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CN113563206A - Antifungal compound, preparation method and application thereof - Google Patents

Antifungal compound, preparation method and application thereof Download PDF

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CN113563206A
CN113563206A CN202110458386.0A CN202110458386A CN113563206A CN 113563206 A CN113563206 A CN 113563206A CN 202110458386 A CN202110458386 A CN 202110458386A CN 113563206 A CN113563206 A CN 113563206A
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alkyl
membered
cycloalkyl
aryl
heteroaryl
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孙飘扬
黄建
祝令建
于秀招
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Shengdi Pharmaceutical Co Ltd
Shanghai Senhui Medicine Co Ltd
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Shengdi Pharmaceutical Co Ltd
Shanghai Senhui Medicine Co Ltd
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    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
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Abstract

The disclosure provides a class of antifungal compounds, methods of preparation, and uses thereof. Specifically, the present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or an isomer thereof, which has an antifungal effect.

Description

Antifungal compound, preparation method and application thereof
Technical Field
The disclosure belongs to the field of medicine, and particularly relates to an antifungal compound and a preparation method thereof.
Background
The development of antifungal therapeutic regimens has been a continuing challenge facing today's society. Currently available drugs for the treatment of fungal infections include amphotericin B, a macrolide polyene that interacts with mycolic sterols: flucytosine, a flucytosine that interacts with fungal protein and DNA biosynthesis, and a variety of azole antifungal Drugs that inhibit fungal membrane-sterol biosynthesis (e.g., ketoconazole, itraconazole, and fluconazole) (Alexander et al, Drugs,1997,54, 657.). Even though amphotericin B has a wide range of activity and is considered as the "gold standard" for antifungal therapy, its use is limited by infusion-related reactions and nephrotoxicity (warneck, j.antipicrob. chemither., 1998,41, 95.). The use of fluorocytosine is also limited due to the development of resistant microorganisms and their narrow spectrum of activity. The widespread use of azole antifungals is causing the emergence of clinically resistant strains of the Candida species (Candida spp).
The antifungal medicine has been developed more slowly than other antibacterial medicines, the main reason is that many fungi have certain characteristics of eukaryotic cells, which brings difficulty to drug selection, and with the increasing incidence rate and mortality rate of fungal infection in patients with impaired immune function, the search for a sensitive, broad-spectrum and safe antifungal medicine is urgent, and in recent years, with the development of molecular mycology, a series of antifungal compounds with novel action mechanisms are discovered.
Allylamine (Allyamine) is a highly potent, low toxicity antifungal drug derived from heterocyclic spironaphthalene (hetereoylic Spironaphene). The antifungal spectrum includes Aspergillus, Candida and Schering spore hyphae. Since the discovery of high broad-spectrum antifungal activity of naftifine, the research on antifungal activity of naftifine has progressed rapidly, and has been developed into a new class of antifungal structural compounds with high activity (Bioorganic & Medicinal Chemistry 2000,8, 2487-. Allylamine antifungal drugs block the synthesis of ergosterol by fungal cells by inhibiting Squalene Epoxidase (SE) enzyme, thereby disrupting cell membrane production. The difference in amino acid sequence of SE between fungi and mammals may be the molecular basis for selectivity of allylamine antifungal drugs. The side chain moieties of such drug structures bind to the lipophilic site of SE, leading to inactivation of SE conformational changes, thereby causing squalene accumulation and ergosterol deficiency. The increase in cell membrane permeability due to squalene accumulation leads to fungal cell death. The compounds which are on the market or are being researched at present are naftifine, terbinafine, butenafine, tolnaftate and the like, wherein the naftifine, the terbinafine and the butenafine are sequentially on the market at home and abroad, and with the continuous deep research of the compounds, more allylamine derivative antifungal drugs are continuously used in clinic.
Disclosure of Invention
The present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or an isomer thereof,
Figure BDA0003041324670000021
wherein,
R1and R2Each independently selected from alkyl, hydroxy, cyano, alkoxy, -NRa1Ra2Cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl being optionally substituted by one or more groups selected from deuterium, halogen, cyano, hydroxy, amino, nitro, alkyl, haloalkyl, alkoxy, -NRa1Ra2，-CORa2，-SRa1，-SO2Ra2，-SO2ORa2，-SO2NRa1Ra2Cycloalkyl, heterocyclyl, aryl, heteroaryl; or
R1And R2The nitrogen atom which is jointly bound thereto forms a heterocyclic ring of the formula (a), where the hetero atom of the formula (a)
Figure BDA0003041324670000022
The ring is heterocyclyl, heteroaryl, spiroheterocyclyl, bridged heterocyclyl containing at least one nitrogen atom; said heterocyclyl, heteroaryl, spiroheterocycle, bridged heterocycle is optionally substituted with a group selected from halogen, hydroxy, amino, cyano, nitro, -SH, alkyl, haloalkyl, alkoxy, -NRa1Ra2Substituted with the substituent(s);
ring A is selected from aryl, heteroaryl;
each A is optionally substituted by RASubstituted, RAIndependently selected from halogen, cyano, hydroxy, azido, nitro, alkyl, alkoxy, oxo, ═ NRa1，-SRa1，-ORa1，-NRa1Ra2，-CORa2，-CONRa1Ra2，-COORa2，-N(Ra2)-C(O)Ra2，-N(Ra2)-C(O)ORa2，-N(Ra2)-C(O)-NRa2Ra2，-N(Ra2)-SO2Ra2，-SO2Ra2，-SO2ORa2，-SO2NRa1Ra2，-O-SO2-NRa1Ra2，-O(CO)-NRa1Ra2Cycloalkyl, heterocyclyl, aryl, heteroaryl;
wherein R isAEach independently optionally substituted with a group selected from halogen, cyano, hydroxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, haloalkyl, alkoxy, and hydroxyalkyl;
wherein A and RAThe heteroaryl group of (a) comprises heteroatoms independently selected from S, N and O;
R3and R4Each independently selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, cycloalkyl;
v is selected from
Figure BDA0003041324670000031
Wherein R is5Selected from alkyl, alkoxy, cycloalkyl, heterocyclyl, silyl, alkenylene, alkynylene; or
V is selected from
Figure BDA0003041324670000032
The R is6Selected from aryl, heteroaryl, said aryl, heteroaryl being optionally substituted by one or more substituents selected from halogen, cyano, hydroxy, azido, amino, nitro, alkyl, haloalkyl, alkoxy, -NRa1Ra2Substituted with the substituent(s);
Ra1selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, -CH2-COORa2and-C (O) -NH2，
Ra2Selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein said alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are independently optionally substituted with one or more substituents selected from halogen, cyano, hydroxy, -COORa3Alkyl, haloalkyl, hydroxyalkyl and alkoxy;
wherein R isa3Selected from hydrogen, alkyl and haloalkyl;
n is selected from 1,2,3,4, 5, 6, 7, 8, 9, 10.
In alternative embodiments, R1And R2Each independently selected from C1-6Alkyl, hydroxy, cyano, C1-6Alkoxy, -NRa1Ra2，C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-10Aryl, 5-to 10-membered heteroaryl, said C1-6Alkyl radical, C1-6Alkoxy radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-10Aryl, 5-10 membered heteroaryl optionally substituted with 1,2,3,4, 5, 6 substituents selected from deuterium, halogen, cyano, hydroxy, amino, nitro, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy, -NRa1Ra2，-CORa2，-SRa1，-SO2Ra2，-SO2ORa2，-SO2NRa1Ra2，C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-10Aryl, substituent of 5-10 membered heteroaryl; or
R1And R2The nitrogen atom which is jointly bound thereto forms a heterocyclic ring of the formula (a), where the hetero atom of the formula (a)
Figure BDA0003041324670000041
The ring is a 3-12 membered heterocyclyl containing at least one nitrogen atom, a 5-10 membered heteroaryl, a 3-12 membered spiroheterocycle, a 3-12 membered bridged heterocycle; the 3-12 membered heterocyclic group, the 5-10 membered heteroaryl group, the 3-12 membered spiroheterocyclic ring and the 3-12 membered bridged heterocyclic ring are optionally substituted by 1-3 selected from halogen, hydroxyl, amino, cyano, nitro, -SH and C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy, -NRa1Ra2Substituted with the substituent(s);
ring A is selected from C6-10Aryl, 5-10 membered heteroaryl;
each A is optionally substituted by 0, 1,2,3,4, 5, 6, 7RASubstituted, RAIndependently selected from halogen, cyano, hydroxy, azido, nitro, C1-6Alkyl radical, C1-6Alkoxy, oxo, ═ NRa1，-SRa1，-ORa1，-NRa1Ra2，-CORa2，-CONRa1Ra2，-COORa2，-N(Ra2)-C(O)Ra2，-N(Ra2)-C(O)ORa2，-N(Ra2)-C(O)-NRa2Ra2，-N(Ra2)-SO2Ra2，-SO2Ra2，-SO2ORa2，-SO2NRa1Ra2，-O-SO2-NRa1Ra2，-O(CO)-NRa1Ra2，C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-10Aryl, 5-10 membered heteroaryl;
wherein R isAC of (A)1-6Alkyl radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-10Aryl, 5-10 membered heteroaryl, each independently optionally substituted by 1,2,3 substituents selected from halogen, cyano, hydroxy, C1-6Alkyl radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-10Aryl, 5-to 10-membered heteroaryl, C1-6Haloalkyl, C1-6Alkoxy and hydroxyalkyl;
wherein A and RAThe heteroaryl group of (a) comprises 1,2,3,4, 5 heteroatoms independently selected from S, N and O;
R3and R4Each independently selected from hydrogen, deuterium, halogen, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C3-8A cycloalkyl group;
v is selected from
Figure BDA0003041324670000042
Wherein R is5Is selected from C1-6Alkyl radical, C1-6Alkoxy radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C1-6Silyl radical, C1-6Alkenylene radical, C1-6An alkynylene group; or
V is selected from
Figure BDA0003041324670000043
The R is6Is selected from C6-10Aryl, 5-to 10-membered heteroAryl radical, said C6-10Aryl, 5-to 10-membered heteroaryl optionally substituted with 1,2,3,4, 5, 6 substituents selected from the group consisting of halogen, cyano, hydroxy, azido, amino, nitro, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy, -NRa1Ra2Substituted with the substituent(s);
Ra1selected from hydrogen, C1-6Alkyl radical, C1-6Haloalkyl, hydroxyalkyl, -CH2-COORa2and-C (O) -NH2，
Ra2Selected from hydrogen, C1-6Alkyl, hydroxyalkyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-10Aryl and 5-10 membered heteroaryl; wherein said C1-6Alkyl, hydroxyalkyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-10Aryl and 5-10 membered heteroaryl are independently optionally substituted by 1,2,3 substituents selected from halogen, cyano, hydroxy, -COORa3，C1-6Alkyl radical, C1-6Haloalkyl, hydroxyalkyl, and C1-6Substituent substitution of alkoxy;
wherein R isa3Selected from hydrogen, C1-6Alkyl and C1-6A haloalkyl group.
In an alternative embodiment ring A is selected from
Figure BDA0003041324670000051
Preference is given to
Figure BDA0003041324670000052
m is selected from 0, 1,2,3,4, 5, 6, 7;
o is selected from 0, 1,2,3,4, 5, 6;
p is selected from 0, 1,2, 3;
s is selected from 3,4, 5;
z is selected from O, S or NH;
wherein R isAAs described above.
In alternative embodiments, wherein ring A is selected from
Figure BDA0003041324670000053
m is selected from 0, 1,2,3,4, 5, 6, 7;
o is selected from 0, 1,2,3,4, 5;
p is selected from 0, 1,2, 3;
wherein R isAAs described above;
R1，R2each independently selected from C1-6Alkyl radical, C3-12Cycloalkyl radical, said C1-6Alkyl radical, C3-12Cycloalkyl is substituted with aryl, heteroaryl; the aryl group is preferably C6-10Aryl, said heteroaryl preferably being 5-10 membered heteroaryl.
In alternative embodiments, V is
Figure BDA0003041324670000061
Wherein R is5Is selected from C1-6Alkyl radical, C3-8A cycloalkyl group.
In alternative embodiments, V is
Figure BDA0003041324670000062
Wherein R is5Is selected from C1-6An alkyl group.
In alternative embodiments, R3And R4Each independently selected from hydrogen.
In alternative embodiments, n is 1.
In alternative embodiments, ring A is selected from
Figure BDA0003041324670000063
Wherein R is3And R4Each independently selected from hydrogen;
v is
Figure BDA0003041324670000064
Wherein R is5Is selected from C1-6Alkyl radical, C3-8Cycloalkyl, preferably C1-6An alkyl group;
wherein n is 1;
m is selected from 0, 1,2,3, 4;
RAas described above.
In alternative embodiments, ring A is selected from
Figure BDA0003041324670000065
In an alternative embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof, or an isomer thereof, is a compound of formula (II),
Figure BDA0003041324670000066
wherein R is1，R2Each independently selected from C1-6Alkyl radical, C3-12Cycloalkyl radical, said C1-6Alkyl radical, C3-12Cycloalkyl is substituted with aryl, heteroaryl; the aryl group is preferably C6-10Aryl, preferably 5-10 membered heteroaryl; or
R1，R2The nitrogen atom to which it is attached constitutes a 3-12 membered heterocyclic group;
R5is selected from C1-6An alkyl group.
In alternative embodiments, compounds of formula (II) wherein R1，R2Each independently selected from C1-6Alkyl radical, C3-12A cycloalkyl group; or
R1，R2The nitrogen atom to which it is attached constitutes a 3-12 membered heterocyclic group;
R5is selected from C1-6An alkyl group.
In alternative embodiments, compounds of formula (II) wherein R1，R2Each independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; or
R1，R2Atoms connected with the heterocyclic ring form a ternary heterocyclic group, a quaternary heterocyclic group, a five-membered heterocyclic group, a six-membered heterocyclic group, a seven-membered heterocyclic group and an eight-membered heterocyclic group;
R5is a tert-butyl group.
In alternative embodiments, the compound R of formula (II)1Is methyl or cyclopropyl, R2Is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or R1，R2Atoms connected with the heterocyclic ring form a ternary heterocyclic group, a quaternary heterocyclic group, a five-membered heterocyclic group and a six-membered heterocyclic group;
R5is a tert-butyl group.
The present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, or an isomer thereof, which is
Figure BDA0003041324670000071
In the present disclosure, the acid moiety of a pharmaceutically acceptable salt may be specifically selected from the group consisting of halogen, formate, acetate, benzoate, benzenesulfonate, camphorsulfonate, citrate, edisylate, fumarate, glucoheptonate, gluconate, glycollate, lactate, lactobionate, dodecylsulfate, malate, maleate, methanesulfonate, naphthoate, naphthalenesulfonate, nitrate, stearate, oleate, oxalate, pamoate, phosphate, hydrogenphosphate, dihydrogenphosphate, polygalacturonate, succinate, sulfate, sulfosalicylate, tartrate, p-toluenesulfonate, trifluoroacetate, preferably from halogen, acetate, methanesulfonate or p-toluenesulfonate, most preferably chloride, bromide, iodide, acetate, methanesulfonate, benzenesulfonate or p-toluenesulfonate.
In the disclosure, according to the ion valence number of the acid radical part of the actual pharmaceutically acceptable salt, the monovalent acid radical part can be selected to form a salt with a compound shown in formula (I), the divalent acid radical can be selected to form a salt with a compound shown in formula (I) or two compounds shown in formula (I), and the trivalent acid radical can be selected to form a salt with a compound shown in formula (I), or two compounds shown in formula (I), or three compounds shown in formula (I).
In an alternative embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof, or an isomer thereof, is
Figure BDA0003041324670000081
Any formula or structure given in this disclosure is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically-labeled compounds have the structure depicted in the formulae given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, including but not limited to2H (deuterium, D),3H(tri)，11C，13C，14C，15N，18F，31P，32P，35S，36cl and125I. various isotopically-labeled compounds of the present disclosure, for example, those into which a radioactive isotope such as3H，13C and14c, such isotopically labeled compounds are useful in metabolic studies, reaction kinetic studies, detection or imaging techniques.
The present disclosure provides a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, or an isomer thereof,
Figure BDA0003041324670000091
a compound of formula (I-a) with R2-X1Reacting in a solvent to form a compound shown as a formula (I-b), and exchanging acid radicals of the compound shown as the formula (I-b) to obtain the compound shown as the formula (I), wherein R is2As defined above, X1Is a leaving groupAnd X is the acid moiety of a pharmaceutically acceptable salt.
The present disclosure provides a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, or an isomer thereof,
Figure BDA0003041324670000092
reacting the compound shown in the formula (I-f) with the compound shown in the formula (I-e) in a solvent to form the compound shown in the formula (I-d), and exchanging acid radicals of the compound shown in the formula (I-d) to obtain the compound shown in the formula (I), wherein q is selected from 1,2,3,4, 5, 6, 7, 8, 9, 10 and X1Is a leaving group and X is the acid moiety of a pharmaceutically acceptable salt.
X described in the disclosure1Are leaving groups, in particular optionally sulfonic acid-based leaving groups, such as OTs (p-toluenesulfonate), OMs (methanesulfonate), OTf (trifluoromethanesulfonate); or a halide ion, which may be selected from iodide, chloride or bromide.
In an alternative embodiment, a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt, or isomer thereof, wherein q is selected from 1,2,3, 4.
In an alternative embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof, or an isomer thereof, wherein the acid moiety of the pharmaceutically acceptable salt is preferably chloride, bromide, iodide, acetate, benzenesulfonate, methanesulfonate or p-toluenesulfonate.
The present disclosure provides a method for preparing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or an isomer thereof, in at least one solvent selected from toluene, dioxane, tetrahydrofuran, o-xylene, t-butyl ether, t-butyl alcohol, t-amyl alcohol, ethylene glycol dimethyl ether, ethylene glycol monomethyl ether, isopropyl ether, N-dimethylacetamide, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, ethyl acetate, isopropyl acetate, butyl acetate, acetonitrile, isopropanol, ethanol, and acetone.
In an alternative embodiment, the reaction solvent is acetonitrile, a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, or an isomer thereof.
The present disclosure also provides a pharmaceutical composition comprising at least one of the foregoing compounds or a pharmaceutically acceptable salt thereof, or an isomer thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.
In certain embodiments, the unit dose of the pharmaceutical composition is from 0.001mg to 1000 mg.
In certain embodiments, the pharmaceutical composition comprises from 0.01% to 99.99% of the aforementioned compound, based on the total weight of the composition.
In certain embodiments, the pharmaceutical composition comprises 0.1% to 99.9% of the aforementioned compound.
In certain embodiments, the pharmaceutical composition comprises 0.5% to 99.5% of the aforementioned compound.
In certain embodiments, the pharmaceutical composition comprises 1% to 99% of the aforementioned compound.
In certain embodiments, the pharmaceutical composition comprises 2% to 98% of the aforementioned compound.
In certain embodiments, the pharmaceutical composition comprises from 0.01% to 99.99% of a pharmaceutically acceptable carrier, diluent or excipient, based on the total weight of the composition.
In certain embodiments, the pharmaceutical composition comprises 0.1% to 99.9% of a pharmaceutically acceptable carrier, diluent, or excipient.
In certain embodiments, the pharmaceutical composition comprises 0.5% to 99.5% of a pharmaceutically acceptable carrier, diluent, or excipient.
In certain embodiments, the pharmaceutical composition comprises 1% to 99% of a pharmaceutically acceptable carrier, diluent, or excipient.
In certain embodiments, the pharmaceutical composition comprises 2% to 98% of a pharmaceutically acceptable carrier, diluent or excipient.
The disclosure also relates to application of the compound shown in the formula (I) or a pharmaceutically acceptable salt thereof, or an isomer thereof, or a pharmaceutical composition containing the compound shown in the formula I or the pharmaceutically acceptable salt thereof, or the isomer thereof in preparing a medicament for treating diseases or infections caused by fungi.
The fungus in the present disclosure is dermatophyte, filamentous fungus, biphase fungus, darkling spore fungus, trichophyton, dog microsporum, Epidermophyton floccosum, Trichophyton rubrum, Trichophyton mentagrophytes, dermatitidis blastomyces, Histoplasma capsulatum, Trichosporon schenckii, Candida albicans, Candida parapsilosis, Pityrosporum ovale or yeast.
The fungal-induced disease described in the present disclosure is selected from tinea manuum, tinea pedis, tinea corporis, tinea cruris, tinea versicolor and cutaneous candidiasis.
The present disclosure provides a method of treating a disease or infection caused by a fungus by administering to a patient an effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or an isomer thereof.
Unless stated to the contrary, terms used in the specification and claims have the following meanings.
The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-dimethylpentyl, 2-dimethylhexyl, 3-dimethylpentyl, 2-ethylhexyl, 3-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-ethyl, 2-2, 2-2, 2-2, or, 2, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halo, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate.
The term "alkylene" refers to a saturated straight or branched chain aliphatic hydrocarbon group having 2 residues derived from the parent alkane by removal of two hydrogen atoms from the same carbon atom or two different carbon atoms, and is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkylene group containing 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH)2-), 1-ethylidene (-CH (CH)3) -), 1, 2-ethylene (-CH)2CH2) -, 1-propylene (-CH (CH)2CH3) -), 1, 2-propylene (-CH)2CH(CH3) -), 1, 3-propylene (-CH)2CH2CH2-) 1, 4-butylene (-CH2CH2CH2CH2-) and the like. The alkylene group may be substituted or unsubstituted, and when substituted, the substituent may be atSubstituted at any available point of attachment.
The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
The term "spirocycloalkyl" refers to a 5 to 20 membered polycyclic group sharing one carbon atom (referred to as a spiro atom) between monocyclic rings, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. Spirocycloalkyl groups are classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multi spirocycloalkyl group, preferably a single spirocycloalkyl group and a double spirocycloalkyl group, according to the number of spiro atoms shared between rings. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered.
Non-limiting examples of spirocycloalkyl groups include:
Figure BDA0003041324670000122
the term "fused cyclic alkyl" refers to a 5 to 20 membered all carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyls according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicycloalkyl. Non-limiting examples of fused ring alkyl groups include:
Figure BDA0003041324670000121
the term "bridged cycloalkyl" refers to a 5 to 20 membered all carbon polycyclic group in which any two rings share two carbon atoms not directly attached, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. They may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic, depending on the number of constituent rings. Non-limiting examples of bridged cycloalkyl groups include:
Figure BDA0003041324670000131
the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, where the ring to which the parent structure is attached is cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate.
The term "heterocyclyl" refers to a saturated or partially unsaturated mono-or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more of the ring atoms is selected from nitrogen, oxygen, or S (O)m(wherein m is an integer from 0 to 2) but excludes the ring moiety of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably from 3 to 6 ring atoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like, with piperidinyl, pyrrolidinyl being preferred. Polycyclic heterocyclic radicals including spiro, fusedAnd heterocyclic groups that are cyclic and bridged.
The term "spiroheterocyclyl" refers to a 5-to 20-membered polycyclic heterocyclic group in which one atom (referred to as the spiro atom) is shared between monocyclic rings, and in which one or more ring atoms is selected from nitrogen, oxygen, or S (O)m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. The spiro heterocyclic group is classified into a mono-spiro heterocyclic group, a di-spiro heterocyclic group or a multi-spiro heterocyclic group, preferably a mono-spiro heterocyclic group and a di-spiro heterocyclic group, according to the number of spiro atoms shared between rings. More preferred are 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono spiroheterocyclic groups. Non-limiting examples of spiro heterocyclic groups include:
Figure BDA0003041324670000141
the term "fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system in which one or more ring atoms is selected from nitrogen, oxygen or S (O)m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:
Figure BDA0003041324670000142
the term "bridged heterocyclyl" refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms which are not directly attached, which may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system in which one or more ring membersAnd is selected from nitrogen, oxygen or S (O)m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:
Figure BDA0003041324670000143
the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is heterocyclyl, non-limiting examples of which include:
Figure BDA0003041324670000151
and the like.
The heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate.
The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:
Figure BDA0003041324670000152
the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate, preferably phenyl.
The term "condensed ring aryl group" may be an unsaturated aromatic condensed ring structure having 8 to 14 ring atoms, preferably 8 to 12 ring atoms, which are bonded by two or more ring structures sharing two adjacent atoms with each other. For example, all unsaturated fused ring aryl groups such as naphthalene, phenanthrene, etc., and partially saturated fused ring aryl groups such as benzo 3-8 membered saturated monocyclic cycloalkyl, benzo 3-8 membered partially saturated monocyclic cycloalkyl, specific examples being 2, 3-dihydro-1H-indenyl, IH-indenyl, 1,2,3, 4-tetrahydronaphthyl, 1, 4-dihydronaphthyl, etc.
The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 12 membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl and the like, preferably imidazolyl, pyrazolyl, pyrimidinyl or thiazolyl; more preferably pyrazolyl or thiazolyl. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:
Figure BDA0003041324670000161
heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups.
The term "fused heteroaryl group" may be an unsaturated aromatic fused ring structure having 5 to 14 ring atoms (wherein at least one hetero atom is contained) and being formed by two or more ring structures sharing two adjacent atoms with each other, while including a carbon atom, a nitrogen atom and a sulfur atom, may be oxo, preferably "5-12-membered fused heteroaryl group", "7-12-membered fused heteroaryl group", "9-12-membered fused heteroaryl group" and the like, for example, benzofuranyl, benzoisothiofuranyl, benzothienyl, indolyl, isoindole, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolyl, 2-quinolinone, 4-quinolinone, 1-isoquinolinone, isoquinolyl, acridinyl, phenanthridinyl, benzodiazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, phenazinyl, Pteridinyl, purinyl, naphthyridinyl, phenazine, phenothiazine, and the like.
The fused heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
The term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate groups.
The term "alkylthio" refers to-S- (alkyl) and-S- (unsubstituted cycloalkyl) groups, wherein alkyl is as defined above. Non-limiting examples of alkylthio groups include: methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio. Alkylthio groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups substituted independently with one or more substituents selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.
The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
The term "haloalkyl" refers to an alkyl group substituted with a halogen, wherein alkyl is as defined above.
The term "deuterated alkyl" refers to an alkyl group substituted with a deuterium atom, wherein alkyl is as defined above.
The term "hydroxy" refers to an-OH group.
The term "oxo" refers to an ═ O group. For example, a carbon atom is linked to an oxygen atom via a double bond, wherein a ketone or aldehyde group is formed.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "amino" refers to the group-NH2。
The term "cyano" refers to — CN.
The term "nitro" means-NO2。
The term "carboxy" refers to-C (O) OH.
The term "aldehyde" refers to — CHO.
The term "carboxylate" refers to-C (O) O (alkyl) or-C (O) O (cycloalkyl), wherein alkyl, cycloalkyl are as defined above.
The term "acyl halide" refers to a compound containing a group that is-C (O) -halogen.
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.
"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.
Detailed Description
The preparation of the compounds, pharmaceutically acceptable salts, described in this disclosure is further described below in conjunction with the examples, which are not intended to limit the scope of the disclosure.
Experimental procedures, in which specific conditions are not noted in the examples of the present disclosure, are generally performed under conventional conditions, or under conditions recommended by manufacturers of raw materials or commercial products. Reagents of specific sources are not indicated, and conventional reagents are purchased in the market.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. delta.) of 10-6The units in (ppm) are given. NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d)6) Deuterated chloroform (CDCl)3) Deuterated methanol (CD)3OD), internal standard Tetramethylsilane (TMS).
MS was determined using an Agilent 1200/1290 DAD-6110/6120 Quadrupole MS LC MS (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS).
High Performance Liquid Chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 HPLC.
Example 1
(E) -N, N, N,6, 6-tetramethyl-N- (naphthalen-1-ylmethyl) hept-2-en-4-ynyl-1-ammonium iodide
Figure BDA0003041324670000181
Under an ice-water bath, 1-a (10g,34.4mmol) was dissolved in 60mL acetonitrile, followed by the addition of methyl iodide (9.75g,68.8mmol), followed by stirring at room temperature for about 18 hours, and suction filtration gave 11.5g of Compound 1, purity > 99%, LCMS (ESI): 306.1[ M + ].
1HNMR(CDCl3,400MHz)：8.63(d,J＝8.8Hz,1H),7.94-7.84(m,3H),7.69(t,J＝7.6Hz,1H),7.55-7.45(m,2H),6.41(d,J＝15.6Hz,1H),6.10-6.02(m,1H),5.56(s,2H),4.84(d,J＝7.6Hz,2H),3.19(s,6H),1.22(s,9H)。
Example 2
(E) Ammonium (E) -N, N, N,6, 6-tetramethyl-N- (naphthalen-1-ylmethyl) hept-2-en-4-ynyl-1-p-toluenesulfonate
Figure BDA0003041324670000191
Under an ice-water bath, 1-a (10g,34.4mmol) was dissolved in 35mL of acetonitrile, followed by addition of methyl p-toluenesulfonate (8.36g, 44.7mmol), followed by stirring at room temperature for about 18 hours and suction filtration to give 10.2g of Compound 2, purity > 99%, LC-Ms (ESI): 306.1[ M + ].
1HNMR(CDCl3,400MHz)：8.49(d,J＝7.2Hz,1H)；7.91-7.77(m,5H)；7.48-7.39(m,3H)；7.19(d,J＝7.6Hz,2H)；6.23(d,J＝15.6Hz,1H)；6.01–5.93(m,1H)；5.40(s,2H)；4.61(d,J＝7.6Hz,2H)；3.08(s,6H)；2.36(s,3H)；1.21(s,9H)。
Example 3
(E) Ammonium (E) -N, N, N,6, 6-tetramethyl-N- (naphthalen-1-ylmethyl) hept-2-en-4-ynyl-1-acetate
Figure BDA0003041324670000192
Dissolving compound 2(1.0g,2.09mmol) in small amount of acetonitrile, performing anion exchange treatment with 6% ammonium acetate-acetic acid-acetonitrile as mobile phase through C18 reverse phase silica gel column, collecting eluate, concentrating, and dryingThe organic solvent and the aqueous phase were lyophilized to give 600mg of product, LC-Ms (ESI): 306.1[ M ]+]。
1HNMR(CDCl3,400MHz)：8.35(d,J＝7.6Hz,1H)；7.95(d,J＝7.6Hz,1H)；7.88(d,J＝7.6Hz,1H)；7.77(d,J＝6.8Hz,1H)；7.65-7.61(m,1H)；7.55-7.50(m,2H)；6.18(d,J＝15.6Hz,1H)；6.09–6.02(m,1H)；5.27(s,2H)；4.44(d,J＝6.8Hz,2H)；3.06(s,6H)；2.05(s,3H)；1.24(s,9H)。
Example 4
(E) Ammonium (E) -N, N, N,6, 6-tetramethyl-N- (naphthalen-1-ylmethyl) hept-2-en-4-ynyl-1-methanesulfonate
Figure BDA0003041324670000201
1-a (1.0g,3.4mmol) was dissolved in 10mL of acetonitrile at room temperature, followed by addition of methyl methanesulfonate (0.75g,6.8mmol), heating to 50 ℃ and stirring for about 18 hours, the reaction was concentrated and purified by C18 reverse phase column to give 0.9g of Compound 4 with purity of 98.5%, LC-Ms (ESI): 306.1[ M ]+]。
1HNMR(CDCl3,400MHz)：8.47(d,J＝8.4Hz,1H)；7.92(d,J＝8.0Hz,1H)；7.88-7.83(m,2H)；7.69-7.65(m,1H)；7.55-7.46(m,2H)；6.30(d,J＝15.2Hz,1H)；6.08–5.99(m,1H)；5.33(s,2H)；4.55(d,J＝7.6Hz,2H)；3.08(s,6H)；2.89(s,3H)；1.22(s,9H)。

Claims (16)

1. A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, or an isomer thereof,
Figure FDA0003041324660000011
wherein,
R1and R2Each independently selected from alkyl, hydroxy, cyano, alkoxy, -NRa1Ra2Cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkoxy, cycloalkyl, heterocyclyl, arylHeteroaryl is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxy, amino, nitro, alkyl, haloalkyl, alkoxy, -NRa1Ra2，-CORa2，-SRa1，-SO2Ra2，-SO2ORa2，-SO2NRa1Ra2Cycloalkyl, heterocyclyl, aryl, heteroaryl; or
R1And R2The nitrogen atom which is jointly bound thereto forms a heterocyclic ring of the formula (a), where the hetero atom of the formula (a)
Figure FDA0003041324660000012
The ring is heterocyclyl, heteroaryl, spiroheterocyclyl, bridged heterocyclyl containing at least one nitrogen atom; said heterocyclyl, heteroaryl, spiroheterocycle, bridged heterocycle is optionally substituted with a group selected from halogen, hydroxy, amino, cyano, nitro, -SH, alkyl, haloalkyl, alkoxy, -NRa1Ra2Substituted with the substituent(s);
ring A is selected from aryl, heteroaryl;
each A is optionally substituted with RASubstituted, RASelected from halogen, cyano, hydroxy, azido, nitro, alkyl, alkoxy, oxo, ═ NRa1，-SRa1，-ORa1，-NRa1Ra2，-CORa2，-CONRa1Ra2，-COORa2，-N(Ra2)-C(O)Ra2，-N(Ra2)-C(O)ORa2，-N(Ra2)-C(O)-NRa2Ra2，-N(Ra2)-SO2Ra2，-SO2Ra2，-SO2ORa2，-SO2NRa1Ra2，-O-SO2-NRa1Ra2，-O(CO)-NRa1Ra2Cycloalkyl, heterocyclyl, aryl, heteroaryl;
wherein R isAAlkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, each independently optionally selected from halogen, cyano, hydroxyAlkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, haloalkyl, alkoxy and hydroxyalkyl;
wherein A and RAThe heteroaryl group of (a) comprises heteroatoms independently selected from S, N and O;
R3and R4Each independently selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, cycloalkyl;
v is selected from
Figure FDA0003041324660000021
-C≡C-R5Wherein R is5Selected from alkyl, alkoxy, cycloalkyl, heterocyclyl, silyl, alkenylene, alkynylene; or
V is selected from
Figure FDA0003041324660000022
The R is6Selected from aryl, heteroaryl, said aryl, heteroaryl being optionally selected from halogen, cyano, hydroxy, azido, amino, nitro, alkyl, haloalkyl, alkoxy, -NRa1Ra2Substituted with the substituent(s);
Ra1selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, -CH2-COORa2and-C (O) -NH2，
Ra2Selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein said alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are independently optionally substituted with one or more substituents selected from halogen, cyano, hydroxy, -COORa3Alkyl, haloalkyl, hydroxyalkyl and alkoxy;
wherein R isa3Selected from hydrogen, alkyl and haloalkyl;
n is selected from 1,2,3,4, 5, 6, 7, 8, 9, 10.
2. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, or an isomer thereof, wherein
R1And R2Each of which isIndependently selected from C1-6Alkyl, hydroxy, cyano, C1-6Alkoxy, -NRa1Ra2，C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-10Aryl, 5-to 10-membered heteroaryl, said C1-6Alkyl radical, C1-6Alkoxy radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-10Aryl, 5-10 membered heteroaryl optionally substituted with 1-6 substituents selected from deuterium, halogen, cyano, hydroxy, amino, nitro, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy, -NRa1Ra2，-CORa2，-SRa1，-SO2Ra2，-SO2ORa2，-SO2NRa1Ra2，C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-10Aryl, substituent of 5-10 membered heteroaryl; or
R1And R2The nitrogen atom which is jointly bound thereto forms a heterocyclic ring of the formula (a), where the hetero atom of the formula (a)
Figure FDA0003041324660000023
The ring is a 3-12 membered heterocyclyl containing at least one nitrogen atom, a 5-10 membered heteroaryl, a 3-12 membered spiroheterocycle, a 3-12 membered bridged heterocycle; the 3-12 membered heterocyclic group, the 5-10 membered heteroaryl group, the 3-12 membered spiroheterocyclic ring and the 3-12 membered bridged heterocyclic ring are optionally substituted by 1-3 selected from halogen, hydroxyl, amino, cyano, nitro, -SH and C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy, -NRa1Ra2Substituted with the substituent(s);
ring A is selected from C6-10Aryl, 5-10 membered heteroaryl;
each A is optionally substituted with 0-7RASubstituted, RAIndependently selected from halogen, cyano, hydroxy, azido, nitro, C1-6Alkyl radical, C1-6Alkoxy, oxo, ═ NRa1，-SRa1，-ORa1，-NRa1Ra2，-CORa2，-CONRa1Ra2，-COORa2，-N(Ra2)-C(O)Ra2，-N(Ra2)-C(O)ORa2，-N(Ra2)-C(O)-NRa2Ra2，-N(Ra2)-SO2Ra2，-SO2Ra2，-SO2ORa2，-SO2NRa1Ra2，-O-SO2-NRa1Ra2，-O(CO)-NRa1Ra2，C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-10Aryl, 5-10 membered heteroaryl;
wherein R isAC of (A)1-6Alkyl radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-10Aryl, 5-10 membered heteroaryl, each independently optionally substituted by 1-3 substituents selected from halogen, cyano, hydroxy, C1-6Alkyl radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-10Aryl, 5-to 10-membered heteroaryl, C1-6Haloalkyl, C1-6Alkoxy and hydroxyalkyl;
wherein A and RAThe heteroaryl group of (a) comprises 1 to 5 heteroatoms independently selected from S, N and O;
R3and R4Each independently selected from hydrogen, deuterium, halogen, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C3-8A cycloalkyl group;
v is selected from
Figure FDA0003041324660000031
-C≡C-R5Wherein R is5Is selected from C1-6Alkyl radical, C1-6Alkoxy radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C1-6Silyl radical, C1-6Alkenylene radical, C1-6An alkynylene group; or
V is selected from
Figure FDA0003041324660000032
The R is6Is selected from C6-10Aryl, 5-to 10-membered heteroaryl, said C6-10Aryl, 5-to 10-membered heteroaryl optionally substituted with 1 to 6 substituents selected from halogen, cyano, hydroxy, azidoAmino, nitro, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy, -NRa1Ra2Substituted with the substituent(s);
Ra1selected from hydrogen, C1-6Alkyl radical, C1-6Haloalkyl, hydroxyalkyl, -CH2-COORa2and-C (O) -NH2，
Ra2Selected from hydrogen, C1-6Alkyl, hydroxyalkyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-10Aryl and 5-10 membered heteroaryl; wherein said C1-6Alkyl, hydroxyalkyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-10Aryl and 5-10 membered heteroaryl are independently optionally substituted with 1-3 substituents selected from halogen, cyano, hydroxy, -COORa3，C1-6Alkyl radical, C1-6Haloalkyl, hydroxyalkyl, and C1-6Substituent substitution of alkoxy;
wherein R isa3Selected from hydrogen, C1-6Alkyl and C1-6A haloalkyl group.
3. A compound of formula (I) according to claim 2 or a pharmaceutically acceptable salt thereof, or an isomer thereof, ring a being selected from
Figure FDA0003041324660000041
Preference is given to
Figure FDA0003041324660000042
m is selected from 0, 1,2,3,4, 5, 6, 7;
o is selected from 0, 1,2,3,4, 5, 6;
p is selected from 0, 1,2, 3;
s is selected from 3,4, 5;
z is selected from O, S or NH;
wherein R isAAs claimed in claim 2.
4. A compound of formula (I) according to claim 3 or a pharmaceutically acceptable salt thereof, or an isomer thereof, wherein ring a is selected from
Figure FDA0003041324660000043
m is selected from 0, 1,2,3,4, 5, 6, 7;
o is selected from 0, 1,2,3,4, 5, 6;
p is selected from 0, 1,2, 3;
wherein R isAAs claimed in claim 2;
R1，R2each independently selected from C1-6Alkyl radical, C3-12Cycloalkyl radical, said C1-6Alkyl radical, C3-12Cycloalkyl is substituted with aryl, heteroaryl; the aryl group is preferably C6-10Aryl, said heteroaryl preferably being 5-10 membered heteroaryl.
5. The compound of formula (I) or a pharmaceutically acceptable salt thereof, or an isomer thereof according to claim 4, wherein Ring A is selected from the group consisting of
Figure FDA0003041324660000044
Wherein R is3And R4Each independently selected from hydrogen;
v is
Figure FDA0003041324660000045
Wherein R is5Is selected from C1-6Alkyl radical, C3-8Cycloalkyl, preferably C1-6An alkyl group;
wherein n is 1;
m is selected from 0, 1,2,3,4, preferably 0;
RAas claimed in claim 2.
6. The compound of formula (I) according to any one of claims 3 to 5, or a pharmaceutically acceptable salt thereof, or an isomer thereof, which is a compound of formula (II),
Figure FDA0003041324660000051
wherein R is1，R2Each independently selected from C1-6Alkyl radical, C3-12Cycloalkyl radical, said C1-6Alkyl radical, C3-12Cycloalkyl is substituted with aryl, heteroaryl; the aryl group is preferably C6-10Aryl, preferably 5-10 membered heteroaryl; or
R1，R2The nitrogen atom to which it is attached constitutes a 3-12 membered heterocyclic group;
R5is selected from C1-6An alkyl group.
7. A compound of formula (I) according to claim 6 or a pharmaceutically acceptable salt thereof, or an isomer thereof,
wherein R is1，R2Each independently selected from C1-6Alkyl radical, C3-12A cycloalkyl group; or
R1，R2The nitrogen atom to which it is attached constitutes a 3-12 membered heterocyclic group;
R5is selected from C1-6An alkyl group.
8. A compound of formula (I) according to any one of claims 6 or 7, or a pharmaceutically acceptable salt, or isomer thereof, wherein R1，R2Each independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, preferably R1Is methyl or cyclopropyl, R2Is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or
R1，R2Atoms connected with the heterocyclic ring form a ternary heterocyclic group, a quaternary heterocyclic group, a five-membered heterocyclic group, a six-membered heterocyclic group, a seven-membered heterocyclic group and an eight-membered heterocyclic group; preferably a ternary heterocyclic group, a quaternary heterocyclic group, a five-membered heterocyclic group and a six-membered heterocyclic group;
R5is a tert-butyl group.
9. A compound of formula (I) according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, or an isomer thereof, which is
Figure FDA0003041324660000061
10. A compound of formula (I) according to any one of claims 1 to 9, the acid moiety of the pharmaceutically acceptable salt being selected from halogen, formate, acetate, benzoate, benzenesulfonate, camphorsulfonate, citrate, ethanedisulfonate, fumarate, glucoheptonate, gluconate, glucuronate, isethionate, lactate, lactobionate, dodecylsulfate, malate, maleate, methanesulfonate, naphthoate, naphthalenesulfonate, nitrate, stearate, oleate, oxalate, pamoate, phosphate, hydrogenphosphate, dihydrogenphosphate, polygalacturonate, succinate, sulfate, sulfosalicylate, tartrate, p-toluenesulfonate, trifluoroacetate, preferably from halogen, acetate, methanesulfonate or p-toluenesulfonate, most preferably chloride, bromide, iodide, acetate, methanesulfonate, benzenesulfonate or p-toluenesulfonate.
11. A compound of formula (I) according to claim 10 or a pharmaceutically acceptable salt thereof, or an isomer thereof, which is
Figure FDA0003041324660000062
12. A process for the preparation of a compound of formula (I) as claimed in any one of claims 10 or 11 or a pharmaceutically acceptable salt thereof, or an isomer thereof,
Figure FDA0003041324660000071
a compound of formula (I-a) with R2-X1Reacting in a solvent to form a compound shown as a formula (I-b), and exchanging acid radicals of the compound shown as the formula (I-b) to obtain the compound shown as the formula (I), wherein R is2As defined in any one of claims 1 to 11; or
Figure FDA0003041324660000072
Reacting a compound shown in a formula (I-f) with a compound shown in a formula (I-e) in a solvent to form a compound shown in a formula (I-d), and exchanging acid radicals of the compound shown in the formula (I-d) to obtain the compound shown in the formula (I);
wherein q is selected from 1,2,3,4, 5, 6, 7, 8, 9, 10, preferably 1,2,3, 4;
said X1Is a leaving group;
x is the acid moiety of a pharmaceutically acceptable salt.
13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, or an isomer thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
14. Use of a compound of formula (I) according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, or an isomer thereof or a pharmaceutical composition according to claim 13 for the manufacture of a medicament for the treatment of a fungal disease or infection.
15. The use according to claim 14, wherein the fungus is dermatophyte, aspergillus, filamentous fungus, biphasic fungus, phaeosporium, trichophyton, microsporum canis, epidermophyton floccosum, trichophyton rubrum, trichophyton mentagrophytes, blastomyces dermatitidis, histoplasma capsulatum, trichosporon schenckii, candida albicans, candida parapsilosis, pityrosporum ovale or yeast.
16. The fungal disease according to claim 14 selected from the group consisting of tinea manuum, tinea pedis, tinea corporis, tinea cruris, tinea versicolor and cutaneous candidiasis.
CN202110458386.0A 2020-04-28 2021-04-27 Antifungal compound, preparation method and application thereof Pending CN113563206A (en)

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Citations (1)

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Publication number Priority date Publication date Assignee Title
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