CN109053630B - Benzothiazole derivative and application thereof - Google Patents

Benzothiazole derivative and application thereof Download PDF

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CN109053630B
CN109053630B CN201810958721.1A CN201810958721A CN109053630B CN 109053630 B CN109053630 B CN 109053630B CN 201810958721 A CN201810958721 A CN 201810958721A CN 109053630 B CN109053630 B CN 109053630B
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thiazol
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cyclopropanecarboxamide
phenoxy
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庄春林
缪震元
张�浩
陈啸飞
蔡振宇
张万年
徐丽娟
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Second Military Medical University SMMU
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Abstract

The invention discloses a precursor drug of benzothiazole derivatives or isomers, salts or solvates thereof, which is shown as a general formula I:

Description

Benzothiazole derivative and application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a benzothiazole derivative and application thereof as a programmed cell necrosis inhibitor.
Background
Apoptosis is a Caspase-independent mode of cell death mediated by death receptors. When apoptosis is blocked, receptors of TNF- α and TNF- α family, Toll-like receptors 3 and 4, and interferon-alpha receptors, are capable of inducing apoptosis in cells when activated by corresponding ligands.
Research shows that protein kinases RIPK1 and RIPK3 form a complex and activate MLKL protein, and MLKL is polymerized to be directly positioned on a cell membrane and cause the cell membrane to break, so that the key mechanism for inducing programmed cell necrosis is realized. Programmed cell necrosis, due to the release of cellular contents, causes infiltration of a large number of inflammatory cells in the body to induce a severe inflammatory response. The disorder, overactivation or overactive interaction of RIPK1/RIPK3 kinase has a close correlation with various diseases, for example, the literature (Neotrophosis is active in childrens with inflammation bone diseases and conditions to inflammation in inflammation. am J gastroenterol.2014 Feb; 109(2):279-87.) reports that RIPK1/RIPK3 kinase-mediated necrosis is related to inflammatory bowel disease; the literature (necrosis Is an infectious Therapeutic Target in Experimental Therapeutic patent. cell Mol gastric hepatol Hepatol.2016 Jul; 2(4): 519) 535.) reports a correlation between necrosis and acute pancreatitis; the literature (Type I interference inductors in macrophages along with Salmonella enterica serovar. Nat Immunol.2012 Oct; 13(10):954-62.) reports that necrosis is associated with Salmonella infection; the literature (Liver-responsive pathological necrosis with type 1 microbial infection and type-2-mediated tissue repair reduction bacterial infection. immunity.2015 Jan 20; 42(1):145-58.) reports that necrosis is associated with Listeria infection; necrosis has been reported in the literature to be associated with Vaccinia virus infection (Vaccinium viruses induced by microorganisms in the tissue by A STAT3-dependent mechanism. PLoS one.2014 Nov 24; 9(11): e 113690); the literature (CaMKII a RIP3 substrate formatting iso-and oxidative stress-induced myogenic Necrtopsis. Nat Med.2016Feb; 22(2):175-82.) reports that necrosis is associated with ischemic cardiomyopathy; the literature (Chemical inhibitor of non-porous cell death with thermal biological potential for isochemical brain in therapy. Natchem biol.2005 Jul; 1(2):112-9.) reports that necrosis is associated with ischemic stroke; the literature (neuropathies activation in Alzheimer's disease. Nat Neurosci.2017 Sep; 20(9): 1236-; necrosis has been reported in the literature to be associated with atherosclerosis (Targeting pathological necrosis for therapeutic and diagnostic interventions in atherosclerosis. Sci adv.2016 Jul 22; 2(7): e 1600224.).
Therefore, the identification and discovery of the inhibitor of programmed cell necrosis are of great significance for the clinical treatment of diseases related to programmed cell necrosis.
Disclosure of Invention
The first purpose of the invention is to provide a benzothiazole derivative.
The second purpose of the invention is to provide the application of the benzothiazole derivative serving as RIPK1 and RIPK3 kinase inhibitors.
The third purpose of the invention is to provide the application of the benzothiazole derivative as the programmed cell necrosis inhibitor.
The fourth purpose of the invention is to provide the application of the benzothiazole derivative in preparing a medicine for preventing and treating programmed cell necrosis related diseases or preparing a medicine for treating inflammatory, infectious, ischemic or degenerative related diseases or tissue injury caused by RIPK1 and RIPK3 kinase disorder, over-activation or over-interaction.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
in a first aspect, the present invention provides a prodrug of a benzothiazole derivative or its isomer, salt or solvate, represented by formula I:
Figure BDA0001773292360000021
wherein R is1Is alkyl, amino, hydroxy, -NR5CO-W1、-NR5CO-W1-O-W2、-NR5CO-W1-SH、-NR5CO-W1-NR6、-NR5COOR6、NR5CO-CO-、-NR5CONR6、-NR5CONR6-W1、-CONR5；R5、R6Each independently selected from hydrogen, saturated or unsaturated chain alkyl, cycloalkyl, saturated or unsaturated heterocycle, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; w1、W2Each independently selected from hydrogen, saturated or unsaturated chain alkyl, cycloalkyl, saturated or unsaturated heterocycle, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
R2、R3each independently selected from hydrogen, halogen, amino, nitro, hydroxy, cyano, alkyl, alkoxy, alkylamino, aminoalkyl, acyl, amido, thioalkyl, trifluoromethyl, trifluoromethoxy, carboxy, alkoxycarbonyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, saturated or unsaturated heterocycle;
R4is R7CO-、-R7CO-W3、-R7CO-W3-R8、R7CO-W3-O-、-R7CO-W3-O-W4、-R7CO-W3-NR8、R7CO-CO-、R7CONR8-、R7CONR8-W3-、R7CONR8-W3-O-、-CONR8、-SO2R7、-R7-W3、R7CS-、-R7CS-W3、-R7CS-W3-R8、R7CS-W3-O-、-R7CS-W3-O-W4、R7CS-W3-S-、R7CS-W3-NR8-、R7CS-CS-、R7CSNR8-、R7CSNR8-W3-、R7CSNR8-W3-O-or-CSNR8；
R7、R8Each independently selected from hydrogen, saturated or unsaturated chain alkyl, cycloalkyl, saturated or unsaturated heterocycle, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; w3、W4Each independently selected from hydrogen, saturated or unsaturated chain alkyl, cycloalkyl, saturated or unsaturated heterocycle, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
x is oxygen, sulfur or imino (-NH-);
y is oxygen, sulfur or imino (-NH-);
z is oxygen,
Figure BDA0001773292360000022
Or an imino group (-NH-).
Preferably, in the formula I, X is sulfur; y is oxygen; z is imino (-NH-) or
Figure BDA0001773292360000023
More preferably, in formula I, R1is-NR5CO-W1、-NR5CO-W1-O-W2、-NR5CO-W1-SH、-NR5CO-W1-NR6、-NR5COOR6、NR5CO-CO-、-NR5CONR6、-NR5CONR6-W1、-CONR5；
R5、R6Each independently is hydrogen;
W1、W2each independentlySelected from hydrogen, saturated or unsaturated chain alkyl, cycloalkyl, saturated or unsaturated heterocycle, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
R2、R3each independently selected from hydrogen, halogen, amino, nitro, hydroxy, cyano, alkyl, alkoxy, alkylamino, aminoalkyl, acyl, amido, thioalkyl, trifluoromethyl, trifluoromethoxy, carboxy, alkoxycarbonyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, saturated or unsaturated heterocycle;
R4is R7CO-、-R7CO-W3、-R7CO-W3-R8、R7CO-W3-O-、-R7CO-W3-O-W4、-R7CO-W3-NR8、R7CO-CO-、R7CONR8-、R7CONR8-W3-、R7CONR8-W3-O-、-CONR8、-SO2R7、-R7-W3、R7CS-、-R7CS-W3、-R7CS-W3-R8、R7CS-W3-O-、-R7CS-W3-O-W4、R7CS-W3-S-、R7CS-W3-NR8-、R7CS-CS-、R7CSNR8-、R7CSNR8-W3-、R7CSNR8-W3-O-or-CSNR8；
R7、R8Each independently selected from hydrogen, saturated or unsaturated chain alkyl, cycloalkyl, saturated or unsaturated heterocycle, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; w3、W4Each independently selected from hydrogen, saturated or unsaturated chain alkyl, cycloalkyl, saturated or unsaturated heterocycle, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
x is sulfur;
y is oxygen;
z is imino (-NH-)) or
Figure BDA0001773292360000031
In the above general structure, each substituent is not selected from the following combinations: r1is-NR5CO-W1、R2Is 7-cyano, R3Is 4-fluoro, R4Is R7CO-, Z is imino (-NH-), W1Is cyclopropyl, R5Is hydrogen, R7Is 3-trifluoromethyl benzyl, X is sulfur, Y is oxygen, the compound is TAK-632, and the chemical structural formula is as follows:
Figure BDA0001773292360000032
most preferably, the benzothiazole derivatives are selected from one of the following structures:
benzyl (7-cyano-6- (4-fluoro-3- (2,2, 2-trifluoroacetylamino) phenoxy) benzo [ d ] thiazol-2-yl) carbamate;
allyl (7-cyano-6- (4-fluoro-3- (2,2, 2-trifluoroacetylamino) phenoxy) benzo [ d ] thiazol-2-yl) carbamate;
benzyl (7-cyano-6- (4-fluoro-3- (2- (3- (trifluoromethyl) phenyl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) carbamate;
n- (7-cyano-6- (4-fluoro-3- (2- (3- (trifluoromethyl) phenyl) acetylamino) phenoxy) benzo [ d ] thiazol-2-yl) nonanamide;
n- (7-cyano-6- (4-fluoro-3- (2- (3- (trifluoromethyl) phenyl) acetylamino) phenoxy) benzo [ d ] thiazol-2-yl) propanamide;
n- (7-cyano-6- (4-fluoro-3- (2- (3- (trifluoromethyl) phenyl) acetylamino) phenoxy) benzo [ d ] thiazol-2-yl) benzamide;
n- (7-cyano-6- (4-fluoro-3- (2- (4-nitrophenyl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (7-cyano-6- (4-fluoro-3- (2-phenylacetamido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (5- ((7-cyano-2- (cyclopropanecarboxamido) benzo [ d ] thiazol-6-yl) oxy) -2-fluorophenyl) -3- (trifluoromethyl) benzamide;
n- (7-cyano-6- (4-fluoro-3- (2- (3-fluorophenyl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (7-cyano-6- (4-fluoro-3- (2- (2-fluoro-3- (trifluoromethyl) phenyl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (6- (4-fluoro-3- (2- (3- (trifluoromethyl) phenyl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (6- (4-fluoro-3- (2- (2-fluoro-3- (trifluoromethyl) phenyl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (6- (3- (2- (3, 5-bis (trifluoromethyl) phenyl) acetamido) -4-fluorophenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (6- (4-fluoro-3- (2- (3-nitrophenyl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (6- (4-fluoro-3- (2- (3- (trifluoromethyl) phenyl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) cyclohexanecarboxamide;
n- (6- (4-fluoro-3- (2- (2- (trifluoromethyl) phenyl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (6- (4-fluoro-3- (2- (m-tolyl) acetylamino) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (6- (4-fluoro-3- (3- (3- (trifluoromethyl) phenyl) propionylamino) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (6- (4-fluoro-3- (2- (pyridin-2-yl) acetylamino) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (6- (4-fluoro-3- (2- (4-fluoro-3 (trifluoromethyl) phenyl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (6- (3- (2- (2-chloro-3- (trifluoromethyl) phenyl) acetylamino) -4-fluorophenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (6- (4-fluoro-3- (2- (3-methoxyphenyl) acetylamino) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (6- (4-fluoro-3- (2- (3- (trifluoromethoxy) phenyl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (6- (3- (2- (benzo [ d ] [1,3] dioxol-5-yl) acetylamino) -4-fluorophenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (6- (4-fluoro-3- (2- (6- (trifluoromethyl) pyridin-2-yl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (5- ((2- (cyclopropanecarboxamido) benzo [ d ] thiazol-6-yl) oxy) -2-fluorophenyl) -1- (3- (trifluoromethyl) phenyl) cyclopropane-1-carboxamide;
n- (6- (4-fluoro-3- (2- (3- (trifluoromethyl) phenyl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) cyclobutanecarboxamide;
n- (6- (4-fluoro-3- (2- (1-methyl-1H-indol-3-yl) acetylamino) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (6- (4-fluoro-3- (2- (3- (trifluoromethyl) phenyl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopentanecarboxamide;
n- (6- (4-fluoro-3- (2- (3- (trifluoromethyl) phenyl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) isobutyramide;
n- (6- (3- (2- (3-cyanophenyl) acetylamino) -4-fluorophenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (6- (3- (2- (3, 4-dimethylphenyl) acetylamino) -4-fluorophenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (6- (4-fluoro-3- (2- (3- (trifluoromethyl) phenyl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) tetrahydro-2H-pyran-4-carboxamide;
n- (6- (4-fluoro-3- (2- (3-hydroxyphenyl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (6- (4-fluoro-3- (3- (3- (trifluoromethyl) phenyl) ureido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (6- (4-fluoro-3- (3- (4- (trifluoromethoxy) phenyl) ureido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (6- (4-fluoro-3- (3- (3-methoxyphenyl) ureido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (6- (4-fluoro-3- (3- (m-tolyl) ureido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
ethyl 3- (3- (5- ((2- (cyclopropanecarboxamido) benzo [ d ] thiazol-6-yl) oxy) -2-fluorophenyl) ureido) benzoate;
n- (6- (3- (3- (3-acetylphenyl) ureido) -4-fluorophenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (6- (3- (3- (3-bromophenyl) ureido) -4-fluorophenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (6- (4-fluoro-3- (3- (3- (trifluoromethyl) phenyl) thioureido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (6- (4-fluoro-3- (3- (3- (trifluoromethoxy) phenyl) ureido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (6- (4-fluoro-3- (3- (6- (trifluoromethyl) pyridin-2-yl) ureido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (6- (4-fluoro-3- ((3- (trifluoromethyl) benzyl) amino) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (6- (3- ((benzo [ d ] [1,3] dioxol-5-ylmethyl) amino) -4-fluorophenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (6- (4-fluoro-3- ((3- (trifluoromethyl) phenyl) sulfonamido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide.
The second aspect of the invention provides an application of a benzothiazole derivative shown in the general formula I or a prodrug of an isomer, a salt or a solvate thereof as an RIPK1 or RIPK3 kinase inhibitor.
The third aspect of the invention provides an application of a benzothiazole derivative shown in the general formula I or a prodrug of an isomer, a salt or a solvate thereof as a programmed cell necrosis inhibitor.
The fourth aspect of the invention provides an application of a benzothiazole derivative shown in the general formula I or a prodrug of an isomer, a salt or a solvate thereof in preparing a medicine for preventing and treating programmed cell necrosis related diseases or preparing a medicine for treating inflammatory, infectious, ischemic or degenerative related diseases or tissue injury caused by RIPK1 or RIPK3 kinase disorder, over-activation or over-interaction.
The inflammatory, infectious, ischemic or degenerative related diseases or tissue damage is mediated by RIPK1/RIPK3 kinase, or is initiated by programmed cell necrosis.
The inflammatory, infectious, ischemic or degenerative related diseases are selected from: systemic inflammatory syndrome, acetaminophen-induced liver injury, acute pancreatitis, inflammatory bowel disease, sepsis, salmonella infection, listeria infection, vaccinia virus infection, alzheimer's disease, ischemic cardiomyopathy, ischemic stroke, atherosclerosis.
The tissue damage comprises: liver damage, hepatotoxicity or hepatocyte necrosis.
The fifth aspect of the invention also provides a pharmaceutical composition, which comprises a precursor drug of the benzothiazole derivative shown in the general formula I or an isomer, a salt or a solvate thereof and a pharmaceutically acceptable auxiliary material.
The salt is a salt formed by reacting a compound with an inorganic acid, an organic acid, an alkali metal, an alkaline earth metal or the like. These salts include (but are not limited to): (1) salts with the following inorganic acids: such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, diphosphoric acid, hydrobromic acid; (2) salts with organic acids such as acetic acid, lactic acid, succinic acid, p-toluenesulfonic acid, salicylic acid, oxalic acid, succinic acid, tartaric acid, methanesulfonic acid, maleic acid, fumaric acid or arginine. Other salts include those formed with alkali or alkaline earth metals (e.g., sodium, potassium, calcium or magnesium), in the form of esters, carbamates, or other conventional "prodrugs". The compounds have one or more asymmetric centers. Thus, these compounds may exist as racemic mixtures, individual enantiomers, individual diastereomers, mixtures of diastereomers, cis or trans isomers. The term "precursor of a compound" refers to a compound which, when administered by a suitable method, undergoes a metabolic or chemical reaction in the patient to convert the precursor to a compound of formula (I), or a salt or solution of a compound of formula (I).
The dosage form of the pharmaceutical composition of the present invention may be various, as long as it is a dosage form that enables the active ingredient to efficiently reach the body of a mammal. Such as may be selected from: a solution, suspension, tablet, capsule, powder, granule, or syrup. Depending on the type of disease to be treated by the compounds of the present invention, one skilled in the art may select a dosage form that is convenient to use.
The terms: the term "isomer" as used herein includes: geometric isomers, enantiomers, diastereomers (e.g., cis-trans isomers, conformational isomers); the term "solvate" as used herein means a compound carrying a solvent molecule, e.g., the solvate may be a hydrate; in the present invention, the term "comprising" means that various ingredients can be used together in the mixture or composition of the present invention. Thus, the terms "consisting essentially of and" consisting of are encompassed by the term "comprising"; in the present invention, a "pharmaceutically acceptable" ingredient is one that is suitable for use in humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio; in the present invention, the "pharmaceutically acceptable carrier" is a pharmaceutically or food acceptable solvent, suspending agent or excipient for delivering the compound of formula (I), isomer, solvate, precursor, or pharmaceutically acceptable salt thereof of the present invention to animals or humans. The carrier may be a liquid or a solid.
Due to the adoption of the technical scheme, the invention has the following advantages and beneficial effects:
the benzothiazole derivative or the isomer, the salt or the solvate of the benzothiazole derivative can be used as an RIPK1 and RIPK3 kinase inhibitor and can also be used as a programmed cell necrosis inhibitor to effectively inhibit cell necrosis; can be used for preparing medicaments for preventing and treating diseases related to programmed cell necrosis, or preparing medicaments for treating inflammatory, infectious, ischemic or degenerative related diseases or tissue injury caused by disorder, over-activation or over-interaction of RIPK1 and RIPK3 kinases.
Detailed Description
In order to more clearly illustrate the invention, the invention is further described below in connection with preferred embodiments. It is to be understood by persons skilled in the art that the following detailed description is illustrative and not restrictive, and is not to be taken as limiting the scope of the invention.
The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. All raw materials without the synthesis method are purchased from manufacturers such as exploration platforms, Aladdin, Sigma-Aldrich and the like, and are all analytically pure.
Example 1
Benzyl (7-cyano-6- (4-fluoro-3- (2,2, 2-trifluoroacetylamino) phenoxy) benzo [ d ] thiazol-2-yl) carbamate
The synthetic route is as follows:
Figure BDA0001773292360000061
step a: synthesis of 2- (3-amino-4-fluorophenoxy) -5-nitrobenzonitrile.
To a solution of 3-amino-4-fluorophenol (3g, 22.42mmol) and 2-fluoro-5-nitrobenzonitrile (4.19g, 24.66mmol) in DMF (20mL) at room temperature was added K2CO3(4.89g, 35.4 mmol). The solution was stirred at 80 ℃ for 8h, and the solution was extracted with ethyl acetate, washed with saturated sodium chloride and dried over anhydrous sodium sulfate, insoluble material was filtered off, filtered and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 5: 1-4: 1), and the obtained solution was concentrated under reduced pressure to give 1.95g of a pale yellow solid with a yield of 35%.
Step b: synthesis of N- (5- (2-cyano-4-nitrophenoxy) -2-fluorophenyl) -2,2, 2-trifluoroacetamide.
To a solution of 2- (3-amino-4-fluorophenoxy) -5-nitrobenzonitrile (1.95g, 7.14mmol) in THF (30mL) at 0 deg.C was added trifluoroacetic anhydride (1.21mL, 8.56mmol), and the solution was stirred at room temperature for 1.5 h. The reaction mixture was diluted with ethyl acetate, washed successively with water, an aqueous sodium bicarbonate solution and saturated sodium chloride, and dried over anhydrous sodium sulfate, insoluble materials were filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate ═ 5: 1-4: 1), and the obtained solution was concentrated under reduced pressure to obtain 2.38g of a pale yellow solid, yield 90%.
Step c: synthesis of N- (5- (4-amino-2-cyanophenoxy) -2-fluorophenyl) -2,2, 2-trifluoroacetamide.
To N- (5- (2-cyano-4-nitrophenoxy) -2-fluorophenyl) -2,2, 2-trifluoroacetyl (2.38g, 6.45mmol) in EtOH/H2To a solution (50mL) of O (5:1) was added ammonium chloride (1.72g, 32.23mmol), then to the solution was added iron powder (1.8g, 32.23mmol), and the solution was stirred at 0 ℃ for 30min, after which the reaction was heated to 55 ℃ for 2 h. Insoluble material was then filtered off over celite, the residue was collected and the mixture was adjusted to pH 8 with sodium bicarbonate solution. The reaction mixture was diluted with DCM, dried over anhydrous sodium sulfate, the insoluble material filtered off, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 4: 1-3: 1), and the obtained solution was concentrated under reduced pressure to obtain 1.08g of a white solid with a yield of 49%.
Step d: synthesis of N- (5- ((2-amino-7-cyanobenzo [ d ] thiazol-6-yl) oxy) -2-fluorophenyl) -2,2, 2-trifluoroacetamide.
Potassium thiocyanate (1.104g, 11.37mmol) was suspended in acetic acid (10mL) and the solution was stirred at room temperature for 10 min. A solution of N- (5- (4-amino-2-cyanophenoxy) -2-fluorophenyl) -2,2, 2-trifluoroacetamide (950mg, 2.84mmol) in acetic acid (10mL) was added to the suspension, and the mixture was further stirred at room temperature for 10min, a solution of bromine (676mg, 4.26mmol) in acetic acid (5mL) was added to the mixture, and the mixture was stirred at room temperature for 3h, the resulting yellow insoluble matter was filtered off and washed with acetic acid, the filtrate and the washing solution were combined, and the mixture was concentrated under reduced pressure, extracted with ethyl acetate, washed successively with water, a sodium bicarbonate solution and a saturated saline solution, and dried over anhydrous sodium sulfate, the insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: petroleum ether/ethyl acetate ═ 2: 1-1: 1), and the resulting solution was concentrated under reduced pressure to give 1.05g of a white solid in a yield of 95%.
Step e: synthesis of benzyl (7-cyano-6- (4-fluoro-3- (2,2, 2-trifluoroacetylamino) phenoxy) benzo [ d ] thiazol-2-yl) carbamate.
N- (5- ((2-amino-7-cyanobenzo [ d ]]Thiazol-6-yl) oxy) -2-fluorophenyl) -2,2, 2-trifluoroacetamide (500mg, 1.26mmol) was dissolved in pyridine (10mL), benzyl chloride (428mg, 2.52mmol) was added slowly under nitrogen atmosphere, stirred at room temperature overnight, the reaction solution was evaporated to dryness directly, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 3: 1-2: 1) to give 200mg of a white solid in 30% yield.1H NMR(300MHz,DMSO-d6)δ12.56(s,1H),11.38(s,1H),8.01(d,1H,J＝9Hz),7.34-7.49(m,7H),7.21-7.25(m,1H),7.13(d,1H,J＝9Hz),5.31(s,2H)；MS(ESI):m/z[M+H]+:531.48.
Example 2
Allyl (7-cyano-6- (4-fluoro-3- (2,2, 2-trifluoroacetylamino) phenoxy) benzo [ d ] thiazol-2-yl) carbamate
Figure BDA0001773292360000081
Preparation of reference example 1 with N- (5- ((2-amino-7-cyanobenzo [ d)]Thiazol-6-yl) oxy) -2-fluorophenyl) -2,2, 2-trifluoroacetamide (500mg, 1.26mmol) was dissolved in pyridine (10mL), allyl chloroformate (303mg, 2.52mmol) was slowly added under a nitrogen atmosphere, the mixture was stirred at room temperature overnight, the reaction solution was directly evaporated to dryness, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 3: 1-2: 1) to yield 250mg of a white solid in 41% yield.1H NMR(300MHz,DMSO-d6)δ12.55(s,1H),11.39(s,1H),8.01(d,1H,J＝9Hz),7.46(t,1H,J＝9.6Hz),7.35-7.36(m,1H),7.21-7.24(m,1H),7.13(d,1H,J＝9Hz),5.95-6.06(m,1H),5.28-5.45(m,2H),4.76(d,2H,J＝4.8Hz)；MS(ESI):m/z[M+H]+:481.33.
Example 3
Benzyl (7-cyano-6- (4-fluoro-3- (2- (3- (trifluoromethyl) phenyl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) carbamate
The synthetic route is as follows:
Figure BDA0001773292360000082
step f: synthesis of benzyl (6- (3-amino-4-fluorophenoxy) -7-cyanobenzo [ d ] thiazol-2-yl) carbamate.
To a solution of sodium borohydride (280mg, 7.4mmol) in ethanol (10mL) was added methanol (0.5mL) and the product of example 1 (196mg, 0.37mmol) was added to the suspension at 0 deg.C. The reaction mixture was stirred at 0 ℃ for 0.5h, then at room temperature for 0.5h, the mixture was diluted with ethyl acetate (20mL), and the resulting mixture was filtered to concentrate the mixture in vacuo, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered of insoluble material, dried under reduced pressure, and purified by silica gel chromatography (eluent: petroleum ether/ethyl acetate 2: 1-1: 1) to give 150mg of a pale yellow solid in 94% yield, which was directly subjected to the next reaction without purification.
Step g synthesis of benzyl (7-cyano-6- (4-fluoro-3- (2- (3- (trifluoromethyl) phenyl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) carbamate.
The compound benzyl (6- (3-amino-4-fluorophenoxy) -7-cyanobenzo [ d]Thiazol-2-yl) carbamate (40mg, 0.09mmol) and 2- (3- (trifluoromethyl) phenyl) acetic acid (20mg, 0.11mmol) were dissolved in pyridine (5mL), 2- (7-oxybenzotriazole) -N, N' -tetramethyluronium Hexafluorophosphate (HATU) (68mg, 0.18mmol) was added to the solution at room temperature, the mixture was stirred at 80 ℃ for 3h, the reaction mixture was concentrated under reduced pressure, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered through insoluble sodium sulfateThe residue was dried under reduced pressure, purified by silica gel chromatography (eluent: petroleum ether/ethyl acetate 1:1), and recrystallized from ethyl acetate and petroleum ether to give 33mg of a white solid in a yield of 59%.1H NMR(300MHz,DMSO-d6)δ12.54(s,1H),10.22(s,1H),7.83-7.97(m,2H),7.57-7.68(m,4H),7.37-7.46(m,6H),6.98-7.07(m,2H),5.30(s,2H),3.88(s,2H)；MS(ESI):m/z[M+H]+:621.39.
Example 4
N- (7-cyano-6- (4-fluoro-3- (2- (3- (trifluoromethyl) phenyl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) nonanamide
Figure BDA0001773292360000091
N- (5- ((2-amino-7-cyanobenzo [ d ]]Thiazol-6-yl) oxy) -2-fluorophenyl) -2,2, 2-trifluoroacetamide (300mg, 0.76mmol) was dissolved in pyridine (10mL), nonanoyl chloride (267mg, 1.51mmol) was added slowly under nitrogen, the reaction was stirred at room temperature overnight, the reaction was evaporated to dryness directly, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 3: 1-2: 1) to yield 150mg of a white solid in 31% yield. The last two steps of preparation refer to step f and step g in example 3,1H NMR(300MHz,DMSO-d6)δ12.66(s,1H),10.23(s,1H),7.98(d,1H,J＝9Hz),7.82-7.85(m,1H),7.68(s,1H),7.52-7.62(m,3H),7.38(t,1H,J＝9.3Hz),7.06(d,1H,J＝9Hz),6.94-6.99(m,1H),3.88(s,2H),2.50-2.53(m,2H),1.60-1.62(m,2H),1.25-1.27(m,10H),0.83-0.87(m,3H)；MS(ESI):m/z[M+H]+:637.40.
example 5
N- (7-cyano-6- (4-fluoro-3- (2- (3- (trifluoromethyl) phenyl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) propanamide
Figure BDA0001773292360000092
N- (5- ((2-amino-7-cyanobenzo [ d ]]Thiazol-6-yl) oxy) -2-fluoroPhenyl) -2,2, 2-trifluoroacetamide (300mg, 0.76mmol) was dissolved in pyridine (10mL), propionyl chloride (140mg, 1.51mmol) was slowly added under a nitrogen atmosphere, stirred at room temperature overnight, the reaction solution was directly evaporated to dryness, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 3: 1-2: 1) to yield 160mg of a white solid in 39% yield. The last two steps of preparation refer to step f and step g in example 3,1H NMR(600MHz,DMSO-d6)δ12.62(s,1H),10.22(s,1H),7.97(d,1H,J＝9Hz),7.82-7.86(m,1H),7.68(s,1H),7.60-7.61(m,2H),7.53-7.56(m,1H),7.37(t,1H,J＝9.6Hz),7.06(d,1H,J＝8.4Hz),6.96-6.97(m,1H),3.88(s,2H),2.54(q,2H,J＝7.2Hz),1.12(t,3H,J＝7.8Hz)；MS(ESI):m/z[M+H]+:543.0.
example 6
N- (7-cyano-6- (4-fluoro-3- (2- (3- (trifluoromethyl) phenyl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) benzamide
Figure BDA0001773292360000101
N- (5- ((2-amino-7-cyanobenzo [ d ] thiazol-6-yl) oxy) -2-fluorophenyl) -2,2, 2-trifluoroacetamide (300mg, 0.76mmol) was dissolved in pyridine (10mL), benzoyl chloride (212mg, 1.51mmol) was slowly added under a nitrogen atmosphere, the mixture was stirred at room temperature overnight, the reaction solution was directly evaporated to dryness, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate ═ 3: 1-2: 1) to give 154mg of a white solid in a yield of 41%.
The last two steps of preparation refer to step f and step g in example 3,1H NMR(300MHz,DMSO-d6)δ12.21(s,1H),10.25(s,1H),8.13(d,2H,J＝6.9Hz),8.02(d,1H,J＝8.7Hz),7.87(s,1H),7.57-7.68(m,7H),7.38(t,1H,J＝9.3Hz),6.99-7.11(m,2H),3.89(s,2H)；MS(ESI):m/z[M+H]+:590.9.
example 7
N- (7-cyano-6- (4-fluoro-3- (2- (4-nitrophenyl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide
Figure BDA0001773292360000102
N- (5- ((2-amino-7-cyanobenzo [ d ] thiazol-6-yl) oxy) -2-fluorophenyl) -2,2, 2-trifluoroacetamide (526mg, 1.41mmol) was dissolved in pyridine (15mL), cyclopropanecarbonyl chloride (296mg, 2.83mmol) was slowly added under a nitrogen atmosphere, the mixture was stirred at room temperature overnight, the reaction mixture was directly evaporated to dryness, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate ═ 3: 1-2: 1) to give 515mg of white solid in 78% yield.
Preparation reference example 3 to a solution of sodium borohydride (636mg, 16.8mmol) in ethanol (20mL) was added methanol (1mL) and the product of the previous step (390mg, 0.84mmol) was added to the suspension at 0 ℃. The reaction mixture was stirred at 0 ℃ for 0.5h, then at room temperature for 0.5h, the mixture was diluted with ethyl acetate (20mL), and the resulting mixture was filtered, concentrated in vacuo, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered of insoluble material, dried under reduced pressure, and purified by silica gel chromatography (eluent: petroleum ether/ethyl acetate 2: 1-1: 1) to give 300mg of a pale yellow solid in 97% yield, which was directly subjected to the next reaction without purification.
The product of the previous step (30mg, 0.08mmol) and p-nitrophenylacetic acid (18mg, 0.097mmol) were dissolved in pyridine (5mL), 2- (7-benzotriazole oxide) -N, N' -tetramethylurea hexafluorophosphate (61mg, 0.16mmol) was added to the solution at room temperature, the mixture was stirred at 80 ℃ for 3h, the reaction mixture was concentrated under reduced pressure, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered of insoluble matter, dried under reduced pressure, purified by silica gel chromatography (eluent: petroleum ether/ethyl acetate 1:1), recrystallized with ethyl acetate and petroleum ether to give 33mg of a white solid with a yield of 70%.1H NMR(300MHz,DMSO-d6)δ12.98(s,1H),10.27(s,1H),8.18(d,2H,J＝8.4Hz),7.95-8.00(m,1H),7.83-7.84(m,1H),7.58(d,2H,J＝8.4Hz),7.37(t,1H,J＝9.9Hz),7.07(d,1H,J＝9Hz),6.95-6.98(m,1H),3.94(s,2H),1.98-2.04(m,1H),0.99-1.01(m,4H)；MS(ESI):m/z[M+H]+:532.0.
Example 8
N- (7-cyano-6- (4-fluoro-3- (2-phenylacetylamino) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide
Figure BDA0001773292360000111
Preparation reference example 7 was prepared by replacing p-nitroacetophenone in the last step with phenylacetic acid, dissolving phenylacetic acid (13mg, 0.097mmol) and the product of the previous step (30mg, 0.08mmol) in pyridine (5mL), adding 2- (7-benzotriazol oxide) -N, N' -tetramethylurea hexafluorophosphate (61mg, 0.16mmol) to the solution at room temperature, stirring the mixture at 80 ℃ for 3h, concentrating the reaction mixture under reduced pressure, extracting with ethyl acetate, washing with saturated sodium chloride, drying over anhydrous sodium sulfate, filtering off insoluble matter, drying under reduced pressure, purifying with silica gel chromatography (eluent: petroleum ether/ethyl acetate 1:1), recrystallizing with ethyl acetate and petroleum ether to give a white solid 20mg, yield 53%.1H NMR(300MHz,DMSO-d6)δ12.99(s,1H),10.15(s,1H),7.98(d,1H,J＝9Hz),7.84-7.87(m,1H),7.30-7.39(m,6H),7.06(d,1H,J＝9Hz),6.94-6.98(m,1H),1.98-2.01(m,1H),0.99-1.02(m,4H)；MS(ESI):m/z[M+H]+:487.0.
Example 9
N- (5- ((7-cyano-2- (cyclopropanecarboxamido) benzo [ d ] thiazol-6-yl) oxy) -2-fluorophenyl) -3- (trifluoromethyl) benzamide
Figure BDA0001773292360000112
Preparation of reference example 7, p-nitroacetoacetate in the last step was replaced with 3-trifluoromethylbenzoic acid, 3-trifluoromethylbenzoic acid (18mg, 0.097mmol) and the product of the previous step (30mg, 0.08mmol) were dissolved in pyridine (5mL), and the solution was added thereto at room temperatureTo the solution was added 2- (7-benzotriazol oxide) -N, N' -tetramethyluronium hexafluorophosphate (61mg, 0.16mmol), the mixture was stirred at 80 ℃ for 3h, the reaction mixture was concentrated under reduced pressure, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered of insoluble matter, dried under reduced pressure, purified with silica gel chromatography (eluent: petroleum ether/ethyl acetate ═ 1:1), and recrystallized with ethyl acetate and petroleum ether to give 20mg of white solid in 50% yield.1H NMR(300MHz,DMSO-d6)δ12.99(s,1H),10.50(s,1H),8.23-8.28(m,2H),7.97-8.06(m,2H),7.78(t,1H,J＝7.8Hz),7.50-7.53(m,1H),7.43(t,1H,J＝9.6Hz),7.11-7.18(m,2H),1.99-2.04(m,1H),0.99-1.02(m,4H)；MS(ESI):m/z[M+H]+:541.0.
Example 10
N- (7-cyano-6- (4-fluoro-3- (2- (3-fluorophenyl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide
Figure BDA0001773292360000113
Preparation reference example 7, p-nitrophenylacetic acid in the last step was replaced with 3-fluorophenylacetic acid, 3-fluorophenylacetic acid (15mg, 0.097mmol) and the product of the previous step (30mg, 0.08mmol) were dissolved in pyridine (5mL), 2- (7-benzotriazole oxide) -N, N' -tetramethylurea hexafluorophosphate (61mg, 0.16mmol) was added to the solution at room temperature, the mixture was stirred at 80 ℃ for 3 hours, the reaction mixture was concentrated under reduced pressure, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered of insoluble matter, dried under reduced pressure, and purified by silica gel chromatography (eluent: petroleum ether/ethyl acetate ═ 1:1), recrystallized from ethyl acetate and petroleum ether to give 22mg of a white solid in 55% yield. ,1H NMR(300MHz,DMSO-d6)δ12.99(s,1H),10.18(s,1H),7.99(d,1H,J＝9Hz),7.83-7.86(m,1H),7.31-7.40(m,2H),7.04-7.15(m,4H),6.95-6.99(m,1H),3.78(s,2H),1.98-2.04(m,1H),0.99-1.02(m,4H)；MS(ESI):m/z[M+H]+:505.0.
example 11
N- (7-cyano-6- (4-fluoro-3- (2- (2-fluoro-3- (trifluoromethyl) phenyl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide
Figure BDA0001773292360000121
Preparation reference example 7, p-nitroacetophenone in the last step was replaced with 2-fluoro-3- (trifluoromethyl) phenylacetic acid, 2-fluoro-3- (trifluoromethyl) phenylacetic acid (29mg, 0.13mmol) and the product of the previous step (30mg, 0.08mmol) were dissolved in pyridine (5mL), 2- (7-benzotriazol oxide) -N, N' -tetramethylurea hexafluorophosphate (83mg, 0.22mmol) was added to the solution at room temperature, the mixture was stirred at 80 ℃ for 3h, the reaction mixture was concentrated under reduced pressure, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered of insoluble substances, dried under reduced pressure, purified with silica gel chromatography (eluent: petroleum ether/ethyl acetate ═ 1:1), recrystallized with ethyl acetate and petroleum ether, 33mg of a white solid was obtained in 55% yield.1H NMR(300MHz,DMSO-d6)δ12.95(s,1H),10.28(s,1H),7.98(d,1H,J＝9Hz),7.82-7.85(m,1H),7.65-7.74(m,2H),7.34-7.41(m,2H),7.08(d,1H,J＝9Hz),6.95-7.00(m,1H),3.96(s,2H),1.98-2.03(m,1H),0.98-1.01(m,4H)；HRMS(ESI,positive)m/z calcd for C27H17F5N4O3S[M+H]+:573.1014；found 573.1024.
Example 12
N- (6- (4-fluoro-3- (2- (3- (trifluoromethyl) phenyl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide
Figure BDA0001773292360000122
Preparation of reference example 1 to a solution of 3-amino-4-fluorophenol (3g, 23.6mmol) and 1-fluoro-4-nitrobenzene (3.6g, 25.9mmol) in DMF (30mL) at room temperature was added K2CO3(4.89g, 35.4 mmol). The solution was stirred at 80 ℃ for 8h, and the solution was extracted with ethyl acetate, washed with saturated sodium chloride and dried over anhydrous sodium sulfateThe insoluble matter was filtered off, filtered and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate ═ 5: 1-4: 1), and the obtained solution was concentrated under reduced pressure to obtain 4.3g of a pale yellow solid in a yield of 74%.
The latter three steps are carried out with reference to example 1, the fourth step is followed by the reaction preparation reference example 7, p-nitrophenylacetic acid in the last step is replaced by 3-trifluoromethylphenylacetic acid, 3-trifluoromethylphenylacetic acid (101mg, 0.41mmol) and the product of the previous step (30mg, 0.08mmol) are dissolved in pyridine (10mL), 2- (7-benzotriazol oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (259mg, 0.68mmol) is added to the solution at room temperature, the mixture is stirred at 80 ℃ for 3h, the reaction mixture is concentrated under reduced pressure, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered of insoluble matter, dried under reduced pressure, purified with silica gel chromatography (eluent: petroleum ether/ethyl acetate 1:1), recrystallized with ethyl acetate and petroleum ether, 100mg of a white solid was obtained in 56% yield.1H NMR(600MHz,DMSO-d6)δ12.61(s,1H),10.11(s,1H),7.67-7.72(m,3H),7.63(d,1H,J＝2.4Hz),7.59-7.61(m,2H),7.53-7.56(m,1H),7.26-7.29(m,1H),7.10(dd,1H,J＝2.4,8.4Hz),6.78-6.81(m,1H),3.86(s,2H),1.98-2.00(m,1H),0.93-0.96(m,4H)；HRMS(ESI,positive)m/z calcd for C26H19F4N3O3S[M+H]+:530.1156；found 530.1169.
Example 13
N- (6- (4-fluoro-3- (2- (2-fluoro-3- (trifluoromethyl) phenyl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide
Figure BDA0001773292360000131
Preparation of reference example 12, 3-trifluoromethylphenylacetic acid in the last step was replaced with 2-fluoro-3- (trifluoromethyl) phenylacetic acid, 2-fluoro-3- (trifluoromethyl) phenylacetic acid (35mg, 0.14mmol) and the product of the previous step (30mg, 0.08mmol) were dissolved in pyridine (10mL), and 2- (7-benzotriazol oxide) was added to the solution at room temperature-N, N' -tetramethyluronium hexafluorophosphate (91mg, 0.24mmol), the mixture was stirred at 80 ℃ for 3h, the reaction mixture was concentrated under reduced pressure, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, the insoluble material was filtered, dried under reduced pressure, purified by silica gel chromatography (eluent: petroleum ether/ethyl acetate 1:1), and recrystallized from ethyl acetate and petroleum ether to give 25mg of a white solid in 38% yield.1H NMR(600MHz,DMSO-d6)δ12.60(s,1H),10.17(s,1H),7.66-7.72(m,4H),7.63(d,1H,J＝3Hz),7.37(t,1H,J＝7.8Hz),7.27-7.31(m,1H),7.09(dd,1H,J＝2.4,9Hz),6.79-6.82(m,1H),3.93(s,2H),1.98-2.01(m,1H),0.92-0.96(m,4H)；HRMS(ESI,positive)m/z calcd for C26H18F5N3O3S[M+H]+:548.1056；found 548.1074.
Example 14
N- (6- (3- (2- (3, 5-bis (trifluoromethyl) phenyl) acetamido) -4-fluorophenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide
Figure BDA0001773292360000132
Preparation reference example 12, 3-trifluoromethylphenylacetic acid in the last step was replaced with 3, 5-bistrifluoromethylphenylacetic acid, 3, 5-bistrifluoromethylphenylacetic acid (38mg, 0.14mmol) and the product of the last step (30mg, 0.08mmol) were dissolved in pyridine (10mL), 2- (7-oxybenzotriazole) -N, N' -tetramethylurea hexafluorophosphate (91mg, 0.24mmol) was added to the solution at room temperature, the mixture was stirred at 80 ℃ for 3h, the reaction mixture was concentrated under reduced pressure, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered of insoluble matter, dried under reduced pressure, purified with silica gel chromatography (eluent: petroleum ether/ethyl acetate ═ 1:1), recrystallized with ethyl acetate and petroleum ether to give 32mg of a white solid, the yield thereof was found to be 46%.1H NMR(600MHz,DMSO-d6)δ12.59(s,1H),10.15(s,1H),8.01(s,2H),7.98(s,1H),7.71(d,1H,J＝9Hz),7.65-7.67(m,1H),7.62(d,1H,J＝2.4Hz),7.27-7.30(m,1H),7.09(dd,1H,J＝2.4,8.4Hz),6.79-6.82(m,1H),3.31(s,2H),1.98-2.01(m,1H),0.93-0.96(m,4H)；HRMS(ESI,positive)m/z calcd for C27H18F7N3O3S[M+H]+:598.1024；found 598.1032.
Example 15
N- (6- (4-fluoro-3- (2- (3-nitrophenyl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide
Figure BDA0001773292360000141
Preparation reference example 12, 3-trifluoromethylphenylacetic acid in the last step was replaced with 3-nitrophenylacetic acid, 3-nitrophenylacetic acid (25mg, 0.14mmol) and the product of the previous step (30mg, 0.08mmol) were dissolved in pyridine (10mL), to the solution was added 2- (7-benzotriazol oxide) -N, N' -tetramethyluronium hexafluorophosphate (91mg, 0.24mmol) at room temperature, the mixture was stirred at 80 ℃ for 3 hours, the reaction mixture was concentrated under reduced pressure, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered of insoluble matter, dried under reduced pressure, purified with silica gel chromatography (eluent: petroleum ether/ethyl acetate ═ 1:1), and recrystallized with ethyl acetate and petroleum ether to give 20mg of a white solid in 33% yield.1H NMR(600MHz,DMSO-d6)δ12.59(s,1H),10.14(s,1H),8.20(s,1H),8.09-8.11(m,1H),7.74-7.76(m,1H),7.70-7.71(m,2H),7.59-7.62(m,2H),7.28(t,1H,J＝10.2Hz),7.09(dd,1H,J＝2.4,8.4Hz),6.78-6.80(m,1H),3.92(s,2H),1.98-2.01(m,1H),0.94-0.95(m,4H)；HRMS(ESI,positive)m/z calcd for C25H19FN4O5S[M+H]+:507.1127；found 507.1151.
Example 16
N- (6- (4-fluoro-3- (2- (3- (trifluoromethyl) phenyl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) cyclohexanecarboxamide
Figure BDA0001773292360000142
The previous four steps refer to example 12, the fifth step: n- (5- (2-aminobenzo [ d ] thiazol-6-yl) oxy) -2-fluorophenyl) -2,2, 2-trifluoroacetamide (200mg, 0.53mmol) was dissolved in pyridine (10mL), cyclohexanecarboxyl chloride (155mg, 1.06mmol) was added slowly under a nitrogen atmosphere, stirred at room temperature overnight, the reaction was evaporated to dryness directly, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 3: 1-2: 1) to give 248mg of white solid in 75% yield.
Sixth step and seventh step preparation referring to example 12,1H NMR(600MHz,DMSO-d6)δ12.23(s,1H),10.11(s,1H),7.69-7.71(m,2H),7.67(s,1H),7.62(d,1H,J＝2.4Hz),7.59-7.60(m,2H),7.53-7.55(m,1H),7.28(t,1H,J＝10.2Hz),7.09(dd,1H,J＝2.4,9Hz),6.78-6.80(m,1H),3.86(s,2H),2.53-2.55(m,1H),1.27-1.44(m,10H)；HRMS(ESI,positive)m/z calcd for C29H25F4N3O3S[M+H]+:572.1602；found 572.1633.
example 17
N- (6- (4-fluoro-3- (2- (2- (trifluoromethyl) phenyl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide
Figure BDA0001773292360000151
Preparation reference example 12, 3-trifluoromethylphenylacetic acid in the last step was replaced with 2-trifluoromethylphenylacetic acid, 2-trifluoromethylphenylacetic acid (34mg, 0.14mmol) and the product of the previous step (30mg, 0.08mmol) were dissolved in pyridine (10mL), to the solution was added 2- (7-benzotriazol oxide) -N, N' -tetramethyluronium hexafluorophosphate (91mg, 0.24mmol) at room temperature, the mixture was stirred at 80 ℃ for 3 hours, the reaction mixture was concentrated under reduced pressure, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered of insoluble matter, dried under reduced pressure, purified with silica gel chromatography (eluent: petroleum ether/ethyl acetate ═ 1:1), and recrystallized with ethyl acetate and petroleum ether to give 20mg of a white solid with a yield of 32%.1H NMR(600MHz,DMSO-d6)δ12.60(s,1H),10.10(s,1H),7.67-7.71(m,3H),7.63(d,1H,J＝2.4Hz),7.61(t,1H,J＝7.8Hz),7.44-7.49(m,2H),7.22(t,1H,J＝10.2Hz),7.10(dd,1H,J＝2.4,8.4Hz),6.78-6.80(m,1H),4.00(s,2H),1.98-2.01(m,1H),0.94-0.96(m,4H)；HRMS(ESI,positive)m/z calcd for C26H19F4N3O3S[M+H]+:530.1156；found 530.1173.
Example 18
N- (6- (4-fluoro-3- (2- (m-tolyl) acetylamino) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide
Figure BDA0001773292360000152
Preparation reference example 12, 3-trifluoromethylphenylacetic acid in the last step was replaced with 3-methylphenylacetic acid, 3-methylphenylacetic acid (21mg, 0.14mmol) and the product of the previous step (30mg, 0.08mmol) were dissolved in pyridine (10mL), to the solution was added 2- (7-benzotriazol oxide) -N, N' -tetramethyluronium hexafluorophosphate (91mg, 0.24mmol) at room temperature, the mixture was stirred at 80 ℃ for 3 hours, the reaction mixture was concentrated under reduced pressure, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered of insoluble matter, dried under reduced pressure, purified with silica gel chromatography (eluent: petroleum ether/ethyl acetate ═ 1:1), and recrystallized with ethyl acetate and petroleum ether to give 21mg of a white solid with a yield of 38%.1H NMR(600MHz,DMSO-d6)δ12.60(s,1H),9.98(s,1H),7.70-7.72(m,2H),7.62(d,1H,J＝2.4Hz),7.24-7.28(m,1H),7.18(t,1H,J＝7.8Hz),7.08-7.11(m,3H),7.02(d,1H,J＝7.2Hz),6.77-6.79(m,1H),3.67(s,2H),2.26(s,3H),1.98-2.01(m,1H),0.94-0.96(m,4H)；HRMS(ESI,positive)m/z calcd for C26H22FN3O3S[M+H]+:476.1439；found 476.1449.
Example 19
N- (6- (4-fluoro-3- (3- (3- (trifluoromethyl) phenyl) propionylamino) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide
Figure BDA0001773292360000153
Preparation reference example 12, 3-trifluoromethylphenylacetic acid was replaced with 3-methylpropanoic acid in the last step, 3-methylpropanoic acid (30mg, 0.14mmol) and the product of the previous step (30mg, 0.08mmol) were dissolved in pyridine (10mL), to this solution was added 2- (7-benzotriazol oxide) -N, N' -tetramethyluronium hexafluorophosphate (91mg, 0.24mmol) at room temperature, the mixture was stirred at 80 ℃ for 3 hours, the reaction mixture was concentrated under reduced pressure, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered of insoluble matter, dried under reduced pressure, purified with silica gel chromatography (eluent: petroleum ether/ethyl acetate ═ 1:1), and recrystallized with ethyl acetate and petroleum ether to give 25mg of a white solid with a yield of 39%.1H NMR(600MHz,DMSO-d6)δ12.61(s,1H),9.79(s,1H),7.73(d,1H,J＝11.4Hz),7.66-7.67(m,1H),7.63(d,1H,J＝2.4Hz),7.59(s,1H),7.48-7.54(m,3H),7.23-7.26(m,1H),7.10(dd,1H,J＝2.4,8.4Hz),6.76-6.79(m,1H),2.96(t,2H,J＝8.4Hz),2.74(t,2H,J＝7.8Hz),1.98-2.01(m,1H),0.94-0.96(m,4H)；HRMS(ESI,positive)m/z calcd for C27H21F4N3O3S[M+H]+:544.1313；found 544.1324.
Example 20
N- (6- (4-fluoro-3- (2- (pyridin-2-yl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide
Figure BDA0001773292360000161
Preparation of reference example 12, 3-trifluoromethylphenylacetic acid in the last step was replaced with 2-pyridineacetic acid hydrochloride, 2-pyridineacetic acid hydrochloride (24mg, 0.14mmol) and the product of the previous step (30mg, 0.08mmol) were dissolved in pyridine (10mL), 2- (7-benzotriazol oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (91mg, 0.24mmol) was added to the solution at room temperature, the mixture was stirred at 80 ℃ for 3 hours, the reaction mixture was concentrated under reduced pressure, extracted with ethyl acetate, washed with saturated sodium chloride, and anhydrous sulfurSodium acid was dried, the insoluble material was filtered, dried under reduced pressure, and purified by silica gel chromatography (eluent: petroleum ether/ethyl acetate 1:1), and recrystallized from ethyl acetate and petroleum ether to give 23mg of a white solid in a yield of 42%.1H NMR(600MHz,DMSO-d6)δ12.60(s,1H),10.21(s,1H),8.49(d,1H,J＝4.2Hz),7.70-7.76(m,3H),7.63(d,1H,J＝2.4Hz),7.36(d,1H,J＝7.8Hz),7.25-7.29(m,2H),7.10(dd,1H,J＝2.4,9Hz),6.77-6.80(m,1H),3.93(s,2H),1.98-2.01(m,1H),0.94-0.95(m,4H)；HRMS(ESI,positive)m/z calcd for C24H19FN4O3S[M+H]+:463.1325；found 463.1248.
Example 21
N- (6- (4-fluoro-3- (2- (4-fluoro-3 (trifluoromethyl) phenyl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide
Figure BDA0001773292360000162
Preparation reference example 12, 3-trifluoromethylphenylacetic acid in the last step was replaced with 4-fluoro-3-trifluoromethylphenylacetic acid, 4-fluoro-3-trifluoromethylphenylacetic acid (31mg, 0.14mmol) and the product of the previous step (30mg, 0.08mmol) were dissolved in pyridine (10mL), 2- (7-benzotriazol oxide) -N, N' -tetramethylurea hexafluorophosphate (91mg, 0.24mmol) was added to the solution at room temperature, the mixture was stirred at 80 ℃ for 3 hours, the reaction mixture was concentrated under reduced pressure, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered of insoluble substances, dried under reduced pressure, purified with silica gel chromatography (eluent: petroleum ether/ethyl acetate ═ 1:1), recrystallized with ethyl acetate and petroleum ether, 26mg of a white solid was obtained in a yield of 40%.1H NMR(600MHz,DMSO-d6)δ12.60(s,1H),10.09(s,1H),7.65-7.72(m,4H),7.62(d,1H,J＝2.4Hz),7.43(t,1H,J＝9Hz),7.27(t,1H,J＝10.2Hz),7.09(dd,1H,J＝2.4,9Hz),6.78-6.81(m,1H),3.84(s,2H),1.98-2.01(m,1H),0.93-0.95(m,4H)；HRMS(ESI,positive)m/z calcd for C26H18F5N3O3S[M+H]+:548.1062；found 548.1069.
Example 22
N- (6- (3- (2- (2-chloro-3- (trifluoromethyl) phenyl) acetamido) -4-fluorophenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide
Figure BDA0001773292360000171
Preparation reference example 12, 3-trifluoromethylphenylacetic acid in the last step was replaced with 2-chloro-3-trifluoromethylphenylacetic acid, 2-chloro-3-trifluoromethylphenylacetic acid (33mg, 0.14mmol) and the product of the previous step (30mg, 0.08mmol) were dissolved in pyridine (10mL), 2- (7-benzotriazol oxide) -N, N' -tetramethylurea hexafluorophosphate (91mg, 0.24mmol) was added to the solution at room temperature, the mixture was stirred at 80 ℃ for 3 hours, the reaction mixture was concentrated under reduced pressure, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered of insoluble substances, dried under reduced pressure, purified with silica gel chromatography (eluent: petroleum ether/ethyl acetate ═ 1:1), recrystallized with ethyl acetate and petroleum ether, 21mg of a white solid was obtained in 31% yield.1H NMR(600MHz,DMSO-d6)δ12.60(s,1H),10.19(s,1H),7.74(d,1H,J＝2.4Hz),7.70-7.72(m,3H),7.62(d,1H,J＝2.4Hz),7.50(t,1H,J＝7.8Hz),7.28(t,1H,J＝9Hz),7.10(dd,1H,J＝2.4,8.4Hz),6.78-6.81(m,1H),4.06(s,2H),1.98-2.01(m,1H),0.94-0.95(m,4H)；MS(ESI):m/z[M+H]+:563.9.
Example 23
N- (6- (4-fluoro-3- (2- (3-methoxyphenyl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide
Figure BDA0001773292360000172
Preparation of reference example 12, 3-trifluoromethylphenylacetic acid in the last step was replaced with 3-methoxyphenylacetic acid, 3-methoxyphenylacetic acid (23mg, 0.14mmol) and the product of the previous step (30mg, 0.08mmol) were dissolved in pyridine (10mL), and 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethyluronhexakis were added to the solution at room temperatureFluorophosphate (91mg, 0.24mmol), the mixture was stirred at 80 ℃ for 3h, the reaction mixture was concentrated under reduced pressure, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, the insoluble material was filtered, dried under reduced pressure, purified by silica gel chromatography (eluent: petroleum ether/ethyl acetate 1:1), and recrystallized with ethyl acetate and petroleum ether to give 30mg of white solid in 52% yield.1H NMR(300MHz,DMSO-d6)δ12.63(s,1H),10.02(s,1H),7.70-7.73(m,2H),7.64(d,1H,J＝2.4Hz),7.19-7.30(m,2H),7.10(dd,1H,J＝2.4,8.7Hz),6.86-6.88(m,2H),6.77-6.81(m,2H),3.72(s,3H),3.69(s,2H),1.99-2.01(m,1H),0.94-0.96(m,4H)；HRMS(ESI,positive)m/z calcd for C26H22FN3O4S[M+H]+:492.1388；found 492.1399.
Example 24
N- (6- (4-fluoro-3- (2- (3- (trifluoromethoxy) phenyl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide
Figure BDA0001773292360000181
Preparation reference example 12, 3-trifluoromethylphenylacetic acid in the last step was replaced with 3-trifluoromethylphenylacetic acid, 3-trifluoromethylphenylacetic acid (31mg, 0.14mmol) and the product of the last step (30mg, 0.08mmol) were dissolved in pyridine (10mL), 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (91mg, 0.24mmol) was added to the solution at room temperature, the mixture was stirred at 80 ℃ for 3 hours, the reaction mixture was concentrated under reduced pressure, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered of insoluble matter, dried under reduced pressure, purified with a silica gel column (eluent: petroleum ether/ethyl acetate ═ 1:1), recrystallized from ethyl acetate and petroleum ether to give 32mg of a white solid, the yield thereof was found to be 49%.1H NMR(300MHz,DMSO-d6)δ12.63(s,1H),10.11(s,1H),7.63-7.73(m,3H),7.44(t,1H,J＝8.1Hz),7.22-7.34(m,4H),7.10(d,1H,J＝8.7Hz),6.78-6.81(m,1H),3.80(s,1H),1.99-2.01(m,1H),0.93-0.95(m,4H)；HRMS(ESI,positive)m/z calcd for C26H19F4N3O4S[M+H]+:546.1105；found 546.1121.
Example 25
N- (6- (3- (2- (benzo [ d ] [1,3] dioxol-5-yl) acetamido) -4-fluorophenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide
Figure BDA0001773292360000182
Preparation reference example 12, substituting 3-trifluoromethylphenylacetic acid in the last step for piperonylic acid, dissolving piperonylic acid (25mg, 0.14mmol) and the product of the previous step (30mg, 0.08mmol) in pyridine (10mL), adding 2- (7-benzotriazol-N, N' -tetramethyluronium hexafluorophosphate (91mg, 0.24mmol) to the solution at room temperature, stirring the mixture at 80 ℃ for 3h, concentrating the reaction mixture under reduced pressure, extracting with ethyl acetate, washing with saturated sodium chloride, drying over anhydrous sodium sulfate, filtering off the insoluble matter, drying under reduced pressure, purifying with silica gel chromatography (eluent: petroleum ether/ethyl acetate 1:1), recrystallizing with ethyl acetate and petroleum ether to obtain a white solid 30mg, yield 50%.1H NMR(300MHz,DMSO-d6)δ12.62(s,1H),9.96(s,1H),7.63-7.73(m,3H),7.27(t,1H,J＝10.2Hz),7.10(dd,1H,J＝2.4,8.7Hz),6.74-6.86(m,4H),5.96(s,2H),3.62(s,1H),1.98-2.01(m,1H),0.93-0.95(m,4H)；HRMS(ESI,positive)m/z calcd for C26H20FN3O5S[M+H]+:506.1180；found 506.1189.
Example 26
N- (6- (4-fluoro-3- (2- (6- (trifluoromethyl) pyridin-2-yl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide
Figure BDA0001773292360000183
Preparation of reference example 12, 3-trifluoromethylphenylacetic acid was replaced with 2- (6- (trifluoromethyl) pyridin-2-yl in the last step]Acetic acid, 2- (6- (trifluoromethyl) pyridine-2-Base of]Acetic acid (29mg, 0.14mmol) and the product of the previous step (30mg, 0.08mmol) were dissolved in pyridine (10mL), 2- (7-benzotriazol oxide) -N, N' -tetramethyluronium hexafluorophosphate (91mg, 0.24mmol) was added to the solution at room temperature, the mixture was stirred at 80 ℃ for 3h, the reaction mixture was concentrated under reduced pressure, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered of the insoluble matter, dried under reduced pressure, purified by silica gel chromatography (eluent: petroleum ether/ethyl acetate ═ 1:1), recrystallized with ethyl acetate and petroleum ether to give 30mg of a white solid with a yield of 41%.1H NMR(300MHz,DMSO-d6)δ12.62(s,1H),10.21(s,1H),8.03(t,1H,J＝7.8Hz),7.64-7.73(m,5H),7.27(t,1H,J＝9.9Hz),7.10(dd,1H,J＝2.1,8.7Hz),6.79-6.83(m,1H),4.08(s,1H),1.98-2.01(m,1H),0.93-0.95(m,4H)；HRMS(ESI,positive)m/z calcd for C25H18F4N4O3S[M+H]+:531.1109；found 531.1120.
Example 27
N- (5- ((2- (cyclopropanecarboxamido) benzo [ d ] thiazol-6-yl) oxy) -2-fluorophenyl) -1- (3- (trifluoromethyl) phenyl) cyclopropane-1-carboxamide
Figure BDA0001773292360000191
Preparation of reference example 12, 3-trifluoromethylphenylacetic acid in the last step was replaced with 1- (3- (trifluoromethyl) phenyl) cyclopropane-1-carboxylic acid, 1- (3- (trifluoromethyl) phenyl) cyclopropane-1-carboxylic acid (32mg, 0.14mmol) and the product of the previous step (30mg, 0.08mmol) were dissolved in pyridine (10mL), 2- (7-oxybenzotriazole) -N, N' -tetramethylurea hexafluorophosphate (91mg, 0.24mmol) was added to the solution at room temperature, the mixture was stirred at 80 ℃ for 3 hours, the reaction mixture was concentrated under reduced pressure, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered of insoluble matter, dried under reduced pressure, purified by silica gel chromatography (eluent: petroleum ether/ethyl acetate 1:1), recrystallization from ethyl acetate and petroleum ether gave 18mg of a white solid in 29% yield.1H NMR(300MHz,DMSO-d6)δ12.64(s,1H),8.62(s,1H),7.59-7.75(m,6H),7.28-7.31(m,1H),7.22(t,1H,J＝9.9Hz),7.10(dd,1H,J＝2.4,8.7Hz),6.82-6.87(m,1H),1.98-2.01(m,1H),1.48-1.52(m,2H),1.18-1.25(m,2H),0.91-0.97(m,4H)；MS(ESI):m/z[M+H]+:556.0.
Example 28
N- (6- (4-fluoro-3- (2- (3- (trifluoromethyl) phenyl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) cyclobutanecarboxamide
Figure BDA0001773292360000192
The previous four steps refer to example 12, the fifth step: n- (5- (2-aminobenzo [ d ]]Thiazol-6-yl) oxy) -2-fluorophenyl) -2,2, 2-trifluoroacetamide (100mg, 0.27mmol) was dissolved in pyridine (10mL), cyclopropanecarbonyl chloride (64mg, 0.54mmol) was added slowly under nitrogen atmosphere, the reaction mixture was stirred at room temperature overnight, the reaction solution was evaporated to dryness directly, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 3: 1-2: 1) to give 75mg of a white solid in 70% yield. Sixth step and seventh step preparation referring to example 12,1H NMR(300MHz,DMSO-d6)δ12.20(s,1H),10.13(s,1H),7.68-7.71(m,3H),7.64(d,1H,J＝2.4Hz),7.54-7.61(m,3H),7.28(t,1H,J＝9.9Hz),7.10(dd,1H,J＝2.4,8.7Hz),6.77-6.82(m,1H),3.86(s,2H),3.67-3.42(m,1H),1.80-2.28(m,6H)；HRMS(ESI,positive)m/z calcd for C27H21F4N3O3S[M+H]+:544.1313；found 544.1330.
example 29
N- (6- (4-fluoro-3- (2- (1-methyl-1H-indol-3-yl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide
Figure BDA0001773292360000201
Preparation of reference example 12, 3-trifluoromethylphenylacetic acid was replaced by 1-methyl-3-indole in the last stepAcetic acid, 1-methyl-3-indoleacetic acid (23mg, 0.14mmol) and the product of the previous step (30mg, 0.08mmol) were dissolved in pyridine (10mL), 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (91mg, 0.24mmol) was added to the solution at room temperature, the mixture was stirred at 80 ℃ for 3h, the reaction mixture was concentrated under reduced pressure, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered of insoluble matter, dried under reduced pressure, purified with silica gel chromatography (eluent: petroleum ether/ethyl acetate ═ 1:1), recrystallized with ethyl acetate and petroleum ether to give 25mg of white solid in 38% yield.1H NMR(600MHz,DMSO-d6)δ12.59(s,1H),9.90(s,1H),7.69-7.72(m,2H),7.62(d,1H,J＝2.4Hz),7.57-7.59(m,1H),7.37-7.38(m,1H),7.24-7.27(m,1H),7.21(s,1H),7.11-7.14(m,1H),7.09(dd,1H,J＝3,9Hz),6.99-7.01(m,1H),6.75-6.78(m,1H),3.80(s,2H),3.74(s,3H),1.97-1.99(m,1H),0.93-0.96(m,4H)；HRMS(ESI,positive)m/z calcd for C28H23FN4O3S[M+H]+:515.1548；found 515.1560.
Example 30
N- (6- (4-fluoro-3- (2- (3- (trifluoromethyl) phenyl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopentanecarboxamide
Figure BDA0001773292360000202
The previous four steps refer to example 12, the fifth step: n- (5- (2-aminobenzo [ d ]]Thiazol-6-yl) oxy) -2-fluorophenyl) -2,2, 2-trifluoroacetamide (100mg, 0.27mmol) was dissolved in pyridine (10mL), cyclobutylcarbonyl chloride (71mg, 0.54mmol) was added slowly under nitrogen atmosphere, stirred at room temperature overnight, the reaction solution was evaporated to dryness directly, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 3: 1-2: 1) to give 80mg of a white solid in a yield of 72%. Sixth step and seventh step preparation referring to example 12,1H NMR(600MHz,DMSO-d6)δ12.30(s,1H),10.11(s,1H),7.67-7.74(m,3H),7.63(d,1H,J＝1.8Hz),7.53-7.61(m,3H),7.27(t,1H,J＝7.2Hz),7.10(dd,1H,J＝1.8,8.4Hz),6.78-6.80(m,1H),3.86(s,2H),2.95-2.98(m,1H),1.55-1.91(m,4H)；HRMS(ESI,positive)m/z calcd for C28H23F4N3O3S[M+H]+:558.1649；found 558.1477.
example 31
N- (6- (4-fluoro-3- (2- (3- (trifluoromethyl) phenyl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) isobutyramide
Figure BDA0001773292360000211
The previous four steps refer to example 12, the fifth step: n- (5- (2-aminobenzo [ d ]]Thiazol-6-yl) oxy) -2-fluorophenyl) -2,2, 2-trifluoroacetamide (100mg, 0.27mmol) was dissolved in pyridine (10mL), isopropanoyl chloride (57mg, 0.54mmol) was added slowly under nitrogen, stirred at room temperature overnight, the reaction was evaporated to dryness directly, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 3: 1-2: 1) to give 113mg of a white solid in a yield of 95%. Sixth step and seventh step preparation referring to example 12,1H NMR(300MHz,DMSO-d6)δ12.30(s,1H),10.14(s,1H),7.68-7.73(m,3H),7.64(d,1H,J＝2.4Hz),7.53-7.62(m,3H),7.28(t,1H,J＝10.2Hz),7.10(dd,1H,J＝2.4,9.3Hz),6.77-6.82(m,1H),3.86(s,2H),2.74-2.83(m,1H),1.13-1.18(m,4H)；HRMS(ESI,positive)m/z calcd for C26H21F4N3O3S[M+H]+:532.1313；found 532.1325.
example 32
N- (6- (3- (2- (3-cyanophenyl) acetylamino) -4-fluorophenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide
Figure BDA0001773292360000212
Preparation of reference example 12 by substituting 3-trifluoromethylphenylacetic acid for 3-cyanophenylacetic acid in the last step3-cyanophenylacetic acid (23mg, 0.14mmol) and the product of the previous step (30mg, 0.08mmol) were dissolved in pyridine (10mL), 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (91mg, 0.24mmol) was added to the solution at room temperature, the mixture was stirred at 80 ℃ for 3 hours, the reaction mixture was concentrated under reduced pressure, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered of insoluble matter, dried under reduced pressure, purified by silica gel chromatography (eluent: petroleum ether/ethyl acetate ═ 1:1), recrystallized with ethyl acetate and petroleum ether to give 32mg of white solid, yield 55%.1H NMR(300MHz,DMSO-d6)δ12.62(s,1H),10.12(s,1H),7.70-7.14(m,4H),7.62-7.64(m,2H),7.51(t,1H,J＝7.8Hz),7.28(t,1H,J＝9.9Hz,),7.09(dd,1H,J＝2.1,8.7Hz,q),6.77-6.82(m,1H),3.83(s,2H),1.98-2.21(m,1H),0.93-0.95(m,4H)；HRMS(ESI,positive)m/z calcd for C26H19FN4O3S[M+H]+:487.1352；found 487.1244.
Example 33
N- (6- (3- (2- (3, 4-dimethylphenyl) acetylamino) -4-fluorophenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide
Figure BDA0001773292360000213
Preparation reference example 12, 3-trifluoromethylphenylacetic acid in the last step was replaced with 3, 4-dimethylphenylacetic acid, 3, 4-dimethylphenylacetic acid (23mg, 0.14mmol) and the product of the previous step (30mg, 0.08mmol) were dissolved in pyridine (10mL), 2- (7-oxybenzotriazole) -N, N' -tetramethylurea hexafluorophosphate (91mg, 0.24mmol) was added to the solution at room temperature, the mixture was stirred at 80 ℃ for 3 hours, the reaction mixture was concentrated under reduced pressure, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered of insoluble matter, dried under reduced pressure, purified with a silica gel column (eluent: petroleum ether/ethyl acetate ═ 1:1), recrystallized with ethyl acetate and petroleum ether to give 26mg of a white solid, the yield thereof was found to be 45%.1H NMR(300MHz,DMSO-d6)δ12.63(s,1H),9.96(s,1H),7.70-7.72(m,1H),7.62(d,1H,J＝2.1Hz),7.26(t,1H,J＝9.9Hz),6.99-7.11(m,4H),6.76-6.80(m,1H),6.77-6.80(m,1H),3.63(s,2H),2.15-2.16(m,6H),1.98-2.01(m,1H),0.94-0.96(m,4H)；HRMS(ESI,positive)m/z calcd for C27H24FN3O3S[M+H]+:490.1595；found 490.1597.
Example 34
N- (6- (4-fluoro-3- (2- (3- (trifluoromethyl) phenyl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) tetrahydro-2H-pyran-4-carboxamide
Figure BDA0001773292360000221
The previous four steps refer to example 12, the fifth step: n- (5- (2-aminobenzo [ d ]]Thiazol-6-yl) oxy) -2-fluorophenyl) -2,2, 2-trifluoroacetamide (100mg, 0.27mmol) was dissolved in pyridine (10mL), tetrahydropyran-4-carbonyl chloride (80mg, 0.54mmol) was added slowly under nitrogen atmosphere, stirred at room temperature overnight, the reaction solution was evaporated to dryness directly, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 3: 1-2: 1) to give 128mg of a white solid in 98% yield. Sixth step and seventh step preparation referring to example 12,1H NMR(300MHz,DMSO-d6)δ12.35(s,1H),10.13(s,1H),7.68-7.73(m,3H),7.64(d,1H,J＝2.4Hz),7.53-7.61(m,3H),7.28(t,1H,J＝10.2Hz),7.10(dd,1H,J＝2.4,8.7Hz),6.77-6.80(m,1H),3.86-3.92(m,4H),3.35-3.72(m,2H),2.76-2.83(m,1H),1.68-1.79(m,4H)；HRMS(ESI,positive)m/z calcd for C28H23F4N3O4S[M+H]+:574.1418；found 574.1428.
example 35
N- (6- (4-fluoro-3- (2- (3-hydroxyphenyl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide
Figure BDA0001773292360000222
Preparation reference example 12, 3-trifluoromethylphenylacetic acid in the last step was replaced with 3-hydroxyphenylacetic acid, 3-hydroxyphenylacetic acid (21mg, 0.14mmol) and the product of the previous step (30mg, 0.08mmol) were dissolved in pyridine (10mL), to the solution was added 2- (7-benzotriazol oxide) -N, N' -tetramethyluronium hexafluorophosphate (91mg, 0.24mmol) at room temperature, the mixture was stirred at 80 ℃ for 3 hours, the reaction mixture was concentrated under reduced pressure, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered of insoluble matter, dried under reduced pressure, purified with silica gel chromatography (eluent: petroleum ether/ethyl acetate ═ 1:1), and recrystallized with ethyl acetate and petroleum ether to give 26mg of a white solid with a yield of 46%.1H NMR(300MHz,DMSO-d6)δ12.63(s,1H),9.99(s,1H),9.33(s,1H),7.70-7.75(m,2H),7.64(d,1H,J＝2.4Hz),7.27(t,1H,J＝10.5Hz),7.05-7.12(m,2H),6.70-6.80(m,3H),6.62(d,1H,J＝9Hz),3.62(s,1H)1.98-1.99(m,1H),0.93-0.95(m,4H)；MS(ESI):m/z[M+H]+:478.0.
Example 36
N- (6- (4-fluoro-3- (3- (3- (trifluoromethyl) phenyl) ureido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide
The synthetic route is as follows:
Figure BDA0001773292360000231
step g-1: synthesis of N- (6- (4-fluoro-3- (3- (3- (trifluoromethyl) phenyl) ureido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropane carboxamide.
The compound N- (6- (3-amino-4-fluorophenoxy) benzo [ d]Thiazol-2-yl) cyclopropanecarboxamide (40mg, 0.12mmol) was dissolved in DMF (5mL), the compound 1-isocyanato-3- (trifluoromethyl) benzene (32mg, 0.17mmol) was added and stirred at room temperature for 12h, diluted with ethyl acetate, washed with sodium bicarbonate solution and saturated sodium chloride, dried over anhydrous sodium sulfate, the insoluble filtered, dried under reduced pressure and purified by silica gel chromatography (eluent: petroleum ether/ethyl acetate ═ 1:1), giving 20mg of a pale yellow solid in 32% yield.1H NMR(600MHz,DMSO-d6)δ12.60(s,1H),9.43(s,1H),8.75(s,1H),7.90-7.93(m,2H),7.72(d,1H,J＝9Hz),7.63(d,1H,J＝2.4Hz),7.49-7.53(m,2H),7.25-7.32(m,2H),7.12(dd,1H,J＝2.4,9Hz),6.66-6.68(m,1H),1.97-2.01(m,1H),0.94-0.96(m,4H).HRMS(ESI,positive)m/z calcd for C25H18F4N4O3S[M+H]+:531.1109；found 531.1118.
Example 37
N- (6- (4-fluoro-3- (3- (4- (trifluoromethoxy) phenyl) ureido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide
Figure BDA0001773292360000232
Referring to the synthetic route of example 36, the compound N- (6- (3-amino-4-fluorophenoxy) benzo [ d]Thiazol-2-yl) cyclopropanecarboxamide (40mg, 0.12mmol) was dissolved in DMF (5mL), 4-trifluoromethoxyphenyl isocyanate (34mg, 0.17mmol) was added, stirred at room temperature for 12h, diluted with ethyl acetate, washed with sodium bicarbonate solution and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered of the insoluble, dried under reduced pressure, purified by silica gel chromatography (eluent: petroleum ether/ethyl acetate 1:1) to give 3mg of a pale yellow solid in a yield of 0.04%.1H NMR(300MHz,DMSO-d6)δ12.63(s,1H),9.29(s,1H),8.71(s,1H),7.90(dd,1H,J＝2.7,6.6Hz),7.74(d,1H,J＝8.7Hz),7.66(d,1H,J＝2.1Hz),7.49-7.54(m,2H),7.23-7.30(m,3H),7.13(dd,1H,J＝2.1,8.7Hz),6.64-6.69(m,1H),1.91-2.04(m,1H),0.94-0.97(m,4H)；HRMS(ESI,positive)m/z calcd for C25H20FN3O4S[M+H]+:547.1058；found 547.1066.
Example 38
N- (6- (4-fluoro-3- (3- (3-methoxyphenyl) ureido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide
Figure BDA0001773292360000241
By referring to the synthetic route of example 36, willCompound N- (6- (3-amino-4-fluorophenoxy) benzo [ d]Thiazol-2-yl) cyclopropanecarboxamide (40mg, 0.12mmol) was dissolved in DMF (5mL), 3-methoxyphenyl isocyanate (25mg, 0.17mmol) was added, stirred at room temperature for 12h, diluted with ethyl acetate, washed with sodium bicarbonate solution and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered of the insoluble, dried under reduced pressure, purified by silica gel chromatography (eluent: petroleum ether/ethyl acetate 1:1) to give 32mg of a pale yellow solid in a yield of 54%.1H NMR(600MHz,DMSO-d6)δ12.81(s,1H),9.12(s,1H),8.86(s,1H),7.90-7.93(m,1H),7.72(d,1H,J＝8.4Hz),7.63(d,1H,J＝2.4Hz),7.23-7.27(m,1H),7.10-7.18(m,3H),6.89(d,1H,J＝9.6Hz),6.63-6.65(m,1H),6.57(dd,1H,J＝1.2,7.2Hz),3.71(s,3H),1.97-2.01(m,1H),0.93-0.96(m,4H)；
Example 39
N- (6- (4-fluoro-3- (3- (m-tolyl) ureido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide
Figure BDA0001773292360000242
Referring to the synthetic route of example 36, the compound N- (6- (3-amino-4-fluorophenoxy) benzo [ d]Thiazol-2-yl) cyclopropanecarboxamide (40mg, 0.12mmol) was dissolved in DMF (5mL), 3-methylphenyl isocyanate (23mg, 0.17mmol) was added, stirred at room temperature for 12h, diluted with ethyl acetate, washed with sodium bicarbonate solution and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered of the insoluble, dried under reduced pressure, purified by silica gel chromatography (eluent: petroleum ether/ethyl acetate 1:1) to give 32mg of a pale yellow solid in a yield of 56%.1H NMR(600MHz,DMSO-d6)δ12.62(s,1H),9.03(s,1H),8.65(s,1H),7.95-7.96(m,1H),7.72(d,1H,J＝8.4Hz),7.63(d,1H,J＝2.4Hz),7.11-7.27(m,5H),6.78(d,1H,J＝7.2Hz),6.62-6.65(m,1H),2.25(s,3H),1.98-2.01(m,1H),0.94-0.95(m,4H).
Example 40
3- (3- (5- ((2- (cyclopropanecarboxamido) benzo [ d ] thiazol-6-yl) oxy) -2-fluorophenyl) ureido) benzoic acid ethyl ester
Figure BDA0001773292360000243
Referring to the synthetic route of example 36, the compound N- (6- (3-amino-4-fluorophenoxy) benzo [ d]Thiazol-2-yl) cyclopropanecarboxamide (40mg, 0.12mmol) was dissolved in DMF (5mL), then 3- (ethoxycarbonyl) phenyl isocyanate (30mg, 0.17mmol) was added, stirred at room temperature for 12h, diluted with ethyl acetate, washed with sodium bicarbonate solution and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered of insoluble matter, dried under reduced pressure, purified by silica gel chromatography (eluent: petroleum ether/ethyl acetate ═ 1:1), yielding 35mg of a pale yellow solid in 55% yield.1H NMR(600MHz,DMSO-d6)δ12.61(s,1H),9.35(s,1H),8.66(s,1H),8.07-8,.08(m,1H),7.91-7.93(m,1H),7.73(d,1H,J＝9Hz),7.65(d,1H,J＝3.6Hz),7.56-7.61(m,2H),7.41(t,1H,J＝8.4Hz),7.24-7.28(m,1H),7.12-7.14(m,1H),6.65-6.68(m,1H),4.29(q,2H,J＝7.2Hz),1.98-2.01(m,1H),1.30(t,3H,J＝7.2Hz),0.94-0.95(m,4H).
EXAMPLE 41
N- (6- (3- (3- (3-acetylphenyl) ureido) -4-fluorophenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide
Figure BDA0001773292360000251
Referring to the synthetic route of example 36, the compound N- (6- (3-amino-4-fluorophenoxy) benzo [ d]Thiazol-2-yl) cyclopropanecarboxamide (40mg, 0.12mmol) was dissolved in DMF (5mL), 3-acetylphenyl isocyanate (27mg, 0.17mmol) was added, stirred at room temperature for 12h, diluted with ethyl acetate, washed with sodium bicarbonate solution and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered of insoluble matter, dried under reduced pressure, purified with silica gel chromatography (eluent: petroleum ether/ethyl acetate ═ 1:1), yielding 30mg of a pale yellow solid in 50% yield.1H NMR(600MHz,DMSO-d6)δ12.61(s,1H),9.32(s,1H),8.69(s,1H),7.98(t,1H,J＝2.4Hz),7.91-7.93(m,1H),7.73(d,1H,J＝9Hz),7.58-7.65(m,3H),7.42(t,1H,J＝7.8Hz),7.25-7.28(m,1H),7.12(dd,1H,J＝2.4,8.4Hz),6.65-6.67(m,1H),2.54(s,3H),1.97-2.01(m,1H),0.93-0.96(m,4H).
Example 42
N- (6- (3- (3- (3-bromophenyl) ureido) -4-fluorophenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide
Figure BDA0001773292360000252
Referring to the synthetic route of example 36, the compound N- (6- (3-amino-4-fluorophenoxy) benzo [ d]Thiazol-2-yl) cyclopropanecarboxamide (40mg, 0.12mmol) was dissolved in DMF (5mL), 3-bromophenyl isocyanate (30mg, 0.17mmol) was added, stirred at room temperature for 12h, diluted with ethyl acetate, washed with sodium bicarbonate solution and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered of insoluble matter, dried under reduced pressure, purified by silica gel chromatography (eluent: petroleum ether/ethyl acetate ═ 1:1), yielding 35mg of a pale yellow solid in 54% yield.1H NMR(600MHz,DMSO-d6)δ12.61(s,1H),9.26(s,1H),8.71(s,1H),7.89-7.91(m,1H),7.79(t,1H,J＝1.8Hz),7.73(d,1H,J＝8.4Hz),7.63(d,1H,J＝2.4Hz),7.21-7.27(m,3H),7.12-7.16(m,2H),6.65-6.68(m,1H),1.99-2.01(m,1H),0.94-0.96(m,4H).
Example 43
N- (6- (4-fluoro-3- (3- (3- (trifluoromethyl) phenyl) thioureido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide
Figure BDA0001773292360000253
Referring to the synthetic route of example 36, the compound N- (6- (3-amino-4-fluorophenoxy) benzo [ d]Thiazol-2-yl) cyclopropanecarboxamide (40mg, 0.12mmol) was dissolved in DMF (5mL), 3- (trifluoromethyl) phenyl isothiocyanate (34mg, 0.17mmol) was added, stirred at room temperature for 12h, diluted with ethyl acetate, washed with sodium bicarbonate solution and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered of the insoluble, dried under reduced pressure, purified by silica gel chromatography (eluent: petroleum ether/ethyl acetate 1:1) to obtainTo a pale yellow solid, 12mg, yield 18%.1H NMR(600MHz,DMSO-d6)δ12.61(s,1H),10.22(s,1H),9.78(s,1H),7.94-7.95(m,1H),7.72-7.75(m,2H),7.66(d,1H,J＝2.4Hz),7.56(t,1H,J＝7.8Hz),7.46-7.49(m,1H),7.37-7.38(m,1H),7.28-7.31(m,1H),7.14(dd,1H,J＝2.4,8.4Hz),6.92-6.95(m,1H),1.97-2.01(m,1H),0.93-0.96(m,4H).
Example 44
N- (6- (4-fluoro-3- (3- (3- (trifluoromethoxy) phenyl) ureido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide
The synthetic route is as follows:
Figure BDA0001773292360000261
step g-2 Synthesis of N- (6- (4-fluoro-3- (3- (trifluoromethoxy) phenyl) ureido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide.
3- (trifluoromethoxy) aniline (50mg, 0.28mmol) was dissolved in dry DCM (5mL), triethylamine (56mg, 0.52mmol) and triphosgene (27mg, 0.094mmol) were added to the reaction solution, and after stirring at room temperature for three hours, N- (6- (3-amino-4-fluorophenoxy) benzo [ d ] was added to the reaction solution]Thiazol-2-yl) cyclopropanecarboxamide (96mg, 0.28mmol) was reacted for 2h, the reaction was evaporated to dryness and the residue was purified directly on a chromatographic column (eluent: dichloromethane/methanol 100:3) to yield 32mg of a white solid in 20% yield.1H NMR(600MHz,DMSO-d6)δ12.61(s,1H),9.40(s,1H),8.73(s,1H),7.89-7.91(m,1H),7.72(d,1H,J＝8.4Hz),7.61-7.64(m,2H),7.39(t,1H,J＝8.4Hz),7.24-7.29(m,2H),7.12(dd,1H,J＝2.4,8.4Hz),6.94-6.96(m,1H),6.65-6.68(m,1H),1.97-2.01(m,1H),0.93-0.96(m,4H).
Example 45
N- (6- (4-fluoro-3- (3- (6- (trifluoromethyl) pyridin-2-yl) ureido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide
Figure BDA0001773292360000262
Referring to the synthetic route of example 44, 2-amino-6- (trifluoromethyl) pyridine (45mg, 0.28mmol) was dissolved in dry DCM (5mL), triethylamine (56mg, 0.52mmol) and triphosgene (27mg, 0.094mmol) were added to the reaction solution, and after stirring at room temperature for three hours, N- (6- (3-amino-4-fluorophenoxy) benzo [ d ] was added to the reaction solution]Thiazol-2-yl) cyclopropanecarboxamide (96mg, 0.28mmol) was reacted for 2h, the reaction was evaporated to dryness and the residue was purified directly on a chromatographic column (eluent: dichloromethane/methanol 100:3) to yield 30mg of a white solid in 20% yield.1H NMR(600MHz,DMSO-d6)δ12.61(s,1H),10.25(s,1H),10.09(s,1H),7.97-8.02(m,2H),7.80-7.81(m,1H),7.73(d,1H,J＝8.4Hz),7.65(d,1H,J＝2.4Hz),7.51(d,1H,J＝7.8Hz),7.28-7.31(m,1H),7.13(dd,1H,J＝3,8.4Hz),6.70-6.72(m,1H),1.97-2.01(m,1H),0.93-0.96(m,4H).
Example 46
N- (6- (4-fluoro-3- ((3- (trifluoromethyl) benzyl) amino) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide
The synthetic route is as follows:
Figure BDA0001773292360000271
step g-3: synthesis of N- (6- (4-fluoro-3- ((3- (trifluoromethyl) benzyl) amino) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide.
The compound N- (6- (3-amino-4-fluorophenoxy) benzo [ d]Thiazol-2-yl) cyclopropanecarboxamide (40mg, 0.12mmol) and 3- (trifluoromethyl) benzaldehyde (21mg, 0.12mmol) were dissolved in methanol (5mL) and 1 drop of acetic acid was added for catalysis, stirred at room temperature overnight, sodium cyanoborohydride (15mg, 0.24mmol) was added, stirred overnight, the solvent was evaporated to dryness, purified by silica gel chromatography (eluent: dichloromethane/methanol 100:3) to yield 19mg of a white solid in 32% yield.1HNMR(300MHz,DMSO-d6)δ12.59(s,1H),7.44-7.65(m,6H),6.91-7.04(m,2H),6.55(d,1H,J＝5.1Hz),6.25(dd,1H,J＝2.4,7.2Hz),6.08-6.10(m,1H),4.38(d,2H,J＝5.7Hz),1.98-2.02(m,1H),0.93-0.94(m,4H)；HRMS(ESI,positive)m/z calcd for C25H19F4N3O2S[M-H]-:500.1061；found 500.1046.
Example 47
N- (6- (3- ((benzo [ d ] [1,3] dioxol-5-ylmethyl) amino) -4-fluorophenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide
Figure BDA0001773292360000272
Referring to the synthetic route of example 46, the compound N- (6- (3-amino-4-fluorophenoxy) benzo [ d]Thiazol-2-yl) cyclopropanecarboxamide (40mg, 0.12mmol) and piperonal (18mg, 0.12mmol) were dissolved in methanol (5mL) and 1 drop of acetic acid was added for catalysis, stirred at room temperature overnight, sodium cyanoborohydride (15mg, 0.24mmol) was added, stirred overnight, the solvent was evaporated to dryness, purified by silica gel chromatography (eluent: dichloromethane/methanol 100:3) to yield 15mg of a white solid in 26% yield.1H NMR(300MHz,DMSO-d6)δ12.59(s,1H),7.64(d,1H,J＝8.7Hz),7.47(d,1H,J＝2.1Hz),6.95-7.01(m,2H),6.84-6.85(m,1H),6.69-6.78(m,2H),6.30-6.41(m,1H),6.23(dd,1H,J＝2.7,7.5Hz),6.05-6.10(m,1H),5.95-5.97(s,2H),4.17(d,2H,J＝5.4Hz),1.95-2.04(m,1H),0.93-0.96(m,4H)；MS(ESI):m/z[M+H]+:478.0.
Example 48
N- (6- (4-fluoro-3- ((3- (trifluoromethyl) phenyl) sulfonamido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide
The synthetic route is as follows:
Figure BDA0001773292360000281
step g-4: synthesis of N- (6- (4-fluoro-3- ((3- (trifluoromethyl) phenyl) sulfonamido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide.
N- (6- (3-amino-4-fluorophenoxy) benzo [ d]Thiazol-2-yl) cyclopropanecarboxamide (50mg, 0.14mmol) was dissolved in pyridine (10mL), and 3- (trifluoro-3) was slowly added under a nitrogen atmosphereMethyl) benzenesulfonyl chloride (68mg, 0.28mmol), stirred at room temperature overnight, the reaction solution was directly evaporated to dryness, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 2: 1-1: 1) to give 32mg of a white solid in 42% yield.1H NMR(600MHz,DMSO-d6)δ12.64(s,1H),10.48(s,1H),8.01(d,1H,J＝7.8Hz),7.94-7.98(m,2H),7.80(t,1H,J＝7.8Hz),7.71(d,1H,J＝8.4Hz),7.60(d,1H,J＝3Hz),7.20(t,1H,J＝9.6Hz),7.01(dd,1H,J＝2.4,9Hz),6.88-6.91(m,1H),6.74-6.75(m,1H),1.98-2.01(m,1H),0.95-0.96(m,4H)；MS(ESI):m/z[M+H]+:551.9.
Example 49
RPK1, RIPK3 kinase assays
Using KINOMEscanTMThe kinase activity of the synthetic compounds and partial intermediates of examples 1-48 of the invention, and the comparative compound TAK-632 on RIPK1 and RIPK3 was tested by the RIPK1 and RIPK3 kinase detection methods.
DNA-labeled RIPK1 and RIPK3 kinase-labeled T7 phage strain lysates were detected using qPCR. The kinase, ligand affinity beads and test compound were combined in binding buffer (20% SeaBlock, 0.17 × PBS, 0.05% Tween 20, 6mM DTT). The compounds were diluted 3-fold, set at 10 points, incubated with shaking for 1h at room temperature, and the beads were washed with wash buffer (1 × PBS, 0.05% Tween 20), then resuspended in elution buffer (1 × PBS, 0.05% Tween 20, 0.5 μ M non-biotinylated affinity ligand), and incubated with shaking for 30min at room temperature. K was calculated by qPCR measurement of kinase concentration in the eluatedThe values, calculated as follows (Hill Slope set to-1), are shown in Table 1:
Figure BDA0001773292360000282
example 50
Anti-apoptosis assay
Tumor cells were induced by addition of TNF-. alpha. (20ng/ml) after 30min pretreatment with z-VAD-fmk (20. mu.M) and Smac mimic (10nM)Necrosis of the head. The synthetic compounds of examples 1-48 of the invention, the comparative compound TAK-632, and the cells of the combination were incubated for 16 hours. Cell activity was tested using the CellTiter-Glo luminescent cell viability assay kit (Promega). Chemiluminescence values were recorded using a BioTek 312e microplate reader (BioTek Instruments, Winooski, VT) and IC calculated50The values, results are shown in Table 1.
TABLE 1 RIPK1, RIPK3 kinase Activity and anti-apoptotic Activity of Compounds
Figure BDA0001773292360000283
Figure BDA0001773292360000291
N.d. means no test
The experimental results show that the benzothiazole derivative has excellent anti-cell necrosis activity, is obviously superior to positive control TAK-632, has different degrees of RIPK activity improved compared with TAK-632, can be used as an RIPK1/RIPK3 double-target inhibitor or an RIPK1/RIPK3 selective inhibitor, is used for preparing anti-TNF-induced systemic immune syndrome (SIRS) and anti-acetaminophen (APAP) -induced hepatotoxicity drugs, and is used for preparing anti-Alzheimer disease, anti-ischemic cardiomyopathy, anti-ischemic stroke, anti-atherosclerosis, anti-acute pancreatitis, anti-children inflammatory bowel disease, anti-sepsis, anti-Salmonella infection, anti-Listeria infection, anti-vaccinia virus infection and other inflammation or infection related diseases.
Therefore, the compound and the salt thereof can be used for preparing the anti-programmed cell necrosis inhibitor.
The foregoing shows and describes the general principles, essential features, and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are given by way of illustration of the principles of the present invention, and that various changes and modifications may be made without departing from the spirit and scope of the invention as defined by the appended claims. The scope of the invention is defined by the appended claims and equivalents thereof.

Claims (7)

1. A benzothiazole derivative, characterized in that: the benzothiazole derivative is selected from one of the following structures:
n- (7-cyano-6- (4-fluoro-3- (2- (2-fluoro-3- (trifluoromethyl) phenyl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (6- (4-fluoro-3- (2- (3- (trifluoromethyl) phenyl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (6- (4-fluoro-3- (2- (2-fluoro-3- (trifluoromethyl) phenyl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (6- (3- (2- (3, 5-bis (trifluoromethyl) phenyl) acetamido) -4-fluorophenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (6- (4-fluoro-3- (2- (3-nitrophenyl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (6- (4-fluoro-3- (2- (3- (trifluoromethyl) phenyl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) cyclohexanecarboxamide;
n- (6- (4-fluoro-3- (2- (2- (trifluoromethyl) phenyl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (6- (4-fluoro-3- (2- (m-tolyl) acetylamino) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (6- (4-fluoro-3- (3- (3- (trifluoromethyl) phenyl) propionylamino) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (6- (4-fluoro-3- (2- (pyridin-2-yl) acetylamino) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (6- (4-fluoro-3- (2- (4-fluoro-3 (trifluoromethyl) phenyl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (6- (4-fluoro-3- (2- (3-methoxyphenyl) acetylamino) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (6- (4-fluoro-3- (2- (3- (trifluoromethoxy) phenyl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (6- (3- (2- (benzo [ d ] [1,3] dioxol-5-yl) acetylamino) -4-fluorophenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (6- (4-fluoro-3- (2- (6- (trifluoromethyl) pyridin-2-yl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (6- (4-fluoro-3- (2- (3- (trifluoromethyl) phenyl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) cyclobutanecarboxamide;
n- (6- (4-fluoro-3- (2- (1-methyl-1H-indol-3-yl) acetylamino) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (6- (4-fluoro-3- (2- (3- (trifluoromethyl) phenyl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopentanecarboxamide;
n- (6- (4-fluoro-3- (2- (3- (trifluoromethyl) phenyl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) isobutyramide;
n- (6- (3- (2- (3-cyanophenyl) acetylamino) -4-fluorophenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (6- (3- (2- (3, 4-dimethylphenyl) acetylamino) -4-fluorophenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (6- (4-fluoro-3- (2- (3- (trifluoromethyl) phenyl) acetamido) phenoxy) benzo [ d ] thiazol-2-yl) tetrahydro-2H-pyran-4-carboxamide;
n- (6- (4-fluoro-3- (3- (3- (trifluoromethyl) phenyl) ureido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (6- (4-fluoro-3- (3- (4- (trifluoromethoxy) phenyl) ureido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (6- (4-fluoro-3- (3- (3-methoxyphenyl) ureido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (6- (4-fluoro-3- (3- (m-tolyl) ureido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
ethyl 3- (3- (5- ((2- (cyclopropanecarboxamido) benzo [ d ] thiazol-6-yl) oxy) -2-fluorophenyl) ureido) benzoate;
n- (6- (3- (3- (3-acetylphenyl) ureido) -4-fluorophenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (6- (3- (3- (3-bromophenyl) ureido) -4-fluorophenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (6- (4-fluoro-3- (3- (3- (trifluoromethyl) phenyl) thioureido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide;
n- (6- (4-fluoro-3- (3- (3- (trifluoromethoxy) phenyl) ureido) phenoxy) benzo [ d ] thiazol-2-yl) cyclopropanecarboxamide.
2. Use of the benzothiazole derivatives of claim 1 in the preparation of RIPK1 or RIPK3 kinase inhibitors.
3. Use of the benzothiazole derivative according to claim 1 for preparing an inhibitor of programmed cell necrosis.
4. Use of the benzothiazole derivatives according to claim 1 in the preparation of drugs for the prevention and treatment of diseases associated with programmed cell necrosis, or for the preparation of drugs for inflammatory, infectious, ischemic or degenerative related diseases or tissue injuries caused by RIPK1 or RIPK3 kinase disorders, overactivation or overactive interactions.
5. Use according to claim 4, characterized in that: the inflammatory, infectious, ischemic or degenerative related diseases or tissue damage is mediated by RIPK1/RIPK3 kinase, or is initiated by programmed cell necrosis.
6. Use according to claim 4, characterized in that: the inflammatory, infectious, ischemic or degenerative related diseases are selected from: systemic inflammatory syndrome, acetaminophen-induced tissue damage, acute pancreatitis, inflammatory bowel disease, sepsis, salmonella infection, listeria infection, vaccinia virus infection, alzheimer's disease, ischemic cardiomyopathy, ischemic stroke, atherosclerosis.
7. A pharmaceutical composition characterized by: comprising the benzothiazole derivative of claim 1 and a pharmaceutically acceptable excipient.
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