Membrane associated tyrosine and threonine kinase inhibitors and uses thereof

Abstract

The present disclosure relates to a PKMYT1 inhibitor compound represented by formula (I) or a pharmaceutically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition containing the compound or the pharmaceutically acceptable salt thereof, and a use thereof in prevention or treatment of PKMYT1 related diseases. X1 to X5, R1 to R4, R7 and R8 in the formula (I) are as defined in the specification. # imgabs0 #

Description

Membrane-associated tyrosine and threonine kinase inhibitors and their applications

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of and priority to the following four Chinese invention patent applications, the entire contents of which are hereby incorporated by reference in their entirety:

[0003] Patent application No. 202211163314.4 filed with the State Intellectual Property Office of China on September 23, 2022;

[0004] Patent application No. 202310505509.0 filed with the State Intellectual Property Office of China on May 6, 2023;

[0005] Patent application No. 202310799876.6 filed with the State Intellectual Property Office of China on June 30, 2023; and

[0006] Patent application No. 202311040531.9 submitted to the State Intellectual Property Office of China on August 17, 2023. Technical Field

[0007] The present application belongs to the field of medicine and relates to a cyclized compound or a pharmaceutically acceptable salt thereof as a PKMYT1 inhibitor, a preparation method thereof, a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof, and its use in preventing or treating diseases related to PKMYT1. Background Art

[0008] 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, thereby maintaining the survival of tumor cells.

[0009] 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.

[0010] 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.

[0011] Summary of the Invention

[0012] In one aspect, the present application relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0013] in,

[0014] X 1 Select N or CR 9 ;

[0015] Indicates a single bond or a double bond;

[0016] X 2 Selected from CR 5 R 6 NR 5 , CR 5 and N;

[0017] X 3 Selected from CR 5 'R 6 '、NR 5 '、CR 5 ' and N;

[0018] X 4 、X 5 Independently selected from (C(R 10 )2) n NR 10 and O;

[0019] R 1 、R 3independently selected from hydrogen, hydroxy, amino, nitro, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C9 cycloalkyl-O-, 4-9 membered heterocyclyl-O-, C1-C6 alkyl-C(O)O-, C3-C9 cycloalkyl-C(O)O-, 4-9 membered heterocyclyl-C(O)O-, P(O)(OH)2O- and NH2C(O)O-, said C1-C6 alkyl, C1-C6 alkoxy, C3-C9 cycloalkyl-O-, 4-9 membered heterocyclyl-O-, C1-C6 alkyl-C(O)O-, C3-C9 cycloalkyl-C(O)O-, 4-9 membered heterocyclyl-C(O)O-, P(O)(OH)2O- and NH2C(O)O-, said C1-C6 alkyl, C1-C6 alkoxy, C3-C9 cycloalkyl-O-, 4-9 membered heterocyclyl-O-, C1-C6 alkyl-C(O)O-, C3-C9 cycloalkyl-C(O)O-, 4-9 membered heterocyclyl-C(O)O-, P(O)(OH)2O- or NH2C(O)O- being optionally substituted by one or more R 11 replace;

[0020] R 2 Selected from hydrogen, cyano, halogen, C1-C6 alkyl, C3-C9 cycloalkyl, 4-9 membered heterocyclic group, C6-C 10 aryl, 5-9 membered heteroaryl, C(=O)H, C2-C6 alkenyl and C2-C6 alkynyl, the C1-C6 alkyl, C3-C9 cycloalkyl, 4-9 membered heterocyclyl, C6-C 10 Aryl, 5-9 membered heteroaryl, C(=O)H, C2-C6 alkenyl or C2-C6 alkynyl are optionally substituted by one or more R a replace;

[0021] or R 1 、R 2 and the atoms to which they are connected together form a 5-8 membered heterocyclic ring or a 5-9 membered heteroaromatic ring;

[0022] R 4 、R 6 、R 6 '、R 10 independently selected from hydrogen, deuterium, amino, hydroxyl, mercapto, halogen, cyano, C1-C6 alkyl, C3-C9 cycloalkyl, 4-9 membered heterocyclyl, C6-C 10 aryl, 5-9 membered heteroaryl, C2-C6 alkenyl, C2-C6 alkynyl and --C(=O)NH2, the amino, hydroxyl, thiol, C1-C6 alkyl, C3-C9 cycloalkyl, 4-9 membered heterocyclyl, C6-C 10 Aryl, 5-9 membered heteroaryl, C2-C6 alkenyl, C2-C6 alkynyl or -C(=O)NH2 is optionally substituted by one or more R a replace;

[0023] R 5 and R 5 ' and the atoms connected thereto together form a C3-C9 saturated or partially saturated carbon ring, a C6-C 10Aromatic ring, 5-8 membered heterocyclic ring and 5-9 membered heteroaromatic ring, the C3-C9 saturated or partially saturated carbon ring, C6-C 10 Aromatic ring, 5-8 membered heterocyclic ring or 5-9 membered heteroaromatic ring is optionally replaced by one or more R a replace;

[0024] R 7 、R 8 independently selected from hydrogen, halogen, and C1-C6 alkyl, said C1-C6 alkyl being optionally substituted with deuterium;

[0025] R 9 is selected from hydrogen, hydroxy, amino, cyano, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl and C(=O)H, wherein the hydroxy, amino, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl or C(=O)H is optionally substituted by one or more R a replace;

[0026] R 11 Selected from C1-C 10 Alkyl, C3-C9 cycloalkyl, 4-9 membered heterocyclyl, C1-C6 alkoxy, C3-C9 cycloalkyl-O-, 4-9 membered heterocyclyl-O-, C1-C6 alkyl-C(O)O-, C3-C9 cycloalkyl-C(O)O-, 4-9 membered heterocyclyl-C(O)O-, P(O)(OH)2O, NH2C(O)O- and C1-C6 alkyl-OC(O)O-;

[0027] n is selected from 0, 1 and 2;

[0028] R a independently selected from deuterium, halogen, oxo, hydroxy, amino, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, C6-C 10 Aryl and 5-9 membered heteroaryl, the hydroxyl, amino, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic, C6-C 10 Aryl or 5-9 membered heteroaryl is optionally substituted with one or more R b replace;

[0029] R b independently selected from halogen, hydroxy, amino, cyano, C1-C3 alkyl, NH(C1-C3 alkyl), N(C1-C3 alkyl)2, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, C1-C6 alkoxy, C6-C 10 Aryl and 5-9 membered heteroaryl, the C1-C3 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic group, C1-C6 alkoxy, C6-C 10 Aryl or 5-9 membered heteroaryl is optionally substituted with one or more Rc replace;

[0030] R c Independently selected from halogen, hydroxy, amino, cyano and C1-C3 alkyl.

[0031] In some embodiments, R 4 、R 6 、R 6 '、R 10 independently selected from hydrogen, amino, hydroxy, mercapto, halogen, cyano, C1-C6 alkyl, C3-C9 cycloalkyl, 4-9 membered heterocyclyl, C6-C 10 aryl, 5-9 membered heteroaryl, C2-C6 alkenyl, C2-C6 alkynyl and -C(=O)NH2, the amino, hydroxyl, thiol, C1-C6 alkyl, C3-C9 cycloalkyl, 4-9 membered heterocyclyl, C6-C 10 Aryl, 5-9 membered heteroaryl, C2-C6 alkenyl, C2-C6 alkynyl or -C(=O)NH2 is optionally substituted by one or more R a Replacement; R 7 、R 8 are independently selected from halogen and C1-C6 alkyl; R a independently selected from halogen, oxo, hydroxy, amino, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, C6-C 10 Aryl and 5-9 membered heteroaryl, the hydroxyl, amino, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic, C6-C 10 Aryl or 5-9 membered heteroaryl is optionally substituted with one or more R b Replacement; R b independently selected from halogen, hydroxy, amino, cyano, NH (C1-C3 alkyl), N (C1-C3 alkyl) 2, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, C1-C6 alkoxy, C6-C 10 Aryl and 5-9 membered heteroaryl, the C3-C6 cycloalkyl, 4-7 membered heterocyclic group, C1-C6 alkoxy, C6-C 10 Aryl or 5-9 membered heteroaryl is optionally substituted with one or more R c replace.

[0032] In some embodiments, R b independently selected from halogen, hydroxy, amino, cyano, C1-C3 alkyl, NH(C1-C3 alkyl), N(C1-C3 alkyl)2, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, C1-C6 alkoxy, C6-C 10 Aryl and 5-9 membered heteroaryl, the C3-C6 cycloalkyl, 4-7 membered heterocyclic group, C1-C6 alkoxy, C6-C 10Aryl or 5-9 membered heteroaryl is optionally substituted with one or more R c Replacement; R c Independently selected from halogen, hydroxy, amino, cyano and C1-C3 alkyl.

[0033] In some embodiments, X 2 Selected from CR 5 R 6 NR 5 and CR 5 .

[0034] In some embodiments, X 2 Selected from CR 5 R 6 and CR 5 .

[0035] In some embodiments, X 2 CR 5 R 6 In some embodiments, X 2 CR 5 .

[0036] In some embodiments, X 3 Selected from CR 5 'R 6 '、NR 5 ' and CR 5 '.

[0037] In some embodiments, X 3 Selected from CR 5 'R 6 ' and CR 5 '.

[0038] In some embodiments, X 3 CR 5 'R 6 '. In some embodiments, X 3 CR 5 '.

[0039] In some embodiments, X 4 、X 5 independently selected from a bond, C(R 10 )2 and O.

[0040] In some embodiments, X 4 Selected from bonds and C(R 10 )2.

[0041] In some embodiments, X 4 、X 5 Independently selected from (C(R 10 )2)n , and n is 0, which means X 4 、X 5 are independently selected from bonds.

[0042] In some embodiments, X 4 is a bond, -CH2-, -CH(CH3)- or In some embodiments, X 4 In some embodiments, X 4 It is -CH2-.

[0043] In some embodiments, X 5 Selected from bonds and C(R 10 )2.

[0044] In some embodiments, X 5 is the key.

[0045] In some embodiments, X 5 is a bond, -O-, -CH(CH3)-, -C(CH3)2- or

[0046] In some embodiments, X 4 and X 5 All are keys.

[0047] In some embodiments, X 4 is -CH2- and X 5 is the key.

[0048] In some embodiments, R 1 、R 3 In some embodiments, R 1 is hydroxyl group, R 3 For hydrogen.

[0049] In some embodiments, R 2 For hydrogen.

[0050] In some embodiments, R 1 In some embodiments, R 2 and R 3 In some embodiments, R 1 is a hydroxyl group, and R 2 and R 3 All are hydrogen.

[0051] In some embodiments, R 1is selected from hydroxy, C1-C6 alkoxy, C1-C6 alkyl-C(O)O-, 4-9 membered heterocyclyl-C(O)O-, P(O)(OH)2O- and NH2C(O)O-, wherein the C1-C6 alkoxy, C1-C6 alkyl-C(O)O-, 4-9 membered heterocyclyl-C(O)O-, P(O)(OH)2O- and NH2C(O)O- are optionally substituted by one or more R 11 In some embodiments, R 11 Selected from C1-C 10 Alkyl, 4-9 membered heterocyclyl, C1-C6 alkyl-C(O)O-, P(O)(OH)2O and C1-C6 alkyl-OC(O)O-.

[0052] In some embodiments, R 1 is selected from hydroxy, C1-C6 alkoxy, C1-C6 alkyl-C(O)O-, 5-membered or 6-membered heterocyclyl-C(O)O-, P(O)(OH)2O- and NH2C(O)O-, wherein the C1-C6 alkoxy, C1-C6 alkyl-C(O)O-, 5-membered or 6-membered heterocyclyl-C(O)O-, P(O)(OH)2O- and NH2C(O)O- are optionally substituted by one or more R 11 In some embodiments, R 11 Selected from C1-C 10 Alkyl, 5-membered or 6-membered heterocyclic group, C1-C6 alkyl-C(O)O-, P(O)(OH)2O- and C1-C6 alkyl-OC(O)O-.

[0053] In some embodiments, R 1 -OH,

[0054] In some embodiments, R 4 、R 6 、R 6 '、R 10 independently selected from hydrogen, amino, hydroxy, mercapto, halogen, cyano, C1-C6 alkyl, C3-C9 cycloalkyl, 4-9 membered heterocyclyl, C6-C 10 aryl, 5-9 membered heteroaryl, C2-C6 alkenyl, C2-C6 alkynyl and -C(=O)NH2, the amino, hydroxyl, thiol, C1-C6 alkyl, C3-C9 cycloalkyl, 4-9 membered heterocyclyl, C6-C 10 Aryl, 5-9 membered heteroaryl, C2-C6 alkenyl, C2-C6 alkynyl or -C(=O)NH2 is optionally substituted by one or more R a replace.

[0055] In some embodiments, R 4 、R6 、R 6 '、R 10 independently selected from hydrogen, amino, hydroxy, C1-C6 alkyl, C3-C9 cycloalkyl, 4-9 membered heterocyclyl, C6-C 10 Aryl and 5-9 membered heteroaryl, the amino, hydroxyl, C1-C6 alkyl, C3-C9 cycloalkyl, 4-9 membered heterocyclic, C6-C 10 Aryl or 5-9 membered heteroaryl is optionally substituted with one or more R a replace.

[0056] In some embodiments, R 4 、R 6 、R 6 '、R 10 independently selected from hydrogen, amino, hydroxy, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl and 5-6 membered heteroaryl, wherein the amino, hydroxy, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl is optionally substituted by one or more R a replace.

[0057] In some embodiments, R 4 Selected from hydrogen, amino, hydroxy, C1-C6 alkyl, C3-C9 cycloalkyl, 4-9 membered heterocyclic group, C6-C 10 Aryl and 5-9 membered heteroaryl, the amino, hydroxyl, C1-C6 alkyl, C3-C9 cycloalkyl, 4-9 membered heterocyclic, C6-C 10 Aryl or 5-9 membered heteroaryl is optionally substituted with one or more R a replace.

[0058] In some embodiments, R 4 is selected from hydrogen, amino, hydroxy, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl and 5-6 membered heteroaryl, wherein the amino, hydroxy, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl is optionally substituted by one or more R a replace.

[0059] In some embodiments, R 4 Selected from -H, -CH3, -CH(CH3)2, -OCH3, -N(CH3)2, -CF3, -CHF2, -C(CH3)2(OH),

[0060] In some embodiments, R 4 Selected from H and C1-C3 alkyl.

[0061] In some embodiments, R 4 is selected from H and methyl.

[0062] In some embodiments, R 4 is H. In some embodiments, R 4 It is a methyl group.

[0063] In some embodiments, each R 10 Independently selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl.

[0064] In some embodiments, R 5 and R 5 ' and the atoms to which they are connected together form a C4-C7 saturated or partially saturated carbocyclic ring, a benzene ring, a 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring, wherein the C4-C7 saturated or partially saturated carbocyclic ring, a benzene ring, a 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring is optionally replaced by one or more R a In some embodiments, R 5 and R 5 ' and the atoms connected thereto together form a benzene ring and a 5-6 membered heteroaromatic ring, wherein the benzene ring or the 5-6 membered heteroaromatic ring is optionally replaced by one or more R a replace.

[0065] In some embodiments, X 2 CR 5 , X 3 CR 5 ', X 4 and X 5 All are keys.

[0066] In some embodiments, X 2 CR 5 , X 3 CR 5 ', X 4 -CH2-, X 5 is the key.

[0067] In some embodiments, X 2 CR 5 , X 3 CR 5 ', and R 5 and R 5 ' and the atoms connected thereto together form a benzene ring and a 5-6 membered heteroaromatic ring, wherein the benzene ring or the 5-6 membered heteroaromatic ring is optionally replaced by one or more R a replace.

[0068] In some embodiments, X 2 CR 5 , X 3 CR 5 ', and R 5 and R 5' and the atoms to which they are connected together form a benzene ring, a pyridine ring, a pyrazole ring, a thiazole ring, an isothiazole ring, a pyrrole ring or a furan ring, wherein the benzene ring, the pyridine ring, the pyrazole ring, the thiazole ring, the isothiazole ring, the pyrrole ring or the furan ring is optionally replaced by one or more R a replace.

[0069] In some embodiments, X 2 CR 5 , X 3 CR 5 ', and R 5 and R 5 ' and the atoms to which they are connected together form a benzene ring or a pyridine ring, wherein the benzene ring or the pyridine ring is optionally substituted by one or more R a replace.

[0070] In some embodiments, R 7 、R 8 Independently selected from halogen and C1-C6 alkyl.

[0071] In some embodiments, R 7 、R 8 Independently selected from C1-C3 alkyl.

[0072] In some embodiments, R 7 and R 8 All are methyl.

[0073] In some embodiments, X 1 is N.

[0074] In some embodiments, X 1 CR 9 .

[0075] In some embodiments, X 1 For CCH3.

[0076] In some embodiments, X 1 N, R 4 It is a methyl group.

[0077] In some embodiments, R 9 is selected from hydrogen, hydroxy, amino, halogen and C1-C3 alkyl, wherein the hydroxy, amino, C1-C3 alkyl is optionally replaced by one or more R a replace.

[0078] In some embodiments, R 9 is selected from hydrogen and methyl.

[0079] In some embodiments, R 10is selected from hydrogen, amino, hydroxy, C1-C3 alkyl and C3-C6 cycloalkyl, wherein the hydroxy, amino, C1-C3 alkyl or C3-C6 cycloalkyl is optionally replaced by one or more R a replace.

[0080] In some embodiments, R 10 For H.

[0081] In some embodiments, n is selected from 0 and 1.

[0082] In some embodiments, R a independently selected from halogen, oxo, hydroxy, amino, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, C6-C 10 Aryl and 5-9 membered heteroaryl, the hydroxyl, amino, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic, C6-C 10 Aryl or 5-9 membered heteroaryl is optionally substituted with one or more R b replace.

[0083] In some embodiments, R a independently selected from cyano, halogen, hydroxy, amino, C1-C6 alkyl and C3-C6 cycloalkyl, wherein the hydroxy, amino, C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by one or more R b replace.

[0084] In some embodiments, R a independently selected from halogen, hydroxy, amino, C1-C6 alkyl and C3-C6 cycloalkyl, wherein the hydroxy, amino, C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by one or more R b replace.

[0085] In some embodiments, R a independently selected from cyano, halogen, hydroxyl, C1-C6 alkyl and C3-C6 cycloalkyl, wherein the hydroxyl, C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by one or more R b replace.

[0086] In some embodiments, R a independently selected from halogen, hydroxy, C1-C6 alkyl and C3-C6 cycloalkyl, wherein the hydroxy, C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by one or more R b replace.

[0087] In some embodiments, R bindependently selected from halogen, hydroxy, amino, cyano, NH (C1-C3 alkyl), N (C1-C3 alkyl) 2, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, C1-C6 alkoxy, C6-C 10 Aryl and 5-9 membered heteroaryl, the C3-C6 cycloalkyl, 4-7 membered heterocyclic group, C1-C6 alkoxy, C6-C 10 Aryl or 5-9 membered heteroaryl is optionally substituted with one or more R c replace.

[0088] In some embodiments, R b independently selected from amino, NH (C1-C3 alkyl), N (C1-C3 alkyl) 2, C3-C6 cycloalkyl, 4-7 membered heterocyclyl and C1-C6 alkoxy, wherein the C3-C6 cycloalkyl, 4-7 membered heterocyclyl and C1-C6 alkoxy are optionally substituted by one or more R c replace.

[0089] In some embodiments, R b independently selected from halogen, hydroxy, C1-C3 alkyl, N(C1-C3 alkyl)2, C3-C6 cycloalkyl, 4-7 membered heterocyclyl and C1-C6 alkoxy, wherein the C1-C3 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl and C1-C6 alkoxy are optionally substituted by one or more R c replace.

[0090] In some embodiments, R b independently selected from halogen, hydroxy, C1-C3 alkyl and C3-C6 cycloalkyl, wherein the hydroxy, C1-C3 alkyl and C3-C6 cycloalkyl are optionally replaced by one or more R c replace.

[0091] In some embodiments, R c Independently selected from halogen and C1-C3 alkyl.

[0092] In some embodiments, R c In some embodiments, R c are independently selected from halogen (eg, F).

[0093] In some embodiments, R a Independently selected from cyano, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 alkoxy-C1-C3 alkylene, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy and hydroxymethyl.

[0094] In some embodiments, R aIndependently selected from cyano, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy and hydroxymethyl.

[0095] In some embodiments, R a Independently selected from halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy and hydroxymethyl.

[0096] In some embodiments, R a Independently selected from halogen, C1-C3 alkyl, C1-C3 alkoxy and C1-C3 haloalkyl.

[0097] In some embodiments, R a Independently selected from -OH, -CH3, -C2H5, -OCH3, -OCH2CH3, -CH2CF3, -F, -OCF2H, -OCF3, -CN, -CF3, -CH2OH, -OCH2F, -CHF2, -CH2CH2OCH3, -CH(CH3)2, -N(CH3)2, -CH2N(CH3)2, -CH2OCH3,

[0098] In some embodiments, R 4 is selected from hydrogen, amino, hydroxy, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl and 5-6 membered heteroaryl, wherein the amino, hydroxy, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl is optionally substituted by one or more R a Replace; and R a Independently selected from halogen (eg, F), hydroxyl, and C1-C6 alkyl (eg, methyl).

[0099] In some embodiments, X 2 CR 5 , X 3 CR 5 ', and R 5 and R 5 ' and the atoms connected thereto together form a benzene ring and a 5-6 membered heteroaromatic ring, wherein the benzene ring or the 5-6 membered heteroaromatic ring is optionally replaced by one or more R a Replacement; R a independently selected from halogen, hydroxy, amino, cyano, C1-C6 alkyl and C3-C6 cycloalkyl, wherein the hydroxy, amino, C1-C6 alkyl and C3-C6 cycloalkyl are optionally replaced by one or more R b Replacement; R bindependently selected from halogen, hydroxy, C1-C3 alkyl, N (C1-C3 alkyl) 2, C3-C6 cycloalkyl, 4-7 membered heterocyclyl and C1-C6 alkoxy, wherein the C1-C3 alkyl, N (C1-C3 alkyl) 2, C3-C6 cycloalkyl, 4-7 membered heterocyclyl and C1-C6 alkoxy are optionally substituted by one or more R c Replacement; R c are independently selected from halogen.

[0100] In some embodiments, X 2 CR 5 , X 3 CR 5 ', and R 5 and R 5 ' and the atoms to which they are connected together form a benzene ring, a pyridine ring, a pyrazole ring, a thiazole ring, an isothiazole ring, a pyrrole ring or a furan ring, wherein the benzene ring, the pyridine ring, the pyrazole ring, the thiazole ring, the isothiazole ring, the pyrrole ring or the furan ring is optionally substituted by one or more (e.g., 1 or 2) R a Replacement; R a Independently selected from -OH, -CH3, -C2H5, -OCH3, -OCH2CH3, -CH2CF3, -F, -OCF2H, -OCF3, -CN, -CF3, -CH2OH, -OCH2F, -CHF2, -CH2CH2OCH3, -CH(CH3)2, -N(CH3)2, -CH2N(CH3)2, -CH2OCH3,

[0101] In some embodiments, the 5-6 membered heterocyclyl, 4-7 membered heterocyclyl, 4-9 membered heterocyclyl, 4-6 membered heterocycle, 5-6 membered heterocycle, or 5-8 membered heterocycle each independently contains 1, 2, or 3 heteroatoms independently selected from N, O, and S. In some embodiments, the 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, 4 membered heterocycle, 5 membered heterocycle, or 6 membered heterocycle each independently contains 1 or 2 heteroatoms independently selected from N or O.

[0102] In some embodiments, the 5-6 membered heteroaryl, 5-9 membered heteroaryl, 5-6 membered heteroaromatic ring, or 5-9 membered heteroaromatic ring each contain, independently of one another, 1, 2, or 3 heteroatoms independently selected from N, O, and S. In some embodiments, the 5-membered heteroaryl, 6 membered heteroaryl, 5 membered heteroaromatic ring, or 6 membered heteroaromatic ring each contain, independently of one another, 1 or 2 heteroatoms independently selected from N, O, and S.

[0103] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof of the present application is selected from the compound of formula (II) or a pharmaceutically acceptable salt thereof,

[0104] Among them, R 5 and R 5 ' and its connected atoms together form C6-C 10 Aromatic ring and 5-9 membered heteroaromatic ring, the C6-C 10 The aromatic ring or 5-9 membered heteroaromatic ring is optionally replaced by one or more R a Replacement; R 1 、R 2 、R 3 、R 4 、R 7 、R 8 、X 1 、X 4 、X 5 、R a As defined above.

[0105] In some embodiments, the R 5 and R 5 ' and the atoms to which they are connected together form a benzene ring, a pyridine ring, a pyrazole ring, a thiazole ring or an isothiazole ring, wherein the benzene ring, the pyridine ring, the pyrazole ring, the thiazole ring or the isothiazole ring is optionally replaced by one or more R a replace.

[0106] In some embodiments, the R 5 and R 5 ' and the atoms to which they are connected together form a benzene ring, a pyridine ring or a pyrazole ring, wherein the benzene ring, the pyridine ring or the pyrazole ring is optionally replaced by one or more R a replace.

[0107] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof of the present application is selected from the compound of formula (III) or a pharmaceutically acceptable salt thereof,

[0108] Among them, X 6 、X 7 Independently selected from CH or N, said CH is optionally substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy; X is selected from NR a or O; R 1 、R 2 、R 3 、R 4 、R 7 、R 8 、X 1 、X 4 、X 5 、R a As defined above.

[0109] In some embodiments, X in the compound of formula (III) 6、X 7 Independently selected from CH, C-(C1-C3 alkyl), C-halogen or N.

[0110] In some embodiments, X in the compound of formula (III) 6 、X 7 are independently selected from CH, C-halogen or N.

[0111] In some embodiments, the compound of formula (I) of the present application or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof,

[0112] 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.

[0113] 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.

[0114] 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.

[0115] 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.

[0116] 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 disease mediated by PKMYT1.

[0117] In some embodiments, the PKMYT1-mediated disease is a tumor. In some embodiments, the PKMYT1-mediated disease is liver cancer.

[0118] Definitions and Explanations of Terms

[0119] Unless otherwise indicated, the terms used in this disclosure have the following meanings. The definitions of groups and terms described in this disclosure, 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 particular term should not be considered as undefined or unclear unless specifically defined, but should be understood according to its ordinary 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.

[0120] In this article Indicates the attachment site.

[0121] In this paper, the bonds depicted by solid and dashed lines Indicates a single bond or a double bond.

[0122] The term "tautomer" refers to functional group isomers resulting from the rapid shift of an atom in a molecule between two positions. The compounds of the present disclosure may exhibit tautomerism. Tautomeric compounds may exist as two or more interconvertible species. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer usually result in a mixture whose physical and chemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates, while in phenols, the enol form predominates. The present disclosure encompasses all tautomeric forms of the compounds.

[0123] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and diastereomers.

[0124] The compounds of the present invention may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds, so that the compounds of the present invention may exist in specific geometric or stereoisomeric forms. Specific geometric or stereoisomeric forms may be cis and trans isomers, E and Z geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures or other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, all of which are within the definition of the compounds of the present invention 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 which are within the definition of the compounds of the present invention and mixtures thereof. Compounds of the present disclosure 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 reagents.

[0125] 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.

[0126] 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.

[0127] When any variable (such as n, 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.

[0128] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a bond.

[0129] When one of the variables is selected from a chemical bond or does not exist, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a bond, it means that the structure is actually AZ.

[0130] 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.

[0131] 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 "C1-C6 alkyl" may further include "C1-C3 alkyl". The term "C1-C3 haloalkyl" refers to a C1-C3 alkyl substituted by one or more halogens such as F, Cl, Br or I, including mono-, poly- or fully substituted.

[0132] The term "alkylene" refers to a saturated straight or branched aliphatic hydrocarbon group having two residues derived from the same carbon atom or two different carbon atoms of a parent alkane group by removing two hydrogen atoms, and is an alkylene group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, preferably an alkylene group containing 1, 2, 3, 4, 5, or 6 carbon atoms (i.e., C1-C6 alkylene group), more preferably an alkylene group containing 1, 2, or 3 carbon atoms (i.e., C1-C3 alkylene group). Non-limiting examples of alkylene groups include, but are not limited to, methylene, -CH(CH3)-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2CH2CH2-, and the like.

[0133] The term "alkoxy" refers to a group generated by the loss of a hydrogen atom from a hydroxyl group of a straight-chain or branched alcohol, and can be understood as "alkyloxy" or "alkyl-O-". The term "C1-C 10 "Alkoxy" can be understood as "C1-C 10 Alkyloxy" or "C1-C 10 Alkyl-O-"; the term "C1-C6 alkoxy" can be understood as "C1-C6 alkyloxy" or "C1-C6 alkyl-O-". The "C1-C 10 "Alkoxy" may include "C1-C6 alkoxy" and "C1-C3 alkoxy" and the like, and the "C1-C6 alkoxy" may further include "C1-C3 alkoxy". The term "C1-C3 haloalkoxy" refers to C1-C3 haloalkyl-O-.

[0134] 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-C 10 "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.

[0135] 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).

[0136] The term "cycloalkyl" refers to a saturated carbon ring that exists in the form of a monocyclic, fused, bridged, or spirocyclic ring. Unless otherwise indicated, the carbon ring is usually 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 to 10 (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 to 6 carbon atoms. Specific examples include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0137] The term "cycloalkyloxy" may be understood as "cycloalkyl-O-".

[0138] The term "heterocyclyl" or "heterocycle" refers to a saturated or partially saturated (heteroaromatic as a whole that is not aromatic) monocyclic, fused, spiro or bridged ring group, which contains 1 to 5 heteroatoms or heteroatomic groups (i.e., heteroatom-containing 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 "4-9 membered heterocyclyl" refers to a heterocyclyl group having 4, 5, 6, 7, 8 or 9 ring atoms, and containing 1, 2, 1-3 or 1-5 heteroatoms or heteroatomic groups independently selected from the above-mentioned heteroatoms or heteroatomic groups in its ring atoms. “4-7 membered heterocyclyl” and “4-9 membered heterocyclyl” may respectively contain 1-3 (1, 2 or 3) heteroatoms independently selected from N, O and S. “4-9 membered heterocyclyl” includes “4-7 membered heterocyclyl”, wherein specific examples of 4 membered heterocyclyl include but are not limited to azetidinyl 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. "4-9 membered heterocyclyl" may include "5-9 membered heterocyclyl", "4-7 membered heterocyclyl", "5-6 membered heterocyclyl", "6-8 membered heterocyclyl", "4-9 membered heterocycloalkyl", "5-9 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. Although some bicyclic heterocyclyl groups in the present disclosure partially contain a benzene ring or a heteroaromatic ring, the heterocyclyl group as a whole is still non-aromatic.

[0139] The term "heterocycloalkyl" refers to a saturated cyclic group in the form of a monocyclic, fused, bridged or spirocyclic ring, wherein the ring atoms of the ring contain 1, 2, 1-3 or 1-5 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 "4-9 membered heterocycloalkyl" refers to a heterocycloalkyl group having 4, 5, 6, 7, 8 or 9 ring atoms, wherein the ring atoms contain 1-5 heteroatoms or heteroatomic groups independently selected from the above-mentioned heteroatoms or heteroatomic groups. “4-7 membered heterocycloalkyl” and “4-9 membered heterocycloalkyl” may respectively contain 1-3 (1, 2 or 3) heteroatoms independently selected from N, O and S. “4-9 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, tetrahydrothienyl, 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.

[0140] 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, 6-12 or 6-10 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.

[0141] The term "heteroaryl" or "heteroaromatic ring" refers to a monocyclic or fused polycyclic ring system with aromatic character, which contains at least one (1, 2 or 3) ring atom selected from N, O, S, and the remaining ring atoms are C. The term "5-9 membered heteroaryl" is understood to include monocyclic or bicyclic aromatic ring systems: which have 5, 6, 7, 8 or 9 ring atoms, in particular 5 or 6 or 9 ring atoms, and which contain 1 to 5, preferably 1 to 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 1-3, preferably 1-2, heteroatoms independently selected from N, O and S.

[0142] The term "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.

[0143] The term "hydroxymethyl" refers to -CH2OH.

[0144] The term "hydroxy" refers to an -OH group.

[0145] The term "cyano" refers to a -CN group.

[0146] The term "mercapto" refers to a -SH group.

[0147] The term "amino" refers to a -NH2 group.

[0148] The term "nitro" refers to a -NO2 group.

[0149] The term "therapeutically effective amount" means an amount of a compound of the present disclosure that: (i) treats a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) delays the onset of one or more symptoms of a particular disease, condition, or disorder as described herein. The amount of a compound of the present disclosure 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 one skilled in the art based on their knowledge and this disclosure.

[0150] 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.

[0151] 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.

[0152] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or their salts and a pharmaceutically acceptable excipient. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present disclosure to an organism.

[0153] 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.

[0154] 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".

[0155] The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but where 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 disclosure 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.

[0156] Certain isotopically labeled compounds of the present disclosure (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. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emitting isotopes, such as 15 O. 13 N. 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the disclosure 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.

[0157] The pharmaceutical compositions of the present disclosure can be prepared by combining the compounds of the present disclosure 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.

[0158] Typical routes of administration of the disclosed compounds, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0159] The pharmaceutical composition of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, emulsification methods, freeze-drying methods, and the like.

[0160] 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 disclosure to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, and the like for oral administration to a patient.

[0161] 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.

[0162] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

[0163] In all administration methods of the compound of formula (I) described herein, the daily dosage is 0.01 mg / kg to 200 mg / kg body weight, preferably 0.05 mg / kg to 50 mg / kg body weight, more preferably 0.1 mg / kg to 30 mg / kg body weight, in the form of single or divided doses.

[0164] The compounds disclosed herein 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 the same with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples disclosed herein.

[0165] The chemical reactions of the embodiments of the present disclosure are carried out in a suitable solvent that is compatible with the chemical transformations of the present disclosure and the reagents and materials required. In order to obtain the compounds of the present disclosure, it is sometimes necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.

[0166] The present disclosure uses the following abbreviations: DCM: dichloromethane; LiHMDS: lithium bis(trimethylsilyl)amide; DMF: N,N-dimethylformamide; TsOH·H2O: p-toluenesulfonic acid monohydrate; LiTMP: lithium tetramethylpiperidinium; B(OiPr)3: triisopropyl borate; B(OMe)3: trimethyl borate; NMP: N-methylpyrrolidone; DME: ethylene glycol dimethyl ether; KOAc: potassium acetate; AcOH: acetic acid; t BuOH: tert-butyl alcohol; NaO t Bu: sodium tert-butoxide; tBuLi: tert-butyllithium; n-BuLi: n-butyllithium; dppf: 1,1'-bis(diphenylphosphino)ferrocene; Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride; Pd(dppf)Cl2·DCM: [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex; Pd2(dba)3: tris(dibenzylideneacetone)palladium; Pd(dba)2: di(dibenzylideneacetone)palladium; rt: room temperature; min: minute; h: hour; Me: methyl; MeOH: methanol; EtOH: ethanol; i Pr: isopropyl; Boc: tert-butyloxycarbonyl; (Boc)2O: di-tert-butyl dicarbonate; EtOAc: ethyl acetate; THF: tetrahydrofuran; TEA / Et3N: triethylamine; Xphos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl; XphosPdG1: chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II); SPhos: 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl; t-BuXPhos-Pd-G3: methanesulfonic acid(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) ); PPh3: triphenylphosphine; Pd(PPh3)4: tetrakis(triphenylphosphine)palladium; meCgPPh: 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphoryladamantane; dioxane: 1,4-dioxane; Ni-Raney: Raney nickel; DMAP: 4-dimethylaminopyridine; B2Pin2: diboronic acid pinacol ester; Tf: trifluoromethanesulfonyl; DPPA: diphenylphosphoryl azide; Sn2 n Bu6: hexabutylditin; Dess-Martin: Dess-Martin periodinane; Et3SiH: triethylsilane; Pd(OAc)2: palladium acetate; PCy3: tricyclohexylphosphine; MOMO: methoxymethoxy; PhNTf2: N-phenylbis(trifluoromethanesulfonyl)imide; DPPF: 1,1'-bis(diphenylphosphino)ferrocene; m-CPBA: m-chloroperbenzoic acid; TMSCN: trimethylsilyl cyanide; ACN: acetonitrile; NBS: N-bromosuccinimide; AcCl: acetyl chloride; DMAP: 4-dimethylaminopyridine; tBuONO: tert-butyl nitrite; cataCXium A Pd G3: [n-butylbis(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate; TEMP: 2,2,6,6-tetramethylpiperidine; NIS: N-iodosuccinimide; DIAD: diisopropyl azodicarboxylate; TMSI: iodotrimethylsilane; DCE: 1,2-dichloroethane; PhNTf2: N-phenylbis(trifluoromethanesulfonyl)imide; xantphos: 4,5-bis(diphenylphosphino-9,9-dimethylxanthene); DIPEA: N,N-diisopropylethylamine; ATP: adenosine triphosphate; CDK1: cyclin-dependent kinase 1; ADP: adenosine diphosphate; FBS: fetal bovine serum.

[0167] The invention is described in detail below by way of examples, but this is not intended to limit the present disclosure in any way. While the present disclosure has been described in detail herein, including specific embodiments thereof, various modifications thereof will be readily apparent to those skilled in the art without departing from the spirit and scope of the present disclosure. All reagents used in the present disclosure were commercially available and used without further purification.

[0168] Unless otherwise specified, the ratios expressed for mixed solvents are volume ratios.

[0169] Unless otherwise stated, % refers to wt%.

[0170] Compounds are manually or Software naming, commercially available compounds use supplier catalog names.

[0171] 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.

[0172] The eluent mentioned below can be a mixed eluent formed by two or more solvents, and the ratio thereof is the volume ratio of each solvent.

[0173] Example 1: Preparation of 5-amino-4-(3-hydroxy-2,6-dimethylphenyl)-4,7-dihydro-6H-1,3,4,7-tetraazadibenzo[cd,f]azulen-6-one (Compound 1)

[0174] Step 1: Synthesis of 6-chloro-5-iodo-N-(3-methoxy-2,6-dimethylphenyl)pyrimidin-4-amine (1c)

[0175] 4,6-Dichloro-5-iodopyrimidine 1a (2.0 g, 7.3 mmol) was dissolved in anhydrous N-methylpyrrolidone (4 mL), and 3-methoxy-2,6-dimethylaniline 1b (2.3 g, 15 mmol) and p-toluenesulfonic acid monohydrate (14 mg, 73 μmol) were added. The mixture was then reacted at 150°C for 1 hour. The reaction mixture was cooled to room temperature and directly purified by reverse-phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to obtain compound 1c (1.5 g, 53% yield). m / z (ESI): 390.1 [M+H] + .

[0176] Step 2: Synthesis of 6-amino-4-chloro-7-(3-methoxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (1d)

[0177] Malononitrile (0.066 g, 1.0 mmol) was dissolved in anhydrous ethylene glycol dimethyl ether (2 mL), and sodium tert-butoxide (0.15 g, 1.5 mmol) was added. After stirring at room temperature for 30 minutes, 1c (0.10 g, 0.25 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (8.1 mg, 10 μmol) were added. The atmosphere was replaced with nitrogen three times, and the mixture was reacted at 90°C for 3 hours under nitrogen protection. 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 obtain compound 1d (62 mg, 73% yield). m / z (ESI): 328.1 [M+H] + .

[0178] Step 3: Synthesis of 6-amino-4-(2-aminophenyl)-7-(3-methoxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (1f)

[0179] Compound 1d (62 mg, 0.19 mmol) and 2-aminophenylboronic acid 1e (52 mg, 0.38 mmol) were dissolved in a mixture of 1,4-dioxane (3 mL) and water (0.3 mL) at room temperature. Tris(bisbenzylideneacetone)bispalladium (8.7 mg, 9.5 μmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphoryladamantane (11 mg, 38 μmol), and cesium carbonate (0.19 g, 0.57 mmol) were then added. The atmosphere was replaced with nitrogen, and the reaction was continued at 100°C for 3 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 compound 1f (43 mg, 59% yield). m / z(ESI):385.4[M+H] + .

[0180] Step 4: Synthesis of 5-amino-4-(3-methoxy-2,6-dimethylphenyl)-4,7-dihydro-6H-1,3,4,7-tetraazadibenzo[cd,f]azulen-6-one (1 g)

[0181] Compound 1f (43 mg, 0.11 mmol) was dissolved in 7N methanolic hydrochloric acid (10 mL) and reacted at 110°C in a sealed tube for 8 hours. After the reaction mixture cooled 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 compound 1g (19 mg, 45% yield). m / z (ESI): 386.3 [M+H] + .

[0182] Step 5: Synthesis of 5-amino-4-(3-hydroxy-2,6-dimethylphenyl)-4,7-dihydro-6H-1,3,4,7-tetraazadibenzo[cd,f]azulen-6-one (Compound 1)

[0183] At room temperature, compound 1g (19 mg, 49 μmol) was dissolved in anhydrous 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 compound 1 (10 mg, 55% yield) as a white solid. m / z (ESI): 372.4 [M+H] + .

[0184] 1H NMR (400MHz, DMSO-d6): δ9.64(s,1H),9.14(s,1H),8.51(d,J=8.0Hz,1H),8.3 3(s,1H),7.27(t,J=8.0Hz,1H),7.13-6.93(m,6H),1.79(s,3H),1.70(s,3H).

[0185] Example 2: Preparation of 5-amino-4-(3-hydroxy-2,6-dimethylphenyl)-2-methyl-4,7-dihydro-6H-1,3,4,7-tetraazadibenzo[cd,f]azulen-6-one (Compound 2)

[0186] Compound 2 was prepared by replacing compound 1a with compound 2a using a method similar to that of Example 1.

[0187] m / z(ESI):386.3[M+H] + ;

[0188] 1 H NMR (400MHz, DMSO-d6): δ9.60(s,1H),9.07(s,1H),8.52(d,J=8.0Hz,1H),7.25(t,J=8.0Hz,1H) ,7.09(t,J=8.0Hz,1H),8.33(s,1H),7.01-6.89(m,4H),2.44(s,3H),1.79(s,3H),1.70(s,3H).

[0189] Example 3: Preparation of 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-11-methyl-4,5-dihydro-1,4,10,12-tetraazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]inden-3(1H)-one (Compound 3)

[0190] Step 1: Synthesis of 6-chloro-5-iodo-N-(3-methoxy-2,6-dimethylphenyl)-2-methylpyrimidin-4-amine (3a)

[0191] At room temperature, 4,6-dichloro-5-iodo-2-methylpyrimidine 2a (5.8 g, 20 mmol) and 3-methoxy-2,6-dimethylaniline 1b (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 (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by normal phase column chromatography (petroleum ether:ethyl acetate = 10:1-2:1) to afford compound 3a (1.8 g, 22% yield) as a white solid. m / z (ESI): 404.1 [M+H] + .

[0192] Step 2: Synthesis of methyl 6-amino-4-chloro-7-(3-methoxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (3b)

[0193] Methyl cyanoacetate (1.6 g, 16 mmol) was dissolved in anhydrous ethylene glycol dimethyl ether (20 mL), and cesium carbonate (7.8 g, 24 mmol) was added. After stirring at room temperature for 30 minutes, compound 3a (1.6 g, 4 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.33 g, 0.4 mmol) were added. The atmosphere was replaced with nitrogen three times, and the mixture was reacted at 85°C under nitrogen for 2 hours. After the reaction mixture was cooled to room temperature, saturated brine (20 mL) was added and extracted three times 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 was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:2) to obtain compound 3b (0.79 g, 53% yield). m / z(ESI):375.2[M+H] + .

[0194] Step 3: Synthesis of methyl 6-amino-4-(2-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(3-methoxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (3d)

[0195] Compound 3b (90 mg, 0.24 mmol), compound 3c (0.12 g, 0.36 mmol), tris(dibenzylideneacetone)dipalladium (22 mg, 24 μmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphoryladamantane (28 mg, 96 μmol), and cesium carbonate (0.16 g, 0.48 mmol) were dissolved in 1,4-dioxane / water (2 mL / 0.4 mL) at room temperature. The atmosphere was replaced with nitrogen three times. The reaction mixture was then moved to 100°C for 16 hours. After the reaction was cooled to room temperature, the insoluble material was filtered off and saturated brine (10 mL) was added. The mixture was extracted three times with ethyl acetate (20 mL * 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 3:1) to obtain the product compound 3d (110 mg, yield 84%). m / z (ESI): 546.3 [M+H] + .

[0196] Step 4: Synthesis of methyl 6-amino-4-(2-(aminomethyl)phenyl)-7-(3-methoxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (3e)

[0197] Compound 3d (90 mg, 0.16 mmol) was dissolved in 4 mL of hydrochloric acid and ethyl acetate (4 M in EtOAc) at room temperature and allowed to react for 16 hours. The reaction mixture was concentrated to obtain a solid residue, compound 3e, which was used directly in the next step without further purification.

[0198] Step 5: Synthesis of 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-11-methyl-4,5-dihydro-1,4,10,12-tetraazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]inden-3(1H)-one (3f)

[0199] Compound 3e (45 mg, 0.10 mmol) obtained in the previous step was dissolved in methanol / tetrahydrofuran / water (2 ml / 2 mL / 2 mL), and lithium hydroxide monohydrate (42 mg, 1.0 mmol) was added. The reaction was then allowed to react at 50°C for 12 hours. 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 3f (30 mg, 72% yield). LC-MS: m / z (ESI): 414.2 [M+H] + .

[0200] Step 6: Synthesis of 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-11-methyl-4,5-dihydro-1,4,10,12-tetraazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]inden-3(1H)-one (3)

[0201] Compound 3f (30 mg, 72 μmol) was dissolved in dichloromethane (4 mL) at room temperature. A solution of boron tribromide (1 mol / L, 2 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 3 (15 mg, 51% yield).

[0202] m / z(ESI):400.2[M+H] + .

[0203] 1 H NMR (400MHz, CD3OD) δ7.80-7.78(m,1H),7.54-7.52(m,2H),7.44-7.42(m,1H),7.17-7.14(m,1H),6.99(d ,J=8.4Hz,1H),5.21-5.16(m,1H),4.22-4.18(m,1H),2.63(s,3H),2.03-1.98(m,3H),1.84-1.78(m,3H).

[0204] Example 4: Preparation of 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-11-methyl-4,5-dihydro-1,4,6,10,12-pentaazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]inden-3(1H)-one (Compound 4)

[0205] Step 1: Synthesis of (2-cyanopyridin-3-yl)boronic acid (4b)

[0206] At -78°C, lithium tetramethylpiperidinium (28.4 mL, 1 M) was dissolved in anhydrous tetrahydrofuran. Triisopropyl borate (2.4 g, 13 mmol) was then added dropwise, followed by the dropwise addition of a solution of 2-cyanopyridine (1.4 g, 13 mmol) in tetrahydrofuran (10 mL). After the addition was complete, the reaction was brought to room temperature and continued for 12 hours. Saturated sodium bicarbonate solution (10 mL) was added to the reaction mixture to quench it. The mixture was extracted three times with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting solid was purified by normal phase chromatography (petroleum ether:ethyl acetate = 1:1 to 0:1) to afford compound 4b (1.5 g, 77% yield). m / z (ESI): 149.2 [M+H] + .

[0207] Step 2: Synthesis of (2-(((tert-Butoxycarbonyl)amino)methyl)pyridin-3-yl)boronic acid (4c)

[0208] At room temperature, compound 4b (1.5 g, 10 mmol) was dissolved in anhydrous methanol (10 mL). Di-tert-butyl dicarbonate (4.4 g, 20 mmol) and Pd / C (10%, 30 mg) were added. The atmosphere was then purged with hydrogen, and the reaction mixture was placed in a 50°C oil bath at 40 psi for 12 hours. After cooling to room temperature, the insoluble material was removed by filtration, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 to 1:3) to afford compound 4c (1.4 g, 55% yield). m / z (ESI): 253.2 [M+H] + .

[0209] Compound 4 was prepared by replacing compound 3c with compound 4c in a manner similar to that of Example 3.

[0210] m / z(ESI):401.2[M+H] + ;

[0211] 1H NMR (400MHz, DMSO-d6) δ9.61(d,J=8.4Hz,1H),8.61(dd,J=4.8,1.6Hz,1H),8.18-8.14(m,1H),8.07(t,J=7.0Hz,1H),7.51(dd,J=8.0,4.8Hz,1H) ,7.11-7.07(m,1H),7.05(s,2H),6.95(d,J=8.0Hz,1H),5.15-5.09(m,1H ),4.11-4.06(m,1H),2.50(m,3H),1.92-1.79(m,3H),1.71-1.58(m,3H).

[0212] Example 5: Preparation of 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-11-methyl-4,5-dihydro-1,4,7,10,12-pentaazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]inden-3(1H)-one (Compound 5)

[0213] Step 1: Synthesis of (3-(((tert-Butoxycarbonyl)amino)methyl)pyridin-4-yl)boronic acid (5b)

[0214] Compound 5a (1.2 g, 5.8 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL) at room temperature. The atmosphere was replaced with nitrogen three times. The reaction mixture was then placed at -78°C and tert-butyl lithium (11 mL, 1.3 mol / L pentane solution) was slowly added dropwise. After the addition was complete, the temperature was slowly raised to -20°C and stirred for 30 minutes. Trimethyl borate (2.4 g, 23 mmol) was then slowly added dropwise. After the addition was complete, the reaction mixture was brought to room temperature for 16 hours. Under an ice bath, saturated aqueous ammonium chloride was slowly added to the reaction mixture to quench the reaction. The mixture was extracted three times with a mixture of dichloromethane / methanol (3 / 1, 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to afford compound 5b (1.2 g, 54.53% yield), which was used directly in the next step. m / z (ESI): 253.2 [M+H] + .

[0215] Compound 5 was prepared by replacing compound 3c with compound 5b using a method similar to Example 3.

[0216] m / z(ESI):401.2[M+H] + ;

[0217] 1H NMR (400MHz, CD3OD) δ8.67-8.65(m,1H),8.56(s,1H),7.83-7.81(m,1H),7.17-7.11(m,1H),6.97-6. 95(m,1H),5.24-5.20(m,1H),4.32-4.28(m,1H),2.60(s,3H),2.00-1.93(m,3H),1.81-1.73(m,3H).

[0218] Example 6: Preparation of 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-11-methyl-4,5-dihydro-1,4,9,10,12-pentaazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]inden-3(1H)-one (Compound 6)

[0219] Step 1: Synthesis of tert-butyl ((2-bromopyridin-3-yl)methyl)carbamate (6b)

[0220] At room temperature, compound 6a (0.50 g, 2.7 mmol) was dissolved in dichloromethane (5 mL), and di-tert-butyl dicarbonate (0.88 g, 4 mmol) and triethylamine (0.54 g, 5.4 mmol) were added. The mixture was stirred for 30 minutes, concentrated in vacuo, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 0:1) to obtain compound 6b (0.70 g, 96% yield).

[0221] Step 2: Synthesis of tert-butyl ((2-(tributyltin)pyridin-3-yl)methyl)carbamate (6c)

[0222] Compound 6b (0.36 g, 1.3 mmol) was dissolved in tetrahydrofuran (4 mL) at room temperature. The atmosphere was replaced with nitrogen three times, and the reaction mixture was moved to -70°C. n-Butyllithium (1.1 mL, 2.5 mol / L tetrahydrofuran solution) was slowly added dropwise to the reaction mixture. After the addition was complete, stirring was continued at the same temperature for 30 minutes. Tri-n-butyltin chloride (0.90 g, 2.8 mmol) was then added dropwise to the reaction mixture. After the addition was complete, stirring was continued at -70°C for 2 hours. The reaction was quenched by the addition of a saturated potassium fluoride solution and stirred at room temperature for 1 hour. The mixture was extracted three times with ethyl acetate (10 mL). The combined organic phases were washed once with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 10:1) to obtain compound 6c (0.20 g, 32% yield).

[0223] Compound 6 was prepared by replacing compound 3c with compound 6c in a manner similar to that of Example 3.

[0224] m / z(ESI):401.2[M+H] + .

[0225] 1 H NMR (400MHz, DMSO-d6) δ8.65-8.64(m,1H),7.78(t,J=7.2Hz,1H),7.65(dd,J=1. 6,7.6Hz,1H),7.40(dd,J=4.4,7.6Hz,1H),7.03(dd,J=8.4,13.6Hz,1H),6.98(br s,2H),6.89(d,J=8.0Hz,1H),6.33-6.13(m,1H),4.92-4.86(m,1H),4.03(dd,J=6.4,14.8Hz,1H),2.47(br s,3H),1.85-1.74(m,3H),1.64-1.53(m,3H).

[0226] Example 7: Preparation of 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-11-methyl-4,5-dihydro-1,4,8,10,12-pentaazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]inden-3(1H)-one (Compound 7)

[0227] Compound 7 was prepared by replacing compound 4b with compound 7a using a method similar to Example 4.

[0228] m / z(ESI):401.2[M+H] + ;

[0229] 1 H NMR (400MHz, DMSO-d6) δ8.65-8.64(m,1H),7.78(t,J=7.2Hz,1H),7.65(dd,J=1. 6,7.6Hz,1H),7.40(dd,J=4.4,7.6Hz,1H),7.03(dd,J=8.4,13.6Hz,1H),6.98(br s,2H),6.89(d,J=8.0Hz,1H),6.33-6.13(m,1H),4.89(ddd,J=3.2,7.6,14.8Hz,1H),4.03(dd,J=6.4,14.8Hz,1H),2.47(br s,3H),1.85-1.74(m,3H),1.64-1.53(m,3H).

[0230] Example 8: Preparation of 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-7,10-dimethyl-1,4,5,7-tetrahydro-3H-1,4,6,7,9,11-hexaazacyclopenta[4,5]cyclooctatetraeno[1,2,3-cd]inden-3-one (Compound 8)

[0231] Step 1: Synthesis of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-3-carbonitrile (8b)

[0232] At room temperature, compound 8a (1.0 g, 5.4 mmol), pinacol diboron (1.6 g, 6.4 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.23 g, 0.54 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) (0.40 g, 0.54 mmol) and potassium acetate (1.1 g, 11 mmol) were dissolved in 1,4-dioxane, the air was replaced with nitrogen three times, and then the reaction was carried out at 95 ° C for 5 hours under nitrogen protection. The reaction mixture was cooled to room temperature and filtered. The solid was washed with ethyl acetate. The organic phase was washed with saturated brine (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1-1:3) to obtain compound 8b (0.60 g, 47% yield). m / z (ESI): 234.3 [M+H] + .

[0233] Step 2: Synthesis of methyl 6-amino-4-(3-cyano-1-methyl-1H-pyrazol-4-yl)-7-(3-methoxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (8c)

[0234] At room temperature, compound 3b (0.37 g, 1.0 mmol), compound 8b (0.3 g, 1.3 mmol), bis(dibenzylideneacetone)palladium (91 mg, 99 μmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphoryladamantane (0.12 g, 0.40 mmol), and cesium carbonate (0.65 g, 2.0 mmol) were dissolved in 1,4-dioxane / water (4 mL / 0.8 mL). The atmosphere was replaced with nitrogen three times. The reaction mixture was then moved to 100°C for 16 hours. After cooling to room temperature, the insoluble matter was removed by filtration. The filtrate was then dried by spin drying. The resulting residue was purified by column chromatography (petroleum ether:ethyl acetate = 1:1 to 1:3) to obtain the product, compound 8c (0.20 mg, 44% yield). m / z (ESI): 446.2 [M+H] + .

[0235] Step 3: Synthesis of methyl 6-amino-4-(3-(aminomethyl)-1-methyl-1H-pyrazol-4-yl)-7-(3-methoxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (8d)

[0236] Compound 8c (0.20 g, 0.45 mmol) and cobalt chloride hexahydrate (0.53 g, 2.2 mmol) were dissolved in anhydrous methanol under ice conditions. Sodium borohydride (85 mg, 2.2 mmol) was then added and the mixture was allowed to warm to room temperature for 2 hours. Water (10 mL) was added to the reaction mixture to quench it. The mixture was extracted three times with ethyl acetate (15 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting solid was used in the next step without purification. m / z (ESI): 450.2 [M+H] + .

[0237] Compound 8 was prepared by replacing compound 3e with compound 8d using a method similar to Example 3.

[0238] m / z(ESI):404.1[M+H] + ;

[0239] 1H NMR (400MHz, DMSO-d6) δ9.58(s,1H),8.07(s,1H),7.83(t,J=6.4Hz,1H),7.08(d,J=8.0Hz,1H),6.94(d,J=8 .4Hz,1H),6.86(s,2H),4.68-4.45(m,1H),4.10-3.92(m,1H),3.87(s,3H),2.40(s,3H),1.90-1.54(m,6H).

[0240] Example 9: Preparation of 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-7,11-dimethyl-4,5-dihydro-1,4,6,10,12-pentaazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]inden-3(1H)-one (Compound 9)

[0241] Step 1: Synthesis of 6-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine cyanide (9b)

[0242] At room temperature, compound 9a (1.0 g, 5.1 mmol), pinacol diboron (1.9 g, 7.6 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.22 g, 0.51 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) (0.37 g, 0.51 mmol) and potassium acetate (1.0 g, 10 mmol) were dissolved in anhydrous 1,4-dioxane (20 mL). The air was replaced with nitrogen three times, and the mixture was reacted at 100 °C under nitrogen protection for 10 h. After the reaction solution was cooled to room temperature, water (20 mL) was added to the reaction solution to quench the reaction. The mixture was extracted three times with ethyl acetate (100 mL*3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by column chromatography (petroleum ether:ethyl acetate = 100:1 to 10:1) to obtain the product, compound 9b (0.65 g, yield 52%). m / z (ESI): 245.1 [M+H] + .

[0243] Step 2: Synthesis of (2-(((tert-Butoxycarbonyl)amino)methyl)-6-methylpyridin-3-yl)boronic acid (9c)

[0244] At room temperature, compound 9b (0.5 g, 2.0 mmol) was dissolved in anhydrous methanol (30 mL). Di-tert-butyl dicarbonate (0.89 g, 4.1 mmol) and Pd / C (10%, 50 mg) were added. The air was then purged with hydrogen, and the reaction mixture was placed in a 50°C oil bath under 50 psi pressure for 10 hours. After the reaction mixture was cooled to room temperature, the insoluble matter was removed by filtration. The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 1:1) to obtain the product, compound 9c (0.12 g, 22% yield). m / z (ESI): 267.2 [M+H] + .

[0245] Compound 9 was prepared by replacing compound 3c with compound 9c in a manner similar to that of Example 3.

[0246] m / z(ESI):415.1[M+H] + ;

[0247] 1 H NMR (400MHz, CD3OD) δ8.13-8.11(m,1H),7.43(d,J=8.0Hz,1H),7.16-7.11(m,1H),6.96(d,J=8.4Hz,1H) ,5.32-5.28(m,1H),4.22-4.18(m,1H),2.64(s,3H),2.59(s,3H),2.00-1.94(m,3H),1.79-1.74(m,3H).

[0248] Example 10: Preparation of 2-amino-6-ethyl-1-(3-hydroxy-2,6-dimethylphenyl)-11-methyl-4,5-dihydro-1,4,10,12-tetraazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]inden-3(1H)-one (Compound 10)

[0249] Step 1: Synthesis of 2-bromo-6-vinylbenzonitrile (10b)

[0250] At room temperature, compound 10a (2.0 g, 6.5 mmol) and vinylboronic acid pinacol ester (0.30 g, 1.5 mmol) were dissolved in a mixture of 1,4-dioxane (20 mL) and water (4 mL). [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.47 g, 0.65 mmol) and potassium carbonate (2.7 g, 19 mmol) were added. The atmosphere was purged with nitrogen three times, and the mixture was allowed to react at 80°C for 12 hours. After cooling to room temperature, the insoluble material was removed by filtration, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:0 to 99:1) to obtain compound 10b (0.90 g, 67% yield).

[0251] Step 2: Synthesis of 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-vinylbenzonitrile (10c)

[0252] At room temperature, compound 10b (0.83 g, 4.0 mmol), pinacol diboron (1.5 g, 6.0 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.29 g, 0.40 mmol), and potassium acetate (0.78 g, 8.0 mmol) were dissolved in 1,4-dioxane. The air was replaced with nitrogen three times, and the mixture was reacted at 85°C under nitrogen for 12 hours. After the reaction mixture was cooled to room temperature, water (50 mL) was added to quench the reaction. The mixture was extracted three times with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by column chromatography (petroleum ether:ethyl acetate = 100:1 to 20:1) to obtain the product, compound 10c (0.95 g, 93% yield).

[0253] Step 3: Synthesis of methyl 6-amino-4-(2-cyano-3-vinylphenyl)-7-(3-methoxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (10d)

[0254] Compound 3b (0.29 g, 0.78 mmol), compound 10c (0.40 g, 1.6 mmol), tris(dibenzylideneacetone)dipalladium (72 mg, 78 μmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphoryladamantane (92 mg, 0.32 mmol), and cesium carbonate (0.51 g, 1.6 mmol) were dissolved in 1,4-dioxane / water (2 mL / 0.4 mL) at room temperature. The atmosphere was replaced with nitrogen three times. The reaction mixture was then moved to 100°C for 4 hours. After the reaction was cooled to room temperature, the insoluble material was filtered off and saturated brine (10 mL) was added. The mixture was extracted three times with ethyl acetate (30 mL * 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:1) to obtain the product compound 10d (0.25 g, yield 65%). m / z (ESI): 468.2 [M+H] + .

[0255] Step 4: Synthesis of methyl 6-amino-4-(2-(((tert-butoxycarbonyl)amino)methyl)-3-ethylphenyl)-7-(3-methoxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (10e)

[0256] At room temperature, compound 10d (0.25 g, 0.53 mmol) was dissolved in anhydrous methanol (10 mL). Di-tert-butyl dicarbonate (0.17 g, 0.80 mmol) and Raney nickel (10 mg, 53 μmol) were added. The atmosphere was then purged with hydrogen and the reaction was continued at room temperature under 45 psi for 3 hours. The insoluble matter was removed by filtration, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 to 1:3) to obtain compound 10e (0.25 g, 82% yield). m / z (ESI): 574.5 [M+H] + .

[0257] Compound 10 was prepared by replacing compound 3d with compound 10e using a method similar to Example 3.

[0258] m / z(ESI):428.2[M+H] + ;

[0259] 1H NMR (400MHz, DMSO-d6) δ9.83-9.69(m,1H),8.26(d,J=6.4Hz,1H),7.67-7.57(m,5H),7.14(dd,J=13.6,8.4Hz,1H),7.02(d,J=8.4Hz,1H),5.09- 5.03(m,1H),4.36-4.31(m,1H),3.04-2.98(m,1H),2.84-2.78(m,1H),2 .68(s,3H),1.98-1.83(m,3H),1.78-1.58(m,3H),1.23(t,J=7.6Hz,3H).

[0260] Example 11: Preparation of 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-6-methoxy-11-methyl-4,5-dihydro-1,4,10,12-tetraazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]inden-3(1H)-one (Compound 11)

[0261] Step 1: Synthesis of (2-cyano-3-methoxyphenyl)boronic acid (11b)

[0262] Compound 11a (4 g, 19 mmol) was dissolved in anhydrous tetrahydrofuran, and a solution of isopropylmagnesium chloride (16 mL, 1.3 M) in tetrahydrofuran was added dropwise at -70°C. After complete addition, the mixture was allowed to react at 0°C for 1 hour. Trimethylborate (2.2 g, 21 mmol) was then added dropwise at -70°C. The mixture was then allowed to react at room temperature for 12 hours. Water (20 mL) was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography (petroleum ether:ethyl acetate = 100:1 to 20:1) to afford compound 11b (2.5 g, 53% yield).

[0263] Step 2: Synthesis of (2-(((tert-Butoxycarbonyl)amino)methyl)-3-methoxyphenyl)boronic acid (11c)

[0264] At room temperature, compound 11b (2 g, 11 mmol) was dissolved in anhydrous methanol (10 mL). Di-tert-butyl dicarbonate (4.9 g, 13 mmol) and Raney nickel (66 mg, 1.1 mmol) were added. The atmosphere was then purged with hydrogen, and the reaction mixture was placed in a 50°C oil bath at 40 psi for 12 hours. After cooling to room temperature, the insoluble material was removed by filtration, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 to 1:3) to obtain compound 11c (1.4 g, 32% yield). m / z (ESI): 280.2 [MH] - .

[0265] Step 3: Synthesis of N-(3-(benzyloxy)-2,6-dimethylphenyl)-6-chloro-5-iodo-2-methylpyrimidin-4-amine (11f)

[0266] At room temperature, compound 11d (5.0 g, 17 mmol) and compound 11e (4.7 g, 21 mmol) were dissolved in N-methylpyrrolidone (50 mL), and p-toluenesulfonic acid monohydrate (0.60 g, 3.5 mmol) was added. The mixture was stirred at 105°C for 12 h. After cooling to room temperature, the reaction mixture was diluted with water (100 mL) and 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 was concentrated. The resulting residue was purified by normal phase chromatography (petroleum ether:ethyl acetate = 50:1) to obtain the desired product, compound 11f (1.2 g, 14% yield). m / z (ESI): 480.1 [M+H] + .

[0267] Step 4: Synthesis of methyl 6-amino-7-(3-(benzyloxy)-2,6-dimethylphenyl)-4-chloro-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (11 g)

[0268] Methyl cyanoacetate (0.50 g, 5.0 mmol) was dissolved in anhydrous ethylene glycol dimethyl ether (12 mL). Cesium carbonate (2.4 g, 7.4 mmol) was added and stirred at room temperature for 30 minutes. Compound 11f (0.60 g, 1.2 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (92 mg, 0.12 mmol) were then added. The atmosphere was replaced with nitrogen three times, and the reaction was continued at 85°C for 3 hours under nitrogen protection. 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 obtain compound 11g (0.21 g, 35% yield). m / z (ESI): 451.1 [M+H] + .

[0269] Step 5: Synthesis of methyl 6-amino-7-(3-(benzyloxy)-2,6-dimethylphenyl)-4-(2-(((tert-butoxycarbonyl)amino)methyl)-3-methoxyphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (11h)

[0270] Compound 11g (0.13 g, 0.36 mmol), compound 11c (0.10 g, 0.36 mmol), bis(dibenzylideneacetone)palladium (32 mg, 36 μmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphoryladamantane (42 mg, 0.14 mmol), and cesium carbonate (0.23 g, 0.71 mmol) were dissolved in 1,4-dioxane / water (5 mL / 1 mL) at room temperature. The atmosphere was replaced with nitrogen three times. The reaction mixture was then moved to 100°C for 16 hours. After the reaction mixture was cooled to room temperature, water (10 mL) was added to dilute the reaction mixture, followed by extraction 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 = 1:1) to obtain the target product, compound 11h (0.10 g, yield 48%). m / z (ESI): 652.4 [M+H] + .

[0271] Step 6: Synthesis of methyl 6-amino-4-(2-(aminomethyl)-3-methoxyphenyl)-7-(3-(benzyloxy)-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (11i)

[0272] Compound 11h (50 mg, 87 μmol) was dissolved in a solution of hydrogen chloride in ethyl acetate (4 M in EtOAc, 4.8 mL) at room temperature and allowed to react for 2 hours. Upon completion of the reaction, the reaction solution was concentrated to obtain a solid residue, compound 11i (40 mg), which was used directly in the next step without purification.

[0273] Step 7: Synthesis of 2-amino-1-(3-(benzyloxy)-2,6-dimethylphenyl)-6-methoxy-11-methyl-4,5-dihydro-1,4,10,12-tetraazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]inden-3(1H)-one (11j)

[0274] Compound 11i (40 mg, 84 μmol) obtained in the previous step was dissolved in methanol / tetrahydrofuran / water (2 ml / 2 mL / 2 mL), and lithium hydroxide monohydrate (10 mg, 0.42 mmol) was added. The reaction was then allowed to react at room temperature for 3 hours. 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 11j (35 mg, yield 89%). LC-MS: m / z (ESI): 520.3 [M+H] + .

[0275] Step 8: Synthesis of 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-6-methoxy-11-methyl-4,5-dihydro-1,4,10,12-tetraazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]inden-3(1H)-one (Compound 11)

[0276] Compound 11j (35 mg, 79 μmol) was dissolved in anhydrous methanol (5 mL) at room temperature, followed by the addition of Pd / C (10%, 7.2 mg). The atmosphere was then purged with hydrogen, and the reaction mixture was maintained at 40 psi for 12 hours at 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% aqueous ammonia:acetonitrile = 20:1 to 1:20) to afford compound 11 (21 mg, 62% yield).

[0277] m / z(ESI):430.1[M+H] + ;

[0278] 1H NMR (400MHz, CDCl3) δ8.84-8.66(m,1H),7.55-7.40(m,2H),7.04-6.92(m,2H),6.80-6.60(m,1H),6.06-5.99(m,2H),5.01(br dd,J=8.8,14.8Hz,1H),4.65-4.55(m,1H),3.95(s,3H),2.82(s,3H),2.02-1.88(m,3H),1.84-1.70(m,3H).

[0279] Example 12: Preparation of 5-amino-4-(3-hydroxy-2,6-dimethylphenyl)-2,8-dimethyl-7,8-dihydro-1,3,4,7,8,9-hexaazabenzo[cd]cyclopenta[f]azulen-6(4H)-one (Compound 12)

[0280] Step 1: Synthesis of N-(4-bromo-2-methyl-pyrazol-3-yl)-N-tert-butoxycarbonyl-carbamic acid tert-butyl ester (12b)

[0281] At room temperature, compound 12a (2.0 g, 11 mmol) was dissolved in anhydrous dichloromethane solution, and then di-tert-butyl dicarbonate (3.7 g, 17 mmol), triethylamine (2.3 g, 23 mmol) and 4-dimethylaminopyridine (0.14 g, 1.1 mmol) were added in sequence. The reaction was continued under the same conditions for 5 hours. Water (20 mL) was added to the reaction to quench the reaction. The reaction was extracted three times with ethyl acetate (100 mL*3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 3:1) to obtain the product compound 12b (3.1 g, yield 73%).

[0282] Step 2: Synthesis of tert-butyl N-tert-butoxycarbonyl-N-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-3-yl]carbamate (12c)

[0283] At room temperature, compound 12b (3.0 g, 8.0 mmol), bis(diphenylphosphino)ferrocene (3.0 g, 12 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.59 g, 0.80 mmol), and potassium acetate (1.6 g, 16 mmol) were dissolved in anhydrous 1,4-dioxane. The air was replaced with nitrogen three times, and the mixture was reacted at 95°C under nitrogen for 5 hours. After the reaction mixture was cooled to room temperature, water (50 mL) was added to quench the reaction. The mixture was extracted three times with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by column chromatography (petroleum ether:ethyl acetate = 100:1 to 20:1) to obtain the product, compound 12c (1.8 g, 53% yield). m / z (ESI): 424.2 [M+H] + .

[0284] Compound 12c was used to replace compound 3c, and compound 12 was prepared using a method similar to Example 3.

[0285] m / z(ESI):390.1[M+H] + ;

[0286] 1 H NMR (400MHz, DMSO-d6) δ7.70(s,1H),7.08(d,J=8.4Hz,1H),6.94(d,J=8.4Hz,1H),6.91(s,2H),3.74(s,3H),2.35(s,3H),1.80(s,3H),1.71(s,3H).

[0287] Example 13: Preparation of 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-6,9-dimethyl-4,6-dihydro-1,4,5,6,8,10-hexaazabenzo[cd]cyclopenta[f]azulen-3(1H)-one (Compound 13)

[0288] Step 1: Synthesis of tert-butyl (4-bromo-1-methyl-1H-pyrazol-3-yl)carbamate (13b)

[0289] Compound 13a (0.3 g, 1.7 mmol) was dissolved in tetrahydrofuran (10 mL) at room temperature, and di-tert-butyl dicarbonate (2.2 g, 10 mmol) and 4-dimethylaminopyridine (20 mg, 0.2 mmol) were added. The reaction was moved to 60°C for 2 hours, then concentrated under vacuum to remove the solvent. The crude product was dissolved in ethanol (10 mL), and sodium hydroxide solution (2 mL, 20% aqueous solution) was added. The reaction was continued at room temperature for 3 hours, and the solvent was removed by vacuum concentration. The crude product was purified by reverse phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to obtain compound 13b (0.32 g, 67% yield). m / z (ESI): 220.0 [M+H-tBu] + .

[0290] Step 2: Synthesis of tert-butyl (1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-3-yl)carbamate (13c)

[0291] At room temperature, compound 13b (320 mg, 1.2 mmol), pinacol diboron (0.61 g, 2.4 mmol), potassium acetate (0.35 g, 3.6 mmol), and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (90 mg, 0.12 mmol) were dissolved in dioxane (10 mL). The atmosphere was replaced with nitrogen three times and the mixture was heated to 80°C for 2 hours. After cooling to room temperature, the reaction mixture was filtered and concentrated in vacuo. The crude product was used directly in the next step without further purification.

[0292] Compound 13c was used to replace compound 3c, and compound 13 was prepared by a method similar to Example 3.

[0293] m / z(ESI):390.1[M+H] + ;

[0294] 1 H NMR(400MHz,DMSO-d6)δ9.60(s,1H),9.54(s,1H),8.11(s,1H),7.07(d,J=8.4Hz,1H),6 .93(d,J=8.4Hz,1H),6.89(s,2H),3.74(s,3H),2.35(s,3H),1.78(s,3H),1.69(s,3H).

[0295] Example 14: Preparation of 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-9-methyl-6-(2,2,2-trifluoroethyl)-4,6-dihydro-1,4,5,6,8,10-hexaazabenzo[cd]cyclopenta[f]azulene-3(1H)-one (Compound 14)

[0296] Step 1: Synthesis of 4-bromo-3-nitro-1-(2,2,2-trifluoroethyl)-1H-pyrazole (14b)

[0297] Compound 14a (2.0 g, 10 mmol) was dissolved in DMF (5 mL) under ice conditions, followed by the addition of cesium carbonate (6.8 g, 21 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.9 g, 10 mmol). The mixture was then allowed to warm to room temperature and allowed to react for 3 hours. Water (20 mL) was added to the reaction mixture to quench it. The mixture was extracted three times with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. The crude product was used directly in the next step without further purification. m / z (ESI): 273.7 [M+H] + .

[0298] Step 2: Synthesis of 4-bromo-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-amine (14c)

[0299] Compound 14b (2.7 g, 9.7 mmol) was dissolved in methanol (20 mL), followed by the addition of iron powder (2.7 g, 49 mmol) and acetic acid (5.8 g, 97 mmol). The mixture was heated to 70°C and allowed to react for 2 hours. After cooling to room temperature, water (20 mL) was added to quench the reaction. The mixture was extracted three times with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 50:1 to 20:1) to obtain the target compound 14c (1.5 g, 62% yield). m / z (ESI): 244.3 [M+H] + .

[0300] Compound 14 was prepared by replacing compound 13a with compound 14c and adopting a method similar to Example 13.

[0301] m / z(ESI):458.2[M+H] + .

[0302] 1H NMR (400MHz, DMSO-d6) δ9.72(s,1H),9.58(s,1H),8.28(s,1H),7.08(d,J=8.3H z,1H),7.01-6.89(m,3H),2.54(s,2H),2.38(s,3H),1.79(s,3H),1.70(s,3H).

[0303] Example 15: Preparation of 5-amino-9-fluoro-4-(3-hydroxy-2,6-dimethylphenyl)-2-methyl-4,7-dihydro-6H-1,3,4,7,10-pentaazadibenzo[cd,f]azulen-6-one (Compound 15)

[0304] Step 1: Synthesis of tert-butyl (5-bromo-2-fluoropyridin-4-yl)carbamate (15b)

[0305] Compound 15a (0.90 g, 4.1 mmol) was dissolved in tert-butanol, followed by the addition of diphenylphosphoryl azide (1.7 g, 6.1 mmol) and triethylamine (0.83 g, 1.1 mL, 8.2 mmol). The reaction was then incubated at 100°C for 16 hours. The solvent was removed by vacuum concentration, and the resulting crude product was purified by normal phase column chromatography (petroleum ether:ethyl acetate = 100:1 to 20:1) to afford compound 15b (1.2 g, 82% yield).

[0306] Step 2: Synthesis of tert-butyl (2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-yl)carbamate (15c)

[0307] At room temperature, compound 15b (1.0 g, 3.4 mmol), pinacol diboron (1.7 g, 6.9 mmol), potassium acetate (1.0 g, 10 mmol), and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (0.25 g, 0.34 mmol) were dissolved in dioxane (10 mL). The atmosphere was replaced with nitrogen three times and the mixture was heated to 85°C for 2 hours. After cooling to room temperature, the reaction mixture was filtered and concentrated in vacuo. The crude product was purified by normal phase column chromatography (petroleum ether:ethyl acetate = 100:1 to 20:1) to afford compound 15c (0.95 g, 83% yield).

[0308] Compound 15 was prepared by replacing compound 3c with compound 15c in a manner similar to that of Example 3.

[0309] m / z(ESI):405.1[M+H] + ;

[0310] 1H NMR(400MHz,DMSO-d6)δ9.71(s,1H),9.62(s,1H),9.17(s,1H),7.11(s,2H),7.09(d,J= 8.0Hz,1H),6.95(d,J=8.4Hz,1H),6.73(s,1H),2.45(s,3H),1.80(s,3H),1.71(s,3H).

[0311] Example 16: Preparation of 5-amino-8-fluoro-4-(3-hydroxy-2,6-dimethylphenyl)-2-methyl-4,7-dihydro-6H-1,3,4,7,10-pentaazadibenzo[cd,f]azulen-6-one (Compound 16)

[0312] Step 1: Synthesis of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine (16b)

[0313] At room temperature, compound 16a (0.50 g, 2.6 mmol), pinacol diboron (0.86 g, 3.4 mmol), potassium acetate (0.64 g, 6.5 mmol), and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (0.19 g, 0.26 mmol) were dissolved in dioxane (15 mL). The air was replaced with nitrogen three times and the mixture was heated to 100°C for 16 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The crude product was purified by normal phase column chromatography (petroleum ether:ethyl acetate = 100:1 to 20:1) to obtain compound 16b (0.30 g, 48% yield). m / z (ESI): 238.2 [MH] - .

[0314] Step 2: Synthesis of 5-amino-8-fluoro-4-(3-methoxy-2,6-dimethylphenyl)-2-methyl-4,7-dihydro-6H-1,3,4,7,10-pentaazadibenzo[cd,f]azulene-6-one (16c)

[0315] Compound 16b (0.20 g, 0.84 mmol), compound 3b (0.17 g, 0.47 mmol), bis(dibenzylideneacetone)palladium (43 mg, 47 μmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphoryladamantane (54 mg, 0.19 mmol), and cesium carbonate (0.30 g, 0.93 mmol) were dissolved in 1,4-dioxane / water (5 mL / 1 mL) at room temperature. The atmosphere was replaced with nitrogen three times. The reaction mixture was then moved to 110°C for 2 hours. After the reaction mixture was cooled to room temperature, water (10 mL) was added to dilute the reaction mixture, followed by extraction 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 = 1:1) to obtain the target product, compound 16c (0.15 g, yield 77%). m / z (ESI): 451.2 [M+H] + .

[0316] Step 3: Synthesis of 5-amino-8-fluoro-4-(3-hydroxy-2,6-dimethylphenyl)-2-methyl-4,7-dihydro-6H-1,3,4,7,10-pentaazadibenzo[cd,f]azulen-6-one (16)

[0317] Compound 16c (0.15 g, 0.36 mmol) was dissolved in dichloromethane (4 mL) at room temperature. A solution of boron tribromide (1 mol / L, 2 mL) in dichloromethane was added and stirred for 30 minutes. The reaction mixture 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 16 (3.4 mg, 2.4% yield).

[0318] m / z(ESI):405.1[M+H] + ;

[0319] 1 H NMR (400MHz, CDCl3) δ9.42(s,1H),8.33(d,J=2.8Hz,1H),7.15(d,J=9.2Hz,1H),6.97(d,J=7.6Hz,1H),2.56(s,3H),1.92(s,3H),1.87(s,3H).

[0320] Example 17: Preparation of 5-amino-4-(3-hydroxy-2,6-dimethylphenyl)-2-methyl-4,7-dihydro-6H-1,3,4,7,8-pentaazadibenzo[cd,f]azulen-6-one (Compound 17)

[0321] Compound 17 was prepared by replacing compound 16b with compound 17a in a manner similar to that of Example 16.

[0322] m / z(ESI):387.2[M+H] + .

[0323] Example 18: Preparation of 5-amino-4-(3-hydroxy-2,6-dimethylphenyl)-2-methyl-4,7-dihydro-6H-1,3,4,7,9-pentaazadibenzo[cd,f]azulen-6-one (Compound 18)

[0324] Compound 18a was used to replace compound 16b, and a method similar to Example 16 was used to prepare compound 18.

[0325] m / z(ESI):387.2[M+H] + .

[0326] 1 H NMR (400MHz, DMSO-d6) δ9.68(s,1H),9.31(s,1H),8.36(s,1H),8.23(d,J=5.2Hz,1H),8.14(d,J=5.2Hz ,1H),7.09(d,J=8.0Hz,1H),7.07(s,2H),6.95(d,J=8.0Hz,1H),2.46(s,3H),1.79(s,3H),1.71(s,3H).

[0327] Example 19: Preparation of 5-amino-4-(3-hydroxy-2,6-dimethylphenyl)-2-methyl-4,7-dihydro-6H-1,3,4,7,10-pentaazadibenzo[cd,f]azulen-6-one (Compound 19)

[0328] Step 1: Synthesis of tert-butyl (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-yl)carbamate (19b)

[0329] At room temperature, compound 19a (5.0 g, 18 mmol), pinacol diboronate (7.0 g, 27 mmol), potassium acetate (3.6 g, 37 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (1.3 g, 1.8 mmol), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.87 g, 1.8 mmol) were dissolved in 1,4-dioxane (20 mL). The air was replaced with nitrogen three times and the mixture was heated to 100°C for 12 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The crude product was recrystallized from acetonitrile and ethyl acetate to obtain compound 19b (2.0 g, 34% yield). m / z (ESI): 319.2 [MH] - .

[0330] Compound 19 was prepared by replacing compound 3c with compound 19b using a method similar to Example 3.

[0331] m / z(ESI):387.2[M+H] + .

[0332] Example 20: Preparation of 5-amino-4-(3-hydroxy-2,6-dimethylphenyl)-2-methyl-4,7-dihydro-6H-1,3,4,7,11-pentaazadibenzo[cd,f]azulen-6-one (Compound 20)

[0333] Compound 20 was prepared by replacing compound 16b with compound 20a in a manner similar to that of Example 16.

[0334] m / z(ESI):387.2[M+H] + ;

[0335] 1 H NMR (400MHz, DMSO-d6) δ9.71 (s, 1H), 8.83-8.81 (m, 2H), 8.24 (dd, J = 4.8, 1.6Hz, 1H), 7.11 -7.07(m,2H),7.05(s,2H),6.96(d,J=8.4Hz,1H),2.46(s,3H),1.81(s,3H),1.72(s,3H).

[0336] Example 21: Preparation of 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-6,10-dimethyl-1,4,5,6-tetrahydro-3H-1,4,6,7,9,11-hexaazacyclopenta[4,5]cyclooctatetraeno[1,2,3-cd]inden-3-one (Compound 21)

[0337] Compound 21 was prepared by replacing compound 8a with compound 21a in a manner similar to that of Example 8.

[0338] m / z(ESI):404.1[M+H] + .

[0339] 1 H NMR (400MHz, DMSO-d6) δ9.62 (s, 1H), 7.97-7.93 (m, 1H), 7.71 (s, 1H), 7.09 (d, J = 8.0Hz, 1H), 6 .95-6.90(m,3H),4.74(brs,1H),4.28(brs,1H),3.91(s,3H),2.42(s,3H),1.87-1.61(m,6H).

[0340] Example 22: Preparation of 2-amino-8-fluoro-1-(3-hydroxy-2,6-dimethylphenyl)-11-methyl-4,5-dihydro-1,4,6,10,12-pentaazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]inden-3(1H)-one (Compound 22)

[0341] Step 1: Synthesis of tert-butyl ((3-bromo-5-fluoropyridin-2-yl)methyl)carbamate (22b)

[0342] Compound 22a (1.0 g, 4.1 mmol) was dissolved in anhydrous methanol (10 mL) at room temperature. Di-tert-butyl dicarbonate (0.90 g, 4.1 mmol) and sodium bicarbonate (0.70 g, 8.2 mmol) were added to the system and reacted at room temperature for 2 hours. Water (20 mL) was added to the reaction to quench the reaction. The mixture was extracted three times with ethyl acetate (100 mL*3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude compound 22b was used directly in the next step without purification. m / z (ESI): 251.0 [M+H-C4H9] + .

[0343] Step 2: Synthesis of tert-butyl ((5-fluoro-3-(tri-n-butyltin)pyridin-2-yl)methylcarbamate (22c)

[0344] Compound 22b (1.0 g, 3.3 mmol), tetrakis(triphenylphosphine)palladium (0.38 g, 0.33 mmol), hexabutyltin (3.8 g, 6.6 mmol), and lithium chloride (0.42 g, 9.9 mmol) were dissolved in anhydrous 1,4-dioxane (15 mL). The air was replaced with nitrogen three times and the mixture was heated to 110°C for 16 hours. After the reaction mixture cooled to room temperature, water (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by column chromatography (petroleum ether:ethyl acetate = 100:1 to 7:1) to obtain compound 22c (0.15 g, 7% yield). m / z (ESI): 517.2 [M+H] + .

[0345] Step 3: Synthesis of methyl 6-amino-4-(2-(((tert-butoxycarbonyl)amino)methyl)-5-fluoropyridin-3-yl)-7-(3-methoxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (22d)

[0346] Compound 22c (0.15 g, 0.28 mmol), compound 3b (73 mg, 0.19 mmol), tetrakis(triphenylphosphine)palladium (22 mg, 19 μmol), cuprous iodide (7.4 mg, 39 μmol), and triphenylphosphine (64 mg, 0.24 mmol) were dissolved in N,N-dimethylformamide (1 mL) at room temperature. The atmosphere was replaced with nitrogen three times, and the reaction mixture was moved to 100°C for 12 hours. Water (30 mL) was added to the reaction mixture to quench it. The mixture was extracted three times with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by column chromatography (petroleum ether:ethyl acetate = 100:1 to 1:2) to afford compound 22d (95 g, 88% yield). m / z (ESI): 565.3 [M+H] + .

[0347] Compound 22d was used to replace compound 3d, and a method similar to Example 3 was used to prepare compound 22.

[0348] m / z(ESI):419.1[M+H] + ;

[0349] 1H NMR (400MHz, CD3OD) δ8.53(d,J=2.8Hz,1H),8.02(dt,J=9.6,2.4Hz,1H),7.14(dd,J=8.4,13.6Hz,1H),6.96(d,J=8 .4Hz,1H),5.31(dd,J=4.0,14.4Hz,1H),4.29(d,J=14.8Hz,1H),2.61(s,3H),2.02-1.92(m,3H),1.83-1.71(m,3H).

[0350] Example 23: Preparation of 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-6-methoxy-11-methyl-4,5-dihydro-1,4,7,10,12-pentaazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]inden-3(1H)-one (Compound 23)

[0351] Step 1: Synthesis of (3-cyano-2-methoxypyridin-4-yl)boronic acid (23b)

[0352] At -30°C, n-butyllithium (2.5 M, 7.1 mmol, 2.8 mL) was added dropwise to a solution of 2,2,6,6-tetramethylpiperidine (1.1 g, 7.8 mmol) in tetrahydrofuran (10 mL), and the temperature was raised to 0°C for 30 minutes. A solution of 3-cyano-2-methoxypyridine (23a, 0.50 g, 3.7 mmol) in tetrahydrofuran (5 mL) was then added dropwise at -78°C. After stirring for 30 minutes, a solution of trimethyl borate (1.4 g, 7.5 mmol) in tetrahydrofuran was added dropwise, and the reaction was continued for another 30 minutes. At -78°C, saturated ammonium chloride solution was added to the reaction to quench the reaction. The reaction solution was concentrated, and then formic acid was added dropwise to adjust the pH of the solution to 5. The solution was extracted with ethyl acetate (50 mL*3). The organic phases were combined, washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the residue, compound 23b (0.40 g, purity 55%), which was used directly in the next step without purification.

[0353] Step 2: Synthesis of methyl 6-amino-7-(3-benzyloxy-2,6-dimethylphenyl)-4-(3-cyano-2-methoxypyridin-4-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (23c)

[0354] Compound 11g (0.20 g, 0.44 mmol), compound 23b (55% purity) (0.19 g, 0.58 mmol), tris(dibenzylideneacetone)dipalladium (19 mg, 44 μmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphoryladamantane (13 mg, 44 μmol) and cesium carbonate (0.29 g, 0.89 mmol) were dissolved in 1,4-dioxane / water (5 mL / 1 mL) at room temperature. The air was replaced with nitrogen three times, and the reaction mixture was moved to 100°C for 2 hours. After the reaction was cooled to room temperature, the insoluble material was filtered off and diluted with water (10 mL). The mixture was then 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 = 1:1) to obtain the product, compound 23c (0.14 g, yield 54%). m / z (ESI): 549.2 [M+H] + .

[0355] Step 3: Synthesis of methyl 6-amino-4-(3-(aminomethyl)-2-methoxypyridin-4-yl)-7-(3-(benzyloxy)-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (23d)

[0356] Compound 23c (0.14 g, 0.24 mmol) and cobalt chloride hexahydrate (0.29 g, 1.2 mmol) were dissolved in anhydrous methanol under ice conditions. Sodium borohydride (46 mg, 1.2 mmol) was then added and the mixture was allowed to warm to room temperature for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. The resulting solid was used directly in the next step without further purification. m / z (ESI): 553.2 [M+H] + .

[0357] Then, compound 23d was used to replace compound 11i, and a method similar to steps 7 and 8 of example 11 was used to prepare compound 23.

[0358] m / z(ESI):431.1[M+H] + ;

[0359] 1H NMR (400MHz, DMSO-d6) δ8.21(d,J=5.2Hz,1H),7.92(t,J=6.8Hz,1H),7.28(dd,J=1.2,5.2Hz,1H),7.16-7.04(m,3H),6.9 5(d,J=8.0Hz,1H),4.86-4.80(m,1H),4.33-4.28(m,1H),3.97(s,3H),2.50(s,3H),1.90-1.78(m,3H),1.71-1.58(m,3H).

[0360] Example 24: Preparation of 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-7-methoxy-11-methyl-4,5-dihydro-1,4,6,10,12-pentaazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]inden-3(1H)-one (Compound 24)

[0361] Step 1: Synthesis of 6-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine cyanide (24b)

[0362] At room temperature, compound 24a (1.0 g, 4.7 mmol), pinacol diboron (1.8 g, 7.0 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.20 g, 0.47 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) (0.35 g, 0.47 mmol) and potassium acetate (0.92 g, 9.4 mmol) were dissolved in anhydrous 1,4-dioxane (20 mL). The air was replaced with nitrogen three times, and the reaction was carried out at 95 °C under nitrogen protection for 10 h. After the reaction solution was cooled to room temperature, water (20 mL) was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (100 mL*3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by column chromatography (petroleum ether:ethyl acetate = 100:1 to 10:1) to obtain the product, compound 24b (0.70 g, yield 57%). m / z (ESI): 261.1 [M+H] + .

[0363] Then, compound 24b was used to replace compound 23b, and a method similar to that of Example 23 was used to prepare compound 24.

[0364] m / z(ESI):431.1[M+H] + ;

[0365] 1 H NMR(400MHz,DMSO-d6)δ8.11-8.02(m,2H),7.11-7.06(m,1H),6.98-6.92(m,4H),5.07-5.00 (m,1H),3.97(s,3H),3.94-3.90(m,1H),2.49(s,3H),1.90-1.81(m,3H),1.70-1.61(m,3H).

[0366] Example 25: Preparation of 2-amino-6-(difluoromethoxy)-1-(3-hydroxy-2,6-dimethylphenyl)-11-methyl-4,5-dihydro-1,4,10,12-tetraazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]inden-3(1H)-one (Compound 25)

[0367] Step 1: Synthesis of 2-bromo-6-(difluoromethoxy)benzonitrile (25b)

[0368] Compound 25a (2.0 g, 10 mmol) was dissolved in a mixture of N,N-dimethylformamide (18 mL) and water (2 mL). Sodium difluorochloroacetate (3.0 g, 20 mmol) and potassium carbonate (1.6 g, 12 mmol) were then added sequentially. The reaction mixture was heated to 100°C for 3 hours. After cooling to room temperature, the insoluble matter was removed by filtration and the mixture was diluted with water (10 mL). The mixture was then extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by normal phase chromatography (petroleum ether:ethyl acetate = 100:1-10:1) to afford compound 25b (1.0 g, 40% yield). m / z (EI): 246.8 [M] + ;

[0369] Step 2: Synthesis of (2-bromo-6-(difluoromethoxy)phenyl)methanamine (25c)

[0370] Compound 25b (1.0 g, 4.0 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL) under ice-cooling conditions. A 1 M solution of borane in tetrahydrofuran (20 mL) was then added dropwise. The temperature was raised to 70°C and allowed to react for 3 hours. After cooling to room temperature, methanol (20 mL) was added dropwise under ice-cooling conditions to quench the reaction. The reaction solution was concentrated, and the resulting product, compound 25c, was used directly in the next step without purification.

[0371] Step 3: Synthesis of tert-butyl (2-bromo-6-(difluoromethoxy)benzyl)carbamate (25d)

[0372] The product, compound 25c (1.0 g, 4.0 mmol), from the previous step was dissolved in anhydrous methanol. Triethylamine (0.60 g, 6.0 mmol) and di-tert-butyl dicarbonate (1.7 g, 8.0 mmol) were then added sequentially and allowed to react at room temperature for 12 hours. The reaction solution was concentrated, and the resulting residue was purified by column chromatography (petroleum ether:ethyl acetate = 100:1 to 10:1) to obtain the product, compound 25d (1.2 g, 85% yield). m / z (ESI): 296.0 [M-56+H] + ;

[0373] Step 4: Synthesis of tert-butyl (2-(difluoromethoxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (25e)

[0374] Compound 25d (0.50 g, 1.4 mmol), pinacol diboron (0.54 g, 2.1 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.10 g, 0.14 mmol), and potassium acetate (0.27 g, 2.8 mmol) were dissolved in anhydrous 1,4-dioxane (15 mL). The air was then purged with argon and the mixture was reacted at 80°C for 16 hours under argon protection. After the reaction solution cooled to room temperature, the insoluble material was filtered and washed with ethyl acetate (30 mL). The filtrate was concentrated to obtain compound 25e, which was used directly in the next step without purification. m / z (ESI): 344.1 [M-56+H] + .

[0375] Then, compound 25e was used to replace compound 11c, and a method similar to steps 5 to 8 of Example 11 was used to prepare compound 25.

[0376] m / z(ESI):466.3[M+H] + ;

[0377] 1 H NMR (400MHz, DMSO-d6) δ9.62(d,J=9.2Hz,1H),7.84-7.82(m,1H),7.62(d,J=8.0Hz,1H),7.53-7.51(m,1H),7.32-7.28(m,2H),7. 10-7.07(m,3H),6.96(d,J=8.0Hz,1H),4.87-4.80(m,1H),4.45-4.31(m,1H),2.54(s,3H),1.91-1.82(m,3H),1.70-1.61(m,3H).

[0378] Example 26: Preparation of 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-11-methyl-6-(trifluoromethoxy)-4,5-dihydro-1,4,10,12-tetraazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]inden-3(1H)-one (Compound 26)

[0379] Step 1: Synthesis of (2-bromo-6-(trifluoromethoxy)phenyl)methanol (26b)

[0380] Compound 26a (1.0 g, 3.5 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) under ice-cooling conditions. A 1 M solution of borane in tetrahydrofuran (14 mL) was then added dropwise. The temperature was raised to 50°C and allowed to react for 16 hours. After cooling to room temperature, 1 M hydrochloric acid solution (20 mL) was added dropwise under ice-cooling conditions to quench the reaction. The reaction mixture was concentrated, diluted with water (10 mL), and extracted with ethyl acetate (30 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 product, compound 26b, was used directly in the next reaction without purification.

[0381] Step 2: Synthesis of 2-bromo-6-(trifluoromethoxy)benzaldehyde (26c)

[0382] Compound 26b (0.90 g, 3.3 mmol) was dissolved in anhydrous dichloromethane (10 mL), and Dess-Martin periodinane (2.1 g, 5.0 mmol) was added portionwise. The mixture was allowed to react at room temperature for 2 hours. Saturated aqueous sodium bicarbonate (10 mL) and sodium thiosulfate (10 mL) were added sequentially to quench the reaction. The mixture was then extracted with ethyl acetate (40 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 column chromatography (petroleum ether:ethyl acetate = 10:1 to 5:1) to afford compound 26c (0.42 g, 44% yield). m / z (EI): 267.9 [M] + ;

[0383] Step 3: Synthesis of tert-butyl (2-bromo-6-(trifluoromethoxy)benzylcarbamate (26d)

[0384] Compound 26c (0.40 g, 1.5 mmol) was dissolved in anhydrous acetonitrile, followed by the addition of tert-butyl carbamate (0.53 g, 4.5 mmol), triethylsilane (0.52 g, 4.5 mmol), and trifluoroacetic acid (0.34 g, 3.0 mmol). The reaction was allowed to react at room temperature for 16 hours. The reaction solution was concentrated and diluted with water (10 mL). The mixture was then extracted with ethyl acetate (30 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 column chromatography (petroleum ether:ethyl acetate = 100:1 to 10:1) to afford compound 26d (0.24 g, 44% yield). m / z (ESI): 313.9 [M-56+H] + ;

[0385] Step 4: Synthesis of tert-butyl (2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethoxy)benzyl)carbamate (26e)

[0386] Compound 26d (37 mg, 0.10 mmol), pinacol diboronate (31 mg, 0.12 mmol), palladium acetate (4.5 mg, 20 μmol), tricyclohexylphosphine (5.6 mg, 20 μmol), and potassium acetate (20 mg, 0.20 mmol) were dissolved in anhydrous 1,4-dioxane (2 mL). The air was then purged with argon and the mixture was reacted at 100°C for 3 hours under argon protection. After the reaction solution was cooled to room temperature, the insoluble material was filtered to remove the resulting product, compound 26e, which was used directly in the next step without purification.

[0387] Then, compound 26e was used to replace compound 3c, and a method similar to steps 3 to 6 of Example 3 was used to prepare compound 26.

[0388] m / z(ESI):484.4[M+H] + ;

[0389] 1 H NMR (400MHz, DMSO-d6) δ9.62(brs,1H),7.96(t,J=7.2Hz,1H),7.75(dt,J=8.0,1.2Hz,1H),7.58(t,J=8.0Hz,1H),7.49-7.47(m,1H),7 .13-7.07(m,3H),H),6.95(d,J=8.0Hz,1H),4.94-4.88(m,1H),4.38-4.32(m,1H),2.50(s,3H),1.90-1.81(m,3H),1.69-1.60(m,3H).

[0390] Example 27: Preparation of 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-11-methyl-3-oxo-1,3,4,5-tetrahydro-1,4,10,12-tetraazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]indene-6-carbonitrile (Compound 27)

[0391] Step 1: Synthesis of 2-bromo-6-(methoxymethoxy)benzonitrile (27b)

[0392] Compound 27a (1.0 g, 5.1 mmol) was dissolved in anhydrous N,N-dimethylformamide under ice conditions. 60% sodium hydroxide (0.61 g, 15 mmol) was then added. After 30 minutes of reaction, bromomethyl methyl ether (1.3 g, 10 mmol) was added and the mixture was allowed to react at room temperature for 6 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. The resulting residue was purified by normal phase chromatography (petroleum ether:ethyl acetate = 100:1 to 10:1) to afford compound 27b (1.2 g, 99% yield).

[0393] Step 2: Synthesis of 2-(methoxymethoxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (27c)

[0394] Compound 27b (0.12 g, 0.5 mmol), pinacol diboronate (0.15 g, 0.60 mmol), palladium acetate (22 mg, 0.10 mmol), tricyclohexylphosphine (28 mg, 0.10 mmol), and potassium acetate (98 mg, 1.0 mmol) were dissolved in anhydrous 1,4-dioxane (5 mL). The air was then purged with argon and the mixture was reacted at 100°C for 2 hours under argon protection. After the reaction solution was cooled to room temperature, the insoluble matter was removed by filtration. The resulting product, compound 27c, was used directly in the next step without purification. m / z (ESI): 290.1 ​​[M+H] + .

[0395] Step 3: Synthesis of methyl 6-amino-4-(2-cyano-3-(methoxymethoxy)phenyl)-7-(3-methoxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (27d)

[0396] At room temperature, compound 3b (80 mg, 0.21 mmol), compound 27c (0.12 g, 0.43 mmol), bis(dibenzylideneacetone)palladium (24 mg, 43 μmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphoryladamantane (12 mg, 43 μmol), and cesium carbonate (0.14 g, 0.43 mmol) were dissolved in 1,4-dioxane / water (5 mL / 0.5 mL). The atmosphere was replaced with nitrogen three times, and the reaction mixture was moved to 80°C for 6 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 obtain the target compound 27d (82 mg, 76% yield). m / z (ESI): 502.2 [M+H] + .

[0397] Step 4: Synthesis of methyl 6-amino-4-(2-(aminomethyl)-3-(methoxymethoxy)phenyl)-7-(3-methoxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (27e)

[0398] Compound 27d (50 mg, 0.10 mmol) was dissolved in anhydrous methanol (10 mL) at room temperature, and Raney nickel (10 mg, 53 μmol) was added. The atmosphere was then purged with hydrogen, and the reaction was continued at room temperature under 45 psi for 8 hours. Insoluble matter was removed by filtration, 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 title compound 27e (50 mg, 99% yield). m / z (ESI): 506.2 [M+H] + .

[0399] Step 5: Synthesis of 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-6-(methoxymethoxy)-11-methyl-4,5-dihydro-1,4,10,12-tetraazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]inden-3(1H)-one (27f)

[0400] Compound 27e (50 mg, 0.10 mmol) was dissolved in methanol / tetrahydrofuran / water (2 ml / 2 mL / 2 mL), and lithium hydroxide monohydrate (42 mg, 1.0 mmol) was added. The reaction mixture was then placed in a 50°C oil bath for 8 hours. 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 27f (47 mg, 99% yield). m / z (ESI): 474.2 [M+H]+ .

[0401] Step 6: Synthesis of 2-amino-6-hydroxy-1-(3-methoxy-2,6-dimethylphenyl)-11-methyl-4,5-dihydro-1,4,10,12-tetraazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]inden-3(1H)-one (27 g)

[0402] Compound 27f (47 mg, 0.10 mmol) was dissolved in 1,4-dioxane hydrochloride (4 mL) at room temperature and allowed to react for 2 hours. After the reaction, 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 27g (40 mg, 93% yield). m / z (ESI): 430.2 [M+H] + .

[0403] Step 7: Synthesis of Intermediate 27h

[0404] Compound 27g (20 mg, 46 μmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL). Cesium carbonate (23 mg, 70 μmol) and N-phenylbis(trifluoromethanesulfonyl)imide (22 mg, 60 μmol) were added sequentially and allowed to react at room temperature for 2 hours. The reaction solution was directly purified by reverse-phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to obtain the target compound 27h (22 mg, 84% yield). m / z (ESI): 562.1 [M+H] + .

[0405] Step 8: Synthesis of 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-11-methyl-3-oxo-1,3,4,5-tetrahydro-1,4,10,12-tetraazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]indene-6-carbonitrile (27i)

[0406] Compound 27h (20 mg, 36 μmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL). Zinc (1.2 mg, 18 μmol), zinc cyanide (4.2 mg, 36 μmol), tris(dibenzylideneacetone)dipalladium (3.2 mg, 3.6 μmol), and 1,1'-bis(diphenylphosphino)ferrocene (2.0 mg, 3.6 μmol) were added sequentially. The atmosphere was replaced with nitrogen three times, and the reaction mixture was moved to 130°C for 6 hours. After cooling to room temperature, the reaction mixture was directly purified by reverse-phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to obtain the target compound 27i (12 mg, 76% yield).

[0407] Step 9: Synthesis of 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-11-methyl-3-oxo-1,3,4,5-tetrahydro-1,4,10,12-tetraazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]indene-6-carbonitrile (27)

[0408] Compound 27i (12 mg, 27 μmol) was dissolved in dichloromethane (5 mL) at room temperature. A solution of boron tribromide (1 mol / L, 2 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 27 (9.6 mg, 84% yield).

[0409] m / z(ESI):425.3[M+H] + ;

[0410] 1 H NMR (400MHz, DMSO-d6) δ9.62(d,J=9.2Hz,1H),8.12(t,J=6.8Hz,1H)8.07(d,J=8.0Hz,1H),7.97(d,J=8.0Hz,1H),7.66(t,J=8. 0Hz,1H),7.13-7.07(m,3H),6.96(d,J=8.0Hz,1H),5.11-5.06(m,1H),4.39-4.33(m,1H),1.90-1.81(m,3H),1.70-1.61(m,3H).

[0411] Example 28: Preparation of 2-amino-7-cyclopropyl-1-(3-hydroxy-2,6-dimethylphenyl)-11-methyl-4,5-dihydro-1,4,6,10,12-pentaazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]inden-3(1H)-one (Compound 28)

[0412] Step 1: Synthesis of 5-bromo-2-cyclopropylpyridine-1-oxide (28b)

[0413] Compound 28a (2.5 g, 12.6 mmol) was dissolved in anhydrous dichloromethane under ice-cooling conditions, followed by the addition of m-chloroperbenzoic acid (2.6 g, 12.6 mmol). The mixture was then allowed to react at room temperature for 12 hours. Saturated aqueous ammonium chloride (30 mL) was added to quench the reaction, which was then adjusted to pH 11 with 1 M NaOH solution. The mixture was extracted with ethyl acetate (30 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, compound 28b, was used directly in the next step without further purification. m / z (ESI): 214.0 [M+H] + ;

[0414] Step 2: Synthesis of 3-bromo-6-cyclopropylpyridine cyanide (28c)

[0415] Compound 28b (1.5 g, 7.0 mmol) was dissolved in anhydrous acetonitrile (5 mL). Triethylamine (2.1 g, 21 mmol) and trimethylsilyl cyanide (2.8 g, 28 mmol) were added sequentially, and the reaction temperature was raised to 95°C for 12 hours. The reaction was quenched by the addition of saturated aqueous ammonium chloride (30 mL). The pH was then adjusted to 11 with 1 M NaOH solution, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by column chromatography (petroleum ether:ethyl acetate = 100:1 to 10:1) to afford compound 28c (1.0 g, 64% yield). m / z (ESI): 223.0 [M+H] + ;

[0416] Then, compound 28 was prepared by replacing compound 8a with compound 28c in a manner similar to that of Example 8.

[0417] m / z(ESI):441.2[M+H] + ;

[0418] 1 H NMR(400MHz, DMSO-d6)δ9.59(d,J=5.6Hz,1H),8.03-7.95(m,2H),7.35(d,J=8.0Hz,1H),7.10-7.07(m,1H),6.98-6.94(m,3H), 5.06-5.00(m,1H),3.98-3.93(m,1H),2.48(s,3H),2.21-2.15(m,1H),1.89-1.80(m,3H),1.70-1.61(m,3H),1.05-1.00(m,4H).

[0419] Example 29: Preparation of 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-11-methyl-7-(trifluoromethyl)-4,5-dihydro-1,4,6,10,12-pentaazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]inden-3(1H)-one (Compound 29)

[0420] Compound 29 was prepared by replacing compound 8a with compound 29a in a manner similar to that of Example 8.

[0421] m / z(ESI):469.1[M+H] + ;

[0422] 1 H NMR(400MHz, DMSO-d6)δ9.65(d,J=6.0Hz,1H),8.44(d,J=8.4Hz,1H),8.14-8.11(m,1H),8.01(d,J=8.4Hz,1H),7.16-7.1 0(m,3H),6.96(d,J=8.0Hz,1H),5.26-5.20(m,1H),4.19-4.13(m,1H),2.52(s,3H),1.90-1.81(m,3H),1.70-1.62(m,3H).

[0423] Example 30: Preparation of 2-amino-7-fluoro-1-(3-hydroxy-2,6-dimethylphenyl)-6-methoxy-11-methyl-4,5-dihydro-1,4,10,12-tetraazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]inden-3(1H)-one (Compound 30)

[0424] Step 1: Synthesis of 6-bromo-3-fluoro-2-methoxybenzonitrile (30b)

[0425] At room temperature, compound 30a (1.0 g, 4.6 mmol) was dissolved in anhydrous methanol, followed by the addition of 30% sodium methoxide (1.0 g, 5.5 mmol). The reaction was allowed to react at room temperature for 16 hours. Saturated aqueous ammonium chloride was added to quench the reaction, and the solution was concentrated to remove the methanol. The mixture was extracted with ethyl acetate (30 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 product, compound 30b, was used directly in the next reaction without further purification. m / z (EI): 228.9 [M] + ;

[0426] Then, compound 30b was substituted for compound 25b, and a method similar to that of Example 25 was used to prepare compound 30.

[0427] m / z(ESI):448.1[M+H] + ;

[0428] 1 H NMR (400MHz, CD3OD) δ7.48-7.46(m,1H),7.31-7.29(m,1H),7.14-7.10(m,1H),6.95(d,J=8.4Hz,1H), 5.40-5.29(m,1H),4.98-4.87(m,1H),4.07(s,3H),2.58(s,3H),1.99-1.93(m,3H),1.79-1.74(m,3H).

[0429] Example 31: Preparation of 2-amino-7-cyclopropyloxy-1-(3-hydroxy-2,6-dimethylphenyl)-11-methyl-4,5-dihydro-1,4,6,10,12-pentaazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]inden-3(1H)-one (Compound 31)

[0430] Step 1: Synthesis of 3-bromo-6-cyclopropyloxycyanopyridine (31b)

[0431] Cyclopropanol (0.64 g, 11 mmol) was dissolved in tetrahydrofuran (15 mL) under an ice bath. 60% sodium hydroxide (0.76 g, 19 mmol) was added and the reaction continued for 30 minutes. Compound 31a (2.0 g, 9.2 mmol) was then added and the mixture was allowed to warm to room temperature and continued to react for 3 hours. The reaction was quenched with saturated aqueous ammonium chloride (20 mL) and 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 resulting residue was purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 5:1) to afford compound 31b (1.6 g, 72% yield). m / z (ESI): 238.9 [M+H] + ;

[0432] Step 2: Synthesis of 6-cyclopropyloxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine cyanide (31c)

[0433] Compound 31b (1.0 g, 4.2 mmol), pinacol diboron (1.6 g, 6.3 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.31 g, 0.42 mmol), and potassium acetate (1.0 g, 10 mmol) were dissolved in anhydrous 1,4-dioxane (10 mL). The air was then purged with argon and the mixture was reacted at 100°C for 3 hours under argon protection. After the reaction solution was cooled to room temperature, the insoluble matter was removed by filtration and washed with ethyl acetate (30 mL). The filtrate was concentrated, and the resulting residue was purified by column chromatography (petroleum ether:ethyl acetate = 5:1 to 2:1) to obtain the product, compound 31c (0.73 g, yield 61%). m / z (ESI): 205.1 [M-C6H 10 +H] + .

[0434] Then, compound 31c was substituted for compound 8b, and a method similar to Example 8 was used to prepare compound 31.

[0435] m / z(ESI):457.2[M+H] + ;

[0436] 1 H NMR(400MHz, DMSO-d6)δ9.60(d,J=7.2Hz,1H),8.13(d,J=8.8Hz,1H),8.02(t,J=7.2Hz,1H),7.12-7.10(m,1H),7.07-6.93(m,4H) ,5.05-5.00(m,1H),4.33-4.29(m,1H),3.96-3.90(m,1H),2.48(s,3H),1.89-1.80(m,3H),1.70-1.61(m,3H),0.85-0.73(m,2H).

[0437] Example 32: Preparation of 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-7-(hydroxymethyl)-11-methyl-4,5-dihydro-1,4,6,10,12-pentaazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]inden-3(1H)-one (Compound 32)

[0438] Step 1: Synthesis of 5-bromo-2-(hydroxymethyl)pyridine-1-oxide (32b)

[0439] Compound 32a (5.0 g, 27 mmol) was dissolved in anhydrous dichloromethane under ice-cooling conditions, followed by the addition of m-chloroperbenzoic acid (8.1 g, 40 mmol). The mixture was then allowed to react at room temperature for 12 hours. The reaction mixture was filtered, the filter cake washed with dichloromethane (20 mL), and the filtrate concentrated. The resulting residue was purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:2) to afford compound 32b (2.2 g, 40% yield). m / z (ESI): 187.9 [M-OH+H] + ;

[0440] Step 2: Synthesis of 5-bromo-2-(methoxymethyl)pyridine-1-oxide (32c)

[0441] Compound 32b (1.2 g, 5.9 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL) under ice conditions. 60% sodium hydroxide (0.48 g, 12 mmol) was added and the mixture was allowed to warm to room temperature for 1 hour. Methyl iodide (1.3 g, 8.8 mmol) was then added under ice conditions. The temperature was raised to 70°C and allowed to react for 3 hours. The reaction was quenched with saturated aqueous ammonium chloride (20 mL) and 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 resulting residue was purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:1) to afford compound 32c (0.7 g, 54% yield).

[0442] Compound 32 was prepared by replacing compound 28b with compound 32c in a manner similar to that of Example 28.

[0443] m / z(ESI):431.1[M+H] + ;

[0444] 1 H NMR(400MHz, DMSO-d6)δ9.73(s,1H),8.19(d,J=8.0Hz,1H),8.03-8.01(m,1H),7.59(d,J=8.0Hz,1H),7.12-7.03(m,3H),6.96(d,J =8.0Hz,1H),5.5(brs,1H),5.10-5.06(m,1H),4.65(s,2H),4.06-4.00(m,1H),2.54(m,3H),1.89-1.81(m,3H),1.70-1.61(m,3H).

[0445] Example 33: Preparation of 5-amino-8-cyclopropyl-4-(3-hydroxy-2,6-dimethylphenyl)-2-methyl-7,8-dihydro-1,3,4,7,8,9-hexaazabenzo[cd]cyclopenta[f]azulen-6(4H)-one (Compound 33)

[0446] Step 1: Synthesis of 1-cyclopropyl-1H-pyrazol-5-amine (33b)

[0447] Cyclopropylhydrazine dihydrochloride 33a (0.96 g, 6.3 mmol) and 3,3-diethoxypropionitrile (0.9 g, 6.3 mmol) were dissolved in ethanol (15 mL) and then heated to 80°C for 10 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain the desired product, compound 33b (0.28 g, 36% yield). m / z (ESI): 124.1 [M+H] + .

[0448] Step 2: Synthesis of 4-bromo-1-cyclopropyl-1H-pyrazol-5-amine (33c)

[0449] Compound 33b (0.28 g, 2.3 mmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL), and N-bromosuccinimide (0.41 g, 2.3 mmol) was added. The mixture was stirred at room temperature for 5 minutes. The resulting reaction solution was purified by reverse phase chromatography (C18, 0.05% ammonia water:acetonitrile = 20:1 to 1:20) to obtain the product, compound 33c (0.40 g, yield 79%). m / z (ESI): 202.1 [M+H] + .

[0450] Step 3: Synthesis of N-(4-bromo-1-cyclopropyl-1H-pyrazol-5-yl)acetamide (33d)

[0451] Compound 33c (0.40 g, 2.0 mmol) and triethylamine (0.40 g, 4 mmol) were dissolved in dichloromethane (5 mL) under an ice bath, and acetyl chloride (0.24 g, 3 mmol) was slowly added dropwise. The mixture was allowed to warm to room temperature and the reaction continued for 5 minutes. The reaction was quenched by the addition of saturated sodium bicarbonate solution (5 mL), and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and 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 compound 33d (0.31 g, 64% yield). m / z (ESI): 244.2 [M+H] + .

[0452] Step 4: Synthesis of N-(1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-5-yl)acetamide (33e)

[0453] Compound 33d (0.10 g, 0.41 mmol), pinacol diboronate (0.21 g, 0.82 mmol), potassium acetate (0.12 g, 1.2 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (32 mg, 0.04 mmol) were dissolved in anhydrous dioxane (5 mL) at room temperature. The atmosphere was replaced with nitrogen three times, and the reaction mixture was moved to 90°C for 2 hours. After the reaction mixture was cooled to room temperature, the insoluble material was filtered to remove, and the filtrate was dried by rotary evaporation. The crude product was used directly in the next step.

[0454] Step 5: Synthesis of methyl 4-(5-acetylamino-1-cyclopropyl-1H-pyrazol-4-yl)-6-amino-7-(3-methoxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (33f)

[0455] At room temperature, the crude compound 33e was dissolved in acetonitrile / water (5 mL / 1 mL). 3b (75 mg, 0.20 mmol), palladium acetate (4.5 mg, 0.02 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (16 mg, 0.04 mmol), and potassium carbonate (83 mg, 0.6 mmol) were added with stirring. The reaction was moved to 70°C for 2 hours. After the reaction solution was cooled to room temperature, it was filtered and the filtrate was dried by rotary evaporation. The crude product was purified by reverse phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to obtain the product, compound 33f (50 mg, 25% yield). m / z (ESI): 504.6 [M+H] + .

[0456] Step 6: Synthesis of 5-amino-8-cyclopropyl-4-(3-methoxy-2,6-dimethylphenyl)-2-methyl-7,8-dihydro-1,3,4,7,8,9-hexaazabenzo[cd]cyclopenta[f]azulene-6(4H)-one (33 g)

[0457] Acetyl chloride (5 mL) was slowly added dropwise to ethanol (10 mL) under an ice bath, followed by the addition of compound 33f (50 mg, 99 μmol). The reaction was moved to 60°C for 4 hours, 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 the desired product, compound 33g (41 mg, 96% yield). m / z (ESI): 430.2 [M+H]+ .

[0458] Step 7: Synthesis of 5-amino-8-cyclopropyl-4-(3-hydroxy-2,6-dimethylphenyl)-2-methyl-7,8-dihydro-1,3,4,7,8,9-hexaazabenzo[cd]cyclopenta[f]azulen-6(4H)-one (33)

[0459] Compound 33g (13 mg, 30 μmol) was dissolved in anhydrous dichloromethane (5 mL). Boron tribromide (1.0 mL, 1 mol / L dichloromethane solution) was slowly added dropwise under ice-cooling. The reaction was allowed to react at room temperature for 2 hours. The reaction was 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 (10 mg, 79% yield).

[0460] m / z(ESI):416.2[M+H] + .

[0461] 1 H NMR (400MHz, DMSO-d6) δ9.59 (s, 1H), 9.53 (s, 1H), 8.11 (s, 1H), 7.07 (d, J = 8.3Hz, 1H), 6.98-6.86 (m, 3H), 3.63(tt,J=7.5,3.9Hz,1H),2.36(s,3H),1.78(s,3H),1.69(s,3H),1.11-1.03(m,2H),0.95-0.90(m,2H).

[0462] Example 34: Preparation of 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,7,9-trimethyl-4,5-dihydro-1,4,5,6,8,10-hexaazabenzo[cd]cyclopenta[f]azulen-3(1H)-one (Compound 34)

[0463] Step 1: Synthesis of tert-butyl (1,3-dimethyl-1H-pyrazol-5-yl)carbamate (34b)

[0464] Compound 34a (1.0 g, 9.0 mmol) was dissolved in tetrahydrofuran (10 mL) at room temperature. Di-tert-butyl dicarbonate (3.0 g, 13.5 mmol) and 4-dimethylaminopyridine (0.11 g, 0.9 mmol) were added to the reaction mixture. The mixture was reacted at 60°C for 2 hours and then concentrated in vacuo to remove the solvent. The crude product was dissolved in ethanol (10 mL) and sodium hydroxide solution (3 mL, 20% aqueous solution) was added. The reaction was continued at room temperature for 3 hours. The solvent was then concentrated in vacuo to remove the solvent. The crude product was purified by reverse phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to obtain compound 34b (1.6 g, 82% yield). m / z (ESI): 212.1 [M+H] + .

[0465] Step 2: Synthesis of tert-butyl (4-bromo-1,3-dimethyl-1H-pyrazol-5-yl)carbamate (34c)

[0466] Compound 34b (1.6 g, 7.6 mmol) was dissolved in N,N-dimethylformamide (15 mL), followed by the addition of N-bromosuccinimide (1.6 g, 9.1 mmol) and allowed to react at room temperature for 2 hours. The solvent was removed by vacuum concentration, and the crude product was purified by reverse phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to afford compound 34c (2.0 g, 91% yield). m / z (ESI): 290.0 [M+H] + .

[0467] Step 3: Synthesis of tert-butyl (1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-5-yl)carbamate (34d)

[0468] Compound 34c (0.12 g, 6.9 mmol), pinacol diboronate (2.3 g, 9.0 mmol), bis(dibenzylideneacetone)palladium (0.39 g, 0.69 mmol), tricyclohexylphosphine (0.39 g, 1.4 mmol), and potassium acetate (1.4 g, 14 mmol) were dissolved in anhydrous 1,4-dioxane (10 mL). The atmosphere was purged with argon and the reaction was continued at 90°C under argon for 2 hours. After the reaction solution was cooled to room temperature, the insoluble material was removed by filtration. The filtrate was concentrated to obtain the crude product, compound 34d, which was used directly in the next step without purification.

[0469] Then, compound 34d was used to replace compound 3c, and a method similar to steps 3 to 6 of Example 3 was used to prepare compound 34.

[0470] m / z(ESI):404.3[M+H] + .

[0471] 1 H NMR (400MHz, DMSO-d6) δ9.58(s,1H),9.11(s,1H),7.08(d,J=8.0Hz,1H),6.94(d,J=8.0 Hz,1H),6.88(s,2H),3.67(s,3H),2.44(s,3H),2.36(s,3H),1.79(s,3H),1.70(s,3H).

[0472] Example 35: Preparation of 2-amino-6-ethyl-1-(3-hydroxy-2,6-dimethylphenyl)-11-methyl-4,5-dihydro-1,4,7,10,12-pentaazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]inden-3(1H)-one (Compound 35)

[0473] Step 1: 2-Vinyl Nicotine Nitrile (35b)

[0474] At room temperature, compound 35a (2.0 g, 14 mmol), vinyl pinacol borate (3.3 g, 22 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (1.0 g, 1.4 mmol), and potassium carbonate (4.0 g, 29 mmol) were dissolved in 1,4-dioxane / water (10 mL / 1 mL). The atmosphere was replaced with nitrogen three times, and the reaction mixture was moved to 90°C for 6 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 obtain the target compound 35b (1.7 g, 92% yield). m / z (ESI): 131.2 [M+H] + .

[0475] Step 2: (3-Cyano-2-vinylpyridin-4-yl)boronic acid (35c)

[0476] 2,2,6,6-Tetramethylpiperidine (0.23 g, 1.6 mmol) was dissolved in tetrahydrofuran (3 mL), the air was replaced with argon, and then the temperature was lowered to -78°C. Under this condition, n-butyllithium (1.6 M, 1.0 mL) was slowly added dropwise. After the addition was complete, the temperature was raised to 0°C and stirred for 30 minutes. Then, a solution of compound 35b (0.10 g, 0.76 mmol) in tetrahydrofuran (3 mL) was slowly added dropwise at -78°C. After the addition was complete, stirring was continued for 30 minutes. Then, a solution of trimethyl borate (0.16 g, 1.5 mmol) in tetrahydrofuran (3 mL) was added dropwise at -78°C. After the addition was complete, stirring was continued for 30 minutes. The reaction mixture was heated to room temperature for 3 hours, and then the pH was adjusted to 3-4 with 6M hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude compound 35c, which was directly used in the next reaction without purification.

[0477] Step 3: 6-amino-4-(3-cyano-2-vinylpyridin-4-yl)-7-(3-methoxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid methyl ester (35d)

[0478] At room temperature, compound 35c (45 mg, 0.26 mmol), compound 3b (32 mg, 85 μmol), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (6.2 mg, 8.5 μmol), and cesium carbonate (56 mg, 0.17 mmol) were dissolved in 1,4-dioxane / water (3 mL / 0.3 mL). The air was replaced with nitrogen three times, and the mixture was reacted at 85°C under a nitrogen atmosphere for 6 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% ammonia:acetonitrile = 20:1 to 1:20) to obtain compound 35d (35 mg, 87% yield). m / z (ESI): 469.2 [M+H] + .

[0479] Step 4: 6-amino-4-(3-(aminomethyl)-2-ethylpyridin-4-yl)-7-(3-methoxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid methyl ester (35e)

[0480] At room temperature, compound 35d (35 mg, 74.71 μmol) was dissolved in anhydrous methanol (10 mL), and Raney nickel (10 mg, 53 μmol) was added. The air was replaced with hydrogen, and the mixture was allowed to react at room temperature for 8 hours. The insoluble material was removed by filtration, 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 obtain compound 35e (10 mg, 28% yield). m / z (ESI): 475.3 [M+H] + .

[0481] Step 5: 2-Amino-6-ethyl-1-(3-methoxy-2,6-dimethylphenyl)-11-methyl-4,5-dihydro-1,4,7,10,12-pentaazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]inden-3(1H)-one (35f)

[0482] Compound 35e (10 mg, 21 μmol) was dissolved in methanol / tetrahydrofuran / water (1 ml / 5 mL / 1 mL), and lithium hydroxide monohydrate (9.0 mg, 0.21 mmol) was added. The mixture was reacted at 60°C for 8 hours. 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 compound 35f (8 mg, yield 85%). m / z (ESI): 443.2 [M+H] + .

[0483] Step 6: 2-Amino-6-ethyl-1-(3-hydroxy-2,6-dimethylphenyl)-11-methyl-4,5-dihydro-1,4,7,10,12-pentaazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]inden-3(1H)-one (35)

[0484] Compound 35f (8 mg, 18 μmol) was dissolved in anhydrous dichloromethane (3 mL) at room temperature, followed by the addition of a dichloromethane solution of boron tribromide (1 mol / L, 2 mL). The reaction was allowed to react for 30 minutes. The reaction was quenched with methanol (5 mL), concentrated, and the pH adjusted to 14 with aqueous ammonia. The product was then purified by reverse-phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to afford compound 35 (5 mg, 64% yield).

[0485] m / z(ESI):429.3[M+H] + ;

[0486] 1H NMR (400MHz, DMSO-d6) δ9.60(d,J=9.6Hz,1H),8.55(d,J=4.8Hz,1H),8.08(t,J=7.2Hz,1H),7.50(d,J=4.8Hz,1H),7.15-7.07(m,3H),6.95(d,J =8.4Hz,1H),5.06-5.00(m,1H),4.32-4.26(m,1H),3.13-2.93(m,2H),2 .50(m,3H),1.90-1.81(m,3H),1.69-1.60(m,3H),1.27(t,J=7.2Hz,3H).

[0487] Example 36: Preparation of 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-6,11-dimethyl-4,5-dihydro-1,4,7,10,12-pentaazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]inden-3(1H)-one (Compound 36)

[0488] Step 1: (3-Cyano-2-methylpyridin-4-yl)boronic acid (36b)

[0489] 2,2,6,6-Tetramethylpiperidine (2.2 g, 15 mmol) was dissolved in tetrahydrofuran (10 mL), and the air was replaced with argon. The mixture was cooled to -78°C and n-butyllithium (1.6 M, 9.5 mL) was slowly added dropwise. After the addition was complete, the temperature was raised to 0°C and stirred for 30 minutes. Then, a solution of compound 36a (0.90 g, 7.6 mmol) in tetrahydrofuran (10 mL) was slowly added dropwise at -78°C. After the addition was complete, the mixture was stirred for 30 minutes. Then, a solution of trimethyl borate (2.4 g, 23 mmol) in tetrahydrofuran (10 mL) was added dropwise at -78°C. After the addition was complete, the mixture was stirred for 30 minutes. The mixture was then warmed to room temperature and reacted for 3 hours. The pH was adjusted to 3-4 with 6 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain crude compound 36b, which was used directly in the next step without purification.

[0490] Step 2: 6-amino-4-(3-cyano-2-methylpyridin-4-yl)-7-(3-methoxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid methyl ester (36c)

[0491] At room temperature, compound 36b (39 mg, 0.24 mmol), compound 3b (30 mg, 80 μmol), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (5.8 mg, 8.0 μmol), and cesium carbonate (52 mg, 0.16 mmol) were dissolved in 1,4-dioxane / water (5 mL / 0.5 mL). The atmosphere was replaced with nitrogen three times, and the reaction mixture was heated to 85°C for 2 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% ammonia water:acetonitrile = 20:1 to 1:20) to obtain compound 36c (30 mg, 82% yield). m / z (ESI): 457.2 [M+H] + .

[0492] Step 3: 6-amino-4-(3-(aminomethyl)-2-methylpyridin-4-yl)-7-(3-methoxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid methyl ester (36d)

[0493] At room temperature, compound 36c (30 mg, 66 μmol) was dissolved in anhydrous methanol (15 mL), and Raney nickel (10 mg) was added. The air was purged with hydrogen, and the reaction was allowed to react at room temperature for 8 hours. The insoluble matter was removed by filtration, 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 compound 36d (10 mg, 33% yield). m / z (ESI): 461.2 [M+H] + .

[0494] Step 4: 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-6,11-dimethyl-4,5-dihydro-1,4,7,10,12-pentaazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]inden-3(1H)-one (36e)

[0495] At room temperature, compound 36d (5 mg, 11 μmol) was dissolved in tetrahydrofuran (5 mL) and methanol (2 mL), followed by the addition of lithium hydroxide monohydrate (4.6 mg, 0.11 mmol) and water (1 mL). The reaction was then allowed to react at 60°C for 3 hours. After cooling to room temperature, the pH was adjusted to 6-7 with 1M hydrochloric acid and 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 compound 36e (2 mg, 42% yield). m / z (ESI): 429.2 [M+H] + .

[0496] Step 5: 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-6,11-dimethyl-4,5-dihydro-1,4,7,10,12-pentaazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]inden-3(1H)-one (36)

[0497] Compound 36e (2 mg, 4.7 μmol) was dissolved in anhydrous dichloromethane (3 mL) at room temperature. A 1 M solution of boron tribromide in dichloromethane (1 mL) was added and the mixture was allowed to react at room temperature for 30 minutes. Upon completion, the reaction was quenched with methanol (1 mL). The reaction solution was concentrated, and the pH was adjusted to 13-14 with aqueous ammonia. The product was then purified by reverse-phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to afford compound 36 (1 mg, 51% yield).

[0498] m / z(ESI):415.3[M+H] + .

[0499] 1 H NMR (400MHz, DMSO-d6) δ9.63(brs,1H),8.47(d,J=5.2Hz,1H),8.18(t,J=6.8Hz,1H),7.49(dd,J=5.2,1.2Hz,1H),7.15-7.07(m,3 H),6.96(d,J=8.4Hz,1H),5.06-5.00(m,1H),4.28-4.22(m,1H),2.67(s,1H),2.52(s,3H),1.90-1.81(m,3H),1.69-1.60(m,3H).

[0500] Example 37: Preparation of 5-amino-4-(3-hydroxy-2,6-dimethylphenyl)-2-methyl-4,7-dihydro-6H-8-thia-1,3,4,7,9-pentaazabenzo[cd]cyclopenta[f]azulen-6-one (Compound 37)

[0501] Step 1: tert-Butyl isothiazol-5-ylcarbamate (37b)

[0502] At room temperature, isothiazole-5-carboxylic acid 37a (1.0 g, 7.7 mmol), diphenylphosphoryl azide (2.1 g, 7.7 mmol), and triethylamine (0.78 g, 7.7 mmol) were dissolved in tert-butanol and heated to 100°C for 12 hours. After cooling to room temperature, the mixture was concentrated in vacuo to remove the tert-butanol. The residue was then dissolved in water and extracted three times 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 resulting residue was purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:1) to afford compound 37b (0.55 g, 36% yield). m / z (ESI): 201.0 [M+H] + ;

[0503] Step 2: tert-Butyl (4-iodoisothiazol-5-yl)carbamate (37c)

[0504] Compound 37b (0.40 g, 2.0 mmol) was dissolved in anhydrous dichloromethane (10 mL), and N-iodosuccinimide (0.54 g, 2.4 mmol) was added. The reaction was allowed to react at room temperature for 12 hours. Saturated aqueous sodium chloride (10 mL) was added to the reaction mixture to quench the reaction. The mixture was extracted three times with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by normal phase column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:1) to obtain compound 37c (0.61 g, 94% yield). m / z (ESI): 326.9 [M+H] + ;

[0505] Step 3: tert-Butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isothiazol-5-yl)carbamate (37d)

[0506] Compound 37c (0.40 g, 1.2 mmol), pinacol diboron (0.47 g, 1.8 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (57 mg, 0.12 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) (89 mg, 0.12 mmol), and potassium acetate (0.24 g, 2.4 mmol) were dissolved in anhydrous 1,4-dioxane (10 mL). The air was replaced with nitrogen three times, and the mixture was reacted at 100°C under nitrogen for 8 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The resulting residue, compound 37d, was used directly in the next reaction without purification.

[0507] Step 4: 6-amino-4-(5-((tert-butoxycarbonyl)amino)isothiazol-4-yl)-7-(3-methoxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid methyl ester (37e)

[0508] The crude product 37d (0.30 g, 0.92 mmol) from the previous step, compound 3b (0.34 g, 0.92 mmol), tris(dibenzylideneacetone)dipalladium (84 mg, 92 μmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphoryladamantane (54 mg, 0.19 mmol), and cesium carbonate (0.90 g, 2.8 mmol) were dissolved in 1,4-dioxane / water (5 mL / 1 mL). The atmosphere was replaced with nitrogen three times. The reaction mixture was then moved to 80°C for 2 hours. After the reaction was cooled to room temperature, water (5 mL) was added to dilute the reaction mixture, followed by extraction 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 to 1:2) to obtain the product, compound 37e (90 mg, yield 18%). m / z (ESI): 539.3 [M+H] + .

[0509] Step 5: 6-amino-4-(5-aminoisothiazol-4-yl)-7-(3-methoxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid methyl ester (37f)

[0510] Compound 37e (90 mg, 0.17 mmol) was dissolved in 2M EtOAc (3 mL) and allowed to react at room temperature for 16 hours. The reaction mixture was concentrated to obtain the crude product, Compound 37f, which was used directly in the next step without further purification.

[0511] Step 6: 5-amino-4-(3-methoxy-2,6-dimethylphenyl)-2-methyl-4,7-dihydro-6H-8-thia-1,3,4,7,9-pentaazabenzo[cd]cyclopenta[f]azulen-6-one (37 g)

[0512] Compound 37f (70 mg, 0.15 mmol) obtained in the previous step was dissolved in methanol / tetrahydrofuran / water (2 ml / 2 mL / 2 mL), followed by the addition of lithium hydroxide monohydrate (63 mg, 1.5 mmol). The reaction was allowed to proceed at 60°C for 12 hours. The reaction solution was concentrated, and the resulting residue was directly purified by reverse-phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to afford compound 37g (40 mg, 67% yield). m / z (ESI): 407.3 [M+H] + .

[0513] Step 7: 5-amino-4-(3-hydroxy-2,6-dimethylphenyl)-2-methyl-4,7-dihydro-6H-8-thia-1,3,4,7,9-pentaazabenzo[cd]cyclopenta[f]azulene-6-one (37)

[0514] Compound 37g (30 mg, 74 μmol) was dissolved in anhydrous dichloromethane (4 mL), followed by the addition of a dichloromethane solution of boron tribromide (1 mol / L, 2 mL). The reaction was allowed to react at room temperature for 30 minutes. The reaction solution was quenched with methanol (5 mL), concentrated, and the pH adjusted to 13-14 with aqueous ammonia. The solution was then purified by reverse-phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to afford compound 37 (12 mg, 41% yield).

[0515] m / z(ESI):393.1[M+H] + .

[0516] 1 H NMR (400MHz, DMSO-d6) δ8.62(s,1H),7.25-7.19(m,1H),7.08(d,J=8.4Hz,1H),6.98-6.91(m,3H),2.38(s,3H),1.79(s,3H),1.70(s,3H).

[0517] Example 38: Preparation of 5-amino-4-(3-hydroxy-2,6-dimethylphenyl)-2-methyl-4,7-dihydro-6H-8-thia-1,3,4,7,10-pentaazabenzo[cd]cyclopenta[f]azulen-6-one (Compound 38)

[0518] Step 1: tert-Butyl (4-bromothiazol-5-yl)carbamate (38b)

[0519] Compound 38a (0.45 g, 2.3 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL), and N-bromosuccinimide (0.36 g, 2.0 mmol) was added. The mixture was allowed to react at room temperature for 5 minutes. The reaction solution was directly purified by reverse-phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to obtain compound 38b (0.55 g, 88% yield). m / z (ESI): 279.1 [M+H] + .

[0520] Step 2: tert-Butyl [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol-5-yl]carbamate (38c)

[0521] Compound 38b (0.25 g, 0.90 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan-2-yl (0.46 g, 1.8 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.14 g, 0.18 mmol), and potassium acetate (0.26 g, 2.7 mmol) were dissolved in 1,4-dioxane (5 mL). The air was replaced with nitrogen three times. The reaction was then incubated at 100°C for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, filtered to remove insoluble matter, and the filtrate was concentrated. The crude product, compound 38c, was used directly in the next reaction without purification. m / z(ESI):327.2[M+H] + .

[0522] Step 3: 6-amino-4-(5-((tert-butoxycarbonyl)amino)thiazol-4-yl)-7-(3-methoxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid methyl ester (38d)

[0523] The crude product from the previous step, compound 38c (0.26 g, 0.80 mmol), compound 3b (0.10 g, 0.27 mmol), tris(dibenzylideneacetone)dipalladium (25 mg, 27 μmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphoryladamantane (16 mg, 53 μmol), and cesium carbonate (0.26 g, 0.80 mmol) were dissolved in 1,4-dioxane and water (5 mL / 0.5 mL). The air was replaced with nitrogen three times, and the mixture was reacted at 100°C under a nitrogen atmosphere for 12 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 compound 38d (19 mg, 14% yield). m / z(ESI):539.2[M+H] + .

[0524] Step 4: 6-amino-4-(5-aminothiazol-4-yl)-7-(3-methoxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid methyl ester (38e)

[0525] Compound 38d (19 mg, 35 μmol) was dissolved in anhydrous dichloromethane (3 mL). A 4 M solution of hydrogen chloride in dioxane (3 mL) was added to the reaction mixture under ice-cooling conditions. The mixture was then allowed to react at room temperature for 1 hour. The solvent was then concentrated to remove the solvent. The pH was then adjusted to neutral with ammonia (25% ammonia in water). The mixture was then purified by reverse-phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to afford compound 38e (15 mg, 97% yield). m / z (ESI): 439.3 [M+H] + .

[0526] Step 5: 5-amino-4-(3-methoxy-2,6-dimethylphenyl)-2-methyl-4,7-dihydro-6H-8-thia-1,3,4,7,10-pentaazabenzo[cd]cyclopenta[f]azulene-6-one (38f)

[0527] Compound 38e (15 mg, 35 μmol) was dissolved in a mixture of tetrahydrofuran (2 mL), methanol (2 mL), and water (2 mL). Lithium hydroxide monohydrate (43 mg, 1.0 mmol) was added and the mixture was heated to 50°C for 1 hour. After the reaction mixture was cooled to room temperature, the insoluble matter was removed by filtration, and the filtrate was concentrated. The crude product was purified by reverse phase chromatography (C18, 0.05% ammonia water:acetonitrile = 20:1 to 1:20) to obtain compound 38f (8 mg, 58% yield). m / z (ESI): 407.2 [M+H] + .

[0528] Step 6: 5-amino-4-(3-hydroxy-2,6-dimethylphenyl)-2-methyl-4,7-dihydro-6H-8-thia-1,3,4,7,10-pentaazabenzo[cd]cyclopenta[f]azulen-6-one (38)

[0529] Compound 38f (8 mg, 20 μmol) was dissolved in anhydrous dichloromethane (3 mL). A dichloromethane solution of boron tribromide (0.1 mL, 1 mol / L) was slowly added dropwise under ice-cooling. The mixture was then allowed to react at room temperature for 2 hours. The reaction was quenched with methanol (2 mL). The reaction solution was concentrated to remove the solvent, and the pH was adjusted to neutral with ammonia (25% ammonia in water). The mixture was then purified by reverse-phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to afford compound 38 (3.8 mg, 49% yield).

[0530] m / z(ESI):393.4[M+H] + .

[0531] 1 H NMR (400MHz, DMSO-d6) δ10.11(s,1H),9.60(s,1H),8.47(s,1H),7.08(d,J=8.3Hz ,1H),6.94(d,J=8.3Hz,1H),6.85(s,2H),2.37(s,3H),1.79(s,3H),1.71(s,3H).

[0532] Example 39: Preparation of 2-amino-6-(difluoromethoxy)-1-(3-hydroxy-2,6-dimethylphenyl)-11-methyl-4,5-dihydro-1,4,7,10,12-pentaazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]inden-3(1H)-one (Compound 39)

[0533] Step 1: (4-iodo-2-methoxypyridin-3-yl)methanol (39b)

[0534] Compound 39a (10 g, 38 mmol) was dissolved in anhydrous ethanol (120 mL). Sodium borohydride (2.1 g, 57 mmol) was slowly added to the reaction mixture under an ice bath, and then the mixture was allowed to react at room temperature for 3 hours. A small amount of water (10 mL) was slowly added to the reaction system to quench the reaction, and the reaction solution was concentrated to remove the ethanol. The mixture was then extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the product, compound 39b (9.6 g, 95% yield). m / z (ESI): 266.0 [M+H] +.

[0535] Step 2: 2-((4-iodo-2-methoxypyridin-3-yl)methyl)isoindoline-1,3-dione (39c)

[0536] Compound 39b (6.0 g, 23 mmol) was dissolved in anhydrous tetrahydrofuran (80 mL), followed by the addition of phthalimide (4.0 g, 27 mmol) and triphenylphosphine (12 g, 45 mmol). The atmosphere was purged with nitrogen three times, and the mixture was cooled to 0°C under nitrogen. Diisopropyl azodicarboxylate (9.2 g, 45 mmol) was then slowly added dropwise. The mixture was then allowed to warm to room temperature and allowed to react for 16 hours. The reaction mixture was concentrated, and the residue was dissolved in water and extracted with ethyl acetate (60 mL x 3). The organic phases were combined, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. The resulting residue was purified by normal phase chromatography (petroleum ether:ethyl acetate = 4:1 to 3:2) to afford compound 39c (6.0 g, 67% yield). m / z (ESI): 394.9 [M+H] + .

[0537] Step 3: 2-((2-Hydroxy-4-iodopyridin-3-yl)methyl)isoindoline-1,3-dione (39d)

[0538] Compound 39c (6.0 g, 15 mmol) was dissolved in anhydrous acetonitrile (80 mL), and trimethylsilyl iodide (12 g, 60 mmol) was added. The reaction mixture was heated to 60°C for 4 hours. Saturated aqueous sodium thiosulfate (60 mL) was added to quench the reaction. The reaction solution was concentrated to remove the acetonitrile and then extracted three times with ethyl acetate (60 mL x 3). The organic phases were combined, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by normal phase column chromatography (dichloromethane:methanol = 10:1 to 10:2) to obtain compound 39d (4.7 g, 80% yield). m / z (ESI): 380.9 [M+H] + .

[0539] Step 4: 2-((2-(difluoromethoxy)-4-iodopyridin-3-yl)methyl)isoindoline-1,3-dione (39e)

[0540] Compound 39d (4.7 g, 12 mmol) was dissolved in anhydrous acetonitrile (60 mL), and diethyl (bromodifluoromethyl)phosphonate (4.9 g, 18 mmol) and potassium fluoride (1.5 g, 24 mmol) were added sequentially. The mixture was then heated to 60°C and reacted for 16 hours. The reaction mixture was concentrated to remove the acetonitrile, and the residue was dissolved in water (30 mL) and extracted with ethyl acetate (60 mL x 3). The organic phases were combined, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by normal phase chromatography (petroleum ether:ethyl acetate = 4:1 to 3:2) to afford compound 39e (2.8 g, 53% yield). m / z (ESI): 430.9 [M+H] + .

[0541] Step 5: tert-Butyl ((2-(difluoromethoxy)-4-iodopyridin-3-yl)methylcarbamate (39f)

[0542] Compound 39e (2.8 g, 6.5 mmol) was dissolved in ethanol (30 mL), and 85% hydrazine hydrate (1.1 g, 33 mmol) was added. The mixture was then heated to 45°C and reacted for 2 hours. After the reaction mixture cooled to room temperature, di-tert-butyl dicarbonate (2.0 g, 6.5 mmol), triethylamine (0.21 g, 20 mmol), and 4-dimethylaminopyridine (1.4 g, 6.5 mmol) were added sequentially. The reaction was continued at room temperature for 3 hours. The reaction solution was concentrated to remove the organic solvent, and the residue was dissolved in water (30 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by normal column chromatography (petroleum ether:ethyl acetate = 10:1 to 5:1) to obtain compound 39f (1.7 g, 65% yield).

[0543] Step 6: tert-Butyl ((2-(difluoromethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methyl)carbamate (39 g)

[0544] Compound 39f (40 mg, 0.10 mmol), pinacol diboronate (31 mg, 0.12 mmol), palladium acetate (4.5 mg, 20 μmol), tricyclohexylphosphine (5.6 mg, 20 μmol), and potassium acetate (29 mg, 0.30 mmol) were dissolved in anhydrous 1,4-dioxane (2 mL). The air was then purged with argon and the mixture was reacted at 95°C for 2 hours under argon protection. After the reaction solution cooled to room temperature, the insoluble material was removed by filtration, and the filtrate was concentrated. The crude product, compound 39g, was used directly in the next step without purification. m / z (ESI): 401.4 [M+H]+ .

[0545] Step 7: 6-amino-7-(3-(benzyloxy)-2,6-dimethylphenyl)-4-(3-(((tert-butoxycarbonyl)amino)methyl)-2-(difluoromethoxy)pyridin-4-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid methyl ester (39h)

[0546] The crude product, compound 39g (40 mg, 0.1 mmol), compound 11g (40 mg, 88 μmol), bis(dibenzylideneacetone)palladium (5.0 mg, 8.8 μmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphoryladamantane (5.2 mg, 18 μmol), and potassium carbonate (0.29 g, 0.89 mmol) were dissolved in 1,4-dioxane / water (5 mL / 1 mL). The atmosphere was replaced with nitrogen three times, and the reaction mixture was moved to 80°C for 3 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 compound 39h (12 mg, 20% yield). m / z (ESI): 689.8 [M+H] + .

[0547] Step 8: Methyl 6-amino-4-(3-(aminomethyl)-2-(difluoromethoxy)pyridin-4-yl)-7-(3-(benzyloxy)-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (39i)

[0548] Compound 39h (12 mg, 17 μmol) was dissolved in anhydrous methanol (5 mL). Acetyl chloride (5 mL) was then added dropwise to the solution in an ice bath. After the addition was complete, the mixture was allowed to react at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated to obtain the crude product, compound 39i (8 mg), which was used directly in the next step without purification. m / z (ESI): 589.8 [M+H] + .

[0549] Step 9: 2-amino-1-(3-(benzyloxy)-2,6-dimethylphenyl)-6-(difluoromethoxy)-11-methyl-4,5-dihydro-1,4,7,10,12-pentaazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]inden-3(1H)-one (39j)

[0550] Compound 39i (8 mg, 14 μmol) obtained in the previous step was dissolved in methanol / tetrahydrofuran / water (5 ml / 5 mL / 5 mL), followed by the addition of lithium hydroxide monohydrate (5.7 mg, 0.14 mmol). The mixture was allowed to react at room temperature for 3 hours. 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 afford the target compound 39j (5.1 mg, 67% yield). m / z (ESI): 557.6 [M+H] + .

[0551] Step 10: 2-amino-6-(difluoromethoxy)-1-(3-hydroxy-2,6-dimethylphenyl)-11-methyl-4,5-dihydro-1,4,7,10,12-pentaazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]inden-3(1H)-one (39)

[0552] Compound 39j (5.1 mg, 79 μmol) was dissolved in anhydrous methanol (5 mL), and Pd / C (10%, 1.1 mg) was added. The atmosphere was then purged with hydrogen and the reaction was allowed to proceed at room temperature for 8 hours. The insoluble material was removed by filtration, 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 compound 39 (2.8 mg, 65% yield).

[0553] m / z(ESI):467.4[M+H] + .

[0554] 1 H NMR (400MHz, DMSO-d6) δ9.65(s,1H),8.32(d,J=5.3Hz,1H),8.02(t,J=7.0Hz,1H),7.81(t,J=72.6Hz,1H),7.59(d,J=5.3Hz,1H),7.21(s,2H), 7.13(dd,J=12.0,8.2Hz,1H),6.98(d,J=8.2Hz,1H),5.00-4.88(m,1H) ,4.40-4.26(m,1H),2.53(s,3H),1.94-1.81(m,3H),1.74-1.63(m,3H).

[0555] Example 40: Preparation of 2-amino-6-(fluoromethoxy)-1-(3-hydroxy-2,6-dimethylphenyl)-11-methyl-4,5-dihydro-1,4,7,10,12-pentaazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]inden-3(1H)-one (Compound 40)

[0556] Step 1: 2-((2-(Fluoromethoxy)-4-iodopyridin-3-yl)methyl)isoindoline-1,3-dione (40a)

[0557] Compound 39d (2.0 g, 5.3 mmol) was dissolved in anhydrous N,N-dimethylformamide (20 mL) at room temperature. 4-Methylbenzenesulfonic acid fluoromethyl ester (4.3 g, 21 mmol) and potassium fluoride (1.2 g, 21 mmol) were added sequentially, and the mixture was heated to 40°C for 2 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was diluted with water (20 mL) and extracted three times with ethyl acetate (50 mL x 3). The organic phases were combined and washed three times with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by normal phase chromatography (petroleum ether:ethyl acetate = 10:1 to 2:1) to obtain compound 40a (0.18 g, yield 8.3%). m / z (ESI): 413.1 [M+H] + .

[0558] Then, compound 40a was used to replace compound 39e, and a method similar to step 5 to step 10 of example 39 was used to prepare compound 40.

[0559] m / z(ESI):449.4[M+H] + ;

[0560] 1 H NMR (400MHz, DMSO-d6) δ8.27(d,J=5.6Hz,1H),7.96(t,J=6.8Hz,1H),7.46(d,J=4.8Hz,1H),7.13-7.05(m,3H),6.94(d,J=8.4H z,1H),6.16(td,J=52.8,2.4Hz,2H),4.92-4.87(m,1H),4.38-4.32(m,1H),2.53(s,3H),1.89-1.80(m,3H),1.69-1.60(m,3H).

[0561] Example 41: Preparation of 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-11-methyl-6-(trifluoromethoxy)-4,5-dihydro-1,4,7,10,12-pentaazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]inden-3(1H)-one (Compound 41)

[0562] Step 1: 2-((4-iodo-2-(trifluoromethoxy)pyridin-3-yl)methyl)isoindoline-1,3-dione (41a)

[0563] Compound 39d (1.4 g, 3.7 mmol) was dissolved in 1,2-dichloroethane (20 mL), and 1-(trifluoromethyl)-1,2-benzidoxyl-3(1H)-one (1.7 g, 5.2 mmol) was added. The mixture was then heated to 80°C and allowed to react for 16 hours. The reaction solution was concentrated to remove the solvent, and the resulting residue was directly purified by reverse phase chromatography (C18, 0.05% formic acid:acetonitrile = 20:1 to 1:20) to obtain compound 41a (0.17 g, 12% yield). m / z (ESI): 448.9 [M+H] + .

[0564] Then, compound 41a was used to replace compound 39e, and a method similar to step 5 to step 10 of example 39 was used to prepare compound 41.

[0565] m / z(ESI):485.3[M+H] + ;

[0566] 1 H NMR (400MHz, DMSO-d6) δ8.38(d,J=5.2Hz,1H),8.17-8.13(m,1H),7.69(d,J=6.8Hz,1H),7.25-7.15(m,3H),7.12-7.08( m,1H),6.96(d,J=8.4Hz,1H),5.00-4.93(m,1H),4.33-4.27(m,1H),2.53(s,3H),1.90-1.81(m,3H),1.70-1.61(m,3H).

[0567] Example 42: Preparation of 5-amino-8-(difluoromethyl)-4-(3-hydroxy-2,6-dimethylphenyl)-2-methyl-7,8-dihydro-1,3,4,7,8,9-hexaazabenzo[cd]cyclopenta[f]azulene-6(4H)-one (Compound 42)

[0568] Step 1: Ethyl 4-bromo-1-(difluoromethyl)-1H-pyrazole-5-carboxylate (42b)

[0569] Compound 42a (5.0 g, 23 mmol) was dissolved in anhydrous acetonitrile (4 mL). Sodium difluorochloroacetate (7.1 g, 46 mmol) and potassium carbonate (6.3 g, 46 mmol) were added sequentially. The mixture was then heated to 85°C for 16 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The resulting residue was purified by normal phase column chromatography (petroleum ether:ethyl acetate = 10:1 to 5:1) to obtain the target compound 42b (0.68 g, 11% yield). m / z (ESI): 269.0 [M+H] + .

[0570] Step 2: 4-Bromo-1-(difluoromethyl)-1H-pyrazole-5-carboxylic acid (42c)

[0571] Compound 42b (0.48 g, 1.8 mmol) was dissolved in EtOH:H₂O = 1:1 (4 mL), and sodium hydroxide (0.14 g, 3.6 mmol) was added. The mixture was allowed to react at room temperature for 0.5 h. After completion of the reaction, the pH was adjusted to 2-3 with 1N hydrochloric acid, and then 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 was concentrated. The crude product, compound 42c, was used directly in the next step without further purification. m / z (ESI): 240.9 [M+1] + .

[0572] Step 3: tert-Butyl (4-bromo-1-(difluoromethyl)-1H-pyrazol-5-yl)carbamate (42d)

[0573] Compound 42c (0.38 g, 1.6 mmol) was dissolved in tert-butanol (8 mL), and N,N-diisopropylethylamine (0.31 g, 2.4 mmol) and diphenylphosphoryl azide (0.65 g, 2.4 mmol) were added sequentially. The temperature was then raised to 85°C and the reaction mixture was allowed to react for 16 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The resulting residue was purified by normal phase column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:1) to obtain compound 42d (0.17 g, 34% yield). m / z (ESI): 312.1 [M+1] + .

[0574] Step 4: tert-Butyl (1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-5-yl)carbamate (42e)

[0575] Compound 42d (0.50 g, 1.6 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (0.81 g, 3.2 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.25 g, 0.32 mmol), and sodium carbonate (0.33 g, 3.2 mmol) were dissolved in 1,4-dioxane (10 mL). The atmosphere was replaced with nitrogen three times, and the mixture was reacted at 80°C under nitrogen for 2 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The resulting residue, compound 42e, was used directly in the next reaction without purification. m / z(ESI):360.4[M+H] + .

[0576] Step 5: 6-amino-4-(5-((tert-butoxycarbonyl)amino)-1-(difluoromethyl)-1H-pyrazol-4-yl)-7-(3-methoxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid methyl ester (42f)

[0577] Compound 42e (0.35 g, 0.97 mmol), compound 3b (0.33 g, 0.88 mmol), palladium acetate (42 mg, 0.19 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (77 mg, 0.19 mmol), and cesium carbonate (0.61 g, 1.9 mmol) were dissolved in 1,4-dioxane / water (5 mL / 0.5 mL). The atmosphere was replaced with nitrogen three times, and the mixture was reacted at 85°C under nitrogen for 2 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The resulting residue was purified by reverse phase chromatography (C18, 0.05% formic acid:acetonitrile = 20:1 to 1:20) to obtain compound 42f (0.30 g, 60% yield). m / z (ESI): 572.3 [M+H] + .

[0578] Step 6: 6-amino-4-(5-amino-1-(difluoromethyl)-1H-pyrazol-4-yl)-7-(3-methoxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid methyl ester (42 g)

[0579] Compound 42f (0.30 g, 0.52 mmol) was dissolved in 1,4-dioxane (5 mL), and then a 4 mol / L dioxane hydrochloride solution (2 mL) was slowly added. The mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated, and the resulting residue was purified by reverse phase chromatography (C18, 0.05% formic acid:acetonitrile = 20:1 to 1:20) to obtain compound 42g (0.16 g, 65% yield). m / z (ESI): 472.3 [M+H] + .

[0580] Step 7: 5-amino-8-(difluoromethyl)-4-(3-methoxy-2,6-dimethylphenyl)-2-methyl-7,8-dihydro-1,3,4,7,8,9-hexaazabenzo[cd]cyclopenta[f]azulene-6(4H)-one (42h)

[0581] Compound 42g (40 mg, 85 μmol) was dissolved in N,N-dimethylformamide:methanol (1:5) (2 mL), followed by the addition of potassium carbonate (24 mg, 0.17 mol) and the reaction was allowed to proceed at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated, and the resulting residue was purified by reverse phase chromatography (C18, 0.05% formic acid:acetonitrile = 20:1 to 1:20) to afford compound 42h (30 mg, 80% yield). m / z (ESI): 440.3 [M+H] + .

[0582] Step 8: 5-amino-8-(difluoromethyl)-4-(3-hydroxy-2,6-dimethylphenyl)-2-methyl-7,8-dihydro-1,3,4,7,8,9-hexaazabenzo[cd]cyclopenta[f]azulene-6(4H)-one (42)

[0583] Compound 42h (15 mg, 34 μmol) was dissolved in dichloromethane, followed by the addition of a dichloromethane solution of boron tribromide (2 mL, 2 mol / L). The mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, methanol (5 mL) was slowly added dropwise to the reaction mixture under an ice bath to quench the reaction. The pH was then adjusted to 14 with aqueous ammonia. The reaction mixture was concentrated, and the resulting residue was purified by reverse-phase chromatography (C18, 0.05% formic acid:acetonitrile = 20:1 to 1:20) to afford compound 42 (2.3 mg, 16% yield).

[0584] m / z(ESI):426.3[M+H] + .

[0585] 1H NMR (400MHz, CD3OD) δ8.05(s,1H),7.66-7.37(m,1H),7.02(d,J=8.4Hz,1H),6.85(d,J=8.4Hz,1H),2.38(s,3H),1.79(s,3H),1.74(s,3H).

[0586] Example 43: Preparation of 5-amino-4-(3-hydroxy-2,6-dimethylphenyl)-8-(2-methoxyethyl)-2-methyl-7,8-dihydro-1,3,4,7,8,9-hexaazabenzo[cd]cyclopenta[f]azulen-6(4H)-one (Compound 43)

[0587] Step 1: 1-(2-Methoxyethyl)-1H-pyrazol-5-amine (43b)

[0588] Compound 43a (1.0 g, 6.1 mmol) was dissolved in anhydrous ethanol (20 mL), and cyanoacetaldehyde diethyl acetal (0.87 g, 6.1 mmol) was added. The mixture was reacted at 90°C for 12 hours. The solvent was removed by vacuum concentration, and the resulting crude compound 43b was used directly in the next step without purification.

[0589] Step 2: tert-Butyl (1-(2-methoxyethyl)-1H-pyrazol-5-yl)carbamate (43c)

[0590] The crude compound 43b obtained in the previous step was dissolved in ethanol (20 mL), and di-tert-butyl dicarbonate (1.3 g, 61 mmol) and triethylamine (6.1 g, 61 mmol) were added in sequence. ℃ The reaction was allowed to proceed for 1 hour. The solvent was removed by vacuum concentration, and the resulting residue was purified by reverse phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to afford compound 43c (0.99 g, 67% yield over two steps). m / z (ESI): 242.2 [M+H] + .

[0591] Step 3: tert-Butyl (4-bromo-1-(2-methoxyethyl)-1H-pyrazol-5-yl)carbamate (43d)

[0592] Compound 43c (0.99 g, 4.1 mmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL), and N-bromosuccinimide (0.73 g, 4.1 mmol) was added. The mixture was allowed to react at room temperature for 1 hour. The reaction solution was directly purified by reverse-phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to obtain the target compound 43d (1.1 g, 87% yield). m / z (ESI): 320.2 [M+H] + .

[0593] Step 4: Tert-butyl (1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1H-pyrazol-5-yl)carbamate (43e)

[0594] Compound 43d (0.60 g, 1.9 mmol), pinacol diboronate (0.97 g, 3.8 mmol), tricyclohexylphosphine (0.11 g, 0.38 mmol), tris(dibenzylideneacetone)dipalladium (0.18 g, 0.2 mmol), and potassium acetate (0.56 g, 5.7 mmol) were dissolved in anhydrous 1,4-dioxane. The atmosphere was purged with argon three times, and the mixture was reacted at 80°C under nitrogen for 2 hours. After the reaction mixture was cooled to room temperature, the insoluble matter was removed by filtration, and the filtrate was concentrated. The resulting crude compound 43e was used directly in the next reaction without purification.

[0595] Step 5: 6-amino-7-(3-(benzyloxy)-2,6-dimethylphenyl)-4-(5-((tert-butoxycarbonyl)amino)-1-(2-methoxyethyl)-1H-pyrazol-4-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid methyl ester (43f)

[0596] The crude product 43e (0.70 g, 1.9 mmol) obtained in the previous step, compound 11g (0.13 g, 0.28 mmol), palladium acetate (6.3 mg, 28 μmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (23 mg, 56 μmol), and potassium carbonate (0.12 g, 0.84 mmol) were dissolved in acetonitrile and water (10 ml / 1 mL). The atmosphere was purged with argon three times. The reaction mixture was placed in a 70°C oil bath for 2 hours. After cooling to room temperature, the insoluble material was removed by filtration. 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 obtain compound 43f (20 mg, 11% yield). m / z (ESI): 656.8 [M+H] + .

[0597] Step 6: 5-amino-4-(3-(benzyloxy)-2,6-dimethylphenyl)-8-(2-methoxyethyl)-2-methyl-7,8-dihydro-1,3,4,7,8,9-hexaazabenzo[cd]cyclopenta[f]azulene-6(4H)-one (43 g)

[0598] Compound 43f (20 mg, 31 μmol) was dissolved in anhydrous methanol under ice-cooling conditions, and acetyl chloride (5 mL) was slowly added dropwise. After the addition was complete, the mixture was allowed to warm to room temperature and allowed to react for 4 hours. The solvent was removed by vacuum concentration, and the solid residue was dissolved in tetrahydrofuran / water (5 mL / 5 mL). Lithium hydroxide monohydrate (84 mg, 2 mmol) was added and the mixture was reacted at 60°C for 8 hours. The solvent was removed by vacuum concentration, and the resulting residue was purified by reverse phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to obtain compound 43g (12 mg, 75% yield). m / z (ESI): 524.6 [M+H] + .

[0599] Step 7: Preparation of 5-amino-4-(3-hydroxy-2,6-dimethylphenyl)-8-(2-methoxyethyl)-2-methyl-7,8-dihydro-1,3,4,7,8,9-hexaazabenzo[cd]cyclopenta[f]azulene-6(4H)-one (Compound 43)

[0600] Compound 43g (12 mg, 23 μmol) was dissolved in methanol (5 mL), and palladium / carbon (10 mg, 10% Pd, approximately 55% water content) was added. The air was replaced with hydrogen three times and the mixture was allowed to react at room temperature for 2 hours. The reaction solution 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 compound 43 (7 mg, 70% yield).

[0601] m / z(ESI):434.4[M+H] + .

[0602] 1 H NMR(400MHz,DMSO-d6)δ9.62(s,1H),9.53(s,1H),8.10(s,1H),7.08(d,J=8.3Hz,1H),7.00-6.84(m,3 H),4.14(t,J=5.2Hz,2H),3.66(t,J=5.2Hz,2H),3.26(s,3H),2.36(s,3H),1.79(s,3H),1.70(s,3H).

[0603] Example 44: Preparation of 5-amino-4-(3-hydroxy-2,6-dimethylphenyl)-1,2,9-trimethyl-7,9-dihydro-3,4,7,9,10-pentaazabenzo[cd]cyclopenta[f]azulen-6(4H)-one (Compound 44)

[0604] Step 1: 4-Hydroxy-5,6-dimethylpyridin-2(1H)-one (44b)

[0605] Compound 44a (30 g, 142 mmol) was dissolved in water (300 mL), and sodium hydroxide (57 g, 1.4 mol) was added. The temperature was then raised to 120°C for 2 hours. After cooling to room temperature, the reaction solution was neutralized with 6N hydrochloric acid to pH 7, filtered, and the filter cake was washed with water and dried to obtain compound 44b (16 g, yield 80%). m / z (ESI): 140.0 [M+H] + .

[0606] Step 2: 3-Bromo-5,6-dimethylpyridine-2,4-diol (44c)

[0607] Compound 44b (11.5 g, 82.6 mmol) was dissolved in anhydrous dichloromethane (50 mL). Bromine (13.2 g, 82.6 mmol) was slowly added dropwise under an ice bath. After the addition was complete, the mixture was allowed to warm to room temperature and allowed to react for 2 hours. The reaction was quenched with saturated aqueous sodium thiosulfate (10 mL), filtered, and the filter cake washed with dichloromethane. The solid was then dried to yield compound 44c (13 g, 73% yield). m / z (ESI): 217.9 [M+H] + .

[0608] Step 3: 3-Bromo-2,4-dichloro-5,6-dimethylpyridine (44d)

[0609] Compound 44c (9.9 g, 45 mmol) was dissolved in phosphorus oxychloride (6 mL), and N,N-dimethylformamide (0.16 g, 2.3 mmol) was added dropwise. The temperature was then raised to 110°C and the reaction mixture was allowed to react for 2 hours. The reaction mixture was concentrated to remove most of the phosphorus oxychloride. Water (100 mL) was then added and stirred for 30 minutes. The mixture was then extracted with ethyl acetate (200 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 resulting residue was purified by normal phase chromatography (petroleum ether:ethyl acetate = 10:1 to 1:1) to afford compound 44d (7.1 g, 62% yield). m / z (ESI): 253.8 [M+H] + .

[0610] Step 4: 3-Bromo-4-chloro-N-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethylpyridin-2-amine (44e)

[0611] Compound 44d (1.0 g, 3.9 mmol), 3-methoxy-2,6-dimethylaniline 1b (0.88 g, 5.9 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.23 g, 0.39 mmol), tris(dibenzylideneacetone)dipalladium (0.36 g, 0.39 mmol), and cesium carbonate (2.6 g, 7.9 mmol) were dissolved in anhydrous 1,4-dioxane. The atmosphere was replaced with nitrogen three times, and the reaction was incubated at 100°C under nitrogen for 12 hours. The reaction mixture was cooled to room temperature, filtered to remove insoluble matter, and the filtrate was concentrated to dryness. The resulting residue was purified by reverse phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to afford compound 44e (0.25 g, 17% yield). m / z (ESI): 369.0 [M+H] + .

[0612] Step 5: 2-Amino-4-chloro-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (44f)

[0613] Malononitrile (0.18 g, 2.7 mmol) was dissolved in anhydrous ethylene glycol dimethyl ether (12 mL), and sodium tert-butoxide (0.39 g, 4.1 mmol) was added. After stirring at room temperature for 30 minutes, compound 44e (0.25 g, 0.67 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (54 mg, 67 μmol) were added. The atmosphere was replaced with nitrogen three times, and the reaction was continued at 80°C for 2 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 44f (0.12 g, 46% yield). m / z (ESI): 355.2 [M+H] + .

[0614] Step 6: 3-Bromo-1-methyl-1H-pyrazol-4-amine (44h)

[0615] At room temperature, compound 44g (1.0 g, 4.8 mmol) and ammonium chloride (1.6 g, 29 mmol) were dissolved in a mixture of ethanol (15 mL) and water (15 mL). Iron powder (1.6 g, 29 mmol) was added and the mixture was heated to 70°C for 2 hours. The insoluble matter was removed by filtration and washed with ethanol. The filtrate was concentrated to obtain the crude product, compound 44h, which was used directly in the next step without purification. m / z (ESI): 175.9 [M+H] + .

[0616] Step 7: tert-Butyl (3-bromo-1-methyl-1H-pyrazol-4-yl)carbamate (44i)

[0617] Compound 44h (0.85 g, 4.8 mmol) and sodium bicarbonate (3.3 g, 39 mmol) were dissolved in a mixture of ethanol (25 mL) and water (25 mL). Di-tert-butyl dicarbonate (1.6 g, 7.2 mmol) was then added and allowed to react at room temperature for 16 hours. The reaction solution was concentrated to remove the ethanol and then extracted with ethyl acetate (50 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 = 10:1-3:1) to obtain compound 44i (0.70 g, 52% yield). m / z (ESI): 275.9 [M+H] + .

[0618] Step 8: Tert-butyl (1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-4-yl)carbamate (44j)

[0619] Compound 44i (0.25 g, 0.91 mmol), pinacol diboron (0.25 g, 1.0 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (67 mg, 91 μmol), and potassium acetate (0.18 g, 1.8 mmol) were dissolved in anhydrous ethylene glycol dimethyl ether (10 mL) at room temperature. The air was replaced with nitrogen three times, and the mixture was reacted at 100°C under nitrogen for 3 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The resulting residue, compound 44j, was used directly in the next reaction without purification.

[0620] Step 9: Tert-butyl (3-(2-amino-3-cyano-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1-methyl-1H-pyrazol-4-yl)carbamate (44k)

[0621] The crude product from the previous step, compound 44j (0.25 g, 0.77 mmol), compound 44f (90 mg, 0.26 mmol), tris(dibenzylideneacetone)dipalladium (24 mg, 26 μmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphoryladamantane (30 mg, 0.10 mmol), and cesium carbonate (0.17 g, 0.52 mmol) were dissolved in 1,4-dioxane / water (5 mL / 1 mL) at room temperature. The atmosphere was replaced with nitrogen three times. The reaction mixture was then moved to 100°C for 2 hours. After the reaction mixture was cooled to room temperature, water (10 mL) was added to dilute the reaction mixture, followed by extraction 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 to 4:1) to obtain the target product, compound 44k (70 mg, yield 52%). m / z (ESI): 516.3 [M+H] + .

[0622] Step 10: 5-amino-4-(3-methoxy-2,6-dimethylphenyl)-1,2,9-trimethyl-7,9-dihydro-3,4,7,9,10-pentaazabenzo[cd]cyclopenta[f]azulene-6(4H)-one (441)

[0623] Compound 44k (70 mg, 0.14 mmol) was dissolved in methanol (5 mL) at room temperature, followed by the addition of concentrated hydrochloric acid (5 mL). The reaction mixture was allowed to react at 115°C under sealed conditions for 20 hours. The solvent was then 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 the target compound 44l (3 mg, 5% yield). m / z (ESI): 417.4 [M+H] + .

[0624] Step 11: 5-amino-4-(3-hydroxy-2,6-dimethylphenyl)-1,2,9-trimethyl-7,9-dihydro-3,4,7,9,10-pentaazabenzo[cd]cyclopenta[f]azulene-6(4H)-one (44)

[0625] Compound 441 (3.0 mg, 7.2 μmol) was dissolved in dichloromethane (3 mL) at room temperature, followed by the addition of boron tribromide (180 mg, 72 μmol) and stirring for 1 hour. 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 44 (2.3 mg, 79% yield).

[0626] m / z(ESI):403.4[M+H] + .

[0627] 1 H NMR (400MHz, DMSO-d6) δ9.49(s,1H),8.94(s,1H),7.29(s,1H),7.05(d,J=8.0Hz,1H),6.90(d ,J=8.0Hz,1H),6.76(s,2H),3.79(s,3H),2.57(s,3H),2.27(s,3H),1.78(s,3H),1.69(s,3H).

[0628] Example 45: Preparation of 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-11-methyl-3-oxo-1,3,4,5-tetrahydro-1,4,7,10,12-pentaazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]indene-6-carbonitrile (Compound 45)

[0629] Step 1: 4-Bromo-2-hydroxynicotinonitrile (45b)

[0630] Compound 45a (2.0 g, 9.2 mmol) was dissolved in glacial acetic acid (30 mL) and heated to 100°C for 16 hours. After the reaction was cooled to room temperature, the insoluble matter was removed by filtration. The filtrate was concentrated, and the resulting residue was purified by reverse phase chromatography (C18, 0.05% formic acid:acetonitrile = 20:1 to 1:20) to obtain compound 45b (1.5 g, yield 82%). m / z (ESI): 199.0 [M+H] + .

[0631] Step 2: 3-(Aminomethyl)-4-bromopyridin-2-ol (45c)

[0632] Compound 45b (1.5 g, 7.5 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL). A solution of borane tetrahydrofuran complex in tetrahydrofuran (1 mol / L, 15 mL) was added. The air was replaced with nitrogen three times, and the reaction mixture was moved to 50°C for 2 hours. After the reaction mixture cooled to room temperature, dilute hydrochloric acid (1 mol / L, 50 mL) was added and stirred at room temperature for 20 minutes. The organic phase was separated and discarded. The aqueous phase was concentrated to obtain the crude product, compound 45c, which was used directly in the next reaction without purification. m / z (ESI): 203.0 [M+H] + .

[0633] Step 3: tert-Butyl ((4-bromo-2-hydroxypyridin-3-yl)methyl)carbamate (45d)

[0634] Compound 45c (1.5 g, 7.5 mmol) was dissolved in anhydrous methanol (30 mL), and triethylamine (1.5 g, 15 mmol) and di-tert-butyl dicarbonate (3.2 g, 15 mmol) were added. The mixture was allowed to react at room temperature 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 afford compound 45d (0.88 g, 40% yield). m / z (ESI): 303.0 [M+H] + .

[0635] Step 4: tert-Butyl ((4-(5,5-dimethyl-1,3,2-dioxaborolan-2-yl)-2-hydroxypyridin-3-yl)methyl)carbamate (45e)

[0636] Compound 45d (0.15 g, 0.5 mmol), neopentyl glycol diboronate (0.17 g, 0.75 mmol), palladium acetate (22 mg, 0.10 mmol), tricyclohexylphosphine (28 mg, 0.10 mmol), and potassium acetate (98 mg, 1.0 mmol) were dissolved in anhydrous 1,4-dioxane (5 mL). The air was then purged with argon and the mixture was reacted at 95°C for 2 hours under argon protection. After the reaction solution was cooled to room temperature, the insoluble matter was removed by filtration. The resulting product, compound 45e, was used directly in the next step without purification. m / z (ESI): 337.2 [M+H] + .

[0637] Step 5: 6-amino-4-(3-(((tert-butoxycarbonyl)amino)methyl)-2-hydroxypyridin-4-yl)-7-(3-methoxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid methyl ester (45f)

[0638] Compound 45e (0.11 g, 0.31 mmol), compound 3b (0.10 g, 0.28 mmol), bis(dibenzylideneacetone)palladium (24 mg, 43 μmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphoryladamantane (12 mg, 43 μmol), and cesium carbonate (0.14 g, 0.43 mmol) were dissolved in 1,4-dioxane / water (5 mL / 0.5 mL). The atmosphere was replaced with nitrogen three times, and the reaction mixture was moved to 100°C for 2 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 obtain compound 45f (42 mg, 24% yield). m / z (ESI): 563.3 [M+H] + .

[0639] Step 6: 6-amino-4-(3-(aminomethyl)-2-hydroxypyridin-4-yl)-7-(3-methoxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid methyl ester (45 g)

[0640] Compound 45f (42 mg, 75 μmol) was dissolved in a hydrogen chloride-dioxane solution (4 mol / L, 2 mL) and allowed to react at room temperature for 30 minutes. After the reaction was complete, the reaction solution was concentrated. The resulting product, compound 45g, was used directly in the next step without purification. m / z (ESI): 463.2 [M+H] + .

[0641] Step 7: 2-amino-6-hydroxy-1-(3-methoxy-2,6-dimethylphenyl)-11-methyl-4,5-dihydro-1,4,7,10,12-pentaazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]inden-3(1H)-one (45h)

[0642] Compound 45g (35 mg, 75 μmol) was dissolved in methanol / tetrahydrofuran / water (2 ml / 2 mL / 2 mL), and lithium hydroxide monohydrate (42 mg, 1.0 mmol) was added. The reaction was then heated to 50°C for 1 hour. 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 compound 45h (25 mg, 78% yield). m / z (ESI): 431.2 [M+H] + .

[0643] Step 8: 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-11-methyl-3-oxo-1,3,4,5-tetrahydro-1,4,7,10,12-pentaazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]inden-6-yl trifluoromethanesulfonate (45i)

[0644] Compound 45h (5.0 mg, 12 μmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL). Cesium carbonate (4.2 mg, 13 μmol) and N-phenylbis(trifluoromethanesulfonyl)imide (4.4 mg, 12 μmol) were added sequentially and reacted at room temperature for 10 minutes. The reaction solution was directly purified by reverse-phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to obtain the target compound 45i (5.8 mg, 89% yield). m / z (ESI): 563.2 [M+H] + .

[0645] Step 9: 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-11-methyl-3-oxo-1,3,4,5-tetrahydro-1,4,7,10,12-pentaazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]indene-6-carbonitrile (45j)

[0646] Compound 45i (5.0 mg, 8.9 μmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL). Zinc (0.6 mg, 8.9 μmol), zinc cyanide (1.0 mg, 8.9 μmol), tris(dibenzylideneacetone)dipalladium (0.8 mg, 0.89 μmol), and 1,1'-bis(diphenylphosphino)ferrocene (0.20 mg, 0.17 μmol) were added sequentially. The atmosphere was replaced with nitrogen three times, and the reaction mixture was moved to 90°C for 3 hours. After cooling to room temperature, the reaction mixture was directly purified by reverse-phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to obtain the target compound 45j (3.2 mg, 82% yield).

[0647] Step 10: 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-11-methyl-3-oxo-1,3,4,5-tetrahydro-1,4,7,10,12-pentaazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]indene-6-carbonitrile (45)

[0648] Compound 45j (3.2 mg, 7.3 μmol) was dissolved in dichloromethane (5 mL) at room temperature, and a dichloromethane solution of boron tribromide (1 mol / L, 2 mL) was added. The mixture was stirred for 10 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 45 (1.0 mg, 32% yield).

[0649] m / z(ESI):426.4[M+H] + .

[0650] 1H NMR (400MHz, DMSO-d6) δ9.62(d,J=8.4Hz,1H),8.81(d,J=4.8Hz,1H),8.23(t,J=6.8Hz,1H),8.03(dd,J=5.2,1.2Hz,1H),7.24(brs,2H),7. 11(dd,J=12.0,8.0Hz,1H),6.96(d,J=8.0Hz,1H),5.24-5.18(m,1H),4.45-4.39(m,1H),2.51(s,3H),1.90-1.81(m,3H),1.70-1.61(m,3H).

[0651] Example 46: Preparation of 2-amino-6-cyclopropyl-1-(3-hydroxy-2,6-dimethylphenyl)-11-methyl-4,5-dihydro-1,4,7,10,12-pentaazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]inden-3(1H)-one (Compound 46)

[0652] Step 1: 2-amino-6-cyclopropyl-1-(3-methoxy-2,6-dimethylphenyl)-11-methyl-4,5-dihydro-1,4,7,10,12-pentaazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]inden-3(1H)-one (46a)

[0653] Compound 45i (8.6 mg, 15 μmol), cyclopropylboronic acid (13 mg, 0.15 mmol), bis(dibenzylideneacetone)palladium (0.87 mg, 1.5 μmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphoryladamantane (0.89 mg, 3.1 μmol), and potassium carbonate (6.3 mg, 46 μmol) were dissolved in 1,4-dioxane / water (5 mL / 0.5 mL). The atmosphere was replaced with nitrogen three times. The reaction mixture was then moved to 90°C for 0.5 h. The reaction mixture was cooled to room temperature, filtered, 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 compound 46a (3.6 mg, 52% yield). m / z (ESI): 455.4 [M+H] + .

[0654] Step 2: 2-amino-6-cyclopropyl-1-(3-hydroxy-2,6-dimethylphenyl)-11-methyl-4,5-dihydro-1,4,7,10,12-pentaazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]inden-3(1H)-one (Compound 46)

[0655] Compound 46a (3.6 mg, 7.3 μmol) was dissolved in anhydrous dichloromethane (5 mL), and a dichloromethane solution of boron tribromide (1 mol / L, 2 mL) was added. The mixture was allowed to react at room temperature for 30 minutes. The reaction solution was quenched with methanol (5 mL), the pH adjusted to 14 with aqueous ammonia, 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 46 (2.2 mg, 63% yield).

[0656] m / z(ESI):441.4[M+H] + ;

[0657] 1 H NMR (400MHz, DMSO-d6) δ9.61(d,J=9.6Hz,1H),8.45(d,J=5.2Hz,1H),8.12-8.08(m,1H),7.44-7.40(m,1H),7.21-7.08(m,3H),6.96(d,J=8 .4Hz,1H),5.16–5.06(m,1H),4.52-4.48(m,1H),2.53(s,3H),2.05-1.95(m,1H),1.91-1.82(m,3H),1.70-1.61(m,3H),0.90-0.78(m,4H).

[0658] Example 47: Preparation of 2-amino-6-ethoxy-1-(3-hydroxy-2,6-dimethylphenyl)-11-methyl-4,5-dihydro-1,4,7,10,12-pentaazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]inden-3(1H)-one (Compound 47)

[0659] Compound 47 was prepared by replacing compound 23a with compound 47a in a manner similar to that of Example 23.

[0660] m / z(ESI):445.4[M+H] + ;

[0661] 1H NMR(400MHz, DMSO-d6)δ9.60(brs,1H),8.18(d,J=5.2Hz,1H),7.92(t,J=6.8Hz,1H),7. 24(dd,J=8.4,1.2Hz,1H),7.12-7.08(m,3H),6.95(d,J=8.4Hz,1H),4.84–4.78(m,1H), 4.40(q,J=6.8Hz,2H),4.33-4.28(m,1H),2.53(s,3H),1.89-1.80(m,3H),1.69-1.60(m,3H),1.41(t,J=6.8Hz,3H).

[0662] Example 48: Preparation of 2-amino-6-hydroxy-1-(3-hydroxy-2,6-dimethylphenyl)-11-methyl-4,5-dihydro-1,4,7,10,12-pentaazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]inden-3(1H)-one (Compound 48)

[0663] Compound 45h (5.0 mg, 12 μmol) was dissolved in anhydrous dichloromethane (5 mL), and boron tribromide (0.50 mL, 1 mol / L dichloromethane solution) was slowly added dropwise under ice-cooling. The reaction was allowed to react at room temperature for 2 hours, 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 afford compound 48 (4 mg, 80% yield).

[0664] m / z(ESI):417.4[M+H] + .

[0665] 1 H NMR (400MHz, DMSO-d6) δ7.69(t,J=6.8Hz,1H),7.41(d,J=6.8Hz,1H),7.14-7.02(m,3H),6.94(d,J=8.2Hz, 1H),6.47(m,1H),4.68-4.46(m,1H),4.35-4.17(m,1H),2.48(s,3H),1.89-1.75(m,3H),1.72-1.55(m,3H).

[0666] Example 49: Preparation of 2-amino-7-fluoro-1-(3-hydroxy-2,6-dimethylphenyl)-11-methyl-3-oxo-1,3,4,5-tetrahydro-1,4,10,12-tetraazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]indene-6-carbonitrile (Compound 49)

[0667] Step 1: 2-(Benzyloxy)-6-bromo-3-fluorobenzonitrile (49b)

[0668] Benzyl alcohol (0.25 g, 2.3 mmol) was dissolved in anhydrous N,N-dimethylformamide (3 mL) under ice-cooling conditions. 60% sodium hydroxide (0.12 g, 3.0 mmol) was then added. After 30 minutes, compound 49a (0.50 g, 2.3 mmol) was added, and the temperature was raised to 50°C for 1 hour. Water (10 mL) was added to the reaction system 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 (30 mL x 3), 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 compound 49b (0.51 g, 72% yield).

[0669] Step 2: tert-Butyl (6-bromo-3-fluoro-2-hydroxybenzyl)carbamate (49c)

[0670] Compound 49b (0.20 g, 0.65 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL) at room temperature. A solution of borane tetrahydrofuran complex in tetrahydrofuran (3.3 mL, 1 M, 3.27 mmol) was then added. The air was replaced with nitrogen three times, and the reaction mixture was moved to 50°C for 2 hours. After cooling to room temperature, the mixture was quenched with 1N hydrochloric acid and stirred for 30 minutes. The mixture was then extracted with ethyl acetate (50 mL x 3). The combined organic phases were spin-dried and dissolved in dichloromethane (10 mL). Triethylamine (0.28 g, 2.7 mmol) and di-tert-butyl dicarbonate (0.40 g, 1.8 mmol) were added at room temperature, and the mixture was stirred at room temperature for 30 minutes. The residue was filtered, concentrated, and purified by reverse-phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to afford the target compound 49c (0.12 g, 44% yield). m / z(ESI):320.2[M+H] + .

[0671] Step 3: tert-Butyl (3-fluoro-2-hydroxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (49d)

[0672] Compound 49c (50 mg, 0.16 mmol), pinacol diboronate (79 mg, 0.31 mmol), palladium acetate (3.5 mg, 16 μmol), tricyclohexylphosphine (4.4 mg, 16 μmol), and potassium acetate (46 mg, 0.47 mmol) were dissolved in anhydrous 1,4-dioxane (5 mL). The air was then purged with argon and the mixture was reacted at 100°C for 2 hours under argon protection. After the reaction solution was cooled to room temperature, the insoluble material was removed by filtration. The resulting product 49d was used directly in the next step without purification. m / z (ESI): 368.2 [M+H]+.

[0673] Step 4: 6-amino-4-(2-(((tert-butoxycarbonyl)amino)methyl)-4-fluoro-3-hydroxyphenyl)-7-(3-methoxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid methyl ester (49e)

[0674] Compound 49d (67 mg, 0.18 mmol), compound 3b (45 mg, 0.12 mmol), tris(dibenzylideneacetone)dipalladium (11 mg, 12 μmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphoryladamantane (3.5 mg, 12 μmol), and cesium carbonate (117 mg, 0.36 mmol) were dissolved in 1,4-dioxane / water (5 mL / 0.5 mL) at room temperature. The atmosphere was replaced with nitrogen three times, and the reaction mixture was moved to 80°C for 6 hours. The reaction mixture was cooled to room temperature, filtered to remove insoluble material, 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 the target compound 49e (31 mg, 45% yield). m / z (ESI): 580.2 [M+H] + .

[0675] Step 5: 6-amino-4-(2-(aminomethyl)-4-fluoro-3-hydroxyphenyl)-7-(3-methoxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid methyl ester (49f)

[0676] Compound 49e (25 mg, 43 μmol) was dissolved in 1,4-dioxane hydrochloride (2 mL) at room temperature and allowed to react for 2 hours. After the reaction was complete, the reaction solution was concentrated, and the resulting product 49f was used directly in the next step without purification. m / z (ESI): 480.2 [M+H] + .

[0677] Step 6: 2-amino-7-fluoro-6-hydroxy-1-(3-methoxy-2,6-dimethylphenyl)-11-methyl-4,5-dihydro-1,4,10,12-tetraazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]inden-3(1H)-one (49 g)

[0678] Compound 49f (21 mg, 43 μmol) was dissolved in methanol / tetrahydrofuran / water (2 ml / 2 mL / 2 mL), and lithium hydroxide monohydrate (52 mg, 1.2 mmol) was added. The reaction mixture was placed in a 50°C oil bath for 1 hour. 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 49g (19 mg, 97% yield). m / z (ESI): 448.2 [M+H] + .

[0679] Step 7: 2-Amino-7-fluoro-1-(3-methoxy-2,6-dimethylphenyl)-11-methyl-3-oxo-1,3,4,5-tetrahydro-1,4,10,12-tetraazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]inden-6-yl trifluoromethanesulfonate (49h)

[0680] Compound 49g (19 mg, 42 μmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL). Cesium carbonate (28 mg, 85 μmol) and N-phenylbis(trifluoromethanesulfonyl)imide (23 mg, 64 μmol) were added sequentially and allowed to react at room temperature for 1 hour. The reaction mixture was directly purified by reverse-phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to obtain the target compound 49h (22 mg, 88% yield). m / z (ESI): 580.2 [M+H] + .

[0681] Step 8: 2-Amino-7-fluoro-1-(3-methoxy-2,6-dimethylphenyl)-11-methyl-3-oxo-1,3,4,5-tetrahydro-1,4,10,12-tetraazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]indene-6-carbonitrile (49i)

[0682] Compound 49h (10 mg, 17 μmol) was dissolved in anhydrous N,N-dimethylformamide (3 mL). Zinc (0.6 mg, 8.7 μmol), zinc cyanide (2 mg, 17 μmol), tris(dibenzylideneacetone)dipalladium (1.6 mg, 1.8 μmol), and 1,1'-bis(diphenylphosphino)ferrocene (1 mg, 1.8 μmol) were added sequentially. The atmosphere was replaced with nitrogen three times, and the reaction mixture was moved to 90°C for 30 minutes. After cooling to room temperature, the reaction mixture was directly purified by reverse-phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to obtain the target compound 49i (6 mg, 76% yield). m / z (ESI): 457.2 [M+H] + .

[0683] Step 9: 2-Amino-7-fluoro-1-(3-methoxy-2,6-dimethylphenyl)-11-methyl-3-oxo-1,3,4,5-tetrahydro-1,4,10,12-tetraazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]indene-6-carbonitrile (49)

[0684] Compound 49i (6 mg, 14 μmol) was dissolved in dichloromethane (3 mL) at room temperature. A solution of boron tribromide (1 mol / L, 1 mL) in dichloromethane was added and stirred for 30 minutes. The reaction mixture was quenched with methanol (5 mL) and the pH was adjusted to 14 with aqueous ammonia. The reaction mixture was then concentrated, and the resulting residue was purified by reverse-phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to afford compound 49 (4.5 mg, 71% yield).

[0685] m / z(ESI):443.3[M+H] + .

[0686] 1 H NMR (400MHz, DMSO-d6) δ9.60 (s, 1H), 8.16-8.13 (m, 2H), 7.63 (t, J = 8.8Hz, 1H), 7.13-7.07 (m, 3H), 6.95 (d ,J=8.0Hz,1H),5.20-5.10(m,1H),4.35-4.29(m,1H),2.49(s,3H),1.90-1.81(m,3H),1.70-1.61(m,3H).

[0687] Biological activity and related properties test examples

[0688] Test Example 1: PKMYT1 enzyme activity inhibition experiment

[0689] Experimental principle: After PKMYT1 is incubated with the compound, it phosphorylates the substrate CDK1 under the action of ATP. Promega's ADP-Glo TM The detection kit quantifies the ADP produced by the reaction, thereby reflecting the enzyme activity.

[0690] Experimental instruments: Labcyte Echo550 pipetting system; Perkin Elmer Envision microplate reader; Eppendorf 5810R centrifuge.

[0691] Experimental Materials:

[0692] 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 final compound concentration in the reaction system was adjusted to 1% DMSO, starting at 1 μM and followed by a three-fold serial dilution. 50 nL / well of the test compound solution was added, followed by 3 μL / well of MYT1 diluted in Kinase Dilution Buffer. After incubation for 15 minutes, 2 μL / well of a reaction mixture consisting of the substrate CDK1 diluted in Kinase Dilution Buffer and ATP diluted in Kinase Assay Buffer III was added to initiate the enzyme reaction. The final concentrations of MYT1, ATP, and CDK1 were 2 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 detection reagent was added, and after incubation for 30 minutes, the fluorescence signal was read using an Envision microplate reader.

[0693] Data Analysis:

[0694] Calculate the compound inhibition percentage and use XLfit software to fit the compound IC 50 value.

[0695] The experiment was set up with blank and DMSO groups: the blank group reaction system consisted of 1% DMSO and reaction mixture solution, and the compound inhibition rate was considered 100% at this time; the DMSO group reaction system consisted of 1% DMSO, PKMYT1 (2nM / μL), and reaction mixture solution, and the compound inhibition rate was considered 0 at this time. Compound inhibition percentage = (100-100*(experimental well - blank well) / (DMSO group - blank well))%

[0696] 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.

[0697] The inhibitory activity of the compounds of the present application on PKMYT1 was determined by the above test, and the measured IC 50 See Table 1 for values.

[0698] Table 1 IC of compounds against PKMYT1 activity inhibition 50 value

[0699] Test Example 2: Compound Inhibition of Tumor Cell Proliferation

[0700] 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.

[0701] Experimental instruments: Envision microplate reader from Perkin Elmer; 5810R centrifuge from Eppendorf; automatic cell counter from Countstar.

[0702] Experimental Materials:

[0703] Experimental method: The cultured cells were resuspended (adherent cells needed to be rinsed with PBS and digested with 0.25% Trypsin-EDTA) and then counted to obtain cell density and viability information. 3000 HCC1569 cells / well were diluted with RPMI Medium 1640 culture medium containing 10% FBS and added to a 96-well plate (90 μL / well), and 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 a 96-well plate, so that the final concentration of the compound in the reaction system started from 25 μM, and was 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 CTG was added to measure the compound's inhibition on tumor cell growth, and the inhibition rate and half-maximal inhibitory concentration (IC) were calculated. 50 ).

[0704] Data Analysis:

[0705] Calculate the % compound inhibition and use XLfit software to fit the compound IC 50 .

[0706] The experiment set up blank wells and DMSO wells. The blank wells contained 100 μL of RPMI Medium 1640 containing 10% FBS, at which point the compound's inhibition rate on tumor cell growth was considered 100%; the DMSO wells contained 0.25% DMSO, at which point the compound's inhibition rate on tumor cell growth was considered 0. Compound inhibition percentage = (100 * (DMSO well - experimental well) / (DMSO well - blank well))%

[0707] 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.

[0708] Table 2 IC of compounds against HCC1569 cell growth inhibition 50

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, in: X 1 Select N or CR 9 ; Indicates a single bond or a double bond; X 2 Selected from CR 5 R 6 NR 5 , CR 5 and N; X 3 Selected from CR 5 'R 6 '、NR 5 '、CR 5 ' and N; X 4 、X 5 Independently selected from (C(R 10 )2) n NR 10 and O; R 1 、R 3 independently selected from hydrogen, hydroxy, amino, nitro, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C9 cycloalkyl-O-, 4-9 membered heterocyclyl-O-, C1-C6 alkyl-C(O)O-, C3-C9 cycloalkyl-C(O)O-, 4-9 membered heterocyclyl-C(O)O-, P(O)(OH)2O and NH2C(O)O-, said C1-C6 alkyl, C1-C6 alkoxy, C3-C9 cycloalkyl-O-, 4-9 membered heterocyclyl-O-, C1-C6 alkyl-C(O)O-, C3-C9 cycloalkyl-C(O)O-, 4-9 membered heterocyclyl-C(O)O-, P(O)(OH)2O and NH2C(O)O-, said C1-C6 alkyl, C1-C6 alkoxy, C3-C9 cycloalkyl-O-, 4-9 membered heterocyclyl-O-, C1-C6 alkyl-C(O)O-, C3-C9 cycloalkyl-C(O)O-, 4-9 membered heterocyclyl-C(O)O-, P(O)(OH)2O or NH2C(O)O- optionally substituted by one or more R 11 replace; R 2 Selected from hydrogen, cyano, halogen, C1-C6 alkyl, C3-C9 cycloalkyl, 4-9 membered heterocyclic group, C6-C 10 aryl, 5-9 membered heteroaryl, C(=O)H, C2-C6 alkenyl and C2-C6 alkynyl, the C1-C6 alkyl, C3-C9 cycloalkyl, 4-9 membered heterocyclyl, C6-C 10 Aryl, 5-9 membered heteroaryl, C(=O)H, C2-C6 alkenyl or C2-C6 alkynyl are optionally substituted by one or more R a replace; or R 1 、R 2 and the atoms to which they are connected together form a 5-8 membered heterocyclic ring or a 5-9 membered heteroaromatic ring; R 4 、R 6 、R 6 '、R 10 independently selected from hydrogen, deuterium, amino, hydroxyl, mercapto, halogen, cyano, C1-C6 alkyl, C3-C9 cycloalkyl, 4-9 membered heterocyclyl, C6-C 10 aryl, 5-9 membered heteroaryl, C2-C6 alkenyl, C2-C6 alkynyl and -C(=O)NH2, the amino, hydroxyl, thiol, C1-C6 alkyl, C3-C9 cycloalkyl, 4-9 membered heterocyclyl, C6-C 10 Aryl, 5-9 membered heteroaryl, C2-C6 alkenyl, C2-C6 alkynyl or -C(=O)NH2 is optionally substituted by one or more R a replace; R 5 and R 5 ' and the atoms connected thereto together form a C3-C9 saturated or partially saturated carbon ring, a C6-C 10 Aromatic ring, 5-8 membered heterocyclic ring and 5-9 membered heteroaromatic ring, the C3-C9 saturated or partially saturated carbon ring, C6-C 10 Aromatic ring, 5-8 membered heterocyclic ring or 5-9 membered heteroaromatic ring is optionally replaced by one or more R a replace; R 7 、R 8 independently selected from hydrogen, halogen, and C1-C6 alkyl, said C1-C6 alkyl being optionally substituted with deuterium; R 9 is selected from hydrogen, hydroxy, amino, cyano, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl and C(=O)H, wherein the hydroxy, amino, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl or C(=O)H is optionally substituted by one or more R a replace; R 11 Selected from C1-C 10 Alkyl, C3-C9 cycloalkyl, 4-9 membered heterocyclyl, C1-C6 alkoxy, C3-C9 cycloalkyl-O-, 4-9 membered heterocyclyl-O-, C1-C6 alkyl-C(O)O-, C3-C9 cycloalkyl-C(O)O-, 4-9 membered heterocyclyl-C(O)O-, P(O)(OH)2O, NH2C(O)O- and C1-C6 alkyl-OC(O)O-; n is selected from 0, 1 and 2; R a independently selected from deuterium, halogen, oxo, hydroxy, amino, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, C6-C 10 Aryl and 5-9 membered heteroaryl, the hydroxyl, amino, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic, C6-C 10 Aryl or 5-9 membered heteroaryl is optionally substituted with one or more R b replace; R b independently selected from halogen, hydroxy, amino, cyano, C1-C3 alkyl, NH(C1-C3 alkyl), N(C1-C3 alkyl)2, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, C1-C6 alkoxy, C6-C 10 Aryl and 5-9 membered heteroaryl, the C1-C3 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic group, C1-C6 alkoxy, C6-C 10 Aryl or 5-9 membered heteroaryl is optionally substituted with one or more R c replace; R c Independently selected from halogen, hydroxy, amino, cyano and C1-C3 alkyl.

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein X 2 Selected from CR 5 R 6 NR 5 and CR 5 , or X 2 Selected from CR 5 R 6 and CR 5 , or X 2 CR 5 R 6 , or X 2 CR 5 .

3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein X 3 Selected from CR 5 'R 6 '、NR 5 ' and CR 5 ', or X 3 Selected from CR 5 'R 6 ' and CR 5 ', or X 3 CR 5 'R 6 ', or X 3 CR 5 '.

4. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein: X 4 、X 5 independently selected from a bond, C(R 10 )2 and O; or X 4 is a bond, -CH2-, -CH(CH3)- or or X 5 is a bond, -O-, -CH(CH3)-, -C(CH3)2- or or X 4 and X 5 All are keys; or X 4 is -CH2- and X 5 is the key.

5. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R 1 、R 3 are independently selected from hydrogen and hydroxy; or R 1 is hydroxyl group, R 3 For hydrogen.

6. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein: R 2 For hydrogen.

7. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein: R 4 、R 6 、R 6 '、R 10 independently selected from hydrogen, amino, hydroxy, mercapto, halogen, cyano, C1-C6 alkyl, C3-C9 cycloalkyl, 4-9 membered heterocyclyl, C6-C 10 aryl, 5-9 membered heteroaryl, C2-C6 alkenyl, C2-C6 alkynyl and -C(=O)NH2, the amino, hydroxyl, thiol, C1-C6 alkyl, C3-C9 cycloalkyl, 4-9 membered heterocyclyl, C6-C 10 Aryl, 5-9 membered heteroaryl, C2-C6 alkenyl, C2-C6 alkynyl or -C(=O)NH2 is optionally substituted by one or more R a Replace; or R 4 、R 6 、R 6 '、R 10 independently selected from hydrogen, amino, hydroxy, C1-C6 alkyl, C3-C9 cycloalkyl, 4-9 membered heterocyclyl, C6-C 10 Aryl and 5-9 membered heteroaryl, the amino, hydroxyl, C1-C6 alkyl, C3-C9 cycloalkyl, 4-9 membered heterocyclic, C6-C 10 Aryl or 5-9 membered heteroaryl is optionally substituted with one or more R a Replace, or, R 4 、R 6 、R 6 '、R 10 independently selected from hydrogen, amino, hydroxy, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl and 5-6 membered heteroaryl, wherein the amino, hydroxy, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl is optionally substituted by one or more R a Replace; or R 4 Selected from hydrogen, amino, hydroxy, C1-C6 alkyl, C3-C9 cycloalkyl, 4-9 membered heterocyclic group, C6-C 10 Aryl and 5-9 membered heteroaryl, the amino, hydroxyl, C1-C6 alkyl, C3-C9 cycloalkyl, 4-9 membered heterocyclic, C6-C 10 Aryl or 5-9 membered heteroaryl is optionally substituted with one or more R a Replace; or R 4 Selected from -H, -CH3, -CH(CH3)2, -OCH3, -N(CH3)2, -CF3, -CHF2, -C(CH3)2(OH), or R 4 is selected from H and methyl; or Each R 10 Independently selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl.

8. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein: R 5 and R 5 ' and the atoms to which they are connected together form a C4-C7 saturated or partially saturated carbocyclic ring, a benzene ring, a 5-6 heterocyclic ring or a 5-6 membered heteroaromatic ring, wherein the C4-C7 saturated or partially saturated carbocyclic ring, a benzene ring, a 5-6 heterocyclic ring or a 5-6 membered heteroaromatic ring is optionally replaced by one or more R a Replace, or, R 5 and R 5 ' and the atoms connected thereto together form a benzene ring and a 5-6 membered heteroaromatic ring, wherein the benzene ring or the 5-6 membered heteroaromatic ring is optionally replaced by one or more R a Replace; or X 2 CR 5 , X 3 CR 5 ', and R 5 and R 5 ' and the atoms to which they are connected together form a benzene ring or a 5-6 membered heteroaromatic ring, wherein the benzene ring or the 5-6 membered heteroaromatic ring is optionally substituted by one or more R a Replace; or X 2 CR 5 , X 3 CR 5 ', and R 5 and R 5 ' and the atoms to which they are connected together form a benzene ring, a pyridine ring, a pyrazole ring, a thiazole ring, an isothiazole ring, a pyrrole ring or a furan ring, wherein the benzene ring, the pyridine ring, the pyrazole ring, the thiazole ring, the isothiazole ring, the pyrrole ring or the furan ring is optionally replaced by one or more R a replace.

9. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein R 7 、R 8 are independently selected from halogen and C1-C6 alkyl; or, R 7 、R 8 are independently selected from C1-C3 alkyl; or R 7 and R 8 All are methyl.

10. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein: X 1 Selected from N; or X 1 Selected from CR 9 ,and R 9 is selected from hydrogen, hydroxy, amino, halogen and C1-C3 alkyl, wherein the hydroxy, amino, C1-C3 alkyl is optionally replaced by one or more R a Replace, or, R 9 is selected from hydrogen and methyl.

11. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein: n is selected from 0 and 1.

12. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein R a independently selected from halogen, oxo, hydroxy, amino, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, C6-C 10 Aryl and 5-9 membered heteroaryl, the hydroxyl, amino, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic, C6-C 10 Aryl or 5-9 membered heteroaryl is optionally substituted with one or more R b Replace; or, R a independently selected from cyano, halogen, hydroxy, amino, C1-C6 alkyl and C3-C6 cycloalkyl, wherein the hydroxy, amino, C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by one or more R b Replace; or, R a independently selected from halogen, hydroxy, cyano, C1-C6 alkyl and C3-C6 cycloalkyl, wherein the hydroxy, C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by one or more R b Replace; or, R a independently selected from cyano, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 alkoxy-C1-C3 alkylene, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy and hydroxymethyl; or, R a are independently selected from cyano, halogen, C1-C3 alkyl, C1-C3 alkoxy and C1-C3 haloalkyl; or, R a Independently selected from -OH, -CH3, -C2H5, -OCH3, -OCH2CH3, -CH2CF3, -F, -OCF2H, -OCF3, -CN, -CF3, -CH2OH, -OCH2F, -CHF2, -CH2CH2OCH3, -CH(CH3)2, -N(CH3)2, -CH2N(CH3)2, -CH2OCH3, 13. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein: R b independently selected from halogen, hydroxy, amino, cyano, C1-C3 alkyl, NH(C1-C3 alkyl), N(C1-C3 alkyl)2, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, C1-C6 alkoxy, C6-C 10 Aryl and 5-9 membered heteroaryl, the C3-C6 cycloalkyl, 4-7 membered heterocyclic group, C1-C6 alkoxy, C6-C 10 Aryl or 5-9 membered heteroaryl is optionally substituted with one or more R c Replace; or, R b independently selected from halogen, hydroxy, amino, cyano, NH (C1-C3 alkyl), N (C1-C3 alkyl) 2, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, C1-C6 alkoxy, C6-C 10 Aryl and 5-9 membered heteroaryl, the C3-C6 cycloalkyl, 4-7 membered heterocyclic group, C1-C6 alkoxy, C6-C 10 Aryl or 5-9 membered heteroaryl is optionally substituted with one or more R c Replace; or, R b independently selected from amino, NH (C1-C3 alkyl), N (C1-C3 alkyl) 2, C3-C6 cycloalkyl, 4-7 membered heterocyclyl and C1-C6 alkoxy, wherein the C3-C6 cycloalkyl, 4-7 membered heterocyclyl and C1-C6 alkoxy are optionally substituted by one or more R c Replace; or, R b independently selected from halogen, hydroxy, C1-C3 alkyl and C3-C6 cycloalkyl, wherein the hydroxy, C1-C3 alkyl and C3-C6 cycloalkyl are optionally replaced by one or more R c Replace; or, R b independently selected from halogen, hydroxy, C1-C3 alkyl, N(C1-C3 alkyl)2, C3-C6 cycloalkyl, 4-7 membered heterocyclyl and C1-C6 alkoxy, wherein the C1-C3 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl and C1-C6 alkoxy are optionally substituted by one or more 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 are independently selected from halogen and C1-C3 alkyl, or R c Selected from C1-C3 alkyl, or R c are independently selected from halogen.

15. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, selected from the compound of formula (II) or a pharmaceutically acceptable salt thereof, in, R 5 and R 5 ' and its connected atoms together form C6-C 10 Aromatic ring and 5-9 membered heteroaromatic ring, the C6-C 10 The aromatic ring or 5-9 membered heteroaromatic ring is optionally replaced by one or more R a Replacement; R 1 、R 2 、R 3 、R 4 、R 7 、R 8 、X 1 、X 4 、X 5 、R a As defined in any one of claims 1 to 14.

16. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, selected from the compound of formula (III) or a pharmaceutically acceptable salt thereof, in, X 6 、X 7 Independently selected from CH or N, said CH is optionally substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy; X is selected from NR a or O; R 1 、R 2 、R 3 、R 4 、R 7 、R 8 、X 1 、X 4 、X 5 、R a As defined in any one of claims 1 to 14.

17. The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof is selected from the following compounds or pharmaceutically acceptable salts thereof:

18. A pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17 and a pharmaceutically acceptable excipient.

19. 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 according to any one of claims 1 to 17, or a pharmaceutical composition according to claim 18 to a mammal, preferably a human, in need of such treatment.

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