WO2021143729A1 - Compound, composition and functional molecule with multi-target inhibiting effect and use thereof - Google Patents

Abstract

The present invention relates to a compound, a composition and a functional molecule with a multi-target inhibiting effect and the use thereof. The compound is a compound having a structure represented by formula (I). Specifically, K is (II). The compound has an inhibiting effect on the two targets of BET and kinase, and can simultaneously act on different signal pathways for tumor cell growth to achieve better therapeutic effects.

Description

Multi-target inhibitory compound, composition, functional molecule and application thereof

This application claims the priority of a Chinese patent application filed with the Chinese Patent Office on January 15, 2020, the application number is 2020100400404, and the invention title is "Multi-target inhibitory compounds, compositions, functional molecules and their applications", all of which The content is incorporated in this application by reference.

Technical field

The present invention relates to the technical field of medicinal chemistry, in particular to compounds, compositions, functional molecules and their applications for multi-target inhibitory action.

Background technique

Complex diseases can usually be attributed to the imbalance of a variety of signaling pathways and physiological processes, and these diseases are difficult to cure through the specific regulation of a single target. As an effective strategy, multi-drug suppression has received extensive attention in the current development of anti-cancer drugs. Compared with single target or combination therapy, it has the following advantages: 1) Multi-target drugs can avoid drug interaction problems; 2) Compared with combination therapy, it can show a more predictable pharmacokinetic curve; 3) It ensures simultaneous presence in the tissues to reduce acute and delayed toxicity, in contrast to combination therapy; 4) It usually has a synergistic effect to reduce the dose, so it can avoid the related toxicity problems of a single dose. In recent years, many studies have shown that the combined application of BET inhibitors and kinase inhibitors can enhance anti-tumor effects by simultaneously targeting dysfunctional signal kinase pathways and epigenetic cell reprogramming. In addition, the combined application of BET inhibitors can reduce the probability of acquired resistance to kinase drugs. However, most of the reported dual-target inhibitors of BET and kinase were discovered accidentally, or were further modified from these known inhibitors, and their therapeutic effects were poor, limiting their applications.

Summary of the invention

Based on this, it is necessary to provide a multi-target inhibitory compound, composition, functional molecule and its application. The compound has an inhibitory effect on both BET and kinase dual targets, and can simultaneously act on different signal pathways for tumor cell growth to achieve better therapeutic effects.

A compound having the structure shown in formula (I)

Where K is

X ₁ , X ₂ and X ₃ are each independently selected from -CR ₉ or N;

Y is -CR ₉ or N;

Z is a single bond, -NR ₉ or O;

R _1, R ₂ and R ₃ are each independently selected from: H, substituted or unsubstituted C ₁ - ₃₀ alkyl group, a substituted or unsubstituted cycloalkyl group having 3 to 30 ring atoms, a substituted or unsubstituted, containing 3-30 ring atoms heterocyclic group, substituted or unsubstituted aryl group containing 5-30 ring atoms, substituted or unsubstituted heteroaryl group containing 5-30 ring atoms, amino, cyano, iso Cyano, isocyanate, thiocyanate, isothiocyanate, hydroxyl, trifluoromethyl, nitro or halogen;

R ₄ and R ₅ are each independently selected from: H, substituted or unsubstituted C ₁ - ₃₀ alkyl group, a substituted or unsubstituted cycloalkyl group having 3 to 30 ring atoms;

R _6, R _7, R ₈ and R ₉ are each independently selected from: H, substituted or unsubstituted C ₁ - ₃₀ alkyl group, a substituted or unsubstituted C ₁ - ₃₀ alkoxy, substituted or unsubstituted containing from 3 -8 ring atoms cycloalkyl, substituted or unsubstituted heterocyclic groups containing 3-8 ring atoms, substituted or unsubstituted aryl groups containing 5-30 ring atoms, substituted or unsubstituted aryl groups containing 5 -30 ring atoms heteroaryl, silyl, keto, carbonyl, carboxy, ester, alkoxycarbonyl, aryloxycarbonyl, amino, cyano, carbamoyl, haloformyl, isocyano, Isocyanate group, thiocyanate group, isothiocyanate group, hydroxyl group, nitro group or halogen.

A prodrug, functional molecule, composition, pharmaceutically acceptable salt, or solvate of PROTAC technology, including the above-mentioned compound, or being formed by the above-mentioned compound.

The above-mentioned compounds, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, the above-mentioned compositions, the above-mentioned prodrugs or the above-mentioned functional molecules are prepared for the prevention or treatment of bromodomain proteins and/or kinases in organisms Disorder-related cell abnormal proliferation, morphological changes, and motor function related diseases, as well as angiogenesis or cancer metastasis related diseases in medicine.

A prodrug, pharmaceutically acceptable salt, or solvate formed from the above compound.

A functional molecule of PROTAC technology, formed by the above compounds.

A composition comprising the above-mentioned compound, the above-mentioned prodrug, pharmaceutically acceptable salt, or solvate, or the above-mentioned functional molecule of PROTAC technology.

The above-mentioned compounds, the above-mentioned prodrugs, pharmaceutically acceptable salts, or solvates, the above-mentioned functional molecules of PROTAC technology, and the above-mentioned compositions are prepared for the prevention or treatment of bromodomain protein and/or kinase disorders in organisms Use in medicine for diseases related to abnormal cell proliferation, morphological changes, hypermotor function, and diseases related to angiogenesis or cancer metastasis.

A treatment method including the following steps:

An effective amount of the above-mentioned compound, the above-mentioned prodrug, a pharmaceutically acceptable salt or solvate, the above-mentioned functional molecule of the PROTAC technology, or the above-mentioned composition is administered to the subject to be treated.

Beneficial effects:

So far, 61 bromodomains have been found on 46 different proteins in the human genome. According to their protein functions, they can be divided into 8 families. The BET (Bromodomain and Extra-terminal) family is the second category of the BRD family, including four members: BRD2, BRD3, BRD4 and BRDT. Compared with BRD2, BRD3 and BRDT, BRD4 is widely expressed in the human body and is the most in-depth researched member of the BET family. The technical personnel of the present invention discovered that by designing BRD4-based multi-target inhibitors, specifically, the KAc binding group (K in formula (I), also called Kac pocket mimic) of the BET inhibitor was compared with a typical kinase inhibitor Binding group

The fusion design can realize the use of a small molecule to act on the different signal pathways of tumor cell growth at the same time, which can affect the occurrence and development of tumor cells from multiple aspects, achieve better therapeutic effects, and reduce drug resistance due to bypass activation. This possibility provides a new idea for drug research and development, especially the development of anti-tumor drugs.

Detailed ways

In order to facilitate the understanding of the present invention, a more comprehensive description of the present invention will be given below, and preferred embodiments of the present invention will be given. However, the present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the understanding of the disclosure of the present invention more thorough and comprehensive.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the technical field of the present invention. The terms used in the specification of the present invention herein are only for the purpose of describing specific embodiments, and are not intended to limit the present invention. The term "and/or" as used herein includes any and all combinations of one or more related listed items.

Definition of Terms

Unless otherwise noted, the terms used in the present invention have the following definitions:

If there are stereoisomers in the compounds of the present invention, they should be understood to include R configuration, S configuration and racemates unless otherwise specified.

In the present invention, "substituted" means to be replaced by one or more groups. When multiple groups are selected from the same series of candidate substituents, they may be the same or different.

In the present invention, "optionally" means that the defined group can be selected from a series of candidate groups or not.

In the present invention, "substituted or unsubstituted" means that the defined group may be substituted or unsubstituted. When a group is substituted, as defined, should be understood to be optionally substituted by a group accepted in the art, including but not limited to: C ₁ - ₃₀ alkyl group, a cycloalkyl group having 3 to 30 ring atoms, comprising Heterocyclic groups with 3-30 ring atoms, aryl groups with 5-30 ring atoms, heteroaryl groups with 5-30 ring atoms, silyl groups, carbonyl groups, alkoxycarbonyl groups, aryloxycarbonyl groups, amino groups Formyl, haloformyl, formyl, -NRR', cyano, isocyano, isocyanate, thiocyanate, isothiocyanate, hydroxyl, trifluoromethyl, nitro or halogen, and The above-mentioned groups can also be further substituted with substituents acceptable in the art; it is understandable that R and R'in -NRR' are each independently substituted by groups acceptable in the art, including but not limited to H, C _{1 -6} alkyl groups, cycloalkyl groups containing 3-8 ring atoms, heterocyclic groups containing 3-8 ring atoms, aryl groups containing 5-20 ring atoms or heteroaromatic groups containing 5-10 ring atoms group; a C ₁ - ₆ alkyl group, a cycloalkyl group having 3 to 8 ring atoms, heterocyclic group containing 3-8 ring atoms, an aryl group containing 5 to 20 ring atoms or a 5-10 hetero ring atoms of the aryl group optionally further substituted with one or more of the following groups: C ₁ - ₆ alkyl group, a cycloalkyl group having 3 to 8 ring atoms, a heterocyclic group of 3-8 ring atoms , Halogen, hydroxyl, nitro or amino.

The "alkyl" in the present invention means a saturated linear and branched alkyl group with a specific number of atoms, and specific examples include but are not limited to methyl, ethyl, propyl, isopropyl, butyl , Isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, etc. The C ₁ -C ₆ alkyl group refers to an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl , 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl- 2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1 ,3-Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl.

"Heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent in which one or more ring atoms are selected from nitrogen, oxygen or S(O) _m (where m is an integer from 0 to 2) The heteroatom is preferably a nitrogen or oxygen heteroatom; but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. A 4-10 membered heterocyclic group means that the ring contains 4 to 10 ring atoms, of which 1 to 3 are heteroatoms; preferably, the heterocyclyl ring contains 5 to 6 ring atoms, of which 1 to 2 are heteroatoms. In one embodiment, the monocyclic heterocyclic group is dihydrofuranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, benzopiperidinyl, piperazinyl, morpholinyl, thiomorpholinyl or homopiperyl. Azinyl and so on.

"Aryl" refers to an all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) with a conjugated π-electron system, preferably 6 to 10 members, more preferably phenyl and naphthyl , Phenyl is most preferred. The aryl ring can be fused to a heteroaryl, heterocyclic or cycloalkyl ring, and the aryl can be substituted or unsubstituted.

A 5-10 membered "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 10 ring atoms, where the heteroatoms include oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5-membered or 6-membered, including but not limited to: furan, benzofuran, thiophene, benzothiophene, pyrrole, pyrazole, triazole, imidazole, oxazole, oxadiazole, thiazole, tetrazole , Indole, carbazole, pyrroloimidazole, pyrrolopyrrole, thienopyrrole, thienothiophene, furopyrrole, furofuran, thienofuran, benzisoxazole, benzisothiazole, benzimidazole, Pyridine, pyrazine, pyridazine, pyrimidine, triazine, quinoline, isoquinoline, naphthalene, quinoxaline, phenanthridine, primary pyridine, quinazoline, quinazolinone, and derivatives thereof. The heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, and the ring connected to the parent structure is a heteroaryl ring. Heteroaryl groups can be optionally substituted or unsubstituted.

The "C _2-6 alkenyl group" means a straight or branched chain alkenyl group having a double bond with 2 to 6 carbon atoms, and specific examples include vinyl, propenyl, butenyl, and isobutylene. Group, pentenyl, hexenyl, etc.

"Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbyl substituent. A 3-8 membered cycloalkyl group is meant to include 3 to 8 carbon atoms. In one embodiment, the 3-8 membered monocyclic cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl , Cycloheptatrienyl, cyclooctyl, etc. Polycyclic cycloalkyls include spiro, fused, and bridged cycloalkyls. Cycloalkyl groups may be optionally substituted with one or more substituents.

The "alkoxy group" in the present invention means all linear or branched isomers with a specific number of carbon atoms, and specific examples include, but are not limited to, methoxy, ethoxy, n-propoxy, iso Propoxy, n-butoxy, etc.

The "halogen" means fluorine, chlorine, bromine, and iodine.

In the present invention, the substituent "amino" includes primary, secondary and tertiary amino groups. Specifically, the amino group includes -NR ₂₀ R ₂₁ , wherein R ₂₀ and R ₂₁ are hydrogen atoms or any optional groups, such as H, substituted or unsubstituted Linear alkyl, substituted or unsubstituted branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl Wait.

In the present invention, if it is not specified that the substitution occurs on a specific atom, it means that it can occur on any atom whose substituent number has not yet reached saturation. When multiple substituents are selected from the same series, they may be the same or different.

In the present invention, the substitution on the benzene ring, aromatic heterocycle or heterocycle, if it is not specified to occur on a specific atom, it means that it can occur at any position that is not substituted by other atoms except hydrogen and. When multiple substituents are selected from the same series, they may be the same or different.

In the present invention, interrupted by waves

The single key of represents the connection position, for example:

Indicates that the carbon at the 2 position of propane is the connection site,

Indicates that N is the connection site. In the present invention, a certain substitutable site may be substituted by one or more substituents, and when there are multiple substituents at the substitutable site, the multiple substituents may be the same or different from each other.

In the present invention, the straight line running through the ring indicates that the corresponding substituent connected to the straight line optionally replaces the substitutable positions on the ring, and multiple positions may be substituted by the same or different substituents, for example:

(n ₁ is 1, 2, 3, 4 or 5) means that R ₂₀ optionally replaces the substitutable positions on the benzene ring, and multiple positions on the benzene ring can be _{substituted by R 20.} When the benzene ring contains multiple substituents In this case, multiple substituents may be the same or different from each other.

It is understandable that when a group of the present invention contains multiple substituents, the multiple substituents may be the same or different.

"Pharmaceutically acceptable salt" means that the compound represented by formula (I) maintains the desired biological activity and has minimal toxic and side effects. The pharmaceutically acceptable salt can be obtained directly during the preparation and purification of the compound, or can be obtained indirectly by reacting the free acid or free base of the compound with another suitable base or acid.

The term "solvate" is used herein to describe a molecular complex comprising a compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules (such as ethanol). The term "hydrate" is used when the solvent is water.

Instructions

When used in therapy, the compounds of the present invention are usually administered in the form of a standard pharmaceutical composition. It contains one or more effective therapeutic doses of the compound represented by general formula (I), and pharmaceutically acceptable excipients. The pharmaceutically acceptable excipients are pharmaceutically acceptable carriers, excipients or sustained release agents.

The compounds and pharmaceutical compositions provided by the present invention can be in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions and aerosols, etc., and can be present in a suitable solid or liquid carrier or Diluent. The pharmaceutical composition of the present invention can also be stored in a suitable sterilization device for injection or drip infusion. The pharmaceutical composition may also contain odorants, fragrances and the like.

In the present invention, the pharmaceutical composition contains a safe and effective amount (such as 0.1-99.9 parts by weight, preferably 1-90 parts by weight) of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof; and The remaining pharmaceutically acceptable excipients, wherein the total weight of the composition is 100 parts by weight. Alternatively, the pharmaceutical composition of the present invention contains 0.1-99.9% by weight of the total weight, preferably 1-90% by weight of the total weight of the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof; and A quantity of pharmaceutically acceptable excipients, wherein the total weight of the composition is 100% by weight.

The preferred ratio of the compound represented by the general formula (I) to the pharmaceutically acceptable carrier, excipient or sustained-release agent is that the compound represented by the general formula (I) as the active ingredient accounts for more than 60% of the total weight, and the remainder It accounts for 0-40% of the total weight, and the amount of the remaining part is preferably 1-20%, most preferably 1-10%.

The compound represented by the general formula (I) or the pharmaceutical composition containing the compound represented by the general formula (I) can be used clinically on mammals, including humans and animals, and the route of administration can include oral, nasal inhalation, transdermal absorption, Pulmonary administration or gastrointestinal tract, etc. The preferred route of administration is oral. It is preferably a unit dosage form, and each dosage contains the active ingredient from 0.01 mg to 200 mg, preferably 0.5 mg to 100 mg, to be taken once or in divided doses. Regardless of the method of administration, the individual's optimal dose should be determined based on the specific treatment. Usually, start with a small dose and gradually increase the dose until the most suitable dose is found.

The pharmaceutical composition of the present invention can be administered orally, intravenously, intramuscularly, or subcutaneously. From the standpoint of ease of preparation and administration, the preferred pharmaceutical compositions are solid compositions, especially tablets and solid-filled or liquid-filled capsules. Oral administration of the pharmaceutical composition is preferred.

Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, etc., while liquid carriers include sterile water, polyethylene glycol, non-ionic surfactants and edible oils (such as corn oil). , Peanut oil and sesame oil), etc., as long as it is suitable for the characteristics of the active ingredient and the specific mode of administration required. Adjuvants commonly used in the preparation of pharmaceutical compositions may also be advantageously included, such as flavoring agents, colors, preservatives, and antioxidants such as vitamin E, vitamin C, BHT and BHA.

Injectable preparations include, but are not limited to, sterile, injectable, aqueous, oily solutions, suspensions, emulsions, and the like. These preparations can also be formulated with suitable parenteral diluents, dispersing agents, wetting agents, suspending agents and the like. Such injectable formulations can be sterilized by filtration in a bacteria-retaining filter. These preparations can also be formulated with a bactericide, which is dissolved or dispersed in an injectable medium or by other methods known in the art.

Detailed description

The invention provides a compound having a structure represented by formula (I)

Where K is

X ₁ , X ₂ and X ₃ are each independently selected from -CR ₉ or N; Y is -CR ₉ or N;

Z is a single bond, -NR ₉ or O; further, Z is a single bond, NH or O; understandably, when Z is a single bond, R ₁ and

connection.

R _1, R ₂ and R ₃ are each independently selected from: H, substituted or unsubstituted C ₁ - ₃₀ alkyl, substituted or unsubstituted C ₁ - ₃₀ alkoxy, substituted or unsubstituted ring containing from 3 to 30 Atom cycloalkyl, substituted or unsubstituted heterocyclic group containing 3-30 ring atoms, substituted or unsubstituted aryl group containing 5-30 ring atoms, substituted or unsubstituted 5-30 ring Heteroaryl, amino, cyano, isocyano, isocyanate, thiocyanate, isothiocyanate, hydroxyl, trifluoromethyl, nitro or halogen of atoms;

R ₄ and R ₅ are each independently H, substituted or unsubstituted C ₁ - ₃₀ alkyl group, a substituted or unsubstituted cycloalkyl group having 3 to 30 ring atoms;

R _6, R _7, R ₈ and R ₉ are each independently selected from: H, substituted or unsubstituted C ₁ - ₃₀ alkyl group, a substituted or unsubstituted C ₁ - ₃₀ alkoxy, substituted or unsubstituted containing from 3 -8 ring atoms cycloalkyl, substituted or unsubstituted heterocyclic groups containing 3-8 ring atoms, substituted or unsubstituted aryl groups containing 5-30 ring atoms, substituted or unsubstituted aryl groups containing 5 -30 ring atoms heteroaryl, silyl, keto, carbonyl, carboxy, ester, alkoxycarbonyl, aryloxycarbonyl, amino, cyano, carbamoyl, haloformyl, isocyano, Isocyanate group, thiocyanate group, isothiocyanate group, hydroxyl group, nitro group or halogen.

Further, R _1, R ₂ and R ₃ are each independently selected from: H, substituted or unsubstituted C ₁ - ₂₀ alkyl, substituted or unsubstituted C ₁ - ₂₀ alkoxy, substituted or unsubstituted 3- comprising Cycloalkyl groups with 20 ring atoms, substituted or unsubstituted heterocyclic groups with 3-20 ring atoms, substituted or unsubstituted aryl groups with 5-20 ring atoms, substituted or unsubstituted 5- Heteroaryl, amino, cyano, isocyan, isocyanate, thiocyanate, isothiocyanate, hydroxyl, trifluoromethyl, nitro or halogen with 20 ring atoms.

Still _further, R _1, R ₂ and R ₃ are each independently selected from: H, C ₁ - ₆ alkyl, C ₁ - ₆ alkoxy group, a cycloalkyl group having 3 to 8 ring atoms, containing 3 heterocyclyl 8 ring atoms, aryl group containing 5-10 ring atoms, a heteroaryl group, halogen, cyano or isocyano 5 to 10 ring atoms; wherein, C ₁ - ₆ alkyl, C ₁ - ₆ alkoxy group, a cycloalkyl group having 3 to 8 ring atoms, heterocyclic group containing 3-8 ring atoms, aryl group containing 5-10 ring atoms, containing 5 to 10 ring atoms heteroaryl optionally substituted with one or more of the following groups: C ₁ - ₆ alkyl, C ₁ - ₆ alkoxy group, a cycloalkyl group having 3 to 8 ring atoms, containing 3-8 ring atoms The heterocyclic group, cyano group, halogen, trifluoromethyl, hydroxy, nitro or -NR ₁₀ R ₁₁ .

Furthermore, at least one of _{R 1} , R ₂ and R _{3 is not H.}

Still further, R _{1 is} selected from: H, C ₁ - ₆ alkyl, C ₁ - ₆ alkoxy group, a cycloalkyl group having 3 to 8 ring atoms, a heterocyclic group containing 3-10 ring atoms, an aryl group containing 5 to 20 ring atoms, an aryl group containing 5-20 heteroaryl, halogen, cyano or isocyano ring atom; a C ₁ - ₆ alkyl, C ₁ - ₆ alkoxy, comprising A cycloalkyl group with 3-8 ring atoms, a heterocyclic group with 3-10 ring atoms, an aryl group with 5-20 ring atoms, and a heteroaryl group with 5-20 ring atoms are optionally substituted by one or a plurality of the following groups: C ₁ - ₆ alkyl, C ₁ - ₆ alkoxy group, a cycloalkyl group having 3 to 8 ring atoms, heterocyclic group containing 3-10 ring atoms, containing 5-10 One ring atom aryl, heteroaryl containing 5-10 ring atoms, cyano, halogen, trifluoromethyl, hydroxyl, nitro or -NR ₁₀ R ₁₁ .

Still further, R _{1 is} selected from: H, C ₁ - ₆ alkyl, C ₁ - ₆ alkoxy group, a cycloalkyl group having 3 to 8 ring atoms, a heterocyclic group of 3-8 ring atoms, an aryl group containing 5-10 ring atoms, an aryl group containing 5-10 heteroaryl, halogen, cyano or isocyano ring atom; a C ₁ - ₆ alkyl, C ₁ - ₆ alkoxy, comprising A cycloalkyl group with 3-8 ring atoms, a heterocyclic group with 3-8 ring atoms, an aryl group with 5-10 ring atoms, and a heteroaryl group with 5-10 ring atoms are optionally substituted by one or a plurality of the following groups: C ₁ - ₆ alkyl, C ₁ - ₆ alkoxy group, a cycloalkyl group having 3 to 8 ring atoms, a heterocyclic group of 3-8 ring atoms, cyano, halogen , Trifluoromethyl, hydroxyl, nitro or -NR ₁₀ R _11.

Further, R ₁₀ and R ₁₁ are each independently: H, C ₁ - ₆ alkyl group, a cycloalkyl group having 3 to 8 ring atoms, a heterocyclic group containing 3-8 ring atoms, containing 5-10 aryl or heteroaryl containing 5 to 10 ring atoms ring atoms; a C ₁ - ₆ alkyl group, a cycloalkyl group having 3 to 8 ring atoms, a heterocyclic ring containing 3 to 8 atoms, group containing 5-10 ring atoms, or an aryl group containing 5-10 ring atoms of the heteroaryl group is optionally further substituted by one or more of the following groups: C ₁ - ₆ alkyl group, containing 3-8 rings -Atomic cycloalkyl, heterocyclic group containing 3-8 ring atoms, halogen, hydroxy, nitro or amino; R ₁₀ and R ₁₁ can form a 5-6 membered ring with the N atom connected to _{R 10} and R ₁₁ .

Furthermore, the heterocyclic group and the heteroaryl group contain at least one nitrogen atom; furthermore, the heterocyclic group and the heteroaryl group contain 1, 2, or 3 nitrogen atoms.

Further, R _{1 is} selected from: a heteroaryl group containing 5 ring atoms, and the heteroaryl group contains two nitrogen atoms; further, R _{1 is} selected from: a heteroaryl group containing 5 ring atoms, and The heteroaryl group contains one nitrogen atom and one oxygen atom. Further, R _{1 is} selected from: a heteroaryl group containing 6 ring atoms, and the heteroaryl group contains 1 or 2 nitrogen atoms. Further, R _{1 is} selected from: a heteroaryl group containing 10 ring atoms, and the heteroaryl group contains 1 or 2 nitrogen atoms.

Furthermore, the aryl group is selected from: phenyl or naphthyl; more preferably phenyl;

Further, the heteroaryl group is selected from; pyridyl, pyrimidinyl, pyrazolyl, benzimidazolyl, benzopyrazolyl, indolyl, quinolinyl, isoquinolinyl, thiazolyl, oxazolyl , Isoxazolyl or pyrazolopyridyl.

Still further, R _{1 is} selected from the group consisting M, said M group consisting of: C ₁ - ₆ alkoxy, halogen, or the following groups:

Wherein, W is -CR ₂₀ or -N; V is -CR ₂₀ R ₂₀ , -NR ₂₁ or -O.

Still further, R _{1 is} selected from the group consisting M, said M group consisting of: C ₁ - ₆ alkoxy, halogen, or the following groups:

Wherein, R _{20 is} each independently selected from: H, C _1-6 alkyl, C _1-6 alkoxy, cycloalkyl containing 3-8 ring atoms, heterocyclic group containing 3-8 ring atoms , Aryl groups containing 5-20 ring atoms, heteroaryl groups containing 5-20 ring atoms, halogen, cyano, isocyano or -NR ₁₀ R ₁₁ ; the C _1-6 alkyl group, C _{1 -6} alkoxy, cycloalkyl containing 3-8 ring atoms, heterocyclic group containing 3-8 ring atoms, aryl containing 5-20 ring atoms, heterocyclic group containing 5-20 ring atoms Aryl groups are optionally substituted by one or more of the following groups: C _1-6 alkyl, C _1-6 alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, C _1-6 alkane Group substituted 3-8 membered cycloalkyl group, C _1-6 alkyl group substituted 3-8 membered heterocyclic group, halogen or cyano group;

Further, R _{20 is} each independently selected from: H, C _1-6 alkyl, C _1-6 alkoxy, cycloalkyl containing 3-8 ring atoms, heterocyclic ring containing 3-8 ring atoms Group, aryl group containing 5-10 ring atoms, heteroaryl group containing 5-10 ring atoms, halogen, cyano, isocyano or -NR ₁₀ R ₁₁ ; the C _1-6 alkyl group, C _1-6 alkoxy groups, cycloalkyl groups containing 3-8 ring atoms, heterocyclic groups containing 3-8 ring atoms, aryl groups containing 5-10 ring atoms, those containing 5-10 ring atoms Heteroaryl groups are optionally substituted with one or more of the following groups: C _1-6 alkyl or 3-8 membered cycloalkyl.

Furthermore, _{each of R 20 is} independently selected from: H, C _1-6 alkyl, C _1-6 alkoxy, cycloalkyl containing 5-6 ring atoms, heterocycle containing 5-6 ring atoms Cyclic, phenyl, halogen, cyano or -NR ₁₀ R ₁₁ ; the C _1-6 alkyl, phenyl, cycloalkyl containing 5-6 ring atoms, or those containing 5-6 ring atoms The heterocyclyl is optionally substituted with one or more of the following groups: C _1-4 alkyl substituted or 3-6 membered cycloalkyl.

Furthermore, R _{20 is} selected from: H, C _1-6 alkyl, 3-6 membered cycloalkyl substituted C _1-6 alkyl, C _1-6 alkoxy, phenyl, cyano, halogen,- NR ₁₀ R ₁₁ , 5-6 membered cycloalkyl, 5-6 membered heterocyclic group, alkyl substituted phenyl, alkyl substituted 5-6 membered cycloalkyl, or alkyl substituted 5-6 membered heterocyclic group; Furthermore, the 5-6 membered heterocyclic group contains at least one nitrogen atom; furthermore, the 5-6 membered heterocyclic group includes

Furthermore, the alkyl substituted 5-6 heterocyclic group is a C _1-4 alkyl substituted 5-6 heterocyclic group, and the alkyl substituted 5-6 membered cycloalkyl is a C _1-4 alkyl substituted 5-6 membered group. Cycloalkyl, alkyl-substituted phenyl is C _1-4 alkyl-substituted phenyl; further, alkyl-substituted 5-6 heterocyclyl is

Furthermore, R _{20 is} selected from: H, cyano, methoxy, methyl, ethyl, n-propyl, isopropyl, primary butyl, sec-butyl, tert-butyl, cyclopropyl, cyclopropyl Group substituted methyl, cyclobutyl, cyclopentyl, cyclohexyl, fluorine, chlorine, phenyl, pyridyl, pyrimidinyl, triazinyl,

Or -NR ₁₀ R ₁₁ .

n ₁ is 1, 2, 3, 4 or 5; n ₂ is 1, 2, 3 or 4; n ₃ is 1, 2 or 3; n ₄ is 1 or 2; n ₅ is 1, 2, 3, 4 , 5 or 6; n ₆ is an integer of 1-9; n ₇ is 1, 2, 3, 4 or 5; n ₈ is 1, 2, 3 or 4; n ₉ is an integer of 1-8; and when present In the case of a plurality of R ₂₀ , the plurality of R _20s are the same as or different from each other.

R _{21 is} selected from: H, C _1-6 alkyl, or cycloalkyl containing 3-8 ring atoms.

Furthermore, R _{21 is} selected from: H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, phenyl, pyridyl, pyrimidinyl or triazinyl.

Still further, R ₂ and R ₃ are each independently selected from: H, substituted or unsubstituted C ₁ - ₆ alkyl group, a substituted or unsubstituted C ₁ - ₆ alkoxy group, a substituted or unsubstituted containing from 3 to 8 Cycloalkyl, halogen or cyano groups of ring atoms;

Furthermore, R _{2 is} selected from: H, halogen, methyl, ethyl, n-propyl or isopropyl.

Furthermore, R _{2 is} selected from: H or halogen. Furthermore, R _{3 is} selected from: H.

R ₁₀ and R ₁₁ are each independently: H, C ₁ - ₆ alkyl group, a cycloalkyl group having 3 to 8 ring atoms, a heterocyclic group containing 3-8 ring atoms, containing 5 to 10 ring atoms aryl or heteroaryl containing 5-10 ring atoms; a C ₁ - ₆ alkyl group, a cycloalkyl group having 3 to 8 ring atoms, a heterocyclic group containing 3-8 ring atoms, comprising aryl or 5-10 ring atoms containing 5-10 ring atoms of heteroaryl is optionally further substituted by one or more of the following groups: C ₁ - ₆ alkyl, cycloalkyl containing 3 to 8 ring atoms, Alkyl, heterocyclic group containing 3-8 ring atoms, halogen, hydroxy, nitro or amino; R ₁₀ and R ₁₁ can form a 5-6 membered ring with the N atom connected to _{R 10} and R _11. Understandably, this includes _{the case where R 10} and R ₁₁ form a ring, and also includes the case where R ₁₀ and R _{11 do} not form a ring.

Still further, R ₁₀ and R ₁₁ are each independently: H, C ₁ - ₆ alkyl group, a cycloalkyl group having 5-6 ring atoms, a heterocyclic group of 5-6 ring atoms containing 5 or an aryl group having 10 ring atoms; a C ₁ - ₆ alkyl group, a cycloalkyl group containing 5-6 ring atoms, heterocyclic group containing 5-6 ring atoms, containing 5 to 10 ring atoms, aryl group optionally further substituted with one or more of the following groups: C ₁ - ₆ alkyl group, a cycloalkyl group containing 5-6 ring atoms, or a heterocyclyl ring containing 5-6 atoms.

Still further, R ₁₀ and R ₁₁ are each independently: H, C ₁ - ₆ alkyl group, a cycloalkyl group having 5-6 ring atoms,

Or phenyl, m is 1, 2, 3, 4, 5 or 6; furthermore, m is 1.

Still further, R ₄ and R ₅ are each independently selected from: H, substituted or unsubstituted C ₁ - ₆ alkyl group, a substituted or unsubstituted cycloalkyl group having 3 to 8 ring atoms; and R ₄ and R _{5 is} not H at the same time. Furthermore, R ₄ is a methyl group. Further, R _{5 is} selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Furthermore, R _{5 is} selected from: methyl, cyclopropyl, isopropyl or cyclopentyl.

Still _{further, R 6, R 7, R} 8 and R ₉ are each independently selected from: H, substituted or unsubstituted C ₁ - ₆ alkyl group, a substituted or unsubstituted C ₁ - ₆ alkoxy group, a substituted or unsubstituted Substituted cycloalkyl groups containing 3-8 ring atoms, substituted or unsubstituted heterocyclic groups containing 3-8 ring atoms, substituted or unsubstituted aryl groups containing 5-10 ring atoms, substituted or unsubstituted Substituted heteroaryl, silyl, keto, carbonyl, carboxyl, ester, alkoxycarbonyl, aryloxycarbonyl, amino, cyano, carbamoyl, haloformyl, containing 5-10 ring atoms, Isocyanate, isocyanate, thiocyanate, isothiocyanate, hydroxyl, nitro, or halogen.

Still further, R ₆ is a substituted or unsubstituted C ₁ - ₆ alkyl. Further, R _{6 is} selected from: methyl, ethyl, n-propyl or isopropyl. Furthermore, R ₆ is methyl or ethyl. Furthermore, R ₆ may be in the S configuration or the R configuration.

Still further, R _7, R ₈ and R ₉ are each independently selected from: H, C ₁ - ₆ alkyl or C ₁ - ₆ alkoxy. Furthermore, R ₇ is H or methoxy; R ₈ is H or methoxy; R ₉ is H.

Furthermore, the compound has a structure represented by formula (II):

The definition of each group in the structure shown in formula (II) is as described above;

Further, X ₁ , X ₂ and X ₃ are each independently selected from -CR ₉ or N; Y is CR ₉ or N; Z is a single bond, NH or O; at least one of _{X 1} , X ₂ and X ₃ It is -CR _9; R ₉ is H, C ₁ - ₆ alkyl or C ₁ - ₆ alkoxy;

R _{1 is} selected from the group M, and the group M is as described above, which will not be repeated here;

R _{2 is} selected from H, C _1-4 alkyl or halogen; R ₃ is H; R ₅ is C _1-4 alkyl or 3-6 membered cycloalkyl, and further, R ₅ is methyl, cyclopropyl R ₆ is a C _1-4 alkyl group, and R ₆ is a methyl group or an ethyl group.

Furthermore, the compound has a structure represented by any one of formulas (II-1) to (II-13):

Furthermore, in formulas (II-1) to (II-3), at least one R ₂₀ is a C _1-6 alkyl group or a cycloalkyl group having 3-8 ring atoms.

Further, in formulas (II-1) to (II-13), R ₂₀ is H, C _1-4 alkyl, cycloalkyl having 3-8 ring atoms, or phenyl.

Further, in formulas (II-1) to (II-13), R ₂₁ is H, C _1-4 alkyl or cycloalkyl having 3-8 ring atoms; further, R ₂₁ is H, methyl Group, ethyl, n-propyl or isopropyl.

Furthermore, in formulas (II-1) to (II-13), R ₂ is H, F or methyl.

Furthermore, in formulas (II-1) to (II-13), R ₅ is an isopropyl group.

Furthermore, in formulas (II-1) to (II-13), R ₆ is a methyl group or an ethyl group.

Furthermore, it has the structure shown in formula (V) or formula (V-1):

The definitions of each group in the structure shown in formula (V) and (V-1) are as described above;

Further, the above-mentioned compound has a structure represented by formula (III) or formula (IV):

The definition of each group in the structure shown in formula (III) or formula (IV) is as described above;

Furthermore, X ₁ , X ₂ and X ₃ are each independently selected from -CR ₉ or N; Y is CR ₉ or N; Z is a single bond, NH or O; X ₁ , X ₂ and X ₃ are at least one of -CR _9; R ₉ is H, C ₁ - ₆ alkyl or C ₁ - ₆ alkoxy.

Furthermore, it has a structure represented by formula (III-1) or formula (IV-1):

Further, R _{1 is} selected from the group M, and the group M is as described above, and will not be repeated here;

R ₂ is selected from: H or halo; R ₃ is H; R ₇ and R ₈ are each independently selected from: H, C ₁ - ₆ alkyl or C ₁ - ₆ alkoxy. Furthermore, R ₇ and R ₈ are each independently H or C _1-4 alkoxy.

Further, the above-mentioned compound is selected from any of the following compounds:

At present, most of the reported dual-target inhibitors of BET and kinase were discovered accidentally, or were further modified from these known inhibitors. In order to overcome this limitation, the present invention proposes a more rational strategy, combining the KAc binding group (K in formula (I)) of the BET inhibitor with the binding group of the hinge region extracted from typical kinase inhibitors

The fusion design provides a new idea for drug research and development, especially the development of anti-tumor drugs.

And so far, 61 bromodomains have been found on 46 different proteins in the human genome. According to their protein functions, they can be divided into 8 major families. The BET (Bromodomain and Extra-terminal) family is the second category of the BRD family and includes four members: BRD2, BRD3, BRD4 and BRDT. Compared with BRD2, BRD3 and BRDT, BRD4 is widely expressed in the human body and is the most in-depth researched member of the BET family. The technicians of the present invention have discovered that by designing BRD4-based multi-target inhibitors, it is possible to use a small molecule to act on different signal pathways of tumor cell growth at the same time, which can affect the occurrence and development of tumor cells from multiple aspects and achieve better treatment. Effect, while reducing the possibility of resistance due to bypass activation.

The present invention also provides a preparation method of the above compound, which includes the following steps:

S101: Provide a structural compound represented by formula (I-1);

Wherein, P represents halogen;

Wherein, the definition of each group in the structure compound represented by formula (I-1) is as described above, and the details are not repeated here.

S102: Provide a structural compound represented by formula (I-2);

The definition of each group in the structure compound represented by the formula (I-2) is as described above, and will not be repeated here.

Furthermore, step S102 includes the following steps:

S1021: reacting compound A with amino acid NH ₂ R ₁ CHCOOH to obtain compound B;

S1022: Compound C is obtained by reducing the ring of compound B with sulfosene;

S1023: Reductive amination of compound C with the corresponding ketone to obtain compound D;

S1024: reacting compound D with haloalkyl to obtain compound E;

S1025: reacting compound E with tert-butyl carbamate and coupling to obtain compound F;

S1026: Remove Boc from compound F to obtain compound G, which is the structure compound represented by formula (I-2).

S103: Substituting the structural compound represented by formula (I-1) and the structural compound represented by formula (I-2) to obtain K as

The structure compound represented by formula (I).

Further, step S103 includes the following steps:

Make compound G and

Under the catalysis of acetic acid, a compound of formula (I) with Z being O is obtained _{through S N Ar;}

Furthermore, step S103 includes the following steps:

S1031: Make compound G and

Under the catalysis of acetic acid, compound H is obtained _{by S N Ar;}

Wherein P is halogen;

S1032: The methoxy group of compound H is removed under the action of concentrated hydrochloric acid to obtain compound I.

S1033: Compound I is chlorinated under the action of phosphorus oxychloride to obtain compound J.

S1034a: Compound J is coupled with corresponding boronic acid or boronic acid ester to obtain compound K through Suzukui coupling.

To the compound of formula (I) where Z is a single bond.

S1034b: Compound J and the corresponding amine

Compound L is obtained by CN coupling, and Z is obtained

It is a compound of the structure represented by formula (I) _{of -NR 9.}

Appreciated, when prepared in the preceding step continued to give the desired product may not necessarily before subsequent steps, for example: when Z is O, R ₁ is methyl, compound H is the desired compound.

In addition, the preparation of the above compound includes the following steps:

S201: Provide a structural compound represented by formula (I-3);

Wherein, the definition of each group in the structure compound represented by formula (I-3) is as described above, and will not be repeated here.

S202: Provide a structural compound represented by formula (I-4) or formula (I-5);

P represents halogen;

The definitions of the groups in the structural compounds represented by formulas (I-4) and (I-5) are as described above, and will not be repeated here.

Further, step S202 includes the following steps:

Compound M1 and 3,5-dimethylisoxazole-4-boronic acid are coupled through Suzukui to obtain compound N1, which is the structural compound represented by formula (I-4).

Further, step S202 includes the following steps:

Compound M2 and 3,5-dimethylisoxazole-4-boronic acid are coupled through Suzukui to obtain compound N2, which is the structural compound represented by formula (I-5).

S203: The structure compound represented by formula (I-3) is reacted with the structure compound represented by formula (I-4) or formula (I-5) to obtain K as

The compound of the structure represented by formula (I).

Furthermore, step S203 includes the following steps:

S2031: Compound N2 and

Compound O is obtained by CN coupling.

S2032: The methoxy group of compound O is removed under the action of concentrated hydrochloric acid to obtain compound P.

S2033: Compound P is chlorinated under the action of phosphorus oxychloride to obtain compound Q.

S2034: Compound Q is coupled with corresponding boronic acid or boronic acid ester to obtain compound R through Suzukui coupling.

Compound R is K is

The compound of the structure represented by formula (I).

Appreciated, when prepared in the preceding step continued to give the desired product may not necessarily before subsequent steps, for example: when Z is O, R ₁ is a methyl group, the compound O is the desired compound.

The step of reacting the structural compound represented by formula (I-3) and the structural compound represented by formula (I-4) reacts with the structural compound represented by formula (I-3) and the structural compound represented by formula (I-5) The steps are basically the same, and the difference lies in the positions of the substituents, which will not be repeated here.

In addition, it should be noted that, in the above reaction steps, the reaction conditions and reagents of each step can all adopt the existing reaction conditions and reagents, which are not particularly limited here, and it should be understood that they are all within the protection scope of the present invention. .

The present invention also provides a composition comprising the above-mentioned compound, its pharmaceutically acceptable salt or pharmaceutically acceptable solvate, and pharmaceutically acceptable excipients. It is understandable that according to the different pharmaceutical dosage forms, the drugs in the required dosage forms, including but not limited to: tablets, capsules, injections, decoctions, syrups, etc., should be understood as all falling within the protection scope of the present invention.

The present invention also provides a prodrug prepared from the above-mentioned compound.

The present invention also provides a functional molecule, which is the PROTAC technology functional molecule of the above-mentioned compound.

The present invention also provides the bromine domain of the above-mentioned compound, its pharmaceutically acceptable salt, pharmaceutically acceptable solvate, the above-mentioned composition, the above-mentioned prodrug or the above-mentioned functional molecule in preparation for prevention or treatment and in vivo Protein and/or kinase disorders related to abnormal cell proliferation, morphological changes, and motor function related diseases, as well as angiogenesis or cancer metastasis related diseases in medicine.

Furthermore, the drug is a BRD4 and kinase dual target inhibitor drug.

Furthermore, the drug is a drug for treating or preventing tumors.

The present invention also provides a treatment method, which comprises administering an effective amount of the above-mentioned compound, its pharmaceutically acceptable salt, pharmaceutically acceptable solvate, the above-mentioned composition, the above-mentioned prodrug, or the above-mentioned functional molecule.

Specific examples are listed below to illustrate the present invention.

It is understood that the raw materials in the following examples can be obtained from commercial sources, or prepared by methods known in the art, or prepared according to the methods described herein. The structure of the compound was determined by nuclear magnetic resonance ( ¹ H-NMR) and or mass spectrometry (MS). The NMR measurement was performed with a Mercury-400 nuclear magnetic resonance instrument manufactured by Varian Company, and the measurement solvent was deuterated chloroform (CDCl ₃ ), deuterated dimethyl sulfoxide (DMSO-d ₆ ), and TMS was an internal standard. The measurement of MS uses Thermo Finnigan LQ-Deca XP (ESI) liquid chromatography-mass spectrometer.

Example 1

(a) Compound 1A (25g, 113.64mmol), D-alanine (11.12g, 125.0mmol), potassium carbonate (17.25g, 125.0mmol) are dissolved in 500ml of ethanol: water = 3:1 mixed solvent, 80 Heat to reflux at ℃ for 8 hours, monitor the reaction with a TLC plate, cool to room temperature after the reaction, evaporate the solvent, dissolve in water, adjust the pH to 1-2 with 1N HCl, a large amount of yellow solid precipitates, filter, and wash with 200ml petroleum ether The solid was dried in a vacuum drying oven to obtain 28.7 g of a yellow solid, namely compound 1B, with a yield of 88%.

¹ H NMR (400MHz, CDCl ₃ ) δ 8.35 (d, J = 6.9 Hz, 1H), 8.06 (d, J = 9.1 Hz, 1H), 6.90 (s, 1H), 6.85 (d, J = 9.2 Hz , 1H), 4.33 (p, J=7.0 Hz, 1H), 1.67 (d, J=7.0 Hz, 3H).

(b) Compound 1B (28.7g, 99.31mmol), potassium carbonate (27.41g, 198.62mmol) were dissolved in 500ml of water, and sodium dithionite (86.45g, 496.55mmol) was slowly added in batches, and reacted at 60°C for 8h to obtain colorless The clear and transparent solution contained a large amount of white precipitate. The reaction was monitored with a TLC panel. After the reaction, the reaction was cooled to room temperature, filtered, and the solid was washed with 200 ml of water, and dried in a vacuum drying oven to obtain 9 g of white solid, namely compound 1C, with a yield of 38%.

¹ H NMR(400MHz,DMSO-d ₆ )δ10.31(s,1H), 6.82(d,J=2.1Hz,1H), 6.74(dd,J=8.2,2.1Hz,1H), 6.65(d, J=8.3Hz, 1H), 6.29(s, 1H), 3.87–3.77(m, 1H), 1.25(d, J=6.6Hz, 3H).

(c) Compound 1C (9g, 37.34mmol), phenylsilane (11.90g, 113.14mmol), acetone (8.3ml, 112.02mmol) and dibutyltin dichloride (17.02g, 56.01mmol) were dissolved in 100ml of THF, React at room temperature overnight, monitor the reaction with a TLC plate. After the reaction, the solvent is evaporated to dryness, and the silica gel sample is purified by flash chromatography column, eluting with a gradient of EA/PE=10-20%, to obtain 8.8 g of a colorless oily liquid, namely compound 1D , The yield is 87%.

¹ H NMR (400MHz, Chloroform-d) δ 10.03 (s, 1H), 6.96 (d, J = 1.9 Hz, 1H), 6.88 (dd, J = 8.3, 2.0 Hz, 1H), 6.73 (d, J ＝8.3Hz,1H), 4.13(q,J＝6.8Hz,1H),3.95-3.80(m,1H),1.33(d,J＝6.7Hz,3H),1.26(d,J＝6.1Hz,3H ), 1.20(d,J=6.7Hz,3H).

(d) Dissolve compound 1D (8.8g, 31.08mmol) in anhydrous 20ml DMF, add NaH (1.25g, 46.62mmol) in batches in an ice-water bath, stir at 0°C for 30min, and slowly add methyl iodide (2.9ml, 46.62mmol) ), react at room temperature for 2 hours, monitor the reaction with a TLC plate. After the reaction is complete, pour the reaction solution into 100ml ice water to quench, extract with 100ml*2DCM, combine the organic layers, wash once with 150ml saturated brine, dry with anhydrous sodium sulfate, and evaporate Dry solvent, organic phase silica gel mixed sample was purified by flash chromatography column, and EA/PE=10-20% gradient elution was used to obtain 8.8 g of colorless oily liquid, namely compound 1E, with a yield of 95%.

¹ H NMR(400MHz,DMSO-d ₆ )δ7.04–6.93(m,3H), 4.15(q,J=6.7Hz,1H), 3.90(hept,J=6.5Hz,1H), 3.25(s, 3H), 1.24 (d, J = 6.6 Hz, 3H), 1.17 (d, J = 6.6 Hz, 3H), 0.97 (d, J = 6.7 Hz, 3H).

(e) Compound 1E (50mg, 0.168mmol), tert-butyl carbamate (80mg, 0.673mmol) and cesium carbonate (110mg, 0.336mmol) were dissolved in 5ml of 1.4-dioxane and _{ventilated with N 2 for} 1 min Then, add palladium acetate (4mg, 0.0168mmol) and Xphos (17mg, 0.0336mmol), and then _{ventilate with N 2 for} 1 min, and react at 85°C for 2 days. Monitor the reaction with a TLC plate. After the reaction, filter through Celite and evaporate to dryness. The solvent and silica gel were mixed with samples to be purified by a flash chromatography column, using EA/PE=20-50% gradient elution to obtain 40 mg of colorless oily liquid, namely compound 1F, with a yield of 71%.

¹ H NMR(400MHz, Chloroform-d)δ7.09(s,1H), 6.84(d,J=8.6Hz,1H), 6.76(dd,J=8.5,2.2Hz,1H), 6.69(s,1H) ), 4.15 (q, J = 6.8 Hz, 1H), 3.88 (h, J = 6.6 Hz, 1H), 3.34 (s, 3H), 1.52 (s, 9H), 1.33 (d, J = 6.7 Hz, 3H ), 1.20 (d, J = 6.6 Hz, 3H), 1.08 (d, J = 6.8 Hz, 3H).

(f) Compound 1F (40mg, 0.120mmol) was dissolved in 5ml 4N HCl/dioxane, and reacted at room temperature for 1d. Monitor the reaction with a TLC plate. After the reaction, pour the reaction solution into 20ml of water and solid sodium hydroxide Sum up to pH=7, extract with 50ml*2DCM, combine the organic layers, wash once with 100ml saturated brine, dry with anhydrous sodium sulfate, evaporate the solvent, and purify the organic phase silica gel with a flash chromatography column using EA/PE=20 -50% gradient elution to obtain 22 mg of brown oily liquid, namely compound 1G, with a yield of 80%.

¹ H NMR (400MHz, Chloroform-d) δ6.66 (d, J = 8.4Hz, 1H), 6.21-6.10 (m, 2H), 4.05 (q, J = 6.8Hz, 1H), 3.74 (hept, J ＝6.7Hz,1H),3.57(s,2H), 3.24(s,3H), 1.19(d,J＝6.7Hz,3H), 1.13(d,J＝6.6Hz,3H),1.01(d,J =6.8Hz,3H).

(g) Compound 1G (2.021g, 8.7mmol), 4-methoxy-2-chloropyrimidine (1.6g, 11.3mmol) dissolved in 20ml acetic acid/1.4-dioxane=1:10, reacted at 100°C 8h, monitor the reaction with a TLC plate. After the reaction, pour the reaction solution into 100ml water, neutralize the solid sodium hydroxide to pH=7, and extract with 100ml*2DCM. Combine the organic layers and wash once with 150ml saturated brine, anhydrous sulfuric acid After drying with sodium, evaporating the solvent, the organic phase silica gel was mixed and purified by a flash chromatography column, using EA/PE=20-50% gradient elution, to obtain 1.118 g of a white foamy solid, namely compound 1H, with a yield of 37.8%.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.40(s,1H), 8.18(d,J=5.6Hz,1H), 7.45(d,J=2.2Hz,1H), 7.28(dd,J= 8.7,2.3Hz,1H), 6.97(d,J=8.7Hz,1H), 6.25(d,J=5.6Hz,1H), 4.08(q,J=6.6Hz,1H), 3.92(s,3H) , 3.83 (p, J = 6.7Hz, 1H), 3.24 (s, 3H), 1.26 (d, J = 6.6 Hz, 3H), 1.19 (d, J = 6.6 Hz, 3H), 0.98 (d, J = 6.8Hz, 3H).

(h) Compound 1H (1.118g, 3.3mmol) was dissolved in 20ml 4N HCl/dioxane, heated to reflux overnight at 80°C, and monitored the reaction with a TLC plate. After the reaction, the reaction solution was poured into 50ml of water. Sodium oxide solid neutralized to pH=7, 50ml*2DCM extraction, combined organic layers, washed with 100ml saturated brine once, dried with anhydrous sodium sulfate, evaporated the solvent, organic phase silica gel mixed sample was purified by flash chromatography column, using MeOH /DCM=2-10% gradient elution to obtain 700 mg of white solid, namely compound 1I, with a yield of 65.3%.

¹ H NMR(400MHz,DMSO-d ₆ )δ10.77(s,1H),8.80(s,1H),7.72(d,J=6.5Hz,1H), 7.21(d,J=2.1Hz,1H) ,7.13–6.95(m,2H),5.80–5.73(m,1H), 4.11(q,J=6.7Hz,1H), 3.81(p,J=6.6Hz,1H), 3.25(s,3H), 1.26 (d, J = 6.6 Hz, 3H), 1.19 (d, J = 6.6 Hz, 3H), 0.98 (d, J = 6.8 Hz, 3H).

(i) Compound 1I (700mg, 2.14mmol) was dissolved in 10ml of phosphorus oxychloride, refluxed at 80°C for 2h, and the reaction was monitored with a TLC plate. After the reaction, the reaction solution was slowly poured into ice water for quenching. Sodium hydroxide was solid Neutralize to pH=7, extract with 50ml*2DCM, combine the organic layers, wash once with 100ml saturated brine, dry with anhydrous sodium sulfate, evaporate the solvent, and purify the organic phase silica gel with a flash chromatography column using EA/PE= Gradient elution was 20-33%, and 145 mg of red foamy solid was obtained, namely compound 1J, with a yield of 20%.

¹ H NMR (300MHz, DMSO-d ₆ ) δ 9.89 (s, 1H), 8.40 (d, J = 5.1 Hz, 1H), 7.41 (d, J = 2.2 Hz, 1H), 7.17 (dd, J = 8.6, 2.2 Hz, 1H), 6.99 (d, J = 8.7 Hz, 1H), 6.91 (d, J = 5.2 Hz, 1H), 4.09 (q, J = 6.5 Hz, 1H), 3.79 (p, J = 6.6Hz, 1H), 3.24 (s, 3H), 1.28 (d, J = 6.6 Hz, 3H), 1.21 (d, J = 6.8 Hz, 3H), 0.97 (d, J = 6.7 Hz, 3H).

(j) Compound 1j (80mg, 0.231mmol), phenylboronic acid (43mg, 0.347mmol), potassium carbonate (40mg, 0.263mmol) dissolved in 10ml 1.4-dioxane: water = 4:1, exchange _{with N 2} After 1 min of air, add Pa(dppf)Cl2 (18.8mg, 0.023mmol), and then _{ventilate with N 2 for} 1 min, react at 80℃ for 4h, monitor the reaction with a TLC plate, after the reaction, extract with 50mlH ₂ O/50ml*2DCM Combine the organic layers, wash once with 100ml saturated brine, dry with anhydrous sodium sulfate, evaporate the solvent, and purify the organic phase silica gel with a flash chromatography column using EA/PE=10-330% gradient elution to obtain a light yellow 30 mg of solid, compound 1, yield 33%.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.56(s,1H), 8.54(d,J=5.1Hz,1H), 8.18(dd,J=6.7,3.0Hz,2H), 7.66(s, 1H), 7.56 (dd, J = 5.1, 1.9 Hz, 3H), 7.38 (d, J = 5.1 Hz, 1H), 7.28 (dd, J = 8.7, 2.2 Hz, 1H), 7.02 (d, J = 8.7 Hz, 1H), 4.10 (q, J = 6.7 Hz, 1H), 3.91 (p, J = 6.6 Hz, 1H), 3.26 (s, 3H), 1.28 (d, J = 6.6 Hz, 3H), 1.21 ( d,J=6.8Hz,3H),0.97(d,J=6.7Hz,3H).LC-MS(ESI)[M+H] ⁺ :388.19.

Example 2

The compound of Example 2 was prepared by the same method as in Example 1, except that pyridine-3-boronic acid was used instead of phenylboronic acid in step (j) of Example 1.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.67(s,1H), 9.35(d,J=2.2Hz,1H), 8.74(dd,J=4.8,1.6Hz,1H), 8.59(d, J = 5.2Hz, 1H), 8.49 (dt, J = 8.0, 2.0 Hz, 1H), 7.63-7.54 (m, 2H), 7.47 (d, J = 5.1 Hz, 1H), 7.30 (dd, J = 8.7 ,2.1Hz,1H),7.03(d,J=8.7Hz,1H), 4.11(q,J=6.7Hz,1H), 3.89(p,J=6.6Hz,1H), 3.26(s,3H), 1.28(d,J=6.6Hz,3H),1.21(d,J=6.5Hz,3H),0.99(d,J=6.7Hz,3H).LC-MS(ESI)[M+H] ⁺ :388.22 .

Example 3

The compound of Example 3 was prepared in the same manner as in Example 1, except that pyridine-4-boronic acid was used instead of phenylboronic acid in step (j) of Example 1.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.73(s,1H), 8.82–8.75(m,2H), 8.64(d,J=5.1Hz,1H), 8.12–8.05(m,2H), 7.58 (d, J = 2.2 Hz, 1H), 7.50 (d, J = 5.1 Hz, 1H), 7.31 (dd, J = 8.7, 2.2 Hz, 1H), 7.03 (d, J = 8.7 Hz, 1H), 4.11(q,J=6.7Hz,1H), 3.89(p,J=6.7Hz,1H), 3.26(s,3H), 1.27(d,J=6.6Hz,3H), 1.21(d,J=6.5 Hz,3H),0.99(d,J=6.7Hz,3H).LC-MS(ESI)[M+H] ⁺ :389.12

Example 4

The compound of Example 4 was prepared in the same manner as in Example 1, except that pyrimidine-5-boronic acid was used instead of phenylboronic acid in step (j) of Example 1.

¹ H NMR(400MHz, DMSO-d ₆ )δ9.75(s,1H), 9.50(s,2H), 9.35(s,1H), 8.64(d,J=5.1Hz,1H), 7.60–7.52( m, 2H), 7.29 (dd, J = 8.7, 2.2 Hz, 1H), 7.04 (d, J = 8.7 Hz, 1H), 4.11 (q, J = 6.7 Hz, 1H), 3.89 (p, J = 6.7 Hz, 1H), 3.26 (s, 3H), 1.28 (d, J = 6.7 Hz, 3H), 1.21 (d, J = 6.5 Hz, 3H), 0.99 (d, J = 6.7 Hz, 3H). LC- MS(ESI)[M+H] ⁺ :390.08.

Example 5

The compound of Example 5 was prepared in the same manner as in Example 1, except that 3-cyanophenylboronic acid was used instead of phenylboronic acid in step (j) of Example 1.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.68(s,1H),8.64-8.55(m,2H),8.49(dt,J=8.0,1.4Hz,1H),8.04(dt,J=7.7 ,1.4Hz,1H),7.77(t,J=7.9Hz,1H),7.59(s,1H),7.49(d,J=5.2Hz,1H),7.24(dd,J=8.6,2.2Hz,1H ), 7.02 (d, J = 8.7 Hz, 1H), 4.11 (q, J = 6.7 Hz, 1H), 3.88 (p, J = 6.6 Hz, 1H), 3.26 (s, 3H), 1.26 (d, J =6.6Hz,3H),1.22(d,J=6.8Hz,3H),0.99(d,J=6.7Hz,3H).

LC-MS(ESI)[M+H] ⁺ :413.06.

Example 6

The compound of Example 6 was prepared by the same method as in Example 1, except that pyrazole-4-boronic acid pinacol ester was used instead of phenylboronic acid in step (j) of Example 1.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.40(s,1H), 8.38(d,J=5.2Hz,1H), 8.29(s,2H), 7.53(d,J=2.3Hz,1H) ,7.36(dd,J=8.6,2.2Hz,1H), 7.10(d,J=5.2Hz,1H), 7.01(d, J=8.7Hz,1H),4.09(q,J=6.6Hz,1H) , 3.87 (p, J = 6.7Hz, 1H), 3.25 (s, 3H), 1.29 (d, J = 6.6 Hz, 3H), 1.21 (d, J = 6.5 Hz, 3H), 0.99 (d, J = 6.7Hz,3H).LC-MS(ESI)[M+H] ⁺ :378.19.

Example 7

The compound of Example 7 was prepared in the same manner as in Example 1, except that 2-methoxyphenylboronic acid was used instead of phenylboronic acid in step (j) of Example 1.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.52(s,1H), 8.46(d,J=5.2Hz,1H),7.93(dd,J=7.6,1.8Hz,1H), 7.70–7.60( m, 1H), 7.50 (td, J = 7.9, 7.3, 1.8 Hz, 1H), 7.31 (d, J = 5.2 Hz, 1H), 7.21 (dd, J = 11.1, 7.7 Hz, 2H), 7.10 (t ,J=7.5Hz,1H),6.98(d,J=8.7Hz,1H),4.08(q,J=6.7Hz,1H),3.88(s,3H),3.87–3.78(m,1H),3.25 (s,3H),1.22(d,J=6.8Hz,3H),1.19(d,J=6.5Hz,3H),0.97(d,J=6.7Hz,3H).LC-MS(ESI)[M +H] ⁺ :418.24.

Example 8

The compound of Example 8 was prepared in the same manner as in Example 1, except that 3-methoxyphenylboronic acid was used instead of phenylboronic acid in step (j) of Example 1.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.57(s,1H), 8.53(d,J=5.2Hz,1H), 7.77-7.68(m,2H), 7.63(s,1H), 7.47( t,J=7.9Hz,1H), 7.39(d,J=5.2Hz,1H), 7.28(dd,J=8.8,2.1Hz,1H), 7.14(dd,J=8.2,2.5Hz,1H), 7.01(d,J=8.7Hz,1H), 4.10(q,J=6.7Hz,1H), 3.91(q,J=6.7Hz,1H), 3.86(s,3H), 3.26(s,3H), 1.26(d,J=6.6Hz,3H),1.21(d,J=6.5Hz,3H),0.99(d,J=6.7Hz,3H).LC-MS(ESI)[M+H] ⁺ :418.21 .

Example 9

The compound of Example 9 was prepared in the same manner as in Example 1, except that 4-methoxyphenylboronic acid was used instead of phenylboronic acid in step (j) of Example 1.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.50 (s, 1H), 8.47 (d, J = 5.3 Hz, 1H), 8.19-8.12 (m, 2H), 7.60 (s, 1H), 7.31 ( dd, J = 8.8, 3.4 Hz, 2H), 7.09 (d, J = 8.5 Hz, 2H), 7.01 (d, J = 8.7 Hz, 1H), 4.10 (q, J = 6.7 Hz, 1H), 3.91 ( q, J = 6.6Hz, 1H), 3.85 (s, 3H), 3.26 (s, 3H), 1.28 (d, J = 6.6 Hz, 3H), 1.22 (d, J = 6.6 Hz, 3H), 0.99 ( d,J=6.6Hz,3H).LC-MS(ESI)[M+H] ⁺ :418.24

Example 10

The compound of Example 10 was prepared in the same manner as in Example 1, except that 2-methylphenylboronic acid was used instead of phenylboronic acid in step (j) of Example 1.

¹ H NMR(400MHz,Chloroform-d)δ7.51(s,1H),7.48(d,J=3.9Hz,2H),7.38(t,J=7.4Hz,1H),7.34–7.30(m,2H ), 7.28 (s, 1H), 7.03 (d, J = 8.6 Hz, 1H), 6.91 (d, J = 8.5 Hz, 1H), 6.89–6.83 (m, 1H), 4.24–4.09 (m, 1H) ,3.90(p,J=6.6Hz,1H),3.38(s,3H),2.47(s,3H),1.27(d,J=6.7Hz,3H),1.24(d,J=6.5Hz,3H) ,1.13(d,J=6.7Hz,3H).LC-MS(ESI)[M+H] ⁺ :402.26.

Example 11

The compound of Example 11 was prepared in the same manner as in Example 1, except that 3-methylphenylboronic acid was used instead of phenylboronic acid in step (j) of Example 1.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.56(s,1H), 8.55–8.49(m,1H), 7.96(d,J=9.6Hz,2H), 7.65–7.59(m,1H), 7.43(t,J=7.5Hz,1H),7.36(t,J=6.2Hz,2H),7.31-7.18(m,1H),7.02(d,J=8.8Hz,1H), 4.10(q,J ＝6.7Hz,1H), 3.89(p,J＝6.7Hz,1H), 3.26(s,3H),2.41(s,3H), 1.26(d,J＝6.6Hz,3H),1.21(d,J ＝6.5Hz,3H),0.99(d,J＝6.7Hz,3H).LC-MS(ESI)[M+H] ⁺ :402.23.

Example 12

The compound of Example 12 was prepared in the same manner as in Example 1, except that 4-methylphenylboronic acid was used instead of phenylboronic acid in step (j) of Example 1.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.53(s,1H), 8.50(d,J=5.2Hz,1H), 8.08(d,J=7.9Hz,2H), 7.65(s,1H) ,7.39–7.31(m,3H),7.27(dd,J=8.8,2.1Hz,1H), 7.01(d,J=8.7Hz,1H), 4.10(q,J=6.7Hz,1H), 3.91( p, J = 6.7Hz, 1H), 3.26 (s, 3H), 2.40 (s, 3H), 1.28 (d, J = 6.7 Hz, 3H), 1.22 (d, J = 6.7 Hz, 3H), 0.99 ( d,J=6.7Hz,3H).LC-MS(ESI)[M+H] ⁺ :402.23.

Example 13

The compound of Example 13 was prepared in the same manner as in Example 1, except that 2-aminophenylboronic acid was used instead of phenylboronic acid in step (j) of Example 1.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.53(s,1H), 8.42(dd,J=5.5,0.9Hz,1H), 7.69(d,J=8.0Hz,1H), 7.34(d, J=2.2Hz,1H), 7.31–7.24(m,1H), 7.24–7.11(m,2H), 7.00(d,J=8.8Hz,3H), 6.80(d,J=8.2Hz,1H), 6.59 (td, J = 7.4, 1.3 Hz, 1H), 4.09 (p, J = 7.9, 7.3 Hz, 1H), 3.86 (p, J = 6.7 Hz, 1H), 3.26 (s, 3H), 1.27 (d ,J=6.6Hz,3H),1.21(d,J=6.5Hz,3H),0.99(d,J=6.6Hz,3H).

LC-MS(ESI)[M+H] ⁺ :403.15.

Example 14

The compound of Example 14 was prepared in the same manner as in Example 1, except that 3-aminophenylboronic acid was used instead of phenylboronic acid in step (j) of Example 1.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.51(s,1H), 8.48(d,J=5.1Hz,1H), 7.63(d,J=2.3Hz,1H), 7.37–7.25(m, 3H), 7.25–7.13 (m, 2H), 7.02 (d, J = 8.7 Hz, 1H), 6.73 (dt, J = 8.1, 1.6 Hz, 1H), 5.29 (s, 2H), 4.10 (q, J ＝6.7Hz,1H),3.90(p,J＝6.6Hz,1H), 3.26(s,3H),1.25(d,J＝6.6Hz,3H), 1.21(d,J＝6.5Hz,3H), 0.98(d,J=6.7Hz,3H).LC-MS(ESI)[M+H] ⁺ :403.21.

Example 15

The compound of Example 15 was prepared in the same manner as in Example 1, except that 4-aminophenylboronic acid was used instead of phenylboronic acid in step (j) of Example 1.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.33(s,1H),8.34(d,J=5.3Hz,1H),7.92(d,J=8.3Hz,2H),7.71(s,1H) ,7.19(dd,J=21.1,7.3Hz,2H), 7.00(d,J=8.7Hz,1H), 6.65(d,J=8.3Hz,2H), 5.77(s,2H), 4.10(q, J = 6.7Hz, 1H), 3.94 (p, J = 6.7 Hz, 1H), 3.26 (s, 3H), 1.29 (d, J = 6.5 Hz, 3H), 1.22 (t, J = 5.3 Hz, 3H) ,0.99(d,J=6.7Hz,3H).LC-MS(ESI)[M+H] ⁺ :403.25.

Example 16

The compound of Example 16 was prepared in the same manner as in Example 1, except that 2-methyl-4-fluorophenylboronic acid was used instead of phenylboronic acid in step (j) of Example 1.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.56(s,1H), 8.49(d,J=5.0Hz,1H), 7.57–7.47(m,2H), 7.21(ddd,J=9.7,6.0 ,2.4Hz,2H),7.14(td,J=8.6,2.7Hz,1H),6.98–6.89(m,2H),4.05(q,J=6.7Hz,1H),3.74(p,J=6.6Hz ,1H),3.21(s,3H),2.40(s,3H),1.15(t,J＝6.8Hz,6H),0.94(d,J＝6.7Hz,3H).LC-MS(ESI)[M +H] ⁺ :420.23.

Example 17

The compound of Example 17 was prepared in the same manner as in Example 1, except that 2,4-difluorophenylboronic acid was used instead of phenylboronic acid in step (j) of Example 1.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.62 (s, 1H), 8.53 (d, J = 5.1 Hz, 1H), 8.09 (td, J = 8.8, 6.7 Hz, 1H), 7.56 (d, J = 2.3 Hz, 1H), 7.43 (ddd, J = 11.7, 9.2, 2.5 Hz, 1H), 7.32-7.19 (m, 2H), 7.13 (dd, J = 5.2, 2.4 Hz, 1H), 6.97 (d ,J=8.7Hz,1H),4.07(q,J=6.7Hz, 1H), 3.82(p,J=6.7Hz,1H), 3.23(s,3H),1.21(d,J=6.6Hz,3H ), 1.17(d,J=6.6Hz,3H),0.95(d,J=6.7Hz,3H).LC-MS(ESI)[M+H] ⁺ :424.22.

Example 18

The compound of Example 18 was prepared in the same manner as in Example 1, except that 3-chloro-4-fluorophenylboronic acid was used instead of phenylboronic acid in step (j) of Example 1.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.60(s,1H), 8.54(d,J=5.2Hz,1H), 8.35(dd,J=7.3,2.2Hz,1H), 8.17(ddd, J = 8.7, 4.7, 2.2 Hz, 1H), 7.59 (t, J = 8.9 Hz, 1H), 7.53 (d, J = 2.3 Hz, 1H), 7.42 (d, J = 5.2 Hz, 1H), 7.22 ( dd, J = 8.7, 2.2 Hz, 1H), 6.99 (d, J = 8.7 Hz, 1H), 4.09 (q, J = 6.7 Hz, 1H), 3.84 (p, J = 6.6 Hz, 1H), 3.24 ( s, 3H), 1.24 (d, J = 6.6 Hz, 3H), 1.19 (d, J = 6.6 Hz, 3H), 0.97 (d, J = 6.7 Hz, 3H).LC-MS(ESI)[M+ H] ⁺ :440.14.

Example 19

The compound of Example 19 was prepared in the same manner as in Example 1, except that 2,4-dimethoxyphenylboronic acid was used instead of phenylboronic acid in step (j) of Example 1.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.40(s,1H), 8.38(d,J=5.2Hz,1H), 8.00(d,J=8.6Hz,1H), 7.61(d,J= 2.3Hz, 1H), 7.30 (d, J = 5.2 Hz, 1H), 7.24 (dd, J = 8.7, 2.2 Hz, 1H), 6.96 (d, J = 8.7 Hz, 1H), 6.72–6.62 (m, 2H), 4.06 (q, J = 6.7 Hz, 1H), 3.87 (s, 3H), 3.83 (s, 3H), 3.82 (m, 1H) 3.23 (s, 3H), 1.22 (d, J = 6.6 Hz) ,3H), 1.17(d,J=6.5Hz,3H),0.96(d,J=6.7Hz,3H).LC-MS(ESI)[M+H] ⁺ :448.26.

Example 20

The compound of Example 20 was prepared in the same manner as in Example 1, except that 4-fluoro-2-methoxyphenylboronic acid was used in place of phenylboronic acid in step (j) of Example 1.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.49(s,1H),8.44(d,J=5.2Hz,1H),7.97(dd,J=8.7,7.1Hz,1H),7.59(d, J = 2.3Hz, 1H), 7.29–7.18 (m, 2H), 7.10 (dd, J = 11.5, 2.4 Hz, 1H), 6.99–6.87 (m, 2H), 4.06 (q, J = 6.7 Hz, 1H ), 3.88(s,3H), 3.80(q,J=6.6Hz,1H), 3.23(s,3H), 1.18(dd,J=13.5,6.6Hz,6H),0.95(d,J=6.7Hz ,3H).LC-MS(ESI)[M+H] ⁺ :436.23.

Example 21

The compound of Example 21 was prepared in the same manner as in Example 1, except that 4-(4-morpholinyl)phenylboronic acid was used instead of phenylboronic acid in step (j) of Example 1.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.40(s,1H), 8.39(d,J=5.3Hz,1H), 8.08–8.01(m,2H), 7.60(d,J=2.3Hz, 1H), 7.33–7.20 (m, 2H), 7.00 (dd, J = 15.8, 8.8 Hz, 3H), 4.08 (q, J = 6.7 Hz, 1H), 3.88 (p, J = 6.7 Hz, 1H), 3.74(t,J=4.8Hz,4H), 3.24(s,3H) 3.23(d,J=5.8Hz,4H), 1.26(d,J=6.7Hz,3H), 1.19(d,J=6.5Hz ,3H),0.97(d,J=6.8Hz,3H).LC-MS(ESI)[M+H] ⁺ :473.31.

Example 22

The compound of Example 22 was prepared in the same manner as in Example 1, except that 4-(4-methyl-1-piperazinyl)phenylboronic acid was used instead of phenylboronic acid in step (j) of Example 1.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.39(s,1H), 8.38(d,J=5.2Hz,1H), 8.03(d,J=8.9Hz,2H), 7.60(d,J= 2.3Hz, 1H), 7.32–7.20 (m, 2H), 7.00 (dd, J = 14.8, 8.8 Hz, 3H), 4.08 (q, J = 6.7 Hz, 1H), 3.88 (p, J = 6.6 Hz, 1H), 3.27 (t, J = 5.0 Hz, 4H), 3.24 (s, 3H), 2.44 (t, J = 5.0 Hz, 4H), 2.21 (s, 3H), 1.27 (d, J = 6.6 Hz, 3H),1.23-1.15(m,3H),0.97(d,J=6.7Hz,3H).LC-MS(ESI)[M+H] ⁺ :486.26.

Example 23

The compound of Example 23 was prepared by the same method as in Example 1, except that 3.5-dimethylpyrazole-4-boronic acid pinacol ester was used instead of phenylboronic acid in step (j) of Example 1.

¹ H NMR(400MHz,DMSO-d ₆ )δ12.58(s,1H),9.24(s,1H),8.37(d,J=5.2Hz,1H),7.39(dd,J=8.7,2.2Hz, 1H), 7.32 (d, J = 2.2 Hz, 1H), 6.98 (d, J = 8.7 Hz, 1H), 6.82 (d, J = 5.3 Hz, 1H), 4.07 (q, J = 6.7 Hz, 1H) ,3.78(h,J=6.7Hz,1H),3.25(s,3H),2.42(s,6H),1.24(d,J=6.7Hz,3H),1.17(d,J=6.6Hz,3H) ,0.98(d,J=6.7Hz,3H).LC-MS(ESI)[M+H] ⁺ :406.19.

Example 24

The compound of Example 24 was prepared in the same manner as in Example 1, except that N-ethylpyrazole-5-boronic acid was used instead of phenylboronic acid in step (j) of Example 1.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.47(s,1H), 8.51(d,J=5.2Hz,1H), 7.55(d,J=2.0Hz,1H), 7.33–7.23(m, 2H), 7.15 (d, J = 5.2 Hz, 1H), 7.02 (d, J = 8.6 Hz, 1H), 6.95 (d, J = 2.0 Hz, 1H), 4.72 (q, J = 7.1 Hz, 2H) ,4.10(q,J=6.7Hz,1H), 3.82(p,J=6.7Hz,1H), 3.26(s,3H), 1.30–1.24(m,6H), 1.19(d,J=6.6Hz, 3H),0.99(d,J=6.7Hz,3H).LC-MS(ESI)[M+H] ⁺ :406.22.

Example 25

The compound of Example 25 was prepared in the same manner as in Example 1, except that N-isopropylpyrazole-5-boronic acid pinacol ester was used instead of phenylboronic acid in step (j) of Example 1.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.47(s,1H), 8.51(d,J=5.1Hz,1H), 7.57(d,J=1.9Hz,1H), 7.34(dd,J= 8.7, 2.2Hz, 1H), 7.22 (s, 1H), 7.11 (d, J = 5.1 Hz, 1H), 7.01 (d, J = 8.7 Hz, 1H), 6.87 (d, J = 2.0 Hz, 1H) , 5.75 (q, J = 6.6 Hz, 1H), 4.10 (q, J = 6.7 Hz, 1H), 3.81 (p, J = 6.6 Hz, 1H), 3.26 (s, 3H), 1.39 (d, J = 6.5Hz,6H),1.28–1.23(m,3H),1.19(d,J=6.6Hz,3H),0.99(d,J=6.7Hz,3H).LC-MS(ESI)[M+H] ⁺ :420.22.

Example 26

Except that N-methyl-4-methylpyrazole-5-boronic acid pinacol ester was used instead of phenylboronic acid in step (j) of Example 1, the same method as in Example 1 was used to prepare Example 26 Compound.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.58(s,1H),8.56(d,J=5.0Hz,1H),7.39(s,1H),7.35(q,J=2.2Hz,2H) ,7.04–6.92(m,2H),4.09(q,J=6.7Hz,1H), 4.00(s,3H), 3.79(p,J=6.6Hz,1H), 3.25(s,3H), 2.15( s,3H),1.23(d,J=6.6Hz,3H),1.18(d,J=6.5Hz,3H),0.98(d,J=6.7Hz,3H).LC-MS(ESI)[M+ H] ⁺ :406.16.

Example 27

Except that N-methyl-3-methylpyrazole-5-boronic acid pinacol ester was used instead of phenylboronic acid in step (j) of Example 1, the same method as in Example 1 was used to prepare Example 27 Compound.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.51(s,1H), 8.49(d,J=5.1Hz,1H), 7.31(dd,J=4.6,2.5Hz,2H), 7.10(d, J = 5.2 Hz, 1H), 7.01 (d, J = 9.2 Hz, 1H), 6.73 (s, 1H), 4.14 (s, 3H), 4.09 (q, J = 6.7 Hz, 1H), 3.82 (p, J = 6.6Hz, 1H), 3.26 (s, 3H), 2.19 (s, 3H), 1.26 (d, J = 6.6 Hz, 3H), 1.19 (d, J = 6.5 Hz, 3H), 0.98 (d, J=6.7Hz,3H).LC-MS(ESI)[M+H] ⁺ :406.20.

Example 28

The compound of Example 28 was prepared in the same manner as in Example 1, except that N-methylpyrazole-5-boronic acid pinacol ester was used instead of phenylboronic acid in step (j) of Example 1.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.53(s,1H), 8.51(d,J=5.1Hz,1H), 7.54(d,J=2.0Hz,1H), 7.32(d,J= 8.6Hz, 2H), 7.16 (d, J = 5.1 Hz, 1H), 7.05-6.93 (m, 2H), 4.22 (s, 3H), 4.09 (q, J = 6.7 Hz, 1H), 3.81 (p, J = 6.6Hz, 1H), 3.25 (s, 3H), 1.25 (d, J = 6.7 Hz, 3H), 1.18 (d, J = 6.5 Hz, 3H), 0.98 (d, J = 6.7 Hz, 3H) .LC-MS(ESI)[M+H] ⁺ :392.18.

Example 29

The compound of Example 29 was prepared by the same method as in Example 1, except that N-methylpyrazole-3-boronic acid pinacol ester was used instead of phenylboronic acid in step (j) of Example 1.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.51(s,1H), 8.45(d,J=5.1Hz,1H), 7.87(d,J=2.2Hz,1H), 7.58(d,J= 2.2Hz, 1H), 7.34 (dd, J = 8.7, 2.2 Hz, 1H), 7.24 (d, J = 5.1 Hz, 1H), 7.01 (d, J = 8.7 Hz, 1H), 6.88 (d, J = 2.2Hz, 1H), 4.10 (q, J = 6.7 Hz, 1H), 3.95 (s, 3H), 3.88 (q, J = 6.6 Hz, 1H), 3.26 (s, 3H), 1.28 (d, J = 6.8Hz,3H),1.21(d,J=6.6Hz,3H),0.99(d,J=6.7Hz,3H).LC-MS(ESI)[M+H] ⁺ :392.21.

Example 30

The compound of Example 30 was prepared in the same manner as in Example 1, except that pyrazole-3-boronic acid was used instead of phenylboronic acid in step (j) of Example 1.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 13.32 (s, 1H), 9.50 (s, 1H), 8.47 (d, J = 5.1 Hz, 1H), 7.92 (s, 1H), 7.59 (s, 1H),7.40–7.33(m,1H),7.30(d,J=5.1Hz,1H), 7.01(d,J=8.7Hz,1H), 6.91(s,1H), 4.10(q,J=6.7 Hz, 1H), 3.89 (p, J = 6.6 Hz, 1H), 3.26 (s, 3H), 1.29 (d, J = 6.6 Hz, 3H), 1.21 (d, J = 6.5 Hz, 3H), 0.99 ( d,J=6.6Hz,3H).LC-MS(ESI)[M+H] ⁺ :378.14.

Example 31

The compound of Example 31 was prepared in the same manner as in Example 1, except that 3-methylpyrazole-4-boronic acid pinacol ester was used instead of phenylboronic acid in step (j) of Example 1.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 12.98 (s, 1H), 9.25 (s, 1H), 8.35 (d, J = 5.2 Hz, 1H), 8.12 (s, 1H), 7.41-7.34 ( m, 2H), 7.03–6.96 (m, 2H), 4.08 (q, J = 6.7 Hz, 1H), 3.83 (p, J = 6.7 Hz, 1H), 3.25 (s, 3H), 2.57 (s, 3H) ), 1.26(d,J=6.6Hz,3H),1.18(d,J=6.4Hz,3H),0.98(d,J=6.7Hz,3H).LC-MS(ESI)[M+H] ⁺ :388.19.

Example 32

The compound of Example 32 was prepared by the same method as in Example 1, except that N-methylpyrazole-4-boronic acid pinacol ester was used instead of phenylboronic acid in step (j) of Example 1.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.39(s,1H), 8.38(d,J=4.5Hz,2H), 8.08(s,1H),7.49(d,J=2.3Hz,1H) ,7.37(dd,J=8.9,2.1Hz,1H),7.03(dd,J=13.1,6.9Hz,2H),4.09(q,J=6.7Hz,1H),3.92(s,3H),3.86( td,J=12.8,6.1Hz,1H), 3.26(s,3H), 1.28(d,J=6.6Hz,3H), 1.21(d,J=6.5Hz,3H),0.99(d,J=6.7 Hz,3H).LC-MS(ESI)[M+H] ⁺ :392.22

Example 33

Except that N-methyl-3-methylpyrazole-4-boronic acid pinacol ester was used instead of phenylboronic acid in step (j) of Example 1, the same method as in Example 1 was used to prepare Example 33 Compound.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.26(s,1H), 8.35(d,J=5.2Hz,1H), 8.28(s,1H), 7.40-7.33(m,2H), 6.96( dd, J = 22.9, 6.9 Hz, 2H), 4.08 (q, J = 6.7 Hz, 1H), 3.82 (m, 4H), 3.25 (s, 3H), 2.48 (s, 3H), 1.26 (d, J ＝6.6Hz,3H), 1.18(d,J＝6.6Hz,3H), 0.98(d,J＝6.7Hz,3H). LC-MS(ESI)[M+H] ⁺ :406.25.

Example 34

The compound of Example 34 was prepared by the same method as in Example 1, except that 1H-benzimidazole-5-boronic acid pinacolate was used instead of phenylboronic acid in step (j) of Example 1.

¹ H NMR(400MHz,DMSO-d ₆ )δ12.69(s,1H), 9.50(s,1H), 8.48(d,J=5.2Hz,2H), 8.33(s,1H), 8.05(d, J = 8.6Hz, 1H), 7.67 (s, 2H), 7.41 (d, J = 5.2 Hz, 1H), 7.32-7.25 (m, 1H), 7.00 (d, J = 8.7 Hz, 1H), 4.09 ( q, J = 6.6Hz, 1H), 3.93 (m, 1H), 3.25 (s, 3H), 1.26 (d, J = 6.6 Hz, 3H), 1.22 (d, J = 6.2 Hz, 3H), 0.98 ( d,J=6.7Hz,3H).LC-MS(ESI)[M+H] ⁺ :428.14

Example 35

In addition to using 1H-benzimidazole in step (j) of Example 1, 4-fluoro-2-methyl-1-(isopropyl)-6-(4,4,5,5-tetramethyl- Except for 1,3,2-dioxaborolan-2-yl) instead of phenylboronic acid, the compound of Example 35 was prepared in the same manner as in Example 1. LC-MS(ESI)[M+H] ⁺ :502.22.

Example 36

The compound of Example 36 was prepared in the same manner as in Example 1, except that indole-4-boronic acid pinacolate was used instead of phenylboronic acid in step (j) of Example 1.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.40 (s, 1H), 9.52 (s, 1H), 8.52 (d, J = 5.2 Hz, 1H), 7.73-7.64 (m, 2H), 7.59 ( dd, J = 8.1, 1.0 Hz, 1H), 7.51 (t, J = 2.8 Hz, 1H), 7.36-7.28 (m, 2H), 7.24 (t, J = 7.7 Hz, 1H), 7.07 (s, 1H) ), 6.99 (d, J = 8.7 Hz, 1H), 4.07 (q, J = 6.7 Hz, 1H), 3.85 (p, J = 6.6 Hz, 1H), 3.26 (s, 3H), 1.16 (dd, J ＝6.6,2.6Hz,6H),0.97(d,J＝6.7Hz,3H).LC-MS(ESI)[M+H] ⁺ :427.28.

Example 37

The compound of Example 37 was prepared in the same manner as in Example 1, except that 2-methyl-2H-indazole-5-boronic acid pinacol ester was used in place of phenylboronic acid in step (j) of Example 1.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.50(s,1H),9.00(s,1H),8.52(d,J=5.3Hz,1H), 7.86(d,J=7.0Hz,1H) ,7.78(d,J=8.5Hz,1H),7.49–7.40(m,2H),7.41–7.27(m,2H),7.03(d,J=8.7Hz,1H), 4.20(s,3H), 4.08 (q, J = 6.7Hz, 1H), 3.80 (p, J = 6.7Hz, 1H), 3.26 (s, 3H), 1.18 (dd, J = 11.0, 6.8 Hz, 6H), 0.97 (d, J ＝6.7Hz,3H).LC-MS(ESI)[M+H] ⁺ :442.25.

Example 38

The compound of Example 38 was prepared by the same method as in Example 1, except that quinoline-5-boronic acid was used instead of phenylboronic acid in step (j) of Example 1.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.74(s,1H), 8.99(dd,J=4.1,1.7Hz,1H), 8.77–8.70(m,1H), 8.64(d,J=5.0 Hz, 1H), 8.18 (dt, J = 8.2, 1.2 Hz, 1H), 7.94-7.80 (m, 2H), 7.71 (s, 1H), 7.58 (dd, J = 8.7, 4.1 Hz, 1H), 7.15 (t,J=6.8Hz,2H),6.94(d,J=8.7Hz,1H), 4.00(q,J=6.6Hz,1H),3.59–3.39(m,1H),3.22(s,3H) ,1.00(d,J=6.5Hz,3H),0.90(d,J=6.7Hz,3H),0.84(d,J=8.9Hz,3H).LC-MS(ESI)[M+H] ⁺ : 439.20.

Example 39

The compound of Example 39 was prepared in the same manner as in Example 1, except that quinoline-4-boronic acid was used instead of phenylboronic acid in step (j) of Example 1.

¹ H NMR(400MHz,Chloroform-d)δ9.05(d,J=4.4Hz,1H), 8.62(d,J=4.9Hz,1H), 8.33-8.20(m,2H), 7.80(ddd,J ＝8.4,6.8,1.4Hz,1H),7.62–7.54(m,3H),7.45(s,1H),7.05(d,J＝4.9Hz,1H), 6.96(dd,J＝8.5,2.2Hz, 1H), 6.89 (d, J = 8.6 Hz, 1H), 4.14 (q, J = 6.8 Hz, 1H), 3.75-3.64 (m, 1H), 3.36 (s, 3H), 1.12 (d, J = 6.5 Hz,3H),1.07(d,J=6.8Hz,3H),0.99(d,J=6.6Hz,3H).LC-MS(ESI)[M+H] ⁺ :439.19.

Example 40

The compound of Example 40 was prepared in the same manner as in Example 1, except that isoquinoline-4-boronic acid was used instead of phenylboronic acid in step (j) of Example 1.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.73(s,1H), 9.44(s,1H), 8.70(s,1H), 8.64(d,J=4.9Hz,1H), 8.35(d, J = 8.4Hz, 1H), 8.25 (d, J = 8.0 Hz, 1H), 7.88-7.64 (m, 3H), 7.16 (dd, J = 14.7, 6.7 Hz, 2H), 6.93 (d, J = 8.7 Hz, 1H), 3.98 (q, J = 6.6 Hz, 1H), 3.53 (s, 1H), 3.20 (s, 3H), 0.98 (d, J = 6.5 Hz, 3H), 0.88 (d, J = 6.7 Hz,3H),0.82(d,J=12.6Hz,3H).LC-MS(ESI)[M+H] ⁺ :439.14.

Example 41

The compound of Example 41 was prepared in the same manner as in Example 40, except that D-2-aminobutyric acid was used instead of D-alanine in step (a) of Example 40.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.75(s,1H), 9.47(d,J=0.9Hz,1H), 8.73(s,1H), 8.66(d,J=5.0Hz,1H) ,8.43–8.33(m,1H),8.31–8.20(m,1H),7.89–7.66(m,3H),7.20(d,J=4.9Hz,2H),6.94(d,J=8.7Hz,1H ), 3.68(t,J=7.2Hz,1H),3.52(m,1H),3.22(s,3H),1.30(m,2H),0.89(dd,J=5.8Hz,6H),0.75(t ,J=7.4Hz,3H).LC-MS(ESI)[M+H] ⁺ :453.18.

Example 42

The compound of Example 42 was prepared in the same manner as in Example 40 except that cyclopentanone was used instead of acetone in step (c) of Example 40.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.80 (s, 1H), 9.46 (s, 1H), 8.72 (s, 1H), 8.66 (d, J = 4.9 Hz, 1H), 8.35 (d, J = 8.4Hz, 1H), 8.31–8.19 (m, 1H), 7.88–7.63 (m, 3H), 7.17 (t, J = 6.8 Hz, 2H), 6.95 (d, J = 8.6 Hz, 1H), 3.96(q,J=6.7Hz,1H),3.22(s,3H),2.07–1.89(m,1H),1.65(s,2H),1.52–1.22(m,2H),1.08–0.90(m, 4H),0.87(t,J=6.5Hz,3H).LC-MS(ESI)[M+H] ⁺ :465.18.

Example 43

The compound of Example 43 was prepared by the same method as in Example 1, except that isoquinoline-5-boronic acid was used instead of phenylboronic acid in step (j) of Example 1.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.72(s,1H), 9.45–9.39(m,1H), 8.63(d,J=5.0Hz,1H), 8.52(d,J=6.0Hz, 1H), 8.28 (d, J = 8.2 Hz, 1H), 8.19 (d, J = 6.0 Hz, 1H), 8.02 (dd, J = 7.2, 1.2 Hz, 1H), 7.81 (dd, J = 8.2, 7.2 Hz, 1H), 7.70 (s, 1H), 7.13 (d, J = 5.0 Hz, 2H), 6.93 (d, J = 8.7 Hz, 1H), 3.98 (q, J = 6.5 Hz, 1H), 3.55 ( m, 1H), 3.20 (s, 3H), 0.99 (d, J = 6.5 Hz, 3H), 0.88 (d, J = 6.7 Hz, 3H), 0.85-0.72 (m, 3H). LC-MS (ESI ) [M+H] ⁺ :439.12.

Example 44

Except that 4-methoxy-2-chloro-5-fluoropyrimidine was used in place of 4-methoxy-2-chloropyrimidine in step (g) of Example 38, the same method as in Example 38 was used to prepare and implement The compound of Example 44.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.82(s,1H), 9.00(dd,J=4.1,1.7Hz,1H), 8.75(d,J=2.0Hz,1H), 8.49–8.22( m, 2H), 7.93 (dd, J = 8.4, 7.2 Hz, 1H), 7.87 (dt, J = 7.2, 1.4 Hz, 1H), 7.64 (d, J = 2.2 Hz, 1H), 7.59 (dd, J ＝8.6,4.1Hz,1H), 7.09(dd,J＝8.9,2.2Hz,1H), 6.94(d,J＝8.7Hz,1H), 4.00(d,J＝6.7Hz,1H),3.61-3.39 (m,1H),3.21(s,3H),1.00(d,J=6.5Hz,3H),0.89(d,J=6.7Hz,3H),0.84(d,J=6.6Hz,3H).LC -MS(ESI)[M+H] ⁺ :457.18.

Example 45

Except that 4-methoxy-2-chloro-5-fluoropyrimidine was used in place of 4-methoxy-2-chloropyrimidine in step (g) of Example 40, the same method as in Example 40 was used to prepare and implement The compound of Example 45.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.82(s,1H), 9.49(s,1H), 8.73(dd,J=16.2,1.7Hz,2H), 8.28(d,J=7.9Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.81 (dddd, J = 23.5, 8.0, 6.8, 1.3 Hz, 2H), 7.64 (s, 1H), 7.11-7.04 (m, 1H), 6.92 (d,J=8.7Hz,1H),3.97(q,J=6.7Hz,1H),3.55-3.47(m,1H),3.19(s,3H),0.98(d,J=6.5Hz,3H) ,0.87(d,J=6.7Hz,3H),0.82(d,J=5.7Hz,3H).LC-MS(ESI)[M+H] ⁺ :457.10.

Example 46

Except that 4-methoxy-2-chloro-5-fluoropyrimidine was used in place of 4-methoxy-2-chloropyrimidine in step (g) of Example 43, the same method as in Example 43 was used to prepare the implementation. The compound of Example 46.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.80(s,1H),9.44(s,1H),8.73(d,J=2.0Hz,1H), 8.53(d,J=6.0Hz,1H) , 8.33 (d, J = 8.2 Hz, 1H), 8.02 (d, J = 7.1 Hz, 1H), 7.84 (t, J = 7.5 Hz, 2H), 7.63 (s, 1H), 7.08 (d, J = 8.8Hz,1H),6.92(d,J=8.6Hz,1H),3.97(q,J=6.7Hz,1H),3.57–3.47(m,1H),3.19(s,3H),0.97(d, J=6.5Hz,3H),0.87(d,J=6.7Hz,3H),0.84-0.73(m,3H).LC-MS(ESI)[M+H] ⁺ :457.14

Example 47

(a) The compound of Example 47A was prepared by the same method as in Example 1, except that N-Boc indole-3-boronic acid pinacol ester was used instead of phenylboronic acid in step (j).

¹ H NMR(400MHz, Chloroform-d) δ8.47–8.38(m,2H), 8.29–8.19(m,2H), 7.41(ddd,J=8.5,7.2,1.3Hz,1H), 7.38–7.28( m, 3H), 7.18–7.09 (m, 2H), 6.95 (d, J = 8.6 Hz, 1H), 4.20 (q, J = 6.8 Hz, 1H), 3.91 (hept, J = 6.6 Hz, 1H), 3.41 (s, 3H), 1.74 (s, 9H), 1.24 (d, J = 2.4 Hz, 3H), 1.22 (d, J = 2.3 Hz, 3H), 1.14 (d, J = 6.8 Hz, 3H).

(b) Compound 47A (60mg, 0.118mmol) was dissolved in 10ml 4N HCl/1.4-dioxane, and reacted at room temperature for 2h. Monitor the reaction with a TLC plate. After the reaction is over, pour the reaction solution into 50ml of water. The sodium solid was neutralized to pH=7, and extracted with 50ml*2DCM. The organic layers were combined, washed once with 100ml of saturated brine, dried with anhydrous sodium sulfate, and the solvent was evaporated. The organic phase silica gel was mixed and purified by a flash chromatography column using EA/ PE=20-50% gradient elution to obtain 15 mg of yellow solid, namely compound 47, with a yield of 31%.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.80 (d, J = 2.9 Hz, 1H), 9.27 (s, 1H), 8.60 (d, J = 7.8 Hz, 1H), 8.31 (dd, J = 8.5,4.1Hz,2H),7.51–7.45(m,2H),7.40(dd,J=8.7,2.2Hz,1H),7.27–7.11(m,3H),7.01(d,J=8.7Hz,1H ), 4.09 (q, J = 6.7 Hz, 1H), 3.85 (p, J = 6.6 Hz, 1H), 3.28 (s, 3H), 1.23 (d, J = 6.2 Hz, 3H), 1.18 (d, J ＝6.5Hz,3H),1.00(d,J＝6.7Hz,3H).LC-MS(ESI)[M+H] ⁺ :427.27.

Example 48

Except that in step (a) of Example 47, 4-(4-BOC-1-piperazinyl)phenylboronic acid was used instead of N-Boc indole-3-boronic acid pinacol ester, the same as in Example 47 was used. The compound of Example 48 was prepared by the method described above.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.41(s,1H), 8.40(d,J=5.3Hz,1H), 8.05(d,J=8.6Hz,2H), 7.63(d,J= 2.3Hz, 1H), 7.31 (dd, J = 8.7, 2.1 Hz, 1H), 7.24 (d, J = 5.3 Hz, 1H), 7.01 (dd, J = 8.8, 4.6 Hz, 3H), 4.10 (q, J=6.7Hz,1H),3.91(p,J=6.7Hz,1H), 3.26(s,3H), 3.20(t,J=5.1Hz,4H), 2.85(t,J=5.0Hz,4H) ,1.28(d,J＝6.6Hz,3H),1.21(d,J＝6.7Hz,3H),0.99(d,J＝6.7Hz,3H).LC-MS(ESI)[M+H] ⁺ : 472.26.

Example 49

(a) Compound 14 (60mg, 0.149mmol) was dissolved in 10ml methanol, added acetic acid (20μl, 0.300mmol), paraformaldehyde (5mg, 0.164mmol), reacted at room temperature for 2h, added sodium borohydride (7mg, 0.164mmol) After reacting at room temperature overnight, monitor the reaction with a TLC plate. After the reaction is complete, pour the reaction solution into 50ml water, extract with 50ml*2DCM, combine the organic layers, wash once with 100ml saturated brine, dry with anhydrous sodium sulfate, and evaporate the solvent. The organic phase silica gel sample was purified by a flash chromatography column, and EA/PE=20-50% gradient elution was used to obtain 20 mg of a pale yellow solid, namely compound 49, with a yield of 32.2%.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.50(s,1H), 8.49(d,J=5.2Hz,1H), 7.58(d,J=2.2Hz,1H), 7.37(dd,J= 8.7, 2.2 Hz, 1H), 7.33 (dt, J = 7.6, 1.3 Hz, 1H), 7.30-7.20 (m, 3H), 7.01 (d, J = 8.7 Hz, 1H), 6.72 (ddd, J = 8.0 ,2.4,1.0Hz,1H),4.09(q,J=6.7Hz,1H), 3.88(p,J=6.7Hz,1H), 3.26(s,3H), 2.76(s,3H),1.25(d ,J=6.6Hz,3H),1.20(d,J=6.5Hz,3H),0.99(d,J=6.7Hz,3H).LC-MS(ESI)[M+H] ⁺ :417.25

Example 50

The compound of Example 50 was prepared in the same manner as in Example 49, except that acetaldehyde was used instead of paraformaldehyde in step (a) of Example 49.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.50(s,1H), 8.49(d,J=5.2Hz,1H), 7.59(d,J=2.2Hz,1H), 7.45–7.28(m, 3H), 7.23(dd,J=8.8,6.4Hz,2H), 7.00(d,J=8.7Hz,1H), 6.78–6.66(m,1H), 4.10(q,J=6.7Hz,1H), 3.89(p,J=6.6Hz,1H), 3.26(s,3H), 3.13(q,J=7.1Hz,2H), 1.28–1.14(m,9H),0.99(d,J=6.7Hz,3H ).LC-MS(ESI)[M+H] ⁺ :431.26.

Example 51

The compound of Example 51 was prepared in the same manner as in Example 49, except that acetone was used instead of paraformaldehyde in step (a) of Example 49.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.49(s,1H), 8.49(d,J=5.2Hz,1H), 7.57(d,J=2.2Hz,1H), 7.38(dd,J= 8.7,2.2Hz,1H),7.32–7.26(m,2H),7.21(dd,J=9.3,6.4Hz,2H),6.99(d,J=8.7Hz,1H),6.73(dt,J=7.9 ,1.5Hz,1H), 5.61(d,J=8.0Hz,1H), 4.10(q,J=6.7Hz,1H), 3.89(p,J=6.6Hz,1H), 3.65(q,J=6.6 Hz, 1H), 3.26 (s, 3H), 1.26 (d, J = 6.6 Hz, 3H), 1.21 (d, J = 6.6 Hz, 3H), 1.19-1.14 (m, 6H), 0.99 (d, J ＝6.7Hz,3H).LC-MS(ESI)[M+H] ⁺ :445.24

Example 52

The compound of Example 52 was prepared in the same manner as in Example 49 except that cyclopentanone was used instead of paraformaldehyde in step (a) of Example 49.

¹ H NMR(400MHz,Chloroform-d)δ8.45(d,J=5.2Hz,1H),7.46-7.33(m,2H),7.31(q,J=3.8,3.0Hz,2H),7.29(m ,1H),7.19–7.16(m,1H),7.14(d,J=2.3Hz,1H),7.12(d,J=5.2Hz,1H), 6.94(d,J=8.6Hz,1H), 6.75 (ddd,J=7.9,2.4,1.0Hz,1H), 4.20(q,J=6.8Hz,1H), 3.98(p,J=6.7Hz,1H), 3.90(p,J=6.2Hz,1H) ,3.40(s,3H),2.08(td,J=14.7,13.4,6.8Hz,2H),1.78(q,J=6.0,4.6Hz,2H),1.72-1.62(m,2H),1.52(dt ,J＝13.4,6.7Hz,2H),1.34(d,J＝6.7Hz,3H),1.28(d,J＝6.5Hz,3H),1.15(d,J＝6.8Hz,3H).LC-MS (ESI)[M+H] ⁺ :471.20.

Example 53

The compound of Example 53 was prepared in the same manner as in Example 49, except that cyclohexanone was used instead of paraformaldehyde in step (a) of Example 49.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.49(s,1H), 8.49(d,J=5.2Hz,1H), 7.53(d,J=2.2Hz,1H), 7.40(dd,J= 8.7, 2.2Hz, 1H), 7.32 (s, 1H), 7.27 (d, J = 7.5 Hz, 1H), 7.24-7.15 (m, 2H), 7.00 (d, J = 8.7 Hz, 1H), 6.75 ( d, J = 8.0Hz, 1H), 5.63 (m, 1H), 4.10 (q, J = 6.7 Hz, 1H), 3.88 (p, J = 6.5 Hz, 1H), 3.26 (s, 3H), 1.96 ( d,J=12.6Hz,2H),1.73(d,J=12.7Hz,2H),1.61(d,J=12.6Hz,2H),1.28–1.22(m,7H),1.21(d,J=6.6 Hz,3H),0.99(d,J=6.7Hz,3H).LC-MS(ESI)[M+H] ⁺ :485.16.

Example 54

The compound of Example 54 was prepared in the same manner as in Example 49, except that cyclopentylformaldehyde was used instead of paraformaldehyde in step (a) of Example 49. LC-MS(ESI)[M+H] ⁺ :485.24

Example 55

The compound of Example 55 was prepared in the same manner as in Example 49, except that cyclohexylformaldehyde was used instead of paraformaldehyde in step (a) of Example 49. LC-MS(ESI)[M+H] ⁺ :499.26

Example 56

Compound 14 (100mg, 0.249mmol), phenylboronic acid (61mg, 0.498mmol), 2.6-lutidine (30μl, 0.0.249mmol), anhydrous copper acetate (3mg, 0.012mmol), myristic acid (12mg, 0.150mmol) ) Dissolve in 10ml toluene/acetonitrile=5:1, react at 50℃ for 8h, monitor the reaction with a TLC plate. After the reaction is complete, filter the reaction solution with celite, evaporate the solvent, and purify the silica gel sample with a flash chromatography column EA/PE=20-50% gradient elution was used to obtain 31 mg of yellow foamy solid, namely compound 56, with a yield of 26%.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.53(s,1H),8.52(d,J=5.1Hz,1H),8.39(s,1H),7.91(d,J=2.0Hz,1H) ,7.57(dt,J=7.7,1.2Hz,1H),7.52(d,J=2.2Hz,1H),7.42–7.33(m,2H),7.30–7.19(m,4H),7.14(dq,J ＝6.9,1.4Hz,2H),6.93-6.81(m, 2H),4.08(q,J＝6.7Hz,1H), 3.86(p,J＝6.6Hz,1H), 3.24(s,3H),1.23 (d,J=6.6Hz,3H),1.16(d,J=6.6Hz,3H),0.96(d,J=6.7Hz,3H).LC-MS(ESI)[M+H] ⁺ :479.19.

Example 57

(a) Compound 57A (500mg, 2.357mmol) pinacol ester borane (1ml, 7.071mmol), TEA (1.3ml, 9.428mmol) dissolved in 20ml 1.4-dioxane, ventilated _{with N 2 for 1min} Then, add palladium acetate (27mg, 0.118mmol) and Johnphos (166mg, 0.471mmol), and then _{ventilate with N 2 for} 1 min, and react at 80°C for 8 hours. Monitor the reaction with a TLC plate. After the reaction, filter through Celite and evaporate to dryness. The solvent and silica gel were mixed with samples to be purified by flash chromatography column, using EA/PE=0-10% gradient elution, to obtain 470 mg of light yellow solid, namely compound 57B, with a yield of 76.9%.

¹ H NMR (400MHz, Chloroform-d) δ 7.14 (dd, J = 7.3, 1.3 Hz, 1H), 6.99 (t, J = 7.6 Hz, 1H), 6.58 (dd, J = 7.9, 1.3 Hz, 1H ),3.33-3.25(m,2H),3.06(t,J=6.5Hz,2H),2.02-1.91(m,2H),1.35s,12H).

(b) The compound of Example 57 was prepared by the same method as in Example 1, except that 57B was used instead of phenylboronic acid in step (j) of Example 1.

¹ H NMR (400MHz, Chloroform-d) δ8.42 (d, J = 5.1Hz, 1H), 7.46 (d, J = 2.3 Hz, 1H), 7.09-6.97 (m, 2H), 6.88 (d, J =8.5Hz, 1H), 6.81 (d, J = 5.1 Hz, 1H), 6.74 (d, J = 7.4 Hz, 1H), 6.55 (d, J = 8.0 Hz, 1H), 4.14-4.07 (m, 1H) ), 3.89 (p, J = 6.6 Hz, 1H), 3.35 (s, 3H), 3.32 (t, J = 5.6 Hz, 2H), 2.81 (dt, J = 6.2, 3.1 Hz, 2H), 1.87 (q ,J=5.9Hz,2H),1.26(d,J=6.9Hz,3H),1.22(d,J=6.6Hz,3H),1.10(d,J=6.8Hz,3H).LC-MS(ESI )[M+H] ⁺ :443.24.

Example 58

Except that in step (a) of Example 57, 2-methyl 3-aminobromobenzene was used instead of 5-bromo-1,2,3,4-tetrahydroquinoline, it was prepared in the same manner as in Example 57 The compound of Example 58.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.50(s,1H), 8.44(d,J=5.0Hz,1H), 7.62–7.56(m,1H), 7.23(dd,J=8.7,2.2 Hz, 1H), 7.02–6.90 (m, 2H), 6.80 (d, J = 5.0 Hz, 1H), 6.71 (dd, J = 8.0, 1.3 Hz, 1H), 6.61 (dd, J = 7.6, 1.3 Hz ,1H),5.00(s,2H),4.04(q,J=6.7Hz,1H),3.75(p,J=6.6Hz,1H),3.21(s,3H),2.05(s,3H),1.15 (dd,J=9.5,6.6Hz,6H),0.94(d,J=6.7Hz,3H).LC-MS(ESI)[M+H] ⁺ :417.19.

Example 59

It was prepared by the same method as in Example 57 except that 6-methyl 3-aminobromobenzene was used in place of 5-bromo-1,2,3,4-tetrahydroquinoline in step (a) of Example 57 The compound of Example 59.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.49(s,1H), 8.45(d,J=5.0Hz,1H), 7.62–7.56(m,1H), 7.24(dd,J=8.7,2.2 Hz, 1H), 6.94 (dd, J = 8.5, 3.6 Hz, 2H), 6.82 (d, J = 5.0 Hz, 1H), 6.68 (d, J = 2.4 Hz, 1H), 6.56 (dd, J = 8.1 ,2.5Hz,1H),5.00(s,2H),4.04(q,J=6.6Hz,1H),3.77(p,J=6.6Hz,1H),3.21(s,3H),2.19(s,3H) ), 1.15(t,J=6.0Hz,6H),0.94(d,J=6.8Hz,3H).LC-MS(ESI)[M+H] ⁺ :417.20.

Example 60

(a) Cyclopropionylacetone (5g, 39.632mmol) was dissolved in 20ml of ethanol, cooled to 0°C, and 10ml of hydrazine monohydrate (3ml, 60mmol) in ethanol was slowly added dropwise, heated to reflux at 80°C for 3h, using a TLC plate The reaction was monitored. After the reaction, the reaction solution was poured into 50ml of water, neutralized with 1N HCl to pH=7, and extracted with 100ml*2DCM. The organic layers were combined, washed once with 200ml of saturated brine, dried with anhydrous sodium sulfate, and the solvent was evaporated. Further purification is directly cast to the next step.

(b) Compound 60B (4.9g, 40.108mmol) was dissolved in 50ml DCM, cooled to -20°C, NIS (11g, 48.130mmol) was added, and reacted at -20°C for 4h. The reaction was monitored with a TLC plate. After the reaction, the reaction The solution was poured into 50ml water, extracted with 50ml*2DCM, combined the organic layers, washed once with 100ml saturated brine, dried over anhydrous sodium sulfate, evaporated to dry the solvent, and directly cast to the next step without further purification.

(c) Compound 60C (10g, 40.311mmol) was dissolved in 50ml of DCM, added DMAP (5.5g, 44.342mmol) and di-tert-butyl dicarbonate (18g, 80.622mmol), reacted at room temperature for 2h, and monitored the reaction with a TLC plate. After finishing, pour the reaction solution into 50ml water, extract with 50ml*2DCM, combine the organic layers, wash with 100ml saturated brine once, dry with anhydrous sodium sulfate, evaporate the solvent, and purify the organic phase silica gel sample by flash chromatography column, use EA/PE=0-6% gradient elution to obtain 10 g of a light yellow oily liquid, namely compound 60D, with a yield of 71.4%.

¹ H NMR(400MHz,Chloroform-d)δ2.54(s,3H),1.90–1.76(m,1H),1.63(s,9H), 1.01(tt,J=5.4,2.6Hz,2H),0.97 --0.84(m,2H).

(d) Compound 60D (4g, 11.488mmol) was dissolved in 20ml of anhydrous THF, cooled to -78°C, 2M n-BuLi (8.8ml, 17.232mmol) was added dropwise under _{N 2 protection, and reacted at -78°C for 1h} , At this temperature, add isopropanol pinacol borate (4.7ml, 22.976mmol) dropwise, react at -78°C for 1 hour, and at room temperature for 2 hours. Monitor the reaction with a TLC plate. After the reaction is complete, pour the reaction solution It was quenched into 100ml saturated aqueous ammonium chloride solution, extracted with 100ml*2DCM, combined the organic layers, washed once with 200ml saturated brine, dried with anhydrous sodium sulfate, evaporated to dryness, and the organic phase silica gel was mixed and purified by a flash chromatography column. EA/PE=0-8% gradient elution to obtain 2 g of colorless oily liquid, namely compound 60E, with a yield of 50%.

¹ H NMR (400MHz, Chloroform-d) δ 2.65 (s, 3H), 2.27 (tt, J = 8.5, 5.1 Hz, 1H), 1.61 (s, 9H), 1.32 (s, 12H), 1.00 (dt ,J=5.9,3.0Hz,2H),0.88(dt,J=8.5,3.1Hz,2H).

(e) Compound 60 was prepared by the same method as in Example 1, except that 60E was used instead of phenylboronic acid in step (j) of Example 1.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 12.45 (s, 1H), 9.23 (s, 1H), 8.37 (d, J = 5.2 Hz, 1H), 7.39 (dd, J = 8.7, 2.2 Hz, 1H), 7.31 (d, J = 2.3 Hz, 1H), 6.95 (t, J = 6.8 Hz, 2H), 4.05 (q, J = 6.7 Hz, 1H), 3.78 (p, J = 6.7 Hz, 1H) ,3.22(s,3H),2.40(s,3H),2.31(m,1H),1.22(d,J=6.5Hz,3H),1.15(d,J=6.5Hz,3H),0.96(d, J=6.7Hz,3H),0.87(m,2H),0.80(d,J=5.9Hz,2H).LC-MS(ESI)[M+H] ⁺ :432.62.

Example 61

(a) Compound 61A (8g, 97.430mmol) was dissolved in 100ml THF, cooled to -78°C, 2.5M n-BuLi (46.8ml, 146.145mmol) was added dropwise under _{N 2 protection, and reacted at -78°C for 1h.} At this temperature, add cyclopropanaldehyde (8.2g, 194.86mmol) dropwise, react at room temperature for 16h, monitor the reaction with a TLC plate, after the reaction is over, pour the reaction solution into 200ml saturated aqueous ammonium chloride for quenching, 200ml*2DCM Extract, combine the organic layers, wash once with 250ml of saturated brine, dry with anhydrous sodium sulfate, evaporate the solvent, and purify the organic phase silica gel with a flash chromatography column using MeOH/DCM = 1-3% gradient elution to obtain light 10 g of yellow oily liquid, compound 61B, with a yield of 67.4%.

¹ H NMR(400MHz,Chloroform-d)δ7.22(d,J=1.8Hz,1H), 6.20(d,J=1.8Hz,1H), 4.38(s,1H), 4.02(d,J=8.0 Hz, 1H), 3.77 (s, 3H), 1.27 (dtd, J = 13.0, 8.2, 4.9 Hz, 1H), 0.66-0.48 (m, 2H), 0.42 (dq, J = 9.4, 4.8 Hz, 1H) ,0.26(dq,J=9.9,4.9Hz,1H).

(b) Compound 61B (9g, 59.133mmol) was dissolved in 100ml DCM, TFA (26.27ml, 354.798mmol), Et ₃ SiH (56.52ml, 354.798mmol) was added, and the reaction was carried out at 40°C for 36 hours. The reaction was monitored by TLC plate. Then, pour the reaction solution into 50ml water, adjust the pH to 8-9, extract with 200ml*2DCM, combine the organic layers, wash once with 250ml saturated brine, dry with anhydrous sodium sulfate, evaporate the solvent, and mix the organic phase with silica gel. Purification by flash chromatography column, using EA/PE=10-30% gradient elution, to obtain 3.689 g of colorless oily liquid, namely compound 61C, with a yield of 46.1%.

¹ H NMR (400MHz, Chloroform-d) δ 7.36 (d, J = 1.9 Hz, 1H), 6.12 (d, J = 1.8 Hz, 1H), 3.76 (s, 3H), 2.50 (d, J = 6.8 Hz, 2H), 0.99 (dddt, J = 13.4, 8.0, 4.9, 1.9 Hz, 1H), 0.63-0.46 (m, 2H), 0.17 (dt, J = 5.9, 4.6 Hz, 2H).

(c) Compound 61C (3.689g, 27.085mmol) was dissolved in 20ml DCM, cooled to -20°C, NBS (5.5g, 29.794mmol) was added, and reacted at -20°C for 4h. The reaction was monitored with a TLC plate. After the reaction, the The reaction solution was poured into 50ml water, extracted with 50ml*2DCM, combined the organic layers, washed once with 100ml saturated brine, dried with anhydrous sodium sulfate, evaporated to dryness, and the organic phase silica gel mixed sample was purified by flash chromatography column using EA/PE= 0-10% gradient elution, 3.9 g of light yellow oily liquid was obtained, namely compound 61D, with a yield of 67.2%.

¹ H NMR (400MHz, Chloroform-d) δ 7.39 (s, 1H), 3.86 (s, 3H), 2.63 (d, J = 6.6 Hz, 2H), 0.96 (dq, J = 12.2, 6.1 Hz, 1H ),0.58–0.42(m,2H),0.27(t,J=5.2Hz,2H).

(d) Compound 61D (3.9g, 18.132mmol) was dissolved in 20ml of THF, cooled to -78°C, 1.6M n-BuLi (18ml, 27.198mmol) was added dropwise under _{N 2 protection, and reacted at -78°C for 1h.} At this temperature, add isopropanol pinacol borate (7.4ml, 36.264mmol) dropwise, react at -78°C for 1 hour, and at room temperature for 2 hours. Monitor the reaction with a TLC plate. After the reaction is over, pour the reaction solution into 70ml Quench in saturated aqueous ammonium chloride solution, extract with 70ml*2DCM, combine the organic layers, wash once with 100ml saturated brine, dry with anhydrous sodium sulfate, evaporate the solvent, and purify the organic phase silica gel with a flash chromatography column using EA/ PE=0-10% gradient elution, 3.5 g of light yellow oily liquid was obtained, namely compound 61E, with a yield of 73.7%.

¹ H NMR (400MHz, Chloroform-d) δ 7.68 (d, J = 1.1 Hz, 1H), 3.86 (s, 3H), 2.82 (d, J = 6.7 Hz, 2H), 1.30 (s, 12H), 0.94(ddtd,J=8.1,6.5,5.0,1.6Hz,1H), 0.48–0.36(m,2H), 0.33–0.22(m,2H).

(e) The compound of Example 61 was prepared by the same method as in Example 1, except that 61E was used instead of phenylboronic acid in step (j) of Example 1.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.18(s,1H), 8.34(d,J=5.3Hz,1H), 8.02(s,1H), 7.30(dd,J=8.7,2.1Hz, 1H), 7.24(d,J=2.2Hz,1H),7.07–6.90(m,2H),4.09(q,J=6.7Hz,1H), 3.87–3.74(m,4H), 3.26(s,3H) ), 3.23 (d, J = 6.7 Hz, 2H), 1.26 (d, J = 6.7 Hz, 4H), 1.18 (d, J = 6.5 Hz, 3H), 0.99 (d, J = 6.7 Hz, 3H), 0.34–0.25(m,2H),0.11(p,J=4.5,4.0Hz,2H).LC-MS(ESI)[M+H] ⁺ :446.33.

Example 62

(a) Compound 62A (100mg, 0.772mmol), isoquinoline-4-boronic acid (152mg, 0.926mmol), potassium carbonate (214mg, 1.544mmol) dissolved in 10ml 1.4-dioxane: water = 4:1 After ventilating with N2 for 1 min, add Pa(dppf)Cl2 (64mg, 0.077mmol), then ventilate with N2 for 1 min, and react at 80℃ for 8h. Monitor the reaction with a TLC plate. After the reaction, 50mlH ₂ O/50ml* Extract with 2DCM, combine the organic layers, wash once with 100ml saturated brine, dry with anhydrous sodium sulfate, evaporate the solvent, and purify the organic phase silica gel with a flash chromatography column using MeOH/DCM=1 to 3% gradient elution to obtain White foamy solid, compound 62B, yield 34.1%.

¹ H NMR(400MHz,Chloroform-d)δ9.37(d,J=0.8Hz,1H),8.60(s,1H),8.46(s,1H),8.09(dt,J=8.0,1.1Hz,1H ), 7.72 (ddddd, J = 13.2, 11.8, 8.0, 6.4, 1.5 Hz, 3H), 5.38 (s, 2H).

(b) Compound 1E (107mg, 0.360mmol), compound 62B (77mg, 0.300mmol), sodium tert-butoxide (58mg, 0.720mmol) were dissolved in 10ml of 1.4-dioxane, and after ventilating _{with N 2 for 1 min} , Add Pa ₂ (dba)3 (28mg, 0.036mmol) and Xphos (29mg, 0.072mmol), and then _{ventilate with N 2 for} 1 min, and react at 100°C for 8 hours. Monitor the reaction with a TLC plate. After the reaction, diatomaceous earth After filtration, the solvent was evaporated, and the silica gel sample was purified by flash chromatography column, using MeOH/DCM=1-3% gradient elution, to obtain 18 mg of pale yellow foamy solid, namely compound 62, with a yield of 12.7%.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.96(s,1H),9.46(s,1H),8.73(s,1H),8.61(s,1H),8.26(dd,J=7.5,2.0 Hz, 1H), 7.86–7.72 (m, 3H), 7.59 (s, 1H), 7.03 (s, 1H), 6.92 (d, J = 8.6 Hz, 1H), 3.96 (d, J = 7.1 Hz, 1H ),3.48(m,1H),3.18(s,3H),0.94(m,3H),0.85(d,J=6.7Hz,3H),0.78(m,3H).LC-MS(ESI)[M +H] ⁺ :473.14.

Example 63

Except that in step (a) of Example 62, 5-methyl-4-chloro-2-aminopyrimidine was used instead of 4,5-dichloro-2-aminopyrimidine, the same method as in Example 62 was used to prepare and implement The compound of Example 63.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.58 (s, 1H), 9.43 (s, 1H), 8.53 (s, 2H), 8.25 (dd, J = 7.3, 1.9 Hz, 1H), 7.83- 7.72(m,2H),7.69(s,2H),7.05-6.98(m,1H),6.88(d,J=8.7Hz,1H),3.94(q,J=6.7Hz,1H), 3.39(m ,1H),3.17(s,3H),1.96(s,3H),0.92(d,J=6.5Hz,3H),0.85(d,J=6.7Hz,3H),0.75(m 3H).LC- MS(ESI)[M+H] ⁺ :453.19.

Example 64

The compound of Example 64 was prepared in the same manner as in Example 62, except that 3-aminobromobenzene was used instead of 4,5-dichloro-2-aminopyrimidine in step (a) of Example 62.

¹ H NMR(400MHz, Chloroform-d)δ9.26(s,1H), 8.52(s,1H), 8.08-7.97(m,2H), 7.73-7.59(m,2H), 7.45-7.36(m, 1H), 7.15 (d, J = 6.0 Hz, 2H), 7.03 (dd, J = 7.6, 1.4 Hz, 1H), 6.87 (d, J = 9.0 Hz, 1H), 6.75–6.68 (m, 2H), 6.01 (s, 1H), 4.17 (q, J = 6.8 Hz, 1H), 3.82 (hept, J = 6.7 Hz, 1H), 3.36 (s, 3H), 1.28 (d, J = 6.6 Hz, 3H), 1.22(d,J=6.5Hz,3H),1.12(d,J=6.8Hz,3H).LC-MS(ESI)[M+H] ⁺ :388.19.

Example 65

(a) Compound 65A (212mg, 1.232mmol), phenylboronic acid (100mg, 0.821mmol), potassium carbonate (227mg, 1.643mmol) dissolved in 10ml 1.4-dioxane: water = 4:1, exchange _{with N 2} After ventilating for 1 min, add Pa(dppf)Cl2 (67mg, 0.082mmol), and then _{ventilate with N 2 for} 1 min, and react at 80°C for 8 hours. Monitor the reaction with a TLC plate. After the reaction is complete, extract with 50mlH ₂ O/50ml*2DCM. Combine the organic layers, wash once with 100ml saturated brine, dry with anhydrous sodium sulfate, evaporate the solvent, and purify the organic phase silica gel sample through a flash chromatography column, eluting with a gradient of EA/PE=10-50%, to obtain an orange oil Liquid 87mg, compound 65B, yield 62.3%.

¹ H NMR(400MHz,Chloroform-d)δ7.62–7.56(m,2H),7.49–7.41(m,2H),7.40–7.35(m,1H),7.26(d,J=7.8Hz,1H) ,7.05-7.00(m,1H), 6.95(d,J=2.1Hz,1H), 6.75-6.68(m,1H), 3.69(s,2H).

(b) Compound 1E (106mg, 0.355mmol), compound 65B (50mg, 0.295mmol), sodium tert-butoxide (57mg, 0.570mmol) were dissolved in 10ml of 1.4-dioxane, after 1 minute ventilation _{with N 2} , Add Pa2(dba)3 (28mg, 0.036mmol) and Xphos (29mg, 0.072mmol), and then _{ventilate with N 2 for} 1 min, and react at 100°C for 8 hours. Monitor the reaction with a TLC plate. After the reaction, filter through Celite , The solvent was evaporated to dryness, the silica gel sample was mixed and purified by a flash chromatography column, using MeOH/DCM=1-3% gradient elution, to obtain 34 mg of a white foamy solid, namely compound 65, with a yield of 29.8%.

¹ H NMR(400MHz,DMSO-d ₆ )δ8.12(s,1H), 7.60–7.52(m,2H), 7.43(t,J=7.7Hz,2H), 7.38–7.29(m,1H), 7.32–7.22(m,2H), 7.05–6.92(m,3H), 6.65(dd,J=6.5,2.3Hz,2H), 4.07(q,J=6.7Hz,1H), 3.79(p,J= 6.6Hz, 1H), 3.22 (s, 3H), 1.22 (d, J = 6.7 Hz, 3H), 1.18 (d, J = 6.5 Hz, 3H), 0.97 (d, J = 6.7 Hz, 3H). LC -MS(ESI)[M+H] ⁺ :386.07

Example 66

The compound of Example 66 was prepared in the same manner as in Example 65 except that 3-cyanophenylboronic acid was used instead of phenylboronic acid in step (a) of Example 65.

¹ H NMR(400MHz,DMSO-d ₆ )δ8.17(s,1H), 8.02(t,J=1.8Hz,1H),7.96-7.88(m,1H),7.81(dt,J=7.8,1.3 Hz, 1H), 7.64 (t, J = 7.8 Hz, 1H), 7.35-7.26 (m, 2H), 7.12-7.01 (m, 2H), 6.96 (d, J = 9.0 Hz, 1H), 6.69-6.62 (m, 2H), 4.08 (q, J = 6.7 Hz, 1H), 3.79 (p, J = 6.6 Hz, 1H), 3.22 (s, 3H), 1.23 (d, J = 6.7 Hz, 3H), 1.18 (d,J=6.5Hz,3H),0.97(d,J=6.7Hz,3H).LC-MS(ESI)[M+H] ⁺ :411.08.

Example 67

The compound of Example 67 was prepared in the same manner as in Example 65 except that pyridine-4-boronic acid was used instead of phenylboronic acid in step (a) of Example 65.

¹ H NMR(400MHz, Chloroform-d)δ8.66(d,J=5.1Hz,2H), 7.53–7.47(m,2H), 7.38(t,J=7.8Hz,1H), 7.32–7.26(m ,1H), 7.13(ddd,J=22.4,7.8,1.9Hz,2H), 6.91(d,J=8.3Hz,1H), 6.69(d,J=9.7Hz,2H),5.88(s,1H) , 4.20 (q, J = 6.8 Hz, 1H), 3.79 (dq, J = 36.6, 6.8 Hz, 1H), 3.39 (s, 3H), 1.30 (d, J = 6.7 Hz, 3H), 1.28-1.25 ( m,3H),1.15(d,J=6.8Hz,3H).LC-MS(ESI)[M+H] ⁺ :387.22.

Example 68

The compound of Example 68 was prepared in the same manner as in Example 65 except that 2-methoxyphenylboronic acid was used instead of phenylboronic acid in step (a) of Example 65.

¹ H NMR(400MHz,DMSO-d ₆ )δ8.07(s,1H), 7.37–7.29(m,1H), 7.28–7.20(m,2H), 7.14(d,J=1.9Hz,1H), 7.10(d,J=8.3Hz,1H),7.03-6.91(m,3H), 6.85(d,J=7.6Hz,1H), 6.70-6.63(m,2H),4.08(q,J=6.6Hz ,1H),3.78(m,1H),3.77(s,3H),3.23(s,3H),1.24(d,J＝6.7Hz,3H),1.18(d,J＝6.6Hz,3H),0.98 (d,J=6.6Hz,3H).LC-MS(ESI)[M+H] ⁺ :416.08.

Example 69

(a) Compound 69A (7.5g, 65.692mmol) was dissolved in 40ml DCM, TEA (9ml, 65.692mmol), DMAP (800mg, 6.6mmol), di-tert-butyl dicarbonate (17g, 78.831mmol) were added and reacted at room temperature for 2h Monitor the reaction with a TLC plate. After the reaction is complete, pour the reaction solution into 100ml water, extract with 100ml*2DCM, combine the organic layers, wash once with 200ml saturated brine, dry with anhydrous sodium sulfate, evaporate the solvent, and mix the organic phase with silica gel. The sample was purified by a flash chromatography column, using EA/PE=20-50% gradient elution, to obtain 11.101 g of a white solid, namely compound 69B, with a yield of 78.9%.

¹ H NMR (400MHz, Chloroform-d) δ 10.75 (s, 1H), 6.46 (q, J = 1.0 Hz, 1H), 2.38 (d, J = 1.1 Hz, 3H), 1.56 (s, 9H).

(b) Dissolve compound 69B (1g, 4.667mmol) in anhydrous 20ml DMF, add NaH (374mg, 9.334mmol) in batches in an ice-water bath, stir at 0°C for 30min, slowly add methyl iodide (0.436ml, 7mmol), room temperature After reaction for 2h, the reaction was monitored by TLC plate. After the reaction, the reaction solution was poured into 50ml ice water to quench, 50ml*2DCM was extracted, the organic layers were combined, washed once with 100ml saturated brine, dried with anhydrous sodium sulfate, and the solvent was evaporated. The organic phase silica gel sample was purified by flash chromatography column, using EA/PE=0-10% gradient elution, to obtain 765 mg of colorless oily liquid, namely compound 69C, with a yield of 71.8%.

¹ H NMR (400MHz, Chloroform-d) δ 6.49 (d, J = 1.2 Hz, 1H), 3.56 (s, 3H), 2.36 (d, J = 1.0 Hz, 3H), 1.59 (s, 9H).

(c) Compound 69C (765mg, 3.351mmol) was dissolved in 10ml of DCM, cooled to -20°C, added NBS (703mg, 3.686mmol), reacted at room temperature for 4h, and monitored the reaction with a TLC plate. After the reaction, the reaction solution was poured into Extract with 50ml*2DCM in 50ml water, combine the organic layers, wash once with 100ml saturated brine, dry with anhydrous sodium sulfate, evaporate the solvent, and purify the organic phase silica gel sample by flash chromatography column, using EA/PE=0-10% Gradient elution gave 970 mg of white solid, ie compound 69D, with a yield of 94.2%.

¹ H NMR (400MHz, Chloroform-d) δ3.49 (s, 3H), 2.31 (s, 3H), 1.59 (s, 9H).

(d) Compound 69D (200mg, 0.651mmol), 2-aminopyridine-4-boronic acid (370mg, 2mmol), potassium carbonate (180mg, 1.302mmol) dissolved in 10ml 1.4-dioxane: water = 4:1 After ventilating with N2 for 1 min, add Pa(dppf)Cl2 (54 mg, 0.065 mmol), then ventilate with N2 for 1 min, and react at 80°C for 8 hours. Monitor the reaction with a TLC plate. After the reaction is complete, _{extract with H 2} O/DCM Twice, combine the organic layers, wash once with 50ml of saturated brine, dry with anhydrous sodium sulfate, evaporate the solvent, and purify the organic phase silica gel with a flash chromatography column using MeOH/DCM = 1-3% gradient elution to obtain 117 mg of brown solid, compound 69E, yield 56.1%.

¹ H NMR (400MHz, Chloroform-d) δ 7.95 (s, 1H), 6.75-6.53 (m, 2H), 5.65-4.43 (s, 2H), 3.51 (s, 3H), 2.44 (s, 3H) ,1.21(s,9H).

(e) Compound 69E (117mg, 0.365mmol), compound 1E (163mg, 0.548mmol), sodium tert-butoxide (72mg, 0.730mmol) was dissolved in 10ml 1.4-dioxane, after 1 minute ventilation _{with N 2} , Add Pa2(dba)3 (34mg, 0.040mmol) and Xphos (35mg, 0.080mmol), then _{ventilate with N 2 for} 1 min, and react at 100°C for 8 hours. Monitor the reaction with a TLC plate. After the reaction, filter through Celite , The solvent was evaporated, the silica gel sample was mixed and purified by flash chromatography column, using MeOH/DCM=1 to 3% gradient elution. 75 mg of yellow foamy solid was obtained, namely compound 69F, with a yield of 46.9%.

¹ H NMR (400MHz, Chloroform-d) δ 8.16 (d, J = 5.4 Hz, 1H), 6.92 (s, 1H), 6.91-6.87 (m, 2H), 6.84-6.79 (m, 2H), 6.76 (s, 1H), 4.21 (q, J = 6.8 Hz, 1H), 3.91 (p, J = 6.6 Hz, 1H), 3.55 (s, 3H), 3.39 (s, 3H), 2.47 (s, 3H) , 1.59 (s, 9H), 1.33 (d, J = 6.7 Hz, 3H), 1.28 (d, J = 6.5 Hz, 3H), 1.15 (d, J = 6.8 Hz, 3H).

(f) Compound 69F (75mg, 0.140mmol) was dissolved in 10ml 4N HCl/1.4-dioxane, and reacted at room temperature for 2h. Monitor the reaction with a TLC plate. After the reaction is over, pour the reaction solution into 50ml of water. The sodium solid was neutralized to pH=7, extracted with 50ml*2DCM, combined the organic layers, washed once with 100ml saturated brine, dried over anhydrous sodium sulfate, evaporated to dryness, and the organic phase silica gel mixed sample was purified by flash chromatography using MeOH/ DCM = 1-3% gradient elution to obtain 15 mg of yellow solid, namely compound 69, with a yield of 24.6%.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.01(s,1H), 8.04(d,J=5.5Hz,1H), 7.82(q,J=4.8Hz,1H), 7.28(d,J= 2.2Hz, 1H), 7.17 (dd, J = 8.7, 2.2 Hz, 1H), 6.97 (d, J = 8.7 Hz, 1H), 6.76 (d, J = 1.6 Hz, 1H), 6.68 (dd, J = 5.5, 1.7 Hz, 1H), 4.09 (q, J = 6.7 Hz, 1H), 3.82 (p, J = 6.7 Hz, 1H), 3.25 (s, 3H), 2.84 (d, J = 4.6 Hz, 3H) ,2.34(s,3H),1.28(d,J=6.6Hz,3H),1.24-1.16(m,3H),0.99(d,J=6.7Hz,3H).LC-MS(ESI)[M+ H] ⁺ :437.24

Example 70

The compound of Example 70 was prepared in the same manner as in Example 69 except that 4-cyclopropyl-2-aminothiazole was used instead of 4-methyl-2-aminothiazole in step (a) of Example 69.

¹ H NMR(400MHz,DMSO-d ₆ )δ8.96(s,1H), 8.06(d,J=5.4Hz,1H), 7.77(q,J=4.8Hz,1H), 7.28(d,J= 2.3Hz, 1H), 7.18 (dd, J = 8.7, 2.2 Hz, 1H), 6.97 (d, J = 8.7 Hz, 1H), 6.86 (d, J = 1.6 Hz, 1H), 6.76 (dd, J = 5.4, 1.6 Hz, 1H), 4.09 (q, J = 6.7 Hz, 1H), 3.81 (p, J = 6.7 Hz, 1H), 3.25 (s, 3H), 2.79 (d, J = 4.7 Hz, 3H) ,2.11(tt,J=8.1,5.1Hz,1H),1.28(d,J=6.6Hz,3H),1.21(d,J=6.6Hz,3H),0.99(d,J=6.7Hz,3H) ,0.95–0.86(m,4H).LC-MS(ESI)[M+H] ⁺ :463.25.

Example 71

(a) Compound 71A (5g, 45.390mmol) was dissolved in 40ml DCM, cooled to -20°C, NBS (8.9g, 50mmol) was added, and reacted at 0°C for 4h. The reaction was monitored with a TLC plate. After the reaction, the reaction solution was poured. Pour into 100ml water, extract with 100ml*2DCM, combine the organic layers, wash with 150ml saturated brine once, dry with anhydrous sodium sulfate, evaporate the solvent, and purify the organic phase silica gel sample by flash chromatography column, using EA/PE=20-50 % Gradient elution to obtain 1.364 g of a reddish brown oily liquid, namely compound 71B, with a yield of 15.9%.

¹ H NMR (400MHz, Chloroform-d) δ 7.63 (s, 1H), 7.02 (s, 1H), 4.42 (p, J = 6.7 Hz, 1H), 1.49 (d, J = 6.7 Hz, 6H).

(b) Compound 71B (100mg, 0.725mmol), 2-aminopyridine-4-boronic acid (412mg, 2.175mmol), potassium carbonate (201mg, 1.450mmol) dissolved in 10ml 1.4-dioxane: water = 4:1 After ventilating with N _{2 for 1 min, add Pa(dppf) Cl 2} (60 mg, 0.073 mmol), and then ventilate with N 2 for 1 min, and react at 80°C for 8 h. Monitor the reaction with a TLC plate. After the reaction, 50ml H 2 O/ Extract with 50ml*2DCM, combine the organic layers, wash once with 100ml saturated brine, dry with anhydrous sodium sulfate, evaporate the solvent, and purify the organic phase silica gel with a flash chromatography column using MeOH/DCM = 1-3% gradient elution , 58 mg of black oily liquid was obtained, namely compound 71C, with a yield of 39.5%.

¹ H NMR(400MHz,DMSO-d ₆ )δ7.98(s,1H),7.95(d,J=5.2Hz,1H), 7.00(s,1H), 6.50(dd,J=5.3,1.6Hz, 1H), 6.44 (d, J = 1.5 Hz, 1H), 6.06 (s, 2H), 4.51-4.34 (m, 1H), 1.41 (d, J = 6.7 Hz, 6H).

(c) Compound 71C (58mg, 0.247mmol), compound 1E (128mg, 0.371mmol), sodium tert-butoxide (56mg, 0.494mmol) was dissolved in 10ml 1.4-dioxane, and after ventilating _{with N 2 for 1 min} , Add Pa2(dba)3 (27mg, 0.025mmol) and Xphos (28mg, 0.050mmol), then _{ventilate with N 2 for} 1 min, and react at 100°C for 8 hours. Monitor the reaction with a TLC plate. After the reaction, filter through Celite After evaporating the solvent, the silica gel sample was mixed and purified by a flash chromatography column, using MeOH/DCM=1-3% gradient elution, to obtain 10 mg of beige solid, namely compound 71, with a yield of 8.3%. LC-MS(ESI)[M+H] ⁺ :419.23.

Example 72

The compound of Example 72 was prepared in the same manner as in Example 71, except that N-isopropyl-2-methylimidazole was used instead of N-isopropylimidazole in step (a) of Example 71.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.05(s,1H), 8.16(d,J=5.2Hz,1H), 7.30(d,J=2.2Hz,1H), 7.22(dd,J= 8.7, 2.2 Hz, 1H), 6.98 (d, J = 8.7 Hz, 1H), 6.89 (s, 1H), 6.72 (s, 1H), 6.67 (dd, J = 5.3, 1.5 Hz, 1H), 4.51 ( p,J=7.0Hz,1H),4.09(q,J=6.7Hz,1H), 3.82(p,J=6.6Hz,1H), 3.37(s,3H), 3.25(s,3H), 1.44( d, J = 7.0Hz, 6H), 1.28 (d, J = 6.6 Hz, 3H), 1.21 (d, J = 6.6 Hz, 3H), 0.99 (d, J = 6.7 Hz, 3H). LC-MS( ESI)[M+H] ⁺ :433.23.

Example 73

(a) Compound 73A (5g, 35.663mmol) was dissolved in 100ml of anhydrous THF, cooled to 0°C, 2M LDA (37ml, 53.495mmol) was added dropwise under the protection of _{N 2 and reacted at 0°C for 1h, at this temperature} , Add methyl isobutyrate (8.3ml, 71.326mmol) dropwise, react at room temperature for 16h, monitor the reaction with a TLC plate, after the reaction is over, pour the reaction solution into 100ml saturated ammonium chloride aqueous solution for quenching, and extract with 100ml*2DCM , Combine the organic layers, wash once with 200 ml of saturated brine, dry with anhydrous sodium sulfate, and evaporate the solvent to obtain a black liquid, which is directly used for the next step without further purification.

(b) Compound 73B (7.5g, 35.663mmol) was dissolved in 20ml DMF, N,N-dimethylformamide dimethyl acetal (10ml, 71.327mmol) was added, heated to reflux at 90°C for 8h, and the reaction was monitored with a TLC panel After the reaction, _{extract with 100ml H 2} 0/100ml*2DCM, combine the organic layers, wash once with 200ml saturated brine, dry with anhydrous sodium sulfate, evaporate the solvent to obtain a black solid, and directly cast to the next step without further purification.

(c) Compound 73C (9.5g, 35.663mmol) was dissolved in 20ml of ethanol, cooled to 0°C, 20ml of hydrazine monohydrate (10ml, 178.317mmol) in ethanol was slowly added, and reacted at room temperature for 4 hours. The reaction was monitored with a TLC plate. After finishing, pour the reaction solution into 100ml water, neutralize with 1N HCl, extract with 100ml*2DCM, combine the organic layers, wash once with 200ml saturated brine, dry with anhydrous sodium sulfate, evaporate the solvent, and mix the organic phase with silica gel. Purified by flash chromatography column, using EA/PE=10-33% gradient elution. 4.4 g of black oily liquid was obtained, namely compound 73D, and the combined yield of steps a-c was 52.3%.

¹ H NMR (400MHz, Chloroform-d) δ 12.03 (s, 1H), 8.42 (d, J = 5.3 Hz, 1H), 8.02 (s, 1H), 7.10 (d, J = 5.3 Hz, 1H), 4.01(hept,J=7.0Hz,1H), 2.59(s,3H), 1.40(d,J=7.0Hz,6H).

(d) Compound 73D (304mg, 1.297mmol) was dissolved in 10ml of DCM, cooled to 0°C, and MCPBA (660mg, 4.541mmol) was added in batches. The reaction was carried out at room temperature for 8 hours. The reaction was monitored with a TLC plate. After the reaction, 50ml of H ₂ O/ Extract with 50ml*2DCM, combine the organic layers, wash once with 100ml saturated brine, dry with anhydrous sodium sulfate, evaporate the solvent, and purify the organic phase silica gel with a flash chromatography column using MeOH/DCM = 1-3% gradient elution 293 mg of white foamy solid was obtained, namely compound 73E, with a yield of 84.7%.

¹ H NMR (400MHz, Chloroform-d) δ 10.92 (s, 1H), 8.75 (d, J = 5.3 Hz, 1H), 8.12 (s, 1H), 7.61 (d, J = 5.4 Hz, 1H), 3.93(h,J=7.0Hz,1H), 3.38(s,3H), 1.40(d,J=7.0Hz,6H).

(e) Compound 73E (1g, 2.730mmol) was dissolved in 1ml of acetic acid, 1.3ml of sulfonyl chloride was added, and reacted at 60°C for 7 hours. The reaction was monitored with a TLC plate. After the reaction, the reaction solution was poured into ice water and sodium hydroxide was used. The solid was neutralized to pH=7, extracted with 50ml*2DCM, combined the organic layers, washed once with 100ml saturated brine, dried over anhydrous sodium sulfate, evaporated to dryness, and the organic phase silica gel mixed sample was purified by flash chromatography column using EA/PE = 10-50% gradient elution to obtain 555 mg of beige solid, namely compound 73F, with a yield of 66.4%.

¹ H NMR (400MHz, Chloroform-d) δ 11.76 (s, 1H), 8.51 (d, J = 5.4, 1H), 8.07 (s, 1H), 7.36 (d, J = 5.4, 1H), 3.93 ( hept,J=7.0Hz,1H),1.41(d,J=6.9,6H).

(f) Compound 73F (36mg, 0.162mmol) was dissolved in 5ml DMF, added cesium carbonate (116mg, 0.356mmol), reacted at room temperature for 1h, added SEMCl (63mg, 0.372mmol), reacted at room temperature for 2h, and monitored the reaction with a TLC plate. After the completion, _{extract with 50ml H 2} O/50ml*2DCM, combine the organic layers, wash with 100ml saturated brine once, dry with anhydrous sodium sulfate, evaporate the solvent, and purify the organic phase silica gel sample by flash chromatography using EA/PE= 0-10% gradient elution, 46 mg of colorless oily liquid was obtained, namely compound 73G, with a yield of 63%.

¹ H NMR (400MHz, Chloroform-d) δ8.49 (t, J = 1.1Hz, 1H), 8.13 (s, 1H), 7.31 (dd, J = 5.3, 0.7 Hz, 1H), 5.40 (t, J ＝0.8Hz,2H),3.83-3.73(m,1H),3.65-3.53(m,2H),1.35(dt,J＝6.9,0.9Hz,6H),0.97-0.85(m,2H),-0.02 (s,J=0.7Hz,9H).

(g) Compound 73G (100mg, 0.283mmol), compound 1G (100mg, 0.425mmol), potassium phosphate (121mg, 0.567mmol) were dissolved in 10ml of 1.4-dioxane, _{ventilated with N 2 for} 1 min, then added Palladium acetate (26mg, 0.029mmol) and BINAP (18mg, 0.029mmol), _{ventilate with N 2 for} 1 min, react at 90°C for 8 hours, monitor the reaction with a TLC plate, after the reaction, filter through Celite, and evaporate the solvent. The silica gel sample was purified by a flash chromatography column, and EA/PE=30-50% gradient elution was used to obtain 106 mg of a light yellow solid, namely compound 73H, with a yield of 66.3%.

(h) Compound 73H (106mg, 0.253mmol) was dissolved in 10ml 4N HCl/1.4-dioxane, and reacted at room temperature for 2h. Monitor the reaction with a TLC plate. After the reaction is over, pour the reaction solution into 50ml of water. The sodium solid was neutralized to pH=7, extracted with 50ml*2DCM, combined the organic layers, washed once with 100ml saturated brine, dried over anhydrous sodium sulfate, evaporated to dryness, and the organic phase silica gel mixed sample was purified by flash chromatography using MeOH/ DCM = 1-3% gradient elution to obtain 15 mg of yellow solid, namely compound 73, with a yield of 19.2%.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 12.94 (s, 1H), 9.16 (s, 1H), 8.32 (d, J = 5.3 Hz, 1H), 8.01 (s, 1H), 7.37 (dd, J = 8.7, 2.2 Hz, 1H), 7.26 (s, 1H), 7.01–6.92 (m, 2H), 4.06 (q, J = 6.7 Hz, 1H), 3.80 (p, J = 6.7 Hz, 1H), 3.24(s,3H),1.24(d,J=6.8Hz,3H),1.17(d,J=6.5Hz,3H),0.96(d,J=6.7Hz,3H).LC-MS(ESI)[ M+H] ⁺ :420.31.

Example 74

The compound of Example 74 was prepared in the same manner as in Example 73 except that methyl cyclopentanecarboxylate was used instead of methyl isobutyrate in step (a) of Example 73. LC-MS(ESI)[M+H] ⁺ :446.34.

Example 75

The compound of Example 75 was prepared in the same manner as in Example 73 except that methyl cyclohexanecarboxylate was used instead of methyl isobutyrate in step (a) of Example 73. LC-MS(ESI)[M+H] ⁺ :460.39.

Example 76

The compound of Example 76 was prepared in the same manner as in Example 73 except that methyl benzoate was used instead of methyl isobutyrate in step (a) of Example 73.

¹ H NMR(400MHz,DMSO-d ₆ )δ13.42(d,J=23.5Hz,1H), 9.36(s,1H), 8.28(d,J=5.9Hz,1H), 8.07(s,1H) , 7.60–7.34 (m, 6H), 7.20 (d, J = 11.8 Hz, 1H), 6.85 (d, J = 8.7 Hz, 1H), 6.56 (d, J = 5.2 Hz, 1H), 4.07 (q, J = 6.7Hz, 1H), 3.78 (d, J = 10.3 Hz, 1H), 3.24 (s, 3H), 1.24 (d, J = 5.7 Hz, 3H), 1.18 (d, J = 6.5 Hz, 3H) ,0.97(d,J=6.7Hz,3H).LC-MS(ESI)[M+H] ⁺ :454.35.

Example 77

(a) Compound 77A (10g, 45.45mmol) was dissolved in 30ml of DCE, added cyclopropylamine (6.29ml, 90.91mmol), heated to reflux at 80°C for 12h, and monitored the reaction with a TLC panel. After the reaction, the solvent was evaporated to dryness, 40mlH _{Extract with 2} O/40ml*2DCM, combine the organic layers, wash with 100ml saturated brine once, dry with anhydrous sodium sulfate, and evaporate the solvent to obtain 10.2g of yellow solid, compound 77B, with a yield of 87%.

¹ H NMR(400MHz,Chloroform-d)δ8.05(s,1H), 7.96(d,J=9.1Hz,1H), 7.45(d,J=2.0Hz,1H), 6.77(dd,J=9.1 ,2.0Hz,1H), 2.60-2.50(m,1H), 0.97-0.88(m,2H), 0.69-0.61(m,2H).

(b) Compound 77B (10g, 38.90mmol) was dissolved in 25ml of ethanol, ammonium chloride aqueous solution (194.55mmol, 10mlH ₂ O) was added, and then reduced iron powder (10.89g, 194.55mmol) was added, and reacted at 80°C for 1 hour. The reaction was monitored on a TLC plate. After the reaction was completed, filtered through Celite, _{extracted with 100ml H 2} O/100ml*2DCM, combined the organic layers, washed once with 200ml saturated brine, dried over anhydrous sodium sulfate, evaporated to dryness to obtain a black solid 5.2g, Namely compound 77C, yield 59%.

¹ H NMR (400MHz, Chloroform-d) δ 7.13 (d, J = 2.1Hz, 1H), 6.79 (dd, J = 8.1, 2.1 Hz, 1H), 6.53 (d, J = 8.1 Hz, 1H), 3.59-3.03(m,2H),2.45-2.32(m,1H),0.76(q,J=6.4Hz,2H),0.57-0.44(m,2H).

(c) Compound 77C (5.2g, 22.90mmol) was dissolved in 15ml of dry DCM, cooled to 0°C, DIPEA (7.98ml, 45.80mmol) and 2-bromopropionyl bromide (3.12ml.29.77mmol) were added, 80 React at ℃ for 8 hours, monitor the reaction with a TLC plate. After the reaction is complete, _{extract with 40ml H 2} O/40ml*2DCM, combine the organic layers, wash once with 100ml saturated brine, dry with anhydrous sodium sulfate, and pass the organic phase silica gel sample through the flash chromatography column Purification, EA/PE=0-30% gradient elution was used to obtain 2 g of solid, namely compound 77D, with a yield of 31%.

¹ H NMR(400MHz,Chloroform-d)δ9.10(s,1H), 7.18(d,J=1.8Hz,1H), 6.91(dd,J=8.2,1.9Hz,1H), 6.64(d,J ＝8.2Hz,1H),4.04(q,J＝6.8Hz,1H),2.46-2.36(m,1H),1.24(d,J＝6.9Hz,3H),1.04-0.96(m,1H),0.85 -0.77 (m, 1H), 0.68-0.60 (m, 1H), 0.60-0.52 (m, 1H).

(d) Dissolve compound 77D (2g, 7.11mmol) in 8ml of anhydrous DMF, add NaH (0.52g, 21.34mmol) in batches in an ice-water bath, stir at 0°C for 30min, and slowly add methyl iodide (0.67ml, 10.67mmol) ), react at room temperature for 2 hours, monitor the reaction with a TLC plate. After the reaction is complete, pour the reaction solution into 100ml ice water for quenching, extract with 50ml*2DCM, combine the organic layers, wash once with 100ml saturated brine, dry with anhydrous sodium sulfate, and evaporate Dry solvent, organic phase silica gel mixed sample was purified by flash chromatography column, and EA/PE=0-25% gradient elution was used to obtain 1.8 g of earth-colored solid, namely compound 77E, with a yield of 86%.

¹ H NMR (400MHz, Chloroform-d) δ 7.14 (d, J = 2.2 Hz, 1H), 6.91 (dd, J = 8.5, 2.1 Hz, 1H), 6.70 (d, J = 8.5 Hz, 1H), 4.03(q,J=6.9Hz,1H), 3.24(s,3H), 2.37-2.28(m,1H), 1.10(d,J=6.9Hz,3H), 0.97-0.90(m,1H),0.79 -0.80 (m, 1H), 0.62-0.52 (m, 1H), 0.52-0.42 (m, 1H).

(e) Compound 77E (50mg, 0.169mmol), 4-methoxy-2-aminopyrimidine (32mg, 0.254mmol), sodium tert-butoxide (33mg, 0.339mmol) dissolved in 10ml 1.4-dioxane, After ventilating with N _{2 for} 1 min, add Pa2 (dba) 3 (16 mg, 0.017 mmol) and Xphos (17 mg, 0.034 mmol), then _{ventilate with N 2 for} 1 min, and react at 100°C for 8 hours. Monitor the reaction with a TLC plate. After the completion, the diatomaceous earth was filtered, the solvent was evaporated, and the silica gel sample was purified by flash chromatography column, using EA/PE=20-50% gradient elution, to obtain 16 mg of light yellow solid, namely compound 77, with a yield of 27.8%.

¹ H NMR(400MHz, Chloroform-d)δ8.18–8.06(m,1H), 7.61(s,1H), 7.31(d,J=2.3Hz,1H), 7.30–7.26(m,1H), 6.89 (d,J=8.5Hz,1H), 6.19(dd,J=5.7,0.7Hz,1H), 4.12(q,J=6.8Hz,1H), 3.97(s,3H), 3.36(s,3H) ,2.40(tt,J＝6.7,3.7Hz,1H),1.22–1.17(m,3H),0.93(tdd,J＝11.2,7.6,4.4Hz,1H),0.83–0.72(m,1H),0.69 –0.54(m,2H).LC-MS(ESI)[M+H] ⁺ :340.18

Example 78

(a) Compound 78A (200mg, 1.544mmol), 3-cyanophenylboronic acid (341mg, 2.316mmol), potassium carbonate (427mg, 3.088mmol) are dissolved in 10ml 1.4-dioxane: water = 4:1, After ventilating with N _{2 for} 1 min, add Pa(dppf) Cl2 (126 mg, 0.154 mmol), then _{ventilate with N 2 for} 1 min, and react at 80°C for 4 hours. Monitor the reaction with a TLC plate. After the reaction, 50mlH ₂ O/50ml *2 Extract with DCM, combine the organic layers, wash once with 100ml saturated brine, dry with anhydrous sodium sulfate, evaporate the solvent, and purify the organic phase silica gel with a flash chromatography column using MeOH/DCM = 1-3% gradient elution, 100 mg of white solid was obtained, namely compound 78B, with a yield of 33%.

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.51 (t, J = 1.6 Hz, 1H), 8.41 (d, J = 1.6 Hz, 1H), 8.40-8.33 (m, 1H), 8.00-7.93 ( m, 1H), 7.73 (t, J = 7.8 Hz, 1H), 7.26 (dd, J = 5.2, 1.0 Hz, 1H), 6.81 (s, 2H).

(b) Compound 78B (100mg, 0.584mmol), compound 77E (226mg, 0.643mmol), sodium tert-butoxide (98mg, 1.168mmol) were dissolved in 10ml of 1.4-dioxane, and after ventilation _{with N 2 for 1 min} , Add Pa2(dba)3 (47mg, 0.06mmol) and Xphos (49mg, 0.120mmol), then _{ventilate with N 2 for} 1 min, and react at 100°C for 8 hours. Monitor the reaction with a TLC plate. After the reaction, filter through Celite , The solvent was evaporated, the silica gel sample was purified by flash chromatography column, and EA/PE=10-33-50% gradient elution was used to obtain 30 mg of light yellow solid, namely compound 78, with a yield of 14.4%.

¹ H NMR(400MHz, DMSO-d ₆ ) δ9.72(s,1H), 8.64-8.59(m,2H), 8.53-8.46(m,1H), 8.07-7.97(m,1H), 7.89-7.81 (m,1H),7.77(t,J=7.8Hz,1H),7.51(dd,J=5.2,1.0Hz,1H),7.31-7.18(m,1H),7.00(d,J=8.6Hz, 1H),4.05–4.00(m,1H),3.98(t,J=6.8Hz,1H), 3.25(s,3H), 1.10(d,J=6.8Hz,3H),0.90–0.72(m,2H ),0.61(dd,J=9.3,5.4Hz,1H),0.45(q,J=3.9Hz,1H).LC-MS(ESI)[M+H] ⁺ :411.14.

Example 79

The compound of Example 79 was prepared in the same manner as in Example 78, except that phenylboronic acid was used instead of 3-cyanophenylboronic acid in step (a) of Example 78.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.62(s,1H), 8.55(d,J=5.2Hz,1H), 8.24–8.13(m,2H), 7.82(d,J=2.2Hz, 1H),7.59–7.51(m,3H),7.42–7.33(m,2H),7.01(d,J=8.7Hz,1H),4.05-4.00(m,1H),3.98(q,J=6.8Hz ,1H),3.25(s,3H),1.12–1.10(m,3H),0.87(dd,J＝19.3,6.9Hz,1H),0.77(q,J＝6.3Hz,1H),0.60(d, J=4.7Hz,1H),0.44(d,J=4.2Hz,1H). LC-MS(ESI)[M+H] ⁺ :386.23.

Example 80

(a) Compound 1J (50mg, 0.145mmol), 3-tert-butylpyrazole-5-amine (18mg, 0.145mmol) was dissolved in 5ml of isopropanol, added 4 drops of concentrated hydrochloric acid, reacted at 80℃ for 8h, TLC The reaction was monitored by the plate. After the reaction, the reaction _{solution was neutralized by NH 3} /MeOH, the solvent was evaporated, and the silica gel sample was purified by flash chromatography column using MeOH/DCM=2-10% gradient elution to obtain 6 mg of gray solid, which is the compound 80, the yield was 13.8%. LC-MS(ESI)[M+H] ⁺ :386.23.

Example 81

Except that 3-methylpyrazol-5-amine was used instead of 3-tert-butylpyrazol-5-amine in step (a) of Example 80, the same method as in Example 80 was used to prepare Example 81 Compound. LC-MS(ESI)[M+H] ⁺ :407.21.

Example 82

The compound of Example 82 was prepared in the same manner as in Example 80 except that 1H-indazol-3-amine was used in place of 3-tert-butylpyrazol-5-amine in step (a) of Example 80. LC-MS(ESI)[M+H] ⁺ :443.26.

Example 83

5-amino-3-methyl-1-methylpyrazole (29mg, 0.260mmol), compound 1J (60mg, 0.173mmol), potassium phosphate (111mg, 0.347mmol) dissolved in 10ml 1.4-dioxane After ventilating with N _{2 for} 1 min, add Pa2 (dba) 3 (16 mg, 0.026 mmol) and BINAP (22 mg, 0.052 mmol), then _{ventilate with N 2 for} 1 min, and react at 90°C for 8 hours. Monitor the reaction with a TLC plate. After the completion of the reaction, celite was filtered, the solvent was evaporated, and the silica gel sample was purified by flash chromatography column using MeOH/DCM=2-3% gradient elution to obtain 10 mg of gray solid, namely compound 83, with a yield of 12.8%.

¹ H NMR(400MHz,Chloroform-d)δ8.08(d,J=5.7Hz,1H), 7.20(s,1H), 7.11(d,J=2.3Hz,1H), 7.07(dd,J=8.6 ,2.3Hz,1H),6.88(d,J=8.6Hz,1H),6.61(s,1H),5.98(s,1H),5.92(d,J=5.7Hz,1H),4.18(q,J ＝6.8Hz,1H), 3.87(hept,J＝6.6Hz,1H), 3.69(s,3H), 3.36(s,3H), 2.28(s,3H), 1.32(d,J＝6.7Hz,3H ),1.25(d,J=6.6Hz,3H),1.12(d,J=6.8Hz,3H).LC-MS(ESI)[M+H] ⁺ :421.25.

Example 84

Except that 5-amino-3-tert-butyl-1-methylpyrazole was used in place of 5-amino-3-methyl-1-methylpyrazole in step (a) of Example 83, the same as in Example 83 was used. The compound of Example 84 was prepared in the same way as in 83.

¹ H NMR(400MHz,Chloroform-d)δ8.07(d,J=5.7Hz,1H), 7.19(s,1H), 7.09(d,J=7.4Hz,2H), 6.89(d,J=8.7 Hz, 1H), 6.42 (s, 1H), 6.05 (s, 1H), 5.92 (d, J = 5.8 Hz, 1H), 4.19 (q, J = 6.8 Hz, 1H), 3.89 (p, J = 6.7 Hz, 1H), 3.71 (s, 3H), 3.37 (s, 3H), 1.35 (m, 3H), 1.33 (s, 9H), 1.27 (d, J = 6.8 Hz, 3H), 1.13 (d, J ＝6.8Hz,3H).LC-MS(ESI)[M+H] ⁺ :463.31.

Example 85

Except that in step (a) of Example 83, 2-methyl-4,5,6,7-tetrahydro-2H-indazol-3-amine was used instead of 5-amino-3-methyl-1-methyl Except for pyrazole, the compound of Example 85 was prepared in the same manner as in Example 83. LC-MS(ESI)[M+H] ⁺ :461.45.

Example 86

Except that 5-amino-3-methyl-1-isopropylpyrazole was used in place of 5-amino-3-methyl-1-methylpyrazole in step (a) of Example 83, the same as in Example The compound of Example 86 was prepared by the same method in 83. LC-MS(ESI)[M+H] ⁺ :449.48.

Example 87

Except that in step (a) of Example 83, 1-methyl-1H-indazol-3-amine was used instead of 5-amino-3-methyl-1-methylpyrazole, the same as in Example 83 was used. The compound of Example 87 was prepared by the method described above.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.67(s,1H), 8.93(s,1H), 8.09(d,J=5.7Hz,1H), 7.84(d,J=8.2Hz,1H) ,7.58(d,J=8.5Hz,1H),7.45-7.30(m,2H),7.25(d,J=2.2Hz,1H),7.06(t,J=7.5Hz,1H),6.81(t, J = 6.9Hz, 2H), 4.12 (m, 1H), 4.03 (d, J = 6.8 Hz, 1H), 3.99 (s, 3H), 3.22 (s, 3H), 1.18 (d, J = 6.6 Hz, 3H), 1.13 (d, J = 6.5 Hz, 3H), 0.94 (d, J = 6.7 Hz, 3H).

Example 88

Except that 5-amino-3-cyclopropyl-1-methylpyrazole was used in place of 5-amino-3-methyl-1-methylpyrazole in step (a) of Example 83, the same as in Example 83 was used. The compound of Example 88 was prepared in the same way as in 83.

¹ H NMR(400MHz,DMSO-d ₆ )δ8.99(d,J=13.3Hz,2H),8.00(d,J=5.7Hz,1H),7.31(dd,J=8.8,2.2Hz,1H) ,7.22-7.17(m,1H),6.86(d,J=8.8Hz,1H), 6.12(d,J=5.6Hz,1H),6.00(s,1H),4.04(q,J=6.7Hz, 1H), 3.72(p,J=6.6Hz,1H),3.56(s,3H),3.22(s,3H),1.78(td,J=8.5,4.3Hz,1H),1.21(d,J=6.2 Hz, 3H), 1.16 (d, J = 6.5 Hz, 3H), 0.94 (d, J = 6.7 Hz, 3H), 0.88-0.75 (m, 2H), 0.61 (dt, J = 5.0, 2.9 Hz, 2H ).LC-MS(ESI)[M+H] ⁺ :388.19.

Example 89

Except that 5-amino-3-phenyl-1-methylpyrazole was used instead of 5-amino-3-methyl-1-methylpyrazole in step (a) of Example 83, the same as in Example 83 was used. The compound of Example 89 was prepared in the same manner as in. LC-MS(ESI)[M+H] ⁺ :483.34.

Example 90

Except for replacing 5-amino-3-methyl-1-methylpyrazole with 1-methyl-3-amino-pyrazolo[3,4-b]pyridine in step (a) of Example 83, The compound of Example 90 was prepared by the same method as in Example 83.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.97(s,1H),8.98(s,1H),8.50(dd,J=4.5,1.6Hz,1H), 8.29(dd,J=8.2,1.7 Hz, 1H), 8.11 (d, J = 5.7 Hz, 1H), 7.29 (d, J = 8.7 Hz, 1H), 7.19 (d, J = 2.3 Hz, 1H), 7.07 (dd, J = 8.1, 4.5 Hz, 1H), 6.80 (d, J = 8.8 Hz, 2H), 3.99 (m, 4H), 3.49 (m, 1H), 3.20 (s, 3H), 1.14-1.04 (m, 6H), 0.90 (d ,J=6.7Hz,3H).LC-MS(ESI)[M+H] ⁺ :458.50.

Example 91

Except that 5-amino-3-methyl-1-tert-butylpyrazole was used in place of 5-amino-3-methyl-1-methylpyrazole in step (a) of Example 83, the same as in Example 83 was used. The compound of Example 91 was prepared in the same way as in 83. LC-MS(ESI)[M+H] ⁺ :463.26.

Example 92

Except that 5-amino-3-methyl-1-phenylpyrazole was used in place of 5-amino-3-methyl-1-methylpyrazole in step (a) of Example 83, the same as in Example 83 was used. The compound of Example 92 was prepared in the same manner as in.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.06(s,1H),8.96(s,1H),7.95(d,J=5.6Hz,1H),7.54–7.46(m,2H),7.47– 7.38(m,2H),7.34–7.23(m,2H),6.85(d,J=9.2Hz,1H),6.31(s,1H),6.02(d,J=5.7Hz,1H),4.03(q ,J=6.7Hz,1H),3.68(p,J=6.6Hz,1H),3.21(s,3H),2.23(s,3H),1.15(dd,J=12.4,6.5Hz,6H),0.93 (d,J=6.7Hz,3H).LC-MS(ESI)[M+H] ⁺ :483.49.

Example 93

Except that 4-fluoro-1-methyl-1H-indazole-3-amine was used in place of 5-amino-3-methyl-1-methylpyrazole in step (a) of Example 83, the use and implementation of The compound of Example 93 was prepared in the same manner as in Example 83.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.27(s,1H),8.98(s,1H),8.01(d,J=5.7Hz,1H),7.45(d,J=8.5Hz,1H) ,7.38(td,J＝8.0,4.8Hz,1H), 7.15(d,J＝11.3Hz,2H), 6.82(dd,J＝10.6,7.5Hz,1H), 6.62(d,J＝9.4Hz, 1H), 6.32 (d, J = 5.8 Hz, 1H), 4.00 (m, 4H), 3.71–3.54 (m, 1H), 3.17 (s, 3H), 1.18 (d, J = 6.6 Hz, 3H), 1.12(d,J=6.6Hz,3H),0.91(d,J=6.7Hz,3H).LC-MS(ESI)[M+H] ⁺ :475.58.

Example 94

(a) Compound 94A (4g, 14.2mmol), 3.5-dimethylisoxazole-4-boronic acid (1g, 7.1mmol), sodium bicarbonate (1.2g, 14.2mmol) dissolved in 40ml 1.4-dioxane ：Water=4:1, after ventilating with N2 for 1 min, add tetrakistriphenylphosphine palladium (820mg, 0.71mmol), then ventilate with N2 for 1 min, react at 700C for 2h, monitor the reaction with a TLC plate, after the reaction is complete , 100mlH2O/100ml*2DCM extraction, combine the organic layers, wash once with 100ml saturated brine, dry with anhydrous sodium sulfate, evaporate the solvent, and purify the organic phase silica gel sample by flash chromatography using EA/PE=0-10% Gradient elution yielded 1.237 g of a white solid, namely compound 94B, with a yield of 69.1%.

¹ H NMR (400MHz, Chloroform-d) δ 7.52 (ddt, J = 8.4, 3.6, 1.5 Hz, 1H), 7.43 (dt, J = 3.5, 1.8 Hz, 1H), 7.34 (td, J = 7.8, 3.1Hz, 1H), 7.24-7.15 (m, 1H), 2.43 (d, J = 3.1 Hz, 3H), 2.29 (d, J = 3.1 Hz, 3H).

(b) Compound 94B (1.6g, 6.4mmol), 2-amino-4-methoxypyrimidine (600mg, 4.8mmol), sodium tert-butoxide (921mg, 9.6mmol) dissolved in 20ml 1.4-dioxane After ventilating with N2 for 1 minute, add Pa2(dba)3 (440mg, 0.48mmol) and Xphos (458mg, 0.96mmol), and then ventilate with N2 for 1 minute, then react at 1000C for 8 hours, monitor the reaction with a TLC plate, and the reaction is complete Afterwards, the diatomaceous earth was filtered, the solvent was evaporated, and the silica gel sample was purified by flash chromatography column, using EA/PE=10-33% gradient elution, to obtain 510 mg of white solid, namely compound 94C, with a yield of 90%.

¹ H NMR(400MHz,Chloroform-d)δ8.17(d,J=5.7Hz,1H), 7.64(d,J=1.8Hz,1H), 7.63–7.58(m,1H), 7.41(t,J =7.9Hz,1H),7.16(s,1H),6.98–6.88(m,1H),6.29–6.18(m,1H),3.96(s,3H),2.46(s,3H),2.33(s, 3H).

(c) Compound 94C (510mg, 1.72mmol) was dissolved in 10ml 4N HCl/dioxane, heated to reflux overnight at 800C, and monitored the reaction with a TLC plate. After the reaction, the reaction solution was poured into 50ml of water and sodium hydroxide The solid was neutralized to pH=7, extracted with 50ml*2DCM, combined the organic layers, washed once with 100ml saturated brine, dried over anhydrous sodium sulfate, evaporated to dryness, and the organic phase silica gel was mixed with samples to be purified by flash chromatography using MeOH/DCM = 2-10% gradient elution to obtain 341 mg of white solid, ie compound 94D, with a yield of 70%.

(d) Compound 94D (341mg, 1.2mmol) was dissolved in 10ml phosphorous oxychloride, refluxed at 800C for 2h, and the reaction was monitored with a TLC plate. After the reaction, the reaction solution was slowly poured into ice water for quenching, and sodium hydroxide solid Sum up to pH=7, extract with 50ml*2DCM, combine the organic layers, wash once with 100ml saturated brine, dry with anhydrous sodium sulfate, evaporate the solvent, and purify the organic phase silica gel with a flash chromatography column using EA/PE=20 -33% gradient elution, 254 mg of white solid was obtained, namely compound 94E, with a yield of 70%.

(e) Compound 94E (80mg, 0.266mmol), phenylboronic acid (65mg, 0.532mmol), potassium carbonate (74mg, 0.532mmol) dissolved in 10ml 1.4-dioxane: water=4:1, ventilate with N2 After 1 min, Pa(dppf)Cl2 (22mg, 0.053mmol) was added, and N2 was used to ventilate for 1 min. The reaction was carried out at 800C for 4h. The reaction was monitored with a TLC plate. After the reaction was completed, 50mlH2O/50ml*2DCM was extracted, and the organic layers were combined. Wash once with 100ml saturated brine, dry with anhydrous sodium sulfate, evaporate the solvent, mix the organic phase silica gel and purify it through a flash chromatography column, eluting with a gradient of EA/PE=10-33%, to obtain 30mg of a white solid, namely compound 94, The yield was 33%.

¹ H NMR (400MHz, DMSO-d6) δ 9.83 (s, 1H), 8.58 (d, J = 5.2 Hz, 1H), 8.21-8.07 (m, 2H), 7.94-7.87 (m, 2H), 7.55 (dd,J=5.2,2.1Hz,3H),7.46-7.38(m,2H),6.99(dt,J=7.7,1.3Hz,1H), 2.44(s,3H), 2.26(s,3H). LC-MS(ESI)[M+H]+:343.16.

Example 95

The compound of Example 95 was prepared in the same manner as in Example 94 except that 1-Boc-pyrazole-4-boronic acid pinacol ester was used instead of phenylboronic acid in step (e) of Example 94.

¹ H NMR (400MHz, DMSO-d6) δ 13.30 (s, 1H), 9.65 (s, 1H), 8.42 (d, J = 5.2 Hz, 1H), 8.15 (s, 1H), 7.94 (d, J ＝8.3Hz,1H),7.83(d,J＝2.0Hz,1H), 7.41(t,J＝7.9Hz,1H), 7.16(d,J＝5.2Hz,1H), 6.96(d,J＝7.5 Hz,1H),2.44(s,3H),2.27(s,3H).LC-MS(ESI)[M+H]+:333.16

Example 96

Except for using 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) in step (e) of Example 94 The compound of Example 96 was prepared by the same method as in Example 94 except that -1H-pyrazole-1-carboxylic acid tert-butyl ester was substituted for phenylboronic acid. LC-MS(ESI)[M+H]+:361.15.

Example 97

The compound of Example 97 was prepared in the same manner as in Example 94 except that pyridine-4-boronic acid was used instead of phenylboronic acid in step (e) of Example 94.

¹ H NMR(400MHz,DMSO-d6)δ9.97(s,1H),8.84-8.74(m,2H),8.69(d,J=5.1Hz,1H),8.11-8.02(m,2H),7.97 –7.88(m,1H),7.81(t,J=1.9Hz,1H),7.56(d,J=5.1Hz,1H),7.44(t,J=7.9Hz,1H),7.01(dt,J= 7.6,1.3Hz,1H),2.44(s,3H),2.26(s, 3H).LC-MS(ESI)[M+H]+:344.12.

Example 98

The compound of Example 98 was prepared in the same manner as in Example 94, except that pyridine-3-boronic acid was used instead of phenylboronic acid in step (e) of Example 94.

¹ H NMR(400MHz,DMSO-d6)δ9.92(s,1H), 9.34(d,J=2.2Hz,1H), 8.74(dd,J=4.8,1.6Hz,1H), 8.64(d,J =5.1Hz, 1H), 8.49 (dt, J = 8.1, 1.9 Hz, 1H), 7.90 (dt, J = 8.3, 1.3 Hz, 1H), 7.85 (t, J = 1.9 Hz, 1H), 7.63-7.55 (m, 1H), 7.53 (d, J = 5.1 Hz, 1H), 7.43 (t, J = 7.9 Hz, 1H), 7.00 (dt, J = 7.8, 1.2 Hz, 1H), 2.44 (s, 3H) ,2.26(s,3H).LC-MS(ESI)[M+H]+:344.11

Example 99

The compound of Example 99 was prepared in the same manner as in Example 94 except that pyrimidine-5-boronic acid was used instead of phenylboronic acid in step (e) of Example 94.

¹ H NMR(400MHz,DMSO-d6)δ9.99(s,1H),9.49(s,2H),9.36(s,1H),8.69(d,J=5.1Hz,1H),7.91-7.85(m ,1H),7.83(t,J=1.9Hz,1H),7.61(d,J=5.1Hz,1H),7.45(t,J=7.9Hz,1H),7.01(dt,J=7.7,1.2Hz ,1H),2.44(s,3H),2.26(s,3H).LC-MS(ESI)[M+H]+:345.10.

Example 100

The compound of Example 100 was prepared in the same manner as in Example 94 except that 4-bromo-2-iodo-1-methoxybenzene was used in place of 3-bromoiodobenzene in step (a) of Example 94. LC-MS(ESI)[M+H]+:373.15.

Example 101

Except that pyridine-3-boronic acid was used instead of phenylboronic acid in step (e) of Example 94, the compound of Example 101 was prepared in the same manner as in Example 94. LC-MS(ESI)[M+H]+ :374.07.

Example 102

Except for using 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) in step (e) of Example 94 The compound of Example 102 was prepared in the same manner as in Example 94 except that -1H-pyrazole-1-carboxylic acid tert-butyl ester was substituted for phenylboronic acid. LC-MS(ESI)[M+H]+: 391.15.

Example 103

The compound of Example 103 was prepared in the same manner as in Example 94, except that 4-bromoiodobenzene was used instead of 3-bromoiodobenzene in step (a) of Example 94.

Example 104

The compound of Example 104 was prepared in the same manner as in Example 94 except that 5-bromo-2-iodo-1-methoxybenzene was used in place of 3-bromoiodobenzene in step (a) of Example 94.

Example 105

The compound of Example 105 was prepared in the same manner as in Example 94, except that 3.5-dimethylisoxazole-4-boronic acid was used instead of phenylboronic acid in step (e) of Example 94. LC-MS(ESI)[M+H]+:362.19

Example 106

The compound of Example 106 was prepared in the same manner as in Example 94, except that 3.5-dimethylisoxazole-4-boronic acid was used instead of phenylboronic acid in step (e) of Example 94. LC-MS(ESI)[M+H]+: 362.19.

Example 107

The compound of Example 107 was prepared in the same manner as in Example 94 except that 3.5-dimethylisoxazole-4-boronic acid was used instead of phenylboronic acid in step (e) of Example 94. LC-MS(ESI)[M+H]+:392.22

Example 108

The compound of Example 108 was prepared in the same manner as in Example 94, except that 3.5-dimethylisoxazole-4-boronic acid was used instead of phenylboronic acid in step (e) of Example 94. LC-MS(ESI)[M+H]+:392.20.

Example 109

The compound of Example 109 was prepared in the same manner as in Example 94, except that 3-cyanophenylboronic acid was used instead of phenylboronic acid in step (e) of Example 94.

¹ H NMR(400MHz,DMSO-d6)δ9.91(s,1H), 8.66(d,J=5.2Hz,1H), 8.59(d,J=1.8Hz,1H), 8.49(dt,J=8.2 ,1.4Hz,1H),8.04(dt,J=7.8,1.4Hz,1H),7.88(dt,J=8.3,1.2Hz,1H),7.82(t,J=1.9Hz,1H),7.78(t ,J=7.8Hz,1H),7.57(d,J=5.2Hz,1H),7.43(t,J=7.9Hz,1H),7.01(dt,J=7.8,1.2Hz,1H),2.44(s ,3H),2.27(s,3H).LC-MS(ESI)[M+H]+:368.12.

Example 110

Except that 1-ethyl-3-methylpyrazole-4-boronic acid pinacol ester was used instead of phenylboronic acid in step (j) of Example 1, the same method as in Example 1 was used to prepare Example 110 Compound.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.23(s,1H), 8.35(d,J=5.2Hz,1H), 8.32(s,1H), 7.41–7.33(m,2H), 6.99( d,J=8.6Hz,1H), 6.95(d,J=5.2Hz,1H), 4.17–3.97(m,3H), 3.82(p,J=6.6Hz,1H), 3.26(s,3H), 2.50 (s, 3H), 1.40 (t, J = 7.3 Hz, 3H), 1.26 (d, J = 6.7 Hz, 3H), 1.19 (d, J = 6.5 Hz, 3H), 0.99 (d, J = 6.7 Hz,3H).LC-MS(ESI)[M+H] ⁺ :420.4.

Example 111

Except that 1-isopropyl-3-methylpyrazole-4-boronic acid pinacol ester was used instead of phenylboronic acid in step (j) of Example 1, the same method as in Example 1 was used to prepare Example 111 compound of.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.22(s,1H), 8.35(d,J=5.7Hz,2H), 7.40–7.34(m,2H), 7.01–6.94(m,2H), 4.47(hept,J=6.7Hz,1H),4.07(t,J=6.8Hz,1H), 3.82(p,J=6.6Hz,1H), 3.26(s,3H), 2.50(s,3H), 1.44 (d, J = 6.6 Hz, 6H), 1.26 (d, J = 6.6 Hz, 3H), 1.18 (d, J = 6.6 Hz, 3H), 0.99 (d, J = 6.7 Hz, 3H). LC- MS(ESI)[M+H] ⁺ : 434.4.

Example 112

Except that 1-phenyl-3-methylpyrazole-4-boronic acid pinacol ester was used instead of phenylboronic acid in step (j) of Example 1, the same method as in Example 1 was used to prepare Example 112. Compound.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.32(s,1H),9.11(s,1H),8.44(d,J=5.2Hz,1H),7.93-7.85(m,2H),7.54( t,J=7.9Hz,2H),7.43-7.29(m,3H),7.15(d,J=5.2Hz,1H),7.00(d,J=8.6Hz,1H),4.08(q,J=6.7 Hz, 1H), 3.84 (p, J = 6.6 Hz, 1H), 3.26 (s, 3H), 2.63 (s, 3H), 1.27-1.21 (m, 3H), 1.17 (d, J = 6.5 Hz, 3H ),0.99(d,J=6.7Hz,3H).LC-MS(ESI)[M+H] ⁺ :468.3.

Example 113

The compound of Example 113 was prepared in the same manner as in Example 1, except that 1,5-dimethylpyrazole-4-boronic acid pinacol ester was used instead of phenylboronic acid in step (j) of Example 1.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.25(s,1H),8.35(d,J=5.2Hz,1H),7.99(s,1H),7.40–7.31(m,2H),7.04– 6.90(m,2H),4.08(q,J=6.7Hz,1H), 3.80(s,4H), 3.26(s,3H), 2.67(s,3H), 1.27(d,J=6.6Hz,3H ), 1.19(d,J=6.5Hz,3H),0.99(d,J=6.7Hz,3H).LC-MS(ESI)[M+H] ⁺ :406.3.

Example 114

Except that 3-methyl-5-cyclobutylpyrazole-4-boronic acid pinacol ester was used instead of phenylboronic acid in step (j) of Example 1, the same method as in Example 1 was used to prepare Example 114 compound of.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 12.65 (d, J = 41.9 Hz, 1H), 9.19 (s, 1H), 8.36 (d, J = 5.2 Hz, 1H), 7.39 (d, J = 8.6Hz,1H),7.33-7.28(m,1H),6.99(d,J=8.7Hz,1H), 6.72(d,J=5.2Hz,1H),4.07(q,J=6.7Hz,1H) , 3.80 (p, J = 6.6Hz, 1H), 3.25 (s, 3H), 2.51 (s, 3H), 2.36 (m, 1H), 2.23 (m, 4H), 1.90 (h, J = 9.3 Hz, 1H), 1.79 (m, 1H), 1.24 (d, J = 6.5 Hz, 3H), 1.17 (d, J = 6.5 Hz, 3H), 0.98 (d, J = 6.7 Hz, 3H). LC-MS( ESI)[M+H] ⁺ :446.4.

Example 115

Except that 3-ethyl-5-cyclopropylpyrazole-4-boronic acid pinacol ester was used instead of phenylboronic acid in step (j) of Example 1, the same method as in Example 1 was used to prepare Example 115 compound of.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 12.45 (s, 1H), 9.22 (s, 1H), 8.39 (d, J = 5.2 Hz, 1H), 7.41 (dd, J = 8.7, 2.2 Hz, 1H), 7.33 (d, J = 2.2 Hz, 1H), 7.01-6.91 (m, 2H), 4.07 (q, J = 6.7 Hz, 1H), 3.80 (p, J = 6.6 Hz, 1H), 3.25 ( s, 3H), 2.89 (d, J = 7.9 Hz, 2H), 2.25 (m, 1H), 1.26-1.21 (m, 3H), 1.18 (d, J = 6.5 Hz, 3H), 1.14 (d, J ＝7.6Hz,3H),0.98(d,J＝6.7Hz,3H),0.94–0.73(m,4H).LC-MS(ESI)[M+H] ⁺ :446.3.

Example 116

Except that 3-cyclopropyl-1,5-dimethylpyrazole-4-boronic acid pinacol ester was used instead of phenylboronic acid in step (j) of Example 1, it was prepared by the same method as in Example 1. The compound of Example 116.

¹ H NMR (400MHz, Chloroform-d) δ 8.38 (d, J = 5.1 Hz, 1H), 7.65 (d, J = 11.3 Hz, 1H), 7.22-7.10 (m, 2H), 7.03 (d, J =5.2Hz,1H), 6.87(d,J=8.4Hz,1H), 4.15(q,J=6.8Hz,1H), 3.86(p,J=6.6Hz,1H), 3.72(s,3H), 3.35(s,3H),2.48(s,3H),2.06(tt,J=8.0,5.4Hz,1H), 1.27(d,J=6.6Hz,3H),1.21(d,J=6.6Hz,3H ), 1.10(d,J=6.8Hz,3H),0.92(tt,J=8.3,2.4Hz,4H).LC-MS(ESI)[M+H] ⁺ :446.36.

Example 117

Except that 5-cyclopropyl-1,3-dimethylpyrazole-4-boronic acid pinacol ester was used instead of phenylboronic acid in step (j) of Example 1, it was prepared by the same method as in Example 1. The compound of Example 117.

¹ H NMR (400MHz, Chloroform-d) δ 8.38 (d, J = 5.2 Hz, 1H), 7.29 (d, J = 5.6 Hz, 1H), 7.20 (d, J = 7.5 Hz, 2H), 6.92- 6.87 (m, 1H), 6.85 (d, J = 5.2 Hz, 1H), 4.16 (q, J = 6.8 Hz, 1H), 3.89 (m, 4H), 3.37 (s, 3H), 2.43 (s, 3H) ), 1.84 (tt, J = 8.3, 5.4 Hz, 1H), 1.30 (d, J = 6.7 Hz, 3H), 1.22 (d, J = 6.6 Hz, 3H), 1.11 (d, J = 6.8 Hz, 3H ),1.07–0.95(m,2H),0.56–0.43(m,2H).LC-MS(ESI)[M+H] ⁺ :464.34.

Example 118

Except that in step (c) of Example 1, cyclopentanone was used instead of acetone and in step (j), 3-cyclopropyl-1,5-dimethylpyrazole-4-boronic acid pinacol ester was used instead of phenylboronic acid. Otherwise, the compound of Example 118 was prepared by the same method as in Example 1.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.35(s,1H), 8.41(d,J=5.2Hz,1H), 7.47–7.33(m,2H), 6.99–6.91(m,2H), 4.04(q,J=6.7Hz,1H), 3.69(s,4H), 3.25(s,3H), 2.46(s,3H), 2.22–2.13(m,1H), 2.11–1.90(m,3H) ,1.75–1.41(m,5H),0.94(d,J=6.7Hz,3H),0.88–0.82(m,2H),0.80(dt,J=4.7,2.3Hz,2H).LC-MS(ESI )[M+H] ⁺ :472.38.

Example 119

Except that in step (c) of Example 1, cyclobutanone was used instead of acetone and in step (j), 3-cyclopropyl-1,5-dimethylpyrazole-4-boronic acid pinacol ester was used instead of phenylboronic acid. Otherwise, the compound of Example 119 was prepared by the same method as in Example 1.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.37(s,1H), 8.42(d,J=5.1Hz,1H), 7.46(dd,J=8.6,2.2Hz,1H), 7.14(d, J = 2.2Hz, 1H), 7.01-6.89 (m, 2H), 3.92 (q, J = 6.7 Hz, 1H), 3.75 (q, J = 8.1 Hz, 1H), 3.70 (s, 3H), 3.25 ( s, 3H), 2.47 (s, 3H), 2.28-2.12 (m, 3H), 2.00 (t, J = 9.1 Hz, 1H), 1.85-1.63 (m, 3H), 0.87 (dd, J = 10.7, 7.6Hz,6H),0.80(td,J=5.9,5.5,3.2Hz,1H).LC-MS(ESI)[M+H] ⁺ :458.39.

Example 120

Except that D-2-aminobutyric acid was used instead of D-alanine in step (a) of Example 1, and 3-cyclopropyl-1,5-dimethylpyrazole-4- was used in step (j). The compound of Example 120 was prepared by the same method as in Example 1, except that boronic acid pinacol ester was substituted for phenylboronic acid.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.29(s,1H), 8.41(d,J=5.2Hz,1H), 7.46–7.37(m,2H), 7.01–6.92(m,2H), 3.74 (td, J = 7.0, 2.8 Hz, 2H), 3.69 (s, 3H), 3.25 (s, 3H), 2.48 (s, 3H), 2.22-2.13 (m, 1H), 1.41-1.25 (m, 2H),1.23(d,J=6.6Hz,3H),1.06(d,J=6.5Hz,3H),0.89–0.76(m,7H).LC-MS(ESI)[M+H] ⁺ :460.37 .

Example 121

Except that in step (a) of Example 1, 5-bromo-1,3-difluoro-2-nitrobenzene was used instead of 2-fluoro-4-bromonitrobenzene and 3-cyclopropane was used in step (j). The compound of Example 121 was prepared in the same manner as in Example 1 except that phenyl-1,5-dimethylpyrazole-4-boronic acid pinacol ester was substituted for phenylboronic acid.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.52(s,1H), 8.45(d,J=5.2Hz,1H), 7.61(dd,J=16.1,2.1Hz,1H), 7.13–7.04( m, 1H), 7.03 (d, J = 5.2 Hz, 1H), 4.12 (q, J = 6.7 Hz, 1H), 3.83 (q, J = 6.6 Hz, 1H), 3.70 (s, 3H), 3.28 ( d, J = 5.9Hz, 3H), 2.48 (s, 3H), 2.20 (ddd, J = 13.0, 8.2, 5.0 Hz, 1H), 1.24 (d, J = 6.6 Hz, 3H), 1.20 (d, J ＝6.6Hz,3H),0.97(d,J＝6.8Hz,3H),0.86(dq,J＝8.2,2.7Hz,2H),0.81(dq,J＝6.9,4.3,3.5Hz,2H).LC -MS(ESI)[M+H] ⁺ :464.3.

Example 122

(a) 2,6-Dibromo-3-aminopyridine (500mg, 1.985mmol), Boc-D-alanine (700mg, 3.970mmol) dissolved in 10mL of anhydrous pyridine, cooled to 0℃, slowly added 1 -Propyl phosphoric anhydride in ethyl acetate (9.2mL, 5.955mmol) solution, react at room temperature for 24h, monitor the reaction with a TLC plate, after the reaction is over, pour the reaction solution into ice water, and neutralize the reaction solution to pH=7, 50mL *2 Extract with DCM, combine the organic layers, wash once with 100 mL of saturated brine, dry with anhydrous sodium sulfate, evaporate the solvent, and purify the organic phase silica gel with a flash chromatography column using EA/PE=10-100% gradient elution, 555 mg of a white solid was obtained, that is, intermediate 122B, with a yield of 66.1%.

¹ H NMR (400MHz, Chloroform-d) δ 8.80 (s, 1H), 8.57 (d, J = 8.5 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 5.15 (s, 1H), 4.35 (d, J = 10.7Hz, 1H), 1.48 (m, 3H), 1.46 (s, 9H).

(b) Intermediate 122B (555mg, 0.310mmol) was dissolved in 10mL 4N HCl/dioxane, and reacted at room temperature for 2h. Monitor the reaction with a TLC plate. After the reaction, pour the reaction solution into 50mL of water. Sodium hydroxide is solid Neutralize to pH=7, extract with 50mL*2DCM, combine the organic layers, wash with 100mL saturated brine once, dry with anhydrous sodium sulfate, evaporate the solvent, and purify the organic phase silica gel with a flash chromatography column using MeOH/DCM= 1-3% gradient elution to obtain 220 mg of brown oily liquid, that is, intermediate 122C, with a yield of 52.1%.

¹ H NMR(400MHz,Methanol-d ₄ )δ8.04(d,J＝8.3Hz,1H), 7.62(d,J＝8.3Hz,1H), 4.41(q,J＝7.0Hz,1H), 1.73 (d,J=7.1Hz,3H).LC-MS(ESI)[M+H] ⁺ :323.81.

(c) Intermediate 122C (100mg, 0.310mmol) was dissolved in 20mL of 1.2-dichloroethane, a small amount of methanol was added to aid solubility, sodium acetate (77mg, 0.930mmol) and acetone (114μL, 1.550mmol) were slowly added, and cooled To 0°C, add sodium triacetoxyborohydride (66mg, 0.620mmol), react at room temperature overnight, monitor the reaction with a TLC plate, after the reaction is over, pour the reaction solution into 50mL of water, extract with 50mL*2 DCM, and combine the organic layers. Wash once with 100mL saturated brine, dry with anhydrous sodium sulfate, evaporate the solvent, and purify the organic phase silica gel with a flash chromatography column using EA/PE=20-100% gradient elution to obtain 45mg of colorless oily liquid, namely Intermediate 122D, the yield was 45.3%.

¹ H NMR (400MHz, Chloroform-d) δ 10.45 (s, 1H), 8.72-8.21 (m, 1H), 7.49-7.27 (m, 1H), 3.29 (q, J = 7.1 Hz, 1H), 2.85 (hept,J=6.5Hz,1H),1.36(d,J=7.2Hz,3H),1.08(dd,J=9.7,6.3Hz,6H).LC-MS(ESI)[M+H] ⁺ : 365.93.

(d) Intermediate 122D (1.13g, 3.524mmol) was dissolved in 20mL DMF, added NN-diisopropylethylamine (2.4mL, 14.098mmol), reacted overnight at 160°C, monitored the reaction with a TLC plate, and the reaction was over Afterwards, the reaction solution was poured into 100mL water, extracted with 100mL*2DCM, combined the organic layers, washed once with 100mL saturated brine, dried with anhydrous sodium sulfate, evaporated to dryness, and the organic phase silica gel sample was purified by flash chromatography column using EA /PE=20-100% gradient elution to obtain 900 mg of yellow solid, that is, intermediate 122E, with a yield of 66.5%.

¹ H NMR (400MHz, Chloroform-d) δ 10.51 (s, 1H), 6.84 (d, J = 7.8 Hz, 1H), 6.69 (d, J = 7.8 Hz, 1H), 4.61 (p, J = 6.8 Hz,1H),4.22(q,J＝6.8Hz,1H),1.30(dd,J＝6.8,3.8Hz,6H),1.23(d,J＝6.9Hz,3H).LC-MS(ESI)[ M+H] ⁺ :284.09.

(e) Intermediate 122E (900mg, 3.167mmol) was dissolved in anhydrous 20mL DMF, NaH (253mg, 6.334mmol) was added in batches in an ice water bath, stirred at 0°C for 30min, and methyl iodide (395μL, 6.334mmol) was slowly added at room temperature After reaction for 2 hours, the reaction was monitored by a TLC plate. After the reaction, the reaction solution was poured into 100 mL of ice water to quench, and extracted with 100 mL * 2 DCM. The organic layers were combined, washed with 150 mL of saturated brine once, dried with anhydrous sodium sulfate, and the solvent was evaporated. The organic phase silica gel sample was purified by flash chromatography column, using EA/PE=20-100% gradient elution, to obtain 700mg of colorless oily liquid, namely intermediate 122F, with a yield of 74.1%.

¹ H NMR (400MHz, Chloroform-d) δ 6.85 (d, J = 8.0 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 4.59 (p, J = 6.8 Hz, 1H), 4.25 ( q, J = 6.8Hz, 1H), 3.24 (s, 3H), 1.28 (d, J = 6.8 Hz, 3H), 1.21 (d, J = 6.9 Hz, 3H), 1.18 (d, J = 6.8 Hz, 3H).

(f) 3-Cyclopropyl-1,5-dimethylpyrazole-4-boronic acid pinacol ester (468mg, 1.785mmol), 2-amino-4-chloropyrimidine (254mg, 1.960mmol), potassium carbonate (494mg, 3.570mmol) dissolved in 10mL1.4-dioxane: water = 4:1, _{after ventilating with N 2 for} 1 min, add Pa(dppf) ₂ Cl ₂ (15mg, 0.018mmol), then use N2 After aeration for 1 min, react at 80°C for 4 hours. Monitor the reaction with a TLC plate. After the reaction, _{extract with 50 mL H 2} O/50 mL*2 DCM. Combine the organic layers, wash with 100 mL saturated brine once, dry with anhydrous sodium sulfate, and evaporate the solvent. The organic phase silica gel sample was mixed and purified by a flash chromatography column, using MeOH/DCM=1-3% gradient elution, to obtain 140 mg of white solid, that is, intermediate 122H, with a yield of 34.2%.

¹ H NMR (400MHz, Chloroform-d) δ 8.26 (d, J = 5.2 Hz, 1H), 6.95 (dd, J = 5.3, 1.6 Hz, 1H), 5.10 (s, 2H), 3.72 (d, J =1.6Hz,3H), 2.47(d,J=1.6Hz,3H), 2.09–1.93(m,1H), 0.97–0.80(m,4H).

(g) Intermediate 122H (100mg, 0.436mmol), intermediate 122F (156.06mg, 0.523mmol), cesium carbonate (284.20mg, 0.872mmol) dissolved in 10mL 1.4-dioxane, ventilated _{with N 2} After 1 min, Pa ₂ (dba) ₃ (41mg, 0.044mmol) and BINAP (28mg, 0.044mmol) were added, and _{after ventilating with N 2 for} 1 min, the reaction was carried out at 100°C for 8 hours. The reaction was monitored by a TLC plate. After the reaction, the silicon After filtering through algae earth, the solvent was evaporated, and the silica gel sample was mixed and purified by a flash chromatography column using MeOH/DCM=2-3% gradient elution to obtain 43 mg of white solid, namely compound 122, with a yield of 22.1%.

¹ H NMR (400MHz, Chloroform-d) δ 7.96-7.82(m, 1H), 7.28-7.21(m, 1H), 7.14-7.04(m, 1H), 6.76-6.69(m, 1H), 6.54( tdd,J=7.0,4.4,2.4Hz,1H), 4.11(dqt,J=13.8,6.9,2.8Hz,1H), 3.84–3.67(m,1H), 3.28–3.11(m,3H), 2.86– 2.67(m,3H),2.06–1.90(m,3H),1.59–1.47(m,1H),0.85–0.77(m,3H),0.76–0.65(m,6H),0.41(tdd,J=6.7 ,3.9,2.0Hz,4H).LC-MS(ESI)[M+H] ⁺ :447.4.

Example 123

Except that 4-methoxy-2-chloro-5-fluoropyrimidine was substituted for 4-methoxy-2-chloropyrimidine in step (g) of Example 1, and 3-cyclopropyl-pyrimidine was used in step (j). The compound of Example 123 was prepared by the same method as in Example 1, except that 1,5-dimethylpyrazole-4-boronic acid pinacol ester was substituted for phenylboronic acid.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.50(s,1H), 8.52(d,J=2.3Hz,1H), 7.42-7.32(m,2H), 6.96(d,J=8.6Hz, 1H), 4.07 (q, J = 6.7 Hz, 1H), 3.78 (h, J = 6.7 Hz, 1H), 3.70 (s, 3H), 3.24 (s, 3H), 2.27 (s, 3H), 2.07- 1.96(m,1H),1.22(d,J=6.7Hz,3H),1.18(d,J=6.6Hz,3H),0.97(d,J=6.7Hz,3H),0.78(t,J=7.4 Hz,4H).LC-MS(ESI)[M+H] ⁺ :464.4.

Example 124

Except that in the step of Example 62, 3-cyclopropyl-1,5-dimethylpyrazole-4-boronic acid pinacol ester was used instead of isoquinoline-4-boronic acid, the same method as in Example 62 was used. Methods The compound of Example 124 was prepared.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.69(s,1H),8.55(s,1H),7.42(d,J=2.3Hz,1H),7.33(dd,J=8.7,2.2Hz, 1H), 6.97 (d, J = 8.7 Hz, 1H), 4.07 (q, J = 6.7 Hz, 1H), 3.77 (p, J = 6.7 Hz, 1H), 3.69 (s, 3H), 3.24 (s, 3H), 2.20 (s, 3H), 1.84 (tt, J = 7.4, 5.4 Hz, 1H), 1.18 (t, J = 6.9 Hz, 6H), 0.96 (d, J = 6.7 Hz, 3H), 0.82- 0.65(m,4H).LC-MS(ESI)[M+H] ⁺ :480.4.

Example 125

Except that in the step of Example 63, 3-cyclopropyl-1,5-dimethylpyrazole-4-boronic acid pinacol ester was used instead of isoquinoline-4-boronic acid, the same method as in Example 63 was used. Methods The compound of Example 125 was prepared.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.33(s,1H),8.36(s,1H),7.51(d,J=2.2Hz,1H),7.32(dd,J=8.7,2.2Hz, 1H), 6.94 (d, J = 8.7 Hz, 1H), 4.06 (d, J = 6.8 Hz, 1H), 3.76 (p, J = 6.6 Hz, 1H), 3.69 (s, 3H), 3.23 (s, 3H), 2.15 (s, 3H), 2.07 (s, 3H), 1.72–1.57 (m, 1H), 1.17 (t, J = 6.6 Hz, 6H), 0.96 (d, J = 6.7 Hz, 3H), 0.80–0.62(m,4H).LC-MS(ESI)[M+H] ⁺ :460.5.

Example 126

Except that 4-methoxy-2-chloro-5-fluoropyrimidine was substituted for 4-methoxy-2-chloropyrimidine in step (g) of Example 1, and 3-cyclobutyl-pyrimidine was used in step (j). The compound of Example 126 was prepared by the same method as in Example 1, except that 1,5-dimethylpyrazole-4-boronic acid pinacol ester was substituted for phenylboronic acid.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.44(s,1H), 8.49(d,J=2.3Hz,1H), 7.35(dd,J=8.7,2.2Hz,1H), 7.31(d, J = 2.2Hz, 1H), 6.96 (d, J = 8.7 Hz, 1H), 4.07 (q, J = 6.7 Hz, 1H), 3.78 (m, 4H), 3.60 (p, J = 8.6 Hz, 1H) ,3.24(s,3H),2.28(d,J=1.4Hz,3H),2.21-2.07(m,4H),1.91-1.82(m,1H),1.78(ddd,J=15.6,7.5,3.1Hz ,1H),1.22(d,J=6.7Hz,3H),1.17(d,J=6.6Hz,3H),0.97(d,J=6.7Hz,3H).LC-MS(ESI)[M+H ] ⁺ :478.3.

Example 127

Except that 4-methoxy-2-chloro-5-fluoropyrimidine was substituted for 4-methoxy-2-chloropyrimidine in step (g) of Example 1, and 3-cyclopentyl- The compound of Example 127 was prepared in the same manner as in Example 1, except that 1,5-dimethylpyrazole-4-boronic acid pinacol ester was substituted for phenylboronic acid.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.46(s,1H), 8.51(d,J=2.2Hz,1H), 7.33(d,J=7.2Hz,2H), 6.95(d,J= 9.3Hz, 1H), 4.07 (q, J = 6.7 Hz, 1H), 3.74 (m, 4H), 3.24 (m, 4H), 2.25 (d, J = 1.6 Hz, 3H), 1.87–1.75 (m, 2H), 1.70–1.55 (m, 4H), 1.48 (d, J = 5.2 Hz, 2H), 1.21 (d, J = 6.6 Hz, 3H), 1.17 (d, J = 6.6 Hz, 3H), 0.97 ( d,J=6.7Hz,3H).LC-MS(ESI)[M+H] ⁺ :492.3.

Example 128

Except that D-2-aminobutyric acid was used instead of D-alanine in step (a) of Example 1, and 4-methoxy-2-chloro-5-fluoropyrimidine was used instead of 4-methyl in step (g). Oxy-2-chloropyrimidine and in step (j), 3-cyclopropyl-1,5-dimethylpyrazole-4-boronic acid pinacol ester was used instead of phenylboronic acid, and the same as in Example 1 was used. Methods The compound of Example 128 was prepared.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.49(s,1H), 8.52(d,J=2.3Hz,1H),7.44-7.36(m,2H), 6.96(d,J=8.7Hz, 1H), 3.77–3.71(m,1H), 3.70(s,3H), 3.32(m,1H), 3.24(s,3H), 2.28(d,J=1.6Hz,3H),2.01(q,J ＝6.8,6.4Hz,1H),1.39–1.25(m,2H),1.21(d,J＝6.7Hz,3H),1.06(d,J＝6.5Hz,3H),0.84–0.70(m,7H) .LC-MS(ESI)[M+H] ⁺ :478.2.

Example 129

Except that D-2-aminobutyric acid was used instead of D-alanine in step (a) of Example 1, and 4-methoxy-2-chloro-5-fluoropyrimidine was used instead of 4-methyl in step (g). Oxy-2-chloropyrimidine and in step (j), 3-cyclobutyl-1,5-dimethylpyrazole-4-boronic acid pinacol ester was used instead of phenylboronic acid, and the same as in Example 1 was used. Methods The compound of Example 129 was prepared.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.44(s,1H), 8.49(d,J=2.3Hz,1H), 7.39(d,J=2.3Hz,1H), 7.35(dd,J= 8.7, 2.2 Hz, 1H), 6.96 (d, J = 8.7 Hz, 1H), 3.78 (s, 3H), 3.72 (dt, J = 12.7, 6.9 Hz, 2H), 3.61 (t, J = 8.6 Hz, 1H), 3.24 (s, 3H), 2.29 (d, J = 1.6 Hz, 3H), 2.20-2.09 (m, 4H), 1.94-1.81 (m, 1H), 1.81-1.67 (m, 1H), 1.32 (dtd,J=27.3,15.1,14.6,7.9Hz,2H),1.21(d,J=6.7Hz,3H),1.05(d,J=6.5Hz,3H),0.81(t,J=7.4Hz, 3H).LC-MS(ESI)[M+H] ⁺ :492.3.

Example 130

Except that D-2-aminobutyric acid was used instead of D-alanine in step (a) of Example 1, and 4-methoxy-2-chloro-5-fluoropyrimidine was used instead of 4-methyl in step (g). Oxy-2-chloropyrimidine and 3-cyclopentyl-1,5-dimethylpyrazole-4-boronic acid pinacol ester in step (j) instead of phenylboronic acid, the same as in Example 1 Methods The compound of Example 130 was prepared.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.45(s,1H), 8.51(d,J=2.2Hz,1H), 7.38(d,J=2.3Hz,1H), 7.34(dd,J= 8.7,2.3Hz,1H), 6.95(d,J=8.7Hz,1H), 3.77–3.66(m,5H), 3.24(m,4H), 2.25(d,J=1.5Hz,3H), 1.88– 1.78(m,2H),1.69–1.57(m,4H),1.48(d,J=5.0Hz,2H),1.30(ddt,J=25.6,14.4,7.1Hz,2H),1.20(d,J= 6.7Hz,3H),1.05(d,J=6.5Hz,3H),0.81(t,J=7.4Hz,3H).LC-MS(ESI)[M+H] ⁺ :506.3.

Activity test

1. The method for testing the enzyme activity of the bromine domain (BRD4BD1) of a series of compounds of the present invention

Fluorescence Anisotropy (FA) was used to test the binding activity of the compound to BRD4BD1.

Expression and purification of BRD4BD1 domain: The colony of newly transformed plasmid DNA from E. coli BL21(DE3)-condon plus-RIL cells was placed in 50 mL of 50 ug/mL kanamycin and 34 ug/mL chloramphenicol. Grow overnight at 37°C in Terrific Broth medium (start culture). The starter culture was then diluted 100-fold in 1 L of fresh TB medium, and the cells were grown at 37°C to an optical density of approximately 0.8 at OD600, and then the temperature was lowered to 16°C. When the system was equilibrated at 16°C, the optical density at OD600 was about 1.2, and 0.2mmol isopropyl-β-D-thiogalactopyranoside (IPTG) was used to induce protein expression at 16°C overnight. The bacteria were harvested by centrifugation (4000×g, 20 minutes, 4°C) and stored as a pellet at -80°C. Resuspend the cells expressing His6 labeled protein in lysis buffer [50mmol 4-hydroxyethylpiperazine ethanesulfonic acid (HEPES), pH 7.5 at 25℃, 500mmol NaCl, 10mmol imidazole, 5% glycerol and freshly added 0.5mmol of tris(2-carboxyethyl)teng hydrochloride (TCEP) and 1mmol of phenylmethanesulfonyl fluoride (PMSF)] and used JN3000PLUS high pressure homogenizer (JNBIO-Guangzhou, China) at 4°C. The lysate was clarified by centrifugation (12,000 x g at 4°C for 1 hour) and applied to a nickel-nitriloacetic acid sepharose column. The column was washed once with 50 mL of washing buffer containing 30 mmol of imidazole. Use imidazole in the elution buffer (100-250mmol imidazole in 50mmol HEPES, pH 7.5 at 25°C, 500mmol NaCl, 5% glycerol) to elute protein. All fractions were collected and monitored by SDS-polyacrylamide gel electrophoresis (Bio-Rad CriterionTM Precast Gels, 4-12% Bis-Tris, 1.0 mm, from Bio-Rad, CA). After adding 1 mmol dithiothreitol (DTT), the eluted protein was treated with tobacco plaque virus (TEV) protease at 4° C. overnight to remove the His6 tag. The protein was concentrated and further purified by size exclusion chromatography on a Superdex7516/60HiLoad gel filtration column. The samples were monitored by SDS-polyacrylamide gel electrophoresis, and gel filtration buffer, 10mmol Hepes pH7.5, 500mM NaCl, 1mmol DTT was concentrated to 8-10mg/mL and used for protein binding determination and crystallization.

The fluorescent substrate is (+)-JQ1 linked to fluorescent molecules, and the working concentration is 5nM. BRD4(I) protein working concentration is 10nM, total reaction system is 40uL, buffer is 50mM 4-hydroxyethylpiperazine ethanesulfonic acid (HEPES) pH7.4, 150mM NaCl, 0.5mM3-[3-(cholamidopropyl )Dimethylamino]propanesulfonic acid inner salt (CHAPS). The initial screening concentration of the compound is 1uM, and the ICs0 of the compound whose inhibition rate is greater than 60% under this condition is determined. Taking into account the solubility of the compound and the influence of DMSO on the determination, the final concentration of DMSO was selected as 0.2%. All measurements were performed under these conditions. After all the ingredients are mixed, the anisotropy value is measured after 4h reaction at room temperature in the dark or overnight at 4C. The test uses Corning's all-black, low-side, NBS surface 384-well microtiter plate (Cat. No. CLS3575). The test instrument is BioTek synergy2 detector. The excitation is 485nM and the emission is 530nM. Take the buffer as the system reading blank value.

Numerical processing: Inhibition rate = (C-F)/(C-B)×100%

Among them: C: the anisotropy value of the fluorescence substrate and protein completely binding

B: Fluorescence substrate anisotropy background value

F: The anisotropy value of the compound at the corresponding concentration.

The compound concentration and the corresponding inhibition rate were used to draw the S curve. The IC50 of the corresponding compound was obtained.

2. CDK9 activity test method of a series of compounds of the present invention

2.1 Reagents and consumables

Reagent name|	supplier	Item No.	batch number
AurA	Carna	05-101	09CBS-0998G
Caliper substrate 21	GL	116370	P180307-CL116370
DMSO	Sigma	D8418-1L	SHBG3288V
384-well-plate|	Corming	3573	12619003
Danusertib(PHA-739358)	Selleckchem	S1107	lot06

2.2 Instrument

Centrifuge (manufacturer: Eppendorf, model: 5430)

Microplate reader (manufacturer: Perkin Elmer, model: Caliper EZReader IⅡ)

Echo 550 (manufacturer: Labcyte, model: Echo 550)

2.3 Test method

(1) Prepare 1xKinase buffer.

(2) Preparation of compound concentration gradient: the test compound test concentration is 1000nM, 333nM and 111nM, diluted in a 384source plate to a 100% DMSO solution with a final concentration of 100 times. Use a dispenser Echo550 to transfer 250 nL 100 times the final concentration of the compound to the target 3573 plate.

(3) Use 1xKinase buffer to prepare a kinase solution of 2.5 times the final concentration.

(4) Add 10 μL of 2.5 times the final concentration of kinase solution to the compound well and the positive control well; add 10 μL of 1xKinase bufer to the negative control well.

(5) Centrifuge at 1000 rpm for 30 seconds, shake and mix, and incubate at room temperature for 10 minutes.

(6) Use 1xKinase buffer to prepare a mixed solution of 5/3 times the final concentration of ATP and Kinase substrate21.

(7) Add 15 μL of a mixed solution of 5/3 times the final concentration of ATP and substrate to initiate the reaction.

(8) Centrifuge the 384-well plate at 1000 rpm for 30 seconds, shake and mix, and incubate at room temperature for 20 minutes.

(9) Add 30 μL of stop detection solution to stop the kinase reaction, centrifuge at 1000 rpm for 30 seconds, shake and mix.

(10) Use Caliper EZ Reader II to read the conversion rate.

3. Aurora A activity test method of a series of compounds of the present invention

The instruments, consumables and test methods used in the Aurora A enzyme activity test method are the same as those shown in the CDK9 activity test method.

Some compounds of the present invention inhibit the bromodomain protein BRD4 and kinases such as CDK9 and Aurora A:

+++: represents the IC _{50 of the} compound is less than or equal to 50nM

++: The IC _{50 of the} representative compound is greater than 50nM but less than or equal to 200nM

+: The IC _{50 of the} representative compound is greater than 200nM

_{Table 1 The inhibitory activity IC 50} value (nM) of some compounds of the present invention on BRD4BD1 protein

It can be seen that the above-mentioned compounds all have a kinase core structure, and tests have shown that they can inhibit many kinds of compounds. The inhibitory activities of the following compounds on CDK9 and Aurora A kinase are shown in the table below:

_{Table 2 The inhibitory activity IC 50} value (nM) of some compounds of the present invention on CDK9 protein

Compound number

CDK9

Compound number

CDK9

To	IC 50 (nM)	To	IC 50 (nM)
14	+++	49	+++
37	+++	57	++
38	++	62	+++
40	+++	63	++
45	+++	To	To

_{Table 3 The inhibitory activity IC 50} value (nM) of some compounds of the present invention on Aurora A protein

The technical features of the above-mentioned embodiments can be combined arbitrarily. In order to make the description concise, all possible combinations of the various technical features in the above-mentioned embodiments are not described. However, as long as there is no contradiction in the combination of these technical features, All should be considered as the scope of this specification.

The above-mentioned embodiments only express several implementation modes of the present invention, and their description is relatively specific and detailed, but they should not be understood as a limitation on the scope of the invention patent. It should be pointed out that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can be made, and these all fall within the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention should be subject to the appended claims.

Claims (20)

1. A compound having the structure shown in formula (I)

   

   Where K is

   

   X ₁ , X ₂ and X ₃ are each independently selected from -CR ₉ or N;

   Y is -CR ₉ or N;

   Z is a single bond, -NR ₉ or O;

   R ₁ , R ₂ and R ₃ are each independently selected from: H, substituted or unsubstituted C _1-30 alkyl, substituted or unsubstituted C _1-30 alkoxy, substituted or unsubstituted containing 3-30 rings Atom cycloalkyl, substituted or unsubstituted heterocyclic group containing 3-30 ring atoms, substituted or unsubstituted aryl group containing 5-30 ring atoms, substituted or unsubstituted 5-30 ring Heteroaryl, amino, cyano, isocyano, isocyanate, thiocyanate, isothiocyanate, hydroxyl, trifluoromethyl, nitro or halogen of atoms;

   R ₄ and R ₅ are each independently selected from: H, substituted or unsubstituted C _1-30 alkyl, or substituted or unsubstituted cycloalkyl containing 3-30 ring atoms;

   R ₆ , R ₇ , R ₈ and R ₉ are each independently selected from: H, substituted or unsubstituted C _1-30 alkyl, substituted or unsubstituted C _1-30 alkoxy, substituted or unsubstituted containing 3 -8 ring atoms cycloalkyl, substituted or unsubstituted heterocyclic groups containing 3-8 ring atoms, substituted or unsubstituted aryl groups containing 5-30 ring atoms, substituted or unsubstituted aryl groups containing 5 -30 ring atoms heteroaryl, silyl, keto, carbonyl, carboxy, ester, alkoxycarbonyl, aryloxycarbonyl, amino, cyano, carbamoyl, haloformyl, isocyano, Isocyanate group, thiocyanate group, isothiocyanate group, hydroxyl group, nitro group or halogen.
2. The compound of claim 1, wherein R _{1 is} selected from: substituted or unsubstituted C _1-20 alkyl, substituted or unsubstituted C _1-20 alkoxy, substituted or unsubstituted C 1-20 alkoxy, substituted or unsubstituted C 1-20 Cycloalkyl groups with three ring atoms, substituted or unsubstituted heterocyclic groups containing 3-20 ring atoms, substituted or unsubstituted aryl groups containing 5-20 ring atoms, or substituted or unsubstituted 5- Heteroaryl, amino, cyano, isocyano, isocyanate, thiocyanate, isothiocyanate, hydroxyl, nitro or halogen with 20 ring atoms;

   R ₂ and R ₃ are each independently selected from: H, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _1-6 alkoxy, substituted or unsubstituted ring containing 3-8 ring atoms Alkyl, halogen or cyano;

   R ₄ and R ₅ are each independently H, substituted or unsubstituted C _1-6 alkyl, or substituted or unsubstituted cycloalkyl containing 3-8 ring atoms; and R ₄ and R _{5 are} not H at the same time .
3. The compound according to claim 1, characterized in that it has a structure represented by formula (II), formula (III) or formula (IV):

   

   Among them, at least one of _{X 1} , X ₂ and X _{3 is -CR 9} ;

   Z is a single bond, -NH or O.
4. The compound according to claim 3, wherein R _{1 is} selected from the group consisting of H, C _1-6 alkyl, C _1-6 alkoxy, cycloalkyl containing 3-8 ring atoms, and 3- A heterocyclic group with 10 ring atoms, an aryl group with 5-20 ring atoms, a heteroaryl group with 5-20 ring atoms, a halogen, a cyano group or an isocyano _{group; the C 1-6} alkyl group, C _1-6 alkoxy group, cycloalkyl group containing 3-8 ring atoms, heterocyclic group containing 3-10 ring atoms, aryl group containing 5-20 ring atoms, 5-20 ring atoms The heteroaryl group is optionally substituted by one or more of the following groups: C _1-6 alkyl, C _1-6 alkoxy, cycloalkyl containing 3-8 ring atoms, containing 3-10 ring atoms The heterocyclic group containing 5-10 ring atoms, heteroaryl containing 5-10 ring atoms, cyano, halogen, trifluoromethyl, hydroxyl, nitro or -NR ₁₀ R ₁₁ ;

   R ₁₀ and R ₁₁ are each independently: H, C _1-6 alkyl, cycloalkyl containing 3-8 ring atoms, heterocyclyl containing 3-8 ring atoms, and 5-10 ring atoms Aryl group or heteroaryl group containing 5-10 ring atoms; the C _1-6 alkyl group, cycloalkyl group containing 3-8 ring atoms, heterocyclic group containing 3-8 ring atoms, containing Aryl groups with 5-10 ring atoms or heteroaryl groups with 5-10 ring atoms are optionally further substituted by one or more of the following groups: C _1-6 alkyl, ring with 3-8 ring atoms Alkyl, heterocyclic group containing 3-8 ring atoms, halogen, hydroxy, nitro or amino; R ₁₀ and R ₁₁ can form a 5-6 membered ring with the N atom connected to _{R 10} and R _11.
5. The compound according to claim 3, wherein R _{1 is} selected from the group consisting of H, C _1-6 alkyl, C _1-6 alkoxy, cycloalkyl containing 3-8 ring atoms, and 3- A heterocyclic group with 8 ring atoms, an aryl group with 5-10 ring atoms, a heteroaryl group with 5-10 ring atoms, a halogen, a cyano group or an isocyano _{group; the C 1-6} alkyl group, C _1-6 alkoxy group, cycloalkyl group with 3-8 ring atoms, heterocyclic group with 3-8 ring atoms, aryl group with 5-10 ring atoms, 5-10 ring atoms The heteroaryl group is optionally substituted by one or more of the following groups: C _1-6 alkyl, C _1-6 alkoxy, cycloalkyl containing 3-8 ring atoms, containing 3-8 ring atoms The heterocyclic group, cyano group, halogen, trifluoromethyl, hydroxyl, nitro or -NR ₁₀ R ₁₁ ;

   R ₁₀ and R ₁₁ are each independently: H, C _1-6 alkyl, cycloalkyl containing 3-8 ring atoms, heterocyclyl containing 3-8 ring atoms, and 5-10 ring atoms Aryl group or heteroaryl group containing 5-10 ring atoms; the C _1-6 alkyl group, cycloalkyl group containing 3-8 ring atoms, heterocyclic group containing 3-8 ring atoms, containing Aryl groups with 5-10 ring atoms or heteroaryl groups with 5-10 ring atoms are optionally further substituted by one or more of the following groups: C _1-6 alkyl, ring with 3-8 ring atoms Alkyl, heterocyclic group containing 3-8 ring atoms, halogen, hydroxy, nitro or amino; R ₁₀ and R ₁₁ can form a 5-6 membered ring with the N atom connected to _{R 10} and R _11.
6. The compound according to claim 4 or 5, wherein the heterocyclic group and the heteroaryl group contain at least one nitrogen atom.
7. The compound according to claim 4 or 5, wherein the aryl group is selected from: phenyl or naphthyl;

   The heteroaryl group is selected from; pyridyl, pyrimidinyl, imidazolyl, pyrazolyl, benzimidazolyl, benzopyrazolyl, indolyl, quinolinyl, isoquinolinyl, thiazolyl, oxazole Group, isoxazolyl or pyrazolopyridyl.
8. The compound of claim 3, wherein R _{1 is} selected from: C _1-6 alkoxy, halogen or the following groups:

   

   Among them, W is -CR ₂₀ or -N; V is -CR ₂₀ R ₂₀ , -NR ₂₁ or -O;

   Wherein, R _{20 is} selected from: H, C _1-6 alkyl, C _1-6 alkoxy, cycloalkyl containing 3-8 ring atoms, heterocyclic group containing 3-8 ring atoms, containing 5 An aryl group with -20 ring atoms, a heteroaryl group with 5-20 ring atoms, halogen, cyano, isocyano or -NR ₁₀ R ₁₁ ; the C _1-6 alkyl group, C _1-6 alkane An oxy group, a cycloalkyl group containing 3-8 ring atoms, a heterocyclic group containing 3-8 ring atoms, an aryl group containing 5-20 ring atoms, or a heteroaryl group containing 5-20 ring atoms Optionally substituted by one or more of the following groups: C _1-6 alkyl, C _1-6 alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, C _1-6 alkyl substituted 3-8 membered cycloalkyl, C _1-6 alkyl substituted 3-8 membered heterocyclic group, halogen or cyano;

   R _{21 is} selected from: H, C _1-6 alkyl, or cycloalkyl containing 3-8 ring atoms;

   R ₁₀ and R _{11 are the} same as in claim 4.
9. The compound of claim 3, wherein R _{1 is} selected from: C _1-6 alkoxy, halogen or the following groups:

   

   Wherein, R _{20 is} selected from: H, C _1-6 alkyl, C _1-6 alkoxy, cycloalkyl containing 3-8 ring atoms, heterocyclic group containing 3-8 ring atoms, containing 5 An aryl group with -20 ring atoms, a heteroaryl group with 5-20 ring atoms, halogen, cyano, isocyano or -NR ₁₀ R ₁₁ ; the C _1-6 alkyl group, C _1-6 alkane An oxy group, a cycloalkyl group containing 3-8 ring atoms, a heterocyclic group containing 3-8 ring atoms, an aryl group containing 5-20 ring atoms, or a heteroaryl group containing 5-20 ring atoms Optionally substituted by one or more of the following groups: C _1-6 alkyl, C _1-6 alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, C _1-6 alkyl substituted 3-8 membered cycloalkyl, C _1-6 alkyl substituted 3-8 membered heterocyclic group, halogen or cyano;

   R _{21 is} selected from: H, C _1-6 alkyl, or cycloalkyl containing 3-8 ring atoms;

   n ₁ is 1, 2, 3, 4 or 5; n ₂ is 1, 2, 3 or 4; n ₃ is 1, 2 or 3; n ₄ is 1 or 2; n ₅ is 1, 2, 3, 4 , 5 or 6; n ₆ is an integer of 1-9; n ₇ is 1, 2, 3, 4 or 5; n ₈ is 1, 2, 3 or 4; n ₉ is an integer of 1-8; and when present When there are multiple R ₂₀ , the multiple R ₂₀ are the same or different from each other;

   R ₁₀ and R _{11 are the} same as in claim 4.
10. The compound according to claim 8 or 9, wherein R _{20 is} each independently selected from: H, methyl, ethyl, n-propyl, isopropyl, primary butyl, sec-butyl, tert-butyl , Cyclopropyl, cyclopropyl substituted methyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, pyrimidinyl, triazinyl,

    

    Or -NR ₁₀ R _11, R ₁₀ and R ₁₁ are each independently: H, C ₁ - ₆ alkyl group, a cycloalkyl group having 5-6 ring atoms,

    

    Or phenyl, m is 1, 2, 3, 4, 5 or 6; and/or

    R _{21 is} selected from: H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, phenyl, pyridyl, pyrimidinyl or triazinyl; and/or

    R _{2 is} selected from: H, halogen, methyl, ethyl, n-propyl or isopropyl; and/or

    R _{5 is} selected from: methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; and/or

    R _{6 is} selected from: methyl, ethyl, n-propyl or isopropyl.
11. The compound of claim 1, wherein the compound has a structure represented by any one of formulas (II-1) to (II-13):

    

    

    R _{20 is} as defined in claim 8.
12. The compound of claim 1, wherein the compound has a structure represented by formula (III-1) or formula (IV-1):

    
13. The compound according to claim 1, characterized in that it is selected from the following compounds:

    

    

    

    

    

    

    

    

    

    
14. A prodrug, pharmaceutically acceptable salt, or solvate characterized by being formed by the compound of any one of claims 1-13.
15. A functional molecule of PROTAC technology, characterized in that it is formed by the compound of any one of claims 1-13.
16. A composition characterized by comprising the compound of any one of claims 1-3, the prodrug, pharmaceutically acceptable salt, or solvate of claim 14, or the compound of claim 15 The functional molecule of PROTAC technology.
17. The compound according to any one of claims 1-13, the prodrug, pharmaceutically acceptable salt, or solvate according to claim 14, the functional molecule of PROTAC technology according to claim 15, and the functional molecule according to claim 16. The composition is used for the prevention or treatment of diseases related to abnormal cell proliferation, morphological changes, and hyperkinesia related to bromodomain protein and/or kinase disorders in organisms and diseases related to angiogenesis or cancer metastasis. Use in medicine.
18. The use according to claim 17, wherein the drug is a BRD4 and kinase dual target inhibitor drug; and/or

    The drug is an anti-tumor drug.
19. A treatment method, characterized in that it comprises the following steps:

    The function of applying an effective amount of the compound of any one of claims 1-13, the prodrug, pharmaceutically acceptable salt or solvate of claim 14 and the PROTAC technology of claim 15 to the subject to be treated Molecule, or the composition of claim 16.
20. The treatment method according to claim 19, characterized in that the treatment method is used for the treatment of abnormal cell proliferation, morphological changes, and motor hyperactivity related diseases related to bromodomain protein and/or kinase disorders in the organism, and diseases related to Diseases related to angiogenesis or cancer metastasis.