CN116531373A - Thiazole compound, its pharmaceutical composition and application - Google Patents

Abstract

The invention discloses a thiazole compound, a pharmaceutical composition and application thereof. The invention provides application of thiazole compounds in preparation of medicines; the medicine is used for treating and/or treating diseases mediated by Abeta 40 and/or Abeta 42 proteins or used for treating and/or preventing neurodegenerative diseases, alzheimer disease or aging, and the thiazole compounds are selected from compounds shown as formula I and the like or pharmaceutically acceptable salts thereof. The compound has good inhibition effect on Abeta 40 and Abeta 42 proteins, and is expected to treat and/or prevent neurodegenerative diseases, alzheimer disease or aging drugs.

Description

Thiazole compounds, pharmaceutical compositions and applications thereof

Technical Field

The present invention relates to a thiazole compound, a pharmaceutical composition and application thereof.

Background Art

Alzheimer’s disease (commonly known as senile dementia, Alzheimer’s disease, AD) is a progressive neurodegenerative disease with cognitive and behavioral disorders as the main clinical manifestations. It is the most common senile dementia, mainly manifested by impaired recognition ability and rapid decline of memory function. The main pathophysiological characteristics are the deposition of β-amyloid protein (β-amyloid, Aβ) in the brain to form senile plaques, hyperphosphorylation of tau protein to form neurofibrillary tangles, brain glucose metabolism disorders and neuron/synapse loss. Due to the long course of the disease and the poor self-care ability of patients, it brings serious mental and economic burdens to families and society. However, there are currently no drugs that can prevent or delay the progression of the disease worldwide. The drugs currently sold on the market for the treatment of AD are only symptomatic drugs, which can only control or improve cognitive and functional symptoms for a period of time, and cannot prevent or delay the deterioration of the disease.

Studies have shown that benfotiamine can reduce the deposition of β-amyloid (Aβ) and phosphorylation of Tau protein in the brain and reduce the pathological damage of Alzheimer's disease by inhibiting the activity of Glycogen synthase kinase-3 (GSK-3). Therefore, the synthesis method and crystal form of benfotiamine and its application in the treatment of Alzheimer's disease have been studied and reported.

At present, the disclosed benfotiamine derivatives are mainly obtained by modifying the benzene ring in benfotiamine, such as CN111233927A, CN111233925A, and CN111233926A. In order to achieve better AD treatment effects and better meet market demand, it is urgent to develop new thiamine compounds.

Summary of the invention

The technical problem to be solved by the present invention is to overcome the defect of the existing single Alzheimer's disease treatment drugs, and provide a thiazole compound, its pharmaceutical composition and application. The compound of the present invention has a good inhibitory effect on Aβ40 and Aβ42 proteins, and is expected to treat and/or prevent neurodegenerative diseases, Alzheimer's disease or aging drugs.

The present invention solves the above technical problems through the following technical solutions.

The present invention provides an application of a substance A in the preparation of a drug; the drug is a drug for treating and/or preventing a disease mediated by Aβ40 and/or Aβ42 protein, or a drug for treating and/or preventing a neurodegenerative disease, Alzheimer's disease or aging.

The substance A is selected from the compounds shown in the following formula I, formula II or formula III or pharmaceutically acceptable salts thereof,

wherein R ³ is independently phenyl, phenyl substituted by one or more R ^1a , 5- to 10-membered heteroaryl, or 5- to 10-membered heteroaryl substituted by one or more R ^2a ; the 5- to 10-membered heteroaryl or the 5- to 10-membered heteroaryl substituted by one or more R ^2a contains 1 or 2 N atoms;

R ⁴ is independently C _1-4 alkyl, phenyl, phenyl substituted by one or more R ^1a , 5- to 10-membered heteroaryl, or 5- to 10-membered heteroaryl substituted by one or more R ^2a ; wherein the 5- to 10-membered heteroaryl or the 5- to 10-membered heteroaryl substituted by one or more R ^2a contains 1 or 2 N atoms;

R ^1a and R ^2a are independently halogen, C _1-4 alkyl, C _1-4 alkyl substituted by one or more R ^b1 , -N(R ^b2 R ^b3 ), -C(═O)-N(R ^b2 R ^b3 ) or -C(═O)-OR ^b4 ;

R ^b1 is independently halogen or C _1-4 alkyl;

R ^b2 , R ^b3 and R ^b4 are independently H or C _1-4 alkyl; or R ^b2 and R ^b3 together with the connected N form a 4-7 membered heterocycloalkyl or a 4-7 membered heterocycloalkyl substituted by one or more R ^{b5; the 4-7 membered heterocycloalkyl or the 4-7 membered heterocycloalkyl substituted by one or more R b5 contains} 1 or 2 N atoms;

R ^b5 is independently halogen, C _1-4 alkyl, or C _1-4 alkyl substituted by one or more R ^b6 ;

R ^b6 is independently halogen or phenyl;

L ¹ and L ² are independently NH, methylene, -C(=O)-, -C(=O)-NH-, -C(=O)-(CH ₂ )-, or -(C _1-4 alkylene)-C(=O)-NH- (the right side may be connected to the thiazole shown);

R ¹ and R ² are independently R ¹² -(C _1-4 alkylene)o-; o is 0 or 1;

^R12 is independently halogen, OH, N( ^{Rb2Rb3 )} , -C(=O)-N ^{(Rb2Rb3 )} , -C(=O) ^-ORb4 , -OC(=O) ^-Rb7 or

R ^b7 is independently C _1-4 alkyl or phenyl;

X- ^is a halogen anion.

In a certain embodiment of the present invention, some groups in the substance A are defined as follows (the groups not mentioned are the same as those described in any embodiment of the present application, hereinafter referred to as "in a certain embodiment"), R ³ and R ⁴ are independently 5- to 10-membered heteroaryl or 5- to 10-membered heteroaryl in 5- to 10-membered heteroaryl substituted by one or more R ^2a , and the 5- to 10-membered heteroaryl or 5- to 10-membered heteroaryl in 5- to 10-membered heteroaryl substituted by one or more R ^2a is independently 6-membered heteroaryl containing 1 or 2 N atoms; for example pyridyl, pyrimidinyl or pyridazinyl; for example

In one embodiment, R ^1a , R ^2a , R ^b1 , R ^b5 , R ^b6 and R ¹² are independently halogen, and the halogen is independently fluorine, chlorine or bromine; for example, fluorine or chlorine.

In one embodiment, R4, ^Rb1 , ^Rb2 , ^Rb3 , ^Rb4 and ^Rb7 are independently _C1-4 alkyl, ^R1a and ^R2a are independently _C1-4 alkyl or _C1-4 alkyl substituted by one or more ^Rb1 , ^Rb5 is independently _C1-4 alkyl or _C1-4 alkyl substituted by one or more ^Rb6 , and _{the C1-4} alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert ^- butyl, for example _, methyl or ethyl.

In one embodiment, R ^b2 and R ^b3 together with the attached N form a 4-7 membered heterocycloalkyl or a 4-7 membered heterocycloalkyl in a 4-7 membered heterocycloalkyl substituted by one or more R ^b5 , wherein the 4-7 membered heterocycloalkyl is independently a piperidinyl, for example

In one embodiment, ^L1 and ^L2 are independently _C1-4 alkylene in -( _C1-4 alkylene)-C(＝O)-NH-, ^R1 and ^R2 are independently _C1-4 alkylene in ^R12- ( _C1-4 alkylene)o-; the _C1-4 alkylene is independently _-CH2- , _-CH2CH2- , _-CH ( _CH3 )- _, -CH( _CH3 ) _CH2- or -C( _CH3 ) _2- , for example _-CH2- or _-CH2CH2- .

In one embodiment, ^X- is a Br anion.

In one embodiment, R ^b2 , R ^b3 and R ^b4 are independently H, methyl or ethyl.

In one embodiment, -N(R ^b2 R ^b3 ) is independently -NH ₂ .

In a certain embodiment, -C(=O)-N(R ^b2 R ^b3 ) is independently -C(=O)-NH ₂ , -C(=O)-N(CH ₃ )H or -C(=O)-N(CH ₃ ) ₂ .

In one embodiment, -C(=O)-OR ^b4 is independently -C(=O)-OH, -C(=O)-OC ₂ H ₅ , or -C(=O)-O-CH ₃ .

In one embodiment, R ^b6 is independently phenyl.

In one embodiment, R ^b5 is independently C _1-4 alkyl substituted with one or more R ^b6 ; for example, benzyl.

In one embodiment, ^Rb2 and ^Rb3 together with the attached N form

In one embodiment, R ³ is 5- to 10-membered heteroaryl or 5- to 10-membered heteroaryl substituted with one or more R ^2a .

In one embodiment, R ⁴ is independently C _1-4 alkyl, phenyl, or a 5- to 10-membered heteroaryl substituted with one or more R ^2a .

In one embodiment, R ^1a and R ^2a are independently F, -CH ₃ , -NH ₂ , -C(=O)-NH ₂ , -C(=O)-N(CH ₃ )H, -C(=O)-OH, -C(=O)-O-CH ₃ ,

In one embodiment, when ^L1 is independently NH, ^R12 is independently halogen, OH, N ^{(Rb2Rb3 )} , -C(=O)-N( ^Rb2Rb3 ), -OC(=O) ^{-Rb7 or}

In one embodiment, when ^L2 is independently ^methylene , ^R12 is independently halogen, N( ^Rb2Rb3 ), -C(=O)-N( ^Rb2Rb3 ), -OC(=O ^{) -Rb7} or

In one embodiment, R ¹² is independently F, Cl, OH, -C(=O)-OC ₂ H ₅ , -C(=O)-N(CH ₃ )H, -C(=O)-N(CH ₃ ) ₂ , In one embodiment, R ¹ and R ² are independently R ¹² , R ¹² (CH ₂ )- or R ¹² (CH ₂ ) ₂ -;

In one embodiment, ^R1 and ^R2 are independently -( _CH2 )-Cl, -( _CH2 )-OH, -C(=O) _-OC2H5 , -C(=O)-N( _CH3 ) _H , -C(=O)-N( _CH3 ) ₂ , -(CH ₂ ) ₂ -Cl, -(CH ₂ ) ₂ -OH, -(CH ₂ ) ₂ -F or

In one embodiment, ^L1 and ^L2 are independently NH, methylene, -C(=O)-, -C(=O)-NH-, -C(=O)-( _{CH2)-, -(CH2 )} -C(=O)-NH-, or -( _CH2 ) _3- C(=O)-NH-.

In one embodiment, R ³ and R ⁴ are independently

In one embodiment, ^R4 is independently methyl, phenyl or

In one embodiment, R ⁴ is independently methyl.

In one embodiment of the present invention,

In Formula I,

R ³ is 5- to 10-membered heteroaryl or 5- to 10-membered heteroaryl substituted by one or more R ^2a ;

R ^2a is independently halogen, C _1-4 alkyl, -N(R ^b2 R ^b3 ), -C(═O)-N(R ^b2 R ^b3 ), or -C(═O)-OR ^b4 ;

R ^b2 , R ^b3 and R ^b4 are independently H or C _1-4 alkyl; or R ^b2 and R ^b3 together with the attached N form a 4-7 membered heterocycloalkyl or a 4-7 membered heterocycloalkyl substituted by one or more R ^b5 ;

R ^b5 is independently C _1-4 alkyl substituted by one or more R ^b6 ;

R ^b6 is independently phenyl;

L ¹ is NH, methylene or -C(=O)-;

R ¹ is R ¹² -(C _1-4 alkylene)o-; o is 0 or 1;

^R12 is independently halogen, OH, N( ^{Rb2Rb3 )} , -C(=O)-N ^{(Rb2Rb3 )} or

In a certain embodiment of the present invention, some groups in the substance A are defined as follows (the groups not mentioned are the same as those described in any embodiment of the present application, hereinafter referred to as "in a certain embodiment"),

In formula I, R ³ is phenyl or phenyl substituted by one or more R ^1a ;

R ^1a is independently halogen, C _1-4 alkyl, or C _1-4 alkyl substituted by one or more R ^b1 ;

R ^b1 is independently halogen;

L ¹ is NH or -(C _1-4 alkylene)-C(=O)-NH- (N is connected to the thiazole ring);

R ¹ is R ¹² -(C _1-4 alkylene)o-; o is 0 or 1;

^R12 is independently halogen, OH, N( ^{Rb2Rb3 )} , -C(=O)-N ^{(Rb2Rb3 )} , -C(=O) ^-ORb4 or R ^b4 is independently H or C _1-4 alkyl; for example, halogen, OH or -C(=O)-OR ^b4 ; for example, halogen or OH.

In one embodiment of the present invention,

In Formula II,

R ⁴ is C _1-4 alkyl, phenyl, 5- to 10-membered heteroaryl, or 5- to 10-membered heteroaryl substituted by one or more R ^2a ;

R ^2a is independently C _1-4 alkyl or -N(R ^b2 R ^b3 );

R ^b2 and R ^b3 are independently H;

L ² is methylene or -C(=O)-(CH ₂ )-;

R ² is R ¹² -(C _1-4 alkylene)o-; o is 0 or 1;

^R12 is halogen, OH, -OC(=O) ^-Rb7 or

R ^b7 is independently C _1-4 alkyl or phenyl;

X ^- is a halogen anion;

For example, when ^L2 is methylene, ^R12 is halogen, -OC(=O) ^-Rb7 or

In one embodiment, the thiazole compound is selected from the following structures:

The present invention also provides a thiazole compound or a pharmaceutically acceptable salt thereof as shown in the following formula I, formula II or formula III:

wherein R ¹ , R ² , R ³ , R ⁴ , L ¹ , L ² and X ^- are as defined above for R ¹ , R ² , R ³ , R ⁴ , L ¹ , L ² and X ^- in substance A; and

In Formula I,

R ³ is 5- to 10-membered heteroaryl or 5- to 10-membered heteroaryl substituted by one or more R ^2a ;

R ^2a is independently halogen, C _1-4 alkyl, -N(R ^b2 R ^b3 ), -C(═O)-N(R ^b2 R ^b3 ), or -C(═O)-OR ^b4 ;

R ^b2 , R ^b3 and R ^b4 are independently H or C _1-4 alkyl; or R ^b2 and R ^b3 together with the connected N form a 4-7 membered heterocycloalkyl or a 4-7 membered heterocycloalkyl substituted by one or more R ^{b5; the 4-7 membered heterocycloalkyl or the 4-7 membered heterocycloalkyl substituted by one or more R b5 contains} 1 or 2 N atoms;

R ^b5 is independently C _1-4 alkyl substituted by one or more R ^b6 ;

R ^b6 is independently phenyl;

L ¹ is NH, methylene or -C(=O)-;

R ¹ is R ¹² -(C _1-4 alkylene)o-; o is 0 or 1;

^R12 is independently halogen, OH, N( ^{Rb2Rb3 )} , -C(=O)-N ^{(Rb2Rb3 )} or

when for When R ^b2 is C _1-4 alkyl, R ^b3 is independently H or C _1-4 alkyl; or R ^b2 and R ^b3 together with the attached N form a 4-7 membered heterocycloalkyl or a 4-7 membered heterocycloalkyl substituted by one or more R ^b5 ; the 4-7 membered heterocycloalkyl or the 4-7 membered heterocycloalkyl substituted by one or more R ^b5 contains 1 or 2 N atoms;

or,

In Formula I,

R ³ is phenyl or phenyl substituted by one or more R ^1a ;

R ^1a is independently halogen, C _1-4 alkyl, or C _1-4 alkyl substituted by one or more R ^b1 ;

R ^b1 is independently halogen;

L ¹ is NH or -(C _1-4 alkylene)-C(=O)-NH- (N is connected to the thiazole ring);

R ¹ is R ¹² -(C _1-4 alkylene)o-; o is 0 or 1;

^R12 is independently halogen, OH, N( ^{Rb2Rb3 )} , -C(=O) ^-ORb4 or For example, halogen, OH or -C(=O)-OR ^b4 ;

In Formula II,

R ⁴ is C _1-4 alkyl, phenyl, 5- to 10-membered heteroaryl, or 5- to 10-membered heteroaryl substituted by one or more R ^2a ;

R ^2a is independently C _1-4 alkyl or -N(R ^b2 R ^b3 );

R ^b2 and R ^b3 are independently H;

L ² is methylene or -C(=O)-(CH ₂ )-;

R ² is R ¹² -(C _1-4 alkylene)o-; o is 0 or 1;

^R12 is halogen, -OC(=O) ^-Rb7 or

R ^b7 is independently C _1-4 alkyl or phenyl;

X- ^is a halogen anion.

In a certain embodiment of the present invention, in the thiazole compound or a pharmaceutically acceptable salt thereof, the thiazole compound is selected from the following structures:

In the present invention, the substance A and the thiazole compound or a pharmaceutically acceptable salt thereof can be synthesized by methods similar to those known in the chemical field, and the steps and conditions thereof can refer to the steps and conditions of similar reactions in the art, especially according to the description herein. The starting materials are usually from commercial sources, such as Aldrich, or can be easily prepared using methods known to those skilled in the art (obtained through SciFinder, Reaxys online database).

In the present invention, the substance A and thiazole compounds or pharmaceutically acceptable salts thereof can also be prepared by peripherally modifying the prepared substance A and thiazole compounds or pharmaceutically acceptable salts thereof using conventional methods in the art to obtain other substances A and thiazole compounds.

The necessary raw materials or reagents for preparing substance A and thiazole compounds or pharmaceutically acceptable salts thereof can be obtained commercially or prepared by synthetic methods known in the art. The free base or its acid-added salt can be prepared by the method described in the following experimental section. The term pharmaceutically acceptable salt refers to a pharmaceutically acceptable salt as defined herein and has all the effects of the parent compound.

The present invention also provides a pharmaceutical composition, which comprises a therapeutically effective amount of the thiazole compound or a pharmaceutically acceptable salt thereof as described above and a pharmaceutical excipient (or a pharmaceutically acceptable carrier).

The present invention also provides a use of the substance A as described above, the thiazole compound as described above, or a pharmaceutically acceptable salt thereof in the preparation of an Aβ40 and/or Aβ42 protein inhibitor. In the application, the Aβ40 and/or Aβ42 protein inhibitor can be used in mammals; it can also be used in vitro, mainly for experimental purposes, for example: as a standard sample or control sample for comparison, or prepared into a kit according to conventional methods in the art to provide rapid detection of the effect of inhibiting Aβ40 and/or Aβ42 protein.

The present invention also provides a use of the above-mentioned thiazole compound or a pharmaceutically acceptable salt thereof in the preparation of a drug. The drug can be used to treat and/or prevent diseases mediated by Aβ40 and/or Aβ42 proteins; the thiazole compound or a pharmaceutically acceptable salt thereof is a therapeutically effective amount.

The present invention also provides a method for inhibiting Aβ40 and/or Aβ42 protein, which comprises administering a therapeutically effective amount of the substance A described above, the thiazole compound described above, or a pharmaceutically acceptable salt thereof to a patient.

The present invention also provides a method for treating and/or preventing diseases mediated by Aβ40 and/or Aβ42 proteins, which comprises administering to a patient a therapeutically effective amount of the substance A described above, the thiazole compound described above, or a pharmaceutically acceptable salt thereof.

In addition to the foregoing, when used in the specification and claims of the present application, the following terms have the meanings indicated below unless otherwise specifically stated.

As used herein, the substance A described in the present invention, the thiazole compound described above, or its pharmaceutically acceptable salt may contain one or more chiral centers and exist in different optically active forms. When the compound contains one chiral center, the compound contains enantiomers. The present invention includes these two isomers and mixtures of isomers, such as racemic mixtures. Enantiomers can be separated by methods known in the art, such as crystallization and chiral chromatography. When the substance A, the thiazole compound described above, or its pharmaceutically acceptable salt contains more than one chiral center, diastereomers may exist. The present invention includes optically pure specific isomers and mixtures of diastereomers that have been separated. Diastereomers can be separated by methods known in the art, such as crystallization and preparative chromatography. The term "stereoisomer" includes conformational isomers and configurational isomers, wherein configurational isomers mainly include cis-trans isomers and optical isomers. The compounds of the present invention may exist in the form of stereoisomers, and therefore encompass all possible stereoisomer forms, including but not limited to cis-trans isomers, enantiomers, diastereomers, atropisomers, etc. The compounds of the present invention may also exist in any combination or any mixture of the aforementioned stereoisomers, such as meso-, racemic-, equal mixtures of atropisomers, etc., and also in the form of single enantiomers, single diastereomers or mixtures thereof, or single atropisomers or mixtures thereof. When the compounds of the present invention contain olefin double bonds, unless otherwise specified, they include cis-isomers and trans-isomers, and any combination thereof.

As mentioned above, the present invention provides compounds represented by the above-mentioned structures, or their cis-trans isomers, meso-isomers, racemates, enantiomers, diastereomers, atropisomers, tautomers or mixtures thereof, wherein "their mixtures" include any mixture of any stereoisomers (e.g., cis-trans isomers, enantiomers, diastereomers, atropisomers), tautomers and/or mixtures (meso-isomers, racemates) mentioned above, such as a mixture of cis-trans isomers, a mixture of enantiomers and diastereomers, a mixture of diastereomers, a mixture of atropisomers, or a mixture of cis-trans isomers and racemates, a mixture of enantiomers and a mixture of diastereomers, a mixture of cis-trans isomers and tautomers, a mixture of atropisomers and a mixture of diastereomers, etc.

The term "tautomer" refers to functional isomers that result from the rapid shift of an atom between two positions in a molecule.

The substance A, the thiazole compound as described above, or a pharmaceutically acceptable salt thereof is intended to cover any isotope-labeled (or "radiolabeled") variant of the substance A, the thiazole compound as described above, or a pharmaceutically acceptable salt thereof. Such a variant may be obtained by replacing one or more atoms in the substance A, the thiazole compound as described above, or a pharmaceutically acceptable salt thereof with an atomic mass or mass number different from the atomic mass or mass number usually found in nature. The radionuclide used will depend on the specific application of the radiolabeled variant. For example, for in vitro receptor labeling and competition assays, ³ H or ¹⁴ C are often useful. For radioimaging applications, ¹¹ C or ¹⁸ F are often useful.

Certain isotopic variants of the compounds of the invention, particularly isotopic variants in which one or more radioactive isotopes have been incorporated, can be useful, for example, to investigate the mechanism of action or the distribution of the active component in vivo; compounds labeled with ³ H or ¹⁴ C isotopes are particularly suitable for this purpose due to their relatively easy preparability and detectability. In addition, the incorporation of isotopes such as deuterium can produce special therapeutic benefits due to the better metabolic stability of the compound, for example, to extend the half-life in vivo or to reduce the effective dose required; therefore, such modifications of the compounds of the invention can also constitute preferred embodiments of the invention in some cases. Isotopic variants of the compounds of the invention can be prepared by methods known to those skilled in the art, for example, by the methods described below and in the operating examples, by using corresponding isotopically modified specific reagents and/or starting compounds.

In this application, "pharmaceutical composition" refers to a preparation comprising a compound of the present invention and a medium generally accepted in the art for delivering biologically active compounds to mammals (e.g., humans). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote administration of the organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

In this application, "pharmaceutically acceptable" refers to substances (such as pharmaceutical excipients) that do not affect the biological activity or properties of the compounds of the present invention and are relatively non-toxic, that is, the substance can be administered to an individual without causing adverse biological reactions or interacting in an adverse manner with any components contained in the composition.

The term "pharmaceutical excipient" or "pharmaceutically acceptable carrier" refers to excipients and additives used in the production of drugs and the preparation of prescriptions. It is all substances contained in pharmaceutical preparations except the active ingredients. See Part IV of the Pharmacopoeia of the People's Republic of China (2015 Edition), or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition). Excipients are mainly used to provide a safe, stable and functional pharmaceutical composition, and can also provide methods to dissolve the active ingredient at a desired rate after the subject receives the administration, or promote the effective absorption of the active ingredient after the subject receives the composition. The pharmaceutical excipient may be an inert filler, or provide a certain function, such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredient of the composition. The pharmaceutical excipients may include one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesive agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents and sweeteners.

The pharmaceutical composition of the present invention can be prepared according to the disclosed content using any method known to those skilled in the art, such as conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding or lyophilizing processes.

When used as a drug, the substance A, the thiazole compound as described above, or a pharmaceutically acceptable salt thereof can be administered in any form of a pharmaceutical composition. These compositions can be prepared according to methods well known in the pharmaceutical field and can be administered in various ways, depending on the local or systemic treatment and the area to be treated. Administration can be topical (including epidermal and transdermal, ocular and mucosal, including intranasal, vaginal and rectal delivery), pulmonary (for example, by inhalation or insufflation of powder or aerosol, including by sprayer; intratracheal or intranasal), oral (solid and liquid preparations) or parenteral administration. Examples of solid oral preparations include, but are not limited to, powders, capsules, caplets, soft capsules and tablets. Examples of liquid preparations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs and solutions. Examples of topical preparations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops or serum preparations. Examples of formulations for parenteral administration include, but are not limited to, solutions for injection, dry preparations that can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, emulsions, ointments, gels, drops, suppositories, sprays, liquids, and powders. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic preparations; aerosols: such as nasal sprays or inhalers. Oral administration may include dosage forms formulated for once-daily or twice-daily (BID) administration. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or injection or infusion; or intracranial administration such as intrathecal or intraventricular administration. Parenteral administration may be in the form of a single bolus dose, or may be by continuous infusion pump. Conventional pharmaceutical carriers, water, powder or oily bases, thickeners, etc. may be necessary or required. The pharmaceutical composition of the present invention may also be a controlled release or delayed release dosage form (e.g., liposomes or microspheres).

The term "treat" refers to therapeutic treatment or palliative measures. When referring to a specific condition, treatment means: (1) alleviating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade leading to or causing the condition or (b) one or more biological manifestations of the condition, (3) ameliorating one or more symptoms, effects, or side effects associated with the condition, or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of the condition or one or more biological manifestations of the condition. "Treatment" may also mean prolonging survival as compared to expected survival if not receiving treatment.

The term "prevent" refers to the reduction of the risk of acquiring or developing a disease or disorder.

The term "therapeutically effective amount" refers to an amount of a compound that is sufficient to effectively treat a disease or condition described herein when administered to a patient."Therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted as needed by those skilled in the art.

The term "patient" refers to any animal that is about to or has been administered the compound or composition according to embodiments of the present invention, preferably a mammal, and most preferably a human. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being the most preferred.

Unless otherwise indicated, the following definitions used herein shall apply. For purposes of the present invention, chemical elements are consistent with the Periodic Table of the Elements, CAS version, and Handbook of Chemistry and Physics, 75th edition, 1994. In addition, general principles of organic chemistry can be found in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for use by patients) acid or base. When the compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, bismuth salts, ammonium salts, and the like. When the compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. The pharmaceutically acceptable acid includes inorganic acids and organic acids. For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

In this specification, groups and substituents thereof can be selected by those skilled in the art to provide stable structural moieties and compounds. When substituents are described by conventional chemical formulas written from left to right, the substituents also include chemically equivalent substituents obtained when the structural formula is written from right to left.

Certain chemical groups defined herein are preceded by a shorthand notation to indicate the total number of carbon atoms present in the group. For example, C ₁ -C ₄ alkyl or C _1-4 alkyl refers to an alkyl group as defined below having a total of 1, 2, 3 or 4 carbon atoms. The total number of carbon atoms in the shorthand notation does not include carbons that may be present in substituents of the group.

As used herein, numerical ranges defined in substituents such as 0 to 4, 1-4, 1 to 3, etc. indicate integers within the range, such as 1-6 is 1, 2, 3, 4, 5, 6.

The term "comprising" is an open expression, that is, including the contents specified in the present invention but not excluding other contents.

The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent as long as the valence state of the particular atom is normal and the compound after the substitution is stable.

In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced by a specific substituent. Further, when the group is substituted by more than one of the substituents, the substituents are independent of each other, that is, the more than one substituents may be different or the same. Unless otherwise indicated, a substituent group may be substituted at each substitutable position of the substituted group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a specific group, the substituents may be substituted at each position in the same or different manner.

In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to the group type or range. It is particularly pointed out that the present invention includes each independent secondary combination of the members of these group types and ranges. The term " _Cx - _Cy alkyl" or " _Cxy alkyl" refers to a straight or branched saturated hydrocarbon containing x to y carbon atoms. For example, the term " _C1 - _C6 alkyl" or " _C1-6 alkyl" specifically refers to the independently disclosed methyl, ethyl, _C3 alkyl, _C4 alkyl, _C5 alkyl and _C6 alkyl; " _C1-4 alkyl" specifically refers to the independently disclosed methyl, ethyl, _C3 alkyl (i.e., propyl, including n-propyl and isopropyl), _C4 alkyl (i.e., butyl, including n-butyl, isobutyl, sec-butyl and tert-butyl).

As used herein, the terms "part", "moiety", "chemical moiety", "group", "chemical group" refer to a specific fragment or functional group in a molecule. A chemical moiety is generally considered to be a chemical entity embedded in or attached to a molecule.

When a substituent is listed without indicating the atom through which it is attached in a chemical formula (including a specific compound), such a substituent may be bonded via any atom thereof. Combinations of substituents and/or their variants are permissible only if such combinations result in stable compounds.

When any variable (e.g., ^Ra ) appears multiple times in the definition of a compound, the definition of the variable at each position is independent of the definition of the other positions, and their meanings are independent of each other and do not affect each other. Therefore, if a group is substituted with 1, 2, or 3 ^Ra groups, that is, the group may be substituted with up to 3 ^Ras , where the definition of ^Ra at one position is independent of the definition of ^Ra at the other positions. In addition, combinations of substituents and/or variables are allowed only if the combination produces a stable compound.

When there is no explicit indication of a substituent in the listed groups, such groups are only unsubstituted. For example, when "C _1-4 alkyl" is not preceded by "substituted or unsubstituted", it only refers to "C _1-4 alkyl" itself or "unsubstituted C _1-4 alkyl".

In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as a linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl", it should be understood that the "alkyl" represents a linked alkylene group.

In some specific structures, when an alkyl group is clearly indicated as a linking group, the alkyl group represents a linked alkylene group, for example, the C _1-4 alkyl in the group "halo-C _1-4 alkyl" should be understood as a C _1-4 alkylene group.

The term "halogen" refers to fluorine, chlorine, bromine or iodine, in particular to F, Cl or Br.

In the present application, as a group or as part of other groups (for example, in haloalkyl, deuterated alkyl, etc.), the term "alkyl" refers to a saturated aliphatic hydrocarbon group including branched and straight chains with a specified number of carbon atoms, consisting only of carbon atoms and hydrogen atoms, having, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6, most preferably 1 to 4) carbon atoms, and connected to the rest of the molecule by a single bond, wherein propyl is _C3 alkyl (including isomers, such as n-propyl or isopropyl); butyl is C4 alkyl (including isomers, such as n-butyl, sec-butyl, isobutyl or tert-butyl); pentyl is _C5 alkyl (including isomers, such as n-pentyl, 1-methyl-butyl, 1-ethyl-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, isopentyl, tert-pentyl or neopentyl); hexyl is _C5 alkyl (including isomers, such as n-pentyl, 1-methyl-butyl, 1-ethyl-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, isopentyl, tert-pentyl or neopentyl); ₆ -alkyl (including isomers, such as 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). For example, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, n-octyl, nonyl and decyl and the like alkyl.

In the present application, the term "alkylene" as a group or part of other groups means a saturated divalent hydrocarbon group derived from a saturated straight or branched hydrocarbon group by removing two hydrogen atoms; that is, one hydrogen in an alkyl group is replaced, and the definition of alkyl is as described above. Examples of alkylene groups include methylene ( _-CH2- ), ethylene {including _-CH2CH2- or -CH( _CH3 )-}, isopropylene {including -CH( _CH3 ) _CH2- or -C( _CH3 ) _2- } _, and the like.

In the present application, as a group or part of other groups, the term "cycloalkyl" means a saturated monocyclic or polycyclic hydrocarbon group consisting only of carbon atoms and hydrogen atoms (e.g., having 3 to 15 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 7 carbon atoms), which may include a bridged ring system or a spiro ring system, and which may be connected to the rest of the molecule via a single bond via any suitable carbon atom, or may be cyclically connected or spirocyclically connected. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, and the like.

In the present application, as a group or part of other groups, the term "aryl" refers to an aromatic group of a conjugated hydrocarbon ring system consisting of carbon atoms that satisfies the 4n+2 rule, and each ring has aromaticity. In a certain embodiment, "aryl" refers to an aromatic group having 6 to 18 (preferably 6 to 10) carbon atoms. Examples of aryl include, but are not limited to, phenyl or naphthyl.

In the present application, as a group or part of other groups, the term "heteroaryl" means a conjugated ring system group having carbon atoms and 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur in the ring. Unless otherwise specifically indicated in this specification, the heteroaryl group can be a monocyclic, bicyclic, tricyclic or more ring system. When it is a bicyclic, tricyclic or more ring and ring (condensed ring), it can also include being fused with a cycloalkyl or heterocyclic group as defined herein, provided that the heteroaryl group is connected to the rest of the molecule through a single bond via an atom on the aromatic ring. Preferably, a 5-10-membered heteroaryl group containing 1, 2, 3 or 4 heteroatoms selected from N, O and S is included, and more preferably a 5-6-membered heteroaryl group containing 1, 2, 3 or 4 heteroatoms selected from N, O and S is included. Examples of heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, oxadiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, indolyl, furanyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolizinyl, isoxazolyl, thiadiazolyl, isoindolyl, indazolyl, isoindazolyl, purinyl, quinolyl, and isoquinolyl.

The "-" at the end of a group means that the group is connected to other fragments in the molecule through this site.

It should be understood that as used herein, the singular forms, such as "a," and "an," include plural references unless otherwise specified.

The term "one or more" or "one or more than two" means 1, 2, 3, 4, 5, 6, 7, 8, 9 or more.

Unless otherwise specified, the present invention adopts conventional methods of mass spectrometry and elemental analysis, and each step and condition can refer to conventional operating steps and conditions in the art.

Unless otherwise indicated, the present invention employs standard nomenclature and standard laboratory procedures and techniques of analytical chemistry, synthetic organic chemistry, and optics. In some cases, standard techniques are used for chemical syntheses and chemical analyses.

In addition, it should be noted that, unless otherwise explicitly stated, the description method "... independently are" used in the present invention should be understood in a broad sense, meaning that the individuals described are independent of each other and can independently be the same or different specific groups. In more detail, the description method "... independently are" can mean that in different groups, the specific options expressed by the same symbols do not affect each other; it can also mean that in the same group, the specific options expressed by the same symbols do not affect each other.

Those skilled in the art will appreciate that, according to the conventions used in the art, the structural formulas used in this application to describe groups It means that the corresponding group R is connected to other fragments and groups in the compound through this site.

Unless otherwise specified, all technical and scientific terms used herein have the standard meaning in the field to which the claimed subject matter belongs. If there are multiple definitions for a term, the definition herein shall prevail.

Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

The reagents and raw materials used in the present invention are commercially available.

The positive and progressive effect of the present invention is that the compounds provided by the present invention have a good inhibitory effect on Aβ40 and Aβ42 proteins, and are expected to treat and/or prevent neurodegenerative diseases, Alzheimer's disease or aging drugs.

DETAILED DESCRIPTION

The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

In order to make the purpose and technical scheme of the present invention clearer, the embodiments of the present invention are described in detail below in conjunction with examples. However, it will be appreciated by those skilled in the art that the following examples are only used to illustrate the present invention and should not be considered as limiting the scope of the present invention. Those who do not specify specific conditions in the examples are all carried out according to the conditions recommended by normal conditions or manufacturers. Those who do not specify manufacturers for reagents or instruments used are all conventional products that can be purchased and obtained on the market.

The structure of the compound is determined by nuclear magnetic resonance ( ¹ H NMR) or mass spectrometry (MS). NMR measurements are performed using a Bruker AVANCE-500 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD ₃ OD), deuterated water (D ₂ O) and the like as the measuring solvent, tetramethylsilane (TMS) as the internal standard, and chemical shifts (δ) given in parts per million (ppm).

The MS measurement instrument was an Agilent (ESI) mass spectrometer (manufacturer: Agilent, model: Agilent 6110).

Preparation method for high performance liquid chromatography:

Instrument model: Elite P3500, chromatographic column: Welch Ultimate XB-C18 (30×250mm, 10μm); chromatographic column temperature, 25℃; flow rate: 42mL/min; detection wavelength: 254nm; elution gradient: (0min: 10% A, 90% B; 25min: 90% A, 10% B; 35min: 90% A, 10% B; 38min: 10% A, 90% B; 40min: 10% A, 90% B); mobile phase: A: MeOH, B: 0.05% formic acid aqueous solution.

The compounds synthesized in the following examples are based on the compounds represented by the molecular formulas, and the Chinese and English names are for reference only.

Example 1: Synthesis of 5-(2-chloroethyl)-4-methyl-N-(pyridin-2-yl)thiazolyl-2-amine (Compound 28)

Step 1: Into a reaction flask, the aforementioned compound 35A (0.32 g, 2.0 mmol), compound 31a (0.158 g, 1.0 mmol), anhydrous potassium phosphate (0.85 g, 4 mmol), X-Phos (0.19 g, 0.4 mmol) and 1,4-dioxane (5 mL) were added in sequence, nitrogen was replaced three times, Pd ₂ (dba) ₃ (0.18 g, 0.2 mmol) was added, nitrogen was protected, and the reaction was carried out at 80 °C for 8 hours; the reaction was cooled to room temperature, MeOH/DCM (1/10, 20 mL) was added for slurrying, filtered, the mother liquor was concentrated under reduced pressure, and the residue was purified to obtain compound 31 (40 mg, off-white solid).

Step 2: Add compound 31 (0.3 g, 1.3 mmol) and tetrahydrofuran (10 mL) to a reaction flask, cool to 0°C, add thionyl chloride (0.74 g, 6.24 mmol), stir at 0°C for 0.5 hour, naturally warm to room temperature and react for 1 hour. Concentrate under reduced pressure, and the residue is used to prepare the title compound 28 (0.12 g, light yellow solid) by HPLC.

MS m/z(ESI):254[M+1] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ8.26(d,J＝5.0Hz,1H),7.63(t,J＝7.8Hz,1H),6.97(d,J＝8.4Hz,1H),6.92– 6.82(m,1H),3.70(t,J＝7.0Hz,2H),3.12(t,J＝7.0Hz,2H),2.22(s,3H).

Example 2: Synthesis of 5-(2-chloroethyl)-4-methyl-N-(pyridin-3-yl)thiazol-2-amine (Compound 29)

Step 1: Compound 32 (white solid) was prepared by the same synthetic route as in Step 1 of Example 1 except that the raw material 31a was replaced by 32a.

Step 2: Add compound 32 (0.15 g, 0.63 mmol) and tetrahydrofuran (10 mL) to the reaction flask, cool to 5°C, add thionyl chloride (0.37 g, 3.15 mmol.) dropwise, stir at room temperature for 16 hours, concentrate under reduced pressure, separate and purify the residue by preparative HPLC, collect the target fraction and lyophilize to obtain the title compound 29 (0.04 g, off-white solid).

MS m/z(ESI):254[M+1] ⁺

¹ H NMR (400MHz, DMSO-d6) δ10.18(s,1H),8.71(d,J＝2.6Hz,1H),8.22–8.01(m,2H),7.30(dd,J＝8.5,4.8Hz ,1H),3.74(t,J＝6.5Hz,2H),3.06(t,J＝6.7Hz,2H),2.17(d,J＝2.2Hz,3H).

Example 3: Synthesis of 5-(2-chloroethyl)-4-methyl-N-(pyridin-4-yl)thiazol-2-amine (Compound 30)

Steps: Add compound 35 (0.3 g, 1.27 mmol) dissolved in thionyl chloride (4 mL) to the reaction bottle, then add a drop of DMF, and stir the reaction at room temperature for 2 hours. After the reaction is completed, remove the thionyl chloride by rotary evaporation, add saturated sodium bicarbonate solution (30 mL) to quench, and extract with ethyl acetate (20 mL*3); combine the organic phases, dry with sodium sulfate, and spin dry to obtain a crude product, which is purified by column chromatography (A: DCM, B: MeOH; A/B = 100% to 90%), collect the target component, and distill under reduced pressure to obtain the title compound 30 (0.169 g, yellow solid).

MS m/z(ESI):254[M+1] ⁺

¹ H NMR (400MHz, DMSO-d6) δ10.45 (s, 1H), 8.30 (d, J = 5.5Hz, 2H), 7.50 (d, J = 5.6Hz, 2H), 3.73 (t, J = 6.6 Hz, 2H), 3.07 (t, J = 6.7Hz, 2H), 2.18 (s, 3H).

Example 4: Synthesis of 2-(4-methyl-2-(pyridin-2-ylamino)thiazol-5-yl)ethanol (Compound 31)

As described in step 1 of Example 1, the title compound 31 (off-white solid) was obtained:

MS m/z(ESI):236[M+1] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ8.27 (d, J = 5.0 Hz, 1H), 8.15 (s, 1H), 7.66 (t, J = 7.8 Hz, 1H), 6.99 (d, J = 8.4 Hz,1H),6.95–6.85(m,1H),3.71(t,J＝6.6Hz,2H),2.87(t,J＝6.7Hz,2H),2.22(s,3H).

Example 5: Synthesis of 2-(4-methyl-2-(pyridin-3-ylamino)thiazol-5-yl)ethyl-1-ol (Compound 32)

As described in step 1 of Example 2, the title compound 32 was obtained (white solid):

MS m/z(ESI):236[M+1] ⁺

¹ H NMR (400MHz, DMSO-d6) δ10.08(s,1H),8.70(s,1H),8.10(dd,J＝14.1,6.5Hz,2H),7.28(dd,J＝8.3,4.7Hz ,1H),4.77(t,J＝5.1Hz,1H),3.51(q,J＝6.1Hz,2H),2.73(t,J＝6.5Hz,2H),2.14(s,3H).

Example 6: Synthesis of 3-((4-amino-2-methylpyrimidin-5-yl)methyl)-4-methyl-5-(3-phosphoryloxy)propyl)thiazol-3-yl hydrochloride (Compound 33)

Steps: Add compound 39 (4.8 g, 0.0134 mol) and toluene (20 mL) to the reaction bottle, stir evenly, add pyrophosphoric acid (11.9 g, 0.067 mol), heat to 110°C, and stir for 3 hours. Lower the temperature to 60-70°C, add hydrochloric acid (10 mL), and stir for 16 hours; separate toluene, add acetone (50 mL) to the aqueous phase, stir, cool to 25°C, filter, separate and purify the filter cake by preparative HPLC, collect the target component and freeze-dry to obtain the title compound 33 (0.3 g, white solid).

MS m/z(ESI):180[M+1] ⁺ /2,359[M] ⁺

¹ H NMR (400MHz, DMSO-d6) δ9.99 (s, 1H), 9.16 (s, 2H), 8.35 (s, 1H), 5.60 (s, 2H), 3.87 (d, J = 6.9Hz, 2H ), 3.01 (d, J = 15.1Hz, 2H), 2.53 (d, J = 14.5Hz, 6H), 1.90 (p, J = 6.8Hz, 2H).

Example 7: Synthesis of 3-((4-amino-2-methylpyrimidin-5-yl)methyl)-5-(3-chloropropyl)-4-methylthiazol-3-yl bromide (Compound 34)

Step 1: Add the aforementioned compound 39D (3.1 g, 0.02 mol) and tetrahydrofuran (60 mL) into a reaction bottle, cool to about 5°C, add thionyl chloride (5.9 g, 0.05 mol) dropwise, and stir at room temperature for 16 hours; concentrate under reduced pressure, add water (20 mL) and DCM (20 mL) to the residue and stir, separate the layers, extract the aqueous phase with DCM twice, 20 mL each time; concentrate the combined organic phases to give a crude product of compound 34A (2.7 g, oil).

Step 2: Compound 34A (2.5 g), compound 39b (3.7 g, 0.013 mol) and DMF (5 mL) were added to a reaction flask, the reaction solution was heated to 110°C and stirred for 2 hours; the temperature was cooled to room temperature and filtered. The filter cake was slurried with acetonitrile, filtered, and the filter cake was rinsed with methyl tert-butyl ether. The filter cake was dried to obtain the title compound 34 (0.9 g, off-white solid).

MS m/z(ESI):149[M+1] ⁺ /2

¹ H NMR (400MHz, CD ₃ OD) δ8.13 (s, 1H), 5.41 (s, 2H), 3.66 (t, J = 6.1Hz, 2H), 3.17 (t, J = 7.5Hz, 2H), 2.62(s,3H),2.48(s,3H),2.17(p,J=6.6Hz,2H).

Example 8: Synthesis of (2)-(4-methyl-2-(pyridin-4-ylamino)thiazol-5-yl)ethanol (Compound 35)

Step 1: Add compound 35a (5.9 g, 0.036 mol) and water (20 mL) to a reaction flask, add a catalytic amount of concentrated sulfuric acid (12 drops) dropwise with stirring, stir at 100 ° C for 2 hours, add thiourea (2.3 g, 0.030 mol), and continue stirring at 100 ° C for 2 hours; cool to room temperature, add methanol (40 mL), concentrate under reduced pressure, add ethyl acetate (20 mL) to the residue for slurry, stir at room temperature for 10 minutes, filter, and dry the filter cake under reduced pressure to obtain compound 35A (6.0 g, off-white solid).

Step 2: Compound 35A (0.51 g), compound 35b (0.51 g, 3.2 mmol), Cs2CO3 (1.0 g, 3.2 mmol), BINAP (0.71 g, 1.15 mmol) and 1,4-dioxane (10 mL) were added to the reaction bottle, and the atmosphere was replaced with nitrogen three times under stirring. Pd2(dba)3 (0.53 g, 0.58 mmol) was added and the atmosphere was replaced with nitrogen three times. The reaction solution was stirred at 80°C for 8 hours, cooled to room temperature, filtered, the mother liquor was concentrated and dried, and the residue was purified by silica gel column (eluent: DCM:MeOH=20:1), the target component was collected, and concentrated under reduced pressure; the crude product was separated and purified by preparative HPLC, the target component was collected and lyophilized to obtain the title compound 35 (50 mg, white solid).

MS m/z(ESI):236[M+1] ⁺

¹ H NMR (400MHz, DMSO-d6) δ8.31(d,J＝5.5Hz,2H),8.12(s,1H),7.51(d,J＝5.4Hz,2H),3.52(t,J＝6.5 Hz, 2H), 2.74 (t, J = 6.5Hz, 2H), 2.17 (s, 3H).

Example 9: Synthesis of 2-(4-methyl-2-(pyrimidin-2-ylamino)thiazol-5-yl)ethyl-1-ol (Compound 36)

The title compound 36 (white solid) was prepared by the same synthetic route as in Step 1 of Example 1, except that the starting material 31a in Step 1 of Example 1 was replaced by 36a.

MS m/z(ESI):237[M+1] ⁺

¹ H NMR (400MHz, DMSO-d6) δ11.34 (s, 1H), 8.54 (d, J = 4.8Hz, 2H), 6.93 (t, J = 4.9Hz, 1H), 4.73 (t, J = 5.3 Hz, 1H), 3.51 (q, J = 6.2Hz, 2H), 2.74 (t, J = 6.7Hz, 2H), 2.13 (s, 3H).

Example 10: Synthesis of 2-(4-methyl-2-(pyrimidin-5-ylamino)thiazol-5-yl)ethanol (Compound 37)

The title compound 37 (white solid) was prepared by the same synthetic route as in Step 1 of Example 1, except that the starting material 31a in Step 1 of Example 1 was replaced by 37a.

MS m/z(ESI):237[M+1] ⁺

¹ H NMR (400MHz, DMSO-d6) δ10.29(s,1H),9.05(s,2H),8.71(s,1H),4.78(t,J＝5.2Hz,1H),3.51(q,J ＝6.1Hz,2H),2.73(t,J＝6.5Hz,2H),2.16(s,3H).

Example 11: Synthesis of 2-(4-methyl-2-((2-methylpyrimidin-5-yl)amino)thiazol-5-yl)ethanol (Compound 38)

The title compound 38 (white solid) was prepared by the same synthetic route as in Step 1 of Example 1, except that the starting material 31a in Step 1 of Example 1 was replaced by 38a.

MS m/z(ESI):251[M+1] ⁺

¹ H NMR (400MHz, DMSO-d6) δ10.11 (s, 1H), 8.93 (s, 2H), 4.76 (t, J = 5.3Hz, 1H), 3.51 (q, J = 6.2Hz, 2H), 2.72(t,J＝6.6Hz,2H),2.14(s,3H).

Example 12: Synthesis of 3-((4-amino-2-methylpyrimidin-5-yl)methyl)-5-(3-hydroxypropyl)-4-methylthiazolium bromide (Compound 39)

Step 1: Add compound 39a (19.5 g, 0.15 mol), methanol (200 mL), p-toluenesulfonic acid (1.3 g, 0.0075 mol) to a reaction flask, heat to 85°C, and stir to react for 4 hours. After vacuum concentration, add 50 mL of saturated sodium bicarbonate solution, extract the organic phase with ethyl acetate, separate the liquids, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under vacuum to obtain compound 39A (22 g, colorless oily liquid).

Step 2: Add compound 39A (12.0 g) and 120 mL of DCM to a reaction bottle, slowly add liquid bromine (10.5 g, 0.066 mol) dropwise at room temperature for about 90 minutes, and stir for two hours; add saturated sodium bicarbonate solution dropwise under an ice bath to quench the reaction, then add saturated sodium bicarbonate solution until no more bubbles appear, separate the liquids, take the organic phase, extract the aqueous phase twice with DCM, combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate to obtain compound 39B (14.0 g, light yellow oily liquid).

Step 3: Add compound 39B (14.0 g), thioformamide (4.5 g, 0.074 mol) and 150 mL of ethanol into a reaction flask and stir at room temperature for 24 hours; concentrate under reduced pressure, and purify the residue by column chromatography (developing solvent: DCM:MeOH=50:～20:1) to obtain compound 39C (2.0 g, light yellow oily liquid).

Step 4: Add lithium aluminum hydride (2.5 mol/L in THF, 2.25 mL, 0.0056 mol) to the reaction flask and protect with nitrogen. Dissolve compound 39C (1.0 g) in 10 mL of anhydrous tetrahydrofuran and drip into the reaction flask under ice bath. Add the mixture over 5 minutes and warm to room temperature and stir for 90 minutes. Slowly add 2 mL of 30% NaOH aqueous solution under ice bath. Add 5 mL of water after the addition. Extract the organic phase with ethyl acetate, filter and separate the filtrate. Dry the organic phase with anhydrous sodium sulfate and concentrate under reduced pressure to obtain compound 39D (0.5 g, light yellow oily liquid).

Step 5: Add compound 39D (0.8 g), compound 39b (2.8 g, 0.01 mol.) and 20 mL of DMF into a reaction flask, stir at 110°C for 2 hours, and a solid will precipitate; cool to room temperature, filter, dissolve the solid in water, and prepare the title compound 39 (60 mg, white solid) from the liquid phase.

MS m/z(ESI):140[M+1] ⁺ /2,279[M] ⁺

1H NMR (400MHz, DMSO-d6) δ9.93(s,1H),8.41(s,1H),5.52(s,2H),3.45(t,J＝6.1Hz,2H),3.00(t,J＝ 7.4Hz, 2H), 2.56 (s, 3H), 2.52 (s, 3H), 1.76 (p, J = 6.4Hz, 2H).

Example 13: Synthesis of 3-((4-amino-2-methylpyrimidin-5-yl)methyl)-5-(3-fluoropropyl)-4-methylthiazol-3-yl bromide (Compound 40)

The title compound 40 (white solid) was prepared by the same synthetic route as in Example 7, except that thionyl chloride in the step of Example 7 was replaced by BAST.

¹ H NMR (400MHz, CD ₃ OD) δ8.28 (s, 1H), 5.51 (s, 2H), 4.59 (t, J = 5.5Hz, 1H), 4.47 (t, J = 5.6Hz, 1H), 3.14(t,J＝7.6Hz,2H),2.62(s,3H),2.57(s,3H),2.20–2.02(m,2H).

Example 14: Synthesis of 5-(2-chloroethyl)-4-methyl-N-phenylthiazol-2-amine (Compound 41)

Steps: Add compound 42 (0.2 g, 0.85 mmol), thionyl chloride (0.1 g, 0.85 mmol) and DCM (10 mL) into a reaction bottle, heat under reflux and stir for 2 hours; concentrate under reduced pressure, and separate and purify the residue by column chromatography (eluent: DCM:MeOH=100:0-95:5) to obtain the title compound 41 (92 mg, off-white solid).

MS m/z(ESI):253[M+1] ⁺

¹ H NMR (400MHz, DMSO-d6) δ9.97 (s, 1H), 7.57 (d, J = 8.0Hz, 2H), 7.26 (t, J = 7.7Hz, 2H), 6.89 (t, J = 7.3 Hz,1H),3.73(t,J＝6.7Hz,2H),3.05(t,J＝6.7Hz,2H),2.15(s,3H).

Example 15: Synthesis of 2-(4-methyl-2-(phenylamino)thiazol-5-yl)ethanol (Compound 42)

The title compound 42 (off-white solid) was prepared by the same synthetic route as in Step 1 of Example 1, except that the raw material 31a in Step 1 of Example 1 was replaced by 42a.

MS m/z(ESI):235[M+1] ⁺

¹ H NMR (400MHz, DMSO-d6) δ9.85 (s, 1H), 7.55 (d, J = 7.9Hz, 2H), 7.25 (t, J = 7.9Hz, 2H), 6.87 (t, J = 7.3 Hz,1H),4.75(s,1H),3.50(d,J＝4.7Hz,2H),2.71(t,J＝6.6Hz,2H),2.13(s,3H).

Example 16: Synthesis of 6-((5-(2-hydroxyethyl)-4-methylthiazol-2-yl)amino)-N-methylnicotinamide (Compound 43)

Procedure: Add compound 43a (58 mg, 0.86 mmol), HATU (327 mg, 0.86 mmol) and N,N-dimethylacetamide (3 mL) to compound 49 (120 mg, 0.43 mmol), and then add DIPEA (0.4 mL, 2.15 mmol). Stir the reaction at room temperature overnight. Concentrate under reduced pressure. Purify the residue by forward column to obtain 90 mg of crude product. Slurry with methanol to obtain the title compound 43 (50 mg, yellow solid).

MS m/z(ESI):293[M+1] ⁺

¹ H NMR (400MHz, DMSO-d6) δ11.30 (s, 1H), 8.70 (d, J = 2.4Hz, 1H), 8.35 (d, J = 4.7Hz, 1H), 8.03 (dd, J = 8.7 ,2.4Hz,1H),6.99(d,J＝8.7Hz,1H),4.76(d,J＝5.3Hz,1H),3.54(q,J＝6.0Hz,2H),2.77(q,J＝4.9 Hz,5H),2.16(s,3H).

Example 17: Synthesis of (6-((5-(2-hydroxyethyl)-4-methylthiazol-2-yl)amino)pyridin-3-yl)(piperidin-1-yl)methanone (Compound 44)

Procedure: Add HATU (407 mg, 1.07 mmol) and N,N-dimethylacetamide (3 mL) to compound 49 (150 mg, 0.54 mmol). Then add compound 44a (0.1 mL, 1.07 mmol) and DIPEA (0.3 mL), stir and react overnight at room temperature. Concentrate under reduced pressure, purify the residue by forward column, and then purify by reverse column to obtain the title compound (75 mg, yellow solid).

MS m/z(ESI):347[M+1] ⁺

¹ H NMR (400MHz, CDCl ₃ ) δ8.33 (d, J = 2.1 Hz, 1H), 7.60 (dd, J = 8.5, 2.1 Hz, 1H), 6.86 (d, J = 8.5 Hz, 1H), 3.76 (t,J＝6.4Hz,2H),3.70–3.37(m,4H),2.84(t,J＝6.4Hz,2H),2.18(s,3H),1.65(t,J＝5.5Hz,6H) .

Example 18: Synthesis of (4-benzylpiperidin-1-yl)(6-((5-(2-hydroxyethyl)-4-methylthiazol-2-yl)amino)pyridin-3-yl)methyl ketone (Compound 45)

The title compound 45 (yellow solid) was prepared by the same synthetic route as in Example 17, except that the raw material 44a in the step of Example 17 was replaced by 45a.

MS m/z(ESI):437[M+1] ⁺

¹ H NMR (400MHz, DMSO-d6) δ8.26 (d, J＝2.2Hz, 1H), 7.67 (dd, J＝8.6, 2.3Hz, 1H), 7.27 (t, J＝7.5Hz, 2H), 7.21–7.14(m,3H),7.01(d,J＝8.5Hz,1H),3.53(t,J＝6.7Hz,2H),3.32(br,4H),2.76(t,J＝6.7Hz,2H ),2.52(d,J＝7.1Hz,2H),2.15(s,3H),1.84–1.70(m,1H),1.58(s,2H),1.15(qd,J＝12.4,4.2Hz,2H) .

Example 19: Synthesis of 6-((5-(2-hydroxyethyl)-4-methylthiazol-2-yl)amino)nicotinamide (Compound 46)

The title compound 46 (yellow solid) was prepared by the same synthetic route as in Example 16, except that the raw material 43a in the step of Example 16 was replaced by ammonium chloride.

MS m/z(ESI):279[M+1] ⁺

¹ H NMR (400MHz, DMSO-d6) δ8.83 (d, J＝2.3Hz, 1H), 8.19 (dd, J＝8.7, 2.3Hz, 1H), 8.02 (s, 1H), 7.44 (s, 1H ),7.25(d,J＝8.7Hz,1H),3.57(t,J＝6.2Hz,2H),2.80(t,J＝6.2Hz,2H),2.23(s,3H).

Example 20: Synthesis of 6-(5-(2-hydroxyethyl)-4-methylthiazol-2-yl)amino)nicotinate (Compound 47)

The title compound 47 (yellow solid) was prepared by the same synthetic route as in Step 1 of Example 1, except that the starting material 31a in Step 1 of Example 1 was replaced by 47a.

MS m/z(ESI):294[M+1] ⁺

¹ H NMR (400MHz, DMSO-d6) δ11.54(s,1H),8.78(d,J＝2.3Hz,1H),8.09(dd,J＝8.7,2.2Hz,1H),7.04(d,J ＝8.8Hz,1H),4.92-4.62(m,1H),3.82(s,3H),3.54(q,J＝6.1Hz,2H),2.77(t,J＝6.7Hz,2H),2.17(s ,3H).

Example 21: Synthesis of methyl 5-((5-(2-hydroxyethyl)-4-methylthiazol-2-yl)amino)nicotinate (Compound 48)

Steps: Add compound 48a (0.65 g, 3.0 mmol), 35A (0.39 g, 2.0 mmol), Pd2(dba)3 (0.28 g, 0.3 mmol), X-phos (0.24 g, 0.5 mmol), potassium phosphate (1.27 g, 6.0 mmol) and 1,4-dioxane (15 mL) to a reaction bottle, protect with nitrogen, and stir at 100°C for 8 hours. Filter, reduce the pressure of the filtrate, separate and purify the residue by column chromatography (mobile phase: DCM/MeOH=90/10), collect the target fraction and concentrate under reduced pressure to obtain the title compound 48 (25 mg, ginger yellow solid).

MS m/z(ESI):294[M+1] ⁺

¹ H NMR (400MHz, DMSO-d6) δ10.36 (s, 1H), 8.94 (d, J = 2.4Hz, 1H), 8.67 (s, 1H), 8.60 (d, J = 1.4Hz, 1H), 4.79(t,J＝5.2Hz,1H),3.88(s,3H),3.53(d,J＝5.7Hz,2H),2.75(t,J＝6.4Hz,2H),2.18(s,3H).

Example 22: Synthesis of 6-((5-(2-hydroxyethyl)-4-methylthiazol-2-yl)amino)nicotinic acid (Compound 49)

Steps: Compound 47 (431 mg, 1.47 mmol) was dissolved in methanol (20 mL), and lithium hydroxide (70 mg, 2.94 mmol) and water (5 mL) were added. The mixture was stirred and reacted at room temperature for 20 hours. The methanol was removed by concentration under reduced pressure. The residue was dissolved in water (10 mL), washed with ethyl acetate (20 mL), and the pH of the aqueous phase was adjusted to 4 with concentrated hydrochloric acid to precipitate a solid. The mixture was filtered, and the filter cake was washed with water (10 mL*2) and dried to obtain the title compound 49 (290 mg, yellow solid).

MS m/z(ESI):280[M+1] ⁺

¹ H NMR (400MHz, DMSO-d6) δ8.75 (dd, J＝2.3, 0.8Hz, 1H), 8.07 (dd, J＝8.7, 2.3Hz, 1H), 7.02 (dd, J＝8.7, 0.8Hz ,1H),3.54(t,J＝6.7Hz,2H),2.77(t,J＝6.7Hz,2H),2.16(s,3H).

Example 23: Synthesis of 5-((5-(2-hydroxyethyl)-4-methylthiazol-2-yl)amino)nicotinic acid (Compound 50)

Steps: Add compound 48 (88 mg, 0.3 mmol), lithium hydroxide (36 mg, 1.5 mmol) and ethanol (1.5 mL) and water (0.5 mL) into a reaction bottle and stir at room temperature for 2 hours. Add 1 mol/L dilute hydrochloric acid dropwise to adjust the pH to 6-7. A large amount of solid precipitates, which is filtered. The filter cake is washed with water and dried to obtain the title compound 50 (46 mg, off-white solid).

MS m/z(ESI):280[M+1] ⁺

¹ H NMR (400MHz, DMSO-d6) δ10.33 (s, 1H), 8.94 (d, J = 2.1Hz, 1H), 8.66–8.53 (m, 2H), 4.80 (s, 1H), 3.54 (t ,J＝6.5Hz,2H),2.76(s,2H),2.18(s,3H).

Example 24: Synthesis of 2-(4-methyl-2-(pyridin-2-ylamino)thiazol-5-yl)acetic acid (Compound 51)

The title compound 51 (grey solid) was prepared by the same synthetic route as Example 23.

MS m/z(ESI):250[M+1] ⁺

¹ H NMR (400MHz, DMSO-d6) δ11.12(s,1H),8.24(s,1H),7.65(t,J＝7.2Hz,1H),7.01(d,J＝8.2Hz,1H), 6.92–6.78(m,1H),3.60(s,2H),2.13(s,3H).

Example 25: Synthesis of 2-(4-methyl-2-(pyridin-3-ylamino)thiazol-5-yl)acetic acid (Compound 52)

The title compound 52 (grey solid) was prepared by the same synthetic route as Example 23.

MS m/z(ESI):250[M+1] ⁺

¹ H NMR (400MHz, DMSO-d6) δ10.09(s,1H),8.71(d,J＝2.6Hz,1H),8.13(dd,J＝8.3,2.6Hz,1H),8.07(dd,J ＝4.7,1.3Hz,1H),7.27(dd,J＝8.4,4.7Hz,1H),3.38(s,2H),2.11(s,3H).

Example 26: Synthesis of 2-(4-methyl-2-(pyridin-4-ylamino)thiazol-5-yl)acetic acid (Compound 53)

The title compound 53 (off-white solid) was prepared by the same synthetic route as Example 23.

MS m/z(ESI):250[M+1] ⁺

¹ H NMR (400MHz, DMSO-d6) δ10.45 (s, 1H), 8.34 (d, J = 5.6Hz, 2H), 7.53 (d, J = 5.4Hz, 2H), 3.66 (s, 2H), 2.18(s,3H).

Example 27: Synthesis of ethyl 2-(4-methyl-2-(pyridin-2-ylamino)thiazol-5-yl)acetate (Compound 54)

Step 1: Add compound 58a (5.0 g, 34.68 mmol) dissolved in DCM (80 mL) into the reaction bottle, then add Br2 (5.54 g, 34.68 mmol) dissolved in DCM (20 mL) dropwise to the reaction system, and stir the reaction in an ice bath for 1 hour; after the reaction, add saturated sodium bisulfate solution (20 mL) to quench, and extract with ethyl acetate (20 mL*3); combine the organic phases, dry with sodium sulfate, and spin-dry to obtain the crude product as compound 58A (6.0 g, yellow oily liquid).

Step 2: Add compound 58A (6.0 g) dissolved in ethanol (40 mL) into the reaction bottle, and then add thiourea (2.05 g, 26.9 mmol), and stir the reaction at 80°C for 2 hours. After the reaction, add water (20 mL) to quench, extract with ethyl acetate (20 mL*3), combine the organic phases, dry over sodium sulfate and spin dry to obtain a crude product, pass through a column machine (A: PE, B: EtOAc; A/B = 100% to 50%) to obtain the main peak, and spin dry to obtain compound 58B (0.76 g, yellow solid).

Step 3: The title compound 54 (white solid) was prepared by the same synthetic route as in Step 1 of Example 1, except that the starting material 35A in Step 1 of Example 1 was replaced by 58B.

MS m/z(ESI):278[M+1] ⁺

¹ H NMR (400MHz, CDCl ₃ ) δ8.33 (d, J = 5.0Hz, 1H), 7.65–7.50 (m, 1H), 6.94–6.77 (m, 2H), 4.31–4.14 (m, 2H), 3.67(d,J＝1.8Hz,2H),2.28(s,3H),1.28(td,J＝7.1,1.7Hz,3H).

Example 28: Synthesis of ethyl 2-(4-methyl-2-(pyridin-3-ylamino)thiazol-5-yl)acetate (Compound 55)

The title compound 55 (white solid) was prepared by the same synthetic route as in Example 2, except that the starting material 35A in Example 2 was replaced by 58B.

MS m/z(ESI):278[M+1] ⁺

¹ H NMR (400MHz, CDCl ₃ ) δ8.65 (d, J＝2.4Hz, 1H), 8.33–8.22 (m, 2H), 7.96 (d, J＝8.4Hz, 1H), 7.34 (dd, J＝ 8.3, 4.8Hz, 1H), 4.20 (q, J = 7.1Hz, 2H), 3.63 (s, 2H), 2.24 (s, 3H), 1.29 (t, J = 7.2Hz, 3H).

Example 29: Synthesis of ethyl 2-(4-methyl-2-(pyridin-4-ylamino)thiazol-5-yl)acetate (Compound 56)

The title compound 56 (yellow solid) was prepared by the same synthetic route as in Example 21, except that the starting material 48a in the step of Example 21 was replaced by 35b and 35A was replaced by 58B.

MS m/z(ESI):278[M+1] ⁺

¹ H NMR (400MHz, DMSO-d6) δ10.47 (s, 1H), 8.33 (d, J = 5.3Hz, 2H), 7.52 (d, J = 5.5Hz, 2H), 4.09 (d, J = 7.1 Hz,2H),3.75(s,2H),2.17(s,3H),1.19(t,J=7.1Hz,3H).

Example 30: Synthesis of ethyl 2-(4-methyl-2-(phenylamino)thiazol-5-yl)acetate (Compound 57)

The title compound 57 (yellow solid) was prepared by the same synthetic route as in Example 21, except that the starting material 48a in the step of Example 21 was replaced by 42a and 35A was replaced by 58B.

MS m/z(ESI):277[M+1] ⁺

¹ H NMR (400MHz, DMSO-d6) δ9.97 (s, 1H), 7.58 (d, J = 7.8Hz, 2H), 7.28 (t, J = 7.9Hz, 2H), 6.91 (t, J = 7.3 Hz,1H),4.10(q,J＝7.1Hz,2H),3.70(s,2H),2.14(s,3H),1.20(t,J＝7.1Hz,3H).

Example 31: Synthesis of 2-(4-methyl-2-(pyridin-4-ylamino)thiazol-5-yl)acetamide (Compound 58)

Steps: Compound 51 (50 mg), DCM (3 mL), NH ₄ Cl (21 mg, 0.4 mmol), HATU (152 mg, 0.4 mmol) and DIPEA (50 mg, 0.4 mmol) were added to a reaction flask in sequence, and the resulting reaction solution was stirred at room temperature overnight; filtered, the filter cake was purified by HPLC, the target fraction was collected, concentrated under reduced pressure, and lyophilized to obtain the title compound 58 (18 mg, yellow solid).

MS m/z(ESI):249[M+1] ⁺

¹ H NMR (400MHz, DMSO-d6) δ8.23(d,J＝4.8Hz,1H),8.13(s,1H),7.63(t,J＝7.7Hz,1H),7.43(s,1H), 7.09–6.77(m,3H),3.41(s,2H),2.15(s,3H).

Example 32: Synthesis of N-methyl-2-(4-methyl-2-(pyrimidin-2-ylamino)thiazol-5-yl)acetamide (Compound 59)

Steps: Add compound 51 (0.1 g, 0.4 mmol) dissolved in DCM (4 mL) to a reaction flask, then add HATU (0.23 g, 0.6 mmol), stir the reaction at room temperature under nitrogen for 1 hour, then add 43a (0.1 g) and DIPEA (0.13 g, 1.0 mmol), stir the reaction at room temperature under nitrogen for 2 hours, and then the reaction is completed. Spin dry column chromatography (DCM: MeOH = 10: 1) to obtain a crude product, which is then reversed with C18 to obtain the title compound 59 (10 mg, white solid).

MS m/z(ESI):263[M+1] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ8.26 (d, J = 4.7Hz, 1H), 8.14 (s, 1H), 7.65 (t, J = 7.9Hz, 1H), 6.98 (d, J = 8.3 Hz,1H),6.90(t,J＝6.1Hz,1H),3.56(s,2H),2.74(s,3H),2.23(s,3H).

Example 33: Synthesis of N,N-dimethyl-2-(4-methyl-2-(pyridin-2-ylamino)thiazol-5-yl)acetamide (Compound 60)

The title compound 60 (white solid) was prepared by the same synthetic route as in Example 32, except that the starting material 43a in the step of Example 32 was replaced by 60a.

MS m/z(ESI):277[M+1] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ8.27(d,J＝5.0Hz,1H),7.69(t,J＝7.7Hz,1H),7.01(d,J＝8.4Hz,1H),6.96– 6.88(m,1H),3.81(s,2H),3.14(s,3H),2.97(s,3H),2.24(s,3H).

Example 34: Synthesis of N,N-dimethyl-2-(4-methyl-2-(pyridin-3-ylamino)thiazol-5-yl)acetamide (Compound 61)

Steps: Add compound 52 (0.1 g, 0.402 mmol), HATU (0.228 g, 0.602 mmol,) and DCM (5 mL) to the reaction bottle. Stir the reaction solution at 30 ° C for half an hour. Add compound 60a (66 mg, 0.804 mmol) under nitrogen replacement, and the reaction solution is stirred at room temperature for 12 hours and LCMS monitors the reaction. The reaction solution is concentrated under reduced pressure, and the residue is dissolved in DMSO (2 mL) and purified by C18 reverse column to obtain the title compound 61 (60 mg, white solid).

MS m/z(ESI):277[M+1] ⁺

¹ H NMR (400MHz, CDCl ₃ ) δ8.64 (s, 1H), 8.25 (d, J = 4.8Hz, 1H), 8.02 (d, J = 8.4Hz, 1H), 7.30 (dd, J = 8.4, 4.6Hz,1H),3.71(s,2H),3.11(s,3H),3.01(s,3H),2.25(s,3H).

Example 35: Synthesis of N-(5-(2-hydroxyethyl)-4-methylthiazol-2-yl)pyridineamide (Compound 62)

Step 1: Compound 35A (3.2 g, 0.02 mol), DIPEA (5.2 g, 0.04 mol) and DCM (50 mL) were added to a reaction flask in sequence, and TBSCl (3.3 g, 0.022 mol) was added under stirring. The mixture was stirred at 20-25 °C for 16 hours, filtered, washed with water twice, 20 mL each time, and the organic phase was concentrated under reduced pressure to obtain a crude compound 62A.

Step 2: Compound 62A (0.27 g, 1.0 mmol), DCM (10 mL), compound 62a (0.12 g, 1.0 mmol), HATU (0.38 g, 1.0 mmol) and DIPEA (0.26 g, 2.0 mmol) were added to the reaction flask in sequence. The resulting reaction solution was stirred at room temperature for 16 hours, washed with water twice, 10 mL each time, and concentrated under reduced pressure. The residue was separated and purified by preparative HPLC, and the target fraction was collected and lyophilized to obtain the title compound 62 (71 mg, off-white solid).

MS m/z(ESI):264[M+1] ⁺

¹ H NMR (400MHz, DMSO-d6) δ11.60 (s, 1H), 8.72 (ddd, J＝4.8, 1.7, 1.0Hz, 1H), 8.14 (dt, J＝7.8, 1.2Hz, 1H), 8.07 (td,J＝7.7,1.7Hz,1H),7.69(ddd,J＝7.6,4.7,1.3Hz,1H),4.82(t,J＝5.2Hz,1H),3.56(td,J＝6.5,5.2 Hz, 2H), 2.82 (t, J = 6.5Hz, 2H), 2.21 (s, 3H).

Example 36: Synthesis of N-(5-(2-hydroxyethyl)-4-methylthiazol-2-yl)nicotinamide (Compound 63)

The title compound 63 (off-white solid) was prepared by the same synthetic route as in Example 35, except that the raw material 62a in the step of Example 35 was replaced by nicotinic acid.

MS m/z(ESI):264[M+1] ⁺

¹ H NMR (400MHz, DMSO-d6) δ9.19(d,J＝2.2Hz,1H),8.77(dd,J＝4.8,1.6Hz,1H),8.41(dd,J＝7.8,2.1Hz,1H ),7.58(dd,J＝8.0,5.0Hz,1H),3.56(t,J＝6.5Hz,2H),2.80(t,J＝6.5Hz,2H),2.21(s,3H).

Example 37: Synthesis of N-(5-(2-hydroxyethyl)-4-methylthiazol-2-yl)isonicotinamide (Compound 64)

The title compound 64 (white solid) was prepared by the same synthetic route as in Example 35, except that the raw material 62a in the step of Example 35 was replaced by isonicotinic acid.

MS m/z(ESI):264[M+1] ⁺

¹ H NMR (400MHz, DMSO-d6) δ8.79–8.75(m,2H),7.95(dd,J＝4.5,1.7Hz,2H),4.82(t,J＝5.3Hz,1H),3.56(q ,J＝6.1Hz,2H),2.80(t,J＝6.4Hz,2H),2.22(s,3H).

Example 38: Synthesis of N-(5-(2-hydroxyethyl)-4-methylthiazol-2-yl)2-methylnicotinamide (Compound 65)

The title compound 65 (off-white solid) was prepared by the same synthetic route as in Example 35, except that the raw material 62a in the step of Example 35 was replaced by 2-methylnicotinic acid.

MS m/z(ESI):278[M+1] ⁺

¹ H NMR (400MHz, DMSO-d6) δ12.41(s,1H),8.56(dd,J＝4.9,1.7Hz,1H),7.92(dd,J＝7.9,1.8Hz,1H),7.34(dd ,J＝7.7,5.0Hz,1H),3.57(d,J＝6.5Hz,2H),2.80(t,J＝6.5Hz,2H),2.56(s,3H),2.20(s,3H).

Example 39: Synthesis of N-(5-(2-hydroxyethyl)-4-methylthiazol-2-yl)5-methylnicotinamide (Compound 66)

The title compound 66 (off-white solid) was prepared by the same synthetic route as in Example 35, except that the raw material 62a in the step of Example 35 was replaced by 5-methylnicotinic acid.

MS m/z(ESI):278[M+1] ⁺

¹ H NMR (400MHz, DMSO-d6) δ12.55(s,1H),8.99(s,1H),8.60(s,1H),8.22(s,1H),3.56(t,J＝6.6Hz,2H ),2.80(t,J＝6.5Hz,2H),2.37(s,3H),2.21(s,3H).

Example 40: Synthesis of ethyl 2-(4-methyl-2-(pyridinylamide)thiazol-5-yl)acetate (Compound 67)

Steps: Add compound 62a (0.25 g, 2.0 mmol), HATU (1.14 g, 3.0 mmol) and DCM (10 mL) into a reaction bottle, stir at room temperature for half an hour, then add compound 58B (0.4 g, 2.0 mmol) and DIPEA (0.65 g, 5.0 mmol) and continue stirring until the reaction is complete as monitored by TLC; add water (5 mL) to wash twice, extract with DCM (10 mL), dry the organic phase with anhydrous sodium sulfate, concentrate, purify the residue with a column machine, collect the target component to obtain the title compound 67 (265 mg, off-white solid).

MS m/z(ESI):306[M+1] ⁺

¹ H NMR (400MHz, DMSO-d6) δ11.75 (s, 1H), 8.75 (d, J = 4.6Hz, 1H), 8.17 (d, J = 7.8Hz, 1H), 8.09 (t, J = 7.7 Hz,1H),7.75–7.67(m,1H),4.12(q,J＝7.1Hz,2H),3.84(s,2H),2.22(s,3H),1.21(t,J＝7.1Hz,3H ).

Example 41: Synthesis of ethyl 2-(4-methyl-2-(nicotinamide)thiazol-5-yl)acetate (Compound 68)

The title compound 68 (off-white solid) was prepared by the same synthetic route as in Example 40, except that the raw material 62a in the step of Example 40 was replaced by nicotinic acid.

MS m/z(ESI):306[M+1] ⁺

¹ H NMR (400MHz, DMSO-d6) δ12.73 (s, 1H), 9.19 (s, 1H), 8.77 (d, J = 3.4Hz, 1H), 8.40 (d, J = 7.9Hz, 1H), 7.62–7.51(m,1H),4.12(q,J＝7.1Hz,2H),3.82(s,2H),2.22(s,3H),1.21(t,J＝7.1Hz,3H).

Example 42: Synthesis of ethyl 2-(2-(isonicotinamide)-4-methylthiazol-5-yl)acetate (Compound 69)

The title compound 69 (yellow solid) was prepared by the same synthetic route as in Example 40, except that the raw material 62a in the step of Example 40 was replaced by isonicotinic acid.

MS m/z(ESI):306[M+1] ⁺

¹ H NMR (400MHz, DMSO-d6) δ12.85 (s, 1H), 8.78 (d, J = 5.5Hz, 2H), 7.95 (d, J = 5.6Hz, 2H), 4.11 (q, J = 7.1 Hz, 2H), 3.82 (s, 2H), 2.22 (s, 3H), 1.20 (t, J = 7.1Hz, 3H).

Example 43: Synthesis of ethyl 2-(4-methyl-2-(5-methylnicotinamide)thiazol-5-yl)acetate (Compound 70)

The title compound 70 (white solid) was prepared by the same synthetic route as in Example 40, except that the raw material 62a in the step of Example 40 was replaced by 5-methylnicotinic acid.

MS m/z(ESI):320[M+1] ⁺

¹ H NMR (400MHz, DMSO-d6) δ12.65(s,1H),9.00(s,1H),8.62(s,1H),8.23(s,1H),4.12(q,J＝7.1Hz,2H ),3.82(s,2H),2.38(s,3H),2.23(s,3H),1.21(t,J=7.1Hz,3H).

Example 44: Synthesis of ethyl 2-(4-methyl-2-(pyridazine-4-carboxamide)thiazol-5-yl)acetate (Compound 71)

The title compound 71 (yellow solid) was prepared by the same synthetic route as in Example 40, except that the starting material 62a in the step of Example 40 was replaced by pyridazine-4-carboxylic acid.

MS m/z(ESI):307[M+1] ⁺

¹ H NMR (400MHz, DMSO-d6) δ13.10(s,1H),9.71(dd,J＝2.3,1.3Hz,1H),9.48(dd,J＝5.3,1.2Hz,1H),8.18(dd ,J＝5.3,2.3Hz,1H),4.12(q,J＝7.1Hz,2H),3.84(s,2H),2.23(s,3H),1.21(t,J＝7.1Hz,3H).

Example 45: Synthesis of ethyl 2-(4-methyl-2-(pyridazine-3-carboxamide)thiazol-5-yl)acetate (Compound 72)

The title compound 72 (off-white solid) was prepared by the same synthetic route as in Example 40, except that the raw material 62a in the step of Example 40 was replaced by pyridazine-3-carboxylic acid.

MS m/z(ESI):307[M+1] ⁺

¹ H NMR (400MHz, DMSO-d6) δ12.46(s,1H),9.47(d,J＝4.8Hz,1H),8.31(d,J＝8.5Hz,1H),8.00–7.94(m,1H ), 4.12 (q, J = 7.0Hz, 2H), 3.85 (s, 2H), 2.23 (s, 3H), 1.21 (t, J = 7.1Hz, 3H).

Example 46: Synthesis of N-(5-(2-hydroxyethyl)-4-methylthiazol-2-yl)pyridazine-4-carboxamide (Compound 73)

Step 1: Add compound 35A (4.75 g, 0.03 mol) and DCM (80 mL) to a reaction flask, place the reaction flask in an ice bath, add TBSCl (4.75 g, 0.0315 mol) dropwise, and monitor the completion of the reaction by TLC spot plate. Wash with water twice, 10 mL each time, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain compound 62A (8.0 g, orange-yellow oily liquid).

Step 2: Add compound 62A (0.545 g, 2.0 mmol), HATU (1.14 g, 3.0 mmol) and DCM (10 mL) to the reaction bottle, stir at room temperature for half an hour, then add pyridazine-4-carboxylic acid (0.248 g, 2.0 mmol) and DIPEA (0.65 g, 5.0 mmol) and continue stirring until the reaction is complete as monitored by TLC; filter, slurry the filter cake with MeOH/DCM (2 mL/10 mL) for two hours, filter, wash the filter cake with ethyl acetate and dry to obtain compound 73A (450 mg, yellow solid).

Step 3: Add compound 73A (0.45 g, 1.2 mmol), hydrofluoric acid pyridine (0.36 g, 3.6 mmol) and tetrahydrofuran (15 mL) to the reaction bottle, stir at room temperature for 7 hours until the reaction is complete, filter, and slurry the filter cake with MeOH/DCM (2 mL/10 mL) overnight, filter, and wash the filter cake with ethyl acetate and dry to give the title compound 73 (284 mg, yellow solid).

MS m/z(ESI):265[M+1] ⁺

¹ H NMR (400MHz, DMSO-d6) δ13.02(s,1H),9.69(dd,J＝2.2,1.3Hz,1H),9.45(dd,J＝5.3,1.1Hz,1H),8.15(dd ,J＝5.3,2.2Hz,1H),4.83(s,1H),3.57(dt,J＝10.2,4.2Hz,2H),2.79(t,J＝6.4Hz,2H),2.22(s,3H) .

Example 47: Synthesis of N-(5-(2-hydroxyethyl)-4-methylthiazol-2-yl)pyridazine-3-carboxamide (Compound 74)

The title compound 74 (off-white solid) was prepared by the same synthetic route as in Example 46, except that the raw material pyridazine-4-carboxylic acid in the step of Example 46 was replaced by pyridazine-3-carboxylic acid.

MS m/z(ESI):265[M+1] ⁺

¹ H NMR (400MHz, DMSO-d6) δ12.32 (s, 1H), 9.46 (d, J = 4.4Hz, 1H), 8.29 (d, J = 8.5Hz, 1H), 7.97 (dd, J = 8.3 ,5.1Hz,1H),4.84(d,J＝4.9Hz,1H),3.58(d,J＝5.6Hz,2H),2.83(s,2H),2.23(s,3H).

Example 48: Synthesis of 2-(3-fluorophenyl)-N-(5-(2-hydroxyethyl)-4-methylthiazol-2-yl)acetamide (Compound 75)

Step 1: Using the method of Step 1 and Step 2 of Example 46, replace pyridazine-4-carboxylic acid with 2-(3-fluorophenyl)acetic acid to obtain Compound 75A, and directly proceed to the next step.

Step 2: Add concentrated HCl to the reaction flask, adjust pH to 3-4, and stir at room temperature for 2 hours until the reaction is complete. Filter the reaction solution, and directly prepare and purify the filtrate to obtain the title compound 75 (294 mg, white solid)

MS m/z(ESI):295[M+1] ⁺

¹ H NMR (400MHz, DMSO-d6) δ12.09 (s, 1H), 7.36 (td, J = 8.1, 6.2Hz, 1H), 7.20–7.03 (m, 3H), 4.75 (s, 1H), 3.73 (s,2H),3.50(t,J＝6.6Hz,2H),2.74(t,J＝6.6Hz,2H),2.16(s,3H).

Example 49: Synthesis of N-(5-(2-chloroethyl)-4-methylthiazol-2-yl)-2-(3-fluorophenyl)acetamide (Compound 76)

Steps: Add compound 75 (294 mg, 1.0 mol) and DCM (5 mL) to a reaction flask, place the reaction flask in an ice bath, add thionyl chloride (357 mg, 3.0 mol) dropwise, monitor the reaction completion by TLC spot plate, and concentrate to dryness to obtain the title compound 76 (125 mg, brown oily liquid).

MS m/z(ESI):313[M+1] ⁺

¹ H NMR (400MHz, DMSO-d6) δ12.19 (s, 1H), 7.36 (td, J＝8.1, 6.3Hz, 1H), 7.17–7.12 (m, 2H), 7.08 (td, J＝8.8, 2.3Hz, 1H), 3.79–3.70 (m, 4H), 3.09 (t, J = 6.6Hz, 2H), 2.18 (s, 3H).

Example 50: Synthesis of 2-(4-methyl-2-((2-methylpyrimidin-4-yl)methyl)thiazol-5-yl)ethan-1-ol (Compound 77)

Step 1: Dissolve compound 39D (14.3 g, 100 mmol) in 150 g DCM, stir, add imidazole (13.6 g, 200 mmol), TBSCl (10.2 g, 150 mmol); stir at 25 °C for 16 hours, wash with water, add DCM to extract the organic phase; purify by column to obtain compound 77A (17.1 g, oily liquid).

Step 2: Dissolve compound 77b (5.52 g, 40 mmol) in 300 g DCM, stir, add N,O-dimethylhydroxylamine (3.66 g, 60 mmol), DIPEA (10.4 g, 80 mmol); HATU (30.4 g, 80 mmol), stir at 25°C for 16 hours, and purify by column to obtain compound 77B (7.5 g, oily liquid).

Step 3: Dissolve compound 77B (7.0 g) in 80 mL of tetrahydrofuran, cool to -40°C with stirring, and protect with nitrogen; add butyl lithium (1.7 g, 27 mmol), stir at -40°C for 1 hour, add compound 77A (7 g, 27 mmol), stir and react at -40°C to 0°C for two hours; then add saturated ammonium chloride solution to quench, extract with ethyl acetate, and then purify by column to obtain compound 77C (5.1 g, oily liquid).

Step 4: Add compound 77C (1.1 g, 0.003 mol.), hydrazine hydrate (3.3 g), potassium hydroxide (0.84 g, 0.015 mol) and ethylene glycol (10 mL) into a 250 mL three-necked flask, heat to 180 ° C and reflux with stirring for 2 hours; after the reaction is completed, add water to quench the reaction, extract with DCM, separate the organic phase with silica gel column, wash out the product with DCM: MeOH = 10:1, concentrate under reduced pressure to obtain the crude product, then prepare separation, and freeze-dry to obtain the title compound 77 (0.1 g, white solid).

MS m/z(ESI):250[M+1] ⁺

¹ H NMR (400MHz, DMSO-d6) δ8.61 (d, J = 5.1Hz, 1H), 7.27 (d, J = 5.1Hz, 1H), 4.30 (s, 2H), 3.51 (t, J = 6.5 Hz, 2H), 2.79 (t, J = 6.5Hz, 3H), 2.58 (s, 3H), 2.21 (s, 3H).

Example 51: Synthesis of (5-(2-hydroxyethyl)-4-methylthiazol-2-yl)(2-methylpyrimidin-4-yl)methanone (Compound 78)

Steps: Dissolve compound 77C (1.7 g) in 50 mL of tetrahydrofuran under nitrogen protection; add 2.3 g of pyridine hydrogen fluoride, stir at 20°C for 2 hours, then purify by column to obtain 0.44 g of crude product, prepare and purify, and lyophilize to obtain the title compound 78 (0.073 g, off-white solid).

MS m/z(ESI):264[M+1] ⁺

¹ H NMR (400MHz, DMSO-d6) δ9.00 (dd, J＝5.2, 2.2Hz, 1H), 7.89 (d, J＝4.9Hz, 1H), 4.97 (t, J＝5.3Hz, 1H), 3.65(q,J＝5.9Hz,2H), 3.01(td,J＝6.2,2.2Hz,2H), 2.73(d,J＝2.1Hz,3H), 2.39(d,J＝2.1Hz,3H).

Example 52: Synthesis of N-(5-(2-hydroxyethyl)-4-methylthiazol-2-yl)-4-phenylbutanamide (Compound 79)

Step 1: Add compound 62A (2.7 g, 0.01 mol), HATU (3.8 g, 0.01 mol) and DCM (20 mL) to a reaction flask, stir at room temperature for half an hour, then add compound 79a (1.6 g, 0.01 mmol) and DIPEA (1.3 g, 0.01 mmol) and continue stirring until the reaction is complete as monitored by TLC. Directly proceed to the next step.

Step 2: Add HCl to the reaction flask, adjust the pH to 3-4, and stir at room temperature for 2 hours until the reaction is complete; filter the reaction solution, and directly prepare and purify the filtrate to obtain the title compound 79 (0.99 g, white solid).

MS m/z(ESI):305[M+1] ⁺

¹ H NMR (400MHz, DMSO-d6) δ11.78 (s, 1H), 7.31–7.23 (m, 2H), 7.18 (dd, J = 7.9, 2.2Hz, 3H), 4.76 (t, J = 5.3Hz ,1H),3.56–3.47(m,2H),2.75(t,J＝6.6Hz,2H),2.57(t,J＝7.7Hz,2H),2.38(t,J＝7.4Hz,2H),2.15 (s,3H),1.87(q,J=7.6Hz,2H).

Example 53: Synthesis of N-(5-(2-chloroethyl)-4-methylthiazol-2-yl)-4-phenylbutanamide (Compound 80)

Steps: Add compound 79 (210 mg, 0.69 mmol.) and DCM (10 mL) to a reaction flask, place the reaction flask in an ice bath, add thionyl chloride (0.41 g, 3.45 mmol) dropwise, and monitor the completion of the reaction using a TLC spot plate; concentrate to dryness, and the obtained brown-yellow oil is used to prepare the title compound 80 (76 mg, yellow solid) using a liquid phase.

MS m/z(ESI):323[M+1] ⁺

¹ H NMR (400MHz, DMSO-d6) δ11.89(s,1H),7.27(t,J＝7.5Hz,2H),7.21–7.13(m,3H),3.75(t,J＝6.7Hz,2H ),3.09(t,J＝6.7Hz,2H),2.58(t,J＝7.7Hz,2H),2.40(t,J＝7.4Hz,2H),2.17(s,3H),1.87(p,J =7.5Hz,2H).

Example 54: Synthesis of 2-(2,7-dimethyl-5H-pyridyl[4,5-d]thiazolo[3,2-a]pyrimidin-8-yl)ethanol)formamide (Compound 89)

Steps: Dissolve compound 82a (5.0 g, 14.8 mmol) in 20 g of ethanol; cool in an ice bath, add sodium ethoxide (2.0 g, 29.6 mmol), and stir for 0.5 hour; filter, concentrate the filtrate, add 20 g of acetonitrile to the residue, add 4,4'-dinitrodiphenyl disulfide (4.6 g, 14.8 mmol), stir at room temperature for 3 hours, heat to reflux and stir for 3 hours; filter, concentrate the filtrate to prepare the title compound 89 (0.04 g, yellow solid).

MS m/z(ESI):263[M+1] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ8.01 (s, 1H), 5.24 (s, 2H), 3.68 (t, J = 5.9Hz, 2H), 2.76 (t, J = 5.9Hz, 2H), 2.44(d,J＝2.7Hz,3H),2.21(s,3H).

Example 55: Synthesis of 3-((4-amino-2-methylpyrimidin-5-yl)methyl)-5-(2-(benzoyloxy)ethyl)-4-methylthiazole-3-bromide amine salt (Compound 91)

Step 1: Add compound 39D (7.2 g, 0.05 mol) and DCM (50 ml) into a 100 ml single-necked bottle, add triethylamine (6.1 g, 0.06 mol) under stirring, and then add compound benzoyl chloride (7.0 g, 0.05 mol) dropwise under stirring. After the addition is complete, stir at room temperature overnight; distill off the solvent under reduced pressure at 50°C, and quickly pass through a column to obtain compound 91A (3.7 g, colorless transparent liquid).

Step 2: Add compound 91A (3.7 g), acetonitrile (3.7 g) and DMF (13.0 g) into a 250 ml single-mouth bottle, add compound 39b (2.3 g, 0.00925 mol) under stirring, keep stirring at 100-110°C for 3 hours; cool to room temperature, the product precipitates, filter, add methanol (15 mL) to the filter cake, slurry, filter, and dry the filter cake in vacuo at 40°C to obtain the title compound 91 (3.5 g, light yellow solid).

MS m/z(ESI):369[M] ⁺

¹ H NMR (500MHz, DMSO-d6) δ9.99 (s, 1H), 9.40–8.63 (m, 2H), 8.42 (s, 1H), 8.16–7.88 (m, 2H), 7.70 (t, J＝ 7.4Hz,1H),7.57(t,J＝7.8Hz,2H),5.57(s,2H),4.50(t,J＝5.8Hz,2H),3.51(t,J＝5.8Hz,2H),2.59 (s,3H),2.56(s,3H).

Example 56: Synthesis of 4-methyl-3-(2-oxo-2-phenylethyl)-5-(2-(phosphoryloxy)ethyl)thiazol-3-yl hydrochloride (Compound 94)

Steps: Add compound 95 (3.4 g, 0.01 mol) and toluene (20 mL) to the reaction bottle, stir evenly, add pyrophosphoric acid (8.9 g, 0.05 mol), heat to 110°C, stir for 3 hours, reduce the temperature to 60-70°C, add concentrated hydrochloric acid (10 mL), stir for 16 hours; separate toluene, add 50 mL of acetone to the aqueous phase, stir, and cool to 25°C, filter, purify the filter cake with preparative liquid phase, collect the target component and lyophilize to obtain the title compound (2.3 g, white solid).

MS m/z(ESI):342[M] ⁺

¹ H NMR (400MHz, D ₂ O) δ9.63 (d, J = 2.1Hz, 1H), 8.00–7.94 (m, 2H), 7.73–7.66 (m, 1H), 7.53 (t, J = 8.0Hz ,2H),4.01(q,J＝6.0Hz,2H),3.19(t,J＝5.8Hz,2H),2.27(d,J＝2.4Hz,3H).

Example 57: Synthesis of 5-(2-hydroxyethyl)-4-methyl-3-(2-oxo-2-phenylethyl)thiazol-3-yl bromide (Compound 95)

Steps: Add compound 39D (1.58 g, 0.011 mol), compound 95b (2.0 g, 0.01 mol) and tetrahydrofuran (10 mL) into a reaction flask. Heat the resulting reaction solution to reflux, stir for 2 hours, cool to room temperature, filter, and dry the filter cake to obtain the title compound 95 (1.1 g, off-white solid).

MS m/z(ESI):262[M] ⁺

¹ H NMR (400MHz, DMSO-d6) δ9.99 (s, 1H), 8.06 (d, J = 7.7Hz, 2H), 7.78 (t, J = 7.3Hz, 1H), 7.65 (t, J = 7.6 Hz,2H),6.41(s,2H),5.26(t,J＝4.9Hz,1H),3.67(q,J＝5.3Hz,2H),3.06(t,J＝5.6Hz,2H),2.33( s,3H).

Example 58: Synthesis of 5-(2-hydroxyethyl)-4-methyl-3-(2-oxopropyl)thiazol-3-yl bromide (Compound 96)

Steps: Compound 39D (1.43 g, 10.0 mmol), tetrahydrofuran (10 mL) and 96b (1.44 g, 10.5 mmol) were added to a reaction flask in sequence; the resulting reaction solution was refluxed at 80°C for 4 hours, cooled to room temperature, acetonitrile was added for slurrying, filtered, the filter cake was rinsed with acetonitrile, and vacuum dried to obtain the title compound 96 (2.5 g, off-white solid).

MS m/z(ESI):200[M] ⁺

¹ H NMR (400MHz, DMSO-d6) δ9.92 (s, 1H), 5.75 (s, 2H), 3.63 (t, J = 5.3Hz, 2H), 3.03 (t, J = 5.2Hz, 2H), 2.30(d,J＝8.5Hz,6H).

Biological tests

In the following examples, comparative example 1 was tested without adding the test sample stock solution, and the culture medium was used as a blank control to perform biological tests, and the results are listed in Table 1.

Experimental materials and methods

(1) BCA protein concentration determination kit was purchased from Biotech, Aβ40 and Aβ42 detection kits were purchased from Wako, and cell culture-related reagents were purchased from Gibico.

(2) HEK293APP/sw overexpressing cell culture: The cells were cultured in a 48-well plate with DMEM culture medium (containing 10% FBS, 100 μg/mL G418 (Geneticin) and double antibody). When the cell density was 70%, 4 mM test sample stock solution (the test sample was dissolved in DMEM culture medium) was taken and diluted to 400 μM with DMEM culture medium. 500 μL was added to each well and cultured for 24 hours.

(3) Take the culture supernatant and add BCA reagent to incubate at room temperature for 30 minutes. Then measure the absorbance of each well at OD570 nm on a microplate reader and calculate the total protein concentration based on the protein standard curve. At the same time, take the supernatant to determine the concentration of Aβ40 and/or Aβ42. Add the supernatant to the coated 96-well plate and incubate overnight at 4°C. After removing and washing the reagent, add HRP (horseradish oxidase) labeled antibody and incubate at 4°C for 2 hours. After removing and washing the reagent, add TMB colorimetric solution and incubate at room temperature for 30 minutes. After adding the stop solution to terminate the reaction, measure the absorbance of each well at OD450 nm on a microplate reader and calculate the concentration of Aβ40 and/or Aβ42 based on the standard curve of Aβ40 and/or Aβ42. Finally, adjust the concentration of Aβ40 and/or Aβ42 with the total protein concentration to obtain the final concentration.

According to the above experimental results, compared with the blank of comparative example 1, Aβ42 and/or Aβ40 in all examples were reduced, indicating that the thiamine compounds of the example structures have an inhibitory effect on Aβ42 and/or Aβ40.

Claims (10)

1. Use of a substance A in the preparation of a drug, characterized in that the drug is a drug for treating and/or preventing diseases mediated by Aβ40 and/or Aβ42 proteins or a drug for treating and/or preventing neurodegenerative diseases, Alzheimer's disease or aging, The substance A is a compound shown in the following formula I, formula II or formula III or a pharmaceutically acceptable salt thereof, wherein R ³ is independently phenyl, phenyl substituted by one or more R ^1a , 5- to 10-membered heteroaryl, or 5- to 10-membered heteroaryl substituted by one or more R ^2a ; the 5- to 10-membered heteroaryl or the 5- to 10-membered heteroaryl substituted by one or more R ^2a contains 1 or 2 N atoms; R ⁴ is independently C _1-4 alkyl, phenyl, phenyl substituted by one or more R ^1a , 5- to 10-membered heteroaryl, or 5- to 10-membered heteroaryl substituted by one or more R ^2a ; wherein the 5- to 10-membered heteroaryl or the 5- to 10-membered heteroaryl substituted by one or more R ^2a contains 1 or 2 N atoms; R ^1a and R ^2a are independently halogen, C _1-4 alkyl, C _1-4 alkyl substituted by one or more R ^b1 , -N(R ^b2 R ^b3 ), -C(═O)-N(R ^b2 R ^b3 ) or -C(═O)-OR ^b4 ; R ^b1 is independently halogen or C _1-4 alkyl; R ^b2 , R ^b3 and R ^b4 are independently H or C _1-4 alkyl; or R ^b2 and R ^b3 together with the attached N form a 4-7 membered heterocycloalkyl or a 4-7 membered heterocycloalkyl substituted by one or more R ^{b5; the 4-7 membered heterocycloalkyl or the 4-7 membered heterocycloalkyl substituted by one or more R b5 contains} 1 or 2 N atoms; R ^b5 is independently halogen, C _1-4 alkyl, or C _1-4 alkyl substituted by one or more R ^b6 ; R ^b6 is independently halogen or phenyl; L ¹ and L ² are independently NH, methylene, -C(=O)-, -C(=O)-NH-, -C(=O)-(CH ₂ )-, or -(C _1-4 alkylene)-C(=O)-NH-; R ¹ and R ² are independently R ¹² -(C _1-4 alkylene)o-; o is 0 or 1; ^R12 is independently halogen, OH, N( ^{Rb2Rb3 )} , -C(=O)-N ^{(Rb2Rb3 )} , -C(=O) ^-ORb4 , -OC(=O) ^-Rb7 or R ^b7 is independently C _1-4 alkyl or phenyl; X- ^is a halogen anion. 2. The application according to claim 1, characterized in that the application satisfies one or more of the following conditions: (1) R ³ and R ⁴ are independently 5- to 10-membered heteroaryl or a 5- to 10-membered heteroaryl in a 5- to 10-membered heteroaryl substituted by one or more R ^2a , wherein the 5- to 10-membered heteroaryl or a 5- to 10-membered heteroaryl in a 5- to 10-membered heteroaryl substituted by one or more R ^2a is independently a 6-membered heteroaryl containing 1 or 2 nitrogen atoms; for example, pyridyl, pyrimidinyl or pyridazinyl; for example (2) R ^1a , R ^2a , R ^b1 , R ^b5 , R ^b6 and R ¹² are independently halogen, wherein the halogen is independently fluorine, chlorine or bromine; for example, fluorine or chlorine; (3) ^R4 , ^Rb1 , ^Rb2 , ^Rb3 , ^Rb4 and ^Rb7 are independently _C1-4 alkyl, ^R1a and ^R2a are independently _C1-4 alkyl or _C1-4 alkyl substituted by one or more ^Rb1 , ^Rb5 is independently _C1-4 alkyl or _C1-4 alkyl substituted by one or more ^Rb6 , and the _C1-4 alkyl is independently methyl, ethyl, n _- propyl, isopropyl, n _- butyl, isobutyl, sec-butyl or tert-butyl, such as methyl or ethyl; (4) R ^b2 and R ^b3 together with the attached N form a 4-7 membered heterocycloalkyl group or a 4-7 membered heterocycloalkyl group substituted by one or more R ^b5 , wherein the 4-7 membered heterocycloalkyl group is independently a piperidinyl group, for example (5) ^L1 and ^L2 are independently C1-4 alkylene in -( _C1-4 alkylene)-C(=O) _-NH- , ^R1 and ^R2 are independently _C1-4 alkylene in ^R12- ( _C1-4 alkylene)o-; the _C1-4 alkylene is independently _-CH2- , _-CH2CH2- , _-CH ( _CH3 )-, _-CH ( _CH3 ) _CH2- or -C( _CH3 ) _2- , for example _-CH2- or _-CH2CH2- ; (6) X- ^is a Br anion. 3. The application according to claim 1, characterized in that the application satisfies one or more of the following conditions: (1) R ^b2 , R ^b3 and R ^b4 are independently H, methyl or ethyl; for example, -N(R ^b2 R ^b3 ) is independently -NH ₂ ; -C(＝O)-N(R ^b2 R ^b3 ) is independently -C(＝O)-NH ₂ , -C(＝O)-N(CH ₃ )H or -C(＝O)-N(CH ₃ ) ₂ ; -C(＝O)-OR ^b4 is independently -C(＝O)-OH, -C(＝O)-OC ₂ H ₅ , -C(＝O)-O-CH ₃ ; (2) R ^b5 is independently a C _1-4 alkyl group substituted by one or more R ^{b6 groups} , such as benzyl; (3) When ^Rb2 and ^Rb3 together with the attached N form a 4-7 membered heterocycloalkyl or a 4-7 membered heterocycloalkyl substituted with one or more ^Rb5 , ^Rb2 and ^Rb3 together with the attached N form (4) R ³ is a 5- to 10-membered heteroaryl group or a 5- to 10-membered heteroaryl group substituted by one or more R ^2a ; (5) R ⁴ is independently C _1-4 alkyl, phenyl or a 5- to 10-membered heteroaryl substituted by one or more R ^2a ; (6) R ¹ and R ² are independently R ¹² , R ¹² (CH ₂ )- or R ¹² (CH ₂ ) ₂ -; (7) When ^L1 is independently NH, ^R12 is independently halogen, OH, N( ^Rb2Rb3 ), -C(=O)-N ^{(Rb2Rb3 )} , ^-OC (=O) ^-Rb7 or (8) When ^L2 is independently methylene, ^R12 is independently halogen, N( ^{Rb2Rb3 )} , -C(=O)-N ^{(Rb2Rb3 )} , -OC(=O) ^-Rb7 or 4. The application according to claim 1, characterized in that the application satisfies one or more of the following conditions: (1) R ¹² is independently F, Cl, OH, -C(=O)-OC ₂ H ₅ , -C(=O)-N(CH ₃ )H, -C(=O)-N(CH ₃ ) ₂ , For example, ^R1 and ^R2 are independently -( _CH2 )-Cl, -( _CH2 )-OH, -C(=O) _-OC2H5 , -C(=O)-N( _CH3 )H, -C( ₌ O)-N( _CH3 ) ₂ , -(CH ₂ ) ₂ -Cl, -(CH ₂ ) ₂ -OH, -(CH ₂ ) ₂ -F or (2) L ¹ and L ² are independently NH, methylene, -C(=O)-, -C(=O)-NH-, -(CH ₂ )-C(=O)-NH-, or -(CH ₂ ) ₃ -C(=O)-NH-; (3) R ³ and R ⁴ are independently Or R ⁴ is independently methyl. 5. The use according to claim 1, characterized in that, wherein the substance A is any of the following: Solution (1) In Formula I, R ³ is 5- to 10-membered heteroaryl or 5- to 10-membered heteroaryl substituted by one or more R ^2a ; R ^2a is independently halogen, C _1-4 alkyl, -N(R ^b2 R ^b3 ), -C(═O)-N(R ^b2 R ^b3 ), or -C(═O)-OR ^b4 ; R ^b2 , R ^b3 and R ^b4 are independently H or C _1-4 alkyl; or R ^b2 and R ^b3 together with the attached N form a 4-7 membered heterocycloalkyl or a 4-7 membered heterocycloalkyl substituted by one or more R ^b5 ; R ^b5 is independently C _1-4 alkyl substituted by one or more R ^b6 ; R ^b6 is independently phenyl; L ¹ is NH, methylene or -C(=O)-; R ¹ is R ¹² -(C _1-4 alkylene)o-; o is 0 or 1; ^R12 is independently halogen, OH, N( ^{Rb2Rb3 )} , -C(=O)-N ^{(Rb2Rb3 )} or Solution (2) In formula I, R ³ is phenyl or phenyl substituted by one or more R ^1a ; R ^1a is independently halogen, C _1-4 alkyl, or C _1-4 alkyl substituted by one or more R ^b1 ; R ^b1 is independently halogen; ^L1 is NH or -( _C1-4alkylene )-C(=O)-NH-; R ¹ is R ¹² -(C _1-4 alkylene)o-; o is 0 or 1; R ¹² is independently halogen, OH or -C(=O)-OR ^b4 ; R ^b4 is independently H or C _1-4 alkyl; Solution (3) In Formula II, R ⁴ is C _1-4 alkyl, phenyl, 5- to 10-membered heteroaryl, or 5- to 10-membered heteroaryl substituted by one or more R ^2a ; R ^2a is independently C _1-4 alkyl or -N(R ^b2 R ^b3 ); R ^b2 and R ^b3 are independently H; L ² is methylene or -C(=O)-(CH ₂ )-; R ² is R ¹² -(C _1-4 alkylene)o-; o is 0 or 1; ^R12 is halogen, OH, -OC(=O) ^-Rb7 or R ^b7 is independently C _1-4 alkyl or phenyl; X- ^is a halogen anion. 6. The use according to claim 1, characterized in that the substance A is any of the following structures: 7. A thiazole compound or a pharmaceutically acceptable salt thereof, as shown in Formula I, Formula II or Formula III: wherein R ¹ , R ² , R ³ , R ⁴ , L ¹ , L ² and X ^- are as defined in any one of claims 1 to 6; and In Formula I, R ³ is 5- to 10-membered heteroaryl or 5- to 10-membered heteroaryl substituted by one or more R ^2a ; R ^2a is independently halogen, C _1-4 alkyl, -N(R ^b2 R ^b3 ), -C(═O)-N(R ^b2 R ^b3 ), or -C(═O)-OR ^b4 ; R ^b5 is independently C _1-4 alkyl substituted by one or more R ^b6 ; R ^b6 is independently phenyl; ^L1 is NH, ^{methylene or -C(=O)-; R12 is independently halogen, OH, N(Rb2Rb3 ) ,} -C(=O)-N ^{(Rb2Rb3 )} or when for When R ^b2 is C _1-4 alkyl, R ^b3 is independently H or C _1-4 alkyl; or R ^b2 and R ^b3 together with the attached N form a 4-7 membered heterocycloalkyl or a 4-7 membered heterocycloalkyl substituted by one or more R ^b5 ; the 4-7 membered heterocycloalkyl or the 4-7 membered heterocycloalkyl substituted by one or more R ^b5 contains 1 or 2 N atoms; or, In Formula I, R ³ is phenyl or phenyl substituted by one or more R ^1a ; R ^1a is independently halogen, C _1-4 alkyl, or C _1-4 alkyl substituted by one or more R ^b1 ; R ^b1 is independently halogen; ^L1 is NH or -( _C1-4alkylene )-C(=O)-NH-; R ¹ is R ¹² -(C _1-4 alkylene)o-; o is 0 or 1; ^R12 is independently halogen, OH, N( ^{Rb2Rb3 )} , -C(=O) ^-ORb4 or In Formula II, R ⁴ is C _1-4 alkyl, phenyl, 5- to 10-membered heteroaryl, or 5- to 10-membered heteroaryl substituted by one or more R ^2a ; R ^2a is independently C _1-4 alkyl or -N(R ^b2 R ^b3 ); R ^b2 and R ^b3 are independently H; L ² is methylene or -C(=O)-(CH ₂ )-; ^R12 is halogen, -OC(=O) ^-Rb7 or R ^b7 is independently C _1-4 alkyl or phenyl; X- ^is a halogen anion. 8. A thiazole compound or a pharmaceutically acceptable salt thereof, The thiazole compound is selected from the following structures: 9. A pharmaceutical composition comprising a therapeutically effective amount of the thiazole compound or a pharmaceutically acceptable salt thereof according to claim 7 or 8 and a pharmaceutical excipient. 10. Use of the substance A according to any one of claims 1 to 6 in the preparation of an Aβ40 and/or Aβ42 protein inhibitor.