PKMYT1 inhibitor and application 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. # imgabs0 #

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit and priority of the following 1 Chinese invention patent application, the entire contents of which are hereby incorporated by reference in their entirety:

[0003] Patent application No. 202310848312.7 submitted to the State Intellectual Property Office on July 11, 2023. Technical Field

[0004] The present disclosure relates to a cyclopentadienyl compound or a pharmaceutically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof, and use thereof in preventing or treating PKMYT1-related diseases. Background Art

[0005] Continuous exposure of the genomic DNA of cells to a variety of harmful factors from inside or outside the body may cause DNA damage. Therefore, cells have evolved a series of complex DNA damage response mechanisms to cope with these harmful factors, thereby maintaining the integrity of the genome and avoiding the occurrence of diseases including tumors due to genomic instability. The activation of the cell cycle checkpoint pathway is one of the important mechanisms. The 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 thus rely more on the G2 checkpoint to repair DNA damage to maintain the survival of tumor cells.

[0006] Membrane-associated tyrosine and threonine kinase (Myt1 kinase, also known as PKMYT1) is encoded by the PKMYT1 gene. PKMYT1 inhibits the activity of cdc2 by phosphorylating cdc2 Thr-14 and Tyr-15, thereby regulating the cell cycle, causing the cell cycle to stop at the G2-M checkpoint and repair DNA damage. Studies have shown that inhibition of PKMYT1 will lead to the activation of cdc2, forcing cells to enter mitosis prematurely and unable to repair DNA damage, thereby killing rapidly proliferating tumor cells.

[0007] Therefore, PKMYT1 inhibitors have the potential to inhibit tumor proliferation, and the development of PKMYT1 inhibitors can provide a new strategy for tumor targeted therapy. Summary of the invention

[0008] The present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0009]

[0010] in,

[0011] X is selected from N and CR;

[0012] X 1 Selected from N and CR 9 ;

[0013] represents a single bond or a double bond;

[0014] X 2 Selected from CR 5 R 6 NR 5 and CR 5 ;

[0015] X 3 Selected from CR 5 'R 6 '、NR 5 ' and CR 5 ';

[0016] X 4 , X 5 Independently selected from (C(R 10 )2) n NR 10 and O;

[0017] R is selected from hydrogen, hydroxy, cyano, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl and C(=O)H, wherein the hydroxy, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl or C(=O)H is optionally replaced by one or more R a replace;

[0018] 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-, wherein the 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- is optionally substituted by one or more R 11 replace;

[0019] R 2is 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 with one or more R a replace;

[0020] 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;

[0021] 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 with one or more R a replace;

[0022] R 5 and R 5 ' and the atoms connected to it 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 carbocyclic ring, C6-C 10 The aromatic ring, 5-8 membered heterocyclic ring or 5-9 membered heteroaromatic ring is optionally substituted with one or more R a replace;

[0023] R 7 , R 8 independently selected from hydrogen, halogen and C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with deuterium;

[0024] or R 1 , R 7 and the atoms to which they are connected together form a 5-8 membered heterocyclic ring or a 5-9 membered heteroaromatic ring, wherein the 5-8 membered heterocyclic ring or the 5-9 membered heteroaromatic ring is optionally substituted by one or more R a replace;

[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, hydroxyl, 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, hydroxyl, amino, cyano, C1-C3 alkyl, NH(C1-C3 alkyl), N(C1-C3 alkyl)2, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, C1-C3 alkoxy, C6-C 10 Aryl and 5-9 membered heteroaryl, the C1-C3 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic group, C1-C3 alkoxy, C6-C 10 Aryl or 5-9 membered heteroaryl is optionally substituted with one or more R c replace;

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

[0031] In some embodiments, X 2 Selected from CR 5 R 6 and CR 5 .

[0032] In some embodiments, X 2 Selected from CR 5 .

[0033] In some embodiments, X 3 Selected from CR 5 'R 6 ' and CR 5 '.

[0034] In some embodiments, X 3 Selected from CR 5 '.

[0035] In some embodiments, X 4 , X 5 are independently selected from a bond, C(R 10 )2 and O.

[0036] In some embodiments, X 4 Selected from bonds and C(R 10 )2.

[0037] In some embodiments, X 4 Select from keys.

[0038] In some embodiments, X 5 Select from keys.

[0039] In some embodiments, X 4 and X 5 All are keys.

[0040] In some embodiments, R 1 , R 3 are independently selected from hydrogen and hydroxy.

[0041] In some embodiments, R 1 , R 3 One of them is hydrogen and the other is hydroxyl.

[0042] In some embodiments, R 2 For hydrogen.

[0043] In some embodiments, R 4 , R 6 , R 6 '、R 10 independently selected from hydrogen, 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 10Aryl, 5-9 membered heteroaryl, C2-C6 alkenyl, C2-C6 alkynyl or -C(=O)NH2 is optionally substituted with one or more R a replace.

[0044] In some embodiments, 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.

[0045] 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.

[0046] In some embodiments, R 4 selected from H and optionally one or more R a Substituted C1-C3 alkyl.

[0047] In some embodiments, R 4 is selected from H, methyl, difluoromethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxypropan-2-yl and methoxymethyl.

[0048] In some embodiments, R 4 Selected from H, methyl, difluoromethyl, hydroxymethyl, 1-hydroxyethyl and 2-hydroxypropan-2-yl.

[0049] In some embodiments, R 4 Selected from H and methyl.

[0050] In some embodiments, R 4 Selected from methyl, methoxymethyl and hydroxymethyl.

[0051] In some embodiments, R 5 and R 5' and the atoms connected thereto 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 replace.

[0052] 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 substituted by one or more R a replace.

[0053] In some embodiments, the R 5 and R 5 ' and the atoms connected thereto 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 substituted by one or more R a replace.

[0054] In some embodiments, the R 5 and R 5 ' and the atoms to which it is connected together form an optionally one or more R a Substituted pyrazole ring.

[0055] In some embodiments, R 7 , R 8 Independently selected from halogen and C1-C6 alkyl.

[0056] In some embodiments, R 7 , R 8 Independently selected from C1-C3 alkyl.

[0057] In some embodiments, R 7 , R 8 are independently selected from methyl.

[0058] In some embodiments, R 1 , R 7 and the atoms to which it is connected together form an optionally substituted one or more R a Substituted 5-6 membered heteroaryl ring.

[0059] In some embodiments, R 1 , R 7 and the atoms to which it is connected together form an optionally substituted one or more R a Substituted pyrazole ring.

[0060] In some embodiments, R is selected from H, hydroxyl, cyano, halogen, C1-C6 alkyl and C3-C6 cycloalkyl, wherein the hydroxyl, C1-C6 alkyl or C3-C6 cycloalkyl is optionally replaced by one or more Ra replace.

[0061] In some embodiments, R is selected from H, halogen, and optionally substituted by one or more R a Substituted C1-C3 alkyl.

[0062] In some embodiments, R is selected from H, halogen, and methyl.

[0063] In some embodiments, X 1 Selected from N.

[0064] 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.

[0065] In some embodiments, R 9 is selected from hydrogen and methyl.

[0066] In some embodiments, n is selected from 0 and 1.

[0067] In some embodiments, n is 0.

[0068] In some embodiments, R a independently selected from halogen, oxo, hydroxyl, 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.

[0069] In some embodiments, R a independently selected from halogen, hydroxyl, amino, C1-C6 alkyl, C3-C6 cycloalkyl and 4-7 membered heterocyclic group, wherein the hydroxyl, amino, C1-C6 alkyl, C3-C6 cycloalkyl and 4-7 membered heterocyclic group are optionally substituted by one or more R b replace.

[0070] In some embodiments, R a independently selected from halogen, hydroxyl, C1-C6 alkyl, C3-C6 cycloalkyl and 4-7 membered heterocyclic group, wherein the hydroxyl, C1-C6 alkyl, C3-C6 cycloalkyl and 4-7 membered heterocyclic group are optionally substituted by one or more R b replace.

[0071] In some embodiments, R aindependently selected from halogen, hydroxyl, C1-C6 alkyl and oxetanyl, wherein the hydroxyl, C1-C6 alkyl and oxetanyl are optionally substituted by one or more R b replace.

[0072] In some embodiments, R b independently selected from halogen, hydroxyl, amino, cyano, C1-C3 alkyl, NH(C1-C3 alkyl), N(C1-C3 alkyl)2, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, C1-C3 alkoxy, C6-C 10 Aryl and 5-9 membered heteroaryl, the C1-C3 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic group, C1-C3 alkoxy, C6-C 10 Aryl or 5-9 membered heteroaryl is optionally substituted with one or more R c replace.

[0073] In some embodiments, R b independently selected from halogen, hydroxy, amino, C1-C3 alkyl, NH(C1-C3 alkyl), N(C1-C3 alkyl)2, C3-C6 cycloalkyl, 4-7 membered heterocyclyl and C1-C3 alkoxy, wherein the C1-C3 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl and C1-C3 alkoxy are optionally substituted by one or more R c replace.

[0074] In some embodiments, R b independently selected from halogen, hydroxy, C1-C3 alkyl and C1-C3 alkoxy, wherein the C1-C3 alkyl and C1-C3 alkoxy are optionally substituted by one or more R c replace.

[0075] In some embodiments, R c Independently selected from C1-C3 alkyl.

[0076] In some embodiments, R a Independently selected from halogen, OH, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxyethyl, methoxyethyl and oxetanyl.

[0077] In some embodiments, R a Independently selected from OH, methyl, difluoromethyl, methoxy, hydroxyethyl, methoxyethyl and oxetanyl.

[0078] In some embodiments, represents a single bond, and X 2 Selected from CR 5 , X 3 Selected from CR 5 '.

[0079] In some embodiments, represents a single bond, and X 2 Selected from CR 5 , X 3 Selected from CR 5 ';R 5 and R 5 ' and the atoms connected to it 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 substituted with one or more R a replace.

[0080] In some embodiments, represents a single bond, and X 2 Selected from CR 5 , X 3 Selected from CR 5 ';R 5 and R 5 ' and the atoms connected thereto 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 substituted by one or more R a replace.

[0081] In some embodiments, represents a single bond, and X 2 Selected from CR 5 , X 3 Selected from CR 5 ';R 5 and R 5 ' and the atoms to which it is connected together form an optionally one or more R a Substituted pyrazole ring.

[0082] In some embodiments, represents a double bond, and X 2 Selected from CR 5 , X 3 Selected from CR 5 '.

[0083] In some embodiments, represents a double bond; and X 2 Selected from CR 5 , X 3 Selected from CR 5 ';R 5 and R 5 ' and the atoms connected to it 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 substituted with one or more R a replace.

[0084] In some embodiments, represents a double bond; and X 2 Selected from CR 5 , X 3 Selected from CR 5 ';R 5 and R 5 ' and the atoms connected thereto 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 substituted by one or more R a replace.

[0085] In some embodiments, represents a double bond, and X 2 Selected from CR 5 , X 3 Selected from CR 5 ';R 5 and R 5 ' and the atoms to which it is connected together form an optionally one or more R a Substituted pyrazole ring.

[0086] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof of the present disclosure is selected from the compound of formula (II) or a pharmaceutically acceptable salt thereof,

[0087]

[0088] Among them, R 5 and R 5 ' and the atoms connected to it 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 substituted with one or more R a Replacement; R 1 , R 2 , R 3 , R 4 , R 7 , R 8 ,X,X 1 and R a As defined above.

[0089] In some embodiments, the R 5 and R 5 ' and the atoms connected thereto 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 substituted by one or more R a In some embodiments, the R 5 and R 5 ' and the atoms to which it is connected together form an optionally one or more R a Substituted pyrazole ring.

[0090] In some embodiments, the compound of formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof,

[0091]

[0092]

[0093] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0094] In another aspect, the present disclosure 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.

[0095] In another aspect, the present disclosure provides 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.

[0096] In another aspect, the present disclosure provides 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.

[0097] In another aspect, the present disclosure 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.

[0098] In some embodiments, the PKMYT1-mediated disease is a tumor.

[0099] Definitions and explanations of terms

[0100] Unless otherwise specified, the terms used in this disclosure have the following meanings, and the groups and term definitions recorded in this disclosure, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in examples, etc., can be arbitrarily combined and combined with each other. A specific term should not be considered as uncertain or unclear in the absence of special definition, but should be understood according to the common meaning in the art. When a trade name appears in this article, it is intended to refer to its corresponding commodity or its active ingredient.

[0101] The term "tautomer" refers to functional group isomers resulting from the rapid movement of an atom in two positions in a molecule. The compounds of the present disclosure may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Tautomers generally exist in equilibrium, and attempts to separate a single tautomer usually produce a mixture whose physical and chemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical characteristics within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; while in phenols, the enol form predominates. The present disclosure includes all tautomeric forms of the compounds.

[0102] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and diastereomers.

[0103] 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 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-type and Z-type geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures or other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, all of which are within the definition of the compounds of the present invention and their mixtures. Additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus atoms may be present in substituents such as alkyl groups, and all of these isomers and their mixtures involved in all substituents are also included within the definition of the compounds of the present invention. The 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 chiral reagents.

[0104] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced 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 oxo (i.e., =O), it means that two hydrogen atoms are replaced, and oxo will not occur on an aromatic group.

[0105] The term "optional" or "optionally" refers to that the event or situation described subsequently may or may not occur, and the description includes the occurrence of the event or situation and the non-occurrence of the event or situation. For example, ethyl is "optionally" substituted by halogen, meaning that ethyl can 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 substitution or substitution pattern that may not exist and / or cannot be synthesized in space will not be introduced.

[0106] When any variable (such as n, R a , R b ) occurs 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 2 R b is replaced, then each R b All have independent options.

[0107] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a bond.

[0108] 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.

[0109] In this article, C m -C n It means having an integer number of carbon atoms in the range of 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.

[0110] The term "alkyl" refers to a group of the formula C n H 2n+1 The term "C1-C 10The term "alkyl" is understood to mean a straight or branched saturated hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Specific examples of the alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2- 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 or branched saturated alkyl group having 1 to 3 carbon atoms. The "C1-C 10 "C1-C6 alkyl" or "C1-C3 alkyl" may include the range of "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-substituted, poly-substituted or fully substituted.

[0111] 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, which can be understood as "alkyloxy" or "alkyl-O-". 10 "Alkoxy" can be understood as "C1-C 10 Alkyloxy" or "C1-C 10 The term "C1-C6 alkoxy" can be understood as "C1-C6 alkyloxy" or "C1-C6 alkyl-O-". 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-.

[0112] The term "alkenyl" refers to a straight 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 group containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, "C2-C10 "Alkenyl" is preferably "C2-C6 alkenyl", further preferably "C2-C4 alkenyl", and further preferably C2 or C3 alkenyl. It will be understood that when the alkenyl contains more than one double bond, the double bonds may be separated or conjugated with each other. 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.

[0113] 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 straight-chain 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 "alkynyl group" may include "C2-C3 alkynyl group". Examples of "C2-C3 alkynyl group" include ethynyl (-C≡CH), prop-1-ynyl (-C≡CCH3), prop-2-ynyl (-CH2C≡CH).

[0114] The term "cycloalkyl" refers to a saturated carbon ring that exists in the form of a monocyclic ring, a fused ring, a bridged ring, or a spirocyclic ring. Unless otherwise indicated, the carbon ring is usually a 3- to 10-membered ring. The term "C3-C 10 The term "cycloalkyl" may be understood to mean a saturated monocyclic, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, spiro[4.5]decyl, etc. The term "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.

[0115] The term "cycloalkyloxy" may be understood as "cycloalkyl-O-".

[0116] The term "heterocyclyl" 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., heteroatomic groups containing heteroatoms) in the ring atoms, and the "heteroatoms or heteroatomic groups" include but are not limited to nitrogen atoms (N), oxygen atoms (O), sulfur atoms (S), phosphorus atoms (P), boron atoms (B), -S(=O)2-, -S(=O)-, -P(=O)2-, -P(=O)-, -NH-, -S(=O)(=NH)-, -C(=O)NH- or -NHC(=O)NH-, etc. The term "4-10 membered heterocyclyl" refers to a heterocyclyl group having 4, 5, 6, 7, 8, 9 or 10 ring atoms, and containing 1 to 5 heteroatoms or heteroatomic groups independently selected from the above-mentioned in the ring atoms. “4-10 membered heterocyclyl” includes “4-7 membered heterocyclyl”, wherein specific examples of 4 membered heterocyclyl include but are not limited to azetidinyl 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]pyrrole-2(1H)-yl; specific examples of 5,6-membered bicyclic groups include, but are not limited to, hexahydropyrrolo[1,2-a]pyrazine-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 group, specific examples of which include, but are not limited to, dihydroisoquinolinyl and the like. "4-10 membered heterocyclyl" may include "5-10 membered heterocyclyl", "4-7 membered heterocyclyl", "5-6 membered heterocyclyl", "6-8 membered heterocyclyl", "4-10 membered heterocycloalkyl", "5-10 membered heterocycloalkyl", "4-7 membered heterocycloalkyl", "5-6 membered heterocycloalkyl", "6-8 membered heterocycloalkyl", etc., and "4-7 membered heterocyclyl" may further include "4-6 membered heterocyclyl", "5-6 membered heterocyclyl", "4-7 membered heterocycloalkyl", "4-6 membered heterocycloalkyl", "5-6 membered heterocycloalkyl", etc. Although some bicyclic heterocyclyls in the present disclosure partially contain a benzene ring or a heteroaromatic ring, the heterocyclyl as a whole is still non-aromatic.

[0117] 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 to 5 heteroatoms or heteroatomic groups (i.e., heteroatomic groups containing heteroatoms), wherein the "heteroatoms or heteroatomic groups" include, but are not limited to, nitrogen atoms (N), oxygen atoms (O), sulfur atoms (S), phosphorus atoms (P), boron atoms (B), -S(=O)2-, -S(=O)-, -NH-, -S(=O)(=NH)-, -C(=O)NH- or -NHC(=O)NH-, etc. The term "4-10 membered heterocycloalkyl" refers to a heterocycloalkyl group having 4, 5, 6, 7, 8, 9 or 10 ring atoms, wherein the ring atoms of the heterocycloalkyl group contain 1 to 5 heteroatoms or heteroatomic groups independently selected from the above. “4-10 membered heterocycloalkyl” includes “4-7 membered heterocycloalkyl”, wherein specific examples of 4 membered heterocycloalkyl include but are not limited to azetidinyl, oxetanyl or 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-dioxane, thiomorpholinyl, 1,3-dithianyl or 1,4-dithianyl; specific examples of 7 membered heterocycloalkyl include but are not limited to azepanyl, oxetanyl or thiepanyl.

[0118] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π electron system. The aryl group may have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. The term "C6-C 20 The term "aryl" is understood to mean 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 or a ring having 14 carbon atoms ("C 14 The term "C6-C 10 "Aryl" is understood to mean 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.

[0119] The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system with aromaticity, which contains at least one ring atom selected from N, O, S, and the remaining ring atoms are C. The term "5-10 membered heteroaryl" is understood to include monocyclic or bicyclic aromatic ring systems: it has 5, 6, 7, 8, 9 or 10 ring atoms, especially 5 or 6 or 9 or 10 ring atoms, and it contains 1-5, preferably 1-3 heteroatoms independently selected from N, O and S. In particular, the heteroaryl group is selected from thienyl, furanyl, 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 azinyl, 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 which contains 1-3, preferably 1-2 heteroatoms independently selected from N, O and S.

[0120] The term "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.

[0121] The term "hydroxymethyl" refers to -CH2OH.

[0122] The term "hydroxy" refers to an -OH group.

[0123] The term "cyano" refers to a -CN group.

[0124] The term "mercapto" refers to a -SH group.

[0125] The term "amino" refers to a -NH2 group.

[0126] The term "nitro" refers to a -NO2 group.

[0127] The term "therapeutically effective amount" means an amount of a compound of the present disclosure that (i) treats or prevents a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder 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 own knowledge and the present disclosure.

[0128] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with 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.

[0129] 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 an organic acid, and a salt formed between a compound and an inorganic base or an organic base.

[0130] 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.

[0131] The term "pharmaceutically acceptable excipients" refers to those excipients that have no significant irritation to the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0132] The word "comprise" or "comprises" and its English variations such as comprises or comprising are to be construed in an open and non-exclusive sense, ie, "including but not limited to".

[0133] 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 may be incorporated into 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.

[0134] 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.

[0135] The pharmaceutical compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients, for example, they can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.

[0136] 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, intravenous administration.

[0137] 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.

[0138] 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, etc., for oral administration to patients.

[0139] Solid oral compositions can be prepared by conventional mixing, filling or tableting methods. For example, they can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into particles to obtain a tablet or dragee core. Suitable excipients include, but are not limited to, adhesives, diluents, disintegrants, lubricants, glidants or flavoring agents, etc.

[0140] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

[0141] In all administration methods of the compounds 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.

[0142] 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 embodiments with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples disclosed herein.

[0143] The chemical reactions of the specific embodiments of the present disclosure are carried out in a suitable solvent, which must be suitable for the chemical changes 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 the synthesis steps or reaction processes based on the existing embodiments.

[0144] The present disclosure uses the following abbreviations: DCM: dichloromethane; Boc: tert-butyloxycarbonyl; TsOH·H2O: p-toluenesulfonic acid monohydrate; NMP: N-methylpyrrolidone; DME: ethylene glycol dimethyl ether; KOAc: potassium acetate; Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride; Pd(dppf)Cl2·DCM: [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex; rt: room temperature; h: hour; Me: methyl; MeOH: methanol; EtOH: ethanol; EtONa: sodium ethoxide ; (Boc)2O: di-tert-butyl dicarbonate; THF: tetrahydrofuran; TEA / Et3N: triethylamine; 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); DMAP: 4-dimethylaminopyridine; B2Pin2: diboronic acid pinacol ester; Pd(OAc)2: palladium acetate; PCy3: tricyclohexylphosphine; AcCl: acetyl chloride; tBuONO: tert-butyl nitrite; M: mole / liter; THP: tetrahydropyran-2-yl; NIS: N-iodosuccinimide; DMF: N,N-dimethylformamide; Bn: benzyl; MeCN: acetonitrile; Pb2(dba)3: tris(dibenzylideneacetone)dipalladium; MeCgPPh: 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphoryladamantane; con.HCl: concentrated hydrochloric acid. DETAILED DESCRIPTION

[0145] The invention is described in detail below by way of examples, but this does not imply any adverse limitation of the present disclosure. The present disclosure has been described in detail herein, and specific embodiments thereof are disclosed therein, and various modifications to the specific embodiments of the present disclosure will be 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 are commercially available and can be used without further purification.

[0146] Unless otherwise specified, the ratios expressed for mixed solvents are volume mixing ratios.

[0147] Unless otherwise stated, % refers to wt %.

[0148] Compounds are manually or The software names were used, and commercially available compounds were named using the supplier's catalog names.

[0149] 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 inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved.

[0150] The eluent mentioned below may be a mixed eluent formed by two or more solvents, the ratio of which is the volume ratio of each solvent.

[0151] Example 1: Preparation of 4-(3-hydroxy-2,6-dimethylphenyl)-2,9-dimethyl-7,9-dihydro-1,3,4,7,8,9-hexaazabenzo[cd]cyclopenta[f]azulen-6(4H)-one (Compound 1)

[0152]

[0153] Step 1: Synthesis of tert-butyl (4-bromo-1-methyl-1H-pyrazol-3-yl)carbamate (1b)

[0154] At room temperature, 1a (0.3 g, 1.7 mmol) was dissolved in tetrahydrofuran (10 mL), and di-tert-butyl dicarbonate (2.2 g, 10 mmol) and 4-dimethylaminopyridine (20 mg, 0.2 mmol) were added to the system. The reaction was moved to 60 ° C for 2 hours and then vacuum concentrated to remove the solvent. The crude product was dissolved in ethanol (10 mL), and sodium hydroxide solution (2 mL, 20% aqueous solution) was added to the reaction. 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 water: acetonitrile = 20:1 to 1:20) to obtain 1b (0.32 g, yield 67%). m / z (ESI): 220.0 [M + H-tBu] + .

[0155] 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 (1c)

[0156] At room temperature, 1b (320 mg, 1.2 mmol), pinacol diboron (0.61 g, 2.4 mmol), potassium acetate (0.35 g, 3.6 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (90 mg, 0.12 mmol) were dissolved in dioxane (10 mL), the air was replaced with nitrogen three times, and the mixture was heated to 80 °C for 2 hours. After the system cooled to room temperature, the reaction solution was filtered and concentrated in vacuo, and the crude product was used directly in the next step without purification.

[0157] Step 3: Synthesis of 6-chloro-5-iodo-N-(3-methoxy-2,6-dimethylphenyl)-2-methylpyrimidin-4-amine (1f)

[0158] At room temperature, 1d (2.9 g, 10 mmol) and 1e (3.0 g, 20 mmol) were dissolved in N-methylpyrrolidone (10 mL), and p-toluenesulfonic acid monohydrate (95 mg, 0.5 mmol) was added, and then reacted at 100 ° C for 48 h. After the reaction was cooled to room temperature, water (20 mL) was added to dilute the reaction, and then extracted with ethyl acetate (100 mL*3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by normal phase chromatography (petroleum ether: ethyl acetate = 10: 1-2: 1) to obtain a white solid 1f (1.0 g, yield 25%). m / z (ESI): 404.1 [M+H] + .

[0159] Step 4: Synthesis of methyl 6-amino-4-chloro-7-(3-methoxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (1 g)

[0160] Methyl cyanoacetate (1.0 g, 10 mmol) was dissolved in anhydrous ethylene glycol dimethyl ether (10 mL), cesium carbonate (4.9 g, 15 mmol) was added, and 1f (1.0 g, 2.5 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (0.16 g, 0.2 mmol) were added after stirring at room temperature for 30 minutes. The air was replaced with nitrogen three times, and then the reaction was carried out at 85 ° C for 2 hours under nitrogen protection. After the reaction solution was cooled to room temperature, saturated brine (20 mL) was added, and ethyl acetate (50 mL*3) was used for extraction three times. 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 residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1 to 1:2) to obtain the product 1g (0.79 g, yield 84%). m / z(ESI):375.2[M+H] + .

[0161] Step 5: Synthesis of methyl 4-chloro-7-(3-methoxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (1h)

[0162] Dissolve 1g (0.30g, 0.80mmol) in anhydrous tetrahydrofuran (5mL), slowly add tert-butyl nitrite (0.41g, 4.0mmol), and then heat to 90℃ for 1 hour. After the reaction is cooled to room temperature, the reaction solution is concentrated, and the residue is purified by reverse phase chromatography (C18, 0.05% ammonia water: acetonitrile = 20:1~1:20) to obtain the product 1h (0.18g, yield 62%). m / z (ESI): 360.1 [M+H] + .

[0163] Step 6: Synthesis of methyl 4-(3-((tert-butoxycarbonyl)amino)-1-methyl-1H-pyrazol-4-yl)-7-(3-methoxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (1i)

[0164] Compound 1h (53 mg, 0.15 mmol), 1c (0.14 g, 0.44 mmol), palladium acetate (3.3 mg, 15 μmol), 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (12 mg, 29 μmol), potassium carbonate (61 mg, 0.44 mmol) were dissolved in 1,4-dioxane (2 mL) and water (0.2 mL). The reaction was moved to 70 ° C for 2 hours. After the reaction solution was cooled to room temperature, it was filtered and dried. The crude product was purified by reverse phase chromatography (C18, 0.05% ammonia water: acetonitrile = 20:1~1:20) to obtain product 1i (50 mg, yield 65%). m / z (ESI): 521.2 [M+H] + .

[0165] Step 7: Synthesis of methyl 4-(3-amino-1-methyl-1H-pyrazol-4-yl)-7-(3-methoxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (1j)

[0166] Under ice bath conditions, compound 1i (50 mg, 0.1 mmol) was dissolved in anhydrous methanol (5 mL), and then acetyl chloride (5 mL) was slowly added dropwise, and then the temperature was raised to room temperature for 2 hours. The reaction solution was concentrated, and the obtained crude product 1j was directly used in the next step without purification.

[0167] Step 8: Synthesis of 4-(3-methoxy-2,6-dimethylphenyl)-2,9-dimethyl-7,9-dihydro-1,3,4,7,8,9-hexaazabenzo[cd]cyclopenta[f]azulene-6(4H)-one (1k)

[0168] The compound 1j (50 mg, 0.12 mmol) obtained in the previous step was dissolved in methanol / tetrahydrofuran / water (2 ml / 2 mL / 2 mL), and then lithium hydroxide monohydrate (42 mg, 1.0 mmol) was added, and then reacted at room temperature for 8 hours. The reaction solution was concentrated, and the obtained residue was purified by reverse phase chromatography (C18, 0.05% ammonia water: acetonitrile = 20:1 to 1:20) to obtain the target compound 1k (29 mg, yield 74%). LC-MS: m / z (ESI): 389.2 [M+H] + .

[0169] Step 9: Synthesis of 4-(3-hydroxy-2,6-dimethylphenyl)-2,9-dimethyl-7,9-dihydro-1,3,4,7,8,9-hexaazabenzo[cd]cyclopenta[f]azulene-6(4H)-one (Compound 1)

[0170] At room temperature, 1k (29 mg, 74 μmol) was dissolved in dichloromethane (4 mL), and a dichloromethane solution of boron tribromide (1 mol / L, 2 mL) was added and stirred for 30 minutes. The reaction solution was quenched with methanol (5 mL), and then the reaction solution was concentrated. The residue was purified by reverse phase chromatography (C18, 0.05% ammonia water: acetonitrile = 20:1 to 1:20) to obtain compound 1 (20 mg, yield 72%).

[0171] m / z(ESI):375.3[M+H] + .

[0172] 1 H NMR(400MHz,DMSO-d6)δ10.69(s,1H),9.62(s,1H),8.45(s,1H),7.99(s,1H),7.06(d,J =8.3Hz,1H),6.92(d,J=8.3Hz,1H),3.83(s,3H),2.52(s,3H),1.77(s,3H),1.66(s,3H).

[0173] Example 2: Preparation of 4-(3-hydroxy-2,6-dimethylphenyl)-2,8-dimethyl-7,8-dihydro-1,3,4,7,8,9-hexaazabenzo[cd]cyclopenta[f]azulene-6(4H)-one (Compound 2)

[0174]

[0175] Step 1: Synthesis of N-(4-bromo-2-methyl-pyrazol-3-yl)-N-tert-butoxycarbonyl-carbamic acid tert-butyl ester (2b)

[0176] At room temperature, compound 2a (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, and then the reaction was continued under the same conditions for 5 hours. Water (20 mL) was added to the reaction to quench the reaction, and the reaction was extracted 3 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 normal phase chromatography (petroleum ether: ethyl acetate = 1:0 to 3:1) to obtain product 2b (3.1 g, yield 73%).

[0177] 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 (2c)

[0178] Under room temperature, compound 2b (3.0 g, 8.0 mmol), biboronic acid pinacol borate (3.0 g, 12 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (0.59 g, 0.80 mmol), potassium acetate (1.6 g, 16 mmol) were dissolved in anhydrous 1,4-dioxane, the air was replaced with nitrogen three times, and then reacted at 95 ° C for 5 hours under nitrogen protection. After the reaction solution was cooled to room temperature, water (50 mL) was added to the reaction solution to quench the reaction, and ethyl acetate (50 mL*3) was used for extraction three times. The organic phases were combined, washed with saturated sodium chloride aqueous solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by normal phase chromatography (petroleum ether: ethyl acetate = 100: 1 to 20: 1) to obtain product 2c (1.8 g, yield 53%). m / z (ESI): 424.2 [M+H] + .

[0179] Then, compound 1c was replaced by compound 2c, and compound 2 was prepared by a method similar to Example 1.

[0180] m / z(ESI):375.3[M+H] + .

[0181] 1 H NMR(400MHz,DMSO-d6)δ7.78(s,1H),7.74-7.65(m,1H),7.34(s,1H),7.02(d,J=8.4Hz,1H ),6.91(d,J=8.4Hz,1H),4.20(s,1H),3.65(s,3H),2.41(s,3H),1.76(s,3H),1.66(s,3H).

[0182] Example 3: Preparation of 5,9-dimethyl-1-(5-methyl-1H-indazol-4-yl)-4,5-dihydro-1,4,5,6,8,10-hexaazabenzo[cd]cyclopenta[f]azulene-3(1H)-one (Compound 3)

[0183]

[0184]

[0185] Step 1: Synthesis of tert-butyl (4-bromo-1-methyl-1H-pyrazol-5-yl)carbamate (3a)

[0186] At room temperature, 2a (2.0 g, 11 mmol) was dissolved in tetrahydrofuran (20 mL), and di-tert-butyl dicarbonate (3.2 g, 15 mmol) and 4-dimethylaminopyridine (0.14 g, 1.1 mmol) were added to the system, and then reacted at room temperature for 5 hours, vacuum concentrated to remove the solvent, and the crude product was dissolved in ethanol (20 mL), and sodium hydroxide solution (5 mL, 20% aqueous solution) was added to the reaction. The reaction was continued at room temperature for 16 hours, and the solvent was removed by vacuum concentration. The obtained product 3a (2.6 g, yield 82%) can be directly used in the next step without purification.

[0187] Step 2: Synthesis of tert-butyl (1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl))-1H-pyrazol-5-yl)carbamate (3b)

[0188] Compound 3a (2.3 g, 8.7 mmol), pinacol diboron (3.2 g, 12.5 mmol), tris(dibenzylideneacetone)dipalladium (0.38 g, 0.42 mmol), tricyclohexylphosphine (0.23 g, 0.83 mmol) and potassium acetate (1.6 g, 16.7 mmol) were dissolved in anhydrous 1,4-dioxane (10 mL), and then the air was replaced with argon, and then reacted at 80 ° C for 8 hours under argon protection. After the reaction solution was cooled to room temperature, the insoluble matter was filtered out, and the obtained product 3b was directly used in the next step without purification. Step 3: Synthesis of N-(6-chloro-5-iodo-2-methylpyrimidin-4-yl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine (3d)

[0189] 4,6-dichloro-5-iodo-2-methylpyrimidine (2.8 g, 9.7 mmol), 3c (1.5 g, 6.5 mmol), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (0.52 g, 0.65 mmol) and cesium carbonate (6.3 g, 19 mmol) were dissolved in 1,4-dioxane (20 mL), and then the air was replaced with argon, and then reacted at 95 ° C for 10 hours under argon protection. After the reaction was cooled to room temperature, saturated ammonium chloride (10 mL) aqueous solution was added to the reaction to quench, and then extracted with ethyl acetate (150 mL*3). The organic phases were combined and washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1 to 3:1) to obtain the target product 3d (4.2 g, yield 67%). m / z (ESI): 484.0 [M+H] + .

[0190] Step 4: Synthesis of methyl 6-amino-4-chloro-2-methyl-7-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (3e)

[0191] Methyl cyanoacetate (1.6 g, 16 mmol) was dissolved in anhydrous ethylene glycol dimethyl ether (20 mL), cesium carbonate (7.8 g, 24 mmol) was added, and 3d (2.0 g, 4.1 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (0.30 g, 0.4 mmol) were added after stirring at room temperature for 30 minutes. The air was replaced with nitrogen three times, and then the reaction was carried out at 80 ° C for 2 hours under nitrogen protection. After the reaction solution was cooled to room temperature, saturated brine (20 mL) was added, and it was extracted with ethyl acetate (50 mL*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 residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1 to 3:1) to obtain the product 3e (0.86 g, yield 36%). m / z (ESI): 455.1 [M+H] + .

[0192] Step 5: Synthesis of methyl 4-chloro-2-methyl-7-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (3f)

[0193] 3e (0.22 g, 0.48 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), tert-butyl nitrite (0.25 g, 2.4 mmol) was slowly added dropwise, and then the temperature was raised to 80°C for 1 hour. After the reaction was cooled to room temperature, the reaction solution was concentrated, and the residue was purified by reverse phase chromatography (C18, 0.05% ammonia water: acetonitrile = 20:1 to 1:20) to obtain the product 3f (0.14 g, yield 66%). m / z (ESI): 440.1 [M+H] + .

[0194] Step 6: Synthesis of methyl 4-(3-((tert-butoxycarbonyl)amino)-1-methyl-1H-pyrazol-4-yl)-2-methyl-7-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (3 g)

[0195] Compound 3f (70 mg, 0.16 μmol), 3b (51 mg, 0.16 mmol), palladium acetate (3.6 mg, 16 μmol), 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (13 mg, 32 μmol), potassium carbonate (44 mg, 0.32 mmol) were dissolved in 1,4-dioxane / water (2 / 0.2 mL). The air was replaced with nitrogen three times, and then the reaction was carried out at 75 ° C for 2 hours under nitrogen protection. After the reaction solution was cooled to room temperature, it was filtered, the filtrate was dried, and the obtained crude product was purified by reverse phase chromatography (C 18 , 0.05% ammonia water: acetonitrile = 20:1-1:20) to obtain 3g (50mg, yield 52%) of product. m / z (ESI): 601.3 [M+H] + .

[0196] Step 7: Synthesis of methyl 4-(3-amino-1-methyl-1H-pyrazol-4-yl)-2-methyl-7-(5-methyl-1H-indazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (Compound 3h)

[0197] At room temperature, compound 3g (50 mg, 83 μmol) was dissolved in a 1,4-dioxane hydrochloride solution (4 M, 4 mL) and then reacted for 2 hours under the same conditions. After the reaction was completed, the reaction solution was concentrated and the obtained solid residue 3h (25 mg, yield 72%) was directly used in the next step without purification.

[0198] Step 8: Synthesis of 5,9-dimethyl-1-(5-methyl-1H-indazol-4-yl)-4,5-dihydro-1,4,5,6,8,10-hexaazabenzo[cd]cyclopenta[f]azulene-3(1H)-one (Compound 37)

[0199] Compound 3h (25 mg, 60 μmol) was dissolved in methanol / tetrahydrofuran / water (2 ml / 2 mL / 2 mL), lithium hydroxide monohydrate (25 mg, 0.6 mmol) was added, and the mixture was reacted at room temperature for 6 hours. The reaction solution was concentrated and the residue was purified by reverse phase chromatography (C 18 , 0.05% ammonia water: acetonitrile = 20:1-1:20) to obtain the target compound 3 (15 mg, yield 65%).

[0200] LC-MS: m / z(ESI):385.3[M+H] + .

[0201] 1H NMR (400MHz, DMSO-d6) δ10.98(s,1H),8.62(s,1H),8.58(s,1H),7.71(d,J=8.4Hz,1H),7.65 (s,1H),7.46(d,J=8.0Hz,1H),7.43(d,J=8.0Hz,1H),3.95(s,3H),2.65(s,3H),2.14(s,3H).

[0202] Example 4: Preparation of 1-(1H-indazol-4-yl)-5,9-dimethyl-4,5-dihydro-1,4,5,6,8,10-hexaazabenzo[cd]cyclopenta[f]azulene-3(1H)-one (Compound 4)

[0203]

[0204] Compound 4 was prepared by replacing compound 3c with compound 4a and adopting a method similar to steps 3 to 8 of Example 3.

[0205] m / z(ESI):371.2[M+H] + .

[0206] 1 H NMR(400MHz,DMSO-d6)δ13.46(s,1H),8.40(s,1H),8.02(s,1H),7.95(s,1H),7.71(d, J=8.4Hz,1H),7.55(t,J=8.0Hz,1H),7.43(d,J=8.0Hz,1H),3.90(s,3H),2.55(s,3H).

[0207] Example 5: Preparation of 4-(3-hydroxy-2,6-dimethylphenyl)-2-(methoxymethyl)-9-methyl-7,9-dihydro-1,3,4,7,8,9-hexaazabenzo[cd]cyclopenta[f]azulene-6(4H)-one (Compound 5)

[0208]

[0209] Step 1: Synthesis of 2-(methoxymethyl)pyrimidine-4,6-diol (5b)

[0210] Under room temperature, malonamide 5a (50 g, 0.49 mol) was dissolved in anhydrous ethanol (1000 mL), ethyl 2-methoxyacetate (69 g, 0.59 mol) and sodium ethoxide (67 g, 0.98 mol) were added in sequence, and then the temperature was raised to 80°C for 16 hours. After the reaction was cooled to room temperature, it was filtered, and the filter cake was washed with ethanol (100 mL) to obtain compound 5b (30 g, yield 39%).

[0211] m / z(ESI):157.1[M+H] + .

[0212] Step 2: Synthesis of 4,6-dichloro-2-(methoxymethyl)pyrimidine (5c)

[0213] Under room temperature, compound 5b (27 g, 0.17 mol) was dissolved in anhydrous 1,4-dioxane (300 mL), phosphorus oxychloride (106 g, 0.69 mol) was added, and then the temperature was raised to 100 ° C for 16 hours. After the reaction was cooled to room temperature, water (50 mL) was slowly added to the reaction system to quench the reaction, and then extracted with ethyl acetate (300 mL*3), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by normal phase chromatography (petroleum ether: ethyl acetate = 10:1 to 1:1) to obtain compound 5c (10 g, yield 30%).

[0214] m / z(ESI):193.1[M+H] + .

[0215] Step 3: Synthesis of 6-chloro-2-(methoxymethyl)pyrimidin-4-ol (5d)

[0216] Compound 5c (8.0 g, 41 mmol) was dissolved in anhydrous 1,4-dioxane (80 mL), concentrated hydrochloric acid (36%-38%, 6.0 g, 60 mmol) was slowly added under ice bath conditions, and then the temperature was raised to 90°C for reaction for 2 hours. After the reaction was cooled to room temperature, water (50 mL) was added to the reaction system for dilution, and then extracted with ethyl acetate (100 mL*3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by normal phase chromatography (petroleum ether: ethyl acetate = 10:1-1:2) to obtain compound 5d (5.9 g, yield 82%).

[0217] m / z(ESI):174.9[M+H] + .

[0218] Step 4: Synthesis of 6-chloro-5-iodo-2-(methoxymethyl)pyrimidin-4-ol (5e)

[0219] Under room temperature, compound 5d (1.0 g, 5.7 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL), N-iodosuccinimide (2.6 g, 11 mmol) was added, and then the temperature was raised to 85°C for 2 hours. After the reaction was cooled to room temperature, the reaction was poured into ice water (30 mL), and then extracted with ethyl acetate (50 mL*3), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by normal phase chromatography (petroleum ether: ethyl acetate = 10:1 to 1:2) to obtain compound 5e (1.5 g, yield 87%).

[0220] m / z(ESI):301.0[M+H] + .

[0221] Step 5: Synthesis of 4,6-dichloro-5-iodo-2-(methoxymethyl)pyrimidine (5f)

[0222] Compound 5e (1.6 g, 5.3 mmol) was dissolved in anhydrous 1,4-dioxane (20 mL), phosphorus oxychloride (3.3 g, 21 mmol) was added, and then the temperature was raised to 100°C for 2 hours. After the reaction was cooled to room temperature, water (10 mL) was slowly added to the reaction system to quench the reaction, and then extracted with ethyl acetate (20 mL*3), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by normal phase chromatography (petroleum ether: ethyl acetate = 10:1 to 1:1) to obtain compound 5f (1.1 g, yield 65%).

[0223] Step 6: Synthesis of N-(3-(benzyloxy)-2,6-dimethylphenyl)-6-chloro-5-iodo-2-methylpyrimidin-4-amine (5h)

[0224] Compound 5f (0.60 g, 1.9 mmol) and compound 5g (1.3 g, 5.7 mmol) were dissolved in N-methylpyrrolidone (10 mL), and p-toluenesulfonic acid monohydrate (36 mg, 0.19 mmol) was added, and then stirred at 110°C for 4 h. After the reaction was cooled to room temperature, water (20 mL) was added to dilute the reaction, and then extracted with ethyl acetate (50 mL*3), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by normal phase chromatography (petroleum ether: ethyl acetate = 10:1-2:1) to obtain compound 5h (0.18 g, yield 20%).

[0225] m / z(ESI):480.1[M+H] + .

[0226] Step 7: Synthesis of methyl 6-amino-7-(3-(benzyloxy)-2,6-dimethylphenyl)-4-chloro-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (5i)

[0227] Methyl cyanoacetate (93 mg, 0.94 mmol) was dissolved in anhydrous ethylene glycol dimethyl ether (10 mL), cesium carbonate (0.46 g, 1.4 mmol) was added, and 5h (0.12 g, 0.24 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (8.6 mg, 12 μmol) were added after stirring at room temperature for 30 minutes. The air was replaced with nitrogen three times, and then the reaction was carried out at 85 ° C for 8 hours under nitrogen protection. After the reaction solution was cooled to room temperature, saturated brine (20 mL) was added, and ethyl acetate (50 mL*3) was used for extraction three times. The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by normal phase silica gel chromatography (petroleum ether: ethyl acetate = 10:1 to 1:2) to obtain product 5i (42 mg, yield 37%).

[0228] m / z(ESI):451.2[M+H] + .

[0229] Step 8: Synthesis of methyl 7-(3-(benzyloxy)-2,6-dimethylphenyl)-4-chloro-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (5j)

[0230] 5i (42 mg, 93 μmol) was dissolved in anhydrous tetrahydrofuran (5 mL), tert-butyl nitrite (48 mg, 0.47 mmol) was slowly added dropwise, and then the temperature was raised to 80°C for 1 hour. After the reaction was cooled to room temperature, the reaction solution was concentrated, and the residue was purified by reverse phase chromatography (C18, 0.05% ammonia water: acetonitrile = 20:1-1:20) to obtain product 5j (29 mg, yield 72%).

[0231] m / z(ESI):436.2[M+H] + .

[0232] Step 9: Synthesis of methyl 7-(3-(benzyloxy)-2,6-dimethylphenyl)-4-(3-((tert-butoxycarbonyl)amino)-1-methyl-1H-pyrazol-4-yl)-2-(methoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (5k)

[0233] Compound 5j (20 mg, 43 μmol) was dissolved in acetonitrile / water (4 mL / 0.5 mL), and 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (3.5 mg, 8.6 μmol), palladium acetate (0.96 mg, 4.3 μmol), potassium carbonate (18 mg, 0.13 mmol) and compound 1c (28 mg, 86 μmol) were added in sequence. The air was replaced with argon, and then the temperature was raised to 70°C for 2 hours. The insoluble matter was filtered off, and the filtrate was concentrated. The residue was purified by reverse phase chromatography (C18, 0.05% ammonia water: acetonitrile = 20:1 to 1:20) to obtain compound 5k (14 mg, yield 52%).

[0234] m / z(ESI):627.7[M+H] + .

[0235] Step 10: Synthesis of 4-(3-(benzyloxy)-2,6-dimethylphenyl)-2-(methoxymethyl)-9-methyl-7,9-dihydro-1,3,4,7,8,9-hexaazabenzo[cd]cyclopenta[f]azulene-6(4H)-one (5l)

[0236] Under ice bath conditions, acetyl chloride (1.5 mL) was slowly added dropwise to anhydrous methanol (3 mL), and then compound 5k (14 mg, 22 μmol) was added and reacted at room temperature for 2 hours. The reaction solution was concentrated, and the pH was adjusted to neutral with ammonia (25% ammonia in water), and then purified by reverse phase chromatography (C18, 0.05% ammonia: acetonitrile = 20:1 to 1:20) to obtain compound 5l (10 mg, yield 91%).

[0237] m / z(ESI):495.6[M+H] + .

[0238] Step 11: Synthesis of 4-(3-hydroxy-2,6-dimethylphenyl)-2-(methoxymethyl)-9-methyl-7,9-dihydro-1,3,4,7,8,9-hexaazabenzo[cd]cyclopenta[f]azulene-6(4H)-one (Compound 5)

[0239] Compound 51 (5.0 mg, 10 μmol) was dissolved in anhydrous methanol (3 mL), 10% palladium carbon (containing 55% water, 4 mg) was added, the air was replaced with hydrogen 3 times, and the reaction was carried out at room temperature for 2 hours. The reaction solution was filtered, the filtrate was concentrated, and the obtained residue was purified by reverse phase column chromatography (C18, 0.05% ammonia water: acetonitrile = 20:1 to 1:20) to obtain compound 5 (3.0 mg, yield 73%).

[0240] m / z(ESI):405.3[M+H] + .

[0241] 1 H NMR (400MHz, DMSO-d6) δ10.74(s,1H),8.47(s,1H),8.08(s,1H),7.07(d,J=8.2Hz,1H), 6.93(d,J=8.2Hz,1H),4.46(s,2H),3.84(s,3H),3.31(s,3H),1.78(s,3H),1.67(s,3H).

[0242] Example 6: Preparation of 4-(3-hydroxy-2,6-dimethylphenyl)-2-(hydroxymethyl)-9-methyl-7,9-dihydro-1,3,4,7,8,9-hexaazabenzo[cd]cyclopenta[f]azulen-6(4H)-one (Compound 6)

[0243]

[0244] Compound 51 (5.0 mg, 10 μmol) was dissolved in anhydrous dichloromethane (5 mL), and a dichloromethane solution of boron tribromide (0.50 mL, 1 mol / L) was slowly added under ice bath, and the reaction was allowed to react at room temperature for 2 hours. Under ice bath conditions, the reaction was quenched with methanol (5 mL), and the solvent was removed by distillation under reduced pressure. The pH was adjusted to 14 with ammonia water (25% ammonia in water), and the crude product was purified by reverse phase chromatography (C18, 0.05% ammonia water: acetonitrile = 20:1 to 1:20) to obtain compound 6 (3 mg, yield 76%).

[0245] m / z(ESI):391.3[M+H] + .

[0246] 1 H NMR (400MHz, DMSO-d6) δ10.73(s,1H),9.64(s,1H),8.49(s,1H),8.05(s,1H),7.06(d,J=8.3Hz,1H),6.9 2(d,J=8.3Hz,1H),5.07(t,J=6.1Hz,1H),4.51(d,J=6.1Hz,2H),3.85(s,3H),1.78(s,3H),1.67(s,3H).

[0247] Example 7: Preparation of 5-chloro-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 7)

[0248]

[0249] Step 1: Synthesis of methyl 4,6-dichloro-7-(3-methoxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (7a)

[0250] At room temperature, compound 1g (0.30g, 0.80mmol) and cuprous chloride (0.48g, 4.8mmol) were dissolved in anhydrous tetrahydrofuran, and tert-butyl nitrite (0.50g, 4.8mmol) was added dropwise thereto. After the addition was complete, the temperature was raised to 50°C for 3 hours. 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 7a (0.16g, yield 51%).

[0251] m / z(ESI):394.3[M+H] + .

[0252] Step 2: Synthesis of 4-[5-[di(tert-butoxycarbonyl)amino]-1-methyl-pyrazol-4-yl]-6-chloro-7-(3-methoxy-2,6-dimethyl-phenyl)-2-methyl-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid methyl ester (7b)

[0253] Compound 7a (0.16 g, 0.41 mmol), 2c (0.17 g, 0.41 mmol), tris(dibenzylideneacetone)dipalladium (37 mg, 41 μmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphoryladamantane (14 mg, 48 μmol), cesium carbonate (0.79 g, 2.4 mmol) were dissolved in 1,4-dioxane (5 mL) and water (0.5 mL). After replacing the air with nitrogen, the mixture was moved to 80 °C for 2 hours. After the reaction solution was cooled to room temperature, the insoluble matter was removed by filtration, the filter cake was washed with ethyl acetate, the organic phases were combined and concentrated, and the crude product was purified by reverse phase chromatography (C18, 0.05% ammonia water: acetonitrile = 20:1 to 1:20) to obtain compound 7b (0.22 g, yield 83%).

[0254] m / z(ESI):655.3[M+H] + .

[0255] Then, compound 1i was replaced by compound 7b, and compound 7 was prepared by a method similar to Example 1.

[0256] m / z(ESI):409.3[M+H] + .

[0257] 1H NMR (400MHz, DMSO-d6) δ9.73(s,1H),7.95(s,1H),7.10(d,J=8.3Hz,1H),6.96(d,J=8.3Hz,1H),3.85(s,3H),2.51(s,3H),1.74(s,3H),1.64(s,3H).

[0258] Biological activity and related properties test examples

[0259] Test Example 1: Compound inhibition of tumor cell proliferation

[0260] Brief introduction to experimental principle: After the compound is co-incubated with tumor cells for 7 days, the ATP in the living cells is quantified using the CTG kit of Promega, thereby reflecting the effect of the compound on the proliferation of tumor cells.

[0261] Experimental instruments: Envision microplate reader from Perkin Elmer; 5810R centrifuge from Eppendorf, automatic cell counter from Countstar.

[0262] Experimental Materials:

[0263] Reagents brand Part Number McCoy's 5A Gibco 16600082 HCC1569 cell line ATCC CRL-2330 RPMI Medium 1640 Gibco A10491-01 FBS Gibco 10099-141C 0.25%Trypsin-EDTA Gibco 25200-172 PBS HyClone SH30256.01 96-well plate Corning 3610 CelltiterGlo assay kit (CTG) Promega G7573

[0264] Experimental method: 3000 HCC1569 cells / well were diluted with McCoy's 5A or RPMI Medium 1640 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 then diluted 4 times, and the final DMSO concentration was 0.25%. After the compound and cells were incubated in a 37°C, 5% CO2 incubator for 7 days, 50 μL / well CTG was added to measure the inhibition of the compound on the growth of tumor cells, and the inhibition rate and half inhibitory concentration (IC 50 ).

[0265] Data Analysis:

[0266] Calculate the % compound inhibition and use XLfit software to fit the compound IC 50 .

[0267] The experiment set up blank wells and DMSO wells. The blank wells were 100 μL of RPMI Medium 1640 or McCoy's 5A culture medium containing 10% FBS, and the inhibition rate of the compound on tumor cell growth was considered to be 100% at this time; the DMSO wells were 0.25% DMSO added to the cell wells, and the inhibition rate of the compound on tumor cell growth was considered to be 0 at this time.

[0268] Compound inhibition percentage = (100*(DMSO well - experimental well) / (DMSO well - blank well))%

[0269] The inhibitory effect of the compounds of the present application on the growth of tumor cells was determined by the above test, and the measured IC 50 The values ​​are shown in Table 2 below.

[0270] Table 2 IC of compounds against HCC1569 cell growth inhibition 50

[0271] Compound No. <![CDATA[IC 50 (nM)]]> 1 70 2 22 3 408 5 417 6 320

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, in: X is selected from N and CR; X 1 Selected from N and CR 9 ; represents a single or double bond; X 2 Selected from CR 5 R 6 NR 5 and CR 5 ; X 3 Selected from CR 5 'R 6 '、NR 5 ' and CR 5 '; X 4 , X 5 Independently selected from (C(R 10 )2) n NR 10 and O; R is selected from hydrogen, hydroxy, cyano, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl and C(=O)H, wherein the hydroxy, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl or C(=O)H is optionally replaced by one or more R a replace; 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-, wherein the 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- is optionally substituted by one or more R 11 replace; R 2 is 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 with 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 with one or more R a replace; R 5 and R 5 ' and the atoms connected to it 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 carbocyclic ring, C6-C 10 The aromatic ring, 5-8 membered heterocyclic ring or 5-9 membered heteroaromatic ring is optionally substituted by one or more R a replace; R 7 , R 8 independently selected from hydrogen, halogen and C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with deuterium; or R 1 , R 7 and the atoms to which they are connected together form a 5-8 membered heterocyclic ring or a 5-9 membered heteroaromatic ring, wherein the 5-8 membered heterocyclic ring or the 5-9 membered heteroaromatic ring is optionally substituted by one or more R a replace; 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, hydroxyl, 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, hydroxyl, amino, cyano, C1-C3 alkyl, NH(C1-C3 alkyl), N(C1-C3 alkyl)2, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, C1-C3 alkoxy, C6-C 10 Aryl and 5-9 membered heteroaryl, the C1-C3 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic group, C1-C3 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 and CR 5 ; Or, X 2 Selected from 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 ' and CR 5 '; or, X 3 Selected from CR 5 '.

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

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 , R 3 One of them is hydrogen and the other is hydroxyl.

6. A 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. A 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, 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 with 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.

8. A 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 connected thereto 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 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 substituted 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 Independently selected from C1-C3 alkyl.

10. A 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.

11. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, selected from the compound of formula (II) or a pharmaceutically acceptable salt thereof, in, R 5 and R 5 ' and the atoms connected to it 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 substituted with one or more R a Replacement; R 1 , R 2 , R 3 , R 4 , R 7 , R 8 ,X,X 1 and R a As defined in any one of claims 1 to 10.

12. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein represents a single bond, and X 2 Selected from CR 5 , X 3 Selected from CR 5 '.

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

14. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13 and a pharmaceutically acceptable excipient.

15. Use of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, or the pharmaceutical composition according to claim 14, in the preparation of a medicament for preventing or treating a PKMYT1-mediated disease.

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