Fused tricyclic PKMYT1 inhibitors

Abstract

The invention belongs to the field of medicines, and particularly provides a thick tricyclic PKMYT1 inhibitor compound, pharmaceutically acceptable salt thereof, or an isomer thereof, and preparation, a pharmaceutical composition and medical application of the compound. # imgabs0 #

Description

Technical Field

[0001] The present disclosure belongs to the field of medicine, and specifically relates to a fused tricyclic compound, a pharmaceutically acceptable salt thereof, an isomer thereof, a preparation method thereof, a pharmaceutical composition thereof, and a medical use thereof. Background Art

[0002] Cyclin E is a cyclin of cyclin-dependent kinase 2 (CDK2). It binds to CDK2 in the G1 phase to form an activated CDK2-Cyclin E complex, which promotes the transition of the cell cycle from the G1 phase to the S phase at the initiation of DNA replication. The Cyclin E1 (CCNE1) gene is the main protein encoded by Cyclin E, and thus plays an important role in regulating the transition from the G1 phase to the S phase of the cell cycle. Some studies have shown that overexpression of CCNE1 protein can lead to increased expression levels of the Cyclin E protein it encodes, thereby increasing the activity of the CDK2-Cyclin E complex, triggering premature cell cycle conversion, increasing DNA replication pressure and genomic instability. Amplification of CCNE1 is common in many tumor types, especially in highly malignant gynecological and digestive tract cancers, such as ovarian cancer (HGSOC), uterine cancer, and gastroesophageal cancer, and is associated with resistance to cytotoxic and targeted therapies.

[0003] CCNE1 itself is not considered a druggable target. Current research is to treat it by acting on its downstream cell cycle protein CDK2, using multi-target CDK inhibitors. Therefore, the lack of treatment options for CCNE1-amplified tumors makes the development of new therapies for this type of tumor a key unmet need. In order to study the therapeutic targets of CCNE1-amplified tumors, Mount Sinai Hospital in Toronto, Canada, the University of Toronto, and Repare Therapeutics in the United States, etc., collaborated to find that CCNE1 amplification and PKMYT1 inhibition constitute a synthetic lethal pair. This result was published in the journal Nature on April 20, 2022. They conducted a genome-scale CRISPR-Cas9-based synthetic lethality screening in a cell model of CCNE1 amplification. The results showed that PKMYT1 is essential in CCNE1-amplified cells, but not in other healthy cells with normal CCNE1 levels. Therefore, PKMYT1 is a synthetic lethal gene for CCNE1, and PKMYT1 inhibitors can be used to treat CCNE1-amplified tumor diseases. Furthermore, the protein encoded by the FBXW7 gene is the target protein recognition component of the cullin-RING ubiquitin ligase. The FBXW7 protein targets and binds to CCNE1 through the ubiquitin-dependent protein degradation pathway. Therefore, FBXW7 inactivation mutations will lead to increased CCNE1 levels. PKMYT1 inhibitors can also be used to treat tumor diseases with FBXW7 inactivation mutations.

[0004] PKMYT1 kinase, also known as MYT1, is a member of the WEE family of kinases. It phosphorylates the threonine 14 site of CDK1 kinase during cell cycle transitions, rendering the CDK1-Cyclin B complex inactive, negatively regulating the cell cycle checkpoints from G2 to M, and has an important influence on tumor cell proliferation, migration, and xenograft tumor formation. Summary of the invention

[0005] The problem to be solved by the present disclosure is to provide a PKMYT1 inhibitor with a novel structure, which can be used to treat tumor diseases with CCNE1 amplification or FBXW7 inactivation mutation.

[0006] The technical solution of the present disclosure is as follows:

[0007] In a first aspect, the present disclosure provides a compound represented by the following general formula (I'), a pharmaceutically acceptable salt thereof or an isomer thereof,

[0008]

[0009] X 1 Select from N or CR 1 ;

[0010] X 2 Selected from N or C;

[0011] X 3 Selected from N or C;

[0012] X 4 Select from N or CR 4 ;

[0013] X 5 Select from N or CR 5 ;

[0014] X 6 Select from N or CR 2 ;

[0015] Ring A is selected from phenyl, cycloalkenyl, heterocycloalkenyl or heteroaryl;

[0016] R 1 Selected from -H, -OH, -CN, -N(R 1a )(R 1b ), halogen, C 1-6 Alkyl, C 1-6 Alkoxy, -COOH, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl-S(O) 2 -, Hydroxyl C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkyl-C 1-6 Alkyl, C 3-8 Cycloalkyl-O-, 3-8 membered heterocyclyl, 3-8 membered heterocycloalkenyl, phenyl, 5-6 membered heteroaryl; wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkyl-C 1-6 Alkyl, C 3-8 Cycloalkyl-O-, 3-8 membered heterocyclyl, 3-8 membered heterocycloalkenyl, phenyl, 5-6 membered heteroaryl, optionally substituted with one or more R 1c Substitute, the R 1c Selected from OH, -CN, -N(R 1a )(R 1b ), halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl or C 1-6 Alkoxy;

[0017] R 2 Selected from -H, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group;

[0018] R 3 Selected from -H, deuterium, -OH, -CN, halogen, -N(R 1a )(R 1b ), C 1-6 Alkyl-S(O) 2 -、C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 Alkyl-, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, 3-14 membered heterocyclic group or C 3-8 Cycloalkyl;

[0019] R 4 , R 5 are independently selected from -H, -OH, -CN, -N(R 1a )(R 1b ), halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy;

[0020] R 6 , R 7 are independently selected from H, -OH, -CN, -N(R 1a )(R 1b ), halogen, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group;

[0021] R 1a , R 1b are independently selected from H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, or R 1a , R 1band the nitrogen atom to which it is connected form a 3-10 membered ring;

[0022] m is selected from 0, 1, 2 or 3.

[0023] In another preferred embodiment,

[0024] X 1 Select from N or CR 1 ;

[0025] X 2 Selected from N or C;

[0026] X 3 Selected from N or C;

[0027] X 4 Select from N or CR 4 ;

[0028] X 5 Select from N or CR 5 ;

[0029] X 6 Select from N or CR 2 ;

[0030] Ring A is selected from phenyl, cycloalkenyl, heterocycloalkenyl or heteroaryl;

[0031] R 1 Selected from -H, -OH, -CN, -N(R 1a )(R 1b ), halogen, C 1-4 Alkyl, C 1-4 Alkoxy, -COOH, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkyl-S(O) 2 -, Hydroxyl C 1-4 Alkyl, C 3-6 Cycloalkyl, C 5-6 Cycloalkenyl, C 3-6 Cycloalkyl-C 1-4 Alkyl, C 3-6 Cycloalkyl-O-, 3-6 membered heterocyclyl, 3-6 membered heterocycloalkenyl, phenyl, 5-6 membered heteroaryl; wherein the C 1-4 Alkyl, C 3-6 Cycloalkyl, C 5-6 Cycloalkenyl, C 3-6 Cycloalkyl-C 1-4 Alkyl, C 3-6 Cycloalkyl-O-, 3-6 membered heterocyclyl, 3-6 membered heterocycloalkenyl, phenyl, 5-6 membered heteroaryl, optionally substituted with one or more R1c Substitute, the R 1c Selected from halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy;

[0032] R 2 Selected from -H, halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl or C 3-6 Cycloalkyl;

[0033] R 3 Selected from -H, deuterium, -OH, -CN, halogen, -N(R 1a )(R 1b ), C 1-4 Alkyl-S(O) 2 -、C 2-4 Alkynyl, C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl-, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, 3-14 membered heterocyclic group or C 3-6 Cycloalkyl;

[0034] R 4 , R 5 are independently selected from -H, -OH, -CN, -N(R 1a )(R 1b ), halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 alkyl;

[0035] R 6 , R 7 are independently selected from H, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, hydroxyl C 1-4 Alkyl, halogenated C 1-4 Alkyl or C 3-6 Cycloalkyl;

[0036] R 1a , R 1b are independently selected from H or C 1-4 Alkyl, or R 1a , R 1b and the nitrogen atom to which it is connected form a 3-10 membered ring;

[0037] m is selected from 0, 1, 2 or 3.

[0038] In another preferred embodiment, the compound represented by the general formula (I'), its pharmaceutically acceptable salt or its isomer has the structure represented by the following formula (I):

[0039]

[0040] X 1 Select from N or CR 1 ;

[0041] X 2 Selected from N or C;

[0042] X 3 Selected from N or C;

[0043] X 4 Select from N or CR 4 ;

[0044] X 5 Select from N or CR 5 ;

[0045] Ring A is selected from phenyl, cycloalkenyl, heterocycloalkenyl or heteroaryl;

[0046] R 1 Selected from -H, -OH, -CN, -N(R 1a )(R 1b ), halogen, C 1-4 Alkyl, C 1-4 Alkoxy, -COOH, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkyl-S(O) 2 -, Hydroxyl C 1-4 Alkyl, C 3-6 Cycloalkyl, C 5-6 Cycloalkenyl, C 3-6 Cycloalkyl-C 1-4 Alkyl, C 3-6 Cycloalkyl-O-, 3-6 membered heterocyclyl, 3-6 membered heterocycloalkenyl, phenyl, 5-6 membered heteroaryl; wherein the C 1-4 Alkyl, C 3-6 Cycloalkyl, C 5-6 Cycloalkenyl, C 3-6 Cycloalkyl-C 1-4 Alkyl, C 3-6 Cycloalkyl-O-, 3-6 membered heterocyclyl, 3-6 membered heterocycloalkenyl, phenyl, 5-6 membered heteroaryl, optionally substituted with one or more R 1c Substitute, the R 1c Selected from halogen, C 1-4Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy;

[0047] R 2 Selected from -H, halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl or C 3-6 Cycloalkyl;

[0048] R 3 Selected from -OH, -CN, halogen, -N(R 1a )(R 1b ), C 1-4 Alkyl-S(O) 2 -、C 2-4 Alkynyl, C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl-, halogenated C 1-4 Alkyl or C 3-6 Cycloalkyl;

[0049] R 4 , R 5 are independently selected from -H, -OH, -CN, -N(R 1a )(R 1b ), halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 alkyl;

[0050] R 6 , R 7 are independently selected from halogen, C 1-4 Alkyl, C 1-4 Alkoxy, hydroxyl C 1-4 Alkyl, halogenated C 1-4 Alkyl or C 3-6 Cycloalkyl;

[0051] R 1a , R 1b are independently selected from H or C 1-4 Alkyl, or R 1a , R 1b and the nitrogen atom to which it is connected form a 3-10 membered ring;

[0052] m is selected from 0, 1, 2 or 3.

[0053] In another preferred embodiment, wherein X 1 Select from N or CR 1 ; R 1 Selected from -CH 3, -H, -OH, -Cl, -F, -Br, -COOH, -CN, -CH 2 CH 3 、-CH(CH 3 ) 2 、-CH 2 CH(CH 3 ) 2 , -CF 3 , -CHF 2 、-CH 2 F, -CF 2 CH 3 、-CF(CH 3 ) 2 、-OCH 3 、-OCH(CH 3 ),-OCF 3 、-OCH 2 CF 3 、-N(CH 3 ) 2 、-CH=CH 2 、-C(CH 3 )=CH 2 、-C≡CH、-S(O) 2 CH 3 ,

[0054] In another preferred embodiment, wherein X 1 Selected from CR 1 .

[0055] In another preferred embodiment, wherein R 1 Selected from -H, -OH, -F, -Cl, -Br, -CF 3 、-CH 3 or

[0056] In another preferred embodiment, wherein X 2 For C.

[0057] In another preferred embodiment, wherein X 2 N

[0058] In another preferred embodiment, wherein X 3 For C.

[0059] In another preferred embodiment, wherein X 3 is N.

[0060] In another preferred embodiment, wherein X 6 is N.

[0061] In another preferred embodiment, wherein X 6 CR 2 .

[0062] In another preferred embodiment, wherein X 4 CR 4 ; R 4 Selected from -H, -F, -Cl, -Br or -CH 3 .

[0063] In another preferred embodiment, wherein R 4 Selected from -H or -F.

[0064] In another preferred embodiment, wherein X 5 CR 5 ; R 5 Selected from -H, -F, -Cl, -Br or -CH 3 .

[0065] In another preferred embodiment, wherein R 5 Selected from -H or -F.

[0066] In another preferred embodiment, wherein R 4 and R 5 are independently selected from H or -F, and R 4 and R 5 Not the same.

[0067] In another preferred embodiment, wherein X 1 CR 1 , X 2 C, X 3 C, X 4 CR 4 , X 5 CR 5 , R 1 , R 4 , R 5 As defined in any of the preceding schemes.

[0068] In another preferred embodiment, wherein ring A is selected from phenyl, C 5-6 cycloalkenyl, 5-6 membered heterocycloalkenyl or 5-6 membered heteroaryl.

[0069] In another preferred embodiment, ring A is selected from phenyl.

[0070] In another preferred embodiment, ring A is selected from 5-6 membered heteroaryl groups.

[0071] In another preferred embodiment, wherein ring A is selected from

[0072] In another preferred embodiment, wherein ring A is selected from

[0073] In another preferred embodiment, wherein ring A is selected from

[0074] In another preferred embodiment, wherein ring A is selected from

[0075] In another preferred embodiment, wherein R 3 Selected from H, D, -CN, -OH, -F, -Cl, -Br, -CH 3 、-CH 2 CF 3 or -CF 3 ; m is selected from 0, 1 or 2.

[0076] In another preferred embodiment, wherein R 3 Selected from -CN, -OH, -F, -Cl, -Br, -CH 3 or -CH 2 CF 3 ; m is selected from 0, 1 or 2.

[0077] In another preferred embodiment, wherein R 3 Selected from -H or deuterium.

[0078] In another preferred embodiment, wherein R 2 Selected from -H, -F, -Cl, -Br, -CH 3 、-CH 2 CH 3 , -CF 3 、-CH 2 CF 3 or In another preferred embodiment, wherein R 2 Selected from -H.

[0079] In another preferred embodiment, the structural unit for In another preferred embodiment, the structural unit Selected from

[0080]

[0081] In another preferred embodiment, the structural unit Selected from

[0082]

[0083] In another preferred embodiment, the structural unit Selected from

[0084] In another preferred embodiment, the structural unit Selected from

[0085] In another preferred embodiment, wherein R 6 , R 7 are independently selected from -CH 3 、-CH 2 CH 3 、-CH(CH 3 ) 2 、-Cl、-F、-Br、-OCH 3 、-CH 2 OH.

[0086] In another preferred embodiment, wherein R 6 , R 7 All selected from -CH 3 .

[0087] In another preferred embodiment, the compound, its pharmaceutically acceptable salt or its isomer has the following structure:

[0088]

[0089] Among them, X 1 , X 4 , X 5 , Ring A, R 2 , R 3 , R 6 , R 7 , m is as described in any of the previous schemes.

[0090] In another preferred embodiment, the compound, its pharmaceutically acceptable salt or its isomer has the following structure:

[0091]

[0092] Among them, ring A, R 1 , R 2 , R 3 , m is as described in any of the previous schemes.

[0093] In another preferred embodiment, wherein R 1 Selected from halogen, C 1-4 Alkyl, halogenated C 1-4 alkyl;

[0094] R 4 , R 5 Each independently selected from -H or halogen;

[0095] Ring A is selected from phenyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkenyl;

[0096] R 3 Selected from -H, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy.

[0097] In another preferred embodiment, the compound, its pharmaceutically acceptable salt or its isomer has the following structure:

[0098]

[0099]

[0100]

[0101] Description and Definition

[0102] Unless otherwise specified, the scientific and technical terms used in this document have the meanings commonly understood by those skilled in the art. When the definitions of terms provided in this document are inconsistent with the meanings commonly understood by those skilled in the art, the definitions and interpretations of the terms provided in this document shall prevail.

[0103] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0104] The term "pharmaceutically acceptable salt" refers to a salt of an acidic functional group (e.g., -COOH, -OH, -SO 3 H, etc.) with an appropriate inorganic or organic cation (base), including salts with alkali metals or alkaline earth metals, ammonium salts, and salts with nitrogen-containing organic bases; and basic functional groups (e.g., -NH 2 The invention also includes salts formed with suitable inorganic or organic anions (acids), including salts formed with inorganic acids or organic acids (such as carboxylic acids, etc.).

[0105] The terms "therapeutically effective amount" and "effective amount" refer to an amount sufficient to produce a beneficial or desired effect when the disclosed compound is administered to a subject; the effect may be to prevent the generation of tumors, and / or inhibit the growth of tumors, and / or limit the spread of tumors, and / or reduce the volume of tumors, and / or improve clinical symptoms or indicators related to cancer. However, it should be recognized that the total daily dosage of the disclosed compound must be determined by the attending physician within the scope of reliable medical judgment.

[0106] The term "isomer" includes geometric isomers and stereoisomers, such as atropisomers, cis-trans isomers, enantiomers, diastereomers, tautomers, and racemic mixtures and other mixtures thereof, all of which are within the scope of the present disclosure. The term "enantiomer" refers to stereoisomers that are mirror images of each other.

[0107] The term "tautomer" refers to a type of functional group isomer that has different hydrogen attachment points due to one or more double bond displacements, for example, a ketone and its enol form are keto-enol tautomers. The term "diastereomer" refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are non-mirror images. The term "cis-trans isomer" refers to different spatial configurations in which double bonds or single bonds of ring carbon atoms in a molecule cannot rotate freely. The term "atropisomer" refers to a stereoisomer that can be separated because single bond rotation is hindered or rotates very slowly.

[0108] Stereoisomers of the disclosed compounds can be prepared by chiral synthesis or chiral reagents or other conventional techniques. For example, one enantiomer of a compound of the disclosed compounds can be prepared by asymmetric catalysis technology or chiral auxiliary derivatization technology. Or a compound of a single stereo configuration can be obtained from a mixture by chiral resolution technology. Or it can be prepared directly using chiral starting materials. The separation of optically pure compounds in the disclosed compounds is usually accomplished by preparative chromatography, using a chiral chromatographic column to achieve the purpose of separating chiral compounds.

[0109] The compounds disclosed herein may have atropisomers, and such structures can be regarded as extensions of the chiral center. The judgment method is as follows: Take the following binaphthol as an example:

[0110]

[0111] Looking along the C1-C1' axis, the groups on both sides of the carbon center C1 closer to the observer are ranked first in the order of priority; the groups on both sides of C1' on the other end are ranked third and fourth, and then ranked according to the priority of the groups, clockwise for R configuration and counterclockwise for S configuration. It should be noted that the results are the same regardless of which end of the CC axis is observed. In this disclosure, the compound structure is represented by solid line bonds. , indicating that it is above the plane, for example Taking the three-fused ring as a plane, the structural part represented by the real bond in the benzene ring structure is located above the plane.

[0112] It is known to those skilled in the art that when a cyclic compound has a coplanar delocalized system and the number of π electrons is 4n+2, the ring is aromatic. The expression of the aromatic structure in the compound can be expressed by a dotted line representing electron delocalization or by alternating single and double bonds. For example, the structure of a benzene ring can be drawn as It can also be

[0113] The term "optionally substituted" as used herein refers to two situations in which one or more hydrogen atoms of the substituted group may be "substituted" or "unsubstituted" with one or more substituents.

[0114] When the substituent appears in the structure Indicates that the atom is a bonding atom, for example Indicates that the C atom on the pyrimidine ring is a bonding atom. A dash "-" in a substituent structure indicates the point of attachment for the substituent, e.g. -OCH 3 Attached through oxygen atoms.

[0115] When a substituent has a bond that crosses two atoms in a ring, the substituent may be bonded to any atom in the ring. It means that the substituent R can be substituted at any position on the benzene ring.

[0116] When a substituent is listed without indicating the atom via which the substituent is attached to a given group or to a given formula, then the substituent may be attached via any bondable atom thereof.

[0117] In the present disclosure, the structural unit Ring A is fused to the structure on the left, and due to the shared double bond, ring A is defined as "heterocycloalkenyl", "cycloalkenyl", "phenyl" or "heteroaryl". for When ring A is R 3 is methyl, and m is 1.

[0118] The term "alkyl" refers to a group derived from a branched or straight chain saturated aliphatic alkane having a specified number of carbon atoms by removing one hydrogen. 1-10 "Alkyl" refers to a group including C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C7 , C 8 , C 9 , C 10 Alkyl groups, including "C 1-6 Alkyl", "C 1-4 Alkyl", "C 1-3 "Alkyl"; specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, sec-butyl, 2-methylbutyl, 1,1-dimethylbutyl, etc.

[0119] The term "haloalkyl" refers to a group obtained by replacing one or more hydrogen atoms in an alkyl group with halogen atoms, such as "fluoromethyl" including monofluoromethyl, difluoromethyl and trifluoromethyl. Preferably, the "haloalkyl" described in the present disclosure is "haloC 1-6 Alkyl", "halogenated C 1-4 Alkyl". Alkyl is as defined above.

[0120] The term "hydroxyalkyl" refers to a group derived from an alkyl group in which one or more hydrogen atoms are replaced by a hydroxy group. The "hydroxyalkyl" described in the present disclosure includes "hydroxyC 1-6 Alkyl", "Hydroxy C 1-4 "alkyl"; specific examples include but are not limited to -CH 2 OH, -CH 2 CH 2 OH, -CH(OH)CH 3 、-CH 2 CH 2 CH 2 OH, wait.

[0121] The term "alkoxy" refers to an alkyl group as defined herein attached to another group through an oxygen atom, i.e., "alkyl-O-". 1-6 Alkoxy (structure C 1-6 Alkyl-O-), "C 1-4 "alkoxy", specific examples include but are not limited to methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, etc.; preferably, the "alkoxy" described in the present disclosure is C 1-4 Alkoxy, more preferably C 1-3 Alkoxy.

[0122] The term "haloalkoxy" refers to a group in which one or more hydrogen atoms in an alkoxy group are replaced by halogen. Preferably, the "haloalkoxy" is a "haloC 1-6 Alkoxy", "halogenated C 1-4Alkoxy". Specific examples of "fluoromethoxy" described in the present disclosure include monofluoromethoxy, difluoromethoxy, trifluoromethoxy; and also include but are not limited to: -OCH 2 CF 3 、-OCHFCH 3 etc. Alkoxy is as defined above.

[0123] The term "alkenyl" refers to a radical derived from a straight-chain or branched alkene (containing at least one double bond) by removing a hydrogen atom, including "C 2-6 Alkenyl", "C 2-5 Alkenyl", "C 2-4 Alkenyl", "C 2-3 Examples include, but are not limited to, -CH=CH 2 、-CH=CHCH 3 、-C(CH 2 )=CH 2 、-CH=CHCH 2 CH 3 、-CH 2 CH=CHCH 3 wait.

[0124] The term "alkynyl" refers to a radical derived from a straight-chain or branched alkyne (containing at least one triple bond) by removing a hydrogen atom, including "C 2-5 Alkynyl", "C 2-4 Alkynyl", "C 2-3 "Alkynyl", specific examples include but are not limited to: -C≡CH, -C≡CHCH 3 、CH≡CHCH 2 -, CH≡CC≡C-, etc.

[0125] The term "cycloalkyl" refers to a saturated cyclic group derived from a monocyclic cycloalkane by removing a hydrogen atom, and the carbon atoms in the cycloalkyl group may be further oxidized to form C(O). The cycloalkyl group includes "3-8 membered cycloalkyl", "3-6 membered cycloalkyl", "3-5 membered cycloalkyl", "4-6 membered cycloalkyl". Specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0126] The term "cycloalkenyl" refers to a "cycloalkyl" in which one or more of the ring bonds is a double bond and the cycloalkenyl is not aromatic. The carbon atoms in the cycloalkenyl may be further oxidized to form C(O). The cycloalkenyl includes "C 3-8 Cycloalkenyl", "C 3-6 Cycloalkenyl", "C 3-5 Cycloalkenyl", "C 5-6 Specific examples include but are not limited to

[0127] The term "heterocyclic group" refers to a monocyclic or polycyclic group in which at least one of the ring atoms is a heteroatom; the heteroatom is generally selected from N, O, and S; the carbon atoms or heteroatoms in the heterocyclic group may be further oxidized, i.e., to form C(O), N(O), SO, SO 2 ; The polycyclic group refers to a polycyclic group formed by connecting two or more cyclic group structures by spiral, bridge, condensed, etc. Preferably, the heteroatoms are independently selected from 1-3 N and / or O. The heterocyclic group includes "3-14 membered heterocyclic group", "3-10 membered heterocyclic group", "3-8 membered heterocyclic group", "3-6 membered heterocyclic group", "3-5 membered heterocyclic group", "4-6 membered heterocyclic group", "5-6 membered heterocyclic group". Specific examples include but are not limited to azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, etc.

[0128] The term "heterocycloalkenyl" means that one or more of the ring bonds in the "heterocyclic group" is a double bond and the heterocyclic ring is not aromatic. Preferably, the heteroatoms are independently selected from 1-3 N and / or O. The heterocyclic group includes "3-8 membered heterocycloalkenyl", "3-6 membered heterocycloalkenyl", "3-5 membered heterocycloalkenyl", "5-6 membered heterocycloalkenyl". Specific examples include, but are not limited to: wait.

[0129] The term "aryl" refers to a monocyclic or polycyclic group composed of ring carbon atoms and having aromatic properties. Specific examples include, but are not limited to, phenyl and naphthyl.

[0130] The term "heteroaryl" refers to a monocyclic group with aromatic properties in which at least one ring atom is a heteroatom, and the heteroatom is generally selected from N, O, and S; the carbon atoms or heteroatoms in the heterocyclic group may be further oxidized, i.e., to form C(O), N(O), SO, SO 2 ; Preferably, the heteroatoms are independently selected from 1-3 N and / or O. The heteroaryl group includes "5-6 membered heteroaryl"; specific examples include but are not limited to pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, pyrazinyl, pyridazinyl, triazinyl, oxazolyl, isoxazolyl, thiazolyl, isoxazolyl, pyridinyl, pyrimidinyl.

[0131] In the present invention, unless otherwise specified, the "ring" mentioned herein may include all types of rings in the present invention, such as cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclyl, aryl, and heteroaryl. 1a , R 1b and the nitrogen atom to which it is connected form a 3-10 membered ring”, the “3-10 membered ring” may include a heterocyclic group, a heterocyclic alkenyl group, and a heteroaryl group that meet the defined conditions.

[0132] The combination of substituents and / or variables described in the present disclosure should be allowed only when these combinations produce stable compounds or useful synthetic intermediates, and those skilled in the art can exclude situations that are obviously beyond the conventional knowledge in the art and unreasonable situations from the present disclosure. A stable compound or a stable structure refers to a compound that is stable enough to withstand chemical reactions, be isolated with useful purity, and be formulated into an effective therapeutic drug. DETAILED DESCRIPTION

[0133] In the examples disclosed herein, the naming of the title compound is converted from the compound structure with the aid of Chemdraw. If there is any inconsistency between the compound name and the compound structure, it can be determined by combining relevant information and reaction routes; if it cannot be confirmed by other means, the given compound structure shall prevail.

[0134] The preparation methods of some compounds in the present disclosure refer to the preparation methods of the aforementioned similar compounds. Those skilled in the art should be aware that when using or referring to the preparation methods cited, the feed ratio of reactants, reaction solvent, reaction temperature, etc. can be appropriately adjusted according to the different reactants.

[0135] 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 them 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.

[0136] Experimental equipment summary:

[0137] The structures of the compounds disclosed herein are determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Varian 400M or Bruker Ascend 400 NMR instrument, and the measurement solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD), deuterated chloroform (CDCl 3 ) or heavy water (D 2 O), and the internal standard was tetramethylsilane (TMS).

[0138] The starting materials in the embodiments of the present disclosure are known and commercially available, or can be synthesized using or according to methods known in the art.

[0139] The reagents used in the embodiments of the present invention and their corresponding chemical names are as follows:

[0140] abbreviation Chemical name DMAP 4-Dimethylaminopyridine xantPhos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene <![CDATA[Pd 2 dba 3 ]]> Tris(dibenzylideneacetone)dipalladium

[0141] Example 1

[0142] Reaction route:

[0143]

[0144] 1-2: 5-bromo-3-methylpyridin-2-amine (5 g, 26.7 mmol) was dissolved in acetonitrile (100 ml), N-bromosuccinimide (4.76 g, 26.7 mmol) was added at room temperature, and the resulting mixture was stirred for 16 hours at room temperature. LCMS monitoring showed that the reaction was complete. The reaction solution was concentrated, and the crude product was separated by column chromatography on silica gel plates to obtain the product 5,6-dibromo-3-methylpyridin-2-amine (6 g). MS (ESI) M / Z: 265.0 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ7.42(s,1H),4.57(br,2H),2.07(s,3H).

[0145] 1-3: 5,6-dibromo-3-methylpyridin-2-amine (6 g, 22.64 mmol) was dissolved in dichloromethane (120 ml), and DMAP (2.76 g, 22.64 mmol) and Boc were added at 0°C. 2 O (5.43 g, 24.9 mmol). Warm to room temperature and continue stirring for 16 hours. LCMS monitoring shows that the reaction is complete. Add dichloromethane (200 ml) to the reaction solution and wash with aqueous ammonium chloride solution (200 ml × 3) and then with saturated brine (200 ml). The organic phase is dried over anhydrous magnesium sulfate, filtered and the solvent is removed by rotation. The crude product is separated by column chromatography on a silica gel plate to obtain the product tert-butyl (tert-butyloxycarbonyl) (5,6-dibromo-3-methylpyridin-2-yl) carbamate (3.0 g). MS (ESI) M / Z: 310.0 [M+H-56] + .

[0146] 1-4: Dissolve tert-butyl (tert-butyloxycarbonyl) (5,6-dibromo-3-methylpyridin-2-yl) carbamate (2.3 g, 4.96 mmol), 3-methoxy-2,6-dimethylaniline (748 mg, 4.96 mmol), cesium carbonate (3.26 g, 10 mmol), 4,5-bis (diphenylphosphine) -9,9-dimethylxanthene (58 mg, 0.1 mmol) and tris (dibenzylideneacetone) dipalladium (46 mg, 0.05 mmol) in DME (50 ml) solution in sequence, and heat the system to 90 ° C under nitrogen protection and continue stirring for 16 hours. LCMS monitoring shows that the reaction is complete. Ethyl acetate (100 ml) was added to the reaction solution, and then washed with water (100 ml × 3) several times, and then washed with saturated brine (100 ml) and dried over anhydrous sodium sulfate, filtered and then spin-dried. The crude product was eluted by column chromatography on a silica gel column to give the product (5-bromo-6-((3-methoxy-2,6-dimethylphenyl)amino)-3-methylpyridin-2-yl)(tert-butoxycarbonyl)carbamic acid tert-butyl ester (1.7 g). MS (ESI) M / Z: 536.0 [M+H] + .

[0147] 1-5: Dissolve tert-butyl (5-bromo-6-((3-methoxy-2,6-dimethylphenyl)amino)-3-methylpyridin-2-yl)(tert-butoxycarbonyl)carbamate (1.7 g, 3.17 mmol) in dichloromethane (30 ml) and place in an ice-water bath. Add trifluoroacetic acid (5 ml) dropwise to the above solution and continue stirring the resulting mixture for three hours. LCMS monitoring showed that the reaction was complete. After the reaction solution was concentrated, the pH value was adjusted to weak alkalinity with triethylamine and then purified by normal phase to obtain 3-bromo-N2-(3-methoxy-2,6-dimethylphenyl)-5-methylpyridine-2,6-methylamine (720 mg). MS (ESI) M / Z: 336.1 [M+H] + . 1 HNMR (400MHz, CDCl 3 ;

[0148] 1-6: 3-Bromo-N2-(3-methoxy-2,6-dimethylphenyl)-5-methylpyridine-2,6-methylamine (720 mg, 2.15 mmol) was dissolved in ethanol (10 ml). 2-Bromo-1,1-dimethoxyethane (727 mg, 4.3 mmol) was added to the above solution, and finally hydrobromic acid (0.2 ml, 40% aqueous solution) was added dropwise to the above solution. The resulting mixture was heated to 90°C overnight. LCMS monitoring showed that the reaction was complete. The reaction solution was concentrated and re-dissolved in ethyl acetate (50 ml), washed with saturated sodium bicarbonate aqueous solution, and the organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The crude product was purified by normal phase to obtain 6-bromo-N-(3-methoxy-2,6-dimethylphenyl)-8-methylimidazo[1,2-a]pyridine-5-amine (400 mg). MS (ESI) M / Z: 360.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ): δ7.79(s,1H),7.68(d,J=1.0Hz,1H),7.52(d,J=1.0Hz,1H),7.18(s,1H),6.99(d,J =8.4Hz,1H),6.72(d,J=8.4Hz,1H),3.75(s,3H),2.43(s,3H),1.87(d,J=11.2Hz,6H).

[0149] 1-7: Malononitrile (221 mg, 3.34 mmol) and sodium hydride (134 mg, 3.34 mmol) were dissolved in ethylene glycol dimethyl ether (20 ml) solution. After stirring at room temperature for 5 minutes, 6-bromo-N-(3-methoxy-2,6-dimethylphenyl)-8-methylimidazo[1,2-a]pyridine-5-amine (400 mg, 1.11 mmol) and bis(diphenylphosphino)ferrocenepalladium dichloride (82 mg, 0.1 mmol) were added and the system was heated to 120°C under nitrogen protection and continued to stir for 2 hours. LCMS monitoring showed that the reaction was complete. After the reaction solution was cooled to room temperature, ethyl acetate (100 ml) was added and then washed several times with water (100 ml × 3), then washed with saturated brine (100 ml) and dried over anhydrous sodium sulfate, filtered and spin-dried. The crude product was eluted by column chromatography on a silica gel column to obtain the product 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-5-methyl-1H-imidazo[1,2-a]pyrrolo[3,2-e]pyridine-3-carbonitrile (180 mg). MS (ESI) M / Z: 346.2 [M+H] + .

[0150] 1-8: Dissolve 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-5-methyl-1H-imidazo[1,2-a]pyrrolo[3,2-e]pyridine-3-carbonitrile (180 mg) in dichloromethane (10 ml), and then add 2 ml of concentrated sulfuric acid to the above solution. Continue stirring at room temperature for 1 hour. LCMS monitoring shows that the reaction is complete. After adding dichloromethane (20 ml), the reaction solution is washed several times with water (20 ml × 3), then washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, and then spin-dried to obtain the crude product 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-5-methyl-1H-imidazo[1,2-a]pyrrolo[3,2-e]pyridine-3-carboxamide (120 mg). MS (ESI) M / Z: 364.2 [M+H] + .

[0151] 1: Dissolve 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-5-methyl-1H-imidazo[1,2-a]pyrrolo[3,2-e]pyridine-3-carboxamide (120 mg, 0.33 mmol) in dichloromethane (2 ml) solution and add boron tribromide solution (5 ml, 1 M). Continue stirring at room temperature for 48 hours. LCMS monitoring shows that the ratio of raw material to product is 1:1. Add dichloromethane (10 ml × 3) to the reaction solution and spin dry several times, then add methanol (5 ml) to quench and spin dry. The crude product is prepared by reverse phase to obtain the product 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-5-methyl-1H-imidazo[1,2-a]pyrrolo[3,2-e]pyridine-3-carboxamide (1 mg). MS (ESI) M / Z: 350.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ): δ10.40–9.46(m,1H),7.79(s,1H),7.30(s,1H),7.27–7.16(m,2H),7.07(d,J =8.4Hz,1H),6.84(s,2H),6.35(s,2H),6.30(s,1H),1.79(s,3H),1.70(s,3H).

[0152] Example 2

[0153] Reaction route:

[0154]

[0155] 2-2: Dissolve 4-bromo-3-nitrobenzene-1,2-diamine (2.7 g, 11.6 mmol) in formic acid (23 ml) and reflux at 110 degrees Celsius for three hours. After LCMS monitoring shows that the starting material disappears, cool and concentrate to dryness under reduced pressure. Add ammonia solution (26 ml) to the residue and stir for 30 minutes. Collect the solid, wash with water, and dry to obtain 5-bromo-4-nitro-1H-benzo[d]imidazole (2.53 g). MS (ESI) M / Z: 241.92 [M+H] + .

[0156] 2-3: 5-bromo-4-nitro-1H-benzo[d]imidazole (2.53 g, 10.5 mmol) was dissolved in dimethyl carbonate (25 ml), and DBU (1.5 ml, 10.5 mmol) was added. The mixture was reacted at 90°C overnight. After LCMS monitoring showed that the starting material disappeared, the mixture was cooled, and sodium bicarbonate aqueous solution (100 ml) was added. The mixture was extracted with ethyl acetate (100 ml) twice, and the organic phases were combined. The organic phases were first washed with saturated brine (20 ml), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 5-bromo-1-methyl-4-nitro-1H-benzo[d]imidazole (1.55 g). MS (ESI) M / Z: 257.6 [M+H] + .

[0157] 2-4: 5-Bromo-1-methyl-4-nitro-1H-benzo[d]imidazole (1.55 g, 6.1 mmol) was added to ethanol (30 ml) and water (15 ml), and then iron powder (2 g, 36.3 mmol) and ammonium chloride (1.94 g, 36.3 mmol) were added. The reaction solution was stirred at 80 degrees Celsius for 2 hours. After LCMS monitoring showed that the starting material disappeared, it was cooled and filtered. The filtrate was added with saturated brine (60 ml), and extracted twice with ethyl acetate (100 ml). The organic phases were combined, washed with saturated brine (20 ml), and then dried over anhydrous sodium sulfate. Finally, the residue was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 5-bromo-1-methyl-1H-benzo[d]imidazole-4-amine (800 mg). MS (ESI) M / Z: 226.23 [M+H] + .

[0158] 2-5: 5-Bromo-1-methyl-1H-benzo[d]imidazol-4-amine (800 mg, 3.54 mmol) and p-toluene acid (2.03 mg, 10.6 mmol) were dissolved in acetonitrile (14 ml), and sodium nitrite (488 mg, 7.08 mmol) and potassium iodide (1.48 mg, 8.85 mmol) were added to a water (7 ml) solution in an ice-water bath, and the mixture was reacted at room temperature overnight. After LCMS monitoring showed that the starting material disappeared, water (20 ml) was added, and ethyl acetate (30 ml) was extracted twice, and the organic phases were combined, washed with saturated brine (10 ml), and then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 5-bromo-4-iodo-1-methyl-1H-benzo[d]imidazole (700 mg). MS (ESI) M / Z: 337.13 [M+H] + .

[0159] 2-6: 5-Bromo-4-iodo-1-methyl-1H-benzo[d]imidazole (600 mg, 1.78 mmol), 3-methoxy-2,6-dimethylaniline (269 mg, 1.78 mmol), xantPhos (102 mg, 0.18 mmol), tris(dibenzylideneacetone)dipalladium (82 mg, 0.09 mmol) and cesium carbonate (1.5 g, 4.5 mmol) were added to toluene (20 ml), replaced with nitrogen three times, and the reaction solution was stirred at 100 degrees Celsius for 3 hours. After LCMS monitoring showed that the starting material disappeared, it was cooled, water (50 ml) was added, and it was extracted with ethyl acetate (100 ml) twice, and the organic phases were combined, washed with saturated brine (20 ml), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by column chromatography to give 5-bromo-N-(3-methoxy-2,6-dimethylphenyl)-1-methyl-1H-benzo[d]imidazol-4-amine (200 mg). MS (ESI) M / Z: 360.16 [M+H]+.

[0160] 2-7: Dissolve malononitrile (33 mg, 0.50 mmol) in dioxane (2 ml), add sodium tert-butoxide (80 mg, 0.83 mmol), replace with nitrogen, and react at room temperature for 30 minutes. Then add 5-bromo-N-(3-methoxy-2,6-dimethylphenyl)-1-methyl-1H-benzo[d]imidazol-4-amine (60 mg, 0.17 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (14 mg, 0.017 mmol), replace with nitrogen, and react at 120 degrees Celsius for 2 hours. After LCMS monitoring shows that the starting material disappears, cool, add water (20 ml), extract with ethyl acetate (20 ml) twice, combine the organic phases, wash the organic phase with saturated brine (10 ml), then dry with anhydrous sodium sulfate, and concentrate to dryness under reduced pressure. The resulting residue was purified by column chromatography to give 7-amino-8-(3-methoxy-2,6-dimethylphenyl)-3-methyl-3,8-dihydroimidazole[4,5-g]indole-6-carbonitrile (20 mg). MS (ESI) M / Z: 346.4 [M+H] + .

[0161] 2-8: 7-amino-8-(3-methoxy-2,6-dimethylphenyl)-3-methyl-3,8-dihydroimidazole [4,5-g] indole-6-carbonitrile (20 mg, 0.06 mmol) was dissolved in sulfuric acid (0.5 ml) and reacted at room temperature for 1 hour. After LCMS monitoring showed that the starting material disappeared, it was cooled and the pH value was adjusted to neutral with sodium hydroxide aqueous solution. It was extracted with ethyl acetate (20 ml * 2), the organic phase was dried, concentrated to dryness, and the crude product was directly used in the next step. MS (ESI) M / Z: 364.4 [M+H] + .

[0162] 2: The crude product of the previous step was dissolved in dichloromethane (1 ml), and boron tribromide (0.17 ml, 0.34 mmol) was added, and the reaction was allowed to react overnight at room temperature. After LCMS monitoring showed that the raw material disappeared, sodium bicarbonate aqueous solution (20 ml) was added, and ethyl acetate (20 ml) was extracted twice, and the organic phases were combined, and the organic phases were first washed with saturated brine (10 ml), then dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The crude product was prepared and purified to obtain 7-amino-8-(3-hydroxy-2,6-dimethylphenyl)-3-methyl-3,8-dihydroimidazole [4,5-g] indole-6-carboxamide (1.34 mg). MS (ESI) M / Z: 350.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ9.37(s,1H),7.76(s,1H),7.66(d,J=8.5Hz,1H),7.20(d,J=8.5Hz,1H),7.02(d,J=8.2Hz, 1H),6.89(d,J=8.2Hz,1H),6.66(s,2H),6.28(s,2H),3.78(s,3H),1.74(s,3H),1.65(s,3H).

[0163] Example 3

[0164] Reaction route:

[0165]

[0166] 3-2: Dissolve 2-methyl-3-nitroaniline (10 g, 65.7 mmol) in acetonitrile (100 ml), cool to 0 degrees Celsius, add N-bromosuccinimide (12.9 g, 72.3 mmol) in batches, stir at room temperature for 30 minutes, and concentrate under reduced pressure. The resulting residue is purified by column chromatography to give 4-bromo-2-methyl-3-nitroaniline (12.7 g). MS (ESI) M / Z: 274.18 [M+H+CH 3 CN + ].

[0167] 3-3: 4-bromo-2-methyl-3-nitroaniline (12.7 g, 55 mmol) was dissolved in acetic acid (425 ml), and a solution of sodium nitrite (4.17 g, 60.5 mmol) in water (21 ml) was added in batches, and the mixture was reacted at room temperature overnight. After LCMS monitoring showed that the starting material disappeared, water (400 ml) was added, and after stirring for half an hour, 5-bromo-4-nitro-1H-indazole (7 g) was obtained by filtration. MS (ESI) M / Z: 242.15 [M+H] + .

[0168] 3-4: Dissolve 5-bromo-4-nitro-1H-indazole (7 g, 28.92 mmol) in N,N-dimethylformamide (150 ml), add potassium carbonate (8.0 g, 57.84 mmol), iodomethane (4.93 g, 34.7 mmol) and react at room temperature overnight. After LCMS monitoring shows that the raw material disappears, add water (100 ml) and ethyl acetate (300 ml) for extraction, dry the organic phase, concentrate under reduced pressure, and purify by column chromatography to obtain 5-bromo-1-methyl-4-nitro-1H-indazole (7 g). MS (ESI) M / Z: 256.16 [M+H] + .

[0169] 3-5&3-6: 5-bromo-1-methyl-4-nitro-1H-indazole (7 g, 27.3 mmol) was dissolved in ethanol (130 ml), and iron powder (9 g, 164 mmol) was added under stirring. A solution of ammonium chloride (8.8 g, 164 mmol) in water (65 ml) was added to the reaction solution, and the mixture was reacted at 80 degrees Celsius for 2 hours. After LCMS monitoring showed that the raw material disappeared, the reaction solution was added with aqueous solution (50 ml) and ethyl acetate extraction (100 ml), stirred and filtered, extracted with ethyl acetate twice, and the organic phases were combined. The organic phases were first washed with saturated brine (50 ml), then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain 5-bromo-1-methyl-1H-indazole-4-amine (2.3 g) and 5-bromo-2-methyl-2H-indazole-4-amine (0.9 g). MS (ESI) M / Z: 227.92 [M+H] +.

[0170] 3-7: 5-bromo-1-methyl-1H-indazol-4-amine (2.3 g, 10.17 mmol) was dissolved in concentrated hydrochloric acid (8.7 ml) and water (2.2 ml), cooled to -15 degrees Celsius, and an aqueous solution (11 ml) of sodium nitrite (0.77 g, 11.2 mmol) was added dropwise over 20 minutes, and stirred at 0 degrees Celsius for 30 minutes. The solution was added dropwise to a solution of potassium iodide (15.3 g, 91.56 mmol) in water (110 ml), and the reaction was allowed to react overnight at room temperature. After LCMS monitoring showed that the raw material disappeared, the reaction solution was diluted with an aqueous solution (50 ml), and sodium hydroxide was added to adjust the pH to alkaline, extracted twice with ethyl acetate, and the organic phases were combined, washed with saturated brine (50 ml), then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain 5-bromo-4-iodo-1-methyl-1H-indazole (2 g). MS (ESI) M / Z: 336.7 [M+H] + .1H NMR (400MHz, CDCl 3 )δ7.79(s,1H),7.52(d,J=8.8Hz,1H),7.22(d,J=8.8Hz,1H),4.04(s,3H).

[0171] 3-8: 5-Bromo-4-iodo-1-methyl-1H-indazole (550 mg, 1.63 mmol), 3-methoxy-2,6-dimethylaniline (280 mg, 1.63 mmol), xantPhos (95 mg, 0.16 mmol), tris(dibenzylideneacetone)dipalladium (150 mg, 0.16 mmol) and cesium carbonate (1.33 g, 4.1 mmol) were added to toluene (30 ml), replaced with nitrogen three times, and the reaction solution was stirred at 100 degrees Celsius for 3 hours. After LCMS monitoring showed that the raw material disappeared, it was cooled, water (100 ml) was added, and it was extracted with ethyl acetate (100 ml) twice, and the organic phases were combined, and the organic phase was first washed with saturated brine (40 ml), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by column chromatography to give 5-bromo-N-(3-fluoro-5-methoxy-2,6-dimethylphenyl)-1-methyl-1H-indazol-4-amine (400 mg). MS (ESI) M / Z: 380.34 [M+H] + .

[0172] 3-9: Dissolve malononitrile (105 mg, 1.6 mmol) in N,N-dimethylformamide (5 ml), add sodium tert-butoxide (230 mg, 2.4 mmol), replace with nitrogen, and react at room temperature for 30 minutes. Then add 5-bromo-N-(3-fluoro-5-methoxy-2,6-dimethylphenyl)-1-methyl-1H-indazol-4-amine (150 mg, 0.4 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (33 mg, 0.04 mmol), replace with nitrogen, and stir the reaction solution at 140 degrees Celsius for 3 hours. After LCMS monitoring showed that the raw material disappeared, the mixture was cooled, water (30 ml) was added, and the mixture was extracted twice with ethyl acetate (20 ml). The organic phases were combined, washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to give 2-amino-1-(3-fluoro-5-methoxy-2,6-dimethylphenyl)-6-methyl-1,6-dihydropyrrolo[2,3-e]indazole-3-carbonitrile (50 mg). MS (ESI) M / Z: 364.42 [M+H] + .

[0173] 3-10: 2-amino-1-(3-fluoro-5-methoxy-2,6-dimethylphenyl)-6-methyl-1,6-dihydropyrrolo[2,3-e]indazole-3-carbonitrile (50 mg, 0.14 mmol) was dissolved in sulfuric acid (1 ml) and reacted at room temperature for 1 hour. After LCMS monitoring showed that the starting material disappeared, the mixture was cooled, the pH value was adjusted to neutral with aqueous sodium hydroxide solution, extracted with ethyl acetate (20 ml × 2), the organic phase was dried and concentrated to obtain the crude product of 2-amino-1-(3-fluoro-5-methoxy-2,6-dimethylphenyl)-6-methyl-1,6-dihydropyrrolo[2,3-e]indazole-3-carboxamide, which was directly used in the next step. MS (ESI) M / Z: 382.17 [M+H] +.

[0174] 3: 2-amino-1-(3-fluoro-5-methoxy-2,6-dimethylphenyl)-6-methyl-1,6-dihydropyrrolo[2,3-e]indazole-3-carboxamide was dissolved in dichloromethane (4 ml), and 2M boron tribromide solution (0.63 ml, 1.26 mmol) was added, and the reaction was allowed to react overnight at room temperature. After LCMS monitoring showed that the starting material disappeared, the reaction solution was poured into an aqueous sodium bicarbonate solution (20 ml), extracted twice with ethyl acetate (30 ml), and the organic phases were combined. The organic phases were first washed with saturated brine (10 ml), then dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The crude product was prepared and purified to give 2-amino-1-(3-fluoro-5-hydroxy-2,6-dimethylphenyl)-6-methyl-1,6-dihydropyrrolo[2,3-e]indazole-3-carboxamide (5.51 mg). MS (ESI) M / Z: 368.2 [M+H] + . 1 HNMR (400 MHz, DMSO-d 6 )δ10.15(s,1H),7.88(d,J=8.9Hz,1H),7.29(d,J=8.8Hz,1H),6.91(d,J=11.2Hz, 1H),6.75(s,2H),6.56(d,J=15.3Hz,3H),3.99(s,3H),1.65(s,3H),1.62(s,3H).

[0175] Example 4

[0176] Reaction route:

[0177]

[0178] 4-1: Dissolve 5-bromo-2-methyl-2H-indazol-4-amine (900 mg, 4.0 mmol) in concentrated hydrochloric acid (4.4 ml) and water (1.1 ml), cool to -15 degrees Celsius, add sodium nitrite (302 mg, 4.4 mmol) in water (5.1 ml) dropwise over 20 minutes, and stir at 0 degrees Celsius for 30 minutes. Add the solution dropwise to a solution of potassium iodide (6 g, 35.8 mmol) in water (51 ml), and react at room temperature overnight. After LCMS monitoring shows that the raw material disappears, the reaction solution is diluted with an aqueous solution (100 ml), sodium hydroxide is added to adjust the pH to alkaline, and extracted twice with ethyl acetate. The organic phases are combined, the organic phases are first washed with saturated brine (50 ml), then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product is purified by column chromatography to obtain 5-bromo-4-iodo-2-methyl-2H-indazole (300 mg). MS (ESI) M / Z: 336.7 [M+H] + .

[0179] 4-2: 5-bromo-4-iodo-2-methyl-2H-indazole (300 mg, 0.9 mmol), 3-methoxy-2,6-dimethylaniline (151 mg, 0.9 mmol), xantPhos (52 mg, 0.09 mmol), tris(dibenzylideneacetone)dipalladium (82 mg, 0.09 mmol) and cesium carbonate (724 mg, 2.2 mmol) were added to toluene (6 ml), replaced with nitrogen three times, and the reaction solution was stirred at 100 degrees Celsius for 3 hours. After LCMS monitoring showed that the raw material disappeared, it was cooled, water (50 ml) was added, and it was extracted with ethyl acetate (100 ml×2), and the organic phases were combined, and the organic phase was first washed with saturated brine (20 ml), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by column chromatography to give 5-bromo-N-(3-fluoro-5-methoxy-2,6-dimethylphenyl)-2-methyl-2H-indazol-4-amine (150 mg). MS (ESI) M / Z: 378.2 [M+H] + .

[0180] 4-3: Dissolve malononitrile (105 mg, 1.6 mmol) in N,N-dimethylformamide (5 ml), add sodium tert-butoxide (260 mg, 2.4 mmol), replace with nitrogen, and react at room temperature for 30 minutes. Then add 5-bromo-N-(3-fluoro-5-methoxy-2,6-dimethylphenyl)-2-methyl-2H-indazol-4-amine (150 mg, 0.4 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (33 mg, 0.04 mmol), replace with nitrogen, and stir the reaction solution at 140 degrees Celsius for 3 hours. After LCMS monitoring showed that the raw material disappeared, the mixture was cooled, water (50 ml) was added, and the mixture was extracted with ethyl acetate (100 ml x 2). The organic phases were combined, washed with saturated brine (40 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to give 2-amino-1-(3-fluoro-5-methoxy-2,6-dimethylphenyl)-7-methyl-1,7-dihydropyrrolo[2,3-e]indazole-3-carbonitrile (50 mg). MS (ESI) M / Z: 364.42 [M+H] + .

[0181] 4-4: 2-amino-1-(3-fluoro-5-methoxy-2,6-dimethylphenyl)-7-methyl-1,7-dihydropyrrolo[2,3-e]indazole-3-carbonitrile (50 mg, 0.14 mmol) was dissolved in sulfuric acid (1 ml) and reacted at room temperature for 1 hour. After LCMS monitoring showed that the starting material disappeared, the mixture was cooled, the pH value was adjusted to neutral with aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate (20 ml × 2). The organic phase was dried and concentrated to obtain the crude product of 2-amino-1-(3-fluoro-5-methoxy-2,6-dimethylphenyl)-7-methyl-1,7-dihydropyrrolo[2,3-e]indazole-3-carboxamide, which was directly used in the next step. MS (ESI) M / Z: 382.17 [M+H] + .

[0182] 4: The crude product of 2-amino-1-(3-fluoro-5-methoxy-2,6-dimethylphenyl)-7-methyl-1,7-dihydropyrrolo[2,3-e]indazole-3-carboxamide from the previous step was dissolved in dichloromethane (4 ml), and 2M boron tribromide solution (0.63 ml, 1.26 mmol) was added, and the reaction was allowed to react overnight at room temperature. After LCMS monitoring showed that the starting material disappeared, the reaction solution was poured into an aqueous sodium bicarbonate solution (20 ml), extracted with ethyl acetate (30 ml × 2), and the organic phases were combined. The organic phases were first washed with saturated brine (10 ml), then dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The crude product was prepared and purified to obtain 2-amino-1-(3-fluoro-5-hydroxy-2,6-dimethylphenyl)-7-methyl-1,7-dihydropyrrolo[2,3-e]indazole-3-carboxamide (12 mg). MS (ESI) M / Z: 368.3 [M+H]+ . 1 H NMR (400 MHz, DMSO-d 6 )δ10.10(s,1H),7.77(d,J=9.1Hz,1H),7.27(d,J=9.0Hz,1H),6.89(d,J=10.8Hz,2 H),6.69(s,2H),6.33(s,2H),4.00(s,3H),3.28(s,3H),1.66(s,3H),1.63(s,3H).

[0183] Example 5

[0184] Reaction route:

[0185]

[0186] 5-2: 4-bromo-2,6-dimethylaniline (5 g, 0.025 mol) was dissolved in acetic acid (170 ml), sodium nitrite (1.9 g, 0.0275 mol) was dissolved in water (17 ml) and added to the reaction solution, and the reaction solution was stirred at room temperature overnight. After LCMS monitoring showed that the raw material disappeared, water (500 ml) was added and filtered to obtain the product 5-bromo-7-methylindazole (3.5 g). MS (ESI) M / Z: 211.17 [M+H] + .

[0187] 5-3: Dissolve 5-bromo-7-methylindazole (5 g, 0.024 mol) in concentrated sulfuric acid (100 ml) and cool to 0 degrees Celsius. Add nitric acid (5 ml) dropwise and react at 0 degrees Celsius for 1 hour. After LCMS monitoring shows that the starting material disappears, the reaction solution is added to ice water, filtered, and dried to obtain the product 5-bromo-7-methyl-4-nitroindazole (5.9 g). MS (ESI) M / Z: 256.09 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.29(s,1H),7.64(s,1H),2.63(s,3H).C 8 H 6 Bn 3 O 2 .

[0188] 5-4: 5-bromo-7-methyl-4-nitroindazole (5.9 g, 23.05 mmol) was dissolved in N,N-dimethylformamide (120 ml), potassium carbonate (6.4 g, 0.046 mol) and iodomethane (3.9 g, 0.028 mol) were added, and the reaction solution was stirred at room temperature overnight. After LCMS monitoring showed that the starting material disappeared, it was cooled, water (400 ml) was added, and it was extracted with ethyl acetate (100 ml) twice, and the organic phases were combined, washed with saturated brine (40 ml), and then dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the product 5-bromo-1,7-dimethyl-4-nitroindazole (5.9 g) MS (ESI) M / Z: 270.1 [M+H] + .

[0189] 5-5&5-6: 5-bromo-1,7-dimethyl-4-nitroindazole (5.9 g, 21.85 mmol) was dissolved in ethanol (120 ml), iron powder (7.2 g, 0.13 mmol) and ammonium chloride (7.1 g, 0.13 mmol) dissolved in water (60 ml) were added to the reaction solution, and the reaction solution was stirred at 80 degrees Celsius for 2 hours. After LCMS monitoring showed that the raw material disappeared, it was cooled, water (200 ml) was added, and it was extracted with ethyl acetate (100 ml) twice, and the organic phases were combined, washed with saturated brine (40 ml), and then dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 5-bromo-1,7-dimethyl-1H-indole-4-amine (1.2 g) and 5-bromo-2,7-dimethyl-2H-indazole-4-amine (1.9 g). MS (ESI) M / Z: 242.01 [M+H] + . 1 HNMR (400MHz, CDCl 3 )δ7.83(s,1H),7.07(s,1H),4.26(s,3H),2.62(s,3H).C 9 H 10 Bn 3 .

[0190] 5-7: Dissolve 5-bromo-1,7-dimethyl-1H-indole-4-amine (500 mg, 2.1 mmol) in concentrated hydrochloric acid (2.4 ml) and water (0.6 ml), cool to -15 degrees Celsius, add sodium nitrite (158 mg, 2.3 mmol) in water (2.8 ml) dropwise over 20 minutes, and stir at 0 degrees Celsius for 30 minutes. Add the solution dropwise to a solution of potassium iodide (3.1 g, 18.7 mmol) in water (28 ml), and react at room temperature overnight. After LCMS monitoring shows that the starting material disappears, the reaction solution is diluted with aqueous solution (50 ml), sodium hydroxide is added to adjust the pH to alkaline, and extracted twice with ethyl acetate. The organic phases are combined, the organic phases are first washed with saturated brine (50 ml), then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product is purified by column chromatography to obtain 5-bromo-4-iodo-1,7-dimethyl-1H-indazole (560 mg). MS (ESI) M / Z: 353.13 [M+H] + . 1 H NMR (400 MHz, CDCl 3 )δ7.73(s,1H),7.24(s,1H),4.25(s,3H),2.65(s,3H).C 9 H 8 BrN 2 .

[0191] 5-8: 4-Bromo-4-iodo-1,7-dimethyl-1H-indazole (560 mg, 1.6 mmol), 3-methoxy-2,6-dimethylaniline (241 mg, 1.6 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (92.2 mg, 0.16 mmol), tris(dibenzylideneacetone)dipalladium (73.1 mg, 0.08 mmol) and cesium carbonate (1.3 g, 3.99 mmol) were added to toluene (20 ml), replaced with nitrogen three times, and the reaction solution was stirred at 98 degrees Celsius overnight. After LCMS monitoring showed that the raw material disappeared, it was cooled, water (100 ml) was added, and it was extracted with ethyl acetate (100 ml) twice, and the organic phases were combined, and the organic phase was first washed with saturated brine (40 ml), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by column chromatography to give 5-bromo-N-(3-methoxy-2,6-dimethylphenyl)-1,7-dimethyl-1H-indol-4-amine (420 mg). MS (ESI) M / Z: 376.33 [M+H] + .

[0192] 5-9: Dissolve malononitrile (190.6 mg, 0.72 mmol) in N,N-dimethylformamide (6 ml), add sodium tert-butoxide (416 mg, 4.33 mmol), replace with nitrogen, and react at room temperature for 30 minutes. Then add 5-bromo-N-(3-methoxy-2,6-dimethylphenyl)-1,7-dimethyl-1H-indol-4-amine (270 mg, 0.72 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (58.8 mg, 0.072 mmol), replace with nitrogen, and stir the reaction solution at 140 degrees Celsius for 3 hours. After LCMS monitoring showed that the raw material disappeared, the mixture was cooled, water (30 ml) was added, and the mixture was extracted twice with ethyl acetate (30 ml). The organic phases were combined, washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to give 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-1,6-dihydropyrrolo[2,3-e]indazole-3-carbonitrile (160 mg). MS (ESI) M / Z: 360.48 [M+H] + .

[0193] 5-10: 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-1,6-dihydropyrrolo[2,3-e]indazole-3-carbonitrile (160 mg, 0.45 mmol) was dissolved in sulfuric acid (3.2 ml) and reacted at room temperature for 1 hour. After LCMS monitoring showed that the starting material disappeared, the mixture was cooled, the pH value was adjusted to neutral with aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate (40 ml × 2). The organic phase was dried and concentrated to obtain the crude product of 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-1,6-dihydropyrrolo[2,3-e]indazole-3-carboxamide, which was directly used in the next step. MS (ESI) M / Z: 378.0 [M+H] + .

[0194] 5: The crude product of 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-1,6-dihydropyrrolo[2,3-e]indazole-3-carboxamide from the previous step was dissolved in dichloromethane (2.5 ml), and a 2M dichloromethane solution of boron tribromide (0.8 ml, 1.6 mmol) was added, and the mixture was reacted overnight at room temperature. After LCMS monitoring showed that the starting material disappeared, the reaction solution was poured into an aqueous sodium bicarbonate solution (40 ml), and extracted twice with ethyl acetate (40 ml), and the organic phases were combined, washed with saturated brine (10 ml), and then dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The crude product was prepared and purified to obtain 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1,6-dihydropyrrolo[2,3-e]indazole-3-carboxamide (22.24 mg). MS (ESI) M / Z: 364.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.62(s,1H),7.59(s,1H),7.16(d,J=8.3Hz,1H),7.01(d,J=8.2Hz,1H),6. 68(s,2H),6.38(s,3H),4.21(s,3H),2.79(s,3H),1.74(s,3H),1.64(s,3H).

[0195] Example 6

[0196] Reaction route:

[0197]

[0198] 6-1: Dissolve 5-bromo-2,7-dimethyl-2H-indole-4-amine (1 g, 4.17 mmol) in concentrated hydrochloric acid (4.8 ml) and water (1.2 ml), cool to -15 degrees Celsius, add sodium nitrite (316 mg, 4.58 mmol) in water (5.6 ml) dropwise over 20 minutes, and stir at 0 degrees Celsius for 30 minutes. Add the solution dropwise to a solution of potassium iodide (6.3 g, 37.5 mmol) in water (56 ml), and react at room temperature overnight. After LCMS monitoring shows that the starting material disappears, the reaction solution is diluted with an aqueous solution (50 ml), and sodium hydroxide is added to adjust the pH to alkaline, and extracted twice with ethyl acetate, the organic phases are combined, the organic phases are first washed with saturated brine (50 ml), then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product is purified by column chromatography to obtain 5-bromo-4-iodo-2,7-dimethyl-2H-indazole (760 mg). MS (ESI) M / Z: 351.09 [M+H] + . 1 H NMR (400 MHz, CDCl 3)δ7.76(s,1H),7.25(s,1H),4.20(s,3H),2.53(s,3H).C 9 H 8 BrN 2 .

[0199] 6-2: 4-Bromo-4-iodo-2,7-dimethyl-1H-indazole (760 mg, 2.17 mmol), 3-methoxy-2,6-dimethylaniline (327 mg, 2.17 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (125 mg, 0.22 mmol), tris(dibenzylideneacetone)dipalladium (99.2 mg, 0.11 mmol) and cesium carbonate (1.76 g, 5.41 mmol) were added to toluene (30 ml), replaced with nitrogen three times, and the reaction solution was stirred at 98 degrees Celsius overnight. After LCMS monitoring showed that the raw material disappeared, it was cooled, water (100 ml) was added, and it was extracted with ethyl acetate (100 ml) twice, and the organic phases were combined, and the organic phase was first washed with saturated brine (40 ml), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by column chromatography to give 5-bromo-N-(3-methoxy-2,6-dimethylphenyl)-2,7-dimethyl-2H-indol-4-amine (350 mg). MS (ESI) M / Z: 374.35 [M+H] + .

[0200] 6-3: Dissolve malononitrile (211.8 mg, 0.8 mmol) in N,N-dimethylformamide (6 ml), add sodium tert-butoxide (462 mg, 4.81 mmol), replace with nitrogen, and react at room temperature for 30 minutes. Then add 5-bromo-N-(3-methoxy-2,6-dimethylphenyl)-2,7-dimethyl-2H-indol-4-amine (300 mg, 0.8 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (65.4 mg, 0.08 mmol), replace with nitrogen, and stir the reaction solution at 140 degrees Celsius for 3 hours. After LCMS monitoring showed that the raw material disappeared, the mixture was cooled, water (120 ml) was added, and the mixture was extracted twice with ethyl acetate (100 ml). The organic phases were combined, washed with saturated brine (40 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to give 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-5,7-dimethyl-1,7-dihydropyrrolo[2,3-e]indazole-3-carbonitrile (40 mg). MS (ESI) M / Z: 360.41 [M+H] + .

[0201] 6-4: 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-5,7-dimethyl-1,7-dihydropyrrolo[2,3-e]indazole-3-carbonitrile (40 mg, 0.11 mmol) was dissolved in sulfuric acid (0.8 ml) and reacted at room temperature for 1 hour. After LCMS monitoring showed that the starting material disappeared, the mixture was cooled, the pH value was adjusted to neutral with aqueous sodium hydroxide solution, extracted with ethyl acetate (40 ml × 2), the organic phase was dried and concentrated to obtain the crude product of 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-5,7-dimethyl-1,7-dihydropyrrolo[2,3-e]indazole-3-carboxamide, which was directly used in the next step. MS (ESI) M / Z: 378.23 [M+H] + .

[0202] 6: The crude product of 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-5,7-dimethyl-1,7-dihydropyrrolo[2,3-e]indazole-3-carboxamide from the previous step was dissolved in dichloromethane (2 ml), and a 2M dichloromethane solution of boron tribromide (0.3 ml, 0.66 mmol) was added, and the mixture was reacted overnight at room temperature. After LCMS monitoring showed that the starting material disappeared, the reaction solution was poured into an aqueous sodium bicarbonate solution (50 ml), and extracted twice with ethyl acetate (100 ml), and the organic phases were combined, washed with saturated brine (10 ml), and then dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The crude product was prepared and purified to obtain 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,7-dimethyl-1,7-dihydropyrrolo[2,3-e]indazole-3-carboxamide (11.73 mg). MS (ESI) M / Z: 364.41 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.58(s,1H),7.56(s,1H),7.14(d,J=8.3Hz,1H),7.00(d,J=8.2Hz,1H),6 .66(d,J=14.5Hz,3H),6.17(s,2H),3.98(s,3H),1.75(s,3H),1.66(s,3H).

[0203] Example 7

[0204] Reaction route:

[0205]

[0206] 7-2: In a single-mouth bottle, 4-bromo-2-methyl-6-nitrophenol (5 g, 21.6 mmol) was dissolved in methanol (40 ml), and iron powder (10 g, 179 mmol) and ammonium chloride (10 g, 189 mmol) in water (10 ml) were added. The reaction system was stirred at 45°C for 6.3 hours. LCMS detected that the raw material disappeared and the product was generated. The reaction solution was filtered with a sand core funnel and the filtrate was collected. Extracted with ethyl acetate (50 ml × 3), the organic phases were combined, washed with saturated brine (50 ml × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 2-amino-4-bromo-6-methylphenol (3 g). MS (ESI) M / Z: 201.9 [M+H] + .

[0207] 7-3: In a single-mouth bottle, 2-amino-4-bromo-6-methylphenol (5 g, 24.9 mmol) was dissolved in trimethyl orthoacetate (5.2 ml), and p-toluenesulfonic acid (0.3 g, 1.74 mmol) was added. After the addition was completed, the reaction solution was reacted at 85 degrees Celsius for 5 hours. LCMS detected that the raw material disappeared and the product was generated, and the reaction solution was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to obtain 5-bromo-2,7-dimethylbenzo[d]oxazole (4.4 g). MS (ESI) M / Z: 226.0 [M+H] + .

[0208] 7-4: In a single-mouth bottle, 5-bromo-2,7-dimethylbenzo[d]oxazole (4 g, 17.8 mmol) was dissolved in concentrated sulfuric acid (27 ml), and a solution of concentrated nitric acid (3 ml) in concentrated sulfuric acid (3 ml) was added dropwise at 0 degrees Celsius, and then the reaction system was heated to room temperature and stirred for 1 hour. LCMS detected that the starting material disappeared and the product was generated. Ice water was added to the reaction solution to quench, and sodium bicarbonate aqueous solution was added to adjust the pH value to neutral. The mixed solution was extracted with ethyl acetate (15 ml × 3), and the organic phases were combined, washed with saturated brine (10 ml × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 5-bromo-2,7-dimethyl-4-nitrobenzo[d]oxazole (3.4 g). MS (ESI) M / Z: 271.1 [M+H] +

[0209] 7-5: Dissolve 5-bromo-2,7-dimethyl-4-nitrobenzo[d]oxazole (3 g, 11.1 mmol) in methanol (20 ml), add zinc powder (8 g, 123 mmol) and ammonium chloride (8 g, 151 mmol) in water (5 ml), and stir the reaction system at 45 degrees Celsius for 6 hours. LCMS detected that the raw material disappeared and the product was generated. The reaction solution was filtered and the filtrate was collected. Extract with ethyl acetate (50 ml × 3), combine the organic phases, wash the organic phases with saturated brine (50 ml × 3), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The resulting mixture was purified by silica gel column chromatography and further purified by reverse chromatographic column to obtain 5-bromo-2,7-dimethylbenzo[d]oxazole-4-amine (1.5 g) 1 H NMR (400 MHz, DMSO-d 6 )δ7.13(s,1H),5.36(br,s,2H),2.58(s,3H),2.29(s,3H).

[0210] 7-6: In a 20 ml sealed tube, 5-bromo-2,7-dimethylbenzo[d]oxazol-4-amine (200 mg, 0.83 mmol) was dissolved in acetonitrile (2 ml), tert-butyl nitrite (128 mg, 1.24 mmol) and diiodomethane (400 mg, 1.49 mmol) were added under nitrogen flow, the reaction tube was sealed, stirred for 30 minutes, the oil bath was raised to 65 degrees Celsius and stirred for 2 hours. LCMS detected the formation of the product, the reaction solution was extracted with ethyl acetate (10 ml × 3), the organic phases were combined, washed with saturated brine (5 ml × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to give 5-bromo-4-iodo-2,7-dimethylbenzo[d]oxazole (100 mg) MS (ESI) M / Z: 352.0 [M+H] + .

[0211] 7-7: In a sealed tube, 5-bromo-4-iodo-2,7-dimethylbenzo[d]oxazole (550 mg, 1.6 mmol) was dissolved in 1,4-dioxane (4 ml), and 3-((4-methoxybenzyl)oxy)-2,6-dimethylaniline (485 mg, 1.9 mmol), cesium carbonate (1 g, 3.2 mmol), Pd 2 dba 3(183 mg, 0.2 mmol), XantPhos (174 mg, 0.3 mmol) replaced the reaction system with a nitrogen system, sealed the container, and stirred the reaction system at 100 degrees Celsius overnight. LCMS detected that the raw material disappeared and the product was generated. The reaction solution was poured into ice water and extracted with ethyl acetate (30 ml × 3). The organic phases were combined, washed with saturated brine (10 ml × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to obtain 5-bromo-N-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-2,7-dimethylbenzo[d]oxazol-4-amine (250 mg). MS (ESI) M / Z: 481.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ7.36(d,J=8.6Hz,2H),7.25(s,1H),6.93(d,J=8.6Hz,3H),6.86–6.79(m,2H),5. 08–4.94(m,2H),3.75(s,3H),2.38(s,3H),2.32(s,3H),1.98(s,3H),1.95(s,3H).

[0212] 7-8: Sodium hydride (27 mg, 0.68 mmol) was added to a 10 ml sealed tube, and ethylene glycol dimethyl ether (0.5 ml) was added under nitrogen flow, and then the container was sealed. A solution of propylene glycol dimethyl ether (0.5 ml) (38 mg, 0.57 mmol) was added to the sealed tube at 0 degrees Celsius. Stir at room temperature for 30 minutes. Subsequently, a solution of 5-bromo-N-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-2,7-dimethylbenzo[d]oxazol-4-amine (55 mg, 0.11 mmol) in ethylene glycol dimethyl ether (0.5 ml) and 1,1-bis(diphenylphosphino)diferropalladium dichloride (8.3 mg, 0.011 mmol) were added to the sealed tube under nitrogen flow. The reaction tube was sealed, heated to 120 degrees in an oil bath, and stirred overnight. LCMS detected the formation of product. The reaction solution was poured into ice water and extracted with ethyl acetate (30 ml × 3). The organic phases were combined, washed with saturated brine (10 ml × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by thin layer silica gel plate to give 7-amino-8-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-2,4-dimethyl-8H-oxazolo[5,4-g]indole-6-carbonitrile (34 mg) MS (ESI) M / Z: 467.6 [M+H] + . 1H NMR (400MHz, DMSO) δ7.42(d,J=8.6Hz,2H),7.26–7.21(m,1H),7.21–7.13(m,1H),7.05(s,1H),6.97(d,J=8 .6Hz,2H),6.43(s,2H),5.08(dd,J=33.4,11.4Hz,2H),3.76(s,3H),2.43(s,3H),1.81(s,3H),1.73(s,3H).

[0213] 7: 7-amino-8-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-2,4-dimethyl-8H-oxazolo[5,4-g]indole-6-carbonitrile (34 mg, 0.07 mmol) was dissolved in concentrated sulfuric acid (1 ml) at room temperature. The reaction solution was stirred at room temperature for 1 hour. After LCMS monitoring showed that the starting material disappeared, crushed ice was added to the reaction solution to quench, and then the pH value was adjusted to 9 with sodium bicarbonate solution. The mixed solution was extracted with ethyl acetate (20 ml × 3), and the organic phases were combined. The organic phases were first washed with saturated brine (20 ml × 3), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to obtain the final product 7-amino-8-(3-hydroxy-2,6-dimethylphenyl)-2,4-dimethyl-8H-oxazolo[5,4-g]indole-6-carboxamide (5.35 mg). MS (ESI) M / Z: 365.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 9.43 (s, 1H), 7.51 (s, 1H), 7.05 (d, J = 8.3 Hz, 1H), 6.90 (d, J = 8.2 Hz, 1H), 6.69 (s, 2H), 6.39 (s, 2H), 3.30 (s, 3H), 2.42 (s, 3H), 1.75 (s, 3H), 1.66 (s, 3H). Example 8

[0214] Reaction route:

[0215]

[0216] 8-2: 5-bromo-4-iodo-1-methyl-1H-indazole (1.4 g, 4.2 mmol), 3-methoxy-2,6-dimethylaniline (0.63 g, 4.2 mmol), xantPhos (241 mg, 0.42 mmol), tris(dibenzylideneacetone)dipalladium (379 mg, 0.42 mmol) and cesium carbonate (3.3 g, 10.5 mmol) were added to toluene (30 ml), replaced with nitrogen three times, and the reaction solution was stirred at 100 degrees Celsius for 3 hours. After LCMS monitoring showed that the raw material disappeared, it was cooled, water (50 ml) was added, and it was extracted with ethyl acetate (100 ml) twice, and the organic phases were combined, and the organic phase was first washed with saturated brine (20 ml), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by column chromatography to give 5-bromo-N-(3-methoxy-2,6-dimethylphenyl)-1-methyl-1H-indazol-4-amine (1.08 g). MS (ESI) M / Z: 360.07 [M+H] + .

[0217] 8-3: Dissolve malononitrile (792 mg, 12 mmol) in N,N-dimethylformamide (30 ml), add sodium tert-butoxide (1.73 g, 18 mmol), replace with nitrogen, and react at room temperature for 30 minutes. Then add 5-bromo-N-(3-methoxy-2,6-dimethylphenyl)-1-methyl-1H-indazol-4-amine (1.08 g, 3 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (245 mg, 0.3 mmol), replace with nitrogen, and stir the reaction solution at 140 degrees Celsius for 3 hours. After LCMS monitoring showed that the raw material disappeared, the mixture was cooled, water (120 ml) was added, and the mixture was extracted twice with ethyl acetate (100 ml). The organic phases were combined, washed with saturated brine (40 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to give 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-6-methyl-1,6-dihydropyrrolo[2,3-e]indazole-3-carbonitrile (300 mg). MS (ESI) M / Z: 346.39 [M+H] + .

[0218] 8-4: 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-6-methyl-1,6-dihydropyrrolo[2,3-e]indazole-3-carbonitrile (300 mg, 0.87 mmol) was dissolved in sulfuric acid (8 ml) and reacted at room temperature for 1 hour. After LCMS monitoring showed that the starting material disappeared, the mixture was cooled, the pH value was adjusted to neutral with aqueous sodium hydroxide solution, extracted with ethyl acetate (40 ml × 2), the organic phase was dried and concentrated to obtain the crude product of 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-6-methyl-1,6-dihydropyrrolo[2,3-e]indazole-3-carboxamide, which was directly used in the next step. MS (ESI) M / Z: 364.41 [M+H] + .

[0219] 8: The crude 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-6-methyl-1,6-dihydropyrrolo[2,3-e]indazole-3-carboxamide from the previous step was dissolved in dichloromethane (15 ml), and a 2M dichloromethane solution of boron tribromide (3.3 ml, 6.6 mmol) was added, and the mixture was reacted overnight at room temperature. After LCMS monitoring showed that the starting material disappeared, the reaction solution was poured into an aqueous sodium bicarbonate solution (50 ml), and extracted twice with ethyl acetate (100 ml), and the organic phases were combined, washed with saturated brine (10 ml), and then dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The crude product was prepared and purified to obtain R-2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-6-methyl-1,6-dihydropyrrolo[2,3-e]indazole-3-carboxamide (72.61 mg). MS (ESI) M / Z: 350.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.63(s,1H),7.87(d,J=8.7Hz,1H),7.27(d,J=8.8Hz,1H),7.17(d,J=8.2Hz,1H),7.03(d ,J=8.2Hz,1H),6.72(s,2H),6.45(d,J=8.9Hz,3H),3.98(s,3H),1.75(s,3H),1.66(s,3H).C 19 H 19 N 5 O 2 The above compound was separated by SFC to obtain 8, 20.27 mg:

[0220] SFC conditions were as follows: instrument: SFC-150 mg / m (water), chiral column: Daicel OD (25*250 mm, 10 μm), temperature: 30 °C, mobile phase: CO 2 / EtOH [0.5% NH 3(7M MeOH)] = 65 / 35, flow rate: 100 ml / min, back pressure: 100 bar, detection wavelength: 214 nm, cycle time: 8 min. SFC Rt = 1.347 min, [a] D 20 =+43.3°(c=0.08900,MeOH), 1 H NMR (400MHz, DMSO) δ9.64(s,1H),7.87(d,J=8.8Hz,1H),7.26(d,J=8.8Hz,1H),7.17(d,J=8.4Hz,1H),7.03(d,J=8.4Hz ,1H),6.72(s,2H),6.46(d,J=0.6Hz,1H),6.44(s,2H),3.98(s,3H),1.75(s,3H),1.66(s,3H).MS(ESI)M / Z:350.4[M+H] + .

[0221] Example 9

[0222] Reaction route:

[0223]

[0224] 9-2: In a single-mouth bottle, 5-bromo-2-methylbenzo[d]thiazole (4 g, 17.54 mmol) was dissolved in concentrated sulfuric acid (10 ml) at 0 degrees Celsius, and concentrated nitric acid (5 ml) was added dropwise, and then the reaction system was heated to room temperature and stirred for 1 hour. LCMS detected that the raw material disappeared and the product was generated. Ice water was added to the reaction solution to quench, and sodium bicarbonate aqueous solution was added to adjust the pH value to neutral. The mixed solution was extracted with ethyl acetate (200 ml × 3), and the organic phases were combined. The organic phases were washed with saturated brine (100 ml × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to obtain 5-bromo-2-methyl-4-nitrobenzo[d]thiazole (4.57 g). MS (ESI) M / Z: 275.0 [M+H] + .

[0225] 9-3: In a single-mouth bottle, 5-bromo-2-methyl-4-nitrobenz[d]thiazole (4.57 g, 16.73 mmol) was dissolved in methanol (50 ml) and N,N-dimethylformamide (50 ml), and zinc powder (10.94 g, 167.3 mmol) and a saturated aqueous solution of ammonium chloride (50 ml) were added. The reaction system was stirred overnight at room temperature. LCMS detected that the starting material disappeared and the product was generated. Ice water was added to the reaction solution to quench it, and the filtrate was collected by suction. It was extracted with ethyl acetate (200 ml × 3), and the organic phases were combined, washed with saturated brine (50 ml × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 5-bromo-2-methyl-4-nitrobenz[d]thiazole (1.57 g). MS (ESI) M / Z: 243.2 [M+H] + . 1 H NMR (400MHz, DMSO) δ7.35 (d, J = 8.5 Hz, 1H), 7.13 (d, J = 8.5 Hz, 1H), 5.62 (s, 2H), 2.78 (s, 3H).

[0226] 9-4: In a single-mouth bottle, 5-bromo-2-methyl-4-nitrobenz[d]thiazole (1.57 g, 6.46 mmol) was dissolved in DMF (15 ml), N-iodosuccinimide (1.598 g, 7.1 mmol) was added at 0 degrees Celsius, and then the reaction system was heated to room temperature and stirred overnight. LCMS detected that the raw material disappeared and the product was generated. Ice water was added to the reaction solution to quench, and it was extracted with ethyl acetate (100 ml × 3). The organic phases were combined, washed with saturated brine (50 ml × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to obtain 5-bromo-7-iodo-2-methylbenzo[d]thiazole-4-amine (2.0 g). MS (ESI) M / Z: 371.1 [M+H] + . 1 H NMR (400MHz, DMSO) δ7.64(s,1H),5.81(s,2H),2.77(s,3H).

[0227] 9-5: 5-Bromo-7-iodo-2-methylbenzo[d]thiazol-4-amine (2.0 g, 5.42 mmol) was dissolved in 1,4-dioxane (20 ml), and 2,4,6-trimethyl-1,3,5,2,4,6-trimethoxytriborane (6.1 ml, 10.84 mmol) and PdCl were added. 2(dppf) (390 mg, 0.542 mmol) and cesium carbonate (3.523 g, 10.84 mol), the replacement reaction system is a nitrogen system, and stirred at 85 degrees Celsius for 12 hours. LCMS detected that the raw material disappeared and the product was generated. Pure water was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (100 ml × 3). The organic phases were combined, washed with saturated brine (50 ml × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to obtain 5-bromo-2,7-dimethylbenzo[d]thiazole-4-amine (1.1 g). MS (ESI) M / Z: 259.1 [M+H] + .

[0228] 9-6: In a single-mouth bottle, 5-bromo-2,7-dimethylbenzo[d]thiazol-4-amine (1.0 g, 3.89 mmol) was dissolved in acetonitrile (10 ml), and tert-butyl nitrite (601 mg, 5.84 mmol) and diiodomethane (2.085 g, 7.78 mmol) were added under nitrogen flow. After stirring for 30 minutes, the oil bath was raised to 65 degrees Celsius and stirred for 2 hours. LCMS detected the formation of the product, and water was added to the reaction solution to quench it. The reaction solution was extracted with ethyl acetate (100 ml × 3), and the organic phases were combined, washed with saturated brine (50 ml × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to obtain 5-bromo-4-iodo-2,7-dimethylbenzo[d]thiazole (590 mg). MS (ESI) M / Z: 370.1 [M+H] + .

[0229] 9-7: In a sealed tube, 5-bromo-4-iodo-2,7-dimethylbenzo[d]thiazole (490 mg, 1.33 mmol) was dissolved in ethylene glycol dimethyl ether (8 ml), and 3-((4-methoxybenzyl)oxy)-2,6-dimethylaniline (360 mg, 1.398 mmol), cesium carbonate (1.083 g, 3.325 mmol), Pd 2 dba 3(121.8 mg, 0.133 mmol), XantPhos (154 mg, 0.266 mmol) replaced the reaction system with a nitrogen system, sealed the container, and stirred the reaction system at 100 degrees Celsius overnight. LCMS detected that the raw material disappeared and the product was generated. The reaction solution was poured into ice water and extracted with ethyl acetate (100 ml × 3). The organic phases were combined, washed with saturated brine (50 ml × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to obtain 5-bromo-N-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-2,7-dimethylbenzo[d]thiazole-4-amine (260 mg). MS (ESI) M / Z: 497.3 [M+H] + .

[0230] 9-8: Sodium hydride (84.5 mg, 0.2.112 mmol) was added to a 10 ml sealed tube, and ethylene glycol dimethyl ether (1 ml) was added under nitrogen flow, and then the container was sealed. A solution of propylene glycol cyanide (139.4 mg, 0.2.112 mmol) in ethylene glycol dimethyl ether (1 ml) was added to the sealed tube at 0 degrees Celsius. Stir at room temperature for 30 minutes. Subsequently, a solution of 5-bromo-N-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-2,7-dimethylbenzo[d]thiazol-4-amine (210 mg, 0.422 mmol) in ethylene glycol dimethyl ether (3 ml) and 1,1-bis(diphenylphosphino)diferropalladium dichloride (154.4 mg, 0.2112 mmol) were added to the sealed tube under nitrogen flow. The reaction tube was sealed, heated to 120 degrees in an oil bath, and stirred overnight. LCMS detected the formation of product. The reaction solution was poured into ice water and extracted with ethyl acetate (100 ml × 3). The organic phases were combined, washed with saturated brine (30 ml × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by thin layer silica gel plate to obtain 7-amino-8-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-2,4-dimethyl-8H-thiazolo[5,4-g]indole-6-carbonitrile (160 mg). MS (ESI) M / Z: 483.4 [M+H] + .

[0231] 9: 7-amino-8-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-2,4-dimethyl-8H-thiazolo[5,4-g]indole-6-carbonitrile (160 mg, 0.332 mmol) was dissolved in concentrated sulfuric acid (2 ml) at room temperature. The reaction solution was stirred at room temperature for 1 hour. After LCMS monitoring showed that the starting material disappeared, crushed ice was added to the reaction solution to quench, and then the pH value was adjusted to 8 with sodium bicarbonate solution. The mixed solution was extracted with ethyl acetate (50 ml × 3), and the organic phases were combined. The organic phases were first washed with saturated brine (20 ml × 3), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to obtain the final product 7-amino-8-(3-hydroxy-2,6-dimethylphenyl)-2,4-dimethyl-8H-thiazolo[5,4-g]indole-6-carboxamide (45.24 mg). MS (ESI) M / Z: 381.3 [M+H] + . 1 H NMR (400MHz, DMSO) δ9.37(s,1H),7.67(s,1H),7.03(d,J=8.3Hz,1H),6.89(d,J=8.2H z,1H),6.75(s,2H),6.42(s,2H),2.52(s,3H),2.50(s,3H),1.73(s,3H),1.64(s,3H).

[0232] Example 10

[0233] Reaction route:

[0234]

[0235] 10-2: Dissolve 4-bromo-3-nitro-1,2-phenylenediamine (2 g, 8.6 mmol) in acetic acid (16 ml), add sodium nitrite (584 mg, 9 mol), stir at room temperature for 15 minutes, and heat to 60°C for 2 hours. After LCMS monitoring shows that the starting material disappears, cool, add water (50 ml) and filter to obtain the product 5-bromo-4-nitro-1H-benzo[d][1,2,3]triazole (1.42 g). MS (ESI) M / Z: 241.1 [M+H] + .

[0236] 10-3: 5-bromo-4-nitro-1H-benzo[d][1,2,3]triazole (1.42 g, 5.9 mmol) was dissolved in N,N-dimethylformamide (28 ml), potassium tert-butoxide (0.98 g, 8.7 mmol) was added under ice-water bath, stirred for half an hour, and then iodomethane (1.24 g, 8.7 mmol) was added, and the reaction solution was stirred at room temperature for 2 hours. After TLC monitoring showed that the raw material disappeared, it was cooled, water (100 ml) was added, and it was extracted with ethyl acetate (100 ml) twice, and the organic phases were combined, and the organic phases were first washed with saturated brine (40 ml), then dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The obtained crude product was directly used in the next step.

[0237] 10-4: The crude product of the previous step was dissolved in ethanol (17 ml), iron powder (1.79 g, 32.5 mmol), ammonium chloride (1.75 g, 32.5 mmol) and water (7.5 ml) were added, and the reaction solution was stirred at 80 degrees Celsius for 2 hours. After TLC monitoring showed that the starting material disappeared, it was cooled, and water (100 ml) and ethyl acetate (100 ml) were added for extraction and filtration. The filtrate was separated, and the organic phase was first washed with saturated brine (40 ml), then dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by column chromatography to obtain 5-bromo-1-methyl-1H-benzo[d][1,2,3]triazole-4-amine (450 mg). MS (ESI) M / Z: 226.95 [M+H] + .

[0238] 10-5: 5-Bromo-1-methyl-1H-benzo[d][1,2,3]triazol-4-amine (650 mg, 2.87 mmol) was dissolved in concentrated hydrochloric acid (3.1 ml) and water (0.8 ml), cooled to -15 degrees Celsius, and an aqueous solution (3.6 ml) of sodium nitrite (218 mg, 3.16 mmol) was added dropwise over 20 minutes, and stirred at 0 degrees Celsius for 30 minutes. The reaction solution was added dropwise to a solution of potassium iodide (4.32 g, 25.9 mmol) in water (36 ml), and reacted at room temperature overnight. After LCMS monitoring showed that the starting material disappeared, the reaction solution was diluted with an aqueous solution (50 ml), and sodium hydroxide was added to adjust the pH to alkaline, extracted twice with ethyl acetate, and the organic phases were combined, washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography to give 5-bromo-4-iodo-1-methyl-1H-benzo[d][1,2,3]triazole (520 mg). MS (ESI) M / Z: 338.0 [M+H] + . 1 H NMR (400 MHz, CDCl 3 )δ7.70(d,J=8.6Hz,1H),7.38(d,J=8.6Hz,1H),4.29(s,3H).C7 H 5 BrN 3 .

[0239] 10-6: 5-Bromo-4-iodo-1-methyl-1H-benzo[d][1,2,3]triazole (520 mg, 1.54 mmol), 3-methoxy-2,6-dimethylaniline (233 mg, 1.54 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (89.2 mg, 0.15 mmol), tris(dibenzylideneacetone)dipalladium (141 mg, 0.15 mmol) and cesium carbonate (1.25 g, 3.85 mmol) were added to toluene (10 ml), replaced with nitrogen three times, and the reaction solution was stirred at 100 degrees Celsius overnight. After LCMS monitoring showed that the starting material disappeared, it was cooled, water (50 ml) was added, and it was extracted with ethyl acetate (50 ml) twice, and the organic phases were combined, washed with saturated brine (10 ml), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by column chromatography to give 5-bromo-N-(3-methoxy-2,6-dimethylphenyl)-1-methyl-1H-benzo[d][1,2,3]triazol-4-amine (280 mg). MS (ESI) M / Z: 361.36 [M+H]+.

[0240] 10-7: Malononitrile (154 mg, 2.33 mmol) was dissolved in N,N-dimethylformamide (8 ml), sodium tert-butoxide (336 mg, 3.49 mmol) was added, the atmosphere was replaced with nitrogen, and the reaction was carried out at room temperature for 30 minutes. 5-Bromo-N-(3-methoxy-2,6-dimethylphenyl)-1-methyl-1H-benzo[d][1,2,3]triazol-4-amine (210 mg, 0.58 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (47.5 mg, 0.058 mmol) were added thereto, the atmosphere was replaced with nitrogen, and the reaction solution was stirred at 140 degrees Celsius for 3 hours. After LCMS monitoring showed that the raw material disappeared, the mixture was cooled, water (30 ml) was added, and the mixture was extracted twice with ethyl acetate (30 ml). The organic phases were combined, washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to give 7-amino-8-(3-methoxy-2,6-dimethylphenyl)-3-methyl-3,8-dihydro-[1,2,3]triazolo[4,5-g]indole-6-carbonitrile (120 mg). MS (ESI) M / Z: 347.43 [M+H] + .

[0241] 10-8: 7-amino-8-(3-methoxy-2,6-dimethylphenyl)-3-methyl-3,8-dihydro-[1,2,3]triazolo[4,5-g]indole-6-carbonitrile (120 mg, 0.34 mmol) was dissolved in sulfuric acid (2 ml) and reacted at room temperature for 1 hour. After LCMS monitoring showed that the starting material disappeared, the mixture was cooled, the pH value was adjusted to neutral with aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate (40 ml × 2). The organic phase was dried and concentrated to obtain the crude product of 7-amino-8-(3-methoxy-2,6-dimethylphenyl)-3-methyl-3,8-dihydro-[1,2,3]triazolo[4,5-g]indole-6-carboxamide, which was used directly in the next step. MS (ESI) M / Z: 365.28 [M+H] + .

[0242] 10: The crude product of the previous step was dissolved in dichloromethane (4 ml), and a 2M dichloromethane solution of boron tribromide (0.4 ml, 0.8 mmol) was added, and the reaction was allowed to react overnight at room temperature. After LCMS monitoring showed that the raw material disappeared, the reaction solution was poured into an aqueous sodium bicarbonate solution (20 ml), extracted twice with ethyl acetate (20 ml), and the organic phases were combined. The organic phases were first washed with saturated brine (10 ml), then dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The crude product was prepared and purified to obtain 7-amino-8-(3-hydroxy-2,6-dimethylphenyl)-3-methyl-3,8-dihydro-[1,2,3]triazolo[4,5-g]indole-6-carboxamide (17.51 ​​mg). MS (ESI) M / Z: 351.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.49(s,1H),8.02(d,J=8.7Hz,1H),7.42(d,J=8.8Hz,1H),7.09(d,J=8.3Hz,1H),6.96(d,J=8.2Hz,1H),6.82(s,2H),6.41(s,2H),4.23(s,3H),1.75(s,3H),1.66(s,3H). Example 11

[0243]

[0244] Example 11 (1.37 mg) The synthesis method refers to Example 5.

[0245] MS (ESI) M / Z: 382.3 [M+H] + .

[0246] 1H NMR (400MHz, DMSO-d 6)δ10.16(s,1H),8.75(s,1H),7.61(s,1H),6.90(d,J=11.2Hz,1H),6.71( s,2H),6.49(s,2H),4.22(s,3H),2.79(s,3H),1.65(s,3H),1.62(s,3H).

[0247] Example 12

[0248]

[0249] Example 12 (4.4 mg) The synthesis method refers to Example 5.

[0250] MS (ESI) M / Z: 383.0 [M+H] + . 1H NMR (400MHz, DMSO) δ10.02(s,1H),7.52(s,1H),6.81(d,J=11.0Hz,1H),6.7 1(s,2H),6.55(s,2H),2.50(s,3H),2.44(s,3H),1.66(s,3H),1.62(s,3H).

[0251] Example 13

[0252] Reaction route:

[0253]

[0254] 5-Bromoisoquinolin-8-amine (5.0 g, 22.4 mmol), methylboronic acid (4.0 g, 67.2 mmol), potassium carbonate (9.27 g, 67.2 mmol) were dissolved in dioxane (100 ml) and water (10 ml), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (900 mg, 1.1 mmol) was added. Nitrogen was replaced three times, and the reaction solution was stirred at 100 degrees Celsius overnight. After TLC monitoring showed that the raw material disappeared, water (100 ml) was added, and ethyl acetate (100 ml) was extracted twice, and the organic phases were combined, washed with saturated brine (80 ml), and then dried over anhydrous sodium sulfate. Finally, the residue was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 5-methylisoquinolin-8-amine (3.5 g). MS (ESI) M / Z: 158.7 [M+H] + .

[0255] Dissolve 5-methylisoquinolin-8-amine (3.5 g, 27.2 mmol) in acetonitrile (80 ml) and add N-bromosuccinimide (4.85 g, 27.2 mmol). Stir at room temperature overnight to react. After TLC monitoring shows that the starting material disappears, add water (100 ml) and extract with ethyl acetate (100 ml) twice. Combine the organic phases, wash the organic phase with saturated brine (50 ml), then dry with anhydrous sodium sulfate, and finally concentrate under reduced pressure. The residue is purified by silica gel column chromatography to obtain 7-bromo-5-methylisoquinolin-8-amine (3.2 g). MS (ESI) M / Z: 237.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 )δ9.33(s,1H),8.56(d,J=5.9Hz,1H),7.67(d,J=5.9Hz,1H),7.54(s,1H),4.80(s,2H),2.53(s,3H).C 10 H 9 Bn 2 .

[0256] 7-Bromo-5-methylisoquinolin-8-amine (1.5 g, 6.3 mmol) was dissolved in hydrochloric acid (37%, 7 ml) and water (1.8 ml), cooled to -15 degrees Celsius, and a solution of sodium nitrite (480 mg, 6.9 mmol) in water (8.4 ml) was added dropwise, and the mixture was stirred at 0 degrees Celsius for 30 minutes after the addition. The above reaction solution was slowly added dropwise to a solution of potassium iodide (9.4 g, 56.7 mmol) in water (84 ml), and the mixture was stirred at room temperature overnight. After TLC monitoring showed that the raw material disappeared, the mixture was cooled, quenched by adding a saturated sodium sulfite solution (30 ml) and a saturated sodium bicarbonate solution (30 ml), and extracted with dichloromethane (50 ml * 2), the organic phase was washed with brine, dried over sodium sulfate, and concentrated to obtain a crude product, and the residue was finally concentrated under reduced pressure and purified by silica gel column chromatography to obtain product A (1.1 g). 1 HNMR (400MHz, CDCl 3 )δ9.55(s,1H),8.65(d,J=5.8Hz,1H),7.68(d,J=5.9Hz,1H),7.62(s,1H),2.65(s,3H).

[0257] The above product A (1.1 g, 4.26 mmol), 3-methoxy-2,6-dimethylaniline (600 mg, 4.26 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (240 mg, 0.43 mmol), cesium carbonate (3.4 g, 10.6 mmol) were dissolved in toluene (22 ml), and tris(dibenzylideneacetone)dipalladium (180 mg, 0.2 mmol) was added. The reaction liquid was replaced with nitrogen three times and reacted at 100 degrees Celsius overnight. After TLC monitoring showed that the raw material disappeared, it was cooled, water (50 ml) was added, and ethyl acetate (20 ml*2) was extracted, the organic phase was washed with brine, dried with sodium sulfate, and concentrated to dryness to obtain a crude product. Finally, the residue obtained by decompression concentration was purified by silica gel column chromatography to obtain 1.3 g of crude product B, MS (ESI) M / Z: 327.39 [M+H] + .

[0258] Subsequently, malononitrile (728.83 mg, 11.04 mmol) was dissolved in N,N-dimethylformamide (15 ml), sodium tert-butoxide (1.59 g, 16.56 mmol) was added, nitrogen was replaced, and the reaction was carried out at room temperature for 30 minutes. The above crude product B (900 mg, 2.76 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (225 mg, 0.28 mmol) were added, nitrogen was replaced, and the reaction was carried out at 130°C for 3 hours. After LCMS monitoring showed that the raw material disappeared, water (30 ml) was added, and ethyl acetate (20 ml) was extracted twice, and the organic phases were combined, washed with saturated brine (30 ml), and then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-5-methyl-1H-pyrrolo[3,2-h]isoquinoline-3-carbonitrile (420 mg). MS (ESI) M / Z: 357.39 [M+H] + .

[0259] 2-Amino-1-(3-methoxy-2,6-dimethylphenyl)-5-methyl-1H-pyrrolo[3,2-h]isoquinoline-3-carbonitrile (420 mg, 1.18 mmol) was dissolved in sulfuric acid (5 ml) and reacted at room temperature for 1 hour. After TLC monitoring showed that the starting material disappeared, the mixture was cooled, the pH value was adjusted to neutral with aqueous sodium hydroxide solution, and extracted with ethyl acetate (30 ml*2). The organic phase was dried and concentrated to dryness to obtain a crude product, and finally concentrated under reduced pressure to obtain 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-5-methyl-1H-pyrrolo[3,2-h]isoquinoline-3-carboxamide (500 mg)

[0260] 2-Amino-1-(3-methoxy-2,6-dimethylphenyl)-5-methyl-1H-pyrrolo[3,2-h]isoquinoline-3-carboxamide (500 mg, 1.37 mmol) was dissolved in dichloromethane (20 ml), and then a 2M dichloromethane solution of boron tribromide (4 ml, 8.0 mmol) was added and stirred at room temperature overnight. After LCMS monitoring showed that the starting material disappeared, an aqueous sodium bicarbonate solution (50 ml) was slowly added, extracted with ethyl acetate, washed with saturated brine, dried with sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-5-methyl-1H-pyrrolo[3,2-h]isoquinoline-3-carboxamide (3.36+52.84 mg). MS (ESI) M / Z: 361.44 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.79(s,1H),8.26–8.16(m,2H),8.15(s,1H),7.76(d,J=5.9Hz,1H),7.23(d,J=8.3Hz,1H ),7.07(d,J=8.2Hz,1H),6.93(s,2H),6.53(s,2H),2.67(s,3H),1.77(s,3H),1.68(s,3H).

[0261]

[0262]

[0263]

[0264]

[0265] Biological activity test method:

[0266] Experimental Example 1. Enzyme Inhibitory Activity of the Disclosed Compounds

[0267] The enzymatic activity of some of the compounds in the examples was verified using the ADP-GLO method.

[0268] Experimental Materials:

[0269] PKMYT1 enzyme protein was purchased from Thermo Scientific (Cat. No. A33387), and ADP-GLO kit was purchased from Promega (Cat. No. V9103).

[0270] PKMYT1 enzyme activity reaction buffer: 70mM HEPES, 3mM MgCl 2 ,3mM MnCl 2,50μg ml-1PEG20000, 3μM sodium orthovanadate, 1.2mM DTT.

[0271] Experimental steps:

[0272] Using an ultra-micropipette, the test compound (concentration: 3.33mM, dissolved in DMSO) was diluted with 10uM as the highest starting concentration, and then diluted with 10 gradients (10000nM, 3333nM, 1111nM, 370nM, 123nM, 41nM, 13.7nM, 4.6nM, 1.5nM, 0.5nM) at a ratio of 1:3, and added to a 384-well reaction plate. Two replicate wells were set for each concentration; 16 wells were set for positive and negative controls, with the positive control being the replicate wells of 1uM positive compound and the negative control being the replicate wells of DMSO. The reaction plate with the added compound was centrifuged at 2500rpm for 1 minute.

[0273] Add the prepared enzyme solution to the reaction plate, 5uL per well, the final concentration of the enzyme is 10nM. Centrifuge at 1000rpm for 1 minute. Place in an incubator at 30℃ for 15 minutes.

[0274] Add the prepared ATP substrate solution to the reaction plate, 5uL per well, and the final concentration of ATP is 5uM. Centrifuge at 1000rpm for 1 minute. Seal the plate with aluminum foil and place it in an incubator at 30℃ for 90 minutes.

[0275] Add 10uL ADP-glo TM Reagent to stop the kinase reaction and consume unconsumed ATP, leaving only ADP and very low ATP background. Centrifuge at 1000 rpm for 1 minute. Seal the plate with aluminum foil and react at room temperature for 60 minutes.

[0276] Add 20uL of kinase detection reagent to convert ADP into ATP, introduce luciferase and luciferin to detect ATP. Centrifuge at 1000rpm for 1 minute. Seal the plate with aluminum foil and react at room temperature for 60 minutes.

[0277] The ADP-GLO luminescence signal value was read by the microplate reader PHERAstar and analyzed. The average inhibition rate of the positive control duplicate wells was set as the relative inhibition rate of 100%, and the average inhibition rate of the negative control duplicate wells was set as the relative inhibition rate of 0%. The ADP-GLO readings were converted into relative inhibition rates, and the 4-parameter model was used to fit the compound IC 50 .

[0278] The experimental results show that the compound has good enzyme inhibitory activity. See Table 1 for specific results.

[0279] Table 1 PKMYT1 enzyme activity inhibition test results

[0280]

[0281]

[0282] Example 2. Cytostatic Activity of the Disclosed Compounds

[0283] The biological activities of the compounds of the present invention were verified using CTG assay (HCC1569).

[0284] Experimental Materials:

[0285] HCC1569 cells were purchased from ATCC (Cat. No. CRL-2330) and cultured at 37°C, 5% CO 2 Cell culture incubator. HCC1569 complete culture medium: RPMI-1640 liquid culture medium (Cat. No.: Gibico 11875-093), 20% FBS (Cat. No.: Gibico 10099-141), 1% Pen Strep (Cat. No.: Gibico 15070-063).

[0286] Test compound: Compound of the Examples of the present disclosure.

[0287] Experimental steps:

[0288] 75cm 2 HCC1569 cells in the culture flask were digested with 2 mL of trypsin for 2-3 minutes, and then neutralized with 2 mL of 1640 complete medium. Centrifuged at 1200 rpm for 5 minutes. Resuspended the cells with 4 mL of 1640 complete medium. 500 ul of the cell suspension was taken for cell counting using a Vi-CELL-XR cell counter.

[0289] Using a Multidrop instrument, 333 HCC1569 cells were seeded per well (50 uL 1640 Growth Media) in a 384-well plate, and drugs were added 24 hours later.

[0290] Using an ultra-micropipette, the test compound (concentration: 3.33mM, dissolved in DMSO) was diluted with 10uM as the highest starting concentration, and then diluted in 10 gradients at a ratio of 1:3 (10000nM, 3333nM, 1111nM, 370nM, 123nM, 41nM, 13.7nM, 4.6nM, 1.5nM, 0.5nM) for drug treatment. Two replicate wells were set for each concentration; 14 wells were set for positive and negative controls, the positive control was a replicate well of 10uM positive compound, and the negative control was a replicate well of DMSO.

[0291] After the addition of drugs, the cells were placed in a 37°C incubator and cultured for 6 days. After 6 days, 25ul CTG buffer was added to each well for CTG assay detection, and the plate was read using an ELISA reader. The CTG readings were analyzed. The average inhibition rate of the positive control duplicate wells was set as the relative inhibition rate of 100%, and the average inhibition rate of the negative control duplicate wells was set as the relative inhibition rate of 0%. The CTG readings were converted into relative inhibition rates, and the inhibition rates (inhibition%) of the test compounds at various concentrations on the cells were calculated according to the following formula: Inhibition% = (bx) / (ba)*100%;

[0292] a=CTG value (highest concentration), b=CTG value (blank well), x=CTG value (test well value).

[0293] IC using GraphPad PRISM 8 50 Perform calculations.

[0294] (1) Perform statistics on the concentrations and inhibition rates corresponding to 10000nM, 3333nM, 1111nM, 370nM, 123nM, 41nM, 13.7nM, 4.6nM, 1.5nM, and 0.5nM. Perform statistical calculations using Log10 (A compound concentration). (2) Input the data into GraphPad PRISM 8 and select Analysis. (3) Select Nonlinear regression (curve fit). (4) Select Log (inhibitor) vs. response-Variable slope. (5) Select the calculation formula and calculate it according to the following formula; Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC50-X)*HillSlope)), X: logarithm of dose or concentration, Y: response value, Top and Bottom: peak and bottom values. (6) Fit the data to obtain IC 50 (7) Adjust the fitting conditions according to the specific data. Make appropriate constraint adjustments to Bottom, Top and HillSlope. The curve that best fits the actual situation has been achieved.

[0295] The experiment showed that the compound has good HCC1569 cell inhibitory activity. See Table 2 for specific results.

[0296] Table 2 Test results of the inhibitory activity of compounds on HCC1569

[0297]

Claims

1. A compound represented by general formula (I'), a pharmaceutically acceptable salt thereof or an isomer thereof, X 1 Select from N or CR 1 ; X 2 Selected from N or C; X 3 Selected from N or C; X 4 Select from N or CR 4 ; X 5 Select from N or CR 5 ; X 6 Select from N or CR 2 ; Ring A is selected from phenyl, cycloalkenyl, heterocycloalkenyl or heteroaryl; R 1 Selected from -H, -OH, -CN, -N(R 1a )(R 1b ), halogen, C 1-6 Alkyl, C 1-6 Alkoxy, -COOH, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl-S(O)2-, hydroxyl C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkyl-C 1-6 Alkyl, C 3-8 Cycloalkyl-O-, 3-8 membered heterocyclyl, 3-8 membered heterocycloalkenyl, phenyl, 5-6 membered heteroaryl; wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkyl-C 1-6 Alkyl, C 3-8 Cycloalkyl-O-, 3-8 membered heterocyclyl, 3-8 membered heterocycloalkenyl, phenyl, 5-6 membered heteroaryl, optionally substituted with one or more R 1c Substitution, the R 1c Selected from OH, -CN, -N(R 1a )(R 1b ), halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl or C 1-6 Alkoxy; R 2 Selected from -H, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group; R 3 Selected from -H, deuterium, -OH, -CN, halogen, -N(R 1a )(R 1b ), C 1-6 Alkyl-S(O)2-, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 Alkyl-, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, 3-14 membered heterocyclic group or C 3-8 Cycloalkyl; R 4 , R 5 are independently selected from -H, -OH, -CN, -N(R 1a )(R 1b ), halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy; R 6 , R 7 are independently selected from H, -OH, -CN, -N(R 1a )(R 1b ), halogen, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group; R 1a , R 1b are independently selected from H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, or R 1a , R 1b and the nitrogen atom to which it is connected form a 3-10 membered ring; m is selected from 0, 1, 2 or 3.

2. The compound as claimed in claim 1, its pharmaceutically acceptable salt or its isomer, wherein: X 1 Select from N or CR 1 ; X 2 Selected from N or C; X 3 Selected from N or C; X 4 Select from N or CR 4 ; X 5 Select from N or CR 5 ; X 6 Select from N or CR 2 ; Ring A is selected from phenyl, cycloalkenyl, heterocycloalkenyl or heteroaryl; R 1 Selected from -H, -OH, -CN, -N(R 1a )(R 1b ), halogen, C 1-4 Alkyl, C 1-4 Alkoxy, -COOH, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkyl-S(O)2-, hydroxyl C 1-4 Alkyl, C 3-6 Cycloalkyl, C 5-6 Cycloalkenyl, C 3-6 Cycloalkyl-C 1-4 Alkyl, C 3-6 Cycloalkyl-O-, 3-6 membered heterocyclyl, 3-6 membered heterocycloalkenyl, phenyl, 5-6 membered heteroaryl; wherein the C 1-4 Alkyl, C 3-6 Cycloalkyl, C 5-6 Cycloalkenyl, C 3-6 Cycloalkyl-C 1-4 Alkyl, C 3-6 Cycloalkyl-O-, 3-6 membered heterocyclyl, 3-6 membered heterocycloalkenyl, phenyl, 5-6 membered heteroaryl, optionally substituted with one or more R 1c Substitution, the R 1c Selected from halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl or C 1-4 Alkoxy; R 2 Selected from -H, halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl or C 3-6 Cycloalkyl; R 3 Selected from -H, deuterium, -OH, -CN, halogen, -N(R 1a )(R 1b ), C 1-4 Alkyl-S(O)2-, C 2-4 Alkynyl, C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl-, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, 3-14 membered heterocyclic group or C 3-6 Cycloalkyl; R 4 , R 5 are independently selected from -H, -OH, -CN, -N(R 1a )(R 1b ), halogen, C 1-4 Alkyl, C 1-4 Alkoxy or halogenated C 1-4 alkyl; R 6 , R 7 are independently selected from H, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, hydroxyl C 1-4 Alkyl, halogenated C 1-4 Alkyl or C 3-6 Cycloalkyl; R 1a , R 1b are independently selected from H or C 1-4 Alkyl, or R 1a , R 1b and the nitrogen atom to which it is connected form a 3-10 membered ring; m is selected from 0, 1, 2 or 3.

3. The compound according to claim 1, its pharmaceutically acceptable salt or its isomer, wherein: X 1 Select from N or CR 1 ; R 1 Selected from -CH3, -H, -OH, -Cl, -F, -Br, -COOH, -CN, -CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CF3, -CHF2, -CH2F, -CF2C H3, -CF(CH3)2, -OCH3, -OCH(CH3), -OCF3, -OCH2CF3, -N(CH3)2, -CH=CH2, -C(CH3)=CH2, -C≡CH, -S(O)2CH3, Preferably, R 1 Selected from -H, -OH, -F, -Cl, -Br, -CF3, -CH3 or 4. The compound according to claim 1 or 2, its pharmaceutically acceptable salt or its isomer, wherein: X 2 For C.

5. The compound according to claim 1 or 2, its pharmaceutically acceptable salt or its isomer, wherein: X 2 is N.

6. The compound according to any one of claims 1 to 3, its pharmaceutically acceptable salt or its isomer, wherein: X 3 For C.

7. The compound according to any one of claims 1 to 3, its pharmaceutically acceptable salt or its isomer, wherein: X 3 is N.

8. The compound according to any one of claims 1 to 6, its pharmaceutically acceptable salt or its isomer, wherein: X 6 is N.

9. The compound according to any one of claims 1 to 6, its pharmaceutically acceptable salt or its isomer, wherein: X 6 CR 2 .

10. The compound according to any one of claims 1 to 8, its pharmaceutically acceptable salt or its isomer, wherein: X 4 CR 4 ; R 4 Selected from -H, -F, -Cl, -Br or -CH3.

11. The compound according to any one of claims 1 to 9, its pharmaceutically acceptable salt or its isomer, wherein: X 5 CR 5 ; R 5 Selected from -H, -F, -Cl, -Br or -CH3.

12. The compound according to any one of claims 1 to 10, its pharmaceutically acceptable salt or its isomer, wherein: Ring A is selected from phenyl, C 5-6 cycloalkenyl, 5-6 membered heterocycloalkenyl or 5-6 membered heteroaryl.

13. The compound according to any one of claims 1 to 11, its pharmaceutically acceptable salt or its isomer, wherein: Ring A is selected from 14. The compound according to any one of claims 1 to 12, its pharmaceutically acceptable salt or its isomer, wherein: R 3 is selected from H, D, -CN, -OH, -F, -Cl, -Br, -CH3, -CH2CF3 or -CF3; m is selected from 0, 1 or 2.

15. The compound according to any one of claims 1 to 13, its pharmaceutically acceptable salt or its isomer, wherein: R 2 Selected from -H, -F, -Cl, -Br, -CH3, -CH2CH3, -CF3, -CH2CF3 or Preferably, R 2 Selected from -H.

16. The compound according to any one of claims 1 to 14, its pharmaceutically acceptable salt or its isomer, wherein: Structural unit Selected from 17. The compound according to any one of claims 1 to 15, its pharmaceutically acceptable salt or its isomer, wherein: R 6 , R 7 Each independently selected from -CH3, -CH2CH3, -CH(CH3)2, -Cl, -F, -Br, -OCH3 or -CH2OH; Preferably, R 6 , R 7 are all selected from -CH3.

18. The compound according to any one of claims 1 to 16, its pharmaceutically acceptable salt or its isomer, which has the following structure: in, X 1 , X 4 , X 5 , Ring A, R 1 , R 2 , R 3 , R 6 , R 7 , m as described in any one of claims 1-16.

19. The compound according to any one of claims 1 to 18, its pharmaceutically acceptable salt or its isomer, wherein R 1 Selected from halogen, C 1-4 Alkyl, halogenated C 1-4 alkyl; R 4 , R 5 Each independently selected from -H or halogen; Ring A is selected from phenyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkenyl; R 3 Selected from -H, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy.

20. The compound according to any one of claims 1 to 19, its pharmaceutically acceptable salt or isomer thereof, which has the following structure:

21. A pharmaceutical composition comprising the compound according to any one of claims 1 to 20, a pharmaceutically acceptable salt or an isomer thereof, and one or more pharmaceutically acceptable carriers.

22. Use of the compound according to any one of claims 1 to 20, its pharmaceutically acceptable salt or isomer thereof, or the pharmaceutical composition according to claim 21 in the preparation of a medicament for preventing and / or treating tumor diseases caused by overexpression of CCNE1 and / or inactivating mutation of FBXW7.

23. A method for treating a neoplastic disease caused by CCNE1 overexpression and / or FBXW7 inactivating mutation, comprising administering to a subject a therapeutically or prophylactically effective amount of a compound according to any one of claims 1 to 20, a pharmaceutically acceptable salt or isomer thereof, or a pharmaceutical composition according to claim 21.

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