CN110437220B

CN110437220B - Triazole compound and application thereof

Info

Publication number: CN110437220B
Application number: CN201910626136.6A
Authority: CN
Inventors: 蔡倩; 涂正超; 张章; 刘吉生; 陈琛; 王雨婷
Original assignee: Jinan University
Current assignee: Jinan University
Priority date: 2018-07-13
Filing date: 2019-07-11
Publication date: 2022-12-27
Anticipated expiration: 2039-07-11
Also published as: CN110437220A

Abstract

The invention provides a triazole compound with a structure shown in a formula (A) or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a prodrug molecule thereof, or a metabolite thereof or a solvate thereof, the triazole compound can effectively inhibit kinase, especially FLT3 kinase, and further regulate the activation of multiple downstream pathways, and can be used for preparing medicines for preventing and treating various diseases related to FLT3 kinase, such as leukemia, tumors, psoriasis, prostatic hyperplasia and metabolic diseases.

Description

Triazole compound and application thereof

Technical Field

The invention relates to the field of medicinal chemistry, and particularly relates to a triazole compound and application thereof.

Background

The protein kinase can catalyze the phosphorylation of hydroxyl at tyrosine, serine and threonine residues in proteins, plays an important role in cell signal transduction pathways, and manages and controls a series of important cell functions. Excessive or inappropriate expression of protein kinases plays an important role in the development and progression of many diseases. Aiming at protein kinase, small molecule inhibitors are developed, and have special application in treating diseases.

FLT3 (Fms-like tyrosine kinase 3, also called Flk 2), fms-like tyrosine kinase 3, is a member of the PDGFR (the platelet growth factor receptor) family and belongs to type iii receptor tyrosine kinase. FLT3 plays an important regulatory role in proliferation and differentiation of blood stem cells. In Acute Myeloid Leukemia (AML), activating mutations or overexpression of FLT3 was found (Heinrich Mini-Reviews in Medicinal Chemistry (2004) 4 (3): 255-271, kiyoi et al. Int J Hemato (2005) 82.

The most common FLT3 mutation is an internal tandem repeat (internal tandem duplication) mutation. In addition, some other important mutations occur in the Tyrosine Kinase Domain (TKD), mainly point mutations in the activation loop (PM point mutations). These mutations cause FLT3 autophosphorylation, thereby activating downstream signaling, leading to a poorer clinical prognosis for leukemia patients with such mutations.

At present, kinase inhibitors have become an important means for treating some related diseases. Inhibition of the activity of some key kinases is an important approach to cure the associated disease or slow the progression of the disease. Targeted inhibition against wild-type and mutant FLT3 has also been a hotspot. Significant progress has been made as a targeted drug for the treatment of acute myeloid leukemia by the development of small molecule tyrosine kinase inhibitors that compete with FLT3 kinase for ATP binding sites to inhibit its activity. At present, a plurality of FLT3 kinase small-molecule inhibitors enter clinical research, including Quizartinib and the like. However, in treatment, patients are found to develop certain drug resistance to the drugs. In addition, the existing drugs such as Quizartinib and the like have large side effects. Therefore, the novel FLT3 kinase small molecule inhibitor is developed to treat related diseases such as acute myeloid leukemia and the like, and has a larger research space.

Disclosure of Invention

Aiming at the problems, the invention provides a novel triazole compound which has better inhibitory activity on FLT3 kinase.

The specific technical scheme is as follows:

a triazole compound having a structure represented by formula (a) or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, or a metabolite thereof, or a solvate thereof:

wherein X, Y are each independently selected from: c or N;

z is selected from: -C (R) ⁶ ) ₂ -、-NR ⁶ -、-C(R ⁶ )＝C(R ⁶ ) Or without any atoms;

ar1 and Ar2 are respectively and independently selected from: an aromatic or heteroaromatic ring;

R ¹ selected from: hydrogen, halogen, aryl, C _1-12 Alkyl, halogen substituted C _1-12 Alkyl radical, C _1-12 Alkoxy, amino substituted C _1-12 Alkoxy radical, C _1-12 Alkylamino substituted C _1-12 Alkoxy radical, C _1-12 Alkylamino radical, C _1-12 Alkanoyl, amino substituted C _1-12 Alkyl, heterocyclyl substituted C _1-12 Alkoxy, aminosulfonyl, C _1-12 Aminocarbonyl group, C _1-12 Alkyl amino sulfone group, C _1-12 Alkylthio radical, C _1-12 Alkyl sulfoxide group, C _1-12 Alkyl sulfone group, C _1-12 Alkyl-substituted aryl, C _1-12 Alkyl-substituted heteroaryl, C _1-12 Alkylaryl carbonyl, C _3-7 Cycloalkyl radical, C _3-7 Heterocycloalkyl radical, C _3-7 Heterocyclic ringsAlkoxy radical, C _3-7 Heterocyclic aminoacyl, C _2-12 Alkenyl-substituted C _1-12 Alkyl, alkynyl substituted C _1-12 Alkyl, nitro, sulfonate, ester, C _3-7 Heterocycloalkyl-substituted C _1-12 Alkylamino radical, C _1-12 Alkylamino substituted C _1-12 Alkylamino wherein aryl and heterocycloalkyl are optionally substituted with 0-3R ³ Substituted by groups;

R ² selected from: hydrogen, halogen, cyano, amido, sulfonamido, C _1-12 Alkyl, halogen substituted C _1-12 Alkyl radical, C _1-12 Alkoxy, amino substituted C _1-12 Alkoxy radical, C _1-12 Alkylamino radical, C _1-12 Alkanoyl, amino substituted C _1-12 Alkyl, aminosulfonyl, C _1-12 Aminocarbonyl group, C _1-12 Alkyl amino sulfone group, C _1-12 Alkylthio radical, C _1-12 Alkyl sulfoxide group, C _1-12 Alkylsulfonyl radical, C _1-12 Alkyl-substituted aryl, C _1-12 Alkyl-substituted heteroaryl, C _3-7 Heterocycloalkyl, C _3-7 Heterocyclic alkoxy radical, C _3-7 Heterocyclic aminoacyl, aryl mercapto, aryl sulfoxide, aryl sulfone, C _1-12 Amide group, C _2-12 Alkenyl substituted C _1-12 Alkyl, alkynyl substituted C _1-12 Alkyl, ester groups, wherein aryl and heterocycloalkyl are optionally substituted with 0-3R ¹ Substituted by groups;

R ³ selected from: hydrogen, halogen, aryl, trifluoromethyl, C _1-12 Alkyl, halogen substituted C _1-12 Alkyl radical, C _1-12 Alkoxy, amino substituted C _1-12 Alkoxy radical, C _1-12 Alkylamino radical, C _1-12 Alkanoyl, amino substituted C _1-12 Alkyl, aminosulfonyl, C _1-12 Aminocarbonyl group, C _1-12 Alkyl amino sulfone group, C _1-12 Alkylthio radical, C _1-12 Alkyl sulfoxide group, C _1-12 Alkyl sulfone group, C _1-12 Alkyl-substituted aryl, C _1-12 Alkyl-substituted heteroaryl, C _3-7 Heterocycloalkyl, C3-7 heterocycloalkoxy, C _3-7 Heterocyclic aminoacyl, C _2-12 Alkenyl-substituted C _1-12 Alkyl, alkynyl substituted C _1-12 Alkyl, nitro, sulfonate, ester groups, wherein aryl and heterocycloalkyl are optionally substituted with 0-3R ¹ Substituted by groups;

R ⁴ selected from: substituted or unsubstituted five to seven membered heterocyclic, heteroaromatic, fused heteroaromatic, aromatic ring;

R ⁶ selected from: hydrogen, C _1-12 An alkyl group.

In some embodiments, ar1 and Ar2 are each independently selected from: c _6-10 Aromatic ring or C _5-10 A heteroaromatic ring.

In some embodiments, ar1 and Ar2 are each independently selected from: a benzene ring, a naphthalene ring, a pyridine ring, a benzopyridine ring, a pyrimidine ring, a benzothiazole ring, an indole ring, a quinoline ring, an isoquinoline ring, a pyridazine ring, a benzopyrazolidine ring, a benzimidazole ring, a benzotriazol ring, a benzofuran ring, a pyridopyrazole ring, a pyridoimidazole ring, a pyridothiazole ring.

In some of these embodiments, Z is selected from: -NR ⁶ -；R ⁶ Selected from: hydrogen, C _1-6 An alkyl group.

In some of these embodiments, the R is characterized ⁴ Selected from the group consisting of formulae (III), (IV), (V), (VI), (VII), (VIII), (IX):

wherein X, Y, Z are each independently selected from: C. n, O, S; r ⁵ Mono-or polysubstituted at any position of the aromatic ring or heterocyclic ring;

R ⁵ selected from: hydrogen, halogen, aryl, C _1-12 Alkyl, halogen substituted C _1-12 Alkyl radical, C _1-12 Alkoxy, amino substituted C _1-12 Alkoxy radical, C _1-12 Alkylamino radical, C _1-12 Alkanoyl, amino substituted C _1-12 Alkyl, aminosulfonyl, C _1-12 Aminocarbonyl group, C _1-12 Alkyl amino sulfone group, C _1-12 Alkylthio radical, C _1-12 Alkyl sulfoxide group, C _1-12 Alkyl sulfone group, C _1-12 Alkyl-substituted aryl, C _1-12 Alkyl-substituted heteroaryl, C _3-7 Heterocycloalkyl radical, C _3-7 Heterocyclic alkoxy radical, C _3-7 Heterocyclic aminoacyl, C _2-12 Alkenyl-substituted C _1-12 Alkyl, alkynyl substituted C _1-12 Alkyl, nitro, sulfonate, ester groups, wherein aryl and heterocycloalkyl are optionally substituted with 0-3R ¹ And (4) substituting the group.

In some of these embodiments, the R ⁴ Selected from the group consisting of:

in some of these embodiments, the R ⁵ Selected from: hydrogen, C _1-12 Alkyl, halo-substituted C _1-12 Alkyl radical, C _1-12 An alkoxy group.

In some of these embodiments, the R ⁵ Selected from: hydrogen, C _1-6 Alkyl, halo-substituted C _1-6 Alkyl radical, C _1-6 An alkoxy group.

In some of these embodiments, the R ⁴ Selected from:

in some of these embodiments, the R ¹ Selected from: hydrogen, halogen, C _1-12 Alkyl, halogen substituted C _1-12 Alkyl, amino substituted C _1-12 Alkoxy radical, C _1-12 Alkylamino substituted C _1-12 Alkoxy radical, C _3-7 Heterocycloalkyl-substituted C _1-12 Alkoxy radical, C _1-12 Alkylamino radical, C _1-12 Alkanoyl group, aminosulfonyl group, C _1-12 Aminocarbonyl group, C _1-12 Alkyl amino sulfone group, C _1-12 Alkyl sulfone group, C _1-12 Alkyl substituted C _6-10 Aryl radical, C _1-12 Alkyl substituted C _5-10 Heteroaryl group, C _1-12 Alkylaryl carbonyl, C _3-7 Cycloalkyl radical, C _3-7 Heterocycloalkyl radical, C _1-12 Alkoxy radical, C _3-7 Heterocyclic alkoxy radical, C _3-7 Heterocyclic aminoacyl, nitro, sulfonate, ester, C _3-7 Heterocycloalkyl-substituted C _1-12 Alkylamino radical, C _1-12 Alkylamino substituted C _1-12 An alkylamino group.

In some of these embodiments, the R ¹ Selected from: hydrogen, halogen, C _1-12 Alkoxy radical, C _1-12 Alkyl, halogen substituted C _1-12 Alkyl radical, C _1-12 Alkylamino substituted C _1-12 Alkoxy radical, C _3-7 Heterocycloalkyl-substituted C _1-12 Alkoxy, sulfonate, ester, nitro, C _3-7 Heterocycloalkyl-substituted C _1-12 Alkylamino radical, C _1-12 Alkylamino substituted C _1-12 An alkylamino group.

In some of these embodiments, the R ¹ Selected from: hydrogen, halogen, C _1-6 Alkoxy radical, C _1-6 Alkyl, halogen substituted C _1-6 Alkyl radical, C _5-6 Heterocycloalkyl-substituted C _1-6 Alkoxy, amino substituted C _1-6 Alkoxy radical, C _1-6 Alkylamino substituted C _1-6 Alkoxy, methanesulfonate, nitro, C _3-7 Heterocycloalkyl-substituted C _1-6 Alkylamino radical, C _1-6 Alkylamino substituted C _1-6 An alkylamino group.

In some of these embodiments, the R ¹ Selected from: hydrogen, halogen, methoxy, trifluoromethoxy, nitro, methyl, 2-morpholinoethoxy, 2-dimethylaminoethoxy, 2-piperidin-1-ylethoxy, methanesulfonate, 2-tetrahydropyrrole-1-ylethoxy, 3-dimethylaminopropoxy, 3-morpholinopropoxy, 2-morpholinoethylamino, 2-dimethylaminoethylamino.

In some of these embodiments, the R ² Selected from: the R is ² Selected from: hydrogen, halogen, cyano, C _1-12 Alkylthio radical, C _1-12 Alkyl sulfonyl, amide, sulfonamido.

In some of these embodiments, the R ² Selected from: hydrogen, halogen, cyano、C _1-6 Alkylthio radical, C _1-6 An alkylsulfonyl group.

In some of these embodiments, the R ² Selected from: hydrogen, halogen, cyano, methylthio, methylsulfonyl.

In some of these embodiments, the R ³ Selected from the group consisting of: hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 An alkoxy group.

In some of these embodiments, the R ³ Selected from: hydrogen, halogen, methoxy, methyl.

In some of these embodiments, Z is NH;

ar1 and Ar2 are both benzene rings;

R ⁴ selected from:

R ¹ selected from the group consisting of: hydrogen, 2-morpholinoethoxy, 2-dimethylaminoethoxy, 2-piperidin-1-ylethoxy, halogen, methoxy, nitro, methyl, 3-dimethylaminopropoxy, 3-morpholinopropoxy;

R ² selected from: hydrogen, halogen, cyano, methylthio, methylsulfonyl;

R ³ selected from: hydrogen, halogen, methoxy, methyl.

In some of these embodiments, the triazole compound is selected from the following compounds:

the invention also provides application of the compound.

The specific technical scheme is as follows:

the triazole compound or the pharmaceutically acceptable salt thereof, or the stereoisomer thereof, or the prodrug molecule thereof, or the metabolite thereof, or the solvate thereof is applied to the preparation of a kinase inhibitor.

In some of these embodiments, the kinase is FLT3 kinase.

In some of these embodiments, the FLT3 kinase comprises: wild type FLT3 kinase, mutant FLT3 kinase.

In some of these embodiments, the mutant FLT3 kinase comprises one or more of FLT3/ITD, FLT3/835Y, FLT/F691L, FLT/K663Q, FLT/D835V, and FLT3/D835H mutant kinase.

The triazole compound or the pharmaceutically acceptable salt thereof, or the stereoisomer thereof, or the prodrug molecule thereof, or the metabolite thereof, or the solvate thereof can be applied to the preparation of medicines for preventing or treating FLT3 kinase-related diseases.

In some of these embodiments, the FLT3 kinase-associated disease comprises: tumor, psoriasis, prostatic hyperplasia, and metabolic disease.

In some of these embodiments, the tumor comprises: leukemia, breast cancer, prostate cancer, ovarian cancer, testicular cancer, stomach cancer, lung cancer, liver cancer, esophageal cancer, melanoma, colon cancer, prostate cancer, pancreatic cancer, thyroid cancer, brain cancer.

In some of these embodiments, the FLT3 kinase associated disease is acute myeloid leukemia.

The invention also aims to provide a kinase inhibitor, and the specific technical scheme is as follows:

a kinase inhibitor, the active component of which comprises the triazole compound and the pharmaceutically acceptable salt thereof or the prodrug molecule thereof or the metabolite thereof or the solvate thereof.

In some of these embodiments, the kinase inhibitor inhibits the activity of FLT3 kinase.

The invention also aims to provide a pharmaceutical composition for preventing or treating FLT3 kinase related diseases, and the specific technical scheme is as follows:

a pharmaceutical composition for preventing or treating FLT3 kinase related diseases comprises the triazole compound and pharmaceutically acceptable salts thereof or prodrug molecules thereof or metabolites thereof or solvates thereof.

In some embodiments, the pharmaceutical composition is prepared from the triazole compound or the pharmaceutically acceptable salt thereof, or the stereoisomer thereof, or the prodrug molecule thereof, or the metabolite thereof, or the solvate thereof, and pharmaceutically acceptable auxiliary materials.

A pharmaceutical composition for preventing or treating FLT3 kinase related diseases is prepared from an active ingredient and pharmaceutically acceptable auxiliary materials, wherein the active ingredient comprises the triazole compound or pharmaceutically acceptable salts thereof or stereoisomers thereof or prodrug molecules thereof or metabolites thereof or solvates thereof.

In some of these embodiments, the FLT3 kinase-associated disease comprises: at least one of tumor, psoriasis, prostate hyperplasia, and metabolic disease.

Based on the technical scheme, the invention has the following beneficial effects:

the triazole compound and pharmaceutically acceptable salts, solvates, isomers, acids, esters, metabolites or prodrugs thereof provided by the invention can effectively inhibit kinases, especially FLT3 kinase, including FLT-ITD mutant kinase and Kit kinase, and further regulate activation of downstream multiple pathways, and can be used for preparing medicines for preventing and treating various diseases related to FLT3 kinase, such as leukemia, tumors, psoriasis, prostatic hyperplasia and metabolic diseases.

Detailed Description

In the compounds of the invention, when any variable (e.g. R) ¹ 、R ² Etc.) occur more than one time in any constituent, then the definition of each occurrence is independent of the definition of each other occurrence. Also, combinations of substituents and variables are permissible only if such combinations result in stable compounds. The line drawn from a substituent into the ring system indicates that the indicated bond can be attached to any ring atom that can be substituted. If the ring system is polycyclic, it means that such a bond is only attached to any suitable carbon atom of the adjacent ring. It is to be understood that substituents and substitution patterns on the compounds of the present invention may be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by those skilled in the art and by the methods set forth below from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms, so long as the structure is stable. The phrase "optionally substituted with one or more substituents" is considered equivalent to the phrase "optionally substituted with at least one substituent" and preferred embodiments in this case will have 0-3 substituents.

The terms "alkyl" and "alkylene" as used herein are intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "C _1-5 Alkyl radical "middle" C _1-5 The definition of "includes groups having 1,2,3, 4, or 5 carbon atoms in a linear or branched arrangement. For example, "C _1-5 Alkyl "specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl. The term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms. For example, "cycloalkyl" includes cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, and the like.

The term "heterocycle" or "heterocyclyl" as used herein refers to a 5-to 7-membered aromatic or non-aromatic heterocycle containing 1 to 4 heteroatoms selected from O, N and S, and includes bicyclic groups. "Heterocyclyl" thus includes the above-mentioned heteroaryl groups, as well as the dihydro and tetrahydro analogues thereof. Further examples of "heterocyclyl" include, but are not limited to: imidazolyl, indolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinoxalinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, l, 4-dioxanyl, pyrrolidinyl, dihydroimidazolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidyl, dihydropyrrolyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, tetrahydrofuranyl and tetrahydrothienyl, and N-oxides thereof. Attachment of the heterocyclic substituent may be through a carbon atom or through a heteroatom.

As understood by those skilled in the art, "halogen" as used herein is meant to include fluorine, chlorine, bromine and iodine.

Unless otherwise defined, alkyl, cycloalkyl, aryl, and heterocyclyl substituents may be unsubstituted or substituted. For example, (C) _1-6 ) Alkyl groups may be substituted with one, two or three substituents selected from OH, halogen, alkoxy, dialkylamino or heterocyclyl, e.g. morpholinyl, piperidinyl and the like.

The invention includes free forms of the compounds of formula a, formula i and formula ii, as well as pharmaceutically acceptable salts and stereoisomers thereof. Some specific exemplary compounds herein are protonated salts of amine-based compounds. The term "free form" refers to the amine compound in a non-salt form. Included pharmaceutically acceptable salts include not only the exemplary salts of the particular compounds described herein, but also all typical pharmaceutically acceptable salts of the free forms of the compounds of formulas A, I and II. The free form of a particular salt of the compound may be isolated using techniques known in the art. For example, the free form can be regenerated by treating the salt with a dilute aqueous solution of a suitable base, such as a dilute aqueous NaOH solution, a dilute aqueous potassium carbonate solution, dilute aqueous ammonia, and a dilute aqueous sodium bicarbonate solution. The free forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of the invention such acid and base salts are otherwise pharmaceutically equivalent to their respective free forms.

Pharmaceutically acceptable salts of the invention can be synthesized from compounds of the invention containing a basic or acidic moiety by conventional chemical methods. In general, salts of basic compounds are prepared by ion exchange chromatography or by reaction of the free base with a stoichiometric amount or excess of an inorganic or organic acid in the form of the desired salt in an appropriate solvent or combination of solvents. Similarly, salts of acidic compounds are formed by reaction with suitable inorganic or organic bases.

Thus, pharmaceutically acceptable salts of the compounds of the present invention include the conventional non-toxic salts of the compounds of the present invention formed by the reaction of a basic compound of the present invention and an inorganic or organic acid. For example, conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, as well as those prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid, and the like.

If the compounds of the invention are acidic, suitable "pharmaceutically acceptable salts" refer to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic and organic bases, salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Particularly preferred are ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases including salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N' -dibenzylethylenediamine, diethylamine, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, histidine, hydroxycobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, piperdine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

Berg et al, "Pharmaceutical Salts" J.pharm.Sci.1977:66:1-19 describe in more detail the preparation of the pharmaceutically acceptable salts described above and other typical pharmaceutically acceptable salts.

In addition to standard methods known in the literature or exemplified in experimental procedures, the compounds of the invention can be prepared using reactions as shown in the following schemes. The following illustrative schemes are therefore for illustrative purposes and are not limited to the compounds listed or any particular substituents. The number of substituents shown in the schemes does not necessarily correspond to the number used in the claims and for the sake of clarity a single substituent is shown attached to the compound allowing multiple substituents under the definitions of formula a, formula i and ii above.

According to the compounds shown in the formulas I and II, aryl acetylene and aryl azide are used as starting materials, a 1,2,3-triazole parent nucleus structure is synthesized through a copper-catalyzed 1,3-dipolar cycloaddition key step, and a substituent group structure is further constructed through simple substitution reaction and the like. Or a 1,2,3-triazole parent nucleus structure is constructed by multi-component reaction in one step, and a substituent group structure is constructed by simple substitution reaction and the like.

Metabolites of the compounds and pharmaceutically acceptable salts thereof to which this application relates, and prodrugs that can be converted in vivo to the structures of the compounds and pharmaceutically acceptable salts thereof to which this application relates, are also included in the claims of this application.

The compounds of formula a, formula i or ii may be used in combination with other drugs known to treat or ameliorate similar conditions. When administered in combination, the mode of administration and dosage of the original drug is maintained, while the compound of formula A, formula I or II is administered simultaneously or subsequently. When the compound of formula A, formula I or II is administered simultaneously with one or more other drugs, it is preferred to use a pharmaceutical composition containing both one or more known drugs and the compound of formula A, formula I or II. The combination also includes administering the compound of formula A, formula I or II in an overlapping time period with one or more other known agents. When a compound of formula A, formula I or II is administered in combination with one or more other drugs, the dosage of the compound of formula A, formula I or II or the known drug may be lower than when they are administered alone.

Drugs or active ingredients that may be used in combination with a compound of formula a, formula i or formula ii include, but are not limited to:

estrogen receptor modulators, androgen receptor modulators, retinal-like receptor modulators, cytotoxins/cytostatics, antiproliferatives, protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protein kinase inhibitors, reverse transcriptase inhibitors, angiogenesis inhibitors, cell proliferation and survival signal inhibitors, drugs that interfere with cell cycle checkpoints and apoptosis inducers, cytotoxic drugs, tyrosine protein inhibitors, EGFR inhibitors, VEGFR inhibitors, serine/threonine protein inhibitors, bcr-Abl inhibitors, c-Kit inhibitors, met inhibitors, raf inhibitors, MEK inhibitors, MMP inhibitors, topoisomerase inhibitors, histidine deacetylase inhibitors, proteasome inhibitors, CDK inhibitors, bcl-2 family protein inhibitors, MDM2 family protein inhibitors, IAP family protein inhibitors, STAT family protein inhibitors, PI3K inhibitors, AKT inhibitors, integrin blockers, interferon- α, interleukin-12, COX-2 inhibitors, p53 activators, VEGF antibodies, EGF antibodies, and the like.

In one embodiment, drugs or active ingredients that may be used in combination with a compound of formula a, formula i or ii include, but are not limited to: aldesleukin, alendronic acid, interferon, a Qu Nuoying, allopurinol sodium, palonosetron hydrochloride, altretamine, aminoglutethimide, amifostine, amrubicin, ambridine, anastrozole, dolasetron, aranesp, arglabin, arsenic trioxide, aroxin, 5-azacytidine, azathioprine, BCG or tie BCG, betamethasone acetate, betamethasone sodium phosphate formulations, sodium betamethasone phosphate formulations, and combinations thereof bexarotene, bleomycin sulfate, bromouracil, bortezomib, busulfan, calcitonin, aleuzumab injection, capecitabine, carboplatin, kang Shide, cefesone, west Mo Bai interleukin, daunorubicin, chlorambucil, cisplatin, cladribine, chlorine Qu Linsuan, cyclophosphamide, cytarabine, dacarbazine, actinomycin D, daunorubicin liposome, dexamethasone, and pharmaceutically acceptable salts thereof dexamethasone phosphate, estradiol valerate, dinil interleukin 2, dibumel, deslorelin, delazoxan, diethylstilbestrol, DAFUKANG, docetaxel, doxifluridine, doxorubicin, dronabinol, azulene-166-chitosan complex, eligard, labyrine, epirubicin hydrochloride, aprepirubicin, epirubicin, alfacitinin, erythropoietin, eptaplatin, levamisole, estradiol formulations, 17-beta-estradiol, estramustine sodium phosphate, ethisterol, amifostine, hydroxyphosphoric acid, valpiride, etoposide, faprazole, tamoxifen formulations, filgrastim, finasteride, feristine, floxuridine, fluconazole, fludarabine, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil, flumethamine, foglisentan, 1-beta-D-arabinosyl-thiabendazole-5' -testosterone Fotemustine, fulvestrant, gamma globulin, gemcitabine, gemtuzumab ozogamicin, imatinib mesylate, carmustine wafer capsule, goserelin, glanesilone hydrochloride, histrelin, and metin, hydrocortisone, erythro-hydroxynonyladenine, hydroxyurea, titatane Bei Mo mab, idarubicin, ifosfamide, interferon alpha, interferon-alpha 2, interferon alpha-2A, interferon alpha-2B, interferon alpha-nl, interferon alpha-n 3, interferon beta, interferon gamma-la, interleukin-2, intron A, iressa, irinotecan, katerel, lentinan sulfate, letrozole, leucovorin, leuprorelin acetate, levotetramisoimidazole, levofolinic acid, levothyroxine sodium preparation, lomustine, levothyroxine sodium lonidamine, dronabinol, mechlorethamine, mecobalamin, medroxyprogesterone acetate, megestrol acetate, melphalan, esterified estrogen, 6-ryopurine, mesna, methotrexate, methyl aminolevulinate, miltefosine, milbemycin, mitomycin C, mitotane, mitoxantrone, trilobanone, trilostane, doxorubicin citrate liposome, nedaplatin, pegylated filgrastim, omprex interleukin, neupogen, nilutamide, tamoxifen, NSC-631570, recombinant human interleukin 1-beta, octreotide, ondansetron hydrochloride, hydrocortisone oral solution, oxaliplatin, paclitaxel, prednisone sodium phosphate formulation, pemetrexed, winter Luo Xin, staphyline, streptolysin formulation, piroctone hydrochloride, bordetellurocin, plicamycin, sodium, nemamfenamiphene, and nemaderin, <xnotran> , , , , , , , -186, , -A, , , , , , , , , , , , -89, , , , , tastolactone, , , , , , , , , , , , , , , , A , , , , , , , , , , , , , , , , , , , acolbifene, r-lb, affinitak, , , asoprisnil, , , BAY43-9006, , CCI-779, CDC-501, , , , , , DN-101, -MTC, dSLIM, , edotecarin, , , A , , , -166DOTMP, , γ, -PEG, ixabepilone, , L-651582, </xnotran> Lanopeptide, lasofoxifene, libra, lonafamib, milbexifene, minox Qu Suanzhi, MS-209, liposomal MTP-PE, MX-6, nafarelin, nemorubicin, neovastat, nolatret, orlistat, oncomelanism, ono-TCS, osidem, paclitaxel polyglutamate, sodium pamoate, PN-401, QS-21, quartzocean, R-154, raloxifene, ranpirnase, 13-cis-tretinoid, satraplatin, seocalcitol, T-138067, tarceva, paclitaxel, thymosin alpha l, gastrofurin, tipifarnib, tirapazamine, TLK-286, toremifene, trans-7R, varespradine, lanvapreotide, valtaprotenin, vezapine, vinpocetine, MIDZ-100, and mixtures or combinations thereof.

The invention is further described in the following examples, which are not intended to limit the scope of the invention.

Example 1: preparation of 1- (5-tert-butylisoxazol-3-yl) -3- (4- (1- (4- (2-morpholinoethoxy) phenyl) -1H-1,2,3-triazol-4-yl) phenyl) urea (named CL-101)

1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(1-(4-(2-morpholinoethoxy)phenyl)-1H-1,2,3-triazol-4-yl)phenyl)urea

Synthetic route a:

step a preparation of 4-Azidophenol (Compound 2)

P-iodophenol (22g, 0.1mol), naN ₃ (13g, 0.2mol), sodium ascorbate (1g, 5mmol), cuI (1.9g, 10mmol), N, N' -dimethylethylenediamine (1.32g, 15mmol), 300ml of a mixed solution of ethanol and water (7:3) was added thereto, and the mixture was refluxed under argon atmosphereAnd reacting for 2h. After the raw material was completely converted, the mixture was diluted with water, extracted twice with ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated to obtain compound 2 (13.3 g).

Step b preparation of 4-Nitrophenylacetylene (1-ethyl-4-nitrobenzene) (Compound 4)

4-nitroiodobenzene (20g, 80mmol), trimethylethynyl silicon (11g, 112mmol), pd (PPh) ₃ ) ₂ Cl ₂ (0.56g, 0.8 mmol) and CuI (0.15g, 0.8 mmol) were reacted at 60 ℃ for 3.5 hours under an argon atmosphere, after completion of the reaction, filtered using celite, the filtrate was diluted with water, extracted 2 to 3 times with ethyl acetate, the organic phase was collected, dried using anhydrous sodium sulfate, and concentrated. The crude product was dissolved in tetrahydrofuran, and 1M tetrabutylammonium fluoride (98 mL) solution was added and the reaction stirred for 1 hour. After the conversion of the starting material has taken place, saturated NH is used ₄ After quenching with aqueous Cl, the reaction was extracted 2 times with dichloromethane, the combined organic phases were collected, concentrated under reduced pressure, and passed through a silica gel column using petroleum ether/ethyl acetate to afford compound 4 (5.9 g, 50% yield).

Step c: preparation of 4- (4- (4-nitrophenyl) -1H-1,2,3-triazol-1-yl) phenol (Compound 5)

4-(4-(4-nitrophenyl)-1H-1,2,3-triazol-1-yl)phenol(5)

Compound 2 (13.5g, 0.1mol), compound 4 (14.7g, 0.1mol) and CuI (1.9g, 10mmol) in DMF (100 mL) were reacted at 60 ℃ for 4h, after the reaction was completed, the reaction mixture was poured into water, extracted 2-3 times with ethyl acetate, the organic phase was collected, dried over anhydrous sodium sulfate, concentrated and quickly separated through a silica gel column to give compound 5 (28 g).

Step d preparation of 4- (2- (4- (4- (4-nitrophenyl) -1H-1,2,3-triazol-1-yl) phenoxy) ethyl) morpholine (Compound 6)

4-(2-(4-(4-(4-nitrophenyl)-1H-1,2,3-triazol-1-yl)phenoxy)ethyl)morpholine(6)

Compound 5 (10.5g, 37.2mmol), N- (2-chloroethyl) morpholine hydrochloride (8.3g, 44.6 mmol) and cesium carbonate (36g, 112mmol) were stirred in DMF (100 mL) at 60 ℃ overnight. After completion of the reaction, the reaction mixture was poured into water, extracted 2 to 3 times with ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated with silica gel column to obtain pure compound 6 (13.2 g).

Step e: preparation of 4- (1- (4- (2-morpholinoethoxy) phenyl) -1H-1,2,3-triazol-4-yl) aniline (Compound 7)

4-(1-(4-(2-morpholinoethoxy)phenyl)-1H-1,2,3-triazol-4-yl)aniline(7)

Compound 6 (9.8g, 24.9mmol), iron powder (6.96g, 125mmol) and NH ₄ Cl (5.3 g, 100mmol) was refluxed in 90% ethanol solution for 6 hours until the starting material was completely converted. Filtering with diatomaceous earth, washing the filter cake with hot ethanol solution for 2 times, concentrating the mother liquor, and pouring saturated Na ₂ CO ₃ The solution was extracted twice with DCM, and the organic phase was collected, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 7 (8.2 g).

Step f.preparation of 1- (5-tert-butylisoxazol-3-yl) -3- (4- (1- (4- (2-morpholinoethoxy) phenyl) -1H-1,2,3-triazol-4-yl) phenyl) urea (CL-101)

1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(1-(4-(2-morpholinoethoxy)phenyl)-1H-1,2,3-triazol-4-yl)phenyl)urea(CL-101)

Compound 7 (150mg, 0.41mmol), phenyl (5-tert-butylisoxazol-3-amino) carboxylate (compound 8, 128mg, 0.48mmol) and triethylamine (123mg, 1.21mmol) were reacted in 5ml of DMF at 60 ℃ with stirring for 4 hours. The reaction mixture was poured into water and extracted 2 times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by a silica gel column to give compound CL-101 (170 mg).

Compound CL-101 can also be synthesized according to Synthesis method B:

the synthesis method B comprises the following steps:

step a: preparation of 4- (4- (4-aminophenyl) -1H-1,2,3-triazol-1-yl) phenol (Compound 10)

4-(4-(4-aminophenyl)-1H-1,2,3-triazol-1-yl)phenol(10)

P-iodophenol (22g, 0.1mol)，NaN ₃ (13g, 0.2mol), p-aminophenylacetylene (11.7g, 0.1mol), sodium ascorbate (1g, 5mmol), cuSO ₄ ·5H ₂ O (2.5g, 10mmol) and potassium carbonate (27.6g, 20mmol) were added to a mixed solution of DMSO and water (9:1) in an amount of 100ml, and the mixture was reacted at 80 ℃ for 10 hours under an argon atmosphere. After complete conversion of the raw material, it was diluted with water, extracted twice with ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated to obtain compound 10 (20 g, yield: 80%).

Step b: preparation of 1- (5-tert-butyl-isoxazol-3-yl) -3- (4- (1- (4-hydroxyphenyl) -1H-1,2,3-triazol-4-yl) phenyl) urea (Compound 11)

1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(1-(4-hydroxyphenyl)-1H-1,2,3-triazol-4-yl)phenyl)urea

Compound 10 (252mg, 1mmol), phenyl (5-tert-butylisoxazol-3-amino) carboxylate (compound 8, 260mg, 1mmol) and triethylamine (300mg, 3mmol) were reacted with stirring in DMF (5 mL) at 60 ℃ for 4 hours. The reaction mixture was poured into water, and extracted 2 times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column on silica gel to give compound 11 (376 mg, yield: 90%).

Step c: preparation of CL-101

Compound 11 (94mg, 0.2mmol), N- (2-chloroethyl) morpholine hydrochloride (45mg, 0.3mmol), potassium carbonate (110mg, 0.8mmol) and Bu ₄ NI (7.4 mg, 0.02mmol) was stirred in DMF (2 mL) at 60 ℃ overnight. After completion of the reaction, the reaction mixture was poured into water, extracted 2-3 times with ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated using a silica gel column to obtain compound CL-101 (95.6 mg, yield: 90%).

¹ H NMR(400MHz,d ⁶ -DMSO)δ9.58(s,1H),9.12(s,H),8.98(s,1H),7.87(d,J＝8.8Hz,2H),7.84(d,J＝8.8Hz,2H),7.58(d,J＝8.8Hz,2H),7.18(d,J＝8.8Hz,2H),6.53(s,1H),4.18(t,J＝5.6Hz,2H),3.59(t,J＝4.8Hz,4H),2.72(t,J＝5.6Hz,2H),2.50-2.52(m,4H),1.31(s,9H). ¹³ C NMR(101MHz,d ⁶ -DMSO)δ185.4,163.7,163.6,156.5,152.2,144.1,135.3,131.2,129.9,126.7,124.0,123.9,120.7,97.9,71.4,71.0,62.2,58.8,37.7,33.6.ESI-MS m/z 532.1(M+H) ⁺ 。

Example 2: preparation of 1- (5- (tert-butyl) isoxazol-3-yl) -3- (4- (1- (4- (2-dimethylamino) ethoxyphenyl) -1H-1,2,3-triazol-4-yl) phenyl) urea (named CL-102)

1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(1-(4-(2-(dimethylamino)ethoxy)phenyl)-1H-1,2,3-triazol-4-yl)phenyl)urea

The synthesis method is basically the same as in example 1.

¹ H NMR(400MHz,d ⁶ -DMSO)δ9.70(s,1H),9.35(s,H),9.11(s,1H),7.85(d,J＝8.8Hz,4H),7.57(d,J＝8.8Hz,2H),7.18(d,J＝8.8Hz,2H),6.52(s,1H),4.25(t,J＝5.6Hz,2H),3.04(t,J＝5.6Hz,4H),2.50(s,6H),1.28(s,9H). ¹³ C NMR(101MHz,d ⁶ -DMSO)δ180.6,158.8,158.5,151.9,147.5,139.5,130.8,126.4,125.0,122.0,119.3,119.1,116.0,93.0,65.1,57.0,44.8,32.9,28.8.ESI-MS m/z 490.1(M+H) ⁺ 。

Example 3: preparation of 1- (5- (tert-butyl) isoxazol-3-yl) -3- (4- (1- (4- (2-piperidin-1-yl) ethoxyphenyl) -1H-1,2,3-triazol-4-yl) phenyl) urea (named CL-103)

1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(1-(4-(2-(piperidin-1-yl)ethoxy)phenyl)-1H-1,2,3-triazol-4-yl)phenyl)urea

The synthesis method is basically the same as in example 1.

¹ H NMR(400MHz,d ⁶ -DMSO)δ9.58(s,1H),9.11(s,H),8.97(s,1H),7.82-7.88(m,4H),7.58(d,J＝8.8Hz,2H),7.17(d,J＝8.8Hz,2H),6.52(s,1H),4.15(t,J＝5.6Hz,2H),2.70(t,J＝5.6Hz,4H),2.45-2.51(m,4H),1.48-1.52(m,4H),1.38-1.40(m,2H),1.30(s,9H). ¹³ C NMR(101MHz,d ⁶ -DMSO)δ180.7,159.0,158.8,151.8,147.4,139.3,130.5,126.4,125.1,122.0,119.3,119.2,115.9,92.9,66.5,57.7,54.9,33.0,28.8,26.0,24.4.ESI-MS m/z 530.2(M+H) ⁺ 。

Example 4: preparation of 4- (4- (4- (3- (5- (tert-butyl) isoxazol-3-yl) urea) phenyl) -1H-1,2,3-triazol-1-yl) phenyl) methanesulfonate (named CL-104)

4-(4-(4-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)phenyl)-1H-1,2,3-triazol-1-yl)phenylmethanesulfonate

The synthesis method is basically the same as in example 1.

¹ H NMR(400MHz,d ⁶ -DMSO)δ9.56(s,1H),9.26(s,H),8.96(s,1H),8.07(d,J＝8.8Hz,2H),7.87(d,J＝8.8Hz,2H),7.63(d,J＝8.8Hz,2H),7.59(d,J＝8.8Hz,2H),6.52(s,1H),3.47(s,3H),1.30(s,9H). ¹³ C NMR(101MHz,d ⁶ -DMSO)δ180.7,158.8,151.8,149.0,147.8,139.5,135.9,126.5,124.8,124.4,122.1,119.6,119.3,38.0,33.0,28.8.ESI-MS m/z 497.1(M+H) ⁺ 。

Example 5: preparation of 1- (5-methylisoxazol-3-yl) -3- (4- (1- (4- (2-morpholinoethoxy) phenyl) -1H-1,2,3-triazol-4-yl) phenyl) urea (named CL-105)

1-(5-methylisoxazol-3-yl)-3-(4-(1-(4-(2-morpholinoethoxy)phenyl)-1H-1,2,3-triazol-4-yl)phenyl)urea

The synthesis method is basically the same as in example 1.

¹ H NMR(400MHz,d ⁶ -DMSO)δ9.77(s,1H),9.60(s,H),9.14(s,1H),7.85-7.89(m,4H),7.58(d,J＝8.8Hz,2H),7.23(d,J＝8.8Hz,2H),6.57(s,1H),4.46(t,J＝5.6Hz,2H),3.80-3.85(m,4H),2.04-3.47(m,6H),2.37(s,3H). ¹³ C NMR(101MHz,d ⁶ -DMSO)δ170.6,159.0,158.1,151.9,147.6,139.6,131.1,126.4,124.9,122.0,119.3,119.0,116.2,96.1,64.0,55.6,52.5,45.9,12.6.ESI-MS m/z 490.2(M+H) ⁺ 。

Example 6: preparation of 1- (4- (1- (4- (2-morpholinoethoxy) phenyl) -1H-1,2,3-triazol-4-yl) phenyl) -3- (thiazol-2-yl) urea (named CL-106)

1-(4-(1-(4-(2-morpholinoethoxy)phenyl)-1H-1,2,3-triazol-4-yl)phenyl)-3-(thiazol-2-yl)urea

The synthesis method is basically the same as in example 1.

¹ H NMR(400MHz,d ⁶ -DMSO)δ10.61(s,1H),9.13(s,H),9.12(s,1H),7.88(d,J＝8.8Hz,2H),7.84(d,J＝8.8Hz,2H),7.61(d,J＝8.8Hz,2H),7.38(d,J＝3.6Hz,1H),7.18(d,J＝8.8Hz,2H),7.13(d,J＝3.6Hz,1H),4.18(t,J＝5.6Hz,2H),3.59(t,J＝4.8Hz,4H),2.72(t,J＝5.6Hz,2H),2.50(m,4H).ESI-MS m/z 492.2(M+H) ⁺ 。

Example 7: preparation of methyl 2- (3- (4- (1- (4- (2-morpholinoethoxy) phenyl) -1H-1,2,3-triazol-4-yl) phenyl) ureido) thiophene-3-carboxylate (named CL-107)

Methyl 2-(3-(4-(1-(4-(2-morpholinoethoxy)phenyl)-1H-1,2,3-triazol-4-yl)phenyl)ureido)thiophene-3-carboxylate

The synthesis method is basically the same as in example 1.

¹ H NMR(400MHz,d ⁶ -DMSO)δ10.51(s,1H),10.46(s,H),9.12(s,1H),7.91(d,J＝8.8Hz,2H),7.85(d,J＝8.8Hz,2H),7.65(d,J＝8.8Hz,2H),7.18(d,J＝8.8Hz,2H),7.15(d,J＝2.0Hz,1H),6.92(d,J＝2.0Hz,1H),4.17(t,J＝5.6Hz,2H),3.87(s,3H),3.60(t,J＝4.4Hz,4H),2.73(t,J＝5.6Hz,2H),2.50-2.52(m,4H). ¹³ C NMR(101MHz,d ⁶ -DMSO)δ165.2,158.9,151.5,151.0,147.4,139.4,130.6,126.5,125.2,123.9,122.0,119.2,119.1,116.1,115.9,110.4,66.6,66.2,57.4,54.1,52.0.ESI-MS m/z 548.1(M+H) ⁺ 。

Example 8: preparation of ethyl 2- (3- (4- (1- (4- (2-morpholinoethoxy) phenyl) -1H-1,2,3-triazol-4-yl) phenyl) ureido) thiazole-5-carboxylate (named CL-108)

ethyl2-(3-(4-(1-(4-(2-morpholinoethoxy)phenyl)-1H-1,2,3-triazol-4-yl)phenyl)ureido)thiazole-5-carboxylate

The synthesis method is basically the same as in example 1.

¹ H NMR(400MHz,d ⁶ -DMSO)δ11.16(s,1H),9.26(s,H),9.12(s,1H),8.07(s,1H),7.90(d,J＝8.8Hz,2H),7.83(d,J＝8.8Hz,2H),7.62(d,J＝8.8Hz,2H),7.17(d,J＝8.8Hz,2H),4.27(q,J＝6.8Hz,2H),4.17(t,J＝5.6Hz,2H),3.59(t,J＝4.4Hz,4H),2.73(t,J＝5.6Hz,2H),2.50-2.52(m,4H),1.29(t,J＝6.8Hz,3H). ¹³ C NMR(101MHz,d ⁶ -DMSO)δ164.3,161.9,158.9,152.0,147.3,145.3,138.6,130.6,126.4,125.7,122.0,120.8,119.5,119.4,115.9,66.6,66.2,61.2,57.4,54.1,14.7.ESI-MS m/z 564.1(M+H) ⁺ 。

Example 9: preparation of 4-bromo-N- (4- (1- (4- (2-morpholinoethoxy) phenyl) -1H-1,2,3-triazol-4-yl) phenyl) benzamide (designated CL-109)

The synthesis procedure was essentially the same as in example 1, and the intermediate (compound 7 described in example 1) was prepared by stirring the corresponding acid chloride in dichloromethane at room temperature.

¹ H NMR(400MHz,d ⁶ -DMSO)δ10.46(s,1H),9.14(s,1H),7.88-7.95(m,6H),7.85(d,J＝8.8Hz,2H),7.77(d,J＝8.8Hz,2H),7.19(d,J＝8.8Hz,2H),4.19(t,J＝5.6Hz,2H),3.60(t,J＝4.4Hz,4H),2.74(t,J＝5.6Hz,2H),2.50-2.52(m,4H). ¹³ C NMR(101MHz,d ⁶ -DMSO)δ165.0,158.7,147.3,139.7,134.1,131.8,130.6,130.4,126.4,126.0,125.8,122.0,121.5,119.9,116.1,66.6,66.2,57.3,54.2.ESI-MS m/z 548.1(M+H) ⁺ 。

Example 10: preparation of 1- (4- (1- (4- (2-morpholinoethoxy) phenyl) -1H-1,2,3-triazol-4-yl) phenyl) -3- (pyridin-2-yl) urea (designated CL-10)

1-(4-(1-(4-(2-morpholinoethoxy)phenyl)-1H-1,2,3-triazol-4-yl)phenyl)-3-(pyridin-2-yl)urea

The synthesis method is basically the same as in example 1.

¹ H NMR(400MHz,d ⁶ -DMSO)δ10.70(s,1H),9.51(s,1H),9.12(s,1H),8.29-8.31(m,1H),7.83-7.89(m,5H),7.66(d,J＝8.8Hz,2H),7.47-7.50(m,1H),7.18(d,J＝8.8Hz,2H),7.01-7.04(m,1H),4.17(t,J＝5.6Hz,2H),3.59(t,J＝4.4Hz,4H),2.73(t,J＝5.6Hz,2H),2.50-2.52(m,4H). ¹³ C NMR(101MHz,d ⁶ -DMSO)δ158.9,153.3,152.6,147.5,147.4,139.5,139.1,130.6,126.4,125.1,122.0,119.5,119.3,118.0,115.9,112.4,66.6,66.2,57.4,54.1.ESI-MS m/z 486.1(M+H) ⁺ 。

Example 11: (E) Preparation of (E) -3- (3,5-bis- (trifluoromethyl) -phenyl) -N- (4- (1- (4- (2-morpholinoethoxy) phenyl) -1H-1,2,3-triazol-4-yl) phenyl) acrylamide (named CL-111)

(E)-3-(3,5-bis(trifluoromethyl)phenyl)-N-(4-(1-(4-(2-morpholinoethoxy)phenyl)-1H-1,2,3-triazol-4-yl)phenyl)acrylamide

The synthesis method is basically the same as in example 9.

¹ H NMR(400MHz,d ⁶ -DMSO)δ10.66(s,1H),9.15(s,1H),8.35(s,2H),8.14(s,1H),7.77-7.95(m,7H),7.17-7.23(m,2H),4.18(t,J＝5.6Hz,2H),3.60(t,J＝4.4Hz,4H),2.73(t,J＝5.6Hz,2H),2.50-2.52(m,4H).ESI-MS m/z 632.2(M+H) ⁺ 。

Example 12: preparation of 1- (4-methyl-3-trifluoromethylphenyl) -3- (4- (1- (4- (2-morpholinoethoxy) phenyl) -1H-1,2,3-triazol-4-yl) phenyl) urea (named CL-112)

1-(4-methyl-3-(trifluoromethyl)phenyl)-3-(4-(1-(4-(2-morpholinoethoxy)phenyl)-1H-1,2,3-triazol-4-yl)phenyl)urea

The synthesis method is basically the same as in example 9.

¹ H NMR(400MHz,d ⁶ -DMSO)δ9.10(s,1H),9.04(s,1H),8.95(s,1H),7.96-7.97(m,1H),7.83-7.86(m,3H),7.59(d,J＝8.4Hz,2H),7.51(d,J＝8.4Hz,1H),7.36(d,J＝8.4Hz,1H),7.17(d,J＝8.8Hz,2H),4.17(t,J＝5.6Hz,2H),3.59(t,J＝4.4Hz,4H),2.73(t,J＝5.6Hz,2H),2.50-2.52(m,4H).ESI-MS m/z 567.2(M+H) ⁺ 。

Example 13: preparation of 1- (4- (1- (4- (2-morpholinoethoxy) phenyl) -1H-1,2,3-triazol-4-yl) phenyl) -3- (3,4,5-trimethoxyphenyl) urea (named CL-113)

1-(4-(1-(4-(2-morpholinoethoxy)phenyl)-1H-1,2,3-triazol-4-yl)phenyl)-3-(3,4,5-trimethoxyphenyl)urea

The synthesis method is basically the same as in example 1.

¹ H NMR(400MHz,d ⁶ -DMSO)δ9.09(s,1H),8.83(s,1H),8.73(s,1H),7.84(d,J＝8.8Hz,2H),7.83(d,J＝8.2Hz,2H),7.58(d,J＝8.8Hz,2H),7.17(d,J＝8.8Hz,2H),6.82(s,2H),4.17(t,J＝5.6Hz,2H),3.76(s,6H),3.62(s,3H),3.59(t,J＝4.4Hz,4H),2.72(t,J＝5.6Hz,2H),2.50-2.52(m,4H). ¹³ C NMR(101MHz,d ⁶ -DMSO)δ158.9,153.3,152.9,147.6,140.1,139.5,136.2,132.9,130.6,126.4,122.0,119.1,118.9,115.9,96.4,66.6,66.2,60.6,57.4,56.1,54.1.ESI-MS m/z 575.2(M+H) ⁺ 。

Example 14: preparation of 1- (4-ethylphenyl) -3- (4- (1- (4- (2-morpholinoethoxy) phenyl) -1H-1,2,3-triazol-4-yl) phenyl) -urea (named CL-114)

1-(4-ethylphenyl)-3-(4-(1-(4-(2-morpholinoethoxy)phenyl)-1H-1,2,3-triazol-4-yl)phenyl)urea

The synthesis method is basically the same as in example 1.

¹ H NMR(400MHz,d ⁶ -DMSO)δ8.62(s,1H),8.36(s,1H),8.20(s,1H),7.39(d,J＝8.84Hz,2H),7.38(d,J＝8.8Hz,2H),7.13(d,J＝8.8Hz,2H),6.93(d,J＝8.4Hz,2H),6.71(d,J＝8.8Hz,2H),6.67(d,J＝8.8Hz,2H),3.71(t,J＝5.6Hz,2H),3.13(t,J＝4.4Hz,4H),2.27(t,J＝5.6Hz,2H),2.04-2.12(m,6H),0.70(t,J＝7.2Hz,3H). ¹³ C NMR(101MHz,d ⁶ -DMSO)δ158.8,153.0,147.6,140.3,137.8,137.7,130.6,128.5,126.4,124.3,122.0,119.1,118.9,118.8,115.9,66.6,66.2,57.4,54.1,28.0,16.3.ESI-MS m/z 513.2(M+H) ⁺ 。

Example 15: preparation of 1- (4-tert-butylphenyl) -3- (4- (1- (4- (2-morpholinoethoxy) phenyl) -1H-1,2,3-triazol-4-yl) phenyl) -urea (named CL-115)

1-(4-(tert-butyl)phenyl)-3-(4-(1-(4-(2-morpholinoethoxy)phenyl)-1H-1,2,3-triazol-4-yl)phenyl)urea

The synthesis method is basically the same as in example 1.

¹ H NMR(400MHz,d ⁶ -DMSO)δ9.88(s,1H),9.62(s,1H),9.14(s,1H),7.81-7.86(m,4H),7.57(d,J＝8.4Hz,2H),7.38(d,J＝8.4Hz,2H),7.28(d,J＝8.4Hz,2H),7.17(d,J＝8.4Hz,2H),4.17(t,J＝5.6Hz,2H),3.58(t,J＝4.4Hz,4H),2.72(t,J＝5.6Hz,2H),2.48-2.50(m,4H),1.26(s,9H). ¹³ C NMR(101MHz,d ⁶ -DMSO)δ158.9,153.0,147.6,144.6,140.3,137.5,130.6,126.4,125.9,124.3,122.0,119.1,118.7,118.5,115.9,66.6,66.2,57.3,54.0,34.2,31.7.ESI-MS m/z541.2(M+H) ⁺ 。

Example 16: preparation of 1- (4- (1- (3-bromo-4- (2-morpholinoethoxy) phenyl) -1H-1,2,3-triazol-4-yl) phenyl) -3- (5-tert-butylisoxazol-3-yl) -urea (named CL-116)

1-(4-(1-(3-bromo-4-(2-morpholinoethoxy)phenyl)-1H-1,2,3-triazol-4-yl)phenyl)-3-(5-(tert-butyl)isoxazol-3-yl)urea

The synthesis method is basically the same as in example 1.

¹ H NMR(400MHz,d ⁶ -DMSO)δ9.59(s,1H),9.19(s,1H),9.00(s,1H),8.18(d,J＝2.8Hz,1H),7.92(dd,J＝8.8Hz,2.8Hz,1H),7.85(d,J＝8.8Hz,2H),7.64(d,J＝8.8Hz,2H),7.36(d,J＝8.8Hz,1H),6.53(s,1H),4.26(t,J＝5.6Hz,2H),3.58(t,J＝4.4Hz,4H),2.77(t,J＝5.6Hz,2H),2.54(t,J＝4.4Hz,4H),1.30(s,9H).ESI-MS m/z 610.2(M+H) ⁺ 。

Example 17: preparation of 1- (4- (1- (4- (2-morpholinoethoxy) phenyl) -1H-1,2,3-triazol-4-yl) phenyl) -3- (5-trifluoromethylthiazol-2-yl) -urea (named CL-117)

1-(4-(1-(4-(2-morpholinoethoxy)phenyl)-1H-1,2,3-triazol-4-yl)phenyl)-3-(5-(trifluoromethyl)thiazol-2-yl)urea

The synthesis method is basically the same as in example 1.

¹ H NMR(400MHz,d ⁶ -DMSO)δ11.08(s,1H),9.28(s,1H),9.13(s,1H),7.83-7.90(m,5H),7.61(d,J＝8.8Hz,2H),7.17(d,J＝8.8Hz,1H),4.17(t,J＝5.6Hz,2H),3.59(t,J＝4.4Hz,4H),2.73(t,J＝5.6Hz,2H),2.49-2.50(m,4H).ESI-MS m/z 560.1(M+H) ⁺ 。

Example 18: preparation of 1- (5-tert-butylthiazol-2-yl) -3- (4- (1- (4- (2-morpholinoethoxy) phenyl) -1H-1,2,3-triazol-4-yl) phenyl) -urea (named CL-118)

1-(5-(tert-butyl)thiazol-2-yl)-3-(4-(1-(4-(2-morpholinoethoxy)phenyl)-1H-1,2,3-triazol-4-yl)phenyl)urea

The synthesis method is basically the same as in example 1.

¹ H NMR(400MHz,d ⁶ -DMSO)δ10.75(s,1H),9.13(s,1H),9.03(s,1H),7.88(d,J＝8.8Hz,2H),7.84(d,J＝8.8Hz,2H),7.59(d,J＝8.8Hz,2H),7.18(d,J＝8.8Hz,1H),6.65(s,1H),4.17(t,J＝5.6Hz,2H),3.59(t,J＝4.4Hz,4H),2.72(t,J＝5.6Hz,2H),2.48-2.50(m,4H),1.26(s,9H).ESI-MS m/z 560.1(M+H) ⁺ 。

Example 19: preparation of 1- (5- (tert-butyl) isoxazol-3-yl) -3- (4- (1- (2-chloro-4- (2-tetrahydropyrrole-1-yl)) ethoxyphenyl) -1H-1,2,3-triazol-4-yl) phenyl) urea (designated as CL-119)

1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(1-(2-chloro-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,3-triazol-4-yl)phenyl)urea

The synthesis method is basically the same as in example 1.

¹ H NMR(400MHz,d ⁶ -DMSO)δ9.58(s,1H),9.01(s,1H),8.87(s,1H),7.88(d,J＝8.4Hz,2H),7.66(d,J＝8.8Hz,1H),7.58(d,J＝8.8Hz,2H),7.39(d,J＝2.4Hz,1H),7.16(dd,J＝8.8Hz,J＝2.4Hz,1H),6.53(s,1H),4.23(t,J＝5.6Hz,2H),2.87(t,J＝5.6Hz,2H),2.53-2.59(m,4H),1.70-1.74(m,4H),1.31(s,9H).ESI-MS m/z 550.2(M+H) ⁺ 。

Example 20: preparation of 1- (5- (tert-butyl) isoxazol-3-yl) -3- (4- (1- (4- (3-dimethylaminopropoxy) -3-methoxyphenyl) -1H-1,2,3-triazol-4-yl) phenyl) urea (named CL-120)

1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(1-(4-(3-(dimethylamino)propoxy)-3-methoxyphenyl)-1H-1,2,3-triazol-4-yl)phenyl)urea

The synthesis method is basically the same as in example 1.

¹ H NMR(400MHz,d ⁶ -DMSO)δ9.61(s,1H),9.15(s,1H),9.05(s,1H),7.87(d,J＝8.4Hz,2H),7.59(d,J＝8.4Hz,2H),7.52(d,J＝2.4Hz,1H),7.45(dd,J＝8.4Hz,J＝2.4Hz,1H),7.16(d,J＝8.4Hz,1H),6.53(s,1H),4.07(t,J＝6.4Hz,2H),3.90(s,3H),2.44(t,J＝7.2Hz,2H),2.21(s,6H),1.87-1.93(m,2H),1.30(s,9H).ESI-MS m/z 534.2(M+H) ⁺ .

Example 21: preparation of 1- (5-tert-butylisoxazol-3-yl) -3- (4- (1- (2-chloro-4- (2-morpholinoethoxy) phenyl) -1H-1,2,3-triazol-4-yl) phenyl) urea (named CL-121)

1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(1-(2-chloro-4-(2-morpholinoethoxy)phenyl)-1H-1,2,3-triazol-4-yl)phenyl)urea

The synthesis method is basically the same as in example 1.

¹ H NMR(400MHz,d ⁶ -DMSO)δ9.56(s,1H),8.95(s,1H),8.87(s,1H),7.88(d,J＝8.8Hz,2H),7.65(d,J＝8.8Hz,1H),7.58(d,J＝8.8Hz,2H),7.39(d,J＝2.8Hz,1H),7.16(dd,J＝8.8Hz,J＝2.8Hz,1H),6.53(s,1H),4.24(t,J＝6.4Hz,2H),3.60(t,J＝4.8Hz,4H),2.73(t,J＝6.0Hz,2H),2.49-2.51(m,4H),1.31(s,9H).ESI-MS m/z 566.2(M+H) ⁺ 。

Example 22: preparation of 1- (5-tert-butylisoxazol-3-yl) -3- (4- (1- (2-bromo-4- (2-morpholinoethoxy) phenyl) -1H-1,2,3-triazol-4-yl) phenyl) urea (named CL-122)

1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(1-(2-bromo--4-(2-morpholinoethoxy)phenyl)-1H-1,2,3-triazol-4-yl)phenyl)urea

The synthesis method is basically the same as in example 1.

¹ H NMR(300MHz,d ⁶ -DMSO)δ9.57(s,1H),8.96(s,1H),8.84(s,1H),7.88(d,J＝8.7Hz,2H),7.56-7.63(m,3H),7.51(d,J＝2.7Hz,1H),7.21(dd,J＝8.7Hz,J＝2.7Hz,1H),6.53(s,1H),4.24(t,J＝5.7Hz,2H),3.60(t,J＝5.7Hz,4H),2.73(t,J＝5.7Hz,2H),2.49-2.51(m,4H),1.31(s,9H).ESI-MS m/z 610.2(M+H) ⁺ 。

Example 23: preparation of 1- (5-tert-butylisoxazol-3-yl) -3- (4- (1- (4- (2-morpholinoethoxy-2-trifluoromethyl) phenyl) -1H-1,2,3-triazol-4-yl) phenyl) urea (named CL-123)

1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(1-(4-(2-morpholinoethoxy)-2-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)phenyl)urea

The synthesis method is basically the same as in example 1.

¹ H NMR(400MHz,d ⁶ -DMSO)δ9.57(s,1H),8.97(s,1H),8.84(s,1H),7.87(d,J＝8.8Hz,2H),7.71(d,J＝8.8Hz,1H),7.58(d,J＝8.8Hz,2H),7.49-7.52(m,1H),7.46-7.48(m,1H),6.53(s,1H),4.30(t,J＝5.6Hz,2H),3.59(t,J＝4.4Hz,4H),2.73(t,J＝5.6Hz,2H),2.49-2.51(m,4H),1.30(s,9H).ESI-MS m/z 600.2(M+H) ⁺ .

Example 24: preparation of 1- (5-tert-butylisoxazol-3-yl) -3- (4- (1- (2-fluoro-4- (2-morpholinoethoxy) phenyl) -1H-1,2,3-triazol-4-yl) phenyl) urea (named CL-124)

1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(1-(2-fluoro--4-(2-morpholinoethoxy)phenyl)-1H-1,2,3-triazol-4-yl)phenyl)urea

The synthesis method is basically the same as in example 1.

¹ H NMR(400MHz,d ⁶ -DMSO)δ9.58(s,1H),8.98(s,1H),8.90(s,1H),7.89(d,J＝8.8Hz,2H),7.75(t,J＝8.8Hz,1H),7.58(d,J＝8.8Hz,2H),7.22-7.25(m,1H),7.01-7.04(m,1H),6.53(s,1H),4.21(t,J＝5.6Hz,2H),3.59(t,J＝4.8Hz,4H),2.73(t,J＝5.6Hz,2H),2.49-2.51(m,4H),1.30(s,9H).ESI-MS m/z 550.2(M+H) ⁺ 。

Example 25: preparation of 1- (5-tert-butylisoxazol-3-yl) -3- (4- (1- (4- (2-morpholinoethoxy) -2-nitrophenyl) -1H-1,2,3-triazol-4-yl) phenyl) urea (named CL-125)

1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(1-(4-(2-morpholinoethoxy)-2-nitrophenyl)-1H-1,2,3-triazol-4-yl)phenyl)urea

The synthesis method is basically the same as in example 1.

¹ H NMR(400MHz,d ⁶ -DMSO)δ9.59(s,1H),9.00(s,1H),8.99(s,1H),7.81-7.88(m,4H),7.51-7.61(m,3H),6.54(s,1H),4.31(t,J＝7.2Hz,2H),3.59(t,J＝6.0Hz,4H),2.76(t,J＝7.2Hz,2H),2.49-2.51(m,4H),1.31(s,9H).ESI-MS m/z 577.2(M+H) ⁺ 。

Example 26: preparation of 1- (5-tert-butylisoxazol-3-yl) -3- (2-methoxy-4- (1- (4- (2-morpholinoethoxy) phenyl) -1H-1,2,3-triazol-4-yl) phenyl) urea (named CL-126)

1-(5-(tert-butyl)isoxazol-3-yl)-3-(2-methoxy-4-(1-(4-(2-morpholinoethoxy)phenyl)-1H-1,2,3-triazol-4-yl)phenyl)urea

The synthesis method is basically the same as in example 1.

¹ H NMR(400MHz,d ⁶ -DMSO)δ10.12(s,1H),9.18(s,1H),8.77(s,1H),8.24(d,J＝7.6Hz,1H),7.84(d,J＝7.6Hz,2H),7.59(s,1H),7.50(d,J＝7.6Hz,1H),7.18(d,J＝7.6Hz,2H),6.51(s,1H),4.17(t,J＝5.6Hz,2H),3.99(s,3H),3.59(t,J＝4.8Hz,4H),2.72(t,J＝5.6Hz,2H),2.49-2.51(m,4H),1.31(s,9H).ESI-MS m/z 562.2(M+H) ⁺ 。

Example 27: preparation of 1- (5-tert-butylisoxazol-3-yl) -3- (2-fluoro-4- (1- (4- (2-morpholinoethoxy) phenyl) -1H-1,2,3-triazol-4-yl) phenyl) urea (named CL-127)

1-(5-(tert-butyl)isoxazol-3-yl)-3-(2-fluoro-4-(1-(4-(2-morpholinoethoxy)phenyl)-1H-1,2,3-triazol-4-yl)phenyl)urea

The synthesis method is basically the same as in example 1.

¹ H NMR(400MHz,d ⁶ -DMSO)δ9.94(s,1H),9.20(s,1H),8.96(s,1H),8.26(t,J＝8.4Hz,1H),7.82(d,J＝8.8Hz,2H),7.77-7.81(m,2H),7.19(d,J＝8.8Hz,2H),6.52(s,1H),4.18(t,J＝5.6Hz,2H),3.60(t,J＝4.8Hz,4H),2.72(t,J＝5.6Hz,2H),2.49-2.51(m,4H),1.31(s,9H).ESI-MS m/z 550.1(M+H) ⁺ 。

Example 28: preparation of 1- (5-tert-butylisoxazol-3-yl) -3- (2-chloro-4- (1- (4- (2-morpholinoethoxy) phenyl) -1H-1,2,3-triazol-4-yl) phenyl) urea (named CL-128)

1-(5-(tert-butyl)isoxazol-3-yl)-3-(2-chloro-4-(1-(4-(2-morpholinoethoxy)phenyl)-1H-1,2,3-triazol-4-yl)phenyl)urea

The synthesis method is basically the same as in example 1.

¹ H NMR(400MHz,d ⁶ -DMSO)δ10.31(s,1H),9.23(s,1H),8.80(s,1H),8.31(t,J＝8.8Hz,1H),8.02(d,J＝2.0Hz,1H),7.88(dd,J＝8.8Hz,2.0Hz,1H),7.82(d,J＝8.8Hz,2H),7.18(d,J＝8.8Hz,2H),6.50(s,1H),4.18(t,J＝5.6Hz,2H),3.59(t,J＝4.8Hz,4H),2.72(t,J＝5.6Hz,2H),2.49-2.51(m,4H),1.31(s,9H).ESI-MS m/z 566.2(M+H) ⁺ 。

Example 29: preparation of 1- (5-tert-butylisoxazol-3-yl) -3- (2-methyl-4- (1- (4- (2-morpholinoethoxy) phenyl) -1H-1,2,3-triazol-4-yl) phenyl) urea (named CL-129)

1-(5-(tert-butyl)isoxazol-3-yl)-3-(2-methyl-4-(1-(4-(2-morpholinoethoxy)phenyl)-1H-1,2,3-triazol-4-yl)phenyl)urea

The synthesis method is basically the same as in example 1.

¹ H NMR(400MHz,d ⁶ -DMSO)δ9.94(s,1H),9.11(s,1H),8.35(s,1H),8.03(d,J＝8.8Hz,2H),7.83(d,J＝8.4Hz,1H),7.78(d,J＝2.0Hz,1H),7.70(dd,J＝8.4Hz,2.0Hz,1H),7.17(d,J＝8.8Hz,2H),6.48(s,1H),4.17(t,J＝5.6Hz,2H),3.59(t,J＝4.8Hz,4H),2.72(t,J＝5.6Hz,2H),2.49-2.51(m,4H),2.23(s,3H),1.31(s,9H).ESI-MS m/z 546.2(M+H) ⁺ 。

Example 30: preparation of 1- (5-tert-butylisoxazol-3-yl) -3- (3-fluoro-4- (1- (4- (2-morpholinoethoxy) -phenyl) -1H-1,2,3-triazol-4-yl) phenyl) -urea (named CL-130)

1-(5-(tert-butyl)isoxazol-3-yl)-3-(3-fluoro-4-(1-(4-(2-morpholinoethoxy)phenyl)-1H-1,2,3-triazol-4-yl)phenyl)urea

The synthesis method is basically the same as in example 1.

¹ H NMR(400MHz,d ⁶ -DMSO)δ9.68(s,1H),9.18(s,1H),8.89(d,J＝3.2Hz,1H),8.08(t,J＝8.4Hz,1H),7.83(d,J＝9.2Hz,2H),7.70(dd,J＝9.2Hz,2.0Hz,1H),7.27(dd,J＝8.4Hz,2.0Hz,1H),7.16(d,J＝9.2Hz,2H),6.54(s,1H),4.18(t,J＝5.6Hz,2H),3.59(t,J＝4.4Hz,4H),2.72(t,J＝5.6Hz,2H),2.49-2.51(m,4H),2.23(s,3H),1.31(s,9H).ESI-MS m/z 550.2(M+H) ⁺ 。

Example 31: preparation of 1- (5-tert-butylisoxazol-3-yl) -3- (4- (1- (3-chloro-4- (2-morpholinoethoxy) -phenyl) -1H-1,2,3-triazol-4-yl) phenyl) -urea (named CL-131)

1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(1-(3-chloro-4-(2-morpholinoethoxy)phenyl)-1H-1,2,3-triazol-4-yl)phenyl)urea

The synthesis method is basically the same as in example 1.

¹ H NMR(400MHz,d ⁶ -DMSO)δ9.58(s,1H),9.18(s,1H),8.98(s,1H),8.05(d,J＝2.4Hz,1H),7.83-7.89(m,3H),7.58(d,J＝8.8Hz,2H),7.41(d,J＝8.8Hz,1H),6.53(s,1H),4.27(t,J＝5.6Hz,2H),3.58(t,J＝4.4Hz,4H),2.76(t,J＝5.6Hz,2H),2.49-2.51(m,4H),1.30(s,9H).ESI-MS m/z 566.2(M+H) ⁺ 。

Example 32: preparation of 1- (5-tert-butylisoxazol-3-yl) -3- (4- (1- (3-methoxy-4- (2-morpholinoethoxy) -phenyl) -1H-1,2,3-triazol-4-yl) phenyl) -urea (named CL-132)

1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(1-(3-methoxy-4-(2-morpholinoethoxy)phenyl)-1H-1,2,3-triazol-4-yl)phenyl)urea

The synthesis method is basically the same as in example 1.

¹ H NMR(400MHz,d ⁶ -DMSO)δ9.57(s,1H),9.15(s,1H),8.96(s,1H),7.87(d,J＝8.8Hz,2H),7.59(d,J＝8.8Hz,2H),7.52(d,J＝2.4Hz,1H),7.43(dd,J＝8.8Hz,2.4Hz,1H),7.20(d,J＝8.8Hz,1H),6.53(s,1H),4.16(t,J＝5.6Hz,2H),3.89(s,3H),3.59(t,J＝4.4Hz,4H),2.73(t,J＝5.6Hz,2H),2.49-2.51(m,4H),1.31(s,9H).ESI-MS m/z 562.2(M+H) ⁺ 。

Example 33: preparation of 1- (5-tert-butylisoxazol-3-yl) -3- (4- (1- (2-chloro-4- (2-morpholinoethoxy) -phenyl) -1H-1,2,3-triazol-4-yl) -2-fluorophenyl) -urea (named CL-133)

1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(1-(2-chloro-4-(2-morpholinoethoxy)phenyl)-1H-1,2,3-triazol-4-yl)-2-fluorophenyl)urea

The synthesis method is basically the same as in example 1.

¹ H NMR(400MHz,d ⁶ -DMSO)δ9.92(s,1H),8.95(s,2H),8.26(t,J＝8.8Hz,1H),7.78(d,J＝8.4Hz,1H),7.70(d,J＝8.8Hz,1H),7.66(d,J＝8.8Hz,1H),7.40(d,J＝2.4Hz,1H),7.16(dd,J＝8.8Hz,2.4Hz,1H),6.52(s,1H),4.23(t,J＝5.6Hz,2H),3.59(t,J＝4.4Hz,4H),2.73(t,J＝5.6Hz,2H),2.49-2.51(m,4H),1.30(s,9H).ESI-MS m/z 584.2(M+H) ⁺ 。

Example 34: preparation of 1- (5-tert-butylisoxazol-3-yl) -3- (4- (1- (3-methyl-4- (2-morpholinoethoxy) -phenyl) -1H-1,2,3-triazol-4-yl) phenyl) -urea (named CL-134)

1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(1-(3-methyl-4-(2-morpholinoethoxy)phenyl)-1H-1,2,3-triazol-4-yl)phenyl)urea

The synthesis method is basically the same as in example 1.

¹ H NMR(400MHz,d ⁶ -DMSO)δ9.58(s,1H),9.09(s,1H),8.97(s,1H),7.87(d,J＝8.8Hz,2H),7.74(d,J＝2.4Hz,1H),7.70(dd,J＝8.8Hz,2.4Hz,1H),7.58(d,J＝8.8Hz,2H),7.17(d,J＝8.8Hz,1H),6.53(s,1H),4.19(t,J＝5.6Hz,2H),3.59(t,J＝4.4Hz,4H),2.73(t,J＝5.6Hz,2H),2.49-2.51(m,4H),2.26(s,3H),1.31(s,9H).ESI-MS m/z 546.2(M+H) ⁺ 。

Example 35: preparation of 1- (5-tert-butylisoxazol-3-yl) -3- (4- (1- (3-trifluoromethyl-4- (2-morpholinoethoxy) -phenyl) -1H-1,2,3-triazol-4-yl) phenyl) -urea (named CL-135)

1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(1-(3-trifluoromethyl-4-(2-morpholinoethoxy)phenyl)-1H-1,2,3-triazol-4-yl)phenyl)urea

The synthesis method is basically the same as in example 1.

¹ H NMR(400MHz,d ⁶ -DMSO)δ9.59(s,1H),9.28(s,1H),8.97(s,1H),8.16-8.21(m,2H),7.86(d,J＝8.8Hz,2H),7.59(dd,J＝8.8Hz,2.4Hz,1H),7.53-7.56(m,1H),6.53(s,1H),4.33(t,J＝5.6Hz,2H),3.57(t,J＝4.4Hz,4H),2.75(t,J＝5.6Hz,2H),2.49-2.51(m,4H),1.31(s,9H).ESI-MS m/z 600.2(M+H) ⁺ 。

Example 36: preparation of 1- (5-tert-butylisoxazol-3-yl) -3- (4- (1- (2-chloro-4- (2-dimethylaminoethoxy) -phenyl) -1H-1,2,3-triazol-4-yl) phenyl) -urea (named CL-136)

1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(1-(2-chloro-4-(2-(dimethylamino)ethoxy)phenyl)-1H-1,2,3-triazol-4-yl)phenyl)urea

The synthesis method is basically the same as in example 1.

¹ H NMR(400MHz,d ⁶ -DMSO)δ9.57(s,1H),8.97(s,1H),8.86(s,1H),7.87(d,J＝8.8Hz,2H),7.64(d,J＝8.8Hz,1H),7.56(d,J＝8.8Hz,2H),7.38(d,J＝2.4Hz,1H),7.15(dd,J＝8.8Hz,2.4Hz,1H),6.53(s,1H),4.19(t,J＝5.6Hz,2H),2.65(t,J＝5.6Hz,2H),2.23(s,6H),1.30(s,9H).ESI-MS m/z 524.2(M+H) ⁺ 。

Example 37: preparation of 1- (5-tert-butylisoxazol-3-yl) -3- (4- (1- (2-chloro-4- (3-morpholinopropoxy) -phenyl) -1H-1,2,3-triazol-4-yl) phenyl) -urea (named CL-137)

1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(1-(2-chloro-4-(3-morpholinopropoxy)phenyl)-1H-1,2,3-triazol-4-yl)phenyl)urea

The synthesis method is basically the same as in example 1.

¹ H NMR(400MHz,d ⁶ -DMSO)δ9.59(s,1H),9.01(s,1H),8.86(s,1H),7.89(d,J＝8.8Hz,2H),7.65(d,J＝8.8Hz,1H),7.58(d,J＝8.8Hz,2H),7.36(d,J＝2.4Hz,1H),7.14(dd,J＝8.8Hz,2.4Hz,1H),6.54(s,1H),4.15(t,J＝6.0Hz,2H),3.59(t,J＝4.4Hz,4H),2.43(t,J＝6.0Hz,2H),2.39-2.41(m,4H),1.88-1.95(m,2H),1.31(s,9H).ESI-MS m/z 580.2(M+H) ⁺ 。

Example 38: preparation of 1- (5-tert-butylisoxazol-3-yl) -3- (4- (1- (4- (2-morpholinoethoxy) -3-nitrophenyl) -1H-1,2,3-triazol-4-yl) phenyl) -urea (named CL-138)

1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(1-(-4-(2-morpholinoethoxy)-3-nitrophenyl)-1H-1,2,3-triazol-4-yl)phenyl)urea

The synthesis method is basically the same as in example 1.

¹ H NMR(400MHz,d ⁶ -DMSO)δ9.58(s,1H),9.27(s,1H),8.97(s,1H),8.49(d,J＝2.8Hz,1H),8.25(dd,J＝8.8Hz,2.8Hz,1H),7.86(d,J＝8.4Hz,2H),7.67(d,J＝8.8Hz,1H),7.59(d,J＝8.8Hz,2H),6.53(s,1H),4.38(t,J＝5.6Hz,2H),3.57(t,J＝4.4Hz,4H),2.75(t,J＝5.6Hz,2H),2.49-2.51(m,4H),1.31(s,9H).ESI-MS m/z 577.2(M+H) ⁺ 。

Example 39: preparation of 1- (5-tert-butylisoxazol-3-yl) -3- (4- (1- (2-chloro-4- (2-morpholinoethoxy) -phenyl) -1H-1,2,3-triazol-4-yl) -3-fluorophenyl) -urea (named CL-139)

1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(1-(2-chloro-4-(2-morpholinoethoxy)phenyl)-1H-1,2,3-triazol-4-yl)-3-fluorophenyl)urea

The synthesis method is basically the same as in example 1.

¹ H NMR(400MHz,d ⁶ -DMSO)δ9.98(s,1H),9.20(s,1H),8.68(d,J＝3.2Hz,1H),8.10(t,J＝8.8Hz,1H),7.65-7.68(m,3H),7.40(d,J＝2.8Hz,1H),7.29(dd,J＝8.8Hz,1.6Hz,1H),7.17(dd,J＝8.8Hz,2.4Hz,1H),6.54(s,1H),4.23(t,J＝5.6Hz,2H),3.59(t,J＝4.4Hz,4H),2.73(t,J＝5.6Hz,2H),2.49-2.51(m,4H),1.30(s,9H).ESI-MS m/z 584.1(M+H) ⁺ 。

Example 40: preparation of 1- (5-tert-butylisoxazol-3-yl) -3- (3-methyl-4- (1- (4- (2-morpholinoethoxy) -phenyl) -1H-1,2,3-triazol-4-yl) -phenyl) -urea (named CL-140)

1-(5-(tert-butyl)isoxazol-3-yl)-3-(3-methyl-4-(1-(4-(2-morpholinoethoxy)phenyl)-1H-1,2,3-triazol-4-yl)phenyl)urea

The synthesis method is basically the same as in example 1.

¹ H NMR(400MHz,d ⁶ -DMSO)δ9.58(s,1H),8.89(s,2H),7.88(d,J＝9.2Hz,2H),7.74(d,J＝8.0Hz,1H),7.41-7.44(m,2H),7.17(d,J＝9.2Hz,2H),6.54(s,1H),4.17(t,J＝5.6Hz,2H),3.59(t,J＝4.4Hz,4H),2.72(t,J＝5.6Hz,2H),2.49-2.51(m,4H),1.30(s,9H).ESI-MS m/z 546.2(M+H) ⁺ 。

Example 41: preparation of 1- (5-tert-butylisoxazol-3-yl) -3- (4- (1- (2-chloro-4- (2-morpholinoethylamino) phenyl) -1H-1,2,3-triazol-4-yl) phenyl) -urea (named CL-141)

1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(1-(2-chloro-4-((2-morpholinoethyl)amino)phenyl)-1H-1,2,3-triazol-4-yl)phenyl)urea

The synthesis method is basically the same as in example 1.

¹ H NMR(400MHz,d ⁶ -DMSO)δ10.42(s,1H),8.83(s,1H),7.94(d,J＝8.0Hz,2H),7.41(d,J＝8.0Hz,2H),7.33(d,J＝8.4Hz,1H),6.81(s,1H),6.66(d,J＝8.0Hz,1H),6.49(s,1H),5.98(s,2H),3.83(t,J＝5.6Hz,2H),3.64(t,J＝4.4Hz,4H),2.46-2.53(m,6H),1.28(s,9H).ESI-MS m/z565.1(M+H) ⁺ 。

Example 42: preparation of 1- (5-tert-butylisoxazol-3-yl) -3- (4- (1- (2-chloro-4- (2-dimethylamino) ethylaminophenyl) -1H-1,2,3-triazol-4-yl) phenyl) -urea (named CL-142)

1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(1-(2-chloro-4-((2-(dimethylamino)ethyl)amino)phenyl)-1H-1,2,3-triazol-4-yl)phenyl)urea

The synthesis method is basically the same as in example 1.

¹ H NMR(400MHz,d ⁶ -DMSO)δ10.33(s,1H),8.89(s,1H),7.95(d,J＝8.0Hz,2H),7.40(d,J＝8.0Hz,2H),7.33(d,J＝8.8Hz,1H),6.81(s,1H),6.66(d,J＝8.0Hz,1H),6.49(s,1H),5.98(s,2H),3.79(t,J＝5.6Hz,2H),2.45-2.50(m,2H),2.21(s,6H),1.28(s,9H).ESI-MS m/z 523.1(M+H) ⁺ 。

Example 43: preparation of 1- (5- (tert-butyl) isoxazol-3-yl) -3- (4- (4- (4- (2-morpholinoethoxy) phenyl) -1H-1,2,3-triazol-1-yl) phenyl) urea (named CL-201)

1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(4-(4-(2-morpholinoethoxy)phenyl)-1H-1,2,3-triazol-1-yl)phenyl)urea

Scheme a:

step a, synthesis of p-ethynylphenol (4-ethylphenol) (compound 12)

P-iodophenol (22g, 100mmol), trimethylethynylsilicon (13.7g, 140mmol), pd (PPh) ₃ ) ₂ Cl ₂ (700mg, 1mmol), cuI (190mg, 1mmol) in DMF (150 mL) under argon 60 ℃ for 4 hours. Filtering, diluting the filtrate with water, and extracting with ethyl acetate for 2-3 times. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was dissolved in THF, 1M tetrabutylammonium fluoride (100 mL) was added and stirred for 1 hour with saturated NH ₄ After quenching with aqueous Cl, the reaction mixture was extracted 3 times with dichloromethane, the combined organic phases were collected, concentrated, and passed through a silica gel column using petroleum ether/ethyl acetate to afford compound 12 (9.4 g, 80%).

Step b Synthesis of 1-azido-4-nitrobenzene (1-azido-4-nitrobenzene) (Compound 13)

4-Nitro iodobenzene (23g, 92mmol), naN ₃ (8.9g, 137mmol), cuI (1.75g, 9.2mmol), L-sodium ascorbate (1.82g, 9.2mmol), N, N' -dimethylethylenediamine (1.2g, 13.7 mmol) in DMSO: h ₂ O (volume ratio 9, 1,200mL) for 5h. After completion of the reaction, the reaction mixture was poured into water, extracted twice with ethyl acetate, the organic phases were collected, dried over anhydrous sodium sulfate, concentrated and applied to a silica gel column using petroleum ether/ethyl acetate to obtain compound 13 (11.7 g, yield 78%).

Step c Synthesis of 4- (1- (4-nitrophenyl) -1H-1,2,3-triazol-4-yl) phenol (4- (1- (4-nitrophenyl) -1H-1,2,3-triazol-4-yl) phenol) (Compound 14)

Compound 12 (8.4 g,71.1 mmol), compound 13 (11.7 g,71.1 mmol), cuI (1.35g, 7.1 mmol) were reacted in DMF (100 mL) at 60 ℃ for 4 hours. After the reaction, water (100 mL) was added, ethyl acetate was used for extraction 2-3 times, and the organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then rapidly separated using a silica gel column to obtain compound 14 (18 g). ESI-MS M/z 283.1 (M + H) ⁺ )。

Step d Synthesis of 4- (2- (4- (1- (4-nitrophenyl) -1H-1,2,3-triazol-4-yl) phenoxy) ethyl) morpholine (4- (2- (4- (1- (4-nitrophenyl) -1H-1,2,3-triazol-4-yl) phenoxy) ethyl) morpholine) (Compound 15)

Compound 14 (17.5g, 62mmol), N- (2-chloroethyl) morpholine hydrochloride (13.8g, 74.4mmol), cesium carbonate (60g, 186mmol) in DMF (200 mL) was stirred overnight at 60 ℃ until the reaction was complete. Water (200 mL) was added, extraction was performed 2-3 times with ethyl acetate, the organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure and flash-passed through a silica gel column to give compound 15 (20 g). ESI-MS M/z 396.1 (M + H) ⁺ )。

Step e Synthesis of 4- (4- (4- (2-morpholinoethoxy) phenyl) -1H-1,2,3-triazol-1-yl) aniline (4- (4- (2-morpholinoethoxy) phenyl) -1H-1,2,3-triazol-1-yl) aniline) (Compound 16)

Compound 15 (16.4g, 41.5mmol), iron powder (11.6g, 208mmol), NH ₄ Cl (8.9 g, 167mmol) was refluxed in 90% ethanol for 5 hours until the starting material had been completely converted. Filtering with diatomaceous earth, washing the filter cake with hot ethanol solution, concentrating the mother liquor, and adding saturated Na ₂ CO ₃ The solution was extracted twice with DCM, and the organic phase was collected, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 16 (13.6 g, 90%). ESI-MS M/z 366.1 (M + H) ⁺ )。

Step f.preparation of 1- (5-tert-butylisoxazol-3-yl) -3- (4- (4- (4- (2-morpholinoethoxy) phenyl) -1H-1,2,3-triazol-1-yl) phenyl) urea (named CL-201)

Compound 16 (200mg, 0.54mmol), compound 8 (170mg, 0.65mmol), triethylamine (164mg, 1.62mmol) were stirred in DMF (5 mL) at 60 ℃ for 5 hours. Water (10 mL) was added, extraction was performed 2 times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and compound CL-201 (240 mg) was isolated using a silica gel column.

Scheme B: synthesis of method B was performed analogously to Compound CL-101.

¹ H NMR(400MHz,d ⁶ -DMSO)δ9.64(s,1H),9.12(s,H),9.10(s,1H),7.86-7.89(m,4H),7.70(d,J＝8.8Hz,2H),7.07(d,J＝8.8Hz,2H),6.54(s,1H),4.14(t,J＝5.6Hz,2H),3.60(t,J＝4.8Hz,4H),2.72(t,J＝5.6Hz,2H),2.50-2.52(m,4H),1.31(s,9H). ¹³ C NMR(101MHz,d ⁶ -DMSO)δ180.7,158.8,158.7,151.8,147.6,139.8,131.8,130.0,127.1,121.1,119.6,118.9,115.4,93.0,66.4,65.6,57.3,53.9,33.0,28.8.ESI-MS m/z 532.1(M+H) ⁺ 。

Example 44: preparation of 1- (4- (4- (4- (2-morpholinoethoxy) phenyl) -1H-1,2,3-triazol-1-yl) phenyl) -3- (thiazol-2-yl) urea (named CL-202)

1-(4-(4-(4-(2-morpholinoethoxy)phenyl)-1H-1,2,3-triazol-1-yl)phenyl)-3-(thiazol-2-yl)urea

The synthesis method is substantially the same as in example 43.

¹ H NMR(400MHz,d ⁶ -DMSO)δ10.82(s,1H),9.45(s,H),9.13(s,1H),7.85-7.89(m,4H),7.73(d,J＝8.8Hz,2H),7.39(d,J＝3.6Hz,1H),7.14(d,J＝3.6Hz,1H),7.07(d,J＝8.8Hz,2H),4.15(t,J＝5.6Hz,2H),3.61(t,J＝4.4Hz,4H),2.75(m,2H),2.50-2.52(m,4H). ¹³ C NMR(101MHz,d ⁶ -DMSO)δ160.1,158.9,152.5,147.6,139.6,131.9,127.1,123.4,121.2,119.7,118.9,115.4,112.9,66.5,65.7,57.4,554.0.ESI-MS m/z 492.2(M+H) ⁺ 。

Example 45: preparation of ethyl 2- (3- (4- (4- (4- (2-morpholinoethoxy) phenyl) -1H-1,2,3-triazol-1-yl) phenyl) urea) thiazole-5-carboxylate (designated as CL-203)

2-(3-(4-(4-(4-(2-morpholinoethoxy)phenyl)-1H-1,2,3-triazol-1-yl)phenyl)ureido)thiazole-5-carboxylate

The synthesis method is substantially the same as in example 43.

¹ H NMR(400MHz,d ⁶ -DMSO)δ11.27(s,1H),9.44(s,1H),9.13(s,1H),8.09(s,1H),7.90(d,J＝8.8Hz,2H),7.87(d,J＝8.8Hz,2H),7.83(d,J＝8.4Hz,2H),7.07(d,J＝8.4Hz,2H),4.27(q,J＝7.2Hz,2H),4.14(t,J＝5.6Hz,2H),3.60(t,J＝4.4Hz,4H),2.72(t,J＝5.6Hz,2H),2.50-2.52(m,4H),1.29(t,J＝7.2Hz,3H). ¹³ C NMR(101MHz,d ⁶ -DMSO)δ164.3,161.9,158.9,147.6,139.0,132.3,127.1,123.4,121.2,120.8,120.1,118.9,115.4,66.6,65.8,61.2,57.5,54.1,14.7.ESI-MS m/z 564.2(M+H) ⁺ 。

Example 46: preparation of 1- (5-tert-butylisoxazol-3-yl) -3- (4- (4- (4- (3-dimethylaminopropoxy) phenyl) -1H-1,2,3-triazol-1-yl) phenyl) urea (named CL-204)

1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(4-(4-(3-(dimethylamino)propoxy)phenyl)-1H-1,2,3-triazol-1-yl)phenyl)urea

The synthesis method is substantially the same as in example 43.

¹ H NMR(400MHz,d ⁶ -DMSO)δ9.73(s,1H),9.37(s,H),9.11(s,1H),7.84-7.87(m,4H),7.69(d,J＝8.8Hz,2H),7.04(d,J＝8.8Hz,2H),6.53(s,1H),4.05(t,J＝6.0Hz,2H),2.45(t,J＝7.2Hz,2H),2.22(s,6H),1.90-1.94(m,2H),1.30(s,9H). ¹³ C NMR(101MHz,d ⁶ -DMSO)δ180.7,159.1,158.5,151.9,147.6,139.7,131.8,129.1,127.1,123.3,121.1,119.6,118.9,115.3,93.0,66.2,56.0,45.4,33.0,28.8,27.1..ESI-MS m/z 504.2(M+H) ⁺ 。

Example 47: preparation of 1- (5-tert-butylisoxazol-3-yl) -3- (2-fluoro-4- (4- (4- (2-morpholinoethoxy) phenyl) -1H-1,2,3-triazol-1-yl) phenyl) urea (named CL-205)

1-(5-(tert-butyl)isoxazol-3-yl)-3-(2-fluoro-4-(4-(4-(2-morpholinoethoxy)phenyl)-1H-1,2,3-triazol-1-yl)phenyl)urea

The synthesis method is substantially the same as in example 43.

¹ H NMR(400MHz,d ⁶ -DMSO)δ9.93(s,1H),9.16(s,H),9.02(s,1H),8.33-8.35(m,1H),7.91-7.95(m,1H),7.83(d,J＝8.8Hz,2H),7.78(d,J＝8.8Hz,1H),7.07(d,J＝8.8Hz,2H),6.52(s,1H),4.14(t,J＝6.0Hz,2H),3.59(t,J＝4.8Hz,4H),2.71(t,J＝6.0Hz,2H),2.48-2.50(m,4H),1.31(s,9H). ¹³ C NMR(101MHz,d ⁶ -DMSO)δ180.9,158.7(d,J＝45.2Hz),152.3(d,J＝242.3Hz),151.5,147.7,131.8(d,J＝10.0Hz),127.5(d,J＝10.6Hz),127.1,123.1,121.6,119.0,116.4,115.5,108.0(d,J＝24.2Hz),92.8,66.7,65.9,57.5,54.1,33.0,28.8.ESI-MS m/z 550.2(M+H) ⁺ 。

Example 48: preparation of 1- (5-tert-butylisoxazol-3-yl) -3- (2,6-difluoro-4- (4- (4- (2-morpholinoethoxy) phenyl) -1H-1,2,3-triazol-1-yl) phenyl) urea (named CL-206)

1-(5-(tert-butyl)isoxazol-3-yl)-3-(2,6-difluoro-4-(4-(4-(2-morpholinoethoxy)phenyl)-1H-1,2,3-triazol-1-yl)phenyl)urea

The synthesis method is substantially the same as in example 43.

¹ H NMR(400MHz,d ⁶ -DMSO)δ9.96(s,1H),9.25(s,H),8.46(s,1H),7.87(d,J＝8.4Hz,2H),7.83(d,J＝8.4Hz,2H),7.09(d,J＝8.8Hz,2H),6.44(s,1H),4.15(t,J＝5.6Hz,2H),3.59(t,J＝4.4Hz,4H),2.73(t,J＝5.6Hz,2H),2.48-2.50(m,4H),1.29(s,9H).ESI-MS m/z 568.2(M+H) ⁺ 。

Example 49: preparation of 1- (5-tert-butylisoxazol-3-yl) -3- (2-methyl-4- (4- (4- (2-morpholinoethoxy) phenyl) -1H-1,2,3-triazol-1-yl) phenyl) urea (named CL-207)

1-(5-(tert-butyl)isoxazol-3-yl)-3-(3-fluoro-4-(4-(4-(2-morpholinoethoxy)phenyl)-1H-1,2,3-triazol-1-yl)phenyl)urea

The synthesis method is substantially the same as in example 43.

¹ H NMR(400MHz,d ⁶ -DMSO)δ9.76(s,1H),9.32(s,H),8.98(d,J＝1.2Hz,1H),7.87(d,J＝8.8Hz,2H),7.76-7.82(m,2H),7.38(dd,J＝8.8Hz,1.2Hz,1H),7.06(d,J＝8.8Hz,2H),6.54(s,1H),4.14(t,J＝5.6Hz,2H),3.59(t,J＝4.4Hz,4H),2.71(t,J＝5.6Hz,2H),2.48-2.50(m,4H),1.31(s,9H).ESI-MS m/z 550.1(M+H) ⁺ 。

Example 50: preparation of 1- (5-tert-butylisoxazol-3-yl) -3- (2-methyl-4- (4- (4- (2-morpholinoethoxy) phenyl) -1H-1,2,3-triazol-1-yl) phenyl) urea (named CL-208)

1-(2-bromo-4-(4-(4-(2-morpholinoethoxy)phenyl)-1H-1,2,3-triazol-1-yl)phenyl)-3-(5-(tert-butyl)isoxazol-3-yl)urea

The synthesis method is substantially the same as in example 43.

¹ H NMR(400MHz,d ⁶ -DMSO)δ10.41(s,1H),9.21(s,H),8.72(s,1H),8.32(d,J＝8.8Hz,1H),8.25(d,J＝2.0Hz,1H),7.96(dd,J＝8.8Hz,2.0Hz,1H),7.84(d,J＝8.8Hz,2H),7.07(d,J＝8.8Hz,2H),6.49(s,1H),4.14(t,J＝5.6Hz,2H),3.59(t,J＝4.4Hz,4H),2.71(t,J＝5.6Hz,2H),2.48-2.50(m,4H),1.31(s,9H).ESI-MS m/z 610.1(M+H) ⁺ 。

Example 51: preparation of 1- (5-tert-butylisoxazol-3-yl) -3- (2-chloro-4- (4- (4- (2-morpholinoethoxy) phenyl) -1H-1,2,3-triazol-1-yl) phenyl) urea (named CL-101) (named CL-209)

1-(5-(tert-butyl)isoxazol-3-yl)-3-(2-chloro-4-(4-(4-(2-morpholinoethoxy)phenyl)-1H-1,2,3-triazol-1-yl)phenyl)urea

The synthesis method is substantially the same as in example 43.

¹ H NMR(400MHz,d ⁶ -DMSO)δ10.34(s,1H),9.20(s,H),8.88(s,1H),8.42(d,J＝8.8Hz,1H),8.11(d,J＝2.4Hz,1H),7.93(dd,J＝9.2Hz,2.4Hz,1H),7.83(d,J＝8.8Hz,2H),7.08(d,J＝8.8Hz,2H),6.50(s,1H),4.14(t,J＝5.6Hz,2H),3.59(t,J＝4.4Hz,4H),2.71(t,J＝5.6Hz,2H),2.48-2.52(m,4H),1.31(s,9H). ¹³ C NMR(101MHz,d ⁶ -DMSO)δ180.9,159.0,158.6,151.6,147.7,136.0,132.3,127.1,123.2,123.1,122.1,121.0,119.6,119.0,115.5,92.9,66.7,65.9,57.5,54.1,33.0,28.8.ESI-MS m/z 566.2(M+H) ⁺ 。

Example 52: preparation of 1- (5-tert-butylisoxazol-3-yl) -3- (4- (5-methylsulfanyl-1- (4- (2-morpholinoethoxy) phenyl) -1H-1,2,3-triazol-4-yl) phenyl) -urea (named CL-301)

1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(5-(methylthio)-1-(4-(2-morpholinoethoxy)phenyl)-1H-1,2,3-triazol-4-yl)phenyl)urea

Synthesis of intermediate 17 Compound CL-301 was synthesized essentially the same as in example 1, following the procedures reported in the literature (Wang, W.et al Angew. Chem. Int.Ed.2016,55, 649-653).

¹ H NMR(400MHz,d ⁶ -DMSO)δ9.60(s,1H),9.02(s,1H),8.20(d,J＝8.8Hz,2H),7.62(d,J＝8.8Hz,2H),7.58(d,J＝8.8Hz,2H),7.18(d,J＝8.4Hz,2H),6.52(s,1H),4.20(t,J＝5.6Hz,2H),3.59(t,J＝4.8Hz,4H),2.74(t,J＝5.6Hz,2H),2.50-2.52(m,4H),2.12(s,3H),130(t,J＝7.2Hz,3H). ¹³ C NMR(101MHz,d ⁶ -DMSO)δ180.7,159.8,158.8,151.8,147.5,139.7,129.2,127.9,127.8,127.7,124.9,119.0,115.4,92.9,66.7,66.2,57.4,54.1,33.0,28.8,18.5.ESI-MS m/z 578.2(M+H) ⁺ 。

Example 53: preparation of 1- (5-tert-butylisoxazol-3-yl) -3- (4- (5-methylsulfonyl-1- (4- (2-morpholinoethoxy) phenyl) -1H-1,2,3-triazol-4-yl) phenyl) -urea (named CL-302)

1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(5-(methylsulfonyl)-1-(4-(2-morpholinoethoxy)phenyl)-1H-1,2,3-triazol-4-yl)phenyl)urea

The compound CL-302 is obtained from CL-301 by oxidation with mCPBA in dichloromethane. The compound CL-301 (200mg, 0.34mmol) and mCPBA (180mg, 1mmol) were dissolved in 5ml of dichloromethane and the reaction was stirred at room temperature for 3 hours. The raw materials can react completely, and are extracted for 2 times by ethyl acetate and sodium carbonate aqueous solution, washed twice by saturated salt water, combined with organic phase, dried by anhydrous sodium sulfate, decompressed and concentrated, and separated by silica gel column to obtain the compound CL-302.

ESI-MS m/z 610.2(M+H) ⁺ 。

Example 54: preparation of 1- (5-tert-butylisoxazol-3-yl) -3- (4- (5-iodo-1- (4- (2-morpholinoethoxy) phenyl) -1H-1,2,3-triazol-4-yl) phenyl) -urea (named CL-303)

1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(5-iodo-1-(4-(2-morpholinoethoxy)phenyl)-1H-1,2,3-triazol-4-yl)phenyl)urea

The synthesis of compound CL-303 is essentially the same as in example 52.

¹ H NMR(400MHz,d ⁶ -DMSO)δ9.57(s,1H),9.44(s,1H),9.13(s,1H),7.90(d,J＝8.4Hz,2H),762(d,J＝8.4Hz,2H),7.52(d,J＝8.8Hz,2H),7.18(d,J＝8.8Hz,2H),6.52(s,1H),4.21(t,J＝5.6Hz,2H),3.60(t,J＝4.4Hz,4H),2.78(t,J＝5.6Hz,2H),2.50-2.52(m,4H),1.30(s,9H).ESI-MS m/z 658.1(M+H) ⁺ 。

Example 55: preparation of 1- (5-tert-butylisoxazol-3-yl) -3- (4- (5-cyano-1- (4- (2-morpholinoethoxy) phenyl) -1H-1,2,3-triazol-4-yl) phenyl) -urea (named CL-304)

1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(5-cyano-1-(4-(2-morpholinoethoxy)phenyl)-1H-1,2,3-triazol-4-yl)phenyl)urea

The compound CL-304 is obtained by coupling CL-303 with CuCN in DMF at 100 ℃.

ESI-MS m/z 557.1(M+H) ⁺ 。

Example 56 Activity test experiment

The kinase inhibition activity of the triazole compound is detected by a Z-lyte fluorescence resonance energy transfer method, and the inhibition activity of the triazole compound on cancer cell proliferation is tested by a CCK-8 method:

the protein kinases FLT3, FLT3-ITD and their corresponding substrate kits were all purchased from Thermo Fisher Scientific. All reactions were carried out in 384 microwell plates, with an enzyme reaction volume of 10 microliters. The reaction buffer composition was 50mM HEPES pH 7.5, 10mM MgCl ₂ ，1mM EGTA，0.01％BRIJ-35。

The compounds used in the control experiments were as follows:

staurosporine: staurosporine (Staurosporine) is a typical adenosine triphosphate competitive kinase inhibitor that has high binding affinity to many kinases but little selectivity and is used as a common research tool in control experiments.

Cabozantinib: is a potent VEGFR2 inhibitor and also inhibits c-Met, ret, kit, flt-1/3/4, tie2 and AXL, for use in control assays for FLT3 kinase, purchased from Selleck, inc.

1. The specific steps of the kinase inhibition activity test are as follows:

firstly, a proper amount of 5 mul of protein kinase and 5 mul of corresponding substrate (the final reaction concentration is 2 mul) mixed solution are added into a micro-porous plate, and then an Echo520 ultrasonic micro-liquid transfer system (Labcyte company, USA) is used for addingAdding ATP with corresponding concentration into a series of compounds diluted in gradient, shaking, mixing for 5min, and reacting in a thermostat at 29 deg.C for 1.5h; then adding 5 μ l of detection solution (Development Reagent) with corresponding concentration, shaking and mixing for 5min, placing in a thermostat at 29 deg.C, and reacting for 1h; finally, 5 mul of Stop solution (Stop Reagent) is added, after oscillation and uniform mixing, an Envision Multilabel Reader multifunctional microplate Reader of PE company is used for detection, the wavelength of excitation light is 400nm, and the wavelength of emission light is 445nm and 520nm respectively. The assay was set up with test wells (plus compound, enzyme, substrate and ATP), 0% phosphorylated wells (plus DMSO, substrate and ATP) 100% phosphorylated wells (plus phosphorylated substrate only), 0% inhibitory wells (plus DMSO, enzyme, substrate and ATP), respectively. Calculating the inhibition rate of the compound on enzyme reaction according to the fluorescence ratio, and analyzing and calculating the IC of the compound by GraphPad software ₅₀ The value is obtained. The inhibition results of the compounds on FLT3 and mutant kinase are shown in table 1.

2. Activity assay for inhibition of cancer cell proliferation (CCK-8), the procedure was as follows:

1) Cell inoculation: various tumor cells in the logarithmic growth phase of cells were seeded at the same density in different 96-well plates (3000-10000 cells/100. Mu.l/well), respectively.

2) Preparing a working solution: the corresponding culture medium required by cell culture is used as a diluent (containing or not containing a solvent DMSO), the stock solution of the test substance and the control compound is diluted to obtain working solution with series concentration of which the required concentration is 3 times of the final concentration, and the content of the solvent DMSO in each concentration group is consistent with that of a solvent control group.

3) Co-incubation: after 24hr of inoculation, 100. Mu.l/well of the mother liquor of the compound series concentration was added to a 96-well plate, mixed well and co-cultured for 72hr. All groups were at least 3 replicates with 6 concentrations of each compound. Blank control group: only the culture medium is added, and cells and medicines are not added, so that the interference of the culture medium on the color comparison is eliminated.

4) And (3) measuring absorbance: after the medium was aspirated from the 96-well plate, 10. Mu.l of CCK-8 solution was added to each well, and after co-culturing for 4hr, the mixture was sufficiently shaken to be uniform, and the absorbance values at A450 and A650 were measured on a microplate reader.

5) Data processing: obtaining the A450-A650 original data to obtain each processing holeCell viability (calculated as follows); the cell viability data and corresponding compound concentrations were then input into GraphPad Prism 5Demo software and IC of compounds on different cells was calculated using a non-linear regression model ₅₀ The value is obtained. Calculation of cell viability: cell survival rate (%) = [ (As-Ac)/(Ab-Ac)]×100％](As: experimental wells; ab: vehicle control wells; ac: blank wells). The results are shown in Table 1.

Inhibition of FLT3 kinase wild type, mutant and cancer cell inhibition by compounds of Table 1

From the above table results, it can be seen that: the triazole compound (especially compounds CL-102, CL-103, CL-118, CL-201, CL-101, CL-112, CL-113, CL-116, CL-131, CL132, CL-135, CL-120, CL-205 and the like) has strong inhibitory activity to wild type and mutant FLT3 kinase, and can effectively inhibit the proliferation of MV4-11 tumor cells at the cellular level. Some compounds have good inhibitory activity on wild-type FLT3 kinase, but have relatively weak inhibitory activity on mutant FLT3 kinase, such as (CL-303, CL-104, CL-106, CL-115, CL-105).

The technical features of the above-mentioned embodiments can be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the following embodiments are not described, however, as long as there is no contradiction between the combinations of the technical features, the combinations should be considered as the scope of the present description.

The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

Claims

1. A triazole compound having a structure represented by formula (a) or a pharmaceutically acceptable salt thereof:

wherein X, Y are each independently selected from: c or N;

ar1 and Ar2 are both: a benzene ring;

R ¹ selected from: hydrogen, halogen, C _1-6 Alkoxy radical, C _1-6 Alkyl, halogen substituted C _1-6 Alkyl radical, C _5-6 Heterocycloalkyl-substituted C _1-6 Alkoxy, amino substituted C _1-6 Alkoxy radical, C _1-6 Alkylamino substituted C ₁ - ₆ Alkoxy, methanesulfonate, nitro, C _3-7 Heterocycloalkyl-substituted C _1-6 Alkylamino radical, C _1-6 Alkylamino substituted C _1-6 An alkylamino group;

R ² selected from: hydrogen, halogen, cyano, methyl, C _1-6 Alkylthio radical, C _1-6 An alkylsulfonyl group;

R ³ selected from the group consisting of: hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 An alkoxy group;

R ⁴ selected from:

the R is ⁵ Selected from: hydrogen, C _1-6 Alkyl, halogen substituted C _1-6 Alkyl radical, C _1-6 An alkoxy group;

R ⁶ selected from: hydrogen, C _1-12 An alkyl group.

2. The triazole compound or a pharmaceutically acceptable salt thereof according to claim 1, which has a structure represented by formula (I) or formula (II):

3. the triazole-based compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein Z is selected from: -NR ⁶ -；R ⁶ Selected from: hydrogen, C _1-6 An alkyl group.

4. The triazole compound or the pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R is ⁴ Selected from:

5. the triazole-based compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R is ¹ Selected from: hydrogen, halogen, methoxy, trifluoroMethoxy, nitro, methyl, 2-morpholinoethoxy, 2-dimethylaminoethoxy, 2-piperidin-1-ylethoxy, mesylate, 2-tetrahydropyrrole-1-ylethoxy, 3-dimethylaminopropoxy, 3-morpholinopropoxy, 2-morpholinoethylamino, 2-dimethylaminoethylamino; and/or the presence of a catalyst in the reaction mixture,

the R is ² Selected from: hydrogen, halogen, cyano, methylthio, methylsulfonyl; and/or the presence of a catalyst in the reaction mixture,

the R is ³ Selected from: hydrogen, halogen, methoxy, methyl.

6. The triazole-based compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2,

z is NH;

ar1 and Ar2 are both benzene rings;

R ⁴ selected from:

R ¹ selected from: hydrogen, 2-morpholinoethoxy, 2-dimethylaminoethoxy, 2-piperidin-1-ylethoxy, halogen, methoxy, nitro, methyl, 3-dimethylaminopropoxy, 3-morpholinopropoxy;

R ² selected from the group consisting of: hydrogen, halogen, cyano, methylthio, methylsulfonyl;

R ³ selected from: hydrogen, halogen, methoxy, methyl.

7. The triazole compound or the pharmaceutically acceptable salt thereof according to claim 1 or 2, which is selected from the following compounds:

8. use of a triazole-type compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof for the preparation of a FLT3 kinase inhibitor.

9. Use of a triazole-type compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for preventing or treating a disorder associated with FLT3 kinase.

10. The use according to claim 9, wherein the FLT3 kinase associated disease is leukemia.

11. The use according to claim 10, wherein the FLT3 kinase associated disease is acute myeloid leukemia.

12. A pharmaceutical composition for preventing or treating a FLT3 kinase-associated disease, which is prepared from an active ingredient comprising the triazole compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.