Novel compounds having Anti-cancer therapeutic activity

Abstract

The present invention relates to a novel compound having the structure of chemical formula 1. The compound according to the present invention can inhibit interaction of MBD2-p66ɑ (GATAD2A), and thus can be effectively used to inhibit cancer metastasis and prevent or treat cancer.

Description

Novel compounds with cancer therapeutic activity

[0001] The present invention relates to a novel compound having the structure of Formula 1. The compound of the present invention can inhibit the interaction of MBD2-p66α(GATAD2A) and, accordingly, can be usefully used to inhibit cancer metastasis and to prevent or treat cancer.

[0002] The present invention was made with the support of the Korean government under Ministry of Science and ICT Project No. 202000000000876, "Development of optimized cancer metastasis inhibitory compounds targeting MBD2-p66α interactions."

[0003] Over the past few decades, basic and clinical research has been continuously conducted worldwide to treat various diseases, including cancer, and the development of new therapeutic agents has been actively pursued based on studies of signal transduction processes and gene mechanisms of action.

[0004] To date, numerous natural product, protein / peptide-based, and chemically synthesized therapeutics have been developed and are in use. However, most of them not only cause disease recurrence or side effects due to damage to normal cells in vivo, but also frequently fail to work in patients depending on the diverse causes of the disease. Furthermore, resistance to these treatments or the recurrence of the disease following treatment are currently common issues.

[0005] To date, most therapeutic agents are based on inhibiting signal transduction receptors present on the surface of cancer cells and kinases / dephosphorylation enzymes crucial for intracellular signal transduction. However, since these receptors and enzymes are also involved in the survival of normal cells, anticancer drugs are highly likely to cause severe side effects in normal cells.

[0006] Recently, the development of therapeutic agents targeting transcription factors and epigenomes involved in gene expression regulation has also emerged. However, since these factors are also necessary for maintaining normal cells in vivo, it is currently difficult to find new targets that can exert efficacy while minimizing side effects.

[0007] The Mi-2 / NuRD chromatin remodeling complex (CRC) is attracted by DNA methylation and maintains transcriptional repression, and also possesses HDAC as a member. Since the Mi-2 / NuRD complex can directly bind not only to DNA methylation sites but also to DNA methylation enzymes, it performs a crucial epigenetic function in the repression of gene expression. It is known that MBD2 knockout (MBD2 - / -) mice exhibit normal survival and reproduction without significant harmful effects (Hendrich B, Guy J, Ramsahoye B, Wilson VA, Bird A, Closely related proteins MBD2 and MBD3 play distinctive but interacting roles in mouse development. Genes Dev, 2001, 15: 710). Furthermore, it is known that reducing MBD2 expression in cancer cell lines and animal models of tumor transplantation exhibits tumor growth inhibitory effects (Slack A, Bovenzi V, Bigey P, Ivanov MA, Ramchandani S, Bhattacharya S, tenOever B, Lamrihi B, Scherman D, Szyf M, Antisense MBD2 gene therapy inhibits tumorigenesis. J Gene Med, 2002, 4: 381; Sansom OJ, Berger J, Bishop SM, Hendrich B, Bird A, Clarke AR, Deficiency of Mbd2 suppresses intestinal tumorigenesis.Nat Genet, 2003, 34: 145; Mian OY, Wang SZ, Zhu SZ, Gnanapragasam MN, Graham L, Bear HD, Ginder GD, Methyl-binding domain protein 2-dependent proliferation and survival of breast cancer cells. Mol Cancer Res, 2011, 9: 1152).

[0008] In prior research, while investigating the mechanism of globin gene transcriptional regulation by the transcription factor CP2c (also named TFCP2, LSF, LBP1, and USF) in a mouse erythroleukemia (MEL) cell line model, the inventors of the present invention confirmed that the attenuation of MBD2 expression is essential for the normal erythropoiesis process (Kim MY, Kim JS, Son SH, Lim CS, Eum HY, Ha DH, Park MA, Baek EJ, Ryu BY, Kang HC, Uversky VN, Kim CG, Mbd2-CP2c loop drives adult-type globin gene expression and definitive erythropoiesis. Nucleic Acids Res, 2018, 46: 4933). MEL cell lines are cancer cells that have stopped differentiating in the proerythroblast stage during the erythrocyte differentiation process, but when the culture medium is treated with chemo-inducing agents such as dimethyl sulfoxide (DMSO) or hexamethylene bisacetamid (HMBA), they exhibit globin gene expression along with terminal differentiation.

[0009] Furthermore, it was confirmed that CP2c forms a CBP complex with CP2b and PIAS1 proteins and is involved in erythroid cell-specific globin gene transcription (Kang HC, Chae JH, Lee YH, Park MA, Shin JH, Kim SH, Ye SK, Cho YS, Fiering S, Kim CG, Erythroid cell-specific alpha-globin gene regulation by the CP2 transcription factor family. Mol Cell Biol, 2005, 25: 6005; Kang HC, Chae JH, Jeon J, Kim W, Ha DH, Shin JH, Kim CG, Kim CG, PIAS1 regulates CP2c localization and active promoter complex formation in erythroid cell-specific alpha-globin expression. Nucleic Acids Res, 2010, 38; 5456), and it was revealed that p66α(GATAD2A), a member of the Mi-2 / NuRD CRC, directly binds to CP2c (Kang HC, Chung BM, Chae JH, Yang SI, Kim CG, Kim CG, Identification and characterization of four novel peptide motifs that recognize distinct regions of the transcription factor CP2. FEBS J, 2005, 272: 1265).

[0010] Furthermore, p66α inhibits the transcriptional activity of the CBP transcription factor complex (CP2c, CP2b, and PIAS1) through binding with CP2c, and when MEL cell lines with attenuated p66α expression were intravenously injected into immunodeficient mice, not only was splenomegaly observed in normal control cells significantly suppressed, but tumor formation in the blood, spleen, and liver was also significantly inhibited (Kim MY, Kim JS, Son SH, Lim CS, Eum HY, Ha DH, Park MA, Baek EJ, Ryu BY, Kang HC, Uversky VN, Kim CG, Mbd2-CP2c loop drives adult-type globin gene expression and definitive erythropoiesis. Nucleic Acids Res, 2018, 46; 4933; Kim MY, Choi S, Lee SU, Kim JS, Son SH, Lim YS; Kim BJ, Ryu BY, Uversky VN, Lee YJ, Kim CG, Development of a MEL cell-derived allograft mouse model for cancer research. Cancers, 2019, 11, 1707), it was confirmed that while the expression of p66α is maintained constant during the induction of erythrocyte differentiation in MEL cells and during erythrocyte differentiation in the bone marrow, the expression of MBD2, which is known to directly bind to p66α as another member of Mi-2 / NuRD CRC, decreases sharply (Kim MY, Kim JS, Son SH, Lim CS, Eum HY, Ha DH, Park MA, Baek EJ, Ryu BY, Kang HC, Uversky VN, Kim CG, Mbd2-CP2c loop drives adult-type globin gene expression and definitive erythropoiesis. Nucleic Acids Res, 2018, 46; 4933).

[0011] Transcriptional activity of the CBP complex not only showed an inverse correlation with MBD2 expression, but MEL cell lines with attenuated MBD2 expression also exhibited spontaneous erythropoietic differentiation (Kim MY, Kim JS, Son SH, Lim CS, Eum HY, Ha DH, Park MA, Baek EJ, Ryu BY, Kang HC, Uversky VN, Kim CG, Mbd2-CP2c loop drives adult-type globin gene expression and definitive erythropoiesis. Nucleic Acids Res, 2018, 46; 4933). In addition, it was confirmed that MBD2 is involved in the activation of the CBP complex through interaction with p66α. Furthermore, it was revealed that Mi-2 / NuRD CRC present in undifferentiated MEL cells is a typical CRC (restrictive Mi-2 / NuRD CRC) possessing MBD2 that suppresses the expression of target genes, whereas during normal erythrocyte differentiation, CRC (permissive Mi-2 / NuRD CRC) without MBD2 binds to the globin gene promoter and assists in the transcriptional activation of the CBP complex (Kim MY, Kim JS, Son SH, Lim CS, Eum HY, Ha DH, Park MA, Baek EJ, Ryu BY, Kang HC, Uversky VN, Kim CG, Mbd2-CP2c loop drives adult-type globin gene expression and definitive erythropoiesis. Nucleic Acids Res, 2018, 46; 4933).

[0012] As such, MBD2 does not affect the survival of normal cells, and since the MBD2-p66α interaction plays an important role in the gene expression suppression function of Mi-2 / NuRD CRC, it is considered that the MBD2-p66α interaction can be a useful target for the development of anticancer drugs. The inventors of the present invention have developed a novel compound invention that can be utilized as a cancer treatment by newly synthesizing compounds acting on the above target and confirming their anticancer effects.

[0013] The present invention aims to provide a novel compound that inhibits cancer metastasis and has cancer preventive or therapeutic activity.

[0014] In addition, the present invention aims to provide a pharmaceutical composition for the prevention or treatment of cancer.

[0015] In addition, the present invention aims to provide a method for preventing or treating cancer comprising the step of administering a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof to a subject.

[0016] To achieve the above objective, one aspect of the present invention provides a compound of the following formula 1 or a pharmaceutically acceptable salt thereof.

[0017] [Chemical Formula 1]

[0018]

[0019] In the above formula,

[0020] n is 0 or 1, and

[0021] m is an integer from 0 to 2, and

[0022] X is hydrogen or alkyl, and

[0023] Ring A is a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl, and

[0024] R1 is or And,

[0025] R2 and R3 are each independently selected from hydrogen or the following substituent group I, and

[0026] R2 are identical or different when m is 2, each independently selected from hydrogen or the following substituent group I, or fused together with the carbon bonded thereto, a substituted or unsubstituted C 3-8 Forming a carbocycle group or a substituted or unsubstituted 3 to 8-membered heterocycle group,

[0027] The above substituent group I is -OH, substituted or unsubstituted C 1-10 Alkyl groups, substituted or unsubstituted C 2-10 Alkenyl group, substituted or non-substituted C 3-20 Carbocycle group, substituted or non-substituted C 3-20 Cycloalkyl group, substituted or unsubstituted C 6-30 Aryl group, substituted or unsubstituted 3 to 30-membered heterocyclic group, substituted or unsubstituted C 1-10 Alkoxy group, substituted or non-substituted C 2-10 Alkenyloxy group, substituted or unsubstituted C 3-10 Cycloalkyloxy group, substituted or unsubstituted C 6-30 Aryloxy group, substituted or unsubstituted 3 to 30-membered heterocyclooxy group, substituted or unsubstituted C 1-10 Alkyl carbonyl group, substituted or unsubstituted C 2-10 Alkenyl carbonyl group, substituted or unsubstituted C 3-10 Cycloalkylcarbonyl group, substituted or unsubstituted C 6-30 Aryl carbonyl group, substituted or unsubstituted 3 to 30-membered heterocyclic carbonyl group, substituted or unsubstituted C 1-10 Alkylthio groups, substituted or unsubstituted C 2-10 Alkenylthio group, substituted or non-substituted C 3-10 Cycloalkylthio groups, substituted or unsubstituted C 6-30Arylthio group, substituted or unsubstituted 3 to 30-membered heterocyclic thio group, aldehyde group, carboxyl group, halogen group, C 1-10 It consists of a haloalkyl group, a hydroxyl group, a substituted or unsubstituted amino group, an imine group, a cyano group, a nitro group, an amide group, a thiol group, a sulfonyl group, a sulfino group, and a phosphate group.

[0028] In addition, to achieve the above objective, another aspect of the present invention provides a composition for the prevention or treatment of cancer comprising the compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0029] In addition, to achieve the above objective, another aspect of the present invention provides a method for preventing or treating cancer comprising the step of administering to a subject a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof.

[0030] The novel compounds of the present invention, their pharmaceutically acceptable salts, and their isomers bind to MBD2 at the MBD2-p66α interaction site within Mi-2 / NuRD CRC, thereby inhibiting the interaction with p66α. Through this, they exhibit activity that inhibits various cancer metastases and can be usefully utilized as pharmaceutical compositions for the prevention or treatment of cancer.

[0031] In particular, the compound of the present invention exhibits selective toxicity to cancer cells and high safety to normal cells. It has characteristics suitable for use as a cancer treatment substance through the regulation of cancer stem cells, regulation of EMT marker expression levels, and the effect of restoring drug resistance to anticancer agents such as cisplatin.

[0032] However, the effects of the present invention are not limited to those mentioned above, and other unmentioned effects will be clearly understood by those skilled in the art from the description below.

[0033] Figure 1 shows the results of confirming the effect of compounds 9-004 and 10-062, and 10-058 (ABA) and APC on changing the expression levels of EMT-related markers.

[0034] Figure 2 shows the results of verifying cancer stem cell characteristics through CD44 / CD24 population analysis using the above compounds.

[0035] Figure 3 shows the results of confirming the protein expression patterns of the epithelial marker CDH1 and the mesenchymal marker VIM using the above compounds by immunofluorescence.

[0036] Figure 4 shows the results of re-verifying changes in cell motility through a wound healing assay using the above compounds.

[0037] Figure 5 shows the results of verifying the change in chemo-resistance to cisplatin using the above compounds.

[0038] The present invention will be described in detail below.

[0039]

[0040] In this specification, when a part is described as "comprising" a certain component, it means that, unless specifically stated otherwise, it does not exclude other components but may include additional components. However, the term "comprising" also encompasses, in a more restrictive sense as a specific embodiment thereof, "comprising" essentially or necessarily composed of and "comprising." In this regard, in this specification, terms such as "comprising" or "having" are intended to specify the existence of the implemented features, numbers, steps, components, or combinations thereof, and should be understood as not precluding the existence or addition of one or more other features, numbers, steps, components, or combinations thereof.

[0041] In this specification, enantiomers refer to two stereoisomers of a compound that are mirror images of each other but cannot be superimposed.

[0042] In this specification, diastereomers refer to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, and reactivity. A mixture of diastereomers can be separated under high-resolution analytical procedures such as electrophoresis and chromatography.

[0043] In this specification, geometric isomers refer to the cis type, in which atoms or groups of atoms of the same type are on the same side around the double bond, the trans type, in which atoms or groups of atoms of the same type are on opposite sides around the double bond, or the E type or Z type according to the CIP priority.

[0044] In this specification, tautomers or tautomer forms refer to structural isomers of different energies that are compatible through a low energy barrier. For example, proton tautomers (also known as protic tautomers) involve interconversion through the transfer of protons, e.g., keto-enol and imine-enamine isomerization. Valence tautomers involve interconversion by the retransfer of some bonding electrons.

[0045] In this specification, a solvate refers to an aggregate or complex of one or more solvent molecules and a compound of the present invention. Examples of solvents forming a solvate include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and ethanolamine. A hydrate refers to a complex in which the solvent molecule is water.

[0046] In this specification, the term "acceptable salt" refers to a salt of an active compound prepared with an acid or a base, depending on a specific substituent based on the compound described herein. If the compound according to the invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting such a neutral compound with a sufficient amount of the desired base in a solvent-free or suitable inert solvent.

[0047] Acceptable salts include, for example, alkali metal salts (e.g., sodium or potassium salts); alkaline earth metal salts (e.g., calcium or magnesium salts); ammonium salts; aliphatic amine salts (e.g., trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine or procaine salts); aralkyl amine salts (e.g., N,N-dibenzylethylenediamine salts); heterocyclic aromatic amine salts (e.g., pyridine salts, picolino salts, quinoline salts or isoquinoline salts); quaternary ammonium salts (e.g., tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzyltributylammonium salts, methyltrioctylammonium salts or tetrabutylammonium salts); and basic amino acid salts (e.g., arginine salts or lysine salts). Acid salts are, for example, inorganic acid salts (e.g., hydrochloride, sulfate salt, nitrate salt, phosphate salt, carbonate salt, hydrogen carbonate or perchlorate); organic acid salts (e.g., acetate, propionate, lactate, malate, fumarate, tartaric acid salt, malate, fumarate, citrate salt, ascorbate or formic acid); sulfonates (e.g., methanesulfonate, isothionate, benzenesulfonate or p-toluenesulfonate); and acidic amino acid salts (e.g., aspartate or glutamate). Solvents of the compounds of the present invention include, but are not limited to, alcoholates and hydrates.

[0048] In this specification, where a quantity, concentration, or other value or parameter is given as an enumeration of a range, a preferred range, a preferred upper limit, and a preferred lower limit, it should be understood that any pair of any upper range limit or preferred value and any lower range limit or preferred value, regardless of whether the range is disclosed separately, specifically discloses all ranges that may be formed. Where a range of numerical values ​​is mentioned in this specification, unless otherwise described, for example, without limiting terms such as greater than or less than, the range is intended to include its endpoint value and all integers and fractions within that range. The scope of the invention is not intended to be limited to the specific value mentioned when defining the range.

[0049] As used herein, the term "prevention" refers to any act of suppressing or delaying the onset of a disease by administering the composition; "treatment" refers to any act of improving or beneficially altering the symptoms of an individual suspected of or suffering from the disease by administering the composition; and "improvement" refers to any act of at least reducing parameters related to the condition, such as the degree of symptoms, by administering the composition.

[0050] In this specification, the term "substitution" may mean that a hydrogen atom bonded to a compound or to each of the substituents listed in the group of substituents is replaced by any substituent. In this case, the substitution location is not limited to the location where the hydrogen atom bonded to the compound or to each of the substituents listed in the group of substituents exists, that is, any location where the hydrogen atom can be substituted by a substituent. If two or more substitutions occur, the two or more substituents may be identical or different from each other. Conversely, "non-substitution" may mean that no hydrogen atom bonded to a carbon atom is replaced by any substituent.

[0051] Any substituent applicable to the above "substitution" may be appropriately selected from the substituents listed in the substituent groups described herein, but the range of substituents applicable to the substitution is not limited to these substituent groups.

[0052] Substituents preferably applicable to the above "substitution" are, in detail, halogen groups, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 alkynyl group, C 3-10 Carbocycle group, C 3-10 Cycloalkyl group, C 6-30 Aryl group, 3 to 30-membered heterocyclic group, C 1-10 Alkoxy group, C 2-10 Alkenyloxy group, C 2-10 alkynoyloxy group, C 3-10 Cycloalkyloxy group, C 6-30 Aryloxy group, 3 to 30 heterocyclic oxy group, C 1-10 Alkyl carbonyl group, C 1-10 alkenyl carbonyl group, C 1-10 Alkyl carboxyl group, C 1-10 Alkenylcarboxylic group, C 1-10 Cycloalkylcarbonyl group, C 6-30 Aryl carbonyl group, 3 to 30 heterocyclic carbonyl group, C 1-10 Alkylthio group, C 1-10 alkenylthio group, C 1-10 Cycloalkylthio group, C 6-30 It can be selected from the group consisting of an arylthio group, a 3 to 30 heterocyclic thio group, an aldehyde group, a carboxyl group, a hydroxyl group, an amino group, an imine group, a cyano group, a nitro group, an amide group, a thiol group, a sulfone group, and a phosphate group.

[0053] If a substituent is not separately described or mentioned in the chemical formulas described in this specification, it may be considered that hydrogen is bonded, and in some cases, a substituent may be absent depending on the ring constituent elements forming the heterocycle.

[0054] In this specification, the term “group” as described means that it is combined with a preceding substituent, for example, alkyl, to form the term “alkyl group,” and that the alkyl can be bonded to any position of the compound or substituent, or is bonded.

[0055] In this specification, halogens may include Cl, F, Br, and I.

[0056] In this specification, alkyl refers to the number of carbon atoms indicated (i.e., C) either itself or as part of another substituent, unless otherwise noted. 1-10 It means a straight-chain or branched-chain monovalent hydrocarbon having 1 to 10 carbons.

[0057] Examples of alkyls include methyl, ethyl, propyl, n-propyl, isopropyl, butyl, n-butyl, isobutyl, tert-butyl, sec-butyl, 1-methyl-butyl, 1-ethyl-butyl, pentyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 4-methyl-2-pentyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, n-heptyl, 1-methylhexyl, cyclopropyl, cyclobutyl, cyclopentyl, 3-methylcyclopentyl, 2,3-dimethylcyclopentyl, cyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl, 2,3-dimethylcyclohexyl, 3,4,5-trimethylcyclohexyl, Examples include 4-tert-butylcyclohexyl, cycloheptyl, cyclooctyl, octyl, n-octyl, tert-octyl, 1-methylheptyl, 2-ethylhexyl, 2-propylpentyl, n-nonyl, 2,2-dimethylheptyl, 1-ethyl-propyl, 1,1-dimethyl-propyl, isohexyl, 2-methylpentyl, 4-methylhexyl, 5-methylhexyl, etc., but these are non-limiting examples and the scope of the invention is not limited to them.

[0058] In this specification, the alkenyl may be a straight chain or a branched chain. Alkenyls are, for example, ethenyl, 1-propenyl, 2-propenyl or 1-methylethenyl, ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl or 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl, 3,3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propphenyl, 1-ethyl-1-methyl-2-propphenyl, 1-ethyl-2-methyl-1-propphenyl, 1-ethyl-2-methyl-2-propphenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl,Examples include 2-octenyl, 3-octenyl, 4-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, 4-decenyl, and 5-decenyl, but are not limited to these.

[0059] In this specification, alkynyl may be a straight chain or a branched chain, for example, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 1-fentinyl, 2-fentinyl, 3-fentinyl, 4-fentinyl, 1-methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 3-methyl-1-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 1-hexinyl, 2-hexinyl, 3-hexinyl, 4-hexinyl, 5-hexinyl, 1-methyl-2-fentinyl, 1-methyl-3-fentinyl, 1-methyl-4-fentinyl, 2-methyl-3-fentinyl, Examples include 2-methyl-4-fentinyl, 3-methyl-1-fentinyl, 3-methyl-4-fentinyl, 4-methyl-1-fentinyl, 4-methyl-2-fentinyl, 1,1-dimethyl-2-butinyl, 1,1-dimethyl-3-butinyl, 1,2-dimethyl-3-butinyl, 2,2-dimethyl-3-butinyl, 3,3-dimethyl-1-butinyl, 1-ethyl-2-butinyl, 1-ethyl-3-butinyl, 2-ethyl-3-butinyl, 1-ethyl-1-methyl-2-propynyl, and 2,5-hexadinyl, but are not limited to these.

[0060] In this specification, haloalkyl is synonymous with "alkyl halides" and "alkyls substituted with halogens," and may refer to an alkyl in which any hydrogen atom in the alkyl group is substituted with any halogen, for example, a halogen atom selected from Cl, F, Br, and I. For example, -CF3, -CH2Cl, -CH2CF3, -C(Cl2)CF3, etc. are haloalkyl groups, but the scope of the present invention is not limited to these.

[0061] In this specification, an alkoxy refers to a substituent in which oxygen is bonded to an alkyl group, and this may be a straight chain, a branched chain, or a cyclic chain. Examples of alkoxy groups specifically include methoxy, ethoxy, n-propoxy, isopropoxy, i-propyloxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy, neopentyloxy, isopentyloxy, n-hexyloxy, 3,3-dimethylbutyloxy, 2-ethylbutyloxy, n-octyloxy, n-nonyloxy, n-decyloxy, benzyloxy, p-methylbenzyloxy, or their monohalogenated and polyhalogenated variants, but the scope of the present invention is not limited to these.

[0062] In this specification, "amino" is intended to encompass monovalent primary amines, monovalent secondary amines, and monovalent tertiary amines. That is, an amino group refers to both a monovalent group in which two hydrogen atoms are bonded to a nitrogen atom and a monovalent group in which at least one hydrogen atom is substituted with another substituent. In the above, the group in which two hydrogen atoms are bonded to a nitrogen atom may be an unsubstituted amino group, and the group in which at least one hydrogen atom is substituted with another substituent may be a substituted amino group. Meanwhile, in an amino group comprising two substituents, each substituent may be the same or different from one another.

[0063] In this specification, “carbocycle” and “carbocyclic” mean a ring in which the ring constituent atoms are carbon. A carbocycle may be aliphatic or aromatic, saturated or unsaturated, and monocyclic or polycyclic. A polycyclic ring may be a fused, bridged, or spiro-polycyclic ring. A monocyclic carbocycle may have 3 to 17 carbon atoms, more specifically 3 to 14 carbon atoms, more specifically 3 to 10 carbon atoms, and particularly specifically 3 to 7 carbon atoms.

[0064] In this specification, cycloalkyl refers to a monovalent aliphatic carbocycle in which one hydrogen atom is missing from any position among the carbon atoms constituting the ring. Examples of cycloalkyls include, butyl cyclopentyl, 3-methylcyclopentyl, 2,3-dimethylcyclopentyl, cyclohexylene 3-methylcyclohexyl, 4-methylcyclohexyl, 2,3-dimethylcyclohexyl, 3,4,5-trimethylcyclohexyl, 4-tert-butylcyclohexyl, cycloheptyl, cyclooctyl, etc., but are not limited thereto.

[0065] In this specification, aryl refers to a ring comprising a polyunsaturated, typically aromatic hydrocarbon ring, wherein the aryl may be monocyclic or polycyclic. In the case of polycyclic, it includes a form in which only an aromatic hydrocarbon ring is fused and a form in which an aliphatic hydrocarbon ring is fused together with an aromatic hydrocarbon. Examples of such aryls include monocyclic aryls such as phenyl groups, biphenyl groups, terphenyl groups, and quadrphenyl groups, and polycyclic aryls such as naphthyl groups, anthracenyl groups, phenanthrenyl groups, pyrenyl groups, and benzopyrenyl groups.

[0066] In this specification, a heterocycle refers to a ring comprising 1 to 5 heteroatoms selected from non-carbon atoms, namely O, N, P, and S, as ring constituent atoms. The heterocycle may be aromatic, aliphatic, single-ring, or polycyclic, and non-limiting examples include thiophenyl groups, furanyl groups, pyrrolyl groups, imidazolyl groups, thiazolyl groups, oxazolyl groups, oxadiazolyl groups, pyridinyl groups, bipyridinyl groups, pyrimidinyl groups, triazolyl groups, pyridazinyl groups, pyrazinyl groups, pyridopyrimidyl groups, pyridopyrazinyl groups, pyrazinopyrazinyl groups, isooxazolyl groups, thiadiazolyl groups, etc., but the scope of the invention is not limited to these.

[0067] In this specification, heteroaryl refers to an aromatic heterocycle and may be a single ring or a polycyclic ring. A polycyclic ring includes not only a form in which a plurality of aromatic rings are fused, but also a form in which an aromatic ring and an aliphatic ring are fused. Examples of heteroaryls include pyridinyl groups, pyrrolyl groups, furanyl groups, thiophenyl groups, acridyl groups, quinolinyl groups, quinazolinyl groups, quinoxalinyl groups, phthalazinyl groups, isoquinolinyl groups, indolyl groups, carbazolyl groups, benzoxazolyl groups, benzimidazolyl groups, benzothiazolyl groups, benzocarbazolyl groups, benzothiophen groups, dibenzothiophen groups, benzofuranyl groups, phenanthrolinyl groups, phenothiazinyl groups, dibenzofuranyl groups, and fluorenyl groups, but the scope of the present invention is not limited to these.

[0068] In this specification, Oxy is "-OR oxy As a substituent that can be represented as ", where R oxy is, respectively, of substitution or non-substitution, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-10 Carbocycle, C 3-10 Cycloalkyl, C 6-30 Aryl, 3 to 30-membered heterocycle, C 1-10 They may be haloalkyls, and the definitions of each of these are as previously explained.

[0069] In this specification, carbonyl is "-C(=O)R car As a substituent that can be represented as ", where R car is, respectively, of substitution or non-substitution, C 1-10 Alkyl, C 2-10 Alkenyl, substituted, or non-substituted C 3-10 Carbocycle, C 3-10 Cycloalkyl, C 6-30 Aryl, 3 to 30-membered heterocycle, C 1-10 They may be haloalkyls, and the definitions of each of these are as previously explained.

[0070] In this specification, thio is "-SR thioAs a substituent that can be represented as ", where R thio is, respectively, of substitution or non-substitution, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-10 Carbocycle, C 3-10 Cycloalkyl, C 6-30 Aryl, 3 to 30-membered heterocycle, C 1-10 They may be haloalkyls, and the definitions of each of these are as previously explained.

[0071] In this specification, the imine or imino is a monovalent primary ketimine (-C(NH)R i-1 ), secondary ketimine (-C(NR i-2 )R i-1 ), primary aldimin(-C(NH)H), secondary aldimin(-C(NR i-1 It is intended to have a meaning that encompasses ) H). In this case, R i-1 and R i-2 are independently, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-10 Carbocycle, C 3-10 Cycloalkyl, C 6-30 Aryl, 3 to 30-membered heterocycle, C 1-10 They may be haloalkyls, each of which may be substituted or unsubstituted, and the definitions of each are as previously explained.

[0072] In this specification, sulfone is "-S(=O)2R s As a substituent that can be represented as ", where R s is, respectively, of substitution or non-substitution, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-10 Carbocycle, C 3-10 Cycloalkyl, C 6-30 Aryl, 3 to 30-membered heterocycle, C 1-10 They may be haloalkyls, and the definitions of each of these are as previously explained.

[0073] In this specification, phosphoric acid is "-OP(=O)(OH)2" or "-OP(=O)(OH)(ORP As a substituent that can be represented as )", wherein R P is, respectively, of substitution or non-substitution, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-10 Carbocycle, C 3-10 Cycloalkyl, C 6-30 Aryl, 3 to 30-membered heterocycle, C 1-10 They may be haloalkyls, and the definitions of each of these are as previously explained.

[0074]

[0075] The compound according to the present invention is represented by the following chemical formula 1.

[0076] [Chemical Formula 1]

[0077]

[0078] In the above formula,

[0079] n is 0 or 1, and

[0080] m is an integer from 0 to 2, and

[0081] X is hydrogen or alkyl, and

[0082] Ring A is a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl, and

[0083] R1 is or And,

[0084] R2 and R3 are each independently selected from hydrogen or the following substituent group I, and

[0085] R2 are identical or different when m is 2, each independently selected from hydrogen or the following substituent group I, or fused together with the carbon bonded thereto, a substituted or unsubstituted C 3-8 Forming a carbocycle group or a substituted or unsubstituted 3 to 8-membered heterocycle group,

[0086] The above substituent group I is -OH, substituted or unsubstituted C 1-10 Alkyl groups, substituted or unsubstituted C 2-10 Alkenyl group, substituted or non-substituted C 3-20 Carbocycle group, substituted or non-substituted C 3-20 Cycloalkyl group, substituted or unsubstituted C 6-30 Aryl group, substituted or unsubstituted 3 to 30-membered heterocyclic group, substituted or unsubstituted C 1-10 Alkoxy group, substituted or non-substituted C 2-10 Alkenyloxy group, substituted or unsubstituted C 3-10 Cycloalkyloxy group, substituted or unsubstituted C 6-30 Aryloxy group, substituted or unsubstituted 3 to 30-membered heterocyclooxy group, substituted or unsubstituted C 1-10 Alkyl carbonyl group, substituted or unsubstituted C 2-10 Alkenyl carbonyl group, substituted or unsubstituted C 3-10 Cycloalkylcarbonyl group, substituted or unsubstituted C 6-30 Aryl carbonyl group, substituted or unsubstituted 3 to 30-membered heterocyclic carbonyl group, substituted or unsubstituted C 1-10 Alkylthio groups, substituted or unsubstituted C 2-10 Alkenylthio group, substituted or non-substituted C 3-10 Cycloalkylthio groups, substituted or unsubstituted C 6-30 Arylthio group, substituted or unsubstituted 3 to 30-membered heterocyclic thio group, aldehyde group, carboxyl group, halogen group, C 1-10 It consists of a haloalkyl group, a hydroxyl group, a substituted or unsubstituted amino group, an imine group, a cyano group, a nitro group, an amide group, a thiol group, a sulfonyl group, a sulfino group, and a phosphate group.

[0087] In one specific example, the compound of Formula 1 may be represented by any one of the following Formulas 1-1-1 to 1-1-4, Formula 1-2-1, and Formula 1-2-2.

[0088] [Chemical Formula 1-1-1]

[0089]

[0090] [Chemical Formula 1-1-2]

[0091]

[0092] [Chemical Formula 1-1-3]

[0093]

[0094] [Chemical Formula 1-1-4]

[0095]

[0096] [Chemical Formula 1-2-1]

[0097]

[0098] [Chemical Formula 1-2-2]

[0099]

[0100] In the above formula,

[0101] A 1a To A 1c Each is independently carbon or nitrogen, and

[0102] A 1d To A 1f Each is independently carbon, nitrogen, or oxygen, and

[0103] A 1g and A 1h Each is independently carbon, nitrogen, or oxygen, and

[0104] A 1i is carbon or nitrogen, and

[0105] m, X, R2 and R3 are as previously defined.

[0106] In one specific example, X can be a hydrogen or methyl group.

[0107] In one specific example, R3 is hydrogen, , , , , or It could be.

[0108] In one specific example, ring A is , , , , , , , , , , , or And,

[0109] m is an integer from 0 to 2, and

[0110] R2 may be selected from the above substituent group I.

[0111] In one specific example, ring A is , , , , , , , , , , , , , , , , , , , , or And,

[0112] R2 is hydrogen, , , , , , or It could be.

[0113] The above compound or its pharmaceutically acceptable salt may be a compound selected from the group consisting of the compounds in the table below or its pharmaceutically acceptable salt:

[0114]

[0115] No. Compound Chemical Formula 18-087 28-094 38-082 48-084 58-092 69-002 79-003 89-004 99-038 109-039 119-021 129-041 1310-040 1410-041 1510-042 1610-043 1710-044 1812-076 1912-077 2012-086 2112-027 2212-065 2312-069 2413-006 2513-005 2613-009 2713-013 2813-007 2913-014 3014-011 3114-014 3214-008 3314-012 3413-093 3513-082 3613-095 3713-058 3813-075 3913-097 4014-057 4114-064 4214-079 4314-065 4414-080 4515-021 4615-022 478-093 488-097 498-098 509-016 519-015 529-037 539-032 549-051 5510-062 5610-054 5710-055 5810-053 5910-056 6012-047 6113-002 6213-003 6313-028 6413-072 6514-003 6613-094 6714-017 6815-009 6915-014 7015-015

[0116]

[0117] Another aspect of the present invention provides, in addition to the compound, an acceptable salt of the compound, its enantiomer, its diastereomer, its solvate, its geometric isomer and / or its tautomer. Another aspect of the present invention provides a composition for the prevention or treatment of cancer comprising, as an active ingredient, at least one of the compound according to the present invention, its pharmaceutically acceptable salt, its enantiomer, its diastereomer, its solvate, its geometric isomer and / or its tautomer.

[0118] The above compounds, their pharmaceutically acceptable salts, isomers, etc., may have activity that inhibits the interaction of MBD2-p66α. Specifically, at the MBD2-p66α interaction site within Mi-2 / NuRD CRC, they may bind to MBD2 and have activity that inhibits the interaction with p66α.

[0119] Accordingly, the compounds of the present invention, their pharmaceutically acceptable salts, isomers, etc., can inhibit the metastasis of cancer and can be usefully used to prevent, improve, and / or treat cancer.

[0120] Suitable dosages of the pharmaceutical composition of the present invention may be prescribed in various ways depending on factors such as the formulation method, mode of administration, patient's age, body weight, sex, pathological condition, food, time of administration, route of administration, excretion rate, and response sensitivity. The dosage of the pharmaceutical composition of the present invention may be 0.001 to 1000 mg / kg based on an adult.

[0121] The pharmaceutical composition of the present invention can be administered orally or parenterally.

[0122] The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier included in the pharmaceutical composition of the present invention is one that is commonly used in the manufacture of pharmaceuticals and includes, but is not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. In addition to the above components, the pharmaceutical composition of the present invention may further include a lubricant, a wetting agent, a sweetener, a flavoring agent, an emulsifier, a suspending agent, a preservative, etc. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington's Pharmaceutical Sciences (22nd ed., 2013).

[0123] The pharmaceutical composition of the present invention may include various bases and / or additives that are necessary and appropriate for the formulation of the formulation, and may be prepared by further including known compounds such as nonionic surfactants, silicone polymers, extender pigments, fragrances, preservatives, fungicides, oxidation stabilizers, organic solvents, ionic or nonionic thickeners, emollients, antioxidants, free radical destroyers, opacifiers, stabilizers, emollients, silicones, α-hydroxy acids, defoaming agents, moisturizers, vitamins, insect repellents, fragrances, preservatives, surfactants, anti-inflammatory agents, substance P antagonists, fillers, polymers, propellants, basicizing or acidifying agents, or coloring agents, to the extent that the effect is not reduced.

[0124] The above cancer may be at least one selected from the group consisting of breast cancer, colorectal cancer, gastric cancer, liver cancer, lung cancer, kidney cancer, pancreatic cancer, head and neck squamous cell carcinoma, esophageal cancer, ovarian cancer, cervical cancer, endometrial cancer, lymphoma, mesothelioma, melanoma, sarcoma, osteosarcoma, liposarcoma, thyroid cancer, cerebrovascular tumor, and hematological cancer, but is not limited thereto.

[0125] Another aspect of the present invention provides a method for preventing or treating cancer comprising the step of administering a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof to a subject.

[0126] The compounds included in the pharmaceutical composition of the present invention or pharmaceutically acceptable salts thereof may be administered by oral administration as intended, in an amount effective for the treatment or prevention of an individual or patient. It should be understood that the dosage for a specific individual or patient should be determined based on various relevant factors such as the patient's weight, age, race, gender, health status, diet, time of administration, method of administration, and severity of the disease, and may be appropriately adjusted by a professional. For example, a physician may start the dosage of the pharmaceutical composition of the present invention at a level lower than required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved, and may easily determine and prescribe the dosage as needed.

[0127] The present invention will be explained in detail below through manufacturing examples and experimental examples.

[0128]

[0129] However, the following manufacturing examples and experimental examples are intended to specifically illustrate the present invention, and the content of the present invention is not limited by the following manufacturing examples and experimental examples.

[0130]

[0131] Synthesis method [1] and [2]

[0132]

[0133] [1]

[0134] Boc-Gly-OH (1 eq) and the corresponding amine (1 eq) were dissolved in DCM (0.2 molar), then EDCI (1.1 eq), HOBt (1.1 eq), and EIPEA (3–10 eq) were added, and the mixture was stirred at room temperature for 1 to 24 hours. After the reaction was finished, the solvent was removed by concentrating under reduced pressure, and the compound was obtained by MPLC (Hex:EA or MC:MeOH) purification.

[0135] [2]

[0136] Each compound obtained in [1] was dissolved in DCM (0.15 molar), TFA (15 eq) was added, and the mixture was stirred at room temperature for 1 to 3 hours. After the reaction was finished, the solvent was removed by concentrating under reduced pressure, and the compounds were obtained by purifying with prep HPLC.

[0137]

[0138] Synthesis method [3] and [4]

[0139]

[0140] [3]

[0141] tert-butyl pyrrolidin-3-ylcarbamate (1 eq) and the corresponding carboxylic acid (1 eq) were dissolved in DCM (0.1 molar), then EDCI (1.2 eq), HOBt (1.2 eq), and EIPEA (3 eq) were added, and the mixture was stirred at room temperature for 3 hours. After the reaction was complete, the solvent was removed by concentrating under reduced pressure, and the compound was obtained by MPLC (Hex:EA) purification.

[0142] [4]

[0143] The compound (1 eq) obtained in [3] was dissolved in DCM (0.1 molar), TFA (5 eq) was added, and the mixture was stirred at room temperature. After the reaction was complete, the solvent was removed under reduced pressure and used in the next step without further purification.

[0144]

[0145] Synthesis method [5] and [6]

[0146]

[0147] [5]

[0148] tert-butyl pyrrolidin-3-ylcarbamate (1 eq) and its isocyanate (1.2 eq) were dissolved in DCM (0.1 molar), then DIPEA (1.1 eq) was added and stirred at room temperature for 24 hours. After the reaction was complete, the solvent was removed under reduced pressure, and the compound was obtained by purification using MPLC (Hex:EA).

[0149] [6]

[0150] The compound (1 eq) obtained from [5] was dissolved in DCM (0.1 molar), TFA (5 eq) was added, and the mixture was stirred at room temperature. After the reaction was complete, the solvent was removed under reduced pressure and used in the next step without further purification.

[0151]

[0152] Synthesis method [7] and [8]

[0153]

[0154] [7]

[0155] tert-butyl 3-aminopyrrolidine-1-carboxylate (1 eq) was dissolved in DCM (0.1 molar), DIPEA (1.3 eq) was added, and 2-bromoacetyl chloride (1.2 eq) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 24 hours. After the reaction was complete, the reaction solution was diluted with EA, washed with sat. NaHCO3(aq) and brine, and the organic solvent layer was separated and dried with MgSO4. After filtration, the solvent was removed from the filtrate under reduced pressure, and the compound was obtained by purification using MPLC (Hex:EA).

[0156] [8]

[0157] The compound (1 eq) obtained in [7] was dissolved in MeOH (0.14 molar), NaI (3 eq) and NH4OH (1 eq) were added, and the mixture was stirred at room temperature for 48 hours. After the reaction was finished, the solvent was removed under reduced pressure and purified by prep HPLC to obtain the compound.

[0158]

[0159] Synthesis method [9] and

[0010]

[0160]

[0161] [9]

[0162] The corresponding carboxylic acid (1 eq) and the corresponding amine (1 eq) were dissolved in DCM (0.1 molar), then EDCI (1.2 eq), HOBt (1.2 eq), and EIPEA (4 eq) were added, and the mixture was stirred at room temperature for 24 hours. After the reaction was finished, the solvent was removed by concentrating under reduced pressure, and the compound was obtained by MPLC (Hex:EA or MC:MeOH) purification.

[0163]

[0010]

[0164] Each compound obtained in [3] was dissolved in DCM (0.1 molar), TFA (15 eq) was added, and the mixture was stirred at room temperature for 1 to 6 hours. After the reaction was finished, the solvent was removed by concentrating under reduced pressure, and the compounds were purified by prep HPLC.

[0165]

[0166] Synthesis method

[0011] and

[0012]

[0167]

[0168]

[0011]

[0169] (tert-butoxycarbonyl)proline (1 eq) and the corresponding amine (1 eq) were dissolved in DCM (0.2 molar), then EDCI (1.2 eq), HOBt (1.2 eq), and EIPEA (4 eq) were added, and the mixture was stirred at room temperature for 24 hours. After the reaction was complete, the solvent was removed by concentrating under reduced pressure, and the compound was obtained by MPLC (Hex:EA or MC:MeOH) purification.

[0170]

[0012]

[0171] Each compound obtained in

[0011] was dissolved in DCM (0.15 molar), TFA (15 eq) was added, and the mixture was stirred at room temperature for at least 1 hour. After the reaction was finished, the solvent was removed by concentrating under reduced pressure, and the compounds were obtained by purifying with prep HPLC.

[0172]

[0173] [Preparation Example 1]

[0174] 1-1. tert-butyl (2-oxo-2-((pyridin-3-ylmethyl)amino)ethyl)carbamate (JSJ-008-079)

[0175]

[0176] A compound was obtained by proceeding with the method of [1]. (Colorless sticky oil, yield 96%)

[0177] 1 H NMR (CDCl3, 400MHz) δ8.521 (m, 2H), 7.658-7.639 (m, 2H) 7.289-7.258 (m, 1H), 6.862 (brs, 1H), 5.305 (brs, 1H), 4.490-4.475 (m, 2H), 3.849-3.835 (m, 1H), 1.423 (s, 9H).

[0178] 1-2. 2-amino-N-(pyridin-3-ylmethyl)acetamide (8-082) DN206465-1

[0179]

[0180] 1-1. The compound was obtained by proceeding with the method of [2]. (Colorless sticky oil, yield 88%)

[0181] 1 H NMR (DMSO-d6, 400MHz) δ9.042-9.014 (m, 1H), 8.695-8.677 (m, 2H), 8.097-8.077 (m, 3H), 7.718 (dd,J= 7.76 Hz, 5.32 Hz, 1H), 4.472 (d,J= 5.84 Hz), 3.674-3.645 (m, 2H).

[0182]

[0183] [Preparation Example 2]

[0184] 2-1. tert-butyl (2-oxo-2-((pyridin-2-ylmethyl)amino)ethyl)carbamate (8-083)

[0185]

[0186] A compound was obtained by proceeding with the method of [1]. (Colorless sticky oil, yield 94%)

[0187] 1 H NMR (CDCl3, 400MHz) δ8.522 (d, J= 4.68 Hz, 1H), 7.696-7.654 (m, 1H), 7.290 (s, 1H), 7.227-7.196 (m, 1H), 5.192 (brs, 1H), 4.587 (d, J= 5.12 Hz, 2H), 3.895-3.881 (m, 2H), 1.453 (s, 9H).

[0188] 2-2. 2-amino-N-(pyridin-2-ylmethyl)acetamide (8-084) DN206466-1

[0189]

[0190] 2-1. A compound was obtained by proceeding with the method of [2]. (Colorless sticky oil, yield 99%)

[0191] 1 H NMR (DMSO-d6, 400MHz) δ8.995 (t, J= 5.62 Hz, 1H), 8.588 (d, J= 4.48 Hz, 1H), 8.075 (brs, 2H), 7.941-7.899 (m, 1H), 7.460 (d, J = 7.88 Hz, 1H), 7.430-7.398 (m, 1H), 4.501 (d, J = 5.8 Hz, 2H), 3.676-3.666 (m, 2H).

[0192]

[0193] [Preparation Example 3]

[0194] 3-1. tert-butyl (2-((benzo[d][1,3]dioxol-5-ylmethyl)amino)-2-oxoethyl)carbamate (8-081)

[0195]

[0196] The compound was obtained by proceeding with the method of [1]. (Pale yellow solid, yield 73.7%)

[0197] 1H NMR (CDCl3, 400MHz) δ6.761-6.714 (m, 3H), 6.370 (brs, 1H), 5.940 (s, 2H), 5.123 (brs, 1H), 4.359 (d,J= 5.76, 2H), 3.808 (d,J= 5.80 Hz, 2H), 1.433 (s, 9H).

[0198] 3-2. 2-amino-N-(benzo[d][1,3]dioxol-5-ylmethyl)acetamide (8-087) DN206467-1

[0199]

[0200] 3-1. The compound was obtained by proceeding with the method of [2]. (white solid, yield 95%)

[0201] 1 H NMR (DMSO-d6, 400MHz) δ8.766-8.738 (m, 1H), 8.017 (brs, 2H), 6.873-6.853 (m, 2H), 6.763 (d, J= 8.2 Hz, 1H), 5.985 (s, 2H), 4.251 (d,J= 5.84 Hz, 2H), 3.588 (s, 2H).

[0202]

[0203] [Preparation Example 4]

[0204] 4-1. tert-butyl (2-oxo-2-(((tetrahydro-2H-pyran-3-yl)methyl)amino)ethyl)carbamate (8-090)

[0205]

[0206] A compound was obtained by proceeding with the method of [1]. )Colorless sticky oil, yield 87%)

[0207] 1H NMR (CDCl3, 400MHz) δ6.234 (brs, 1H), 5.114 (brs, 1H), 3.847-3.799 (m, 2H), 3.771-3.756 (m, 2H), 3.442-3.381 (m, 1H), 3.193-3.162 (m, 3H), 1.849-1.757 (m, 2H), 1.667-1.525 (m, 2H), 1.415 (s, 9H), 1.314-1.245 (m, 1H).

[0208] 4-2. 2-amino-N-((tetrahydro-2H-pyran-3-yl)methyl)acetamide (8-092) DN206468-1

[0209]

[0210] 4-1. A compound was obtained by proceeding with the method of [2]. (Colorless sticky oil, yield 99%)

[0211] 1 H NMR (DMSO-d6, 400MHz) δ8.337-8.310 (m, 1H), 7.993 (brs, 2H), 3.766-3.681 (m, 2H), 3.538-3.526 (m, 2H), 3.326-3.266 (m, 1H), 3.092-3.065 (m, 1H), 3.041-2.995 (m, 2H), 1.764-1.723 (m, 1H), 1.695-1.678 (m, 1H), 1.670-1.646 (m, 1H), 1.639-1.540 (m, 1H), 1.488-1.451 (m, 1H).

[0212]

[0213] [Preparation Example 5]

[0214] 5-1. tert-butyl (2-(cyclopentylamino)-2-oxoethyl)carbamate (8-088)

[0215]

[0216] The compound was obtained by proceeding with the method of [1]. (Colorless sticky oil, yield 71.1%)

[0217] 1 H NMR (CDCl3, 400MHz) δ6.039 (brs, 1H), 5.161 (brs, 1H), 4.230-4.179 (m, 1H), 3.746 (d,J= 5.76 Hz, 2H), 2.013-1.938 (m, 2H), 1.696-1.580 (m, 4H), 1.456 (s, 9H), 1.427-1.364 (m, 2H).

[0218] 5-2. 2-amino-N-cyclopentylacetamide (8-093) DN206469-1

[0219]

[0220] 5-1. A compound was obtained by proceeding with the method of [2]. (Colorless sticky oil, yield 45.8%)

[0221] 1 H NMR (DMSO-d6, 400MHz) δ8.039 (d, J= 6.88 Hz, 1H), 7.993 (brs, 2H), 4.075-4.058 (m, 1H), 3.506-3.464 (m, 2H), 1.863-1.785 (m, 2H), 1.674-1.557 (m, 2H), 1.541-1.471 (m, 2H), 1.421-1.359 (m, 2H).

[0222]

[0223] [Preparation Example 6]

[0224] 6-1. tert-butyl (2-(((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)amino)-2-oxoethyl)carbamate (8-091)

[0225]

[0226] A compound was obtained by proceeding with the method of [1]. (White solid, yield 99%)

[0227] 1 H NMR (CDCl3, 400MHz) δ6.822-6.778 (m, 2H), 6.750-6.725 (m, 1H), 6.294 (brs, 1H), 5.099 (brs, 1H), 4.344 (d,J= 5.68 Hz, 2H), 4.238 (s, 4H), 3.807 (d, J= 5.84 Hz, 2H), 1.435 (s, 9H).

[0228] 6-2. 2-amino-N-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)acetamide (8-094) DN206470-1

[0229]

[0230] 6-1. The compound was obtained by proceeding with the method of [2]. (White solid, yield 99%)

[0231] 1 H NMR (DMSO-d6, 400MHz) δ8.733-8.705 (m, 1H), 8.014 (brs, 2H), 6.812-6.791 (m, 2H), 6.748-6.723 (m, 1H), 4.223-4.208 (m, 6H), 3.597-3.554 (m, 2H).

[0232]

[0233] [Preparation Example 7]

[0234] 7-1. tert-butyl (S)-3-(2-((tert-butoxycarbonyl)amino)acetamido)pyrrolidine-1-carboxylate (8-095)

[0235]

[0236] A compound was obtained by proceeding with the method of [1]. (Yellow sticky oil, yield 99%)

[0237] 1 H NMR (CDCl3, 400MHz) δ6.287 (brs, 1H), 5.096 (brs, 1H), 4.474-4.432 (m, 1H), 3.769-3.757 (m, 2H), 3.635-3.591 (m, 1H), 3.434-3.433 (m, 2H), 3.216-3.161 (m, 1H), 2.188-2.045 (m, 1H), 1.613-1.612 (m, 1H), 1.458-1.457 (m, 18H).

[0238] 7-2. (S)-2-amino-N-(pyrrolidin-3-yl)acetamide (8-097) DN206471-1

[0239]

[0240] 7-1. The compound was obtained by proceeding with the method of [2]. (Colorless sticky oil, yield 99%)

[0241] 1 H NMR (DMSO-d6, 400MHz) δ9.142 (brs, 1H), 8.969 (brs, 1H), 8.074 (brs, 2H), 4.365-4.319 (m, 1H), 3.592-3.476 (m, 2H) 3.429-3.387 (m, 1H), 3.281-3.162 (m, 2H), 2.990-2.948 (m, 1H), 2.204-2.116 (m, 1H), 1.868-1.786 (m, 1H).

[0242]

[0243] [Preparation Example 8]

[0244] 8-1. tert-butyl (R)-3-((2-((tert-butoxycarbonyl)amino)acetamido)methyl)pyrrolidine-1-carboxylate (8-096)

[0245]

[0246] A compound was obtained by proceeding with the method of [1]. (yellow sticky oil, yield 92%)

[0247] 1 H NMR (CDCl3, 400MHz) δ6.300 (brs, 1H), 5.096 (brs, 1H), 3.772 (d, J= 5.92, 2H), 3.489-3.237 (m, 5H), 3.063-2.941 (m, 1H), 2.396-2.388 (m, 1H), 2.006-1.929 (m, 1H), 1.611-1.595 (m, 1H), 1.461-1.455 (m, 18H).

[0248] 8-2. (S)-2-amino-N-(pyrrolidin-3-ylmethyl)acetamide (8-098) DN206472-1

[0249]

[0250] 8-1. The compound was obtained by proceeding with the method of [2]. (Colorless sticky oil, yield 99%)

[0251] 1 H NMR (DMSO-d6, 400MHz) δ8.849 (brs, 1H), 8.523-8.497 (m, 1H), 8.026 (brs, 2H), 3.558 (m, 2H), 3.258-3.132 (m, 5H), 2.845-2.784 (m, 1H), 2.452-2.330 (m, 1H), 2.042-1.959 (m, 1H), 1.639-1.546 (m, 1H).

[0252]

[0253] [Preparation Example 9]

[0254] 9-1. tert-butyl (2-(((1,4-dioxan-2-yl)methyl)amino)-2-oxoethyl)carbamate (8-099)

[0255]

[0256] The compound was obtained by proceeding with the method of [1]. (Colorless sticky oil, yield 73.7%)

[0257] 1 H NMR (CDCl3, 400MHz) δ6.351 (brs, 1H), 5.093 (brs, 1H), 3.799-3.3.785 (m, 2H), 3.762-3.637 (m, 5H), 3.612-3.548 (m, 1H), 3.514-3.454 (m, 1H), 3.346-3.3.292 (m, 1H), 3.193-3.127 (m, 1H), 1.464 (s, 9H).

[0258] 9-2. N-((1,4-dioxan-2-yl)methyl)-2-aminoacetamide (9-002) DN206473-1

[0259]

[0260] Compound 9-1 was processed according to the method of [2] to obtain the compound. (Colorless sticky oil, yield 99%)

[0261] 1 H NMR (DMSO-d6, 400MHz) δ8.441 (t, J= 5.36 Hz, 1H), 8.003 (brs, 2H), 3.746-3.689 (m, 2H), 3.648-3.620 (m, 1H), 3.583-3.528 (m, 4H), 3.476-3.421 (m, 1H), 3.232-3.141 (m, 3H).

[0262]

[0263] [Preparation Example 10]

[0264] 10-1. tert-butyl (2-oxo-2-(((tetrahydro-2H-pyran-2-yl)methyl)amino)ethyl)carbamate (8-100)

[0265]

[0266] A compound was obtained by proceeding with the method of [1]. (Colorless sticky oil, yield 98%)

[0267] 1 H NMR (CDCl3, 400MHz) δ6.351 (brs, 1H), 5.102 (brs, 1H), 3.971-3.943 (m, 1H), 3.799-3.785 (m, 2H), 3.589-3.530 (m, 1H), 3.441-3.346 (m, 2H), 3.090-3.025 (m, 1H), 1.851-1.827 (m, 1H), 1.579-1.498 (m, 4H), 1.459 (s, 9H), 1.330-1.240 (m, 1H).

[0268] 10-2. 2-amino-N-((tetrahydro-2H-pyran-2-yl)methyl)acetamide (9-003) DN206474-1

[0269]

[0270] A compound was obtained by proceeding with the method of [2] for 10-1 compounds. (Colorless sticky oil, yield 31.8%)

[0271] 1 H NMR (DMSO-d6, 400MHz) δ8.395-8.368 (m, 1H), 7.980 (brs, 2H), 3.887-3.855 (m, 1H), 3.543 (d, J= 5.36 Hz, 2H), 3.349-3.267 (m, 2H), 3.238-3.169 (m, 1H), 3.126-3.061 (m, 1H), 1.768-1.767 (m, 1H), 1.562-1.530 (m, 1H), 1.452-1.403 (m, 3H), 1.205-1.126 (m, 1H).

[0272]

[0273] [Preparation Example 11]

[0274] 11-1. tert-butyl (2-((chroman-3-ylmethyl)amino)-2-oxoethyl)carbamate (9-001)

[0275]

[0276] A compound was obtained by proceeding with the method of [1]. (Colorless sticky oil, yield 93%)

[0277] 1 H NMR (CDCl3, 400MHz) δ7.108-7.070 (m, 1H), 7.037-7.019 (m, 1H), 6.868-6.831 (m, 1H), 6.804-6.783 (m, 1H), 6.391 (brs, 1H), 5.029 (brs, 1H), 4.192-4.161 (m, 1H), 3.963-3.918 (m, 1H), 3.773-3.750 (m, 2H), 3.349 (t,J= 6.6 Hz, 2H), 2.905 (dd,J= 16.4 Hz, 5.6 Hz, 1H), 2.557 (dd,J= 16.4 Hz, 7.2 Hz, 1H), 2.346-2.290 (m, 1H), 1.465 (s, 9H).

[0278] 11-2. 2-amino-N-(chroman-3-ylmethyl)acetamide (9-004) DN206475-1

[0279]

[0280] 11-1. A compound was obtained by proceeding with the method of [2]. (White solid, yield 63.7%)

[0281] 1H NMR (DMSO-d6, 400MHz) δ8.525-8.498 (m, 1H), 8.028 (brs, 2H), 7.078-7.038 (m, 2H), 6.842-6.806 (m, 1H), 6.739 (d, J= 7.96 Hz, 1H), 4.198-4.174 (m, 1H), 3.849-3.801 (m, 1H), 3.580 (s, 2H), 3.219-3.199 (m, 2H), 3.319 (dd,J= 16.34 Hz, 5.2 Hz, 1H), 2.558-2.536 (m, 1H), 2.150-2.131 (m, 1H).

[0282]

[0283] [Preparation Example 12]

[0284] 12-1. tert-butyl (2-oxo-2-(((tetrahydrofuran-2-yl)methyl)amino)ethyl)carbamate (9-013)

[0285]

[0286] A compound was obtained by proceeding with the method of [1]. (Colorless sticky oil, yield 93%)

[0287] 1 H NMR (CDCl3, 400MHz) δ6.371 (brs, 1H), 5.138 (brs, 1H), 3.996-3.936 (m, 1H), 3.878-3.719 (m, 4H), 3.580-3.552 (m, 1H), 3.237-3.190 (m, 1H), 2.050-1.865 (m, 3H), 1.614-1.500 (m, 1H), 1.457 (s, 9H).

[0288] 12-2. 2-amino-N-((tetrahydrofuran-2-yl)methyl)acetamide (9-015) DN207344

[0289]

[0290] 12-1. A compound was obtained by proceeding with the method of [2]. (Colorless sticky oil, yield 99%)

[0291] 1 H NMR (DMSO-d6, 400MHz) δ8.464-8.451 (m, 1H), 8.046 (brs, 2H), 3.873-3.812 (m, 1H), 3.788-3.708 (m, 1H), 3.649-3.595 (m, 1H), 3.557-3.544 (m, 2H), 3.275-3.228 (m, 1H), 3.215-3.127 (m, 1H), 1.936-1.756 (m, 3H), 1.539-1.455 (m, 1H).

[0292]

[0293] [Preparation Example 13]

[0294] 13-1. tert-butyl (R)-3-(2-((tert-butoxycarbonyl)amino)acetamido)pyrrolidine-1-carboxylate (9-014)

[0295]

[0296] A compound was obtained by proceeding with the method of [1]. (White solid, yield 75%)

[0297] 1 H NMR (CDCl3, 400MHz) δ6.249 (brs, 1H), 5.072 (brs, 1H), 4.464-4.450 (m, 1H), 3.774-3.636 (m, 2H), 3.619-3.594 (m, 1H), 3.442-3.400 (m, 2H), 3.245-3.137 (m, 1H), 2.171-2.105 (m, 1H), 1.846-1.836 (m, 1H), 1.459-1.412 (m, 18H).

[0298] 13-2. (R)-2-amino-N-(pyrrolidin-3-yl)acetamide (9-016) DN207352

[0299]

[0300] 13-1 The compound was obtained by proceeding with the method of [2]. (White solid, yield 99%)

[0301] 1 H NMR (DMSO-d6, 400MHz) δ9.144 (brs, 1H), 8.952 (brs, 1H), 8.069 (brs, 2H), 4.364-4.317 (m, 1H), 3.552-3.448 (m, 3H), 3.272-3.260 (m, 2H), 2.986-2.940 (m, 1H), 2.199-2.112 (m, 1H), 1.861-1.778 (m, 1H).

[0302]

[0303] [Preparation Example 14]

[0304] 14-1. tert-butyl (2-((chroman-2-ylmethyl)amino)-2-oxoethyl)carbamate (9-020)

[0305]

[0306] A compound was obtained by proceeding with the method of [1]. (White solid, yield 76%)

[0307] 1 H NMR (CDCl3, 400MHz) δ7.106-7.036 (m, 2H), 6.870-6.831 (m, 1H), 6.790 (d,J= 8.12 Hz, 1H), 6.524 (brs, 1H), 5.114 (brs, 1H), 4.113-4.069 (m, 1H), 3.838-3.824 (m, 2H), 3.780-3.720 (m, 1H), 3.454-3.388 (m, 1H), 2.874-2.830 (m, 1H), 2.790-2.735 (m, 1H), 2.015-1.966 (m, 1H), 1.808-1.747 (m, 1H), 1.436 (s, 9H).

[0308] 14-2. 2-amino-N-(chroman-2-ylmethyl)acetamide (9-021) DN207345

[0309]

[0310] 14-1. The compound was obtained by proceeding with the method of [2]. (White solid, yield 99%)

[0311] 1 H NMR (DMSO-d6, 400MHz) δ8.587 (t, J= 5.64 Hz, 1H), 8.017 (brs, 2H), 7.086-7.052 (m, 2H), 6.840-6.803 (m, 1H), 6.754-6.732 (m, 1H), 4.087-4.040 (m, 1H), 3.603 (s, 2H), 3.457-3.429 (m, 2H), 2.854-2.670 (m, 2H), 2.007-1.960 (m, 1H), 1.721-1.660 (m, 1H).

[0312]

[0313] [Preparation Example 15]

[0314] 15-1. tert-butyl (2-oxo-2-((quinolin-2-ylmethyl)amino)ethyl)carbamate (9-034)

[0315]

[0316] The compound was obtained by proceeding with the method of [1]. (Light yellow solid, yield 72.5%)

[0317] 1H NMR (CDCl3, 400MHz) δ8.146 (d,J= 8.44 Hz, 1H), 8.048 (d,J= 8.44 Hz, 1H), 7.823 (d,J= 8.12 Hz, 1H), 7.754-7.700 (m, 2H), 7.552 (t,J= 7.96 Hz, 1H), 7.359 (d,J= 8.44 Hz, 1H), 5.274 (brs, 1H), 4.760 (d,J= 4.72 Hz, 2H), 3.976-3.943 (m, 2H), 1.471 (s, 9H).

[0318] 15-2. 2-amino-N-(quinolin-2-ylmethyl)acetamide (9-038)

[0319]

[0320] 15-1. A compound was obtained by proceeding with the method of [2]. (Colorless sticky oil, yield 8.5%)

[0321] 1 H NMR (CD3OD, 400MHz) δ8.660 (d, J= 8.56 Hz, 1H), 8.158-8.094 (m, 2H), 7.973-7.931 (m, 1H), 7.783-7.737 (m, 2H), 4.870 (s, 2H), 3.869 (s, 2H).

[0322]

[0323] [Preparation Example 16]

[0324] 16-1. tert-butyl (2-oxo-2-((quinolin-3-ylmethyl)amino)ethyl)carbamate (9-033)

[0325]

[0326] The compound was obtained by proceeding with the method of [1]. (yellow sticky oil, yield 68.9%)

[0327] 1H NMR (CDCl3-d6, 400MHz) δ8.846 (s, 1H), 8.107-8.086 (m, 2H), 7.808-7.788 (m, 1H), 7.732-7.691 (m, 1H), 7.579-7.541 (m, 1H), 6.841 (brs, 1H), 5.238 (brs, 1H), 4.668-4.653 (m, 2H), 3.881-3.867 (m, 2H), 1.417 (s, 9H).

[0328] 16-2. 2-amino-N-(quinolin-3-ylmethyl)acetamide (9-039)

[0329]

[0330] 16-1. A compound was obtained by proceeding with the method of [2]. (colorless sticky oil, yield 18%)

[0331] 1 H NMR (CD3OD, 400MHz) δ9.075 (s, 1H), 8.753 (s, 1H), 8.183-8.154 (m, 2H), 8.013 (t, J= 8.40 Hz, 1H), 7.873-7.834 (m, 1H), 4.759 (s, 2H), 3.810 (s, 2H).

[0332]

[0333] [Preparation Example 17]

[0334] 17-1. tert-butyl (2-oxo-2-((pyrimidin-5-ylmethyl)amino)ethyl)carbamate (9-035)

[0335]

[0336] A compound was obtained by proceeding with the method of [1]. (white sticky solid, yield 77%)

[0337] 1H NMR (CDCl3, 400MHz) δ9.148 (s, 1H), 8.696 (s, 2H), 6.830 (brs, 1H), 5.146 (brs, 1H), 4.483 (d,J= 6.12 Hz, 2H), 3.834 (d,J= 6.00 Hz, 2H), 1.437 (s, 9H).

[0338] 17-2. 2-amino-N-(pyrimidin-5-ylmethyl)acetamide (9-041) DN207831

[0339]

[0340] 17-1. A compound was obtained by proceeding with the method of [2]. (Yellow sticky solid, yield 99%)

[0341] 1 H NMR (DMSO-d6, 400MHz) δ9.102 (s, 1H), 8.984-8.956 (m, 1H), 8.749 (s, 2H), 8.042 (m, 2H), 4.407 (d, J= 5.84 Hz, 2H), 3.653-3.639 (m, 2H).

[0342]

[0343] [Preparation Example 18]

[0344] 18-1. tert-butyl 2-((2-((tert-butoxycarbonyl)amino)acetamido)methyl)piperidine-1-carboxylate (10-031)

[0345]

[0346] A compound was obtained by proceeding with the method of [1]. (white sticky solid, yield 97%)

[0347] 1H NMR (CDCl3-d, 400MHz) δ6.378 (brs, 1H), 5.053 (brs, 1H), 4.397-4.365 (m, 1H), 3.952-3.921 (m, 1H), 3.837-3.701 (m, 3H), 3.206-3.174 (m, 1H), 2.872-2.808 (m, 1H), 1.635-1.609 (m, 5H), 1.461-1.453 (m, 18H).

[0348] 18-2. 2-amino-N-(piperidin-2-ylmethyl)acetamide (10-040) DN207348

[0349]

[0350] 18-1. A compound was obtained by proceeding with the method of [2]. (Colorless sticky oil, yield 99%)

[0351] 1 H NMR (DMSO-d6+ TFA, 400MHz) δ8.640-8.345 (m, 2H), 8.041 (m, 2H), 3.593-3.550 (m, 2H), 3.419-3.352 (m, 1H), 3.322-3.260 (m, 2H), 3.072 (m, 1H), 2.897-2.811 (m, 1H), 1.839-1.707 (m, 3H), 1.610-1.311 (m, 3H).

[0352] 13 C NMR (DMSO-d6+ TFA, 400 MHz) δ167.379, 55.888, 44.454, 41.132, 40.716, 26.188, 22.111, 21.582.

[0353]

[0354] [Preparation Example 19]

[0355] 19-1. tert-butyl (S)-2-((2-((tert-butoxycarbonyl)amino)acetamido)methyl)piperidine-1-carboxylate (10-032)

[0356]

[0357] A compound was obtained by proceeding with the method of [1]. (white sticky solid, yield 97%)

[0358] 1 H NMR (CDCl3-d, 400MHz) δ6.373 (brs, 1H), 5.055 (brs, 1H), 4.362 (m, 1H), 3.853-3.924 (m, 1H), 3.863-3.655 (m, 3H), 3.204-3.174 (m, 1H), 2.871-2.807 (m, 1H), 1.626-1.608 (m, 5H), 1.460-1.453 (m, 18H).

[0359] 19-2. (S)-2-amino-N-(piperidin-2-ylmethyl)acetamide (10-041) DN207349

[0360]

[0361] 19-1. A compound was obtained by proceeding with the method of [2]. (Colorless sticky oil, yield 99%)

[0362] 1 H NMR (DMSO-d6+ TFA, 400MHz) δ8.6230-8.3489 (m, 2H), 8.052 (m, 2H), 3.618-3.575 (m, 2H), 3.447-3.395 (m, 1H), 3.379-3.296 (m, 2H), 3.097 (m, 1H), 2.922-2.834 (m, 1H), 1.863-1.728 (m, 3H), 1.637-1.339 (m, 3H).

[0363] 1H NMR (MeOD-d4, 400MHz) δ3.737 (s, 2H), 3.506-3.461 (m, 2H), 3.429-3.397 (m, 1H), 3.282-3.241 (m, 1H), 3.024-2.9530 (m, 1H), 1.973-1.884 (m, 3H), 1.767-1.465 (m, 3H).

[0364] 13 C NMR (MeOD-d4, 400MHz) δ167.374, 56.889, 44.738, 41.355, 40.132, 26.021, 21.745, 21.411.

[0365]

[0366] [Preparation Example 20]

[0367] 20-1. tert-butyl 3-((2-((tert-butoxycarbonyl)amino)acetamido)methyl)piperidine-1-carboxylate (10-033)

[0368]

[0369] The compound was obtained by proceeding with the method of [1]. (white sticky solid, crude product) The crude product was used in the next step without further purification.

[0370] 20-2. 2-amino-N-(piperidin-3-ylmethyl)acetamide (10-042) DN207350

[0371]

[0372] 20-1. The compound was obtained by proceeding with the method of [2]. (Colorless oil, yield 99%)

[0373] 1H NMR (MeOD-d4, 400MHz) δ3.715 (s, 2H), 3.380-3.347 (m, 2H), 3.257-3.242 (m, 2H), 2.951-2.881 (m, 1H), 2.754-2.694 (m, 1H), 2.050-1.912 (m, 3H), 1.793-1.683 (m, 1H), 1.368-1.274 (m, 1H).

[0374] 13 C NMR (MeOD-d4, 400 MHz) δ166.374, 46.607, 43.880, 41.640, 40.001, 34.336, 25.826, 21.538.

[0375]

[0376] [Preparation Example 21]

[0377] 21-1. tert-butyl (S)-3-((2-((tert-butoxycarbonyl)amino)acetamido)methyl)piperidine-1-carboxylate (10-034)

[0378]

[0379] The compound was obtained by proceeding with the method of [1]. (white sticky solid, crude product) The crude product was used in the next step without further purification.

[0380] 21-2. (R)-2-amino-N-(piperidin-3-ylmethyl)acetamide (10-043) DN207351

[0381]

[0382] 21-1. The compound was obtained by proceeding with the method of [2]. (Colorless oil, yield 99%)

[0383] 1H NMR (MeOD-d4, 400MHz) δ3.715 (s, 2H), 3.380-3.348 (m, 2H), 3.268-3.241 (m, 2H), 2.951-2.880 (m, 1H), 2.753-2.693 (m, 1H), 2.051-1.911 (m, 3H), 1.793-1.684 (m, 1H), 1.374-1.274 (m, 1H).

[0384] 13 C NMR (MeOD-d4, 400MHz) δ166.381, 46.606, 43.874, 41.639, 40.001, 34.335, 25.827, 21.538.

[0385]

[0386] [Preparation Example 22]

[0387] 22-1. tert-butyl (2-oxo-2-((pyrazin-2-ylmethyl)amino)ethyl)carbamate (10-035)

[0388]

[0389] A compound was obtained by proceeding with the method of [1]. (White sticky solid, yield 82%)

[0390] 1 H NMR (CDCl3-d, 400MHz) δ8.610 (s, 1H), 8.506 (m, 2H), 7.126 (brs, 1H), 5.176 (brs, 1H), 4.651-4.637 (m, 2H), 3.891-3.877 (m, 2H), 1.455 (s, 9H).

[0391] 22-2. 2-amino-N-(pyrazin-2-ylmethyl)acetamide (10-044) DN207835

[0392]

[0393] 22-1. Compound was obtained by proceeding with the method of [2]. (Yellow sticky oil, yield 33.3%)

[0394] 1 H NMR (DMSO-d6, 400MHz) δ9.043-9.015 (m, 1H), 8.654-8.566 (m, 3H), 8.029 (m, 2H), 4.514 (d, J= 5.8, 2H), 3.687-3.643 (m, 2H).

[0395] 13 C NMR (MeOD-d4, 400MHz) δ166.882, 153.841, 144.464, 143.916, 143.874, 42.686

[0396]

[0397] [Preparation Example 23]

[0398] 23-1. tert-butyl (3-((2-((tert-butoxycarbonyl)amino)acetamido)methyl)phenyl)carbamate (12-022)

[0399]

[0400] The compound was obtained by proceeding with the method of [1]. (White solid, yield 58.3%)

[0401] 1 H NMR (CDCl3-d, 400MHz) δ7.327 (s, 1H), 7.247-7.236 (m, 2H), 6.957-6.931 (m, 1H), 6.483 (s, 1H), 6.331 (m, 1H), 5.093 (m, 1H), 4.442-4.427 (m, 2H), 3.835-3.820 (m, 2H), 1.514 (s, 9H), 1.436 (s, 9H).

[0402] 23-2. 2-amino-N-(3-aminobenzyl)acetamide (12-027) DN207666

[0403]

[0404] 23-1. A compound was obtained by proceeding with the method of [2]. (colorless sticky solid, yield 14.5%)

[0405] 1 H NMR (MeOD-d4, 400MHz) δ7.486-7.447 (m, 1H), 7.355-7.336 (m, 1H), 7.287 (m, 1H), 7.223 (dd, J= 7.92, 1.36Hz, 1H), 4.491 (s, 2H), 3.754 (s, 2H).

[0406]

[0407] [Preparation Example 24]

[0408] 24-1. tert-butyl (2-((4-((tert-butoxycarbonyl)amino)benzyl)amino)-2-oxoethyl)carbamate (12-054)

[0409]

[0410] A compound was obtained by proceeding with the method of [1]. (White solid, yield 79%)

[0411] 1 H NMR (CDCl3-d, 400MHz) δ7.3270-7.3059 (m, 2H), 7.2018-7.1806 (m, 2H), 6.4697 (brs, 1H), 6.297 (m, 1H), 5.082 (brs, 1H), 4.401 (d, J= 5.72 Hz, 2H), 3.810 (d, J= 5.88 Hz, 2H), 1.515 (s, 9H), 1.434 (s, 9H).

[0412] 24-2. 2-amino-N-(4-aminobenzyl)acetamide (12-065) DN207841

[0413]

[0414] 24-1. The compound was obtained by proceeding with the method of [2]. (sticky ivory solid, yield 30.6%)

[0415] 1 H NMR (MeOD-d4, 400MHz) δ7.504-7.483 (m, 2H), 7.375-7.354 (m, 2H), 4.500 (s, 2H), 3.755 (s, 2H).

[0416] 13 C NMR (MeOD-d4, 400MHz) δ165.888, 137.703, 132.356, 128.891, 121.681, 42.159, 40.101.

[0417]

[0418] [Preparation Example 25]

[0419] 25-1. tert-butyl (2-((2-((tert-butoxycarbonyl)amino)benzyl)amino)-2-oxoethyl)carbamate (12-068)

[0420]

[0421] A compound was obtained by proceeding with the method of [1]. (White solid, yield 90%)

[0422] 1 H NMR (CDCl3-d, 400MHz) δ8.132 (brs, 1H), 7.786-7.766 (m, 1H), 7.306-7.302 (m, 1H), 7.238-7.186 (m, 1H), 7.063-6.997 (m, 1H), 6.745 (m, 1H), 5.017 (brs, 1H), 4.389-4.373 (m, 2H), 3.801-3.787 (m, 2H), 1.535 (s, 9H), 1.277-1.259 (m, 9H).

[0423] 25-2. 2-amino-N-(2-aminobenzyl)acetamide (12-069) DN207842

[0424]

[0425] 25-1. A compound was obtained by proceeding with the method of [2]. (Colorless sticky solid, yield 29.4%)

[0426] 1 H NMR (MeOD-d4, 400MHz) δ7.444-7.369 (m, 2H), 7.323-7.263 (m, 2H), 4.450 (s, 2H), 3.750 (m, 2H).

[0427]

[0428] [Preparation Example 26]

[0429] 26-1. tert-butyl (S)-(2-(((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)amino)-2-oxoethyl)carbamate (15-016)

[0430]

[0431] The compound was obtained by proceeding with the method of [1]. (White sticky solid, yield 64.4%)

[0432] 1 H NMR (CDCl3-d, 400MHz) δ6.889-6.832 (m, 4H), 6.509 (m, 1H), 5.064 (m, 1H), 4.305-4.250 (m, 2H), 3.974-3.926 (m, 1H), 3.818-3.803 (m, 2H), 3.724-3.662 (m, 1H), 3.577-3.511 (m, 1H), 1.437 (s,, 9H).

[0433] 26-2. (s)-N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)propionamide (15-021) DN208835

[0434]

[0435] 26-1. The compound was obtained by proceeding with the method of [2]. (White sticky solid, yield 99%)

[0436] 1 H NMR (MeOD-d4, 400MHz) δ6.881-6.815 (m, 4H), 4.326-4.254 (m, 2H), 4.000-3.942 (m, 1H), 3.726 (s, 2H), 3.595-3.580 (m, 2H).

[0437]

[0438] [Preparation Example 27]

[0439] 27-1. tert-butyl (R)-(2-(((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)amino)-2-oxoethyl)carbamate (15-017)

[0440]

[0441] A compound was obtained by proceeding with the method of [1]. (White sticky solid, yield 81%)

[0442] 1 H NMR (CDCl3-d, 400MHz) δ6.888-6.831 (m, 4H), 6.531 (m, 1H), 5.079 (m, 1H), 4.034-4.249 (m, 2H), 3.974-3.925 (m, 1H), 3.818-3.804 (m, 2H), 3.721-3.659 (m, 1H), 3.577-3.510 (m, 1H), 1.437 (s, 9H).

[0443] 27-2. (R)-2-amino-N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)acetamide (15-022) DN208836

[0444]

[0445] 27-1 The compound was obtained by proceeding with the method of [2]. (White sticky solid, yield 99%)

[0446] 1 H NMR (MeOD-d4, 400MHz) δ6.881-6.814 (m, 4H), 4.281-4.253 (m, 2H), 4.000-3.941 (m, 1H), 3.727 (s, 2H), 3.632-3.544 (m, 2H).

[0447]

[0448] [Preparation Example 28]

[0449] 28-1. tert-butyl (1-(2-phenylacetyl)pyrrolidin-3-yl)carbamate (9-027)

[0450]

[0451] [3] The compound was obtained by proceeding with the method of [3]. (Colorless sticky oil, yield 90%)

[0452] 1 H NMR (CDCl3-d6, 400MHz) δ7.313-7.225 (m, 5H), 4.587 (m, 1H), 4.208 (m, 1H), 3.741-3.693 (m, 1H), 3.677-3.654 (m, 1H), 3.633-3.616 (m, 1H), 3.603-6.464 (m, 2H), 3.387-3.301 (m, 1H), 2.200-2.072 (m, 1H), 1.937-1.733 (m, 1H), 1.435 (s, 9H).

[0453] 28-2. tert-butyl (2-oxo-2-((1-(2-phenylacetyl)pyrrolidin-3-yl)amino)ethyl)carbamate (9-030)

[0454]

[0455] 28-1. The compound was obtained by proceeding with the method of [1]. (White sticky solid, yield 71.5%)

[0456] 1 H NMR (CDCl3-d6, 400MHz) δ7.347-7.306 (m, 2H), 7.274-7.239 (m, 3H), 6.318 (brs, 1H), 5.083-5.009 (m, 1H), 4.472-4.416 (m, 1H), 3.800-3.672 (m, 3H), 3.656-3.628 (m, 2H), 3.609-3.510 (m, 2H), 3.427-3.305 (m, 1H), 2.260-2.088 (m, 1H), 1.996-1.919 (m, 1H), 1.456 (s, 9H).

[0457] 28-3. 2-amino-N-(1-(2-phenylacetyl)pyrrolidin-3-yl)acetamide (9-032) DN207346

[0458]

[0459] 28-2 The compound was obtained by proceeding with the method of [2]. (White solid, yield 68%)

[0460] 1 H NMR (DMSO-d6+ TFA, 400MHz) δ8.634-8.591 (m, 1H), 7.984 (m, 2H), 7.321-7.284 (m, 2H), 7.242-7.205 (m, 3H), 4.362-4.232 (m, 1H), 3.748-3.673 (m, 1H), 3.635-3.581 (m, 3H), 3.554-3.510 (m, 2H), 3.449-3.389 (m, 1H), 3.323-3.217 (m, 1H), 2.184-1.999 (m, 1H), 1.906-1.705 (m, 1H).

[0461]

[0462] [Preparation Example 29]

[0463] 29-1. tert-butyl (1-pivaloylpyrrolidin-3-yl)carbamate (9-026)

[0464]

[0465] [3] The compound was obtained by proceeding with the method of [3]. (Colorless sticky oil, yield 88%)

[0466] 1 H NMR (CDCl3, 400MHz) δ4.568 (brs, 1H), 4.173-4.132 (m, 1H), 3.769-3.728 (m, 1H), 3.687-3.620 (m, 3H), 2.099-2.048 (m, 1H), 1.788-1.781 (m, 1H), 1.445 (s, 9H), 1.251 (s, 9H).

[0467] 29-2. tert-butyl (2-oxo-2-((1-pivaloylpyrrolidin-3-yl)amino)ethyl)carbamate (9-031)

[0468]

[0469] 29-1 Compound was obtained by proceeding with the method of [1]. (Colorless sticky oil, yield 57.1%)

[0470] 1 H NMR (CDCl3, 400MHz) δ6.587 (brs, 1H), 5.205 (brs, 1H), 4.456-4.444 (m, 1H), 3.805-3.716 (m, 3H), 3.671-3.638 (m, 2H), 3.528-3.491 (m, 1H), 2.177-2.136 (m, 1H), 1.853-1.705 (m, 1H), 1.448 (s, 9H), 1.243 (s, 9H).

[0471] 29-3. 2-amino-N-(1-pivaloylpyrrolidin-3-yl)acetamide (9-037) DN207347

[0472]

[0473] 31-2 The compound was obtained by proceeding with the method of [2]. (Hydroscoic white solid, yield 99%)

[0474] 1 H NMR (DMSO-d6, 400MHz) δ8.588 (d, J= 6.56 Hz, 1H), 8.009 (brs, 2H), 4.247-4.237 (m, 1H), 3.744-3.365 (m, 6H), 2.088-2.051 (m, 1H), 1.911-1.774 (m, 1H), 1.164 (s, 9H).

[0475]

[0476] [Preparation Example 30]

[0477] 30-1. tert-butyl (1-(benzylcarbamoyl)pyrrolidin-3-yl)carbamate (9-044)

[0478]

[0479] A compound was obtained by proceeding with the method of [5]. (white solid, yield 96%)

[0480] 1 H NMR (CDCl3-d, 400MHz) δ7.334-7.302 (m, 4H), 7.288-7.252 (m, 1H), 4.653 (brs, 1H), 4.485-4.472 (m, 1H), 4.437-4.423 (m, 1H), 4.220 (brs, 1H), 3.637-3.597 (m, 1H), 3.497-3.396 (m, 2H), 3.235-3.199 (m, 1H), 2.211-2.127 (m, 1H), 1.904-1.841 (m, 1H), 1.442 (s, 9H).

[0481] 30-2. tert-butyl (2-((1-(benzylcarbamoyl)pyrrolidin-3-yl)amino)-2-oxoethyl)carbamate (9-050)

[0482]

[0483] 30-1. The compound was obtained by proceeding with the method of [1]. (White scitky solid, yield 51.5%)

[0484] 1 H NMR (CDCl3-d, 400MHz) δ7.332-7.274 (m, 5H), 6.472-6.455 (m, 1H), 5.143 (m, 1H), 4.547-4.455 (m, 2H), 4.430-4.416 (m, 2H), 3.812-3.694 (m, 2H), 3.644-3.602 (m, 1H), 3.464-3.428 (m, 2H), 3.298-3.263 (m, 1H), 2.238-2.151 (m, 1H), 1.967-1.892 (m, 1H), 1.445 (s, 9H).

[0485] 30-3. 3-(2-aminoacetamido)-N-benzylpyrrolidine-1-carboxamide (9-051) DN207833

[0486]

[0487] 30-2. The compound was obtained by proceeding with the method of [2]. (Pale yellow solid, yield 34.6%)

[0488] 1H NMR (CD3OD, 400 MHz) δ7.70 (d, J= 7.8 Hz, 2H), 7.57 (d, J= 7.7 Hz, 2H), 6.75 (s, 1H), 6.34 (s, 1H), 5.23 (s, 2H), 4.46 (s, 2H), 4.21-4.16 (m, 2H), 3.97-3.92 (m, 4H), 3.55-3.51 (m, 4H), 2.39-2.33 (m, 2H), 1.23 (t,J= 7.2 Hz, 3H), 0.94 (t,J= 7.5 Hz, 3H).

[0489]

[0490] [Preparation Example 31]

[0491] 31-1. tert-butyl (1-(phenethylcarbamoyl)pyrrolidin-3-yl)carbamate (10-036)

[0492]

[0493] A compound was obtained by proceeding with the method of [5]. (white solid, yield 98%)

[0494] 1 H NMR (CDCl3-d, 400MHz) δ7.329-7.292 (m, 2H), 7.242-7.189 (m, 3H), 4.634 (brs, 1H), 4.192 (m, 2H), 3.545-3.469 (m, 3H), 3.379-3.343 (m, 2H), 3.157-3.122 (m, 1H), 2.839-2.804 (m, 2H), 2.163-2.097 (m, 1H), 1.864-1.817 (m, 1H), 1.444 (s, 9H).

[0495] 31-2. tert-butyl (2-oxo-2-((1-(phenethylcarbamoyl)pyrrolidin-3-yl)amino)ethyl)carbamate (10-049)

[0496]

[0497] 31-1. A compound was obtained by proceeding with the method of [1]. (White solid, yield 63.7%)

[0498] 1 H NMR (CDCl3-d, 400MHz) δ7.315-7.296 (m, 2H), 7.248-7.788 (m, 3H), 6.403 (brs, 1H), 5.119 (brs, 1H), 4.480-4.441 (m, 1H), 4.234-4.206 (m, 1H), 3.812-3.700 (m, 2H), 3.572-3.465 (m, 3H), 3.377-3.341 (m, 2H), 3.210-3.174 (m, 1H), 2.836-2.802 (m, 2H), 2.219-2.135 (m, 1H), 1.939-1.864 (m, 1H), 1.448 (s, 9H).

[0499] 31-3. 3-(2-aminoacetamido)-N-phenethylpyrrolidine-1-carboxamide (10-053) DN207836

[0500]

[0501] 31-2. Compound was obtained by proceeding with the method of [2]. (Colorless sticky oil, yield 61.1%)

[0502] 1 H NMR (DMSO-d6, 400MHz) δ8.582 (d, J=6.6 Hz, 1H), 7.976 (m, 3H), 7.313-7.275 (m, 2H), 7.212-7.183 (m, 3H), 6.330-6.304 (m, 1H), 4.259-4.247 (m, 1H), 3.578-3.424 (m, 2H), 3.320-3.286 (m, 2H), 3.240-3.188 (m, 2H), 3.120 (dd, J= 10.6, 3.56 Hz, 1H), 2.729-2.673 (m, 2H), 2.104-2.018 (m, 1H), 1.800-1.727 (m, 1H).

[0503] 1 H NMR (DMSO-d6+ TFA, 400MHz) δ8.579 (d, J= 6.68 Hz, 1H), 7.969 (m, 3H), 7.283-7.245 (m, 2H), 7.188-7.169 (m, 3H), 4.269-4.257 (m, 1H), 3.550-3.507 (m, 2H), 3.469-3.428 (m, 1H), 3.332-3.297 (m, 2H), 3.248-3.210 (m, 2H), 3.162-3.127 (m, 1H) 2.732-2.679 (m, 2H), 2.076-2.009 (m, 1H), 1.812-1.755 (m, 1H).

[0504] 13 C NMR (DMSO-d6+ TFA, 400MHz) δ166.169, 156.932, 140.176, 128.977, 128.642, 126.312, 51.289, 49.224, 43.855, 42.160, 40.163, 36.647, 30.997.

[0505]

[0506] [Preparation Example 32]

[0507] 32-1. tert-butyl (1-(phenylcarbamoyl)pyrrolidin-3-yl)carbamate (10-037)

[0508]

[0509] A compound was obtained by proceeding with the method of [5]. (White solid, yield 99%)

[0510] 1H NMR (CDCl3-d, 400MHz) δ7409-7.389 (m, 2H), 7.306-7.287 (m, 2H), 7.051-7.014 (m, 1H), 6.150 (s, 1H), 4.705 (brs, 1H), 4.281 (brs, 1H), 3.757-3.717 (m, 1H), 3.600-3.543 (m, 2H), 3.365-3.331 (m, 1H), 2.277-2.193 (m, 1H), 1.972-1.894 (m, 1H), 1.458 (s, 9H).

[0511] 32-2. tert-butyl (2-oxo-2-((1-(phenylcarbamoyl)pyrrolidin-3-yl)amino)ethyl)carbamate (10-050)

[0512]

[0513] 32-1. The compound was obtained by proceeding with the method of [1]. (White solid, yield 78%)

[0514] 1 H NMR (CDCl3-d, 400MHz) δ7.394-7.374 (m, 2H), 7.302-7.284 (m, 2H), 7.055-7.018 (m, 1H), 6.675-6.665 (m, 1H), 6.222 (s, 1H), 5.199 (brs, 1H), 4.539-4.501 (m, 1H), 3.842-3.697 (m, 3H), 3.570-3.534 (m, 2H), 3.398-3.363 (m, 1H), 2.281-2.195 (m, 1H), 2.022-1.961 (m, 1H), 1.449 (s, 9H).

[0515] 32-3. 3-(2-aminoacetamido)-N-phenylpyrrolidine-1-carboxamide (10-054) DN207837

[0516]

[0517] 32-2 The compound was obtained by proceeding with the method of [2]. (Colorless sticky oil, yield 99%)

[0518] 1 H NMR (DMSO-d6, 400MHz) δ8.653 (d, J=6.6 Hz, 1H), 8.208 (s, 1H), 8.005 (m, 2H), 7.5206-7.5012 (m, 2H), 7.248-7.209 (m, 2H), 6.950-6.913 (m, 1H), 4.327-4.315 (m, 1H), 3.562-3.533 (m, 3H), 3.510-3.448 (m, 2H), 3.326-3.290 (m, 1H), 2.151-2.104 (m, 1H), 1.876-1.820 (m, 1H).

[0519] 1 H NMR (DMSO-d6+ TFA, 400MHz) δ8.643 (d, J=6.6 Hz, 1H), 8.200 (s, 1H), 7.992 (m, 2H), 7.517-7.498 (m, 2H), 7.238-7.198 (m, 2H), 6.940-6.904 (m, 1H), 4.329-4.316 (m, 1H), 3.625-3.475 (m, 5H), 3.332-3.296 (m, 1H), 2.145-2.098 (m, 1H), 1.864-1.821 (m, 1H).

[0520] 13 C NMR (DMSO-d6+ TFA, 400 MHz) δ166.255, 154.345, 140.860, 128.686, 122.108, 119.993, 51.668, 49.258, 44.271, 30.984.

[0521]

[0522] [Preparation Example 33]

[0523] 33-1. tert-butyl (R)-(1-(phenylcarbamoyl)pyrrolidin-3-yl)carbamate (10-038)

[0524]

[0525] A compound was obtained by proceeding with the method of [5]. (White solid, yield 99%)

[0526] 1 H NMR (CDCl3-d, 400MHz) δ7.409-7.389 (m, 2H), 7.307-7.288 (m, 2H), 7.052-7.015 (m, 1H), 6.147 (s, 1H), 4.708 (brs, 1H)., 4.290 (brs, 1H), 3.756-3.718 (m, 1H), 3.619-3.545 (m, 2H), 3.367-3.333 (m, 1H), 2.279-2.194 (m, 1H), 1.972-1.910 (m, 1H), 1.459 (s, 9H).

[0527] 33-2. tert-butyl (R)-(2-oxo-2-((1-(phenylcarbamoyl)pyrrolidin-3-yl)amino)ethyl)carbamate (10-051)

[0528]

[0529] 33-1 The compound was obtained by proceeding with the method of [1]. (White solid, yield 70%)

[0530] 1 H NMR (CDCl3-d, 400MHz) δ7.396-7.377 (m, 2H), 7.304-7.286 (m, 2H), 7.056-7.019 (m, 1H), 6.625-6.613 (m, 1H), 6.209 (brs, 1H), 5.178 (brs, 1H), 4.543-4.504 (m, 1H), 3.801-3.704 (m, 3H), 3.572-3.537 (m, 2H), 3.402-3.367 (m, 1H), 2.289-2.202 (m, 1H), 2.026-1.952 (m, 1H), 1.447 (s, 9H).

[0531] 33-3. (R)-3-(2-aminoacetamido)-N-phenylpyrrolidine-1-carboxamide (10-055) DN207838

[0532]

[0533] 33-2 The compound was obtained by proceeding with the method of [2]. (Colorless sticky oil, yield 99%)

[0534] 1 H NMR (DMSO-d6, 400MHz) δ8.669 (d. J= 6.6 Hz, 1H), 8.214 (s, 1H), 8.031 (m, 2H), 7.522-7.502 (m, 2H), 7.247-7.207 (m, 2H), 6.930 (t, J= 7.32 Hz, 1H), 4.327-4.315 (m, 1H), 3.628-3.536 (m, 3H), 3.510-3.475 (m, 2H), 3.326-3.290 (m, 1H), 2.169-2.082 (m, 1H), 1.878-1.808 (m, 1H).

[0535] 13 C NMR (DMSO-d6, 400 MHz) δ166.274, 154.338, 140.891, 128.731, 122.123, 119.968, 51.674, 49.252, 44.299, 30.999.

[0536]

[0537] [Preparation Example 34]

[0538] 34-1. tert-butyl (R)-(1-(phenethylcarbamoyl)pyrrolidin-3-yl)carbamate (10-039)

[0539]

[0540] A compound was obtained by proceeding with the method of [5]. (White solid, yield 99%)

[0541] 1H NMR (CDCl3-d, 400MHz) δ7.330-7.293 (m, 2H), 7243-7.190 (m, 3H), 5.300 (s, 1H), 4.607 (brs, 1H), 4.181 (m, 1H), 3.546-3.471 (m, 3H), 3.378-3.344 (m, 2H), 3.157-3.122 (m, 1H), 2.840-2.806 (m, 2H), 2.165-2.099 (m, 1H), 1.865-1.817 (m, 1H), 1.444 (s, 9H).

[0542] 34-2. tert-butyl (R)-(2-oxo-2-((1-(phenethylcarbamoyl)pyrrolidin-3-yl)amino)ethyl)carbamate (10-052)

[0543]

[0544] 34-1. The compound was obtained by proceeding with the method of [1]. (White solid, yield 65.1%)

[0545] 1 H NMR (CDCl3-d, 400MHz) δ7.334-7.297 (m, 2H), 7.249-7.189 (m, 3H), 6.396-6.383 (m, 1H), 5.108 (brs, 1H), 4.480-4.440 (m, 1H), 4.234-4.205 (m, 1H), 3.812-3.698 (m, 2H), 3.573-3.467 (m, 3H), 3.376-3.341 (m, 2H), 3.215-3.180 (m, 1H), 2.838-2.803 (m, 2H), 2.201-2.136 (m, 1H), 1.942-1.828 (m, 1H), 1.449 (s, 9H).

[0546] 34-3. (R)-3-(2-aminoacetamido)-N-phenethylpyrrolidine-1-carboxamide (10-056) DN207839

[0547]

[0548] 34-2 The compound was obtained by proceeding with the method of [2]. (Colorless sticky oil, yield 99%)

[0549] 1 H NMR (DMSO-d6, 400MHz) δ8.488 (d, J=6.64, 1H), 8.039 (m, 2H), 7.315-7.277 (m, 2H), 7.207-7.188 (m, 3H), 6.345-6.320 (m, 1H), .4.262-4.237 (m, 1H), 3.560-3.520 (m, 2H), 3.469-3.428 (m,1H), 3.324-3.290 (m, 2H), 3.241-3.191 (m, 2H), 3.140-3.105 (m, 1H), 2.733-2.694 (m, 2H), 2.083-2.036 (m, 1H), 1.806-1.749 (m, 1H).

[0550] 13 C NMR (DMSO-d6, 400MHz) δ166.206, 156.828, 140.284, 129.050, 128.781, 126.430, 51.265, 49.239, 43.856, 42.193, 36.771, 31.099

[0551]

[0552] [Preparation Example 35]

[0553] 35-1. tert-butyl (R)-(1-(benzylcarbamoyl)pyrrolidin-3-yl)carbamate (10-059)

[0554]

[0555] A compound was obtained by proceeding with the method of [5]. (White solid, yield 100%)

[0556] 1H NMR (CDCl3-d, 400MHz) δ7.339-7.310 (m, 4H), 7.293-7.287 (m, 1H), 4.645 (brs, 1H), 4.482-4.469 (m, 1H), 4.439-4.426 (m, 2H), 4.230 (m, 1H), 3.640-3.599 (m, 1H), 3.500-3.425 (m, 2H), 3.239-3.203 (m, 1H), 2.215-2.131 (m, 1H), 1.908-1.830 (m, 1H), 1.442 (s, 9H).

[0557] 35-2. tert-butyl (R)-(2-((1-(benzylcarbamoyl)pyrrolidin-3-yl)amino)-2-oxoethyl)carbamate (10-061)

[0558]

[0559] 35-1. Compound was obtained by proceeding with the method of [1]. (transparent sticky oil, yield 36.8%)

[0560] 1 H NMR (CDCl3-d, 400MHz) δ7.357-7.279 (m, 5H), 6.397 (brs, 1H), 5.105 (brs, 1H), 4.517-4.460 (m, 2H), 4.433-4.419 (m, 2H), 3.772-3.741 (m, 2H), 3.714-3.616 (m, 1H), 3.467-3.432 (m, 2H), 3.283-3.247 (m, 1H), 2.247-2.137 (m, 1H), 1.965-1.888 (m, 1H), 1.448 (s, 9H).

[0561] 35-3. (R)-3-(2-aminoacetamido)-N-benzylpyrrolidine-1-carboxamide (10-062) DN207834

[0562]

[0563] 35-2 Compound was obtained by proceeding with the method of [2]. (Colorless sticky oil, yield 21.3%)

[0564] 1 H NMR (DMSO-d6, 400MHz) δ8.612 (d, J= 6.68, 1H), 7.998 (m, 2H), 7.324-7.263 (m, 4H), 7.227-7.193 (m, 1H), 6.830-6.802 (m, 1H), 4.296-4.227 (m, 3H), 3.560-3.472 (m, 3H), 3.379-3.344 (m, 2H), 3.183-3.148 (m, 1H), 2.124-2.038 (m, 1H), 1.821-1.750 (m, 1H).

[0565] 1 H NMR (DMSO-d6+ TFA, 400MHz) δ8.603 (d, J= 6.64, 1H), 7.983 (m, 2H), 7.316-7.260 (m, 4H), 7.222-7.185 (m, 1H), 6.826 (m, 1H), 4.271-4.259 (m, 3H), 3.556-3.472 (m, 3H), 3.381-3.346 (m, 2H), 3.190-3.155 (m, 1H), 2.1211-2.035 (m, 1H), 1.823-1.753 (m, 1H).

[0566] 13 C NMR (DMSO-d6+ TFA, 400MHz) δ166.192, 156.897, 141.584, 128.489, 127.526, 126.834, 51.383, 49.263, 43.953, 43.642, 40.604, 31.108.

[0567]

[0568] [Preparation Example 36]

[0569] 36-1. tert-butyl (R)-(1-((2-fluorobenzyl)carbamoyl)pyrrolidin-3-yl)carbamate (12-023)

[0570]

[0571] A compound was obtained by proceeding with the method of [5]. (White solid, yield 76%)

[0572] 1 H NMR (CDCl3-d, 400MHz) δ7.417-7.375 (m, 1H), 7.238-7.220 (m, 1H), 7.123-7.082 (m, 1H), 7.056-7.007 (m, 1H), 4.597-4.568 (m, 2H), 4.481-4.466 (m, 2H), 4.213 (brs, 1H), 3.626-3.585 (m, 1H), 3.486-3.410 (m, 2H), 3.223-3.187 (m, 1H), 2.203-2.119 (m, 1H), 1.896-1.818 (m, 1H), 1.440 (s, 9H).

[0573] 36-2. (R)-3-amino-N-(2-fluorobenzyl)pyrrolidine-1-carboxamide (12-031)

[0574]

[0575] 36-1 The compound was obtained by proceeding with the method of [6].

[0576] 36-3. tert-butyl (R)-(2-((1-((2-fluorobenzyl)carbamoyl)pyrrolidin-3-yl)amino)-2-oxoethyl)carbamate (12-044)

[0577]

[0578] 36-2. Compound was obtained by proceeding with the method of [1]. (sticky white solid, yield 52.2%)

[0579] 1H NMR (CDCl3-d, 400MHz) δ7.410-7.368 (m, 1H), 7.246-7.222 (m, 1H), 7.120-7.085 (m, 1H), 7.056-7.010 (m, 1H), 6.348 (brs, 1H), 5.071 (brs, 1H), 4.626-4.598 (m, 1H), 4.493-4.460 (m, 3H), 3.081-3.688 (m, 2H), 3.644-3.602 (m, 1H), 3.454-3.419 (m, 2H), 3.265-3.229 (m, 1H), 2.236-2.150 (m, 1H), 1.952-1.875 (m, 1H), 1.439 (s, 9H).

[0580] 36-4. (R)-3-(2-aminoacetamido)-N-(2-fluorobenzyl)pyrrolidine-1-carboxamide (12-047) DN207840

[0581]

[0582] 36-3 The compound was obtained by proceeding with the method of [2]. (colorless sticky solid, yield 9.5%)

[0583] 1 H NMR (MeOD-d4, 400MHz) δ7.401-7.359 (m, 1H), 7.301-7.245 (m, 1H), 7.155-7.115 (m, 1H), 7.085-7.036 (m, 1H), 4.453-4.433 (m, 3H), 4.001 (m, 1H), 3.666-3.627 (m, 3H), 3.512-3.476 (m, 2H), 2.291-2.203 (m, 1H), 2.010-1.935 (m, 1H).

[0584] 13C NMR (MeOD-d4, 400MHz) δ165.675, 157.773, 129.045, 129.001, 128.395, 128.314, 126.895, 126.751, 123.741, 123.705, 114.664, 114.447, 50.740, 49.323, 43.364, 40.038, 37.302, 30.500.

[0585]

[0586] [Preparation Example 37]

[0587] 37-1. tert-butyl ((2S)-1-(((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)amino)-1-oxopropan-2-yl)carbamate (12-070)

[0588]

[0589] [9] The compound was obtained by proceeding with the method of [9]. (sticky white solid, yield 89%)

[0590] 1 H NMR (CDCl3-d, 400MHz) δ6.882-6.826 (m, 4H), 6.580-6.567 (m, 1H), 4.884 (brs, 1H), 4.281-4.245 (m, 2H), 4.149-4.095 (m, 1H), 3.977-3.903 (m, 1H), 3.679-3.530 (m, 2H), 1.414 (d, J= 3.88 Hz, 9H), 1.365 (d, J= 7.12 Hz, 3H).

[0591] 37-2. (2S)-2-amino-N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)propanamide (12-076) DN207843

[0592]

[0593] 37-1 The compound was obtained by proceeding with the method of

[0010] . (white sticky solid, yield 99%)

[0594] 1 H NMR (MeOD-d4, 400MHz) δ6.882-6.816 (m, 4H), 4.326-4.268 (m, 2H), 3.998-3.925 (m, 2H), 3.589-3.570 (m, 2H), 1.532-1.510 (m, 3H).

[0595] 13 C NMR (MeOD-d4, 400MHz) δ170.084, 143.142, 142.906, 142.851, 121.232, 121.139, 121.115, 116.839, 116.689, 71.770, 71.630, 65.486, 39.558, 16.233, 16.181.

[0596]

[0597] [Preparation Example 38]

[0598] 38-1. tert-butyl ((2S)-1-(((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate (12-071)

[0599]

[0600] The compound was obtained by proceeding with the method of [9]. (white sticky solid, yield 75%)

[0601] 1H NMR (CDCl3-d, 400MHz) δ7.252-7.180 (m, 5H), 6.846-6.801 (m, 4H), 6.156 (brs, 1H), 5.300 (brs, 1H), 4.996 (m, 1H), 4.325-4.095 (m, 2H), 3.863-3.815 (m, 0.5H), 3.701-3.553 (m, 1H), 3.156-3.488 (m, 1H), 3.436-3.370 (m, 0.5H), 3.116-2.997 (m, 2H), 1.393 (d, J = 5.92 Hz, 9H).

[0602] 38-2. (2S)-2-amino-N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-3-phenylpropanamide (12-077) DN207941

[0603]

[0604] 38-1. Compound was obtained by proceeding with the method of

[0010] . (white sticky solid, yield 89%)

[0605] 1 H NMR (MeOD-d4, 400MHz) δ7.339-7.237 (m, 5H), 6.867-6.817 (m, 4H), 4.220-4.053 (m, 3H), 3.850-3.544 (m, 2H), 3.437-3.368 (m, 1H), 3.210-3.074 (m, 2H).

[0606] 13C NMR (MeOD-d4, 400MHz)δ168.543, 143.127, 142.872, 142.833, 134.101, 134.075, 129.072, 129.036, 128.707, 127.526, 127.497, 121,169, 121,120, 121,096, 116,919, 116,829, 116,657, 71,640, 71,461, 65,413, 65,246, 54,371, 39,530, 39,390, 37,264.

[0607]

[0608] [제조예 39]

[0609] 39-1. tert-butyl ((2S)-4-amino-1-(((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)amino)-1,4-dioxobutan-2-yl)carbamate (12-081)

[0610]

[0611] The compound was obtained by the method of [9]. (white solid, yield 72.5%)

[0612] 1 H NMR (CDCl3-d, 400MHz)δ7.168 (brs, 1H), 6.888-6.822 (m, 4H), 6.064 (brs, 1H), 5.720 (brs, 1H), 5.366 (brs, 1H), 4.482 (m, 1H), 4.291-4.225 (m, 2H), 3.981-3.915 (m, 1H), 3.686-3.490 (m, 2H), 2.996-2.937 (m, 1H), 2.590-2.536 (m, 1H), 1.440 (d, J= 2.84 Hz, 9H).

[0613] 39-2. (2S)-2-amino-N1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)succinamide (12-086) DN207844

[0614]

[0615] 39-1 The compound was obtained by proceeding with the method of

[0010] . (white sticky solid, yield 97%)

[0616] 1 H NMR (MeOD-d4, 400MHz) δ6.892-6.815 (m, 4H), 4.315-4.255 (m, 2H), 4.239-4.205 (m, 1H), 3.994-3.928 (m, 1H), 3.653-3.604 (m, 1H), 3.569-3.511 (m, 1H), 2.926-2.870 (m, 1H), 2.838-2.770 (m, 1H).

[0617] 13 C NMR (MeOD-d4, 400MHz) δ171.789, 168.536, 143.139, 142.876, 121.217, 121.128, 116.892, 116.666, 71.682, 71.623, 65.492, 65.455, 49.934, 49.896, 39.585, 39.557, 34.794.

[0618]

[0619] [Preparation Example 40]

[0620] 40-1. tert-butyl ((2S)-1-((1-(benzylcarbamoyl)pyrrolidin-3-yl)amino)-1-oxopropan-2-yl)carbamate (12-093)

[0621]

[0622] The compound was obtained by proceeding with the method of [9]. (sticky ivory solid, yield 38%)

[0623] 1H NMR (CDCl3-d, 400MHz) δ7.333-7.283 (m, 5H), 6.515 (brs, 1H), 4.896 (brs, 1H), 4.497-4.423 (m, 4H), 4.131-4.078 (m, 1H), 3.661-3.613 (m, 1H), 3.471-3.427 (m, 2H), 3.259-3.224 (m, 1H), 2.215-2.164 (m, 1H), 1.943-1.862 (m, 1H), 1.434 (m, 9H), 1.348-1.323 (m, 3H).

[0624] 40-2. 3-((S)-2-aminopropanamido)-N-benzylpyrrolidine-1-carboxamide (13-002) DN207942

[0625]

[0626] 40-1. The compound was obtained by proceeding with the method of

[0010] . (sticky ivory solid, yield 24.1%)

[0627] 1 H NMR (MeOD-d4, 400MHz) δ7.317-7.274 (m, 4H), 7.248-7.214 (m, 1H), 4.417 (m, 1H), 4.371 (s, 2H), 3.896-3.850 (m, 1H), 3.676-3.630 (m, 1H), 3.510-3.476 (m, 2H), 3.338-3.322 (m, 1H), 2.292-2.204 (m, 1H), 2.010-1.943 (m, 1H), 1.511-1.476 (m, 3H).

[0628] 13 C NMR (MeOD-d4, 400MHz) δ169.507, 157.895, 140.195, 127.941, 126.891, 126.863, 126.482, 50.692, 50.596, 49.404, 48.785, 43.600, 43.392, 30.466, 16.269.

[0629]

[0630] [Preparation Example 41]

[0631] 41-1. tert-butyl ((2S)-1-((1-(benzylcarbamoyl)pyrrolidin-3-yl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate (12-94)

[0632]

[0633] The compound was obtained by proceeding with the method of [9]. (Colorless sticky solid, yield 37.9%)

[0634] 1 H NMR (CDCl3-d, 400MHz) δ7.347-7.275 (m, 7H), 7.224-7.173 (m, 3H), 5.808-5.732 (m, 1H), 5.029 (brs, 1H), 4.437-4.381 (m, 4H), 4.255-4.220 (m, 1H), 3.579-3.513 (m, 1H), 3.386-2.905 (m, 5H), 2.140-2.034 (m, 1H), 1.783-1.751 (m, 1H), 1.413 (d, J= 2.08 Hz, 9H).

[0635] 41-2. 3-((S)-2-amino-3-phenylpropanamido)-N-benzylpyrrolidine-1-carboxamide (13-003) DN207943

[0636]

[0637] 41-1 Compound was obtained by proceeding with the method of

[0010] . (Colorless sticky solid, yield 37.9%)

[0638] 1H NMR (MeOD-d4, 400MHz) δ7.403-7.225 (m, 10H), 4.380-4.310 (m, 3H), 4.006-3.968 (m, 1H), 3.600-3.557 (m, 1H), 3.408-3.350 (m, 1H), 3.301-3.265 (m, 1H), 3.227-3.163 (m, 1H), 3.150-3.072 (m, 2H), 2.125-2.010 (m, 1H), 1.695-1.623 (m, 1H).

[0639] 13 C NMR (MeOD-d4, 400MHz) δ167.858, 157.765, 140.162, 134.225, 129.108, 128.692, 127.934, 127.510, 126.899, 126.483, 54.249, 50.452, 49.158, 43.583, 43.137, 37.378, 30.543.

[0640]

[0641] [Preparation Example 42]

[0642] 42-1. tert-butyl (R)-(2-oxo-2-((1-(phenylcarbamoyl)pyrrolidin-3-yl)amino)ethyl)carbamate (12-097)

[0643]

[0644] [9] The compound was obtained by proceeding with the method of [9]. (Colorless sticky oil, yield 65.7%)

[0645] 1 H NMR (CDCl3-d, 400MHz) δ9.127 (s, 1H), 9.538 (s, 2H), 7.286-7.239 (m, 3H), 7.162-7.143 (m, 2H), 6.351 (m, 1H), 5.002 (brs, 1H), 4.362-4.304 (m, 3H), 3.131-3.008 (m, 2H), 1.402 (s, 9H).

[0646] 42-2. (S)-2-amino-3-phenyl-N-(pyrimidin-5-ylmethyl)propanamide (13-005) DN207944

[0647]

[0648] 42-1 Compound was obtained by proceeding with the method of

[0010] . (Colorless sticky oil, yield 13.4%)

[0649] 1 H NMR (MeOD-d4, 400MHz) δ9.087 (s, 1H), 8.620 (s, 2H), 7.316-7.299 (m, 3H), 7.212-7.188 (m, 2H), 4.459-4.421 (m, 1H), 4.344-4.306 (m, 1H), 4.069-4.031 (m, 1H), 3.147-3.077 (m, 2H).

[0650] 13 C NMR (MeOD-d4, 400MHz) δ168.282, 156.838, 156.487, 134.008, 132.219, 128.966, 128.686, 127.520, 54.416, 38.085, 37.189.

[0651]

[0652] [Preparation Example 43]

[0653] 43-1. tert-butyl (S)-(1-oxo-3-phenyl-1-((pyrazin-2-ylmethyl)amino)propan-2-yl)carbamate (12-100)

[0654]

[0655] [9] The compound was obtained by proceeding with the method of [9]. (Colorless sticky oil, yield 69.4%)

[0656] 1H NMR (CDCl3-d, 400MHz) δ8.506-8.441 (m, 3H), 7.248-7.167 (m, 5H), 6.712 (brs, 1H), 5.025-4.965 (m, 1H), 4.549-4.536 (m, 2H), 4.413-4.396 (m, 1H), 3.143-3.039 (m, 2H), 1.408 (s, 9H).

[0657] 43-2. (S)-2-amino-3-phenyl-N-(pyrazin-2-ylmethyl)propanamide (13-007) DN207946

[0658]

[0659] 43-1 Compound was obtained by proceeding with the method of

[0010] . (Colorless sticky oil, yield 9%)

[0660] 1 H NMR (MeOD-d4, 400MHz) δ8.578-8.568 (m, 1H), 8.534-8.527 (m, 1H), 8.490-8.487 (m, 1H), 7.360-7.303 (m, 3H), 7.288-7.248 (m, 2H), 4.602-4.490 (m, 2H), 4.153-4.116 (m, 1H), 3.254-3.201 (m, 1H), 3.133-3.080 (m, 1H).

[0661]

[0662] [Preparation Example 44]

[0663] 44-1. tert-butyl (S)-(1-oxo-1-((pyrimidin-5-ylmethyl)amino)propan-2-yl)carbamate (12-096)

[0664]

[0665] [9] The compound was obtained by proceeding with the method of [9]. (Colorless sticky oil, yield 77%)

[0666] 1 H NMR (CDCl3-d, 400MHz) δ9.138 (s, 1H), 8.677 (s, 2H), 6.940 (brs, 1H), 4.897 (brs, 1H), 4.538-4.396 (m, 2H), 4.191-4.156 (m, 1H), 1.421 (s, 9H), 1.388-1.370 (m, 3H).

[0667] 44-2. (S)-2-amino-N-(pyrimidin-5-ylmethyl)propanamide (13-006) DN207945

[0668]

[0669] 44-1 Compound was obtained by proceeding with the method of

[0010] . (Colorless sticky oil, yield 1.3%)

[0670] 1 H NMR (MeOD-d4, 400MHz) δ9.099 (s, 1H), 8.782 (s, 2H), 4.554-4.437 (m, 2H), 3.962 (q, J= 14.16, 7.08 Hz, 1H), 1.530 (d, J= 7.08Hz, 3H).

[0671] 13 C NMR (MeOD-d4, 400MHz) δ169.853, 156.853, 156.310, 132.651, 133.228, 38.173, 15.981.

[0672]

[0673] [Preparation Example 45]

[0674] 45-1. tert-butyl (S)-(4-amino-1,4-dioxo-1-((pyrimidin-5-ylmethyl)amino)butan-2-yl)carbamate (12-098)

[0675]

[0676] [9] A compound was obtained by proceeding with the method of [9]. (Colorless sticky oil, yield 27.4%) The crude product was used in the next step without further purification.

[0677] 45-2. (S)-2-amino-N1-(pyrimidin-5-ylmethyl)succinamide (13-009) DN207945

[0678]

[0679] 45-1 Compound was obtained by proceeding with the method of

[0010] . (Colorless sticky oil, yield 54.8%)

[0680] 1 H NMR (MeOD-d4, 400MHz) δ9.093 (s, 1H), 8.785 (s, 2H), 4.544-4.460 (m, 2H), 4.225 (q, J= 8.08, 5.04 Hz, 1H), 2.901 (dd, J= 16.96, 5.04 Hz, 1H), 2.817 (dd, J= 16.96, 8.08 Hz, 1H).

[0681]

[0682] [Preparation Example 46]

[0683] 46-1. tert-butyl (S)-(1-oxo-1-((pyrazin-2-ylmethyl)amino)propan-2-yl)carbamate (12-099)

[0684]

[0685] [9] The compound was obtained by proceeding with the method of [9]. (Colorless sticky oil, yield 31%)

[0686] 1H NMR (CDCl3-d, 400MHz) δ8.596 (s, 1H), 8.498 (s, 2H), 7.132 (brs, 1H), 4.993 (brs, 1H), 4.639-4.614 (m, 2H), 4.247 (m, 1H), 1.439 (s, 9H), 1.409-1.392 (m, 3H).

[0687] 46-2. (S)-2-amino-N-(pyrazin-2-ylmethyl)propanamide (13-013) DN207948

[0688]

[0689] 46-1 Compound was obtained by proceeding with the method of

[0010] . (Colorless sticky oil, yield 19.6%)

[0690] 1 H NMR (MeOD-d4, 400MHz) δ8.635 (s, 1H), 8.603-8.593 (m, 1H), 8.538-8.531 (m, 1H), 4.667-4.577 (m, 2H), 4.022 (q, J= 14.12, 7.08 Hz, 1H), 1.559 (d, J= 7.08 Hz, 3H).

[0691]

[0692] [Preparation Example 47]

[0693] 47-1. tert-butyl (S)-(4-amino-1,4-dioxo-1-((pyrazin-2-ylmethyl)amino)butan-2-yl)carbamate (13-001)

[0694]

[0695] [9] The compound was obtained by proceeding with the method of [9]. (White solid, yield 64.6%) The crude product was used in the next step without further purification.

[0696] 47-2. (S)-2-amino-N1-(pyrazin-2-ylmethyl)succinamide (13-014) DN207949

[0697]

[0698] 47-1 Compound was obtained by proceeding with the method of

[0010] . (Colorless sticky oil, yield 15.9%)

[0699] 1 H NMR (MeOD-d4, 400MHz) δ8.643 (s, 1H), 8.602-8.597 (m, 1H), 8.539-8.533 (m, 1H), 4.678-4.582 (m, 2H), 4.282 (q, J= 8.64, 4.64 Hz, 1H), 2.956 (dd, J 17.04, 4.64 Hz, 1H), 2.821 (dd, J= 17.04, 8.64 Hz, 1H).

[0700]

[0701] [Preparation Example 48]

[0702] 48-1. tert-butyl ((2S)-4-amino-1-((1-(benzylcarbamoyl)pyrrolidin-3-yl)amino)-1,4-dioxobutan-2-yl)carbamate (13-012)

[0703]

[0704] [9] The compound was obtained by proceeding with the method of [9]. (White solid, yield 41.4% (crude yield)) The crude product was used in the next step without further purification.

[0705] 48-2. (2S)-2-amino-N1-(1-(benzylcarbamoyl)pyrrolidin-3-yl)succinamide (13-028) DN207950

[0706]

[0707] 48-1 Compound was obtained by proceeding with the method of

[0010] . (Colorless sticky oil, yield 76%)

[0708] 1 H NMR (MeOD-d4, 400MHz) δ7.319-7.286 (m, 4H), 7.250-7.216 (m, 1H), 4.423-4.389 (m, 1H), 4.371 (s, 2H), 4.159-4.116 (m, 1H), 3.669-3.627 (m, 1H), 3.507-3.473 (m, 2H), 3.369-3.322 (m, 1H), 2.888-2.719 (m, 2H), 2.278-2.192 (m, 1H), 2.010-1.926 (m, 1H).

[0709]

[0710] [Preparation Example 49]

[0711] 49-1. tert-butyl (S)-(4-amino-1-(((5-methylpyrazin-2-yl)methyl)amino)-1,4-dioxobutan-2-yl)carbamate (13-070)

[0712]

[0713] [9] The compound was obtained by proceeding with the method of [9]. (Colorless sticky oil, yield 99%)

[0714] 1 H NMR (CDCl3-d, 400MHz) δ8.457 (s, 1H), 8.368 (s, 1H), 7.653 (brs, 1H), 6.172-6.153 (m, 1H), 6.000 (brs, 1H), 5.540 (brs, 1H), 4.639-4.500 (m, 3H), 3.696 -3.630 (m, 1H), 3.123-3.068 (m, 1H), 3.032-2.986 (m, 1H), 2.625-2.572 (m, 1H), 2.550 (s, 3H),

[0715] 49-2. (S)-2-amino-N1-((5-methylpyrazin-2-yl)methyl)succinamide (13-075) DN208406

[0716]

[0717] 49-1 Compound was obtained by proceeding with the method of

[0010] . (Colorless sticky oil, yield 4.7%)

[0718] 1 H NMR (MeOD-d4, 400MHz) δ8.503-8.497 (m, 2H), 4.626-4.534 (m, 2H), 4.262 (q, J= 8.68, 4.60 Hz, 1H), 2.938 (dd, J= 17.0, 4.60 Hz, 1H), 2.808 (dd, J= 17.0, 8.68 Hz, 1H), 2.562 (s, 3H).

[0719]

[0720] [Preparation Example 50]

[0721] 50-1. tert-butyl (S)-(3-hydroxy-1-oxo-1-((pyrazin-2-ylmethyl)amino)propan-2-yl)carbamate (13-081)

[0722]

[0723] [9] The compound was obtained by proceeding with the method of [9]. (Colorless sticky oil, yield 78%)

[0724] 1 H NMR (CDCl3-d, 400MHz) δ8.608 (s, 1H), 8.516-8.486 (m, 2H), 7.373 (brs, 1H), 5.566 (m, 1H), 4.748-4.611 (m, 2H), 4.256 (m, 1H), 4.158-4.410 (m, 1H), 3.706-3.667 (m, 1H), 3.494 (m, 1H), 1.460 (s, 9H).

[0725] 50-2. (S)-2-amino-3-hydroxy-N-(pyrazin-2-ylmethyl)propanamide (13-082) DN208407

[0726]

[0727] 50-1. Compound was obtained by proceeding with the method of

[0010] . (Colorless sticky oil, yield 13.4%)

[0728] 1 H NMR (MeOD-d4, 400MHz) δ8.661 (s, 1H), 8.603-8.593 (m, 1H), 8.542-8.535 (m, 1H), 4.652-4.643 (m, 2H), 4.050-4.024 (m, 1H), 4.005-3.966 (m, 1H), 3.934-3.890 (m, 1H).

[0729]

[0730] [Preparation Example 51]

[0731] 51-1. tert-butyl (S)-(3-methyl-1-oxo-1-((pyrazin-2-ylmethyl)amino)butan-2-yl)carbamate (13-085)

[0732]

[0733] [9] The compound was obtained by proceeding with the method of [9]. (Colorless sticky oil, yield 86%)

[0734] 1 H NMR (CDCl3-d, 400MHz) δ8.609 (S, 1h), 8.514-8.505 (m, 2H), 6.987 (brs, 1H), 5.090-5.071 (m, 1H), 4.642-4.629 (m, 2H), 4.023-3.987 (m, 1H), 2.215-2.167 (m, 1H), 1.439 (s, 9H), 0.981-0.964 (m, 3H), 0.932-0.915 (m, 3H).

[0735] 51-2. (S)-2-amino-3-methyl-N-(pyrazin-2-ylmethyl)butanamide (13-093) DN208408

[0736]

[0737] 51-1 Compound was obtained by proceeding with the method of

[0010] . (yellow sticky solid, yield 30.8%)

[0738] 1 H NMR (MeOD-d4, 400MHz) δ8.665 (s, 1H), 8.611-8.601 (m, 1H), 8.545-8.538 (m, 1H), 4.647-4.637 (m, 2H), 3.728 (d, J= 5.68 Hz, 1H), 2.272-2.188 (m, 1H), 1.089-1.057 (m, 6H).

[0739]

[0740] [Preparation Example 52]

[0741] 52-1. tert-butyl ((2S)-1-((1-(benzylcarbamoyl)pyrrolidin-3-yl)amino)-3-hydroxy-1-oxopropan-2-yl)carbamate (13-088)

[0742]

[0743] [9] The compound was obtained by proceeding with the method of [9] (white sticky solid, yield 38.2%). The crude product was used in the next step without further purification.

[0744] 52-2. 3-((S)-2-amino-3-hydroxypropanamido)-N-benzylpyrrolidine-1-carboxamide (13-094) DN208409

[0745]

[0746] 52-1 The compound was obtained by proceeding with the method of

[0010] . (White solid, yield 85%)

[0747] 1 H NMR (MeOD-d4, 400MHz) δ8.7.319-7.286 (m, 4H), 7.250-7.218 (m, 1H), 4.449-4.372 (m, 1H), 4.372 (s, 2H), 3.936-3.866 (m, 2H), 3.836-3.791 (m, 1H), 3.672-3.629 (m, 1H), 3.509-3.474 (m, 2H), 3.334-3.325 (m, 1H), 2.294-2.198 (m, 1H), 2.011-1.960 (m, 1H).

[0748]

[0749] [Preparation Example 53]

[0750] 53-1. tert-butyl ((2S)-3-hydroxy-1-oxo-1-((pyrazin-2-ylmethyl)amino)butan-2-yl)carbamate (13-090)

[0751]

[0752] The compound was obtained by proceeding with the method of [9]. (White sticky solid, yield 75%)

[0753] 1 H NMR (CDCl3-d, 400MHz) δ8.598 (s, 1H), 8.498-8.480 (m, 2H), 7.391 (m, 1H), 5.557-5.538 (m, 1H), 4.786-4.730 (m, 1H), 4.589-4.534 (m, 1H), 4.443-4.428 (m, 1H), 4.150-4.096 (m, 1H), 3.641 (m, 1H), 1.460 (s, 9H), 1.226-1.210 (m, 3H).

[0754] 53-2. (2S)-2-amino-3-hydroxy-N-(pyrazin-2-ylmethyl)butanamide (13-095) DN208410

[0755]

[0756] 53-1 The compound was obtained by proceeding with the method of

[0010] . (White sticky solid, yield 9.1%)

[0757] 1 H NMR (MeOD-d4, 400MHz) δ8.675-8.672 (m, 1H), 8.607-8.596 (m, 1H), 8.545-8.538 (m, 1H), 4.650-4.641 (m, 2H), 4.104-4.072 (m, 1H), 3.738-3.722 (m, 1H), 1.318 (d, J= 6.40 Hz, 3H).

[0758] 13 C NMR (MeOD-d4, 400MHz) δ167.498, 153.294, 144.055, 143.428, 143.159, 65.878, 59.002, 42.284, 18.844.

[0759]

[0760] [Preparation Example 54]

[0761] 54-1. tert-butyl ((2S)-4-amino-1,4-dioxo-1-((1-(pyrazin-2-yl)ethyl)amino)butan-2-yl)carbamate (13-091)

[0762]

[0763] The compound was obtained by proceeding with the method of [9]. (White sticky solid, yield 68%)

[0764] 1 ¹H NMR (CDCl3-d, 400MHz)δ8.

[0765] 54-2. (2S)-2-amino-N1-(1-(pyrazin-2-yl)ethyl)succinamide (13-097) DN208411

[0766]

[0767] 54-1 Compound was obtained by proceeding with the method of

[0010] . (White sticky solid, yield 10.5%)

[0768] 1 H NMR (MeOD-d4, 400MHz) δ8.642-8.639 (m, 1H), 8.613-8.603 (m, 1H), 8.524-8.518 (m, 1H), 5.209-5.156 (m, 1H), 4.274-4.241 (m, 1H), 2.900 (dd, J= 17.04, 4.36 Hz, 1H), 2.723 (dd, J= 17.04, 9.08 Hz, 1H), 1.563 (d, J= 7.04, 3H).

[0769]

[0770] [Preparation Example 55]

[0771] 55-1. tert-butyl ((2S)-1-((1-(benzylcarbamoyl)pyrrolidin-3-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (14-001)

[0772]

[0773] [9] The compound was obtained by proceeding with the method of [9]. (White sticky solid, yield 86%)

[0774] 1H NMR (CDCl3-d, 400MHz) δ7.356-7.276 (m, 5H), 6.339-6.322 (m, 1H), 5.015-4.995 (m, 1H), 4.532-4.421 (m, 4H), 3.869-3.787 (m, 1H), 3.665-3.611 (m, 1H), 3.464-3.430 (m, 2H), 3.270-3.236 (m, 1H), 2.216-2.102 (m, 2H), 1.945-1.899 (m, 1H), 1.435 (s, 9H), 0.960-0.889 (m, 6H).

[0775] 55-2. 3-((S)-2-amino-3-methylbutanamido)-N-benzylpyrrolidine-1-carboxamide (14-003) DN208412

[0776]

[0777] 55-1 Compound was obtained by proceeding with the method of

[0010] . (White sticky solid, yield 16.3%)

[0778] 1 H NMR (MeOD-d4, 400MHz) δ7.312-7.279 (m, 4H), 7.248-7.216 (m, 1H), 4.445-4.410 (m, 1H), 4.364 (s, 2H), 3.646-3.577 (m, 2H), 3.527-3.489 (m, 2H), 3.391-3.355 (m, 1H), 2.294-2.206 (m, 1H), 2.188-2.103 (m, 1H), 2.041-1.968 (m, 1H), 1.048-1.022 (m, 6H).

[0779] 13 C NMR (MeOD-d4, 400MHz) δ168.028, 157.841, 140.228, 127.933, 126.856, 126.459, 58.289, 50.715, 49.523, 43.547, 43.401, 30.151, 22.800, 17.421, 16.610.

[0780]

[0781]

[0782] [Preparation Example 56]

[0783] 56-1. tert-butyl ((2S)-3-hydroxy-1-oxo-1-((pyrimidin-5-ylmethyl)amino)butan-2-yl)carbamate (14-005)

[0784]

[0785] [9] The compound was obtained by proceeding with the method of [9]. (White sticky solid, yield 78%) The crude product was used in the next step without further purification.

[0786] 56-2. (2S)-2-amino-3-hydroxy-N-(pyrimidin-5-ylmethyl)butanamide (14-008) DN208413

[0787]

[0788] 56-1 Compound was obtained by proceeding with the method of

[0010] . (White sticky solid, yield 9.1%)

[0789] 1 H NMR (MeOD-d4, 400MHz) δ7-9.103 (s, 1H), 8.820 (s, 2H), 4.563-4.471 (m, 2H), 4.116-4.053 (m, 1H), 3.710-3.695 (m, 1H), 1.268 (d, J = 6.40 Hz, 3H).

[0790]

[0791] [Preparation Example 57]

[0792] 57-1. tert-butyl (S)-(3-methyl-1-oxo-1-((pyrimidin-5-ylmethyl)amino)butan-2-yl)carbamate (14-004)

[0793]

[0794] A compound was obtained by proceeding with the method of [9]. (White solid, yield 79%)

[0795] 1 H NMR (CDCl3-d, 400MHz) δ9.145 (s, 1H), 8.693 (s, 2H), 6.658 (m, 1H), 4.963 (m, 1H), 4.534-4.414 (m, 2H), 3.900-3.862 (m, 1H), 2.191-2.177 (m, 1H), 1.427 (s, 9H), 0.972-0.919 (m, 6H).

[0796] 57-2. (S)-2-amino-3-methyl-N-(pyrimidin-5-ylmethyl)butanamide (14-011) DN208414

[0797]

[0798] 57-1 Compound was obtained by proceeding with the method of

[0010] . (White sticky solid, yield 14.5%)

[0799] 1 H NMR (MeOD-d4, 400MHz) δ9.016 (s, 1H), 8.814 (s, 2H), 4.568-4.446 (m, 2H), 3.678 (d, J= 5.68 Hz, 1H), 2.241-2.158 (m, 1H), 1.059-1.025 (m, 6H).

[0800] 13 C NMR (MeOD-d4, 400MHz) δ168.388, 156.896, 156.517, 132.627, 58.432, 38.149, 30.074, 17.389, 16.473.

[0801]

[0802] [Preparation Example 58]

[0803] 58-1. tert-butyl (S)-(3-hydroxy-1-oxo-1-((pyrimidin-5-ylmethyl)amino)propan-2-yl)carbamate (14-007)

[0804]

[0805] The compound was obtained by proceeding with the method of [9]. (White sticky solid, yield 84%)

[0806] 1 H NMR (MwOD-d4, 400MHz) δ9.055 (s, 1H), 8.780 (s, 2H), 4.530-4.438 (m, 2H), 4.143-4.118 (m, 1H), 3.832-3.742 (m, 2H), 1.467 (s, 9H).

[0807] 58-2. (S)-2-amino-3-hydroxy-N-(pyrimidin-5-ylmethyl)propanamide (14-014) DN208416

[0808]

[0809] 58-1 Compound was obtained by proceeding with the method of

[0010] . (White sticky solid, yield 37.4%)

[0810] 1 H NMR (MeOD-d4, 400MHz) δ9.095 (s, 1H), 8.795 (s, 2H), 4.561-4.478 (m, 2H), 3.991-3.959 (m, 1H), 3.941-3.869 (m, 2H).

[0811] 13 C NMR (MeOD-d4, 400MHz) δ167.244, 156.793, 156.252, 132.628, 60.066, 54.802, 38.209.

[0812]

[0813] [Preparation Example 59]

[0814] 59-1. tert-butyl ((2S)-1-((1-(benzylcarbamoyl)pyrrolidin-3-yl)amino)-3-hydroxy-1-oxobutan-2-yl)carbamate (14-016)

[0815]

[0816] [9] The compound was obtained by proceeding with the method of [9]. (White sticky solid, yield 28.2% (crude yield)) The crude product was used in the next step without further purification.

[0817] 59-2. 3-((2S)-2-amino-3-hydroxybutanamido)-N-benzylpyrrolidine-1-carboxamide (14-017) DN208417

[0818]

[0819] 59-1 Compound was obtained by proceeding with the method of

[0010] . (White sticky solid, yield 24.7%)

[0820] 1 H NMR (MeOD-d4, 400MHz) δ7.321-7.287 (m, 4H), 7.252-7.209 (m, 1H), 4.448-4.423 (m, 1H), 4.372 (s, 2H), 4.041-3.958 (m, 1H), 3.674-3.601 (m, 1H), 3.565-3.548 (m, 1H), 3.522-3.449 (m, 2H), 3.385-3.376 (m, 1H), 2.298-2.212 (m, 1H), 2.011-1.949 (m, 1H), 1.309-1.239 (m, 3H).

[0821]

[0822] [Preparation Example 60]

[0823] 60-1. tert-butyl (S)-(4-amino-1,4-dioxo-1-((pyridin-2-ylmethyl)amino)butan-2-yl)carbamate (14-062)

[0824]

[0825] [9] The compound was obtained by proceeding with the method of [9]. (White solid, yield 98%)

[0826] 1 H NMR (CDCl3-d, 400MHz) δ8.530-8.518 (m, 1H), 7.709-7.631 (m, 2H), 7.197-7.167 (m, 1H), 6.156-6.136 (m, 1H), 5.905 (brs, 1H), 5.414 (brs, 1H), 4.633-4.519 (m, 2H) 3.682-3.624 (m, 1H), 3.125-3.015 (m, 2H), 2.634-2.582 (m, 1H), 1.464 (s, 9H).

[0827] 60-2. (S)-2-amino-N1-(pyridin-2-ylmethyl)succinamide (14-065) DN208566

[0828]

[0829] 60-1 Compound was obtained by proceeding with the method of

[0010] . (Colorless sticky oil, yield 99%)

[0830] 1 H NMR (MeOD-d4, 400MHz) δ8.662-8.650 (m, 1H), 8.203-8.160 (m, 1H), 7.714-7.694 (m, 1H), 7.663-7.631 (m, 1H), 4.741-4.644 (m, 2H), 4.316-4.283 (m, 1H), 3.004-2.949 (m, 1H), 2.915-2.853 (m, 1H).

[0831]

[0832] [Preparation Example 61]

[0833] 61-1. tert-butyl (S)-(4-amino-1,4-dioxo-1-((pyridin-3-ylmethyl)amino)butan-2-yl)carbamate (14-067)

[0834]

[0835] [9] The compound was obtained by proceeding with the method of [9]. (Colorless sticky oil, yield 67.6%)

[0836] 1 H NMR (MeOD-d4, 400MHz) δ8.509 (s, 1H), 8.435-8.424 (m, 1H), 7.827-7.808 (m, 1H), 7.420-7.388 (m, 1H), 4.503-4.407 (m, 3H), 2.735-2.622 (m, 2H), 1.456 (s, 9H).

[0837] 61-2. (S)-2-amino-N1-(pyridin-3-ylmethyl)succinamide (14-080)

[0838]

[0839] 61-1 Compound was obtained by proceeding with the method of

[0010] . (Colorless sticky oil, yield 99%)

[0840] 1 H NMR (MeOD-d4, 400MHz) δ8.909-8.806 (m, 2H), 8.322-8.302 (m, 1H), 7.925 (m, 1H), 4.677-4.564 (m, 2H), 4.265-4.233 (m, 1H), 2.961-2.829 (m, 2H).

[0841]

[0842] [Preparation Example 62]

[0843] 62-1. tert-butyl ((S)-4-amino-1,4-dioxo-1-(((R)-1-(phenylcarbamoyl)pyrrolidin-3-yl)amino)butan-2-yl)carbamate (15-010)

[0844]

[0845] [9] The compound was obtained by proceeding with the method of [9]. (White solid, yield 99% (crude))

[0846] 1 H NMR (CDCl3-d, 400MHz) δ7.413-7.393 (m, 2H), 7.304-7.284 (m, 2H), 7.047-7.000 (m, 1H), 6.205 (m, 1H), 6.044-6.003 (m, 1H), 5.868-5.838 (m, 1H), 5.463-5.436 (m, 1H), 4.495-453 (m, 1H), 3.627-3.553 (m, 3H), 3.413-3.342 (m, 1H), 2.952-2.903 (m, 1H), 2.595-2.521 (m, 1H), 2.275-2.223 (m, 1H), 2.011-1.968 (m, 1H), 1.446 (,s, 9H).

[0847] 62-2. (S)-2-amino-N1-((R)-1-(phenylcarbamoyl)pyrrolidin-3-yl)succinamide (15-014) DN208833

[0848]

[0849] 62-1 The compound was obtained by proceeding with the method of

[0010] . (White sticky solid, yield 8.6%)

[0850] 1H NMR (MeOD-d4, 400MHz) δ7.429-7.409 (m, 2H), 7.302-7.262 (m, 2H), 7.063-7.026 (m, 1H), 4.476-4.453 (m, 1H), 4.182-4.140 (m, 1H), 3.763-3.721 (m, 1H), 3.633-3.598 (m, 2H), 3.501-3.408 (m, 1H), 2.910-2.744 (m, 2H), 2.339-2.233 (m, 1H), 2.076-1.985 (m, 1H).

[0851]

[0852] [Preparation Example 63]

[0853] 63-1. tert-butyl ((2S,3R)-3-hydroxy-1-oxo-1-(((R)-1-(phenylcarbamoyl)pyrrolidin-3-yl)amino)butan-2-yl)carbamate (15-011)

[0854]

[0855] The compound was obtained by proceeding with the method of [9]. (White sticky solid, yield 46.3%)

[0856] 1 H NMR (CDCl3-d, 400MHz) δ7.042-7.381 (m, 2H), 7.310-7.288 (m, 2H), 7.057-7.018 (m, 1H), 6.998 (m, 1H), 6.138 (s, 1H), 5.485 (m, 1H), 4.533-4.492 (m, 1H), 4.418-4.379 (m, 1H), 4.001-3.958 (m, 1H), 3.787-3.734 (m, 1H), 3.602-3.561 (m, 2H), 3.406-3.316 (m, 1H), 2.299-2.230 (m, 1H), 2.011-1.913 (m, 1H), 1.601 (s, 9H), 1.199-1.183 (m, 3H).

[0857] 63-2. (R)-3-((2S,3R)-2-amino-3-hydroxybutanamido)-N-phenylpyrrolidine-1-carboxamide (15-015) DN208834

[0858]

[0859] 63-1 The compound was obtained by proceeding with the method of

[0010] . (White sticky solid, yield 99%)

[0860] 1 H NMR (MeOD-d4, 400MHz) δ7.425-7.403 (m, 2H), 7.300-7.260 (m, 2H), 7.062-7.025 (m, 1H), 4.482-4.447 (m, 1H), 4.049-3.975 (m, 1H), 3.769-3.712 (m, 1H), 3.646-3.583 (m, 3H), 3.510-3.461 (m, 1H), 2.341-2.253 (m, 1H), 2.094-1.958 (m, 1H), 1.314-1.272 (m, 3H).

[0861]

[0862] [Preparation Example 64]

[0863] 64-1. tert-butyl 2-((pyrazin-2-ylmethyl)carbamoyl)pyrrolidine-1-carboxylate (13-055)

[0864]

[0865] A compound was obtained by proceeding with the method of

[0011] . (Colorless sticky oil, yield 86%)

[0866] 1H NMR (CDCl3-d, 400MHz) δ8.597 (s, 1H), 8.497 (m, 2H), 7.735 (brs, 0.5H), 7.042 (brs, 0.5H), 4.626 (m, 2H), 4.387-4.295 (m, 1H), 3.495-3.364 (m, 2H), 2.383-2.312 (m, 1H), 2.208-2.175 (m, 1H), 1.901 (m, 2H), 1.384 (s, 9H).

[0867] 64-2. N-(pyrazin-2-ylmethyl)pyrrolidine-2-carboxamide (13-058) DN208404

[0868]

[0869] 64-1 Compound was obtained by proceeding with the method of

[0012] . (Colorless sticky oil, yield 6.1%)

[0870] 1 H NMR (MeOD-d4, 400MHz) δ8.645 (s, 1H), 8.607-8.597 (m, 1H), 8.543-8.537 (m, 1H), 4.649-4.640 (m, 2H), 4.373-4.336 (m, 1H), 3.444-3.382 (m, 1H), 3.365-3.321 (m, 1H), 2.519-2.421 (m, 1H), 2.159-2.048 (m, 3H).

[0871]

[0872] [Preparation Example 65]

[0873] 65-1. tert-butyl 2-((1-(benzylcarbamoyl)pyrrolidin-3-yl)carbamoyl)pyrrolidine-1-carboxylate (13-071)

[0874]

[0875] A compound was obtained by proceeding with the method of

[0011] . (Colorless sticky oil, yield 79%) The crude product was used in the next step without further purification.

[0876] 65-2. N-benzyl-3-(pyrrolidine-2-carboxamido)pyrrolidine-1-carboxamide (13-072) DN208405

[0877]

[0878] 65-1 Compound was obtained by proceeding with the method of

[0012] . (Colorless sticky oil, yield 9.3%)

[0879] 1 H NMR (MeOD-d4, 400MHz) δ7.319-7.285 (m, 4H), 7.250-7.207 (m, 1H), 4.442-4.419 (m, 1H), 4.370 (s, 2H), 4.229-4.183 (m, 1H), 3.676-3.621 (m, 1H), 3.512-3.478 (m, 2H), 3.427-3.392 (m, 1H), 3.368-3.309 (m, 2H), 2.457-2.367 (m, 1H), 2.295-2.225 (m, 1H), 2.107-1.949 (m, 4H).

[0880]

[0881] [Preparation Example 66]

[0882] 66-1. tert-butyl (S)-2-((pyrimidin-5-ylmethyl)carbamoyl)pyrrolidine-1-carboxylate (14-006)

[0883]

[0884] A compound was obtained by proceeding with the method of

[0011] (white sticky oil, yield 69.6%). The crude product was used in the next step without further purification.

[0885] 66-2. (S)-N-(pyrimidin-5-ylmethyl)pyrrolidine-2-carboxamide (14-012) DN208415

[0886]

[0887] 66-1 Compound was obtained by proceeding with the method of

[0012] . (colorless sticky oil, yield 10.5%)

[0888] 1 H NMR (MeOD-d4, 400MHz) δ9.107 (s, 1H), 8.796 (s, 2H), 4.570-4.454 (m, 2H), 4.319-4.281 (m, 1H), 3.453-3.406 (m, 1H), 3.389-3.361 (m, 1H), 2.492-2.411 (m, 1H), 2.117-2.1.992 (m, 3H).

[0889]

[0890] * 13 C NMR (MeOD-d4, 400MHz) δ168.539, 156.912, 156.370, 132.536, 59.806, 45.874, 38.359, 29.360, 23.647.

[0891]

[0892] [Preparation Example 67]

[0893] 67-1. tert-butyl (S)-2-(((5-methylpyrazin-2-yl)methyl)carbamoyl)pyrrolidine-1-carboxylate (014-055)

[0894]

[0895] A compound was obtained by proceeding with the method of

[0011] . (Yellow sticky oil, yield 79%)

[0896] 1H NMR (CDCl3-d, 400MHz) δ8.458 (s, 1H), 8.365 (s, 1H), 7.718 (m, 0.5H), 6.976 (m, 0.5H), 4.562 (m, 2H), 4.378-4.281 (m, 1H), 3.490-3.351 (m, 2H), 2.554 (s, 3H), 2.373 (m, 1H), 2.176 (m, 1H), 1.894 (m, 2H), 1.425 (s, 9H).

[0897] 67-2. (S)-N-((5-methylpyrazin-2-yl)methyl)pyrrolidine-2-carboxamide (14-057) DN208564

[0898]

[0899] 67-1 Compound was obtained by proceeding with the method of

[0012] . (Colorless sticky oil, yield 82%)

[0900] 1 H NMR (MeOD-d4, 400MHz) δ8.509-8.499 (m, 2H), 4.634-4.550 (m, 2H), 4.351-4.314 (m, 1H), 3.457-3.358 (m, 2H), 2.564 (s, 3H), 2.491-2.436 (m, 1H), 2.119-2.046 (m, 3H).

[0901] 13 C NMR (MeOD-d4, 400MHz) δ168.525, 152.668, 149.934, 143.801, 141.955, 59.810, 45.928, 42.069, 29.473, 23.639, 19.498.

[0902]

[0903] [Preparation Example 68]

[0904] 68-1. tert-butyl (S)-2-((pyridin-2-ylmethyl)carbamoyl)pyrrolidine-1-carboxylate (14-061)

[0905]

[0906] A compound was obtained by proceeding with the method of

[0011] . (White solid yield 85%)

[0907] 1 H NMR (CDCl3-d, 400MHz) δ8.546 (m, 1H), 7.673 (m, 1H), 7.285-7.212 (m, 2H), 4.674-4.543 (m, 2H), 4.416-4.300 (m, 1H), 3.534-3.395 (m, 2H), 2.368-2.333 (m, 2H), 1.926-1.913 (m, 2H), 1.375 (s, 9H).

[0908] 68-2. (S)-N-(pyridin-2-ylmethyl)pyrrolidine-2-carboxamide (14-064) DN208565

[0909]

[0910] 68-1 Compound was obtained by proceeding with the method of

[0012] . (Colorless sticky oil, yield 9.3%)

[0911] 1 H NMR (MeOD-d4, 400MHz) δ8.626-8.614 (m, 1H), 8.098-8.055 (m, 1H), 7.617-7.597 (m, 1H), 7.572-7.540 (m, 1H), 4.716-4.600 (m, 2H), 4.387-4.349 (m, 1H), 3.433-7.354 (m, 2H), 2.528-2.451 (m, 1H), 2.168-2.057 (m, 3H).

[0912]

[0913] [Preparation Example 69]

[0914] 69-1. tert-butyl (S)-2-((pyridin-3-ylmethyl)carbamoyl)pyrrolidine-1-carboxylate (14-066)

[0915]

[0916] A compound was obtained by proceeding with the method of

[0011] . (Colorless sticky oil, yield 99%)

[0917] 1 H NMR (CDCl3-d, 400MHz) δ8.525 (m, 2H), 7.632-7.615 (m, 1H), 7.454 (brs, 0.5H), 7.266 (m, 1H), 6.476 (brs, 0.5H), 4.617-4.340 (m, 3H), 3.431-3.342 (m, 2H), 2.411-2.178 (m, 1H), 1.908 (m, 3H), 1.440 (s. 9H).

[0918] 69-2. (S)-N-(pyridin-3-ylmethyl)pyrrolidine-2-carboxamide (14-079) DN208599

[0919]

[0920] 69-1 Compound was obtained by proceeding with the method of

[0012] . (Colorless sticky oil, yield 11.1%)

[0921] 1 H NMR (MeOD-d4, 400MHz) δ8.803-8.753 (m, 2H), 8.426-8.406 (m, 1H), 7.959-7.928 (m, 1H), 4.699-4.582 (m, 2H), 4.382-4.345 (m, 1H), 3.453-3.349 (m, 2H), 2.506-2.441 (m, 1H), 2.119-2.022 (m, 3H).

[0922]

[0923] [Preparation Example 70]

[0924] 70-1. tert-butyl (S)-2-(((R)-1-(phenylcarbamoyl)pyrrolidin-3-yl)carbamoyl)pyrrolidine-1-carboxylate (15-005)

[0925]

[0926] The compound was obtained by proceeding with the method of

[0011] . (White solid, yield 73.3%)

[0927] 1 H NMR (CDCl3-d, 400MHz) δ7.404-7.384 (m, 2H), 7.305-7.286 (m, 2H), 7.049-7.013 (m, 1H), 6.128 (m, 1H), 4.493 (m, 1H), 4.259 (m, 1H), 3.766 (m, 1H), 3.589-3.558 (m, 2H), 3.406-3.320 (m, 3H), 2.397 (m, 1H), 2.275-2.238 (m, 1H), 2.049-1.885 (m, 4H), 1.603 (m, 1H), 1.448 (s, 9H).

[0928] 70-2. (R)-N-phenyl-3-((S)-pyrrolidine-2-carboxamido)pyrrolidine-1-carboxamide (15-009) DN208832

[0929]

[0930] 70-1 The compound was obtained by proceeding with the method of

[0012] . (White sticky solid, yield 99%)

[0931] 1H NMR (MeOD-d4, 400MHz) δ7.428-7.407 (m, 2H), 7.301-7.262 (m, 2H), 7.063-7.026 (m, 1H), 4.481-4.470 (m, 1H), 4.258-4.212 (m, 1H), 3.772-3.729 (m, 1H), 3.636-3.301 (m, 2H), 3.501-3.404 (m, 2H), 3.378-3.360 (m, 1H), 2.476-2.396 (m, 1H), 2.320-2.253 (m, 1H), 2.118-1.994 (m, 4H).

[0932]

[0933] [Experimental Example 1]

[0934] In order to determine whether the compounds of the present invention prepared according to the above manufacturing example exhibit characteristics suitable for application as cancer treatments, compounds 9-003, 9-041, 10-044, 9-004, 10-062, and 9-051 were tested according to the criteria in Tables 2 and 3 below.

[0935]

[0936] Classification Detailed Indicator Acceptance Criteria Minimum Acceptance Optimal Level Pharmacological Property Off-target number maxTc > 0.5 nonenone -logE > 10 nonenone migration in Mesenchymal type cancer cells (MI 50, μM) 10.0 Sphere Forming ability (SFI 50, μM) 0.7 0.1 Cancer metastasis inhibitory activity in xenograft model (μg / kg) ~ tens ~ several Cytotoxicity in Mesenchymal stem cells (μM) > 10.0 > 500 Pharmacokinetic property t 1 / 2 2 hr > 2 hr C max(ng / ml*hr) at 10 mpk PO 100 > 100 AUC (ng / ml*hr) at 10 mpk PO 200 > 200 Vz (L / Kg) 3 > 3 BA (%F) 30 > 50

[0937]

[0938] 구분세부지표허용기준최소허용최적수준In vitro ADMEMetabolic stability(Hu / Ra / Mo; % remaining during 30 min)90>90Plasma stability(Hu / Ra; %remaining)30 min90>90120 min70>70CYP inhibition (A2, C9, C19, D6, A4; % of control activity, IC50 μM)10>10GIT-PAMPA(insolubility)negativenegativeGIT-PAMPA(permeability; P 10-6cm / sec)1.5>1.5Plasma protein binding (Hu / Ra; % bound)50>90Tox. & Safety PharmacologyhERG inhibition (patch clamp IC50, μM)10>10AMES test (TA98 / TA100)negativenegativeRodent 2 weeks toxicity study (mg / kg)200> 500

[0939]

[0940] The test results of the compounds of the invention 9-003, 9-041, 10-044, 9-004, 10-062, and 9-051 are shown in Tables 4 to 6 below. Compounds ABA [2-amino-N-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-acetamide] and APC [3-(2-amino-acetylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester], known to inhibit cancer metastasis and have preventive and therapeutic effects against cancer, were used as a control group.

[0941] Similarity ensemble approach (SEA) analysis, migration assay, and sphere forming assay were performed on metastatic triple-negative breast cancer cell line MDA-MB-231 LM1 and colorectal cancer cell line HCT116, and the results are shown in Table 4. In addition, to evaluate side effects on normal cells, a cytotoxic effect assay was performed on three adult stem cell lines LA-196, LT-17, and LT-18, normal lung cell line BEAS-2B, and triple-negative breast cancer cell line MDA-MB-231, and the results are shown in Table 5.

[0942]

[0943] 화합물SEA analysisoff target numberMigration assayMI50 (μM)Sphere forming assaySFI50 (μM)MDA-MB-231 LM1MDA-MB-231 LM1ABA00.07 ± 0.01 μM0.157 ± 0.67 μMAPC00.95 ± 0.1 μM0.578 ± 0.22 μM9-00300.13 ± 0.01 μM0.078 ± 0.043 μM9-00400.15 ± 0.02 μM0.035 ± 0.007 μM9-04100.14 ± 0.01 μM0.099 ± 0.015 μM10-04400.08 ± 0.01 μM0.283 ± 0.19 μM9-05100.08 ± 0.008 μM0.058 ± 0.033 μM10-06200.06 ± 0.01 μM0.069 ± 0.038 μM

[0944]

[0945] 화합물Cytotoxic effect assayGI50 (μM)LA-196Lt-17LT-18BEAS2BMDA-MB-231 LM1ABA397.4±0.61376.7±0.74410.4±1.00499.2±1.43379.7±0.84APC637.9±7.8375±19.9411.9±10614.8±55.7416.9±69.99-003347.1±16339.1±45.8478.3±21.9551.4±14.1327.6±74.69-004363.2±8.4317.1±26.1341.9±4.7575.1±78.8310.4±52.29-041218.1±110.984±5.4167.5±0.2244.4±38.573.7±1.110-044201.7±0.7203.3±1.1201.3±0.887.39±0.7188.9±1.09-05117.3, 16.215.3, 17.116.4, 17.516.7, 8.60.6, 0.410-062486.9±0.92479.4±1.43480.6±0.90516.2±0.70510.2±0.71

[0946]

[0947] The results of the in vitro ADME test are shown in Tables 6 and 7 below.

[0948]

[0949] in vitroADME compoundMicrosomal stability(% remaining during 30min)PAMPAPe(10-6cm / sec)Plasma stability (% remaining)HumanHumanRatRatHumanRatMouse30 min120 min30 min120 minABA77.875.77783.29 (High)98.190.899.595.19-00394.8>100>10027.16 (high)>100>100>10098.39-00474.869.388.269.83 (high)94.372.8>10091.89-041>100>100>10026.55 (high)>100>10097.296.39-05179.482.092.70.003 (Low)91.572.395.690.110-06277.173.671.256.53 (High)94.694.7>100>100

[0950]

[0951] in vitro ADME compoundCYP450 inhibition assay (% of control activity)Plasma protein binding assay (% bound)CYP1A2CYP2C9CYP2C19CYP2D6CYP3A4HumanRatABA47.073.379.884.579.820.543.69-00389.5>10094.899.888.2>99.916.59-0046 7>10091.1>10087.621.339.19-04188.788.097.287.921.019.610.6 9-05155.970.375.679.674.910-062>100>100>100>100>10023.939.2

[0952]

[0953] The PK test results are shown in Tables 8 and 9 below.

[0954]

[0955] in vitro PK compound IV (1 mpk) T1 / 2 (hr) AUCall (hr*ng / ml) Cl_obs (ml / min / kg) ABAND(Actual) 0.16 (MEDI) ND(Actual) 81.33 (MEDI) ND(Actual) 1268 6.1±287 4.10(MEDI) 9-00 40.21±0.19 45.45±12.15 223 97.7±5 263.99-04 10.1±0.01 10.5±1.41 46 2.7±17 9.29-051 ND(Actual) 0.16(Medicilon) ND(Actual) 81.33(Medicilon) ND(Actual) 1268 6.1(Medicilon)

[0956]

[0957] in vitro PK Compound PO (10 mpk) Cmax (ng / ml) Tmax (hr) AUCall (hr*ng / ml) T1 / 2 (hr) BA (%) ABA 14.5±2.6(actual) 4 14.25(MEDI) 0.3±0.1(actual) 0.33(MEDI) 34.6±13.3(actual) 25 5.3±35.16(MEDI) 15.7±20.1(actual) 0.4±0.21(MEDI) ND(actual) 31.16(MEDI) 9 - 0 0 4 3 8 1.15±6 4.6 20.25±0.01 6 8.2±15.5 30.2 2±0.07 36.73±3.69 -041 26.8±4.4 0.3±0.04 1.0±4.1 2.4±0.5 399 -051 14.5±2.6 (Actual) 41 4.25 (Medicilon) 0.3±0.1 (Actual) 0.33 (Medicilon) 34.6±13.3 (Actual) 25 5.3 (Medicilon) 15.7±20.1 (Actual) 0.4 (Medicilon) ND (Actual) 31.16 (Medicilon)

[0958]

[0959] It was confirmed that the compounds of the present invention have inhibitory activity against cancer cells and can therefore be utilized as cancer treatment substances. In particular, 9-004, 9-041, 10-044, 10-062, etc. exhibited excellent lethal effects against cancer cells while also demonstrating safety against normal cells and all passed in vitro ADME.

[0960]

[0961] [Experimental Example 2]

[0962] The inhibitory effect of the compounds of the present invention prepared according to the above preparation example on cancer was confirmed. In cancer cells treated with the compounds, changes in the expression levels of CDH1, VIM, FOXA1, FBXO31, and LARP7, which are markers of epithelial mesenchymal transition (EMT) associated with cancer cell metastasis, were confirmed (Fig. 1), and cancer stem cell characteristics were verified through CD44 / CD24 population analysis (Fig. 2). In addition, the protein expression patterns of the EMT markers CDH1 and VIM were confirmed by immune fluorescence (Fig. 3), changes in cell motility were re-verified through a wound healing assay (Fig. 4), and changes in chemoresistance to the anticancer drug cisplatin were verified (Fig. 5).

[0963] Among the compounds of the present invention, 9-004 showed the most excellent effect in inducing changes in the expression of EMT-related factors and exhibited particularly excellent effects for use as a cancer treatment substance, such as changing the cancer stem cell population or overcoming drug resistance to cisplatin.

[0964]

[0965] Although the present invention has been described in detail above only with respect to the manufacturing and experimental examples, it is obvious to those skilled in the art that various modifications and variations are possible within the scope of the technical spirit of the invention, and it is natural that such modifications and variations fall within the scope of the appended claims.

Claims

1. A compound of the following chemical formula 1 or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In the above formula, n is 0 or 1, and m is an integer from 0 to 2, and X is hydrogen or alkyl, and Ring A is a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl, and R1 is or And, R2 and R3 are each independently selected from hydrogen or the following substituent group I, and R2 are identical or different when m is 2, each independently selected from hydrogen or the following substituent group I, or fused together with the carbon bonded thereto, a substituted or unsubstituted C 3-8 Forming a carbocycle group or a substituted or unsubstituted 3 to 8-membered heterocycle group, The above substituent group I is -OH, substituted or unsubstituted C 1-10 Alkyl groups, substituted or unsubstituted C 2-10 Alkenyl group, substituted or non-substituted C 3-20 Carbocycle group, substituted or non-substituted C 3-20 Cycloalkyl group, substituted or unsubstituted C 6-30 Aryl group, substituted or unsubstituted 3 to 30-membered heterocyclic group, substituted or unsubstituted C 1-10 Alkoxy group, substituted or non-substituted C 2-10 Alkenyloxy group, substituted or unsubstituted C 3-10 Cycloalkyloxy group, substituted or unsubstituted C 6-30 Aryloxy group, substituted or unsubstituted 3 to 30-membered heterocyclooxy group, substituted or unsubstituted C 1-10 Alkyl carbonyl group, substituted or unsubstituted C 2-10 Alkenyl carbonyl group, substituted or unsubstituted C 3-10 Cycloalkylcarbonyl group, substituted or unsubstituted C 6-30 Aryl carbonyl group, substituted or unsubstituted 3 to 30-membered heterocyclic carbonyl group, substituted or unsubstituted C 1-10 Alkylthio groups, substituted or unsubstituted C 2-10 Alkenylthio group, substituted or non-substituted C 3-10 Cycloalkylthio groups, substituted or unsubstituted C 6-30 Arylthio group, substituted or unsubstituted 3 to 30-membered heterocyclic thio group, aldehyde group, carboxyl group, halogen group, C 1-10 It consists of a haloalkyl group, a hydroxyl group, a substituted or unsubstituted amino group, an imine group, a cyano group, a nitro group, an amide group, a thiol group, a sulfonyl group, a sulfino group, and a phosphate group.

2. In Claim 1, A compound in which the compound of Formula 1 is represented by any one of the following Formulas 1-1-1 to 1-1-4, Formula 1-2-1, and Formula 1-2-2, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1-1-1] [Chemical Formula 1-1-2] [Chemical Formula 1-1-3] [Chemical Formula 1-1-4] [Chemical Formula 1-2-1] [Chemical Formula 1-2-2] In the above formula, A 1a To A 1c Each is independently carbon or nitrogen, and A 1d To A 1f Each is independently carbon, nitrogen, or oxygen, and A 1g and A 1h Each is independently carbon, nitrogen, or oxygen, and A 1i is carbon or nitrogen, and m, X, R2 and R3 are as defined in Paragraph 1.

3. In Claim 1, A compound of Formula 1 or a pharmaceutically acceptable salt thereof, wherein X is a hydrogen or methyl group.

4. In Claim 1, R3 is hydrogen, , , , , or A compound of Formula 1 or a pharmaceutically acceptable salt thereof that is.

5. In Claim 1, Ring A is , , , , , , , , , , , or And, m is an integer from 0 to 2, and A compound of Formula 1 or a pharmaceutically acceptable salt thereof, wherein R2 is selected from the substituent group I.

6. In Claim 1, Ring A is , , , , , , , , , , , , , , , , , , , , or And, R2 is hydrogen, , , , , , or A compound of Formula 1 or a pharmaceutically acceptable salt thereof that is.

7. In Claim 1, Compounds selected from the group consisting of the compounds in the table below or pharmaceutically acceptable salts thereof: .

8. A composition for the prevention or treatment of cancer comprising, as an active ingredient, a compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.

9. In Claim 8, A composition for the prevention or treatment of cancer, wherein the above compound or a pharmaceutically acceptable salt thereof binds to MBD2 at the MBD2-p66α interaction site within the Mi-2 / NuRD chromatin remodeling complex and inhibits interaction with p66α.

10. In claim 8, A composition for the prevention or treatment of cancer, wherein the cancer is at least one selected from the group consisting of breast cancer, colorectal cancer, stomach cancer, liver cancer, lung cancer, kidney cancer, pancreatic cancer, head and neck squamous cell carcinoma, esophageal cancer, ovarian cancer, cervical cancer, endometrial cancer, lymphoma, mesothelioma, melanoma, sarcoma, osteosarcoma, liposarcoma, thyroid cancer, uterine cancer, and blood cancer.

11. A method for preventing or treating cancer comprising the step of administering to a subject a pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof.

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