EA040849B1 - OXYGEN-CONTAINING ARYLPHOSPHORIC COMPOUND AS EGFR KINASE INHIBITOR - Google Patents

Description

This application claims priority on the following applications:

CN201710592778.X, application date 07/19/2017;

CN201711277584.7, application date 12/06/2017;

CN201810130633.2, application date 02/08/2018; And

CN201810355614.X, application date 04/19/2018.

The field of technology to which the invention belongs

The present application relates to an oxygen-containing arylphosphorus compound as an EGFR kinase inhibitor, and specifically discloses a compound represented by formula (I) and a pharmaceutically acceptable salt thereof.

Background of the invention

Lung cancer is one of the most common malignant tumors. Approximately 1.6 million new cases of lung cancer occur each year worldwide, and lung cancer causes 1.4 million deaths each year. Among them, non-small cell lung cancer (NSCLC) accounts for approximately 80-85% of all lung cancers (10th Lung Cancer Forum).

TKI (tyrosine kinase inhibitor) EGFR (epidermal growth factor receptor) as a small molecule inhibitor competitively binds to EGFR through endogenous ligands and inhibits tyrosine kinase activation, which leads to blocking of the EGFR signaling pathway and ultimately to a series of biological effects such as suppression tumor cell proliferation and metastasis and stimulation of tumor cell apoptosis, and this represents one of the main targets of lung cancer treatment.

Osimertinib (AZD9291) is a third generation EGFR-TKI targeting drug. Since it has a higher sensitivity for drug resistance due to the T790M mutation, patients also develop drug resistance (Clin Cancer Res; 21 (17), 2015). In 2015, drug resistance analysis in 15 patients with AZD9291 was first described in Nature Medicine, 21, 560-562, 2015, where the third resulting mutation, i.e., the C797S EGFR mutation, was one of the main mechanisms that lead to drug resistance to osimertinib, which accounts for approximately 40%. At the same time, drug resistance to AZD9291 was also reported at several conferences, and at one of them, 2015 WCLC, Oxnard GR reported a drug resistance analysis in 67 patients in which the frequency of C797S was approximately 22%; as of 2017 ASCO, Piotrowska also reported 23 cases and C797S cases also accounted for approximately 22%; and in 2017 ASCO, Zhou Caicun et al., reported an analysis of the mechanisms of drug resistance in 99 patients in whom the incidence of C797S was approximately 22%. Therefore, overcoming resistance to AZD9291 associated with the C797S mutation and providing patients with a safer and more effective fourth-generation EGFR inhibitor C797S/T790M is of great research importance.

In 2016 Nature, 534, 129-132, 2016, the compound EAI045 was reported to be able to overcome drug resistance to osimertinib associated with C797S. EAI045 belongs to an allosteric inhibitor that exhibits a better tumor suppression effect in an in vivo pharmacodynamic mouse model with L858R/T790M/C797S mutations in combination with an anti-EGFR monoclonal antibody such as cetuximab; but this compound has not been entered into clinical trials. In 2017, Nature Communications, 8:14768, 2017, it was reported that brigatinib (AP26113) in combination with an anti-EGFR monoclonal antibody (such as cetuximab) can overcome drug resistance to the third generation targeted drug, osimertinib, which is due to the C797S mutation. Both the combination of brigatinib with panitumumab and cetuximab have been shown to exhibit good antitumor efficacy according to the results obtained in the PC9 mouse pharmacodynamic model (EGFR-C797S/T790M/del19).

WO 2012051587A1 discloses Comparative Example 1 but does not provide any data on its effect.

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Brief description of the invention

The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

where ring A is selected from phenyl, thienyl, pyridyl, pyrazinyl, pyrazolyl, cyclopentanonyl, cyclopentenyl, thiazolyl, isothiazolyl and pyrrolyl, wherein said phenyl, thienyl, pyridyl, pyrazinyl, pyrazolyl, cyclopentanonyl, cyclopentenyl, thiazolyl, isothiazolyl and pyrrolyl are optionally substituted with R6,

R ₁ is selected from H, halogen, C _1-6 alkyl and C _1-6 heteroαalkyl containing 1, 2 or 3 heteroatoms or heteroatomic groups independently selected from N, -O- and -S-, where C _1-6 alkyl and C _1-6 heteroalkyl containing 1, 2 or 3 heteroatoms or heteroatomic groups independently selected from N, -O- and -S- optionally substituted with 1, 2 or 3 R-groups;

R2 is selected from H, halogen, CN, OH, NO2, NH2, C _3-12 cycloalkyl and 3-12 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms or heteroatomic groups independently selected from N, -O- and -S -, where said NH2, C _3-12 picloalkyl and 3-12 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms or heteroatomic groups independently selected from N, -O- and -S- are optionally substituted with 1, 2 or 3 R groups;

R ₃ is selected from H, halogen, C _3-6 cycloαalkyloxy, -O(CH ₂ ) _n NRaR _b , C _1-6 alkyl and C _3-6 cycloalkyl, wherein said C _1-6 alkyl and C _3-6 cycloalkyl are optional substituted with 1, 2 or 3 R groups;

n is selected from 0, 1, 2, 3 or 4;

each of Ra and R _b is independently selected from H, C _1-5 alkyl and C _1-5 heteroalkyl containing 1, 2 or 3 heteroatoms or heteroatomic groups independently selected from N, -O-, -S- and -S( =O) ₂ -, and while the specified C _1-5 alkyl and C _1-5 heteroalkyl containing 1, 2 or 3 heteroatoms or heteroatomic groups, independently selected from N, -O-, -S- and -S (= O) ₂ -, optionally substituted with 1, 2 or 3 R groups;

or alternatively Ra and R _b are linked together to form a 5-6 membered heterocyclic ring containing 1, 2 or 3 heteroatoms or heteroatomic groups independently selected from -C(=O)N(R)-, N, -O - and -S-;

R ₄ is H;

I, CN, CH3, CH3CH2, CH3CH2CH2, (CH3)2CH, wherein said CH3, CH3CH2, CH3CH2CH2, (CH3)2CH, ⁰ and I are optionally substituted with 1, 2 or 3 R

R5 is selected from H, F, Cl, Br,

groups;

or alternatively R ₄ and R ₅ are linked together to form a 5-6 membered ring containing 1, 2 or 3 atoms independently selected from N, S or O, where the 5-6 membered ring is optionally substituted with 1, 2 or 3 R groups;

each R6 is independently selected from H, halo, CN, OH, NH2, C _1-6 alkylα, ═O, ═S, or C _1-6 heteroalkyl containing 1, 2, or 3 heteroatoms or heteroatomic groups independently selected from N, -O- and -S-;

each of R ₇ and R ₈ is independently selected from H or C _1-6 alkylα;

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R is selected from halo, CN, OH, NH2, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 heteroalkyl containing 1, 2 or 3 heteroatoms or heteroatomic groups independently selected from N, -O- and - S-, 3-6-membered heterocycloalkyl containing 1, 2 or 3 heteroatoms or heteroatomic groups independently selected from N, -O- and -S-, phenyl and 5-6-membered heteroaryl containing 1, 2 or 3 heteroatoms or heteroatomic groups independently selected from N, -O- and -S-, where the specified C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 heteroalkyl containing 1, 2 or 3 heteroatoms or heteroatomic groups, independently selected from N, -O- and -S-, 3-6 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms or heteroatomic groups independently selected from N, -O- and -S-, phenyl and 5-6 membered heteroaryl , containing 1, 2 or 3 heteroatoms or heteroatomic groups independently selected from N, -O- and -S-, optionally substituted with 1, 2 or 3 R'-groups;

R' is selected from H, F, Cl, Br, I, CN, OH, NH2, CH3, CH3CH2, CH3CH2CH2, (CHe^CH, CH3O, CF3, CHF2 and CH2F.

In some embodiments of the present application, the above R is selected from F, Cl, Br, I, ,N ^{1 1}

CN, OH, NH2, CH ₃ , CH ₃ CH2, CH3CH2CH2, (CH ₃ ) 2CH, CH ₃ O, (CH ₃ ) 2N,

^4CF3 _? Oh,

In some embodiments of the present application, the above R1 is selected from H, halogen, C _1-3 alkyl and C _1-3 heteroalkyl containing 1, 2 or 3 heteroatoms or heteroatomic groups independently selected from N, -O- and -S-, where said C _1-3 alkyl and C _1-3 heteroalkyl containing 1, 2 or 3 heteroatoms or heteroatomic groups independently selected from N, -O- and -S- are optionally substituted with 1, 2 or 3 R-groups.

In some embodiments of the present application, the above R1 is selected from H, F, Cl, Br, I, CH ₃ , CH ₃ CH ₂ , CH ₃ CH ₂ CH ₂ , (CH ₃ ) ₂ CH, CH ₃ O, CH ₃ CH ₂ O, CH ₃ CH ₂ CH ₂ O, (CH ₃ ) ₂ CHO, where the indicated CH ₃ , CH ₃ CH ₂ , CH ₃ CH ₂ CH ₂ , (CH ₃ ) ₂ CH, CH ₃ O, CH ₃ CH ₂ O , CH ₃ CH ₂ CH ₂ O, (CH ₃ ) ₂ CHO are optionally substituted with 1, 2 or 3 R groups.

In some embodiments of the present application, the above R2 is selected from H, halogen,

CN, OH, NH2, NO2, -NHR, -N(R)2,

In some embodiments of the present application, the above R2 is selected from H, F, Cl, Br,

CN, OH, NH2, NO2, l

*CF ₃ , oh, , -NHCH2CH3, -NHCH ₃ ,

In some embodiments of the present application, the structural unit is selected from

N

-N(CH3)2 and ι

In some embodiments of the present application, the above R ₆ is selected from H, F, Cl, Br, CN, OH, NH2, CH ₃ , CH ₃ CH ₂ , CH ₃ CH ₂ CH ₂ , (CH ₃ ) ₂ CH, CH ₃ O , =S and =O.

In some embodiments of the present application, each of the above Ra and R _b is independently selected from H, CH ₃ , CH ₃ CH ₂

-S(=O) ₂ CH ₃ optionally substituted with 1, 2 or 3 R groups.

and -S(=O)2CH3, where said CH3, CH3CH2,

In some embodiments of the present application, the above R ₃ is selected from H, F, Cl, Br,

CH3, CH3CH2, (CH ₃ ) ₂ CH, h

In some embodiments of the present application, the above R ₅ is selected from H, Cl, Br,

CN, CH3, CH3CH2, CH3CH2CH2, (CH3)2CH,

- 3 040849 .R ₅

In some embodiments of the present application, the structural unit '' ^N '' is selected from

applications, each of the above R ₇ and R ₈ is independently selected from H or CH3 in some embodiments of the present.

In some embodiments, the implementation of the present maceutically acceptable salt is selected from the application, the above compound or its pharmaceutical

where R1, R2, R3, R4, R ₅ , R6, R ₇ and R ₈ are defined above.

In some embodiments of the present application, the above compound or a pharmaceutically acceptable salt thereof is selected from

- 4 040849 where R1, R ₃ , R4, R5, R7, R ₈ , R and R' are defined above.

This application also provides the following compounds or their pharmaceutically acceptable -

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The present invention also provides a pharmaceutical composition containing a therapeutically effective amount of the above compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The present invention also contemplates the use of the above compound or a pharmaceutically acceptable salt thereof or the above pharmaceutical composition for the preparation of a medicament for the treatment of cancer.

In some embodiments of the present invention, the cancer is lung cancer.

In the present invention, still other embodiments are obtained from any combination

- 9 040849 of the above variables.

technical effect

The compounds of the present invention exhibit excellent antiproliferative activity against a three mutant EGFR Ba/F ₃ cell (A19del/T790M/C797S) and phosphorylation activity in a three mutant EGFR Ba/F ₃ cell model (A19del/T790M/C797S).

The compounds of the present invention show unexpected inhibitory activity compared to Comparative Example 1.

Definitions and representations

Unless otherwise noted, the following terms and expressions used in this document have the following meanings. A particular term or expression should not be considered vague or obscure in the absence of a specific definition, but should be understood according to its generally accepted meaning. Whenever a trade name is mentioned in this document, it is intended to refer to the relevant product or its active ingredient. The term pharmaceutically acceptable as used herein refers to those compounds, materials, compositions and/or dosage forms which, within the scope of careful medical judgment, are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reactions or other problems or complications commensurate with an acceptable benefit/risk ratio.

The term pharmaceutically acceptable salt refers to a salt of a compound of this application that is derived from a compound containing a specific substituent found in this application and a relatively non-toxic acid or base. If the compound of the present application contains a relatively acidic functional group, its base addition salt can be obtained by bringing into contact the neutral form of such a compound with a sufficient amount of a base in pure solution or a suitable inert solvent. If the compound of the present application contains a relatively basic functional group, its acid addition salt can be obtained by bringing into contact the neutral form of such a compound with a sufficient amount of acid in pure solution or a suitable inert solvent. Examples of the pharmaceutically acceptable acid addition salt include inorganic acid salts, organic acid salts, ammonium salts, and organic acid salts such as glucuronic acid. Certain specific compounds of the present application contain basic and acid functional groups that can be converted into both a base addition salt and an acid addition salt.

Pharmaceutically acceptable salts in accordance with the present application can be synthesized from the original compound containing an acidic fragment or a basic fragment, using traditional chemical methods. In general, such a salt is prepared by reacting the free acid or base form of the compound with a stoichiometric amount of the appropriate base or acid in water, or in an organic solvent, or a mixture thereof. In general, an anhydrous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.

In addition to the salt form, the compound provided herein also exists in the form of a prodrug. The prodrug of the compound described herein is a compound that readily undergoes chemical change under physiological conditions and is converted to the compound of the present application. In addition, the prodrug can be converted to the compounds of the present application by a chemical or biochemical method in an in vivo environment.

Some of the compounds of this application may be in unsolvated or solvated form, including in the form of a hydrate. In general, the solvated form is equivalent to the unsolvated form, and both of them are covered by the scope of this application.

Compounds in accordance with the present application may exist in specific geometric or stereoisomeric forms. All such compounds contemplated in the present invention include cis- and trans-isomers, pairs of (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers, (D)-isomers, -isomers and racemic mixtures thereof, and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of this application. Other asymmetric carbon atoms may be present as substituents such as alkyl. All such isomers and mixtures thereof are included within the scope of this application.

Unless otherwise noted, the term enantiomer or optical isomer refers to stereoisomers that are mirror images of each other.

Unless otherwise indicated, the term cis-trans isomer or geometric isomer is due to the inability of the double bond or single bond of the carbon atoms in the ring to rotate freely.

Unless otherwise noted, the term diastereomer refers to stereoisomers in which the molecules have two or more chiral centers and are not mirror images of each other.

Unless otherwise noted, (D) or (+) means right hand rotation, (L) or (-) means right hand rotation

- 10 040849 to the left, (DL) or (±) means racemization.

Unless otherwise indicated, the absolute configuration of a stereogenic center is represented by a solid wedge () and a dashed wedge ( )> and the relative stereogenic center configuration is represented by a straight solid () and a direct dashed)

A wavy line (^) represents a solid wedge bond (^) or a dotted wedge bond ('' ) or represents a straight solid bond (^) and a straight dotted bond (' Y

In particular, compounds according to the present application may be provided. Unless otherwise indicated, the terms tautomer or tautomeric form refer to the fact that the various functional isomers are in dynamic equilibrium at room temperature and can be quickly converted into one another. If tautomers are possible (for example, in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as prototype tautomers) involve interconversions by proton transfer, such as keto-enol isomerization and imine-enamine isomerization. The valence tautomer involves the interconversion of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between two tautomers of pentan-2,4-dione and 4-hydroxypent-3-en-2-one.

Unless otherwise indicated, the term enriched in one isomer, enriched in isomer, enriched in one enantiomer, or enriched in enantiomer refers to that the content of one of the isomers or enantiomers is less than 100%, and the content of the isomer or enantiomer is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, or 98% or more, or 99% or more, or 99.5% or more, or 99.6% or more, or 99.7% or more, or 99.8% or more, or 99.9% or more.

Unless otherwise indicated, the term isomer excess or enantiomer excess refers to the difference between the relative percentages of two isomers or enantiomers. For example, if the content of one of the isomers or enantiomers is 90% and the other is 10%, then the excess of the isomer or enantiomer (ee value) is 80%.

Optically active (R)- and (S)-isomers, as well as D- and L-isomers can be obtained using chiral synthesis, or chiral reagents, or other conventional techniques. If an enantiomer of a particular compound of this application is desired, it can be obtained by asymmetric synthesis, or by derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group is cleaved off to obtain the pure desired enantiomers. Alternatively, if the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), it forms a diastereomeric salt with an appropriate optically active acid or base, and then the separation of the diastereomers is carried out by a conventional method well known from the art technique, followed by extraction to obtain the pure enantiomer. In addition, the separation of enantiomers and diastereomers in general is carried out by the use of chromatography using a chiral stationary phase, and optionally in combination with a chemical derivatization method (eg formation of carbamates from amines). The compounds of this application may contain unnatural proportions of atomic isotopes of one or more of the atoms that form the compound. For example, the compound may be labeled with a radioactive isotope such as tritium ( ³ H), iodine-125 ( ¹²⁵ I), or C-14 ( ¹⁴ C). Any changes in the isotopic composition of a compound according to this application, whether radioactive or not, are included within the scope of this application.

The term pharmaceutically acceptable carrier refers to any formulation or vehicle capable of delivering an effective amount of the active agent of the present application without adversely affecting the biological activity of the active agent and without toxic side effects to the host or patient. Exemplary carriers include water, oils, vegetables and minerals, cream bases, lotion bases, ointment bases, etc. Such bases include suspensions, tackifiers, transdermal penetration enhancers, and the like. Their formulations are well known to those skilled in the cosmetic or topical medicament field.

The term excipient generally means the carrier, diluent and/or medium necessary to formulate an effective pharmaceutical composition.

The term effective amount or therapeutically effective amount in relation to drugs or pharmacologically active agents means a sufficient amount of a drug or agent that is not toxic, but can provide the desired effect. In the case of an oral dosage form in accordance with the present application, the effective amount of one active substance in the composition means the amount

- 11 040849 required to achieve the desired effect, if used in combination with another active substance in the composition. The determination of an effective amount will vary for each individual depending on the age and general condition of the subject, as well as the specific active substance. An appropriate effective amount in each case can be determined by one of ordinary skill in the art by routine experimentation.

The terms active ingredient, therapeutic agent, active substance or active agent means a chemical compound that can provide effective treatment for the target disorder, disease or condition.

Optional or optional means that the event or situation described below may, but need not, occur, and the description includes cases in which the event or situation occurs and cases in which the event or situation does not occur.

The term substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent (which may include heavy hydrogen and hydrogen variants), provided that the valence state of the particular atom is normal and the substituted compound is stable. If the substituent is oxygen (i.e. =O), this means that two hydrogen atoms have been replaced. Oxygen substitution does not occur in the aromatic group. The term "optionally substituted" means that it may or may not be substituted unless otherwise indicated; the type and number of substituents may be arbitrary as long as it is chemically achievable.

If any variable (for example, R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 R, then that group may optionally be substituted with no more than two R, and R in each case has an independent parameter. In addition, a combination of substituents and/or variants thereof is allowed only if such a combination leads to the formation of stable compounds.

If the number of linking groups is 0, such as -(CRR) ₀ -, this means that the linking group is a single bond.

When one of the variables is selected from a single link, this means that the two groups linked by the single link are connected directly. For example, when the L in A-L-Z is a single bond, the A-L-Z structure is actually A-Z.

If the substitute is free, this means that the substitute does not exist. For example, if X is free in A-X, the structure is actually A. If a substituent can be bonded to more than one atom on the ring, the substituent may be bonded to any atom on the ring.

For example, the structural unit or means that the substituent R can be in any position on cyclohexyl or cyclohexadiene. If it is not specified for these substituents which atom is attached to the substituted group, such substituent may be bonded through any of its atoms, for example, pyridyl as a substituent may be bonded to the substituted group through any one of the carbon atoms on the pyridine ring. If a countable linking group does not specify a direction for linking, then the direction for linking is arbitrary. For example, the linking group L in is -M-W-, then -M( A B

W- can link ring A and ring B in a direction similar to ( A ) - WMi in ) reading order from left to right, and provide a formation of ⁴ in the opposite direction of reading order from left to right. Combinations of linking groups, substituents and/or variants thereof are permitted only if such combinations result in the formation of stable compounds.

Unless otherwise indicated, the term hetero refers to a heteroatom or heteroatom group (i.e., an atomic group containing a heteroatom) including an atom other than carbon (C) and hydrogen (H), and an atomic group containing such heteroatoms, including, e.g. oxygen (O), nitrogen (N), sulfur (S), silicon (Si), germanium (Ge), aluminum (Al), boron (B), -O-, -S-, =O, =S , -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O) ₂ - and -C(=O)N( H)-, -N(H)-, -C(=NH)-, -S(=O) ₂ N(H)- or -S(=O)N(H)-, each of which is optionally substituted.

Unless otherwise indicated, a ring refers to substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl, or heteroaryl. The so-called ring includes a single ring, a bicyclic ring, a helical ring, an articulated ring, or a bridging ring. The number of atoms on a ring is usually defined as the number of ring members. For example, a 5-7 membered ring means that there are 5-7 atoms on the ring. Unless otherwise indicated, the ring optionally contains 1-3 heteroatoms. Thus, a 5-7 membered ring includes, for example, phenyl, pyridine and piperidinyl; on the other hand, the term 5-7-term

- 12 040849 heterocycloalkyl ring includes pyridyl and piperidinyl, but excluding phenyl. The term ring also includes a ring system containing at least one ring, where each ring independently corresponds to the above definition.

Unless otherwise indicated, the term heterocycle or heterocyclyl refers to a stable monocyclic, bicyclic, or tricyclic ring containing a heteroatom or heteroatomic group, which may be saturated, partially unsaturated, or unsaturated (aromatic) and may contain carbon atoms and 1, 2, 3, or 4 a ring heteroatom independently selected from N, O and S, wherein any of the above heterocycles can be coupled to a benzene ring to form a bicyclic ring. The nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O)p, p is 1 or 2). The nitrogen atom may be substituted or unsubstituted (ie, N or NR, where R is H or another substituent already defined herein). The heterocycle can be attached to side groups of any heteroatom or carbon atom to form a stable structure. If the resulting compound is stable, the heterocycles described herein may undergo substitution at the carbon or nitrogen position. The nitrogen atom on the heterocycle is optionally quaternized. In a preferred embodiment, when the total number of S and O atoms in the heterocycle is more than 1, the heteroatoms are not adjacent to each other. In another preferred embodiment, the total number of S and O atoms of the heterocycle is not more than 1. The term aromatic heterocyclic group or heteroaryl, as used herein, refers to a stable 5-, 6-, or 7-membered monocyclic or bicyclic or 7-, 8- , a 9- or 10-membered bicyclic heterocyclic aromatic ring that contains carbon atoms and 1, 2, 3, or 4 ring heteroatoms independently selected from N, O, and S. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or other substituents already defined herein). The nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O) _p , p is 1 or 2). It is worth noting that the total number of S and O atoms of an aromatic heterocycle is no more than 1. A bridged ring is also included in the definition of a heterocycle. A bridging ring is formed when one or more atoms (ie C, O, N, or S) link two non-adjacent carbon or nitrogen atoms. Preferably, the bridged ring includes, without limitation, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and one carbon-nitrogen group. It is worth noting that the bridge always converts a monocyclic ring into a tricyclic ring. In a bridged ring, a substituent on the ring may also be present on the bridge. Примеры гетероциклических соединений включают без ограничения акридинил, азоцинил, бензимидазолил, бензофуранил, бензотиолфуранил, бензотиолфенил, бензоксазолил, бензоксазолинил, бензотиазолил, бензотриазолил, бензотетразолил, бензизоксазолил, бензизотиазолил, бензимидазолинил, карбазолил, 4aH-карбазолил, карбазолинил, хроманил, бензопиран, циннолинил декагидрохинолинил, 2H ,6H1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuranyl, furyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, N-indazolyl, indolynyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isoindolyl, isoindolinyl , isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl , hydroxyindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, benzoxanthinyl, phenoloxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidinoni l, 4-piperidinonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinazolinyl, 4 quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-tipdiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3, 4-thiadiazolyl, thianthrenyl, thiazolyl, isothiazolylthiophenyl, thienooxazolyl, thienothiazolyl, thienoimidazolyl, thienyl, triazinyl, 1H-1,2,3-triazolyl, 2H-1,2,3triazolyl, 1H-1,2,4-triazolyl, 4H- 1,2,4-triazolyl and xanthenyl. Articulated ring and spiro ring connections are also included.

Unless otherwise indicated, the term hydrocarbyl or its hyponyms (e.g., alkyl, alkenyl, alkynyl, aryl, etc.), alone or as part of another substituent, refers to a straight, branched chain, or cyclic hydrocarbon radical, or a combination thereof. , it may be fully saturated (eg, alkyl), mono- or polyunsaturated (eg, alkenyl, alkynyl, and aryl), may be mono- or polysubstituted, and may be monovalent (eg, methyl), divalent (eg, methylene), or polyvalent (for example, methenyl), may include a divalent or polyvalent group, contain the specified number of carbon atoms (for example, C1-C12 represents 1-12 carbon atoms, _C1-12 are selected from C1, C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C u, C s and C ₁₂ C ₃ _ ₁₂ are selected from C ₃ , C ₄ , C ₅ , C 6 , C ₇ , C ₈ , C ₉ , C _u , C s and C ₁₂ ). Hydrocarbyl includes but is not limited to aliphatic hydrocarbyl and aromatic hydrocarbyl, aliphatic hydrocarbyl includes linear and cyclic hydrocarbyl, specifically includes but is not limited to alkyl, alkenyl and alkynyl, and aromatic hydrocarbyl includes but is not limited to 6-12 membered aromatic hydrocarbyl such as phenyl, naphthyl, etc. P. In some embodiments, the term hydrocarbyl means direct

- 13 040849 or a branched group or a combination thereof, which may be fully saturated, mono- or polyunsaturated and may include a divalent or polyvalent radical. Examples of a saturated hydrocarbyl radical include, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, and a homolog or isomer of n-pentyl, n-hexyl , n-heptyl, n-octyl, etc. The unsaturated hydrocarbyl group contains one or more double or triple bonds and examples include, but are not limited to, vinyl, 2-propenyl, butenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl). ), ethynyl, 1st 3-propynyl, 3-butynyl and higher homologues and isomers.

Unless otherwise indicated, the term heterohydrocarbyl or its hyponyms (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.), alone or in combination with another term, means a stable straight, branched, or cyclic hydrocarbon radical, or any combination thereof, which contain the specified number of carbon atoms and at least one heteroatom.

Unless otherwise indicated, the term heteroalkyl, alone or in combination with another term, means a stable straight chain hydrocarbon radical, a branched radical, or a combination thereof, containing the indicated number of carbon atoms and at least one heteroatom. In a specific embodiment, the heteroatom is selected from B, O, N, and S, where the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. The heteroatom or heteroatomic group may be located at any internal position of the heterohydrocarbyl, including the position where the hydrocarbyl is attached to the rest of the molecule. But the terms alkoxy, alkylamino, and alkylthio (or thioalkoxy) refer to the conventional expression which means an alkyl that is attached to the rest of the molecule via an oxygen atom, an amino, or a sulfur atom, respectively. Examples of heteroalkyl include, without limitation -OCH ₃ , -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -N(CH ₃ )2, -CH2-CH2-O-CH3, -CH2.CH2-NH-CH3, -CH2 -CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -S(O)2-CH3, -CH2-CH2-S(O) 2-CH3, -CH=CH-O-CH3, -CH2-CH=N-OCH3 and -CH=CHN(CH ₃ )-CH ₃ . He more than two heteroatoms may be continuous, for example, -CH ₂ -NH-OCH ₃ .

Unless otherwise indicated, the term cyclohydrocarbyl, heterocyclohydrocarbyl, or its hyponyms (such as aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, etc.), alone or in combination with other terms, is a cyclized hydrocarbyl or heterohydrocarbyl, respectively. In addition, in the case of heterohydrocarbyl or heterocyclohydrocarbyl (eg, heteroalkyl or heterocycloalkyl), the heteroatom may occupy the position where the heterocyclic ring is attached to the rest of the molecule. Examples of cyclohydrocarbyl include, without limitation, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Non-limiting examples of heterocyclic groups include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophene -2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.

Unless otherwise indicated, the term alkyl refers to a straight or branched saturated hydrocarbon group which may be mono- (eg, -CH2F) or polysubstituted (eg, -CF ₃ ) and may be monovalent (eg, methyl), divalent (eg, methylene) or polyvalent (for example, methenyl). Examples of alkyl include methyl (Me), ethyl (Et), propyl (such as n-propyl and isopropyl), butyl (such as n-butyl, isobutyl, sec-butyl, tert-butyl), pentyl (such as n- pentyl, isopentyl, neopentyl), etc.

Unless otherwise indicated, alkenyl refers to an alkyl group containing one or more carbon-carbon double bonds at any position in the chain, which may be monosubstituted or polysubstituted, and may be monovalent, divalent, or polyvalent. Examples of alkenyl include vinyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, and the like. The term alkenyloxy refers to an alkenyl group, each of which is attached to the rest of the molecule via an oxygen atom, examples include, without limitation CH ₂ =CH ₂ -O-, CH3CH=CH-O-.

Unless otherwise indicated, alkynyl refers to an alkyl group containing one or more carbon-carbon triple bonds at any position in the chain, which may be monosubstituted or polysubstituted, and may be monovalent, divalent, or polyvalent. Examples of alkynyl include ethynyl, propynyl, butynyl, pentynyl, and the like.

Unless otherwise indicated, cycloalkyl includes any stable cyclic or polycyclic hydrocarbyl, and any carbon atom is saturated, which may be monosubstituted or polysubstituted, and may be monovalent, divalent or polyvalent. Examples of such cycloalkyl include, without limitation, cyclopropyl, norbornanyl, [2.2.2]bicyclooctane, [4.4.0]bicyclodecanyl, and the like. However, the term cycloalkyloxy refers to a cycloalkyl group, each of which is attached to the rest of the molecule via a ky- 14 040849 atom.

- Ζ / ΠΤ°'' , □ L>° U of oxygen, examples include without limitation ’ ’ ’

Unless otherwise indicated, cycloalkenyl includes any stable cyclic or polycyclic hydrocarbyl containing one or more unsaturated carbon-carbon double bonds at any position on the ring, which may be monosubstituted or polysubstituted and be monovalent, divalent or polyvalent. Examples of such cycloalkenyl include, without limitation, cyclopentenyl, cyclohexenyl, and the like.

Unless otherwise indicated, cycloalkynyl includes any stable cyclic or polycyclic hydrocarbyl containing one or more carbon-carbon triple bonds at any position on the ring, which may be monosubstituted or polysubstituted and may be monovalent, divalent or polyvalent.

Unless otherwise indicated, the term halogen or halo, alone or as part of another substituent, refers to a fluorine, chlorine, bromine or iodine atom. In addition, the term haloalkyl is intended to include both monohaloalkyl and polyhaloalkyl. For example, the term halo(C1- _C4 )alkyl is intended to include, without limitation, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Unless otherwise indicated, examples of haloalkyl include, without limitation, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.

Alkoxy is any alkyl as defined above, having the indicated number of carbon atoms attached via an oxygen bridge. Unless otherwise stated, C ₁ . ₆ alkoxy includes C1, C2, C ₃ , C ₄ , C 5 and C ₆ alkoxy. Examples of alkoxy include, without limitation, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, t-butoxy, n-pentyloxy, and S-pentyloxy.

Unless otherwise indicated, the term aryl refers to a polyunsaturated aromatic substituent which may be mono- or polysubstituted, may be monovalent, divalent or polyvalent, may be a single ring or multiple rings (e.g. 1-3 rings; where at least one the ring is aromatic) that are articulated together or covalently bonded.

Unless otherwise indicated, the term heteroaryl refers to an aryl (or ring) containing one to four heteroatoms. In an illustrative example, the heteroatom is selected from B, N, O and S, where the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. A heteroaryl may be attached to the rest of the molecule via a heteroatom. Non-limiting examples of aryl or heteroaryl include phenyl, naphthyl, biphenyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, phenyl-oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidinyl, benzothiazolyl, purinyl, benzimidazolyl, indolyl, isoquinolyl, quinoxalinyl, quinolinyl, 1-naphthyl, 2-naphthyl, 4biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2oxazolyl, 4-oxazolyl, 2-phenyl-4- oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1isoquinolinyl, 5-isoquinolinyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl and 6-quinolinyl. The substituent on any of the above aryl or heteroaryl ring systems is selected from the acceptable substituents described below.

Unless otherwise indicated, in combination with other terms (such as aryloxy, arylthio, aralkyl), aryl includes the aryl and heteroaryl rings defined above. Thus, the term aralkyl is intended to include groups (eg, benzyl, phenethyl, pyridylmethyl, etc.) where an aryl is attached to an alkyl, including alkyl where a carbon atom (eg, methylene) has been replaced by an atom such as oxygen eg phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like.

The term leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (eg, an affine substitution reaction). For example, exemplary leaving groups include triflate; chlorine, bromine and iodine; a sulfonate such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonate, and the like; acyloxy such as acetoxy, trifluoroacetoxy, and the like.

The term protecting group includes, without limitation, an amino protecting group, a hydroxy protecting group, or a thiol protecting group. The term amino protecting group refers to a protecting group suitable for preventing side reactions at the nitrogen position of an amino group. Exemplary amino protecting groups include, without limitation, formyl; acyl such as an alkanoyl (eg acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl such as t-butoxycarbonyl (Boc); arylmethoxycarbonyl such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc); arylmethyl such as benzyl (Bn), trityl (Tr), 1,1-di(4'-methoxyphenyl)methyl; silyl such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), etc. The term hydroxy protecting group refers to a protecting group suitable for preventing side reactions of hydroxyl groups. Illustrative

- 15 040849 protective groups for hydroxy groups include, without limitation, alkyl, such as methyl, ethyl and tert-butyl; acyl such as alkanoyl (eg acetyl); arylmethyl such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (benzhydryl, DPM); silyl such as trimethylsilyl (TMS), tert-butyldimethylsilyl (TBS), etc.

The compounds of the present application may be prepared by a variety of synthetic methods well known to those skilled in the art, including the following exemplary embodiments, embodiments formed by combining them with other chemical synthetic methods, and equivalent alternatives known to the person skilled in the art. Preferred embodiments include, without limitation, examples of the present invention.

The solvents used in this application are commercially available. The following abbreviations are used in this application:

aq. means water;

equiv. denotes an equivalent;

CDI stands for carbonyldiimidazole;

DCM is dichloromethane;

PE stands for petroleum ether;

DMF is N,N-dimethylformamide;

DMSO stands for dimethyl sulfoxide;

EtOAc is ethyl acetate;

EtOH is ethanol;

MeOH is methanol;

BOC is tert-butylcarbonyl, which is a protecting group for an amino group;

HOAc is acetic acid;

Na(OAc) ₃ BH is sodium borohydride acetate;

THF stands for tetrahydrofuran;

Boc2O is di-tert-butyl dicarbonate;

TFA stands for trifluoroacetic acid;

Cu(acac) ₂ denotes copper acetylacetonate;

DIEA stands for diisopropylethylamine;

Xantphos is 9,9-dimethyl-4,5-bisdiphenylphosphenoxanthene;

Pd(OAc)2 is palladium acetate;

Pd(dppf)Cl ₂ is [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride;

K ₃ PO ₄ is potassium phosphate;

K ₂ CO ₃ is potassium carbonate;

NaHCO ₃ is sodium bicarbonate;

Na ₂ CO ₃ is sodium carbonate;

HCl is hydrogen chloride;

Pd/C stands for palladium on carbon;

ICl stands for iodine chloride;

NaH is sodium hydride;

DMAP stands for 4-dimethylaminopyridine;

DIPEA/DIEA is N,N-diisopropylethylamine;

DPPF is 1,1'-bis(diphenylphosphino)ferrocene;

DCE stands for 1,2-dichloroethane;

DME stands for dimethoxyethane.

Compounds were named manually or using ChemDraw® software, and for commercially available compounds, their names from the supplier's catalog were used.

Detailed description

The application is described in detail below with the help of the following examples, but does not mean any adverse limitations of the application. The present application has been defined herein, where specific embodiments of the present application are disclosed. Various variations and modifications will be made to the embodiments of the present application without departing from the spirit and scope of the present application, which will be obvious to a person skilled in the art.

Example 1 Compound 1A

In a protective atmosphere of nitrogen gas, 5-bromobenzothiophene (10 g, 46.93 mmol), K ₃ PO ₄ (9.96 g, 46.93 mmol) and Cu(acac) ₂ (644 mg, 1.16 mmol, 0, 05 eq.) was dissolved in a solution of DMF in liquid ammonia (2 M, 50 ml). The reaction was allowed to proceed in the reaction solution in a high-pressure reactor at

- 16 040849

100° C. for 12 hours. The reaction solution was filtered, and the filtrate was concentrated to give a crude product. The crude product was purified by column chromatography to give compound 1A.

ΊI NMR (400 MHz, CDC13) δ=7.65 (d, J=8.5 Hz, 1H), 7.39 (d, J=5.3 Hz, 1H), 7.16 (d, J= 5.3 Hz, 1H), 7.11 (s, 1H), 6.79 (dd, J=1.8, 8.5 Hz, 1H), 3.67 (br s, 2H).

Connection 1B:

Compound 1A (3.8 g, 25.47 mmol) and NaHCO ₃ (4.28 g, 50.93 mmol) were dissolved in 50 ml of DCM, and then iodine chloride (4.96 g, 30.56 mmol) was added dropwise , 1.56 ml) and allowed the reaction to proceed in the reaction solution at 20° C. for 1 hour. After completion of the reaction, 100 ml of DCM was added to the reaction solution and washed with water and brine, respectively. The organic phases were combined, dried and concentrated to give compound 1B.

Connection 1C:

Compound 1B (0.6 g, 2.18 mmol), dimethylphosphine oxide (364.76 mg, 3.27 mmol), Xantphos (126.19 mg, 218.10 µmol), Pd(OAc) ₂ (48.96 mg , 218.10 µmol) and K ₃ PO ₄ (694.41 mg, 3.27 mmol) were dissolved in 10 ml of DMF and 2 ml of H ₂ O and reacted at 120°C in a protective atmosphere of nitrogen gas for 24 h. After completion of the reaction, the reaction solution was concentrated and purified by column chromatography to obtain compound 1C.

Connection 1D:

Compound 1C (0.3 g, 1.33 mmol) was dissolved in 5 ml EtOH and 2,4,5 trichloropyrimidine (488.59 mg, 2.66 mmol, 303.47 μl) and DIEA (688.54 mg , 5.33 mmol, 927.95 µl). The reaction solution was refluxed under nitrogen gas protection for 24 hours. After completion of the reaction, the reaction solution was concentrated and purified by column chromatography to give compound 1D.

Connection 1E:

The compounds 1-chloro-2-fluoro-4-methoxy-5-nitrobenzene and 3-methyl-3,9-diazaspiro[5.5]undecane were dissolved in 30 ml of DMF, and then K ₂ CO ₃ (5.04 g, 36 .48 mmol). The reaction was carried out at 60° C. under a nitrogen gas protective atmosphere for 8 hours. After completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated and purified by column chromatography to obtain compound 1E.

L NMR (400 MHz, CDCl ₃ ) δ=8.05 (s, 1H), 6.57 (s, 1H), 3.96 (s, 3H), 3.19-3.11 (m, 4H) , 2.42 (m, 4H), 2.31 (s, 3H), 1.71-1.67 (m, 4H), 1.65-1.61 (m, 4H).

Connection 1F:

Compound 1E (3.1 g, 8.76 mmol) was dissolved in 30 ml EtOH and iron powder (2.94 g,

- 17 040849

52.57 mmol) and an aqueous solution of ammonium chloride (4.69 g of ammonium chloride dissolved in 10 ml of water).

The reaction was carried out at 90° C. for 2 hours under a protective atmosphere of nitrogen gas. After completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated to give the compound

1F.

1H NMR (400 MHz, DMSO-d6) δ=6.71 (s, 1H), 6.66 (s, 1H), 4.73 (br s, 2H), 3.77 (s, 3H), 3 .25 (m, 2H), 3.06 (m, 2H), 2.81 (m, 4H), 2.74 (s, 3H), 1.89 (m, 2H), 1.74 (m, 2H), 1.60(m, 2H), 1.49(m, 2H).

Compound 1:

Compound 1D (100 mg, 268.67 µmol) and compound 1F (87.01 mg, 268.67 µmol) were dissolved in 4 ml t-butanol and methyl sulfonic acid (103.28 mg, 1.07 mmol, 76.50 µl). The reaction was carried out at 90° C. for 12 hours. After completion of the reaction, the reaction solution was concentrated, brought to a pH of approximately 9 with saturated NaHCO ₃ and extracted three times with DCM. The organic phases were collected, dried and concentrated to give the crude product. The crude product was purified by preparative HPLC to give compound 1 (40.16 mg, 63.98 µmol).

1H NMR (400 MHz, MeOD) δ=8.54 (br s, 1H), 8.17 (d, J=9.0 Hz, 1H), 8.09 (s, 1H), 8.02 (d , J=5.6Hz, 1H), 7.91-7.80(m, 3H), 6.74(s, 1H), 3.88(s, 3H), 3.30-3.16( m, 4H), 2.96-2.88 (m, 4H), 2.84 (s, 3H), 1.99 (s, 3H)), 1.95 (s, 3H), 1.83 ( brs, 3H), 1.73 (brs, 4H).

Example 2 Compound 2A

In addition to the separate replacement of 1-chloro-2-fluoro-4-methoxy-5-nitrobenzene and 3-methyl-3,9diazaspiro[5.5]undecane compounds by 1-fluoro-5-methoxy-2-methyl-4-nitrobenzene and 2- methyl-2,7diazaspiro[3.5]nonane, compound 2A was obtained in accordance with the method for obtaining compound 1E.

Connection 2B:

In addition to replacing compound 1E with compound 2A, compound 2B was prepared according to the method for preparing compound 1F.

1H NMR (400 MHz, CDCl3) δ=6.57 (s, 1H), 6.53 (s, 1H), 4.64 (s, 1H), 3.86-3.82 (m, 1H), 3.91-3.79 (m, 1H), 3.37 (s, 4H), 2.78-2.69 (m, 4H), 2.58-2.49 (m, 3H), 2, 19 (d, J=15.8 Hz, 3H), 1.97-1.89 (m, 4H).

Compound 2:

In addition to replacing compound 1F with compound 2B, compound 2 was obtained according to the method for preparing compound 1.

- 18 040849

1H NMR (400 MHz, CD3OD) δ=8.54 (br s, 1H), 8.17 (d, J=9.0 Hz, 1H), 8.09 (s, 1H), 8.02 (d , J=5.6 Hz,

1H), 7.91-7.80 (m, 3H), 6.74 (s, 1H), 3.88 (s, 3H), 3.30-3.16 (m, 4H), 2.96 -2.88 (m, 4H), 2.84 (s, 3H), 1.99 (s,

3H), 1.95 (s, 3H), 1.83 (brs, 3H), 1.73 (brs, 4H).

Example 3 Compound 3A

The compounds tert-butyl 4-oxopiperidine-1-carboxylate (20 g, 100.38 mmol) and 1-methylpiperazine (12.06 g, 120.45 mmol, 13.36 ml) were dissolved in 200 ml of ethanol and AcOH ( 6.03 g, 100.38 mmol, 5.74 ml) and NaBH(OAc) ₃ (42.55 g, 200.76 mmol). The reaction was carried out at 20° C. for 12 hours. After completion of the reaction, the reaction was quenched by adding methanol (10 ml) and water (10 ml) and then extracted with ethyl acetate (500 ml). The organic phase was collected, dried and concentrated to give compound 3A.

Connection 3B:

Compound 3A (16 g, 56.46 mmol) was dissolved in HCl/MeOH (50 ml, 4 M) and the reaction was allowed to proceed at 0° C. for 12 hours. After completion of the reaction, the reaction solution was concentrated to give compound 3B.

Connection 3C:

In addition to the separate replacement of 1-chloro-2-fluoro-4-methoxy-5-nitrobenzene and 3-methyl-3,9diazaspiro[5.5]undecane compounds by 4-fluoro-2-methoxy-1-nitrobenzene and 1-methyl-4- (4-piperidinyl)piperazine, compound 3C was obtained in accordance with the method for obtaining compound 1E.

1H NMR (400 MHz, CDCl ₃ ) δ=8.02-7.88 (m, 1H), 6.40 (dd, J=2.5, 9.5 Hz, 1H), 6.29 (d, J=2.5 Hz, 1H), 3.99-3.84 (m, 5H), 3.26-2.86 (m, 4H), 2.65-2.41 (m, 8H), 2 .29 (s, 3H), 2.00-1.92 (m, 2H), 1.59 (dq, J=4.0, 12.0 Hz, 2H).

3D connection:

In addition to replacing compound 1E with compound 3C, compound 3D was prepared according to the method for preparing compound 1F.

1 H NMR (400 MHz, CDCl ₃ ) δ=6.56 (d, J=8.3 Hz, 1H), 6.45 (d, J=2.4 Hz, 1H), 6.34 (dd, J =2.4, 8.6 Hz, 1H), 3.76 (s, 3H), 3.45 (br d, J=12.2 Hz, 3H), 2.75-2.47 (m, 7H ), 2.46-2.36 (m, 3H), 2.31-2.20 (m, 5H), 1.85 (br d, J=12.5 Hz, 2H), 1.64 (dq , J=3.8, 12.0 Hz, 2H).

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Compound 3:

In addition to replacing compound 1F with compound 3D, compound 3 was obtained according to the method for preparing compound 1.

1H NMR (400 MHz, CD3OD) δ=8.14 (d, J=8.8 Hz, 1H), 8.04-7.87 (m, 4H), 7.36 (br d, J=8, 6 Hz, 1H), 6.59 (d, J=2.2 Hz, 1H), 5.98 (br d, J=8.1 Hz, 1H), 3.83 (s, 3H), 3, 64-3.57 (m, 3H), 2.96-2.56 (m, 10H), 2.47 (s, 4H), 2.02 (br d, J=12.5 Hz, 2H), 1.95 (s, 3H), 1.91 (s, 3H), 1.71-1.60 (m, 2H).

Example 4 Compound 4A

Under a protective atmosphere of nitrogen gas, naphthalene-2-amine (4 g, 27.94 mmol) was dissolved in a stirred solution of 120 ml DCM and 40 ml MeOH and benzyltrimethylammonium dichloroiodide (9.72 g, 27.94 mmol) was added. The reaction was allowed to proceed in the reaction solution at 20° C. for 0.5 hours. After completion of the reaction, the reaction solution was washed with sodium bicarbonate solution, and the organic phase was collected and concentrated to give a crude product. The crude product was purified by column chromatography to give compound 4A.

1H NMR (400 MHz, CDCl3) δ=8.00 (d, J=8.4 Hz, 1H), 7.66 (dd, J=8.3, 17.6 Hz, 2H), 7.54 ( ddd, J=1.2, 7.2, 8.4 Hz, 1H), 7.37-7.29 (m, 1H), 6.99 (d, J=8.8 Hz, 1H), 4 .47 (brs, 2H).

Connection 4B:

In addition to replacing compound 1B with compound 4A, compound 4B was prepared according to the method for preparing compound 1C.

1H NMR (400 MHz, CDCl3) δ=7.66 (d, J=8.8 Hz, 2H), 7.51-7.45 (m, 1H), 7.45-7.37 (m, 1H ), 7.25-7.17 (m, 1H), 6.76 (dd, J=3.6, 8.8 Hz, 1H), 6.51 (br s, 2H), 2.05 (s , 3H), 2.01 (s, 2H);

LC-MS (ESI): mass/charge: 220.1 [M+1].

Connection 4C:

In addition to replacing compound 1C with compound 4B, compound 4C was prepared according to the method for preparing compound 1D.

¹ H-NMR (400 MHz, CDCl3) δ=13.05 (s, 1H), 8.62 (dd, J=4.0, 9.2 Hz, 1H), 8.24 (s, 1H), 8.04 (d, J=9.6Hz, 1H), 7.89 (d, J=8.0Hz, 1H), 7.71 (d, J=8.4Hz, 1H), 7. 56 (dd, J=7.2, 7.2Hz, 1H), 7.48 (dd, J=7.2, 7.2Hz, 1H),

2.18 (s, 3H), 2.14 (s, 3H). Compound 4:

In addition to replacing compound 1D with compound 4C, compound 4 was obtained according to the method for preparing compound 1. 1H NMR (400 MHz, MeOD) δ=8.45 (s, 1H), 8.24-8.17 (m, 2H), 8.11 (s, 1H), 8.06 (d, J=9.2 Hz, 1H), 7.98 (s, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.63 (ddd, J=1.2, 7.2, 7.2 Hz, 1H), 7.53 (dd, J=7.2, 7.2 Hz,

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1H), 6.75 (s, 1H), 3.89 (s, 3H), 3.32-3.12 (m, 4H), 2.98-2.90 (m, 4H), 2.88 (s, 3H), 2.14 (s, 3H), 2.10 (s, 3H),

2.05-1.49 (m, 8H); LC-MS (ESI): mass/charge: 653.0 [M+1].

Example 5 Compound 5

In addition to the respective replacement of compounds 1D and 1F with compounds 4C and 2B, compound 5 was obtained in accordance with the method for preparing compound 1.

1H NMR (400 MHz, CD3OD) δ=8.56 (br s, 1H), 8.30-8.21 (m, 2H), 8.06 (s, 1H), 8.02 (d, J= 9.2 Hz, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.67-7.61 (m, 1H), 7.61-7.53 (m, 2H), 6.62 (d, J=2.0 Hz, 1H), 6.11 (d, J=8.8 Hz, 1H), 3.87 (s, 4H), 3.84 (s, 3H), 3.09-2.97 (m, 4H), 2.88 (s, 3H), 2.10 (s, 3H), 2.07 (s, 3H), 2.04-1.94 (m, 4H);

LCMS (ESI): mass/charge: 591.1 [M+1].

Example 6 Compound 6

In addition to the respective replacement of compounds 1D and 1F with compounds 4C and 3D, compound 6 was obtained in accordance with the method for preparing compound 1.

1H NMR (400 MHz, CD3OD) δ=8.54 (br s, 1H), 8.30-8.22 (m, 2H), 8.06 (s, 1H), 8.02 (d, J= 9.2 Hz, 1H), 7.97 (d, J=8.0 Hz, 1H), 7.67-7.62 (m, 1H), 7.60-7.49 (m, 2H), 6.63 (d, J=2.4 Hz, 1H), 6.13 (d, J=8.0 Hz, 1H), 3.85 (s, 3H), 3.63 (d, J=12 .4 Hz, 2H), 2.79 (br s, 6H), 2.71-2.61 (m, 3H), 2.61-2.38 (m, 5H), 2.11 (s, 3H ), 2.07 (s, 3H), 2.02 (br d, J=12.8 Hz, 2H), 1.72-1.61 (m, 2H);

LCMS (ESI): mass/charge: 634.1 [M+1].

Example 7 Compound 7A

Dissolve 7-nitroquinoline (7 g, 40.19 mmol) in 120 ml methanol and add Pd/C (10%, 1 g) under nitrogen atmosphere. After purging with hydrogen 3 times, the reaction solution was stirred at 20° C. under a hydrogen atmosphere for 12 hours. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated to give compound 7A.

1H NMR (400 MHz, CDCla) δ=8.75 (dd, J=1.8, 4.3 Hz, 1H), 7.98 (dd, J=0.8, 8.0 Hz, 1H), 7.61 (d, J=8.8 Hz, 1H), 7.22 (d, J=2.3 Hz, 1H), 7.13 (dd, J=4.4, 8.2 Hz, 1H ), 6.98 (dd, J=2.3, 8.5 Hz, 1H), 3.98 (brs, 2H).

Connection 7V

I

Compound 7A (2.5 g, 17.34 mmol) was dissolved in 75 ml of AcOH and ICl (3.10 g, 19.07 mmol, 973.85 μl) was dissolved in 25 ml of acetic acid, which was added dropwise to the reaction solution . The reaction solution was stirred at 20° C. for 1 hour. After completion of the reaction, the reaction solution was subjected to rotary evaporation to remove acetic acid, and the residue was extracted with ethyl acetate and diluted, and then washed successively with water and saturated brine. The organic phase was collected, dried and concentrated to give the crude product. The crude product was purified by column chromatography to give compound 7B.

1H NMR (400 MHz, CDCl ₃ ) δ=8.88 (dd, J=1.5, 4.3 Hz, 1H), 7.95 (dd, J=1.5, 8.0 Hz, 1H) , 7.58 (d, J=8.5 Hz, 1H), 7.21 (dd, J=4.3, 8.0 Hz, 1H), 7.04 (d, J=8.5 Hz, 1H), 5.10-4.63 (m, 2H).

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Compound 7C

In addition to replacing compound 1B with compound 7B, compound 7C was prepared according to the method for preparing compound 1C.

¹ H NMR (400 MHz, CDCl ₃ ) δ=8.63 (dd, J=1.8, 4.3 Hz, 1H), 7.88 (td, J=1.5, 7.9 Hz, 1H ), 7.61 (d, J=9.0 Hz, 1H), 7.10 (dd, J=4.4, 8.1 Hz, 1H), 6.80 (dd, J=3.9, 8.8 Hz, 1H), 6.73-6.23 (m, 1H), 2.07 (s, 3H), 2.03 (s, 3H).

Connection 7D

In addition to replacing compound 1C with compound 7C, compound 7D was prepared according to the method for preparing compound 1D.

¹ H NMR (400 MHz, CDCl3) 5=13.31 (s, 1H), 8.93 (dd, J=3.9, 9.2 Hz, 1H), 8.82 (dd, J=1, 8, 4.3Hz, 1H), 8.27(s, 1H), 8.14(d, J=8.3Hz, 1H), 8.01(d, J=9.3Hz, 1H) , 7.38 (dd, J=4.3, 8.3 Hz, 1H), 2.19 (s, 3H), 2.15 (s, 3H).

Compound 7

In addition to replacing compound 3D with compound 7D, compound 7 was obtained according to the method for preparing compound 1.

¹ H NMR (400 MHz, CD3OD) 5=8.92-8.79 (m, 2H), 8.50 (br s, 1H), 8.23 (br d, J=8.3 Hz, 1H) , 8.07 (s, 1H), 7.90 (d, J=9.3 Hz, 1H), 7.69 (d, J=8.6 Hz, 1H), 7.43 (dd, J= 4.3, 8.2 Hz, 1H), 6.69 (d, J=2.4 Hz, 1H), 6.53 (dd, J=2.4, 8.8 Hz, 1H), 3, 85 (s, 3H), 3.74 (br d, J=12.2 Hz, 2H), 2.99-2.65 (m, 10H), 2.62-2.56 (m, 1H), 2.55 (s, 3H), 2.16 (s, 3H), 2.12 (s, 3H), 2.04 (br d, J=12.5 Hz, 2H), 1.76-1, 65(m, 2H).

Example 8 Compound 8A

Dissolve 4-nitrobenzene-1,2-diamine (10 g, 65.30 mmol) in 100 ml ethanol and add glyoxal (4.55 g, 78.36 mmol, 4.10 ml) with stirring at 80°C for 15 hours After completion of the reaction, the mixture was filtered and the filter cake was dried to obtain compound 10A.

¹ H NMR (400 MHz, DMSO-d ₆ ) 5=9.18 (s, 2H), 8.93 (d, J=2.4 Hz, 1H), 8.58 (dd, J=2.4 , 9.2 Hz, 1H), 8.36 (d, J=9.2 Hz, 1H); LC-MS (ESI): mass/charge: 176.1 [M+1].

Connection 8V

In addition to replacing compound 1E with compound 8A, compound 8B was prepared according to the method for preparing compound 1F.

lH NMR (400 MHz, DMSO-d6) 5=8.60 (d, J=1.6 Hz, 1H), 8.45 (d, J=1.6 Hz, 1H), 7.73 (d, J=9.2Hz, 1H), 7.24(dd, J=2.4, 9.2Hz, 1H), 6.92(d, J=2.4Hz, 1H), 6.08( s, 2H). LC-MS (ESI): mass/charge: 146.2 [M+1].

Compound 8C

In addition to replacing compound 7A with compound 8B, compound 8C was prepared according to the method for preparing compound 7B.

¹ H NMR (400 MHz, DMSO-d ₆ ) 5=8.76 (d, J=1.6 Hz, 1H), 8.56 (d, J=1.6 Hz, 1H), 7.80 ( d, J=9.2 Hz, 1H), 7.45 (d, J=9.2 Hz, 1H), 6.38 (brs, 2H). LC-MS (ESI): mass/charge: 271.9 [M+1].

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Connection 8D

In addition to replacing compound 1B with compound 8C, compound 8D was prepared according to the method for preparing compound 1C.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ=8.61 (d, J=1.6 Hz, 1H), 8.49 (d, J=1.6 Hz, 1H), 7.82 ( d, J=9.2 Hz, 1H), 7.22 (d, J=9.2 Hz, 1H), 6.38 (br s, 2H), 1.89 (s, 3H), 1.85 (s, 3H). LC-MS (ESI): mass/charge: 222.1 [M+1].

Compound 8E

In addition to replacing compound 1C with compound 8D, compound 8E was prepared according to the method for preparing compound 1D.

¹ H NMR (400 MHz, CDCl ₃ ) δ=13.20 (s, 1H), 9.12 (dd, J=4.0, 9.6 Hz, 1H), 8.75 (s, 1H), 8.68 (s, 1H), 8.23 (s, 1H), 8.21 (d, J=9.6 Hz, 1H), 2.08 (s, 3H), 2.05 (s, 3H); LC-MS (ESI): mass/charge: 367.9 [M+1].

Compound 8

In addition to the respective replacement of compounds 1D and 1F with compounds 8E and 2B, compound 8 was obtained in accordance with the method for preparing compound 1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ=12.90 (s, 1H), 9.09-8.96 (m, 1H), 8.87 (dd, J=2.0, 7, 6 Hz, 2H), 8.31-8.24 (m, 2H), 8.20 (s, 1H), 7.93 (d, J=9.2 Hz, 1H), 7.37 (s, 1H), 6.74 (s, 1H), 3.78 (s, 3H), 3.10 (s, 4H), 2.77 (t, J=5.2 Hz, 4H), 2.33 ( s, 3H), 2.12 (s, 3H), 2.05 (s, 3H), 2.02 (s, 3H), 1.84 (t, J=5.2 Hz, 4H); LC-MS (ESI): mass/charge: 607.1 [M+1].

Example 9 Compound 9

In addition to the respective replacement of compounds 1D and 1F with compounds 4C and 2B, compound 9 was obtained in accordance with the method for preparing compound 1.

¹ H NMR (400 MHz, CD3OD) δ=8.57 (s, 1H), 8.27 (d, J=8.8 Hz, 1H), 8.24-8.19 (m, 1H), 8 .08 (s, 1H), 8.00 (d, J=9.1 Hz, 1H), 7.93 (d, J=7.7 Hz, 1H), 7.68-7.53 (m, 3H), 6.65 (s, 1H), 3.84 (s, 3H), 3.58-3.50 (m, 4H), 2.792.71 (m, 4H), 2.66 (s, 3H ), 2.12 (s, 3H), 2.09 (s, 3H), 1.98-1.90 (m, 4H), 1.79 (s, 3H).

Example 10 Compound 10

In addition to replacing compound 1D with compound 7D, compound 10 was obtained in accordance with the method for preparing compound 1.

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1H NMR (400 MHz, CD3OD) δ=8.83 (dd, J=1.7, 4.4 Hz, 1H), 8.71 (dd, J=3.7, 9.0 Hz, 1H), 8.49 (brs, 1H),

8.20 (br d, J=8.1 Hz, 1H), 8.11 (s, 1H), 8.06 (s, 1H), 8.00 (d, J=9.3 Hz, 1H) , 7.43 (dd, J=4.3, 8.2 Hz, 1H), 6.78 (s,

1H), 3.89 (s, 3H), 3.24 (br s, 4H), 3.04-2.92 (m, 4H), 2.86 (s, 3H), 2.16 (s, 3H), 2.12 (s, 3H), 1.93-1.59 (m, 8H).

Example 11 Compound 11A

In addition to the respective replacement of 1-chloro-2-fluoro-4-methoxy-5-nitrobenzene and 3-methyl-3,9diazaspiro[5.5]undecane compounds by 1-chloro-2-fluoro-4-methoxy-5-nitrobenzene and 1- methyl-4-(piperidin-4-yl)piperazine, compound 11A was obtained in accordance with the method for obtaining compound 1E.

L NMR (400 MHz, CD3OD) δ=6.79 (s, 1H), 6.68 (s, 1H), 3.84 (s, 3H), 3.24-2.76 (m, 8H), 2.72 (br s, 1H), 2.71-2.65 (m, 2H), 2.02 (br d, J=10.8 Hz, 2H), 1.89-1.71 (m, 2H).

Connection 11B

In addition to replacing compound 1E with compound 11A, compound 11B was obtained in accordance with the method for obtaining compound 1F.

¹ H NMR (400 MHz, CDCls) δ=8.04 (s, 1H), 6.56 (s, 1H), 4.02-3.91 (m, 3H), 3.65 (br d, J =12.1 Hz, 2H), 2.81-2.73 (m, 2H), 2.66 (br s, 4H), 2.56-2.37 (m, 5H), 2.31 (s , 3H), 1.98 (br d, J=12.2 Hz, 2H), 1.84-1.71 (m, 2H).

Compound 11

In addition to the separate replacement of compounds 1D and 1F with compounds 4C and 11B, compound 11 was obtained in accordance with the method for preparing compound 1.

L NMR (400 MHz, CD3OD) δ=8.23 (br d, J=8.7 Hz, 2H), 8.16-8.10 (m, 1H), 8.02 (br d, J=8 .1 Hz, 1H), 7.76-7.55 (m, 3H), 6.85 (s, 1H), 4.01 (br s, 2H), 3.92 (s, 5H), 3, 73 (br s, 3H), 3.69-3.56 (m, 2H), 3.50 (br d, J=10.1 Hz, 2H), 3.08 (s, 3H), 2.86 (br t, J=11.5 Hz, 2H), 2.36 (br d, J=11.5 Hz, 2H), 2.17 (s, 3H), 2.14 (s, 3H), 2 .11-2.02 (m, 2H).

Example 12 Compound 12

In addition to the corresponding replacement of compounds 1D and 1F with compounds 2B and 7D, compound 12 obtained

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1H NMR (400 MHz, CD3OD) δ=8.84 (br d, J=2.7 Hz, 1H), 8.79 (br dd, J=3.7, 9.0 Hz, 1H), 8, 50 (br s, 1H), 8.22 (br d, J=8.1 Hz, 1H), 8.08 (s, 1H), 7.90 (br d, J=9.0 Hz, 1H) , 7.74 (s, 1H), 7.44 (dd, J=4.3, 8.2 Hz, 1H), 6.71 (s, 1H), 4.01 (br s, 4H), 3 .84 (s, 3H), 2.95 (s, 3H), 2.82 (br s, 4H), 2.16 (s, 3H), 2.13 (s, 3H), 2.08 (s , 3H), 2.03 (brs, 4H).

Example 13 Compound 13A

Dissolve 6-nitro-1H-indazole (25 g, 153.25 mmol) in 200 ml DMF, NaH (6.74 g, 168.57 mmol, 60% purity) was added in portions at 0°C, followed by MeI ( 23.93 g, 168.57 mmol, 10.49 ml) were added in portions at 0°C. The reaction was carried out at 25° C. for 1 hour. After completion of the reaction, the reaction solution was poured into 500 ml of water and extracted with EtOAc. The organic phase was collected and washed successively with 20 ml of water and 20 ml of brine. The organic phase was collected, dried and concentrated to give the crude product. The crude product was purified by column chromatography to give compound 13A.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ=8.71 (d, J=0.7 Hz, 1H), 8.29 (d, J=0.7 Hz, 1H), 8.03- 7.97 (m, 1H), 7.967.92 (m, 1H), 4.19 (s, 3H).

Connection 13V:

In addition to replacing compound 1E with compound 13A, compound 13B was obtained in accordance with the method for obtaining compound 1F.

1H NMR (400 MHz, DMSO-d ₆ ) δ=7.68 (s, 1H), 7.36 (d, J=8.6 Hz, 1H), 6.50 (dd, J=2.0, 8.6 Hz, 1H), 6.45(s, 1H), 5.32(s, 2H), 3.81(s, 3H).

Compound 13C:

In addition to replacing compound 7A with compound 13B, compound 13C was prepared according to the method for preparing compound 7B.

1H NMR (400 MHz, CDCl3) δ=7.76 (s, 1H), 7.40 (d, J=8.5 Hz, 1H), 6.61 (d, J=8.3 Hz, 1H) , 4.38 (s, 3H).

Connection 13D:

In addition to replacing compound 1B with compound 13C, compound 13D was prepared according to the method for preparing compound 1C.

1 H NMR (400 MHz, DMSO-d ₆ ) δ=7.81 (d, J=1.7 Hz, 1H), 7.50 (dd, J=1.1, 8.7 Hz, 1H), 6 .55 (dd, J=3.2, 8.8 Hz, 1H), 6.50 (s, 2H), 4.05 (s, 3H), 1.93 (s, 3H), 1.89 ( s, 3H).

Compound 13E:

In addition to replacing compound 1C with compound 13D, compound 13E was prepared according to the method for preparing compound 1D.

1H NMR (400 MHz, DMSO-d ₆ ) δ=10.38 (s, 1H), 8.43 (s, 1H), 8.22 (s, 1H), 8.00 (br d, J=8 .6 Hz, 1H), 7.24 (dd, J=2.8, 8.4 Hz, 1H), 4.41 (s, 3H), 1.88 (s, 3H), 1.84 (s , 3H).

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Compound 13

In addition to replacing compound 1D with compound 13E and replacing compound 1F with compound 2B, compound 13 was prepared according to the method for preparing compound 1.

1H NMR (400 MHz, DMSO-d ₆ ) δ=9.56 (br s, 1H), 8.33 (s, 1H), 8.19 (d, J=1.5 Hz, 1H), 8, 11 (s, 1H), 7.96 (dd, J=1.1, 8.4 Hz, 1H), 7.55 (s, 1H), 7.25 (s, 1H), 7.18 (dd , J=2.9, 8.6 Hz, 1H), 6.53 (s, 1H), 4.37 (s, 3H), 3.72 (s, 3H), 3.21 (s, 4H) , 2.57 (br s, 4H), 2.39 (s, 3H), 1.79 (s, 3H), 1.76 (s, 7H).

Example 14 Compound 14A

Dissolve 2,3-dihydro-1H-inden-1-one (10 g, 75.67 mmol, 9.09 ml) in 100 ml concentrated sulfuric acid and KNO ₃ (8.03 g, 79.45 mmol ) at 0°С. The reaction was carried out at 0-5°C for 1.5 hours. After completion of the reaction, the reaction solution was poured into 300 ml of water. After filtration, the filter cake was dissolved in EtOAc, dried and then concentrated to give the crude product. The crude product was purified by column chromatography to give compound 14A.

1 H NMR (400 MHz, DMSO-d ₆ ) δ=8.60 (d, J=2.0 Hz, 1H), 8.48 (dd, J=2.3, 8.5 Hz, 1H), 7 .69 (d, J=8.3 Hz, 1H), 3.34-3.27 (m, 2H), 2.90-2.83 (m, 2H).

14V connection

In addition to replacing compound 1E with compound 14A, compound 14B was obtained in accordance with the method for obtaining compound 1F.

1H NMR (400 MHz, DMSO-d ₆ ) δ=7.29-7.25 (m, 1H), 7.02 (s, 1H), 6.98 (br d, J=8.3 Hz, 1H ), 3.81 (br s, 2H), 3.09-3.00 (m, 2H), 2.74-2.66 (m, 2H); LCMS (ESI) mass/charge: 147.9 [M+1].

Compound 14C

In addition to replacing compound 7A with compound 14B, compound 14C was prepared according to the method for preparing compound 7B.

1H NMR (400 MHz, CDCI3) δ=7.26 (d, J=8.3 Hz, 1H), 7.09 (d, J=8.1 Hz, 1H), 5.49 (s, 2H) , 2.86-2.81 (m, 2H), 2.65-2.60 (m, 2H); LCMS (ESI) mass/charge: 273.9 [M+1].

Connection 14D

In addition to replacing compound 1B with compound 14C, compound 14D was prepared according to the method for preparing compound 1C. LCMS (ESI) mass/charge: 223.9 [M+1].

Compound 14E

In addition to replacing compound 1C with compound 14D, compound 14E was prepared according to the method for preparing compound 1D.

1H NMR (400 MHz, DMSO-D6) δ=13.09 (s, 1H), 8.84 (dd, J=3.5, 8.8 Hz, 1H), 8.24 (s, 1H), 7.71 (d, J=8.3 Hz, 1H), 3.21-3.16 (m, 2H), 2.80-2.75 (m, 2H), 2.08 (s, 3H) , 2.04 (s, 3H);

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LC-MS (ESI) mass/charge: 369.9 [M+1]. Compound 14

In addition to replacing compound 1D with compound 14E, compound 14 was obtained in accordance with the method for preparing compound 1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ=12.60 (s, 1H), 8.61 (br d, J=6.6 Hz, 1H), 8.30 (br s, 1H), 8.15 (s, 1H), 8.07 (s, 1H), 7.75 (s, 1H), 7.63 (br d, J=8.6 Hz, 1H), 6.87 (s, 1H), 3.84 (s, 3H), 3.08-3.01 (m, 2H), 2.93 (m, 4H), 2.74-2.67 (m, 2H), 2.60 (m, 4H), 2.36 (s, 3H), 1.93 (s, 3H), 1.90 (s, 3H), 1.60 (m, 8H); LCMS (ESI) mass/charge: 657.0 [M+1].

Example 15 Compound 15A

DMAP (376 mg, 3.08 mmol) was added to a solution of 5-nitro-1H-indole (10 g, 61.6 mmol) and Boc ₂ O (14.1 g, 64.7 mmol, 14.9 ml) in tetrahydrofuran (100 ml) at room temperature and stirred for 1 hour. After completion of the reaction, the reaction solution was concentrated and suspended with petroleum ether to obtain compound 15A.

1 H NMR (400 MHz, CDCl ₃ ) δ ppm 8.52 (d, J=1.88 Hz, 1H), 8.17-8.35 (m, 2H), 7.76 (d, J=3, 76 Hz, 1H), 7.28 (s, 1H), 6.74 (d, J=3.64 Hz, 1H), 1.72 (s, 9H), 1.59 (s, 7H).

Connection 15V

In addition to replacing compound 15A with a 7-nitroquinoline compound, compound 15B was prepared according to the method for preparing compound 7A.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 1.58 (s, 13H), 3.41 (s, 1H), 3.52 (br s, 2H), 6.32 (d, J=3.67 Hz, 1H), 6.64 (dd, J=8.68, 2.20 Hz, 1H), 6.77 (d, J=2.20 Hz, 1H), 7.19 (s, 1H), 7.36-7.51(m, 1H), 7.74-7.93(m, 1H).

Compound 15C

In addition to replacing compound 15B with compound 1A, compound 15C was prepared according to the method for preparing compound 1B.

1H NMR (400 MHz, CDCl ₃ ) δ 1.58 (s, 9H), 6.34 (d, J=3.67 Hz, 1H), 6.69 (d, J=8.68 Hz, 1H) , 7.19 (s, 1H), 7.43-7.56 (m, 1H), 7.83 (br d, J=8.44 Hz, 1H).

Compound 15D

In addition to replacing compound 1B with compound 15C, compound 15D was prepared according to the method for preparing compound 1C.

1H NMR (400 MHz, m) δ ppm 1.57 (s, 9H), 2.88 (s, 3H), 3.01 (s, 3H), 6.47-6.56 (m, 1H), 6.59 (d, J=3.91 Hz, 1H), 6.75 (dd, J=9.05, 4.16 Hz, 4H).

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In addition to replacing compound 1C with compound 15D, compound 15E was prepared according to the method for preparing compound 1D.

Compound 15F

Compound 15E

Compound 15E (1.5 g, 3.29 mmol) was dissolved in 20 ml of DCM, and TFA (3.76 g, 32.9 mmol, 2.44 ml) was added thereto. The reaction was carried out at room temperature for 1 hour. After completion of the reaction, the organic phase was concentrated and purified by preparative HPLC to give compound 15F.

1H NMR (400 MHz, CDCl3) δ ppm 11.88 (s, 1H), 8.45 (d, J=8.8 Hz, 1H), 7.65 (d, J=8.8 Hz, 1H) , 7.28 (s, 1H), 6.41 (s, 1H), 2.07 (s, 3H), 2.03 (s, 3H).

15G connection

Sodium hydride (59.9 mg, 1.49 mmol, 60% purity) and methyl iodide (211 mg, 1.49 mmol, 92.9 µl) were added to a solution of compound 15F (0.53 g, 1.49 mmol) in DMF (10 ml) and the solution were cooled to 0°C and the reaction was allowed to proceed for 1 hour. After completion of the reaction, it was quenched by adding water, extracted with ethyl acetate and the organic phase was washed with saturated solution, dried over anhydrous sodium sulfate, concentrated and purified by preparative thin layer chromatography to give compound 15G.

1H NMR (400 MHz, CDCl3) δ ppm 8.52-8.49 (m, 1H), 8.21 (s, 1H), 7.61-7.59 (m, 1H), 7.20 (s , 1H), 6.31 (s, 1H), 3.87 (s, 3H), 2.03 (s, 3H), 1.99 (s, 3H).

Compound 15

In addition to replacing compound 1D with compound 15G and replacing compound 1F with compound 2B, compound 15 was obtained in accordance with the method for preparing compound 1.

¹ H NMR (400 MHz, CDCl3) δ ppm 11.31 (s, 1H), 8.59 (s, 1H), 8.41 (dd, J=9.16, 3.76 Hz, 1H), 7 .51 (d, J=9.29 Hz, 1H), 7.37 (s, 1H), 7.28 (s, 1H), 6.34 (d, J=3.01 Hz, 1H), 3 .86 (m, 8H), 3.72 (s, 3H), 2.76 (m, 7H), 2.11 (s, 3H), 2.03-1.98 (m, 9H).

Example 16 Compound 16A

In addition to replacing compound 1A with a 2,3-dihydro-1H-inden-5-amine compound, compound 16A was prepared according to the method for preparing compound 1B.

1H NMR (400 MHz, CDCl ₃ ) δ=7.26 (d, J=8.0 Hz, 1H), 7.01 (d, J=8.0 Hz, 1H), 2.96-2.96 (m, 4H), 2.76-2.73 (m, 2H).

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Connection 16V

In addition to replacing compound 1B with compound 16A, compound 16B was prepared according to the method for preparing compound 1C. In addition to replacing compound 1B with compound 16A, compound 16B was prepared according to the method for preparing compound 1C.

'H-NMR (400 MHz, CDCl3) δ=7.11 (d, J=8.0 Hz, 1H), 6.47 (d, J=8.0 Hz, 1H), 2.84-2, 76 (m, 4H), 2.082.06 (m, 2H), 1.84 (s, 3H), 1.81 (s, 3H).

Compound 16C

In addition to replacing compound 1C with compound 16B, compound 16C was prepared according to the method for preparing compound 1D.

1H NMR (400 MHz, CDCl3) δ=12.18 (s, 1H), 8.41 (dd, J=3.9, 8.4 Hz, 1H), 8.19 (s, 1H), 7, 47 (d, J=7.8 Hz, 1H), 2.93 (t, J=7.4 Hz, 4H), 2.15 (q, J=7.3 Hz, 2H), 1.93 ( s, 3Н), 1.89 (s, 3Н).

Compound 16

In addition to replacing compound 1D with compound 16C and replacing compound 1F with compound 2B, compound 16 was obtained in accordance with the method for preparing compound 1.

1H NMR (400 MHz, DMSO-d ₆ ) δ=11.50 (s, 1H), 8.33 (br s, 1H), 8.09 (br dd, J=3.2, 8.1 Hz, 1H), 8.06 (s, 1H), 7.86 (s, 1H), 7.47 (s, 1H), 7.26 (d, J=8.3 Hz, 1H), 6.68 ( s, 1H), 3.77 (s, 3H), 3.45 (br s, 3H), 2.97 (br t, J=7.1 Hz, 2H), 2.80 (br t, J= 7.3 Hz, 2H), 2.73 (br s, 4H), 2.56-2.52 (m, 4H), 2.07 (s, 3H), 2.05-1.97 (m, 2H), 1.87(brs, 4H), 1.80(s, 3H), 1.76(s, 3H).

Example 17 Compound 17A

In addition to replacing the 2,4,5-trichloropyrimidine compound with the compound

2,4-dichloro-5-methoxypyrimidine and replacing compound 1C with compound 4B, compound 17 was obtained in accordance with the method for obtaining compound 1D.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 12.78 (s, 1H), 8.65-9.42 (m, 1H), 8.02 (d, J=9.29 Hz, 1H), 7 .68 (d, J=8.56 Hz, 1H), 7.49-7.57 (m, 1H), 7.40-7.46 (m, 1H), 7.31-7.39 (m , 1H), 7.36 (s, 1H), 2.50 (s, 3H), 2.09 (s, 3H), 2.06 (s, 3H).

Connection 17V

Compound 17A (0.94 g, 2.60 mmol) was dissolved in 25 ml DCE and BBr ₃ (6.51 g, 25.9 mmol, 2.50 ml) was added. After purging with nitrogen gas 3-5 times, the mixture was stirred at room temperature of approximately 25°C for 2 hours and stirred at 80°C for 1 hour. The reaction solution was cooled to 0°C and the pH was adjusted to 7-8 by adding a saturated solution of NaHCO ₃ . After filtration, the filtrate was extracted with DCM and the organic phase was dried and concentrated to give compound 17B.

Ή NMR (400 MHz, DMSO-d6) δ ppm 2.05 (s, 3H), 2.08 (s, 3H), 6.54 (s, 1H), 7.47-7.53 (m, 1H ), 7.60 (ddd, J=8.50, 6.91, 1.47 Hz, 1H), 7.78 (s, 1H), 7.92-8.04 (m, 2H), 8, 13 (d, J=9.54 Hz, 1H), 8.64 (dd, J=9.41, 3.55 Hz, 1H), 12.73 (br s, 1H). LCMS (ESI): mass/charge: 348.0 [M+1].

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Compound 17C

Compound 17B (0.2 g, 575 µmol) and Ν,N-dimethylcarbamoyl chloride (92.7 mg, 862 µmol, 79.3 µl) were dissolved in 4 ml DMF, K ₂ CO ₃ (158 mg, 1.15 mmol) was added ) and stirred at 25° C. for 2 hours. After completion of the reaction, the reaction solution was diluted with EtOAc and washed twice with brine, and the organic phase was dried and concentrated to give compound 17C.

1H NMR (400 MHz, CDCI3) δ ppm 2.13 (d, J=13.05 Hz, 6H), 3.07 (s, 3H), 3.28 (s, 3H), 7.46 (t, J=7.03Hz, 1H), 7.51-7.57(m, 1H), 7.69(d, J=8.78Hz, 1H), 7.88(d, J=8.03 Hz, 1H), 8.04 (d, J=9.29 Hz, 1H), 8.15 (s, 1H), 8.80 (dd, J=9.16, 3.89 Hz, 1H), 12.87 (s, 1H). LC-MS (ESI): mass/charge: 419.0 [M+1].

Compound 17

In addition to replacing compound 1D with compound 7C and replacing compound 1F with compound 2B, compound 17 was obtained in accordance with the method for preparing compound 1.

'H NMR (400 MHz, DMSO-d6) δ ppm 1.85 (br s, 4H), 2.03 (s, 3H), 2.07 (br d, J=10.03 Hz, 6 H), 2.40 (s, 3H), 2.75 (br s, 4H), 2.92 (s, 3H), 3.12-3.18 (m, 4H), 3.22 (s, 4H), 3.80 (s, 3H), 6.71 (s, 1H), 7.43-7.51 (m, 1H), 7.52-7.66 (m, 2H), 7.80 (s, 1H), 7.86-8.03 (m, 4H), 8.33 (s, 1H), 8.71 (br d, J=5.87 Hz, 1H), 12.52 (s, 1H) . LCMS (ESI): mass/charge: 658.1 [M+1].

Example 18 Compound 18A

The compounds 4-methoxy-3-nitrophenol (1.25 g, 7.39 mmol) and 2-bromo-1,1-dimethoxyethane (1.60 g, 8.13 mmol) were dissolved in DMF (15 ml) and K was added ₂ CO ₃ (1.12 g, 8.13 mmol) and the mixture was stirred at 100° C. for 4 hours. The reaction was quenched by adding 10 ml of water and extracted three times with 100 ml of ethyl acetate. The organic phases were combined, washed twice with brine, dried and concentrated to give the crude product.

'H NMR (400 MHz, CDCl ₃ ) δ ppm 1.28-1.25 (m, 6H), 3.78-3.65 (m, 4H), 3.92 (s, 3H), 4.02 -4.00 (m, 2H), 4.85 (m, 1H), 7.28-7.15 (m, 1H), 7.03 (d, J=9.2 Hz, 1H), 7, 46(s, 1H).

Connection 18V

Compound 18A (1.95 g, 6.88 mmol) was dissolved in THF (30 ml) and a solution of hydrochloric acid (0.5 M, 223.80 ml) was added, followed by stirring at 70° C. for 12 hours. The reaction was quenched by adding 10 ml of water and extracted three times with 100 ml of ethyl acetate. The organic phases were combined, washed twice with brine, dried and concentrated to give compound 18B.

1 H NMR (400 MHz, CDCl ₃ ) δ ppm: 3.95 (s, 3H), 4.65 (s, 2H), 7.09 (m, 1H), 7.25 (d, J=9.2 Hz, 1H), 7.46(s, 1H), 9.86(s, 1H).

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Compound 18C

At 25°C, compound 18B (200 mg, 947 µmol) was dissolved in 10 ml of a stirred DCE solution, followed by the sequential addition of pyrazin-2-ylmethylamine (206 mg, 1.89 mmol), acetic acid (113 mg, 1.89 mmol, 108 μl) and sodium borohydride acetate (602 mg, _2.84 mmol) and stirring at room temperature for 12 h. DCM. The organic phase was dried over anhydrous Na ₂ SO ₄ , concentrated and purified by thin layer chromatography to give compound 18C.

¹ I-NMR (400 MHz, CDCl ₃ ) δ ppm 8.64 (s, 1H), 8.38-8.40 (m, 3H), 7.24-7.42 (m, 1H), 6, 93-7.21 (m, 2H), 4.03-4.30 (m, 4H), 3.91 (s, 3H), 3.01-3.18 (m, 2H).

Compound 18D

In addition to replacing compound 1E with compound 18C, compound 18D was obtained in accordance with the method for obtaining compound 1F.

1H NMR (400 MHz, CDCI3) δ ppm 8.67 (s, 1H), 8.54-8.57 (m, 1H), 8.49 (d, J=2.38 Hz, 1H), 6, 70 (d, J=8.78Hz, 1H), 6.37 (d, J=2.89Hz, 1H), 6.27 (dd, J=8.78, 2.89Hz, 1H), 4.03-4.10 (m, 4H), 3.82 (s, 3H), 3.06 (t, J=5.21 Hz, 2H).

Compound 18

In addition to replacing compound 1F with compound 18D and replacing compound 1D with compound 4C, compound 18 was obtained in accordance with the method for preparing compound 1.

1H NMR (400 MHz, CD ₃ OD) δ ppm 2.05-2.19 (m, 7H), 2.79 (br s, 2H), 3.61-3.75 (m, 2H), 3, 86 (s, 3H), 4.04 (s, 2H), 6.54 (dd, J=8.80, 2.81 Hz, 1H), 6.88 (d, J=8.93 Hz, 1H ), 7.48-7.54 (m, 1H), 7.60 (br t, J=7.70 Hz, 1H), 7.82 (d, J=2.69 Hz, 1H), 7. 93 (br d, J=7.95 Hz, 1H), 8.03 (d, J=9.05 Hz, 1H), 8.11-8.22 (m, 2H), 8.31 (dd, J=9.05, 3.91 Hz, 1H), 8.44-8.67 (m, 4H).

Example 19 Compound 19A

In addition to replacing the pyrazin-2-ylmethylamine compound with a pyridin-3-ylmethylamine compound, compound 19A was prepared according to the method for preparing compound 18A.

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Connection 19V

In addition to replacing compound 1E with compound 19A, compound 19B was obtained in accordance with the method for obtaining compound 1F.

Compound 19

In addition to replacing compound 1F with compound 19B and replacing compound 1D with compound 4C, compound 19 was prepared according to the method for preparing compound 1.

1H NMR (400 MHz, CD3OD) δ=8.60-8.42 (m, 3H), 8.29 (dd, J=3.9, 9.0 Hz, 1H), 8.21 (d, J =8.2Hz, 1H), 8.17(s, 1H), 8.04(d, J=9.0Hz, 1H), 7.94(d, J=8.1Hz, 1H), 7.85-7.79 (m, 2H), 7.62 (ddd, J=1.5, 6.9, 8.5 Hz, 1H), 7.53 (t, J=7.5 Hz, 1H), 7.48-7.43 (m, 1H), 6.89 (d, J=8.8 Hz, 1H), 6.54 (dd, J=3.2, 8.8 Hz, 1H ), 3.89-3.84 (m, 5H), 3.74-3.55 (m, 2H), 2.67 (br t, J=5.0 Hz, 2H), 2.19- 2.06 (m, 7H).

Example 20 Compound 20A

In addition to the corresponding replacement of 1-chloro-2-fluoro-4-methoxy-5-nitrobenzene and 3-methyl-3,9diazaspiro[5.5]undecane compounds with 1-fluoro-5-methoxy-2-methyl-4-nitrobenzene and butyl 2,7diazaspiro[3.5]onan-2-carboxylate, compound 20A was obtained according to the method for preparing compound 1E.

1 H NMR (400 MHz, CDCl ₃ ) δ ppm: 1.48 (s, 9H), 1.90-1.98 (m, 4H), 2.26 (s, 3H), 2.91-2.95 (m, 4H), 3.73 (s, 4H), 3.96 (s, 3H), 6.54 (s, 1H), 7.82-7.86 (m, 1H).

Connection 20V

Compound 20A (2.14 g, 5.47 mmol) was dissolved in DCM (15 ml), TFA (6.23 g, 54.67 mmol, 4.05 ml) was added thereto, and the mixture was stirred at 25° C. for 1 hour. The reaction solution was concentrated under reduced pressure to give compound 20B.

1H NMR (400 MHz, CD3OD) δ ppm 2.05-2.09 (m, 4H), 2.28 (s, 3H), 2.98-3.02 (m, 4H), 3.33 (s , 4H), 3.94 (s, 3H), 6.74 (s, 1H), 7.78 (s, 1H).

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Compound 20C

Compound 20B and 2-chloroacetaldehyde compound were dissolved in 5 ml DCM and acetic acid (43.19 μl) and sodium borohydride acetate (218.2 mg, 1.03 mmol) were added. The reaction was carried out at 20° C. for 2 hours. The reaction was quenched with water and extracted with ethyl acetate to give an organic phase. The organic phase was washed once with brine, dried over anhydrous sodium sulfate and concentrated to give the crude product. The crude product was purified using preparative thin layer chromatography plate to give compound 20C.

¹ H NMR (400 MHz, CD3OD) δ ppm 7.77 (s, 1H), 6.72 (s, 1H), 3.93-3.95 (m, 3H), 3.60-3.64 ( m, 2H), 3.41 (s, 4H), 3.04 (t, J=6.15 Hz, 2H), 2.95-2.99 (m, 4H), 2.26 (s, 3H ), 2.03 (s, 2H), 1.97-2.00 (m, 4H).

Compound 20D

Compound 20C was dissolved in 5 ml EtOH and a solution of dimethylamine in ethanol (2 M, 10.8 ml) was added. The mixture was heated to 90° C. and the reaction was allowed to proceed for 12 hours. After completion of the reaction, the reaction solution was concentrated to give compound 20D.

Compound 20E

In addition to replacing compound 1E with compound 20D, compound 20E was prepared according to the method for preparing compound 1F.

1H NMR (400 MHz, CD ₃ OD) δ ppm 1.94-1.97 (m, 3H), 2.16 (s, 3H), 2.41-2.46 (m, 6H), 2.58 -2.66 (m, 3H), 2.67-2.79 (m, 4H), 3.01 (t, J=6.53 Hz, 2H), 3.50-3.56 (m, 4H ), 3.82 (s, 3H), 6.62 (d, J=2.76 Hz, 2H).

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Compound 20

In addition to replacing compound 1F with compound 20E and replacing compound 1D with compound 4C, compound 20 was prepared according to the method for preparing compound 1.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm = 12.48 (br s, 1H), 8.38 (br d, J=5.9 Hz, 1H), 8.28 (br s, 2H) , 8.14 (s, 1H), 8.05 (br d, J=8.6 Hz, 1H), 7.98-7.94 (m, 2H), 7.91 (br d, J=10 .0 Hz, 2H), 7.59 (br t, J=7.3 Hz, 1H), 7.527.47 (m, 1H), 7.45 (s, 1H), 6.70 (s, 1H) , 3.77-3.75 (m, 3H), 3.38 (s, 4H), 2.88 (br t, J=6.0 Hz, 2H), 2.72 (br s, 4H), 2.48-2.44 (m, 2H), 2.28 (s, 6H), 2.06 (s, 3H), 2.03 (s, 3H), 1.99 (s, 3H), 1 .86 (brs, 4H).

Example 21 Compound 21A

In addition to replacing compound 20B with compound 1E, compound 21A was obtained in accordance with the method for obtaining compound 1F.

Connection 21B

In addition to replacing compound 1F with compound 21A and replacing compound 1D with compound 4C, compound 21B was prepared according to the method for preparing compound 1.

1H NMR (400 MHz, CDCl ₃ ) δ=12.46 (s, 1H), 8.64 (dd, J=3.5, 9.3 Hz, 1H), 8.14 (s, 1H), 8 .07 (s, 1H), 7.95 (d, J=9.3 Hz, 1H), 7.87 (br d, J=7.8 Hz, 1H), 7.74 (d, J=8 .5 Hz, 1H), 7.56 (t, J=7.4 Hz, 1H), 7.50-7.44 (m, 1H), 7.41 (s, 1H), 3.87 (s , 3H), 3.71 (s, 3H), 2.77 (br s, 4H), 2.51 (br s, 4H), 2.19 (s, 3H), 2.16 (s, 3H) , 2.01 (brs, 4H).

Compound 21

Compounds 21B (0.1 g, 169 µmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (392 mg, 1.69 mmol) were dissolved in 5 ml DMF, DIPEA (87.4 mg, 676 µmol) was added and heated to 40° With stirring for 2 hours After completion of the reaction, the reaction solution was concentrated, quenched by adding saturated salt solution and was extracted with EtOAc, and the organic phase was dried and concentrated. The crude product was purified by preparative HPLC to give compound 21.

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1H NMR (400 MHz, CD3OD) δ ppm 1.79 (s, 3H), 1.87-1.97 (m, 4H), 2.10 (s, 3H), 2.13 (s, 2H), 2.66-2.85 (m, 4H), 3.20 (q, J=9.78 Hz, 2H), 3.84 (s, 3H), 4.65 (br s, 5H), 4 .78-4.85(m, 2H), 6.66(s, 1H), 7.54-7.67(m,

3H), 7.94 (d, J=8.29 Hz, 1H), 8.01 (d, J=8.95 Hz, 1H), 8.08 (s, 1H), 8.22 (dd, J=9.17, 4.03 Hz, 1H), 8.27 (d,

J=8.80 Hz, 1H). LC-MS (ESI): mass/charge: 673.0 [M+1]. Example 22 Compound 22A

The compound 2,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine and compound 4B were dissolved in 25 ml of isobutanol, then methyl sulfonic acid (842.54 mg, 8.77 mmol, 624.10 μl ) and allowed the reaction to proceed at 110° C. for 12 hours. After completion of the reaction, the reaction solution was concentrated and the crude product was purified by column chromatography to obtain compound 22A.

1H NMR (400 MHz, DMSO-d6) δ=8.83 (br d, J=5.6 Hz, 1H), 8.20 (br d, J=9.0 Hz, 1H), 8.08 ( br d, J=8.1 Hz, 1H), 8.03-7.95 (m, 3H), 7.77 (br d, J=3.7 Hz, 1H), 7.62 (br t, J=7.5 Hz, 1H), 7.55-7.47 (m, 3H), 6.82 (br d, J=2.9 Hz, 1H), 2.39 (s, 3H), 2 .11 (brd, J=13.2 Hz, 6H).

Connection 22V

Compounds 22A (100 mg, 190.49 µmol) and 2B were dissolved in a stirred solution of 2 ml of toluene and 0.4 ml of tert-butanol, followed by the sequential addition of Pd ₂ (dba) ₃ (17.4 mg, 19.1 µmol), XPhos (18.2 mg, 38.1 µmol) and K ₂ CO ₃ (52.6 mg, 380 µmol) and stirred at 100°C for 12 hours. After completion of the reaction, water was added to the reaction solution and extracted three times with using DCM. The organic phase was dried over anhydrous Na ₂ SO ₄ , concentrated and purified by thin layer chromatography to give compound 22B.

Compound 22

Compound 22B was dissolved in a stirred solution of 2 ml of i-PrOH and 1 ml of THF and NaOH (13.0 mg, 327 μmol) was dissolved in 2 ml of water, added to the stirred solution, and then the reaction was allowed to proceed at 100°C for 8 h After completion of the reaction, the reaction was quenched by adding water and extracted with EtOAc and the organic phase was concentrated. The crude product was separated by preparative thin layer chromatography to give compound 22.

1H NMR (400 MHz, CD3OD) δ=8.86 (dd, J=4.1, 9.2 Hz, 1H), 8.16 (d, J=8.8 Hz, 1H), 8.03 ( s, 1H), 8.01 (d, J=9.3Hz, 1H), 7.91 (d, J=8.3Hz, 1H), 7.73 (d, J=8.0Hz, 1H), 7.62 (t, J=7.7 Hz, 1H), 7.52-7.46 (m, 1H), 7.25 (d, J=7.8 Hz, 1H), 6, 94 (d, J=3.5 Hz, 1H), 6.71 (s, 1H), 6.55 (d, J=3.5 Hz, 1H), 3.89 (s, 3H), 3. 67 (s, 4H), 2.84-2.78 (m, 4H), 2.73 (s, 3H), 2.18 (s, 3H), 2.15 (s, 3H), 2.05 (s, 3H), 2.01-1.96 (m, 4H).

Example 23 Compound 23A

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Compound 5-bromo-2,4-dichloro-pyrimidine (1.04 g, 4.56 mmol) and compound 4B (0.5 g, 2.28 mmol, eq.) were dissolved in ethanol (10 ml) and DIEA was added (1.18 g, 9.12 mmol, 1.59 ml). The reaction mixture was heated to approximately 90°C with stirring for 12 hours Then the reaction solution was concentrated, quenched with water and extracted three times with EtOAc and the organic phase was concentrated to obtain compound 23A.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 8.48 (dd, J=9.16, 3.89 Hz, 1H), 8.38 (s, 1H), 8.05 (d, J=9, 29 Hz, 1H), 7.91 (d, J=8.03 Hz, 1H), 7.73 (d, J=8.53 Hz, 1H), 7.54-7.61 (m, 1H), 7.47 -7.53 (m, 1H), 2.16 (s, 3H), 2.19 (s, 3H).

Compound 23

In addition to replacing compound 1D with compound 23A and replacing compound 1F with compound 2B, compound 23 was prepared according to the method for preparing compound 1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.83 (br s, 4H), 1.94 (s , 3H), 2.03 (d, J=13.20 Hz, 5H), 2.00 -2.06 (m, 1H), 2.44 (br s, 3H), 2.70 (br s, 4H), 3.28 (br s, 4H), 3.77 (s, 3H), 6 .68 (s, 1H), 7.42 (s, 1H), 7.47-7.53 (m, 1H), 7.54-7.62 (m, 1H), 7.87-7.97 (m, 3H), 8.06 (d, J=8.80 Hz, 1H), 8.18-8.24 (m, 2H), 8.37 (brs, 1H).

Example 24 Compound 24A

Compound 23 (0.1 g, 153 µmol) and tributyl(1-ethoxyvinyl)stannan (111 mg, 307 µmol) were dissolved in 3 ml of toluene and Pd(PPh ₃ ) ₂ Cl ₂ (10.8 mg, 15, 4 µmol), CuBr (6.63 mg, 46.2 µmol, 1.41 µl) and PPh ₃ (12.1 mg, 46.2 µmol) in parts. The mixture was stirred at 110° C. under a protective atmosphere of nitrogen gas for 12 hours. After completion of the reaction, the reaction solution was quenched by adding KF solution and extracted three times with EtOAc. The organic phase was dried over anhydrous Na ₂ SO ₄ , concentrated and purified using thin layer chromatography to obtain compound 24A.

Compound 24

Compound 24A was dissolved in HCl/dioxane (4 M, 65.94 μl) and the reaction was allowed to proceed at room temperature for half an hour. After completion of the reaction, a saturated NaHCO ₃ solution was added to the reaction solution and the pH was adjusted to about 9. The mixture was extracted three times with EtOAc and washed successively with water and brine.

The organic phase was concentrated. The crude product was purified by preparative HPLC to give compound 24.

1H NMR (400 MHz, DMSO-D6) δ=11.17 (s, 1H), 9.36-9.28 (m, 1H), 8.85 (s, 1H), 8.28 (br d, J=13.3 Hz, 2H), 8.06 (br d, J=9.0 Hz, 1H), 7.96 (br s, 1H), 7.57 (br dd, J=3.3, 6.3 Hz, 3H), 7.25 (br s, 1H), 6.55 (br s, 1H),

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3.74 (s, 3H), 3.31 (br s, 3H), 2.55 (m, 4H), 2.53-2.52 (m, 6H), 2.47 (br s, 4H) , 1.81 (brs, 4H), 1.79-1.75 (m, 6H).

Example 25 Compound 25

Compound 24 (0.1 g, 153 µmol) and cyclopropylboronic acid (52.9 mg, 615 µmol) were dissolved in a stirred solution of 5 ml toluene and 0.5 ml water and Pd(OAc) ₂ (3.46 mg, 15.4 µmol), K ₃ PO ₄ (81.7 mg, 384 µmol) and P(Cy) ₃ (8.63 mg, 30.8 µmol, 9.98 µl). The reaction solution was heated to 110°C and stirred for 12 hours. After completion of the reaction, the reaction solution was filtered and concentrated, and the crude product was purified by preparative HPLC to obtain compound 25.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.55-0.66 (m, 2H), 0.85-0.96 (m, 2H), 1.71-1.78 (m, 1H), 1.83 (br s, 4H), 1.96-2.01 (m, 3H), 2.03 (s, 3H), 2.07 (s, 3H), 2.45 (br s, 3H), 2.70 (br s, 5H), 3.30 (br d, J=7.09 Hz, 4H), 3.79 (s, 3H), 6.67 (s, 1H), 7.44-7.53 (m, 2H), 7.57 (br t, J=7.58 Hz, 1H), 7.71 (s, 1H), 7.85 (s, 1H), 7. 91 (br d, J=8.07 Hz, 1H), 7.96 (d, J=9.17 Hz, 1H), 8.03 (d, J=8.56 Hz, 1H), 8.37 (br s, 1H), 8.56 (dd, J=9.17, 3.55 Hz, 1H), 12.25 (s, 1H). LCMS (ESI): mass/charge: 611.2 [M+1].

Example 26 Compound 26

Compound 24 (0.1 g, 153 µmol) was dissolved in 5 ml DMF and zinc dust (5.03 mg, 76.9 µmol), Pd ₂ (dba) ₃ (28.2 mg, 30.7 µmol) was added sequentially , DPPF (17.1 mg, 30.8 µmol) and Zn(CN) ₂ (36.1 mg, 307 µmol, 19.5 µl). The reaction solution was heated to 120°C and further stirred for 12 hours. After completion of the reaction, the reaction solution was filtered and concentrated, and the crude product was purified by preparative HPLC to obtain compound 26.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.83 (br s, 4H), 2.04 (br d, J=13.20 Hz, 8H), 1.91-2.12 (m, 1H), 2.40 (br s, 3H), 2.73 (br s, 4H), 3.21 (br s, 4H), 3.76 (s, 3H), 6.70 (s, 1H) , 7.24 (s, 1H), 7.48-7.54 (m, 1H), 7.54-7.61 (m, 1H), 7.88 (br s, 2H), 8.10 ( br d, J=8.31 Hz, 1H), 8.33 (br s, 2H), 8.46 (s, 1H), 8.78 (br s, 1H). LCMS (ESI): mass/charge: 596.2 [M+1].

Example 27 Compound 27A

Compound 24 (0.1 g, 153 µmol) was dissolved in 5 ml EtOH and Pd(dppf)Cl ₂ (11.3 mg, 15.40 µmol) and Et ₃ N (46.7 mg, 461 µmol, 64 .2 μl). The reaction solution was allowed to proceed at 80° C. for 24 hours under a carbon monoxide atmosphere (50 psi). After completion of the reaction, the reaction solution was filtered and concentrated, and the crude product was purified using preparative TLC to obtain compound 27A.

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Connection 27V

Compound 27A (60 mg, 93.3 µmol) was dissolved in 2 ml of EtOH and N ₂ H ₄ -H ₂ O (95.4 mg, 1.87 mmol, 92.6 µl) was added to the obtained. The reaction solution was heated to 100° C. and further stirred for 6 hours. After completion of the reaction, the reaction solution was filtered and concentrated to give compound 27B without further purification.

Compound 27

Compound 27B (30 mg, 47.7 µmol) and HOAc (210 mg, 3.50 mmol) were dissolved in 2 ml of triethylorthoacetate. The reaction solution was heated to 120°C and further stirred for 1 hour. After completion of the reaction, the reaction solution was filtered and concentrated, and the crude product was purified by preparative HPLC to obtain compound 27.

1H NMR (400 MHz, CD3OD) δ=9.17 (br d, J=6.5 Hz, 1H), 8.71 (s, 1H), 8.55 (br s, 1H), 8.16 ( br d, J=8.5 Hz, 1H), 8.02 (br d, J=7.3 Hz, 1H), 7.69-7.60 (m, 3H), 7.42 (br s, 1H), 6.58 (s, 1H), 4.64 (br s, 4H), 3.83 (br s, 3H), 2.85 (br s, 3H), 2.66 (br s, 6H ), 1.97 (br d, J=13.1 Hz, 6H), 1.92 (br s, 4H), 1.30 (br s, 4H).

Example 28 Compound 28A

In addition to replacing the pyrazin-2-ylmethylamine compound with a piperazin-2-one compound, compound 28A was prepared according to the method for preparing compound 18A.

¹ H NMR (400 MHz, CDCl3) δ ppm 7.44 (d, J=2.89 Hz, 1H), 7.23-7.34 (m, 1H), 7.16 (dd, J=9, 16, 3.01 Hz, 1H), 4.13 (t, J=5.21 Hz, 2H), 3.95 (s, 3H), 3.37-3.49 (m, 2H), 3, 33 (s, 2H), 2.92 (t, J=5.27 Hz, 2H), 2.84 (br t, J=5.27 Hz, 2H).

28V connection:

In addition to replacing compound 1E with compound 28A, compound 28B was obtained in accordance with the method for obtaining compound 1F.

1H NMR (400 MHz, CDCl3) δ ppm 2.85 (dt, J=15.50, 5.36 Hz, 4H) 3.31 (s, 2H) 3.35-3.51 (m, 2H) 3 .82 (s, 3H) 3.89-4.17 (m, 2H), 6.36 (d, J=2.89 Hz, 1H), 6.70 (d, J=8.66 Hz, 1H ), 7.29 (s, 1H).

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Compound 28

In addition to replacing compound 1F with compound 28B and replacing compound 1D with compound 4C, compound 28 was obtained in accordance with the method for preparing compound 1.

1H NMR (400 MHz, CD ₃ OD) δ ppm 2.18 (s, 3H), 2.21 (s, 3H), 3.45 (br s, 2H), 3.53-3.73 (m, 4H), 3.82 (br s, 2H), 3.88 (s, 3H), 3.97-4.24 (m, 2H), 6.99 (br d, J=8.44 Hz, 1H ), 7.11 (d, J=8.98 Hz, 1H), 7.31 (br s, 1H), 7.65-7.78 (m, 2H), 8.08 (br d, J= 8.19 Hz, 2H), 8.15-8.33 (m, 3H).

Example 29 Compound 29A

In addition to replacing the pyrazin-2-ylmethylamine compound with a methanesulfonamide compound, compound 29A was prepared according to the method for preparing compound 18A.

Connection 29V

In addition to replacing compound 1E with compound 29A, compound 29B was obtained in accordance with the method for obtaining compound 1F.

Compound 29

In addition to replacing compound 1F with compound 29B and replacing compound 1D with compound 4C, compound 29 was prepared according to the method for preparing compound 1.

1H NMR (400 MHz, CD3OD) δ ppm 2.18 (s, 3H), 2.21 (s, 3H), 3.45 (br s, 2H), 3.53-3.73 (m, 4H) , 3.82 (br s, 2H), 3.88 (s, 3H), 3.97-4.24 (m, 2H), 6.99 (br d, J=8.44 Hz, 1H), 7.11 (d, J=8.98 Hz, 1H), 7.31 (br s, 1H), 7.65-7.78 (m, 2H), 8.08 (br d, J=8, 19 Hz, 2H), 8.15-8.33 (m, 3H).

Example 30 Compound 30A

In addition to the respective replacement of the compounds 1-chloro-2-fluoro-4-methoxy-5-nitrobenzene and 3-methyl-3,9-39 040849 diazaspiro[5.5]undecane with compound 20B and compound 2-chloroethanol, compound 30A was obtained in accordance with the method obtaining compound 1E.

Connection 30V

In addition to replacing compound 1E with compound 30A, compound 30B was prepared according to the method for preparing compound 1F.

Compound 30

In addition to replacing compound 1F with compound 30B and replacing compound 1D with compound 4C, compound 30 was prepared according to the method for preparing compound 1.

1H NMR (400 MHz, CD3OD) δ ppm 1.78 (s, 3H), 1.95-2.06 (m, 4H), 2.09 (s, 3H), 2.13 (s, 3H), 2.71-2.83 (m, 4H), 3.24-3.31 (m, 1H), 3.71-3.81 (m, 1H), 3.85 (s, 3H), 3, 88-3.96 (m, 4H), 4.58-4.86 (m, 7H), 6.67 (s, 1H), 7.53-7.59 (m, 1H), 7.61- 7.68 (m, 2H), 7.94 (d, J=8.07 Hz, 1H), 8.02 (d, J=9.17 Hz, 1H), 8.09 (s, 1H), 8.21 (dd, J=9.05, 3.91 Hz, 1H), 8.30 (br d, J=8.93 Hz, 1H), 8.55 (s, 1H).

Example 31 Compound 31A

Compound 20B (200 mg, 686 µmol) and acetone (199 mg, 3.43 mmol, 252.34 µl) were dissolved in 4 ml of methanol, acetic acid (82.4 mg, 1.37 mmol, 78.52 µl) was added) and stirred at 25°C for 1 hour. The reaction solution was cooled, NaBH ₃ CN (86.2 mg, 1.37 mmol) was added and stirred at 0°C for 1 hour. After completion of the reaction, the reaction solution was concentrated, saturated sodium bicarbonate solution and extracted three times with DCM. The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated to give compound 31A.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.15 (d, J=6.27 Hz, 6H), 1.99-2.03 (m, 5 H), 2.25 (s, 4H) , 2.91-2.97(m, 1H), 2.91-2.97(m, 1H), 2.91-2.97(m, 1H), 2.91-2.97(m, 3H), 3.44 (s, 3H), 3.96 (s, 3H), 6.55-6.56 (m, 1H), 7.83 (s, 1H). LCMS (ESI): mass/charge: 334.1 [M+1].

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Connection 31B

In addition to replacing compound 1E with compound 31A, compound 31B was prepared according to the method for preparing compound 1F.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 1.33 (d, J=6.60 Hz, 5H), 1.82 (br d, J=7.34 Hz, 4H), 2.07 (s, 3H), 2.25 (br s, 1H), 2.72 (br s, 4H), 3.28-3.53 (m, 4H), 3.74 (s, 3H), 4.00-4 .14 (m, 2H), 6.42 (s, 1H), 7.96 (s, 1H). LC-MS (ESI): mass/charge: 304.1 [M+1]

Compound 31

In addition to replacing compound 1F with compound 32B, compound 31 was prepared according to the method for preparing compound 1.

¹ H NMR (400 MHz, MeOD) δ ppm 1.23 (d, J=6.60 Hz, 6H) 1.66 (s, 2H) 1.70 (s, 1H) 1.93 (s, 3H) 1.96 (s, 7H) 2.75 (br s, 4H) 4.58 (s, 8H) 6.64 (s, 1H) 7.48 (s, 1H) 7.87 (d, J=5 .38 Hz, 2H) 8.07-8.17 (m, 3H) 8.55 (s, 1H). LC-MS (ESI): mass/charge: 639.1 [M+1].

Example 32 Compound 32A

In addition to the respective replacement of 1-chloro-2-fluoro-4-methoxy-5-nitrobenzene and 3-methyl-3,9diazaspiro[5.5]undecane compounds by 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene and 2- methyl-2,7diazaspiro[3.5]nonane, compound 32A was obtained in accordance with the method for obtaining compound 1E.

1H NMR (400 MHz, CDClj) δ ppm 2.44 (s, 3H), 3.15-3.22 (m, 4H), 3.19 (s, 8H), 3.98 (s, 3H), 6.57(s, 1H), 8.23(s, 1H).

Connection 32V

In addition to replacing compound 23 with compound 32A and replacing compound tributyl(1ethoxyvinyl)stannan with tributyl(vinyl)stannan, compound 32B was prepared according to the method for preparing compound 24A.

1H NMR (400 MHz, CDCl3) δ ppm 1.27 (s, 2H), 1.80-2.01 (m, 4H), 2.39 (s, 3H), 2.91 (s, 2H), 2.96-3.03 (m, 4H), 3.51 (s, 1H), 3.93-4.04 (m, 3H), 5.27-5.35 (m, 1H), 5, 71 (d, J=17.69 Hz, 1H), 6.51 (s, 1H), 6.72 (dd, J=17.63, 10.98 Hz, 1H), 8.04 (s, 1H ), 8.12 (s, 1H).

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Compound 32C

In addition to replacing compound 49A with compound 32B, compound 32C was prepared according to the method for preparing compound 49B.

Compound 32

In addition to replacing compound 1F with compound 32C and replacing compound 1D with compound 23A, compound 32 was prepared according to the method for preparing compound 1.

1H NMR (400 MHz, CDCl3) δ ppm 0.58-0.55 (m, 3H) 1.93-2.07 (m, 4H) 2.11-2.05 (s, 9H) 2.74- 2.71 (m, 4H) 2.76 (s, 3H), 3.86 (d, J=2.89 Hz, 8H), 7.19 (d, J=3.14 Hz, 1H), 7 .28 (s, 1H), 7.37 (s, 1H), 7.51 (d, J=9.29 Hz, 1H), 8.06 (s, 1H), 8.11 (s, 1H) , 8.41 (dd, J=9.16, 3.76 Hz, 1H), 8.59 (s, 1H), 11.31 (s, 1H).

Example 33 Compound 33

In addition to replacing compound 1D with compound 23A and replacing compound 1F with compound 31B, compound 33 was obtained according to the method for preparing compound 1.

1H NMR (400 MHz, CD3OD) δ ppm 1.22 (d, J=6.36 Hz, 6H) 1.70 (s, 3H) 1.89-2.02 (m, 4H) 2.10 (d , J=13.45 Hz, 6H) 2.76 (br s, 4H) 3.85 (s, 3H) 4.64 (s, 4H) 6.65 (s, 1H) 7.55-7, 60 (m, 2H) 7.61-7.69 (m, 1H) 7.96 (d, J=8.31 Hz, 1H) 8.02-8.10 (m, 2H) 8.19 (s , 1H) 8.38 (d, J=8.80 Hz, 1H) 8.56 (s, 1H). LCMS (ESI) mass/charge: 677.0 [M+1].

Example 34 Compound 34A

In addition to replacing the 2,4,5-trichloropyrimidine compound with a 5-bromo-2,4-dichloropyrimidine compound, compound 34A was prepared according to the method for preparing compound 8E.

¹ H NMR (400 MHz, CD3OD) δ ppm 2.17 (s, 3H), 2.21 (s, 3H), 8.28 (d, J=9.54 Hz, 1H), 8.54 (s , 1H), 8.87 (d, J=2.01 Hz, 1H), 8.90 (d, J=2.01 Hz, 1H), 9.04 (dd, J=9.41, 4, 14 Hz, 1H).

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Connection 34V.

In addition to the corresponding replacement of 1-chloro-2-fluoro-4-methoxy-5-nitrobenzene and 3-methyl-3,9diazaspiro[5.5]undecane compounds by 2-fluoro-4-methoxy-5-nitrotoluene compounds and 3B, compound 34B was obtained in in accordance with the method for obtaining compound 1E.

1H NMR (400 MHz, CDCl3-d) δ=7.74 (s, 1H), 6.47 (s, 1H), 3.86 (s, 3H), 3.27 (br d, J=12, 2 Hz, 2H), 2.712.52 (m, 10 H), 2.44 (br s, 1H), 2.37-2.29 (m, 1H), 2.68-2.27 (m, 1H ), 2.24 (s, 3H), 2.16 (s, 3H), 1.92 (br d, J=12.2 Hz, 2H), 1.73-1.59 (m, 2H).

Compound 34C

In addition to replacing compound 1E with compound 34B, compound 34C was prepared according to the method for preparing compound 1F.

1 H NMR (400 MHz, CDCl ₃ -d) δ=6.57 (d, J=5.0 Hz, 2H), 3.87-3.80 (m, 3H), 3.08 (br d, J =12.0 Hz, 2H), 2.84-2.41(m, 11H), 2.38-2.27(m, 5H), 2.21-2.13(m, 3H), 1 .97-1.87 (m, 2H), 1.76-1.61 (m, 2H).

Compound 34

In addition to replacing compound 1F with compound 34C and replacing compound 1D with compound 34A, compound 34 was prepared according to the method for preparing compound 1.

1H NMR (400 MHz, CD3OD) δ ppm 1.64-1.82 (m, 2H), 2.09 (s, 3H), 2.14 (s, 3H), 2.18 (s, 3H), 2.43 (s, 3H), 2.50 (br t, J=11.43 Hz, 2H), 2.72 (br t, J=11.13 Hz, 6H), 2.82 (br s, 3H), 3.15-3.25(m, 2H), 3.37(s, 1H), 3.86(s, 3H), 6.76(s, 1H), 7.61(s, 1H ), 7.99 (d, J=9.41 Hz, 1H), 8.23 (s, 1H), 8.55 (br s, 1H), 8.83 (dd, J=17.12, 1 .83 Hz, 2H), 8.97 (dd, J=9.48, 4.10 Hz, 1H).

Example 35 Compound 35

In addition to replacing compound 1F with compound 3D and replacing compound 1D with compound 16C, compound 35 was obtained in accordance with the method for preparing compound 1.

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1H NMR (400 MHz, CD3OD) δ ppm 1.71 (br dd, J=12.05, 3.26 Hz, 2H), 1.82 (s, 3H), 1.85 (s, 3H), 1.982 .12 (m, 3H), 2.17 (quin, J=7.34 Hz, 2H), 2.61 (s, 3H), 2.72 (br t, J=11.54 Hz, 3 H) , 2.94-2.98 (m, 10H), 3.15 (br t, J=7.15 Hz, 3H), 3.68 (br d, J=12.55 Hz, 2H), 3. 86 (s, 3H), 6.34 (dd, J=8.91, 2.13 Hz, 1H), 6.65 (d, J=2.26 Hz,

1H), 7.43 (d, J=8.03 Hz, 1H), 7.62 (d, J=8.78 Hz, 1H), 8.00 (s, 1H), 8.52 (br s , 1H).

Example 36 Compound 36

In addition to replacing compound 1F with compound 2B and replacing compound 1D with compound 34A, compound 36 was obtained in accordance with the method for preparing compound 1.

1H NMR (400 MHz, CD3OD) δ ppm 2.00-2.05 (m, 4H), 2.08 (s, 3H), 2.14 (s, 3H), 2.17 (s, 3H), 2.85 (s, 7H), 2.80-2.84 (m, 2H), 3.85 (d, J=4.65 Hz, 5H), 3.80-3.88 (m, 1H) , 3.85-3.87 (m, 1H), 6.73 (s, 1H), 7.62 (s, 1H), 7.98 (d, J=9.54 Hz, 1H), 8, 22 (s, 1H), 8.57 (s, 1H), 8.83 (dd, J=18.95, 1.71 Hz, 2H), 8.95 (dd, J=9.48, 4, 10 Hz, 1H).

Example 37 Compound 37

In addition to replacing compound 1D with compound 34A and replacing compound 1F with compound 20C, compound 37 was obtained in accordance with the method for preparing compound 1.

1H NMR (400 MHz, MeOD) δ ppm 1.99-2.03 (m, 4H), 2.06 (s, 3H), 2.12 (s, 3H), 2.16 (s, 3H), 2.54 (s, 6H), 2.77-2.80 (m, 2H), 2.82 (br d, J=6.53 Hz, 4H), 3.17 (t, J=6, 02 Hz, 2H), 3.71 (s, 4H), 3.84 (s, 4H), 6.70 (s, 1H), 7.61 (s, 1H), 7.95 (br d, J =9.54Hz, 1H), 8.19(d, J=1.51Hz, 1H), 8.54(brs, 1H), 8.79(d, J=1.26Hz, 1H) , 8.84 (s, 1H), 8.92 (br dd, J=9.16, 3.39 Hz, 1H).

Example 38 Compound 38A

In addition to replacing the 2,4,5-trichloropyrimidine compound with a 5-bromo-2,4-dichloropyrimidine compound and replacing compound 1C with compound 16B, compound 38A was prepared according to the method for preparing compound 1D.

1H NMR (400 MHz, CD3OD) δ ppm 1.89 (s, 2H), 1.89-1.89 (m, 1H), 1.92 (s, 3H), 2.12-2.20 (m , 2H), 2.95 (t, J=7.34 Hz, 2H), 3.08-3.16 (m, 2H), 7.49 (d, J=8.07 Hz, 1H), 7 .96 (d, J=3.91 Hz, 1H), 8.37 (s, 1H).

Compound 38

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In addition to replacing compound 1F with compound 3D and replacing compound 1D with compound 38A, compound 38 was obtained in accordance with the method for preparing compound 1.

1H NMR (400 MHz, MeOD) δ ppm 1.66-1.76 (m, 2H), 1.82 (d, J=13.30 Hz, 6 H), 2.04 (br d, J=11 .80 Hz, 2H), 2.17 (quin, J=7.40 Hz, 2H), 2.63 (s, 4H), 2.70 (br t, J=11.80 Hz, 2H), 2 .97 (br t, J=7.28 Hz, 12 H), 3.17 (br t, J=7.28 Hz, 2H), 3.67 (br d, J=12.30 Hz, 2H) , 3.85 (s, 3H), 6.29 (dd, J=8.78, 2.01 Hz, 1H), 6.63 (d, J=2.26 Hz, 1H), 7.44 ( d, J=8.28 Hz, 1H), 7.57 (d, J=8.78 Hz, 1H), 8.09 (s, 1H), 8.52 (br s, 1H).

Example 39 Compound 39

In addition to replacing compound 10E with compound 4C, compound 39 was obtained in accordance with the method for preparing compound 20.

¹ H NMR (400 MHz, CD3OD) δ=9.11 (dd, J=9.54, 4.27 Hz, 1H), 8.85 (s, 1H), 8.80 (s, 1H), 8 .57 (s, 1H), 8.12 (s, 1H), 7.98 (d, J=9.54 Hz, 1H), 7.63 (s, 1H), 6.73 (s, 1H) , 3.85 (s, 3H), 3.55 (s, 4H), 3.03 (t, J=6.53 Hz, 2H), 2.82-2.88 (m, 4H), 2, 65 (t, J=6.65 Hz, 2H), 2.46 (s, 6H), 2.17 (s, 3H), 2.12-2.15 (m, 1H), 2.13 ( d, J=3.51 Hz, 5 H), 1.98-2.03 (m, 4H).

Example 40 Compound 40

In addition to replacing compound 1F with compound 32B and replacing compound 1D with compound 34A, compound 40 was prepared according to the method for preparing compound 1.

1H NMR (400 MHz, CD3OD) δ ppm 0.86 (br t, J=7.34 Hz, 3H), 1.22-1.28 (m, 2H), 2.03 (s, 4H), 2 .14 (s, 3H), 2.18 (s, 3H), 2.51 (q, J=7.46 Hz, 2H), 2.85 (br s, 4H), 2.89 (s, 3H ), 3.86 (s, 3H), 3.90 (s, 4H), 6.79 (s, 1H), 7.67 (s, 1H), 8.00 (d, J=9.54 Hz , 1H), 8.26 (s, 1H), 8.56 (br s, 1H), 8.82 (d, J=1.83 Hz, 1H), 8.87 (d, J=1.83 Hz, 1H).

Example 41 Compound 41A

In addition to replacing the 1-chloro-2-fluoro-4-methoxy-5-nitrobenzene compound with the 1-bromo-2-fluoro-4methoxy-5-nitrobenzene compound and replacing the 3-methyl-3,9-diazaspiro[5.5]undecane compound with the 1methyl -4-(piperidin-4-yl)piperazine, compound 41A was obtained in accordance with the method for obtaining compound 1E.

'H-NMR (400 MHz, CDCl ₃ ) δ ppm 1.72-1.83 (m, 2H), 1.98 (br d, J=12.10 Hz, 4H), 2.29 (s, 3H ), 2.64 (br d, J=4.28 Hz, 5H), 2.70-2.79 (m, 4H), 3.61 (br d, J=12.23 Hz, 2H), 3 .94 (s, 3H), 6.54-6.60 (m, 1H), 8.18-8.21 (m, 1H).

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Connection 41B

In addition to replacing compound 23 with compound 41A and replacing compound tributyl(1ethoxyvinyl)stannan with tributyl(vinyl)stannan, compound 41B was prepared according to the method for preparing compound 24A.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 1.26-1.42 (m, 1H), 1.27-1.41 (m, 1H), 1.66 (s, 3H), 1.68- 1.78 (m, 2H), 1.99 (br d, J=11.86 Hz, 2H), 2.31 (s, 2H), 2.39 (ddt, J=11.20, 7.57 , 3.58, 3.58 Hz, 2H), 2.50 (br s, 2H), 2.66 (br s, 2H), 2.71-2.79 (m, 2H), 3.48 ( br d, J=12.59 Hz, 2H), 3.96 (s, 3H), 5.26-5.32 (m, 1H), 5.69 (d, J=17.61 Hz, 1H) , 6.51 (s, 1H), 6.71 (dd, J=17.67, 10.94 Hz, 1H), 8.10 (s, 1H).

Compound 41C

In addition to replacing compound 1E with compound 41B, compound 41C was obtained in accordance with the method for obtaining compound 1F.

Compound 41

In addition to replacing compound 1F with compound 41C and replacing compound 1D with compound 34A, compound 41 was obtained in accordance with the method for preparing compound 1.

1H NMR (400 MHz, CD3OD) δ=8.90 (d, J=1.8 Hz, 1H), 8.87 (d, J=1.8 Hz, 1H), 8.82 (br s, 1H ), 8.26 (s, 1H), 8.05 (br d, J=9.7 Hz, 1H), 7.48 (s, 1H), 6.91 (s, 1H), 3.87 ( s, 3H), 3.38 (br s, 6H), 3.33 (d, J=1.7 Hz, 2H), 3.26 (br s, 4H), 3.12-3.02 (m , 1H), 2.95 (br t, J=11.7 Hz, 2H), 2.88 (s, 3H), 2.56 (q, J=7.5 Hz, 2H), 2.18 ( s, 3H), 2.14 (s, 3H), 1.99-1.85 (m, 2H), 0.96 (br t, J=7.2 Hz, 3H).

Example 42 Compound 42A

In addition to replacing compound 1A with a benzo[d]thiazol-5-amine compound, compound 42A was prepared according to the method for preparing compound 1B.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 4.37 (br s, 2H), 6.91 (d, J=8.56 Hz, 1H), 7.62-7.75 (m, 1H), 9.00 (s, 1H).

Connection 42V

In addition to replacing compound 1B with compound 42A, compound 42B was prepared according to the method

- 46 040849 for the preparation of compound 1C.

Compound 42C

In addition to replacing compound 1C with compound 42B, compound 42C was prepared according to the method for preparing compound 1D.

1H NMR (400 MHz, DMSO-d6) δ ppm 2.02 (s, 3H), 2.05 (s, 3H), 8.43 (d, J=9.16 Hz, 1H), 8.47 ( s, 1H), 8.67 (dd, J=9.16, 3.26 Hz, 1H), 9.53-9.60 (m, 1H), 12.82 (s, 1H).

Compound 42

In addition to replacing compound 1D with compound 42C and replacing compound 1F with compound 3D, compound 42 was obtained in accordance with the method for preparing compound 1.

1H NMR (400 MHz, CD3OD) δ ppm 1.61-1.73 (m, 2H), 2.00-2.06 (m, 1H), 2.04 (br d, J=14.43 Hz, 1H), 2.08 (s, 2H), 2.07-2.09 (m, 1H), 2.12 (s, 3H), 2.30 (s, 3H), 2.34-2.44 (m, 2H), 2.54 (br s, 4H), 2.67-2.77 (m, 4H), 3.73 (br d, J=12.47 Hz, 2H), 3.85 ( s, 3H), 6.53 (dd, J=8.68, 2.32 Hz, 1H), 6.68 (d, J=2.32 Hz, 1H), 7.66 (d, J=8 .68Hz, 1H), 8.03(s, 1H), 8.08(d, J=9.17Hz, 1H), 8.77(dd, J=9.17, 3.55Hz, 1H ), 9.30 (s, 1H).

Example 43 Compound 43

In addition to replacing compound 1D with compound 7D and replacing compound 1F with compound 3D, compound 43 was prepared according to the method for preparing compound 1.

¹ H NMR (400 MHz, MeOD) δ ppm 1.67-1.79 (m, 2H), 2.06 (br d, J=12.10 Hz, 2H), 2.14 (s, 3H), 2.17 (s, 3H), 2.63 (s, 3H), 2.77 (br t, J=11.37 Hz, 2H), 2.95 (br s, 6H), 3.76 (br d, J=12.35 Hz, 2H), 3.86 (s, 3H), 4.60 (br s, 2H), 6.55 (dd, J=8.68, 2.45 Hz, 1H) , 6.70 (d, J=2.32Hz, 1H), 7.45 (dd, J=8.13, 4.34Hz, 1H), 7.71 (d, J=8.68Hz, 1H), 7.93 (d, J=9.29 Hz, 1H), 8.08 (s, 1H), 8.25 (br d, J=8.07 Hz, 1H), 8.45 (br s, 1H), 8.84 (dd, J=4.28, 1.59 Hz, 1H), 8.88 (dd, J=9.11, 3.73 Hz, 1H).

Example 44 Compound 44A

In addition to the corresponding replacement of 1-chloro-2-fluoro-4-methoxy-5-nitrobenzene and 3-methyl-3,9diazaspiro[5.5]undecane compounds with 1-fluoro-5-methoxy-2-methyl-4-nitrobenzene compounds and N, N-dimethylpiperidin-4-amine, compound 44A was obtained in accordance with the method for obtaining compound 1E.

¹ H NMR (400 MHz, CDCl3) δ=7.83 (s, 1H), 6.55 (s, 1H), 3.94 (s, 3H), 3.34 (br d, J=12.5 Hz, 2H), 2.72 (dt, J=2.0, 11.9 Hz, 2H), 2.35 (s, 6H), 2.32-2.27 (m, 1H), 2, 25 (s, 3H), 1.97 (br d, J=12.5 Hz, 2H), 1.70 (dq, J=3.8, 12.0 Hz, 2H).

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44V connection

In addition to replacing compound 1E with compound 44A, compound 44B was prepared according to the method for preparing compound 1F.

¹ H-NMR (400 MHz, CDCl3) δ=6.58 (s, 1H), 6.57 (s, 1H), 3.82 (s, 3H), 3.56 (br s, 2H), 3 .08 (brd, J=12.0 Hz, 2H), 2.61 (dt, J=1.6, 11.6 Hz, 2H), 2.34 (s, 6H), 2.30-2, 20 (m, 1H), 2.18 (s, 3H), 1.93-1.85 (m, 2H), 1.731.64 (m, 2H).

Compound 44

In addition to replacing compound 1F with compound 44B and replacing compound 1D with compound 34A, compound 44 was prepared according to the method for preparing compound 1.

¹ H NMR (400 MHz, CD3OD) δ=8.93 (dd, J=4.3, 9.5 Hz, 1H), 8.83 (d, J=1.8 Hz, 1H), 8.79 (d, J=2.0 Hz, 1H), 8.19 (s, 1H), 7.95 (d, J=9.5 Hz, 1H), 7.60 (s, 1H), 6.72 (s, 1H), 3.84 (s, 3H), 3.16 (br d, J=11.8 Hz, 2H), 2.69 (br t, J=11.0 Hz, 2H), 2 .53-2.47(m, 1H), 2.45(s, 6H), 2.16(s, 3H), 2.12(s, 3H), 2.07(s, 3H), 2, 04-1.99 (m, 2H), 1.71 (dq, J=3.8, 11.9 Hz, 2H).

Example 45 Compound 45A

In addition to the respective replacement of 1-chloro-2-fluoro-4-methoxy-5-nitrobenzene and 3-methyl-3,9diazaspiro[5.5]undecane compounds by 1-fluoro-5-methoxy-2-methyl-4-nitrobenzene and 1- methylpiperazine, compound 45A was obtained in accordance with the method for obtaining compound 1E.

Connection 45V

In addition to replacing compound 1E with compound 45A, compound 45B was prepared according to the method for preparing compound 1F.

Compound 45

In addition to replacing compound 1D with compound 34A and replacing compound 1F with compound 45B, compound 45 was obtained in accordance with the method for preparing compound 1.

1H NMR (400 MHz, CD3OD) δ=8.97 (dd, J=4.3, 9.4 Hz, 1H), 8.86 (d, J=2.0 Hz, 1H), 8.82 ( d, J=2.0 Hz, 1H), 8.55 (br s, 1H), 8.24 (s, 1H), 8.01 (d, J=9.3 Hz, 1H), 7.67 (s, 1H), 6.78 (s, 1H), 3.88 (s, 3H), 3.30-3.12 (m, 2H), 3.09-2.96 (m, 4H), 2.82 (br s, 3H), 2.51 (s, 3H), 2.18 (s, 3H), 2.15 (s, 3H), 2.10 (s, 3H).

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Example 46 Compound 46A

In addition to the corresponding replacement of 1-chloro-2-fluoro-4-methoxy-5-nitrobenzene and 3-methyl-3,9diazaspiro[5.5]undecane compounds with 1-fluoro-5-methoxy-4-nitro-2-vinylbenzene compounds and N, N-dimethylpiperidin-4-amine 23A, compound 46A was obtained in accordance with the method for obtaining compound 1E.

1H NMR (400 MHz, CDCl ₃ ) δ=8.12 (s, 1H), 7.29 (s, 1H), 6.84-6.63 (m, 1H), 6.53 (s, 1H) , 5.71 (dd, J=1.0, 17.6 Hz, 1H), 5.30 (dd, J=1.0, 11.0 Hz, 1H), 4.00-3.96 (m , 3H), 3.51 (s, 5H), 3.00 (br d, J=6.6 Hz, 1H), 2.82-2.72 (m, 2H), 2.55 (s, 1H ), 2.39 (s, 6H), 2.00 (br d, J=12.5 Hz, 2H), 1.79-1.67 (m, 2H).

Connection 46V

In addition to replacing compound 1E with compound 46A, compound 46B was prepared according to the method for preparing compound 1F.

Compound 46

In addition to replacing compound 1D with compound 34A and replacing compound 1F with compound 46B, compound 46 was obtained according to the method for preparing compound 1.

¹ H NMR (400 MHz, CD3OD) δ=8.84 (s, 2H), 8.80 (br s, 1H), 8.57 (s, 1H), 8.22 (s, 1H), 7, 96 (d, J=9.5 Hz, 1H), 7.69 (s, 1H), 6.79 (s, 1H), 3.85 (s, 3H), 3.22-3.08 (m , 3H), 2.87-2.78 (m, 8H), 2.50 (q, J=7.3 Hz, 2H), 2.16 (s, 4H), 2.12 (s, 4H) , 2.09-1.82 (m, 2H), 0.85 (br t, J=7.3 Hz, 3H).

Example 47 Compound 47A

In addition to the corresponding replacement of 1-chloro-2-fluoro-4-methoxy-5-nitrobenzene and 3-methyl-3,9diazaspiro[5.5]undecane compounds by 1-fluoro-5-methoxy-2-methyl-4-nitrobenzene compounds and N1, N1,N2trimethylethane-1,2-diamine, compound 47A was obtained in accordance with the method for obtaining compound 1E.

1H NMR (400 MHz, CDCl ₃ ) δ=7.80 (s, 1H), 6.55 (s, 1H), 3.93 (s, 3H), 3.23-3.16 (m, 2H) , 2.87 (s, 3H), 2.53-2.47 (m, 2H), 2.24 (s, 9H).

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Connection 47V

In addition to replacing compound 1E with compound 47A, compound 47B was prepared according to the method for preparing compound 1F.

¹ H NMR (400 MHz, CD ₃ OD-d ₄ ) δ=6.70 (s, 1H), 6.60 (s, 1H), 5.00-4.78 (m, 1H), 4.91 (s, 3H), 3.81 (s, 3H), 3.02-2.95 (m, 2H), 2.60 (s, 3H), 2.46-2.40 (m, 2H), 2.24 (s, 5H), 2.26-2.22 (m, 1H), 2.15 (s, 3H).

Compound 47:

In addition to replacing compound 1D with compound 34A and replacing compound 1F with compound 47B, compound 47 was obtained in accordance with the method for preparing compound 1.

¹ H NMR (400 MHz, CD3OD) δ=8.98 (dd, J=4.2, 9.5 Hz, 1H), 8.85 (d, J=2.0 Hz, 1H), 8.80 (d, J=1.8 Hz, 1H), 8.53 (br s, 1H), 8.25 (s, 1H), 8.04 (d, J=9.4 Hz, 1H), 7, 71 (s, 1H), 6.86 (s, 1H), 3.88 (s, 3H), 3.26 (t, J=6.6 Hz, 2H), 3.08-2.99 (m , 2H), 2.69 (s, 9H), 2.17 (s, 3H), 2.12 (d, J=7.6 Hz, 6H).

Example 48 Compound 48A

Compound 34A (100 mg, 242 μmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatricyclohexane was dissolved in water and 1,4-dioxane, and then Pd(dppf)Cl ₂ was added (8.87 mg, 12.1 µmol) and K ₂ CO ₃ (66.9 mg, 484 µmol). The reaction solution was heated to a temperature of 110° C. and stirred for 1 hour under a nitrogen atmosphere. After completion of the reaction, the reaction mixture was concentrated, ethyl acetate was added, washed three times with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness and purified by preparative thin layer chromatography to give compound 48A.

Compound 48

In addition to replacing compound 1D with compound 34A and replacing compound 1F with compound 34C, compound 48 was obtained in accordance with the method for preparing compound 1.

1H NMR (400 MHz, CD3OD) δ ppm 9.03 (br s, 1H), 8.95 (s, 2H), 8.18 (d, J=9.41 Hz, 1H), 7.90 (s , 1H), 7.59 (s, 1H), 7.37 (s, 1H), 3.98-4.00 (m, 1H), 3.99 (s, 2H), 3.97 (s, 1H), 3.82 (br d, J=10.51 Hz, 5H), 3.70 (br d, J=10.27 Hz, 3H), 3.27-3.37 (m, 5H), 3.09 (s, 3H), 2.48-2.65 (m, 4H), 2.36 (d, J=12.59 Hz, 6H), 2.20 (d, J=14.55 Hz , 7H).

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Example 49 Compound 49A

Compound 34 (150 mg, 215 µmol, 1 eq.) and 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2 dioxaborolane (72.5 mg, 431 µmol) were added to a mixed solvent of dimethyl ether ethylene glycol and water, then Pd(PPh ₃ ) ₄ (24.9 mg, 21.60 µmol) and Na ₂ CO ₃ (45.7 mg, 431 µmol) were added and stirred at 90° C. for 6 h under protective atmosphere gaseous nitrogen. After completion of the reaction, DCM was added to the reaction solution and washed three times with water. The organic phase was dried and concentrated to give the crude product. The crude product was separated by preparative thin layer chromatography to give compound 49A.

Connection 49V

Compound 49A (90 mg, 113.71 µmol) was dissolved in MeOH (10 mL) and wet palladium-carbon (20 mg, 113.71 µmol, 10% purity, 50% water content) was added. The reaction system was purged with a hydrogen balloon and stirred at 20-30° C. for 18 hours at atmospheric pressure. After completion of the reaction, the reaction system was filtered and the filtrate was concentrated to give compound 49B.

Compound 49

MnO ₂ (39.4 mg, 453 µmol, 10 eq.) was added to a solution of compound 49B (30 mg, 45.33 µmol, 1 eq.) in toluene and the mixture was stirred at 30°C for 12 h. After completion of the reaction the mixture was diluted with DCM and filtered. The filtrate was concentrated to give the crude product. The crude product was separated by thin layer chromatography to give compound 49.

¹ H-NMR (400 MHz, CD3OD) δ=9.14 (dd, J=4.2, 9.5 Hz, 1H), 8.83 (d, J=2.0 Hz, 1H), 8, 77 (d, J=2.0 Hz, 1H), 8.07 (s, 1H), 7.99 (d, J=9.8 Hz, 1H), 7.71 (s, 1H), 6, 77 (s, 1H), 3.87 (s, 3H), 3.19 (br d, J=13.2 Hz, 2H), 2.84-2.48 (m, 10H), 2.47- 2.38 (m, 1H), 2.35 (s, 3H), 2.17 (s, 3H), 2.14 (s, 3H), 2.09 (s, 3H), 2.03 (br d, J=12.0 Hz, 2H), 1.79-1.66 (m, 2H), l.34(d, J=6.8 Hz, 6H).

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Example 50.

Compound 50

Compound 34 (0.1 g, 143 µmol, 1 eq.) and cyclopropylboronic acid (49.4 mg, 575.87 µmol, 4 eq.) were added to a mixed solvent of toluene and water, and Pd(OAc) ₂ (3 .23 mg, 14.4 µmol, 0.1 eq.), tricyclohexylphosphine (8.07 mg, 28.7 µmol, 0.2 eq.) and K ₂ CO ₃ (76.4 mg, 359.9 µmol, 2.5 eq.). The mixture was stirred at 90° C. for 6 hours under a protective atmosphere of nitrogen gas. After completion of the reaction, the reaction system was diluted by adding DCM and washed once with water, and the organic phase was dried and concentrated to obtain the crude product. The crude product was separated by acid preparative high performance liquid chromatography to give compound 50.

¹ H NMR (400 MHz, CD3OD) δ=9.19 (dd, J=4.2, 9.5 Hz, 1H), 8.82 (d, J=1.7 Hz, 1H), 8.75 (d, J=2.0 Hz, 1H), 8.52 (br s, 1H), 7.96 (d, J=9.5 Hz, 1H), 7.88 (s, 1H), 7, 70 (s, 1H), 6.73 (s, 1H), 3.85 (s, 3H), 3.18 (br d, J=11.7 Hz, 2H), 3.02 (br s, 8H ), 2.71 (br t, J=11.7 Hz, 3H), 2.67 (s, 3H), 2.18-2.09 (m, 9H), 2.04 (br d, J= 11.0 Hz, 2H), 1.83-1.71 (m, 3H), 1.08-1.01 (m, 2H), 0.66-0.60 (m, 2H).

Example 51 Compound 51A

In addition to replacing the 2,4,5-trichloropyrimidine compound with a 5-bromo-2,4-dichloropyrimidine compound and replacing compound 1C with compound 42B, compound 51A was prepared according to the method for preparing compound 1D.

Compound 51

In addition to replacing compound 1D with compound 51A and replacing compound 1F with compound 34C, compound 51 was prepared according to the method for preparing compound 1.

1H NMR (400 MHz, CD3OD) δ ppm 9.31 (s, 1H), 8.55 (dd, J=9.17, 3.42 Hz, 1H), 8.15 (s, 1H), 8, 07 (d, J=9.17 Hz, 1H), 7.67 (s, 1H), 6.72 (s, 1H), 3.84 (s, 3H), 3.31 (dt, J=3 .21, 1.64 Hz, 2H), 2.63-2.98 (m, 10H), 2.52.59 (m, 1H), 2.48 (s, 3H), 2.12 (s, 3H) , 2.09 (s, 3H), 2.04 (s, 3H), 2.01 (br s, 2H), 1.64-1.76 (m, 2H).

Example 52 Compound 52A

In addition to the corresponding replacement of 1-chloro-2-fluoro-4-methoxy-5-nitrobenzene and 3-methyl-3,9diazaspiro[5.5]undecane compounds by 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene compounds and N, N-dimethylpiperidin-4-amine, compound 52A was obtained in accordance with the method for obtaining compound 1E.

Connection 52V

- 52 040849

Compound 52A (0.1 g, 279 µmol, 1 eq), 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (234 mg, 1.40 mmol, 5 eq) was dissolved in a mixed solvent of DME and H ₂ O and Pd(PPh ₃ ) ₄ (32.2 mg, 27.9 µmol, 0.1 eq) and Na ₂ CO ₃ (59.1 mg, 558 µmol, 2 eq) were added. The reaction system was purged 3 times with nitrogen gas and stirred at 110° C. for 12 hours under nitrogen. The reaction solution was diluted with DCM, washed three times with water, and separated. The organic phase was dried over anhydrous sodium sulfate and then filtered. The filtrate was evaporated to dryness to give compound 52B.

Compound 52C

In addition to replacing compound 49A with compound 52B, compound 52C was prepared according to the method for preparing compound 49B.

Compound 52

In addition to replacing compound 1D with compound 34A and replacing compound 1F with compound 52C, compound 52 was obtained in accordance with the method for preparing compound 1.

1H NMR (400 MHz, CD3OD) δ ppm 0.96 (d, J=6.85 Hz, 6H), 1.74-1.86 (m, 2H), 2.10 (br d, J=12, 47 Hz, 2H), 2.14 (s, 3H) 2.17 (s, 3H), 2.64 (s, 6H), 2.85 (br t, J=11.19 Hz, 3H), 3 .13 (br d, J=11.86 Hz, 3H), 3.85 (s, 3H), 6.86 (s, 1H), 7.58 (s, 1H), 7.96 (d, J =9.29Hz, 1H), 8.26(s, 1H), 8.80(d, J=1.83Hz, 1H), 8.85(d, J=1.83Hz, 1H).

Example 53 Compound 53A

In addition to replacing the 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane compound with a cyclopropylboronic acid compound, compound 53A was prepared according to the method for preparing compound 52B.

Connection 53V

In addition to replacing compound 1E with compound 53A, compound 53B was prepared according to the method for preparing compound 1F.

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Compound 53

In addition to replacing compound 1D with compound 34A and replacing compound 1F with compound 53B, compound 53 was obtained in accordance with the method for preparing compound 1.

1H NMR (400 MHz, CD3OD) δ ppm 0.28 (br d, J=3.91 Hz, 2H), 0.59 (br d, J=7.83 Hz, 2H), 1.81-1, 97 (m, 2H), 2.16 (d, J=14.43 Hz, 9H), 2.78 (s, 6H), 2.80-2.88 (m, 2H), 3.05 ( br t, J=11.86 Hz, 1H), 3.47 (br d, J=12.23 Hz, 2H), 3.86 (s, 3H), 6.77 (s, 1H), 7, 17 (s, 1H), 7.95 (d, J=9.54 Hz, 1H), 8.24 (s, 1H), 8.56 (s, 1H), 8.80 (d, J=1 .83 Hz, 1H), 8.86 (d, J=1.83 Hz, 1H).

Example 54 Compound 54A

In addition to the respective replacement of 1-chloro-2-fluoro-4-methoxy-5-nitrobenzene and 3-methyl-3,9diazaspiro[5.5]undecane compounds by 1-chloro-2-fluoro-4-methoxy-5-nitrobenzene and 1- methyl-4-(piperidin-4-yl)piperazine, compound 54A was obtained in accordance with the method for obtaining compound 1E.

¹ H NMR (400 MHz, CD3OD) δ=6.79 (s, 1H), 6.68 (s, 1H), 3.84 (s, 3H), 3.24-2.76 (m, 8H) , 2.72 (br s, 1H), 2.71-2.65 (m, 2H), 2.02 (br d, J=10.8 Hz, 2H), 1.89-1.71 (m , 2H).

Connection 54V

In addition to replacing compound 1E with compound 54A, compound 54B was prepared according to the method for preparing compound 1F.

1H NMR (400 MHz, CDCl ₃ ) δ=8.04 (s, 1H), 6.56 (s, 1H), 4.02-3.91 (m, 3H), 3.65 (br d, J =12.1 Hz, 2H), 2.81-2.73(m, 2H), 2.66(brs, 4H), 2.56-2.37(m, 5H), 2.31( s, 3H), 1.98 (br d, J=12.2 Hz, 2H), 1.84-1.71 (m,

2H).

Compound 54

In addition to replacing compound 1D with compound 34A and replacing compound 1F with compound 11B, compound 54 was prepared according to the method for preparing compound 1.

1H NMR (400 MHz, CD3OD) δ=8.88 (dd, J=4.2, 9.4 Hz, 1H), 8.85 (d, J=1.7 Hz, 1H), 8.81 ( d, J=1.7Hz, 1H), 8.27(s, 1H), 8.15(d, J=9.4Hz, 1H), 7.97(s, 1H), 6.78( s, 1H), 3.90 (s, 3H), 3.39 (br d, J=11.1 Hz, 2H), 2.95-2.56 (m, 10 H), 2.48 (br t, J=11.6 Hz, 1H), 2.41 (s, 3H), 2.15 (d, J=14.4 Hz, 6H), 2.01 (br d, J=11.6 Hz , 2H),

- 54 040849

1.82-1.67 (m, 2H).

Example 55 Compound 55A

In addition to replacing compound 52A with 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene compound, compound 55A was prepared according to the method for preparing compound 52B.

¹ H NMR (400 MHz, CDCl ₃ ) δ=7.95 (d, J=7.9 Hz, 1H), 6.78 (d, J=12.3 Hz, 1H), 5.36-5, 26 (m, 2H), 3.97 (s, 3H), 2.14 (s, 3H).

Connection 55V

In addition to the corresponding replacement of 1-chloro-2-fluoro-4-methoxy-5-nitrobenzene and 3-methyl-3,9diazaspiro[5.5]undecane compounds by compounds 55A and 1-methyl-4-(piperidin-4-yl)piperazine, compound 55B was obtained in accordance with the method for obtaining compound 1E.

Compound 55C

In addition to replacing compound 49A with compound 55B, compound 55C was prepared according to the method for preparing compound 49B.

Compound 55

In addition to replacing compound 1D with compound 34A and replacing compound 1F with compound 55C, compound 55 was prepared according to the method for preparing compound 1.

1H NMR (400 MHz, CD3OD) δ=8.83 (d, J=1.8 Hz, 2H), 8.79 (d, J=1.8 Hz, 1H), 8.24 (s, 1H) , 7.94 (br d, J=9.8 Hz, 1H), 7.53 (s, 1H), 6.84 (s, 1H), 3.83 (s, 3H), 3.45-3 .37 (m, 2H), 3.08 (br d, J=10.9 Hz, 2H), 2.91-2.47 (m, 1H), 2.79 (br t, J=11.1 Hz, 8H), 2.41 (br s, 1H), 2.33 (s, 3H), 2.14 (d, J=14.4 Hz, 6H), 2.03 (br d, J=11 .0 Hz, 2H), 1.77-1.64 (m, 2H), 1.30 (s, 2H), 0.95 (br d, J=6.8 Hz, 6H).

Example 56 Compound 56A

In addition to replacing compound 52A with 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene compound, compound 56A was prepared according to the method for preparing compound 53A.

1H NMR (400 MHz, CDCl ₃ ) δ=7.57 (d, J=7.8 Hz, 1H), 6.76 (d, J=11.4 Hz, 1H), 3.94 (s, 3H ), 2.08-1.92 (m, 1H), 1.09-0.94 (m, 2H), 0.81-0.65 (m, 2H).

- 55 040849

Connection 56V

In addition to the respective replacement of the compound 1-chloro-2-fluoro-4-methoxy-5-nitrobenzene and 3-methyl-3,9diazaspiro[5.5]undecane by compounds 56A and 1-methyl-4-(piperidin-4-yl)piperazine, the compound 56B was obtained in accordance with the method for obtaining compound 1E.

1H NMR (400 MHz, CDCl ₃ ) δ=7.51 (s, 1H), 6.57-6.48 (m, 1H), 3.94 (s, 3H), 3.63 (br d, J =12.0 Hz, 2H), 2.83-2.45 (m, 11H), 2.43-2.36 (m, 1H), 2.31 (s, 3H), 2.06-1, 93 (m, 4H), 1.79-1.67 (m, 2H), 1.34-1.21 (m, 1H), 1.07-0.94 (m, 2H), 0.78- 0.69 (m, 2H).

Compound 56C

In addition to replacing compound 1E with compound 56B, compound 56C was prepared according to the method for preparing compound 1F.

1 H NMR (400 MHz, CDCl ₃ ) δ=6.62-6.51 (m, 1H), 6.13 (s, 1H), 3.84-3.80 (m, 3H), 3.33- 3.21(m, 2H), 2.81-2.40(m, 12H), 2.32(s, 3H), 1.93(brd, J=11.5Hz, 2H), 1, 78-1.68 (m, 2H), 1.31-1.17 (m, 1H), 0.92-0.84 (m, 2H), 0.67-0.53 (m, 2H).

Compound 56

In addition to replacing compound 1D with compound 34A and replacing compound 1F with compound 56C, compound 56 was prepared according to the method for preparing compound 1.

1H NMR (400 MHz, CD3OD) δ=8.85-8.79 (m, 2H), 8.77 (d, J=1.8 Hz, 1H), 8.20 (s, 1H), 7, 98-7.86 (m, 1H), 7.11 (s, 1H), 6.73 (s, 1H), 3.82 (s, 3H), 3.38 (br d, J=11.7 Hz, 2H), 2.87-2.49 (m, 10 H), 2.42 (br t, J=11.6 Hz, 1H), 2.33 (s, 3H), 2.13 (d , J=14.4 Hz, 6H), 2.02 (br d, J=10.9 Hz, 2H), 1.79-1.64 (m, 2H), 1.42-1.07 (m , 2H), 0.89-0.86 (m, 2H), 0.56 (br d, J=7.8 Hz, 2H), 0.25 (br d, J=3.8 Hz, 2H) .

Example 57 Compound 57A

In addition to replacing the 1-chloro-2-fluoro-4-methoxy-5-nitrobenzene compound with the 1-fluoro-5methoxy-2-methyl-4-nitrobenzene compound, compound 57A was prepared according to the method for preparing compound 1E.

1H NMR (400 MHz, CDCl3) δ=7.75 (s, 1H), 6.48 (s, 1H), 3.87 (s, 3H), 2.93-2.85 (m, 4H), 2.33 (br s, 4H), 2.23 (s, 3H), 2.16 (s, 3H), 1.61-1.53 (m, 8H).

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Connection 57B

In addition to replacing compound 1E with compound 57A, compound 57B was prepared according to the method for preparing compound 1F.

1 H NMR (400 MHz, CDCl ₃ ) δ=6.62 (s, 1H), 6.58 (s, 1H), 3.85 (s, 3H), 3.61-3.50 (m, 2H) , 2.82-2.75 (m, 4H), 2.41 (br s, 4H), 2.32 (s, 3H), 2.19 (s, 3H), 1.65-1.60 ( m, 8H).

Compound 57

In addition to replacing compound 1D with compound 34A and replacing compound 1F with compound 57B, compound 57 was prepared according to the method for preparing compound 1.

1H NMR (400 MHz, CD3OD) δ=8.89 (dd, J=4.2, 9.5 Hz, 1H), 8.81 (d, J=1.7 Hz, 1H), 8.77 ( d, J=2.0 Hz, 1H), 8.58 (s, 1H), 8.16 (s, 1H), 7.91 (d, J=9.5 Hz, 1H), 7.58 ( s, 1H), 6.73 (s, 1H), 3.83 (s, 3H), 3.16 (br s, 4H), 2.89-2.82 (m, 4H), 2.81 ( s, 3H), 2.12 (d, J=14.2 Hz, 6H), 2.04 (s, 3H), 1.84 (br s, 4H), 1.73 (br s, 4H).

Example 58 Compound 58A

In addition to replacing the 1-chloro-2-fluoro-4-methoxy-5-nitrobenzene compound with the 1-fluoro-5methoxy-4-nitro-2-vinylbenzene compound, compound 58A was prepared according to the method for preparing compound 1E.

1H NMR (400 MHz, CDCl3) δ=8.03 (s, 1H), 6.64 (dd, J=11.0, 17.9 Hz, 1H), 6.45 (s, 1H), 5, 61 (dd, J=1.1, 17.7 Hz, 1H), 5.19 (dd, J=1.1, 10.9 Hz, 1H), 3.89 (s, 3H), 3.02 -2.93 (m, 4H), 2.36-2.28 (m, 4H), 2.23 (s, 3H), 1.56 (td , J=5.5, 15.1 Hz, 8H ).

Connection 58V

In addition to replacing compound 49A with compound 58A, compound 58B was prepared according to the method for preparing compound 49B.

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Compound 58

In addition to replacing compound 1D with compound 34A and replacing compound 1F with compound 58B, compound 58 was prepared according to the method for preparing compound 1.

1H NMR (400 MHz, CD3OD) δ=8.88-8.82 (m, 2H), 8.80 (d, J=1.7 Hz, 1H), 8.57 (s, 1H), 8, 21 (s, 1H), 7.96 (d, J=9.5 Hz, 1H), 7.64 (s, 1H), 6.83 (s, 1H), 3.85 (s, 3H), 3.13 (br s, 4H), 2.92-2.83 (m, 4H), 2.79 (s, 3H), 2.49 (q, J=7.6 Hz, 2H), 2. 14 (d, J=14.4 Hz, 6H), 1.85 (br s, 4H), 1.74 (br s, 4H), 0.84 (br t, J=7.5 Hz, 3H) .

Example 59 Compound 59

-f -G

In addition to the respective replacement of compounds 1D and 1F with compounds 8E and 3D, compound 59 was obtained in accordance with the method for preparing compound 1.

¹ H NMR (400 MHz, CD3OD) δ=9.08 (d, J=4.2, 9.5 Hz, 1H), 8.79 (d, J=1.8 Hz, 1H), 8.75 (d, J=1.8 Hz, 1H), 8.53 (s, 1H), 8.04 (s, 1H), 7.92 (d, J=9.5 Hz, 1H), 7.57 (d, J=8.7Hz, 1H), 6.63 (d, J=2.3Hz, 1H), 6.46 (d, J=2.3, 8.7Hz, 1H), 3 .82 (s, 3H), 3.74-3.66 (m, 6H), 3.70 (d, J=12.2 Hz, 2H), 2.69 (t, J=11.6 Hz, 3H), 2.55 (s, 1H), 2.52 (s, 3H), 2.12 (s, 3H), 2.09 (s, 3H), 2.00 (d, J=12.2 Hz, 2H), 1.67 (q, J=3.7, 12.0 Hz, 2H).

Example 60 Compound 60

In addition to the respective replacement of compounds 1D and 1F with compounds 34A and 3D, compound 60 was obtained in accordance with the method for preparing compound 1.

1H NMR (400 MHz, CD3OD) δ=8.98 (dd, J=4.2, 9.5 Hz, 1H), 8.82 (d, J=2.0 Hz, 1H), 8.78 ( d, J=2.0 Hz, 1H), 8.52 (s, 1H), 8.18 (s, 1H), 7.98 (d, J=9.5 Hz, 1H), 7.59 ( d, J=8.7 Hz, 1H), 6.67 (d, J=2.4 Hz, 1H), 6.50 (dd, J=2.4, 8.7 Hz, 1H), 3, 84 (s, 3H), 3.73 (br d, J=12.7 Hz, 2H), 2.97-2.61 (m, 10 H), 2.60-2.52 (m, 1H) , 2.49 (s, 3H), 2.14 (s, 3H), 2.11 (s, 3H), 2.03 (br d , J=12.3 Hz, 2H), 1.78-1 .63 (m, 2H).

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Example 61 Compound 61

In addition to the corresponding replacement of compounds 1D and 1F with compounds 8E and 34C, compound 61 was obtained in accordance with the method for preparing compound 1.

1H NMR (400M Hz, CD3OD) δ=9.05 (dd, J=4.2, 9.5 Hz, 1H), 8.80 (d, J=1.7 Hz, 1H), 8.75 ( d, J=1.8 Hz, 1H), 8.53 (s, 1H), 8.06 (s, 1H), 7.92 (d, J=9.5 Hz, 1H), 7.59 ( s, 1H), 6.69 (s, 1H), 3.81 (s, 3H), 3.14 (br d, J=11.7 Hz, 2H), 3.01-2.54 (m, 11 H), 2.52 (s, 3H), 2.13 (s, 2H), 2.16-2.12 (m, 1H), 2.10 (s, 3H), 2.08 (s, 3H), 2.00 (br d, J=11.7 Hz, 2H), 1.79-1.65 (m, 2H).

Example 62 Compound 62

In addition to replacing compound 1D with compound 8E, compound 62 was prepared according to the method for preparing compound 1.

1H NMR (400 MHz, DMSO-d6) δ=12.92 (s, 1H), 9.08-8.94 (m, 1H), 8.87 (dd, J=2.0, 9.2 Hz , 2H), 8.35 (s, 1H), 8.29-8.21 (m, 2H), 8.04 (d, J=9.6 Hz, 1H), 7.72 (s, 1H) , 6.90 (s, 1H), 3.84 (s, 3H), 3.00-2.92 (m, 4H), 2.562.53 (m, 4H), 2.32 (s, 3H), 2.06 (s, 3H), 2.02 (s, 3H), 1.65-1.54 (m, 8H); LC-MS (ESI): mass/charge: 655.0 [M+1].

Comparative Example 1 Comparative Compound 1A

Dissolve 4-nitrobenzene-1,2-diamine (10 g, 65.30 mmol) in HCOOH (9.03 g, 187.92 mmol, 7.40 ml) and add hydrochloric acid solution (5 M, 100.00 ml ). The mixture was stirred at 110° C. for 15 hours. After completion of the reaction, the reaction solution was brought to neutrality with 2 M sodium hydroxide solution and a large amount of solids precipitated. After filtration, the filter cake was dried to give the crude product. The crude product was recrystallized from water to obtain comparative compound 1A.

1H NMR (400 MHz, CD ₃ OD-d ₆ ) δ=8.55 (d, J=1.6 Hz, 1H), 8.44 (s, 1H), 8.22-8.19 (m, 1H), 7.74 (d, J=8.8 Hz, 1H).

Comparative connection 1B

In addition to replacing Compound 1E with Comparative Compound 1A, Comparative Compound 1B was prepared according to the method for preparing Compound 1F.

1H NMR (400 MHz, CD3OD-d6) δ=7.93 (s, 1H), 7.37 (d, J=8.8 Hz, 1H), 6.93 (s, 1H), 6.78- 6.75(m, 1H).

Reference compound 1C rA

Η ₂ νΎ^ ^ν

I

Comparative compound 1B (7.8 g, 58.58 mmol) was dissolved in 100 ml AcOH, iodine (14.87

- 59 040849 g, 58.58 mmol) and sodium acetate (9.61 g, 117.16 mmol) and the reaction mixture was stirred at 25°C for 2 hours. After completion of the reaction, acetic acid was removed by concentration under reduced pressure and the reaction mixture was adjusted to pH approximately 9 with 1 M sodium hydroxide solution. The mixture was extracted with dichloromethane and washed successively with water and brine, and the organic phase was collected and dried. Concentration gave the crude product. The crude product was subjected to column chromatography to obtain comparative compound 1C.

1H-NMR (400 MHz, CD ₃ OD-d ₆ ) δ=8.00 (s, 1H), 7.34 (m, J=8.8 Hz, 1H), 6.84 (d, J=8 .8 Hz, 1H).

Comparative connection 1D

In addition to replacing Compound 1B with Comparative Compound 1C and replacing Compound 1F with Compound 31B, Comparative Compound 1D was prepared according to the method for preparing Compound 1C.

1H NMR (400 MHz, CD ₃ OD-d ₆ ) δ=7.88 (s, 1H), 7.44 (d, J=5.2 Hz, 1H), 6.61-6.58 (m, 1H), 2.03(s, 1H), 1.99(s, 1H).

Comparative connection 1E

YayL

H

II O

In addition to replacing Compound 1C with Comparative Compound 1D, Comparative Compound 1E was prepared according to the method for preparing Compound 1D.

1H NMR (400 MHz, DMSO-d ₆ ) δ=12.84 (s, 1H), 12.33 (s, 1H), 8.43-8.36 (m, 3H), 7.82 (d, J=9.6 Hz, 1H), 2.03 (s, 3H), 1.99 (s, 3H).

Reference Compound 1

In addition to the respective replacement of compounds 1D and 1F with comparative compound 1E and compound 3D, comparative compound 1 was prepared according to the method for preparing compound 1.

1H NMR (400 MHz, CD3OD-d6) δ=8.50 (s, 1H), 8.36-8.08 (m, 2H), 8.00 (s, 1H), 7.82-7.68 (m, 1H), 7.59 (br s, 1H), 6.63 (d, J=1.8 Hz, 1H), 6.24 (br s, 1H), 3.84 (s, 3H) , 3.66 (br d, J=11.9 Hz, 2H), 3.13-2.78 (m, 8H), 2.76-2.56 (m, 6H), 2.01 (br d , J=14.1 Hz, 8H), 1.80-1.59 (m, 2H).

Experimental Example 1 Enzyme Activity Experiment (1) Experimental procedure

1. Getting a connection

1) Place 10 µl of compounds to be tested and reference compounds diluted to 10 mM in an Echo LDV plate and dilute them according to the compound profile with Echo.

2. Reaction steps

1) Received 1xenzyme reaction buffer: 1xenzyme buffer, 5 mm MgCl ₂ , 1 mm DTT (dithiothreitol), water.

2) A mixed solution of 10 nM enzyme (final concentration 5 nM) and 2 μM substrate (final concentration 1 μM) and a solution containing only the substrate were prepared with diluted enzyme reaction buffer.

3) Add 5 µl of substrate to A1-H1, J24-P24 (well position number) and add 5 µl of enzyme/substrate mixture to the remaining wells.

4) Centrifugation was carried out at 1000 rpm at 23° C. for 30 seconds.

5) Incubation was carried out at 23°C for 15 minutes.

6) 5 µl of 40 µM ATP (EGFR (Δ19del/T790M/C797S), final concentration of ATP 20 µM prepared with 1 x enzyme buffer solution was added.

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7) Centrifugation was carried out at 1000 rpm. at 23°C for 30 s.

8) Incubation was carried out at 23°C for 60 min.

9) 10 µl of 250 nM TK-cryptate antibody (final concentration 125 nM) and 1xD2 (final concentration in 1/2-fold) prepared with detection buffer was added.

10) Centrifugation was carried out at 1000 rpm at 23° C. for 30 seconds.

11) Incubation was carried out at 23°C for 60 minutes.

12) The data was read using Envision and the ratio was calculated to give the IC ₅₀ of the compound to inhibit enzymatic activity.

Experimental results: IC ₅₀ compounds according to the present application to suppress the enzymatic activity of EGFR (A19del/T790M/C797S) are shown in table. 1.

Conclusion: from the table. 1 shows that the preferred compounds of the present application have strong inhibitory effects on EGFR enzymatic activity (A19del/T790M/C797S).

Experimental Example 2 Enzyme Activity Experiment (2)

1. Gradient compound dilution: 40 µl of a solution of test compound (which was diluted to 0.1 mM) and reference compound (at 0.1 and 0.03 mM), respectively, were taken and added to a 384-well Echo PP plate. Dilution and transfer of compounds was performed using Echo from Labcyte Inc. with a 3-fold concentration gradient, 11 dose points in total and 100 nL of compounds per well. The maximum concentration of test compounds in kinase reaction solutions was 1000 nM. The maximum concentration of the reference compound (crizotinib and AP26113) in the kinase reaction solution was 1000 nM. The maximum concentration of the reference compound (AZD9291) in the kinase reaction solution was 300 nM.

2. Enzymatic reaction (1) In a 384-well test plate, except for wells A1-H1 and I24-P24, 5 µl of a mixed solution of 2xEGFR WT and TK peptide (0.1 nM EGFR WT, 2 µM TA) or 5 µl of a mixed solution of 2xEGFR C797S T790M L858R and TK peptide (0.4 nM EGFR C797S/T790M/L858R, 2 µM TK); 5 μl of kinase reaction buffer was added to wells A1-H1 and I24-P24 as a 100% inhibition control. The plate was centrifuged at 1000 rpm for 60 s. The test plate was incubated at 23°C for 15 minutes.

(2) 5 μl of 2x ATP solution (EGFR WT: ATP at 50 μM; EGFR (C797S/T790M/L858R): ATP at 20 μM) was added to the test plate in each well and centrifuged at 1000 rpm for 60 seconds.

(3) The test plate was covered with a seal film and incubated at 23°C for 90 minutes.

(4) 2x detection solution (4 nM TK antibody and 125 nM XL665), 10 µl per well, was added to the test plates, and centrifuged at 1000 rpm for 60 seconds, and covered with a sealing film, the obtained was incubated at 23°C within 60 min.

(5) Plates were read on an Envision multi-channel detector.

Data analysis. Data analysis was performed according to formula 205 using XLfit software to obtain IC ₅₀ compounds.

Experimental results. IC ₅₀ compounds according to the present application to suppress the enzymatic activity of EGFR (WT) and EGFR (C797S/T790M/L858R) are shown in table. 1.

Conclusion. From Table. 1 shows that the compounds of the present application have better selectivity for EGFR enzyme activity (WT) and better inhibition of EGFR enzyme activity (C797S/T790M/L858R).

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Example Connections EGFR (WT) 1C ₅₀ (nM) EGFR (A19del/T790M/C797S) 1C ₅₀ (nM) EGFR (L858R/T790M/C797S) 1C ₅₀ (nM) 1 - 2.64 - 2 - 0.613 - 5 - 1.63 - 6 - 2.54 - 8 - 0.792 - 9 - 0.485 - 13 - 5.79 - 16 - 0.491 - 17 - 856 - 18 - 25.3 - 19 - 12.9 - 20 - <0.0508 - 21 - 30.6 - 23 - 0.0517 - 25 - 1.79 - 26 - 0.679 - 28 - 185 - 29 - 67.6 - 34 7.92 0.218 0.16 41 5.12 0.212 0.26 44 eleven 0.281 0.21

Table 1

Experimental Example 3 Anti-proliferative effect experiment on cells (1)

Experimental way

1) Cell culture and subculture (1) A431 medium: 88% DMEM + 10% fetal bovine serum + 1% L-glutamine + 1% double antibody (2) A431 cells were isolated and subcultured every 3-4 days, with the number of cells for the 3 day passage was 5e6 cells per T75 culture flask, and the number of cells for the 4 day passage was 3e6 cells per T75 culture flask.

2) Day 1 Cell Plate Preparation (1) Phosphate buffer, trypsin and culture medium were placed in a water bath at 37°C for preheating.

(2) The stock medium was removed from the cell culture flask and washed once with 6 ml of PBS.

(3) Pipette 5 ml of phosphate buffer into a culture flask to wash the cells (reseeding 17), and then discard the liquid.

(4) 3.5 ml of trypsin was added to the cell culture flask, and the trypsin was removed with gentle shaking after complete contact with the cells, and then the culture flask was placed in an incubator containing 5% CO2 at 37°C for about 1 minute;

(5) Cells were resuspended in 10 ml of cell culture medium and approximately 0.6 ml of cell suspension was taken for counting (ViCell XR);

(6) The cell suspension was diluted with medium to a cell density of 5e4 cells per ml required for seeding (cell concentration: 2500 cells per well);

(7) 100 μl of phosphate buffer solution was added to each well along the edge of the cell plate, while 50 μl of cell suspension was added to other wells, and the plate was incubated overnight in an incubator containing 5% CO ₂ at 37°C.

3) Day 2 Dose Addition (1) 9 μl of compound (concentration: 1 mM) was added to a shallow Echo well plate.

(2) A shallow well plate was centrifuged at 1000 rpm for 10 seconds, and the cell plate was removed from the incubator.

(3) According to the microplate scheme, compounds were diluted at a 3-fold concentration gradient with Echo, each compound was diluted to 10 concentration gradients, and 250 nl of diluted compounds were respectively added to the cell plate, and then the cell plate was returned to the incubator and further incubated for 3 days .

4) Day 5 CTG Addition and Plate Reading (1) After incubation for 72 hours, 25 μl of CellTiter Glo was added to each well of the cell plate followed by shaking the plate for 10 minutes in the dark.

(2) The plate was read on Envision.

Data Analysis: Using computer approximation, the corresponding concentration of the compound at the inhibition level of 50% was recorded as the IC ₅₀ of the compound to inhibit cellular activity.

Experimental results:

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IC5 ₀ compounds according to the present application to suppress the activity of A431 cells are shown in table. 2.

Conclusion:

From Table. 2 shows that the compounds of the present application have good selectivity for A431 cells.

Experimental Example 4 Antiproliferative effect experiment on cells (2) Experimental method

For Ba/F ₃ Cell Suspension (EGFR A19del/T790M/C797S)

Compounds to be tested were diluted at a 3-fold concentration gradient with Echo to give 10 dose concentrations from 10 μM to 0.508 nM. Compounds were transferred to a 384-well plate with 125 nl of compound per well. Cell density was adjusted and 2000 Ba/F ₃ cells (EGFR A19del/T790M/C797S) were seeded in each well in a volume of 50 μl, incubated in a CO ₂ incubator at 37°C for 3 days. After 3 days, 25 ml detection reagent was added.

The plate was incubated at room temperature for 10 minutes and then read using Envision.

Data analysis:

Readings were converted to degree of inhibition (%) using the following formula: (Max-Sample)/(Max-Min)x 100%((maximum concentration-sample reading)/(maximum concentration-minimum concentration^ 100%)

IC ₅₀ data were obtained by parametric curve fitting (Model 205 in Activity Base, IDBS).

Experimental results:

The values of the IC ₅₀ compounds according to this application to suppress the activity of cells Ba/F ₃ (EGFR A19del/T790M/C797S) are shown in table. 2.

Conclusion:

From Table. 2 shows that the preferred compounds of the present application have a strong inhibitory effect on Ba/F ₃ cells with three mutations (EGFR A19del/T790M/C797S). Comparative Example 1 had almost no inhibitory effect on Ba/F ₃ cells with three mutations (EGFR A19del/T790M/C797S).

Experimental Example 5 Cell Phosphorylation Inhibition Experiment Experimental Method

Test compounds and reference compounds were diluted with 100% DMSO to 10 mM or 1 mM and then gradient diluted with Echo at 150 nl per well, with a 3-fold concentration gradient and a dose-response curve with ten dose points. The final concentration of compounds was 100 μM or 10 μM. The cells of the suspension were centrifuged at 1000 rpm for 5 min, suspended in Hank's balanced salt solution and added to a 384-well plate containing compounds at 10 μl/120,000/well (cell density 1.2 x 10 ⁷ ), followed by centrifugation at 1200 rpm for 30 s and incubated at 37°C for 30 min. Added 5 μl of EGF (which was diluted with 0.1% Hank's balanced salt solution in BSA) to each well, in which the final concentration of EGF was 1 μm. The plate was centrifuged at 1200 rpm for 30 s and incubated at 37°C for 20 min. 5 μl of 4x lysis buffer containing blocking solution was added to each well, and then the plate was centrifuged at 1200 rpm for 30 s and incubated at 37°C for 30 min. 5 μl of a mixture of 0.25xEu and D2 was added to each well and the plate was centrifuged at 1200 rpm for 30 s, covered with a light-shielding seal and incubated at room temperature (22-26°C) for 4-24 h. Fluorescence signals were read at 665 nm/620 nm using a microplate reader.

Experimental results.

The IC50 values of the compounds of the present application for suppressing the activity of phosphorylation of cells pEGFR Ba/F ₃ (EGFR A19del/T790M/C797S) are shown in table. 2.

Conclusion:

Since spontaneous EGFR phosphorylation, namely dimerization, can activate its kinase pathway located inside the cell, and many tumors have high or abnormal expression of EGFR, this plays a very important role in the development of malignant tumors. Suppression of activity of pEGFR Ba/F ₃ (A19del/T790M/C797S) cells can demonstrate the most demonstrative inhibitory effect of a compound on phosphorylation in a Ba/F ₃ triple mutant cell model (A19del/T790M/C797S), so as to specifically screen for compounds in vitro. From Table. 2 shows that the compounds of the present application have an excellent inhibitory effect on the phosphorylation activity of Ba/F ₃ cells (A19del/T790M/C797S), while comparative example 1 has almost no inhibitory effect on the phosphorylation of Ba/F3 cells (A19del/T790M/ C797S).

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table 2

Test compounds Antiproliferative effect on A431 EGFRWT cells Antiproliferative effect on Ba/ _F3 cells (A19del/T790M/C7 Effect on cell phosphorylation EGFR Ba/F ₃ (A19del/T790M/C7 1С ₅₀ (nM) 97S) 1С ₅₀ (nM) 97S) 1С ₅₀ (nM) 2 811 178 68 3 3239 638 187 4 3751 556 278 5 890 313 96 6 997 361 187 7 - - 533 8 - 275 133 9 282 149 149 10 - 6026 - eleven - 180 - 12 1256 239 203 13 >10000 3620 1725 14 - 351 - 15 - 583 - 16 - 211 - 17 - 4753 - 18 - 1646 - 19 - 1220 - 20 - 214 - 21 - 1959 - 22 - 249 - 23 - 103 34 24 - 4085 - 25 - 642 - 26 - 764 - 27 - 2713 - 28 - 2657 - 29 - 1594 - thirty - 290 - 31 - 242 - 32 - 79 57 33 - 162 - 34 154 22 19 35 533 36 168 45 25 37 357 56 94 38 - 371 - 39 - 187 195 40 561 31 24 41 245 9 25 42 - 442 - 43 - 496 - 44 - - 9 45 - 87 27 48 - 152 - 51 - 36 - 54 - 39 - 57 - 26.8 - 58 - 18.6 - 59 534 54.3 534 60 271 47.6 271 61 58 32.2 58 Comparative example 1 - >5000 1014.0

Experimental Example 6 In Vivo Efficacy Study (1)

Experimental way

An in vivo efficacy experiment was performed on BALB/c nude mice with xenografts (CDX) derived from subcutaneously implanted Ba/F ₃ (A19del/T790M/C797S). BALB/c nude mice, female, 6-8 weeks old, weighing 18-20 g, were maintained in an SPF medium and each cage was ventilated separately (5 mice per cage). All cages, bedding and water were sterilized prior to use. All animals had free access to standard certified commercial and laboratory food. A total of 48 mice purchased from Beijing

-64040849

Weitonglihua was used for research. Each mouse was implanted with cells in the right flank for tumor growth. The experiment was started when the average tumor volume reached about 80-120 mm ³ . Test compounds were administered orally daily, with compound birgatinib (15 mg/kg), compound 34 (5, 15, 45 mg/kg, respectively), and compound 41 (5, 15, 45 mg/kg, respectively) administered for 13 consecutive days . The data are shown in table. 3. Tumor volume was measured twice a week with a two-dimensional caliper, measured in mm ³ and calculated by the following formula: V=0.5axb ² where a and b are the long axis diameter and the short axis diameter of the tumor, respectively. Antitumor efficacy was determined by dividing the mean increase in tumor volume in animals treated with the compound by the average increase in tumor volume in untreated animals. The TGI (tumor suppression value) was used to evaluate the tumor suppression effect of the test drug in vivo, where the TGI of the compound birgatinib group (15 mg/kg) was 8.6%, the TGI of the compound 34 group (45 mg/kg, administered alone) was 101% and the TGI of the Compound 41 group (45 mg/kg administered alone) was 109%.

On day 14 post-administration, blood plasma was collected from mice by submandibular blood collection before the last administration and 2 hours after the last administration, and blood plasma samples were collected from mice at 1, 4, 8 and 24 hours after administration for the efficacy experiment groups. Approximately 100 μl of blood was collected each time, placed in a tube with anticoagulants and centrifuged at 8000 rpm for 7 min to collect blood plasma, which was stored at -80°C. Mouse lung tissues and tumors were collected 2 hours after injection and stored at -80°C, while the tumors were divided into two parts (where the tumor mass for PD analysis did not exceed 100 mg) for detection and data analysis.

The results of the experiments, see table. 3 and 4.

Table 3

Test compounds Dose Tumor volume (mm ³ ) Day 0 Day 2 Day 5 Day 8 Day 10 Day 12 Day 13 Idle control No data 85 143 315 582 765 929 1048 Birgatinib 15 mg/kg/day 84 124 292 477 646 880 965 Compound 34 5 mg/kg/day 84 108 212 395 505 748 881 15 mg/kg/day 84 76 107 126 176 292 326 45 mg/kg/day 84 56 32 35 42 73 68 Compound 41 5 mg/kg/day 84 103 203 348 485 707 814 15 mg/kg/day 84 68 69 82 115 146 211 45 mg/kg/day 84 47 24 7 4 0 0

Table 4

’ ' ----Test compounds Test values —— brigatinib Compound 34 Compound 41 Dose (mg/kg/day) 15.0 15.0 15.0 Т1/2 (Ch.) 5.57 10.0 20.5 AUCo-Last (nM.H.) 32808 57037 121718 Blood plasma (nM), 2 hours 5177 3553 6990 Tumor (nmol/kg), 2 hours 5807 16667 18567 Lung (nmol/kg), 2 hours 10217 32533 29567

Conclusion.

The compounds of the present application demonstrate a strong antitumor effect in a BALB/c nude mouse drug resistance model with xenografts (CDX) obtained by subcutaneous implantation of Ba/F ₃ (Δ19del/T790M/C797S). The half-life and degree of exposure in blood plasma and tissues for the compounds of the present application were significantly improved, indicating that the compounds of the present application have a good pharmacokinetic effect in mice.

Experimental Example 7 In Vivo Pharmacodynamic Study (2)

Experimental way

1. Cell culture: PC-9 lung cancer cells were cultured as a monolayer in vitro, culture conditions: RPMI-1640 (cell culture medium) plus 10% fetal bovine serum, 100 U/ml penicillin and 100 μg/ml streptomycin were cultured in an incubator with 5% CO ₂ at 37°C. Cells were typically digested with trypsin-EDTA twice a week for passage. When the saturation of the cells was 80-90% and the number reached the requirements, the cells were collected and counted. The density was 5x106 cells.

2. Cell inoculation. 0.2 ml (containing 5x106 cells) of PC9 cell suspension (PBS: matrigel=1:1) was inoculated subcutaneously in the right flank of each mouse, 64 mice in total. 7 days after inoculum

- 65 040849 when the average measured tumor volume reached 169 mm ³ , animals were randomly grouped hierarchically based on tumor volume and animal weight, and administration to each group was started. PBS was a phosphate buffer solution and Matrigel was a matrix.

3. Introduction, dose. Days 0-9: 50 mg/kg; days 10-21: 25 mg/kg; oral administration; administration frequency:

once a day x3 weeks.

Tumor Measurement and Experimental Performance

Tumor diameter was measured twice a week with a caliper. The formula for calculating tumor volume was: V=0.5axb ² where a and b are the long axis diameter and the short axis diameter of the tumor, respectively.

The antitumor effect of the compound was evaluated by TGI (%).

Relative tumor volume (RTV) was calculated according to the tumor measurement results. The calculation formula was RTV=V _t /V ₀ , where V ₀ was the tumor volume measured at the time of administration to the group (ie, at DO) and V _t was the corresponding mouse tumor volume measured at the specific time. Data were collected on the same day for TRTV and CRTV.

TGI (%) reflected the degree of suppression of tumor growth.

TGI (%)=[(1-(mean tumor volume at end of treatment in treatment group-mean tumor volume at start of treatment in treatment group))/(mean tumor volume at end of treatment in solvent control group-mean tumor volume in the beginning of treatment in the control group with the introduction of the solvent)] x 100%

After the completion of the experiments, the mass of the tumor was measured and TGI (%) was calculated.

Experimental results: see table. 5. TGI of compound 34 on day 23 was 100%.

_________________________________________________ Table 5

Test compounds Dose Tumor volume (mm ³ ) Day 0 Day 2 Day 6 Day 9 Day 13 Day 16 Day 20 Day 23 Idle control / 186 257 285 326 482 527 637 921 Compound 34 50 mg/kg (days 0-9) 25 mg/kg (days 10-21) 185 198 92 75 40 45 76 111 Compound 41 50 mg/kg (days 0-9) 25 mg/kg (days 10-21) 184 198 54 44 36 thirty 37 42

Conclusion.

In a subcutaneously transplanted PC-9 tumor (Δ19del) mouse model, the compounds of the present application have a significant inhibitory effect on tumor growth and a tumor shrinking effect, indicating good antitumor effects.

Claims (19)

CLAIM 1. A compound of formula (I) or a pharmaceutically acceptable salt thereof where ring A is selected from phenyl, thienyl, pyridyl, pyrazinyl, pyrazolyl, cyclopentanonyl, cyclopentenyl, thiazolyl, isothiazolyl and pyrrolyl, wherein said phenyl, thienyl, pyridyl, pyrazinyl, pyrazolyl, cyclopentanonyl, cyclopentenyl, thiazolyl, isothiazolyl and pyrrolyl are optionally substituted with R6; R1 is selected from H, halogen, C _1-6 alkyl and C _1-6 heteroalkyl containing 1, 2 or 3 heteroatoms independently selected from N, -O- and -S-, where C _1-6 alkyl and C _{1- 6} heteroalkyl containing 1, 2 or 3 heteroatoms, independently selected from N, -O- and -S-, optionally substituted with 1, 2 or 3 R-groups; R ₂ is selected from H, halogen, CN, OH, NO ₂ , NH ₂ , C _3-12 cycloalkyl and 3-12 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, -O- and -S -, where said NH2, C _3-12 cycloalkyl and 3-12 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, -O- and -S- are optionally substituted with 1, 2 or 3 R-groups ; R ₃ is selected from H, halogen, C _3-6 cycloalkyloxy, -O(CH ₂ )nNR _a R _b , C _1-6 alkyl and C _3-6 cycloalkyl, wherein said C _1-6 alkyl and C _3-6 cycloalkyl optionally substituted with 1, 2 or 3 R groups; - 66 040849 n is selected from 0, 1, 2, 3 or 4; each of Ra and R _b is independently selected from H, C _1-5 alkyl and C _1-5 heteroalkyl containing 1, 2 or 3 heteroatoms independently selected from N, -O-, -S and -S(=O) ₂ -, and while the specified C _1-5 alkyl and C _1-5 heteroalkyl containing 1, 2 or 3 heteroatoms, independently selected from N, -O-, -S- and -S(=O) ₂ -, optionally substituted with 1, 2 or 3 R-groups; or alternatively R _a and R _b are linked together to form a 5-6 membered heterocyclic ring containing 1, 2 or 3 heteroatoms or heteroatomic groups independently selected from -C(=O)N(R)-, N, - O- and -S-; R ₄ is H; Br, I, CN, CH3, CH3CH2, CH3CH2CH2, (CH3)2CH, R ₅ is selected from H, F, Cl, '0' is O^N. '' while the indicated CH ₃ , CH ₃ CH ₂ , CH ₃ CH ₂ CH ₂ , (CHz) ₂ CH, ' ΝΗ ¹ optionally substituted with 1, 2 or 3 R groups; or alternatively R4 and _R5 are bonded together to form a 5-6 membered ring containing 1, 2 or 3 atoms independently selected from N, S or O, where the 5-6 membered ring is optionally substituted with 1, 2 or 3 R groups; each R ₆ is independently selected from H, halogen, CN, OH, NH ₂ , C _1-6 alkyl, ═O, ═S or C _1-6 heteroalkyl containing 1, 2 or 3 heteroatoms independently selected from N, - O- and -S-; each of R ₇ and R ₈ is independently selected from H or C _1-6 alkyl; R is selected from halo, CN, OH, NH ₂ , C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 heteroalkyl containing 1, 2 or 3 heteroatoms independently selected from N, -O- and -S- , 3-6-membered heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, -O- and -S-, phenyl and 5-6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N , -O- and -S-, where the specified C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 heteroalkyl containing 1, 2 or 3 heteroatoms, independently selected from N, -O- and -S-, 3-6 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, -O and -S-, phenyl and 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, -O - and -S-, optionally substituted with 1, 2 or 3 R'groups; R' is selected from H, F, Cl, Br, I, CN, OH, NH2, CH3, CH3CH2, CH3CH2CH2, (CH3^CH, CH3O, CF3, CHF2 and CH2F. 2. The compound or pharmaceutically acceptable salt thereof according to claim 1, where R is selected from F, Cl, Br, I, CN, OH, NH ₂ , CH ₃ , CH ₃ CH ₂ , CH ₃ CH ₂ CH ₂ , (CH _h ) ₂ CH, CH ₃ O, (CH ₃ ) ₂ N, 3. A compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R1 is selected from H, halogen, C _1-3 alkyl and C _1-3 heteroalkyl containing 1, 2 or 3 heteroatoms independently selected from N, -O - and -S-, where said C _1-3 alkyl and C _1-3 heteroalkyl containing 1, 2 or 3 heteroatoms independently selected from N, -O- and -S- are optionally substituted with 1, 2 or 3 R- groups. 4. A compound or pharmaceutically acceptable salt thereof according to claim 3, wherein R1 is selected from H, F, Cl, Br, I, CH ₃ , CH ₃ CH ₂ , CH ₃ CH ₂ CH ₂ , (CH 3 _{) 2} CH, CH ₃ O, CH ₃ CH ₂ O, CH ₃ CH ₂ CH ₂ O and (CH _s ) ₂ CHO, where the indicated CH ₃ , CH ₃ CH ₂ , CH ₃ CH ₂ CH ₂ , (CH _s ) ₂ CH, CH ₃ O, CH ₃ CH ₂ O, CH ₃ CH ₂ CH ₂ O and (CH ₃ ) ₂ CHO are optionally substituted with 1, 2 or 3 R groups. 5. The compound or pharmaceutically acceptable salt thereof according to claim 1, where R ₂ is selected from H, halogen, CN, 1 , ; OH, NH2, NO2, -NHR, -N(R)2, 6. A compound or pharmaceutically acceptable salt thereof according to claim 5, wherein R ₂ is selected from H, F, Cl, Br, CN, .N. OH, NH2, NO2, -NHCH2CH3, -NHCH3, -N(CH3)2 and I 7. A compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R ₆ is selected from H, F, Cl, Br, CN, OH, NH2, CH3, CH3CH2, CH3CH2CH2, (CH3)2CH, CH3O, =S, and =O. 8. The compound or its pharmaceutically acceptable salt according to claim 1, where the structural unit - 67 040849 selected from / 9. A compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein Ra and R _b are each independently selected from H, CH3, CH3CH2, -S(=O) ₂ CH ₃ optionally substituted with 1, 2 or 3 R groups. and -S(=O)2CH3, where said CH3, CH3CH2, And 10. A compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, where R ₃ is selected from H, F, Cl, Br, CH ₃ , CH ₃ CH ₂ , (CH ₃ ) ₂ CH, '0 '0 11. The compound or pharmaceutically acceptable salt thereof according to claim 1, where R5 is selected from H, Cl, Br, CN, CH3, CH3CH2, CH3CH2CH2, (CH3)2CH, 12. The compound or its pharmaceutically acceptable salt according to claim 1 or 2, where the structural unit is ^4 oA 9 L G N . .Br - selected from 13. A compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R ₇ and R ₈ are each independently selected from H or CH ₃ . 14. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, which is selected from Where R1 is defined in any one of claims 1 or 3-4, R ₂ is defined in any one of claims 1 or 5-6, R ₃ is defined in claim 1 or 10, R4 and R ₅ are defined in claim 1 or 11, R ₆ is defined in claim 1 or 7, R ₇ and R ₈ are defined in claim 1 or 13. 15. The compound or pharmaceutically acceptable salt thereof according to claim 14, which is selected from - 68 040849 where R1, R3, R4, R5, R ₇ , R8, R and R' are defined in paragraph 14. 16. The compound or pharmaceutically acceptable salt thereof according to claim 1, which is selected from - 69 040849 - 70 040849 - 71 040849 17. A pharmaceutical composition containing a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16 and a pharmaceutically acceptable carrier. - 72 040849 18. The use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16 or a pharmaceutical composition according to claim 17 for the preparation of a medicament for the treatment of cancer. 19. Use according to claim 18, wherein the cancer is lung cancer.