Patent Application
20240368104
The present invention relates to a dialkoxynaphtho[2,3-c]furan-1(3H)-one derivative and a pharmaceutical composition including the same.
The Justicia genus of the Acanthaceae family consists of about 600 species. Representative Justicia genus plants include Justicia procumbens, Justicia pectoralis, Justicia gendarussa, Justicia anselliana, Justicia adhatoda, and the like. Among them, Justicia procumbens, which is a yearly plant, includes Justicidin A (9-(1,3-benzodioxol-5-yl)-4,6,7-trimethoxy-3H-benzo[f][2]benzofuran-1-one), Justicidin B (4-(1,3-benzodioxol-5-yl)-6,7-dimethoxy-1H-benzo[f][2]benzofuran-3-one), and the like as active ingredients, and grows in Korea, Japan, China, India, etc. Existing therapeutic agents for allergic diseases include steroids which suppress immune responses, but are limited to a local or temporary use due to various side effects caused by non-selective immune suppression. Anti-leukotrienes, anti-histamines and the like are the most commonly used therapeutic agents for allergic diseases, but are involved in controlling at the lower stages of the allergy-inducing mechanism, and thus have a limitation in that they have an effect of temporarily alleviating symptoms. In particular, anti-leukotrienes do not have a good medicinal effect on the treatment of asthma as compared to inhaler corticosteroid (ICS), and thus their use are limited only to patients who cannot use inhalant agents, patients who have side effects on ICS, or asthma patients with allergic rhinitis (Workshop report, global strategy for asthma management and prevention (updated 2017). The GINA reports are available on www.ginasthma.org.). Besides, there is an anti-IgE antibody therapeutic agent (Omalizumab) which is used as a therapeutic agent for severe asthma, and anti-IL-5 antibody therapeutic agents (Mepolizumab, Reslizumab) have been recently developed, but there is a need to develop a new concept of therapeutic agent effective for allergic diseases due to high costs and a limited improvement effect on severe asthma patients (Corren J, Weinstein S, Janka L, Zangrilli J, Garin M. Phase 3 study of reslizumab in patients with poorly controlled asthma: Effects across a broad range of eosinophil counts. Chest. 2016, 150 (4): 799-810, Djukanović R, Wilson S J, Kraft M, Jarjour N N, Steel M, Chung K F, Bao W, Fowler-Taylor A, Matthews J, Busse W W, Holgate S T, Fahy J V. Effects of treatment with anti-immunoglobulin E antibody omalizumab on airway inflammation in allergic asthma. Am J Respir Crit Care Med. 2004 Sep. 15; 170 (6): 583-93).
Severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) refers to a severe acute respiratory syndrome coronavirus 2, which has been first known in 2019, and is classified as a positive-sense single-stranded RNA virus. The disease infected by this virus has been named Coronavirus infection disease-19 (Coronavirus disease 2019), and is also called COVID-19 for short. The World Health Organization (WHO) has officially announced a coronavirus pandemic. As of November 2020, it has been found that the number of infected people in South Korea is more than 27,000, and about 47.4 million people are infected around the world and this trend continues to spread. Currently, Remdesivir, an Ebola virus therapeutic agent, is the only one formulated as a therapeutic agent for COVID-19, but its effect has been questioned, and plasma treatment, etc., is used as an alternative therapy. In addition, clinical trials for COVID 19 have been conducted on Kaletra (main ingredient: Lopinavir), a human immunodeficiency virus (HIV) therapeutic agent, etc. Accordingly, there is an urgent need for developing a therapeutic agent for SARS-Cov-2.
One object of the present invention is to provide a 6,7-dialkoxynaphtho[2,3-c]furan-1(3H)-one compound, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a hydrate thereof, or a solvate thereof.
In addition, one object of the present invention is to provide a pharmaceutical composition including a 6,7-dialkoxynaphtho[2,3-c]furan-1(3H)-one compound.
Furthermore, one object of the present invention is to provide a pharmaceutical composition for an anti-viral purpose including a 6,7-dialkoxynaphtho[2,3-c]furan-1(3H)-one compound.
Moreover, one object of the present invention is to provide a pharmaceutical composition for preventing or treating at least one of SARS-COV-2 infection disease, influenza virus infection disease, dengue virus infection disease, Zika virus infection disease and severe fever with thrombocytopenia syndrome virus infection disease, which includes a 6,7-dialkoxynaphtho[2,3-c]furan-1(3H)-one compound.
Besides, one object of the present invention is to provide a pharmaceutical composition for preventing or treating a respiratory disease, which includes a 6,7-dialkoxynaphtho[2,3-c]furan-1(3H)-one compound.
In addition, one object of the present invention is to provide a pharmaceutical composition for preventing or treating an allergic disease, which includes a 6,7-dialkoxynaphtho[2,3-c]furan-1(3H)-one compound.
Furthermore, one object of the present invention is to provide a method for preventing or treating a virus infection disease; a respiratory disease; or an allergic disease; which includes administering a 6,7-dialkoxynaphtho[2,3-c]furan-1(3H)-one compound into a subject in need thereof.
Moreover, one object of the present invention is to provide a use of a 6, 7-dialkoxynaphtho[2,3-c]furan-1(3H)-one compound for preventing or treating a virus infection disease; a respiratory disease; or an allergic disease.
Besides, one object of the present invention is to provide a use of a 6,7-dialkoxynaphtho[2,3-c]furan-1(3H)-one compound for manufacturing a medicament for preventing or treating a virus infection disease; a respiratory disease; or an allergic disease.
Hereinafter, in the present specification, “substituted or unsubstituted” may refer to being substituted or unsubstituted with at least one of halogen, hydroxy (—OH), —C(═O)R, alkoxy, amine, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl.
In the present specification, R of —C(═O)R may be hydrogen, alkyl, hydroxy, alkoxy, amine, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl. R of —C(═O)R may be substituted or unsubstituted.
In the present specification, halogen may be F, Cl, Br or I. For example, the halogen may be F or Cl.
In the present specification, alkoxy may be linear or branched alkoxy. The alkoxy may be substituted or unsubstituted. For example, the alkoxy may be substituted or unsubstituted C1-C20 linear or branched alkoxy. The C1-C20 linear or branched alkoxy may include C1-C15. C1-C10. C1-C8, C1-C5 and/or C1-C3 linear or branched alkoxy. Here, the description of the alkyl group to be described later may be applied to the alkyl group included in the alkoxy.
In the present specification, “and/or” may be used as a term referring to all combinations which may be derived from a plurality of configurations.
In the present specification, amine may include —NH2, alkylamine, cycloalkylamine, cycloalkenylamine, heterocycloalkylamine, arylamine, and/or heteroarylamine. In the present specification, the amine, in which only one alkyl is substituted for nitrogen and another substituent (for example, a phenyl group) different from alkyl is further substituted, may be also defined as alkylamine. For example, in the present specification, methylphenylamine may be interpreted as alkylamine or arylamine.
In alkylamine, cycloalkylamine, cycloalkenylamine, heterocycloalkylamine, arylamine and heteroarylamine, the description of alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, and heteroaryl to be described later may be applied to alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl and heteroaryl.
In the present specification, alkyl may be linear or branched alkyl, and may be substituted or unsubstituted. The alkyl may be C1-C20 alkyl. The C1-C20 alkyl may include C1-C15. C1-C10, C1-C8, C1-C5 and C1-C3 alkyl.
Examples of the alkyl may include methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl, i-butyl, 2-ethylbutyl, 3,3-dimethylbutyl, n-pentyl, i-pentyl, neopentyl, t-pentyl, cyclopentyl, 1-methylpentyl, 3-methylpentyl, 2-ethylpentyl, 4-methyl-2-pentyl, n-hexyl, 1-methylhexyl, 2-ethylhexyl, 2-butylhexyl, cyclohexyl, 4-methylcyclohexyl, 4-t-butylcyclohexyl, n-heptyl, 1-methylheptyl, 2,2-dimethylheptyl, 2-ethylheptyl, 2-butylheptyl, n-octyl, t-octyl, 2-ethyloctyl, 2-butyloctyl, 2-hexyloctyl, 3,7-dimethyloctyl, cyclooctyl, n-nonyl, n-decyl, adamantyl, 2-ethyldecyl, 2-butyldecyl, 2-hexyldecyl, 2-octyldecyl, n-undecyl, n-dodecyl, 2-ethyldodecyl, 2-butyldodecyl, 2-hexyldodecyl, 2-octyldodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, 2-ethylhexadecyl, 2-butylhexadecyl, 2-hexylhexadecyl, 2-octylhexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, n-icosyl, 2-ethylicosyl, 2-butylicosyl, 2-hexylicosyl, 2-octylicosyl, n-henicosyl, n-docosyl, n-tricosyl, n-tetracosyl, n-pentacosyl, n-hexacosyl, n-heptacosyl, n-octacosyl, n-nonacosyl, n-triacontyl, and the like, but an example is not limited thereto.
In the present specification, the above description of alkyl may be applied to alkenyl except for including one or more carbon-carbon double bonds.
In the present specification, cycloalkyl may be substituted or unsubstituted. The cycloalkyl may be C3-C20 cycloalkyl. The C3-C20 cycloalkyl may include C3-C15, C3-C10 and/or C3-C5 cycloalkyl. In the present specification, a substituent of the cycloalkyl may be bonded to an adjacent group to form a ring. Examples of the cycloalkyl may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and/or the like, but an example is not limited thereto.
In the present specification, heterocycloalkyl may be substituted or unsubstituted. The heterocycloalkyl may be monocyclic, bicyclic alkyl, or spiroalkyl. When the heterocycloalkyl is bicyclic alkyl or spiroalkyl, only one ring of the two rings may include a heteroatom, and both rings may include a heteroatom. The heterocycloalkyl may be C2-C20 heterocycloalkyl. The C2-C20 heterocycloalkyl may include C2-C15, C2-C10 and C2-C5 heterocycloalkyl. In the present specification, a substituent of the heterocycloalkyl may be bonded to an adjacent group to form a ring. In the present specification, the heterocycloalkyl may include at least one heteroatom selected from N, O, S, P and B in a ring. For example, in the present specification, the heterocycloalkyl may include at least one or at least two heteroatoms selected from N, O and S in a ring and, for example, may include N as a heteroatom in a ring. When the heterocycloalkyl includes two or more heteroatoms in the ring, the heteroatoms may be the same as or different from each other. Examples of the heterocycloalkyl may include pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, tetrahydropyran, tetrahydrothiopyran, piperazine, morpholine, thiomorpholine, quinuclidine, and the like, but an example is not limited thereto.
In the present specification, the above description of heterocycloalkyl may be applied to heterocycloalkenyl except for including one or more carbon-carbon double bonds in a ring.
In the present specification, aryl may be substituted or unsubstituted. The aryl may be C6-C20 aryl. The C6-C20 aryl may include C6-C15, C6-C10 and/or C6-C8 aryl. In the present specification, a substituent of the aryl may be bonded to an adjacent group to form a ring.
In the present specification, “being bonded to an adjacent group to form a ring” may refer to being bonded to an adjacent group to form a substituted or unsubstituted hydrocarbon ring, or a substituted or unsubstituted hetero ring. The hydrocarbon ring may include an aliphatic hydrocarbon ring and an aromatic hydrocarbon ring. The hetero ring may include an aliphatic hetero ring and an aromatic hetero ring. The hydrocarbon ring and the hetero ring may be monocyclic or polycyclic. In addition, the ring formed by bonding with an adjacent group may form a bicyclic ring (including a bridge structure) and/or a spiro ring.
Hereinafter, as an example, described are a cyclohexane group in which a substituent is bonded to an adjacent group to form a benzene ring with an alkoxy group substituted, a piperidine group in which a substituent is bonded to an adjacent group to form a thiophene ring, a piperidine group in which a substituent is bonded to an adjacent group to form a spirocyclic group, a piperidine group (quinuclidine) in which a substituent is bonded to an adjacent group to form a bridge structure, a cyclohexane group in which a substituent is bonded to an adjacent group to form a benzene ring, a cyclohexane group in which a substituent is bonded to an adjacent group to form a benzene ring, a cyclohexane group in which a substituent is bonded to an adjacent group to form a benzene ring with a benzene ring substituted, a heterocyclohexane group in which a substituent is bonded to an adjacent group to form heteroaryl with —CF3 substituted, and a tetrahydroisoquinoline group with a methyl group substituted in which a substituent is bonded to an adjacent group.
Examples of the aryl group may include phenyl, naphthyl, fluorenyl, anthracenyl, phenanthryl, biphenyl, terphenyl, quaterphenyl, quinquephenyl, sexiphenyl, triphenylenyl, pyrenyl, benzo fluoranthenyl, chrycenyl, and the like, but an example is not limited thereto.
In the present specification, may refer to a portion to be connected.
In the present specification, the heteroaryl group may be substituted or unsubstituted. The heteroaryl group may be C2-C20 heteroaryl group. The C2-C20 heteroaryl group may include C2-C15, C2-C10, C2-C5, C3-C20, C3-C15. C3-C10 and/or C3-C5 heteroaryl group. In the present specification, the heteroaryl group may include at least one heteroatom selected from N, O, S, P and B in a ring. For example, in the present specification, the heteroaryl group may include one or more heteroatoms selected from N, O and S and, for example, may include N as a heteroatom. When the heteroaryl group includes two or more heteroatoms in the ring, the heteroatoms may be the same as or different from each other. For example, in the present specification, the heteroaryl group may be C2-C15, C2-C10, C2-C5, C3-C20, C3-C15. C3-C10 or C3-C5 heteroaryl group including N as a heteroatom.
Examples of the heteroaryl group may include benzoimidazolyl, benzofuranyl, quinolyl, naphthoquinonyl, benzodioxazolyl, quinoxalyl, benzothiophenyl, tetrathienopyridyl, piperidyl, piperidone ethylketal, tetrahydronaphthalenyl, morpholinyl, piperazinyl, pyrrolidinyl, thiophenyl, thiomorpholinyl, furanyl, imidazolnyl, pyrazolnyl, pyrimidinyl, dibenzofuranyl, quinuclidinyl, indolyl, azaindolyl, quinazolinyl, naphthopyridinyl, purinyl, isoindolyl, benzodioxinyl, dihydrobenzodioxinyl, benzothiazolinyl, tetrahydroisoindolyl, chromenyl, benzothiophenyl, benztriazolyl, benzoxadiazolyl, indazolyl, isoquinolinyl, indolinyl, azaindolinyl, pyrimidopyridinyl, pyridopyrimidinyl, imidazopyridinyl, dihydroimidazopyrimidinyl, furopyridinyl, insoindolinyl and the like, but an example is not limited thereto.
In the present specification, the above description of the aryl group may be applied to the arylene group except for being a divalent group.
In the present specification, the above description of the heteroaryl group may be applied to the heteroarylene group except for being a divalent group.
The compound of the present specification may include not only pharmaceutically acceptable salts, but also all the salts, stereoisomers, hydrates and solvates, which may be prepared by a conventional method.
In the present specification, the “hydrate” may refer to one in which a compound according to one example, a pharmaceutically acceptable salt thereof or a stereoisomer thereof and water are bound by a non-covalent intermolecular force, and may include a stoichiometric or non-stoichiometric amount of water. Specifically, the hydrate may include water at a molar ratio of about 0.25 mol to about 10 mol based on 1 mol of an active ingredient, more specifically about 0.5 mol, about 1 mol, about 1.5 mol, about 2 mol, about 2.5 mol, about 3 mol, about 5 mol, etc.
In the present specification, the “solvate” may refer to one in which a compound according to one example, a pharmaceutically acceptable salt thereof or a stereoisomer thereof and a solvent other than water are bound by an intermolecular force, and may include a stoichiometric or non-stoichiometric amount of the solvent. Specifically, the solvate may include a solvent molecule at a molar ratio of about 0.25 mol to about 10 mol based on 1 mol of an active component, more specifically about 0.5 mol, about 1 mol, about 1.5 mol, about 2 mol, about 2.5 mol, about 3 mol, about 5 mol, etc.
According to one example of the present invention, there may be provided a 6,7-dialkoxynaphtho[2,3-c]furan-1(3H)-one compound of formula 1 below, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a hydrate thereof, or a solvate thereof. The 6,7-dialkoxynaphtho[2,3-c]furan-1(3H)-one compound of formula 1 may be a 6,7-dimethoxynaphtho[2,3-c]furan-1(3H)-one compound.
In above formula 1,
In above formula 2,
Above formula 2 may be represented by formulas 2-1 to 2-8 below.
In above formulas 2-1 to 2-8, R1 may be the same as defined in above formula 1 or 2. In above formulas 2-1 to 2-8, R1 may be hydrogen, halogen, substituted or unsubstituted C1-C10 linear or branched alkyl, NR4R5, —OR6, —N═CHR7, substituted or unsubstituted C2-C20 heteroaryl, or substituted or unsubstituted C2-C10 heterocycloalkyl including at least one of N, O and S as a heteroatom in a ring. R4 to R7 may be the same as defined in formula 1. The C2-C10 heterocycloalkyl may include one N in the ring and may further include one or more heteroatoms selected from N, O and S in the ring.
may be
including a substituted or unsubstituted ring which is formed by R9 being bonded to an adjacent group may be
The compound represented by above formula 1 may be one selected from the group consisting of the following compounds:
According to one example of the present invention, there may be provided a 6,7-dialkoxynaphtho[2,3-c]furan-1(3H)-one compound of formula 3 below, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a hydrate thereof, or a solvate thereof. The 6,7-dialkoxynaphtho[2,3-c]furan-1(3H)-one compound of formula 3 may be a 6,7-dimethoxynaphtho[2,3-c]furan-1(3H)-one compound.
In above formula 3, Ar1′ may be substituted or unsubstituted C6-C12 arylene group, or substituted or unsubstituted C2-C12 heteroarylene group including at least one of N, O and S as a heteroatom in a ring. q may be 0 or 1.
(wherein at least one of the hydrogen of
may be substituted with halogen). R1′ including a ring formed by a substituent of the C6-C20 aryl being bonded to an adjacent group may be substituted or unsubstituted naphthalenyl, or substituted or unsubstituted tetrahydroquinolinyl, for example,
r may be an integer of 0 or more and 2 or less.
In above formula 4, X1′ to X4′ may be each independently CH or N, and R1′ and r may be the same as defined in above formula 3.
Above formula 4 may be represented by formulas 4-1 to 4-4 below.
In above formulas 4-1 to 4-4, R1′ may be the same as defined in above formula 3 or 4.
(wherein at least one of the hydrogen of
may be substituted with halogen), or
The compound represented by above formula 3 may be one selected from the group consisting of the following compounds:
According to another example of the present invention, there may be provided one compound selected from the group consisting of the following compounds.
The compounds represented by formulas 1 and 3 and the compounds of [212], [224] and [228] of the present invention may be used in the form of pharmaceutically acceptable salt, and acid addition salt formed by pharmaceutically acceptable free acid may be useful as salt. The acid addition salt may be obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc., non-toxic organic acids such as aliphatic mono- and di-carboxylates, phenyl-substituted alkanoate, hydroxy alkanoate and alkandioate, aromatic acids, and aliphatic and aromatic sulfonic acids, etc., and organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc. The types of these pharmaceutically non-toxic salts may include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyn-1,4-dioate, hexan-1,6-dioate, benzoate, chlorobenzoate, methyl benzoate, dinitro benzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalen-1-sulfonate, naphthalen-2-sulfonate, mandelate, etc., but the types of salts meant in the present invention are not limited to those listed salts.
For example, the free acid may be selected from the group consisting of citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, benzoic acid, gluconic acid, methanesulfonic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glutamic acid, aspartic acid, silicylic acid, malonic acid, malic acid, benzenesulfonic acid, hydrochloric acid, bromic acid, nitric acid, sulfuric acid, and phosphoric acid.
The acid addition salt according to the present invention may be prepared by a conventional method and, for example, the acid addition salt may be prepared by dissolving the compound of formula 1 in an organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile, or the like and filtering and drying the resulting precipitate which is obtained by adding an organic acid or an inorganic acid thereto, or by distilling the solvent and an excess of the acid under reduced pressure and then drying and crystallizing under the organic solvent.
In addition, a pharmaceutically acceptable metal salt may be prepared by using a base. An alkali metal or alkaline earth metal salt may be obtained, for example, by dissolving a compound in an excessive amount of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. In this case, it may be pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt. In addition, the corresponding salt may be obtained by reacting the alkali metal or alkaline earth metal salt with an appropriate silver salt (e.g., silver nitrate).
According to one example of the present invention, there may be provided a pharmaceutical composition including the above-described compound, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the hydrate thereof or the solvate thereof as active ingredients.
According to one example of the present invention, there may be provided a pharmaceutical composition for an anti-viral purpose including the above-described compound, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the hydrate thereof or the solvate thereof as active ingredients.
The composition may be an anti-viral composition for one or more of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2), influenza virus, dengue virus, Zika virus, and severe fever with thrombocytopenia syndrome virus (SFTS).
According to one example of the present invention, there may be provided a pharmaceutical composition for preventing or treating a virus infection disease, which includes the above-described compound, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the hydrate thereof or the solvate thereof as active ingredients.
The virus infection disease may be one or more of SARS-COV-2 infection disease, influenza virus infection disease, dengue virus infection disease, Zika virus infection disease, and severe fever with thrombocytopenia syndrome virus infection disease. The SARS-COV-2 infection disease may be coronavirus infection disease-19 (COVID-19). The composition may inhibit intracellular infection and proliferation of one or more of SARS-COV-2, influenza virus, dengue virus, Zika virus, and severe fever with thrombocytopenia syndrome virus.
According to one example of the present invention, there may be provided a pharmaceutical composition for preventing or treating an allergic disease, which includes the above-described compound, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the hydrate thereof or the solvate thereof as active ingredients.
The allergic disease may be at least one selected from the group consisting of rhinitis, asthma, atopic dermatitis, allergic conjunctivitis, allergic otitis media, allergic gastrointestinal infection, anaphylaxis and hives.
According to one example of the present invention, there may be provided a pharmaceutical composition for preventing or treating a respiratory disease, which includes the above-described compound, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the hydrate thereof or the solvate thereof as active ingredients.
The respiratory disease may include an allergic respiratory disease and a non-allergic respiratory disease. The respiratory disease may be at least one selected from the group consisting of cold, pneumonia, bronchitis, chronic obstructive pulmonary disease and rhinitis.
The respiratory disease may be asthma. The asthma may include allergic asthma and non-allergic asthma.
The composition may inhibit the expression of interleukin-5. The composition may exhibit an effect of preventing or treating a respiratory disease, such as improving sputum discharge capacity.
The pharmaceutical composition according to one example may further include at least one of a pharmaceutically acceptable additive, in addition to the compound represented by above formula 1, the optical isomer thereof or the pharmaceutically acceptable salt thereof. For example, the pharmaceutical composition according to one example may further include at least one of diluent or excipient such as carrier, filler, extender, binder, humectant, disintegrant, surfactant, etc. as a pharmaceutically acceptable additive.
The pharmaceutical composition according to one example may further include at least one of a pharmaceutically acceptable additive, in addition to the compound represented by above formula 3, the optical isomer thereof or the pharmaceutically acceptable salt thereof. For example, the pharmaceutical composition according to one example may further include at least one of diluent or excipient such as carrier, filler, extender, binder, humectant, disintegrant, surfactant, etc. as a pharmaceutically acceptable additive.
The pharmaceutical composition according to one example may further include at least one of a pharmaceutically acceptable additive, in addition to the compound of [212], [224] or [228], the optical isomer thereof or the pharmaceutically acceptable salt thereof. For example, the pharmaceutical composition according to one example may further include at least one of diluent or excipient such as carrier, filler, extender, binder, humectant, disintegrant, surfactant, etc. as a pharmaceutically acceptable additive.
According to one example of the present invention, the present invention may provide a method for preventing or treating a virus infection disease, which includes administering the above-described compound, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the hydrate thereof or the solvate thereof into a subject in need thereof.
According to one example of the present invention, the present invention may provide a use of the above-described compound, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the hydrate thereof or the solvate thereof for preventing or treating a virus infection disease.
According to one example of the present invention, the present invention may provide a use of the above-described compound, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the hydrate thereof or the solvate thereof for manufacturing a medicament for preventing or treating a virus infection disease.
According to one example of the present invention, the present invention may provide a method for preventing or treating a respiratory disease, which includes administering the above-described compound, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the hydrate thereof or the solvate thereof into a subject in need thereof.
According to one example of the present invention, the present invention may provide a use of the above-described compound, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the hydrate thereof or the solvate thereof for preventing or treating a respiratory disease.
According to one example of the present invention, the present invention may provide a use of the above-described compound, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the hydrate thereof or the solvate thereof for manufacturing a medicament for preventing or treating a respiratory disease.
According to one example of the present invention, the present invention may provide a method for preventing or treating an allergic disease, which includes administering the above-described compound, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the hydrate thereof or the solvate thereof into a subject in need thereof.
According to one example of the present invention, the present invention may provide a use of the above-described compound, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the hydrate thereof or the solvate thereof for preventing or treating an allergic disease.
According to one example of the present invention, the present invention may provide a use of the above-described compound, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the hydrate thereof or the solvate thereof for manufacturing a medicament for preventing or treating an allergic disease.
In the present specification, the term “subject” may refer to animals, and may be typically mammals, on which treatment using the composition of the present invention may exhibit a beneficial effect. The mammals may refer to mammals including humans, and the term “administration” may refer to providing a predetermined material to a subject through any appropriate method. It is apparent to those skilled in the art that the therapeutically effective dosage and the number of administration for active ingredient of the present invention may vary depending on a desired effect.
In the present invention, the term “mammals including humans” may mean mammals such as monkey, cow, horse, dog, cat, rabbit, rat, mouse, etc., and in particular may include humans. In addition, the subjects may include all the subjects having a symptom of respiratory disease, or having a risk of developing the symptom.
In the present specification, the term “prevention” may refer to a delay of occurrence of disease, disorder or condition. If the occurrence of disease, disorder or condition is delayed for an expected period of time, the prevention may be considered as complete.
In the present specification, the term “treatment” may refer to one which partially or completely reduces, ameliorates, alleviates, inhibits or delays the occurrence of a certain disease, disorder and/or condition, reduces a severity thereof, or reduces the occurrence of at least one symptom or property thereof.
The pharmaceutical composition of the present invention may be formulated into a dosage form of tablet, pill, powder, granule, capsule, suspension, liquid for internal use, emulsion, syrup, aerosol, solution for injection, etc., according to a conventional method for preventing and treating a virus infection disease, a respiratory disease, or an allergic disease.
The pharmaceutical composition of the present invention may be orally or parenterally administered (for example, applied or injected intravenously, subcutaneously or intraperitoneally).
In the present specification, the term “oral administration” may refer to a method of injecting a drug for ameliorating a pathological symptom into a mouth. In the present specification, the term “parenteral administration” may mean a method of administering subcutaneously, intramuscularly, intravenously and intraperitoneally through a tube, excluding administration through the mouth.
A solid preparation for oral administration may include tablets, pills, powders, granules, capsules, etc., and this solid preparation may be prepared by mixing at least one excipient, for example, starch, calcium carbonate, sucrose, lactose, gelatin, etc., in a complex composition. In addition, lubricants such as magnesium stearate and talc may be also used in addition to simple excipients. A liquid preparation for oral administration may include a suspending agent, liquid for internal use, emulsion, syrup, etc., but may also include various excipients, for example, humectant, sweetening agent, flavoring agent, preservative, etc. in addition to water and liquid paraffin, which are the frequently used simple diluents.
A preparation for parenteral administration may include a sterilized aqueous solution, non-aqueous solvent, suspending agent, emulsion, freeze-dried preparation, suppository, etc. The non-aqueous solvent and the suspending agent may include propylene glycol, polyethylene glycol, vegetable oil like olive oil, injectable ester like ethyl oleate, etc.
The pharmaceutically acceptable additive according to the present invention may be included in an amount of 0.1 to 99.9 parts by weight, specifically in an amount of about 0.1 to 50 parts by weight with regard to the composition, but an example is not limited thereto.
A dosage of the pharmaceutical composition according to the present invention may need to be a pharmaceutically effective amount. The “pharmaceutically effective amount” may mean an amount enough to prevent or treat diseases at a reasonable benefit/risk ratio applicable to medical treatment, and a level of effective dose may be variously selected by those skilled in the art according to factors such as a formulation method, a patient's condition and weight, a patient's gender, an age, a degree of disease, a drug form, an administration route and period, an excretion rate, reaction sensitivity, etc. The effective amount may vary depending on a route of disposal, a use of excipient, and possibility of being used with other drugs, as recognized by those skilled in the art.
An amount effective for preventing or treating a virus infection disease, a respiratory disease, or an allergic disease may refer to an amount capable of providing a desired outcome or an objective or subjective advantage in a subject, as a single or multiple dose alone or in combination with one or more other compositions (other therapeutic agents for a virus infection disease, a respiratory disease, an allergic disease, or the like).
A dose or dosage of the pharmaceutical composition according to the present invention may vary in a range thereof depending on a patient's weight, age, gender, health condition and diet, an administration time, an administration method, an excretion rate, and a severity of a disease, but may be taken once or several times by dividing the amount of 0.001 mg/kg to 1000 mg/kg on an adult basis.
(1) The present invention may provide a compound of formula 1 below, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a hydrate thereof or a solvate thereof:
(2) In (1), Ar1—R1 may be represented by formula 2 below:
(3) In (1) or (2), above Ar1—R1 or formula 2 may be represented by formulas 2-1 to 2-8 below:
(4) In (1), (2) or (3), R1 may be hydrogen, halogen, substituted or unsubstituted C1-C10 linear or branched alkyl, —NR4R5, —OR6, —N═CHR7,
(5) In (1), (2), (3) or (4), R1 may be hydrogen, fluroine, chlorine, —CH3,
(6) In (1), (2), (3), (4) or (5), the compound represented by above formula 1 may be one selected from the group consisting of the following compounds:
(7) The present invention may provide a compound of formula 3 below, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a hydrate thereof or a solvate thereof:
(wherein at least one of the hydrogen of
may be substituted with halogen), and r may be an integer of 0 or more and 2 or less,
(8) In (7), (Ar1′)q—(R1′)r may be represented by formula 4 below:
(9) In (7) or (8), (Ar1′)q—(R1′)r or formula 4 may be represented by formulas 4-1 to 4-4 below:
(10) In (7), (8) or (9), Rr may be halogen, —NR4′R5′, —OR6′, —C(═O)CX3 (wherein X is halogen), —NO2
(wherein at least one of the hydrogen of
may be substituted with halogen), or
(11) In (7), (8), (9) or (10), R1′ may be chlorine,
(12) In (7), (8), (9), (10) or (11), the compound represented by above formula 3 may be one selected from the group consisting of the following compounds:
(13) The present invention may provide a compound below, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a hydrate thereof or a solvate thereof:
(14) In (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12) or (13), there may be provided the compound, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the hydrate thereof or the solvate thereof, wherein the salt is acid addition salt formed by pharmaceutically acceptable free acid.
(15) In (14), the free acid may be selected from the group consisting of citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, benzoic acid, gluconic acid, methanesulfonic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glutamic acid, aspartic acid, silicylic acid, malonic acid, malic acid, benzenesulfonic acid, hydrochloric acid, bromic acid, nitric acid, sulfuric acid, and phosphoric acid.
(16) The present invention may provide a pharmaceutical composition for an anti-viral purpose including the compound, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the hydrate thereof or the solvate thereof according to (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14) or (15) as an active ingredient.
(17) In (16), the composition may be an anti-viral composition for one or more of SARS-COV-2, influenza virus, avian influenza virus, dengue virus, Zika virus, and severe fever with thrombocytopenia syndrome virus (SFTS).
(18) The present invention may provide a pharmaceutical composition for preventing or treating a virus infection disease, including the compound, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the hydrate thereof or the solvate thereof according to (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14) or (15) as an active ingredient.
(19) In (18), the virus infection disease may be one or more of SARS-COV-2 infection disease, influenza virus infection disease, avian influenza virus infection disease, dengue virus infection disease, Zika virus infection disease, and severe fever with thrombocytopenia syndrome virus infection disease.
(20) In (18), the virus infection disease may be COVID-19. In (19), the SARS-COV-2 infection disease may be COVID-19.
(21) In (18), (19) or (20), the composition may inhibit intracellular infection and proliferation of one or more of SARS-COV-2, influenza virus, avian influenza virus, dengue virus, Zika virus, and severe fever with thrombocytopenia syndrome virus.
(22) The present invention may provide a pharmaceutical composition for preventing or treating a respiratory disease, including the compound, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the hydrate thereof or the solvate thereof according to (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14) or (15) as an active ingredient.
(23) In (21), the respiratory disease may be at least one selected from the group consisting of asthma, cold, pneumonia, bronchitis, chronic obstructive pulmonary disease and rhinitis.
(24) In (22) or (23), the composition may inhibit the expression of interleukin-5.
(25) The present invention may provide a pharmaceutical composition for preventing or treating an allergic disease, including the compound, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the hydrate thereof or the solvate thereof according to (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14) or (15) as an active ingredient.
(26) In (25), the allergic disease may be at least one selected from the group consisting of rhinitis, asthma, atopic dermatitis, allergic conjunctivitis, allergic otitis media, allergic gastrointestinal infection, anaphylaxis and hives.
(27) The present invention may provide a method for preventing or treating a virus infection disease, which includes administering the compound, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the hydrate thereof or the solvate thereof according to (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14) or (15) into a subject in need thereof.
(28) The present invention may provide a use of the compound, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the hydrate thereof or the solvate thereof according to (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14) or (15) for preventing or treating a virus infection disease.
(29) The present invention may provide a use of the compound, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the hydrate thereof or the solvate thereof according to (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14) or (15) for manufacturing a medicament for preventing or treating a virus infection disease.
(30) The present invention may provide a method for preventing or treating a respiratory disease, which includes administering the compound, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the hydrate thereof or the solvate thereof according to (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14) or (15) into a subject in need thereof.
(31) The present invention may provide a use of the compound, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the hydrate thereof or the solvate thereof according to (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14) or (15) for preventing or treating a respiratory disease.
(32) The present invention may provide a use of the compound, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the hydrate thereof or the solvate thereof according to (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14) or (15) for manufacturing a medicament for preventing or treating a respiratory disease.
(33) The present invention may provide a method for preventing or treating an allergic disease, which includes administering the compound, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the hydrate thereof or the solvate thereof according to (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14) or (15) into a subject in need thereof.
(31) The present invention may provide a use of the compound, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the hydrate thereof or the solvate thereof according to (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14) or (15) for preventing or treating an allergic disease.
(32) The present invention may provide a use of the compound, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the hydrate thereof or the solvate thereof according to (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14) or (15) for manufacturing a medicament for preventing or treating an allergic disease.
The numerical values described in the present specification as above should be interpreted to include a range of equivalents thereof, unless otherwise stated.
Matters mentioned in each of the composition, use; and preventive and/or therapeutic method according to the present invention are applied the same, if not contradictory to each other.
The 6,7-dimethoxynaphtho[2,3-c]furan-1(3H)-one compound according to one example of the present invention can exhibit an effect of inhibiting the intracellular infection and proliferation of various viruses including SARS-COV-2, thereby showing an excellent effect of preventing or treating a wide range of virus infection diseases. In addition, the compound according to one example can have an excellent effect of inhibiting interleukin-5 mainly involved in the induction of allergy and asthma, thereby providing an excellent effect of preventing or treating a respiratory disease.
Hereinafter, the present invention will be described in more detail through preparation examples and examples. However, these preparation examples and examples are provided only for the purpose of illustrating the present invention, and thus the present invention is not limited thereto.
Furthermore, the present invention may include the compound represented by above formula 1, the compound represented by compound 3, the compound of [212], the compound of [224], or the compound of [228]; and the pharmaceutically acceptable salt thereof; as well as the solvate; the stereoisomer; the hydrate, and the like, which may be prepared therefrom.
In Method 1, an R group may be introduced into a pyrimidine compound substituted with X by using anhydrous potassium carbonate, anhydrous sodium carbonate, sodium hydride, etc., in an organic solvent such as acetonitrile, tetrahydrofuran, dimethylformamide, dioxane, etc. R may be defined in the same manner as in R1 described above.
In Reaction Formula 1, the pyrimidine compound may be replaced with an aryl group or a heteroaryl group and, for example, the pyrimidine compound may be replaced with the above-described —(Ar1—R1), etc.
In Method 2, an intermediate compound was synthesized through a Suzuki-Miyaura coupling reaction as shown in Reaction Formula 2 below. Borate was synthesized by heating and stirring a dichloromethane complex of Pd(dppf)Cl2 and potassium acetate in a dioxane solvent at 60-110° C. for 3 to 48 hours.
Ar of Method 2 may be —(Ar1—R1) in formula 1 described above.
In order to synthesize a target material, the compound synthesized in above Reaction Formula 2 was subjected to Suzuki coupling as shown in Reaction Formula 3 below, so as to synthesize compound 1 as the target material.
In Reaction Formula 3, a compound in which X is OTf was mainly used. The reactants, Pd(dppf)Cl2—CH2Cl2, and lithium hydroxide hydrate were heated in a dioxane solvent at 80-110° C. for 8 to 48 hours to synthesize the compound of one Example.
Hereinafter, the present invention will be described in more detail through examples. The following Examples are provided only for the purpose of illustrating the present invention, and thus the scope of the present invention is not limited thereto.
An intermediate was synthesized according to Reaction Formula 1 described above.
After 2 g (10.33 mmol) of 5-bromo-2-chloro pyrimidine and 4.07 g (31.02 mmol) of 2-morpholinoethan-1-ol were dissolved in 30 mL of tetrahydrofuran, 1.24 g (28.41 mmol) of sodium hydride was added thereto at 20° C. A reaction temperature was raised up to 25° C. and reacted for five hours. The reaction was quenched by addition of 50 mL of purified water and extracted with DCM (dichloromethane 3×30 mL). The organic layer was washed with brine (2×10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was recrystallized with DCM/hexane to obtain 1.884 g (6.53 mmol, 63.2%) of 4-(2-((5-bromopyridi-2-yl)oxy)ethyl)morpholine as a title compound. Mass (M+H+): 290.0
After 2 g (10.33 mmol) of 5-bromo-2-chloro pyrimidine and 0.808 g (11.36 mmol) of cyclopropyl methylamine were dissolved in 30 mL of acetonitrile, 4.3 g (31.11 mmol) of anhydrous potassium carbonate was added thereto at 20° C. The resulting mixture was heated and stirred under reflux for eight hours. After cooling, the residual inorganic material was filtered, removed, and distilled under reduced pressure. After 15 mL of purified water was added to the residue, the resulting mixture was extracted twice with 15 ml of dichloromethane, dried over anhydrous sodium sulfate, filtered, washed, and distilled under reduced pressure to obtain 2.32 g (10.17 mmol, 98.3%) of 5-bromo-N-(cyclopropylmethyl)pyrimidin-2-amine. Mass (M+H+): 230.0
After 1.2 g (5.26 mmol) of 5-bromo-N-(cyclopropylmethyl)pyrimidin-2-amine was dissolved in 30 mL of tetrahydrofuran, 1.49 g (10.49 mmol) of iodomethane was added at 20° C. After a reaction temperature was lowered to 0° C., 0.918 g (21.04 mmol) of sodium hydride was added thereto, and the reaction was performed at the same temperature for five hours. After 20 mL of purified water was added to complete the reaction and perform distillation under reduced pressure, 20 ml of purified water was added to the residue and extracted with dichloromethane (DCM)(3×30 mL). The organic layer was washed with brine (2×10 mL), dried over anhydrous Na2SO4, filtered, and distilled under reduced pressure to obtain 1.25 g (5.16 mmol, 98.4%) of 5-bromo-N-(cyclopropylmethyl)-N-methylpyrimidine-2-amine as a title compound. Mass (M+H+): 244.1
After 1.2 g (4.95 mmol) of 5-bromo-N-(cyclopropylmethyl)-N-methylpyrimidin-2-amine synthesized in Intermediate Synthesis Example 3 was dissolved in 20 ml of dioxane, 1.5 g (5.90 mmol) of bis(panacolato)diborane, 1.46 g (14.87 mmol) of KOAc, and 0.4 g (0.48 mmol) of Pd(dppf)Cl2—CH2Cl2 were added thereto. After bubbling the reaction solvent with nitrogen, a reaction temperature was raised up to 80° C., and then the reaction was performed for three hours. After cooling to 25° C., 20 ml of ethyl acetate was injected and then stirred. The reaction solution was passed through a celite pad, filtered and distilled under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.2 g (4.14 mmol, 83.7%) of N-(cyclopropylmethyl)-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine as a title compound. Mass (M+H+): 289.2
Intermediates used in the following examples were prepared by using intermediates prepared similarly to the method for preparing intermediates described above.
After 0.5 g (1.27 mmol) of 6,7-dimethoxy-3-oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl trifluoromethanesulfonate was dissolved in 30 ml of 1,4-dioxane, 0.42 g (1.27 mmol) of(S)-2-amino-5-methoxytetralin(S)-mandelate salt and 0.528 g (3.82 mmol) of anhydrous potassium carbonate were added thereto, after which a temperature was raised up to 95° C. and then the resulting mixture was reacted for 15 hours. After cooling down to 25° C., 30 ml of ethyl acetate (EA) was added thereto, and the resulting mixture was stirred. After filtration and washing with ethyl acetate, distillation was performed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 275 mg (0.65 mmol, 51.6%) of(S)-6,7-dimethoxy-9-((5-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)amino)naphtho[2,3-c]furan-1(3H)-one as a title compound.
Mass (M+H+): 420.2
1H-NMR (500 Mhz, DMSO-d6): 0.82-0.83 (m, 1H), 1.20 (s, 1H), 1.70-1.75 (m, 1H), 2.10-2.15 (m, 1H), 2.74-2.82 (m, 2H), 3.08-3.09 (m, 1H), 3.71 (s, 3H), 3.83 (s, 3H), 3.87 (s, 3H), 4.21-4.25 (m, 1H), 5.31 (s, 2H), 6.35 (d, J=4.45 Hz, 1H), 6.64 (d, J=7.75 Hz, 1H), 6.71 (d, J=8.05 Hz, 1H), 7.04 (t, J=8.0 Hz, 1H), 7.20 (s, 1H), 7.29 (s, 1H), 7.47 (s, 1H)
After 1.0 g (2.54 mmol) of 6,7-dimethoxy-3-oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl trifluoromethanesulfonate was dissolved in 30 ml of acetonitrile, 0.322 g (2.79 mmol) of cis-dimethylmorpholine and 0.80 g (5.78 mmol) of anhydrous potassium carbonate were added thereto, after which a temperature was raised up to 80° C. and then the resulting mixture was reacted for 20 hours. After cooling down to 25° C., 30 ml of ethyl acetate was added thereto, and the resulting mixture was stirred. After filtration and washing with ethyl acetate, distillation was performed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 511 mg (1.42 mmol, 55.9%) of 9-((2S,6R)-2,6-dimethylmorpholino)-6,7-dimethoxynaphtho[2,3-c]furan-1(3H)-one as a title compound.
Mass (M+H+): 358.2
1H-NMR (500 Mhz, DMSO-d6): δ 1.08 (s, 6H), 2.86 (d, J=11.15 Hz, 2H), 3.27-3.29 (m, 2H), 3.89-3.91 (m, 8H), 5.35 (s, 2H), 7.37 (s, 1H), 7.64 (s, 1H), 7.78 (s, 1H)
After 1.0 g (2.54 mmol) of 6,7-dimethoxy-3-oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl trifluoromethanesulfonate was dissolved in 30 ml of acetonitrile, 0.49 g (2.79 mmol) of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride and 1.056 g (7.64 mmol) of anhydrous potassium carbonate were added thereto, after which a temperature was raised up to 80° C. and then the resulting mixture was reacted for 2 days. After cooling down to 25° C., 30 ml of ethyl acetate was added thereto, and the resulting mixture was stirred. After filtration and washing with ethyl acetate, distillation was performed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 353 mg (0.92 mmol, 36.2%) of 9-((2S,6R)-2,6-dimethylmorpholino)-6,7-dimethoxynaphtho[2,3-c]furan-1(3H)-one as a title compound.
Mass (M+H+): 381.45
1H-NMR (500 Mhz, DMSO-d6): δ 2.94 (s, 2H), 3.50-3.57 (m, 2H), 3.64 (s, 3H), 3.84 (s, 3H), 4.24-4.41 (m, 2H), 5.36 (s, 2H), 6.78 (d, J=4.9 Hz, 1H), 7.27 (d, 1H), 7.34 (s, 1H), 7.57 (s, 1H), 7.63 (s, 1H)
After 1.0 g (2.54 mmol) of 6,7-dimethoxy-3-oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl trifluoromethanesulfonate was dissolved in 30 ml of acetonitrile, 0.317 g (2.79 mmol) of 3,5-methylpiperidine and 1.056 g (7.64 mmol) of anhydrous potassium carbonate were added thereto, after which a temperature was raised up to 80° C. and then the resulting mixture was reacted for two days. After cooling down to 25° C., 30 ml of ethyl acetate was added thereto, and the resulting mixture was stirred. After filtration and washing with ethyl acetate, distillation was performed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 690 mg (1.94 mmol, 76.3%) of 9-(3,5-dimethylpiperidin-1-yl)-6,7-dimethoxynaphtho[2,3-c]furan-1(3H)-one as a title compound.
Mass (M+H+): 356.2
1H-NMR (500 Mhz, DMSO-d6): δ 0.73-0.81 (m, 6H), 1.85-1.87 (m, 4H), 2.91-2.92 (m, 2H), 3.01 (t, J=10.9 Hz, 2H), 3.77 (s, 3H), 3.84 (s, 3H), 5.31 (s, 2H), 7.30 (s, 1H), 7.51 (s, 1H), 7.61 (s, 1H)
After 1.0 g (2.54 mmol) of 6,7-dimethoxy-3-oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl trifluoromethanesulfonate was dissolved in 30 ml of acetonitrile, 0.249 g (2.79 mmol) of 2-methoxy-N-methylethan-1-amine and 1.056 g (7.64 mmol) of anhydrous potassium carbonate were added thereto, after which a temperature was raised up to 80° C. and then the resulting mixture was reacted for three days. After cooling down to 25° C., 30 ml of ethyl acetate was added thereto, and the resulting mixture was stirred. After filtration and washing with ethyl acetate, distillation was performed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 460 mg (1.38 mmol, 54.3%) of 6,7-dimethoxy-9-((2-methoxyethyl)(methyl)amino)naphtho[2,3-c]furan-1(3H)-one as a title compound.
Mass (M+H+): 332.2
1H-NMR (500 Mhz, DMSO-d6): δ 2.92 (s, 3H), 3.12 (s, 3H), 3.23 (s, 4H), 3.82 (s, 3H), 3.84 (s, 3H), 5.32 (s, 2H), 7.30 (s, 1H), 7.58 (s, 1H), 7.86 (s, 1H)
After 1.0 g (2.54 mmol) of 6,7-dimethoxy-3-oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl trifluoromethanesulfonate was dissolved in 30 ml of acetonitrile, 0.325 g (2.79 mmol) of N1,N1-diethylethan-1,2-diamine and 1.056 g (7.64 mmol) of anhydrous potassium carbonate were added thereto, after which a temperature was raised up to 80° C. and then the resulting mixture was reacted for one day. After cooling down to 25° C., 30 ml of ethyl acetate was added thereto, and the resulting mixture was stirred. After filtration and washing with ethyl acetate, distillation was performed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 505 mg (1.40 mmol, 55.1%) of 9-((2-(diethylamino)ethyl)amino)-6,7-dimethoxynaphtho[2,3-c]furan-1(3H)-one as a title compound.
Mass (M+H+): 359.2
1H-NMR (500 Mhz, DMSO-d6): δ 0.85 (t, J=7.15 Hz, 6H), 2.39-2.42 (m, 4H), 2.54 (t, J=6.0 Hz, 2H), 3.65-3.68 (m, 2H), 3.82 (d, J=2.3 Hz, 6H), 5.21 (s, 2H), 6.86-6.88 (m, 1H), 7.00 (s, 1H), 7.19 (s, 1H), 7.49 (s, 1H)
After 1.13 g of 6,7-dimethoxy-3-oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl trifluoromethanesulfonate was dissolved in 30 ml of 1,4-dioxane, lithium hydroxy hydrate and Pd(dppf)Cl2, and CH2Cl2 were added thereto and stirred. After 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine was added, nitrogen bubbling was performed on the solvent to remove oxygen and substitute nitrogen, after which a temperature was raised up to 60° C. and the resulting mixture was reacted for four hours. After cooling down to 25° C., 30 ml of ethyl acetate was added thereto, and the resulting mixture was stirred. After filtration and washing with ethyl acetate, distillation was performed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 370 mg (0.71 mmol, 52%) of 6,7-dimethoxy-9-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)naphtho[2,3-c]furan-1(3H)-one as a title compound.
Mass (M+H+): 421.2
1H-NMR (500 Mhz, CDCl3): 2.86-2.94 (m, 5H), 3.57 (d, J=12.5 Hz, 2H), 3.89-3.94 (m, 5H), 4.06 (s, 3H), 5.02 (d, J=12.05 Hz, 2H), 5.41 (s, 2H), 7.08 (s, 1H), 7.21 (s, 1H), 7.76 (s, 1H), 8.43 (s, 2H)
The compound of Example 8 was synthesized by the same method as that of the compound of Example 7 except for using (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl) morpholine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 436.2
1H-NMR (500 Mhz, DMSO-d6): δ 1.15 (t, J=13.75 Hz, 6H), 2.58-2.61 (m, 2H), 3.59-3.62 (m, 2H), 3.73 (s, 3H), 3.92 (s, 3H), 4.59 (d, J=11.45 Hz, 2H), 5.42 (s, 2H), 7.07 (s, 1H), 7.50 (s, 1H), 7.94 (s, 1H), 8.41 (s, 2H)
The compound of Example 9 was synthesized by the same method as that of the compound of Example 7 except for using 2-(piperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 406.2
1H-NMR (500 Mhz, CDCl3): δ 1.68 (s, 6H), 3.88 (s, 7H), 4.03 (s, 3H), 5.36 (s, 2H), 7.19 (d J=6.3 Hz, 2H), 7.69 (s, 1H), 8.36 (s, 2H)
The compound of Example 10 was synthesized by the same method as that of the compound of Example 7 except for using 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)thiomorpholine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 423.2
1H-NMR (500 Mhz, CDCl3): δ 2.76 (s, 4H), 3.85 (s, 3H), 4.04 (s, 3H), 4.07 (s, 4H), 5.37 (s, 2H), 7.13-7.25 (m, 4H), 7.70 (s, 1H), 8.22 (s, 1H)
The compound of Example 11 was synthesized by the same method as that of the compound of Example 7 except for using N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 366.1
1H-NMR (500 Mhz, DMSO-d6): δ 3.13 (s, 6H), 3.66 (s, 3H), 3.86 (s, 3H), 5.36 (s, 2H), 7.01 (s, 1H), 7.44 (s, 1H), 7.87 (s, 1H), 8.31 (s, 2H)
The compound of Example 12 was synthesized by the same method as that of the compound of Example 7 except for using 5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 362.2
1H-NMR (500 Mhz, CDCl3): 3.03 (t, J=5.7 Hz, 2H), 3.25 (s, 3H), 4.06 (s, 3H), 4.33 (br, 2H), 4.99 (s, 2H), 5.40 (s, 2H), 6.88 (d, J=5.15 Hz, 1H), 7.16 (t, J=5.15 Hz, 1H), 7.25 (s, 1H), 7.73 (s, 1H), 8.46 (s, 2H)
The compound of Example 13 was synthesized by the same method as that of the compound of Example 7 except for using 4-(2-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)oxy)ethyl)morpholine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 452.2
1H-NMR (500 Mhz, CD3OD): 2.63-2.64 (m, 4H), 2.88 (t, J=5.45 Hz, 2H), 3.70 (t, J=4.75 Hz, 4H), 3.79 (s, 3H), 4.00 (s, 3H), 4.66 (t, J=5.45 Hz, 2H), 5.45 (s, 2H), 7.03 (s, 1H), 7.45 (s, 1H), 7.97 (s, 1H), 8.60 (s, 2H)
The compound of Example 14 was synthesized by the same method as that of the compound of Example 7 except for using N-(3,4-dimethylphenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 442.2
1H-NMR (500 Mhz, DMSO-d6): δ 2.15 (s, 3H), 2.18 (s, 3H), 3.74 (s, 3H), 3.93 (s, 3H), 5.44 (s, 2H), 7.03 (d, J=0.65 Hz, 1H), 7.09 (s, 1H), 7.52 (s, 2H), 7.56 (d, J=8.1 Hz, 1H), 7.96 (s, 1H), 8.48 (s, 2H), 9.63 (s, 1H)
The compound of Example 15 was synthesized by the same method as that of the compound of Example 7 except for using ethyl 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl) piperidin-3-carboxylate instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 478.2
1H-NMR (500 Mhz, DMSO-d6): 1.15 (t, J=6.4 HZ, 3H), 1.48-1.53 (m, 1H), 1.68-1.74 (m, 2H), 1.99-2.02 (m, 1H), 2.53-2.57 (m, 1H), 3.13-3.26 (m, 2H), 3.74 (s, 3H), 3.92 (s, 3H), 4.05-4.09 (m, 2H), 4.45-4.48 (m, 1H), 4.69-4.72 (m, 1H), 5.45 (s, 2H), 7.07 (s, 1H), 7.50 (s, 1H), 7.94 (s, 1H), 8.40 (s, 2H)
The compound of Example 16 was synthesized by the same method as that of the compound of Example 7 except for using N-(3-(1H-imidazol-1-yl) propyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 446.2
1H-NMR (500 Mhz, DMSO-d6): 1.99-2.03 (m, 2H), 3.30-3.34 (m, 2H), 3.74 (s, 3H), 3.92 (s, 3H), 4.03-4.07 (m, 2H), 5.42 (s, 2H), 6.86 (s, 1H), 7.08 (s, 1H), 7.19 (s, 1H), 7.50 (s, 2H), 7.64 (s, 1H), 7.93 (s, 1H), 8.31 (s, 2H)
The compound of Example 17 was synthesized by the same method as that of the compound of Example 7 except for using (R)-3-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)oxy) quinuclidine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 448.2
1H-NMR (500 Mhz, DMSO-d6): 1.43-1.45 (m, 1H), 1.61-1.69 (m, 2H), 1.91-1.95 (m, 1H), 2.18 (s, 1H), 2.68-2.87 (m, 6H), 3.31-3.34 (m, 1H), 3.72 (s, 3H), 3.92 (s, 3H), 5.45 (s, 2H), 6.98 (s, 1H), 7.54 (s, 1H), 8.00 (s, 1H), 8.63 (s, 2H)
The compound of Example 18 was synthesized by the same method as that of the compound of Example 7 except for using N-(2-methoxyethyl)-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 410.2
1H-NMR (500 Mhz, DMSO-d6): δ 3.20 (s, 3H), 3.26-3.33 (m, 3H), 3.57 (t, J=5.75 Hz, 2H), 3.73 (s, 3H), 3.84-3.87 (m, 2H), 3.92 (s, 3H), 5.42 (s, 2H), 7.07 (s, 1H), 7.50 (s, 1H), 7.93 (s, 1H), 8.38 (s, 2H)
The compound of Example 19 was synthesized by the same method as that of the compound of Example 7 except for using ethyl (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)-D-propionate instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 464.2
1H-NMR (500 Mhz, CD3OD): 1.24 (t, J=6.85 Hz, 3H), 2.08-2.15 (m, 3H), 2.40-2.45 (m, 1H), 3.76-3.83 (m, 4H), 3.99 (s, 3H), 4.16-4.20 (m, 2H), 4.54 (s, 2H), 5.42 (s, 2H), 7.12 (s, 1H), 7.41 (s, 1H), 7.90 (s, 1H), 8.36 (s, 2H)
The compound of Example 20 was synthesized by the same method as that of the compound of Example 7 except for using 2-(benzo[d][1,3]dioxol-5-yloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 459.1
1H-NMR (500 Mhz, DMSO-d6): δ 3.74 (s, 3H), 3.93 (s, 3H), 5.45 (s, 2H), 6.05 (s, 2H), 6.73 (dd, J=8.35, 2.35 Hz, 1H), 6.93 (s, 1H), 6.95-6.96 (m, 1H), 6.99 (s, 1H), 7.55 (s, 1H), 8.02 (s, 1H), 8.67 (s, 2H)
The compound of Example 21 was synthesized by the same method as that of the compound of Example 7 except for using 2-(naphthalen-1-ylmethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 465.1
1H-NMR (500 Mhz, DMSO-d6): δ 3.74 (s, 3H), 3.93 (s, 3H), 5.45 (s, 2H), 6.97 (s, 1H), 7.47-7.58 (m, 5H), 7.86 (t, J=8.15 Hz, 2H), 8.01 (d, J=7.7 Hz, 2H), 8.69 (s, 2H)
The compound of Example 22 was synthesized by the same method as that of the compound of Example 7 except for using (S)—N-(5-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 498.2
1H-NMR (500 Mhz, DMSO-d6): 1.60-1.71 (m, 1H), 2.13-2.16 (m, 1H), 2.50-2.55 (m, 2H), 2.71-2.78 (m, 1H), 2.86-2.91 (m, 1H), 3.07-3.10 (m, 1H), 3.75 (s, 6H), 3.93 (s, 3H), 5.42 (s, 2H), 6.66-6.68 (m, 1H), 6.71-6.73 (m, 1H), 7.03-7.07 (m, 1H), 7.10 (s, 1H), 7.42-7.43 (m, 1H), 7.50 (s, 1H), 7.93 (s, 1H), 8.33 (s, 2H)
The compound of Example 23 was synthesized by the same method as that of the compound of Example 7 except for using N-isopropyl-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 394.2
1H-NMR (500 Mhz, DMSO-d6): 1.18 (d, J=6.75 Hz, 6H), 3.01 (s, 3H), 3.74 (s, 3H), 3.92 (s, 3H), 5.05-5.11 (m, 1H), 5.42 (s, 2H), 7.10 (s, 1H), 7.50 (s, 1H), 7.92 (s, 1H), 8.37 (s, 2H)
It was synthesized by the same method.
Mass (M+H+): 533.3
1H-NMR (500 Mhz, DMSO-d6): δ 1.05-1.10 (m, 6H), 1.90-1.98 (m, 3H), 2.23-2.40 (m, 2H), 2.76-2.84 (m, 1H), 3.30-3.41 (m, 2H), 3.68-3.73 (m, 5H), 3.92-4.18 (m, 5H), 5.00-5.13 (m, 1H), 5.42 (s, 2H), 7.05 (s, 1H), 7.50 (s, 1H), 7.93 (s, 1H), 8.32-8.39 (m, 2H)
The compound of Example 25 was synthesized by the same method as that of the compound of Example 7 except for using 2-(sec-butoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 395.2
1H-NMR (500 Mhz, DMSO-d6): 0.92-0.96 (m, 3H), 1.33 (d, J=6.15 Hz, 3H), 1.67-1.77 (m, 2H), 3.72 (s, 3H), 3.93 (s, 3H), 5.10-5.14 (m, 1H), 5.45 (s, 2H), 6.99 (s, 1H), 7.53 (s, 1H), 8.00 (s, 1H), 8.62 (s, 2H)
The compound of Example 26 was synthesized by the same method as that of the compound of Example 7 except for using 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 353.1
1H-NMR (500 Mhz, DMSO-d6): δ 3.72 (s, 3H), 3.93 (s, 3H), 4.00 (s, 3H), 5.45 (s, 2H), 6.97 (s, 1H), 7.54 (s, 1H), 8.01 (s, 1H), 8.65 (s, 2H)
The compound of Example 27 was synthesized by the same method as that of the compound of Example 7 except for using methyl (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)-D-valinate instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 452.2
1H-NMR (500 Mhz, DMSO-d6): δ 1.00 (dd, J=23.45, 6.85 Hz, 6H), 2.15-2.18 (m, 1H), 3.61 (s, 3H), 3.73 (s, 3H), 3.93 (s, 3H), 4.30-4.33 (m, 1H), 5.45 (s, 2H), 7.04 (s, 1H), 7.50 (s, 1H), 7.63 (d, J=7.4 Hz, 1H), 7.93 (s, 1H), 8.34 (s, 2H)
The compound of Example 28 was synthesized by the same method as that of the compound of Example 7 except for using N-(2-(cyclohex-1-en-1-yl)ethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 446.2
1H-NMR (500 Mhz, DMSO-d6): δ 1.47-1.54 (m, 4H), 1.91-1.94 (m, 4H), 2.18-2.19 (m, 2H), 3.4-3.42 (m, 2H), 3.73 (s, 3H), 3.92 (s, 3H), 5.42 (s, 2H), 7.07 (s, 1H), 7.23-7.26 (m, 1H), 7.50 (s, 1H), 8.29 (s, 2H)
The compound of Example 29 was synthesized by the same method as that of the compound of Example 7 except for using (Z)—N,N-dimethyl-2-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazin-2-yl)imino) ethan-1-amine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 393.2
1H-NMR (500 Mhz, DMSO-d6): δ 3.06 (s, 3H), 3.14 (s, 3H), 3.25 (s, 2H), 3.66 (s, 3H), 3.93 (s, 3H), 5.45 (s, 2H), 7.06 (s, 1H), 7.51 (s, 1H), 7.99 (s, 1H), 8.29 (s, 2H), 8.65 (s, 1H)
The compound of Example 30 was synthesized by the same method as that of the compound of Example 7 except for using 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazin-2-amine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 338.2
1H-NMR (500 Mhz, DMSO-d6): δ 3.68 (s, 3H), 3.9 (s, 3H), 5.42 (s, 2H), 6.59 (s, 2H), 7.11 (s, 1H), 7.48 (s, 1H), 7.93 (s, 1H), 8.00 (s, 2H)
The compound of Example 31 was synthesized by the same method as that of the compound of Example 7 except for using N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazin-2-amine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 366.2
1H-NMR (500 Mhz, DMSO-d6): δ 3.15 (s, 6H), 3.67 (s, 3H), 3.92 (s, 3H), 5.43 (s, 2H), 7.14 (s, 1H), 7.49 (s, 1H), 7.95 (s, 1H), 8.17 (s, 1H), 8.29 (s, 1H)
The compound of Example 32 was synthesized by the same method as that of the compound of Example 7 except for using 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 323.1
1H-NMR (500 Mhz, DMSO-d6): δ 3.63 (s, 3H), 3.93 (s, 3H), 5.49 (s, 2H), 6.86 (s, 1H), 7.55 (s, 1H), 8.07 (s, 1H), 8.74 (s, 1H), 8.80 (s, 1H), 8.79 (s, 1H)
The compound of Example 33 was synthesized by the same method as that of the compound of Example 7 except for using (R)—N-(2-methoxyethyl)-N-methyl-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)pyrrolidin-2-carboxamide instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 507.3
1H-NMR (500 Mhz, DMSO-d6): δ 1.07 (s, 2H), 1.8-2.1 (m, 3H), 2.25-2.30 (m, 1H), 2.82 (s, 1H), 3.04 (s, 1H), 3.13 (s, 2H), 3.19 (s, 2H), 3.30-3.40 (m, 1H), 3.55-3.56 (m, 1H), 3.68-3.71 (m, 3H), 3.73 (s, 3H), 3.92 (s, 3H), 4.99-5.01 (m, 1H), 5.42 (s, 2H), 7.06 (s, 1H), 7.50 (s, 1H), 7.93 (s, 1H), 8.30 (s, 2H), 8.41 (s, 1H)
The compound of Example 34 was synthesized by the same method as that of the compound of Example 7 except for using 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 360.1
1H-NMR (500 Mhz, DMSO-d6): δ 3.52 (s, 3H), 3.92 (s, 3H), 5.41 (s, 2H), 6.45 (s, 1H), 6.95-7.03 (m, 2H), 7.38 (s, 1H), 7.42-7.48 (m, 2H), 7.9 (s, 1H), 11.19 (s, 1H)
The compound of Example 35 was synthesized by the same method as that of the compound of Example 7 except for using 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 340.1
1H-NMR (500 Mhz, DMSO-d6): δ 3.66 (s, 3H), 3.93 (s, 3H), 5.45 (s, 2H), 6.84 (s, 1H), 7.33 (d, J=8.6 Hz, 1H), 7.54-8.04 (m, 2H), 8.23 (s, 1H)
The compound of Example 36 was synthesized by the same method as that of the compound of Example 7 except for using 2-hydroxyethyl (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)-D-prolinate instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 480.2
1H-NMR (500 Mhz, DMSO-d6): δ 1.95-2.10 (m, 2H), 2.30-2.40 (m, 1H), 3.50-3.53 (m, 2H), 3.6-3.7 (m, 2H), 3.72 (s, 3H), 3.92 (s, 3H), 3.97-4.01 (m, 1H), 4.07-4.10 (m, 1H), 4.60-4.62 (m, 1H), 4.70-4.75 (m, 1H), 5.42 (s, 2H), 7.03 (s, 1H), 7.51 (s, 1H), 7.94 (s, 1H), 8.36 (s, 1H), 8.43 (s, 1H)
The compound of Example 37 was synthesized by the same method as that of the compound of Example 7 except for using N-(2-proxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 424.2
1H-NMR (500 Mhz, DMSO-d6): δ 0.77-0.80 (m, 3H), 1.43-1.46 (m, 2H), 3.25-3.32 (m, 2H), 3.40-3.48 (m, 4H), 3.68 (s, 3H), 3.87 (s, 3H), 5.36 (s, 2H), 7.02 (s, 1H), 7.25-7.26 (m, 1H), 7.45 (s, 1H), 7.87 (s, 1H), 8.25 (s, 2H)
The compound of Example 38 was synthesized by the same method as that of the compound of Example 7 except for using methyl (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)-L-propyl-D-alaniate instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 521.2
1H-NMR (500 Mhz, DMSO-d6): δ 1.22 (d, J=7.15 Hz, 3H), 1.95-1.99 (m, 3H), 2.20-2.25 (m, 1H), 3.55 (s, 3H), 3.60-3.65 (m, 1H), 3.72 (s, 3H), 3.75-3.80 (m, 1H), 3.92 (s, 3H), 4.26-4.32 (m, 1H), 4.52-4.54 (m, 1H), 5.42 (s, 2H), 7.06 (s, 1H), 7.50 (s, 1H), 7.94 (s, 1H), 8.28 (d, J=6.6 Hz, 1H), 8.30-8.43 (m, 2H)
The compound of Example 39 was synthesized by the same method as that of the compound of Example 7 except for using (S)—N—((S)-1-(4-fluorophenyl)ethyl)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)pyrrolidin-2-carboxamide instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 557.3
1H-NMR (500 Mhz, DMSO-d6): δ 1.32 (d, J=6.85 Hz, 3H), 1.92-193 (m, 3H), 2.20-2.30 (m, 1H), 3.63-3.66 (m, 5H), 3.93 (s, 3H), 4.52 (d, J=8.6 Hz, 1H), 4.90 (t, J=8.0 Hz, 1H), 5.43 (s, 2H), 7.04-7.07 (m, 3H), 7.29 (br, 2H), 7.51 (s, 1H), 7.95 (s, 1H), 8.35 (d, J=8.0 Hz, 1H), 8.36-8.42 (m, 2H)
The compound of Example 40 was synthesized by the same method as that of the compound of Example 7 except for using (R)—N—((R)-1-(4-fluorophenyl)ethyl)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)pyrrolidin-2-carboxamide instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 373.1
1H-NMR (500 Mhz, DMSO-d6): δ 3.49 (s, 3H), 3.89 (s, 3H), 5.43 (s, 2H), 6.82 (s, 1H), 7.51 (s, 1H), 7.78-7.80 (m, 1H), 7.99 (s, 1H), 8.03 (s, 1H), 8.16 (d, J=8.85 Hz, 1H), 8.95-8.97 (m, 2H)
The compound of Example 41 was synthesized by the same method as that of the compound of Example 7 except for using (S)—N-((5-methylfuran-2-yl)methyl)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)pyrrolidin-2-carboxamide instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 529.2
1H-NMR (500 Mhz, DMSO-d6): δ 1.90 (br, 3H), 2.09 (s, 3H), 2.18 (br, 1H), 3.52-3.71 (m, 5H), 3.87 (s, 3H), 4.11 (br, 2H), 4.49 (d, J=8.6 Hz, 1H), 5.37 (s, 2H), 5.84 (s, 1H), 5.97 (s, 1H), 7.01 (s, 1H), 7.45 (s, 1H), 7.88 (s, 1H), 8.30-8.40 (br, 3H)
The compound of Example 42 was synthesized by the same method as that of the compound of Example 7 except for using N-(2-propoxyethyl)-N-propyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazin-2-amine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 466.3
1H-NMR (500 Mhz, DMSO-d6): δ 0.82-0.89 (m, 6H), 1.45-1.52 (m, 2H), 1.60-1.68 (m, 2H), 3.35 (t, J=6.3 Hz, 2H), 3.59 (t, J=6.3 Hz, 4H), 3.73 (s, 3h), 3.78 (t, J=5.7 Hz, 2h), 3.92 (s, 3h), 5.54 (s, 2H), 7.08 (s, 1H), 7.50 (s, 1H), 7.93 (s, 1H), 8.38 (s, 2H)
The compound of Example 43 was synthesized by the same method as that of the compound of Example 7 except for using 2-(dibenzo[b,d]furan-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 411.1
1H-NMR (500 Mhz, DMSO-d6): δ 3.53 (s, 3H), 3.90 (s, 3H), 5.46 (s, 2H), 6.93 (s, 1H), 7.38 (t, J=7.45 Hz, 1H), 7.48 (dd, J=8.6, 1.7 Hz, 1H), 7.1-7.54 (m, 2H), 7.74 (d, J=8.6 Hz, 1H), 7.81 (d, J=8.05 Hz, 1H), 7.99 (s, 1H), 8.12-8.15 (m, 2H)
The compound of Example 44 was synthesized by the same method as that of the compound of Example 7 except for using ethyl (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)glycinate instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 424.1
1H-NMR (500 Mhz, DMSO-d6): δ 1.11 (t, J=6.70 Hz, 3H), 3.67 (s, 3H), 3.88 (s, 3H), 4.02-4.06 (m, 4H), 5.37 (s, 2H), 6.98 (s, 1H), 7.46 (s, 1H), 7.66 (t, J=6.3 Hz, 1H), 7.89 (s, 1H), 8.29 (s, 2H)
The compound of Example 45 was synthesized by the same method as that of the compound of Example 7 except for using ethyl (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)-L-prolyglycinate instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 521.2
1H-NMR (500 Mhz, DMSO-d6): δ 1.14 (dd, J=9.75, 4.55 Hz, 3H), 1.95-2.02 (m, 3H), 2.22-2.24 (m, 1H), 3.50-3.55 (m, 1H), 3.73 (s, 3H), 3.76-3.78 (m, 3H), 3.92 (s, 3H), 4.00-4.05 (m, 2H), 4.56 (t, J=1.7 Hz, 1H), 5.42 (s, 2H), 7.06 (s, 1H), 7.50 (s, 1H), 7.94 (s, 1H), 8.30-8.40 (m, 3H)
The compound of Example 46 was synthesized by the same method as that of the compound of Example 7 except for using 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) quinoline instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 372.2
1H-NMR (500 Mhz, DMSO-d6): δ 3.57 (s, 3H), 3.94 (s, 3H), 5.49 (s, 2H), 6.94 (s, 1H), 7.57 (s, 1H), 7.66-7.68 (m, 1H), 7.81-7.83 (m, 1H), 8.04-8.05 (m, 2H), 8.11 (d, J=8.6 Hz, 1H), 8.44 (d, J=1.7 Hz, 1H), 8.86 (d, J=2.3 Hz, 1H)
The compound of Example 47 was synthesized by the same method as that of the compound of Example 7 except for using (1r,4r)-4-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)amino)cyclohexan-1-ol instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 436.2
1H-NMR (500 Mhz, DMSO-d6): δ 1.31-1.28 (m, 4H), 1.78 (d, J=12.0 Hz, 2H), 1.88 (d, J=11.2 Hz, 2H), 3.30-3.40 (m, 1H), 3.65-3.67 (m, 1H), 3.69 (s, 3H), 3.87 (s, 3H), 4.47 (d, J=4.25 Hz, 1H), 5.36 (s, 2H), 7.04 (s, 1H), 7.18 (d, J=8.0 Hz, 1H), 7.44 (s, 1H), 7.87 (s, 1H), 8.24 (s, 2H)
The compound of Example 48 was synthesized by the same method as that of the compound of Example 7 except for using N-hexyl-N-(2-(hexyloxy)ethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 550.4
1H-NMR (500 Mhz, DMSO-d6): δ 0.80-0.84 (m, 6H), 1.20-1.22 (m, 5H), 1.25-1.27 (m, 7H), 1.42-1.50 (m, 2H), 1.6-1.65 (m, 2H), 3.38 (t, 2H), 3.55-3.60 (m, 4H), 3.73 (s, 3H), 3.75-3.78 (m, 2H), 3.92 (s, 3H), 5.42 (s, 2H), 7.08 (s, 1H), 7.50 (s, 1H), 7.93 (s, 1H), 8.37 (s, 2H)
The compound of Example 49 was synthesized by the same method as that of the compound of Example 7 except for using (1S)-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)cyclopentan-1-carboxamide instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 435.2
1H-NMR (500 Mhz, DMSO-d6): δ 1.19 (s, 2H), 1.93-1.98 (m, 3H), 2.20-2.23 (m, 1H), 3.73 (s, 3H), 3.92 (s, 3H), 4.44-4.46 (m, 1H), 5.42 (s, 2H), 7.07 (s, 1H), 7.39 (s, 1H), 7.50 (s, 1H), 7.93 (s, 1H), 8.40 (br, 2H)
The compound of Example 50 was synthesized by the same method as that of the compound of Example 7 except for using N-((5-methylfuran-2-yl)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 432.2
1H-NMR (500 Mhz, DMSO-d6): δ 2.21 (s, 3H) 3.73 (s, 3H), 3.93 (s, 3H), 4.50 (d, J=5.75 Hz, 2H), 5.45 (s, 2H), 5.95 (d, J=1.15 Hz, 1H), 6.13 (d, J=2.85 Hz, 1H), 7.06 (s, 1H), 7.54 (s, 1H), 7.76 (t, J=6.3 Hz, 1H), 7.93 (s, 1H), 8.83 (s, 2H)
The compound of Example 51 was synthesized by the same method as that of the compound of Example 7 except for using 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)morpholine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 408.1
1H-NMR (500 Mhz, DMSO-d6): δ 3.64-3.65 (m, 4H), 3.68 (s, 3H), 3.72-3.74 (m, 4H), 3.87 (s, 3H), 5.37 (s, 2H), 7.02 (s, 1H), 7.45 (s, 1H), 7.89 (s, 1H), 8.38 (s, 2H)
The compound of Example 52 was synthesized by the same method as that of the compound of Example 7 except for using 2-(benzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 361.1
1H-NMR (500 Mhz, DMSO-d6): δ 3.57 (s, 3H), 3.90 (s, 3H), 5.43 (s, 2H), 6.88 (s, 1H), 6.99-7.00 (m, 1H), 7.25 (dd, J=8.6, 1.7 Hz, 1H), 7.50 (s, 1H), 7.61 (s, 1H), 7.69 (d, J=8.6 Hz, 1H), 7.95 (s, 1H), 8.05 (s, 1H)
The compound of Example 53 was synthesized by the same method as that of the compound of Example 7 except for using phenyl (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl) methanone instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 431.1
1H-NMR (500 Mhz, DMSO-d6): δ 3.71 (s, 3H), 3.94 (s, 3H), 5.46 (s, 2H), 7.09 (s, 1H), 7.34 (d, J=3.7 Hz, 1H), 7.55 (s, 1H), 7.57-7.60 (m, 2H), 7.67-7.68 (m, 1H), 7.84 (d, J=3.75 Hz, 1H), 7.89-7.91 (m, 2H), 8.06 (s, 1H)
The compound of Example 54 was synthesized by the same method as that of the compound of Example 7 except for using (2S,6R)-2,6-dimethyl-4-(2-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)oxy)ethyl)morpholine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 480.3
1H-NMR (500 Mhz, DMSO-d6): δ 1.02 (d, J=6.3 Hz, 6H), 1.71 (t, J=10.3 Hz, 2H), 2.71 (t, J=5.75 Hz, 2H), 2.83 (d, J=10.0 Hz, 2H), 3.53-3.54 (m, 2H), 3.72 (s, 3H), 3.93 (s, 3H), 4.49 (t, J=5.7 Hz, 2H), 5.45 (s, 2H), 6.97 (s, 1H), 7.54 (s, 1H), 8.01 (s, 1H), 8.63 (s, 2H)
The compound of Example 55 was synthesized by the same method as that of the compound of Example 7 except for using (S)—N-(1-(4-fluorophenyl)ethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 460.1
1H-NMR (500 Mhz, DMSO-d6): δ 1.07-1.14 (m, 3H), 3.64 (s, 3H), 3.86 (s, 3H), 5.12-5.14 (m, 1H), 5.35 (s, 2H), 7.05 (s, 1H), 7.39-7.43 (m, 4H), 7.86-7.87 (m, 2H), 8.23 (s, 2H)
The compound of Example 56 was synthesized by the same method as that of the compound of Example 7 except for using 3-acetyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-chroman-2-one instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 431.1
1H-NMR (500 Mhz, DMSO-d6): δ 2.60 (s, 3H), 3.61 (s, 3H), 3.93 (s, 3H), 5.45 (s, 2H), 6.87 (s, 1H), 7.54 (s, 1H), 7.59 (d, J=8.6 Hz, 1H), 7.73 (dd, J=8.6, 2.0 Hz, 1H), 7.97 (d, J=2.3 Hz, 1H), 8.00 (s, 1H), 8.67 (s, 2H)
The compound of Example 57 was synthesized by the same method as that of the compound of Example 7 except for using 2-(3,5-dimethylpiperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 434.2
1H-NMR (500 Mhz, DMSO-d6): δ 0.74-0.82 (m, 2H), 0.86 (d, J=6.6 Hz, 6H), 1.53-1.55 (m, 2H), 2.32 (t, J=12.3 Hz, 2H), 3.68 (s, 3H), 3.87 (s, 3H), 4.70-4.72 (m, 2H), 5.37 (s, 2H), 7.03 (s, 1H), 7.45 (s, 1H), 7.88 (s, 1H), 8.32 (s, 2H)
The compound of Example 58 was synthesized by the same method as that of the compound of Example 7 except for using N1,N1-diethyl-N2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl) ethan-1,2-diamine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 464.2
1H-NMR (500 Mhz, DMSO-d6): δ 0.89-0.92 (m, 6H), 2.41-2.50 (m, 6H), 3.35 (d, J=5.7 Hz, 2H), 3.68 (s, 3H), 3.87 (s, 3H), 5.37 (s, 2H), 7.02-7.06 (m, 2H), 7.45 (s, 1H), 7.87 (s, 1H), 8.25 (s, 2H)
The compound of Example 59 was synthesized by the same method as that of the compound of Example 7 except for using 2-(3-methylpiperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine. Mass (M+H+): 420.2
1H-NMR (500 Mhz, DMSO-d6): δ 0.85-0.87 (m, 3H), 1.12-1.14 (m, 1H), 1.40-1.43 (m, 1H), 1.50-1.55 (m, 1H), 1.65-1.67 (m, 1H), 1.75-1.77 (m, 1H), 2.55 (t, J=11.75 Hz, 1H), 2.85 (t, J=12.25 Hz, 1H), 3.69 (s, 3H), 3.87 (s, 3H), 4.59-4.62 (m, 2H), 5.37 (s, 2H), 7.03 (s, 1H), 7.45 (s, 1H), 7.88 (s, 1H), 8.32 (s, 2H)
The compound of Example 60 was synthesized by the same method as that of the compound of Example 7 except for using 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl) piperidin-3-carboxylic acid instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 450.2
1H-NMR (500 Mhz, DMSO-d6): δ 1.14-1.15 (m, 1H), 1.40-1.42 (m, 1H), 1.53-1.55 (m, 1H), 1.67-1.69 (m, 1H), 1.95-1.97 (m, 1H), 2.25-2.27 (m, 1H), 2.93-2.99 (m, 2H), 3.68 (s, 3H), 3.87 (s, 3H), 4.52-4.55 (m, 1H), 4.74-4.76 (m, 1H), 5.36 (s, 2H), 7.03 (s, 1H), 7.44 (s, 1H), 7.87 (s, 1H), 8.32 (s, 2H)
The compound of Example 61 was synthesized by the same method as that of the compound of Example 7 except for using (1R)-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)cyclopentan-1-carboxylic acid instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 436.2
1H-NMR (500 Mhz, DMSO-d6): δ 1.11-1.23 (m, 3H), 1.90-2.01 (m, 3H), 3.70 (s, 3H), 3.88 (s, 3H), 4.47-4.91 (m, 1H), 5.39 (s, 2H), 7.02 (s, 1H), 7.48 (s, 1H), 7.91 (s, 1H), 8.34-8.39 (m, 2H)
The compound of Example 62 was synthesized by the same method as that of the compound of Example 7 except for using (2S,6S)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl) morpholine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 436.2
1H-NMR (500 Mhz, CDCl3): δ 1.29 (d, J=6.3 Hz, 6H), 3.63-3.64 (m, 2H), 3.89 (s, 3H), 4.03 (d, J=13.15 Hz, 2H), 4.05 (s, 3H), 4.16-4.17 (m, 2H), 5.39 (s, 2H), 7.19 (d, J=11.45 Hz, 2H), 7.72 (s, 1H), 8.40 (s, 2H)
The compound of Example 63 was synthesized by the same method as that of the compound of Example 7 except for using 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)thiomorpholine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 424.2
1H-NMR (500 Mhz, DMSO-d6): δ 2.64-2.68 (m, 4H), 3.74 (s, 3H), 3.92 (s, 3H), 4.13-4.15 (m, 4H), 5.42 (s, 2H), 7.08 (s, 1H), 7.51 (s, 1H), 7.94 (s, 1H), 8.42 (s, 2H)
The compound of Example 64 was synthesized by the same method as that of the compound of Example 7 except for using N-(2-methylbutyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 408.2
1H-NMR (500 Mhz, DMSO-d6): δ 0.87-0.90 (m, 6H), 1.12-1.18 (m, 1H), 1.44-1.47 (m, 1H), 1.65-1.69 (m, 1H), 3.15-3.20 (m, 2H), 3.73 (s, 3H), 3.88 (s, 3H), 5.41 (s, 2H), 7.08 (s, 1H), 7.40 (t, J=6.0 Hz, 1H), 7.49 (s, 1H), 7.92 (s, 1H), 8.28 (s, 2H)
The compound of Example 65 was synthesized by the same method as that of the compound of Example 7 except for using N-methyl-N-(2-methylbutyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 422.2
1H-NMR (500 Mhz, DMSO-d6): δ 0.78-0.86 (m, 6H), 1.02-1.14 (m, 3H), 3.10 (s, 3H), 3.50-3.53 (m, 2H), 3.66 (s, 3H), 3.86 (s, 3H), 5.36 (s, 2H), 7.00 (s, 1H), 7.44 (s, 1H), 7.86 (s, 1H), 8.30 (s, 2H)
The compound of Example 66 was synthesized by the same method as that of the compound of Example 7 except for using N-butyl-N-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 422.2
1H-NMR (500 Mhz, DMSO-d6): δ 0.80-0.88 (m, 3H), 1.10-1.12 (m, 3H), 1.21-1.30 (m, 2H), 1.54-1.55 (m, 2H), 3.55-3.61 (m, 4H), 3.69 (s, 3H), 3.88 (s, 3H), 5.37 (s, 2H), 7.04 (s, 1H), 7.45 (s, 1H), 7.88 (s, 1H), 8.32 (s, 2H)
The compound of Example 67 was synthesized by the same method as that of the compound of Example 7 except for using N-(cyclopropylmethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 392.2
1H-NMR (500 Mhz, DMSO-d6): δ 0.18 (d, J=4.6 Hz, 2H), 0.37 (d, J=8.25 Hz, 2H), 1.01-1.05 (m, 1H), 3.15-3.23 (m, 2H), 3.68 (s, 3H), 3.87 (s, 3H), 5.36 (s, 2H), 7.03 (s, 1H), 7.41-7.44 (m, 2H), 7.86 (s, 1H), 8.24 (s, 2H)
The compound of Example 68 was synthesized by the same method as that of the compound of Example 7 except for using N-(cyclopropylmethyl)-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 406.2
1H-NMR (500 Mhz, CDCl3): 0.26-0.35 (m, 2H), 0.47-0.56 (m, 2H), 1.12-1.22 (m, 1H), 3.31 (s, 3H), 3.62 (d, J=6.6 Hz, 2H), 3.85 (s, 3H), 4.06 (s, 3H), 5.35 (s, 2H), 7.17 (d, J=4.85 Hz, 2H), 7.68 (s, 1H), 8.38 (s, 2H)
The compound of Example 69 was synthesized by the same method as that of the compound of Example 7 except for using N-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 378.2
1H-NMR (500 Mhz, DMSO-d6): δ 0.47 (s, 2H), 0.63 (s, 2H), 2.73 (s, 1H), 3.68 (s, 3H), 3.86 (s, 3H), 5.41 (s, 2H), 7.02 (s, 1H), 7.44 (s, 1H), 7.53 (s, 1H), 7.91 (s, 1H), 8.27 (s, 2H)
The compound of Example 70 was synthesized by the same method as that of the compound of Example 7 except for using N-cyclopropyl-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 392.2
1H-NMR (500 Mhz, DMSO-d6): δ 0.65 (s, 2H), 0.79-0.81 (m, 2H), 2.83-2.84 (m, 1H), 3.11 (s, 3H), 3.69 (s, 3H), 3.89 (s, 3H), 5.41 (s, 2H), 7.03 (s, 1H), 7.47 (s, 1H), 7.90 (s, 1H), 8.39 (s, 2H)
The compound of Example 71 was synthesized by the same method as that of the compound of Example 7 except for using N-butyl-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 408.2
1H-NMR (500 Mhz, CDCl3): 0.91-0.94 (m, 3H), 1.30-1.37 (m, 2H), 1.6-1.65 (m, 2H), 3.21 (s, 3H), 3.65-3.70 (m, 2H), 3.84 (s, 3H), 4.01 (s, 3H), 5.34 (s, 2H), 7.16 (d, J=6.85 Hz, 2H), 7.66 (s, 1H), 8.35 (s, 2H)
The compound of Example 72 was synthesized by the same method as that of the compound of Example 7 except for using N,N-bis(2-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 454.2
1H-NMR (500 Mhz, CDCl3): δ 3.37 (s, 6H), 3.68 (s, 4H), 3.89 (s, 3H), 4.04 (s, 7H), 5.37 (s, 2H), 7.13-7.22 (m, 2H), 7.71 (s, 1H), 8.44 (s, 2H)
The compound of Example 73 was synthesized by the same method as that of the compound of Example 7 except for using N,N-dibutyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 450.3
1H-NMR (500 Mhz, CDCl3): δ 1.019 (t, J=6.85 Hz 6H), 1.41-1.48 (m, 4H), 1.69-1.75 (m, 4H), 3.69 (t, J=7.45, 4H), 3.79 (s, 3H), 4.01 (s, 3H), 5.42 (s, 2H), 7.23 (s, 1H), 7.28 (s, 1H), 7.74 (s, 1H), 8.43 (s, 2H)
The compound of Example 74 was synthesized by the same method as that of the compound of Example 7 except for using N,N-diethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 394.2
1H-NMR (500 Mhz, CDCl3): δ 1.50 (s, 6H), 1.62 (s, 4H), 3.85 (s, 3H), 4.00 (s, 3H), 5.33 (s, 2H), 7.14 (s, 1H), 7.17 (s, 1H), 7.66 (s, 1H), 8.36 (s, 2H)
The compound of Example 75 was synthesized by the same method as that of the compound of Example 7 except for using N-ethyl-N-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 408.1
1H-NMR (500 Mhz, DMSO-d6): δ 1.12-1.21 (m, 9H), 3.47-3.54 (m, 2H), 3.69 (s, 3H), 3.87 (s, 3H), 4.93-4.97 (m, 1H), 5.36 (s, 2H), 7.06 (s, 1H), 7.44 (s, 1H), 7.88 (s, 1H), 8.37 (s, 2H)
The compound of Example 76 was synthesized by the same method as that of the compound of Example 7 except for using N-butyl-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 408.2
1H-NMR (500 Mhz, DMSO-d6): δ 0.83-0.89 (m, 3H), 1.24-1.32 (m, 2H), 1.52-1.59 (m, 2H), 3.10 (s, 3H), 3.60 (s, 2H), 3.67 (s, 3H), 3.87 (s, 3H), 5.36 (s, 2H), 7.02 (s, 1H), 7.44 (s, 1H), 7.87 (s, 1H), 8.33 (s, 2H)
The compound of Example 77 was synthesized by the same method as that of the compound of Example 7 except for using 2-(propyl (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)amino) ethan-1-ol instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 424.2
1H-NMR (500 Mhz, DMSO-d6): δ 0.84 (t, J=7.45 Hz, 3H), 1.57-1.62 (m, 2H), 3.55-3.60 (m, 4H), 3.65-3.66 (m, 2H), 3.70 (s, 3H), 3.88 (s, 3H), 5.38 (s, 2H), 7.06 (s, 1H), 7.46 (s, 1H), 7.90 (s, 1H), 8.38 (s, 2H)
The compound of Example 78 was synthesized by the same method as that of the compound of Example 7 except for using N-cyclohexyl-N-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 448.3
1H-NMR (500 Mhz, DMSO-d6): δ 1.12-1.14 (m, 4H), 1.29-1.31 (m, 2H), 1.51-1.53 (m, 3H), 1.68-1.72 (m, 4H), 3.53 (s, 2H), 3.71 (s, 3H), 3.88 (s, 3H), 4.55 (s, 1H), 5.37 (s, 2H), 7.06 (s, 1H), 7.46 (s, 1H), 7.88 (s, 1H), 8.40 (s, 2H)
The compound of Example 79 was synthesized by the same method as that of the compound of Example 7 except for using N-cyclohexyl-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 434.2
1H-NMR (500 Mhz, DMSO-d6): δ 1.10-1.13 (m, 1H), 1.27-1.35 (m, 2H), 1.48-1.58 (m, 3H), 1.63-1.65 (m, 2H), 1.73-1.75 (m, 2H), 3.01 (s, 3H), 3.69 (s, 3H), 3.87 (s, 3H), 4.55-4.61 (m, 1H), 5.37 (s, 2H), 7.05 (s, 1H), 7.45 (s, 1H), 7.89 (s, 1H), 8.38 (s, 2H)
The compound of Example 80 was synthesized by the same method as that of the compound of Example 7 except for using 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl) piperidin-3-ol instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 422.2
1H-NMR (500 Mhz, DMSO-d6): δ 1.39-1.41 (m, 2H), 1.72 (s, 1H), 1.86-1.89 (m, 1H), 3.02-3.06 (m, 1H), 3.19 (s, 1H), 3.52 (s, 1H), 3.69 (s, 3H), 3.86 (s, 3H), 4.23 (d, J=12.3 Hz, 1H), 4.38 (d, J=10.9 Hz, 1H), 5.36 (s, 2H), 7.03 (s, 1H), 7.44 (s, 1H), 7.88 (s, 1H), 8.38 (s, 2H)
The compound of Example 81 was synthesized by the same method as that of the compound of Example 7 except for using 2-(ethyl(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)amino) ethan-1-ol instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 410.2
1H-NMR (500 Mhz, DMSO-d6): δ 1.09-1.14 (m, 3H), 3.57-3.67 (m, 6H), 3.70 (s, 3H), 3.88 (s, 3H), 5.42 (s, 2H), 7.06 (s, 1H), 7.46 (s, 1H), 7.89 (s, 1H), 8.38 (s, 2H)
The compound of Example 82 was synthesized by the same method as that of the compound of Example 7 except for using (R)-(1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)pyrrolidin-2-yl) methanol instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 422.2
1H-NMR (500 Mhz, DMSO-d6): δ 1.86-2.03 (m, 4H), 3.37-3.40 (m, 1H), 3.47-3.52 (m, 1H), 3.55-3.63 (m, 2H), 3.70 (s, 3H), 3.87 (s, 3H), 4.19-4.20 (m, 1H), 5.38 (s, 2H), 7.06 (s, 1H), 7.46 (s, 1H), 7.90 (s, 1H), 8.43 (s, 2H)
The compound of Example 83 was synthesized by the same method as that of the compound of Example 7 except for using (S)-(1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)pyrrolidin-2-yl) methanol instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 422.2
1H-NMR (500 Mhz, DMSO-d6): § 1.86-2.02 (m, 4H), 3.36-3.40 (m, 1H), 3.47-3.52 (m, 1H), 3.55-3.64 (m, 2H), 3.70 (s, 3H), 3.87 (s, 3H), 4.18-4.19 (m, 1H), 5.38 (s, 2H), 7.06 (s, 1H), 7.46 (s, 1H), 7.90 (s, 1H), 8.42 (s, 2H)
The compound of Example 84 was synthesized by the same method as that of the compound of Example 7 except for using N-cyclopentyl-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 420.2
1H-NMR (500 Mhz, DMSO-d6): δ 1.50-1.62 (m, 4H), 1.64-1.69 (m, 2H), 1.75-1.81 (m, 2H), 3.00 (s, 3H), 3.69 (s, 3H), 3.87 (s, 3H), 5.14-5.21 (m, 1H), 5.37 (s, 2H), 7.05 (s, 1H), 7.45 (s, 1H), 7.89 (s, 1H), 8.38 (s, 2H)
The compound of Example 85 was synthesized by the same method as that of the compound of Example 7 except for using 2,2′-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl) azanediyl)bis(ethan-1-ol) instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 426.2
1H-NMR (500 Mhz, DMSO-d6): δ 3.59 (s, 4H), 3.69 (s, 7H), 3.88 (s, 3H), 4.74 (s, 2H), 5.37 (s, 2H), 7.04 (s, 1H), 7.45 (s, 1H), 7.88 (s, 1H), 8.33 (s, 2H)
The compound of Example 86 was synthesized by the same method as that of the compound of Example 7 except for using N,N-diisobutyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 450.3
1H-NMR (500 Mhz, DMSO-d6): δ 0.82 (d, J=6.55 Hz, 12H), 2.08-2.17 (m, 2H), 3.44 (d, J=7.15 Hz, 4H), 3.66 (s, 3H), 3.85 (s, 3H), 5.36 (s, 2H), 7.00 (s, 1H), 7.44 (s, 1H), 7.87 (s, 1H), 8.32 (s, 2H)
The compound of Example 87 was synthesized by the same method as that of the compound of Example 7 except for using N,N-didecyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 618.5
1H-NMR (500 Mhz, DMSO-d6): δ 0.73-0.75 (m, 6H), 1.16-1.22 (m, 28H), 1.54 (s, 4H), 3.52 (s, 4H), 3.67 (s, 3H), 3.86 (s, 3H), 5.36 (s, 2H), 7.03 (s, 1H), 7.44 (s, 1H), 7.87 (s, 1H), 8.33 (s, 2H)
The compound of Example 88 was synthesized by the same method as that of the compound of Example 7 except for using 2-(6-methoxybenzo[d][1,3]dioxol-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 395.1
1H-NMR (500 Mhz, DMSO-d6): 3.50 (s, 3H), 3.63 (s, 3H), 3.91 (s, 3H), 5.39-5.43 (m, 2H), 6.05 (d, J=4.0 Hz, 2H), 6.70 (s, 1H), 6.83 (s, 1H), 6.92 (s, 1H), 7.44 (s, 1H), 7.87 (s, 1H)
The compound of Example 89 was synthesized by the same method as that of the compound of Example 7 except for using 8-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)-1,4-dioxa-8-azaspiro[4.5]decane instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 464.2
1H-NMR (500 Mhz, DMSO-d6): δ 1.69 (t, J=5.7 Hz, 4H), 3.74 (s, 3H), 3.89-3.92 (m, 11H), 5.42 (s, 2H), 7.08 (s, 1H), 7.50 (s, 1H), 7.93 (s, 1H), 8.39 (s, 2H)
The compound of Example 90 was synthesized by the same method as that of the compound of Example 7 except for using methyl N-methyl-N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)glycinate instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 424.2
1H-NMR (500 Mhz, DMSO-d6): δ 3.24 (s, 3H), 3.64 (s, 3H), 3.72 (s, 3H), 3.92 (s, 3H), 4.48 (d, J=9.15 Hz, 2H), 5.42 (s, 2H), 7.02 (s, 1H), 7.51 (s, 1H), 7.94 (s, 1H), 8.40-8.44 (m, 2H)
The compound of Example 91 was synthesized by the same method as that of the compound of Example 7 except for using N-cyclopentyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 406.2
1H-NMR (500 Mhz, DMSO-d6): δ 1.56-1.57 (m, 4H), 1.71-1.72 (m, 2H), 1.95-2.05 (m, 2H), 3.77 (s, 3H), 3.92 (s, 3H), 4.29 (t, J=6.6 Hz, 1H), 5.44 (s, 2H), 7.15 (s, 1H), 7.52 (s, 1H), 7.97 (s, 1H), 8.52 (s, 2H)
The compound of Example 92 was synthesized by the same method as that of the compound of Example 7 except for using N-cyclopentyl-N-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 434.2
1H-NMR (500 Mhz, DMSO-d6): § 1.19 (t, J=6.85 Hz, 3H), 1.57-1.59 (m, 4H), 1.72-1.73 (m, 2H), 1.89-1.90 (m, 2H), 3.53-3.56 (m, 2H), 3.74 (s, 3H), 3.92 (s, 3H), 5.00-5.03 (m, 1H), 5.42 (s, 2H), 7.11 (s, 1H), 7.50 (s, 1H), 7.93 (s, 1H), 8.42 (s, 2H)
The compound of Example 93 was synthesized by the same method as that of the compound of Example 7 except for using N-cyclopentyl-N-propyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 448.2
1H-NMR (500 Mhz, DMSO-d6): δ 0.85 (s, 3H), 1.54-1.91 (m, 12H), 3.70 (s, 3H), 3.88 (s, 3H), 4.89-4.95 (m, 1H), 5.38 (s, 2H), 5.75-5.96 (br, 3H), 7.06 (s, 1H), 7.46 (s, 1H), 7.89 (s, 1H), 8.37 (s, 2H)
The compound of Example 94 was synthesized by the same method as that of the compound of Example 7 except for using N-(2,2-dimethoxyethyl)-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine of instead 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 440.2
1H-NMR (500 Mhz, DMSO-d6): δ 3.20 (s, 3H), 3.30 (s, 6H), 3.73-3.76 (m, 5H), 3.92 (s, 3H), 4.63 (t, J=5.15 Hz, 1H), 5.42 (s, 2H), 7.06 (s, 1H), 7.50 (s, 1H), 7.93 (s, 1H), 8.40 (s, 2H)
The compound of Example 95 was synthesized by the same method as that of the compound of Example 7 except for using N,N-dioctyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 562.4
1H-NMR (500 Mhz, DMSO-d6): δ 0.79-0.82 (m, 6H), 1.21-1.27 (m, 24H), 1.62-1.63 (m, 4H), 3.72 (s, 3H), 3.91 (s, 3H), 5.41 (s, 2H), 7.07 (s, 1H), 7.48 (s, 1H), 7.92 (s, 1H), 8.37 (s, 2H)
The compound of Example 96 was synthesized by the same method as that of the compound of Example 7 except for using (S)—N-(5-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 512.3
1H-NMR (500 Mhz, DMSO-d6): δ 1.97-1.99 (m, 2H), 2.59-2.61 (m, 1H), 2.79-2.83 (m, 1H), 2.93-3.00 (m, 2H), 3.12 (s, 3H), 3.74 (s, 6H), 3.92 (s, 3H), 4.97-4.99 (m, 1H), 5.41 (s, 2H), 6.71 (dd, J=24.65, 8.3 Hz, 2H), 7.05-7.10 (m, 2H), 7.50 (s, 1H), 7.92 (s, 1H), 8.39 (s, 2H)
The compound of Example 97 was synthesized by the same method as that of the compound of Example 7 except for using (S)-2-(2-(methoxymethyl)pyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 436.2
1H-NMR (500 Mhz, DMSO-d6): δ 1.88-1.99 (m, 7H), 3.32 (t, J=8.05, 1H), 3.45-3.51 (m, 1H), 3.54-3.56 (m, 2H), 3.70 (s, 3H), 3.88 (s, 3H), 4.26-4.28 (m, 1H), 5.38 (s, 2H), 7.04 (s, 1H), 7.46 (s, 1H), 7.90 (s, 1H), 8.39 (s, 2H)
The compound of Example 98 was synthesized by the same method as that of the compound of Example 7 except for using isopropyl (6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d][1,3]dioxol-5-yl)carbonate instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 467.2
1H-NMR (500 Mhz, DMSO-d6): δ 0.62 (d, J=6.0 Hz, 3H), 0.88 (d, J=6.3 Hz, 3H), 3.62 (s, 3H), 3.86 (s, 3H), 4.39-4.41 (m, 1H), 5.35-5.41 (m, 2H), 6.12 (s, 2H), 6.80 (s, 1H), 6.84 (s, 1H), 7.02 (s, 1H), 7.42 (s, 1H), 7.89 (s, 1H)
The compound of Example 99 was synthesized by the same method as that of the compound of Example 7 except for using cyclohexyl (6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d][1,3]dioxol-5-yl)carbonate instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 507.2
1H-NMR (500 Mhz, DMSO-d6): δ 0.70-0.73 (m, 1H), 0.93-1.12 (m, 6H), 1.18-1.20 (m, 1H), 1.27-1.30 (m, 1H), 1.41-1.42 (m, 1H), 3.59 (s, 3H), 3.84 (s, 3H), 4.17-4.18 (m, 1H), 5.36 (s, 2H), 6.10 (s, 2H), 6.78 (s, 1H), 6.83 (s, 1H), 7.00 (s, 1H), 7.40 (s, 1H), 7.88 (s, 1H)
The compound of Example 101 was synthesized by the same method as that of the compound of Example 7 except for using N-(sec-butyl)-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 408.2
1H-NMR (500 Mhz, DMSO-d6): δ 0.82 (t, J=7.45 Hz, 3H), 1.17 (d, J=6.85 Hz, 3H), 1.51-1.65 (m, 2H), 3.00 (s, 3H), 3.74 (s, 3H), 3.90 (s, 3H), 4.86-4.91 (m, 1H), 5.42 (s, 2H), 7.10 (s, 1H), 7.51 (s, 1H), 7.94 (s, 1H), 8.44 (s, 2H)
The compound of Example 101 was synthesized by the same method as that of the compound of Example 7 except for using N-(2-(cyclohex-1-en-1-yl)ethyl)-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 460.3
1H-NMR (500 Mhz, DMSO-d6): δ 1.13 (t, J=7.15 Hz, 1H), 1.42-1.45 (m, 2H), 1.49-1.53 (m, 2H), 1.88 (br, 2H), 1.93-1.97 (m, 3H), 2.22 (t, J=6.85 Hz, 2H), 3.73 (s, 3H), 3.77 (t, J=7.15 Hz, 2H), 3.92 (s, 3H), 3.99 (q, J=7.15 Hz, 1H), 5.39 (s, 1H), 5.42 (s, 2H), 7.06 (s, 1H), 7.50 (s, 1H), 7.93 (s, 1H), 8.39 (s, 2H)
The compound of Example 102 was synthesized by the same method as that of the compound of Example 7 except for using (R)-2-(2-(methoxymethyl)pyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 436.2
1H-NMR (500 Mhz, DMSO-d6): δ 1.95-2.00 (m, 6H), 3.37 (t, J=8.6 Hz, 1H), 3.52-3.61 (m, 4H), 3.74 (s, 3H), 3.92 (s, 3H), 4.32-4.34 (m, 1H), 5.43 (s, 2H), 7.09 (s, 1H), 7.51 (s, 1H), 7.95 (s, 1H), 8.46 (s, 2H)
The compound of Example 103 was synthesized by the same method as that of the compound of Example 7 except for using N-methyl-N-((5-methylfuran-2-yl)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 446.2
1H-NMR (500 Mhz, DMSO-d6): δ 2.20 (d, J=0.55 Hz, 3H), 3.16 (s, 3H), 3.73 (s, 3H), 3.92 (s, 3H), 4.86 (br, 2H), 5.42 (s, 2H), 5.97-5.98 (m, 1H), 6.20 (d, J=2.9 Hz, 1H), 7.06 (s, 1H), 7.51 (s, 1H), 7.94 (s, 1H), 8.43 (s, 2H)
The compound of Example 104 was synthesized by the same method as that of the compound of Example 7 except for using (1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl) piperidin-2-yl) methanol instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 436.2
1H-NMR (500 Mhz, DMSO-d6): δ 1.39-1.72 (m, 6H), 1.93-1.96 (m, 1H), 2.95-3.00 (m, 1H), 3.13 (s, 1H), 3.51-3.54 (m, 1H), 3.64-3.68 (m, 1H), 3.75 (s, 3H), 3.94 (s, 3H), 5.42 (s, 2H), 7.10 (s, 1H), 7.51 (s, 1H), 7.94 (s, 1H), 8.41 (s, 2H)
The compound of Example 105 was synthesized by the same method as that of the compound of Example 7 except for using N-(cyclopropylmethyl)-N-propyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 434.2
1H-NMR (500 Mhz, DMSO-d6): δ 0.30-0.32 (m, 2H), 0.45-0.47 (m, 2H), 0.89 (t, J=7.45 Hz, 3H), 1.13-1.16 (m, 1H), 1.62-1.68 (m, 2H), 3.54 (d, J=6.6 Hz, 2H), 3.60-3.62 (m, 2H), 3.74 (s, 3H), 3.92 (s, 3H), 5.42 (s, 2H), 7.10 (s, 1H), 7.50 (s, 1H), 7.93 (s, 1H), 8.38 (s, 2H)
The compound of Example 106 was synthesized by the same method as that of the compound of Example 7 except for using N-ethyl-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 380.2
1H-NMR (500 Mhz, DMSO-d6): δ 1.16 (t, J=6.85 Hz, 3H), 3.18 (s, 3H), 3.70-3.74 (m, 5H), 3.92 (s, 3H), 5.42 (s, 2H), 7.09 (s, 1H), 7.51 (s, 1H), 7.94 (s, 1H), 8.43 (s, 2H)
The compound of Example 107 was synthesized by the same method as that of the compound of Example 7 except for using 2-(4-methylpiperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 420.2
1H-NMR (500 Mhz, DMSO-d6): δ 0.93 (d, J=6.3 Hz, 3H), 1.11-1.13 (m, 2H), 1.65-1.72 (m, 3H), 2.92-2.97 (m, 2H), 3.74 (s, 3H), 3.92 (s, 3H), 4.71 (d, J=13.2 Hz, 2H), 5.42 (s, 2H), 7.09 (s, 1H), 7.50 (s, 1H), 7.93 (s, 1H), 8.39 (s, 2H)
The compound of Example 108 was synthesized by the same method as that of the compound of Example 7 except for using N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 352.1
1H-NMR (500 Mhz, DMSO-d6): δ 2.87 (d, J=4.85 Hz, 3H), 3.73 (s, 3H), 3.92 (s, 3H), 5.41 (s, 2H), 7.07 (s, 1H), 7.30 (m, 1H) 7.49 (s, 1H), 7.92 (s, 1H), 8.30 (br, 2H)
The compound of Example 109 was synthesized by the same method as that of the compound of Example 7 except for using N-(3,4-dimethylphenyl)-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 456.2
1H-NMR (500 Mhz, DMSO-d6): δ 2.20 (d, J=3.15 Hz, 6H), 3.49 (s, 3H), 3.74 (s, 3H), 3.92 (s, 3H), 5.42 (s, 2H), 7.05-7.16 (m, 4H), 7.50 (s, 1H), 7.94 (s, 1H), 8.38 (s, 2H)
The compound of Example 110 was synthesized by the same method as that of the compound of Example 7 except for using (R)-2-(2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 475.2
1H-NMR (500 Mhz, DMSO-d6): δ 1.64 (s, 4H), 1.92-2.07 (m, 4H), 2.45 (m, 9H), 3.50-3.58 (m, 2H), 3.73 (s, 3H), 3.92 (s, 3H), 5.42 (s, 2H), 7.07 (s, 1H), 7.50 (s, 1H), 7.93 (s, 1H), 8.36 (d, J=2.3 Hz, 2H)
The compound of Example 111 was synthesized by the same method as that of the compound of Example 7 except for using N-methyl-N-(2-morpholinoethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 465.2
1H-NMR (500 Mhz, DMSO-d6): δ 2.43-2.57 (m, 6H), 3.18 (s, 3H), 3.52 (t, J=4.3 Hz, 4H), 3.73 (s, 3H), 3.80 (t, J=6.85 Hz, 2H), 3.92 (s, 3H), 5.41 (s, 2H), 7.06 (s, 1H), 7.49 (s, 1H), 7.92 (s, 1H), 8.36 (s, 2H)
The compound of Example 112 was synthesized by the same method as that of the compound of Example 7 except for using N-methyl-N-(3-morpholinopropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 479.2
1H-NMR (500 Mhz, DMSO-d6): δ 2.03-2.09 (m, 2H), 3.02-3.07 (m, 2H), 3.13-3.21 (m, 4H), 3.42-3.44 (m, 2H), 3.69-3.76 (m, 7H), 3.92-3.94 (m, 6H), 5.43 (s, 2H), 7.08 (s, 1H), 7.51 (s, 1H), 7.95 (s, 1H), 8.42 (s, 2H), 10.34 (br, 1H)
The compound of Example 113 was synthesized by the same method as that of the compound of Example 7 except for using (R)-2-(2-ethylpiperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 434.2
1H-NMR (500 Mhz, DMSO-d6): δ 0.82 (t, J=7.45 Hz, 3H), 1.38-1.41 (m, 1H), 1.52-1.69 (m, 7H), 2.91-2.93 (m, 1H), 3.73 (s, 3H), 3.92 (s, 3H), 4.67-4.70 (m, 1H), 4.87-4.89 (m, 1H), 5.41 (s, 2H), 7.08 (s, 1H), 7.49 (s, 1H), 7.92 (s, 1H), 8.35 (s, 2H)
The compound of Example 114 was synthesized by the same method as that of the compound of Example 7 except for using 2,2,6,6-tetramethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)morpholine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 464.2
1H-NMR (500 Mhz, DMSO-d6): § 1.19 (s, 12H), 3.70 (s, 4H), 3.73 (s, 3H), 3.93 (s, 3H), 5.43 (s, 2H), 7.08 (s, 1H), 7.51 (s, 1H), 7.94 (s, 1H), 8.41 (s, 2H)
The compound of Example 115 was synthesized by the same method as that of the compound of Example 7 except for using N-methyl-N-(tetrahydro-2H-pyran-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 436.2
1H-NMR (500 Mhz, DMSO-d6): δ 1.61 (d, J=11.45 Hz, 2H), 1.84-1.86 (m, 2H), 3.07 (s, 3H), 3.41-3.46 (m, 2H), 3.74 (s, 3H), 3.93-3.95 (m, 5H), 4.88-4.91 (m, 1H), 5.42 (s, 2H), 7.09 (s, 1H), 7.51 (s, 1H), 7.93 (s, 1H), 8.40 (s, 2H)
The compound of Example 116 was synthesized by the same method as that of the compound of Example 7 except for using 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) quinoline instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 386.1
1H-NMR (500 Mhz, DMSO-d6): δ 2.68 (s, 3H), 3.52 (s, 3H), 3.93 (s, 3H), 5.46 (s, 2H), 6.89 (s, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.54 (s, 1H), 7.65 (d, J=8.0 Hz, 1H), 7.91 (s, 1H), 7.99-8.01 (m, 2H), 8.27 (d, J=8.55 Hz, 1H)
The compound of Example 117 was synthesized by the same method as that of the compound of Example 7 except for using 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) quinolin-4-ol instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 388.1
1H-NMR (500 Mhz, DMSO-d6): δ 3.56 (s, 3H), 3.93 (s, 3H), 5.44 (s, 2H), 6.05-6.07 (m, 1H), 6.88 (s, 1H), 7.52 (s, 1H), 7.62-7.63 (m, 2H), 7.97-8.00 (m, 3H), 11.88 (br, 1H)
The compound of Example 118 was synthesized by the same method as that of the compound of Example 7 except for using 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) quinoline instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 372.1
1H-NMR (500 Mhz, DMSO-d6): δ 3.52 (s, 3H), 3.94 (s, 3H), 5.47 (s, 2H), 6.88 (s, 1H), 7.55-7.59 (m, 3H), 7.97 (s, 1H), 8.01 (s, 1H), 8.09 (d, J=8.0 Hz, 1H), 8.45 (d, J=8.0 Hz, 1H), 8.93 (s, 1H)
The compound of Example 119 was synthesized by the same method as that of the compound of Example 7 except for using 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl) quinoline instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 440.1
1H-NMR (500 Mhz, DMSO-d6): δ 3.40 (s, 3H), 3.93 (s, 3H), 5.45-5.50 (m, 2H), 6.55 (s, 1H), 7.55 (s, 1H), 7.69-7.71 (m, 1H), 7.85 (d, J=7.45 Hz, 1H), 8.03 (s, 1H), 8.20 (d, J=7.45 Hz, 1H), 8.56-8.57 (m, 1H), 8.76 (s, 1H)
The compound of Example 120 was synthesized by the same method as that of the compound of Example 7 except for using 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) quinoline instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 386.1
1H-NMR (500 Mhz, DMSO-d6): δ 2.46 (s, 3H), 3.52 (s, 3H), 3.93 (s, 3H), 5.45 (s, 2H), 6.89 (s, 1H), 7.54 (s, 1H), 7.63-7.65 (m, 1H), 7.88 (s, 1H), 8.00 (s, 1H), 8.06 (d, J=8.0 Hz, 1H), 8.14 (s, 1H), 8.82 (s, 1H)
The compound of Example 121 was synthesized by the same method as that of the compound of Example 7 except for using (2S,6R)-2,6-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 435.1
1H-NMR (500 MHz, DMSO-d6): 1.16 (s, 6H), 3.63 (m, 2H), 3.66 (s, 3H), 3.91 (s, 3H), 4.22 (m, 2H), 5.39 (m, 2H), 6.94 (m, 1H), 7.04 (s, 1H), 7.47 (s, 1H), 7.58 (m, 1H), 7.89 (s, 1H), 8.09 (s, 1H).
The compound of Example 122 was synthesized by the same method as that of the compound of Example 7 except for using 2-(4,4-difluoropiperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 441.0
1H-NMR (500 MHZ, DMSO-d6): 2.03 (brm, 4H), 3.66 (s, 3H), 3.76 (brm, 4H), 3.91 (s, 3H), 5.40 (s, 2H), 7.03 (m, 2H), 7.47 (s, 1H), 7.60 (m, 1H), 7.90 (s, 1H), 8.01 (s, 1H).
The compound of Example 123 was synthesized by the same method as that of the compound of Example 7 except for using 2-(piperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 405.1
1H-NMR (500 MHz, DMSO-d6): 1.58 (m, 6H), 3.58 (m, 4H), 3.67 (s, 3H), 3.92 (s, 3H), 5.40 (s, 2H), 6.90 (d, 1H), 7.06 (s, 1H), 7.47 (s, 1H), 7.52 dd, 1H), 7.89 (s, 1H), 8.06 (s, 1H).
The compound of Example 124 was synthesized by the same method as that of the compound of Example 7 except for using 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 407.1
1H-NMR (500 MHz, DMSO-d6): 3.53 (brm, 4H), 3.67 (s, 3H), 3.72 (s, 3H), 3.92 (brm, 4H), 5.41 (s, 2H), 6.94 (m, 1H), 7.04 (s, 1H), 7.49 (s, 1H), 7.60 (m, 1H), 7.91 (s, 1H), 8.11 (s, 1H).
The compound of Example 125 was synthesized by the same method as that of the compound of Example 7 except for using 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) quinoline instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+):
1H-NMR (500 Mhz, DMSO-d6): δ 3.34 (s, 3H), 3.92 (s, 3H), 5.43-5.48 (m, 2H), 6.54 (s, 1H), 7.48-7.52 (m, 2H), 7.66-7.72 (m, 2H), 7.98 (s, 1H), 8.09-8.10 (m, 1H), 8.43-8.44 (m, 1H), 8.61 (s, 1H)
The compound of Example 126 was synthesized by the same method as that of the compound of Example 7 except for using 2-(3-methylpiperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 419.1
1H-NMR (500 MHz, DMSO-d6): 0.91 (d, 3H), 1.14 (m, 1H), 1.48 (m, 1H), 1.60 (m, 1H), 1.70 (m, 1H), 1.79 (m, 1H), 2.51 (m, 1H), 2.80 (m, 1H), 3.67 (s, 3H), 3.92 (s, 3H), 4.28 (m, 2H), 5.40 (s, 2H), 6.91 (d, 1H), 7.06 (s, 1H), 7.47 (s, 1H), 7.51 (d, 1H), 7.88 (s, 1H), 8.06 (s, 1H).
The compound of Example 127 was synthesized by the same method as that of the compound of Example 7 except for using 2-(3,5-dimethylpiperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 433.1
1H-NMR (500 MHz, DMSO-d6): 0.79 (m, 1H), 0.93 (d, 6H), 1.60 (m, 2H), 1.80 (m, 1H), 2.31 (m, 2H), 3.67 (s, 3H), 3.92 (s, 3H), 4.38 (m, 2H), 5.40 (s, 2H), 6.93 (d, 1H), 7.07 (s, 1H), 7.48 (s, 1H), 7.52 (d, 1H), 7.89 (s, 1H), 8.06 (s, 1H).
After 3 g (7.6 mmol) of 6,7-dimethoxy-3-oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl trifluoromethanesulfonate, 1.6 g (8.7 mmol) of tert-butyl piperazin-1-carboxylate, and 3.2 g (22.8 mmol) of anhydrous potassium carbonate were injected into 100 ml of acetonitrile, the resulting mixture was stirred under reflux for 18 hours, and then stirred again with the addition of purified water to filter the crystallized solid, which was then recrystallized with ethyl acetate and purified by silica gel column chromatography to obtain 1.37 g (yield: 42%) of tert-butyl 4-(6,7-dimethoxy-3-oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl) piperazin-1-carboxylate. After that, the resulting solid was dissolved in dichloromethane, and then TFA was injected thereto and stirred at room temperature for 18 hours. The reactant was dried under reduced pressure and then recrystallized with methanol/ester to obtain 0.77 g (2.34 mmol, 74%) of 6,7-dimethoxy-9-(piperazin-1-yl)naphtho[2,3-c]furan-1(3H)-one as a title compound.
Mass (M+H+): 329.1
1H-NMR (500 MHz, DMSO-d6): 2.92 (brm, 4H), 5.21 (brm, 4H), 3.89 (s, 6H), 5.36 (s, 2H), 7.35 (s, 1H), 7.59 (s, 1H), 7.80 (s, 1H).
For the compound of Example 129, 6,7-dimethoxy-9-(piperazin-1-yl)naphto[2,3-c]furan-1(3H)-one (300 mg, 0.91 mmol), 192 mg of 5-bromo-2-fluoropyridine, and 253 mg of anhydrous potassium carbonate were injected into 5 ml of dimethylformamide, stirred under reflux for 18 hours, filtered with the injection of purified water, and purified by silica gel column chromatography to obtain 137 mg (0.28 mmol, 31%) of 9-(4-(5-bromopyridin-2-yl) piperazin-1-yl)-6,7-dimethoxycinaphto[2,3-c]furan-1(3H)-one as a title compound.
Mass (M+H+): 485.1
1H-NMR (500 MHz, DMSO-d6): 3.39 (brm, 4H), 3.90˜3.99 (s+brm, 10H), 5.39 (s, 2H), 6.91 (d, 1H), 7.39 (s, 1H), 7.66 (s, 1H), 7.69 (d, 1H), 7.87 (s, 1H), 8.18 (s, 1H).
The compound of Example 130 was synthesized by the same method as that of the compound of Example 129 except for using 4,6-dichloro-2-(methylthio)pyrimidine instead of 5-bromo-2-fluoropyridine.
Mass (M+H+): 487.1
1H-NMR (500 MHz, DMSO-d6): 2.42 (s, 3H), 2.47 (brm, 4H), 3.34 (brm, 4H), 3.90 (s, 3H), 3.92 (s, 3H), 5.39 (s, 2H), 6.76 (s, 1H), 7.40 (s, 1H), 7.68 (s, 1H), 7.86 (s, 1H).
The compound of Example 131 was synthesized by the same method as that of the compound of Example 129 except for using 5-bromo-2-chloropyrimidine instead of 5-bromo-2-fluoropyridine.
Mass (M+H+): 486.1
1H-NMR (500 MHZ, DMSO-d6): 2.46 (brm, 4H), 3.27 (brm, 4H), 3.90 (s, 3H), 3.92 (s, 3H), 5.38 (s, 2H), 7.39 (s, 1H), 7.67 (s, 1H), 7.88 (s, 1H), 8.47 (s, 2H).
5 g (12.7 mmol) of 6,7-dimethoxy-3-oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl trifluoromethanesulfonate, 3.88 g (15.2 mmol) of bis(pinacolato)diborane, 3.75 g (38.2 mmol) of potassium acetate, and 1.04 g (1.27 mmol) of Pd(dppf)Cl2-CH2Cl2 were added to 1,4-dioxane. After bubbling the reaction solvent with nitrogen, a reaction temperature was raised up to 80° C., and then the reaction was performed for three hours. After cooling to 25° C., 20 ml of ethyl acetate was injected and then stirred. The reaction solution was passed through a celite pad, filtered and distilled under reduced pressure. The residue was dissolved in dichloromethane, and then activated carbon was injected thereto, stirred, filtered, and distilled under reduced pressure. Methanol was injected into the distilled residue, stirred, filtered, and washed to obtain 4.01 g (10.83 mmol, 85.0%) of 6,7-dimethoxy-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphtho[2,3-c]furan-1(3H)-one as an intermediate.
As the intermediate, 2.0 g (5.4 mmol) of 6,7-dimethoxy-9-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)naphtho[2,3-c]furan-1(3H)-one, 1.12 g (5.4 mmol) of 5-bromoquinoline and 1.49 g (10.78 mmol) of anhydrous potassium carbonate were added to 1,4-dioxane. After bubbling the reaction solvent with nitrogen, 0.18 g (0.256 mmol) of Pd(PPh3)Cl2 was injected thereto, and a reaction temperature was raised to 110° C., and then the reaction was performed for 18 hours. After cooling to 25° C., 20 ml of ethyl acetate was injected and then stirred. The reaction solution was passed through a celite pad, filtered and distilled under reduced pressure. The residue was dissolved in dichloromethane, and then activated carbon was injected thereto, stirred, filtered, and distilled under reduced pressure. The distilled residue was purified by column chromatography to obtain 1.34 g (3.62 mmol, 67.0%) of 6,7-dimethoxy-9-(quinolin-5-yl)naphtho[2,3-c]furan-1(3H)-one as a title compound.
Mass (M+H+): 372.1
1H-NMR (500 MHz, DMSO-d6): 3.35 (s, 3H), 3.93 (s, 3H), 5.49 (s, 2H), 6.49 (s, 1H), 7.32 (dd, J=8.6, 4.0 Hz, 1H), 7.45-7.46 (m, 1H), 7.53 (dd, J=7.15, 1.15 Hz, 1H), 7.57 (s, 1H), 7.86-7.89 (m, 1H), 8.07 (s, 1H), 8.14-8.16 (m, 1H), 8.88-8.89 (m, 1H).
The compound of Example 133 was synthesized by the same method as that of the compound of Example 132 except for using 8-bromo-3-methoxyisoquinoline instead of 5-bromoquinoline.
Mass (M+H+): 402.1
1H-NMR (500 MHz, DMSO-d6): 2.47 (d, J=1.75 Hz, 1H), 3.39 (s, 3H), 3.86 (s, 3H), 3.93 (s, 3H), 5.49-5.53 (m, 2H), 6.56 (s, 1H), 7.28 (d, J=0.55 Hz, 1H), 7.29-7.31 (m, 1H), 7.56 (s, 1H), 7.74-7.76 (m, 1H), 7.93-7.95 (m, 1H), 8.06 (s, 1H), 8.16 (s, 1H).
The compound of Example 134 was synthesized by the same method as that of the compound of Example 132 except for using 4-bromo-8-fluoro-2-methylquinoline instead of 5-bromoquinoline.
Mass (M+H+): 404.1
1H-NMR (500 MHz, DMSO-d6): 2.73 (s, 3H), 3.4 (s, 3H), 3.93 (s, 3H), 5.47-5.54 (m, 2H), 6.48 (s, 1H), 6.86 (d, 8.3 Hz, 1H), 7.26-7.28 (m, 1H), 7.48-7.49 (m, 2H), 7.50-7.60 (m, 1H), 7.58 (s, 1H), 8.10 (s, 1H).
The compound of Example 135 was synthesized by the same method as that of the compound of Example 132 except for using 6-bromo-4-(piperazin-1-yl) quinoline instead of 5-bromoquinoline.
Mass (M+H+): 456.2
1H-NMR (500 MHz, DMSO-d6): 2.89-2.97 (m, 3H), 3.08-3.12 (m, 1H), 3.24-3.34 (m, 4H), 3.54 (s, 3H), 3.93 (s, 3H), 5.44-5.47 (m, 2H), 6.93 (s, 1H), 7.03 (d, J=5.15 Hz, 1H), 7.54 (s, 1H), 7.65-7.67 (m, 1H), 8.00-8.02 (m, 2H), 8.04 (d, J=8.6 Hz, 1H), 8.74 (d, J=5.15 Hz, 1H).
The compound of Example 136 was synthesized by the same method as that of the compound of Example 132 except for using 4-bromo-2-methyl-8-(trifluoromethyl) quinoline instead of 5-bromoquinoline.
Mass (M+H+): 454.1
1H-NMR (500 MHz, DMSO-d6): 2.75 (s, 3H), 3.42 (s, 3H), 3.94 (s, 3H), 5.48-5.54 (m, 2H), 6.51 (s, 1H), 7.36 (d, J=8.55 Hz, 1H), 7.43 (t, J=7.45 Hz, 1H), 7.54 (s, 1H), 7.60 (s, 1H), 8.09-8.12 (m, 2H).
The compound of Example 137 was synthesized by the same method as that of the compound of Example 132 except for using 4-bromo-8-fluoroquinoline instead of 5-bromoquinoline.
Mass (M+H+): 390.1
1H-NMR (500 MHz, DMSO-d6): 3.39 (s, 3H), 3.93 (s, 3H), 5.51-5.55 (m, 2H), 6.46 (s, 1H), 6.93 (d, J=8.6 Hz, 1H), 7.34-7.37 (m, 1H), 7.55-7.57 (m, 1H), 7.59-7.60 (m, 2H), 8.11 (s, H), 9.07 (d, J=4.3 Hz, 1H).
The compound of Example 138 was synthesized by the same method as that of the compound of Example 132 except for using 6-bromo-4-chloroquinoline instead of 5-bromoquinoline.
Mass (M+H+): 406.1
1H-NMR (500 MHz, DMSO-d6): 3.54 (s, 3H), 3.94 (s, 3H), 5.47 (s, 2H), 6.88 (s, 1H), 7.56 (s, 1H), 7.82 (d, J=4.55 Hz, 1H), 7.87 (dd, J=8.5 Hz, 1.7 Hz, 1H), 8.03 (s, 1H), 8.16 (d, J=1.45 Hz, 1H), 8.21 (d, J=8.6 Hz, 1H), 8.91 (d, J=4.9 Hz, 1H).
The compound of Example 139 was synthesized by the same method as that of the compound of Example 132 except for using 4-bromo-6,8-difluoro-2-methylquinoline instead of 5-bromoquinoline.
Mass (M+H+): 422.1
1H-NMR (500 MHz, DMSO-d6): 2.72 (s, 3H), 3.45 (s, 3H), 3.93 (s, 3H), 5.55-5.53 (m, 2H), 6.50 (s, 1H), 6.59-6.61 (m, 1H), 7.53 (s, 1H), 7.59 (s, 1H), 7.64-7.68 (m, 1H), 8.10 (s, 1H).
The compound of Example 140 was synthesized by the same method as that of the compound of Example 132 except for using 4-bromo-8-methoxyquinoline instead of 5-bromoquinoline.
Mass (M+H+): 402.1
1H-NMR (500 MHz, DMSO-d6): 3.36 (s, 3H), 3.93 (s, 3H), 3.98 (s, 3H), 5.47-5.54 (m, 2H), 6.45 (s, 1H), 6.60 (dd, J=8.6 Hz, 1.15 Hz, 1H), 7.15 (d, J=7.15 Hz, 1H), 7.27 (t, J=8.05 Hz, 1H), 7.47 (d, J=4.3 Hz, 1H), 7.58 (s, 1H), 8.09 (s, 1H), 8.95 (d, J=4.3 Hz, 1H).
The compound of Example 141 was synthesized by the same method as that of the compound of Example 132 except for using 4-bromo-7-methoxy-2-methylquinoline instead of 5-bromoquinoline.
Mass (M+H+): 416.2
1H-NMR (500 MHz, DMSO-d6): 2.66 (s, 3H), 3.38 (s, 3H), 3.87 (s, 3H), 3.93 (s, 3H), 5.46-5.50 (m, 2H), 6.49 (s, 1H), 6.91-6.93 (m, 2H), 7.19 (s, 1H), 7.41 (d, J=1.75 Hz, 1H), 7.56 (s, 1H), 8.07 (s, 1H).
The compound of Example 142 was synthesized by the same method as that of the compound of Example 132 except for using 5-bromo-2-(4-chloropiperidin-1-yl)pyridine instead of 5-bromoquinoline.
Mass (M+H+): 439.2
1H-NMR (500 MHz, DMSO-d6): 1.78 (m, 2H), 2.13 (m, 2H), 3.41 (m, 2H), 3.67 (s, 3H), 3.92 (s, 3H), 4.00 (m, 2H), 4.45 (m, 1H), 5.40 (s, 2H), 6.97 (d, 1H), 7.04 (s, 1H), 7.48 (s, 1H), 7.56 (d, 1H), 7.90 (s, 1H), 8.09 (s, 1H).
For the compound of Example 143, 6,7-dimethoxy-9-(piperazin-1-yl)naphto[2,3-c]furan-1(3H)-one (300 mg, 0.91 mmol), chloroethyl morpholine (340 mg, 1.83 mmol), and anhydrous potassium carbonate (503 mg, 3.64 mmol) were injected into 10 ml of dimethylformamide, stirred under reflux for 18 hours, filtered with the injection of purified water, and purified by silica gel column chromatography to obtain 223 mg (0.505 mmol, 56%) of 6,7-dimethoxy-9-(4-(2-morpholinoethyl) piperazin-1-yl)naphtho[2,3-c]furan-1(3H)-one as a title compound.
Mass (M+H+): 442.2
1H-NMR (500 MHz, DMSO-d6): 2.40 (m, 4H), 2.46 (m, 4H), 2.54 (t, 2H), 3.27 (brm, 2H), 3.54 (t, 2H), 3.60 (brm, 2H), 3.89 (s, 3H), 3.91 (s, 3H), 4.14 (t, 2H), 5.38 (s, 2H), 7.38 (s, 1H), 7.66 (s, 1H), 7.81 (s, 1H).
After 1 g (2.5 mmol) of 6,7-dimethoxy-3-oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl trifluoromethanesulfonate, 980 mg (7.5 mmol) of hydroxy ethyl piperazine, and 0.7 g (5.1 mmol) of anhydrous potassium carbonate were injected into 20 ml of acetonitrile, the resulting mixture was stirred under reflux for seven hours and stirred again with the addition of purified water to filter the crystallized solid, which was then recrystallized with ethyl acetate and purified by silica gel column chromatography to obtain 0.703 g (1.89 mmol, 76%) of 9-(4-(2-hydroxyethyl) piperazin-1-yl)-6,7-dimethoxynaphtho[2,3-c]furan-1(3H)-one as a title compound.
Mass (M+H+): 373.1
1H-NMR (500 MHz, DMSO-d6): 2.46 (m, 2H), 2.53 (brm, 4H), 3.30 (brm, 4H), 3.53 (m, 2H), 3.88 (s, 3H), 3.89 (s, 3H), 4.41 (t, 1H), 5.36 (s, 2H), 7.35 (s, 1H), 7.60 (s, 1H), 7.76 (s, 1H).
After 1 g (2.5 mmol) of 6,7-dimethoxy-3-oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl trifluoromethanesulfonate, 980 mg (7.5 mmol) of hydroxy ethyl piperazine, and 0.7 g (5.1 mmol) of anhydrous potassium carbonate were injected into 20 ml of acetonitrile, the resulting mixture was stirred under reflux for seven hours and stirred again with the addition of purified water to filter the crystallized solid, which was then recrystallized with ethyl acetate and purified by silica gel column chromatography to obtain 0.703 g (1.89 mmol, 76%) of 9-(4-(2-hydroxyethyl) piperazin-1-yl)-6,7-dimethoxynaphtho[2,3-c]furan-1(3H)-one as a title compound.
Mass (M+H+): 373.1
1H-NMR (500 MHz, DMSO-d6): 2.46 (m, 2H), 2.53 (brm, 4H), 3.30 (brm, 4H), 3.53 (m, 2H), 3.88 (s, 3H), 3.89 (s, 3H), 4.41 (t, 1H), 5.36 (s, 2H), 7.35 (s, 1H), 7.60 (s, 1H), 7.76 (s, 1H).
The compound of Example 146 was synthesized by the same method as that of the compound of Example 132 except for using 7-bromo-2,8-dimethylquinolin-4-ol instead of 5-bromoquinoline.
Mass (M+H+): 416.1
1H-NMR (500 MHz, DMSO-d6): 2.06 (s, 3H), 2.41 (s, 3H), 3.51 (s, 3H), 3.93 (s, 3H), 5.47-5.48 (m, 2H), 5.99 (s, 1H), 6.59 (s, 1H), 7.02 (d, J=8.3 Hz, 1H), 7.54 (s, 1H), 7.98-8.00 (m, 2H), 10.38 (s, 1H).
The compound of Example 147 was synthesized by the same method as that of the compound of Example 132 except for using 6-bromo-2-methylquinolin-4-ol instead of 5-bromoquinoline.
Mass (M+H+): 402.1
1H-NMR (500 MHz, DMSO-d6): 2.36 (s, 3H), 3.54 (s, 3H), 3.92 (s, 3H), 5.44 (s, 2H), 5.93 (s, 1H), 6.86 (s, 1H), 7.51 (s, 1H), 7.58 (s, 2H), 7.95 (d, J=7.45 Hz, 2H), 11.69 (s, 1H).
The compound of Example 148 was synthesized by the same method as that of the compound of Example 132 except for using 4-bromo-6-fluoroquinoline instead of 5-bromoquinoline.
Mass (M+H+): 390.1
1H-NMR (500 MHz, DMSO-d6) 3.40 (s, 3H), 3.94 (s, 3H), 5.50-5.54 (m, 2H), 6.46 (s, 1H), 6.79 (d, J=9.75 Hz, 1H), 7.53 (d, J=4.3 Hz, 1H), 7.59 (s, 1H), 7.63-7.67 (m, 1H), 8.11 (s, 1H), 8.19-8.21 (m, 1H), 9.02 (d, J=4.3 Hz, 1H).
The compound of Example 149 was synthesized by the same method as that of the compound of Example 132 except for using 4-bromo-8-methoxy-2-methylquinoline instead of 5-bromoquinoline.
Mass (M+H+): 416.1
1H-NMR (500 MHz, DMSO-d6) 2.68 (s, 3H), 3.37 (s, 3H), 3.93 (s, 3H), 3.96 (s, 3H), 5.46-5.53 (m, 2H), 6.46 (s, 1H), 6.55 (d, J=1.15 Hz, 1H), 7.09-7.11 (m, 1H), 7.17-7.19 (m, 1H), 7.35 (s, 1H), 7.57 (s, 1H), 8.07 (s, 1H).
The compound of Example 150 was synthesized by the same method as that of the compound of Example 132 except for using 4-bromo-7-methoxyquinoline instead of 5-bromoquinoline.
Mass (M+H+): 402.1
1H-NMR (500 MHz, DMSO-d6) 3.37 (s, 3H), 3.90 (s, 3H), 3.93 (s, 3H), 5.47-5.54 (m, 2H), 6.46 (s, 1H), 6.98-7.02 (m, 2H), 7.31 (d, J=4.6 Hz, 1H), 7.58 (s, 1H), 8.09 (s, 1H), 8.93 (d, J=4.15 Hz, 1H).
The compound of Example 151 was synthesized by the same method as that of the compound of Example 132 except for using (S)-2-(5-bromopyrimidin-2-yl)-1-phenyl-1,2,3,4-tetrahydroisoquinoline instead of 5-bromoquinoline.
Mass (M+H+): 530.2
1H-NMR (500 MHz, DMSO-d6) 2.84-2.88 (m, 2H), 2.98-3.05 (m, 1H), 3.64-3.69 (m, 1H), 3.71 (s, 3H), 3.92 (s, 3H), 4.37-4.40 (m, 1H), 5.43 (s, 2H), 7.08 (s, 2H), 7.22-7.28 (m, 9H), 7.51 (s, 1H), 7.58 (s, 1H), 7.94 (s, 1H), 8.48 (d, J=1.75 Hz, 1H).
The compound of Example 152 was synthesized by the same method as that of the compound of Example 132 except for using 7-bromo-4-(piperazin-1-yl) quinoline instead of 5-bromoquinoline.
Mass (M+H+): 456.2
1H-NMR (500 MHz, DMSO-d6) 1.75 (s, 4H), 2.94-2.98 (m, 4H), 3.52 (s, 3H), 3.93 (s, 3H), 5.46 (s, 2H), 6.90 (s, 1H), 7.01 (d, J=5.15 Hz, 1H), 7.49 (dd, J=8.6 Hz, 1.7 Hz, 1H), 7.54 (s, 1H), 7.87 (d, J=1.4 Hz, 1H), 8.00 (s, 1H), 8.11 (d, J=8.55 Hz, 1H), 8.70 (d, J=4.9 Hz, 1H).
The compound of Example 153 was synthesized by the same method as that of the compound of Example 132 except for using 7-bromo-3-(trifluoromethyl) naphthalen-1-ol instead of 5-bromoquinoline.
Mass (M+H+): 456.1
1H-NMR (500 MHz, DMSO-d6) 3.54 (s, 3H), 3.93 (s, 3H), 5.46 (s, 2H), 6.86 (s, 1H), 7.54 (s, 1H), 7.81 (d, J=8.3 Hz, 1H), 8.01 (s, 1H), 8.10-8.14 (m, 4H).
The compound of Example 154 was synthesized by the same method as that of the compound of Example 132 except for using 7-bromo-8-methylquinolin-4-ol instead of 5-bromoquinoline.
Mass (M+H+): 402.1
1H-NMR (500 MHz, DMSO-d6) 2.02 (s, 3H), 3.52 (s, 3H), 3.93 (s, 3H), 5.48 (s, 2H), 6.12 (d, J=7.4 Hz, 1H), 6.59 (s, 1H), 7.06 (d, J=8.3 Hz, 1H), 7.54 (s, 1H), 7.84-7.85 (m, 1H), 8.00-8.04 (m, 2H), 11.13 (d, J=3.8 Hz, 1H).
The compound of Example 155 was synthesized by the same method as that of the compound of Example 132 except for using 4-bromo-6-methoxy-2-methylquinoline instead of 5-bromoquinoline.
Mass (M+H+): 416.1
1H-NMR (500 MHz, DMSO-d6) 2.64 (s, 3H), 3.39 (s, 3H), 3.44 (s, 3H), 3.93 (s, 3H), 5.47-5.51 (m, 2H), 6.32 (d, J=2.85 Hz, 1H), 6.52 (s, 1H), 7.29 (s, 1H), 7.36 (dd, J=12.0 Hz, 2.9 Hz, 1H), 7.57 (s, 1H), 7.94 (d, J=9.15 Hz, 1H), 8.08 (s, 1H).
The compound of Example 156 was synthesized by the same method as that of the compound of Example 7 except for using 5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-4,5,6,7-tetrahydrothien[3,2-c]pyridine instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 459.1
1H-NMR (500 MHZ, DMSO-d6) 2.91 (t, J=5.45 Hz, 2H), 3.67 (s, 3H), 3.92 (s, 3H), 4.00-4.03 (m, 2H), 663-4.71 (m, 2H) 5.41 (s, 2H), 6.94 (d, J=5.15 Hz, 1H), 7.02 (d, J=8.85 Hz, 1H), 7.06 (s, 1H), 7.33 (d, J=5.15 Hz, 1H), 7.49 (s, 1H), 7.59 (dd, J=8.85 Hz, 2.55 Hz, 1H), 7.90 (s, 1H), 8.11 (d, J=0.6 Hz, 1H).
The compound of Example 157 was synthesized by the same method as that of the compound of Example 132 except for using 5-(4-bromophenyl)-4,6-dimethoxypyrimidine instead of 5-bromoquinoline.
Mass (M+H+): 459.2
1H-NMR (500 MHz, DMSO-d6) 3.62 (s, 3H), 3.90 (s, 6H), 3.92 (s, 3H), 5.44 (s, 2H), 6.94 (s, 1H), 7.37-6.39 (m, 2H), 7.50-7.52 (m, 3H), 7.95 (s, 1H), 8.51 (s, 1H).
The compound of Example 158 was synthesized by the same method as that of the compound of Example 132 except for using N-(2-(1,3-oxolan-2-yl)ethyl)-5-bromo-N-methylpyrimidin-2-amine instead of 5-bromoquinoline.
Mass (M+H+): 452.2
1H-NMR (500 MHZ, CDCl3) 2.09-2.12 (m, 2H), 3.29 (s, 3H), 3.87-3.89 (m, 7H), 3.98-4.00 (m, 2H), 4.05 (s, 3H), 5.00 (t, J=4.6 Hz, 1H), 5.39 (d, J=0.85 Hz, 2H), 7.19-7.20 (m, 2H), 7.71 (s, 1H), 8.41 (s, 2H).
The compound of Example 159 was synthesized by the same method as that of the compound of Example 132 except for using 5-bromo-2-(4-methylpiperidin-1-yl)pyridine instead of 5-bromoquinoline.
Mass (M+H+): 419.1
1H-NMR (500 MHZ, DMSO-d6): 0.94 (s, 3H), 1.14 (m, 2H), 1.62 (m, 1H), 1.69 (m, 1H), 2.84 (m, 2H), 2.84 (s, 2H), 3.68 (s, 3H), 3.93 (s, 3H), 4.35 (t, 2H), 5.40 (s, 2H), 6.90 (d, 1H), 7.07 (s, 1H), 7.49 (dd, 2H), 7.90 (d, 1H), 8.01 (d, 1H).
The compound of Example 160 was synthesized by the same method as that of the compound of Example 132 except for using 5-bromo-N,N-diethylpyridin-2-amine instead of 5-bromoquinoline.
Mass (M+H+): 393.1
1H-NMR (500 MHz, DMSO-d6): 1.15 (m, 6H), 3.55 (m, 4H), 3.68 (s, 3H), 3.92 (s, 3H), 5.40 (s, 2H), 6.67 (t, 1H), 7.11 (s, 1H), 7.47 (t, 2H), 7.88 (s, 1H), 8.05 (d, 1H).
The compound of Example 161 was synthesized by the same method as that of the compound of Example 132 except for using N-(2-(1,3-dioxolan-2-yl)ethyl)-5-bromo-N-methylpyridin-2-amine instead of 5-bromoquinoline.
Mass (M+H+): 451.1
1H-NMR (500 MHz, DMSO-d6): 1.90 (q, 2H), 3.05 (s, 3H), 3.59 (m, 2H), 3.68 (s, 3H), 3.76 (m, 2H), 3.89 (m, 2H), 3.92 (s, 3H), 4.87 (m, 1H), 5.41 (s, 2H), 6.70 (d, 1H), 7.08 (s, 1H), 7.48 (s, 1H), 7.53 (d, 1H), 7.89 (s, 1H), 8.06 (s, 1H).
The compound of Example 162 was synthesized by the same method as that of the compound of Example 132 except for using 5-bromo-N-(2,2-dimethoxyethyl)-N-methylpyridin-2-amine instead of 5-bromoquinoline.
Mass (M+H+): 439.2
1H-NMR (500 MHz, DMSO-d6): 3.08 (s, 3H), 3.30 (s, 6H), 3.67 (s, 3H), 3.69 (m, 2H), 3.92 (s, 3H), 4.59 (t, 1H), 5.40 (s, 2H), 6.84 (d, 1H), 7.06 (s, 1H), 7.48 (s, 1H), 7.54 (d, 1H), 7.89 (s, 1H), 8.06 (s, 1H).
The compound of Example 163 was synthesized by the same method as that of the compound of Example 132 except for using 5-bromo-N,N-dimethylpyridin-2-amine instead of 5-bromoquinoline.
Mass (M+H+): 365.2
1H-NMR (500 MHz, DMSO-d6): 3.09 (s, 6H), 3.67 (s, 3H), 3.91 (s, 3H), 5.39 (s, 2H), 6.74 (d, 1H), 7.06 (S, 1H) 7.47 (S, 1H), 7.53 (t, 1H), 7.88 (s, 1H), 8.06 (d, 1H).
The compound of Example 164 was synthesized by the same method as that of the compound of Example 132 except for using (S)-5-bromo-N-(5-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-N-methylpyridin-2-amine instead of 5-bromoquinoline.
Mass (M+H+): 511.2
1H-NMR (500 MHz, DMSO-d6): 1.95 (m, 2H), 2.60 (m, 1H), 2.80 (m, 1H), 2.92 (m, 2H), 2.97 (s, 3H), 3.68 (s, 3H), 3.74 (s, 3H), 4.00 (s, 3H), 4.85 (m, 1H), 5.39 (s, 2H), 6.74 (d, 1H), 6.77 (d, 1H), 6.79 (d, 1H), 7.06 (m, 1H), 7.09 (d, 1H), 7.47 (s, 1H), 7.53 (q, 1H), 7.83 (s, 1H), 8.05 (d, 1H).
The compound of Example 165 was synthesized by the same method as that of the compound of Example 7 except for using 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl) piperidin-4-ol instead of 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.
Mass (M+H+): 421.0
1H-NMR (500 MHz, DMSO-d6): 1.41 (m, 2H), 1.80 (m, 2H), 3.13 (m, 2H), 3.67 (s, 3H), 3.71 (m, 1H), 3.92 (s, 3H), 4.08 (m, 2H), 4.70 (d, 1H), 5.40 (s, 2H), 6.92 (d, 1H), 7.06 (s, 1H), 7.47 (s, 1H), 7.53 (d, 1H), 7.89 (s, 1H), 8.07 (d, 1H).
The compound of Example 166 was synthesized by the same method as that of the compound of Example 132 except for using 8-(5-bromopyridin-2-yl)-1,4-dioxa-8-azaspiro[4.5]decane instead of 5-bromoquinoline.
Mass (M+H+): 463.2
1H-NMR (500 MHz, DMSO-d6): 1.68 (m, 4H), 3.67 (s, 3H), 3.70 (m, 4H), 3.91 (s+m, 7H), 5.40 (s, 2H), 6.97 (d, 1H), 7.05 (s, 1H), 7.48 (s, 1H), 7.55 (d, 1H), 7.89 (s, 1H), 8.08 (d, 1H).
The compound of Example 167 was synthesized by the same method as that of the compound of Example 132 except for using 1-(5-bromopyridin-2-yl)-4-methylpiperazine instead of 5-bromoquinoline.
Mass (M+H+): 420.1
1H-NMR (500 MHz, DMSO-d6): 2.22 (s, 3H), 2.42 (m, 4H), 3.56 (m, 4H), 3.67 (s, 3H), 3.92 (s, 3H), 5.40 (s, 2H), 6.92 (d, 1H), 7.04 (d, 1H), 7.48 (s, 1H), 7.56 (d, 1H), 7.90 (s, 1H), 8.08 (d, 1H).
The compound of Example 168 was synthesized by the same method as that of the compound of Example 132 except for using 5-bromo-N-(2-methoxyethyl)-N-methylpyridin-2-amine instead of 5-bromoquinoline.
Mass (M+H+): 409.2
1H-NMR (500 MHz, DMSO-d6): 3.27 (s, 3H), 3.50 (s, 3H), 3.61 (t, 2H), 3.73 (s, 3H), 3.92 (s, 2H), 3.93 (s, 3H), 5.45 (s, 2H), 7.02 (s, 1H), 7.28 (br, 1H), 7.54 (s, 1H), 7.95 (br, 1H), 7.99 (s, 1H), 8.07 (s, 1H).
After 5 g (13.14 mmol) of 9-(6-hydroxybenzo[d][1,3]dioxol-5-yl)-6,7-dimethoxynaphtho[2,3-c]furan-1(3H)-one, 1.7 g (13.8 mmol) of picolic acid, 0.8 g (6.54 mmol) of DMAP, and 3.0 g (15.6 mmol) of EDC-HCl were injected into 30 ml of dichloromethane, the resulting mixture was stirred at room temperature for two hours. After 20 ml of purified water was injected into the reactant and separated in layers, 20% hydrochloric acid was diluted 50 times and injected in the organic layer, and separated in layers. The organic layer was dried over anhydrous sodium sulfate, filtered, washed, and distilled under reduced pressure. The residue was dissolved in methanol, 5 ml of 35% hydrochloric acid was injected thereto, and the resulting mixture was stirred for three hours. The reactant was distilled under reduced pressure and the residue was dissolved in dichloromethane, after which tert-butylmethyl ester was slowly added dropwise thereto and stirred, and then the resulting solid was filtered and washed to obtain 2.7 g (5.56 mmol, 42.3%) of 6-(6,7-dimethoxy-3-oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl)benzo[d][1,3]dioxol-5-yl picolate as a title compound.
Mass (M+H+): 486.1
1H-NMR (500 MHz, DMSO-d6): 3.96 (s, 3H), 3.84 (s, 3H), 5.41 (s, 2H), 6.19 (s, 2H), 6.94 (s, 1H), 6.95 (s, 1H), 7.17 (s, 1H), 7.35-7.37 (m, 2H), 7.47-7.48 (m, 1H), 7.84 (s, 1H), 8.50-8.51 (m, 1H).
1 g (4.80 mmol) of 7-bromoquinoline and 4.33 g of paraformaldehyde were dissolved in 30 ml of acetic acid. 1.5 g of NaBH4CN was slowly added dropwise to the reaction solution, and the resulting mixture was stirred for 20 minutes. The reaction solution was neutralized with sodium hydroxide and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, washed, and distilled under reduced pressure to obtain 1.05 g (4.64 mmol, m/z (M+H+): 228.0, 96.6%) of 7-bromo-1-methyl-1,2,3,4-tetrahydroquinoline as an intermediate. The compound of Example 170 was synthesized by the same method as that of the compound of Example 132 except for using 7-bromo-1-methyl-1,2,3,4-tetrahydroquinoline instead of 5-bromoquinoline.
Mass (M+H+): 390.1
1H-NMR (500 MHz, DMSO-d6): 1.95-1.99 (m, 2H), 2.80-2.83 (m, 5H), 3.28 (br, 2H), 3.63 (s, 3H), 3.91 (s, 3H), 5.40 (s, 2H), 6.66-6.70 (br, 2H), 7.06 (s, 2H), 7.47 (s, 1H), 7.90 (s, 1H).
The compound of Example 171 was synthesized by the same method as that of the compound of Example 132 except for using 5-bromo-N-cyclopropyl-N-methylpyridin-2-amine instead of 5-bromoquinoline.
Mass (M+H+): 391.2
1H-NMR (500 MHz, DMSO-d6): 0.65 (m, 2H), 0.90 (m, 2H), 2.59 (m, 1H), 3.11 (s, 3H), 3.66 (s, 3H), 3.91 (s, 3H), 5.39 (s, 2H), 7.05 (s, 1H), 7.10 (d, 1H), 7.46 (s, 1H), 7.57 (t, 3H), 7.88 (s, 1H), 8.09 (d, 1H).
The compound of Example 172 was synthesized by the same method as that of the compound of Example 132 except for using (S)-5-bromo-N-(5-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)pyridin-2-amine instead of 5-bromoquinoline.
Mass (M+H+): 497.2
1H-NMR (500 MHz, DMSO-d6): 2.69 (m, 2H), 2.85 (m, 2H), 3.75 (s, 3H), 3.83 (s, 3H), 3.93 (s, 3H), 4.20 (m, 1H), 5.44 (s, 2H), 6.78 (d, 2H), 7.10 (t, 2H) 7.32 (d, 2H), 7.56 (d, 1H), 8.03 (d, 2H)
The compound of Example 173 was synthesized by the same method as that of the compound of Example 132 except for using 3-bromo-5-(2-methoxyethoxy)pyridine instead of 5-bromoquinoline.
Mass (M+H+): 396.1
1H-NMR (500 MHz, DMSO-d6): 2.63 (s, 3H), 3.05-3.17 (m, 3H), 3.27 (s, 1H), 3.61 (s, 3H), 3.92 (s, 3H), 5.41 (s, 2H), 6.93 (s, 1H), 7.11 (s, 1H), 7.18-7.20 (m, 1H), 7.28-7.30 (m, 1H), 7.49 (s, 1H), 7.93 (s, 1H).
The compound of Example 174 was synthesized by the same method as that of the compound of Example 132 except for using 5-bromo-N,N-bis(2-methoxyethyl)pyridin-2-amine instead of 5-bromoquinoline.
Mass (M+H+): 453.2
1H-NMR (500 MHz, DMSO-d6): 3.28 (s, 6H), 3.55 (m, 4H), 3.68 (t, 3H), 3.72 (m, 4H), 3.91 (s, 3H), 5.40 (s, 2H), 6.77 (d, 1H), 7.08 (s, 1H), 7.47 (s, 1H), 7.52 (d, 1H), 8.04 (s, 1H), 8.26 (d, 1H).
The compound of Example 175 was synthesized by the same method as that of the compound of Example 132 except for using 5-bromo-N-cyclohexyl-N-methylpyridin-2-amine instead of 5-bromoquinoline.
Mass (M+H+): 432.51
1H-NMR (500 MHz, DMSO-d6): 1.25 (m, 2H), 1.38 (m, 2H), 1.65 (m, 2H), 1.77 (m, 2H), 1.79 (m, 2H), 2.90 (s, 3H), 3.68 (s, 3H), 3.92 (s, 3H), 4.44 (m, 1H), 5.43 (s, 2H), 6.71 (d, 1H), 7.09 (s, 1H), 7.48 (s, 1H), 7.51 (d, 1H), 7.88 (s, 1H), 8.06 (d, 1H).
The compound of Example 176 was synthesized by the same method as that of the compound of Example 132 except for using 5-bromo-N-methyl-N-(2-methylbutyl)pyridin-2-amine instead of 5-bromoquinoline.
Mass (M+H+): 421.2
1H-NMR (500 MHz, DMSO-d6): 0.65 (m, 2H), 0.90 (m, 6H), 1.19 (m, 1H), 1.52 (m, 1H), 1.88 (m, 1H), 3.27 (s, 3H), 3.58 (m, 1H), 3.73 (s, 3H), 3.88 (s, 3H), 3.93 (s, 3H), 5.44 (s, 2H), 7.01 (s, 1H), 7.31 (d, 1H), 7.58 (s, 1H), 8.00 (m, 2H), 8.04 (d, 1H).
The compound of Example 177 was synthesized by the same method as that of the compound of Example 132 except for using 5-bromo-N-cyclopentyl-N-methylpyridin-2-amine instead of 5-bromoquinoline.
Mass (M+H+): 419.2
1H-NMR (500 MHz, DMSO-d6): 1.58 (m, 4H), 1.70 (m, 2H), 1.81 (m, 2H), 2.90 (s, 3H), 3.69 (s, 3H), 3.92 (s, 3H), 5.06 (t, 1H), 5.40 (s, 2H), 6.73 (d, 1H), 7.10 (s, 1H), 7.48 (s, 1H), 7.52 (dd, 1H), 7.89 (s, 1H), 8.05 (d, 1H).
The compound of Example 178 was synthesized by the same method as that of the compound of Example 132 except for using 5-bromo-N-ethyl-N-methylpyridin-2-amine instead of 5-bromoquinoline.
Mass (M+H+): 379.2
1H-NMR (500 MHz, DMSO-d6): 1.12 (t, 3H), 3.04 (s, 3H), 3.61 (q, 2H), 3.68 (s, 3H), 3.92 (s, 3H), 5.40 (s, 2H), 6.71 (d, 1H), 7.09 (s, 1H), 7.48 (s, 1H), 7.51 (dd, 1H), 7.89 (s, 1H), 8.05 (d, 1H).
The compound of Example 179 was synthesized by the same method as that of the compound of Example 132 except for using 5-bromo-N-methyl-N-((5-methylfuran-2-yl)methyl)pyridin-2-amine instead of 5-bromoquinoline.
Mass (M+H+): 445.2
1H-NMR (500 MHz, DMSO-d6): 2.20 (s, 3H), 3.07 (s, 3H), 3.67 (s, 3H), 3.92 (s, 3H), 4.74 (s, 3H), 5.41 (s, 2H), 5.96 (d, 1H), 6.17 (d, 1H), 6.83 (d, 1H), 7.06 (s, 1H), 7.49 (s, 1H), 7.55 (dd, 1H), 7.90 (s, 1H), 8.09 (d, 1H).
The compound of Example 180 was synthesized by the same method as that of the compound of Example 132 except for using 5-bromo-N-butyl-N-methylpyridin-2-amine instead of 5-bromoquinoline.
Mass (M+H+): 407.2
1H-NMR (500 MHz, DMSO-d6): 0.91 (t, 3H), 1.31 (m, 2H), 1.56 (m, 2H), 3.05 (s, 3H), 3.55 (m, 2H), 3.68 (s, 3H), 3.92 (s, 3H), 5.40 (s, 2H), 6.69 (d, 1H), 7.08 (s, 1H), 7.48 (s, 1H), 7.50 (dd, 1H), 7.89 (s, 1H), 8.05 (d, 1H).
The compound of Example 181 was synthesized by the same method as that of the compound of Example 132 except for using 5-bromo-N-isobutyl-N-methylpyridin-2-amine instead of 5-bromoquinoline.
Mass (M+H+): 407.2
1H-NMR (500 MHz, DMSO-d6): 0.89 (d, 6H), 2.06 (m, 1H), 3.07 (s, 3H), 3.39 (m, 2H), 3.67 (s, 3H), 3.92 (s, 3H), 5.41 (s, 2H), 6.70 (d, 1H), 7.08 (s, 1H), 7.48 (s, 1H), 7.51 (dd, 1H), 7.89 (s, 1H), 8.05 (d, 1H).
The compound of Example 182 was synthesized by the same method as that of the compound of Example 132 except for using 5-bromo-N-ethyl-N-isopropylpyridin-2-amine instead of 5-bromoquinoline.
Mass (M+H+): 407.2
1H-NMR (500 MHz, DMSO-d6): 1.16 (t, 3H), 1.18 (d, 6H), 3.41 (q, 2H), 3.69 (s, 3H), 3.92 (s, 3H), 4.84 (m, 1H), 5.40 (s, 2H), 6.68 (d, 1H), 7.13 (s, 1H), 7.48 (s, 1H), 7.52 (dd, 1H), 7.88 (s, 1H), 8.07 (d, 1H).
The compound of Example 183 was synthesized by the same method as that of the compound of Example 132 except for using 5-bromo-N-(cyclopropylmethyl)-N-methylpyridin-2-amine instead of 5-bromoquinoline.
Mass (M+H+): 405.2
1H-NMR (500 MHz, DMSO-d6): 1.22 (t, 3H), 3.72 (m, 5H), 3.74 (s, 3H), 3.94 (s, 3H), 5.45 (s, 2H), 7.03 (d, 1H), 7.30 (br, 1H), 7.55 (s, 1H), 8.01 (m, 2H), 8.05 (d, 1H).
The compound of Example 184 was synthesized by the same method as that of the compound of Example 132 except for using 4-bromo-2-chloropyridine instead of 5-bromoquinoline.
Mass (M+H+): 356.0
1H-NMR (500 MHz, DMSO-d6): 3.66 (s, 3H), 3.93 (s, 3H), 5.46 (s, 2H), 6.77 (s, 1H), 7.44-7.45 (m, 1H), 7.54 (s, 1H), 7.57 (s, 1H), 8.03 (s, 1H), 8.54 (d, J=5.15 Hz, 1H).
The compound of Example 185 was synthesized by the same method as that of the compound of Example 132 except for using 5-bromo-2-chloropyridine instead of 5-bromoquinoline.
Mass (M+H+): 356.0
1H-NMR (500 MHz, DMSO-d6): 3.67 (s, 3H), 3.93 (s, 3H), 5.45 (s, 2H), 6.84 (s, 1H), 7.54 (s, 1H), 7.66 (dd, J=8.0 Hz, 0.55 Hz, 1H), 7.91 (dd, J=8.05 Hz, 2.6 Hz, 1H), 8.02 (s, 1H), 8.41 (t, J=0.85 Hz, 1H).
The compound of Example 186 was synthesized by the same method as that of the compound of Example 132 except for using 4-bromo-2-fluoropyridine instead of 5-bromoquinoline.
Mass (M+H+): 340.0
1H-NMR (500 MHz, DMSO-d6): 3.65 (s, 3H), 3.93 (s, 3H), 5.46 (s, 2H), 6.78 (s, 1H), 7.26 (s, 1H), 7.36-7.37 (m, 1H), 7.54 (s, 1H), 8.03 (s, 1H), 8.37 (d, J=5.15 Hz, 1H).
The compound of Example 187 was synthesized by the same method as that of the compound of Example 132 except for using 2-((5-bromopyridin-3-yl)oxy)-N,N-dimethylethan-1-amine instead of 5-bromoquinoline.
Mass (M+H+): 409.2
1H-NMR (500 MHz, DMSO-d6): 2.81-2.82 (m, 6H), 3.51-3.53 (m, 2H), 3.68 (s, 3H), 3.93 (s, 3H), 4.48-4.51 (m, 2H), 5.47 (s, 2H), 6.90 (s, 1H), 7.56 (s, 1H), 7.71-7.75 (m, 1H), 8.04 (s, 1H), 8.34 (s, 1H), 8.56 (s, 1H).
The compound of Example 188 was synthesized by the same method as that of the compound of Example 132 except for using 5-bromo-N-isopropyl-N-methylpyridin-2-amine instead of 5-bromoquinoline.
Mass (M+H+): 393.1
1H-NMR (500 MHz, DMSO-d6): 1.15 (d, J=6.85 Hz, 6H), 2.86 (s, 3H), 3.68 (s, 3H), 3.92 (s, 3H), 4.89-4.93 (m, 1H), 5.40 (s, 2H), 6.71 (d, J=8.85 Hz, 1H), 7.09 (s, 1H), 7.47 (s, 1H), 7.51-7.53 (m, 1H), 7.88 (s, 1H), 8.05 (t, J=2.0 Hz, 1H).
The compound of Example 189 was synthesized by the same method as that of the compound of Example 132 except for using 2-(5-bromopyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline instead of 5-bromoquinoline.
Mass (M+H+): 453.1
1H-NMR (500 MHz, DMSO-d6): 3.03 (t, J=5.7 Hz, 2H), 3.71 (s, 3H), 3.91-3.92 (m, 2H), 3.93 (s, 3H), 4.87 (s, 2H), 5.44 (s, 2H), 7.04 (s, 1H), 7.24-7.27 (m, 4H), 7.41 (br, 1H), 7.54 (s, 1H), 7.99-8.01 (m, 2H), 8.15 (d, J=2.0 Hz, 1H).
The compound of Example 190 was synthesized by the same method as that of the compound of Example 132 except for using 7-bromo-2-methyl-1,2,3,4-tetrahydroisoquinoline instead of 5-bromoquinoline.
Mass (M+H+): 390.2
1H-NMR (500 MHz, DMSO-d6): 3.61-3.81 (m, 6H), 3.93 (s, 3H), 4.17-4.20 (m, 2H), 5.45 (s, 2H), 6.86 (s, 1H), 7.43-7.44 (m, 1H), 7.53 (s, 1H), 7.98 (s, 1H), 8.12 (d, J=7.45 Hz, 1H), 8.38 (d, J=2.9 Hz, 1H).
The compound of Example 191 was synthesized by the same method as that of the compound of Example 132 except for using 5-bromo-N-cyclopentyl-N-ethylpyridin-2-amine instead of 5-bromoquinoline.
Mass (M+H+): 433.1
1H-NMR (500 MHZ, DMSO-d6): 1.18 (t, 3H), 1.57 (m, 4H), 1.71 (m, 2H), 1.87 (m, 2H), 3.45 (q, 2H), 3.70 (s, 3H), 3.92 (s, 3H), 4.80 (m, 1H), 5.40 (s, 2H), 6.73 (d, 1H), 7.12 (s, 1H), 7.48 (s, 1H), 7.52 (dd, 1H), 7.89 (s, 1H), 8.06 (d, 1H).
The compound of Example 192 was synthesized by the same method as that of the compound of Example 132 except for using 5-bromo-N-methyl-N-((tetrahydrofuran-2-yl)methyl)pyridin-2-amine instead of 5-bromoquinoline.
Mass (M+H+): 435.1
1H-NMR (500 MHZ, DMSO-d6): 1.55 (m, 1H), 1.79 (m, 1H), 1.86 (m, 1H), 1.94 (m, 1H), 3.11 (s, 3H), 3.51 (m, 1H), 3.62 (m, 1H), 3.68 (s, 3H), 3.78 (m, 2H), 3.92 (s, 3H), 4.10 (m, 1H), 5.40 (s, 2H), 6.73 (d, 1H), 7.08 (s, 1H), 7.48 (s, 1H), 7.52 (dd, 1H), 7.89 (s, 1H), 8.05 (d, 1H).
The compound of Example 193 was synthesized by the same method as that of the compound of Example 132 except for using 5-bromo-N-ethyl-N-((tetrahydrofuran-2-yl)methyl)pyridin-2-amine instead of 5-bromoquinoline.
Mass (M+H+): 449.1
1H-NMR (500 MHz, DMSO-d6): 1.14 (t, 3H), 1.55 (m, 1H), 1.79 (m, 1H), 1.86 (m, 1H), 1.94 (m, 1H), 3.43 (m, 1H), 3.63 (m, 3H), 3.69 (s, 3H), 3.78 (m, 2H), 3.92 (s, 3H), 4.10 (m, 1H), 5.40 (s, 2H), 6.72 (d, 1H), 7.10 (s, 1H), 7.48 (s, 1H), 7.52 (dd, 1H), 7.89 (s, 1H), 8.05 (d, 1H).
The compound of Example 194 was synthesized by the same method as that of the compound of Example 132 except for using 5-bromo-N-(2,3-dihydro-1H-indan-2-yl)-N-methylpyridin-2-amine instead of 5-bromoquinoline.
Mass (M+H+): 467.2
1H-NMR (500 MHz, DMSO-d6): 2.90 (s, 3H), 3.07 (m, 2H), 3.14 (m, 2H), 3.69 (s, 3H), 3.93 (s, 3H), 5.45 (s, 2H), 6.56 (m, 1H), 6.83 (d, 1H), 7.10 (s, 1H), 7.14 (d, 1H), 7.25 (d, 2H), 7.48 (s, 1H), 7.57 (q, 1H), 7.89 (s, 1H), 8.09 (d, 1H).
The compound of Example 195 was synthesized by the same method as that of the compound of Example 132 except for using 5-bromo-N-(2,3-dihydro-1H-indan-2-yl)-N-ethylpyridin-2-amine instead of 5-bromoquinoline.
Mass (M+H+): 481.2
1H-NMR (500 MHz, DMSO-d6): 1.16 (t, 3H), 3.07 (m, 2H), 3.15 (m, 2H), 3.27 (s, 3H), 3.52 (m, 2H), 3.69 (s, 3H), 3.92 (s, 3H), 5.38 (s, 2H), 5.42 (m, 1H), 6.78 (d, 1H), 7.14 (m, 3H), 7.25 (d, 2H), 7.48 (s, 1H), 7.57 (q, 1H), 7.89 (s, 1H), 8.09 (d, 1H).
The compound of Example 196 was synthesized by the same method as that of the compound of Example 132 except for using 5-bromo-N-methyl-N-(2-(1-methyl-1H-indol-3-yl)ethyl)pyridin-2-amine instead of 5-bromoquinoline.
Mass (M+H+): 508.2
1H-NMR (500 MHz, DMSO-d6): 2.98 (m, 2H), 3.08 (s, 3H), 3.70 (d, 6H), 3.71 (m, 2H), 3.92 (s, 3H), 5.41 (s, 2H), 6.75 (d, 1H), 6.99 (m, 1H), 7.08 (d, 1H), 7.11 (m, 2H), 7.17 (s, 1H), 7.36 (d, 1H), 7.48 (s, 1H), 7.61 (d, 1H), 7.89 (s, 1H), 8.12 (s, 1H).
The compound of Example 197 was synthesized by the same method as that of the compound of Example 132 except for using 5-bromo-N-ethyl-N-(2-(1-ethyl-1H-indol-3-yl)ethyl)pyrimidin-2-amine instead of 5-bromoquinoline.
Mass (M+H+): 536.3
1H-NMR (500 MHz, DMSO-d6): 3.00 (m, 5H), 3.09 (m, 4H), 3.67 (d, 6H), 3.77 (m, 2H), 3.92 (s, 3H), 5.72 (s, 2H), 6.74 (d, 2H), 7.11 (d, 2H), 7.48 (s, 1H), 7.72 (d, 2H), 7.85 (d, 1H), 7.89 (s, 1H), 8.06 (s, 1H), 8.35 (d, 1H).
The compound of Example 198 was synthesized by the same method as that of the compound of Example 132 except for using 5-bromo-N-methyl-N-(thiophen-2-ylmethyl)pyridin-2-amine instead of 5-bromoquinoline.
Mass (M+H+): 447.2
1H-NMR (500 MHz, DMSO-d6): 3.05 (s, 3H), 3.68 (s, 1H), 3.92 (s, 3H), 5.05 (q, 2H), 5.43 (s, 2H), 6.81 (d, 1H), 6.95 (q, 1H), 7.06 (s, 2H), 7.34 (d, 1H), 7.48 (s, 1H), 7.60 (d, 1H), 7.90 (s, 1H), 8.13 (d, 1H).
The compound of Example 199 was synthesized by the same method as that of the compound of Example 132 except for using 5-bromo-N-ethyl-N-(thiophen-2-ylmethyl)pyridin-2-amine instead of 5-bromoquinoline.
Mass (M+H+): 461.0
1H-NMR (500 MHz, DMSO-d6): 1.15 (t, 3H), 3.57 (m, 2H), 3.68 (s, 3H), 3.92 (s, 3H), 4.99 (q, 2H), 5.41 (s, 2H), 6.79 (d, 1H), 6.94 (q, 1H), 7.08 (s, 2H), 7.34 (d, 1H), 7.48 (s, 1H), 7.60 (d, 1H), 7.89 (s, 1H), 8.12 (d, 1H).
The compound of Example 200 was synthesized by the same method as that of the compound of Example 132 except for using 3-bromo-5-isopropoxypyridine instead of 5-bromoquinoline.
Mass (M+H+): 380.1
1H-NMR (500 MHz, DMSO-d6): 1.31 (dd, J=6.0 Hz, 2.0 Hz, 6H), 3.68 (s, 3H), 3.93 (s, 3H), 4.82-4.85 (m, 1H), 5.47 (s, 2H), 6.91 (s, 1H), 7.56 (s, 1H), 7.95-7.96 (br, 1H), 8.05 (s, 1H), 8.42 (br, 1H), 8.60 (br, 1H).
The compound of Example 201 was synthesized by the same method as that of the compound of Example 132 except for using 5-bromo-2-chloro-N,N-dimethylpyridin-3-amine instead of 5-bromoquinoline.
Mass (M+H+): 399.1
1H-NMR (500 MHz, DMSO-d6): 2.77 (s, 6H), 3.68 (s, 3H), 3.93 (s, 3H), 5.44 (s, 2H), 6.93 (s, 1H), 7.53 (s, 1H), 7.58 (d, J=2.0 Hz, 1H), 8.00-8.01 (m, 2H).
The compound of Example 202 was synthesized by the same method as that of the compound of Example 132 except for using 5-bromo-2-(3-(m-tolyl) piperidin-1-yl)pyridine instead of 5-bromoquinoline.
Mass (M+H+): 395.3
1H-NMR (500 MHz, DMSO-d6): 1.61-1.93 (m, 5H), 2.28 (s, 3H), 2.71-2.74 (m, 1H), 2.87-2.93 (m, 2H), 3.68 (s, 3H), 3.92 (s, 3H), 4.40-4.51 (m, 1H), 5.40 (s, 2H), 6.96 (d, J=8.55 Hz, 1H), 7.02 (d, J=7.45 Hz, 1H), 7.07 (s, 1H), 7.10-7.134 (m, 2H), 7.19 (t, J=7.45 Hz, 1H), 7.48 (s, 1H), 7.54 (dd, J=8.9 Hz, 0.23 Hz, 1H), 7.89 (s, 1H), 8.08 (d, J=2.0 Hz, 1H).
The compound of Example 203 was synthesized by the same method as that of the compound of Example 132 except for using 4-((6-bromo-1H-indol-3-yl)methyl)morpholine instead of 5-bromoquinoline.
Mass (M+H+): 459.3
1H-NMR (500 MHz, DMSO-d6): 3.13-3.17 (m, 2H), 3.38-3.41 (m, 2H), 3.53 (s, 3H), 3.69 (t, J=12.2 Hz, 2H), 3.92-3.97 (m, 5H), 4.51-4.55 (m, 2H), 5.43 (s, 2H), 6.89 (s, 1H), 7.08 (d, J=8.25 Hz, 1H), 7.42 (s, 1H), 7.50 (s, 1H), 7.69 (s, 1H), 7.90 (d, J=7.95 Hz, 1H), 7.93 (s, 1H), 10.35 (br, 1H), 11.60 (s, 1H).
The compound of Example 204 was synthesized by the same method as that of the compound of Example 132 except for using 2-(5-bromo-2-methoxypyridin-3-yl)-1H-benzo[d]imidazole instead of 5-bromoquinoline.
Mass (M+H+): 468.1
1H-NMR (500 MHz, DMSO-d6): 3.69 (s, 3H), 3.95 (s, 3H), 4.25 (s, 3H), 5.49 (s, 2H), 7.01 (s, 1H), 7.45-7.47 (m, 2H), 7.58 (s, 1H), 7.77-7.79 (m, 2H), 8.05 (s, 1H), 8.51 (s, 1H), 8.68 (d, J=2.3 Hz, 1H)
The compound of Example 205 was synthesized by the same method as that of the compound of Example 132 except for using 1-(5-bromopyrimidin-2-yl)-N,N-dimethylpiperidin-4-amine instead of 5-bromoquinoline.
Mass (M+H+): 449.2
1H-NMR (500 MHz, DMSO-d6): 1.35-1.37 (m, 2H), 1.83-1.86 (m, 2H), 2.18 (s, 6H), 2.32-2.42 (m, 1H), 2.94-2.99 (m, 2H), 3.73 (s, 3H), 3.92 (s, 3H), 4.72 (d, J=13.45 Hz, 2H), 5.42 (s, 2H), 7.08 (s, 1H), 7.50 (s, 1H), 7.93 (s, 1H), 8.37 (s, 2H).
The compound of Example 206 was synthesized by the same method as that of the compound of Example 132 except for using 5-bromo-N-methyl-N-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-2-amine instead of 5-bromoquinoline.
Mass (M+H+): 432.1
1H-NMR (500 MHz, DMSO-d6): 3.00 (s, 6H), 3.67 (s, 3H), 3.94 (s, 3H), 5.46 (s, 2H), 6.94 (s, 1H), 7.55 (s, 1H), 7.82 (d, 1H), 8.02 (s, 1H), 8.04 (d, 1H), 8.44 (s, 1H), 9.09 (s, 1H).
The compound of Example 207 was synthesized by the same method as that of the compound of Example 132 except for using 5-bromo-N-ethyl-N-(1-ethyl-1H-1,2,4-triazol-3-yl)pyridin-2-amine instead of 5-bromoquinoline.
Mass (M+H+): 460.1
1H-NMR (500 MHz, DMSO-d6): 1.14 (t, 6H), 3.46 (q, 4H), 3.67 (s, 3H), 3.94 (s, 3H), 5.46 (s, 2H), 6.94 (s, 1H), 7.55 (s, 1H), 7.80 (d, 1H), 8.00 (s, 1H), 8.01 (d, 1H), 8.43 (s, 1H), 9.06 (s, 1H).
The compound of Example 208 was synthesized by the same method as that of the compound of Example 132 except for using 5-bromo-N-methyl-N-(2-(trifluoromethyl)benzyl)pyridin-2-amine instead of 5-bromoquinoline.
Mass (M+H+): 509.2
1H-NMR (500 MHz, DMSO-d6): 3.15 (s, 3H), 3.67 (s, 3H), 3.92 (s, 3H), 5.06 (s, 2H), 5.41 (s, 2H), 6.78 (d, 1H), 7.04 (s, 1H), 7.27 (d, 1H), 7.46 (m, 2H), 7.60 (m, 2H), 7.74 (d, 1H), 7.90 (s, 1H), 8.06 (d, 1H).
The compound of Example 209 was synthesized by the same method as that of the compound of Example 132 except for using 5-bromo-N-ethyl-N-(2-(trifluoromethyl)benzyl)pyridin-2-amine instead of 5-bromoquinoline.
Mass (M+H+): 523.1
1H-NMR (500 MHZ, DMSO-d6): 1.19 (t, 3H), 3.65 (q, 4H), 3.67 (s, 3H), 3.92 (s, 3H), 4.99 (s, 2H), 5.41 (s, 2H), 6.73 (d, 1H), 7.05 (s, 1H), 7.32 (d, 1H), 7.46 (m, 2H), 7.58 (m, 2H), 7.74 (d, 1H), 7.89 (s, 1H), 8.06 (d, 1H).
The compound of Example 210 was synthesized by the same method as that of the compound of Example 132 except for using 1-(4-bromophenyl)-2,2,2-trifluoroethan-1-one instead of 5-bromoquinoline.
Mass (M+H+): 417.1
1H-NMR (500 MHz, DMSO-d6): 3.60 (s, 2H), 3.93 (s, 3H), 5.46 (s, 2H), 7.64 (s, 1H), 7.68 (d, 2H), 8.01 (s, 1H), 8.17 (d, 2H).
The compound of Example 211 was synthesized by the same method as that of the compound of Example 132 except for using (S)-4-benzyl-3-(5-bromopyridin-2-yl) oxazolidin-2-one instead of 5-bromoquinoline.
Mass (M+H+): 407.2
1H-NMR (500 MHz, DMSO-d6): 3.20 (m, 2H), 3.68 (s, 3H), 4.00 (s, 3H), 4.30 (m, 1H), 4.48 (m, 1H), 5.15 (m, 1H), 5.45 (s, 2H), 6.96 (d, 1H), 7.26 (m, 5H), 7.53 (s, 1H), 7.93 (d, 1H), 7.99 (s, 1H), 8.19 (d, 1H), 8.47 (d, 1H).
After 2 g (5.26 mmol) of 9-(6-hydroxybenzo[d][1,3]dioxol-5-yl)-6,7-dimethoxynaphtho[2,3-c]furan-1(3H)-one and 20 ml of 2N sodium hydroxide were injected into dichloromethane, the resulting mixture was stirred at 40° C. for two hours and separated in layers. After 20 ml of ethyl acetate was injected into an aqueous layer of the reactant, the resulting mixture was stirred at 40° C. for two hours to precipitate a solid, which was then filtered, washed and dried under reduced pressure to obtain 1.8 g (4.28 mmol, 81%) of 1-(6-hydroxybenzo[d][1,3]dioxol-5-yl)-3-(hydroxymethyl)-6,7-dimethoxy-2-naphthoate sodium (1) as a title compound.
Mass (M+H+): 421.2
1H-NMR (500 MHz, DMSO-d6): 3.54 (s, 3H), 3.86 (s, 3H), 4.37 (d, 1H), 4.67 (d, 1H), 4.48 (m, 1H), 5.46 (br, 1H), 5.89 (s, 1H), 5.97 (s, 1H), 6.52 (d, 2H), 6.56 (s, 1H), 7.23 (s, 1H), 7.65 (s, 1H), 11.48 (s, 1H).
The compound of Example 213 was synthesized by the same method as that of the compound of Example 132 except for using 5-bromo-N-(3,4-dimethylphenyl)-N-methylpyrimidin-2-amine instead of 5-bromoquinoline.
Mass (M+H+): 456.1
1H-NMR (500 MHz, DMSO-d6): 2.21 (d, J=2.85 Hz, 6H), 3.50 (s, 3H), 3.74 (s, 3H), 3.92 (s, 3H), 5.42 (s, 2H), 7.07 (s, 1H), 7.10-7.13 (m, 1H), 7.15-7.17 (m, 2H), 7.50 (s, 1H), 7.94 (s, 1H), 8.41 (s, 2H).
The compound of Example 214 was synthesized by the same method as that of the compound of Example 132 except for using N-(5-bromopyridin-2-yl)-N,5-dimethyl-1,3,4-thiadiazol-2-amine instead of 5-bromoquinoline.
Mass (M+H+): 449.1
1H-NMR (500 MHz, DMSO-d6): 2.42 (s, 3H), 3.64 (s, 3H), 3.79 (s, 3H), 3.93 (s, 3H), 5.44 (s, 2H), 6.97 (s, 1H), 7.16 (dd, J=8.3, 0.55 Hz, 1H), 7.51 (s, 1H), 7.72 (dd, J=8.3, 2.25 Hz, 1H), 7.95 (s, 1H), 8.32 (t, J=2.3 Hz, 1H).
The compound of Example 215 was synthesized by the same method as that of the compound of Example 132 except for using 5-bromo-N-methyl-N-(1-methyl-5-(methylthio)-1H-1,2,4-triazol-3-yl)pyridin-2-amine instead of 5-bromoquinoline.
Mass (M+H+): 478.1
1H-NMR (500 MHz, DMSO-d6): 2.65 (s, 3H), 3.60 (s, 3H), 3.67 (s, 3H), 3.70 (s, 3H), 3.93 (s, 3H), 5.43 (s, 2H), 7.00 (s, 1H), 7.51 (s, 1H), 7.73-7.75 (m, 1H), 7.96 (s, 1H), 8.04-8.05 (m, 1H), 8.27-8.28 (m, 1H).
The compound of Example 216 was synthesized by the same method as that of the compound of Example 132 except for using 5-bromo-N-methyl-N-(3-(trifluoromethyl)phenyl)pyrimidin-2-amine instead of 5-bromoquinoline.
Mass (M+H+): 495.2
1H-NMR (500 MHz, DMSO-d6): 3.51 (s, 3H), 3.69 (s, 3H), 3.92 (s, 3H), 5.42 (s, 2H), 6.84 (dd, J=8.6 Hz, 0.6 Hz, 1H), 7.05 (s, 1H), 7.49 (s, 1H), 7.51-7.53 (m, 1H), 7.59 (dd, J=8.6 Hz, 2.3 Hz, 1H), 7.64 (t, J=7.75 Hz, 1H), 7.69-7.71 (m, 2H), 7.93 (s, 1H), 8.17 (dd, J=2.3 Hz, 0.85 Hz, 1H).
The compound of Example 217 was synthesized by the same method as that of the compound of Example 132 except for using 4-bromo-N,N-dimethyl-2-nitroaniline instead of 5-bromoquinoline.
Mass (M+H+): 409.1
1H-NMR (500 MHz, DMSO-d6): 2.90 (s, 6H), 3.67 (s, 3H), 3.92 (s, 3H), 5.41 (s, 2H), 7.01 (s, 1H), 7.26 (d, J=8.6 Hz, 1H), 7.50 (s, 1H), 7.52 (d, J=2.3 Hz, 1H), 7.77 (d, J=2.3 Hz, 1H), 7.93 (s, 1H).
The compound of Example 218 was synthesized by the same method as that of the compound of Example 132 except for using 4-((5-bromopyridin-2-yl)(methyl)amino)benzonitrile instead of 5-bromoquinoline.
Mass (M+H+): 452.2
1H-NMR (500 MHz, DMSO-d6): 3.57 (s, 3H), 3.70 (s, 3H), 3.93 (s, 3H), 5.43 (s, 2H), 7.01 (s, 1H), 7.14 (dd, J=8.3 Hz, 0.55 Hz, 1H), 7.52 (s, 1H), 7.54 (s, 1H), 7.56 (s, 1H), 7.76 (dd, J=8.9 Hz, 2.6 Hz, 1H), 7.83 (s, 1H), 7.85 (s, 1H), 7.97 (s, 1H), 8.24 (dd, J=1.7 Hz, 0.85 Hz, 1H).
The compound of Example 219 was synthesized by the same method as that of the compound of Example 132 except for using 4-(6-bromopyridazin-3-yl)morpholine instead of 5-bromoquinoline.
Mass (M+H+): 408.1
1H-NMR (500 MHz, DMSO-d6): 3.60-3.61 (m, 2H), 3.64-3.66 (m, 5H), 3.71-3.72 (m, 2H), 3.75-3.77 (m, 2H), 3.93 (s, 3H), 5.47 (s, 2H), 6.99 (s, 1H), 7.37 (s, 1H), 7.52 (s, 1H), 7.54 (d, J=9.45 Hz, 1H), 8.01 (s, 1H).
The compound of Example 220 was synthesized by the same method as that of the compound of Example 132 except for using 4-(3-bromoimidazo[1,2-b]pyridazin-6-yl)morpholine instead of 5-bromoquinoline.
Mass (M+H+): 477.2
1H-NMR (500 MHz, DMSO-d6): 3.12-3.14 (m, 4H), 3.56 (t, J=4.6 Hz, 4H), 3.67 (s, 3H), 3.93 (s, 3H), 5.46 (q, J=14.6 Hz, 2H), 7.18 (s, 1H), 7.19 (d, J=10.05 Hz, 1H), 7.52 (s, 1H), 7.83 (s, 1H), 7.97 (d, J=10.0 Hz, 1H), 8.01 (s, 1H).
The compound of Example 221 was synthesized by the same method as that of the compound of Example 132 except for using 5-bromo-2,2-difluorobenzo[d][1,3]dioxole instead of 5-bromoquinoline.
Mass (M+H+): 401.0
1H-NMR (500 MHz, DMSO-d6): 3.64 (s, 3H), 3.92 (s, 3H), 5.43 (s, 2H), 6.88 (s, 1H), 7.17 (dd, J=8.3, 1.45 Hz, 1H), 7.45 (d, J=1.75 Hz, 1H), 7.50 (s, 1H), 7.52 (s, 1H), 7.96 (s, 1H).
The compound of Example 222 was synthesized by the same method as that of the compound of Example 132 except for using 5-bromo-N-methyl-N-phenylpyridin-2-amine instead of 5-bromoquinoline.
Mass (M+H+): 427.1
1H-NMR (500 MHz, DMSO-d6): 3.47 (s, 3H), 3.69 (s, 3H), 3.92 (s, 3H), 5.41 (s, 2H), 6.63 (dd, J=10.6, 0.85 Hz, 1H), 7.06 (s, 1H), 7.22-7.25 (m, 1H), 7.36-7.40 (m, 2H), 7.44-7.48 (m, 4H), 7.91 (s, 1H), 8.15 (dd, J=2.25, 0.9 Hz, 1H).
The compound of Example 223 was synthesized by the same method as that of the compound of Example 132 except for using 1-(5-bromopyridin-2-yl)-N,N-dimethyl-5-(methylthio)-1H-1,2,4-triazol-3-amine instead of 5-bromoquinoline.
Mass (M+H+): 478.1
1H-NMR (500 MHz, DMSO-d6): 2.45-2.47 (m, 3H), 3.41 (s, 3H), 3.55 (s, 3H), 3.67 (s, 3H), 3.92 (s, 3H), 5.42 (s, 2H), 6.92 (d, J=8.6 Hz, 1H), 6.98 (s, 1H), 7.51 (s, 1H), 7.75 (dd, J=8.85, 2.55 Hz, 1H), 7.95 (s, 1H), 8.17 (d, J=1.75 Hz, 1H).
After 2 g (5.26 mmol) of 9-(6-hydroxybenzo[d][1,3]dioxol-5-yl)-6,7-dimethoxynaphtho[2,3-c]furan-1(3H)-one and 20 ml of 2N sodium hydroxide were injected into dichloromethane, the resulting mixture was stirred at 40° C. for two hours and separated in layers. After 20 ml of ethyl acetate was injected into an aqueous layer of the reactant, the resulting mixture was stirred at 40° C. for two hours to precipitate a solid, which was then filtered, washed and dried under reduced pressure to obtain 1.8 g (4.28 mmol, 81%) of 1-(6-hydroxybenzo[d][1,3]dioxol-5-yl)-3-(hydroxymethyl)-6,7-dimethoxy-2-naphthoic acid sodium salt as an intermediate.
After 1 g (2.38 mmol) of the intermediate was injected into 5 ml of toluene and 1 ml of dimethylformamide, 0.7 ml of thionyl chloride was slowly added dropwise thereto, stirred for 17 hours, crystallized in methanol, and then filtered and washed to obtain 0.79 g (1.89 mmol) of 1-(6-hydroxybenzo[d][1,3]dioxol-5-yl)-3-(hydroxymethyl)-6,7-dimethoxy-2-naphthoyl chloride as a title compound.
Mass (M+H+): 415.2
1H-NMR (500 MHz, DMSO-d6): 3.64 (s, 3H), 3.95 (s, 3H), 5.38 (s, 2H), 5.98 (d, 2H), 6.61 (d, 2H), 6.93 (s, 1H), 7.43 (s, 1H), 7.85 (s, 1H), 9.09 (s, 1H)
The compound of Example 225 was synthesized by the same method as that of the compound of Example 132 except for using N-(5-bromopyridin-2-yl)-N-methylbenzo[d]thiazol-2-amine instead of 5-bromoquinoline.
Mass (M+H+): 484.1
1H-NMR (500 MHz, DMSO-d6): 3.67 (s, 3H), 3.87 (s, 3H), 3.97 (s, 3H), 5.46 (s, 2H), 6.98 (s, 1H), 7.26 (m, 1H), 7.47 (m, 2H), 7.56 (m, 2H), 7.84 (d, 1H), 7.92 (d, 1H), 7.99 (s, 1H), 8.45 (d, 1H).
The compound of Example 226 was synthesized by the same method as that of the compound of Example 132 except for using 5-bromo-N-ethyl-N-(pyridin-4-ylmethyl)pyridin-2-amine instead of 5-bromoquinoline.
Mass (M+H+): 456.2
1H-NMR (500 MHz, DMSO-d6): 3.62 (m, 2H), 3.67 (s, 3H), 3.91 (s, 3H), 4.84 (d, 2H), 5.40 (s, 1H), 6.73 (d, 1H), 7.05 (s, 1H), 7.25 (d, 2H), 7.47 (s, 1H), 7.55 (d, 1H), 7.89 (s, 1H), 8.06 (s, 1H), 8.47 (d, 2H).
After 2 g (5.26 mmol) of 9-(6-hydroxybenzo[d][1,3]dioxol-5-yl)-6,7-dimethoxynaphtho[2,3-c]furan-1(3H)-one and 20 ml of 2N sodium hydroxide were injected into dichloromethane, the resulting mixture was stirred at 40° C. for two hours and separated in layers. After 20 ml of ethyl acetate was injected into an aqueous layer of the reactant, the resulting mixture was stirred at 40° C. for two hours to precipitate a solid, which was then filtered, washed and dried under reduced pressure to obtain 1.8 g (4.28 mmol, 81%) of 1-(6-hydroxybenzo[d][1,3]dioxol-5-yl)-3-(hydroxymethyl)-6,7-dimethoxy-2-naphthoic acid sodium salt.
After 1 g (2.38 mmol) of the intermediate, 545 mg (2.85 mmol) of EDC HCl, 386 mg (2.85 mmol) of HOBt, and 2.0 ml of DIEA were injected into 10 ml of dichloromethane, 0.3 ml of cis-2,6-dimethyl morpholine was slowly injected thereto, after which the resulting mixture was stirred at room temperature for 24 hours, and then ethyl acetate and purified water were injected thereto, filtered, washed, and distilled under reduced pressure. The residue was purified by column chromatography to obtain 0.85 g of the title compound (1.08 mmol, 43.1%).
Mass (M+H+): 785.2
1H-NMR (500 MHz, DMSO-d6): 3.64 (s, 3H), 3.90 (s, 3H), 3.94 (d, 6H), 5.03 (d, 2H), 5.31 (t, 1H), 5.39 (s. 2H), 5.98 (d, 2H), 6.16 (s, 2H), 6.55 (s, 1H), 6.61 (s, 1H), 6.93 (s, 1H), 7.15 (s, 1H), 7.43 (s, 1H), 7.51 (s, 1H), 7.85 (s, 1H), 7.94 (s, 1H), 7.98 (s, 1H), 8.11 (s, 1H), 8.97 (s, 2H).
After 2 g (5.26 mmol) of 9-(6-hydroxybenzo[d][1,3]dioxol-5-yl)-6,7-dimethoxynaphtho[2,3-c]furan-1(3H)-one and 20 ml of 2N sodium hydroxide were injected into dichloromethane, the resulting mixture was stirred at 40° C. for two hours and separated in layers. After 20 ml of ethyl acetate was injected into an aqueous layer of the reactant, the resulting mixture was stirred at 40° C. for two hours to precipitate a solid, which was then filtered, washed and dried under reduced pressure to obtain 1.8 g (4.28 mmol, 81%) of 1-(6-hydroxybenzo[d][1,3]dioxol-5-yl)-3-(hydroxymethyl)-6,7-dimethoxy-2-naphthoic acid sodium salt as an intermediate.
After 500 mg (1.2 mmol) of 1-(6-hydroxybenzo[d][1,3]dioxol-5-yl)-3-(hydroxymethyl)-6,7-dimethoxy-2-naphthoic acid sodium salt, 0.18 ml of tetramethyl orthosilicate, and 0.1 ml of isopropylamine were injected into 10 ml of toluene, the resulting mixture was stirred under reflux for eight hours. Ethyl acetate and purified water were injected and separated in layers, after which the separated organic layer was distilled under reduced pressure. The distilled residue was purified by column chromatography to obtain 150 mg (0.34 mmol, 28.3%) of 1-(6-hydroxybenzo[d][1,3]dioxol-5-yl)-3-(hydroxymethyl)-N-isopropyl-6,7-dimethoxy-2-naphthoamide as a title compound.
Mass (M+H+): 438.0
1H-NMR (500 MHz, DMSO-d6): 0.91 (q, 6H), 3.58 (s, 3H), 3.77 (m, 1H), 3.85 (s, 3H), 4.61 (m, 2H), 5.15 (t, 1H), 5.94 (d, 2H), 6.53 (s, 1H), 6.59 (s, 1H), 6.65 (s, 1H), 7.31 (s, 1H), 7.37 (d, 1H), 7.81 (s, 1H), 8.82 (s, 1H)
The compound of Example 230 was synthesized by the same method as that of the compound of Example 132 except for using 5-bromo-N-methylpyridin-2-amine instead of 5-bromoquinoline.
Mass (M+H+): 351.2
1H-NMR (500 MHz, DMSO-d6): 2.83 (d, 3H), 3.68 (s, 3H), 3.93 (s, 3H), 5.40 (s, 2H), 6.54 (d, 1H), 7.67 (d, 1H), 7.09 (s, 1H), 7.41 (d, 1H), 7.48 (s, 1H), 7.88 (s, 1H), 7.96 (d, 1H).
The compound of Example 230 was synthesized by the same method as that of the compound of Example 132 except for using N-(5-bromopyridin-2-yl)-N-methylacetamide instead of 5-bromoquinoline.
Mass (M+H+): 393.1
1H-NMR (500 MHz, DMSO-d6): 2.13 (s, 3H), 3.39 (s, 3H), 3.66 (s, 3H), 3.94 (s, 3H), 5.46 (s, 2H), 6.90 (s, 1H), 7.54 (s, 1H), 7.72 (d, 1H), 7.89 (d, 1H), 8.01 (s, 1H), 8.44 (s, 1H).
The compound of Example 231 was synthesized by the same method as that of the compound of Example 132 except for using N-(5-bromopyridin-2-yl)-N,5-dimethyl-1,3,4-oxadiazol-2-amine instead of 5-bromoquinoline.
Mass (M+H+): 433.0
1H-NMR (500 MHz, DMSO-d6): 3.28 (s, 3H), 3.66 (m, 6H), 3.94 (s, 3H), 5.45 (s, 2H), 6.95 (s, 1H), 7.53 (s, 1H), 7.88 (d, 1H), 7.99 (s, 1H), 8.10 (d, 1H), 8.37 (s, 1H).
The compound of Example 232 was synthesized by the same method as that of the compound of Example 132 except for using 5-bromo-N-(2,4-dimethoxybenzyl)-N-methylpyridin-2-amine instead of 5-bromoquinoline.
Mass (M+H+): 501.2
1H-NMR (500 MHZ, DMSO-d6): 3.13 (s, 3H), 3.72 (S, 3H), 3.73 (s, 3H), 3.76 (s, 3H), 3.93 (s, 3H), 4.78 (d, 2H), 5.44 (s, 2H), 6.49 (dd, 1H), 6.59 (d, 1H), 7.03 (s, 1H), 7.10 (br, 1H), 7.30 (d, 1H), 7.53 (s, 1H), 7.57 (s, 1H), 7.97 (d, 1H), 8.10 (s, 1H).
The compound of Example 233 was synthesized by the same method as that of the compound of Example 132 except for using N-(5-bromopyridin-2-yl)-N-methylpivalamide instead of 5-bromoquinoline.
Mass (M+H+): 435.0
1H-NMR (500 MHz, DMSO-d6): 3.24 (s, 3H), 3.62 (s, 3H), 3.94 (s, 3H), 5.47 (s, 2H), 6.82 (s, 1H), 7.55 (s, 1H), 7.59 (d, 1H), 7.94 (d, 1H), 8.02 (s, 1H), 8.44 (s, 1H).
The compound of Example 234 was synthesized by the same method as that of the compound of Example 132 except for using N-(5-bromopyridin-2-yl)-6-chloro-N-methylnicotinamide instead of 5-bromoquinoline.
Mass (M+H+): 490.1
1H-NMR (500 MHz, DMSO-d6): 3.55 (s, 3H), 3.66 (s, 3H), 3.93 (s, 3H), 5.44 (s, 2H), 6.69 (s, 1H), 7.42 (m, 1H), 7.46 (m, 1H), 7.53 (s, 1H), 7.79 (d, 1H), 7.99 (s, 1H), 8.28 (s, 1H), 8.34 (s, 1H).
The compound of Example 235 was synthesized by the same method as that of the compound of Example 132 except for using N-(5-bromopyridin-2-yl)-N-methylmorpholin-4-carboxamide instead of 5-bromoquinoline.
Mass (M+H+): 464.2
1H-NMR (500 MHz, DMSO-d6): 3.26 (s, 3H), 3.31 (m, 4H), 3.55 (m, 4H), 3.68 (s, 3H), 3.93 (s, 3H), 5.44 (s, 2H), 6.97 (s, 1H), 7.17 (d, 1H), 7.52 (s, 1H), 7.72 (d, 1H), 7.97 (s, 1H), 8.27 (s, 1H).
The compound of Example 236 was synthesized by the same method as that of the compound of Example 132 except for using N-(4-((5-bromopyridin-2-yl)(methyl)amino)phenyl)-N-methylacetamide instead of 5-bromoquinoline.
Mass (M+H+): 498.2
1H-NMR (500 MHz, DMSO-d6): 3.50 (s, 3H), 3.69 (s, 3H), 3.92 (s, 3H), 5.42 (s, 2H), 6.87-6.89 (m, 1H), 7.4 (s, 1H), 7.50 (s, 1H), 7.59-7.61 (m, 3H), 7.73-7.75 (m, 1H), 7.85-7.86 (m, 1H), 7.93 (s, 1H), 8.17 (t, J=0.85 Hz, 1H).
The compound of Example 237 was synthesized by the same method as that of the compound of Example 132 except for using 3-((5-bromopyridin-2-yl)(methyl)amino)benzonitrile instead of 5-bromoquinoline.
Mass (M+H+): 452.1
1H-NMR (500 MHZ, DMSO-d6): 3.50 (s, 3H), 3.70 (s, 3H), 3.93 (s, 3H), 5.44 (s, 2H), 6.89 (d, J=8.6 Hz, 1H), 7.04 (s, 1H), 7.50 (s, 1H), 7.59-7.62 (m, 3H), 7.74-7.75 (m, 1H), 7.87 (s, 1H), 7.93 (s, 1H), 8.17 (d, J=2.3 Hz, 1H).
The compound of Example 238 was synthesized by the same method as that of the compound of Example 132 except for using 1-(5-bromopyridin-2-yl)-N,N-dimethylpiperidin-4-amine instead of 5-bromoquinoline.
Mass (M+H+): 448.2
1H-NMR (500 MHz, DMSO-d6): 1.72-1.76 (m, 2H), 2.16-2.19 (m, 2H), 2.73 (d, J=5.15 Hz, 6H), 2.99-3.03 (m, 2H), 3.40-3.44 (m, 1H), 3.70 (s, 3H), 3.93 (s, 3H), 4.55-4.57 (m, 2H), 5.43 (s, 2H), 7.03 (s, 1H), 7.28 (br, 1H), 7.52 (s, 1H), 7.96 (s, 1H), 8.11 (s, 1H), 10.62 (br, 1H).
The compound of Example 239 was synthesized by the same method as that of the compound of Example 132 except for using 4-((5-bromopyridin-2-yl)(methyl)amino)benzenethiol instead of 5-bromoquinoline.
Mass (M+H+): 459.0
1H-NMR (500 MHz, DMSO-d6): 2.71 (s, 3H), 3.67 (s, 3H), 3.92 (s, 3H), 5.42 (s, 2H), 6.71 (d, J=8.6 Hz, 2H), 6.85 (d, J=8.3 Hz, 1H), 6.89 (s, 1H), 7.40 (d, J=8.85 Hz, 2H), 7.51 (s, 1H), 7.66 (dd, J=8.3, 2.3 Hz, 1H), 7.97 (s, 1H), 8.36 (d, J=0.55 Hz, 1H).
The compound of Example 240 was synthesized by the same method as that of the compound of Example 132 except for using 7-(5-bromopyridin-2-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine instead of 5-bromoquinoline.
Mass (M+H+): 512.2
1H-NMR (500 MHz, DMSO-d6): 3.66 (s, 3H), 3.92 (s, 3H), 4.21-4.22 (m, 2H), 4.29-4.30 (m, 2H), 5.06 (s, 2H), 5.42 (s, 2H), 7.02 (s, 1H), 7.19 (d, J=8.35 Hz, 1H), 7.50 (s, 1H), 7.70 (dd, J=8.6, 2.3 Hz, 1H), 7.93 (s, 1H), 8.18 (d, J=1.75 Hz, 1H).
The compound of Example 241 was synthesized by the same method as that of the compound of Example 132 except for using 3-((5-bromopyridin-2-yl)(methyl)amino)-1-methyl-1H-pyrazol-4-carbonitrile instead of 5-bromoquinoline.
Mass (M+H+): 456.2
1H-NMR (500 MHz, DMSO-d6): 3.67 (s, 3H), 3.92 (s, 3H), 4.16 (d, J=8.05 Hz, 6H), 5.51 (s, 2H), 7.00 (s, 1H), 7.60 (s, 1H), 8.11 (s, 1H), 8.40 (d, J=9.15 Hz, 1H), 8.72 (dd, J=9.15, 2.0 Hz, 1H), 9.22 (s, 1H), 9.27 (dd, J=1.7 Hz, 1H).
After 4 g (23.2 mmol) of 4-bromoaniline, 9.6 g (69.8 mmol) of anhydrous potassium carbonate, and 3.4 ml (24.4 mmol) of 1,5-dibromopentane were injected into 60 ml of dimethylformamide, the resulting mixture was stirred at 100° C. for 18 hours, cooled, injected into ethyl acetate and purified water, separated in layers, added purified water and then separated in layers, dried over anhydrous sodium carbonate, filtered, washed, and distilled under reduced pressure. The residue was purified by column chromatography to obtain 3.8 g (15.8 mmol, 68%) of 1-(4-bromophenyl) piperidine as an intermediate.
After 1.6 g (6.7 mmol) of 1-(4-bromophenyl) piperidine, 550 mg (0.7 mmol) of PdCl2(dppf)CH2Cl2, 2.5 g (10.0 mmol) of bis(pinacolato)diborane, and 1.98 g (20.1 mmol) of potassium acetate were injected into 20 ml of 1,4-dioxane, the resulting mixture was heated at 100° C., stirred for 18 hours, distilled under reduced pressure, and purified by column chromatography to obtain 1.2 g (4.17 mmol, 62%) of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) piperidine as an intermediate.
After 1.5 g (3.8 mmol) of 6,7-dimethoxy-3-oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl trifluoromethanesulfonate, 1.2 g (4.2 mmol) of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) piperidine, 310 mg (0.38 mmol) of PdCl2(dppf)CH2Cl2, and 3.2 g (15.2 mmol) of K3PO4 were injected into 30 ml of 1,4-dioxane, the resulting mixture was stirred at 80 to 90° C. for 20 hours, distilled under reduced pressure, separated in layers with ethyl acetate and purified water, dried over anhydrous sodium sulfate, filtered and washed. The reactant was distilled under reduced pressure, after which the residue was recrystallized with methanol to obtain 1.2 g (2.97 mmol, 78%) of 6,7-dimethoxy-9-(4-(piperidin-1-yl)phenyl)naphtho[2,3-c]furan-1(3H)-one as a title compound.
Mass (M+H+): 404.2
1H-NMR (500 MHz, DMSO-d6): 1.54 (m, 2H), 1.63 (m, 4H), 3.22 (t, 4H), 3.62 (s, 3H), 3.91 (s, 3H), 5.38 (s, 2H), 7.00 (d, 2H), 7.05 (s, 1H), 7.17 (d, 2H), 7.45 (s, 1H), 7.86 (s, 1H).
The compound of Example 243 was synthesized by the same method as that of the compound of Example 242 except for using 3-bromoaniline instead of 4-bromoaniline.
Mass (M+H+): 404.2
1H-NMR (500 MHz, DMSO-d6): 1.52 (m, 2H), 1.57 (m, 4H), 3.13 (t, 4H), 3.59 (s, 3H), 3.91 (s, 3H), 5.40 (s, 2H), 6.70 (d, 1H), 6.84 (s, 1H), 6.98 (s, 1H), 7.00 (d, 1H), 7.29 (t, 1H), 7.47 (s, 1H), 7.90 (s, 1H).
The compound of Example 244 was synthesized by the same method as that of the compound of Example 242 except for using bis(2-bromoethyl) ester instead of 1,5-dibromopentane.
Mass (M+H+): 406.2
1H-NMR (500 MHZ, DMSO-d6): 3.10 (t, 4H), 3.59 (s, 3H), 3.69 (t, 4H), 3.91 (s, 3H), 5.41 (s, 2H), 6.77 (d, 1H), 6.88 (s, 1H), 6.96 (s, 1H), 7.03 (s, 1H), 7.33 (t, 1H), 7.47 (s, 1H), 7.91 (s, 1H).
The compound of Example 245 was synthesized by the same method as that of the compound of Example 242 except for using bis(2-bromoethyl) ester instead of 1,5-dibromopentane.
Mass (M+H+): 406.2
1H-NMR (500 MHz, DMSO-d6): 3.20 (t, 4H), 3.61 (s, 3H), 3.75 (t, 4H), 3.91 (s, 3H), 5.39 (s, 2H), 7.02 (s, 1H), 7.03 (d, 2H), 7.21 (d, 2H), 7.46 (s, 1H), 7.87 (s, 1H).
The compound of Example 246 was synthesized by the same method as that of the compound of Example 242 except for using iodomethane instead of 1,5-dibromopentane.
Mass (M+H+): 350.2
1H-NMR (500 MHz, DMSO-d6): 2.73 (d, 3H), 3.63 (s, 3H), 3.90 (s, 3H), 5.37 (s, 2H), 5.85 (q, 1H), 6.62 (d, 1H), 7.07 (d, 2H), 7.11 (s, 1H), 7.43 (s, 1H), 7.82 (s, 1H).
The compound of Example 247 was synthesized by the same method as that of the compound of Example 242 except for using iodomethane instead of 1,5-dibromopentane.
Mass (M+H+): 364.1
1H-NMR (500 MHz, DMSO-d6): 3.08 (s, 6H), 3.62 (s, 3H), 3.91 (s, 3H), 5.41 (s, 2H), 6.96 (s, 1H), 7.36 (brm, 4H), 7.48 (s, 1H), 7.91 (s, 1H).
After 10 g (58.1 mmol) of 4-bromoaniline, 32 g (231.5 mmol) of anhydrous potassium carbonate, and 14 ml (173.4 mmol) of iodoethane were injected into acetonitrile, the resulting mixture was heated and stirred at 60° C. for 18 hours. The reactant was filtered, washed and distilled under reduced pressure. The resulting product was purified by column chromatography to obtain 4.3 g (18.8 mmol, 30%) of 4-bromo-N,N-diethylaniline as intermediate 1, and 5.28 g (26.4 mmol, 46%) of 4-bromo-N-ethylaniline as intermediate 2.
After 2 g (9.99 mmol) of 4-bromo-N-ethylaniline as intermediate 2 and 0.62 ml (14.98 mmol) of iodomethane were injected into 30 ml of tetrahydrofuran, 1.3 g (30.0 mmol) of sodium hydride (55% mineral oil) was slowly injected thereto. The reactant was stirred for five hours, after which methanol was injected and distilled under reduced pressure. Dichloromethane and purified water were injected into the concentrate to separate in layers, and then the organic layer was dried over anhydrous sodium sulfate, filtered, washed, and concentrated under reduced pressure. The concentrate was purified by column chromatography to obtain 2.03 g (9.49 mmol, 95%) of 4-bromo-N-ethyl-N-methylaniline as an intermediate.
After 2.03 g (9.49 mmol) of 4-bromo-N-ethyl-N-methylaniline as an intermediate, 774 mg (0.95 mmol) of PdCl2(dppf)CH2Cl2, 2.89 g (11.38 mmol) of bis(pinacolato)diborane, and 2.77 g (28.5 mmol) of potassium acetate were injected into 20 ml of 1,4-dioxane, the resulting mixture was heated at 100° C., stirred for 18 hours, distilled under reduced pressure, and purified by column chromatography to obtain 1.77 g (6.78 mmol, 72%) of N-ethyl-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline as an intermediate.
After 2.65 g (6.75 mmol) of 6,7-dimethoxy-3-oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl trifluoromethanesulfonate, 1.77 g (6.78 mmol) of N-ethyl-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline, 551 mg (0.67 mmol) of PdCl2(dppf)CH2Cl2, and 5.73 g (27.0 mmol) of K3PO4 were injected into 30 ml of 1,4-dioxane, the resulting mixture was stirred at 80-90° C. for 20 hours, distilled under reduced pressure, separated in layers with ethyl acetate and purified water, dried over anhydrous sodium sulfate, filtered and washed. The reactant was distilled under reduced pressure, and the residue was purified by column chromatography to obtain 2.06 g (5.46 mmol, 81%) of 9-(4-(ethyl(methyl)amino)phenyl)-6,7-dimethoxynaphtho[2,3-c]furan-1(3H)-one as a title compound.
Mass (M+H+): 378.2
1H-NMR (500 MHz, DMSO-d6): 1.09 (t, 3H), 2.92 (s, 3H), 3.44 (q, 2H), 3.62 (s, 3H), 3.91 (s, 3H), 5.37 (s, 2H), 6.77 (d, 2H), 7.11 (s, 1h), 7.15 (d, 2H), 7.44 (s, 1H), 7.83 (s, 1H).
The compound of Example 249 was synthesized by the same method as that of Step 3, 4) of Example 248 using 4-bromo-N,N-diethylaniline as intermediate 1 produced in Step 1) of Example 248.
Mass (M+H+): 392.1
1H-NMR (500 MHz, DMSO-d6): 1.31 (t, 6H), 3.39 (q, 4H), 3.63 (s, 3H), 3.91 (s, 3H), 5.37 (s, 2H), 6.73 (d, 2H), 7.13 (s, 1H), 7.15 (d, 2H), 7.44 (s, 1H), 7.82 (s, 1H).
The compound of Example 250 was synthesized by the same method as that of Step 3, 4) of Example 248 using 4-bromo-N-ethylaniline as intermediate 2 produced in Step 1) of Example 248.
Mass (M+H+): 364.2
1H-NMR (500 MHz, DMSO-d6): 1.19 (t, 3H), 3.07 (q, 2H), 3.62 (s, 3H), 3.90 (s, 3H), 5.37 (s, 2H), 5.79 (brm, 1H), 6.64 (d, 2H), 7.06 (d, 2H), 7.11 (s, 1H), 7.43 (s, 1H), 7.82 (s, 1H).
The compound of Example 251 was synthesized by the same method as that of the compound of Example 242 except for using 1,4-dibromobutane instead of 1,5-dibromopentane.
Mass (M+H+): 390.1
1H-NMR (500 MHz, DMSO-d6): 1.97 (t, 4H), 3.29 (t, 4H), 3.62 (s, 3H), 3.92 (s, 3H), 5.35 (s, 2H), 6.62 (d, 2H), 7.12 (s, 1H), 7.15 (d, 2H), 7.44 (s, 1H), 7.83 (s, 1H).
The compound of Example 252 was synthesized by the same method as that of the compound of Example 242 except for using 1,4-dibromobutane instead of 1,5-dibromopentane and using 3-bromoaniline instead of 4-bromoaniline.
Mass (M+H+): 390.2
1H-NMR (500 MHz, DMSO-d6): 1.93 (m, 4H), 3.24 (m, 4H), 3.59 (s, 3H), 3.91 (s, 3H), 5.41 (s, 2H), 6.54 (m, 1H), 6.59 (d, 1H), 6.71 (m, 1H), 7.02 (s, 1H), 7.29 (t, 1H), 7.47 (s, 1H), 7.90 (s, 1H).
The compound of Example 253 was synthesized by the same method as that of Step 3, 4) of Example 248 using 4-bromo-N-ethylaniline as intermediate 2 produced in Step 1) of Example 248 and using 2-bromoethyl methyl ester instead of iodomethane of Step 2) of Example 248.
Mass (M+H+): 422.1
1H-NMR (500 MHz, DMSO-d6): 1.15 (dt, 3H), 3.28 (dq, 2H), 3.28 (m, 2H), 3.51 (m, 2H), 3.63 (d, 3H), 3.91 (d, 3H), 5.38 (d, 2H), 6.64 (d, 1H), 6.75 (d, 1H), 7.08 (d, 1H), 7.13 (m, 2H), 7.44 (d, 1H), 7.83 (d, 1H).
300 mg (0.86 mmol) of 9-(4-(ethylamino)phenyl)-6,7-dimethoxynaphtho[2,3-c]furan-1(3H)-one, 360 mg (2.58 mmol) of anhydrous potassium carbonate, and 650 mg (2.58 mmol) of 3-bromomethyl pyridine bromate were injected into 10 ml of dimethylformamide. The resulting mixture was stirred at 80-90° C. for eight hours, after which ethyl acetate and purified water were injected to separate in layers, and then the organic layer was dried with anhydrous sodium sulfate, filtered, and washed. The filtered reaction solution was distilled under reduced pressure, and the residue was recrystallized with methanol to obtain 184 mg (0.417 mmol, 49%) of 9-(4-(ethyl(pyridin-3-ylmethyl)amino)phenyl)-6,7-dimethoxynaphtho[2,3-c]furan-1(3H)-one as a title compound.
Mass (M+H+): 455.2
1H-NMR (500 MHz, DMSO-d6): 1.17 (t, 3H), 3.53 (q, 2H), 3.60 (s, 3H), 3.90 (s, 3H), 4.64 (s, 2H), 5.37 (s, 2H), 6.79 (s, 2H), 7.06 (s, 1H), 7.14 (d, 2H), 7.33 (m, 1H), 7.44 (s, 1H), 7.66 (d, 1H), 7.83 (s, 1H), 8.43 (d, 1H), 8.51 (s, 1H).
The compound of Example 255 was synthesized by the same method as that of the compound of Example 254 except for using 6,7-dimethoxy-9-(4-(methylamino)phenyl)naphtho[2,3-c]furan-1(3H)-one instead of 9-(4-(ethylamino)phenyl)-6,7-dimethoxynaphtho[2,3-c]furan-1(3H)-one.
Mass (M+H+): 441.2
1H-NMR (500 MHz, DMSO-d6): 3.07 (s, 3H), 3.60 (s, 3H), 3.90 (s, 3H), 4.68 (s, 2H), 5.38 (s, 2H), 6.86 (d, 2H), 7.04 (s, 1H), 7.16 (d, 2H), 7.33 (m, 1H), 7.44 (s, 1H), 7.65 (d, 1H), 7.84 (s, 1H), 8.44 (d, 1H), 8.51 (s, 1H).
The compound of Example 256 was synthesized by the same method as that of the compound of Example 255 except for using 2-bromodethyl methyl ester instead of 3-bromomethyl pyridine bromate.
Mass (M+H+): 408.21
1H-NMR (500 MHz, DMSO-d6): 2.97 (s, 3H), 3.26 (s, 3H), 3.53 (m, 4H), 3.63 (s, 3H), 3.91 (s, 3H), 5.38 (s, 2H), 6.78 (d, 2H), 7.10 (s, 1H), 7.15 (d, 2H), 7.44 (s, 1H), 7.84 (s, 1H).
The compound of Example 257 was synthesized by the same method as that of the compound of Example 242 except for using iodomethane instead of 1,5-dibromopentane and using 3-bromoaniline instead of 4-bromoaniline.
Mass (M+H+): 350.2
1H-NMR (500 MHz, DMSO-d6): 2.65 (d, 3H), 3.59 (s, 3H), 3.91 (s, 3H), 5.40 (s, 2H), 5.68 (q, 1H), 6.44 (d, 1H), 6.47 (d, 1H), 6.61 (d, 1H), 7.00 (s, 1H), 7.18 (t, 1H), 7.46 (s, 1H), 7.89 (s, 1H).
The compound of Example 258 was synthesized by the same method as that of the compound of Example 242 except for using iodoethane instead of 1,5-dibromopentane and using 3-bromoaniline instead of 4-bromoaniline.
Mass (M+H+): 364.2
1H-NMR (500 MHz, DMSO-d6): 1.13 (t, 1H), 3.01 (q, 2H), 3.59 (s, 3H), 3.91 (s, 3H), 5.40 (s, 2H), 5.58 (m, 1H), 6.46 (d, 2H), 6.63 (d, 1H), 7.00 (s, 1H), 7.17 (t, 1H), 7.46 (s, 1H), 7.89 (s, 1H).
After 20 g (50.98 mmol) of 9-(6-hydroxybenzo[d][1,3]dioxol-5-yl)-6,7-dimethoxynaphtho[2,3-c]furan-1(3H)-one and 6.8 g (152.9 mmol) of sodium hydride (55% mineral oil) were injected into 30 ml of methanol, the resulting mixture was stirred for 30 minutes, and then the pH was adjusted to 1.0 with 20% hydrochloric acid and stirred at room temperature for one hour. The resulting solid was filtered, washed and dried under reduced pressure to obtain 13.2 g (50.7 mmol, 99.4%) of 9-hydroxy-6,7-dimethoxynaphtho[2,3-c]furan-1(3H)-one as an intermediate. After 13.2 g (50.7 mmol) of 9-hydroxy-6,7-dimethoxynaphtho[2,3-c]furan-1(3H)-one, 28.3 g (168.5 mmol) of anhydrous potassium carbonate, and 9.6 ml (153.4 mmol) of iodomethane were slowly added dropwise, the resulting mixture was stirred under reflux for 20 hours. The reactant was cooled, filtered, washed, distilled under reduced pressure, and recrystallized with methanol and purified water to obtain a solid, which was then dried under reduced pressure to obtain 13.43 g (48.9 mmol, 96.5%) of 6,7,9-trimethoxynaphtho[2,3-c]furan-1(3H)-one as an intermediate.
After 13.43 g (48.9 mmol) of 6,7,9-trimethoxynaphtho[2,3-c]furan-1(3H)-one and 26.3 g (146.9 mmol) of N-brorosuccinimide were injected into 30 ml of dimethylformamide, the resulting mixture was stirred for four hours. After an aqueous sodium hydrogen carbonate solution was injected into the reactant, the resulting mixture was stirred to precipitate a solid, which was then filtered and washed. After the resulting solid was stirred in a methanol solvent, the resulting mixture was filtered and washed to obtain 14.91 g (42.2 mmol, 86.2%) of 4-bromo-6,7,9-trimethoxynaphtho[2,3-c]furan-1(3H)-one as an intermediate.
14.91 g (42.2 mmol) of 4-bromo-6,7,9-trimethoxynaphtho[2,3-c]furan-1(3H)-one, 12.87 g (50.6 mmol) of bis(pinacolado)diborane, and 12.43 g (126.6 mmol) of potassium acetate were injected into 60 ml of 1,4-dioxane. The reactant was bubbled with nitrogen gas for ten minutes, after which 1.72 g (4.22 mmol) of Pd(dppf)Cl2 was injected thereto, stirred under reflux for 18 hours, filtered through a celite pad, washed, distilled under reduced pressure, and purified by column chromatography to obtain 11.3 g (28.2 mmol, 67.0%) of 6,7,9-trimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphtho[2,3-c]furan-1(3H)-one as an intermediate.
After 3.56 g (15.0 mmol) of 5-bromo-2,2-difluorobenzo[d][1,3]dioxole, 6.02 g (15.0 mmol) of 6,7,9-trimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphtho[2,3-c]furan-1(3H)-one, and 4.15 g (30.0 mmol) of anhydrous potassium carbonate were injected into 30 ml of 1,4-dioxane, nitrogen bubbling was performed for ten minutes, and then 0.53 g (0.755 mmol) of Pd(PPh3)Cl2 was injected thereto and stirred under reflux for 24 hours. The reactant was cooled, filtered through a celite pad, washed, distilled under reduced pressure, and recrystallized in a methanol solvent to obtain 4.92 g (11.4 mmol, 76.1%) of 4-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-6,7,9-trimethoxynaphtho[2,3-c]furan-1(3H)-one as a title compound.
Mass (M+H+): 431.2
1H-NMR (500 MHz, DMSO-d6): 3.70 (s, 3H), 3.92 (s, 3H), 4.21 (s, 3H), 5.15-5.28 (m, 2H), 6.92 (s, 1H), 7.27 (dd, J=8.3, 1.7 Hz, 1H), 7.55-7.57 (m, 2H), 7.61 (s, 1H).
The compound of Example 260 was synthesized by the same method as that of the compound of Example 259 except for using 8-(5-bromopyridin-2-yl)-1,4-dioxa-8-azaspiro[4.5]decane instead of 5-bromo-2,2-difluorobenzo[d][1,3]dioxole.
Mass (M+H+): 493.2
1H-NMR (500 MHz, DMSO-d6): 1.67 (t, J=5.7 Hz, 4H), 3.67-3.69 (m, 4H), 3.72 (s, 3H), 3.91 (s, 4H), 3.92 (s, 3H), 4.19 (s, 3H), 5.21-5.32 (m, 2H), 7.00-7.01 (m, 2H), 7.60 (s, 1H), 7.61-7.63 (m, 1H), 8.18 (d, J=2.05 Hz, 1H).
The compound of Example 261 was synthesized by the same method as that of the compound of Example 259 except for using 5-bromo-N-butyl-N-methylpyridin-2-amine instead of 5-bromo-2,2-difluorobenzo[d][1,3]dioxole.
Mass (M+H+): 437.0
1H-NMR (500 MHz, DMSO-d6): 0.91 (t, J=7.15 Hz, 3H), 1.32-1.36 (m, 2H), 1.57-1.60 (m, 2H), 3.18 (s, 3H), 3.61 (t, J=7.7 Hz, 2H), 3.75 (s, 3H), 3.92 (s, 3H), 4.21 (s, 3H), 5.22-5.34 (m, 2H), 6.95 (s, 1H), 7.62 (s, 1H), 7.90 (br, 1H), 8.qq (d, J=2.3 Hz, 1H).
The compound of Example 262 was synthesized by the same method as that of the compound of Example 259 except for using 5-bromobenzo[d][1,3]dioxole instead of 5-bromo-2,2-difluorobenzo[d][1,3]dioxole.
Mass (M+H+): 395.0
1H-NMR (500 MHZ, DMSO-d6): 3.69 (s, 3H), 3.92 (s, 3H), 4.19 (s, 3H), 5.14-5.26 (m, 2H), 6.08-6.11 (m, 2H), 6.89 (dd, J=7.7, 1.7 Hz, 1H), 6.99 (s, 1H), 7.04 (d, J=1.7 Hz, 1H), 7.05-7.06 (m, 1H), 7.60 (s, 1H)
The compound of Example 263 was synthesized by the same method as that of the compound of Example 259 except for using 5-bromo-N-methyl-N-(3-(trifluoromethyl)phenyl)pyridin-2-amine instead of 5-bromo-2,2-difluorobenzo[d][1,3]dioxole.
Mass (M+H+): 525.1
1H-NMR (500 MHz, DMSO-d6): 3.51 (s, 3H), 3.74 (s, 3H), 3.92 (s, 3H), 4.20 (s, 3H), 5.18-5.35 (m, 2H), 6.88 (d, J=8.85 Hz, 1H), 6.99 (s, 1H), 7.57-7.59 (m, 1H), 7.61 (s, 1H), 7.67 (t, J=7.7 Hz, 1H), 7.71-7.72 (m, 2H), 7.75 (s, 1H), 8.27 (t, J=1.75 Hz, 1H).
The compound of Example 264 was synthesized by the same method as that of the compound of Example 259 except for using 1-(5-bromopyridin-2-yl)-3-(dimethylamino)-1H-pyrazol-4-carbonitrile instead of 5-bromo-2,2-difluorobenzo[d][1,3]dioxole.
Mass (M+H+): 486.2
1H-NMR (500 MHz, DMSO-d6): 3.04 (s, 6H), 3.71 (s, 3H), 3.93 (s, 3H), 4.23 (s, 3H), 5.19-5.37 (m, 2H), 6.91 (s, 1H), 7.64 (s, 1H), 7.95 (d, J=8.3 Hz, 1H), 8.12 (dd, J=8.55, 2.3 Hz, 1H), 8.57 (d, J=2.25 Hz, 1H), 9.22 (s, 1H).
The compound of Example 265 was synthesized by the same method as that of the compound of Example 259 except for using 5-bromo-N-(2-methoxyethyl)-N-methylpyridin-2-amine instead of 5-bromo-2,2-difluorobenzo[d][1,3]dioxole.
Mass (M+H+): 439.1
1H-NMR (500 MHZ, DMSO-d6): 3.19 (s, 3H), 3.27 (s, 3H), 3.58 (t, J=5.45 Hz, 2H), 3.75 (s, 3H), 3.81-3.83 (m, 2H), 3.93 (s, 3H), 4.21 (s, 3H), 5.22-5.31 (m, 2H), 6.95 (s, 1H), 7.19 (br, 1H), 7.62 (s, 1H), 7.89 (br, 1H), 8.12 (d, J=2.0 Hz, 1H).
The compound of Example 266 was synthesized by the same method as that of the compound of Example 259 except for using (S)-5-bromo-N-(5-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-N-methylpyridin-2-amine instead of 5-bromo-2,2-difluorobenzo[d][1,3]dioxole.
Mass (M+H+): 541.3
1H-NMR (500 MHz, DMSO-d6): 1.94 (m, 2H), 2.92 (m, 2H), 2.97 (m, 2H), 3.26 (s, 3H), 3.73 (s, 3H), 3.74 (s, 3H), 3.92 (s, 3H), 4.19 (s, 3H), 4.83 (m, 1H), 5.20 (d, 2H), 6.69 (d, 1H), 6.73 (d, 1H), 6.80 (d, 1H), 7.04 (s, 1H), 7.07 (m, 1H), 7.61 (s, 1H), 7.62 (d, 1H), 8.16 (s, 1H).
The compound of Example 267 was synthesized by the same method as that of the compound of Example 259 except for using 4-(5-bromopyridin-2-yl)morpholine instead of 5-bromo-2,2-difluorobenzo[d][1,3]dioxole.
Mass (M+H+): 437.2
1H-NMR (500 MHz, DMSO-d6): 3.52 (m, 4H), 3.71 (m, 4H), 3.72 (s, 3H), 3.93 (s, 3H), 4.20 (s, 3H), 5.24 (d, 2H), 6.97 (m, 2H), 7.61 (s, 1H), 7.67 (d, 1H), 8.22 (s, 1H).
The compound of Example 268 was synthesized by the same method as that of the compound of Example 259 except for using 5-bromo-N-(2,3-dihydro-1H-indan-2-yl)-N-methylpyridin-2-amine instead of 5-bromo-2,2-difluorobenzo[d][1,3]dioxole.
Mass (M+H+): 497.2
1H-NMR (500 MHZ, DMSO-d6): 2.95 (s, 3H), 3.10 (m, 2H), 3.18 (m, 2H), 3.75 (s, 3H), 4.00 (s, 3H), 4.20 (s, 3H), 5.27 (d, 2H), 5.53 (br, 1H), 7.02 (s, 1H), 7.15 (s, 1H), 7.16 (s, 1H), 7.24 (s, 1H), 7.25 (s, 1H), 7.62 (s, 1H), 7.79 (br, 1H), 8.19 (d, 1H).
After 2.85 g (7.49 mmol) of 9-(6-hydroxybenzo[d][1,3]dioxol-5-yl)-6,7-dimethoxynaphtho[2,3-c]furan-1(3H)-one, 1.95 g (8.97 mmol) of Boc-L-valine, 0.64 g (5.32 mmol) of DMAP, and 2.15 g (11.21 mmol) of EDC-HCl were injected into 30 ml of dichloromethane, the resulting mixture was stirred at room temperature for two hours. After 20 ml of purified water was injected into the reactant and separated in layers, 20% hydrochloric acid was diluted 50 times and injected in the organic layer, and separated in layers. The organic layer was dried over anhydrous sodium sulfate, filtered, washed, and distilled under reduced pressure. The residue was dissolved in methanol, 5 ml of 35% hydrochloric acid was injected thereto, and the resulting mixture was stirred for three hours. The reactant was distilled under reduced pressure and the residue was dissolved in dichloromethane, after which tert-butylmethyl ester was slowly added dropwise thereto and stirred, and then the resulting solid was filtered and washed to obtain 3.07 g (5.94 mmol, 79.5%) of 6-(6,7-dimethoxy-3-oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl)benzo[d][1,3]dioxol-5-yl L-valinate hydrochloride as a title compound.
Mass (M+H+): 480.2
1H-NMR (500 Mhz, DMSO-d6): δ 0.02-0.17 (m, 6H), 0.85-0.95 (m, 1H), 1.24-1.38 (m, 1H), 3.65 (d, J=2.6 Hz, 3H), 3.90 (d, J=3.15 Hz, 3H), 5.36-5.44 (m, 2H), 6.17-6.19 (m, 2H), 6.83 (d, J=11.75 Hz, 1H), 6.90 (d, J=3.15 Hz, 1H), 7.05 (d, J=41.8 Hz, 1H), 7.46 (s, 1H), 7.95 (d, J=4.3 Hz, 1H), 8.37 (br, 2H)
The compound of Example 270 was synthesized by the same method as that of the compound of Example 269 except for using N-Boc-isoleucine instead of N-Boc-valine.
Mass (M+H+): 494.2
1H-NMR (500 MHz, CDCl3): 3.66-3.73 (m, 2H), 3.81 (s, 3H), 3.84 (s, 3H), 4.01 (s, 3H), 4.04 (s, 3H), 5.98-5.99 (m, 1H), 6.04-6.06 (m, 2H), 6.10 (s, 2H), 6.64 (s, 1H), 6.94 (d=J=3.7 Hz, 1H), 7.14 (s, 2H), 7.74 (s, 1H).
The compound of Example 271 was synthesized by the same method as that of the compound of Ex ample 269 except for using isonicotinic acid instead of N-Boc-valine.
Mass (M+H+): 486.1
1H-NMR (500 MHz, DMSO-d6): 3.67 (s, 3H), 3.84 (s, 3H), 5.39 (s, 2H), 6.19 (s, 2H), 6.90 (s, 1H), 6.98 (s, 1H), 7.19-7.20 (m, 3H), 7.37 (s, 1H), 7.86 (s, 1H), 8.56 (dd, J=4.3, 1.75 Hz, 2H).
The compound of Example 272 was synthesized by the same method as that of the compound of Example 269 except for using nicotinic acid instead of N-Boc-valine.
Mass (M+H+): 486.1
1H-NMR (500 MHz, DMSO-d6): 3.67 (s, 3H), 3.84 (s, 3H), 5.35-5.42 (m, 2H), 6.19 (s, 2H), 6.92 (s, 1H), 6.97 (s, 1H), 7.19 (s, 1H), 7.32-7.35 (m, 1H), 7.37 (s, 1H), 7.70-7.72 (m, 1H), 7.86 (s, 1H), 8.39 (dd, J=1.45, 0.85 Hz, 1H), 8.63 (dd, J=4.85, 1.70 Hz, 1H).
The compound of Example 273 was synthesized by the same method as that of the compound of Example 269 except for using N-Boc-proline instead of N-Boc-valine.
Mass (M+H+): 478.1
1H-NMR (500 MHz, DMSO-d6): 0.21-0.23 (m, 1H), 0.66-0.79 (m, 1H), 1.03-1.07 (m, 1H), 1.41-1.52 (m, 1H), 2.73-2.78 (m, 1H), 2.89-2.91 (m, 1H), 3.65 (d, J=3.7 Hz, 3H), 3.91 (d, J=4.0 Hz, 3H), 4.05-4.19 (m, 1H), 5.40-5.45 (m, 2H), 6.18-6.20 (m, 2H), 6.80 (s, 1H), 6.95 (d, J=4.3 Hz, 1H), 7.01 (s, 1H), 7.04 (s, 1H), 7.49 (d, J=2.85 Hz, 1H), 7.97 (d, J=6.3 Hz, 1H).
The compound of Example 274 was synthesized by the same method as that of the compound of Example 269 except for using acetic acid instead of N-Boc-valine.
Mass (M+H+): 423.1
1H-NMR (500 MHz, DMSO-d6): 1.56 (s, 3H), 3.63 (s, 3H), 3.91 (s, 3H), 5.38-5.46 (m, 2H), 6.14 (d, J=2.0 Hz, 2H), 6.83 (s, 1H), 6.84 (s, 1H), 6.94 (s, 1H), 7.46 (s, 1H), 7.92 (s, 1H).
The compound of Example 275 was synthesized by the same method as that of the compound of Example 269 except for using isobutyric acid instead of N-Boc-valine.
Mass (M+H+): 451.1
1H-NMR (500 MHz, DMSO-d6): 0.25 (d, J=7.15 Hz, 3H), 0.52 (d, J=6.85 Hz, 3H), 2.11-2.15 (m, 1H), 3.64 (s, 3H), 3.90 (s, 3H), 5.41 (s, 2H), 6.15 (s, 2H), 6.81 (s, 1H), 6.88 (s, 1H), 6.92 (s, 1H), 7.45 (s, 1H), 7.92 (s, 1H).
The compound of Example 276 was synthesized by the same method as that of the compound of Example 269 except for using pivalic acid instead of N-Boc-valine.
Mass (M+H+): 465.2
1H-NMR (500 MHz, DMSO-d6): 0.51 (s, 9H), 3.64 (s, 3H), 3.90 (s, 3H), 5.41 (s, 2H), 6.15 (s, 2H), 6.82 (s, 1H), 6.89 (s, 1H), 6.91 (s, 1H), 7.45 (s, 1H), 7.92 (s, 1H).
After 0.6 g (1.58 mmol) of 9-(6-hydroxybenzo[d][1,3]dioxol-5-yl)-6,7-dimethoxynaphtho[2,3-c]furan-1(3H)-one and 0.5 ml (3.48 mmol) of diethylchlorophosphate were injected into 10 ml of dichloromethane in a reactor, the resulting mixture was cooled to 0-5° C., and then 0.44 ml (6.32 mmol) of triethylamine was slowly added dropwise thereto, heated to room temperature, and stirred for 17 hours. After 10 ml of purified water was injected and separated in layers, 10 ml of purified water was injected again, separated in layers, dried over anhydrous sodium sulfate, filtered, washed, and distilled under reduced pressure. The residue was purified by column chromatography to obtain 480 mg (0.92 mmol, 59%) of 6-(6,7-dimethoxy-3-oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl)benzo[d][1,3]dioxol-5-yl diethyl phosphate as a title compound.
Mass (M+H+): 517.1
1H-NMR (500 MHz, DMSO-d6): 0.67 (t, 3H), 0.95 (t, 3H), 3.28 (q, 2H), 3.62 (q, 2H), 3.67 (s, 3H), 3.91 (s, 3H), 5.42 (s, 2H), 6.14 (s, 2H), 6.87 (s, 2H), 6.95 (s, 1H), 7.48 (s, 1H), 7.94 (s, 1H).
After 0.65 g (1.71 mmol) of 9-(6-hydroxybenzo[d][1,3]dioxol-5-yl)-6,7-dimethoxynaphtho[2,3-c]furan-1(3H)-one and 0.3 ml (2.05 mmol) of phenyl dichlorophosphate were injected into 10 ml of dichloromethane in a reactor, the resulting mixture was cooled to 0-5° C., and then 0.7 ml (5.13 mmol) of triethylamine was slowly added dropwise thereto, and heated to room temperature, after which 0.8 ml (8.6 mmol) of isopropylamine was injected and stirred for 17 hours. After 10 ml of purified water was injected and separated in layers, 10 ml of purified water was injected again, separated in layers, dried over anhydrous sodium sulfate, filtered, washed, and distilled under reduced pressure. The residue was purified by column chromatography to obtain 890 mg (1.54 mmol, 90%) of 6-(6,7-dimethoxy-3-oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl)benzo[d][1,3]dioxol-5-yl phenyl isopropylphosphoramidate as a title compound.
Mass (M+H+): 578.1
1H-NMR (500 MHz, DMSO-d6): 0.54 (d, 3H), 0.58 (d, 2H), 2.22 (m, 1H), 3.44 (s, 3H), 3.92 (s, 3H), 5.39 (m, 1H), 5.41 (m, 2H), 6.13 (s, 2H), 6.51 (d, 2H), 6.85 (m, 2H), 7.10 (m, 2H), 7.14 (s, 1H), 7.47 (s, 1H), 7.93 (s, 1H).
The compound of Example 279 was synthesized by the same method as that of the compound of Example 278 except for using 4-(2-aminoethyl)morpholine instead of isopropylamine.
Mass (M+H+): 649.2
1H-NMR (500 MHz, DMSO-d6): 1.88 (m, 2H), 2.04 (m, 4H), 2.22 (m, 2H), 3.44 (m, 4H), 3.48 (s, 3H), 3.92 (s, 3H), 5.36 (m, 1H), 5.40 (dd, 2H), 6.13 (s, 2H), 6.54 (d, 2H), 6.83 (d, 2H), 7.02 (t, 1H), 7.08 (m, 2H), 7.21 (s, 1H), 7.46 (s, 1H), 7.92 (s, 1H).
The compound of Example 280 was synthesized by the same method as that of the compound of Example 279 except for using phenyl phosphonic dichloride instead of phenyl dichlorophosphate.
Mass (M+H+): 633.2
1H-NMR (500 MHz, DMSO-d6): 2.07 (m, 2H), 2.11 (m, 4H), 2.52 (m, 2H), 3.43 (m, 4H), 3.60 (s, 3H), 3.91 (s, 3H), 5.06 (m, 1H), 5.39 (dd, 2H), 6.12 (s, 2H), 6.77 (m, 2H), 6.83 (s, 1H), 6.85 (s, 1H), 7.01 (m, 2H), 7.27 (m, 2H), 7.44 (s, 1H), 7.92 (s, 1H).
The compound of Example 281 was synthesized by the same method as that of the compound of Example 278 except for using phenyl phosphonic dichloride instead of phenyl dichlorophosphate.
Mass (M+H+): 562.2
1H-NMR (500 MHz, DMSO-d6): 0.75 (d, 3H), 0.80 (d, 3H), 2.79 (m, 1H), 3.56 (s, 3H), 3.92 (s, 3H), 5.06 (t, 1H), 5.39 (dd, 2H), 6.11 (d, 2H), 6.75 (s, 1H), 6.81 (m, 3H), 6.99 (m, 2H), 7.20 (s, 1H), 7.27 (t, 1H), 7.44 (s, 1H), 7.91 (s, 1H).
In order to confirm the inhibitory effect of the novel 6,7-dimethoxynaphtho[2,3-c]furan-1(3H)-one derivatives against SARS-COV-2 infection, the Vero cell line was cultured for 24 hours, dosed with example compounds at ten concentrations ranging from 0.1 micro M (micro gram) to 50 micro M, and infected with the SARS-COV-2 provided from the Korea Centers for Disease Control and Prevention (KCDC). Specifically, the Vero cells were seeded at 1.2×104 per well into a 384-well tissue culture plate. On the next day, the compound at a concentration of 50 micro M was serially diluted two-fold to prepare compounds at ten concentrations and treated with Vero cells. Soon after, the cells treated with the compound were infected with SARS-COV-2 (COVID 19) and cultured at 37° C. for 24 hours. Then, the cells were fixed and permeabilized. After that, the cells were treated with anti-SARS-COV-2 Nucleocapsid (N) primary antibody and then stained by treatment with Alexa Fluor 488-conjugated IgG secondary antibody and Hoechst 33342. Fluorescent expression was obtained using an Operetta large image analyzer (Perkin Elmer). The resulting image were used with Columbus software to calculate the percentage of infected cells and measure the inhibitory efficacy of the drug, which were then summarized in Table 2, and the response curve and 50% inhibitory effect (IC50) values according to the drug concentration are derived with XLFit (IDBS) software, and the results and cytotoxicity (CC50) of the test substances are summarized in Table 1 and
As confirmed in Table 1 and
In order to confirm the inhibitory effect of the novel 6,7-dimethoxynaphtho[2,3-c]furan-1(3H)-one derivatives against IL-5 expression, Th2 cells were cultured using mouse splenocytes, and dosed with the test drugs prepared in Examples 1 to 95 at a concentration of 1 nM, so that IL-5 was measured through an ELISA test. Specifically, after spleens were collected from Balb/C mice, CD4+ T cells were isolated therefrom and were seeded at 1-2×106 per well into a 48-well tissue culture plate coated with anti-CD3 (5 ug/ml) and anti-CD28 (1 ug/ml). At this time, the culture medium was incubated with IL-2 (20 ng/ml), IL-4 (100 ng/ml), anti-IFNγ (10 ug/ml), anti-IL12 (10 ug/ml), and a derivative of 1 nM for two days, transferred to a new tissue culture plate, and further cultured for three days to induce differentiation into Th2 cells. After replacing with a new medium containing anti-IFNγ (10 ug/ml), anti-IL12 (10 ug/ml) and a derivative of 1 nM, polarization of Th2 cells was induced using PMA and A23187. After two days of culture, the cells were centrifuged and the culture medium was taken to perform IL-5 ELISA. IL-5 ELISA was performed according to the test method of the kit manufacturer. As a result, an inhibitory ratio of IL-5 expression was derived with Th0 cells, which did not induce Th2 differentiation, as 100% inhibition and with Th2 cells, which were not treated with the novel derivative, as a control for 0% inhibition.
As confirmed in Table 2, it was found that the Example compounds show excellent inhibitory activity against IL-5 expression. As a result, it was confirmed that the Example compounds show excellent an anti-allergic effect and an asthma treatment effect.
In order to confirm the inhibitory effect of the novel 6,7-dimethoxynaphtho[2,3-c]furan-1(3H)-one derivatives against IL-4 expression, the RBL-2H3 cell line was used to measure the ability for inhibiting IL-4 secretion. The RBL-2H3 cell line was purchased from the American Type Culture Collection (ATCC #CRL-2256). The cells were diluted at a concentration of 1×106 cells/ml in RPMI medium containing 15% fetal bovine serum (FBS) and antibiotics (penicillin at 100 U/mL, streptomycin at 100 μg/mL), distributed at 200 μl/well in a 48 well plate, and cultured in a 37° C., 5% CO2 incubator for 24 hours. In 24 hours later, the cells were pre-treated one hour before with a test drug and AS1517499 (STAT6 inhibitor) as a control drug, and treated with 1 uM of A23187 for six hours to induce an immune response, after which a group not containing the drug was used as a control. In order to measure a secretion level of cytokine IL-4, the medium was collected from the well plate and centrifuged at 125×g for five minutes to remove a residue, and 100 μl of the medium was used to measure an amount of IL-4 secreted from the cells by using IL-4 enzyme-linked immunosorbent assay (ELISA, Komabiotech). A degree of inhibition of cell secretion by the drug was calculated using [Equation 1] below.
First of all, 288 kinds of materials were treated at a single concentration of 10 uM so as to select 60 kinds of materials which inhibit secretion of IL-4 by 75% or more (
After that, a repeated experiment and a two-concentration (10, 3 uM) test were performed using the selected 60 kinds of materials so as to select the final eight kinds, and the IC50 value was calculated and shown in Table 3.
In addition, the IL-4 secretion inhibitory activity (%) in RBL-2H3 cells upon 10, 3 uM treatment is shown in
In order to confirm the inhibitory effect of the novel 6,7-dimethoxynaphtho[2,3-c]furan-1(3H)-one derivatives against infection with influenza virus standard strain H1N1, MDCK cell line was cultured for 24 hours, and then the example compounds were administered at five concentrations ranging from 0.01 micro M to 100 micro M, and infected with A/Puerto Rico/08/1934 (A/PR/8/34; H1N1). Specifically, the MDCK cells were seeded at 2.0×104 per well into a 96-well tissue culture plate. On the next day, the compound at a concentration of 100 micro M was serially diluted ten-fold to prepare compounds at five concentrations and treated with the MDCK cells. Soon after, the cells treated with the compound were infected with H1N1 and cultured at 37° C. for 66 hours. After that, the cells were treated with EZ-CYTOX and the survival of living cells was measured at UV450 nm in three to four hours later.
The results and the 50% half maximal effective concentration (EC50) and cytotoxicity (CC50) of the test materials are summarized in Table 4.
As confirmed in Table 4, it was found that the example compounds show excellent inhibitory activity against influenza virus standard strain H1N1. Thus, it is confirmed that the example compounds exhibit an excellent anti-viral effect against influenza virus standard strain H1N1. From this, it is confirmed that the compounds may exhibit excellent preventive or therapeutic effects against an influenza virus infection disease.
In order to confirm the inhibitory effect of the novel 6,7-dimethoxynaphtho[2,3-c]furan-1(3H)-one derivatives against infection with dengue virus, Vero E6 cell line was cultured for 24 hours, and then the compound of Example 221 was administered at eight concentrations ranging from 0.0625 micro M to 3 micro M, and infected with dengue virus. Specifically, the Vero cells were seeded at 2.5×104 per well into a 96-well tissue culture plate. On the next day, a compound having a concentration of 0.0625 micro M was prepared from a compound having a concentration of 3 micro M and treated to Vero E6 cells, and then the cells treated with the compound were immediately infected with dengue virus (0.01 MOI) and cultured at 37° C. for five days.
In addition, in order to confirm the inhibitory effect against infection with Zika virus, Vero cell line was cultured for 24 hours, and then the compound of Example 221 was administered at eight concentrations ranging from 0.25 micro M to 5 micro M, and infected with Zika virus. Specifically, the Vero cells were seeded at 2.5×104 per well into a 96-well tissue culture plate. On the next day, a compound having a concentration of 0.25 micro M was prepared from a compound having a concentration of 5 micro M and treated to Vero cells, and then the cells treated with the compound were immediately infected with Zika virus (0.02 MOI) and cultured at 37° C. for five days.
After that, the cells were treated with EZ-CYTOX and the survival of living cells was measured at UV450 nm in three to four hours later.
The results and the cytotoxicity (CC50) of the test materials are summarized in Table 5.
It was confirmed that the compound of Example 221 protects from cytopathic effects induced by dengue virus and Zika virus, and this result suggests that the compound of Example 221 may be an anti-Flavivirus agent.
In order to confirm the inhibitory effect of the novel 6,7-dimethoxynaphtho[2,3-c]furan-1(3H)-one derivatives against virus infection with severe fever with thrombocytopenia syndrome (hereinafter, SFTS), the Vero cell line was cultured for 24 hours, dosed with example compounds at ten concentrations ranging from 0.5 micro M (micro gram) to 50 micro M, and infected with SFTS virus (KADGH; NCCP43261). Specifically, the Vero cells were seeded at 1.2×104 per well into a 384-well tissue culture plate. On the next day, the compound at a concentration of 50 micro M was serially diluted two-fold to prepare compounds at ten concentrations and treated with Vero cells. Soon after, the cells treated with the compound were infected with SFTS virus and cultured at 37° C. for 24 hours. Then, the cells were fixed and permeabilized. After that, the cells were treated with an anti-Ab10 primary antibody and then stained by treatment with an goat anti-Human IgG (H+L) secondary antibody and Alexa Fluor 488. Fluorescent expression was obtained using an Operetta large image analyzer (Perkin Elmer). The response curve and 50% inhibitory effect (IC50) values according to the drug concentration are derived with XLFit (IDBS) software, and the results and cytotoxicity (CC50) of the test substances are summarized in Table 6.
As confirmed in Table 6, it was found that the example compounds show excellent inhibitory activity against SFTS virus as well as low toxicity. Thus, it is confirmed that the example compounds exhibit an excellent anti-viral effect against SFTS virus, and it is confirmed that the compounds may exhibit excellent preventive or therapeutic effects against a SFTS virus infection disease.
In order to confirm an inhibitory effect of novel 6, 7-dimethoxynaphtho[2,3-c]furan-1(3H)-one derivatives against inflammation, splenocytes were isolated by using a spleen which is isolated from Balb/c mice. The isolated splenocytes were diluted at a concentration of 5×106 cells/mL in RPMI medium containing 10% fetal bovine serum (FBS) and antibiotics (penicillin at 100 U/mL, streptomycin at 100 μg/mL), distributed at 500 μl/well in a 24 well plate, and cultured in a 37° C., 5% CO2 incubator for 48 hours. When splenocytes were distributed, an immune reaction was induced by treating with 5 μg/mL of Concanavalin A, and at this time, the splenocytes were treated with the materials selected in Experimental Example 3 at a concentration of 1 uM. First, in order to measure Th2 cytokines, the medium was collected from the 24-well plate, and only the supernatant was separated through centrifugation at 800×g for five minutes, after which 100 μl of the supernatant per well was used in an enzyme-linked immunosorbent assay (ELISA, Komabiotech) experiment so as to measure a degree of secretion of Th2 cytokines IL-4 and IL-5. A degree of inhibition against secretion of cytokines by the test material was calculated using [Equation 2] below, and the measurement results are shown in Table 7.
As confirmed in Table 7, the mouse splenocytes were treated with the derivatives at a concentration of 1 uM, and thus it was confirmed that IL-4 and IL-5 secretion are remarkably inhibited in most of the experimental groups compared to the normal group. In particular, it was observed that the secretion of the cytokine IL-4 is relatively low compared to IL-5. From the above results, it is considered that the novel 6,7-dimethoxynaphtho[2,3-c]furan-1(3H)-one derivatives have a medicinal effect on respiratory diseases such as asthma as well as an anti-inflammatory effect through the inhibition of actual cytokines.
The novel 6,7-dimethoxynaphtho[2,3-c]furan-1(3H)-one derivatives were used to measure changes in several indicators related to asthma, a type of respiratory disease, in the Balb/c mouse asthma model. In detail, five-week-old Balb/c mice were purchased and acclimated for one week, after which the mice were sensitized systemically by intraperitoneal injection with 0.1% ovalbumin (OVA 1 mg/mL, Al(OH)3 20 mg/mL) at 100 μl/mouse on days 0 and 14 from a week after the acclimation. From a week (day 21) after a final systemic sensitization, the compound of Example 73 was orally administered everyday at 10 mg/kg to mice for ten days, and dexamethasone was intraperitoneally administered at 1 mg/kg as a positive control group. In one hour later, 0.2% ovalbumin solution was sprayed with a nebulizer (PARIBoy SX, GmbH, Germany) so as to be inhaled for one hour. In five hours after the final sensitization (day 30), an autopsy was performed, and 1 mL of phosphate buffer solution was flowed through a tracheotomy to collect a bronchoalveolar lavage fluid (BALF). The collected BALF was centrifuged at 3000 rpm for ten minutes, and the supernatant was used to measure bioactive materials (IL-4, IL-5), and pellets were used to measure the number of inflammatory cells. In addition, an IgE concentration in the isolated BALF was measured using IgE enzyme-linked immunosorbent assay (ELISA, Komabiotech), and IL-4 and IL-5 were measured using their respective enzyme-linked immunosorbent assay (ELISA, IL-4: Enzo #ADI-900-043, IL-5: R&D system #M5000).
The results are shown in Table 8 and
## p < 0.01 vs. Induced
In addition, the BALF pellets were re-dissolved by adding 0.5 mL of phosphate buffer solution, and then 0.1 mL for each thereof was added to a 96-well plate and centrifuged at 800 rpm for five minutes to attach cells to the bottom (three wells per sample). Then, the cells were stained with Diff Quik staining solution (Sysmex) and the number of cells was measured with a flow cytometer.
The results were shown in
As can be seen in Table 8,
| Number | Date | Country | Kind |
|---|---|---|---|
| 10-2021-0041955 | Mar 2021 | KR | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/IB2022/052939 | 3/30/2022 | WO |
