CN108530444B - Novel NAMPT and IDO dual inhibitor and preparation method and medical application thereof - Google Patents

Novel NAMPT and IDO dual inhibitor and preparation method and medical application thereof Download PDF

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CN108530444B
CN108530444B CN201810594278.4A CN201810594278A CN108530444B CN 108530444 B CN108530444 B CN 108530444B CN 201810594278 A CN201810594278 A CN 201810594278A CN 108530444 B CN108530444 B CN 108530444B
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蒋晟
郝海平
郭长缨
吴筱星
姚和权
张阔军
邱亚涛
郑啸
陈东
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Yaokang Zhongtuo (Jiangsu) Pharmaceutical Technology Co.,Ltd.
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Abstract

The invention discloses a novel NAMPT and IDO dual inhibitor, a preparation method and medical application thereof, and in particular relates to a furazan compound or pharmaceutically acceptable salts, solvates, prodrugs, esters, racemates and isomers thereof, a pharmaceutical composition containing the compound, and application of the compound or the pharmaceutical composition in preparing antitumor drugs. The invention reasonably splices the active fragments of the IDO inhibitor and the NAMPT inhibitor to obtain the furazan IDO/NAMPT dual-target inhibitor, and on one hand, the dual-target inhibitor inhibits NAD+Thereby exhibiting a stronger tumor-inhibiting activity; on the other hand, the inhibition of the IDO activity can effectively promote the proliferation of T cells, thereby enhancing the attack capability of the body to tumor cells. The furazan IDO/NAMPT double-target inhibitor or the pharmaceutical composition thereof has wide application prospect and is expected to become an anti-tumor drug.

Description

Novel NAMPT and IDO dual inhibitor and preparation method and medical application thereof
Technical Field
The invention belongs to the field of biotechnology drugs, and particularly relates to furazan compounds shown in formula I or pharmaceutically acceptable salts, solvates, prodrugs, esters, racemates and isomers thereof, pharmaceutical compositions containing the compounds, and applications of the compounds or the pharmaceutical compositions in preparation of antitumor drugs.
Figure BDA0001691645820000011
Background
Cancer is a major disease which troubles human health, and the research and development of novel antitumor drugs are major subjects and long-term tasks in the field of biological medicine. Numerous studies have shown that abnormal cellular metabolism is one of the important hallmarks of cancer. Nicotinamide adenine dinucleotide (NAD for short)+) Is an indispensable substance in the process of electron transfer and plays an important role in the processes of energy metabolism and signal transduction. In addition, NAD+And the reduced NADH thereof have important significance for maintaining the reducing environment in the cells so as to protect the cells from being damaged by oxidative stress. Thus, intracellular NAD+Is a critical factor in determining cell fate. Tumor cells have an uncontrollable proliferation rate, a rapid metabolic rate, and a significantly increased level of oxidative stress relative to normal cells, and thus tumor cells are sensitive to NAD+The level change is more sensitive. NAD (nicotinamide adenine dinucleotide)+Key enzymes of the in vivo biosynthetic pathway have become important targets for anticancer drugs. NAD (nicotinamide adenine dinucleotide)+The in vivo synthetic pathway includes a de novo synthetic pathway and a salvage synthetic pathway。
Indoleamine-2,3-dioxygenase (IDO) is a monomeric enzyme containing heme, is widely expressed in various tissues of mammals and is highly expressed in various tumor cells. IDO is the first enzyme in the tryptophan metabolic pathway in vivo and is the rate-limiting enzyme, which catalyzes the conversion of tryptophan to N-formyl kynurenine by oxidation, which is hydrolyzed to kynurenine, which then enters the kynurenine metabolic pathway to quinolinic acid, kynurenine, and other metabolites. Wherein quinolinic acid is NAD+Starting materials for the de novo synthetic pathway. On the other hand, excessive expression of IDO can cause local tryptophan depletion, increase metabolites such as kynurenic acid and the like, inhibit proliferation of T cells, activate regulatory T cells, further cause immune tolerance, and prevent an organism from recognizing and removing tumor cells. Therefore, inhibition of IDO activity can effectively prevent degradation of tryptophan surrounding tumor cells, on the one hand, inhibit NAD in tumor cells+On the other hand, the proliferation of T cells is promoted, thereby enhancing the attack capability of the body to tumor cells. In addition, the IDO inhibitor can be used together with chemotherapeutic drugs to reduce drug resistance of tumor cells, thereby enhancing the antitumor activity of conventional cytotoxic therapy. The administration of an IDO inhibitor also enhances the therapeutic efficacy of the therapeutic vaccine in cancer patients. Therefore, the research of IDO inhibitors has become a hot spot area for tumor immunotherapy. However, at present, no IDO inhibitor is available on the market as a medicament, and the search for a novel efficient IDO inhibitor has important theoretical significance and application value.
NAD+The salvage synthesis route is to use nicotinic acid, nicotinamide or nicotinamide ribose as starting materials. Due to much NAD+Nicotinamide can be rapidly liberated again by consuming enzymes such as poly-ADP-ribose polymerase (PARP) and Sirtuins (SIRT), and thus NAD from nicotinamide is used as a raw material+The salvage synthesis pathway is the most economical, predominant NAD+The biosynthetic pathway (Galli U.et al.J.Med.chem.2013,22,56(16): 6279-96). And nicotinamide phosphoribosyltransferase (nicotinamide phosphoribosyltransferase)sferase, NAMPT for short) is used to control nicotinamide to NAD+The rate-limiting enzyme of transformation. In view of the abnormal exuberance of energy metabolism by tumor cells, NAD is more desirable+Rapid and timely recruitment, tumor cells are more dependent on NAMPT and are more sensitive to NAMPT inhibition. Therefore, NAMPT is considered as a potent anti-cancer target and NAMPT inhibitors have been the focus of extensive research. Currently, two NAMPT inhibitors CHS-828 and FK866 have entered the clinical trial phase (Montecucco F. et al. curr. drug targets.2013,1,14(6): 637-43). However, the results of clinical trials of these two compounds are not ideal and patients do not show significant therapeutic effects after administration. Moreover, the pharmacokinetic properties of these two compounds are poor and also show dose-dependent toxicities such as thrombocytopenia and gastrointestinal toxic side effects. Therefore, the NAMPT inhibitor with novel structure and good drug-forming property needs to be further researched and developed.
Figure BDA0001691645820000021
Chinese patent application 201480028214.8 discloses an IDO inhibitor, Chinese patent application 201380036899.6 discloses a NAMPT inhibitor, the two inhibitors have poor drug properties, single treatment effect, weak curative effect and large toxic and side effects, and the invention reasonably splices the active fragments of the IDO inhibitor and the NAMPT inhibitor to obtain a furazan IDO/NAMPT double-target inhibitor, on one hand, the double inhibition of NAD is realized+Thereby exhibiting a stronger tumor-inhibiting activity; on the other hand, the inhibition of the IDO activity can effectively promote the proliferation of T cells, thereby enhancing the attack capability of the body to tumor cells. The furazan IDO/NAMPT double-target inhibitor or the pharmaceutical composition thereof has wide application prospect and is expected to become an anti-tumor drug.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a furazan indoleamine 2, 3-dioxygenase/nicotinamide phosphoribosyltransferase double-target inhibitor, which is used for solving the problems of weak curative effect, large toxic and side effect and the like of the existing anticancer drugs.
In the compounds of the invention, when any variable (e.g. R)1，R2Etc.) occur more than one time in any constituent, then the definition of each occurrence is independent of the definition of each other occurrence. Also, combinations of substituents and variables are permissible only if such combinations result in stable compounds. The line drawn from a substituent into the ring system indicates that the indicated bond can be attached to any ring atom that can be substituted. If the ring system is polycyclic, it means that such a bond is only attached to any suitable carbon atom of the adjacent ring. It is to be understood that substituents and substitution patterns on the compounds of the invention may be selected by one of ordinary skill in the art to provide compounds of interest that are chemically stable and that can be readily synthesized from readily available starting materials by those of ordinary skill in the art and by methods set forth below. If a substituent is itself substituted with more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms, so long as the structure is stabilized.
As used herein, the terms related thereto such as "alkyl", "aryl", "heteroaryl", "halogen", and the like, do not differ significantly from the general meaning of the terms in the art.
For example, the term "alkyl" refers to a compound having 1-6 (C)1-C6) A linear or branched saturated hydrocarbon group having a carbon number. Representative saturated hydrocarbon groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, tert-butyl, neopentyl, n-hexyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 4-methyl-2-pentyl. It should be noted that, when the number of carbon atoms thereof is not particularly limited, it refers only to the number of carbon atoms of the alkyl moiety specified therein, and does not include the number of carbon atoms on the substituent of the alkyl group.
The term "heteroaryl" as used herein represents a stable monocyclic ring of 5 to 6 atoms in the ring or a bicyclic carbocyclic ring of 5 to 6 atoms in each ring, wherein at least one ring is aromatic and contains at least one heteroatom independently selected from O, N and S. Heteroaryl groups within the scope of this definition include, but are not limited to: imidazolyl, thiazolyl, pyrazolyl, furyl, thienyl, oxazolyl, furazanyl, isoxazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, pyridonyl, pyrimidinyl, pyrrolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolyl, dihydronaphthyridinyl, benzothienyl, indazolyl, benzofurazanyl, benzoxazolyl, naphthyridinyl, pyrazolopyridinyl, pyrrolopyridyl, tetrazolopyridinyl, tetrahydroimidazopyridinyl, tetrahydropyrazolopyridinyl, thiazolopyridinyl. The term "heteroaryl" is also understood to include any N-oxide derivative of a nitrogen-containing heteroaryl group.
Those of ordinary skill in the art will know the meaning of the following terms or abbreviations.
The term "pharmaceutically acceptable salt" refers to salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of mammals, especially humans, without excessive toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, such as the medically acceptable salts of amines, carboxylic acids, and other types of compounds, are well known in the art.
The term "isomer" refers to two or more compounds that are identical in molecular composition but differ in structure and properties.
The term "racemate" refers to an equimolar mixture of a chiral molecule and its enantiomer having optical activity, which is formed by mixing equal amounts of molecules having opposite optical rotation directions and the same optical activity, and whose optical activity is offset by the interaction between these molecules, and thus is optically inactive.
The term "solvate" refers to a mixture of a compound and a solvent, e.g., a crystalline form is a solvate.
The term "prodrug" refers to a compound that is rapidly converted in vivo by hydrolysis in blood to yield the parent compound having the above formula.
As understood by those skilled in the art, "halogen" as used herein includes chlorine, fluorine, bromine and iodine.
Unless otherwise defined, alkyl, alkenyl, alkynyl, cycloalkyl, cyclicAlkenyl, aryl, heteroaryl and heterocyclyl are unsubstituted or substituted. E.g. C1-C6The alkyl group may be substituted with a substituent such as a hydroxyl group, a halogen group, an alkoxy group, an alkylamino group or a heterocyclic group, for example, a morpholinyl group, a piperidinyl group or the like.
The compounds of the present invention may form salts. The "salt" in the present application means an acid salt with an inorganic acid or an organic acid, and a basic salt with an inorganic base or an organic base. In addition, when the compounds have a basic moiety (e.g., pyridine, imidazole, etc.) and an acidic moiety (e.g., carboxylic acid), zwitterions ("inner salts") may form and are also included within the term "salt(s)" as used herein. Pharmaceutically acceptable salts of the invention can be synthesized from compounds of the invention containing a basic or acidic moiety by conventional chemical methods. In general, salts of basic compounds are prepared by ion exchange chromatography or by reaction of the free base with a stoichiometric amount or excess of an inorganic or organic acid in the form of the desired salt in an appropriate solvent or combination of solvents. Similarly, salts of the compounds are formed by reaction with a suitable inorganic or organic base. Pharmaceutically acceptable, non-toxic, physiologically acceptable salts are preferred, although other salts are also useful.
Exemplary non-toxic acid salts include salts prepared from inorganic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, sulfamic acid, phosphoric acid, nitric acid, and the like, as well as salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, acetic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, glycerophosphoric acid, salicylic acid, sulfanilic acid, fumaric acid, 2-acetoxy-benzoic acid, fumaric acid, p-toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid, isethionic acid, and trifluoroacetic acid, and the like.
Exemplary non-toxic basic salts include salts from inorganic bases such as aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganous, potassium, sodium, zinc and the like, as well as salts from organic bases including salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, glycine, caffeine, choline, N' -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, methylglucamine, histidine, lysine, isopropylamine, morpholine, piperidine, polyamine resins, procaine, purines, theobromine, and the like, Triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
The term "free form" as opposed to "salt" form means that the compound of formula I is present in a non-salt form. The free forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of the invention such acid and base salts are otherwise pharmaceutically equivalent to their respective free forms.
In order to achieve the purpose, the invention provides the following technical scheme:
a novel dual NAMPT and IDO inhibitor characterized by: the furazan compound has a general formula I, and pharmaceutically acceptable salts, solvates, prodrugs, esters, racemates and isomers thereof. The general formula I is:
Figure BDA0001691645820000051
r in the above general formula I1Is independently selected from hydrogen, deuterium, halogen, nitro, cyano, hydroxyl, mercapto, O-carboxyl, C-carboxyl, sulfonic acid group, phosphoric acid group, phosphorous acid group, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl, aryl, heteroaryl, heterocycloalkyl, C3-C6Cycloalkyl- (C)1-C6Alkyl group), aryl group (C)1-C6Alkyl), heteroaryl (C)1-C6Alkyl), heterocycloalkyl (C)1-C6Alkyl group), C3-C6Cycloalkyl- (C)2-C6Alkenyl), aryl (C)2-C6Alkenyl), heteroaryl (C)2-C6Alkenyl), heterocycloalkyl (C)2-C6Alkenyl), C3-C6Cycloalkyl- (C)2-C6Alkynyl), aryl (C)2-C6Alkynyl), heteroaryl (C)2-C6Alkynyl), heterocycloalkyl (C)2-C6Alkynyl group), (C)3-C6Cycloalkyl) -O- (CH2)q-、(C3-C6Cycloalkyl) - (C)1-C6Alkoxy), aryl-O- (CH)2) q-, aryl- (C)1-C6Alkoxy), heteroaryl-O- (CH)2) q-, heteroarylalkoxy, heterocycloalkyl-O- (CH)2) q-, heterocycloalkyl- (C)1-C6Alkoxy group), (C)3-C6Cycloalkyl) -S- (CH2)q-、(C3-C6Cycloalkyl) - (C)1-C6Alkanethiol), aryl-S- (CH)2) q-, aryl- (C)1-C6Alkanethiol), heteroaryl-S- (CH)2) q-, heteroarylalkylmercapto, heterocycloalkyl-S- (CH)2) q-, heterocycloalkyl- (C)1-C6Alkanemercapto group, aryl group (C)2-C6Alkenyl), heteroaryl (C)2-C6Alkenyl group), (C)3-C6Cycloalkyl) - (C)2-C6Alkenyl), heterocycloalkyl (C)2-C6Alkenyl), C1-C6Alkoxy- (CH)2)q-、C2-C6Alkenyloxy (CH)2)q-、C1-C6Alkanemercapto- (CH)2)q-、C2-C6Alkenylmercapto, halo (C)1-C6Alkyl), halo (C)2-C6Alkenyl), amino (C)1-C6Alkyl), amino (C)2-C6Alkenyl group, hydroxy group (C)1-C6Alkyl), hydroxy (C)2-C6Alkenyl), mercapto (C)1-C6Alkyl), mercapto (C)2-C6Alkenyl), cyano (C)1-C6Alkyl), cyano (C)2-C6Alkenyl), nitro (C)1-C6Alkyl), nitro (C)2-C6Alkenyl), O-carboxy (C)1-C6Alkyl), O-carboxy (C)2-C6Alkenyl), C-carboxy (C)1-C6Alkyl), C-carboxy (C)2-C6Alkenyl group, sulfonic acid group (C)1-C6Alkyl group), sulfonic acid group (C)2-C6Alkenyl), phosphate group (C)1-C6Alkyl), a phosphite group (C)1-C6Alkyl), phosphoric acid group (C)2-C6Alkenyl), phosphite (C)2-C6Alkenyl group), (C)1-C6Alkylamino) - (C1-C6Alkoxy group), (C)1-C6Alkylamino) oxy- (CH2)q、(C1-C6Alkanethiol group) - (C1-C6Alkoxy group), (C)1-C6Alkanethiol) oxy- (CH2)q-, halo (C)1-C6Alkoxy) - (CH2)q-, (halo C)1-C6Alkyl) -O- (CH2)q-, hydroxy (C)1-C6Alkoxy) - (CH2)q-, (hydroxy group C)1-C6Alkyl) oxy- (CH2)q-, cyano (C)1-C6Alkoxy) - (CH2)q-, (cyano group C)1-C6Alkyl) -O- (CH2)q-、-(CH2)qNRaRb、-(CH2)q(C＝O)NRaRb、-(CH2)q-NRc(C＝O)Rd、-(CH2)q-NRc(C＝O)ORd、-(CH2)q-(C＝O)-(C1-C6Alkyl), - (CH)2)q- (C ═ O) aryl, - (CH)2)q- (C ═ O) heteroaryl, - (CH)2)q-(C＝O)-(C3-C6Cycloalkyl), - (CH)2)q-(C＝O)O-(C1-C6Alkyl), - (CH)2)q- (C ═ O) Oaryl, - (CH)2)q-(C＝O)S-(C1-C6Alkyl), - (CH)2)q- (C ═ O) S aryl, - (CH)2)q-O(C＝O)-(C1-C6Alkyl), - (CH)2)q-O (C ═ O) aryl, - (CH)2)q-(S＝O)2NRaRb、-(CH2)q-NRc(S＝O)Rd、-(CH2)q-(S＝O)2(C1-C6Alkyl), - (CH)2)q-(S＝O)2Aryl, - (CH)2)q-(S＝O)2-heterocycloalkyl, - (CH)2)q-(S＝O)2Heteroaryl, - (CH)2)q-(S＝O)2Haloalkyl, - (CH)2)q-(S＝O)-(C1-C6Alkyl), - (CH)2)q- (S ═ O) aryl, - (CH)2)q- (S ═ O) -heterocycloalkyl, - (CH)2)q- (S ═ O) heteroaryl, - (CH)2)q- (S ═ O) haloalkyl and- (CH)2)q-(P＝O)RcRd1,2, 3,4 or 5;
wherein q is 0-4, RaAnd RbHydrogen and C simultaneously or not1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, hydroxy (C)1-C6Alkyl), halo (C)1-C6Alkyl group), C1-C6Alkoxy radical, C1-C6alkyl-NH- (C)1-C6Alkyl) -, (C)1-C6Alkyl radical)2-N-(C1-C6Alkyl) -, C3-C6Cycloalkyl, aryl-NH-, heteroaryl, heterocycloalkyl, C3-C6Cycloalkyl- (C)1-C6Alkyl group), aryl group (C)1-C6Alkyl), heteroaryl (C)1-C6Alkyl) and heterocycloalkyl (C)1-C6Alkyl), or RaAnd RbTogether with the nitrogen atom to which they are attached form a 5-or 6-membered heterocycloalkyl group, wherein said heterocycloalkyl group contains one or more additional heteroatoms independently selected from N, O or S, RcAnd RdHydrogen and C simultaneously or not1-C6Alkyl, aryl, heteroaryl, and heteroaryl,C2-C6Alkenyl radical, C2-C6Alkynyl, hydroxy (C)1-C6Alkyl), halo (C)1-C6Alkyl group), C1-C6Alkoxy radical, C3-C6Cycloalkyl, aryl, heteroaryl, and heterocycloalkyl;
said aryl, heteroaryl, C3-C6Cycloalkyl, heterocycloalkyl can be independently substituted with aryl, heteroaryl, C3-C6Cycloalkyl or heterocycloalkyl fused;
said aryl, heteroaryl, C3-C6Cycloalkyl, heterocycloalkyl are unsubstituted or optionally substituted with one or more substituents, which are the same or different and are independently selected from: deuterium, halogen, nitro, amino, hydroxy, cyano, sulfonamide, O-carboxy, C-carboxy, mercapto, oxo, C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Alkanemercapto, halogeno (C)1-C6Alkyl), hydroxy (C)1-C6Alkyl), mercapto (C)1-C6Alkyl group), C3-C6Cycloalkyl radical, C6-C12Aryl, heteroaryl, heterocycloalkyl, - (CH)2)qNRaRb、-(CH2)q-(S＝O)2NRaRb、-(CH2)q(C＝O)NRaRbWherein q is 0-4, RaAnd RbHydrogen and C simultaneously or not1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, hydroxy (C)1-C6Alkyl), halo (C)1-C6Alkyl group), C1-C6Alkoxy radical, C3-C6One or more of cycloalkyl, aryl, heteroaryl and heterocycloalkyl, or RaAnd RbMay form, together with the nitrogen atom to which they are attached, a 5-or 6-membered heterocycloalkyl group, wherein said heterocycloalkyl group contains one or more additional heteroatoms independently selected from N, O or S;
l in the general formula I is aryl, heteroaryl, C3-C6Cycloalkyl radical, C3-C6Cycloalkenyl, heterocycloalkyl, C1-C8Alkyl radical, C2-C8Alkenyl radical, C2-C8Alkynyl, aryl- (C)1-C6Alkyl), heteroaryl- (C)1-C6Alkyl group), (cycloalkyl group) - (C)1-C6Alkyl) or (heterocycloalkyl) - (C)1-C6Alkyl) or more than one of the alkyl);
said C1-C8Alkyl radical, C2-C8Alkenyl and C2-C8Alkynyl groups may be substituted or unsubstituted with: -O-, -S-, -NH-, -S (═ O)2-、-S(＝O)-、-(C＝O)-、-O(C＝O)-、-(C＝O)O-、-O(C＝O)O-、-NH(C＝O)-、-(C＝O)NH-、-S(C＝O)-、-(C＝O)S-、-NH(C＝O)2NH-、-NH(C＝S)2NH-、NH(C＝O)2O-is separated 1,2, 3 or 4 times;
said C1-C8Alkyl radical, C2-C8Alkenyl radical, C2-C8Alkynyl, aryl, heteroaryl, C3-C6Cycloalkyl and heterocycloalkyl are unsubstituted or substituted with one or more substituents, which are the same or different, and are independently selected from: halogen, nitro, amino, hydroxy, cyano, sulfonamido, O-carboxy, C-carboxy, mercapto, C-carboxy1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Alkoxy radical, C2-C6Alkenyloxy radical, C1-C6Alkanemercapto group, C1-C6Alkylamino, halo (C)1-C6Alkyl), hydroxy (C)1-C6Alkyl), mercapto (C)1-C6Alkyl), cyano (C)1-C6Alkyl), nitro (C)1-C6Alkyl), O-carboxy (C)1-C6Alkyl), C-carboxy (C)1-C6Alkyl group), (C)1-C6Alkoxy group) - (C1-C6Alkyl group), (C)1-C6Alkylamino) - (C1-C6Alkyl group), (C)1-C6Alkylamino) - (C1-C6Alkyl group) - (C1-C6Alkoxy group), (C)1-C6Alkanethiol group) - (C1-C6Alkyl group), (C)1-C6Alkanethiol group) - (C1-C6Alkyl group) - (C1-C6Alkoxy), amino (C)1-C6Alkoxy), amino (C)1-C6Alkoxy group) - (C1-C6Alkyl), halo (C)1-C6Alkoxy group) - (C1-C6Alkyl), hydroxy (C)1-C6Alkoxy group) - (C1-C6Alkyl), cyano (C)1-C6Alkoxy) (C1-C6Alkyl group), C3-C6Cycloalkyl radical, C6-C12One or more of aryl, heterocycloalkyl and heteroaryl;
e in the general formula I is O, S or N-C ≡ N;
x in the general formula I is C0-C4Alkyl radical, C2-C4Alkenyl radical, C3-C6Cycloalkyl or (CH)2)nNH, wherein n is 0 to 4;
r in the general formula I2Is aryl, heteroaryl, C3-C6Cycloalkyl radical, C3-C6Cycloalkenyl or heterocycloalkyl;
said aryl, heteroaryl, C3-C6Cycloalkyl radical, C3-C6Cycloalkenyl or heterocycloalkyl are unsubstituted or optionally substituted with one or more substituents, which are the same or different and are independently selected from: deuterium, halogen, nitro, cyano, hydroxy, mercapto, O-carboxy, C-carboxy, sulfonic, phosphoric, phosphorous, C-carboxy1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl, aryl, heteroaryl, heterocycloalkyl, C3-C 6Cycloalkyl- (C)1-C6Alkyl group), aryl group (C)1-C6Alkyl), heteroaryl (C)1-C6Alkyl), heterocycloalkyl (C)1-C6Alkyl group), C3-C6Cycloalkyl- (C)2-C6Alkenyl), aryl (C)2-C6Alkenyl), heteroaryl (C)2-C6Alkenyl), heterocycloalkyl (C)2-C6Alkenyl), C3-C6Cycloalkyl- (C)2-C6Alkynyl), aryl (C)2-C6Alkynyl), heteroaryl (C)2-C6Alkynyl), heterocycloalkyl (C)2-C6Alkynyl group), (C)3-C6Cycloalkyl) -O- (CH2)q-、(C3-C6Cycloalkyl) - (C)1-C6Alkoxy), aryl-O- (CH)2) q-, aryl- (C)1-C6Alkoxy), heteroaryl-O- (CH)2) q-, heteroarylalkoxy, heterocycloalkyl-O- (CH)2) q-, heterocycloalkyl- (C)1-C6Alkoxy group), (C)3-C6Cycloalkyl) -S- (CH2)q-、(C3-C6Cycloalkyl) - (C)1-C6Alkanethiol), aryl-S- (CH)2) q-, aryl- (C)1-C6Alkanethiol), heteroaryl-S- (CH)2) q-, heteroarylalkylmercapto, heterocycloalkyl-S- (CH)2) q-, heterocycloalkyl- (C)1-C6Alkanemercapto group, aryl group (C)2-C6Alkenyl), heteroaryl (C)2-C6Alkenyl group), (C)3-C6Cycloalkyl) - (C)2-C6Alkenyl), heterocycloalkyl (C)2-C6Alkenyl), C1-C6Alkoxy- (CH)2)q-、C2-C6Alkenyloxy (CH)2)q-、C1-C6Alkanemercapto- (CH)2)q-、C2-C6Alkenylmercapto, halo (C)1-C6Alkyl), halo (C)2-C6Alkenyl), amino (C)1-C6Alkyl), amino (C)2-C6Alkenyl group, hydroxy group (C)1-C6Alkyl), hydroxy (C)2-C6Alkenyl), mercapto (C)1-C6Alkyl), mercapto (C)2-C6Alkenyl), cyano (C)1-C6Alkyl), cyano (C)2-C6Alkenyl), nitro (C)1-C6Alkyl), nitro (C)2-C6Alkenyl), O-carboxy (C)1-C6Alkyl), O-carboxy (C)2-C6Alkenyl), C-carboxy (C)1-C6Alkyl), C-carboxy (C)2-C6Alkenyl group, sulfonic acid group (C)1-C6Alkyl group), sulfonic acid group (C)2-C6Alkenyl), phosphate group (C)1-C6Alkyl), a phosphite group (C)1-C6Alkyl), phosphoric acid group (C)2-C6Alkenyl), phosphite (C)2-C6Alkenyl group), (C)1-C6Alkylamino) - (C1-C6Alkoxy group), (C)1-C6Alkylamino) oxy- (CH2)q、(C1-C6Alkanethiol group) - (C1-C6Alkoxy group), (C)1-C6Alkanethiol) oxy- (CH2)q-, halo (C)1-C6Alkoxy) - (CH2)q-, (halo C)1-C6Alkyl) -O- (CH2)q-, hydroxy (C)1-C6Alkoxy) - (CH2)q-, (hydroxy group C)1-C6Alkyl) oxy- (CH2)q-, cyano (C)1-C6Alkoxy) - (CH2)q-, (cyano group C)1-C6Alkyl) -O- (CH2)q-、-(CH2)qNRaRb、-(CH2)q(C＝O)NRaRb、-(CH2)q-NRc(C＝O)Rd、-(CH2)q-NRc(C＝O)ORd、-(CH2)q-(C＝O)-(C1-C6Alkyl), - (CH)2)q- (C ═ O) aryl, - (CH)2)q- (C ═ O) heteroaryl, - (CH)2)q-(C＝O)-(C3-C6Cycloalkyl), - (CH)2)q-(C＝O)O-(C1-C6Alkyl), - (CH)2)q- (C ═ O) Oaryl, - (CH)2)q-(C＝O)S-(C1-C6Alkyl), - (CH)2)q- (C ═ O) S aryl, - (CH)2)q-O(C＝O)-(C1-C6Alkyl), - (CH)2)q-O (C ═ O) aryl, - (CH)2)q-(S＝O)2NRaRb、-(CH2)q-NRc(S＝O)Rd、-(CH2)q-(S＝O)2(C1-C6Alkyl), - (CH)2)q-(S＝O)2Aryl, - (CH)2)q-(S＝O)2-heterocycloalkyl, - (CH)2)q-(S＝O)2Heteroaryl, - (CH)2)q-(S＝O)2Haloalkyl, - (CH)2)q-(S＝O)-(C1-C6Alkyl), - (CH)2)q- (S ═ O) aryl, - (CH)2)q- (S ═ O) -heterocycloalkyl, - (CH)2)q- (S ═ O) heteroaryl, - (CH)2)q- (S ═ O) haloalkyl and- (CH)2)q-(P＝O)RcRd；
Wherein q is 0-4, RaAnd RbHydrogen and C simultaneously or not1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, hydroxy (C)1-C6Alkyl), halo (C)1-C6Alkyl group), C1-C6Alkoxy radical, C1-C6alkyl-NH- (C)1-C6Alkyl) -, (C)1-C6Alkyl radical)2-N- (C1-C6 alkyl) -, C3-C6Cycloalkyl, aryl-NH-, heteroaryl, heterocycloalkyl, C3-C6Cycloalkyl- (C)1-C6Alkyl group), aryl group (C)1-C6Alkyl), heteroaryl (C)1-C6Alkyl), heterocycloalkyl (C)1-C6Alkyl) or RaAnd RbMay form together with the nitrogen atom to which they are attached a 5-or 6-membered heterocycloalkyl group, wherein said heterocycloalkyl group contains one or more additional heteroatoms independently selected from N, O or S, RcAnd RdHydrogen and C simultaneously or not1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, hydroxy (C)1-C6Alkyl), halo (C)1-C6Alkyl group), C1-C6Alkoxy radical, C3-C6Cycloalkyl, aryl, heteroaryl, heterocycloalkyl;
said aryl, heteroaryl, C3-C6Cycloalkyl, heterocycloalkyl can be independently substituted with aryl, heteroaryl, C3-C6Cycloalkyl or heterocycloalkyl fused;
said aryl, heteroaryl, C3-C6Cycloalkyl, heterocycloalkyl are unsubstituted or optionally substituted with one or more substituents, which are the same or different and are independently selected from: deuterium, halogen, nitro, amino, hydroxy, cyano, sulfonamide, O-carboxy, C-carboxy, mercapto, oxo, C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Alkanemercapto, halogeno (C)1-C6Alkyl), hydroxy (C)1-C6Alkyl), mercapto (C)1-C6Alkyl group), C3-C6Cycloalkyl radical, C6-C12Aryl, heteroaryl, heterocycloalkyl, - (CH)2)qNRaRb、-(CH2)q-(S＝O)2NRaRb、-(CH2)q(C＝O)NRaRbWherein q is 0-4, RaAnd RbHydrogen and C simultaneously or not1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, hydroxy (C)1-C6Alkyl), halo (C)1-C6Alkyl group), C1-C6Alkoxy radical, C3-C6Cycloalkyl, aryl, heteroaryl, heterocycloalkyl, or RaAnd RbMay form, together with the nitrogen atom to which they are attached, a 5-or 6-membered heterocycloalkyl group, wherein said heterocycloalkyl group contains one or more additional heteroatoms independently selected from N, O or S.
In the general formula I, R2Preferably, it is
Figure BDA0001691645820000081
The compound having the general formula I is selected from:
Figure BDA0001691645820000091
Figure BDA0001691645820000101
Figure BDA0001691645820000111
Figure BDA0001691645820000121
Figure BDA0001691645820000131
Figure BDA0001691645820000141
Figure BDA0001691645820000151
Figure BDA0001691645820000161
or a pharmaceutically acceptable salt thereof.
The furazan compound shown in the general formula I and pharmaceutically acceptable salts, solvates, prodrugs, racemates and isomers thereof can be applied to preparation of indoleamine-2,3-dioxygenase inhibitors, nicotinamide phosphoribosyltransferase inhibitors or indoleamine-2,3-dioxygenase and nicotinamide phosphoribosyltransferase dual inhibitors.
The furazan compound and the pharmaceutically acceptable salt, prodrug and stereoisomer thereof or the pharmaceutical composition consisting of the furazan compound and the pharmaceutically acceptable salt, solvate, prodrug, racemate and isomer thereof can be applied to the preparation of medicaments for treating tumor hyperproliferative diseases of human beings and other mammals.
The furazan compound and the pharmaceutically acceptable salt, prodrug and stereoisomer thereof or the pharmaceutical composition consisting of the furazan compound and the pharmaceutically acceptable salt, solvate, prodrug, racemate and isomer thereof and a pharmaceutically acceptable carrier can be applied to the preparation of medicaments for preventing or treating tumors; the tumor prevention or treatment medicine comprises but is not limited to cancer immunotherapy medicine, cancer chemotherapy medicine or cancer targeted therapy medicine.
Furthermore, the furazan compound, the pharmaceutically acceptable salt, the prodrug, the stereoisomer and the pharmaceutical composition thereof can be used for preventing or treating lymphoma, non-small cell lung cancer, head and neck cell cancer, glioma, neuroblastoma, squamous lung cancer, adenocarcinoma of lung, bladder cancer, gastric cancer, colon cancer, colorectal cancer, renal cancer, cholangiocarcinoma, gastric cancer, esophageal squamous carcinoma, ovarian cancer, pancreatic cancer, breast cancer, prostate cancer, liver cancer, brain cancer, melanoma, multiple myeloma, skin cancer, epithelial cell cancer, leukemia, cervical cancer and other cancers, including metastatic lesions of tissues or organs far away from the primary tumor site.
The preparation method of the novel dual NAMPT and IDO inhibitor is characterized in that: the synthetic route of the compound with the general formula I is as follows:
Figure BDA0001691645820000171
in some embodiments, the compounds and pharmaceutically acceptable salts thereof to which this application relates may be combined with currently used or in development cytotoxic/cytostatic agents, estrogen receptor modulators, androgen receptor modulators, retinoids receptor modulators, antiproliferative agents, protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, angiogenesis inhibitors, cell proliferation and survival signaling inhibitors, drugs that interfere with cell cycle checkpoints and apoptosis inducers, cytotoxic drugs, tyrosine protein inhibitors, EGFR inhibitors, VEGFR inhibitors, serine/threonine protein inhibitors, Bcr-Abl inhibitors, c-Kit inhibitors, Met inhibitors, Raf inhibitors, MEK inhibitors, MMP inhibitors, topoisomerase inhibitors, histone deacetylase inhibitors, and pharmaceutically acceptable salts thereof, The clinical effects of the combination of drugs such as proteasome inhibitors, CDK inhibitors, Bcl-2 family protein inhibitors, MDM2 family protein inhibitors, IAP family protein inhibitors, STAT family protein inhibitors, PI3K inhibitors, AKT inhibitors, COX-2 inhibitors, integrin blockers, P53 activators, VEGF antibodies, PD-1 antibodies, PD-L1 antibodies, PD-L2 antibodies, CTLA-4 antibodies, and EGF antibodies are increased.
The compounds referred to herein and their pharmaceutically acceptable salts may be used in the treatment of, but are not limited to, the following diseases according to the following methods:
a method of treating breast cancer in humans or other mammals using pharmaceutical compositions comprising compounds having the structure of formula I and pharmaceutically acceptable salts thereof as described herein includes but is not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.
A method of treating respiratory cancer in humans or other mammals using pharmaceutical compositions comprising compounds having the structure of formula I and pharmaceutically acceptable salts thereof to which this application refers include, but are not limited to, small cell lung cancer, non-small cell lung cancer, bronchial adenocarcinoma and pleuropulmonary blastoma.
A method of treating brain cancer in humans or other mammals using pharmaceutical compositions comprising compounds having the structure of formula I and pharmaceutically acceptable salts thereof as referred to herein includes but is not limited to brain stem and sub-ocular gliomas, cerebellar and cerebral astrocytomas, ependymomas, and neuroectodermal and pineal tumors.
A method for treating tumors of female and male reproductive organs of a human or other mammals by using a pharmaceutical composition containing a compound having a structure of formula I and a pharmaceutically acceptable salt thereof, which is related to the application; tumors of the male reproductive organs that can be treated include, but are not limited to, prostate and testicular cancer; tumors of the female reproductive organs that can be treated include, but are not limited to, cervical, endometrial, ovarian, vaginal and vulvar cancers, as well as intrauterine tumors.
A method of treating cancer of the digestive tract in humans or other mammals, including but not limited to anal, colon, colorectal, esophageal, gastric, pancreatic, rectal, small bowel and salivary gland cancers, using a pharmaceutical composition comprising a compound having the structure of formula I and pharmaceutically acceptable salts thereof to which this application relates.
A method of treating urinary tract cancer in humans or other mammals, including but not limited to bladder, penile, kidney, renal pelvis, ureter and urinary tract cancer, using pharmaceutical compositions comprising compounds of formula I and pharmaceutically acceptable salts thereof to which this application is directed.
A method of treating ocular cancer in humans and other mammals using pharmaceutical compositions containing compounds having the structure of formula I and pharmaceutically acceptable salts thereof to which this application refers, which may be treated for diseases including but not limited to intraocular melanoma and retinoblastoma.
A method of treating liver cancer in humans and other mammals using pharmaceutical compositions containing compounds having the structure of formula I and pharmaceutically acceptable salts thereof to which this application refers includes but is not limited to hepatoma (hepatocellular carcinoma with or without fibroplasia), cholangiocarcinoma (intrahepatic cholangiocarcinoma) and mixed hepatocellular cholangiocarcinoma.
A method of treating skin cancer in humans or other mammals using pharmaceutical compositions containing compounds having the structure of formula I and pharmaceutically acceptable salts thereof as referred to herein includes but is not limited to squamous cell carcinoma, kaposi's sarcoma, malignant melanoma, merck's cell skin cancer, and non-melanoma cell cancer.
A method of treating head and neck cancer in humans or other mammals, including but not limited to, larynx, hypopharynx, nasopharynx, oropharynx cancers, and lip and oral cavity cancers, using a pharmaceutical composition comprising a compound having the structure of formula I and pharmaceutically acceptable salts thereof to which this application is directed.
A method of treating lymphomas in humans and other mammals, including but not limited to AIDS-related lymphomas, non-hodgkin's lymphomas, cutaneous T-cell lymphomas, systemic T-cell lymphomas, hodgkin's lymphomas, and central nervous system lymphomas, using pharmaceutical compositions comprising compounds having the structure of formula I and pharmaceutically acceptable salts thereof as contemplated herein.
A method of treating sarcomas in humans and other mammals, including but not limited to soft tissue sarcomas, osteosarcomas, malignant fibrous histiocytomas, lymphosarcomas, and rhabdomyosarcomas, using pharmaceutical compositions comprising compounds having the structure of formula I and pharmaceutically acceptable salts thereof as contemplated herein.
A method of treating leukemia in humans or other mammals using pharmaceutical compositions comprising compounds having the structure of formula I and pharmaceutically acceptable salts thereof as referred to herein includes, but is not limited to, acute myelogenous leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia. Dosage form and dosage range
The compounds of the present invention may be administered to a mammal, preferably a human, alone or in pharmaceutical compositions in combination with a pharmaceutically acceptable carrier, adjuvant or diluent, in accordance with standard pharmaceutical techniques. The compounds can be administered orally or subcutaneously, intramuscularly, intraperitoneally, intravenously, rectally, and topically, ocularly, pulmonarily, nasally, parenterally.
In one embodiment, the compound of formula I is administered to a patient for the treatment or control of cancer in a dosage range of 0.1 to 500 mg/day/kg body weight per oral administration. Suitable modes of administration are single daily administration or multiple administrations of two, three, four etc. times daily administration or administration using sustained release techniques. For large mammals, the preferred dosage range is 0.1-1500 mg/day/kg body weight. The dosage of the composition is 1-500 mg for patients with the average weight of 70 kg. For some particularly highly active compounds, the daily dose for adult patients may be as low as 0.1 mg/day.
In one embodiment, the compound having the structure shown in formula I is used for treating or controlling patients with cancers and the like, and the dosage of the compound is 0.1-500 mg/day/kg of body weight through intravenous injection. Suitable modes of administration are single daily administration or multiple administrations of two, three, four etc. times daily administration or administration using sustained release techniques. For large mammals, the preferred dosage range is 0.1-1500 mg/day/kg body weight. The dosage of the composition is 1-500 mg for patients with the average weight of 70 kg. For some particularly highly active compounds, the daily dose for adult patients may be as low as 0.1 mg/day.
Dosage forms
The pharmaceutical compositions according to the invention containing the active ingredient can be formulated in a form suitable for oral administration, for example as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard capsules, soft capsules, syrups or tinctures. Compositions intended for oral administration may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
Tablets contain the active ingredient in association with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These adjuvants may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents (granulation) and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn starch or alginic acid; binding agents such as starch, gelatin, polyvinylpyrrolidone or acacia; and lubricating agents such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or coated by known techniques to mask the unpleasant taste of the drug or to prolong disintegration and absorption in the gastrointestinal tract and thereby provide a drug effect that lasts longer. For example, water-soluble taste-masking materials such as hydroxypropyl-methylcellulose or hydroxypropylcellulose, or time-delay materials such as ethylcellulose, cellulose acetate butyrate may be used. Tablet dosage forms may be 0.1 mg/tablet, 0.2 mg/tablet, 0.25 mg/tablet, 0.5 mg/tablet, 1 mg/tablet, 2 mg/tablet, 5 mg/tablet, 10 mg/tablet, 25 mg/tablet, 50 mg/tablet, 100 mg/tablet, and 250 mg/tablet. Other dosage forms such as capsules and the like may be referred to for similar dosages.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, sodium carbonate or kaolin; or making into soft gelatin capsule, wherein the active ingredient is mixed with water soluble carrier such as polyethylene glycol or oily medium such as peanut oil, liquid paraffin or olive oil. Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such adjuvants are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, or acacia; the aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, for example sucrose, saccharin or aspartame. Oily suspensions may be prepared by suspending the active ingredient in a vegetable oil, for example arachis oil, sesame oil, coconut oil, or olive oil, or in a mineral oil such as liquid paraffin. Such oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
Sweetening agents such as those set forth above, and flavoring agents may be added to provide a formulation suitable for oral administration, and the compositions may be stored by the addition of antioxidants such as butylated hydroxyanisole or alpha-tocopherol.
Dispersible powders or granules are suitably prepared by adding water to prepare an aqueous suspension to provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are illustrated by the examples mentioned above. Other adjuvants such as sweetening, flavoring and coloring agents may also be present. These compositions can be stored by the addition of an antioxidant such as ascorbic acid.
The compositions of the present invention may be prepared in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, for example arachis oil or olive oil, or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifiers may be naturally occurring phosphatides, for example soy bean lecithin, and esters, or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with alkylene oxides, for example polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening agents, flavoring agents, antioxidants and preservatives.
Syrups and tinctures can be prepared using sweetening agents such as glycerin, propylene glycol, sorbitol, or sucrose. Such formulations may also contain humectants, flavoring agents, coloring agents, antioxidants, and preservatives.
The compositions of the present invention may be prepared as sterile injectable aqueous solutions. Among the acceptable vehicles and solvents, water, ringer's solution and isotonic sodium chloride solution may be employed.
The sterile injectable preparation can also be prepared as a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. For example, microemulsions are prepared by first dissolving the active ingredient in a mixture of soybean oil and lecithin, then placing the oil solution into a mixture of water and glycerin and treating.
Such pharmaceutical compositions may be in the form of sterile injectable solutions or oily suspensions for intramuscular or subcutaneous administration. Such suspensions may be formulated according to the known art using dispersing or wetting agents and suspending agents as mentioned above. The sterile injectable preparation may also be formulated as a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. In addition, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
Combination drug
The compounds of formula I may be combined with other drugs known to treat or ameliorate similar conditions. When the combination is administered, the mode of administration and the dosage of the original drug remain unchanged, while the compound of formula I is administered simultaneously, in advance or subsequently. When the compound of formula I is administered simultaneously with one or more other drugs, it is preferable to use a pharmaceutical composition containing both one or more known drugs and the compound of formula I. The pharmaceutical combination also includes administration of the compound of formula (la) in an overlapping time period with one or more other known drugs. When the compound of formula I is used in combination with one or more other drugs, the dose of the compound of formula I or known drug may be lower than the dose when they are administered alone.
Drugs or active ingredients that may be used in pharmaceutical combination with the compounds of formula I include, but are not limited to: cytotoxin/cytostatic agents, estrogen receptor modulators, androgen receptor modulators, retinal-like receptor modulators, antiproliferative agents, protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, angiogenesis inhibitors, cell proliferation and survival signal inhibitors, agents that interfere with cell cycle checkpoints and apoptosis inducers, cytotoxic agents, tyrosine protein inhibitors, EGFR inhibitors, VEGFR inhibitors, serine/threonine protein inhibitors, Bcr-Abl inhibitors, c-Kit inhibitors, Met inhibitors, Raf inhibitors, MEK inhibitors, MMP inhibitors, topoisomerase inhibitors, histone deacetylase inhibitors, proteasome inhibitors, CDK inhibitors, Bcl-2 family protein inhibitors, MDM2 family protein inhibitors, anti-proliferative agents, protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, angiogenesis inhibitors, cell proliferation and survival signal inhibitors, IAP family protein inhibitors, STAT family protein inhibitors, PI3K inhibitors, AKT inhibitors, COX-2 inhibitors, integrin blockers, P53 activators, VEGF antibodies, PD-1 antibodies, PD-L1 antibodies, PD-L2 antibodies, CTLA-4 antibodies, EGF antibodies and the like.
In one embodiment, agents that may be used in combination with the compounds of formula I include, but are not limited to: aldesleukin, alendronic acid, interferon, atrazine, allopurinol sodium, palonosetron hydrochloride, hexamethylmelamine, aminoglutethimide, amifostine, amrubicin, ambrolidine, anastrozole, dolasetron, aranesp, arglabin, arsenic trioxide, anoxin, 5-azacytidine, azathioprine, bacillus calmette, betamethasone acetate, betamethasone sodium phosphate, bexarotene, bleomycin sulfate, bromouroxime, bortezomib, busulfan, calcitonin, alezomab injection, capecitabine, carboplatin, liposomes, constantadine, cefesone, cemocludoxine, daunorubin, chlorambucil, cladribine, cyclophosphamide, cytarabine, dacarbazine, actinomycin D, daunomycin, deslimacide, deslimelin, estramustine phosphate, estramustine, 2-valproex, valprohexadine, dolac, dolichol, naltrex, dolichol, naltrexone, and other drugs, Delavodine, diethylstilbestrol, tolbutan, docetaxel, doxycycline, doxifluridine, doxorubicin, dronabinol, chitosan complex, latrexed, epirubicin hydrochloride, aprepitant, epirubicin, efletin, erythropoietin, eptaplatin, levamisole, estradiol formulations, 17-beta-estradiol, estramustine sodium phosphate, ethinylestradiol, hydroxyphosphoric acid, pirimid, etoposide, fadrozole, tamoxifen formulations, filgrastim, floxuridine, fluconazole, fludarabine, 5-fluorodeoxyuridine nucleoside phosphate, 5-fluorouracil, flumethisterone, flutamide, fulvestrant, 1-beta-D-arabinofuranose-5' -stearin phosphate, fotemustine, fulvestrant, valacystin, valacyclin, gemcitabine, gemtuzumab, gemfibrozil, gemma, gemtuzumab, gemfibrozil, gemma, and gemma, Imatinib, carmustine wafer capsule, goserelin, glanesilolone hydrochloride, histrelin, and meclizine, hydrocortisone, erythro-hydroxynonyladenine, hydroxyurea, tematopimox, idarubicin, ifosfamide, interferon alpha 2, interferon alpha-2A, interferon alpha-2B, interferon alpha-n 1, interferon alpha-n 3, interferon beta, interferon gamma-1 a, interleukin-2, intron A, iressa, irinotecan ketrey, lentinan sulfate, letrozole, leucovorin, leuprorelin acetate, levotetramisoimidazole, levofolinic acid calcium salt, levothyroxine sodium preparation, lomustine, lonidamine, dronabinol acetate, mecobalamin, medroxyprogesterone acetate, and mecobalamin, Megestrol acetate, melphalan, esterified estrogen, 6-mercaptopurine, mesna, methotrexate, aminolevulinate, miltefosine, milbemycin, mitomycin C, mitotane, mitoxantrone, trilobatin, trilostane, doxorubicin citrate liposome, nedaplatin, pegylated filgrastim, opulmkin, neupogogen, nilutamide, tamoxifen, NSC-631570, recombinant human interleukin 1-beta, octreotide, ondansetron hydrochloride, hydrocortisone oral solution, oxaliplatin, paclitaxel, docetaxel, cabazitaxel, prednisone sodium phosphate, pemetrexed, pentostatin, streptolysin, dermatan hydrochloride, pbroxburgh, plicamycin, phenam sodium, prednimustine, prednisone, seletesilon, bimetalone, procarbazine, human recombinant erythropoeitin, human erythropoietin, Raltitrexed, rivilex, rhenium-186 etidronate, rituximab, dygulme, dygulen-A, romopeptide, pilocarpine hydrochloride tablets, samostin, semustine, cilostan, oxybuzosin, sodium methylprednisolone, pamoic acid, streptozocin, strontium chloride-89, levothyroxine sodium, tamoxifen, tamsulosin, talloprone, tastilactone, temozolomide, teniposide, testosterone propionate, methyltestosterone, thioguanine, thiotepa, thyrotropin, tiludronic acid, topotecan, toremifene, tositumomab, trolizumab, trolsulvin, retinoic acid, methotrexate tablets, trimethamiltrazone, triptorelin acetate, pamidrin, trexaparidin, forskolin, vinblastine, vincristine, vinorelbine, vincristine, doxorubicin, forskolin, valtrerubicin, vincristine, vinorelbine, vincristine, trekkonectin, vinorelbine, trekkonectin, trexitin, trekkonectin, vinorelbine, trexitin, trekkonectin, trekkonetin, tretin, trekkonetin, tretin, trekkonetin, tretin, etc., and so, trekkonetin, etc., vinorelbine, vilulizine, dexpropinimine, stastin ester, pindoline, paclitaxel protein stable formulations, acolbifene, affinitak, aminopterin, azoxifene, ascorisil, atamestane, atrasentan, avastin, CCI-779, CDC-501, celebrex, cetuximab, clinacatto, cyproterone acetate, gemcitabine, doxorubicin-MTC, ibandronic acid, lanreotide, lasofoxifene, mirepredxifene, minodronate, liposomal MTP-PE, nafarelin, nolatrexed, paclitaxel polyglutamate, seocalcitol, erlotinib, paclitaxel liposome, tipifarnib, SAHA, tizamine, vapreotide, vatalanib, verteporteporfin, vinflunine, or combinations thereof.
The invention has the beneficial effects that: the furazan compound disclosed by the invention shows remarkable inhibitory activity on indoleamine 2,3-dioxygenase and nicotinamide phosphoribosyltransferase in an in vitro activity test experiment, can doubly inhibit biosynthesis of NAD + so as to inhibit growth and proliferation of tumor cells, can effectively promote proliferation of T cells so as to enhance the attack capability of organisms on the tumor cells, has remarkable anti-tumor activity, and is expected to become an anti-tumor medicament.
Detailed Description
In order to better illustrate the technical content of the present invention, the present invention is further described below with reference to specific examples, but the examples are not intended to limit the scope of the present invention.
Synthetic route for Compounds of general formula I (Synthesis of A series of Compounds)
Figure BDA0001691645820000231
Example 1
Preparation of (Z) -N- (2- ((4- (N- (3-bromo-4-fluorophenyl) -N' -hydroxyformamidyl) -1,2, 5-oxadiazol-3-yl) amino) ethyl) imidazo [1,2-a ] pyridine-6-carboxamide
(1) Preparation of (Z) -4-amino-N' -hydroxy-N- (3-bromo-4-fluorophenyl) -1,2, 5-oxadiazole-3-carboximidamide
Figure BDA0001691645820000241
To compound 1(5g,34.96mmol) was added dropwise acetic acid (5Ml), hydrochloric acid (4N) (5mL), NaNO in that order at 0 ℃2(2.42g, 34.96mmol) in water (5mL) and allowed to warm to room temperature for 18h, ethyl acetate (25mL) was added and the layers were separated and the aqueous layer was extracted with ethyl acetate(2X 25mL) and the organic phases were combined, washed with saturated brine (25mL), dried over anhydrous sodium sulfate and concentrated to give intermediate 2(4.5 g). To a solution of compound 2(4.5g) and 3-bromo-4-fluoroaniline (11.8g, 62.0mmol) in methanol (20ml) under nitrogen was added NaHCO3(7.8g, 93.0mmol) in water (20mL), at 50 ℃ for 12 hours, TLC check complete reaction, concentration, addition of ethyl acetate (20mL), separation of layers, extraction of the aqueous phase with ethyl acetate (2X 20mL), combination of organic phases, washing with saturated brine (20mL), drying over anhydrous sodium sulfate, concentration, column chromatography to give (Z) -4-amino-N- (4-bromo-3-fluorophenyl) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxylic acid (V-1) (7.32g, 75%). The hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.45(s,1H),8.83(s,1H),8.08(dd,J＝3.6,2.4Hz,1H),7.71(m,1H),7.60(t,J＝8.8Hz,1H),6.59(s,2H)ppm.
(2) preparation of (Z) -4- ((2-aminoethyl) amino) -N- (4-bromo-3-fluorophenyl) -N' -hydroxy-1, 2,5-1,2, 5-oxadiazole-3-carboximidamide (II-1)
Figure BDA0001691645820000242
Compound V-1(7g,22.2mmol) was dissolved in tetrahydrofuran, anhydrous potassium carbonate (9g,6.66mmol) and catalytic amount of KI were added, and a solution of N-Boc-2-chloroethylamine (4.0g,22.2mmol) in tetrahydrofuran was slowly added dropwise to the above solution with stirring at room temperature, and reacted at room temperature for 6 hours. After the reaction was completed, the reaction mixture was filtered, and the filtrate was concentrated and subjected to column chromatography to obtain a compound intermediate compound (7.12g, 70%). The intermediate compound (7.12g,15.6mol) was dissolved in ethyl acetate (20ml), and a saturated solution of HCl in ethyl acetate (10ml) was passed through to react at room temperature for 8 hours. After the reaction was complete, ethyl acetate extraction (30 ml. times.3) was carried out, the organic phases were combined and saturated NaHCO was used3The solution was washed (50ml), with brine (50ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed to give compound II-1(5.03g, 90%). its nmr hydrogen spectrum was:1H NMR(400MHz,DMSO):δ11.42(s,1H),8.85(s,1H),7.18(t,J＝8.8Hz,1H),7.10(dd,J＝3.2,2.8Hz,1H),6.76(m,1H),6.05(s,1H),3.22(s,2H),2.76(s,2H)ppm.
(3) preparation of (Z) -N- (2- ((4- (N- (3-bromo-4-fluorophenyl) -N' -hydroxyformamidyl) -1,2, 5-oxadiazol-3-yl) amino) ethyl) imidazo [1,2-a ] pyridine-6-carboxamide
Figure BDA0001691645820000251
Imidazole [1,2-a ]]Pyridine-6-carboxylic acid (50mg,0.28mmol) was dissolved in DCM, and II-1(100mg,0.28mmol), EDCI (91mg,0.48mmol), HOBt (47.25mg,0.35mmol), and triethylamine (0.07ml,0.48mmol) were added in that order, and the reaction was stirred at room temperature for 5 h. After the reaction was completed, water (20ml) was added, extraction was performed with ethyl acetate (20 ml. times.3), and the organic phases were combined and saturated NaHCO was used3The solution (10mL) was washed, saturated ammonium chloride solution (10mL) was washed, water (10mL) was washed, dried over anhydrous sodium sulfate, concentrated, and column-chromatographed to give the title compound (116mg, 85%).
The hydrogen spectrum of nuclear magnetic resonance is as follows: 1H NMR (400MHz, DMSO). delta.11.23 (s,1H),9.86(s,1H),8.74(s,1H),8.34(s,1H),7.67(d, J ═ 3.5Hz,1H),7.60(m,1H),7.44(s,2H),6.94(m,1H),6.78(m,1H),6.60(m,1H),6.05(s,1H),3.59-3.43(m,4H) ppm.
The carbon spectrum is as follows: 13C NMR (125MHz, DMSO). delta. 165.8,163.2,154.3,148.7,145.2,142.3,138.5,134.2,131.3,119.7,118.6,116.2,113.8,110.7,48.3,35.2.
The mass spectrum is as follows: MS (EI, M/z):503(M + +1).
Example 2
The difference from example 1 is that: (Z) -N- (2- ((4- (N- (3-bromo-4-fluorophenyl) -N' -hydroxymethylimidyl) -1,2, 5-oxadiazol-3-yl) amino) propyl) imidazo [1,2-a ] pyridine-6-carboxamide is prepared by replacing N-Boc-2-chloroethylamine in step (2) of the synthetic method with N-Boc-3-chloropropylamine as follows:
Figure BDA0001691645820000252
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.06(s,1H),9.86(s,1H),8.83(s,1H),8.44(s,1H),7.71(d,J＝3.6Hz,1H),7.65(m,1H),7.46(s,2H),6.93(m,1H),6.76(m,1H),6.64(m,1H),6.05(s,1H),3.35(m,2H),3.05(m,2H),1.93(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ165.8,1634.5,155.3,147.2,145.2,143.2,138.4,134.2,129.3,119.7,117.2,113.2,110.6,42.1,41.2,27.8.
the mass spectrum is as follows: MS (EI, M/z):517 (M)++1).
Example 3
The difference from example 1 is that: (Z) -N- (2- ((4- (N- (3-bromo-4-fluorophenyl) -N' -hydroxymethylimidyl) -1,2, 5-oxadiazol-3-yl) amino) butyl) imidazo [1,2-a ] pyridine-6-carboxamide is prepared by replacing N-Boc-2-chloroethylamine in step (2) of the synthetic method with N-Boc-4-chlorobutylamine:
Figure BDA0001691645820000261
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.06(s,1H),9.83(s,1H),8.79(s,1H),8.44(s,1H),7.91(d,J＝3.5Hz,1H),7.71(m,1H),7.37(s,2H),6.86(m,1H),6.78(m,1H),6.56(m,1H),6.06(s,1H),3.25(m,2H),3.05(m,2H),1.50-1.48(m,4H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ167.8,163.5,155.2,153.3,148.7,147.2,145.2,143.2,134.4,133.2,129.3,119.2,118.6,117.2,116.7,114.2,110.2,42.1,39.2,27.8,26.1.
the mass spectrum is as follows: MS (EI, M/z):531 (M)++1).
Example 4
The difference from example 1 is that: (Z) -N- (2- ((4- (N- (3-bromo-4-fluorophenyl) -N' -hydroxymethylimidyl) -1,2, 5-oxadiazol-3-yl) amino) pentyl) imidazole [1,2-a ] pyridine-6-carboxamide is prepared by replacing N-Boc-2-chloroethylamine in the step (2) of the synthetic method with N-Boc-5-chloropentylamine and has the following structural formula:
Figure BDA0001691645820000262
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.06(s,1H),9.86(s,1H),8.89(s,1H),8.31(s,1H),7.78(d,J＝3.5Hz,1H),7.61(m,1H),7.47(s,2H),6.96(m,1H),6.94(m,1H),6.82(m,1H),6.62(m,1H),6.06(s,1H),3.25-3.20(m,4H),1.60-1.57(m,4H),1.32(s,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ165.8,163.3,155.1,153.2,147.8,146.2,145.0,143.4,134.7,133.2,129.2,118.7,117.6,113.2,108.6,42.1,39.2,31.2,29.8,23.1.
the mass spectrum is as follows: MS (EI, M/z):545 (M)++1).
Example 5
The difference from example 1 is that: (Z) -N- (2- ((4- (N- (3-bromo-4-fluorophenyl) -N' -hydroxymethylimidyl) -1,2, 5-oxadiazol-3-yl) amino) hexyl) imidazo [1,2-a ] pyridine-6-carboxamide is prepared by replacing N-Boc-2-chloroethylamine in step (2) of the synthetic method with N-Boc-6-chlorohexylamine, and has the following structural formula:
Figure BDA0001691645820000271
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.06(s,1H),9.88(s,1H),8.79(s,1H),8.41(s,1H),7.81(d,J＝3.5Hz,1H),7.70(m,1H),7.37(s,1H),6.96(m,1H),6.48(m,1H),6.36(m,1H),3.32-3.27(m,4H),1.60-1.57(m,4H),1.32(s,2H),1.20(s,2H)ppm.
the carbon spectrum is as follows: δ 167.8,164.5,156.7, 153.3,148.7,147.2,145.2,135.4,129.3,118.7,117.2,115.2,107.6,42.1,41.2,30.5,27.8,26.2.
The mass spectrum is as follows: MS (EI, M/z):585 (M)++1).
Example 6
The difference from example 1 is that: (Z) -N- (2- ((4- (N- (3-bromo-4-fluorophenyl) -N' -hydroxyformamidyl) -1,2, 5-oxadiazol-3-yl) amino) heptyl) imidazo [1,2-a ] pyridine-6-carboxamide is prepared by replacing N-Boc-2-chloroethylamine in step (2) of the synthetic method with N-Boc-7-chloroheptylamine, and has the following structural formula:
Figure BDA0001691645820000272
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.06(s,1H),9.88(s,1H),8.63(s,1H),8.31(s,1H),7.79(d,J＝3.7Hz,1H),7.65(m,1H),7.47(s,2H),6.94(m,1H),6.86(m,1H),6.67(m,1H),6.05(s,1H),3.38-3.23(m,4H),1.63-1.59(m,4H),1.36-1.28(m,6H)ppm.
the carbon spectrum is as follows:13C NMR(400MHz,DMSO):δ165.8,163.5,154.8,152.3,147.8,145.2,143.2,138.4,134.3,130.4,119.8,118.3,117.2,116.5,114.2,110.9,43.2,41.2,31.3,30.5,27.8,26.2,23.5.
the mass spectrum is as follows: MS (EI, M/z):573 (M)++1).
Example 7
The difference from example 1 is that: replacing 3-bromo-4-fluoroaniline in the step (1) of the synthesis method with 4-fluoroaniline, and obtaining (Z) -N- (2- ((4- (N- (4-fluorophenyl) -N' -hydroxymethylamino) -1,2, 5-oxadiazol-3-yl) amino) ethyl) imidazo [1,2-a ] pyridine-6-carboxamide having the following structural formula:
Figure BDA0001691645820000281
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.14(s,1H),9.87(s,1H),8.64(s,1H),8.34(s,1H),7.71(d,J＝3.5Hz,1H),7.60(m,1H),7.48(s,2H),6.90(m,2H),6.75(m,2H),6.08(s,1H),3.56-3.42(m,4H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ165.8,163.5,157.3,152.9,147.3,145.2,138.5,134.8,134.0,133.3,129.6,120.2,116.8,115.2,48.3,37.2.
the mass spectrum is as follows: MS (EI, M/z):425 (M)++1).
Example 8
The difference from example 1 is that: the structural formula of the (Z) -N- (2- ((4- (N- (4-fluorophenyl) -N' -hydroxymethyl imidyl) -1,2, 5-oxadiazol-3-yl) amino) propyl) imidazole [1,2-a ] pyridine-6-carboxamide prepared by replacing 3-bromo-4-fluoroaniline in the step (1) of the synthetic method with 4-fluoroaniline and replacing N-Boc-2-chloroethylamine in the step (2) with N-Boc-3-chloropropylamine is as follows:
Figure BDA0001691645820000282
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.14(s,1H),9.87(s,1H),8.78(s,1H),8.43(s,1H),7.79(d,J＝3.6Hz,1H),7.65(m,1H),7.45(s,2H),6.87(m,2H),6.54(m,2H),6.05(s,1H),3.54(m,2H),3,18(m,2H),1.85(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ166.8,164.5,152.3,147.6,145.2,144.3,140.9,138.2,135.2,133.3,128.0,125.2,122.7,118.3,114.2,112.5,110.6,46.3,45.2,29.8.
the mass spectrum is as follows: MS (EI, M/z):439 (M)++1).
Example 9
The difference from example 1 is that: the structural formula of the (Z) -N- (2- ((4- (N- (4-methoxy-2-fluorophenyl) -N' -hydroxymethyl imidyl) -1,2, 5-oxadiazole-3-yl) amino) ethyl) imidazole [1,2-a ] pyridine-6-formamide prepared by replacing 3-bromo-4-fluoroaniline in the step (1) of the synthesis method with 4-methoxy-2-fluoroaniline is as follows:
Figure BDA0001691645820000291
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ10.64(s,1H),9.75(s,1H),8.76(s,1H),8.67(s,1H),7.71(d,J＝3.8Hz,1H),7.64(m,1H),7.32(s,2H),6.93(m,1H),6.72(m,1H),6.32(m,1H),6.05(s,1H),3.82(s,3H),3.44-3.34(m,4H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ165.8,164.5,159.3,153.6,149.2,147.9,145.1,138.2,135.2,130.3,118.0,116.2,114.9,110.7,104.3,56.3,48.6,39.8.
the mass spectrum is as follows: MS (EI, M/z):455 (M)++1).
Example 10
The difference from example 1 is that: the structural formula of the (Z) -N- (2- ((4- (N- (4-methoxy-2-fluorophenyl) -N' -hydroxymethyl imidyl) -1,2, 5-oxadiazole-3-yl) amino) propyl) imidazole [1,2-a ] pyridine-6-formamide prepared by replacing 3-bromo-4-fluoroaniline in the step (1) of the synthesis method with 4-methoxy-2-fluoroaniline and replacing N-Boc-2-chloroethylamine in the step (2) with N-Boc-3-chloropropylamine is as follows:
Figure BDA0001691645820000292
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ10.54(s,1H),9.85(s,1H),8.79(s,1H),8.63(s,1H),7.61(d,J＝3.5Hz,1H),7.64(m,1H),7.41(s,2H),6.95(m,1H),6.72(m,1H),6.52(m,1H),6.07(s,1H),3.67(s,3H),3.34(m,2H),3.12(m,2H),1.75(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ165.8,163.5,159.3,153.2,149.0,147.2,145.9,138.2,136.2,130.3,118.6,114.2,105.9,55.8,41.8,39.8,28.8.
the mass spectrum is as follows: MS (EI, M/z):469 (M)++1).
Example 11
The difference from example 1 is that: the structural formula of the (Z) -N- (2- ((4- (N' -hydroxy-N- (4- (2-methoxyethoxy) phenyl) imidyl) -1,2, 5-oxadiazol-3-yl) amino) ethyl) imidazole [1,2-a ] pyridine-6-carboxamide prepared by replacing 3-bromo-4-fluoroaniline in the step (1) of the synthesis method with 4- (2-methoxyethoxy) aniline is as follows:
Figure BDA0001691645820000301
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.04(s,1H),9.85(s,1H),8.73(s,1H),8.38(s,1H),7.89-7.84(m,3H),7.61(m,1H),7.55(s,2H),6.53(m,2H),6.05(s,1H),3.75(s,3H),4.31(m,2H),3.79(m,2H),3.50(m,2H),3.43(m,3H),3.23(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ165.8,163.5,152.3,149.3,147.6,145.2,138.2,135.2,130.3,128.0,116.3,115.2,114.7,76.3,69.8,57.5,46.7,39.2.
the mass spectrum is as follows: MS (EI, M/z):481 (M)++1).
Example 12
The difference from example 1 is that: the structural formula of (Z) -N- (2- ((4- (N' -hydroxy-N- (4- (2-methoxyethoxy) phenyl) cimetidyl) -1,2, 5-oxadiazol-3-yl) amino) propyl) imidazo [1,2-a ] pyridine-6-carboxamide prepared by substituting 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with 4- (2-methoxyethoxy) aniline and N-Boc-2-chloroethylamine in step (2) with N-Boc-3-chloropropylamine is as follows:
Figure BDA0001691645820000302
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.14(s,1H),9.88(s,1H),8.68(s,1H),8.34(s,1H),7.79-7.74(m,3H),7.51(m,1H),7.45(s,2H),6.54(m,2H),6.05(s,1H),4.34(m,2H),3.85(s,3H),3.69(m,2H),3.52-3.44(m,5H),3.23(m,2H),1.83(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ165.8,163.5,152.3,149.3,147.6,145.2,138.2,135.2,130.3,128.0,116.3,115.2,114.7,79.3,69.8,59.5,41.7,39.2,27.6.
the mass spectrum is as follows: MS (EI, M/z):495 (M)++1).
Example 13
The difference from example 1 is that: the structural formula of (Z) -N- (2- ((4- (N- (3, 5-dimethoxy) -N' -hydroxyformamidyl) -1,2, 5-oxadiazol-3-yl) amino) ethyl) imidazo [1,2-a ] pyridine-6-carboxamide prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic method with 3, 5-dimethoxyaniline is as follows:
Figure BDA0001691645820000311
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.07(s,1H),9.88(s,1H),8.78(s,1H),8.63(s,1H),7.79(d,J＝3.5Hz,1H),7.65(m,1H),7.48(s,2H),6.12(s,2H),6.07(s,1H),5.86(s,1H),3.84(s,6H),3.52-3.46(m,4H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ165.8,163.5,159.3,152.0,148.1,147.3,146.2,134.2,116.2,114.5,97.2,90.3,56.3,47.1,39.8.
the mass spectrum is as follows: MS (EI, M/z):467 (M)++1).
Example 14
The difference from example 1 is that: the structural formula of the (Z) -N- (2- ((4- (N- (3, 5-dimethoxy) -N' -hydroxymethylimidyl) -1,2, 5-oxadiazol-3-yl) amino) ethyl) imidazo [1,2-a ] pyridine-6-carboxamide prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic method with 3, 5-dimethoxyaniline and N-Boc-2-chloroethylamine in step (2) with N-Boc-3-chloropropylamine is as follows:
Figure BDA0001691645820000312
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.07(s,1H),9.78(s,1H),8.76(s,1H),8.63(s,1H),7.71(d,J＝3.5Hz,1H),7.67(m,1H),7.41(m,2H),6.23(s,2H),6.05(s,1H),5.75(s,1H),3.84(s,6H),3.52(m,2H),3.20(m,2H),1.86(s,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ165.2,162.5,160.3,153.2,148.9,147.0,146.2,136.2,117.2,113.5,98.2,92.3,46.3,39.8.
the mass spectrum is as follows: MS (EI, M/z):481 (M)++1).
Example 15
The difference from example 1 is that: the structural formula of (Z) -N- (2- ((4- (N- (2-fluoro-4- (4-pyridin-yloxy) -N' -hydroxyformamido) -1,2, 5-oxadiazol-3-yl) amino) ethyl) imidazo [1,2-a ] pyridine-6-carboxamide prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with 2-fluoro-4- (4-pyridyloxy) aniline is as follows:
Figure BDA0001691645820000321
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ10.57(s,1H),9.82(s,1H),8.73(s,1H),8.67(s,1H),8.38(d,J＝6.5Hz,2H),7.78(d,J＝3.5Hz,1H),7.60(m,1H),7.48(s,2H),7.05(m,2H),6.78(m,1H),6.61(m,1H),6.32(m,1H),6.05(s,1H),3.50-3.47(m,4H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ167.8,163.5,158.2,152.3,149.4,147.9,146.2,145.0,136.2,134.2,132.5,123.4,118.8,116.3,115.4,114.5,110.2,102.3,48.1,37.8.
the mass spectrum is as follows: MS (EI, M/z):518 (M)++1).
Example 16
The difference from example 1 is that: (Z) -N- (2- ((4- (N- (2-fluoro-4- (4-pyridin-yloxy) -N' -hydroxyformamido) -1,2, 5-oxadiazol-3-yl) amino) propyl) imidazo [1,2-a ] pyridine-6-carboxamide is prepared by substituting 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with 2-fluoro-4- (4-pyridyloxy) aniline and N-Boc-2-chloroethylamine in step (2) with N-Boc-3-chloropropylamine as and has the following structural formula:
Figure BDA0001691645820000322
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ10.59(s,1H),9.88(s,1H),8.89(s,1H),8.63(s,1H),8.41(d,J＝6.7Hz,2H),7.77(d,J＝3.7Hz,1H),7.63(m,1H),7.45(m,2H),7.05(m,2H),6.83(m,1H),6.61(m,1H),6.34(m,1H),6.05(s,1H),3.54(m,2H),3.47(m,2H),1.78(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ165.8,163.5,159.2,152.3,148.4,147.9,147.3,137.2,134.2,132.5,124.7,117.8,115.5,111.2,103.3,42.3,27.8.
the mass spectrum is as follows: MS (EI, M/z):532 (M)++1).
Example 17
The difference from example 1 is that: (Z) -N- (2- ((4- (N- (4- ((2-aminopyridin-4-yl) oxy) -2-fluorophenyl) -N' -hydroxyformami-dine) -1,2, 5-oxadiazol-3-yl) amino) ethyl) imidazole [1,2-a ] pyridine-6-carboxamide is prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic method with 4- (4-amino-3-fluorophenoxy) pyridin-2-amine and has the following structural formula:
Figure BDA0001691645820000331
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ10.59(s,1H),9.88(s,1H),8.79(s,1H),8.63(s,1H),7.83(m,1H),7.75(m,1H),7.65(m,2H),7.48(s,2H),6.83-6.80(m,2H),6.61(m,1H),6.32(s,1H),6.05(s,1H),5.80(s,1H),3.50-3.43(m,4H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ165.7,163.6,158.2,152.3,148.4,148.0,146.3,145.8,138.2,134.2,129.7,123.8,118.8,116.3,115.2,111.3,110.5,101.3,95.4,47.2,39.8.
the mass spectrum is as follows: MS (EI, M/z):533 (M)++1).
Example 18
The difference from example 1 is that: by substituting 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with 4- (4-amino-3-fluorophenoxy) pyridin-2-amine and N-Boc-2-chloroethylamine in step (2) with N-Boc-3-chloropropylamine, the resulting (Z) -N- (2- ((4- (N- (4- ((2-aminopyridin-4-yl) oxy) -2-fluorophenyl) -N' -hydroxymethylimidazole) -1,2, 5-oxadiazol-3-yl) amino) propyl) imidazo [1,2-a ] pyridine-6-carboxamide has the following structural formula:
Figure BDA0001691645820000332
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ10.56(s,1H),9.87(s,1H),8.86(s,1H),8.63(s,1H),7.98(m,1H),7.79(m,1H),7.65(m,2H),7.45(s,2H),6.79-6.73(m,2H),6.51(m,1H),6.42(s,1H),6.05(s,1H),5.76(s,1H),3.56(m,2H),3.43(m,2H),1.67(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ165.8,163.3,159.2,152.3,149.7,148.1,147.3,146.8,145.2,138.6,134.8,134.0,130.7,123.8,117.9,116.8,115.2,114.3,110.3,101.3,97.4,41.2,39.8,27.7.
the mass spectrum is as follows: MS (EI, M/z):547 (M)++1).
Example 19
The difference from example 1 is that: the structural formula of (Z) -N- (2- ((4- (N- (2-fluoro-4- ((2- (methylcarbamoyl) pyridin-4-yl) oxy) phenyl) -N' -hydroxymethylimidazole) -1,2, 5-oxadiazol-3-yl) amino) ethyl) imidazole [1,2-a ] pyridine-6-carboxamide prepared by substituting 3-bromo-4-fluoroaniline in step (1) of the synthetic method with 4- (4-amino-3-fluorophenoxy) -N-methylpyridinamide is as follows:
Figure BDA0001691645820000341
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ10.52(s,1H),9.88(s,1H),8.86(s,1H),8.63(m,1H),8.09-7.98(m,2H),7.76(d,J＝3.5Hz,1H),7.63-7.60(m,2H),7.53(s,2H),6.82(m,1H),6.61(m,1H),6.32(m,1H),6.05(s,1H),3.51-3.42(m,4H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ165.7,164.6,163.1,160.2,158.2,152.4,151.5,147.3,146.8,145.1,138.2,134.2,130.7,123.7,118.8,116.3,115.7,114.3,113.2,110.3,109.4,48.2,39.8,26.3.
the mass spectrum is as follows: MS (EI, M/z):575 (M)++1).
Example 20
The difference from example 1 is that: by substituting 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with 4- (4-amino-3-fluorophenoxy) -N-methylpyridinamide and N-Boc-2-chloroethylamine in step (2) with N-Boc-3-chloropropylamine, the formula of (Z) -N- (2- ((4- (N- (2-fluoro-4- ((2- (methylcarbamoyl) pyridin-4-yl) oxy) phenyl) -N' -hydroxymethylimid) -1,2, 5-oxadiazol-3-yl) amino) propyl) imidazo [1,2-a ] pyridine-6-carboxamide is as follows:
Figure BDA0001691645820000342
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ10.53(s,1H),9.86(s,1H),8.88(s,1H),8.64(m,1H),8.09-7.98(m,2H),7.71(d,J＝3.6Hz,1H),7.65-7.62(m,2H),7.53(s,1H),6.83(m,1H),6.56(m,1H),6.32(m,1H),6.05(s,1H),3.35(m,2H),3.15(m,2H),1.73(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ165.8,164.8,163.1,158.2,158.2,152.4,149.5,148.1,146.8,145.4,138.2,134.1,130.0,123.7,117.8,116.3,115.4,113.7,112.3,109.4,42.2,39.2,28.8,26.3.
the mass spectrum is as follows: MS (EI, M/z):589(M + +1).
Example 21
The difference from example 1 is that: the structural formula of (Z) -N- (2- ((4- (N- (4-cyclopentylphenyl) -N' -hydroxyformamidyl) -1,2, 5-oxadiazol-3-yl) amino) ethyl) imidazo [1,2-a ] pyridine-6-carboxamide prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic method with 4-cyclopentylaniline is as follows:
Figure BDA0001691645820000351
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.06 5(s,1H),9.87(s,1H),8.78(s,1H),8.61(s,1H),7.79(d,J＝3.5Hz,1H),7.60(m,1H),7.48(s,2H),6.95(m,2H),6.87(m,2H),6.05(s,1H),3.52-3.47(m,4H),2.75(m,1H),1.73-1.68(m,8H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ165.8,163.5,152.6,147.3,145.1,138.2,136.2,134.3,130.5,127.2,116.0,115.8,114.3,48.3,45.2,39.8,34.5,25.1.
the mass spectrum is as follows: MS (EI, M/z):475 (M)++1).
Example 22
The difference from example 1 is that: the structural formula of (Z) -N- (2- ((4- (N- (4-cyclopentylphenyl) -N' -hydroxymethylimidyl) -1,2, 5-oxadiazol-3-yl) amino) propyl) imidazo [1,2-a ] pyridine-6-carboxamide is as follows, prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic method with 4-cyclopentylaniline and N-Boc-2-chloroethylamine in step (2) with N-Boc-3-chloropropylamine:
Figure BDA0001691645820000352
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.06(s,1H),9.88(s,1H),8.89(s,1H),8.61(s,1H),7.71(d,J＝3.5Hz,1H),7.53(m,1H),7.48(s,2H),6.95(m,2H),6.87(m,2H),6.05(s,1H),3.52(m,2H),3.22(m,2H),2.79(m,1H),1.93-1.68(m,10H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ165.8,163.5,152.3,147.3,138.6,137.2,134.8,134.2,129.6,127.6,116.0,115.8,113.3,46.3,42.8,39.8,34.6,28.5,25.1.
the mass spectrum is as follows: MS (EI, M/z):489 (M)++1).
Example 23
The difference from example 1 is that: replacing 3-bromo-4-fluoroaniline in the step (1) of the synthesis method with 4-isopropylaniline, and obtaining (Z) -N- (2- ((4- (N- (4-isopropylphenyl) -N' -hydroxyformamidyl) -1,2, 5-oxadiazol-3-yl) amino) ethyl) imidazole [1,2-a ] pyridine-6-carboxamide with the following structural formula:
Figure BDA0001691645820000361
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.06(s,1H),9.87(s,1H),8.84(s,1H),8.67(s,1H),7.71(d,J＝3.5Hz,1H),7.60(m,1H),7.48(s,2H),6.95(m,2H),6.67(m,2H),6.05(s,1H),3.52-3.47(m,4H),2.75(m,1H),1.23(d,J＝6.5Hz,6H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ165.8,163.5,152.3,147.6,145.2,138.2,134.3,132.5,130.3,129.6,126.2,116.3,116.0,114.5,48.3,39.8,33.2,23.1.
the mass spectrum is as follows: MS (EI, M/z):449 (M)++1).
Example 24
The difference from example 1 is that: replacing 3-bromo-4-fluoroaniline in the step (1) of the synthesis method with 4-isopropylaniline, replacing N-Boc-2-chloroethylamine in the step (2) with N-Boc-3-chloropropylamine, and obtaining (Z) -N- (2- ((4- (N- (4-isopropylphenyl) -N' -hydroxymethylimidyl) -1,2, 5-oxadiazol-3-yl) amino) propyl) imidazole [1,2-a ] pyridine-6-carboxamide with the following structural formula:
Figure BDA0001691645820000362
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.16(s,1H),9.88(s,1H),8.89(s,1H),8.66(s,1H),7.71(d,J＝3.5Hz,1H),7.53(t,J＝5.0Hz,1H),7.44(s,2H),6.98(m,2H),6.63(m,2H),6.05(s,1H),3.50(m,2H),3.25(m,2H),2.75(m,1H),1.87(m,2H),1.20(d,J＝6.5Hz,6H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ165.9,163.5,152.3,148.6,147.1,138.7,138.0,134.3,132.5,129.6,126.2,116.0,114.2,42.3,39.2,33.2,28.5,23.1.
the mass spectrum is as follows: MS (EI, M/z):463 (M)++1).
Example 25
The difference from example 1 is that: the structural formula of the (Z) -N- (2- ((4- (N- (2, 5-dimethylphenyl) -N' -hydroxyformamidyl) -1,2, 5-oxadiazol-3-yl) amino) ethyl) imidazole [1,2-a ] pyridine-6-carboxamide prepared by replacing 3-bromo-4-fluoroaniline in the step (1) of the synthesis method with 3, 5-dimethylaniline is as follows:
Figure BDA0001691645820000371
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.06(s,1H),9.87(s,1H),8.85(s,1H),8.53(s,1H),7.71(d,J＝3.5Hz,1H),7.50(t,J＝4.6Hz,1H),7.48(s,2H),6.85(t,J＝5.6Hz,1H),6.57(s,2H),6.05(s,1H),3.50-3.45(m,4H),2.75(s,6H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ165.8,163.1,150.6,147.1,145.2,144.3,139.2,138.2,134.3,132.5,120.7,117.3,116.5,114.3,49.3,39.7,21.1.
the mass spectrum is as follows: MS (EI, M/z):435 (M)++1).
Example 26
The difference from example 1 is that: the structural formula of the (Z) -N- (2- ((4- (N- (2, 5-dimethylphenyl) -N' -hydroxyimidyl) -1,2, 5-oxadiazol-3-yl) amino) propyl) imidazole [1,2-a ] pyridine-6-carboxamide prepared by replacing 3-bromo-4-fluoroaniline in the step (1) of the synthetic method with 3, 5-dimethylaniline and replacing N-Boc-2-chloroethylamine in the step (2) with N-Boc-3-chloropropylamine is as follows:
Figure BDA0001691645820000372
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.06(s,1H),9.88(s,1H),8.77(s,1H),8.63(s,1H),7.78(d,J＝3.8Hz,1H),7.43(t,J＝4.6Hz,1H),7.32(s,2H),6.88(t,J＝5.8Hz,1H),6.53(m,2H),6.05(s,1H),3.45(m,2H),3.10(m,2H),2.78(s,6H),1.83(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ165.2,164.1,149.6,148.0,146.2,143.7,138.7,136.2,134.3,132.5,121.7,118.0,116.3,114.2,42.3,38.7,29.7,21.1.
the mass spectrum is as follows: MS (EI, M/z):449 (M)++1).
Example 27
The difference from example 1 is that: the structural formula of the (Z) -N- (2- ((4- (N- (4-methyl-2, 5-bistrifluoromethylphenyl) -N' -hydroxyformamido) -1,2, 5-oxadiazol-3-yl) amino) ethyl) imidazo [1,2-a ] pyridine-6-carboxamide prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic method with 4-methyl-3, 5-trifluoromethylaniline is as follows:
Figure BDA0001691645820000381
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.06(s,1H),9.88(s,1H),8.83(s,1H),8.73(s,1H),8.61(s,1H),7.77(d,J＝3.7Hz,1H),7.53(t,J＝4.6Hz,1H),7.43(s,2H),7.03(s,2H),6.05(s,1H),3.50-3.45(m,4H),2.18(s,3H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ166.8,163.1,150.6,148.1,145.3,142.5,136.2,134.3,134.0,132.5,128.6,123.2,118.3,116.2,115.6,114.1,48.3,38.1,15.2.
the mass spectrum is as follows: MS (EI, M/z):557 (M)++1).
Example 28
The difference from example 1 is that: the structural formula of (Z) -N- (2- ((4- (N- (4-methyl-2, 5-bistrifluoromethylphenyl) -N' -hydroxymethylimidyl) -1,2, 5-oxadiazol-3-yl) amino) propyl) imidazo [1,2-a ] pyridine-6-carboxamide prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with 4-methyl-3, 5-trifluoromethylaniline and replacing N-Boc-2-chloroethylamine in step (2) with N-Boc-3-chloropropylamine is as follows:
Figure BDA0001691645820000382
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.05(s,1H),9.78(s,1H),8.77(s,1H),8.36(s,1H),7.65(d,J＝3.7Hz,1H),7.49(t,J＝4.6Hz,1H),7.48(s,2H),7.03(s,2H),6.05(s,1H),3.35(m,2H),3.10(m,2H),2.13(s,3H),1.78(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ165.8,163.2,152.3,147.6,145.0,142.1,138.2,134.3,132.5,129.5,128.7,123.2,118.0,117.3,115.2,112.3,42.3,38.9,28.7,16.1.
the mass spectrum is as follows: MS (EI, M/z):571 (M)++1).
Example 29
The difference from example 1 is that: the structural formula of (Z) -N- (2- ((4-N- (4- (1H-pyrazol-1-yl) phenyl-N' -hydroxymethyl) -1,2, 5-oxadiazol-3-yl) amino) ethyl) imidazo [1,2-a ] pyridine-6-carboxamide prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic method with 4- (1H-pyrazol-1-yl) aniline is as follows:
Figure BDA0001691645820000391
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.06(s,1H),9.88(s,1H),8.83(s,1H),8.41(s,1H),7.98(m,1H),7.87(m,1H),7.71(d,J＝3.7Hz,1H),7.53-7.46(m,5H),6.80(s,2H),6.46(t,J＝3.4Hz,1H),6.05(s,1H),3.55-3.47(m,4H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ165.8,163.1,152.3,147.3,145.5,141.2,138.6,135.2,134.3,134.0,132.2,129.6,126.8,120.7,116.3,114.3,108.6,48.3,39.6.
the mass spectrum is as follows: mS(EI,m/z):473(M++1).
Example 30
The difference from example 1 is that: (Z) -N- (2- ((4-N- (4- (1H-pyrazol-1-yl) phenyl-N' -hydroxymethyl) -1,2, 5-oxadiazol-3-yl) amino) propyl) imidazo [1,2-a ] pyridine-6-carboxamide is prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with 4- (1H-pyrazol-1-yl) aniline and N-Boc-2-chloroethylamine in step (2) with N-Boc-3-chloropropylamine, and has the following structural formula:
Figure BDA0001691645820000392
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.26(s,1H),9.89(s,1H),8.93(s,1H),8.52(s,1H),7.98(m,1H),7.87(m,1H),7.76(d,J＝3.7Hz,1H),7.53-7.46(m,5H),6.68(s,2H),6.42(d,J＝3.6Hz,1H),6.15(s,1H),3.45(m,2H),3.27(m,2H),1.89(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ164.8,162.1,152.6,147.5,145.3,142.5,138.2,135.3,134.5,133.2,130.7,128.6,126.7,123.2,118.3,116.6,109.0,42.9,39.8,26.1.
the mass spectrum is as follows: MS (EI, M/z):487 (M)++1).
Example 31
The only steps with the embodiment are as follows: the structural formula of (Z) -N- (2- ((4- (N- (4- ((furan-2-ylmethyl) carbamoyl) phenyl) -N' -hydroxymethylimidazole) -1,2, 5-oxadiazol-3-yl) amino) ethyl) imidazo [1,2-a ] pyridine-6-carboxamide prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with 4-amino-N- (furan-2-ylmethyl) aniline is as follows:
Figure BDA0001691645820000401
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.06(s,1H),9.88(s,1H),8.83(s,1H),8.79(s,1H),7.79(d,J＝3.7Hz,1H),7.55-7.58(m,6H),6.97(m,2H),6.38-6.34(m,2H),6.05(s,1H),4.85(s,1H),3.50-3.48(m,4H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ167.8,165.3,163.1,152.6,147.3,145.2,145.1,143.5,142.1,141.0,138.6,134.8,134.0,129.6,118.6,116.3,113.2,110.5,109.3,48.3,39.6,35.4.
the mass spectrum is as follows: MS (EI, M/z):530 (M)++1).
Example 32
The difference from example 1 is that: (Z) -N- (2- ((4- (N- (4- ((furan-2-ylmethyl) carbamoyl) phenyl) -N' -hydroxymethylimidazole) -1,2, 5-oxadiazol-3-yl) amino) propyl) imidazole [1,2-a ] pyridine-6-carboxamide is prepared by substituting 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with 4-amino-N- (furan-2-ylmethyl) aniline and N-Boc-2-chloroethylamine in step (2) with N-Boc-3-chloropropylamine as follows:
Figure BDA0001691645820000402
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.08(s,1H),9.76(s,1H),8.83(s,1H),8.76(s,1H),7.68(d,J＝4.0Hz,1H),7.56-7.52(m,6H),6.93(m,2H),6.37-6.35(m,2H),6.08(s,1H),4.79(s,1H),3.35(m,2H),3.15(m,2H),1.75(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ167.8,165.6,163.1,153.2,147.1,145.3,143.6,142.9,141.4,138.8,134.8,131.3,118.6,116.4,114.1,112.0,110.3,42.3,39.6,34.5,25.4.
the mass spectrum is as follows: MS (EI, M/z):544 (M)++1).
Example 33
The difference from example 1 is that: (Z) -N- (2- ((4- (N- (4- (butylcarbamoyl) phenyl) -N' -hydroxymethylimidazole) -1,2, 5-oxadiazol-3-yl) amino) ethyl) imidazo [1,2-a ] pyridine-6-carboxamide is prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with 4-amino-N-butylbenzamide and has the following structural formula:
Figure BDA0001691645820000411
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.08(s,1H),9.76(s,1H),8.83(s,1H),8.76(s,1H),8.69(s,1H),7.71(d,J＝4.0Hz,1H),7.55-7.52(m,5H),6.97(m,2H),6.08(s,1H),3.50(m,2H),3.32-3.30(m,4H),1.57(m,2H),1.32(m,2H),1.08(m,3H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ166.8,165.6,163.1,152.3,147.0,145.2,142.3,138.7,133.9,132.3,129.2,126.2,119.6,115.1,114.3,48.3,38.7,32.1,20.1,15.4.
the mass spectrum is as follows: MS (EI, M/z):506 (M)++1).
Example 34
The difference from example 1 is that: (Z) -N- (2- ((4- (N- (4- (butylcarbamoyl) phenyl) -N' -hydroxymethylimidazole) -1,2, 5-oxadiazol-3-yl) amino) propyl) imidazo [1,2-a ] pyridine-6-carboxamide is prepared by substituting 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with 4-amino-N-butylbenzamide and N-Boc-2-chloroethylamine in step (2) with N-Boc-3-chloropropylamine, and has the following structural formula:
Figure BDA0001691645820000412
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.06(s,1H),9.86(s,1H),8.87(s,1H),8.69(s,1H),8.41(s,1H),7.78(d,J＝4.0Hz,1H),7.55-7.52(m,5H),6.77(m,2H),6.05(s,1H),3.35-3.32(m,4H),3.18(m,2H),3.18(m,2H),1.85(m,2H),1.58(m,2H),1.45(m,2H),0.88(m,3H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ167.8,165.6,164.2,150.2,147.1,145.4,141.2,137.7,134.9,134.0,131.3,126.2,118.6,116.3,114.1,42.3,39.3,32.2,28.7,19.1,13.4.
the mass spectrum is as follows: MS (EI, M/z):520 (M)++1).
Example 35
The difference from example 1 is that: (Z) -N- (2- ((4- (N- (4- (ethylcarbamoyl) phenyl) -N' -hydroxymethylimidazole) -1,2, 5-oxadiazol-3-yl) amino) ethyl) imidazole [1,2-a ] pyridine-6-carboxamide is prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with 4-amino-N-ethylbenzamide and has the following structural formula:
Figure BDA0001691645820000421
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.26(s,1H),9.89(s,1H),8.88(s,1H),8.78(s,1H),8.41(s,1H),7.79(d,J＝3.5Hz,1H),7.55-7.52(m,5H),6.93(m,2H),6.05(s,1H),3.50(m,2H),3.32-3.29(m,4H),1.07(m,3H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ166.8,165.6,163.1,152.3,148.0,146.5,141.3,136.8,134.9,132.7,123.9,118.6,116.2,114.3,49.6,34.7,32.3,15.4.
the mass spectrum is as follows: MS (EI, M/z):478 (M)++1).
Example 36
The difference from example 1 is that: (Z) -N- (2- ((4- (N- (4- (ethylcarbamoyl) phenyl) -N' -hydroxymethylimi) -1,2, 5-oxadiazol-3-yl) amino) propyl) imidazo [1,2-a ] pyridine-6-carboxamide is prepared by substituting 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with 4-amino-N-ethylbenzamide and N-Boc-2-chloroethylamine in step (2) with N-Boc-3-chloropropylamine and has the following structural formula:
Figure BDA0001691645820000422
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.24(s,1H),9.87(s,1H),8.83(s,1H),8.79(s,1H),8.46(s,1H),7.89(d,J＝3.5Hz,1H),7.50-7.47(m,5H),6.90(m,2H),6.12(s,1H),3.35-3.28(m,4H),3.12(m,2H),1.87(m,2H),1.04(m,3H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ166.8,164.6,162.1,150.3,148.5,147.2,142.3,138.8,134.7,130.8,124.2,117.6,116.4,113.4,42.6,39.8,34.7,23.3,14.8.
the mass spectrum is as follows: MS (EI, M/z):492 (M)++1).
Example 37
The difference from example 1 is that: the structural formula of (Z) -N- (2- ((4- (N- (3, 5-dimethyl-4- ((2-piperidin-1-yl) ethylcarbamoyl) phenyl) -N' -hydroxymethylimidazole) -1,2, 5-oxadiazol-3-yl) amino) ethyl) imidazo [1,2-a ] pyridine-6-carboxamide prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with 4-amino-2, 6-dimethyl-N- (2- (piperidin-1-yl) benzamide is as follows:
Figure BDA0001691645820000431
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.26(s,1H),9.89(s,1H),8.88(s,1H),8.74(s,1H),8.61(s,1H),7.81(d,J＝3.9Hz,1H),7.60(t,J＝4.9Hz,1H),7.48(s,2H),6.93(s,2H),6.05(s,1H),3.60(m,2H),3.50(m,2H),3.32(m,2H),2.60(m,2H),2.48(s,6H),2.32(m,4H),1.47(m,4H),1.17(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ166.8,167.6,163.1,153.2,149.5,148.0,136.8,134.9,132.7,128.8,116.5,114.3,113.4,56.2,53.4,49.6,39.2,37.7,25.3,24.6,15.4.
the mass spectrum is as follows: MS (EI, M/z):589 (M)++1).
Example 38
The difference from example 1 is that: replacing 3-bromo-4-fluoroaniline in the step (1) of the synthesis method with 4-amino-2, 6-dimethyl-N- (2- (piperidine-1-yl) benzamide, replacing the N-Boc-2-chloroethylamine in the step (2) with N-Boc-3-chloropropylamine, the structural formula of the prepared (Z) -N- (2- ((4- (N- (3, 5-dimethyl-4- ((2-piperidin-1-yl) propylcarbamoyl) phenyl) -N' -hydroxyformamidine) -1,2, 5-oxadiazol-3-yl) amino) propyl) imidazo [1,2-a ] pyridine-6-carboxamide is as follows:
Figure BDA0001691645820000432
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.19(s,1H),9.79(s,1H),8.98(s,1H),8.78(s,1H),8.67(s,1H),7.77(d,J＝3.9Hz,1H),7.67(m,1H),7.26(s,2H),6.88(s,2H),6.05(s,1H),3.60(m,2H),3.36(m,2H),3.12(m,2H),2.38(s,6H),2.22-2.20(m,6H),1.85(m,2H),1.47(m,4H),1.27(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ167.8,165.6,163.1,152.3,147.5,147.0,146.5,138.8,134.9,134.0,127.2,118.6,114.3,112.9,56.9,52.0,41.6,39.7,32.3,27.5,25.9,22.4,15.4.
the mass spectrum is as follows: MS (EI, M/z):603 (M)++1).
Example 39
The difference from example 1 is that: the structural formula of (Z) -N- (2- ((4- (N- (3, 5-dimethyl-4- ((2-morpholinoethyl) carbamoyl) phenyl) -N' -hydroxymethylimi) -1,2, 5-oxadiazol-3-yl) amino) ethyl) imidazo [1,2-a ] pyridine-6-carboxamide prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with 4-amino-2, 6-dimethyl-N- (2- (morpholin-1-yl) benzamide is as follows:
Figure BDA0001691645820000441
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.06(s,1H),9.86(s,1H),8.88(s,1H),8.74(s,1H),8.66(s,1H),7.79(d,J＝3.9Hz,1H),7.60(t,J＝5.0Hz,1H),7.48(s,2H),6.93(s,2H),6.05(s,1H),3.60(m,2H),3.52-3.50(m,6H),3.42(m,2H),2.56(m,2H),2.48(s,6H),2.32(m,4H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ166.8,165.6,164.1,152.2,147.5,147.0,145.3,138.8,134.9,134.0,128.8,116.5,114.3,112.4,69.8,55.2,54.5,49.6,40.2,36.5,17.8.
the mass spectrum is as follows: MS (EI, M/z):591 (M)++1).
Example 40
The difference from example 1 is that: replacing 3-bromo-4-fluoroaniline in the step (1) of the synthesis method with 4-amino-2, 6-dimethyl-N- (2- (morpholine-1-yl) benzamide, replacing the N-Boc-2-chloroethylamine in the step (2) with N-Boc-3-chloropropylamine, the structural formula of the prepared (Z) -N- (2- ((4- (N- (3, 5-dimethyl-4- ((2-morpholinopropyl) carbamoyl) phenyl) -N' -hydroxymethyl) -1,2, 5-oxadiazol-3-yl) amino) propyl) imidazole [1,2-a ] pyridine-6-carboxamide is as follows:
Figure BDA0001691645820000442
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.12(s,1H),9.88(s,1H),8.92(s,1H),8.84(s,1H),8.75(s,1H),7.60(d,J＝4.2Hz,1H),7.67(t,J＝5.0Hz,1H),7.58(s,2H),6.99(s,2H),6.15(s,1H),3.60(m,2H),3.52(m,2H),3.42(m,2H),3.19(m,2H),2.59(m,2H),2.48(s,6H),2.42(m,4H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ167.3,165.6,164.1,152.8,147.6,147.2,144.3,138.5,133.9,132.7,129.8,127.4,116.5,115.3,113.4,66.8,53.2,52.5,41.6,38.2,35.2,27.8,18.3.
the mass spectrum is as follows: MS (EI, M/z):605 (M)++1).
EXAMPLE 41
The difference from example 1 is that: (Z) -N- (2- ((4- (N- (4- (3- (diethylamino) propionamido) phenyl) -N' -hydroxymethyl) -1,2, 5-oxadiazol-3-yl) amino) ethyl) imidazo [1,2-a ] pyridine-6-carboxamide is prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with N- (4-aminophenyl) -3- (diethylamino) propionamide:
Figure BDA0001691645820000451
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.26(s,1H),9.89(s,1H),8.88(s,1H),8.74(s,1H),8.61(s,1H),7.81(d,J＝3.9Hz,1H),7.60(t,J＝4.9Hz,1H),7.48(s,2H),6.93(s,2H),6.05(s,1H),3.60(m,2H),3.50(m,2H),3.32(m,2H),2.60(m,2H),2.48(s,6H),2.32(m,4H),1.47(m,4H),1.17(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ166.8,167.6,163.1,153.2,149.5,148.0,136.8,134.9,132.7,128.8,116.5,114.3,113.4,56.2,53.4,49.6,39.2,37.7,25.3,24.6,15.4.
the mass spectrum is as follows: MS (EI, M/z):549 (M)++1).
Example 42
The difference from example 1 is that: (Z) -N- (2- ((4- (N- (4- (3- (diethylamino) propionamido) phenyl) -N' -hydroxymethylimidazole) -1,2, 5-oxadiazol-3-yl) amino) ethyl) imidazo [1,2-a ] pyridine-6-carboxamide is prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with N- (4-aminophenyl) -3- (diethylamino) propionamide and N-Boc-2-chloroethylamine in step (2) with N-Boc-3-chloropropylamine, and has the following structural formula:
Figure BDA0001691645820000452
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.12(s,1H),9.88(s,1H),8.92(s,1H),8.84(s,1H),8.75(s,1H),7.60(d,J＝4.2Hz,1H),7.67(t,J＝5.0Hz,1H),7.58(s,2H),6.99(s,2H),6.15(s,1H),3.60(m,2H),3.52(m,2H),3.42(m,2H),3.19(m,2H),2.59(m,2H),2.48(s,6H),2.42(m,4H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ167.3,165.6,164.1,152.8,147.6,147.2,144.3,138.5,133.9,132.7,129.8,127.4,116.5,115.3,113.4,66.8,53.2,52.5,41.6,38.2,35.2,27.8,18.3.
the mass spectrum is as follows: MS (EI, M/z):563 (M)++1).
Example 43
The difference from example 1 is that: the structural formula of (Z) -N- (2- ((4- (N' -hydroxy-N- (4-propionamidophenyl) formamidine-1, 2, 5-oxadiazol-3-yl) amino) ethyl) imidazo [1,2-a ] pyridine-6-carboxamide prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic method with N- (4-aminophenyl) propionamide is as follows:
Figure BDA0001691645820000461
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ10.56(s,1H),10.16(s,1H),9.88(s,1H),8.78(s,1H),8.53(s,1H),7.64(d,J＝3.9Hz,1H),7.50(t,J＝5.0Hz,1H),7.48(s,2H),7.08(d,J＝4.9Hz,2H),6.77(d,J＝5.2Hz,2H),6.05(s,1H),3.52-3.50(m,4H),2.56(m,2H),2.48(s,6H),1.02(t,J＝2.8Hz,3H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ170.3,165.6,163.1,153.8,147.5,145.3,138.3,134.9,133.7,128.8,116.5,115.9,114.3,49.6,37.2,30.5,10.8.
the mass spectrum is as follows: MS (EI, M/z):478 (M)++1).
Example 44
The difference from example 1 is that: (Z) -N- (2- ((4- (N' -hydroxy-N- (4-propionamidophenyl) imidazole-1, 2, 5-oxadiazol-3-yl) amino) propyl) imidazole [1,2-a ] pyridine-6-carboxamide is prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic method with N- (4-aminophenyl) propionamide and N-Boc-2-chloroethylamine in step (2) with N-Boc-3-chloropropylamine, and has the following structural formula:
Figure BDA0001691645820000462
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ10.62(s,1H),10.03(s,1H),9.79(s,1H),8.92(s,1H),8.64(s,1H),7.68(d,J＝4.9Hz,1H),7.57(t,J＝5.3Hz,1H),7.58(s,2H),7.02(d,J＝4.8Hz,2H),6.78(d,J＝5.2Hz,2H),6.15(s,1H),3.60(m,2H),3.45(m,2H),3.12(m,2H),2.48(s,2H),1.67(m,2H),1.72(m,2H),1.12(t,J＝2.8Hz,3H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ172.3,165.6,163.1,153.2,148.2,145.3,138.5,134.9,133.7,129.8,128.4,122.4,116.5,116.3,115.3,66.8,41.6,39.2,35.2,30.6,28.8,10.3.
the mass spectrum is as follows: MS (EI, M/z):492 (M)++1).
Example 45
The difference from example 1 is that: the structural formula of (Z) -N- (2- ((4- (3-chlorobenzoylamino) phenyl) -N' -hydroxymethyl-1, 2, 5-oxadiazol-3-yl) amino) ethyl) imidazo [1,2-a ] pyridine-6-carboxamide prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic method with N- (4-aminophenyl) -3-chlorobenzamide and replacing N-Boc-2-chloroethylamine in step (2) with N-Boc-3-chloropropylamine is as follows:
Figure BDA0001691645820000471
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ10.56(s,1H),10.26(s,1H),9.89(s,1H),8.74(s,1H),8.63(s,1H),7.95-7.90(m,2H),7.82(d,J＝3.9Hz,1H),7.79-7.70(m,3H),7.48(s,2H),7.40(d,J＝2.9Hz,2H),6.72(d,J＝4.9Hz,2H),6.13(s,1H),3.42-3.40(m,4H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ165.3,164.6,163.1,153.8,148.5,144.3,138.2,138.9,135.7,134.2,133.2,132.7,130.9,127.8,125.4,121.3,116.9,116.0,114.3,49.6,37.2.
the mass spectrum is as follows: MS (EI, M/z):560 (M)++1).
Example 46
The difference from example 1 is that: the structural formula of (Z) -N- (2- ((4- (3-chlorobenzoylamino) phenyl) -N' -hydroxymethyl-1, 2, 5-oxadiazol-3-yl) aminopropyl) imidazo [1,2-a ] pyridine-6-carboxamide prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic method with N- (4-aminophenyl) -3-chlorobenzamide and replacing N-Boc-2-chloroethylamine in step (2) with N-Boc-3-chloropropylamine is as follows:
Figure BDA0001691645820000472
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ10.43(s,1H),10.35(s,1H),9.88(s,1H),8.76(s,1H),8.53(s,1H),7.95-7.90(m,2H),7.82(d,J＝3.9Hz,1H),7.69-7.60(m,3H),7.48(s,2H),7.32(d,J＝2.3Hz,2H),6.78(d,J＝4.9Hz,2H),6.06(s,1H),3.42(m,2H),3.12(m,2H)
ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ166.3,165.6,162.1,152.8,147.5,145.2,137.2,138.9,135.7,134.2,133.2,131.3,129.9,127.8,124.4,122.3,116.9,116.3,114.3,49.6,41.3,27.2.
the mass spectrum is as follows: MS (EI, M/z):574 (M)++1).
Example 47
The difference from example 1 is that: the structural formula of (Z) -N- (2- ((4-N' -hydroxy-N- (4- (3-phenylamino) phenylamido) phenyl) imidazole) -1,2, 5-oxadiazol-3-yl) amino) ethyl) imidazo [1,2-a ] pyridine-6-carboxamide is as follows, obtained by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic method with N- (4-aminophenyl) -3-phenylaminobenzamide:
Figure BDA0001691645820000481
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ10.49(s,1H),10.16(s,1H),9.88(s,1H),8.74(s,1H),8.67(s,1H),8.23(s,2H),7.98(d,J＝4.9Hz,1H),7.82(d,J＝3.9Hz,1H),7.69(t,J＝3.9Hz,1H),7.38-7.32(m,4H),7.08-7.02(m,3H),6.77(d,J＝5.9Hz,2H),6.03(s,1H),3.42-3.40(m,4H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ165.3,164.7,162.1,152.8,147.5,145.3,141.3,139.2,138.0,134.7,134.2,133.2,132.7,131.9,129.8,126.7,124.4,122.3,120.7,116.9,114.3,
49.6,39.2.
the mass spectrum is as follows: MS (EI, M/z):633 (M)++1).
Example 48
The difference from example 1 is that: (Z) -N- (2- ((4-N' -hydroxy-N- (4- (3-phenylamino) phenylamido) phenyl) imidazole) -1,2, 5-oxadiazol-3-yl) amino) propyl) imidazole [1,2-a ] pyridine-6-carboxamide is prepared by substituting 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with N- (4-aminophenyl) -3-phenylaminobenzamide and N-Boc-2-chloroethylamine in step (2) with N-Boc-3-chloropropylamine, and the formula of the resulting compound is as follows:
Figure BDA0001691645820000482
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ10.49(s,1H),10.16(s,1H),9.88(s,1H),8.74(s,1H),8.36(s,1H),8.30(s,2H),7.98(d,J＝4.9Hz,1H),7.79(d,J＝3.9Hz,1H),7.65(d,J＝3.9Hz,1H),7.54(t,J＝3.9Hz,1H),7.48-7.42(m,7H),7.08-7.02(m,3H),6.77(d,J＝5.9Hz,2H),6.12(s,1H),3.52(m,2H),3.18(m,2H),1.72(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ166.2,163.7,161.1,153.8,148.5,146.4,142.3,140.0,138.2,135.7,134.6,133.2,131.9,130.9,127.8,125.7,124.4,121.3,119.7,117.2,113.9,41.6,39.2,18.3.
the mass spectrum is as follows: MS (EI, M/z):647 (M)++1).
Example 49
The difference from example 1 is that: the structural formula of (Z) -N- (2- ((4-N' -hydroxy-N- (4- (2-methoxyacetamido) phenyl) formamidyl) -1,2, 5-oxadiazol-3-yl) amino) ethyl) imidazo [1,2-a ] pyridine-6-carboxamide prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic method with N- (4-aminophenyl) -2-methoxyacetamide is as follows:
Figure BDA0001691645820000491
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ10.54(s,1H),9.87(s,1H),9.65(s,1H),8.75(s,1H),8.65(s,1H),7.79(m,1H),7.60(m,1H),7.48(d,J＝3.6Hz,2H),7.32(d,J＝5.6Hz,2H),6.75(d,J＝5.6Hz,2H),6.04(s,1H),4.20(s,2H),3.45(m,4H),3.20(s,3H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ169.2,165.3,163.5,152.2,147.9,145.9,138.4,134.9,133.9,133.2,130.6,128.7,122.7,117.3,116.2,114.2,71.4,56.3,48.9,39.9.
the mass spectrum is as follows: MS (EI, M/z):494 (M)++H).
Example 50
The difference from example 1 is that: (Z) -N- (2- ((4-N' -hydroxy-N- (4- (2-methoxyacetamido) phenyl) formamidyl) -1,2, 5-oxadiazol-3-yl) amino) ethyl) imidazo [1,2-a ] pyridine-6-carboxamide is prepared by substituting 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with N- (4-aminophenyl) -2-methoxyacetamide and N-Boc-2-chloroethylamine in step (2) with N-Boc-3-chloropropylamine, and the formula of the resulting compound is as follows:
Figure BDA0001691645820000492
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ10.54(s,1H),9.87(s,1H),9.65(s,1H),8.67(s,1H),8.34(s,1H),7.79(m,1H),7.60(m,1H),7.48(d,J＝3.6Hz,2H),7.32(d,J＝5.6Hz,2H),6.79(d,J＝5.6Hz,2H),6.04(s,1H),4.30(s,2H),3.40(s,3H),3.32(m,2H),3.18(m,2H),1.88(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ169.2,165.3,162.5,152.2,147.9,145.1,138.4,134.9,133.9,133.2,130.6,128.7,122.7,117.3,116.2,114.2,71.9,57.3,41.9,38.9,28.8.
the mass spectrum is as follows: MS (EI, M/z):508 (M)++H).
Example 51
The difference from example 1 is that: the structural formula of the (Z) -N- (2- ((4-N' -hydroxy-N- (4- (4-methoxybenzamido) phenyl) formamidyl) -1,2, 5-oxadiazol-3-yl) amino) ethyl) imidazo [1,2-a ] pyridine-6-carboxamide prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic method with N- (4-aminophenyl) -4-methoxybenzamide is as follows:
Figure BDA0001691645820000501
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.04(s,1H),10.20(s,1H),9.87(s,1H),8.74(s,1H),8.65(s,1H),7.95(d,J＝6.4Hz,2H),7.79(m,1H),7.60(m,1H),7.45(m,4H),7.05(d,J＝6.4Hz,2H),6.74(d,J＝6.4Hz,2H),6.04(s,1H),3.80(s,3H),3.45(m,4H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ166.5,165.2,164.4,163.6,152.9,147.9,147.2,145.6,138.4,134.9,133.9,130.2,128.6,127.7,126.5,126.7,117.9,116.3,115.2,114.3,55.4,48.9,39.9.
the mass spectrum is as follows: MS (EI, M/z):556 (M)++H).
Example 52
The difference from example 1 is that: (Z) -N- (2- ((4-N' -hydroxy-N- (4- (4-methoxybenzamido) phenyl) formamidyl) -1,2, 5-oxadiazol-3-yl) amino) propyl) imidazo [1,2-a ] pyridine-6-carboxamide is prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with N- (4-aminophenyl) -4-methoxybenzamide and N-Boc-2-chloroethylamine in step (2) with N-Boc-3-chloropropylamine, and has the following structural formula:
Figure BDA0001691645820000502
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.04(s,1H),10.20(s,1H),9.87(s,1H),8.67(s,1H),8.34(s,1H),7.95(d,J＝6.4Hz,2H),7.79(m,1H),7.60(m,1H),7.45(m,4H),7.05(d,J＝6.4Hz,2H),6.74(d,J＝6.4Hz,2H),6.04(s,1H),3.80(s,3H),3.35(m,2H),3.15(m,2H),1.83(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ166.5,165.1,164.4,163.6,153.9,148.2,147.2,145.6,138.4,134.9,133.9,130.2,128.6,127.7,126.5,126.7,117.9,116.3,115.2,114.3,55.9,41.9,39.9,28.1.
the mass spectrum is as follows: MS (EI, M/z):570 (M)++H).
Example 53
The difference from example 1 is that: the structural formula of the (Z) -N- (2- ((4-N' -hydroxy-N- (4- (phenylthio) phenyl) imidazole) -1,2, 5-oxadiazol-3-yl) amino) ethyl) imidazole [1,2-a ] pyridine-6-carboxamide prepared by replacing 3-bromo-4-fluoroaniline in the step (1) of the synthesis method with 4-phenylthioaniline is as follows:
Figure BDA0001691645820000511
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.75(s,1H),8.61(m,1H),7.79(m,1H),7.63(m,1H),7.45(m,7H),7.05(m,4H),6.08(s,1H),3.42(m,4H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ166.5,163.2,152.9,147.9,145.2,138.7,136.5,135.2,134.8,134.0,132.0,131.3,129.8,128.6,127.3,125.6,116.6,115.4,114.9,48.4,39.9.
the mass spectrum is as follows: MS (EI, M/z):515 (M)++H).
Example 54
The difference from example 1 is that: the structural formula of (Z) -N- (2- ((4-N' -hydroxy-N- (4- (phenylthio) phenyl) cimetidine) -1,2, 5-oxadiazol-3-yl) amino) propyl) imidazole [1,2-a ] pyridine-6-carboxamide prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic method with 4-thiophenylaniline and N-Boc-2-chloroethylamine in step (2) with N-Boc-3-chloropropylamine is as follows:
Figure BDA0001691645820000512
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.65(s,1H),8.34(m,1H),7.79(m,1H),7.63(m,1H),7.45(m,7H),7.05(m,4H),6.08(s,1H),3.40(m,2H),3.18(m,2H),1.80(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ165.5,163.2,152.9,148.9,145.2,138.4,136.5,135.6,134.8,134.2,132.0,131.1,129.8,128.6,127.3,125.6,116.6,115.4,114.2,41.4,39.2,28.3.
the mass spectrum is as follows: MS (EI, M/z):529 (M)++H).
Example 55
The difference from example 1 is that: the structural formula of (Z) -N- (2- ((4-N- (4- ((4-chlorophenyl) thio) phenyl) -N' hydroxycarbamimidoyl) -1,2, 5-oxadiazol-3-yl) amino) ethyl) imidazo [1,2-a ] pyridine-6-carboxamide prepared by substituting 3-bromo-4-fluoroaniline in step (1) of the synthetic method with 4- ((4-chlorophenyl) thio) aniline is as follows:
Figure BDA0001691645820000521
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.00(s,1H),9.89(s,1H),8.75(s,1H),8.65(m,1H),7.78(m,3H),7.63(m,1H),7.45(d,J＝4.8Hz,2H),7.19(d,J＝4.8Hz,2H),7.08(m,4H),6.08(s,1H),3.42(m,4H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ166.5,163.2,152.9,147.9,145.2,138.7,136.5,135.1,134.3,133.2,132.8,130.8,130.0,129.8,128.6,125.3,116.6,115.4,114.9,48.4,39.9.
the mass spectrum is as follows: MS (EI, M/z):549 (M)++H).
Example 56
The difference from example 1 is that: (Z) -N- (2- ((4-N- (4- ((4-chlorophenyl) thio) phenyl) -N' hydroxycarbamimidoyl) -1,2, 5-oxadiazol-3-yl) amino) propyl) imidazo [ e ] prepared by substituting 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with 4- ((4-chlorophenyl) thio) aniline and N-Boc-2-chloroethylamine in step (2) with N-Boc-3-chloropropylamine
[1,2-a ] pyridine-6-carboxamide the following:
Figure BDA0001691645820000522
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.00(s,1H),9.89(s,1H),8.65(s,1H),8.35(m,1H),7.78(m,3H),7.63(m,1H),7.45(d,J＝4.8Hz,2H),7.19(d,J＝4.8Hz,2H),7.08(m,4H),6.08(s,1H),3.42(m,2H),3.12(m,2H),1.82(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ166.5,163.2,152.9,147.9,145.2,138.7,136.5,135.1,134.3,133.2,132.8,130.8,130.0,129.8,128.6,125.3,116.6,115.4,114.9,48.4,39.9.
the mass spectrum is as follows: MS (EI, M/z):563 (M)++H).
Example 57
The difference from example 1 is that: the structural formula of (Z) -N- (2- ((4-N- (4-diethylamino) phenyl) -N' hydroxycarbamimidoyl) -1,2, 5-oxadiazol-3-yl) amino) ethyl) imidazo [1,2-a ] pyridine-6-carboxamide prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic method with 4-diethylaminoaniline is as follows:
Figure BDA0001691645820000531
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ10.64(s,1H),9.87(s,1H),8.75(s,1H),8.61(m,1H),7.79(m,1H),7.63(m,1H),7.48(d,J＝4.8Hz,2H),6.69(d,J＝4.4Hz,2H),6.46(d,J＝4.4Hz,2H),6.02(s,1H),3.42(m,8H),1.29(t,J＝8.4Hz,6H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ166.5,163.2,152.9,147.1,145.2,139.7,138.5,135.2,134.8,130.7,128.6,127.0,117.0,116.3,114.8,113.6,48.4,47.6,38.4,13.9.
the mass spectrum is as follows: MS (EI, M/z):478 (M)++H).
Example 58
The difference from example 1 is that: (Z) -N- (2- ((4-N- (4-diethylamino) phenyl) -N' hydroxycarbamimidoyl) -1,2, 5-oxadiazol-3-yl) amino) propyl) imidazo [1,2-a ] pyridine-6-carboxamide is prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with 4-diethylaminoaniline and N-Boc-2-chloroethylamine in step (2) with N-Boc-3-chloropropylamine, and has the following structural formula:
Figure BDA0001691645820000532
the hydrogen spectrum of nuclear magnetic resonance is as follows:1h NMR (400MHz, DMSO): δ 10.64(s,1H),9.87(s,1H),8.65(s,1H),8.31(m,1H),7.79(m,1H),7.63(m,1H),7.48(d, J ═ 4.8Hz,2H),6.63(d, J ═ 4.4Hz,2H),6.36(d, J ═ 4.4Hz,2H),6.02(s,1H),3.42(m,6H),3.12(m,2H),1.82(m,6H),1.19(t, J ═ 8.4Hz,6H) ppm.13C NMR(125MHz,DMSO):δ166.5,164.2,152.1,147.1,145.2,139.4,137.5,135.2,134.8,131.7,128.6,127.0,117.0,116.3,114.8,113.6,48.4,41.6,39.4,28.9,15.9.
The mass spectrum is as follows: MS (EI, M/z):492 (M)++H).
Example 59
The difference from example 1 is that: the structural formula of (Z) -N- (2- ((4-N- (4-dimethylamino) phenyl) -N' hydroxycarbamimidoyl) -1,2, 5-oxadiazol-3-yl) amino) ethyl) imidazo [1,2-a ] pyridine-6-carboxamide prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic method with 4-dimethylaminoaniline is as follows:
Figure BDA0001691645820000541
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ10.64(s,1H),9.89(s,1H),8.75(s,1H),8.65(m,1H),7.79(m,1H),7.60(m,1H),7.43(d,J＝4.4Hz,2H),6.75(d,J＝4.4Hz,2H),6.49(d,J＝4.4Hz,2H),6.03(s,1H),3.42(m,4H),3.09(s,6H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ166.5,163.2,152.9,148.5,147.9,145.2,138.7,135.2,134.8,131.3,127.3,117.6,116.6,114.4,113.9,48.4,41.4,39.9.
the mass spectrum is as follows: MS (EI, M/z):450 (M)++H).
Example 60
The difference from example 1 is that: (Z) -N- (2- ((4-N- (4-dimethylamino) phenyl) -N' hydroxycarbamimidoyl) -1,2, 5-oxadiazol-3-yl) amino) propyl) imidazo [1,2-a ] pyridine-6-carboxamide is prepared by substituting 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with 4-dimethylaminoaniline and N-Boc-2-chloroethylamine in step (2) with N-Boc-3-chloropropylamine, and the formula of the resulting compound is as follows:
Figure BDA0001691645820000542
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ10.64(s,1H),9.89(s,1H),8.65(s,1H),8.35(m,1H),7.73(m,1H),7.60(m,1H),7.45(d,J＝4.4Hz,2H),6.75(d,J＝4.4Hz,2H),6.46(d,J＝4.4Hz,2H),6.03(s,1H),3.42(m,2H),3.12(m,2H),3.03(s,6H),1.83(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ167.5,164.2,152.9,148.5,147.9,145.6,138.7,135.2,134.2,131.3,125.3,117.6,116.6,114.4,113.9,41.9,41.2,39.9,28.5.
the mass spectrum is as follows: MS (EI, M/z):464 (M)++H).
Example 61
The difference from example 1 is that: replacing 3-bromo-4-fluoroaniline in the step (1) of the synthesis method with 4- (1-morpholinyl) aniline to prepare (Z) -N- (2- ((4- (N- (4-morpholinyl phenyl) -N '-hydroxymethyl imino) -1,2, 5-diazol-3-yl) amino) ethyl) imidazole [1,2-a ] pyridine-6-formamide, wherein the structural formula of the (Z) -N- (2- ((4- (N- (4-morpholinyl phenyl) -N' -hydroxymethyl imino) -1,2, 5-diazole-3-yl) amino) ethyl) imidazole [1,2-a ] pyridine-6-formamide is as follows:
Figure BDA0001691645820000551
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ10.54(s,1H),9.86(s,1H),8.63(s,1H),8.32(s,1H),7.72(d,J＝3.6Hz,1H),7.60(m,1H),7.48(s,2H),6.70(m,2H),6.55(m,2H),6.08(s,1H),3.73(t,J＝8.0Hz,4H),3.48(m,4H),3.10(t,J＝8.0Hz,4H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ165.7,163.6,157.2,152.9,147.1,145.2,138.6,134.9,134.1,133.3,129.6,119.2,114.8,115.2,66.5,53.9,48.6,39.2.
the mass spectrum is as follows: MS (EI, M/z):492 (M)++H).
Example 62
The difference from example 1 is that: the structural formula of the (Z) -N- (2- ((4- (N- (4-morpholinylphenyl) -N' -hydroxyformamidyl) -1,2, 5-oxadiazol-3-yl) amino) propyl) imidazole [1,2-a ] pyridine-6-carboxamide prepared by replacing 3-bromo-4-fluoroaniline in the step (1) of the synthetic method with 4- (1-morpholinyl) aniline and replacing N-Boc-2-chloroethylamine in the step (2) with N-Boc-3-chloropropylamine is as follows:
Figure BDA0001691645820000552
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ10.54(s,1H),9.87(s,1H),8.76(s,1H),8.42(s,1H),7.79(d,J＝3.6Hz,1H),7.64(m,1H),7.48(s,2H),6.80(m,2H),6.54(m,2H),6.05(s,1H),3.75(t,J＝8.0Hz,4H),3.54(m,2H),3.18(m,2H),3.04(t,J＝8.0Hz,4H)，1.85(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ166.9,164.5,152.4,147.6,145.3,144.1,140.9,138.6,135.2,133.3,128.0,125.2,122.7,118.3,114.2,112.5,110.6,66.0,54.2,46.3,45.2,29.8.
the mass spectrum is as follows: MS (EI, M/z):506 (M)++H).
Example 63
The difference from example 1 is that: the structural formula of (Z) -N- (2- ((4- (N' -hydroxy-N- (4- (4-methylpiperazin-1-yl) phenyl) carbamimidoyl) -1,2, 5-oxadiazol-3-yl) amino) ethyl) imidazo [1,2-a ] pyridine-6-carboxamide prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic method with 4- (4-methylpiperazinyl) aniline is as follows:
Figure BDA0001691645820000561
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ10.09(s,1H),9.86(s,1H),8.43(s,1H),8.13(s,1H),7.71(d,J＝6.4Hz,1H),7.48(m,3H),7.07(m,1H),6.69(m,2H),6.50(m,3H),6.08(s,1H),3.50-3.43(m,8H),2.38(t,J＝6.4Hz,4H),2.21(s,3H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ166.8,163.5,148.9,147.9,145.3,140.1,136.5,134.8,134.0,133.7,132.6,127.6,126.2,117.8,115.2,114.3,113.6,57.3,52.1,48.3,46.5,39.2.
the mass spectrum is as follows: MS (EI, M/z) 505 (M)++H).
Example 64
The difference from example 1 is that: (Z) -N- (2- ((4- (N' -hydroxy-N- (4- (4-methylpiperazin-1-yl) phenyl) cimetidyl) -1,2, 5-oxadiazol-3-yl) amino) propyl) imidazo [1,2-a ] pyridine-6-carboxamide is prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with 4- (4-methylpiperazinyl) aniline and N-Boc-2-chloroethylamine in step (2) with N-Boc-3-chloropropylamine as and has the following structural formula:
Figure BDA0001691645820000562
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ10.39(s,1H),9.88(s,1H),8.43(s,1H),8.15(s,1H),7.73(d,J＝6.4Hz,1H),7.48(m,3H),7.09(m,1H),6.69(m,2H),6.53(m,3H),6.08(s,1H),3.49(m,8H),2.38(t,J＝6.4Hz,4H),2.21(s,3H),1.80(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ166.8,163.5,148.9,147.9,145.3,140.1,136.5,134.8,134.0,133.7,132.6,127.6,126.2,117.8,115.2,114.3,113.6,57.3,52.1,48.3,46.5,39.2,28.9.
the mass spectrum is as follows: MS (EI, M/z):519 (M)++H).
Example 65
The difference from example 1 is that: the structural formula of (Z) -N- (2- ((4- (N' -hydroxy-N- (4- (piperidin-1-yl) phenyl) carbamimidoyl) -1,2, 5-oxadiazol-3-yl) amino) ethyl) imidazo [1,2-a ] pyridine-6-carboxamide prepared by substituting 3-bromo-4-fluoroaniline in step (1) of the synthetic method with 4- (1-piperazinyl) aniline is as follows:
Figure BDA0001691645820000571
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ10.49(s,1H),9.82(s,1H),8.42(s,1H),8.11(s,1H),7.71(d,J＝6.4Hz,1H),7.46(m,3H),7.03(m,1H),6.69(m,2H),6.50(m,3H),6.08(s,1H),3.47(m,8H),1.58(m,6H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ166.4,163.1,148.9,147.4,145.3,140.0,136.5,134.5,134.3,133.7,132.2,127.1,126.1,117.6,115.2,114.1,113.6,54.2,48.3,39.2,25.6,24.3.
the mass spectrum is as follows: MS (EI, M/z):490 (M)++H).
Example 66
The difference from example 1 is that: (Z) -N- (2- ((4- (N' -hydroxy-N- (4- (piperidin-1-yl) phenyl) carbamimidoyl) -1,2, 5-oxadiazol-3-yl) amino) propyl) imidazo [1,2-a ] pyridine-6-carboxamide is prepared by substituting 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with 4- (1-piperazinyl) aniline and N-Boc-2-chloroethylamine in step (2) with N-Boc-3-chloropropylamine, and has the following structural formula:
Figure BDA0001691645820000572
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ10.39(s,1H),9.86(s,1H),8.45(s,1H),8.17(s,1H),7.73(d,J＝6.4Hz,1H),7.46(m,3H),7.06-7.00(m,1H),6.66(m,2H),6.52(m,3H),6.08(s,1H),3.46(m,8H),1.75(m,8H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ166.6,163.5,148.7,147.4,145.3,140.5,136.1,134.8,134.0,133.3,132.6,127.3,126.2,117.8,115.6,114.3,113.3,54.3,42.5,41.5,28.8,25.5,24.2.
the mass spectrum is as follows: MS (EI, M/z):504 (M)++H).
Example 67
The difference from example 1 is that: the structural formula of the (Z) -N- (2- ((4- (N' -hydroxy-N- (4-morpholinyl-3- (trifluoromethyl) phenyl) imidyl) -1,2, 5-oxadiazol-3-yl) amino) ethyl) imidazo [1,2-a ] pyridine-6-carboxamide prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic method with 3-trifluoromethyl-4- (1-morpholinyl) aniline is as follows:
Figure BDA0001691645820000581
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ10.39(s,1H),9.86(s,1H),8.40(s,1H),8.11(s,1H),7.71(d,J＝6.4Hz,1H),7.45(m,3H),7.02(m,2H),6.49(m,3H),6.01(s,1H),3.70(t,J＝8.0Hz,4H),3.50(m,4H),3.14(t,J＝8.0Hz,4H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ166.8,163.0,148.9,147.5,145.8,136.9,134.9,134.6,134.3,133.9,133.2,132.2,126.6,125.2,120.8,115.9,115.1,114.5,113.8,113.3,66.3,53.1,48.3,39.2.
the mass spectrum is as follows: MS (EI, M/z):560 (M)++H).
Example 68
The difference from example 1 is that: the structural formula of (Z) -N- (2- ((4- (N' -hydroxy-N- (4-morpholinyl-3- (trifluoromethyl) phenyl) imidyl) -1,2, 5-oxadiazol-3-yl) amino) propyl) imidazo [1,2-a ] pyridine-6-carboxamide is prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic method with 3-trifluoromethyl-4- (1-morpholinyl) aniline and replacing N-Boc-2-chloroethylamine in step (2) with N-Boc-3-chloropropylamine:
Figure BDA0001691645820000582
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ10.43(s,1H),9.81(s,1H),8.41(s,1H),8.13(s,1H),7.72(d,J＝6.4Hz,1H),7.45(m,3H),7.01(m,2H),6.48(m,3H),6.05(s,1H),3.72(t,J＝8.0Hz,4H),3.35(m,2H),3.14(m,6H),1.85(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ166.4,163.3,148.5,147.7,145.3,136.9,135.4,134.7,134.3,133.7,133.1,132.2,126.6,125.1,120.4,115.4,115.1,114.3 113.8,113.0,66.0,53.4,42.9,41.3,29.2.
the mass spectrum is as follows: MS (EI, M/z):574 (M)++H).
Example 69
The difference from example 1 is that: the structural formula of the (Z) -N- (2- ((4- (ethyl (hydroxyethyl) amino) -3-fluorophenyl-N '-hydroxy-imidyl) -1,2, 5-oxadiazol-3-yl) amino) propyl) imidazo [1,2-a ] pyridine-6-carboxamide prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic method with 3-fluoro-4- (N-ethyl-N' - (2-hydroxyethyl) amino) aniline is as follows:
Figure BDA0001691645820000591
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ10.36(s,1H),9.84(s,1H),8.41(s,1H),8.12(s,1H),7.73(d,J＝6.4Hz,1H),7.45(m,3H),7.05(m,2H),6.75(s,1H),6.51(m,2H),6.26(m,1H),4.85(s,1H),4.20(t,J＝7.2Hz,2H),3.73(m,2H),3.45(m,6H),1.21(t,J＝8.0Hz,3H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ166.5,163.0,156.3,148.9,147.5,145.8,136.9,135.4,134.9,134.2,133.8,132.9,127.6,126.2,116.8,115.9,114.1,112.5,105.3,61.3,58.1,48.3,47.1,39.2,12.5.
the mass spectrum is as follows: MS (EI, M/z):512 (M)++H).
Example 70
The difference from example 1 is that: the structural formula of (Z) -N- (2- ((4- (ethyl (hydroxyethyl) amino) -3-fluorophenyl-N '-hydroxy-imidyl) -1,2, 5-oxadiazol-3-yl) amino) propyl) imidazo [1,2-a ] pyridine-6-carboxamide prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthesis procedure with 3-fluoro-4- (N-ethyl-N' - (2-hydroxyethyl) amino) aniline and N-Boc-2-chloroethylamine in step (2) with N-Boc-3-chloropropylamine is as follows:
Figure BDA0001691645820000592
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ10.46(s,1H),9.80(s,1H),8.44(s,1H),8.16(s,1H),7.71(d,J＝6.4Hz,1H),7.42(m,3H),7.05(m,2H),6.75(s,1H),6.53(m,2H),6.26(m,1H),4.82(s,1H),4.23(t,J＝7.2Hz,2H),3.71(m,2H),3.38(m,4H),3.18(m,2H),1.23(t,J＝8.0Hz,3H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ166.0,163.5,156.3,148.3,147.2,145.8,136.9,135.6,134.9,134.1,133.1,132.4,127.3,126.5,116.2,115.9,114.5,112.4,105.3,61.3,58.6,48.3,47.8,39.2,28.3,12.2.
the mass spectrum is as follows: MS (EI, M/z):526 (M)++H).
Example 71
The difference from example 1 is that: the structural formula of (Z) -N- (2- ((4- (N- (4- (2, 6-dimethylmorpholinyl) -2-methoxyphenyl) -N' -hydroxyimidyl) -1,2, 5-oxadiazol-3-yl) amino) ethyl) imidazo [1,2-a ] pyridine-6-carboxamide prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic method with 2-methoxy-4- (2, 6-dimethylmorpholinyl) aniline is as follows:
Figure BDA0001691645820000601
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ10.59(s,1H),9.96(s,1H),8.41(s,1H),8.11(s,1H),7.71(d,J＝6.4Hz,1H),7.49(m,3H),7.00(m,2H),6.46(m,1H),6.21(m,3H),6.11(m,1H),3.90(s,3H),3.55(m,6H),3.14(m,4H),1.11(d,J＝6.4Hz,6H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ166.8,163.0,148.8,148.3,147.2,145.6,140.9,136.9,135.6,134.7,133.6,132.2,126.6,122.2,118.8,115.9,114.1,104.5,98.5,73.3,68.9,55.1,48.3,39.2,19.7.
the mass spectrum is as follows: MS (EI, M/z) 550 (M)++H).
Example 72
The difference from example 1 is that: (Z) -N- (2- ((4- (N- (4- (2, 6-dimethylmorpholinyl) -2-methoxyphenyl) -N' -hydroxyimi-do) -1,2, 5-oxadiazol-3-yl) amino) propyl) imidazole [1,2-a ] pyridine-6-carboxamide is prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic method with 2-methoxy-4- (2, 6-dimethylmorpholinyl) aniline and N-Boc-2-chloroethylamine in step (2) with N-Boc-3-chloropropylamine as shown in the following formula:
Figure BDA0001691645820000611
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ10.45(s,1H),9.94(s,1H),8.42(s,1H),8.11(s,1H),7.73(d,J＝6.4Hz,1H),7.39(m,3H),7.06(m,2H),6.46(m,1H),6.21(m,3H),6.11(m,1H),3.86(s,3H),3.55(m,2H),3.30(m,4H),3.14(m,4H),1.86(m,2H),1.11(d,J＝6.4Hz,6H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ166.2,163.3,148.5,148.2,147.7,145.6,140.9,136.5,135.6,134.3,133.4,132.2,126.0,122.1,118.3,115.4,114.1,104.5,98.5,73.3,68.9,55.0,42.3,41.3,28.4,19.3.
the mass spectrum is as follows: MS (EI, M/z):590 (M)++H).
Example 73
The difference from example 1 is that: the structural formula of the (Z) -N- (2- ((4- (N' -hydroxy-N- (4- (3-hydroxypyrrol-1-yl) phenyl) imidyl) -1,2, 5-oxadiazol-3-yl) amino) ethyl) imidazo [1,2-a ] pyridine-6-carboxamide prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic method with 4- (3-hydroxypyrrol-1-yl) aniline is as follows:
Figure BDA0001691645820000612
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ10.43(s,1H),9.89(s,1H),8.46(s,1H),8.18(s,1H),7.72(d,J＝6.4Hz,1H),7.45(m,3H),7.01(m,2H),6.65(m,2H),6.49(m,3H),6.05(s,1H),5.39(s,1H),3.69(m,1H),3.42(m,5H),3.15(m,3H),1.75(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ166.4,163.3,148.5,147.3,145.6,139.9,136.4,135.4,134.2,133.3,132.7,127.6,126.1,118.4,116.4,114.6,113.3,71.8,65.0,49.4,48.1,41.3,39.2.
the mass spectrum is as follows: MS (EI, M/z):492 (M)++H).
Example 74
The difference from example 1 is that: (Z) -N- (2- ((4- (N' -hydroxy-N- (4- (3-hydroxypyrrol-1-yl) phenyl) carbamimidoyl) -1,2, 5-oxadiazol-3-yl) amino) propyl) imidazo [1,2-a ] pyridine-6-carboxamide is prepared by substituting 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with 4- (3-hydroxypyrrol-1-yl) aniline and N-Boc-2-chloroethylamine in step (2) with N-Boc-3-chloropropylamine as follows:
Figure BDA0001691645820000621
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ10.33(s,1H),9.99(s,1H),8.46(s,1H),8.28(s,1H),7.72(d,J＝6.4Hz,1H),7.55(m,3H),7.11(m,2H),6.65(m,2H),6.54(m,3H),6.15(s,1H),5.39(s,1H),3.69(m,1H),3.39(m,3H),3.15(m,5H),1.75(m,4H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ166.4,163.3,148.9,147.3,145.6,138.9,136.4,135.4,134.5,133.1,130.7,127.6,125.1,116.4,115.4,113.6,111.3,71.8,65.0,49.4,43.1,41.3,38.2,28.4.
the mass spectrum is as follows: MS (EI, M/z):506 (M)++H).
Example 75
The difference from example 1 is that: (Z) -N- (2- ((4- (N' -hydroxy-N- (4- (morpholin-1-ylsulfonyl) phenyl) carbamimidoyl) -1,2, 5-oxadiazol-3-yl) amino) ethyl) imidazo [1,2-a ] pyridin-6-ylcarboxamide prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with 4- (morpholin-1-ylsulfonyl) aniline has the following structural formula:
Figure BDA0001691645820000622
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.14(s,1H),9.87(s,1H),8.64(s,1H),8.34(s,1H),7.71(d,J＝3.6Hz,1H),7.60(m,1H),7.48(s,2H),6.90(m,2H),6.75(m,2H),6.08(s,1H),3.64(t,J＝7.2Hz,4H),3.48(m,4H),2.99(t,J＝7.2Hz,4H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ165.8,163.5,148.3,147.9,146.3,141.2,136.5,134.8,134.0,133.3,132.6,131.2,129.3,126.8,115.2,114.5,112.9,65.7,48.9,47.1,39.2.
the mass spectrum is as follows: MS (EI, M/z):556 (M)++H).
Example 76
The difference from example 1 is that: (Z) -N- (2- ((4- (N' -hydroxy-N- (4- (morpholin-1-ylsulfonyl) phenyl) carbamimidoyl) -1,2, 5-oxadiazol-3-yl) amino) propyl) imidazo [1,2-a ] pyridin-6-ylcarboxamide prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with 4- ((morpholin-1-ylsulfonyl) aniline and N-Boc-2-chloroethylamine in step (2) with N-Boc-3-chloropropylamine has the following structural formula:
Figure BDA0001691645820000631
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.62(s,1H),8.31(s,1H),7.71(d,J＝3.6Hz,1H),7.60(m,1H),7.48(s,2H),6.90(m,2H),6.75(m,2H),6.08(s,1H),3.69(t,J＝7.2Hz,4H),3.33(m,4H),2.99(t,J＝7.2Hz,4H),1.80(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ165.9,162.5,149.3,147.9,144.3,140.2,136.5,134.8,134.0,133.3,132.6,131.2,128.3,126.8,115.2,114.5,111.9,65.7,46.9,43.1,41.3,29.2.
the mass spectrum is as follows: MS (EI, M/z):570 (M)++H).
Example 77
The difference from example 1 is that: (Z) -N- (2- ((4- (N' -hydroxy-N- (4- (4-methylpiperazin-1-yl) sulfonyl) phenyl) carbamimidoyl) -1,2, 5-oxadiazol-3-yl) amino) ethyl) imidazo [1,2-a ] pyridin-6-ylcarboxamide prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with 4- ((4- (methylpiperazin-1-yl) sulfonyl) aniline has the following structural formula:
Figure BDA0001691645820000632
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.14(s,1H),9.83(s,1H),8.64(s,1H),8.30(s,1H),7.71(d,J＝3.6Hz,1H),7.60(m,1H),7.48(s,2H),6.90(m,2H),6.75(m,2H),6.08(s,1H),3.54(m,4H),3.08(m,4H),2.39(m,4H),2.09(s,3H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ165.8,163.5,148.3,147.9,146.3,141.2,136.5,134.8,134.0,133.3,132.6,131.2,129.3,126.8,115.2,114.5,112.9,57.7,49.9,48.8,48.1,46.7,39.2.
the mass spectrum is as follows: MS (EI, M/z):569 (M)++H).
Example 78
The difference from example 1 is that: (Z) -N- (2- ((4- (N' -hydroxy-N- (4- (4-methylpiperazin-1-yl) sulfonyl) phenyl) carbamimidoyl) -1,2, 5-oxadiazol-3-yl) amino) propyl) imidazo [1,2-a ] pyridin-6-ylcarboxamide prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with 4- ((4- (methylpiperazin-1-yl) sulfonyl) aniline and N-Boc-2-chloroethylamine in step (2) with N-Boc-3-chloropropylamine has the following structural formula:
Figure BDA0001691645820000641
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.14(s,1H),9.83(s,1H),8.64(s,1H),8.30(s,1H),7.71(d,J＝3.6Hz,1H),7.60(m,1H),7.48(s,2H),6.90(m,2H),6.75(m,2H),6.08(s,1H),3.34(m,2H),3.08(m,6H),2.39(m,4H),2.09(s,3H),1.88(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ165.8,163.5,148.3,147.9,146.3,141.2,136.5,134.8,134.0,133.3,132.6,131.2,129.3,126.8,115.2,114.5,112.9,56.7,48.9,46.8,43.1,42.7,29.2.
the mass spectrum is as follows: MS (EI, M/z):583 (M)++H).
Example 79
The difference from example 1 is that: (Z) -N- (2- ((4- (N-tert-butylsulfamoyl) phenyl) carbamimidoyl) -1,2, 5-oxadiazol-3-yl) amino) ethyl) imidazo [1,2-a ] pyridin-6-ylcarboxamide prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with 4- ((N-tert-butylsulfamoyl) aniline has the following structural formula:
Figure BDA0001691645820000642
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.10(s,1H),9.77(s,1H),8.41(s,1H),8.13(s,1H),7.71(d,J＝3.6Hz,1H),7.40(m,4H),7.20(m,2H),6.97(m,1H),6.85(m,2H),6.45(m,1H),6.08(s,1H),3.44(m,4H),1.29(s,9H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ167.8,164.5,148.3,147.9,145.3,142.2,136.5,134.8,134.0,133.3,132.6,130.2,129.3,126.8,115.2,114.5,112.9,48.7,46.3,39.9,29.2.
the mass spectrum is as follows: MS (EI, M/z):542 (M)++H).
Example 80
The difference from example 1 is that: (Z) -N- (2- ((4- (N-tert-butylsulfamoyl) phenyl) carbamimidoyl) -1,2, 5-oxadiazol-3-yl) amino) propyl) imidazo [1,2-a ] pyridin-6-ylcarboxamide prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with 4- ((N-tert-butylsulfamoyl) aniline and N-Boc-2-chloroethylamine in step (2) with N-Boc-3-chloropropylamine has the following structural formula:
Figure BDA0001691645820000651
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.10(s,1H),9.77(s,1H),8.44(s,1H),8.13(s,1H),7.71(d,J＝3.6Hz,1H),7.40(m,4H),7.20(m,2H),7.07(m,1H),6.80(m,2H),6.45(m,1H),6.08(s,1H),3.25(m,4H),1.88(m,2H),1.29(s,9H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ167.8,164.5,148.3,147.9,145.3,142.2,136.5,134.8,134.0,133.3,132.6,130.2,129.3,126.8,115.2,114.5,112.9,47.7,42.9,41.3,29.7.
the mass spectrum is as follows: MS (EI, M/z):556 (M)++H).
Example 81
The difference from example 1 is that: the structural formula of (Z) -N- (2- ((4- (N- (4- (2, 4-difluorophenyl) sulfamoyl) phenyl) carbamimidoyl) -1,2, 5-oxadiazol-3-yl) amino) ethyl) imidazo [1,2-a ] pyridin-6-ylcarboxamide prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic method with 4- ((N- (2, 4-difluorophenyl) sulfamoyl) aniline is as follows:
Figure BDA0001691645820000652
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.14(s,1H),9.97(s,1H),9.67(s,1H),8.41(s,1H),8.13(s,1H),7.71(d,J＝3.6Hz,1H),7.47(m,5H),7.08(m,1H),6.76(m,3H),6.55(m,2H),6.08(s,1H),3.54(m,4H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ165.8,163.5,160.2,154.3,148.3,147.9,145.3,141.2,136.5,135.6,134.3,133.5,132.6,131.2,130.3,129.4,126.8,119.2,115.7,114.5,112.9,111.3,105.8,48.9,39.2.
the mass spectrum is as follows: MS (EI, M/z):598 (M)++H).
Example 82
The difference from example 1 is that: (Z) -N- (2- ((4- (N- (4- (2, 4-difluorophenyl) sulfamoyl) phenyl) carbamimidoyl) -1,2, 5-oxadiazol-3-yl) amino) propyl) imidazo [1,2-a ] pyridin-6-ylcarboxamide prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with 4- ((N- (2, 4-difluorophenyl) sulfamoyl) aniline and N-Boc-2-chloroethylamine in step (2) with N-Boc-3-chloropropylamine has the following structural formula:
Figure BDA0001691645820000661
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.04(s,1H),9.97(s,1H),9.63(s,1H),8.41(s,1H),8.10(s,1H),7.72(d,J＝3.6Hz,1H),7.43(m,5H),7.01(m,1H),6.76(m,3H),6.45(m,2H),6.08(s,1H),3.34(m,4H),1.86(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ166.8,164.5,160.2,154.3,149.3,147.9,146.3,142.2,136.5,135.6,134.3,133.5,132.6,131.2,130.3,129.4,126.8,119.2,115.7,114.5,112.9,111.3,105.8,43.9,41.4,29.2.
the mass spectrum is as follows: MS (EI, M/z):612 (M)++H).
Example 83
The difference from example 1 is that: the structural formula of (Z) -N- (2- ((4-N' -hydroxy- (N- (4- (3-methoxy-p-diaza-2-yl) sulfamoyl) phenyl) carbamimidoyl) -1,2, 5-oxadiazol-3-yl) amino) ethyl) imidazo [1,2-a ] pyridin-6-ylcarboxamide prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with 4- ((N- (3-methoxy-p-diaza-2-yl) sulfamoyl) aniline is as follows:
Figure BDA0001691645820000662
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.04(s,2H),9.97(s,1H),8.44(s,1H),8.13(s,1H),8.03(m,1H),7.71(d,J＝3.6Hz,1H),7.50(m,6H),7.08(m,1H),6.79(m,2H),6.45(m,1H),6.08(s,1H),4.04(s,3H),3.36(m,4H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ165.8,163.5,149.3,148.9,148.1,147.5,145.3,141.2,136.5,135.4,134.5,133.3,132.6,131.9,131.3,130.5,129.3,126.8,115.8,114.5,112.2,55.7,48.9,39.0.
the mass spectrum is as follows: MS (EI, M/z):594 (M)++H).
Example 84
The difference from example 1 is that: (Z) -N- (2- ((4-N' -hydroxy- (N- (4- (3-methoxy-p-diaza-2-yl) sulfamoyl) phenyl) carbamimidoyl) -1,2, 5-oxadiazol-3-yl) amino) propyl) imidazo [1,2-a ] pyridin-6-ylcarboxamide prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with 4- ((N- (3-methoxy-p-diaza-2-yl) sulfamoyl) aniline and N-Boc-2-chloroethylamine in step (2) with N-Boc-3-chloropropylamine has the following structural formula:
Figure BDA0001691645820000671
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.14(s,2H),9.97(s,1H),8.44(s,1H),8.16(s,1H),8.03(m,1H),7.71(d,J＝3.6Hz,1H),7.50(m,6H),7.08(m,1H),6.79(m,2H),6.45(m,1H),6.08(s,1H),4.04(s,3H),3.36(m,2H),3.16(m,2H),1.86(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ165.8,164.5,150.3,148.9,148.1,146.5,145.3,142.2,136.5,135.4,134.5,133.3,132.6,131.9,131.3,130.5,129.3,127.8,115.8,114.5,113.2,55.7,43.9,42.1,29.0.
the mass spectrum is as follows: MS (EI, M/z):608 (M)++H).
Example 85
The difference from example 1 is that: (Z) -N- (2- ((4- (N' -hydroxy-N- (4- (N- (2-hydroxyethyl) sulfamoyl) phenyl) carbamimidoyl) -1,2, 5-oxadiazol-3-yl) amino) ethyl) imidazo [1,2-a ] pyridin-6-ylcarboxamide prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with 4- ((N- (2-hydroxyethyl) sulfamoyl) aniline has the following structural formula:
Figure BDA0001691645820000672
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.14(s,1H),9.87(s,1H),8.45(s,1H),8.14(s,1H),7.71(d,J＝3.6Hz,1H),7.50(m,3H),7.32(m,3H),6.99(m,1H),6.85(m,2H),6.45(m,1H),6.08(s,1H),4.85(s,1H),3.48(m,8H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ165.8,163.5,148.3,147.9,146.1,140.2,136.5,135.4,134.7,134.1,133.3,132.6,130.2,126.9,115.2,114.5,112.9,60.7,48.9,45.1,39.2.
the mass spectrum is as follows: MS (EI, M/z):530 (M)++H).
Example 86
The difference from example 1 is that: (Z) -N- (2- ((4- (N' -hydroxy-N- (4- (N- (2-hydroxyethyl) sulfamoyl) phenyl) carbamimidoyl) -1,2, 5-oxadiazol-3-yl) amino) ethyl) imidazo [1,2-a ] pyridin-6-ylcarboxamide prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with 4- ((N- (2-hydroxyethyl) sulfamoyl) aniline and N-Boc-2-chloroethylamine in step (2) with N-Boc-3-chloropropylamine has the following structural formula:
Figure BDA0001691645820000681
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.24(s,1H),9.97(s,1H),8.45(s,1H),8.14(s,1H),7.76(d,J＝3.6Hz,1H),7.54(m,3H),7.32(m,3H),6.99(m,1H),6.85(m,2H),6.45(m,1H),6.08(s,1H),4.65(s,1H),3.40(m,6H),3.13(m,2H),1.70(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ166.8,164.5,149.3,147.9,146.1,140.2,137.5,136.4,135.4,134.1,133.3,132.6,130.2,126.9,115.2,114.5,112.9,60.1,45.9,43.1,41.8,29.2.
the mass spectrum is as follows: MS (EI, M/z):544 (M)++H).
Example 87
The difference from example 1 is that: (Z) -N- (2- ((4- (N- (4- (N-ethyl-N-propylsulfamoyl) phenyl) -N' -hydroxycarbamimidoyl) -1,2, 5-oxadiazol-3-yl) amino) ethyl) imidazo [1,2-a ] pyridin-6-ylcarboxamide prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with 4- ((N-ethyl-N-propyl) sulfamoyl) aniline has the following structural formula:
Figure BDA0001691645820000682
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.24(s,1H),9.87(s,1H),8.45(s,1H),8.10(s,1H),7.71(d,J＝3.6Hz,1H),7.50(m,5H),6.99(m,1H),6.75(m,2H),6.45(m,1H),6.08(s,1H),3.45(m,4H),3.18(m,4H),1.58(m,4H),1.18(t,J＝7.2Hz,3H),0.89(t,J＝7.2Hz,3H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ167.8,164.5,149.3,147.9,146.1,141.2,136.5,135.4,134.7,133.7,132.6,130.2,128.6,126.9,115.2,114.5,112.9,52.7,48.9,41.1,39.2,21.1,12.9,11.3.
the mass spectrum is as follows: MS (EI, M/z):556 (M)++H).
Example 88
The difference from example 1 is that: (Z) -N- (2- ((4- (N- (4- (N-ethyl-N-propylsulfamoyl) phenyl) -N' -hydroxycarbamimidoyl) -1,2, 5-oxadiazol-3-yl) amino) propyl) imidazo [1,2-a ] pyridin-6-ylcarboxamide prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with 4- ((N-ethyl-N-propyl) sulfamoyl) aniline and N-Boc-2-chloroethylamine in step (2) with N-Boc-3-chloropropylamine has the following structural formula:
Figure BDA0001691645820000691
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.24(s,1H),9.97(s,1H),8.55(s,1H),8.19(s,1H),7.77(d,J＝3.6Hz,1H),7.51(m,5H),6.99(m,1H),6.75(m,2H),6.45(m,1H),6.18(s,1H),3.25(m,6H),3.08(m,2H),1.58(m,4H),1.08(t,J＝7.2Hz,3H),0.83(t,J＝7.2Hz,3H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ168.8,165.5,149.3,147.9,146.1,142.2,136.5,135.4,134.7,133.7,132.6,130.2,128.0,126.9,115.2,114.5,110.9,52.7,43.9,41.1,39.2,28.4,21.1,13.9,12.3.
the mass spectrum is as follows: MS (EI, M/z):570 (M)++H).
Example 89
The difference from example 1 is that: (Z) -N- (2- ((4- (N' -hydroxy-N- (4- (4-methylsulfonyl) piperazin-1-yl) phenyl) carbamimidoyl) -1,2, 5-oxadiazol-3-yl) amino) ethyl) imidazo [1,2-a ] pyridin-6-ylcarboxamide prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with 4- ((4-methylsulfonyl) piperazin-1-yl) aniline has the following structural formula:
Figure BDA0001691645820000692
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ10.44(s,1H),9.87(s,1H),8.67(s,1H),8.63(s,1H),7.73(d,J＝3.6Hz,1H),7.60(m,1H),7.48(m,2H),6.69(m,2H),6.50(m,2H),6.08(s,1H),3.45(m,4H),3.28(m,4H),3.19(m,4H),2.87(s,3H),2.58(m,4H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ167.8,164.5,152.3,147.9,146.1,141.2,136.5,134.7,133.7,130.2,128.6,117.2,114.5,113.9,52.7,48.9,41.1,39.2
the mass spectrum is as follows: MS (EI, M/z):569 (M)++H).
Example 90
The difference from example 1 is that: (Z) -N- (2- ((4- (N' -hydroxy-N- (4- (4-methylsulfonyl) piperazin-1-yl) phenyl) carbamimidoyl) -1,2, 5-oxadiazol-3-yl) amino) propyl) imidazo [1,2-a ] pyridin-6-ylcarboxamide prepared by substituting 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with 4- ((4-methylsulfonyl) piperazin-1-yl) aniline and N-Boc-2-chloroethylamine in step (2) with N-Boc-3-chloropropylamine has the following structural formula:
Figure BDA0001691645820000701
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ10.44(s,1H),9.87(s,1H),8.67(s,1H),8.63(s,1H),7.73(d,J＝3.6Hz,1H),7.60(m,1H),7.48(m,2H),6.69(m,2H),6.50(m,2H),6.08(s,1H),3.35(m,2H),3.18-3.15(m,6H),2.87(s,3H),2.48(m,4H),1.78(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ165.8,163.2,152.5 147.9,145.1,139.5,138.7,134.8,133.7,130.2,127.6,118.2,114.5,113.7,52.7,47.9,41.8,37.2,28.9.
the mass spectrum is as follows: MS (EI, M/z):583 (M)++H).
Example 91
The difference from example 1 is that: the structural formula of (Z) -N- (2- ((4- (N' -hydroxy-N- (4- (methylsulfonylamino) phenyl) cimidyl) -1,2, 5-oxadiazol-3-yl) amino) ethyl) imidazo [1,2-a ] pyridine-6-carboxamide prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic method with 4- (methylsulfonylamino) aniline is as follows:
Figure BDA0001691645820000702
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.04(s,1H),10.04(s,1H),9.87(s,1H),8.40(s,1H),8.11(s,1H),7.71(d,J＝3.6Hz,1H),7.50(m,3H),7.05(m,1H),6.65(d,J＝4.8Hz,2H),6.48(m,3H),6.08(s,1H),3.42(m,4H),3.25(s,3H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ166.5,163.2,148.9,147.4,145.3,136.4,135.2,134.4,133.5,132.0,128.8,127.3,125.1,118.8,117.5,115.6,114.3,48.3,42.6,38.9.
the mass spectrum is as follows: MS (EI, M/z) 500 (M)++H).
Example 92
The difference from example 1 is that: (Z) -N- (2- ((4- (N' -hydroxy-N- (4- (methylsulfonylamino) phenyl) cimetidyl) -1,2, 5-oxadiazol-3-yl) amino) propyl) imidazo [1,2-a ] pyridine-6-carboxamide is prepared by substituting 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with 4- (methylsulfonylamino) aniline and N-Boc-2-chloroethylamine in step (2) with N-Boc-3-chloropropylamine, and has the following structural formula:
Figure BDA0001691645820000711
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ10.84(s,1H),10.04(s,1H),9.87(s,1H),8.40(s,1H),8.11(s,1H),7.71(d,J＝3.6Hz,1H),7.52(m,3H),7.05(m,1H),6.65(d,J＝4.8Hz,2H),6.54(m,3H),6.08(s,1H),3.38(m,2H),3.25(s,3H),3.13(m,1H),1.88(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ167.5,164.2,149.9,147.4,145.3,136.4,135.2,134.2,133.5,132.0,127.8,126.3,125.1,118.8,117.5,115.6,114.3,43.3,42.6,41.9,29.6.
the mass spectrum is as follows: MS (EI, M/z):514 (M)++H).
Example 93
The difference from example 1 is that: the structural formula of (Z) -N- (3- ((4- (N- (4- (cyano-3, 5-dimethylphenyl) -N' -hydroxymethylimidyl) -1,2, 5-oxadiazol-3-yl) amino) ethyl) imidazo [1,2-a ] pyridine-6-carboxamide prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic method with 4-cyano-3, 5-dimethylaniline is as follows:
Figure BDA0001691645820000712
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.40(s,1H),8.11(s,1H),7.71(d,J＝3.6Hz,1H),7.50(m,3H),7.04(m,1H),6.94(s,2H),6.45(d,J＝4.8Hz,2H),6.08(s,1H),3.47(m,4H),2.25(s,6H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ166.5,164.2,148.9,148.2,147.2,145.3,142.4,136.6,135.2,134.4,133.5,132.0,126.8,117.8,115.6,114.3,113.4,107.5,48.3,39.6,21.9.
the mass spectrum is as follows: MS (EI, m/z):460(M++H).
example 94
The difference from example 1 is that: the structural formula of the (Z) -N- (3- ((4- (N- (4- (cyano-3, 5-dimethylphenyl) -N' -hydroxycimetidyl) -1,2, 5-oxadiazol-3-yl) amino) propyl) imidazo [1,2-a ] pyridine-6-carboxamide prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic method with 4-cyano-3, 5-dimethylaniline and replacing N-Boc-2-chloroethylamine in step (2) with N-Boc-3-chloropropylamine is as follows:
Figure BDA0001691645820000721
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.40(s,1H),8.11(s,1H),7.61(d,J＝3.6Hz,1H),7.40(m,3H),7.01(m,1H),6.94(s,2H),6.35(d,J＝4.8Hz,2H),6.08(s,1H),3.37(m,2H),3.17(m,2H),2.35(s,6H),1.87(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ167.5,164.2,149.7,148.2,147.2,145.8,142.4,136.6,135.2,134.4,133.5,132.0,126.8,117.3,115.1,114.3,113.4,108.5,42.3,41.4,29.6,21.9.
the mass spectrum is as follows: MS (EI, M/z):474 (M)++H).
Example 95
The difference from example 1 is that: the structural formula of ethyl (Z) -4- (N' -hydroxy-4- ((2- (imidazo [1,2-a ] pyridine-6-carboxamido) ethyl) amino) -1,2, 5-oxadiazole-3-carboximidamide) benzoate prepared by replacing 3-bromo-4-fluoroaniline in the step (1) of the synthesis method with 4-aminobenzeneacetate is as follows:
Figure BDA0001691645820000722
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.14(s,1H),9.87(s,1H),8.40(s,1H),8.15(s,1H),7.71(d,J＝3.6Hz,1H),7.48(m,5H),7.03(m,1H),6.67(d,J＝4.8Hz,2H),6.44(m,1H),6.08(s,1H),4.42(q,J＝9.6Hz,2H),3.35(m,4H),1.32(t,J＝9.6Hz,3H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ167.5,165.4,163.2,148.9,147.4,145.4,142.3,136.4,135.2,134.5,133.4,132.5,130.0,126.8,120.5,117.3,115.1,114.8,60.6,48.3,39.6,15.9.
the mass spectrum is as follows: MS (EI, M/z):479 (M)++H).
Example 96
The difference from example 1 is that: the structural formula of ethyl (Z) -4- (N' -hydroxy-4- ((2- (imidazo [1,2-a ] pyridine-6-carboxamido) ethyl) amino) -1,2, 5-oxadiazole-3-carboximidamide) benzoate prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic method step with 4-aminophenylacetate and replacing N-Boc-2-chloroethylamine in step (2) with N-Boc-3-chloropropylamine is as follows:
Figure BDA0001691645820000731
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.14(s,1H),9.87(s,1H),8.43(s,1H),8.15(s,1H),7.73(d,J＝3.6Hz,1H),7.48(m,5H),7.03(m,1H),6.69(d,J＝4.8Hz,2H),6.54(m,1H),6.08(s,1H),4.42(q,J＝9.6Hz,2H),3.35(m,2H),3.15(m,2H),1.83(m,4H),1.32(t,J＝9.6Hz,3H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ168.5,166.4,163.1,148.9,147.4,145.4,141.3,136.4,135.2,134.5,133.4,132.5,131.0,127.8,120.5,117.3,115.1,114.8,60.6,43.3,42.6,29.4,15.9.
the mass spectrum is as follows: MS (EI, M/z):493 (M)++H).
Example 97
The difference from example 1 is that: the structural formula of (E) -N- (2- ((4- ((Z) -N- (3-bromo-4-fluorophenyl) -N' -hydroxymethylimidazole) -1,2, 5-oxadiazol-3-yl) amino) ethyl) -3- (pyridin-3-yl) carboxamide prepared by replacing the imidazo [1,2-a ] pyridine-6-carboxylic acid in step (3) of the synthetic method with trans-3- (3-pyridyl) acrylic acid is as follows:
Figure BDA0001691645820000732
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.23(s,1H),9.86(s,1H),8.84(s,1H),8.63(dd,J＝3.5,2.3Hz,1H),8.21(s,1H),7.89(m,1H),7.71(d,J＝3.5Hz,1H),7.35(m,1H),6.96(m,1H),6.87(m,1H),6.76(m,1H),6.46(m,1H),6.05(s,1H),3.59-3.43(m,4H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ166.8,163.2,154.3,148.7,147.2,146.3,141.2,135.5,133.2,131.3,29.6,126.2,123.8,118.7,117.5,114.2,108.6,48.3,35.2.
the mass spectrum is as follows: MS (EI, M/z):490 (M)++1).
Example 98
The difference from example 1 is that: (E) -N- (2- ((4- ((Z) -N- (3-bromo-4-fluorophenyl) -N' -hydroxymethylimidazole) -1,2, 5-oxadiazol-3-yl) amino) propyl) -3- (pyridin-3-yl) carboxamide is prepared by replacing N-Boc-2-chloroethylamine in step (2) of the synthetic procedure with N-Boc-3-chloropropylamine and imidazo [1,2-a ] pyridine-6-carboxylic acid in step (3) with trans-3- (3-pyridyl) acrylic acid by the following structural formula:
Figure BDA0001691645820000741
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.06(s,1H),9.86(s,1H),8.83(s,1H),8.23(dd,J＝3.5,2.4Hz,1H),8.11(s,1H),7.90(m,1H),7.71(d,J＝3.5Hz,1H),7.25(m,1H),6.76(m,1H),6.78(m,1H),6.76(m,1H),6.34(m,1H),6.05(s,1H),3.35(m,2H),3.05(m,2H),1.93(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ167.8,164.5,153.3,148.7,147.2,145.2,143.2,133.4,131.2,129.3,128.6,124.2,121.8,116.7,115.2,113.2,107.6,42.1,41.2,27.8.
the mass spectrum is as follows: MS (EI, M/z):504 (M)++1).
Example 99
The difference from example 1 is that: the structural formula of (E) -N- (2- ((4- ((Z) -N- (4-fluorophenyl) -N' -hydroxymethylimidazole) -1,2, 5-oxadiazol-3-yl) amino) ethyl) -3- (pyridin-3-yl) carboxamide prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with 4-fluoroaniline and replacing imidazo [1,2-a ] pyridine-6-carboxylic acid in step (3) with trans-3- (3-pyridyl) acrylic acid is as follows:
Figure BDA0001691645820000742
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.14(s,1H),9.87(s,1H),8.84(s,1H),8.63(dd,J＝3.5,2.3Hz,1H),8.41(s,1H),7.89(m,1H),7.71(d,J＝3.5Hz,1H),7.35(m,1H),6.86(m,1H),6.87(m,1H),6.53(m,1H),6.36(m,1H),6.08(s,1H),3.56-3.42(m,4H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ166.8,163.5,153.3,148.9,147.3,146.2,140.9,136.5,133.2,131.3,129.6,125.2,120.8,117.6,115.2,112.5,107.6,46.3,37.2.
the mass spectrum is as follows: MS (EI, M/z):412 (M)++1).
Example 100
The difference from example 1 is that: the structural formula of (E) -N- (2- ((4- ((Z) -N- (4-fluorophenyl) -N' -hydroxymethylimidazole) -1,2, 5-oxadiazol-3-yl) amino) propyl) -3- (pyridin-3-yl) carboxamide prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with 4-fluoroaniline, replacing N-Boc-2-chloroethylamine in step (2) with N-Boc-3-chloropropylamine, and replacing imidazo [1,2-a ] pyridine-6-carboxylic acid in step (3) with trans-3- (3-pyridyl) acrylic acid is as follows:
Figure BDA0001691645820000751
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.14(s,1H),9.87(s,1H),8.78(s,1H),8.53(dd,J＝3.0,2.3Hz,1H),8.41(s,1H),7.79(m,1H),7.51(d,J＝3.5Hz,1H),7.25(m,1H),6.75(m,1H),6.87(m,1H),6.54(m,1H),6.37(m,1H),6.05(s,1H),3.54-3.43(m,4H),2.35(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ166.8,164.5,152.3,147.6,145.2,144.3,140.9,138.2,135.2,133.3,128.0,125.2,122.7,118.3,114.2,112.5,110.6,46.3,45.2,29.8.
the mass spectrum is as follows: MS (EI, M/z) 426 (M)++1).
Example 101
The difference from example 1 is that: the structural formula of (E) -N- (2- ((4- ((Z) -N- (2-fluoro-4-methoxyphenyl) -N' -hydroxymethylimidazole) -1,2, 5-oxadiazol-3-yl) amino) ethyl) -3- (pyridin-3-yl) carboxamide prepared by substituting 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with 4-methoxyethoxyaniline and imidazo [1,2-a ] pyridine-6-carboxylic acid in step (3) with trans-3- (3-pyridyl) acrylic acid is as follows:
Figure BDA0001691645820000752
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.24(s,1H),9.65(s,1H),8.78(s,1H),8.63(dd,J＝3.2,2.4Hz,1H),8.41(s,1H),7.88(m,1H),7.77(m,2H),7.61(d,J＝3.5Hz,1H),7.47(t,J＝3.3Hz,1H),6.45(m,2H),6.32(m,1H),6.05(s,1H),4.34(m,2H),3.72(m,2H),3.45(s,3H),3.35-3.23(m,4H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ167.8,163.5,149.3,148.1,146.2,136.6,134.8,131.3,129.6,125.7,123.9,117.3,115.2,76.3,62.1,59.8,48.6,39.2.
the mass spectrum is as follows: MS (EI, M/z):468 (M)++1).
Example 102
The difference from example 1 is that: (E) -N- (2- ((4- ((Z) -N- (2-fluoro-4-methoxyphenyl) -N' -hydroxymethyl) -1,2, 5-oxadiazol-3-yl) amino) propyl) -3- (pyridin-3-yl) carboxamide is prepared by substituting 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with 4-methoxyethoxyaniline, N-Boc-2-chloroethylamine in step (2) with N-Boc-3-chloropropylamine, and imidazo [1,2-a ] pyridine-6-carboxylic acid in step (3) with trans-3- (3-pyridyl) acrylic acid, and has the following structural formula:
Figure BDA0001691645820000761
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.24(s,1H),9.88(s,1H),8.87(s,1H),8.63(dd,J＝3.2,2.4Hz,1H),8.41(s,1H),7.98(m,1H),7.87(m,2H),7.71(d,J＝3.5Hz,1H),7.43(t,J＝3.4Hz,1H),6.65(m,2H),6.42(m,1H),6.05(s,1H),4.31(m,2H),3.73(m,2H),3.45(s,3H),3.35(m,2H),3.18(m,2H),1.78(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ168.8,164.5,148.2,147.8,145.3,136.6,133.8,130.3,128.6,124.7,120.9,116.3,114.8,76.3,62.1,59.8,42.6,29.2.
the mass spectrum is as follows: MS (EI, M/z):482 (M)++1).
Example 103
The difference from example 1 is that: the structural formula of (E) -N- (2- ((4- ((Z) -N- (4-isopropylphenyl) -N' -hydroxymethylimidazole) -1,2, 5-oxadiazol-3-yl) amino) ethyl) -3- (pyridin-3-yl) carboxamide prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with 4-isopropylaniline and replacing imidazo [1,2-a ] pyridine-6-carboxylic acid in step (3) with trans-3- (3-pyridyl) acrylic acid is as follows:
Figure BDA0001691645820000762
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.06(s,1H),9.87(s,1H),8.84(s,1H),8.63(dd,J＝3.2,2.4Hz,1H),8.41(s,1H),7.89(m,1H),7.71(d,J＝3.5Hz,1H),7.55(t,J＝4.5Hz,1H),6.95(m,2H),6.67(m,2H),6.41(d,J＝3.5Hz,1H),6.05(s,1H),3.52-3.47(m,4H),2.75(m,1H),1.23(d,J＝6.5Hz,6H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ166.8,163.5,149.6,148.2,146.1,136.2,134.3,132.5,129.6,126.2,123.8,116.3,48.3,39.8,33.2,23.1.
the mass spectrum is as follows: MS (EI, M/z):436 (M)++1).
Example 104
The difference from example 1 is that: (E) -N- (2- ((4- ((Z) -N- (4-isopropylphenyl) -N' -hydroxymethyl imidazole) -1,2, 5-oxadiazol-3-yl) amino) propyl) -3- (pyridin-3-yl) carboxamide is prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with 4-isopropylaniline, N-Boc-2-chloroethylamine in step (2) with N-Boc-3-chloropropylamine, and imidazo [1,2-a ] pyridine-6-carboxylic acid in step (3) with trans-3- (3-pyridyl) acrylic acid, and has the following structural formula:
Figure BDA0001691645820000771
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.16(s,1H),9.88(s,1H),8.89(s,1H),8.66(dd,J＝3.5,2.6Hz,1H),8.41(s,1H),7.89(m,1H),7.71(d,J＝3.5Hz,1H),7.53(t,J＝5.0Hz,1H),6.98(m,2H),6.63(m,2H),6.41(d,J＝3.5Hz,1H),6.05(s,1H),3.50(m,2H),3.25(m,2H),2.75(m,1H),1.87(m,2H),1.23(d,J＝6.5Hz,6H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ166.9,163.5,149.6,148.2,147.1,136.2,134.3,132.5,129.6,126.2,123.8,116.0,42.3,33.2,28.5,23.1.
the mass spectrum is as follows: MS (EI, M/z):436 (M)++1).
Example 105
The difference from example 1 is that: the structural formula of (E) -N- (2- ((4- ((Z) -N- (4- (1H-pyrazol-1-yl) phenyl-N' -hydroxymethylimidazole) -1,2, 5-oxadiazol-3-yl) amino) ethyl) -3- (pyridin-3-yl) carboxamide prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with 4- (1H-pyrazol-1-yl) aniline and imidazo [1,2-a ] pyridine-6-carboxylic acid in step (3) with trans-3- (3-pyridinyl) acrylic acid is as follows:
Figure BDA0001691645820000781
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.06(s,1H),9.88(s,1H),8.83(s,1H),8.63(dd,J＝3.6,2.5Hz,1H),8.41(s,1H),7.98(m,1H),7.87(m,1H),7.71(d,J＝3.7Hz,1H),7.53-7.46(m,4H),6.80(s,2H),6.46(d,J＝3.4Hz,1H),6.05(s,1H),3.55-3.47(m,4H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ166.8,163.1,149.6,148.1,147.3,141.5,136.6,134.3,132.5,129.6,126.8,123.8,120.7,116.3,108.6,48.3,39.6.
the mass spectrum is as follows: MS (EI, M/z):460 (M)++1).
Example 106
The difference from example 1 is that: replacing 3-bromo-4-fluoroaniline in the step (1) of the synthesis method with 4- (1H-pyrazol-1-yl) aniline, replacing N-Boc-2-chloroethylamine in the step (2) with N-Boc-3-chloropropylamine, replacing imidazo [1,2-a ] pyridine-6-carboxylic acid in the step (3) with trans-3- (3-pyridyl) acrylic acid, the structural formula of the prepared (E) -N- (2- ((4- ((Z) -N- (4- (1H-pyrazol-1-yl) phenyl-N' -hydroxymethyl) -1,2, 5-oxadiazol-3-yl) amino) propyl) -3- (pyridin-3-yl) formamide is as follows:
Figure BDA0001691645820000782
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.26(s,1H),9.89(s,1H),8.93(s,1H),8.74(dd,J＝3.7,2.8Hz,1H),8.52(s,1H),7.98(m,1H),7.87(m,1H),7.71(d,J＝3.7Hz,1H),7.53-7.46(m,4H),6.68(s,2H),6.42(d,J＝3.6Hz,1H),6.15(s,1H),3.45(m,2H),3.27(m,2H),1.89(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ166.8,164.1,150.6,149.5,148.3,147.0,142.5,136.2,134.3,132.5,128.6,126.7,123.2,118.3,116.6,109.0,42.9,26.1.
the mass spectrum is as follows: MS (EI, M/z):474 (M)++1).
Example 107
The difference from example 1 is that: the structural formula of N- (furan-2-ylmethyl) -4- ((Z) -N' -hydroxy- ((2- ((E) -3- (pyridin-3-yl) acrylamido) ethyl) amino-1, 2, 5-oxadiazole-3-carboximidamide prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with 4-amino-N- (furan-2-ylmethyl) benzamide and imidazole [1,2-a ] pyridine-6-carboxylic acid in step (3) with trans-3- (3-pyridinyl) acrylic acid is as follows:
Figure BDA0001691645820000791
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.06(s,1H),9.88(s,1H),8.83(s,1H),8.79(s,1H),8.63(dd,J＝3.6,2.5Hz,1H),8.41(s,1H),7.98(m,1H),7.87(m,1H),7.71(d,J＝3.7Hz,1H),7.55-7.58(m,4H),6.97(m,2H),6.46(d,J＝3.4Hz,1H),6.38-6.34(m,2H),6.05(s,1H),4.85(s,1H),3.50-3.48(m,4H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ167.8,166.3,163.1,149.6,148.1,147.3,145.2,143.5,142.1,141.0,136.6,134.8,132.3,129.6,126.2,122.9,118.6,116.3,110.5,48.3,39.6,35.4.
the mass spectrum is as follows: MS (EI, M/z):517 (M)++1).
Example 108
The difference from example 1 is that: replacing 3-bromo-4-fluoroaniline in the step (1) of the synthesis method with 4-amino-N- (furan-2-ylmethyl) benzamide, replacing N-Boc-2-chloroethylamine in the step (2) with N-Boc-3-chloropropylamine, replacing imidazo [1,2-a ] pyridine-6-carboxylic acid in the step (3) with trans-3- (3-pyridyl) acrylic acid, the structural formula of the prepared N- (furan-2-ylmethyl) -4- ((Z) -N' -hydroxy- ((2- ((E) -3- (pyridin-3-yl) acrylamido) propyl) amino-1, 2, 5-oxadiazole-3-carboximidamide is as follows:
Figure BDA0001691645820000792
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.08(s,1H),9.76(s,1H),8.83(s,1H),8.76(s,1H),8.69(dd,J＝3.5,2.7Hz,1H),8.41(s,1H),7.98(m,1H),7.88(m,1H),7.71(d,J＝4.0Hz,1H),7.56-7.52(m,4H),6.93(m,2H),6.41(d,J＝3.5Hz,1H),6.37-6.35(m,2H),6.08(s,1H),4.79(s,1H),3.35(m,2H),3.15(m,2H),1.75(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ167.8,165.6,163.1,149.1,148.1,147.1,145.3,143.6,142.9,141.4,136.8,133.8,131.3,129.2,126.2,123.9,117.6,114.1,112.9,112.0,42.3,37.6,25.4.
the mass spectrum is as follows: MS (EI, M/z):531 (M)++1).
Example 109
The difference from example 1 is that: the structural formula of N-butyl-4- ((Z) -N' -hydroxy- ((2- ((E) -3- (pyridin-3-yl) acrylamido) ethyl) amino-1, 2, 5-oxadiazole-3-carboximidamide prepared by substituting 3-bromo-4-fluoroaniline in step (1) of the synthetic method step with 4-amino-N-butylbenzamide and imidazo [1,2-a ] pyridine-6-carboxylic acid in step (3) with trans-3- (3-pyridinyl) acrylic acid is as follows:
Figure BDA0001691645820000801
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.08(s,1H),9.76(s,1H),8.83(s,1H),8.76(s,1H),8.69(dd,J＝3.5,2.7Hz,1H),8.41(s,1H),7.98(m,1H),7.71(d,J＝4.0Hz,1H),7.55-7.52(m,3H),6.97(m,2H),6.46(d,J＝3.5Hz,1H),6.08(s,1H),3.50-3.46(m,4H),3.32(m,2H),1.57(m,2H),1.32(m,2H),0.78(m,3H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ166.8,167.6,163.1,149.5,148.1,147.0,142.3,136.7,133.9,132.3,129.2,126.2,124.9,119.6,115.1,48.3,38.7,20.1,15.4.
the mass spectrum is as follows: MS (EI, M/z):493 (M)++1).
Example 110
The difference from example 1 is that: replacing 3-bromo-4-fluoroaniline in the step (1) of the synthesis method with 4-amino-N-butylbenzamide, replacing N-Boc-2-chloroethylamine in the step (2) with N-Boc-3-chloropropylamine, replacing imidazo [1,2-a ] pyridine-6-carboxylic acid in the step (3) with trans-3- (3-pyridyl) acrylic acid, the structural formula of the prepared N-butyl-4- ((Z) -N' -hydroxyl- ((2- ((E) -3- (pyridine-3-yl) acrylamide) propyl) amino-1, 2, 5-oxadiazole-3-formamidyl) benzamide is as follows:
Figure BDA0001691645820000802
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.06(s,1H),9.86(s,1H),8.87(s,1H),8.69(s,1H),8.52(dd,J＝3.5,2.7Hz,1H),8.41(s,1H),7.88(m,1H),7.71(d,J＝4.0Hz,1H),7.55-7.52(m,3H),6.77(m,2H),6.36(d,J＝3.5Hz,1H),6.05(s,1H),3.35-3.32(m,4H),3.18(m,2H),1.85(m,2H),1.58(m,2H),1.45(m,2H),0.88(m,3H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ167.8,165.6,164.2,149.5,148.2,147.1,143.4,137.7,134.9,131.3,128.2,126.2,123.2,118.6,114.1,42.3,39.3,32.2,28.7,19.1,13.4.
the mass spectrum is as follows: MS (EI, M/z):507 (M)++1).
Example 111
The difference from example 1 is that: the structural formula of (E) -N- (2- ((4- ((Z) -N- (3-bromo-4-fluorophenyl) -N' -hydroxymethylimidazole) -1,2, 5-oxadiazol-3-yl) amino) ethyl) -3- (pyridin-4-yl) carboxamide prepared by replacing the imidazo [1,2-a ] pyridine-6-carboxylic acid in step (3) of the synthetic method with trans-3- (4-pyridyl) acrylic acid is as follows:
Figure BDA0001691645820000811
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.70(d,J＝3.2Hz,2H),8.41(s,1H),7.53(d,J＝3.2Hz,2H),7.32(d,J＝3.6Hz,1H),6.94(m,1H),6.84(s,3H),6.08(s,1H),3.47(m,4H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ166.5,164.2,155.9,149.2,147.2,144.3,142.4,141.6,134.2,126.4,123.5,119.0,118.8,117.8,110.6,48.3,39.6.
the mass spectrum is as follows: MS (EI, M/z):490 (M)++H).
Example 112
The difference from example 1 is that: (E) -N- (2- ((4- ((Z) -N- (3-bromo-4-fluorophenyl) -N' -hydroxymethylimidazole) -1,2, 5-oxadiazol-3-yl) amino) propyl) -3- (pyridin-4-yl) carboxamide is prepared by replacing N-Boc-2-chloroethylamine in step (2) of the synthetic procedure with N-Boc-3-chloropropylamine and imidazo [1,2-a ] pyridine-6-carboxylic acid in step (3) with trans-3- (4-pyridyl) acrylic acid by the following structural formula:
Figure BDA0001691645820000812
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.14(s,1H),9.87(s,1H),8.70(d,J＝3.2Hz,2H),8.48(s,1H),7.53(d,J＝3.2Hz,2H),7.32(d,J＝3.6Hz,1H),6.94(m,1H),6.84(s,3H),6.08(s,1H),3.35(m,2H),3.18(m,2H),1.85(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ167.5,164.2,156.9,149.2,147.2,144.3,142.4,141.6,134.2,126.4,123.5,119.1,118.8,117.8,110.6,42.3,41.6,29.3.
the mass spectrum is as follows: MS (EI, M/z):504 (M)++H).
Example 113
The difference from example 1 is that: the structural formula of (E) -N- (2- ((4- ((Z) -N- (3-trifluoromethylphenyl) -N' -hydroxymethylimidazole) -1,2, 5-oxadiazol-3-yl) amino) ethyl) -3- (pyridin-4-yl) carboxamide prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with 3-trifluoromethylaniline and replacing imidazo [1,2-a ] pyridine-6-carboxylic acid in step (3) with trans-3- (4-pyridyl) acrylic acid is as follows:
Figure BDA0001691645820000821
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.70(d,J＝3.2Hz,2H),8.43(s,1H),7.53(d,J＝3.2Hz,2H),7.32(m,3H),6.99(m,1H),6.74(m,2H),6.04(s,1H),3.47(m,4H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ166.5,164.2,149.2,147.4,145.2,144.3,141.4,134.6,131.2,129.4,126.5,124.0,123.8,120.8,119.6,115.8,48.8,39.6.
the mass spectrum is as follows: MS (EI, M/z):462 (M)++H).
Example 114
The difference from example 1 is that: (E) -N- (2- ((4- ((Z) -N- (3-trifluoromethylphenyl) -N' -hydroxymethyl imidazole) -1,2, 5-oxadiazol-3-yl) amino) propyl) -3- (pyridin-4-yl) carboxamide is prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with 3-trifluoromethylaniline, N-Boc-2-chloroethylamine in step (2) with N-Boc-3-chloropropylamine, and imidazo [1,2-a ] pyridine-6-carboxylic acid in step (3) with trans-3- (4-pyridyl) acrylic acid, and has the following structural formula:
Figure BDA0001691645820000822
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.70(d,J＝3.2Hz,2H),8.43(s,1H),7.55(d,J＝3.2Hz,2H),7.30(m,3H),6.99(m,1H),6.74(m,2H),6.04(s,1H),3.37(m,2H),3.17(m,2H),1.85(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ166.1,164.2,149.2,147.4,145.1,144.3,141.0,134.6,131.2,129.4,127.5,124.1,123.8,120.2,119.6,115.8,42.8,40.7,29.6.
the mass spectrum is as follows: MS (EI, M/z):476 (M)++H).
Example 115
The difference from example 1 is that: the structural formula of (E) -N- (2- ((4- ((Z) -N- (2-fluoro-4-methoxyphenyl) -N' -hydroxymethylimidazole) -1,2, 5-oxadiazol-3-yl) amino) ethyl) -3- (pyridin-4-yl) carboxamide prepared by substituting 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with 4-methoxyethoxyaniline and imidazo [1,2-a ] pyridine-6-carboxylic acid in step (3) with trans-3- (4-pyridyl) acrylic acid is as follows:
Figure BDA0001691645820000831
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.70(d,J＝3.2Hz,2H),8.41(s,1H),7.81(d,J＝4.8Hz,2H),7.53(d,J＝3.2Hz,2H),7.32(d,J＝3.6Hz,1H),6.74(d,J＝3.6Hz,1H),6.54(d,J＝4.8Hz,2H),6.04(s,1H),4.31(t,J＝8.4Hz,2H),3.74(t,J＝8.4Hz,2H),3.54(m,4H),3.36(s,3H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ166.9,164.1,149.9,149.2,147.2,144.3,141.4,134.6,129.2,126.4,123.5,116.0,115.8,72.8,69.6,59.6,48.3,39.6.
the mass spectrum is as follows: MS (EI, M/z):468 (M)++H).
Example 116
The difference from example 1 is that: (E) -N- (2- ((4- ((Z) -N- (2-fluoro-4-methoxyphenyl) -N' -hydroxymethyl) -1,2, 5-oxadiazol-3-yl) amino) propyl) -3- (pyridin-4-yl) carboxamide is prepared by substituting 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with 4-methoxyethoxyaniline, N-Boc-2-chloroethylamine in step (2) with N-Boc-3-chloropropylamine, and imidazo [1,2-a ] pyridine-6-carboxylic acid in step (3) with trans-3- (4-pyridinyl) acrylic acid, and has the following structural formula:
Figure BDA0001691645820000832
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.70(d,J＝3.2Hz,2H),8.41(s,1H),7.82(d,J＝4.8Hz,2H),7.54(d,J＝3.2Hz,2H),7.31(d,J＝3.6Hz,1H),6.78(d,J＝3.6Hz,1H),6.54(d,J＝4.8Hz,2H),6.04(s,1H),4.31(t,J＝8.4Hz,2H),3.74(t,J＝8.4Hz,2H),3.46(s,3H),3.29(m,2H),3.13(m,2H),1.89(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ166.9,164.1,149.9,149.2,147.2,144.3,141.4,134.6,129.2,126.4,123.5,116.0,115.8,73.8,69.2,58.6,42.3,40.6,28.4.
the mass spectrum is as follows: MS (EI, M/z):482 (M)++H).
Example 117
The difference from example 1 is that: (Z) -N- (2- ((4-N- (3-bromo-4-fluorophenyl) -N' hydroxycarbamimidoyl) -1,2, 5-oxadiazol-3-yl) amino) ethyl) -1H-pyrrolo [3,2-c ] pyridine-3-carboxamide is prepared by replacing the imidazo [1,2-a ] pyridine-6-carboxylic acid in step (3) of the synthetic procedure with 1H-pyrrolo [3,2-c ] pyridine-3-carboxylic acid and has the following structural formula:
Figure BDA0001691645820000841
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),9.49(m,2H),8.70(s,1H),8.43(m,1H),7.38(d,J＝5.2Hz,1H),6.87(m,3H),6.64(m,1H),6.02(s,1H),3.48(m,4H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ164.5,163.2,155.8,148.6,147.9,147.2,142.6,134.1,129.3,125.1,122.6,119.8,118.2,117.4,114.3,110.4,108.7,48.6,39.6.
the mass spectrum is as follows: MS (EI, M/z):503 (M)++H).
Example 118
The difference from example 1 is that: (Z) -N- (2- ((4-N- (3-bromo-4-fluorophenyl) -N' hydroxycarbamimidoyl) -1,2, 5-oxadiazol-3-yl) amino) propyl) -1H-pyrrolo [3,2-c ] pyridine-3-carboxamide is prepared by replacing N-Boc-2-chloroethylamine in step (2) of the synthetic procedure with N-Boc-3-chloropropylamine and imidazo [1,2-a ] pyridine-6-carboxylic acid in step (3) with 1H-pyrrolo [3,2-c ] pyridine-3-carboxylic acid, and has the following structural formula:
Figure BDA0001691645820000842
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),9.49(m,2H),8.34(m,2H),7.38(d,J＝5.2Hz,1H),6.87(m,3H),6.64(m,1H),6.02(s,1H),3.48(m,2H),3.13(m,2H),1.79(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ164.5,163.2,155.8,148.6,147.9,147.2,142.6,134.1,129.3,125.1,122.6,119.8,118.2,117.4,114.3,110.4,108.7,41.6,39.6,28.6.
the mass spectrum is as follows: MS (EI, M/z):517 (M)++H).
Example 119
The only difference from example 1 is that: (Z) -N- (2- ((4-N- (4-isopropylphenyl) -N' hydroxycarbamimidoyl) -1,2, 5-oxadiazol-3-yl) amino) ethyl) -1H-pyrrole [3,2-c ] pyridine-3-carboxamide is prepared by substituting 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with 4-isopropylaniline and imidazo [1,2-a ] pyridine-6-carboxylic acid in step (3) with 1H-pyrrole [3,2-c ] pyridine-3-carboxylic acid, and has the following structural formula:
Figure BDA0001691645820000851
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),9.49(m,2H),8.76(s,1H),8.43(d,J＝5.2Hz,1H),7.38(d,J＝5.2Hz,1H),6.97(d,J＝5.6Hz,2H),6.84(m,1H),6.67(d,J＝5.6Hz,2H),6.02(s,1H),3.45(m,4H),2.84(m,1H),1.23(d,J＝9.6Hz,6H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ164.5,163.2,148.6,147.9,147.2,138.6,134.9,134.1,129.3,126.1,125.6,122.8,116.2,114.4,108.7,48.6,39.6,33.2,23.6.
the mass spectrum is as follows: MS (EI, M/z):449 (M)++H).
Example 120
The difference from example 1 is that: replacing 3-bromo-4-fluoroaniline in the step (1) of the synthesis method with 4-isopropylaniline, replacing N-Boc-2-chloroethylamine in the step (2) with N-Boc-3-chloropropylamine, replacing imidazo [1,2-a ] pyridine-6-carboxylic acid in the step (3) of the synthesis method with 1H-pyrrole [3,2-c ] pyridine-3-carboxylic acid, the resulting (Z) -N- (2- ((4-N- (4-isopropylphenyl) -N' hydroxycarbamimidoyl) -1,2, 5-oxadiazol-3-yl) amino) propyl) -1H-pyrrolo [3,2-c ] pyridine-3-carboxamide has the following structural formula:
Figure BDA0001691645820000852
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),9.49(m,2H),8.76(s,1H),8.53(d,J＝5.2Hz,1H),7.34(d,J＝5.2Hz,1H),6.97(d,J＝5.6Hz,2H),6.84(m,1H),6.67(d,J＝5.6Hz,2H),6.02(s,1H),3.35(m,2H),3.12(m,2H),2.84(m,1H),1.75(m,2H),1.23(d,J＝9.6Hz,6H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ164.5,163.2,148.6,147.9,147.2,138.6,134.4,133.5,129.3,126.4,125.6,122.8,116.2,114.4,108.7,41.6,39.2,33.2,28.5,23.6.
the mass spectrum is as follows: MS (EI, M/z):463 (M)++H).
Example 121
The difference from example 1 is that: (Z) -N- (2- ((4-N- (4-fluorophenyl) -N' hydroxycarbamimidoyl) -1,2, 5-oxadiazol-3-yl) amino) ethyl) -1H-pyrrolo [3,2-c ] pyridine-3-carboxamide is prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic procedure with 4-fluoroaniline and imidazole [1,2-a ] pyridine-6-carboxylic acid in step (3) with 1H-pyrrolo [3,2-c ] pyridine-3-carboxylic acid and has the following structural formula:
Figure BDA0001691645820000861
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.14(s,1H),9.87(s,1H),9.60(s,1H),9.45(s,1H),8.64(s,1H),8.43(m,1H),7.46(m,1H),6.87(m,3H),6.75(m,2H),6.08(s,1H),3.44(m,4H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ164.5,163.2,158.3,148.9,148.1,147.4,134.5,133.4,129.7,125.7,122.6,120.2,116.6,114.9,108.9,48.9,39.2.
the mass spectrum is as follows: MS (EI, M/z):425 (M)++H).
Example 122
The difference from example 1 is that: (Z) -N- (2- ((4- (N- (4-fluorophenyl) -N' -hydroxymethyl) -1,2, 5-oxadiazol-3-yl) amino) propyl) -1H-pyrrolo [3,2-c ] pyridine-3-acrylamide was prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic method with 4-fluoroaniline, N-Boc-2-chloroethylamine in step (2) with N-Boc-3-chloropropylamine, and imidazo [1,2-a ] pyridine-6-carboxylic acid in step (3) with 1H-pyrrolo [3,2-c ] pyridine-3-carboxylic acid, and has the following structural formula:
Figure BDA0001691645820000862
its nuclear magnetic resonance hydrogen spectrumComprises the following steps:1H NMR(400MHz,DMSO):δ11.10(s,1H),9.87(s,1H),9.60(s,1H),9.43(s,1H),8.64(s,1H),8.42(m,1H),7.36(m,1H),6.87(m,3H),6.75(m,2H),6.12(s,1H),3.28(m,4H),188(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ164.9,163.2,158.9,148.9,148.3,147.4,135.2,133.4,129.7,125.7,122.4,120.2,116.6,114.2,108.9,41.9,39.5,28.2.
the mass spectrum is as follows: MS (EI, M/z):439 (M)++H).
Example 123
The difference from example 1 is that: (Z) -N- (2- ((4- (N' -hydroxy-N- (4- (2-methoxyethoxy) phenyl) carbamimidoyl) -1,2, 5-oxadiazol-3-yl) amino) ethyl) -1H-pyrrolo [3,2-c ] pyridine-3-acrylamide is prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic method step with 4-methoxyethoxyaniline and replacing imidazo [1,2-a ] pyridine-6-carboxylic acid in step (3) with 1H-pyrrolo [3,2-c ] pyridine-3-carboxylic acid, and has the following structural formula:
Figure BDA0001691645820000871
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.14(s,1H),9.87(s,1H),9.60(s,1H),9.45(s,1H),8.64(s,1H),8.43(m,1H),7.76(m,2H),7.46(m,1H),6.87(m,1H),6.65(m,2H),6.08(s,1H),4.33(t,J＝6.8Hz,2H),3.73(t,J＝6.8Hz,2H),3.48(m,4H),3.35(s,3H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ164.2,163.2,149.5,148.9,148.1,147.4,134.5,130.4,129.3,125.7,122.6,116.6,114.9,113.9,108,72.4,69.6,58.2,48.9,39.5.
the mass spectrum is as follows: MS (EI, M/z):481 (M)++H).
Example 124
The difference from example 1 is that: (Z) -N- (2- ((4- (N' -hydroxy-N- (4- (2-methoxyethoxy) phenyl) imidyl) -1,2, 5-oxadiazol-3-yl) amino) propyl) -1H-pyrrolo [3,2-c ] pyridine-3-acrylamide is prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic method with 4-methoxyethoxyaniline, N-Boc-2-chloroethylamine in step (2) with N-Boc-3-chloropropylamine, and imidazo [1,2-a ] pyridine-6-carboxylic acid in step (3) with 1H-pyrrolo [3,2-c ] pyridine-3-carboxylic acid, and has the following structural formula:
Figure BDA0001691645820000872
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.14(s,1H),9.87(s,1H),9.60(s,1H),9.45(s,1H),8.64(s,1H),8.43(m,1H),7.76(m,2H),7.46(m,1H),6.87(m,1H),6.65(m,2H),6.08(s,1H),4.33(t,J＝6.8Hz,2H),3.73(t,J＝6.8Hz,2H),3.39(s,3H),3.21(m,4H),1.81(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ164.5,163.2,149.5,148.4,148.1,147.4,134.0,130.2,129.3,125.7,122.6,116.6,114.9,113.9,108,72.4,69.6,58.2,41.9,39.5,28.6.
the mass spectrum is as follows: MS (EI, M/z):494 (M)++H).
Example 125
The difference from example 1 is that: (Z) -N- (2- ((4- (N' -hydroxy-N- (4-morpholin-1-ylsulfonyl) phenyl) imidyl) -1,2, 5-oxadiazol-3-yl) amino) ethyl) -1H-pyrrolo [3,2-c ] pyridine-3-acrylamide was prepared by replacing 3-bromo-4-fluoroaniline in step (1) of the synthetic method step with 4- (morpholin-1-ylsulfonyl) aniline and imidazole [1,2-a ] pyridine-6-carboxylic acid in step (3) with 1H-pyrrolo [3,2-c ] pyridine-3-carboxylic acid as follows:
Figure BDA0001691645820000881
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.14(s,1H),9.87(s,1H),9.60(s,1H),9.45(s,1H),8.44(s,1H),8.35(m,1H),7.56(m,3H),6.80(m,3H),6.04(s,1H),4.63(t,J＝7.2Hz,4H),3.44(m,4H),2.93(t,J＝7.2Hz,4H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ164.0,163.2,148.5,147.8,147.4,140.5,134.4,130.6,129.7,129.0,125.7,122.6,114.2,112.6,108.9,65.4,48.9,47.3,39.2.
the mass spectrum is as follows: MS (EI, M/z):456 (M)++H).
Example 126
The difference from example 1 is that: (Z) -N- (2- ((4- (N' -hydroxy-N- (4-morpholinosulfamoyl) phenyl) imidyl) -1,2, 5-oxadiazol-3-yl) amino) propyl) -1H-pyrrole [3 ] which is prepared by replacing 3-bromo-4-fluoroaniline in the step (1) of the synthetic method with 4- (morpholin-1-ylsulfonyl) aniline, N-Boc-2-chloroethylamine in the step (2) with N-Boc-3-chloropropylamine, and imidazo [1,2-a ] pyridine-6-carboxylic acid in the step (3) with 1H-pyrrole [3,2-c ] pyridine-3-carboxylic acid, the structural formula of 2-c ] pyridine-3-acrylamide is as follows:
Figure BDA0001691645820000882
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.10(s,1H),9.87(s,1H),9.62(s,1H),9.41(s,1H),8.44(s,1H),8.31(m,1H),7.56(m,3H),6.80(m,3H),6.04(s,1H),4.63(t,J＝7.2Hz,4H),3.24(m,4H),2.95(t,J＝7.2Hz,4H),1.86(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ164.2,163.2,148.8,147.9,147.0,140.5,134.4,130.3,129.7,129.1,125.7,122.3,114.2,112.6,108.9,65.4,47.9,41.3,39.2,27.8.
the mass spectrum is as follows: MS (EI, M/z):570 (M)++H).
Synthetic route of the Compound represented by the general formula I (synthetic route of B series Compound)
Figure BDA0001691645820000891
Example 127
(Z) -N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (3- (pyridin-3-ylmethyl) urea) ethyl) amino) -1,2, 5-oxadiazole-3-carboximidamide was prepared as follows:
Figure BDA0001691645820000892
triphosgene (148mg,0.5mmol) was dissolved in anhydrous toluene, 3-aminomethylpyridine (108mg,1mmol) in toluene solution was added dropwise to the solution at 0 ℃ under nitrogen, and triethylamine (0.27ml,2mmol) in toluene solution was added dropwise to the solution; heating to room temperature, and reacting for 2 h; then heating to 70 ℃ for reaction for 1h to obtain a crude product of the compound VII-1, concentrating, and directly putting into the next reaction. Adding 3- (isocyanotomethyl) -pyridine tetrahydrofuran solution (5mL) slowly and dropwise into compound II-1(315mg,1mmol) tetrahydrofuran solution (5mL) at 0 ℃ under nitrogen protection, heating to room temperature for reaction for 16h, concentrating, adding water (10mL), adding ethyl acetate (20mL), separating layers, extracting the aqueous phase with ethyl acetate (2X 10mL), combining the organic phases, washing with saturated saline (30mL), drying with anhydrous sodium sulfate, concentrating, and performing column chromatography to obtain the target product (246mg, 50%). The hydrogen spectrum of nuclear magnetic resonance is as follows:1h NMR (400MHz, DMSO) < delta > 11.04(s,1H),9.87(s,1H),8.59(s,1H),8.37(m,1H),7.87(m,1H),7.37(m,1H),6.90(m,2H),6.74(m,1H),6.44(s,1H),6.02(s,2H),4.48(s,2H),3.43(m,4H) ppm, whose carbon spectrum is:13c NMR (125MHz, DMSO). delta. 163.5,157.2,155.9,149.2,148.1,147.2,143.3,136.4,135.6,134.2,123.4,119.5,118.8,117.8,110.6,48.3,45.9,41.6. the mass spectrum is: MS (EI, M/z):493 (M)++H).
Example 128
The difference from example 127 is that: (Z) -N- (3-bromo-4-fluorophenyl) -N ' -hydroxy-4- ((2- (pyridin-3-ylmethyl) urea) ethyl) amino) -1 prepared by replacing (Z) -4- ((2-aminoethyl) amino) -N- (4-bromo-3-fluorophenyl) -N ' -hydroxy-1, 2, 5-oxadiazole-3-carboximidamide (II-1) with (Z) -4- ((2-aminopropyl) amino) -N- (4-bromo-3-fluorophenyl) -N ' -hydroxy-1, 2, 5-oxadiazole-3-carboximidamide, the structural formula of the 2, 5-oxadiazole-3-formamidine is as follows:
Figure BDA0001691645820000901
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.63(s,1H),8.37(m,1H),7.87(m,1H),7.37(m,1H),6.90(m,2H),6.74(m,1H),6.45(s,1H),6.02(s,2H),4.48(s,2H),3.35(m,4H),1.85(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ163.5,157.7,155.9,149.2,148.1,146.2,143.3,136.4,135.6,134.2,123.4,119.5,118.8,117.8,110.6,50.3,45.3,41.9,28.6.
the mass spectrum is as follows: MS (EI, M/z):507 (M)++H).
Example 129
The difference from example 127 is that: (Z) -4- ((2-aminoethyl) amino) -N- (4-bromo-3-fluorophenyl) -N '-hydroxy-1, 2, 5-oxadiazole-3-carboximidamide (II-1) was replaced by (Z) -4- ((2-aminoethyl) amino) -N- (3, 5-dimethylphenyl) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboximidamide, the structural formula of the prepared (Z) -N- (3, 5-dimethylphenyl) -N' -hydroxy-4- ((2- (3- (pyridin-3-ylmethyl) urea) ethyl) amino) -1,2, 5-oxadiazole-3-carboximidamide is as follows:
Figure BDA0001691645820000902
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.59(s,1H),8.37(m,1H),7.87(m,1H),7.37(m,1H),6.80(s,2H),6.54(s,1H),6.43(s,1H),6.02(s,2H),4.48(s,2H),3.40(m,4H),2.26(s,6H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ163.5,157.2,148.2,147.7,147.2,144.3,139.4,136.6,135.7,134.2,123.4,119.9,117.8,49.0,45.3,41.9,21.6.
the mass spectrum is as follows: MS (EI, M/z):425 (M)++H).
Example 130
The difference from example 127 is that: (Z) -4- ((2-aminoethyl) amino) -N- (4-bromo-3-fluorophenyl) -N '-hydroxy-1, 2, 5-oxadiazol-3-carboximidamide (II-1) was replaced by (Z) -4- ((2-aminopropyl) amino) -N- (3, 5-dimethylphenyl) -N' -hydroxy-1, 2, 5-oxadiazol-3-carboximidamide, the structural formula of the prepared (Z) -N- (3, 5-dimethylphenyl) -N' -hydroxy-4- ((2- (3- (pyridin-3-ylmethyl) urea) propyl) amino) -1,2, 5-oxadiazole-3-carboximidamide is as follows:
Figure BDA0001691645820000911
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.59(s,1H),8.37(m,1H),7.87(m,1H),7.37(m,1H),6.80(s,2H),6.54(s,1H),6.43(s,1H),6.02(s,2H),4.48(s,2H),3.36(m,4H),2.26(s,6H),1.86(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ163.5,157.2,148.2,147.7,147.2,144.3,139.4,136.6,135.7,134.2,123.4,119.9,117.8,49.9,45.3,41.2,28.6,21.6.
the mass spectrum is as follows: MS (EI, M/z):439 (M)++H).
Example 131
The difference from example 127 is that: (Z) -4- ((2-aminoethyl) amino) -N- (4-bromo-3-fluorophenyl) -N '-hydroxy-1, 2, 5-oxadiazole-3-carboximidamide (II-1) was replaced by (Z) -4- ((2-aminoethyl) amino) -N- (4-trifluoromethylphenyl) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboximidamide, the structural formula of the prepared (Z) -N' -hydroxy-4- ((2- (3- (pyridine-3-ylmethyl) urea) ethyl) amino) -N- (4- (trifluoromethyl) phenyl) -1,2, 5-oxadiazole-3-imidazole is as follows:
Figure BDA0001691645820000912
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.59(s,1H),8.37(m,1H),7.87(m,1H),7.37(m,3H),6.60(d,J＝6.4Hz,2H),6.44(s,1H),6.02(s,2H),4.48(s,2H),3.53(m,4H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ163.5,157.2,148.9,147.8,147.3,141.3,135.6,134.9,134.3,126.4,125.5,124.8,123.8,116.6,48.3,45.9,41.6.
the mass spectrum is as follows: MS (EI, M/z):465 (M)++H).
Example 132
The difference from example 127 is that: (Z) -4- ((2-aminoethyl) amino) -N- (4-bromo-3-fluorophenyl) -N '-hydroxy-1, 2, 5-oxadiazol-3-carboximidamide (II-1) was replaced by (Z) -4- ((2-aminopropyl) amino) -N- (4-trifluoromethylphenyl) -N' -hydroxy-1, 2, 5-oxadiazol-3-carboximidamide, the structural formula of the prepared (Z) -N' -hydroxy-4- ((2- (3- (pyridine-3-ylmethyl) urea) ethyl) amino) -N- (4- (trifluoromethyl) phenyl) -1,2, 5-oxadiazole-3-imidazole is as follows:
Figure BDA0001691645820000921
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.59(s,1H),8.37(m,1H),7.89(m,1H),7.37(m,3H),6.60(d,J＝6.4Hz,2H),6.44(s,1H),6.00(s,2H),4.46(s,2H),3.38(m,4H),1.85(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ163.5,157.2,148.9,147.8,146.3,142.3,135.6,134.9,134.3,126.4,125.5,124.8,123.4,116.6,50.3,45.9,41.6,28.9.
the mass spectrum is as follows: MS (EI, M/z):479 (M)++H).
Example 133
The difference from example 127 is that: (Z) -N ' -hydroxy-N- (4- (morpholin-1-ylsulfonyl) phenyl) -4- ((2- (3-pyridin-3-ylmethyl) ureido) ethyl) amino) -1 prepared by replacing (Z) -4- ((2-aminoethyl) amino) -N- (4-bromo-3-fluorophenyl) -N ' -hydroxy-1, 2,5-1,2, 5-oxadiazole-3-carboximidamide (II-1) with (Z) -4- ((2-aminoethyl) amino) -N- (4- (morpholin-1-ylsulfonyl) phenyl) -N ' -hydroxy-1, 2, 5-oxadiazole-3-carboximidamide, the structural formula of the 2, 5-oxadiazole-3-formamidine is as follows:
Figure BDA0001691645820000922
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.59(s,1H),8.37(m,1H),7.87(m,1H),7.57(d,J＝5.6Hz,2H),7.30(m,1H),6.83(d,J＝5.6Hz,2H),6.44(s,1H),6.02(s,2H),4.43(s,2H),3.43(m,8H),2.93(t,J＝8.8Hz,4H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ163.5,157.2,148.7,147.4,146.9,140.3,136.4,135.6,134.2,130.4,129.5,123.8,112.8,65.6,48.3,47.9,45.3,41.6.
the mass spectrum is as follows: MS (EI, m)/z):546(M++H).
Example 134
The difference from example 127 is that: (Z) -N ' -hydroxy-N- (4- (morpholinesulfonyl) phenyl) -4- ((2- (3-pyridin-3-ylmethyl) ureido) propyl) amino) -1 prepared by replacing (Z) -4- ((2-aminoethyl) amino) -N- (4-bromo-3-fluorophenyl) -N ' -hydroxy-1, 2,5-1,2, 5-oxadiazole-3-carboximidamide (II-1) with (Z) -4- ((2-aminopropyl) amino) -N- (4- (morpholin-1-ylsulfonyl) phenyl) -N ' -hydroxy-1, 2, 5-oxadiazole-3-carboximidamide (Z), the structural formula of the 2, 5-oxadiazole-3-formamidine is as follows:
Figure BDA0001691645820000931
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.59(s,1H),8.37(m,1H),7.87(m,1H),7.57(d,J＝5.6Hz,2H),7.30(m,1H),6.83(d,J＝5.6Hz,2H),6.44(s,1H),6.02(s,2H),4.43(s,2H),3.69(t,J＝8.8Hz,4H),3.33(m,4H),2.93(t,J＝8.8Hz,4H),1.83(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ163.5,157.2,148.7,147.4,146.9,140.3,136.4,135.6,134.2,130.4,129.5,123.8,112.8,65.6,50.3,47.9,45.3,41.6,29.6.
the mass spectrum is as follows: MS (EI, M/z):560 (M)++H).
Example 135
The difference from example 127 is that: (Z) -N ' -hydroxy-N- (4- (2-hydroxyethyl) sulfonamido) phenyl) -4- ((2- (3-pyridin-3-ylmethyl) ureido) ethyl) amino) -1 prepared by substituting (Z) -4- ((2-aminoethyl) amino) -N- (4- (2-hydroxyethyl) sulfonamido) phenyl) -N ' -hydroxy-1, 2, 5-oxadiazole-3-carboxamide (II-1) with (Z) -4- ((2-aminoethyl) amino) -N- (4- (2-hydroxyethyl) sulfonamido) phenyl) -N ' -hydroxy-1, 2, 5-oxadiazole-3-carboxamide, the structural formula of the 2, 5-oxadiazole-3-formamidine is as follows:
Figure BDA0001691645820000932
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.59(s,1H),8.33(m,1H),7.87(m,1H),7.37(m,2H),7.17(d,J＝5.6Hz,2H),6.77(d,J＝5.6Hz,2H),6.44(s,1H),6.02(s,2H),4.68(s,1H),4.48(s,2H),3.43(m,8H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ163.5,157.2,149.2,148.1,147.6,140.3,136.1,135.6,134.8,134.2,130.4,123.5,112.8,61.8,48.6,45.8,45.2,41.6.
the mass spectrum is as follows: MS (EI, M/z):520 (M)++H).
Example 136
The difference from example 127 is that: (Z) -N ' -hydroxy-N- (4- (2-hydroxyethyl) sulfonamido) phenyl) -4- ((2- (3-pyridin-3-ylmethyl) ureido) propyl) amino) -1,2, 5-oxadiazole-3-carboxylic acid (II-1) prepared by replacing (Z) -4- ((2-aminoethyl) amino) -N- (4-bromo-3-fluorophenyl) -N ' -hydroxy-1, 2, 5-oxadiazole-3-carboxylic acid (II-1) with (Z) -4- ((2-aminopropyl) amino) -N- (4- (2-hydroxyethyl) sulfonamido) phenyl) -N ' -hydroxy-1, 2, 5-oxadiazole-3-carboxylic acid, the structural formula of the 2, 5-oxadiazole-3-formamidine is as follows:
Figure BDA0001691645820000941
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.59(s,1H),8.33(m,1H),7.87(m,1H),7.37(m,2H),7.17(d,J＝5.6Hz,2H),6.77(d,J＝5.6Hz,2H),6.44(s,1H),6.02(s,2H),4.68(s,1H),4.48(s,2H),3.40(m,8H),1.80(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ163.6,157.2,149.2,148.1,147.6,140.3,136.1,135.6,134.8,134.0,130.1,123.5,112.8,61.1,50.6,45.8,45.2,41.6,29.3.
the mass spectrum is as follows: MS (EI, M/z):534 (M)++H).
Example 137
The difference from example 127 is that: (Z) -N ' -hydroxy-N- (4- (4-methylpiperazin-1-yl) phenyl) -4- ((2- (3-pyridin-3-ylmethyl) thioureido) ethyl) amino) -1 prepared by replacing (Z) -4- ((2-aminoethyl) amino) -N- (4-bromo-3-fluorophenyl) -N ' -hydroxy-1, 2, 5-oxadiazol-3-imidazole (II-1) with (Z) -4- ((2-aminoethyl) amino) -N- (4- (4-methylpiperazin-1-yl) phenyl) -N ' -hydroxy-1, 2, 5-oxadiazol-3-imidazole, the structural formula of the 2, 5-oxadiazole-3-formamidine is as follows:
Figure BDA0001691645820000942
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,2H),8.59(s,1H),8.32(m,1H),7.87(m,1H),7.30(m,2H),6.64(d,J＝5.6Hz,2H),6.44(d,J＝5.6Hz,2H),6.04(s,2H),4.78(s,2H),3.89(m,2H),3.44(m,6H),2.34(t,J＝9.6Hz,4H),2.29(s,3H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ183.5,162.2,148.9,147.2,146.5,139.6,136.2,135.3,134.4,128.6,123.2,117.4,114.5,57.8,52.8,50.6,48.3,46.9,46.3.
the mass spectrum is as follows: MS (EI, M/z):511 (M)++H).
Example 138
The difference from example 127 is that: wherein (Z) -N ' -hydroxy-N- (4- (4-methylpiperazin-1-yl) phenyl) -4- ((2- (3-pyridin-3-ylmethyl) thioureido) propyl) amino) -1 is prepared by replacing (Z) -4- ((2-aminoethyl) amino) -N- (4-bromo-3-fluorophenyl) -N ' -hydroxy-1, 2, 5-oxadiazol-3-carboximidamide (II-1) with (Z) -4- ((2-aminopropyl) amino) -N- (4- (4-methylpiperazin-1-yl) phenyl) -N ' -hydroxy-1, 2, 5-oxadiazol-3-carboximidamide (Z), the structural formula of the 2, 5-oxadiazole-3-formamidine is as follows:
Figure BDA0001691645820000951
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,2H),8.59(s,1H),8.32(m,1H),7.87(m,1H),7.30(m,2H),6.64(d,J＝5.6Hz,2H),6.44(d,J＝5.6Hz,2H),6.04(s,2H),4.72(s,2H),3.69(m,2H),3.35(m,6H),2.34(t,J＝9.6Hz,4H),2.21(s,3H),1.91(s,3H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ183.2,162.2,148.9,147.2,146.5,139.6,136.2,135.3,134.4,128.6,123.2,117.4,114.5,57.8,52.8,50.6,46.3,44.9,42.3,29.4.
the mass spectrum is as follows: MS (EI, M/z) 525 (M)++H).
Example 139
The difference from example 127 is that: (Z) -N ' -hydroxy-N- (4- (2-methoxyethoxy) phenyl) -4- ((2- (3-pyridin-3-ylmethyl) thioureido) ethyl) amino) -1 prepared by substituting (Z) -4- ((2-aminoethyl) amino) -N- (4-bromo-3-fluorophenyl) -N ' -hydroxy-1, 2, 5-oxadiazole-3-carboximidamide (II-1) with (Z) -4- ((2-aminoethyl) amino) -N- (4-methoxyethoxy) phenyl) -N ' -hydroxy-1, 2, 5-oxadiazole-3-carboximidamide, the structural formula of the 2, 5-oxadiazole-3-formamidine is as follows:
Figure BDA0001691645820000952
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.04(s,1H),9.85(s,2H),8.59(s,1H),8.37(m,1H),7.82(m,3H),7.31(m,2H),6.57(d,J＝5.6Hz,2H),6.04(s,1H),4.78(s,2H),4.36(t,J＝9.2Hz,2H),3.78(m,4H),3.49(m,2H),3.35(s,3H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ183.5,163.5,149.2,148.9,147.8,146.5,136.2,135.4,134.4,129.6,123.2,116.8,115.8,72.6,68.3,59.9,50.3,48.6,46.6.
the mass spectrum is as follows: MS (EI, M/z):487 (M)++H).
Example 140
The difference from example 127 is that: (Z) -N ' -hydroxy-N- (4- (2-methoxyethoxy) phenyl) -4- ((2- (3-pyridin-3-ylmethyl) thioureido) ethyl) amino) -1 prepared by substituting (Z) -4- ((2-aminoethyl) amino) -N- (4-bromo-3-fluorophenyl) -N ' -hydroxy-1, 2, 5-oxadiazole-3-carboximidamide (II-1) with (Z) -4- ((2-aminopropyl) amino) -N- (4-methoxyethoxy) phenyl) -N ' -hydroxy-1, 2, 5-oxadiazole-3-carboximidamide, the structural formula of the 2, 5-oxadiazole-3-formamidine is as follows:
Figure BDA0001691645820000961
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.04(s,1H),9.85(s,2H),8.54(s,1H),8.37(m,1H),7.82(m,3H),7.31(m,2H),6.57(d,J＝5.6Hz,2H),6.04(s,1H),4.66(s,2H),4.31(t,J＝9.2Hz,2H),3.65(m,4H),3.35(s,3H),3.30(m,2H),1.86(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ183.5,163.5,149.2,148.9,147.8,146.5,136.2,135.4,134.4,129.6,123.2,116.8,115.8,72.4,68.1,59.4,50.3,44.6,42.6,30.3.
the mass spectrum is as follows: MS (EI, M/z):501 (M)++H).
Synthetic route of the Compound represented by the general formula I (synthetic route of C series Compound)
Figure BDA0001691645820000962
Example 141
Preparation of (Z) -N- (3-bromo-4-fluorophenyl) -4- ((2- ((E) -2-cyano-3- (pyridin-4-yl) guanidino) ethyl) amino) -N' -hydroxy-1, 2,5-1,2, 5-oxadiazole-3-carboximidamide, according to the following specific procedure:
Figure BDA0001691645820000963
sodium hydride (1.53g,63.83mmol) was added to DMF at 0 deg.C, 4-aminopyridine (5g,53.2mmol) and compound X (9.32g,63.83mmol) were added to the suspension in that order, and the mixture was allowed to react at room temperature for 24 h. After the reaction is finished, adding saturated ammonium chloride solution for quenching, and adding NaHCO3Adjusting Ph to 8, CH in solution2Cl2Extraction (50X 3mL), combining the organic phases, washing with brine, concentration, and column chromatography gave compound IX (9g, 90%). Compound IX (100mg,0.52mmol) and compound II-1(186mg,0.52mmol) were dissolved in pyridine, DMAP (6mg,0.052mmol) was added, and the mixture was heated to 50 ℃ to react for 24 hours. After the reaction was completed, the solvent was removed by rotary drying, and column chromatography was performed to give the objective compound (104mg, 40%). The hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.89(s,1H),8.47(d,J＝5.2Hz,2H),7.35(d,J＝5.2Hz,2H),6.90(m,2H),6.72(m,1H),6.02(s,1H),3.78(m,2H),3.43(m,2H),2.47(s,1H) ppm, its carbon spectrum is:13c NMR (125MHz, DMSO). delta. 163.5,158.2,155.9,154.8,149.2,147.1,142.2,134.2,119.5,118.8,117.8,116.6,110.7,109.3,48.3,35.9, mass spectrum: MS (EI, M/z):503 (M)++H).
Example 142
The difference from example 141 is that: (Z) -N- (3-bromo-4-fluorophenyl) -4- ((2- ((E) -2-cyano-3- (pyridin-4-yl) guanidino) propyl) amino) -N ' -hydroxy-1, 2, 5-oxadiazol-3-carboximidamide (II-1) prepared by replacing (Z) -4- ((2-aminoethyl) amino) -N- (4-bromo-3-fluorophenyl) -N ' -hydroxy-1, 2, 5-oxadiazol-3-carboximidamide (II-1) with (Z) -4- ((2-aminopropyl) amino) -N- (4-bromo-3-fluorophenyl) -N ' -hydroxy-1, the structural formula of the 2,5-1,2, 5-oxadiazole-3-imidazole is as follows:
Figure BDA0001691645820000971
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.00(s,1H),9.86(s,1H),8.82(s,1H),8.45(d,J＝5.2Hz,2H),7.35(d,J＝5.2Hz,2H),6.90(m,2H),6.72(m,1H),6.06(s,1H),3.58(m,2H),3.33(m,2H),2.47(s,1H),1.80(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ163.1,157.2,155.9,154.1,149.2,146.1,140.2,134.2,119.5,118.8,117.8,116.6,110.7,109.3,41.3,33.9,28.4.
the mass spectrum is as follows: MS (EI, M/z):517 (M)++H).
Example 143
The difference from example 141 is that: (Z) -N-4- ((2- ((E) -2-cyano-3- (pyridin-4-yl) guanidino) ethyl) amino) -N ' -hydroxy-N- (4- (trifluoromethyl) phenyl) -1 prepared by replacing (Z) -4- ((2-aminoethyl) amino) -N- (4-bromo-3-fluorophenyl) -N ' -hydroxy-1, 2, 5-oxadiazole-3-carboximidamide (II-1) with (Z) -4- ((2-aminoethyl) amino) -N- (4-trifluoromethylphenyl) -N ' -hydroxy-1, 2, 5-oxadiazole-3-carboximidamide, the structural formula of the 2, 5-oxadiazole-3-formamidine is as follows:
Figure BDA0001691645820000972
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.79(s,1H),8.47(m,1H),7.37(m,4H),6.60(d,J＝5.2Hz,2H),6.04(s,1H),3.78(s,2H),3.43(m,2H),2.48(s,1H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ163.5,158.5,155.2,150.8,147.2,141.3,134.4,126.6,125.2,124.4,117.5,116.8,110.6,48.3,35.9.
the mass spectrum is as follows: MS (EI, M/z):475 (M)++H).
Example 144
The difference from example 141 is that: (Z) -N-4- ((2- ((E) -2-cyano-3- (pyridin-4-yl) guanidino) propyl) amino) -N ' -hydroxy-N- (4- (trifluoromethyl) phenyl) -1 prepared by substituting (Z) -4- ((2-aminoethyl) amino) -N- (4-bromo-3-fluorophenyl) -N ' -hydroxy-1, 2, 5-oxadiazol-3-carboximidamide (II-1) with (Z) -4- ((2-aminopropyl) amino) -N- (4-trifluoromethylphenyl) -N ' -hydroxy-1, 2, 5-oxadiazol-3-carboximidamide, the structural formula of the 2, 5-oxadiazole-3-formamidine is as follows:
Figure BDA0001691645820000981
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.79(s,1H),8.45(m,1H),7.37(m,4H),6.62(d,J＝5.2Hz,2H),6.04(s,1H),3.58(s,2H),3.23(m,2H),2.48(s,1H),1.83(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ163.4,157.5,154.2,150.8,147.2,142.3,134.4,126.6,125.2,124.4,117.5,116.8,110.6,41.3,34.9,30.3.
the mass spectrum is as follows: MS (EI, M/z):489 (M)++H).
Example 145
The difference from example 141 is that: (Z) -N- (3-bromo-4-fluorophenyl) -4- ((2- ((E) -2-cyano-3- (pyridin-3-yl) guanidino) ethyl) amino) -N' -hydroxy-1, 2,5-1,2, 5-oxadiazole-3-carboximidamide, prepared by replacing 4-aminopyridine with 3-aminopyridine, has the following structural formula:
Figure BDA0001691645820000982
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.79(s,1H),8.53(m,1H),8.13(m,1H),7.43(m,1H),7.17(m,1H),6.87(m,2H),6.64(m,1H),6.02(s,1H),3.82(m,2H),3.48(m,2H),2.49(s,1H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ163.5,158.2,155.8,148.2,146.9,142.1,137.6,135.6,134.3,132.1,127.6,119.8,118.2,117.4,116.5,110.8,48.6,37.6.
the mass spectrum is as follows: MS (EI, M/z):503 (M)++H).
Example 146
The difference from example 141 is that: (Z) -N- (3-bromo-4-fluorophenyl) -4- ((2- ((E) -2-cyano-3- (pyridin-3-yl) guanidinoethyl) amino) -N' -hydroxy- The structural formula of the 1,2,5-1,2, 5-oxadiazole-3-imidazole is as follows:
Figure BDA0001691645820000991
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.79(s,1H),8.53(m,1H),8.13(m,1H),7.42(m,1H),7.15(m,1H),6.87(m,2H),6.64(m,1H),6.02(s,1H),3.52(m,2H),3.28(m,2H),2.49(s,1H),1.82(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ164.5,158.2,155.2,148.1,146.3,142.7,137.2,135.6,134.3,132.1,127.6,119.8,118.2,117.4,116.5,110.8,41.6,34.6,30.4.
the mass spectrum is as follows: MS (EI, M/z):517 (M)++H).
Example 147
The difference from example 141 is that: (Z) -4- ((2- ((E) -2-cyano-3- (pyridin-3-yl) guanidino) ethyl) amino) -N- (4-fluorophenyl) -N ' -hydroxy-1, 2, 5-oxadiazole-3-carboximidamide (II-1) prepared by replacing 4-aminopyridine with 3-aminopyridine and replacing (Z) -4- ((2-aminoethyl) amino) -N- (4-bromo-3-fluorophenyl) -N ' -hydroxy-1, 2, 5-oxadiazole-3-carboximidamide (II-1) with (Z) -4- ((2-aminoethyl) amino) -N- (4-fluorophenyl) -N ' -hydroxy-1, the structural formula of the 2, 5-oxadiazole-3-formamidine is as follows:
Figure BDA0001691645820000992
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.79(s,1H),8.50(m,1H),8.13(m,1H),7.33(m,1H),7.17(m,1H),6.97(d,J＝5.2Hz,2H),6.74(d,J＝5.2Hz,2H),6.02(s,1H),3.82(m,2H),3.48(m,2H),2.49(s,1H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ163.5,158.2,157.8,148.2,146.9,138.6,135.6,134.1,133.3,132.1,127.6,119.8,117.2,116.4,48.6,37.6.
the mass spectrum is as follows: MS (EI, M/z):425 (M)++H).
Example 148
The difference from example 141 is that: (Z) -4- ((2- ((E) -2-cyano-3- (pyridin-3-yl) guanidino) propyl) amino) -N- (4-fluorophenyl) -N ' -hydroxy-1, 2, 5-oxadiazol-3-carboximidamide (II-1) prepared by replacing 4-aminopyridine with 3-aminopyridine and replacing (Z) -4- ((2-aminoethyl) amino) -N- (4-bromo-3-fluorophenyl) -N ' -hydroxy-1, 2, 5-oxadiazol-3-carboximidamide (II-1) with (Z) -4- ((2-aminopropyl) amino) -N- (4-fluorophenyl) -N ' -hydroxy-1, the structural formula of the 2, 5-oxadiazole-3-formamidine is as follows:
Figure BDA0001691645820001001
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.02(s,1H),9.84(s,1H),8.79(s,1H),8.52(m,1H),8.13(m,1H),7.33(m,1H),7.17(m,1H),6.97(d,J＝5.2Hz,2H),6.74(d,J＝5.2Hz,2H),6.02(s,1H),3.56(m,2H),3.38(m,2H),2.49(s,1H),1.88(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ163.5,158.2,157.8,148.2,146.9,138.6,135.6,134.5,133.3,132.1,127.6,119.8,117.2,116.4,41.6,34.6,29.4.
the mass spectrum is as follows: MS (EI, M/z):439 (M)++H).
Synthetic route of the Compound represented by the general formula I (synthetic method of D series Compound)
Figure BDA0001691645820001002
Example 149
Preparation of (Z) -N- (2- ((4- (3-bromo-4-fluorophenyl) -N' -hydroxymethylimidazole) -1,2,5-1,2, 5-oxadiazol-3-yl) amino) ethyl) -2- (pyridin-3-yl) cyclopropane-1-carboxamide as follows:
Figure BDA0001691645820001011
3-bromopyridine (157g,0.994mol), n-butyl acrylate (192g,1.50mmol), Pd (OAc) under nitrogen protection2(2.3g,10.2mmol,)、PPh3(5.2g,19.8mmol)、K2CO3(276g,2.00mol) was added to DMF (200ml) and heated to 130 ℃ for 20 h. Cooled to room temperature, filtered, the filtrate was concentrated, water was added thereto, extracted with ethyl acetate (500 ml. times.3), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to give compound 8(160 g). Compound 8(70g, 0.34mol) was dissolved in ethanol (150ml), and potassium hydroxide (40g,0.71mol) was dissolved in water (150ml), which was added to the above solution, and heated under reflux for 3 hours. After the reaction was completed, Ph was adjusted to 6.0 with 12M HCl, and precipitate was separated, filtered, and the filter cake was collected to obtain compound 9(50g, 98%). Compound 9(50g,0.34mol) and N, O-dimethylhydroxylamine hydrochloride (65g,0.67mol) were dissolved in dichloromethane (1L), EDCI (127g,0.66mol) and DMAP (80g,0.65mol) were added in this order, and the reaction was stirred at room temperature for 2 h. After completion of the reaction, 200ml of water was added, extraction was performed with dichloromethane (1L. times.2), the organic phases were combined, washed with saturated brine (500 ml. times.3), dried over anhydrous sodium sulfate, and concentrated to obtain 70g of crude compound 10. Trimethylsulfanyliodide (145g,0.67mol) was dissolved in DMSO (500ml) at 0 ℃,sodium hydrogen (26g,1.1mol) was added to the above solution. After stirring at room temperature for 1h, compound 10(66g,0.34mol) was added to the solution described above and the reaction was continued at room temperature for 1 h. After the reaction was completed, it was quenched by addition of saturated ammonium chloride solution (400mL), extracted with ethyl acetate (3X 1L), and the organic phases were combined, washed with water (3X 500mL), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to give compound 11(56g, 80%) as a yellow oil. Compound 11(50g,0.24mol) was dissolved in ethanol, potassium hydroxide (40g,0.71mol) was dissolved in water (100mL), added to the above solution, heated under reflux for 3h, after completion of the reaction, water (300mL) was added, dichloromethane (3X 100mL) was extracted, the pH of the aqueous phase was adjusted to 6.0 with 12M HCl, and then the aqueous phase was concentrated to give a solid, methanol was added to the solid, insoluble material was filtered off, and the filtrate was concentrated to give 34g of crude compound 12 as pale yellow. Compound 12(1.0g,6.13mmol) was dissolved in anhydrous dichloromethane (5mL), sulfoxide chloride (10mL,138mmol) and 1 drop of DMF were added, and the mixture was heated to 40 ℃ and reacted for 5 h. Cooled to room temperature and concentrated to give crude compound 13(1.34 g). Compound II-1 was dissolved in anhydrous DMF, triethylamine (1.0g,10mmol) was added, and the prepared acid chloride compound 13(0.18g,0.99mmol) was dissolved in anhydrous DMF and added dropwise to II-1(461.82mg,1.29mmol) and reacted at room temperature for 4 h. The reaction mixture was concentrated, and column chromatography was performed to give the objective compound (149mg, 30%).
The synthesis was as in example 1. The hydrogen spectrum of nuclear magnetic resonance is as follows:1h NMR (400MHz, DMSO) < delta > 11.04(s,1H),9.87(s,1H),8.37(m,2H),8.01(s,1H),7.58(m,1H),7.12(m,1H),6.74(m,3H),6.08(s,1H),3.47(m,4H),3.17(m,1H),2.83(m,1H),1.83(m,2H) ppm, whose carbon spectrum is:13c NMR (125MHz, DMSO). delta. 174.5,163.2,155.9,151.2,148.2,147.3,143.4,142.6,135.2,134.5,123.4,119.0,118.8,117.8,110.6,48.3,39.6,27.8,25.2,16.4. mass spectra are: MS (EI, M/z):504 (M)++H).
Example 150
The difference from example 149 is that: (Z) -N- (2- ((4- (3-bromo-4-fluorophenyl) -N ' -hydroxymethylate) -1,2,5-1,2, 5-oxadiazol-3-yl) propyl) -2- (pyridin-3-yl) cyclopropane-1-propyl) -2- (pyridin-3-yl) cyclopropane-1-yl) prepared by replacing (Z) -4- ((2-aminoethyl) amino) -N- (4-bromo-3-fluorophenyl) -N ' -hydroxy-1, 2, 5-oxadiazol-3-yl (II-1) with (Z) -4- ((2-aminopropyl) amino) -N- (4-bromo-3-fluorophenyl) -N ' -hydroxy-1, 2, 5-oxadiazol-3-yl) amino) propyl) -2- (pyridin-3-yl) cyclopropane-3-yl (II-1) The structural formula of formamide is as follows:
Figure BDA0001691645820001021
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.37(m,2H),8.01(s,1H),7.52(m,1H),7.11(m,1H),6.75(m,3H),6.04(s,1H),3.37(m,2H),3.17(m,3H),2.83(m,1H),1.83(m,4Hppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ174.5,163.2,155.9,151.2,148.2,147.3,143.4,142.6,135.2,134.5,123.4,119.0,118.8,117.8,110.6,41.3,38.6,29.4,27.8,25.2,17.4.
the mass spectrum is as follows: MS (EI, M/z):518 (M)++H).
Example 151
The difference from example 149 is that: (Z) -N- (2- ((4- (N' -hydroxy-N- (4- (2-methoxyethoxy) phenyl) carbamimidoyl) -,2, 5-oxadiazol-3-yl) amino) ethyl) -2- (pyridin-3-yl) cyclopropane-1-yl- The structural formula of formamide is as follows:
Figure BDA0001691645820001022
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.38(m,2H),8.08(s,1H),7.73(m,3H),7.22(m,1H),6.54(d,J＝4.8Hz,1H),6.08(s,1H),4.32(t,J＝8.4Hz,2H),3.74(t,J＝8.4Hz,2H),3.54(m,4H),3.36(s,3H),3.13(m,1H),2.86(m,1H),1.89(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ174.5,164.1,150.9,149.7,149.2,148.5,147.2,143.3,135.4,134.6,129.2,123.4,116.8,114.8,72.6,69.3,58.5,48.3,39.6,26.7,24.5,17.8.
the mass spectrum is as follows: mS(EI,m/z):482(M++H).
Example 152
The difference from example 149 is that: (Z) -N- (2- ((4- (N ' -hydroxy-N- (4- (2-methoxyethoxy) phenyl) carbamimidoyl) -1,2, 5-oxadiazol-3-yl) amino) ethyl) -2- (pyridin-3-yl) cyclopropane-1-carboxylic acid prepared by substituting (Z) -4- ((2-aminoethyl) amino) -N- (4-methoxyethoxyphenyl) -N ' -hydroxy-1, 2, 5-oxadiazol-3-carboxylic acid (II-1) with (Z) -4- ((2-aminopropyl) amino) -N- (4-methoxyethoxyphenyl) -N ' -hydroxy-1, 2, 5-oxadiazol-3-yl) amino) ethyl) -2- (pyridin-3-yl) cyclopropane-1-carboxylic acid The structural formula of formamide is as follows:
Figure BDA0001691645820001031
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.24(s,1H),9.87(s,1H),8.38(m,2H),8.08(s,1H),7.70(m,3H),7.22(m,1H),6.54(d,J＝4.8Hz,1H),6.08(s,1H),4.30(t,J＝8.4Hz,2H),3.72(t,J＝8.4Hz,2H),3.42(s,3H),3.34(m,2H),3.18(m,3H),2.79(m,1H),1.84(m,4H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ174.5,164.1,150.9,149.7,149.2,148.5,147.2,143.3,135.4,134.6,129.2,123.4,116.8,114.8,72.6,69.3,58.5,48.3,39.6,26.7,24.5,17.8.
the mass spectrum is as follows: MS (EI, M/z):496 (M)++H).
Synthetic route of the Compound represented by the general formula I (synthetic method of E series Compound)
Figure BDA0001691645820001032
Example 153
Preparation of (Z) -N- (2- ((4- (N- (3-bromo-4-fluorophenyl) -N' -hydroxymethylimidyl) -1,2, 5-oxadiazol-3-yl) amino) ethyl) -1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridine-2-acrylamide using the following specific steps:
Figure BDA0001691645820001041
compound II-1(1g,2.79mmol) was dissolved in anhydrous toluene, and compound 14(1.1g,5.58mmol) was added to the above solution, and the temperature was raised to 120 ℃ under nitrogen protection, and reacted for 30 min. Cooled to room temperature, filtered, and the filter cake washed with toluene to give compound VIII-1(1.3g, 90%). Compound 15(114mg,0.96mmol) and compound VIII-1(500mg,0.96mmol) were dissolved in ethanol, the temperature was raised to 90 ℃ and the reaction was stopped after 2 hours. Cooled to room temperature, concentrated, and subjected to column chromatography to give the title compound (193mg, 40%). The hydrogen spectrum of nuclear magnetic resonance is as follows:1h NMR (400MHz, DMSO) < delta > 11.14(s,1H),9.87(s,1H),8.65(s,1H),8.11(m,1H),7.19(m,1H),6.87(m,2H),6.65(m,1H),6.04(s,2H),5.20(s,2H),4.45(s,2H),3.36(m,4H) ppm, whose carbon spectrum is:13c NMR (125MHz, DMSO). delta. 163.5,158.2,155.3,150.9,148.1,147.4,146.6,142.5,134.5,133.4,124.7,119.7,118.6,117.2,110.6,58.4,57.3,48.9,41.2. mass spectra are: MS (EI, M/z) 505 (M)++H).
Example 154
The difference from the embodiment 153 is that: (Z) -N- (2- ((4- (N- (3-bromo-4-fluorophenyl) -N ' -hydroxymethylamino) -1,2, 5-oxadiazol-3-yl) propyl) -1,2, 5-oxadiazol-3-carbonitrile prepared by substituting (Z) -4- ((2-aminopropyl) amino) -N- (4-bromo-3-fluorophenyl) -N ' -hydroxy-1, 2, 5-oxadiazol-3-carbonitrile (II-1) with (Z) -4- ((2-aminopropyl) amino) -N- (4-bromo-3-fluorophenyl) -N ' -hydroxymethylimidyl) -1,2, 5-oxadiazol-3-yl) amino) propyl) -1, the structural formula of the 3-dihydro-2H-pyrrole [3,4-c ] pyridine-2-acrylamide is as follows:
Figure BDA0001691645820001042
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.04(s,1H),9.89(s,1H),8.65(s,1H),8.11(m,1H),7.19(m,1H),6.87(m,2H),6.65(m,1H),6.04(s,2H),5.20(s,2H),4.45(s,2H),3.34(m,4H),1.84(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ163.2,158.2,154.3,150.9,148.1,147.2,146.6,142.5,134.2,133.4,124.7,119.7,118.6,117.2,110.6,58.9,57.3,49.9,41.0,28.4.
the mass spectrum is as follows: MS (EI, M/z):519 (M)++H).
Example 155
The difference from the embodiment 153 is that: (Z) -N- (2- ((4- (N ' -hydroxy-N- (4- (2-methoxyethoxy) phenyl) carbamimidoyl) -1,2, 5-oxadiazol-3-yl) amino) ethyl) -1 obtained by substituting (Z) -4- ((2-aminoethyl) amino) -N- (4-methoxyethoxyphenyl) -N ' -hydroxy-1, 2, 5-oxadiazol-3-carboxamid (II-1) with (Z) -4- ((2-aminoethyl) amino) -N- (4-methoxyethoxyphenyl) -N ' -hydroxy-1, 2, 5-oxadiazol-3-yl) amino) ethyl) -1, the structural formula of the 3-dihydro-2H-pyrrole [3,4-c ] pyridine-2-acrylamide is as follows:
Figure BDA0001691645820001051
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.04(s,1H),9.89(s,1H),8.60(s,1H),8.11(m,1H),7.79(m,2H),7.19(m,1H),6.57(m,2H),6.05(s,2H),5.20(s,2H),4.45(s,2H),4.33(t,J＝6.8Hz,2H),3.73(t,J＝6.8Hz,2H),3.48(m,4H),3.35(s,3H)ppm
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ163.5,157.2,150.9,149.7,148.1,147.4,146.7,134.5,133.4,129.7,124.7,116.6,115.2,72.4,69.5,59.4,58.1,57.3,48.7,41.2
the mass spectrum is as follows: MS (EI, M/z):482 (M)++H).
Example 156
The difference from the embodiment 153 is that: (Z) -N- (2- ((4- (N ' -hydroxy-N- (4- (2-methoxyethoxy) phenyl) carbamimidoyl) -1,2, 5-oxadiazol-3-yl) amino) propyl) -1 obtained by substituting (Z) -4- ((2-aminoethyl) amino) -N- (4-bromoethyl-3-fluorophenyl) -N ' -hydroxy-1, 2, 5-oxadiazol-3-carbamimidoyl (II-1) with (Z) -4- ((2-aminopropyl) amino) -N- (4-methoxyethoxyphenyl) -N ' -hydroxy-1, 2, 5-oxadiazol-3-yl) amino) propyl) -1, the structural formula of the 3-dihydro-2H-pyrrole [3,4-c ] pyridine-2-acrylamide is as follows:
Figure BDA0001691645820001052
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.04(s,1H),9.89(s,1H),8.60(s,1H),8.11(m,1H),7.79(m,2H),7.19(m,1H),6.57(m,2H),6.05(s,2H),5.20(s,2H),4.45(s,2H),4.33(t,J＝6.8Hz,2H),3.73(t,J＝6.8Hz,2H),3.42(s,3H),3.32(m,4H),1.82(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ163.1,157.2,150.9,149.3,148.1,147.4,146.7,134.5,133.0,128.7,124.7,116.6,115.2,72.4,69.5,59.4,58.1,57.3,50.4,41.7,28.7.
the mass spectrum is as follows: MS (EI, M/z):497 (M)++H).
Example 157
The difference from the embodiment 153 is that: (Z) -N- (2- ((4- (N- (4-trifluorophenyl) -N ' -hydroxymethylimino) -1,2, 5-oxadiazol-3-yl) amino) ethyl) -1, 3-dihydro-2H-pyrrolo [3 ] which was prepared by replacing (Z) -4- ((2-aminoethyl) amino) -N- (4-bromo-3-fluorophenyl) -N ' -hydroxy-1, 2, 5-oxadiazol-3-carboximidamide (II-1) with (Z) -4- ((2-aminoethyl) amino) -N- (4-trifluoromethylphenyl) -N ' -hydroxy-1, 2, 5-oxadiazol-3-yl) amino) ethyl) -1, 3-dihydro-2H-pyrrolo [3 ], the structural formula of 4-c ] pyridine-2-acrylamide is as follows:
Figure BDA0001691645820001061
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.24(s,1H),9.84(s,1H),8.65(s,1H),8.10(m,1H),7.32(d,J＝4.8Hz,2H),7.19(m,1H),6.67(d,J＝4.8Hz,2H),6.04(s,2H),5.20(s,2H),4.45(s,2H),3.56(m,4H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ163.5,158.2,151.3,147.9,147.1,146.4,141.5,134.5,133.4,126.4,125.3,124.7,124.1,116.7,58.4,57.3,48.9,41.2.
the mass spectrum is as follows: MS (EI, M/z):477 (M)++H).
Example 158
The difference from the embodiment 153 is that: (Z) -N- (2- ((4- (N- (4-trifluorophenyl) -N ' -hydroxymethylimino) -1,2, 5-oxadiazol-3-yl) amino) propyl) -1, 3-dihydro-2H-pyrrolo [3 ] which was prepared by replacing (Z) -4- ((2-aminoethyl) amino) -N- (4-bromo-3-fluorophenyl) -N ' -hydroxy-1, 2, 5-oxadiazol-3-carboximidamide (II-1) with (Z) -4- ((2-aminopropyl) amino) -N- (4-trifluoromethylphenyl) -N ' -hydroxy-1, 2, 5-oxadiazol-3-yl) amino) propyl) -1, 3-dihydro-2H-pyrrolo [3 ], the structural formula of 4-c ] pyridine-2-acrylamide is as follows:
Figure BDA0001691645820001062
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.04(s,1H),9.84(s,1H),8.65(s,1H),8.12(m,1H),7.34(d,J＝4.8Hz,2H),7.19(m,1H),6.67(d,J＝4.8Hz,2H),6.04(s,2H),5.20(s,2H),4.45(s,2H),3.33(m,4H),1.86(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ163.5,158.3,151.3,145.3,147.1,146.4,140.5,134.5,133.4,127.4,125.3,124.7,123.1,116.7,58.4,57.3,50.9,41.2,29.5.
the mass spectrum is as follows: MS (EI, M/z):491 (M)++H).
Example 159
The difference from the embodiment 153 is that: (Z) -N- (2- ((4- (N- (4- (ethylcarbamoyl) phenyl-N ' -hydroxymethylimino) -1,2, 5-oxadiazol-3-yl) amino) ethyl) -1 obtained by substituting (Z) -4- ((2-aminoethyl) amino) -N- (4-bromo-3-fluorophenyl) -N ' -hydroxy-1, 2, 5-oxadiazol-3-carboximidamide (II-1) with (Z) -4- ((2-aminoethyl) amino) -N- (4- (ethylcarbamoyl) phenyl) -N ' -hydroxy-1, 2, 5-oxadiazol-3-yl) amino) ethyl) -1, preparation of 3-dihydro-2H-pyrrolo [3,4-c ] pyridine-2-acrylamide the structural formula of acrylamide is as follows:
Figure BDA0001691645820001071
the hydrogen spectrum of nuclear magnetic resonance is as follows:1h NMR (400MHz, DMSO): δ 11.04(s,1H),9.87(s,1H),8.65(s,1H),8.45(s,1H),8.11(m,1H),7.54(d, J ═ 4.8Hz,2H),7.19(m,1H),6.94(d, J ═ 4.8Hz,2H),6.04(s,2H),5.20(s,2H),4.45(s,2H),3.46(m,4H),3.28(q, J ═ 8.0Hz,2H),1.04(t, J ═ 8.0Hz,3H) ppm.13C NMR(125MHz,DMSO):δ167.5,163.5,158.2,150.3,147.9,147.2,146.1,141.4,134.6,133.5,125.5,124.4,118.7,116.7,58.3,57.1,48.9,41.2,34.9,15.6.
The mass spectrum is as follows: mS(EI,m/z):480(M++H).
Example 160
The difference from the embodiment 153 is that: wherein (Z) -N- (2- ((4- (N- (4- (ethylcarbamoyl) phenyl-N ' -hydroxymethylimino) -1,2, 5-oxadiazol-3-yl) amino) propyl) -1 is prepared by replacing (Z) -4- ((2-aminoethyl) amino) -N- (4-bromo-3-fluorophenyl) -N ' -hydroxy-1, 2, 5-oxadiazol-3-carboximidamide (II-1) with (Z) -4- ((2-aminopropyl) amino) -N- (4- (ethylcarbamoyl) phenyl) -N ' -hydroxy-1, 2, 5-oxadiazol-3-yl) amino) propyl) -1, preparation of 3-dihydro-2H-pyrrolo [3,4-c ] pyridine-2-acrylamide the structural formula of acrylamide is as follows:
Figure BDA0001691645820001072
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.65(s,1H),8.45(s,1H),8.11(m,1H),7.54(d,J＝4.8Hz,2H),7.19(m,1H),6.94(d,J＝4.8Hz,2H),6.04(s,2H),5.20(s,2H),4.45(s,2H),3.45(m,4H),3.18(q,J＝8.0Hz,2H),1.85(m,2H),1.04(t,J＝8.0Hz,3H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ167.1,163.5,158.2,150.0,147.9,147.2,145.1,141.4,134.6,133.5,125.5,123.4,118.7,116.7,58.3,57.1,50.9,41.2,34.9,28.0,15.6.
the mass spectrum is as follows: MS (EI, M/z):494 (M)++H).
Example 161
The difference from the embodiment 153 is that: (Z) -N- (2- ((4- (N- (3, 5-dimethyl-4- ((2-morpholinoethyl) carbamoyl) phenyl) -N ' -hydroxyformamidine) -1 prepared by substituting (Z) -4- ((2-aminoethyl) amino) -N- (4- (N- (3, 5-dimethyl-4- ((2-morpholinoethyl) carbamoyl) phenyl) -N ' -hydroxy-1, 2, 5-oxadiazole-3-formamidine (II-1) with (Z) -4- ((2-aminoethyl) amino) -N- (4- (N- (3, 5-dimethyl-4- ((2-morpholinoethyl) carbamoyl) phenyl) -N ' -hydroxyformamidine) -1, the structural formula of 2, 5-oxadiazol-3-yl) amino) ethyl) -1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridine-2-acrylamide is as follows:
Figure BDA0001691645820001081
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.85(s,1H),8.65(s,1H),8.11(m,1H),7.19(m,1H),6.97(s,2H),6.04(s,2H),5.20(s,2H),4.45(s,2H),3.56(m,6H),2.46(m,12H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ167.4,163.5,157.2,150.9,148.4,147.7,147.2,146.6,137.5,134.5,133.4,127.6,124.7,113.7,66.9,58.4,57.3,55.6,54.7,48.9,41.2,37.2,18.9.
the mass spectrum is as follows: MS (EI, M/z):593 (M)++H).
Example 162
The difference from the embodiment 153 is that: (Z) -N- (2- ((4- (N- (3, 5-dimethyl-4- ((2-morpholinoethyl) carbamoyl) phenyl) -N ' -hydroxyformamidine) -1 prepared by substituting (Z) -4- ((2-aminoethyl) amino) -N- (4- (N- (3, 5-dimethyl-4- ((2-morpholinoethyl) carbamoyl) phenyl) -N ' -hydroxy-1, 2, 5-oxadiazole-3-formamidine (II-1) with (Z) -4- ((2-aminopropyl) amino) -N- (4- (N- (3, 5-dimethyl-4- ((2-morpholinoethyl) carbamoyl) phenyl) -N ' -hydroxyformamidine) -1, the structural formula of 2, 5-oxadiazol-3-yl) amino) propyl) -1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridine-2-acrylamide is as follows:
Figure BDA0001691645820001082
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.04(s,1H),9.77(s,1H),8.83(s,1H),8.65(s,1H),8.11(m,1H),7.19(m,1H),6.97(s,2H),6.08(s,2H),5.20(s,2H),4.45(s,2H),3.56(m,6H),3.36(m,4H),2.46(m,12H),1.86(m,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ167.4,163.5,157.2,150.9,148.4,147.7,147.2,146.6,137.5,134.5,133.4,127.6,124.7,113.7,66.9,58.4,57.3,55.4,54.3,50.7,41.9,37.2,28.9,18.9.
the mass spectrum is as follows: MS (EI, M/z):607 (M)++H).
Example 163
The difference from the embodiment 153 is that: (Z) -N- (2- ((4- (3- (diethylamino) propionylamino) phenyl) -N ' -hydroxymethylamino) -1,2, 5-oxadiazol-3-yl) ethyl) -1 obtained by replacing (Z) -4- ((2-aminoethyl) amino) -N- (4- (3- (diethylamino) propionylamino) phenyl) -N ' -hydroxy-1, 2, 5-oxadiazol-3-methanil (II-1) with (Z) -4- ((2-aminoethyl) amino) -N- (4- (3- (diethylamino) propionylamino) phenyl) -N ' -hydroxymethylimidyl) -1,2, 5-oxadiazol-3-yl) amino) ethyl) -1, the structural formula of the 3-dihydro-2H-pyrrole [3,4-c ] pyridine-2-acrylamide is as follows:
Figure BDA0001691645820001091
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ10.84(s,1H),9.89(s,1H),9.80(s,1H),8.65(s,1H),8.11(m,1H),7.34(d,J＝4.4Hz,2H),7.19(m,1H),6.77(d,J＝4.4Hz,2H),6.04(s,2H),5.20(s,2H),4.45(s,2H),3.76(t,J＝8.4Hz,2H),3.55(m,4H),3.06(q,J＝8.8Hz,4H),2.55(t,J＝8.4Hz,2H),1.16(t,J＝8.8Hz,6H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ173.4,163.5,157.2,150.9,148.4,147.2,146.6,135.5,134.5,133.4,128.6,124.7,122.6,116.7,58.4,57.3,56.6,49.7,48.9,41.2,33.2,13.9.
the mass spectrum is as follows: MS (EI, M/z):551 (M)++H).
Example 164
The difference from the embodiment 153 is that: (Z) -N- (2- ((4- (3- (diethylamino) propionylamino) phenyl) -N ' -hydroxymethylimid) -1,2, 5-oxadiazol-3-yl) amino) propyl) -1 obtained by substituting (Z) -4- ((2-aminoethyl) amino) -N- (4- (3- (diethylamino) propionylamino) phenyl) -N ' -hydroxy-1, 2, 5-oxadiazol-3-methanil (II-1) with (Z) -4- ((2-aminopropyl) amino) -N- (4- (3- (diethylamino) propionylamino) phenyl) -N ' -hydroxymethylimid) -1,2, 5-oxadiazol-3-yl) amino) propyl) -1, the structural formula of the 3-dihydro-2H-pyrrole [3,4-c ] pyridine-2-acrylamide is as follows:
Figure BDA0001691645820001092
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ10.64(s,1H),9.89(s,1H),9.40(s,1H),8.65(s,1H),8.11(m,1H),7.34(d,J＝4.4Hz,2H),7.19(m,1H),6.77(d,J＝4.4Hz,2H),6.04(s,2H),5.20(s,2H),4.45(s,2H),3.76(t,J＝8.4Hz,2H),3.35(m,4H),3.06(q,J＝8.8Hz,4H),2.55(t,J＝8.4Hz,2H),1.88(m,2H),1.16(t,J＝8.8Hz,6H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ173.4,163.5,157.2,150.9,148.4,147.2,146.6,135.5,134.5,133.4,128.6,124.7,122.6,116.7,58.4,57.3,56.6,51.2,49.7,41.2,33.2,13.3.
the mass spectrum is as follows: MS (EI, M/z):565 (M)++H).
Example 165
The difference from the embodiment 153 is that: (Z) -N- (2- ((4- (N ' -hydroxy-N- (4-propionylaminophenyl) carbamimidoyl-1, 2, 5-oxadiazol-3-yl) amino) ethyl) -1, 3-dihydro-2H-pyrrole [3 ] which is prepared by replacing (Z) -4- ((2-aminoethyl) amino) -N- (4-bromo-3-fluorophenyl) -N ' -hydroxy-1, 2, 5-oxadiazol-3-carboxamid (II-1) with (Z) -4- ((2-aminoethyl) amino) -N- (4-propionylamino) phenyl) -N ' -hydroxy-1, 2, 5-oxadiazol-3-yl) amino) ethyl) -1, 3-dihydro-2H-pyrrol [3 ], the structural formula of 4-c ] pyridine-2-acrylamide is as follows:
Figure BDA0001691645820001101
the hydrogen spectrum of nuclear magnetic resonance is as follows:1h NMR (400MHz, DMSO): δ 11.04(s,1H),10.20(s,1H),9.87(s,1H),8.65(s,1H),8.11(m,1H),7.35(d, J ═ 6.4Hz,2H),7.19(m,1H),6.75(d, J ═ 6.4Hz,2H),6.04(s,2H),5.20(s,2H),4.45(s,2H),3.56(m,4H),2.36(q, J ═ 8.4Hz,2H),1.36(t, J ═ 8.4Hz,3H) ppm.13C NMR(125MHz,DMSO):δ172.4,163.5,157.2,150.9,147.7,147.2,146.6,134.5,133.4,132.6,128.6,124.7,122.5,116.7,58.4,57.3,48.9,41.2,30.2,11.9.
The mass spectrum is as follows: MS (EI, M/z):480 (M)++H).
Example 166
The difference from the embodiment 153 is that: (Z) -N- (2- ((4- (N '-hydroxy-N- (4-propionylamino) phenyl) -N' -hydroxy-1, 2, 5-oxadiazol-3-yl) amino) propyl) -1, 3-dihydro-2H-pyrrole [3 ] which is prepared by replacing (Z) -4- ((2-aminoethyl) amino) -N- (4-bromo-3-fluorophenyl) -N '-hydroxy-1, 2, 5-oxadiazol-3-methanil (II-1) with (Z) -4- ((2-aminopropyl) amino) -N- (4-propionylamino) phenyl) -N' -hydroxy-1, 2, 5-oxadiazol-3-yl) amino) propyl) -1, 3-dihydro-2H-pyrrole [3 ], the structural formula of 4-c ] pyridine-2-acrylamide is as follows:
Figure BDA0001691645820001102
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.00(s,1H),10.20(s,1H),9.67(s,1H),8.62(s,1H),8.11(m,1H),7.35(d,J＝6.4Hz,2H),7.19(m,1H),6.73(d,J＝6.4Hz,2H),6.04(s,2H),5.20(s,2H),4.45(s,2H),3.36(m,4H),2.34(q,J＝8.4Hz,2H),186(m,2H),1.16(t,J＝8.4Hz,3H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ173.4,162.5,158.2,151.9,147.7,147.2,146.6,134.5,133.4,131.6,128.6,123.7,122.5,115.7,58.4,57.3,50.9,41.2,30.2,28.9,11.9.
the mass spectrum is as follows: MS (EI, M/z):494 (M)++H).
Example 167
The difference from the embodiment 153 is that: (Z) -N- (2- ((4- (N ' -hydroxy-N- (4-morpholin-1-ylsulfonyl) phenyl) carbamimidoyl) -1,2, 5-oxadiazol-3-yl) ethyl) -1 obtained by replacing (Z) -4- ((2-aminoethyl) amino) -N- (4-bromo-3-fluorophenyl) -N ' -hydroxy-1, 2, 5-oxadiazol-3-yl (II-1) with (Z) -4- ((2-aminoethyl) amino) -N- (4-morpholin-1-ylsulfonyl) phenyl) -N ' -hydroxy-1, 2, 5-oxadiazol-3-yl) amino) ethyl) -1, the structural formula of the 3-dihydro-2H-pyrrole [3,4-c ] pyridine-2-acrylamide is as follows:
Figure BDA0001691645820001111
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.65(s,1H),8.11(m,1H),7.55(d,J＝6.4Hz,2H),7.13(m,1H),6.65(d,J＝6.4Hz,2H),6.04(s,2H),5.20(s,2H),4.45(s,2H),3.36(m,8H),2.96(t,J＝8.4Hz,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ163.5,157.2,150.9,147.7,147.2,146.6,140.5,134.5,133.4,130.6,129.6,124.7,112.5,65.5,58.4,57.3,48.9,47.3,41.2.
the mass spectrum is as follows: MS (EI, M/z):558 (M)++H).
Example 168
The difference from the embodiment 153 is that: (Z) -N- (2- ((4- (N ' -hydroxy-N- (4-morpholinosulfamoyl) phenyl) carbamimidoyl) -1,2, 5-oxadiazol-3-yl) propyl) -1,2, 5-oxadiazol-3-yl) obtained by replacing (Z) -4- ((2-aminoethyl) amino) -N- (4-bromo-3-fluorophenyl) -N ' -hydroxy-1, 2, 5-oxadiazol-3-yl (II-1) with (Z) -4- ((2-aminopropyl) amino) -N- (4-morpholin-1-ylsulfonyl) phenyl) -N ' -hydroxy-1, 2, 5-oxadiazol-3-yl) amino) propyl) -1, the structural formula of the 3-dihydro-2H-pyrrole [3,4-c ] pyridine-2-acrylamide is as follows:
Figure BDA0001691645820001121
the hydrogen spectrum of nuclear magnetic resonance is as follows:1h NMR (400MHz, DMSO): δ 11.14(s,1H),9.87(s,1H),8.65(s,1H),8.10(m,1H),7.45(d, J ═ 6.4Hz,2H),7.23(m,1H),6.65(d, J ═ 6.4Hz,2H),6.04(s,2H),5.20(s,2H),4.45(s,2H),3.66(t, J ═ 8.4Hz,4H)3.36(m,4H),2.96(t, J ═ 8.4Hz,2H),1.84(m,2H) ppm.13C NMR(125MHz,DMSO):δ164.5,157.2,150.3,148.3,147.2,146.2,140.5,134.5,133.4,131.6,129.6,123.7,111.5,65.5,58.4,57.3,50.9,47.3,41.2,28.5.
The mass spectrum is as follows: MS (EI, M/z):572 (M)++H).
Example 169
The difference from the embodiment 153 is that: (Z) -N- (2- ((4- (N ' -hydroxy-N- (4-morpholin-1-ylphenyl) carbamimidoyl) -1,2, 5-oxadiazol-3-yl) ethyl) -1 obtained by replacing (Z) -4- ((2-aminoethyl) amino) -N- (4-bromo-3-fluorophenyl) -N ' -hydroxy-1, 2, 5-oxadiazol-3-methanimid (II-1) with (Z) -4- ((2-aminoethyl) amino) -N- (4-morpholin-1-yl) phenyl) -N ' -hydroxy-1, 2, 5-oxadiazol-3-yl) amino) ethyl) -1, the structural formula of the 3-dihydro-2H-pyrrole [3,4-c ] pyridine-2-acrylamide is as follows:
Figure BDA0001691645820001122
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ10.64(s,1H),9.87(s,1H),8.65(s,1H),8.11(m,1H),7.19(m,1H),6.65(d,J＝6.4Hz,2H),6.45(d,J＝6.4Hz,2H),6.04(s,2H),5.20(s,2H),4.45(s,2H),3.76(t,J＝8.4Hz,4H),3.45(m,4H),3.16(t,J＝8.4Hz,2H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ163.5,157.2,150.9,147.7,147.2,146.6,139.4,134.5,133.4,128.6,124.7,117.5,113.7,66.5,58.4,57.3,53.3,48.9,41.2.
the mass spectrum is as follows: MS (EI, M/z):494 (M)++H).
Example 170
The difference from the embodiment 153 is that: (Z) -N- (2- ((4- (N ' -hydroxy-N- (4-morpholin-1-ylphenyl) carbamimidoyl) -1,2, 5-oxadiazol-3-yl) propyl) -1 obtained by replacing (Z) -4- ((2-aminoethyl) amino) -N- (4-bromo-3-fluorophenyl) -N ' -hydroxy-1, 2, 5-oxadiazol-3-methanimid (II-1) with (Z) -4- ((2-aminopropyl) amino) -N- (4-morpholin-1-yl) phenyl) -N ' -hydroxy-1, 2, 5-oxadiazol-3-yl) amino) propyl) -1, the structural formula of the 3-dihydro-2H-pyrrole [3,4-c ] pyridine-2-acrylamide is as follows:
Figure BDA0001691645820001131
the hydrogen spectrum of nuclear magnetic resonance is as follows:1h NMR (400MHz, DMSO): δ 10.54(s,1H),9.87(s,1H),8.65(s,1H),8.11(m,1H),7.19(m,1H),6.63(d, J ═ 6.4Hz,2H),6.40(d, J ═ 6.4Hz,2H),6.04(s,2H),5.20(s,2H),4.45(s,2H),3.76(t, J ═ 8.4Hz,4H),3.35(m,4H),3.16(t, J ═ 8.4Hz,2H),1.88(m,2H) ppm.13C NMR(125MHz,DMSO):δ163.5,157.2,150.9,147.7,147.2,146.6,139.4,134.5,133.4,128.6,124.7,117.5,113.7,66.5,58.4,57.3,53.3,50.9,41.2,28.4.
The mass spectrum is as follows: MS (EI, M/z):508 (M)++H).
Example 171
The difference from the embodiment 153 is that: (Z) -N- (2- ((4- (N ' -hydroxy-N- (4-isopropylphenyl) carbamimidoyl) -1,2, 5-oxadiazol-3-yl) amino) ethyl) -1, 3-dihydro-2H-pyrrole [3 ] which is prepared by replacing (Z) -4- ((2-aminoethyl) amino) -N- (4-bromo-3-fluorophenyl) -N ' -hydroxy-1, 2, 5-oxadiazol-3-carboxamid (II-1) with (Z) -4- ((2-aminoethyl) amino) -N- (4-isopropyl) phenyl) -N ' -hydroxy-1, 2, 5-oxadiazol-3-yl) amino) ethyl) -1, 3-dihydro-2H-pyrrol [3 ], the structural formula of 4-c ] pyridine-2-acrylamide is as follows:
Figure BDA0001691645820001132
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.65(s,1H),8.11(m,1H),7.19(m,1H),6.95(d,J＝6.4Hz,2H),6.75(d,J＝6.4Hz,2H),6.04(s,2H),5.20(s,2H),4.45(s,2H),3.50(m,4H),2.88(m,1H),1.30(d,J＝8.4Hz,6H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ163.5,157.2,150.9,147.9,147.2,146.6,138.4,134.9,133.9,133.2,126.6,124.7,116.7,58.4,57.3,48.9,41.2,33.2,23.9.
the mass spectrum is as follows: MS (EI, M/z):451 (M)++H).
Example 172
The difference from the embodiment 153 is that: (Z) -N- (2- ((4- (N ' -hydroxy-N- (4-isopropylphenyl) carbamino) -1,2, 5-oxadiazol-3-yl) amino) propyl) -1,2, 5-oxadiazol-3-yl) obtained by substituting (Z) -4- ((2-aminopropyl) amino) -N- (4-morpholin-1-yl) phenyl) -N ' -hydroxy-1, 2, 5-oxadiazol-3-yl) with (Z) -4- ((2-aminopropyl) amino) -N- (4-morpholin-1-yl) phenyl) -N ' -hydroxy-1, 2, 5-oxadiazol-3-yl) amino) propyl) -1, the structural formula of the 3-dihydro-2H-pyrrole [3,4-c ] pyridine-2-acrylamide is as follows:
Figure BDA0001691645820001141
the hydrogen spectrum of nuclear magnetic resonance is as follows:1H NMR(400MHz,DMSO):δ11.14(s,1H),9.87(s,1H),8.65(s,1H),8.21(m,1H),7.13(m,1H),6.92(d,J＝6.4Hz,2H),6.65(d,J＝6.4Hz,2H),6.04(s,2H),5.20(s,2H),4.55(s,2H),3.35(m,4H),2.88(m,1H),1.82(m,2H),1.20(d,J＝8.4Hz,6H)ppm.
the carbon spectrum is as follows:13C NMR(125MHz,DMSO):δ163.2,156.2,151.9,147.6,147.0,145.6,138.4,134.9,133.9,133.2,126.6,124.7,116.7,58.4,57.3,50.2,41.5,33.5,28.4,23.1.
the mass spectrum is as follows: MS (EI, M/z):465 (M)++H).
Comparative test
Determination of in vitro enzyme inhibitory Activity
Method for measuring IDO1 enzyme activity
Firstly, adding 15 mul of buffer solution (PH:7-8) of sodium hydrogen phosphate into pores of a microporous plate, adding 5 mul of reaction buffer solution containing a proper amount of IDO-1 enzyme and the heterocyclic urea compound prepared by the invention, uniformly mixing, reacting for 3 hours at room temperature, detecting the light absorption value with the wavelength of 320nm by using an Envision multilabel reader multifunctional enzyme-linked immunosorbent assay instrument of PE company, calculating the inhibition rate of the heterocyclic urea compound on enzyme reaction according to the absorption ratio, and analyzing by using GraphPad software to calculate the IC50 value of the heterocyclic urea compound.
Method for testing NAMPT enzyme activity
(1) Buffer 1 was prepared from 10. mu.L of 10 XNAMPT buffer, 10. mu.L of 10 XNicotinamide, 10. mu.L of 10 XPRPP, 10. mu.L of 10 XATP 10. mu.L, 2. mu.L of NMNAT1 enzyme, and 48. mu.L of heavy water to 90. mu.L.
(2) Buffer 2 was prepared containing 50 XWST-12. mu.L, 50 XADH 2. mu.L, 50 XDiaphorase 2. mu.L, 10 XEtOH 10. mu.L and 4. mu.L of weighted water to a volume of 20. mu.L.
(3) mu.L of buffer 1 was added to each well of the plate, followed by 2. mu.L of 50 Xcompound, 2. mu.L DMSO was added to the blank control, and 2. mu.L FK866(1mM) was added to the positive control. mu.L of recombinant NAMPT was added to each well to initiate the enzymatic reaction, mixed well and incubated at 30 ℃ for 60 min. After the reaction is finished, 20 mu L of buffer solution 2 is added for color development, and the absorption value at 450nm of the reaction time of 5-35min is dynamically detected.
The results of the measurement of the IDO1 and NAMPT enzyme inhibitory activities of the respective furazan compounds are shown in Table 1.
A:IC50<1nM；B:IC50＝100nM-1μM；C:IC50>1μM
Figure BDA0001691645820001142
Figure BDA0001691645820001151
Figure BDA0001691645820001161
Figure BDA0001691645820001171
Figure BDA0001691645820001181
Figure BDA0001691645820001191
Figure BDA0001691645820001201
From the results in table 1 it can be seen that: compared with a positive control (INCB24360), the furazan compound prepared by the invention has obvious activity of inhibiting the listed IDO1 enzyme; meanwhile, compared with a positive control (FK866), the NAMPT enzyme inhibitor has obvious NAMPT enzyme inhibiting activity.
The heterocyclic urea compounds provided by the embodiments of the present invention, the pharmaceutical compositions and the applications thereof are described in detail above, and the principles and embodiments of the present invention are explained herein by using specific examples, which are merely used to help understand the method and the core concept of the present invention; meanwhile, for a person skilled in the art, according to the idea of the present invention, there may be variations in the specific embodiments and the application scope, and in summary, the content of the present specification should not be construed as a limitation to the present invention.

Claims (6)

1. A dual NAMPT and IDO inhibitor, characterized by: the furazan compound has a general formula I and pharmaceutically acceptable salts thereof; the general formula I is:
Figure FDA0003112562440000011
r in the general formula I1Is independently selected from C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Alkoxy- (CH)2)q-, heteroaryl-O- (CH)2) q-, heteroarylalkoxy, aryl, cyano, - (CH)2)q(C＝O)NRaRb、-(CH2)q-NRc(C＝O)Rdaryl-S- (CH)2)q-、-(CH2)qNRaRbHeterocycloalkyl, - (CH)2)q-S(＝O)2-heterocycloalkyl, - (CH)2)q-S(＝O)2NRaRb、-(CH2)q-(C＝O)-(C1-C6Alkyl), heterocycloalkyl (C)1-C6Alkyl), 1,2, 3,4 or 5;
wherein q is 0-4, RaAnd RbHydrogen and C simultaneously or not1-C6Alkyl, heterocycloalkyl (C)1-C6Alkyl group), (C)1-C6Alkyl radical)2-N-(C1-C6Alkyl) -, aryl-NH-, C1-C6Alkoxy, hydroxy (C)1-C6Alkyl), heteroaryl, or RaAnd RbTogether with the nitrogen atom to which they are attached form a 5-or 6-membered heterocycloalkyl group, wherein said heterocycloalkyl group contains one or more additional heteroatoms independently selected from N, O or S, RcAnd RdHydrogen and C simultaneously or not1-C6Alkyl, hydroxy (C)1-C6Alkyl group), C1-C6Alkoxy radical, C3-C6Cycloalkyl, aryl, heteroaryl, and heterocycloalkyl;
the aryl and the heteroaryl areBase, C3-C6Cycloalkyl, heterocycloalkyl are unsubstituted or optionally substituted with one or more substituents, which are the same or different and are independently selected from: halogen, amino, hydroxy, cyano, C1-C6Alkyl, halo (C)1-C6Alkyl group), C3-C6Cycloalkyl, - (CH)2)q’NRa’Rb’、-(CH2)q’-S(＝O)2NRa’Rb’、-(CH2)q’(C＝O)NRa’Rb’Wherein q' is 0-4, Ra’And Rb’Hydrogen and C simultaneously or not1-C6Alkyl, hydroxy (C)1-C6Alkyl), one or more of aryl, heteroaryl and heterocycloalkyl, or Ra’And Rb’May form, together with the nitrogen atom to which they are attached, a 5-or 6-membered heterocycloalkyl group, wherein said heterocycloalkyl group contains one or more additional heteroatoms independently selected from N, O or S;
l in the general formula I is C3-C8An alkyl group;
e in the general formula I is O, S or N-C ≡ N;
x in the general formula I is C0-C4Alkyl radical, C2-C4Alkenyl radical, C3-C6Cycloalkyl or (CH)2)nNH, wherein n is 0 to 4;
r in the general formula I2Is composed of
Figure FDA0003112562440000021
The alkyl refers to a straight chain or branched chain saturated hydrocarbon group with 1-6 carbon atoms;
the heteroaryl group represents a stable monocyclic ring of 5 to 6 atoms in the ring or a bicyclic carbocyclic ring of 5 to 6 atoms in each ring, wherein at least one ring is aromatic and contains at least one heteroatom independently selected from O, N and S.
2. A dual NAMPT and IDO inhibitor, characterized by: the inhibitor is selected from:
Figure FDA0003112562440000022
Figure FDA0003112562440000031
Figure FDA0003112562440000041
Figure FDA0003112562440000051
Figure FDA0003112562440000061
Figure FDA0003112562440000071
Figure FDA0003112562440000081
Figure FDA0003112562440000091
or a pharmaceutically acceptable salt thereof.
3. Use of the dual NAMPT and IDO inhibitors of claim 1 and pharmaceutically acceptable salts thereof in the preparation of indoleamine 2,3-dioxygenase inhibitor, nicotinamide phosphoribosyltransferase inhibitor or dual indoleamine 2,3-dioxygenase and nicotinamide phosphoribosyltransferase inhibitor products.
4. Use of the dual NAMPT and IDO inhibitors of claim 1 and pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment of hyperproliferative tumor diseases in humans and other mammals.
5. Use of the dual NAMPT and IDO inhibitors of claim 1 and pharmaceutically acceptable salts thereof for the preparation of a medicament for the prevention or treatment of tumors; the tumor preventing or treating medicine is cancer immunotherapy medicine, cancer chemotherapy medicine or cancer target treatment medicine.
6. Use of the dual NAMPT and IDO inhibitors of claim 1 and pharmaceutically acceptable salts thereof for the preparation of a medicament for the prevention or treatment of lymphoma, non-small cell lung cancer, head and neck cell cancer, glioma, neuroblastoma, squamous lung cancer, adenocarcinoma of the lung, bladder cancer, stomach cancer, colon cancer, colorectal cancer, renal cancer, cholangiocarcinoma, gastric cancer, esophageal squamous carcinoma, ovarian cancer, pancreatic cancer, breast cancer, prostate cancer, liver cancer, brain cancer, melanoma, multiple myeloma, skin cancer, epithelial cell cancer, leukemia, and cervical cancer.
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