, followed by the addition of sodium methoxide (160 mg, 3.0 mmol). The reaction was moved to 82°C and refluxed for 30 minutes. After the reaction mixture cooled to room temperature, the solvent was removed by distillation under reduced pressure. The resulting residue was adjusted to a neutral pH with saturated ammonium chloride solution and extracted three times with ethyl acetate (15 mL). The organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure. The resulting crude product 24c was used directly in the next step.

[0386] 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)

[0387] 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. The reaction was then moved to 120°C for 30 minutes. After the reaction solution cooled to room temperature, ice water was added to quench the reaction. The pH was then adjusted to neutral with ammonia (25% ammonia in water). The product was extracted three times with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse-phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to afford 24d (15 mg, 36% yield). m / z (ESI): 412.0 [M+H] + .

[0388] Step 4: 1-amino-2-(3-hydroxy-2,6-dimethylphenyl)-7-(pyridin-4-yl)-2,8-dihydro-9H-2,3,5,8-tetraazabenzo[cd]azulene-9-one (24)

[0389] Under ice-cooling conditions, 24d (15 mg, 36 μmol) was dissolved in anhydrous dichloromethane (5 mL), and boron tribromide (1 mL, 1 mol / L dichloromethane solution) was slowly added dropwise. The reaction was allowed to react at room temperature for 30 minutes, quenched with methanol (5 mL), and the solvent was removed by distillation under reduced pressure. The pH was adjusted to neutral with ammonia (25% ammonia in water) and purified by reverse-phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to obtain compound 24 (2.2 mg, 15% yield). m / z (ESI): 399.2 [M+H] + .

[0390] 1 H NMR(400MHz,DMSO-d6)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).

[0391] Example 25: Preparation of 1-amino-2-(3-hydroxy-2,6-dimethylphenyl)-7-(pyridin-3-yl)-2,8-dihydro-9H-2,3,5,8-tetraazabenzo[cd]azulene-9-one (Compound 25)

[0392] Compound 25 was prepared by a method similar to Example 24, using 3-ethynylpyridine 25a instead of compound 24a.

[0393] m / z(ESI):399.2[M+H] + .

[0394] 1H NMR(400MHz, DMSO-d6)δ9.61(s,1H),8.78-8.70(m,2H),8.60(dd,J=4.8,1.6Hz,1H),7.44(dd,J=7.8,5.0Hz,1 H),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).

[0395] Example 26: Preparation of 1-amino-2-(3-hydroxy-2,6-dimethylphenyl)-4,7-dimethyl-2,8-dihydro-9H-2,3,5,8-tetraazabenzo[cd]azulene-9-one (Compound 26)

[0396] Step 1: 6-amino-4-chloro-7-(3-methoxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (26a)

[0397] Compound 10c (0.34 g, 1.0 mmol) was dissolved in concentrated sulfuric acid (5 mL) at room temperature and reacted at 60°C for 1 hour. After cooling to room temperature, the reaction was quenched by adding ice water. The pH was then adjusted to neutral with aqueous ammonia (25% ammonia in water). Extraction was performed three times with ethyl acetate (15 mL). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse-phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to afford product 26a (0.31 g, 86% yield).

[0398] m / z(ESI):360.2[M+H] + .

[0399] Step 2: 6-amino-7-(3-methoxy-2,6-dimethylphenyl)-2-methyl-4-(3-(trimethylsilyl)prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (26c)

[0400] At room temperature, 26a (60 mg, 0.17 mmol), 26b (47 mg, 0.33 mmol), cuprous iodide (3.2 mg, 17 μmol), and bistriphenylphosphine palladium dichloride (12 mg, 17 μmol) were added to a 100 mL three-necked flask. The atmosphere was replaced with nitrogen three times, and then anhydrous tetrahydrofuran (10 mL) was added. The mixture was stirred at room temperature for 5 minutes, followed by the addition of anhydrous triethylamine (0.17 g, 1.7 mmol). The reaction mixture was then heated to 60°C for 8 hours. The reaction mixture was cooled to room temperature, filtered to remove insoluble matter, and the filtrate was dried by rotary evaporation. The resulting residue was purified by reverse-phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to afford product 26c (40 mg, 67% yield).

[0401] m / z(ESI):436.2[M+H] + .

[0402] 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)

[0403] At room temperature, compound 26c (80 mg, 0.18 mmol) was dissolved in water (3 mL). Concentrated sulfuric acid (3 mL) was slowly added dropwise until completely dissolved, and the reaction mixture was moved to 120°C for 2 hours. After the reaction mixture cooled to room temperature, ice water was added to quench the reaction. The pH was then adjusted to neutral with ammonia (25% ammonia in water). The mixture was extracted three times with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse-phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to afford 26d (17 mg, 25% yield). m / z (ESI): 364.2 [M+H] + .

[0404] Step 4: 1-amino-2-(3-hydroxy-2,6-dimethylphenyl)-4,7-dimethyl-2,8-dihydro-9H-2,3,5,8-tetraazabenzo[cd]azulene-9-one (26)

[0405] Under ice-cooling conditions, 26d (17 mg, 47 μmol) was dissolved in anhydrous dichloromethane (5 mL), and boron tribromide (1 mL, 1 mol / L dichloromethane solution) was slowly added dropwise. The reaction mixture was then allowed to warm to room temperature for 2 hours, quenched with methanol (10 mL), and the solvent removed by distillation under reduced pressure. The pH was adjusted to neutral with ammonia (25% ammonia in water) and purified by reverse-phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to afford compound 26 (1 mg, 7% yield). m / z (ESI): 350.2 [M+H] + .

[0406] 1 H NMR(400MHz,DMSO-d6)δ9.64(s,1H),7.06(d,J=8.0Hz,1H),6.92(d,J=8.0Hz,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).

[0407] Example 28: Preparation of 6-amino-7-(3-hydroxy-2,6-dimethylphenyl)-4-phenyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (Compound 28)

[0408] Step 1: 6-amino-7-(3-methoxy-2,6-dimethylphenyl)-4-phenyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (28b)

[0409] At room temperature, 12a (40 mg, 0.12 mmol), 28a (45 mg, 0.37 mmol), bis(dibenzylideneacetone)palladium (5.6 mg, 6.1 μmol), 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 / 0.2 mL). The atmosphere was replaced with nitrogen three times. The reaction mixture was then moved to 100°C for 4 hours. After cooling to room temperature, the insoluble material was removed by filtration, and the filtrate was dried by rotary evaporation. The resulting residue was purified by reverse phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to afford product 28b (37 mg, 82% yield).

[0410] m / z(ESI):370.2[M+H] + .

[0411] Step 2: 6-amino-7-(3-methoxy-2,6-dimethylphenyl)-4-phenyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (28c)

[0412] 28b (37 mg, 0.10 mmol) was dissolved in concentrated sulfuric acid (8 mL) at room temperature and then heated to 60°C for 1 hour. After the reaction solution was cooled to room temperature, ice water was added and the pH was adjusted to neutral with ammonia (25% ammonia in water). The solvent was removed by distillation under reduced pressure. The crude product was purified by reverse phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to afford 28c (30 mg, 77% yield). m / z (ESI): 388.2 [M+H] + .

[0413] Step 3: 6-amino-7-(3-hydroxy-2,6-dimethylphenyl)-4-phenyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (28)

[0414] At room temperature, 28c (30 mg, 77 μmol) was dissolved in anhydrous dichloromethane (5 mL). A dichloromethane solution of boron tribromide (1 mol / L, 5 mL) was added and stirred for 30 minutes. The reaction was quenched with methanol (10 mL), and the reaction solution was concentrated. The resulting residue was purified by reverse phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to afford solid compound 28 (25 mg, 54% yield). m / z (ESI): 374.2 [M+H] + .

[0415] 1 H NMR(400MHz,DMSO-d6)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).

[0416] Example 29: Preparation of 8-amino-7-(5-methyl-1H-indazol-4-yl)-7H-imidazo[1,2-c]pyrrolo[3,2-e]pyrimidine-9-carboxamide (Compound 29)

[0417] Step 1: 4-Bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (29b)

[0418] 4-Bromo-5-methyl-1H-indazole (4.5 g, 21 mmol) and 3,4-dihydro-2H-pyran (3.6 g, 42 mmol) were dissolved in anhydrous dichloromethane at room temperature. p-Toluenesulfonic acid monohydrate (0.37 g, 2.1 mmol) was then added and allowed to react at this temperature for 3 hours. The reaction was quenched with saturated aqueous ammonium chloride (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous Na2SO4, filtered, and the filtrate concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1 to 10:1) to afford the desired product 29b (11.2 g, 87% yield). m / z (ESI): 295.1 [M+H] + .

[0419] Step 2: 5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine (29c)

[0420] 29b (6.0 g, 20 mmol) was dissolved in a 0.4 M ammonia solution in 1,4-dioxane (60 mL). (R)-(-)-1-[(S)-2-(dicyclohexylphosphino)ferrocene]ethyldi-tert-butylphosphine (0.11 g, 0.2 mmol), bis(tri(2-methylphenyl)phosphine)palladium (0.15 g, 0.2 mmol), and sodium tert-butoxide (5.8 g, 60 mmol) were added. The reaction was heated to 100°C for 16 hours. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous Na2SO4, filtered, and the filtrate concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 2:1) to afford the desired product 29c (4.4 g, 93% yield). m / z(ESI):232.2[M+H] + .

[0421] Step 3: N-(6-chloro-5-iodopyrimidin-4-yl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine (29d)

[0422] 4,6-Dichloro-5-iodopyrimidine (6.8 g, 25 mmol) and 29c (4.4 g, 19 mmol) were dissolved in N,N-dimethylaniline (20 mL). Tris(dibenzylideneacetone)dipalladium (1.3 g, 19 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (0.80 g, 19 mmol), and cesium carbonate (15.6 g, 48 mmol) were added. The reaction mixture was heated to 140°C for 5 hours. After cooling to room temperature, saturated aqueous ammonium chloride (10 mL) was gradually added to the reaction mixture to quench the reaction. The mixture was then extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1 to 5:1) to afford the desired product 29d (0.60 g, 7% yield).

[0423] m / z(ESI):470.2[M+H] + .

[0424] 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)

[0425] Malononitrile (0.13 g, 1.9 mmol) was dissolved in anhydrous ethylene glycol dimethyl ether (4 mL), followed by the addition of sodium tert-butoxide (0.49 g, 5.0 mmol) and the reaction mixture was allowed to react at room temperature for 30 minutes. 29d (0.6 g, 1.3 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.19 g, 0.26 mmol) were then added, and the reaction mixture was heated to 80°C for 1 hour. After the reaction mixture cooled to room temperature, saturated aqueous ammonium chloride (20 mL) was gradually added to quench the reaction mixture, followed by extraction with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous Na2SO4, filtered, and the filtrate concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 to 2:1) to afford the desired product 29e (0.35 g, 62% yield).

[0426] MS (ESI) m / z: 408.2 [M+H] + .

[0427] 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)

[0428] At room temperature, compound 29e (90 mg, 0.22 mmol) was dissolved in N-methylpyrrolidone (3 mL), and aqueous ammonia (0.27 g, 0.22 mmol) was added. The mixture was then heated to 130°C and allowed to react for 16 hours. After cooling to room temperature, water (10 mL) was gradually added to dilute the reaction mixture, followed by extraction with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 to 1:3) to afford the desired product 29f (45 mg, 49% yield). MS (ESI) m / z: 389.2 [M+H] + .

[0429] 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 (29 g)

[0430] At room temperature, compound 29f (40 mg, 0.10 mmol) was dissolved in DMF, and then a 40% aqueous solution of chloroacetaldehyde (20 mg, 0.10 mmol) was added dropwise. The mixture was then heated to 60°C and allowed to react for 1 hour. Saturated sodium bicarbonate solution (10 mL) was slowly added to the reaction system, followed by extraction with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate concentrated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:ethanol = 80:1 to 70:1) to afford the desired product 29g (30 mg, 67% yield). MS (ESI) m / z: 413.2 [M+H] + .

[0431] Step 7: 8-amino-7-(5-methyl-1H-indazol-4-yl)-7H-imidazo[1,2-c]pyrrolo[3,2-e]pyrimidine-9-carbonitrile (29h)

[0432] Compound 29g (50 mg, 0.12 mmol) was dissolved in anhydrous dichloromethane (4 mL) under ice-cooling conditions, and trifluoroacetic acid (69 mg, 0.61 mmol) was added dropwise. The mixture was then warmed to room temperature and reacted for 4 hours. Saturated sodium bicarbonate solution (15 mL) was slowly added to the reaction system, followed by extraction with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate concentrated. The resulting residue was purified by preparative chromatography on a C18 column (0.05% ammonia:acetonitrile = 20:1 to 1:20) to afford the desired product 29h (25 mg, 62% yield). MS (ESI) m / z: 329.2 [M+H] + .

[0433] Step 8: 8-amino-7-(5-methyl-1H-indazol-4-yl)-7H-imidazo[1,2-c]pyrrolo[3,2-e]pyrimidine-9-carboxamide (29)

[0434] Compound 29h (10 mg, 30 μmol) was dissolved in anhydrous acetonitrile (1 mL) under ice-cooling conditions, and concentrated sulfuric acid (1.0 mL) was added dropwise. The mixture was then warmed to room temperature for 2 hours. Saturated sodium bicarbonate solution (10 mL) was slowly added to the reaction system, followed by extraction with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate concentrated. The resulting residue was purified by preparative chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to afford the desired product 29 (1.5 mg, 13% yield). MS (ESI) m / z: 347.2 [M+H] + .

[0435] 1 H NMR (400MHz, CDCl3-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).

[0436] Example 30: Preparation of 8-amino-7-(4-fluoro-3-hydroxy-2,6-dimethylphenyl)-5-methyl-7H-imidazo[1,2-c]pyrrolo[3,2-e]pyrimidine-9-carboxamide (Compound 30)

[0437] Step 1: 2,6-Dibromo-4-fluoro-3-methoxyaniline (30b)

[0438] At room temperature, 4-fluoro-3-methoxyaniline 30a (4 g, 28 mmol) was dissolved in acetic acid, and bromine (11 g, 71 mmol) was added dropwise. The reaction was allowed to react at room temperature for 2 hours. Saturated sodium bicarbonate solution (30 mL) was slowly added to the reaction system, and then extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 70:1 to 60:1) to obtain the desired product 30b (6.8 g, 57% yield). MS (ESI) m / z: 299.9 [M+H] + .

[0439] Step 2: 2,6-Dimethyl-4-fluoro-3-methoxyaniline (30c)

[0440] At room temperature, 30b (4.0 g, 13 mmol) was dissolved in 1,4-dioxane / water (40 mL / 4 mL). Methylboronic acid (4.0 g, 70 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.98 g, 1.3 mmol), and potassium carbonate (11 g, 80 mmol) were then added. The atmosphere was purged with nitrogen three times, and the mixture was reacted at 100°C for 6 hours. Saturated ammonium chloride solution (20 mL) was slowly added to the reaction system, followed by extraction with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1 to 10:1) to afford the desired product 30c (1.0 g, 45% yield). MS (ESI) m / z: 170.2 [M+H] + .

[0441] Then, a similar method to Example 10 was used to replace compound 1b with compound 30c to prepare compound 30.

[0442] MS (ESI) m / z: 369.2 [M+H] + .

[0443] 1 H NMR (400MHz, CDCl3-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).

[0444] Example 31: Preparation of 8-amino-3-((dimethylamino)methyl)-7-(3-hydroxy-2,6-dimethylphenyl)-7H-imidazo[1,2-c]pyrrolo[3,2-e]pyrimidine-9-carboxamide (Compound 31)

[0445] Step 1: 4,6-Diamino-7-(3-methoxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (31a)

[0446] Compound 12a (0.11 g, 0.34 mmol) was dissolved in N-methylpyrrolidone (2 mL), and aqueous ammonia (17 mg, 1.01 mmol) was added. The mixture was then reacted at 130°C under sealed conditions for 16 hours. The reaction mixture was cooled to room temperature and concentrated. The resulting residue was purified by reverse-phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to obtain the target compound 31a (60 mg, 58% yield). MS (ESI) m / z: 309.2 [M+H] + .

[0447] 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)

[0448] Compound 31a (60 mg, 0.19 mmol) was dissolved in anhydrous DMF (2 mL), and then 2,6-lutidine (0.13 g, 1.2 mmol), formic acid (0.27 g, 5.8 mmol), 2-bromomalondialdehyde (0.18 g, 1.2 mmol) and The mixture was stirred for 2 hours at 65°C. After the reaction mixture was cooled to room temperature, the reaction solution was directly purified by reverse phase chromatography (C18, 0.05% ammonia water:acetonitrile = 20:1 to 1:20) to obtain the target compound 31b (26 mg, 37% yield). MS (ESI) m / z: 360.2 [M+H] + .

[0449] 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)

[0450] Compound 31b (26 mg, 72 μmol) was dissolved in concentrated sulfuric acid (1 mL) at room temperature and allowed to react for 1 hour. Ice water was added to the reaction flask to quench the reaction, and the pH of the solution was adjusted to alkaline with aqueous ammonia. The mixture was then extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. The resulting residue was purified by reverse-phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to afford the target compound 31c (18 mg, 66% yield). MS (ESI) m / z: 379.2 [M+H] + .

[0451] Step 4: 8-amino-3-((dimethylamino)methyl)-7-(3-methoxy-2,6-dimethylphenyl)-7H-imidazo[1,2-c]pyrrolo[3,2-e]pyrimidine-9-carboxamide (31d)

[0452] Compound 31c (18 mg, 48 μmol) and dimethylamine (4.3 mg, 95 μmol) were dissolved in anhydrous tetrahydrofuran, followed by the addition of tetraisopropyl titanate (27 mg, 95 μmol). Stirring continued at room temperature for 30 minutes, followed by the addition of sodium borohydride (3.6 mg, 95 mmol), and continued stirring for 30 minutes. Upon completion of the reaction, methanol (1 mL) was added to the reaction flask and stirred for 30 minutes to quench the reaction. Water was then added, and the insoluble material was removed by filtration. The filtrate was concentrated, and the resulting residue was purified by reverse-phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to afford the target compound 31d (10 mg, 52% yield). MS (ESI) m / z: 407.2 [M+H] + .

[0453] 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)

[0454] 31d (10 mg, 25 μmol) was dissolved in anhydrous dichloromethane (1 mL). Boron tribromide (1 mL, 1 mol / L dichloromethane solution) was slowly added dropwise under ice-cooling. The reaction was allowed to react at room temperature for 30 minutes. The reaction was quenched with methanol (1 mL) and the solvent was removed by distillation under reduced pressure. The pH was adjusted to neutral with ammonia (25% ammonia in water) and purified by reverse-phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to obtain compound 31 (6 mg, 62% yield). m / z (ESI): 394.4 [M+H] + .

[0455] 1H NMR(400MHz,DMSO-d6)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).

[0456] Example 32: Preparation of 8-amino-7-(3-hydroxy-2,6-dimethylphenyl)-3-(methoxymethyl)-7H-imidazo[1,2-c]pyrrolo[3,2-e]pyrimidine-9-carboxamide (Compound 32)

[0457] 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)

[0458] Compound 31c (40 mg, 0.11 mmol) was dissolved in anhydrous tetrahydrofuran at room temperature, followed by the addition of sodium borohydride (8.0 mg, 0.21 mmol). The reaction was allowed to 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 reverse-phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to afford the target compound 32a (35 mg, 87% yield). m / z (ESI): 381.2 [M+H] + .

[0459] 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)

[0460] At room temperature, compound 32a (27 mg, 71 μmol) was dissolved in anhydrous dichloromethane, and diethylaminosulfur trifluoride was added. The mixture was reacted for 5 minutes. Anhydrous methanol (1 mL) was then added and the reaction continued for 30 minutes. The reaction solution was concentrated, and the resulting residue was purified by reverse-phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to obtain the target compound 32b (35 mg, 87% yield). m / z (ESI): 395.2 [M+H] + .

[0461] 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)

[0462] At room temperature, compound 32b (12 mg, 30 μmol) was dissolved in anhydrous dichloromethane, and boron tribromide (1 mL, 1 mol / L dichloromethane solution) was slowly added dropwise. The reaction was allowed to react at room temperature for 30 minutes, quenched with methanol (1 mL), and the solvent was removed by distillation under reduced pressure. The pH was adjusted to neutral with ammonia (25% ammonia in water) and purified by reverse phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to obtain compound 32 (7 mg, 60% yield). m / z (ESI): 381.2 [M+H] + .

[0463] 1 H NMR (400MHz, DMSO-d6) 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).

[0464] Example 33: Preparation of 1-amino-2-(3-hydroxy-2,6-dimethylphenyl)-7-(pyridin-2-yl)-2,8-dihydro-9H-2,3,5,8-tetraazabenzo[cd]azulene-9-one (Compound 33)

[0465] Step 1: 6-amino-7-(3-methoxy-2,6-dimethylphenyl)-4-(pyridin-2-ylethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (33b)

[0466] At room temperature, compound 22a (0.20 g, 0.58 mmol), 2-ethynylpyridine 33a (0.12 g, 1.2 mmol), N-methyldicyclohexylamine (0.29 g, 1.5 mmol), and [9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene](2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (17 mg, 58 μmol) were dissolved in anhydrous acetonitrile. The atmosphere was replaced with nitrogen three times, and the reaction mixture was moved to 90°C for 12 hours. After cooling to room temperature, the insoluble material was removed by filtration, and the filtrate was dried by spin drying. The resulting residue was purified by reverse-phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to afford product 33b (42 mg, 18% yield).

[0467] m / z(ESI):413.2[M+H] + .

[0468] 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)

[0469] At room temperature, 33b (20 mg, 48 μmol) was dissolved in toluene (2 mL), followed by the addition of silver trifluoromethanesulfonate (2.5 mg, 9.7 μmol). The reaction was moved to 110°C for 2 hours. After cooling to room temperature, the insoluble material was removed by filtration, and the filtrate was dried by rotary evaporation. The resulting residue was purified by reverse-phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to afford 33c (12 mg, 60% yield).

[0470] m / z(ESI):413.2[M+H] + .

[0471] Step 3: 1-amino-2-(3-hydroxy-2,6-dimethylphenyl)-7-(pyridin-2-yl)-2,8-dihydro-9H-2,3,5,8-tetraazabenzo[cd]azulene-9-one (33)

[0472] 33c (12 mg, 29 μmol) was dissolved in anhydrous dichloromethane (4 mL), and boron tribromide (1 mL, 1 mol / L dichloromethane solution) was slowly added dropwise. The reaction was allowed to react at room temperature for 30 minutes, quenched with methanol (5 mL), and the solvent was removed by distillation under reduced pressure. The pH was adjusted to neutral with ammonia (25% ammonia in water) and purified by reverse phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to obtain compound 33 (5.6 mg, 48% yield). m / z (ESI): 399.3 [M+H] + .

[0473] 1 H NMR(400MHz, DMSO-d6)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).

[0474] Example 34: Preparation of 1-amino-7-(2-((dimethylamino)methyl)phenyl)-2-(3-hydroxy-2,6-dimethylphenyl)-2,8-dihydro-9H-2,3,5,8-tetraazabenzo[cd]azulene-9-one (Compound 34)

[0475] Step 1: 1-(3-ethynylphenyl)-N,N-dimethylmethanamine (34b)

[0476] 3-Ethynylbenzaldehyde 34a (0.50 g, 3.8 mmol) and dimethylamine (2.9 mL, 2 mol / L tetrahydrofuran solution) were dissolved in anhydrous dichloromethane (10 mL). Glacial acetic acid (23 mg, 0.38 mmol) was added and stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (3.3 g, 15 mmol) was then added, and the reaction continued at room temperature for 4 hours. 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 solution and extracted three times with ethyl acetate (20 mL). The organic phases were combined, washed once with saturated brine (30 mL), filtered and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford crude product 34b (0.20 g, 33% yield) as a yellow oil.

[0477] 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)

[0478] 22a (0.16 g, 0.46 mmol) was dissolved in ultra-dry tetrahydrofuran (2.9 mL), followed by the addition of 34b (0.15 g, 0.93 mmol), bistriphenylphosphine palladium dichloride (53 mg, 46 μmol), cuprous iodide (4.4 mg, 23 μmol), and triethylamine (94 mg, 0.93 mmol). The atmosphere was replaced with nitrogen three times, and the reaction mixture was moved to 60°C for 8 hours. After cooling to room temperature, the reaction mixture was added to water (40 mL) and extracted three times with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by normal-phase silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 0:1, then dichloromethane:methanol = 10:1) to afford 34c (0.11 g, 44% yield) as a yellow solid.

[0479] m / z(ESI):469.3[M+H] + .

[0480] 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.

[0481] m / z(ESI):455.3[M+H] + .

[0482] 1 H NMR (400MHz, DMSO-d6) 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).

[0483] Example 35: Preparation of 1-amino-2-(3-hydroxy-2,6-dimethylphenyl)-7-(1-methyl-1H-imidazol-4-yl)-2,8-dihydro-9H-2,3,5,8-tetraazabenzo[cd]azulene-9-one (Compound 35)

[0484] Compound 35 was prepared by a method similar to Example 34, using Compound 35a instead of Compound 34b in Example 34.

[0485] m / z(ESI):402.3[M+H] + ;

[0486] 1 H NMR (400MHz, DMSO-d6) 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).

[0487] Example 36: Preparation of 1-amino-2-(3-hydroxy-2,6-dimethylphenyl)-7-(2-methylphenyl)-2,8-dihydro-9H-2,3,5,8-tetraazabenzo[cd]azulene-9-one (Compound 36)

[0488] Compound 36 was prepared by a method similar to Example 34, using Compound 36a instead of Compound 34b in Example 34.

[0489] m / z(ESI):412.3[M+H] + ;

[0490] 1 H NMR (400MHz, DMSO-d6)9.59(s,1H),8.47(s,1H),8.05(s,1H),7.31-7.23(m,4H),7.08(d,J=8.0 Hz,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).

[0491] Biological activity and related properties test examples

[0492] Test Example 1: PKMYT1 enzyme activity inhibition experiment

[0493] Principle: After incubation with a compound, PKMYT1 phosphorylates its substrate CDK1 in the presence of ATP. ADP generated is quantified using the Promega ADP-Glo ​​assay kit, reflecting enzyme activity.

[0494] Experimental instruments: Labcyte Echo550 pipetting system; Perkin Elmer Envision microplate reader; Eppendorf 5810R centrifuge.

[0495] Experimental Materials:

[0496] Experimental Method: Test compounds were diluted to various concentrations in dimethyl sulfoxide (DMSO) using an Echo pipetting system and transferred to a 384-well plate. The reaction system was diluted three-fold starting from a 1 μM final concentration, to a final DMSO concentration of 1%. PKMYT1 (3 μL / well) was added, and after a 15-minute incubation, the enzyme reaction was initiated by adding 2 μL / well of a reaction mixture consisting of the substrate CDK1 and ATP. The final concentrations of PKMYT1, ATP, and CDK1 were 4.5 ng / μL, 25 μM, and 20 ng / μL, respectively. After a 40-minute reaction, 5 μL / well of ADP-Glo ​​reagent was added and incubated for 40 minutes. Then, 10 μL / well of kinase assay reagent was added, and after a 30-minute incubation, the fluorescence signal was read using an Envision microplate reader.

[0497] Data Analysis:

[0498] Calculate the compound inhibition percentage and use XLfit software to fit the compound IC 50 value.

[0499] The experiment set up a blank group and a DMSO group: the blank group reaction system was 0.2% DMSO and reaction mixture solution, and the compound inhibition rate was considered to be 100% at this time; the DMSO group reaction system was 0.2% DMSO, PKMYT1 (100nM) and reaction mixture solution, and the compound inhibition rate was considered to be 0 at this time.

[0500] Compound inhibition percentage = (100-100*(experimental well-blank well) / (DMSO group-blank well))%

[0501] Among them, experimental wells, blank wells, and DMSO group refer to the fluorescence signals read by the experimental group, blank group, and DMSO group, respectively.

[0502] The biological activity of the compounds of the present application was determined by the above test, and the measured IC 50 See Table 1 for values.

[0503] Table 1 IC of compounds for inhibition of PKMYT1 kinase activity 50 value

[0504] Test Example 2: Compound Inhibition of Tumor Cell Proliferation

[0505] Brief introduction to experimental principle: After incubating the compound with tumor cells for 7 days, the ATP in the living cells is quantified using Promega's CTG kit to reflect the effect of the compound on tumor cell proliferation.

[0506] Experimental instruments: Envision microplate reader from Perkin Elmer; 5810R centrifuge from Eppendorf; automatic cell counter from Countstar.

[0507] Experimental Materials:

[0508] Experimental method: 1000 SKOV3 cells / well or 3000 HCC1569 cells / well were diluted with McCoy's 5A or RPMI Medium 1640 containing 10% FBS and added to 96-well plates (90 μL / well). The cells were cultured in a 37°C, 5% CO2 incubator for 24 hours. The test compound was diluted to different concentrations in dimethyl sulfoxide (DMSO) and added to the 96-well plate. The final concentration of the compound in the reaction system started from 25 μM and was serially diluted 4-fold to a final DMSO concentration of 0.25%. After the compound and cells were incubated for 7 days in a 37°C, 5% CO2 incubator, 50 μL / well of CTG was added to measure the inhibition of tumor cell growth by the compound, and the inhibition rate and half inhibitory concentration (IC50) were calculated. 50 ).

[0509] Data Analysis:

[0510] Calculate the % compound inhibition and use XLfit software to fit the compound IC 50 .

[0511] The experiment set up blank wells and DMSO wells. The blank wells contained 100 μL of RPMI Medium 1640 or McCoy's 5A medium containing 10% FBS, and the inhibition rate of the compound on tumor cell growth at this time was considered to be 100%; the DMSO wells were prepared by adding 0.25% DMSO to the cell wells, and the inhibition rate of the compound on tumor cell growth at this time was considered to be 0.

[0512] Compound inhibition percentage = (100*(DMSO well - experimental well) / (DMSO well - blank well))%

[0513] The inhibition of tumor cell growth by the compounds of the present application was determined by the above test, and the measured IC 50 The values ​​are shown in Table 2 below.

[0514] Table 2 IC values ​​of the compounds in the examples for inhibition of HCC1569 cell growth50

[0515] Each document cited herein, including any cross-referenced patent or patent application and any patent application or patent to which this application claims priority, is hereby incorporated by reference in its entirety unless expressly excluded or otherwise limited. Further, to the extent that any meaning or definition of a term in this document conflicts with any meaning or definition of the same term in a document incorporated by reference, the meaning or definition assigned to that term in this document shall govern.

[0516] Although specific embodiments of the present disclosure have been illustrated and described, those skilled in the art will appreciate that, where feasible, the technical features described in one embodiment may be applied to another embodiment, or combined with the technical features described in another embodiment. Therefore, those skilled in the art will be able to make various changes and modifications to the embodiments of the present disclosure without departing from the spirit and scope of the present disclosure.

Claims

1. 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 to ring B; X is selected from N or CR X ; R X independently selected from hydrogen, halogen, CN, OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, C6-C 12 Aryl, C2-C6 alkenyl, C2-C6 alkynyl or C(=O)H, the OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, C6-C 12 Aryl, C2-C6 alkenyl, C2-C6 alkynyl or C(=O)H is optionally replaced by R a replace; Ring B is selected from C6-C 12 Aryl or 6-10 membered heteroaryl, the C6-C 12 Aryl or 6-10 membered heteroaryl is optionally replaced by R b replace; R 1 Selected from hydrogen, halogen, CN, OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl or C(=O)H, the OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl or C(=O)H is optionally replaced by R a replace; R 2 、R 3 independently selected from hydrogen, halogen, CN, OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 12 Aryl, 5-10 membered heteroaryl, C2-C6 alkenyl, C2-C6 alkynyl or C(=O)H, the OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 12 Aryl, 5-10 membered heteroaryl, C2-C6 alkenyl, C2-C6 alkynyl or C(=O)H is optionally replaced by R a replace; or R 2 、R X The atoms to which it is attached together form a 6-10 membered heterocyclic group, wherein the 6-10 membered heterocyclic group is optionally replaced by R a replace; R 4 Selected from hydrogen, halogen, CN, OH, SH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 12 aryl, 5-10 membered heteroaryl, C2-C6 alkenyl, C2-C6 alkynyl or C(=O)H, said OH, SH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 12 Aryl, 5-10 membered heteroaryl, C2-C6 alkenyl, C2-C6 alkynyl or C(=O)H is optionally replaced by R a replace; R 5 Selected from hydrogen, halogen, CN, OH, SH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 12 aryl, 5-10 membered heteroaryl, C2-C6 alkenyl, C2-C6 alkynyl or C(=O)H, said OH, SH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 12 Aryl, 5-10 membered heteroaryl, C2-C6 alkenyl, C2-C6 alkynyl or C(=O)H is optionally replaced by R a replace; R 6 Selected from O, S, CR 6a R 6b or NR 6a ; R 7 Selected from O, S, CR 7a R 7b or NR 7a ; R 6a 、R 6b 、R 7a 、R 7b independently selected from hydrogen, halogen, CN, OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 12 Aryl or 5-10 membered heteroaryl, the OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 12 Aryl or 5-10 membered heteroaryl is optionally replaced by R a replace; or R 6a 、R 5 The atoms to which it is attached together form a 5-10 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein the 5-10 membered heterocyclic group or the 5-10 membered heteroaryl group is optionally replaced by R a replace; or R 7a 、R 5 The atoms to which it is attached together form a 5-10 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein the 5-10 membered heterocyclic group or the 5-10 membered heteroaryl group is optionally replaced by R a replace; R a 、R b Independently selected from halogen, CN, =O, OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-7 membered heterocyclic group, C6-C 12 Aryl or 5-10 membered heteroaryl, the OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-7 membered heterocyclic group, C6-C 12 Aryl or 5-10 membered heteroaryl is optionally replaced by R c replace; R c is selected from halogen, CN, =O, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclic group, wherein the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclic group is optionally replaced by R d replace; R d Selected from halogen, CN, OH, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclyl.

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein ring A is selected from Alternatively, Ring A is selected from 3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein X is selected from CR X ; or X is selected from CH.

4. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R X is selected from hydrogen, halogen, OH, C1-C6 alkyl or phenyl, wherein the OH, C1-C6 alkyl or phenyl is optionally replaced by R a Replace; or, R X is selected from hydrogen, halogen, OH or C1-C6 alkyl, wherein the OH or C1-C6 alkyl is optionally replaced by R a Replace; or, R X is selected from hydrogen or phenyl.

5. A 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, and the phenyl or 6-9 membered heteroaryl is optionally replaced by R b Replace; or Ring B is selected from phenyl and The phenyl group and All were R b Replace; or Ring B is selected from phenyl, said phenyl being optionally substituted by R b Replace; or Ring B is selected from described Optional R b replace.

6. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R 1 Selected from hydrogen, halogen, CN, OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl or C(=O)H, said OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl or C(=O)H is optionally replaced by R a Replace; or R 1 is selected from hydrogen, halogen, NH2 or C1-C6 alkyl, wherein the NH2 or C1-C6 alkyl is optionally replaced by R a Replace; or R 1 is selected from NH2, wherein the NH2 is optionally replaced by R a replace.

7. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein R 2 、R 3 independently selected from hydrogen, halogen, CN, OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 12 Aryl, 5-10 membered heteroaryl or C(=O)H, said OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 12 Aryl, 5-10 membered heteroaryl or C(=O)H is optionally replaced by R a Replace; or R 2 、R 3 independently selected from hydrogen, halogen, OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-10 membered heterocycloalkyl, the OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-10 membered heterocycloalkyl is optionally replaced by R a Replace; or R 2 、R 3 are independently selected from hydrogen; or R 2 、R X The atoms to which it is attached together form a 6-7 membered heterocyclic group, wherein the 6-7 membered heterocyclic group is optionally replaced by R a Replace; or R 3 is selected from hydrogen, and R 2 、R X The atoms to which it is attached together form a 6-7 membered heterocyclic group, wherein the 6-7 membered heterocyclic group is optionally R a replace.

8. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R 4 Selected from hydrogen, halogen, CN, OH, SH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C9 aryl, 5-10 membered heteroaryl, C2-C6 alkenyl or C2-C6 alkynyl, the OH, SH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C9 aryl, 5-10 membered heteroaryl, C2-C6 alkenyl or C2-C6 alkynyl are optionally replaced by R a Replace; or R 4 Selected from hydrogen, halogen, OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, 5-10 membered heteroaryl or C2-C6 alkynyl, the OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, 5-10 membered heteroaryl or C2-C6 alkynyl is optionally replaced by R a Replace; or R 4 Selected from hydrogen, halogen, OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, phenyl, C2-C6 alkynyl, The OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, phenyl, C2-C6 alkynyl, Optional R a Replace; or R 4 Selected from hydrogen, R a OH substituted by R a substituted NH2, C1-C3 alkyl optionally substituted by halogen, C3-C6 cycloalkyl, phenyl optionally substituted by halogen, C2-C3 alkynyl optionally substituted by C3-C6 cycloalkyl, described Optionally substituted with C1-C3 alkyl; or R 4 is selected from hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl.

9. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein R 5 Selected from hydrogen, halogen, CN, OH, SH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C2-C6 alkenyl or C2-C6 alkynyl, the OH, SH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally replaced by R a Replace; or R 5 Selected from hydrogen, halogen, OH, C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-10 membered heterocycloalkyl, the OH, C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-10 membered heterocycloalkyl is optionally replaced by R a Replace; or R 5 Selected from hydrogen, C1-C6 alkyl or C3-C 10 Cycloalkyl, the C1-C6 alkyl or C3-C 10 The cycloalkyl group is optionally replaced by R a Replacement; or R 5 Selected from hydrogen or C1-C6 alkyl.

10. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein R 6 Selected from O, CR 6a R 6b or NR 6a ;or R 6 Selected from O or NR 6a ;or R 6 Selected from O or NR 6a , where R 6a 、R 5 The atoms to which it is attached together form a 5-6 membered heterocyclic group or a 5-6 membered heteroaryl group, wherein the 5-6 membered heterocyclic group or the 5-6 membered heteroaryl group is optionally replaced by R a replace.

11. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein R 7 Selected from O, CR 7a R 7b or NR 7a ; or R 7 Selected from O or NR 7a .

12. 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 Independently selected from hydrogen, OH, C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-10 membered heterocycloalkyl, the OH, C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-10 membered heterocycloalkyl is optionally replaced by R a Replace; or R 6a 、R 6b 、R 7a 、R 7b Independently selected from C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-10 membered heterocycloalkyl, the C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-10 membered heterocycloalkyl is optionally replaced by R a Replace; or R 6a 、R 5 The atoms to which it is attached together form a 5-8 membered heterocyclic group or a 5-8 membered heteroaryl group, wherein the 5-8 membered heterocyclic group or the 5-8 membered heteroaryl group is optionally replaced by R a Replace; or R 7a 、R 5 The atoms to which it is attached together form a 5-8 membered heterocyclic group or a 5-8 membered heteroaryl group, wherein the 5-8 membered heterocyclic group or the 5-8 membered heteroaryl group is optionally replaced by R a replace.

13. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein R a 、R b Independently selected from halogen, =O, OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-7 membered heterocyclic group or phenyl, the OH, NH2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-7 membered heterocyclic group or phenyl group is optionally replaced by R c Replace; or R a 、R b independently selected from halogen, =O, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl or phenyl, wherein the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl or phenyl is optionally replaced by R c Replace; or R a 、R b independently selected from halogen, =O, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally replaced by R c replace.

14. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein R c is selected from halogen, =O, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclic group, wherein the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclic group is optionally replaced by R d Replace; or R c is selected from OH, NH2 or C1-C6 alkyl, wherein the OH, NH2 or C1-C6 alkyl is optionally replaced by R d replace.

15. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein R d Selected from halogen, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclyl.

16. 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 compound of formula (II) or a pharmaceutically acceptable salt thereof, in, Ring B, X, R 1 、R 2 、R 3 、R 4 As defined in claim 1.

17. 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 compound of formula (III) or a pharmaceutically acceptable salt thereof, in, Ring B, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 As defined in claim 1.

18. 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 compound of formula (IV) or a pharmaceutically acceptable salt thereof, in, Ring B, X, R 1 、R 2 、R 3 、R 5 、R 7 As defined in claim 1.

19. 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 pharmaceutically acceptable salts thereof, 20. A pharmaceutical composition comprising the compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

21. A method for treating a disease mediated by PKMYT1 in a mammal, wherein: The method comprises administering a therapeutically effective amount of the compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 20 to a mammal, preferably a human, in need of such treatment. Preferably, the disease mediated by PKMYT1 is a tumor, such as breast cancer.

22. Use of the compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 20, in the preparation of a medicament for preventing or treating a PKMYT1-mediated disease, preferably, the PKMYT1-mediated disease is a tumor, such as breast cancer.

23. Use of the compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 20, in preventing or treating a PKMYT1-mediated disease, preferably, the PKMYT1-mediated disease is a tumor, such as breast cancer.

24. The compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 20 for use in preventing or treating a PKMYT1-mediated disease, preferably, the PKMYT1-mediated disease is a tumor, such as breast cancer.

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