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WO2025170275A1 - Novel eif2b agonist and composition for preventing or treating metabolic diseases comprising same - Google Patents

Novel eif2b agonist and composition for preventing or treating metabolic diseases comprising same

Info

Publication number
WO2025170275A1
WO2025170275A1 PCT/KR2025/001480 KR2025001480W WO2025170275A1 WO 2025170275 A1 WO2025170275 A1 WO 2025170275A1 KR 2025001480 W KR2025001480 W KR 2025001480W WO 2025170275 A1 WO2025170275 A1 WO 2025170275A1
Authority
WO
WIPO (PCT)
Prior art keywords
acetamido
eif
propiolamide
chlorophenyl
chlorophenoxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/KR2025/001480
Other languages
French (fr)
Korean (ko)
Inventor
최예린
안홍찬
박영혜
김소영
강성은
장민아
한재석
쿠수마페드호
이나라
박소영
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Industry Academy Cooperation Foundation of Soonchunhyang University
Daegu Gyeongbuk Medical Innovation Foundation
Original Assignee
Industry Academy Cooperation Foundation of Soonchunhyang University
Daegu Gyeongbuk Medical Innovation Foundation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Industry Academy Cooperation Foundation of Soonchunhyang University, Daegu Gyeongbuk Medical Innovation Foundation filed Critical Industry Academy Cooperation Foundation of Soonchunhyang University
Publication of WO2025170275A1 publication Critical patent/WO2025170275A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/18—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides
    • C07C235/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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Definitions

  • the purpose of the present invention is to provide a novel compound that modulates the activity of downstream regulators involved in the integrated stress response.
  • Another object of the present invention is to provide a composition for treating metabolic diseases comprising the above compound.
  • the present invention provides a compound selected from a diamide derivative represented by the following chemical formula 1, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof:
  • n’, n”, m’ and m may be the same or different and are one of 0 to 2,
  • L is one of (C3-C10)cycloalkyl, (C5-C10)spirocycloalkyl and (C5-C10)bicycloalkyl,
  • a 1 and A 2 may be the same or different and are -CONH- or -NHCO-,
  • M’ and M may be the same or different and are one of (C1-C5)alkyl, (C2-C5)alkene, (C2-C5)alkyne; and heteroalkyl of 2 to 5 members containing one or more heteroatoms selected from O and S,
  • Ar 1 and Ar 2 may be the same or different, and are one of an unsubstituted or substituted (C5-C10)aryl and an unsubstituted or substituted 5 to 12-membered heteroaryl comprising one or more heteroatoms selected from the group consisting of N, O and S, wherein the substituted (C5-C10)aryl or the substituted 5 to 12-membered heteroaryl may be substituted with one or more of (C1-C5)alkyl, (C1-C5)alkoxy, halogen, trifluoromethyl, difluoromethyl and difluoroethyl.
  • the present invention provides a pharmaceutical composition for preventing or treating metabolic diseases, comprising the above compound as an active ingredient.
  • the present invention provides a reagent composition for activating eIF2B comprising the above compound as an active ingredient.
  • novel compound according to the present invention can directly and significantly activate eIF2B, a protein that mediates integrated stress response signaling.
  • Figure 1 illustrates the mechanism of the Puromycin incorporation assay method used to verify the in vivo efficacy of a novel compound synthesized according to the present invention.
  • Figures 2a and 2b show the activity of a novel compound measured using the method of Figure 1.
  • Figure 3 shows the activity of the novel compound as a function of relative fluorescence intensity.
  • Figure 5 shows the results of enzyme activity analysis of the novel compound.
  • Figure 7 shows the experimental design and results for confirming the in vivo activity of a novel compound using an animal model.
  • Figure 8 shows the liver toxicity of the novel compound confirmed by ALT and AST levels.
  • Figure 9 shows the liver toxicity of the novel compound confirmed by histological changes.
  • Figure 10 shows the effect of a novel compound on macrophages.
  • the present inventors synthesized a novel compound that significantly activates eIF2B based on the fact that inhibition of protein synthesis by eIF2 ⁇ phosphorylation operates by inhibiting the activity of a GDP/GTP exchange enzyme called eIF2B, and further confirmed that the compound is effective in treating metabolic diseases related to eIF2B, thereby completing the present invention.
  • the present invention provides a novel compound selected from a diamide derivative represented by the following chemical formula 1, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof:
  • n', n”, m’ and m may be the same or different and are one of 0 to 2
  • L is one of (C3-C10)cycloalkyl, (C5-C10)spirocycloalkyl and (C5-C10)bicycloalkyl
  • a 1 and A 2 may be the same or different and are -CONH- or -NHCO-
  • M’ and M” may be the same or different and are one of (C1-C5)alkyl, (C2-C5)alkene, (C2-C5)alkyne; and 2 to 5 membered heteroalkyl containing one or more heteroatoms selected from O and S
  • Ar 1 and Ar 2 may be the same or different and are one of unsubstituted or substituted (C5-C10)aryl and unsubstituted or substituted 5 to 12 membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O and S.
  • substituted (C5-C10)aryl or substituted heteroaryl having 5 to 12 atoms may be substituted with one or more of (C1-C5)alkyl, (C1-C5)alkoxy, halogen, trifluoromethyl, difluoromethyl and difluoroethyl.
  • the compound is a compound in which n', n", m' and m" in the above chemical formula 1 may be the same or different and are 0 or 1
  • L is one of (C3-C7)cycloalkyl, (C6-C8)spirocycloalkyl and (C5-C8)bicycloalkyl
  • M' and M" may be the same or different and are one of (C2-C3)alkene, (C2-C3)alkyne; and one of 2 to 4 membered heteroalkyls containing one or more heteroatoms selected from O and S
  • Ar 1 and Ar 2 may be the same or different, and are one of unsubstituted or substituted (C5-C7)aryl and unsubstituted or substituted 5 to 10 membered heteroaryls containing one or more heteroatoms selected from the group consisting of N, O and S, and the substituted (C5-C7)aryl or the substituted 5 to 10 membered Heteroaryl may be substitute
  • the compound is a compound in which L in the above formula 1 is one of (C4-C6)cycloalkyl, spirocycloheptyl and bicyclopentyl, M' and M" may be the same or different, and are one of ethylene, acetylene and 2 to 4 membered heteroalkyl containing one heteroatom of O or S, Ar 1 and Ar 2 may be the same or different, and are one of unsubstituted or substituted phenyl and unsubstituted or substituted 5 to 10 membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O and S, wherein the substituted phenyl is substituted with one or more and three or less of trifluoromethyl, chlorine, fluorine, methoxy, methyl, ethyl and tert-butyl, and the substituted 5 to 10 membered heteroaryl is substituted with one or more and three or more of fluorine, methoxy, trifluor
  • the above 5 to 10-membered heteroaryl is one of pyridine, quinoline, thiazole, pyrimidazole, coumarone, 7-azaindole, benzimidazole, naphthyl, indazole, thionaphthene, benzothiazole, pyrimidine and pyrazole, and the above substituted 5 to 10-membered heteroaryl may be substituted with one of fluorine, methoxy, trifluoromethyl, difluoromethyl and difluoroethyl.
  • the diamide derivative represented by the above chemical formula 1 may be any one selected from the following group of compounds:
  • the above compound can activate eIF2B.
  • eIF2B eukaryotic initiation factor 2B
  • eIF2B eukaryotic initiation factor 2B
  • the present invention provides a pharmaceutical composition for preventing or treating metabolic diseases, comprising as an active ingredient a compound selected from a diamide derivative represented by the above chemical formula 1, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.
  • the above metabolic disease may be selected from the group consisting of obesity, diabetes, arteriosclerosis, hyperlipidemia, fatty liver, and liver fibrosis, and preferably, the composition may be for anti-obesity use.
  • the pharmaceutical composition according to the present invention can be prepared according to conventional methods in the pharmaceutical field.
  • the pharmaceutical composition can be combined with an appropriate pharmaceutically acceptable carrier depending on the formulation, and, if necessary, can be prepared by further including excipients, diluents, dispersants, emulsifiers, buffers, stabilizers, binders, disintegrants, solvents, etc.
  • the appropriate carriers, etc., which do not inhibit the activity and properties of the compound according to the present invention, can be selected differently depending on the dosage form and formulation.
  • the pharmaceutical composition according to the present invention can be applied in any dosage form, and more specifically, it can be formulated and used as an oral dosage form, an external preparation, a suppository, and a parenteral dosage form of a sterile injection solution according to a conventional method.
  • the pharmaceutical composition can be administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment and not causing adverse effects.
  • the effective dosage level of the pharmaceutical composition may vary depending on the intended use, the patient's age, sex, weight, and health condition, the type and severity of the disease, the activity and sensitivity of the drug, the method of administration, the time of administration, the route of administration, and the excretion rate, the duration of treatment, the drugs used in combination or concurrently, and other factors well known in the medical field.
  • it may generally be administered once or several times daily at a dosage of 0.001 to 1000 mg/kg, preferably 0.01 to 100 mg/kg.
  • the above dosage does not limit the scope of the present invention in any way.
  • the pharmaceutical composition according to the present invention can be administered to any animal that may develop a metabolic disease, particularly obesity, and the animal may include, for example, humans and primates, as well as livestock such as cows, pigs, horses, and dogs.
  • the pharmaceutical composition according to the present invention can be administered via an appropriate route of administration depending on the formulation form, and can be administered via various routes, either oral or parenteral, as long as it can reach the target tissue.
  • the method of administration is not particularly limited, and can be administered by conventional methods such as oral, rectal, intravenous, intramuscular, or skin application, respiratory inhalation, intrauterine epidural, or intracerebroventricular injection.
  • the pharmaceutical composition according to the present invention can be used alone for the prevention or treatment of metabolic diseases, or can be used in combination with surgery or other drug treatments.
  • the present invention provides a health food composition for preventing or improving metabolic diseases, which comprises as an active ingredient a compound selected from a diamide derivative represented by the above chemical formula 1, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.
  • the above metabolic disease may be selected from the group consisting of obesity, diabetes, arteriosclerosis, hyperlipidemia, fatty liver, and liver fibrosis, and preferably, the composition may be for anti-obesity use.
  • the health food composition according to the present invention may be manufactured into powder, granules, tablets, capsules, syrup, or beverages for the purpose of preventing or improving metabolic diseases.
  • the form the health food may take, and it may be formulated in the same manner as the pharmaceutical composition and used as a functional food or added to various foods.
  • the above health food composition may be manufactured by further including food additives (food additives) commonly used in the industry and other appropriate auxiliary ingredients.
  • food additives food additives
  • suitability as a food additive may be determined by the specifications and standards for the relevant item, as stipulated in the General Provisions and General Test Methods of the Food Additives Codex approved by the Ministry of Food and Drug Safety.
  • the above health food composition has the advantage of not having side effects that may occur with long-term use of general medicines as it uses food as a raw material, and is highly portable, so it can be taken as a supplement for preventing or improving metabolic diseases.
  • the present invention provides a reagent composition for activating eIF2B, which comprises as an active ingredient a compound selected from a diamide derivative represented by the above chemical formula 1, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.
  • the above compound can enhance the expression or activity of eIF2B.
  • tert -Butyl (6-(2-(4-chlorophenoxy)acetamido)spiro[3.3]heptan-2-yl)carbamate] was dissolved in 20% TFA/CH 2 Cl 2 and the solution was stirred at room temperature for 4 h. The solution was evaporated under reduced pressure and the crude product was used in the next step without further purification.
  • tert -Butyl (6-(2-(pyridin-2-yloxy)acetamido)spiro[3.3]heptan-2-yl)carbamate] (50 mg, 0.14 mmol) was diluted with 20% TFA/CH 2 Cl 2 (1 mL, 0.14 M) and the solution was stirred at room temperature for 2 h. The organic solvent was removed under reduced pressure and the crude product was used in the next step without further purification.
  • tert -Butyl ( E )-(3-(3-(4-chlorophenyl)acrylamido)cyclobutyl)carbamate [ tert -Butyl ( E )-(3-(3-(4-chlorophenyl)acrylamido)cyclobutyl)carbamate] (130 mg, 0.37 mmol) was stirred in 10% TFA/CH 2 Cl 2 at room temperature for 4 h. The organic solvent was removed under reduced pressure and the crude product was used in the next step without further purification.
  • tert -Butyl (3-(2-((2,6-dichlorobenzyl)thio)acetamido)cyclobutyl) carbamate [ tert -butyl (3-(2-((2,6-dichlorobenzyl)thio)acetamido)cyclobutyl) carbamate] (100 mg, 0.24 mmol) was diluted in 20% TFA/CH 2 Cl 2 (1.2 mL, 0.2 M) and the solution was stirred at room temperature for 4 h. The organic solvent was removed under reduced pressure and the crude product was used in the next step without further purification.
  • the mixture was diluted with EtOAc, and the organic phase was washed three times with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure.
  • tert-butyl (3-(2-(mesityloxy)acetamido)cyclobutyl)carbamate] (1.0 equiv., 111 mg, 0.306 mmol) was diluted in 20% TFA/DCM (255 ⁇ l/ 1.28 ml) at room temperature. After stirring for 4 h, the reaction mixture was evaporated without further purification.
  • N -(3-aminocyclobutyl)-2-(mesityloxy)acetamide 1.0 equiv., 80 mg, 0.305 mmol
  • DMF 1.5 ml
  • 2-(mesityloxy)acetic acid 1.1 equiv., 65 mg, 0.335 mmol
  • DIPEA 5.0 equiv., 266 ⁇ l, 1.525 mmol
  • HATU 2.0 equiv., 232 mg, 0.610 mmol
  • the reaction was diluted with EtOAc, and the organic phase was washed three times with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was suspended in a minimum amount of ethyl acetate and treated with hexane. The formed precipitate was purified to obtain 90 mg (82%) of the product as a pale yellow solid.
  • N -(3-aminocyclobutyl)-3-(2-chlorophenoxy)propanamide 1.0 equiv., 60 mg, 0.223 mmol
  • DMF 1.1 ml
  • 3-(2-chlorophenoxy)propanoic acid 1.1 equiv., 49 mg, 0.246 mmol
  • DIPEA 5.0 equiv., 195 ⁇ l, 1.116 mmol
  • HATU 2.0 equiv., 170 mg, 0.447 mmol
  • tert -butyl (3-(3-(2-fluorophenoxy)propanamido)cyclobutyl)carbamate (1.0 equiv., 40 mg, 0.108 mmol) was diluted in 20% TFA/DCM (255 ⁇ l/1.23 ml) at room temperature. After stirring for 4 h, the reaction mixture was evaporated without further purification.
  • N -(3-aminocyclobutyl)quinoline-3-carboxamide 1.0 equiv dissolved in CH 2 Cl 2 were added 2-(4-chlorophenoxy)acetyl chloride (1.5 equiv) and triethylamine (5 equiv).
  • the reaction mixture was stirred at room temperature, diluted with ethyl acetate, and washed with 10% aqueous lithium chloride (X3) and brine.
  • the organic layer was dried over anhydrous MgSO 4 and concentrated under reduced pressure.
  • N -((1 r ,4 r )-4-aminocyclohexyl)-2-methoxyisonicotinamide 1.0 equiv
  • 2-(4-chlorophenoxy)acetyl chloride 1.5 equiv
  • triethylamine 5 equiv
  • N -((1 r ,4 r )-4-aminocyclohexyl)-2-(4-chlorophenoxy)acetamide [ N -((1 r ,4 r )-4-aminocyclohexyl)-2-(4-chlorophenoxy)acetamide] (1.0 equiv), quinoline-3-carboxylic acid (1.2 equiv), N , N -diisopropylethylamine (2.5 equiv), EDCI (1.5 equiv), and HOBt (1.5 equiv) dissolved in DMF was stirred at room temperature overnight.
  • reaction mixture was diluted with ethyl acetate and washed with 10% aqueous lithium chloride (X3) and brine.
  • the organic layer was dried over anhydrous MgSO 4 and concentrated under reduced pressure.
  • the residue was purified through filtration (EtOAc/ n -hexane) to obtain compound 13 (EIF-013) , N -((1 r ,4 r )-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)quinoline-3-carboxamide, as a white solid with 99% purity.
  • N -(3-(aminomethyl)cyclobutyl)-3-(4-chlorophenyl)propiolamide 1.0 equiv., 22 mg, 0.084 mmol
  • DMF 449 ⁇ l
  • 3-(4-chlorophenyl)propiolic acid 1.1 equiv., 16 mg, 0.092 mmol
  • DIPEA 5.0 equiv., 78 ⁇ l, 0.449 mmol
  • HATU 2.0 equiv., 68.2 mg, 0.179 mmol.
  • N -(3-(aminomethyl)cyclobutyl)-2-((5-fluoropyridin-2-yl)oxy)acetamide 1.0 equiv., 22 mg, 0.085 mmol
  • DMF 424 ⁇ l
  • 2-((5-fluoropyridin-2-yl)oxy)acetic acid 1.1 equiv., 15 mg, 0.085 mmol
  • DIPEA 3.0 equiv., 45 ⁇ l, 0.255 mmol
  • HATU 2.0 equiv., 64.6 mg, 0.170 mmol.
  • tert-butyl (3-(aminomethyl)cyclopentyl)carbamate [ tert -butyl (3-(aminomethyl)cyclopentyl)carbamate] in DMF (1.0 ml)
  • 2-((5-fluoropyridin-2-yl)oxy)acetic acid 1.1 equiv., 35.1 mg, 0.205 mmol
  • DIPEA 3.0 equiv., 98 ⁇ l, 0.560 mmol
  • HATU 2.0 equiv., 142 mg, 0.373 mmol.
  • tert-butyl (3-((2-((5-fluoropyridin-2-yl)oxy) acetamido )methyl)cyclopentyl)carbamate] (1.0 equiv., 30 mg, 0.082 mmol) was diluted with 20% TFA/DCM (68 ⁇ l/ 340 ⁇ l) at room temperature. After stirring for 3 h, the reaction mixture was evaporated without further purification.
  • N -((3-aminocyclopentyl)methyl)-2-((5-fluoropyridin-2-yl)oxy)acetamide (1.0 equiv., 20 mg, 0.075 mmol) in DMF (374 ⁇ l) was added 2-((5-fluoropyridin-2-yl)oxy)acetic acid (1.1 equiv., 14 mg, 0.082 mmol), DIPEA (3.0 equiv., 39 ⁇ l, 0.224 mmol), and HATU (2.0 equiv., 56.9 mg, 0.150 mmol).
  • N -(3-aminocyclobutyl)-3-(4-chlorophenyl)propiolamide [ N -(3-aminocyclobutyl)-3-(4-chlorophenyl)propiolamide] in DMF (505 ⁇ l)
  • 3-(4-chlorophenyl)propiolic acid 1.1 equiv., 20.1 mg, 0.111 mmol
  • DIPEA 3.0 equiv., 53 ⁇ l, 0.303 mmol
  • HATU 2.0 equiv., 77 mg, 0.202 mmol
  • N -((1 r ,4 r )-4-aminocyclohexyl)pivalamide 1.0 equiv., 50 mg, 0.252 mmol
  • DMF 1.3 ml
  • 3-(4-chlorophenyl)propiolic acid 1.1 equiv., 50 mg, 0.277 mmol
  • DIPEA 3.0 equiv., 132 ⁇ l, 0.756 mmol
  • HATU 2.0 equiv., 192 mg, 0.504 mmol.
  • the reaction mixture was stirred at room temperature overnight.
  • the mixture was diluted with EtOAc, and the organic phase was washed three times with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure.
  • the residue was diluted with hexane and the formed precipitate was filtered and collected to obtain 73 mg (80%) of a white solid product.
  • the activity of the novel compound was measured using a method called Puromycin incorporation assay, as shown in Fig. 1.
  • the integrated stress response is initiated by the phosphorylation of eIF2 ⁇ , and phosphorylated eIF2 ⁇ inhibits protein synthesis.
  • the inhibition of protein synthesis by eIF2 ⁇ phosphorylation works by inhibiting the activity of a GDP/GTP exchange enzyme called eIF2B.
  • eIF2B a GDP/GTP exchange enzyme
  • Thapsigargin is a drug that inhibits SERCA calcium channels, altering calcium concentration in the endoplasmic reticulum (ER), thereby inducing the integrated stress response. It is widely used in research on the integrated stress response.
  • the enzyme assay involves loading GDP conjugated with BODIPY (a fluorescent substance) onto the eIF2 enzyme complex, then adding this to a sample containing eIF2B.
  • BODIPY a fluorescent substance
  • the process of BODIPY-conjugated GDP being released by the activity of eIF2B can be observed through fluorescence (Fig. 4).
  • the EC 50 for the new compounds was also confirmed. Referring to Fig. 6, while the negative control compound 35 showed no effect on GEF activity at all, ISRIB and compounds 43 showed similar activation of eIF2B. In addition, the EC 50 of ISRIB was approximately 20 nM, which is similar to the previously reported EC 50 , and compound 43 also showed an EC 50 of approximately 24 nM, which is comparable to that of ISRIB.
  • mice were fed a high-fat diet for a total of 8 weeks, during which time ISRIB was treated as a positive control and DMSO as a negative control.
  • body weight changes were investigated.
  • novel compounds 43 and 52 when administered to high-fat diet-fed obese mice, exhibited effects comparable to those of the control drug ISRIB.
  • the ALT and AST levels which indicate the degree of liver damage, were checked.
  • ALT and AST levels did not change significantly due to ISRIB, and novel compounds 43 and 52 also did not induce changes in ALT and AST levels in the liver after in vivo administration.

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Abstract

The present invention relates to a novel eIF2B agonist and a composition for preventing or treating metabolic diseases, comprising same. More specifically, the present invention provides a novel diamide derivative, stereoisomer thereof, solvate thereof or pharmaceutically acceptable salt thereof that activates eIF2B. The novel compound according to the present invention directly and significantly activates eIF2B, a protein that mediates integrated stress response signaling, and thus can be used as an effective therapeutic composition for eIF2B-associated metabolic diseases.

Description

신규한 eIF2B 작용제 및 이를 포함하는 대사질환 예방 또는 치료용 조성물Novel eIF2B agonist and composition for preventing or treating metabolic diseases comprising the same

본 발명은 신규한 eIF2B 작용제 및 이의 의학적 용도에 관한 것으로, 보다 상세하게는, eIF2B 인산화 또는 이에 따른 하위 신호전달경로를 조절하는 신규 화합물 및 이를 포함하는 대사질환의 예방 또는 치료용 조성물에 관한 것이다. The present invention relates to a novel eIF2B agonist and its medical use, and more particularly, to a novel compound that regulates eIF2B phosphorylation or a downstream signaling pathway thereof and a composition comprising the same for preventing or treating metabolic diseases.

세포가 스트레스를 받을 경우 세포의 항상성이 저해되며, 이때 항상성 복원을 위한 방어기전으로 유도되는 반응으로 통합 스트레스 반응(Integrated Stress Response, ISR)이 있다. 통합 스트레스 반응은 모든 진핵생물에 공통적인 세포 스트레스 반응으로, 네 가지 인산화 효소인 PERK (PKR-like ER kinase), GCN2 (general control nonderepressible 2), PKR (protein kinase R) 및 HRI (heme-regulated inhibitor kinase)에 의해 단백질 합성 개시인자인 진핵생물 개시 인자 2 알파(eukaryotic initiation factor 2 alpha, eIF2α)가 인산화 되면서 신호전달이 시작되며, 인산화된 elF2α는 세포 내 전반적인 단백질 합성 과정을 저해하며 이를 통해 세포가 스트레스에 대응할 수 있는 시간을 확보하게 된다. 이 때 eIF2α 인산화에 의한 단백질 합성의 저해는 eIF2B라는 GDP/GTP 교환 효소의 활성을 저해함으로써 작동한다. eIF2B는 진핵생물에서 발견되는 단백질 복합체로, 비활성 eIF2-GDP를 활성 eIF2-GTP로 전환시키나, elF2α의 인산화에 의해 저해되어 안정한 eIF2α-P-GDP-eIF2B 복합체를 유도하고 번역(translation) 개시를 억제한다.When cells are stressed, cellular homeostasis is disrupted, and the integrated stress response (ISR) is a defense mechanism that is induced to restore homeostasis. The integrated stress response is a cellular stress response common to all eukaryotes. Signal transduction begins when eukaryotic initiation factor 2 alpha (eIF2α), a protein synthesis initiation factor, is phosphorylated by four kinases: PERK (PKR-like ER kinase), GCN2 (general control nonderepressible 2), PKR (protein kinase R), and HRI (heme-regulated inhibitor kinase). Phosphorylated eIF2α inhibits the overall protein synthesis process in the cell, allowing the cell time to respond to stress. At this time, the inhibition of protein synthesis by eIF2α phosphorylation works by inhibiting the activity of a GDP/GTP exchange enzyme called eIF2B. eIF2B is a protein complex found in eukaryotes that converts inactive eIF2-GDP to active eIF2-GTP, but this is inhibited by phosphorylation of eIF2α, leading to a stable eIF2α-P-GDP-eIF2B complex and inhibiting translation initiation.

대부분의 단백질이 합성되지 못하는 상황에서 ATF4 (activating transcription factor 4)라는 전사조절인자의 합성이 증진되며, 이렇게 유도된 ATF4는 핵으로 이동하여, 여러 하위표적 유전자들의 전사를 증가시키게 된다. ATF4의 하위 유전자는 GADD34 (Growth arrest and DNA damage-inducible 34), tRNA syntheases 등이 있으며, 상기 인산화에 의해 억제된 단백질 합성을 재개함으로써 스트레스를 극복한 세포가 새로운 단백질을 합성할 수 있도록 유도하게 된다. 그러나, 세포의 스트레스가 해소되지 못하고 악화되었을 때, 상기의 유전자들에 의해 증가한 단백질 합성과 CHOP (C/EBP homologous protein)을 포함하는 세포 사멸 유전자들에 의하여 세포는 사멸하게 된다. In a situation where most proteins cannot be synthesized, the synthesis of a transcriptional regulator called ATF4 (activating transcription factor 4) is increased, and the induced ATF4 moves to the nucleus and increases the transcription of several downstream target genes. Downstream genes of ATF4 include GADD34 (Growth arrest and DNA damage-inducible 34) and tRNA syntheses, and by resuming protein synthesis inhibited by the above phosphorylation, cells that have overcome stress are induced to synthesize new proteins. However, when cellular stress is not relieved and worsens, the cells die due to the increased protein synthesis caused by the above genes and apoptotic genes including CHOP (C/EBP homologous protein).

최근 통합 스트레스 반응 및 이의 신호전달의 조절 장애가 염증, 바이러스 감염, 당뇨병, 암 및 신경변성 질환 등 다양한 질환과 관련되어 병리학적 의미가 있음을 여러 연구를 통해 밝혀지고 있고, 이의 조절제에 관한 연구도 이루어지고 있으나, 여전히 보다 유용한 새로운 조절제의 필요성이 계속적으로 강조되고 있다.Recently, numerous studies have revealed that dysregulation of the integrated stress response and its signaling pathways has pathological implications in various diseases such as inflammation, viral infection, diabetes, cancer, and neurodegenerative diseases, and research is also being conducted on its modulators. However, the need for new, more useful modulators continues to be emphasized.

본 발명의 목적은 통합 스트레스 반응과 관련된 하위 조절인자의 활성을 조절하는 신규한 화합물을 제공하는 데에 있다.The purpose of the present invention is to provide a novel compound that modulates the activity of downstream regulators involved in the integrated stress response.

본 발명의 다른 목적은 상기의 화합물을 포함하는 대사질환 치료 조성물을 제공하는 데에 있다.Another object of the present invention is to provide a composition for treating metabolic diseases comprising the above compound.

본 발명의 또 다른 목적은 상기의 화합물을 포함하는 eIF2B 활성화용 조성물을 제공하는 데에 있다.Another object of the present invention is to provide a composition for activating eIF2B comprising the above compound.

상기의 목적을 달성하기 위하여, 본 발명은 하기 화학식 1로 표시되는 디아마이드 유도체, 이의 입체이성질체, 이의 용매화물 또는 이의 약학적으로 허용가능한 염에서 선택된, 화합물을 제공한다:To achieve the above purpose, the present invention provides a compound selected from a diamide derivative represented by the following chemical formula 1, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof:

[화학식 1][Chemical Formula 1]

상기 화학식 1에서,In the above chemical formula 1,

n’, n”, m’및 m”은 각각 같거나 다를 수 있고, 0 내지 2 중 하나이고, n’, n”, m’ and m” may be the same or different and are one of 0 to 2,

L은 (C3-C10)사이클로알킬, (C5-C10)스피로사이클로알킬 및 (C5-C10)바이사이클로알킬 중 하나이고,L is one of (C3-C10)cycloalkyl, (C5-C10)spirocycloalkyl and (C5-C10)bicycloalkyl,

A1 및 A2 는 각각 같거나 다를 수 있으며, -CONH- 또는 -NHCO-이고,A 1 and A 2 may be the same or different and are -CONH- or -NHCO-,

M’및 M”은 각각 같거나 다를 수 있으며, (C1-C5)알킬, (C2-C5)알켄, (C2-C5)알킨; 및 O 및 S로부터 선택된 하나 이상의 헤테로원자를 포함하는 2 내지 5 원자의 헤테로알킬 중 하나이고,M’ and M” may be the same or different and are one of (C1-C5)alkyl, (C2-C5)alkene, (C2-C5)alkyne; and heteroalkyl of 2 to 5 members containing one or more heteroatoms selected from O and S,

Ar1 및 Ar2는 각각 같거나 다를 수 있으며, 비치환 또는 치환된 (C5-C10)아릴 및 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 비치환 또는 치환된 5 내지 12 원자의 헤테로아릴 중 하나이며, 상기 치환된 (C5-C10)아릴 또는 치환된 5 내지 12 원자의 헤테로아릴은 (C1-C5)알킬, (C1-C5)알콕시, 할로겐, 트리플루오로메틸, 디플루오로메틸 및 디플루오로에틸 중 1개 이상이 치환될 수 있다.Ar 1 and Ar 2 may be the same or different, and are one of an unsubstituted or substituted (C5-C10)aryl and an unsubstituted or substituted 5 to 12-membered heteroaryl comprising one or more heteroatoms selected from the group consisting of N, O and S, wherein the substituted (C5-C10)aryl or the substituted 5 to 12-membered heteroaryl may be substituted with one or more of (C1-C5)alkyl, (C1-C5)alkoxy, halogen, trifluoromethyl, difluoromethyl and difluoroethyl.

본 발명은 상기의 화합물을 유효성분으로 포함하는 대사질환 예방 또는 치료용 약학 조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing or treating metabolic diseases, comprising the above compound as an active ingredient.

본 발명은 상기의 화합물을 유효성분으로 포함하는 대사질환 예방 또는 개선용 건강식품 조성물을 제공한다.The present invention provides a health food composition for preventing or improving metabolic diseases, which comprises the above compound as an active ingredient.

또한, 본 발명은 상기의 화합물을 유효성분으로 포함하는 eIF2B 활성화용 시약 조성물을 제공한다.In addition, the present invention provides a reagent composition for activating eIF2B comprising the above compound as an active ingredient.

본 발명에 따른 신규 화합물은 통합 스트레스 반응 신호전달을 매개하는 단백질인 eIF2B를 직접적으로 유의하게 활성화할 수 있다.The novel compound according to the present invention can directly and significantly activate eIF2B, a protein that mediates integrated stress response signaling.

본 발명에 따른 신규 화합물을 이용하여 eIF2B와 관련된 대사질환에서 독성없이 유의한 치료 효과를 확인한 바, 이를 비만 등의 대사질환 치료 조성물로 활용할 수 있다.By using the novel compound according to the present invention, a significant therapeutic effect without toxicity was confirmed in a metabolic disease related to eIF2B, and thus it can be utilized as a composition for treating metabolic diseases such as obesity.

도 1은 본 발명에 따라 합성된 신규 화합물의 생체 내 효능을 검증하기 위해 이용한 Puromycin incorporation assay 방법의 메커니즘을 설명한 것이다.Figure 1 illustrates the mechanism of the Puromycin incorporation assay method used to verify the in vivo efficacy of a novel compound synthesized according to the present invention.

도 2a 및 2b는 도 1의 방법을 이용하여 신규 화합물의 활성을 측정한 것이다.Figures 2a and 2b show the activity of a novel compound measured using the method of Figure 1.

도 3은 신규 화합물의 활성을 상대적 형광 세기로 나타낸 것이다.Figure 3 shows the activity of the novel compound as a function of relative fluorescence intensity.

도 4는 신규 화합물의 효소 활성 분석 메커니즘을 설명한 것이다.Figure 4 illustrates the enzyme activity analysis mechanism of the novel compound.

도 5는 신규 화합물의 효소 활성 분석 결과를 나타낸 것이다.Figure 5 shows the results of enzyme activity analysis of the novel compound.

도 6은 신규 화합물의 EC50을 분석한 것이다.Figure 6 shows the analysis of the EC 50 of the new compound.

도 7은 동물 모델을 이용하여 신규 화합물의 생체 내 활성을 확인하기 위한 실험 설계 및 그 결과를 나타낸 것이다.Figure 7 shows the experimental design and results for confirming the in vivo activity of a novel compound using an animal model.

도 8은 신규 화합물의 간 독성을 ALT 및 AST 수치로 확인한 것이다.Figure 8 shows the liver toxicity of the novel compound confirmed by ALT and AST levels.

도 9는 신규 화합물의 간 독성을 조직학적 변화로 확인한 것이다.Figure 9 shows the liver toxicity of the novel compound confirmed by histological changes.

도 10은 신규 화합물이 대식세포에 미치는 영향을 확인한 것이다.Figure 10 shows the effect of a novel compound on macrophages.

이하, 본 발명을 상세하게 설명하기로 한다.Hereinafter, the present invention will be described in detail.

본 발명자는 eIF2α 인산화에 의한 단백질 합성의 저해가 eIF2B라는 GDP/GTP 교환 효소의 활성을 저해함으로써 작동함을 바탕으로, eIF2B를 유의적으로 활성화하는 신규한 화합물을 합성하였고, 또한 상기 화합물이 eIF2B와 관련된 대사질환 치료에 효과가 있음을 확인함으로써, 본 발명을 완성하였다.The present inventors synthesized a novel compound that significantly activates eIF2B based on the fact that inhibition of protein synthesis by eIF2α phosphorylation operates by inhibiting the activity of a GDP/GTP exchange enzyme called eIF2B, and further confirmed that the compound is effective in treating metabolic diseases related to eIF2B, thereby completing the present invention.

본 발명은 하기 화학식 1로 표시되는 디아마이드 유도체, 이의 입체이성질체, 이의 용매화물 또는 이의 약학적으로 허용가능한 염에서 선택된, 신규한 화합물을 제공한다:The present invention provides a novel compound selected from a diamide derivative represented by the following chemical formula 1, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof:

[화학식 1][Chemical Formula 1]

상기 화학식 1에서,In the above chemical formula 1,

n’, n”, m’및 m”은 각각 같거나 다를 수 있고, 0 내지 2 중 하나이고, L은 (C3-C10)사이클로알킬, (C5-C10)스피로사이클로알킬 및 (C5-C10)바이사이클로알킬 중 하나이고, A1 및 A2 는 각각 같거나 다를 수 있으며, -CONH- 또는 -NHCO-이고, M’및 M”은 각각 같거나 다를 수 있으며, (C1-C5)알킬, (C2-C5)알켄, (C2-C5)알킨; 및 O 및 S로부터 선택된 하나 이상의 헤테로원자를 포함하는 2 내지 5 원자의 헤테로알킬 중 하나이고, Ar1 및 Ar2는 각각 같거나 다를 수 있으며, 비치환 또는 치환된 (C5-C10)아릴 및 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 비치환 또는 치환된 5 내지 12 원자의 헤테로아릴 중 하나이며, 상기 치환된 (C5-C10)아릴 또는 치환된 5 내지 12 원자의 헤테로아릴은 (C1-C5)알킬, (C1-C5)알콕시, 할로겐, 트리플루오로메틸, 디플루오로메틸 및 디플루오로에틸 중 1개 이상이 치환될 수 있다.n', n”, m’ and m” may be the same or different and are one of 0 to 2, L is one of (C3-C10)cycloalkyl, (C5-C10)spirocycloalkyl and (C5-C10)bicycloalkyl, A 1 and A 2 may be the same or different and are -CONH- or -NHCO-, M’ and M” may be the same or different and are one of (C1-C5)alkyl, (C2-C5)alkene, (C2-C5)alkyne; and 2 to 5 membered heteroalkyl containing one or more heteroatoms selected from O and S, Ar 1 and Ar 2 may be the same or different and are one of unsubstituted or substituted (C5-C10)aryl and unsubstituted or substituted 5 to 12 membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O and S. and the substituted (C5-C10)aryl or substituted heteroaryl having 5 to 12 atoms may be substituted with one or more of (C1-C5)alkyl, (C1-C5)alkoxy, halogen, trifluoromethyl, difluoromethyl and difluoroethyl.

보다 상세하게는, 상기 화합물은 상기 화학식 1에서 n’, n”, m’ 및 m”은 각각 같거나 다를 수 있고, 0 또는 1이고, L은 (C3-C7)사이클로알킬, (C6-C8)스피로사이클로알킬 및 (C5-C8)바이사이클로알킬 중 하나이고, M’및 M”은 각각 같거나 다를 수 있으며, (C2-C3)알켄, (C2-C3)알킨; 및 O 및 S로부터 선택된 하나 이상의 헤테로원자를 포함하는 2 내지 4 원자의 헤테로알킬 중 하나이고, Ar1 및 Ar2는 각각 같거나 다를 수 있으며, 비치환 또는 치환된 (C5-C7)아릴 및 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 비치환 또는 치환된 5 내지 10 원자의 헤테로아릴 중 하나이며, 상기 치환된 (C5-C7)아릴 또는 치환된 5 내지 10 원자의 헤테로아릴은 (C1-C4)알킬, (C1-C3)알콕시, 할로겐, 트리플루오로메틸, 디플루오로메틸 및 디플루오로에틸 중 1개 이상 3개 이하로 치환될 수 있다.More specifically, the compound is a compound in which n', n", m' and m" in the above chemical formula 1 may be the same or different and are 0 or 1, L is one of (C3-C7)cycloalkyl, (C6-C8)spirocycloalkyl and (C5-C8)bicycloalkyl, M' and M" may be the same or different and are one of (C2-C3)alkene, (C2-C3)alkyne; and one of 2 to 4 membered heteroalkyls containing one or more heteroatoms selected from O and S, Ar 1 and Ar 2 may be the same or different, and are one of unsubstituted or substituted (C5-C7)aryl and unsubstituted or substituted 5 to 10 membered heteroaryls containing one or more heteroatoms selected from the group consisting of N, O and S, and the substituted (C5-C7)aryl or the substituted 5 to 10 membered Heteroaryl may be substituted with one or more and three or less of (C1-C4)alkyl, (C1-C3)alkoxy, halogen, trifluoromethyl, difluoromethyl, and difluoroethyl.

바람직하게는, 상기 화합물은 상기 화학식 1에서 L은 (C4-C6)사이클로알킬, 스피로사이클로헵틸 및 바이사이클로펜틸 중 하나이고, M’ 및 M”은 각각 같거나 다를 수 있으며, 에틸렌, 아세틸렌 및 O 또는 S의 헤테로원자를 하나 포함하는 2 내지 4 원자의 헤테로알킬 중 하나이고, Ar1 및 Ar2는 각각 같거나 다를 수 있으며, 비치환 또는 치환된 페닐 및 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 비치환 또는 치환된 5 내지 10 원자의 헤테로아릴 중 하나이며, 상기 치환된 페닐은 트리플루오로메틸, 염소, 플루오린, 메톡시, 메틸, 에틸 및 tert-부틸 중 1개 이상 3개 이하가 치환되고, 상기 치환된 5 내지 10 원자의 헤테로아릴은 플루오린, 메톡시, 트리플루오로메틸, 디플루오로메틸 및 디플루오로에틸 중 1개 이상 3개 이하로 치환될 수 있다.Preferably, the compound is a compound in which L in the above formula 1 is one of (C4-C6)cycloalkyl, spirocycloheptyl and bicyclopentyl, M' and M" may be the same or different, and are one of ethylene, acetylene and 2 to 4 membered heteroalkyl containing one heteroatom of O or S, Ar 1 and Ar 2 may be the same or different, and are one of unsubstituted or substituted phenyl and unsubstituted or substituted 5 to 10 membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O and S, wherein the substituted phenyl is substituted with one or more and three or less of trifluoromethyl, chlorine, fluorine, methoxy, methyl, ethyl and tert-butyl, and the substituted 5 to 10 membered heteroaryl is substituted with one or more and three or more of fluorine, methoxy, trifluoromethyl, difluoromethyl and difluoroethyl. It can be replaced by the following.

이 때, 상기 5 내지 10 원자의 헤테로아릴은 피리딘, 퀴놀린, 티아졸, 피리미다졸, 쿠마론, 7-아자인돌, 벤조이미다졸, 나프틸, 인다졸, 싸이오나프텐, 벤조티아졸, 피리미딘 및 피라졸 중 하나이고, 상기 치환된 5 내지 10 원자의 헤테로아릴은 플루오린, 메톡시, 트리플루오로메틸, 디플루오로메틸 및 디플루오로에틸 중 하나가 치환될 수 있다.At this time, the above 5 to 10-membered heteroaryl is one of pyridine, quinoline, thiazole, pyrimidazole, coumarone, 7-azaindole, benzimidazole, naphthyl, indazole, thionaphthene, benzothiazole, pyrimidine and pyrazole, and the above substituted 5 to 10-membered heteroaryl may be substituted with one of fluorine, methoxy, trifluoromethyl, difluoromethyl and difluoroethyl.

보다 바람직하게는, 상기 화학식 1로 표시되는 디아마이드 유도체는 하기 화합물 군으로부터 선택되는 어느 하나일 수 있다:More preferably, the diamide derivative represented by the above chemical formula 1 may be any one selected from the following group of compounds:

N,N'-(사이클로헥산-1,3-디일)비스(2-(4-클로로페녹시)아세트아마이드[N,N'-(cyclohexane-1,3-diyl)bis(2-(4-chlorophenoxy)acetamide)] (EIF-001), N,N'-(사이클로펜탄-1,3-디일)비스(2-(4-클로로페녹시)아세트아마이드)[N,N'-(cyclopentane-1,3-diyl)bis(2-(4-chlorophenoxy)acetamide)] (EIF-002), N,N'-(스피로[3.3]헵탄-2,6-디일)비스(2-(4-클로로페녹시)아세트아마이드)[N,N'-(spiro[3.3]heptane-2,6-diyl)bis(2-(4-chlorophenoxy)acetamide)] (EIF-004), N,N'-(스피로[3.3]헵탄-2,6-디일)비스(2-(피리딘-2-일옥시)아세트아마이드)[N,N'-(spiro[3.3]heptane-2,6-diyl)bis(2-(pyridin-2-yloxy)acetamide)] (EIF-005), (2E,2'E)-N,N'-(사이클로부탄-1,3-디일)비스(3-(4-클로로페닐)아크릴아마이드)[(2E,2'E)-N,N'-(cyclobutane-1,3-diyl)bis(3-(4-chlorophenyl)acrylamide)] (EIF-006), 2-(4-클로로페녹시)-N-(3-(2-((2,6-디클로로벤질)티오)아세트아미도)사이클로부틸)아세트아마이드[2-(4-chlorophenoxy)-N-(3-(2-((2,6-dichlorobenzyl)thio)acetamido)cyclobutyl)acetamide] (EIF-007), N,N'-(사이클로부탄-1,3-디일)비스(2-(메시틸옥시)아세트아마이드)[N,N'-(cyclobutane-1,3-diyl)bis(2-(mesityloxy)acetamide)] (EIF-008), N,N'-(사이클로부탄-1,3-디일)비스(3-(2-클로로페녹시)프로판아마이드[N,N'-(cyclobutane-1,3-diyl)bis(3-(2-chlorophenoxy)propanamide)] (EIF-009), N,N'-(사이클로부탄-1,3-디일)비스(2-((5-플루오로피리딘-2-일)옥시)아세트아마이드)[N,N'-(cyclobutane-1,3-diyl)bis(2-((5-fluoropyridin-2-yl)oxy)acetamide) (EIF-010), N-(3-(2-(4-클로로페녹시)아세트아미도)사이클로부틸)퀴놀린-3-카르복사마이드[N-(3-(2-(4-chlorophenoxy)acetamido)cyclobutyl)quinoline-3-carboxamide] (EIF-011), N-((1r,4r)-4-(2-(4-클로로페녹시)아세트아미도)사이클로헥실)-2-메톡시이소니코틴아마이드[N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-2-methoxyisonicotinamide] (EIF-012), N-((1r,4r)-4-(2-(4-클로로페녹시)아세트아미도)사이클로헥실)퀴놀린-3-카르복사마이드[N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)quinoline-3-carboxamide] (EIF-013), N-((1r,4r)-4-(2-(4-클로로페녹시)아세트아미도)사이클로헥실)티아졸-5-카르복사마이드[N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)thiazole-5-carboxamide] (EIF-014), N-((1r,4r)-4-(2-(4-클로로페녹시)아세트아미도)사이클로헥실)이미다졸[1,2-a]피리딘-6-카르복사마이드[N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)imidazo[1,2-a]pyridine-6-carboxamide] (EIF-015), N-((1r,4r)-4-(2-(4-클로로페녹시)아세트아미도)사이클로헥실)벤조퓨란-2-카르복사마이드[N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)benzofuran-2-carboxamide] (EIF-016), (1r,4r)-4-((2-(2,4-디플루오로페녹시)아세트아미도)메틸)-N-(이미다조[1,2-a]피리딘-6-일)사이클로헥산-1-카르복사마이드[(1r,4r)-4-((2-(2,4-difluorophenoxy)acetamido)methyl)-N-(imidazo[1,2-a]pyridin-6-yl)cyclohexane-1-carboxamide] (EIF-023), (1r,4r)-4-((2-(2,4-디플루오로페녹시)아세트아미도)메틸)-N-(피리딘-4-일)사이클로헥산-1-카르복사마이드[(1r,4r)-4-((2-(2,4-difluorophenoxy)acetamido)methyl)-N-(pyridin-4-yl)cyclohexane-1-carboxamide] (EIF-024), (1r,4r)-4-((3-(4-플루오로페녹시)프로판아미도)메틸)-N-(이미다조[1,2-a]피리딘-6-일)사이클로헥산-1-카르복사마이드[(1r,4r)-4-((3-(4-fluorophenoxy)propanamido)methyl)-N-(imidazo[1,2-a]pyridin-6-yl)cyclohexane-1-carboxamide] (EIF-025), N-((1r,4r)-4-(2-(4-클로로페녹시)아세트아미도)사이클로헥실)-1H-피롤로[2,3-b]피리딘-5-카르복사마이드[N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide] (EIF-026), N-((1r,4r)-4-(2-(4-클로로페녹시)아세트아미도)사이클로헥실)-1H-벤조[d]이미다졸-6-카르복사마이드[N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-1H-benzo[d]imidazole-6-carboxamide] (EIF-027), 3-(4-클로로페닐)-N-((3-(3-(4-클로로페닐)프로피올아미도)사이클로부틸)메틸)프로이올아마이드[3-(4-chlorophenyl)-N-((3-(3-(4-chlorophenyl)propiolamido)cyclobutyl)methyl)propiolamide] (EIF-028), (E)-3-(4-클로로페닐)-N-((3-((E)-3-(4-클로로페닐)아크릴아미도)사이클로부틸)메틸)아크릴아마이드[(E)-3-(4-chlorophenyl)-N-((3-((E)-3-(4-chlorophenyl)acrylamido)cyclobutyl)methyl)acrylamide] (EIF-029), 2-((5-플루오로피리딘-2-일)옥시)-N-((3-(2-((5-플루오로피리딘-2-일)옥시)아세트아미도)사이클로부틸)메틸)아세트아마이드[2-((5-fluoropyridin-2-yl)oxy)-N-((3-(2-((5-fluoropyridin-2-yl)oxy)acetamido)cyclobutyl)methyl)acetamide] (EIF-030), N-(3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)바이사이클로[1.1.1]펜탄-1-일)-3-(4-클로로페닐)프로피올아마이드[N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(4-chlorophenyl)propiolamide] (EIF-032), N-(3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)바이사이클로[1.1.1]펜탄-1-일)-3-페닐프로피올아마이드[N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-phenylpropiolamide] (EIF-033), 2-((5-플루오로피리딘-2-일)옥시)-N-((3-(2-((5-플루오로피리딘-2-일)옥시)아세트아미도)사이클로펜틸)메틸)아세트아마이드[2-((5-fluoropyridin-2-yl)oxy)-N-((3-(2-((5-fluoropyridin-2-yl)oxy)acetamido)cyclopentyl)methyl)acetamide] (EIF-034), 3-(4-클로로페닐)-N-((3-(3-(4-클로로페닐)프로피올아미도)사이클로펜틸)메틸)프로피올아마이드[3-(4-chlorophenyl)-N-((3-(3-(4-chlorophenyl)propiolamido)cyclopentyl)methyl)propiolamide] (EIF-035), N,N'-(사이클로부탄-1,3-디일)비스(3-(4-클로로페닐)프로피올아마이드)[N,N'-(cyclobutane-1,3-diyl)bis(3-(4-chlorophenyl)propiolamide)] (EIF-036), N,N'-(사이클로펜탄-1,3-디일)비스(3-(4-사이클로펜틸)프로피올아마이드)[N,N'-(cyclopentane-1,3-diyl)bis(3-(4-chlorophenyl)propiolamide)] (EIF-037), N-(3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)바이사이클로[1.1.1]펜탄-1-일)-3-(3-플루오로페닐)프로피올아마이드[N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(3-fluorophenyl)propiolamide] (EIF-038), N-(3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)바이사이클로[1.1.1]펜탄-1-일)-3-(p-톨릴)프로피올아마이드[N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(p-tolyl)propiolamide] (EIF-039), N-(3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)바이사이클로[1.1.1]펜탄-1-일)-3-(2-플루오로페닐)프로피올아마이드[N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(2-fluorophenyl)propiolamide] (EIF-040), N-(3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)바이사이클로[1.1.1]펜탄-1-일)-3-(3-클로로페닐)프로피올아마이드[N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(3-chlorophenyl)propiolamide] (EIF-041), N-(3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)바이사이클로[1.1.1]펜탄-1-일)-3-(4-(트리플루오로메틸)페닐)프로피올아마이드[N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(4-(trifluoromethyl)phenyl)propiolamide] (EIF-042), N-(3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)바이사이클로[1.1.1]펜탄-1-일)-3-(4-플루오로페닐)프로피올아마이드[N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(4-fluorophenyl)propiolamide] (EIF-043), N-(3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)바이사이클로[1.1.1]펜탄-1-일)-3-(4-에틸페닐)프로피올아마이드[N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(4-ethylphenyl)propiolamide] (EIF-044), 3-(4-(터트-부틸)페닐)-N-(3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)바이사이클로[1.1.1]펜탄-1-일)프로파올아마이드[3-(4-(tert-butyl)phenyl)-N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)propiolamide] (EIF-045), N-(3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)바이사이클로[1.1.1]펜탄-1-일)-3-(나프탈렌-2-일)프로피올아마이드[N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(naphthalen-2-yl)propiolamide] (EIF-046), N-(3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)바이사이클로[1.1.1]펜탄-1-일)-3-(2-클로로페닐)프로피올아마이드[N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(2-chlorophenyl)propiolamide] (EIF-047), N,N'-(사이클로헥산-1,3-디일)비스(3-(4-클로로페닐)프로피올아마이드)[N,N'-(cyclohexane-1,3-diyl)bis(3-(4-chlorophenyl)propiolamide)] (EIF-048), N,N'-((1r,4r)-사이클로헥산-1,4-디일)비스(3-(4-클로로페닐)프로피올아마이드[N,N'-((1r,4r)-cyclohexane-1,4-diyl)bis(3-(4-chlorophenyl)propiolamide)] (EIF-049), N-((1r,4r)-4-(2-(4-클로로페녹시)아세트아미도)사이클로헥실)벤조퓨란-6-카르복사마이드[N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)benzofuran-6-carboxamide] (EIF-050), N-((1r,4r)-4-(2-(4-클로로페녹시)아세트아미도)사이클로헥실)-1H-인다졸-6-카르복사마이드[N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-1H-indazole-6-carboxamide] (EIF-051), N-((1r,4r)-4-(2-(4-클로로페녹시)아세트아미도)사이클로헥실)니코틴아마이드[N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)nicotinamide] (EIF-052), N-((1r,4r)-4-(2-(1H-벤조[d]이미다졸-2-일)아세트아미도)사이클로헥실)-2-(4-클로로페녹시)아세트아마이드[N-((1r,4r)-4-(2-(1H-benzo[d]imidazol-2-yl)acetamido)cyclohexyl)-2-(4-chlorophenoxy)acetamide] (EIF-053), 2-(벤조퓨란-2-일)-N-((1r,4r)-4-(2-(4-클로로페녹시)아세트아미도)사이클로헥실)아세트아마이드[2-(benzofuran-2-yl)-N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)acetamide] (EIF-054), 2-(벤조[b]티오펜-2-일)-N-((1r,4r)-4-(2-(4-클로로페녹시)아세트아미도)사이클로헥실)아세트아마이드[2-(benzo[b]thiophen-2-yl)-N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)acetamide] (EIF-055), 3-(4-클로로페닐)-N-(3-(2-(o-톨릴옥시)아세트아미도)사이클로부틸)프로피올아마이드[3-(4-chlorophenyl)-N-(3-(2-(o-tolyloxy)acetamido)cyclobutyl)propiolamide] (EIF-056), 3-(4-클로로페닐)-N-(3-(2-(m-톨릴옥시)아세트아미도)사이클로부틸)프로피올아마이드[3-(4-chlorophenyl)-N-(3-(2-(m-tolyloxy)acetamido)cyclobutyl)propiolamide] (EIF-057), 3-(4-클로로페닐)-N-(3-(2-(2-플루오로페녹시)아세트아미도)사이클로부틸)프로피올아마이드[3-(4-chlorophenyl)-N-(3-(2-(2-fluorophenoxy)acetamido)cyclobutyl)propiolamide] (EIF-058), 3-(4-클로로페닐)-N-(3-(2-(3-플루오로페녹시)아세트아미도)사이클로부틸)프로피올아마이드[3-(4-chlorophenyl)-N-(3-(2-(3-fluorophenoxy)acetamido)cyclobutyl)propiolamide] (EIF-059), 3-(4-클로로페닐)-N-(3-(2-(p-톨릴톡시)아세트아미도)사이클로부틸)프로피올아마이드[3-(4-chlorophenyl)-N-(3-(2-(p-tolyloxy)acetamido)cyclobutyl)propiolamide] (EIF-060), 3-(4-클로로페닐)-N-(3-(2-(2,4-디플루오로페녹시)아세트아미도)사이클로부틸)프로피올아마이드[3-(4-chlorophenyl)-N-(3-(2-(2,4-difluorophenoxy)acetamido)cyclobutyl)propiolamide] (EIF-061), N-(3-(2-(2-클로로페녹시)아세트아미도)사이클로부틸)-3-(4-클로로페닐)프로피올아마이드[N-(3-(2-(2-chlorophenoxy)acetamido)cyclobutyl)-3-(4-chlorophenyl)propiolamide] (EIF-062), N-(3-(2-(4-클로로-2-메틸페녹시)아세트아미도)사이클로부틸)-3-(4-클로로페닐)프로피올아마이드[N-(3-(2-(4-chloro-2-methylphenoxy)acetamido)cyclobutyl)-3-(4-chlorophenyl)propiolamide] (EIF-063), N-(3-(2-(4-클로로페녹시)아세트아미도)사이클로부틸)-3-(4-클로로페닐)프로피올아마이드[N-(3-(2-(4-chlorophenoxy)acetamido)cyclobutyl)-3-(4-chlorophenyl)propiolamide] (EIF-064), (1r,4r)-N-(벤조[d]티아졸-2-일)-4-((2-(4-클로로-3-플루오로페녹시)아세트아미도)메틸)사이클로헥산-1-카르복사마이드[(1r,4r)-N-(benzo[d]thiazol-2-yl)-4-((2-(4-chloro-3-fluorophenoxy)acetamido)methyl)cyclohexane-1-carboxamide] (EIF-065), (1r,4r)-N-(벤조[d]티아졸-2-일)-4-((2-(2,4-디플루오로페녹시)아세트아미도)메틸)사이클로헥산-1-카르복사마이드[(1r,4r)-N-(benzo[d]thiazol-2-yl)-4-((2-(2,4-difluorophenoxy)acetamido)methyl)cyclohexane-1-carboxamide] (EIF-066), N-((3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)사이클로부틸)메틸)-5-(디플루오로메틸)피라진-2-카르복사마이드[N-((3-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclobutyl)methyl)-5-(difluoromethyl)pyrazine-2-carboxamide] (EIF-067), N-((3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)사이클로부틸)메틸)니코틴아마이드[N-((3-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclobutyl)methyl)nicotinamide] (EIF-068), N-((3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)사이클로부틸)메틸)벤조퓨란-6-카르복사마이드[N-((3-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclobutyl)methyl)benzofuran-6-carboxamide] (EIF-069), N-((3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)사이클로부틸)메틸)-1-(2,2-디플루오로에틸)-1H-피라졸-3-카르복사마이드[N-((3-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclobutyl)methyl)-1-(2,2-difluoroethyl)-1H-pyrazole-3-carboxamide] (EIF-070), 및 N-((3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)사이클로부틸)메틸)피콜린아마이드(3-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclobutyl)methyl)picolinamide] (EIF-071).N,N'-(cyclohexane-1,3-diyl)bis(2-(4-chlorophenoxy)acetamide) (EIF-001), N,N'-(cyclopentane-1,3-diyl)bis(2-(4-chlorophenoxy)acetamide) (EIF-002), N,N'-(spiro[3.3]heptane-2,6-diyl)bis(2-(4-chlorophenoxy)acetamide) (EIF-004), N,N'-(spiro[3.3]heptane-2,6-diyl)bis(2-(pyridin-2-yloxy)acetamide)[N,N'-(spiro[3.3]heptane-2,6-diyl)bis(2-(pyridin-2-yloxy)acetamide)] (EIF-005), (2E,2'E)-N,N'-(cyclobutane-1,3-diyl)bis(3-(4-chlorophenyl)acrylamide)[(2E,2'E)-N,N'-(cyclobutane-1,3-diyl)bis(3-(4-chlorophenyl)acrylamide)] (EIF-006), 2-(4-chlorophenoxy)-N-(3-(2-((2,6-dichlorobenzyl)thio)acetamido)cyclobutyl)acetamide [2-(4-chlorophenoxy)-N-(3-(2-((2,6-dichlorobenzyl)thio)acetamido)cyclobutyl)acetamide] (EIF-007), N,N'-(cyclobutane-1,3-diyl)bis(2-(mesityloxy)acetamide) [N,N'-(cyclobutane-1,3-diyl)bis(2-(mesityloxy)acetamide)] (EIF-008), N,N'-(cyclobutane-1,3-diyl)bis(3-(2-chlorophenoxy)propanamide) (EIF-009), N,N'-(cyclobutane-1,3-diyl)bis(2-((5-fluoropyridin-2-yl)oxy)acetamide) (EIF-010), N-(3-(2-(4-chlorophenoxy)acetamido)cyclobutyl)quinoline-3-carboxamide (EIF-011), N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-2-methoxyisonicotinamide [N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-2-methoxyisonicotinamide] (EIF-012), N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)quinoline-3-carboxamide [N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)quinoline-3-carboxamide] (EIF-013), N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)thiazole-5-carboxamide [N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)thiazole-5-carboxamide] (EIF-014), N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)imidazole[1,2-a]pyridine-6-carboxamide [N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)imidazo[1,2-a]pyridine-6-carboxamide] (EIF-015), N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)benzofuran-2-carboxamide (EIF-016), (1r,4r)-4-((2-(2,4-difluorophenoxy)acetamido)methyl)-N-(imidazo[1,2-a]pyridin-6-yl)cyclohexane-1-carboxamide (EIF-023), (1r,4r)-4-((2-(2,4-difluorophenoxy)acetamido)methyl)-N-(pyridin-4-yl)cyclohexane-1-carboxamide] (EIF-024), (1r,4r)-4-((3-(4-fluorophenoxy)propanamido)methyl)-N-(imidazo[1,2-a]pyridin-6-yl)cyclohexane-1-carboxamide] (EIF-025), N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide [N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide] (EIF-026), N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-1H-benzo[d]imidazole-6-carboxamide [N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-1H-benzo[d]imidazole-6-carboxamide] (EIF-027), 3-(4-chlorophenyl)-N-((3-(3-(4-chlorophenyl)propiolamido)cyclobutyl)methyl)propiolamide [3-(4-chlorophenyl)-N-((3-(3-(4-chlorophenyl)propiolamido)cyclobutyl)methyl)propiolamide] (EIF-028), (E)-3-(4-chlorophenyl)-N-((3-((E)-3-(4-chlorophenyl)acrylamido)cyclobutyl)methyl)acrylamide [(E)-3-(4-chlorophenyl)-N-((3-((E)-3-(4-chlorophenyl)acrylamido)cyclobutyl)methyl)acrylamide] (EIF-029), 2-((5-fluoropyridin-2-yl)oxy)-N-((3-(2-((5-fluoropyridin-2-yl)oxy)acetamido)cyclobutyl)methyl)acetamide [2-((5-fluoropyridin-2-yl)oxy)-N-((3-(2-((5-fluoropyridin-2-yl)oxy)acetamido)cyclobutyl)methyl)acetamide] (EIF-030), N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(4-chlorophenyl)propiolamide [N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(4-chlorophenyl)propiolamide] (EIF-032), N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-phenylpropiolamide [N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-phenylpropiolamide] (EIF-033), 2-((5-fluoropyridin-2-yl)oxy)-N-((3-(2-((5-fluoropyridin-2-yl)oxy)acetamido)cyclopentyl)methyl)acetamide [2-((5-fluoropyridin-2-yl)oxy)-N-((3-(2-((5-fluoropyridin-2-yl)oxy)acetamido)cyclopentyl)methyl)acetamide] (EIF-034), 3-(4-chlorophenyl)-N-((3-(3-(4-chlorophenyl)propiolamido)cyclopentyl)methyl)propiolamide [3-(4-chlorophenyl)-N-((3-(3-(4-chlorophenyl)propiolamido)cyclopentyl)methyl)propiolamide] (EIF-035), N,N'-(cyclobutane-1,3-diyl)bis(3-(4-chlorophenyl)propiolamide) [N,N'-(cyclobutane-1,3-diyl)bis(3-(4-chlorophenyl)propiolamide)] (EIF-036), N,N'-(cyclopentane-1,3-diyl)bis(3-(4-cyclopentyl)propiolamide)] (EIF-037), N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(3-fluorophenyl)propiolamide [N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(3-fluorophenyl)propiolamide] (EIF-038), N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(p-tolyl)propiolamide [N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(p-tolyl)propiolamide] (EIF-039), N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(2-fluorophenyl)propiolamide [N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(2-fluorophenyl)propiolamide] (EIF-040), N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(3-chlorophenyl)propiolamide [N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(3-chlorophenyl)propiolamide] (EIF-041), N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(4-(trifluoromethyl)phenyl)propiolamide [N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(4-(trifluoromethyl)phenyl)propiolamide] (EIF-042), N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(4-fluorophenyl)propiolamide [N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(4-fluorophenyl)propiolamide] (EIF-043), N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(4-ethylphenyl)propiolamide [N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(4-ethylphenyl)propiolamide] (EIF-044), 3-(4-(tert-butyl)phenyl)-N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)propiolamide] (EIF-045), N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(naphthalen-2-yl)propiolamide] (EIF-046), N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(naphthalen-2-yl)propiolamide] (EIF-046), N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(2-chlorophenyl)propiolamide] (EIF-047), N,N'-(cyclohexane-1,3-diyl)bis(3-(4-chlorophenyl)propiolamide)[N,N'-(cyclohexane-1,3-diyl)bis(3-(4-chlorophenyl)propiolamide)] (EIF-048), N,N'-((1r,4r)-cyclohexane-1,4-diyl)bis(3-(4-chlorophenyl)propiolamide)] (EIF-049), N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)benzofuran-6-carboxamide] (EIF-050), N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)benzofuran-6-carboxamide] (EIF-051), N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)nicotinamide [N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)nicotinamide] (EIF-052), N-((1r,4r)-4-(2-(1H-benzo[d]imidazol-2-yl)acetamido)cyclohexyl)-2-(4-chlorophenoxy)acetamide [N-((1r,4r)-4-(2-(1H-benzo[d]imidazol-2-yl)acetamido)cyclohexyl)-2-(4-chlorophenoxy)acetamide] (EIF-053), 2-(Benzofuran-2-yl)-N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)acetamide [2-(benzofuran-2-yl)-N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)acetamide] (EIF-054), 2-(Benzo[b]thiophen-2-yl)-N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)acetamide [2-(benzo[b]thiophen-2-yl)-N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)acetamide] (EIF-055), 3-(4-chlorophenyl)-N-(3-(2-(o-tolyloxy)acetamido)cyclobutyl)propiolamide [3-(4-chlorophenyl)-N-(3-(2-(o-tolyloxy)acetamido)cyclobutyl)propiolamide] (EIF-056), 3-(4-chlorophenyl)-N-(3-(2-(m-tolyloxy)acetamido)cyclobutyl)propiolamide [3-(4-chlorophenyl)-N-(3-(2-(m-tolyloxy)acetamido)cyclobutyl)propiolamide] (EIF-057), 3-(4-chlorophenyl)-N-(3-(2-(2-fluorophenoxy)acetamido)cyclobutyl)propiolamide (EIF-058), 3-(4-chlorophenyl)-N-(3-(2-(3-fluorophenoxy)acetamido)cyclobutyl)propiolamide (EIF-059), 3-(4-chlorophenyl)-N-(3-(2-(p-tolyloxy)acetamido)cyclobutyl)propiolamide (EIF-060), 3-(4-chlorophenyl)-N-(3-(2-(2,4-difluorophenoxy)acetamido)cyclobutyl)propiolamide (EIF-061), N-(3-(2-(2-chlorophenoxy)acetamido)cyclobutyl)-3-(4-chlorophenyl)propiolamide [N-(3-(2-(2-chlorophenoxy)acetamido)cyclobutyl)-3-(4-chlorophenyl)propiolamide] (EIF-062), N-(3-(2-(4-chloro-2-methylphenoxy)acetamido)cyclobutyl)-3-(4-chlorophenyl)propiolamide [N-(3-(2-(4-chloro-2-methylphenoxy)acetamido)cyclobutyl)-3-(4-chlorophenyl)propiolamide] (EIF-063), N-(3-(2-(4-chlorophenoxy)acetamido)cyclobutyl)-3-(4-chlorophenyl)propiolamide (EIF-064), (1r,4r)-N-(benzo[d]thiazol-2-yl)-4-((2-(4-chloro-3-fluorophenoxy)acetamido)methyl)cyclohexane-1-carboxamide (EIF-065), (1r,4r)-N-(benzo[d]thiazol-2-yl)-4-((2-(2,4-difluorophenoxy)acetamido)methyl)cyclohexane-1-carboxamide [(1r,4r)-N-(benzo[d]thiazol-2-yl)-4-((2-(2,4-difluorophenoxy)acetamido)methyl)cyclohexane-1-carboxamide] (EIF-066), N-((3-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclobutyl)methyl)-5-(difluoromethyl)pyrazine-2-carboxamide [N-((3-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclobutyl)methyl)-5-(difluoromethyl)pyrazine-2-carboxamide] (EIF-067), N-((3-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclobutyl)methyl)nicotinamide [N-((3-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclobutyl)methyl)nicotinamide] (EIF-068), N-((3-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclobutyl)methyl)benzofuran-6-carboxamide [N-((3-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclobutyl)methyl)benzofuran-6-carboxamide] (EIF-069), N-((3-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclobutyl)methyl)-1-(2,2-difluoroethyl)-1H-pyrazole-3-carboxamide [N-((3-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclobutyl)methyl)-1-(2,2-difluoroethyl)-1H-pyrazole-3-carboxamide] (EIF-070), and N-((3-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclobutyl)methyl)picolinamide] (EIF-071).

상기 화합물은 eIF2B를 활성화할 수 있다.The above compound can activate eIF2B.

본 명세서에서, "eIF2B (eukaryotic initiation factor 2B)"는 모든 진핵세포에서 단백질 합성 개시 및 그 조절에 필요한 단백질 복합체로, 비활성 eIF2-GDP를 활성 eIF2-GTP로 전환시키나, elF2α의 인산화에 의해 저해되어 안정한 eIF2α-P-GDP-eIF2B 복합체를 유도하고 번역(translation) 개시를 억제한다.In this specification, "eIF2B (eukaryotic initiation factor 2B)" is a protein complex required for the initiation and regulation of protein synthesis in all eukaryotic cells, which converts inactive eIF2-GDP into active eIF2-GTP, but is inhibited by phosphorylation of eIF2α, thereby inducing a stable eIF2α-P-GDP-eIF2B complex and inhibiting translation initiation.

본 발명에 따른 화합물은 스트레스에 의해 억제된 단백질 합성에 관련된 eIF2B를 활성화하여 통합 스트레스 반응을 조절하고, 이를 표적으로 하는 관련 질환, 바람직하게는 대사질환, 보다 바람직하게는 비만의 예방, 개선 또는 치료하는데 활용할 수 있다.The compound according to the present invention can be used to regulate the integrated stress response by activating eIF2B involved in protein synthesis suppressed by stress, and to prevent, improve or treat related diseases targeting this, preferably metabolic diseases, more preferably obesity.

본 발명은 상기 화학식 1로 표시되는 디아마이드 유도체, 이의 입체이성질체, 이의 용매화물 또는 이의 약학적으로 허용가능한 염에서 선택된 화합물을 유효성분으로 포함하는 대사질환 예방 또는 치료용 약학 조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing or treating metabolic diseases, comprising as an active ingredient a compound selected from a diamide derivative represented by the above chemical formula 1, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

상기 대사질환은 비만, 당뇨, 동맥경화, 고지혈, 지방간 및 간섬유화로 이루어진 군에서 선택될 수 있고, 바람직하게는 상기 조성물은 항비만용일 수 있다.The above metabolic disease may be selected from the group consisting of obesity, diabetes, arteriosclerosis, hyperlipidemia, fatty liver, and liver fibrosis, and preferably, the composition may be for anti-obesity use.

본 발명에 따른 약학 조성물은 약학적 분야의 통상적인 방법에 따라 제조될 수 있다. 상기 약학 조성물은 제형에 따라 약학적으로 허용가능한 적절한 담체와 배합될 수 있고, 필요에 따라, 부형제, 희석제, 분산제, 유화제, 완충제, 안정제, 결합제, 붕해제, 용제 등을 더 포함하여 제조될 수 있다. 상기 적절한 담체 등은 본 발명에 따른 화합물의 활성 및 특성을 저해하지 않는 것으로, 투여 형태 및 제형에 따라 달리 선택될 수 있다.The pharmaceutical composition according to the present invention can be prepared according to conventional methods in the pharmaceutical field. The pharmaceutical composition can be combined with an appropriate pharmaceutically acceptable carrier depending on the formulation, and, if necessary, can be prepared by further including excipients, diluents, dispersants, emulsifiers, buffers, stabilizers, binders, disintegrants, solvents, etc. The appropriate carriers, etc., which do not inhibit the activity and properties of the compound according to the present invention, can be selected differently depending on the dosage form and formulation.

본 발명에 따른 약학 조성물은 어떠한 제형으로도 적용될 수 있고, 보다 상세하게는 통상의 방법에 따라 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 비경구형 제형으로 제형화하여 사용될 수 있다.The pharmaceutical composition according to the present invention can be applied in any dosage form, and more specifically, it can be formulated and used as an oral dosage form, an external preparation, a suppository, and a parenteral dosage form of a sterile injection solution according to a conventional method.

본 발명에 따른 약학 조성물에 있어서, 상기 약학 조성물은 약학적으로 유효한 양으로 투여될 수 있다. In the pharmaceutical composition according to the present invention, the pharmaceutical composition can be administered in a pharmaceutically effective amount.

본 명세서에서, "약학적으로 유효한 양"이란, 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분하며 부작용을 일으키지 않을 정도의 양을 의미한다.As used herein, “pharmaceutically effective amount” means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment and not causing adverse effects.

상기 약학 조성물의 유효 용량 수준은 사용 목적, 환자의 연령, 성별, 체중 및 건강 상태, 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 방법, 투여 시간, 투여 경로 및 배출 비율, 치료 기간, 배합 또는 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 달리 결정될 수 있다. 예를 들어, 일정하지는 않지만, 일반적으로 0.001 내지 1000mg/kg으로, 바람직하게는 0.01 내지 100mg/kg을 일일 1회 내지 수회 투여될 수 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다.The effective dosage level of the pharmaceutical composition may vary depending on the intended use, the patient's age, sex, weight, and health condition, the type and severity of the disease, the activity and sensitivity of the drug, the method of administration, the time of administration, the route of administration, and the excretion rate, the duration of treatment, the drugs used in combination or concurrently, and other factors well known in the medical field. For example, although not fixed, it may generally be administered once or several times daily at a dosage of 0.001 to 1000 mg/kg, preferably 0.01 to 100 mg/kg. The above dosage does not limit the scope of the present invention in any way.

본 발명에 따른 약학 조성물은 대사질환, 특히 비만이 발생할 수 있는 임의의 동물에 투여할 수 있고, 상기 동물은 예를 들어, 인간 및 영장류뿐만 아니라 소, 돼지, 말, 개 등의 가축 등을 포함할 수 있다.The pharmaceutical composition according to the present invention can be administered to any animal that may develop a metabolic disease, particularly obesity, and the animal may include, for example, humans and primates, as well as livestock such as cows, pigs, horses, and dogs.

본 발명에 따른 약학 조성물은 제제 형태에 따른 적당한 투여 경로로 투여될 수 있고, 목적 조직에 도달할 수 있는 한 경구 또는 비경구의 다양한 경로를 통하여 투여될 수 있다. 투여 방법은 특히 한정할 필요 없이, 예를 들면, 경구, 직장 또는 정맥, 근육, 피부 도포, 호흡기내 흡입, 자궁내 경막 또는 뇌혈관내(intracere-broventricular) 주사 등의 통상적인 방법으로 투여될 수 있다.The pharmaceutical composition according to the present invention can be administered via an appropriate route of administration depending on the formulation form, and can be administered via various routes, either oral or parenteral, as long as it can reach the target tissue. The method of administration is not particularly limited, and can be administered by conventional methods such as oral, rectal, intravenous, intramuscular, or skin application, respiratory inhalation, intrauterine epidural, or intracerebroventricular injection.

본 발명에 따른 약학 조성물은 대사질환의 예방 또는 치료를 위하여 단독으로 사용될 수 있고, 수술 또는 다른 약물치료 등과 병용하여 사용될 수 있다.The pharmaceutical composition according to the present invention can be used alone for the prevention or treatment of metabolic diseases, or can be used in combination with surgery or other drug treatments.

본 발명은 상기 화학식 1로 표시되는 디아마이드 유도체, 이의 입체이성질체, 이의 용매화물 또는 이의 약학적으로 허용가능한 염에서 선택된 화합물을 유효성분으로 포함하는 대사질환 예방 또는 개선용 건강식품 조성물을 제공한다.The present invention provides a health food composition for preventing or improving metabolic diseases, which comprises as an active ingredient a compound selected from a diamide derivative represented by the above chemical formula 1, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

상기 대사질환은 비만, 당뇨, 동맥경화, 고지혈, 지방간 및 간섬유화로 이루어진 군에서 선택될 수 있고, 바람직하게는 상기 조성물은 항비만용일 수 있다.The above metabolic disease may be selected from the group consisting of obesity, diabetes, arteriosclerosis, hyperlipidemia, fatty liver, and liver fibrosis, and preferably, the composition may be for anti-obesity use.

본 발명에 따른 건강식품 조성물은 대사질환의 예방 또는 개선 목적으로, 분말, 과립, 정제, 캡슐, 시럽 또는 음료 등으로 제조될 수 있다. 상기 건강식품이 취할 수 있는 형태에는 제한이 없으며, 상기 약학 조성물과 동일한 방식으로 제제화되어 기능성 식품으로 이용하거나, 각종 식품에 첨가될 수 있다. The health food composition according to the present invention may be manufactured into powder, granules, tablets, capsules, syrup, or beverages for the purpose of preventing or improving metabolic diseases. There is no limitation on the form the health food may take, and it may be formulated in the same manner as the pharmaceutical composition and used as a functional food or added to various foods.

상기 건강식품은 통상적인 의미의 식품을 모두 포함할 수 있다. 예를 들어, 음료 및 각종 드링크, 과실 및 그의 가공식품(과일통조림, 잼 등), 어류, 육류 및 그 가공식품(햄, 베이컨 등), 빵류 및 면류, 쿠키 및 스낵류, 유제품(버터, 치즈 등) 등이 가능하며, 통상적인 의미에서의 식품을 모두 포함할 수 있다. 또한, 동물을 위한 사료로 이용되는 식품도 포함할 수 있다.The above health foods can include all foods in the conventional sense. For example, they include beverages and various drinks, fruits and their processed foods (canned fruit, jam, etc.), fish, meats and their processed foods (ham, bacon, etc.), breads and noodles, cookies and snacks, dairy products (butter, cheese, etc.), and all foods in the conventional sense. They can also include foods used as animal feed.

상기 건강식품 조성물은 당업계에서 통상적으로 사용되는 식품학적으로 허용 가능한 식품 첨가제(식품 첨가물) 및 적절한 기타 보조 성분을 더 포함하여 제조될 수 있다. 식품 첨가물로서의 적합 여부는 다른 규정이 없는 한, 식품의약품안전처에 승인된 식품첨가물공전의 총칙 및 일반시험법 등에 따라 해당 품목에 관한 규격 및 기준에 의하여 판정할 수 있다. The above health food composition may be manufactured by further including food additives (food additives) commonly used in the industry and other appropriate auxiliary ingredients. Unless otherwise specified, suitability as a food additive may be determined by the specifications and standards for the relevant item, as stipulated in the General Provisions and General Test Methods of the Food Additives Codex approved by the Ministry of Food and Drug Safety.

상기 건강식품 조성물은 식품을 원료로 하여 일반 약품의 장기 복용 시 발생할 수 있는 부작용 등이 없는 장점이 있고, 휴대성이 뛰어나, 대사질환 예방 또는 개선을 위한 보조제로 섭취될 수 있다.The above health food composition has the advantage of not having side effects that may occur with long-term use of general medicines as it uses food as a raw material, and is highly portable, so it can be taken as a supplement for preventing or improving metabolic diseases.

또한, 본 발명은 상기 화학식 1로 표시되는 디아마이드 유도체, 이의 입체이성질체, 이의 용매화물 또는 이의 약학적으로 허용가능한 염에서 선택된 화합물을 유효성분으로 포함하는 eIF2B 활성화용 시약 조성물을 제공한다.In addition, the present invention provides a reagent composition for activating eIF2B, which comprises as an active ingredient a compound selected from a diamide derivative represented by the above chemical formula 1, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

상기 화합물은 eIF2B의 발현 또는 활성을 향상시킬 수 있다.The above compound can enhance the expression or activity of eIF2B.

이하, 본 발명의 이해를 돕기 위하여 실시예를 들어 상세하게 설명하기로 한다. 다만 하기의 실시예는 본 발명의 내용을 예시하는 것일 뿐 본 발명의 범위가 하기 실시예에 한정되는 것은 아니다. 본 발명의 실시예는 당업계에서 평균적인 지식을 가진 자에게 본 발명을 보다 완전하게 설명하기 위해 제공되는 것이다.Hereinafter, to aid understanding of the present invention, examples will be given in detail. However, the following examples are intended only to illustrate the scope of the present invention and are not intended to limit its scope. These examples are provided to more fully explain the present invention to those of average skill in the art.

<합성예><Synthesis example>

화합물 1 (EIF-001):Compound 1 (EIF-001):

CH2Cl2 (2 mL, 0.17 M) 내 용해된 사이클로헥산-1,3-디아민[cyclohexane-1,3-diamine] (38 mg, 0.33 mmol), 2-(4-클로로페녹시)아세틸 클로라이드[2-(4-chlorophenoxy)acetyl chloride] (171 mg, 0.83 mmol) 및 트리에틸아민 (100 mg, 1 mmol) 용액을 실온에서 2시간 동안 교반하였다. 용액을 CH2Cl2에서 희석시키고 NaHCO3, NH4Cl 및 염수(brine)로 순차적으로 세척하였다. 유기 용액을 Na2SO4로 건조시키고 농축시켰다. 조(crude) 화합물을 MPLC (5% MeOH/ CH2Cl2)로 정제하여 화합물 1 (EIF-001)을 수득하였다 (90 mg, 60% 수율). A solution of cyclohexane-1,3-diamine (38 mg, 0.33 mmol), 2-(4-chlorophenoxy)acetyl chloride (171 mg, 0.83 mmol), and triethylamine (100 mg, 1 mmol) dissolved in CH 2 Cl 2 (2 mL, 0.17 M) was stirred at room temperature for 2 h. The solution was diluted in CH 2 Cl 2 and washed sequentially with NaHCO 3 , NH 4 Cl, and brine. The organic solution was dried over Na 2 SO 4 and concentrated. The crude compound was purified by MPLC (5% MeOH/ CH 2 Cl 2 ) to give compound 1 (EIF-001) (90 mg, 60% yield).

N,N'-(사이클로헥산-1,3-디일)비스(2-(4-클로로페녹시)아세트아마이드[N,N'-(cyclohexane-1,3-diyl)bis(2-(4-chlorophenoxy)acetamide)]N,N'-(cyclohexane-1,3-diyl)bis(2-(4-chlorophenoxy)acetamide)

1H NMR (400 MHz, DMSO-d6) δ 8.05 (d, J = 8.1 Hz, 2H), 7.34 (t, J = 6.1 Hz, 4H), 6.96 (t, J = 6.3 Hz, 4H), 4.46 (s, 4H), 3.78 - 3.59 (m, 2H), 1.92 - 1.52 (m, 4H), 1.43 - 1.03 (m, 4H). 1H NMR (400 MHz, DMSO-d 6 ) δ 8.05 (d, J = 8.1 Hz, 2H), 7.34 (t, J = 6.1 Hz, 4H), 6.96 (t, J = 6.3 Hz, 4H), 4.46 (s, 4H), 3.78 - 3.59 (m, 2H), 1.92 - 1.52 (m, 4H), 1.43 - 1.03 (m, 4H).

MS (ESI+) m/z calcd for C22H24Cl2N2O4 [M+H]+ 451.12; found 450.93 MS (ESI + ) m/z calcd for C 22 H 24 Cl 2 N 2 O 4 [M+H] + 451.12; found 450.93

화합물 2 (EIF-002):Compound 2 (EIF-002):

CH2Cl2 (2 mL, 0.2 M) 내 터트-부틸(3-아미노사이클로펜틸)카르바메이트[tert-butyl (3-aminocyclopentyl)carbamate] (85 mg, 0.42 mmol), 2-(4-클로로페녹시)아세틸 클로라이드 (131 mg, 0.64 mmol) 및 트리에틸아민 (86 mg, 0.85 mmol) 용액을 실온에서 4시간 동안 교반하였다. 용액을 CH2Cl2에서 희석시키고 NaHCO3 및 염수로 세척한 다음, Na2SO4로 건조시키고 농축시켰다. 조 생성물(crude)을 MPLC (EtOAc:hexane=1:1)로 정제하여 생성물을 수득하였다 (143 mg, 91% 수율). A solution of tert -butyl (3-aminocyclopentyl)carbamate (85 mg, 0.42 mmol), 2-(4-chlorophenoxy)acetyl chloride (131 mg, 0.64 mmol), and triethylamine (86 mg, 0.85 mmol) in CH 2 Cl 2 (2 mL, 0.2 M) was stirred at room temperature for 4 h. The solution was diluted in CH 2 Cl 2 , washed with NaHCO 3 and brine, dried over Na 2 SO 4 , and concentrated. The crude product was purified by MPLC (EtOAc:hexane=1:1) to give the product (143 mg, 91% yield).

1H NMR (400 MHz, CDCl3) δ 7.29 - 7.27 (m, 2H), 6.89 (d, J = 9.0 Hz, 2H), 6.46 (d, J = 6.9 Hz, 1H), 4.88 - 4.72 (m, 1H), 4.57 - 4.49 (m, J = 7.3 Hz, 1H), 4.44 (s, 2H), 4.35 - 4.23 (m, 1H), 2.47 - 2.34 (m, 1H), 2.29 - 2.20 (m, 1H), 2.02 - 1.92 (m, 2H), 1.88 (td, J = 7.2, 1.9 Hz, 2H), 1.45 (s, 9H). 1H NMR (400 MHz, CDCl 3 ) δ 7.29 - 7.27 (m, 2H), 6.89 (d, J = 9.0 Hz, 2H), 6.46 (d, J = 6.9 Hz, 1H), 4.88 - 4.72 (m, 1H), 4.57 - 4.49 (m, J = 7.3 Hz, 1H), 4.44 (s, 2H), 4.35 - 4.23 (m, 1H), 2.47 - 2.34 (m, 1H), 2.29 - 2.20 (m, 1H), 2.02 - 1.92 (m, 2H), 1.88 (td, J = 7.2, 1.9 Hz, 2H), 1.45 (s, 9H).

터트-부틸(3-(2-(4-클로로페녹시)아세트아미도)사이클로펜틸)카르바메이트[tert-Butyl(3-(2-(4-chlorophenoxy)acetamido)cyclopentyl)carbamate] (74 mg, 0.2 mmol)를 20% TFA/CH2Cl2에 용해시키고 용액을 실온에서 4시간 동안 교반하였다. 용액을 감압 하에서 제거하고 조 생성물을 추가 정제없이 다음 단계에서 사용하였다. tert -Butyl(3-(2-(4-chlorophenoxy)acetamido)cyclopentyl)carbamate] (74 mg, 0.2 mmol) was dissolved in 20% TFA/CH 2 Cl 2 and the solution was stirred at room temperature for 4 h. The solution was evaporated under reduced pressure and the crude product was used in the next step without further purification.

CH2Cl2 (1 mL, 0.2 M) 내 N-(3-아미노사이클로펜틸)-2-(4-클로로페녹시)아세트아마이드[N-(3-aminocyclopentyl)-2-(4-chlorophenoxy)acetamide] (54 mg, 0.2 mmol), 2-(4-클로로페녹시)아세틸 클로라이드 (61 mg, 0.3 mmol) 및 트리에틸아민 (81 mg, 0.8 mmol) 용액을 실온에서 4시간 동안 교반하였다. 용액을 CH2Cl2에서 희석시키고 NaHCO3, 및 염수로 세척한 후 Na2SO4로 건조시키고 농축시켰다. 조 생성물을 MPLC (EtOAc:hexane=2:1)로 정제하여 화합물 2 (EIF-002)를 수득하였다 (86 mg, 96% 수율). A solution of N -(3-aminocyclopentyl)-2-(4-chlorophenoxy)acetamide [ N -(3-aminocyclopentyl)-2-(4-chlorophenoxy)acetamide] ( 54 mg, 0.2 mmol), 2- (4-chlorophenoxy)acetyl chloride (61 mg, 0.3 mmol), and triethylamine (81 mg, 0.8 mmol) in CH 2 Cl 2 (1 mL, 0.2 M) was stirred at room temperature for 4 h. The solution was diluted in CH 2 Cl 2 , washed with NaHCO 3 and brine, dried over Na 2 SO 4 , and concentrated. The crude product was purified by MPLC (EtOAc:hexane=2:1) to give compound 2 (EIF-002) (86 mg, 96% yield).

N,N'-(사이클로펜탄-1,3-디일)비스(2-(4-클로로페녹시)아세트아마이드)[N,N'-(cyclopentane-1,3-diyl)bis(2-(4-chlorophenoxy)acetamide)]N,N'-(cyclopentane-1,3-diyl)bis(2-(4-chlorophenoxy)acetamide)

1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 7.6 Hz, 2H), 7.42 - 7.23 (m, 4H), 7.04 - 6.88 (m, 4H), 4.46 (s, 4H), 4.27 (dd, J = 13.6, 6.7 Hz, 2H), 2.02 - 1.92 (m, 2H), 1.75 (t, J = 7.1 Hz, 2H), 1.45 (dd, J = 7.2, 4.4 Hz, 2H). 1H NMR (400 MHz, DMSO-d 6 ) δ 8.15 (d, J = 7.6 Hz, 2H), 7.42 - 7.23 (m, 4H), 7.04 - 6.88 (m, 4H), 4.46 (s, 4H), 4.27 (dd, J = 13.6, 6.7 Hz, 2H), 2.02 - 1.92 (m, 2H), 1.75 (t, J = 7.1 Hz, 2H), 1.45 (dd, J = 7.2, 4.4 Hz, 2H).

MS (ESI+) m/z calcd for C21H22Cl2N2O4 [M+H]+ 437.11; found 437.02. MS (ESI + ) m/z calcd for C 21 H 22 Cl 2 N 2 O 4 [M+H] + 437.11; found 437.02.

화합물 4 (EIF-004):Compound 4 (EIF-004):

CH2Cl2 (2 mL, 0.22 M) 내 터트-부틸(6-아미노스피로[3.3]헵탄-2-일)카르바메이트[tert-butyl(6-aminospiro[3.3]heptan-2-yl)carbamate] (100 mg, 0.44 mmol), 2-(4-클로로페녹시)아세틸 클로라이드 (136 mg, 0.66 mmol) 및 트리에틸아민 (89 mg, 0.88 mmol) 용액을 실온에서 2시간 동안 교반하였다. 용액을 CH2Cl2에서 희석시키고 NaHCO3, 및 염수로 세척한 후 Na2SO4로 건조시키고 농축시켰다. 조 생성물을 MPLC (EtOAc:hexane=1:1)로 정제하여 생성물을 수득하였다 (110 mg, 63% 수율). A solution of tert -butyl(6-aminospiro[3.3]heptan-2-yl)carbamate (100 mg, 0.44 mmol), 2- (4-chlorophenoxy)acetyl chloride (136 mg, 0.66 mmol), and triethylamine (89 mg, 0.88 mmol) in CH 2 Cl 2 (2 mL, 0.22 M) was stirred at room temperature for 2 h. The solution was diluted in CH 2 Cl 2 , washed with NaHCO 3 and brine, dried over Na 2 SO 4 , and concentrated. The crude product was purified by MPLC (EtOAc:hexane=1:1) to give the product (110 mg, 63% yield).

1H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J = 7.8 Hz, 1H), 7.35 (d, J = 8.7 Hz, 2H), 7.08 (d, J = 8.1 Hz, 1H), 6.97 (d, J = 8.9 Hz, 2H), 4.42 (s, 2H), 4.22 - 4.07 (m, 1H), 3.89 - 3.71 (m, 1H), 2.32 - 2.23 (m, 2H), 2.17 - 2.05 (m, 2H), 2.04 - 1.93 (m, 2H), 1.92 - 1.81 (m, 2H), 1.36 (s, 9H). 1H NMR (400 MHz, DMSO-d 6 ) δ 8.27 (d, J = 7.8 Hz, 1H), 7.35 (d, J = 8.7 Hz, 2H), 7.08 (d, J = 8.1 Hz, 1H), 6.97 (d, J = 8.9 Hz, 2H), 4.42 (s, 2H), 4.22 - 4.07 (m, 1H), 3.89 - 3.71 (m, 1H), 2.32 - 2.23 (m, 2H), 2.17 - 2.05 (m, 2H), 2.04 - 1.93 (m, 2H), 1.92 - 1.81 (m, 2H), 1.36 (s, 9H).

터트-부틸 (6-(2-(4-클로로페녹시)아세트아미도)스피로[3.3]헵탄-2-일)카르바메이트[tert-Butyl (6-(2-(4-chlorophenoxy)acetamido)spiro[3.3]heptan-2-yl)carbamate]를 20% TFA/CH2Cl2에 용해시키고 용액을 실온에서 4시간 동안 교반하였다. 용액을 감압 하에서 제거하고 조 생성물을 추가 정제없이 다음 단계에서 사용하였다.tert -Butyl (6-(2-(4-chlorophenoxy)acetamido)spiro[3.3]heptan-2-yl)carbamate [ tert -Butyl (6-(2-(4-chlorophenoxy)acetamido)spiro[3.3]heptan-2-yl)carbamate] was dissolved in 20% TFA/CH 2 Cl 2 and the solution was stirred at room temperature for 4 h. The solution was evaporated under reduced pressure and the crude product was used in the next step without further purification.

CH2Cl2 (1 mL, 0.14 M) 내 N-(6-아미노스피로[3.3]헵탄-2-일)-2-(4-클로로페녹시)아세트아마이드[N-(6-aminospiro[3.3]heptan-2-yl)-2-(4-chlorophenoxy)acetamide] (40mg, 0.14 mmol), 2-(4-클로로페녹시)아세틸 클로라이드 (43 mg, 0.21 mmol) 및 트리에틸아민 (71 mg, 0.7 mmol)을 실온에서 4시간 동안 교반하였다. 용액을 CH2Cl2에서 희석시키고 NaHCO3, 및 염수로 세척한 후 Na2SO4로 건조시키고 농축시켰다. 조 생성물을 MPLC (EtOAc:hexane=4:1)로 정제하여 화합물 4 (EIF-004)를 수득하였다 (85 mg, 65% 수율). N -( 6 -aminospiro[3.3] heptan -2-yl)-2-(4-chlorophenoxy)acetamide [ N -(6-aminospiro[3.3]heptan-2-yl)-2-(4-chlorophenoxy)acetamide] (40 mg, 0.14 mmol), 2-(4-chlorophenoxy)acetyl chloride (43 mg, 0.21 mmol), and triethylamine (71 mg, 0.7 mmol) in CH 2 Cl 2 (1 mL, 0.14 M) were stirred at room temperature for 4 h. The solution was diluted in CH 2 Cl 2 , washed with NaHCO 3 and brine, dried over Na 2 SO 4 , and concentrated. The crude product was purified by MPLC (EtOAc:hexane=4:1) to obtain compound 4 (EIF-004) (85 mg, 65% yield).

N,N'-(스피로[3.3]헵탄-2,6-디일)비스(2-(4-클로로페녹시)아세트아마이드)[N,N'-(spiro[3.3]heptane-2,6-diyl)bis(2-(4-chlorophenoxy)acetamide)]N,N'-(spiro[3.3]heptane-2,6-diyl)bis(2-(4-chlorophenoxy)acetamide)

1H NMR (400 MHz, DMSO-d6) δ 8.29 (d, J = 7.8 Hz, 2H), 7.43 - 7.31 (m, 4H), 7.07 - 6.91 (m, 4H), 4.43 (s, 4H), 4.24 - 4.08 (m, 2H), 2.40 - 2.29 (m, 2H), 2.23 - 2.09 (m, 2H), 2.09 - 1.94 (m, 4H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.29 (d, J = 7.8 Hz, 2H), 7.43 - 7.31 (m, 4H), 7.07 - 6.91 (m, 4H), 4.43 (s, 4H), 4.24 - 4.08 (m, 2H), 2.40 - 2.29 (m, 2H), 2.23 - 2.09 (m, 2H), 2.09 - 1.94 (m, 4H).

MS (ESI+) m/z calcd for C23H24Cl2N2O4 [M+H]+ 463.12; not observed. MS (ESI + ) m/z calcd for C 23 H 24 Cl 2 N 2 O 4 [M+H] + 463.12; not observed.

화합물 5 (EIF-005):Compound 5 (EIF-005):

DMF (1.5 mL, 0.15 M) 내 2-(피리딘-2-일옥시)아세트산[2-(pyridin-2-yloxy)acetic acid] (44 mg, 0.29 mmol), 터트-부틸(6-아미노스피로[3.3]헵탄-2-일)카르바메이트 (50 mg, 0.22 mmol), N,N-디이소프로필에틸렌아민[N,N-diisopropylethylamine] (71.4 mg, 0.55 mmol), N-3-디메틸아미노프로필-N'-에틸카르보디이마이드 하이드로클로라이드[N-3-dimethylaminopropyl-N'-ethylcarbodiimide hydrochloride] (63.9 mg, 0.33 mmol) 및 1-하이드록시멘조트리아졸[1-hydroxybenzotriazole] (44.8 mg, 0.33 mmol) 용액을 실온에서 밤새 교반하였다. 용액을 EtOAc로 희석하고 염수로 세척한 후, Na2SO4로 건조 및 농축하였다. 조 생성물을 MPLC (5% MeOH/ CH2Cl2)로 정제하여 생성물을 수득하였다 (50 mg, 62% 수율).A solution of 2-(pyridin-2-yloxy)acetic acid (44 mg, 0.29 mmol), tert-butyl(6-aminospiro[3.3]heptan-2-yl)carbamate (50 mg, 0.22 mmol), N,N -diisopropylethylamine (71.4 mg, 0.55 mmol), N -3-dimethylaminopropyl- N ' -ethylcarbodiimide hydrochloride ( 63.9 mg, 0.33 mmol), and 1-hydroxybenzotriazole (44.8 mg, 0.33 mmol) in DMF (1.5 mL, 0.15 M ) was stirred at room temperature overnight. The solution was diluted with EtOAc, washed with brine, dried over Na 2 SO 4 , and concentrated. The crude product was purified by MPLC (5% MeOH/ CH 2 Cl 2 ) to give the product (50 mg, 62% yield).

1H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J = 7.6 Hz, 1H), 7.56 (dd, J = 6.8, 1.7 Hz, 1H), 7.41 (ddd, J = 8.9, 6.6, 2.1 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H), 6.34 (d, J = 9.1 Hz, 1H), 6.19 (td, J = 6.7, 1.3 Hz, 1H), 4.45 (s, 2H), 4.13 - 3.97 (m, 1H), 3.91 - 3.73 (m, 1H), 2.34 - 2.24 (m, 2H), 2.11 (td, J = 11.9, 7.1 Hz, 2H), 1.94 - 1.83 (m, 4H), 1.36 (s, 9H). 1H NMR (400 MHz, DMSO-d 6 ) δ 8.39 (d, J = 7.6 Hz, 1H), 7.56 (dd, J = 6.8, 1.7 Hz, 1H), 7.41 (ddd, J = 8.9, 6.6, 2.1 Hz, 1H), 7.08 (d, J = 8.0) Hz, 1H), 6.34 (d, J = 9.1 Hz, 1H), 6.19 (td, J = 6.7, 1.3 Hz, 1H), 4.45 (s, 2H), 4.13 - 3.97 (m, 1H), 3.91 - 3.73 (m, 1H), 2.34 - 2.24 (m, 2H), 2.11 (td, J = 11.9, 7.1 Hz, 2H), 1.94 - 1.83 (m, 4H), 1.36 (s, 9H).

터트-부틸 (6-(2-(피리딘-2-일옥시)아세트아미도)스피로[3.3]헵탄-2-일)카르바메이트[tert-Butyl (6-(2-(pyridin-2-yloxy)acetamido)spiro[3.3]heptan-2-yl)carbamate] (50 mg, 0.14 mmol)를 20% TFA/ CH2Cl2 (1 mL, 0.14 M)로 희석시키고 용액을 실온에서 2시간 동안 교반하였다. 감압 하에서 유기 용매를 제거하고 조 생성물을 추가 정제없이 다음 단계에서 사용하였다. tert -Butyl (6-(2-(pyridin-2-yloxy)acetamido)spiro[3.3]heptan-2-yl)carbamate] (50 mg, 0.14 mmol) was diluted with 20% TFA/CH 2 Cl 2 (1 mL, 0.14 M) and the solution was stirred at room temperature for 2 h. The organic solvent was removed under reduced pressure and the crude product was used in the next step without further purification.

DMF (1 mL, 0.13 M) 내 2-(피리딘-2-일옥시)아세트산 (26 mg, 0.17 mmol), N-(6-아미노스피로[3.3]헵탄-2-일)-2-(피리딘-2-일옥시)아세트아마이드[N-(6-aminospiro[3.3]heptan-2-yl)-2-(pyridin-2-yloxy)acetamide] (34 mg, 0.13 mmol), N,N-디이소프로필에틸렌아민 (84 mg, 0.65 mmol), N-3-디메틸아미노프로필-N'-에틸카르보디이마이드 하이드로클로라이드 (50 mg, 0.26 mmol) 및 1-하이드록시멘조트리아졸 (35 mg, 0.26 mmol) 용액을 실온에서 밤새 교반하였다. 용액을 EtOAc로 희석하고 염수로 세척하였다. 형성된 침전물을 여과를 통해 수집하여 화합물 5 (EIF-005)를 수득하였다 (27 mg, 52% 수율).A solution of 2-(pyridin-2-yloxy)acetic acid (26 mg, 0.17 mmol), N -(6-aminospiro[3.3]heptan-2-yl)-2-(pyridin-2-yloxy)acetamide [ N -(6-aminospiro[3.3]heptan-2-yl)-2-(pyridin-2-yloxy)acetamide] (34 mg, 0.13 mmol), N,N -diisopropylethyleneamine (84 mg, 0.65 mmol), N -3-dimethylaminopropyl- N '-ethylcarbodiimide hydrochloride (50 mg, 0.26 mmol), and 1-hydroxymenthotriazole (35 mg, 0.26 mmol) in DMF (1 mL, 0.13 M) was stirred at room temperature overnight. The solution was diluted with EtOAc and washed with brine. The formed precipitate was collected by filtration to obtain compound 5 (EIF-005) (27 mg, 52% yield).

N,N'-(스피로[3.3]헵탄-2,6-디일)비스(2-(피리딘-2-일옥시)아세트아마이드)[N,N'-(spiro[3.3]heptane-2,6-diyl)bis(2-(pyridin-2-yloxy)acetamide)]N,N'-(spiro[3.3]heptane-2,6-diyl)bis(2-(pyridin-2-yloxy)acetamide)[N,N'-(spiro[3.3]heptane-2,6-diyl)bis(2-(pyridin-2-yloxy)acetamide)]

1H NMR (400 MHz, DMSO-d6) δ 8.41 (d, J = 7.5 Hz, 2H), 7.56 (d, J = 5.5 Hz, 2H), 7.49 - 7.34 (m, 2H), 6.34 (d, J = 9.1 Hz, 2H), 6.19 (t, J = 6.4 Hz, 2H), 4.46 (s, 4H), 4.19 - 3.99 (m, 2H), 2.43 - 2.28 (m, 2H), 2.26 - 2.13 (m, 2H), 2.03 - 1.83 (m, 4H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.41 (d, J = 7.5 Hz, 2H), 7.56 (d, J = 5.5 Hz, 2H), 7.49 - 7.34 (m, 2H), 6.34 (d, J = 9.1 Hz, 2H), 6.19 (t, J = 6.4 Hz, 2H), 4.46 (s, 4H), 4.19 - 3.99 (m, 2H), 2.43 - 2.28 (m, 2H), 2.26 - 2.13 (m, 2H), 2.03 - 1.83 (m, 4H).

MS (ESI+) m/z calcd for C21H24N4O4 [M+H]+ 397.19; found 397.14. MS (ESI + ) m/z calcd for C 21 H 24 N 4 O 4 [M+H] + 397.19; found 397.14.

화합물 6 (EIF-006):Compound 6 (EIF-006):

DMF (2 mL, 0.25 M) 내 터트-부틸 (3-아미노사이클로부틸)카르바메이트[tert-Butyl (3-aminocyclobutyl)carbamate] (93 mg, 0.5 mmol), (E)-3-(4-클로로페닐)아크릴산[(E)-3-(4-chlorophenyl)acrylic acid] (110 mg, 0.6 mmol), EDCI (193 mg, 1 mmol) 및 DIPEA (194 mg, 1.5 mmol) 용액을 실온에서 12시간 동안 교반하였다. 용액을 EtOAc로 희석하고 NaHCO3로 세척한 후, Na2SO4로 건조 및 농축하였다. 조 생성물을 MPLC (EtOAc:hexane=1:1)로 정제하여 생성물을 수득하였다 (140 mg, 80% 수율).A solution of tert -Butyl (3-aminocyclobutyl)carbamate (93 mg, 0.5 mmol), ( E )-3-(4-chlorophenyl)acrylic acid (110 mg, 0.6 mmol), EDCI (193 mg , 1 mmol), and DIPEA (194 mg, 1.5 mmol) in DMF (2 mL, 0.25 M) was stirred at room temperature for 12 h. The solution was diluted with EtOAc, washed with NaHCO 3 , dried over Na 2 SO 4 , and concentrated. The crude product was purified by MPLC (EtOAc:hexane=1:1) to obtain the product (140 mg, 80% yield).

1H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 7.3 Hz, 1H), 7.58 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 1.9 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 6.62 (d, J = 7.6 Hz, 1H), 3.99 - 3.84 (m, 1H), 3.73 - 3.58 (m, 1H), 2.28 - 2.06 (m, 2H), 1.91 - 1.68 (m, 1H), 1.38 (s, 9H). 1H NMR (400 MHz, DMSO-d 6 ) δ 8.36 (d, J = 7.3 Hz, 1H), 7.58 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 1.9 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 6.62 (d, J = 7.6 Hz, 1H), 3.99 - 3.84 (m, 1H), 3.73 - 3.58 (m, 1H), 2.28 - 2.06 (m, 2H), 1.91 - 1.68 (m, 1H), 1.38 (s, 9H).

터트-부틸 (E)-(3-(3-(4-클로로페닐)아크릴아미도)사이클로부틸)카르바메이트[tert-Butyl (E)-(3-(3-(4-chlorophenyl)acrylamido)cyclobutyl)carbamate] (130 mg, 0.37 mmol)를 실온에서 4시간 동안 10% TFA/ CH2Cl2에서 교반하였다. 유기 용매를 감압 하에서 제거하고 조 생성물을 추가 정제없이 다음 단계에서 사용하였다.tert -Butyl ( E )-(3-(3-(4-chlorophenyl)acrylamido)cyclobutyl)carbamate [ tert -Butyl ( E )-(3-(3-(4-chlorophenyl)acrylamido)cyclobutyl)carbamate] (130 mg, 0.37 mmol) was stirred in 10% TFA/CH 2 Cl 2 at room temperature for 4 h. The organic solvent was removed under reduced pressure and the crude product was used in the next step without further purification.

DMF (2 mL, 0.18 M) 내 (E)-N-(3-아미노사이클로부틸)-3-(4-클로로페닐)아크릴아마이드[(E)-N-(3-aminocyclobutyl)-3-(4-chlorophenyl)acrylamide] (93 mg, 0.37 mmol), (E)-3-(4-클로로페닐)아크릴산 (81 mg, 0.44 mmol), DIPEA (143 mg, 1.1 mmol), EDCI (143 mg, 0.74 mmol) 및 HOBt (100 mg, 0.74 mmol) 용액을 실온에서 5시간 동안 교반하였다. 혼합물을 EtOAc로 희석하고 NaHCO3로 세척하였다. 생성된 침전물을 여과하고 물로 세척하였다. 고체를 감압 하에서 건조하여 화합물 6 (EIF-006)을 수득하였다 (150 mg, 95% 수율).A solution of ( E )- N -(3-aminocyclobutyl)-3-(4-chlorophenyl)acrylamide [( E )- N -(3-aminocyclobutyl)-3-(4-chlorophenyl)acrylamide] (93 mg, 0.37 mmol), ( E )-3-(4-chlorophenyl)acrylic acid (81 mg, 0.44 mmol), DIPEA (143 mg, 1.1 mmol), EDCI (143 mg, 0.74 mmol), and HOBt (100 mg, 0.74 mmol) in DMF (2 mL, 0.18 M) was stirred at room temperature for 5 h. The mixture was diluted with EtOAc and washed with NaHCO 3 . The resulting precipitate was filtered and washed with water. The solid was dried under reduced pressure to give compound 6 (EIF-006) (150 mg, 95% yield).

(2E,2'E)-N,N'-(사이클로부탄-1,3-디일)비스(3-(4-클로로페닐)아크릴아마이드)[(2E,2'E)-N,N'-(cyclobutane-1,3-diyl)bis(3-(4-chlorophenyl)acrylamide)](2E,2'E)-N,N'-(cyclobutane-1,3-diyl)bis(3-(4-chlorophenyl)acrylamide)[(2E,2'E)-N,N'-(cyclobutane-1,3-diyl)bis(3-(4-chlorophenyl)acrylamide)]

1H NMR (400 MHz, DMSO-d6) δ 8.46 (d, J = 7.4 Hz, 2H), 7.60 (dd, J = 8.5, 1.9 Hz, 4H), 7.48 (d, J = 8.5 Hz, 4H), 7.42 (d, J = 2.2 Hz, 2H), 6.61 (s, 2H), 4.14 - 3.91 (m, 2H), 2.27 (t, J = 6.7 Hz, 2H), 1.88 (dd, J = 9.3, 2.5 Hz, 2H). 1H NMR (400 MHz, DMSO-d 6 ) δ 8.46 (d, J = 7.4 Hz, 2H), 7.60 (dd, J = 8.5, 1.9 Hz, 4H), 7.48 (d, J = 8.5 Hz, 4H), 7.42 (d, J = 2.2 Hz, 2H), 6.61 (s, 2H), 4.14 - 3.91 (m, 2H), 2.27 (t, J = 6.7 Hz, 2H), 1.88 (dd, J = 9.3, 2.5 Hz, 2H).

MS (ESI+) m/z calcd for C22H20Cl2N2O2 [M+H]+ 415.10; not observed. MS (ESI + ) m/z calcd for C 22 H 20 Cl 2 N 2 O 2 [M+H] + 415.10; not observed.

화합물 7 (EIF-007):Compound 7 (EIF-007):

DMF (2 mL, 0.25 M) 내 터트-부틸 (3-아미노사이클로부틸)카르바메이트 (93 mg, 0.5 mmol), (E)-3-(4-클로로페닐)아크릴산 (110 mg, 0.6 mmol), EDCI (193 mg, 1 mmol) 및 DIPEA (194 mg, 1.5 mmol) 용액을 실온에서 12시간 동안 교반하였다. 용액을 EtOAc로 희석시키고 NaHCO3로 세척한 다음, Na2SO4로 건조 및 농축시켰다. 조 생성물을 MPLC (EtOAc:hexane=1:1)로 정제하여 생성물을 수득하였다 (100 mg, 79% 수율).A solution of tert-butyl (3-aminocyclobutyl)carbamate (93 mg, 0.5 mmol), ( E )-3-(4-chlorophenyl)acrylic acid (110 mg, 0.6 mmol), EDCI (193 mg, 1 mmol), and DIPEA (194 mg, 1.5 mmol) in DMF (2 mL, 0.25 M) was stirred at room temperature for 12 h. The solution was diluted with EtOAc, washed with NaHCO 3 , dried over Na 2 SO 4 , and concentrated. The crude product was purified by MPLC (EtOAc:hexane=1:1) to give the product (100 mg, 79% yield).

1H NMR (400 MHz, DMSO-d6) δ 8.20 (d, J = 7.0 Hz, 1H), 7.48 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 7.8 Hz, 1H), 7.18 (d, J = 7.7 Hz, 1H), 4.18 - 3.97 (m, 3H), 3.86 - 3.52 (m, 1H), 3.21 (s, 2H), 2.23 - 2.00 (m, 2H), 1.77 (m, 2H), 1.37 (s, 9H). 1H NMR (400 MHz, DMSO-d 6 ) δ 8.20 (d, J = 7.0 Hz, 1H), 7.48 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 7.8 Hz, 1H), 7.18 (d, J = 7.7 Hz, 1H), 4.18 - 3.97 (m, 3H), 3.86 - 3.52 (m, 1H), 3.21 (s, 2H), 2.23 - 2.00 (m, 2H), 1.77 (m, 2H), 1.37 (s, 9H).

터트-부틸 (3-(2-((2,6-디클로로벤질)티오)아세트아미도)사이클로부틸)카르바메이트[tert-butyl (3-(2-((2,6-dichlorobenzyl)thio)acetamido)cyclobutyl) carbamate] (100 mg, 0.24 mmol)를 20% TFA/ CH2Cl2 (1.2 mL, 0.2 M)에 희석시키고 용액을 실온에서 4시간 동안 교반하였다. 유기 용매를 감압 하에서 제거하고 조 생성물을 추가 정제없이 다음 단계에서 사용하였다.tert -Butyl (3-(2-((2,6-dichlorobenzyl)thio)acetamido)cyclobutyl) carbamate [ tert -butyl (3-(2-((2,6-dichlorobenzyl)thio)acetamido)cyclobutyl) carbamate] (100 mg, 0.24 mmol) was diluted in 20% TFA/CH 2 Cl 2 (1.2 mL, 0.2 M) and the solution was stirred at room temperature for 4 h. The organic solvent was removed under reduced pressure and the crude product was used in the next step without further purification.

CH2Cl2 (2 mL, 0.12 M) 내 N-(3-아미노사이클로부틸)-2-((2,6-디클로로벤질)티오)아세트아마이드[N-(3-aminocyclobutyl)-2-((2,6-dichlorobenzyl)thio)acetamide] (76 mg, 0.24 mmol), 2-(4-클로로페녹시)아세틸 클로라이드 (59 mg, 0.29 mmol) 및 Et3N (72 mg, 0.71 mmol) 용액을 실온에서 4시간 동안 교반하였다. 혼합물을 CH2Cl2로 희석하고 NaHCO3로 세척한 다음, Na2SO4로 건조하고 농축시켰다. 조 생성물을 MPLC (EtOAc:hexane=4:1)로 정제하여 화합물 7 (EIF-007)을 수득하였다 (40 mg, 34% 수율).A solution of N -(3-aminocyclobutyl)-2-((2,6-dichlorobenzyl)thio)acetamide [ N -(3-aminocyclobutyl)-2-((2,6-dichlorobenzyl)thio)acetamide] ( 76 mg, 0.24 mmol), 2- (4-chlorophenoxy)acetyl chloride (59 mg, 0.29 mmol), and Et 3 N (72 mg, 0.71 mmol) in CH 2 Cl 2 (2 mL, 0.12 M) was stirred at room temperature for 4 h. The mixture was diluted with CH 2 Cl 2 , washed with NaHCO 3 , dried over Na 2 SO 4 , and concentrated. The crude product was purified by MPLC (EtOAc:hexane=4:1) to give compound 7 (EIF-007) (40 mg, 34% yield).

2-(4-클로로페녹시)-N-(3-(2-((2,6-디클로로벤질)티오)아세트아미도)사이클로부틸)아세트아마이드[2-(4-chlorophenoxy)-N-(3-(2-((2,6-dichlorobenzyl)thio)acetamido)cyclobutyl)acetamide]2-(4-chlorophenoxy)-N-(3-(2-((2,6-dichlorobenzyl)thio)acetamido)cyclobutyl)acetamide

1H NMR (400 MHz, DMSO-d6) δ 8.33 (d, J = 7.3 Hz, 1H), 8.22 (d, J = 7.1 Hz, 1H), 7.48 (d, J = 8.3 Hz, 2H), 7.42 - 7.28 (m, 3H), 7.06 - 6.91 (m, 2H), 4.46 (s, 2H), 4.42 - 4.18 (m, 1H), 4.08 (s, 2H), 3.99 - 3.79 (m, 1H), 3.22 (s, 2H), 2.32 - 2.23 (m, 1H), 2.22 - 2.11 (m, 1H), 1.91 (m, 2H). 1H NMR (400 MHz, DMSO-d 6 ) δ 8.33 (d, J = 7.3 Hz, 1H), 8.22 (d, J = 7.1 Hz, 1H), 7.48 (d, J = 8.3 Hz, 2H), 7.42 - 7.28 (m, 3H), 7.06 - 6.91 (m, 2H), 4.46 (s, 2H), 4.42 - 4.18 (m, 1H), 4.08 (s, 2H), 3.99 - 3.79 (m, 1H), 3.22 (s, 2H), 2.32 - 2.23 (m, 1H), 2.22 - 2.11 (m, 1H), 1.91 (m, 2H).

MS (ESI+) m/z calcd for C21H21Cl3N2O3S [M+H]+ 487.04; not observed. MS (ESI + ) m/z calcd for C 21 H 21 Cl 3 N 2 O 3 S [M+H] + 487.04; not observed.

화합물 8 (EIF-008):Compound 8 (EIF-008):

DMF (2.0 ml) 내 교반된 터트-부틸 (3-아미노사이클로부틸)카르바메이트 (1.0 equiv., 100 mg, 0.537 mmol) 용액에 2-(메시틸옥시)아세트산[2-(mesityloxy)acetic acid] (1.1 equiv., 115 mg, 0.591 mmol), EDC (2.0 equiv., 206 mg, 1.074 mmol), HOBt (2.0 equiv., 145 mg, 1.074 mmol) 및 DIPEA (3.0 equiv., 0.281 ml, 1.611 mmol)를 첨가하였다. 반응 혼합물을 실온에서 밤새 교반하였다. 혼합물을 EtOAc로 희석한 다음, 유기상을 염수로 3차례 세척하고 황산 마그네슘으로 건조시킨 후 감압 하에서 여과하고 농축시켰다. 반응 혼합물을 MPLC (EtOAc/n-Hexane = 1 :1)로 정제하여 생성물 118 mg (61%)을 백색 고체로 수득하였다.To a stirred solution of tert-butyl (3-aminocyclobutyl)carbamate (1.0 equiv., 100 mg, 0.537 mmol) in DMF (2.0 ml) were added 2-(mesityloxy)acetic acid (1.1 equiv., 115 mg, 0.591 mmol), EDC (2.0 equiv., 206 mg, 1.074 mmol), HOBt (2.0 equiv., 145 mg, 1.074 mmol), and DIPEA (3.0 equiv., 0.281 ml, 1.611 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, and the organic phase was washed three times with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The reaction mixture was purified by MPLC (EtOAc/ n -Hexane = 1:1) to obtain 118 mg (61%) of the product as a white solid.

1H NMR (400 MHz, DMSO-d6) δ 8.24 (d, J = 7.7 Hz, 1H), 7.09 (d, J = 7.8 Hz, 1H), 6.82 (s, 2H), 4.11 (s, 2H), 4.00 - 3.88 (m, 1H), 3.69 - 3.59 (m, 1H), 2.33 - 2.26 (m, 2H), 2.18 (s, 9H), 1.96 - 1.89 (m, 2H), 1.37 (s, 9H). 1H NMR (400 MHz, DMSO-d 6 ) δ 8.24 (d, J = 7.7 Hz, 1H), 7.09 (d, J = 7.8 Hz, 1H), 6.82 (s, 2H), 4.11 (s, 2H), 4.00 - 3.88 (m, 1H), 3.69 - 3.59 (m, 1H), 2.33 - 2.26 (m, 2H), 2.18 (s, 9H), 1.96 - 1.89 (m, 2H), 1.37 (s, 9H).

MS (ESI+) m/z calcd for C20H31N2O4 [M + H]+ 363.22; found 363.73.MS (ESI + ) m/z calcd for C 20 H 31 N 2 O 4 [M + H] + 363.22; found 363.73.

터트-부틸 (3-(2-(메시틸옥시)아세트아미도)사이클로부틸)카르바메이트 [tert-butyl (3-(2-(mesityloxy)acetamido)cyclobutyl)carbamate] (1.0 equiv., 111 mg, 0.306 mmol) 교반 용액을 실온에서 20% TFA/DCM (255 μl/ 1.28 ml)에 희석시켰다. 4시간 동안 교반한 후, 반응 혼합물을 추가 정제없이 증발시켰다.tert-butyl (3-(2-(mesityloxy)acetamido)cyclobutyl)carbamate [ tert -butyl (3-(2-(mesityloxy)acetamido)cyclobutyl)carbamate] (1.0 equiv., 111 mg, 0.306 mmol) was diluted in 20% TFA/DCM (255 μl/ 1.28 ml) at room temperature. After stirring for 4 h, the reaction mixture was evaporated without further purification.

DMF (1.5 ml) 내 N-(3-아미노사이클로부틸)-2-(메시틸옥시)아세트아마이드[N-(3-aminocyclobutyl)-2-(mesityloxy)acetamide] (1.0 equiv., 80 mg, 0.305 mmol) 교반 용액에 2-(메시틸옥시)아세트산 (1.1 equiv., 65 mg, 0.335 mmol), DIPEA (5.0 equiv., 266 μl, 1.525 mmol) 및 HATU (2.0 equiv., 232 mg, 0.610 mmol)를 첨가하였다. 반응 혼합물을 실온에서 밤새 교반하였다. 혼합물을 EtOAc로 희석시킨 다음, 유기상을 염수로 3차례 세척하고 황산 마그네슘으로 건조시킨 후, 감압 하에서 여과 및 농축시켰다. 잔류물을 최소량의 에틸 아세테이트에 현탁시키고 헥산을 처리하였다. 형성된 침전물을 여과를 통해 모아서 담갈색 고체의 화합물 8 (EIF-008) 96 mg (70%)을 수득하였다.To a stirred solution of N -(3-aminocyclobutyl)-2-(mesityloxy)acetamide [ N -(3-aminocyclobutyl)-2-(mesityloxy)acetamide] (1.0 equiv., 80 mg, 0.305 mmol) in DMF (1.5 ml) were added 2-(mesityloxy)acetic acid (1.1 equiv., 65 mg, 0.335 mmol), DIPEA (5.0 equiv., 266 μl, 1.525 mmol), and HATU (2.0 equiv., 232 mg, 0.610 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, and the organic phase was washed three times with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was suspended in a minimum amount of ethyl acetate and treated with hexane. The formed precipitate was collected by filtration to obtain 96 mg (70%) of compound 8 (EIF-008) as a light brown solid.

N,N'-(사이클로부탄-1,3-디일)비스(2-(메시틸옥시)아세트아마이드)[N,N'-(cyclobutane-1,3-diyl)bis(2-(mesityloxy)acetamide)]N,N'-(cyclobutane-1,3-diyl)bis(2-(mesityloxy)acetamide)

1H NMR (400 MHz, DMSO-d6) δ 8.25 (d, J = 8.3 Hz, 2H), 6.83 (s, 4H), 4.15 - 4.07 (m, 5H), 2.66 - 2.59 (m, 2H), 2.39 - 2.32 (m, 1H), 2.19 - 2.17 (m, 20H). 1H NMR (400 MHz, DMSO-d 6 ) δ 8.25 (d, J = 8.3 Hz, 2H), 6.83 (s, 4H), 4.15 - 4.07 (m, 5H), 2.66 - 2.59 (m, 2H), 2.39 - 2.32 (m, 1H), 2.19 - 2.17 (m, 20H).

MS (ESI+) m/z calcd for C26H35N2O4 [M + H]+ 439.25; found 439.19.MS (ESI + ) m/z calcd for C 26 H 35 N 2 O 4 [M + H] + 439.25; found439.19.

화합물 9 (EIF-009):Compound 9 (EIF-009):

DMF (1.34 ml) 내 터트-부틸 (3-아미노사이클로부틸)카르바메이트 (1.0 equiv., 50 mg, 0.268 mmol)의 교반 용액에 3-(2-클로로페녹시)프로판산[3-(2-chlorophenoxy)propanoic acid] (1.1 equiv., 59.2 mg, 0.295 mmol), DIPEA (3.0 equiv., 0.141 ml, 0.805 mmol) 및 HATU (2.0 equiv., 204 mg, 0.537 mmol)를 첨가하였다. 반응 혼합물을 실온에서 밤새 교반하였다. 반응물을 EtOAc로 희석시킨 다음 유기상을 염수로 3차례 세척하고 황산 나트륨으로 건조시키고 감압 하에서 여과 및 농축시켰다. 잔류물을 최소량의 에틸 아세테이트에 현탁시키고 헥산을 처리하였다. 형성된 침전물을 정제하여 담황색 고체의 생성물 90 mg (82%)을 수득하였다.To a stirred solution of tert-butyl (3-aminocyclobutyl)carbamate (1.0 equiv., 50 mg, 0.268 mmol) in DMF (1.34 ml) were added 3-(2-chlorophenoxy)propanoic acid (1.1 equiv., 59.2 mg, 0.295 mmol), DIPEA (3.0 equiv., 0.141 ml, 0.805 mmol), and HATU (2.0 equiv., 204 mg, 0.537 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was diluted with EtOAc, and the organic phase was washed three times with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was suspended in a minimum amount of ethyl acetate and treated with hexane. The formed precipitate was purified to obtain 90 mg (82%) of the product as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ 8.21 (d, J = 7.3 Hz, 1H), 7.40 (d, J = 7.9 Hz, 1H), 7.31 - 7.26 (m, 1H), 7.19 (d, J = 7.7 Hz, 1H), 7.16 - 7.13 (m, 1H), 6.94 (m, 1H), 4.21 (d, J = 6.1 Hz, 2H), 3.86 - 3.76 (m, 1H), 3.64 - 3.54 (m, 1H), 2.56 - 2.52 (m, 2H), 2.45 - 2.40 (m, 2H), 1.80 - 1.73 (m, 2H), 1.37 (s, 9H). 1H NMR (400 MHz, DMSO-d 6 ) δ 8.21 (d, J = 7.3 Hz, 1H), 7.40 (d, J = 7.9 Hz, 1H), 7.31 - 7.26 (m, 1H), 7.19 (d, J = 7.7 Hz, 1H), 7.16 - 7.13 (m, 1H), 6.94 (m, 1H), 4.21 (d, J = 6.1 Hz, 2H), 3.86 - 3.76 (m, 1H), 3.64 - 3.54 (m, 1H), 2.56 - 2.52 (m, 2H), 2.45 - 2.40 (m, 2H), 1.80 - 1.73 (m, 2H), 1.37 (s, 9H).

MS (ESI+) m/z calcd for C18H26ClN2O4 [M + H]+ 369.15; found 369.00.MS (ESI + ) m/z calcd for C 18 H 26 ClN 2 O 4 [M + H] + 369.15; found 369.00.

터트-부틸 (3-(3-(2-클로로페녹시)프로판아미도)사이클로부틸)카르바메이트[tert-butyl (3-(3-(2-chlorophenoxy)propanamido)cyclobutyl)carbamate] (1.0 equiv., 40 mg, 0.108 mmol)의 교반 용액을 실온에서 20% TFA/DCM (75 μl / 542 μl)에 희석시켰다. 20시간 동안 교반 후, 반응 혼합물을 추가 정제없이 증발시켰다.A stirred solution of tert -butyl (3-(3-(2-chlorophenoxy)propanamido)cyclobutyl)carbamate (1.0 equiv., 40 mg, 0.108 mmol) was diluted in 20% TFA/DCM (75 μl / 542 μl) at room temperature. After stirring for 20 h, the reaction mixture was evaporated without further purification.

DMF (1.1 ml) 내 N-(3-아미노사이클로부틸)-3-(2-클로로페녹시)프로판아마이드[N-(3-aminocyclobutyl)-3-(2-chlorophenoxy)propanamide] (1.0 equiv., 60 mg, 0.223 mmol)의 교반 용액에 3-(2-클로로페녹시)프로판산 (1.1 equiv., 49 mg, 0.246 mmol), DIPEA (5.0 equiv., 195 μl, 1.116 mmol) 및 HATU (2.0 equiv., 170 mg, 0.447 mmol)를 첨가하였다. 반응 혼합물을 밤새 실온에서 교반하였다. 혼합물을 EtOAc로 희석한 다음, 유기 상을 염수로 3차례 세척하고, 황산 마그네슘으로 건조시킨 후, 감압 하에서 여과 및 농축시켰다. 잔류물을 최소량의 에틸 아세테이트에 현탁시키고 헥산을 처리하였다. 형성된 침전물을 정제하여 백색 고체의 화합물 9 (EIF-009) 83 mg (78%)를 수득하였다.To a stirred solution of N -(3-aminocyclobutyl)-3-(2-chlorophenoxy)propanamide [ N -(3-aminocyclobutyl)-3-(2-chlorophenoxy)propanamide] (1.0 equiv., 60 mg, 0.223 mmol) in DMF (1.1 ml) were added 3-(2-chlorophenoxy)propanoic acid (1.1 equiv., 49 mg, 0.246 mmol), DIPEA (5.0 equiv., 195 μl, 1.116 mmol), and HATU (2.0 equiv., 170 mg, 0.447 mmol). The reaction mixture was stirred overnight at room temperature. The mixture was diluted with EtOAc, and the organic phase was washed three times with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was suspended in a minimal amount of ethyl acetate and treated with hexane. The formed precipitate was purified to obtain 83 mg (78%) of compound 9 (EIF-009) as a white solid.

N,N'-(사이클로부탄-1,3-디일)비스(3-(2-클로로페녹시)프로판아마이드[N,N'-(cyclobutane-1,3-diyl)bis(3-(2-chlorophenoxy)propanamide)]N,N'-(cyclobutane-1,3-diyl)bis(3-(2-chlorophenoxy)propanamide)

1H NMR (400 MHz, DMSO-d6) δ 8.26 (d, J = 7.3 Hz, 2H), 7.41 - 7.39 (m, 2H), 7.31 - 7.27 (m, 2H), 7.16 - 7.14 (m, 2H), 6.96 - 6.92 (m, 2H), 4.27 - 4.22 (m, 4H), 3.93 - 3.83 (m, 2H), 2.57 - 2.53 (m, 4H), 2.49 - 2.45 (m, 2H), 1.83 - 1.76 (m, 2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.26 (d, J = 7.3 Hz, 2H), 7.41 - 7.39 (m, 2H), 7.31 - 7.27 (m, 2H), 7.16 - 7.14 (m, 2H), 6.96 - 6.92 (m, 2H), 4.27 - 4.22 (m, 4H), 3.93 - 3.83 (m, 2H), 2.57 - 2.53 (m, 4H), 2.49 - 2.45 (m, 2H), 1.83 - 1.76 (m, 2H).

MS (ESI+) m/z calcd for C22H25Cl2N2O4 [M + H]+ 451.11; found 451.00.MS (ESI + ) m/z calcd for C 22 H 25 Cl 2 N 2 O 4 [M + H] + 451.11; found 451.00.

화합물 10 (EIF-010):Compound 10 (EIF-010):

DMF (1.34 ml) 내 터트-부틸 (3-아미노사이클로부틸)카르바메이트 (1.0 equiv., 50 mg, 0.268 mmol)의 교반 용액에 2-((5-플루오로피리딘-2-일)옥시)아세트산[2-((5-fluoropyridin-2-yl)oxy)acetic acid] (1.1 equiv., 50.5 mg, 0.295 mmol), DIPEA (3.0 equiv., 0.141 ml, 0.805 mmol) 및 HATU (2.0 equiv., 204 mg, 0.537 mmol)를 첨가하였다. 반응 혼합물을 실온에서 밤새 교반하였다. 혼합물을 EtOAc로 희석시킨 다음, 유기 상을 염수로 3차례 세척하고, 황산 나트륨으로 건조시킨 다음, 감압 하에서 여과 및 농축시켰다. 잔류물을 최소량의 에틸 아세테이트에 현탁시키고 헥산을 처리하였다. 형성된 침전물을 정제하여 담황색 고체의 생성물 81 mg (82%)을 수득하였다.To a stirred solution of tert-butyl (3-aminocyclobutyl)carbamate (1.0 equiv., 50 mg, 0.268 mmol) in DMF (1.34 ml) were added 2-((5-fluoropyridin-2-yl)oxy)acetic acid [2-((5-fluoropyridin-2-yl)oxy)acetic acid] (1.1 equiv., 50.5 mg, 0.295 mmol), DIPEA (3.0 equiv., 0.141 ml, 0.805 mmol), and HATU (2.0 equiv., 204 mg, 0.537 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, and the organic phase was washed three times with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was suspended in a minimal amount of ethyl acetate and treated with hexane. The formed precipitate was purified to give 81 mg (82%) of the product as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ 8.20 (d, J = 7.3 Hz, 1H), 8.11 - 8.10 (m, 1H), 7.74 - 7.70 (m, 1H), 7.14 (d, J = 7.6 Hz, 1H), 6.96 - 6.92 (m, 1H), 4.64 (s, 2H), 3.87 - 3.75 (m, 1H), 3.64 - 3.54 (m, 1H), 2.46 - 2.39 (m, 2H), 1.84 - 1.76 (m, 2H), 1.36 (s, 9H). 1H NMR (400 MHz, DMSO-d 6 ) δ 8.20 (d, J = 7.3 Hz, 1H), 8.11 - 8.10 (m, 1H), 7.74 - 7.70 (m, 1H), 7.14 (d, J = 7.6 Hz, 1H), 6.96 - 6.92 (m, 1H), 4.64 (s, 2H), 3.87 - 3.75 (m, 1H), 3.64 - 3.54 (m, 1H), 2.46 - 2.39 (m, 2H), 1.84 - 1.76 (m, 2H), 1.36 (s, 9H).

MS (ESI+) m/z calcd for C16H23FN3O4 [M + H]+ 340.16; found 340.02.MS (ESI + ) m/z calcd for C 16 H 23 FN 3 O 4 [M + H] + 340.16; found 340.02.

터트-부틸 (3-(3-(2-플루오로페녹시)프로판아미도)사이클로부틸)카르바메이트[tert-butyl (3-(3-(2-fluorophenoxy)propanamido)cyclobutyl)carbamate] (1.0 equiv., 40 mg, 0.108 mmol) 교반 용액을 실온에서 20% TFA/DCM (255 μl / 1.23 ml)에 희석시켰다. 4시간 동안 교반한 후, 반응 혼합물을 추가 정제없이 증발시켰다. tert -butyl (3-(3-(2-fluorophenoxy)propanamido)cyclobutyl)carbamate (1.0 equiv., 40 mg, 0.108 mmol) was diluted in 20% TFA/DCM (255 μl/1.23 ml) at room temperature. After stirring for 4 h, the reaction mixture was evaporated without further purification.

DMF (442 μl) 내 N-(3-아미노사이클로부틸)-2-((5-플루오로피리딘-2-일)옥시)아세트아마이드[N-(3-aminocyclobutyl)-2-((5-fluoropyridin-2-yl)oxy)acetamide] (1.0 equiv., 21.2 mg, 0.088 mmol)의 교반 용액에 2-((5-플루오로피리딘-2-일)옥시)아세트산 (1.1 equiv., 16.6 mg, 0.097 mmol), DIPEA (5.0 equiv., 77 μl, 0.442 mmol) 및 HATU (2.0 equiv., 67.2 mg, 0.177 mmol)를 첨가하였다. 반응 혼합물을 실온에서 밤새 교반하였다. 혼합물을 EtOAc로 희석하고 나서, 유기 상을 염수로 3차례 세척하고, 황산 마그네슘으로 건조시킨 후, 감압 하에서 여과 및 농축시켰다. 잔류물을 최소량의 에틸 아세테이트에 현탁시키고 헥산으로 처리하였다. 형성된 침전물을 여과를 통해 모아 담갈색 고체의 화합물 10 (EIF-010) 83 mg (78%)을 수득하였다. N -(3-aminocyclobutyl)-2-((5- fluoropyridin -2-yl)oxy)acetamide in DMF (442 μl) To a stirred solution of (1.0 equiv., 21.2 mg, 0.088 mmol) were added 2-((5-fluoropyridin-2-yl)oxy)acetic acid (1.1 equiv., 16.6 mg, 0.097 mmol), DIPEA (5.0 equiv., 77 μl, 0.442 mmol) and HATU (2.0 equiv., 67.2 mg, 0.177 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, and the organic phase was washed three times with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was suspended in a minimum amount of ethyl acetate and treated with hexane. The formed precipitate was collected by filtration to give 83 mg (78%) of compound 10 (EIF-010) as a light brown solid.

N,N'-(사이클로부탄-1,3-디일)비스(2-((5-플루오로피리딘-2-일)옥시)아세트아마이드)[N,N'-(cyclobutane-1,3-diyl)bis(2-((5-fluoropyridin-2-yl)oxy)acetamide)N,N'-(cyclobutane-1,3-diyl)bis(2-((5-fluoropyridin-2-yl)oxy)acetamide)[N,N'-(cyclobutane-1,3-diyl)bis(2-((5-fluoropyridin-2-yl)oxy)acetamide)

1H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 3.0 Hz, 2H), 7.45 - 7.38 (m, 2H), 6.83 (dd, J = 9.0, 3.6 Hz, 2H), 6.64 - 6.62 (m, 2H), 4.75 (s, 4H), 4.22 - 4.12 (m, 2H), 2.89 - 2.82 (m, 2H), 2.11 - 2.03 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.00 (d, J = 3.0 Hz, 2H), 7.45 - 7.38 (m, 2H), 6.83 (dd, J = 9.0, 3.6 Hz, 2H), 6.64 - 6.62 (m, 2H), 4.75 (s, 4H), 4.22 - 4.12 (m, 2H), 2.89 - 2.82 (m, 2H), 2.11 - 2.03 (m, 2H).

MS (ESI+) m/z calcd for C18H19F2N4O4 [M + H]+ 393.13; found 393.10.MS (ESI + ) m/z calcd for C 18 H 19 F 2 N 4 O 4 [M + H] + 393.13; found 393.10.

화합물 11 (EIF-011):Compound 11 (EIF-011):

DMF 내 터트-부틸 (3-아미노사이클로부틸)카르바메이트 (1.0 equiv), 퀴놀린-3-카르복실산[quinoline-3-carboxylic acid] (1.2 equiv), N,N-디이소프로필에틸아민 (2.5 equiv), EDCI (1.5 equiv) 및 HOBt (1.5 equiv) 용액을 실온에서 밤새 교반하였다. 반응 혼합물을 에틸 아세테이트로 희석시키고 10% 수성 염화 리튬 (Х3) 및 염수로 세척하였다. 유기 층을 무수 MgSO4로 건조시키고, 감압 하에서 농축시켰다. 백색 고체의 터트-부틸 (3-(퀴놀린-3-카르복사미도)사이클로부틸)카르바메이트[tert-butyl (3-(quinoline-3-carboxamido)cyclobutyl)carbamate] 76.5 mg (86%)을 수득하였다.A solution of tert-butyl (3-aminocyclobutyl)carbamate (1.0 equiv), quinoline-3-carboxylic acid (1.2 equiv), N , N -diisopropylethylamine (2.5 equiv), EDCI (1.5 equiv), and HOBt (1.5 equiv) in DMF was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with 10% aqueous lithium chloride (X3) and brine. The organic layer was dried over anhydrous MgSO 4 and concentrated under reduced pressure. 76.5 mg (86%) of tert -butyl (3-(quinoline-3-carboxamido)cyclobutyl)carbamate was obtained as a white solid.

1H NMR (400 MHz, DMSO-d6) δ 9.27 (dd, J = 3.8, 2.3 Hz, 1H), 8.97 (d, J = 6.7 Hz, 1H), 8.83 (dd, J = 5.3, 2.0 Hz, 1H), 8.13 - 8.06 (m, 2H), 7.91 - 7.83 (m, 1H), 7.73 - 7.67 (m, 1H), 7.20 (d, J = 7.2 Hz, 1H), 4.12 - 4.03 (m, 1H), 3.70 (dd, J = 15.4, 7.7 Hz, 1H), 2.64 - 2.53 (m, 2H), 2.06 - 1.93 (m, 2H), 1.40 (s, 9H); LCMS (ESI), m/z = 342.00 [M+1]+. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.27 (dd, J = 3.8, 2.3 Hz, 1H), 8.97 (d, J = 6.7 Hz, 1H), 8.83 (dd, J = 5.3, 2.0 Hz, 1H), 8.13 - 8.06 (m, 2H), 7.91 - 7.83 (m, 1H), 7.73 - 7.67 (m, 1H), 7.20 (d, J = 7.2 Hz, 1H), 4.12 - 4.03 (m, 1H), 3.70 (dd, J = 15.4, 7.7 Hz, 1H), 2.64 - 2.53 (m, 2H), 2.06 - 1.93 (m, 2H), 1.40 (s, 9H); LCMS (ESI), m/z = 342.00 [M+1] + .

CH2Cl2 내 터트-부틸 (3-(퀴놀린-3-카르복사미도)사이클로부틸)카르바메이트 (1.0 equiv) 용액에 TFA (1.0 equiv)를 실온에서 첨가하고 5시간 동안 교반하였다. 용매를 감압 하에서 증발시켰다.To a solution of tert-butyl (3-(quinoline-3-carboxamido)cyclobutyl)carbamate (1.0 equiv) in CH 2 Cl 2 was added TFA (1.0 equiv) at room temperature and stirred for 5 h. The solvent was evaporated under reduced pressure.

CH2Cl2 내 용해된 N-(3-아미노사이클로부틸)퀴놀린-3-카르복사마이드[N-(3-aminocyclobutyl)quinoline-3-carboxamide] (1.0 equiv) 용액에 2-(4-클로로페녹시)아세틸 클로라이드 (1.5 equiv) 및 트리에틸아민 (5 equiv)을 첨가하였다. 반응 혼합물을 실온에서 교반하고, 에틸 아세테이트로 희석시킨 다음, 10% 수성 염화 리튬 (Х3) 및 염수로 세척하였다. 유기 층을 무수 MgSO4로 건조시키고, 감압 하에서 농축시켰다. 잔류물을 여과 (EtOAc/n-hexane)를 통해 정제하여, 99% 순도의 베이지색 고체로 화합물 11 (EIF-011), N-(3-(2-(4-클로로페녹시)아세트아미도)사이클로부틸)퀴놀린-3-카르복사마이드[N-(3-(2-(4-chlorophenoxy)acetamido)cyclobutyl) quinoline-3-carboxamide] 62.2 mg (66%)을 수득하였다.To a solution of N -(3-aminocyclobutyl)quinoline-3-carboxamide [ N -(3-aminocyclobutyl)quinoline-3-carboxamide] (1.0 equiv) dissolved in CH 2 Cl 2 were added 2-(4-chlorophenoxy)acetyl chloride (1.5 equiv) and triethylamine (5 equiv). The reaction mixture was stirred at room temperature, diluted with ethyl acetate, and washed with 10% aqueous lithium chloride (X3) and brine. The organic layer was dried over anhydrous MgSO 4 and concentrated under reduced pressure. The residue was purified through filtration (EtOAc/ n -hexane) to obtain 62.2 mg (66%) of compound 11 (EIF-011) , N -( 3- (2-(4-chlorophenoxy)acetamido)cyclobutyl) quinoline-3-carboxamide, as a beige solid with 99% purity.

N-(3-(2-(4-클로로페녹시)아세트아미도)사이클로부틸)퀴놀린-3-카르복사마이드[N-(3-(2-(4-chlorophenoxy)acetamido)cyclobutyl)quinoline-3-carboxamide]N-(3-(2-(4-chlorophenoxy)acetamido)cyclobutyl)quinoline-3-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 9.29 (dd, J = 5.2, 2.1 Hz, 1H), 8.99 (d, J = 6.6 Hz, 1H), 8.84 (dd, J = 11.3, 1.8 Hz, 1H), 8.34 (d, J = 7.0 Hz, 1H), 8.14 - 8.06 (m, 2H), 7.91 - 7.84 (m, 1H), 7.74 - 7.67 (m, 1H), 7.40 - 7.33 (m, 2H), 7.04 - 6.96 (m, 2H), 4.50 (d, J = 5.1 Hz, 7H), 4.15 (dt, J = 16.1, 7.9 Hz, 2H), 4.08 - 3.97 (m, 2H), 2.70 - 2.61 (m, 4H), 2.18 - 2.08 (m, 4H); LCMS (ESI), m/z = 410.00 [M+1]+. 1H NMR (400 MHz, DMSO-d 6 ) δ 9.29 (dd, J = 5.2, 2.1 Hz, 1H), 8.99 (d, J = 6.6 Hz, 1H), 8.84 (dd, J = 11.3, 1.8 Hz, 1H), 8.34 (d, J = 7.0 Hz, 1H), 8.14 - 8.06 (m, 2H), 7.91 - 7.84 (m, 1H), 7.74 - 7.67 (m, 1H), 7.40 - 7.33 (m, 2H), 7.04 - 6.96 (m, 2H), 4.50 (d, J = 5.1 Hz, 7H), 4.15 (dt, J = 16.1, 7.9 Hz, 2H), 4.08 - 3.97 (m, 2H), 2.70 - 2.61 (m, 4H), 2.18 - 2.08 (m, 4H); LCMS (ESI), m/z = 410.00 [M+1] + .

화합물 12 (EIF-012):Compound 12 (EIF-012):

CH2Cl2 내 용해된 터트-부틸 ((1r,4r)-4-아미노사이클로헥실)카르바메이트[tert-butyl ((1r,4r)-4-aminocyclohexyl)carbamate] (1.0 equiv) 용액에 2-(4-클로로페녹시)아세틸 클로라이드 (1.5 equiv) 및 트리에틸아민 (5 equiv)을 첨가하였다. 반응 혼합물을 실온에서 교반하고, 에틸 아세테이트로 희석한 다음, 10% 수성 염화 리튬 (Х3) 및 염수로 세척하였다. 유기 층을 무수 MgSO4로 건조시키고, 감압 하에서 농축시켰다. 잔류물을 여과 (EtOAc/n-hexane)를 통해 정제하여, 순도 98%의 백색 고체, 터트-부틸 ((1r,4r)-4-(2-(4-클로로페녹시)아세트아미도)사이클로헥실)카르바메이트[tert-butyl ((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)carbamate] 779 mg (85%)를 수득하였다 (순도 98%).To a solution of tert -butyl ((1 r ,4 r )-4-aminocyclohexyl)carbamate ( 1.0 equiv) dissolved in CH 2 Cl 2 were added 2-(4 - chlorophenoxy)acetyl chloride (1.5 equiv) and triethylamine (5 equiv). The reaction mixture was stirred at room temperature, diluted with ethyl acetate, and washed with 10% aqueous lithium chloride (X3) and brine. The organic layer was dried over anhydrous MgSO 4 and concentrated under reduced pressure. The residue was purified through filtration (EtOAc/ n -hexane) to obtain 779 mg ( 85% ) of tert -butyl ((1 r ,4 r )-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)carbamate as a white solid with a purity of 98% (purity 98%).

1H NMR (400 MHz, DMSO-d6) δ 7.92 (d, J = 8.0 Hz, 1H), 7.37 - 7.30 (m, 2H), 7.00 - 6.94 (m, 2H), 6.71 (d, J = 7.8 Hz, 1H), 4.44 (s, 2H), 3.59 - 3.48 (m, 1H), 3.22 - 3.11 (m, 1H), 1.82 - 1.69 (m, 4H), 1.36 (d, J = 13.0 Hz, 9H), 1.32 - 1.14 (m, 4H); LCMS (ESI), m/z = 410.00 [M+1]+. 1H NMR (400 MHz, DMSO-d 6 ) δ 7.92 (d, J = 8.0 Hz, 1H), 7.37 - 7.30 (m, 2H), 7.00 - 6.94 (m, 2H), 6.71 (d, J = 7.8 Hz, 1H), 4.44 (s, 2H), 3.59 - 3.48 (m, 1H), 3.22 - 3.11 (m, 1H), 1.82 - 1.69 (m, 4H), 1.36 (d, J = 13.0 Hz, 9H), 1.32 - 1.14 (m, 4H); LCMS (ESI), m/z = 410.00 [M+1] + .

CH2Cl2 내 터트-부틸 ((1r,4r)-4-(2-(4-클로로페녹시)아세트아미도)사이클로헥실)카르바메이트 (1.0 equiv) 용액에 실온에서 TFA (1.0 equiv)를 첨가하고, 혼합물을 5시간 동안 교반하였다. 용매는 감압 하에서 증발시켰다.To a solution of tert-butyl ((1 r ,4 r )-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)carbamate (1.0 equiv) in CH 2 Cl 2 was added TFA (1.0 equiv) at room temperature, and the mixture was stirred for 5 h. The solvent was evaporated under reduced pressure.

CH2Cl2 내 용해된 N-((1r,4r)-4-아미노사이클로헥실)-2-메톡시이소니코틴아마이드[N-((1r,4r)-4-aminocyclohexyl)-2-methoxyisonicotinamide] (1.0 equiv) 용액에 2-(4-클로로페녹시)아세틸 클로라이드 (1.5 equiv) 및 트리에틸아민 (5 equiv)을 첨가하였다. 반응 혼합물을 실온에서 교반하고, 에틸 아세테이트로 희석시킨 후 10% 수성 염화 리튬 (Х3) 및 염수로 세척하였다. 유기 층을 무수 MgSO4로 건조시키고, 감압 하에서 농축시켰다. 잔류물을 여과 (EtOAc/n-hexane)를 통해 정제하여, 순도 98%의 백색 고체로 화합물 12 (EIF-012), N-((1r,4r)-4-(2-(4-클로로페녹시)아세트아미도)사이클로헥실)-2-메톡시이소니코틴아마이드 16 mg (33%)를 수득하였다.To a solution of N -((1 r ,4 r )-4-aminocyclohexyl)-2-methoxyisonicotinamide [ N -((1 r ,4 r )-4-aminocyclohexyl)-2-methoxyisonicotinamide] (1.0 equiv) dissolved in CH 2 Cl 2 were added 2-(4-chlorophenoxy)acetyl chloride (1.5 equiv) and triethylamine (5 equiv). The reaction mixture was stirred at room temperature, diluted with ethyl acetate and washed with 10% aqueous lithium chloride (X3) and brine. The organic layer was dried over anhydrous MgSO 4 and concentrated under reduced pressure. The residue was purified through filtration (EtOAc/ n -hexane) to obtain 16 mg (33%) of compound 12 (EIF-012) , N -((1 r ,4 r )-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-2-methoxyisonicotinamide, as a white solid with a purity of 98%.

N-((1r,4r)-4-(2-(4-클로로페녹시)아세트아미도)사이클로헥실)-2-메톡시이소니코틴아마이드[N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-2-methoxyisonicotinamide]N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-2-methoxyisonicotinamide

1H NMR (400 MHz, DMSO-d6) δ 8.46 (d, J = 7.8 Hz, 1H), 8.27 (d, J = 5.3 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.38 - 7.31 (m, 3H), 7.17 (s, 1H), 7.01 - 6.95 (m, 2H), 4.46 (s, 2H), 3.89 (s, 3H), 3.76 - 3.58 (m, 2H), 1.90 - 1.78 (m, 4H), 1.45 - 1.33 (m, 4H); LCMS (ESI), m/z = 418.00 [M+1]+. 1H NMR (400 MHz, DMSO-d 6 ) δ 8.46 (d, J = 7.8 Hz, 1H), 8.27 (d, J = 5.3 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.38 - 7.31 (m, 3H), 7.17 (s, 1H), 7.01 - 6.95 (m, 2H), 4.46 (s, 2H), 3.89 (s, 3H), 3.76 - 3.58 (m, 2H), 1.90 - 1.78 (m, 4H), 1.45 - 1.33 (m, 4H); LCMS (ESI), m/z = 418.00 [M+1] + .

화합물 13 (EIF-013):Compound 13 (EIF-013):

DMF 내 용해된 N-((1r,4r)-4-아미노사이클로헥실)-2-(4-클로로페녹시)아세트아마이드[N-((1r,4r)-4-aminocyclohexyl)-2-(4-chlorophenoxy)acetamide] (1.0 equiv), 퀴놀린-3-카르복실산 (1.2 equiv), N,N-디이소프로필에틸아민 (2.5 equiv), EDCI (1.5 equiv) 및 HOBt (1.5 equiv) 용액을 실온에서 밤새 교반하였다. 반응 혼합물을 에틸 아세테이트로 희석하고 10% 수성 염화 리튬 (Х3) 및 염수로 세척하였다. 유기 층을 무수 MgSO4로 건조시키고, 감압 하에서 농축시켰다. 잔류물을 여과 (EtOAc/n-hexane)를 통해 정제하여, 99% 순도의 흰색 고체로 화합물 13 (EIF-013), N-((1r,4r)-4-(2-(4-클로로페녹시)아세트아미도)사이클로헥실)퀴놀린-3-카르복사마이드를 수득하였다.A solution of N -((1 r ,4 r )-4-aminocyclohexyl)-2-(4-chlorophenoxy)acetamide [ N -((1 r ,4 r )-4-aminocyclohexyl)-2-(4-chlorophenoxy)acetamide] (1.0 equiv), quinoline-3-carboxylic acid (1.2 equiv), N , N -diisopropylethylamine (2.5 equiv), EDCI (1.5 equiv), and HOBt (1.5 equiv) dissolved in DMF was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with 10% aqueous lithium chloride (X3) and brine. The organic layer was dried over anhydrous MgSO 4 and concentrated under reduced pressure. The residue was purified through filtration (EtOAc/ n -hexane) to obtain compound 13 (EIF-013) , N -((1 r ,4 r )-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)quinoline-3-carboxamide, as a white solid with 99% purity.

N-((1r,4r)-4-(2-(4-클로로페녹시)아세트아미도)사이클로헥실)퀴놀린-3-카르복사마이드[N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)quinoline-3-carboxamide]N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)quinoline-3-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 9.26 (d, J = 2.1 Hz, 1H), 8.80 (d, J = 1.9 Hz, 1H), 8.62 (d, J = 7.7 Hz, 1H), 8.09 (t, J = 7.4 Hz, 2H), 7.99 (d, J = 8.1 Hz, 1H), 7.89 - 7.83 (m, 1H), 7.69 (t, J = 7.5 Hz, 1H), 7.38 - 7.31 (m, 2H), 7.02 - 6.95 (m, 2H), 4.47 (s, 2H), 3.86 - 3.62 (m, 2H), 1.98 - 1.81 (m, 4H), 1.51 - 1.37 (m, 4H); LCMS (ESI), m/z = 438.00 [M+1]+. 1H NMR (400 MHz, DMSO-d 6 ) δ 9.26 (d, J = 2.1 Hz, 1H), 8.80 (d, J = 1.9 Hz, 1H), 8.62 (d, J = 7.7 Hz, 1H), 8.09 (t, J = 7.4 Hz, 2H), 7.99 (d, J = 8.1 Hz, 1H), 7.89 - 7.83 (m, 1H), 7.69 (t, J = 7.5 Hz, 1H), 7.38 - 7.31 (m, 2H), 7.02 - 6.95 (m, 2H), 4.47 (s, 2H), 3.86 - 3.62 (m, 2H), 1.98 - 1.81 (m, 4H), 1.51 - 1.37 (m, 4H); LCMS (ESI), m/z = 438.00 [M+1] + .

화합물 14 (EIF-014):Compound 14 (EIF-014):

DMF 내 용해된 N-((1r,4r)-4-아미노사이클로헥실)-2-(4-클로로페녹시)아세트아마이드 (1.0 equiv), 티아졸-5-카르복실산[thiazole-5-carboxylic acid] (1.2 equiv), N,N-디이소프로필에틸아민 (2.5 equiv), EDCI (1.5 equiv) 및 HOBt (1.5 equiv) 용액을 실온에서 밤새 교반하였다. 반응 혼합물을 에틸 아세테이트로 희석하고 10% 수성 염화 리튬 (Х3) 및 염수로 세척하였다. 유기 층을 무수 MgSO4로 건조시키고, 감압 하에서 농축시켰다. 잔류물을 여과 (EtOAc/n-hexane)를 통해 정제하여, 99% 순도의 백색 고체 화합물 14 (EIF-014), N-((1r,4r)-4-(2-(4-클로로페녹시)아세트아미도)사이클로헥실)티아졸-5-카르복사마이드 60.2 mg (86%)을 수득하였다.A solution of N -((1 r ,4 r )-4-aminocyclohexyl)-2-(4-chlorophenoxy)acetamide (1.0 equiv), thiazole-5-carboxylic acid (1.2 equiv), N , N -diisopropylethylamine (2.5 equiv), EDCI (1.5 equiv), and HOBt (1.5 equiv) dissolved in DMF was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with 10% aqueous lithium chloride (X3) and brine. The organic layer was dried over anhydrous MgSO 4 and concentrated under reduced pressure. The residue was purified through filtration (EtOAc/ n -hexane) to obtain 60.2 mg (86%) of white solid compound 14 (EIF-014) , N -((1 r ,4 r )-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)thiazole-5-carboxamide with 99% purity.

N-((1r,4r)-4-(2-(4-클로로페녹시)아세트아미도)사이클로헥실)티아졸-5-카르복사마이드[N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)thiazole-5-carboxamide]N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)thiazole-5-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 9.20 (s, 1H), 8.48 (d, J = 8.7 Hz, 2H), 7.96 (d, J = 8.1 Hz, 1H), 7.37 - 7.31 (m, 2H), 7.01 - 6.94 (m, 2H), 4.46 (s, 2H), 3.73 - 3.58 (m, 2H), 1.92 - 1.75 (m, 4H), 1.46 - 1.31 (m, 4H); LCMS (ESI), m/z = 394.00 [M+1]+. 1H NMR (400 MHz, DMSO-d 6 ) δ 9.20 (s, 1H), 8.48 (d, J = 8.7 Hz, 2H), 7.96 (d, J = 8.1 Hz, 1H), 7.37 - 7.31 (m, 2H), 7.01 - 6.94 (m, 2H), 4.46 (s, 2H), 3.73 - 3.58 (m, 2H), 1.92 - 1.75 (m, 4H), 1.46 - 1.31 (m, 4H); LCMS (ESI), m/z = 394.00 [M+1] + .

화합물 15 (EIF-015):Compound 15 (EIF-015):

DMF 내 용해된 N-((1r,4r)-4-아미노사이클로헥실)-2-(4-클로로페녹시)아세트아마이드 (1.0 equiv), 이미다졸[1,2-a]피리딘-6-카르복실산[imidazo[1,2-a]pyridine-6-carboxylic acid] (1.2 equiv), N,N-디이소프로필에틸아민 (2.5 equiv), EDCI (1.5 equiv) 및 HOBt (1.5 equiv) 용액을 실온에서 밤새 교반하였다. 반응 혼합물을 에틸 아세테이트로 희석하고 10% 수성 염화 리튬 (Х3) 및 염수로 세척하였다. 유기 층을 무수 MgSO4로 건조시키고, 감압 하에서 농축시켰다. 잔류물을 여과 (EtOAc/n-hexane)를 통해 정제하여, 99% 순도의 담황색 고체 화합물 15 (EIF-015), N-((1r,4r)-4-(2-(4-클로로페녹시)아세트아미도)사이클로헥실)이미다졸 [1,2-a]피리딘-6-카르복사마이드 57.6 mg (76%)을 수득하였다.A solution of N -((1 r ,4 r )-4-aminocyclohexyl)-2-(4-chlorophenoxy)acetamide (1.0 equiv), imidazo[1,2- a ]pyridine-6-carboxylic acid (1.2 equiv), N , N -diisopropylethylamine (2.5 equiv), EDCI (1.5 equiv), and HOBt (1.5 equiv) dissolved in DMF was stirred at room temperature overnight . The reaction mixture was diluted with ethyl acetate and washed with 10% aqueous lithium chloride (X3) and brine. The organic layer was dried over anhydrous MgSO 4 and concentrated under reduced pressure. The residue was purified through filtration (EtOAc/ n -hexane) to obtain 57.6 mg (76%) of a pale yellow solid compound 15 (EIF-015) , N -((1 r ,4 r )-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)imidazole [1,2- a ]pyridine-6-carboxamide with 99% purity.

N-((1r,4r)-4-(2-(4-클로로페녹시)아세트아미도)사이클로헥실)이미다졸 [1,2-a]피리딘-6-카르복사마이드[N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido) cyclohexyl)imidazo[1,2-a]pyridine-6-carboxamide]N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)imidazole [1,2-a]pyridine-6-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.34 (d, J = 7.7 Hz, 1H), 8.06 (s, 1H), 7.98 (d, J = 8.1 Hz, 1H), 7.67 - 7.57 (m, 3H), 7.38 - 7.31 (m, 2H), 7.01 - 6.94 (m, 2H), 4.47 (s, 2H), 3.80 - 3.59 (m, 2H), 1.93 - 1.78 (m, 4H), 1.48 - 1.33 (m, 4H); LCMS (ESI), m/z = 427.00 [M+1]+. 1H NMR (400 MHz, DMSO-d 6 ) δ 9.08 (s, 1H), 8.34 (d, J = 7.7 Hz, 1H), 8.06 (s, 1H), 7.98 (d, J = 8.1 Hz, 1H), 7.67 - 7.57 (m, 3H), 7.38 - 7.31 (m, 2H), 7.01 - 6.94 (m, 2H), 4.47 (s, 2H), 3.80 - 3.59 (m, 2H), 1.93 - 1.78 (m, 4H), 1.48 - 1.33 (m, 4H); LCMS (ESI), m/z = 427.00 [M+1] + .

화합물 16 (EIF-016):Compound 16 (EIF-016):

DMF 내 N-((1r,4r)-4-아미노사이클로헥실)-2-(4-클로로페녹시)아세트아마이드 (1.0 equiv), 벤조퓨란-2-카르복실산[benzofuran-2-carboxylic acid] (1.2 equiv), N,N-디이소프로필에틸아민 (2.5 equiv), EDCI (1.5 equiv) 및 HOBt (1.5 equiv) 용액을 실온에서 밤새 교반하였다. 반응 혼합물을 에틸 아세테이트로 희석하고 10% 수성 염화 리튬 (Х3) 및 염수로 세척하였다. 유기 층을 무수 MgSO4로 건조시키고, 감압 하에서 농축시켰다. 잔류물을 여과 (EtOAc/n-hexane)를 통해 정제하여, 99% 순도의 베이지색 고체 화합물 16 (EIF-016), N-((1r,4r)-4-(2-(4-클로로페녹시)아세트아미도)사이클로헥실)벤조퓨란-2-카르복사마이드 55.1 mg (72%)을 수득하였다.A solution of N -((1 r ,4 r )-4-aminocyclohexyl)-2-(4-chlorophenoxy)acetamide (1.0 equiv), benzofuran-2-carboxylic acid (1.2 equiv), N , N -diisopropylethylamine (2.5 equiv), EDCI (1.5 equiv), and HOBt (1.5 equiv) in DMF was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with 10% aqueous lithium chloride (X3) and brine. The organic layer was dried over anhydrous MgSO 4 and concentrated under reduced pressure. The residue was purified by filtration (EtOAc/ n -hexane) to obtain 55.1 mg (72%) of beige solid compound 16 (EIF-016) , N -((1 r ,4 r )-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)benzofuran-2-carboxamide with 99% purity.

N-((1r,4r)-4-(2-(4-클로로페녹시)아세트아미도)사이클로헥실)벤조퓨란-2-카르복사마이드[N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)benzofuran-2-carboxamide]N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)benzofuran-2-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 8.1 Hz, 1H), 7.98 (d, J = 8.1 Hz, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.65 (d, J = 8.3 Hz, 1H), 7.53 (s, 1H), 7.48 - 7.43 (m, 1H), 7.37 - 7.30 (m, 3H), 7.01 - 6.95 (m, 2H), 4.46 (s, 2H), 3.81 - 3.58 (m, 2H), 1.89 - 1.78 (m, 4H), 1.54 - 1.34 (m, 4H); LCMS (ESI), m/z = 427.00 [M+1]+. 1H NMR (400 MHz, DMSO-d 6 ) δ 8.52 (d, J = 8.1 Hz, 1H), 7.98 (d, J = 8.1 Hz, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.65 (d, J = 8.3 Hz, 1H), 7.53 (s, 1H), 7.48 - 7.43 (m, 1H), 7.37 - 7.30 (m, 3H), 7.01 - 6.95 (m, 2H), 4.46 (s, 2H), 3.81 - 3.58 (m, 2H), 1.89 - 1.78 (m, 4H), 1.54 - 1.34 (m, 4H); LCMS (ESI), m/z = 427.00 [M+1] + .

화합물 23 (EIF-023):Compound 23 (EIF-023):

DMF 내 용해된 4-(((터트-부톡시카르보닐)아미노)메틸)사이클로헥산-1-카르복실산[4-(((tert-butoxycarbonyl)amino)methyl)cyclohexane-1-carboxylic acid] (100 mg, 0.39 mmol), EDCI (150 mg, 0.78 mmol), HOBt (119 mg, 0.78 mmol) 및 DIPEA (151 mg, 1.17 mmol)의 용액에 이미다조[1,2-a]피리딘-6-아민[Imidazo[1,2-a]pyridin-6-amine] (78 mg, 0.58 mmol)을 첨가하고, 용액을 실온에서 밤새 교반하였다. 용액을 EtOAc에 희석시키고 NaHCO3로 세척한 다음, Na2SO4로 건조 및 농축시켰다. 조 생성물을 MPLC (10% MeOH/ CH2Cl2)로 정제하여 생성물을 수득하였다 (140 mg, 97% 수율).To a solution of 4-(((tert-butoxycarbonyl)amino)methyl)cyclohexane-1-carboxylic acid (100 mg , 0.39 mmol), EDCI (150 mg, 0.78 mmol), HOBt (119 mg, 0.78 mmol), and DIPEA (151 mg, 1.17 mmol) in DMF was added imidazo[1,2- a ]pyridin-6-amine (78 mg, 0.58 mmol), and the solution was stirred at room temperature overnight. The solution was diluted in EtOAc, washed with NaHCO 3 , dried over Na 2 SO 4 , and concentrated. The crude product was purified by MPLC (10% MeOH/ CH 2 Cl 2 ) to obtain the product (140 mg, 97% yield).

1H NMR (400 MHz, CDCl3) δ 9.21 (d, J = 1.1 Hz, 1H), 7.63 (s, 1H), 7.61 (d, J = 0.9 Hz, 1H), 7.56 (s, 1H), 7.52 (d, J = 9.5 Hz, 1H), 6.88 (dd, J = 9.5, 1.7 Hz, 1H), 4.60 (s, 1H), 3.00 (t, J = 6.4 Hz, 2H), 2.22 (ddd, J = 12.0, 7.7, 3.3 Hz, 1H), 2.01 (d, J = 11.1 Hz, 2H), 1.89 (d, J = 11.9 Hz, 2H), 1.64 - 1.53 (m, 3H), 1.45 (s, 9H), 1.04 - 0.93 (m, 2H). 1H NMR (400 MHz, CDCl 3 ) δ 9.21 (d, J = 1.1 Hz, 1H), 7.63 (s, 1H), 7.61 (d, J = 0.9 Hz, 1H), 7.56 (s, 1H), 7.52 (d, J = 9.5 Hz, 1H), 6.88 (dd, J = 9.5, 1.7 Hz, 1H), 4.60 (s, 1H), 3.00 (t, J = 6.4 Hz, 2H), 2.22 (ddd, J = 12.0, 7.7, 3.3 Hz, 1H), 2.01 (d, J = 11.1 Hz, 2H), 1.89 (d, J = 11.9 Hz, 2H), 1.64 - 1.53 (m, 3H), 1.45 (s, 9H), 1.04 - 0.93 (m, 2H).

터트-부틸 ((4-(이미다조[1,2-a]피리딘-6-일카르바모일)사이클로헥실)메틸)카르바메이트[tert-Butyl ((4-(imidazo[1,2-a]pyridin-6-ylcarbamoyl)cyclohexyl)methyl)carbamate] (40 mg, 0.1 mmol)를 20% TFA/ CH2Cl2에서 희석시키고 용액을 실온에서 4시간 동안 교반하였다. 유기 용매는 감압 하에 제거하고 조 생성물을 추가 정제없이 다음 과정에 사용하였다. tert -Butyl ((4-(imidazo[1,2- a ]pyridin-6-ylcarbamoyl)cyclohexyl)methyl)carbamate] (40 mg, 0.1 mmol) was diluted in 20% TFA/CH 2 Cl 2 and the solution was stirred at room temperature for 4 h. The organic solvent was removed under reduced pressure and the crude product was used in the next step without further purification.

DMF 내 용해된 4-(아미노메틸)-N-(이미다조[1,2-a]피리딘-6-일)사이클로헥산-1-카르복사마이드[4-(aminomethyl)-N-(imidazo[1,2-a]pyridin-6-yl)cyclohexane-1-carboxamide] (27 mg, 0.1 mmol), EDCI (38 mg, 0.2 mmol), HOBt (30 mg, 0.2 mmol) 및 DIPEA (51 mg, 0.4 mmol) 용액에 2-(2,4-디플루오로페녹시)아세트산[2-(2,4-difluorophenoxy)acetic acid] (38 mg, 0.2 mmol)을 첨가하고, 용액을 실온에서 밤새 교반하였다. 용액을 EtOAc에서 희석시키고 NaHCO3로 세척한 다음, Na2SO4로 건조 및 농축시켰다. 조 생성물을 MPLC (10% MeOH/ CH2Cl2)로 정제하여 화합물 23 (EIF-023)을 수득하였다 (32 mg, 70% 수율).To a solution of 4-(aminomethyl)- N -(imidazo[1,2- a ]pyridin-6-yl)cyclohexane-1-carboxamide (27 mg, 0.1 mmol), EDCI (38 mg, 0.2 mmol), HOBt (30 mg, 0.2 mmol), and DIPEA ( 51 mg, 0.4 mmol) in DMF was added 2-(2,4-difluorophenoxy)acetic acid (38 mg, 0.2 mmol), and the solution was stirred at room temperature overnight. The solution was diluted in EtOAc, washed with NaHCO 3 , dried over Na 2 SO 4 , and concentrated. The crude product was purified by MPLC (10% MeOH/ CH 2 Cl 2 ) to obtain compound 23 (EIF-023) (32 mg, 70% yield).

(1r,4r)-4-((2-(2,4-디플루오로페녹시)아세트아미도)메틸)-N-(이미다조[1,2-a]피리딘-6-일)사이클로헥산-1-카르복사마이드[(1r,4r)-4-((2-(2,4-difluorophenoxy)acetamido)methyl)-N-(imidazo[1,2-a]pyridin-6-yl)cyclohexane-1-carboxamide](1r,4r)-4-((2-(2,4-difluorophenoxy)acetamido)methyl)-N-(imidazo[1,2-a]pyridin-6-yl)cyclohexane-1-carboxamide

1H NMR (400 MHz, CDCl3) δ 9.24 (d, J = 1.1 Hz, 1H), 8.19 (s, 1H), 7.60 (s, 1H), 7.56 (s, 1H), 7.49 (d, J = 9.5 Hz, 1H), 6.98 - 6.87 (m, 3H), 6.86 - 6.80 (m, 1H), 6.78 (t, J = 6.0 Hz, 1H), 4.51 (s, 2H), 3.25 (t, J = 6.6 Hz, 2H), 2.26 (tt, J = 12.0, 3.3 Hz, 1H), 2.04 - 1.97 (m, 2H), 1.89 (d, J = 11.0 Hz, 2H), 1.61 (qd, J = 13.0, 3.3 Hz, 3H), 1.02 (qd, J = 13.1, 3.2 Hz, 2H). 1H NMR (400 MHz, CDCl 3 ) δ 9.24 (d, J = 1.1 Hz, 1H), 8.19 (s, 1H), 7.60 (s, 1H), 7.56 (s, 1H), 7.49 (d, J = 9.5 Hz, 1H), 6.98 - 6.87 (m, 3H), 6.86 - 6.80 (m, 1H), 6.78 (t, J = 6.0 Hz, 1H), 4.51 (s, 2H), 3.25 (t, J = 6.6 Hz, 2H), 2.26 (tt, J = 12.0, 3.3 Hz, 1H), 2.04 - 1.97 (m, 2H), 1.89 (d, J = 11.0 Hz, 2H), 1.61 (qd, J = 13.0, 3.3 Hz, 3H), 1.02 (qd, J = 13.1, 3.2 Hz, 2H).

MS (ESI+) m/z calcd for C23H24F2N4O3 [M+H]+ 443.19; found 443.10. MS (ESI + ) m/z calcd for C 23 H 24 F 2 N 4 O 3 [M+H] + 443.19; found 443.10.

화합물 24 (EIF-024):Compound 24 (EIF-024):

DMF 내 용해된 4-(((터트-부톡시카르보닐)아미노)메틸)사이클로헥산-1-카르복실산 (100 mg, 0.39 mmol), EDCI (150 mg, 0.78 mmol), HOBt (119 mg, 0.78 mmol) 및 DIPEA (151 mg, 1.17 mmol) 용액에 피리딘-4-아민[pyridin-4-amine] (55 mg, 0.58 mmol)을 첨가하고, 용액을 실온에서 밤새 교반하였다. 용액을 EtOAc에서 희석시키고 NaHCO3로 세척한 다음, Na2SO4로 건조 및 농축시켰다. 조 생성물을 MPLC (10% MeOH/ CH2Cl2)로 정제하여 생성물을 수득하였다 (55 mg, 42% 수율).To a solution of 4-(((tert-butoxycarbonyl)amino)methyl)cyclohexane-1-carboxylic acid (100 mg, 0.39 mmol), EDCI (150 mg, 0.78 mmol), HOBt (119 mg, 0.78 mmol), and DIPEA (151 mg, 1.17 mmol) in DMF was added pyridin-4-amine (55 mg, 0.58 mmol), and the solution was stirred at room temperature overnight. The solution was diluted in EtOAc, washed with NaHCO 3 , dried over Na 2 SO 4 , and concentrated. The crude product was purified by MPLC (10% MeOH/ CH 2 Cl 2 ) to give the product (55 mg, 42% yield).

1H NMR (400 MHz, CDCl3) δ 8.47 (d, J = 6.3 Hz, 2H), 8.14 (s, 1H), 7.52 (dd, J = 5.0, 1.3 Hz, 2H), 4.66 (s, 1H), 2.99 (t, J = 6.3 Hz, 2H), 2.22 (tt, J = 12.1, 3.3 Hz, 1H), 2.00 (d, J = 11.8 Hz, 2H), 1.88 (d, J = 11.3 Hz, 2H), 1.65 - 1.51 (m, 3H), 1.04 - 0.90 (m, 2H). 1H NMR (400 MHz, CDCl 3 ) δ 8.47 (d, J = 6.3 Hz, 2H), 8.14 (s, 1H), 7.52 (dd, J = 5.0, 1.3 Hz, 2H), 4.66 (s, 1H), 2.99 (t, J = 6.3 Hz, 2H), 2.22 (tt, J = 12.1, 3.3 Hz, 1H), 2.00 (d, J = 11.8 Hz, 2H), 1.88 (d, J = 11.3 Hz, 2H), 1.65 - 1.51 (m, 3H), 1.04 - 0.90 (m, 2H).

터트-부틸 ((4-(피리딘-4-일카르바모일)사이클로헥실)메틸)카르바메이트[tert-Butyl ((4-(pyridin-4-ylcarbamoyl)cyclohexyl)methyl)carbamate] (55 mg, 0.16 mmol)를 20% TFA/ CH2Cl2에서 희석시키고 용액을 실온에서 밤새 교반하였다. 유기 용매는 감압 하에서 제거되고 조 생성물은 추가 정제없이 다음 과정에 사용되었다. tert -Butyl ((4-(pyridin-4-ylcarbamoyl)cyclohexyl)methyl)carbamate] (55 mg, 0.16 mmol) was diluted in 20% TFA/CH 2 Cl 2 and the solution was stirred at room temperature overnight. The organic solvent was removed under reduced pressure and the crude product was used in the next process without further purification.

DMF 내 용해된 4-(아미노메틸)-N-(이미다조[1,2-a]피리딘-6-일)사이클로헥산-1-카르복사마이드 (27 mg, 0.1 mmol), EDCI (38 mg, 0.2 mmol), HOBt (30 mg, 0.2 mmol) 및 DIPEA (51 mg, 0.4 mmol) 용액에 2-(2,4-디플루오로페녹시)아세트산 (38 mg, 0.2 mmol)을 첨가하고 용액을 실온에서 밤새 교반하였다. 용액을 EtOAc에서 희석시키고 NaHCO3로 세척한 다음, Na2SO4로 건조 및 농축시켰다. 조 생성물을 MPLC (10% MeOH/ CH2Cl2)로 정제하여 화합물 24 (EIF-024)를 수득하였다 (55 mg, 80% 수율).To a solution of 4-(aminomethyl)- N -(imidazo[1,2- a ]pyridin-6-yl)cyclohexane-1-carboxamide (27 mg, 0.1 mmol), EDCI (38 mg, 0.2 mmol), HOBt (30 mg, 0.2 mmol), and DIPEA (51 mg, 0.4 mmol) in DMF was added 2-(2,4-difluorophenoxy)acetic acid (38 mg, 0.2 mmol), and the solution was stirred at room temperature overnight. The solution was diluted in EtOAc, washed with NaHCO 3 , dried over Na 2 SO 4 , and concentrated. The crude product was purified by MPLC (10% MeOH/ CH 2 Cl 2 ) to give compound 24 (EIF-024) (55 mg, 80% yield).

(1r,4r)-4-((2-(2,4-디플루오로페녹시)아세트아미도)메틸)-N-(피리딘-4-일)사이클로헥산-1-카르복사마이드[(1r,4r)-4-((2-(2,4-difluorophenoxy)acetamido)methyl)-N-(pyridin-4-yl)cyclohexane-1-carboxamide](1r,4r)-4-((2-(2,4-difluorophenoxy)acetamido)methyl)-N-(pyridin-4-yl)cyclohexane-1-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.39 (d, J = 6.2 Hz, 2H), 8.06 (t, J = 5.7 Hz, 1H), 7.56 (d, J = 6.2 Hz, 2H), 7.32 (ddd, J = 11.6, 8.9, 2.9 Hz, 1H), 7.11 (td, J = 9.3, 5.4 Hz, 1H), 7.03 (dd, J = 12.6, 4.7 Hz, 1H), 4.57 (s, 2H), 3.00 (t, J = 6.3 Hz, 2H), 2.29 (t, J = 12.1 Hz, 1H), 1.85 (d, J = 11.4 Hz, 2H), 1.74 (d, J = 11.2 Hz, 2H), 1.52 - 1.28 (m, 3H), 1.02 - 0.83 (m, 2H). 1H NMR (400 MHz, DMSO-d 6 ) δ 10.20 (s, 1H), 8.39 (d, J = 6.2 Hz, 2H), 8.06 (t, J = 5.7 Hz, 1H), 7.56 (d, J = 6.2 Hz, 2H), 7.32 (ddd, J = 11.6, 8.9, 2.9 Hz, 1H), 7.11 (td, J = 9.3, 5.4 Hz, 1H), 7.03 (dd, J = 12.6, 4.7 Hz, 1H), 4.57 (s, 2H), 3.00 (t, J = 6.3 Hz, 2H), 2.29 (t, J = 12.1 Hz, 1H), 1.85 (d, J = 11.4 Hz, 2H), 1.74 (d, J = 11.2 Hz, 2H), 1.52 - 1.28 (m, 3H), 1.02 - 0.83 (m, 2H).

MS (ESI+) m/z calcd for C21H23F2N3O3 [M+H]+ 404.18; found 404.10. MS (ESI + ) m/z calcd for C 21 H 23 F 2 N 3 O 3 [M+H] + 404.18; found 404.10.

화합물 25 (EIF-025):Compound 25 (EIF-025):

DMF 내 용해된 4-(아미노메틸)-N-(이미다조[1,2-a]피리딘-6-일)사이클로헥산-1-카르복사마이드 (35 mg, 0.13 mmol), EDCI (50 mg, 0.26 mmol), HOBt (40 mg, 0.26 mmol) 및 DIPEA (67 mg, 0.52 mmol) 용액에 3-(4-플루오로페녹시)프로판산[3-(4-fluorophenoxy)propanoic acid] (48 mg, 0.26 mmol)을 첨가하고, 용액을 실온에서 밤새 교반하였다. 용액을 EtOAc에서 희석시키고 NaHCO3로 세척한 다음, Na2SO4로 건조 및 농축시켰다. 조 생성물을 MPLC (10% MeOH/ CH2Cl2)로 정제하여 화합물 25 (EIF-025)를 수득하였다 (42 mg, 70% 수율).To a solution of 4-(aminomethyl)- N -(imidazo[1,2- a ]pyridin-6-yl)cyclohexane-1-carboxamide (35 mg, 0.13 mmol), EDCI (50 mg, 0.26 mmol), HOBt (40 mg, 0.26 mmol), and DIPEA (67 mg, 0.52 mmol) in DMF was added 3-(4-fluorophenoxy)propanoic acid (48 mg, 0.26 mmol), and the solution was stirred at room temperature overnight. The solution was diluted in EtOAc, washed with NaHCO 3 , dried over Na 2 SO 4 , and concentrated. The crude product was purified by MPLC (10% MeOH/ CH 2 Cl 2 ) to obtain compound 25 (EIF-025) (42 mg, 70% yield).

(1r,4r)-4-((3-(4-플루오로페녹시)프로판아미도)메틸)-N-(이미다조[1,2-a]피리딘-6-일)사이클로헥산-1-카르복사마이드[(1r,4r)-4-((3-(4-fluorophenoxy)propanamido)methyl)-N-(imidazo[1,2-a]pyridin-6-yl)cyclohexane-1-carboxamide](1r,4r)-4-((3-(4-fluorophenoxy)propanamido)methyl)-N-(imidazo[1,2-a]pyridin-6-yl)cyclohexane-1-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 9.22 (d, J = 1.0 Hz, 1H), 8.07 - 7.90 (m, 2H), 7.52 (d, J = 9.4 Hz, 2H), 7.15 (dd, J = 9.7, 2.0 Hz, 1H), 7.14 - 7.07 (m, 2H), 6.96 - 6.88 (m, 2H), 4.15 (t, J = 6.1 Hz, 2H), 2.97 (t, J = 6.3 Hz, 2H), 2.54 (t, J = 6.2 Hz, 2H), 2.30 (tt, J = 12.1, 3.2 Hz, 1H), 1.87 (d, J = 12.5 Hz, 2H), 1.81 (d, J = 10.8 Hz, 2H), 1.55 - 1.32 (m, 3H), 0.94 (qd, J = 12.9, 2.9 Hz, 2H). 1H NMR (400 MHz, DMSO-d 6 ) δ 9.93 (s, 1H), 9.22 (d, J = 1.0 Hz, 1H), 8.07 - 7.90 (m, 2H), 7.52 (d, J = 9.4 Hz, 2H), 7.15 (dd, J = 9.7, 2.0 Hz, 1H), 7.14 - 7.07 (m, 2H), 6.96 - 6.88 (m, 2H), 4.15 (t, J = 6.1 Hz, 2H), 2.97 (t, J = 6.3 Hz, 2H), 2.54 (t, J = 6.2 Hz, 2H), 2.30 (tt, J = 12.1, 3.2 Hz, 1H), 1.87 (d, J = 12.5 Hz, 2H), 1.81 (d, J = 10.8 Hz, 2H), 1.55 - 1.32 (m, 3H), 0.94 (qd, J = 12.9, 2.9 Hz, 2H).

MS (ESI+) m/z calcd for C24H27FN4O3 [M+H]+ 439.22; found 439.18. MS (ESI + ) m/z calcd for C 24 H 27 FN 4 O 3 [M+H] + 439.22; found439.18.

화합물 26 (EIF-026):Compound 26 (EIF-026):

DMF에 용해된 N-((1r,4r)-4-아미노사이클로헥실)-2-(4-클로로페녹시)아세트아마이드 (1.0 equiv), 1H-피롤로[2,3-b]피리딘-5-카르복실산[1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid] (1.2 equiv), N,N-디이소프로필에틸아민 (2.5 equiv), EDCI (1.5 equiv) 및 HOBt (1.5 equiv) 용액을 실온에서 밤새 교반하였다. 반응 혼합물을 에틸 아세테이트로 희석시키고 10% 수성 염화 리튬 (Х3) 및 염수로 세척하였다. 유기 층을 무수 MgSO4로 건조시키고 감압 하에서 농축시켰다. 잔류물을 여과 (EtOAc/n-hexane)를 통해 정제하여 96% 순도의 백색 고체, 화합물 26 (EIF-026), N-((1r,4r)-4-(2-(4-클로로페녹시)아세트아미도)사이클로헥실)-1H-피롤로 [2,3-b]피리딘-5-카르복사마이드 59.3 mg (75%)을 수득하였다.A solution of N -((1 r ,4 r )-4-aminocyclohexyl)-2-(4-chlorophenoxy)acetamide (1.0 equiv), 1 H -pyrrolo[2,3- b ]pyridine-5-carboxylic acid (1.2 equiv), N , N -diisopropylethylamine (2.5 equiv), EDCI (1.5 equiv), and HOBt (1.5 equiv) in DMF was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with 10 % aqueous lithium chloride (X3) and brine. The organic layer was dried over anhydrous MgSO 4 and concentrated under reduced pressure. The residue was purified by filtration (EtOAc/ n -hexane) to give 59.3 mg (75%) of a white solid with 96% purity, compound 26 (EIF-026) , N -((1 r ,4 r )-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-1 H -pyrrolo [2,3- b ]pyridine-5-carboxamide.

N-((1r,4r)-4-(2-(4-클로로페녹시)아세트아미도)사이클로헥실)-1H-피롤로[2,3-b]피리딘-5-카르복사마이드[N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide]N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 11.88 (s, 1H), 8.71 (d, J = 2.0 Hz, 1H), 8.42 (d, J = 1.8 Hz, 1H), 8.27 (d, J = 7.8 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.56 - 7.52 (m, 1H), 7.38 - 7.31 (m, 2H), 7.01 - 6.95 (m, 2H), 6.54 (dd, J = 3.4, 1.8 Hz, 1H), 4.47 (s, 2H), 3.82 - 3.60 (m, 2H), 1.92 - 1.78 (m, 4H), 1.48 - 1.35 (m, 4H); LCMS (ESI), m/z = 426.90 [M+1]+. 1H NMR (400 MHz, DMSO-d 6 ) δ 11.88 (s, 1H), 8.71 (d, J = 2.0 Hz, 1H), 8.42 (d, J = 1.8 Hz, 1H), 8.27 (d, J = 7.8 Hz, 1H), 8.00 (d, J = 8.0) Hz, 1H), 7.56 - 7.52 (m, 1H), 7.38 - 7.31 (m, 2H), 7.01 - 6.95 (m, 2H), 6.54 (dd, J = 3.4, 1.8 Hz, 1H), 4.47 (s, 2H), 3.82 - 3.60 (m, 2H), 1.92 - 1.78 (m, 4H), 1.48 - 1.35 (m, 4H); LCMS (ESI), m/z = 426.90 [M+1] + .

화합물 27 (EIF-027):Compound 27 (EIF-027):

DMF 내 용해된 N-((1r,4r)-4-아미노사이클로헥실)-2-(4-클로로페녹시)아세트아마이드 (1.0 equiv), 1H-벤조[d]이미다졸-6-카르복실산[1H-benzo[d]imidazole-6-carboxylic acid] (1.2 equiv), N,N-디이소프로필에틸아민 (2.5 equiv), EDCI (1.5 equiv) 및 HOBt (1.5 equiv) 용액을 실온에서 밤새 교반하였다.A solution of N -((1 r ,4 r )-4-aminocyclohexyl)-2-(4-chlorophenoxy)acetamide (1.0 equiv), 1 H -benzo[ d ]imidazole-6-carboxylic acid (1.2 equiv), N , N -diisopropylethylamine (2.5 equiv), EDCI (1.5 equiv), and HOBt (1.5 equiv) dissolved in DMF was stirred at room temperature overnight .

반응 혼합물을 에틸 아세테이트로 희석시키고 10% 수성 염화 리튬 (Х3) 및 염수로 세척하였다. 유기 층을 무수 MgSO4로 건조시키고 감압 하에서 농축시켰다. 잔류물을 여과 (EtOAc/n-hexane)를 통해 정제하여 98% 담황색 고체, 화합물 27 (EIF-027), N-((1r,4r)-4-(2-(4-클로로페녹시)아세트아미도)사이클로헥실)-1H-벤조[d]이미다졸-6-카르복사마이드 13.7 mg (30%)을 수득하였다.The reaction mixture was diluted with ethyl acetate and washed with 10% aqueous lithium chloride (X3) and brine. The organic layer was dried over anhydrous MgSO 4 and concentrated under reduced pressure. The residue was purified by filtration (EtOAc/ n -hexane) to yield 13.7 mg (30%) of 98% pale yellow solid, compound 27 (EIF-027) , N -((1 r ,4 r )-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-1 H -benzo[ d ]imidazole-6-carboxamide.

N-((1r,4r)-4-(2-(4-클로로페녹시)아세트아미도)사이클로헥실)-1H-벤조[d]이미다졸-6-카르복사마이드[N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-1H-benzo[d]imidazole-6-carboxamide]N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-1H-benzo[d]imidazole-6-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 12.65 (d, J = 23.6 Hz, 1H), 8.32 (d, J = 14.8 Hz, 1H), 8.26 - 7.96 (m, 3H), 7.78 - 7.52 (m, 2H), 7.36 (d, J = 8.9 Hz, 2H), 6.99 (d, J = 8.9 Hz, 2H), 4.47 (s, 2H), 3.82 - 3.58 (m, 2H), 1.95 - 1.75 (m, 4H), 1.52 - 1.33 (m, 4H); LCMS (ESI), m/z = 427.00 [M+1]+. 1H NMR (400 MHz, DMSO-d 6 ) δ 12.65 (d, J = 23.6 Hz, 1H), 8.32 (d, J = 14.8 Hz, 1H), 8.26 - 7.96 (m, 3H), 7.78 - 7.52 (m, 2H), 7.36 (d, J = 8.9 Hz, 2H), 6.99 (d, J = 8.9 Hz, 2H), 4.47 (s, 2H), 3.82 - 3.58 (m, 2H), 1.95 - 1.75 (m, 4H), 1.52 - 1.33 (m, 4H); LCMS (ESI), m/z = 427.00 [M+1] + .

화합물 28 (EIF-028):Compound 28 (EIF-028):

DMF (1.0 ml) 내 터트-부틸((3-아미노사이클로부틸)메틸)카르바메이트[tert-butyl ((3-aminocyclobutyl)methyl)carbamate] (1.0 equiv., 40 mg, 0.200 mmol) 교반된 용액에 3-(4-클로로페닐)프로피올산[3-(4-chlorophenyl)propiolic acid] (1.1 equiv., 39.7 mg, 0.220 mmol), DIPEA (3.0 equiv., 105 μl, 0.599 mmol) 및 HATU (2.0 equiv., 152 mg, 0.399 mmol)를 첨가하였다. 반응 혼합물을 실온에서 밤새 교반하고, EtOAc로 희석시킨 다음, 유기 상을 염수로 3차례 세척하고, 황산 마그네슘으로 건조시킨 후, 감압 하에서 여과 및 농축시켰다. 잔류물을 최소량의 에틸 아세테이트에 현탁시키고 헥산으로 처리하였다. 형성된 침전물을 여과로 모아 베이지색 고체 생성물 69 mg (90%)을 수득하였다.tert-butyl ((3-aminocyclobutyl)methyl)carbamate [ tert -butyl ((3-aminocyclobutyl)methyl)carbamate] in DMF (1.0 ml) To a stirred solution of 3-(4-chlorophenyl)propiolic acid (1.1 equiv., 39.7 mg, 0.220 mmol), DIPEA (3.0 equiv., 105 μl, 0.599 mmol) and HATU (2.0 equiv., 152 mg, 0.399 mmol) were added. The reaction mixture was stirred at room temperature overnight, diluted with EtOAc, and the organic phase was washed three times with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was suspended in a minimum amount of ethyl acetate and treated with hexane. The formed precipitate was collected by filtration to give 69 mg (90%) of the beige solid product.

1H NMR (400 MHz, DMSO-d6) δ 9.01 (d, J = 7.6 Hz, 1H), 7.61 - 7.56 (m, 2H), 7.55 - 7.51 (m, 2H), 6.81 (t, J = 5.9 Hz, 1H), 4.07 (h, J = 8.3 Hz, 1H), 2.92 (t, J = 6.2 Hz, 2H), 2.27 - 2.20 (m, 2H), 2.08 - 2.03 (m, 1H), 1.65 - 1.58 (m, 2H), 1.37 (s, 9H). 1H NMR (400 MHz, DMSO-d 6 ) δ 9.01 (d, J = 7.6 Hz, 1H), 7.61 - 7.56 (m, 2H), 7.55 - 7.51 (m, 2H), 6.81 (t, J = 5.9 Hz, 1H), 4.07 (h, J = 8.3) Hz, 1H), 2.92 (t, J = 6.2 Hz, 2H), 2.27 - 2.20 (m, 2H), 2.08 - 2.03 (m, 1H), 1.65 - 1.58 (m, 2H), 1.37 (s, 9H).

MS (ESI+) m/z calcd for C19H24ClN2O3 [M + H]+ 363.14; found 363.15.MS (ESI + ) m/z calcd for C 19 H 24 ClN 2 O 3 [M + H] + 363.14; found 363.15.

터트-부틸 ((3-(3-(4-클로로페닐)프로피올아미도)사이클로부틸)메틸)카르바메이트[tert-butyl ((3-(3-(4-chlorophenyl)propiolamido)cyclobutyl)methyl)carbamate] (1.0 equiv., 30 mg, 0.083 mmol) 교반된 용액을 20% TFA/DCM (69 μl/ 344 μl)로 실온에서 희석시키고, 4시간 동안 교반한 후 반응 혼합물을 추가 정제없이 증발시켰다. tert -butyl ((3-(3-(4-chlorophenyl)propiolamido)cyclobutyl)methyl)carbamate] (1.0 equiv., 30 mg, 0.083 mmol) The stirred solution was diluted with 20% TFA/DCM (69 μl/ 344 μl) at room temperature, stirred for 4 h, and the reaction mixture was evaporated without further purification.

DMF (449 μl) 내 N-(3-(아미노메틸)사이클로부틸)-3-(4-클로로페닐)프로피올아마이드[N-(3-(aminomethyl)cyclobutyl)-3-(4-chlorophenyl)propiolamide] (1.0 equiv., 22 mg, 0.084 mmol) 교반된 용액에 3-(4-클로로페닐)프로피올산 (1.1 equiv., 16 mg, 0.092 mmol), DIPEA (5.0 equiv., 78 μl, 0.449 mmol) 및 HATU (2.0 equiv., 68.2 mg, 0.179 mmol)를 첨가하였다. 반응 혼합물을 실온에서 밤새 교반하고, 혼합물을 EtOAc로 희석시켰다. 유기 상을 염수로 3차례 세척한 다음, 황산 마그네슘으로 건조시키고, 감압 하에서 여과 및 농축시켰다. 잔류물을 최소량의 에틸 아세테이트에 현탁시키고 헥산을 처리하였다. 형성된 침전물을 여과하여 모아, 연주황색 고체, 화합물 28 (EIF-028) 13.9 mg (38%)을 수득하였다.To a stirred solution of N -(3-(aminomethyl)cyclobutyl)-3-(4-chlorophenyl)propiolamide [ N -(3-(aminomethyl)cyclobutyl)-3-(4-chlorophenyl)propiolamide] (1.0 equiv., 22 mg, 0.084 mmol) in DMF (449 μl) were added 3-(4-chlorophenyl)propiolic acid (1.1 equiv., 16 mg, 0.092 mmol), DIPEA (5.0 equiv., 78 μl, 0.449 mmol), and HATU (2.0 equiv., 68.2 mg, 0.179 mmol). The reaction mixture was stirred at room temperature overnight, and the mixture was diluted with EtOAc. The organic phase was washed three times with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was suspended in a minimal amount of ethyl acetate and treated with hexane. The formed precipitate was collected by filtration, yielding 13.9 mg (38%) of compound 28 (EIF-028) as a pale orange solid.

3-(4-클로로페닐)-N-((3-(3-(4-클로로페닐)프로피올아미도)사이클로부틸)메틸)프로이올아마이드[3-(4-chlorophenyl)-N-((3-(3-(4-chlorophenyl)propiolamido)cyclobutyl)methyl)propiolamide]3-(4-chlorophenyl)-N-((3-(3-(4-chlorophenyl)propiolamido)cyclobutyl)methyl)propiolamide

1H NMR (400 MHz, DMSO) δ 9.04 (d, J = 7.6 Hz, 1H), 8.83 (t, J = 5.8 Hz, 1H), 7.61 - 7.57 (m, 4H), 7.56 - 7.51 (m, 4H), 4.15 - 4.05 (m, 1H), 3.16 (t, J = 6.2 Hz, 2H), 2.33 - 2.26 (m, 2H), 2.15 - 2.09 (m, 1H), 1.71 - 1.63 (m, 2H). 1 H NMR (400 MHz, DMSO) δ 9.04 (d, J = 7.6 Hz, 1H), 8.83 (t, J = 5.8 Hz, 1H), 7.61 - 7.57 (m, 4H), 7.56 - 7.51 (m, 4H), 4.15 - 4.05 (m, 1H), 3.16 (t, J = 6.2 Hz, 2H), 2.33 - 2.26 (m, 2H), 2.15 - 2.09 (m, 1H), 1.71 - 1.63 (m, 2H).

MS (ESI+) m/z calcd for C23H19Cl2N2O2 [M + H]+ 425.07; found 425.05.MS (ESI + ) m/z calcd for C 23 H 19 Cl 2 N 2 O 2 [M + H] + 425.07; found 425.05.

화합물 29 (EIF-029):Compound 29 (EIF-029):

DMF (1.0 ml) 내 터트-부틸((3-아미노사이클로부틸)메틸)카르바메이트 (1.0 equiv., 40 mg, 0.200 mmol) 교반된 용액에 (E)-3-(4-클로로페닐)아크릴산 (1.0 equiv., 36.5 mg, 0.220 mmol), DIPEA (3.0 equiv., 105 μl, 0.599 mmol) 및 HATU (2.0 equiv., 152 mg, 0.399 mmol)를 첨가하였다. 반응 혼합물을 실온에서 밤새 교반하고, 혼합물을 EtOAc로 희석시켰다. 유기 상은 염수로 3차례 세척한 다음, 황산 마그네슘으로 건조시키고, 감압 하에서 여과 및 농축시켰다. 잔류물을 MPLC (EtOAc/n-Hexane = 1:1)로 정제하여 백색 고체 생성물 57 mg (78%)을 수득하였다.To a stirred solution of tert-butyl((3-aminocyclobutyl)methyl)carbamate (1.0 equiv., 40 mg, 0.200 mmol) in DMF (1.0 ml) were added ( E )-3-(4-chlorophenyl)acrylic acid (1.0 equiv., 36.5 mg, 0.220 mmol), DIPEA (3.0 equiv., 105 μl, 0.599 mmol), and HATU (2.0 equiv., 152 mg, 0.399 mmol). The reaction mixture was stirred at room temperature overnight, and the mixture was diluted with EtOAc. The organic phase was washed three times with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by MPLC (EtOAc/ n -Hexane = 1:1) to give 57 mg (78%) of the white solid product.

1H NMR (400 MHz, DMSO-d6) δ 8.31 (d, J = 7.8 Hz, 1H), 7.58 - 7.55 (m, 2H), 7.49 - 7.46 (m, 2H), 7.38 (d, J = 15.8 Hz, 1H), 6.82 (t, J = 5.8 Hz, 1H), 6.56 (d, J = 15.8 Hz, 1H), 4.13 (h, J = 8.3 Hz, 1H), 2.94 (t, J = 6.3 Hz, 2H), 2.30 - 2.20 (m, 2H), 2.06 - 1.92 (m, 1H), 1.61 - 1.54 (m, 2H), 1.38 (s, 9H). 1H NMR (400 MHz, DMSO-d 6 ) δ 8.31 (d, J = 7.8 Hz, 1H), 7.58 - 7.55 (m, 2H), 7.49 - 7.46 (m, 2H), 7.38 (d, J = 15.8 Hz, 1H), 6.82 (t, J = 5.8 Hz, 1H), 6.56 (d, J = 15.8 Hz, 1H), 4.13 (h, J = 8.3 Hz, 1H), 2.94 (t, J = 6.3 Hz, 2H), 2.30 - 2.20 (m, 2H), 2.06 - 1.92 (m, 1H), 1.61 - 1.54 (m, 2H), 1.38 (s, 9H).

MS (ESI+) m/z calcd for C19H26ClN2O3 [M + H]+ 365.16; found 365.15.MS (ESI + ) m/z calcd for C 19 H 26 ClN 2 O 3 [M + H] + 365.16; found 365.15.

터트-부틸 (E)-((3-(3-(4-클로로페닐)아크릴아미도)사이클로부틸)메틸)카르바메이트[tert-butyl (E)-((3-(3-(4-chlorophenyl)acrylamio)cyclobutyl)methyl)carbamate] (1.0 equiv., 30 mg, 0.082 mmol) 교반된 용액을 실온에서 20% TFA/DCM (69 μl/ 343 μl)로 희석시켰다. 4시간 동안 교반한 후, 반응 혼합물을 추가 정제없이 증발시켰다.tert-Butyl ( E )-((3-(3-(4-chlorophenyl)acrylamido)cyclobutyl)methyl)carbamate [ tert -butyl ( E )-((3-(3-(4-chlorophenyl)acrylamio)cyclobutyl)methyl)carbamate] (1.0 equiv., 30 mg, 0.082 mmol) The stirred solution was diluted with 20% TFA/DCM (69 μl/ 343 μl) at room temperature. After stirring for 4 h, the reaction mixture was evaporated without further purification.

DMF (411 μl) 내 (E)-N-(3-(아미노메틸)사이클로부틸)-3-(4-클로로페닐)아크릴아마이드[(E)-N-(3-(aminomethyl)cyclobutyl)-3-(4-chlorophenyl)acrylamide] (1.0 equiv., 22 mg, 0.082 mmol) 교반된 용액에 (E)-3-(4-클로로페닐)아크릴산 (1.1 equiv., 15 mg, 0.082 mmol), DIPEA (3.0 equiv., 43 μl, 0.247 mmol) 및 HATU (2.0 equiv., 62.5 mg, 0.164 mmol)를 첨가하였다. 반응 혼합물을 실온에서 밤새 교반하고, 혼합물을 EtOAc로 희석시켰다. 유기 상을 염수로 3차례 세척한 다음, 황산 마그네슘으로 건조시키고, 감압 하에서 여과 및 농축시켰다. 잔류물을 최소량의 에틸 아세테이트에 현탁시키고, 헥산을 처리하였다. 형성된 침전물을 여과하여 모아 백색 고체의 화합물 29 (EIF-029) 9.4 mg (26%)을 수득하였다.To a stirred solution of ( E )- N -(3-(aminomethyl)cyclobutyl)-3-(4-chlorophenyl)acrylamide [( E )- N -(3-(aminomethyl)cyclobutyl)-3-(4-chlorophenyl)acrylamide] (1.0 equiv., 22 mg, 0.082 mmol) in DMF (411 μl) were added ( E )-3-(4-chlorophenyl)acrylic acid (1.1 equiv., 15 mg, 0.082 mmol), DIPEA (3.0 equiv., 43 μl, 0.247 mmol), and HATU (2.0 equiv., 62.5 mg, 0.164 mmol). The reaction mixture was stirred at room temperature overnight, and the mixture was diluted with EtOAc. The organic phase was washed three times with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was suspended in a minimal amount of ethyl acetate and treated with hexane. The formed precipitate was collected by filtration, yielding 9.4 mg (26%) of compound 29 (EIF-029) as a white solid.

(E)-3-(4-클로로페닐)-N-((3-((E)-3-(4-클로로페닐)아크릴아미도)사이클로부틸)메틸)아크릴아마이드[(E)-3-(4-chlorophenyl)-N-((3-((E)-3-(4-chlorophenyl)acrylamido)cyclobutyl)methyl)acrylamide](E)-3-(4-chlorophenyl)-N-((3-((E)-3-(4-chlorophenyl)acrylamido)cyclobutyl)methyl)acrylamide

1H NMR (400 MHz, DMSO-d6) δ 8.34 (d, J = 7.8 Hz, 1H), 8.14 (t, J = 5.8 Hz, 1H), 7.60 - 7.56 (m, 4H), 7.48 - 7.45 (m, 4H), 7.44 - 7.34 (m, 2H), 6.64 (d, J = 15.8 Hz, 1H), 6.56 (d, J = 15.8 Hz, 1H), 4.22 - 4.11 (m, 1H), 3.22 (t, J = 6.2 Hz, 2H), 2.35 - 2.28 (m, 2H), 2.16 - 2.01 (m, 1H), 1.68 - 1.60 (m, 2H). 1H NMR (400 MHz, DMSO-d 6 ) δ 8.34 (d, J = 7.8 Hz, 1H), 8.14 (t, J = 5.8 Hz, 1H), 7.60 - 7.56 (m, 4H), 7.48 - 7.45 (m, 4H), 7.44 - 7.34 (m, 2H), 6.64 (d, J = 15.8 Hz, 1H), 6.56 (d, J = 15.8 Hz, 1H), 4.22 - 4.11 (m, 1H), 3.22 (t, J = 6.2 Hz, 2H), 2.35 - 2.28 (m, 2H), 2.16 - 2.01 (m, 1H), 1.68 - 1.60 (m, 2H).

MS (ESI+) m/z calcd for C23H23Cl2N2O2 [M + H]+ 425.11; found 425.05.MS (ESI + ) m/z calcd for C 23 H 23 Cl 2 N 2 O 2 [M + H] + 425.11; found 425.05.

화합물 30 (EIF-030):Compound 30 (EIF-030):

DMF (1.0 ml) 내 터트-부틸 ((3-아미노사이클로부틸)메틸)카르바메이트 (1.0 equiv., 40 mg, 0.200 mmol) 교반된 용액에 2-((5-플루오로피리딘-2-일)옥시)아세트산 (1.0 equiv., 34.2 mg, 0.200 mmol), DIPEA (3.0 equiv., 105 μl, 0.599 mmol) 및 HATU (2.0 equiv., 152 mg, 0.399 mmol)를 첨가하였다. 반응 혼합물을 실온에서 밤새 교반하였고, 혼합물은 EtOAc로 희석시켰다. 유기 상은 염수로 3차례 세척한 후, 황산 마그네슘으로 건조시키고 감압 하에서 여과 및 농축시켰다. 잔류물을 최소량의 에틸 아세테이트에 현탁시키고 헥산을 처리하였다. 형성된 침전물을 여과를 통해 모아 아이보리색 고체 생성물 58 mg (77%)을 수득하였다.To a stirred solution of tert-butyl ((3-aminocyclobutyl)methyl)carbamate (1.0 equiv., 40 mg, 0.200 mmol) in DMF (1.0 ml) were added 2-((5-fluoropyridin-2-yl)oxy)acetic acid (1.0 equiv., 34.2 mg, 0.200 mmol), DIPEA (3.0 equiv., 105 μl, 0.599 mmol), and HATU (2.0 equiv., 152 mg, 0.399 mmol). The reaction mixture was stirred at room temperature overnight, and the mixture was diluted with EtOAc. The organic phase was washed three times with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was suspended in a minimum amount of ethyl acetate and treated with hexane. The formed precipitate was collected by filtration to obtain 58 mg (77%) of an ivory-colored solid product.

1H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 8.10 (d, J = 3.1 Hz, 1H), 7.74 - 7.69 (m, 1H), 6.97 - 6.94 (m, 1H), 6.78 (t, J = 5.7 Hz, 1H), 4.62 (s, 2H), 4.11 - 3.98 (m, 1H), 2.92 (t, J = 6.3 Hz, 2H), 2.22 - 2.15 (m, 2H), 2.02 - 1.93 (m, 1H), 1.63 - 1.55 (m, 2H), 1.37 (s, 9H). 1H NMR (400 MHz, DMSO-d 6 ) δ 8.16 (s, 1H), 8.10 (d, J = 3.1 Hz, 1H), 7.74 - 7.69 (m, 1H), 6.97 - 6.94 (m, 1H), 6.78 (t, J = 5.7 Hz, 1H), 4.62 (s, 2H), 4.11 - 3.98 (m, 1H), 2.92 (t, J = 6.3 Hz, 2H), 2.22 - 2.15 (m, 2H), 2.02 - 1.93 (m, 1H), 1.63 - 1.55 (m, 2H), 1.37 (s, 9H).

MS (ESI+) m/z calcd for C17H25FN3O4 [M + H]+ 354.16; found 354.15.MS (ESI + ) m/z calcd for C 17 H 25 FN 3 O 4 [M + H] + 354.16; found 354.15.

터트-부틸 ((3-(2-((5-플루오로피리딘-2-일)옥시)아세트아미도)사이클로부틸)메틸)카르바메이트[tert-butyl ((3-(2-((5-fluoropyridin-2-yl)oxy)acetamido)cyclobutyl)methyl)carbamate] (1.0 equiv., 30 mg, 0.085 mmol) 교반된 용액을 실온에서 20% TFA/DCM (71 μl / 354 μl)로 희석시켰다. 3시간 동안 교반한 후, 반응 혼합물을 추가 정제없이 증발시켰다.tert-butyl ((3-(2-(( 5 -fluoropyridin-2-yl)oxy)acetamido)cyclobutyl)methyl)carbamate] (1.0 equiv., 30 mg, 0.085 mmol) The stirred solution was diluted with 20% TFA/DCM (71 μl/354 μl) at room temperature. After stirring for 3 h, the reaction mixture was evaporated without further purification.

DMF (424 μl) 내 N-(3-(아미노메틸)사이클로부틸)-2-((5-플루오로피리딘-2-일)옥시)아세트아마이드[N-(3-(aminomethyl)cyclobutyl)-2-((5-fluoropyridin-2-yl)oxy)acetamide] (1.0 equiv., 22 mg, 0.085 mmol) 교반된 용액에 2-((5-플루오로피리딘-2-일)옥시)아세트산 (1.1 equiv., 15 mg, 0.085 mmol), DIPEA (3.0 equiv., 45 μl, 0.255 mmol) 및 HATU (2.0 equiv., 64.6 mg, 0.170 mmol)를 첨가하였다. 반응 혼합물을 실온에서 밤새 교반하고, 혼합물을 EtOAc로 희석시켰다. 유기 상을 염수로 3차례 세척한 다음, 황산 마그네슘으로 건조시키고, 감압 하에서 여과 및 농축시켰다. 잔류물을 최소량의 에틸 아세테이트에 현탁시키고 헥산을 처리하였다. 형성된 침전물을 여과로 모아, 베이지색 고체의 화합물 30 (EIF-030) 28 mg (78%)을 수득하였다.To a stirred solution of N -(3-(aminomethyl)cyclobutyl)-2-((5-fluoropyridin-2-yl)oxy)acetamide [ N -(3-(aminomethyl)cyclobutyl)-2-((5-fluoropyridin-2-yl)oxy)acetamide] (1.0 equiv., 22 mg, 0.085 mmol) in DMF (424 μl) were added 2-((5-fluoropyridin-2-yl)oxy)acetic acid (1.1 equiv., 15 mg, 0.085 mmol), DIPEA (3.0 equiv., 45 μl, 0.255 mmol), and HATU (2.0 equiv., 64.6 mg, 0.170 mmol). The reaction mixture was stirred at room temperature overnight, and the mixture was diluted with EtOAc. The organic phase was washed three times with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was suspended in a minimal amount of ethyl acetate and treated with hexane. The formed precipitate was collected by filtration, yielding 28 mg (78%) of compound 30 (EIF-030) as a beige solid.

2-((5-플루오로피리딘-2-일)옥시)-N-((3-(2-((5-플루오로피리딘-2-일)옥시)아세트아미도)사이클로부틸)메틸)아세트아마이드[2-((5-fluoropyridin-2-yl)oxy)-N-((3-(2-((5-fluoropyridin-2-yl)oxy)acetamido)cyclobutyl)methyl)acetamide]2-((5-fluoropyridin-2-yl)oxy)-N-((3-(2-((5-fluoropyridin-2-yl)oxy)acetamido)cyclobutyl)methyl)acetamide

1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 7.8 Hz, 1H), 8.10 - 8.09 (m, 2H), 7.98 (t, J = 5.9 Hz, 1H), 7.74 - 7.69 (m, 2H), 6.97 - 6.74 (m, 2H), 4.66 (s, 2H), 4.62 (s, 2H), 4.09 - 3.99 (m, 1H), 3.09 (t, J = 6.3 Hz, 2H), 2.20 - 2.13 (m, 2H), 2.08 - 1.96 (m, 1H), 1.64 - 1.57 (m, 2H). 1H NMR (400 MHz, DMSO-d 6 ) δ 8.15 (d, J = 7.8 Hz, 1H), 8.10 - 8.09 (m, 2H), 7.98 (t, J = 5.9 Hz, 1H), 7.74 - 7.69 (m, 2H), 6.97 - 6.74 (m, 2H), 4.66 (s, 2H), 4.62 (s, 2H), 4.09 - 3.99 (m, 1H), 3.09 (t, J = 6.3 Hz, 2H), 2.20 - 2.13 (m, 2H), 2.08 - 1.96 (m, 1H), 1.64 - 1.57 (m, 2H).

MS (ESI+) m/z calcd for C19H21F2N4O4 [M + H]+ - 407.15; found 407.10.MS (ESI + ) m/z calcd for C 19 H 21 F 2 N 4 O 4 [M + H] + - 407.15; found 407.10.

HATU 커플링의 일반적인 절차General procedure for HATU coupling

DMF (0.2M) 내 카르복실산 (1.1 equiv.) 및 N-(3-아미노바이사이클로[1.1.1]펜탄-1-일)-2-(4-클로로-3-플루오로페녹시)아세트아마이드 TFA 염[N-(3-aminobicyclo[1.1.1]pentan-1-yl)-2-(4-chloro-3-fluorophenoxy)acetamide TFA salt] (1.0 equiv.) 교반 용액에 HATU (1.5 equiv.) 및 DIPEA (4.0 equiv.)를 주변 온도에서 첨가하였다. 17시간 동안 교반한 후에, 반응 혼합물을 H2O로 퀀칭하고 EtOAc로 희석하였다. 유기 층을 증류수로 세척하고 Na2SO4로 건조시켰다. 조 생성물을 진공에서 농축하고 플래시 컬럼 크로마토그래피로 정제하였다 (EIF-032, 33, 38-47).To a stirred solution of carboxylic acid (1.1 equiv.) and N -(3-aminobicyclo[1.1.1] pentan -1-yl)-2-(4-chloro-3-fluorophenoxy)acetamide TFA salt] (1.0 equiv.) in DMF (0.2 M) were added HATU (1.5 equiv.) and DIPEA (4.0 equiv.) at ambient temperature. After stirring for 17 h, the reaction mixture was quenched with H 2 O and diluted with EtOAc. The organic layer was washed with distilled water and dried over Na 2 SO 4 . The crude product was concentrated in vacuo and purified by flash column chromatography (EIF-032, 33, 38-47).

화합물 32 (EIF-032):Compound 32 (EIF-032):

DMF (0.2M, 12.6 ml) 내 2-(4-클로로-3-플루오로페녹시)아세트산[2-(4-chloro-3-fluorophenoxy)acetic acid] (1.1 equiv., 568 mg, 2.77 mmol) 및 터트-부틸 (3-아미노바이사이클로[1.1.1]펜탄-1-일)카르바메이트[tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate] (1.0 equiv., 500 mg, 2.52 mmol)의 교반된 용액에 주변 온도에서 HATU (2.0 equiv., 1.92 g, 5.04 mmol) 및 DIPEA (3.0 equiv., 1.32 ml, 7.57 mmol)를 첨가하였다. 17시간 동안 교반한 후에, 반응 혼합물을 H2O로 퀀칭하고 EtOAc로 희석하였다. 유기 층을 증류수로 세척하고 Na2SO4로 건조시켰다. 잔류물을 여과 (EtOAc/n-Hexane)로 정제하고 건조시켜, 담갈색 고체의 생성물 869 mg (90%)을 수득하였다.To a stirred solution of 2-(4-chloro-3-fluorophenoxy)acetic acid (1.1 equiv., 568 mg, 2.77 mmol) and tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate ( 1.0 equiv., 500 mg, 2.52 mmol) in DMF (0.2 M, 12.6 ml) at ambient temperature was added HATU (2.0 equiv., 1.92 g, 5.04 mmol) and DIPEA (3.0 equiv., 1.32 ml, 7.57 mmol). After stirring for 17 h, the reaction mixture was quenched with H 2 O and diluted with EtOAc. The organic layer was washed with distilled water and dried over Na 2 SO 4 . The residue was purified by filtration (EtOAc/ n -Hexane) and dried to give 869 mg (90%) of the product as a light brown solid.

1H NMR (DMSO-d6, 400 MHz) δ 8.69 (s, 1H), 7.55 (s, 1H), 7.49 (t, J = 8.9 Hz, 1H), 7.07 (dd, J = 11.4, 2.9 Hz, 1H), 6.84 (ddd, J = 9.0, 2.9, 1.2 Hz, 1H), 4.46 (s, 2H), 2.13 (s, 6H), 1.37 (s, 9H). 1H NMR (DMSO-d 6 , 400 MHz) δ 8.69 (s, 1H), 7.55 (s, 1H), 7.49 (t, J = 8.9 Hz, 1H), 7.07 (dd, J = 11.4, 2.9 Hz, 1H), 6.84 (ddd, J = 9.0, 2.9, 1.2 Hz, 1H), 4.46 (s, 2H), 2.13 (s, 6H), 1.37 (s, 9H).

DCM (1.08 μl) 내 터트-부틸 (3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)바이사이클로[1.1.1]펜탄-1-일)카르바메이트[tert-butyl (3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)carbamate] (1.0 equiv., 100 mg, 0.26 mmol) 교반 용액에 주변 온도에서 TFA (217 μl)를 첨가하였다. 4시간 동안 교반한 후, 반응 혼합물을 추가 정제없이 증발시켰다. To a stirred solution of tert-butyl (3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1] pentan -1-yl)carbamate] (1.0 equiv., 100 mg, 0.26 mmol) in DCM (1.08 μl) at ambient temperature was added TFA (217 μl). After stirring for 4 h, the reaction mixture was evaporated without further purification.

일반적인 절차를 통해 3-(4-클로로페닐)프로피올산 (14.1 mg, 0.078 mmol) 및 N-(3-아미노바이사이클로[1.1.1]펜탄-1-일)-2-(4-클로로-3-플루오로페녹시)아세트아마이드 TFA 염 (31.1 mg, 0.078 mmol)을 반응시킨 후, 여과 (EtOAc/n-Hexane)하여 아이보리 고체의 화합물 32 (EIF-032) 13.7 mg (39%)을 수득하였다.3-(4-Chlorophenyl)propiolic acid (14.1 mg, 0.078 mmol) and N -(3-aminobicyclo[1.1.1]pentan-1-yl)-2-(4-chloro-3-fluorophenoxy)acetamide TFA salt (31.1 mg, 0.078 mmol) were reacted by a general procedure, followed by filtration (EtOAc/ n -Hexane) to give 13.7 mg (39%) of compound 32 (EIF-032) as an ivory solid.

N-(3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)바이사이클로[1.1.1]펜탄-1-일)-3-(4-클로로페닐)프로피올아마이드[N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(4-chlorophenyl)propiolamide]N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(4-chlorophenyl)propiolamide

1H NMR (DMSO-d6, 400 MHz) δ 9.44 (s, 1H), 8.76 (s, 1H), 7.60 - 7.48 (m, 5H), 7.08 (dd, J = 11.4, 2.9 Hz, 1H), 6.85 (ddd, J = 9.0, 2.9, 1.2 Hz, 1H), 4.48 (s, 2H), 2.26 (s, 6H). 1H NMR (DMSO-d 6 , 400 MHz) δ 9.44 (s, 1H), 8.76 (s, 1H), 7.60 - 7.48 (m, 5H), 7.08 (dd, J = 11.4, 2.9 Hz, 1H), 6.85 (ddd, J = 9.0, 2.9, 1.2 Hz, 1H), 4.48 (s, 2H), 2.26 (s, 6H).

MS (ESI+) m/z calcd for C22H17Cl2FN2O3 [M + H]+ 447.06; found 447.13.MS (ESI + ) m/z calcd for C 22 H 17 Cl 2 FN 2 O 3 [M + H] + 447.06; found 447.13.

화합물 33 (EIF-033):Compound 33 (EIF-033):

일반적인 절차를 통해 3-페닐프로피올산[3-phenylpropiolic acid] (11.4 mg, 0.078 mmol) 및 N-(3-아미노바이사이클로[1.1.1]펜탄-1-일)-2-(4-클로로-3-플루오로페녹시)아세트아마이드 TFA 염 (31.1 mg, 0.078 mmol)을 반응시킨 후, 여과 (EtOAc/n-Hexane = 1:1)하여 백색 고체의 화합물 33 (EIF-033) 15.1 mg (47%)을 수득하였다.3-phenylpropiolic acid (11.4 mg, 0.078 mmol) and N -(3-aminobicyclo[1.1.1]pentan-1-yl)-2-(4-chloro-3-fluorophenoxy)acetamide TFA salt (31.1 mg, 0.078 mmol) were reacted using a general procedure, followed by filtration (EtOAc/ n -Hexane = 1:1) to obtain 15.1 mg (47%) of compound 33 (EIF-033) as a white solid.

N-(3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)바이사이클로[1.1.1]펜탄-1-일)-3-페닐프로피올아마이드[N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-phenylpropiolamide]N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-phenylpropiolamide

1H NMR (DMSO-d6, 400 MHz) δ 9.42 (s, 1H), 8.77 (s, 1H), 7.58 - 7.44 (m, 6H), 7.08 (dd, J = 11.4, 2.9 Hz, 1H), 6.85 (ddd, J = 8.9, 2.8, 1.2 Hz, 1H), 4.49 (s, 2H), 2.26 (s, 6H). 1H NMR (DMSO-d 6 , 400 MHz) δ 9.42 (s, 1H), 8.77 (s, 1H), 7.58 - 7.44 (m, 6H), 7.08 (dd, J = 11.4, 2.9 Hz, 1H), 6.85 (ddd, J = 8.9, 2.8, 1.2 Hz, 1H), 4.49 (s, 2H), 2.26 (s, 6H).

MS (ESI+) m/z calcd for C22H18ClFN2O3FN2O3 [M + H]+ 413.10; found 413.16.MS (ESI + ) m/z calcd for C 22 H 18 ClFN 2 O 3 FN 2 O 3 [M + H] + 413.10; found 413.16.

화합물 34 (EIF-034):Compound 34 (EIF-034):

DMF (1.0 ml) 내 터트-부틸 (3-(아미노메틸)사이클로펜틸)카르바메이트[tert-butyl (3-(aminomethyl)cyclopentyl)carbamate] (1.0 equiv., 40 mg, 0.200 mmol)의 교반 용액에 2-((5-플루오로피리딘-2-일)옥시)아세트산 (1.1 equiv., 35.1 mg, 0.205 mmol), DIPEA (3.0 equiv., 98 μl, 0.560 mmol) 및 HATU (2.0 equiv., 142 mg, 0.373mmol)를 첨가하였다. 반응 혼합물을 실온에서 밤새 교반하고, 혼합물을 EtOAc로 희석하였다. 유기 상을 염수로 3차례 세척한 다음, 황산 마그네슘으로 건조시키고 감압 하에서 여과 및 농축시켰다. 잔류물을 최소량의 에틸 아세테이트에 현탁시키고 헥산을 처리하였다. 형성된 침전물을 여과하여 모아 진 노랑색 고체의 생성물 46 mg (67%)을 수득하였다.tert-butyl (3-(aminomethyl)cyclopentyl)carbamate [ tert -butyl (3-(aminomethyl)cyclopentyl)carbamate] in DMF (1.0 ml) To a stirred solution of (1.0 equiv., 40 mg, 0.200 mmol) were added 2-((5-fluoropyridin-2-yl)oxy)acetic acid (1.1 equiv., 35.1 mg, 0.205 mmol), DIPEA (3.0 equiv., 98 μl, 0.560 mmol) and HATU (2.0 equiv., 142 mg, 0.373 mmol). The reaction mixture was stirred at room temperature overnight, and the mixture was diluted with EtOAc. The organic phase was washed three times with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was suspended in a minimum amount of ethyl acetate and treated with hexane. The formed precipitate was filtered to give 46 mg (67%) of the product as a yellow solid.

1H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J = 7.7 Hz, 1H), 7.57 - 7.54 (m, 1H), 7.43 - 7.38 (m, 1H), 6.82 (t, J = 6.0 Hz, 1H), 6.39 - 6.29 (m, 1H), 6.18 (td, J = 6.7, 1.4 Hz, 1H), 4.45 (s, 2H), 4.00 (h, J = 8.2 Hz, 1H), 2.92 (t, J = 6.3 Hz, 2H), 2.24 - 2.17 (m, 2H), 2.02 - 1.93 (m, 1H), 1.60 - 1.52 (m, 2H), 1.38 (s, 9H). 1H NMR (400 MHz, DMSO-d 6 ) δ 8.37 (d, J = 7.7 Hz, 1H), 7.57 - 7.54 (m, 1H), 7.43 - 7.38 (m, 1H), 6.82 (t, J = 6.0 Hz, 1H), 6.39 - 6.29 (m, 1H), 6.18 (td, J = 6.7, 1.4 Hz, 1H), 4.45 (s, 2H), 4.00 (h, J = 8.2 Hz, 1H), 2.92 (t, J = 6.3 Hz, 2H), 2.24 - 2.17 (m, 2H), 2.02 - 1.93 (m, 1H), 1.60 - 1.52 (m, 2H), 1.38 (s, 9H).

터트-부틸 (3-((2-((5-플루오로피리딘-2-일)옥시)아세트아미도)메틸)사이클로펜틸)카르바메이트[tert-butyl (3-((2-((5-fluoropyridin-2-yl)oxy)acetamido)methyl)cyclopentyl)carbamate] (1.0 equiv., 30 mg, 0.082 mmol)의 교반된 용액을 실온에서 20% TFA/DCM (68 μl/ 340 μl)로 희석시켰다. 3시간 동안 교반한 후, 반응 혼합물을 추가 정제없이 증발시켰다. tert-butyl (3-((2-((5-fluoropyridin-2-yl)oxy) acetamido )methyl)cyclopentyl)carbamate] (1.0 equiv., 30 mg, 0.082 mmol) was diluted with 20% TFA/DCM (68 μl/ 340 μl) at room temperature. After stirring for 3 h, the reaction mixture was evaporated without further purification.

DMF (374 μl) 내 N-((3-아미노사이클로펜틸)메틸)-2-((5-플루오로피리딘-2-일)옥시)아세트아마이드[N-((3-aminocyclopentyl)methyl)-2-((5-fluoropyridin-2-yl)oxy)acetamide] (1.0 equiv., 20 mg, 0.075 mmol)의 교반 용액에 2-((5-플루오로피리딘-2-일)옥시)아세트산 (1.1 equiv., 14 mg, 0.082 mmol), DIPEA (3.0 equiv., 39 μl, 0.224 mmol) 및 HATU (2.0 equiv., 56.9 mg, 0.150 mmol)를 첨가하였다. 반응 혼합물을 실온에서 밤새 교반하고, 혼합물을 EtOAc로 희석시켰다. 유기 상을 염수로 3차례 세척한 다음, 황산 마그네슘으로 건조시키고, 감압 하에서 여과 및 농축시켰다. 잔류물을 최소량의 에틸 아세테이트에 현탁시키고 헥산을 처리하였다. 형성된 침전물을 여과를 통해 모아 진 노랑색 고체의 화합물 34 (EIF-034) 23 mg (74%)을 수득하였다.To a stirred solution of N -((3-aminocyclopentyl)methyl)-2-((5-fluoropyridin-2-yl)oxy)acetamide [ N -((3-aminocyclopentyl)methyl)-2-((5-fluoropyridin-2-yl)oxy)acetamide] (1.0 equiv., 20 mg, 0.075 mmol) in DMF (374 μl) was added 2-((5-fluoropyridin-2-yl)oxy)acetic acid (1.1 equiv., 14 mg, 0.082 mmol), DIPEA (3.0 equiv., 39 μl, 0.224 mmol), and HATU (2.0 equiv., 56.9 mg, 0.150 mmol). The reaction mixture was stirred at room temperature overnight, and the mixture was diluted with EtOAc. The organic phase was washed three times with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was suspended in a minimal amount of ethyl acetate and treated with hexane. The formed precipitate was collected by filtration to yield 23 mg (74%) of compound 34 (EIF-034) as a yellow solid.

2-((5-플루오로피리딘-2-일)옥시)-N-((3-(2-((5-플루오로피리딘-2-일)옥시)아세트아미도)사이클로펜틸)메틸)아세트아마이드[2-((5-fluoropyridin-2-yl)oxy)-N-((3-(2-((5-fluoropyridin-2-yl)oxy)acetamido)cyclopentyl)methyl)acetamide]2-((5-fluoropyridin-2-yl)oxy)-N-((3-(2-((5-fluoropyridin-2-yl)oxy)acetamido)cyclopentyl)methyl)acetamide

1H NMR (400 MHz, DMSO-d6) δ 8.10 (d, J = 3.5 Hz, 2H), 8.04 (t, J = 5.8 Hz, 1H), 7.98 (d, J = 7.5 Hz, 1H), 7.74 - 7.68 (m, 2H), 6.97 - 6.93 (m, 2H), 4.65 (d, J = 13.5 Hz, 4H), 4.04 - 3.94 (m, 1H), 3.05 (t, J = 6.4 Hz, 2H), 2.02 - 1.90 (m, 2H), 1.81 - 1.73 (m, 1H), 1.61 - 1.52 (m, 1H), 1.46 - 1.37 (m, 1H), 1.34 - 1.25 (m, 1H), 1.08 - 1.01 (m, 1H). 1H NMR (400 MHz, DMSO-d 6 ) δ 8.10 (d, J = 3.5 Hz, 2H), 8.04 (t, J = 5.8 Hz, 1H), 7.98 (d, J = 7.5 Hz, 1H), 7.74 - 7.68 (m, 2H), 6.97 - 6.93 (m, 2H), 4.65 (d, J = 13.5 Hz, 4H), 4.04 - 3.94 (m, 1H), 3.05 (t, J = 6.4 Hz, 2H), 2.02 - 1.90 (m, 2H), 1.81 - 1.73 (m, 1H), 1.61 - 1.52 (m, 1H), 1.46 - 1.37 (m, 1H), 1.34 - 1.25 (m, 1H), 1.08 - 1.01 (m, 1H).

MS (ESI+) m/z calcd for C20H23F2N4O4 [M + H]+ - 421.16; found 421.05.MS (ESI + ) m/z calcd for C 20 H 23 F 2 N 4 O 4 [M + H] + - 421.16; found 421.05.

화합물 35 (EIF-035):Compound 35 (EIF-035):

DMF (1.0 ml) 내 터트-부틸 (3-(아미노메틸)사이클로펜틸)카르바메이트 (1.0 equiv., 40 mg, 0.200 mmol) 교반된 용액에 3-(4-클로로페닐)프로피올산 (1.1 equiv., 37.1 mg, 0.205 mmol), DIPEA (3.0 equiv., 98 μl, 0.560 mmol) 및 HATU (2.0 equiv., 142 mg, 0.373 mmol)를 첨가하였다. 반응 혼합물을 실온에서 밤새 교반하였다. 혼합물을 EtOAc로 희석시키고 나서 유기 상을 염수로 3차례 세척하고, 황산 마그네슘으로 건조시킨 다음, 감압 하에서 여과 및 농축시켰다. 잔류물을 최소량의 에틸 아세테이트에 현탁시키고 헥산을 처리하였다. 형성된 침전물을 여과하여 모아 아이보리색 고체의 생성물 23 mg (33%)을 수득하였다.To a stirred solution of tert-butyl (3-(aminomethyl)cyclopentyl)carbamate (1.0 equiv., 40 mg, 0.200 mmol) in DMF (1.0 ml) were added 3-(4-chlorophenyl)propiolic acid (1.1 equiv., 37.1 mg, 0.205 mmol), DIPEA (3.0 equiv., 98 μl, 0.560 mmol), and HATU (2.0 equiv., 142 mg, 0.373 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, and the organic phase was washed three times with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was suspended in a minimum amount of ethyl acetate and treated with hexane. The formed precipitate was collected by filtration to obtain 23 mg (33%) of the product as an ivory-colored solid.

1H NMR (400 MHz, DMSO-d6) δ 8.85 (t, J = 5.8 Hz, 1H), 7.63 - 7.57 (m, 2H), 7.57 - 7.50 (m, 2H), 6.87 (d, J = 7.5 Hz, 1H), 3.71 (q, J = 7.5 Hz, 1H), 3.14 - 3.04 (m, 2H), 2.03 - 1.95 (m, 2H), 1.78 - 1.70 (m, 1H), 1.65 - 1.56 (m, 1H), 1.44 - 1.39 (m, 1H), 1.37 (s, 9H), 1.33 - 1.26 (m, 1H), 1.05 - 0.97 (m, 1H). 1H NMR (400 MHz, DMSO-d 6 ) δ 8.85 (t, J = 5.8 Hz, 1H), 7.63 - 7.57 (m, 2H), 7.57 - 7.50 (m, 2H), 6.87 (d, J = 7.5 Hz, 1H), 3.71 (q, J = 7.5) Hz, 1H), 3.14 - 3.04 (m, 2H), 2.03 - 1.95 (m, 2H), 1.78 - 1.70 (m, 1H), 1.65 - 1.56 (m, 1H), 1.44 - 1.39 (m, 1H), 1.37 (s, 9H), 1.33 - 1.26 (m, 1H), 1.05 - 0.97 (m, 1H).

터트-부틸 (3-((3-(4-클로로페닐)프로피올아미도)메틸)사이클로펜틸)카르바메이트[tert-butyl (3-((3-(4-chlorophenyl)propiolamido)methyl)cyclopentyl)carbamate] (20 mg, 0.053 mmol) 교반 용액을 실온에서 20% TFA/DCM (44 μl/ 221 μl)로 희석시켰다. 3시간 동안 교반한 후, 반응 혼합물을 추가 정제없이 증발시켰다. A stirred solution of tert -butyl (3-((3-(4-chlorophenyl)propiolamido)methyl)cyclopentyl)carbamate (20 mg, 0.053 mmol) was diluted with 20% TFA/DCM (44 μl/ 221 μl) at room temperature. After stirring for 3 h, the reaction mixture was evaporated without further purification.

DMF (265 μl) 내 N-((3-아미노사이클로펜틸)메틸)-3-(4-클로로페닐)프로피올아마이드[N-((3-aminocyclopentyl)methyl)-3-(4-chlorophenyl)propiolamide (1.0 equiv., 15 mg, 0.053 mmol)의 교반 용액에 3-(4-클로로페닐)프로피올산 (1.1 equiv., 10.5 mg, 0.058 mmol), DIPEA (3.0 equiv., 28 μl, 0.159 mmol) 및 HATU (2.0 equiv., 40.4 mg, 0.106 mmol)를 첨가하였다. 반응 혼합물을 실온에서 밤새 교반하였다. 혼합물을 EtOAc로 희석하고, 유기 상을 염수로 3차례 세척한 다음, 황산 마그네슘으로 건조시키고 감압 하에서 여과 및 농축시켰다. 잔류물을 최소량의 에틸 아세테이트에 현탁시키고 헥산을 처리하였다. 형성된 침전물을 여과하여 모아 베이지색 고체의 화합물 35 (EIF-035) 15 mg (64%)을 수득하였다. N -((3-aminocyclopentyl)methyl)-3-(4-chlorophenyl)propiolamide [ N -((3-aminocyclopentyl)methyl)-3-(4-chlorophenyl)propiolamide in DMF (265 μl) To a stirred solution of (1.0 equiv., 15 mg, 0.053 mmol) were added 3-(4-chlorophenyl)propiolic acid (1.1 equiv., 10.5 mg, 0.058 mmol), DIPEA (3.0 equiv., 28 μl, 0.159 mmol), and HATU (2.0 equiv., 40.4 mg, 0.106 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, and the organic phase was washed three times with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was suspended in a minimum amount of ethyl acetate and treated with hexane. The formed precipitate was collected by filtration to give 15 mg (64%) of compound 35 (EIF-035) as a beige solid.

3-(4-클로로페닐)-N-((3-(3-(4-클로로페닐)프로피올아미도)사이클로펜틸)메틸)프로피올아마이드[3-(4-chlorophenyl)-N-((3-(3-(4-chlorophenyl)propiolamido)cyclopentyl)methyl)propiolamide]3-(4-chlorophenyl)-N-((3-(3-(4-chlorophenyl)propiolamido)cyclopentyl)methyl)propiolamide

1H NMR (400 MHz, DMSO-d6) δ 8.89 (t, J = 7.2 Hz, 2H), 7.59 (dd, J = 8.6, 3.1 Hz, 4H), 7.56 - 7.49 (m, 4H), 4.05 (p, J = 7.3 Hz, 1H), 3.16 - 3.11 (m, 2H), 2.11 - 2.01 (m, 2H), 1.87 - 1.79 (m, 1H), 1.71 - 1.63 (m, 1H), 1.53 - 1.45 (m, 1H), 1.41 - 1.33 (m, 1H), 1.19 - 1.07 (m, 1H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.89 (t, J = 7.2 Hz, 2H), 7.59 (dd, J = 8.6, 3.1 Hz, 4H), 7.56 - 7.49 (m, 4H), 4.05 (p, J = 7.3 Hz, 1H), 3.16 - 3.11 (m, 2H), 2.11 - 2.01 (m, 2H), 1.87 - 1.79 (m, 1H), 1.71 - 1.63 (m, 1H), 1.53 - 1.45 (m, 1H), 1.41 - 1.33 (m, 1H), 1.19 - 1.07 (m, 1H).

MS (ESI+) m/z calcd for C24H21Cl2N2O2 [M + H]+ - 439.09; found 439.15.MS (ESI + ) m/z calcd for C 24 H 21 Cl 2 N 2 O 2 [M + H] + - 439.09; found439.15.

화합물 36 (EIF-036):Compound 36 (EIF-036):

DMF (1.0 ml) 내 터트-부틸 (3-아미노사이클로부틸)카르바메이트 (1.0 equiv., 40 mg, 0.215 mmol)의 교반 용액에 3-(4-클로로페닐)프로피올산 (1.1 equiv., 42.7 mg, 0.236 mmol), DIPEA (3.0 equiv., 113 μl, 0.644 mmol) 및 HATU (1.5 equiv., 122 mg, 0.322 mmol)를 첨가하였다. 반응 혼합물을 실온에서 밤새 교반하였다. 혼합물을 EtOAc로 희석하고, 유기 상을 염수로 3차례 세척한 다음, 황산 마그네슘으로 건조시키고 감압 하에서 여과 및 농축시켰다. 잔류물을 최소량의 에틸 아세테이트에 현탁시키고 헥산을 처리하였다. 형성된 침전물을 여과하여 모아 아이보리색 고체 생성물 60 mg (80%)을 수득하였다.To a stirred solution of tert-butyl (3-aminocyclobutyl)carbamate (1.0 equiv., 40 mg, 0.215 mmol) in DMF (1.0 ml) were added 3-(4-chlorophenyl)propiolic acid (1.1 equiv., 42.7 mg, 0.236 mmol), DIPEA (3.0 equiv., 113 μl, 0.644 mmol), and HATU (1.5 equiv., 122 mg, 0.322 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, and the organic phase was washed three times with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was suspended in a minimum amount of ethyl acetate and treated with hexane. The formed precipitate was collected by filtration to give 60 mg (80%) of the product as an ivory solid.

1H NMR (400 MHz, DMSO-d6) δ 9.09 (d, J = 7.0 Hz, 1H), 7.59 - 7.58 (m, 2H), 7.56 - 7.52 (m, 2H), 7.20 (d, J = 7.7 Hz, 1H), 3.83 (h, J = 7.9 Hz, 1H), 3.63 (q, J = 8.1 Hz, 1H), 2.50 - 2.43 (m, 2H), 1.87 - 1.80 (m, 2H), 1.37 (s, 9H). 1H NMR (400 MHz, DMSO-d 6 ) δ 9.09 (d, J = 7.0 Hz, 1H), 7.59 - 7.58 (m, 2H), 7.56 - 7.52 (m, 2H), 7.20 (d, J = 7.7 Hz, 1H), 3.83 (h, J = 7.9) Hz, 1H), 3.63 (q, J = 8.1 Hz, 1H), 2.50 - 2.43 (m, 2H), 1.87 - 1.80 (m, 2H), 1.37 (s, 9H).

터트-부틸 (3-(3-(4-클로로페닐)프로피올아미도)사이클로부틸)카바메이트[tert-butyl (3-(3-(4-chlorophenyl)propiolamido)cyclobutyl)carbamate] (1.0 equiv., 30 mg, 0.086 mmol)의 교반 용액을 실온에서 20% TFA/DCM (72 μl/ 358 μl)로 희석시켰다. 5시간 동안 교반한 후, 반응 혼합물을 추가 정제없이 증발시켰다.A stirred solution of tert -butyl (3-(3-(4-chlorophenyl)propiolamido)cyclobutyl)carbamate (1.0 equiv., 30 mg, 0.086 mmol) was diluted with 20% TFA/DCM (72 μl/ 358 μl) at room temperature. After stirring for 5 h, the reaction mixture was evaporated without further purification.

DMF (505 μl) 내 N-(3-아미노사이클로부틸)-3-(4-클로로페닐)프로피올아마이드[N-(3-aminocyclobutyl)-3-(4-chlorophenyl)propiolamide] (1.0 equiv., 25 mg, 0.101 mmol)의 교반 용액에 3-(4-클로로페닐)프로피올산 (1.1 equiv., 20.1 mg, 0.111 mmol), DIPEA (3.0 equiv., 53 μl, 0.303 mmol) 및 HATU (2.0 equiv., 77 mg, 0.202 mmol)를 첨가하였다. 반응 혼합물을 실온에서 밤새 교반하였다. 혼합물을 EtOAc로 희석하고, 유기 상을 염수로 3차례 세척한 다음, 황산 마그네슘으로 건조시키고 감압 하에서 여과 및 농축시켰다. 잔류물을 최소량의 에틸 아세테이트에 현탁시키고 헥산을 처리하였다. 형성된 침전물을 여과하여 모아 아이보리색 고체 화합물 36 (EIF-036) 4.0 mg (9%)을 수득하였다. N -(3-aminocyclobutyl)-3-(4-chlorophenyl)propiolamide [ N -(3-aminocyclobutyl)-3-(4-chlorophenyl)propiolamide] in DMF (505 μl) To a stirred solution of (1.0 equiv., 25 mg, 0.101 mmol) were added 3-(4-chlorophenyl)propiolic acid (1.1 equiv., 20.1 mg, 0.111 mmol), DIPEA (3.0 equiv., 53 μl, 0.303 mmol), and HATU (2.0 equiv., 77 mg, 0.202 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, and the organic phase was washed three times with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was suspended in a minimum amount of ethyl acetate and treated with hexane. The formed precipitate was collected by filtration to give 4.0 mg (9%) of an ivory solid compound 36 (EIF-036) .

N,N'-(사이클로부탄-1,3-디일)비스(3-(4-클로로페닐)프로피올아마이드)[N,N'-(cyclobutane-1,3-diyl)bis(3-(4-chlorophenyl)propiolamide)]N,N'-(cyclobutane-1,3-diyl)bis(3-(4-chlorophenyl)propiolamide)

1H NMR (400 MHz, DMSO-d6) δ 9.26 (d, J = 7.1 Hz, 2H), 7.62 - 7.59 (m, 4H), 7.56 - 7.53 (m, 4H), 4.37 - 4.28 (m, 2H), 2.57 - 2.49 (m, 2H), 2.29 - 2.26 (m, 2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.26 (d, J = 7.1 Hz, 2H), 7.62 - 7.59 (m, 4H), 7.56 - 7.53 (m, 4H), 4.37 - 4.28 (m, 2H), 2.57 - 2.49 (m, 2H), 2.29 - 2.26 (m, 2H).

MS (ESI+) m/z calcd for C22H17Cl2N2O2 [M + H]+ - 411.06; found 411.12.MS (ESI + ) m/z calcd for C 22 H 17 Cl 2 N 2 O 2 [M + H] + - 411.06; found 411.12.

화합물 37 (EIF-037):Compound 37 (EIF-037):

DMF (1.0 ml) 내 터트-부틸 (3-아미노사이클로부틸)카르바메이트 (1.0 equiv., 50 mg, 0.215 mmol)의 교반 용액에 3-(4-클로로페닐)프로피올산 (1.1 equiv., 49.6 mg, 0.275 mmol), DIPEA (3.0 equiv., 131 μl, 0.749 mmol) 및 HATU (1.5 equiv., 142 mg, 0.374 mmol)을 첨가하였다. 반응 혼합물을 실온에서 밤새 교반하였다. 혼합물을 EtOAc로 희석하고, 유기 상을 염수로 3차례 세척한 다음, 황산 마그네슘으로 건조시키고 감압 하에서 여과 및 농축시켰다. 잔류물을 최소량의 에틸 아세테이트에 현탁시키고 헥산을 처리하였다. 형성된 침전물을 여과하여 모아 갈색 고체 생성물 80 mg (86%)을 수득하였다. To a stirred solution of tert-butyl (3-aminocyclobutyl)carbamate (1.0 equiv., 50 mg, 0.215 mmol) in DMF (1.0 ml) were added 3-(4-chlorophenyl)propiolic acid (1.1 equiv., 49.6 mg, 0.275 mmol), DIPEA (3.0 equiv., 131 μl, 0.749 mmol), and HATU (1.5 equiv., 142 mg, 0.374 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, and the organic phase was washed three times with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was suspended in a minimum amount of ethyl acetate and treated with hexane. The formed precipitate was collected by filtration to give 80 mg (86%) of the brown solid product.

1H NMR (400 MHz, DMSO-d6) δ 8.87 (t, J = 6.3 Hz, 1H), 7.59 (dd, J = 8.7, 2.3 Hz, 2H), 7.53 (dd, J = 8.5, 1.5 Hz, 2H), 6.92 (t, J = 7.5 Hz, 1H), 4.19 - 4.00 (m, 1H), 3.93 - 3.74 (m, 1H), 1.99 - 1.88 (m, 1H), 1.84 - 1.77 (m, 1H), 1.69 (t, J = 6.9 Hz, 1H), 1.56 - 1.48 (m, 1H), 1.38 (s, 9H), 1.28 - 1.19 (m, 2H). 1H NMR (400 MHz, DMSO-d 6 ) δ 8.87 (t, J = 6.3 Hz, 1H), 7.59 (dd, J = 8.7, 2.3 Hz, 2H), 7.53 (dd, J = 8.5, 1.5 Hz, 2H), 6.92 (t, J = 7.5 Hz, 1H), 4.19 - 4.00 (m, 1H), 3.93 - 3.74 (m, 1H), 1.99 - 1.88 (m, 1H), 1.84 - 1.77 (m, 1H), 1.69 (t, J = 6.9 Hz, 1H), 1.56 - 1.48 (m, 1H), 1.38 (s, 9H), 1.28 - 1.19 (m, 2H).

터트-부틸 (3-(3-(4-클로로페닐)프로피올아미도)사이클로펜틸)카바메이트[tert-butyl (3-(3-(4-chlorophenyl)propiolamido)cyclopentyl)carbamate] (1.0 equiv., 42 mg, 0.117 mmol)의 교반 용액을 실온에서 20% TFA/DCM (97 μl/ 486 μl)로 희석시켰다. 3시간 동안 교반한 후, 반응 혼합물을 추가 정제없이 증발시켰다.A stirred solution of tert -butyl (3-(3-(4-chlorophenyl)propiolamido)cyclopentyl)carbamate (1.0 equiv., 42 mg, 0.117 mmol) was diluted with 20% TFA/DCM (97 μl/ 486 μl) at room temperature. After stirring for 3 h, the reaction mixture was evaporated without further purification.

DMF (422 μl) 내 터트-부틸 (3-(3-(4-클로로페닐)프로피올아미도)사이클로펜틸)카르바메이트[tert-butyl (3-(3-(4-chlorophenyl)propiolamido)cyclopentyl)carbamate] (1.0 equiv., 30.6 mg, 0.084 mmol)의 교반 용액에 3-(4-클로로페닐)프로피올산 (1.1 equiv., 16.8 mg, 0.093 mmol), DIPEA (3.0 equiv., 44 μl, 0.253 mmol) 및 HATU (2.0 equiv., 64 mg, 0.169 mmol)를 첨가하였다. 반응 혼합물을 실온에서 밤새 교반하였다. 혼합물을 EtOAc로 희석하고, 유기 상을 염수로 3차례 세척한 다음, 황산 마그네슘으로 건조시키고 감압 하에서 여과 및 농축시켰다. 잔류물을 최소량의 에틸 아세테이트에 현탁시키고 헥산을 처리하였다. 형성된 침전물을 여과하여 모아 아이보리색 고체 화합물 37 (EIF-037) 21 mg (57%)을 수득하였다.To a stirred solution of tert -butyl (3-(3-(4-chlorophenyl)propiolamido)cyclopentyl)carbamate (1.0 equiv., 30.6 mg, 0.084 mmol) in DMF (422 μl) were added 3-(4-chlorophenyl)propiolic acid (1.1 equiv., 16.8 mg, 0.093 mmol), DIPEA (3.0 equiv., 44 μl, 0.253 mmol), and HATU (2.0 equiv., 64 mg, 0.169 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, and the organic phase was washed three times with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was suspended in a minimal amount of ethyl acetate and treated with hexane. The formed precipitate was collected by filtration to obtain 21 mg (57%) of ivory solid compound 37 (EIF-037) .

N,N'-(사이클로펜탄-1,3-디일)비스(3-(4-사이클로펜틸)프로피올아마이드)[N,N'-(cyclopentane-1,3-diyl)bis(3-(4-chlorophenyl)propiolamide)]N,N'-(cyclopentane-1,3-diyl)bis(3-(4-chlorophenyl)propiolamide)

1H NMR (400 MHz, DMSO-d6) δ 8.93 (t, J = 7.7 Hz, 2H), 7.61 - 7.57 (m, 4H), 7.55 - 7.51 (m, 4H), 4.28 - 4.01 (m, 2H), 2.05 - 1.97 (m, 1H), 1.91 - 1.84 (m, 1H), 1.78 (t, J = 6.8 Hz, 1H), 1.62 - 1.55 (m, 1H), 1.51 - 1.39 (m, 2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.93 (t, J = 7.7 Hz, 2H), 7.61 - 7.57 (m, 4H), 7.55 - 7.51 (m, 4H), 4.28 - 4.01 (m, 2H), 2.05 - 1.97 (m, 1H), 1.91 - 1.84 (m, 1H), 1.78 (t, J = 6.8 Hz, 1H), 1.62 - 1.55 (m, 1H), 1.51 - 1.39 (m, 2H).

MS (ESI+) m/z calcd for C23H19Cl2N2O2 [M + H]+ 425.07- ; found 425.17.MS (ESI + ) m/z calcd for C 23 H 19 Cl 2 N 2 O 2 [M + H] + 425.07 - ; found 425.17.

화합물 38 (EIF-038):Compound 38 (EIF-038):

일반적인 절차를 통해 3-(3-플루오로페닐)프로피올산[3-(3-fluorophenyl)propiolic acid] (12.8 mg, 0.078 mmol) 및 N-(3-아미노바이사이클로[1.1.1]펜탄-1-일)-2-(4-클로로-3-플루오로페녹시)아세트아마이드 TFA 염 (31.1 mg, 0.078 mmol)을 반응시킨 후, 컬럼 크로마토그래피 (EtOAc/n-Hexane = 1:1)를 수행하여 아이보리색 고체 화합물 38 (EIF-038) 22.6 mg (67%)을 수득하였다.3-(3-fluorophenyl)propiolic acid (12.8 mg, 0.078 mmol) and N -(3-aminobicyclo[1.1.1]pentan-1-yl)-2-(4-chloro-3-fluorophenoxy)acetamide TFA salt (31.1 mg, 0.078 mmol) were reacted through a general procedure, and then column chromatography (EtOAc/ n -Hexane = 1:1) was performed to obtain 22.6 mg (67%) of ivory solid compound 38 (EIF-038) .

N-(3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)바이사이클로[1.1.1]펜탄-1-일)-3-(3-플루오로페닐)프로피올아마이드[N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(3-fluorophenyl)propiolamide]N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(3-fluorophenyl)propiolamide

1H NMR (DMSO-d6, 400 MHz) δ 9.47 (s, 1H), 8.77 (s, 1H), 7.54 - 7.36 (m, 5H), 7.08 (dd, J = 11.4, 2.9 Hz, 1H), 6.85 (dd, J = 8.9, 2.8 Hz, 1H), 4.49 (s, 2H), 2.27 (s, 6H). 1 H NMR (DMSO-d 6 , 400 MHz) δ 9.47 (s, 1H), 8.77 (s, 1H), 7.54 - 7.36 (m, 5H), 7.08 (dd, J = 11.4, 2.9 Hz, 1H), 6.85 (dd, J = 8.9, 2.8 Hz, 1H), 4.49 (s, 2H), 2.27 (s, 6H).

MS (ESI+) m/z calcd for C22H17ClF2N2O3 [M + H]+ 431.09; found 431.22.MS (ESI + ) m/z calcd for C 22 H 17 ClF 2 N 2 O 3 [M + H] + 431.09; found 431.22.

화합물 39 (EIF-039):Compound 39 (EIF-039):

일반적인 절차를 통해 3-(p-톨릴)프로피올산[3-(p-tolyl)propiolic acid] (12.5 mg, 0.078 mmol) 및 N-(3-아미노바이사이클로[1.1.1]펜탄-1-일)-2-(4-클로로-3-플루오로페녹시)아세트아마이드 TFA 염 (31.1 mg, 0.078 mmol)을 반응시킨 후, 컬럼 크로마토그래피 (EtOAc/n-Hexane = 1:1)를 수행하여 아이보리색 고체 화합물 39 (EIF-039) 24.2 mg (72%)을 수득하였다.3-( p -tolyl ) propiolic acid (12.5 mg, 0.078 mmol) and N -(3-aminobicyclo[1.1.1]pentan-1-yl)-2-(4-chloro-3-fluorophenoxy)acetamide TFA salt (31.1 mg, 0.078 mmol) were reacted through a general procedure, and then column chromatography (EtOAc/ n -Hexane = 1:1) was performed to obtain 24.2 mg (72%) of ivory solid compound 39 (EIF-039) .

N-(3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)바이사이클로[1.1.1]펜탄-1-일)-3-(p-톨릴)프로피올아마이드[N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(p-tolyl)propiolamide]N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(p-tolyl)propiolamide

1H NMR (DMSO-d6, 400 MHz) δ 9.37 (s, 1H), 8.77 (s, 1H), 7.50 (t, J = 9.0 Hz, 1H), 7.45 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 7.07 (dd, J = 11.4, 2.8 Hz, 1H), 6.85 (ddd, J = 9.0, 2.9, 1.2 Hz, 1H), 4.48 (s, 2H), 2.34 (s, 3H), 2.26 (s, 6H). 1 H NMR (DMSO-d 6 , 400 MHz) δ 9.37 (s, 1H), 8.77 (s, 1H), 7.50 (t, J = 9.0 Hz, 1H), 7.45 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 7.07 (dd, J = 11.4, 2.8 Hz, 1H), 6.85 (ddd, J = 9.0, 2.9, 1.2 Hz, 1H), 4.48 (s, 2H), 2.34 (s, 3H), 2.26 (s, 6H).

MS (ESI+) m/z calcd for C23H20ClFN2O3 [M + H]+ 427.11; found 427.24.MS (ESI + ) m/z calcd for C 23 H 20 ClFN 2 O 3 [M + H] + 427.11; found 427.24.

화합물 40 (EIF-040):Compound 40 (EIF-040):

일반적인 절차를 통해 3-(2-플루오로페닐)프로피올산[3-(2-fluorophenyl) propiolic acid] (12.8 mg, 0.078 mmol) 및 N-(3-아미노바이사이클로[1.1.1]펜탄-1-일)-2-(4-클로로-3-플루오로페녹시)아세트아마이드 TFA 염 (31.1 mg, 0.078 mmol)을 반응시킨 후, 컬럼 크로마토그래피 (EtOAc/n-Hexane = 1:1)를 수행하여 백색 고체 화합물 40 (EIF-040) 24.2 mg (72%)을 수득하였다. 3-(2-fluorophenyl) propiolic acid (12.8 mg, 0.078 mmol) and N -(3-aminobicyclo[1.1.1]pentan-1-yl)-2-(4-chloro-3-fluorophenoxy)acetamide TFA salt (31.1 mg, 0.078 mmol) were reacted through a general procedure, and then column chromatography (EtOAc/ n -Hexane = 1:1) was performed to obtain 24.2 mg (72%) of white solid compound 40 (EIF-040) .

N-(3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)바이사이클로[1.1.1]펜탄-1-일)-3-(2-플루오로페닐)프로피올아마이드[N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(2-fluorophenyl)propiolamide]N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(2-fluorophenyl)propiolamide

1H NMR (DMSO-d6, 400 MHz) δ 9.50 (s, 1H), 8.76 (s, 1H), 7.63 (td, J = 7.5, 1.8 Hz, 1H), 7.57 (tdd, J = 7.5, 5.5, 1.7 Hz, 1H), 7.50 (t, J = 8.9 Hz, 1H), 7.38 (t, J = 9.2 Hz, 1H), 7.30 (td, J = 7.6, 1.0 Hz, 1H), 7.08 (dd, J = 11.4, 2.9 Hz, 1H), 6.85 (ddd, J = 8.9, 3.0, 1.2 Hz, 1H), 4.49 (s, 2H), 2.27 (s, 6H). 1H NMR (DMSO-d 6 , 400 MHz) δ 9.50 (s, 1H), 8.76 (s, 1H), 7.63 (td, J = 7.5, 1.8 Hz, 1H), 7.57 (tdd, J = 7.5, 5.5, 1.7 Hz, 1H), 7.50 (t, J = 8.9 Hz, 1H), 7.38 (t, J = 9.2 Hz, 1H), 7.30 (td, J = 7.6, 1.0 Hz, 1H), 7.08 (dd, J = 11.4, 2.9 Hz, 1H), 6.85 (ddd, J = 8.9, 3.0, 1.2 Hz, 1H), 4.49 (s, 2H), 2.27 (s, 6H).

MS (ESI+) m/z calcd for C22H17ClF2N2O3 [M + H]+ 431.09; found 431.17.MS (ESI + ) m/z calcd for C 22 H 17 ClF 2 N 2 O 3 [M + H] + 431.09; found431.17.

화합물 41 (EIF-041):Compound 41 (EIF-041):

일반적인 절차를 통해 3-(3-클로로페닐)프로피올산[3-(3-chlorophenyl)propiolic acid] (14.1 mg, 0.078 mmol) 및 N-(3-아미노바이사이클로[1.1.1]펜탄-1-일)-2-(4-클로로-3-플루오로페녹시)아세트아마이드 TFA 염 (31.1 mg, 0.078 mmol)을 반응시킨 후, 컬럼 크로마토그래피 (EtOAc/n-Hexane = 1:1)를 수행하여 백색 고체 화합물 41 (EIF-041) 23.4 mg (67%)을 수득하였다.3-(3-chlorophenyl)propiolic acid (14.1 mg, 0.078 mmol) and N -(3-aminobicyclo[1.1.1]pentan-1-yl)-2-(4-chloro-3-fluorophenoxy)acetamide TFA salt (31.1 mg, 0.078 mmol) were reacted through a general procedure, and then column chromatography (EtOAc/ n -Hexane = 1:1) was performed to obtain 23.4 mg (67%) of white solid compound 41 (EIF-041) .

N-(3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)바이사이클로[1.1.1]펜탄-1-일)-3-(3-클로로페닐)프로피올아마이드[N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(3-chlorophenyl)propiolamide]N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(3-chlorophenyl)propiolamide

1H NMR (DMSO-d6, 400 MHz) δ 9.46 (s, 1H), 8.76 (s, 1H), 7.65 (t, J = 1.9 Hz, 1H), 7.59 (ddd, J = 7.8, 2.2, 1.4 Hz, 1H), 7.54 (dt, J = 7.8, 1.4 Hz, 1H), 7.51 - 7.47 (m, 2H), 7.08 (dd, J = 11.4, 2.8 Hz, 1H), 6.85 (ddd, J = 9.0, 2.9, 1.2 Hz, 1H), 4.49 (s, 2H), 2.27 (s, 6H). 1H NMR (DMSO-d 6 , 400 MHz) δ 9.46 (s, 1H), 8.76 (s, 1H), 7.65 (t, J = 1.9 Hz, 1H), 7.59 (ddd, J = 7.8, 2.2, 1.4 Hz, 1H), 7.54 (dt, J = 7.8, 1.4 Hz, 1H), 7.51 - 7.47 (m, 2H), 7.08 (dd, J = 11.4, 2.8 Hz, 1H), 6.85 (ddd, J = 9.0, 2.9, 1.2 Hz, 1H), 4.49 (s, 2H), 2.27 (s, 6H).

MS (ESI+) m/z calcd for C22H17Cl2FN2O3 [M + H]+ 447.06; found 447.13.MS (ESI + ) m/z calcd for C 22 H 17 Cl 2 FN 2 O 3 [M + H] + 447.06; found 447.13.

화합물 42 (EIF-042):Compound 42 (EIF-042):

일반적인 절차를 통해 3-(4-(트리플루오로메틸)페닐)프로피올산[3-(4-(trifluoromethyl)phenyl)propiolic acid] (16.7 mg, 0.078 mmol) 및 N-(3-아미노바이사이클로[1.1.1]펜탄-1-일)-2-(4-클로로-3-플루오로페녹시)아세트아마이드 TFA 염 (31.1 mg, 0.078 mmol)을 반응시킨 후, 컬럼 크로마토그래피 (EtOAc/n-Hexane = 1:1)를 수행하여 아이보리색 고체 화합물 42 (EIF-042) 24.3 mg (65%)을 수득하였다.3-(4-(trifluoromethyl)phenyl)propiolic acid (16.7 mg, 0.078 mmol) and N -(3-aminobicyclo[1.1.1]pentan-1-yl)-2-(4-chloro-3-fluorophenoxy)acetamide TFA salt (31.1 mg, 0.078 mmol) were reacted through a general procedure, and then column chromatography (EtOAc/ n -Hexane = 1:1) was performed to obtain 24.3 mg (65%) of ivory solid compound 42 (EIF-042) .

N-(3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)바이사이클로[1.1.1]펜탄-1-일)-3-(4-(트리플루오로메틸)페닐)프로피올아마이드[N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(4-(trifluoromethyl)phenyl)propiolamide]N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(4-(trifluoromethyl)phenyl)propiolamide

1H NMR (DMSO-d6, 400 MHz) δ 9.54 (s, 1H), 8.77 (s, 1H), 7.84 (d, J = 8.2 Hz, 2H), 7.79 (d, J = 8.2 Hz, 2H), 7.50 (t, J = 8.9 Hz, 1H), 7.08 (dd, J = 11.3, 2.8 Hz, 1H), 6.85 (dd, J = 8.9, 2.9 Hz, 1H), 4.49 (s, 2H), 2.27 (s, 6H). 1H NMR (DMSO-d 6 , 400 MHz) δ 9.54 (s, 1H), 8.77 (s, 1H), 7.84 (d, J = 8.2 Hz, 2H), 7.79 (d, J = 8.2 Hz, 2H), 7.50 (t, J = 8.9 Hz, 1H), 7.08 (dd, J = 11.3, 2.8 Hz, 1H), 6.85 (dd, J = 8.9, 2.9 Hz, 1H), 4.49 (s, 2H), 2.27 (s, 6H).

MS (ESI+) m/z calcd for C23H17ClF4N2O3 [M + H]+ 481.09; found 481.21.MS (ESI + ) m/z calcd for C 23 H 17 ClF 4 N 2 O 3 [M + H] + 481.09; found 481.21.

화합물 43 (EIF-043):Compound 43 (EIF-043):

일반적인 절차를 통해 3-(4-플루오로페닐)프로피올산[3-(4-fluorophenyl)propiolic acid] (12.8 mg, 0.078 mmol) 및 N-(3-아미노바이사이클로[1.1.1]펜탄-1-일)-2-(4-클로로-3-플루오로페녹시)아세트아마이드 TFA 염 (31.1 mg, 0.078 mmol)을 반응시킨 후, 여과 (DCM) 하여 아이보리색 고체 화합물 43 (EIF-043) 14.3 mg (42%)을 수득하였다. 3-(4-fluorophenyl)propiolic acid (12.8 mg, 0.078 mmol) and N -(3-aminobicyclo[1.1.1]pentan-1-yl)-2-(4-chloro-3-fluorophenoxy)acetamide TFA salt (31.1 mg, 0.078 mmol) were reacted using a general procedure, and then filtered (DCM) to obtain 14.3 mg (42%) of ivory solid compound 43 (EIF-043) .

N-(3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)바이사이클로[1.1.1]펜탄-1-일)-3-(4-플루오로페닐)프로피올아마이드[N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(4-fluorophenyl)propiolamide]N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(4-fluorophenyl)propiolamide

1H NMR (DMSO-d6, 400 MHz) δ 9.40 (s, 1H), 8.76 (s, 1H), 7.63 (dd, J = 8.6, 5.6 Hz, 2H), 7.50 (t, J = 8.9 Hz, 1H), 7.32 (t, J = 8.9 Hz, 2H), 7.08 (dd, J = 11.4, 2.9 Hz, 1H), 6.85 (ddd, J = 9.0, 3.0, 1.3 Hz, 1H), 4.48 (s, 2H), 2.26 (s, 6H). 1H NMR (DMSO-d 6 , 400 MHz) δ 9.40 (s, 1H), 8.76 (s, 1H), 7.63 (dd, J = 8.6, 5.6 Hz, 2H), 7.50 (t, J = 8.9 Hz, 1H), 7.32 (t, J = 8.9 Hz, 2H), 7.08 (dd, J = 11.4, 2.9 Hz, 1H), 6.85 (ddd, J = 9.0, 3.0, 1.3 Hz, 1H), 4.48 (s, 2H), 2.26 (s, 6H).

MS (ESI+) m/z calcd for C22H17ClF2N2O3 [M + H]+ 431.09; found 431.22.MS (ESI + ) m/z calcd for C 22 H 17 ClF2N 2 O 3 [M + H] + 431.09; found431.22.

화합물 44 (EIF-044):Compound 44 (EIF-044):

일반적인 절차를 통해 3-(4-에틸페닐)프로피올산[3-(4-ethylphenyl)propiolic acid] (13.6 mg, 0.078 mmol) 및 N-(3-아미노바이사이클로[1.1.1]펜탄-1-일)-2-(4-클로로-3-플루오로페녹시)아세트아마이드 TFA 염 (31.1 mg, 0.078 mmol)을 반응시킨 후, 컬럼 크로마토그래피 (EtOAc/n-Hexane = 1:1)를 수행하여 백색 고체 화합물 44 (EIF-044) 25.7 mg (75%)을 수득하였다. 3-(4-ethylphenyl)propiolic acid (13.6 mg, 0.078 mmol) and N -(3-aminobicyclo[1.1.1]pentan-1-yl)-2-(4-chloro-3-fluorophenoxy)acetamide TFA salt (31.1 mg, 0.078 mmol) were reacted through a general procedure, and then column chromatography (EtOAc/ n -Hexane = 1:1) was performed to obtain 25.7 mg (75%) of white solid compound 44 (EIF-044) .

N-(3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)바이사이클로[1.1.1]펜탄-1-일)-3-(4-에틸페닐)프로피올아마이드[N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(4-ethylphenyl)propiolamide]N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(4-ethylphenyl)propiolamide

1H NMR (DMSO-d6, 400 MHz) δ 9.36 (s, 1H), 8.75 (s, 1H), 7.50 (t, J = 8.9 Hz, 2H), 7.47 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.3 Hz, 2H), 7.08 (dd, J = 11.4, 2.8 Hz, 1H), 6.85 (ddd, J = 9.0, 2.9, 1.2 Hz, 1H), 4.48 (s, 2H), 2.64 (q, J = 7.5 Hz, 2H), 2.26 (s, 6H), 1.18 (t, J = 7.6 Hz, 3H). 1 H NMR (DMSO-d 6 , 400 MHz) δ 9.36 (s, 1H), 8.75 (s, 1H), 7.50 (t, J = 8.9 Hz, 2H), 7.47 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.3 Hz, 2H), 7.08 (dd, J = 11.4, 2.8 Hz, 1H), 6.85 (ddd, J = 9.0, 2.9, 1.2 Hz, 1H), 4.48 (s, 2H), 2.64 (q, J = 7.5 Hz, 2H), 2.26 (s, 6H), 1.18 (t, J) = 7.6 Hz, 3H).

MS (ESI+) m/z calcd for C24H22ClFN2O3 [M + H]+ 441.13; found 441.21.MS (ESI + ) m/z calcd for C 24 H 22 ClFN 2 O 3 [M + H] + 441.13; found 441.21.

화합물 45 (EIF-045):Compound 45 (EIF-045):

일반적인 절차를 통해 3-(4-(터트-부틸)페닐)프로피올산[3-(4-(tert-butyl)phenyl)propiolic acid] (15.8 mg, 0.078 mmol) 및 N-(3-아미노바이사이클로[1.1.1]펜탄-1-일)-2-(4-클로로-3-플루오로페녹시)아세트아마이드 TFA 염 (31.1 mg, 0.078 mmol)을 반응시킨 후, 컬럼 크로마토그래피 (EtOAc/n-Hexane = 1:1)를 수행하여 아이보리색 고체 화합물 45 (EIF-045) 27.7 mg (76%)을 수득하였다. 3-(4-(tert-butyl)phenyl)propiolic acid (15.8 mg, 0.078 mmol) and N -(3-aminobicyclo[1.1.1]pentan-1-yl)-2-(4- chloro -3-fluorophenoxy)acetamide TFA salt (31.1 mg, 0.078 mmol) were reacted through a general procedure, and then column chromatography (EtOAc/ n -Hexane = 1:1) was performed to obtain 27.7 mg (76%) of ivory solid compound 45 (EIF-045) .

3-(4-(터트-부틸)페닐)-N-(3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)바이사이클로[1.1.1]펜탄-1-일)프로파올아마이드[3-(4-(tert-butyl)phenyl)-N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)propiolamide]3-(4-(tert-butyl)phenyl)-N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)propiolamide

1H NMR (DMSO-d6, 400 MHz) δ 9.36 (s, 1H), 8.76 (s, 1H), 7.57 - 7.46 (m, 5H), 7.08 (dd, J = 11.4, 2.8 Hz, 1H), 6.85 (ddd, J = 9.0, 2.9, 1.1 Hz, 1H), 4.48 (s, 2H), 2.26 (s, 6H), 1.28 (s, 9H). 1H NMR (DMSO-d 6 , 400 MHz) δ 9.36 (s, 1H), 8.76 (s, 1H), 7.57 - 7.46 (m, 5H), 7.08 (dd, J = 11.4, 2.8 Hz, 1H), 6.85 (ddd, J = 9.0, 2.9, 1.1 Hz, 1H), 4.48 (s, 2H), 2.26 (s, 6H), 1.28 (s, 9H).

MS (ESI+) m/z calcd for C26H26ClFN2O3 [M + H]+ 469.16; found 469.28.MS (ESI + ) m/z calcd for C 26 H 26 ClFN 2 O 3 [M + H] + 469.16; found 469.28.

화합물 46 (EIF-046):Compound 46 (EIF-046):

일반적인 절차를 통해 3-(나프탈렌-2-일)프로피올산[3-(naphthalen-2-yl)propiolic acid] (15.3 mg, 0.078 mmol) 및 N-(3-아미노바이사이클로[1.1.1]펜탄-1-일)-2-(4-클로로-3-플루오로페녹시)아세트아마이드 TFA 염 (31.1 mg, 0.078 mmol)을 반응시킨 후, 컬럼 크로마토그래피 (EtOAc/n-Hexane = 1:1)를 수행하여 아이보리색 고체 화합물 46 (EIF-046) 27.5 mg (76%)을 수득하였다. 3-(naphthalen-2-yl)propiolic acid (15.3 mg, 0.078 mmol) and N -(3-aminobicyclo[1.1.1]pentan-1-yl)-2-(4-chloro-3-fluorophenoxy)acetamide TFA salt (31.1 mg, 0.078 mmol) were reacted through a general procedure, and then column chromatography (EtOAc/ n -Hexane = 1:1) was performed to obtain 27.5 mg (76%) of ivory solid compound 46 (EIF-046) .

N-(3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)바이사이클로[1.1.1]펜탄-1-일)-3-(나프탈렌-2-일)프로피올아마이드[N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(naphthalen-2-yl)propiolamide]N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(naphthalen-2-yl)propiolamide

1H NMR (DMSO-d6, 400 MHz) δ 9.47 (s, 1H), 8.77 (s, 1H), 8.23 (m, 1H), 8.00 - 7.96 (m, 3H), 7.64 - 7.56 (m, 3H), 7.50 (t, J = 8.9 Hz, 1H), 7.08 (dd, J = 11.4, 2.9 Hz, 1H), 6.86 (ddd, J = 9.0, 2.8, 1.2 Hz, 1H), 4.49 (s, 2H), 2.29 (s, 6H). 1 H NMR (DMSO-d 6 , 400 MHz) δ 9.47 (s, 1H), 8.77 (s, 1H), 8.23 (m, 1H), 8.00 - 7.96 (m, 3H), 7.64 - 7.56 (m, 3H), 7.50 (t, J = 8.9 Hz, 1H), 7.08 (dd, J = 11.4, 2.9 Hz, 1H), 6.86 (ddd, J = 9.0, 2.8, 1.2 Hz, 1H), 4.49 (s, 2H), 2.29 (s, 6H).

MS (ESI+) m/z calcd for C26H20ClFN2O3 [M + H]+ 463.11; found 463.18.MS (ESI + ) m/z calcd for C 26 H 20 ClFN 2 O 3 [M + H] + 463.11; found 463.18.

화합물 47 (EIF-047):Compound 47 (EIF-047):

일반적인 절차를 통해 3-(2-클로로페닐)프로피올산[3-(2-chlorophenyl)propiolic acid] (14.1 mg, 0.078 mmol) 및 N-(3-아미노바이사이클로[1.1.1]펜탄-1-일)-2-(4-클로로-3-플루오로페녹시)아세트아마이드 TFA 염 (31.1 mg, 0.078 mmol)을 반응시킨 후, 컬럼 크로마토그래피 (EtOAc/n-Hexane = 1:1)를 수행하여 담황색 고체 화합물 47 (EIF-047) 19.1 mg (54%)을 수득하였다. 3-(2-chlorophenyl)propiolic acid (14.1 mg, 0.078 mmol) and N -(3-aminobicyclo[1.1.1]pentan-1-yl)-2-(4-chloro-3-fluorophenoxy)acetamide TFA salt (31.1 mg, 0.078 mmol) were reacted through a general procedure, and then column chromatography (EtOAc/ n -Hexane = 1:1) was performed to obtain 19.1 mg (54%) of pale yellow solid compound 47 (EIF-047) .

N-(3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)바이사이클로[1.1.1]펜탄-1-일)-3-(2-클로로페닐)프로피올아마이드[N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(2-chlorophenyl)propiolamide]N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(2-chlorophenyl)propiolamide

1H NMR (DMSO-d6, 400 MHz) δ 9.49 (s, 1H), 8.76 (s, 1H), 7.68 (dd, J = 7.7, 1.7 Hz, 1H), 7.61 (dd, J = 8.1, 1.1 Hz, 1H), 7.54 - 7.48 (m, 2H), 7.43 (td, J = 7.5, 1.2 Hz, 1H), 7.08 (dd, J = 11.4, 2.8 Hz, 1H), 6.85 (dd, J = 9.1, 2.9 Hz, 1H), 4.49 (s, 2H), 2.28 (s, 6H). 1H NMR (DMSO-d 6 , 400 MHz) δ 9.49 (s, 1H), 8.76 (s, 1H), 7.68 (dd, J = 7.7, 1.7 Hz, 1H), 7.61 (dd, J = 8.1, 1.1 Hz, 1H), 7.54 - 7.48 (m, 2H), 7.43 (td, J = 7.5, 1.2 Hz, 1H), 7.08 (dd, J = 11.4, 2.8 Hz, 1H), 6.85 (dd, J = 9.1, 2.9 Hz, 1H), 4.49 (s, 2H), 2.28 (s, 6H).

MS (ESI+) m/z calcd for C22H17Cl2FN2O3 [M + H]+ 447.06; found 447.16.MS (ESI + ) m/z calcd for C 22 H 17 Cl 2 FN 2 O 3 [M + H] + 447.06; found 447.16.

화합물 48 (EIF-048):Compound 48 (EIF-048):

DMF (1.1 ml) 내 터트-부틸 (3-아미노사이클로헥실)카르바메이트[tert-butyl (3-aminocyclohexyl)carbamate] (1.0 equiv., 50 mg, 0.233 mmol)의 교반 용액에 3-(4-클로로페닐)프로피올산 (1.1 equiv., 46.3 mg, 0.257 mmol), DIPEA (3.0 equiv., 122 μl, 0.70 mmol) 및 HATU (2.0 equiv., 177 mg, 0.467 mmol)를 첨가하였다. 반응 혼합물을 실온에서 밤새 교반하였다. 혼합물을 EtOAc로 희석하고, 유기 상을 염수로 3차례 세척한 다음, 황산 마그네슘으로 건조시키고 감압 하에서 여과 및 농축시켰다. 잔류물을 MPLC (EtOAc : n-Hexane = 1:1)로 정제하여 담황색 고체 생성물 66 mg (72%)을 수득하였다.tert-butyl (3-aminocyclohexyl)carbamate [ tert -butyl (3-aminocyclohexyl)carbamate] in DMF (1.1 ml) To a stirred solution of (1.0 equiv., 50 mg, 0.233 mmol) were added 3-(4-chlorophenyl)propiolic acid (1.1 equiv., 46.3 mg, 0.257 mmol), DIPEA (3.0 equiv., 122 μl, 0.70 mmol), and HATU (2.0 equiv., 177 mg, 0.467 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, and the organic phase was washed three times with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by MPLC (EtOAc: n -Hexane = 1:1) to give 66 mg (72%) of the product as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ 8.79 (d, J = 7.8 Hz, 1H), 7.64 - 7.58 (m, 2H), 7.57 - 7.50 (m, 2H), 6.86 (d, J = 8.0 Hz, 1H), 4.09 - 3.97 (m, 1H), 3.67 (s, 1H), 1.55 - 1.49 (m, 6H), 1.44 - 1.33 (m, 10H), 1.29 - 1.22 (m, 1H). 1H NMR (400 MHz, DMSO-d 6 ) δ 8.79 (d, J = 7.8 Hz, 1H), 7.64 - 7.58 (m, 2H), 7.57 - 7.50 (m, 2H), 6.86 (d, J = 8.0 Hz, 1H), 4.09 - 3.97 (m, 1H), 3.67 (s, 1H), 1.55 - 1.49 (m, 6H), 1.44 - 1.33 (m, 10H), 1.29 - 1.22 (m, 1H).

MS (ESI+) m/z calcd for C20H26ClN2O2 [M + Na]+ 399.15; found 399.26.MS (ESI + ) m/z calcd for C 20 H 26 ClN 2 O 2 [M + Na] + 399.15; found 399.26.

터트-부틸 (3-(3-(4-클로로페닐)프로피올아미도)사이클로헥실)카르바메이트[tert-butyl (3-(3-(4-chlorophenyl)propiolamido)cyclohexyl)carbamate] (1.0 equiv., 40 mg, 0.106 mmol)의 교반 용액을 실온에서 20% TFA/DCM (88 μl/ 442 μl)로 희석시켰다. 4시간 동안 교반한 후, 반응 혼합물을 추가 정제없이 증발시켰다.A stirred solution of tert -butyl (3-(3-(4-chlorophenyl)propiolamido)cyclohexyl)carbamate (1.0 equiv., 40 mg, 0.106 mmol) was diluted with 20% TFA/DCM (88 μl/ 442 μl) at room temperature. After stirring for 4 h, the reaction mixture was evaporated without further purification.

DMF (531 μl) 내 N-(3-아미노사이클로헥실)-3-(4-클로로페닐)프로피올아마이드[N-(3-aminocyclohexyl)-3-(4-chlorophenyl)propiolamide] (1.0 equiv., 29.4 mg, 0.106 mmol)의 교반 용액에 3-(4-클로로페닐)프로피올산 (1.1 equiv., 21.1 mg, 0.117 mmol), DIPEA (3.0 equiv., 56 μl, 0.319 mmol) 및 HATU (2.0 equiv., 81 mg, 0.212 mmol)를 첨가하였다. 반응 혼합물을 실온에서 밤새 교반하였다. 혼합물을 EtOAc로 희석하고, 유기 상을 염수로 3차례 세척한 다음, 황산 마그네슘으로 건조시키고 감압 하에서 여과 및 농축시켰다. 잔류물을 최소량의 에틸 아세테이트에 현탁시키고 헥산을 처리하였다. 형성된 침전물을 여과하여 모아 아이보리색 고체 화합물 48 (EIF-048) 17.4 mg (37%)을 수득하였다. N - (3-aminocyclohexyl)-3-(4-chlorophenyl)propiolamide in DMF (531 μl) To a stirred solution of (1.0 equiv., 29.4 mg, 0.106 mmol) were added 3-(4-chlorophenyl)propiolic acid (1.1 equiv., 21.1 mg, 0.117 mmol), DIPEA (3.0 equiv., 56 μl, 0.319 mmol), and HATU (2.0 equiv., 81 mg, 0.212 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, and the organic phase was washed three times with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was suspended in a minimum amount of ethyl acetate and treated with hexane. The formed precipitate was collected by filtration to give 17.4 mg (37%) of an ivory solid compound 48 (EIF-048) .

N,N'-(사이클로헥산-1,3-디일)비스(3-(4-클로로페닐)프로피올아마이드)[N,N'-(cyclohexane-1,3-diyl)bis(3-(4-chlorophenyl)propiolamide)]N,N'-(cyclohexane-1,3-diyl)bis(3-(4-chlorophenyl)propiolamide)

1H NMR (400 MHz, DMSO-d6) δ 8.86 (d, J = 7.9 Hz, 2H), 7.63 - 7.59 (m, 4H), 7.55 - 7.52 (m, 4H), 4.12 - 4.09 (m, 2H), 1.64 - 1.61 (m, 6H), 1.39 - 1.34 (m, 2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.86 (d, J = 7.9 Hz, 2H), 7.63 - 7.59 (m, 4H), 7.55 - 7.52 (m, 4H), 4.12 - 4.09 (m, 2H), 1.64 - 1.61 (m, 6H), 1.39 - 1.34 (m, 2H).

MS (ESI+) m/z calcd for C24H21Cl2N2O2 [M + H]+ 439.09-; found 439.19.MS (ESI + ) m/z calcd for C 24 H 21 Cl 2 N 2 O 2 [M + H] + 439.09 - ; found439.19.

화합물 49 (EIF-049):Compound 49 (EIF-049):

DMF (1.3 ml) 내 N-((1r,4r)-4-아미노사이클로헥실)피발아마이드[N-((1r,4r)-4-aminocyclohexyl)pivalamide] (1.0 equiv., 50 mg, 0.252 mmol)의 교반 용액에 3-(4-클로로페닐)프로피올산 (1.1 equiv., 50 mg, 0.277 mmol), DIPEA (3.0 equiv., 132 μl, 0.756 mmol) 및 HATU (2.0 equiv., 192 mg, 0.504 mmol)를 첨가하였다. 반응 혼합물을 실온에서 밤새 교반하였다. 혼합물을 EtOAc로 희석하고, 유기 상을 염수로 3차례 세척한 다음, 황산 마그네슘으로 건조시키고 감압 하에서 여과 및 농축시켰다. 잔류물을 헥산으로 희석시키고 형성된 침전물을 여과하여 모아 백색 고체 생성물 73 mg (80%)을 수득하였다.To a stirred solution of N -((1 r ,4 r )-4-aminocyclohexyl)pivalamide [ N -((1 r ,4 r )-4-aminocyclohexyl)pivalamide] (1.0 equiv., 50 mg, 0.252 mmol) in DMF (1.3 ml) were added 3-(4-chlorophenyl)propiolic acid (1.1 equiv., 50 mg, 0.277 mmol), DIPEA (3.0 equiv., 132 μl, 0.756 mmol), and HATU (2.0 equiv., 192 mg, 0.504 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, and the organic phase was washed three times with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was diluted with hexane and the formed precipitate was filtered and collected to obtain 73 mg (80%) of a white solid product.

1H NMR (400 MHz, DMSO-d6) δ 8.73 (d, J = 7.8 Hz, 1H), 7.61 - 7.57 (m, 2H), 7.56 - 7.48 (m, 2H), 6.72 (d, J = 8.1 Hz, 1H), 3.52 - 5.50 (m, 1H), 3.17 (s, 1H), 1.84 - 1.71 (m, 4H), 1.37 (s, 9H), 1.31 - 1.12 (m, 4H). 1H NMR (400 MHz, DMSO-d 6 ) δ 8.73 (d, J = 7.8 Hz, 1H), 7.61 - 7.57 (m, 2H), 7.56 - 7.48 (m, 2H), 6.72 (d, J = 8.1 Hz, 1H), 3.52 - 5.50 (m, 1H), 3.17 (s, 1H), 1.84 - 1.71 (m, 4H), 1.37 (s, 9H), 1.31 - 1.12 (m, 4H).

MS (ESI+) m/z calcd for C20H26ClN2O2 [M + Na]+ 399.15; found 399.24.MS (ESI + ) m/z calcd for C 20 H 26 ClN 2 O 2 [M + Na] + 399.15; found 399.24.

터트-부틸 (4-(3-(4-클로로페닐)프로피올아미도)사이클로헥실)카르바메이트[tert-butyl (4-(3-(4-chlorophenyl)propiolamido)cyclohexyl)carbamate] (1.0 equiv., 40 mg, 0.106 mmol)의 교반 용액을 실온에서 20% TFA/DCM (88 μl/ 442 μl)로 희석시켰다. 4시간 동안 교반한 후, 반응 혼합물을 추가 정제없이 증발시켰다.A stirred solution of tert -butyl (4-(3-(4-chlorophenyl)propiolamido)cyclohexyl)carbamate (1.0 equiv., 40 mg, 0.106 mmol) was diluted with 20% TFA/DCM (88 μl/ 442 μl) at room temperature. After stirring for 4 h, the reaction mixture was evaporated without further purification.

DMF (555 μl) 내 N-((1r,4r)-4-아미노사이클로헥실)-3-(4-클로로페닐)프로피올아마이드[N-((1r,4r)-4-aminocyclohexyl)-3-(4-chlorophenyl)propiolamide] (1.0 equiv., 30.7 mg, 0.111 mmol)의 교반 용액에 3-(4-클로로페닐)프로피올산 (1.1 equiv., 22.0 mg, 0.122 mmol), DIPEA (3.0 equiv., 58 μl, 0.333 mmol) 및 HATU (1.5 equiv., 63 mg, 0.166 mmol)를 첨가하였다. 반응 혼합물을 실온에서 밤새 교반하였다. 혼합물을 EtOAc로 희석하고, 유기 상을 염수로 3차례 세척한 다음, 황산 마그네슘으로 건조시키고 감압 하에서 여과 및 농축시켰다. 잔류물을 최소량의 에틸 아세테이트에 현탁시키고 헥산을 처리하였다. 형성된 침전물을 여과하여 모아 아이보리색 고체 화합물 49 (EIF-049) 13 mg (27%)을 수득하였다. N -((1 r ,4 r )-4-aminocyclohexyl)-3-(4-chlorophenyl)propiolamide [ N -((1 r ,4 r )-4-aminocyclohexyl)-3-(4-chlorophenyl)propiolamide] in DMF (555 μl) To a stirred solution of (1.0 equiv., 30.7 mg, 0.111 mmol) were added 3-(4-chlorophenyl)propiolic acid (1.1 equiv., 22.0 mg, 0.122 mmol), DIPEA (3.0 equiv., 58 μl, 0.333 mmol), and HATU (1.5 equiv., 63 mg, 0.166 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, and the organic phase was washed three times with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was suspended in a minimum amount of ethyl acetate and treated with hexane. The formed precipitate was collected by filtration to give 13 mg (27%) of an ivory solid compound 49 (EIF-049) .

N,N'-((1r,4r)-사이클로헥산-1,4-디일)비스(3-(4-클로로페닐)프로피올아마이드[N,N'-((1r,4r)-cyclohexane-1,4-diyl)bis(3-(4-chlorophenyl)propiolamide)]N,N'-((1r,4r)-cyclohexane-1,4-diyl)bis(3-(4-chlorophenyl)propiolamide)

1H NMR (400 MHz, DMSO-d6) δ 8.79 (d, J = 7.9 Hz, 2H), 7.60 (d, J = 8.7 Hz, 4H), 7.53 (d, J = 8.5 Hz, 4H), 3.57 (s, 2H), 1.83 (d, J = 7.7 Hz, 4H), 1.30 (t, J = 9.5 Hz, 4H). 1H NMR (400 MHz, DMSO-d 6 ) δ 8.79 (d, J = 7.9 Hz, 2H), 7.60 (d, J = 8.7 Hz, 4H), 7.53 (d, J = 8.5 Hz, 4H), 3.57 (s, 2H), 1.83 (d, J = 7.7 Hz, 4H), 1.30 (t, J = 9.5 Hz, 4H).

화합물 50 (EIF-050):Compound 50 (EIF-050):

DMF 내 용해된 N-((1r,4r)-4-아미노사이클로헥실)-2-(4-클로로페녹시)아세트아마이드 (1.0 equiv), 벤조퓨란-5-카르복실산[benzofuran-6-carboxylic acid] (1.2 equiv), N,N-디이소프로필에틸아민 (2.5 equiv), EDCI (1.5 equiv) 및 HOBt (1.5 equiv) 용액을 실온에서 밤새 교반하였다. 반응 혼합물을 에틸 아세테이트로 희석시키고 10% 수성 염화 리튬 (Х3) 및 염수로 세척하였다. 유기 층을 무수 MgSO4로 건조시키고, 감압 하에서 농축시켰다. 98% 순도의 백색 고체 화합물 50 (EIF-050), N-((1r,4r)-4-(2-(4-클로로페녹시)아세트아미도)사이클로헥실)벤조퓨란-6-카르복사마이드 21.9 mg (36%)을 수득하였다.A solution of N -((1 r ,4 r )-4-aminocyclohexyl)-2-(4-chlorophenoxy)acetamide (1.0 equiv), benzofuran-5-carboxylic acid (1.2 equiv), N , N -diisopropylethylamine (2.5 equiv), EDCI (1.5 equiv) and HOBt (1.5 equiv) dissolved in DMF was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with 10% aqueous lithium chloride (Х3) and brine. The organic layer was dried over anhydrous MgSO 4 and concentrated under reduced pressure. Compound 50 (EIF-050) was obtained as a white solid with a purity of 98%. 21.9 mg (36%) of N -((1 r ,4 r )-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)benzofuran-6-carboxamide was obtained.

N-((1r,4r)-4-(2-(4-클로로페녹시)아세트아미도)사이클로헥실)벤조퓨란-6-카르복사마이드[N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)benzofuran-6-carboxamide]N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)benzofuran-6-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 8.28 (d, J = 7.8 Hz, 1H), 8.13 (d, J = 2.2 Hz, 1H), 8.09 (s, 1H), 7.98 (d, J = 8.1 Hz, 1H), 7.79 (dd, J = 8.2, 1.2 Hz, 1H), 7.71 (d, J = 8.1 Hz, 1H), 7.38 - 7.33 (m, 2H), 7.03 (d, J = 1.3 Hz, 1H), 7.01 - 6.96 (m, 2H), 4.47 (s, 2H), 3.82 - 3.60 (m, 2H), 1.94 - 1.79 (m, 4H), 1.50 - 1.34 (m, 4H); LCMS (ESI), m/z = 426.90 [M+1]+. 1H NMR (400 MHz, DMSO-d 6 ) δ 8.28 (d, J = 7.8 Hz, 1H), 8.13 (d, J = 2.2 Hz, 1H), 8.09 (s, 1H), 7.98 (d, J = 8.1 Hz, 1H), 7.79 (dd, J = 8.2, 1.2 Hz, 1H), 7.71 (d, J = 8.1 Hz, 1H), 7.38 - 7.33 (m, 2H), 7.03 (d, J = 1.3 Hz, 1H), 7.01 - 6.96 (m, 2H), 4.47 (s, 2H), 3.82 - 3.60 (m, 2H), 1.94 - 1.79 (m, 4H), 1.50 - 1.34 (m, 4H); LCMS (ESI), m/z = 426.90 [M+1] + .

화합물 51 (EIF-051):Compound 51 (EIF-051):

DMF 내 용해된 N-((1r,4r)-4-아미노사이클로헥실)-2-(4-클로로페녹시)아세트아마이드 (1.0 equiv), 1H-인다졸-6-카르복실산[1H-indazole-6-carboxylic acid] (1.2 equiv), N,N-디이소프로필에틸아민 (2.5 equiv), EDCI (1.5 equiv) 및 HOBt (1.5 equiv) 용액을 실온에서 밤새 교반하였다. 반응 혼합물을 에틸 아세테이트로 희석시키고 10% 수성 염화 리튬 (Х3) 및 염수로 세척하였다. 유기 층을 무수 MgSO4로 건조시키고, 감압 하에서 농축시켰다. 잔류물을 여과 (EtOAc/n-hexane)로 정제하여 96% 순도의 담황색 고체 화합물 51 (EIF-051) N-((1r,4r)-4-(2-(4-클로로페녹시)아세트아미도)사이클로헥실)-1H-인다졸-6-카르복사마이드 11 mg (17%)을 수득하였다.A solution of N -((1 r ,4 r )-4-aminocyclohexyl)-2-(4-chlorophenoxy)acetamide (1.0 equiv), 1 H -indazole -6-carboxylic acid (1.2 equiv), N , N -diisopropylethylamine (2.5 equiv), EDCI (1.5 equiv), and HOBt (1.5 equiv) dissolved in DMF was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with 10% aqueous lithium chloride (X3) and brine. The organic layer was dried over anhydrous MgSO 4 and concentrated under reduced pressure. The residue was purified by filtration (EtOAc/ n -hexane) to obtain 11 mg (17%) of 96% pure pale yellow solid compound 51 (EIF-051) N -((1 r ,4 r )-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-1 H -indazole-6-carboxamide.

N-((1r,4r)-4-(2-(4-클로로페녹시)아세트아미도)사이클로헥실)-1H-인다졸-6-카르복사마이드[N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-1H-indazole-6-carboxamide]N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-1H-indazole-6-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 13.32 (s, 1H), 8.36 (d, J = 7.8 Hz, 1H), 8.13 (s, 1H), 8.03 (s, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 8.9 Hz, 2H), 4.47 (s, 2H), 3.82 - 3.61 (m, 2H), 1.94 - 1.78 (m, 4H), 1.51 - 1.34 (m, 4H); LCMS (ESI), m/z = 426.90 [M+1]+. 1H NMR (400 MHz, DMSO-d 6 ) δ 13.32 (s, 1H), 8.36 (d, J = 7.8 Hz, 1H), 8.13 (s, 1H), 8.03 (s, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 8.9 Hz, 2H), 4.47 (s, 2H), 3.82 - 3.61 (m, 2H), 1.94 - 1.78 (m, 4H), 1.51 - 1.34 (m, 4H); LCMS (ESI), m/z = 426.90 [M+1] + .

화합물 52 (EIF-052):Compound 52 (EIF-052):

DMF 내 용해된 N-((1r,4r)-4-아미노사이클로헥실)-2-(4-클로로페녹시)아세트아마이드 (1.0 equiv), 니코틴산[nicotinic acid] (1.2 equiv), N,N-디이소프로필에틸아민 (2.5 equiv), EDCI (1.5 equiv) 및 HOBt (1.5 equiv) 용액을 실온에서 밤새 교반하였다. 반응 혼합물을 에틸 아세테이트로 희석시키고 10% 수성 염화 리튬 (Х3) 및 염수로 세척하였다. 유기 층을 무수 MgSO4로 건조시키고, 감압 하에서 농축시켰다. 잔류물을 여과 (EtOAc/n-hexane)로 정제하여 99% 순도의 아이보리색 고체 화합물 52 (EIF-052) N-((1r,4r)-4-(2-(4-클로로페녹시)아세트아미도)사이클로헥실)니코틴아마이드 23.1 mg (42%)을 수득하였다.A solution of N -((1 r ,4 r )-4-aminocyclohexyl)-2-(4-chlorophenoxy)acetamide (1.0 equiv), nicotinic acid (1.2 equiv), N , N -diisopropylethylamine (2.5 equiv), EDCI (1.5 equiv), and HOBt (1.5 equiv) dissolved in DMF was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with 10% aqueous lithium chloride (X3) and brine. The organic layer was dried over anhydrous MgSO 4 and concentrated under reduced pressure. The residue was purified by filtration (EtOAc/ n -hexane) to obtain 23.1 mg (42%) of 99% pure ivory solid compound 52 (EIF-052) N -((1 r ,4 r )-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)nicotinamide.

N-((1r,4r)-4-(2-(4-클로로페녹시)아세트아미도)사이클로헥실)니코틴아마이드[N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)nicotinamide]N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)nicotinamide

1H NMR (400 MHz, DMSO-d6) δ 8.99 (d, J = 1.7 Hz, 1H), 8.69 (dd, J = 4.8, 1.5 Hz, 1H), 8.47 (d, J = 7.8 Hz, 1H), 8.20 - 8.14 (m, 1H), 8.00 (d, J = 8.1 Hz, 1H), 7.50 (dd, J = 7.7, 4.8 Hz, 1H), 7.39 - 7.32 (m, 2H), 7.03 - 6.95 (m, 2H), 4.47 (s, 2H), 3.81 - 3.59 (m, 2H), 1.93 - 1.77 (m, 4H), 1.48 - 1.33 (m, 4H); LCMS (ESI), m/z = 388.21 [M+1]+. 1H NMR (400 MHz, DMSO-d 6 ) δ 8.99 (d, J = 1.7 Hz, 1H), 8.69 (dd, J = 4.8, 1.5 Hz, 1H), 8.47 (d, J = 7.8 Hz, 1H), 8.20 - 8.14 (m, 1H), 8.00 (d, J = 8.1 Hz, 1H), 7.50 (dd, J = 7.7, 4.8 Hz, 1H), 7.39 - 7.32 (m, 2H), 7.03 - 6.95 (m, 2H), 4.47 (s, 2H), 3.81 - 3.59 (m, 2H), 1.93 - 1.77 (m, 4H), 1.48 - 1.33 (m, 4H); LCMS (ESI), m/z = 388.21 [M+1] + .

화합물 53 (EIF-053):Compound 53 (EIF-053):

DMF 내 용해된 N-((1r,4r)-4-아미노사이클로헥실)-2-(4-클로로페녹시)아세트아마이드 (1.0 equiv), 2-(1H-벤조[d]이미다졸-2-일)아세트산[2-(1H-benzo[d]imidazol-2-yl)acetic acid] (1.2 equiv), N,N-디이소프로필에틸아민 (2.5 equiv), EDCI (1.5 equiv) 및 HOBt (1.5 equiv) 용액을 실온에서 밤새 교반하였다. 반응 혼합물을 에틸 아세테이트로 희석시키고 10% 수성 염화 리튬 (Х3) 및 염수로 세척하였다. 유기 층을 무수 MgSO4로 건조시키고, 감압 하에서 농축시켰다. 잔류물을 여과 (EtOAc/n-hexane)로 정제하여 97% 순도의 아이보리색 고체 화합물 53 (EIF-053) N-((1r,4r)-4-(2-(1H-벤조[d]이미다졸-2-일)아세트아미도)사이클로헥실) -2-(4-클로로페녹시)아세트아마이드 12 mg (19%)을 수득하였다.A solution of N -((1 r ,4 r )-4-aminocyclohexyl)-2-(4-chlorophenoxy)acetamide (1.0 equiv), 2-(1 H -benzo[ d ]imidazol-2- yl )acetic acid (1.2 equiv), N , N -diisopropylethylamine (2.5 equiv), EDCI (1.5 equiv), and HOBt (1.5 equiv) dissolved in DMF was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with 10% aqueous lithium chloride (X3) and brine. The organic layer was dried over anhydrous MgSO 4 and concentrated under reduced pressure. The residue was purified by filtration (EtOAc/ n -hexane) to obtain 12 mg (19%) of ivory solid compound 53 (EIF-053) N -((1 r ,4 r )-4-(2-(1 H -benzo[ d ]imidazol-2-yl)acetamido)cyclohexyl) -2-(4-chlorophenoxy)acetamide with 97% purity.

N-((1r,4r)-4-(2-(1H-벤조[d]이미다졸-2-일)아세트아미도)사이클로헥실)-2-(4-클로로페녹시)아세트아마이드[N-((1r,4r)-4-(2-(1H-benzo[d]imidazol-2-yl)acetamido)cyclohexyl)-2-(4-chlorophenoxy)acetamide]N-((1r,4r)-4-(2-(1H-benzo[d]imidazol-2-yl)acetamido)cyclohexyl)-2-(4-chlorophenoxy)acetamide

1H NMR (400 MHz, DMSO-d6) δ 12.32 (s, 1H), 8.30 (d, J = 7.8 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 7.1 Hz, 1H), 7.44 (d, J = 6.9 Hz, 1H), 7.34 (d, J = 8.9 Hz, 2H), 7.16 - 7.07 (m, 2H), 6.97 (d, J = 9.0 Hz, 2H), 4.46 (s, 2H), 3.71 (s, 2H), 3.63 - 3.48 (m, 2H), 1.87 - 1.73 (m, 4H), 1.39 - 1.22 (m, 4H); LCMS (ESI), m/z = 441.34 [M+1]+. 1H NMR (400 MHz, DMSO-d 6 ) δ 12.32 (s, 1H), 8.30 (d, J = 7.8 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 7.1 Hz, 1H), 7.44 (d, J = 6.9) Hz, 1H), 7.34 (d, J = 8.9 Hz, 2H), 7.16 - 7.07 (m, 2H), 6.97 (d, J = 9.0 Hz, 2H), 4.46 (s, 2H), 3.71 (s, 2H), 3.63 - 3.48 (m, 2H), 1.87 - 1.73 (m, 4H), 1.39 - 1.22 (m, 4H); LCMS (ESI), m/z = 441.34 [M+1] + .

화합물 54 (EIF-054):Compound 54 (EIF-054):

DMF 내 용해된 N-((1r,4r)-4-아미노사이클로헥실)-2-(4-클로로페녹시)아세트아마이드 (1.0 equiv), 2-(벤조퓨란-2-일)아세트산[2-(benzofuran-2-yl)acetic acid] (1.2 equiv), N,N-디이소프로필에틸아민 (2.5 equiv), EDCI (1.5 equiv) 및 HOBt (1.5 equiv) 용액을 실온에서 밤새 교반하였다. 반응 혼합물을 에틸 아세테이트로 희석시키고 10% 수성 염화 리튬 (Х3) 및 염수로 세척하였다. 유기 층을 무수 MgSO4로 건조시키고, 감압 하에서 농축시켰다. 잔류물을 여과 (EtOAc/n-hexane)로 정제하여 96% 순도의 아이보리색 고체 화합물 54 (EIF-054) 2-(벤조퓨란-2-일)-N-((1r,4r)-4-(2-(4-클로로페녹시)아세트아미도)사이클로헥실)아세트아마이드 22.6 mg (35%)을 수득하였다.A solution of N -((1 r ,4 r )-4-aminocyclohexyl)-2-(4-chlorophenoxy)acetamide (1.0 equiv), 2-(benzofuran-2-yl)acetic acid (1.2 equiv), N , N -diisopropylethylamine (2.5 equiv), EDCI (1.5 equiv), and HOBt (1.5 equiv) dissolved in DMF was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with 10% aqueous lithium chloride (X3) and brine. The organic layer was dried over anhydrous MgSO 4 and concentrated under reduced pressure. The residue was purified by filtration (EtOAc/ n -hexane) to obtain 22.6 mg (35%) of ivory solid compound 54 (EIF-054) 2-(benzofuran-2-yl)- N -((1 r ,4 r )-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)acetamide with 96% purity.

2-(벤조퓨란-2-일)-N-((1r,4r)-4-(2-(4-클로로페녹시)아세트아미도)사이클로헥실)아세트아마이드[2-(benzofuran-2-yl)-N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)acetamide]2-(benzofuran-2-yl)-N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)acetamide

1H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 7.7 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.59 - 7.53 (m, 1H), 7.50 (d, J = 7.9 Hz, 1H), 7.34 (d, J = 8.9 Hz, 2H), 7.27 - 7.17 (m, 2H), 6.97 (d, J = 8.9 Hz, 2H), 6.67 (s, 1H), 4.46 (s, 2H), 3.65 (s, 2H), 3.63 - 3.48 (m, 2H), 1.88 - 1.73 (m, 4H), 1.40 - 1.22 (m, 4H); LCMS (ESI), m/z = 441.23 [M+1]+. 1H NMR (400 MHz, DMSO-d 6 ) δ 8.12 (d, J = 7.7 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.59 - 7.53 (m, 1H), 7.50 (d, J = 7.9 Hz, 1H), 7.34 (d, J = 8.9 Hz, 2H), 7.27 - 7.17 (m, 2H), 6.97 (d, J = 8.9 Hz, 2H), 6.67 (s, 1H), 4.46 (s, 2H), 3.65 (s, 2H), 3.63 - 3.48 (m, 2H), 1.88 - 1.73 (m, 4H), 1.40 - 1.22 (m, 4H); LCMS (ESI), m/z = 441.23 [M+1] + .

화합물 55 (EIF-055):Compound 55 (EIF-055):

DMF 내 용해된 N-((1r,4r)-4-아미노사이클로헥실)-2-(4-클로로페녹시)아세트아마이드 (1.0 equiv), 2-(벤조[b]티오펜-2-일)아세트산[2-(benzo[b]thiophen-2-yl)acetic acid] (1.2 equiv), N,N-디이소프로필에틸아민 (2.5 equiv), EDCI (1.5 equiv) 및 HOBt (1.5 equiv) 용액을 실온에서 밤새 교반하였다. 반응 혼합물을 에틸 아세테이트로 희석시키고 10% 수성 염화 리튬 (Х3) 및 염수로 세척하였다. 유기 층을 무수 MgSO4로 건조시키고, 감압 하에서 농축시켰다. 잔류물을 여과 (EtOAc/n-hexane)로 정제하여 95% 순도의 백색 고체 화합물 55 (EIF-055) 2-(벤조[b]티오펜-2-일)-N-((1r,4r)-4-(2-(4-클로로페녹시)아세트아미도)사이클로헥실)아세트아마이드 14 mg (21%)을 수득하였다.A solution of N -((1 r ,4 r )-4-aminocyclohexyl)-2-(4-chlorophenoxy)acetamide (1.0 equiv), 2-(benzo[ b ]thiophen-2-yl)acetic acid (1.2 equiv), N , N -diisopropylethylamine (2.5 equiv), EDCI (1.5 equiv), and HOBt (1.5 equiv) dissolved in DMF was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with 10 % aqueous lithium chloride (X3) and brine. The organic layer was dried over anhydrous MgSO 4 and concentrated under reduced pressure. The residue was purified by filtration (EtOAc/ n -hexane) to obtain 14 mg (21%) of 2-(benzo[ b ]thiophen - 2-yl)- N -((1 r ,4 r )-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)acetamide as a white solid with 95% purity as compound 55 (EIF-055).

2-(벤조[b]티오펜-2-일)-N-((1r,4r)-4-(2-(4-클로로페녹시)아세트아미도)사이클로헥실)아세트아마이드[2-(benzo[b]thiophen-2-yl)-N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)acetamide]2-(benzo[b]thiophen-2-yl)-N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)acetamide

1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 7.7 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 7.7 Hz, 1H), 7.76 (d, J = 7.3 Hz, 1H), 7.38 - 7.25 (m, 4H), 7.20 (s, 1H), 6.97 (d, J = 9.0 Hz, 2H), 4.45 (s, 2H), 3.71 (s, 2H), 3.65 - 3.46 (m, 2H), 1.86 - 1.72 (m, 4H), 1.40 - 1.19 (m, 4H); LCMS (ESI), m/z = 457.15 [M+1]+. 1H NMR (400 MHz, DMSO-d 6 ) δ 8.15 (d, J = 7.7 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 7.7 Hz, 1H), 7.76 (d, J = 7.3 Hz, 1H), 7.38 - 7.25 (m, 4H), 7.20 (s, 1H), 6.97 (d, J = 9.0 Hz, 2H), 4.45 (s, 2H), 3.71 (s, 2H), 3.65 - 3.46 (m, 2H), 1.86 - 1.72 (m, 4H), 1.40 - 1.19 (m, 4H); LCMS (ESI), m/z = 457.15 [M+1] + .

화합물 56 (EIF-056):Compound 56 (EIF-056):

DMF 내 용해된 N-(3-아미노사이클로부틸)-3-(4-클로로페닐)프로피올아마이드 (1.0 equiv), 2-(o-톨릴옥시)아세트산[2-(o-tolyloxy)acetic acid] (1.2 equiv), N,N-디이소프로필에틸아민 (2.5 equiv), EDCI (1.5 equiv) 및 HOBt (1.5 equiv) 용액을 실온에서 밤새 교반하였다. 반응 혼합물을 에틸 아세테이트로 희석시키고 10% 수성 염화 리튬 (Х3) 및 염수로 세척하였다. 유기 층을 무수 MgSO4로 건조시키고, 감압 하에서 농축시켰다. 잔류물을 실리카 겔 크로마토그래피 (60% EtOAc/n-hexane)로 정제하여 97% 순도의 백색 고체 화합물 56 (EIF-056) 3-(4-클로로페닐)-N-(3-(2-(o-톨릴옥시)아세트아미도)사이클로부틸)프로피올아마이드 11.9 mg (24%)을 수득하였다.A solution of N -(3-aminocyclobutyl)-3-(4-chlorophenyl)propiolamide (1.0 equiv), 2-( o -tolyloxy)acetic acid (1.2 equiv), N , N -diisopropylethylamine (2.5 equiv), EDCI (1.5 equiv), and HOBt (1.5 equiv) dissolved in DMF was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with 10% aqueous lithium chloride (X3) and brine. The organic layer was dried over anhydrous MgSO 4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (60% EtOAc/ n -hexane) to give 11.9 mg (24%) of 3-(4-chlorophenyl)- N -(3-(2-( o -tolyloxy)acetamido)cyclobutyl) propiolamide as a white solid with 97% purity (EIF-056) .

3-(4-클로로페닐)-N-(3-(2-(o-톨릴옥시)아세트아미도)사이클로부틸)프로피올아마이드[3-(4-chlorophenyl)-N-(3-(2-(o-tolyloxy)acetamido)cyclobutyl)propiolamide]3-(4-chlorophenyl)-N-(3-(2-(o-tolyloxy)acetamido)cyclobutyl)propiolamide

1H NMR (400 MHz, DMSO-d6) δ 9.10 (d, J = 7.1 Hz, 1H), 8.18 (d, J = 7.4 Hz, 1H), 7.63 - 7.58 (m, 2H), 7.58 - 7.52 (m, 2H), 7.18 - 7.11 (m, 2H), 6.87 (t, J = 7.2 Hz, 1H), 6.81 (d, J = 8.1 Hz, 1H), 4.47 (d, J = 2.4 Hz, 2H), 4.03 - 3.88 (m, 2H), 2.59 - 2.52 (m, 2H), 2.23 (s, 3H), 2.03 - 1.90 (m, 2H); LCMS (ESI), m/z = 397.19 [M+1]+. 1H NMR (400 MHz, DMSO-d 6 ) δ 9.10 (d, J = 7.1 Hz, 1H), 8.18 (d, J = 7.4 Hz, 1H), 7.63 - 7.58 (m, 2H), 7.58 - 7.52 (m, 2H), 7.18 - 7.11 (m, 2H), 6.87 (t, J = 7.2 Hz, 1H), 6.81 (d, J = 8.1 Hz, 1H), 4.47 (d, J = 2.4 Hz, 2H), 4.03 - 3.88 (m, 2H), 2.59 - 2.52 (m, 2H), 2.23 (s, 3H), 2.03 - 1.90 (m, 2H); LCMS (ESI), m/z = 397.19 [M+1] + .

화합물 57 (EIF-057):Compound 57 (EIF-057):

DMF 내 용해된 N-(3-아미노사이클로부틸)-3-(4-클로로페닐)프로피올아마이드 (1.0 equiv), 2-(m-톨릴옥시)아세트산[2-(m-tolyloxy)acetic acid] (1.2 equiv), N,N-디이소프로필에틸아민 (2.5 equiv), EDCI (1.5 equiv) 및 HOBt (1.5 equiv) 용액을 실온에서 밤새 교반하였다. 반응 혼합물을 에틸 아세테이트로 희석시키고 10% 수성 염화 리튬 (Х3) 및 염수로 세척하였다. 유기 층을 무수 MgSO4로 건조시키고, 감압 하에서 농축시켰다. 잔류물을 실리카 겔 크로마토그래피 (60% EtOAc/n-hexane)로 정제하여 95% 순도의 백색 고체 화합물 57 (EIF-057) 3-(4-클로로페닐)-N-(3-(2-(m-톨릴옥시)아세트아미도)사이클로부틸)프로피올아마이드 21.3 mg (42%)을 수득하였다.A solution of N -(3-aminocyclobutyl)-3-(4-chlorophenyl)propiolamide (1.0 equiv), 2-( m -tolyloxy)acetic acid (1.2 equiv), N , N -diisopropylethylamine (2.5 equiv), EDCI (1.5 equiv), and HOBt (1.5 equiv) dissolved in DMF was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with 10% aqueous lithium chloride (X3) and brine. The organic layer was dried over anhydrous MgSO 4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (60% EtOAc/ n -hexane) to give 21.3 mg (42%) of 3-(4-chlorophenyl)- N -(3-(2-( m -tolyloxy)acetamido)cyclobutyl) propiolamide as a white solid with 95% purity (EIF-057) .

3-(4-클로로페닐)-N-(3-(2-(m-톨릴옥시)아세트아미도)사이클로부틸)프로피올아마이드[3-(4-chlorophenyl)-N-(3-(2-(m-tolyloxy)acetamido)cyclobutyl)propiolamide]3-(4-chlorophenyl)-N-(3-(2-(m-tolyloxy)acetamido)cyclobutyl)propiolamide

1H NMR (400 MHz, DMSO-d6) δ 9.10 (d, J = 7.0 Hz, 1H), 8.29 (d, J = 7.3 Hz, 1H), 7.63 - 7.58 (m, 2H), 7.57 - 7.52 (m, 2H), 7.21 - 7.14 (m, 1H), 6.83 - 6.70 (m, 3H), 4.46 - 4.39 (m, 2H), 4.03 - 3.87 (m, 2H), 2.59 - 2.51 (m, 2H), 2.31 - 2.23 (m, 3H), 2.05 - 1.93 (m, 2H); LCMS (ESI), m/z = 397.23 [M+1]+. 1H NMR (400 MHz, DMSO-d 6 ) δ 9.10 (d, J = 7.0 Hz, 1H), 8.29 (d, J = 7.3 Hz, 1H), 7.63 - 7.58 (m, 2H), 7.57 - 7.52 (m, 2H), 7.21 - 7.14 (m, 1H), 6.83 - 6.70 (m, 3H), 4.46 - 4.39 (m, 2H), 4.03 - 3.87 (m, 2H), 2.59 - 2.51 (m, 2H), 2.31 - 2.23 (m, 3H), 2.05 - 1.93 (m, 2H); LCMS (ESI), m/z = 397.23 [M+1] + .

화합물 58 (EIF-058):Compound 58 (EIF-058):

DMF 내 용해된 N-(3-아미노사이클로부틸)-3-(4-클로로페닐)프로피올아마이드 (1.0 equiv), 2-(2-플루오로페녹시)아세트산[2-(2-fluorophenoxy)acetic acid] (1.2 equiv), N,N-디이소프로필에틸아민 (2.5 equiv), EDCI (1.5 equiv) 및 HOBt (1.5 equiv) 용액을 실온에서 밤새 교반하였다. 반응 혼합물을 에틸 아세테이트로 희석시키고 10% 수성 염화 리튬 (Х3) 및 염수로 세척하였다. 유기 층을 무수 MgSO4로 건조시키고, 감압 하에서 농축시켰다. 잔류물을 실리카 겔 크로마토그래피 (50% EtOAc/n-hexane)로 정제하여 97% 순도의 백색 고체 화합물 58 (EIF-058) 3-(4-클로로페닐)-N-(3-(2-(2-플루오로페녹시)아세트아미도)사이클로부틸)프로피올아마이드 21.7 mg (44%)을 수득하였다.A solution of N -(3-aminocyclobutyl)-3-(4-chlorophenyl)propiolamide (1.0 equiv), 2-(2-fluorophenoxy)acetic acid (1.2 equiv), N , N -diisopropylethylamine (2.5 equiv), EDCI (1.5 equiv), and HOBt (1.5 equiv) dissolved in DMF was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with 10% aqueous lithium chloride (X3) and brine. The organic layer was dried over anhydrous MgSO 4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (50% EtOAc/ n -hexane) to give 21.7 mg (44% ) of 3-(4-chlorophenyl)- N -(3-(2-(2-fluorophenoxy)acetamido)cyclobutyl)propiolamide as a white solid with 97% purity.

3-(4-클로로페닐)-N-(3-(2-(2-플루오로페녹시)아세트아미도)사이클로부틸)프로피올아마이드[3-(4-chlorophenyl)-N-(3-(2-(2-fluorophenoxy)acetamido)cyclobutyl)propiolamide]3-(4-chlorophenyl)-N-(3-(2-(2-fluorophenoxy)acetamido)cyclobutyl)propiolamide

1H NMR (400 MHz, DMSO-d6) δ 9.10 (d, J = 7.1 Hz, 1H), 8.33 (d, J = 7.3 Hz, 1H), 7.64 - 7.58 (m, 2H), 7.57 - 7.52 (m, 2H), 7.28 - 7.19 (m, 1H), 7.16 - 7.09 (m, 1H), 7.08 - 7.02 (m, 1H), 7.02 - 6.91 (m, 1H), 4.55 (d, J = 3.1 Hz, 2H), 4.02 - 3.85 (m, 2H), 2.59 - 2.52 (m, 2H), 2.03 - 1.90 (m, 2H); LCMS (ESI), m/z = 401.18 [M+1]+. 1H NMR (400 MHz, DMSO-d 6 ) δ 9.10 (d, J = 7.1 Hz, 1H), 8.33 (d, J = 7.3 Hz, 1H), 7.64 - 7.58 (m, 2H), 7.57 - 7.52 (m, 2H), 7.28 - 7.19 (m, 1H), 7.16 - 7.09 (m, 1H), 7.08 - 7.02 (m, 1H), 7.02 - 6.91 (m, 1H), 4.55 (d, J = 3.1 Hz, 2H), 4.02 - 3.85 (m, 2H), 2.59 - 2.52 (m, 2H), 2.03 - 1.90 (m, 2H); LCMS (ESI), m/z = 401.18 [M+1] + .

화합물 59 (EIF-059):Compound 59 (EIF-059):

DMF 내 용해된 N-(3-아미노사이클로부틸)-3-(4-클로로페닐)프로피올아마이드 (1.0 equiv), 2-(3-플루오로페녹시)아세트산[2-(3-fluorophenoxy)acetic acid] (1.2 equiv), N,N-디이소프로필에틸아민 (2.5 equiv), EDCI (1.5 equiv) 및 HOBt (1.5 equiv) 용액을 실온에서 밤새 교반하였다. 반응 혼합물을 에틸 아세테이트로 희석시키고 10% 수성 염화 리튬 (Х3) 및 염수로 세척하였다. 유기 층을 무수 MgSO4로 건조시키고, 감압 하에서 농축시켰다. 잔류물을 실리카 겔 크로마토그래피 (50% EtOAc/n-hexane)로 정제하여 96% 순도의 백색 고체 화합물 59 (EIF-059) 3-(4-클로로페닐)-N-(3-(2-(3-플루오로페녹시)아세트아미도)사이클로부틸)프로피올아마이드 19.2 mg (38%)을 수득하였다.A solution of N -(3-aminocyclobutyl)-3-(4-chlorophenyl)propiolamide (1.0 equiv), 2-(3-fluorophenoxy)acetic acid (1.2 equiv), N , N -diisopropylethylamine (2.5 equiv), EDCI (1.5 equiv), and HOBt (1.5 equiv) dissolved in DMF was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with 10% aqueous lithium chloride (X3) and brine. The organic layer was dried over anhydrous MgSO 4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (50% EtOAc/ n -hexane) to give 19.2 mg (38%) of 3-(4-chlorophenyl)- N -(3-(2-(3-fluorophenoxy)acetamido)cyclobutyl)propiolamide as a white solid compound 59 (EIF-059) with 96% purity.

3-(4-클로로페닐)-N-(3-(2-(3-플루오로페녹시)아세트아미도)사이클로부틸)프로피올아마이드[3-(4-chlorophenyl)-N-(3-(2-(3-fluorophenoxy)acetamido)cyclobutyl)propiolamide]3-(4-chlorophenyl)-N-(3-(2-(3-fluorophenoxy)acetamido)cyclobutyl)propiolamide

1H NMR (400 MHz, DMSO-d6) δ 9.11 (d, J = 6.9 Hz, 1H), 8.35 (d, J = 7.1 Hz, 1H), 7.64 - 7.57 (m, 2H), 7.55 (d, J = 8.5 Hz, 2H), 7.37 - 7.30 (m, 1H), 6.87 - 6.76 (m, 3H), 4.49 (s, 2H), 4.03 - 3.86 (m, 2H), 2.59 - 2.51 (m, 2H), 2.04 - 1.92 (m, 2H); LCMS (ESI), m/z = 401.18 [M+1]+. 1H NMR (400 MHz, DMSO-d 6 ) δ 9.11 (d, J = 6.9 Hz, 1H), 8.35 (d, J = 7.1 Hz, 1H), 7.64 - 7.57 (m, 2H), 7.55 (d, J = 8.5 Hz, 2H), 7.37 - 7.30 (m, 1H), 6.87 - 6.76 (m, 3H), 4.49 (s, 2H), 4.03 - 3.86 (m, 2H), 2.59 - 2.51 (m, 2H), 2.04 - 1.92 (m, 2H); LCMS (ESI), m/z = 401.18 [M+1] + .

화합물 60 (EIF-060):Compound 60 (EIF-060):

DMF 내 용해된 N-(3-아미노사이클로부틸)-3-(4-클로로페닐)프로피올아마이드 (1.0 equiv), 2-(p-톨릴옥시)아세트산[2-(p-tolyloxy)acetic acid] (1.2 equiv), N,N-디이소프로필에틸아민 (2.5 equiv), EDCI (1.5 equiv) 및 HOBt (1.5 equiv) 용액을 실온에서 밤새 교반하였다. 반응 혼합물을 에틸 아세테이트로 희석시키고 10% 수성 염화 리튬 (Х3) 및 염수로 세척하였다. 유기 층을 무수 MgSO4로 건조시키고, 감압 하에서 농축시켰다. 잔류물을 실리카 겔 크로마토그래피 (50% EtOAc/n-hexane)로 정제하여 96% 순도의 백색 고체 화합물 60 (EIF-060) 3-(4-클로로페닐)-N-(3-(2-(p-톨릴톡시)아세트아미도)사이클로부틸)프로피올아마이드 7.1 mg (14%)을 수득하였다.A solution of N -(3-aminocyclobutyl)-3-(4-chlorophenyl)propiolamide (1.0 equiv), 2-( p -tolyloxy)acetic acid (1.2 equiv), N , N -diisopropylethylamine (2.5 equiv), EDCI (1.5 equiv), and HOBt (1.5 equiv) dissolved in DMF was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with 10% aqueous lithium chloride (X3) and brine. The organic layer was dried over anhydrous MgSO 4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (50% EtOAc/ n -hexane) to give 7.1 mg (14%) of 3-(4-chlorophenyl)- N -(3-(2-( p -tolylthoxy)acetamido)cyclobutyl)propiolamide as a white solid compound 60 (EIF-060) with 96% purity.

3-(4-클로로페닐)-N-(3-(2-(p-톨릴톡시)아세트아미도)사이클로부틸)프로피올아마이드[3-(4-chlorophenyl)-N-(3-(2-(p-tolyloxy)acetamido)cyclobutyl)propiolamide]3-(4-chlorophenyl)-N-(3-(2-(p-tolyloxy)acetamido)cyclobutyl)propiolamide

1H NMR (400 MHz, DMSO-d6) δ 9.09 (d, J = 7.0 Hz, 1H), 8.28 (d, J = 7.4 Hz, 1H), 7.64 - 7.57 (m, 2H), 7.58 - 7.51 (m, 2H), 7.10 (d, J = 8.2 Hz, 2H), 6.89 - 6.81 (m, 2H), 4.40 (d, J = 2.5 Hz, 2H), 4.03 - 3.87 (m, 2H), 2.58 - 2.51 (m, 2H), 2.24 (s, 3H), 2.04 - 1.93 (m, 2H); LCMS (ESI), m/z = 397.21 [M+1]+. 1H NMR (400 MHz, DMSO-d 6 ) δ 9.09 (d, J = 7.0 Hz, 1H), 8.28 (d, J = 7.4 Hz, 1H), 7.64 - 7.57 (m, 2H), 7.58 - 7.51 (m, 2H) , 7.10 (d, J = 8.2) Hz, 2H), 6.89 - 6.81 (m, 2H), 4.40 (d, J = 2.5 Hz, 2H), 4.03 - 3.87 (m, 2H), 2.58 - 2.51 (m, 2H), 2.24 (s, 3H), 2.04 - 1.93 (m, 2H); LCMS (ESI), m/z = 397.21 [M+1] + .

화합물 61 (EIF-061):Compound 61 (EIF-061):

DMF 내 용해된 N-(3-아미노사이클로부틸)-3-(4-클로로페닐)프로피올아마이드 (1.0 equiv), 2-(2,4-디플루오로페녹시)아세트산[2-(2,4-difluorophenoxy)acetic acid] (1.2 equiv), N,N-디이소프로필에틸아민 (2.5 equiv), EDCI (1.5 equiv) 및 HOBt (1.5 equiv) 용액을 실온에서 밤새 교반하였다. 반응 혼합물을 에틸 아세테이트로 희석시키고 10% 수성 염화 리튬 (Х3) 및 염수로 세척하였다. 유기 층을 무수 MgSO4로 건조시키고, 감압 하에서 농축시켰다. 잔류물을 실리카 겔 크로마토그래피 (50% EtOAc/n-hexane)로 정제하여 96% 순도의 담황색 고체 화합물 61 (EIF-061) 3-(4-클로로페닐)-N-(3-(2-(2,4-디플루오로페녹시)아세트아미도)사이클로부틸)프로피올아마이드 6.4 mg (12%)을 수득하였다.A solution of N -(3-aminocyclobutyl)-3-(4-chlorophenyl)propiolamide (1.0 equiv), 2-(2,4-difluorophenoxy)acetic acid (1.2 equiv), N , N -diisopropylethylamine (2.5 equiv), EDCI (1.5 equiv), and HOBt (1.5 equiv) dissolved in DMF was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with 10% aqueous lithium chloride (X3) and brine. The organic layer was dried over anhydrous MgSO 4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (50% EtOAc/ n -hexane) to obtain 6.4 mg (12%) of 3-(4-chlorophenyl)- N -(3-(2-(2,4-difluorophenoxy)acetamido)cyclobutyl)propiolamide as a pale yellow solid compound 61 (EIF-061) with 96% purity.

3-(4-클로로페닐)-N-(3-(2-(2,4-디플루오로페녹시)아세트아미도)사이클로부틸)프로피올아마이드[3-(4-chlorophenyl)-N-(3-(2-(2,4-difluorophenoxy)acetamido)cyclobutyl)propiolamide]3-(4-chlorophenyl)-N-(3-(2-(2,4-difluorophenoxy)acetamido)cyclobutyl)propiolamide

1H NMR (400 MHz, DMSO-d6) δ 9.10 (d, J = 7.1 Hz, 1H), 8.33 (d, J = 7.4 Hz, 1H), 7.63 - 7.57 (m, 2H), 7.58 - 7.51 (m, 2H), 7.35 - 7.29 (m, 1H), 7.13 - 7.06 (m, 1H), 7.05 - 6.99 (m, 1H), 4.54 (d, J = 3.1 Hz, 2H), 4.01 - 3.87 (m, 2H), 2.58 - 2.52 (m, 2H), 2.01 - 1.90 (m, 2H); LCMS (ESI), m/z = 419.21 [M+1]+. 1H NMR (400 MHz, DMSO-d 6 ) δ 9.10 (d, J = 7.1 Hz, 1H), 8.33 (d, J = 7.4 Hz, 1H), 7.63 - 7.57 (m, 2H), 7.58 - 7.51 (m, 2H), 7.35 - 7.29 (m, 1H), 7.13 - 7.06 (m, 1H), 7.05 - 6.99 (m, 1H), 4.54 (d, J = 3.1 Hz, 2H), 4.01 - 3.87 (m, 2H), 2.58 - 2.52 (m, 2H), 2.01 - 1.90 (m, 2H); LCMS (ESI), m/z = 419.21 [M+1] + .

화합물 62 (EIF-062):Compound 62 (EIF-062):

DMF 내 용해된 N-(3-아미노사이클로부틸)-3-(4-클로로페닐)프로피올아마이드 (1.0 equiv), 2-(2-클로로페녹시)아세트산[2-(2-chlorophenoxy)acetic acid] (1.2 equiv), N,N-디이소프로필에틸아민 (2.5 equiv), EDCI (1.5 equiv) 및 HOBt (1.5 equiv) 용액을 실온에서 밤새 교반하였다. 반응 혼합물을 에틸 아세테이트로 희석시키고 10% 수성 염화 리튬 (Х3) 및 염수로 세척하였다. 유기 층을 무수 MgSO4로 건조시키고, 감압 하에서 농축시켰다. 잔류물을 실리카 겔 크로마토그래피 (60% EtOAc/n-hexane)로 정제하여 95% 순도의 백색 고체 화합물 62 (EIF-062) N-(3-(2-(2-클로로페녹시)아세트아미도)사이클로부틸)-3-(4-클로로페닐)프로피올아마이드 6.2 mg (12%)을 수득하였다.A solution of N -(3-aminocyclobutyl)-3-(4-chlorophenyl)propiolamide (1.0 equiv), 2-(2-chlorophenoxy)acetic acid (1.2 equiv), N , N -diisopropylethylamine (2.5 equiv), EDCI (1.5 equiv), and HOBt (1.5 equiv) dissolved in DMF was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with 10% aqueous lithium chloride (X3) and brine. The organic layer was dried over anhydrous MgSO 4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (60% EtOAc/ n -hexane) to give 6.2 mg (12%) of white solid compound 62 (EIF-062) N -(3-(2-(2-chlorophenoxy)acetamido)cyclobutyl)-3-(4-chlorophenyl)propiolamide with 95% purity.

N-(3-(2-(2-클로로페녹시)아세트아미도)사이클로부틸)-3-(4-클로로페닐)프로피올아마이드[N-(3-(2-(2-chlorophenoxy)acetamido)cyclobutyl)-3-(4-chlorophenyl)propiolamide]N-(3-(2-(2-chlorophenoxy)acetamido)cyclobutyl)-3-(4-chlorophenyl)propiolamide

1H NMR (400 MHz, DMSO-d6) δ 9.11 (d, J = 7.1 Hz, 1H), 8.21 (d, J = 7.4 Hz, 1H), 7.64 - 7.58 (m, 2H), 7.57 - 7.52 (m, 2H), 7.47 - 7.41 (m, 1H), 7.33 - 7.24 (m, 1H), 7.03 - 6.93 (m, 2H), 4.59 (d, J = 2.8 Hz, 2H), 4.04 - 3.89 (m, 2H), 2.61 - 2.52 (m, 2H), 2.00 - 1.90 (m, 2H); LCMS (ESI), m/z = 418.20 [M+1]+. 1H NMR (400 MHz, DMSO-d 6 ) δ 9.11 (d, J = 7.1 Hz, 1H), 8.21 (d, J = 7.4 Hz, 1H), 7.64 - 7.58 (m, 2H), 7.57 - 7.52 (m, 2H), 7.47 - 7.41 (m, 1H), 7.33 - 7.24 (m, 1H), 7.03 - 6.93 (m, 2H), 4.59 (d, J = 2.8 Hz, 2H), 4.04 - 3.89 (m, 2H), 2.61 - 2.52 (m, 2H), 2.00 - 1.90 (m, 2H); LCMS (ESI), m/z = 418.20 [M+1] + .

화합물 63 (EIF-063):Compound 63 (EIF-063):

DMF 내 용해된 N-(3-아미노사이클로부틸)-3-(4-클로로페닐)프로피올아마이드 (1.0 equiv), 2-(4-클로로-2-메틸페녹시)아세트산[2-(4-chloro-2-methylphenoxy) acetic acid] (1.2 equiv), N,N-디이소프로필에틸아민 (2.5 equiv), EDCI (1.5 equiv) 및 HOBt (1.5 equiv) 용액을 실온에서 밤새 교반하였다. 반응 혼합물을 에틸 아세테이트로 희석시키고 10% 수성 염화 리튬 (Х3) 및 염수로 세척하였다. 유기 층을 무수 MgSO4로 건조시키고, 감압 하에서 농축시켰다. 잔류물을 실리카 겔 크로마토그래피 (50% EtOAc/n-hexane)로 정제하여 97% 순도의 백색 고체 화합물 63 (EIF-063) N-(3-(2-(4-클로로-2-메틸페녹시)아세트아미도)사이클로부틸)-3-(4-클로로페닐)프로피올아마이드 8.7 mg (16%)을 수득하였다.A solution of N -(3-aminocyclobutyl)-3-(4-chlorophenyl)propiolamide (1.0 equiv), 2-(4-chloro-2-methylphenoxy)acetic acid (1.2 equiv), N , N -diisopropylethylamine (2.5 equiv), EDCI (1.5 equiv), and HOBt (1.5 equiv) dissolved in DMF was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with 10% aqueous lithium chloride (X3) and brine. The organic layer was dried over anhydrous MgSO 4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (50% EtOAc/ n -hexane) to give 8.7 mg (16%) of white solid compound 63 (EIF-063) N -(3-(2-(4-chloro-2-methylphenoxy)acetamido)cyclobutyl)-3-(4-chlorophenyl)propiolamide with 97% purity.

N-(3-(2-(4-클로로-2-메틸페녹시)아세트아미도)사이클로부틸)-3-(4-클로로페닐)프로피올아마이드[N-(3-(2-(4-chloro-2-methylphenoxy)acetamido)cyclobutyl)-3-(4-chlorophenyl)propiolamide]N-(3-(2-(4-chloro-2-methylphenoxy)acetamido)cyclobutyl)-3-(4-chlorophenyl)propiolamide

1H NMR (400 MHz, DMSO-d6) δ 9.10 (d, J = 7.0 Hz, 1H), 8.21 (d, J = 7.3 Hz, 1H), 7.64 - 7.58 (m, 2H), 7.57 - 7.52 (m, 2H), 7.26 - 7.21 (m, 1H), 7.19 (dd, J = 8.7, 2.6 Hz, 1H), 6.82 (d, J = 8.7 Hz, 1H), 4.49 (d, J = 2.9 Hz, 2H), 4.01 - 3.87 (m, 2H), 2.59 - 2.52 (m, 2H), 2.22 (s, 3H), 2.01 - 1.90 (m, 2H); LCMS (ESI), m/z = 431.19 [M+1]+. 1H NMR (400 MHz, DMSO-d 6 ) δ 9.10 (d, J = 7.0 Hz, 1H), 8.21 (d, J = 7.3 Hz, 1H), 7.64 - 7.58 (m, 2H), 7.57 - 7.52 (m, 2H), 7.26 - 7.21 (m, 1H), 7.19 (dd, J = 8.7, 2.6 Hz, 1H), 6.82 (d, J = 8.7 Hz, 1H), 4.49 (d, J = 2.9 Hz, 2H), 4.01 - 3.87 (m, 2H), 2.59 - 2.52 (m, 2H), 2.22 (s, 3H), 2.01 - 1.90 (m, 2H); LCMS (ESI), m/z = 431.19 [M+1] + .

화합물 64 (EIF-064):Compound 64 (EIF-064):

CH2Cl2 내 용해된 N-(3-아미노사이클로부틸)-3-(4-클로로페닐)프로피올아마이드 (1.0 equiv)에 2-(4-클로로페녹시)아세틸 클로라이드 (1.5 equiv) 및 트리에틸아민 (5 equiv)을 첨가하였다. 반응 혼합물을을 실온에서 교반하였다. 반응 혼합물을 에틸 아세테이트로 희석시키고 10% 수성 염화 리튬 (Х3) 및 염수로 세척하였다. 유기 층을 무수 MgSO4로 건조시키고, 감압 하에서 농축시켰다. 잔류물을 실리카 겔 크로마토그래피 (60% EtOAc/n-hexane)로 정제하여 95% 순도의 백색 고체 화합물 64 (EIF-064) N-(3-(2-(4-클로로페녹시)아세트아미도)사이클로부틸)-3-(4-클로로페닐)프로피올아마이드 8.7 mg (16%)을 수득하였다.To N- (3-aminocyclobutyl)-3-(4-chlorophenyl)propiolamide (1.0 equiv) dissolved in CH 2 Cl 2 were added 2-(4-chlorophenoxy)acetyl chloride (1.5 equiv) and triethylamine (5 equiv). The reaction mixture was stirred at room temperature. The reaction mixture was diluted with ethyl acetate and washed with 10% aqueous lithium chloride (X3) and brine. The organic layer was dried over anhydrous MgSO 4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (60% EtOAc/ n -hexane) to give 8.7 mg (16%) of white solid compound 64 (EIF-064) N -(3-(2-(4-chlorophenoxy)acetamido)cyclobutyl)-3-(4-chlorophenyl)propiolamide with 95% purity.

N-(3-(2-(4-클로로페녹시)아세트아미도)사이클로부틸)-3-(4-클로로페닐)프로피올아마이드[N-(3-(2-(4-chlorophenoxy)acetamido)cyclobutyl)-3-(4-chlorophenyl)propiolamide]N-(3-(2-(4-chlorophenoxy)acetamido)cyclobutyl)-3-(4-chlorophenyl)propiolamide

1H NMR (400 MHz, DMSO-d6) δ 9.10 (d, J = 7.0 Hz, 1H), 8.34 (d, J = 7.3 Hz, 1H), 7.63 - 7.58 (m, 2H), 7.55 (d, J = 8.6 Hz, 2H), 7.38 - 7.32 (m, 2H), 7.02 - 6.95 (m, 2H), 4.47 (d, J = 2.8 Hz, 2H), 4.02 - 3.87 (m, 2H), 2.58 - 2.52 (m, 2H), 2.03 - 1.92 (m, 2H); LCMS (ESI), m/z = 417.20 [M+1]+. 1H NMR (400 MHz, DMSO-d 6 ) δ 9.10 (d, J = 7.0 Hz, 1H), 8.34 (d, J = 7.3 Hz, 1H), 7.63 - 7.58 (m, 2H), 7.55 (d, J = 8.6 Hz, 2H), 7.38 - 7.32 (m, 2H), 7.02 - 6.95 (m, 2H), 4.47 (d, J = 2.8 Hz, 2H), 4.02 - 3.87 (m, 2H), 2.58 - 2.52 (m, 2H), 2.03 - 1.92 (m, 2H); LCMS (ESI), m/z = 417.20 [M+1] + .

화합물 65 (EIF-065):Compound 65 (EIF-065):

벤조[d]티아졸-2-아민[Benzo[d]thiazol-2-amine] (175 mg, 1.17 mmol)을 DMF 내 용해된 4-(((터트-부톡시카르보닐)아미노)메틸)사이클로헥산-1-카르복실산[4-(((tert-butoxycarbonyl)amino)methyl)cyclohexane-1-carboxylic acid] (200 mg, 0.78 mmol), EDCI (300 mg, 1.55 mmol), HOBt (238 mg, 1.55 mmol) 및 DIPEA (301 mg, 2.33 mmol) 용액에 첨가하고, 밤새 실온에서 교반하였다. 용액을 EtOAc로 희석시키고 NaHCO3로 세척한 다음, Na2SO4로 건조시키고 농축시켰다. 조 생성물을 MPLC (EtOAc:hexane=1:1)로 정제하여 생성물을 수득하였다 (100 mg, 33% 수율).Benzo[ d ] thiazol-2-amine (175 mg, 1.17 mmol) was added to a solution of 4-((( tert -butoxycarbonyl)amino)methyl)cyclohexane-1-carboxylic acid (200 mg, 0.78 mmol), EDCI (300 mg, 1.55 mmol), HOBt (238 mg, 1.55 mmol), and DIPEA (301 mg, 2.33 mmol) in DMF and stirred overnight at room temperature. The solution was diluted with EtOAc, washed with NaHCO 3 , dried over Na 2 SO 4 , and concentrated. The crude product was purified by MPLC (EtOAc:hexane=1:1) to obtain the product (100 mg, 33% yield).

1H NMR (400 MHz, DMSO-d6) δ 12.27 (s, 1H), 7.96 (d, J = 7.6 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.50 - 7.38 (m, 1H), 7.35 - 7.21 (m, 1H), 6.83 (t, J = 5.7 Hz, 1H), 2.80 (t, J = 6.3 Hz, 2H), 2.49 - 2.41 (m, 1H), 1.90 (d, J = 11.0 Hz, 2H), 1.76 (d, J = 11.0 Hz, 2H), 1.50 - 1.28 (m, 12H), 0.92 (dd, J = 23.7, 11.3 Hz, 2H). 1H NMR (400 MHz, DMSO-d 6 ) δ 12.27 (s, 1H), 7.96 (d, J = 7.6 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.50 - 7.38 (m, 1H), 7.35 - 7.21 (m, 1H), 6.83 (t, J = 5.7 Hz, 1H), 2.80 (t, J = 6.3 Hz, 2H), 2.49 - 2.41 (m, 1H), 1.90 (d, J = 11.0 Hz, 2H), 1.76 (d, J = 11.0 Hz, 2H), 1.50 - 1.28 (m, 12H), 0.92 (dd, J = 23.7, 11.3 Hz, 2H).

20% TFA/ CH2Cl2 내 터트-부틸 ((4-(벤조[d]티아졸-2-일카르바모일))사이클로헥실)메틸)카르바메이트[tert-butyl ((4-(benzo[d]thiazol-2-ylcarbamoyl)cyclohexyl)methyl)carbamate] (90 mg, 0.23 mmol) 용액을 실온에서 2시간 동안 교반하였다. 유기 용액을 감압 하에서 제거하였다.A solution of tert-butyl ((4-(benzo[ d ]thiazol-2-ylcarbamoyl))cyclohexyl)methyl)carbamate] ( 90 mg, 0.23 mmol) in 20% TFA/ CH 2 Cl 2 was stirred at room temperature for 2 h. The organic solution was removed under reduced pressure.

DMF (1 mL, 0.1 M) 내 용해된 4-(아미노메틸)-N-(벤조[d]티아졸-2-일)사이클로헥산-1-카르복사마이드[4-(aminomethyl)-N-(benzo[d]thiazol-2-yl)cyclohexane-1-carboxamide] (29 mg, 0.1 mmol), 2-(4-클로로-3-플루오로페녹시)아세트산 (25 mg, 0.12 mmol), EDCI (39 mg, 0.2 mmol), HOBt (27 mg, 0.2 mmol) 및 DIPEA (39 mg, 0.3 mmol) 용액을 실온에서 12시간 동안 교반하였다. 용액을 EtOAc로 희석시키고 NaHCO3로 세척한 다음, Na2SO4로 건조시키고 농축시켰다. 조 생성물을 MPLC (EtOAc:hexane=1:1)로 정제하여 화합물 65 (EIF-065)를 수득하였다 (35 mg, 70% 수율).A solution of 4-(aminomethyl)- N -(benzo[ d ]thiazol-2-yl)cyclohexane-1-carboxamide (29 mg, 0.1 mmol), 2-(4-chloro - 3-fluorophenoxy)acetic acid (25 mg, 0.12 mmol), EDCI (39 mg, 0.2 mmol), HOBt (27 mg, 0.2 mmol ), and DIPEA (39 mg, 0.3 mmol) in DMF (1 mL, 0.1 M) was stirred at room temperature for 12 h. The solution was diluted with EtOAc, washed with NaHCO 3 , dried over Na 2 SO 4 , and concentrated. The crude product was purified by MPLC (EtOAc:hexane=1:1) to obtain compound 65 (EIF-065) (35 mg, 70% yield).

(1r,4r)-N-(벤조[d]티아졸-2-일)-4-((2-(4-클로로-3-플루오로페녹시)아세트아미도)메틸)사이클로헥산-1-카르복사마이드[(1r,4r)-N-(benzo[d]thiazol-2-yl)-4-((2-(4-chloro-3-fluorophenoxy)acetamido)methyl)cyclohexane-1-carboxamide](1r,4r)-N-(benzo[d]thiazol-2-yl)-4-((2-(4-chloro-3-fluorophenoxy)acetamido)methyl)cyclohexane-1-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 12.31 (s, 1H), 8.15 (t, J = 5.9 Hz, 1H), 7.97 (d, J = 7.9 Hz, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.52 (t, J = 8.9 Hz, 1H), 7.47 - 7.39 (m, 1H), 7.35 - 7.24 (m, 1H), 7.08 (dd, J = 11.4, 2.8 Hz, 1H), 6.87 (ddd, J = 9.0, 2.8, 1.0 Hz, 1H), 4.55 (s, 2H), 3.01 (t, J = 6.4 Hz, 2H), 2.47 (dd, J = 12.1, 3.3 Hz, 1H), 1.90 (d, J = 11.0 Hz, 2H), 1.74 (d, J = 11.0 Hz, 2H), 1.52 - 1.31 (m, 3H), 0.93 (qd, J = 12.9, 2.7 Hz, 2H). 1H NMR (400 MHz, DMSO-d 6 ) δ 12.31 (s, 1H), 8.15 (t, J = 5.9 Hz, 1H), 7.97 (d, J = 7.9 Hz, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.52 (t, J = 8.9) Hz, 1H), 7.47 - 7.39 (m, 1H), 7.35 - 7.24 (m, 1H), 7.08 (dd, J = 11.4, 2.8 Hz, 1H), 6.87 (ddd, J = 9.0, 2.8, 1.0 Hz, 1H), 4.55 (s, 2H), 3.01 (t, J = 6.4 Hz, 2H), 2.47 (dd, J = 12.1, 3.3 Hz, 1H), 1.90 (d, J = 11.0 Hz, 2H), 1.74 (d, J = 11.0 Hz, 2H), 1.52 - 1.31 (m, 3H), 0.93 (qd, J = 12.9, 2.7 Hz, 2H).

MS (ESI+) m/z calcd for C23H23ClFN3O3S [M+H]+ 476.12; found 476.22. MS (ESI + ) m/z calcd for C 23 H 23 ClFN 3 O 3 S [M+H] + 476.12; found 476.22.

화합물 66 (EIF-066):Compound 66 (EIF-066):

DMF (1 mL, 0.1 M) 내 용해된 4-(아미노메틸)-N-(벤조[d]티아졸-2-일)사이클로헥산-1-카르복사마이드 (29 mg, 0.1 mmol), 2-(2,4-디플루오로페녹시)아세트산 (23 mg, 0.12 mmol), EDCI (39 mg, 0.2 mmol), HOBt (27 mg, 0.2 mmol) 및 DIPEA (39 mg, 0.3 mmol) 용액을 실온에서 12시간 동안 교반하였다. 용액을 EtOAc로 희석시키고 NaHCO3로 세척한 다음, Na2SO4로 건조시키고 농축시켰다. 조 생성물을 MPLC (EtOAc:hexane=1:1)로 정제하여 화합물 66 (EIF-066)을 수득하였다 (30 mg, 64% 수율).A solution of 4-(aminomethyl)- N -(benzo[ d ]thiazol-2-yl)cyclohexane-1-carboxamide (29 mg, 0.1 mmol), 2-(2,4-difluorophenoxy)acetic acid (23 mg, 0.12 mmol), EDCI (39 mg, 0.2 mmol), HOBt (27 mg, 0.2 mmol), and DIPEA (39 mg, 0.3 mmol) in DMF (1 mL, 0.1 M) was stirred at room temperature for 12 h. The solution was diluted with EtOAc, washed with NaHCO 3 , dried over Na 2 SO 4 , and concentrated. The crude product was purified by MPLC (EtOAc:hexane = 1:1) to give compound 66 (EIF-066) (30 mg, 64% yield).

(1r,4r)-N-(벤조[d]티아졸-2-일)-4-((2-(2,4-디플루오로페녹시)아세트아미도)메틸)사이클로헥산-1-카르복사마이드[(1r,4r)-N-(benzo[d]thiazol-2-yl)-4-((2-(2,4-difluorophenoxy)acetamido)methyl)cyclohexane-1-carboxamide](1r,4r)-N-(benzo[d]thiazol-2-yl)-4-((2-(2,4-difluorophenoxy)acetamido)methyl)cyclohexane-1-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 12.29 (s, 1H), 8.14 (t, J = 5.8 Hz, 1H), 7.97 (d, J = 7.7 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.51 (t, J = 8.9 Hz, 1H), 7.43 (t, J = 7.2 Hz, 1H), 7.30 (t, J = 7.5 Hz, 1H), 7.08 (dd, J = 11.4, 2.8 Hz, 1H), 6.87 (dd, J = 8.9, 1.9 Hz, 1H), 4.55 (s, 2H), 3.01 (t, J = 6.3 Hz, 2H), 2.48 - 2.41 (m, 1H), 1.90 (d, J = 11.2 Hz, 2H), 1.75 (d, J = 11.0 Hz, 2H), 1.52 - 1.31 (m, 3H), 1.02 - 0.81 (m, 2H). 1H NMR (400 MHz, DMSO-d 6 ) δ 12.29 (s, 1H), 8.14 (t, J = 5.8 Hz, 1H), 7.97 (d, J = 7.7 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.51 (t, J = 8.9) Hz, 1H), 7.43 (t, J = 7.2 Hz, 1H), 7.30 (t, J = 7.5 Hz, 1H), 7.08 (dd, J = 11.4, 2.8 Hz, 1H), 6.87 (dd, J = 8.9, 1.9 Hz, 1H), 4.55 (s, 2H), 3.01 (t, J = 6.3 Hz, 2H), 2.48 - 2.41 (m, 1H), 1.90 (d, J = 11.2 Hz, 2H), 1.75 (d, J = 11.0 Hz, 2H), 1.52 - 1.31 (m, 3H), 1.02 - 0.81 (m, 2H).

MS (ESI+) m/z calcd for C23H23F2N3O3S [M+H]+ 460.15; found 460.26. MS (ESI + ) m/z calcd for C 23 H 23 F 2 N 3 O 3 S [M+H] + 460.15; found 460.26.

화합물 67 (EIF-067):Compound 67 (EIF-067):

DMF (4 mL, 0.25 M) 내 용해된 터트-부틸 ((3-아미노사이클로부틸)메틸)카르바메이트 (200 mg,1 mmol), 2-(4-클로로-3-플루오로페녹시)아세트산 (245 mg, 1.2 mmol), EDCI (385 mg, 2 mmol), HOBt (270 mg, 2 mmol) 및 DIPEA (388 mg, 3 mmol) 용액을 실온에서 12시간 동안 교반하였다. 용액을 EtOAc로 희석시키고 NaHCO3로 세척한 다음, Na2SO4로 건조시키고 농축시켰다. 조 생성물을 MPLC (EtOAc:hexane=1:1)로 정제하여 생성물을 수득하였다 (260 mg, 67% 수율).A solution of tert-butyl ((3-aminocyclobutyl)methyl)carbamate (200 mg, 1 mmol), 2-(4-chloro-3-fluorophenoxy)acetic acid (245 mg, 1.2 mmol), EDCI (385 mg, 2 mmol), HOBt (270 mg, 2 mmol), and DIPEA (388 mg, 3 mmol) dissolved in DMF (4 mL, 0.25 M) was stirred at room temperature for 12 h. The solution was diluted with EtOAc, washed with NaHCO 3 , dried over Na 2 SO 4 , and concentrated. The crude product was purified by MPLC (EtOAc:hexane = 1:1) to obtain the product (260 mg, 67% yield).

1H NMR (400 MHz, DMSO-d6) δ 8.28 (d, J = 7.8 Hz, 1H), 7.50 (t, J = 8.9 Hz, 1H), 7.08 (dt, J = 11.4, 2.5 Hz, 1H), 6.96 - 6.75 (m, 2H), 4.48 (s, 2H), 4.36 - 3.97 (m, 1H), 2.94 (t, J = 6.3 Hz, 2H), 2.21 (dd, J = 7.7, 2.7 Hz, 2H), 2.10 - 1.92 (m, 2H), 1.72 - 1.56 (m, 1H), 1.38 (s, 9H). 1H NMR (400 MHz, DMSO-d 6 ) δ 8.28 (d, J = 7.8 Hz, 1H), 7.50 (t, J = 8.9 Hz, 1H), 7.08 (dt, J = 11.4, 2.5 Hz, 1H), 6.96 - 6.75 (m, 2H), 4.48 (s, 2H), 4.36 - 3.97 (m, 1H), 2.94 (t, J = 6.3 Hz, 2H), 2.21 (dd, J = 7.7, 2.7 Hz, 2H), 2.10 - 1.92 (m, 2H), 1.72 - 1.56 (m, 1H), 1.38 (s, 9H).

20% TFA/ CH2Cl2 (1 mL, 0.09 M) 내 터트-부틸 ((3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)사이클로부틸)메틸)카르바메이트[tert-butyl ((3-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclobutyl)methyl)carbamate] (35 mg, 0.09 mmol) 용액을 실온에서 5시간 동안 교반하였다. 유기 용액을 감압 하에서 제거하고, 조 생성물을 추가 정제없이 다음 단계에서 사용하였다.A solution of tert-butyl ((3-(2-(4-chloro-3-fluorophenoxy) acetamido )cyclobutyl)methyl)carbamate (35 mg, 0.09 mmol) in 20% TFA/ CH 2 Cl 2 (1 mL, 0.09 M) was stirred at room temperature for 5 h. The organic solution was removed under reduced pressure, and the crude product was used in the next step without further purification.

DMF (1 mL, 0.09 M) 내 용해된 N-(3-(아미노메틸)사이클로부틸)-2-(4-클로로-3-플루오로페녹시)아세트아마이드[N-(3-(aminomethyl)cyclobutyl)-2-(4-chloro-3-fluorophenoxy)acetamide] (26 mg,0.09 mmol), 5-(디플루오로메틸)피라진-2-카르복실산[5-(difluoromethyl)pyrazine-2-carboxylic acid] (19 mg, 0.108 mmol), EDCI (35 mg, 0.18 mmol), HOBt (24 mg, 0.18 mmol) 및 DIPEA (35 mg, 0.27 mmol) 용액을 실온에서 12시간 동안 교반하였다. 용액을 EtOAc로 희석시키고 NaHCO3로 세척한 다음, Na2SO4로 건조시키고 농축시켰다. 조 생성물을 MPLC (EtOAc:hexane=1:1)로 정제하여 화합물 67 (EIF-067)을 수득하였다 (33 mg, 82% 수율).A solution of N -(3-(aminomethyl)cyclobutyl)-2-(4-chloro-3-fluorophenoxy)acetamide (26 mg, 0.09 mmol), 5-(difluoromethyl ) pyrazine-2-carboxylic acid (19 mg, 0.108 mmol), EDCI (35 mg, 0.18 mmol), HOBt (24 mg, 0.18 mmol), and DIPEA (35 mg, 0.27 mmol) in DMF (1 mL, 0.09 M) was stirred at room temperature for 12 h. The solution was diluted with EtOAc, washed with NaHCO 3 , dried over Na 2 SO 4 , and concentrated. The crude product was purified by MPLC (EtOAc:hexane=1:1) to obtain compound 67 (EIF-067) (33 mg, 82% yield).

N-((3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)사이클로부틸)메틸)-5-(디플루오로메틸)피라진-2-카르복사마이드[N-((3-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclobutyl)methyl)-5-(difluoromethyl)pyrazine-2-carboxamide]N-((3-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclobutyl)methyl)-5-(difluoromethyl)pyrazine-2-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 9.11 (t, J = 6.0 Hz, 1H), 9.03 (s, 1H), 8.31 (d, J = 7.8 Hz, 1H), 7.50 (t, J = 8.9 Hz, 1H), 7.38 - 7.01 (m, 2H), 6.85 (dd, J = 8.9, 2.8 Hz, 1H), 4.48 (s, 2H), 4.21 - 4.00 (m, 1H), 3.37 (t, J = 5.9 Hz, 2H), 2.30 - 2.15 (m, 2H), 2.09 (t, J = 7.0 Hz, 1H), 1.85 - 1.64 (m, 2H). 1H NMR (400 MHz, DMSO-d 6 ) δ 9.29 (s, 1H), 9.11 (t, J = 6.0 Hz, 1H), 9.03 (s, 1H), 8.31 (d, J = 7.8 Hz, 1H), 7.50 (t, J = 8.9 Hz, 1H), 7.38 - 7.01 (m, 2H), 6.85 (dd, J = 8.9, 2.8 Hz, 1H), 4.48 (s, 2H), 4.21 - 4.00 (m, 1H), 3.37 (t, J = 5.9 Hz, 2H), 2.30 - 2.15 (m, 2H), 2.09 (t, J = 7.0 Hz, 1H), 1.85 - 1.64 (m, 2H).

MS (ESI+) m/z calcd for C19H18ClF3N4O3 [M+H]+ 443.11; found 443.25. MS (ESI + ) m/z calcd for C 19 H 18 ClF 3 N 4 O 3 [M+H] + 443.11; found 443.25.

화합물 68 (EIF-068):Compound 68 (EIF-068):

DMF (1 mL, 0.09 M) 내 용해된 N-(3-(아미노메틸)사이클로부틸)-2-(4-클로로-3-플루오로페녹시)아세트아마이드 (26 mg,0.09 mmol), 니코틴산 (13 mg, 0.108 mmol), EDCI (35 mg, 0.18 mmol), HOBt (24 mg, 0.18 mmol) 및 DIPEA (35 mg, 0.27 mmol) 용액을 실온에서 12시간 동안 교반하였다. 용액을 EtOAc로 희석시키고 NaHCO3로 세척한 다음, Na2SO4로 건조시키고 농축시켰다. 조 생성물을 MPLC (EtOAc:hexane=1:1)로 정제하여 화합물 68 (EIF-068)을 수득하였다 (31 mg, 87% 수율).A solution of N- (3-(aminomethyl)cyclobutyl)-2-(4-chloro-3-fluorophenoxy)acetamide (26 mg, 0.09 mmol), nicotinic acid (13 mg, 0.108 mmol), EDCI (35 mg, 0.18 mmol), HOBt (24 mg, 0.18 mmol), and DIPEA (35 mg, 0.27 mmol) dissolved in DMF (1 mL, 0.09 M) was stirred at room temperature for 12 h. The solution was diluted with EtOAc, washed with NaHCO 3 , dried over Na 2 SO 4 , and concentrated. The crude product was purified by MPLC (EtOAc:hexane=1:1) to give compound 68 (EIF-068) (31 mg, 87% yield).

N-((3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)사이클로부틸)메틸)니코틴아마이드[N-((3-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclobutyl)methyl)nicotinamide]N-((3-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclobutyl)methyl)nicotinamide

1H NMR (400 MHz, DMSO-d6) δ 8.82 (t, J = 6.1 Hz, 1H), 8.65 (d, J = 4.6 Hz, 1H), 8.32 (d, J = 7.9 Hz, 1H), 8.04 (d, J = 7.5 Hz, 1H), 7.99 (td, J = 7.6, 1.6 Hz, 1H), 7.61 (dd, J = 8.5, 3.6 Hz, 1H), 7.50 (t, J = 8.9 Hz, 1H), 7.07 (dd, J = 11.4, 2.9 Hz, 1H), 6.85 (dd, J = 8.9, 2.9 Hz, 1H), 4.48 (s, 2H), 4.42 - 4.01 (m, 1H), 3.47 - 3.34 (m, 2H), 2.31 - 2.20 (m, 2H), 2.12 - 2.04 (m, 1H), 1.83 - 1.67 (m, 2H). 1H NMR (400 MHz, DMSO-d 6 ) δ 8.82 (t, J = 6.1 Hz, 1H), 8.65 (d, J = 4.6 Hz, 1H), 8.32 (d, J = 7.9 Hz, 1H), 8.04 (d, J = 7.5 Hz, 1H), 7.99 (td, J = 7.6, 1.6 Hz, 1H), 7.61 (dd, J = 8.5, 3.6 Hz, 1H), 7.50 (t, J = 8.9 Hz, 1H), 7.07 (dd, J = 11.4, 2.9 Hz, 1H), 6.85 (dd, J = 8.9, 2.9 Hz, 1H), 4.48 (s, 2H), 4.42 - 4.01 (m, 1H), 3.47 - 3.34 (m, 2H), 2.31 - 2.20 (m, 2H), 2.12 - 2.04 (m, 1H), 1.83 - 1.67 (m, 2H).

MS (ESI+) m/z calcd for C19H19ClFN3O3 [M+H]+ 391.12; found 392.24. MS (ESI + ) m/z calcd for C 19 H 19 ClFN 3 O 3 [M+H] + 391.12; found 392.24.

화합물 69 (EIF-069):Compound 69 (EIF-069):

DMF (0.8 mL, 0.1 M) 내 용해된 N-(3-(아미노메틸)사이클로부틸)-2-(4-클로로-3-플루오로페녹시)아세트아마이드 (26 mg,0.09 mmol), 벤조퓨란-6-카르복실산 (18 mg, 0.11 mmol), EDCI (35 mg, 0.18 mmol), HOBt (24 mg, 0.18 mmol) 및 DIPEA (35 mg, 0.27 mmol) 용액을 실온에서 12시간 동안 교반하였다. 용액을 EtOAc로 희석시키고 염수로 세척한 다음, Na2SO4로 건조시키고 농축시켰다. 조 생성물을 MPLC (0 to 75% EtOAc/hexane)로 정제하여 화합물 69 (EIF-069)를 수득하였다 (17 mg, 43% 수율).A solution of N- (3-(aminomethyl)cyclobutyl)-2-(4-chloro-3-fluorophenoxy)acetamide (26 mg, 0.09 mmol), benzofuran-6-carboxylic acid (18 mg, 0.11 mmol), EDCI (35 mg, 0.18 mmol), HOBt (24 mg, 0.18 mmol), and DIPEA (35 mg, 0.27 mmol) in DMF (0.8 mL, 0.1 M) was stirred at room temperature for 12 h. The solution was diluted with EtOAc, washed with brine, dried over Na 2 SO 4 , and concentrated. The crude product was purified by MPLC (0 to 75% EtOAc/hexane) to give compound 69 (EIF-069) (17 mg, 43% yield).

N-((3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)사이클로부틸)메틸)벤조퓨란-6-카르복사마이드[N-((3-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclobutyl)methyl)benzofuran-6-carboxamide]N-((3-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclobutyl)methyl)benzofuran-6-carboxamide

1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.76 (d, J = 2.1 Hz, 1H), 7.70 - 7.63 (m, 2H), 7.40 - 7.31 (m, 1H), 6.84 (s, 1H), 6.79 (dd, J = 10.3, 2.8 Hz, 1H), 6.71 (dd, J = 8.9, 1.5 Hz, 1H), 6.65 (d, J = 7.0 Hz, 1H), 6.31 (t, J = 5.5 Hz, 1H), 4.48 - 4.34 (m, 3H), 3.59 (t, J = 6.3 Hz, 2H), 2.68 - 2.54 (m, 2H), 2.46 - 2.28 (m, 1H), 1.91 - 1.79 (m, 2H). 1H NMR (400 MHz, CDCl 3 ) δ 8.01 (s, 1H), 7.76 (d, J = 2.1 Hz, 1H), 7.70 - 7.63 (m, 2H), 7.40 - 7.31 (m, 1H), 6.84 (s, 1H), 6.79 (dd, J = 10.3, 2.8 Hz, 1H), 6.71 (dd, J = 8.9, 1.5 Hz, 1H), 6.65 (d, J = 7.0 Hz, 1H), 6.31 (t, J = 5.5 Hz, 1H), 4.48 - 4.34 (m, 3H), 3.59 (t, J = 6.3 Hz, 2H), 2.68 - 2.54 (m, 2H), 2.46 - 2.28 (m, 1H), 1.91 - 1.79 (m, 2H).

MS (ESI+) m/z calcd for C22H20ClFN2O4 [M+H]+ 431.12; found 431.31. MS (ESI + ) m/z calcd for C 22 H 20 ClFN 2 O 4 [M+H] + 431.12; found 431.31.

화합물 70 (EIF-070):Compound 70 (EIF-070):

DMF (0.8 mL, 0.1 M) 내 용해된 N-(3-(아미노메틸)사이클로부틸)-2-(4-클로로-3-플루오로페녹시)아세트아마이드 (26 mg,0.09 mmol), 1-(2,2-디플루오로에틸)-1H-피라졸-3-카르복실산[1-(2,2-difluoroethyl)-1H-pyrazole-3-carboxylic acid] (19 mg, 0.11 mmol), EDCI (35 mg, 0.18 mmol), HOBt (28 mg, 0.18 mmol) 및 DIPEA (35 mg, 0.27 mmol) 용액을 실온에서 16시간 동안 교반하였다. 용액을 EtOAc로 희석시키고 염수로 세척한 다음, Na2SO4로 건조시키고 농축시켰다. 조 생성물을 MPLC (0 to 100% EtOAc/hexane)로 정제하여 화합물 70 (EIF-070)을 수득하였다 (16 mg, 40% 수율).A solution of N -(3-(aminomethyl)cyclobutyl)-2-(4-chloro-3-fluorophenoxy)acetamide (26 mg, 0.09 mmol), 1-(2,2-difluoroethyl)-1 H -pyrazole - 3-carboxylic acid (19 mg, 0.11 mmol), EDCI (35 mg, 0.18 mmol), HOBt (28 mg, 0.18 mmol), and DIPEA (35 mg, 0.27 mmol) in DMF (0.8 mL, 0.1 M) was stirred at room temperature for 16 h. The solution was diluted with EtOAc, washed with brine, dried over Na 2 SO 4 , and concentrated. The crude product was purified by MPLC (0 to 100% EtOAc/hexane) to obtain compound 70 (EIF-070) (16 mg, 40% yield).

N-((3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)사이클로부틸)메틸)-1-(2,2-디플루오로에틸)-1H-피라졸-3-카르복사마이드[N-((3-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclobutyl)methyl)-1-(2,2-difluoroethyl)-1H-pyrazole-3-carboxamide]N-((3-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclobutyl)methyl)-1-(2,2-difluoroethyl)-1H-pyrazole-3-carboxamide

1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 2.3 Hz, 1H), 7.35 (t, J = 8.6 Hz, 1H), 6.97 - 6.82 (m, 2H), 6.79 (dd, J = 10.3, 2.8 Hz, 1H), 6.71 (dd, J = 8.9, 1.5 Hz, 1H), 6.62 (d, J = 7.5 Hz, 1H), 6.11 (t, J = 4.1 Hz, 1H), 4.56 - 4.34 (m, 5H), 3.51 (t, J = 6.6 Hz, 2H), 2.68 - 2.52 (m, , 2H), 2.37 - 2.25 (m, 1H), 1.83 - 1.71 (m, 2H). 1H NMR (400 MHz, CDCl 3 ) δ 7.50 (d, J = 2.3 Hz, 1H), 7.35 (t, J = 8.6 Hz, 1H), 6.97 - 6.82 (m, 2H), 6.79 (dd, J = 10.3, 2.8 Hz, 1H), 6.71 (dd, J = 8.9, 1.5 Hz, 1H), 6.62 (d, J = 7.5 Hz, 1H), 6.11 (t, J = 4.1 Hz, 1H), 4.56 - 4.34 (m, 5H), 3.51 (t, J = 6.6 Hz, 2H), 2.68 - 2.52 (m, , 2H), 2.37 - 2.25 (m, 1H), 1.83 - 1.71 (m, 2H).

MS (ESI+) m/z calcd for C19H20ClF3N4O3 [M+H]+ 445.13; found 445.32. MS (ESI + ) m/z calcd for C 19 H 20 ClF 3 N 4 O 3 [M+H] + 445.13; found 445.32.

화합물 71 (EIF-071):Compound 71 (EIF-071):

DMF (0.8 mL, 0.1 M) 내 용해된 N-(3-(아미노메틸)사이클로부틸)-2-(4-클로로-3-플루오로페녹시)아세트아마이드 (26 mg,0.09 mmol), 피콜린산[picolinic acid] (13 mg, 0.11 mmol), EDCI (35 mg, 0.18 mmol), HOBt (28 mg, 0.18 mmol) 및 DIPEA (35 mg, 0.27 mmol) 용액을 실온에서 16시간 동안 교반하였다. 용액을 EtOAc로 희석시키고 염수로 세척한 다음, Na2SO4로 건조시키고 농축시켰다. 조 생성물을 MPLC (0 to 75% EtOAc/hexane)로 정제하여 화합물 71 (EIF-071)을 수득하였다 (21 mg, 59% 수율).A solution of N- (3-(aminomethyl)cyclobutyl)-2-(4-chloro-3-fluorophenoxy)acetamide (26 mg, 0.09 mmol), picolinic acid (13 mg, 0.11 mmol), EDCI (35 mg, 0.18 mmol), HOBt (28 mg, 0.18 mmol), and DIPEA (35 mg, 0.27 mmol) in DMF (0.8 mL, 0.1 M) was stirred at room temperature for 16 h. The solution was diluted with EtOAc, washed with brine, dried over Na 2 SO 4 , and concentrated. The crude product was purified by MPLC (0 to 75% EtOAc/hexane) to give compound 71 (EIF-071) (21 mg, 59% yield).

N-((3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)사이클로부틸)메틸)피콜린아마이드(3-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclobutyl)methyl)picolinamide]N-((3-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclobutyl)methyl)picolinamide]

1H NMR (400 MHz, CDCl3) δ 8.61 (d, J = 4.6 Hz, 1H), 8.38 (s, 1H), 8.32 (d, J = 7.9 Hz, 1H), 8.07 - 7.91 (m, 1H), 7.57 (dd, J = 6.7, 5.2 Hz, 1H), 7.40 - 7.31 (m, 1H), 6.84 - 6.77 (m, 1H), 6.77 - 6.58 (m, 2H), 4.69 - 4.34 (m, 3H), 3.58 (t, J = 6.4 Hz, 2H), 2.71 - 2.53 (m, 2H), 2.46 - 2.28 (m, 1H), 1.89 - 1.79 (m, 2H). 1H NMR (400 MHz, CDCl 3 ) δ 8.61 (d, J = 4.6 Hz, 1H), 8.38 (s, 1H), 8.32 (d, J = 7.9 Hz, 1H), 8.07 - 7.91 (m, 1H), 7.57 (dd, J = 6.7, 5.2 Hz, 1H), 7.40 - 7.31 (m, 1H), 6.84 - 6.77 (m, 1H), 6.77 - 6.58 (m, 2H), 4.69 - 4.34 (m, 3H), 3.58 (t, J = 6.4 Hz, 2H), 2.71 - 2.53 (m, 2H), 2.46 - 2.28 (m, 1H), 1.89 - 1.79 (m, 2H).

MS (ESI+) m/z calcd for C19H19ClFN3O3 [M+H]+ 392.12; found 392.27. MS (ESI + ) m/z calcd for C 19 H 19 ClFN 3 O 3 [M+H] + 392.12; found 392.27.

<실시예 1> 신규 화합물의 활성 분석<Example 1> Activity analysis of novel compounds

상기 합성예에 따라 합성된 화합물의 생체 내 효능을 검증하기 위하여, 도 1에 나타난 바와 같이, Puromycin incorporation assay 라는 방법을 통해 신규 화합물의 활성을 측정하였다. 통합 스트레스 반응은 eIF2α의 인산화로 시작되며, 인산화된 eIF2α는 단백질 합성을 저해하고, eIF2α 인산화에 의한 단백질 합성의 저해는 eIF2B라는 GDP/GTP exchange 효소의 활성을 저해함으로써 작동한다. 본 실시예의 표적 단백질인 eIF2B의 이러한 작동원리를 이용해 신규 화합물의 단백질 합성 정도를 파악해 화합물의 활성을 측정하였다.In order to verify the in vivo efficacy of the compound synthesized according to the above synthetic example, the activity of the novel compound was measured using a method called Puromycin incorporation assay, as shown in Fig. 1. The integrated stress response is initiated by the phosphorylation of eIF2α, and phosphorylated eIF2α inhibits protein synthesis. The inhibition of protein synthesis by eIF2α phosphorylation works by inhibiting the activity of a GDP/GTP exchange enzyme called eIF2B. Using this operating principle of eIF2B, the target protein of this example, the level of protein synthesis of the novel compound was determined, and the activity of the compound was measured.

ISR의 활성을 유도하기 위해 Thapsigargin이라는 SERCA inhibitor를 이용하였다. Thapsigargin은 SERCA 칼슘 채널을 저해하여 소포체 내 칼슘의 농도를 변화시켜 통합 스트레스 반응을 초래하는 약물로, 통합 스트레스 반응 연구에 광범위하게 쓰인다.To induce ISR activity, we used a SERCA inhibitor called thapsigargin. Thapsigargin is a drug that inhibits SERCA calcium channels, altering calcium concentration in the endoplasmic reticulum (ER), thereby inducing the integrated stress response. It is widely used in research on the integrated stress response.

그 결과, 도 2a, 도 2b 및 도 3에 나타난 바와 같이, 대조 약물인 ISRIB에 비견할 만한 화합물들을 파악할 수 있었다. 71번까지의 화합물의 활성화를 세포 수준에서 확인한 후, 구조적 독창성 및 확장성, 그리고 스트레스에 의해 억제된 단백질 합성률의 복구 능력을 고려하여 43번 및 52번 화합물을 선별하여 다음 실험을 진행하였다.As a result, compounds comparable to the control drug, ISRIB, were identified, as shown in Figures 2a, 2b, and 3. After confirming the activity of compounds up to 71 at the cellular level, compounds 43 and 52 were selected for the next experiment, taking into account their structural uniqueness and scalability, as well as their ability to restore protein synthesis rates suppressed by stress.

<실시예 2> 효소 활성 분석<Example 2> Enzyme activity analysis

단순히 단백질 합성을 복구시는 것으로 eIF2B의 활성에 미치는 영향를 볼 경우 다른 기전에 의한 간접적인 효과를 검증할 수 있기 때문에, 신규 화합물이 직접 eIF2B 효소에 영향을 미치는 지에 대한 검증이 필요하다. 이에 효소 활성 분석(Enzyme assay)을 수행하였다.Since simply restoring protein synthesis and thus affecting eIF2B activity could potentially reveal indirect effects via other mechanisms, it is necessary to verify whether the novel compound directly affects the eIF2B enzyme. Therefore, an enzyme activity assay was performed.

간략하게, Enzyme assay를 설명하면, BODIPY(형광물질)로 접합(conjugation)된 GDP를 eIF2 효소체에 로딩한 후 이를 eIF2B가 포함된 시료에 첨가하면 BODIPY로 conjugation된 GDP가 eIF2B의 활성에 의해 떨어져 나가는 과정을 형광으로 확인할 수 있다. (도 4). 이를 바탕으로 앞서 선별된 43번과 활성화가 높지 않은 35, 36번 화합물을 음성 대조군(negative control)로 사용해 이들 화합물의 eIF2B에 대한 효소 활성 영향을 확인하였다.Briefly, the enzyme assay involves loading GDP conjugated with BODIPY (a fluorescent substance) onto the eIF2 enzyme complex, then adding this to a sample containing eIF2B. The process of BODIPY-conjugated GDP being released by the activity of eIF2B can be observed through fluorescence (Fig. 4). Based on this, the previously selected compound 43 and compounds 35 and 36, which had low activity, were used as negative controls to confirm the effects of these compounds on the enzyme activity of eIF2B.

도 5를 참조하면, 음성 대조군의 경우 eIF2B의 효소 활성에 전혀 영향을 미치지 못하지만, 43번 화합물 및 ISRIB의 경우 eIF2B의 효소 활성을 상당히 증진시킬 수 있다. 더불어, 이들 효소 활성을 정량화한 후 그래프로 나타낸 결과, 도 5(b)에 나타난 바와 같이, GDP/GTP exchange activity를 확인하면, 43번 화합물이 eIF2α 및 인산화된 eIF2α에서 모두 eIF2B의 활성이 증진됨을 확인할 수 있다. 이를 통해 43번 화합물의 활성이 ISRIB과 비견할 만함을 알 수 있다.Referring to Figure 5, the negative control group had no effect at all on the enzymatic activity of eIF2B, but Compound 43 and ISRIB could significantly enhance the enzymatic activity of eIF2B. In addition, as shown in Figure 5(b), when the GDP/GTP exchange activity was confirmed by quantifying these enzymatic activities and displaying them graphically, it was confirmed that Compound 43 enhanced the activity of eIF2B in both eIF2α and phosphorylated eIF2α. This shows that the activity of Compound 43 is comparable to that of ISRIB.

더불어, 신규 화합물에 대한 EC50을 함께 확인하였다. 도 6을 참조하면, 음성 대조군인 35번의 경우 GEF 활성이 전혀 영향을 받지 않는 반면, ISRIB과 43번 화합물의 경우는 비슷하게 eIF2B를 활성화함을 보여주었다. 또한, EC50의 경우 ISRIB은 약 20nM로 기존에 보고된 EC50와 비슷한 양상을 보여주고 있으며, 43번 화합물 역시 약 24nM로 ISRIB과 비견될 정도의 EC50를 나타냄을 확인할 수 있다.In addition, the EC 50 for the new compounds was also confirmed. Referring to Fig. 6, while the negative control compound 35 showed no effect on GEF activity at all, ISRIB and compounds 43 showed similar activation of eIF2B. In addition, the EC 50 of ISRIB was approximately 20 nM, which is similar to the previously reported EC 50 , and compound 43 also showed an EC 50 of approximately 24 nM, which is comparable to that of ISRIB.

즉, 세포 수준에서 선별된 43번이 본 발명의 표적 단백질인 eIF2B의 활성을 직접적으로 조절하며, EC50 역시 ISRIB과 비견될만하다는 것을 재차 확인하였다.That is, it was confirmed once again that the 43 selected at the cellular level directly regulates the activity of eIF2B, the target protein of the present invention, and that the EC 50 is also comparable to that of ISRIB.

<실시예 3> 생체 내 분석<Example 3> In vivo analysis

앞서 세포 수준에서 선별된 43번 및 52번 화합물에 대한 세포 수준 및 효소 활성 수준의 검증이 되었음을 확인하였고, 다음 단계로 실질적으로 생체 내 동물 모델에서 역시 효과가 나타나는지를 검증하였다.We confirmed that compounds 43 and 52, previously screened at the cellular level, were verified at the cellular level and enzyme activity level, and the next step was to verify whether they were also effective in an in vivo animal model.

ISRIB 화합물을 고지방식이 섭취 비만 쥐에 투여하면 체중이 감소한다는 선행연구 결과를 바탕으로, 신규 화합물이 선행연구결과에서 쓰였던 ISRIB와 비슷한 생체 효과를 나타내는지 여부를 확인하기 위해 동물 실험을 진행하였다.Based on the results of a previous study showing that administering the ISRIB compound to high-fat diet-fed obese mice resulted in weight loss, an animal experiment was conducted to determine whether the new compound exhibited similar biological effects to ISRIB, which was used in the previous study.

도 7에 나타난 바와 같이, 생쥐에 고지방식이를 총 8주간 섭취하게 하였으며, 이때 양성 대조군(positive control)으로 ISRIB를, 음성 대조군으로 DMSO를 처리하였으며, 신규 화합물인 43, 52번을 투여한 후 체중 변화를 조사하였다. 그 결과, 43 및 52번의 신규 화합물을 고지방식이 섭취 비만 생쥐에 투여했을 경우, 대조 약물인 ISRIB가 보이는 효과와 비견할 만한 효과를 나타냄을 확인하였다. As shown in Fig. 7, mice were fed a high-fat diet for a total of 8 weeks, during which time ISRIB was treated as a positive control and DMSO as a negative control. After administration of novel compounds 43 and 52, body weight changes were investigated. As a result, it was confirmed that novel compounds 43 and 52, when administered to high-fat diet-fed obese mice, exhibited effects comparable to those of the control drug ISRIB.

다음으로 신규 화합물인 43, 52번 화합물의 생체 내 독성을 확인하기 위해, 간의 손상 정도를 나타내는 ALT, AST 수치를 확인하였다.Next, to confirm the in vivo toxicity of the new compounds 43 and 52, the ALT and AST levels, which indicate the degree of liver damage, were checked.

그 결과, 도 8에 나타난 바와 같이, ISRIB에 의해 ALT, AST 수치는 크게 변화하지 않았으며, 신규 화합물인 43번과 52번 역시 생체 내 투여 후 간에 ALT, AST의 수치 변화를 유도하지 않았다.As a result, as shown in Fig. 8, ALT and AST levels did not change significantly due to ISRIB, and novel compounds 43 and 52 also did not induce changes in ALT and AST levels in the liver after in vivo administration.

또한, 동시에 간 조직의 조직학적 변화를 확인하였는데, 도 9에 나타난 바와 같이, 큰 변화를 나타내지 않았다. In addition, histological changes in liver tissue were confirmed at the same time, and as shown in Figure 9, no significant changes were observed.

이러한 결과를 통해, 신규 화합물인 43번 및 52번이 실질적으로 생체 내에서 효과를 나타내고 있으며, 이때 간 조직에 독성을 나타내지는 않는다는 것을 확인할 수 있다.These results confirm that the novel compounds 43 and 52 are effective in vivo and do not exhibit toxicity to liver tissue.

<실시예 4> 대식세포에 미치는 영향 분석<Example 4> Analysis of the effect on macrophages

선별된 신규 화합물들의 경우, 생체에 투여될 때 체중을 감소시키는 효과를 앞선 실험을 통해 확인하였다. 이러한 결과를 바탕으로 신규 화합물이 대식세포의 극성에 영향을 미치는 지 확인하였다.For the selected novel compounds, their weight-reducing effects when administered to a living organism were confirmed in previous experiments. Based on these results, we examined whether the novel compounds affect macrophage polarity.

그 결과, 도 10에 나타난 바와 같이, 신규 화합물은 대조물질인 ISRIB와 비견될 정도로 스트레스에 의해 감소된 M2 극성을 회복시키는 것을 확인하였다.As a result, as shown in Fig. 10, it was confirmed that the novel compound restored the M2 polarity reduced by stress to a degree comparable to that of the control substance, ISRIB.

이상으로 본 발명 내용의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서, 이러한 구체적 기술은 단지 바람직한 실시양태일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백하다. 즉, 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다.While specific aspects of the present invention have been described in detail above, it should be apparent to those skilled in the art that these specific descriptions merely represent preferred embodiments and are not intended to limit the scope of the present invention. In other words, the substantial scope of the present invention is defined by the appended claims and their equivalents.

Claims (10)

하기 화학식 1로 표시되는 디아마이드 유도체, 이의 입체이성질체, 이의 용매화물 또는 이의 약학적으로 허용가능한 염에서 선택된, 화합물:A compound selected from a diamide derivative represented by the following chemical formula 1, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof: [화학식 1][Chemical Formula 1] 상기 화학식 1에서,In the above chemical formula 1, n’, n”, m’및 m”은 각각 같거나 다를 수 있고, 0 내지 2 중 하나이고, n’, n”, m’ and m” may be the same or different and are one of 0 to 2, L은 (C3-C10)사이클로알킬, (C5-C10)스피로사이클로알킬 및 (C5-C10)바이사이클로알킬 중 하나이고,L is one of (C3-C10)cycloalkyl, (C5-C10)spirocycloalkyl and (C5-C10)bicycloalkyl, A1 및 A2 는 각각 같거나 다를 수 있으며, -CONH- 또는 -NHCO-이고,A 1 and A 2 may be the same or different and are -CONH- or -NHCO-, M’및 M”은 각각 같거나 다를 수 있으며, (C1-C5)알킬, (C2-C5)알켄, (C2-C5)알킨; 및 O 및 S로부터 선택된 하나 이상의 헤테로원자를 포함하는 2 내지 5 원자의 헤테로알킬 중 하나이고,M’ and M” may be the same or different and are one of (C1-C5)alkyl, (C2-C5)alkene, (C2-C5)alkyne; and heteroalkyl of 2 to 5 members containing one or more heteroatoms selected from O and S, Ar1 및 Ar2는 각각 같거나 다를 수 있으며, 비치환 또는 치환된 (C5-C10)아릴 및 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 비치환 또는 치환된 5 내지 12 원자의 헤테로아릴 중 하나이며, 상기 치환된 (C5-C10)아릴 또는 치환된 5 내지 12 원자의 헤테로아릴은 (C1-C5)알킬, (C1-C5)알콕시, 할로겐, 트리플루오로메틸, 디플루오로메틸 및 디플루오로에틸 중 1개 이상이 치환됨.Ar 1 and Ar 2 may be the same or different, and are one of an unsubstituted or substituted (C5-C10)aryl and an unsubstituted or substituted 5 to 12-membered heteroaryl comprising at least one heteroatom selected from the group consisting of N, O and S, wherein the substituted (C5-C10)aryl or the substituted 5 to 12-membered heteroaryl is substituted with at least one of (C1-C5)alkyl, (C1-C5)alkoxy, halogen, trifluoromethyl, difluoromethyl and difluoroethyl. 제 1 항에 있어서,In the first paragraph, 상기 화합물은,The above compound is, 상기 화학식 1에서 n’, n”, m’ 및 m”은 각각 같거나 다를 수 있고, 0 또는 1이고, In the above chemical formula 1, n’, n”, m’ and m” may be the same or different and are 0 or 1, L은 (C3-C7)사이클로알킬, (C6-C8)스피로사이클로알킬 및 (C5-C8)바이사이클로알킬 중 하나이고,L is one of (C3-C7)cycloalkyl, (C6-C8)spirocycloalkyl and (C5-C8)bicycloalkyl, M’및 M”은 각각 같거나 다를 수 있으며, (C2-C3)알켄, (C2-C3)알킨; 및 O 및 S로부터 선택된 하나 이상의 헤테로원자를 포함하는 2 내지 4 원자의 헤테로알킬 중 하나이고,M’ and M” may be the same or different and are one of (C2-C3)alkene, (C2-C3)alkyne; and 2 to 4 membered heteroalkyl containing one or more heteroatoms selected from O and S, Ar1 및 Ar2는 각각 같거나 다를 수 있으며, 비치환 또는 치환된 (C5-C7)아릴 및 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 비치환 또는 치환된 5 내지 10 원자의 헤테로아릴 중 하나이며, 상기 치환된 (C5-C7)아릴 또는 치환된 5 내지 10 원자의 헤테로아릴은 (C1-C4)알킬, (C1-C3)알콕시, 할로겐, 트리플루오로메틸, 디플루오로메틸 및 디플루오로에틸 중 1개 이상 3개 이하로 치환되는 것을 특징으로 하는, 화합물.A compound characterized in that Ar 1 and Ar 2 may be the same or different and are one of an unsubstituted or substituted (C5-C7)aryl and an unsubstituted or substituted 5 to 10-membered heteroaryl comprising one or more heteroatoms selected from the group consisting of N, O and S, wherein the substituted (C5-C7)aryl or the substituted 5 to 10-membered heteroaryl is substituted with one or more and three or fewer of (C1-C4)alkyl, (C1-C3)alkoxy, halogen, trifluoromethyl, difluoromethyl and difluoroethyl. 제 1 항에 있어서, In the first paragraph, 상기 화합물은,The above compound is, 상기 화학식 1에서 L은 (C4-C6)사이클로알킬, 스피로사이클로헵틸 및 바이사이클로펜틸 중 하나이고,In the above chemical formula 1, L is one of (C4-C6)cycloalkyl, spirocycloheptyl, and bicyclopentyl, M’ 및 M”은 각각 같거나 다를 수 있으며, 에틸렌, 아세틸렌 및 O 또는 S의 헤테로원자를 하나 포함하는 2 내지 4 원자의 헤테로알킬 중 하나이고,M’ and M” may be the same or different and are one of ethylene, acetylene and 2 to 4 membered heteroalkyl containing one heteroatom of O or S, Ar1 및 Ar2는 각각 같거나 다를 수 있으며, 비치환 또는 치환된 페닐 및 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 비치환 또는 치환된 5 내지 10 원자의 헤테로아릴 중 하나이며, 상기 치환된 페닐은 트리플루오로메틸, 염소, 플루오린, 메톡시, 메틸, 에틸 및 tert-부틸 중 1개 이상 3개 이하가 치환되고, 상기 치환된 5 내지 10 원자의 헤테로아릴은 플루오린, 메톡시, 트리플루오로메틸, 디플루오로메틸 및 디플루오로에틸 중 1개 이상 3개 이하로 치환되는 것을 특징으로 하는, 화합물.A compound characterized in that Ar 1 and Ar 2 may be the same or different and are one of unsubstituted or substituted phenyl and unsubstituted or substituted 5 to 10-membered heteroaryl comprising at least one heteroatom selected from the group consisting of N, O and S, wherein the substituted phenyl is substituted with at least one and no more than three of trifluoromethyl, chlorine, fluorine, methoxy, methyl, ethyl and tert-butyl, and the substituted 5 to 10-membered heteroaryl is substituted with at least one and no more than three of fluorine, methoxy, trifluoromethyl, difluoromethyl and difluoroethyl. 제 2 항에 있어서,In the second paragraph, 상기 5 내지 10 원자의 헤테로아릴은 피리딘, 퀴놀린, 티아졸, 피리미다졸, 쿠마론, 7-아자인돌, 벤조이미다졸, 나프틸, 인다졸, 싸이오나프텐, 벤조티아졸, 피리미딘 및 피라졸 중 하나이고, The above 5 to 10-atom heteroaryl is one of pyridine, quinoline, thiazole, pyrimidazole, coumarone, 7-azaindole, benzoimidazole, naphthyl, indazole, thionaphthene, benzothiazole, pyrimidine and pyrazole, 상기 치환된 5 내지 10 원자의 헤테로아릴은 플루오린, 메톡시, 트리플루오로메틸, 디플루오로메틸 및 디플루오로에틸 중 하나가 치환되는 것을 특징으로 하는, 화합물.A compound characterized in that the above substituted 5 to 10-membered heteroaryl is substituted with one of fluorine, methoxy, trifluoromethyl, difluoromethyl and difluoroethyl. 제 1 항에 있어서,In the first paragraph, 상기 화학식 1로 표시되는 디아마이드 유도체는 하기 화합물 군으로부터 선택되는 어느 하나인 것을 특징으로 하는, 화합물:A compound characterized in that the diamide derivative represented by the above chemical formula 1 is any one selected from the following compound group: (1) N,N'-(사이클로헥산-1,3-디일)비스(2-(4-클로로페녹시)아세트아마이드[N,N'-(cyclohexane-1,3-diyl)bis(2-(4-chlorophenoxy)acetamide)] (EIF-001),(1) N,N'-(cyclohexane-1,3-diyl)bis(2-(4-chlorophenoxy)acetamide) (EIF-001), (2) N,N'-(사이클로펜탄-1,3-디일)비스(2-(4-클로로페녹시)아세트아마이드)[N,N'-(cyclopentane-1,3-diyl)bis(2-(4-chlorophenoxy)acetamide)] (EIF-002),(2) N,N'-(cyclopentane-1,3-diyl)bis(2-(4-chlorophenoxy)acetamide) [N,N'-(cyclopentane-1,3-diyl)bis(2-(4-chlorophenoxy)acetamide)] (EIF-002), (3) N,N'-(스피로[3.3]헵탄-2,6-디일)비스(2-(4-클로로페녹시)아세트아마이드)[N,N'-(spiro[3.3]heptane-2,6-diyl)bis(2-(4-chlorophenoxy)acetamide)] (EIF-004),(3) N,N'-(spiro[3.3]heptane-2,6-diyl)bis(2-(4-chlorophenoxy)acetamide)[N,N'-(spiro[3.3]heptane-2,6-diyl)bis(2-(4-chlorophenoxy)acetamide)] (EIF-004), (4) N,N'-(스피로[3.3]헵탄-2,6-디일)비스(2-(피리딘-2-일옥시)아세트아마이드)[N,N'-(spiro[3.3]heptane-2,6-diyl)bis(2-(pyridin-2-yloxy)acetamide)] (EIF-005),(4) N,N'-(spiro[3.3]heptane-2,6-diyl)bis(2-(pyridin-2-yloxy)acetamide)[N,N'-(spiro[3.3]heptane-2,6-diyl)bis(2-(pyridin-2-yloxy)acetamide)] (EIF-005), (5) (2E,2'E)-N,N'-(사이클로부탄-1,3-디일)비스(3-(4-클로로페닐)아크릴아마이드)[(2E,2'E)-N,N'-(cyclobutane-1,3-diyl)bis(3-(4-chlorophenyl)acrylamide)] (EIF-006),(5) (2E,2'E)-N,N'-(cyclobutane-1,3-diyl)bis(3-(4-chlorophenyl)acrylamide)[(2E,2'E)-N,N'-(cyclobutane-1,3-diyl)bis(3-(4-chlorophenyl)acrylamide)] (EIF-006), (6) 2-(4-클로로페녹시)-N-(3-(2-((2,6-디클로로벤질)티오)아세트아미도)사이클로부틸)아세트아마이드[2-(4-chlorophenoxy)-N-(3-(2-((2,6-dichlorobenzyl)thio)acetamido)cyclobutyl)acetamide] (EIF-007),(6) 2-(4-chlorophenoxy)-N-(3-(2-((2,6-dichlorobenzyl)thio)acetamido)cyclobutyl)acetamide [2-(4-chlorophenoxy)-N-(3-(2-((2,6-dichlorobenzyl)thio)acetamido)cyclobutyl)acetamide] (EIF-007), (7) N,N'-(사이클로부탄-1,3-디일)비스(2-(메시틸옥시)아세트아마이드)[N,N'-(cyclobutane-1,3-diyl)bis(2-(mesityloxy)acetamide)] (EIF-008),(7) N,N'-(cyclobutane-1,3-diyl)bis(2-(mesityloxy)acetamide) [N,N'-(cyclobutane-1,3-diyl)bis(2-(mesityloxy)acetamide)] (EIF-008), (8) N,N'-(사이클로부탄-1,3-디일)비스(3-(2-클로로페녹시)프로판아마이드[N,N'-(cyclobutane-1,3-diyl)bis(3-(2-chlorophenoxy)propanamide)] (EIF-009),(8) N,N'-(cyclobutane-1,3-diyl)bis(3-(2-chlorophenoxy)propanamide) (EIF-009), (9) N,N'-(사이클로부탄-1,3-디일)비스(2-((5-플루오로피리딘-2-일)옥시)아세트아마이드)[N,N'-(cyclobutane-1,3-diyl)bis(2-((5-fluoropyridin-2-yl)oxy)acetamide) (EIF-010),(9) N,N'-(cyclobutane-1,3-diyl)bis(2-((5-fluoropyridin-2-yl)oxy)acetamide)[N,N'-(cyclobutane-1,3-diyl)bis(2-((5-fluoropyridin-2-yl)oxy)acetamide) (EIF-010), (10) N-(3-(2-(4-클로로페녹시)아세트아미도)사이클로부틸)퀴놀린-3-카르복사마이드[N-(3-(2-(4-chlorophenoxy)acetamido)cyclobutyl)quinoline-3-carboxamide] (EIF-011),(10) N-(3-(2-(4-chlorophenoxy)acetamido)cyclobutyl)quinoline-3-carboxamide [N-(3-(2-(4-chlorophenoxy)acetamido)cyclobutyl)quinoline-3-carboxamide] (EIF-011), (11) N-((1r,4r)-4-(2-(4-클로로페녹시)아세트아미도)사이클로헥실)-2-메톡시이소니코틴아마이드[N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-2-methoxyisonicotinamide] (EIF-012),(11) N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-2-methoxyisonicotinamide [N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-2-methoxyisonicotinamide] (EIF-012), (12) N-((1r,4r)-4-(2-(4-클로로페녹시)아세트아미도)사이클로헥실)퀴놀린-3-카르복사마이드[N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)quinoline-3-carboxamide] (EIF-013),(12) N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)quinoline-3-carboxamide [N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)quinoline-3-carboxamide] (EIF-013), (13) N-((1r,4r)-4-(2-(4-클로로페녹시)아세트아미도)사이클로헥실)티아졸-5-카르복사마이드[N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)thiazole-5-carboxamide] (EIF-014),(13) N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)thiazole-5-carboxamide [N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)thiazole-5-carboxamide] (EIF-014), (14) N-((1r,4r)-4-(2-(4-클로로페녹시)아세트아미도)사이클로헥실)이미다졸[1,2-a]피리딘-6-카르복사마이드[N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)imidazo[1,2-a]pyridine-6-carboxamide] (EIF-015),(14) N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)imidazole[1,2-a]pyridine-6-carboxamide [N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)imidazo[1,2-a]pyridine-6-carboxamide] (EIF-015), (15) N-((1r,4r)-4-(2-(4-클로로페녹시)아세트아미도)사이클로헥실)벤조퓨란-2-카르복사마이드[N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)benzofuran-2-carboxamide] (EIF-016),(15) N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)benzofuran-2-carboxamide [N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)benzofuran-2-carboxamide] (EIF-016), (16) (1r,4r)-4-((2-(2,4-디플루오로페녹시)아세트아미도)메틸)-N-(이미다조[1,2-a]피리딘-6-일)사이클로헥산-1-카르복사마이드[(1r,4r)-4-((2-(2,4-difluorophenoxy)acetamido)methyl)-N-(imidazo[1,2-a]pyridin-6-yl)cyclohexane-1-carboxamide] (EIF-023),(16) (1r,4r)-4-((2-(2,4-difluorophenoxy)acetamido)methyl)-N-(imidazo[1,2-a]pyridin-6-yl)cyclohexane-1-carboxamide [(1r,4r)-4-((2-(2,4-difluorophenoxy)acetamido)methyl)-N-(imidazo[1,2-a]pyridin-6-yl)cyclohexane-1-carboxamide] (EIF-023), (17) (1r,4r)-4-((2-(2,4-디플루오로페녹시)아세트아미도)메틸)-N-(피리딘-4-일)사이클로헥산-1-카르복사마이드[(1r,4r)-4-((2-(2,4-difluorophenoxy)acetamido)methyl)-N-(pyridin-4-yl)cyclohexane-1-carboxamide] (EIF-024),(17) (1r,4r)-4-((2-(2,4-difluorophenoxy)acetamido)methyl)-N-(pyridin-4-yl)cyclohexane-1-carboxamide [(1r,4r)-4-((2-(2,4-difluorophenoxy)acetamido)methyl)-N-(pyridin-4-yl)cyclohexane-1-carboxamide] (EIF-024), (18) (1r,4r)-4-((3-(4-플루오로페녹시)프로판아미도)메틸)-N-(이미다조 [1,2-a]피리딘-6-일)사이클로헥산-1-카르복사마이드[(1r,4r)-4-((3-(4-fluorophenoxy)propanamido)methyl)-N-(imidazo[1,2-a]pyridin-6-yl)cyclohexane-1-carboxamide] (EIF-025),(18) (1r,4r)-4-((3-(4-fluorophenoxy)propanamido)methyl)-N-(imidazo[1,2-a]pyridin-6-yl)cyclohexane-1-carboxamide [(1r,4r)-4-((3-(4-fluorophenoxy)propanamido)methyl)-N-(imidazo[1,2-a]pyridin-6-yl)cyclohexane-1-carboxamide] (EIF-025), (19) N-((1r,4r)-4-(2-(4-클로로페녹시)아세트아미도)사이클로헥실)-1H-피롤로[2,3-b]피리딘-5-카르복사마이드[N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide] (EIF-026),(19) N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide [N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide] (EIF-026), (20) N-((1r,4r)-4-(2-(4-클로로페녹시)아세트아미도)사이클로헥실)-1H-벤조 [d]이미다졸-6-카르복사마이드[N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-1H-benzo[d]imidazole-6-carboxamide] (EIF-027),(20) N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-1H-benzo[d]imidazole-6-carboxamide [N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-1H-benzo[d]imidazole-6-carboxamide] (EIF-027), (21) 3-(4-클로로페닐)-N-((3-(3-(4-클로로페닐)프로피올아미도)사이클로부틸)메틸)프로이올아마이드[3-(4-chlorophenyl)-N-((3-(3-(4-chlorophenyl)propiolamido)cyclobutyl)methyl)propiolamide] (EIF-028),(21) 3-(4-chlorophenyl)-N-((3-(3-(4-chlorophenyl)propiolamido)cyclobutyl)methyl)propiolamide [3-(4-chlorophenyl)-N-((3-(3-(4-chlorophenyl)propiolamido)cyclobutyl)methyl)propiolamide] (EIF-028), (22) (E)-3-(4-클로로페닐)-N-((3-((E)-3-(4-클로로페닐)아크릴아미도)사이클로부틸)메틸)아크릴아마이드[(E)-3-(4-chlorophenyl)-N-((3-((E)-3-(4-chlorophenyl)acrylamido)cyclobutyl)methyl)acrylamide] (EIF-029),(22) (E)-3-(4-chlorophenyl)-N-((3-((E)-3-(4-chlorophenyl)acrylamido)cyclobutyl)methyl)acrylamide [(E)-3-(4-chlorophenyl)-N-((3-((E)-3-(4-chlorophenyl)acrylamido)cyclobutyl)methyl)acrylamide] (EIF-029), (23) 2-((5-플루오로피리딘-2-일)옥시)-N-((3-(2-((5-플루오로피리딘-2-일)옥시)아세트아미도)사이클로부틸)메틸)아세트아마이드[2-((5-fluoropyridin-2-yl)oxy)-N-((3-(2-((5-fluoropyridin-2-yl)oxy)acetamido)cyclobutyl)methyl)acetamide] (EIF-030),(23) 2-((5-fluoropyridin-2-yl)oxy)-N-((3-(2-((5-fluoropyridin-2-yl)oxy)acetamido)cyclobutyl)methyl)acetamide [2-((5-fluoropyridin-2-yl)oxy)-N-((3-(2-((5-fluoropyridin-2-yl)oxy)acetamido)cyclobutyl)methyl)acetamide] (EIF-030), (24) N-(3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)바이사이클로[1.1.1]펜탄-1-일)-3-(4-클로로페닐)프로피올아마이드[N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(4-chlorophenyl)propiolamide] (EIF-032),(24) N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(4-chlorophenyl)propiolamide [N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(4-chlorophenyl)propiolamide] (EIF-032), (25) N-(3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)바이사이클로[1.1.1]펜탄-1-일)-3-페닐프로피올아마이드[N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-phenylpropiolamide] (EIF-033),(25) N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-phenylpropiolamide [N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-phenylpropiolamide] (EIF-033), (26) 2-((5-플루오로피리딘-2-일)옥시)-N-((3-(2-((5-플루오로피리딘-2-일)옥시)아세트아미도)사이클로펜틸)메틸)아세트아마이드[2-((5-fluoropyridin-2-yl)oxy)-N-((3-(2-((5-fluoropyridin-2-yl)oxy)acetamido)cyclopentyl)methyl)acetamide] (EIF-034),(26) 2-((5-fluoropyridin-2-yl)oxy)-N-((3-(2-((5-fluoropyridin-2-yl)oxy)acetamido)cyclopentyl)methyl)acetamide [2-((5-fluoropyridin-2-yl)oxy)-N-((3-(2-((5-fluoropyridin-2-yl)oxy)acetamido)cyclopentyl)methyl)acetamide] (EIF-034), (27) 3-(4-클로로페닐)-N-((3-(3-(4-클로로페닐)프로피올아미도)사이클로펜틸)메틸)프로피올아마이드[3-(4-chlorophenyl)-N-((3-(3-(4-chlorophenyl)propiolamido)cyclopentyl)methyl)propiolamide] (EIF-035),(27) 3-(4-chlorophenyl)-N-((3-(3-(4-chlorophenyl)propiolamido)cyclopentyl)methyl)propiolamide [3-(4-chlorophenyl)-N-((3-(3-(4-chlorophenyl)propiolamido)cyclopentyl)methyl)propiolamide] (EIF-035), (28) N,N'-(사이클로부탄-1,3-디일)비스(3-(4-클로로페닐)프로피올아마이드) [N,N'-(cyclobutane-1,3-diyl)bis(3-(4-chlorophenyl)propiolamide)] (EIF-036),(28) N,N'-(cyclobutane-1,3-diyl)bis(3-(4-chlorophenyl)propiolamide) [N,N'-(cyclobutane-1,3-diyl)bis(3-(4-chlorophenyl)propiolamide)] (EIF-036), (29) N,N'-(사이클로펜탄-1,3-디일)비스(3-(4-사이클로펜틸)프로피올아마이드)[N,N'-(cyclopentane-1,3-diyl)bis(3-(4-chlorophenyl)propiolamide)] (EIF-037),(29) N,N'-(cyclopentane-1,3-diyl)bis(3-(4-cyclopentyl)propiolamide)[N,N'-(cyclopentane-1,3-diyl)bis(3-(4-chlorophenyl)propiolamide)] (EIF-037), (30) N-(3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)바이사이클로 [1.1.1]펜탄-1-일)-3-(3-플루오로페닐)프로피올아마이드[N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(3-fluorophenyl)propiolamide] (EIF-038),(30) N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(3-fluorophenyl)propiolamide [N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(3-fluorophenyl)propiolamide] (EIF-038), (31) N-(3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)바이사이클로 [1.1.1]펜탄-1-일)-3-(p-톨릴)프로피올아마이드[N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(p-tolyl)propiolamide](EIF-039),(31) N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(p-tolyl)propiolamide[N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(p-tolyl)propiolamide](EIF-039), (32) N-(3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)바이사이클로[1.1.1]펜탄-1-일)-3-(2-플루오로페닐)프로피올아마이드[N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(2-fluorophenyl)propiolamide] (EIF-040),(32) N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(2-fluorophenyl)propiolamide [N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(2-fluorophenyl)propiolamide] (EIF-040), (33) N-(3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)바이사이클로[1.1.1]펜탄-1-일)-3-(3-클로로페닐)프로피올아마이드[N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(3-chlorophenyl)propiolamide] (EIF-041), (33) N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(3-chlorophenyl)propiolamide [N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(3-chlorophenyl)propiolamide] (EIF-041), (34) N-(3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)바이사이클로[1.1.1]펜탄-1-일)-3-(4-(트리플루오로메틸)페닐)프로피올아마이드[N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(4-(trifluoromethyl)phenyl)propiolamide] (EIF-042),(34) N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(4-(trifluoromethyl)phenyl)propiolamide [N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(4-(trifluoromethyl)phenyl)propiolamide] (EIF-042), (35) N-(3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)바이사이클로[1.1.1]펜탄-1-일)-3-(4-플루오로페닐)프로피올아마이드[N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(4-fluorophenyl)propiolamide] (EIF-043),(35) N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(4-fluorophenyl)propiolamide [N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(4-fluorophenyl)propiolamide] (EIF-043), (36) N-(3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)바이사이클로[1.1.1]펜탄-1-일)-3-(4-에틸페닐)프로피올아마이드[N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(4-ethylphenyl)propiolamide] (EIF-044),(36) N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(4-ethylphenyl)propiolamide [N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(4-ethylphenyl)propiolamide] (EIF-044), (37) 3-(4-(터트-부틸)페닐)-N-(3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)바이사이클로[1.1.1]펜탄-1-일)프로파올아마이드[3-(4-(tert-butyl)phenyl)-N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)propiolamide] (EIF-045),(37) 3-(4-(tert-butyl)phenyl)-N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)propiolamide [3-(4-(tert-butyl)phenyl)-N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)propiolamide] (EIF-045), (38) N-(3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)바이사이클로[1.1.1]펜탄-1-일)-3-(나프탈렌-2-일)프로피올아마이드[N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(naphthalen-2-yl)propiolamide] (EIF-046),(38) N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(naphthalen-2-yl)propiolamide [N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(naphthalen-2-yl)propiolamide] (EIF-046), (39) N-(3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)바이사이클로[1.1.1]펜탄-1-일)-3-(2-클로로페닐)프로피올아마이드[N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(2-chlorophenyl)propiolamide] (EIF-047),(39) N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(2-chlorophenyl)propiolamide [N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(2-chlorophenyl)propiolamide] (EIF-047), (40) N,N'-(사이클로헥산-1,3-디일)비스(3-(4-클로로페닐)프로피올아마이드) [N,N'-(cyclohexane-1,3-diyl)bis(3-(4-chlorophenyl)propiolamide)] (EIF-048),(40) N,N'-(cyclohexane-1,3-diyl)bis(3-(4-chlorophenyl)propiolamide) [N,N'-(cyclohexane-1,3-diyl)bis(3-(4-chlorophenyl)propiolamide)] (EIF-048), (41) N,N'-((1r,4r)-사이클로헥산-1,4-디일)비스(3-(4-클로로페닐)프로피올아마이드[N,N'-((1r,4r)-cyclohexane-1,4-diyl)bis(3-(4-chlorophenyl)propiolamide)] (EIF-049),(41) N,N'-((1r,4r)-cyclohexane-1,4-diyl)bis(3-(4-chlorophenyl)propiolamide) (EIF-049), (42) N-((1r,4r)-4-(2-(4-클로로페녹시)아세트아미도)사이클로헥실)벤조퓨란-6-카르복사마이드[N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)benzofuran-6-carboxamide] (EIF-050),(42) N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)benzofuran-6-carboxamide [N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)benzofuran-6-carboxamide] (EIF-050), (43) N-((1r,4r)-4-(2-(4-클로로페녹시)아세트아미도)사이클로헥실)-1H-인다졸-6-카르복사마이드[N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-1H-indazole-6-carboxamide] (EIF-051),(43) N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-1H-indazole-6-carboxamide [N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-1H-indazole-6-carboxamide] (EIF-051), (44) N-((1r,4r)-4-(2-(4-클로로페녹시)아세트아미도)사이클로헥실)니코틴아마이드[N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)nicotinamide] (EIF-052),(44) N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)nicotinamide [N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)nicotinamide] (EIF-052), (45) N-((1r,4r)-4-(2-(1H-벤조[d]이미다졸-2-일)아세트아미도)사이클로헥실)-2-(4-클로로페녹시)아세트아마이드[N-((1r,4r)-4-(2-(1H-benzo[d]imidazol-2-yl)acetamido)cyclohexyl)-2-(4-chlorophenoxy)acetamide] (EIF-053)(45) N-((1r,4r)-4-(2-(1H-benzo[d]imidazol-2-yl)acetamido)cyclohexyl)-2-(4-chlorophenoxy)acetamide [N-((1r,4r)-4-(2-(1H-benzo[d]imidazol-2-yl)acetamido)cyclohexyl)-2-(4-chlorophenoxy)acetamide] (EIF-053) (46) 2-(벤조퓨란-2-일)-N-((1r,4r)-4-(2-(4-클로로페녹시)아세트아미도)사이클로헥실)아세트아마이드[2-(benzofuran-2-yl)-N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)acetamide] (EIF-054),(46) 2-(benzofuran-2-yl)-N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)acetamide [2-(benzofuran-2-yl)-N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)acetamide] (EIF-054), (47) 2-(벤조[b]티오펜-2-일)-N-((1r,4r)-4-(2-(4-클로로페녹시)아세트아미도)사이클로헥실)아세트아마이드[2-(benzo[b]thiophen-2-yl)-N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)acetamide] (EIF-055),(47) 2-(benzo[b]thiophen-2-yl)-N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)acetamide [2-(benzo[b]thiophen-2-yl)-N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)acetamide] (EIF-055), (48) 3-(4-클로로페닐)-N-(3-(2-(o-톨릴옥시)아세트아미도)사이클로부틸)프로피올아마이드[3-(4-chlorophenyl)-N-(3-(2-(o-tolyloxy)acetamido)cyclobutyl)propiolamide] (EIF-056),(48) 3-(4-chlorophenyl)-N-(3-(2-(o-tolyloxy)acetamido)cyclobutyl)propiolamide [3-(4-chlorophenyl)-N-(3-(2-(o-tolyloxy)acetamido)cyclobutyl)propiolamide] (EIF-056), (49) 3-(4-클로로페닐)-N-(3-(2-(m-톨릴옥시)아세트아미도)사이클로부틸)프로피올아마이드[3-(4-chlorophenyl)-N-(3-(2-(m-tolyloxy)acetamido)cyclobutyl)propiolamide] (EIF-057),(49) 3-(4-chlorophenyl)-N-(3-(2-(m-tolyloxy)acetamido)cyclobutyl)propiolamide [3-(4-chlorophenyl)-N-(3-(2-(m-tolyloxy)acetamido)cyclobutyl)propiolamide] (EIF-057), (50) 3-(4-클로로페닐)-N-(3-(2-(2-플루오로페녹시)아세트아미도)사이클로부틸)프로피올아마이드[3-(4-chlorophenyl)-N-(3-(2-(2-fluorophenoxy)acetamido)cyclobutyl)propiolamide] (EIF-058),(50) 3-(4-chlorophenyl)-N-(3-(2-(2-fluorophenoxy)acetamido)cyclobutyl)propiolamide [3-(4-chlorophenyl)-N-(3-(2-(2-fluorophenoxy)acetamido)cyclobutyl)propiolamide] (EIF-058), (51) 3-(4-클로로페닐)-N-(3-(2-(3-플루오로페녹시)아세트아미도)사이클로부틸)프로피올아마이드[3-(4-chlorophenyl)-N-(3-(2-(3-fluorophenoxy)acetamido)cyclobutyl)propiolamide] (EIF-059),(51) 3-(4-chlorophenyl)-N-(3-(2-(3-fluorophenoxy)acetamido)cyclobutyl)propiolamide [3-(4-chlorophenyl)-N-(3-(2-(3-fluorophenoxy)acetamido)cyclobutyl)propiolamide] (EIF-059), (52) 3-(4-클로로페닐)-N-(3-(2-(p-톨릴톡시)아세트아미도)사이클로부틸)프로피올아마이드[3-(4-chlorophenyl)-N-(3-(2-(p-tolyloxy)acetamido)cyclobutyl)propiolamide] (EIF-060),(52) 3-(4-chlorophenyl)-N-(3-(2-(p-tolyloxy)acetamido)cyclobutyl)propiolamide [3-(4-chlorophenyl)-N-(3-(2-(p-tolyloxy)acetamido)cyclobutyl)propiolamide] (EIF-060), (53) 3-(4-클로로페닐)-N-(3-(2-(2,4-디플루오로페녹시)아세트아미도)사이클로부틸)프로피올아마이드[3-(4-chlorophenyl)-N-(3-(2-(2,4-difluorophenoxy)acetamido)cyclobutyl)propiolamide] (EIF-061),(53) 3-(4-chlorophenyl)-N-(3-(2-(2,4-difluorophenoxy)acetamido)cyclobutyl)propiolamide [3-(4-chlorophenyl)-N-(3-(2-(2,4-difluorophenoxy)acetamido)cyclobutyl)propiolamide] (EIF-061), (54) N-(3-(2-(2-클로로페녹시)아세트아미도)사이클로부틸)-3-(4-클로로페닐)프로피올아마이드[N-(3-(2-(2-chlorophenoxy)acetamido)cyclobutyl)-3-(4-chlorophenyl)propiolamide] (EIF-062),(54) N-(3-(2-(2-chlorophenoxy)acetamido)cyclobutyl)-3-(4-chlorophenyl)propiolamide [N-(3-(2-(2-chlorophenoxy)acetamido)cyclobutyl)-3-(4-chlorophenyl)propiolamide] (EIF-062), (55) N-(3-(2-(4-클로로-2-메틸페녹시)아세트아미도)사이클로부틸)-3-(4-클로로페닐)프로피올아마이드[N-(3-(2-(4-chloro-2-methylphenoxy)acetamido)cyclobutyl)-3-(4-chlorophenyl)propiolamide] (EIF-063),(55) N-(3-(2-(4-chloro-2-methylphenoxy)acetamido)cyclobutyl)-3-(4-chlorophenyl)propiolamide [N-(3-(2-(4-chloro-2-methylphenoxy)acetamido)cyclobutyl)-3-(4-chlorophenyl)propiolamide] (EIF-063), (56) N-(3-(2-(4-클로로페녹시)아세트아미도)사이클로부틸)-3-(4-클로로페닐)프로피올아마이드[N-(3-(2-(4-chlorophenoxy)acetamido)cyclobutyl)-3-(4-chlorophenyl)propiolamide] (EIF-064),(56) N-(3-(2-(4-chlorophenoxy)acetamido)cyclobutyl)-3-(4-chlorophenyl)propiolamide [N-(3-(2-(4-chlorophenoxy)acetamido)cyclobutyl)-3-(4-chlorophenyl)propiolamide] (EIF-064), (57) (1r,4r)-N-(벤조[d]티아졸-2-일)-4-((2-(4-클로로-3-플루오로페녹시)아세트아미도)메틸)사이클로헥산-1-카르복사마이드[(1r,4r)-N-(benzo[d]thiazol-2-yl)-4-((2-(4-chloro-3-fluorophenoxy)acetamido)methyl)cyclohexane-1-carboxamide] (EIF-065),(57) (1r,4r)-N-(benzo[d]thiazol-2-yl)-4-((2-(4-chloro-3-fluorophenoxy)acetamido)methyl)cyclohexane-1-carboxamide [(1r,4r)-N-(benzo[d]thiazol-2-yl)-4-((2-(4-chloro-3-fluorophenoxy)acetamido)methyl)cyclohexane-1-carboxamide] (EIF-065), (58) (1r,4r)-N-(벤조[d]티아졸-2-일)-4-((2-(2,4-디플루오로페녹시)아세트아미도)메틸)사이클로헥산-1-카르복사마이드[(1r,4r)-N-(benzo[d]thiazol-2-yl)-4-((2-(2,4-difluorophenoxy)acetamido)methyl)cyclohexane-1-carboxamide] (EIF-066),(58) (1r,4r)-N-(benzo[d]thiazol-2-yl)-4-((2-(2,4-difluorophenoxy)acetamido)methyl)cyclohexane-1-carboxamide [(1r,4r)-N-(benzo[d]thiazol-2-yl)-4-((2-(2,4-difluorophenoxy)acetamido)methyl)cyclohexane-1-carboxamide] (EIF-066), (59) N-((3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)사이클로부틸)메틸)-5-(디플루오로메틸)피라진-2-카르복사마이드[N-((3-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclobutyl)methyl)-5-(difluoromethyl)pyrazine-2-carboxamide] (EIF-067),(59) N-((3-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclobutyl)methyl)-5-(difluoromethyl)pyrazine-2-carboxamide [N-((3-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclobutyl)methyl)-5-(difluoromethyl)pyrazine-2-carboxamide] (EIF-067), (60) N-((3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)사이클로부틸)메틸)니코틴아마이드[N-((3-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclobutyl)methyl)nicotinamide] (EIF-068),(60) N-((3-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclobutyl)methyl)nicotinamide [N-((3-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclobutyl)methyl)nicotinamide] (EIF-068), (61) N-((3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)사이클로부틸)메틸)벤조퓨란-6-카르복사마이드[N-((3-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclobutyl)methyl)benzofuran-6-carboxamide] (EIF-069),(61) N-((3-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclobutyl)methyl)benzofuran-6-carboxamide [N-((3-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclobutyl)methyl)benzofuran-6-carboxamide] (EIF-069), (62) N-((3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)사이클로부틸)메틸)-1-(2,2-디플루오로에틸)-1H-피라졸-3-카르복사마이드[N-((3-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclobutyl)methyl)-1-(2,2-difluoroethyl)-1H-pyrazole-3-carboxamide] (EIF-070), 및(62) N-((3-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclobutyl)methyl)-1-(2,2-difluoroethyl)-1H-pyrazole-3-carboxamide [N-((3-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclobutyl)methyl)-1-(2,2-difluoroethyl)-1H-pyrazole-3-carboxamide] (EIF-070), and (63) N-((3-(2-(4-클로로-3-플루오로페녹시)아세트아미도)사이클로부틸)메틸)피콜린아마이드(3-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclobutyl)methyl)picolinamide] (EIF-071).(63) N-((3-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclobutyl)methyl)picolinamide] (EIF-071). 제 1 항에 있어서, In the first paragraph, 상기 화합물은, The above compound is, eIF2B를 활성화시키는 것을 특징으로 하는, 화합물.A compound characterized by activating eIF2B. 제 1 항에 따른 화합물을 유효성분으로 포함하는 대사질환 예방 또는 치료용 약학 조성물.A pharmaceutical composition for preventing or treating metabolic diseases, comprising a compound according to claim 1 as an active ingredient. 제 7 항에 있어서,In paragraph 7, 상기 대사질환은,The above metabolic diseases are, 비만, 당뇨, 동맥경화, 고지혈, 지방간 및 간섬유화로 이루어진 군에서 선택되는 질환인 것을 특징으로 하는, 약학 조성물.A pharmaceutical composition characterized in that the disease is selected from the group consisting of obesity, diabetes, arteriosclerosis, hyperlipidemia, fatty liver, and liver fibrosis. 제 1 항에 따른 화합물을 유효성분으로 포함하는 대사질환 예방 또는 개선용 건강식품 조성물.A health food composition for preventing or improving metabolic diseases, comprising a compound according to Article 1 as an active ingredient. 제 1 항에 따른 화합물을 유효성분으로 포함하는 eIF2B 활성화용 시약 조성물.A reagent composition for activating eIF2B, comprising a compound according to claim 1 as an active ingredient.
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