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

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

Novel eIF2B agonist and composition for preventing or treating metabolic diseases comprising the same

[0001] 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.

[0002] 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.

[0003] 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).

[0004] 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.

[0005] The object of the present invention is to provide a novel compound that modulates the activity of downstream regulators involved in the integrated stress response.

[0006] Another object of the present invention is to provide a composition for treating metabolic diseases comprising the above compound.

[0007] Another object of the present invention is to provide a composition for activating eIF2B comprising the above compound.

[0008] 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:

[0009] [Chemical Formula 1]

[0010]

[0011] In the above chemical formula 1,

[0012] n', n”, m' and m” may be the same or different and are one of 0 to 2,

[0013] L is one of (C3-C10)cycloalkyl, (C5-C10)spirocycloalkyl and (C5-C10)bicycloalkyl,

[0014] A 1 and A 2 may be the same or different, and are -CONH- or -NHCO-,

[0015] 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,

[0016] Ar 1 and Ar 2 are each 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, wherein the substituted (C5-C10)aryl or 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.

[0017] The present invention provides a pharmaceutical composition for preventing or treating metabolic diseases, comprising the above compound as an active ingredient.

[0018] The present invention provides a health food composition for preventing or improving metabolic diseases, which comprises the above compound as an active ingredient.

[0019] In addition, the present invention provides a reagent composition for activating eIF2B comprising the above compound as an active ingredient.

[0020] The novel compound according to the present invention can directly and significantly activate eIF2B, a protein that mediates integrated stress response signaling.

[0021] 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.

[0022] 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.

[0023] Figures 2a and 2b show the activity of a novel compound measured using the method of Figure 1.

[0024] Figure 3 shows the activity of the novel compound as a function of relative fluorescence intensity.

[0025] Figure 4 illustrates the enzyme activity analysis mechanism of the novel compound.

[0026] Figure 5 shows the results of enzyme activity analysis of a novel compound.

[0027] Figure 6 shows the EC of the new compound. 50 It was analyzed.

[0028] Figure 7 shows the experimental design and results for confirming the in vivo activity of a novel compound using an animal model.

[0029] Figure 8 shows the liver toxicity of the novel compound confirmed by ALT and AST levels.

[0030] Figure 9 shows the liver toxicity of the novel compound confirmed by histological changes.

[0031] Figure 10 shows the effect of a novel compound on macrophages.

[0032] Hereinafter, the present invention will be described in detail.

[0033]

[0034] 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.

[0035]

[0036] 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:

[0037] [Chemical Formula 1]

[0038]

[0039] In the above chemical formula 1,

[0040] 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, and A 1 and A 2 are each the same or different, -CONH- or -NHCO-, M' and M" are each 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, and Ar 1 and Ar 2are each 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, wherein the substituted (C5-C10)aryl or 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.

[0041] 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 2 to 4 membered heteroalkyl containing one or more heteroatoms selected from O and S, and Ar 1 and Ar 2 are each the same or different, and are one of unsubstituted or substituted (C5-C7)aryl 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 (C5-C7)aryl or 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.

[0042] 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 is one of ethylene, acetylene and 2 to 4 membered heteroalkyl containing one heteroatom of O or S, and Ar 1 and Ar2 are each the same or different, and are one of unsubstituted or substituted phenyl and 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 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 may be substituted with one or more and three or less of fluorine, methoxy, trifluoromethyl, difluoromethyl and difluoroethyl.

[0043] 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.

[0044] More preferably, the diamide derivative represented by the above chemical formula 1 may be any one selected from the following group of compounds:

[0045] 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 [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) [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 [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[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[(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] (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)[N,N'-(cyclopentane-1,3-diyl)bis(3-(4-chlorophenyl)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] (EIF-042), N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(4-(trifluoromethyl)phenyl)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)-1H-indazole-6-carboxamide [N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-1H-indazole-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)acetamide] (EIF-053), 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 (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 [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 [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).,

[0046]

[0047] The above compound can activate eIF2B.

[0048] 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.

[0049] 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.

[0050]

[0051] 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.

[0052] The 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.

[0053]

[0054] 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.

[0055] 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.

[0056] In the pharmaceutical composition according to the present invention, the pharmaceutical composition can be administered in a pharmaceutically effective amount.

[0057] 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.

[0058] 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.

[0059] 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.

[0060] 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.

[0061] 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.

[0062]

[0063] The present invention provides a health food composition for preventing or improving 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.

[0064] The 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.

[0065]

[0066] 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.

[0067] 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.

[0068] 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.

[0069] 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.

[0070]

[0071] 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.

[0072] The above compound can enhance the expression or activity of eIF2B.

[0073] 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.

[0074]

[0075] <Synthesis example>

[0076] Compound 1 (EIF-001):

[0077] 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 CH2Cl2 (2 mL, 0.17 M) was stirred at room temperature for 2 h. The solution was diluted in CH2Cl2 and washed sequentially with NaHCO3, NH4Cl, and brine. The organic solution was dried over Na2SO4 and concentrated. The crude compound was purified by MPLC (5% MeOH / CH2Cl2) to give compound 1 (EIF-001) (90 mg, 60% yield).

[0078]

[0079] N,N'-(cyclohexane-1,3-diyl)bis(2-(4-chlorophenoxy)acetamide)

[0080] 1 H NMR (400 MHz, DMSO-d6) δ8.05 (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).

[0081] MS (ESI + )m / zcalcd for C 22 H 24 Cl2N2O4[M+H] + 451.12; found 450.93

[0082]

[0083] Compound 2 (EIF-002):

[0084] 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 CH2Cl2 (2 mL, 0.2 M) was stirred at room temperature for 4 h. The solution was diluted in CH2Cl2, washed with NaHCO3 and brine, dried over Na2SO4, and concentrated. The crude product was purified by MPLC (EtOAc:hexane=1:1) to give the product (143 mg, 91% yield).

[0085]

[0086] 1 H NMR (400 MHz, CDCl3)δ7.29 - 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).

[0087]

[0088] Tert-Butyl(3-(2-(4-chlorophenoxy)acetamido)cyclopentyl)carbamate (74 mg, 0.2 mmol) was dissolved in 20% TFA / CH2Cl2 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.

[0089]

[0090]

[0091] A solution of N-(3-aminocyclopentyl)-2-(4-chlorophenoxy)acetamide (54 mg, 0.2 mmol), 2-(4-chlorophenoxy)acetamide (61 mg, 0.3 mmol), and triethylamine (81 mg, 0.8 mmol) in CH2Cl2 (1 mL, 0.2 M) was stirred at room temperature for 4 h. The solution was diluted in CH2Cl2, washed with NaHCO3 and brine, dried over Na2SO4, and concentrated. The crude product was purified by MPLC (EtOAc:hexane=2:1) ​​to give compound 2 (EIF-002) (86 mg, 96% yield).

[0092]

[0093] N,N'-(cyclopentane-1,3-diyl)bis(2-(4-chlorophenoxy)acetamide)

[0094] 1 H NMR (400 MHz, DMSO-d6)δ8.15 (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).

[0095] MS (ESI + )m / zcalcd for C 21 H 22 Cl2N2O4[M+H] + 437.11; found 437.02.

[0096]

[0097] Compound 4 (EIF-004):

[0098] 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 CH2Cl2 (2 mL, 0.22 M) was stirred at room temperature for 2 h. The solution was diluted in CH2Cl2, washed with NaHCO3 and brine, dried over Na2SO4, and concentrated. The crude product was purified by MPLC (EtOAc:hexane=1:1) to give the product (110 mg, 63% yield).

[0099]

[0100] 1 H NMR (400 MHz, DMSO-d6) δ8.27 (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).

[0101]

[0102] Tert-Butyl (6-(2-(4-chlorophenoxy)acetamido)spiro[3.3]heptan-2-yl)carbamate was dissolved in 20% TFA / CH2Cl2, 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.

[0103]

[0104]

[0105] 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 CH2Cl2 (1 mL, 0.14 M) were stirred at room temperature for 4 h. The solution was diluted in CH2Cl2, washed with NaHCO3 and brine, dried over Na2SO4, and concentrated. The crude product was purified by MPLC (EtOAc:hexane=4:1) to give compound 4 (EIF-004) (85 mg, 65% yield).

[0106]

[0107] N,N'-(spiro[3.3]heptane-2,6-diyl)bis(2-(4-chlorophenoxy)acetamide)

[0108] 1H NMR (400 MHz, DMSO-d6)δ8.29 (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).

[0109] MS (ESI + )m / zcalcd for C 23 H 24 Cl2N2O4[M+H] + 463.12; not observed.

[0110]

[0111] Compound 5 (EIF-005):

[0112] 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 Na2SO4, and concentrated. The crude product was purified by MPLC (5% MeOH / CH2Cl2) to obtain the product (50 mg, 62% yield).

[0113]

[0114] 1 H NMR (400 MHz, DMSO-d6) δ8.39 (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).

[0115]

[0116] 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 / CH2Cl2 (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.

[0117]

[0118]

[0119] 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 (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).

[0120]

[0121] 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)]

[0122] 1 H NMR (400 MHz, DMSO-d6) δ8.41 (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).

[0123] MS (ESI + )m / zcalcd for C 21 H 24 N4O4[M+H] +397.19; found 397.14.

[0124]

[0125] Compound 6 (EIF-006):

[0126] 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 NaHCO3, dried over Na2SO4, and concentrated. The crude product was purified by MPLC (EtOAc:hexane=1:1) to obtain the product (140 mg, 80% yield).

[0127]

[0128] 1 H NMR (400 MHz, DMSO-d6) δ8.36 (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).

[0129]

[0130] Tert-Butyl (E)-(3-(3-(4-chlorophenyl)acrylamido)cyclobutyl)carbamate (130 mg, 0.37 mmol) was stirred in 10% TFA / CH2Cl2 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.

[0131]

[0132]

[0133] A solution of (E)-N-(3-aminocyclobutyl)-3-(4-chlorophenyl)acrylamide (93 mg, 0.37 mmol), (E)-3-(4-chlorophenyl)acrylamide (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 NaHCO3. 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).

[0134]

[0135] (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)]

[0136] 1H NMR (400 MHz, DMSO-d6) δ8.46 (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).

[0137] MS (ESI + )m / zcalcd for C 22 H 20 Cl2N2O2[M+H] + 415.10; not observed.

[0138]

[0139] Compound 7 (EIF-007):

[0140] 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 NaHCO3, dried over Na2SO4, and concentrated. The crude product was purified by MPLC (EtOAc:hexane=1:1) to give the product (100 mg, 79% yield).

[0141]

[0142] 1H NMR (400 MHz, DMSO-d6) δ8.20 (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).

[0143]

[0144] tert-Butyl (3-(2-((2,6-dichlorobenzyl)thio)acetamido)cyclobutyl) carbamate (100 mg, 0.24 mmol) was diluted in 20% TFA / CH2Cl2 (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.

[0145]

[0146]

[0147] A solution of 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 Et3N (72 mg, 0.71 mmol) in CH2Cl2 (2 mL, 0.12 M) was stirred at room temperature for 4 h. The mixture was diluted with CH2Cl2, washed with NaHCO3, dried over Na2SO4, and concentrated. The crude product was purified by MPLC (EtOAc:hexane=4:1) to give compound 7 (EIF-007) (40 mg, 34% yield).

[0148]

[0149] 2-(4-chlorophenoxy)-N-(3-(2-((2,6-dichlorobenzyl)thio)acetamido)cyclobutyl)acetamide

[0150] 1 H NMR (400 MHz, DMSO-d6) δ8.33 (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).

[0151] MS (ESI + )m / zcalcd for C 21 H 21 Cl3N2O3S [M+H] + 487.04; not observed.

[0152]

[0153] Compound 8 (EIF-008):

[0154] 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.

[0155]

[0156] 1 H NMR (400 MHz, DMSO-d6)δ8.24 (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).

[0157] MS (ESI + )m / zcalcd for C 20 H 31 N2O4[M + H] + 363.22; found 363.73.

[0158]

[0159] A stirred solution of 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.

[0160]

[0161]

[0162] To a stirred solution of 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 through filtration to obtain 96 mg (70%) of compound 8 (EIF-008) as a light brown solid.

[0163]

[0164] N,N'-(cyclobutane-1,3-diyl)bis(2-(mesityloxy)acetamide)

[0165] 1H NMR (400 MHz, DMSO-d6)δ8.25 (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).

[0166] MS (ESI + )m / zcalcd for C 26 H 35 N2O4[M + H] + 439.25; found 439.19.

[0167]

[0168] Compound 9 (EIF-009):

[0169] 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.

[0170]

[0171] 1H NMR (400 MHz, DMSO-d6) δ8.21 (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).

[0172] MS (ESI + )m / zcalcd for C 18 H 26 ClN2O4[M + H] + 369.15; found 369.00.

[0173]

[0174] 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.

[0175]

[0176]

[0177] To a stirred solution of 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.

[0178]

[0179] N,N'-(cyclobutane-1,3-diyl)bis(3-(2-chlorophenoxy)propanamide)

[0180] 1 H NMR (400 MHz, DMSO-d6) δ8.26 (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).

[0181] MS (ESI + )m / zcalcd for C 22 H25 Cl2N2O4[M + H] + 451.11; found 451.00.

[0182]

[0183] Compound 10 (EIF-010):

[0184] 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.

[0185]

[0186] 1 H NMR (400 MHz, DMSO-d6)δ8.20 (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).

[0187] MS (ESI + )m / zcalcd for C16 H 23 FN3O4[M + H] + 340.16; found 340.02.

[0188]

[0189] A stirred solution of 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.

[0190]

[0191]

[0192] To a stirred solution of N-(3-aminocyclobutyl)-2-((5-fluoropyridin-2-yl)oxy)acetamide [N-(3-aminocyclobutyl)-2-((5-fluoropyridin-2-yl)oxy)acetamide] (1.0 equiv., 21.2 mg, 0.088 mmol) in DMF (442 μl) was 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 minimal amount of ethyl acetate and treated with hexane. The formed precipitate was collected by filtration, yielding 83 mg (78%) of compound 10 (EIF-010) as a light brown solid.

[0193]

[0194] 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)

[0195] 1 H NMR (400 MHz, CDCl3)δ8.00 (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).

[0196] MS (ESI + )m / zcalcd for C 18 H 19 F2N4O4[M + H] + 393.13; found 393.10.

[0197]

[0198] Compound 11 (EIF-011):

[0199] 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 MgSO4 and concentrated under reduced pressure. 76.5 mg (86%) of tert-butyl (3-(quinoline-3-carboxamido)cyclobutyl)carbamate was obtained as a white solid.

[0200]

[0201] 1 H NMR (400 MHz, DMSO-d6) δ9.27 (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] + .

[0202]

[0203] To a solution of tert-butyl (3-(quinoline-3-carboxamido)cyclobutyl)carbamate (1.0 equiv) in CH2Cl2 was added TFA (1.0 equiv) at room temperature and stirred for 5 h. The solvent was evaporated under reduced pressure.

[0204]

[0205]

[0206] To a solution of N-(3-aminocyclobutyl)quinoline-3-carboxamide (1.0 equiv) in CH2Cl2 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 MgSO4 and concentrated under reduced pressure. The residue was purified by 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.

[0207]

[0208] N-(3-(2-(4-chlorophenoxy)acetamido)cyclobutyl)quinoline-3-carboxamide

[0209] 1H NMR (400 MHz, DMSO-d6) δ9.29 (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] + .

[0210]

[0211] Compound 12 (EIF-012):

[0212] To a solution of tert-butyl ((1r,4r)-4-aminocyclohexyl)carbamate (1.0 equiv) in CH2Cl2 was 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 MgSO4 and concentrated under reduced pressure. The residue was purified by filtration (EtOAc / n-hexane) to obtain 779 mg (85%) of tert-butyl ((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)carbamate as a white solid with a purity of 98% (purity 98%).

[0213]

[0214] 1 H NMR (400 MHz, DMSO-d6)δ7.92 (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] + .

[0215]

[0216] To a solution of tert-butyl ((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)carbamate (1.0 equiv) in CH2Cl2 was added TFA (1.0 equiv) at room temperature, and the mixture was stirred for 5 h. The solvent was evaporated under reduced pressure.

[0217]

[0218]

[0219] To a solution of N-((1r,4r)-4-aminocyclohexyl)-2-methoxyisonicotinamide [N-((1r,4r)-4-aminocyclohexyl)-2-methoxyisonicotinamide] (1.0 equiv) dissolved in CH2Cl2 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 MgSO4 and concentrated under reduced pressure. The residue was purified by filtration (EtOAc / n-hexane) to obtain 16 mg (33%) of compound 12 (EIF-012), N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-2-methoxyisonicotinamide, as a white solid with a purity of 98%.

[0220]

[0221] N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-2-methoxyisonicotinamide

[0222] 1 H NMR (400 MHz, DMSO-d6) δ8.46 (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] + .

[0223]

[0224] Compound 13 (EIF-013):

[0225] A solution of N-((1r,4r)-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 MgSO4 and concentrated under reduced pressure. The residue was purified by filtration (EtOAc / n-hexane) to obtain compound 13 (EIF-013), N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)quinoline-3-carboxamide, as a white solid with 99% purity.

[0226]

[0227] N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)quinoline-3-carboxamide

[0228] 1H NMR (400 MHz, DMSO-d6) δ9.26 (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] + .

[0229]

[0230] Compound 14 (EIF-014):

[0231] A solution of N-((1r,4r)-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 MgSO4 and concentrated under reduced pressure. The residue was purified through filtration (EtOAc / n-hexane) to obtain 60.2 mg (86%) of a white solid compound 14 (EIF-014), N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)thiazole-5-carboxamide with 99% purity.

[0232]

[0233] N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)thiazole-5-carboxamide

[0234] 1 H NMR (400 MHz, DMSO-d6)δ9.20 (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] + .

[0235]

[0236] Compound 15 (EIF-015):

[0237] A solution of N-((1r,4r)-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 MgSO4 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-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)imidazole [1,2-a]pyridine-6-carboxamide with 99% purity.

[0238]

[0239] N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)imidazole [1,2-a]pyridine-6-carboxamide

[0240] 1 H NMR (400 MHz, DMSO-d6)δ9.08 (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] + .

[0241]

[0242] Compound 16 (EIF-016):

[0243] A solution of N-((1r,4r)-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 MgSO4 and concentrated under reduced pressure. The residue was purified through filtration (EtOAc / n-hexane) to obtain 55.1 mg (72%) of beige solid compound 16 (EIF-016), N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)benzofuran-2-carboxamide with 99% purity.

[0244]

[0245] N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)benzofuran-2-carboxamide

[0246] 1 H NMR (400 MHz, DMSO-d6) δ8.52 (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] + .

[0247]

[0248] Compound 23 (EIF-023):

[0249] 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 NaHCO3, dried over Na2SO4, and concentrated. The crude product was purified by MPLC (10% MeOH / CH2Cl2) to obtain the product (140 mg, 97% yield).

[0250]

[0251] 1 H NMR (400 MHz, CDCl3)δ9.21 (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).

[0252]

[0253] tert-Butyl ((4-(imidazo[1,2-a]pyridin-6-ylcarbamoyl)cyclohexyl)methyl)carbamate] (40 mg, 0.1 mmol) was diluted in 20% TFA / CH2Cl2 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.

[0254]

[0255]

[0256] 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 NaHCO3, dried over Na2SO4, and concentrated. The crude product was purified by MPLC (10% MeOH / CH2Cl2) to obtain compound 23 (EIF-023) (32 mg, 70% yield).

[0257]

[0258] (1r,4r)-4-((2-(2,4-difluorophenoxy)acetamido)methyl)-N-(imidazo[1,2-a]pyridin-6-yl)cyclohexane-1-carboxamide

[0259] 1 H NMR (400 MHz, CDCl3)δ9.24 (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).

[0260] MS (ESI + )m / zcalcd for C 23 H 24 F2N4O3[M+H] + 443.19; found 443.10.

[0261]

[0262] Compound 24 (EIF-024):

[0263] 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 NaHCO3, dried over Na2SO4, and concentrated. The crude product was purified by MPLC (10% MeOH / CH2Cl2) to give the product (55 mg, 42% yield).

[0264]

[0265] 1 H NMR (400 MHz, CDCl3)δ8.47 (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).

[0266]

[0267] tert-Butyl ((4-(pyridin-4-ylcarbamoyl)cyclohexyl)methyl)carbamate] (55 mg, 0.16 mmol) was diluted in 20% TFA / CH2Cl2 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.

[0268]

[0269]

[0270] 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 NaHCO3, dried over Na2SO4, and concentrated. The crude product was purified by MPLC (10% MeOH / CH2Cl2) to give compound 24 (EIF-024) (55 mg, 80% yield).

[0271]

[0272] (1r,4r)-4-((2-(2,4-difluorophenoxy)acetamido)methyl)-N-(pyridin-4-yl)cyclohexane-1-carboxamide

[0273] 1H NMR (400 MHz, DMSO-d6) δ10.20 (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).

[0274] MS (ESI + )m / zcalcd for C 21 H 23 F2N3O3[M+H] + 404.18; found 404.10.

[0275]

[0276] Compound 25 (EIF-025):

[0277] 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 NaHCO3, dried over Na2SO4, and concentrated. The crude product was purified by MPLC (10% MeOH / CH2Cl2) to give compound 25 (EIF-025) (42 mg, 70% yield).

[0278]

[0279] (1r,4r)-4-((3-(4-fluorophenoxy)propanamido)methyl)-N-(imidazo[1,2-a]pyridin-6-yl)cyclohexane-1-carboxamide

[0280] 1 H NMR (400 MHz, DMSO-d6)δ9.93 (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).

[0281] MS (ESI + )m / zcalcd for C 24 H 27 FN4O3[M+H] + 439.22; found 439.18.

[0282]

[0283] Compound 26 (EIF-026):

[0284] A solution of N-((1r,4r)-4-aminocyclohexyl)-2-(4-chlorophenoxy)acetamide (1.0 equiv), 1H-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 MgSO4 and concentrated under reduced pressure. The residue was purified by filtration (EtOAc / n-hexane) to obtain 59.3 mg (75%) of a white solid, compound 26 (EIF-026), N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide with 96% purity.

[0285]

[0286] N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide

[0287] 1H NMR (400 MHz, DMSO-d6) δ11.88 (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] + .

[0288]

[0289] Compound 27 (EIF-027):

[0290] A solution of N-((1r,4r)-4-aminocyclohexyl)-2-(4-chlorophenoxy)acetamide (1.0 equiv), 1H-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.

[0291] 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 MgSO4 and concentrated under reduced pressure. The residue was purified by filtration (EtOAc / n-hexane) to give 13.7 mg (30%) of 98% pale yellow solid, compound 27 (EIF-027), N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-1H-benzo[d]imidazole-6-carboxamide.

[0292]

[0293] N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-1H-benzo[d]imidazole-6-carboxamide

[0294] 1 H NMR (400 MHz, DMSO-d6) δ12.65 (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] + .

[0295]

[0296] Compound 28 (EIF-028):

[0297] 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 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). 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 minimal amount of ethyl acetate and treated with hexane. The formed precipitate was collected by filtration, yielding 69 mg (90%) of the beige solid product.

[0298]

[0299] 1 H NMR (400 MHz, DMSO-d6)δ9.01 (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).

[0300] MS (ESI + )m / zcalcd for C 19 H 24 ClN2O3[M + H] + 363.14; found 363.15.

[0301]

[0302] A stirred solution of tert-butyl ((3-(3-(4-chlorophenyl)propiolamido)cyclobutyl)methyl)carbamate (1.0 equiv., 30 mg, 0.083 mmol) 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.

[0303]

[0304]

[0305] To a stirred solution of 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 a pale orange solid, compound 28 (EIF-028).

[0306]

[0307] 3-(4-chlorophenyl)-N-((3-(3-(4-chlorophenyl)propiolamido)cyclobutyl)methyl)propiolamide

[0308] 1 H NMR (400 MHz, DMSO) δ9.04 (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).

[0309] MS (ESI + )m / zcalcd for C 23 H 19 Cl2N2O2[M + H] + 425.07; found 425.05.

[0310]

[0311] Compound 29 (EIF-029):

[0312] 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 product as a white solid.

[0313]

[0314] 1 H NMR (400 MHz, DMSO-d6) δ8.31 (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).

[0315] MS (ESI + )m / zcalcd for C 19 H 26 ClN2O3[M + H] + 365.16; found 365.15.

[0316]

[0317] A stirred solution of tert-butyl (E)-((3-(3-(4-chlorophenyl)acrylamio)cyclobutyl)methyl)carbamate (1.0 equiv., 30 mg, 0.082 mmol) 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.

[0318]

[0319]

[0320] To a stirred solution of (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.

[0321]

[0322] (E)-3-(4-chlorophenyl)-N-((3-((E)-3-(4-chlorophenyl)acrylamido)cyclobutyl)methyl)acrylamide

[0323] 1 H NMR (400 MHz, DMSO-d6) δ8.34 (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).

[0324] MS (ESI + )m / zcalcd for C 23 H 23 Cl2N2O2[M + H] + 425.11; found 425.05.

[0325]

[0326] Compound 30 (EIF-030):

[0327] 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.

[0328]

[0329] 1 H NMR (400 MHz, DMSO-d6)δ8.16 (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).

[0330] MS (ESI + )m / zcalcd for C 17 H 25 FN3O4[M + H] + 354.16; found 354.15.

[0331]

[0332] A stirred solution of tert-butyl ((3-(2-((5-fluoropyridin-2-yl)oxy)acetamido)cyclobutyl)methyl)carbamate (1.0 equiv., 30 mg, 0.085 mmol) 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.

[0333]

[0334]

[0335] 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.

[0336]

[0337] 2-((5-fluoropyridin-2-yl)oxy)-N-((3-(2-((5-fluoropyridin-2-yl)oxy)acetamido)cyclobutyl)methyl)acetamide

[0338] 1 H NMR (400 MHz, DMSO-d6)δ8.15 (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).

[0339] MS (ESI + )m / zcalcd for C 19 H 21 F2N4O4[M + H] + - 407.15; found 407.10.

[0340]

[0341] General procedure for HATU coupling

[0342] 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 H2O and diluted with EtOAc. The organic layer was washed with distilled water and dried over Na2SO4. The crude product was concentrated in vacuo and purified by flash column chromatography (EIF-032, 33, 38-47).

[0343]

[0344] Compound 32 (EIF-032):

[0345] 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 hours, the reaction mixture was quenched with H2O and diluted with EtOAc. The organic layer was washed with distilled water and dried over Na2SO4. The residue was purified by filtration (EtOAc / n-hexane) and dried to yield 869 mg (90%) of the product as a light brown solid.

[0346]

[0347] 1 H NMR (DMSO-d6, 400 MHz) δ8.69 (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).

[0348]

[0349] 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) was added TFA (217 μl) at ambient temperature. After stirring for 4 h, the reaction mixture was evaporated without further purification.

[0350]

[0351]

[0352] 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 using a general procedure, followed by filtration (EtOAc / n-Hexane) to give 13.7 mg (39%) of compound 32 (EIF-032) as an ivory solid.

[0353]

[0354] N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(4-chlorophenyl)propiolamide

[0355] 1 H NMR (DMSO-d6, 400 MHz) δ9.44 (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).

[0356] MS (ESI + )m / zcalcd for C 22 H 17 Cl2FN2O3[M + H] + 447.06; found 447.13.

[0357]

[0358] Compound 33 (EIF-033):

[0359] 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, and then filtered (EtOAc / n-Hexane = 1:1) to obtain 15.1 mg (47%) of compound 33 (EIF-033) as a white solid.

[0360]

[0361] N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-phenylpropiolamide

[0362] 1 H NMR (DMSO-d6, 400 MHz) δ9.42 (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).

[0363] MS (ESI + )m / zcalcd for C 22 H 18 ClFN2O3FN2O3[M + H] + 413.10; found 413.16.

[0364]

[0365] Compound 34 (EIF-034):

[0366] 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 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 minimal amount of ethyl acetate and treated with hexane. The formed precipitate was filtered and collected to give 46 mg (67%) of the product as a yellow solid.

[0367]

[0368] 1 H NMR (400 MHz, DMSO-d6)δ8.37 (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).

[0369]

[0370] A stirred solution of 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.

[0371]

[0372]

[0373] 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.

[0374]

[0375] 2-((5-fluoropyridin-2-yl)oxy)-N-((3-(2-((5-fluoropyridin-2-yl)oxy)acetamido)cyclopentyl)methyl)acetamide

[0376] 1 H NMR (400 MHz, DMSO-d6) δ8.10 (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).

[0377] MS (ESI + )m / zcalcd for C 20 H 23 F2N4O4[M + H] + - 421.16; found 421.05.

[0378]

[0379] Compound 35 (EIF-035):

[0380] 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.

[0381]

[0382] 1 H NMR (400 MHz, DMSO-d6) δ8.85 (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).

[0383]

[0384] 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.

[0385]

[0386]

[0387] To a stirred solution of N-((3-aminocyclopentyl)methyl)-3-(4-chlorophenyl)propiolamide (1.0 equiv., 15 mg, 0.053 mmol) in DMF (265 μl) 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 minimal amount of ethyl acetate and treated with hexane. The formed precipitate was collected by filtration to obtain 15 mg (64%) of compound 35 (EIF-035) as a beige solid.

[0388]

[0389] 3-(4-chlorophenyl)-N-((3-(3-(4-chlorophenyl)propiolamido)cyclopentyl)methyl)propiolamide

[0390] 1 H NMR (400 MHz, DMSO-d6) δ8.89 (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).

[0391] MS (ESI + )m / zcalcd for C 24 H 21 Cl2N2O2[M + H] + - 439.09; found 439.15.

[0392]

[0393] Compound 36 (EIF-036):

[0394] 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.

[0395]

[0396] 1 H NMR (400 MHz, DMSO-d6) δ9.09 (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).

[0397]

[0398] 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.

[0399]

[0400]

[0401] To a stirred solution of N-(3-aminocyclobutyl)-3-(4-chlorophenyl)propiolamide (1.0 equiv., 25 mg, 0.101 mmol) in DMF (505 μl) 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 minimal amount of ethyl acetate and treated with hexane. The formed precipitate was collected by filtration to obtain 4.0 mg (9%) of ivory-colored solid compound 36 (EIF-036).

[0402]

[0403] N,N'-(cyclobutane-1,3-diyl)bis(3-(4-chlorophenyl)propiolamide)

[0404] 1 H NMR (400 MHz, DMSO-d6) δ9.26 (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).

[0405] MS (ESI + )m / zcalcd for C 22 H17 Cl2N2O2[M + H] + - 411.06; found 411.12.

[0406]

[0407] Compound 37 (EIF-037):

[0408] 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.

[0409]

[0410] 1 H NMR (400 MHz, DMSO-d6) δ8.87 (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).

[0411]

[0412] 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.

[0413]

[0414]

[0415] 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-colored solid compound 37 (EIF-037).

[0416]

[0417] N,N'-(cyclopentane-1,3-diyl)bis(3-(4-chlorophenyl)propiolamide)

[0418] 1 H NMR (400 MHz, DMSO-d6) δ8.93 (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).

[0419] MS (ESI + )m / zcalcd for C 23 H 19 Cl2N2O2[M + H] + 425.07 - ; found 425.17.

[0420]

[0421] Compound 38 (EIF-038):

[0422] 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).

[0423]

[0424] N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(3-fluorophenyl)propiolamide

[0425] 1 H NMR (DMSO-d6, 400 MHz) δ9.47 (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).

[0426] MS (ESI + )m / zcalcd for C 22 H 17 ClF2N2O3[M + H] + 431.09; found 431.22.

[0427]

[0428] Compound 39 (EIF-039):

[0429] 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).

[0430]

[0431] N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(p-tolyl)propiolamide

[0432] 1 H NMR (DMSO-d6, 400 MHz) δ9.37 (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).

[0433] MS (ESI + )m / zcalcd for C 23 H 20 ClFN2O3[M + H] + 427.11; found 427.24.

[0434]

[0435] Compound 40 (EIF-040):

[0436] 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).

[0437]

[0438] N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(2-fluorophenyl)propiolamide

[0439] 1 H NMR (DMSO-d6, 400 MHz) δ9.50 (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).

[0440] MS (ESI + )m / zcalcd for C 22 H 17 ClF2N2O3[M + H] + 431.09; found 431.17.

[0441]

[0442] Compound 41 (EIF-041):

[0443] 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).

[0444]

[0445] N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(3-chlorophenyl)propiolamide

[0446] 1 H NMR (DMSO-d6, 400 MHz) δ9.46 (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).

[0447] MS (ESI + )m / zcalcd for C 22 H 17 Cl2FN2O3[M + H] + 447.06; found 447.13.

[0448]

[0449] Compound 42 (EIF-042):

[0450] 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).

[0451]

[0452] N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(4-(trifluoromethyl)phenyl)propiolamide

[0453] 1 H NMR (DMSO-d6, 400 MHz) δ9.54 (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).

[0454] MS (ESI + )m / zcalcd for C 23 H 17 ClF4N2O3[M + H] + 481.09; found 481.21.

[0455]

[0456] Compound 43 (EIF-043):

[0457] 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 through a general procedure, and then filtered (DCM) to obtain 14.3 mg (42%) of ivory solid compound 43 (EIF-043).

[0458]

[0459] N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(4-fluorophenyl)propiolamide

[0460] 1 H NMR (DMSO-d6, 400 MHz) δ9.40 (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).

[0461] MS (ESI + )m / zcalcd for C 22 H 17 ClF2N2O3[M + H] + 431.09; found 431.22.

[0462]

[0463] Compound 44 (EIF-044):

[0464] 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).

[0465]

[0466] N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(4-ethylphenyl)propiolamide

[0467] 1 H NMR (DMSO-d6, 400 MHz) δ9.36 (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).

[0468] MS (ESI + )m / zcalcd for C 24 H 22 ClFN2O3[M + H] + 441.13; found 441.21.

[0469]

[0470] Compound 45 (EIF-045):

[0471] 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).

[0472]

[0473] 3-(4-(tert-butyl)phenyl)-N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)propiolamide

[0474] 1 H NMR (DMSO-d6, 400 MHz) δ9.36 (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).

[0475] MS (ESI + )m / zcalcd for C 26 H 26 ClFN2O3[M + H] + 469.16; found 469.28.

[0476]

[0477] Compound 46 (EIF-046):

[0478] 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).

[0479]

[0480] N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(naphthalen-2-yl)propiolamide

[0481] 1 H NMR (DMSO-d6, 400 MHz) δ9.47 (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).

[0482] MS (ESI + )m / zcalcd for C 26 H 20 ClFN2O3[M + H] + 463.11; found 463.18.

[0483]

[0484] Compound 47 (EIF-047):

[0485] 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).

[0486]

[0487] N-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-3-(2-chlorophenyl)propiolamide

[0488] 1 H NMR (DMSO-d6, 400 MHz) δ9.49 (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).

[0489] MS (ESI + )m / zcalcd for C 22 H 17 Cl2FN2O3[M + H] + 447.06; found 447.16.

[0490]

[0491] Compound 48 (EIF-048):

[0492] To a stirred solution of tert-butyl (3-aminocyclohexyl)carbamate (1.0 equiv., 50 mg, 0.233 mmol) in DMF (1.1 ml) 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 obtain 66 mg (72%) of a pale yellow solid product.

[0493]

[0494] 1 H NMR (400 MHz, DMSO-d6)δ8.79 (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).

[0495] MS (ESI + )m / zcalcd for C 20 H 26 ClN2O2[M + Na] + 399.15; found 399.26.

[0496]

[0497] 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.

[0498]

[0499] To a stirred solution of N-(3-aminocyclohexyl)-3-(4-chlorophenyl)propiolamide (1.0 equiv., 29.4 mg, 0.106 mmol) in DMF (531 μl) 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 minimal amount of ethyl acetate and treated with hexane. The formed precipitate was collected by filtration to obtain 17.4 mg (37%) of ivory-colored solid compound 48 (EIF-048).

[0500]

[0501] N,N'-(cyclohexane-1,3-diyl)bis(3-(4-chlorophenyl)propiolamide)

[0502] 1H NMR (400 MHz, DMSO-d6) δ8.86 (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).

[0503] MS (ESI + )m / zcalcd for C 24 H 21 Cl2N2O2[M + H] + 439.09 - ; found 439.19.

[0504]

[0505] Compound 49 (EIF-049):

[0506] To a stirred solution of N-((1r,4r)-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.

[0507]

[0508] 1H NMR (400 MHz, DMSO-d6)δ8.73 (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).

[0509] MS (ESI + )m / zcalcd for C 20 H 26 ClN2O2[M + Na] + 399.15; found 399.24.

[0510]

[0511] 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.

[0512]

[0513]

[0514] To a stirred solution of N-((1r,4r)-4-aminocyclohexyl)-3-(4-chlorophenyl)propiolamide (1.0 equiv., 30.7 mg, 0.111 mmol) in DMF (555 μl) 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 minimal amount of ethyl acetate and treated with hexane. The formed precipitate was collected by filtration, yielding 13 mg (27%) of ivory-colored solid compound 49 (EIF-049).

[0515]

[0516] N,N'-((1r,4r)-cyclohexane-1,4-diyl)bis(3-(4-chlorophenyl)propiolamide)

[0517] 1 H NMR (400 MHz, DMSO-d6) δ8.79 (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).

[0518]

[0519] Compound 50 (EIF-050):

[0520] A solution of N-((1r,4r)-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 (X3) and brine. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. 21.9 mg (36%) of white solid compound 50 (EIF-050), N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)benzofuran-6-carboxamide with 98% purity was obtained.

[0521]

[0522] N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)benzofuran-6-carboxamide

[0523] 1 H NMR (400 MHz, DMSO-d6) δ8.28 (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] + .

[0524]

[0525] Compound 51 (EIF-051):

[0526] A solution of N-((1r,4r)-4-aminocyclohexyl)-2-(4-chlorophenoxy)acetamide (1.0 equiv), 1H-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 MgSO4 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-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-1H-indazole-6-carboxamide.

[0527]

[0528] N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-1H-indazole-6-carboxamide

[0529] 1H NMR (400 MHz, DMSO-d6)δ13.32 (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] + .

[0530]

[0531] Compound 52 (EIF-052):

[0532] A solution of N-((1r,4r)-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 MgSO4 and concentrated under reduced pressure. The residue was purified by filtration (EtOAc / n-hexane) to obtain 23.1 mg (42%) of ivory solid compound 52 (EIF-052)N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)nicotinamide with 99% purity.

[0533]

[0534] N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)nicotinamide

[0535] 1 H NMR (400 MHz, DMSO-d6) δ8.99 (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] + .

[0536]

[0537] Compound 53 (EIF-053):

[0538] A solution of N-((1r,4r)-4-aminocyclohexyl)-2-(4-chlorophenoxy)acetamide (1.0 equiv), 2-(1H-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 MgSO4 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-((1r,4r)-4-(2-(1H-benzo[d]imidazol-2-yl)acetamido)cyclohexyl)-2-(4-chlorophenoxy)acetamide with 97% purity.

[0539]

[0540] N-((1r,4r)-4-(2-(1H-benzo[d]imidazol-2-yl)acetamido)cyclohexyl)-2-(4-chlorophenoxy)acetamide

[0541] 1H NMR (400 MHz, DMSO-d6) δ12.32 (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] + .

[0542]

[0543] Compound 54 (EIF-054):

[0544] A solution of N-((1r,4r)-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 MgSO4 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-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)acetamide with 96% purity.

[0545]

[0546] 2-(benzofuran-2-yl)-N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)acetamide

[0547] 1 H NMR (400 MHz, DMSO-d6) δ8.12 (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] + .

[0548]

[0549] Compound 55 (EIF-055):

[0550] A solution of N-((1r,4r)-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 MgSO4 and concentrated under reduced pressure. The residue was purified by filtration (EtOAc / n-hexane) to obtain 14 mg (21%) of 95% pure white solid compound 55 (EIF-055)2-(benzo[b]thiophen-2-yl)-N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)acetamide.

[0551]

[0552] 2-(benzo[b]thiophen-2-yl)-N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)acetamide

[0553] 1H NMR (400 MHz, DMSO-d6) δ8.15 (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] + .

[0554]

[0555] Compound 56 (EIF-056):

[0556] 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 MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (60% EtOAc / n-hexane) to obtain 11.9 mg (24%) of 97% pure white solid compound 56 (EIF-056)3-(4-chlorophenyl)-N-(3-(2-(o-tolyloxy)acetamido)cyclobutyl)propiolamide.

[0557]

[0558] 3-(4-chlorophenyl)-N-(3-(2-(o-tolyloxy)acetamido)cyclobutyl)propiolamide

[0559] 1 H NMR (400 MHz, DMSO-d6)δ9.10 (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] + .

[0560]

[0561] Compound 57 (EIF-057):

[0562] 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 MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (60% EtOAc / n-hexane) to obtain 21.3 mg (42%) of 95% pure white solid compound 57 (EIF-057)3-(4-chlorophenyl)-N-(3-(2-(m-tolyloxy)acetamido)cyclobutyl)propiolamide.

[0563]

[0564] 3-(4-chlorophenyl)-N-(3-(2-(m-tolyloxy)acetamido)cyclobutyl)propiolamide

[0565] 1 H NMR (400 MHz, DMSO-d6)δ9.10 (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] + .

[0566]

[0567] Compound 58 (EIF-058):

[0568] 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 MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (50% EtOAc / n-hexane) to obtain 21.7 mg (44%) of 97% pure white solid compound 58 (EIF-058)3-(4-chlorophenyl)-N-(3-(2-(2-fluorophenoxy)acetamido)cyclobutyl)propiolamide.

[0569]

[0570] 3-(4-chlorophenyl)-N-(3-(2-(2-fluorophenoxy)acetamido)cyclobutyl)propiolamide

[0571] 1H NMR (400 MHz, DMSO-d6) δ9.10 (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] + .

[0572]

[0573] Compound 59 (EIF-059):

[0574] 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 MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (50% EtOAc / n-hexane) to obtain 19.2 mg (38%) of 96% pure white solid compound 59 (EIF-059)3-(4-chlorophenyl)-N-(3-(2-(3-fluorophenoxy)acetamido)cyclobutyl)propiolamide.

[0575]

[0576] 3-(4-chlorophenyl)-N-(3-(2-(3-fluorophenoxy)acetamido)cyclobutyl)propiolamide

[0577] 1 H NMR (400 MHz, DMSO-d6) δ9.11 (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] + .

[0578]

[0579] Compound 60 (EIF-060):

[0580] 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 MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (50% EtOAc / n-hexane) to obtain 7.1 mg (14%) of 96% pure white solid compound 60 (EIF-060)3-(4-chlorophenyl)-N-(3-(2-(p-tolylthoxy)acetamido)cyclobutyl)propiolamide.

[0581]

[0582] 3-(4-chlorophenyl)-N-(3-(2-(p-tolyloxy)acetamido)cyclobutyl)propiolamide

[0583] 1 H NMR (400 MHz, DMSO-d6) δ9.09 (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] + .

[0584]

[0585] Compound 61 (EIF-061):

[0586] 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 MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (50% EtOAc / n-hexane) to obtain 6.4 mg (12%) of pale yellow solid compound 61 (EIF-061)3-(4-chlorophenyl)-N-(3-(2-(2,4-difluorophenoxy)acetamido)cyclobutyl)propiolamide with 96% purity.

[0587]

[0588] 3-(4-chlorophenyl)-N-(3-(2-(2,4-difluorophenoxy)acetamido)cyclobutyl)propiolamide

[0589] 1 H NMR (400 MHz, DMSO-d6)δ9.10 (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]+ .

[0590]

[0591] Compound 62 (EIF-062):

[0592] 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 MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (60% EtOAc / n-hexane) to obtain 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.

[0593]

[0594] N-(3-(2-(2-chlorophenoxy)acetamido)cyclobutyl)-3-(4-chlorophenyl)propiolamide

[0595] 1H NMR (400 MHz, DMSO-d6)δ9.11 (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] + .

[0596]

[0597] Compound 63 (EIF-063):

[0598] 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 MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (50% EtOAc / n-hexane) to obtain 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.

[0599]

[0600] N-(3-(2-(4-chloro-2-methylphenoxy)acetamido)cyclobutyl)-3-(4-chlorophenyl)propiolamide

[0601] 1 H NMR (400 MHz, DMSO-d6) δ9.10 (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] + .

[0602]

[0603] Compound 64 (EIF-064):

[0604] To N-(3-aminocyclobutyl)-3-(4-chlorophenyl)propiolamide (1.0 equiv) dissolved in CH2Cl2 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 MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (60% EtOAc / n-hexane) to obtain 8.7 mg (16%) of 95% pure white solid compound 64 (EIF-064)N-(3-(2-(4-chlorophenoxy)acetamido)cyclobutyl)-3-(4-chlorophenyl)propiolamide.

[0605]

[0606] N-(3-(2-(4-chlorophenoxy)acetamido)cyclobutyl)-3-(4-chlorophenyl)propiolamide

[0607] 1 H NMR (400 MHz, DMSO-d6) δ9.10 (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] + .

[0608]

[0609] Compound 65 (EIF-065):

[0610] 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 NaHCO3, dried over Na2SO4, and concentrated. The crude product was purified by MPLC (EtOAc:hexane=1:1) to obtain the product (100 mg, 33% yield).

[0611]

[0612] 1 H NMR (400 MHz, DMSO-d6)δ12.27 (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).

[0613]

[0614] A solution of tert-butyl ((4-(benzo[d]thiazol-2-ylcarbamoyl))cyclohexyl)methyl)carbamate (90 mg, 0.23 mmol) in 20% TFA / CH2Cl2 was stirred at room temperature for 2 h. The organic solution was removed under reduced pressure.

[0615]

[0616]

[0617] 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 NaHCO3, dried over Na2SO4, and concentrated. The crude product was purified by MPLC (EtOAc:hexane=1:1) to obtain compound 65 (EIF-065) (35 mg, 70% yield).

[0618]

[0619] (1r,4r)-N-(benzo[d]thiazol-2-yl)-4-((2-(4-chloro-3-fluorophenoxy)acetamido)methyl)cyclohexane-1-carboxamide

[0620] 1 H NMR (400 MHz, DMSO-d6)δ12.31 (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).

[0621] MS (ESI + )m / zcalcd for C 23 H 23 ClFN3O3S [M+H] + 476.12; found 476.22.

[0622]

[0623] 화합물 66 (EIF-066):

[0624] 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 NaHCO3, dried over Na2SO4, and concentrated. The crude product was purified by MPLC (EtOAc:hexane=1:1) to give compound 66 (EIF-066) (30 mg, 64% yield).

[0625]

[0626] (1r,4r)-N-(benzo[d]thiazol-2-yl)-4-((2-(2,4-difluorophenoxy)acetamido)methyl)cyclohexane-1-carboxamide

[0627] 1H NMR (400 MHz, DMSO-d6) δ12.29 (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).

[0628] MS (ESI + )m / zcalcd for C 23 H 23 F2N3O3S [M+H] + 460.15; found 460.26.

[0629]

[0630] Compound 67 (EIF-067):

[0631] 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 NaHCO3, dried over Na2SO4, and concentrated. The crude product was purified by MPLC (EtOAc:hexane=1:1) to give the product (260 mg, 67% yield).

[0632]

[0633] 1 H NMR (400 MHz, DMSO-d6) δ8.28 (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).

[0634]

[0635] A solution of tert-butyl ((3-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclobutyl)methyl)carbamate (35 mg, 0.09 mmol) in 20% TFA / CH2Cl2 (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.

[0636]

[0637]

[0638] 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 NaHCO3, dried over Na2SO4, and concentrated. The crude product was purified by MPLC (EtOAc:hexane=1:1) to obtain compound 67 (EIF-067) (33 mg, 82% yield).

[0639]

[0640] N-((3-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclobutyl)methyl)-5-(difluoromethyl)pyrazine-2-carboxamide

[0641] 1H NMR (400 MHz, DMSO-d6)δ9.29 (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).

[0642] MS (ESI + )m / zcalcd for C 19 H 18 ClF3N4O3[M+H] + 443.11; found 443.25.

[0643]

[0644] Compound 68 (EIF-068):

[0645] 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) in DMF (1 mL, 0.09 M) was stirred at room temperature for 12 h. The solution was diluted with EtOAc, washed with NaHCO3, dried over Na2SO4, and concentrated. The crude product was purified by MPLC (EtOAc:hexane=1:1) to give compound 68 (EIF-068) (31 mg, 87% yield).

[0646]

[0647] N-((3-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclobutyl)methyl)nicotinamide

[0648] 1 H NMR (400 MHz, DMSO-d6) δ8.82 (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).

[0649] MS (ESI + )m / zcalcd for C 19 H 19 ClFN3O3[M+H] + 391.12; found 392.24.

[0650]

[0651] Compound 69 (EIF-069):

[0652] 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 Na2SO4, and concentrated. The crude product was purified by MPLC (0 to 75% EtOAc / hexane) to give compound 69 (EIF-069) (17 mg, 43% yield).

[0653]

[0654] N-((3-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclobutyl)methyl)benzofuran-6-carboxamide

[0655] 1 H NMR (400 MHz, CDCl3)δ8.01 (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).

[0656] MS (ESI + )m / zcalcd for C22 H 20 ClFN2O4[M+H] + 431.12; found 431.31.

[0657]

[0658] Compound 70 (EIF-070):

[0659] A solution of N-(3-(aminomethyl)cyclobutyl)-2-(4-chloro-3-fluorophenoxy)acetamide (26 mg, 0.09 mmol), 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), 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 Na2SO4, and concentrated. The crude product was purified by MPLC (0 to 100% EtOAc / hexane) to obtain compound 70 (EIF-070) (16 mg, 40% yield).

[0660]

[0661] N-((3-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclobutyl)methyl)-1-(2,2-difluoroethyl)-1H-pyrazole-3-carboxamide

[0662] 1H NMR (400 MHz, CDCl3)δ7.50 (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).

[0663] MS (ESI + )m / zcalcd for C 19 H 20 ClF3N4O3[M+H] + 445.13; found 445.32.

[0664]

[0665] Compound 71 (EIF-071):

[0666] 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 Na2SO4, and concentrated. The crude product was purified by MPLC (0 to 75% EtOAc / hexane) to give compound 71 (EIF-071) (21 mg, 59% yield).

[0667]

[0668] N-((3-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclobutyl)methyl)picolinamide]

[0669] 1 H NMR (400 MHz, CDCl3)δ8.61 (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).

[0670] MS (ESI + )m / zcalcd for C 19 H 19 ClFN3O3[M+H] + 392.12; found 392.27.

[0671]

[0672] <Example 1> Activity analysis of novel compounds

[0673] 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.

[0674] 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.

[0675] 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.

[0676]

[0677] <Example 2> Enzyme activity analysis

[0678] 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.

[0679] 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.

[0680] 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.

[0681] In addition, EC for new compounds 50 6, the negative control compound 35 showed no effect on GEF activity, whereas ISRIB and compound 43 showed similar activation of eIF2B. In addition, EC 50 In the case of ISRIB, the EC was about 20 nM, which is the previously reported value. 50 It shows a similar pattern, and compound 43 also has an EC of about 24 nM, which is comparable to ISRIB. 50 You can see that it represents .

[0682] That is, the 43 selected at the cellular level directly regulates the activity of eIF2B, the target protein of the present invention, and EC50 It was confirmed once again that it is comparable to ISRIB.

[0683]

[0684] <Example 3> In vivo analysis

[0685] 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.

[0686] 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.

[0687] 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.

[0688]

[0689] 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.

[0690] 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.

[0691] In addition, histological changes in liver tissue were confirmed at the same time, and as shown in Figure 9, no significant changes were observed.

[0692] These results confirm that the novel compounds 43 and 52 are effective in vivo and do not exhibit toxicity to liver tissue.

[0693]

[0694] <Example 4> Analysis of the effect on macrophages

[0695] 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.

[0696] 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.

[0697]

[0698] 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

1. 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: [Chemical Formula 1] In the above chemical formula 1, 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 are each 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, wherein said substituted (C5-C10)aryl or substituted 5 to 12-membered heteroaryl is substituted with at least one of (C1-C5)alkyl, (C1-C5)alkoxy, halogen, trifluoromethyl, difluoromethyl and difluoroethyl.

2. In paragraph 1, The above compound is, In the above chemical formula 1, n', n”, m' and m” 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 2 to 4 membered heteroalkyl containing one or more heteroatoms selected from O and S, Ar 1 and Ar 2 A compound characterized in that each of which may be the same or different, is one of an unsubstituted or substituted (C5-C7)aryl and an 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 (C5-C7)aryl or the substituted 5 to 10-membered heteroaryl is substituted with at least one and no more than three of (C1-C4)alkyl, (C1-C3)alkoxy, halogen, trifluoromethyl, difluoromethyl and difluoroethyl.

3. In paragraph 1, The above compound is, In the above chemical formula 1, L 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 A compound characterized in that each of which may be the same or different, is 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.

4. In paragraph 2, 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, A compound characterized in that the above substituted 5 to 10-membered heteroaryl is substituted with one of fluorine, methoxy, trifluoromethyl, difluoromethyl and difluoroethyl.

5. In paragraph 1, 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'-(cyclohexane-1,3-diyl)bis(2-(4-chlorophenoxy)acetamide) (EIF-001), (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'-(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'-(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'-(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-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'-(cyclobutane-1,3-diyl)bis(2-(mesityloxy)acetamide) [N,N'-(cyclobutane-1,3-diyl)bis(2-(mesityloxy)acetamide)] (EIF-008), (8) N,N'-(cyclobutane-1,3-diyl)bis(3-(2-chlorophenoxy)propanamide) (EIF-009), (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-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-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-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-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-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-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-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-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-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-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-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-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-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-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-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-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-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-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'-(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'-(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-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-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-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-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-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-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-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-(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-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-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'-(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)-cyclohexane-1,4-diyl)bis(3-(4-chlorophenyl)propiolamide) (EIF-049), (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-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-chlorophenoxy)acetamido)cyclohexyl)nicotinamide [N-((1r,4r)-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)nicotinamide] (EIF-052), (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-(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-(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-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-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-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-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-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-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-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-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-chlorophenoxy)acetamido)cyclobutyl)-3-(4-chlorophenyl)propiolamide [N-(3-(2-(4-chlorophenoxy)acetamido)cyclobutyl)-3-(4-chlorophenyl)propiolamide] (EIF-064), (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-(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-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-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-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-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-chloro-3-fluorophenoxy)acetamido)cyclobutyl)methyl)picolinamide] (EIF-071).

6. In paragraph 1, The above compound is, A compound characterized by activating eIF2B.

7. A pharmaceutical composition for preventing or treating metabolic diseases, comprising the compound according to Article 1 as an active ingredient.

8. In paragraph 7, The above metabolic diseases are, A pharmaceutical composition characterized in that the disease is selected from the group consisting of obesity, diabetes, arteriosclerosis, hyperlipidemia, fatty liver, and liver fibrosis.

9. A health food composition for preventing or improving metabolic diseases, comprising the compound according to Article 1 as an active ingredient.

10. A reagent composition for activating eIF2B, comprising a compound according to paragraph 1 as an active ingredient.

Images