WO2023043208A1 - Novel 2-aminobenzothiazole derivative and preparation method therefor - Google Patents

Novel 2-aminobenzothiazole derivative and preparation method therefor Download PDF

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WO2023043208A1
WO2023043208A1 PCT/KR2022/013755 KR2022013755W WO2023043208A1 WO 2023043208 A1 WO2023043208 A1 WO 2023043208A1 KR 2022013755 W KR2022013755 W KR 2022013755W WO 2023043208 A1 WO2023043208 A1 WO 2023043208A1
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trans
cyclohexyl
thiazol
amine
benzo
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PCT/KR2022/013755
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French (fr)
Korean (ko)
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윤화영
정지영
곽진숙
김민정
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부산대학교 산학협력단
고신대학교 산학협력단
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Priority claimed from KR1020220115668A external-priority patent/KR20230040292A/en
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Publication of WO2023043208A1 publication Critical patent/WO2023043208A1/en

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D277/82—Nitrogen atoms

Definitions

  • the present invention provides a novel 2-aminobenzothiazole derivative and a method for preparing the same.
  • eIFs eukaryotic initiation factors
  • mRNAs ribosome subunits
  • initiator tRNAs ribosome subunits
  • 4E-BP eIF4E-binding proteins
  • ternary complex composed of eIF2, GTP, and initiator methionine tRNA (Met-tRNAi).
  • the ternary complex plays an important role in carrying out normal cell functions, and when there is an abnormality in its regulation, it is known to cause various diseases and is drawing attention as a target for the development of new treatments.
  • eIF2 ⁇ Since eIF2 ⁇ has the characteristic of being overexpressed during cell cancerization and regulates intracellular protein synthesis through downstream signaling, phosphorylation of eIF2 ⁇ can be regarded as a cancer cell-specific metabolic control target. It has been reported from a recent study that an anticancer effect can be induced by promoting phosphorylation of eIF2 ⁇ , and it was confirmed that the compound having a urea moiety developed by the Halperin research team has excellent eIF2 ⁇ phosphorylation efficacy and anticancer activity. However, there has been no report of a small molecule candidate with eIF2 ⁇ phosphorylation efficacy that has entered the clinical trial stage to date. Therefore, it is believed that the need for additional research is sufficient, and development of metabolic cancer drugs using this mechanism is in progress.
  • An object of the present invention is to provide a compound selected from 2-aminobenzothiazole derivative compounds, pharmaceutically acceptable salts thereof, solvates thereof, and stereoisomers thereof.
  • Another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer containing the compound as an active ingredient.
  • Another object of the present invention is to provide a pharmaceutical composition for anticancer agents containing the compound as an active ingredient.
  • Another object of the present invention is to provide a method for inhibiting cancer cell metabolism comprising administering the compound.
  • Another object of the present invention is to provide a health functional food composition for preventing or improving cancer containing the compound as an active ingredient.
  • the present invention provides a compound selected from a 2-aminobenzothiazole derivative compound represented by Formula 1 below, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof.
  • R 1 and R 2 may each be the same or different, and hydrogen (H), halogen, trifluoromethyl (CF 3 ), nitro (NO 2 ), (C1 ⁇ C4) alkoxy, trifluoromethoxy (OCF 3 ), cyano (CN), nitro (NO 2 ), (C1 ⁇ C4) alkylsulfonyl and aminosulfonyl (SO 2 NH 2 ).
  • the present invention provides a pharmaceutical composition for preventing or treating cancer containing the compound as an active ingredient.
  • the present invention provides a pharmaceutical composition for anticancer agents containing the compound as an active ingredient.
  • the present invention provides a method for inhibiting cancer cell metabolism comprising administering the compound.
  • the present invention provides a health functional food composition for preventing or improving cancer containing the compound as an active ingredient.
  • the present invention relates to a compound selected from the group consisting of a 2-aminobenzothiazole derivative compound, a pharmaceutically acceptable salt thereof, a solvate thereof, and a stereoisomer thereof, which exhibit anticancer activity through phosphorylation of eIF2 ⁇ . It can be used as a pharmaceutical and health functional food composition for the prevention and improvement of rare cancers such as breast cancer, brain tumor, and sarcoma, as well as leukemia as a metabolizing cancer agent, as it shows cancer cell growth inhibitory effect and in vitro.
  • Figure 1 shows the N- (4-aryloxycyclohexyl)benzothiazol-2-amine [ N- (4-aryloxycyclohexyl)benzothiazole-2-amine] derivative design strategy.
  • Figure 2 shows a synthesis example of N- (4-aryloxycyclohexyl)benzothiazole-2-amine [ N- (4-aryloxycyclohexyl)benzothiazole-2-amine] derivative.
  • the present invention provides a compound selected from a 2-aminobenzothiazole derivative compound represented by Formula 1 below, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof.
  • R 1 and R 2 may each be the same or different, and hydrogen (H), halogen, trifluoromethyl (CF 3 ), nitro (NO 2 ), (C1 ⁇ C4) alkoxy, trifluoromethoxy (OCF 3 ), cyano (CN), nitro (NO 2 ), (C1 ⁇ C4) alkylsulfonyl, and aminosulfonyl (SO 2 NH 2 ).
  • R 1 in Formula 1 is hydrogen (H), fluorine (F), chlorine (Cl), trifluoromethyl (CF 3 ), nitro (NO 2 ) and (C1 ⁇ C2) is selected from the group consisting of alkoxy, R 2 is chlorine (Cl), trifluoromethyl (CF 3 ), trifluoromethoxy (OCF 3 ), cyano (CN), nitro ( NO 2 ), (C1 ⁇ C2)alkylsulfonyl, and aminosulfonyl (SO 2 NH 2 ).
  • R 1 in Formula 1 is hydrogen (H), fluorine (F), chlorine (Cl), trifluoromethyl (CF 3 ), nitro (NO 2 ) and methoxy (OMe),
  • R 2 is chlorine (Cl), trifluoromethyl (CF 3 ), trifluoromethoxy (OCF 3 ), cyano (CN), nitro ( NO 2 ), methylsulfonyl (SO 2 Me) and aminosulfonyl (SO 2 NH 2 ).
  • the 2-aminobenzothiazole derivative compound is N -((1,4-trans)-4-(4-chlorophenoxy)cyclohexyl)benzo[ d ]thiazol-2-amine [ N -((1,4- trans )-4-(4-Chlorophenoxy)cyclohexyl)benzo[ d ]thiazol-2-amine], N -((1,4-trans)-4-(4-(trifluoro) Romethyl)phenoxy)cyclohexyl)benzo[ d ]thiazol-2-amine [ N -((1,4- trans )-4-(4-(Trifluoromethyl)phenoxy)cyclohexyl)benzo[d]thiazol-2 -amine], N -((1,4-trans)-4-(4-(trifluoromethoxy)phenoxy)cyclohexyl)benzo[ d ]thiazol-2-amine [ N -((1,4 - trans )
  • the present invention provides a pharmaceutical composition for preventing or treating cancer containing the compound as an active ingredient.
  • the compound according to the present invention can promote phosphorylation of eukaryotic translation initiation factor 2 ⁇ (eIF2 ⁇ ).
  • eIF2 ⁇ eukaryotic translation initiation factor 2 ⁇
  • the cancer may be blood cancer, breast cancer, sarcoma cancer or brain cancer, but is not limited thereto.
  • the present invention provides a pharmaceutical composition for anticancer agents containing the compound as an active ingredient.
  • the present invention provides a method for inhibiting cancer cell metabolism comprising administering the compound.
  • the compound can promote phosphorylation of eukaryotic translation initiation factor 2 ⁇ (eIF2 ⁇ ) to block metabolism of cancer cells and kill them.
  • eIF2 ⁇ eukaryotic translation initiation factor 2 ⁇
  • the metabolic anti-cancer agent is called the 4th generation anti-cancer agent following chemical anti-cancer agent, targeted anti-cancer agent, and immuno-anticancer agent, and blocks the metabolic activity of cancer cells that actively cause cell division compared to normal cells. It is an anticancer agent that selects and kills only cancer cells, and in particular, it lowers the metabolism of cancer cells by more than 50% and has little damage to normal cells in the process of suppressing cancer cell growth.
  • the pharmaceutically acceptable salt is composed of sodium salt, potassium salt, calcium salt, lithium salt, magnesium salt, cesium salt, aminium salt, ammonium salt, triethylaminium salt and pyridinium salt. It may be one or more basic salts selected from the group, but is not limited thereto.
  • the pharmaceutically acceptable salts are hydrochloric acid, hydrobromic acid, sulfuric acid, sulfurous acid, phosphoric acid, citric acid, acetic acid, maleic acid, fumaric acid, glucoic acid, methanesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, oxalic acid, malonic acid , It may be one or more acid salts selected from the group consisting of glutaric acid, acetic acid, glycolic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid, citric acid and aspartic acid, but Note that it is not limited.
  • the pharmaceutical composition of the present invention may include pharmaceutically acceptable carriers, excipients or diluents in addition to the components described above.
  • the carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • the pharmaceutical composition of the present invention can be formulated and used in the form of oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories or sterile injection solutions according to conventional methods. . Specifically, when formulated, it may be prepared using diluents or excipients such as commonly used fillers, weighting agents, binders, wetting agents, disintegrants, and surfactants. Solid preparations for oral administration include, but are not limited to, tablets, pills, powders, granules, capsules, and the like.
  • Such a solid preparation may be prepared by mixing at least one or more excipients, for example, starch, calcium carbonate, sucrose, lactose, gelatin, etc., in addition to the active ingredient.
  • excipients for example, starch, calcium carbonate, sucrose, lactose, gelatin, etc.
  • lubricants such as magnesium stearate and talc may also be used.
  • It may be prepared by adding various excipients, for example, wetting agents, sweeteners, aromatics, and preservatives, in addition to liquids and liquid paraffin for oral use.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized formulations and tablets.
  • Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspending agents.
  • As a base for suppositories Witepsol, Macrosol, Tween 61, cacao butter, laurin paper, glycerogelatin, and the like may be used.
  • the pharmaceutical composition of the present invention may be prepared as an oral or parenteral formulation, and may be administered by oral, intravenous, intraventricular, intradermal, intramuscular, intraperitoneal, nasal or epidural route, but is limited thereto. indicate that it is not
  • a suitable dosage of the pharmaceutical composition of the present invention varies depending on the condition and weight of the patient, the severity of the disease, the type of drug, and time, but can be appropriately selected by a person skilled in the art, and the daily dosage of the composition is preferably 0.01 It is mg/kg to 100 mg/kg, and it can be divided and administered once a day to several times as needed.
  • the present invention provides a health functional food composition for preventing or improving cancer containing the compound as an active ingredient.
  • the health functional food composition includes various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, colorants and enhancers (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts , organic acids, protective colloidal thickeners, pH regulators, stabilizers, preservatives, glycerin, alcohol, carbonation agents used in carbonated beverages, and the like.
  • it may contain fruit flesh for the manufacture of natural fruit juice, synthetic fruit juice and vegetable beverages. These components may be used independently or in combination.
  • the health functional food composition is any one form of meat, sausage, bread, chocolate, candy, snack, confectionery, pizza, ramen, gum, ice cream, soup, beverage, tea, functional water, drink, alcohol and vitamin complex can be
  • the health functional food composition may further contain food additives, and the suitability as a food additive is determined according to the general rules of the Food Additive Code and general test methods approved by the Ministry of Food and Drug Safety, unless otherwise specified. It is judged according to the relevant standards and standards.
  • Items listed in the Food Additive Code for example, chemical synthetic products such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamic acid, natural additives such as persimmon pigment, licorice extract, crystalline cellulose, goreng pigment, guar gum, and L-glutamic acid and mixed formulations such as sodium formulations, noodle-added alkali formulations, preservative formulations, and tar color formulations.
  • chemical synthetic products such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamic acid
  • natural additives such as persimmon pigment, licorice extract, crystalline cellulose, goreng pigment, guar gum, and L-glutamic acid
  • mixed formulations such as sodium formulations, noodle-added alkali formulations, preservative formulations, and tar color formulations.
  • the content of the composition according to the present invention added to food in the process of preparing the health functional food composition can be appropriately increased or decreased as needed.
  • the phospho-eIF2 ⁇ (Ser51) Sandwich ELISA Kit #7286 was used.
  • the K562 cell line was cultured in serum-free RPMI medium at 37°C and 5% CO 2 .
  • Cells were treated with compounds 1 to 36 at a concentration of 10 ⁇ M. After 6 hours of compound treatment, the cells were lysed with the lysis buffer included in the kit, and 50 ⁇ g of protein was quantified. After that, an ELISA assay was performed according to the manufacturer's protocol to obtain absorbance. The absorbance for each obtained compound was normalized to a value set to 1 for control (DMSO-treated). The results are shown in Table 1.
  • CCK-8 assay (cell counting kit-8 assay, Dojindo, Kumamoto, Japan) was performed.
  • the K562 cell line was cultured in RPMI medium supplemented with 10% FBS and 1% ABAM at 37°C and 5% CO 2 .
  • the cells were treated with compounds 1, 13, 14, 19 to 30, 32, 34 and 36 at concentrations of 0 ⁇ M, 1.25 ⁇ M, 2.5 ⁇ M, 5 ⁇ M, 10 ⁇ M and 20 ⁇ M, respectively. After culturing for 3 days, 10 ⁇ L of CCK-8 solution was treated, followed by culturing for 4 hours. Then, the absorbance at 450 nm was measured to obtain the IC 50 value of each compound. The results are shown in Table 2.

Abstract

The objective of the present invention is to provide a novel derivative that exhibits an anticancer activity through eIF2α phosphorylation efficacy through the strategy of substituting a urea core with a 2-aminobenzothiazole core in which a bioisostere of urea exists in the structure. Benzothiazole has a specific structure in which a 5-membered heterocyclic ring containing a sulfur atom and a nitrogen atom is fused to a phenyl ring. A core having various amine groups can be introduced into a precursor having a chlorine group introduced at position 2 of benzothiazole through a nucleophilic aromatic substitution reaction. The present invention provides a derivative having a novel structure in which a phenoxycycloamine core having various substituents is introduced at position 2 of benzothiazole. The synthesized novel derivative exhibits an eIF2α phosphorylation effect and a cancer cell proliferation inhibitory activity in vitro.

Description

신규 2-아미노벤조티아졸 유도체 및 이의 제조방법Novel 2-aminobenzothiazole derivatives and their preparation method
본 발명은 신규 2-아미노벤조티아졸 유도체 및 이의 제조방법을 제공한다.The present invention provides a novel 2-aminobenzothiazole derivative and a method for preparing the same.
단백질 합성의 조절, 특히 개시단계에서의 조절은 세포의 성장, 증식, 분화 그리고 사멸에 아주 중요한 역할을 한다. 진핵세포에서는 여러 가지의 진핵생물개시인지 (eukaryotic initiation factor; eIF) 가 존재하며, 이는 리보솜 서브유닛 (ribosome subunits), mRNA, 그리고 개시 tRNA (initiator tRNA) 가 적절하게 단백질 합성을 개시하게끔 작용한다. 이런 작용을 위해서는 많은 인자들의 복합체가 단계적으로 결합하여야 한다. 복합체를 이루는 인자 중 대표적으로 eIF4E와 eIF4G가 중요한 역할을 한다. eIF4E와 eIF4G는 비교적 작은 크기의 단백질인 4E-BP (eIF4E-binding proteins) 들에 의해 조절이 된다. 최근 발표된 연구로부터, 4E-BP의 기능을 대신하여 eIF4E와 eIF4G의 결합을 방해하는 저해제가 종양유발 단백질의 세포내 합성을 억제한다는 결과가 있다.Regulation of protein synthesis, especially at the initiation stage, plays a very important role in cell growth, proliferation, differentiation and death. In eukaryotes, several eukaryotic initiation factors (eIFs) exist, which function to properly initiate protein synthesis by ribosome subunits, mRNAs, and initiator tRNAs. For this action, a complex of many factors must combine step by step. Representatively among the factors constituting the complex, eIF4E and eIF4G play an important role. eIF4E and eIF4G are regulated by 4E-BP (eIF4E-binding proteins), which are relatively small proteins. From a recently published study, there is a result that an inhibitor that interferes with the binding of eIF4E and eIF4G instead of the function of 4E-BP inhibits the intracellular synthesis of tumor-inducing proteins.
이처럼, 단백질 합성의 미세한 조절로 종양을 억제하는 연구가 최근 각광받고 있다. 이를 설명할 수 있는 가설로는 “약한 (Weak)” mRNA “강한 (strong)” mRNA 가설이 있다. 종양유발 단백질들은 소위 말하는 “약한” mRNA에 의해 코딩이 되며, 그 합성을 선택적으로 억제하게 되면 정상세포에는 큰 영향을 주지 않으면서 암세포를 사멸시키는 효과를 볼 수 있을 것이라는 가설이며, 이를 뒷받침하는 수많은 연구 결과들이 있다. As such, research on suppressing tumors through fine control of protein synthesis has recently been in the limelight. As a hypothesis that can explain this, there is a “weak” mRNA “strong” mRNA hypothesis. It is hypothesized that tumor-inducing proteins are coded by so-called “weak” mRNAs, and that selective inhibition of their synthesis will have the effect of killing cancer cells without significantly affecting normal cells. There are research results.
단백질 합성의 개시에서 또 하나의 중요한 단계로 eIF2, GTP, 그리고 개시 메티오닌 tRNA (initiator methionine tRNA; Met-tRNAi)로 구성되는 삼성분복합체 (ternary complex)의 형성이 있다. 삼성분복합체는 정상적인 세포 기능을 수행하는데 중요한 역할을 하며, 그 조절에 이상이 있을 경우 여러 가지 질병을 유발하는 것으로 알려져 새로운 치료제 개발의 타겟으로 주목받고 있다.Another important step in the initiation of protein synthesis is the formation of a ternary complex composed of eIF2, GTP, and initiator methionine tRNA (Met-tRNAi). The ternary complex plays an important role in carrying out normal cell functions, and when there is an abnormality in its regulation, it is known to cause various diseases and is drawing attention as a target for the development of new treatments.
세포는 다양한 스트레스 상황에 직면하게 될 때 통합 스트레스 반응 (integrated stress response) 경로를 활성화하여 세포 내 변화에 대응하기 위해 단백질의 합성을 조절한다. 진핵생물에서 통합 스트레스 반응은 진핵생물 번역 개시 인자 (eukaryotic translation initiation factor 2α,eIF2α)의 인산화로 수렴되며, 이는 스트레스를 감지하는 4종의 eIF2α 카이네이즈(HRI, PERK, GCN2, PKR)의 활성화로 인해 매개된다. eIF2α의 인산화가 일어나면 전반적인 단백질 합성은 저해되고, 역설적으로 스트레스에 대처하는 인자인 ATF4 등은 발현이 증가하여 결과적으로 세포의 정상 상태로의 회복을 촉진한다. eIF2α는 세포의 암화 과정에서 과발현 되는 특성을 지니며, 하부 신호전달을 통해 세포 내 단백질의 합성을 조절하므로, eIF2α의 인산화를 암세포 특이적인 대사 조절 표적으로 간주할 수 있다. 최근의 연구로부터 eIF2α의 인산화를 촉진하여 항암 효과를 유도할 수 있음이 보고되었으며, Halperin 연구팀이 개발한 유레아 모핵을 지닌 화합물의 eIF2α 인산화 효능 및 항암 활성이 우수함을 확인하였다. 하지만, 현재까지 임상시험 단계로 진입한 eIF2α 인산화 효능이 있는 저분자 후보물질은 보고된 바가 없다. 따라서 추가 연구의 필요성이 충분하고 사료되며, 이 기전을 이용한 대사항암제를 개발이 진행 중이다.When cells are faced with various stress situations, they activate integrated stress response pathways to regulate protein synthesis to respond to intracellular changes. In eukaryotes, the integrated stress response converges on the phosphorylation of eukaryotic translation initiation factor 2α and eIF2α, which is due to the activation of four stress-sensing eIF2α kinases (HRI, PERK, GCN2, and PKR). mediated When eIF2α phosphorylation occurs, overall protein synthesis is inhibited, and paradoxically, the expression of ATF4, a factor that copes with stress, and the like increases, thereby promoting the recovery of cells to a normal state. Since eIF2α has the characteristic of being overexpressed during cell cancerization and regulates intracellular protein synthesis through downstream signaling, phosphorylation of eIF2α can be regarded as a cancer cell-specific metabolic control target. It has been reported from a recent study that an anticancer effect can be induced by promoting phosphorylation of eIF2α, and it was confirmed that the compound having a urea moiety developed by the Halperin research team has excellent eIF2α phosphorylation efficacy and anticancer activity. However, there has been no report of a small molecule candidate with eIF2α phosphorylation efficacy that has entered the clinical trial stage to date. Therefore, it is believed that the need for additional research is sufficient, and development of metabolic cancer drugs using this mechanism is in progress.
본 발명의 목적은 2-아미노벤조티아졸 유도체 화합물, 이의 약학적으로 허용가능한 염, 이의 용매화물 또는 이의 입체이성질체에서 선택된 화합물을 제공하는 데에 있다.An object of the present invention is to provide a compound selected from 2-aminobenzothiazole derivative compounds, pharmaceutically acceptable salts thereof, solvates thereof, and stereoisomers thereof.
본 발명의 또 다른 목적은 상기 화합물을 유효성분으로 함유하는 암 예방 또는 치료용 약학조성물을 제공하는 데에 있다.Another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer containing the compound as an active ingredient.
본 발명의 또 다른 목적은 상기 화합물을 유효성분으로 함유하는 대사항암제용 약학조성물을 제공하는 데에 있다.Another object of the present invention is to provide a pharmaceutical composition for anticancer agents containing the compound as an active ingredient.
본 발명의 또 다른 목적은 상기 화합물을 투여하는 단계를 포함하는 암세포 대사 억제방법을 제공하는 데에 있다.Another object of the present invention is to provide a method for inhibiting cancer cell metabolism comprising administering the compound.
본 발명의 또 다른 목적은 상기 화합물을 유효성분으로 함유하는 암 예방 또는 개선용 건강기능식품 조성물을 제공하는 데에 있다.Another object of the present invention is to provide a health functional food composition for preventing or improving cancer containing the compound as an active ingredient.
상기 목적을 달성하기 위하여, 본 발명은 하기 화학식 1로 표시되는 2-아미노벤조티아졸 유도체 화합물, 이의 약학적으로 허용가능한 염, 이의 용매화물 또는 이의 입체이성질체에서 선택된 화합물을 제공한다.In order to achieve the above object, the present invention provides a compound selected from a 2-aminobenzothiazole derivative compound represented by Formula 1 below, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof.
[화학식 1][Formula 1]
Figure PCTKR2022013755-appb-img-000001
Figure PCTKR2022013755-appb-img-000001
상기 화학식 1에서, In Formula 1,
R1 및 R2는 각각 동일하거나 다를 수 있고, 수소 (H), 할로겐, 트리플루오로메틸 (CF3), 나이트로 (NO2), (C1~C4)알콕시, 트리플루오로메톡시 (OCF3), 시아노 (CN), 나이트로 (NO2), (C1~C4)알킬술포닐 및 아미노술포닐 (SO2NH2)로 이루어진 군에서 선택된다.R 1 and R 2 may each be the same or different, and hydrogen (H), halogen, trifluoromethyl (CF 3 ), nitro (NO 2 ), (C1~C4) alkoxy, trifluoromethoxy (OCF 3 ), cyano (CN), nitro (NO 2 ), (C1~C4) alkylsulfonyl and aminosulfonyl (SO 2 NH 2 ).
또한, 본 발명은 상기 화합물을 유효성분으로 함유하는 암 예방 또는 치료용 약학조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for preventing or treating cancer containing the compound as an active ingredient.
또한, 본 발명은 상기 화합물을 유효성분으로 함유하는 대사항암제용 약학조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for anticancer agents containing the compound as an active ingredient.
또한, 본 발명은 상기 화합물을 투여하는 단계를 포함하는 암세포 대사 억제방법을 제공한다. In addition, the present invention provides a method for inhibiting cancer cell metabolism comprising administering the compound.
또한, 본 발명은 상기 화합물을 유효성분으로 함유하는 암 예방 또는 개선용 건강기능식품 조성물을 제공한다.In addition, the present invention provides a health functional food composition for preventing or improving cancer containing the compound as an active ingredient.
본 발명은 eIF2α 인산화 효능을 통한 항암 활성을 나타내는 2-아미노벤조티아졸 유도체 화합물, 이의 약학적으로 허용가능한 염, 이의 용매화물 또는 이의 입체이성질체에서 선택된 화합물에 관한 것으로, 합성된 신규 유도체는 eIF2α 인산화 효과 및 인 비트로 (in vitro)에서 암세포 증식 저해 활성을 보여, 대사항암제로서 백혈병, 그 이외에도 유방암, 뇌종양, 육종 등의 희귀암에 대한 예방 및 개선을 위한 제약 및 건강기능식품 조성물로 활용 가능하다.The present invention relates to a compound selected from the group consisting of a 2-aminobenzothiazole derivative compound, a pharmaceutically acceptable salt thereof, a solvate thereof, and a stereoisomer thereof, which exhibit anticancer activity through phosphorylation of eIF2α. It can be used as a pharmaceutical and health functional food composition for the prevention and improvement of rare cancers such as breast cancer, brain tumor, and sarcoma, as well as leukemia as a metabolizing cancer agent, as it shows cancer cell growth inhibitory effect and in vitro.
도 1은 N-(4-아릴옥시사이클로헥실)벤조티아졸-2-아민 [N-(4-aryloxycyclohexyl)benzothiazole-2-amine] 유도체 설계전략을 나타낸다.Figure 1 shows the N- (4-aryloxycyclohexyl)benzothiazol-2-amine [ N- (4-aryloxycyclohexyl)benzothiazole-2-amine] derivative design strategy.
도 2는 N-(4-아릴옥시사이클로헥실)벤조티아졸-2-아민 [N-(4-aryloxycyclohexyl)benzothiazole-2-amine] 유도체의 합성예를 나타낸다.Figure 2 shows a synthesis example of N- (4-aryloxycyclohexyl)benzothiazole-2-amine [ N- (4-aryloxycyclohexyl)benzothiazole-2-amine] derivative.
이하, 본 발명을 보다 상세하게 설명한다.Hereinafter, the present invention will be described in more detail.
단백질 합성의 개시에서 중요한 단계로 eIF2, GTP, 그리고 Met-tRNAi로 구성되는 복합체의 형성이 있다. 이 복합체는 정상적인 세포 기능을 수행하는데 중요한 역할을 하며, 그 조절에 이상이 있을 경우 여러 가지 질병을 유발하는 것으로 알려져 새로운 치료제 개발의 타겟으로 주목받고 있는데, 본 발명자들은 다양한 치환기를 지닌 2-아미노벤조티아졸 유도체 화합물을 합성하였으며, 이렇게 합성된 신규 유도체는 eIF2α 인산화 효과 및 인 비트로(in vitro)에서 암세포 증식 저해 활성을 보이는 것을 확인하고, 본 발명을 완성하였다.An important step in the initiation of protein synthesis is the formation of a complex composed of eIF2, GTP, and Met-tRNAi. This complex plays an important role in carrying out normal cellular functions, and is known to cause various diseases when there is an abnormality in its regulation, attracting attention as a target for the development of new therapeutic agents. A thiazole derivative compound was synthesized, and it was confirmed that the novel derivative thus synthesized showed an eIF2α phosphorylation effect and cancer cell proliferation inhibitory activity in vitro, thereby completing the present invention.
상기 목적을 달성하기 위하여, 본 발명은 하기 화학식 1로 표시되는 2-아미노벤조티아졸 유도체 화합물, 이의 약학적으로 허용가능한 염, 이의 용매화물 또는 이의 입체이성질체에서 선택된 화합물을 제공한다.In order to achieve the above object, the present invention provides a compound selected from a 2-aminobenzothiazole derivative compound represented by Formula 1 below, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof.
[화학식 1][Formula 1]
Figure PCTKR2022013755-appb-img-000002
Figure PCTKR2022013755-appb-img-000002
상기 화학식 1에서, In Formula 1,
R1 및 R2는 각각 동일하거나 다를 수 있고, 수소 (H), 할로겐, 트리플루오로메틸 (CF3), 나이트로 (NO2), (C1~C4)알콕시, 트리플루오로메톡시 (OCF3), 시아노 (CN), 나이트로 (NO2), (C1~C4)알킬술포닐 및 아미노술포닐 (SO2NH2)로 이루어진 군에서 선택될 수 있다.R 1 and R 2 may each be the same or different, and hydrogen (H), halogen, trifluoromethyl (CF 3 ), nitro (NO 2 ), (C1~C4) alkoxy, trifluoromethoxy (OCF 3 ), cyano (CN), nitro (NO 2 ), (C1~C4) alkylsulfonyl, and aminosulfonyl (SO 2 NH 2 ).
바람직하게는, 상기 2-아미노벤조티아졸 유도체 화합물은 화학식 1에서 R1은 수소 (H), 플루오린 (F), 염소 (Cl), 트리플루오로메틸 (CF3), 나이트로 (NO2) 및 (C1~C2)알콕시로 이루어진 군에서 선택되며, R2는 염소 (Cl), 트리플루오로메틸 (CF3), 트리플루오로메톡시 (OCF3), 시아노 (CN), 나이트로 (NO2), (C1~C2)알킬술포닐 및 아미노술포닐 (SO2NH2)로 이루어진 군에서 선택될 수 있다.Preferably, in the 2-aminobenzothiazole derivative compound, R 1 in Formula 1 is hydrogen (H), fluorine (F), chlorine (Cl), trifluoromethyl (CF 3 ), nitro (NO 2 ) and (C1~C2) is selected from the group consisting of alkoxy, R 2 is chlorine (Cl), trifluoromethyl (CF 3 ), trifluoromethoxy (OCF 3 ), cyano (CN), nitro ( NO 2 ), (C1~C2)alkylsulfonyl, and aminosulfonyl (SO 2 NH 2 ).
보다 바람직하게는, 상기 2-아미노벤조티아졸 유도체 화합물은 화학식 1에서 R1은 수소 (H), 플루오린 (F), 염소 (Cl), 트리플루오로메틸 (CF3), 나이트로 (NO2) 및 메톡시(OMe)로 이루어진 군에서 선택되며, R2는 염소 (Cl), 트리플루오로메틸 (CF3), 트리플루오로메톡시 (OCF3), 시아노 (CN), 나이트로 (NO2), 메틸술포닐 (SO2Me) 및 아미노술포닐 (SO2NH2)로 이루어진 군에서 선택될 수 있다.More preferably, in the 2-aminobenzothiazole derivative compound, R 1 in Formula 1 is hydrogen (H), fluorine (F), chlorine (Cl), trifluoromethyl (CF 3 ), nitro (NO 2 ) and methoxy (OMe), R 2 is chlorine (Cl), trifluoromethyl (CF 3 ), trifluoromethoxy (OCF 3 ), cyano (CN), nitro ( NO 2 ), methylsulfonyl (SO 2 Me) and aminosulfonyl (SO 2 NH 2 ).
일 실시예로는, 상기 2-아미노벤조티아졸 유도체 화합물은 N-((1,4-트랜스)-4-(4-클로로페녹시)사이클로헥실)벤조[d]티아졸-2-아민 [N-((1,4-trans)-4-(4-Chlorophenoxy)cyclohexyl)benzo[d]thiazol-2-amine], N-((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)사이클로헥실)벤조[d]티아졸-2-아민 [N-((1,4-trans)-4-(4-(Trifluoromethyl)phenoxy)cyclohexyl)benzo[d]thiazol-2-amine], N-((1,4-트랜스)-4-(4-(트리플루오로메톡시)페녹시)사이클로헥실)벤조[d]티아졸-2-아민 [N-((1,4-trans)-4-(4-(Trifluoromethoxy)phenoxy)cyclohexyl)benzo[d]thiazol-2-amine], 4-(((1,4-트랜스)-4-(벤조[d]티아졸-2-일아미노)사이클로헥실)옥시)벤조나이트릴 [4-(((1,4-trans)-4-(Benzo[d]thiazol-2-ylamino)cyclohexyl)oxy)benzonitrile], N-((1,4-트랜스)-4-(4-나이트로페녹시)사이클로헥실)벤조[d]티아졸-2-아민 [N-((1,4-trans)-4-(4-Nitrophenoxy)cyclohexyl)benzo[d]thiazol-2-amine], N-((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)사이클로헥실)벤조[d]티아졸-2-아민 [N-((1,4-trans)-4-(4-(Methylsulfonyl)phenoxy)cyclohexyl)benzo[d]thiazol-2-amine], 4-(((1,4-트랜스)-4-(벤조[d]티아졸-2-일아미노)사이클로헥실)옥시)벤젠술폰아마이드 [4-(((1,4-trans)-4-(Benzo[d]thiazol-2-ylamino)cyclohexyl)oxy)benzenesulfonamide], N-((1,4-트랜스)-4-(4-클로로페녹시)사이클로헥실)-6-플루오로벤조[d]티아졸-2-아민 [N-((1,4-trans)-4-(4-Chlorophenoxy)cyclohexyl)-6-fluorobenzo[d]thiazol-2-amine], 6-플루오로-N-((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)사이클로헥실)벤조[d]티아졸-2-아민 [6-Fluoro-N-((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)benzo[d]thiazol-2-amine], 6-플루오로-N-((1,4-트랜스)-4-(4-(트리플루오로메톡시)페녹시)사이클로헥실)벤조[d]티아졸-2-아민 [6-Fluoro-N-((1,4-trans)-4-(4-(trifluoromethoxy)phenoxy)cyclohexyl)benzo[d]thiazol-2-amine], 4-(((1,4-트랜스)-4-((6-플루오로벤조[d]티아졸-2-일)아미노)사이클로헥실)옥시)벤조나이트릴 [4-(((1,4-trans)-4-((6-Fluorobenzo[d]thiazol-2-yl)amino)cyclohexyl)oxy)benzonitrile], 6-플루오로-N-((1,4-트랜스)-4-(4-나이트로페녹시)사이클로헥실)벤조[d]티아졸-2-아민 [6-Fluoro-N-((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)benzo[d]thiazol-2-amine], 6-플루오로-N-((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)사이클로헥실)벤조[d]티아졸-2-아민 [6-Fluoro-N-((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)benzo[d]thiazol-2-amine], 4-(((1,4-트랜스)-4-((6-플루오로벤조[d]티아졸-2-일)아미노)사이클로헥실)옥시)벤젠술폰아마이드 [4-(((1,4-trans)-4-((6-Fluorobenzo[d]thiazol-2-yl)amino)cyclohexyl)oxy)benzenesulfonamide], 6-클로로-N-((1,4-트랜스)-4-(4-클로로페녹시)사이클로헥실)벤조[d]티아졸-2-아민 [6-Chloro-N-((1,4-trans)-4-(4-chlorophenoxy)cyclohexyl)benzo[d]thiazol-2-amine], 6-클로로-N-((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)사이클로헥실)벤조[d]티아졸-2-아민 [6-Chloro-N-((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)benzo[d]thiazol-2-amine], 6-클로로-N-((1,4-트랜스)-4-(4-(트리플루오로메톡시)페녹시)사이클로헥실)벤조[d]티아졸-2-아민 [6-Chloro-N-((1,4-trans)-4-(4-(trifluoromethoxy)phenoxy)cyclohexyl)benzo[d]thiazol-2-amine], 4-(((1,4-트랜스)-4-((6-클로로벤조[d]티아졸-2-일)아미노)사이클로헥실)옥시)벤조나이트릴 [4-(((1,4-trans)-4-((6-Chlorobenzo[d]thiazol-2-yl)amino)cyclohexyl)oxy)benzonitrile], 6-클로로-N-((1,4-트랜스)-4-(4-나이트로페녹시)사이클로헥실)벤조[d]티아졸-2-아민 [6-Chloro-N-((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)benzo[d]thiazol-2-amine], 6-클로로-N-((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)사이클로헥실)벤조[d]티아졸-2-아민 [6-Chloro-N-((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)benzo[d]thiazol-2-amine], 4-(((1,4-트랜스)-4-((6-클로로벤조[d]티아졸-2-일)아미노)사이클로헥실)옥시)벤젠술폰아마이드 [4-(((1,4-trans)-4-((6-Chlorobenzo[d]thiazol-2-yl)amino)cyclohexyl)oxy)benzenesulfonamide], N-((1,4-트랜스)-4-(4-클로로페녹시)사이클로헥실)-6-(트리플루오로메틸)벤조[d]티아졸-2-아민 [N-((1,4-trans)-4-(4-Chlorophenoxy)cyclohexyl)-6-(trifluoromethyl)benzo[d]thiazol-2-amine], 6-(트리플루오로메틸)-N-((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)사이클로헥실)벤조[d]티아졸-2-아민 [6-(Trifluoromethyl)-N-((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)benzo[d]thiazol-2-amine], N-((1,4-트랜스)-4-(4-(트리플루오로메톡시)페녹시)사이클로헥실)-6-(트리플루오로메틸)벤조[d]티아졸-2-아민 [N-((1,4-trans)-4-(4-(Trifluoromethoxy)phenoxy)cyclohexyl)-6-(trifluoromethyl)benzo[d]thiazol-2-amine], 4-(((1,4-트랜스)-4-((6-(트리플루오로메틸)벤조[d]티아졸-2-일)아미노)사이클로헥실)옥시)벤조나이트릴 [4-(((1,4-trans)-4-((6-(Trifluoromethyl)benzo[d]thiazol-2-yl)amino)cyclohexyl)oxy)benzonitrile], N-((1,4-트랜스)-4-(4-나이트로페녹시)사이클로헥실)-6-(트리플루오로메틸)벤조[d]티아졸-2-아민 [N-((1,4-trans)-4-(4-Nitrophenoxy)cyclohexyl)-6-(trifluoromethyl)benzo[d]thiazol-2-amine], N-((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)사이클로헥실)-6-(트리플루오로메틸)벤조[d]티아졸-2-아민 [N-((1,4-trans)-4-(4-(Methylsulfonyl)phenoxy)cyclohexyl)-6-(trifluoromethyl)benzo[d]thiazol-2-amine], 4-(((1,4-트랜스)-4-((6-(트리플루오로메틸)벤조[d]티아졸-2-일)아미노)사이클로헥실)옥시)벤젠술폰아마이드 [4-(((1,4-trans)-4-((6-(Trifluoromethyl)benzo[d]thiazol-2-yl)amino)cyclohexyl)oxy)benzenesulfonamide], N-((1,4-트랜스)-4-(4-클로로페녹시)사이클로헥실)-6-나이트로벤조[d]티아졸-2-아민 [N-((1,4-trans)-4-(4-Chlorophenoxy)cyclohexyl)-6-nitrobenzo[d]thiazol-2-amine], 6-나이트로-N-((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)사이클로헥실)벤조[d]티아졸-2-아민 [6-Nitro-N-((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)benzo[d]thiazol-2-amine], 6-나이트로-N-((1,4-트랜스)-4-(4-(트리플루오로메톡시)페녹시)사이클로헥실)벤조[d]티아졸-2-아민 [6-Nitro-N-((1,4-trans)-4-(4-(trifluoromethoxy)phenoxy)cyclohexyl)benzo[d]thiazol-2-amine], 4-(((1,4-트랜스)-4-((6-나이트로벤조[d]티아졸-2-일)아미노)사이클로헥실)옥시)벤조나이트릴 [4-(((1,4-trans)-4-((6-Nitrobenzo[d]thiazol-2-yl)amino)cyclohexyl)oxy)benzonitrile], 6-나이트로-N-((1,4-트랜스)-4-(4-나이트로페녹시)사이클로헥실)벤조[d]티아졸-2-아민 [6-Nitro-N-((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)benzo[d]thiazol-2-amine], N-((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)사이클로헥실)-6-나이트로벤조[d]티아졸-2-아민 [N-((1,4-trans)-4-(4-(Methylsulfonyl)phenoxy)cyclohexyl)-6-nitrobenzo[d]thiazol-2-amine], 4-(((1,4-트랜스)-4-((6-나이트로벤조[d]티아졸-2-일)아미노)사이클로헥실)옥시)벤젠술폰아마이드 [4-(((1,4-trans)-4-((6-Nitrobenzo[d]thiazol-2-yl)amino)cyclohexyl)oxy)benzenesulfonamide], 6-메톡시-N-((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)사이클로헥실)벤조[d]티아졸-2-아민 [6-Methoxy-N-((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)benzo[d]thiazol-2-amine], 4-(((1,4-트랜스)-4-((6-메톡시벤조[d]티아졸-2-일)아미노)사이클로헥실)옥시)벤조나이트릴 [4-(((1,4-trans)-4-((6-Methoxybenzo[d]thiazol-2-yl)amino)cyclohexyl)oxy)benzonitrile], 6-메톡시-N-((1,4-트랜스)-4-(4-나이트로페녹시)사이클로헥실)벤조[d]티아졸-2-아민 [6-Methoxy-N-((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)benzo[d]thiazol-2-amine] 및 6-메톡시-N-((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)사이클로헥실)벤조[d]티아졸-2-아민 [6-Methoxy-N-((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)benzo[d]thiazol-2-amine]으로 이루어진 군에서 선택될 수 있으나, 이에 한정되는 것은 아니다.In one embodiment, the 2-aminobenzothiazole derivative compound is N -((1,4-trans)-4-(4-chlorophenoxy)cyclohexyl)benzo[ d ]thiazol-2-amine [ N -((1,4- trans )-4-(4-Chlorophenoxy)cyclohexyl)benzo[ d ]thiazol-2-amine], N -((1,4-trans)-4-(4-(trifluoro) Romethyl)phenoxy)cyclohexyl)benzo[ d ]thiazol-2-amine [ N -((1,4- trans )-4-(4-(Trifluoromethyl)phenoxy)cyclohexyl)benzo[d]thiazol-2 -amine], N -((1,4-trans)-4-(4-(trifluoromethoxy)phenoxy)cyclohexyl)benzo[ d ]thiazol-2-amine [ N -((1,4 - trans )-4-(4-(Trifluoromethoxy)phenoxy)cyclohexyl)benzo[ d ]thiazol-2-amine], 4-(((1,4-trans)-4-(benzo[ d ]thiazol-2 -ylamino)cyclohexyl)oxy)benzonitrile [4-(((1,4- trans )-4-(Benzo[ d ]thiazol-2-ylamino)cyclohexyl)oxy)benzonitrile], N -((1 ,4-trans)-4-(4-nitrophenoxy)cyclohexyl)benzo[ d ]thiazol-2-amine [ N -((1,4- trans )-4-(4-Nitrophenoxy)cyclohexyl) benzo[ d ]thiazol-2-amine], N -((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)benzo[ d ]thiazol-2-amine [ N -((1,4- trans )-4-(4-(Methylsulfonyl)phenoxy)cyclohexyl)benzo[ d ]thiazol-2-amine], 4-(((1,4-trans)-4-(benzo[ d ] Thiazol-2-ylamino) cyclohexyl) oxy) benzenesulfonamide [4-(((1,4- trans ) -4-(Benzo [ d ] thiazol-2-ylamino) cyclohexyl) oxy) benzenesulfonamide] , N -((1,4-trans S) -4- (4-chlorophenoxy) cyclohexyl) -6-fluorobenzo [ d ] thiazol-2-amine [ N -((1,4- trans )-4-(4-Chlorophenoxy) cyclohexyl )-6-fluorobenzo[ d ]thiazol-2-amine], 6-fluoro- N -((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)benzo[ d ]thiazol-2-amine [6-Fluoro- N -((1,4- trans )-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)benzo[ d ]thiazol-2-amine], 6-fluoro Rho- N -((1,4-trans)-4-(4-(trifluoromethoxy)phenoxy)cyclohexyl)benzo[ d ]thiazol-2-amine [6-Fluoro- N -((1 ,4- trans )-4-(4-(trifluoromethoxy)phenoxy)cyclohexyl)benzo[ d ]thiazol-2-amine], 4-(((1,4-trans)-4-((6-fluorobenzo [ d ]thiazol-2-yl)amino)cyclohexyl)oxy)benzonitrile [4-(((1,4- trans )-4-((6-Fluorobenzo[ d ]thiazol-2-yl)amino )cyclohexyl)oxy)benzonitrile], 6-fluoro- N -((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)benzo[ d ]thiazol-2-amine [6- Fluoro- N -((1,4- trans )-4-(4-nitrophenoxy)cyclohexyl)benzo[ d ]thiazol-2-amine], 6-fluoro- N -((1,4-trans)-4 -(4-(methylsulfonyl)phenoxy)cyclohexyl)benzo[ d ]thiazol-2-amine [6-Fluoro- N -((1,4- trans )-4-(4-(methylsulfonyl)phenoxy )cyclohexyl)benzo[ d ]thiazol-2-amine], 4-(((1,4-trans)-4-((6-fluorobenzo[ d ]thiazol-2-yl)amino)cyclohexyl) Oxy) benzenesulfonamide [4-(((1,4- trans )-4-((6-Flu orobenzo[ d ]thiazol-2-yl)amino)cyclohexyl)oxy)benzenesulfonamide], 6-chloro- N -((1,4-trans)-4-(4-chlorophenoxy)cyclohexyl)benzo[ d ] Thiazol-2-amine [6-Chloro- N -((1,4- trans )-4-(4-chlorophenoxy)cyclohexyl)benzo[ d ]thiazol-2-amine], 6-chloro- N -(( 1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)benzo[ d ]thiazol-2-amine [6-Chloro- N -((1,4- trans )- 4-(4-(trifluoromethyl)phenoxy)cyclohexyl)benzo[ d ]thiazol-2-amine], 6-chloro- N -((1,4-trans)-4-(4-(trifluoromethoxy)phenoxy cy)cyclohexyl)benzo[ d ]thiazol-2-amine [6-Chloro- N -((1,4- trans )-4-(4-(trifluoromethoxy)phenoxy)cyclohexyl)benzo[ d ]thiazol-2 -amine], 4-(((1,4-trans)-4-((6-chlorobenzo[ d ]thiazol-2-yl)amino)cyclohexyl)oxy)benzonitrile [4-((( 1,4- trans )-4-((6-Chlorobenzo[ d ]thiazol-2-yl)amino)cyclohexyl)oxy)benzonitrile], 6-chloro- N -((1,4-trans)-4-( 4-nitrophenoxy)cyclohexyl)benzo[ d ]thiazol-2-amine [6-Chloro- N -((1,4- trans )-4-(4-nitrophenoxy)cyclohexyl)benzo[ d ]thiazol -2-amine], 6-chloro- N -((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)benzo[ d ]thiazol-2-amine [6- Chloro- N -((1,4- trans )-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)benzo[ d ]thiazol-2-amine], 4-(((1,4-trans)-4- ((6-chlorobenzo[ d ]thiazol-2-yl)amino)cyclohexyl)oxy)benzenesulfonamide [4-(((1,4- trans )-4-((6-Chlorobenzo[ d ]thiazol -2-yl)amino)cyclohexyl)oxy)benzenesulfonamide], N -((1,4-trans)-4-(4-chlorophenoxy)cyclohexyl)-6-(trifluoromethyl)benzo[ d ] Thiazol-2-amine [ N -((1,4- trans )-4-(4-Chlorophenoxy)cyclohexyl)-6-(trifluoromethyl)benzo[ d ]thiazol-2-amine], 6-(trifluoro Methyl)- N -((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)benzo[ d ]thiazol-2-amine [6-(Trifluoromethyl)- N - ((1,4- trans )-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)benzo[ d ]thiazol-2-amine], N -((1,4-trans)-4-(4-(tri) Fluoromethoxy)phenoxy)cyclohexyl)-6-(trifluoromethyl)benzo[ d ]thiazol-2-amine [ N -((1,4- trans )-4-(4-(Trifluoromethoxy)phenoxy )cyclohexyl)-6-(trifluoromethyl)benzo[ d ]thiazol-2-amine], 4-(((1,4-trans)-4-((6-(trifluoromethyl)benzo[ d ]thiazole -2-yl)amino)cyclohexyl)oxy)benzonitrile [4-(((1,4- trans )-4-((6-(Trifluoromethyl)benzo[ d ]thiazol-2-yl)amino)cyclohexyl )oxy)benzonitrile], N -((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)-6-(trifluoromethyl)benzo[ d ]thiazol-2-amine [ N -((1,4- trans )-4-(4-Nitrophenoxy)cyclohexyl)-6-(trifluoromethyl)benzo[ d ]thiazol-2-amine], N -((1,4-trans) -4-(4-(methylsulfonyl)phenoxy)cyclohexyl)-6-(trifluoromethyl)benzo[ d ]thiazol-2-amine [ N -((1,4- trans )-4- (4-(Methylsulfonyl)phenoxy)cyclohexyl)-6-(trifluoromethyl)benzo[ d ]thiazol-2-amine], 4-(((1,4-trans)-4-((6-(trifluoromethyl) )benzo[ d ]thiazol-2-yl)amino)cyclohexyl)oxy)benzenesulfonamide [4-(((1,4- trans )-4-((6-(Trifluoromethyl)benzo[ d ]thiazol- 2-yl)amino)cyclohexyl)oxy)benzenesulfonamide], N -((1,4-trans)-4-(4-chlorophenoxy)cyclohexyl)-6-nitrobenzo[ d ]thiazole-2- Amine [ N -((1,4- trans )-4-(4-Chlorophenoxy)cyclohexyl)-6-nitrobenzo[ d ]thiazol-2-amine], 6-nitro- N -((1,4-trans )-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)benzo[ d ]thiazol-2-amine [6-Nitro- N -((1,4- trans )-4-(4- (trifluoromethyl)phenoxy)cyclohexyl)benzo[ d ]thiazol-2-amine], 6-nitro- N -((1,4-trans)-4-(4-(trifluoromethoxy)phenoxy)cyclohexyl ) Benzo[ d ]thiazol-2-amine [6-Nitro- N -((1,4- trans )-4-(4-(trifluoromethoxy)phenoxy)cyclohexyl)benzo[ d ]thiazol-2-amine], 4-(((1,4-trans)-4-((6-nitrobenzo[ d ]thiazol-2-yl)amino)cyclohexyl)oxy)benzonitrile [4-(((1,4 - trans )-4-((6-Nitrobenzo[ d ]thiazol-2-yl)amino)cyclohexyl)oxy)benzonitrile], 6-nitro- N -((1,4-trans)-4-(4- nitrophenoxy)cyclohexyl)benzo[ d ] Thiazol-2-amine [6-Nitro- N -((1,4- trans )-4-(4-nitrophenoxy)cyclohexyl)benzo[ d ]thiazol-2-amine], N -((1,4- trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)-6-nitrobenzo[ d ]thiazol-2-amine [ N -((1,4- trans )-4-(4 -(Methylsulfonyl)phenoxy)cyclohexyl)-6-nitrobenzo[ d ]thiazol-2-amine], 4-(((1,4-trans)-4-((6-nitrobenzo[ d ]thiazol-2 -yl)amino)cyclohexyl)oxy)benzenesulfonamide [4-(((1,4- trans )-4-((6-Nitrobenzo[ d ]thiazol-2-yl)amino)cyclohexyl)oxy)benzenesulfonamide] , 6-methoxy- N -((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)benzo[ d ]thiazol-2-amine [6-Methoxy- N -((1,4- trans )-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)benzo[ d ]thiazol-2-amine], 4-(((1,4-trans)-4-((6 -Methoxybenzo[ d ]thiazol-2-yl)amino)cyclohexyl)oxy)benzonitrile [4-(((1,4- trans )-4-((6-Methoxybenzo[ d ]thiazol-2 -yl)amino)cyclohexyl)oxy)benzonitrile], 6-methoxy- N -((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)benzo[ d ]thiazole-2- Amine [6-Methoxy- N -((1,4- trans )-4-(4-nitrophenoxy)cyclohexyl)benzo[ d ]thiazol-2-amine] and 6-methoxy- N -((1,4- trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)benzo[ d ]thiazol-2-amine [6-Methoxy- N -((1,4- trans )-4-(4- (methylsulfonyl)phenoxy)cyclohexyl)benzo[ d ] thiazol-2-amine], but is not limited thereto.
또한, 본 발명은 상기 화합물을 유효성분으로 함유하는 암 예방 또는 치료용 약학조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for preventing or treating cancer containing the compound as an active ingredient.
바람직하게는, 본 발명에 따른 화합물은 진핵생물 번역 개시 인자 2α(eukaryotic translation initiation factor 2α, eIF2α)의 인산화를 촉진할 수 있다.Preferably, the compound according to the present invention can promote phosphorylation of eukaryotic translation initiation factor 2α (eIF2α).
바람직하게는, 상기 암은 혈액암, 유방암, 육종암 또는 뇌암일 수 있으나, 이에 한정되는 것은 아니다.Preferably, the cancer may be blood cancer, breast cancer, sarcoma cancer or brain cancer, but is not limited thereto.
또한, 본 발명은 상기 화합물을 유효성분으로 함유하는 대사항암제용 약학조성물을 제공한다. In addition, the present invention provides a pharmaceutical composition for anticancer agents containing the compound as an active ingredient.
또한, 본 발명은 상기 화합물을 투여하는 단계를 포함하는 암세포 대사 억제방법을 제공한다.In addition, the present invention provides a method for inhibiting cancer cell metabolism comprising administering the compound.
상기 화합물은 진핵생물 번역 개시 인자 2α(eukaryotic translation initiation factor 2α; eIF2α)의 인산화를 촉진하여 암세포의 대사를 차단하여 사멸시킬 수 있다.The compound can promote phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) to block metabolism of cancer cells and kill them.
상기 대사항암제는 화학항암제, 표적항암제 및 면역항암제의 뒤를 잇는 4세대 항암제로 불리며, 정상세포에 비해 활발하게 세포 분열을 일으키는 암세포 대사 활동을 차단하는 방식으로, 기존 항암 치료제와 달리 암세포 대사과정을 차단하여 암세포만 골라 죽이는 항암제이며, 특히 암세포 대사량을 50 % 이상 낮추고, 암세포 성장을 억제하는 과정에서 정상세포에 대한 피해가 거의 없다는 것이 특징이다. The metabolic anti-cancer agent is called the 4th generation anti-cancer agent following chemical anti-cancer agent, targeted anti-cancer agent, and immuno-anticancer agent, and blocks the metabolic activity of cancer cells that actively cause cell division compared to normal cells. It is an anticancer agent that selects and kills only cancer cells, and in particular, it lowers the metabolism of cancer cells by more than 50% and has little damage to normal cells in the process of suppressing cancer cell growth.
본 발명에서, 상기 약학적으로 허용가능한 염은 나트륨염, 칼륨염, 칼슘염, 리튬염, 마그네슘염, 세슘염, 아미늄(aminium)염, 암모늄염, 트리에칠아미늄염 및 피리디늄염으로 이루어진 군에서 선택된 하나 이상의 염기성 염일 수 있으나, 이에 제한되는 것은 아님을 명시한다.In the present invention, the pharmaceutically acceptable salt is composed of sodium salt, potassium salt, calcium salt, lithium salt, magnesium salt, cesium salt, aminium salt, ammonium salt, triethylaminium salt and pyridinium salt. It may be one or more basic salts selected from the group, but is not limited thereto.
또한, 상기 약학적으로 허용가능한 염은 염산, 브롬산, 황산, 아황산, 인산, 구연산, 초산, 말레산, 퓨마르산, 글루코산, 메탄설폰산, 벤젠설폰산, 캠퍼설폰산, 옥살산, 말론산, 글루타릭산, 아세트산, 글리콘산, 석신산, 타타르산, 4-톨루엔설폰산, 갈락투론산, 엠본산, 글루탐산, 시트르산 및 아스파르탄산으로 이루어진 군에서 선택된 하나 이상의 산성 염일 수 있으나, 이에 제한되는 것은 아님을 명시한다.In addition, the pharmaceutically acceptable salts are hydrochloric acid, hydrobromic acid, sulfuric acid, sulfurous acid, phosphoric acid, citric acid, acetic acid, maleic acid, fumaric acid, glucoic acid, methanesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, oxalic acid, malonic acid , It may be one or more acid salts selected from the group consisting of glutaric acid, acetic acid, glycolic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid, citric acid and aspartic acid, but Note that it is not limited.
본 발명의 약학 조성물은 투여를 위하여, 상기 기재한 성분 이외에 약학적으로 허용 가능한 담체, 부형제 또는 희석제를 포함할 수 있다. 상기 담체, 부형제 및 희석제로는 락토오스, 덱스트로오스, 수크로오스, 소르비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로오스, 메틸 셀룰로오스, 미정질 셀룰로오스, 폴리비닐피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다.For administration, the pharmaceutical composition of the present invention may include pharmaceutically acceptable carriers, excipients or diluents in addition to the components described above. The carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
본 발명의 약학 조성물은 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 또는 멸균 주사용액의 형태로 제형화하여 사용할 수 있다. 상세하게는 제형화할 경우 통상 사용하는 충진제, 중량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다. 경구투여를 위한 고형 제제로는 정제, 환제, 산제, 과립제, 캡슐제 등을 포함하나, 이에 한정되는 것은 아니다. 이러한 고형 제제는 상기 유효성분 외에 적어도 하나 이상의 부형제, 예를 들면, 전분, 칼슘 카보네이트, 수크로오스, 락토오스, 젤라틴 등을 섞어 조제될 수 있다. 또한, 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용될 수 있다. 경구를 위한 액상물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등을 첨가하여 조제될 수 있다. 비경구 투여를 위한 제제는 멸균된 수용액, 비수성 용제, 현탁제, 유제, 동결건조 제제 및 과제를 포함한다. 비수성 용제 및 현탁제로는 프로필렌글리콜, 폴리에틸렌글리콜, 올리브 오일과 같은 식물성 오일, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔, 마크로솔, 트윈 61, 카카오지, 라우린지, 글리세로젤라틴 등이 사용될 수 있다.The pharmaceutical composition of the present invention can be formulated and used in the form of oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories or sterile injection solutions according to conventional methods. . Specifically, when formulated, it may be prepared using diluents or excipients such as commonly used fillers, weighting agents, binders, wetting agents, disintegrants, and surfactants. Solid preparations for oral administration include, but are not limited to, tablets, pills, powders, granules, capsules, and the like. Such a solid preparation may be prepared by mixing at least one or more excipients, for example, starch, calcium carbonate, sucrose, lactose, gelatin, etc., in addition to the active ingredient. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. It may be prepared by adding various excipients, for example, wetting agents, sweeteners, aromatics, and preservatives, in addition to liquids and liquid paraffin for oral use. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized formulations and tablets. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspending agents. As a base for suppositories, Witepsol, Macrosol, Tween 61, cacao butter, laurin paper, glycerogelatin, and the like may be used.
본 발명의 약학 조성물은 경구형 또는 비경구형 제제로 제조할 수 있으며, 경구, 정맥, 뇌실내, 진피내, 근육내, 복막내, 비강 또는 경막외(eidural) 경로로 투여할 수 있으나, 이에 제한되는 것은 아님을 명시한다.The pharmaceutical composition of the present invention may be prepared as an oral or parenteral formulation, and may be administered by oral, intravenous, intraventricular, intradermal, intramuscular, intraperitoneal, nasal or epidural route, but is limited thereto. indicate that it is not
본 발명의 약학 조성물의 적합한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 시간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있는 바, 상기 조성물의 일일 투여량은 바람직하게는 0.01 mg/kg 내지 100 mg/kg이며, 필요에 따라 일일 1회 내지 수회로 나누어 투여할 수 있다.A suitable dosage of the pharmaceutical composition of the present invention varies depending on the condition and weight of the patient, the severity of the disease, the type of drug, and time, but can be appropriately selected by a person skilled in the art, and the daily dosage of the composition is preferably 0.01 It is mg/kg to 100 mg/kg, and it can be divided and administered once a day to several times as needed.
또한, 본 발명은 상기 화합물을 유효성분으로 함유하는 암 예방 또는 개선용 건강기능식품 조성물을 제공한다.In addition, the present invention provides a health functional food composition for preventing or improving cancer containing the compound as an active ingredient.
상기 건강기능식품 조성물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 그 밖에 천연 과일 주스, 합성 과일 주스 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 또한, 건강기능식품 조성물은 육류, 소세지, 빵, 초콜릿, 캔디류, 스넥류, 과자류, 피자, 라면, 껌류, 아이스크림류, 스프, 음료수, 차, 기능수, 드링크제, 알코올 및 비타민 복합제 중 어느 하나의 형태일 수 있다.The health functional food composition includes various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, colorants and enhancers (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts , organic acids, protective colloidal thickeners, pH regulators, stabilizers, preservatives, glycerin, alcohol, carbonation agents used in carbonated beverages, and the like. In addition, it may contain fruit flesh for the manufacture of natural fruit juice, synthetic fruit juice and vegetable beverages. These components may be used independently or in combination. In addition, the health functional food composition is any one form of meat, sausage, bread, chocolate, candy, snack, confectionery, pizza, ramen, gum, ice cream, soup, beverage, tea, functional water, drink, alcohol and vitamin complex can be
또한, 상기 건강기능식품 조성물은 식품첨가물을 추가로 포함할 수 있으며, 식품첨가물로서의 적합 여부는 다른 규정이 없는 한 식품의약품안전처에 승인된 식품첨가물공전의 총칙 및 일반 시험법 등에 따라 해당 품목에 관한 규격 및 기준에 의하여 판정한다.In addition, the health functional food composition may further contain food additives, and the suitability as a food additive is determined according to the general rules of the Food Additive Code and general test methods approved by the Ministry of Food and Drug Safety, unless otherwise specified. It is judged according to the relevant standards and standards.
상기 식품첨가물공전에 수재된 품목으로 예를 들어, 케톤류, 글리신, 구연산 칼륨, 니코틴산, 계피산 등의 화학적 합성품, 감색소, 감초추출물, 결정셀룰로오스, 고랭색소, 구아검 등의 천연첨가물, L-글루타민산나트륨 제제, 면류 첨가 알칼리제, 보존료제제, 타르색소 제제 등의 혼합 제제류 등을 들 수 있다.Items listed in the Food Additive Code, for example, chemical synthetic products such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamic acid, natural additives such as persimmon pigment, licorice extract, crystalline cellulose, goreng pigment, guar gum, and L-glutamic acid and mixed formulations such as sodium formulations, noodle-added alkali formulations, preservative formulations, and tar color formulations.
이때, 건강기능식품 조성물을 제조하는 과정에서 식품에 첨가되는 본 발명에 따른 조성물은 필요에 따라 그 함량을 적절히 가감할 수 있다.At this time, the content of the composition according to the present invention added to food in the process of preparing the health functional food composition can be appropriately increased or decreased as needed.
이하에서는 실시예 및 실험예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예 및 실험예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예 및 실험예에 의해 제한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail through examples and experimental examples. These Examples and Experimental Examples are only for explaining the present invention in more detail, and it is common knowledge in the art that the scope of the present invention is not limited by these Examples and Experimental Examples according to the gist of the present invention. It will be self-evident in the chair.
[합성예][Synthesis Example]
1. One. NN -- (( (1,4-트랜스)-4-(4-(1,4-trans)-4-(4- 클로로페녹시Chlorophenoxy )) 사이클로헥실cyclohexyl )) 벤조[benzo[ dd ]티아졸]thiazole -2--2- 아민amine [ [ NN -((1,4--((1,4- transtrans )-4-(4-Chlorophenoxy)cyclohexyl)benzo[)-4-(4-Chlorophenoxy)cyclohexyl)benzo[ dd ]thiazol-2-amine] (화합물 1)]thiazol-2-amine] (Compound 1)
Figure PCTKR2022013755-appb-img-000003
Figure PCTKR2022013755-appb-img-000003
2-클로로벤조티아졸 (2-chlorobenzothiazole; 76.7 μL, 0.59 mmol)이 함유된 DMF (1.5 mL)에 (1,4-트랜스)-4-(4-클로로페녹시)사이클로헥산-1-아민 ((1,4-trans)-4-(4-chlorophenoxy)cyclohexan-1-amine; 66.6 mg, 0.30 mmol) 및 탄산칼륨 (K2CO3; 81.4 mg, 0.59 mmol)을 주위 온도 (ambient temperature)에서 추가했다. 120 ℃에서 17시간 동안 교반한 후, 상기 혼합물을 물로 퀀칭 (quenching)시키고, 에틸아세테이트 (EtOAc)로 추출했다. 그 후, 합쳐진 유기층을 MgSO4상에서 건조시키고 진공에서 농축시켰다. 잔류물을 실리카겔에서 플래시 컬럼 크로마토그래피 (에틸아세테이트:n-헥산:디클로로메탄=1:20:10)에 의해 정제하여 25.2 mg (12 %)의 화합물 1을 담황색 고체로서 수득하였다.(1,4-trans)-4-(4-chlorophenoxy)cyclohexan-1-amine ( (1,4-trans)-4-(4-chlorophenoxy)cyclohexan-1-amine; 66.6 mg, 0.30 mmol) and potassium carbonate (K 2 CO 3 ; 81.4 mg, 0.59 mmol) at ambient temperature. Added. After stirring at 120 °C for 17 hours, the mixture was quenched with water and extracted with ethyl acetate (EtOAc). The combined organic layers were then dried over MgSO 4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n -hexane: dichloromethane=1:20:10) to give 25.2 mg (12%) of compound 1 as a pale yellow solid.
1H NMR (CDCl3, 500 MHz) δ 7.59 (d, 1H, J = 7.8 Hz), 7.54 (d, 1H, J = 8.1 Hz), 7.30 (t, 1H, J = 7.7 Hz), 7.23 (d, 2H, J = 8.9 Hz), 7.09 (t, 1H, J = 7.6 Hz), 6.83 (d, 2H, J = 8.9 Hz), 5.48 (s, 1H), 4.18 (m, 1H), 3.71 (m, 1H), 2.30 (m, 2H), 2.15 (m, 2H), 1.65 (m, 2H), 1.43 (m, 2H); 13C NMR (CDCl3 , 125 MHz) δ 166.6, 156.3, 152.5, 130.5, 129.5, 126.1, 125.9, 121.7, 120.9, 119.0, 117.5, 75.2, 53.5, 30.4, 29.9. 1H NMR (CDCl 3 , 500 MHz) δ 7.59 (d, 1H, J = 7.8 Hz), 7.54 (d, 1H, J = 8.1 Hz), 7.30 (t, 1H, J = 7.7 Hz), 7.23 (d , 2H, J = 8.9 Hz), 7.09 (t, 1H, J = 7.6 Hz), 6.83 (d, 2H, J = 8.9 Hz), 5.48 (s, 1H), 4.18 (m, 1H), 3.71 (m , 1H), 2.30 (m, 2H), 2.15 (m, 2H), 1.65 (m, 2H), 1.43 (m, 2H); 13 C NMR (CDCl 3 , 125 MHz) δ 166.6, 156.3, 152.5, 130.5, 129.5, 126.1, 125.9, 121.7, 120.9, 119.0, 117.5, 75.2, 53.5, 30.4, 29.9.
2. 2. NN -((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)사이클로헥실)벤조[-((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)benzo[ dd ]티아졸-2-아민 []Thiazol-2-amine [ NN -((1,4-trans)-4-(4-(Trifluoromethyl)phenoxy)cyclohexyl)benzo[-((1,4-trans)-4-(4-(Trifluoromethyl)phenoxy)cyclohexyl)benzo[ dd ]thiazol-2-amine] (화합물 2)]thiazol-2-amine] (Compound 2)
Figure PCTKR2022013755-appb-img-000004
Figure PCTKR2022013755-appb-img-000004
2-클로로벤조티아졸 (2-chlorobenzothiazole; 76.7 μL, 0.59 mmol)이 함유된 DMF (1.5 mL)에 (1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)사이클로헥산-1-아민 ((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexan-1-amine; 76.4 mg, 0.30 mmol) 및 탄산칼륨 (K2CO3; 81.4mg, 0.59 mmol)을 주위 온도 (ambient temperature)에서 추가했다. 120 ℃에서 17시간 동안 교반한 후, 상기 혼합물을 물로 퀀칭 (quenching)시키고, 에틸아세테이트 (EtOAc)로 추출했다. 그 후, 합쳐진 유기층을 MgSO4상에서 건조시키고 진공에서 농축시켰다. 잔류물을 실리카겔에서 플래시 컬럼 크로마토그래피 (에틸아세테이트:n-헥산=1:4)에 의해 정제하여 60.8 mg (53 %)의 화합물 2를 아이보리색 고체로서 수득하였다.(1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexane in DMF (1.5 mL) containing 2-chlorobenzothiazole (76.7 μL, 0.59 mmol) -1-amine ((1,4- trans )-4-(4-(trifluoromethyl)phenoxy)cyclohexan-1-amine; 76.4 mg, 0.30 mmol) and potassium carbonate (K 2 CO 3 ; 81.4 mg, 0.59 mmol) was added at ambient temperature. After stirring at 120 °C for 17 hours, the mixture was quenched with water and extracted with ethyl acetate (EtOAc). The combined organic layers were then dried over MgSO 4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n -hexane=1:4) to give 60.8 mg (53%) of compound 2 as an ivory solid.
1H NMR (CDCl3, 500 MHz) δ 7.59 (d, 1H, J = 7.9 Hz), 7.54 (d, 1H, J = 7.4 Hz), 7.53 (d, 2H, J = 8.5 Hz), 7.30 (t, 1H, J = 7.7 Hz), 7.10 (t, 1H, J = 7.6 Hz), 6.95 (d, 2H, J = 8.6 Hz), 5.46 (s, 1H), 4.31 (m, 1H), 3.74 (m, 1H), 2.32 (m, 2H), 2.18 (m, 2H), 1.69 (m, 2H), 1.46 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 166.6, 160.2, 152.4, 130.4, 127.8, 127.1, 127.1, 127.1, 127.0, 126.2, 125.6, 123.5, 123.4, 123.1, 122.8, 122.6, 121.8, 121.3, 121.0, 119.0, 115.7, 74.8, 53.4, 30.4, 29.7. 1H NMR (CDCl 3 , 500 MHz) δ 7.59 (d, 1H, J = 7.9 Hz), 7.54 (d, 1H, J = 7.4 Hz), 7.53 (d, 2H, J = 8.5 Hz), 7.30 (t , 1H, J = 7.7 Hz), 7.10 (t, 1H, J = 7.6 Hz), 6.95 (d, 2H, J = 8.6 Hz), 5.46 (s, 1H), 4.31 (m, 1H), 3.74 (m , 1H), 2.32 (m, 2H), 2.18 (m, 2H), 1.69 (m, 2H), 1.46 (m, 2H); 13 C NMR (CDCL 3 , 125 MHz) Δ 166.6, 160.2, 152.4, 127.8, 127.1, 127.1, 127.1, 127.0, 126.2, 125.6, 123.5, 123.4, 123.1, 122.8, 122.6, 121.8, 121.3, 121.0, 119.0, 119.0 , 115.7, 74.8, 53.4, 30.4, 29.7.
3. 3. NN -((1,4-트랜스)-4-(4-(트리플루오로메톡시)페녹시)사이클로헥실)벤조[-((1,4-trans)-4-(4-(trifluoromethoxy)phenoxy)cyclohexyl)benzo[ dd ]티아졸-2-아민 []Thiazol-2-amine [ NN -((1,4--((1,4- transtrans )-4-(4-(Trifluoromethoxy)phenoxy)cyclohexyl)benzo[)-4-(4-(Trifluoromethoxy)phenoxy)cyclohexyl)benzo[ dd ]thiazol-2-amine] (화합물 3)]thiazol-2-amine] (Compound 3)
Figure PCTKR2022013755-appb-img-000005
Figure PCTKR2022013755-appb-img-000005
2-클로로벤조티아졸 (2-chlorobenzothiazole; 76.7 μL, 0.59 mmol)이 함유된 DMF (1.5 mL)에 (1,4-트랜스)-4-(4-(트리플루오로메톡시)페녹시)사이클로헥산-1-아민 ((1,4-trans)-4-(4-(trifluoromethoxy)phenoxy)cyclohexan-1-amine; 81.0 mg, 0.30 mmol) 및 탄산칼륨 (K2CO3; 81.4 mg, 0.59 mmol)을 주위 온도 (ambient temperature)에서 추가했다. 120 ℃에서 17시간 동안 교반한 후, 상기 혼합물을 물로 퀀칭 (quenching)시키고, 에틸아세테이트 (EtOAc)로 추출했다. 그 후, 합쳐진 유기층을 MgSO4상에서 건조시키고 진공에서 농축시켰다. 잔류물을 실리카겔에서 플래시 컬럼 크로마토그래피 (에틸아세테이트:n-헥산=1:3)에 의해 정제하여 13.2 mg (11 %)의 화합물 3을 흰색 고체로서 수득하였다.(1,4-trans)-4-(4-(trifluoromethoxy)phenoxy)cyclohexane in DMF (1.5 mL) containing 2-chlorobenzothiazole (76.7 μL, 0.59 mmol) -1-amine ((1,4- trans )-4-(4-(trifluoromethoxy)phenoxy)cyclohexan-1-amine; 81.0 mg, 0.30 mmol) and potassium carbonate (K 2 CO 3 ; 81.4 mg, 0.59 mmol) was added at ambient temperature. After stirring at 120 °C for 17 hours, the mixture was quenched with water and extracted with ethyl acetate (EtOAc). The combined organic layers were then dried over MgSO 4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n -hexane=1:3) to give 13.2 mg (11%) of compound 3 as a white solid.
1H NMR (CDCl3, 500 MHz) δ 7.59 (d, 1H, J = 7.9 Hz), 7.54 (d, 1H, J = 8.1 Hz), 7.30 (t, 1H, J = 7.7 Hz), 7.13 (d, 2H, J = 8.8 Hz), 7.09 (t, 1H, J = 7.6 Hz), 6.88 (d, 2H, J = 9.1 Hz), 5.34 (s, 1H), 4.21 (m, 1H), 3.73 (m, 1H), 2.31 (m, 2H), 2.17 (m, 2H), 1.67 (m, 2H), 1.44 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 166.5, 156.2, 152.5, 142.9, 142.9, 130.5, 126.1, 123.8, 122.6, 121.8, 121.7, 121.0, 119.7, 119.0, 117.6, 116.9, 75.3, 53.4, 30.4, 29.9. 1H NMR (CDCl 3 , 500 MHz) δ 7.59 (d, 1H, J = 7.9 Hz), 7.54 (d, 1H, J = 8.1 Hz), 7.30 (t, 1H, J = 7.7 Hz), 7.13 (d , 2H, J = 8.8 Hz), 7.09 (t, 1H, J = 7.6 Hz), 6.88 (d, 2H, J = 9.1 Hz), 5.34 (s, 1H), 4.21 (m, 1H), 3.73 (m , 1H), 2.31 (m, 2H), 2.17 (m, 2H), 1.67 (m, 2H), 1.44 (m, 2H); 13 C NMR (CDCL 3 , 125 MHz) Δ 166.5, 156.2, 152.5, 142.9, 130.5, 126.1, 123.8, 122.6, 121.8, 121.7, 121.0, 119.7, 119.0, 117.6, 116.9, 75.3, 53.4, 30.4, 29.9 .
4. 4-(((1,4-트랜스)-4-(4. 4-(((1,4-trans)-4-( 벤조[benzo[ dd ]티아졸]thiazole -2--2- 일아미노ylamino )) 사이클로헥실lcyclohexyl )) 옥시oxy )) 벤조나이트릴benzonitrile [4-(((1,4- [4-(((1,4- transtrans )-4-()-4-( Benzo[Benzo[ dd ]thiazol]thiazol -2-ylamino)cyclohexyl)oxy)benzonitrile ] (화합물 4)-2-ylamino)cyclohexyl)oxy)benzonitrile] (Compound 4)
Figure PCTKR2022013755-appb-img-000006
Figure PCTKR2022013755-appb-img-000006
2-클로로벤조티아졸 (2-chlorobenzothiazole; 76.7 μL, 0.59 mmol)이 함유된 DMF (1.5 mL)에 4-(((1,4-트랜스)-4-아미노사이클로헥실)옥시)벤조나이트릴 (4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzonitrile; 63.8 mg, 0.30 mmol) 및 탄산칼륨 (K2CO3; 81.4 mg, 0.59 mmol)을 주위 온도 (ambient temperature)에서 추가했다. 120 ℃에서 17시간 동안 교반한 후, 상기 혼합물을 물로 퀀칭 (quenching)시키고, 에틸아세테이트 (EtOAc)로 추출했다. 그 후, 합쳐진 유기층을 MgSO4상에서 건조시키고 진공에서 농축시켰다. 잔류물을 실리카겔에서 플래시 컬럼 크로마토그래피 (에틸아세테이트:n-헥산=1:3)에 의해 정제하여 66.7 mg (65 %)의 화합물 4를 아이보리색 고체로서 수득하였다.4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzonitrile ( 4-(((1,4- trans )-4-aminocyclohexyl)oxy)benzonitrile; 63.8 mg, 0.30 mmol) and potassium carbonate (K 2 CO 3 ; 81.4 mg, 0.59 mmol) were added at ambient temperature. did. After stirring at 120 °C for 17 hours, the mixture was quenched with water and extracted with ethyl acetate (EtOAc). The combined organic layers were then dried over MgSO 4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n -hexane=1:3) to give 66.7 mg (65%) of compound 4 as an ivory solid.
1H NMR (CDCl3, 500 MHz) δ 7.59 (m, 1H), 7.57 (d, 2H, J = 8.8 Hz), 7.54 (d, 1H, J = 8.1 Hz), 7.30 (t, 1H, J = 7.7 Hz), 7.09 (t, 1H, J = 7.6 Hz), 6.93 (d, 2H, J = 8.8 Hz), 5.46 (s, 1H), 4.32 (m, 1H), 3.75 (m, 1H), 2.32 (m, 2H), 2.16 (m, 2H), 1.69 (m, 2H), 1.46 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 166.4, 161.1, 152.4, 134.2, 130.5, 126.1, 121.8, 120.9, 119.4, 119.0, 116.2, 103.9, 75.0, 53.2, 30.3, 29.7. 1H NMR (CDCl 3 , 500 MHz) δ 7.59 (m, 1H), 7.57 (d, 2H, J = 8.8 Hz), 7.54 (d, 1H, J = 8.1 Hz), 7.30 (t, 1H, J = 7.7 Hz), 7.09 (t, 1H, J = 7.6 Hz), 6.93 (d, 2H, J = 8.8 Hz), 5.46 (s, 1H), 4.32 (m, 1H), 3.75 (m, 1H), 2.32 (m, 2H), 2.16 (m, 2H), 1.69 (m, 2H), 1.46 (m, 2H); 13 C NMR (CDCl 3 , 125 MHz) δ 166.4, 161.1, 152.4, 134.2, 130.5, 126.1, 121.8, 120.9, 119.4, 119.0, 116.2, 103.9, 75.0, 53.2, 30.7, 29.7.
5. 5. NN -- (( (1,4-트랜스)-4-(4-(1,4-trans)-4-(4- 나이트로페녹시nitrophenoxy )) 사이클로헥실cyclohexyl )) 벤조[benzo[ dd ]티아졸]thiazole -2--2- 아민amine [ [ NN -((1,4--((1,4- transtrans )-4-(4-Nitrophenoxy)cyclohexyl)benzo[)-4-(4-Nitrophenoxy)cyclohexyl)benzo[ dd ]thiazol-2-amine] (화합물 5)]thiazol-2-amine] (Compound 5)
Figure PCTKR2022013755-appb-img-000007
Figure PCTKR2022013755-appb-img-000007
2-클로로벤조티아졸 (2-chlorobenzothiazole; 76.7 μL, 0.59 mmol)이 함유된 DMF (1.5 mL)에 (1,4-트랜스)-4-(4-나이트로페녹시)사이클로헥산-1-아민 ((1,4-trans)-4-(4-nitrophenoxy)cyclohexan-1-amine; 69.7 mg, 0.30 mmol) 및 탄산칼륨 (K2CO3; 81.4 mg, 0.59 mmol)을 주위 온도 (ambient temperature)에서 추가했다. 120 ℃에서 17시간 동안 교반한 후, 상기 혼합물을 물로 퀀칭 (quenching)시키고, 에틸아세테이트 (EtOAc)로 추출했다. 그 후, 합쳐진 유기층을 MgSO4상에서 건조시키고 진공에서 농축시켰다. 잔류물을 실리카겔에서 플래시 컬럼 크로마토그래피 (에틸아세테이트:n-헥산=1:1)에 의해 정제하여 32.5 mg (30 %)의 화합물 5를 노란색 고체로서 수득하였다.(1,4-trans)-4-(4-nitrophenoxy)cyclohexan-1-amine in DMF (1.5 mL) containing 2-chlorobenzothiazole (76.7 μL, 0.59 mmol) ((1,4- trans )-4-(4-nitrophenoxy)cyclohexan-1-amine; 69.7 mg, 0.30 mmol) and potassium carbonate (K 2 CO 3 ; 81.4 mg, 0.59 mmol) at ambient temperature. added in After stirring at 120 °C for 17 hours, the mixture was quenched with water and extracted with ethyl acetate (EtOAc). The combined organic layers were then dried over MgSO 4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n -hexane=1:1) to give 32.5 mg (30%) of compound 5 as a yellow solid.
1H NMR (CDCl3, 500 MHz) δ 8.19 (d, 2H, J = 9.1 Hz), 7.59 (d, 1H, J = 7.8 Hz), 7.54 (d, 1H, J = 8.0 Hz), 7.30 (t, 1H, J = 7.7 Hz), 7.10 (t, 1H, J = 7.6 Hz), 6.93 (d, 2H, J = 9.2 Hz), 5.51 (s, 1H), 4.36 (m, 1H), 3.77 (m, 1H), 2.33 (m, 1H), 2.33 (m, 2H), 2.19 (m, 2H), 1.71 (m, 2H), 1.48 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 166.4, 163.0, 152.4, 141.4, 130.5, 126.1, 126.1, 121.8, 120.9, 119.0, 115.4, 75.4, 53.2, 30.3, 29.7. 1 H NMR (CDCl 3 , 500 MHz) δ 8.19 (d, 2H, J = 9.1 Hz), 7.59 (d, 1H, J = 7.8 Hz), 7.54 (d, 1H, J = 8.0 Hz), 7.30 (t , 1H, J = 7.7 Hz), 7.10 (t, 1H, J = 7.6 Hz), 6.93 (d, 2H, J = 9.2 Hz), 5.51 (s, 1H), 4.36 (m, 1H), 3.77 (m , 1H), 2.33 (m, 1H), 2.33 (m, 2H), 2.19 (m, 2H), 1.71 (m, 2H), 1.48 (m, 2H); 13 C NMR (CDCl 3 , 125 MHz) δ 166.4, 163.0, 152.4, 141.4, 130.5, 126.1, 126.1, 121.8, 120.9, 119.0, 115.4, 75.4, 53.2, 30.3, 29.7.
6. 6. NN -- (( (1,4-트랜스)-4-(4-((1,4-trans)-4-(4-( 메틸술포닐methylsulfonyl )) 페녹시phenoxy )) 사이클로헥실cyclohexyl )) 벤조[benzo[ dd ]티아졸]thiazole -2-아민 [-2-amine [ NN -((1,4--((1,4- transtrans )-4-(4-(Methylsulfonyl)phenoxy)cyclohexyl)benzo[)-4-(4-(Methylsulfonyl)phenoxy)cyclohexyl)benzo[ dd ]thiazol-2-amine] (화합물 6)]thiazol-2-amine] (Compound 6)
Figure PCTKR2022013755-appb-img-000008
Figure PCTKR2022013755-appb-img-000008
2-클로로벤조티아졸 (2-chlorobenzothiazole; 76.7 μL, 0.59 mmol)이 함유된 DMF (1.5 mL)에 (1,4-트랜스)-4-(4-(메틸술포닐)페녹시)사이클로헥산-1-아민 ((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexan-1-amine; 87.4 mg, 0.30 mmol) 및 탄산칼륨 (K2CO3; 81.4 mg, 0.59 mmol)을 주위 온도 (ambient temperature)에서 추가했다. 120 ℃에서 17시간 동안 교반한 후, 상기 혼합물을 물로 퀀칭 (quenching)시키고, 에틸아세테이트 (EtOAc)로 추출했다. 그 후, 합쳐진 유기층을 MgSO4상에서 건조시키고 진공에서 농축시켰다. 잔류물을 실리카겔에서 플래시 컬럼 크로마토그래피 (에틸아세테이트:n-헥산=2:1)에 의해 정제하여 47.0 mg (40 %)의 화합물 6을 밝은 노란색 고체로서 수득하였다.(1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexane- 1-amine ((1,4- trans )-4-(4-(methylsulfonyl)phenoxy)cyclohexan-1-amine; 87.4 mg, 0.30 mmol) and potassium carbonate (K 2 CO 3 ; 81.4 mg, 0.59 mmol) Added at ambient temperature. After stirring at 120 °C for 17 hours, the mixture was quenched with water and extracted with ethyl acetate (EtOAc). The combined organic layers were then dried over MgSO 4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n -hexane=2:1) to give 47.0 mg (40%) of compound 6 as a light yellow solid.
1H NMR (CDCl3, 500 MHz) δ 7.85 (d, 2H, J = 8.8 Hz), 7.58 (d, 1H, J = 7.8 Hz), 7.54 (d, 1H, J = 8.1 Hz), 7.30 (m, 1H), 7.09 (m, 1H), 7.00 (d, 2H, J = 8.9 Hz), 5.33 (s, 1H), 4.36 (m, 1H), 3.77 (m, 1H), 3.03 (s, 3H), 2.32 (m, 2H), 2.18 (m, 2H), 1.70 (m, 2H), 1.48 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 166.3, 162.0, 152.5, 132.2, 130.5, 129.8, 126.1, 121.8, 120.9, 119.1, 116.0, 75.1, 53.1, 45.0, 30.3, 29.7. 1 H NMR (CDCl 3 , 500 MHz) δ 7.85 (d, 2H, J = 8.8 Hz), 7.58 (d, 1H, J = 7.8 Hz), 7.54 (d, 1H, J = 8.1 Hz), 7.30 (m , 1H), 7.09 (m, 1H), 7.00 (d, 2H, J = 8.9 Hz), 5.33 (s, 1H), 4.36 (m, 1H), 3.77 (m, 1H), 3.03 (s, 3H) , 2.32 (m, 2H), 2.18 (m, 2H), 1.70 (m, 2H), 1.48 (m, 2H); 13 C NMR (CDCl 3 , 125 MHz) δ 166.3, 162.0, 152.5, 132.2, 130.5, 129.8, 126.1, 121.8, 120.9, 119.1, 116.0, 75.1, 53.1, 45.0, 30.7.3, 29.7.
7. 4-(((1,4-트랜스)-4-(7. 4-(((1,4-trans)-4-( 벤조[benzo[ dd ]티아졸]thiazole -2--2- 일아미노ylamino )) 사이클로헥실cyclohexyl )) 옥시oxy )) 벤젠술폰아마이드Benzenesulfonamide [4-(((1,4- [4-(((1,4- transtrans )-4-()-4-( Benzo[Benzo[ dd ]thiazol]thiazol -2-ylamino)cyclohexyl)oxy)benzenesulfonamide] (화합물 7)-2-ylamino)cyclohexyl)oxy)benzenesulfonamide] (Compound 7)
Figure PCTKR2022013755-appb-img-000009
Figure PCTKR2022013755-appb-img-000009
2-클로로벤조티아졸 (2-chlorobenzothiazole; 76.7 μL, 0.59 mmol)이 함유된 DMF (1.5 mL)에 4-(((1,4-트랜스)-4-아미노사이클로헥실)옥시)벤젠술폰아마이드 (4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzenesulfonamide; 79.8 mg, 0.30 mmol) 및 탄산칼륨 (K2CO3; 81.4 mg, 0.59 mmol)을 주위 온도 (ambient temperature)에서 추가했다. 120 ℃에서 17시간 동안 교반한 후, 상기 혼합물을 물로 퀀칭 (quenching)시키고, 에틸아세테이트 (EtOAc)로 추출했다. 그 후, 합쳐진 유기층을 MgSO4상에서 건조시키고 진공에서 농축시켰다. 잔류물을 실리카겔에서 플래시 컬럼 크로마토그래피 (에틸아세테이트:n-헥산=2:3)에 의해 정제하여 17.2 mg (14 %)의 화합물 7을 아이보리색 고체로서 수득하였다.4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzenesulfonamide ( 4-(((1,4- trans )-4-aminocyclohexyl)oxy)benzenesulfonamide; 79.8 mg, 0.30 mmol) and potassium carbonate (K 2 CO 3 ; 81.4 mg, 0.59 mmol) were added at ambient temperature. did. After stirring at 120 °C for 17 hours, the mixture was quenched with water and extracted with ethyl acetate (EtOAc). The combined organic layers were then dried over MgSO 4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n -hexane=2:3) to give 17.2 mg (14%) of compound 7 as an ivory solid.
1H NMR (CD3OD, 500 MHz) δ 7.82 (d, 2H, J = 8.8 Hz), 7.56 (d, 1H, J = 7.8 Hz), 7.42 (d, 1H, J = 8.1 Hz), 7.24 (m, 1H), 7.05 (d, 2H, J = 8.7 Hz), 7.03 (m, 1H), 4.58 (s, 1H), 4.46 (m, 1H), 3.83 (m, 1H), 2.21 (m, 4H), 1.65 (m, 2H), 1.53 (m, 2H); 13C NMR (CD3OD, 125 MHz) δ 168.3, 162.2, 153.3, 136.5, 131.1, 129.3, 126.9, 122.6, 121.7, 118.8, 116.6, 76.2, 53.6, 31.0, 30.9. 1 H NMR (CD 3 OD, 500 MHz) δ 7.82 (d, 2H, J = 8.8 Hz), 7.56 (d, 1H, J = 7.8 Hz), 7.42 (d, 1H, J = 8.1 Hz), 7.24 ( m, 1H), 7.05 (d, 2H, J = 8.7 Hz), 7.03 (m, 1H), 4.58 (s, 1H), 4.46 (m, 1H), 3.83 (m, 1H), 2.21 (m, 4H) ), 1.65 (m, 2H), 1.53 (m, 2H); 13 C NMR (CD 3 OD, 125 MHz) δ 168.3, 162.2, 153.3, 136.5, 131.1, 129.3, 126.9, 122.6, 121.7, 118.8, 116.6, 76.2, 53.6, 31.0, 30.9.
8. 8. NN -((1,4-트랜스)-4-(4--((1,4-trans)-4-(4- 클로로페녹시Chlorophenoxy )) 사이클로헥실cyclohexyl )-6-)-6- 플루오로벤조[Fluorobenzo[ dd ]티아졸]thiazole -2-아민 [-2-amine [ NN -((1,4--((1,4- transtrans )-4-(4-)-4-(4- ChlorophenoxyChlorophenoxy )) cyclohexylcyclohexyl )-6-fluorobenzo[)-6-fluorobenzo[ dd ]thiazol-2-amine] (화합물 8)]thiazol-2-amine] (Compound 8)
Figure PCTKR2022013755-appb-img-000010
Figure PCTKR2022013755-appb-img-000010
2-클로로-6-플루오로벤조티아졸 (2-chloro-6-fluorobenzothiazole; 55 mg, 0.29 mmol)이 함유된 DMF (1.5 mL)에 (1,4-트랜스)-4-(4-클로로페녹시)사이클로헥산-1-아민 ((1,4-trans)-4-(4-chlorophenoxy)cyclohexan-1-amine; 60.0 mg, 0.27 mmol) 및 탄산칼륨 (K2CO3; 36.8 mg, 0.27 mmol)을 주위 온도 (ambient temperature)에서 추가했다. 120 ℃에서 17시간 동안 교반한 후, 상기 혼합물을 물로 퀀칭 (quenching)시키고, 에틸아세테이트 (EtOAc)로 추출했다. 그 후, 합쳐진 유기층을 MgSO4상에서 건조시키고 진공에서 농축시켰다. 잔류물을 실리카겔에서 플래시 컬럼 크로마토그래피 (에틸아세테이트:n-헥산=1:3)에 의해 정제하여 26.0 mg (24 %)의 화합물 8을 아이보리색 고체로서 수득하였다.(1,4-trans)-4-(4-chlorophenone) in DMF (1.5 mL) containing 2-chloro-6-fluorobenzothiazole (55 mg, 0.29 mmol). cy)cyclohexan-1-amine ((1,4- trans )-4-(4-chlorophenoxy)cyclohexan-1-amine; 60.0 mg, 0.27 mmol) and potassium carbonate (K 2 CO 3 ; 36.8 mg, 0.27 mmol) ) was added at ambient temperature. After stirring at 120 °C for 17 hours, the mixture was quenched with water and extracted with ethyl acetate (EtOAc). The combined organic layers were then dried over MgSO 4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n -hexane=1:3) to give 26.0 mg (24%) of compound 8 as an ivory solid.
1H NMR (CDCl3, 500 MHz) δ 7.45 (dd, 1H, J = 8.7, 4.7 Hz), 7.29 (dd, 1H, J = 8.0, 2.1 Hz), 7.22 (d, 2H, J = 8.7 Hz), 7.02 (td, 1H, J = 8.9, 2.1 Hz), 6.83 (d, 2H, J = 8.7 Hz), 5.33 (s, 1H), 4.19 (m, 1H), 3.71 (m, 1H), 2.29 (m, 2H), 2.15 (m, 2H), 1.65 (m, 2H), 1.43 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 165.9, 159.3, 157.4, 156.2, 148.9, 131.2, 131.1, 129.5, 125.9, 119.4, 119.3, 117.5, 113.8, 113.6, 107.8, 107.6, 75.2, 53.4, 30.4, 29.8. 1H NMR (CDCl 3 , 500 MHz) δ 7.45 (dd, 1H, J = 8.7, 4.7 Hz), 7.29 (dd, 1H, J = 8.0, 2.1 Hz), 7.22 (d, 2H, J = 8.7 Hz) , 7.02 (td, 1H, J = 8.9, 2.1 Hz), 6.83 (d, 2H, J = 8.7 Hz), 5.33 (s, 1H), 4.19 (m, 1H), 3.71 (m, 1H), 2.29 ( m, 2H), 2.15 (m, 2H), 1.65 (m, 2H), 1.43 (m, 2H); 13 C NMR (CDCL 3 , 125 MHz) Δ 165.9, 159.3, 157.4, 156.2, 148.9, 131.2, 131.1, 129.5, 125.9, 119.4, 119.3, 117.5, 113.8, 113.6, 107.8, 107.6, 75.2, 53.4, 30.4, 29.8 .
9. 6-9. 6- 플루오로Fluoro -- NN -((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)사이클로헥실)벤조[-((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)benzo[ dd ]티아졸-2-아민 [6-]Thiazol-2-amine [6- FluoroFluoro -- NN -((1,4--((1,4- transtrans )-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)benzo[)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)benzo[ dd ]thiazol-2-amine] (화합물 9)]thiazol-2-amine] (Compound 9)
Figure PCTKR2022013755-appb-img-000011
Figure PCTKR2022013755-appb-img-000011
2-클로로-6-플루오로벤조티아졸 (2-chloro-6-fluorobenzothiazole; 100 mg, 0.53 mmol)이 함유된 DMF (1.5 mL)에 (1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)사이클로헥산-1-아민 ((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexan-1-amine; 69.0 mg, 0.27 mmol) 및 탄산칼륨 (K2CO3; 73.7 mg, 0.53 mmol)을 주위 온도 (ambient temperature)에서 추가했다. 120 ℃에서 17시간 동안 교반한 후, 상기 혼합물을 물로 퀀칭 (quenching)시키고, 에틸아세테이트 (EtOAc)로 추출했다. 그 후, 합쳐진 유기층을 MgSO4상에서 건조시키고 진공에서 농축시켰다. 잔류물을 실리카겔에서 플래시 컬럼 크로마토그래피 (에틸아세테이트:n-헥산=1:3)에 의해 정제하여 60.8 mg (56 %)의 화합물 9를 아이보리색 고체로서 수득하였다.(1,4-trans)-4-(4-(tri) in DMF (1.5 mL) containing 2-chloro-6-fluorobenzothiazole (2-chloro-6-fluorobenzothiazole; 100 mg, 0.53 mmol) Fluoromethyl)phenoxy)cyclohexan-1-amine ((1,4- trans )-4-(4-(trifluoromethyl)phenoxy)cyclohexan-1-amine; 69.0 mg, 0.27 mmol) and potassium carbonate (K 2 CO 3 ; 73.7 mg, 0.53 mmol) was added at ambient temperature. After stirring at 120 °C for 17 hours, the mixture was quenched with water and extracted with ethyl acetate (EtOAc). The combined organic layers were then dried over MgSO 4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n -hexane=1:3) to give 60.8 mg (56%) of compound 9 as an ivory solid.
1H NMR (CDCl3, 500 MHz) δ 7.53 (d, 2H, J = 8.6 Hz), 7.45 (dd, 1H, J = 8.8, 4.7 Hz), 7.30 (dd, 1H, J = 8.1, 2.5 Hz), 7.02 (td, 1H, J = 9.0, 2.6 Hz), 6.95 (d, 2H, J = 8.6 Hz), 5.27 (s, 1H), 4.32 (m, 1H), 3.74 (m, 1H), 2.32 (m, 2H), 2.18 (m, 2H), 1.69 (m, 2H), 1.46 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 165.9, 165.9, 160.2, 159.4, 157.5, 148.9, 131.3, 131.2, 127.8, 127.1, 127.1, 127.1, 127.1, 125.6, 123.5, 123.4, 123.1, 122.9, 122.6, 121.3, 119.4, 119.4, 115.7, 113.9, 113.7, 107.8, 107.6, 74.8, 72.9, 53.3, 30.4, 29.7. 1 H NMR (CDCl 3 , 500 MHz) δ 7.53 (d, 2H, J = 8.6 Hz), 7.45 (dd, 1H, J = 8.8, 4.7 Hz), 7.30 (dd, 1H, J = 8.1, 2.5 Hz) , 7.02 (td, 1H, J = 9.0, 2.6 Hz), 6.95 (d, 2H, J = 8.6 Hz), 5.27 (s, 1H), 4.32 (m, 1H), 3.74 (m, 1H), 2.32 ( m, 2H), 2.18 (m, 2H), 1.69 (m, 2H), 1.46 (m, 2H); 13 C NMR (CDCL 3 , 125 MHz) Δ 165.9, 165.9, 160.2, 159.4, 157.5, 148.9, 131.3, 131.2, 127.8, 127.1, 127.1, 127.1, 127.1, 125.6, 123.4, 123.1, 122.9, 122.6, 121.3 , 119.4, 119.4, 115.7, 113.9, 113.7, 107.8, 107.6, 74.8, 72.9, 53.3, 30.4, 29.7.
10. 6-10. 6- 플루오로Fluoro -- NN -((1,4-트랜스)-4-(4-(트리플루오로메톡시)페녹시)사이클로헥실)벤조[-((1,4-trans)-4-(4-(trifluoromethoxy)phenoxy)cyclohexyl)benzo[ dd ]티아졸-2-아민 [6-]Thiazol-2-amine [6- FluoroFluoro -- NN -((1,4--((1,4- transtrans )-4-(4-(trifluoromethoxy)phenoxy)cyclohexyl)benzo[)-4-(4-(trifluoromethoxy)phenoxy)cyclohexyl)benzo[ dd ]thiazol-2-amine] (화합물 10)]thiazol-2-amine] (Compound 10)
Figure PCTKR2022013755-appb-img-000012
Figure PCTKR2022013755-appb-img-000012
2-클로로-6-플루오로벤조티아졸 (2-chloro-6-fluorobenzothiazole; 100 mg, 0.53 mmol)이 함유된 DMF (1.5 mL)에 (1,4-트랜스)-4-(4-(트리플루오로메톡시)페녹시)사이클로헥산-1-아민 ((1,4-trans)-4-(4-(trifluoromethoxy)phenoxy)cyclohexan-1-amine; 73.2 mg, 0.27 mmol) 및 탄산칼륨 (K2CO3; 73.7 mg, 0.53 mmol)을 주위 온도 (ambient temperature)에서 추가했다. 120 ℃에서 17시간 동안 교반한 후, 상기 혼합물을 물로 퀀칭 (quenching)시키고, 에틸아세테이트 (EtOAc)로 추출했다. 그 후, 합쳐진 유기층을 MgSO4상에서 건조시키고 진공에서 농축시켰다. 잔류물을 실리카겔에서 플래시 컬럼 크로마토그래피 (에틸아세테이트:n-헥산=1:5)에 의해 정제하여 37.5 mg (33 %)의 화합물 10을 아이보리색 고체로서 수득하였다.(1,4-trans)-4-(4-(tri) in DMF (1.5 mL) containing 2-chloro-6-fluorobenzothiazole (2-chloro-6-fluorobenzothiazole; 100 mg, 0.53 mmol) Fluoromethoxy)phenoxy)cyclohexan-1-amine ((1,4- trans )-4-(4-(trifluoromethoxy)phenoxy)cyclohexan-1-amine; 73.2 mg, 0.27 mmol) and potassium carbonate (K 2 CO 3 ; 73.7 mg, 0.53 mmol) was added at ambient temperature. After stirring at 120 °C for 17 hours, the mixture was quenched with water and extracted with ethyl acetate (EtOAc). The combined organic layers were then dried over MgSO 4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n -hexane=1:5) to give 37.5 mg (33%) of compound 10 as an ivory solid.
1H NMR (CDCl3, 500 MHz) δ 7.45 (dd, 1H, J = 8.8, 4.7 Hz), 7.29 (dd, 1H, J = 8.2, 2.5 Hz), 7.13 (d, 2H, J = 8.6 Hz), 7.01 (td, 1H, J = 9.0, 2.6 Hz), 6.88 (d, 2H, J = 9.1 Hz), 5.21 (s, 1H), 4.21 (m, 1H), 3.73 (m, 1H), 2.31 (m, 2H), 2.17 (m, 2H), 1.67 (m, 2H), 1.44 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 165.8, 159.4, 157.5, 156.2, 148.9, 142.9, 142.9, 131.3, 131.2, 123.8, 122.6, 121.7, 119.7, 119.5, 119.4, 117.6, 116.9, 113.8, 113.7, 107.8, 107.6, 75.3, 53.4, 30.5, 29.9. 1H NMR (CDCl 3 , 500 MHz) δ 7.45 (dd, 1H, J = 8.8, 4.7 Hz), 7.29 (dd, 1H, J = 8.2, 2.5 Hz), 7.13 (d, 2H, J = 8.6 Hz) , 7.01 (td, 1H, J = 9.0, 2.6 Hz), 6.88 (d, 2H, J = 9.1 Hz), 5.21 (s, 1H), 4.21 (m, 1H), 3.73 (m, 1H), 2.31 ( m, 2H), 2.17 (m, 2H), 1.67 (m, 2H), 1.44 (m, 2H); 13 C NMR (CDCL 3 , 125 MHz) Δ 165.8, 159.4, 157.5, 156.2, 148.9, 142.9, 142.9, 131.3, 131.2, 123.8, 122.6, 121.7 , 107.6, 75.3, 53.4, 30.5, 29.9.
11. 4-(((1,4-트랜스)-4-((6-11. 4-(((1,4-trans)-4-((6- 플루오로벤조[Fluorobenzo[ dd ]티아졸]thiazole -2-일)아미노)-2-yl)amino) 사이클로헥실cyclohexyl )옥시)벤조나이트릴 [4-(((1,4-)oxy)benzonitrile [4-(((1,4- transtrans )-4-((6-)-4-((6- Fluorobenzo[Fluorobenzo[ dd ]thiazol]thiazol -2-yl)amino)cyclohexyl)oxy)benzonitrile] (화합물 11)-2-yl)amino)cyclohexyl)oxy)benzonitrile] (Compound 11)
Figure PCTKR2022013755-appb-img-000013
Figure PCTKR2022013755-appb-img-000013
2-클로로-6-플루오로벤조티아졸 (2-chloro-6-fluorobenzothiazole; 100 mg, 0.53 mmol)이 함유된 DMF (1.5 mL)에 4-(((1,4-트랜스)-4-아미노사이클로헥실)옥시)벤조나이트릴 (4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzonitrile; 57.5 mg, 0.27 mmol) 및 탄산칼륨 (K2CO3; 73.7 mg, 0.53 mmol)을 주위 온도 (ambient temperature)에서 추가했다. 120 ℃에서 17시간 동안 교반한 후, 상기 혼합물을 물로 퀀칭 (quenching)시키고, 에틸아세테이트 (EtOAc)로 추출했다. 그 후, 합쳐진 유기층을 MgSO4상에서 건조시키고 진공에서 농축시켰다. 잔류물을 실리카겔에서 플래시 컬럼 크로마토그래피 (에틸아세테이트:n-헥산=1:1)에 의해 정제하여 55.2 mg (56 %)의 화합물 11을 아이보리색 고체로서 수득하였다.4-(((1,4-trans)-4-amino in DMF (1.5 mL) containing 2-chloro-6-fluorobenzothiazole (2-chloro-6-fluorobenzothiazole; 100 mg, 0.53 mmol) Cyclohexyl)oxy)benzonitrile (4-(((1,4- trans )-4-aminocyclohexyl)oxy)benzonitrile; 57.5 mg, 0.27 mmol) and potassium carbonate (K 2 CO 3 ; 73.7 mg, 0.53 mmol) was added at ambient temperature. After stirring at 120 °C for 17 hours, the mixture was quenched with water and extracted with ethyl acetate (EtOAc). The combined organic layers were then dried over MgSO 4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n -hexane=1:1) to give 55.2 mg (56%) of compound 11 as an ivory solid.
1H NMR (CDCl3, 500 MHz) δ 7.57 (d, 2H, J = 8.9 Hz), 7.45 (dd, 1H, J = 8.8, 4.7 Hz), 7.29 (dd, 1H, J = 8.2, 2.5 Hz), 7.01 (td, 1H, J = 9.0, 2.6 Hz), 6.93 (d, 2H, J = 8.8 Hz), 5.20 (d, 1H, J = 6.6 Hz), 4.33 (m, 1H), 3.77 (m, 1H), 2.32 (m, 2H), 2.17 (m, 2H), 1.69 (m, 2H), 1.46 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 165.7, 165.6, 161.1, 159.4, 157.5, 149.0, 134.2, 131.3, 131.2, 119.5, 119.4, 119.4, 116.2, 113.8, 113.6, 107.8, 107.6, 103.9, 75.0, 53.1, 30.3, 29.7. 1 H NMR (CDCl 3 , 500 MHz) δ 7.57 (d, 2H, J = 8.9 Hz), 7.45 (dd, 1H, J = 8.8, 4.7 Hz), 7.29 (dd, 1H, J = 8.2, 2.5 Hz) , 7.01 (td, 1H, J = 9.0, 2.6 Hz), 6.93 (d, 2H, J = 8.8 Hz), 5.20 (d, 1H, J = 6.6 Hz), 4.33 (m, 1H), 3.77 (m, 1H), 2.32 (m, 2H), 2.17 (m, 2H), 1.69 (m, 2H), 1.46 (m, 2H); 13 C NMR (CDCL 3 , 125 MHz) Δ 165.7, 165.6, 161.1, 159.4, 157.5, 134.2, 131.3, 131.2, 119.5, 119.4, 119.4, 116.2, 113.8, 113.8, 107.8, 107.6, 103.9, 75.0, 53.1 , 30.3, 29.7.
12. 6-12. 6- 플루오로Fluoro -- NN -- (( (1,4-트랜스)-4-(4-(1,4-trans)-4-(4- 나이트로페녹시nitrophenoxy )) 사이클로헥실cyclohexyl )) 벤조[benzo[ dd ]티아졸]thiazole -2-아민 [6--2-amine [6- FluoroFluoro -- NN -((1,4--((1,4- transtrans )-4-(4-nitrophenoxy)cyclohexyl)benzo[)-4-(4-nitrophenoxy)cyclohexyl)benzo[ dd ]thiazol-2-amine] (화합물 12)]thiazol-2-amine] (Compound 12)
Figure PCTKR2022013755-appb-img-000014
Figure PCTKR2022013755-appb-img-000014
2-클로로-6-플루오로벤조티아졸 (2-chloro-6-fluorobenzothiazole; 100 mg, 0.53 mmol)이 함유된 DMF (1.5 mL)에 (1,4-트랜스)-4-(4-나이트로페녹시)사이클로헥산-1-아민 ((1,4-trans)-4-(4-nitrophenoxy)cyclohexan-1-amine; 62.8 mg, 0.27 mmol) 및 탄산칼륨 (K2CO3; 73.7 mg, 0.53 mmol)을 주위 온도 (ambient temperature)에서 추가했다. 120 ℃에서 17시간 동안 교반한 후, 상기 혼합물을 물로 퀀칭 (quenching)시키고, 에틸아세테이트 (EtOAc)로 추출했다. 그 후, 합쳐진 유기층을 MgSO4상에서 건조시키고 진공에서 농축시켰다. 잔류물을 실리카겔에서 플래시 컬럼 크로마토그래피 (에틸아세테이트:n-헥산:디클로로메탄=1:3:1)에 의해 정제하여 62.6 mg (61 %)의 화합물 12를 밝은 노란색 고체로서 수득하였다.(1,4-trans)-4-(4-nitro Phenoxy)cyclohexan-1-amine ((1,4- trans )-4-(4-nitrophenoxy)cyclohexan-1-amine; 62.8 mg, 0.27 mmol) and potassium carbonate (K 2 CO 3 ; 73.7 mg, 0.53 mmol) was added at ambient temperature. After stirring at 120 °C for 17 hours, the mixture was quenched with water and extracted with ethyl acetate (EtOAc). The combined organic layers were then dried over MgSO 4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n -hexane: dichloromethane=1:3:1) to give 62.6 mg (61%) of compound 12 as a light yellow solid.
1H NMR (CDCl3, 500 MHz)δ 8.19 (d, 2H, J = 9.3 Hz), 7.45 (dd, 1H, J = 8.8, 4.7 Hz), 7.29 (dd, 1H, J = 8.1, 2.5 Hz), 7.01 (td, 1H, J = 9.0, 2.6 Hz), 6.94 (d, 2H, J = 9.2 Hz), 5.23 (d, 1H, J = 4.3 Hz), 4.38 (m, 1H), 3.78 (m, 1H), 2.34 (m, 2H), 2.20 (m, 2H), 1.72 (m, 2H), 1.48 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 165.7, 165.7, 162.9, 159.4, 157.5, 148.9, 141.4, 131.3, 131.2, 126.1, 119.5, 119.4, 115.4, 113.8, 113.7, 107.8, 107.6, 75.4, 53.1, 30.3, 29.7. 1 H NMR (CDCl 3 , 500 MHz) δ 8.19 (d, 2H, J = 9.3 Hz), 7.45 (dd, 1H, J = 8.8, 4.7 Hz), 7.29 (dd, 1H, J = 8.1, 2.5 Hz) , 7.01 (td, 1H, J = 9.0, 2.6 Hz), 6.94 (d, 2H, J = 9.2 Hz), 5.23 (d, 1H, J = 4.3 Hz), 4.38 (m, 1H), 3.78 (m, 1H), 2.34 (m, 2H), 2.20 (m, 2H), 1.72 (m, 2H), 1.48 (m, 2H); 13 C NMR (CDCL 3 , 125 MHz) Δ 165.7, 165.7, 162.9, 159.4, 157.5, 148.9, 141.4, 131.3, 131.2, 126.1, 119.5, 119.4, 115.4, 113.8, 113.8, 107.8, 107.6, 75.4, 53.1 , 29.7.
13. 6-13. 6- 플루오로Fluoro -- NN -- (( (1,4-트랜스)-4-(4-((1,4-trans)-4-(4-( 메틸술포닐methylsulfonyl )) 페녹시phenoxy )) 사이클로헥실cyclohexyl )) 벤조[benzo[ dd ]티아졸]thiazole -2-아민 [6--2-amine [6- FluoroFluoro -- NN -((1,4--((1,4- transtrans )-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)benzo[)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)benzo[ dd ]thiazol-2-amine] (화합물 13)]thiazol-2-amine] (Compound 13)
Figure PCTKR2022013755-appb-img-000015
Figure PCTKR2022013755-appb-img-000015
2-클로로-6-플루오로벤조티아졸 (2-chloro-6-fluorobenzothiazole; 100 mg, 0.53 mmol)이 함유된 DMF (1.5 mL)에 (1,4-트랜스)-4-(4-(메틸술포닐)페녹시)사이클로헥산-1-아민 (((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexan-1-amine; 71.6 mg, 0.27 mmol) 및 탄산칼륨 (K2CO3; 73.7 mg, 0.53 mmol)을 주위 온도 (ambient temperature)에서 추가했다. 120 ℃에서 17시간 동안 교반한 후, 상기 혼합물을 물로 퀀칭 (quenching)시키고, 에틸아세테이트 (EtOAc)로 추출했다. 그 후, 합쳐진 유기층을 MgSO4상에서 건조시키고 진공에서 농축시켰다. 잔류물을 실리카겔에서 플래시 컬럼 크로마토그래피 (에틸아세테이트:n-헥산=3:2)에 의해 정제하여 51.6 mg (46 %)의 화합물 13을 흰색 고체로서 수득하였다.(1,4-trans)-4-(4-(methyl) in DMF (1.5 mL) containing 2-chloro-6-fluorobenzothiazole (100 mg, 0.53 mmol). Sulfonyl) phenoxy) cyclohexan-1-amine (((1,4- trans ) -4- (4- (methylsulfonyl) phenoxy) cyclohexan-1-amine; 71.6 mg, 0.27 mmol) and potassium carbonate (K 2 CO 3 ; 73.7 mg, 0.53 mmol) was added at ambient temperature After stirring at 120° C. for 17 h, the mixture was quenched with water and extracted with ethyl acetate (EtOAc). Then, the combined organic layers were dried over MgSO 4 and concentrated in vacuo The residue was purified by flash column chromatography on silica gel (ethyl acetate: n -hexane=3:2) to give 51.6 mg (46%) of compound 13 Obtained as a white solid.
1H NMR (CDCl3, 500 MHz) δ 7.85 (d, 2H, J = 8.8 Hz), 7.44 (dd, 1H, J = 8.8, 4.7 Hz), 7.28 (dd, 1H, J = 8.1, 2.4 Hz), 7.02 (m, 1H), 7.00 (d, 2H, J = 8.8 Hz), 5.26 (d, 1H, J = 6.0 Hz), 4.36 (m, 1H), 3.77 (m, 1H), 3.03 (s, 3H), 2.32 (m, 2H), 2.18 (m, 2H), 1.70 (m, 2H), 1.47 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 165.7, 165.7, 162.0, 159.4, 157.5, 149.0, 132.2, 131.3, 131.2, 129.7, 119.5, 119.4, 116.0, 113.8, 113.6, 107.8, 107.6, 75.1, 53.1, 45.0, 30.3, 29.7. 1 H NMR (CDCl 3 , 500 MHz) δ 7.85 (d, 2H, J = 8.8 Hz), 7.44 (dd, 1H, J = 8.8, 4.7 Hz), 7.28 (dd, 1H, J = 8.1, 2.4 Hz) , 7.02 (m, 1H), 7.00 (d, 2H, J = 8.8 Hz), 5.26 (d, 1H, J = 6.0 Hz), 4.36 (m, 1H), 3.77 (m, 1H), 3.03 (s, 3H), 2.32 (m, 2H), 2.18 (m, 2H), 1.70 (m, 2H), 1.47 (m, 2H); 13 C NMR (CDCL 3 , 125 MHz) Δ 165.7, 165.7, 162.0, 159.4, 157.5, 149.0, 132.2, 131.3, 131.2, 129.7, 119.5, 119.4, 116.0, 113.8, 113.8, 107.8, 107.6, 75.1, 53.1, 45.0 , 30.3, 29.7.
14. 4-(((1,4-트랜스)-4-((6-14. 4-(((1,4-trans)-4-((6- 플루오로벤조[Fluorobenzo[ dd ]티아졸]thiazole -2-일)아미노)-2-yl)amino) 사이클로헥실cyclohexyl )옥시)벤젠술폰아마이드 [4-(((1,4-)oxy)benzenesulfonamide [4-(((1,4- transtrans )-4-((6-)-4-((6- Fluorobenzo[Fluorobenzo[ dd ]thiazol]thiazol -2-yl)amino)cyclohexyl)oxy)benzenesulfonamide] (화합물 14)-2-yl) amino) cyclohexyl) oxy) benzenesulfonamide] (Compound 14)
Figure PCTKR2022013755-appb-img-000016
Figure PCTKR2022013755-appb-img-000016
2-클로로-6-플루오로벤조티아졸 (2-chloro-6-fluorobenzothiazole; 55.0 mg, 0.29 mmol)이 함유된 DMF (1.5 mL)에 4-(((1,4-트랜스)-4-아미노사이클로헥실)옥시)벤젠술폰아마이드 (4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzenesulfonamide; 80.0 mg, 0.27 mmol) 및 탄산칼륨 (K2CO3; 36.8 mg, 0.27 mmol)을 주위 온도 (ambient temperature)에서 추가했다. 120 ℃에서 17시간 동안 교반한 후, 상기 혼합물을 물로 퀀칭 (quenching)시키고, 에틸아세테이트 (EtOAc)로 추출했다. 그 후, 합쳐진 유기층을 MgSO4상에서 건조시키고 진공에서 농축시켰다. 잔류물을 실리카겔에서 플래시 컬럼 크로마토그래피 (에틸아세테이트:메탄올=10:1)에 의해 정제하여 17.3 mg (15 %)의 화합물 14를 흰색 고체로서 수득하였다.4-(((1,4-trans)-4-amino in DMF (1.5 mL) containing 2-chloro-6-fluorobenzothiazole (2-chloro-6-fluorobenzothiazole; 55.0 mg, 0.29 mmol) Cyclohexyl)oxy)benzenesulfonamide (4-(((1,4- trans )-4-aminocyclohexyl)oxy)benzenesulfonamide; 80.0 mg, 0.27 mmol) and potassium carbonate (K 2 CO 3 ; 36.8 mg, 0.27 mmol) was added at ambient temperature. After stirring at 120 °C for 17 hours, the mixture was quenched with water and extracted with ethyl acetate (EtOAc). The combined organic layers were then dried over MgSO 4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate:methanol=10:1) to give 17.3 mg (15%) of compound 14 as a white solid.
1H NMR (DMSO-d 6, 500 MHz) δ 8.00 (d, 1H, J = 7.1 Hz), 7.72 (d, 2H, J = 8.8 Hz), 7.58 (dd, 1H, J = 8.7, 2.6 Hz), 7.36 (dd, 1H, J = 8.8, 4.9 Hz), 7.19 (s, 2H), 7.12 (d, 2H, J = 8.9 Hz), 7.03 (td, 1H, J = 9.1, 2.6 Hz), 4.49 (m, 1H), 3.77 (m, 1H), 2.11 (m, 4H), 1.50 (m, 4H); 13C NMR (DMSO-d 6, 125 MHz) δ 165.1, 159.8, 158.1, 156.2, 149.3, 135.9, 131.3, 131.2, 127.7, 118.3, 118.3, 115.4, 112.8, 112.6, 107.9, 107.7, 74.4, 51.8, 29.4, 29.3. 1 H NMR (DMSO- d 6 , 500 MHz) δ 8.00 (d, 1H, J = 7.1 Hz), 7.72 (d, 2H, J = 8.8 Hz), 7.58 (dd, 1H, J = 8.7, 2.6 Hz) , 7.36 (dd, 1H, J = 8.8, 4.9 Hz), 7.19 (s, 2H), 7.12 (d, 2H, J = 8.9 Hz), 7.03 (td, 1H, J = 9.1, 2.6 Hz), 4.49 ( m, 1H), 3.77 (m, 1H), 2.11 (m, 4H), 1.50 (m, 4H); 13 C NMR (DMSO- D 6 , 125 MHz) Δ 165.1, 159.8, 158.1, 156.2, 149.3, 135.9, 131.3, 131.2, 127.7, 118.3, 118.3, 115.4, 112.8, 112.6, 107.9, 107.7, 74.4, 51.8, 29.4 , 29.3.
15. 6-15. 6- 클로로Chloro -- NN -- (( (1,4-트랜스)-4-(4-(1,4-trans)-4-(4- 클로로페녹시Chlorophenoxy )) 사이클로헥실cyclohexyl )) 벤조[benzo[ dd ]티아졸]thiazole -2-아민 [6--2-amine [6- ChloroChloro -- NN -((1,4--((1,4- transtrans )-4-(4-chlorophenoxy)cyclohexyl)benzo[)-4-(4-chlorophenoxy)cyclohexyl)benzo[ dd ]thiazol-2-amine] (화합물 15)]thiazol-2-amine] (Compound 15)
Figure PCTKR2022013755-appb-img-000017
Figure PCTKR2022013755-appb-img-000017
2,6-디클로로벤조티아졸 (2,6-dichlorobenzothiazole; 55.0 mg, 0.27 mmol)이 함유된 DMF (1.5 mL)에 (1,4-트랜스)-4-(4-디클로로페녹시)사이클로헥산-1-아민 ((1,4-trans)-4-(4-chlorophenoxy)cyclohexan-1-amine; 55.2 mg, 0.24 mmol) 및 탄산칼륨 (K2CO3; 33.7 mg, 0.24 mmol)을 주위 온도 (ambient temperature)에서 추가했다. 120 ℃에서 17시간 동안 교반한 후, 상기 혼합물을 물로 퀀칭 (quenching)시키고, 에틸아세테이트 (EtOAc)로 추출했다. 그 후, 합쳐진 유기층을 MgSO4상에서 건조시키고 진공에서 농축시켰다. 잔류물을 실리카겔에서 플래시 컬럼 크로마토그래피 (에틸아세테이트:n-헥산=1:3)에 의해 정제하여 20.0 mg (19 %)의 화합물 15를 흰색 고체로서 수득하였다.(1,4-trans)-4-(4-dichlorophenoxy)cyclohexane- (1,4-trans)-4-(4-dichlorophenoxy)cyclohexane- 1-amine ((1,4- trans )-4-(4-chlorophenoxy)cyclohexan-1-amine; 55.2 mg, 0.24 mmol) and potassium carbonate (K 2 CO 3 ; 33.7 mg, 0.24 mmol) at ambient temperature ( ambient temperature). After stirring at 120 °C for 17 hours, the mixture was quenched with water and extracted with ethyl acetate (EtOAc). The combined organic layers were then dried over MgSO 4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n -hexane=1:3) to give 20.0 mg (19%) of Compound 15 as a white solid.
1H NMR (CDCl3, 500 MHz) δ 7.54 (d, 1H, J = 1.9 Hz), 7.42 (d, 1H, J = 8.6 Hz), 7.25 (m, 1H), 7.22 (d, 2H, J = 9.0 Hz), 6.83 (d, 2H, J = 8.9 Hz), 5.32 (s, 1H), 4.19 (m, 1H), 3.71 (m, 1H), 2.29 (m, 2H), 2.15 (m, 2H), 1.65 (m, 2H), 1.43 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 166.5, 156.2, 151.2, 131.7, 129.6, 126.9, 126.6, 125.9, 120.6, 119.7, 117.5, 75.1, 53.5, 30.4, 29.8. 1 H NMR (CDCl 3 , 500 MHz) δ 7.54 (d, 1H, J = 1.9 Hz), 7.42 (d, 1H, J = 8.6 Hz), 7.25 (m, 1H), 7.22 (d, 2H, J = 9.0 Hz), 6.83 (d, 2H, J = 8.9 Hz), 5.32 (s, 1H), 4.19 (m, 1H), 3.71 (m, 1H), 2.29 (m, 2H), 2.15 (m, 2H) , 1.65 (m, 2H), 1.43 (m, 2H); 13 C NMR (CDCl 3 , 125 MHz) δ 166.5, 156.2, 151.2, 131.7, 129.6, 126.9, 126.6, 125.9, 120.6, 119.7, 117.5, 75.1, 53.5, 30.4, 29.8.
16. 6-16. 6- 클로로Chloro -- NN -((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)사이클로헥실)벤조[-((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)benzo[ dd ]티아졸-2-아민 [6-]Thiazol-2-amine [6- ChloroChloro -- NN -((1,4--((1,4- transtrans )-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)benzo[)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)benzo[ dd ]thiazol-2-amine] (화합물 16)]thiazol-2-amine] (Compound 16)
Figure PCTKR2022013755-appb-img-000018
Figure PCTKR2022013755-appb-img-000018
2,6-디클로로벤조티아졸 (2,6-dichlorobenzothiazole; 100.0 mg, 0.49 mmol)이 함유된 DMF (1.5 mL)에 (1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)사이클로헥산-1-아민 ((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexan-1-amine; 63.5 mg, 0.25 mmol) 및 탄산칼륨 (K2CO3; 67.7 mg, 0.49 mmol)을 주위 온도 (ambient temperature)에서 추가했다. 120 ℃에서 17시간 동안 교반한 후, 상기 혼합물을 물로 퀀칭 (quenching)시키고, 에틸아세테이트 (EtOAc)로 추출했다. 그 후, 합쳐진 유기층을 MgSO4상에서 건조시키고 진공에서 농축시켰다. 잔류물을 실리카겔에서 플래시 컬럼 크로마토그래피 (에틸아세테이트:n-헥산=1:6)에 의해 정제하여 276.0 mg (73 %)의 화합물 16을 흰색 고체로서 수득하였다.(1,4-trans)-4-(4-(trifluoromethyl)phenoxane in DMF (1.5 mL) containing 2,6-dichlorobenzothiazole (2,6-dichlorobenzothiazole; 100.0 mg, 0.49 mmol) c)cyclohexan-1-amine ((1,4- trans )-4-(4-(trifluoromethyl)phenoxy)cyclohexan-1-amine; 63.5 mg, 0.25 mmol) and potassium carbonate (K 2 CO 3 ; 67.7 mg , 0.49 mmol) was added at ambient temperature. After stirring at 120 °C for 17 hours, the mixture was quenched with water and extracted with ethyl acetate (EtOAc). The combined organic layers were then dried over MgSO 4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n -hexane=1:6) to give 276.0 mg (73%) of compound 16 as a white solid.
1H NMR (CDCl3, 500 MHz) δ 7.55 (m, 1H), 7.53 (d, 2H, J = 9.8 Hz), 7.43 (d, 1H, J = 8.6 Hz), 7.25 (m, 1H), 6.95 (d, 2H, J = 8.6 Hz), 5.33 (s, 1H), 4.32 (m, 1H), 3.74 (m, 1H), 2.31 (m, 2H), 2.18 (m, 2H), 1.69 (m, 2H), 1.47 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 166.5, 160.2, 151.1, 131.7, 127.8, 127.1, 127.1, 127.1, 127.1, 127.0, 126.9, 126.6, 125.6, 123.5, 123.4, 123.2, 122.9, 122.6, 121.3, 120.6, 119.6, 115.7, 74.7, 53.4, 30.3, 29.7. 1 H NMR (CDCl 3 , 500 MHz) δ 7.55 (m, 1H), 7.53 (d, 2H, J = 9.8 Hz), 7.43 (d, 1H, J = 8.6 Hz), 7.25 (m, 1H), 6.95 (d, 2H, J = 8.6 Hz), 5.33 (s, 1H), 4.32 (m, 1H), 3.74 (m, 1H), 2.31 (m, 2H), 2.18 (m, 2H), 1.69 (m, 2H), 1.47 (m, 2H); 13 C NMR (CDCL 3 , 125 MHz) Δ 166.5, 160.2, 151.1, 131.7, 127.8, 127.1, 127.1, 127.1, 127.1, 127.0, 126.9, 126.6, 125.6, 123.5, 123.2, 123.2, 122.9, 122.6, 121.3, 120.6, 120.6 , 119.6, 115.7, 74.7, 53.4, 30.3, 29.7.
17. 6-17. 6- 클로로Chloro -- NN -((1,4-트랜스)-4-(4-(트리플루오로메톡시)페녹시)사이클로헥실)벤조[-((1,4-trans)-4-(4-(trifluoromethoxy)phenoxy)cyclohexyl)benzo[ dd ]티아졸-2-아민 [6-]Thiazol-2-amine [6- ChloroChloro -- NN -((1,4--((1,4- transtrans )-4-(4-(trifluoromethoxy)phenoxy)cyclohexyl)benzo[)-4-(4-(trifluoromethoxy)phenoxy)cyclohexyl)benzo[ dd ]thiazol-2-amine] (화합물 17)]thiazol-2-amine] (Compound 17)
Figure PCTKR2022013755-appb-img-000019
Figure PCTKR2022013755-appb-img-000019
2,6-디클로로벤조티아졸 (2,6-dichlorobenzothiazole; 100.0 mg, 0.49 mmol)이 함유된 DMF (1.5 mL)에 (1,4-트랜스)-4-(4-(트리플루오로메톡시)페녹시)사이클로헥산-1-아민 ((1,4-trans)-4-(4-(trifluoromethoxy)phenoxy)cyclohexan-1-amine; 67.4 mg, 0.25 mmol) 및 탄산칼륨 (K2CO3; 67.7 mg, 0.49 mmol)을 주위 온도 (ambient temperature)에서 추가했다. 120 ℃에서 17시간 동안 교반한 후, 상기 혼합물을 물로 퀀칭 (quenching)시키고, 에틸아세테이트 (EtOAc)로 추출했다. 그 후, 합쳐진 유기층을 MgSO4상에서 건조시키고 진공에서 농축시켰다. 잔류물을 실리카겔에서 플래시 컬럼 크로마토그래피 (디클로로메탄:n-헥산:메탄올=25:5:1)에 의해 정제하여 46.5 mg (43 %)의 화합물 17을 흰색 고체로서 수득하였다.(1,4-trans)-4-(4-(trifluoromethoxy)phenoxy cy)cyclohexan-1-amine ((1,4- trans )-4-(4-(trifluoromethoxy)phenoxy)cyclohexan-1-amine; 67.4 mg, 0.25 mmol) and potassium carbonate (K 2 CO 3 ; 67.7 mg , 0.49 mmol) was added at ambient temperature. After stirring at 120 °C for 17 hours, the mixture was quenched with water and extracted with ethyl acetate (EtOAc). The combined organic layers were then dried over MgSO 4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane: n -hexane: methanol=25:5:1) to give 46.5 mg (43%) of compound 17 as a white solid.
1H NMR (CDCl3, 500 MHz) δ 7.55 (d, 1H, J = 2.0 Hz), 7.43 (d, 1H, J = 8.6 Hz), 7.25 (m, 1H), 7.13 (d, 2H, J = 8.7 Hz), 6.88 (d, 2H, J = 9.0 Hz), 5.31 (s, 1H), 4.21 (m, 1H), 3.72 (m, 1H), 2.30 (m, 2H), 2.17 (m, 2H), 1.66 (m, 2H), 1.44 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 166.5, 156.2, 151.2, 143.0, 131.7, 126.9, 126.6, 123.7, 122.6, 121.7, 120.6, 119.7, 117.6, 116.9, 75.3, 53.5, 30.4, 29.8. 1 H NMR (CDCl 3 , 500 MHz) δ 7.55 (d, 1H, J = 2.0 Hz), 7.43 (d, 1H, J = 8.6 Hz), 7.25 (m, 1H), 7.13 (d, 2H, J = 8.7 Hz), 6.88 (d, 2H, J = 9.0 Hz), 5.31 (s, 1H), 4.21 (m, 1H), 3.72 (m, 1H), 2.30 (m, 2H), 2.17 (m, 2H) , 1.66 (m, 2H), 1.44 (m, 2H); 13 C NMR (CDCl 3 , 125 MHz) δ 166.5, 156.2, 151.2, 143.0, 131.7, 126.9, 126.6, 123.7, 122.6, 121.7, 120.6, 119.7, 117.6, 116.5, 0, 75.4.3, 25.4.3
18. 4-(((1,4-트랜스)-4-((6-18. 4-(((1,4-trans)-4-((6- 클로로벤조[Chlorobenzo[ dd ]티아졸]thiazole -2-일)아미노)-2-yl)amino) 사이클로헥실cyclohexyl )옥시)벤조나이트릴 [4-(((1,4-)oxy)benzonitrile [4-(((1,4- transtrans )-4-((6-)-4-((6- Chlorobenzo[Chlorobenzo[ dd ]thiazol]thiazol -2-yl)amino)cyclohexyl)oxy)benzonitrile] (화합물 18)-2-yl)amino)cyclohexyl)oxy)benzonitrile] (Compound 18)
Figure PCTKR2022013755-appb-img-000020
Figure PCTKR2022013755-appb-img-000020
2,6-디클로로벤조티아졸 (2,6-dichlorobenzothiazole; 100.0 mg, 0.49 mmol)이 함유된 DMF (1.5 mL)에 4-(((1,4-트랜스)-4-아미노사이클로헥실)옥시)벤조나이트릴 (4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzonitrile; 52.9 mg, 0.25 mmol) 및 탄산칼륨 (K2CO3; 67.7 mg, 0.49 mmol)을 주위 온도 (ambient temperature)에서 추가했다. 120 ℃에서 17시간 동안 교반한 후, 상기 혼합물을 물로 퀀칭 (quenching)시키고, 에틸아세테이트 (EtOAc)로 추출했다. 그 후, 합쳐진 유기층을 MgSO4상에서 건조시키고 진공에서 농축시켰다. 잔류물을 실리카겔에서 플래시 컬럼 크로마토그래피 (에틸아세테이트:n-헥산=1:3)에 의해 정제하여 65.1 mg (69 %)의 화합물 18을 흰색 고체로서 수득하였다.4-(((1,4-trans)-4-aminocyclohexyl)oxy) Benzonitrile (4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzonitrile; 52.9 mg, 0.25 mmol) and potassium carbonate (K 2 CO 3 ; 67.7 mg, 0.49 mmol) were stirred at ambient temperature (ambient temperature) was added. After stirring at 120 °C for 17 hours, the mixture was quenched with water and extracted with ethyl acetate (EtOAc). The combined organic layers were then dried over MgSO 4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n -hexane=1:3) to give 65.1 mg (69%) of Compound 18 as a white solid.
1H NMR (CDCl3, 500 MHz) δ 7.57 (d, 2H, J = 8.8 Hz), 7.54 (d, 1H, J = 1.9 Hz), 7.42 (d, 1H, J = 8.6 Hz), 7.25 (dd, 1H, J = 8.7, 2.0 Hz), 6.93 (d, 2H, J = 8.8 Hz), 5.37 (s, 1H), 4.33 (m, 1H), 3.75 (m, 1H), 2.31 (m, 2H), 2.17 (m, 2H), 1.69 (m, 2H), 1.46 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 166.4, 161.1, 151.1, 134.2, 131.7, 126.9, 126.6, 120.6, 119.7, 119.3, 116.2, 103.9, 74.9, 53.2, 30.3, 29.6. 1 H NMR (CDCl 3 , 500 MHz) δ 7.57 (d, 2H, J = 8.8 Hz), 7.54 (d, 1H, J = 1.9 Hz), 7.42 (d, 1H, J = 8.6 Hz), 7.25 (dd , 1H, J = 8.7, 2.0 Hz), 6.93 (d, 2H, J = 8.8 Hz), 5.37 (s, 1H), 4.33 (m, 1H), 3.75 (m, 1H), 2.31 (m, 2H) , 2.17 (m, 2H), 1.69 (m, 2H), 1.46 (m, 2H); 13 C NMR (CDCl 3 , 125 MHz) δ 166.4, 161.1, 151.1, 134.2, 131.7, 126.9, 126.6, 120.6, 119.7, 119.3, 116.2, 103.9, 74.9, 53.2, 30.6, 29.6.
19. 6-19. 6- 클로로Chloro -- NN -- (( (1,4-트랜스)-4-(4-(1,4-trans)-4-(4- 나이트로페녹시nitrophenoxy )) 사이클로헥실cyclohexyl )) 벤조[benzo[ dd ]티아졸]thiazole -2-아민 [6--2-amine [6- ChloroChloro -- NN -((1,4--((1,4- transtrans )-4-(4-nitrophenoxy)cyclohexyl)benzo[)-4-(4-nitrophenoxy)cyclohexyl)benzo[ dd ]thiazol-2-amine] (화합물 19)]thiazol-2-amine] (Compound 19)
Figure PCTKR2022013755-appb-img-000021
Figure PCTKR2022013755-appb-img-000021
2,6-디클로로벤조티아졸 (2,6-dichlorobenzothiazole; 100.0 mg, 0.49 mmol)이 함유된 DMF (1.5 mL)에 (1,4-트랜스)-4-(4-나이트로페녹시)사이클로헥산-1-아민 ((1,4-trans)-4-(4-nitrophenoxy)cyclohexan-1-amine; 57.9 mg, 0.25 mmol) 및 탄산칼륨 (K2CO3; 67.7 mg, 0.49 mmol)을 주위 온도 (ambient temperature)에서 추가했다. 120 ℃에서 17시간 동안 교반한 후, 상기 혼합물을 물로 퀀칭 (quenching)시키고, 에틸아세테이트 (EtOAc)로 추출했다. 그 후, 합쳐진 유기층을 MgSO4상에서 건조시키고 진공에서 농축시켰다. 잔류물을 실리카겔에서 플래시 컬럼 크로마토그래피 (에틸아세테이트:n-헥산=1:2)에 의해 정제하여 65.6 mg (66 %)의 화합물 19를 밝은 노란색 고체로서 수득하였다.(1,4-trans)-4-(4-nitrophenoxy)cyclohexane in DMF (1.5 mL) containing 2,6-dichlorobenzothiazole (2,6-dichlorobenzothiazole; 100.0 mg, 0.49 mmol). -1-amine ((1,4- trans )-4-(4-nitrophenoxy)cyclohexan-1-amine; 57.9 mg, 0.25 mmol) and potassium carbonate (K 2 CO 3 ; 67.7 mg, 0.49 mmol) were added at ambient temperature. (ambient temperature). After stirring at 120 °C for 17 hours, the mixture was quenched with water and extracted with ethyl acetate (EtOAc). The combined organic layers were then dried over MgSO 4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n -hexane=1:2) to give 65.6 mg (66%) of compound 19 as a light yellow solid.
1H NMR (CDCl3, 500 MHz) δ 8.19 (d, 2H, J = 9.2 Hz), 7.54 (d, 1H, J = 1.9 Hz), 7.43 (d, 1H, J = 8.6 Hz), 7.25 (m, 1H), 6.94 (d, 2H, J = 9.2 Hz), 5.33 (s, 1H), 4.38 (m, 1H), 3.77 (m, 1H), 2.33 (m, 2H), 2.20 (m, 2H), 1.72 (m, 2H), 1.48 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 166.3, 162.9, 151.2, 141.5, 131.7, 127.0, 126.6, 126.2, 120.6, 119.7, 115.4, 75.4, 53.1, 30.3, 29.7. 1 H NMR (CDCl 3 , 500 MHz) δ 8.19 (d, 2H, J = 9.2 Hz), 7.54 (d, 1H, J = 1.9 Hz), 7.43 (d, 1H, J = 8.6 Hz), 7.25 (m , 1H), 6.94 (d, 2H, J = 9.2 Hz), 5.33 (s, 1H), 4.38 (m, 1H), 3.77 (m, 1H), 2.33 (m, 2H), 2.20 (m, 2H) , 1.72 (m, 2H), 1.48 (m, 2H); 13 C NMR (CDCl 3 , 125 MHz) δ 166.3, 162.9, 151.2, 141.5, 131.7, 127.0, 126.6, 126.2, 120.6, 119.7, 115.4, 75.4, 53.1, 30.3, 29.7.
20. 6-20. 6- 클로로Chloro -- NN -- (( (1,4-트랜스)-4-(4-((1,4-trans)-4-(4-( 메틸술포닐methylsulfonyl )) 페녹시phenoxy )) 사이클로헥실cyclohexyl )) 벤조[benzo[ dd ]티아졸]thiazole -2-아민 [6--2-amine [6- ChloroChloro -- NN -((1,4--((1,4- transtrans )-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)benzo[)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)benzo[ dd ]thiazol-2-amine] (화합물 20)]thiazol-2-amine] (Compound 20)
Figure PCTKR2022013755-appb-img-000022
Figure PCTKR2022013755-appb-img-000022
2,6-디클로로벤조티아졸 (2,6-dichlorobenzothiazole; 100.0 mg, 0.49 mmol)이 함유된 DMF (1.5 mL)에 (1,4-트랜스)-4-(4-(메틸술포닐)페녹시)사이클로헥산-1-아민 ((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexan-1-amine; 66.0 mg, 0.25 mmol) 및 탄산칼륨 (K2CO3; 67.7 mg, 0.49 mmol)을 주위 온도 (ambient temperature)에서 추가했다. 120 ℃에서 17시간 동안 교반한 후, 상기 혼합물을 물로 퀀칭 (quenching)시키고, 에틸아세테이트 (EtOAc)로 추출했다. 그 후, 합쳐진 유기층을 MgSO4상에서 건조시키고 진공에서 농축시켰다. 잔류물을 실리카겔에서 플래시 컬럼 크로마토그래피 (에틸아세테이트:디클로로메탄:메탄올=15:15:1)에 의해 정제하여 28.4 mg (26 %)의 화합물 20을 흰색 고체로서 수득하였다.(1,4-trans)-4-(4-(methylsulfonyl)phenoxy )cyclohexan-1-amine ((1,4- trans )-4-(4-(methylsulfonyl)phenoxy)cyclohexan-1-amine; 66.0 mg, 0.25 mmol) and potassium carbonate (K 2 CO 3 ; 67.7 mg, 0.49 mmol) was added at ambient temperature. After stirring at 120 °C for 17 hours, the mixture was quenched with water and extracted with ethyl acetate (EtOAc). The combined organic layers were then dried over MgSO 4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate:dichloromethane:methanol=15:15:1) to give 28.4 mg (26%) of compound 20 as a white solid.
1H NMR (CDCl3, 500 MHz) δ 7.86 (d, 2H, J = 8.9 Hz), 7.55 (d, 1H, J = 1.9 Hz), 7.43 (d, 1H, J = 8.6 Hz), 7.25 (m, 1H), 7.01 (d, 2H, J = 8.9 Hz), 5.14 (s, 1H), 4.38 (m, 1H), 3.78 (m, 1H), 3.03 (s, 3H), 2.33 (m, 2H), 2.20 (m, 2H), 1.71 (m, 2H), 1.48 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 166.2, 162.0, 151.2, 132.3, 131.8, 129.8, 127.0, 126.6, 120.6, 119.8, 116.0, 75.0, 53.2, 45.0, 30.3, 29.6. 1 H NMR (CDCl 3 , 500 MHz) δ 7.86 (d, 2H, J = 8.9 Hz), 7.55 (d, 1H, J = 1.9 Hz), 7.43 (d, 1H, J = 8.6 Hz), 7.25 (m , 1H), 7.01 (d, 2H, J = 8.9 Hz), 5.14 (s, 1H), 4.38 (m, 1H), 3.78 (m, 1H), 3.03 (s, 3H), 2.33 (m, 2H) , 2.20 (m, 2H), 1.71 (m, 2H), 1.48 (m, 2H); 13 C NMR (CDCl 3 , 125 MHz) δ 166.2, 162.0, 151.2, 132.3, 131.8, 129.8, 127.0, 126.6, 120.6, 119.8, 116.0, 75.0, 53.2, 45.0, 30.6.3, 29.6.
21. 4-(((1,4-트랜스)-4-((6-21. 4-(((1,4-trans)-4-((6- 클로로벤조[Chlorobenzo[ dd ]티아졸]thiazole -2-일)아미노)-2-yl)amino) 사이클로헥실cyclohexyl )옥시)벤젠술폰아마이드 [4-(((1,4-)oxy)benzenesulfonamide [4-(((1,4- transtrans )-4-((6-)-4-((6- Chlorobenzo[Chlorobenzo[ dd ]thiazol]thiazol -2-yl)amino)cyclohexyl)oxy)benzenesulfonamide] (화합물 21)-2-yl) amino) cyclohexyl) oxy) benzenesulfonamide] (Compound 21)
Figure PCTKR2022013755-appb-img-000023
Figure PCTKR2022013755-appb-img-000023
2,6-디클로로벤조티아졸 (2,6-dichlorobenzothiazole; 100.0 mg, 0.49 mmol)이 함유된 DMF (1.5 mL)에 4-(((1,4-트랜스)-4-아미노사이클로헥신)옥시)벤젠술폰아마이드 (4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzenesulfonamide; 66.2 mg, 0.25 mmol) 및 탄산칼륨 (K2CO3; 67.7 mg, 0.49 mmol)을 주위 온도 (ambient temperature)에서 추가했다. 120 ℃에서 17시간 동안 교반한 후, 상기 혼합물을 물로 퀀칭 (quenching)시키고, 에틸아세테이트 (EtOAc)로 추출했다. 그 후, 합쳐진 유기층을 MgSO4상에서 건조시키고 진공에서 농축시켰다. 잔류물을 실리카겔에서 플래시 컬럼 크로마토그래피 (에틸아세테이트:n-헥산=3:2)에 의해 정제하여 42.7 mg (40 %)의 화합물 21을 아이보리색 고체로서 수득하였다.4-(((1,4-trans)-4-aminocyclohexyne)oxy) Benzenesulfonamide (4-(((1,4- trans )-4-aminocyclohexyl)oxy)benzenesulfonamide; 66.2 mg, 0.25 mmol) and potassium carbonate (K 2 CO 3 ; 67.7 mg, 0.49 mmol) were prepared at ambient temperature (ambient temperature). temperature) was added. After stirring at 120 °C for 17 hours, the mixture was quenched with water and extracted with ethyl acetate (EtOAc). The combined organic layers were then dried over MgSO 4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n -hexane=3:2) to give 42.7 mg (40%) of compound 21 as an ivory solid.
1H NMR (DMSO-d 6, 500 MHz) δ 8.14 (d, 1H, J = 6.9 Hz), 7.77 (s, 1H), 7.73 (d, 2H, J = 8.5 Hz), 7.36 (d, 1H, J = 8.5 Hz), 7.22 (m, 1H), 7.19 (s, 2H), 7.12 (d, 2H, J = 8.5 Hz), 4.49 (m, 1H), 3.78 (m, 1H), 2.10 (m, 4H), 1.51 (m, 4H); 13C NMR (DMSO-d 6, 125 MHz) δ 165.8, 159.8, 151.6, 135.9, 131.9, 127.7, 125.6, 124.5, 120.5, 118.8, 115.4, 74.4, 51.9, 29.4, 29.2. 1 H NMR (DMSO- d 6 , 500 MHz) δ 8.14 (d, 1H, J = 6.9 Hz), 7.77 (s, 1H), 7.73 (d, 2H, J = 8.5 Hz), 7.36 (d, 1H, J = 8.5 Hz), 7.22 (m, 1H), 7.19 (s, 2H), 7.12 (d, 2H, J = 8.5 Hz), 4.49 (m, 1H), 3.78 (m, 1H), 2.10 (m, 4H), 1.51 (m, 4H); 13 C NMR (DMSO- d 6 , 125 MHz) δ 165.8, 159.8, 151.6, 135.9, 131.9, 127.7, 125.6, 124.5, 120.5, 118.8, 115.4, 74.4, 51.9, 29.4, 29.2.
22. 22. NN -((1,4-트랜스)-4-(4--((1,4-trans)-4-(4- 클로로페녹시Chlorophenoxy )) 사이클로헥실cyclohexyl )-6-)-6- (트리플루오로메틸)벤조[(trifluoromethyl)benzo[ dd ]티아졸]thiazole -2-아민 [-2-amine [ NN -((1,4--((1,4- transtrans )-4-(4-)-4-(4- ChlorophenoxyChlorophenoxy )) cyclohexylcyclohexyl )-6-(trifluoromethyl)benzo[)-6-(trifluoromethyl)benzo[ dd ]thiazol-2-amine] (화합물 22)]thiazol-2-amine] (Compound 22)
Figure PCTKR2022013755-appb-img-000024
Figure PCTKR2022013755-appb-img-000024
2-클로로-6-트리플루오로메틸벤조티아졸 (2-chloro-6-trifluoromethylbenzothiazole; 50.0 mg, 0.21 mmol)이 함유된 DMF (1.5 mL)에 (1,4-트랜스)-4-(4-클로로페녹시)사이클로헥산-1-아민 ((1,4-trans)-4-(4-chlorophenoxy)cyclohexan-1-amine; 52.1 mg, 0.23 mmol) 및 탄산칼륨 (K2CO3; 29.0 mg, 0.21 mmol)을 주위 온도 (ambient temperature)에서 추가했다. 100 ℃에서 5시간 동안 교반한 후, 상기 혼합물을 물로 퀀칭 (quenching)시키고, 에틸아세테이트 (EtOAc)로 추출했다. 그 후, 합쳐진 유기층을 MgSO4상에서 건조시키고 진공에서 농축시켰다. 잔류물을 실리카겔에서 플래시 컬럼 크로마토그래피 (에틸아세테이트:n-헥산=2:1)에 의해 정제하여 31.4 mg (35 %)의 화합물 22를 흰색 고체로서 수득하였다.(1,4-trans)-4-(4- Chlorophenoxy)cyclohexan-1-amine ((1,4- trans )-4-(4-chlorophenoxy)cyclohexan-1-amine; 52.1 mg, 0.23 mmol) and potassium carbonate (K 2 CO 3 ; 29.0 mg, 0.21 mmol) was added at ambient temperature. After stirring at 100 °C for 5 h, the mixture was quenched with water and extracted with ethyl acetate (EtOAc). The combined organic layers were then dried over MgSO 4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n -hexane=2:1) to give 31.4 mg (35%) of compound 22 as a white solid.
1H NMR (CDCl3, 500 MHz) δ 7.85 (s, 1H), 7.57 (d, 1H, J = 8.6 Hz), 7.54 (d, 1H, J = 8.6 Hz), 7.23 (d, 2H, J = 8.9 Hz), 6.83 (d, 2H, J = 8.9 Hz), 5.81 (s, 1H), 4.20 (m, 1H), 3.74 (m, 1H), 2.30 (m, 2H), 2.16 (m, 2H), 1.66 (m, 2H), 1.47 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 168.3, 156.2, 154.6, 130.4, 129.6, 127.8, 126.0, 125.7, 124.3, 124.0, 123.8, 123.6, 123.5, 123.5, 121.4, 118.6, 118.5, 118.4, 118.4, 118.4, 117.5, 75.0, 53.8, 30.2, 29.7. 1 H NMR (CDCl 3 , 500 MHz) δ 7.85 (s, 1H), 7.57 (d, 1H, J = 8.6 Hz), 7.54 (d, 1H, J = 8.6 Hz), 7.23 (d, 2H, J = 8.6 Hz) 8.9 Hz), 6.83 (d, 2H, J = 8.9 Hz), 5.81 (s, 1H), 4.20 (m, 1H), 3.74 (m, 1H), 2.30 (m, 2H), 2.16 (m, 2H) , 1.66 (m, 2H), 1.47 (m, 2H); 13 C NMR (CDCL 3 , 125 MHz) Δ 168.3, 156.2, 154.6, 130.4, 129.6, 127.8, 126.0, 125.7, 124.3, 124.0, 123.8, 123.6, 123.5, 123.5, 121.4, 118.5, 118.4, 118.4, 118.4, 118.4, 118.4 , 117.5, 75.0, 53.8, 30.2, 29.7.
23. 6-(23. 6 - ( 트리플루오로메틸trifluoromethyl )-)- NN -((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)사이클로헥실)벤조[-((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)benzo[ dd ]티아졸-2-아민 [6-(]Thiazol-2-amine [6-( TrifluoromethylTrifluoromethyl )-)- NN -((1,4--((1,4- transtrans )-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)benzo[)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)benzo[ dd ]thiazol-2-amine] (화합물 23)]thiazol-2-amine] (Compound 23)
Figure PCTKR2022013755-appb-img-000025
Figure PCTKR2022013755-appb-img-000025
2-클로로-6-트리플루오로메틸벤조티아졸 (2-chloro-6-trifluoromethylbenzothiazole; 50.0 mg, 0.21 mmol)이 함유된 DMF (1.5 mL)에 (1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)사이클로헥산-1-아민 ((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexan-1-amine; 59.9 mg, 0.23 mmol) 및 탄산칼륨 (K2CO3; 29.0 mg, 0.21 mmol)을 주위 온도 (ambient temperature)에서 추가했다. 100 ℃에서 5시간 동안 교반한 후, 상기 혼합물을 물로 퀀칭 (quenching)시키고, 에틸아세테이트 (EtOAc)로 추출했다. 그 후, 합쳐진 유기층을 MgSO4상에서 건조시키고 진공에서 농축시켰다. 잔류물을 실리카겔에서 플래시 컬럼 크로마토그래피 (디클로로메탄:n-헥산:메탄올=5:20:1)에 의해 정제하여 25.1 mg (26 %)의 화합물 23을 흰색 폼으로서 수득하였다.(1,4-trans)-4-(4- (trifluoromethyl)phenoxy)cyclohexan-1-amine ((1,4- trans )-4-(4-(trifluoromethyl)phenoxy)cyclohexan-1-amine; 59.9 mg, 0.23 mmol) and potassium carbonate ( K 2 CO 3 ; 29.0 mg, 0.21 mmol) was added at ambient temperature. After stirring at 100 °C for 5 h, the mixture was quenched with water and extracted with ethyl acetate (EtOAc). The combined organic layers were then dried over MgSO 4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane: n -hexane: methanol=5:20:1) to give 25.1 mg (26%) of compound 23 as a white foam.
1H NMR (CDCl3, 500 MHz) δ 7.85 (s, 1H), 7.57 (m, 2H), 7.54 (d, 2H, J = 8.0 Hz), 6.96 (d, 2H, J = 8.2 Hz), 5.82 (s, 1H), 4.34 (m, 1H), 3.78 (m, 1H), 2.33 (m, 2H), 2.20 (m, 2H), 1.71 (m, 2H), 1.51 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 168.2, 160.2, 154.2, 130.2, 127.8, 127.8, 127.2, 127.1, 127.1, 127.1, 125.6, 125.6, 124.5, 124.2, 123.9, 123.7, 123.6, 123.6, 123.6, 123.5, 123.4, 123.2, 123.0, 122.7, 121.3, 121.3, 118.6, 118.5, 118.5, 118.5, 118.4, 115.7, 74.5, 53.7, 30.1, 29.6. 1H NMR (CDCl 3 , 500 MHz) δ 7.85 (s, 1H), 7.57 (m, 2H), 7.54 (d, 2H, J = 8.0 Hz), 6.96 (d, 2H, J = 8.2 Hz), 5.82 (s, 1H), 4.34 (m, 1H), 3.78 (m, 1H), 2.33 (m, 2H), 2.20 (m, 2H), 1.71 (m, 2H), 1.51 (m, 2H); 13 C NMR (CDCL 3 , 125 MHz) Δ 168.2, 160.2, 154.2, 130.2, 127.8, 127.8, 127.2, 127.1, 127.1, 127.1, 125.6, 124.5, 124.2, 123.7, 123.7, 123.6, 123.6, 123.6, 123.5, 123.5 , 123.4, 123.2, 123.0, 122.7, 121.3, 121.3, 118.6, 118.5, 118.5, 118.5, 118.4, 115.7, 74.5, 53.7, 30.1, 29.6.
24. 24. NN -((1,4-트랜스)-4-(4-(-((1,4-trans)-4-(4-( 트리플루오로메톡시trifluoromethoxy )) 페녹시phenoxy )) 사이클로헥실cyclohexyl )-6-(트리플루오로메틸)벤조[)-6-(trifluoromethyl)benzo[ dd ]티아졸-2-아민 [N-((1,4-]thiazol-2-amine [N-((1,4- transtrans )-4-(4-(Trifluoromethoxy)phenoxy)cyclohexyl)-6-(trifluoromethyl)benzo[)-4-(4-(Trifluoromethoxy)phenoxy)cyclohexyl)-6-(trifluoromethyl)benzo[ dd ]thiazol-2-amine] (화합물 24)]thiazol-2-amine] (Compound 24)
Figure PCTKR2022013755-appb-img-000026
Figure PCTKR2022013755-appb-img-000026
2-클로로-6-트리플루오로메틸벤조티아졸 (2-chloro-6-trifluoromethylbenzothiazole; 50.0 mg, 0.21 mmol)이 함유된 DMF (1.5 mL)에 (1,4-트랜스)-4-(4-(트리플루오로메톡시)페녹시)사이클로헥산-1-아민 ((1,4-trans)-4-(4-(trifluoromethoxy)phenoxy)cyclohexan-1-amine; 63.5 mg, 0.23 mmol) 및 탄산칼륨 (K2CO3; 29.0 mg, 0.21 mmol)을 주위 온도 (ambient temperature)에서 추가했다. 100 ℃에서 5시간 동안 교반한 후, 상기 혼합물을 물로 퀀칭 (quenching)시키고, 에틸아세테이트 (EtOAc)로 추출했다. 그 후, 합쳐진 유기층을 MgSO4상에서 건조시키고 진공에서 농축시켰다. 잔류물을 실리카겔에서 플래시 컬럼 크로마토그래피 (에틸아세테이트:n-헥산=1:3)에 의해 정제하여 13.0 mg (13 %)의 화합물 24를 흰색 고체로서 수득하였다.(1,4-trans)-4-(4- (trifluoromethoxy)phenoxy)cyclohexan-1-amine ((1,4- trans )-4-(4-(trifluoromethoxy)phenoxy)cyclohexan-1-amine; 63.5 mg, 0.23 mmol) and potassium carbonate ( K 2 CO 3 ; 29.0 mg, 0.21 mmol) was added at ambient temperature. After stirring at 100 °C for 5 h, the mixture was quenched with water and extracted with ethyl acetate (EtOAc). The combined organic layers were then dried over MgSO 4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n -hexane=1:3) to give 13.0 mg (13%) of Compound 24 as a white solid.
1H NMR (CDCl3, 500 MHz) δ 7.85 (s, 1H), 7.58 (d, 1H, J = 8.8 Hz), 7.56 (d, 1H, J = 8.7 Hz), 7.14 (d, 2H, J = 8.5 Hz), 6.89 (d, 2H, J = 9.1 Hz), 4.25 (m, 1H), 3.75 (m, 1H), 2.31 (m, 2H), 2.19 (m, 2H), 1.70 (m, 2H), 1.51 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 168.3, 156.1, 153.6, 143.0, 143.0, 129.8, 127.8, 125.6, 124.6, 124.4, 124.1, 123.8, 123.8, 123.8, 123.7, 123.7, 123.4, 122.7, 121.7, 121.3, 119.7, 118.6, 118.6, 118.5, 118.5, 118.4, 117.6, 116.9, 75.0, 53.9, 30.0, 29.6. 1 H NMR (CDCl 3 , 500 MHz) δ 7.85 (s, 1H), 7.58 (d, 1H, J = 8.8 Hz), 7.56 (d, 1H, J = 8.7 Hz), 7.14 (d, 2H, J = 8.5 Hz), 6.89 (d, 2H, J = 9.1 Hz), 4.25 (m, 1H), 3.75 (m, 1H), 2.31 (m, 2H), 2.19 (m, 2H), 1.70 (m, 2H) , 1.51 (m, 2H); 13 C NMR (CDCL 3 , 125 MHz) Δ 168.3, 156.1, 153.6, 143.0, 129.8, 127.8, 125.6, 124.6, 124.4, 124.1, 123.8, 123.8, 123.8, 123.7, 123.7, 123.4, 122.7, 121.7, 121.3 , 119.7, 118.6, 118.6, 118.5, 118.5, 118.4, 117.6, 116.9, 75.0, 53.9, 30.0, 29.6.
25. 4-(((1,4-트랜스)-4-((6-25. 4-(((1,4-trans)-4-((6- (트리플루오로메틸)벤조[(trifluoromethyl)benzo[ dd ]티아졸]thiazole -2-일)아미노)사이클로헥실)옥시)벤조나이트릴 [4-(((1,4--2-yl)amino)cyclohexyl)oxy)benzonitrile [4-(((1,4- transtrans )-4-((6-(Trifluoromethyl)benzo[)-4-((6-(Trifluoromethyl)benzo[ dd ]thiazol-2-yl)amino)cyclohexyl)oxy)benzonitrile] (화합물 25)]thiazol-2-yl)amino)cyclohexyl)oxy)benzonitrile] (Compound 25)
Figure PCTKR2022013755-appb-img-000027
Figure PCTKR2022013755-appb-img-000027
2-클로로-6-트리플루오로메틸벤조티아졸 (2-chloro-6-trifluoromethylbenzothiazole; 50.0 mg, 0.21 mmol)이 함유된 DMF (1.5 mL)에 4-(((1,4-트랜스)-4-아미노사이클로헥실)옥시)벤조나이트릴 (4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzonitrile; 50.1 mg, 0.23 mmol) 및 탄산칼륨 (K2CO3; 29.0 mg, 0.21 mmol)을 주위 온도 (ambient temperature)에서 추가했다. 100 ℃에서 5시간 동안 교반한 후, 상기 혼합물을 물로 퀀칭 (quenching)시키고, 에틸아세테이트 (EtOAc)로 추출했다. 그 후, 합쳐진 유기층을 MgSO4상에서 건조시키고 진공에서 농축시켰다. 잔류물을 실리카겔에서 플래시 컬럼 크로마토그래피 (에틸아세테이트:n-헥산=1:2)에 의해 정제하여 57.2 mg (65 %)의 화합물 25를 흰색 고체로서 수득하였다.4-(((1,4-trans)-4 in DMF (1.5 mL) containing 2-chloro-6-trifluoromethylbenzothiazole (2-chloro-6-trifluoromethylbenzothiazole; 50.0 mg, 0.21 mmol) -aminocyclohexyl)oxy)benzonitrile (4-(((1,4- trans )-4-aminocyclohexyl)oxy)benzonitrile; 50.1 mg, 0.23 mmol) and potassium carbonate (K 2 CO 3 ; 29.0 mg, 0.21 mmol) was added at ambient temperature. After stirring at 100 °C for 5 h, the mixture was quenched with water and extracted with ethyl acetate (EtOAc). The combined organic layers were then dried over MgSO 4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n -hexane=1:2) to give 57.2 mg (65%) of compound 25 as a white solid.
1H NMR (CDCl3, 500 MHz) δ 7.84 (s, 1H), 7.57 (m, 3H), 7.54 (d, 1H, J = 8.7 Hz), 6.94 (d, 2H, J = 8.8 Hz), 5.77 (s, 1H), 4.35 (m, 1H), 3.79 (m, 1H), 2.33 (m, 2H), 2.19 (m, 2H), 1.71 (m, 2H), 1.51 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 168.1, 161.1, 154.5, 134.2, 130.4, 127.8, 125.7, 124.4, 124.1, 123.9, 123.6, 123.6, 123.5, 123.5, 123.5, 121.3, 119.3, 118.7, 118.5, 118.5, 118.4, 118.4, 116.2, 104.0, 74.7, 53.5, 30.1, 29.5. 1H NMR (CDCl 3 , 500 MHz) δ 7.84 (s, 1H), 7.57 (m, 3H), 7.54 (d, 1H, J = 8.7 Hz), 6.94 (d, 2H, J = 8.8 Hz), 5.77 (s, 1H), 4.35 (m, 1H), 3.79 (m, 1H), 2.33 (m, 2H), 2.19 (m, 2H), 1.71 (m, 2H), 1.51 (m, 2H); 13 C NMR (CDCL 3 , 125 MHz) Δ 168.1, 161.1, 154.5, 134.2, 130.4, 127.8, 125.7, 124.4, 124.1, 123.9, 123.6, 123.6, 123.5, 123.5, 123.5, 121.3, 119.3, 118.7, 118.5, 118.5, 118.5, 118.5 , 118.4, 118.4, 116.2, 104.0, 74.7, 53.5, 30.1, 29.5.
26. 26. NN -((1,4-트랜스)-4-(4--((1,4-trans)-4-(4- 나이트로페녹시nitrophenoxy )) 사이클로헥실cyclohexyl )-6-)-6- (트리플루오로메틸)벤조[(trifluoromethyl)benzo[ dd ]티아졸]thiazole -2-아민 [-2-amine [ NN -((1,4--((1,4- transtrans )-4-(4-)-4-(4- NitrophenoxyNitrophenoxy )) cyclohexylcyclohexyl )-6-(trifluoromethyl)benzo[)-6-(trifluoromethyl)benzo[ dd ]thiazol-2-amine] (화합물 26)]thiazol-2-amine] (Compound 26)
Figure PCTKR2022013755-appb-img-000028
Figure PCTKR2022013755-appb-img-000028
2-클로로-6-트리플루오로메틸벤조티아졸 (2-chloro-6-trifluoromethylbenzothiazole; 50.0 mg, 0.21 mmol)이 함유된 DMF (1.5 mL)에 (1,4-트랜스)-4-(4-나이트로페녹시)사이클로헥산-1-아민 ((1,4-trans)-4-(4-nitrophenoxy)cyclohexan-1-amine; 54.6 mg, 0.23 mmol) 및 탄산칼륨 (K2CO3; 29.0 mg, 0.21 mmol)을 주위 온도 (ambient temperature)에서 추가했다. 100 ℃에서 5시간 동안 교반한 후, 상기 혼합물을 물로 퀀칭 (quenching)시키고, 에틸아세테이트 (EtOAc)로 추출했다. 그 후, 합쳐진 유기층을 MgSO4상에서 건조시키고 진공에서 농축시켰다. 잔류물을 실리카겔에서 플래시 컬럼 크로마토그래피 (에틸아세테이트:n-헥산=1:3)에 의해 정제하여 44.7 mg (49 %)의 화합물 26을 노란색 고체로서 수득하였다.(1,4-trans)-4-(4- Nitrophenoxy)cyclohexan-1-amine ((1,4- trans )-4-(4-nitrophenoxy)cyclohexan-1-amine; 54.6 mg, 0.23 mmol) and potassium carbonate (K 2 CO 3 ; 29.0 mg , 0.21 mmol) was added at ambient temperature. After stirring at 100 °C for 5 h, the mixture was quenched with water and extracted with ethyl acetate (EtOAc). The combined organic layers were then dried over MgSO 4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n -hexane=1:3) to give 44.7 mg (49%) of compound 26 as a yellow solid.
1H NMR (CDCl3, 500 MHz) δ 8.19 (d, 2H, J = 9.2 Hz), 7.85 (s, 1H), 7.58 (d, 1H, J = 8.5 Hz), 7.55 (d, 1H, J = 8.6 Hz), 6.95 (d, 2H, J = 9.2 Hz), 4.41 (m, 1H), 3.81 (m, 1H), 2.35 (m, 2H), 2.22 (m, 2H), 1.74 (m, 2H), 1.53 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 168.1, 162.9, 154.3, 141.5, 130.3, 127.8, 126.2, 125.6, 124.5, 124.2, 124.0, 123.7, 123.6, 123.6, 123.6, 123.6, 123.5, 121.3, 118.6, 118.5, 118.5, 118.4, 118.4, 115.4, 75.2, 53.5, 30.0, 29.5. 1 H NMR (CDCl 3 , 500 MHz) δ 8.19 (d, 2H, J = 9.2 Hz), 7.85 (s, 1H), 7.58 (d, 1H, J = 8.5 Hz), 7.55 (d, 1H, J = 8.6 Hz), 6.95 (d, 2H, J = 9.2 Hz), 4.41 (m, 1H), 3.81 (m, 1H), 2.35 (m, 2H), 2.22 (m, 2H), 1.74 (m, 2H) , 1.53 (m, 2H); 13 C NMR (CDCL 3 , 125 MHz) Δ 168.1, 162.9, 154.3, 141.5, 130.3, 127.8, 126.2, 125.6, 124.5, 124.2, 124.0, 123.7, 123.6, 123.6, 123.6, 123.6, 123.5, 121.3, 118.6, 118.5 , 118.5, 118.4, 118.4, 115.4, 75.2, 53.5, 30.0, 29.5.
27. 27. NN -((1,4-트랜스)-4-(4-(-((1,4-trans)-4-(4-( 메틸술포닐methylsulfonyl )) 페녹시phenoxy )) 사이클로헥실cyclohexyl )-6-)-6- (트리플루오로메틸)벤조[(trifluoromethyl)benzo[ dd ]티아졸]thiazole -2-아민 [-2-amine [ NN -((1,4--((1,4- transtrans )-4-(4-(Methylsulfonyl)phenoxy)cyclohexyl)-6-(trifluoromethyl)benzo[)-4-(4-(Methylsulfonyl)phenoxy)cyclohexyl)-6-(trifluoromethyl)benzo[ dd ]thiazol-2-amine] (화합물 27)]thiazol-2-amine] (Compound 27)
Figure PCTKR2022013755-appb-img-000029
Figure PCTKR2022013755-appb-img-000029
2-클로로-6-트리플루오로메틸벤조티아졸 (2-chloro-6-trifluoromethylbenzothiazole; 50.0 mg, 0.21 mmol)이 함유된 DMF (1.5 mL)에 (1,4-트랜스)-4-(4-(메틸술포닐)페녹시)사이클로헥산-1-아민 ((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexan-1-amine; 62.0 mg, 0.23 mmol) 및 탄산칼륨 (K2CO3; 29.0 mg, 0.21 mmol)을 주위 온도 (ambient temperature)에서 추가했다. 100 ℃에서 5시간 동안 교반한 후, 상기 혼합물을 물로 퀀칭 (quenching)시키고, 에틸아세테이트 (EtOAc)로 추출했다. 그 후, 합쳐진 유기층을 MgSO4상에서 건조시키고 진공에서 농축시켰다. 잔류물을 실리카겔에서 플래시 컬럼 크로마토그래피 (에틸아세테이트:n-헥산=2:1)에 의해 정제하여 40.5 mg (41 %)의 화합물 27을 흰색 고체로서 수득하였다.(1,4-trans)-4-(4- (methylsulfonyl)phenoxy)cyclohexan-1-amine ((1,4- trans )-4-(4-(methylsulfonyl)phenoxy)cyclohexan-1-amine; 62.0 mg, 0.23 mmol) and potassium carbonate (K 2 CO 3 ; 29.0 mg, 0.21 mmol) was added at ambient temperature. After stirring at 100 °C for 5 h, the mixture was quenched with water and extracted with ethyl acetate (EtOAc). The combined organic layers were then dried over MgSO 4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n -hexane=2:1) to give 40.5 mg (41%) of compound 27 as a white solid.
1H NMR (CDCl3, 500 MHz) δ 7.86 (d, 2H, J = 9.0 Hz), 7.84 (s, 1H), 7.58 (d, 1H, J = 8.5 Hz), 7.55 (d, 1H, J = 8.6 Hz), 7.01 (d, 2H, J = 8.7 Hz), 4.39 (m, 1H), 3.79 (m, 1H), 3.04 (s, 3H), 2.32 (m, 2H), 2.20 (m, 2H), 1.72 (m, 2H), 1.54 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 168.2, 161.9, 153.8, 132.3, 130.0, 129.8, 127.8, 125.6, 124.5, 124.3, 124.0, 123.8, 123.7, 123.7, 123.7, 123.6, 123.4, 121.3, 118.5, 118.5, 118.5, 118.5, 116.0, 74.7, 53.6, 45.0, 29.9, 29.4. 1H NMR (CDCl 3 , 500 MHz) δ 7.86 (d, 2H, J = 9.0 Hz), 7.84 (s, 1H), 7.58 (d, 1H, J = 8.5 Hz), 7.55 (d, 1H, J = 8.6 Hz), 7.01 (d, 2H, J = 8.7 Hz), 4.39 (m, 1H), 3.79 (m, 1H), 3.04 (s, 3H), 2.32 (m, 2H), 2.20 (m, 2H) , 1.72 (m, 2H), 1.54 (m, 2H); 13 C NMR (CDCL 3 , 125 MHz) Δ 168.2, 161.9, 153.8, 130.0, 129.8, 127.8, 125.6, 124.5, 124.3, 124.0, 123.8, 123.7, 123.7, 123.7, 123.6, 123.4, 121.3, 118.5, 118.5 , 118.5, 118.5, 116.0, 74.7, 53.6, 45.0, 29.9, 29.4.
28. 4-(((1,4-트랜스)-4-((6-28. 4-(((1,4-trans)-4-((6- (트리플루오로메틸)벤조[(trifluoromethyl)benzo[ dd ]티아졸]thiazole -2-일)아미노)사이클로헥실)옥시)벤젠술폰아마이드 [4-(((1,4--2-yl)amino)cyclohexyl)oxy)benzenesulfonamide [4-(((1,4- transtrans )-4-((6-(Trifluoromethyl)benzo[)-4-((6-(Trifluoromethyl)benzo[ dd ]thiazol-2-yl)amino)cyclohexyl)oxy)benzenesulfonamide] (화합물 28)]thiazol-2-yl)amino)cyclohexyl)oxy)benzenesulfonamide] (Compound 28)
Figure PCTKR2022013755-appb-img-000030
Figure PCTKR2022013755-appb-img-000030
2-클로로-6-트리플루오로메틸벤조티아졸 (2-chloro-6-trifluoromethylbenzothiazole; 50.0 mg, 0.21 mmol)이 함유된 DMF (1.5 mL)에 4-(((1,4-트랜스)-4-아미노사이클로헥실)옥시)벤젠술폰아마이드 (4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzenesulfonamide; 62.0 mg, 0.23 mmol) 및 탄산칼륨 (K2CO3; 29.0 mg, 0.21 mmol)을 주위 온도 (ambient temperature)에서 추가했다. 100 ℃에서 5시간 동안 교반한 후, 상기 혼합물을 물로 퀀칭 (quenching)시키고, 에틸아세테이트 (EtOAc)로 추출했다. 그 후, 합쳐진 유기층을 MgSO4상에서 건조시키고 진공에서 농축시켰다. 잔류물을 실리카겔에서 플래시 컬럼 크로마토그래피 (에틸아세테이트:n-헥산=2:1)에 의해 정제하여 31.5 mg (32 %)의 화합물 28을 흰색 고체로서 수득하였다.4-(((1,4-trans)-4 in DMF (1.5 mL) containing 2-chloro-6-trifluoromethylbenzothiazole (2-chloro-6-trifluoromethylbenzothiazole; 50.0 mg, 0.21 mmol) -Aminocyclohexyl)oxy)benzenesulfonamide (4-(((1,4- trans )-4-aminocyclohexyl)oxy)benzenesulfonamide; 62.0 mg, 0.23 mmol) and potassium carbonate (K 2 CO 3 ; 29.0 mg, 0.21 mmol) was added at ambient temperature. After stirring at 100 °C for 5 h, the mixture was quenched with water and extracted with ethyl acetate (EtOAc). The combined organic layers were then dried over MgSO 4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n -hexane=2:1) to give 31.5 mg (32%) of compound 28 as a white solid.
1H NMR (DMSO-d 6, 500 MHz) δ 8.41 (d, 1H, J = 6.0 Hz), 8.11 (s, 1H), 7.73 (d, 2H, J = 7.4 Hz), 7.51 (m, 2H), 7.19 (s, 2H), 7.12 (d, 2H, J = 7.4 Hz), 4.50 (m, 1H), 3.84 (m, 1H), 2.12 (m, 4H), 1.53 (m, 4H); 13C NMR (DMSO-d 6, 125 MHz) δ 167.8, 159.8, 155.7, 135.9, 130.9, 128.1, 127.7, 125.9, 123.8, 122.7, 121.7, 121.3, 121.1, 120.8, 120.6, 118.5, 117.7, 115.4, 74.4, 52.0, 29.4, 29.2. 1 H NMR (DMSO- d 6 , 500 MHz) δ 8.41 (d, 1H, J = 6.0 Hz), 8.11 (s, 1H), 7.73 (d, 2H, J = 7.4 Hz), 7.51 (m, 2H) , 7.19 (s, 2H), 7.12 (d, 2H, J = 7.4 Hz), 4.50 (m, 1H), 3.84 (m, 1H), 2.12 (m, 4H), 1.53 (m, 4H); 13 C NMR (DMSO- D 6 , 125 MHz) Δ 167.8, 159.8, 155.7, 135.9, 130.9, 128.1, 127.7, 125.9, 123.8, 122.7, 121.7, 121.3, 121.1, 120.8, 120.6, 118.5, 117.7, 115.4, 74.4 , 52.0, 29.4, 29.2.
29. 29. NN -((1,4-트랜스)-4-(4--((1,4-trans)-4-(4- 클로로페녹시Chlorophenoxy )) 사이클로헥실cyclohexyl )-6-)-6- 나이트로벤조[nitrobenzo[ dd ]티아졸]thiazole -2-아민 [-2-amine [ NN -((1,4--((1,4- transtrans )-4-(4-)-4-(4- ChlorophenoxyChlorophenoxy )) cyclohexylcyclohexyl )-6-nitrobenzo[)-6-nitrobenzo[ dd ]thiazol-2-amine] (화합물 29)]thiazol-2-amine] (Compound 29)
Figure PCTKR2022013755-appb-img-000031
Figure PCTKR2022013755-appb-img-000031
2-클로로-6-나이트로벤조티아졸 (2-chloro-6-nitrobenzothiazole; 70.0 mg, 0.33 mmol)이 함유된 DMF (1.5 mL)에 (1,4-트랜스)-4-(4-클로로페녹시)사이클로헥산-1-아민 ((1,4-trans)-4-(4-chlorophenoxy)cyclohexan-1-amine; 73.6 mg, 0.33 mmol) 및 탄산칼륨 (K2CO3; 45.0 mg, 0.33 mmol)을 주위 온도 (ambient temperature)에서 추가했다. 1시간 동안 교반한 후, 상기 혼합물을 물로 퀀칭 (quenching)시키고, 에틸아세테이트 (EtOAc)로 추출했다. 그 후, 합쳐진 유기층을 MgSO4상에서 건조시키고 진공에서 농축시켰다. 잔류물을 실리카겔에서 플래시 컬럼 크로마토그래피 (에틸아세테이트:n-헥산=1:1)에 의해 정제하여 47.6 mg (36 %)의 화합물 29를 노란색 고체로서 수득하였다.(1,4-trans)-4-(4-chlorophenone) in DMF (1.5 mL) containing 2-chloro-6-nitrobenzothiazole (70.0 mg, 0.33 mmol) cy)cyclohexan-1-amine ((1,4- trans )-4-(4-chlorophenoxy)cyclohexan-1-amine; 73.6 mg, 0.33 mmol) and potassium carbonate (K 2 CO 3 ; 45.0 mg, 0.33 mmol) ) was added at ambient temperature. After stirring for 1 hour, the mixture was quenched with water and extracted with ethyl acetate (EtOAc). The combined organic layers were then dried over MgSO 4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n -hexane=1:1) to give 47.6 mg (36%) of compound 29 as a yellow solid.
1H NMR (CDCl3, 500 MHz) δ 8.49 (d, 1H, J = 2.2 Hz), 8.20 (dd, 1H, J = 8.9, 2.3 Hz), 7.52 (d, 1H, J = 8.9 Hz), 7.22 (d, 2H, J = 9.0 Hz), 6.83 (d, 2H, J = 8.9 Hz), 4.22 (m, 1H), 3.77 (m, 1H), 2.30 (m, 2H), 2.18 (m, 2H), 1.68 (m, 2H), 1.51 (m, 2H); 13C NMR (DMSO-d 6, 125 MHz) δ 170.1, 156.5, 156.1, 142.3, 130.2, 129.6, 126.0, 122.8, 117.8, 117.6, 117.5, 74.7, 54.2, 29.9, 29.6. 1H NMR (CDCl 3 , 500 MHz) δ 8.49 (d, 1H, J = 2.2 Hz), 8.20 (dd, 1H, J = 8.9, 2.3 Hz), 7.52 (d, 1H, J = 8.9 Hz), 7.22 (d, 2H, J = 9.0 Hz), 6.83 (d, 2H, J = 8.9 Hz), 4.22 (m, 1H), 3.77 (m, 1H), 2.30 (m, 2H), 2.18 (m, 2H) , 1.68 (m, 2H), 1.51 (m, 2H); 13 C NMR (DMSO- d 6 , 125 MHz) δ 170.1, 156.5, 156.1, 142.3, 130.2, 129.6, 126.0, 122.8, 117.8, 117.6, 117.5, 74.7, 54.2, 29.9, 29.6.
30. 6-나이트로-30. 6-Nitro- NN -((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)사이클로헥실)벤조[-((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)benzo[ dd ]티아졸-2-아민 [6-Nitro-]Thiazol-2-amine [6-Nitro- NN -((1,4--((1,4- transtrans )-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)benzo[)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)benzo[ dd ]thiazol-2-amine] (화합물 30)]thiazol-2-amine] (Compound 30)
Figure PCTKR2022013755-appb-img-000032
Figure PCTKR2022013755-appb-img-000032
2-클로로-6-나이트로벤조티아졸 (2-chloro-6-nitrobenzothiazole; 50.0 mg, 0.23 mmol)이 함유된 DMF (1.5 mL)에 (1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)사이클로헥산-1-아민 ((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexan-1-amine; 60.4 mg, 0.23 mmol) 및 탄산칼륨 (K2CO3; 32.2 mg, 0.23 mmol)을 주위 온도 (ambient temperature)에서 추가했다. 1시간 동안 교반한 후, 상기 혼합물을 물로 퀀칭 (quenching)시키고, 에틸아세테이트 (EtOAc)로 추출했다. 그 후, 합쳐진 유기층을 MgSO4상에서 건조시키고 진공에서 농축시켰다. 잔류물을 실리카겔에서 플래시 컬럼 크로마토그래피 (에틸아세테이트:n-헥산=1:4)에 의해 정제하여 77.2 mg (76 %)의 화합물 30을 노란색 폼으로서 수득하였다.(1,4-trans)-4-(4-(tri) in DMF (1.5 mL) containing 2-chloro-6-nitrobenzothiazole (2-chloro-6-nitrobenzothiazole; 50.0 mg, 0.23 mmol) Fluoromethyl)phenoxy)cyclohexan-1-amine ((1,4- trans )-4-(4-(trifluoromethyl)phenoxy)cyclohexan-1-amine; 60.4 mg, 0.23 mmol) and potassium carbonate (K 2 CO 3 ; 32.2 mg, 0.23 mmol) was added at ambient temperature. After stirring for 1 hour, the mixture was quenched with water and extracted with ethyl acetate (EtOAc). The combined organic layers were then dried over MgSO 4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n -hexane=1:4) to give 77.2 mg (76%) of compound 30 as a yellow foam.
1H NMR (CDCl3, 500 MHz) δ 8.51 (d, 1H, J = 2.1 Hz), 8.21 (dd, 1H, J = 9.0, 2.1 Hz), 7.54 (d, 2H, J = 8.3 Hz), 7.53 (d, 1H, J = 8.7 Hz), 6.96 (d, 2H, J = 8.6 Hz), 5.66 (s, 1H), 4.35 (m, 1H), 3.83 (m, 1H), 2.34 (m, 2H), 2.21 (m, 2H), 1.72 (m, 2H), 1.52 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 170.0, 160.1, 157.8, 142.2, 130.9, 127.7, 127.2, 127.1, 127.1, 127.1, 125.6, 123.5, 123.4, 123.3, 123.0, 122.7, 122.7, 121.3, 118.3, 117.5, 115.7, 74.5, 53.7, 30.1, 29.6. 1 H NMR (CDCl 3 , 500 MHz) δ 8.51 (d, 1H, J = 2.1 Hz), 8.21 (dd, 1H, J = 9.0, 2.1 Hz), 7.54 (d, 2H, J = 8.3 Hz), 7.53 (d, 1H, J = 8.7 Hz), 6.96 (d, 2H, J = 8.6 Hz), 5.66 (s, 1H), 4.35 (m, 1H), 3.83 (m, 1H), 2.34 (m, 2H) , 2.21 (m, 2H), 1.72 (m, 2H), 1.52 (m, 2H); 13 C NMR (CDCL 3 , 125 MHz) Δ 170.0, 160.1, 157.8, 142.2, 130.9, 127.7, 127.2, 127.1, 127.1, 127.1, 125.6, 123.5, 123.4, 123.3, 123.0, 122.7, 122.7, 121.3, 118.3, 117.5 , 115.7, 74.5, 53.7, 30.1, 29.6.
31. 6-나이트로-31. 6-Nitro- NN -((1,4-트랜스)-4-(4-(트리플루오로메톡시)페녹시)사이클로헥실)벤조[-((1,4-trans)-4-(4-(trifluoromethoxy)phenoxy)cyclohexyl)benzo[ dd ]티아졸-2-아민 [6-Nitro-]Thiazol-2-amine [6-Nitro- NN -((1,4--((1,4- transtrans )-4-(4-(trifluoromethoxy)phenoxy)cyclohexyl)benzo[)-4-(4-(trifluoromethoxy)phenoxy)cyclohexyl)benzo[ dd ]thiazol-2-amine] (화합물 31)]thiazol-2-amine] (Compound 31)
Figure PCTKR2022013755-appb-img-000033
Figure PCTKR2022013755-appb-img-000033
2-클로로-6-나이트로벤조티아졸 (2-chloro-6-nitrobenzothiazole; 70.0 mg, 0.33 mmol)이 함유된 DMF (1.5 mL)에 (1,4-트랜스)-4-(4-(트리플루오로메톡시)페녹시)사이클로헥산-1-아민 ((1,4-trans)-4-(4-(trifluoromethoxy)phenoxy)cyclohexan-1-amine; 89.7 mg, 0.33 mmol) 및 탄산칼륨 (K2CO3; 45.0 mg, 0.33 mmol)을 주위 온도 (ambient temperature)에서 추가했다. 1시간 동안 교반한 후, 상기 혼합물을 물로 퀀칭 (quenching)시키고, 에틸아세테이트 (EtOAc)로 추출했다. 그 후, 합쳐진 유기층을 MgSO4상에서 건조시키고 진공에서 농축시켰다. 잔류물을 실리카겔에서 플래시 컬럼 크로마토그래피 (에틸아세테이트:n-헥산=1:1)에 의해 정제하여 80.5 mg (54 %)의 화합물 31을 노란색 고체로서 수득하였다.(1,4-trans)-4-(4-(tri) in DMF (1.5 mL) containing 2-chloro-6-nitrobenzothiazole (2-chloro-6-nitrobenzothiazole; 70.0 mg, 0.33 mmol) Fluoromethoxy)phenoxy)cyclohexan-1-amine ((1,4- trans )-4-(4-(trifluoromethoxy)phenoxy)cyclohexan-1-amine; 89.7 mg, 0.33 mmol) and potassium carbonate (K 2 CO 3 ; 45.0 mg, 0.33 mmol) was added at ambient temperature. After stirring for 1 hour, the mixture was quenched with water and extracted with ethyl acetate (EtOAc). The combined organic layers were then dried over MgSO 4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n -hexane=1:1) to give 80.5 mg (54%) of compound 31 as a yellow solid.
1H NMR (CDCl3, 500 MHz) δ 8.51 (d, 1H, J = 2.2 Hz), 8.22 (dd, 1H, J = 9.0, 2.3 Hz), 7.54 (d, 1H, J = 8.9 Hz), 7.13 (d, 2H, J = 8.9 Hz), 6.89 (d, 2H, J = 9.1 Hz), 4.26 (m, 1H), 3.79 (m, 1H), 2.32 (m, 2H), 2.20 (m, 2H), 1.70 (m, 2H), 1.54 (m, 2H); 13C NMR (DMSO-d 6, 125 MHz) δ 169.9, 156.0, 154.4, 143.0, 143.0, 142.7, 129.1, 123.7, 123.2, 122.7, 121.7, 119.6, 117.8, 117.6, 117.5, 116.9, 74.6, 54.6, 29.6, 29.3. 1 H NMR (CDCl 3 , 500 MHz) δ 8.51 (d, 1H, J = 2.2 Hz), 8.22 (dd, 1H, J = 9.0, 2.3 Hz), 7.54 (d, 1H, J = 8.9 Hz), 7.13 (d, 2H, J = 8.9 Hz), 6.89 (d, 2H, J = 9.1 Hz), 4.26 (m, 1H), 3.79 (m, 1H), 2.32 (m, 2H), 2.20 (m, 2H) , 1.70 (m, 2H), 1.54 (m, 2H); 13 C NMR (DMSO- d 6 , 125 MHz) δ 169.9, 156.0, 154.4, 143.0, 143.0, 142.7, 129.1, 123.7, 123.2, 122.7, 121.7, 119.6, 117.8, 117.6, 117.5, 116.6, 2 94.6, 2 94.6, 2 94.6
32. 4-(((1,4-트랜스)-4-((6-32. 4-(((1,4-trans)-4-((6- 나이트로벤조[nitrobenzo[ dd ]티아졸]thiazole -2-일)아미노)-2-yl)amino) 사이클로헥실cyclohexyl )옥시)벤조나이트릴 [4-(((1,4-)oxy)benzonitrile [4-(((1,4- transtrans )-4-((6-)-4-((6- Nitrobenzo[Nitrobenzo[ dd ]thiazol]thiazol -2-yl)amino)cyclohexyl)oxy)benzonitrile] (화합물 32)-2-yl)amino)cyclohexyl)oxy)benzonitrile] (Compound 32)
Figure PCTKR2022013755-appb-img-000034
Figure PCTKR2022013755-appb-img-000034
2-클로로-6-나이트로벤조티아졸 (2-chloro-6-nitrobenzothiazole; 70.0 mg, 0.33 mmol)이 함유된 DMF (1.5 mL)에 4-(((1,4-트랜스)-4-아미노사이클로헥실)옥시)벤조나이트릴 (4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzonitrile; 70.5 mg, 0.33 mmol) 및 탄산칼륨 (K2CO3; 45.0 mg, 0.33 mmol)을 주위 온도 (ambient temperature)에서 추가했다. 1시간 동안 교반한 후, 상기 혼합물을 물로 퀀칭 (quenching)시키고, 에틸아세테이트 (EtOAc)로 추출했다. 그 후, 합쳐진 유기층을 MgSO4상에서 건조시키고 진공에서 농축시켰다. 잔류물을 실리카겔에서 플래시 컬럼 크로마토그래피 (에틸아세테이트:메탄올=10:1)에 의해 정제하여 27.3 mg (21 %)의 화합물 32를 노란색 고체로서 수득하였다.4-(((1,4-trans)-4-amino in DMF (1.5 mL) containing 2-chloro-6-nitrobenzothiazole (2-chloro-6-nitrobenzothiazole; 70.0 mg, 0.33 mmol) Cyclohexyl)oxy)benzonitrile (4-(((1,4- trans )-4-aminocyclohexyl)oxy)benzonitrile; 70.5 mg, 0.33 mmol) and potassium carbonate (K 2 CO 3 ; 45.0 mg, 0.33 mmol) was added at ambient temperature. After stirring for 1 hour, the mixture was quenched with water and extracted with ethyl acetate (EtOAc). The combined organic layers were then dried over MgSO 4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate:methanol=10:1) to give 27.3 mg (21%) of compound 32 as a yellow solid.
1H NMR (DMSO-d 6, 500 MHz) δ 8.77 (s, 1H), 8.68 (m, 1H), 8.08 (m, 1H), 7.73 (m, 2H), 7.47 (dd, 1H, J = 8.8, 4.4 Hz), 7.14 (m, 2H), 4.53 (s, 1H), 3.87 (s, 1H), 2.10 (m, 4H), 1.53 (m, 4H); 13C NMR (DMSO-d 6, 125 MHz) δ 170.0, 161.0, 158.4, 140.7, 134.3, 131.0, 122.2, 119.3, 117.7, 117.1, 116.4, 102.5, 74.5, 52.3, 29.3, 29.2. 1 H NMR (DMSO- d 6 , 500 MHz) δ 8.77 (s, 1H), 8.68 (m, 1H), 8.08 (m, 1H), 7.73 (m, 2H), 7.47 (dd, 1H, J = 8.8 , 4.4 Hz), 7.14 (m, 2H), 4.53 (s, 1H), 3.87 (s, 1H), 2.10 (m, 4H), 1.53 (m, 4H); 13 C NMR (DMSO- d 6 , 125 MHz) δ 170.0, 161.0, 158.4, 140.7, 134.3, 131.0, 122.2, 119.3, 117.7, 117.1, 116.4, 102.5, 74.5, 52.3, 29.2, 29.3.
33. 6-나이트로-33. 6-Nitro- NN -- (( (1,4-트랜스)-4-(4-(1,4-trans)-4-(4- 나이트로페녹시nitrophenoxy )) 사이클로헥실cyclohexyl )) 벤조[benzo[ dd ]티아졸]thiazole -2-아민 [6-Nitro--2-Amine [6-Nitro- NN -((1,4--((1,4- transtrans )-4-(4-nitrophenoxy)cyclohexyl)benzo[)-4-(4-nitrophenoxy)cyclohexyl)benzo[ dd ]thiazol-2-amine] (화합물 33)]thiazol-2-amine] (Compound 33)
Figure PCTKR2022013755-appb-img-000035
Figure PCTKR2022013755-appb-img-000035
2-클로로-6-나이트로벤조티아졸 (2-chloro-6-nitrobenzothiazole; 70.0 mg, 0.33 mmol)이 함유된 DMF (1.5 mL)에 (1,4-트랜스)-4-(4-나이트로페녹시)사이클로헥산-1-아민 ((1,4-trans)-4-(4-nitrophenoxy)cyclohexan-1-amine; 77.0 mg, 0.33 mmol) 및 탄산칼륨 (K2CO3; 45.0 mg, 0.33 mmol)을 주위 온도 (ambient temperature)에서 추가했다. 1시간 동안 교반한 후, 상기 혼합물을 물로 퀀칭 (quenching)시키고, 에틸아세테이트 (EtOAc)로 추출했다. 그 후, 합쳐진 유기층을 MgSO4상에서 건조시키고 진공에서 농축시켰다. 잔류물을 실리카겔에서 플래시 컬럼 크로마토그래피 (에틸아세테이트:n-헥산=1:1)에 의해 정제하여 30.2 mg (22 %)의 화합물 33을 밝은 노란색 고체로서 수득하였다.(1,4-trans)-4-(4-nitro Phenoxy)cyclohexan-1-amine ((1,4- trans )-4-(4-nitrophenoxy)cyclohexan-1-amine; 77.0 mg, 0.33 mmol) and potassium carbonate (K 2 CO 3 ; 45.0 mg, 0.33 mmol) was added at ambient temperature. After stirring for 1 hour, the mixture was quenched with water and extracted with ethyl acetate (EtOAc). The combined organic layers were then dried over MgSO 4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n -hexane=1:1) to give 30.2 mg (22%) of compound 33 as a light yellow solid.
1H NMR (DMSO-d 6, 500 MHz) δ 8.78 (d, 1H, J = 5.3 Hz), 8.69 (d, 1H, J = 1.2 Hz), 8.18 (d, 2H, J = 9.0 Hz), 8.09 (dd, 1H, J = 8.9, 1.8 Hz), 7.48 (d, 1H, J = 9.0 Hz), 7.19 (d, 2H, J = 9.0 Hz), 4.61 (m, 1H), 3.89 (m, 1H), 2.12 (m, 4H), 1.56 (m, 4H); 13C NMR (DMSO-d 6, 125 MHz) δ 170.0, 162.9, 158.4, 140.7, 140.6, 131.0, 126.0, 122.1, 117.7, 117.1, 115.8, 75.1, 52.2, 29.3, 29.1. 1 H NMR (DMSO- d 6 , 500 MHz) δ 8.78 (d, 1H, J = 5.3 Hz), 8.69 (d, 1H, J = 1.2 Hz), 8.18 (d, 2H, J = 9.0 Hz), 8.09 (dd, 1H, J = 8.9, 1.8 Hz), 7.48 (d, 1H, J = 9.0 Hz), 7.19 (d, 2H, J = 9.0 Hz), 4.61 (m, 1H), 3.89 (m, 1H) , 2.12 (m, 4H), 1.56 (m, 4H); 13 C NMR (DMSO- d 6 , 125 MHz) δ 170.0, 162.9, 158.4, 140.7, 140.6, 131.0, 126.0, 122.1, 117.7, 117.1, 115.8, 75.1, 52.2, 29.3, 29.1.
34. 34. NN -((1,4-트랜스)-4-(4-(-((1,4-trans)-4-(4-( 메틸술포닐methylsulfonyl )) 페녹시phenoxy )) 사이클로헥실cyclohexyl )-6-)-6- 나이트로벤조[nitrobenzo[ dd ]티아졸]thiazole -2-아민 [-2-amine [ NN -((1,4--((1,4- transtrans )-4-(4-()-4-(4-( MethylsulfonylMethylsulfonyl )) phenoxyphenoxy )) cyclohexylcyclohexyl )-6-nitrobenzo[)-6-nitrobenzo[ dd ]thiazol-2-amine] (화합물 34)]thiazol-2-amine] (Compound 34)
Figure PCTKR2022013755-appb-img-000036
Figure PCTKR2022013755-appb-img-000036
2-클로로-6-나이트로벤조티아졸 (2-chloro-6-nitrobenzothiazole; 70.0 mg, 0.33 mmol)이 함유된 DMF (1.5 mL)에 (1,4-트랜스)-4-(4-(메틸술포닐)페녹시)사이클로헥산-1-아민 ((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexan-1-amine; 87.9 mg, 0.33 mmol) 및 탄산칼륨 (K2CO3; 45.0 mg, 0.33 mmol)을 주위 온도 (ambient temperature)에서 추가했다. 1시간 동안 교반한 후, 상기 혼합물을 물로 퀀칭 (quenching)시키고, 에틸아세테이트 (EtOAc)로 추출했다. 그 후, 합쳐진 유기층을 MgSO4상에서 건조시키고 진공에서 농축시켰다. 잔류물을 실리카겔에서 플래시 컬럼 크로마토그래피 (에틸아세테이트:n-헥산=3:1)에 의해 정제하여 68.4 mg (47 %)의 화합물 34를 노란색 고체로서 수득하였다.(1,4-trans)-4-(4-(methyl) in DMF (1.5 mL) containing 2-chloro-6-nitrobenzothiazole (70.0 mg, 0.33 mmol) Sulfonyl)phenoxy)cyclohexan-1-amine ((1,4- trans )-4-(4-(methylsulfonyl)phenoxy)cyclohexan-1-amine; 87.9 mg, 0.33 mmol) and potassium carbonate (K 2 CO 3 ; 45.0 mg, 0.33 mmol) was added at ambient temperature. After stirring for 1 hour, the mixture was quenched with water and extracted with ethyl acetate (EtOAc). The combined organic layers were then dried over MgSO 4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n -hexane=3:1) to give 68.4 mg (47%) of compound 34 as a yellow solid.
1H NMR (DMSO-d 6, 500 MHz) δ 8.78 (s, 1H), 8.68 (d, 1H, J = 2.2 Hz), 8.09 (dd, 1H, J = 8.9, 2.4 Hz), 7.82 (d, 2H, J = 8.8 Hz), 7.47 (d, 1H, J = 8.9 Hz), 7.19 (d, 2H, J = 8.9 Hz), 4.55 (m, 1H), 3.88 (m, 1H), 3.15 (s, 3H), 2.12 (m, 4H), 1.55 (m, 4H); 13C NMR (DMSO-d 6, 125 MHz) δ 170.0, 161.3, 158.4, 140.7, 132.3, 131.0, 129.3, 122.1, 117.7, 117.1, 115.8, 74.5, 52.3, 44.0, 29.3, 29.1. 1 H NMR (DMSO- d 6 , 500 MHz) δ 8.78 (s, 1H), 8.68 (d, 1H, J = 2.2 Hz), 8.09 (dd, 1H, J = 8.9, 2.4 Hz), 7.82 (d, 2H, J = 8.8 Hz), 7.47 (d, 1H, J = 8.9 Hz), 7.19 (d, 2H, J = 8.9 Hz), 4.55 (m, 1H), 3.88 (m, 1H), 3.15 (s, 3H), 2.12 (m, 4H), 1.55 (m, 4H); 13 C NMR (DMSO- d 6 , 125 MHz) δ 170.0, 161.3, 158.4, 140.7, 132.3, 131.0, 129.3, 122.1, 117.7, 117.1, 115.8, 74.5, 52.3, 44.0, 29.1, 29.1.
35. 4-(((1,4-트랜스)-4-((6-35. 4-(((1,4-trans)-4-((6- 나이트로벤조[nitrobenzo[ dd ]티아졸]thiazole -2-일)아미노)-2-yl)amino) 사이클로헥실cyclohexyl )옥시)벤젠술폰아마이드 [4-(((1,4-)oxy)benzenesulfonamide [4-(((1,4- transtrans )-4-((6-)-4-((6- Nitrobenzo[Nitrobenzo[ dd ]thiazol]thiazol -2-yl)amino)cyclohexyl)oxy)benzenesulfonamide] (화합물 35)-2-yl) amino) cyclohexyl) oxy) benzenesulfonamide] (Compound 35)
Figure PCTKR2022013755-appb-img-000037
Figure PCTKR2022013755-appb-img-000037
2-클로로-6-나이트로벤조티아졸 (2-chloro-6-nitrobenzothiazole; 70.0 mg, 0.33 mmol)이 함유된 DMF (1.5 mL)에 4-(((1,4-트랜스)-4-아미노사이클로헥실)옥시)벤젠술폰아마이드 (4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzenesulfonamide; 88.1 mg, 0.33 mmol) 및 탄산칼륨 (K2CO3; 45.0 mg, 0.33 mmol)을 주위 온도 (ambient temperature)에서 추가했다. 17시간 동안 교반한 후, 상기 혼합물을 물로 퀀칭 (quenching)시키고, 에틸아세테이트 (EtOAc)로 추출했다. 그 후, 합쳐진 유기층을 MgSO4상에서 건조시키고 진공에서 농축시켰다. 잔류물을 실리카겔에서 플래시 컬럼 크로마토그래피 (에틸아세테이트:n-헥산=2:1)에 의해 정제하여 26.8 mg (18 %)의 화합물 35를 노란색 고체로서 수득하였다.4-(((1,4-trans)-4-amino in DMF (1.5 mL) containing 2-chloro-6-nitrobenzothiazole (2-chloro-6-nitrobenzothiazole; 70.0 mg, 0.33 mmol) Cyclohexyl)oxy)benzenesulfonamide (4-(((1,4- trans )-4-aminocyclohexyl)oxy)benzenesulfonamide; 88.1 mg, 0.33 mmol) and potassium carbonate (K 2 CO 3 ; 45.0 mg, 0.33 mmol) was added at ambient temperature. After stirring for 17 hours, the mixture was quenched with water and extracted with ethyl acetate (EtOAc). The combined organic layers were then dried over MgSO 4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n -hexane=2:1) to give 26.8 mg (18%) of compound 35 as a yellow solid.
1H NMR (DMSO-d 6, 500 MHz) δ 8.77 (d, 1H, J = 6.1 Hz), 8.69 (d, 1H, J = 2.4 Hz), 8.09 (dd, 1H, J = 8.9, 2.5 Hz), 7.73 (d, 2H, J = 8.9 Hz), 7.48 (d, 1H, J = 9.0 Hz), 7.19 (s, 2H), 7.12 (d, 2H, J = 8.9 Hz), 4.51 (m, 1H), 3.88 (s, 1H), 2.11 (m, 4H), 1.54 (m, 4H); 13C NMR (DMSO-d 6, 125 MHz) δ 170.0, 159.9, 158.4, 140.7, 136.0, 131.0, 127.8, 122.2, 117.7, 117.1, 115.4, 74.3, 52.3, 40.0, 29.3, 29.2. 1 H NMR (DMSO- d 6 , 500 MHz) δ 8.77 (d, 1H, J = 6.1 Hz), 8.69 (d, 1H, J = 2.4 Hz), 8.09 (dd, 1H, J = 8.9, 2.5 Hz) , 7.73 (d, 2H, J = 8.9 Hz), 7.48 (d, 1H, J = 9.0 Hz), 7.19 (s, 2H), 7.12 (d, 2H, J = 8.9 Hz), 4.51 (m, 1H) , 3.88 (s, 1H), 2.11 (m, 4H), 1.54 (m, 4H); 13 C NMR (DMSO- d 6 , 125 MHz) δ 170.0, 159.9, 158.4, 140.7, 136.0, 131.0, 127.8, 122.2, 117.7, 117.1, 115.4, 74.3, 52.3, 40.0, 29.3, 29.2.
36. 6-36. 6- 메톡시methoxy -- NN -((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)사이클로헥실)벤조[-((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)benzo[ dd ]티아졸-2-아민 [6-]Thiazol-2-amine [6- MethoxyMethoxy -- NN -((1,4--((1,4- transtrans )-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)benzo[)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)benzo[ dd ]thiazol-2-amine] (화합물 36)]thiazol-2-amine] (Compound 36)
Figure PCTKR2022013755-appb-img-000038
Figure PCTKR2022013755-appb-img-000038
2-클로로-6-메톡시벤조티아졸 (2-chloro-6-methoxybenzothiazole; 50.0 mg, 0.25 mmol)이 함유된 DMF (1.5 mL)에 (1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)사이클로헥산-1-아민 ((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexan-1-amine; 64.8 mg, 0.25 mmol) 및 탄산칼륨 (K2CO3; 34.6 mg, 0.25 mmol)을 주위 온도 (ambient temperature)에서 추가했다. 140 ℃에서 17시간 동안 교반한 후, 상기 혼합물을 물로 퀀칭 (quenching)시키고, 에틸아세테이트 (EtOAc)로 추출했다. 그 후, 합쳐진 유기층을 MgSO4상에서 건조시키고 진공에서 농축시켰다. 잔류물을 실리카겔에서 플래시 컬럼 크로마토그래피 (에틸아세테이트:n-헥산=1:3)에 의해 정제하여 18.3 mg (17 %)의 화합물 36을 아이보리색 고체로서 수득하였다.(1,4-trans)-4-(4-(tri) in DMF (1.5 mL) containing 2-chloro-6-methoxybenzothiazole (50.0 mg, 0.25 mmol) Fluoromethyl)phenoxy)cyclohexan-1-amine ((1,4- trans )-4-(4-(trifluoromethyl)phenoxy)cyclohexan-1-amine; 64.8 mg, 0.25 mmol) and potassium carbonate (K 2 CO 3 ; 34.6 mg, 0.25 mmol) was added at ambient temperature. After stirring at 140 °C for 17 h, the mixture was quenched with water and extracted with ethyl acetate (EtOAc). The combined organic layers were then dried over MgSO 4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n -hexane=1:3) to give 18.3 mg (17%) of compound 36 as an ivory solid.
1H NMR (CDCl3, 500 MHz) δ 7.53 (d, 2H, J = 8.6 Hz), 7.44 (d, 1H, J = 8.8 Hz), 7.13 (d, 1H, J = 2.2 Hz), 6.94 (d, 2H, J = 8.6 Hz), 6.90 (dd, 1H, J = 8.8, 2.5 Hz), 4.31 (m, 1H), 3.82 (s, 3H), 3.70 (m, 1H), 2.30 (m, 2H), 2.17 (m, 2H), 1.68 (m, 2H), 1.46 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 165.1, 160.2, 155.4, 146.0, 131.0, 127.8, 127.1, 125.6, 123.5, 123.3, 123.1, 122.8, 122.5, 121.3, 119.2, 115.7, 113.7, 105.7, 74.8, 56.0, 53.4, 30.3, 29.7. 1 H NMR (CDCl 3 , 500 MHz) δ 7.53 (d, 2H, J = 8.6 Hz), 7.44 (d, 1H, J = 8.8 Hz), 7.13 (d, 1H, J = 2.2 Hz), 6.94 (d , 2H, J = 8.6 Hz), 6.90 (dd, 1H, J = 8.8, 2.5 Hz), 4.31 (m, 1H), 3.82 (s, 3H), 3.70 (m, 1H), 2.30 (m, 2H) , 2.17 (m, 2H), 1.68 (m, 2H), 1.46 (m, 2H); 13 C NMR (CDCL 3 , 125 MHz) Δ 165.1, 160.2, 155.4, 146.0, 131.0, 127.8, 127.1, 125.6, 123.5, 123.3, 123.1, 122.8, 122.5, 121.3, 119.2, 115.7, 113.7, 105.7, 74.8, 56.0, 56.0 , 53.4, 30.3, 29.7.
37. 4-(((1,4-트랜스)-4-((6-37. 4-(((1,4-trans)-4-((6- 메톡시벤조[methoxybenzo[ dd ]티아졸]thiazole -2-일)아미노)-2-yl)amino) 사이클로헥실cyclohexyl )옥시)벤조나이트릴 [4-(((1,4-)oxy)benzonitrile [4-(((1,4- transtrans )-4-((6-)-4-((6- Methoxybenzo[Methoxybenzo[ dd ]thiazol]thiazol -2-yl)amino)cyclohexyl)oxy)benzonitrile] (화합물 37)-2-yl)amino)cyclohexyl)oxy)benzonitrile] (Compound 37)
Figure PCTKR2022013755-appb-img-000039
Figure PCTKR2022013755-appb-img-000039
2-클로로-6-메톡시벤조티아졸 (2-chloro-6-methoxybenzothiazole; 70.0 mg, 0.35 mmol)이 함유된 DMF (1.5 mL)에 4-(((1,4-트랜스)-4-아미노사이클로헥실)옥시)벤조나이트릴 (4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzonitrile; 83.4 mg, 0.39 mmol) 및 탄산칼륨 (K2CO3; 48.4 mg, 0.35 mmol)을 주위 온도 (ambient temperature)에서 추가했다. 140 ℃에서 17시간 동안 교반한 후, 상기 혼합물을 물로 퀀칭 (quenching)시키고, 에틸아세테이트 (EtOAc)로 추출했다. 그 후, 합쳐진 유기층을 MgSO4상에서 건조시키고 진공에서 농축시켰다. 잔류물을 실리카겔에서 플래시 컬럼 크로마토그래피 (에틸아세테이트:n-헥산=1:2)에 의해 정제하여 35.9 mg (27 %)의 화합물 37을 아이보리색 고체로서 수득하였다.4-(((1,4-trans)-4-amino in DMF (1.5 mL) containing 2-chloro-6-methoxybenzothiazole (70.0 mg, 0.35 mmol) Cyclohexyl)oxy)benzonitrile (4-(((1,4- trans )-4-aminocyclohexyl)oxy)benzonitrile; 83.4 mg, 0.39 mmol) and potassium carbonate (K 2 CO 3 ; 48.4 mg, 0.35 mmol) was added at ambient temperature. After stirring at 140 °C for 17 h, the mixture was quenched with water and extracted with ethyl acetate (EtOAc). The combined organic layers were then dried over MgSO 4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n -hexane=1:2) to give 35.9 mg (27%) of compound 37 as an ivory solid.
1H NMR (CDCl3, 500 MHz) δ 7.57 (d, 2H, J = 8.8 Hz), 7,44 (d, 1H, J = 8.8 Hz), 7.13 (d, 1H, J = 2.3 Hz), 6.93 (d, 2H, J = 8.8 Hz), 6.90 (m, 1H), 5.51 (s, 1H), 4.34 (m, 1H), 3.82 (s, 3H), 3.73 (m, 1H), 2.31 (m, 2H), 2.17 (m, 2H), 1.70 (m, 2H), 1.47 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 164.8, 161.1, 155.5, 145.6, 134.2, 130.9, 119.4, 119.2, 116.2, 113.8, 105.7, 103.9, 74.9, 56.0, 53.2, 30.2, 29.5. 1 H NMR (CDCl 3 , 500 MHz) δ 7.57 (d, 2H, J = 8.8 Hz), 7,44 (d, 1H, J = 8.8 Hz), 7.13 (d, 1H, J = 2.3 Hz), 6.93 (d, 2H, J = 8.8 Hz), 6.90 (m, 1H), 5.51 (s, 1H), 4.34 (m, 1H), 3.82 (s, 3H), 3.73 (m, 1H), 2.31 (m, 2H), 2.17 (m, 2H), 1.70 (m, 2H), 1.47 (m, 2H); 13 C NMR (CDCl 3 , 125 MHz) δ 164.8, 161.1, 155.5, 145.6, 134.2, 130.9, 119.4, 119.2, 116.2, 113.8, 105.7, 103.9, 74.9, 56.0, 53.2, 30.5.2, 30.5.2
38. 6-38. 6- 메톡시methoxy -- NN -- (( (1,4-트랜스)-4-(4-(1,4-trans)-4-(4- 나이트로페녹시nitrophenoxy )) 사이클로헥실cyclohexyl )) 벤조[benzo[ dd ]티아졸]thiazole -2-아민 [6--2-amine [6- MethoxyMethoxy -- NN -((1,4--((1,4- transtrans )-4-(4-nitrophenoxy)cyclohexyl)benzo[)-4-(4-nitrophenoxy)cyclohexyl)benzo[ dd ]thiazol-2-amine] (화합물 38)]thiazol-2-amine] (Compound 38)
Figure PCTKR2022013755-appb-img-000040
Figure PCTKR2022013755-appb-img-000040
2-클로로-6-메톡시벤조티아졸 (2-chloro-6-methoxybenzothiazole; 70.0 mg, 0.35 mmol)이 함유된 DMF (1.5 mL)에 (1,4-트랜스)-4-(4-나이트로페녹시)사이클로헥산-1-아민 ((1,4-trans)-4-(4-nitrophenoxy)cyclohexan-1-amine; 124.0 mg, 0.53 mmol) 및 탄산칼륨 (K2CO3; 96.8 mg, 0.70 mmol)을 주위 온도 (ambient temperature)에서 추가했다. 120 ℃에서 17시간 동안 교반한 후, 상기 혼합물을 물로 퀀칭 (quenching)시키고, 에틸아세테이트 (EtOAc)로 추출했다. 그 후, 합쳐진 유기층을 MgSO4상에서 건조시키고 진공에서 농축시켰다. 잔류물을 실리카겔에서 플래시 컬럼 크로마토그래피 (에틸아세테이트:n-헥산=1:1)에 의해 정제하여 16.1 mg (12 %)의 화합물 38을 아이보리색 고체로서 수득하였다.(1,4-trans)-4-(4-nitro Phenoxy)cyclohexan-1-amine ((1,4- trans )-4-(4-nitrophenoxy)cyclohexan-1-amine; 124.0 mg, 0.53 mmol) and potassium carbonate (K 2 CO 3 ; 96.8 mg, 0.70 mmol) was added at ambient temperature. After stirring at 120 °C for 17 hours, the mixture was quenched with water and extracted with ethyl acetate (EtOAc). The combined organic layers were then dried over MgSO 4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n -hexane=1:1) to give 16.1 mg (12%) of compound 38 as an ivory solid.
1H NMR (CDCl3, 500 MHz) δ 8.18 (d, 2H, J = 8.5 Hz), 7.44 (d, 1H, J = 8.7 Hz), 7.13 (s, 1H), 6.93 (d, 2H, J = 8.9 Hz), 6.90 (m, 1H), 5.45 (s, 1H), 4.38 (m, 1H), 3.82 (s, 3H), 3.74 (m, 1H), 2.32 (m, 2H), 2.19 (m, 2H), 1.71 (m, 2H), 1.48 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 164.8, 162.9, 155.5, 145.7, 141.4, 131.0, 126.1, 119.2, 115.4, 113.7, 105.7, 75.4, 56.0, 53.2, 30.2, 29.6. 1 H NMR (CDCl 3 , 500 MHz) δ 8.18 (d, 2H, J = 8.5 Hz), 7.44 (d, 1H, J = 8.7 Hz), 7.13 (s, 1H), 6.93 (d, 2H, J = 8.9 Hz), 6.90 (m, 1H), 5.45 (s, 1H), 4.38 (m, 1H), 3.82 (s, 3H), 3.74 (m, 1H), 2.32 (m, 2H), 2.19 (m, 2H), 1.71 (m, 2H), 1.48 (m, 2H); 13 C NMR (CDCl 3 , 125 MHz) δ 164.8, 162.9, 155.5, 145.7, 141.4, 131.0, 126.1, 119.2, 115.4, 113.7, 105.7, 75.4, 56.0, 53.2, 30.6.2, 29.6.2
39. 6-39. 6- 메톡시methoxy -- NN -- (( (1,4-트랜스)-4-(4-((1,4-trans)-4-(4-( 메틸술포닐methylsulfonyl )) 페녹시phenoxy )) 사이클로헥실cyclohexyl )) 벤조[benzo[ dd ]티아졸]thiazole -2-아민 [6--2-amine [6- MethoxyMethoxy -- NN -((1,4--((1,4- transtrans )-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)benzo[)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)benzo[ dd ]thiazol-2-amine] (화합물 39)]thiazol-2-amine] (Compound 39)
Figure PCTKR2022013755-appb-img-000041
Figure PCTKR2022013755-appb-img-000041
2-클로로-6-메톡시벤조티아졸 (2-chloro-6-methoxybenzothiazole; 70.0 mg, 0.35 mmol)이 함유된 DMF (1.5 mL)에 (1,4-트랜스)-4-(4-(메틸술포닐)페녹시)사이클로헥산-1-아민 ((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexan-1-amine; 141.0 mg, 0.53 mmol) 및 탄산칼륨 (K2CO3; 72.6 mg, 0.53 mmol)을 주위 온도 (ambient temperature)에서 추가했다. 120 ℃에서 17시간 동안 교반한 후, 상기 혼합물을 물로 퀀칭 (quenching)시키고, 에틸아세테이트 (EtOAc)로 추출했다. 그 후, 합쳐진 유기층을 MgSO4상에서 건조시키고 진공에서 농축시켰다. 잔류물을 실리카겔에서 플래시 컬럼 크로마토그래피 (에틸아세테이트:n-헥산=2:1)에 의해 정제하여 39.8 mg (26 %)의 화합물 39를 흰색 고체로서 수득하였다.(1,4-trans)-4-(4-(methyl) in DMF (1.5 mL) containing 2-chloro-6-methoxybenzothiazole (70.0 mg, 0.35 mmol) Sulfonyl)phenoxy)cyclohexan-1-amine ((1,4- trans )-4-(4-(methylsulfonyl)phenoxy)cyclohexan-1-amine; 141.0 mg, 0.53 mmol) and potassium carbonate (K 2 CO 3 ; 72.6 mg, 0.53 mmol) was added at ambient temperature. After stirring at 120 °C for 17 hours, the mixture was quenched with water and extracted with ethyl acetate (EtOAc). The combined organic layers were then dried over MgSO 4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate:n-hexane=2:1) to give 39.8 mg (26%) of Compound 39 as a white solid.
1H NMR (CDCl3, 500 MHz) δ 7.85 (d, 2H, J = 8.9 Hz), 7.43 (d, 1H, J = 8.8 Hz), 7.12 (d, 1H, J = 2.5 Hz), 7.00 (d, 2H, J = 8.9 Hz), 6.90 (dd, 1H, J = 8.8, 2.6 Hz), 4.37 (m, 1H), 3.82 (s, 3H), 3.73 (m, 1H), 3.03 (s, 3H), 2.31 (m, 2H), 2.18 (m, 2H), 1.70 (m, 2H), 1.49 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 164.9, 162.0, 155.5, 145.4, 132.2, 130.8, 129.7, 119.1, 116.0, 113.8, 105.7, 75.0, 56.0, 53.3, 45.0, 30.1, 29.5. 1 H NMR (CDCl 3 , 500 MHz) δ 7.85 (d, 2H, J = 8.9 Hz), 7.43 (d, 1H, J = 8.8 Hz), 7.12 (d, 1H, J = 2.5 Hz), 7.00 (d , 2H, J = 8.9 Hz), 6.90 (dd, 1H, J = 8.8, 2.6 Hz), 4.37 (m, 1H), 3.82 (s, 3H), 3.73 (m, 1H), 3.03 (s, 3H) , 2.31 (m, 2H), 2.18 (m, 2H), 1.70 (m, 2H), 1.49 (m, 2H); 13 C NMR (CDCl 3 , 125 MHz) δ 164.9, 162.0, 155.5, 145.4, 132.2, 130.8, 129.7, 119.1, 116.0, 113.8, 105.7, 75.0, 56.0, 53.3, 45.0, 29.5.0, 30.5.0, 30.5.0
[[ 실시예Example 1] One] NN -(4--(4- 아릴옥시사이클로헥실aryloxycyclohexyl )) 벤조티아졸benzothiazole -2--2- 아민amine ( ( NN -(4-aryloxycyclohexyl)benzothiazole-2-amine) 유도체들에 대한 -(4-aryloxycyclohexyl)benzothiazole-2-amine) derivatives eIF2αeIF2α 인산화의 배수 변화 분석 Analysis of fold change in phosphorylation
Cell signaling 사의 Pathscan　phospho-eIF2α (Ser51) Sandwich ELISA Kit #7286를 사용하였다. K562 세포주를 37℃ 및 5% CO2에서 serum-free RPMI 배지에서 배양하였다. 세포에 10 μM의 농도로 상기 화합물 1 내지 36을 처리하였다. 화합물 처리 후 6시간 뒤에 키트에 동봉된 lysis buffer로 세포를 lysis하여 50 μg의 단백질을 정량하여 얻었다. 그 이후 manufacturer's protocol에 따라 ELISA assay를 진행하여 흡광도를 얻었다. 얻어진 각각의 화합물에 대한 흡광도는 control (DMSO-treated)을 1로 둔 값에 표준화되었다. 결과는 표 1과 같다.Cell Signaling's Pathscan　The phospho-eIF2α (Ser51) Sandwich ELISA Kit #7286 was used. The K562 cell line was cultured in serum-free RPMI medium at 37°C and 5% CO 2 . Cells were treated with compounds 1 to 36 at a concentration of 10 μM. After 6 hours of compound treatment, the cells were lysed with the lysis buffer included in the kit, and 50 μg of protein was quantified. After that, an ELISA assay was performed according to the manufacturer's protocol to obtain absorbance. The absorbance for each obtained compound was normalized to a value set to 1 for control (DMSO-treated). The results are shown in Table 1.
Figure PCTKR2022013755-appb-img-000042
Figure PCTKR2022013755-appb-img-000042
[[ 실시예Example 2] K562에 대한 2] for K562 NN -(4--(4- 아릴옥시사이클로헥실aryloxycyclohexyl )) 벤조티아졸benzothiazole -2--2- 아민amine ( ( NN -(4-aryloxycyclohexyl)benzothiazole-2-amine) 유도체들의 항-증식 활성 분석Analysis of anti-proliferative activity of -(4-aryloxycyclohexyl)benzothiazole-2-amine) derivatives
CCK-8 assay (cell counting kit-8 assay, Dojindo, Kumamoto, Japan)을 수행하였다. K562 세포주를 37℃ 및 5% CO2에서 10% FBS와 1% ABAM이 첨가된 RPMI 배지에서 배양하였다. 세포에 각각 0 μM, 1.25 μM, 2.5 μM, 5 μM, 10 μM, 20 μM 농도의 상기 화합물 1, 13, 14, 19 내지 30, 32, 34 및 36을 처리하였다. 3일 동안 배양한 후, 10 μL의 CCK-8 solution을 처리한 후, 4시간 배양하였다. 그 후, 450 nm에서의 흡광도를 측정하여 각각의 화합물의 IC50 value를 구하였다. 결과는 표 2와 같다.CCK-8 assay (cell counting kit-8 assay, Dojindo, Kumamoto, Japan) was performed. The K562 cell line was cultured in RPMI medium supplemented with 10% FBS and 1% ABAM at 37°C and 5% CO 2 . The cells were treated with compounds 1, 13, 14, 19 to 30, 32, 34 and 36 at concentrations of 0 μM, 1.25 μM, 2.5 μM, 5 μM, 10 μM and 20 μM, respectively. After culturing for 3 days, 10 μL of CCK-8 solution was treated, followed by culturing for 4 hours. Then, the absorbance at 450 nm was measured to obtain the IC 50 value of each compound. The results are shown in Table 2.
Figure PCTKR2022013755-appb-img-000043
Figure PCTKR2022013755-appb-img-000043
이상으로 본 발명의 특정한 부분을 상세히 기술한 바, 당업계의 통상의 지식을 가진 자에게 있어서 이러한 구체적인 기술은 단지 바람직한 구현 예일 뿐이며, 이에 본 발명의 범위가 제한되는 것이 아닌 점은 명백하다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항과 그의 등가물에 의하여 정의된다고 할 것이다.Having described specific parts of the present invention in detail above, it is clear that these specific techniques are only preferred embodiments for those skilled in the art, and the scope of the present invention is not limited thereto. Accordingly, the substantial scope of the present invention will be defined by the appended claims and equivalents thereof.

Claims (12)

  1. 하기 화학식 1로 표시되는 2-아미노벤조티아졸 유도체 화합물, 이의 약학적으로 허용가능한 염, 이의 용매화물 또는 이의 입체이성질체에서 선택된 화합물:A compound selected from a 2-aminobenzothiazole derivative compound represented by Formula 1 below, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof:
    [화학식 1][Formula 1]
    Figure PCTKR2022013755-appb-img-000044
    Figure PCTKR2022013755-appb-img-000044
    상기 화학식 1에서, In Formula 1,
    R1 및 R2는 각각 동일하거나 다를 수 있고, 수소 (H), 할로겐, 트리플루오로메틸 (CF3), 나이트로 (NO2), (C1~C4)알콕시, 트리플루오로메톡시 (OCF3), 시아노 (CN), 나이트로 (NO2), (C1~C4)알킬술포닐 및 아미노술포닐 (SO2NH2)로 이루어진 군에서 선택됨.R 1 and R 2 may each be the same or different, and hydrogen (H), halogen, trifluoromethyl (CF 3 ), nitro (NO 2 ), (C1~C4) alkoxy, trifluoromethoxy (OCF 3 ), cyano (CN), nitro (NO 2 ), (C1-C4) alkylsulfonyl and aminosulfonyl (SO 2 NH 2 ).
  2. 청구항 1에 있어서, 상기 2-아미노벤조티아졸 유도체 화합물은 화학식 1에서 R1은 수소 (H), 플루오린 (F), 염소 (Cl), 트리플루오로메틸 (CF3), 나이트로 (NO2) 및 (C1~C2)알콕시로 이루어진 군에서 선택되며, R2는 염소 (Cl), 트리플루오로메틸 (CF3), 트리플루오로메톡시 (OCF3), 시아노 (CN), 나이트로 (NO2), (C1~C2)알킬술포닐 및 아미노술포닐 (SO2NH2)로 이루어진 군에서 선택되는 것을 특징으로 하는 2-아미노벤조티아졸 유도체 화합물, 이의 약학적으로 허용가능한 염, 이의 용매화물 또는 이의 입체이성질체에서 선택된 화합물.The method according to claim 1, wherein the 2-aminobenzothiazole derivative compound in Formula 1, R 1 is hydrogen (H), fluorine (F), chlorine (Cl), trifluoromethyl (CF 3 ), nitro (NO 2 ) and (C1~C2) is selected from the group consisting of alkoxy, R 2 is chlorine (Cl), trifluoromethyl (CF 3 ), trifluoromethoxy (OCF 3 ), cyano (CN), nitro A 2-aminobenzothiazole derivative compound selected from the group consisting of (NO 2 ), (C1~C2)alkylsulfonyl and aminosulfonyl (SO 2 NH 2 ), a pharmaceutically acceptable salt thereof, A compound selected from solvates thereof or stereoisomers thereof.
  3. 청구항 1에 있어서, 상기 2-아미노벤조티아졸 유도체 화합물은 화학식 1에서 R1은 수소 (H), 플루오린 (F), 염소 (Cl), 트리플루오로메틸 (CF3), 나이트로 (NO2) 및 메톡시(OMe)로 이루어진 군에서 선택되며, R2는 염소 (Cl), 트리플루오로메틸 (CF3), 트리플루오로메톡시 (OCF3), 시아노 (CN), 나이트로 (NO2), 메틸술포닐 (SO2Me) 및 아미노술포닐 (SO2NH2)로 이루어진 군에서 선택되는 것을 특징으로 하는 2-아미노벤조티아졸 유도체 화합물, 이의 약학적으로 허용가능한 염, 이의 용매화물 또는 이의 입체이성질체에서 선택된 화합물. The method according to claim 1, wherein the 2-aminobenzothiazole derivative compound in Formula 1, R 1 is hydrogen (H), fluorine (F), chlorine (Cl), trifluoromethyl (CF 3 ), nitro (NO 2 ) and methoxy (OMe), R 2 is chlorine (Cl), trifluoromethyl (CF 3 ), trifluoromethoxy (OCF 3 ), cyano (CN), nitro ( NO 2 ), a 2-aminobenzothiazole derivative compound selected from the group consisting of methylsulfonyl (SO 2 Me) and aminosulfonyl (SO 2 NH 2 ), a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt thereof A compound selected from solvates or stereoisomers thereof.
  4. 청구항 1에 있어서, 상기 2-아미노벤조티아졸 유도체 화합물은 N-((1,4-트랜스)-4-(4-클로로페녹시)사이클로헥실)벤조[d]티아졸-2-아민 [N-((1,4-trans)-4-(4-Chlorophenoxy)cyclohexyl)benzo[d]thiazol-2-amine], N-((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)사이클로헥실)벤조[d]티아졸-2-아민 [N-((1,4-trans)-4-(4-(Trifluoromethyl)phenoxy)cyclohexyl)benzo[d]thiazol-2-amine], N-((1,4-트랜스)-4-(4-(트리플루오로메톡시)페녹시)사이클로헥실)벤조[d]티아졸-2-아민 [N-((1,4-trans)-4-(4-(Trifluoromethoxy)phenoxy)cyclohexyl)benzo[d]thiazol-2-amine], 4-(((1,4-트랜스)-4-(벤조[d]티아졸-2-일아미노)사이클로헥실)옥시)벤조나이트릴 [4-(((1,4-trans)-4-(Benzo[d]thiazol-2-ylamino)cyclohexyl)oxy)benzonitrile], N-((1,4-트랜스)-4-(4-나이트로페녹시)사이클로헥실)벤조[d]티아졸-2-아민 [N-((1,4-trans)-4-(4-Nitrophenoxy)cyclohexyl)benzo[d]thiazol-2-amine], N-((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)사이클로헥실)벤조[d]티아졸-2-아민 [N-((1,4-trans)-4-(4-(Methylsulfonyl)phenoxy)cyclohexyl)benzo[d]thiazol-2-amine], 4-(((1,4-트랜스)-4-(벤조[d]티아졸-2-일아미노)사이클로헥실)옥시)벤젠술폰아마이드 [4-(((1,4-trans)-4-(Benzo[d]thiazol-2-ylamino)cyclohexyl)oxy)benzenesulfonamide], N-((1,4-트랜스)-4-(4-클로로페녹시)사이클로헥실)-6-플루오로벤조[d]티아졸-2-아민 [N-((1,4-trans)-4-(4-Chlorophenoxy)cyclohexyl)-6-fluorobenzo[d]thiazol-2-amine], 6-플루오로-N-((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)사이클로헥실)벤조[d]티아졸-2-아민 [6-Fluoro-N-((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)benzo[d]thiazol-2-amine], 6-플루오로-N-((1,4-트랜스)-4-(4-(트리플루오로메톡시)페녹시)사이클로헥실)벤조[d]티아졸-2-아민 [6-Fluoro-N-((1,4-trans)-4-(4-(trifluoromethoxy)phenoxy)cyclohexyl)benzo[d]thiazol-2-amine], 4-(((1,4-트랜스)-4-((6-플루오로벤조[d]티아졸-2-일)아미노)사이클로헥실)옥시)벤조나이트릴 [4-(((1,4-trans)-4-((6-Fluorobenzo[d]thiazol-2-yl)amino)cyclohexyl)oxy)benzonitrile], 6-플루오로-N-((1,4-트랜스)-4-(4-나이트로페녹시)사이클로헥실)벤조[d]티아졸-2-아민 [6-Fluoro-N-((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)benzo[d]thiazol-2-amine], 6-플루오로-N-((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)사이클로헥실)벤조[d]티아졸-2-아민 [6-Fluoro-N-((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)benzo[d]thiazol-2-amine], 4-(((1,4-트랜스)-4-((6-플루오로벤조[d]티아졸-2-일)아미노)사이클로헥실)옥시)벤젠술폰아마이드 [4-(((1,4-trans)-4-((6-Fluorobenzo[d]thiazol-2-yl)amino)cyclohexyl)oxy)benzenesulfonamide], 6-클로로-N-((1,4-트랜스)-4-(4-클로로페녹시)사이클로헥실)벤조[d]티아졸-2-아민 [6-Chloro-N-((1,4-trans)-4-(4-chlorophenoxy)cyclohexyl)benzo[d]thiazol-2-amine], 6-클로로-N-((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)사이클로헥실)벤조[d]티아졸-2-아민 [6-Chloro-N-((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)benzo[d]thiazol-2-amine], 6-클로로-N-((1,4-트랜스)-4-(4-(트리플루오로메톡시)페녹시)사이클로헥실)벤조[d]티아졸-2-아민 [6-Chloro-N-((1,4-trans)-4-(4-(trifluoromethoxy)phenoxy)cyclohexyl)benzo[d]thiazol-2-amine], 4-(((1,4-트랜스)-4-((6-클로로벤조[d]티아졸-2-일)아미노)사이클로헥실)옥시)벤조나이트릴 [4-(((1,4-trans)-4-((6-Chlorobenzo[d]thiazol-2-yl)amino)cyclohexyl)oxy)benzonitrile], 6-클로로-N-((1,4-트랜스)-4-(4-나이트로페녹시)사이클로헥실)벤조[d]티아졸-2-아민 [6-Chloro-N-((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)benzo[d]thiazol-2-amine], 6-클로로-N-((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)사이클로헥실)벤조[d]티아졸-2-아민 [6-Chloro-N-((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)benzo[d]thiazol-2-amine], 4-(((1,4-트랜스)-4-((6-클로로벤조[d]티아졸-2-일)아미노)사이클로헥실)옥시)벤젠술폰아마이드 [4-(((1,4-trans)-4-((6-Chlorobenzo[d]thiazol-2-yl)amino)cyclohexyl)oxy)benzenesulfonamide], N-((1,4-트랜스)-4-(4-클로로페녹시)사이클로헥실)-6-(트리플루오로메틸)벤조[d]티아졸-2-아민 [N-((1,4-trans)-4-(4-Chlorophenoxy)cyclohexyl)-6-(trifluoromethyl)benzo[d]thiazol-2-amine], 6-(트리플루오로메틸)-N-((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)사이클로헥실)벤조[d]티아졸-2-아민 [6-(Trifluoromethyl)-N-((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)benzo[d]thiazol-2-amine], N-((1,4-트랜스)-4-(4-(트리플루오로메톡시)페녹시)사이클로헥실)-6-(트리플루오로메틸)벤조[d]티아졸-2-아민 [N-((1,4-trans)-4-(4-(Trifluoromethoxy)phenoxy)cyclohexyl)-6-(trifluoromethyl)benzo[d]thiazol-2-amine], 4-(((1,4-트랜스)-4-((6-(트리플루오로메틸)벤조[d]티아졸-2-일)아미노)사이클로헥실)옥시)벤조나이트릴 [4-(((1,4-trans)-4-((6-(Trifluoromethyl)benzo[d]thiazol-2-yl)amino)cyclohexyl)oxy)benzonitrile], N-((1,4-트랜스)-4-(4-나이트로페녹시)사이클로헥실)-6-(트리플루오로메틸)벤조[d]티아졸-2-아민 [N-((1,4-trans)-4-(4-Nitrophenoxy)cyclohexyl)-6-(trifluoromethyl)benzo[d]thiazol-2-amine], N-((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)사이클로헥실)-6-(트리플루오로메틸)벤조[d]티아졸-2-아민 [N-((1,4-trans)-4-(4-(Methylsulfonyl)phenoxy)cyclohexyl)-6-(trifluoromethyl)benzo[d]thiazol-2-amine], 4-(((1,4-트랜스)-4-((6-(트리플루오로메틸)벤조[d]티아졸-2-일)아미노)사이클로헥실)옥시)벤젠술폰아마이드 [4-(((1,4-trans)-4-((6-(Trifluoromethyl)benzo[d]thiazol-2-yl)amino)cyclohexyl)oxy)benzenesulfonamide], N-((1,4-트랜스)-4-(4-클로로페녹시)사이클로헥실)-6-나이트로벤조[d]티아졸-2-아민 [N-((1,4-trans)-4-(4-Chlorophenoxy)cyclohexyl)-6-nitrobenzo[d]thiazol-2-amine], 6-나이트로-N-((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)사이클로헥실)벤조[d]티아졸-2-아민 [6-Nitro-N-((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)benzo[d]thiazol-2-amine], 6-나이트로-N-((1,4-트랜스)-4-(4-(트리플루오로메톡시)페녹시)사이클로헥실)벤조[d]티아졸-2-아민 [6-Nitro-N-((1,4-trans)-4-(4-(trifluoromethoxy)phenoxy)cyclohexyl)benzo[d]thiazol-2-amine], 4-(((1,4-트랜스)-4-((6-나이트로벤조[d]티아졸-2-일)아미노)사이클로헥실)옥시)벤조나이트릴 [4-(((1,4-trans)-4-((6-Nitrobenzo[d]thiazol-2-yl)amino)cyclohexyl)oxy)benzonitrile], 6-나이트로-N-((1,4-트랜스)-4-(4-나이트로페녹시)사이클로헥실)벤조[d]티아졸-2-아민 [6-Nitro-N-((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)benzo[d]thiazol-2-amine], N-((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)사이클로헥실)-6-나이트로벤조[d]티아졸-2-아민 [N-((1,4-trans)-4-(4-(Methylsulfonyl)phenoxy)cyclohexyl)-6-nitrobenzo[d]thiazol-2-amine], 4-(((1,4-트랜스)-4-((6-나이트로벤조[d]티아졸-2-일)아미노)사이클로헥실)옥시)벤젠술폰아마이드 [4-(((1,4-trans)-4-((6-Nitrobenzo[d]thiazol-2-yl)amino)cyclohexyl)oxy)benzenesulfonamide], 6-메톡시-N-((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)사이클로헥실)벤조[d]티아졸-2-아민 [6-Methoxy-N-((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)benzo[d]thiazol-2-amine], 4-(((1,4-트랜스)-4-((6-메톡시벤조[d]티아졸-2-일)아미노)사이클로헥실)옥시)벤조나이트릴 [4-(((1,4-trans)-4-((6-Methoxybenzo[d]thiazol-2-yl)amino)cyclohexyl)oxy)benzonitrile], 6-메톡시-N-((1,4-트랜스)-4-(4-나이트로페녹시)사이클로헥실)벤조[d]티아졸-2-아민 [6-Methoxy-N-((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)benzo[d]thiazol-2-amine] 및 6-메톡시-N-((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)사이클로헥실)벤조[d]티아졸-2-아민 [6-Methoxy-N-((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)benzo[d]thiazol-2-amine]으로 이루어진 군에서 선택되는 것을 특징으로 하는 2-아미노벤조티아졸 유도체 화합물, 이의 약학적으로 허용가능한 염, 이의 용매화물 또는 이의 입체이성질체에서 선택된 화합물. The method according to claim 1, wherein the 2-aminobenzothiazole derivative compound is N-((1,4-trans)-4-(4-chlorophenoxy)cyclohexyl)benzo[d]thiazol-2-amine [N -((1,4-trans)-4-(4-Chlorophenoxy)cyclohexyl)benzo[d]thiazol-2-amine], N-((1,4-trans)-4-(4-(trifluoro Methyl)phenoxy)cyclohexyl)benzo[d]thiazol-2-amine [N-((1,4-trans)-4-(4-(Trifluoromethyl)phenoxy)cyclohexyl)benzo[d]thiazol-2- amine], N-((1,4-trans)-4-(4-(trifluoromethoxy)phenoxy)cyclohexyl)benzo[d]thiazol-2-amine [N-((1,4- trans)-4-(4-(Trifluoromethoxy)phenoxy)cyclohexyl)benzo[d]thiazol-2-amine], 4-(((1,4-trans)-4-(benzo[d]thiazol-2- ylamino)cyclohexyl)oxy)benzonitrile [4-(((1,4-trans)-4-(Benzo[d]thiazol-2-ylamino)cyclohexyl)oxy)benzonitrile], N-((1, 4-trans)-4-(4-nitrophenoxy)cyclohexyl)benzo[d]thiazol-2-amine [N-((1,4-trans)-4-(4-Nitrophenoxy)cyclohexyl)benzo [d]thiazol-2-amine], N-((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)benzo[d]thiazol-2-amine [N- ((1,4-trans)-4-(4-(Methylsulfonyl)phenoxy)cyclohexyl)benzo[d]thiazol-2-amine], 4-(((1,4-trans)-4-(benzo[d] ]Thiazol-2-ylamino)cyclohexyl)oxy)benzenesulfonamide [4-(((1,4-trans)-4-(Benzo[d]thiazol-2-ylamino)cyclohexyl)oxy)benzenesulfonamide], N-((1,4-trans)-4-(4-chlorophenoxy)cyclohexyl)-6-fluorobenzo[d]thiazol-2-amine [N-((1,4- trans)-4-(4-Chlorophenoxy)cyclohexyl)-6-fluorobenzo[d]thiazol-2-amine], 6-fluoro-N-((1,4-trans)-4-(4-(trifluoro) Romethyl)phenoxy)cyclohexyl)benzo[d]thiazol-2-amine [6-Fluoro-N-((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)benzo[d ]thiazol-2-amine], 6-fluoro-N-((1,4-trans)-4-(4-(trifluoromethoxy)phenoxy)cyclohexyl)benzo[d]thiazole-2- Amine [6-Fluoro-N-((1,4-trans)-4-(4-(trifluoromethoxy)phenoxy)cyclohexyl)benzo[d]thiazol-2-amine], 4-(((1,4-trans )-4-((6-fluorobenzo[d]thiazol-2-yl)amino)cyclohexyl)oxy)benzonitrile [4-(((1,4-trans)-4-((6- Fluorobenzo[d]thiazol-2-yl)amino)cyclohexyl)oxy)benzonitrile], 6-fluoro-N-((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)benzo[ d]thiazol-2-amine [6-Fluoro-N-((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)benzo[d]thiazol-2-amine], 6-fluoro-N -((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)benzo[d]thiazol-2-amine [6-Fluoro-N-((1,4-trans )-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)benzo[d]thiazol-2-amine], 4-(((1,4-trans)-4-((6-fluorobenzo[d]thiazol zol-2-yl)amino)cyclohexyl)oxy)benzenesulfonamide [4-(((1,4-trans)-4-((6-Fluorobenzo[d]thiazol-2-yl)amino)cyclohexyl)oxy )benzenesulfonamide], 6-chloro-N-((1,4-trans)-4-(4-chlorophenoxy)cyclohexyl)benzo[d] Thiazol-2-amine [6-Chloro-N-((1,4-trans)-4-(4-chlorophenoxy)cyclohexyl)benzo[d]thiazol-2-amine], 6-chloro-N-(( 1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)benzo[d]thiazol-2-amine [6-Chloro-N-((1,4-trans)- 4-(4-(trifluoromethyl)phenoxy)cyclohexyl)benzo[d]thiazol-2-amine], 6-chloro-N-((1,4-trans)-4-(4-(trifluoromethoxy)phenoxy cy)cyclohexyl)benzo[d]thiazol-2-amine [6-Chloro-N-((1,4-trans)-4-(4-(trifluoromethoxy)phenoxy)cyclohexyl)benzo[d]thiazol-2 -amine], 4-(((1,4-trans)-4-((6-chlorobenzo[d]thiazol-2-yl)amino)cyclohexyl)oxy)benzonitrile [4-((( 1,4-trans)-4-((6-Chlorobenzo[d]thiazol-2-yl)amino)cyclohexyl)oxy)benzonitrile], 6-chloro-N-((1,4-trans)-4-( 4-nitrophenoxy)cyclohexyl)benzo[d]thiazol-2-amine [6-Chloro-N-((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)benzo[d]thiazol -2-amine], 6-chloro-N-((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)benzo[d]thiazol-2-amine [6- Chloro-N-((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)benzo[d]thiazol-2-amine], 4-(((1,4-trans)-4- ((6-chlorobenzo[d]thiazol-2-yl)amino)cyclohexyl)oxy)benzenesulfonamide [4-(((1,4-trans)-4-((6-Chlorobenzo[d]thiazol -2-yl)amino)cyclohexyl)oxy)benzenesulfonamide], N-((1,4-trans)-4-(4-chlorophenoxy)cyclohexyl) -6-(trifluoromethyl)benzo[d]thiazol-2-amine [N-((1,4-trans)-4-(4-Chlorophenoxy)cyclohexyl)-6-(trifluoromethyl)benzo[d] thiazol-2-amine], 6-(trifluoromethyl)-N-((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)benzo[d]thiazole -2-amine [6-(Trifluoromethyl)-N-((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)benzo[d]thiazol-2-amine], N-((1 ,4-trans)-4-(4-(trifluoromethoxy)phenoxy)cyclohexyl)-6-(trifluoromethyl)benzo[d]thiazol-2-amine [N-((1,4 -trans)-4-(4-(Trifluoromethoxy)phenoxy)cyclohexyl)-6-(trifluoromethyl)benzo[d]thiazol-2-amine], 4-(((1,4-trans)-4-((6 -(trifluoromethyl)benzo[d]thiazol-2-yl)amino)cyclohexyl)oxy)benzonitrile [4-(((1,4-trans)-4-((6-(Trifluoromethyl) benzo[d]thiazol-2-yl)amino)cyclohexyl)oxy)benzonitrile], N-((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)-6-(trifluoro methyl)benzo[d]thiazol-2-amine [N-((1,4-trans)-4-(4-Nitrophenoxy)cyclohexyl)-6-(trifluoromethyl)benzo[d]thiazol-2-amine], N-((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)-6-(trifluoromethyl)benzo[d]thiazol-2-amine [N-( (1,4-trans)-4-(4-(Methylsulfonyl)phenoxy)cyclohexyl)-6-(trifluoromethyl)benzo[d]thiazol-2-amine], 4-(((1,4-trans)-4 -((6-(trifluoromethyl)benzo[d]thiazol-2-yl)amino)cyclohexyl)oxy)benzenesulfonamide DE [4-(((1,4-trans)-4-((6-(Trifluoromethyl)benzo[d]thiazol-2-yl)amino)cyclohexyl)oxy)benzenesulfonamide], N-((1,4- trans)-4-(4-chlorophenoxy)cyclohexyl)-6-nitrobenzo[d]thiazol-2-amine [N-((1,4-trans)-4-(4-Chlorophenoxy)cyclohexyl )-6-nitrobenzo[d]thiazol-2-amine], 6-nitro-N-((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)benzo[ d]thiazol-2-amine [6-Nitro-N-((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)benzo[d]thiazol-2-amine], 6-knight Rho-N-((1,4-trans)-4-(4-(trifluoromethoxy)phenoxy)cyclohexyl)benzo[d]thiazol-2-amine [6-Nitro-N-((1 ,4-trans)-4-(4-(trifluoromethoxy)phenoxy)cyclohexyl)benzo[d]thiazol-2-amine], 4-(((1,4-trans)-4-((6-nitrobenzo [d]thiazol-2-yl)amino)cyclohexyl)oxy)benzonitrile [4-(((1,4-trans)-4-((6-Nitrobenzo[d]thiazol-2-yl)amino )cyclohexyl)oxy)benzonitrile], 6-nitro-N-((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)benzo[d]thiazol-2-amine [6- Nitro-N-((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)benzo[d]thiazol-2-amine], N-((1,4-trans)-4-(4-( Methylsulfonyl)phenoxy)cyclohexyl)-6-nitrobenzo[d]thiazol-2-amine [N-((1,4-trans)-4-(4-(Methylsulfonyl)phenoxy)cyclohexyl)- 6-nitrobenzo[d]thiazol-2-amine], 4-(((1,4-trans)-4-((6-nitrobenzo[d]thiazol-2- yl)amino)cyclohexyl)oxy)benzenesulfonamide [4-(((1,4-trans)-4-((6-Nitrobenzo[d]thiazol-2-yl)amino)cyclohexyl)oxy)benzenesulfonamide], 6-methoxy-N-((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)benzo[d]thiazol-2-amine [6-Methoxy-N- ((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)benzo[d]thiazol-2-amine], 4-(((1,4-trans)-4-((6- Methoxybenzo[d]thiazol-2-yl)amino)cyclohexyl)oxy)benzonitrile [4-(((1,4-trans)-4-((6-Methoxybenzo[d]thiazol-2- yl)amino)cyclohexyl)oxy)benzonitrile], 6-methoxy-N-((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)benzo[d]thiazol-2-amine [6-Methoxy-N-((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)benzo[d]thiazol-2-amine] and 6-methoxy-N-((1,4-trans )-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)benzo[d]thiazol-2-amine [6-Methoxy-N-((1,4-trans)-4-(4-( A 2-aminobenzothiazole derivative compound selected from the group consisting of methylsulfonyl) phenoxy) cyclohexyl) benzo [d] thiazol-2-amine], a pharmaceutically acceptable salt thereof, a solvate thereof or a stereoisomer thereof Compounds selected from.
  5. 제1항 내지 제4항 중 어느 한 항에 따른 화합물을 유효성분으로 함유하는 암 예방 또는 치료용 약학조성물.A pharmaceutical composition for preventing or treating cancer containing the compound according to any one of claims 1 to 4 as an active ingredient.
  6. 제5항에 있어서, 상기 화합물은 진핵생물 번역 개시 인자 2α(eukaryotic translation initiation factor 2α; eIF2α)의 인산화를 촉진하는 것을 특징으로 하는 암 예방 또는 치료용 약학조성물.The pharmaceutical composition for preventing or treating cancer according to claim 5, wherein the compound promotes phosphorylation of eukaryotic translation initiation factor 2α (eIF2α).
  7. 제5항에 있어서, 상기 암은 혈액암, 유방암, 육종암 및 뇌암으로 이루어진 군에서 선택되는 하나이상인 것을 특징으로 하는 암 예방 또는 치료용 약학조성물.The pharmaceutical composition for preventing or treating cancer according to claim 5, wherein the cancer is at least one selected from the group consisting of blood cancer, breast cancer, sarcoma cancer and brain cancer.
  8. 제1항 내지 제4항 중 어느 한 항에 따른 화합물을 유효성분으로 함유하는 대사항암제용 약학조성물.Claims 1 to 4 of any one of the compound according to any one of the active ingredient containing a pharmaceutical composition for metabolic cancer agent.
  9. 제8항에 있어서, 상기 화합물은 진핵생물 번역 개시 인자 2α(eukaryotic translation initiation factor 2α; eIF2α)의 인산화를 촉진하여 암세포의 대사를 차단하는 것을 특징으로 하는 대사항암제용 약학조성물.According to claim 8, wherein the compound promotes the phosphorylation of eukaryotic translation initiation factor 2α (eukaryotic translation initiation factor 2α; eIF2α) to block the metabolism of cancer cells, characterized in that the pharmaceutical composition for anticancer agents.
  10. 제1항 내지 제4항 중 어느 한 항에 따른 화합물을 투여하는 단계를 포함하는 암세포 대사 억제방법.A method of inhibiting cancer cell metabolism comprising administering a compound according to any one of claims 1 to 4.
  11. 제10항에 있어서, 상기 화합물은 진핵생물 번역 개시 인자 2α(eukaryotic translation initiation factor 2α; eIF2α)의 인산화를 촉진하여 암세포의 대사를 차단하는 것을 특징으로 하는 암세포 대사 억제방법.The method of claim 10, wherein the compound promotes phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) to block metabolism of cancer cells.
  12. 제1항 내지 제4항 중 어느 한 항에 따른 화합물을 유효성분으로 함유하는 암 예방 또는 개선용 건강기능식품 조성물.A health functional food composition for preventing or improving cancer containing the compound according to any one of claims 1 to 4 as an active ingredient.
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