CN109912584B - BRD4 protein inhibitor with anti-tumor activity and preparation method and application thereof - Google Patents

BRD4 protein inhibitor with anti-tumor activity and preparation method and application thereof Download PDF

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CN109912584B
CN109912584B CN201910222386.3A CN201910222386A CN109912584B CN 109912584 B CN109912584 B CN 109912584B CN 201910222386 A CN201910222386 A CN 201910222386A CN 109912584 B CN109912584 B CN 109912584B
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cyclopentyl
benzenesulfonamide
methoxy
triazol
nmr
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CN109912584A (en
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钱海
黄文龙
毕昕洲
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China Pharmaceutical University
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Abstract

The invention discloses a compound shown as a general formula (I) with anti-tumor activity or pharmaceutically acceptable ester or salt thereof, a preparation method thereof and application thereof as a BRD4 protein inhibitor. Compared with the prior art, the BRD4 small-molecule inhibitor provided by the invention has a novel structure, shows excellent biological activity in tumor proliferation resistance, can be used for cancer diseases including solid tumors such as breast cancer and prostate cancer, hematopoietic system tumors such as acute myelogenous leukemia and multiple myeloma, and has wide development prospect.

Description

BRD4 protein inhibitor with anti-tumor activity and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a BRD4 protein inhibitor with antitumor activity, and a preparation method and application thereof.
Background
Histone acetylation is an important component of epigenetic research and an important means of post-translational modification. Bromodomain (BRD) is a conserved protein domain capable of specifically recognizing acetylated lysine (KAc) in histone, and by combining with acetylated lysine, relevant proteins such as chromatin remodeling factors and transcription factors are enriched in specific gene transcription sites, so that the activity of RNA polymerase II is changed, and the transcription expression of genes is regulated.
Up to now, 61 BRD domains found in humans exist in 42 proteins, and are classified into 8 major families according to their parent protein functions, and the BET (bromodomain and extra terminal domain) protein family is class 2 of the BRD protein family, whose structure comprises two bromodomains and one Extra Terminal (ET) domain of polypeptides, the members including BRD2, BRD3, BRD4 and BRDT. The bromodomain (bromodomain) of this family of proteins is part of a polypeptide that recognizes acetylated lysine residues.
Currently, a number of small molecule inhibitors have been reported that selectively target the BET family of BRD4 proteins. Azepines JQ-1 is the earliest publicly reported inhibitor of the BET protein family, with IC for BRD450Is 39nmol/L, and has good curative effect in treating tumor, HIV and other diseases. However, since the drug metabolism of JQ-1 compounds is not ideal, it is not possible to control JQ-1The study of (1) was stopped at preclinical study and failed to enter clinical study stage. IC of small molecule inhibitors RVX-208 of the pyrimidinones class to BRD4 developed by Resverlogix pharmaceutical company50At 40nmol/L, RVX-208 has now entered clinical trials for high risk cardiovascular disease caused by low levels of high density lipoprotein cholesterol. Compared with JQ-1, the selectivity and the inhibitory activity of isoxazole compounds I-BET151 developed by Kurarin Schker (GSK) on BRD4 protein are not obviously improved, but I-BET151 has better druggability and higher biological activity in the research of acute myelogenous leukemia, pancreatic cancer, glioblastoma and inflammation. In addition, the BRD4 small molecule inhibitors that have been currently in clinical study include CPI-0610 for leukemia and multiple myeloma, I-BET762 developed by GlaxoSmithKline, OTX-015 developed by Merck and Mitsubishi Tanabe, among others.
While these data indicate that BRD4 inhibitors show efficacy in preclinical models of hematologic malignancies and solid tumors, the clinical safety profiles of all BRD4 inhibitors appear similar, with frequent gastrointestinal and bone marrow toxicity leading to dose discontinuation and dose reduction. There is currently an urgent need for improvement in the therapeutic window for BRD4 inhibitors.
Disclosure of Invention
The purpose of the invention is as follows: in order to solve the technical problems, the invention provides a novel BRD4 small-molecule inhibitor compound with anti-tumor bioactivity, a compound with bioactivity, which is obtained by taking a bromodomain protein as a target spot for bioactivity screening, a preparation method and application thereof.
The technical scheme is as follows: in order to achieve the purpose, the invention adopts the following technical scheme:
a compound of formula (I) or a pharmaceutically acceptable ester or salt thereof:
Figure BDA0002004036620000021
wherein:
ring A is a 5-or 6-membered heteroaryl ring, said heteroaryl ring being optionallyAn heteroaryl ring substituted with: c1-6Haloalkyl, halogen, NO2-OH, -CN or optionally substituted C1-6An alkyl group;
R1，R2，R3，R4each independently selected from hydrogen, halogen, trifluoromethoxy, alkoxy, C3-10Cycloalkyl radical, C1-10Alkyl, or R1，R2，R3，R4The following structure is formed:
Figure BDA0002004036620000022
wherein n is 1-5.
Preferably, the ring a is selected from thiazolones, isoxazoles or pyridones, which are heteroaryl rings optionally substituted with: c1-6Haloalkyl, halogen, NO2-OH, -CN or optionally substituted C1-6An alkyl group.
Preferably, the ring A is selected from 3-methylthiazol-2- (3H) -one, thiazol-2 (3H) -one, 3, 5-dimethylisoxazole or 1-methylpyridin-2 (1H) -one.
Preferably, said R1，R2，R3，R4Each independently selected from hydrogen, chlorine, fluorine, bromine, methoxy, hydroxyl, tertiary butyl, trifluoromethoxy, methyl, ethyl, isopropyl, tertiary butyl, nitro, or R1，R2，R3，R4The following structure is formed:
Figure BDA0002004036620000031
wherein n is 1 or 2.
More preferred compounds of the invention having general formula (I) or a pharmaceutically acceptable salt thereof, are selected from:
n-cyclopentyl-5- (3, 5-dimethylisoxazol-4-yl) -2- ((1-phenyl-1H-1, 2, 3-triazol-4-yl) methoxy) benzenesulfonamide (I-a);
2- ((1- (2-chlorophenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3, 5-dimethylisoxazol-4-yl) benzenesulfonamide (I-b);
2- ((1- (3-chlorophenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3, 5-dimethylisoxazol-4-yl) benzenesulfonamide (I-c);
2- ((1- (4-chlorophenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3, 5-dimethylisoxazol-4-yl) benzenesulfonamide (I-d);
2- ((1- (4-fluorophenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3, 5-dimethylisoxazol-4-yl) benzenesulfonamide (I-e);
2- ((1- (3, 4-difluorophenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3, 5-dimethylisoxazol-4-yl) benzenesulfonamide (I-f);
2- ((1- (2-methoxyphenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3, 5-dimethylisoxazol-4-yl) benzenesulfonamide (I-g);
2- ((1- (4-methoxyphenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3, 5-dimethylisoxazol-4-yl) benzenesulfonamide (I-H);
2- ((1- (3-methoxyphenyl) -1H-1,2, 3-triazol-4-yl) methoxy) N-cyclopentyl-5- (3, 5-dimethylisoxazol-4-yl) benzenesulfonamide (I-I);
2- ((1- (3, 4-dimethoxyphenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3, 5-dimethylisoxazol-4-yl) benzenesulfonamide (I-j);
2- ((1- (benzo [ d ] [1,3] dioxin-5-yl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3, 5-dimethylisoxazol-4-yl) benzenesulfonamide (I-k);
2- ((1- (3,4, 5-trimethoxyphenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3, 5-dimethylisoxazol-4-yl) benzenesulfonamide (I-l);
2- ((1- (m-tolyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3, 5-dimethylisoxazol-4-yl) benzenesulfonamide (I-m);
2- ((1- (2-ethylphenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3, 5-dimethylisoxazol-4-yl) benzenesulfonamide (I-N);
2- ((1- (3-isopropylphenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3, 5-dimethylisoxazol-4-yl) benzenesulfonamide (I-o);
2- ((1- (3- (tert-butyl) phenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3, 5-dimethylisoxazol-4-yl) benzenesulfonamide (I-p);
2- ((1- (4- (tert-butyl) phenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3, 5-dimethylisoxazol-4-yl) benzenesulfonamide (I-q);
2- ((1- (4-butylphenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3, 5-dimethylisoxazol-4-yl) benzenesulfonamide (I-r);
2- ((1- (5-chloro-2-methylphenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3, 5-dimethylisoxazol-4-yl) benzenesulfonamide (I-s);
2- ((1- (2-nitrophenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3, 5-dimethylisoxazol-4-yl) benzenesulfonamide (I-t);
2- ((1- (4-nitrophenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3, 5-dimethylisoxazol-4-yl) benzenesulfonamide (I-u);
2- ((1- (4-trifluoromethoxy) phenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3, 5-dimethylisoxazol-4-yl) benzenesulfonamide (I-v);
2- (1-phenyl-1H-1, 2, 3-triazol-4-ylmethoxy) -N-cyclopentyl-5- (2-oxo-2, 3-aminothiazolin-4-yl) benzene
A sulfonamide (II-a);
2- ((1- (2-chlorophenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (2-oxo-2, 3-dihydrothiazol-4-yl) benzenesulfonamide (II-b);
2- ((1- (3-chlorophenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (2-oxo-2, 3-dihydrothiazol-4-yl) benzenesulfonamide (II-c);
2- ((1- (4-chlorophenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (2-oxo-2, 3-dihydrothiazol-4-yl) benzenesulfonamide (II-d);
2- ((1- (4-fluorophenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (2-oxo-2, 3-dihydrothiazol-4-yl) benzenesulfonamide (II-e);
2- ((1- (2-methoxyphenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (2-oxo-2, 3-dihydrothiazol-4-yl) benzenesulfonamide (II-f);
2- ((1- (4-methoxyphenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (2-oxo-2, 3-dihydrothiazol-4-yl) benzenesulfonamide (II-g);
2- (1-phenyl-1H-1, 2, 3-triazol-4-ylmethoxy) -N-cyclopentyl-5- (3-methyl-2-oxo-2, 3-dihydrothiazol-4-yl) benzenesulfonamide (III-a);
2- ((1- (2-chlorophenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3-methyl-2-oxo-2, 3-dihydrothiazol-4-yl) benzenesulfonamide (III-b);
2- ((1- (3-chlorophenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3-methyl-2-oxo-2, 3-dihydrothiazol-4-yl) benzenesulfonamide (III-c);
2- ((1- (4-chlorophenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3-methyl-2-oxo-2, 3-dihydrothiazol-4-yl) benzenesulfonamide (III-d);
2- ((1- (4-fluorophenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3-methyl-2-oxo-2, 3-dihydrothiazol-4-yl) benzenesulfonamide (III-e);
2- ((1- (3, 4-difluorophenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3-methyl-2-oxo-2, 3-dihydrothiazol-4-yl) benzenesulfonamide (III-f);
2- ((1- (2-methoxyphenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3-methyl-2-oxo-2, 3-dihydrothiazol-4-yl) benzenesulfonamide (III-g);
2- ((1- (4-methoxyphenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3-methyl-2-oxo-2, 3-dihydrothiazol-4-yl) benzenesulfonamide (III-H);
2- ((1- (3-methoxyphenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3-methyl-2-oxo-2, 3-dihydrothiazol-4-yl) benzenesulfonamide (III-i);
2- ((1-phenyl-1H-1, 2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) benzenesulfonamide (IV-a);
2- ((1- (2-chlorophenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) benzenesulfonamide (IV-b);
2- ((1- (4-chlorophenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) benzenesulfonamide (IV-c);
2- ((1- (4-fluorophenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) benzenesulfonamide (IV-d);
2- ((1- (3-chlorophenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) benzenesulfonamide (IV-e);
2- ((1- (3-methoxyphenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) benzenesulfonamide (IV-f);
2- ((1- (4-methoxyphenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) benzenesulfonamide (IV-g);
2- ((1- (3, 4-dimethoxyphenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) benzenesulfonamide (IV-H);
2- ((1- (4-nitrophenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) benzenesulfonamide (IV-i);
2- ((1- (4-bromophenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) benzenesulfonamide (IV-j);
2- ((1- (2, 4-dichlorophenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) benzenesulfonamide (IV-k);
2- ((1- (2-nitrophenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) benzenesulfonamide (IV-l);
2- ((1- (4-hydroxyphenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) benzenesulfonamide (IV-m);
2- ((1- (4- (tert-butyl) phenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) benzenesulfonamide (IV-N);
2- ((1- (4-trifluoromethoxy) phenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) benzenesulfonamide (IV-o);
unless otherwise indicated, the following terms used in the specification and claims have the following meanings.
"alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 20 carbon atoms. Preferably an alkyl group having 1 to 10 carbon atoms, more preferably an alkyl group having 1 to 6 carbon atoms, even more preferably an alkyl group having 1 to 3 carbon atoms, and most preferably a methyl group. Non-limiting examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, and the like, as well as various branched chain isomers thereof, and the like. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more groups independently selected from halogen, hydroxy, cyano, nitro, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl.
"cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably the cycloalkyl ring comprises 3 to 10 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like.
"aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring.
The aryl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.
"heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms include oxygen, sulfur, and nitrogen. Preferably 5 to 10 membered. Heteroaryl is preferably 5-or 6-membered, for example furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring joined to the parent structure is a heteroaryl ring.
Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.
"alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.
"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.
The preparation method of the compound is shown as the following reaction formula:
Figure BDA0002004036620000081
wherein, ring A, R1，R2，R3And R4As described above.
General synthetic method
In general, the compounds of the present invention may be prepared by methods such as those illustrated in the following general schemes and the preparation examples that follow. All variables in the following schemes are defined as herein, unless otherwise indicated.
More preferably, the compounds of general formula (I) according to the invention can be synthesized by:
Figure BDA0002004036620000082
a pharmaceutical composition comprising the compound or a pharmaceutically acceptable ester or salt thereof, and a pharmaceutically acceptable adjuvant.
The compound or the pharmaceutically acceptable ester or salt thereof can be applied to the preparation of BRD4 protein inhibitor medicines.
The compound or the pharmaceutically acceptable ester or salt thereof can be applied to the preparation of antitumor drugs.
The novel BRD4 protein inhibitor can be used for treating various cancer diseases, such as Acute Myelocytic Leukemia (AML), Burkitt lymphoma, multiple myeloma, prostatic cancer, melanoma, diffuse large B cell lymphoma, autoimmune diseases such as psoriasis and Crohn's disease, and preventing the diseases.
"pharmaceutical composition" means a mixture containing one or more compounds of the present invention, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, in admixture with other chemical components, such as pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the absorption of the active ingredients by organisms and to facilitate the active ingredients to exert biological activity in organisms.
The technical effects are as follows: compared with the prior art, the BRD4 small-molecule inhibitor provided by the invention has a novel structure, shows excellent biological activity in tumor proliferation resistance, can be used for cancer diseases including solid tumors such as breast cancer and prostate cancer, hematopoietic system tumors such as acute myelogenous leukemia and multiple myeloma, and has wide development prospect.
Detailed Description
Example 1:
(1) preparation of 5- (3, 5-dimethylisoxazol-4-yl) -2-methoxybenzenesulphonyl chloride
Figure BDA0002004036620000091
Compound 4- (4-methoxyphenyl) -3, 5-dimethylisoxazole (4.0g,0.02mol) was dissolved in dichloromethane, stirred in ice bath for 10 minutes, a solution of chlorosulfonic acid (1.55mL,0.024mol) in dichloromethane was slowly added dropwise to the reaction solution, stirred at low temperature for 30 minutes, and then phosphorus pentachloride (4.16g, 0.02mol) was added in portions. The reaction was then transferred to room temperature and stirred for 6 hours. Pouring the reaction solution into an ice-water mixture, performing suction filtration (diatomite assisted filtration) to remove insoluble substances, extracting the filtrate with dichloromethane, combining organic layers, washing with saturated saline solution, drying, performing suction filtration, and performing reduced pressure distillation to remove the organic solvent to obtain a yellow oily substance.
(2) Preparation of N-cyclopentyl-5- (3, 5-dimethylisoxazol-4-yl) -2-methoxybenzenesulphonamide
Figure BDA0002004036620000092
To a solution of compound 5- (3, 5-dimethylisoxazol-4-yl) -2-methoxybenzenesulfonyl chloride (6g, 0.02mol) in ethyl acetate (50mL) under nitrogen atmosphere was added dropwise cyclopentylamine (6mL, 0.06mol), and the mixture was stirred at room temperature for 6 hours. The insoluble matter was removed by suction filtration, the cake was washed with ethyl acetate, and the filtrate was washed with 0.5M aqueous hydrochloric acid and saturated brine 1 to 2 times, respectively, dried over anhydrous sodium sulfate, suction filtered, concentrated, and subjected to silica gel column chromatography using an ethyl acetate-hexane mixture (v: v ═ 5:95) as an eluent, to obtain 5.06g (yield 70%) of a yellow solid.
(3) Preparation of N-cyclopentyl-5- (3, 5-dimethylisoxazol-4-yl) -2-hydroxybenzenesulfonamide
Figure BDA0002004036620000101
The compound N-cyclopentyl-5- (3, 5-dimethylisoxazol-4-yl) -2-methoxybenzenesulphonamide (3.5g, 0.01mol) was dissolved in 50ml of dichloromethane and stirred at 0 ℃ for 10 minutes, 1M solution of boron tribromide (5ml) in dichloromethane was slowly added dropwise, and after completion of the dropwise addition, the reaction was transferred to room temperature and stirred for 2 hours. The reaction solution was cooled and poured into an ice-water mixture, stirred for 30min, allowed to stand for layer separation, and the dichloromethane layer was taken, dried over anhydrous sodium sulfate, filtered with suction, concentrated, and subjected to silica gel column chromatography to obtain 2.3g (yield: 70%) of a pale yellow solid.
(4) Preparation of N-cyclopentyl-5- (3, 5-dimethylisoxazol-4-yl) -2- (prop-2-yn-1-yloxy) benzenesulfonamide
Figure BDA0002004036620000102
The compound N-cyclopentyl-5- (3, 5-dimethylisoxazol-4-yl) -2-hydroxybenzenesulfonamide (2g, 5.9mmol) was dissolved in 40ml of acetonitrile, anhydrous potassium carbonate (0.98g, 8.8mmol) was added, followed by 3-bromopropyne (0.68ml, 7.1mmol) under nitrogen protection, and the reaction was refluxed for 6 hours. Suction filtration was performed to remove the potassium carbonate solid, the cake was washed with ethyl acetate, the solvent was removed by rotary evaporation under reduced pressure, extraction was performed with ethyl acetate, washing was performed with saturated brine 2 to 3 times, drying was performed with anhydrous sodium sulfate, distillation was performed under reduced pressure, separation was performed with silica gel column chromatography, and 1.2g of a brown-yellow solid was obtained using an ethyl acetate-hexane mixture (v: v ═ 1: 5) as an eluent (yield 55%).
(5) Preparation of N-cyclopentyl-5- (3, 5-dimethylisoxazol-4-yl) -2- ((1-phenyl-1H-1, 2, 3-triazol-4-yl) methoxy) benzenesulfonamide
Figure BDA0002004036620000103
The compound N-cyclopentyl-5- (3, 5-dimethylisoxazol-4-yl) -2- (prop-2-yn-1-yloxy) benzenesulfonamide (200mg, 0.53mmol) was dissolved in methanol: to 20ml of a solvent (3:1) containing water was added phenyl azide (63mg, 0.55mmol), and the mixture was dissolved with stirring at room temperature. Then, an aqueous copper sulfate pentahydrate solution (30mg/ml, 1ml) was added to the system, and stirred at room temperature for 10 minutes, and an aqueous L-sodium ascorbate solution (60mg/ml, 1ml) was further added dropwise thereto, and stirring was continued at room temperature for 12 hours. The reaction mixture was concentrated, diluted with an appropriate amount of water, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered under suction, distilled under reduced pressure, separated by silica gel column chromatography, and eluted with a methanol-dichloromethane mixture (v: v ═ 20: 1) to give 200mg of a white solid (yield 76%).
1H NMR(300MHz,CDCl3)δ8.23(s,1H),7.86(s,1H),7.74(d,J＝5.3Hz,2H),7.65– 7.34(m,4H),7.30(d,J＝9.1Hz,1H),5.66(d,J＝5.9Hz,1H),5.46(s,2H),3.63(m,1H), 2.41(s,3H),2.27(s,3H),1.54(m,8H)；13C NMR(75MHz,CDCl3)δ165.03,157.89,153.74, 142.75,136.14,134.07,129.86,129.65,129.33,128.60,123.44,120.88,120.00,114.45, 113.83,62.56,55.28,32.36,22.58,11.16,10.32；LC-MS([M+Na]+):516.17.
Example 2: preparation of 2- ((1- (2-chlorophenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3, 5-dimethylisoxazol-4-yl) benzenesulfonamide (compound I-b)
Synthetic method reference example 1
1H NMR(300MHz,CDCl3)δ8.20(s,1H),7.86(d,J＝2.2Hz,1H),7.69–7.56(m,2H), 7.52–7.42(m,3H),7.30(d,J＝8.5Hz,1H),5.57(d,J＝7.4Hz,1H),5.49(s,2H),3.71– 3.55(m,1H),2.42(s,3H),2.28(s,3H),1.77–1.59(m,4H),1.46(m,4H)；13C NMR(75 MHz,CDCl3)δ165.08,153.68,141.91,134.04,130.65,130.37,129.93,127.61,127.27, 124.67,123.63,113.84,62.73,55.28,32.45,22.57,11.17,10.33.LC-MS([M+Na]+):550.13.
Example 3: preparation of 2- ((1- (3-chlorophenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3, 5-dimethylisoxazol-4-yl) benzenesulfonamide (compound I-c)
Synthetic method reference example 1
1H NMR(300MHz,CDCl3)δ8.23(s,1H),7.86(d,J＝2.2Hz,1H),7.81(t,J＝1.7Hz, 1H),7.63(dt,J＝7.5,1.8Hz,1H),7.53–7.40(m,3H),7.27(s,1H),5.55(d,J＝7.4Hz,1H), 5.46(s,2H),3.63(m,1H),2.42(s,3H),2.27(s,3H),1.75–1.59(m,4H),1.46(s,4H)；13C NMR(75MHz,CDCl3)δ165.07,153.66,136.95,135.18,134.07,130.44,129.91,129.72, 128.66,123.61,120.86,120.24,117.92,114.44,113.81,62.53,55.29,32.41,29.19,22.58, 11.17,10.33.LC-MS([M+Na]+):550.3.
Example 4: preparation of 2- ((1- (4-chlorophenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3, 5-dimethylisoxazol-4-yl) benzenesulfonamide (Compound I-d)
Synthetic method reference example 1
1H NMR(300MHz,CDCl3)δ8.22(s,1H),7.86(d,J＝2.1Hz,1H),7.70(d,J＝8.8Hz, 2H),7.51(d,J＝8.8Hz,2H),7.44(dd,J＝8.5,2.1Hz,1H),7.27(s,1H),5.60(d,J＝7.4Hz, 1H),5.45(s,2H),3.69–3.55(m,1H),2.42(s,3H),2.28(s,3H),1.77–1.63(m,4H),1.51–1.38(m,4H)；13C NMR(75MHz,CDCl3)δ165.06,157.87,153.66,143.00,134.60,134.41, 134.09,129.92,129.69,129.52,123.62,121.16,120.80,114.41,113.81,62.57,55.29,32.41, 22.58,11.17,10.33.LC-MS([M+Na]+) 550.3 melting point: 196 ℃ and 197 ℃.
Example 5: preparation of 2- ((1- (4-fluorophenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3, 5-dimethylisoxazol-4-yl) benzenesulfonamide (Compound I-e)
Synthetic method reference example 1
1H NMR(300MHz,CDCl3)δ8.19(s,1H),7.86(d,J＝2.2Hz,1H),7.76–7.68(m,2H), 7.44(dd,J＝8.5,2.2Hz,1H),7.30(s,1H),7.26–7.20(m,2H),5.58(d,J＝7.4Hz,1H), 5.45(s,2H),3.70–3.56(m,1H),2.42(s,3H),2.27(s,3H),1.78–1.63(m,4H),1.53–1.41 (m,4H)；13C NMR(75MHz,CDCl3)δ165.07,160.44,157.89,153.65,142.91,134.09, 129.94,129.70,123.63,122.15,122.04,121.04,116.52,116.21,113.80,62.62,55.29,32.43, 22.58,11.17,10.33.LC-MS([M+Na]+) 534.4 melting point: 144 ℃ and 145 ℃.
Example 6: preparation of 2- ((1- (3, 4-difluorophenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3, 5-dimethylisoxazol-4-yl) benzenesulfonamide (Compound I-f)
Synthetic method reference example 1
1H NMR(300MHz,CDCl3)δ8.22(s,1H),7.86(s,1H),7.73–7.62(m,1H),7.52– 7.31(m,3H),7.27(s,1H),5.56(d,J＝7.2Hz,1H),5.45(s,2H),3.69–3.54(m,1H),2.42(s, 3H),2.28(s,3H),1.83–1.62(m,4H),1.54–1.38(m,4H)；13C NMR(75MHz,CDCl3)δ 165.06,157.86,153.66,151.64,148.30,143.13,134.11,129.91,129.67,123.64,120.98, 118.10,117.85,115.94,114.40,113.81,110.23,109.94,62.50,55.30,32.38,22.57,11.15, 10.31.LC-MS([M+Na]+) 552.4. melting Point: 179 ℃ and 180 ℃.
Example 7: preparation of 2- ((1- (2-methoxyphenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3, 5-dimethylisoxazol-4-yl) benzenesulfonamide (Compound I-g)
Synthetic method reference example 1
1H NMR(300MHz,CDCl3)δ8.35(s,1H),7.86(d,J＝1.7Hz,1H),7.82(d,J＝7.5Hz, 1H),7.45(d,J＝7.0Hz,2H),7.29(d,J＝8.6Hz,1H),7.19–7.07(m,2H),5.58(d,J＝7.3 Hz,1H),5.46(s,2H),3.92(s,3H),3.65–3.54(m,1H),2.42(s,3H),2.28(s,4H),1.80–1.62 (m,4H),1.50–1.40(m,4H)；13C NMR(75MHz,CDCl3)δ153.83,150.48,134.03,129.92, 124.78,120.79,113.69,111.77,62.90,55.49,55.28,32.39,22.56,11.16,10.33.LC-MS([M+ Na]+) 546.18 melting point: 180 ℃ and 182 ℃.
Example 8: preparation of 2- ((1- (4-methoxyphenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3, 5-dimethylisoxazol-4-yl) benzenesulfonamide (Compound I-H)
Synthetic method reference example 1
1H NMR(300MHz,CDCl3)δ8.11(s,1H),7.85(d,J＝2.0Hz,1H),7.64(d,J＝8.9Hz, 2H),7.44(dd,J＝8.5,2.1Hz,1H),7.29(d,J＝8.7Hz,1H),7.03(d,J＝8.9Hz,2H),5.56(d, J＝7.3Hz,1H),5.45(s,2H),3.88(s,3H),3.67–3.54(m,1H),2.41(s,3H),2.27(s,3H), 1.74–1.60(m,4H),1.50–1.41(m,4H)；13C NMR(75MHz,CDCl3)δ153.70,142.52, 134.06,129.94,123.55,121.78,120.96,114.37,113.77,62.71,55.29,55.18,32.44,29.21, 22.58,11.17,10.33.LC-MS([M+Na]+) 546.4 melting point: 181 ℃ and 183 ℃.
Example 9: preparation of 2- ((1- (3-methoxyphenyl) -1H-1,2, 3-triazol-4-yl) methoxy) N-cyclopentyl-5- (3, 5-dimethylisoxazol-4-yl) benzenesulfonamide (compound I-I)
Synthetic method reference example 1
1H NMR(300MHz,CDCl3)δ8.22(s,1H),7.85(d,J＝2.0Hz,1H),7.47–7.37(m,2H), 7.30(d,J＝8.5Hz,2H),7.24(d,J＝7.9Hz,1H),6.98(dd,J＝8.2,1.7Hz,1H),5.92(d,J＝ 7.4Hz,1H),5.43(s,2H),3.88(s,3H),3.69–3.54(m,1H),2.41(s,3H),2.27(s,3H),1.76– 1.57(m,4H),1.54–1.40(m,4H)；13C NMR(75MHz,CDCl3)δ165.54,160.58,154.23, 143.15,137.62,134.56,130.62,130.36,130.14,123.94,121.47,114.89,114.30,112.36, 106.29,63.03,55.78,55.67,32.86,29.69,23.07,11.66,10.82.LC-MS([M+Na]+) 546.4 melting point: 180 ℃ and 182 ℃.
Example 10: preparation of 2- ((1- (3, 4-dimethoxyphenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3, 5-dimethylisoxazol-4-yl) benzenesulfonamide (compound I-j)
Synthetic method reference example 1
1H NMR(300MHz,CDCl3)δ8.16(s,1H),7.86(d,J＝2.1Hz,1H),7.43(dd,J＝8.4, 2.1Hz,1H),7.32(d,J＝2.3Hz,1H),7.30–7.26(m,1H),7.16(dd,J＝8.6,2.4Hz,1H),6.94 (d,J＝8.7Hz,1H),5.87(d,J＝7.4Hz,1H),5.42(s,2H),3.98(s,3H),3.95(s,3H),3.69– 3.54(m,1H),2.42(s,3H),2.28(s,3H),1.81–1.62(m,4H),1.53–1.41(m,4H)；13C NMR (75MHz,CDCl3)δ165.54,158.39,154.24,149.74,149.56,143.00,134.55,130.39,130.17, 123.99,121.55,114.28,112.49,111.10,104.81,63.11,56.27,56.20,55.80,32.88,29.69, 23.08,11.66,10.83.LC-MS([M+Na]+) 576.4 melting point: 198 ℃ and 199 ℃.
Example 11: preparation of 2- ((1- (benzo [ d ] [1,3] dioxo-5-yl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3, 5-dimethylisoxazol-4-yl) benzenesulfonamide (compound I-k)
Synthetic method reference example 1
1H NMR(300MHz,CDCl3)δ8.10(s,1H),7.85(d,J＝2.2Hz,1H),7.44(dd,J＝8.5, 2.2Hz,1H),7.30(s,1H),7.25(d,J＝2.1Hz,1H),7.15(dd,J＝8.3,2.2Hz,1H),6.92(d,J＝ 8.3Hz,1H),6.09(s,2H),5.58(d,J＝7.4Hz,1H),5.44(s,2H),3.71–3.53(m,1H),2.42(s, 3H),2.28(s,3H),1.83–1.65(m,4H),1.52–1.41(m,4H)；13C NMR(75MHz,CDCl3)δ 165.05,157.91,153.68,147.81,142.54,134.04,130.62,129.93,123.58,121.10,113.85, 113.79,108.08,102.23,101.72,62.66,55.28,32.43,22.58,11.16,10.32.LC-MS([M+Na]+) 560.4 melting point: 230 ℃ and 231 ℃.
Example 12: preparation of 2- ((1- (3,4, 5-trimethoxyphenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3, 5-dimethylisoxazol-4-yl) benzenesulfonamide (compound I-l)
Synthetic method reference example 1
1H NMR(300MHz,CDCl3)δ8.25(s,1H),7.87(d,J＝2.2Hz,1H),7.43(dd,J＝8.4, 2.2Hz,1H),7.25(d,J＝8.5Hz,1H),6.92(s,2H),6.28(d,J＝7.5Hz,1H),5.36(s,2H),3.94 (s,6H),3.89(s,3H),3.70–3.55(m,1H),2.43(s,3H),2.29(s,3H),1.81–1.60(m,4H),1.56 –1.40(m,4H)；13C NMR(75MHz,CDCl3)δ165.09,157.89,153.70,153.44,142.57,134.07, 131.97,129.96,123.67,121.22,113.77,97.96,62.65,60.58,55.98,55.32,32.43,22.58,11.18, 10.34.LC-MS([M+Na]+) 606.20 melting point: 236 ℃ and 237 ℃.
Example 13: preparation of 2- ((1- (m-tolyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3, 5-dimethylisoxazol-4-yl) benzenesulfonamide (compound I-m)
Synthetic method reference example 1
1H NMR(300MHz,CDCl3)δ8.24(s,1H),7.86(d,J＝1.3Hz,1H),7.54(s,1H),7.51– 7.35(m,3H),7.32(d,J＝8.6Hz,1H),7.26(d,J＝7.3Hz,1H),6.10(d,J＝7.4Hz,1H),5.45 (s,2H),3.71–3.55(m,1H),2.44(s,3H),2.41(s,3H),2.27(s,3H),1.68(m,4H),1.55–1.36 (m,4H)；13C NMR(75MHz,CDCl3)δ165.02,165.02,157.90,157.90,153.81,153.81, 142.62,139.58,136.06,134.08,129.80,129.62,129.31,129.08,123.33,120.89,120.59, 117.02,114.48,113.86,62.53,55.29,32.31,22.58,20.90,11.14,10.31.LC-MS([M+Na]+) 530.4 melting point: 156 ℃ and 157 ℃.
Example 14: preparation of 2- ((1- (2-ethylphenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3, 5-dimethylisoxazol-4-yl) benzenesulfonamide (Compound I-N)
Synthetic method reference example 1
1H NMR(300MHz,CDCl3)δ8.00(s,1H),7.85(d,J＝1.3Hz,1H),7.57–7.21(m,6H), 5.95(d,J＝7.3Hz,1H),5.52(s,2H),3.75–3.45(m,1H),2.49(dd,J＝15.0,7.5Hz,2H), 2.41(s,3H),2.27(s,3H),1.81–1.55(m,4H),1.55–1.36(m,4H),1.09(t,J＝7.5Hz,3H)；13C NMR(75MHz,CDCl3)δ154.25,139.79,135.68,134.42,130.70,130.41,129.94,126.85, 124.88,124.22,114.98,114.60,63.46,55.76,33.03,24.26,23.10,14.78,11.53,10.67. LC-MS([M+Na]+) 544.4. melting point: 63-65 ℃.
Example 15: preparation of 2- ((1- (3-isopropylphenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3, 5-dimethylisoxazol-4-yl) benzenesulfonamide (Compound I-o)
Synthetic method reference example 1
1H NMR(300MHz,CDCl3)δ8.25(s,1H),7.86(d,J＝2.2Hz,1H),7.61(s,1H),7.52– 7.39(m,3H),7.36–7.30(m,2H),5.97(d,J＝7.4Hz,1H),5.46(s,2H),3.70–3.55(m,1H), 3.01(d,J＝6.8Hz,1H),2.41(s,3H),2.27(s,3H),1.79–1.58(m,4H),1.54–1.41(m,4H), 1.32(s,3H),1.29(s,3H)；13C NMR(75MHz,CDCl3)δ165.49,158.36,154.27,151.24, 143.17,134.46,130.49,129.70,127.32,124.20,121.45,118.97,118.09,114.43,63.32,55.77, 34.14,33.02,23.74,23.11,11.53,10.67.LC-MS([M+Na]+) 558.4 melting point: 140 ℃ and 142 ℃.
Example 16: preparation of 2- ((1- (3- (tert-butyl) phenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3, 5-dimethylisoxazol-4-yl) benzenesulfonamide (Compound I-p)
Synthetic method reference example 1
1H NMR(300MHz,CDCl3)δ8.24(s,1H),7.86(d,J＝1.1Hz,1H),7.77(s,1H),7.53– 7.40(m,4H),7.33(d,J＝8.5Hz,1H),5.86(d,J＝7.2Hz,1H),5.46(s,2H),3.70–3.53(m, 1H),2.41(s,3H),2.27(s,3H),1.79–1.58(m,4H),1.53–1.42(m,4H),1.38(s,9H)；13C NMR(75MHz,CDCl3)δ165.05,157.92,153.75,153.07,142.58,136.07,134.07,129.91, 129.64,128.95,125.81,123.44,121.21,117.59,117.34,114.48,113.80,62.56,55.28,34.56, 32.38,30.71,22.57,11.16,10.32.LC-MS([M+Na]+) 572.4 melting point: 91-93 ℃.
Example 17: preparation of 2- ((1- (4- (tert-butyl) phenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3, 5-dimethylisoxazol-4-yl) benzenesulfonamide (Compound I-q)
Synthetic method reference example 1
1H NMR(300MHz,CDCl3)δ8.20(s,1H),7.85(d,J＝2.1Hz,1H),7.64(d,J＝8.7Hz, 2H),7.54(d,J＝8.7Hz,2H),7.44(dd,J＝8.5,2.1Hz,1H),7.31(d,J＝8.5Hz,1H),5.81(d, J＝7.4Hz,1H),5.46(s,2H),3.68–3.56(m,1H),2.41(s,3H),2.28(s,3H),1.78–1.57(m, 4H),1.51–1.41(m,4H),1.37(s,9H)；13C NMR(75MHz,CDCl3)δ165.35,164.00,154.26, 152.62,134.45,130.48,126.70,124.20,121.26,120.34,114.45,63.38,55.77,33.02,31.21, 23.11,11.53,10.67.LC-MS([M+Na]+) 572.4 melting point: 186 ℃ and 188 ℃.
Example 18: preparation of 2- ((1- (4-butylphenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3, 5-dimethylisoxazol-4-yl) benzenesulfonamide (compound I-r)
Synthetic method reference example 1
1H NMR(300MHz,CDCl3)δ8.21(s,1H),7.85(d,J＝2.0Hz,1H),7.61(d,J＝8.3Hz, 2H),7.43(dd,J＝8.4,2.0Hz,1H),7.32(d,J＝8.4Hz,3H),5.96(d,J＝7.4Hz,1H),5.45(s, 2H),3.69–3.55(m,1H),2.67(t,J＝7.7Hz,2H),2.41(s,3H),2.27(s,3H),1.78–1.57(m, 6H),1.52–1.34(m,6H),0.95(t,J＝7.3Hz,3H)；13C NMR(75MHz,CDCl3)δ165.03, 157.91,153.78,143.76,134.07,133.99,129.84,129.63,129.18,123.37,120.91,119.96, 113.85,62.57,55.28,34.66,32.92,32.34,29.18,22.57,21.74,13.41,11.14,10.31. LC-MS([M+Na]+) 572.4 melting point: 200 ℃ and 202 ℃.
Example 19: preparation of 2- ((1- (5-chloro-2-methylphenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3, 5-dimethylisoxazol-4-yl) benzenesulfonamide (Compound I-s)
Synthetic method reference example 1
1H NMR(300MHz,CDCl3)δ8.06(s,1H),7.85(d,J＝2.1Hz,1H),7.47(dd,J＝8.5, 2.2Hz,1H),7.44–7.31(m,4H),5.94(d,J＝7.2Hz,1H),5.51(s,2H),3.67–3.55(m,1H), 2.42(s,3H),2.28(s,3H),2.19(s,3H),1.78–1.58(m,4H),1.53–1.40(m,4H)；13C NMR (75MHz,CDCl3)δ165.02,157.88,153.73,142.24,136.22,134.10,132.19,131.75,131.36, 129.83,129.62,125.44,124.12,123.44,114.45,113.95,62.55,59.89,55.24,32.34,29.16, 22.54,20.56,17.06,13.69,11.14,10.30.LC-MS([M+Na]+) 564.13 melting point: 142 ℃ and 144 ℃.
Example 20: preparation of 2- ((1- (2-nitrophenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3, 5-dimethylisoxazol-4-yl) benzenesulfonamide (compound I-t)
Synthetic method reference example 1
1H NMR(300MHz,CDCl3)δ8.16(s,1H),8.12(d,J＝8.0Hz,1H),7.90–7.82(m,2H), 7.80–7.72(m,1H),7.67(d,J＝7.7Hz,1H),7.47(dd,J＝8.4,2.0Hz,1H),7.30(d,1H), 5.63(d,J＝7.4Hz,1H),5.50(s,2H),3.68–3.51(m,1H),2.42(s,3H),2.28(s,3H),1.79– 1.57(m,4H),1.53–1.36(m,4H)；13C NMR(75MHz,CDCl3)δ165.09,157.93,153.62, 142.77,134.17,133.63,130.74,129.93,129.68,129.45,127.63,125.22,124.62,123.61, 114.47,113.99,62.62,55.25,32.40,22.55,11.14,10.30.LC-MS([M+Na]+) 561.4 melting point: 177 ℃ and 178 ℃.
Example 21: preparation of 2- ((1- (4-nitrophenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3, 5-dimethylisoxazol-4-yl) benzenesulfonamide (compound I-u)
Synthetic method reference example 1
1H NMR(300MHz,CDCl3)δ8.50(s,1H),8.41(d,J＝9.0Hz,2H),8.00(d,J＝9.1Hz, 2H),7.87(d,J＝2.1Hz,1H),7.47(dd,J＝8.5,2.2Hz,1H),7.31(d,J＝8.4Hz,1H),6.02(d, J＝7.5Hz,1H),5.46(s,2H),3.73–3.58(m,1H),2.43(s,3H),2.28(s,3H),1.81–1.57(m, 4H),1.54–1.39(m,4H)；13C NMR(75MHz,CDCl3)δ165.10,157.84,153.50,146.94, 143.77,134.16,130.02,125.11,123.92,120.92,120.12,113.85,62.59,55.30,32.50,22.58, 11.18,10.34.LC-MS([M+Na]+) 561.4 melting point: 201 ℃ and 202 ℃.
Example 22: preparation of 2- ((1- (4-trifluoromethoxy) phenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3, 5-dimethylisoxazol-4-yl) benzenesulfonamide (Compounds I-v)
Synthetic method reference example 1
1H NMR(300MHz,CDCl3)δ8.31(s,1H),7.86(d,J＝2.0Hz,1H),7.78(d,J＝8.9Hz, 2H),7.49–7.29(m,4H),6.14(d,J＝7.5Hz,1H),5.44(s,2H),3.70–3.54(m,1H),2.42(s, 3H),2.28(s,3H),1.79–1.58(m,4H),1.54–1.40(m,4H)；13C NMR(75MHz,CDCl3)δ 165.02,157.85,153.74,148.59,143.05,134.42,134.11,129.84,129.60,123.48,121.75, 121.50,121.33,120.92,118.08,114.41,113.84,62.45,55.29,32.31,22.55,11.11,10.28. LC-MS([M+Na]+) 600.4 melting point: 203-.
Example 23: preparation of 2- (1-phenyl-1H-1, 2, 3-triazol-4-ylmethoxy) -N-cyclopentyl-5- (2-oxo-2, 3-aminothiazolin-4-yl) benzenesulfonamide (Compound II-a)
Synthetic method reference example 1
1H NMR(300MHz,DMSO-d6)δ9.01(s,1H),7.94(d,J＝7.4Hz,2H),7.75(d,J＝5.6 Hz,1H),7.65–7.56(m,2H),7.54(d,J＝6.4Hz,1H),7.46(d,J＝7.7Hz,2H),7.24(d,J＝ 7.9Hz,2H),5.34(s,2H),3.42–3.33(m,1H),1.75–1.47(m,4H),1.47–1.26(m,4H).13C NMR(75MHz,DMSO-d6)δ168.44,158.82,141.70,141.16,134.25,131.64,131.53,130.45, 128.34,125.15,117.64,114.95,113.96,54.23,29.74,22.76.LC-MS([M+H]+):498.13.
Example 24: preparation of 2- ((1- (2-chlorophenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (2-oxo-2, 3-dihydrothiazol-4-yl) benzenesulfonamide (compound II-b)
The synthesis method refers to example 1.
1H NMR(300MHz,DMSO-d6)δ8.77(s,1H),7.82(d,J＝7.6Hz,1H),7.74(d,J＝7.0 Hz,2H),7.68–7.54(m,2H),7.46(d,J＝8.5Hz,2H),7.24(d,J＝8.5Hz,2H),5.35(s,2H), 3.34–3.26(m,1H),1.76–1.46(m,4H),1.47–1.28(m,4H).13C NMR(75MHz,DMSO-d6) δ168.40,158.80,141.70,141.18,134.25,131.66,131.51,130.45,128.34,125.13,117.61, 114.94,113.96,54.23,32.39,29.77,22.79.LC-MS([M+H]+):532.5.
Example 25: preparation of 2- ((1- (3-chlorophenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (2-oxo-2, 3-dihydrothiazol-4-yl) benzenesulfonamide (compound II-c)
The synthesis method refers to example 1.
1H NMR(300MHz,DMSO-d6)δ9.08(s,1H),8.05(s,1H),7.96(d,J＝7.8Hz,1H), 7.74(d,J＝6.8Hz,1H),7.68–7.54(m,2H),7.43(d,J＝8.6Hz,2H),7.24(d,J＝8.6Hz, 2H),5.32(s,2H),3.33–3.25(m,1H),1.72–1.46(m,4H),1.45–1.28(m,4H).13C NMR (75MHz,DMSO)δ168.38,158.83,142.37,142.37,141.24,131.55,129.83,121.73,121.23, 117.73,114.95,114.80,55.54,54.26,32.42,22.81.LC-MS([M+H]+) 532.5 melting point: 185 ℃ and 187 ℃.
Example 26: preparation of 2- ((1- (4-chlorophenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (2-oxo-2, 3-dihydrothiazol-4-yl) benzenesulfonamide (compound II-d)
The synthesis method refers to example 1.
1H NMR(300MHz,DMSO-d6)δ9.06(s,1H),7.94(d,J＝8.7Hz,2H),7.78–7.64(m, 3H),7.43(d,J＝7.9Hz,2H),7.23(d,J＝7.9Hz,2H),5.32(s,2H),3.35–3.25(m,1H),1.72 –1.46(m,4H),1.42–1.28(m,4H).13C NMR(75MHz,DMSO-d6)δ168.40,158.79,141.69, 141.17,134.25,131.65,131.51,130.45,128.36,125.14,117.61,114.95,113.95,54.23,32.39, 22.79.LC-MS([M+H]+) 532.5 melting point: 177 and 179 ℃.
Example 27: preparation of 2- ((1- (4-fluorophenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (2-oxo-2, 3-dihydrothiazol-4-yl) benzenesulfonamide (compound II-e)
The synthesis method refers to example 1.
1H NMR(300MHz,DMSO-d6)δ9.06(s,1H),7.97(d,J＝8.8Hz,2H),7.78–7.69(m, 3H),7.46(d,J＝8.6Hz,2H),7.24(d,J＝8.6Hz,2H),5.35(s,2H),3.36–3.28(m,1H),1.74 –1.48(m,4H),1.45–1.26(m,4H).13C NMR(75MHz,DMSO)δ171.99,168.40,158.81, 142.83,141.20,135.15,132.98,131.52,129.78,121.73,121.37,117.67,114.96,113.96, 54.24,32.40,22.79,21.00.LC-MS([M+H]+) 516.5 melting point: 165-167 ℃.
Example 28: preparation of 2- ((1- (2-methoxyphenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (2-oxo-2, 3-dihydrothiazol-4-yl) benzenesulfonamide (compound II-f)
The synthesis method refers to example 1.
1H NMR(300MHz,DMSO-d6)δ8.67(s,1H),7.75(d,J＝6.7Hz,1H),7.63(d,J＝7.6 Hz,1H),7.62–7.53(m,1H),7.45(d,J＝8.3Hz,2H),7.34(d,J＝8.4Hz,1H),7.24(d,J＝ 8.4Hz,2H),7.16(d,J＝7.5Hz,1H),5.28(s,2H),3.35–3.26(m,1H),2.94(s,3H),1.75– 1.49(m,4H),1.44–1.27(m,4H).13C NMR(75MHz,DMSO)δ168.36,158.81,151.46, 141.28,131.57,130.72,125.61,125.39,124.92,120.80,117.65,114.92,113.87,112.92, 56.05,54.23,32.39,22.79.LC-MS([M+H]+) 528.5 melting point: 176 ℃ and 178 ℃.
Example 29: preparation of 2- ((1- (4-methoxyphenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (2-oxo-2, 3-dihydrothiazol-4-yl) benzenesulfonamide (compound II-g)
The synthesis method refers to example 1.
1H NMR(300MHz,DMSO-d6)δ8.94(s,1H),7.87(d,J＝9.0Hz,2H),7.74(d,J＝6.9 Hz,1H),7.46(d,J＝8.6Hz,2H),7.18(dd,J＝15.0,8.8Hz,4H),5.28(s,2H),3.86(s,3H), 3.36–3.27(m,1H),1.74–1.56(m,4H),1.44–1.27(m,4H).13C NMR(75MHz,DMSO-d6) δ168.37,159.22,158.82,142.38,141.26,131.56,129.79,121.68,121.22,117.70,114.94, 114.76,113.86,55.50,54.23,32.40,22.79.LC-MS([M+H]+) 528.5 melting point: 188 ℃ and 190 ℃.
Example 30: preparation of 2- (1-phenyl-1H-1, 2, 3-triazol-4-ylmethoxy) -N-cyclopentyl-5- (3-methyl-2-oxo-2, 3-dihydrothiazol-4-yl) benzenesulfonamide (III-a)
The synthesis method refers to example 1.
1H NMR(300MHz,DMSO-d6)δ9.01(s,1H),7.93(d,J＝7.4Hz,2H),7.73(d,J＝5.6 Hz,1H),7.68–7.58(m,2H),7.53(d,J＝6.4Hz,1H),7.44(d,J＝7.7Hz,2H),7.21(d,J＝ 7.9Hz,2H),5.32(s,2H),3.40–3.31(m,1H),2.95(s,3H),1.74–1.46(m,4H),1.45–1.28 (m,4H).13C NMR(75MHz,DMSO-d6)δ168.42,159.11,143.51,141.26,136.50,131.51, 129.89,128.78,123.04,120.28,120.14,114.42,61.05,54.18,32.39,31.44,22.77.LC-MS ([M+H]+) 512.5. melting point: 176 ℃ and 178 ℃.
Implementation 31: preparation of 2- ((1- (2-chlorophenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3-methyl-2-oxo-2, 3-dihydrothiazol-4-yl) benzenesulfonamide (compound III-b)
The synthesis method refers to example 1.
1H NMR(300MHz,DMSO-d6)δ8.77(s,1H),7.80(d,J＝7.6Hz,1H),7.73(d,J＝7.0 Hz,2H),7.69–7.56(m,2H),7.43(d,J＝8.5Hz,2H),7.22(d,J＝8.5Hz,2H),5.32(s,2H), 3.34–3.26(m,1H),2.94(s,3H),1.75–1.48(m,4H),1.46–1.26(m,4H).13C NMR(75 MHz,DMSO-d6)δ168.43,159.13,142.44,141.30,134.37,131.74,131.50,130.53,128.48, 128.43,127.04,120.28,114.43,113.07,113.07,60.88,54.18,32.40,31.43,22.80.LC-MS ([M+H]546.5 melting point: 176 ℃ and 178 ℃.
Example 32: preparation of 2- ((1- (3-chlorophenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3-methyl-2-oxo-2, 3-dihydrothiazol-4-yl) benzenesulfonamide (compound III-c)
The synthesis method refers to example 1.
1H NMR(300MHz,DMSO-d6)δ9.08(s,1H),8.08(s,1H),7.95(d,J＝7.8Hz,1H), 7.72(d,J＝6.8Hz,1H),7.69–7.56(m,2H),7.43(d,J＝8.6Hz,2H),7.20(d,J＝8.6Hz, 2H),5.32(s,2H),3.33–3.25(m,1H),2.94(s,3H),1.71–1.47(m,4H),1.41–1.28(m,4H). 13C NMR(75MHz,DMSO-d6)δ168.44,159.08,143.71,141.25,137.54,134.18,131.64, 131.53,128.60,123.22,120.33,119.95,118.75,114.45,61.03,54.18,32.39,31.44,22.77. LC-MS([M+H]+) 546.5 melting point: 154 ℃ and 156 ℃.
Example 33: preparation of 2- ((1- (4-chlorophenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3-methyl-2-oxo-2, 3-dihydrothiazol-4-yl) benzenesulfonamide (compound III-d)
The synthesis method refers to example 1.
1H NMR(300MHz,DMSO-d6)δ9.04(s,1H),7.98(d,J＝8.7Hz,2H),7.79–7.62(m, 3H),7.43(d,J＝7.9Hz,2H),7.20(d,J＝7.9Hz,2H),5.31(s,2H),3.34–3.24(m,1H),2.94 (s,3H),1.71–1.47(m,4H),1.40–1.26(m,4H).13C NMR(75MHz,DMSO-d6)δ172.72, 168.44,159.10,143.70,131.53,129.88,123.14,121.85,120.33,114.43,61.01,54.18,32.40, 31.43,22.77.LC-MS(ESI):([M+H]+) 546.4 melting point: 178 ℃ and 180 ℃.
Example 34: preparation of 2- ((1- (4-fluorophenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3-methyl-2-oxo-2, 3-dihydrothiazol-4-yl) benzenesulfonamide (compound III-e)
The synthesis method refers to example 1.
1H NMR(300MHz,DMSO-d6)δ9.05(s,1H),7.99(d,J＝8.8Hz,2H),7.77–7.68(m, 3H),7.45(d,J＝8.6Hz,2H),7.22(d,J＝8.6Hz,2H),5.33(s,2H),3.35–3.27(m,1H),2.96 (s,3H),1.73–1.49(m,4H),1.44–1.28(m,4H).13C NMR(75MHz,DMSO-d6)δ168.44, 159.10,143.70,141.26,135.31,133.05,131.53,129.87,123.14,121.84,120.33,114.43, 61.01,54.18,32.39,31.44,22.77.LC-MS(ESI):([M+H]+) 530.5. melting point: 158 ℃ and 160 ℃.
Example 35: preparation of 2- ((1- (3, 4-difluorophenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3-methyl-2-oxo-2, 3-dihydrothiazol-4-yl) benzenesulfonamide (compound III-f)
The synthesis method refers to example 1.
1H NMR(300MHz,DMSO-d6)δ9.02(s,1H),8.20–8.08(m,1H),7.89–7.80(m,1H), 7.80–7.67(m,2H),7.43(d,J＝8.5Hz,2H),7.20(d,J＝8.5Hz,2H),5.32(s,2H),3.34– 3.24(m,1H),2.94(s,3H),1.73–1.48(m,4H),1.43–1.24(m,4H).13C NMR(75MHz, DMSO-d6)δ168.44,159.08,143.75,141.26,131.53,123.39,120.35,118.92,118.68,117.08, 114.43,113.12,110.55,110.26,61.01,54.18,32.39,31.44,22.78.LC-MS(ESI):Calcd for C24H24F2N5O4S2([M+H]+) 548.5, melting point: 160 ℃ and 162 ℃.
Example 36: preparation of 2- ((1- (2-methoxyphenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3-methyl-2-oxo-2, 3-dihydrothiazol-4-yl) benzenesulfonamide (compound III-g)
The synthesis method refers to example 1.
1H NMR(300MHz,DMSO-d6)δ8.64(s,1H),7.73(d,J＝6.7Hz,1H),7.65(d,J＝7.6 Hz,1H),7.60–7.51(m,1H),7.43(d,J＝8.3Hz,2H),7.34(d,J＝8.4Hz,1H),7.21(d,J＝ 8.4Hz,2H),7.15(d,J＝7.5Hz,1H),5.29(s,2H),3.86(s,3H),3.33–3.24(m,1H),2.94(s, 3H),1.75–1.49(m,4H),1.44–1.27(m,4H).13C NMR(75MHz,DMSO-d6)δ168.45, 159.20,151.62,142.12,141.33,131.50,130.83,126.84,125.82,125.54,120.86,120.22, 114.40,112.97,60.92,56.09,54.19,32.40,31.44,22.79.LC-MS(ESI):Calcd for C25H28N5O5S2([M+H]+) 542.5 melting point: 176 ℃ and 178 ℃.
Example 37: preparation of 2- ((1- (4-methoxyphenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3-methyl-2-oxo-2, 3-dihydrothiazol-4-yl) benzenesulfonamide (compound III-H)
The synthesis method refers to example 1.
1H NMR(300MHz,DMSO-d6)δ8.89(s,1H),7.82(d,J＝9.0Hz,2H),7.73(d,J＝6.9 Hz,1H),7.43(d,J＝8.6Hz,2H),7.18(dd,J＝15.0,8.8Hz,4H),5.29(s,2H),3.84(s,3H), 3.32–3.24(m,1H),2.94(s,3H),1.71–1.49(m,4H),1.41–1.25(m,4H).13C NMR(75 MHz,DMSO-d6)δ168.44,159.31,159.15,143.27,141.28,131.52,129.92,123.02,121.82, 120.26,114.86,114.42,61.08,55.54,54.18,32.40,31.44,22.78.LC-MS(ESI):Calcd for C25H28N5O5S2([M+H]+) 542.5 melting point: 177 and 179 ℃.
Example 38: preparation of 2- ((1- (3-methoxyphenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (3-methyl-2-oxo-2, 3-dihydrothiazol-4-yl) benzenesulfonamide (compound III-i)
The synthesis method refers to example 1.
1H NMR(300MHz,DMSO-d6)δ9.02(s,1H),7.72(d,J＝6.8Hz,1H),7.56–7.48(m, 3H),7.43(d,J＝8.6Hz,2H),7.21(d,J＝8.7Hz,2H),7.12–7.04(m,1H),5.31(s,2H),3.86 (s,3H),3.34–3.25(m,1H),2.94(s,3H),1.70–1.48(m,4H),1.42–1.26(m,4H).LC-MS (ESI):([M+H]+) 542.5 melting point: 174 ℃ and 176 ℃.
Example 39: preparation of 2- ((1-phenyl-1H-1, 2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) benzenesulfonamide (compound IV-a)
The synthesis method refers to example 1.
1H NMR(300MHz,DMSO-d6)δ8.93(s,1H),8.15(s,1H),7.87(m,3H),7.83(d,J＝ 7.7Hz,2H),7.70–7.49(m,3H),7.16(d,J＝7.6Hz,1H),6.49(d,J＝9.5Hz,1H),5.53(d,J ＝5.9Hz,1H),5.50(s,2H),3.53(s,3H),3.39(m,1H),1.39(m,8H).13C NMR(75MHz, DMSO-d6)δ161.04,153.77,143.42,138.63,137.24,136.44,130.85,129.96,129.82,128.89, 125.86,122.86,120.17,119.25,116.25,114.99,62.04,54.70,36.92,32.12,22.57.LC-MS (ESI):([M+H]+):506.3.
Example 40: preparation of 2- ((1- (2-chlorophenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) benzenesulfonamide (compound IV-b)
The synthesis method refers to example 1.
1H NMR(300MHz,DMSO-d6)δ8.72(s,1H),8.16(s,1H),7.91(m,1H),7.81(d,J＝ 8.4Hz,2H),7.64(m,4H),7.15(d,J＝7.1Hz,1H),6.49(d,J＝9.4Hz,1H),5.53(s,2H), 3.52(s,3H),3.37(m,1H),1.36(m,8H).13C NMR(75MHz,DMSO-d6)δ161.05,153.79, 142.59,138.63,137.25,131.78,130.85,130.61,129.80,128.90,128.54,128.30,126.63, 125.84,119.26,116.24,115.01,62.08,54.71,36.92,32.19,22.62.LC-MS(ESI):([M+H]+) 540.3. melting point: 163 ℃ and 165 ℃.
Example 41: preparation of 2- ((1- (4-chlorophenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) benzenesulfonamide (compound IV-c)
The synthesis method refers to example 1.
1H NMR(300MHz,DMSO-d6)δ8.96(s,1H),8.15(s,1H),8.04–7.66(m,6H),7.59(d, J＝6.3Hz,1H),7.14(d,J＝6.7Hz,1H),6.49(d,J＝9.4Hz,1H),5.50(s,2H),3.54(s,3H), 3.40(m,1H),1.40(m,8H).13C NMR(75MHz,DMSO-d6)δ161.05,153.76,143.57,138.63, 137.25,135.25,130.86,129.94,128.92,125.87,122.95,121.87,119.25,116.24,114.99, 62.02,54.69,36.93,32.12,22.58.LC-MS(ESI):([M+H]+) 540.2. melting point: 168 ℃ and 170 ℃.
Example 42: preparation of 2- ((1- (4-fluorophenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) benzenesulfonamide (Compound IV-d)
The synthesis method refers to example 1.
1H NMR (300MHz, DMSO-d6) δ 8.91(s,1H),8.15(s,1H), 8.04-7.72 (M,5H), 7.66-7.44 (M,3H),7.15(d, J ═ 7.7Hz,1H),6.49(d, J ═ 9.2Hz,1H),5.50(s,2H),3.53(s,3H), 3.38(d, J ═ 2.5Hz,1H),1.40(M,8H), 13C NMR (75MHz, DMSO-d6) δ 153.77,143.43, 138.63,137.25,130.85,129.81,128.91,125.86,123.11,122.65,122.53,119.25,116.97, 116.66,116.24,115.00,62.05,54.69,36.92,32.12,22.58.LC-ms esi) (M + H +) 524.3. melting point: 154 ℃ and 156 ℃.
Example 43: preparation of 2- ((1- (3-chlorophenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) benzenesulfonamide (compound IV-e)
The synthesis method refers to example 1.
1H NMR(300MHz,DMSO-d6)δ9.02(s,1H),8.10(d,J＝29.4Hz,2H),7.86(m,4H), 7.64(m,3H),7.15(m,1H),6.49(d,J＝8.8Hz,1H),5.50(s,2H),3.52(s,3H),3.40(m,1H), 1.63–1.23(m,8H).13C NMR(75MHz,DMSO-d6)δ161.04,153.76,143.55,138.62,137.47, 137.24,134.21,131.69,130.85,129.80,128.93,128.71,125.88,123.08,119.99,119.25, 118.80,116.24,115.00,62.02,54.69,36.92,32.13,22.58.LC-MS(ESI):([M+H]+) 540.2. melting point: 162 ℃ and 164 ℃.
Example 44: preparation of 2- ((1- (3-methoxyphenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) benzenesulfonamide (compound IV-f)
The synthesis method refers to example 1.
1H NMR(300MHz,DMSO-d6)δ8.64(s,1H),8.15(s,1H),7.86(m,3H),7.62(m,3H), 7.35(s,1H),7.17(s,2H),6.50(m,1H),5.52(s,2H),3.86(s,3H),3.52(s,3H),3.39(m,1H), 1.41(m,8H).13C NMR(75MHz,DMSO-d6)δ161.07,153.80,151.42,142.28,138.63, 137.23,130.82,129.83,128.85,126.39,125.80,125.48,120.93,119.25,116.28,114.97, 113.06,62.11,56.08,54.74,36.93,32.13,22.58.LC-MS(ESI):([M+H]+) 536.3. melting point: 174 ℃ and 176 ℃.
Example 45: preparation of 2- ((1- (4-methoxyphenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) benzenesulfonamide (compound IV-g)
The synthesis method refers to example 1.
1H NMR (300MHz, DMSO-d6) δ 8.82(s,1H),8.15(s,1H),7.90(s,1H),7.80(d, J ═ 6.8Hz,3H),7.59(d, J ═ 8.6Hz,1H),7.16(d, J ═ 8.6Hz,3H),6.49(d, J ═ 9.3Hz,1H),5.48 (s,2H),3.84(s,3H),3.49(s,3H),3.38(M,2H),1.32(M,8H), 13C NMR (75MHz, DMSO-d6) δ 161.05,159.39,153.79,143.17,138.63,137.24,130.84,129.82,128.87,125.84, 122.80,121.86,119.25,116.26,114.93,62.10,55.56,54.71,36.92,32.11,22.58,: LC-ms esi ([ M + H ] +) melting point: 170 ℃ and 172 ℃.
Example 46: preparation of 2- ((1- (3, 4-dimethoxyphenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) benzenesulfonamide (compound IV-H)
The synthesis method refers to example 1.
1H NMR(300MHz,DMSO-d6)δ8.87(s,1H),8.15(s,1H),7.86(m,3H),7.60(s,1H), 7.44(m,2H),7.17(s,2H),6.49(d,J＝8.8Hz,1H),5.48(s,2H),3.85(s,6H),3.52(s,3H), 3.47(m,1H),1.50–1.27(s,8H).13C NMR(75MHz,DMSO-d6)δ161.05,153.80,149.29, 149.03,143.10,138.63,137.25,130.83,129.84,128.89,125.83,122.95,119.26,116.26, 114.99,112.34,112.00,104.79,62.12,55.80,54.74,36.93,32.13,22.59.LC-MS(ESI):([M+ H]+) 566.3 melting point: 158 ℃ and 160 ℃.
Example 47: preparation of 2- ((1- (4-nitrophenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) benzenesulfonamide (compound IV-i)
The synthesis method refers to example 1.
1H NMR(300MHz,DMSO-d6)δ9.14(s,1H),8.50(m,2H),8.25(s,1H),8.15(s,1H), 7.86(m,2H),7.60(s,1H),7.12(s,1H),6.50(m,1H),5.53(s,2H),3.52(s,3H),3.38(m,1H), 1.40(m,8H).13C NMR(75MHz,DMSO-d6)δ161.05,153.74,146.85,144.01,140.66, 138.62,137.26,130.87,129.81,128.97,125.90,125.63,123.33,120.75,119.26,116.23, 115.00,61.95,54.68,36.93,32.15,22.59.LC-MS(ESI):([M+H]+) 551.3, melting point: 176 ℃ and 178 ℃.
Example 48: preparation of 2- ((1- (4-bromophenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) benzenesulfonamide (compound IV-j)
The synthesis method refers to example 1.
1H NMR(300MHz,DMSO-d6)δ8.96(s,1H),8.15(s,1H),7.99–7.73(m,7H),7.60 (s,1H),7.15(s,1H),6.49(d,J＝9.2Hz,1H),5.77(d,J＝4.1Hz,1H),5.50(s,2H),3.52(s, 3H),3.46(m,1H),1.49(m,4H),1.30(m,4H).13C NMR(75MHz,DMSO-d6)δ161.05, 153.75,143.58,138.63,137.25,135.65,132.86,130.86,129.80,128.92,125.88,122.90, 122.10,121.55,119.26,116.25,114.99,62.02,54.87,54.69,36.92,32.12,22.58.LC-MS (ESI):([M+H]+) 584.2 melting point: 172 ℃ and 174 ℃.
Example 49: preparation of 2- ((1- (2, 4-dichlorophenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) benzenesulfonamide (compound IV-k)
The synthesis method refers to example 1.
1H NMR (300MHz, DMSO-d6) δ 8.73(s,1H),8.18(s,1H),8.05(s,1H),7.83(M,5H), 7.61(M,1H),7.14(d, J ═ 5.5Hz,1H),6.52(M,1H),5.56(s,2H),3.55(s,3H),3.42(M,1H), 1.52(M,4H),1.30(M,5H), 13C NMR (75MHz, DMSO-d6) δ 161.05,153.78,142.70, 138.61,137.23,135.52,133.34,130.84,130.17,129.80,129.61,129.48,128.92,128.67, 126.67,125.84,119.25,116.25,115.00,62.06,54.71,36.93,32.19,22.62.LC-ms (esi) ([ M + H ] +):574.2 melting point: 176 ℃ and 178 ℃.
Example 50: preparation of 2- ((1- (2-nitrophenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) benzenesulfonamide (compound IV-l)
The synthesis method refers to example 1.
1H NMR (300MHz, DMSO-d6) δ 8.83(s,1H), 8.34-8.12 (M,2H), 8.09-7.75 (M,6H), 7.58(d, J ═ 8.1Hz,1H),7.10(d, J ═ 6.7Hz,1H),6.50(d, J ═ 8.9Hz,1H),5.57(s,2H),3.56 (s,3H),3.44(M,1H),1.53(s,4H),1.33(s,4H), 13C NMR (75MHz, DMSO-d6) δ 161.06, 153.79,144.01,143.18,138.63,137.25,134.48,131.37,130.88,129.76,128.95,127.60, 125.84,125.60,119.26,116.25,115.02,62.07,54.70,36.93,32.21,22.62. LC-esi (ms) (M + H ] +): 165-167 ℃.
Example 51: preparation of 2- ((1- (4-hydroxyphenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) benzenesulfonamide (compound IV-m)
The synthesis method refers to example 1.
1H NMR(300MHz,DMSO-d6)δ10.01(s,1H),8.74(s,1H),8.15(s,1H),7.85(m,3H), 7.74–7.54(m,2H),7.18(s,1H),6.97(s,2H),6.49(d,J＝8.9Hz,1H),5.47(s,2H),3.52(s, 3H),3.43(s,1H),1.49(m,4H),1.30(m,4H).13C NMR(75MHz,DMSO-d6)δ168.48, 161.05,157.87,153.79,143.05,138.63,137.23,130.84,128.85,125.82,122.67,122.04, 119.24,116.07,114.97,62.11,54.71,36.92,32.10,28.98,22.58.LC-MS(ESI):([M+H]+) 522.3, melting point: 155 ℃ and 157 ℃.
Example 52: preparation of 2- ((1- (4- (tert-butyl) phenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) benzenesulfonamide (compound IV-N)
The synthesis method refers to example 1.
1H NMR(300MHz,DMSO-d6)δ8.89(s,1H),8.15(s,1H),8.00–7.76(m,5H),7.70– 7.54(m,3H),7.17(d,J＝6.1Hz,1H),6.50(d,J＝8.1Hz,1H),5.50(s,2H),3.56(s,3H), 3.41(m,1H),1.64–1.23(m,17H).13C NMR(75MHz,DMSO-d6)δ161.05,153.79, 151.57,143.28,138.63,137.23,134.13,130.85,129.83,128.89,126.65,125.85,122.80, 119.96,119.25,116.27,115.00,62.10,54.72,36.92,34.49,32.12,30.94,22.57.LC-MS(ESI): ([M+H]+) 562.3 melting point: 152 ℃ and 154 ℃.
Example 53: preparation of 2- ((1- (4-trifluoromethoxy) phenyl) -1H-1,2, 3-triazol-4-yl) methoxy) -N-cyclopentyl-5- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) benzenesulfonamide (compound IV-o)
The synthesis method refers to example 1.
1H NMR(300MHz,DMSO-d6)δ8.99(s,1H),8.08(m,3H),7.96–7.77(m,3H),7.73– 7.54(m,3H),7.15(d,J＝7.1Hz,1H),6.55–6.43(m,1H),5.51(s,2H),3.53(s,3H),3.46 (m,1H),1.50(m,4H),1.28(m,4H).13C NMR(75MHz,DMSO-d6)δ161.05,153.76, 147.99,143.59,138.63,137.24,135.30,130.85,129.81,128.93,125.88,123.17,122.67, 122.22,119.25,116.26,115.00,62.03,54.69,36.93,32.12,22.57.LC-MS(ESI):([M+H]+) 590.3 melting point: 158 ℃ and 160 ℃.
Example 54: cell viability bioassay experiments
The determination principle is as follows: details of the inhibition of cancer cell growth by compounds can be determined by the MTT method. The principle of the MTT method is as follows: yellow thiazole blue can penetrate cell membranes and enter cells, succinate dehydrogenase in mitochondria of living cells can reduce exogenous MTT into blue-violet crystalline formazan deposited in cells, but dead cells do not have the function. Then, formazan was dissolved in dimethyl sulfoxide. At the wavelength of 570nm, the absorbance value is measured by an enzyme linked immunosorbent assay instrument to indirectly obtain the number of living cells.
Experimental materials: MV4-11 (human acute myeloid leukemia cells), cultured in IMDM + 10% FBS medium.
Test method and result analysis:
experimental groups: 190. mu.l of cell suspension + 10. mu.l of drug of different concentrations (final concentration 10-5-10-10)
Blank control group: 200 μ l PBS
Negative control group: 190. mu.l of cell suspension + 10. mu.l of 2% DMSO (final DMSO concentration: 0.1%)
Positive control group: 190. mu.l cell suspension + 10. mu.l of different concentrations of the compound
MTT cell viability assay procedure
a) Seeding cells
At 37 deg.C, 5% CO2Cells were subcultured in IMDM medium containing 10% fetal bovine serum, 1% penicillin and streptomycin under conditions. Transferring the cell suspension into a 10mL centrifuge tube, centrifuging for 3 minutes at 1000 rpm, precipitating the cells, discarding the supernatant, adding the cells into 7mL of new culture medium, gently blowing, calculating the cell concentration by a cell counting method, and then inoculating the cells into a 96-well plate.
b) Cell culture
The inoculated 96-well plate was incubated overnight at 37 ℃ in a 5% CO2 incubator.
c) Dosing
Adding medicines with different concentrations according to different experimental designs, arranging 3-4 compound holes in each group, adding 10 mu l of medicine with corresponding concentration into each hole, and putting the 96-hole plate into an incubator for continuous culture.
d) MTT viability assay
After 24 hours, 48 hours, and 72 hours of incubation after administration, 10 μ l of 5mg/ml MTT was added to each well, and then the 96-well plate was placed in an incubator, and after 4 hours of incubation, the plate was removed, centrifuged, and the supernatant of each well was carefully aspirated, and 100 μ l of Dimethylsulfoxide (DMSO) solution was added to each well, and after incubation for 10min in the incubator, the solution was shaken for about 40 seconds to completely dissolve the formazan crystal.
e) Absorbance was measured and IC was calculated50Value of
The 96-well plate was placed in a microplate reader, and the absorbance at a wavelength of 570nm was detected. And calculating the relative inhibition rate of the compound protein by using the average value of the absorbance of every 3-4 compound pores. Calculating half effective inhibition according to the inhibition rate of different drug concentrations on leukemia cellsConcentration (IC)50). Each set of samples was subjected to 3 replicates.
570nm read, cell viability was calculated and IC50 was calculated from the results, as shown in Table 1 below.
TABLE 1 Structure and Activity data (μmol/L) for BRD4 Small molecule inhibitors
Figure BDA0002004036620000281

Claims (5)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
Figure FDA0003077785740000011
wherein:
the ring A is selected from 3-methylthiazol-2- (3H) -one, thiazol-2 (3H) -one, 3, 5-dimethylisoxazole or 1-methylpyridin-2 (1H) -one, and the R is1，R2，R3，R4Each independently selected from hydrogen, chloro, fluoro, bromo, methoxy, hydroxy, trifluoromethoxy, methyl, ethyl, isopropyl, tert-butyl, butyl or nitro.
2. The compound of claim 1, wherein the compound is selected from the group consisting of:
Figure FDA0003077785740000012
Figure FDA0003077785740000021
Figure FDA0003077785740000031
3. a process for the preparation of a compound according to claim 1, characterized by the following reaction scheme:
Figure FDA0003077785740000041
wherein, ring A, R1，R2，R3And R4The same as claim 1.
4. A pharmaceutical composition comprising a compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
5. Use of a compound according to any one of claims 1-2, or a pharmaceutically acceptable salt thereof, for the manufacture of an anti-neoplastic medicament.
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