Novel tubulin polymerization inhibitor, preparation method therefor, and pharmaceutical composition for treating cancer containing same as active ingredient

Abstract

The present invention relates to a novel tubulin polymerization inhibitor, a preparation method therefor, and a pharmaceutical composition for treating cancer containing same as an active ingredient. A novel tubulin polymerization inhibitor compound or a pharmaceutically acceptable salt thereof according to the present invention exhibits a high inhibitory ability against various cancer cell lines, thereby being able to be effectively used as a pharmaceutical composition for preventing or treating cancer or a health functional food composition for preventing or alleviating cancer.

Description

Novel tubulin polymerization inhibitor, method for manufacturing the same, and pharmaceutical composition for cancer treatment having the same as an active ingredient

[0001] The present invention relates to a novel tubulin polymerization inhibitor, a method for manufacturing the same, and a pharmaceutical composition for treating cancer having the same as an active ingredient.

[0002] Microtubules are highly dynamic structures composed of α- and β-tubulin heterodimers. They are known to play a crucial role in various cellular processes, including cell migration, intracellular transport, and mitosis. Directly targeting microtubules with chemotherapy agents such as paclitaxel and vinca alkaloids has proven highly effective in cancer treatment and has become a cornerstone of cancer therapy. However, the clinical application of microtubule-targeting agents (MTAs) often results in undesirable effects such as neurotoxicity, myelosuppression, and the development of drug resistance. Therefore, there is a need to develop novel MTAs with differentiated mechanisms of action (MOA) capable of reducing systemic toxicity and overcoming drug resistance.

[0003] A recent approach to developing novel MTAs is the design of synergistic dual-target inhibitors. Active efforts have been made to modify MTAs to confer additional inhibitory capabilities on kinases, histone deacetylases, estrogen receptors, or immune-related targets. The only successful example in this field is tirbanibulin (KX-01), which was approved by the U.S. Food and Drug Administration in 2020 under the brand name Klisyri® as a treatment for actinic keratosis. Tirvanibulin exhibits a dual mechanism of action (MOA) that combines microtubule-disrupting activity with Src inhibition; specifically, it binds to the colchicine binding site of β-tubulin to induce microtubule destabilization, whereas its Src inhibitory capability arises from binding to the peptide substrate site of Src, rather than the ATP binding site where typical kinase inhibitors usually bind. Unfortunately, tirvanibulin did not meet the efficacy endpoint in a Phase 2 trial as an anticancer agent for patients with bone metastatic castration-resistant prostate cancer (NCT01074138). Given its dual mechanism of action and low toxicity demonstrated in preclinical and clinical studies, it is considered valuable to develop a new MTA to expand the cancer treatment range of tirvanibulin by enhancing its efficacy through the synthesis of analogs.

[0004] As prior research regarding derivatives of tirvanibulin, the Ye and Chen group have conducted studies on the N-ethyl morpholine portion of tirvanibulin, including changing the carbon chain length and replacing N-ethyl morpholine with N-ethyl-piperazinyl amide. Additionally, WO 2011 / 129936 A2 disclosed derivatives of tirvanibulin for cancer treatment.

[0005] Accordingly, the inventors developed a novel tubulin polymerization inhibitor compound that is a derivative of tirvanibulin and has significantly superior anticancer activity, thereby completing the present invention.

[0006] One objective of the present invention is to provide a tubulin polymerization inhibitory compound of a novel structure having anticancer activity.

[0007] Another objective of the present invention is to provide a method for preparing the tubulin polymerization inhibitory compound.

[0008] Another objective of the present invention is to provide a pharmaceutical composition for the prevention or treatment of cancer containing the tubulin polymerization inhibitor compound having anticancer activity as an active ingredient.

[0009] In order to achieve the above objective,

[0010] According to one aspect, the present invention provides a compound represented by the following chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0011] [Chemical Formula 1]

[0012]

[0013] In the above chemical formula 1,

[0014] X is N or O and;

[0015] Y is N or CR 5 and, here R 5 is H, OH, halogen, or C 1-10 It is alkyl;

[0016] R 1 It is H, halogen, or C 1-10 It is alkyl;

[0017] R 2 is H, C 1-10 Alkyl, C 1-10 It is an alkylsulfonyl or substituted carbonyl, provided that when X is O, it is none, and

[0018] Here, the substituted carbonyl is a 3-6-membered cycloalkyl, unsubstituted, or substituted C 1-10 Substituted with an alkyl, or an unsubstituted or substituted 6-10 aryl, and

[0019] The above substituted C 1-10The alkyl group is a 3-6-membered cycloalkyl, hydroxyl, unsubstituted, or hydroxyl-substituted C 1-10 Alkoxy, 6-10 aryl-C 1-10 Alkoxy, carboxyl, -OC(=O)N(C 1-10 Alkyl)-C 1-10 Alkyl-NH(C 1-10 alkyl) and -NHR 6 Substituted with 1 to 3 substituents selected from, where R 6 H, C 1-10 Alkyl, C 1-10 Alkyl carbonyl, C 1-10 It is an alkyloxycarbonyl or a 6-10 aryl carbonyl, and

[0020] The above-mentioned substituted 6-10 aryl group is substituted with a hydroxyl or amino group;

[0021] R 3 is a halogen, C 1-10 alkyl, or C 1-10 It is an alkoxy;

[0022] R 4a to R 4b are all hydrogen, or R 4a to R 4b One of them is C 1-10 It is alkyl and the remainder is hydrogen, or R 4a and R 4b They are bonded to the same carbon, forming a 3-6 member cycloalkyl group together with the carbon atom to which they are bonded;

[0023] n is an integer of 1 or 2.

[0024] According to another aspect of the present invention, a pharmaceutical composition for the prevention or treatment of cancer is provided, comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0025] According to another aspect of the present invention, a health functional food composition for the prevention or improvement of cancer is provided, comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0026] Furthermore, the present invention provides a method for preventing or treating cancer, comprising the step of administering the above pharmaceutical composition in a therapeutically effective amount to a subject in need thereof.

[0027] In addition, the present invention provides a method for preventing or treating cancer comprising the step of administering a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof in a therapeutically effective amount to a subject in need.

[0028] Furthermore, the present invention provides the use of a compound represented by the above formula 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicine for the prevention or treatment of cancer.

[0029] The novel tubulin polymerization inhibitory compound according to the present invention or the pharmaceutically acceptable salt thereof exhibits high inhibitory ability against various cancer cell lines, so it can be usefully used as a pharmaceutical composition for the prevention or treatment of cancer or as a health functional food composition for the prevention or improvement of cancer.

[0030] FIGS. 1a and 1b are photographs of α-tubulin stained after treatment with the control group and the compound prepared in Example 22 or Example 23, and FIG. 1c is a graph quantifying the intensity of the photographs in FIGS. 1a and 1b. FIG. 1d is a photograph of α-tubulin stained after treatment with the control group, the comparative group, and the compound prepared in Examples 45 and 54, and FIG. 1e is a graph quantifying the intensity of the photograph in FIG. 1d.

[0031] Figures 2a and 2b show the cell cycle after treatment with the control group and the compound prepared in Example 22 or Example 23, and Figure 2c shows the cell ratio by cell cycle. Figures 2d and 2e show the cell cycle after treatment with the control group, the comparative group, and the compounds prepared in Examples 45 and 54 on different cells.

[0032] Figure 3a is a figure analyzing the Src inhibitory effect of the compound prepared in Example 22 via Western blot, and Figure 3b is a figure analyzing the apoptotic effect of the compound prepared in Example 22 or Example 23 via Western blot. Figure 3c is a figure analyzing the Src inhibitory effect of the compounds prepared in Examples 45 and 54 via Western blot.

[0033] Figures 4a and 5a are graphs showing the tumor size of a tumor-implanted mouse model after treatment with the control group and the compound prepared in Example 22 or Example 23, and Figures 4b and 5b are graphs showing the weight of a tumor-implanted mouse model after treatment with the control group and the compound prepared in Example 22 or Example 23.

[0034] The present invention will be described in detail below.

[0035] Embodiments of the present invention may be modified in various different forms, and the scope of the present invention is not limited to the embodiments described below. Furthermore, embodiments of the present invention are provided to more fully explain the present invention to those skilled in the art.

[0036] Furthermore, throughout the specification, the term "comprising" a component means that, unless specifically stated otherwise, it does not exclude other components but rather may include additional components.

[0037] A compound according to the present invention is provided according to the first to seventh aspects.

[0038] First side:

[0039] In the first embodiment of the present invention,

[0040] The compound according to the present invention may be a compound represented by the following chemical formula 1.

[0041] [Chemical Formula 1]

[0042]

[0043] In the above chemical formula 1,

[0044] X is N or O and;

[0045] Y is N or CR 5 and, here CR 5 is H, OH, halogen, or C 1-10 It is alkyl;

[0046] R 1 It is H, halogen, or C 1-10 It is alkyl;

[0047] R 2 is H, C 1-10 Alkyl, C 1-10 It is an alkylsulfonyl or substituted carbonyl, provided that when X is O, it is none, and

[0048] Here, the substituted carbonyl is a 3-6-membered cycloalkyl, unsubstituted, or substituted C 1-10 Substituted with an alkyl or unsubstituted or substituted 6-10 aryl group, and

[0049] The above substituted C 1-10 The alkyl group is a 3-6-membered cycloalkyl, hydroxyl, unsubstituted, or hydroxyl-substituted C 1-10 Alkoxy, 6-10 aryl-C 1-10 Alkoxy, carboxyl, -OC(=O)N(C 1-10 Alkyl)-C 1-10 Alkyl-NH(C 1-10 alkyl) and -NHR 6 Substituted with 1, 2, or 3 substituents selected as, where R 6 H, C 1-10 Alkyl, C 1-10 Alkyl carbonyl, C 1-10 It is an alkyloxycarbonyl or a 6-10 aryl carbonyl, and

[0050] The above-mentioned substituted 6-10 aryl group is substituted with a hydroxyl or amino group;

[0051] R 3 is a halogen, C 1-10 alkyl, or C 1-10 It is an alkoxy;

[0052] R 4ato R 4b are all hydrogen, or R 4a to R 4b One of them is C 1-10 It is alkyl and the remainder is hydrogen, or R 4a and R 4b They are bonded to the same carbon, forming a 3-6 member cycloalkyl group together with the carbon atom to which they are bonded;

[0053] n is an integer of 1 or 2.

[0054] The second embodiment is in the first embodiment,

[0055] The above R 1 It is H, halogen, or C 1-6 It is alkyl;

[0056] The above R 2 is H, C 1-6 Alkyl, C 1-6 It is an alkylsulfonyl, or a substituted carbonyl, and

[0057] Here, the substituted carbonyl is a 3-4-membered cycloalkyl, unsubstituted, or substituted C 1-6 Substituted with an alkyl or substituted phenyl,

[0058] The above substituted C 1-6 The alkyl group is cyclopropyl, hydroxyl, unsubstituted, or hydroxyl-substituted C 1-6 Alkoxy, Phenyl-C 1-6 Alkoxy, carboxyl, -OC(=O)N(C 1-6 Alkyl)-C 1-6 Alkyl-NH(C 1-6 alkyl) and -NHR 6 Substituted with 1, 2, or 3 substituents selected from, where R 6 H, C 1-6 Alkyl, C 1-6 Alkyl carbonyl, C 1-6 It is alkyloxycarbonyl or phenylcarbonyl, wherein the substituted phenyl is substituted with a hydroxyl or amino;

[0059] R 3 is a halogen, C 1-6 alkyl, or C1-6 Alkoxy is,

[0060] R 4a to R 4b are all hydrogen, or R 4a to R 4b One of them is C 1-6 It is alkyl and the remainder is hydrogen, or R 4a and R 4b It may be bonded to the same carbon and together form a 3-5-membered cycloalkyl group with the carbon atom to which they are bonded.

[0061] The third embodiment is in the first embodiment,

[0062] The above R 1 It is H, halogen, or C 1-3 It is alkyl;

[0063] The above R 2 is H, C 1-3 Alkyl, C 1-3 It is an alkylsulfonyl or substituted carbonyl, and

[0064] Here, the substituted carbonyl is a 3-4-membered cycloalkyl, unsubstituted, or substituted C 1-3 Substituted with an alkyl or substituted phenyl,

[0065] The above substituted C 1-3 The alkyl group is cyclopropyl, hydroxyl, unsubstituted, or hydroxyl-substituted C 1-3 Alkoxy, Phenyl-C 1-3 Alkoxy, carboxyl, -OC(=O)N(C 1-3 Alkyl)-C 1-3 Alkyl-NH(C 1-3 alkyl), and -NHR 6 Substituted with 1, 2, or 3 substituents selected from, where R 6 H, C 1-6 Alkyl, C 1-6 Alkyl carbonyl, C 1-6 It is alkyloxycarbonyl or phenylcarbonyl, wherein the substituted phenyl is substituted with a hydroxyl or amino;

[0066] R 3 is a halogen, C1-6 alkyl, or C 1-6 It is an alkoxy,

[0067] R 4a to R 4b are all hydrogen, or R 4a to R 4b One of them is C 1-6 It is alkyl and the remainder is hydrogen, or R 4a and R 4b It may be bonded to the same carbon and together form a 3-5-membered cycloalkyl group with the carbon atom to which they are bonded.

[0068] The fourth embodiment is in the first embodiment,

[0069] R 1 is H, F, or methyl;

[0070] R 2 is H, methyl, methylsulfonyl, ethylsulfonyl, or a substituted carbonyl, provided that when X is O, it is nothing, and

[0071] Here, the substituted carbonyl is a 3-4-membered cycloalkyl, methyl, substituted C 1-3 Substituted with alkyl, or hydroxyl or amino-substituted phenyl, and

[0072] The above substituted C 1-3 Alkyl groups are cyclopropyl, hydroxyl, C 1-3 Alkoxy, hydroxyl-substituted C 1-3 Substituted with 1 to 3 substituents selected from alkoxy, amino, methylamino, t-butoxycarbonylamino, acetylamino, phenylcarbonylamino, benzyloxy, carboxyl, hydroxy or amino substituted phenyl, and methyl(methylaminoethyl)aminocarbonyloxy;

[0073] R 3 is a halogen, C 1-6 alkyl, or C 1-6 It is an alkoxy;

[0074] R 4a and R 4b are all hydrogen, or R 4a is hydrogen and R4b is C 1-6 It is alkyl, or R 4a and R 4b They may form a ternary cycloalkyl group together with the carbon atoms to which they are substituted.

[0075] The fifth embodiment is in the first embodiment,

[0076] X can be N.

[0077] Second side:

[0078] In the first embodiment, the above chemical formula 1 is defined as follows.

[0079] X is O and;

[0080] Y is N and;

[0081] R 1 is H;

[0082] R 2 is nothing;

[0083] R 3 is a halogen, C 1-10 alkyl, or C 1-10 It is an alkoxy;

[0084] n can be an integer of 1.

[0085] The second embodiment is in the first embodiment, R 3 is a halogen, C 1-6 alkyl, or C 1-6 It can be an alkoxy.

[0086] The third embodiment is in the first embodiment, R 3 is a halogen, C 1-3 alkyl, or C 1-3 It can be an alkoxy.

[0087] The fourth embodiment is, in the first embodiment, R 3 It can be F, methyl, or methoxy.

[0088] The fifth embodiment is, in each of the prior embodiments,

[0089] X is O and;

[0090] Y is N and;

[0091] R 1 is H;

[0092] R 2 is nothing;

[0093] R 3 is a halogen or C 1-10 It is alkyl;

[0094] n can be an integer of 2.

[0095] The sixth embodiment is in the fifth embodiment, R 3 is a halogen or C 1-6 It can be an alkyl.

[0096] The seventh embodiment is in the fifth embodiment, R 3 is a halogen or C 1-3 It can be an alkyl.

[0097] The eighth embodiment is in the fifth embodiment, R 3 It can be F or methyl.

[0098] Third Aspect:

[0099] In the first embodiment, the above chemical formula 1 is defined as follows.

[0100] X is O and;

[0101] Y is N and;

[0102] R 1 It is a halogen;

[0103] R 2 is nothing;

[0104] R 3 is a halogen or C 1-10 It is alkyl;

[0105] n can be an integer of 1 or 2.

[0106] The second embodiment is in the first embodiment, R 3 is a halogen or C 1-6 It can be an alkyl.

[0107] The third embodiment is in the first embodiment, R 3is a halogen or C 1-3 It can be an alkyl.

[0108] The fourth embodiment is, in the first embodiment, R 3 It can be F or methyl.

[0109] Fourth side:

[0110] In the first embodiment, the compound is represented by the following chemical formula 1-1, and

[0111] [Chemical Formula 1-1]

[0112]

[0113] In the above chemical formula 1-1,

[0114] X is N and;

[0115] Y is N or CR 5 and, here CR 5 is H, hydroxyl, halogen, or C 1-10 It is alkyl;

[0116] R 1 It is H, halogen, or C 1-10 It is alkyl;

[0117] R 2 is H, C 1-10 Alkyl, C 1-10 It is an alkylsulfonyl or substituted carbonyl, and

[0118] Here, the substituted carbonyl is a 3-6-membered cycloalkyl, unsubstituted, or substituted C 1-10 Substituted with an alkyl, or an unsubstituted or substituted 6-10 aryl, and

[0119] The above substituted C 1-10 The alkyl group is a 3-6-membered cycloalkyl, hydroxyl, unsubstituted, or hydroxyl-substituted C 1-10 Alkoxy, 6-10 aryl-C 1-10 Alkoxy, carboxyl, -OC(=O)N(C 1-10 Alkyl)-C 1-10 Alkyl-NH(C 1-10 alkyl) and -NHR 6 It is substituted with a substituent selected as, where R 6H, C 1-10 Alkyl, C 1-10 Alkyl carbonyl, C 1-10 It is an alkyloxycarbonyl or a 6-10 aryl carbonyl, and

[0120] The above-mentioned substituted 6-10 aryl group is substituted with a hydroxyl or amino group;

[0121] R 3 is a halogen, C 1-10 alkyl, or C 1-10 It is an alkoxy;

[0122] R 4a to R 4b are all hydrogen, or R 4a to R 4b One of them is C 1-10 It is alkyl and the remainder is hydrogen, or R 4a and R 4b is bonded to the same carbon and together forms a 3-6 member cycloalkyl with the carbon atom to which they are bonded;

[0123] n can be an integer of 1.

[0124] In another embodiment,

[0125] C 1-10 Alkyl is C 1-6 alkyl or C 1-3 It can be an alkyl,

[0126] C 1-10 Alkoxy is C 1-6 Alkoxy or C 1-3 It can be an alkoxy,

[0127] The 6-10 aryl group can be phenyl, and

[0128] Halogens can be F or Cl, and

[0129] The 3-6-membered cycloalkyl can be a 3-5-membered cycloalkyl, a 3-4-membered cycloalkyl, or a 3-membered cycloalkyl.

[0130] Fifth Aspect:

[0131] Chemical formula 1 of the first aspect and chemical formula 1-1 of the fourth aspect are defined as follows.

[0132] X is N and;

[0133] Y is N and;

[0134] R 1 halogen or C 1-10 It is alkyl;

[0135] R 2 is H, C 1-10 Alkyl, C 1-10 It is an alkylsulfonyl, or a substituted carbonyl, and

[0136] Here, the substituted carbonyl is a 3-6-membered cycloalkyl, unsubstituted, or substituted C 1-10 Substituted with an alkyl, or an unsubstituted or substituted 6-10 aryl, and

[0137] The above substituted C 1-10 The alkyl group is a 3-6-membered cycloalkyl, hydroxyl, unsubstituted, or hydroxyl-substituted C 1-10 Alkoxy, 6-10 aryl-C 1-10 Alkoxy, carboxyl, -OC(=O)N(C 1-10 Alkyl)-C 1-10 Alkyl-NH(C 1-10 alkyl) and -NHR 6 Substituted with 1 to 3 substituents selected from, where R 6 H, C 1-10 Alkyl, C 1-10 Alkyl carbonyl, C 1-10 It is an alkyloxycarbonyl or a 6-10 aryl carbonyl, and

[0138] The above-mentioned substituted 6-10 aryl group is substituted with a hydroxyl or amino group;

[0139] R 3 is a halogen or C 1-10 It is alkyl;

[0140] R 4a to R 4b are all hydrogen, or R 4a to R 4b One of them is C 1-10 It is alkyl and the remainder is hydrogen, or R 4a and R 4bThey are bonded to the same carbon, forming a 3-6 member cycloalkyl group together with the carbon atom to which they are bonded;

[0141] n can be an integer of 1.

[0142] The second embodiment is in the first embodiment,

[0143] R 1 is a halogen and R 3 It can be a halogen.

[0144] The third embodiment is

[0145] In each of the prior embodiments, R 1 is a halogen and R 3 is C 1-10 It can be an alkyl.

[0146] The fourth embodiment is

[0147] In each of the prior embodiments, R 1 C 1-10 It is alkyl and R 3 It can be a halogen.

[0148] In each of the prior embodiments, the fifth embodiment is R 1 C 1-10 It is alkyl and R 3 is C 1-10 It can be an alkyl.

[0149] The sixth embodiment is, in each of the prior embodiments,

[0150] R 1 halogen or C 1-6 It is alkyl;

[0151] R 2 is H, C 1-6 Alkyl, C 1-6 It is an alkylsulfonyl or substituted carbonyl, and

[0152] Here, the substituted carbonyl is a 3-4-membered cycloalkyl, unsubstituted, or substituted C 1-6 Substituted with an alkyl or substituted phenyl,

[0153] The above substituted C 1-6The alkyl group is cyclopropyl, hydroxyl, unsubstituted, or hydroxyl-substituted C 1-6 Alkoxy, Phenyl-C 1-6 Alkoxy, carboxyl, -OC(=O)N(C 1-6 Alkyl)-C 1-6 Alkyl-NH(C 1-6 alkyl) and -NHR 6 Substituted with a substituent selected from, where R 6 H, C 1-6 Alkyl, C 1-6 Alkyl carbonyl, C 1-6 It is alkyloxycarbonyl or phenylcarbonyl, wherein the substituted phenyl is substituted with a hydroxyl or amino;

[0154] The seventh embodiment is, in each of the prior embodiments,

[0155] R 1 halogen or C 1-3 It is alkyl;

[0156] R 2 is H, C 1-3 Alkyl, C 1-3 It is an alkylsulfonyl or substituted carbonyl, and

[0157] Here, the substituted carbonyl is a 3-4-membered cycloalkyl, unsubstituted, or substituted C 1-3 Substituted with an alkyl or substituted phenyl,

[0158] The above substituted C 1-3 The alkyl group is cyclopropyl, hydroxyl, unsubstituted, or hydroxyl-substituted C 1-3 Alkoxy, Phenyl-C 1-3 Alkoxy, carboxyl, -OC(=O)N(C 1-3 Alkyl)-C 1-3 Alkyl-NH(C 1-3 alkyl) and -NHR 6 Substituted with a substituent selected from, where R 6 H, C 1-6 Alkyl, C 1-6 Alkyl carbonyl, C 1-6 It is alkyloxycarbonyl or phenylcarbonyl, wherein the substituted phenyl is substituted with a hydroxyl or amino;

[0159] R 3 is a halogen or C 1-3 It can be an alkyl.

[0160] The eighth embodiment is, in each of the prior embodiments,

[0161] R 1 is F or methyl;

[0162] R 3 It can be F or methyl.

[0163] Sixth Aspect:

[0164] In the first or fourth aspect, the following embodiments may be provided.

[0165] In the first embodiment, the formula 1 or formula 1-1 is defined as follows.

[0166] X is N and;

[0167] Y is CR 5 and, here R 5 is H, hydroxyl, halogen, or C 1-10 It is alkyl;

[0168] R 1 It is a halogen;

[0169] R 2 is substituted C 1-10 It is an alkyl-substituted carbonyl, and

[0170] The above substituted C 1-10 Alkyl groups are amino, hydroxyl, unsubstituted, or hydroxyl-substituted C 1-10 Alkoxy or -OC(=O)N(C 1-10 Alkyl)-C 1-10 Alkyl-NH(C 1-10 Substituted with alkyl;

[0171] R 3 is a halogen;

[0172] R 4a and R 4b It is all hydrogen;

[0173] n can be an integer of 1.

[0174] The second embodiment is in the first embodiment,

[0175] C 1-10 Alkyl is C 1-6 alkyl or C 1-3 It is alkyl, and C 1-10 Alkoxy is C 1-6 Alkoxy or C 1-3 It can be an alkoxy.

[0176] The third embodiment is in the second embodiment,

[0177] R 1 is F.

[0178] Seventh Aspect:

[0179] In the first embodiment, the above chemical formula 1 is defined as follows.

[0180] X is N or O and;

[0181] Y is N or CR 5 and, here R 5 is H, hydroxyl, F, or methyl;

[0182] R 1 is H, F, or methyl;

[0183] R 2 is H, methyl, methylsulfonyl, ethylsulfonyl, or a substituted carbonyl, provided that when X is O, it is nothing, and

[0184] Here, the substituted carbonyl is a 3-4-membered cycloalkyl, methyl, substituted C 1-3 Substituted with alkyl, or hydroxyl or amino-substituted phenyl, and

[0185] The above substituted C 1-3 Alkyl groups are cyclopropyl, hydroxyl, C 1-3 Alkoxy, hydroxyl-substituted C 1-3 Substituted with 1 to 3 substituents selected from alkoxy, amino, methylamino, t-butoxycarbonylamino, acetylamino, phenylcarbonylamino, benzyloxy, carboxyl, hydroxy or amino substituted phenyl, and methyl(methylaminoethyl)aminocarbonyloxy;

[0186] R 3 is a halogen, C 1-6 alkyl, or C 1-6 It is an alkoxy;

[0187] R 4a and R 4b are all hydrogen, or R 4a is hydrogen and R 4b is C 1-6 It is alkyl, or R 4a and R 4b They together form a ternary cycloalkyl group with the carbon atoms to which they are substituted;

[0188] n can be an integer of 1 or 2.

[0189] The compound represented by the above chemical formula I may be any one selected from the group of compounds below.

[0190] <1> N-benzyl-2-(5-(3-methyl-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)acetamide;

[0191] <2> N-benzyl-2-(5-(2-methyl-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)acetamide;

[0192] <3> N-benzyl-2-(5-(3-methoxy-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)acetamide;

[0193] <4> N-benzyl-2-(5-(2-fluoro-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)acetamide;

[0194] <5> N-benzyl-2-(5-(3-fluoro-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)acetamide;

[0195] <6> N-benzyl-2-(5-(2,6-dimethyl-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)acetamide;

[0196] <7> N-benzyl-2-(5-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)acetamide;

[0197] <8> N-benzyl-2-(5-(2,3-dimethyl-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)acetamide;

[0198] <9> N-benzyl-2-(5-(2,5-dimethyl-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)acetamide;

[0199] <10> N-benzyl-2-(5-(3-fluoro-2-methyl-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)acetamide;

[0200] <11> 2-(5-(2,5-dimethyl-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0201] <12> 2-(5-(2,3-dimethyl-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0202] <13> N-(4-fluorobenzyl)-2-(5-(3-methyl-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)acetamide;

[0203] <14> N-(4-fluorobenzyl)-2-(5-(2-methyl-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)acetamide;

[0204] <15> 2-(5-(2-fluoro-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0205] <16> 2-(5-(2-fluoro-4-(2-(piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0206] <17> 2-(5-(2-fluoro-4-(2-(4-methylpiperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0207] <18> 2-(5-(4-(2-(4-acetylpiperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0208] <19> 2-(5-(4-(2-(4-(cyclopropanecarbonyl)piperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0209] <20> 2-(5-(4-(2-(4-(cyclobutanecarbonyl)piperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0210] <21> 2-(5-(4-(2-(4-(2-cyclopropylacetyl)piperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0211] <22> 2-(5-(2-fluoro-4-(2-(4-(2-hydroxyacetyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0212] <23> 2-(5-(2-fluoro-4-(2-(4-glycylpiperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0213] <24> (R)-2-(5-(2-fluoro-4-(2-(4-(2-hydroxypropanoyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0214] <25> (S)-2-(5-(2-fluoro-4-(2-(4-(2-hydroxypropanoyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0215] <26> 2-(5-(2-fluoro-4-(2-(4-(2-methoxyacetyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0216] <27> (R)-2-(5-(2-fluoro-4-(2-(4-(2-methoxypropanoyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0217] <28> (S)-2-(5-(2-fluoro-4-(2-(4-(2-methoxypropanoyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0218] <29> 2-(5-(2-fluoro-4-(2-(4-(2-methoxy-2-methylpropanoyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0219] <30> 2-(5-(2-fluoro-4-(2-(4-(3-hydroxypropanoyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0220] <31> 2-(5-(2-fluoro-4-(2-(4-(methylglycyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0221] <32> 2-(5-(4-(2-(4-(D-alanyl)piperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0222] <33> 2-(5-(4-(2-(4-(L-alanyl)piperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0223] <34> 2-(5-(4-(2-(4-(3-aminopropanoyl)piperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0224] <35> N-(4-fluorobenzyl)-2-(5-(2-methyl-4-(2-(piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)acetamide;

[0225] <36> N-(4-fluorobenzyl)-2-(5-(4-(2-(4-(2-hydroxyacetyl)piperazine-1-yl)ethoxy)-2-methylphenyl)pyridine-2-yl)acetamide;

[0226] <37> N-(4-fluorobenzyl)-2-(5-(4-(2-(4-glycylpiperazine-1-yl)ethoxy)-2-methylphenyl)pyridine-2-yl)acetamide;

[0227] <38> 2-(5-(2-fluoro-4-(2-(piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-methylbenzyl)acetamide;

[0228] <39> 2-(5-(2-fluoro-4-(2-(4-(2-hydroxyacetyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-methylbenzyl)acetamide;

[0229] <40> 2-(5-(2-fluoro-4-(2-(4-glycylpiperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-methylbenzyl)acetamide;

[0230] <41> 2-(5-(2-methyl-4-(2-(piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-methylbenzyl)acetamide;

[0231] <42> 2-(5-(4-(2-(4-(2-hydroxyacetyl)piperazine-1-yl)ethoxy)-2-methylphenyl)pyridine-2-yl)-N-(4-methylbenzyl)acetamide;

[0232] <43> 2-(5-(2-fluoro-4-(2-(4-glycylpiperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-methylbenzyl)acetamide;

[0233] <44> 2-(5-(2-fluoro-4-(2-(1-glycylpiperidin-4-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0234] <45> 2-(5-(2-fluoro-4-(2-(1-(2-hydroxyacetyl)piperidine-4-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0235] <46> 2-(5-(4-(2-(4-(2-aminoacetyl)piperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-chlorobenzyl)acetamide;

[0236] <47> N-(4-chlorobenzyl)-2-(5-(2-fluoro-4-(2-(4-(2-hydroxyacetyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)acetamide;

[0237] <48> 2-(5-(2-fluoro-4-(2-(4-(methylsulfonyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0238] <49> 2-(5-(4-(2-(4-(ethylsulfonyl)piperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0239] <50> tert-butyl (2-(4-(2-(3-fluoro-4-(6-(2-((4-fluorobenzyl)amino)-2-oxoethyl)pyridine-3-yl)phenoxy)ethyl)piperazine-1-yl)-2-oxoethyl)carbamate

[0240] <51> 2-(5-(4-(2-(4-(2-acetamidoacetyl)piperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0241] <52> N-(2-(4-(2-(3-fluoro-4-(6-(2-((4-fluorobenzyl)amino)-2-oxoethyl)pyridine-3-yl)phenoxy)ethyl)piperazine-1-yl)-2-oxoethyl)benzamide;

[0242] <53> 2-(5-(2-fluoro-4-(2-(4-(3-methoxypropanoyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0243] <54> 2-(5-(4-(2-(4-(2-ethoxyacetyl)piperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0244] <55> 2-(5-(4-(2-(4-(4-(benzyloxy)butanoyl)piperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0245] <56> 4-(4-(2-(3-fluoro-4-(6-(2-((4-fluorobenzyl)amino)-2-oxoethyl)pyridine-3-yl)phenoxy)ethyl)piperazine-1-yl)-4-oxobutanoic acid;

[0246] <57> 2-(5-(2-fluoro-4-(2-(4-(2-isopropoxyacetyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0247] <58> 2-(5-(2-fluoro-4-(2-(1-(2-methoxyacetyl)piperazine-4-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0248] <59> 2-(5-(4-(2-(1-(2-ethoxyacetyl)piperidine-4-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0249] <60> 2-(5-(2-fluoro-4-(2-(1-(2-isopropoxyacetyl)piperidine-4-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0250] <61> 2-(5-(2-fluoro-4-(2-(4-(2-(3-hydroxypropoxy)acetyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0251] <62> 2-(5-(2-fluoro-4-(2-(4-(2-propoxyacetyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0252] <63> 2-(5-(2-fluoro-4-(2-(4-(2-(2-hydroxyethoxy)acetyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0253] <64> 2-(5-(2-fluoro-4-(2-(4-(3-hydroxybenzoyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0254] <65> 2-(5-(4-(2-(4-(3-aminobenzoyl)piperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0255] <66> 2-(5-(2-fluoro-4-(2-(4-(4-hydroxybenzoyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0256] <67> 2-(5-(4-(2-(4-(4-aminobenzoyl)piperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0257] <68> 2-(5-(2-fluoro-4-(2-(1-(3-hydroxypropanoyl)piperidine-4-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0258] <69> 2-(5-(2-fluoro-4-(2-(1-(2-propoxyacetyl)piperidine-4-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0259] <70> 2-(5-(2-fluoro-4-(2-(1-(2-(2-hydroxyethoxy)acetyl)piperidine-4-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0260] <71> 2-(4-(2-(3-fluoro-4-(6-(2-((4-fluorobenzyl)amino)-2-oxoethyl)pyridine-3-yl)phenoxy)ethyl)piperazine-1-yl)-2-oxoethylmethyl(2-(methylamino)ethyl)carbamate;

[0261] <72> 2-(4-(2-(3-fluoro-4-(6-(2-((4-fluorobenzyl)amino)-2-oxoethyl)pyridine-3-yl)phenoxy)ethyl)piperidine-1-yl)-2-oxoethylmethyl(2-(methylamino)ethyl)carbamate;

[0262] <73> (R)-2-(5-(4-(2-(4-(2-ethoxyacetyl)-3-methylpiperazine-1-yl)ethoxy)-2-fluorobenzyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0263] <74> (S)-2-(5-(4-(2-(4-(2-ethoxyacetyl)-3-methylpiperazine-1-yl)ethoxy)-2-fluoromethylpiperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0264] <75> (S)-2-(5-(4-(2-(4-(2-ethoxyacetyl)-2-methylpiperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0265] <76> (R)-2-(5-(4-(2-(4-(2-ethoxyacetyl)-2-methylpiperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0266] <77> 2-(5-(4-(2-(4-(2-ethoxyacetyl)piperazine-1-yl)ethoxy)-2-methylphenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0267] <78> 2-(5-(4-(2-(4-(2-ethoxyacetyl)piperazine-1-yl)ethoxy)-2-methylphenyl)pyridine-2-yl)-N-(4-methylbenzyl)acetamide;

[0268] <79> 2-(5-(4-(2-(4-(2-ethoxyacetyl)piperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-methylbenzyl)acetamide;

[0269] <80> N-(4-fluorobenzyl)-2-(5-(4-(2-(4-(2-hydroxyacetyl)piperazine-1-yl)ethoxy)-2-methylphenyl)pyridine-2-yl)acetamide;

[0270] <81> 2-(5-(4-(2-(4-(2-hydroxyacetyl)piperazine-1-yl)ethoxy)-2-methylphenyl)pyridine-2-yl)-N-(4-methylbenzyl)acetamide;

[0271] <82> 2-(5-(2-fluoro-4-(2-(4-(2-hydroxyacetyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-methylbenzyl)acetamide;

[0272] <83> 2-(5-(2-fluoro-4-(2-(1-(2-hydroxyethyl)piperidine-4-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0273] <84> 2-(5-(4-(2-(1-(2-ethoxyethyl)piperidine-4-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0274] <85> (R)-2-(5-(2-fluoro-4-(2-(1-(2-hydroxypropanoyl)piperidine-4-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0275] <86> (S)-2-(5-(2-fluoro-4-(2-(1-(2-hydroxypropanoyl)piperidine-4-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0276] <87> 2-(5-(2-fluoro-4-(2-(4-hydroxy-1-(2-hydroxyacetyl)piperidine-4-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0277] <88> 2-(5-(2-fluoro-4-(2-(4-fluoro-1-(2-hydroxyacetyl)piperidine-4-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0278] <89> 2-(5-(2-fluoro-4-(2-(1-(2-hydroxyacetyl)-4-methylpiperidine-4-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0279] <90> (R)-2-(5-(4-(2-(4-(2-ethoxyacetyl)-3-ethylpiperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0280] <91> (R)-2-(5-(4-(2-(4-(2-ethoxyacetyl)-3-isopropylpiperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0281] <92> 2-(5-(4-(2-(4-(2-ethoxyacetyl)-4,7-diazaspiro[2.5]octane-7-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0282] <93> (R)-2-(5-(4-(2-(4-(2-ethoxyacetyl)-3-propylpiperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorophenyl)acetamide;

[0283] <94> (R)-2-(5-(2-fluoro-4-(2-(4-(2-methoxyacetyl)-3-methylpiperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide;

[0284] <95> (R)-2-(5-(2-fluoro-4-(2-(4-(2-hydroxyacetyl)-3-methylpiperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide.

[0285] In the present invention, the term "alkyl" comprises straight-chain or branched-chain saturated hydrocarbon residues unless otherwise specified. For example, "C 1-6 "Alkyl" refers to an alkyl group with a skeleton of 1 to 6 carbons. Specifically, C 1-6 Alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, sec-pentyl, neopentyl, hexyl, etc.

[0286] The term “alkoxy” refers to a radical in which an alkyl group is substituted via an oxygen atom. Here, alkyl refers to a saturated hydrocarbon containing either a straight or branched chain. For example, "C 1-6"Alkyl" refers to an alkyl group with a skeleton of 1 to 6 carbons. Specifically, C 1-6 Alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, sec-pentyl, neopentyl, hexyl, etc., and C6 alkyl groups are fully saturated hydrocarbons having six carbons, including all structural isomers that can be formed as saturated hydrocarbons with six carbons. C 1-10 Alkoxy is C 1-6 Alkoxy, C 1-3 It contains alkoxy or methoxy.

[0287] The term “cycloalkyl” means a cyclic hydrocarbon residue forming a ring as a saturated hydrocarbon residue, unless otherwise specified, and “3-6-cycloalkyl” means a cyclic hydrocarbon residue containing 3 to 6 carbons as ring atoms.

[0288] The term “halogen” refers to halogen atoms such as F, Cl, Br, and I, and when it is said to be “halogen” substituted, it means that it has been substituted with one or more halogen atoms. The halogen atoms being substituted can be selected from a range of 1 to 5.

[0289] The term “aryl” refers to a substituent of an aromatic compound containing only carbon atoms in the ring, and 6-10 aryls include phenyl and naphthyl.

[0290] In this specification, the phrase “substituted with a plurality of substituents selected from” may include being substituted with a plurality of different substituents, and additionally includes the same substituent being selected and substituted multiple times.

[0291] The compound represented by Formula 1 according to the present invention may exist in a form including stereoisomers, and the term "stereoisomer" includes R or S isomers (or DL ​​isomers) formed by having an asymmetric carbon or heteroatom (P, S, Si, N, etc.) center, enantiomers or diastereomers, geometric isomers (trans, cis), etc. that may be formed by having two or more asymmetric atomic centers. In the present invention, the term "pharmaceuticalally acceptable salt" refers to a salt that is pharmaceutically acceptable and is formed by ionic bonding with a carboxylic acid or amine functional group when the compound contains such a group.

[0292] The compound represented by Formula 1 of the present invention can be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. The acid addition salt is obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromide, hydroiodide, nitrous acid, phosphoric acid, etc., aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates and alkandioates, aromatic acids, aliphatic and aromatic sulfonic acids, etc., non-toxic organic acids such as trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc. These types of pharmaceutically non-toxic salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphate chloride, bromides, iodides, fluorides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caprates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, malieates, butyne-1,4-dioate, hexane-1,6-dioate, benzoates, chlorobenzoates, methyl benzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, and phthalates. Includes terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, etc.

[0293] The acid addition salt according to the present invention can be prepared by conventional methods, for example, by dissolving a derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc., adding an organic acid or an inorganic acid to produce a precipitate, filtering and drying it, or by vacuum distilling the solvent and excess acid, drying it, and crystallizing it under an organic solvent.

[0294] In addition, pharmaceutically acceptable metal salts can be produced using a base. Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess amount of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. In this case, it is pharmaceutically suitable to produce sodium, potassium, or calcium salts as the metal salts. In addition, the corresponding salts are obtained by reacting the alkali metal or alkaline earth metal salt with a suitable base salt (e.g., silver nitrate).

[0295] Another aspect of the present invention is, as shown in the following reaction scheme 1,

[0296] A method for preparing a compound represented by Chemical Formula 1 is provided, comprising the step of reacting a compound represented by Chemical Formula 2 with a compound represented by Chemical Formula 3 to prepare a compound represented by Chemical Formula 1.

[0297] [Reaction Equation 1]

[0298]

[0299] In the above reaction equation, X, Y, R 1 , R 2 , R 3 , R 4a , R 4b and n are as defined in Chemical Formula 1.

[0300] In the above reaction scheme, the reaction between Formula 2 and Formula 3 is a nucleophilic substitution reaction, and the reaction is carried out under normal organic solvent conditions.

[0301] The reaction temperature is not particularly limited, but can be carried out in the range of 0 to 100°C, 10 to 50°C, and at room temperature.

[0302] The above reaction scheme 1 is an exemplary manufacturing scheme for preparing the compound of formula 1 of the present invention, and in order to carry out the embodiments of the present invention, the manufacturing method can be modified within the scope that can be created by a person skilled in the art.

[0303] Another aspect of the present invention provides a pharmaceutical composition for the prevention or treatment of cancer containing a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0304] At this time, the cancer is one or more selected from the group consisting of liver cancer, thyroid cancer, testicular cancer, oral cancer, leukemia, ovarian cancer, brain cancer, bile duct cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, small intestine cancer, esophageal cancer, kidney cancer, duodenal cancer, eye cancer, urethral cancer, stomach cancer, breast cancer, penile cancer, uterine cancer, prostate cancer, bone cancer, colorectal cancer, vaginal cancer, spinal cord cancer, pancreatic cancer, lung cancer, skin cancer, and laryngeal cancer.

[0305] The above compound or a pharmaceutically acceptable salt thereof has growth-inhibiting activity against cancer cells, and in one embodiment, may be HeLa, SK-OV-3, or B16F10 cancer cells. In addition, the above compound or a pharmaceutically acceptable salt thereof may simultaneously inhibit tubulin and Src kinase, and through such inhibition, may have preventive, remedial, or therapeutic activity against cancer.

[0306] In addition, a pharmaceutical composition for the prevention or treatment of cancer containing a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient may be administered as an individual treatment or administered in combination with other anticancer agents currently in use.

[0307] In addition, a pharmaceutical composition for the prevention or treatment of cancer containing a compound represented by the above chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient can enhance the anticancer effect by co-administering it with an anticancer agent.

[0308] Another aspect of the present invention may be formulated in the form of a pharmaceutical composition comprising a pharmaceutically acceptable carrier containing a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0309] The compound represented by Chemical Formula 1 above or its pharmaceutically acceptable salt may be administered in various oral and parenteral formulations during clinical administration. When formulating, it is prepared using diluents or excipients such as commonly used fillers, volume expanders, binders, wetting agents, disintegrants, and surfactants. Solid formulations for oral administration include tablets, pills, powders, granules, and capsules, and these solid formulations are prepared by mixing at least one excipient, e.g., starch, calcium carbonate, sucrose or lactose, gelatin, etc., with one or more compounds. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, oral liquids, emulsions, and syrups; in addition to commonly used simple diluents such as water and liquid paraffin, they may contain various excipients, such as humectants, sweeteners, flavorings, and preservatives. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, and emulsions. Non-aqueous solvents and suspension agents may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleates.

[0310] A pharmaceutical composition having a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient may be administered parenterally, and parenteral administration is by a method of injecting subcutaneously, intravenously, intramuscularly, or intrathoracically.

[0311] At this time, in order to formulate a parenteral administration formulation, a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be mixed with water together with a stabilizer or a buffer to prepare a solution or suspension, and may be prepared in an ampoule or vial unit dosage form. The composition may be sterilized and / or contain adjuvants such as preservatives, stabilizers, hydrating agents or emulsification promoters, salts and / or buffers for osmotic pressure regulation, and other therapeutically useful substances, and may be formulated according to conventional mixing, granulation, or coating methods.

[0312] Oral dosage forms include, for example, tablets, pills, hard / soft capsules, liquids, suspensions, emulsifiers, syrups, granules, elixirs, troches, etc., and these dosage forms contain, in addition to the active ingredient, diluents (e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine) and lubricants (e.g., silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycol). Tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, and, in some cases, disintegrants or boiling mixtures such as starch, agar, alginic acid or its sodium salts and / or absorbents, coloring agents, flavoring agents, and sweeteners.

[0313] Another aspect of the present invention provides a health functional food for the prevention or improvement of cancer containing a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. In this case, the cancer is the same as previously described.

[0314] The compound represented by Formula 1 according to the present invention may be added directly to food or used together with other food or food ingredients, and may be used appropriately according to conventional methods. The amount of the active ingredient may be appropriately determined according to its purpose of use (for prevention or improvement). Generally, the amount of the compound in the health food may be added in an amount of 0.1 to 90 parts by weight of the total weight of the food. However, in the case of long-term consumption for the purpose of health and hygiene or for health control, the amount may be less than the above range, and the active ingredient may be used in an amount greater than the above range as there is no problem in terms of safety.

[0315] Another aspect of the present invention provides a method for preventing, improving, or treating cancer, comprising the step of administering a pharmaceutical composition or a health functional food containing a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient to a person in need.

[0316] Another aspect of the present invention provides the use or application of a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof in the prevention, improvement, or treatment of cancer.

[0317] The compound represented by Formula 1 of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered in a “pharmaceutically effective amount.” In the present invention, the term “pharmaceutically effective amount” means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment or improvement, and the effective dose level may be determined based on factors including individual type and severity, age, sex, drug activity, sensitivity to the drug, time of administration, route of administration and elimination rate, duration of treatment, concurrently used drugs, and other factors well known in the medical field. For example, effective amounts include 0.001 mg / kg to 1000 mg / kg, 0.01 mg / kg to 100 mg / kg, 0.1 to 20 mg / kg, or 0.1 to 500 mg / kg. The amount of the pharmaceutical composition of the present invention may be selected and administered by a person skilled in the art within an appropriate range.

[0318] The present invention will be explained in detail below through examples.

[0319] However, the embodiments described below are merely specific examples of the present invention in one aspect, and the present invention is not limited thereto.

[0320] <Comparative Example 1> Preparation of N-benzyl-2-(5-(4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)acetamide (Tirvanibulin, KX-01)

[0321]

[0322] Step 1: Preparation of N-benzyl-2-(5-bromopyridine-2-yl)acetamide

[0323] Solution of 2-(5-bromopyridine-2-yl)acetic acid (1.0 equivalent, 4.6 mmol, 1.0 g), benzylamine (1.2 equivalent, 5.6 mmol, 0.6 mL), EDCI·HCl (1.2 equivalent, 5.6 mmol, 1.1 g), Et3N (3.2 equivalent, 15 mmol, 2.0 mL), and HOBt (1.2 equivalent, 5.6 mmol, 750 mg) were added sequentially to dichloromethane (15 mL) at 0°C. The reaction mixture was stirred at room temperature for 18 hours, then poured into water, extracted twice with EtOAc, dried with MgSO4, and concentrated under vacuum. The crude product was purified by flash chromatography in silica gel (hexane / EtOAc, 3:1, Rf = 0.3) to obtain the target compound, which is a white solid (3.6 mmol, 1.1 g, 77%).

[0324] 1 H NMR (400 MHz, DMSO-d6) δ 8.64-8.57 (m, 2H), 7.99 (dd,J= 8.3, 2.5 Hz, 1H), 7.38-7.19 (m, 6H), 4.28 (d,J= 5.9 Hz, 2H), 3.67 (s, 2H). MS (ESI) [M+H] + = 305.0.

[0325] Step 2: Preparation of tirbanibulin

[0326] To a solution of the preceding compound (1.0 equivalent, 2.8 mmol, 870 mg) dissolved in dimethylformamide (18 mL), 4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)morpholine (1.2 equivalents, 3.4 mmol, 1.1 g), PdCl2(dppf)·CH2Cl2 (0.1 equivalents, 0.28 mmol, 230 mg), triphenylphosphine (0.1 equivalents, 0.28 mmol, 73 mg), Cs2CO3 (1.5 equivalents, 4.3 mmol, 1.4 g) and water (1.8 mL) were added at room temperature. The reaction mixture was stirred at 100°C for 2 hours, poured into water, extracted twice with CH2Cl2, dried with MgSO4, and concentrated under vacuum. The crude product was purified by silica gel flash chromatography (CH2Cl2 / MeOH, 20:1, Rf = 0.2) to obtain tirvanibulin (2.3 mmol, 981 mg, 80%) as a white solid. 1 H NMR (500 MHz, DMSO-d6) δ 8.75 (d,J= 2.3 Hz, 1H), 8.63 (t,J= 6.0 Hz, 1H), 7.97 (dd,J= 8.1, 2.5 Hz, 1H), 7.65 (d,J= 8.8 Hz, 2H), 7.40 (d,J= 8.1 Hz, 1H), 7.35-7.20 (m, 5H), 7.06 (d,J= 8.8 Hz, 2H), 4.30 (d,J= 5.9 Hz, 2H), 4.14 (t,J= 5.8 Hz, 2H), 3.71 (s, 2H), 3.58 (t,J= 4.6 Hz, 4H), 2.71 (t,J= 5.7 Hz, 2H), 2.48 (br, 4H).

[0327] <Example 1> Preparation of N-benzyl-2-(5-(3-methyl-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)acetamide

[0328]

[0329] Step 1: Preparation of 4-(2-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)morpholine

[0330] 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1.0 equivalent, 0.43 mmol, 100 mg), K2CO3 (1.5 equivalent, 0.65 mmol, 88 mg), and 4-(2-chloroethyl)morpholine (1.2 equivalent, 0.52 mmol, 79 μL) were added to dimethylformamide (2.0 ml) at room temperature. The reaction mixture was stirred at 70°C for 16 hours. The reaction mixture was cooled to room temperature, poured into water, extracted twice with EtOAc, dried with MgSO4, and concentrated under vacuum. This yielded a crude product, a dark brown oil. This crude product was used in the next step without further purification.

[0331] Step 2: Preparation of N-benzyl-2-(5-(3-methyl-4-(2-morpholineethoxy)phenyl)pyridine-2-yl)acetamide

[0332] To dimethylformamide (2.0 mL), the pre-step product (1.0 equivalent, 0.35 mmol, 100 mg), N-benzyl-2-(5-bromopyridine-2-yl)acetamide (1.0 equivalent, 0.35 mmol, 106 mg), PdCl2(dppf)·CH2Cl2 (0.1 equivalent, 0.035 mmol, 29 mg), PPh3 (0.1 equivalent, 0.035 mmol, 9.2 mg), KF (1.5 equivalent, 0.53 mmol, 31 mg), and water (0.2 mL) were added at room temperature. The reaction mixture was stirred at 100°C for 3 hours, then poured into water and extracted twice with CH2Cl2, dried with MgSO4, and concentrated under vacuum. The prepared mixture was purified by silica gel flash chromatography (CH2Cl2 / MeOH, 20:1, Rf = 0.1) to obtain the target compound, which is a colorless wax (0.112 mmol, 50 mg, 32%).

[0333] 1H NMR (300 MHz, DMSO) δ 8.74 (dd,J= 2.5, 0.8 Hz, 1H), 8.62 (t,J= 6.0 Hz, 1H), 7.95 (dd,J= 8.1, 2.5 Hz, 1H), 7.50 (m, 2H), 7.38 (dd,J= 8.1, 0.8 Hz, 1H), 7.36 - 7.18 (m, 5H), 7.06 (d,J= 8.2 Hz, 1H), 4.30 (d,J= 5.9 Hz, 2H), 4.15 (t,J= 5.7 Hz, 2H), 3.70 (s, 2H), 3.63 - 3.54 (m, 4H), 2.74 (t,J= 5.7 Hz, 2H), 2.22 (s, 3H).

[0334] <Example 2> Preparation of N-benzyl-2-(5-(2-methyl-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)acetamide

[0335] The target compound was obtained by a method similar to that of Example 1. The product was obtained as a colorless wax (0.27 mmol, 118 mg, 76%).

[0336] 1 H NMR (500 MHz, DMSO) δ 8.65 (t,J= 5.9 Hz, 1H), 8.42 (dd,J= 2.4, 0.8 Hz, 1H), 7.70 (dd,J= 7.9, 2.4 Hz, 1H), 7.39 (d,J= 8.0 Hz, 1H), 7.34 - 7.21 (m, 5H), 7.15 (d,J= 8.4 Hz, 1H), 6.93 (d,J= 2.6 Hz, 1H), 6.87 (dd,J= 8.4, 2.7 Hz, 1H), 4.31 (d,J= 5.9 Hz, 2H), 4.11 (t,J= 5.8 Hz, 2H), 3.72 (s, 2H), 3.58 (d,J= 4.7 Hz, 4H), 2.70 (t,J= 5.8 Hz, 2H), 2.48 (m, 4H), 2.22 (s, 3H); HRMS (FAB): calcd. for C 27 H 32 N3O3([M+H] +)446.2444 found 446.2443.

[0337] <Example 3> Preparation of N-benzyl-2-(5-(3-methoxy-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)acetamide

[0338] The target compound was obtained by a method similar to that of Example 1. The product was obtained as a colorless wax (0.044 mmol, 21 mg, 26%).

[0339] 1 H NMR (500 MHz, DMSO) δ 8.78 (dd,J= 2.4, 0.8 Hz, 1H), 8.63 (t,J= 6.0 Hz, 1H), 8.00 (dd,J= 8.1, 2.5 Hz, 1H), 7.40 (d,J= 8.1 Hz, 1H), 7.35 - 7.18 (m, 7H), 7.09 (d,J= 8.4 Hz, 1H), 4.30 (d,J= 6.0 Hz, 2H), 4.12 (t,J= 5.9 Hz, 2H), 3.85 (s, 3H), 3.71 (s, 2H), 3.58 (t,J= 4.7 Hz, 4H), 2.71 (t,J= 5.9 Hz, 2H); HRMS (FAB): calcd. for C 27 H 32 N3O4([M+H] + )462.2393 found 462.2397.

[0340] <Example 4> Preparation of N-benzyl-2-(5-(2-fluoro-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)acetamide

[0341] The target compound was obtained by a method similar to that of Example 1. The product was obtained as a colorless wax (0.14 mmol, 64 mg, 41%).

[0342] 1H NMR (500 MHz, DMSO) δ 8.65 (t,J= 6.0 Hz, 1H), 8.61 (s, 1H), 7.87 (dt,J= 8.2, 1.9 Hz, 1H), 7.50 (t,J= 9.0 Hz, 1H), 7.43 (d,J= 8.1 Hz, 1H), 7.36 - 7.20 (m, 5H), 7.01 (dd,J= 12.9, 2.5 Hz, 1H), 6.93 (dd,J= 8.6, 2.5 Hz, 1H), 4.30 (d,J= 5.9 Hz, 2H), 4.16 (t,J= 5.7 Hz, 2H), 3.73 (s, 2H), 3.58 (t,J= 4.6 Hz, 4H), 2.71 (t,J= 5.7 Hz, 2H), 2.48 (br s, 4H).

[0343] <Example 5> Preparation of N-benzyl-2-(5-(3-fluoro-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)acetamide

[0344] The target compound was obtained by a method similar to that of Example 1. The product was obtained as a colorless wax (0.24 mmol, 107 mg, 68%).

[0345] 1 H NMR (300 MHz, DMSO) δ 8.79 (dd,J= 2.5, 0.8 Hz, 1H), 8.63 (t,J= 6.0 Hz, 1H), 8.01 (dd,J= 8.1, 2.5 Hz, 1H), 7.65 (dd,J= 12.8, 2.2 Hz, 1H), 7.52 (dd,J= 8.5, 1.7 Hz, 1H), 7.41 (d,J= 8.2 Hz, 1H), 7.36 - 7.20 (m, 6H), 4.30 (d,J= 5.9 Hz, 2H), 4.22 (t,J= 5.7 Hz, 2H), 3.72 (s, 2H), 3.62 - 3.53 (m, 4H), 2.73 (t,J= 5.7 Hz, 2H), 2.49 - 2.43 (m, 4H).

[0346] <Example 6> Preparation of N-benzyl-2-(5-(2,6-dimethyl-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)acetamide

[0347] The target compound was obtained by a method similar to that of Example 1, except that Cs2CO3 (1.5 equivalents, 0.60 mmol, 195 mg) was used instead of K2CO3. The product was obtained as a colorless wax (0.040 mmol, 18 mg, 13% over two steps).

[0348] 1 H NMR (400 MHz, DMSO-d6) δ 8.64 (t,J= 6.0 Hz, 1H), 8.24 (d,J= 1.1 Hz, 1H), 7.53 (dd,J= 7.9, 2.3 Hz, 1H), 7.42 (d,J= 7.9 Hz, 1H), 7.35 - 7.19 (m, 5H), 6.75 (s, 2H), 4.32 (d,J= 5.9 Hz, 2H), 4.09 (t,J= 5.8 Hz, 2H), 3.73 (s, 2H), 3.62-3.55 (m, 4H), 2.69 (t,J= 5.8 Hz, 2H), 2.50-2.45 (m, 4H), 1.95 (s, 6H); MS (ESI) [M+H] + = 460.5.

[0349] <Example 7> Preparation of N-benzyl-2-(5-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)acetamide

[0350] The target compound was obtained by a method similar to that of Example 6. The product was obtained as a colorless oil (0.015 mmol, 7 mg, 15% over two steps).

[0351] 1H NMR (400 MHz, DMSO-d6) δ 8.74 (d,J= 2.4 Hz, 1H), 8.64 (t,J= 6.1 Hz, 1H), 7.96 (dd,J= 8.1, 2.4 Hz, 1H), 7.40 (d,J= 8.3 Hz, 1H), 7.38 (s, 2H), 7.36 - 7.21 (m, 5H), 4.31 (d,J= 5.9 Hz, 2H), 3.89 (t,J= 5.7 Hz, 2H), 3.72 (s, 2H), 3.60 (t,J= 4.6 Hz, 4H), 2.71 (t,J= 5.7 Hz, 2H), 2.47-2.39 (m, 4H), 2.31 (s, 6H); MS (ESI) [M+H] + = 460.5.

[0352] <Example 8> Preparation of N-benzyl-2-(5-(2,3-dimethyl-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)acetamide

[0353]

[0354] Step 1: Preparation of 4-(2-(4-bromo-2,3-dimethylphenoxy)ethyl)morpholine

[0355] A solution of 4-bromo-2,3-dimethylphenol (1.1 equivalents, 2.5 mmol, 500 mg) was added to dimethylformamide (2.1 mL), and K2CO3 (1.5 equivalents, 3.7 mmol, 514 mg) and 4-(2-chloroethyl)morpholine (1.0 equivalents, 2.7 mmol, 376 μL) were added at room temperature. The reaction mixture was stirred at 60°C for 18 hours. The reaction mixture was cooled to room temperature, poured into water, extracted twice with EtOAc, dried with MgSO4, and concentrated under vacuum. The crude product was purified by flash chromatography on silica gel (hexane / EtOAc, 1:1, Rf = 0.3) to obtain the target compound (2.2 mmol, 697 mg, 89%) as a yellow oil.

[0356] 1H NMR (500 MHz, MeOD-d4) δ 7.32 (d,J= 8.8 Hz, 1H), 6.71 (d,J= 8.8 Hz, 1H), 4.11 (t,J= 5.5 Hz, 2H), 3.74 - 3.68 (m, 4H), 2.84 (t,J= 5.5 Hz, 2H), 2.63 (t,J= 4.7 Hz, 4H), 2.35 (s, 3H), 2.22 (s, 3H); HRMS (FAB): calcd. for C 14 H 21 BrO2([M+H] + ) 314.0750, found 314.0767.

[0357] Step 2: Preparation of 4-(2-(2,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)morpholine

[0358] The pre-step product (1.0 equivalent, 0.32 mmol, 100 mg), B2(pin)2 (1.2 equivalent, 0.38 mmol, 97 mg), PdCl2(dppf)·CH2Cl2 (0.1 equivalent, 0.032 mmol, 26 mg), PPh3 (0.1 equivalent, 0.032 mmol, 9.0 mg), KF (3.0 equivalent, 0.96 mmol, 56 mg), and water (0.2 mL) were added to dimethylformamide (1.8 mL) at room temperature. The reaction mixture was stirred at 80°C for 12 hours. The reaction mixture was cooled to room temperature, poured into water, extracted twice with EtOAc, dried with MgSO4, and concentrated under vacuum. This yielded a crude product in the form of a brown oil. This crude product was used in the next step without further purification.

[0359] Step 3: Preparation of N-benzyl-2-(5-(2,3-dimethyl-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)acetamide

[0360] To dimethylformamide (2.0 mL), the precursor compound (1.0 equivalent, 0.33 mmol, 90 mg), N-benzyl-2-(5-bromopyridine-2-yl)acetamide (1.0 equivalent, 0.33 mmol, 100 mg), PdCl2(dppf)·CH2Cl2 (0.1 equivalent, 0.033 mmol, 27 mg), PPh3 (0.1 equivalent, 0.033 mmol, 9.0 mg), KF (1.5 equivalent, 0.49 mmol, 29 mg), and water (0.2 mL) were added at room temperature. The reaction mixture was stirred overnight at 100°C. The reaction mixture was cooled to room temperature, poured into water, extracted twice with CH2Cl2, dried with MgSO4, and concentrated under vacuum. The crude product was purified by silica gel flash chromatography (CH2Cl2 / MeOH, 20:1, Rf = 0.2) to obtain the target compound, which is a colorless wax (0.030 mmol, 9.2 mg, 9%).

[0361] 1 H NMR (500 MHz, DMSO-d6) δ 8.65 (t,J= 6.1 Hz, 1H), 8.38 (d,J= 1.9 Hz, 1H), 7.64 (dd,J= 7.9, 2.4 Hz, 1H), 7.39 (d,J= 8.2 Hz, 1H), 7.35-7.20 (m, 5H), 7.02 (d,J= 8.5 Hz, 1H), 6.92 (d,J= 8.5 Hz, 1H), 4.31 (d,J= 5.9 Hz, 2H), 4.11 (t,J= 5.7 Hz, 2H), 3.73 (s, 2H), 3.58 (t,J= 4.7 Hz, 4H), 2.55-2.52(m, 4H), 2.74 (t,J= 5.7 Hz, 2H), 2.16 (s, 3H), 2.11 (s, 3H); HRMS (FAB): calcd. for C 28 H 34 N3O3([M+H] + ) 460.2595, found 460.2605.

[0362] <Example 9> Preparation of N-benzyl-2-(5-(2,5-dimethyl-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)acetamide

[0363] The target compound was obtained by a method similar to that of Example 8. The product was obtained as a pink solid (0.31 mmol, 142 mg, 32%, step 3).

[0364] 1 H NMR (400 MHz, DMSO-d6) δ 8.64 (t,J= 6.1 Hz, 1H), 8.42 (d,J= 2.1 Hz, 1H), 7.68 (dt,J= 8.0, 1.9 Hz, 1H), 7.38 (d,J= 8.0 Hz, 1H), 7.36 - 7.18 (m, 5H), 7.01 (s, 1H), 6.92 (s, 1H), 4.31 (d,J= 5.9 Hz, 2H), 4.13 (t,J= 5.8 Hz, 2H), 3.72 (s, 2H), 3.58 (t,J= 4.7 Hz, 4H), 2.74 (t,J= 5.7 Hz, 2H), 2.21 (s, 3H), 2.14 (s, 3H). ); HRMS (FAB): calcd. for C 28 H 34 N3O3([M+H] + ) 460.2600 found 460.2595.

[0365] <Example 10> Preparation of N-benzyl-2-(5-(3-fluoro-2-methyl-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)acetamide

[0366] The target compound was obtained by a method similar to that of Example 8. The product was obtained in the form of a colorless wax (0.011 mmol, 5.1 mg, 2.7% over three steps).

[0367] 1H NMR (400 MHz, DMSO-d6) δ 8.65 (t,J= 6.0 Hz, 1H), 8.44 (d,J= 2.3 Hz, 1H), 7.72 (dd,J= 8.2, 2.4 Hz, 1H), 7.42 (d,J= 8.0 Hz, 1H), 7.29 (dq,J= 18.5, 8.6 Hz, 5H), 7.13 (t,J= 8.5 Hz, 1H), 7.03 (d,J= 8.6 Hz, 1H), 4.31 (d,J= 5.9 Hz, 2H), 4.19 (t,J= 5.7 Hz, 2H), 3.74 (s, 2H), 3.58 (t,J= 4.7 Hz, 5H), 2.73 (t,J= 5.7 Hz, 2H), 2.14 (d,J= 2.7 Hz, 3H).

[0368] <Example 11> Preparation of 2-(5-(2,5-dimethyl-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0369]

[0370] Step 1: Preparation of 4-(2-(4-bromo-2,5-dimethylphenoxy)ethyl)morpholine

[0371] 4-bromo-2,5-dimethylphenol (1.1 equivalents, 2.9 mmol, 591 mg), K2CO3 (1.5 equivalents, 4.0 mmol, 554 mg), and 4-(2-chloroethyl)morpholine (1.0 equivalent, 2.7 mmol, 400 mg) were added to dimethylformamide (2.1 mL) at room temperature. The reaction mixture was stirred at 60°C for 21 hours. The reaction mixture was cooled to room temperature, poured into water, extracted twice with EtOAc, dried with MgSO4, and concentrated under vacuum. The crude product was purified by silica gel flash chromatography (CH2Cl2 / MeOH, 20:1, Rf = 0.3) to obtain the target compound (2.3 mmol, 737 mg, 88%), which is a colorless oil.

[0372] 1H NMR (300 MHz, MeOD-d4) δ 7.25 (s, 1H), 6.84 (s, 1H), 4.12 (t,J= 5.5 Hz, 2H), 3.79 - 3.67 (m, 4H), 2.83 (t,J= 5.5 Hz, 2H), 2.67 - 2.58 (m, 4H), 2.33 (s, 3H), 2.14 (s, 3H); HRMS (FAB): calcd. for C 14 H 21 BrNO2([M+H] + ) 314.0756, found 314.0761.

[0373] Steps 2 and 3: Preparation of methyl 2-(5-(2,5-dimethyl-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)acetate

[0374] 4-(2-(4-bromo-2,5-dimethylphenoxy)ethyl)morpholine (1.0 equivalent, 0.32 mmol, 100 mg), B2(pin)2 (1.2 equivalent, 0.38 mmol, 97 mg), PdCl2(dppf)·CH2Cl2 (0.1 equivalent, 0.032 mmol, 26 mg), PPh3 (0.1 equivalent, 0.032 mmol, 9.0 mg), KF (3.0 equivalent, 0.96 mmol, 56 mg), and water (0.2 mL) were added to dimethylformamide (1.8 mL) at room temperature. The reaction mixture was stirred at 80°C for 17 hours. The reaction mixture was cooled to room temperature, poured into water, extracted twice with EtOAc, dried with MgSO4, and concentrated under vacuum. This yielded a crude product in the form of a yellow oil. This crude product was used in the next step without further purification.

[0375] A solution of the pre-step product (1.0 equivalent, 0.32 mmol, 110 mg) was added to dimethylformamide (1.8 mL), and methyl 2-(5-bromopyridine-2-yl)acetate (1.2 equivalent, 0.38 mmol, 87 mg), PdCl2(dppf)·CH2Cl2 (0.1 equivalent, 0.032 mmol, 26 mg), PPh3 (0.1 equivalent, 0.032 mmol, 9.0 mg), KF (3.0 equivalent, 0.96 mmol, 56 mg), and water (0.2 mL) were added at room temperature. The reaction mixture was stirred at 80°C for 20 hours. The reaction mixture was cooled to room temperature, poured into water, extracted twice with EtOAc, dried with MgSO4, and concentrated under vacuum. The crude product was purified by silica gel flash chromatography (CH2Cl2 / MeOH, 20:1, Rf = 0.4) to obtain the target compound, which is a brown oil (0.11 mmol, 44 mg, 36% over two steps).

[0376] 1 H NMR (500 MHz, DMSO-d6) δ 8.42 (dd,J= 2.3, 0.8 Hz, 1H), 7.71 (dd,J= 8.0, 2.4 Hz, 1H), 7.39 (dd,J= 8.0, 0.8 Hz, 1H), 7.02 (s, 1H), 6.92 (s, 1H), 4.13 (t,J= 5.8 Hz, 2H), 3.89 (s, 2H), 3.64 (s, 3H), 3.58 (t,J= 4.6 Hz, 4H), 2.74 (t,J= 5.8 Hz, 2H), 2.21 (s, 3H), 2.14 (s, 3H); HRMS (FAB): calcd. for C 22 H 29 N2O4([M+H] + ) 385.2127, found 385.2124.

[0377] Step 4: Preparation of 2-(5-(2,5-dimethyl-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0378] (4-fluorophenyl)methaneamine (1.2 equivalents, 0.13 mmol, 15 μL) and TBD (1.2 equivalents, 0.13 mmol, 19 mg) were added at room temperature to a 1,4-dioxane (1.0 mL) solution of the previous step product (1.0 equivalent, 0.11 mmol, 43 mg). The reaction mixture was stirred at 60°C for 12 hours, then poured into water, extracted twice with EtOAc, dried with MgSO4, and concentrated under vacuum. The crude product was purified by flash chromatography (CH2Cl2 / MeOH, 10:1, Rf = 0.2) on silica gel to obtain the target compound (0.077 mmol, 37 mg, 70%) as a beige solid.

[0379] 1 H NMR (500 MHz, DMSO-d6) δ 8.66 (t,J= 6.0 Hz, 1H), 8.42 (dd,J= 2.5, 0.8 Hz, 1H), 7.68 (dd,J= 8.0, 2.4 Hz, 1H), 7.38 (d,J= 7.6 Hz, 1H), 7.32 (dd,J= 8.6, 5.6 Hz, 2H), 7.14 (t,J= 8.9 Hz, 2H), 7.01 (s, 1H), 6.92 (s, 1H), 4.29 (d,J= 6.0 Hz, 2H), 4.13 (t,J= 5.8 Hz, 2H), 3.71 (s, 2H), 3.58 (t,J= 4.7 Hz, 4H), 2.74 (t,J= 5.7 Hz, 2H), 2.21 (s, 3H), 2.14 (s, 3H); MS (ESI) [M+H] + = 478.4.

[0380] <Example 12> Preparation of 2-(5-(2,3-dimethyl-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0381] The target compound was obtained by a method similar to that of Example 11. The product was obtained in the form of a colorless wax (0.034 mmol, 16 mg, 18% over three steps).

[0382] 1H NMR (500 MHz, DMSO-d6) δ 8.66 (t,J= 6.1 Hz, 1H), 8.38 (d,J= 2.3 Hz, 1H), 7.64 (dd,J= 7.9, 2.3 Hz, 1H), 7.38 (d,J= 8.0 Hz, 1H), 7.32 (dd,J= 8.5, 5.6 Hz, 2H), 7.14 (t,J= 8.8 Hz, 2H), 7.02 (d,J= 8.4 Hz, 1H), 6.92 (d,J= 8.5 Hz, 1H), 4.29 (d,J= 6.0 Hz, 2H), 4.11 (t,J= 5.7 Hz, 2H), 3.72 (s, 2H), 3.58 (t,J= 4.6 Hz, 4H), 2.74 (t,J= 5.7 Hz, 2H), 2.16 (s, 3H), 2.11 (s, 3H); MS (ESI) [M+H] + = 478.7.

[0383] <Example 13> Preparation of N-(4-fluorobenzyl)-2-(5-(3-methyl-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)acetamide

[0384]

[0385] Steps 1 and 2: Preparation of methyl 2-(5-(3-methyl-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)acetate

[0386] DIAD (1.5 equivalents, 1.2 mmol, 240 μL) was added at 0°C to a solution prepared by dissolving 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1.0 equivalent, 0.81 mmol, 190 mg), PPh3 (1.5 equivalents, 1.2 mmol, 319 mg), and 4-(2-hydroxyethyl)-morpholine (1.2 equivalents, 0.97 mmol, 119 μL) in THF (2.0 mL). The reaction mixture was stirred at 50°C for 20 hours. The reaction mixture was cooled to room temperature, poured into water, extracted twice with EtOAc, dried with MgSO4, and concentrated under vacuum. This yielded a crude product in the form of a yellow oil. This crude product was used in the next step without further purification.

[0387] A solution of the pre-step product (1.0 equivalent, 0.81 mmol, 280 mg) was added to dimethylformamide (4.0 mL), and methyl 2-(5-bromopyridine-2-yl)acetate (1.2 equivalent, 0.97 mmol, 224 mg), PdCl2(dppf)·CH2Cl2 (0.1 equivalent, 0.081 mmol, 59 mg), PPh3 (0.1 equivalent, 0.081 mmol, 21 mg), KF (2.5 equivalent, 2.0 mmol, 118 mg), and water (0.40 mL) were added at room temperature. The reaction mixture was stirred at 90°C for 22 hours. The reaction mixture was cooled to room temperature, poured into water, extracted twice with CH2Cl2, dried with Na2SO4, and concentrated under vacuum. The crude product was purified by silica gel flash chromatography (CH2Cl2 / MeOH, 10:1, Rf = 0.4) to obtain the target compound, which is a black oil (0.45 mmol, 166 mg, 55% over two steps).

[0388] 1H NMR (500 MHz, MeOD-d4) δ 8.66 (dd,J= 2.4, 0.9 Hz, 1H), 7.99 (dd,J= 8.1, 2.3 Hz, 1H), 7.48 - 7.41 (m, 3H), 7.03 (d,J= 9.1 Hz, 1H), 4.21 (t,J= 5.4 Hz, 2H), 3.88 (d,J= 9.2 Hz, 1H), 3.75 - 3.65 (m, 7H), 2.88 (t,J= 5.6 Hz, 2H), 2.65 (t,J= 4.8 Hz, 4H), 2.28 (s, 3H).

[0389] Step 3: Preparation of N-(4-fluorobenzyl)-2-(5-(3-methyl-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)acetamide

[0390] Methyl 2-(5-(3-methyl-4-(2-morpholinethoxy)phenyl)pyridine-2-yl)acetate (1.0 equivalent, 0.14 mmol, 50 mg), (4-fluorophenyl)methaneamine (1.2 equivalent, 0.16 mmol, 19 μL) and TBD (1.0 equivalent, 0.14 mmol, 19 mg) were added to 1,4-dioxane (0.68 mL) at room temperature. The reaction mixture was stirred at 60°C for 12 hours, then poured into water, extracted twice with EtOAc, dried with MgSO4, and concentrated under vacuum. The crude product was purified by preparative thin-layer chromatography (CH2Cl2 / MeOH, 10:1, Rf = 0.3) to obtain the target compound (0.073 mmol, 34 mg, 54%), which is a white solid.

[0391] 1H NMR (500 MHz, DMSO-d6) δ 8.74 (d, J = 2.1 Hz, 1H), 8.64 (t, J = 6.1 Hz, 1H), 7.95 (dd,J= 8.1, 2.5 Hz, 1H), 7.54 - 7.47 (m, 2H), 7.38 (d,J= 8.1 Hz, 1H), 7.31 (dd,J= 8.6, 5.7 Hz, 2H), 7.15 (t,J= 8.9 Hz, 2H), 7.06 (d,J= 8.4 Hz, 1H), 4.28 (d,J= 5.9 Hz, 2H), 4.15 (t,J= 5.7 Hz, 2H), 3.69 (s, 2H), 3.58 (t,J= 4.7 Hz, 4H), 2.74 (t,J= 5.7 Hz, 2H), 2.22 (s, 3H); MS (ESI) [M+H] + = 464.4.

[0392] <Example 14> Preparation of N-(4-fluorobenzyl)-2-(5-(2-methyl-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)acetamide

[0393]

[0394] Steps 1 and 2: Preparation of methyl 2-(5-(2-methyl-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)acetate

[0395] 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1.0 equivalent, 0.85 mmol, 200 mg), K2CO3 (1.5 equivalent, 1.3 mmol, 177 mg), and 4-(2-chloroethyl)morpholine (1.0 equivalent, 0.85 mmol, 118 μL) were added to dimethylformamide (4.3 mL) at room temperature. The reaction mixture was stirred overnight at 60°C. The reaction mixture was cooled to room temperature, poured into water, extracted twice with EtOAc, dried with MgSO4, and concentrated under vacuum. This yielded a crude product in the form of a purple oil. This crude product was used in the next step without further purification.

[0396] To dimethylformamide (3.5 mL), the pre-step product (1.0 equivalent, 0.70 mmol, 244 mg), methyl 2-(5-bromopyridine-2-yl)acetate (1.2 equivalent, 0.84 mmol, 194 mg), PdCl2(dppf)·CH2Cl2 (0.1 equivalent, 0.070 mmol, 51 mg), PPh3 (0.1 equivalent, 0.070 mmol, 18 mg), KF (2.5 equivalent, 1.8 mmol, 102 mg), and water (0.35 mL) were added at room temperature. The reaction mixture was stirred at 90°C for 22 hours. The reaction mixture was cooled to room temperature, poured into water, extracted twice with CH2Cl2, dried with Na2SO4, and concentrated under vacuum. The crude product was purified by silica gel flash chromatography (CH2Cl2 / MeOH, 10:1, Rf = 0.2) to obtain the target compound, which is a black oil (0.33 mmol, 124 mg, 39% over two steps).

[0397] 1 H NMR (500 MHz, MeOD-d4) δ 8.39 (dd,J= 2.4, 0.8 Hz, 1H), 7.76 (dd,J= 8.0, 2.3 Hz, 1H), 7.46 (dd,J= 8.0, 0.8 Hz, 1H), 7.15 (d,J= 8.4 Hz, 1H), 6.91 (d,J= 2.6 Hz, 1H), 6.87 (dd,J= 8.4, 2.7 Hz, 1H), 4.18 (t,J= 5.4 Hz, 2H), 3.91 (s, 2H), 3.75 - 3.71 (m, 6H), 2.83 (t,J= 5.5 Hz, 2H), 2.61 (m, 5H), 2.25 (s, 3H).

[0398] Step 3: Preparation of N-(4-fluorobenzyl)-2-(5-(3-methyl-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)acetamide

[0399] The target compound was obtained by a method similar to that of Example 13. The product was obtained in the form of a colorless oil (0.067 mmol, 31 mg, 50%).

[0400] 1 H NMR (500 MHz, DMSO-d6) δ 8.66 (t,J= 5.9 Hz, 1H), 8.43 (dd,J= 2.3, 0.8 Hz, 1H), 7.70 (dd,J= 8.0, 2.4 Hz, 1H), 7.38 (d,J= 8.3 Hz, 1H), 7.35 - 7.28 (m, 2H), 7.14 (m, 3H), 6.93 (d,J= 2.6 Hz, 1H), 6.87 (dd,J= 8.4, 2.7 Hz, 1H), 4.29 (d,J= 5.9 Hz, 2H), 4.11 (t,J= 5.7 Hz, 2H), 3.71 (s, 2H), 3.58 (t,J= 4.7 Hz, 4H), 2.70 (t,J= 5.7 Hz, 2H), 2.49 (d,J= 7.4 Hz, 4H), 2.22 (s, 3H); MS (ESI) [M+H] + = 464.4.

[0401] <Example 15> Preparation of 2-(5-(2-fluoro-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0402]

[0403] Step 1: Preparation of 2-(5-bromopyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0404] Solution of 2-(5-bromopyridine-2-yl)acetic acid (1.0 equivalent, 4.6 mmol, 1.0 g), 4-fluorobenzylamine (1.1 equivalent, 5.1 mmol, 0.56 mL), EDCI·HCl (1.2 equivalent, 5.6 mmol, 1.1 g), Et3N (2.4 equivalent, 11 mmol, 1.6 mL), and HOBt (1.2 equivalent, 5.6 mmol, 750 mg) were added sequentially to dichloromethane (23 mL) at 0°C. The reaction mixture was stirred at room temperature for 18 hours, then poured into water, extracted twice with EtOAc, dried with MgSO4, and concentrated under vacuum. The crude product was purified by flash chromatography on silica gel to obtain the target compound (4.0 mmol, 1.3 g, 86%), which is a white solid.

[0405] 1 H NMR (300 MHz, DMSO-d6) δ 8.61 (d,J= 2.6 Hz, 1H), 7.99 (dd,J= 8.3, 2.5 Hz, 1H), 7.39 - 7.25 (m, 3H), 7.21 - 7.07 (m, 2H), 4.26 (d,J= 5.9 Hz, 2H), 3.66 (s, 2H).

[0406] Steps 2 and 3: Preparation of 2-(5-(2-fluoro-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0407] 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1.0 equivalent, 0.42 mmol, 100 mg), K2CO3 (1.5 equivalent, 0.63 mmol, 87 mg), and 4-(2-chloroethyl)morpholine (1.2 equivalent, 0.42 mmol, 58 μL) were added to dimethylformamide (2.1 ml) at room temperature. The reaction mixture was stirred overnight at 60°C. The reaction mixture was cooled to room temperature, poured into water, extracted twice with EtOAc, dried with MgSO4, and concentrated under vacuum. This yielded a crude product in the form of a purple oil. This crude product was used in the next step without further purification.

[0408] Step 3 product (1.0 equivalent, 0.42 mmol, 147 mg), Step 1 product (1.1 equivalent, 0.046 mmol, 149 mg), PdCl2(dppf)·CH2Cl2 (0.1 equivalent, 0.042 mmol, 33 mg), PPh3 (0.1 equivalent, 0.042 mmol, 11 mg), KF (3.0 equivalent, 1.26 mmol, 73 mg), and water (0.2 mL) were added to dimethylformamide (2.1 mL) at room temperature. The reaction mixture was stirred at 90°C for 13 hours, then poured into water, extracted twice with EtOAc, dried with MgSO4, and concentrated under vacuum. The crude product was purified by silica gel flash chromatography (CH2Cl2 / MeOH, 20:1, Rf = 0.1) to obtain the target compound (0.11 mmol, 53 mg, 27% over two steps) as a brown solid.

[0409] 1H NMR (400 MHz, DMSO-d6) δ 8.66 (t,J= 6.0 Hz, 1H), 8.62 (s, 1H), 7.87 (dt,J= 8.1, 1.9 Hz, 1H), 7.51 (t,J= 9.0 Hz, 1H), 7.43 (d,J= 8.1 Hz, 1H), 7.37 - 7.28 (m, 2H), 7.20 - 7.09 (m, 2H), 7.01 (dd,J= 12.9, 2.5 Hz, 1H), 6.93 (dd,J= 8.6, 2.5 Hz, 1H), 4.28 (d,J= 5.9 Hz, 2H), 4.16 (t,J= 5.7 Hz, 2H), 3.72 (s, 2H), 3.58 (t,J= 4.7 Hz, 4H), 2.71 (t,J= 5.7 Hz, 2H), 2.50 - 2.45 (m, 4H); MS (ESI) [M+H] + = 468.4.

[0410] <Example 16> Preparation of 2-(5-(2-fluoro-4-(2-(piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0411]

[0412] Step 1: Preparation of 2-(5-(2-fluoro-4-hydroxyphenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0413] 2-(5-bromopyridine-2-yl)-N-(4-fluorobenzyl)acetamide (1.2 equivalents, 2.1 mmol, 691 mg), 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1.0 equivalents, 1.8 mmol, 424 mg), PdCl2 (dppf) (0.1 equivalents, 0.18 mmol, 132 mg), and KF (5.0 equivalents, 8.9 mmol, 517 mg) were mixed with a mixture of 1,4-dioxane and water (10:1) (9.0 mL). The reaction mixture was stirred at 80°C for 18 hours, then poured into water, extracted twice with EtOAc and brine, dried with MgSO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel flash chromatography (CH2Cl2 / MeOH, 40:1, Rf = 0.3) to obtain the target compound (1.1 mmol, 401 mg, 63%), which is a beige solid.

[0414] 1 H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H), 8.64 (t,J= 6.0 Hz, 1H), 8.58 (s, 1H), 7.83 (dt,J= 8.3, 2.0 Hz, 1H), 7.45 - 7.36 (m, 2H), 7.34 - 7.26 (m, 2H), 7.19 - 7.09 (m, 2H), 6.78 - 6.66 (m, 2H), 4.28 (d,J= 5.9 Hz, 2H), 3.71 (s, 2H); MS (ESI) [M+H] + = 355.4.

[0415] Step 2: Preparation of tert-butyl-4-(2-(3-fluoro-4-(6-(2-((4-fluorobenzyl)amino)-2-oxoethyl)pyridine-3-yl)phenoxy)ethyl)piperazine-1-carboxylate tert-butyl 4-(2-chloroethyl)piperazine-1-carboxylate (1.2 equivalents, 0.23 mmol, 57 mg) and K2CO3 (1.5 equivalents, 0.29 mmol, 40 mg) were added at room temperature to a solution of the previous step product (1.0 equivalent, 0.19 mmol, 68 mg) dissolved in dimethylformamide (1.0 mL). The reaction mixture was stirred at 60°C, poured into water, and extracted twice with EtOAc and saline solution. The organic layer was dried with MgSO4, filtered, and then concentrated under vacuum. The crude product was purified by silica gel flash chromatography (CH2Cl2 / MeOH, 20:1, Rf = 0.3) to obtain the target compound (0.16 mmol, 91 mg, 84%) as a white solid.

[0416] 1 H NMR (400 MHz, DMSO-d6) δ 8.65 (t,J= 5.9 Hz, 1H), 8.62 (d,J= 2.2 Hz, 1H), 7.90 - 7.83 (m, 1H), 7.50 (t,J= 9.0 Hz, 1H), 7.42 (dd,J= 8.1, 0.9 Hz, 1H), 7.36 - 7.27 (m, 2H), 7.19 - 7.10 (m, 2H), 7.01 (dd,J= 12.9, 2.5 Hz, 1H), 6.93 (dd,J= 8.6, 2.5 Hz, 1H), 4.28 (d,J= 5.9 Hz, 2H), 4.16 (t,J= 5.7 Hz, 2H), 3.72 (s, 2H), 2.73 (t,J= 5.6 Hz, 2H), 2.44 (t,J= 5.1 Hz, 4H), 1.39 (s, 9H); MS (ESI) [M+H] + = 567.7.

[0417] Step 3: Preparation of 2-(5-(2-fluoro-4-(2-(piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0418] 30% TFA was added at room temperature to a solution of the previous step product (1.0 equivalent, 0.12 mmol, 70 mg) dissolved in dichloromethane (1.2 mL). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under vacuum. The residue was dissolved in MeOH and stirred with Amberlite IRN 78 for 30 minutes, then filtered and concentrated under vacuum to obtain the target compound (0.12 mmol, 56 mg, 97%) as a white solid.

[0419] 1 H NMR (400 MHz, DMSO-d6) δ 8.65 (t,J= 6.0 Hz, 1H), 8.62 (d,J= 2.2 Hz, 1H), 7.86 (dt,J= 8.2, 1.7 Hz, 1H), 7.50 (t,J= 9.0 Hz, 1H), 7.42 (dd,J= 8.1, 0.8 Hz, 1H), 7.36 - 7.27 (m, 2H), 7.20 - 7.09 (m, 2H), 7.00 (dd,J= 13.0, 2.5 Hz, 1H), 6.92 (dd,J= 8.6, 2.5 Hz, 1H), 4.28 (d,J= 5.9 Hz, 2H), 4.14 (t,J= 5.8 Hz, 2H), 3.72 (s, 2H), 2.72 - 2.63 (m, 6H), 2.40 (br, 4H); MS (ESI) [M+H] + = 567.7.

[0420] <Example 17> Preparation of 2-(5-(2-fluoro-4-(2-(4-methylpiperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0421] The compound of Example 16 (1.0 equivalent, 0.09 mmol, 40 mg), paraformaldehyde (10 equivalents, 0.86 mmol, 26 mg), and 1 drop of acetic acid were added to dichloromethane (1.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. NaBH3CN (10 equivalents, 0.86 mmol, 54 mg) was added to the reaction mixture and stirred for 6 hours. The reaction mixture was poured into water, extracted twice with EtOAc, washed with brine, dried with MgSO4, and then concentrated under vacuum. The crude product was purified by silica gel flash chromatography (CH2Cl2 / MeOH, 20:1) to obtain the target compound (0.017 mmol, 8.0 mg, 19%), which is a white solid.

[0422] 1 H NMR (300 MHz, DMSO-d6) δ 8.66 (t,J= 6.0 Hz, 1H), 8.62 (d,J= 2.2 Hz, 1H), 7.91 - 7.84 (m, 1H), 7.50 (t,J= 9.0 Hz, 1H), 7.42 (dd,J= 8.2, 0.8 Hz, 1H), 7.36 - 7.28 (m, 2H), 7.19 - 7.09 (m, 2H), 7.00 (dd,J= 13.0, 2.5 Hz, 1H), 6.92 (dd,J= 8.5, 2.5 Hz, 1H), 4.28 (d,J= 5.9 Hz, 2H), 4.14 (t,J= 5.8 Hz, 2H), 3.72 (s, 2H), 2.69 (t,J= 5.7 Hz, 2H), 2.33 (s, 4H), 2.15 (s, 3H); MS (ESI) [M+H] + = 481.5.

[0423] <Example 18> Preparation of 2-(5-(4-(2-(4-acetylpiperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0424] The compound of Example 16 (1.0 equivalent, 0.09 mmol, 40 mg) and acetic anhydride (1.3 equivalent, 0.11 mmol, 11 μL) were added to dichloromethane (1.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into water, extracted twice with EtOAc, washed with salt water, dried with MgSO4, and then concentrated under vacuum without further purification to obtain the target compound (44 mg, 0.09 mmol, 99%) as a yellow solid.

[0425] 1 H NMR (400 MHz, DMSO-d6) δ 8.64 (t,J= 5.9 Hz, 1H), 8.62 (d,J= 1.6 Hz, 1H), 7.90 - 7.83 (m, 1H), 7.50 (dd,J= 9.3, 8.6 Hz, 1H), 7.42 (dd,J= 8.2, 0.9 Hz, 1H), 7.36 - 7.27 (m, 2H), 7.19 - 7.09 (m, 2H), 7.01 (dd,J= 12.9, 2.5 Hz, 1H), 6.93 (dd,J= 8.5, 2.5 Hz, 1H), 4.28 (d,J= 5.9 Hz, 2H), 4.17 (t,J= 5.7 Hz, 2H), 3.72 (s, 2H), 3.43 (q,J= 5.3 Hz, 4H), 2.74 (t,J= 5.7 Hz, 2H), 2.43 (t,J= 5.2 Hz, 2H), 1.98 (s, 3H); MS (ESI) [M+H] + = 509.8.

[0426] <Example 19> Preparation of 2-(5-(4-(2-(4-(cyclopropanecarbonyl)piperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0427] The compound of Example 16 (1.0 equivalent, 0.09 mmol, 40 mg), cyclopropane carboxylic acid (1.3 equivalent, 0.111 mmol, 9 μL), EDCI·HCl (1.5 equivalent, 0.129 mmol, 25 mg), HOBt (1.5 equivalent, 0.129 mmol, 17 mg), and DIPEA (3 equivalent, 0.258 mmol, 45 μL) were mixed in dichloromethane (1.0 mL) and stirred overnight at room temperature. The reaction mixture was poured into water and extracted twice with EtOAc, then washed with brine, dried with MgSO4, and concentrated under vacuum. The crude product was purified by silica gel flash chromatography (CH2Cl2 / MeOH, 10:1) to obtain the target compound (0.082 mmol, 44 mg, 95%), which is a white solid.

[0428] 1 H NMR (400 MHz, DMSO) δ 8.66 (t,J= 5.9 Hz, 1H), 8.63 (d,J= 2.2 Hz, 1H), 7.91 - 7.84 (m, 1H), 7.52 (t,J= 9.0 Hz, 1H), 7.43 (dd,J= 8.1, 0.9 Hz, 1H), 7.37 - 7.30 (m, 2H), 7.19 - 7.11 (m, 2H), 7.02 (dd,J= 12.9, 2.5 Hz, 1H), 6.95 (dd,J= 8.6, 2.5 Hz, 1H), 4.29 (d,J= 5.9 Hz, 2H), 4.19 (t,J= 5.7 Hz, 2H), 3.72 (s, 2H) 3.68 (br, 2H), 3.48 (br, 2H), 2.76 (t,J= 5.7 Hz, 2H), 2.53 (s, 2H), 2.46 (s, 2H), 2.01 - 1.93 (m, 1H), 0.78 - 0.65 (m, 4H); MS (ESI) [M+H] + = 535.9.

[0429] <Example 20> Preparation of 2-(5-(4-(2-(4-(cyclobutanecarbonyl)piperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0430] The target compound was obtained by a method similar to that of Example 19. The product was obtained as a white solid (0.078 mmol, 43 mg, 91%).

[0431] 1 H NMR (400 MHz, DMSO-d6) δ 8.65 (t,J= 5.9 Hz, 1H), 8.62 (d,J= 2.4 Hz, 1H), 7.90 - 7.83 (m, 1H), 7.50 (t,J= 9.0 Hz, 1H), 7.42 (dd,J= 8.1, 0.8 Hz, 1H), 7.36 - 7.27 (m, 2H), 7.20 - 7.09 (m, 2H), 7.01 (dd,J= 13.0, 2.5 Hz, 1H), 6.93 (dd,J= 8.6, 2.5 Hz, 1H), 4.28 (d,J= 5.9 Hz, 2H), 4.16 (t,J= 5.7 Hz, 2H), 3.72 (s, 2H), 3.44 (t,J= 5.1 Hz, 2H), 3.40 - 3.35 (m, 1H) 2.73 (t,J= 5.7 Hz, 2H), 2.47 - 2.33 (m, 4H), 2.22 - 2.01 (m, 4H), 2.00 - 1.81 (m, 1H), 1.79 - 1.66 (m, 1H); MS (ESI) [M+H] + = 549.9.

[0432] <Example 21> Preparation of 2-(5-(4-(2-(4-(2-cyclopropylacetyl)piperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0433] The target compound was obtained by a method similar to that of Example 19. The product was obtained as a white solid (0.077 mmol, 43 mg, 90%).

[0434] 1H NMR (400 MHz, DMSO) δ 8.65 (t,J= 6.0 Hz, 1H), 8.63 - 8.60 (m, 1H), 7.90 - 7.83 (m, 1H), 7.50 (t,J= 9.0 Hz, 1H), 7.42 (dd,J= 8.1, 0.8 Hz, 1H), 7.36 - 7.27 (m, 2H), 7.20 - 7.09 (m, 2H), 7.01 (dd,J= 12.9, 2.5 Hz, 1H), 6.93 (dd,J= 8.6, 2.5 Hz, 1H), 4.28 (d,J= 5.9 Hz, 2H), 4.17 (t,J= 5.6 Hz, 2H), 3.72 (s, 2H), 3.44 (dt,J= 13.3, 5.3 Hz, 4H), 2.74 (t,J= 5.7 Hz, 2H), 2.44 (t,J= 5.2 Hz, 2H), 2.24 (d,J= 6.7 Hz, 2H), 1.00 - 0.87 (m, 1H), 0.49 - 0.37 (m, 2H), 0.14 - 0.06 (m, 2H); MS (ESI) [M+H] + = 549.9.

[0435] <Example 22> Preparation of 2-(5-(2-fluoro-4-(2-(4-(2-hydroxyacetyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0436] The target compound was obtained by a method similar to that of Example 19. Further purification was performed by thin-layer chromatography (CH2Cl2 / MeOH, 20:1). The product was obtained as a white solid (0.077 mmol, 43 mg, 90%).

[0437] 1H NMR (400 MHz, DMSO-d6) δ 8.64 (t,J= 6.0 Hz, 1H), 8.62 (d,J= 2.1 Hz, 1H), 7.86 (dt,J= 8.1, 1.8 Hz, 1H), 7.50 (t,J= 9.0 Hz, 1H), 7.42 (d,J= 8.1 Hz, 1H), 7.36 - 7.27 (m, 2H), 7.19 - 7.09 (m, 2H), 7.01 (dd,J= 12.9, 2.5 Hz, 1H), 6.93 (dd,J= 8.6, 2.5 Hz, 1H), 4.53 (t,J= 5.5 Hz, 1H), 4.28 (d,J= 5.9 Hz, 2H), 4.17 (t,J= 5.6 Hz, 2H), 4.07 (d,J= 5.5 Hz, 2H), 3.72 (s, 2H), 3.47 (br, 2H), 2.75 (t,J= 5.6 Hz, 2H); MS (ESI) [M+H] + = 525.5.

[0438] <Example 23> Preparation of 2-(5-(2-fluoro-4-(2-(4-glycylpiperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0439]

[0440] Step 1: Preparation of tert-butyl(2-(4-(2-(3-fluoro-4-(6-(2-((4-fluorobenzyl)amino)-2-oxoethyl)pyridine-3-yl)phenoxy)ethyl)piperazine-1-yl)-2-oxoethyl)carbamate

[0441] The target compound was obtained by a method similar to that of Example 19. The product was obtained as a white solid (0.038 mmol, 24 mg, 44%).

[0442] 1H NMR (400 MHz, DMSO-d6) δ 8.65 (t,J= 6.0 Hz, 1H), 8.62 (d,J= 2.3 Hz, 1H), 7.87 (dt,J= 8.2, 1.8 Hz, 1H), 7.51 (t,J= 9.0 Hz, 1H), 7.42 (d,J= 7.7 Hz, 1H), 7.36 - 7.30 (m, 2H), 7.21 - 7.11 (m, 2H), 7.01 (dd,J= 12.9, 2.5 Hz, 1H), 6.93 (dd,J= 8.6, 2.5 Hz, 1H), 6.73 (t,J= 5.9 Hz, 1H), 4.28 (d,J= 5.9 Hz, 2H), 4.17 (t,J= 5.6 Hz, 2H), 3.77 (d,J= 5.9 Hz, 2H), 3.72 (s, 2H), 3.44 (br, 4H), 2.75 (t,J= 5.6 Hz, 2H), 2.46 (br, 2H), 1.38 (s, 9H); MS (ESI) [M+H] + = 625.0.

[0443] Step 2: Preparation of 2-(5-(2-fluoro-4-(2-(4-glycylpiperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0444] The product of the previous step (1 equivalent, 0.032 mmol, 20 mg) was dissolved in dichloromethane (1.0 mL), and then 30% TFA was added at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum. The residue was dissolved in methanol and stirred with Amberlite IRN 78 for 30 minutes, then filtered and concentrated under vacuum to obtain the target compound (0.029 mmol, 15 mg, 91%) as a white solid.

[0445] 1H NMR (400 MHz, DMSO-d6) δ 8.66 (t,J= 6.0 Hz, 1H), 8.62 (d,J= 2.3 Hz, 1H), 7.86 (dt,J= 8.2, 1.8 Hz, 1H), 7.50 (t,J= 9.0 Hz, 1H), 7.42 (d,J= 8.1 Hz, 1H), 7.36 - 7.27 (m, 2H), 7.20 - 7.09 (m, 2H), 7.01 (dd,J= 12.9, 2.5 Hz, 1H), 6.93 (dd,J= 8.6, 2.5 Hz, 1H), 4.28 (d,J= 5.9 Hz, 2H), 4.17 (t,J= 5.6 Hz, 2H), 3.72 (s, 2H), 3.47 (t,J= 5.1 Hz, 2H), 3.30 (s, 2H), 2.74 (t,J= 5.7 Hz, 2H), 2.47 - 2.44 (m, 4H); MS (ESI) [M+H] + = 524.8.

[0446] <Example 24> Preparation of (R)-2-(5-(2-fluoro-4-(2-(4-(2-hydroxypropanoyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0447] The target compound was obtained by a method similar to that of Example 19. The resulting white solid was dissolved in methanol (1.7 mL), and K2CO3 (5 equivalents, 0.417 mmol, 57 mg) was added at room temperature. The reaction mixture was stirred for 1 hour, then quenched with saturated NH4Cl, poured into water, extracted twice with EtOAc, washed with brine, dried with MgSO4, and concentrated under vacuum to obtain the target compound (0.087 mmol, 47 mg, 68%, 2-step yield) as a white solid.

[0448] 1H NMR (400 MHz, DMSO-d6) δ 8.62 (d,J= 2.1 Hz, 1H), 8.53 (t,J= 6.0 Hz, 1H), 7.86 (dt,J= 8.3, 1.8 Hz, 1H), 7.50 (t,J= 8.9 Hz, 1H), 7.43 (d,J= 8.1 Hz, 1H), 7.36 - 7.28 (m, 2H), 7.18 - 7.07 (m, 2H), 6.99 (dd,J= 12.9, 2.5 Hz, 1H), 6.93 (dd,J= 8.6, 2.5 Hz, 1H), 4.72 (d,J=6.8 Hz, 1H), 4.42 (p,J= 6.6 Hz, 1H), 4.29 (d,J= 5.9 Hz, 2H), 4.18 (t,J= 5.6 Hz, 2H), 3.73 (s, 2H), 3.51 (br, 4H), 2.76 (t,J= 5.7 Hz, 2H), 1.19 (d,J=6.5 Hz, 3H); MS (ESI) [M+H] + = 539.5.

[0449] <Example 25> Preparation of (S)-2-(5-(2-fluoro-4-(2-(4-(2-hydroxypropanoyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0450] The target compound was obtained by a method similar to that of Example 24. The product was obtained as a white solid (0.057 mmol, 31 mg, 53%, 2-step yield).

[0451] 1H NMR (400 MHz, DMSO) δ 8.62 (s, 1H), 8.53 (t,J= 6.0 Hz, 1H), 7.86 (dt,J= 8.1, 1.8 Hz, 1H), 7.51 (t,J= 9.0 Hz, 1H), 7.43 (d,J= 8.1 Hz, 1H), 7.33 (dd,J= 8.6, 5.6 Hz, 2H), 7.18 - 7.09 (m, 2H), 6.99 (dd,J= 12.9, 2.5 Hz, 1H), 6.94 (dd,J= 8.6, 2.5 Hz, 1H), 4.73 (d,J= 6.8 Hz, 1H), 4.42 (p,J= 6.6 Hz, 1H), 4.30 (d,J= 5.9 Hz, 2H), 4.19 (t,J= 5.7 Hz, 2H), 3.73 (s, 2H), 3.52 (br, 4H), 2.77 (t,J= 5.7 Hz, 2H), 1.19 (d,J= 6.5 Hz, 2H); MS (ESI) [M+H] + = 539.6.

[0452] <Example 26> Preparation of 2-(5-(2-fluoro-4-(2-(4-(2-methoxyacetyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0453] The target compound was obtained by a method similar to that of Example 19. The product was obtained as a white solid (0.13 mmol, 71 mg, quantified).

[0454] 1H NMR (400 MHz, DMSO-d6) δ 8.67 (t,J= 6.0 Hz, 1H), 8.61 (s, 1H), 7.87 (d,J= 8.1 Hz, 1H), 7.51 (t,J= 9.0 Hz, 1H), 7.42 (d,J= 8.1 Hz, 1H), 7.31 (dd,J= 8.4, 5.6 Hz, 2H), 7.15 (t,J= 8.8 Hz, 2H), 7.01 (dd,J= 13.0, 2.5 Hz, 1H), 6.93 (dd,J= 8.6, 2.5 Hz, 1H), 4.28 (d,J= 5.9 Hz, 2H), 4.16 (t,J= 5.7 Hz, 2H), 4.07 (s, 2H), 3.72 (s, 2H), 3.45 (br, 2H), 3.27 (s, 3H), 2.74 (t,J= 5.7 Hz, 2H), 2.46 (br, 2H); MS (ESI) [M+H] + = 539.7.

[0455] <Example 27> Preparation of (R)-2-(5-(2-fluoro-4-(2-(4-(2-methoxypropanoyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0456] The target compound was obtained by a method similar to that of Example 19. The product was obtained as a white solid (0.11 mmol, 61 mg, 68%).

[0457] 1H NMR (400 MHz, DMSO) δ 8.65 (t,J= 6.0 Hz, 1H), 8.61 (s, 1H), 7.87 (d,J= 8.2 Hz, 1H), 7.51 (t,J= 8.9 Hz, 1H), 7.42 (d,J= 8.1 Hz, 1H), 7.32 (dd,J= 8.4, 5.6 Hz, 2H), 7.14 (t,J= 8.8 Hz, 2H), 7.01 (dd,J= 12.9, 2.4 Hz, 1H), 6.94 (dd,J= 8.6, 2.5 Hz, 1H), 4.28 (d,J= 5.9 Hz, 2H), 4.25 - 4.13 (m, 3H), 3.72 (s, 2H), 3.53 (br, 2H), 3.48 (br, 2H), 3.19 (s, 3H), 2.74 (t,J= 5.7 Hz, 2H), 2.46 (br, 1H), 1.20 (d,J= 6.6 Hz, 3H); [M+H] + = 553.5.

[0458] <Example 28> Preparation of (S)-2-(5-(2-fluoro-4-(2-(4-(2-methoxypropanoyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0459] The target compound was obtained by a method similar to that of Example 19. The product was obtained as a white solid (0.075 mmol, 42 mg, 76%).

[0460] 1H NMR (400 MHz, DMSO-d6) δ 8.65 (t,J= 5.9 Hz, 1H), 8.61 (s, 1H), 7.87 (d,J= 8.1 Hz, 1H), 7.51 (t,J= 9.0 Hz, 1H), 7.42 (d,J= 8.1 Hz, 1H), 7.32 (dd,J= 8.4, 5.6 Hz, 2H), 7.14 (dd,J= 10.0, 7.7 Hz, 2H), 7.01 (dd,J= 12.9, 2.5 Hz, 1H), 6.94 (dd,J= 8.5, 2.5 Hz, 1H), 4.28 (d,J= 5.9 Hz, 2H), 4.25 - 4.13 (m, 3H), 3.72 (s, 2H), 3.54 (br, 2H), 3.48 (br, 2H), 3.19 (s, 3H), 2.74 (t,J= 5.6 Hz, 2H), 2.46 (br, 2H), 1.20 (d,J= 6.6) Hz, 3H); [M+H] + = 553.6.

[0461] <Example 29> Preparation of 2-(5-(2-fluoro-4-(2-(4-(2-methoxy-2-methylpropanoyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0462] The target compound was obtained by a method similar to that of Example 19. The product was obtained as a white solid (0.070 mmol, 40 mg, 65%).

[0463] 1H NMR (400 MHz, DMSO-d6) δ 8.65 (t,J= 5.9 Hz, 1H), 8.61 (s, 1H), 7.87 (dt,J= 8.1, 1.9 Hz, 1H), 7.51 (t,J= 9.0 Hz, 1H), 7.42 (d,J= 8.1 Hz, 1H), 7.36 - 7.27 (m, 2H), 7.20 - 7.10 (m, 2H), 7.01 (dd,J= 12.9, 2.5 Hz, 1H), 6.94 (dd,J= 8.6, 2.5 Hz, 1H), 4.28 (d,J= 5.9 Hz, 2H), 4.17 (t,J= 5.6 Hz, 2H), 3.88 (br, 2H), 3.72 (s, 2H), 3.50 (br, 2H), 3.13 (s, 3H), 2.74 (t,J= 5.6 Hz, 2H), 1.31 (s, 6H); MS (ESI) [M+H] + = 567.6.

[0464] <Example 30> Preparation of 2-(5-(2-fluoro-4-(2-(4-(3-hydroxypropanoyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0465] The compound of Example 16 (1.0 equivalent, 0.13 mmol, 60 mg), 3-hydroxypropanoic acid solution (1.3 equivalent, 0.17 mmol, 46 μL), and DMTMM (1.3 equivalent, 0.17 mmol, 46 mg) were mixed in dimethylformamide (1.3 mL) and stirred overnight at room temperature. The reaction mixture was poured into water, extracted twice with EtOAc, washed with saline solution, dried with MgSO4, and concentrated under vacuum. The crude product was purified by flash chromatography (CH2Cl2 / MeOH, 10:1) on silica gel. The resulting mixture was dissolved in methanol, and K2CO3 (5 equivalent, 0.417 mmol, 57 mg) was added at room temperature. The reaction mixture was stirred for 1 hour, poured into water, extracted twice with EtOAc, washed with saline solution, dried with MgSO4, and concentrated under vacuum. The crude product was purified by silica gel flash chromatography (CH2Cl2 / MeOH, 10:1) to obtain the target compound (0.030 mmol, 16 mg, 23%, 2-step yield) as a white solid.

[0466] 1 H NMR (400 MHz, DMSO-d6) δ 8.65 (t,J= 6.0 Hz, 1H), 8.61 (s, 1H), 7.86 (dt,J= 8.1, 1.9 Hz, 1H), 7.50 (t,J= 9.0 Hz, 1H), 7.42 (d,J= 8.1 Hz, 1H), 7.37 - 7.27 (m, 2H), 7.19 - 7.09 (m, 2H), 7.01 (dd,J= 12.9, 2.5 Hz, 1H), 6.93 (dd,J= 8.5, 2.5 Hz, 1H), 4.50 (t,J= 5.4 Hz, 1H), 4.28 (d,J= 5.9 Hz, 2H), 4.17 (t,J= 5.6 Hz, 2H), 3.72 (s, 2H), 3.62 (q,J= 6.3 Hz, 2H), 3.45 (t,J= 5.1 Hz, 4H), 2.75 (t ,J= 5.6 Hz, 2H), 2.50 - 2.41 (m, 4H); MS (ESI) [M+H]+ = 539.6.

[0467] <Example 31> Preparation of 2-(5-(2-fluoro-4-(2-(4-(methylglycyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0468] Step 1: Preparation of tert-butyl(2-(4-(2-(3-fluoro-4-(6-(2-((4-fluorobenzyl)amino)-2-oxoethyl)pyridine-3-yl)phenoxy)ethyl)piperazine-1-yl)-2-oxoethyl)(methyl)carbamate

[0469] Boc-N-methylglycine (1.3 equivalents, 0.17 mmol, 32 mg) and DMTMM (1.3 equivalents, 0.17 mmol, 46 mg) were dissolved in dichloromethane (1.3 mL), after which the compound of Example 16 (1.0 equivalent, 0.13 mmol, 60 mg) was added at room temperature and stirred overnight. The reaction mixture was poured into water, extracted twice with CH2Cl2, washed with brine, dried with MgSO4, and then vacuum concentrated. The crude product was purified by silica gel flash chromatography (CH2Cl2 / MeOH, 10:1) to obtain the target compound (0.10 mmol, 66 mg, 80%), which is a white solid.

[0470] Step 2: Preparation of 2-(5-(2-fluoro-4-(2-(4-(methylglycyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0471] The product of the previous step (1 equivalent, 0.074 mmol, 47 mg) was dissolved in dichloromethane (1.5 mL), and 30% TFA was added at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum. The residue was dissolved in methanol, passed through a column packed with Amberlite IRN 78, and concentrated under vacuum to obtain the target compound (0.074 mmol, 40 mg, quantified) as a white solid.

[0472] 1H NMR (400 MHz, DMSO-d6) δ 8.66 (t,J= 6.0 Hz, 1H), 8.63 (d,J= 2.3 Hz, 1H), 7.87 (dt,J= 8.3, 1.8 Hz, 1H), 7.51 (t,J= 9.0 Hz, 1H), 7.43 (d,J= 8.1 Hz, 1H), 7.37 - 7.28 (m, 2H), 7.22 - 7.10 (m, 2H), 7.02 (dd,J= 12.9, 2.5 Hz, 1H), 6.94 (dd,J= 8.6, 2.5 Hz, 1H), 4.29 (d,J=5.9 Hz, 2H), 4.18 (t,J= 5.6 Hz, 2H), 3.73 (s, 2H), 3.47 (t,J= 5.1 Hz, 2H), 3.41 (t,J= 5.0 Hz, 2H), 3.30 (s, 2H), 2.75 (t,J= 5.6 Hz, 2H), 2.45 (m, 2H), 2.27 (s, 3H); MS (ESI) [M+H] + = 538.6.

[0473] <Example 32> Preparation of 2-(5-(4-(2-(4-(D-alanyl)piperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0474] The target compound was obtained by a method similar to that of Example 31. The product was obtained as a yellow solid (0.085 mmol, 46 mg, 96%, 2-step yield).

[0475] 1H NMR (400 MHz, DMSO-d6) δ 8.66 (t,J= 6.0 Hz, 1H), 8.61 (d,J= 2.2 Hz, 1H), 7.87 (dt,J= 8.2, 1.8 Hz, 1H), 7.51 (t,J= 9.0 Hz, 1H), 7.42 (d,J= 8.1 Hz, 1H), 7.38 - 7.27 (m, 2H), 7.20 - 7.09 (m, 2H), 7.01 (dd,J= 12.9, 2.5 Hz, 1H), 6.93 (dd,J= 8.6, 2.5 Hz, 1H), 4.28 (d,J= 5.9 Hz, 2H), 4.17 (t,J= 5.6 Hz, 2H), 3.73 (m, 3H), 3.50 - 3.43 (m, 4H), 2.74 (t,J= 5.6 Hz, 2H), 2.46 (d,J= 5.5 Hz, 3H), 1.05 (d,J= 6.7 Hz, 3H), MS (ESI) [M+H] + = 538.6.

[0476] <Example 33> Preparation of 2-(5-(4-(2-(4-(L-alanyl)piperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0477] The target compound was obtained by a method similar to that of Example 31. The product was obtained as a yellow solid (0.092 mmol, 49 mg, 89%, 2-step yield).

[0478] 1H NMR (400 MHz, DMSO-d6) δ 8.67 (t,J= 6.0 Hz, 1H), 8.61 (s, 1H), 7.87 (dt,J= 7.8, 2.0 Hz, 1H), 7.51 (t,J= 9.0 Hz, 1H), 7.42 (d,J= 8.1 Hz, 1H), 7.31 (dd,J= 8.4, 5.7 Hz, 2H), 7.15 (t,J= 8.9 Hz, 2H), 7.02 (dd,J= 12.9, 2.5 Hz, 1H), 6.93 (dd,J= 8.6, 2.5 Hz, 1H), 4.28 (d,J= 5.9 Hz, 2H), 4.17 (t,J= 5.6 Hz, 2H), 3.78 (q,J= 6.7 Hz, 1H), 3.72 (s, 2H), 3.47 (m, 4H), 2.74 (t,J= 5.6 Hz, 2H), 2.46 (br, 4H), 1.07 (d,J= 6.7 Hz, 3H). MS (ESI) [M+H] + = 538.6.

[0479] <Example 34> Preparation of 2-(5-(4-(2-(4-(3-aminopropanoyl)piperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0480] The target compound was obtained by a method similar to that of Example 31. The product was obtained as a yellow solid (0.056 mmol, 30 mg, 51%, 2-step yield).

[0481] 1H NMR (400 MHz, DMSO-d6) δ 8.65 (t,J= 6.0 Hz, 1H), 8.61 (d,J= 2.1 Hz, 1H), 7.87 (dt,J= 8.2, 1.8 Hz, 1H), 7.51 (t,J= 9.0 Hz, 1H), 7.43 (d,J= 8.1 Hz, 1H), 7.37 - 7.27 (m, 2H), 7.20 - 7.09 (m, 2H), 7.01 (dd,J= 12.9, 2.5 Hz, 1H), 6.93 (dd,J= 8.6, 2.6 Hz, 1H), 4.28 (d,J= 5.9 Hz, 2H), 4.17 (t,J= 5.7 Hz, 2H), 3.72 (s, 2H), 3.45 (m, 4H), 2.73 (m, 4H), 2.44 (t,J= 5.1 Hz, 2H), 2.37 (t,J= 6.5 Hz, 2H); MS (ESI) [M+H] + = 538.4.

[0482] <Example 35> Preparation of N-(4-fluorobenzyl)-2-(5-(2-methyl-4-(2-(piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)acetamide

[0483]

[0484] Step 1: Preparation of N-(4-fluorobenzyl)-2-(5-(4-hydroxy-2-methylphenyl)pyridine-2-yl)acetamide

[0485] 2-(5-bromopyridine-2-yl)-N-(4-fluorobenzyl)acetamide (1.2 equivalents, 0.41 mmol, 168 mg), PdCl2 (dppf) (0.1 equivalents, 0.034 mmol, 25 mg), and KF (5.0 equivalents, 1.7 mmol, 99 mg) were mixed with a mixture of 1,4-dioxane and water (10:1) (1.7 mL). The reaction mixture was stirred at 80°C for 16 hours, then poured into water, extracted twice with EtOAc and brine, dried with MgSO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel flash chromatography (Hexane / EtOAc, 1:2, Rf = 0.3) to obtain the target compound (0.15 mmol, 52 mg, 43%), which is a brown oil.

[0486] 1 H NMR (400 MHz, DMSO-d6) δ 9.48 (s, 1H), 8.66 (t, J = 6.1 Hz, 1H), 8.41 (d, J = 2.3 Hz, 1H), 7.68 (dd, J = 8.0, 2.4 Hz, 1H), 7.37 (d, J = 8.2 Hz, 1H), 7.32 (dd, J = 8.5, 5.6 Hz, 2H), 7.15 (t, J = 8.8 Hz, 2H), 7.05 (d, J = 8.2 Hz, 1H), 6.75 - 6.66 (m, 2H), 4.29 (d, J = 6.0 Hz, 2H), 3.71 (s, 2H), 2.18 (s, 3H); MS (ESI) [M+H] + = 351.2

[0487] Step 2: Preparation of tert-butyl 4-(2-(4-(6-(2-((4-fluorobenzyl)amino)-2-oxoethyl)pyridine-3-yl)-3-methylphenoxy)ethyl)piperazine-1-carboxylate

[0488] Tert-butyl 4-(2-chloroethyl)piperazine-1-carboxylate (1.2 equivalents, 0.18 mmol, 45 mg) and K2CO3 (1.5 equivalents, 0.22 mmol, 30 mg) were added at room temperature to a solution of the pre-step product (1.0 equivalent, 0.15 mmol, 52 mg) dissolved in dimethylformamide (1.0 mL). The reaction mixture was stirred at 60°C, poured into water, and extracted twice with EtOAc and brine. The organic layer was dried with MgSO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel flash chromatography (CH2Cl2 / MeOH, 10:1, Rf = 0.4) to obtain the target compound (0.075 mmol, 42 mg, 50%) as a yellow oil.

[0489] 1 H NMR (400 MHz, DMSO-d6) δ 8.66 (t, 1H), 8.43 (d, J = 2.3 Hz, 1H), 7.71 (dd, J = 7.9, 2.4 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.33 (dd, J = 8.5, 5.6 Hz, 2H), 7.19 - 7.08 (m, 3H), 6.93 (d, 1H), 6.88 (dd, J = 8.3 Hz, 1H), 4.30 (d, J = 6.0 Hz, 2H), 4.12 (t, J = 5.7 Hz, 2H), 3.72 (s, 2H), 2.74 (t, J = 5.7 Hz, 2H), 2.45 (t, J = 5.0 Hz, 3H), 2.23 (s, 3H), 1.40 (s, 9H); MS (ESI) [M+H] + = 563.2

[0490] Step 3: Preparation of N-(4-fluorobenzyl)-2-(5-(2-methyl-4-(2-(piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)acetamide

[0491] 30% TFA was added at room temperature to a solution of the previous step product (1.0 equivalent, 0.071 mmol, 40 mg) dissolved in dichloromethane (0.7 mL). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under vacuum. The residue was dissolved in MeOH and stirred with Amberlite IRN 78 for 30 minutes, then filtered and concentrated under vacuum to obtain the target compound (0.071 mmol, 33 mg, 83%) as a yellow oil.

[0492] 1 H NMR (400 MHz, DMSO-d6) δ 8.68 (t, J = 6.0 Hz, 1H), 8.43 (d, J = 2.3 Hz, 1H), 7.77 - 7.65 (m, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.32 (dd, J = 8.3, 5.6 Hz, 2H), 7.15 (dt, J = 8.8, 4.7 Hz, 3H), 6.93 (s, 1H), 6.87 (d, J = 8.8 Hz, 1H), 4.29 (d, J = 5.9 Hz, 2H), 4.10 (t, J = 5.9) Hz, 2H), 3.72 (s, 2H), 2.69 (dt, J = 19.1, 5.4 Hz, 5H), 2.42 (m, 4H), 2.23 (s, 3H); MS (ESI) [M+H] + = 463.2

[0493] <Example 36> Preparation of N-(4-fluorobenzyl)-2-(5-(4-(2-(4-(2-hydroxyacetyl)piperazine-1-yl)ethoxy)-2-methylphenyl)pyridine-2-yl)acetamide

[0494] The compound of Example 35 (1.0 equivalent, 0.032 mmol, 15 mg), 2-hydroxyacetic acid (1.5 equivalent, 0.048 mmol, 3.7 mg), EDCI·HCl (1.5 equivalent, 0.048 mmol, 9.2 mg), HOBt (1.5 equivalent, 0.048 mmol, 6.5 mg), and DIPEA (3 equivalent, 0.096 mmol, 17 μL) were mixed in dichloromethane (1.0 mL) and stirred overnight at room temperature. The reaction mixture was poured into water and extracted twice with CH2Cl2, then washed with brine, dried with MgSO4, and concentrated under vacuum. The crude product was purified by silica gel flash chromatography (CH2Cl2 / MeOH, 10:1) to obtain the target compound (0.021 mmol, 11 mg, 66%), which is a white solid.

[0495] 1 H NMR (300 MHz, DMSO-d6) δ 8.68 (t, 1H), 8.44 (d, J = 2.3 Hz, 1H), 7.71 (dd, J = 7.9, 2.4 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.33 (dd, J = 8.4, 5.6 Hz, 2H), 7.22 - 7.09 (m, 3H), 6.93 (s, 1H), 6.88 (dd, J = 8.0 Hz, 1H), 4.56 (t, J = 5.5 Hz, 1H), 4.30 (d, J = 6.0 Hz, 2H), 4.20 - 3.99 (m, 4H), 3.72 (s, 2H), 3.48 (s, 4H), 2.75 (t, J = 5.5 Hz, 2H), 2.23 (s, 2H); MS (ESI) [M+H] + = 521.19

[0496] <Example 37> Preparation of N-(4-fluorobenzyl)-2-(5-(4-(2-(4-glycylpiperazine-1-yl)ethoxy)-2-methylphenyl)pyridine-2-yl)acetamide

[0497]

[0498] Step 1: Preparation of tert-butyl(2-(4-(2-(4-(6-(2-((4-fluorobenzyl)amino)-2-oxoethyl)pyridine-3-yl)-3-methylphenoxy)ethyl)piperazine-1-yl)-2-oxoethyl)carbamate

[0499] Boc-N-methylglycine (1.3 equivalents, 0.032 mmol, 15 mg) and DMTMM (1.3 equivalents, 0.042 mmol, 7.4 mg) were dissolved in dichloromethane (1.0 mL), and then the compound of Example 35 (1.0 equivalent, 0.032 mmol, 15 mg) was added at room temperature and stirred for 2 hours. The reaction mixture was poured into water, extracted twice with CH2Cl2, washed with brine, dried with MgSO4, and then vacuum concentrated. The crude product was purified by silica gel flash chromatography (CH2Cl2 / MeOH, 10:1) to obtain the target compound (0.027 mmol, 17 mg, 86%), which is a yellow oil.

[0500] 1 H NMR (300 MHz, DMSO-d6) δ 8.68 (t, J = 6.0 Hz, 1H), 8.44 (d, J = 2.3 Hz, 1H), 7.71 (dd, J = 8.0, 2.3 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.33 (dd, J = 8.6, 5.6 Hz, 2H), 7.21 - 7.09 (m, 3H), 6.94 (s, 1H), 6.88 (d, J = 9.3 Hz, 1H), 6.77 (t, J = 5.9 Hz, 1H), 4.30 (d, J = 5.9 Hz, 2H), 4.13 (t, J = 5.6 Hz, 2H), 3.75 (d, J = 18.7 Hz, 4H), 3.48 - 3.38 (m, 4H), 2.76 (d, J = 5.7 Hz, 2H), 2.23 (s, 3H), 1.38 (s, 9H); MS (ESI) [M+H] + = 620.23.

[0501] Step 2: Preparation of N-(4-fluorobenzyl)-2-(5-(4-(2-(4-glycylpiperazine-1-yl)ethoxy)-2-methylphenyl)pyridine-2-yl)acetamide

[0502] The product of the previous step (1 equivalent, 0.027 mmol, 17 mg) was dissolved in 1,4-dioxane (1 mL), and then 4N HCl was added at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum to obtain the target compound (0.043 mmol, 27 mg, 150%) as a white solid.

[0503] 1 H NMR (400 MHz, DMSO-d6) δ 11.74 (s, 1H), 8.87 (s, 1H), 8.67 (s, 1H), 8.22 (s, 3H), 8.12 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.48 - 7.25 (m, 3H), 7.17 (t, J = 8.7 Hz, 2H), 7.08 - 6.87 (m, 2H), 4.51 (s, 3H), 4.31 (d, J = 5.8 Hz, 2H), 4.01 - 3.85 (m, 4H), 2.27 (s, 3H); MS (ESI) [M+H] + = 520.16.

[0504] <Example 38> Preparation of 2-(5-(2-fluoro-4-(2-(piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-methylbenzyl)acetamide

[0505]

[0506] Step 1: Preparation of 2-(5-bromopyridine-2-yl)-N-(4-methylbenzyl)acetamide

[0507] Solution of 2-(5-bromopyridine-2-yl)acetic acid (1.0 equivalent, 0.46 mmol, 100 mg), 4-methylbenzylamine (1.2 equivalent, 0.55 mmol, 70 μL), EDCI·HCl (1.5 equivalent, 0.69 mmol, 132 mg), Et3N (5 equivalent, 2.3 mmol, 384 μL), and HOBt (1.5 equivalent, 0.69 mmol, 93 mg) were added sequentially to dichloromethane (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 15 hours, then poured into water, extracted twice with EtOAc, dried with MgSO4, and concentrated under vacuum. The crude product was purified in silica gel by flash chromatography (CH2Cl2 / MeOH, 20:1, Rf = 0.4) to obtain the target compound (0.32 mmol, 102 mg, 69%), which is a yellow solid.

[0508] 1 H NMR (400 MHz, CDCl-3) δ 8.58 (d, J = 2.4 Hz, 1H), 7.96 - 7.82 (m, 1H), 7.31 (d, J = 8.3 Hz, 2H), 7.13 (s, 4H), 4.40 (d, J = 5.7 Hz, 2H), 3.80 (s, 2H), 2.33 (s, 3H). MS (ESI) [M+H] + = 320.95

[0509] Step 2: Preparation of 2-(5-(2-fluoro-4-hydroxyphenyl)pyridine-2-yl)-N-(4-methylbenzyl)acetamide

[0510] The product of the previous step (1.2 equivalents, 0.47 mmol, 150 mg), 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1.0 equivalents, 0.39 mmol, 93 mg), PdCl2 (dppf) (0.1 equivalents, 0.039 mmol, 29 mg), and KF (5.0 equivalents, 1.95 mmol, 113 mg) were mixed with a mixture of 1,4-dioxane and water (10:1) (2.0 mL). The reaction mixture was stirred at 80°C for 12 hours, then poured into water, extracted twice with EtOAc and brine, dried with MgSO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel flash chromatography (Hexane / EtOAc, 1:2, Rf = 0.3) to obtain the target compound (0.19 mmol, 68 mg, 50%), which is a yellow solid.

[0511] 1 H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.59 (d, J = 7.4 Hz, 2H), 7.88 - 7.77 (m, 1H), 7.40 (t, J = 8.7 Hz, 2H), 7.14 (q, J = 8.0 Hz, 4H), 6.73 (dd, 2H), 4.25 (d, J = 5.9 Hz, 2H), 3.70 (s, 2H), 2.27 (s, 3H); MS (ESI) [M+H] + = 351.35

[0512]

[0513] Step 3: Preparation of tert-butyl 4-(2-(3-fluoro-4-(6-(2-((4-methylbenzyl)amino)-2-oxoethyl)pyridine-3-yl)phenoxy)ethyl)piperazine-1-carboxylate

[0514] Tert-butyl 4-(2-chloroethyl)piperazine-1-carboxylate (1.5 equivalents, 0.29 mmol, 72 mg) and K2CO3 (1.5 equivalents, 0.29 mmol, 40 mg) were added at room temperature to a solution of the pre-step product (1.0 equivalent, 0.19 mmol, 68 mg) dissolved in dimethylformamide (1.9 mL). The reaction mixture was stirred at 60°C, poured into water, and extracted twice with EtOAc and brine. The organic layer was dried with MgSO4, filtered, and then concentrated under vacuum. The crude product was purified by silica gel flash chromatography (Hexane / EtOAc, 1:1, Rf = 0.3) to obtain the target compound (0.14 mmol, 79 mg, 74%) as a beige solid.

[0515] 1 H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 2H), 7.87 (d, J = 8.1 Hz, 1H), 7.51 (t, J = 9.0 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.14 (q, J = 7.9 Hz, 4H), 7.01 (dd, 1H), 6.94 (dd, 1H), 4.25 (d, J = 5.9 Hz, 2H), 4.16 (t, J = 5.7 Hz, 2H), 3.72 (s, 2H), 2.74 (t, J = 5.6 Hz, 2H), 2.44 (t, J = 5.0 Hz, 4H), 2.27 (s, 3H); MS (ESI) [M+H] + = 563.18

[0516] Step 4: Preparation of 2-(5-(2-fluoro-4-(2-(piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-methylbenzyl)acetamide

[0517] 30% TFA was added at room temperature to a solution of the previous step product (1.0 equivalent, 0.12 mmol, 69 mg) dissolved in dichloromethane (1.2 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum. The residue was dissolved in MeOH and stirred with Amberlite IRN 78 for 30 minutes, then filtered and concentrated under vacuum to obtain the target compound (0.12 mmol, 57 mg, 100%) as a yellow solid.

[0518] 1 H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 2H), 7.87 (d, J = 8.2 Hz, 1H), 7.50 (t, J = 8.9 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.14 (q, J = 7.9 Hz, 3H), 7.01 (dd, J = 13.0, 2.4 Hz, 1H), 6.93 (dd, J = 8.8, 2.4 Hz, 1H), 4.25 (d, J = 5.8 Hz, 2H), 4.14 (t, J = 5.8 Hz, 2H), 3.72 (s, 2H), 3.17 (d, J = 4.7 Hz, 1H), 2.77 - 2.62 (m, 5H), 2.40 (s, 3H), 2.28 (s, 3H); MS (ESI) [M+H] + = 463.10

[0519] <Example 39> Preparation of 2-(5-(2-fluoro-4-(2-(4-(2-hydroxyacetyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-methylbenzyl)acetamide

[0520] The target compound was obtained by a method similar to that of Example 36. The product was obtained as a white solid (0.038 mmol, 20 mg, 89%).

[0521] 1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 2H), 7.87 (d, J = 8.2 Hz, 1H), 7.51 (t, J = 9.0 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.15 (q, J = 7.9 Hz, 4H), 7.02 (dd, J = 12.9, 2.4 Hz, 1H), 6.94 (dd, 1H), 4.56 (t, J = 5.5 Hz, 1H), 4.25 (d, J = 5.9 Hz, 2H), 4.17 (t, J = 5.6 Hz, 2H), 4.08 (d, J = 5.4 Hz, 2H), 3.72 (s, 2H), 3.47 (s, 4H), 2.75 (t, J = 5.6 Hz, 2H), 2.28 (s, 3H); MS (ESI) [M+H] + = 521.12

[0522] <Example 40> Preparation of 2-(5-(2-fluoro-4-(2-(4-glycylpiperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-methylbenzyl)acetamide

[0523] The target compound was obtained by a method similar to that of Example 37. The product was obtained as a white solid (0.048 mmol, 25 mg, 120%).

[0524] 1 H NMR (400 MHz, DMSO-d6) δ 11.71 (s, 1H), 8.78 (m, 2H), 8.21 (m, 4H), 7.79 - 7.54 (m, 2H), 7.25 - 7.09 (m, 5H), 7.05 (dd, J = 8.4, 2.5 Hz, 1H), 4.55 (s, 2H), 4.44 (d, J = 13.9 Hz, 1H), 4.27 (d, J = 5.8 Hz, 2H), 4.02 - 3.82 (m, 4H), 2.28 (s, 3H); MS (ESI) [M+H] + = 520.16.

[0525] <Example 41> Preparation of 2-(5-(2-methyl-4-(2-(piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-methylbenzyl)acetamide

[0526]

[0527] Step 1: Preparation of 2-(5-(2-methyl-4-(2-(piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-methylbenzyl)acetamide

[0528] 2-(5-bromopyridine-2-yl)-N-(4-methylbenzyl)acetamide (1.2 equivalents, 0.71 mmol, 227 mg), 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1.0 equivalents, 0.60 mmol, 140 mg), PdCl2 (dppf) (0.1 equivalents, 0.060 mmol, 44 mg), and KF (5.0 equivalents, 3.00 mmol, 174 mg) were mixed with a mixture of 1,4-dioxane and water (10:1) (2.0 mL). The reaction mixture was stirred at 80°C for 17 hours, then poured into water, extracted twice with EtOAc and brine, dried with MgSO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel flash chromatography (Hexane / EtOAc, 1:1, Rf = 0.3) to obtain the target compound (0.23 mmol, 81 mg, 38%), which is a yellow solid.

[0529] 1H NMR (400 MHz, DMSO-d6) δ 9.48 (s, 1H), 8.60 (t, J = 5.7 Hz, 1H), 8.40 (d, J = 2.4 Hz, 1H), 7.96 (s, 1H), 7.68 (dd, J = 8.0, 2.4 Hz, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.14 (q, J = 8.0 Hz, 4H), 7.05 (d, J = 8.2 Hz, 1H), 6.82 - 6.56 (m, 2H), 4.26 (d, J = 5.9 Hz, 2H), 3.70 (s, 2H), 2.90 (s, 1H), 2.74 (s, 1H), 2.27 (s, 3H), 2.18 (s, 3H); MS (ESI) [M+H] + = 347.42

[0530] Step 2: Preparation of tert-butyl 4-(2-(3-methyl-4-(6-(2-((4-methylbenzyl)amino)-2-oxoethyl)pyridine-3-yl)phenoxy)ethyl)piperazine-1-carboxylate

[0531] Tert-butyl 4-(2-chloroethyl)piperazine-1-carboxylate (1.5 equivalents, 0.30 mmol, 75 mg) and K2CO3 (1.5 equivalents, 0.30 mmol, 41 mg) were added at room temperature to a solution of the pre-step product (1.0 equivalent, 0.20 mmol, 70 mg) dissolved in dimethylformamide (1.0 mL). The reaction mixture was stirred at 60°C, poured into water, and extracted twice with EtOAc and brine. The organic layer was dried with MgSO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel flash chromatography (CH2Cl2 / MeOH, 10:1, Rf = 0.5) to obtain the target compound (0.10 mmol, 58 mg, 51%) as a yellow oil.

[0532] 1H NMR (400 MHz, DMSO-d6) δ 8.61 (t, J = 6.2 Hz, 1H), 8.42 (s, 1H), 7.71 (d, J = 9.1 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.25 - 7.05 (m, 5H), 6.93 (s, 1H), 6.90 - 6.83 (m, 1H), 4.26 (d, J = 5.9 Hz, 2H), 4.12 (t, J = 5.7 Hz, 2H), 3.71 (s, 2H), 2.73 (t, J = 5.7 Hz, 2H), 2.45 (t, J = 4.8 Hz, 4H), 2.27 (s, 3H), 2.23 (s, 3H), 1.40 (s, 9H); MS (ESI) [M+H] + = 559.22

[0533] Step 3: Preparation of 2-(5-(2-methyl-4-(2-(piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-methylbenzyl)acetamide

[0534] 4N HCl was added at room temperature to a solution in which the product of the previous step (1.0 equivalent, 0.089 mmol, 50 mg) was dissolved in 1,4-dioxane (0.8 mL). The reaction mixture was stirred at room temperature for 40 minutes. The reaction mixture was concentrated under vacuum to obtain the target compound (0.083 mmol, 44 mg, 94%) as a yellow solid.

[0535] 1 H NMR (400 MHz, DMSO-d6) δ 9.60 (s, 2H), 8.81 (t, J = 5.9 Hz, 1H), 8.71 (s, 1H), 8.19 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.30 (d, J = 8.5 Hz, 0H), 7.24 - 7.10 (m, 2H), 7.07 - 6.93 (m, 1H), 4.47 (s, 1H), 4.28 (d, J = 5.8 Hz, 1H), 3.96 (s, 1H), 2.28 (d, J = 2.9 Hz, 3H); MS (ESI) [M+H]+ = 459.18.

[0536] <Example 42> Preparation of 2-(5-(4-(2-(4-(2-hydroxyacetyl)piperazine-1-yl)ethoxy)-2-methylphenyl)pyridine-2-yl)-N-(4-methylbenzyl)acetamide

[0537] The target compound was obtained by a method similar to that of Example 36. The product was obtained as a white solid (0.024 mmol, 12.6 mg, 55%).

[0538] 1 H NMR (400 MHz, DMSO-d6) δ 8.61 (t, J = 5.9 Hz, 1H), 8.43 (d, J = 2.3 Hz, 1H), 7.71 (d, J = 8.9 Hz, 1H), 7.39 (d, J = 8.1 Hz, 1H), 7.15 (dd, J = 9.0, 5.9 Hz, 5H), 6.93 (s, 1H), 6.88 (d, J = 8.9 Hz, 1H), 4.55 (d, J = 5.5 Hz, 1H), 4.26 (d, J = 5.9 Hz, 2H), 4.13 (t, J = 5.6 Hz, 2H), 4.08 (d, J = 5.5 Hz, 2H), 3.71 (s, 2H), 3.47 (s, 4H), 2.75 (t, J = 5.6 Hz, 2H), 2.27 (s, 3H), 2.23 (s, 3H); MS (ESI) [M+H] + = 517.23.

[0539] <Example 43> Preparation of 2-(5-(2-fluoro-4-(2-(4-glycylpiperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-methylbenzyl)acetamide

[0540] The target compound was obtained by a method similar to that of Example 37. The product was obtained as a white solid (0.018 mmol, 11 mg, 106%).

[0541] 1H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1H), 8.79 (s, 1H), 8.65 (s, 1H), 8.42 - 7.99 (m, 3H), 7.69 (s, 1H), 7.29 (d, J = 8.3 Hz, 1H), 7.21 - 7.10 (m, 3H), 7.10 - 6.90 (m, 2H), 4.46 (d, J = 32.0 Hz, 3H), 4.27 (d, J = 5.8 Hz, 2H), 3.91 (s, 4H), 3.83 (d, J = 5.8 Hz, 1H), 3.75 (s, 4H), 2.28 (d, J = 3.0 Hz, 6H); MS (ESI) [M+H] + = 516.16.

[0542] <Example 44> Preparation of 2-(5-(2-fluoro-4-(2-(1-glycylpiperidin-4-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0543]

[0544] Step 1: Preparation of tert-butyl 4-(2-((methylsulfonyl)oxy)ethyl)piperidine-1-carboxylate

[0545] Methanesulfonyl chloride (2 equivalents, 1.7 mmol, 135 μL) was added at 0°C to a solution of tert-butyl-4-(2-hydroxyethyl)piperidine-1-carboxylate (1.0 equivalent, 0.87 mmol, 200 mg) Et3N (2.5 equivalents, 1.7 mmol, 304 μL) in dichloromethane (1.5 mL). The reaction mixture was stirred at room temperature for 15 minutes, then poured into water, extracted twice with EtOAc and brine, dried with MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash chromatography on silica gel (Hexane / EtOAc, 1:1, Rf = 0.5) to obtain the target compound (0.75 mmol, 230 mg, 86%) as a white solid.

[0546] 1H NMR (400 MHz, CDCl3) δ 4.31 (t, J = 6.3 Hz, 2H), 4.12 (d, J = 13.2 Hz, 2H), 3.03 (s, 3H), 2.72 (td, J = 12.9, 2.5 Hz, 2H), 1.71 (dd, J = 11.7, 5.1 Hz, 5H), 1.58 (s, 2H), 1.48 (s, 9H), 1.23 - 1.10 (m, 2H).

[0547] Step 2: Preparation of tert-butyl-4-(2-(3-fluoro-4-(6-(2-((4-fluorobenzyl)amino)-2-oxoethyl)pyridine-3-yl)phenoxy)ethyl)piperidine-1-carboxylate

[0548] The pre-step product (1.2 equivalents, 0.34 mmol, 104 mg) and K2CO3 (1.5 equivalents, 0.42 mmol, 58 mg) were added at room temperature to a solution of 2-(5-(2-fluoro-4-hydroxyphenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide (1.0 equivalents, 0.28 mmol, 100 mg) dissolved in dimethylformamide (1.4 mL). The reaction mixture was stirred at 60°C for 21 hours, then poured into water and extracted twice with EtOAc and brine. The organic layer was dried with MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash chromatography on silica gel (hexane / EtOAc, 1:1, Rf = 0.3) to obtain the target compound (0.23 mmol, 131 mg, 83%) as a brown oil.

[0549] 1H NMR (400 MHz, DMSO-d6) δ 8.66 (t, J = 6.0 Hz, 1H), 8.62 (s, 1H), 7.87 (d, J = 8.3 Hz, 1H), 7.50 (t, J = 9.0 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.32 (dd, J = 8.5, 5.7 Hz, 2H), 7.20 - 7.10 (m, 2H), 7.00 (dd, J = 12.9, 2.5 Hz, 1H), 6.92 (dd, J = 8.6, 2.5 Hz, 1H), 4.29 (d, J = 5.9 Hz, 2H), 4.09 (t, J = 6.1 Hz, 2H), 3.93 (d, J = 12.9 Hz, 2H), 3.72 (s, 2H), 2.68 (s, 2H), 1.70 (d, J = 13.2 Hz, 5H), 1.40 (s, 9H), 1.06 (q, J = 12.4 Hz, 2H). MS (ESI) [M+H] + = 566.4.

[0550] Step 3: Preparation of 2-(5-(2-fluoro-4-(2-(piperidine-4-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0551] The product of the previous step (1.0 equivalent, 0.23 mmol, 130 mg) was dissolved in dichloromethane (1.15 mL), and 30% TFA was added at room temperature. The reaction mixture was stirred at room temperature for 25 minutes. The reaction mixture was concentrated under vacuum. The residue was dissolved in methanol, passed through a column packed with Amberlite IRN 78, and concentrated under vacuum to obtain the target compound (0.22 mmol, 102 mg, 96%) as a yellow oil.

[0552] 1H NMR (400 MHz, DMSO-d6) δ 8.65 (t, J = 7.2 Hz, 1H), 8.62 (d, J = 2.2 Hz, 1H), 7.87 (dt, J = 8.1, 1.9 Hz, 1H), 7.51 (td, J = 9.0, 4.8 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.36 - 7.26 (m, 2H), 7.15 (dd, J = 10.1, 7.6 Hz, 2H), 6.99 (dd, J = 12.9, 2.5 Hz, 1H), 6.92 (dd, J = 8.6, 2.5 Hz, 1H), 4.29 (d, J = 5.9 Hz, 2H), 4.09 (q, J = 6.1 Hz, 2H), 3.73 (s, 2H), 3.16 (d, J = 12.5 Hz, 2H), 2.94 (d, J = 11.2 Hz, 1H), 2.74 (td, J = 12.5, 2.8 Hz, 2H), 1.84 (dd, J = 26.8, 13.0 Hz, 2H), 1.70 (dd, J = 9.8, 5.2 Hz, 3H), 1.38 - 1.10 (m, 2H). MS (ESI) [M+H] + = 465.2.

[0553] Step 4: Preparation of tert-butyl(2-(4-(2-(3-fluoro-4-(6-(2-((4-fluorobenzyl)amino)-2-oxoethyl)pyridine-3-yl)phenoxy)ethyl)piperidine-1-yl)-2-oxoethyl)carbamate

[0554] The target compound was obtained from the product of the preceding step by a method similar to that of Example 31. The product was obtained as a colorless oil (0.016 mmol, 10 mg, 49%).

[0555] 1H NMR (400 MHz, DMSO-d6) δ 8.66 (t, J = 6.1 Hz, 1H), 8.62 (s, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.56 - 7.47 (m, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.32 (dd, J = 8.5, 5.6 Hz, 2H), 7.15 (t, J = 8.9 Hz, 2H), 7.00 (dd, J = 12.9, 2.5 Hz, 1H), 6.93 (dd, 1H), 6.69 (t, J = 5.9 Hz, 1H), 4.29 (d, J = 6.1 Hz, 2H), 4.10 (t, J = 6.2 Hz, 2H), 3.75 (d, J = 17.3 Hz, 6H), 3.44 (d, J = 4.2 Hz, 2H), 2.97 (t, J = 12.6 Hz, 1H), 1.72 (d, J = 19.6 Hz, 5H), 1.38 (s, 9H). MS (ESI) [M+H] + = 622.3.

[0556] Step 5: Preparation of 2-(5-(2-fluoro-4-(2-(1-glycylpiperidine-4-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0557] The target compound was obtained by a method similar to that of Example 23. The product was obtained in the form of yellow wax (0.009 mmol, 5 mg, 48%).

[0558] 1H NMR (400 MHz, DMSO-d6) δ 8.66 (t, 1H), 8.61 (s, 1H), 7.94 - 7.79 (m, 1H), 7.50 (t, J = 8.9 Hz, 1H), 7.42 (d, J = 8.1 Hz, 1H), 7.32 (dd, J = 8.4, 5.6 Hz, 2H), 7.15 (t, J = 8.8 Hz, 2H), 6.99 (dd, J = 12.8 Hz, 1H), 6.92 (dd, 1H), 4.28 (d, J = 5.9 Hz, 2H), 4.09 (t, J = 6.2 Hz, 2H), 3.72 (s, 2H), 3.02 (d, J = 18.4 Hz, 4H), 1.81 - 1.64 (m, 5H). MS (ESI) [M+H + = 521.2.

[0559] <Example 45> Preparation of 2-(5-(2-fluoro-4-(2-(1-(2-hydroxyacetyl)piperidine-4-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0560] The target compound was obtained by a method similar to that of Example 36. The product was obtained as a yellow oil (0.070 mmol, 36.9 mg, 64%).

[0561] 1H NMR (300 MHz, DMSO-d6) δ 8.69 (t, J = 6.1 Hz, 1H), 8.62 (s, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.51 (t, J = 8.9 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.32 (dd, J = 8.5, 5.7 Hz, 2H), 7.16 (t, J = 8.9 Hz, 2H), 7.01 (dd, J = 13.0, 2.5 Hz, 1H), 6.93 (dd, J = 8.5, 2.5 Hz, 1H), 4.47 (t, J) = 5.4 Hz, 1H), 4.29 (d, J = 6.0 Hz, 2H), 4.09 (dd, J = 7.9, 5.0 Hz, 4H), 3.72 (s, 2H), 1.73 (t, J = 10.8 Hz, 5H), 1.33 - 0.96 (m, 4H); MS (ESI) [M+H] + = 524.5

[0562] <Example 46> Preparation of N-(4-chlorobenzyl)-2-(5-(2-fluoro-4-(2-(4-glycylpiperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)acetamide

[0563] The target compound was obtained from 2-(5-bromopyridine-2-yl)-N-(4-fluorobenzyl)acetamide in a total of five steps, similar to the preparation method of Example 23. The product was obtained as a brown solid (0.047 mmol, 26 mg, 73%).

[0564] 1H NMR (400 MHz, DMSO-d6) δ 8.68 (t, J = 6.0 Hz, 1H), 8.63 (s, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.52 (t, J = 9.0 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.39 (d, J = 8.5 Hz, 2H), 7.31 (d, J = 8.2 Hz, 2H), 7.02 (dd, J = 12.8, 2.5 Hz, 1H), 6.94 (dd, 1H), 4.30 (d, J = 6.0 Hz, 2H), 4.18 (t, J = 5.6 Hz, 2H), 3.73 (s, 4H), 3.52 (d, J = 5.9 Hz, 2H), 2.77 (t, J = 5.5 Hz, 2H); MS (ESI) [M+H] + = 540.21

[0565] <Example 47> Preparation of N-(4-chlorobenzyl)-2-(5-(2-fluoro-4-(2-(4-(2-hydroxyacetyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)acetamide

[0566] The target compound was obtained from 2-(5-bromopyridine-2-yl)-N-(4-fluorobenzyl)acetamide in a total of four steps, similar to the preparation method of Example 22. The product was obtained as a yellow solid (0.029 mmol, 16 mg, 21%).

[0567] 1H NMR (400 MHz, DMSO-d6) δ 8.68 (t, J = 6.0 Hz, 1H), 8.63 (s, 1H), 7.93 - 7.83 (m, 1H), 7.51 (t, J = 9.0 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.41 - 7.36 (m, 2H), 7.31 (d, J = 8.5 Hz, 2H), 7.02 (dd, J = 12.9, 2.5 Hz, 1H), 6.94 (dd, J = 8.6, 2.5 Hz, 1H), 4.54 (t, J = 5.5 Hz, 1H), 4.30 (d, J = 5.9 Hz, 2H), 4.18 (t, J = 5.7 Hz, 2H), 4.08 (d, J = 5.2 Hz, 2H), 3.73 (s, 2H), 3.55 - 3.43 (m, 2H), 2.76 (t, J = 5.6 Hz, 2H); MS (ESI) [M+H] + = 541.42

[0568] <Example 48> Preparation of 2-(5-(2-fluoro-4-(2-(4-(methylsulfonyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0569] Et3N (2 equivalents, 0.086 mmol, 12 μL) and MsCl (1.3 equivalents, 0.064 mmol, 5 μL) were added at room temperature to a solution of the compound of Example 16 (1.0 equivalent, 0.043 mmol, 20 mg) dissolved in dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 1 hour, then poured into water and extracted twice with EtOAc and brine. The organic layer was dried with MgSO4, filtered, and then concentrated under vacuum. The crude product was purified by flash chromatography on silica gel (CH2Cl2 / MeOH, 10:1, Rf = 0.5) to obtain the target compound (0.008 mmol, 4 mg, 18%) as a white solid.

[0570] 1H NMR (400 MHz, DMSO-d6) δ 8.65 (t, J = 5.9 Hz, 1H), 8.62 (s, 1H), 7.87 (dd, J = 8.1, 2.1 Hz, 1H), 7.51 (t, J = 9.0 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.32 (dd, J = 8.5, 5.6 Hz, 2H), 7.14 (t, J = 8.9 Hz, 2H), 7.01 (dd, J = 12.9, 2.5 Hz, 1H), 6.94 (dd, J = 8.6, 2.5 Hz, 1H), 4.28 (d, J = 5.9 Hz, 2H), 4.17 (t, J = 5.6 Hz, 2H), 3.72 (s, 2H), 3.12 (t, J = 4.9 Hz, 4H), 2.87 (s, 3H), 2.78 (t, J = 5.5 Hz, 2H), 2.60 (t, J = 5.0 Hz, 4H); MS (ESI) [M+H] + = 545.32

[0571] <Example 49> Preparation of 2-(5-(4-(2-(4-(ethylsulfonyl)piperazine-1-yl)ethoxy)-2-fluorobenzyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0572] The target compound was obtained by a method similar to that of Example 48. The product was obtained as a yellow oil (0.008 mmol, 4.7 mg, 20%).

[0573] 1H NMR (400 MHz, DMSO-d6) δ 8.65 (t, J = 5.9 Hz, 1H), 8.62 (s, 1H), 7.87 (dd, J = 8.1, 2.1 Hz, 1H), 7.51 (t, J = 9.0 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.32 (dd, J = 8.5, 5.6 Hz, 2H), 7.14 (t, J = 8.9 Hz, 2H), 7.01 (dd, J = 12.9, 2.5 Hz, 1H), 6.94 (dd, J = 8.6, 2.5 Hz, 1H), 4.28 (d, J = 5.9 Hz, 2H), 4.17 (t, J = 5.6 Hz, 2H), 3.72 (s, 2H), 3.12 (t, J = 4.9 Hz, 4H), 2.87 (s, 3H), 2.78 (t, J = 5.5 Hz, 2H), 2.60 (t, J = 5.0 Hz, 4H); MS (ESI) [M+H] + = 559.33

[0574] <Example 50> Preparation of tert-butyl(2-(4-(2-(3-fluoro-4-(6-(2-((4-fluorobenzyl)amino)-2-oxoethyl)pyridine-3-yl)phenoxy)ethyl)piperazine-1-yl)-2-oxoethyl)carbamate

[0575] The target compound was obtained by a method similar to that of Example 19. The product was obtained as a white solid (0.014 mmol, 9 mg, 69%).

[0576] 1H NMR (400 MHz, DMSO-d6)δ 8.66 (t, J = 5.8 Hz, 1H), 8.62 (s, 1H), 7.87 (d, J = 8.3 Hz, 1H), 7.51 (t, J = 9.0 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.32 (dd, J = 8.6, 5.6 Hz, 2H), 7.15 (t, J = 8.9 Hz, 2H), 7.02 (dd, J = 12.9, 2.4 Hz, 1H), 6.94 (d, J = 8.6 Hz, 1H), 6.73 (t, 1H), 4.29 (d, J = 6.0 Hz, 2H), 4.18 (t, J = 5.6 Hz, 2H), 3.78 (d, J = 5.9 Hz, 2H), 3.73 (s, 2H), 3.47 - 3.41 (m, 4H), 2.75 (t, J = 5.6 Hz, 2H), 2.49 - 2.39 (m, 4H), 1.38 (s, 9H). MS (ESI) [M+H] + = 624.66

[0577] <Example 51> Preparation of 2-(5-(4-(2-(4-(acetylglycyl)piperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0578] 30% TFA was added at room temperature to a solution of the compound of Example 50 (1.0 equivalent, 0.016 mmol, 10 mg) dissolved in dichloromethane (0.5 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum. The reaction mixture, acetic anhydride (2 equivalents, 0.032 mmol, 3.6 μL), and Et3N (2 equivalents, 0.032 mmol, 5.3 μL) were mixed in dichloromethane (0.4 mL) and stirred at room temperature for 1 hour. The reaction mixture was poured into water, extracted twice with EtOAc, washed with brine, dried with MgSO4, and concentrated under vacuum. The crude product was purified by silica gel flash chromatography (CH2Cl2 / MeOH, 10:1, Rf = 0.4) to obtain the target compound (0.014 mmol, 8 mg, 74%), which is a white solid.

[0579] 1 H NMR (400 MHz, DMSO-d6) Zδ 8.66 (t, J = 6.0 Hz, 1H), 8.62 (s, 1H), 7.95 (t, J = 5.5 Hz, 1H), 7.90 - 7.82 (m, 1H), 7.51 (t, J = 9.0 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.32 (dd, J = 8.4, 5.7 Hz, 2H), 7.15 (t, J = 8.8 Hz, 2H), 7.02 (dd, J = 13.0, 2.4 Hz, 1H), 6.94 (dd, J = 8.5, 2.5 Hz, 1H), 4.29 (d, J = 5.9 Hz, 2H), 4.18 (t, J = 5.6 Hz, 2H), 3.93 (d, J = 5.5 Hz, 2H), 3.73 (s, 2H), 3.50 - 3.40 (m, 4H), 2.76 (t, J = 5.6 Hz, 2H), 2.49 - 2.40 (m, 4H), 1.87 (s, 3H); MS (ESI) [M+H] + = 566.58

[0580] <Example 52> Preparation of N-(2-(4-(2-(3-fluoro-4-(6-(2-((4-fluorobenzyl)amino)-2-oxoethyl)pyridine-3-yl)phenoxy)ethyl)piperazine-1-yl)-2-oxoethyl)benzamide

[0581] The target compound was obtained by a method similar to that of Example 51. The product was obtained as a yellow solid (0.008 mmol, 4.8 mg, 40%).

[0582] 1 H NMR (400 MHz, DMSO-d6) δ 8.66 (t, J = 5.9 Hz, 1H), 8.63 (s, 1H), 8.55 (t, J = 5.7 Hz, 1H), 7.92 - 7.80 (m, 3H), 7.58 - 7.40 (m, 5H), 7.32 (dd, J = 8.6, 5.6 Hz, 2H), 7.15 (t, J = 8.9 Hz, 2H), 7.03 (dd, J = 12.9, 2.5 Hz, 1H), 6.95 (dd, J = 8.6, 2.5 Hz, 1H), 4.29 (d, J = 5.9) Hz, 2H), 4.19 (t, J = 5.6 Hz, 2H), 4.14 (d, J = 5.8 Hz, 2H), 3.73 (s, 2H), 3.51 (d, J = 8.6 Hz, 4H), 2.77 (t, J = 5.6 Hz, 2H), 2.58 - 2.53 (m, 4H); MS (ESI) [M+H] + = 628.37

[0583] <Example 53> Preparation of 2-(5-(2-fluoro-4-(2-(4-(3-methoxypropanoyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0584] The target compound was obtained by a method similar to that of Example 19. The product was obtained as a colorless oil (0.030 mmol, 17 mg, 71%).

[0585] 1H NMR (400 MHz, DMSO-d6) δ 8.67 (t, 1H), 8.62 (s, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.51 (t, J = 9.0 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.32 (t, J = 7.0 Hz, 2H), 7.15 (t, J = 8.7 Hz, 2H), 7.02 (dd, J = 12.9 Hz, 1H), 6.94 (dd, 1H), 4.29 (d, J = 6.0 Hz, 2H), 4.17 (t, J = 5.7 Hz, 2H), 3.72 (s, 2H), 3.54 (t, J = 6.6 Hz, 2H), 3.45 (t, J = 5.0 Hz, 4H), 3.22 (s, 2H), 2.74 (t, J = 5.6 Hz, 2H), 2.59 - 2.52 (m, 4H), 2.45 - 2.41 (m, 2H); MS (ESI) [M+H] + = 553.06

[0586] <Example 54> Preparation of 2-(5-(4-(2-(4-(2-ethoxyacetyl)piperazine-1-yl)ethoxy)-2-fluorobenzyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0587] The target compound was obtained by a method similar to that of Example 19. The product was obtained as a colorless oil (0.026 mmol, 14 mg, 59%).

[0588] 1H NMR (400 MHz, DMSO-d6) δ 8.68 (t, J = 6.0 Hz, 1H), 8.62 (s, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.51 (t, J = 9.0 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.32 (dd, J = 8.3, 5.6 Hz, 2H), 7.15 (t, J = 8.7 Hz, 2H), 7.02 (dd, J = 13.0, 2.5 Hz, 1H), 6.94 (dd, J = 8.6, 2.5 Hz, 1H), 4.29 (d, J) = 5.9 Hz, 2H), 4.17 (t, J = 5.7 Hz, 2H), 4.10 (s, 2H), 3.72 (s, 2H), 3.44 (dd, J = 14.6, 7.8 Hz, 6H), 2.75 (t, J = 5.6 Hz, 2H), 2.49 - 2.41 (m, 4H), 1.12 (t, J = 7.0 Hz, 3H).; MS (ESI) [M+H] + = 553.06

[0589] <Example 55> Preparation of 2-(5-(4-(2-(4-(4-(benzyloxy)butanoyl)piperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0590] The target compound was obtained by a method similar to that of Example 19. The product was obtained as a yellow oil (0.020 mmol, 13 mg, 31%).

[0591] 1H NMR (400 MHz, DMSO-d6) δ 8.68 (t, J = 6.1 Hz, 1H), 8.62 (s, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.51 (t, J = 9.0 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.38 - 7.24 (m, 7H), 7.15 (t, J = 8.7 Hz, 2H), 7.03 (dd, 1H), 6.94 (dd, J = 8.8, 2.4 Hz, 1H), 4.45 (s, 2H), 4.29 (d, J = 5.9 Hz, 2H), 4.17 (t, J = 5.6 Hz, 2H), 3.72 (s, 2H), 3.43 (t, J = 6.1 Hz, 6H), 2.74 (t, J = 5.6 Hz, 2H), 2.49-2.45 (m, 2H), 2.42 (d, J = 5.5 Hz, 2H), 2.36 (t, J = 7.4 Hz, 2H), 1.76 (p, J = 6.8 Hz, 2H); MS (ESI) [M+H] + = 643.56

[0592] <Example 56> Preparation of 4-(4-(2-(3-fluoro-4-(6-(2-((4-fluorobenzyl)amino)-2-oxoethyl)pyridine-3-yl)phenoxy)ethyl)piperazine-1-yl)-4-oxobutanoic acid

[0593] The target compound was obtained by a method similar to that of Example 19. The product was obtained as a white solid (0.024 mmol, 19 mg, 54%).

[0594] 1H NMR (400 MHz, DMSO-d6) zδ 8.70 (t, 1H), 8.65 (s, 1H), 7.92 (d, J = 8.3 Hz, 1H), 7.59 (t, J = 9.0 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.32 (dd, J = 8.2, 5.6 Hz, 1H), 7.15 (t, J = 9.7 Hz, 1H), 7.09 (dd, J = 2.3 Hz, 1H), 7.02 (dd, J = 8.7 Hz, 1H), 4.45 (s, 2H), 4.29 (d, J = 5.9 Hz, 2H), 3.75 (m, 4H), 2.66 - 2.49 (m, 4H), 2.46 (d, J = 6.4 Hz, 4H); MS (ESI) [M+H] + = 567.11

[0595] <Example 57> Preparation of 2-(5-(2-fluoro-4-(2-(4-(2-isopropoxyacetyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0596] The target compound was obtained by a method similar to that of Example 19. The product was obtained as a yellow oil (0.025 mmol, 14 mg, 58%).

[0597] 1H NMR (400 MHz, DMSO-d6) δ 8.68 (t, J = 6.0 Hz, 1H), 8.62 (s, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.51 (t, J = 8.9 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.32 (dd, J = 8.3, 5.6 Hz, 2H), 7.15 (t, J = 8.7 Hz, 2H), 7.02 (d, J = 12.9 Hz, 1H), 6.94 (d, J = 8.8 Hz, 1H), 4.29 (d, J = 5.9 Hz, 2H), 4.17 (t, J = 5.7 Hz, 2H), 4.07 (s, 2H), 3.72 (s, 2H), 3.45 - 3.40 (m, 4H), 2.75 (t, J = 5.6 Hz, 2H), 2.49 - 2.43 (m, 4H), 1.10 (d, J = 6.1 Hz, 5H); MS (ESI) [M+H] + = 567.14

[0598] <Example 58> Preparation of 2-(5-(2-fluoro-4-(2-(1-(2-methoxyacetyl)piperidine-4-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0599] The target compound was obtained from 2-(5-(2-fluoro-4-(2-(piperidin-4-yl)ethoxy)phenyl)pyridin-2-yl)-N-(4-fluorobenzyl)acetamide by a method similar to that of Example 19. The product was obtained as a yellow oil (0.030 mmol, 16 mg, 70%).

[0600] 1H NMR (400 MHz, DMSO-d6) δ 8.67 (t, J = 6.0 Hz, 1H), 8.62 (s, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.51 (t, J = 9.0 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.37 - 7.29 (m, 2H), 7.15 (t, J = 8.7 Hz, 3H), 7.00 (dd, J = 13.0 Hz, 1H), 6.93 (dd, J = 8.7 Hz, 1H), 4.29 (d, J = 6.0 Hz, 2H), 4.20 - 4.04 (m, 2H), 3.72 (s, 2H), 3.28 (s, 3H), 1.77 - 1.61 (m, 5H), 1.28 - 0.92 (m, 4H); MS (ESI) [M+H] + = 538.51

[0601] <Example 59> Preparation of 2-(5-(4-(2-(1-(2-ethoxyacetyl)piperidine-4-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0602] The target compound was obtained from 2-(5-(2-fluoro-4-(2-(piperidin-4-yl)ethoxy)phenyl)pyridin-2-yl)-N-(4-fluorobenzyl)acetamide by a method similar to that of Example 19. The product was obtained as a yellow oil (0.038 mmol, 21 mg, 88%).

[0603] 1H NMR (400 MHz, DMSO-d6) δ 8.68 (t, J = 6.0 Hz, 1H), 8.62 (s, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.51 (t, J = 8.9 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.32 (dd, J = 8.3, 5.7 Hz, 2H), 7.15 (t, J = 8.7 Hz, 2H), 7.00 (dd, J = 12.9 Hz, 1H), 6.93 (dd, 1H), 4.29 (d, J = 6.1 Hz, 2H), 4.10 (td, J = 12.1, 6.0 Hz, 5H), 3.72 (s, 2H), 3.53 - 3.40 (m, 2H), 3.17 (d, J = 5.2 Hz, 3H), 1.87 - 1.66 (m, 5H), 1.12 (t, J = 7.0 Hz, 4H); MS (ESI) [M+H] + = 552.20

[0604] <Example 60> Preparation of 2-(5-(2-fluoro-4-(2-(1-(2-isopropolciacetyl)piperidine-4-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0605] The target compound was obtained from 2-(5-(2-fluoro-4-(2-(piperidin-4-yl)ethoxy)phenyl)pyridin-2-yl)-N-(4-fluorobenzyl)acetamide by a method similar to that of Example 19. The product was obtained as a yellow solid (0.039 mmol, 22 mg, 91%).

[0606] 1H NMR (400 MHz, DMSO-d6) δ 8.68 (t, J = 6.0 Hz, 1H), 8.62 (s, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.51 (t, J = 9.0 Hz, d1H), 7.43 (d, J = 8.1 Hz, 1H), 7.32 (dd, J = 8.4, 5.6 Hz, 2H), 7.15 (t, J = 8.7 Hz, 2H), 7.00 (dd, J = 12.9 Hz, 1H), 6.93 (dd, J = 8.5 Hz, 1H), 4.29 (d, J = 6.0 Hz, 2H), 4.15 - 4.02 (m, 4H), 3.84 (d, J = 13.6 Hz, 1H), 3.72 (s, 2H), 3.59 (p, J = 6.0 Hz, 1H), 2.96 (t, J = 12.8 Hz, 1H), 1.80 - 1.58 (m, 5H), 1.10 (m, 10H); MS (ESI) [M+H] + = 566.10

[0607] <Example 61> Preparation of 2-(5-(2-fluoro-4-(2-(4-(2-(3-hydroxypropoxy)acetyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0608] The compound of Example 55 (1.0 equivalent, 0.034 mmol, 22 mg), 10 wt% Pd / C, and 1N HCl were mixed with a mixture of ethanol and EtOAc (1:1) (3.0 mL). The reaction mixture was stirred at room temperature for 1 hour, filtered through celite, and then concentrated under vacuum. The product was obtained as a yellow solid (0.048 mmol, 26 mg, quant).

[0609] 1H NMR (400 MHz, DMSO-d6) δ 9.49 (s, 1H), 8.81 (d, J = 8.0 Hz, 2H), 8.21 (s, 1H), 7.67 (dd, J = 19.3, 9.5 Hz, 2H), 7.34 (dd, J = 8.3, 5.6 Hz, 2H), 7.16 (t, J = 8.9 Hz, 3H), 7.05 (dd, 1H), 4.50 (s, 2H), 4.28 (dd, J = 18.3, 6.5 Hz, 2H), 3.90 (s, 2H), 3.38 (m, 4H), 3.17 (s, 5H); MS (ESI) [M+H] + = 553.10

[0610] <Example 62> Preparation of 2-(5-(2-fluoro-4-(2-(4-(2-propoxyacetyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0611] The target compound was obtained by a method similar to that of Example 19. The product was obtained as a yellow solid (0.038 mmol, 21 mg, 59%).

[0612] 1H NMR (400 MHz, DMSO-d6) δ 8.67 (t, J = 6.0 Hz, 1H), 8.62 (s, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.51 (t, J = 8.9 Hz, 1H), 7.43 (d, J = 8.2 Hz, 1H), 7.32 (t, J = 7.0 Hz, 2H), 7.15 (t, J = 8.7 Hz, 2H), 7.02 (dd, J = 13.1 Hz, 1H), 6.94 (dd, 1H), 4.29 (d, J = 5.9 Hz, 2H), 4.17 (t, J = 5.7 Hz, 2H), 4.09 (d, J = 6.4 Hz, 3H), 3.72 (s, 2H), 3.51 - 3.40 (m, 4H), 3.39 - 3.35 (m, 2H), 2.75 (t, J = 5.6 Hz, 2H), 2.51 - 2.41 (m, 4H), 1.52 (h, J = 7.0 Hz, 3H), 0.87 (t, J = 7.4 Hz, 4H); MS (ESI) [M+H] + = 567.04

[0613] <Example 63> Preparation of 2-(5-(2-fluoro-4-(2-(4-(2-(2-hydroxyethoxy)acetyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0614] The target compound was obtained by a method similar to that of Example 19. The product was obtained as a yellow solid (0.046 mmol, 26 mg, 72%).

[0615] 1H NMR (400 MHz, DMSO-d6) δ 8.67 (t, J = 5.9 Hz, 1H), 8.62 (s, 1H), 7.92 - 7.85 (m, 1H), 7.52 (t, J = 9.0 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.32 (dd, J = 8.6, 5.6 Hz, 2H), 7.15 (t, J = 8.9 Hz, 2H), 7.02 (dd, J = 12.9, 2.5 Hz, 1H), 6.94 (dd, J = 8.6, 2.5 Hz, 1H), 4.69 (t, J = 5.3) Hz, 1H), 4.29 (d, J = 5.9 Hz, 2H), 4.17 (d, J = 8.1 Hz, 4H), 4.11 (q, J = 5.2 Hz, 2H), 3.73 (s, 2H), 3.57 - 3.40 (m, 8H), 3.17 (d, J = 5.2 Hz, 6H), 2.75 (t, J = 5.6 Hz, 2H), 2.51 (d, J = 1.8 Hz, 4H); MS (ESI) [M+H] + = 569.45

[0616] <Example 64> Preparation of 2-(5-(2-fluoro-4-(2-(4-(3-hydroxybenzoyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0617] The target compound was obtained by a method similar to that of Example 19. The product was obtained as a white solid (0.012 mmol, 7 mg, 18%).

[0618] 1H NMR (400 MHz, DMSO-d6) δ 9.70 (s, 1H), 8.67 (t, J = 6.0 Hz, 1H), 8.62 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.51 (t, J = 9.0 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.32 (dd, J = 8.5, 5.4 Hz, 2H), 7.24 (t, J = 7.8 Hz, 1H), 7.15 (t, J = 8.8 Hz, 2H), 7.02 (dd, J = 12.9, 2.5 Hz, 1H), 6.94 (dd, J = 8.8, 2.5 Hz, 1H), 6.83 (d, J = 8.1 Hz, 1H), 6.77 (d, J = 7.5 Hz, 1H), 6.74 (d, J = 2.5 Hz, 1H), 4.29 (d, J = 5.9 Hz, 2H), 4.18 (t, J = 5.5 Hz, 2H), 3.73 (s, 2H), 3.43 - 3.35 (m, 4H), 3.17 (d, J = 5.1 Hz, 2H), 2.77 (t, J = 5.6 Hz, 2H) ; MS (ESI) [M+H] + = 587.46

[0619] <Example 65> Preparation of 2-(5-(4-(2-(4-(3-aminobenzoyl)piperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0620] The target compound was obtained by a method similar to that of Example 19. The product was obtained as a yellow solid (0.015 mmol, 9 mg, 34%).

[0621] 1H NMR (400 MHz, DMSO-d6) δ 8.67 (t, J = 6.0 Hz, 1H), 8.61 (s, 1H), 7.86 (d, J = 8.2 Hz, 1H), 7.50 (t, J = 8.9 Hz, 1H), 7.42 (d, J = 8.1 Hz, 1H), 7.31 (dd, J = 8.3, 5.7 Hz, 2H), 7.15 (t, J = 8.7 Hz, 2H), 7.08 - 6.99 (m, 2H), 6.93 (dd, J = 8.7 Hz, 1H), 6.59 (d, J = 8.4 Hz, 1H), 6.53 (s, 1H), 6.44 (d, J = 7.4 Hz, 1H), 5.26 (s, 2H), 4.28 (d, J = 5.9 Hz, 2H), 4.17 (t, J = 5.7 Hz, 2H), 3.72 (s, 2H), 3.46 - 3.38 (m, 4H), 2.75 (t, J = 5.5 Hz, 2H), 2.53 - 2.43 (m, 4H); MS (ESI) [M+H] + = 586.09

[0622] <Example 66> Preparation of 2-(5-(2-fluoro-4-(2-(4-(4-hydroxybenzoyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0623] The target compound was obtained by a method similar to that of Example 19. The product was obtained as a yellow solid (0.021 mmol, 12 mg, 50%).

[0624] 1H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 8.66 (t, J = 5.9 Hz, 1H), 8.62 (s, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.51 (t, J = 9.0 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.32 (dd, J = 8.5, 5.6 Hz, 2H), 7.28 - 7.23 (m, 2H), 7.15 (t, J = 8.8 Hz, 2H), 7.02 (dd, J = 13.0, 2.5 Hz, 1H), 6.94 (dd, J = 8.6, 2.5 Hz, 1H), 6.80 (d, J = 8.5 Hz, 2H), 4.29 (d, J = 5.9 Hz, 2H), 4.18 (t, J = 5.6 Hz, 2H), 3.73 (s, 2H), 3.56 - 3.42 (m, 4H), 2.77 (t, J = 5.5 Hz, 2H), 2.55 - 2.40 (m, 4H).; MS (ESI) [M+H] + = 587.02

[0625] <Example 67> Preparation of 2-(5-(4-(2-(4-(4-aminobenzoyl)piperazine-1-yl)ethoxy)-2-fluorobenzyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0626] The target compound was obtained by a method similar to that of Example 19. The product was obtained as a yellow solid (0.022 mmol, 13 mg, 52%).

[0627] 1H NMR (400 MHz, DMSO-d6) δ 8.68 (t, J = 5.9 Hz, 1H), 8.62 (s, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.51 (t, J = 9.0 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.32 (dd, J = 8.2, 5.6 Hz, 2H), 7.14 (dd, J = 19.2, 8.5 Hz, 4H), 7.06 - 7.00 (dd, 1H), 6.94 (dd, J = 8.9 Hz, 1H), 6.54 (d, J = 8.1 Hz, 2H), 5.53 (s, 2H), 4.29 (d, J = 5.9 Hz, 2H), 4.17 (t, J = 5.6 Hz, 2H), 3.72 (s, 2H), 3.50 (s, 4H), 2.76 (t, J = 5.5 Hz, 2H), 2.51 (m, 4H); MS (ESI) [M+H] + = 586.05

[0628] <Example 68> Preparation of 2-(5-(2-fluoro-4-(2-(1-(3-hydroxypropanoyl)piperidine-4-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0629] The target compound was obtained from 2-(5-(2-fluoro-4-(2-(piperidin-4-yl)ethoxy)phenyl)pyridin-2-yl)-N-(4-fluorobenzyl)acetamide by a method similar to that of Example 19. The product was obtained as a white solid (0.020 mmol, 11 mg, 32%).

[0630] 1H NMR (400 MHz, DMSO-d6) δ 8.67 (t, J = 6.0 Hz, 1H), 8.62 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.51 (t, J = 9.0 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.32 (dd, J = 8.4, 5.6 Hz, 2H), 7.15 (t, J = 8.7 Hz, 2H), 7.00 (dd, J = 13.0, 2.5 Hz, 1H), 6.93 (dd, J = 8.5, 2.4 Hz, 1H), 4.50 (t, J) = 5.5 Hz, 1H), 4.29 (d, J = 6.0 Hz, 2H), 4.10 (t, J = 6.2 Hz, 2H), 3.72 (s, 2H), 3.62 (q, J = 6.5 Hz, 2H), 2.47 (m, J = 7.2 Hz, 4H), 1.86 - 1.54 (m, 4H), 1.08 (dd, J = 48.1, 12.2 Hz, 4H); MS (ESI) [M+H] + = 539.13

[0631] <Example 69> Preparation of 2-(5-(2-fluoro-4-(2-(1-(2-propoxyacetyl)piperidine-4-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0632] The target compound was obtained from 2-(5-(2-fluoro-4-(2-(piperidin-4-yl)ethoxy)phenyl)pyridin-2-yl)-N-(4-fluorobenzyl)acetamide by a method similar to that of Example 19. The product was obtained as a white solid (0.044 mmol, 25 mg, 68%).

[0633] 1H NMR (400 MHz, DMSO-d6) δ 8.67 (t, J = 6.1 Hz, 1H), 8.62 (s, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.51 (t, J = 9.0 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.36 - 7.27 (m, 2H), 7.15 (t, J = 8.7 Hz, 2H), 7.00 (dd, J = 12.9, 2.4 Hz, 1H), 6.93 (dd, J = 8.6, 2.5 Hz, 1H), 4.29 (d, J = 6.1 Hz, 3H), 4.09 (q, J = 6.0 Hz, 4H), 3.81 (d, J = 13.6 Hz, 1H), 3.72 (s, 2H), 3.41 - 3.35 (m, 4H), 2.94 (d, J = 18.2 Hz, 2H), 2.81 (s, 1H), 1.84 - 1.63 (m, 5H), 1.52 (h, J = 7.1 Hz, 3H), 0.87 (t, J = 7.3 Hz, 4H).; MS (ESI) [M+H] + = 566.50

[0634] <Example 70> Preparation of 2-(5-(2-fluoro-4-(2-(1-(2-(2-hydroxyethoxy)acetyl)piperidine-4-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0635] The target compound was obtained from 2-(5-(2-fluoro-4-(2-(piperidin-4-yl)ethoxy)phenyl)pyridin-2-yl)-N-(4-fluorobenzyl)acetamide by a method similar to that of Example 19. The product was obtained as a colorless wax (0.012 mmol, 6.8 mg, 28%).

[0636] 1H NMR (400 MHz, DMSO-d6) δ 8.66 (t, J = 6.0 Hz, 1H), 8.62 (s, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.51 (t, J = 9.0 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.32 (dd, J = 8.5, 5.7 Hz, 2H), 7.15 (t, J = 8.9 Hz, 2H), 7.00 (dd, J = 13.0, 2.4 Hz, 1H), 6.93 (dd, J = 8.6, 2.5 Hz, 1H), 4.71 (t, J) = 5.3 Hz, 1H), 4.29 (d, J = 6.0 Hz, 2H), 4.11 (dd, J = 12.2, 5.7 Hz, 4H), 3.73 (s, 2H), 3.48 (dt, J = 14.8, 4.3 Hz, 4H), 2.96 (t, J = 12.7 Hz, 1H), 1.85 - 1.61 (m, 5H), 1.17 (d, J = 11.9 Hz, 2H), 1.04 (d, J = 12.7 Hz, 2H); MS (ESI) [M+H] + = 568.48

[0637] <Example 71> Preparation of 2-(4-(2-(3-fluoro-4-(6-(2-((4-fluorobenzyl)amino)-2-oxoethyl)pyridine-3-yl)phenoxy)ethyl)piperazine-1-yl)-2-oxoethylmethyl (2-(methylamino)ethyl)carbamate

[0638]

[0639] Step 1: Preparation of 2-(4-(2-(3-fluoro-4-(6-(2-((4-fluorobenzyl)amino)-2-oxoethyl)pyridine-3-yl)phenoxy)ethyl)piperazine-1-yl)-2-oxoethyl(4-nitrophenyl)carbamate

[0640] 4-nitrophenyl carbamate (2 equivalents, 0.114 mmol, 23 mg) and DIPEA (1.5 equivalents, 0.086 mmol, 15 μL) were added at room temperature to a solution of the compound of Example 22 (1.0 equivalent, 0.057 mmol, 30 mg) dissolved in dimethylformamide (1.6 mL). The reaction mixture was stirred at room temperature for 1 day, and then concentrated under vacuum. The crude product was purified by flash chromatography on silica gel (CH2Cl2 / MeOH, 10:1, Rf = 0.5) to obtain the target compound (0.043 mmol, 30 mg, 78%) as a yellow oil.

[0641] 1 H NMR (400 MHz, DMSO-d6) δ 8.68 (t, 1H), 8.62 (s, 1H), 8.34 (d, J = 8.9 Hz, 2H), 7.87 (d, J = 8.2 Hz, 1H), 7.53 (dd, J = 18.9, 9.0 Hz, 3H), 7.43 (d, J = 8.1 Hz, 1H), 7.32 (t, J = 7.0 Hz, 2H), 7.15 (t, J = 8.7 Hz, 2H), 7.02 (dd, J = 13.0 Hz, 1H), 6.94 (dd, J = 8.5 Hz, 1H), 5.05 (s, 2H), 4.29 (d, J = 5.8 Hz, 2H), 4.19 (d, J = 5.8 Hz, 2H), 3.72 (s, 2H), 3.55 - 3.45 (m, 4H), 2.76 (q, J = 6.6 Hz, 2H), 2.57 - 2.50 (m, 4H); MS (ESI) [M+H] + = 690.42

[0642] Step 2: Preparation of 2-(4-(2-(3-fluoro-4-(6-(2-((4-fluorobenzyl)amino)-2-oxoethyl)pyridine-3-yl)phenoxy)ethyl)piperazine-1-yl)-2-oxoethyl methyl(2-(methylamino)ethyl)carbamate

[0643] N,Nd-dimethylethane-1,2-diamine (3 equivalents, 0.066 mmol, 7 μL) and Et3N (1.5 equivalents, 0.033 mmol, 5 μL) were added at room temperature to a solution of the pre-step product (1.0 equivalent, 0.022 mmol, 15 mg) dissolved in dimethylformamide (1.6 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated under vacuum. The crude product was purified by high-performance liquid chromatography (HPLC) using 0.1% TFA aqueous solution and acetonitrile as the mobile phase to obtain the target compound (0.011 mmol, 9 mg, 48%) as a yellow oil.

[0644] 1 H NMR (400 MHz, DMSO-d6) δ 8.70 (t, J = 6.0 Hz, 1H), 8.65 (s, 1H), 8.43 (s, 2H), 7.92 (d, J = 8.1 Hz, 1H), 7.59 (t, J = 8.9 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.32 (dd, J = 8.4, 5.6 Hz, 2H), 7.16 (t, J = 8.8 Hz, 2H), 7.09 (dd, 1H), 7.01 (dd, J = 8.5, 2.4 Hz, 1H), 4.86 (d, J = 11.2 Hz, 2H), 4.44 (d, J = 5.6 Hz, 2H), 4.29 (d, J = 5.9 Hz, 2H), 3.75 (s, 3H), 3.63 (s, 4H), 3.12 (d, J = 31.4 Hz, 5H), 2.90 (d, J = 19.0 Hz, 3H), 2.59 (t, J = 5.4 Hz, 3H), 2.52 - 2.48 (m, 4H); MS (ESI) [M+H] + = 639.09

[0645] <Example 72> Preparation of 2-(4-(2-(3-fluoro-4-(6-(2-((4-fluorobenzyl)amino)-2-oxoethyl)pyridine-3-yl)phenoxy)ethyl)piperidine-1-yl)-2-oxoethyl methyl(2-(methylamino)ethyl)carbamate

[0646] The target compound was obtained from 2-(5-(2-fluoro-4-(2-(piperidin-4-yl)ethoxy)phenyl)pyridin-2-yl)-N-(4-fluorobenzyl)acetamide by a method similar to that of Example 71. The product was obtained as a white solid (0.012 mmol, 7.4 mg, 39%).

[0647] 1 H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.78 - 8.64 (m, 2H), 8.39 (s, 2H), 8.13 (d, J = 8.9 Hz, 2H), 7.98 (t, J = 10.3 Hz, 1H), 7.60 - 7.46 (m, 2H), 7.39 - 7.27 (m, 2H), 7.20 - 7.11 (m, 2H), 7.01 (dd, J = 12.9, 2.5 Hz, 1H), 6.97 - 6.87 (m, 3H), 4.97 - 4.66 (m, 2H), 4.28 (dd, J = 11.3, 5.8 Hz, 3H), 4.11 (t, J = 6.5 Hz, 2H), 3.77 (s, 3H), 3.70 - 3.49 (m, 4H), 3.24 - 2.98 (m, 4H), 2.90 (d, J = 18.9 Hz, 3H), 2.59 (d, J = 5.3 Hz, 4H), 1.74 (d, J = 19.7 Hz, 0H), 1.31 - 0.93 (m, 4H); MS (ESI) [M+H] + = 638.06

[0648] <Example 73> Preparation of (R)-2-(5-(4-(2-(4-(2-ethoxyacetyl)-3-methylpiperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0649]

[0650] Step 1: Preparation of tert-butyl (R)-4-(2-hydroxyethyl)-2-methylpiperazine-1-carboxylate

[0651] 4-bromoethanol (5 equivalents, 7.50 mmol, 532 μL), K2CO3 (2.5 equivalents, 3.75 mmol, 518 mg), and KI (0.1 equivalents, 0.15 mmol, 25 mg) were added at room temperature to a solution of tert-butyl (R)-2-methylpiperazine-1-carboxylate (1.0 equivalent, 1.50 mmol, 300 mg) dissolved in acetonitrile (7.5 mL). The reaction mixture was stirred at room temperature for 15 hours, then poured into water, extracted twice with EtOAc, dried with MgSO4, and concentrated under vacuum. The crude product was purified by flash chromatography on silica gel (CH2Cl2 / MeOH, 10:1, Rf = 0.5) to obtain the target compound (1.57 mmol, 383 mg, quant) as a yellow oil.

[0652] 1 H NMR (400 MHz, CDCl3) δ 4.27 (d, J = 13.4 Hz, 1H), 3.91 - 3.79 (m, 1H), 3.63 (t, J = 5.4 Hz, 2H), 3.10 (td, J = 12.8, 3.4 Hz, 1H), 2.81 (d, J = 11.7 Hz, 2H), 2.67 (d, J = 11.3 Hz, 1H), 2.59 - 2.43 (m, 2H), 2.28 (dd, J = 11.3, 4.0 Hz, 1H), 2.11 (td, J = 11.7, 3.5 Hz, 1H), 1.48 (s, 9H), 1.25 (d, J = 6.8 Hz, 3H).

[0653] Step 2: Preparation of tert-butyl (R)-4-(2-chloroethyl)-2-methylpiperazine-1-carboxylate carboxylate

[0654] MsCl (2 equivalents, 3.14 mmol, 243 μL) and Et3N (2.5 equivalents, 3.93 mmol, 548 μL) were added at room temperature to a solution of the pre-step product (1.0 equivalent, 1.57 mmol, 383 mg) dissolved in dichloromethane (2.6 mL). The reaction mixture was stirred at room temperature for 1 day, then poured into water, extracted twice with CH2Cl2, dried with MgSO4, and concentrated under vacuum. The crude product was purified by flash chromatography on silica gel (Hx / EtOAc, 1:2, Rf = 0.6) to obtain the target compound (0.60 mmol, 194 mg, 38%) as a yellow oil.

[0655] 1 H NMR (400 MHz, CDCl3) δ 4.22 (s, 1H), 3.82 (d, J = 13.2 Hz, 1H), 3.58 (t, J = 7.0 Hz, 2H), 3.11 (td, J = 12.7, 3.4 Hz, 1H), 2.85 - 2.56 (m, 4H), 2.28 (dd, J = 11.1, 3.9 Hz, 1H), 2.12 (ddd, J = 12.2, 11.0, 3.5 Hz, 1H), 1.61 (s, 2H), 1.48 (s, 9H), 1.25 (d, J = 6.8 Hz, 3H); MS (ESI) [M+H] + = 322.89

[0656] Step 3: Preparation of tert-butyl (R)-4-(2-(3-fluoro-4-(6-(2-((4-fluorobenzyl)amino)-2-oxoethyl)pyridine-3-yl)phenoxy)ethyl)-2-methylpiperazine-1-carboxylate

[0657] 2-(5-(2-fluoro-4-hydroxyphenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide (1 equivalent, 0.17 mmol, 60 mg) and K2CO3 (1.5 equivalents, 0.26 mmol, 36 mg) were added at room temperature to a solution of the pre-step product (1.5 equivalents, 0.26 mmol, 68 mg) dissolved in dimethylformamide (1.0 mL). The reaction mixture was stirred at room temperature for 16 hours, then poured into water, extracted twice with EtOAc, dried with MgSO4, and concentrated under vacuum. The crude product was purified by flash chromatography on silica gel (Hx / EtOAc, 1:2, Rf = 0.3) to obtain the target compound (0.14 mmol, 81 mg, 82%) as a yellow oil.

[0658] 1 H NMR (400 MHz, DMSO-d6) δ 8.65 (t, J = 6.0 Hz, 1H), 8.62 (s, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.51 (t, J = 9.0 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.32 (dd, J = 8.6, 5.6 Hz, 2H), 7.15 (t, J = 8.9 Hz, 2H), 7.02 (dd, J = 12.9, 2.5 Hz, 1H), 6.94 (dd, J = 8.6, 2.5 Hz, 1H), 4.29 (d, J) = 5.9 Hz, 2H), 4.17 (t, J = 5.7 Hz, 2H), 4.08 (s, 2H), 3.73 (s, 2H), 2.97 (t, J = 12.6 Hz, 1H), 2.89 (d, J = 9.2 Hz, 2H), 2.81 - 2.65 (m, 4H), 2.16 (dd, J = 11.3, 3.9 Hz, 1H), 1.14 (d, J = 6.7 Hz, 4H); MS (ESI) [M+H] + = 581.51

[0659] Step 4: Preparation of (R)-2-(5-(4-(2-(4-(2-ethoxyacetyl)-3-methylpiperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0660] 4N HCl was added at room temperature to a solution in which the product of the previous step (1.0 equivalent, 0.042 mmol, 20 mg) was dissolved in 1,4-dioxane (0.7 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum. The reaction mixture was mixed with 2-ethoxyacetic acid (1.5 equivalent, 0.063 mmol, 6 μL), EDCI·HCl (1.5 equivalent, 0.063 mmol, 12 mg), HOBt (1.5 equivalent, 0.063 mmol, 8.5 mg), and DIPEA (5 equivalent, 0.21 mmol, 37 μL) in dichloromethane (1 mL) and stirred at room temperature for 8 hours. The reaction mixture was poured into water, extracted twice with CH2Cl2, washed with brine, dried with MgSO4, and concentrated under vacuum. The crude product was purified by silica gel flash chromatography (CH2Cl2 / MeOH, 10:1, Rf = 0.4) to obtain the target compound, which is a yellow wax (0.024 mmol, 14 mg, 58%).

[0661] 1H NMR (400 MHz, DMSO-d6) δ 8.67 (t, J = 5.9 Hz, 1H), 8.62 (d, J = 2.3 Hz, 1H), 7.87 (dt, J = 8.1, 2.0 Hz, 1H), 7.51 (t, J = 9.0 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.37 - 7.29 (m, 2H), 7.22 - 7.11 (m, 2H), 7.03 (dd, J = 13.0, 2.5 Hz, 1H), 6.94 (dd, J = 8.6, 2.5 Hz, 1H), 4.29 (d, J = 5.9 Hz, 2H), 4.17 (t, J = 5.7 Hz, 2H), 3.72 (s, 2H), 3.45 (q, J = 7.0 Hz, 2H), 2.93 (d, J = 11.2 Hz, 1H), 2.86 - 2.62 (m, 4H), 2.30 - 1.84 (m, 4H), 1.24 (s, 2H), 1.12 (t, J = 7.0 Hz, 3H); MS (ESI) [M+H] + = 567.53

[0662] <Example 74> Preparation of (S)-2-(5-(4-(2-(4-(2-ethoxyacetyl)-3-methylpiperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0663] The target compound was obtained from tert-butyl (S)-2-methylpiperazine-1-carboxylate in five steps, similar to the preparation method of Example 73. The product was obtained as a yellow wax (0.023 mmol, 13 mg, 55%).

[0664] 1H NMR (400 MHz, DMSO-d6) δ 8.67 (t, J = 5.9 Hz, 1H), 8.62 (d, J = 2.2 Hz, 1H), 7.93 - 7.79 (m, 1H), 7.51 (t, J = 9.0 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.36 - 7.27 (m, 2H), 7.21 - 7.09 (m, 2H), 7.03 (dd, J = 12.9, 2.5 Hz, 1H), 6.94 (dd, J = 8.5, 2.5 Hz, 1H), 4.29 (d, J = 5.9 Hz, 2H), 4.17 (t, J = 5.7 Hz, 2H), 3.72 (s, 2H), 3.45 (q, J = 7.0 Hz, 2H), 2.93 (d, J = 11.3 Hz, 1H), 2.85 - 2.63 (m, 4H), 2.24 - 1.87 (m, 4H), 1.24 (s, 2H), 1.12 (t, J = 7.0 Hz, 3H); MS (ESI) [M+H] + = 567.42

[0665] <Example 75> Preparation of (S)-2-(5-(4-(2-(4-(2-ethoxyacetyl)-2-methylpiperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0666] The target compound was obtained from tert-butyl (S)-3-methylpiperazine-1-carboxylate in five steps, similar to the preparation method of Example 73. The product was obtained as a yellow oil (0.022 mmol, 13 mg, 53%).

[0667] 1H NMR (400 MHz, DMSO-d6) δ 8.67 (t, J = 6.0 Hz, 1H), 8.62 (s, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.51 (t, J = 8.9 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.32 (dd, J = 8.3, 5.5 Hz, 2H), 7.15 (t, J = 8.8 Hz, 2H), 7.00 (dd, 1H), 6.93 (dd, 1H), 4.29 (d, J = 5.9 Hz, 2H), 4.12 (dt, J = 21.6, 7.2 Hz, 4H), 3.84 (t, J = 14.5 Hz, 1H), 3.72 (s, 2H), 3.57 (d, J = 12.9 Hz, 1H), 3.45 (q, J = 6.9 Hz, 2H), 3.02 (dt, J = 13.2, 6.4 Hz, 2H), 2.86 (d, J = 11.9) Hz, 2H), 2.74 (dt, J = 14.3, 7.9 Hz, 2H), 1.24 (s, 2H), 1.12 (t, J = 7.0 Hz, 4H), 1.02 (t, J = 6.0 Hz, 3H); MS (ESI) [M+H] + = 567.42

[0668] <Example 76> Preparation of (R)-2-(5-(4-(2-(4-(2-ethoxyacetyl)-2-methylpiperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0669] The target compound was obtained from tert-butyl (R)-3-methylpiperazine-1-carboxylate in five steps, similar to the preparation method of Example 73. The product was obtained as a yellow wax (0.017 mmol, 9.8 mg, 41%).

[0670] 1H NMR (400 MHz, DMSO-d6) δ 8.67 (t, J = 6.0 Hz, 1H), 8.62 (d, J = 2.3 Hz, 1H), 7.87 (dt, J = 8.3, 1.7 Hz, 1H), 7.51 (t, J = 9.0 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.37 - 7.28 (m, 2H), 7.22 - 7.11 (m, 2H), 7.01 (dd, J = 12.9, 2.5 Hz, 1H), 6.93 (dd, J = 8.7, 2.5 Hz, 1H), 4.29 (d, J = 5.9 Hz, 2H), 4.18 - 4.02 (m, 4H), 3.86 (d, J = 14.7 Hz, 1H), 3.72 (s, 2H), 3.57 (d, J = 12.8 Hz, 1H), 3.46 (q, J = 7.0 Hz, 2H), 3.02 (dt, J = 12.7, 6.0 Hz, 2H), 2.88 (t, J = 15.8 Hz, 2H), 2.81 - 2.64 (m, 2H), 1.12 (t, J = 7.0 Hz, 3H), 1.03 (t, J = 6.1 Hz, 3H); MS (ESI) [M+H] + = 567.42

[0671] <Example 77> Preparation of 2-(5-(4-(2-(4-(2-ethoxyacetyl)piperazine-1-yl)ethoxy)-2-methylphenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0672] The target compound was obtained from the compound of Example 35 by a method similar to that of Example 19. The product was obtained as a brown solid (0.067 mmol, 37 mg, 72%).

[0673] 1¹H NMR (400 MHz, DMSO-d6); δ 8.66 (t, J = 5.9 Hz, 1H), 8.43 (dd, J = 2.4, 0.9 Hz, 1H), 7.71 (dd, J = 8.0, 2.4 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.33 (dd, J = 8.5, 5.6 Hz, 2H), 7.20 - 7.11 (m, 3H), 6.94 (d, J = 2.6 Hz, 1H), 6.88 (dd, J = 8.5, 2.7 Hz, 1H), 4.30 (d, J = 6.0 Hz, 2H), 4.13 (t, J = 5.7) Hz, 2H), 4.10 (s, 2H), 3.72 (s, 2H), 3.46 (q, J = 7.1 Hz, 8H), 2.75 (t, J = 5.7 Hz, 2H), 2.48 (s, 2H), 2.23 (s, 3H), 1.13 (t, J = 6.9 Hz, 3H); MS (ESI) [M+H] + = 549.61

[0674] <Example 78> Preparation of 2-(5-(4-(2-(4-(2-ethoxyacetyl)piperazine-1-yl)ethoxy)-2-methylphenyl)pyridine-2-yl)-N-(4-methylbenzyl)acetamide

[0675] The target compound was obtained from the compound of Example 41 by a method similar to that of Example 19. The product was obtained as a brown solid (0.064 mmol, 35 mg, 71%).

[0676] 1¹H NMR (400 MHz, DMSO-d6); δ 8.59 (t, J = 6.0 Hz, 1H), 8.42 (dd, J = 2.3, 0.9 Hz, 1H), 7.70 (dd, J = 7.9, 2.4 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.21 - 7.09 (m, 5H), 6.93 (d, J = 2.6 Hz, 1H), 6.88 (dd, J = 8.4, 2.7 Hz, 1H), 4.26 (d, J = 5.9 Hz, 2H), 4.13 (t, J = 5.7 Hz, 2H), 4.10 (s, 2H), 3.71 (s, 2H), 3.53 - 3.40 (m, 8H), 2.75 (t, J = 5.7 Hz, 2H), 2.47 (s, 2H), 2.28 (s, 3H), 2.23 (s, 3H), 1.12 (t, J = 7.0 Hz, 3H); MS (ESI) [M+H] + = 545.21

[0677] <Example 79> Preparation of 2-(5-(4-(2-(4-(2-ethoxyacetyl)piperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-methylbenzyl)acetamide

[0678] The target compound was obtained from Example 38 by a method similar to that of Example 19. The product was obtained as a white solid (0.074 mmol, 41 mg, 82%).

[0679] 1¹H NMR (400 MHz, DMSO-d6); δ 8.60 (d, J = 8.4 Hz, 2H), 7.90 - 7.84 (m, 1H), 7.51 (t, J = 8.9 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.15 (q, J = 7.9 Hz, 4H), 7.02 (dd, J = 12.9, 2.5 Hz, 1H), 6.94 (dd, J = 8.6, 2.5 Hz, 1H), 4.26 (d, J = 5.9 Hz, 2H), 4.18 (t, J = 5.6 Hz, 2H), 4.10 (s, 2H), 3.72 (s, 2H), 3.46 (q, J = 7.0 Hz, 8H), 2.75 (t, J = 5.6 Hz, 2H), 2.47 (s, 2H), 2.28 (s, 3H), 1.12 (t, J = 7.0 Hz, 3H); MS (ESI) [M+H] + = 549.45

[0680] <Example 80> Preparation of N-(4-fluorobenzyl)-2-(5-(4-(2-(1-(2-hydroxyacetyl)piperidine-4-yl)ethoxy)-2-methylphenyl)pyridine-2-yl)acetamide

[0681] The target compound was obtained from N-(4-fluorobenzyl)-2-(5-(4-hydroxy-2-methylphenyl)pyridine-2-yl)acetamide in four steps, similar to the preparation method of Example 19. The product was obtained as a yellow solid (0.058 mmol, 30 mg, 67%).

[0682] 1¹H NMR (400 MHz, DMSO-d6); δ 8.65 (d, J = 6.2 Hz, 1H), 8.43 (dd, J = 2.4, 0.9 Hz, 1H), 7.70 (dd, J = 8.0, 2.4 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.32 (dd, J = 8.5, 5.6 Hz, 2H), 7.15 (ddd, J = 8.9, 6.6, 2.2 Hz, 3H), 6.92 (d, J = 2.6 Hz, 1H), 6.87 (dd, J = 8.4, 2.7 Hz, 1H), 4.48 - 4.40 (m, 1H), 4.34 (d, J = 15.1 Hz, 1H), 4.30 (d, J = 5.9 Hz, 2H), 4.16 - 3.98 (m, 4H), 3.72 (s, 2H), 3.69 - 3.60 (m, 1H), 2.94 (t, J = 12.8 Hz, 1H), 2.62 (t, J = 12.5 Hz, 1H), 2.23 (s, 3H), 1.75 (d, J = 11.8 Hz, 2H), 1.72 - 1.65 (m, 2H), 1.21 - 0.99 (m, 2H); MS (ESI) [M+H] + = 520.45

[0683] <Example 81> Preparation of 2-(5-(4-(2-(1-(2-hydroxyacetyl)piperidine-4-yl)ethoxy)-2-methylphenyl)pyridine-2-yl)-N-(4-methylbenzyl)acetamide

[0684] The target compound was obtained from 2-(5-(2-methyl-4-(2-(piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-methylbenzyl)acetamide in four steps, similar to the preparation method of Example 19. The product was obtained as a white solid (0.067 mmol, 34 mg, 61%).

[0685] 1¹H NMR (400 MHz, DMSO-d6); δ 8.60 (d, J = 7.3 Hz, 1H), 8.44 - 8.41 (m, 1H), 7.70 (dd, J = 8.0, 2.4 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.20 - 7.10 (m, 5H), 6.92 (d, J = 2.6 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 4.44 (t, J = 5.3 Hz, 1H), 4.34 (d, J = 13.2 Hz, 1H), 4.26 (d, J = 5.9 Hz, 2H), 4.06 (q, J = 6.4 Hz, 4H), 3.71 (d, J = 4.3 Hz, 2H), 3.66 (d, J = 15.6 Hz, 1H), 2.94 (t, J = 12.8 Hz, 1H), 2.62 (t, J = 12.8 Hz, 1H), 2.28 (s, 3H), 2.23 (s, 3H), 1.75 (d, J = 12.1 Hz, 2H), 1.69 (t, J = 6.3 Hz, 2H), 1.21 - 0.98 (m, 2H); MS (ESI) [M+H] + = 516.45

[0686] <Example 82> Preparation of 2-(5-(2-fluoro-4-(2-(1-(2-hydroxyacetyl)piperidine-4-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-methylbenzyl)acetamide

[0687] The target compound was obtained from 2-(5-(2-fluoro-4-hydroxyphenyl)pyridine-2-yl)-N-(4-methylbenzyl)acetamide in four steps, similar to the preparation method of Example 19. The product was obtained as a white solid (0.083 mmol, 43 mg, 69%).

[0688] 1¹H NMR (400 MHz, DMSO-d6); δ 8.60 (d, J = 8.9 Hz, 2H), 7.87 (d, J = 8.3 Hz, 1H), 7.50 (t, J = 9.0 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.14 (q, J = 7.8 Hz, 4H), 7.00 (d, J = 12.9 Hz, 1H), 6.95 - 6.88 (m, 1H), 4.44 (t, J = 5.4 Hz, 1H), 4.34 (d, J = 13.3 Hz, 1H), 4.25 (d, J = 5.9 Hz, 2H), 4.08 (dt, J = 10.8, 5.9 Hz, 4H), 3.72 (s, 2H), 3.66 (d, J = 19.2 Hz, 1H), 2.94 (t, J = 12.8 Hz, 1H), 2.63 (q, J = 11.9 Hz, 1H), 2.28 (s, 3H), 1.75 (d, J = 11.8 Hz, 2H), 1.72 - 1.66 (m, 2H), 1.10 (dd, J = 37.7, 11.6 Hz, 2H); MS (ESI) [M+H] + = 520.45

[0689] <Example 83> Preparation of 2-(5-(2-fluoro-4-(2-(1-(2-hydroxyethyl)piperidine-4-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-f-fluorobenzyl)acetamide

[0690] 2-bromoethanol (1.5 equivalents, 0.064 mmol, 4.5 μL) and K2CO3 (1.5 equivalents, 0.064 mmol, 8.8 mg) were added at room temperature to a solution of 2-(5-(2-fluoro-4-(2-(piperidin-4-yl)ethoxy)phenyl)pyridin-2-yl)-N-(4-fluorobenzyl)acetamide (1.0 equivalent, 0.043 mmol, 20 mg) dissolved in acetonitrile (1.0 mL). The reaction mixture was stirred at room temperature for 1 day, then poured into water, extracted twice with EtOAc, dried with MgSO4, and concentrated under vacuum. The crude product was purified by flash chromatography in silica gel (CH2Cl2 / MeOH, 10:1, Rf = 0.5) to obtain the target compound (0.022 mmol, 11 mg, 53%) as a yellow oil.

[0691] 1 H NMR (400 MHz, DMSO-d6) δ 8.66 (t, J = 6.0 Hz, 1H), 8.62 (s, 1H), 7.90 - 7.85 (m, 1H), 7.50 (t, J = 9.0 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.37 - 7.27 (m, 2H), 7.23 - 7.11 (m, 2H), 6.99 (dd, J = 12.9, 2.5 Hz, 1H), 6.92 (dd, J = 8.6, 2.5 Hz, 1H), 4.29 (d, J = 5.9 Hz, 2H), 4.08 (t, J = 6.5 Hz, 2H), 3.72 (s, 2H), 3.51 (s, 4H), 2.93 (s, 2H), 1.68 (d, J = 6.7 Hz, 5H), 1.48 (s, 2H), 1.24 (s, 4H); MS (ESI) [M+H] + = 510.21

[0692] <Example 84> Preparation of 2-(5-(4-(2-(1-(2-ethoxyethyl)piperidine-4-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0693] The target compound was obtained by a method similar to that of Example 83. The product was obtained as a yellow solid (0.037 mmol, 20 mg, 85%).

[0694] 1 H NMR (400 MHz, DMSO-d6) δ 8.66 (t, J = 5.9 Hz, 1H), 8.61 (d, J = 2.2 Hz, 1H), 7.87 (dt, J = 8.2, 1.9 Hz, 1H), 7.50 (t, J = 9.0 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.38 - 7.25 (m, 2H), 7.20 - 7.11 (m, 2H), 6.99 (dd, J = 13.0, 2.5 Hz, 1H), 6.92 (dd, J = 8.6, 2.5 Hz, 1H), 4.29 (d, J = 5.9 Hz, 2H), 4.08 (t, J = 6.6 Hz, 2H), 3.72 (s, 2H), 3.52 - 3.38 (m, 6H), 2.87 (s, 2H), 2.55 (s, 2H), 1.67 (q, J = 6.8 Hz, 4H), 1.10 (t, J = 7.0 Hz, 3H); MS (ESI) [M+H] + = 538.62

[0695] <Example 85> Preparation of (R)-2-(5-(2-fluoro-4-(2-(1-(2-hydroxyprohanoyl)piperidine-4-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0696] The target compound was obtained from 2-(5-(2-fluoro-4-(2-(piperidin-4-yl)ethoxy)phenyl)pyridin-2-yl)-N-(4-fluorobenzyl)acetamide by a method similar to that of Example 19. The product was obtained as a yellow wax (0.013 mmol, 8 mg, 20%).

[0697] 1H NMR (400 MHz, DMSO-d6δ 8.66 (t, 1H), 8.62 (s, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.51 (t, J = 9.0 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.32 (dd, J = 8.5, 5.5 Hz, 2H), 7.15 (t, J = 8.9 Hz, 2H), 7.00 (dd, J = 12.9 Hz, 1H), 6.93 (dd, J = 8.5 Hz, 1H), 4.29 (d, J = 5.9 Hz, 2H), 4.11 (t, J = 6.5 Hz, 2H), 3.72 (s, 2H), 3.51 - 3.38 (m, 4H), 1.71 (s, 5H), 1.36 - 1.20 (m, 4H), 1.16 (d, J = 6.4 Hz, 2H), 0.94 (dd, J = 6.9, 5.6 Hz, 2H); MS (ESI) [M+H] + = 538.46

[0698] <Example 86> Preparation of (S)-2-(5-(2-fluoro-4-(2-(1-(2-hydroxypropanoyl)piperidine-4-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0699] The target compound was obtained from 2-(5-(2-fluoro-4-(2-(piperidin-4-yl)ethoxy)phenyl)pyridin-2-yl)-N-(4-fluorobenzyl)acetamide by a method similar to that of Example 19. The product was obtained as a white solid (0.012 mmol, 8 mg, 18%).

[0700] 1H NMR (400 MHz, DMSO-d6) δ 8.66 (t, 1H), 8.62 (s, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.51 (t, J = 9.0 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.36 - 7.28 (m, 2H), 7.15 (t, J = 8.9 Hz, 2H), 7.00 (dd, J = 13.2 Hz, 1H), 6.93 (dd, J = 8.7 Hz, 1H), 4.29 (d, J = 5.9 Hz, 2H), 4.11 (d, J = 6.6) Hz, 2H), 3.72 (s, 2H), 3.33 - 3.04 (m, 4H), 1.73 (d, J = 24.0 Hz, 6H), 1.39 - 1.07 (m, 6H); MS (ESI) [M+H] + = 538.46

[0701] <Example 87> Preparation of 2-(5-(2-fluoro-4-(2-(4-hydroxy-1-(2-hydroxyacetyl)piperidine-4-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0702]

[0703] Step 1: Preparation of tert-butyl 4-hydroxy-4-(2-hydroxyethyl)piperidine-1-carboxylate

[0704] LiBH4 (3 equivalents, 2.1 mmol, 1.05 mL) was added at 0 °C to a solution of tert-butyl 4-(2-ethoxy-2-oxoethyl)-4-hydroxypiperidin-1-carboxylate (1.0 equivalent, 0.70 mmol, 200 mg) dissolved in methanol (0.2 mL) and THF (2.8 mL). The reaction mixture was stirred at room temperature for 30 minutes, then poured into water, extracted twice with EtOAc, dried with MgSO4, and concentrated under vacuum. The crude product was purified by flash chromatography on silica gel (CH2Cl2 / MeOH, 10:1, Rf = 0.5) to obtain the target compound (0.64 mmol, 158 mg, 92%) as a colorless oil.

[0705] 1 H NMR (400 MHz, CDCl3) δ 4.07 (t, J = 5.8 Hz, 2H), 3.93 - 3.78 (m, 2H), 3.25 (ddd, J = 13.7, 11.6, 3.0 Hz, 2H), 1.80 (t, J = 5.8 Hz, 2H), 1.70 (d, J = 13.3 Hz, 2H), 1.63 - 1.50 (m, 6H), 1.48 (d, J = 0.8 Hz, 9H); MS (ESI) [M+H] + = 268.12

[0706] Step 2: Preparation of tert-butyl 4-hydroxy-4-(2-((methylsulfonyl)oxy)ethyl)piperidine-1-carboxylate

[0707] MsCl (2 equivalents, 1.28 mmol, 99 μL) was added at 0 °C to a solution of Et3N (3 equivalents, 1.92 mmol, 99 μL) and a pre-stage product (1.0 equivalent, 0.64 mmol, 158 mg) dissolved in dichloromethane (2.6 mL). The reaction mixture was stirred at room temperature for 13 hours, then poured into water, extracted twice with CH2Cl2, dried with MgSO4, and concentrated under vacuum. The crude product was purified by flash chromatography on silica gel (CH2Cl2 / MeOH, 10:1, Rf = 0.5) to obtain the target compound (0.17 mmol, 44 mg, 21%) as a yellow oil.

[0708] 1 H NMR (400 MHz, CDCl3) δ 4.32 (t, J = 6.7 Hz, 2H), 3.92 - 3.84 (m, 2H), 3.17 (s, 3H), 3.09 - 2.96 (m, 4H), 1.53 - 1.45 (m, 13H); MS (ESI) [M+H] + = 323.93

[0709] Step 3: Preparation of 2-(5-(2-fluoro-4-(2-(4-hydroxypiperidin-4-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0710] 2-(5-(2-fluoro-4-hydroxyphenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide (1 equivalent, 0.09 mmol, 32 mg) and K2CO3 (1.5 equivalents, 0.14 mmol, 19 mg) were added at room temperature to a solution of the pre-step product (1.5 equivalents, 0.14 mmol, 44 mg) dissolved in dimethylformamide (1.0 mL). The reaction mixture was stirred at room temperature for 21 hours, then poured into water, extracted twice with EtOAc, dried with MgSO4, and concentrated under vacuum. The crude product was purified by flash chromatography on silica gel (CH2Cl2 / MeOH, 10:1, Rf = 0.6) to obtain the target compound (0.080 mmol, 46 mg, 89%) as a yellow oil.

[0711] 1 H NMR (400 MHz, DMSO-d6) δ 8.66 (t, 1H), 8.62 (s, 1H), 7.96 (s, 1H), 7.55 - 7.46 (m, 1H), 7.43 (d, J = 8.2 Hz, 1H), 7.37 - 7.28 (m, 2H), 7.15 (t, J = 8.8 Hz, 2H), 7.00 (dd, J = 13.0 Hz, 1H), 6.93 (dd, J = 8.6 Hz, 1H), 4.34 - 4.24 (m, 2H), 3.83 (s, 2H), 3.73 (s, 2H), 3.33 - 3.26 (m, 4H), 2.55 (s, 2H), 2.53 - 2.42 (m, 5H), 1.41 (s, 9H); MS (ESI) [M+H] + = 582.27

[0712] Step 4: Preparation of 2-(5-(2-fluoro-4-(2-(4-hydroxy-1-(2-hydroxyacetyl)piperidine-4-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)

[0713] 4N HCl was added at room temperature to a solution of the previous step product (1.0 equivalent, 0.042 mmol, 20 mg) dissolved in 1,4-dioxane (0.5 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum. The reaction mixture was mixed with glycolic acid (1.5 equivalent, 0.063 mmol, 5 mg), EDCI·HCl (1.5 equivalent, 0.063 mmol, 12 mg), HOBt (1.5 equivalent, 0.063 mmol, 8.5 mg), and DIPEA (5 equivalent, 0.21 mmol, 37 μL) in dichloromethane (1 mL) and stirred at room temperature for 1 day. The reaction mixture was poured into water, extracted twice with CH2Cl2, washed with brine, dried with MgSO4, and concentrated under vacuum. The crude product was purified by silica gel flash chromatography (CH2Cl2 / MeOH, 10:1, Rf = 0.5) to obtain the target compound (0.011 mmol, 6 mg, 26%), which is a yellow solid.

[0714] 1 H NMR (400 MHz, DMSO-d6) δ 8.66 (t, J = 6.0 Hz, 1H), 8.62 (s, 1H), 7.87 (d, J = 8.3 Hz, 1H), 7.51 (t, J = 8.9 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.32 (dd, J = 8.4, 5.6 Hz, 2H), 7.15 (t, J = 8.8 Hz, 2H), 7.00 (dd, 1H), 6.93 (dd, 1H), 4.29 (d, J = 5.9 Hz, 2H), 4.19 - 4.07 (m, 2H), 3.72 (s, 2H), 3.49 (m, 4H), 2.55 (s, 2H), 2.51 - 2.44 (m, 2H), 2.20 - 2.07 (m, 2H) ; MS (ESI) [M+H] + = 542.38

[0715] <Example 88> Preparation of 2-(5-(2-fluoro-4-(2-(4-fluoro-1-(2-hydroxyacetyl)piperidine-4-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0716] The target compound was obtained from tert-butyl 4-(2-ethoxy-2-oxoethyl)-4-fluoropiperidine-1-carboxylate in five steps, similar to the preparation method of Example 87. The product was obtained as a yellow solid (0.009 mmol, 5.3 mg, 24%).

[0717] 1 H NMR (400 MHz, DMSO-d6) δ 8.66 (t, J = 6.0 Hz, 1H), 8.62 (s, 1H), 7.93 - 7.82 (m, 1H), 7.52 (t, J = 9.0 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.32 (dd, J = 8.5, 5.7 Hz, 2H), 7.21 - 7.09 (m, 2H), 7.03 (dd, J = 12.9, 2.5 Hz, 1H), 6.94 (dd, J = 8.7, 2.5 Hz, 1H), 4.55 (t, J = 5.5 Hz, 1H), 4.29 (d, J = 5.9 Hz, 2H), 4.20 (t, J = 6.6 Hz, 2H), 4.11 (t, J = 5.7 Hz, 2H), 3.72 (s, 2H), 3.58 - 3.40 (m, 4H), 2.55 (s, 2H), 2.23 - 2.05 (m, 2H), 2.01 - 1.81 (m, 4H); MS (ESI) [M+H] + = 542.46

[0718] <Example 89> Preparation of 2-(5-(2-fluoro-4-(2-(1-(2-hydroxyethyl)-4-methylpiperidine-4-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0719] The target compound was obtained from tert-butyl 4-(2-ethoxy-2-oxoethyl)-4-methylpiperidine-1-carboxylate in five steps, similar to the preparation method of Example 87. The product was obtained as a yellow solid (0.011 mmol, 6 mg, 27%).

[0720] 1 H NMR (400 MHz, DMSO-d6) δ 8.66 (t, J = 5.9 Hz, 1H), 8.62 (s, 1H), 7.87 (dd, J = 8.2, 2.1 Hz, 1H), 7.51 (t, J = 9.0 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.32 (dd, J = 8.6, 5.6 Hz, 2H), 7.15 (t, J = 8.9 Hz, 2H), 7.01 (dd, J = 13.0, 2.5 Hz, 1H), 6.93 (dd, J = 8.6, 2.5 Hz, 1H), 4.29 (d, J = 6.0 Hz, 2H), 4.12 (t, J = 7.0 Hz, 2H), 4.07 (d, J = 5.4 Hz, 2H), 3.72 (s, 2H), 3.47 - 3.39 (m, 4H), 1.78 (t, J = 7.0 Hz, 2H), 1.42 (dd, J = 35.7, 12.1 Hz, 5H), 1.05 (s, 3H); MS (ESI) [M+H] + = 538.67

[0721] <Example 90> Preparation of (R)-2-(5-(4-(2-(4-(2-ethoxyacetyl)-3-ethylpiperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0722] The target compound was obtained through five steps starting from tert-butyl (R)-2-ethylpiperazine-1-carboxylate, similar to the preparation method of Example 73. The product was obtained as a yellow oil (0.035 mmol, 20 mg, 58%).

[0723] 1H NMR (400 MHz, DMSO-d6) δ 8.64 (m, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.51 (t, J = 9.0 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.32 (dd, J = 8.3, 5.5 Hz, 2H), 7.15 (t, J = 8.7 Hz, 2H), 7.02 (dd, J = 12.8 Hz, 1H), 6.94 (dd, J = 8.7 Hz, 1H), 4.29 (d, J = 5.9 Hz, 2H), 4.17 (d, J = 5.9 Hz, 2H), 3.73 (s, 2H), 3.48 (dd, J = 13.6, 6.6 Hz, 4H), 2.92 (d, J = 10.8 Hz, 2H), 2.84 - 2.65 (m, 4H), 2.02 (d, J = 35.2 Hz, 2H), 1.68 (d, J = 35.0 Hz, 2H), 1.12 (t, J = 7.0 Hz, 4H), 0.90 - 0.67 (m, 4H); MS (ESI) [M+H] + = 581.54

[0724] <Example 91> Preparation of (R)-2-(5-(4-(2-(4-(2-ethoxyacetyl)-3-isopropylpiperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0725] The target compound was obtained through five steps starting from tert-butyl (R)-2-isopropylpiperazine-1-carboxylate, similar to the preparation method of Example 73. The product was obtained as a yellow oil (0.017 mmol, 10 mg, 29%).

[0726] 1H NMR (400 MHz, DMSO-d6) δ 8.66 (t, J = 5.9 Hz, 1H), 8.62 (s, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.51 (t, J = 9.0 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.32 (dd, J = 8.5, 5.6 Hz, 2H), 7.15 (t, J = 8.9 Hz, 2H), 7.01 (dd, J = 13.1, 2.5 Hz, 1H), 6.93 (dd, J = 8.6, 2.5 Hz, 1H), 4.29 (d, J) = 6.0 Hz, 2H), 4.17 (t, J = 5.3 Hz, 2H), 4.06 - 3.95 (m, 2H), 3.72 (s, 2H), 3.55 - 3.37 (m, 4H), 3.09 (d, J = 12.4 Hz, 2H), 2.90 (s, 1H), 2.83 - 2.58 (m, 4H), 2.08 (d, J = 10.4 Hz, 2H), 1.96 (d, J = 12.4 Hz, 2H), 1.12 (t, J = 7.0 Hz, 3H), 0.90 (t, J = 5.6 Hz, 3H), 0.77 (d, J = 6.8 Hz, 2H), 0.71 (d, J = 6.8 Hz, 2H); MS (ESI) [M+H] + = 595.55

[0727] <Example 92> Preparation of 2-(5-(4-(2-(4-(2-ethoxyacetyl)-4,7-diazaspiro[2.5]octane-7-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0728] The target compound was obtained in five steps starting from tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate, similar to the preparation method of Example 73. The product was obtained as a yellow wax (0.025 mmol, 14 mg, 41%).

[0729] 1H NMR (400 MHz, DMSO-d6) δ 8.66 (t, 1H), 8.62 (s, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.51 (t, J = 9.0 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.32 (dd, J = 8.4, 5.5 Hz, 2H), 7.15 (t, J = 8.8 Hz, 2H), 7.01 (dd, 1H), 6.92 (dd, 1H), 4.29 (d, J = 5.9 Hz, 2H), 4.14 (t, J = 5.8 Hz, 2H), 3.72 (s, 2H), 3.30 - 3.16 (m, 4H), 2.69 (d, J = 12.2 Hz, 4H), 1.12 (t, J = 7.0 Hz, 2H), 0.85 (m, 4H); MS (ESI) [M+H] + = 579.52

[0730] <Example 93> Preparation of (R)-2-(5-(4-(2-(4-(2-ethoxyacetyl)-3-propylpiperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0731] The target compound was obtained through five steps starting from tert-butyl (R)-2-propylpiperazine-1-carboxylate, similar to the preparation method of Example 73. The product was obtained as a white solid (0.014 mmol, 8.1 mg, 23%).

[0732] 1H NMR (400 MHz, DMSO-d6) δ 8.66 (t, J = 5.9 Hz, 1H), 8.62 (d, J = 2.3 Hz, 1H), 7.87 (dt, J = 8.3, 1.8 Hz, 1H), 7.51 (t, J = 9.0 Hz, 1H), 7.43 (d, J = 8.2 Hz, 1H), 7.36 - 7.28 (m, 2H), 7.22 - 7.11 (m, 2H), 7.02 (dd, J = 12.9, 2.5 Hz, 1H), 6.94 (dd, J = 8.6, 2.5 Hz, 1H), 4.29 (d, J = 5.9 Hz, 2H), 4.22 - 3.98 (m, 5H), 3.73 (s, 2H), 3.45 (q, J = 7.2 Hz, 2H), 2.89 (s, 2H), 2.72 (td, J = 13.3, 6.6 Hz, 2H), 2.15 - 1.88 (m, 2H), 1.79 - 1.49 (m, 2H), 1.12 (t, J = 7.0 Hz, 3H), 0.92 - 0.80 (m, 3H); MS (ESI) [M+H] + = 595.59

[0733] <Example 94> Preparation of (R)-2-(5-(2-fluoro-4-(2-(4-(2-methoxyacetyl)-3-methylpiperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0734] The target compound was obtained from tert-butyl (R)-4-(2-(3-fluoro-4-(6-(2-((4-fluorobenzyl)amino)-2-oxoethyl)pyridine-3-yl)phenoxy)ethyl)-2-methylpiperazine-1-carboxylate by a method similar to that of Example 73. The product was obtained as a white solid (0.008 mmol, 4.3 mg, 19%).

[0735] 1H NMR (400 MHz, DMSO-d6) δ 8.65 (t, J = 5.9 Hz, 1H), 8.62 (s, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.51 (t, J = 9.0 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.32 (dd, J = 8.4, 5.6 Hz, 2H), 7.15 (t, J = 8.8 Hz, 2H), 7.02 (dd, J = 12.9, 2.5 Hz, 1H), 6.94 (dd, J = 8.5, 2.5 Hz, 1H), 4.29 (d, J) = 5.9 Hz, 2H), 4.17 (t, J = 5.7 Hz, 2H), 4.05 (s, 2H), 3.73 (s, 2H), 3.35 - 3.15 (m, 4H), 2.92 (d, J = 11.6 Hz, 1H), 2.79 (d, J = 11.4 Hz, 1H), 2.71 (dq, J = 13.3, 6.4 Hz, 2H), 2.05 (dd, J = 68.7, 22.9 Hz, 4H), 1.21 (d, J = 27.3 Hz, 4H); MS (ESI) [M+H] + = 553.55

[0736] <Example 95> Preparation of (R)-2-(5-(2-fluoro-4-(2-(4-(2-hydroxyacetyl)-3-methylpiperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide

[0737] The target compound was obtained from tert-butyl (R)-4-(2-(3-fluoro-4-(6-(2-((4-fluorobenzyl)amino)-2-oxoethyl)pyridine-3-yl)phenoxy)ethyl)-2-methylpiperazine-1-carboxylate by a method similar to that of Example 73. The product was obtained as a white solid (0.010 mmol, 5.3 mg, 23%).

[0738] 1H NMR (400 MHz, DMSO-d6) δ 8.66 (t, J = 6.0 Hz, 1H), 8.62 (s, 1H), 7.87 (d, J = 8.3 Hz, 1H), 7.51 (t, J = 9.0 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.32 (dd, J = 8.5, 5.6 Hz, 2H), 7.15 (t, J = 8.9 Hz, 2H), 7.02 (dd, J = 12.9, 2.5 Hz, 1H), 6.94 (dd, 1H), 4.49 (t, J = 5.4 Hz, 2H), 4.29 (d, J = 6.0 Hz, 2H), 4.17 (t, J = 5.6 Hz, 2H), 3.72 (s, 3H), 3.31 - 3.20 (m, 4H), 2.91 (s, 2H), 2.84 - 2.61 (m, 4H), 2.09 (m, 4H); MS (ESI) [M+H] + = 539.54

[0739] The structural formulas of the compounds prepared in Examples 1-95 are summarized in Table 1 below.

[0740]

[0741]

[0742]

[0743]

[0744]

[0745]

[0746]

[0747]

[0748]

[0749]

[0750]

[0751]

[0752]

[0753]

[0754]

[0755] <Experimental Example 1> Analysis of Cell Viability

[0756] HeLa, SK-OV-3, B16F10, and JIMT-1 cells were purchased from ATCC (Manassas, VA). Cells were cultured at 37°C and 5% CO2 in RPMI-1640 and DMEM-1640 medium (Gibco, Thermo Fisher Scientific, Waltham, MA) supplemented with 10% fetal bovine serum (Gibco) and 1% penicillin-streptomycin (Gibco). One day before compound treatment, 4,000 cells of HeLa and SK-OV-3 and 3,000 cells of B15F10 and JIMT-1 were seeded into 96-well plates containing 100 μL of medium, and the next day, the cells were treated with the example compounds dissolved in dimethyl sulfoxide (Sigma-Aldrich, St. Louis, MO). After treating with the compound for 72 hours, add CellTiter-Glo® Reagent in an equal volume (100 μL) as the cell culture medium in each well, and stabilize the plate by placing it on a shaker at room temperature for 10 minutes. Then, quantify the cell viability by measuring the luminescence value with a luminometer on EnVision Multilabel Plate Readers (PerkinElmer, CT).

[0757] EC for each compound 50 EC was measured and is shown in Tables 2 to 4. Tirvanibulin (KX-01) was treated as a control compound and EC was 50 The value was calculated.

[0758] Compound EC 50(nM)HeLaSK-OV-3B16F10KX-01447124 Example 114490.15 Example 215420.091 Example 329650.21 Example 414330.089 Example 547930.21

[0759] Compound EC 50 (nM)HeLaSK-OV-3B16F10KX-01447124 Example 632--Example 7901--Example 872--Example 92.9--Example 1030--Example 112.5--Example 126.2--Example 134.3--Example 142.3--

[0760] Compound EC 50 (nM)HeLaSK-OV-3B16F10 Example 153.7 10.1 22.5 Example 1630.5 49.0 86.6 Example 173.9 16.5 80.7 Example 184.6 10.5 27.0 Example 193.7 4.0 0.6 Example 205.39.8 2.1 Example 213.07.2 0.8 Example 224.07.5 15.5 Example 234.39.1 34.0 Example 24-7.9 Example 256.9 13.7 28.6 Example 262.86.1 14.1 Example 27-7.3 Example 28-7.3 Example 29-50.7 Example 306.48.027.1 Example 3115.641.2144.6 Example 3236.549.3220.8 Example 3336.765.8249.0 Example 3452.7--Example 365.47.6 Example 3714.223.9-Example 396.715.8-Example 4013.826.8-Example 4218.729.3-Example 4373.988.5-Example 4416.37.4-

[0761] Compound EC 50(nM)HeLaSK-OV-3JIMT-1 Example 46 17.5 -- Example 47 4.7 -- Example 48 45.3 -- Example 49 41.4 -- Example 50 4.5 -- Example 51 12 -- Example 52 15 -- Example 53 2.9 7.1 -- Example 54 0.9 2.0 1.1 -- Example 55 20.6 15.9 -- Example 56 28 62 24.5 -- Example 57 4.6 2.4 -- Example 58 3.9 3.8 -- Example 59 2.3 1.7 -- Example 60 19.4 21 -- Example 61 79.3 47.1 -- Example 62 1.7 1.0 63-13.69.1 Example 64-14.4 15.9 Example 65-9.9 8.5 Example 66-13.7 18 Example 67-5.5 4.1 Example 68-4.4 3.8 Example 69-4.5 3.7 Example 70-6.9 6.3 Example 71-55.3 Example 72-35.5 Example 73-0.6 Example 74-1.7 Example 75-1.3 Example 76-4.5 Example 77-2.2 Example 78-5.3 Example 79-3.4 Example 80-4.1 Example 81-4.8 Example 82-4.3 Example 839.130.05.5 Example 8418.339.823.4 Example 854.88.25.3 Example 864.56.74.8 Example 871.84.81.6 Example 884.89.94.2 Example 8913.922.215.8 Example 907.18.74.4 Example 9116.519.015.6 Example 9217.622.015.5 Example 9317.418.617.0 Example 942.47.34.0 Example 954.812.34.4

[0762] Looking at Tables 2 to 5, it was confirmed that the compounds in the examples mostly exhibited excellent inhibitory activity against HeLa, SK-OV-3, B16F10, and JIMT-1 cell lines.

[0763] Therefore, since the compounds of the above examples can excellently inhibit the activity of cancer cell lines, they can be usefully used as a pharmaceutical composition for the prevention or treatment of cancer containing them as an active ingredient.

[0764] <Experimental Example 2> α-Tubulin Staining

[0765] SK-OV-3 cells were seeded onto Lab-Tech 4-well chamber slides and cultured for 12 hours. Subsequently, the cells were treated with DMSO, the compound of Example 22 (50 nM), the compound of Example 23 (50 nM), or KX-01, and cultured at 37°C for 16 hours. Afterward, the cells were fixed with a 4% paraformaldehyde solution and permeated with a solution containing 0.5% Triton X-100 in PBS. Microtubules were immunostained using an anti-tubulin monoclonal antibody (DM1A, Thermo Scientific) and stained with a secondary antibody conjugated with Alexa Fluor™ Plus 488. Nuclei were stained with 4',6-diamidino-2-phenylindole (DAPI). Fluorescence-labeled tubulin and nuclei were analyzed for microtubule expression and the degree of polymerization structure disruption using a BioTek Cytation C10 confocal imaging reader.

[0766] As a result, as shown in Figures 1a to 1c, through α-tubulin staining assay, it was confirmed that Examples 22 and 23 caused significant microtubule disruption at a low compound concentration of 50 nM, whereas KX-01 did not exhibit inhibitory activity compared to the control group.

[0767] In the same way, SK-OV-3 cells were treated for 16 hours with the compounds of Example 45 (10 nM) and 54 (10 nM), as well as KX-01 (10 nM), MMAE (10 nM), DM1 (10 nM), and dxd (10 nM) as control groups, and microtubule expression and the degree of polymerization structure destruction were analyzed by microscopy.

[0768] As a result, as shown in FIGS. 1d and 1e, the compounds of Examples 45 and 54 caused superior microtubule disruption compared to KX-01 and dxd, and demonstrated a level of microtubule disruption ability similar to that of the microtubule inhibitors MMAE and DM1, which are used as payloads for antibody-drug conjugates.

[0769] <Experimental Example 3> Cell Cycle Analysis

[0770] To investigate the effect of the compound of the example on the cell cycle, cell cycle analysis was performed using a fluorescence imaging cell analyzer (NucleoCounter NC-3000, ChemoMetec). Cells were seeded into a 6-well plate, treated with the test compound, and cultured for 24 hours. After harvesting, the cells were suspended in 250 μL of Solution 10 (lysis buffer, ChemoMetec) containing 10 μg / mL DAPI and incubated at 37°C for 5 minutes. Subsequently, 250 μL of Solution 11 (stabilization buffer, ChemoMetec) was added to stabilize the cell suspension. 10 μL of the stained cell suspension was then injected into an NC-Slide A8, and the cell cycle was analyzed using the two-step cell cycle assay protocol of the NucleoCounter NC-3000.

[0771] As a result, it was confirmed that the compounds of Examples 22 and 23 caused significant G2 / M phase arrest in contrast to the control group and the KX-01 treatment group (Figs. 2a and 2b). In addition, it was confirmed that cells treated with these analogs showed a significantly higher level of apoptosis compared to cells treated with KX-01 (Fig. 2c).

[0772] In the same way, it was confirmed in SK-OV-3 and JIMT-1 cell lines that the compounds of Examples 45 and 54 caused superior G2 / M phase arrest compared to the control and comparison groups (KX-01, DM1, dxd).

[0773] <Experimental Example 4> Western blotting

[0774] To evaluate the effect of the compounds on apoptosis, changes in the expression of proteins involved in apoptosis were compared using western blot experiments. SK-OV-3 cells were treated with the compound of Example 22 (50 nM), the compound of Example 23 (50 nM), or PBS (Con, control) for 6 hours, and then proteins were extracted. Equal amounts of proteins were separated by SDS-polyacrylamide gel electrophoresis (SDS-PAGE) and transferred to a polyvinylidene difluoride (PVDF) membrane. After blocking with buffer, the blots were incubated with a primary antibody and then with an appropriate secondary antibody.

[0775] As a result, a decrease in Src autophosphorylation and a decrease in phosphorylation of the downstream protein FAK were confirmed (Fig. 3a).

[0776] In addition, when apoptosis occurs, proteins called PARP and caspase 3, 7, and 9 are cleaved and activated, and simultaneously, the expression of a protein called Bax increases. Experimental results showed that, compared to the KX-01 control group, the compounds of Examples 22 and 23 significantly increased the expression of apoptosis-related proteins. Through this, it was confirmed that the two compounds have a pharmacological effect of inducing apoptosis (Fig. 3b).

[0777] In a similar manner, when the compound of Example 45 (40 nM) and the compound of 54 (40 nM) were treated to JIMT-1 cell lines for 6 hours, an equivalent reduction in Src autophosphorylation compared to the KX-01 control was confirmed (Fig. 3c).

[0778] Through the results of the above experimental examples, it can be seen that the compound of the example enhances pharmacological effects by exhibiting a dual mechanism of action (MOA) that includes both tubulin and Src inhibition.

[0779] <Experimental Example 5> In vivo pharmacokinetics experiment

[0780] Test method

[0781] After administering the drug to 9-week-old ICR mice that had undergone an acclimatization period, blood was collected at a set time. The blood was centrifuged (13,000 rpm, 4 ℃, 2 min) to separate the plasma, which was then stored at -70 ℃.

[0782] 1. PK1

[0783] Test substance 1 (G1)

[0784] Preparation of the administered substance: The concentration of the prepared solution was 0.4 mg / mL (IV), and it was prepared by dissolving or suspending it in DMSO equivalent to 5% of the total volume, then adding PEG400 equivalent to 40% of the total volume, and finally adding sterile distilled water equivalent to 55% of the remaining total volume.

[0785] Test substance 2 (G2)

[0786] Preparation of the administered substance: The concentration of the prepared solution was 0.4 mg / mL (PO), and it was prepared by dissolving or suspending it in DMSO equivalent to 5% of the total volume, adding PEG400 equivalent to 40% of the total volume, and then adding sterile distilled water equivalent to 55% of the remaining total volume.

[0787] After administering each test substance (2 vials of preparation), blood samples were collected from the IV administration group (G1 administration group) at 5 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours. Blood samples were collected from the PO administration group (G2 administration group) at 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours (plasma samples: 3 animals x 2 groups x 7 points x 1 tube = 42 samples).

[0788] Compound IV (2 mg / kg) a AUC last (μg·h / mL)t 1 / 2(h)CL (L / h / kg)Vss (L / kg)KX-01 1.81 ± 0.15 3.49 ± 1.11 1.11 ± 0.10 1.38 ± 0.14 Example 1 1.00 ± 0.10 1.64 ± 0.80 2.00 ± 0.18 1.79 ± 0.38 Example 2 1.04 ± 0.14 1.25 ± 0.20 1.95 ± 0.26 1.77 ± 0.45 Example 4 1.08 ± 0.10 2.93 ± 0.58 1.86 ± 0.18 2.27 ± 0.93

[0789] Compound (10 mg / kg) b AUC last (μg·h / mL)C max (μg / mL)t 1 / 2 (h)F%KX-019.40 ± 0.38 3.69 ± 0.86 2.82 ± 0.34 104 Example 14.20 ± 1.8 23.51 ± 1.39 3.53 ± 0.57 84 Example 22.68 ± 0.1 12.19 ± 0.08 1.25 ± 0.20 52 Example 43.02 ± 0.08 2.35 ± 0.67 3.46 ± 0.99 56

[0790] As a result of performing in vivo PK studies in mice on tirvanibulin (KX-01) and the compounds of the examples, tirvanibulin exhibited an excellent PK profile with a high oral AUC of 9.0 μg·h / mL or higher and perfect oral bioavailability. Although the compounds of Examples 1, 2, and 4 showed slightly inferior parameters, they consistently exhibited adequate oral AUC values ​​exceeding 2.0 μg·h / mL and oral bioavailability exceeding 50%.

[0791] <Experimental Example 6> In vivo tumor transplantation model

[0792] B16F10 melanoma cells were injected subcutaneously into C57BL / 6 wild-type mice (1X10 6After forming a tumor by (cells / mouse), when the tumor size reached approximately 150 mm³, KX-01 (4 mg / kg) and the compounds of Example 22 (4 mg / kg, 8 mg / kg) and Example 23 (2 mg / kg, 4 mg / kg) were administered intraperitoneally 5 times at 2-day intervals, and the tumor size was measured to compare and evaluate the tumor inhibitory effect and dose dependence of each compound.

[0793] Compound B16F10 IC 50 (SKOV3 / HeLa IC 50 )doseTGIKX-01240 nM(140 / 44 nM)8 mpk33% Example 22 15.5 nM(7.5 / 4 nM)4 mpk36%8 mpk62%

[0794] Compound B16F10 IC 50 (SKOV3 / HeLa IC 50 )doseTGIKX-01240 nM(140 / 44 nM)4 mpk2% Example 2334.0 nM(9.1 / 4.3 nM)2 mpk23%4 mpk45%

[0795] To evaluate the effects in disease models, including potential immunogenic effects, the compounds were tested in a B16F10 tumor transplant model. The compounds of Examples 22 and 23 were administered intraperitoneally to mice with B16F10 tumors five times at 2-day intervals, and tumor size was measured. Here, the compound of Example 22 was administered at concentrations of 4 mg / kg and 8 mg / kg, and the compound of Example 23 was administered at concentrations of 2 mg / kg and 4 mg / kg (Tables 8 and 9).

[0796] As a result, as shown in Figures 4a to 5b, a reduction in tumor growth was observed at all dose levels. In addition, the absence of change in the body weight of the animal models indicated that there was no toxicity. Compared to the control group and the KX-01 treatment group, the compounds of Examples 22 and 23 demonstrated superior tumor growth inhibition in the B16F10 transplant model.

[0797] <Experimental Example 7> In vitro ADME experiment

[0798] Cell permeability measurement

[0799] 1 Exam preparation

[0800] 1.1 Preparation of collagen-coated plates for cell culture

[0801] 150 μL of rat tail collagen (0.1 μg / μL in DW) solution was applied to a 12 mm transwell culture plate, left at 37°C for 2 hours, and then the collagen solution was removed.

[0802] 1.2 Preparation of Cell Culture Medium

[0803] For Caco-2 culture, two types of Caco-2 cell culture media were prepared: one containing 20% ​​FBS and 1% penicillin / streptomycin in DMEM medium, and the other containing 10% FBS and 1% penicillin / streptomycin in DMEM medium.

[0804] 1.3 Preparation of Transporter Solution

[0805] The transporter solution was completely dissolved in HBSS to a concentration of 4 mM sodium bicarbonate, 10 mM glucose, and 20 mM HEPES, and the pH was adjusted to 7.4. The transporter solution was warmed in a 37°C water bath before use in the experiment.

[0806] 1.4 Preparation of Test Substances

[0807] The test substance (10 mM DMSO stock solution) was diluted to 5 μM in the transporter solution, and the organic solvent (DMSO) content in the transporter solution used for the permeability test of the test substance was 1%. Representative substances caffeine, talinolol, and atenolol were diluted to 2 μM, 10 μM, and 50 μM, respectively, and then permeability tests were conducted.

[0808] 2 Cell Culture

[0809] Caco-2 cells with a passage number between 40 and 60 were seeded at a density of 2 x 10⁵ cells / well in collagen-coated 12 mm transwell culture plates. The cells were cultured in a cell culture medium containing 20% ​​FBS for 7 days, followed by a cell culture medium containing 10% FBS for 1 day, with the medium replaced every 2 to 3 days throughout the entire culture period. The cells were cultured in an incubator supplied with 5% CO₂ while maintaining a temperature (37°C) and humidity throughout the entire culture period, and all cell culture-related experiments were performed using sterile products inside a biosafety cabinet.

[0810] 3 TEER measurement

[0811] Caco-2 cells cultured and differentiated at 6.2 for 9 days were used in this study. On the day of the study, TEER was measured using an Evom to test the tight junctions of the cells, and transwells of cells with a TEER value of 200 Ω or higher were selected and used in the study.

[0812] 4 Cell Permeability Test

[0813] To evaluate the permeability of a substance moving from the apical plane to the basolateral plane, 0.5 mL of a transporter solution containing the test substance was added to the upper chamber of the transwell, and 1.5 mL of a transporter solution not containing the test substance was added to the lower chamber. After incubation for 120 minutes, a sample was collected from the lower chamber of the transwell. Conversely, to evaluate the permeability of a substance moving from the basolateral plane to the apical plane, 1.5 mL of a transporter solution containing the test substance was added to the lower chamber of the transwell, and 0.5 mL of a transporter solution not containing the test substance was added to the upper chamber. After incubation for 120 minutes, a sample was collected from the upper chamber.

[0814] 5. Sample Pretreatment

[0815] An acetonitrile solution containing 1 μM of the internal standard (IS), chlorpropamide (CPP), was mixed with the analytical sample in a 9:1 ratio, and then centrifuged at 15,000 rpm for 10 minutes. After collecting the supernatant, concentration analysis was performed using a mass spectrometer for quantitative analysis.

[0816] 6. Recovery Rate Evaluation

[0817] To evaluate the recovery rate of the test substance, quantitative analysis was performed on the concentration of the substance (C_last) after a 120-minute transmittance test of the initial concentration of the substance (C_initial), and data was calculated for values ​​where the substance recovery rate was less than 50%.

[0818] Plasma Protein Binding Measurement

[0819] 1. Add a 10 mM DMSO drug-highly concentrated solution to the plasma to make the drug concentration 5 μM.

[0820] 2. Add PBS to the RED plate chamber, attach the membrane insert, and then add plasma containing the drug and react in a shaking incubator (37℃, 4 h).

[0821] 3. After the reaction, collect the plasma and PBS samples, add cold acetonitrile containing an internal standard to terminate the reaction, centrifuge (4000 rpm, 4℃, 10 min), and analyze 100 μL of the supernatant using LC-MS / MS.

[0822] 4. Calculate the ratio of the drug bound to plasma protein according to the following formula.

[0823] Free form (%) = (Buffer chamber / Plasma chamber) × 100

[0824] Bound form (%) = 100 - Free form (%)

[0825] Plasma stability measurement

[0826] 1. Add a 10 mM DMSO drug-highly concentrated solution to the plasma to make the drug concentration 5 μM.

[0827] 2. React the plasma sample in a shaking incubator (37℃, 4 h).

[0828] 3. To terminate the reaction, add cold acetonitrile containing an internal standard and then deproteinize.

[0829] 4. After centrifugation (4000 rpm, 4℃, 15 min), the supernatant is analyzed by LC-MS / MS.

[0830] 5. Calculate plasma stability (%) from the amount of drug remaining in the test sample compared to the 0-hour response sample.

[0831] CYP IC 50 Value measurement

[0832] 1. Add the test drug to microsomes diluted with potassium phosphate buffer and incubate at 37°C for 5 minutes; then, add NADPH and five types of CYP substrates and react at 37°C for 20 minutes. (Final concentration of experimental compound: 10 μM, microsome final concentration: 0.2 mg / mL)

[0833] 2. To terminate the reaction, add cold acetonitrile containing an internal standard solution and then deproteinize.

[0834] 3. After centrifugation (4000 rpm, 4℃°C, 15 min), the supernatant is analyzed by LC-MS / MS.

[0835] MW / cLogP / TPSA ( 2 )523.6 / 2.9 / 100.3Permeability AB (10 -6 cm / s) (ER)0.4 (17.6)Plasma Protein Bindingf u,p % (m, h)8.0 / 8.4Plasma Stability % (m, h)75.4 / 97.5CYP IC 50 (1A2, 2C9, 2C19, 2D6, 3A4)>100 / 22.1 / 14.5 / 40.4 / 27.4

[0836] As a representative derivative, the in vitro ADME characteristics of the compound prepared in Example 23 were evaluated, and it was confirmed that most were within the acceptable range. The unbound fraction in plasma was approximately 8% in both mouse and human species. The compound of Example 23 was found to be stable in human plasma, but exhibited moderate stability in mouse plasma. Single-digit nanomolar EC 50 Given the high cellular efficacy of the compound of Example 23 (Table 4), it is considered likely that drug-drug interactions resulting from CYP inhibition will not cause serious problems.

Claims

1. A compound represented by the following chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In the above chemical formula 1, X is N or O and; Y is N or CR 5 and, here R 5 is H, OH, halogen, or C 1-10 It is alkyl; R 1 It is H, halogen, or C 1-10 It is alkyl; R 2 is H, C 1-10 Alkyl, C 1-10 It is an alkylsulfonyl or substituted carbonyl, provided that when X is O, it is none, and Here, the substituted carbonyl is a 3-6-membered cycloalkyl, unsubstituted, or substituted C 1-10 Substituted with an alkyl or unsubstituted or substituted 6-10 aryl group, and The above substituted C 1-10 The alkyl group is a 3-6-membered cycloalkyl, hydroxyl, unsubstituted, or hydroxyl-substituted C 1-10 Alkoxy, 6-10 aryl-C 1-10 Alkoxy, carboxyl, -OC(=O)N(C 1-10 Alkyl)-C 1-10 Alkyl-NH(C 1-10 alkyl) and -NHR 6 Substituted with 1 to 3 substituents selected from, where R 6 H, C 1-10 Alkyl, C 1-10 Alkyl carbonyl, C 1-10 It is an alkyloxycarbonyl or a 6-10 aryl carbonyl, and The above-mentioned substituted 6-10 aryl group is substituted with a hydroxyl or amino group; R 3 is a halogen, C 1-10 alkyl, or C 1-10 It is an alkoxy; R 4a to R 4b are all hydrogen, or R 4a to R 4b One of them is C 1-10 It is alkyl and the remainder is hydrogen, or R 4a and R 4b They are bonded to the same carbon, forming a 3-6 member cycloalkyl group together with the carbon atom to which they are bonded; n is an integer of 1 or 2.

2. In Paragraph 1, X is O and; Y is N and; R 1 is H; R 2 is nothing; R 3 is a halogen, C 1-10 alkyl, or C 1-10 It is an alkoxy; R 3 halogen or C 1-10 In the case of alkyl, n is an integer of 1 or 2, and R 3 Ga C 1-10 In the case of alkoxy, n is an integer of 2, A compound, its stereoisomer, or its pharmaceutically acceptable salt.

3. In Paragraph 1, X is O and; Y is N and; R 1 It is a halogen; R 2 is nothing; R 3 is a halogen or C 1-10 It is alkyl; n is an integer of 1 or 2, A compound, its stereoisomer, or its pharmaceutically acceptable salt.

4. In Paragraph 1, The above compound is represented by the following chemical formula 1-1, and [Chemical Formula 1-1] In the above chemical formula 1-1, X is N and; Y is N or CR 5 and, here R 5 is H, hydroxyl, halogen, or C 1-10 It is alkyl; R 1 It is H, halogen, or C 1-10 It is alkyl; R 2 is H, C 1-10 Alkyl, C 1-10 It is an alkylsulfonyl or substituted carbonyl, and Here, the substituted carbonyl is a 3-6-membered cycloalkyl, unsubstituted, or substituted C 1-10 Substituted with an alkyl, or an unsubstituted or substituted 6-10 aryl, and The above substituted C 1-10 The alkyl group is a 3-6-membered cycloalkyl, hydroxyl, unsubstituted, or hydroxyl-substituted C 1-10 Alkoxy, 6-10 aryl-C 1-10 Alkoxy, carboxyl, -OC(=O)N(C 1-10 Alkyl)-C 1-10 Alkyl-NH(C 1-10 alkyl) and -NHR 6 Substituted with 1 to 3 substituents selected from, where R 6 H, C 1-10 Alkyl, C 1-10 Alkyl carbonyl, C 1-10 It is an alkyloxycarbonyl or a 6-10 aryl carbonyl, and The above-mentioned substituted 6-10 aryl group is substituted with a hydroxyl or amino group; R 3 is a halogen, C 1-10 alkyl, or C 1-10 It is an alkoxy; R 4a to R 4b are all hydrogen, or R 4a to R 4b One of them is C 1-10 It is alkyl and the remainder is hydrogen, or R 4a and R 4b is bonded to the same carbon and together forms a 3-6 member cycloalkyl with the carbon atom to which they are bonded; n is an integer of 1; A compound, its stereoisomer, or its pharmaceutically acceptable salt.

5. In Paragraph 1 or 4, X is N and; Y is N and; R 1 halogen or C 1-10 It is alkyl; R 2 is H, C 1-10 Alkyl, C 1-10 It is an alkylsulfonyl, or a substituted carbonyl, and Here, the substituted carbonyl is a 3-6-membered cycloalkyl, unsubstituted, or substituted C 1-10 Substituted with an alkyl, or an unsubstituted or substituted 6-10 aryl, and The above substituted C 1-10 The alkyl group is a 3-6-membered cycloalkyl, hydroxyl, unsubstituted, or hydroxyl-substituted C 1-10 Alkoxy, 6-10 aryl-C 1-10 Alkoxy, carboxyl, -OC(=O)N(C 1-10 Alkyl)-C 1-10 Alkyl-NH(C 1-10 alkyl) and -NHR 6 Substituted with 1 to 3 substituents selected from, where R 6 H, C 1-10 Alkyl, C 1-10 Alkyl carbonyl, C 1-10 It is an alkyloxycarbonyl or a 6-10 aryl carbonyl, and The above-mentioned substituted 6-10 aryl group is substituted with a hydroxyl or amino group; R 3 is a halogen, or C 1-10 It is alkyl; R 4a to R 4b are all hydrogen, or R 4a to R 4b One of them is C 1-10 It is alkyl and the remainder is hydrogen, or R 4a and R 4b They are bonded to the same carbon, forming a 3-6 member cycloalkyl group together with the carbon atom to which they are bonded; n is an integer equal to 1, A compound, its stereoisomer, or its pharmaceutically acceptable salt.

6. In Paragraph 1 or 4, X is N and; Y is CR 5 and, here R 5 is H, hydroxyl, halogen, or C 1-10 It is alkyl; R 1 is a halogen; R 2 is substituted C 1-10 It is an alkyl-substituted carbonyl, and The above substituted C 1-10 Alkyl groups are amino, hydroxyl, unsubstituted, or hydroxyl-substituted C 1-10 Alkoxy or -OC(=O)N(C 1-10 Alkyl)-C 1-10 Alkyl-NH(C 1-10 Substituted with alkyl; R 3 is a halogen; R 4a and R 4b It is all hydrogen; n is an integer equal to 1, A compound, its stereoisomer, or its pharmaceutically acceptable salt.

7. In Paragraph 1, X is N or O and; Y is N or CR 5 and, here R 5 is H, hydroxyl, F, or methyl; R 1 is H, F, or methyl; R 2 is H, methyl, methylsulfonyl, ethylsulfonyl, or a substituted carbonyl, provided that when X is O, it is nothing, and Here, the substituted carbonyl is a 3-4-membered cycloalkyl, methyl, substituted C 1-3 Substituted with alkyl, or hydroxyl or amino-substituted phenyl, and The above substituted C 1-3 Alkyl groups are cyclopropyl, hydroxyl, C 1-3 Alkoxy, hydroxyl-substituted C 1-3 Substituted with 1 to 3 substituents selected from alkoxy, amino, methylamino, t-butoxycarbonylamino, acetylamino, phenylcarbonylamino, benzyloxy, carboxyl, hydroxy or amino substituted phenyl, and methyl(methylaminoethyl)aminocarbonyloxy; R 3 is a halogen, C 1-6 alkyl, or C 1-6 It is an alkoxy; R 4a and R 4b are all hydrogen, or R 4a is hydrogen and R 4b is C 1-6 It is alkyl, or R 4a and R 4b They together form a ternary cycloalkyl group with the carbon atoms to which they are substituted; n is an integer of 1 or 2, It is a compound, its stereoisomer, or a pharmaceutically acceptable salt.

8. In Paragraph 1, The above compound is a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, any one of the following: <1> N-benzyl-2-(5-(3-methyl-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)acetamide; <2> N-benzyl-2-(5-(2-methyl-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)acetamide; <3> N-benzyl-2-(5-(3-methoxy-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)acetamide; <4> N-benzyl-2-(5-(2-fluoro-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)acetamide; <5> N-benzyl-2-(5-(3-fluoro-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)acetamide; <6> N-benzyl-2-(5-(2,6-dimethyl-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)acetamide; <7> N-benzyl-2-(5-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)acetamide; <8> N-benzyl-2-(5-(2,3-dimethyl-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)acetamide; <9> N-benzyl-2-(5-(2,5-dimethyl-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)acetamide; <10> N-benzyl-2-(5-(3-fluoro-2-methyl-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)acetamide; <11> 2-(5-(2,5-dimethyl-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <12> 2-(5-(2,3-dimethyl-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <13> N-(4-fluorobenzyl)-2-(5-(3-methyl-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)acetamide; <14> N-(4-fluorobenzyl)-2-(5-(2-methyl-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)acetamide; <15> 2-(5-(2-fluoro-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <16> 2-(5-(2-fluoro-4-(2-(piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <17> 2-(5-(2-fluoro-4-(2-(4-methylpiperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <18> 2-(5-(4-(2-(4-acetylpiperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <19> 2-(5-(4-(2-(4-(cyclopropanecarbonyl)piperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <20> 2-(5-(4-(2-(4-(cyclobutanecarbonyl)piperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <21> 2-(5-(4-(2-(4-(2-cyclopropylacetyl)piperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <22> 2-(5-(2-fluoro-4-(2-(4-(2-hydroxyacetyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <23> 2-(5-(2-fluoro-4-(2-(4-glycylpiperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <24> (R)-2-(5-(2-fluoro-4-(2-(4-(2-hydroxypropanoyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <25> (S)-2-(5-(2-fluoro-4-(2-(4-(2-hydroxypropanoyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <26> 2-(5-(2-fluoro-4-(2-(4-(2-methoxyacetyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <27> (R)-2-(5-(2-fluoro-4-(2-(4-(2-methoxypropanoyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <28> (S)-2-(5-(2-fluoro-4-(2-(4-(2-methoxypropanoyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <29> 2-(5-(2-fluoro-4-(2-(4-(2-methoxy-2-methylpropanoyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <30> 2-(5-(2-fluoro-4-(2-(4-(3-hydroxypropanoyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <31> 2-(5-(2-fluoro-4-(2-(4-(methylglycyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <32> 2-(5-(4-(2-(4-(D-alanyl)piperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <33> 2-(5-(4-(2-(4-(L-alanyl)piperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <34> 2-(5-(4-(2-(4-(3-aminopropanoyl)piperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <35> N-(4-fluorobenzyl)-2-(5-(2-methyl-4-(2-(piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)acetamide; <36> N-(4-fluorobenzyl)-2-(5-(4-(2-(4-(2-hydroxyacetyl)piperazine-1-yl)ethoxy)-2-methylphenyl)pyridine-2-yl)acetamide; <37> N-(4-fluorobenzyl)-2-(5-(4-(2-(4-glycylpiperazine-1-yl)ethoxy)-2-methylphenyl)pyridine-2-yl)acetamide; <38> 2-(5-(2-fluoro-4-(2-(piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-methylbenzyl)acetamide; <39> 2-(5-(2-fluoro-4-(2-(4-(2-hydroxyacetyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-methylbenzyl)acetamide; <40> 2-(5-(2-fluoro-4-(2-(4-glycylpiperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-methylbenzyl)acetamide; <41> 2-(5-(2-methyl-4-(2-(piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-methylbenzyl)acetamide; <42> 2-(5-(4-(2-(4-(2-hydroxyacetyl)piperazine-1-yl)ethoxy)-2-methylphenyl)pyridine-2-yl)-N-(4-methylbenzyl)acetamide; <43> 2-(5-(2-fluoro-4-(2-(4-glycylpiperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-methylbenzyl)acetamide; <44> 2-(5-(2-fluoro-4-(2-(1-glycylpiperidin-4-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <45> 2-(5-(2-fluoro-4-(2-(1-(2-hydroxyacetyl)piperidine-4-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide. <46> 2-(5-(4-(2-(4-(2-aminoacetyl)piperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-chlorobenzyl)acetamide; <47> N-(4-chlorobenzyl)-2-(5-(2-fluoro-4-(2-(4-(2-hydroxyacetyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)acetamide; <48> 2-(5-(2-fluoro-4-(2-(4-(methylsulfonyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <49> 2-(5-(4-(2-(4-(ethylsulfonyl)piperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <50> tert-butyl (2-(4-(2-(3-fluoro-4-(6-(2-((4-fluorobenzyl)amino)-2-oxoethyl)pyridine-3-yl)phenoxy)ethyl)piperazine-1-yl)-2-oxoethyl)carbamate <51> 2-(5-(4-(2-(4-(2-acetamidoacetyl)piperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <52> N-(2-(4-(2-(3-fluoro-4-(6-(2-((4-fluorobenzyl)amino)-2-oxoethyl)pyridine-3-yl)phenoxy)ethyl)piperazine-1-yl)-2-oxoethyl)benzamide; <53> 2-(5-(2-fluoro-4-(2-(4-(3-methoxypropanoyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <54> 2-(5-(4-(2-(4-(2-ethoxyacetyl)piperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <55> 2-(5-(4-(2-(4-(4-(benzyloxy)butanoyl)piperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <56> 4-(4-(2-(3-fluoro-4-(6-(2-((4-fluorobenzyl)amino)-2-oxoethyl)pyridine-3-yl)phenoxy)ethyl)piperazine-1-yl)-4-oxobutanoic acid; <57> 2-(5-(2-fluoro-4-(2-(4-(2-isopropoxyacetyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <58> 2-(5-(2-fluoro-4-(2-(1-(2-methoxyacetyl)piperazine-4-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <59> 2-(5-(4-(2-(1-(2-ethoxyacetyl)piperidine-4-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <60> 2-(5-(2-fluoro-4-(2-(1-(2-isopropoxyacetyl)piperidine-4-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <61> 2-(5-(2-fluoro-4-(2-(4-(2-(3-hydroxypropoxy)acetyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <62> 2-(5-(2-fluoro-4-(2-(4-(2-propoxyacetyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <63> 2-(5-(2-fluoro-4-(2-(4-(2-(2-hydroxyethoxy)acetyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <64> 2-(5-(2-fluoro-4-(2-(4-(3-hydroxybenzoyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <65> 2-(5-(4-(2-(4-(3-aminobenzoyl)piperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <66> 2-(5-(2-fluoro-4-(2-(4-(4-hydroxybenzoyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <67> 2-(5-(4-(2-(4-(4-aminobenzoyl)piperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <68> 2-(5-(2-fluoro-4-(2-(1-(3-hydroxypropanoyl)piperidine-4-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <69> 2-(5-(2-fluoro-4-(2-(1-(2-propoxyacetyl)piperidine-4-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <70> 2-(5-(2-fluoro-4-(2-(1-(2-(2-hydroxyethoxy)acetyl)piperidine-4-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <71> 2-(4-(2-(3-fluoro-4-(6-(2-((4-fluorobenzyl)amino)-2-oxoethyl)pyridine-3-yl)phenoxy)ethyl)piperazine-1-yl)-2-oxoethylmethyl(2-(methylamino)ethyl)carbamate; <72> 2-(4-(2-(3-fluoro-4-(6-(2-((4-fluorobenzyl)amino)-2-oxoethyl)pyridine-3-yl)phenoxy)ethyl)piperidine-1-yl)-2-oxoethylmethyl(2-(methylamino)ethyl)carbamate; <73> (R)-2-(5-(4-(2-(4-(2-ethoxyacetyl)-3-methylpiperazine-1-yl)ethoxy)-2-fluorobenzyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <74> (S)-2-(5-(4-(2-(4-(2-ethoxyacetyl)-3-methylpiperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <75> (S)-2-(5-(4-(2-(4-(2-ethoxyacetyl)-2-methylpiperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <76> (R)-2-(5-(4-(2-(4-(2-ethoxyacetyl)-2-methylpiperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <77> 2-(5-(4-(2-(4-(2-ethoxyacetyl)piperazine-1-yl)ethoxy)-2-methylphenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <78> 2-(5-(4-(2-(4-(2-ethoxyacetyl)piperazine-1-yl)ethoxy)-2-methylphenyl)pyridine-2-yl)-N-(4-methylbenzyl)acetamide; <79> 2-(5-(4-(2-(4-(2-ethoxyacetyl)piperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-methylbenzyl)acetamide; <80> N-(4-fluorobenzyl)-2-(5-(4-(2-(4-(2-hydroxyacetyl)piperazine-1-yl)ethoxy)-2-methylphenyl)pyridine-2-yl)acetamide; <81> 2-(5-(4-(2-(4-(2-hydroxyacetyl)piperazine-1-yl)ethoxy)-2-methylphenyl)pyridine-2-yl)-N-(4-methylbenzyl)acetamide; <82> 2-(5-(2-fluoro-4-(2-(4-(2-hydroxyacetyl)piperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-methylbenzyl)acetamide; <83> 2-(5-(2-fluoro-4-(2-(1-(2-hydroxyethyl)piperidine-4-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <84> 2-(5-(4-(2-(1-(2-ethoxyethyl)piperidine-4-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <85> (R)-2-(5-(2-fluoro-4-(2-(1-(2-hydroxypropanoyl)piperidine-4-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <86> (S)-2-(5-(2-fluoro-4-(2-(1-(2-hydroxypropanoyl)piperidine-4-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <87> 2-(5-(2-fluoro-4-(2-(4-hydroxy-1-(2-hydroxyacetyl)piperidine-4-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <88> 2-(5-(2-fluoro-4-(2-(4-fluoro-1-(2-hydroxyacetyl)piperidine-4-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <89> 2-(5-(2-fluoro-4-(2-(1-(2-hydroxyacetyl)-4-methylpiperidine-4-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <90> (R)-2-(5-(4-(2-(4-(2-ethoxyacetyl)-3-ethylpiperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <91> (R)-2-(5-(4-(2-(4-(2-ethoxyacetyl)-3-isopropylpiperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <92> 2-(5-(4-(2-(4-(2-ethoxyacetyl)-4,7-diazaspiro[2.5]octane-7-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <93> (R)-2-(5-(4-(2-(4-(2-ethoxyacetyl)-3-propylpiperazine-1-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(4-fluorophenyl)acetamide; <94> (R)-2-(5-(2-fluoro-4-(2-(4-(2-methoxyacetyl)-3-methylpiperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide; <95> (R)-2-(5-(2-fluoro-4-(2-(4-(2-hydroxyacetyl)-3-methylpiperazine-1-yl)ethoxy)phenyl)pyridine-2-yl)-N-(4-fluorobenzyl)acetamide.

9. As shown in Reaction Scheme I below, A method for preparing a compound represented by Chemical Formula 1 according to claim 1, comprising the step of reacting a compound represented by Chemical Formula 2 with a compound represented by Chemical Formula 3 to prepare a compound represented by Chemical Formula 1: [Reaction Equation 1] In the above reaction equation, X, Y, R 1 , R 2 , R 3 , R 4a , R 4b and n are as defined in Chemical Formula 1.

10. A pharmaceutical composition for the prevention or treatment of cancer containing, as an active ingredient, a compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition characterized by simultaneously inhibiting tubulin and Src kinase, containing as an active ingredient a compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

12. In Paragraph 9, A pharmaceutical composition characterized in that the above cancer is one or more selected from the group consisting of liver cancer, thyroid cancer, testicular cancer, oral cancer, leukemia, ovarian cancer, brain cancer, bile duct cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, small intestine cancer, esophageal cancer, kidney cancer, duodenal cancer, eye cancer, urethral cancer, stomach cancer, breast cancer, penile cancer, uterine cancer, prostate cancer, bone cancer, colorectal cancer, vaginal cancer, spinal cord cancer, pancreatic cancer, lung cancer, skin cancer, and laryngeal cancer.

13. A health functional food composition for the prevention or improvement of cancer containing, as an active ingredient, a compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

14. A method for the prevention or treatment of cancer, comprising the step of administering a compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof in a therapeutically effective amount to a subject in need thereof.

15. Use of the compound according to paragraph 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicine for the prevention or treatment of cancer.

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