Novel benzamide derivative compound and pharmaceutical composition comprising same

Abstract

The present invention relates to novel benzamide compounds, stereoisomers thereof, pharmaceutically acceptable salts thereof, or hydrates or solvates thereof. The novel compound has NAMPT inhibitory activity, can exhibit a prophylactic or therapeutic effect on diseases treatable by inhibition of NAMPT, and can effectively prevent or treat cancer.

Description

Technical Field

[0001] This invention relates to compounds represented by Formula I, their stereoisomers, their pharmaceutically acceptable salts, or their solvates or hydrates, and their uses. Background Technology

[0002] Nicotinamide phosphoribosyltransferase (NAMPT) is an enzyme that catalyzes the synthesis of nicotinamide mononucleotide (NMN) from nicotinamide (NAM) and 5'-phosphoribose-1'-pyrophosphate (PRPP), playing a crucial role in the cyclic biosynthesis of nicotinamide adenine dinucleotide (NAD+). NAD is essential for multiple signaling pathways, including mono-ADP-ribosylation in the immune system and G protein-coupled receptor signaling, as well as other poly-ADP-ribosylation in DNA repair, and is also indispensable for the deacetylase activity of sirtuin.

[0003] NAD+ is produced through two distinct biosynthetic pathways: the salvage pathway and the de novo synthesis pathway. As the rate-limiting enzyme in the NAD+ salvage pathway, NAMPT is biologically essential and may be associated with many different diseases.

[0004] Therefore, there is a need to develop drugs that can more effectively inhibit NAMPT.

[0005] Related technical documents Patent documents Korean Patent Publication No. 10-2015-0014250 Invention Details Technical issues The present invention can provide benzamide compounds represented by Formula I, their stereoisomers, their pharmaceutically acceptable salts, or their hydrates or solvates.

[0006] This invention provides pharmaceutical compositions comprising a benzamide compound of Formula I, its stereoisomers, pharmaceutically acceptable salts thereof, or hydrates or solvates thereof. This invention also provides pharmaceutical compositions for the prevention or treatment of diseases (e.g., cancer) that can be treated by inhibiting NAMPT, comprising a benzamide compound of Formula I, its stereoisomers, pharmaceutically acceptable salts thereof, or hydrates or solvates thereof as an active ingredient.

[0007] The present invention provides a method for preventing or treating diseases (e.g., cancer) that can be treated by inhibiting NAMPT, comprising administering to an individual a benzamide compound of Formula I, its stereoisomers, pharmaceutically acceptable salts thereof, or their hydrates or solvates.

[0008] The present application can provide a benzamide compound represented by the following formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, for use in the prevention or treatment of a disease (e.g., cancer) that can be treated by inhibiting NAMPT.

[0009] The present application can provide a use of a benzamide compound represented by the following formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, in the manufacture of a medicament for the prevention or treatment of a disease (e.g., cancer) that can be treated by inhibiting NAMPT.

[0010] Technical Solution The present inventors have identified a compound having NAMPT inhibitory activity, having a novel structure, and used it for the prevention and / or treatment of a disease that can be treated by inhibiting NAMPT, thereby completing the present application.

[0011] The present application will be described in more detail below. All combinations of the various elements disclosed herein can be within the scope of the application. In addition, the scope of the application is not intended to be limited to the specific embodiments described below.

[0012] 1) The present application can provide a benzamide compound represented by the following formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof: <Formula I> .

[0013] In the above formula I, R1 is a 6- to 14-membered aryl group, a C2-C8 heterocycloalkenyl group, or a 5- to 12-membered heteroaryl group, wherein at least one H of the R1 can be substituted with a halogen (F, Cl, Br, or I), -NRaRb, -NO2, or -OH; L1 is a C1-C6 alkylene group; L2 is a single bond or a C2-C6 alkynylene group; X is a 6- to 14-membered arylene group, a C2-C8 heterocycloalkenylene group, or a 5- to 12-membered heteroarylene group; at least one H of the X can be substituted with a C1-C6 alkyl group, CF3, a halogen (F, Cl, Br, or I), a C1-C6 alkoxy group, or OH, -CH2- of the X can be replaced with -(C=O)-, in particular, at least one H of the 6- to 14-membered arylene group or the C2-C8 heterocycloalkenylene group of the X can be substituted with a C1-C6 alkyl group, CF3, a halogen (F, Cl, Br, or I), a C1-C6 alkoxy group, or OH, and at least one -CH2- of the C2-C8 heterocycloalkenylene group of the X can each independently be replaced with -(C=O)-; L3 is a single bond, C1-C6 alkylene, C2-C6 alkenylene, C=0, (C=0)NRc, (C=0)NRd-(C1-C6 alkylene), NRy(C=0)-(C1-C6 alkylene), or 0(C=0)-(C1-C6 alkylene); R2 is H, halogen (F, CI, Br, or I), C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C1-C8 heterocycloalkyl, -NRz1Rz2, 6 to 14 membered aryl, or 5 to 12 membered heteroaryl; at least one H of said R2 can be substituted with C1-C6 alkyl, C1-C6 alkoxy, OH, COOH, (C1-C6 alkylene)-NReRf, NRgRh, N02, CF3, (C=0)NRiRj, or halogen (F, CI, Br, or I); L4 is a single bond, C1-C6 alkylene, -NRm-(C1-C6 alkylene)-, or NRn; R3 is H, C1-C6 alkyl, C3-C8 cycloalkyl, 6 to 14 membered aryl, C1-C8 heterocycloalkyl, C2-C8 heterocycloalkenyl, 5 to 12 membered heteroaryl, 6 to 14 membered arylene-C1-C8 heterocycloalkyl, 6 to 14 membered arylene-5 to 12 membered heteroaryl, 5 to 12 membered heteroarylene-6 to 14 membered aryl, 5 to 12 membered heteroarylene-C1-C8 heterocycloalkyl, or 5 to 12 membered heteroarylene-5 to 12 membered heteroaryl; at least one H of said R3 can be substituted with C1-C6 alkyl, C1-C6 alkoxy, phenoxy, OH, (C1-C6 alkylene)-OH, COOH, (C1-C6 alkylene)-COOH, (C1-C6 alkylene)-CN, NRoRp, (C1-C6 alkylene)-NRqRr, (C=0)-(C1-C6 alkyl), (C=0)-(C3-C8 cycloalkyl), (C=0)-(6 to 14 membered aryl), 6 to 14 membered aryl, 6 to 14 membered heteroaryl, 6 to 14 membered heterocyclic aryl, (C=0)NRsRt which can be substituted with halogen, (C=0)-(C1-C6 alkylene)-NRuRv, NRwRx, (C=0)0-(C1-C6 alkyl), N02, CHF2, C F3, OCF3, or halogen (F, CI, Br, or I), and at least one -CH2- of the heterocycloalkenyl of said R3 can be replaced with -(C=0)-; and The Ra to Rj, Rm to Ry, Rz1, and Rz2 are each independently H or C1-C6 alkyl in each case. For example, Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, Ri, Rj, Rm, Rn, Ro, Rp, Rq, Rr, Rs, Rt, Ru, Rv, Rw, Rx, Ry, Rz1, and Rz2 can each independently be H or C1-C6 alkyl in each case.

[0014] In the present application, the term "Cm-Cn" (wherein m and n are each independently an integer of 1 or more) can refer to the number of carbon atoms, for example, "C1-C5 alkyl" can refer to an alkyl group having 1 to 5 carbon atoms.

[0015] In the present application, "substituted" or "substituted with" can be defined to include the implicit condition that the substitution follows the allowable valence of the atom being substituted and results in a stable compound by substitution, for example, a compound that is not naturally modified by rearrangement, cyclization, elimination, etc.

[0016] In the present application, "single bond" can refer to a case where adjacent atoms or atom groups are directly bonded to each other.

[0017] In the present application, unless otherwise specified, "alkyl" can refer to a linear (or straight-chain) saturated hydrocarbon group or a branched (or side-chain) saturated hydrocarbon group. Examples of the alkyl can include at least one selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, i-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl, etc., but are not limited thereto.

[0018] In the present application, unless otherwise specified, "alkylene" can refer to a divalent functional group derived from an alkyl group as defined above, and can include at least one selected from methylene, ethylene, n-propylene, i-propylene, n-butylene, sec-butylene, i-butylene, t-butylene, n-pentylene, n-hexylene, n-heptylene, etc., but is not limited thereto.

[0019] In the present application, unless otherwise specified, "alkynylene" can refer to a divalent functional group derived from an alkynyl group containing at least one carbon-carbon triple bond in the alkyl group. Examples of the alkynylene can include , a hydrocarbon containing at least one , etc., but are not limited thereto.

[0020] In the present application, unless otherwise specified, "alkenyl" can refer to an unsaturated hydrocarbon group containing at least one carbon-carbon double bond in the alkyl group.

[0021] In the present application, unless otherwise indicated, "alkylene" can refer to a divalent functional group derived from an alkyl group as defined above. In the present application, unless otherwise indicated, "alkoxy" can refer to a monovalent group derived from a straight chain or branched saturated hydrocarbon moiety, represented by OCnH2n+1. Examples of the alkoxy group can include at least one selected from the group consisting of methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, t-butoxy, pentoxy, hexyloxy, and the like, but are not limited thereto.

[0022] In the present application, unless otherwise indicated, "cycloalkyl" can refer to a saturated hydrocarbon ring having at least three carbon atoms, which can include monocyclic and polycyclic structures. Further, it is intended to include all bicyclic structures, such as bridged or spiro structures. Examples of the cycloalkyl group can include at least one selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, decahydronaphthyl, spiro[4.4]nonanyl, spiro[3.3]heptanyl, bicyclo[3.1.0]hexanyl, bicyclo[3.1.1]heptanyl, bicyclo[2.2.1]heptanyl, and the like, but are not limited thereto.

[0023] In the present application, unless otherwise indicated, "cycloalkenyl" can refer to a cyclic group including at least one carbon-carbon double bond in the cycloalkyl group, and the cycloalkenyl group is not an aromatic ring. Examples of the cycloalkenyl group can include at least one selected from the group consisting of cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like, but are not limited thereto.

[0024] In the present application, unless otherwise indicated, "heterocycloalkyl" can refer to a cyclic group in which at least one carbon atom constituting a cycloalkyl ring is each independently replaced with a heteroatom or a functional group selected from the group consisting of N, O, S, SO, and SO2. Examples of the heterocycloalkyl group can include at least one selected from the group consisting of oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiophenyl, oxepanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, azetidinyl, aziridinyl, azepanyl, 、 、 、 、 、 、 、 、 、 and the like, but are not limited thereto.

[0025] In the present application, unless otherwise indicated, "heterocycloalkenyl" can refer to a cyclic group in which at least one carbon atom constituting a cycloalkenyl ring is each independently replaced with a heteroatom or a functional group selected from the group consisting of N, O, S, SO, and SO2, and the heterocycloalkenyl group is not an aromatic ring. Examples of the heterocycloalkenyl group can include at least one selected from the group consisting of , 、 、 at least one, but are not limited thereto.

[0026] In the present application, unless otherwise specified, "heteroarylene" can mean a divalent functional group derived from a heteroaryl group as defined above.

[0027] In the present application, unless otherwise specified, "aryl" can mean a monocyclic aromatic ring group, or a polycyclic aromatic ring group having at least one fused or non-fused aromatic ring. Examples of aryl can include at least one selected from the group consisting of phenyl, naphthyl, indenyl, anthryl, and the like, but are not limited thereto.

[0028] In the present application, unless otherwise specified, "arylene" can mean a divalent functional group derived from an aryl group as defined above.

[0029] In the present application, unless otherwise specified, "heteroaryl" can mean a monocyclic or polycyclic aromatic heterocycle containing at least one heteroatom selected from the group consisting of N, O, and S in the ring and having at least one fused or non-fused aromatic ring. Examples of heteroaryl can include at least one selected from the group consisting of thiazolyl, oxazolyl, thienyl, furanyl, pyrrolyl, imidazolyl, isoxazolyl, pyrazolyl, triazolyl, thiadiazolyl, tetrazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzothienyl, benzofuranyl, benzothiazolyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, quinolyl, isoquinolyl, purinyl, and the like, but are not limited thereto.

[0030] In the present application, unless otherwise specified, "heteroarylene" can mean a divalent functional group derived from a heteroaryl group as defined above.

[0031] In the present application, unless otherwise specified, "halogen" can be F, Cl, Br, or I.

[0032] In the present application, when a divalent functional group is described as -AB-, it can include both -AB- and -BA-, for example, the description of -(C1-C6 alkylene)-NRm- can include both X-(C1-C6 alkylene)-NRm-Y and X-NRm-(C1-C6 alkylene)-Y.

[0033] In the present application, may be represented by CO, C=O, C(=O), and the like, may be represented by SO, S=O, S(=O), and the like, may be represented by SO2, S=O2, S(=O)2, and the like.

[0034] Further, the terms and abbreviations used in the present specification have their original meanings unless otherwise defined.

[0035] 2) The embodiment of the present application described in the above 1) can provide a benzamide derivative compound represented by the above Formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof: <Formula I> .

[0036] In the above Formula I, R1is a 6- to 14-membered aryl group, a C2-C8heterocycloalkenyl group including at least one heteroatom or heterofunctional group selected from the group consisting of N, O, S, S(=O), and S(=O)2, or a 5- to 12-membered heteroaryl group including at least one heteroatom selected from the group consisting of N, O, and S, wherein the -H of said R1is unsubstituted, or at least one H thereof is each independently substituted with a halogen (F, Cl, Br, or I), -NRaRb, -NO2, or -OH; L1is a C1-C6alkylene group; L2is a single bond or a C2-C6alkynylene group; X is a 6- to 14-membered arylene group, a C2-C8heterocycloalkenylene group including at least one heteroatom or heterofunctional group selected from the group consisting of N, O, S, S(=O), and S(=O)2, or a 5- to 12-membered heteroarylene group including at least one heteroatom selected from the group consisting of N, O, and S, wherein at least one -H of said X can be substituted with a C1-C6alkyl group, -CF3, a halogen (F, Cl, Br, or I), a C1-C6alkoxy group, or -OH, at least one -CH2- of said X can each independently be replaced with -(C=O)-, and specifically, the -H of said X is unsubstituted, or when said X is a 6- to 14-membered arylene group or a C2-C8heterocycloalkenylene group, at least one -H thereof can each independently be substituted with a C1-C6alkyl group, -CF3, a halogen (F, Cl, Br, or I), a C1-C6alkoxy group, or OH, and when X is a C2-C8heterocycloalkenylene group, -CH2- is unsubstituted, or at least one -CH2- thereof is each independently replaced with -(C=O)-; L3is a single bond, a C1-C6alkylene group, a C2-C6alkenylene group, -C=O, -C(=O)NRc, -C(=O)NRd-(C1-C6alkylene), -NRyC(=O)-(C1-C6alkylene), -NHC(=O), or -OC(=O)-(C1-C6alkylene); R2is H, halogen (F, CI, Br, or I), -NRzlRz2, C1-C6alkyl, C1-C6alkoxy, C3-C8cycloalkyl, C1-C8heterocycloalkyl comprising at least one heteroatom or heterofunctional group selected from N, O, S, SO, and SO2, 6- to 14-membered aryl, or 5- to 12-membered heteroaryl comprising at least one heteroatom selected from N, O, and S, wherein the -H of R2is unsubstituted, or at least one -H of R2is each independently substituted with -C1-C6alkyl, -C1-C6alkoxy, -OH, -COOH, -(C1-C6alkylene)-NReRf, -NRgRh, -NO2, -CF3, -C(=O)NRiRj, or halogen (F, CI, Br, or I); L4is a single bond, -C1-C6alkylene-, -NRm-(C1-C6alkylene)-, or -NRn-, wherein the -H of L4is unsubstituted, or at least one -H of L4is each independently substituted with -C1-C6alkyl; R3is H, C1-C6alkyl, C3-C8cycloalkyl, 6- to 14-membered aryl, C1-C8heterocycloalkyl comprising at least one heteroatom or heterofunctional group selected from N, O, S, SO, and SO2, C2-C8heterocycloalkenyl comprising at least one heteroatom or heterofunctional group selected from N, O, S, SO, and SO2, 5- to 12-membered heteroaryl comprising at least one heteroatom selected from N, O, and S, 6- to 14-membered arylene-C1-C8heterocycloalkyl (wherein the heterocycloalkyl comprises at least one heteroatom or heterofunctional group selected from N, O, S, SO, and SO2), 6- to 14-membered arylene-5- to 12-membered heteroaryl (wherein the heteroaryl comprises at least one heteroatom selected from N, O, and S), 5- to 12-membered heteroarylene-6- to 14-membered aryl (wherein the heteroarylene comprises at least one heteroatom selected from N, O, and S), 5- to 12-membered heteroarylene-C1-C8heterocycloalkyl (wherein the heteroarylene comprises at least one heteroatom selected from N, O, and S, and the heterocycloalkyl comprises at least one heteroatom or heterofunctional group selected from N, O, S, SO, and SO2), or 5- to 12-membered heteroarylene-5- to 12-membered heteroaryl (wherein the heteroarylene or heteroaryl comprises at least one heteroatom selected from N, O, and S); R3 is H, C1-C6 alkyl, C3-C8 cycloalkyl, 6- to 14-membered aryl, C1-C8 heterocyclic alkyl containing at least one heteroatom or heterofunctional group selected from N, O, S, SO and SO2, C2-C8 heterocyclic alkenyl containing at least one heteroatom or heterofunctional group selected from N, O and S, 5- to 12-membered heteroaryl containing at least one heteroatom selected from N, O and S, 6- to 14-membered arylene-C1-C8 heterocyclic alkyl (wherein the heterocyclic alkyl contains at least one heteroatom or heterofunctional group selected from N, O, S, SO and SO2), 6- to 14-membered arylene-5- to 12-membered heteroaryl ... The heteroaryl group described herein comprises at least one heteroatom selected from N, O, and S; 5- to 12-membered heteroaryl-6- to 14-membered aryl (wherein the heteroaryl group comprises at least one heteroatom selected from N, O, and S); 5- to 12-membered heteroaryl-C1-C8 heterocyclic alkyl (wherein the heteroaryl group comprises at least one heteroatom selected from N, O, and S, and the heterocyclic alkyl group comprises at least one heteroatom or heterofunctional group selected from N, O, S, SO, and SO2); or 5- to 12-membered heteroaryl-5- to 12-membered heteroaryl (wherein the heteroaryl group or heteroaryl group comprises at least one heteroatom selected from N, O, and S), wherein the R3- H is unsubstituted, or at least one H of R3 is independently substituted with -C1-C6 alkyl, -C1-C6 alkoxy, phenoxy, -OH, -(C1-C6 alkylene)-OH, -COOH, -(C1-C6 alkylene)-COOH, (C1-C6 alkylene)-CN, -NRoRp, (C1-C6 alkylene)-NRqRr, -C(=O)-(C1-C6 alkyl), -C(=O)-(C3-C8 cycloalkyl), -C=(O)-(6 to 14 aryl), -NO2, -CHF2, -CF3, -OCF3, 6 to 14 aryl, containing at least one selected 6- to 14-membered heteroaryl groups from N, O, and S heteroatoms; 6- to 14-membered heterocyclic aryl groups containing at least one heteroatom or heterofunctional group selected from N, O, S, SO, and SO2; -C(=O)NRsRt (wherein the -H of -C(=O)NRsRt is unsubstituted, or at least one -H is independently substituted by a halogen (F, Cl, Br, or I); -C(=O)-(C1-C6 alkylene)-NRuRv; -NRwRx; or substituted by a halogen (F, Cl, Br, or I); and when R3 is a heterocyclic alkenyl group, at least one -CH2- group may be independently substituted by -(C=O)-. Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, Ri, Rj, Rm, Rn, Ro, Rp, Rq, Rr, Rs, Rt, Ru, Rv, Rw, Rx, Ry, Rz1, and Rz2in each occurrence can each independently be H or C1-C6alkyl.

[0037] 3) According to the embodiments of the application described in 1) or 2) above, it can be provided that said R1is , , , , , , , , or . In this case, it can be provided that said -H of R1is unsubstituted, or at least one -H of R1is each independently substituted with halogen (F, CI, Br, or I), -NRaRb, -NO2, or -OH, where Raand Rbare each independently -H or C1-C6alkyl, and in particular, said -H of R1is unsubstituted, or at least one -H of R1is each independently substituted with halogen (F, CI, Br, or I), -NH2, -NO2, -NHCH3, -N(CH3)2, or -OH.

[0038] 4) According to the embodiments of the application described in 1) to 3) above, it can be provided that said L1is C1-C6alkylene, in particular methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), i-propylene (-CHCH3CH2), n-butylene (-CH2CH2CH2CH2-), s-butylene (-CHCH3CH2CH2-), i-butylene (-CH2CHCH3CH2-), t-butylene (-CCH3CH3CH2-), n-pentylene (-CH2CH2CH2CH2CH2-), n-hexylene (-CH2CH2CH2CH2CH2CH2-), and in particular methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), i-propylene (-CHCH3CH2), n-butylene (-CH2CH2CH2CH2-), n-pentylene (-CH2CH2CH2CH2CH2-), or n-hexylene (-CH2CH2CH2CH2CH2CH2-).

[0039] 5) According to the embodiments of the application described in 1) to 4) above, it can be provided that L2is a single bond or C2-C5alkynylene, and in particular L2is a single bond or ethynylene

[0040] 6) According to the embodiments of the application described in 1) to 5) above, it can be provided that X is , , , , , , , , , , , or . In this case, it can be provided that the -H of X is unsubstituted, or at least one -H each independently is substituted by C1-C6alkyl, halogen (F, Br, Cl or I), -OH, -C1-C6alkoxy, or -CF3, and the -CH2- of X is unsubstituted, or at least one -CH2- each independently is replaced by -(C=0)-, and in particular when X is or , the -H is unsubstituted, or at least one -H each independently is substituted by C1-C6alkyl, halogen (F, Br, Cl or I), -C1-C6alkoxy, -OH, or -CF3, and when X is , -CH2- is unsubstituted, or at least one -CH2- each independently is replaced by -(C=0)-.

[0041] 7) According to the embodiments of the application described in 1) to 6) above, it can be provided that L3is a single bond, C1-C6alkylene, C2-C6alkenylene, -(C=0)-, -(C=0)-NRc-, -C(=0)NRd-(C1-C6alkylene)-, -NRyC(=0)-(C1-C6alkylene), -NHC(=0), or -0(C=0)-(C1-C6alkylene), wherein R°, R° or R each independently is -H or C1-C6alkyl. In particular, it can be provided that L3is a single bond, -(CH2)-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(C=0)-NH(CH2)n-, -NH(C=0)-, -NH(C=0)-(CH2)m, -(C=0)NH-, -(CH=CH)-CH2-, -0(C=0)CH2, or -(C=0)-, wherein n and m each independently is 1, 2, 3 or 4.

[0042] ​8) According to the embodiments of the application described in 1) to 7) above, it can be provided that said R2is H, halogen (F, CI, Br or I), Ci-C6alkyl, Ci-C6alkoxy, -OH, -NH2, , , , , , , , , , , , , or . In this case, it can be provided that said -H of R2is unsubstituted, or at least one -H of R2is each independently substituted with halogen (F, CI, Br or I), -Ci-C6alkoxy, -NH2, -OH, -CF3, -NO2, -Ci-C6alkyl, -(CH2)2-NH2, -(CH2)3-NH2, -(CH2)-NH2, -(C=0)NH2, -NHCH3, -NHCH(CH3)2, or -COOH.

[0043] 9) According to the embodiments of the application described in 1) to 8) above, it can be provided that said L4is a single bond, -Ci-C6alkylene-, -NRm-(Ci-C6alkylene)-, or -NRn-, wherein Rmand Rnare each independently -H or Ci-C6alkyl. In particular, it can be provided that L4is a single bond, -(CH2)-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -NH-, -NHCH2-, -NH(CH2)2-, -NH(CH2)3-, -CH(CH3)-, -CH2NH-, -(CH2)2NH-, or -(CH2)3NH-. In this case, it can be provided that said -H of L4is unsubstituted, or at least one -H thereof is each independently substituted with -Ci-C6alkyl.

[0044] 10) According to the embodiments of the application described in 1) to 9) above, it can be provided that said R3is H, Ci-C6alkyl, , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 or wherein the -H of R3 is unsubstituted, or at least one -H of R3 is each independently substituted with -Ci-C6alkyl, -Ci-C6alkoxy, -phenoxy, -OH, -(Ci-C6alkylene)-OH, -COOH, -(Ci-C6alkylene)-COOH, -(Ci-C6alkylene)-CN, -NR0Rp, (Ci-C6alkylene)-NRqRr, -C(=0)-(Ci-C6alkyl), -C(=0)-(C3-C8cycloalkyl), -C(=0)-(6- to 14-membered aryl), -NO2, -CHF2, -CF3, -OCF3, -C(=0)NRsRt(wherein the -H of -C(=0)NRsRt is unsubstituted, or at least one -H thereof is each independently substituted with halogen (F, CI, Br, or I)), -C(=0)-(Ci-C6alkylene)-NRuRv, -NRwRx, or halogen (F, CI, Br, or I), and when the R3 is heterocycloalkenyl, -CH2- is unsubstituted, or at least one -CH2- is each replaced with -(C=0)-, wherein R0, Rp, Rq, Rr, Rs, Rt, Ru, Rv, Rw, or Rx are each independently at each occurrence H or Ci-C6alkyl. In particular, it can be provided that the -H of R3 is unsubstituted, or at least one -H of R3 is each independently substituted with -Ci-C6alkyl (e.g., -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, etc.), -Ci-C6alkoxy (e.g., -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2), -phenoxy, -OH, -CH2F, -CHF2, -CF3, -OCF3, halogen (F, CI, Br, or I), -(C=0)OCH2CH3, -(C=0)CH3, -(C=0)CH(CH3)2, -(C=0)CHCH3NH2, -NH2, -NHCH3, -N(CH3)2, -COOH, -(C=0)NH2, -(C=0)NHCH3, -(C=0)N(CH3)2, -NO2, -(C=0)NHCH2CF3, -CH(CH3)OH, -CH2(CH3)OH, -CH2CN, -CH(CH3)CN, -C(CH3)CH2CN, -(CH2)2NH2, -(CH2)NH2, -(CH2)3NH2, -(CH2)4NH2, -(CH2)2OH, -(CH2)OH, -(CH2)3OH, -(CH2)4OH, -(CH2)2COOH, -(CH2)COOH, -(CH2)3COOH, , , , or substituted, wherein when said R3 is -CH2- is unsubstituted, or at least one -CH2- is each independently replaced with -(C=0)-.

[0045] 11) According to the embodiments of the present application described in 1) to 10) above, it can be provided that the compound represented by the above formula I is represented by the following formula I-1: <Formula I-1> .

[0046] In the above formula I-1, it can be provided that R1, L1, X, L3, R2, L4, R3 are substantially the same as defined in the above formula I.

[0047] 12) According to the embodiments of the present application described in 1) to 11) above, it can be provided that the compound represented by the above formula I is represented by the following formula I-2: <Formula I-2> .

[0048] In the above formula I-2, it can be provided that R1, L1, X, L3, R2, L4, R3 are substantially the same as defined in the above formula I.

[0049] 13) According to the embodiments of the present application described in 1) to 12) above, it can provide a compound represented by the following formula I-1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof: <Formula I-1> .

[0050] In the above formula I-1, it can be provided that R1, L1, X, L3, R2, L4, R3 are substantially the same as defined in the above formula I.

[0051] According to the embodiments of the present application, in the above formula I-1, it can be provided that R1 is a 5- to 12-membered heteroaryl group comprising at least one heteroatom selected from N, O and S, wherein -H of said R1 is unsubstituted, or at least one H thereof is each independently substituted with halogen (F, Cl, Br, I), -NH2, -NHCH3, -N(CH3)2, -NO2, or -OH.

[0052] 14) According to the embodiments of the present application described in 1) to 13) above, it can be provided that in the above formula I-1, R1 is , , , , or In this case, it can be provided that the -H of R1 is unsubstituted, or at least one H each independently is substituted by halogen (F, CI, Br or I), -NH2, -NO2, -NHCH3, -N(CH3)2 or -OH.

[0053] 15) According to the embodiments of the application described in 1) to 14) above, it can be provided that in the above formula I-1, L1 is a C1-C6 alkylene, in particular methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), i-propylene (-CHCH3CH2), n-butylene (-CH2CH2CH2CH2-), s-butylene (-CHCH3CH2CH2-), i-butylene (-CH2CHCH3CH2-), t-butylene (-CCH3CH3CH2-), n-pentylene (-CH2CH2CH2CH2CH2-), n-hexylene (-CH2CH2CH2CH2CH2CH2-), and in particular methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), i-propylene (-CHCH3CH2), n-butylene (-CH2CH2CH2CH2-), n-pentylene (-CH2CH2CH2CH2CH2-), or n-hexylene (-CH2CH2CH2CH2CH2CH2-).

[0054] 16) According to the embodiments of the application described in 1) to 15) above, it can be provided that in the above formula I-1, X is a 6- to 14-membered arylene, a C2-C8 heterocycloalkylene comprising at least one heteroatom or heterofunctional group selected from N, O, S, S(=O) and S(=O)2, or a 5- to 12-membered heteroarylene comprising at least one heteroatom selected from N, O and S, wherein the -H of X is unsubstituted, or when X is a 6- to 14-membered arylene or a C2-C8 heterocycloalkylene, at least one -H each independently is substituted by C1-C6 alkyl, -CF3, halogen (F, CI, Br or I), -C1-C6 alkoxy or OH, and when X is a C2-C8 heterocycloalkylene, -CH2- is unsubstituted, or at least one -CH2- each independently is replaced by -(C=O)-.

[0055] 17) According to the embodiments of the application described in 1) to 16) above, it can be provided that in the above formula I-1, X is , , or wherein the -H of said X is unsubstituted, or at least one -H of X is each independently substituted with C1-C6alkyl, halogen (F, Br, Cl, or I), -OH, -C1-C6alkoxy, or -CF3, and particularly when said X is unsubstituted, or at least one -H of X is each independently substituted with C1-C6alkyl, halogen (F, Br, Cl, or I), -C1-C6alkoxy, -OH, or -CF3.

[0056] 18) According to the embodiments of the application described in 1) to 17) above, it can be provided that in the above formula I-1, said L3is a single bond, C1-C6alkylene, -(C=0)-, or -C(=0)NRd-(C1-C6alkylene)-, wherein Rdis -H or C1-C6alkyl. In particular, it can be provided that L3is a single bond, -(CH2)-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(C=0)-NH(CH2)n-, -(C=0)NH-, or -(C=0)-, wherein n is 0, 1, 2, 3, or 4.

[0057] 19) According to the embodiments of the application described in 1) to 18) above, it can be provided that in the above formula I-1, said R2is H, halogen (F, Cl, Br, or I), -NRz1Rz2, C1-C6alkyl, C1-C6alkoxy, or C1-C8heterocycloalkyl comprising at least one heteroatom or heterofunction selected from N, O, S, SO, and SO2, wherein the -H of said R2is unsubstituted, or at least one -H of R2is each independently substituted with -C1-C6alkyl, -C1-C6alkoxy, -NRgRh, or halogen (F, Cl, Br, or I), wherein Rg, Rh, Rz1, and Rz2are each independently H or C1-C6alkyl.

[0058] 20) According to the embodiments of the application described in 1) to 19) above, it can be provided that in the above formula I-1, said R2is H, halogen (F, Cl, Br, or I), C1-C6alkyl, C1-C6alkoxy, -NH2, In this case, it can be provided that the -H of said R2is unsubstituted, or at least one -H of R2is each independently substituted with halogen (F, Cl, Br, or I), -C1-C6alkoxy, -NH2, or -C1-C6alkyl.

[0059] ​​21) According to the embodiments of the application described in 1) to 20) above, it can be provided that in the above Formula I-1, L4 is a single bond, -Ci-C6alkylene-, -NRm-(Ci-C6alkylene), or -NRn-, wherein the -H of L4 is unsubstituted, or at least one -H of L4 is each independently substituted with -Ci-C6alkyl, wherein Rmand Rnare each independently H or Ci-C6alkyl.

[0060] 22) According to the embodiments of the application described in 1) to 21) above, it can be provided that in the above Formula I-1, L4 is a single bond, -(CH2)-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -NH-, -NHCH2-, -NH(CH2)2-, -NH(CH2)3-, wherein the -H of L4 is unsubstituted, or at least one -H of L4 is each independently substituted with -Ci-C6alkyl.

[0061] 23) According to the embodiments of the application described in 1) to 22) above, it can be provided that in the above Formula I-1, R3 is H, Ci-C6alkyl, 6 to 14 membered aryl, 5 to 12 membered heteroaryl comprising at least one heteroatom selected from N, O, and S, 5 to 12 membered heteroarylene-6 to 14 membered aryl (wherein the heteroarylene or heteroaryl comprises at least one heteroatom selected from N, O, and S), or 5 to 12 membered heteroarylene-5 to 12 membered heteroaryl (wherein the heteroarylene or heteroaryl comprises at least one heteroatom selected from N, O, and S), wherein the -H of R3 is unsubstituted, or at least one H of R3 is each independently substituted with -Ci-C6alkyl, -Ci-C6alkoxy, -6 to 14 membered heteroaryl comprising at least one heteroatom selected from N, O, and S, -NRwRx, or halogen (F, Cl, Br, or I), wherein R and R are each independently H or Ci-C6alkyl.

[0062] 24) According to the embodiments of the application described in 1) to 23) above, it can be provided that in the above Formula I-1, the R3 is H, Ci-C6alkyl, , , or wherein the -H of R3 is unsubstituted, or at least one -H of R3 is each independently substituted with -Ci-C6alkyl (e.g., -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, etc.), -Ci-C6alkoxy (e.g., -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2), -NH2, -CF3, -OCF3, halogen (F, Cl, Br, or I), or ​

[0063] 25) The embodiments of the application described in 1) to 11) above can provide a compound represented by the following Formula I-2, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof: <Formula I-2> .

[0064] In the above Formula I-2, R1, L1, X, L3, R2, L4, R3 can be substantially the same as defined in the above Formula I.

[0065] 26) The embodiments of the application described in 1) to 11) and 25) above can provide that, in the above Formula I-2, R1is a 5- to 12-membered heteroaryl containing at least one heteroatom selected from N, O and S, wherein the -H of said R1is unsubstituted or at least one H each independently is substituted with halogen (F, Cl, Br, I), -NH2, -NHCH3, -N(CH3)2, -NO2or -OH.

[0066] 27) The embodiments of the application described in 1) to 11), 25) and 26) above can provide that, in the above Formula I-2, R1is or In this case, it can be provided that the -H of said R1is unsubstituted or at least one H each independently is substituted with halogen (F, Cl, Br or I), -NH2, -NO2, -NHCH3, -N(CH3)2or -OH.

[0067] 28) The embodiments of the application described in 1) to 11) and 25) to 27) above can provide that, in the above Formula I-2, L1is a C1-C6 alkylene, in particular methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), i-propylene (-CHCH3CH2), n-butylene (-CH2CH2CH2CH2-), s-butylene (-CHCH3CH2CH2-), i-butylene (-CH2CHCH3CH2-), t-butylene (-CCH3CH3CH2-), n-pentylene (-CH2CH2CH2CH2CH2-), n-hexylene (-CH2CH2CH2CH2CH2CH2-), and in particular methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), i-propylene (-CHCH3CH2), n-butylene (-CH2CH2CH2CH2-), n-pentylene (-CH2CH2CH2CH2CH2-) or n-hexylene (-CH2CH2CH2CH2CH2CH2-).

[0068] 29) According to the embodiments of the application described in 1) to 11) and 25) to 28) above, it can be provided in the above formula I-2 that X is a C2-C8 heterocycloalkenylene comprising at least one heteroatom or heterofunctional group selected from N, O, S, S(=0) and S(=0)2, or a 5- to 12-membered heteroarylene comprising at least one heteroatom selected from N, O and S, wherein the -H of X is unsubstituted, or when X is a C2-C8 heterocycloalkenylene, at least one -H each independently is substituted by C1-C6 alkyl, -CF3, halogen (F, Cl, Br or I), -C1-C6 alkoxy or OH, and when X is a C2-C8 heterocycloalkenylene, -CH2- is unsubstituted, or at least one -CH2- each independently is replaced by -(C=0)-.

[0069] 30) According to the embodiments of the application described in 1) to 11) and 25) to 29) above, it can be provided in the above formula I-2 that X is or wherein the -H of X is unsubstituted, or at least one -H each independently is substituted by C1-C6 alkyl, halogen (F, Br, Cl or I), -OH, -C1-C6 alkoxy, or -CF3, and when X is -CH2- is unsubstituted, or at least one -CH2- each independently is replaced by -(C=0)-.

[0070] 31) According to the embodiments of the application described in 1) to 11) and 25) to 30) above, it can be provided in the above formula I-2 that L3 is a single bond or C1-C6 alkylene, and in particular L3 is a single bond, -(CH2)-, -(CH2)2-, -(CH2)3-, -(CH2)4- or -(CH2)5-.

[0071] 32) According to the embodiments of the application described in 1) to 11) and 25) to 31) above, it can be provided in the above formula I-2 that R2 is H, halogen (F, Cl, Br or I), -NRz1Rz2, or a 6- to 14-membered aryl, wherein the -H of R2 is unsubstituted, or at least one -H of R2 each independently is substituted by -C1-C6 alkyl, -C1-C6 alkoxy, -NRgRh, or halogen (F, Cl, Br or I), wherein Rg, Rh, Rz1and Rz2each independently is H or C1-C6 alkyl.

[0072] 33) According to the embodiments of the application described in 1) to 11) and 25) to 32) above, it can be provided in the above formula I-2 that R2 is H, halogen (F, Cl, Br or I), -NH2, or In this case, it can be provided that the -H of R2 is unsubstituted, or at least one -H of R2 is each independently substituted with halogen (F, CI, Br, or I), -Ci-C6alkoxy, -NH2, or -Ci-C6alkyl.

[0073] 34) According to the embodiments of the application described in 1) to 11) and 25) to 32) above, it can be provided that in the above Formula I-2, L4 is a single bond, -Ci-C6alkylene-, wherein the -H of L4 is unsubstituted, or at least one -H of L4 is each independently substituted with -Ci-C6alkyl.

[0074] 35) According to the embodiments of the application described in 1) to 11) and 25) to 33) above, it can be provided that in the above Formula I-2, L4 is a single bond, -(CH2)-, -(CH2)2-, -(CH2)3-, -(CH2)4-, or -(CH2)5-, wherein the -H of L4 is unsubstituted, or at least one -H of L4 is each independently substituted with -Ci-C6alkyl.

[0075] 36) According to the embodiments of the application described in 1) to 11) and 25) to 34) above, it can be provided that in the above Formula I-2, R3 is a 5- to 12-membered heteroaryl comprising at least one heteroatom selected from N, O, and S, wherein the -H of R3 is unsubstituted, or at least one H of R3 is each independently substituted with -Ci-C6alkyl, -Ci-C6alkoxy, or halogen (F, CI, Br, or I).

[0076] 37) According to the embodiments of the application described in 1) to 11) and 25) to 35) above, it can be provided that in the above Formula I-2, the R3 is wherein the -H of R3 is unsubstituted, or at least one -H of R3 is each independently substituted with -Ci-C6alkyl (e.g., -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, etc.), -Ci-C6alkoxy (e.g., -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2), or halogen (F, CI, Br, or I).

[0077] 38) According to the embodiments of the application described in 1) to 37) above, the application can provide the compounds described in Table 1 below, stereoisomers thereof, pharmaceutically acceptable salts thereof, or hydrates or solvates thereof: [Table 1]

[0078] 39) According to the embodiments of the present application described in 1) to 38) above, the benzamide compounds represented by the above Formula I, the benzamide compounds represented by the above Formula I-1, the benzamide compounds represented by the above Formula I-2, the benzamide compounds 1 to 249 in the above Table 1, stereoisomers thereof, pharmaceutically acceptable salts thereof, or hydrates or solvates thereof of the present application can exhibit NAMPT inhibitory activity.

[0079] 40) According to the embodiments of the present application described in 1) to 39) above, the benzamide compounds represented by the above Formula I, the benzamide compounds represented by the above Formula I-1, the benzamide compounds represented by the above Formula I-2, the benzamide compounds 1 to 249 in the above Table 1, stereoisomers thereof, pharmaceutically acceptable salts thereof, or hydrates or solvates thereof of the present application can effectively inhibit NAMPT at low concentrations, and can be effective in preventing or treating diseases that can be treated by inhibiting NAMPT.

[0080] 41) According to the embodiments of the present application described in 1) to 40) above, the benzamide compounds represented by the above Formula I, the benzamide compounds represented by the above Formula I-1, the benzamide compounds represented by the above Formula I-2, the benzamide compounds 1 to 249 in the above Table 1, stereoisomers thereof, pharmaceutically acceptable salts thereof, or hydrates or solvates thereof of the present application can sufficiently reduce the concentration of NAD in cells.

[0081] 42) According to the embodiments of the present application described in 1) to 41) above, the benzamide compounds represented by the above Formula I, the benzamide compounds represented by the above Formula I-1, the benzamide compounds represented by the above Formula I-2, the benzamide compounds 1 to 249 in the above Table 1, stereoisomers thereof, pharmaceutically acceptable salts thereof, or hydrates or solvates thereof of the present application can exhibit high cytotoxicity against cancer cells, and can sufficiently kill cancer cells at low concentrations.

[0082] 43) According to the embodiments of the present application described in the above 1) to 42), the benzamide compound represented by the above formula I, the benzamide compound represented by the above formula I-1, the benzamide compound represented by the above formula I-2, the benzamide compounds 1 to 249 in the above Table 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof of the present application can exhibit high cytotoxicity against gastric cancer cells or colorectal cancer cells, and can sufficiently kill gastric cancer cells or colorectal cancer cells at a low concentration.

[0083] 44) According to the embodiments of the present application described in the above 1) to 43), the benzamide compound represented by the above formula I, the benzamide compound represented by the above formula I-1, the benzamide compound represented by the above formula I-2, the benzamide compounds 1 to 249 in the above Table 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof of the present application can have little or no side effects, and can exhibit excellent pharmacokinetic properties. For example, the benzamide compound represented by the above formula I, the benzamide compound represented by the above formula I-1, the benzamide compound represented by the above formula I-2, the benzamide compounds 1 to 249 in the above Table 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof can exhibit excellent absorption rate (e.g., high bioavailability), can be appropriately distributed in each tissue according to administration to exhibit desired pharmacological effects (e.g., preventive or therapeutic effects on diseases that can be treated by inhibiting NAMPT) in each tissue, and can be effectively metabolized in vivo.

[0084] In the present application, "stereoisomer" can include diastereoisomers and optical isomers, and the optical isomers include not only enantiomers but also a mixture of enantiomers and racemates.

[0085] In the present application, "pharmaceutically acceptable" can mean that it is physiologically acceptable, and does not generally cause allergic reactions such as gastrointestinal disorders or dizziness, or similar reactions when administered to a subject.

[0086] 45) According to the embodiments of the present application described in the above 1) to 44), in the present application, the "pharmaceutically acceptable salt" can refer to salts conventionally used in the pharmaceutical industry, for example, inorganic ion salts prepared from calcium, potassium, sodium, magnesium, etc.; inorganic acid salts prepared from hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid, sulfuric acid, etc.; organic acid salts prepared from acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, etc.; sulfonic acid salts prepared from methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, etc.; amino acid salts prepared from glycine, arginine, lysine, etc.; amine salts prepared from trimethylamine, triethylamine, ammonia, pyridine, 2-methylpyridine, etc.; and the like, but the types of salts referred to in the present application are not limited to those listed.

[0087] 46) According to the embodiments of the present application described in the above 1) to 45), the pharmaceutically acceptable salt can be a hydrochloride salt. For example, the pharmaceutically acceptable salt can be a hydrochloride salt of the benzamide compound represented by the above Formula I, the benzamide compound represented by the above Formula I-1, the benzamide compound represented by the above Formula I-2, the benzamide compounds 1 to 249 in the above Table 1, or a stereoisomer thereof.

[0088] The pharmaceutically acceptable salt of the present application can be prepared by a conventional method known to those skilled in the art.

[0089] The "hydrate" of the present application can refer to a substance in which a compound represented by Formula I or a pharmaceutically acceptable salt thereof is combined with water through non-covalent intermolecular forces, and can include a stoichiometric or non-stoichiometric amount of water. In particular, the hydrate can include about 0.25 mol to about 10 mol of water based on 1 mol of the active ingredient, more particularly about 0.5 mol, about 1 mol, about 1.5 mol, about 2 mol, about 2.5 mol, about 3 mol, about 5 mol, etc.

[0090] The "solvate" of the present application can refer to a substance in which a compound represented by Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is combined with a solvent other than water through non-covalent intermolecular forces, and can include a stoichiometric or non-stoichiometric amount of the solvent. In particular, the solvate can include about 0.25 mol to about 10 mol of solvent molecules based on 1 mol of the active ingredient, more particularly about 0.5 mol, about 1 mol, about 1.5 mol, about 2 mol, about 2.5 mol, about 3 mol, about 5 mol, etc.

[0091] Pharmaceutical compositions comprising a compound of Formula I 47) The present application can provide a pharmaceutical composition comprising the above benzamide compound represented by the above formula I, the above benzamide compound represented by the above formula I-1, the above benzamide compound represented by the above formula I-2, the above benzamide compounds 1 to 249 in the above Table 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof according to 1) to 46) as an active ingredient.

[0092] 48) The pharmaceutical composition comprising the above benzamide compound represented by the above formula I, the above benzamide compound represented by the above formula I-1, the above benzamide compound represented by the above formula I-2, the above benzamide compounds 1 to 249 in the above Table 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof according to the above 33) can exhibit NAMPT inhibitory activity and can be used for the prevention or treatment of NAMPT enzyme-related diseases.

[0093] 49) The pharmaceutical composition comprising the above benzamide compound represented by the above formula I, the above compound represented by the above formula I-1, the above compounds 1 to 245 in the above Table 14, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof according to the above 47) or 48) can sufficiently reduce the intracellular NAD concentration.

[0094] 50) The pharmaceutical composition comprising the above benzamide compound represented by the above formula I, the above benzamide compound represented by the above formula I-1, the above benzamide compound represented by the above formula I-2, the above benzamide compounds 1 to 249 in the above Table 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof according to the above 47) to 49) can exhibit a preventive or therapeutic effect on cancer.

[0095] 51) The cancer according to the above 47) to 49) can be a solid cancer or a blood cancer, and the cancer can be skin cancer (e.g., melanoma), lymphoma, breast cancer, cervical cancer, uterine cancer, gastrointestinal cancer, lung cancer, ovarian cancer, prostate cancer, colon cancer, rectal cancer, oral cancer, brain cancer, head and neck cancer, throat cancer, testicular cancer, kidney cancer, pancreatic cancer, bone cancer, spleen cancer, liver cancer, bladder cancer, laryngeal cancer, nasal cavity cancer, AIDS-related cancer, esophageal cancer, stomach cancer, pancreatic cancer, colorectal cancer, a virus-related cancer (one selected from among nasopharyngeal cancer, vaginal cancer, vulvar cancer, penile cancer, Kaposi's sarcoma, Burkitt's lymphoma, T-cell lymphoma, Merkel cell carcinoma, etc.), a cancer of blood and bone marrow, such as multiple myeloma, acute and chronic leukemia, such as lymphoblastic leukemia, myeloid leukemia, lymphocytic leukemia, and myelocytic leukemia, etc.

[0096] 52) The pharmaceutical composition of the present application can further comprise at least one pharmaceutically acceptable carrier, in addition to the benzamide compound represented by the above Formula I, the benzamide compound represented by the above Formula I-1, the benzamide compound represented by the above Formula I-2, the benzamide compounds 1 to 249 in the above Table 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, according to the embodiments of the present application described in 47) to 51) above.

[0097] In this case, the pharmaceutically acceptable carrier can be a carrier commonly used in the preparation of formulations, and can be at least one selected from the group consisting of lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, sugar syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, etc., but is not limited thereto.

[0098] In addition, the pharmaceutical composition of the present application can further comprise a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, etc., in addition to the ingredients.

[0099] In addition, the pharmaceutical composition of the present application can be formulated into oral dosage forms such as tablets, powders, granules, pills, capsules, suspensions, emulsions, internal liquid agents, emulsions, syrups, etc., and external agents, suppositories, and sterile solution dosage forms for injection, by using pharmaceutically acceptable carriers and excipients, and thus can be prepared in unit dosage forms or packed in multi-dose containers. These formulations can be prepared according to conventional methods used in the art of formulation or the methods disclosed in Remington's Pharmaceutical Science (19th edition, 1995), and can be formulated into various formulations according to each disease or ingredient. The pharmaceutical composition of the present application can be orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically) administered according to the intended method, and the dose varies depending on the condition and body weight of the patient, the degree of disease, the form of the drug and the route and time of administration, but can be appropriately selected by those skilled in the art. Specifically, the daily dose of the above benzamide compound represented by the above Formula I, the benzamide compound represented by the above Formula I-1, the benzamide compound represented by the above Formula I-2, the benzamide compounds 1 to 249 in the above Table 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof of the present application can be about 0.1 to about 1000 mg / kg based on the weight of the compound represented by the above Formula I, and can be administered once a day or several times a day.

[0100] The pharmaceutical composition of the present application can further comprise at least one component that can exhibit the same or similar effect in addition to or in conjunction with the benzamide compound represented by the above Formula I, the benzamide compound represented by the above Formula I-1, the benzamide compound represented by the above Formula I-2, the benzamide compounds 1 to 249 in the above Table 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof to synergistically enhance the efficacy.

[0101] 53) According to the embodiments of the present application described in 47) to 51) above, the present application can provide a method for preventing or treating a NAMPT enzyme-related disease, which comprises administering to an individual a benzamide compound represented by the above Formula I, a benzamide compound represented by the above Formula I-1, a benzamide compound represented by the above Formula I-2, a benzamide compound 1 to 249 in the above Table 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a pharmaceutical composition comprising the same.

[0102] 54) According to the embodiments of the present application described in 53) above, the method for preventing or treating a NAMPT enzyme-related disease of the present application can comprise administering a therapeutically effective amount of a benzamide compound represented by the above Formula I, a benzamide compound represented by the above Formula I-1, a benzamide compound represented by the above Formula I-2, a benzamide compound 1 to 249 in the above Table 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a pharmaceutical composition comprising the same.

[0103] 55) According to the embodiments of the present application described in 53) or 54) above, in the present application, "a therapeutically effective amount" can mean an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment, and an effective dose level can be determined according to factors well known in the medical field, including the type of disease, the severity, the activity of the drug, the sensitivity to the drug, the time of administration, the route of administration, and the excretion rate, the treatment period, and other drugs used simultaneously. Specifically, it can mean an amount effective to prevent or treat a disease (e.g., cancer) that can be treated by inhibiting NAMPT.

[0104] In the present application, "an individual" can mean a subject in need of prevention or treatment of a disease, and more specifically a mammal such as a human, a monkey, a mouse, a dog, a cat, a horse, a cow, etc., but is not limited thereto.

[0105] 56) According to the embodiments of the present application described in 53) to 55) above, in the present application, "prevention" can mean all actions to inhibit or delay the occurrence of NAMPT enzyme-related diseases by administering the benzamide derivative compound represented by Formula I, the benzamide compound, the benzamide compound represented by Formula I-1 above, the benzamide compound represented by Formula I-2 above, the benzamide compounds 1 to 249 in Table 1 above, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof of the present application.

[0106] 57) According to the embodiments of the present application described in 53) to 56) above, in the present application, "treatment" can mean all actions to improve the symptoms of NAMPT-related diseases or turn them to the favorable by administering the benzamide derivative compound represented by Formula I, the benzamide compound, the benzamide compound represented by Formula I-1 above, the benzamide compound represented by Formula I-2 above, the benzamide compounds 1 to 249 in Table 1 above, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof of the present application.

[0107] 58) The present application can provide the use of the benzamide derivative compound represented by Formula I, the benzamide compound, the benzamide compound represented by Formula I-1 above, the benzamide compound represented by Formula I-2 above, the benzamide compounds 1 to 249 in Table 1 above, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a pharmaceutical composition comprising the same according to 47) to 51) above in the prevention or treatment of NAMPT enzyme-related diseases.

[0108] 59) The present application can provide the use of the benzamide derivative compound represented by Formula I above, the benzamide compound represented by Formula I-1 above, the benzamide compound represented by Formula I-2 above, the benzamide compounds 1 to 249 in Table 1 above, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a pharmaceutical composition comprising the same according to 47) to 51) above in the preparation of a medicament for the prevention or treatment of NAMPT enzyme-related diseases.

[0109] Matters mentioned in each of the present applications, i.e., the benzamide compounds, uses, compositions, and therapeutic methods, can be applied equally as long as they do not contradict each other. In addition, the terms and abbreviations used in the present specification have their original meanings unless otherwise defined.

[0110] Advantageous effects The benzamide derivative compound of the present application, stereoisomers thereof, pharmaceutically acceptable salts thereof, or hydrates or solvates thereof can inhibit NAMPT to achieve a significant effect of preventing or treating NAMPT-related diseases. Accordingly, the urea compound of the present application, stereoisomers thereof, pharmaceutically acceptable salts thereof, or hydrates or solvates thereof can be advantageously used for preventing or treating diseases that can be treated by inhibiting NAMPT (e.g., cancer).

[0111] Embodiments Hereinafter, the present application will be described in more detail by way of Preparation Examples and exemplary examples. However, the following Preparation Examples and exemplary examples are intended to illustrate the present application, and thus the present application is not limited to the Preparation Examples and exemplary examples.

[0112] Each compound of the present application is synthesized by the following method, and a person skilled in the art can use a conventional method obtained by combining the following specific synthesis methods.

[0113] Each compound used in the synthesis is purchased from an external supplier or synthesized using an organic synthesis method obvious to a person skilled in the art, and used without a separate purification process. The compound of each exemplary example is identified by 400 MHz 1H-NMR (BRUKER, 400-MR), liquid chromatography-mass spectrometry (LC-Mass) (Waters, SQD2) analysis.

[0114] <Example> Example 1 : Synthesis of Compound 1 Reagents and conditions: (a) Na2S, DMF, room temperature (r.t), 16 hours (16 h) (b) 3-(chloromethyl)-1-methyl-1H-pyrazole, K2CO3, DMF, room temperature (r.t), 16 hours (16 h) (c) mCPBA, DCM, room temperature (r.t), 16 hours (16 h) (d) Fe, AcOH, 80℃, 2 hours (2 h) (e) HCl, NaNO2, KI, H2O, 0℃-room temperature (0℃-r.t), 1 hour (1 h) (f) PdCl2[PPh3]2, CuI, TEA, ACN, room temperature (r.t), 16 hours (16 h) (g) NaOH, H2O, MeOH, 55℃, 2 hours (2 h) (h) 3-(1H-pyrazol-4-yl)propan-1-amine dihydrochloride, TBTU, TEA, DCM, 12 hours (12 h) Step 1) Synthesis of methyl 4-mercapto-3-nitrobenzoate Methyl 4-fluoro-3-nitrobenzoate (10 g, 46.4 mmol, 1 eq) was dissolved in DMF (80 ml) and to this sodium disulfide (4.32 g, 55.3 mmol, 1.2 eq) was added and stirred for 16 h at room temperature. After completion of the reaction, water (200 ml) was added to the reaction product and stirred while adjusting the pH to 5 with 1 N HCI. During the stirring, yellow solid was produced, filtered and washed with 25% EA / HX in suspension to get the target compound (6.13 g, 28.7 mmol, 62%).

[0115] Step 2) Synthesis of methyl 4-(((1-methyl-1H-pyrazol-3-yl)methyl)thio)-3- nitrobenzoate Methyl 4-mercapto-3-nitrobenzoate (4 g, 18.8 mmol, 1 eq) was dissolved in DMF (40 ml) and to this K2CO3(5.18 g, 37.52 mmol, 2 eq) was added and stirred. When the reaction product turned dark red, 3-(chloromethyl)-1-methyl-1H-pyrazole (2.45 g, 18.8 mmol, 1 eq) was added to the reaction product and stirred for 16 h. When the completion of the reaction was confirmed by TLC, water was added to the reaction product, the precipitate obtained was filtered to get the target compound (5.14 g, 16.7 mmol, 89%).

[0116] Step 3) Synthesis of methyl 4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)-3- nitrobenzoate Methyl 4-(((1-methyl-1H-pyrazol-3-yl)methyl)thio)-3-nitrobenzoate (5.14 g, 16.7 mmol, 1 eq) was dissolved in DCM (100 ml) and to this mCPBA (12.2 g, 50.2 mmol, 3 eq) was added and stirred for 16 h. When the completion of the reaction was confirmed by TLC, the product obtained was diluted with water, neutralized with saturated aqueous NaHC03and extracted with DCM several times. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to get the target compound which was not purified.

[0117] Step 4) Synthesis of methyl 3-amino-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzoate To methyl 4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)-3-nitrobenzoate (16.7 mmol, 1 eq) was added AcOH (100 ml) and iron powder (9.32 g, 16.7 mmol, 10 eq) and stirred at 80 °C for two hours. The catalyst was removed by filtration through celite and the filtrate was concentrated under reduced pressure. The residue was basified with aqueous potassium carbonate solution, extracted with ethyl acetate and the organic layer was concentrated under reduced pressure. The target compound was obtained as a crude product.

[0118] Step 5) Synthesis of methyl 3-iodo-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzoate A solution of sodium nitrite (1.73 g, 1.5 eq) dissolved in water (40 ml) was slowly added dropwise to a suspension of methyl 3-amino-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzoate (16.7 mmol), aqueous concentrated hydrochloric acid (40 ml) and water (40 ml) at 0 °C. The resulting mixture was stirred in an ice bath for 30 minutes, after which a solution of potassium iodide (8.3 g, 3 eq) dissolved in water (40 mL) was added to it at 0 °C. The reaction mixture was stirred at room temperature for one hour, treated with saturated aqueous potassium carbonate solution (pH > 8) and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, 30-50% EA / HX) to obtain the target compound (3.24 g, 46% yield over three steps [(c), (d), (e)]).

[0119] Step 6) Synthesis of methyl 3-((4-fluorophenyl)ethynyl)-4-(((1-methyl-1H-pyrazol-3- yl)methyl)sulfonyl)benzoate To methyl 3-iodo-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzoate (0.84 g, 2 mmol, 1 eq) was added MeCN (10 ml, 0.2 M) and to it was added TEA (0.84 ml, 6 mmol, 3 eq). To the reaction product was added PdCl2[PPh3]2(42 mg, 3 mol%) and CuI (11 mg, 3 mol%) and stirred under a nitrogen atmosphere at room temperature for five minutes. Subsequently, 4-fluorophenylacetylene (0.29 g, 1.2 eq) was added to it. The reaction mixture was stirred at room temperature for 16 hours and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, 40-50% EA / HX) to obtain the target compound (1.7 mmol, 85%).

[0120] Step 7) Synthesis of 3-((4-fluorophenyl)ethynyl)-4-(((1-methyl-1H-pyrazol-3- yl)methyl)sulfonyl)benzoic acid To methyl 3-((4-fluorophenyl)ethynyl)-4-(((1-methyl-1H-pyrazol-3- yl)methyl)sulfonyl)benzoate (0.7 g, 1.7 mmol, 1 eq) was added MeOH (17 ml, 0.1 M), H2O (8.5 ml, 0.2 M) and NaOH (0.17 g, 4.3 mmol, 2.5 eq) and stirred at 55 °C for two hours. When the completion of the reaction was confirmed by TLC, the pH of the reaction product was adjusted to 1 with aqueous 1 N HC1 and extracted with EA. The organic layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to afford the target compound (0.62 g, 92%).

[0121] Step 8) Synthesis of N-(3-(1H-pyrazol-4-yl)propyl)-3-((4-fluorophenyl)ethynyl)-4- (((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide To 3-((4-fluorophenyl)ethynyl)-4-(((1-methyl-1H-pyrazol-3- yl)methyl)sulfonyl)benzoic acid (0.12 g, 0.3 mmol, 1 eq) was added DCM (5 ml) and TBTU (0.14 g, 0.45 mmol, 1.5 eq) and stirred at room temperature for 50 minutes. Subsequently, to the reaction product was added TEA (0.15 ml, 1.11 mmol, 3.7 eq) and 3-(1H-pyrazol-4-yl)propan-1-amine dihydrochloride (71 mg, 0.36 mmol, 1.2 eq) and stirred for 12 hours. To the reaction product was added water and extracted with EA. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure, the resulting residue was purified by column chromatography (silica gel, 3-4% MeOH / DCM) to afford the target compound (0.1 g, 0.20 mmol, 66%).

[0122] 1 H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 1.6 Hz, 1H), 7.94 (d, J = 8.2 Hz,1H), 7.73 – 7.66 (m, 3H), 7.49 (s, 2H), 7.23 (d, J = 2.2 Hz, 1H), 7.13 (t, J= 8.7 Hz, 2H), 6.35 – 6.32 (m, 1H), 6.17 (d, J = 2.2 Hz, 1H), 4.79 (s, 2H), 3.79(s, 3H), 3.55 (q, J = 6.4 Hz, 2H), 2.66 (t, J = 7.4 Hz, 2H), 1.97 (p, J = 7.4 Hz,2H). MS(ESI) m / e MH + 506.2.

[0123] The reagents can be changed in substantially the same manner as the synthetic method of Example 1 described above to synthesize compounds 11, 13, 18, 21, 23, 24, 26 to 28, 30 to 43, and 48 to 70.

[0124] Example 2: Synthesis of Compound 2 Synthesis of 3-((4-fluorophenyl)ethynyl)-N-((imidazo[l,2-a]pyridin-7-yl)methyl)-4-(((l-methyl-lH-pyrazol-3-yl)methyl)sulfonyl)benzamide The target compound was synthesized in the same manner as step 8) of Example 1 using l-{imidazo[l,2-a]pyridin-7-yl}methanamine dihydrochloride.

[0125] 1 H NMR (400 MHz, DMSO) δ 9.47 – 9.44 (m, 1H), 8.52 (d, J = 7.1 Hz, 1H),8.33 (s, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.97 – 7.88 (m, 2H), 7.82 – 7.76 (m,2H), 7.60 (s, 1H), 7.54 (s, 1H), 7.46 (s, 1H), 7.39 (t, J = 8.4 Hz, 2H), 6.89(d, J = 6.7 Hz, 1H), 6.10 (s, 1H), 4.88 (s, 2H), 4.55 (d, J = 5.4 Hz, 2H), 3.72(s, 3H). MS(ESI) m / e MH +528.4.

[0126] The reagents can be changed in essentially the same manner as the method of Example 2 to synthesize compounds 220, 221, 222, and 227.

[0127] Example 3: Synthesis of Compound 3 Synthesis of N-(2-(lH-pyrrolo[3,2-c]pyridin-3-yl)ethyl)-3-((4- fluorophenyl)ethynyl)-4-(((l-methyl-lH-pyrazol-3-yl)methyl)sulfonyl)benzamide The target compound was synthesized in the same manner as step 8) of Example 1 using l-{lH-pyrrolo[3,2-c]pyridin-2-yl}methanamine dihydrochloride.

[0128] 1 H NMR (400 MHz, MeOD) δ 8.91 (s, 1H), 8.15 (d, J = 5.8 Hz, 1H), 8.10(s, 1H), 7.90 (d, J = 8.3 Hz, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.78 – 7.72i (m,2H), 7.45 (m, 2H), 7.32 (s, 1H), 7.24 (t, J = 8.3 Hz, 2H), 6.17 (s, 1H), 4.83(s, 2H), 3.78 – 3.72 (m, 5H), 3.19 (t, J = 7.1 Hz, 2H). MS (ESI) m / e [M-H] - 540.4.

[0129] Example 4: Synthesis of 3-(chloromethyl)-1-(4-(trifluoromethyl)phenyl)-1H- pyrazole Reagents and conditions: (a) 1-iodo-4-(trifluoromethyl)benzene, CuI, K3PO4, (1S,2S)-(+)-N,N'-dimethylcyclohexane-1,2-diamine, 110 °C, 16 hours (16 h) (b) LiAlH4, THF, 0 °C to room temperature (0 °C - r.t), 1 hour (1 h) (c) SOCl2, DCM, room temperature (r.t), 12 hours (12 h) Step 1) Synthesis of methyl 1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxylate Methyl 1H-pyrazole-3-carboxylate (1 g, 7.9 mmol, 1 eq), 1-iodo-4- (trifluoromethyl)benzene (2.15 g, 1 eq), CuI (0.24 g, 1.27 mmol, 0.16 eq), (1S,2S)-(+)-N,N'-dimethylcyclohexane-1,2-diamine (0.28 ml, 1.7 mmol, 0.22 eq), K3PO4 (4 g, 19 mmol, 2.4 eq) and toluene (10 ml, 0.8 M) were added to a pressure tube and stirred at 110 °C for 16 hours. The reaction product was cooled to room temperature, water and EA were added and separated. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure, the resulting residue was purified by column chromatography (silica gel, 10% EA / HX) to give the target compound (1.4 g, 5.2 mmol, 65%).

[0130] Step 2) Synthesis of (1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)methanol Methyl 1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxylate (1 g, 3.7 mmol, 1 eq) was dissolved in anhydrous THF and a lithium aluminum hydride solution (3.7 ml, 1.0 M in THF) was added dropwise at 0 °C. The reaction product was stirred at room temperature for one hour and cooled to 0 °C. Water (1 ml), 1 N aqueous NaOH solution (1 ml) and water (2 ml) were added to the reaction product in sequence, the reaction was complete and filtered through celite. The filtrate was concentrated under reduced pressure to give the target compound which was not purified.

[0131] Step 3) Synthesis of 3-(chloromethyl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole (1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)methanol was dissolved in DCM (20 ml) and SOCl2 (0.54 ml, 2 eq) was added thereto, stirred at room temperature for 12 hours and concentrated under reduced pressure to give the target compound which was not purified.

[0132] Example 5: Synthesis of Compound 4 Reagents and conditions: (a) Na2S, DMF, reflux, two hours (2 h) (b) 3-(chloromethyl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole, K2CO3, DMF, r.t, 0.5 h (c) mCPBA, DCM, r.t, 16 h (d) PdCl2[PPh3]2, CuI, TEA, ACN, r.t, 16 h (e) NaOH, H2O, MeOH, 60 °C, 12 h (f) 3-(1H-pyrazol-4-yl)propan-1-amine dihydrochloride, TBTU, TEA, DCM, 12 h Step 1) Synthesis of methyl 3-iodo-4-mercaptobenzoate Methyl 4-fluoro-3-iodobenzoate (5 g, 17.8 mmol, 1 eq) was dissolved in DMF (20 ml) and to this was added sodium disulfide (1.53 g, 19.6 mmol, 1.1 eq) and stirred for two hours at reflux. To the reaction product was added water, acidified with 1 N HC1 and extracted with EA several times. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain a residue of the target compound as a crude product.

[0133] Step 2) Synthesis of methyl 3-iodo-4-(((1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-3- yl)methyl)thio)benzoate Methyl 3-iodo-4-mercaptobenzoate (0.1 g) was then added to the reaction product and stirred for 30 minutes. To the reaction product was added water and extracted with EA several times. The organic layer was washed with saturated aqueous NH4CI solution, separated, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, 10% EA / HX) to obtain the target compound (78 mg, 0.15 mmol, 42%).

[0134] Step 3) Synthesis of methyl 3-iodo-4-(((1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-3- yl)methyl)sulfonyl)benzoate Methyl 3-iodo-4-(((l-(4-(trifluoromethyl)phenyl)-lH-pyrazol-3- yl)methyl)thio)benzoate (0.1 g, 0.61 mmol, 1 eq) was dissolved in DCM (30 ml) and to this was added mCPBA (0.45 g, 1.83 mmol, 3 eq) and stirred for 16 h. When the completion of the reaction was confirmed by TLC, the resulting product was diluted with water, neutralized with saturated aqueous NaHC03solution and extracted with DCM a few times. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure, the resulting residue was purified by column chromatography (silica gel, 25% EA / HX) to afford the title compound (0.19 g, 0.34 mmol, 57%).

[0135] Step 4) Synthesis of methyl 3-((4-fluorophenyl)ethynyl)-4-(((l-(4- (trifluoromethyl)phenyl)-lH-pyrazol-3-yl)methyl)sulfonyl)benzoate To methyl 3-iodo-4-(((l-(4-(trifluoromethyl)phenyl)-lH-pyrazol-3- yl)methyl)sulfonyl)benzoate (0.1 g, 0.19 mmol, 1 eq) was added MeCN (1 ml, 0.2 M) and to this was added TEA (0.078 ml, 0.56 mmol, 3 eq). To the reaction product was added PdCl2[PPh3]2(4 mg, 3 mol%) and CuI (1 mg, 3 mol%) and stirred for five minutes under nitrogen atmosphere at room temperature. Subsequently, to this was added 4-fluorophenylacetylene (27 mg, 0.22 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 16 h and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, 30% EA / HX) to afford the title compound (86 mg, 0.16 mmol, 85%).

[0136] Step 5) Synthesis of 3-((4-fluorophenyl)ethynyl)-4-(((l-(4- (trifluoromethyl)phenyl)-lH-pyrazol-3-yl)methyl)sulfonyl)benzoic acid To methyl 3-((4-fluorophenyl)ethynyl)-4-(((1-(4-(trifluoromethyl)phenyl)-1H- pyrazol-3-yl)methyl)sulfonyl)benzoate (0.075 g, 0.14 mmol, 1 eq) was added DCM (2.5 ml) and TBTU (0.037 g, 0.21 mmol, 1.5 eq) and stirred at room temperature for 50 min. Subsequently, to the reaction product was added TEA (0.072 ml, 0.52 mmol, 3.7 eq) and 3-(1H-pyrazol-4-yl)propan-1-amine dihydrochloride (0.034 g, 0.17 mmol, 1.2 eq) and stirred for 12 h. To the reaction product was added water and extracted with EA. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure, the resulting residue was purified by column chromatography (silica gel, 2% MeOH / DCM) to afford the target compound.

[0137] Step 6) Synthesis of compound 4: Synthesis of N-(3-(1H-pyrazol-4-yl)propyl)-3-((4- fluorophenyl)ethynyl)-4-(((1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide To methyl 3-((4-fluorophenyl)ethynyl)-4-(((1-(4-(trifluoromethyl)phenyl)-1H- pyrazol-3-yl)methyl)sulfonyl)benzoate (0.075 g, 0.14 mmol, 1 eq) was added DCM (2.5 ml) and TBTU (0.037 g, 0.21 mmol, 1.5 eq) and stirred at room temperature for 50 min. Subsequently, to the reaction product was added TEA (0.072 ml, 0.52 mmol, 3.7 eq) and 3-(1H-pyrazol-4-yl)propan-1-amine dihydrochloride (0.034 g, 0.17 mmol, 1.2 eq) and stirred for 12 h. To the reaction product was added water and extracted with EA. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure, the resulting residue was purified by column chromatography (silica gel, 2% MeOH / DCM) to afford the target compound.

[0138] 1 H NMR (400 MHz, MeOD) δ 8.25 – 8.22 (m, 2H), 7.98 (d, J = 8.1 Hz, 1H),7.87 (d, J = 8.1 Hz, 1H), 7.73 (m, 6H), 7.49 (m, 2H), 7.20 (t, J= 8.5 Hz, 2H),6.53 (s, 1H), 4.99 (s, 2H), 3.45 (d, J = 6.8 Hz, 2H), 2.63 (t, J = 7.4 Hz, 2H),1.98 – 1.92 (m, 2H). MS(ESI) m / e [M-H] - 634.4.

[0139] The reagents can be changed in essentially the same manner as in Example 5 to synthesize compounds 111, 112, 113, 114, 116, 117, 118, 120, 121, 123, 124, 125, 126, 127, 128, 129, 130, 132, 135, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 149, 219, 157, 158, 209, 210, 201, 212, 213, 223, 225, 169, 170, 171, 218, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 217, 191, 192, 204, 205, 206, 207, 208, and 214.

[0140] Example 6: Synthesis of compound 5 Reagents and conditions: (a) 1-(bromomethyl)-2,3-dimethylbenzene, K2CO3, DMF, room temperature (r.t), 0.5 hours (0.5 h) (b) mCPBA, DCM, room temperature (r.t), 16 hours (16 h) (c) PdCl2[PPh3]2, CuI, TEA, ACN, room temperature (r.t), 16 hours (16 h) (d) NaOH, H2O, MeOH, 55 °C, 12 hours (12 h) (e) 3-(1H-pyrazol-4-yl)propan-1-amine dihydrochloride, TBTU, TEA, DCM, 12 hours (12 h) Step 1) Synthesis of methyl 4-((2,3-dimethylbenzyl)thio)-3-iodobenzoate Methyl 4-((2,3-dimethylbenzyl)sulfonyl)-3-iodobenzoate (0.31 g, 0.75 mmol, 1 eq) was dissolved in DCM (30 ml) and to this was added mCPBA (0.55 g, 2.3 mmol, 3 eq) and stirred for 16 h. When the completion of the reaction was confirmed by TLC, the resulting product was diluted with water, neutralized with saturated aqueous NaHC03solution and extracted with DCM several times. The organic layer was dried over MgS04and concentrated under reduced pressure, the resulting residue was purified by column chromatography (silica gel, 20% EA / HX) to obtain the target compound (0.17 g, 0.39 mmol, 52%).

[0141] Step 2) Synthesis of methyl 4-((2,3-dimethylbenzyl)sulfonyl)-3-iodobenzoate Methyl 4-((2,3-dimethylbenzyl)sulfonyl)-3-iodobenzoate (0.31 g, 0.75 mmol, 1 eq) was dissolved in DCM (30 ml) and to this was added mCPBA (0.55 g, 2.3 mmol, 3 eq) and stirred for 16 h. When the completion of the reaction was confirmed by TLC, the resulting product was diluted with water, neutralized with saturated aqueous NaHC03solution and extracted with DCM several times. The organic layer was dried over MgS04and concentrated under reduced pressure, the resulting residue was purified by column chromatography (silica gel, 20% EA / HX) to obtain the target compound (0.17 g, 0.39 mmol, 52%).

[0142] Step 3) Synthesis of methyl 4-((2,3-dimethylbenzyl)sulfonyl)-3-((4-fluorophenyl)ethynyl)benzoate To methyl 4-((2,3-dimethylbenzyl)sulfonyl)-3-iodobenzoate (0.17 g, 0.38 mmol, 1 eq) was added MeCN (2 ml, 0.2 M) and to this was added TEA (0.16 ml, 1.15 mmol, 3 eq). To the reaction product was added PdCl2[PPh3]2(8 mg, 3 mol%) and CuI (2 mg, 3 mol%) and stirred for five minutes under a nitrogen atmosphere at room temperature. Subsequently, 4-fluorophenylacetylene (55 mg, 0.45 mmol, 1.2 eq) was added. The reaction mixture was stirred at room temperature for 16 h and concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain the target compound (0.165 g, 0.38 mmol, 99%).

[0143] Step 4) Synthesis of 4-((2,3-dimethylbenzyl)sulfonyl)-3-((4-fluorophenyl)ethynyl)benzoic acid To methyl 4-((2,3-dimethylbenzyl)sulfonyl)-3-((4-fluorophenyl)ethynyl)benzoate (0.165 g, 0.38 mmol, 1 eq) was added MeOH (1 ml, 0.1 M), H2O (0.5 ml, 0.2 M) and NaOH (0.016 g, 0.4 mmol, 2.5 eq) and stirred at 85 °C for 12 h. When the completion of reaction was confirmed by TLC, the pH of the reaction product was adjusted to 1 with 1 N aqueous HC1 and extracted with EA. The organic layer was washed with water, separated, dried over magnesium sulfate and concentrated under reduced pressure to obtain the target compound as a crude product.

[0144] Step 5) Synthesis of compound 5: Synthesis of N-(3-(lH-pyrazol-4-yl)propyl)-4-((2,3-dimethylbenzyl)sulfonyl)-3-((4-fluorophenyl)ethynyl)benzamide To 4-((2,3-dimethylbenzyl)sulfonyl)-3-((4-fluorophenyl)ethynyl)benzoic acid (0.15 g, 0.35 mmol, 1 eq) was added DCM (5 ml) and TBTU (0.17 g, 0.53 mmol, 1.5 eq) and stirred at room temperature for 50 min. Subsequently, TEA (0.18 ml, 1.3 mmol, 3.7 eq) and 3-(lH-pyrazol-4-yl)propan-l -amine dihydrochloride (0.083 g, 0.42 mmol, 1.2 eq) were added to the reaction product and stirred for 12 h. Water was added to the reaction product and extracted with EA. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure, the resulting residue was purified by column chromatography (silica gel, 3-5% MeOH / DCM) to obtain the target compound (0.07 g, 0.13 mmol, 38%).

[0145] 1 H NMR (400 MHz, DMSO) δ 12.51 (s, 1H), 8.83 (m, 1H), 8.27 (s, 1H),8.00 (d, J = 8.3 Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.77 - 7.70 (m, 2H), 7.52(br, 1H), 7.37 (d, J = 8.5 Hz, 2H), 7.10 (d, J = 7.4 Hz, 1H), 6.95 (t, J = 7.5 Hz,1H), 6.85 (d,J = 7.6 Hz, 1H), 4.91 (s, 2H), 3.32 (m, 2H), 2.48 (m, 2H), 2.19(s, 6H), 1.80 (p, J = 7.0 Hz, 2H). MS (ESI) m / e [M-H] - 528.4.

[0146] Example 7: Synthesis of Compound 6 Scheme: Reagents and conditions (a) Na2S, DMF, r.t, 16 h (b) N-chlorosuccinimide, 2 N HC1 (aq), MeCN, r.t, 16 h (c) Methylamine, EtOH, MeCN, r.t, 1 h (d) Fe, AcOH, 80 °C, 1 h (e) HC1, NaNC, KI, H2O, 0 °C to r.t, 1 h (f) PdCl2[PPh3]2, CuI, TEA, ACN, r.t, 1 h (g) NaOH, H2O, MeOH, 55 °C, 4 h (h) 3-(1 H-pyrazol-4-yl)propan-1 -amine dihydrochloride, TBTU, TEA, DCM, 12 h Step 1) Synthesis of methyl 4-mercapto-3-nitrobenzoate Methyl 4-fluoro-3-nitrobenzoate (10 g, 46.4 mmol, 1 eq) was dissolved in DMF (80 ml) and to this was added sodium sulfide (4.32 g, 55.3 mmol, 1.2 eq) and stirred at room temperature for 16 h. After completion of the reaction, water (200 ml) was added to the reaction product and stirred while adjusting the pH to 5 with 1 N HC1. During the stirring, yellow solid was produced, filtered and washed with 25% EA / HX in the suspension to get the target compound (6.13 g, 28.7 mmol, 62%).

[0147] Step 2) Synthesis of methyl 4-(chlorosulfonyl)-3-nitrobenzoate Methyl 4-mercapto-3-nitrobenzoate (1 g, 4.9 mmol, 1 eq) was added to the reaction product of N-chlorosuccinimide (3.3 g, 24.5 mmol, 5 eq), 2 N aqueous HC1 (5.2 ml, 2 eq) and MeCN (50 ml) in an ice bath and stirred at room temperature for 16 hours. After completion of the reaction, water (20 ml) was added thereto and the MeCN was concentrated under reduced pressure. The residue was extracted with EA several times and washed with saturated aqueous NaHC03 and brine several times. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain a residue of the target compound as a crude product.

[0148] Step 3) Synthesis of methyl 4-(N-methylsulfamoyl)-3-nitrobenzoate Methyl 4-(chlorosulfonyl)-3-nitrobenzoate (0.2 g, 0.71 mmol, 1 eq) was dissolved in MeCN and thereto was added a methylamine solution (33 wt.% in anhydrous ethanol) and stirred at room temperature for one hour. Water was added to the reaction product and the MeCN was concentrated under reduced pressure to obtain a residue, which was then extracted with EA several times. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure, and the obtained residue was purified by column chromatography (silica gel, 20-50% EA / HX) to obtain the target compound (0.13 g, 0.47 mmol, 66%).

[0149] Step 4) Synthesis of methyl 3-amino-4-(N-methylsulfamoyl)benzoate To methyl 3-amino-4-(N-methylsulfamoyl)benzoate (0.128 g, 0.47 mmol, 1 eq) was added AcOH (5 ml) and iron powder (0.26 g, 4.67 mmol, 10 eq) and stirred at 80°C for one hour. The catalyst was removed by filtration through diatomite and the filtrate was concentrated under reduced pressure. The residue was basified with an aqueous potassium carbonate solution, extracted with ethyl acetate, and then the organic layer was concentrated under reduced pressure to obtain the target compound as a crude product.

[0150] Step 5) Synthesis of methyl 3-iodo-4-(N-methylsulfamoyl)benzoate A solution of sodium nitrite (0.03 g, 0.4 mmol, 1.5 eq) dissolved in water (1 ml) was added slowly dropwise to a suspension of 3-amino-4-(N-methylsulfamoyl)benzoic acid methyl ester (0.065 g, 0.27 mmol, 1 eq), concentrated aqueous hydrochloric acid (1 ml) and water (1 ml) at 0 °C. The resulting mixture was stirred in an ice bath for 30 minutes, after which a solution of potassium iodide (0.13 g, 0.8 mmol, 3 eq) dissolved in water (1 mL) was added to it at 0 °C. The reaction mixture was stirred at room temperature for one to two hours, treated with saturated aqueous potassium carbonate (pH > 8) and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure, and the resulting residue was purified by column chromatography (silica gel, 20-60% EA / HX) to give the target compound (0.06 g, 0.17 mmol, 63%).

[0151] Step 6) Synthesis of methyl 3-((4-fluorophenyl)ethynyl)-4-(N-methylsulfamoyl)benzoate To methyl 3-iodo-4-(N-methylsulfamoyl)benzoate (0.06 g, 0.17 mmol, 1 eq) was added MeCN (1 ml) and to it was added TEA (0.071 ml, 0.51 mol, 3 eq). To the reaction product was added PdCl2[PPh3]2(0.0036 mg, 3 mol%) and CuI (0.001 mg, 3 mol%) and stirred under a nitrogen atmosphere at room temperature for five minutes. Subsequently, to it was added 4-fluorophenylacetylene (0.024 g, 0.2 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for one hour and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, 40% EA / HX) to give the target compound (0.059 g, 0.17 mmol, 99%).

[0152] Step 7) Synthesis of 3-((4-fluorophenyl)ethynyl)-4-(N-methylsulfamoyl)benzoic acid To methyl 3-((4-fluorophenyl)ethynyl)-4-(N-methylsulfamoyl)benzoate (0.084 g, 0.25 mmol, 1 eq) was added DCM (5 ml) and TBTU (0.12 g, 0.38 mmol, 1.5 eq) and stirred at room temperature for 50 minutes. Subsequently, to the reaction product was added TEA (0.13 ml, 0.93 mmol, 3.7 eq) and 3-(lH-pyrazol-4-yl)propan-l -amine dihydrochloride (0.060 g, 0.3 mmol, 1.2 eq) and stirred for 12 hours. To the reaction product was added water and extracted with EA. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure, the resulting residue was purified by reverse phase column chromatography (C18 Aq, 40% ACN / 0.1% aqueous formic acid) to afford the target compound (0.02 g, 0.045 mmol, 18%).

[0153] Step 8) Synthesis of compound 6: Synthesis of N-(3-(lH-pyrazol-4-yl)propyl)-3-((4- fluorophenyl)ethynyl)-4-(N-methylsulfamoyl)benzamide To methyl 3-((4-fluorophenyl)ethynyl)-4-(N-methylsulfamoyl)benzoate (0.084 g, 0.25 mmol, 1 eq) was added DCM (5 ml) and TBTU (0.12 g, 0.38 mmol, 1.5 eq) and stirred at room temperature for 50 minutes. Subsequently, to the reaction product was added TEA (0.13 ml, 0.93 mmol, 3.7 eq) and 3-(lH-pyrazol-4-yl)propan-l -amine dihydrochloride (0.060 g, 0.3 mmol, 1.2 eq) and stirred for 12 hours. To the reaction product was added water and extracted with EA. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure, the resulting residue was purified by reverse phase column chromatography (C18 Aq, 40% ACN / 0.1% aqueous formic acid) to afford the target compound (0.02 g, 0.045 mmol, 18%).

[0154] 1 H NMR (400 MHz, MeOD) δ 8.42 (s, 1H), 8.05 – 7.92 (m, 2H), 7.56 –7.48 (m, 4H), 7.18 (t, J = 8.8 Hz, 2H), 6.95 (s, 1H), 3.47 (t, J = 7.1 Hz, 2H),2.94 (s, 3H), 2.63 (t, J = 7.5 Hz, 2H), 1.94 (p, J = 7.3 Hz, 2H). MS(ESI) m / e MH +441.2.

[0155] The reagents can be changed in essentially the same manner as in Example 7 to synthesize compounds 12, 14, 19, 20, 22, 29, 71 to 74, 215 and 216.

[0156] Example 8: Synthesis of Compound 7 Synthesis of 3-((4-fluorophenyl)ethynyl)-4-(((1-methyl-1H-pyrazol-3- yl)methyl)sulfonyl)-N-(2-(6-nitropyridin-3-yl)ethyl)benzamide Scheme: Reagents and conditions (a) tert-Butyl N-[2-(trifluoroboraneyl)ethyl]carbamate potassium, Pd(dppf)Cl2.CH2Cl2, Cs2CO3, H2O, toluene, 80 °C, overnight; (b) 4 N HCl in dioxane, room temperature (rt), overnight; (c) TBTU, TEA, DCM, room temperature (rt), overnight Step 1) Synthesis of tert-butyl (2-(6-nitropyridin-3-yl)ethyl)carbamate Dissolve 5-bromo-2-nitropyridine (1 g, 4.93 mmol, 1.0 eq) in toluene (20 ml, 0.25 M) and add to it tert-butyl N-[2-(trifluoroboraneyl)ethyl]carbamate potassium (1.36 g, 5.41 mmol, 1.1 eq), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (0.302 g, 0.369 mmol, 0.07 eq), Cs2CO3(4.815 g, 14.8 mmol, 3 eq) and H2O (5 ml), heat to 80 °C and stir overnight. After cooling to room temperature, add water and EA and extract the organic layer. Dry the organic layer over MgSO4, filter, concentrate and purify by column chromatography (silica gel, EA / HX). (0.842 g, 64%) Step 2) Synthesis of 2-(6-nitropyridin-3-yl)ethan-1-amine Dissolve tert-butyl (2-(6-nitropyridin-3-yl)ethyl)carbamate (0.842 g, 3.15 mmol, 1 eq) in 4 N HCl dioxane solution (8 ml, 31.5 mmol, 10 eq) and stir at room temperature overnight. Concentrate the reaction mixture and add to it diethyl ether and precipitate. Wash the precipitated solid with diethyl ether and filter under reduced pressure. (0.507 g, 79%) Step 3) Synthesis of compound 7: Synthesis of 3-((4-fluorophenyl)ethynyl)-4-(((1- methyl-1H-pyrazol-3-yl)methyl)sulfonyl)-N-(2-(6-nitropyridin-3-yl)ethyl)benzamide Dissolve 3-((4-fluorophenyl)ethynyl)-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzoic acid (0.1 g, 0.25 mmol, 1 eq) in DCM (0.5 ml, 0.5 M), then add to it 2-(6-nitropyridin-3-yl)ethan-1-amine (0.057 g, 0.28 mmol, 1.1 eq), TBTU (0.12 g, 0.375 mmol, 1.5 eq) and TEA (0.076 ml, 0.55 mmol, 2.2 eq) and stir at room temperature overnight. Dilute the reaction mixture in DCM, then add saturated aqueous NaHCO3, H2O and brine, extract the organic layer. Dry the organic layer over MgSO4, filter, concentrate and precipitate with MC. Wash the precipitated solid with MC and filter under reduced pressure. (0.052 g, 38%) 1 H NMR (400 MHz, MeOD) δ 8.51 (s, 1H), 8.27 (d, J = 8.3 Hz, 1H), 8.10(d, J = 12.5 Hz, 2H), 7.88 (d, J = 8.2 Hz, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.75 –7.69 (m, 2H), 7.43 (s, 1H), 7.21 (t, J = 8.4 Hz, 2H), 6.15 (s, 1H), 4.81 (s,2H), 3.76 – 3.70 (m, 5H), 3.14 (t, J = 6.8 Hz, 2H). MS (ESI) m / e MH + 548.4.

[0157] Example 9: Synthesis of Compound 8 Synthesis of N-(2-(6-aminopyridin-3-yl)ethyl)-3-((4-fluorophenyl)ethynyl)-4-(((1- methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide Procedure: Reagents and conditions (a) Zn, NH4Cl, 1,4-dioxane, H2O, rt, overnight To a solution of 3-((4-fluorophenyl)ethynyl)-4-(((1-methyl-1H-pyrazol-3- yl)methyl)sulfonyl)-N-(2-(6-nitropyridin-3-yl)ethyl)benzamide (0.046 g, 0.084 mmol, 1 eq) in 1,4-dioxane: water (H2O) (3:1 (v / v) (1 ml, 0.084 M) was added zinc dust (0.055 g, 0.84 mmol, 10 eq) and NH4Cl (0.045 g, 0.84 mmol, 10 eq) and stirred at rt overnight. The reaction mixture was washed with MeOH and filtered through celite under reduced pressure. The filtrate was concentrated and purified by reverse phase column chromatography (0.1% formic acid in H2O / acetonitrile). (0.021 g, 47%) 1 H NMR (400 MHz, MeOD) δ 8.13 (s, 1H), 7.90 (d, J = 8.6 Hz, 2H), 7.83(d, J = 8.3 Hz, 1H), 7.78 – 7.73 (m, 2H), 7.63 (d, J = 8.6 Hz, 1H), 7.45 (s, 1H),7.23 (t, J = 8.3 Hz, 2H), 6.74 (d, J = 8.8 Hz, 1H), 6.16 (s, 1H), 4.84 (s, 2H),3.74 (s, 3H), 3.60 (t, J = 6.7 Hz, 2H), 2.82 (t, J = 6.7 Hz, 2H). MS (ESI) m / e MH + 518.4.

[0158] Example 10: Synthesis of Compound 9 Synthesis of N-(3-(1H-pyrazol-4-yl)propyl)-3-((4-fluorophenyl)ethynyl)-4-((3- (trifluoromethyl)benzyl)sulfonyl)benzamide Scheme: Reagents and conditions (a) 1-(chloromethyl)-4-(trifluoromethyl)benzene, TEA, ACN, reflux, 1 h; (b) mCPBA, MC, rt, overnight; (c) Fe, NH4Cl, EtOH, H2O, reflux, 1 h; (d) NaNO2, KI, pTSA, ACN, 0 °C, 1 h; (e) 1-ethynyl-4-fluorobenzene, TEA, Cul, PdCl2(PPh3)2, ACN, reflux, 1 h; (f) NaOH, EtOH, H2O, reflux, 1 h; (g) 3-(1H-pyrazol-4-yl)propan-1-amine dihydrochloride, TBTU, TEA, MC, rt, overnight Step 1) Synthesis of methyl 3-nitro-4-((4-(trifluoromethyl)benzyl)thio)benzoate Methyl 4-mercapto-3-nitrobenzoate (0.1 g, 0.469 mmol, 1 eq) was dissolved in ACN (5 ml, 0.1 M) to which 1-(chloromethyl)-4-(trifluoromethyl)benzene (0.07 ml, 0.469 mmol, 1 eq) and TEA (0.09 ml, 0.61 mmol, 1.3 eq) were added and stirred at reflux for 1 h. After completion of the reaction, the resulting mixture was concentrated to which water was added and extracted with EA. The organic layer was dried over MgSO4, filtered and concentrated to get the product as crude. (0.15 g, 85%) 1 H NMR (400 MHz, CDCl3) δ 8.90 (s, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.71(s, 1H), 7.64 (dd, J = 16.9, 7.6 Hz, 2H), 7.52 (t, J = 8.6 Hz, 2H), 4.32 (s, 2H),3.99 (s, 3H). Step 2) Synthesis of methyl 3-nitro-4-((4-(trifluoromethyl)benzyl)sulfonyl)benzoate Methyl 3-nitro-4-((4-(trifluoromethyl)benzyl)sulfinyl)benzoate (0.15 g, 0.4 mmol, 1 eq) was dissolved in MC (2 ml, 0.2M) to which mCPBA (0.68 g, 3.96 mmol, 10 eq) was added and stirred overnight. After completion of the reaction, saturated aqueous NaHC03solution was added and extracted with MC. The organic layer was dried over MgS04, filtered and concentrated to get the product as crude. (0.138 g, 86%) 1 H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 8.16 (d, J = 8.0 Hz, 1H), 7.69(d, J = 8.1 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.56 – 7.51 (m, 2H), 7.45 (t, J =7.6 Hz, 1H), 4.89 (s, 2H), 4.00 (s, 3H). Step 3) Synthesis of methyl 3-amino-4-((4-(trifluoromethyl)benzyl)sulfonyl)benzoate Methyl 3-nitro-4-((4-(trifluoromethyl)benzyl)sulfonyl)benzoate (0.14 g, 0.342 mmol, 1 eq) was dissolved in ethanol (EtOH): water (H20) (7 ml, 4:1 (v:v), 0.05 M) to which iron powder (0.1 g, 1.71 mmol, 5 eq) and NH4C1 (0.091 g, 1.71 mmol, 5 eq) were added and stirred at reflux for one hour. After cooling to room temperature, the product was filtered through celite, water was added to the filtrate and extracted with EA. The organic layer was dried over MgS04, filtered and concentrated to get the product as crude. (0.12 g, 93.8%) 1 H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 7.4 Hz, 1H), 7.44 – 7.32 (m, 4H),7.28 (d, J = 6.1 Hz, 2H), 5.12 (s, 2H), 4.43 (s, 2H), 3.92 (s, 3H). Step 4) Synthesis of methyl 3-iodo-4-((4-(trifluoromethyl)benzyl)sulfonyl)benzoate Methyl 3-amino-4-((4-(trifluoromethyl)benzyl)sulfonyl)benzoate (0.373 g, 1 mmol, 1 eq) was dissolved in ACN (10 ml, 0.1 M), to which pTSA (0.517 g, 3 mmol, 3 eq) was added, followed by sodium nitrite (0.07 g, 1.02 mmol, 1.02 eq) dissolved in 1 ml water and potassium iodide (0.169 g, 1.02 mmol, 1.02 eq) dissolved in 1 ml water at 0 °C. After one hour of reaction at room temperature, saturated aqueous NaHCO3 solution was added to neutralize to pH 8 or higher, followed by extraction with EA. The organic layer was dried over MgSO4, filtered, concentrated, and purified by column chromatography (silica gel, EA / HX). (0.175 g, 36%) 1 H NMR (400 MHz, CDCl3) δ 8.77 (s, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.86(d, J = 8.1 Hz, 1H), 7.59 (d, J = 5.0 Hz, 1H), 7.44 (d, J = 6.3 Hz, 3H), 4.75 (s,2H), 3.99 (s, 3H). Step 5) Synthesis of methyl 3-((4-fluorophenyl)ethynyl)-4-((4- (trifluoromethyl)benzyl)sulfonyl)benzoate Methyl 3-iodo-4-((4-(trifluoromethyl)benzyl)sulfonyl)benzoate (0.194 g, 0.4 mmol, 1 eq) was dissolved in ACN (4 ml, 0.1 M), to which TEA (0.12 ml, 0.88 mmol, 2.2 eq), PdCl2(PPh3)2(8.4 mg, 0.012 mmol, 3 mol %) and Cul (3 mg, 0.016 mmol, 4 mol %) were added and stirred at room temperature for five minutes. To this, 1-ethynyl-4-fluorobenzene (0.07 ml, 0.6 mmol, 1.5 eq) was added and stirred at 90 °C for one hour. After cooling to room temperature, the resulting product was concentrated and purified by column chromatography (silica gel, EA / HX). (0.183 g, 96.3%) 1H NMR (400 MHz, CDC13) δ 8.40 (s, 1H), 8.01 (d, J = 8.1 Hz, 1H), 7.87(d, J = 8.3 Hz, 1H), 7.71 (t, J = 6.1 Hz, 2H), 7.57 (d, J = 7.1 Hz, 1H), 7.47 - 7.38 (m, 3H), 7.17 (t, J = 7.9 Hz, 2H), 4.76 (s, 2H), 4.01 (s, 3H). Step 6) Synthesis of 3-((4-fluorophenyl)ethynyl)-4-((4- (trifluoromethyl)benzyl)sulfonyl)benzoic acid Methyl 3-((4-fluorophenyl)ethynyl)-4-((4-(trifluoromethyl)benzyl)sulfonyl)benzoate (0.183 g, 0.396 mmol, 1 eq) was dissolved in EtOH (8 ml, 0.05 M) and then to this NaOH (0.079 g, 1.98 mmol, 5 eq) dissolved in H2O (0.8 ml) was added and stirred under reflux for one hour. After cooling to room temperature, the resulting product was concentrated and diluted with water. After adjusting to pH = 5 to 6 with 1 N HC1, the resulting solid was filtered, washed with water and dried. (0.14 g, 76.5%) 1 H NMR (400 MHz, DMSO) δ 8.28 (s, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.84(d, J = 8.3 Hz, 1H), 7.80 - 7.73 (m, 2H), 7.68 (d, J = 7.6 Hz, 1H), 7.58 - 7.51 (m, 1H), 7.51 - 7.47 (m, 1H), 7.45 (s, 1H), 7.38 (t, J = 8.5 Hz, 2H), 5.03 (s, 2H). Step 7) Synthesis of N-(3-(lH-pyrazol-4-yl)propyl)-3-((4-fluorophenyl)ethynyl)-4- ((3-(trifluoromethyl)benzyl)sulfonyl)benzamide Dissolve 3-((4-fluorophenyl)ethynyl)-4-((4-(trifluoromethyl)benzyl)sulfonyl)benzoic acid (0.046 g, 0.1 mmol, 1 eq) in MC, then add to it TBTU (0.048 g, 0.15 mmol, 1.5 eq), TEA (0.03 ml, 0.22 mmol, 2.2 eq) and 3-(1H-pyrazol-4-yl)propan-1-amine dihydrochloride (0.022 g, 0.11 mmol, 1.1 eq) and stir at room temperature overnight. After completion of the reaction, add saturated aqueous NaHCO3solution, neutralize and extract with MC. Dry the organic layer over MgSO4, filter, concentrate and purify by column chromatography (silica gel, EA 100%). (35.7 mg, 62.7%) 1 H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.69 –7.63 (m, 2H), 7.61 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 6.4 Hz, 1H), 7.45 (s, 2H),7.41 – 7.34 (m, 3H), 7.13 (t, J = 8.1 Hz, 2H), 6.35 (s, 1H), 4.70 (s, 2H), 3.51(dd, J = 12.6, 6.3 Hz, 2H), 2.62 (t, J = 7.2 Hz, 2Hff), 1.99 – 1.89 (m, 2H). m / e MH + 570.1.

[0159] Example 11 : Synthesis of Compound 10 Synthesis of N-(3-(1H-pyrazol-4-yl)propyl)-3-((4-fluorophenyl)ethynyl)-4-(((1-(pyridin-4-yl)-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide Scheme: Reagents and conditions (a) 4-iodopyridine, K3PO4, Cul, 1,2-trans dimethylaminocyclohexane, 110 °C, 16 h; (b) 1.0 M LiAlH4in THF, THF, 0 °C, 1 h; (c) SOCl2, MC, 0 °C → reflux; (d) 4-mercapto-3-nitrobenzoic acid methyl ester, K2CO3, DMF, rt, overnight; (e) mCPBA, MC, rt, overnight; (f) Fe, NH4Cl, EtOH, H2O, reflux, 1 h; (g) sodium nitrite (NaNO2), KI, pTSA, ACN, 0 °C, 1 h; (h) 1-ethynyl-4-fluorobenzene, TEA, Cul, PdCl2(PPh3)2, ACN, reflux, 1 h; (i) NaOH, EtOH, H2O, reflux, 1 h; (j) 3-(1H-pyrazol-4-yl)propan-1-amine dihydrochloride, TBTU, TEA, MC, rt, overnight Step 1) Synthesis of ethyl 1-(pyridin-4-yl)-1H-pyrazole-3-carboxylate Ethyl 1H-pyrazole-3-carboxylate (1 g, 7.2 mmol, 1 eq) was added to a pressure tube and dissolved in toluene (30 ml, 0.2 M), then 4-iodopyridine (1.54 g, 7.56 mmol, 1.05 eq), K3PO4(3.8 g, 18 mmol, 2.5 eq), Cul (0.14 g, 0.72 mmol, 0.1 eq) and 1,2-trans dimethylaminocyclohexane (0.22 ml, 1.44 mmol, 0.2 eq) were added thereto and stirred at 110 °C for 16 hours. After completion of the reaction, the resulting mixture was cooled to room temperature, water was added thereto, and extracted with EA. The organic layer was dried with MgSO4, filtered, concentrated, and purified by column chromatography (silica gel, EA / HX). (1.1 g, 70.5%) 1 H NMR (400 MHz, CDCl3) δ 8.71 (d, J = 4.9 Hz, 2H), 8.06 (s, 1H), 7.72(d, J = 4.9 Hz, 2H), 7.04 (s, 1H), 4.46 (q, J = 6.8 Hz, 2H), 1.43 (t, J = 6.9 Hz,3H). Step 2) Synthesis of (1-(pyridin-4-yl)-1H-pyrazol-3-yl)methanol Ethyl 1-(pyridin-4-yl)-1H-pyrazole-3-carboxylate (1.1 g, 5.06 mmol, 1 eq) was dissolved in anhydrous THF (50 ml, 0.1 M), then 1.0 M LiAlH4 solution in THF (7.6 ml, 7.60 mmol, 1.5 eq) was slowly added dropwise at 0 °C and stirred for one hour. After the reaction was completed, water and EA were added, the resulting solid was filtered, and the filtrate was concentrated to obtain the crude product. (0.89 g, 100%) 1 H NMR (400 MHz, MeOD) δ 8.59 (d, J = 5.3 Hz, 2H), 8.42 (s, 1H), 7.87(d, J = 5.4 Hz, 2H), 6.63 (s, 1H), 4.70 (s, 2H). Step 3) Synthesis of 4-(3-(chloromethyl)-1H-pyrazol-1-yl)pyridine (1-(pyridin-4-yl)-1H-pyrazol-3-yl)methanol (0.89 g, 5.06 mmol, 1 eq) was dissolved in MC (25 ml, 0.2 M), then SOCl2 (1.1 ml, 15.2 mmol, 3 eq) was slowly added dropwise at 0 °C and stirred under reflux overnight. After the reaction was completed, the resulting product was concentrated under reduced pressure to obtain the crude product. (1.42 g, 100%) 1 H NMR (400 MHz, MeOD) δ 8.62 (d, J = 5.3 Hz, 2H), 8.45 (s, 1H), 7.89(d, J = 5.4 Hz, 2H), 6.69 (s, 1H), 4.73 (s, 2H). Step 4) Synthesis of methyl 3-nitro-4-(((1-(pyridin-4-yl)-1H-pyrazol-3-yl)methyl)thio)benzoate Dissolve 4-(3-(chloromethyl)-lH-pyrazol-l-yl)pyridine (0.091 g, 0.47 mmol, 1 eq) in DMF (5 ml, 0.1 M), to this add K2CO3(0.13 g, 0.94 mmol, 2 eq) followed by slow addition of 4-mercapto-3-nitrobenzoic acid methyl ester (0.1 g, 0.47 mmol, 1 eq) dissolved in DMF (5 ml, 0.1 M) and stir at room temperature overnight. After completion of the reaction, add water to it, filter the solid obtained and dry to get the product as crude. (0.09 g, 52%) 1 H NMR (400 MHz, MeOD) δ 8.77 (s, 1H), 8.60 (d, J = 5.3 Hz, 2H), 8.42(s, 1H), 8.21 (d, J = 8.6 Hz, 1H), 7.98 (d, J = 8.6 Hz, 1H), 7.87 (d, J = 5.5 Hz,2H), 6.67 (s, 1H), 4.49 (s, 2H), 3.96 (s, 3H). Step 5) Synthesis of 3-nitro-4-(((l-(pyridin-4-yl)-lH-pyrazol-3- yl)methyl)sulfonyl)benzoic acid methyl ester Dissolve 3-nitro-4-(((l-(pyridin-4-yl)-lH-pyrazol-3-yl)methyl)sulfanyl)benzoic acid methyl ester (0.61 g, 1.65 mmol, 1 eq) in MC (8 ml, 0.2 M), to this add mCPBA (2.8 g, 16.46 mmol, 10 eq) and stir overnight. After completion of the reaction, add saturated aqueous NaHC03solution and extract with MC. Dry the organic layer over MgS04, filter and concentrate to get the product as crude. (0.685 g, 100%) 1 H NMR (400 MHz, MeOD) δ 8.50 (s, 1H), 8.43 (s, 1H), 8.36 (d, J = 6.5Hz, 2H), 8.28 (d, J = 7.9 Hz, 1H), 7.99 (s, 1H), 7.95 (d, J = 7.9 Hz, 2H), 7.86(d, J= 7.8 Hz, 1H), 7.47 (t, J = 7.9 Hz, 1H), 6.72 (s,1H), 5.11 (s, 2H), 4.00 (s, 3H). J = 7.9 Hz, 1H), 6.72 (s,1H), 5.11 (s, 2H), 4.00 (s, 3H). Step 6) Synthesis of methyl 3-amino-4-(((1-(pyridin-4-yl)-1H-pyrazol-3- yl)methyl)sulfonyl)benzoate Methyl 3-nitro-4-(((1-(pyridin-4-yl)-1H-pyrazol-3-yl)methyl)sulfonyl)benzoate (0.385 g, 0.96 mmol, 1 eq) was dissolved in ethanol (EtOH): water (H2O) (10 ml, 4:1 (v:v), 0.1 M) to which iron powder (0.27 g, 4.78 mmol, 5 eq) and NH4CI (0.26 g, 4.78 mmol, 5 eq) were added and stirred under reflux for one hour. After cooling to room temperature, the resulting product was filtered through celite, water was added to the filtrate and extracted with EA. The organic layer was dried over MgS04, filtered, concentrated and purified by column chromatography (silica gel, EA / HX). (0.085 g, 24%) 1 H NMR (400 MHz, MeOD) δ 8.55 (d, J = 4.9 Hz, 2H), 8.38 (s, 1H), 7.71(d, J = 5.1 Hz, 2H), 7.51 (s, 1H), 7.46 (d, J = 8.2 Hz, 1H), 7.16 (d, J = 8.2 Hz,1H), 6.53 (s, 1H), 4.68 (s, 2H), 3.90 (s, 3H). Step 7) Synthesis of methyl 3-iodo-4-(((1-(pyridin-4-yl)-1H-pyrazol-3- yl)methyl)sulfonyl)benzoate Methyl 3-amino-4-(((l-(pyridin-4-yl)-lH-pyrazol-3-yl)methyl)sulfonyl)benzoate (0.159 g, 0.427 mmol, 1 eq) was dissolved in ACN (4 ml, 0.1 M) to which pTSA (0.22 g, 1.28 mmol, 3 eq) was added followed by sodium nitrite (NaNO2, 0.03 g, 0.436 mmol, 1.02 eq) dissolved in 0.4 ml water and potassium iodide (0.142 g, 0.854 mmol, 2 eq) dissolved in 0.8 ml water at 0 °C. After one hour of reaction at room temperature, saturated aqueous NaHCO3solution was added to neutralize to pH 8 or higher followed by extraction with EA. The organic layer was dried over MgSO4, filtered and concentrated to give the resulting product as a crude (0.2 g, 100%) 1 H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 8.61 (d, J = 4.9 Hz, 2H), 8.00(s, 2H), 7.92 (s, 1H), 7.43 (d, J = 4.9 Hz, 2H), 6.55 (s, 1H), 4.88 (s, 2H),3.95 (s, 3H). Step 8) Synthesis of Ethyl 3-((4-fluorophenyl)ethynyl)-4-(((l-(pyridin-4-yl)-lH- pyrazol-3-yl)methyl)sulfonyl)benzoate Methyl 3-iodo-4-(((l-(pyridin-4-yl)-lH-pyrazol-3-yl)methyl)sulfonyl)benzoate (0.2 g, 0.414 mmol, 1 eq) was dissolved in ACN (4 ml, 0.1 M) to which TEA (0.13 ml, 0.92 mmol, 2.2 eq), PdCl2(PPh3)2(8.7 mg, 0.012 mmol, 3 mol %) and Cul (3.2 mg, 0.017 mmol, 4 mol %) were added and stirred at room temperature for five minutes. To this, 1-ethynyl-4-fluorobenzene (0.071 ml, 0.62 mmol, 1.5 eq) was added and stirred at 90 °C for one hour. After cooling to room temperature, the resulting product was purified by column chromatography (silica gel, EA / HX).(0.104 g, 51.5%) 1H NMR (400 MHz, CDC13) δ 8.61 (s, 2H), 8.38 (s, 1H), 8.01 (s, 2H), 7.91 (s, 1H), 7.73 - 7.65 (m, 3H), 7.43 (s, 2H), 7.11 (t, J = 8.2 Hz, 2H), 6.55(s, 1H), 4.89 (s, 2H), 3.98 (s, 3H). Step 9) Synthesis of 3-((4-fluorophenyl)ethynyl)-4-(((1-(pyridin-4-yl)-1H-pyrazol-3- yl)methyl)sulfonyl)benzoic acid Ethyl 3-((4-fluorophenyl)ethynyl)-4-(((1-(pyridin-4-yl)-1H-pyrazol-3- yl)methyl)sulfonyl)benzoate (0.104 g, 0.212 mmol, 1 eq) was dissolved in EtOH (4 ml, 0.05 M), then NaOH (0.042 g, 1.062 mmol, 5 eq) dissolved in H2O (0.4 ml) was added thereto, and stirred under reflux for one hour. After cooling to room temperature, the resulting product was concentrated and diluted with water. After adjusting to pH = 5 to 6 with 1 N HC1, the resulting solid was filtered, washed with water and dried. (0.039 g, 40%) Step 10) Synthesis of N-(3-(1H-pyrazol-4-yl)propyl)-3-((4-fluorophenyl)ethynyl)-4- (((1-(pyridin-4-yl)-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide 3-((4-Fluorophenyl)ethynyl)-4-(((1-(pyridin-4-yl)-1H-pyrazol-3- yl)methyl)sulfonyl)benzoic acid (0.039 g, 0.08 mmol, 1 eq) was dissolved in MC, then TBTU (0.039 g, 0.12 mmol, 1.5 eq), TEA (0.025 ml, 0.176 mmol, 2.2 eq), and 3-(1H-pyrazol-4-yl)propan-1-amine dihydrochloride (0.0174 g, 0.088 mmol, 1.1 eq) were added thereto, and stirred at room temperature overnight. After the reaction was completed, saturated aqueous NaHCO3 solution was added, neutralized and extracted with MC. The organic layer was dried with MgSO4, filtered, concentrated, and purified by column chromatography (silica gel, MeOH / MC). (16.2 mg, 35.6%) 1 H NMR (400 MHz, MeOD) δ 8.53 (d,J = 5.2 Hz, 2H), 8.35 (s, 1H), 8.21(s, 1H), 7.98 (d, J = 8.3 Hz, 1H), 7.86 (d, J = 8.3 Hz, 1H), 7.77 – 7.70 (m, 2H),7.64 (d, J = 5.3 Hz, 2H), 7.49 (s, 2H), 7.21 (t, J = 8.2 Hz, 2H), 6.57 (s, 1H),4.99 (s, 2H), 3.45 (t, J = 7.2 Hz, 2H), 2.62 (t, J = 7.2 Hz, 2H), 1.93 (p, J = 6.8Hz, 2H)。MS(ESI) m / e MH + 569.2.

[0160] The reagents can be changed in essentially the same way as the method of Example 11 to synthesize compounds 15, 16, 17 and 25.

[0161] Example 12: Synthesis of Compound 245 (hydrochloride salt of Compound 47) Synthesis of N-(3-(1H-pyrazol-4-yl)propyl)-4-(((1-methyl-1H-pyrazol-3- yl)methyl)sulfonyl)-3-((4-(piperidin-4-yl)phenyl)ethynyl)benzamide hydrochloride Scheme 10: (a) trimethylsilyl acetylene, PdCl2[PPh3]2, CuI, TEA, toluene, 100 °C, 12 h; (b) K2CO3, MeOH, r.t. 1 h; (c) PdCl2[PPh3]2, CuI, TEA, ACN, reflux, 12 h; (d) NaOH, H2O, MeOH, 55 °C; 2 h; (e) (1H-pyrazol-4-yl)propan-1-amine dihydrochloride, TBTU, TEA, DCM, r.t. 12 h; (f) 4 N HC1 in dioxane, 1,4-dioxane, r.t. 12 h Step 1) Synthesis of tert-butyl 4-(4-((trimethylsilyl)ethynyl)phenyl)piperidine-1- carboxylate tert-Butyl 4-(4-ethynylphenyl)piperidine-l-carboxylate (0.31 g, 0.87 mmol, 1 eq) was dissolved in methanol (0.2 M), to which K2CO3(0.6 g, 4.33 mmol, 5 eq) was added and stirred at room temperature for one hour. After completion of the reaction, the resulting mixture was filtered, concentrated and purified by column chromatography (silica gel, 10% EA / HX) to obtain the target compound (0.266 g).

[0162] Step 2) Synthesis of tert-Butyl 4-(4-ethynylphenyl)piperidine-l-carboxylate tert-Butyl 4-(4-ethynylphenyl)piperidine-l-carboxylate (0.31 g, 0.87 mmol, 1 eq) was dissolved in methanol (0.2 M), to which K2CO3(0.6 g, 4.33 mmol, 5 eq) was added and stirred at room temperature for one hour. After completion of the reaction, the resulting mixture was filtered, concentrated and purified by column chromatography (silica gel, 10% EA / HX) to obtain the target compound (0.266 g).

[0163] Step 3) Synthesis of tert-Butyl 4-(4-((5-(methoxycarbonyl)-2-(((l-methyl-lH- pyrazol-3-yl)methyl)sulfonyl)phenyl)ethynyl)phenyl)piperidine-l-carboxylate To methyl 3-iodo-4-(((l-methyl-lH-pyrazol-3-yl)methyl)sulfonyl)benzoate (0.1 g, 0.24 mmol, 1 eq) was added MeCN (2 ml, 0.1 M) and to this was added TEA (0.074 ml, 0.53 mmol, 2.2 eq). To the reaction product was added PdCl2[PPh3]2(5 mg, 3 mol%) and CuI (2 mg, 4 mol%) and stirred at room temperature for five minutes under a nitrogen atmosphere. Subsequently, tert-butyl 4-(4-ethynylphenyl)piperidine-l-carboxylate (0.1 g, 1.5 eq) was added. The reaction mixture was stirred at 90 °C for 12 hours and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, 40-50% EA / HX) to obtain the target compound (0.1 g).

[0164] 1H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 1.1 Hz, 1H), 7.97 (dd, J = 11.4,4.8 Hz, 3H), 7.63 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 2.0 Hz, 2H), 6.13 (d, J = 2.1Hz, 1H), 4.81 (s, 2H), 4.26 (s, 2H), 3.98 (s, 3H), 3.76 (s, 3H), 2.81 (t, J =12.2 Hz, 2H), 2.69 (t, J = 12.2 Hz, 1H), 1.83 (d, J = 13.0 Hz, 2H), 1.65 (d, J =12.4 Hz, 2H), 1.49 (s, 9H). Step 4) Synthesis of 3-((4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)ethynyl)-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzoic acid To tert-butyl 4-(4-((5-(methoxycarbonyl)-2-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)phenyl)ethynyl)phenyl)piperidine-1-carboxylate (0.1 g, 0.173 mmol, 1 eq) was added ethanol (3 ml, 0.05 M), H2O (0.5 ml) and NaOH (0.035 g, 0.87 mmol, 5 eq) and stirred at 100 °C for one hour. When the completion of the reaction was confirmed by TLC, the pH of the reaction product was adjusted to 1 with 1 N aqueous HC1 and extracted with EA. The organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to obtain the target compound (0.082 g, 84%).

[0165] Step 5) Synthesis of tert-butyl 4-(4-((5-((3-(1H-pyrazol-4-yl)propyl)carbamoyl)-2-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)phenyl)ethynyl)phenyl)piperidine-1-carboxylate To 3-((4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)ethynyl)-4-(((1-methyl-1H- pyrazol-3-yl)methyl)sulfonyl)benzoic acid (0.082 g, 0.145 mmol, 1 eq) was added DCM (2 ml), TBTU (0.071 g, 0.22 mmol, 1.5 eq), TEA (0.045 ml, 0.32 mmol, 2.2 eq) and 3-(1H-pyrazol-4-yl)propan-1-amine dihydrochloride (32 mg, 0.16 mmol, 1.1 eq) and stirred for two hours. To the reaction product was added water and extracted with EA. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure, the resulting residue was purified by column chromatography (silica gel, 100% EA) to give the target compound (0.02 g, 21%).

[0166] Step 6) Synthesis of N-(3-(1H-pyrazol-4-yl)propyl)-4-(((1-methyl-1H-pyrazol-3- yl)methyl)sulfonyl)-3-((4-(piperidin-4-yl)phenyl)ethynyl)benzamide hydrochloride tert-Butyl 4-(4-((5-((3-(1H-pyrazol-4-yl)propyl)carbamoyl)-2-(((1-methyl-1H-pyrazol-3- yl)methyl)sulfonyl)phenyl)ethynyl)phenyl)piperidine-1-carboxylate (0.02 g, 0.03 mmol, 1 eq) was dissolved in 1,4-dioxane (1 ml, 0.03 M), then to this was added 4 N HC1 in 1,4-dioxane (0.015 ml, 0.06 mmol, 2 eq) and stirred at room temperature for 12 hours. After completion of the reaction, the resulting solid was filtered and washed with 1,4-dioxane to give the target compound (0.0066 g, 39%).

[0167] 1 H NMR (400 MHz, MeOD) δ 8.20 (s, 3H), 7.96 - 7.86 (m, 3H), 7.70 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 1.9 Hz, 1H), 7.42 (d, J = 8.1 Hz, 2H), 6.18 (d, J = 2.0Hz, 1H), 4.86 (s, 2H), 3.74 (s, 3H), 3.55 (d, J= 12.5 Hz, 2H), 3.51 – 3.44 (m,3H), 3.19 (t, J = 12.6 Hz, 2H), 3.09 – 2.98 (m, 2H), 2.73 (dd, J = 14.4, 7.3 Hz,3H), 2.14 (d, J = 14.3 Hz, 2H), 2.02 – 1.97 (m, 3H). The reagents can be changed in essentially the same manner as in Example 12 to synthesize compounds 83, 84, 85, 86, 87, 88, 89, 90, 91, 105, and 249.

[0168] Example 13: Synthesis of 4-ethynyl-N-(2-(piperidin-1-yl)ethyl)benzamide To 4-ethynylbenzoic acid (2.0 g, 13.7 mmol, 1 eq) was added DMF (20 ml), HATU (07.8 g, 20.5 mmol, 1.5 eq), DIPEA (7 ml, 41.1 mmol, 3) and 2-(piperidin-l-yl)ethan-l-amine (2.7 ml, 15.4 mmol, 1.1 eq) and stirred for 12 hours. To the reaction product was added water, the organic layer was extracted with EA three times, washed with aqueous NH4CI solution, dried over magnesium sulfate, and then concentrated under reduced pressure to obtain the resulting residue, which was purified by column chromatography (silica gel, 10% MeOH / DCM) to obtain the target compound.

[0169] 1 H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 7.9 Hz, 2H), 7.58 (d, J = 7.8 Hz,2H), 7.39 (s, 1H), 3.68 (m, 2H), 3.23 (s, 1H), 2.89-2.99 (m, 6H), 1.80 (m,4H), 1.62 (s, 2H). Example 14: Synthesis of Compound 115 Synthesis of 3-((4-fluorophenyl)ethynyl)-N-((imidazo[l,2-a]pyridin-7-yl)methyl)-4-(N-((l- methyl- lH-pyrazol-3-yl)methyl)sulfamoyl)benzamide Reagents and conditions: (a) NCS, 2 N HC1 (aq), ACN, 0 °C to rt (0 °C-rt), overnight; (b) ACN, 4 h, rt (rt); (c) Zn, NH4CI, 1,4-dioxane, H2O, rt (rt), overnight; (d) NaNO2, KI, HC1, H2O, 0 °C to rt (0 °C-rt), 2 h; (e) PdCl2(PPh3)2, CuI, TEA, ACN, 60 °C, 4 h; (f) 1 N NaOH, EtOH, 60 °C, overnight; (g) 1 -{imidazo[1,2-a]pyridin-7-yl}methanamine dihydrochloride, TBTU, TEA, DCM, rt (rt), overnight.

[0170] Step 1) Synthesis of methyl 4-(chlorosulfonyl)-3-nitrobenzoate To ACN (46 ml, 0.1 M) was added NCS (3.131 g, 23.45 mmol, 5 eq) and 2 N HC1 aqueous solution (4.69 ml, 9.38 mmol, 2 eq) and stirred at 0 °C for 30 min. To this was added methyl 4-mercapto-3-nitrobenzoate (1 g, 4.69 mmol, 1 eq) and stirred at rt overnight. After completion of the reaction, the resulting mixture was concentrated, the resulting concentrate was diluted with EA and then extracted with NaHC03aqueous solution and NaCI aqueous solution successively. The organic layer was dried over MgS04, filtered and concentrated to get the target compound as crude.

[0171] Step 2) Synthesis of methyl 4-(N-((1-methyl-1H-pyrazol-3-yl)methyl)sulfamoyl)-3- nitrobenzoate (1-methyl-1H-pyrazol-3-yl)methanamine (1.042 g, 9.38 mmol, 2 eq) was dissolved in ACN (20 ml, 0.23 M) and methyl 4-(chlorosulfonyl)-3-nitrobenzoate (1.311 g, 4.69 mmol, 1 eq) dissolved in ACN (26 ml, 0.18 M) was added dropwise to the reaction solution. After completion of the reaction, the resulting mixture was extracted with EA and water. The organic layer was dried over MgS04, filtered, concentrated and purified by column chromatography (silica gel, EA / HEX) to get the target compound (0.3 g, 18.4%).

[0172] Step 3) Synthesis of methyl 3-amino-4-(N-((1-methyl-1H-pyrazol-3-yl)methyl)sulfamoyl)benzoate Methyl 4-(N-((l-methyl-lH-pyrazol-3-yl)methyl)sulfamoyl)-3-nitrobenzoate (0.296 g, 0.835 mmol, 1 eq) was dissolved in 1,4-dioxane:H2O (3:1 (v / v)) (8.3 ml, 0.1 M), then to which was added Zn (0.546 g, 8.35 mmol, 10 eq) and NH4CI (0.447 g, 8.35 mmol, 10 eq) and stirred at room temperature overnight. The resulting mixture was washed with MeOH, filtered under reduced pressure and concentrated to give the target compound as a crude product.

[0173] Step 4) Synthesis of methyl 3-iodo-4-(N-((l-methyl-lH-pyrazol-3-yl)methyl)sulfamoyl)benzoate Methyl 3-amino-4-(N-((l-methyl-lH-pyrazol-3-yl)methyl)sulfamoyl)benzoate (0.255 g, 0.79 mmol, 1 eq) and HC1 (7 ml, 0.1 M) were dissolved in H2O (7 ml, 0.1 M) and stirred at 0 °C. To this was added dropwise NaNC (0.082 g, 1.185 mmol, 1.5 eq) dissolved in H2O (7 ml, 0.1 M). The reaction solution was stirred at 0 °C for 30 minutes, then to which was added dropwise KI (0.393 g, 2.37 mmol, 3 eq) dissolved in H2O (7 ml, 0.1 M). The reaction solution was stirred at room temperature for two hours, neutralized to pH 8 or higher with aqueous NaHC03solution, then extracted with EA and water. The organic layer was dried with MgS04, filtered, concentrated and purified by column chromatography (silica gel, EA / HEX) to give the target compound (0.167 g, 48.6%).

[0174] Step 5) Synthesis of methyl 3-((4-fluorophenyl)ethynyl)-4-(N-((l-methyl-lH-pyrazol-3- yl)methyl)sulfamoyl)benzoate Methyl 3-iodo-4-(N-((l-methyl-lH-pyrazol-3-yl)methyl)sulfamoyl)benzoate (0.167 g, 0.38 mmol, 1 eq) was dissolved in ACN (7.6 ml, 0.05 M), then 1-ethynyl-4-fluorobenzene (0.068 g, 0.57 mmol, 1.5 eq), PdCl2(PPh3)2(0.008 g, 0.01 mmol, 0.03 eq), CuI (0.002 g, 0.01 mmol, 0.03 eq) and TEA (0.077 g, 0.76 mmol, 2 eq) were added thereto and degassed with nitrogen (N2). The reaction solution was heated to 60°C and stirred for four hours. After the completion of the reaction, the resulting mixture was filtered through celite and extracted with EA. The organic layer was washed with water, separated, dried over MgS04, filtered and concentrated to obtain the target compound as a crude product.

[0175] Step 6) Synthesis of 3-((4-fluorophenyl)ethynyl)-4-(N-((l-methyl-lH-pyrazol-3- yl)methyl)sulfamoyl)benzoic acid To methyl 3-((4-fluorophenyl)ethynyl)-4-(N-((l-methyl-lH-pyrazol-3- yl)methyl)sulfamoyl)benzoate (0.187 g, 0.438 mmol, 1 eq), EtOH (8 ml, 0.05 M), H20 (4.38 ml, 0.1 M) and NaOH (0.175 g, 4.38 mmol, 10 eq) were added and stirred at 60°C overnight. After the completion of the reaction, the pH of the reaction product was adjusted to 1 with 1 N aqueous HC1 solution and extracted with EA. The organic layer was washed with water, separated, dried over MgS04, filtered and concentrated to obtain the target compound as a crude product.

[0176] Step 7) Synthesis of 3-((4-fluorophenyl)ethynyl)-N-((imidazo[l,2-a]pyridin-7- yl)methyl)-4-(N-((l-methyl-lH-pyrazol-3-yl)methyl)sulfamoyl)benzamide To 3-((4-fluorophenyl)ethynyl)-4-(N-((1-methyl-1H-pyrazol-3- yl)methyl)sulfamoyl)benzoic acid (0.131 g, 0.32 mmol, 1 eq) was added DCM (3.2 ml, 0.1 M) and TBTU (0.154 g, 0.48 mmol, 1.5 eq) and stirred at room temperature for 30 minutes. Subsequently, to the reaction product was added TEA (0.070 g, 0.7 mmol, 2.2 eq) and 1-{imidazo[1,2-a]pyridin-7-yl}methanamine dihydrochloride (0.077 g, 0.352 mmol, 1.1 eq) and stirred for 12 hours. To the reaction product was added water and extracted with DCM. The organic layer was dried over MgS04, filtered, concentrated and then purified by column chromatography (silica gel, MeOH / DCM) to give the title compound (0.03 g, 17.3%).

[0177] 1 H NMR (400 MHz, DMSO) δ 9.36 (s, 1H), 8.54 (s, 1H), 8.51 (d, J = 6.9Hz, 1H), 8.12 (dd, J = 19.3, 8.1 Hz, 2H), 7.90 (s, 1H), 7.55 (dd, J = 8.3,5.7 Hz, 3H), 7.47 (s, 1H), 7.42 (d, J = 1.8 Hz, 1H), 7.24 (t, J = 8.8 Hz,2H), 7.10 (s, 1H), 6.89 (d, J = 6.2 Hz, 1H), 5.81 (d, J = 1.9 Hz, 1H), 4.57(s, 2H), 3.62 (s, 3H). MS MH + 543.6.

[0178] Example 15: Synthesis of Compound 193 Synthesis of N-((imidazo[1,2-a]pyridin-7-yl)methyl)-4-(((1 -methyl-1 H-pyrazol-3- yl)methyl)sulfamoyl)-3-((4-((2-(piperazin-1 -yl)ethyl)carbamoyl)phenyl)ethynyl)benzamide Reagents and conditions: (a) PdCl2(PPh3)2, Cul, TEA, ACN, 60 °C, 1 h; (b) 1 N NaOH, EtOH, 60 °C, 1 h; (c) TBTU, TEA, DCM, rt, overnight; (d) TFA, DCM, rt, overnight Step 1) Synthesis of tert-butyl 4-(2-(4-((5-(methoxycarbonyl)-2-(((1-methyl-1H- pyrazol-3-yl)methyl)sulfonyl)phenyl)ethynyl)benzamido)ethyl)piperazine-1-carboxylate Methyl 3-iodo-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzoate (0.26 g, 0.52 mmol, 1 eq) was dissolved in ACN (3 ml, 0.2 M), to which tert-butyl 4-(2-(4-ethynylbenzamido)ethyl)piperazine-1-carboxylate (0.336 g, 0.84 mmol, 1.5 eq), PdCl2(PPh3)2 (0.013 g, 0.0186 mmol, 0.03 eq), Cul (0.0035 g, 0.0186 mmol, 0.03 eq) and TEA (0.125 g, 1.24 mmol, 2 eq) were added and degassed with nitrogen (N2). The reaction solution was heated to 60 °C and stirred for one hour. After completion of the reaction, the resulting mixture was filtered through celite and extracted with EA. The organic layer was washed with water, separated, dried over MgSO4, filtered and concentrated to get the target compound as a crude product.

[0179] Step 2) Synthesis of 3-((4-((2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)carbamoyl)phenyl)ethynyl)-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzoic acid To tert-butyl 4-(2-(4-((5-(methoxycarbonyl)-2-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)phenyl)ethynyl)benzamido)ethyl)piperazine-1-carboxylate (0.403 g, 0.62 mmol, 1 eq) was added EtOH (12 ml, 0.05 M), H2O (3.1 ml, 0.2 M) and NaOH (0.120 g, 3.1 mmol, 5 eq) and stirred at 60 °C for one hour. When the completion of the reaction was confirmed by TLC, the pH of the reaction product was adjusted to 1 with 1 N aqueous HC1 and extracted with EA. The organic layer was washed with water, separated, dried over MgSO4, filtered and concentrated to get the target compound as a crude product.

[0180] Step 3) Synthesis of tert-butyl 4-(2-(4-((5-(((imidazo[l,2-a]pyridin-7- yl)methyl)carbamoyl)-2-(((l-methyl-lH-pyrazol-3-yl)methyl)sulfonyl)phenyl)ethynyl) benzamido)ethyl)piperazine-l-carboxylate To 3-((4-((2-(4-(tert-butoxycarbonyl)piperazin-l-yl)ethyl)carbamoyl)phenyl)ethynyl)- 4-(((l-methyl-lH-pyrazol-3-yl)methyl)sulfonyl)benzoic acid (0.394 g, 0.62 mmol, 1 eq) was added DCM (3 ml, 0.2 M) and TBTU (0.298 g, 0.93 mmol, 1.5 eq) and stirred at room temperature for 50 min. Subsequently, to the reaction product was added TEA (0.137 g, 1.36 mmol, 2.2 eq) and l-{imidazo[l,2-a]pyridin-7-yl}methanamine dihydrochloride (0.150 g, 0.682 mmol, 1.1 eq) and stirred for 12 h. To the reaction product was added water and extracted with DCM. The organic layer was dried over MgS04, filtered, concentrated and then purified by column chromatography (silica gel, MeOH / DCM) to afford the title compound (0.27 g, 56.4%).

[0181] Step 4) Synthesis of N-(imidazo[l,2-a]pyridin-7-ylmethyl)-4-(((l-methyl-lH- pyrazol-3-yl)methyl)sulfonyl)-3-((4-((2-(piperazin-l-yl)ethyl)carbamoyl)phenyl)ethynyl) benzamide Tert-butyl 4-(2-(4-((5-(((imidazo[l,2-a]pyridin-7-yl)methyl)carbamoyl)-2-(((l- methyl- 1H-pyrazol-3-yl)methyl)sulfonyl)phenyl)ethynyl)benzamido)ethyl)piperazine-l- carboxylate (0.150 g, 0.196 mmol, 1 eq) was dissolved in DCM (2 ml, 0.1 M) and to this was added TFA (0.223 g, 1.96 mmol, 10 eq) and stirred at room temperature overnight. After completion of the reaction, the resulting mixture was concentrated and purified by reverse phase column chromatography (0.1% formic acid in H20 / ACN) to afford the title compound (0.067 g, 51.5%).

[0182] 1H NMR (400 MHz, MeOD) δ 8.51 (s, 1H), 8.28 (s, 1H), 8.23 (s, 1H), 7.96 (s, 1H), 7.91 (d, J = 5.1 Hz, 3H), 7.78 (d, J = 7.5 Hz, 2H), 7.66 (s, 1H), 7.59 (s, 1H), 7.44 (s, 1H), 7.10 (d, J = 6.7 Hz, 1H), 6.17 (s, 1H), 4.85 - 4.83 (m, 2H), 4.70 (s, 2H), 3.72 (s, 3H), 3.57 (s, 3H), 3.50 (s, 1H), 3.22 (s, 2H), 2.79 (s, 2H), 2.75 - 2.57 (m, 4H). MS MH + 665.58.

[0183] The reagents can be varied in essentially the same manner as in Example 15 to synthesize compounds 119, 131, 133, 134, and 136.

[0184] Example 16: Synthesis of Compound 228 Synthesis of 3-((4-aminophenyl)ethynyl)-N-((imidazo[l,2-a]pyridin-7-yl)methyl)-4-(((l- methyl-lH-pyrazol-3-yl)methyl)sulfonyl)benzamide Reagents and conditions: 4-ethynylaniline, TEA, Cul, PdCl2(PPh3)2, ACN, reflux, one hour (1 h); N-((Imidazo[l,2-a]pyridin-7-yl)methyl)-3-iodo-4-(((l-methyl-lH-pyrazol-3- yl)methyl)sulfonyl)benzamide (0.535 g, 1 mmol, 1 eq) was dissolved in ACN (10 ml, 0.1 M) and to this was added TEA (0.3 ml, 2.2 mmol, 2.2 eq), PdCl2(PPh3)2 (21 mg, 0.03 mmol, 3 mol %) and Cul (8 mg, 0.04 mmol, 4 mol %) and stirred at room temperature for five minutes. 4-Ethynylaniline (0.14 g, 1.2 mmol, 1.5 eq) was added and stirred at 90 °C for one hour. After cooling to room temperature, the resulting product was concentrated and purified by column chromatography (silica gel, EA / HX). (0.193 g, 37%) 1 H NMR (400 MHz, CD3OD) δ 8.41 (d, J = 7.0 Hz, 1H), 8.16 – 8.12 (m, 1H),7.87 (d, J = 8.3 Hz, 1H), 7.84 – 7.79 (m, 2H), 7.53 (s, 1H), 7.48 (s, 1H), 7.44– 7.37 (m, 3H), 6.95 (dd, J = 7.1, 1.5 Hz, 1H), 6.69 (d, J = 8.7 Hz, 2H), 6.12(d, J = 2.2 Hz, 1H), 4.85 (s, 2H), 4.64 (s, 2H), 3.72 (s, 3H). The reagents can be varied in essentially the same manner as in Example 16 to synthesize compound 105.

[0185] Example 17: Synthesis of Compound 229 Synthesis of 3-((3-aminophenyl)ethynyl)-N-((imidazo[l,2-a]pyridin-7-yl)methyl)-4-(((l- methyl- lH-pyrazol-3-yl)methyl)sulfonyl)benzamide Reagents and conditions: (a) 3-ethynylphenylamine, PdCl2(PPh3)2, Cul, TEA, ACN, 60 °C, four hours (4 h) N-((imidazo[l,2-a]pyridin-7-yl)methyl)-3-iodo-4-(((l-methyl-lH-pyrazol-3- yl)methyl)sulfonyl)benzamide (0.050 g, 0.093 mmol, 1 eq) was dissolved in ACN (1 ml, 0.1 M), then to this was added 3-ethynylaniline (0.016 g, 0.139 mmol, 1.5 eq), PdCl2(PPh3)2(0.006 g, 0.01 mmol, 0.1 eq), Cul (0.002 g, 0.01 mmol, 0.1 eq) and TEA (0.037 g, 0.37 mmol, 4 eq) and degassed with nitrogen (N2). The reaction solution was heated to 60 °C and stirred for four hours. After completion of the reaction, the resulting mixture was filtered through celite and extracted with EA. The organic layer was washed with water, separated, dried over MgS04, filtered, concentrated and purified by column chromatography (silica gel, MeOH / DCM) to get the title compound (0.002 g, 4%).

[0186] 1 H NMR (400 MHz, MeOD) δ 8.43 (d, J = 7.0 Hz, 1H), 8.23 (s, 1H), 7.92(d, J = 0.7 Hz, 2H), 7.82 (s, 1H), 7.56 (s, 1H), 7.51 (s, 1H), 7.44 (d, J =2.2 Hz, 1H), 7.17 (t, J = 7.8 Hz, 1H), 7.02 (d, J = 1.8 Hz, 1H), 6.98 (dd, J= 11.8, 4.6 Hz, 2H), 6.81 (dd, J = 8.1, 1.5 Hz, 1H), 6.15 (d, J = 2.2 Hz,1H), 4.67 (s, 2H), 3.74 (s, 3H). The reagents can be changed in essentially the same manner as in Example 17 to synthesize compounds 102, 103, 104, 106, 107, 108, 109, 110, 153, 154, 155, 156, 193, 224 and 226.

[0187] Example 18: Synthesis of Compound 230 Synthesis of N-((imidazo[l,2-a]pyridin-7-yl)methyl)-4-(((l-methyl-lH-pyrazol-3- yl)methyl)sulfonyl)-3-((3-(piperazin-l-ylcarbonyl)phenyl)ethynyl)benzamide Reagents and conditions: (a) N-Boc-piperazine, EDC*HCI, HOBt, TEA, DCM, rt, overnight; (b) PdCl2(PPh3)2, CuI, TEA, ACN, reflux, 1 h; (c) TFA, DCM, rt, 3 h. Step 1) Synthesis of tert-butyl 4-(3-ethynylbenzoyl)piperazine-1-carboxylate To DCM (13 ml, 0.1 M) was added 3-ethynylbenzoic acid (0.2 g, 1.37 mmol, 1 eq), EDC*HCI (0.393 g, 2.05 mmol, 1.5 eq) and HOBt (0.296 g, 2.192 mmol, 1.6 eq) and stirred at rt for 15 min. N-Boc-piperazine (0.331 g, 1.781 mmol, 1.3 eq) and TEA (0.416 g, 4.11 mmol, 3 eq) were added and stirred at rt overnight. After completion of the reaction, the reaction solution was concentrated under reduced pressure and purified by column chromatography (silica gel, EA / HEX) to give the desired compound (0.25 g, 58%).

[0188] Step 2) Synthesis of tert-butyl 4-(3-((5-(((imidazo[l,2-a]pyridin-7-yl)methyl)carbamoyl)-2-(((l- methyl- lH-pyrazol-3-yl)methyl)sulfonyl)phenyl)ethynyl)benzoyl)piperazine- 1-carboxylate N-((imidazo[l,2-a]pyridin-7-yl)methyl)-3-iodo-4-(((l-methyl-lH-pyrazol-3- yl)methyl)sulfonyl)benzamide (0.1 g, 0.19 mmol, 1 eq) was dissolved in ACN (1.9 ml, 0.1 M), to which was added 4-(3-ethynylbenzoyl)piperazine- 1 -carboxylic acid tert-butyl ester (0.089 g, 0.285 mmol, 1.5 eq), PdCl2(PPh3)2 (0.013 g, 0.02 mmol, 0.1 eq), CuI (0.004 g, 0.02 mmol, 0.1 eq) and TEA (0.077 g, 0.76 mmol, 4 eq) and degassed with nitrogen (N2). The reaction solution was stirred at reflux for one hour. Upon completion of the reaction, the resulting mixture was filtered through celite and extracted with EA. The organic layer was washed with water, separated, dried over MgS04, filtered, concentrated and purified by column chromatography (silica gel, MeOH / DCM) to give the target compound (0.052 g, 37.9%).

[0189] Step 3) Synthesis of N-((imidazo[l,2-a]pyridin-7-yl)methyl)-4-(((l-methyl- lH-pyrazol-3-yl)methyl)sulfonyl)-3-((3-(piperazine-l-carbonyl)phenyl)ethynyl)benzamide 4-(3-((5-(((imidazo[l,2-a]pyridin-7-yl)methyl)carbamoyl)-2-(((l-methyl- lH-pyrazol-3-yl)methyl)sulfonyl)phenyl)ethynyl)benzoyl)piperazine-l-carboxylic acid tert-butyl ester (0.050 g, 0.069 mmol, 1 eq) was dissolved in DCM (1 ml, 0.07 M) and to which was added TFA (0.079 g, 0.69 mmol, 10 eq) and stirred at room temperature overnight. Upon completion of the reaction, the resulting mixture was concentrated and purified by reverse phase column chromatography (0.1% formic acid in H20 / ACN) to give the title compound (0.013 g, 32.5%).

[0190] 1H NMR (400 MHz, DMSO) δ 9.45 (d, J = 5.5 Hz, 1H), 8.51 (d, J = 6.6 Hz, 1H), 8.34 (s, 1H), 8.16 (s, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.97 - 7.88 (m, 2H), 7.79 (d, J = 7.5 Hz, 1H), 7.75 (s, 1H), 7.60 (t, J = 7.4 Hz, 2H), 7.55 (d, J = 7.2 Hz, 2H), 7.46 (s, 1H), 6.89 (d, J = 6.9 Hz, 1H), 6.09 (s, 1H), 4.88 (s, 2H), 4.54 (d, J = 5.3 Hz, 2H), 3.70 (s, 3H), 3.43 (s, 4H), 2.96 (s, 4H). Example 19: Synthesis of Compound 231 Synthesis of N-((imidazo[l,2-a]pyridin-7-yl)methyl)-4-(((l-methyl-lH- pyrazol-3-yl)methyl)sulfonyl)-3-((l,2,3,4-tetrahydroisoquinolin-6- yl)ethynyl)benzamide Reagents and conditions: (a) (l-diazo-2-oxopropyl)dimethyl phosphonate, K2CO3, MeOH, rt, overnight; (b) PdCl2(PPh3)2, CuI, TEA, ACN, reflux, 1 h; (c) TFA, 4 N HC1 in 1,4-dioxane, DCM, rt, overnight.

[0191] Step 1) Synthesis of tert-butyl 6-ethynyl-3,4-dihydroisoquinoline-2(lH)- carboxylate tert-Butyl 6-formyl-3,4-dihydroisoquinoline-2(lH)-carboxylate (0.25 g, 0.96 mmol, 1 eq) was diluted in MeOH (4 ml, 0.24 M) and to this was added dimethyl (l-diazo-2-oxopropyl)phosphonate (0.221 g, 1.152 mmol, 1.2 eq) and K2CO3 (0.265 g, 1.92 mmol, 2 eq) and stirred at room temperature overnight. After completion of the reaction, the resulting mixture was extracted with DCM and water. The organic layer was washed with aqueous NaCl solution, separated, dried over MgS04, filtered and concentrated to get the target compound as crude.

[0192] Step 2) Synthesis of tert-butyl 6-((5-(((imidazo[l,2-a]pyridin-7-yl)methyl)carbamoyl)- 2-(((l-methyl-lH-pyrazol-3-yl)methyl)sulfonyl)phenyl)ethynyl)-3,4-dihydroisoquinoline- 2(lH)-carboxylate N-((imidazo[l,2-a]pyridin-7-yl)methyl)-3-iodo-4-(((l-methyl-lH-pyrazol-3- yl)methyl)sulfonyl)benzamide (0.1 g, 0.19 mmol, 1 eq) was dissolved in ACN (1.9 ml, 0.1 M) and to this was added tert-butyl 6-ethynyl-3,4-dihydroisoquinoline-2(lH)- carboxylate (0.072 g, 0.281 mmol, 1.5 eq), PdCl2(PPh3)2 (0.013 g, 0.02 mmol, 0.1 eq), Cul (0.004 g, 0.02 mmol, 0.1 eq) and TEA (0.076 g, 0.75 mmol, 4 eq) and degassed with nitrogen (N2). The reaction solution was stirred at reflux for one hour. After completion of the reaction, the resulting mixture was filtered through celite and extracted with EA. The organic layer was washed with water, separated, dried over MgS04, filtered, concentrated and purified by column chromatography (silica gel, MeOH / DCM) to get the target compound (0.046 g, 36.9%).

[0193] Step 3) Synthesis of N-((imidazo[l,2-a]pyridin-7-yl)methyl)-4-(((l-methyl-lH- pyrazol-3-yl)methyl)sulfonyl)-3-((l,2,3,4-tetrahydroisoquinolin-6-yl)ethynyl)benzamide tert-Butyl 6-((5-(((imidazo[l,2-a]pyridin-7-yl)methyl)carbamoyl)-2-(((l- methyl-lH-pyrazol-3-yl)methyl)sulfonyl)phenyl)ethynyl)-3,4-dihydroisoquinoline-2(lH)- carboxylate (0.046 g, 0.069 mmol, 1 eq) was dissolved in DCM (1 ml, 0.07 M) and to this was added TFA (0.079 g, 0.69 mmol, 10 eq) and stirred at room temperature overnight. The reaction product was concentrated and to this was added 4 N HC1 in 1,4-dioxane (0.34 ml, 1.38 mmol, 20 eq) and stirred at room temperature for three hours. After completion of the reaction, the reaction product was concentrated and purified by reverse phase column chromatography (0.1% formic acid in H20 / ACN) to get the title compound (0.013 g, 33%).

[0194] 1 H NMR (400 MHz, DMSO) δ 9.47 (s, 1H), 8.67 (s, 1H), 8.32 (s, 1H),8.05 (d, J = 8.0 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.61 (s, 1H), 7.52 (d, J= 13.1 Hz, 3H), 7.28 (s, 1H), 6.90 (d, J = 6.3 Hz, 1H), 6.10 (s, 1H), 4.90(s, 2H), 4.53 (s, 2H), 3.90 (s, 3H), 3.72 (s, 3H), 2.92 (s, 3H). Example 20: Synthesis of Compound 232 Synthesis of 3-((3-(aminomethyl)phenyl)ethynyl)-N-((imidazo[l,2-a]pyridin-7- yl)methyl)-4-(((l-methyl-lH-pyrazol-3-yl)methyl)sulfonyl)benzamide Reagents and conditions: (a) Boc20, DCM, 0 °C to room temperature (0 °C-rt), overnight; (b) PdCl2(PPh3)2, CuI, TEA, ACN, reflux, four hours (4 h); (c) 4 N HC1 in dioxane, room temperature (rt), overnight Step 1) Synthesis of tert-butyl (3-ethynylbenzyl)carbamate (3-ethynylphenyl)methanamine (0.1 g, 0.76 mmol, 1 eq) was diluted in DCM (1.4 ml, 0.5M) and di-tert-butyl dicarbonate (0.183 g, 0.84 mmol, 1.1 eq) was added at 0 °C, gradually warmed to room temperature and stirred overnight. After completion of the reaction, the resulting mixture was extracted with DCM and H2O. The organic layer was dried over MgSO4, filtered, concentrated and purified by column chromatography (silica gel, EA / HEX) to give the target compound (0.15 g, 85%).

[0195] Step 2) Synthesis of (3-((5-(((imidazo[l,2-a]pyridin-7-yl)methyl)carbamoyl)-2-(((l- methyl-lH-pyrazol-3-yl)methyl)sulfonyl)phenyl)ethynyl)benzyl)carbamate N-((imidazo[l,2-a]pyridin-7-yl)methyl)-3-iodo-4-(((l-methyl-lH-pyrazol-3- yl)methyl)sulfonyl)benzamide (0.2 g, 0.37 mmol, 1 eq) was dissolved in ACN (3.7 ml, 0.1 M) followed by the addition of tert-butyl (3-ethynylbenzyl)carbamate (0.128 g, 0.56 mmol, 1.5 eq), PdCl2(PPh3)2(0.007 g, 0.01 mmol, 0.03 eq), CuI (0.002 g, 0.01 mmol, 0.03 eq) and TEA (0.075 g, 0.74 mmol, 2 eq) and degassed with nitrogen (N2). The reaction solution was stirred at reflux for four hours. After completion of the reaction, the resulting mixture was filtered through celite and extracted with EA. The organic layer was washed with water, separated, dried over MgSO4, filtered, concentrated and purified by column chromatography (silica gel, MeOH / DCM) to give the target compound (0.15 g, 63.5%).

[0196] Step 3) Synthesis of 3-((3-(aminomethyl)phenyl)ethynyl)-N-((imidazo[l,2-a]pyridin-7- yl)methyl)-4-(((l-methyl-lH-pyrazol-3-yl)methyl)sulfonyl)benzamide Tert-butyl (3-((5-(((imidazo[l,2-a]pyridin-7-yl)methyl)carbamoyl)-2-(((l- methyl- lH-pyrazol-3-yl)methyl)sulfonyl)phenyl)ethynyl)benzyl)carbamate (0.05 g, 0.078 mmol, 1 eq) was dissolved in 1,4-dioxane (1 ml, 0.07 M) and to this was added 4 N HC1 in 1,4-dioxane (0.58 ml, 2.34 mmol, 30 eq) and stirred at room temperature overnight. After completion of the reaction, the reaction product was concentrated and purified by reverse phase column chromatography (0.1% formic acid in H20 / ACN). To the purified product was added 4 N HC1 in 1,4-dioxane (0.058 ml, 0.3 M) and stirred at room temperature overnight. The resulting solid was washed with diethyl ether and filtered under reduced pressure to give the title compound (0.017 g, 42.3%).

[0197] 1 H NMR (400 MHz, DMSO) δ 9.84 (t, J = 5.6 Hz, 1H), 8.88 (d, J = 6.9 Hz, 1H), 8.50 (s, 2H), 8.38 (d, J = 1.4 Hz, 1H), 8.34 (d, J = 1.6 Hz, 1H), 8.17 (d, J = 1.9 Hz, 1H), 8.09 (dd, J = 8.3, 1.5 Hz, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.87 (s, 1H), 7.82 (s, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.65 (d, J = 7.7 Hz, 1H), 7.61 - 7.55 (m, 2H), 7.52 (d, J = 7.0 Hz, 1H), 6.09 (d, J = 2.1 Hz, 1H), 4.91 (s, 2H), 4.71 (d, J = 5.5 Hz, 2H), 4.10 (d, J = 5.6 Hz, 2H), 3.70 (s, 3H); MS MH+ 537.05. Example 21 : Synthesis of Compound 233 Synthesis of 4-(((l-(4-aminophenyl)-lH-pyrazol-3-yl)methyl)sulfonyl)-3-((4- fluorophenyl)ethynyl)-N-(imidazo[l,2-a]pyridin-7-ylmethyl)benzamide Reagents and conditions: (a) 1-fluoro-4-nitrobenzene, K2CO3, DMF, rt, 16 h; (b) 1.0 M LiAlH4in THF, THF, 0 °C, 7 h; (c) SOCl2, MeOH, 0 °C → rt; (d) 3-iodo-4- mercaptomethyl benzoate, K2CO3, DMF, rt, 2 h; (e) mCPBA, MeOH, rt, overnight; (f) 1-ethynyl-4-fluorobenzene, TEA, CuI, PdCl2(PPh3)2, ACN, reflux, 1 h; (g) NaOH, EtOH, H2O, reflux, 1 h; (h) 1-{imidazo[l,2-a]pyridin-7- yl}methanamine hydrochloride, TBTU, TEA, MeOH, rt, 7 h, (i) Zn, NH4Cl, 1,4- dioxane, H2O, rt, 5 h Step 1) Synthesis of ethyl 1-(4-nitrophenyl)-lH-pyrazole-3-carboxylate Ethyl 1H-pyrazole-3-carboxylate (1.4 g, 10 mmol, 1 eq) was dissolved in DMF (100 ml, 0.1 M), then K2CO3(1.66 g, 12 mmol, 1.2 eq) and 1-fluoro-4-nitrobenzene (1.55 g, 11 mmol, 1.1 eq) were added and stirred at rt overnight. After the reaction was completed, water was added, the resulting solid was filtered and dried to obtain the crude product. (1.907 g, 73%) Step 2) Synthesis of (l-(4-nitrophenyl)-lH-pyrazol-3-yl)methanol Ethyl 1-(4-nitrophenyl)-lH-pyrazole-3-carboxylate (1.907 g, 7.36 mmol, 1 eq) was dissolved in anhydrous THF (73 ml, 0.1 M), then a solution of 1.0 M LiAlH4in THF (10.9 ml, 10.9 mmol, 1.5 eq) was slowly added dropwise at 0 °C and stirred for 7 h. After the reaction was completed, water and EA were added, the resulting solid was filtered and the filtrate was concentrated to obtain the crude product. (0.468 g) 1 H NMR (400 MHz, CDCl3) δ 8.40 – 8.33 (m, 2H), 8.03 (d, J= 2.6 Hz, 1H), 7.91 – 7.86 (m, 2H), 6.59 (d, J = 2.6 Hz, 1H), 4.84 (s, 2H). Step 3) Synthesis of 3-(chloromethyl)-1-(4-nitrophenyl)-1H-pyrazole (1-(4-nitrophenyl)-1H-pyrazol-3-yl)methanol (0.468 g, 2.135 mmol, 1 eq) was dissolved in DCM (11 ml, 0.2 M) and then SOCl2(0.46 ml, 6.41 mmol, 3 eq) was added slowly dropwise at 0 °C and refluxed overnight. After the reaction was completed, the resulting product was concentrated under reduced pressure to obtain the crude product. (0.432 g, 100%) 1 H NMR (400 MHz, CDCl3) δ 8.37 – 8.30 (m, 2H), 8.00 (d, J = 2.6 Hz, 1H), 7.87 (dd, J = 6.9, 5.0 Hz, 2H), 6.63 (d, J = 2.6 Hz, 1H), 4.68 (s, 2H). Step 4) Synthesis of methyl 3-iodo-4-(((1-(4-nitrophenyl)-1H-pyrazol-3- yl)methyl)thio)benzoate 3-(chloromethyl)-1-(4-nitrophenyl)-1H-pyrazole (0.15 g, 0.5 mmol, 1 eq) was dissolved in DMF (4ml, 0.1 M), K2CO3(0.116 g, 0.84 mmol, 2 eq) was added, then 3-iodo-4-mercaptobenzoic acid methyl ester (0.15 g, 0.5 mmol, 1.2 eq) dissolved in DMF (5 ml, 0.1M) was slowly added, and stirred at room temperature for two hours. After the reaction was completed, water was added, the resulting solid was filtered, dried, and then purified by column chromatography (silica gel, EA / HX). (0.073 g, 29.4%) 1 H NMR (400 MHz, CDCl3) δ 8.45 (d, J = 1.8 Hz, 1H), 8.39 – 8.34 (m, 2H),7.98 (dd, J = 4.6, 3.0 Hz, 2H), 7.89 – 7.84 (m, 2H), 7.42 (d, J= 8.4 Hz, 1H),6.60 (d, J = 2.6 Hz, 1H), 4.33 (s, 2H), 3.92 (d, J = 2.9 Hz, 3H Step 5) Synthesis of methyl 3-iodo-4-(((l-(4-nitrophenyl)-lH-pyrazol-3- yl)methyl)sulfonyl)benzoate Methyl 3-iodo-4-(((l-(4-nitrophenyl)-lH-pyrazol-3-yl)methyl)sulfanyl)benzoate (0.073 g, 0.147 mmol, 1 eq) was dissolved in MC (8 ml, 0.2 M) followed by the addition of mCPBA (0.127 g, 0.735 mmol, 5 eq) and stirred overnight. After completion of the reaction, saturated NaHC03 aqueous solution was added and extracted with MC. The organic layer was dried over MgS04, filtered and concentrated to get the crude product. (0.080 g, 100%) Step 6) Synthesis of methyl 3-((4-fluorophenyl)ethynyl)-4-(((l-(4-nitrophenyl)- lH-pyrazol-3-yl)methyl)sulfonyl)benzoate Methyl 3-iodo-4-(((l-(4-nitrophenyl)-lH-pyrazol-3-yl)methyl)sulfonyl)benzoate (0.447 g, 0.859 mmol, 1 eq) was dissolved in ACN (8.6 ml, 0.1 M) followed by the addition of TEA (0.26 ml, 1.89 mmol, 2.2 eq), PdCl2(PPh3)2(18 mg, 0.025 mmol, 3 mol %) and Cul (6.5 mg, 0.034 mmol, 4 mol %) and stirred for five minutes at room temperature. l-Ethynyl-4-fluorobenzene (0.15 ml, 1.29 mmol, 1.5 eq) was added and stirred at a temperature of 90 °C for one hour. After cooling to room temperature, the resulting product was concentrated and purified by column chromatography (silica gel, EA / HX). (0.125 g, 28%) 1 H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 8.28 (d, J = 9.1 Hz, 2H), 8.02(d, J = 0.8 Hz, 2H), 7.91 (d, J = 2.4 Hz, 1H), 7.72 – 7.65 (m, 4H), 7.11 (t, J =8.6 Hz, 2H), 6.56 (d,J = 2.4 Hz, 1H), 4.90 (s, 2H), 3.98 (s, 3H). Step 7) Synthesis of 3-((4-fluorophenyl)ethynyl)-4-(((1-(4-nitrophenyl)-1H- pyrazol-3-yl)methyl)sulfonyl)benzoic acid Methyl 3-((4-fluorophenyl)ethynyl)-4-(((1-(4-nitrophenyl)-1H-pyrazol-3- yl)methyl)sulfonyl)benzoate (0.125 g, 0.065 mmol, 1 eq) was dissolved in EtOH (1 ml, 0.05 M) followed by addition of NaOH (0.005 g, 0.13 mmol, 2 eq) dissolved in H2O (0.14 ml) and refluxed for one hour. After cooling to room temperature, the resulting product was concentrated and diluted with water. The pH was adjusted to 5 to 6 with 1 N HCI and the resulting solid was filtered, washed with water and dried. (0.1 g, 82%) Step 8) Synthesis of 3-((4-fluorophenyl)ethynyl)-N-(imidazo[1,2-a]pyridin-7- ylmethyl)-4-(((1-(4-nitrophenyl)-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide 3-((4-Fluorophenyl)ethynyl)-4-(((1-(4-nitrophenyl)-1H-pyrazol-3-yl)methyl)sulfonyl)benzoic acid (0.1 g, 0.2 mmol, 1 eq) was dissolved in MC (2 ml, 0.1 M) followed by addition of TBTU (0.1 g, 0.3 mmol, 1.5 eq), TEA (0.06 ml, 0.44 mmol, 2.2 eq) and 1-{imidazo[1,2-a]pyridin-7-yl}methanamine hydrochloride (0.04 g, 0.22 mmol, 1.1 eq) and stirred at room temperature for seven hours. After completion of the reaction, the resulting product was concentrated and purified by column chromatography (silica gel, MeOH / MC). (51 mg, 40.2%) Step 9) Synthesis of 4-(((1-(4-aminophenyl)-1H-pyrazol-3-yl)methyl)sulfonyl)-3- ((4-fluorophenyl)ethynyl)-N-(imidazo[1,2-a]pyridin-7-ylmethyl)benzamide Dissolve 3-((4-fluorophenyl)ethynyl)-N-(imidazo[l,2-a]pyridin-7- ylmethyl)-4-(((l-(4-nitrophenyl)-lH-pyrazol-3-yl)methyl)sulfonyl)benzamide (0.051 g, 0.080 mmol, 1 eq) in 1,4-dioxane:H20 (3: 1 (v:v) (1 ml, 0.084 M), then add zinc powder (0.055 g, 0.84 mmol, 10 eq) and NH4CI (0.045 g, 0.84 mmol, 10 eq), stir at room temperature for five hours. Wash the reaction mixture with MeOH, and filter through celite under reduced pressure. Concentrate the filtrate and purify by reverse phase column chromatography (0.1% formic acid in H20 / acetonitrile).

[0198] 1 H NMR (400 MHz, MeOD) δ 8.48 (d, J = 7.1 Hz, 1H), 8.29 (s, 1H), 8.25(s, 1H), 7.98 – 7.94 (m, 2H), 7.88 (s, 1H), 7.86 (d, J = 2.4 Hz, 1H), 7.78 –7.73 (m, 2H), 7.63 (s, 1H), 7.57 (s, 1H), 7.23 – 7.16 (m, 4H), 7.04 (d, J = 7.1Hz, 1H), 6.71 (d, J = 8.8 Hz, 2H), 6.41 (d, J = 2.4 Hz, 1H), 4.94 (s, 2H), 4.70(s, 2H). Example 22: Synthesis of Compound 122 Reagents and conditions: (a) 4-((methylsulfonyl)oxy)piperidine-1-carboxylic acid tert-butyl ester, K2CO3, DMF, 70 °C (b) 1.0 M LiAlH4in THF, THF, 0 °C, 1 h; (c) MsCl, TEA, THF, 0 °C to rt, 12 h; (d) 3-iodo-4-mercaptobenzoic acid methyl ester, K2CO3, DMF, rt, overnight; (e) mCPBA, MC, rt, overnight; (f) 1-ethynyl-4-fluorobenzene, TEA, CuI, PdCl2(PPh3)2, ACN, reflux, 1 h; (g) NaOH, EtOH, H2O, reflux, 1 h; (h) 1-{imidazo[1,2-a]pyridin-7-yl}methanamine hydrochloride, TBTU, TEA, MC, rt, overnight, (i) 4 N HC1 in dioxane, DCM, rt, 2 h Step 1) Synthesis of 4-(3-(ethoxycarbonyl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester Ethyl 1H-pyrazole-3-carboxylate (1.4 g, 10 mmol, 1 eq) was dissolved in DMF (50 ml, 0.2 M), then K2CO3 (1.66 g, 12 mmol, 1.2 eq) and 4-((methylsulfonyl)oxy)piperidine-1-carboxylic acid tert-butyl ester (3.07 g, 11 mmol, 1.1 eq) were added and stirred at 70 °C for 16 hours. After the reaction was completed, the resulting mixture was cooled to room temperature, water was added and extracted with EA. The organic layer was dried over MgSO4, filtered, concentrated, and purified by column chromatography (silica gel, EA / HX). (1.623 g, 50.2%) Step 2) Synthesis of 4-(3-(hydroxymethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester Ethyl 1H-pyrazole-3-carboxylate (1.4 g, 10 mmol, 1 eq) was dissolved in DMF (50 ml, 0.2 M), then K2CO3 (1.66 g, 12 mmol, 1.2 eq) and 4-((methylsulfonyl)oxy)piperidine-1-carboxylic acid tert-butyl ester (3.07 g, 11 mmol, 1.1 eq) were added and stirred at 70 °C for 16 hours. After the reaction was completed, the resulting mixture was cooled to room temperature, water was added and extracted with EA. The organic layer was dried over MgSO4, filtered, concentrated, and purified by column chromatography (silica gel, EA / HX). (1.623 g, 50.2%) Step 3) Synthesis of 4-(3-(((methylsulfonyl)oxy)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester 4-(3-(hydroxymethyl)-lH-pyrazol-l-yl)piperidine-l-carboxylic acid tert-butyl ester (0.2 g, 0.71 mmol, 1 eq) was dissolved in THF (4 ml, 0.2 M) followed by the addition of TEA (0.12 ml, 0.852 mmol, 1.2 eq) and MsCl (0.06 ml, 0.781 mmol, 1.1 eq) and stirred overnight. After completion of the reaction, water was added and extracted with DCM. The organic layer was dried over MgS04, filtered and concentrated to get the product as crude. (0.204 g, 100%) Step 4) Synthesis of 4-(3-(((2-iodo-4-(methoxycarbonyl)phenyl)thio)methyl)-lH- pyrazol-l-yl)piperidine-l-carboxylic acid tert-butyl ester tert-Butyl 4-(3-(((methylsulfonyl)oxy)methyl)-lH-pyrazol-l-yl)piperidine-l- carboxylate (0.204 g, 0.57 mmol, 1 eq) was dissolved in DMF (5 ml, 0.1 M) followed by the addition of K2C03(0.16 g, 1.134 mmol, 2 eq) followed by the slow addition of methyl 3-iodo-4-mercaptobenzoate (0.2 g, 0.68 mmol, 1.2 eq) dissolved in DMF (5 ml, 0.1 M) and stirred at room temperature for overnight. After completion of the reaction, water was added and the solid obtained was filtered and dried to get the product as crude. (0.193 g, 50.9%) 1 H NMR (400 MHz, CDCl3) δ 8.50 (d, J = 1.7 Hz, 1H), 8.00 (dd, J = 8.2, 1.8Hz, 1H), 7.50 (d, J = 1.3 Hz, 1H), 7.30 (s, 1H), 7.28 (s, 1H), 6.22 (d, J = 1.7Hz, 1H), 4.32 (dd, J = 13.2, 8.8 Hz, 3H), 4.24 (d, J = 5.9 Hz, 2H), 3.93 (d, J =4.6 Hz, 3H), 2.89 (t, J = 12.7 Hz, 2H), 2.23 (qd, J = 12.6, 4.2 Hz, 2H), 1.95 (d, J= 12.3 Hz, 2H), 1.49 (s, 9H). Step 5) Synthesis of tert-butyl 4-(3-(((2-iodo-4- (methoxycarbonyl)phenyl)sulfonyl)methyl)-lH-pyrazol-l-yl)piperidine-l-carboxylate After dissolving tert-butyl 4-(3-(((2-iodo-4- (methoxycarbonyl)phenyl)sulfinyl)methyl)-lH-pyrazol-l-yl)piperidine-l-carboxylate (0.193 g, 0.346 mmol, 1 eq) in MC (2 ml, 0.2 M), mCPBA (0.3 g, 1.731 mmol, 5 eq) was added and stirred overnight. After the reaction was completed, saturated NaHC03 aqueous solution was added and extracted with MC. The organic layer was dried with MgS04, filtered and concentrated to obtain the product as a crude. (0.183 g, 100%) Step 6) Synthesis of tert-butyl 4-(3-(((2-((4-fluorophenyl)ethynyl)-4- (methoxycarbonyl)phenyl)sulfonyl)methyl)-lH-pyrazol-l-yl)piperidine-l-carboxylate After dissolving tert-butyl 4-(3-(((2-iodo-4- (methoxycarbonyl)phenyl)sulfonyl)methyl)-lH-pyrazol-l-yl)piperidine-l-carboxylate (0.183 g, 0.31 mmol, 1 eq) in ACN (4 ml, 0.1 M), TEA (0.1 ml, 0.68 mmol, 2.2 eq), PdCl2(PPh3)2(6.5 mg, 0.009 mmol, 3 mol%) and Cul (2.4 mg, 0.012 mmol, 4 mol%) were added and stirred at room temperature for five minutes. l-Ethynyl-4-fluorobenzene (0.053 ml, 0.47 mmol, 1.5 eq) was added and stirred at 90 °C for one hour. After cooling to room temperature, the product was concentrated and purified by column chromatography (silica gel, EA / HX). (0.1 g, 55.6%) Step 7) Synthesis of 4-(((l-(l-(tert-butoxycarbonyl)piperidin-4-yl)-lH-pyrazol-3- yl)methyl)sulfonyl)-3-((4-fluorophenyl)ethynyl)benzoic acid tert-Butyl 4-(3-(((2-((4-fluorophenyl)ethynyl)-4- (methoxycarbonyl)phenyl)sulfonyl)methyl)-lH-pyrazol-l-yl)piperidine-l- carboxylate (0.10 g, 0.172 mmol, 1 eq) was dissolved in EtOH (4 ml, 0.05 M) and NaOH (0.014 g, 0.344 mmol, 2 eq) dissolved in H2O (0.1 ml) was added and refluxed for one hour. After cooling to room temperature, the resulting product was concentrated to give the title compound as a crude product.

[0199] Step 8) Synthesis of tert-butyl 4-(3-(((2-((4-fluorophenyl)ethynyl)-4- ((imidazo[l,2-a]pyridin-7-ylmethyl)carbamoyl)phenyl)sulfonyl)methyl)-lH-pyrazol- 1-yl)piperidine-l-carboxylate tert-Butyl 4-(((l-(l-(tert-butoxycarbonyl)piperidin-4-yl)-lH-pyrazol-3- yl)methyl)sulfonyl)-3-((4-fluorophenyl)ethynyl)benzoate (0.1 g, 0.172 mmol, 1 eq) was dissolved in MC and TBTU (0.083 g, 0.258 mmol, 1.5 eq), TEA (0.053 ml, 0.38 mmol, 2.2 eq) and l-{imidazo[l,2-a]pyridin-7- yl}methanamine hydrochloride (0.035 g, 0.189 mmol, 1.1 eq) were added and stirred at room temperature overnight. After completion of the reaction, saturated aqueous NaHC03 solution was added, neutralized and extracted with MC. The organic layer was dried over MgS04, filtered, concentrated and purified by column chromatography (silica gel, MeOH / MC). (0.112 g, 93.3%) Step 9) Synthesis of 3-((4-fluorophenyl)ethynyl)-N-(imidazo[l,2-a]pyridin-7- ylmethyl)-4-(((l-(piperidin-4-yl)-lH-pyrazol-3-yl)methyl)sulfonyl)benzamide tert-Butyl 4-(3-(((2-((4-fluorophenyl)ethynyl)-4-((imidazo[l,2-a]pyridin-7- ylmethyl)carbamoyl)phenyl)sulfonyl)methyl)-lH-pyrazol-l-yl)piperidine-l- carboxylate (0.112 g, 0.16 mmol, 1 eq) was dissolved in DCM (1 ml, 0.2 M) and 4 N HC1 in dioxane (0.4 ml, 1.6 mmol, 10 eq) was added and stirred at room temperature for two hours. After completion of the reaction, the resulting mixture was concentrated and purified by reverse phase column chromatography (0.1% formic acid in H2O / ACN) to give the title compound (0.028 g, 32.5%).

[0200] 1 H NMR (400 MHz, MeOD) δ 8.62 (s, 1H), 8.44 (d, J = 7.0 Hz, 1H), 8.09 (dd, J = 8.1, 1.1 Hz, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.83 (s, 1H), 7.76 (s, 1H), 7.56 (s, 1H), 7.38 (d, J = 1.9 Hz, 1H), 7.30 (dd, J = 8.7, 5.4 Hz, 2H), 7.07 –6.98 (m, 4H), 5.91 (d, J = 1.9 Hz, 1H), 4.72 (s, 2H), 4.60 – 4.50 (m, 1H), 3.22(d, J = 12.8 Hz, 2H), 2.79 (td, J = 15.0, 4.7 Hz, 2H), 2.68 (s, 2H), 2.22 – 2.10(m, 3H), 1.97 (d, J = 10.1 Hz, 1H). Example 23: Synthesis of Compound 148 4-((4-aminobenzyl)sulfonyl)-3-((4-fluorophenyl)ethynyl)-N-(imidazo[1,2-a]pyridin-7-ylmethyl)benzamide Reagents and conditions: (a) 1-(chloromethyl)-4-nitrobenzene, K2CO3, DMF, room temperature (rt), 0.5 h (b) mCPBA, DCM, room temperature (rt), 16 h (c) PdCl2[PPh3]2, CuI, TEA, ACN, room temperature (rt), 16 h (d) NaOH, H2O, MeOH, 55℃, 12 h (e) 1-{imidazo[1,2-a]pyridin-7-yl}methylamine hydrochloride, TBTU, TEA, DCM, room temperature (rt), 12 h (f) Zn, NH4Cl, dioxane, H2O, room temperature (rt), 2 h (2 h) Step 1) Synthesis of methyl 3-iodo-4-((4-nitrobenzyl)thio)benzoate 1-(chloromethyl)-4-nitrobenzene (0.24 g, 1.4 mmol, 1 eq) was dissolved in DMF (14 ml), K2CO3(0.39 g, 2.84 mmol, 2 eq) was added. Then to the reaction product, methyl 3-iodo-4-mercaptobenzoate (0.5 g, 1.70 mmol, 1.2 eq) was added and stirred for 30 minutes. To the reaction product, water was added and extracted with EA for several times. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure to get the target compound (0.6 g, 99%) as a crude product.

[0201] Step 2) Synthesis of methyl 3-iodo-4-((4-nitrobenzyl)sulfonyl)benzoate Methyl 3-iodo-4-((4-nitrobenzyl)sulfanyl)benzoate (0.73 g, 1.7 mmol, 1 eq) was dissolved in DCM (8.5 ml, 0.2 M), mCPBA (1.47 g, 8.5 mmol, 5 eq) was added and stirred for 16 hours. After confirming the completion of the reaction by TLC, the resulting product was diluted with water, neutralized with saturated aqueous NaHCO3solution, and extracted with DCM for several times. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, 40% EA / HX) to obtain the target compound (0.23 g, 29.1%).

[0202] Step 3) Synthesis of methyl 3-((4-fluorophenyl)ethynyl)-4-((4-nitrobenzyl)sulfonyl)benzoate To methyl 3-iodo-4-((4-nitrobenzyl)sulfonyl)benzoate (0.23 g, 0.5 mmol, 1 eq), MeCN (5 ml, 0.1 M) was added, followed by the addition of TEA (0.15 ml, 1.1 mmol, 2.2 eq). To the reaction product, PdCl2[PPh3]2(10.5 mg, 3 mol%) and CuI (4 mg, 3 mol%) were added and stirred for five minutes under a nitrogen atmosphere at room temperature. Subsequently, 4-fluorophenylacetylene (0.09 ml, 0.78 mmol, 1.5 eq) was added. The reaction mixture was stirred at room temperature for one hour, concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, 40% EA / HX) to obtain the target compound (0.191 g, 84.1%).

[0203] 1 H NMR (400 MHz, CDCl3) δ 8.38 (d, J = 1.6 Hz, 1H), 8.09 (d, J = 8.7 Hz,2H), 7.99 (dd, J= 8.3, 1.7 Hz, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.67 (dd, J = 8.9,5.3 Hz, 2H), 7.36 (d, J = 8.7 Hz, 2H), 7.15 (t, J = 8.7 Hz, 2H), 4.80 (s, 2H),3.98 (s, 3H). Step 4) Synthesis of 3-((4-fluorophenyl)ethynyl)-4-((4-nitrobenzyl)sulfonyl)benzoic acid To methyl 3-((4-fluorophenyl)ethynyl)-4-((4-nitrobenzyl)sulfonyl)benzoate (0.191 g, 0.421 mmol, 1 eq) was added MeOH (8 ml), H2O (0.3 ml) and NaOH (0.034 g, 0.842 mmol, 2 eq) and stirred at 55 °C for one hour. After confirming the completion of the reaction by TLC, the pH of the reaction product was adjusted to 1 with 1 N aqueous HC1 and extracted with EA. The organic layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to obtain the target compound (0.1 g, 56%).

[0204] Step 5) Synthesis of 3-((4-fluorophenyl)ethynyl)-N-(imidazo[l,2-a]pyridin-7- ylmethyl)-4-((4-nitrobenzyl)sulfonyl)benzamide To 3-((4-fluorophenyl)ethynyl)-4-((4-nitrobenzyl)sulfonyl)benzoic acid (0.1 g, 0.228 mmol, 1 eq) was added DCM (2.3 ml), TBTU (0.1 g, 0.342 mmol, 1.5 eq), TEA (0.07 ml, 0.5 mmol, 2.2 eq) and l-{imidazo[l,2-a]pyridin-7-yl}methanamine hydrochloride (0.046 g, 0.25 mmol, 1.1 eq) and stirred for 12 hours. The reaction product was concentrated under reduced pressure and the residue obtained was purified by column chromatography (silica gel, 10% MeOH / DCM) to obtain the target compound (0.053 g, 40.8%).

[0205] Step 7) Synthesis of 4-((4-aminobenzyl)sulfonyl)-3-((4-fluorophenyl)ethynyl)-N- (imidazo[l,2-a]pyridin-7-ylmethyl)benzamide Dissolve 3-((4-fluorophenyl)ethynyl)-N-(imidazo[l,2-a]pyridin-7- ylmethyl)-4-((4-nitrobenzyl)sulfonyl)benzamide (0.053 g, 0.084 mmol, 1 eq) in 1,4-dioxane: water (H20) (3: 1 (v:v), 1 ml), then add zinc (0.023 g, 0.42 mmol, 5 eq) and NH4CI (0.022 g, 0.42 mmol, 5 eq) and stir at room temperature for two hours. Wash the reaction mixture with MeOH and filter through celite under reduced pressure. Concentrate the filtrate and purify by preparative LC (0.1% formic acid in H20 / acetonitrile). (0.002 g) 1 H NMR (400 MHz, MeOD) δ 8.58 (s, 1H), 8.53 (s, 7H), 8.44 (d, J = 6.8Hz, 1H), 8.06 (d, J = 9.0 Hz, 1H), 7.84 (d, J = 8.3 Hz, 2H), 7.70 (s, 1H), 7.55(s, 2H), 7.42 - 7.36 (m, 2H), 6.99 (dd, J = 14.3, 7.7 Hz, 5H), 6.63 (d, J = 8.6Hz, 1H), 4.71 (s, 2H). MS(ESI) m / e MH + 539.

[0206] Example 24: Synthesis of Compound 234 Synthesis of 3-((4-fluorophenyl)ethynyl)-N-(imidazo[l,2-a]pyridin-7- ylmethyl)-4-((4-nitrobenzyl)sulfonyl)benzamide Reagents and conditions: (a) 3-(chloromethyl)pyrazole hydrochloride, K2CO3, DMF, r.t, 0.5 h (b) TsCl, pyridine, DCM, rt, 12 h (c) mCPBA, DCM, r.t, 16 h (d) PdCl2[PPh3]2, CuI, TEA, ACN, r.t, 16 h (e) NaOH, H2O, MeOH, 55 °C, 12 h (f) 1-{imidazo[1,2-a]pyridin-7-yl}methanamine hydrochloride, TBTU, TEA, DCM, 12 h Step 1) Synthesis of methyl 4-(((1H-pyrazol-3-yl)methyl)thio)-3- iodobenzoate 3-(chloromethyl)pyrazole hydrochloride (0.5 g, 1.70 mmol, 1 eq) was dissolved in DMF (14 ml) and K2CO3(0.39 g, 2.84 mmol, 2 eq) was added. To the reaction product, methyl 3-iodo-4-mercaptobenzoate (0.5 g, 1.70 mmol, 1.2 eq) was added and stirred for 30 min. To the reaction product, water was added and the resulting solid was filtered and dried to obtain the target compound.

[0207] Step 2) Synthesis of methyl 3-iodo-4-(((1-p-tolylsulfonyl-1H-pyrazol-3- yl)methyl)thio)benzoate Methyl 4-(((1H-pyrazol-3-yl)methyl)thio)-3-iodobenzoate (0.05 g, 0.133 mmol, 1 eq) was dissolved in DCM (0.1 M, 1.33 ml) and pyridine (0.027 ml, 5.8 M) and TsCl (0.030 g, 0.16 mmol, 1.2 eq) were added and stirred at room temperature for 12 h. The reaction product was concentrated and then water was added and extracted with DCM. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure and the resulting residue was purified by column chromatography (silica gel, 20% EA / HX) to obtain the target compound (0.041 g, 0.08 mmol, 58.6%).

[0208] Step 3) Synthesis of methyl 3-iodo-4-(((1-p-tolylsulfonyl-1H-pyrazol-3- yl)methyl)sulfonyl)benzoate 3-iodo-4-(((1-p-tolylsulfonyl-1H-pyrazol-3-yl)methyl)sulfanyl)benzoic acid methyl ester (0.041 g, 0.08 mmol, 1 eq) was dissolved in DCM (1 ml), mCPBA (0.07 g, 0.39 mmol, 5 eq) was added and stirred for 16 hours. After confirming the completion of the reaction by TLC, the resulting product was diluted with water, neutralized with saturated aqueous NaHC03solution, and extracted with DCM several times. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure to obtain the resulting residue, which was used directly for the next reaction step without isolation.

[0209] Step 4) Synthesis of 3-((4-fluorophenyl)ethynyl)-4-(((1-p-tolylsulfonyl-1H-pyrazol-3- yl)methyl)sulfonyl)benzoic acid methyl ester To 3-iodo-4-(((1-p-tolylsulfonyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzoic acid methyl ester (0.03 g, 0.052 mmol, 1 eq), MeCN (1 ml) was added, followed by TEA (0.016 ml, 0.114 mmol, 2.2 eq). To the reaction product, PdCl2[PPh3]2(1 mg, 3 mol%) and Cul (0.4 mg, 3 mol%) were added and stirred for five minutes at room temperature under a nitrogen atmosphere. Subsequently, 4-fluorophenylacetylene (0.009 ml, 0.078 mmol, 1.5 eq) was added. The reaction mixture was stirred at room temperature for one hour and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, 40% EA / HX) to obtain the target compound (0.020 g, 69.7%).

[0210] Step 5) Synthesis of 4-(((1H-pyrazol-3-yl)methyl)sulfonyl)-3-((4-fluorophenyl)ethynyl)benzoic acid To 3-((4-fluorophenyl)ethynyl)-4-(((1-p-tolylsulfonyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzoic acid methyl ester (0.020 g, 0.036 mmol, 1 eq), MeOH (1 ml), H20 (1 ml), and NaOH (3 mg, 0.072 mmol, 2 eq) were added and stirred at 55°C for one hour. After confirming the completion of the reaction by TLC, the resulting mixture was concentrated under reduced pressure to obtain the target compound as a crude product.

[0211] Step 6) Synthesis of 4-(((1H-pyrazol-3-yl)methyl)sulfonyl)-3-((4-fluorophenyl)ethynyl)-N- (imidazo[1,2-a]pyridin-7-ylmethyl)benzamide To 4-(((lH-pyrazol-3-yl)methyl)sulfonyl)-3-((4-fluorophenyl)ethynyl)benzoic acid (0.022 g, 0.057 mmol, 1 eq) was added DCM (1 ml), TBTU (0.027 g, 0.09 mmol, 1.5 eq), TEA (0.02 ml, 0.125 mmol, 2.2 eq) and l-{imidazo[l,2-a]pyridin-7-yl}methanamine hydrochloride (0.012 g, 0.063 mmol, 1.1 eq) and stirred for two hours. The reaction product was concentrated under reduced pressure and the resulting residue was purified by column chromatography (silica gel, 10% MeOH / DCM) to give the target compound.

[0212] 1 H NMR (400 MHz, MeOD) δ 8.42 (d, J = 7.0 Hz, 1H), 8.24 (s, 1H), 7.89(t, J = 6.4 Hz, 2H), 7.82 (s, 1H), 7.74 (dd, J = 8.6, 5.4 Hz, 2H), 7.54 (d, J = 7.0Hz, 2H), 7.48 (s, 1H), 7.22 (t, J = 8.7 Hz, 2H), 6.96 (d, J = 7.1 Hz, 1H), 6.25(s, 1H), 4.65 (s, 2H). MS (ESI) m / e MH + 514.

[0213] Example 25: Synthesis of Compound 235 Synthesis of N-(3-(lH-pyrazol-4-yl)propyl)-3-((3-methoxy-4- methylphenyl)ethynyl)-4-(((l-methyl-lH-pyrazol-3-yl)methyl)sulfonyl)benzamide Reagents and conditions: (a) NaOH, H20, MeOH, 60 °C, two hours (2 h); (b) 3-(lH-pyrazol-4-yl)prop-l-en-l-amine dihydrochloride, TBTU, TEA, DCM, twelve hours (12 h), (c) PdCl2[PPh3]2, CuI, TEA, ACN, r.t, one hour (1 h) Step 1) Synthesis of 3-iodo-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzoic acid To methyl 3-iodo-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzoate (1.216 g, 2.9 mmol, 1 eq) was added MeOH (15 ml, 0.2 M), H2O (2 ml) and NaOH (0.23 g, 5.79 mmol, 2 eq) and stirred at 60 °C for two hours. After confirming the completion of the reaction by TLC, the pH of the reaction product was adjusted to 1 with 1 N aqueous HC1 and extracted with EA. The organic layer was washed with water, separated, dried over magnesium sulfate, concentrated under reduced pressure to obtain the target compound (1.18 g, 100%).

[0214] 1 H NMR (400 MHz, DMSO) δ 13.74 (s, 1H), 8.57 (d, J = 1.3 Hz, 1H),8.04 (dd, J = 8.2, 1.4 Hz, 1H), 7.93-- 7.88 (m, 1H), 7.59 (d, J = 2.0 Hz,1H), 6.06 (d, J = 2.1 Hz, 1H), 4.83 (s, 2H), 3.69 (s, 3H). Step 2) Synthesis of N-(3-(1H-pyrazol-4-yl)propyl)-3-iodo-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide To 3-iodo-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzoic acid (0.4 g, 1 mmol, 1 eq) was added DCM (10 ml), TBTU (0.48 g, 1.5 mmol, 1.5 eq), TEA (0.3 ml, 2.2 mmol, 2.2 eq) and 3-(1H-pyrazol-4-yl)propan-1-amine dihydrochloride (0.22 g, 1.1 mmol, 1.1 eq) and stirred for 12 hours. The reaction product was concentrated and the resulting residue was purified by column chromatography (silica gel, 10% MeOH / DCM) to obtain the target compound. (0.16 g, 31.3%) 1 H NMR (400 MHz, MeOD) δ 8.56 (d, J = 1.4 Hz, 1H), 7.92 (d, J= 8.2 Hz, 1H), 7.87 (dd, J = 8.2, 1.5 Hz, 1H), 7.51 – 7.45 (m, 3H), 6.18 (d, J = 2.2 Hz, 1H), 4.83 (s, 2H), 3.77 (s, 3H), 3.43 (t, J = 7.1 Hz, 2H), 3.37 (s, 1H), 2.83(s, 1H), 2.61 (t, J = 7.5 Hz, 2H), 1.91 (p, J = 7.3 Hz, 2H). Step 3) Synthesis of N-(3-(1H-pyrazol-4-yl)propyl)-3-((3-methoxy-4- methylphenyl)ethynyl)-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide To N-(3-(1H-pyrazol-4-yl)propyl)-3-iodo-4-(((1-methyl-1H-pyrazol-3- yl)methyl)sulfonyl)benzamide (0.03 g, 0.058 mmol, 1 eq) was added MeCN (1 ml, 0.1 M) to which was added TEA (0.018 ml, 0.128 mmol, 2.2 eq). To the reaction was added PdCl2[PPh3]2(1.22 mg, 3 mol%) and Cul (0.44 mg, 3 mol%) and stirred for five minutes at room temperature under a nitrogen atmosphere. To this was then added 4-ethynyl-2-methoxy-1-methylbenzene (13 mg, 0.088 mmol, 1.5 eq). The reaction mixture was stirred at room temperature for one hour and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, 10% MeOH / DCM) to afford the target compound (27 mg, 87.7%).

[0215] 1 H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 7.90 (d, J = 8.2 Hz, 1H), 7.84(d, J = 8.2 Hz, 1H), 7.50 (s, 2H), 7.44 (s, 1H), 7.19 (d, J = 4.8 Hz, 3H), 6.16(s, 1H), 4.86 (s, 2H), 3.89 (s, 3H), 3.72 (s, 3H), 3.44 (t, J= 7.0 Hz, 2H), 2.62 (t, J = 7.5 Hz, 2H), 2.24 (s, 3H), 1.97 – 1.88 (m, 2H). The reagents can be changed in essentially the same manner as in Example 25 to synthesize compounds 44, 45, 46 and 75 to 82.

[0216] Example 26: Synthesis of Compound 236 Synthesis of N-(3-(1H-pyrazol-4-yl)propyl)-4-(((1-methyl-1H-pyrazol-3- yl)methyl)sulfonyl)-3-(pyridin-4-ylethynyl)benzamide Compound 236 was prepared in essentially the same manner as the synthesis of compound 235 of Example 25, with the exception that 1-ethynyl-4- (trifluoromethoxy)benzene was used in place of 4-ethynyl-2-methoxy-1- methylbenzene in step 3).

[0217] 1 H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 7.89 (q, J = 8.2 Hz, 2H), 7.80(d, J = 8.7 Hz, 2H), 7.48 (s, 2H), 7.44 (s, 1H), 7.39 (d, J = 8.2 Hz, 2H), 6.16(d, J = 2.0 Hz, 1H), 4.82 (s, 2H), 3.72 (s, 3H), 3.44 (t, J = 7.0 Hz, 2H), 2.62 (t, J = 7.4 Hz, 2H), 1.97 – 1.85 (m, 2H). Example 27: Synthesis of Compound 237 Synthesis of N-(3-(1H-pyrazol-4-yl)propyl)-4-(((1-methyl-1H-pyrazol-3- yl)methyl)sulfonyl)-3-(pyridin-4-ylethynyl)benzamide Compound 237 was prepared in essentially the same manner as the synthesis of compound 235, with the exception that 4-ethynylpyridine was used in place of 4-ethynyl-2-methoxy-l-methylbenzene in step 3) compared to the synthesis of compound 235 of Example 25.

[0218] 1 H NMR (400 MHz, MeOD) δ 8.67 (d, J = 5.9 Hz, 2H), 8.25 (s, 1H), 7.96(s, 2H), 7.71 (d, J = 6.1 Hz, 2H), 7.50 (s, 2H), 7.46 (d, J = 2.1 Hz, 1H), 6.20(d, J = 2.2 Hz, 1H), 4.82 (s, 2H), 3.73 (s, 3H), 3.46 (t, J = 7.1 Hz, 2H), 2.63(t, J = 7.5 Hz, 2H), 1.99 - 1.89 (m, 2H), 1.33 (t, J = 7.3 Hz, 1H). Example 28: Synthesis of Compound 238 Synthesis of 3-((4-fluorophenyl)ethynyl)-N-(imidazo[l,2-a]pyrimidin-6- ylmethyl)-4-(((l-methyl-lH-pyrazol-3-yl)methyl)sulfonyl)benzamide Reagents and conditions: (a) {imidazo[l,2-a]pyrimidin-6-yl}methanamine dihydrochloride, TBTU, TEA, DCM, rt, overnight; (b) 1-ethynyl-4-fluorobenzene, PdCl2(PPh3)2, CuI, TEA, ACN, 60 °C, one hour (1 h) Step 1) Synthesis of N-(imidazo[l,2-a]pyrimidin-6-ylmethyl)-3-iodo-4-(((l- methyl- 1H-pyrazol-3-yl)methyl)sulfonyl)benzamide 3-iodo-4-(((l-methyl-lH-pyrazol-3-yl)methyl)sulfonyl)benzoic acid (0.27 g, 0.67 mmol, 1 eq) was dissolved in DCM (6.7 ml, 0.1 M) followed by addition of {imidazo[l,2-a]pyrimidin-6-yl}methanamine dihydrochloride (0.147 g, 0.8 mmol, 1.2 eq), TBTU (0.257 g, 0.8 mmol, 1.2 eq) and TEA (0.37 ml, 2.68 mmol, 4 eq) and stirred at room temperature overnight. The reaction mixture was diluted in DCM followed by addition of aqueous NaHC03, H20 and brine and the organic layer was extracted. The organic layer was dried over MgS04, filtered, concentrated and purified by reverse phase column chromatography (0.1% formic acid in H20 / ACN) to give the target compound (0.092 g, 25.6%).

[0219] Step 2) Synthesis of 3-((4-fluorophenyl)ethynyl)-N-(imidazo[l,2-a]pyrimidin-6- ylmethyl)-4-(((l-methyl-lH-pyrazol-3-yl)methyl)sulfonyl)benzamide N-(imidazo[l,2-a]pyrimidin-6-ylmethyl)-3-iodo-4-(((l-methyl-lH-pyrazol-3- yl)methyl)sulfonyl)benzamide (0.046 g, 0.08 mmol, 1 eq) was dissolved in ACN (1 ml, 0.1 M) followed by addition of l-ethynyl-4-fluorobenzene (0.014 g, 0.12 mmol, 1.5 eq), PdCl2(PPh3)2(0.001 g, 0.002 mmol, 0.03 eq), CuI (0.00045 g, 0.002 mmol, 0.03 eq) and TEA (0.016 g, 0.16 mmol, 2 eq) and degassed with nitrogen (N2). The reaction solution was heated to 60 °C and stirred for one hour. Upon completion of the reaction, the resulting mixture was filtered through celite and extracted with EA. The organic layer was washed with water, separated, dried over MgS04, filtered, concentrated and purified by column chromatography (silica gel, MeOH / DCM) to give the target compound (0.016 g, 37.8%).

[0220] 1H NMR (400 MHz, DMSO) δ 9.45 (s, 1H), 8.96 (d, J = 2.2 Hz, 1H), 8.57(d, J = 2.4 Hz, 1H), 8.28 (d, J = 1.4 Hz, 1H), 8.01 (dd, J = 8.3, 1.6 Hz,1H), 7.92 (dd, J = 6.6, 4.8 Hz, 2H), 7.76 (dd, J = 8.7, 5.5 Hz, 2H), 7.71 (d,J = 1.1 Hz, 1H), 7.58 (d, J = 2.1 Hz, 1H), 7.37 (t, J = 8.9 Hz, 2H), 6.07 (d,J = 2.1 Hz, 1H), 4.85 (s, 2H), 4.55 (d, J = 4.1 Hz, 2H), 3.69 (s, 3H). Example 29: Synthesis of Compound 239 Synthesis of 4-((3-aminobenzyl)sulfonyl)-3-((4-fluorophenyl)ethynyl)-N- (imidazo[l,2-a]pyridin-7-ylmethyl)benzamide Reagents and conditions: (a) 3-nitrobenzyl chloride, K2CO3, DMF, rt, 2 h (b) m-CPBA, DCM, 0 °C to rt, overnight; (c) 1-ethynyl-4-fluorobenzene, PdCl2(PPh3)2, CuI, TEA, ACN, 60 °C, 1 h; (d) Zn, NH4CI, 1,4-dioxane, H2O, rt, 0.5 h; (e) 1 N NaOH (aq), THF, 70 °C, overnight; (f) 1-{imidazo[l,2-a]pyridin-7-yl}methanamine dihydrochloride, TBTU, TEA, DCM, rt, overnight Step 1) Synthesis of methyl 3-iodo-4-((3-nitrobenzyl)thio)benzoate 3-nitrobenzyl chloride (0.291 g, 1.7 mmol, 1 eq) and K2CO3(0.469 g, 3.4 mmol, 2 eq) were dissolved in DMF (3.4 ml, 0.5 M), then 3-iodo-4-mercaptomethyl benzoate (0.5 g, 1.7 mmol, 1 eq) was added dropwise and stirred at room temperature for two hours. Water was added to the reaction product and extracted with EA. The organic layer was dried with MgSO4, filtered, concentrated, and purified by column chromatography (silica gel, EA / HEX) to obtain the target compound (0.661 g, 90.5%).

[0221] Step 2) Synthesis of 3-iodo-4-((3-nitrobenzyl)sulfonyl)methyl benzoate 3-iodo-4-((3-nitrobenzyl)sulfonyl)methyl benzoate (0.1 g, 0.22 mmol, 1 eq) was dissolved in ACN (2.2 ml, 0.1 M), then 1-ethynyl-4-fluorobenzene (0.039 g, 0.33 mmol, 1.5 eq), PdCl2(PPh3)2(0.005 g, 0.007 mmol, 0.03 eq), CuI (0.001 g, 0.007 mmol, 0.03 eq), and TEA (0.045 g, 0.44 mmol, 2 eq) were added and degassed with nitrogen (N2). The reaction solution was heated to 60°C and stirred for one hour. After the reaction was completed, the resulting mixture was filtered through celite and extracted with EA. The organic layer was washed with water, separated, dried with MgSO4, filtered, concentrated, and purified by column chromatography (silica gel, MeOH / DCM) to obtain the target compound (0.083 g, 83%).

[0222] Step 3) Synthesis of 3-((4-fluorophenyl)ethynyl)-4-((3-nitrobenzyl)sulfonyl)methyl benzoate 3-iodo-4-((3-nitrobenzyl)sulfonyl)methyl benzoate (0.1 g, 0.22 mmol, 1 eq) was dissolved in ACN (2.2 ml, 0.1 M), then 1-ethynyl-4-fluorobenzene (0.039 g, 0.33 mmol, 1.5 eq), PdCl2(PPh3)2(0.005 g, 0.007 mmol, 0.03 eq), CuI (0.001 g, 0.007 mmol, 0.03 eq), and TEA (0.045 g, 0.44 mmol, 2 eq) were added and degassed with nitrogen (N2). The reaction solution was heated to 60°C and stirred for one hour. After the reaction was completed, the resulting mixture was filtered through celite and extracted with EA. The organic layer was washed with water, separated, dried with MgSO4, filtered, concentrated, and purified by column chromatography (silica gel, MeOH / DCM) to obtain the target compound (0.083 g, 83%).

[0223] Step 4) Synthesis of 4-((3-aminobenzyl)sulfonyl)-3-((4-fluorophenyl)ethynyl)methyl benzoate 3-((4-fluorophenyl)ethynyl)-4-((3-nitrobenzyl)sulfonyl)benzoic acid methyl ester (0.083 g, 0.18 mmol, 1 eq) was dissolved in 1,4-dioxane:H2O (3:1 (v / v)) (1.8 ml, 0.1 M), then Zn (0.058 g, 0.9 mmol, 5 eq) and NH3Cl (0.048 g, 0.9 mmol, 5 eq) were added and stirred at room temperature for 0.5 h. After the reaction was completed, the resulting product was filtered and concentrated to obtain the target compound as a crude product.

[0224] Step 5) Synthesis of 4-((3-aminobenzyl)sulfonyl)-3-((4-fluorophenyl)ethynyl)benzoic acid 4-((3-aminobenzyl)sulfonyl)-3-((4-fluorophenyl)ethynyl)benzoic acid methyl ester (0.076 g, 0.18 mmol, 1 eq) was dissolved in THF (1.8 ml, 0.1 M), then 1 N NaOH aqueous solution (0.36 ml, 0.36 mmol, 2 eq) was added, heated to 70 °C, and stirred overnight. After the reaction was completed, the reaction solution was concentrated to obtain the target compound as a crude product.

[0225] Step 6) Synthesis of 4-((3-aminobenzyl)sulfonyl)-3-((4-fluorophenyl)ethynyl)-N-(imidazo[1,2-a]pyridin-7-ylmethyl)benzamide 4-((3-aminobenzyl)sulfonyl)-3-((4-fluorophenyl)ethynyl)benzoic acid (0.040 g, 0.098 mmol, 1 eq) was dissolved in DCM (1 ml, 0.1 M), then 1-{imidazo[1,2-a]pyridin-7-yl}methanamine dihydrochloride (0.019 g, 0.108 mmol, 1.1 eq), TBTU (0.047 g, 0.147 mmol, 1.5 eq), and TEA (0.019 g, 0.196 mmol, 2 eq) were added and stirred at room temperature overnight. After the reaction was completed, water was added to the reaction solution and extracted with DCM. The organic layer was washed with water, separated, dried with MgSO4, filtered, concentrated, and purified by reverse phase column chromatography (0.1% formic acid in H2O / ACN) to obtain the target compound (0.005 g, 9.47%).

[0226] 1H NMR (400 MHz, MeOD) δ 8.38 (d, J = 7.1 Hz, 1H), 8.20 (d, J = 1.4Hz, 1H), 7.86 - 7.75 (m, 3H), 7.69 (dd, J = 8.8, 5.4 Hz, 2H), 7.50 (s, 1H),7.44 (s, 1H), 7.19 (t, J = 8.8 Hz, 2H), 6.95 - 6.84 (m, 2H), 6.57 - 6.49 (m,2H), 6.40 (d, J = 7.6 Hz, 1H), 4.65 (s, 2H), 4.61 (s, 2H). Example 30: Synthesis of Compound 240 Synthesis of 3-((4-aminophenyl)ethynyl)-N-(imidazo[l,2-a]pyridin-6- ylmethyl)-4-(((l-methyl-lH-pyrazol-3-yl)methyl)sulfonyl)benzamide Reagents and conditions: (a) imidazo[l,2-a]pyridin-6-ylmethanamine dihydrochloride, TBTU, TEA, DCM, rt, overnight; (b) 4-ethynylaniline, PdCl2(PPh3)2, CuI, TEA, ACN, 60 °C, three hours (3 h) Step 1) Synthesis of N-(imidazo[l,2-a]pyridin-6-ylmethyl)-3-iodo-4-(((l-methyl- lH-pyrazol-3-yl)methyl)sulfonyl)benzamide 3-iodo-4-(((l-methyl-lH-pyrazol-3-yl)methyl)sulfonyl)benzoic acid (0.1 g, 0.246 mmol, 1 eq) was dissolved in DCM (2.5 ml, 0.1 M), then to this was added imidazo[l,2-a]pyridin-6-ylmethanamine dihydrochloride (0.065 g, 0.295 mmol, 1.2 eq), TBTU (0.158 g, 0.492 mmol, 2 eq) and TEA (0.074 g, 0.739 mmol, 3 eq) and stirred at rt overnight. After completion of the reaction, water was added and extracted with DCM. The organic layer was washed with water, separated, dried over MgS04, filtered, concentrated and purified by column chromatography (silica gel, MeOH / DCM) to get the desired compound (0.033 g, 25%).

[0227] Step 2) Synthesis of 3-((4-aminophenyl)ethynyl)-N-(imidazo[l,2- a]pyridin-6-ylmethyl)-4-(((l-methyl-lH-pyrazol-3-yl)methyl)sulfonyl)benzamide N-(imidazo[l,2-a]pyridin-6-ylmethyl)-3-iodo-4-(((l-methyl-lH-pyrazol-3- yl)methyl)sulfonyl)benzamide (0.033 g, 0.062 mmol, 1 eq) was dissolved in ACN (1 ml, 0.1 M) followed by addition of 4-ethynylaniline (0.0087 g, 0.074 mmol, 1.2 eq), PdCl2(PPh4)2(0.001 g, 0.002 mmol, 0.03 eq), Cul (0.0003 g, 0.002 mmol, 0.03 eq) and TEA (0.0125 g, 0.124 mmol, 2 eq) and degassed with nitrogen (N2). The reaction solution was heated to 60 °C and stirred for three hours. After completion of the reaction, the resulting mixture was filtered through celite and extracted with EA. The organic layer was washed with water, separated, dried over MgS04, filtered, concentrated and purified by column chromatography (silica gel, MeOH / DCM) to get the desired compound (0.0089 g, 27.4%).

[0228] 1 H NMR (400 MHz, MeOD) δ 8.53 (s, 1H), 8.10 (d, J = 1.4 Hz, 1H), 7.91(s, 1H), 7.79 (dt, J = 8.3, 5.0 Hz, 2H), 7.65 (s, 1H), 7.61 (d, J = 9.4 Hz,1H), 7.50 (d, J = 9.3 Hz, 1H), 7.38 (d, J = 2.2 Hz, 1H), 7.35 (d, J = 8.6 Hz,2H), 6.65 (d, J = 8.6 Hz, 2H), 6.09 (d, J = 2.2 Hz, 1H), 4.82 (s, 2H), 4.59(s, 2H), 3.68 (s, 3H). Example 31 : Synthesis of Compound 241 Reagents and conditions: (a) PdCl2[PPh3]2, Cul, TEA, ACN, r.t, 16 h 3-((4-amino-3-fluorophenyl)ethynyl)-N-(imidazo[l,2-a]pyridin-7- ylmethyl)-4-(((l-methyl-lH-pyrazol-3-yl)methyl)sulfonyl)benzamide To N-(imidazo[l,2-a]pyridin-7-ylmethyl)-3-iodo-4-(((l-methyl-lH-pyrazol-3- yl)methyl)sulfonyl)benzamide (0.1 g, 0.2 mmol, 1 eq) was added MeCN (1 ml, 0.2 M) followed by TEA (0.08 ml, 0.6 mmol, 3 eq). To the reaction was added PdCl2[PPh3]2(4 mg, 3 mol%) and Cul (1 mg, 3 mol%) and stirred for five minutes under nitrogen atmosphere at room temperature. To this was then added 4-ethynyl-2-fluoroaniline (35 mg, 1.2 eq). The reaction mixture was stirred at room temperature for 16 hours and concentrated under reduced pressure. The resulting residue was purified by reverse phase chromatography (water / acetonitrile) to give the target compound.

[0229] 1 H NMR (400 MHz, DMSO) δ 9.43 (t, J = 5.8 Hz, 1H), 8.51 (d, J = 7.1 Hz,1H), 8.23 (d, J = 1.5 Hz, 1H), 7.89-7.98 (m, 3H), 7.61 (d, J = 2.1 Hz, 1H), 7.54(d, J = 1.0 Hz, 1H), 7.46 (s, 1H), 7.39 (dd, J = 12.0, 1.7 Hz, 1H), 7.25 (dd, J =8.2, 1.6 Hz, 1H), 6.89 (dd, J = 7.0, 1.5 Hz, 1H), 6.85 – 6.78 (m, 1H), 6.10 (d, J = 2.2 Hz, 1H), 5.88 (s, 2H), 4.87 (s, 2H), 4.54 (d, J = 5.7 Hz, 2H), 3.73 (s,3H). Example 32: Synthesis of Compound 242 Reagents and conditions: (a) PdCl2[PPh3]2, Cul, TEA, ACN, r.t, 16 h (b) NaOH, H2O, MeOH, 55 °C, 2 h (c) 1-{imidazo[l,2-a]pyridin-7-yl}methanamine dihydrochloride, TBTU, TEA, DCM, 12 h Step 1) Synthesis of 3-iodo-4-(((l-methyl-lH-pyrazol-3-yl)methyl)sulfonyl)benzoic acid To methyl 3-iodo-4-(((l-methyl-lH-pyrazol-3-yl)methyl)sulfonyl)benzoate (0.42 g, 1 mmol, 1 eq) was added MeOH (10 ml, 0.1 M), H2O (5 ml, 0.2 M) and NaOH (0.1 g, 2.5 mmol, 2.5 eq) and stirred at 80 °C for two hours. After confirming the completion of the reaction by TLC, the pH of the reaction product was adjusted to 1 with 1 N aqueous HC1 and extracted with EA. The organic layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to obtain the target compound (0.35 g, 86%).

[0230] Step 2) Synthesis of N-(imidazo[l,2-a]pyridin-7-ylmethyl)-3-iodo-4-(((l-methyl-lH- pyrazol-3-yl)methyl)sulfonyl)benzamide To 3-iodo-4-(((l-methyl-lH-pyrazol-3-yl)methyl)sulfonyl)benzoic acid (0.35 g, 0.86 mmol, 1 eq) was added DCM (10 ml) and TBTU (0.42 g, 1 mmol, 1.5 eq) and stirred at room temperature for 50 minutes. Subsequently, TEA (0.45 ml, 1.3 mmol, 3.7 eq) and 1-{imidazo[l,2-a]pyridin-7-yl}methanamine dihydrochloride (92 mg, 0.42 mmol, 1.2 eq) were added to the reaction product and stirred for 12 hours. The solid produced in the reaction product was filtered to obtain the target compound (0.3 g, 65%).

[0231] Step 3) Synthesis of N-(imidazo[l,2-a]pyridin-7-ylmethyl)-4-(((l-methyl-lH-pyrazol-3- yl)methyl)sulfonyl)-3-((4-((2-(piperidin-l-yl)ethyl)carbamoyl)phenyl)ethynyl)benzamide MeCN (1.4 mL, 0.2 M) was added to N-(imidazo[1,2-a]pyridin-7-ylmethyl)-3-iodo-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide (0.15 g, 0.28 mmol, 1 eq), followed by TEA (0.12 mL, 0.84 mmol, 3 eq). PdCl₂[PPh₃]₂ (6 mg, 3 mol%) and CuI (1.6 mg, 3 mol%) were added to the reaction product, and the mixture was stirred at room temperature for five minutes under nitrogen atmosphere. Subsequently, 4-ethynyl-N-(2-(piperidin-1-yl)ethyl)benzamide (86 mg, 1.2 eq) was added. The reaction mixture was stirred at room temperature for 16 hours and concentrated under reduced pressure. The resulting residue was purified by preparative LC to obtain the target compound.

[0232] 1 H NMR (400 MHz, MeOD) δ 8.46 (d, J = 6.1 Hz, 2H), 8.29 (s, 1H), 7.97(s, 4H), 7.88 – 7.78 (m, 3H), 7.56 (m, 2H), 7.46 (s, 1H), 7.01 (d, J = 6.5Hz, 1H), 6.19 (s, 1H), 4.86 (s, 2H), 4.69 (s, 2H), 3.80 (s, 2H), 3.74 (m,3H), 3.31 – 3.25 (m, 2H), 2.68 (s, 3H), 1.90 (s, 4H), 1.71 (s, 2H), 1.31 (s,1H). Example 33: Synthesis of Compound 243 Synthesis of 3-((6-aminopyridin-3-yl)ethynyl)-N-(imidazo[1,2-a]pyridin-7-ylmethyl)-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide Reagents and conditions (a) 5-ethynylpyridin-2-amine, TEA, CuI, PdCl2(PPh3)2, ACN, reflux, 3 h (3 h) N-(imidazo[l,2-a]pyridin-7-ylmethyl)-3-iodo-4-(((l-methyl-lH-pyrazol-3- yl)methyl)sulfonyl)benzamide (50 mg, 0.09 mmol, 1 eq) was dissolved in ACN (1 ml, 0.1 M) and to this was added TEA (0.025 ml, 0.18 mmol, 2 eq), PdCl2(PPh3)2(1.89 mg, 0.0027 mmol, 3 mol %) and Cul (0.51 mg, 0.0027 mmol, 3 mol %) and stirred at room temperature for five minutes. To this was added 5-ethynylpyridin-2-amine (22 mg, 0.186 mmol, 2 eq) and stirred at reflux for three hours. After cooling to room temperature, the resulting mixture was concentrated and purified by reverse phase column chromatography (0.1% formic acid in H2O / ACN) to give the title compound (0.004 g, 8.4%).

[0233] 1 H NMR (400 MHz, MeOD) δ 8.38 (d, J = 7.0 Hz, 1H), 8.21 (d, J = 2.0Hz, 1H), 8.15 (d, J = 0.9 Hz, 1H), 7.86 (dd, J = 8.9, 4.8 Hz, 2H), 7.78 (s,1H), 7.66 (dd, J = 8.7, 2.2 Hz, 1H), 7.51 (s, 1H), 7.46 (s, 1H), 7.41 (d, J =2.1 Hz, 1H), 6.92 (dd, J = 7.0, 1.2 Hz, 1H), 6.58 (d, J = 8.7 Hz, 1H), 6.12(d, J = 2.2 Hz, 1H), 4.80 (s, 2H), 4.62 (s, 2H), 3.70 (s, 3H). Example 34: Synthesis of Compound 244 Synthesis of N-(3-(lH-pyrazol-4-yl)propyl)-3-((4-(dimethylamino)phenyl)ethynyl)- 4-(((l-methyl-lH-pyrazol-3-yl)methyl)sulfonyl)benzamide Compound 244 was prepared in essentially the same manner as the synthesis of compound 235 of Example 25, except that in step 3) 4-ethynyl-N,N- dimethylaniline was used instead of 4-ethynyl-2-methoxy-l-methylbenzene.

[0234] 1 H NMR (400 MHz, MeOD) δ 8.11 (d, J = 1.5 Hz, 1H), 7.87 (d, J = 8.3 Hz,1H), 7.77 (dd, J = 8.3, 1.7 Hz, 1H), 7.54 (d, J = 8.9 Hz, 2H), 7.50 (s, 2H), 7.45(d, J = 2.1 Hz, 1H), 6.79 (d, J = 8.9 Hz, 2H), 6.15 (d, J = 2.2 Hz, 1H), 4.88 (s,2H), 3.75 (s, 3H), 3.45 (t, J = 7.1 Hz, 2H), 3.05 (s, 6H), 2.63 (t, J = 7.5 Hz,2H), 1.97 – 1.88 (m, 2H). Example 35: Synthesis of Compound 162 Synthesis of N-(3-(1H-pyrazol-4-yl)propyl)-3-(2-(4-fluorophenyl)thiazol-5-yl)-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide Reagents and conditions: (a) NBS, DMF, r.t, 1 h (b) bis(pinacolato)diboron, KOAc, PdCl2(dppf), 1,2-dimethoxyethane, 80 °C, 1.5 h (c) N-(3-(1H-pyrazol-4-yl)propyl)-3-iodo-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide, PdCl2(dppf), K2CO3, 1,4-dioxane, H2O, 100 °C, 1 h Step 1) Synthesis of 5-bromo-2-(4-fluorophenyl)thiazole Dissolve 2-(4-fluorophenyl)thiazole (0.27 g, 1.5 mmol, 1 eq) in DMF (3 ml), then add N-bromosuccinimide (0.402 g) to it and stir at room temperature for one hour. After completion of the reaction, add water, filter and dry to get the target compound as a crude product.

[0235] Step 2) Synthesis of 2-(4-fluorophenyl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)thiazole Dissolve 5-bromo-2-(4-fluorophenyl)thiazole (0.05 g, 0.194 mmol, 1 eq) in 1,2- dimethoxyethane (0.2 M, 1 ml), then add bis(pinacolato)diboron (0.058 g, 0.23 mmol, 1.2 eq), KOAc (0.057 g, 0.582 mmol, 3 eq) and PdCl2(dppf) (0.014 g, 0.0194 mmol, 0.1 eq) to it and stir at 80 °C for one hour thirty minutes. After completion of the reaction, the resulting product is filtered through celite and concentrated to get the target compound as a crude product.

[0236] Step 3) Synthesis of N-(3-(lH-pyrazol-4-yl)propyl)-3-(2-(4-fluorophenyl)thiazol-5-yl)-4- (((l-methyl-lH-pyrazol-3-yl)methyl)sulfonyl)benzamide Dissolve N-(3-(lH-pyrazol-4-yl)propyl)-3-iodo-4-(((l-methyl-lH-pyrazol-3- yl)methyl)sulfonyl)benzamide (0.03 g, 0.058 mmol, 1 eq), 2-(4-fluorophenyl)-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)thiazole (0.059 g, 0.194 mmol, 1.5 eq), PdCl2(dppf) (8.5 mg, 0.011 mmol, 0.2 eq) and K2CO3 (17.6 mg, 0.128 mmol, 2.2 eq) in 1,4-dioxane:H2O (3:1 (v / v)) (0.1 M, 0.6 ml), then stir at 100 °C for one hour. After completion of the reaction, the resulting product is filtered through celite, concentrated and purified by column chromatography (silica gel, MeOH / DCM) to get the target compound.

[0237] 1H NMR (400 MHz, MeOD) δ 8.11 - 8.05 (m, 2H), 8.03 (s, 1H), 7.99 (d, J = 1.8 Hz, 1H), 7.62 (d, J = 3.3 Hz, 2H), 7.45 (d, J = 2.2 Hz, 1H), 7.32 - 7.27 (m, 2H), 7.27 - 7.23 (m, 2H), 6.13 (d, J = 2.2 Hz, 1H), 4.41 (s, 2H), 3.74 (s, 3H), 3.43 (t, J = 7.2 Hz, 2H), 2.61 (t, J = 7.5 Hz, 2H), 1.95 - 1.86 (m, 2H). The reagents can be varied in essentially the same manner as in Example 35 to synthesize compounds 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 151, 152, 159, 160, 161, 162, 163, 164, 165, 166, 167, and 168.

[0238] Example 36: Synthesis of Compound 246 Synthesis of 3-(3-(2-aminoethyl)-2-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)-N- (imidazo[l,2-a]pyridin-7-ylmethyl)-4-(((l-methyl-lH-pyrazol-3-yl)methyl)sulfonyl)benzamide Reagents and conditions: (a) bis(pinacolato)diboron, KOAc, Pd(dppf)Cl2, 1,4-dioxane, reflux, 0.5 h; (b) N-(imidazo[l,2-a]pyridin-7-ylmethyl)-3-iodo-4-(((l-methyl- lH-pyrazol-3-yl)methyl)sulfonyl)benzamide, PdCl2(dppf)2, K2CO3, 1,4-dioxane, H2O, reflux, overnight; (c) tert-butyl (2-bromoethyl)carbamate, Cs2CO3, DMF, 80 °C, overnight; (d) 4 N HC1 in dioxane, 4 N HC1 in dioxane, rt, overnight Step 1) Synthesis of 2-methyl-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinazolin- 4(3H)-one Dissolve 7-bromo-2-methylquinazolin-4(3H)-one (0.5 g, 2.1 mmol, 1.0 eq) in 1,4-dioxane (21 ml, 0.1 M) then add bis(pinacolato)diboron (1.06 g, 4.2 mmol, 2 eq), Pd(dppf)Cl2(0.307 g, 0.42 mmol, 0.2 eq) and KOAc (0.412 g, 4.2 mmol, 2 eq) to it. Heat the reaction to reflux and stir for 0.5 h. Once the reaction is complete, cool the resulting product to room temperature and concentrate to give the target compound as a crude product.

[0239] Step 2) Synthesis of N-(imidazo[l,2-a]pyridin-7-ylmethyl)-4-(((l-methyl-lH- pyrazol-3-yl)methyl)sulfonyl)-3-(2-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)benzamide Dissolve N-(imidazo[l,2-a]pyridin-7-ylmethyl)-3-iodo-4-(((l-methyl-lH- pyrazol-3-yl)methyl)sulfonyl)benzamide (0.2 g, 0.374 mmol, 1 eq) in 1,4-dioxane:H2O (3:1 (v:v), 3 ml, 0.1 M) then add 2-methyl-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinazolin-4(3H)-one (0.214 g, 0.747 mmol, 2 eq), PdCl2(dppf)2(0.054 g, 0.075 mmol, 0.2 eq) and K2CO3(0.114 g, 0.822 mmol, 2.2 eq) to it. Heat the reaction to reflux and stir overnight. Once the reaction is complete, filter the resulting mixture through celite and extract with EA. Wash the organic layer with water, separate, dry over MgSO4, filter, concentrate and purify by reverse phase column chromatography (0.1% formic acid in H2O / ACN) to give the target compound (0.019 g, 8.9%).

[0240] Step 3) Synthesis of (2-(7-(5-((imidazo[l,2-a]pyridin-7-ylmethyl)carbamoyl)-2- (((l-methyl-lH-pyrazol-3-yl)methyl)sulfonyl)phenyl)-2-methyl-4-oxoquinazolin-3(4H)- yl)ethyl)carbamic acid tert-butyl ester N-(imidazo[l,2-a]pyridin-7-ylmethyl)-4-(((l-methyl-lH-pyrazol-3-yl)methyl)sulfonyl)-3-(2-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)benzamide (0.019 g, 0.03 mmol, 1.0 eq) was dissolved in DMF (1 ml, 0.03 M), then to this was added tert-butyl (2-bromoethyl)carbamate (0.008 g, 0.036 mmol, 1.2 eq) and Cs2CO3(0.019 g, 0.06 mmol, 2 eq). The reaction product was heated to 80 °C and stirred overnight. After completion of the reaction, the resulting mixture was cooled to room temperature and extracted with EA. The organic layer was washed with water, separated, dried over MgSO4, filtered and concentrated to get the target compound as a crude product.

[0241] Step 4) Synthesis of 3-(3-(2-aminoethyl)-2-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)-N-(imidazo[l,2-a]pyridin-7-ylmethyl)-4-(((l-methyl-lH-pyrazol-3-yl)methyl)sulfonyl)benzamide tert-butyl (2-(7-(5-((imidazo[l,2-a]pyridin-7-ylmethyl)carbamoyl)-2-(((l-methyl-lH-pyrazol-3-yl)methyl)sulfonyl)phenyl)-2-methyl-4-oxoquinolin-3(4H)-yl)ethyl)carbamate (0.019 g, 0.03 mmol, 1 eq) was dissolved in 1,4-dioxane (1 ml, 0.03 M), then to this was added 4 N HC1 in 1,4-dioxane (0.05 ml, 0.2 mmol, 6.6 eq) and stirred at room temperature overnight. After completion of the reaction, the resulting mixture was concentrated and purified by reverse phase column chromatography (0.1% formic acid in H2O / ACN) to get the title compound (0.001 g, 5.4%).

[0242] 1H NMR (400 MHz, MeOD) δ 8.75 (s, 1H), 8.29 (d, J = 8.1 Hz, 1H), 8.18(s, 1H), 8.12 (s, 1H), 8.08 (d, J = 8.0 Hz, 1H), 8.03 (d, J = 8.1 Hz, 1H),7.99 (s, 1H), 7.92 (s, 1H), 7.85 (s, 1H), 7.69 (s, 1H), 7.59 (d, J = 7.9 Hz,1H), 7.48 (d, J = 10.3 Hz, 2H), 6.10 (s, 1H), 4.78 (s, 2H), 4.72 (s, 2H),4.34 – 4.29 (m, 2H), 3.76 (s, 3H), 3.41 (d, J = 6.0 Hz, 2H), 2.73 (s, 3H). MS (ESI) m / e MH+ 611.08.

[0243] Example 37: Synthesis of Compound 247 Synthesis of N-(3-(1H-pyrazol-4-yl)propyl)-3-((4-fluorophenyl)ethynyl)-4- ((oxazol-5-ylmethyl)sulfonyl)benzamide Reagents and conditions: (a) oxazol-5-ylmethanol, SOCl2, DCM, 2 h (b) 3-iodo-4- mercaptomethylbenzoate, K2CO3, DMF, r.t, 1 h (c) mCPBA, DCM, r.t 16 h (d) PdCl2[PPh3]2, CuI, TEA, ACN, r.t, 16 h (e) NaOH, H2O, MeOH, r.t, 4 h (f) 3-(1H-pyrazol-4-yl)prop-1-amine dihydrochloride, TBTU, TEA, DCM, 12 h.

[0244] Step 1) Synthesis of 5-(chloromethyl)oxazole Oxazol-5-ylmethanol (1 g, 10 mmol, 1 eq) was dissolved in DCM (20 ml) and 1.0 M sulfuryl chloride in dichloromethane (11 ml, 11 eq) was added dropwise slowly in an ice bath. The reaction was allowed to warm to room temperature and stirred for two hours. The reaction was concentrated under reduced pressure to give the target compound as a crude product.

[0245] Step 2) Synthesis of methyl 3-iodo-4-((oxazol-5-ylmethyl)thio)benzoate Dissolve 5-(chloromethyl)oxazole (1 g, 6.5 mmol, 1 eq) in DMF (13 ml), to which K2CO3 (1.79 g, 13 mmol, 2 eq) is added. Then to the reaction product, methyl 3-iodo-4-mercapto benzoate (1.9 g, 6.5 mmol, 1 eq) is added and stirred for one hour. To the reaction product, water is added and extracted with EA for several times. The organic layer is dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel, 40% EA / HX) to obtain the target compound (0.22 g, 9%).

[0246] Step 3) Synthesis of methyl 3-iodo-4-((oxazol-5-ylmethyl)sulfonyl)benzoate Dissolve methyl 3-iodo-4-((oxazol-5-ylmethyl)thio)benzoate (0.22 g, 0.59 mmol, 1 eq) in DCM (5 ml), to which mCPBA (0.3 g, 1.17 mmol, 2 eq) is added and stirred for 16 hours. After confirming the completion of the reaction by TLC, the resulting product is diluted with water, neutralized with saturated aqueous NaHCO3 solution, and extracted with DCM for several times. The organic layer is dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is concentrated under reduced pressure to obtain the target compound as a crude product.

[0247] Step 4) Synthesis of methyl 3-((4-fluorophenyl)ethynyl)-4-((oxazol-5-ylmethyl)sulfonyl)benzoate To methyl 3-iodo-4-((oxazol-5-ylmethyl)sulfonyl)benzoate (0.17 g, 0.41 mmol, 1 eq), MeCN (2 ml, 0.2 M) is added, to which TEA (0.074 ml, 0.53 mmol, 0.53 eq) is added. To the reaction product, PdCl2[PPh3]2 (8.4 mg, 3 mol%) and CuI (2.3 mg, 3 mol%) are added and stirred for five minutes under a nitrogen atmosphere at room temperature. Subsequently, 4-fluorophenylacetylene (0.06 g, 0.49 mmol, 1.2 eq) is added. The reaction mixture is stirred at room temperature for 16 hours and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel, 30% EA / HX) to obtain the target compound (0.05 g, 30.5%).

[0248] Step 5) Synthesis of 3-((4-fluorophenyl)ethynyl)-4-((oxazol-5-ylmethyl)sulfonyl)benzoic acid To methyl 3-((4-fluorophenyl)ethynyl)-4-((oxazol-5-ylmethyl)sulfonyl)benzoate (0.05 g, 0.125 mmol, 1 eq) was added MeOH (0.6 ml), H20 (0.3 ml) and NaOH (0.012 g, 0.31 mmol, 2.5 eq) and stirred for four hours. After confirming completion of the reaction by TLC, the pH of the reaction product was adjusted to 1 with 1 N aqueous HC1 and extracted with EA. The organic layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to obtain the target compound.

[0249] Step 6) Synthesis of N-(3-(1H-pyrazol-4-yl)propyl)-3-((4-fluorophenyl)ethynyl)-4- ((oxazol-5-ylmethyl)sulfonyl)benzamide To 3-((4-fluorophenyl)ethynyl)-4-((oxazol-5-ylmethyl)sulfonyl)benzoic acid (0.05 g, 0.125 mmol, 1 eq) was added DCM (2 ml), TBTU (0.06 g, 0.19 mmol, 1.5 eq), TEA (0.064 ml, 0.46 mmol, 3.7 eq) and 1-{imidazo[1,2-a]pyridin-7-yl}methanamine hydrochloride (0.03 g, 0.15 mmol, 1.2 eq) and stirred for 12 hours. The reaction product was concentrated under reduced pressure and the residue obtained was purified by column chromatography (silica gel, 5-10% MeOH / DCM) to obtain the target compound (0.053 g, 40.8%).

[0250] 1 H NMR (400 MHz, DMSO) δ 12.55 (s, 1H), 8.89 (t, J = 5.6 Hz, 1H), 8.32(s, 1H), 8.27 (d, J = 1.2 Hz, 1H), 8.06 - 8.00 (m, 1H), 7.96-7.94 (m, 1H), 7.74(dd, J = 8.6, 5.5 Hz, 2H), 7.53 (s, 1H), 7.39 (t, J = 8.8 Hz, 2H), 7.09 (s, 1H),5.19 (s, 2H), 3.34 - 3.28 (m, 2H), 2.48 (m, 2H), 1.80 (p, J = 7.2 Hz, 2H). MS (ESI) m / e MH + 493.08.

[0251] <Experimental Example> Experimental Example 1: NAMPT enzyme inhibition assay The NAMPT enzyme activity inhibition ability of the compounds of the present application was evaluated using the NAMPT Inhibitor Screening Assay Kit (#7176-1) of BPS bioscience. Recombinant NAMPT protein was added to each well of a black 96-well plate, and dilution buffer was added instead of NAMPT protein in the blank well. A 5-fold concentrated compound solution was added, and pre-incubated for 30 minutes at room temperature (about 22°C) before the start of the reaction in order to allow the compound and protein to bind before the enzyme reaction. At this time, the concentration of NAMPT protein was adjusted and used in the final concentration range of 4-10 ng / μl according to the enzyme activity of each protein batch, and the test compound was serially diluted from 1000 nM to 3 nM at a ratio of 1:3, and about seven concentrations were experimented (n=2). 2-fold concentrated test buffer containing ATP (final concentration 20 μM), nicotinamide (final concentration 20 μM), phosphoribosyl pyrophosphate (PRPP, final concentration 40 μM), and ethanol (final concentration 1.5%) was added, and the plate was incubated at 30°C for two hours, after which the fluorescence of the resulting reaction product was measured with 340 nm excitation and 460 nm emission. The NAMPT enzyme activity (%) was calculated by subtracting the measurement value of the blank well without NAMPT protein from the measurement value of all wells, and then the measurement value of the control well without the compound was taken as 100%. IC 50 was calculated using GraphPad Prism 9 software, and the results are shown in Table 2.

[0252] <Experimental Example 2> Intracellular NAD measurement test For the HCT-116 cell line, the decrease in intracellular NAD+ and NADH levels due to the inhibition of NAMPT enzyme activity by the compounds was evaluated using the NAD / NADH-Glo™ assay (Promega, G9072) product of Promega. Cells were cultured using DMEM (Gibco, 11995-065) containing 10% FBS medium. HCT-116 cells were distributed in a 96-well plate at a density of 2500 cells per well for 24 hours and drug-treated using serum-free DMEM. First, the compounds were dissolved in 100% dimethyl sulfoxide (DMSO) and then diluted in the medium so that the final concentration of DMSO was 0.5%, and drug-treated. The final concentration of the compounds ranged from 0.1 nM to 100 nM. After that, they were further cultured at 37°C and CO2 5% for 24 hours. To perform the NAD / NADH-Glo™ assay, the medium of the drug-treated cells was removed, 50 μL of DPBS was added per well, and left to stand for five minutes at room temperature. The required amount of NAD / NADH-Glo™ assay reagent (reconstituted luciferin assay reagent 1 mL, reductase 5 μL, reductase substrate 5 μL, NAD cycling enzyme 5 μL, NAD cycling substrate 25 μL) was prepared according to the manufacturer's manual, and treated in an amount of 50 μL per well. After cell lysis on a plate shaker at 400 rpm for two minutes, the cells were incubated at room temperature for 30 minutes, and the luminescence was measured. The NAD+ / NADH levels were calculated by subtracting the measurement value of the blank well without cells from the measurement value of all wells, and taking the 0.5% DMSO-treated control as 100%. The IC 50 The results are shown in Table 2 below.

[0253] [Table 2]

[0254] In the above table, A, B, and C are defined as follows.

[0255] NAMPT IC 50 A: <0.5 μM (less than 0.5 μM) / B: <1 μM (0.5 μM or more and less than 1 μM) / C: ≥1 μM (1 μM or more) NAD IC 50A: ≤10 nM (10 nM or less) / B: ≤1 μM (more than 10 nM and 1 μM or less) / C: >1 μM (more than 1 μM) As can be seen from the above table, it can be found that the compounds of the present application exhibit excellent inhibitory activity against NAMPT and also show sufficient inhibitory activity at a low concentration.

[0256] Therefore, the compounds of the present application can have excellent preventive or therapeutic effects on NAMPT-related diseases.

[0257] As can be seen from the above table, it can be found that the compounds of the present application significantly inhibit the production of NAD in the HCT-116 cell line and also sufficiently inhibit the concentration of NAD in cells at a low concentration.

[0258] Therefore, the compounds of the present application can inhibit NAMPT and also sufficiently reduce the concentration of NAD in cells even at a low concentration, and thus can have excellent preventive or therapeutic effects on diseases (e.g., cancer) that can be treated by inhibiting NAMPT.

[0259] <Experimental Example 3> Tumor cytotoxicity test The anti-cancer efficacy of the compounds of the present application was evaluated in HCT116 colorectal cancer cell line using MTT assay. Cells were cultured using DMEM medium containing 10% FBS. Cells were distributed in a 96-well plate at a density of 2500 cells per well, and HCT116 cells were cultured for 24 hours, and then drug treatment was performed using serum-free DMEM. First, the compounds were prepared in 100% dimethyl sulfoxide (DMSO) at a concentration of 0.02 μM to 200 μM, diluted in the medium so that the final concentration of DMSO can reach 0.5%, and drug treatment was performed so that the final concentration of the compound can range from 0.1 nM to 1000 nM. Thereafter, they were further cultured at 37°C and CO25% for 72 hours, and MTT (Sigma-Aldrich, M2128) was added to confirm cytotoxicity. The formazan produced by the enzyme reduction in the mitochondria of living cells was measured using a Spark® Multimode Microplate Reader TECAN device. Cell viability (%) was relatively determined by subtracting the reference 650 nm optical density (O.D.) from the 570 nm optical density (O.D.), in which the 0.5% DMSO-treated control was set as 100% standard. The resulting values were plotted as a function of compound concentration using GraphPad Prism 9 software to calculate the CC 50 (50% cytotoxicity concentration) values, as shown in Table 3 below.

[0260] [Table 3]

[0261] In Table 3 above, A, B and C are defined as follows.

[0262] A: CC 50 ≤ 30 nM (30 nM or less) B: 30 nM < CC 50 ≤ 100 nM (more than 30 nM and 100 nM or less) C: 100 nM < CC 50 ≤ 1 μM (more than 100 nM and 1 μM or less) As can be seen from the above table, it can be found that the compounds of the present application exhibit excellent cytotoxicity against colorectal cancer cell lines even at low concentrations.

[0263] Therefore, it can be seen that the compounds of the present application have excellent preventive or therapeutic effects on various diseases such as cancer by inhibiting NAMPT.

[0264] The present application has been described with reference to one exemplary embodiment of the present application, but those skilled in the art will appreciate that various changes and modifications can be made to the present application without departing from the spirit and scope of the present application, as described in the following patent claim scope.

Claims

1. A benzamide derivative compound represented by the following Formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof: < Formula I > ， wherein in the above Formula I, R1 is a 6- to 14-membered aryl group; a C2-C8 heterocycloalkenyl group; or a 5- to 12-membered heteroaryl group, wherein the -H of R1 is unsubstituted, or at least one H thereof is substituted with a halogen, NRaRb, NO2, or OH; L1 is a C1-C6 alkylene group; L2 is a single bond; or a C2-C6 alkynylene group; X is a 6- to 14-membered arylene group; a C2-C8 heterocycloalkenylene group; or a 5- to 12-membered heteroarylene group, wherein at least one -H of X is unsubstituted, or at least one H of X is substituted with a C1-C6 alkyl group, CF3, a halogen, -C1-C6 alkoxy, or OH, and the -CH2- of X is unsubstituted, or at least one -CH2- of X is each independently replaced with -(C=O)-; L3 is a single bond; a C1-C6 alkylene group; a C2-C6 alkenylene group; C=O; (C=O)NRc; (C=O)NRd-(C1-C6 alkylene); NRy(C=O)-(C1-C6 alkylene); or O(C=O)-(C1-C6 alkylene); R2 is H, a halogen, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C8 cycloalkyl group, a C1-C8 heterocycloalkyl group, -NRz1Rz2, a 6- to 14-membered aryl group, or a 5- to 12-membered heteroaryl group, wherein the -H of R2 is unsubstituted, or at least one -H thereof is substituted with a C1-C6 alkyl group, OH, COOH, (C1-C6 alkylene)-NReRf, NRgRh, NO2, CF3, (C=O)NRiRj, or a halogen; L4 is a single bond, a C1-C6 alkylene group, -NRm-(C1-C6 alkylene)-, or NRn; R3is H, C1-C6alkyl, C3-C8cycloalkyl, 6- to 14-membered aryl, C1-C8heterocycloalkyl, C2-C8heterocycloalkenyl, 5- to 12-membered heteroaryl, 6- to 14-membered arlyene-C1-C8heterocycloalkyl, 6- to 14-membered arlyene-5- to 12-membered heteroaryl, 5- to 12-membered heteroarylene-6- to 14-membered aryl, 5- to 12-membered heteroarylene-C1-C8heterocycloalkyl, or 5- to 12-membered heteroarylene-5- to 12-membered heteroaryl, wherein the -H of R3is unsubstituted, or at least one -H thereof is substituted with C1-C6alkyl, C1-C6alkoxy, phenoxy, OH, (C1-C6alkylene)-OH, COOH, (C1-C6alkylene)-COOH, (C1-C6alkylene)-CN, NRoRp, (C1-C6alkylene)-NRqRr, (C=O)-(C1-C6alkyl), (C=O)-(C3-C8cycloalkyl), (C=O)-(6- to 14-membered aryl), 6- to 14-membered aryl, 6- to 14-membered heteroaryl, 6- to 14-membered heterocycloaryl, (C=O)NRsRtwhich can be substituted with halogen, (C=O)-(C1-C6alkylene)-NRuRv, NRwRx, (C=O)O-(C1-C6alkyl), NO2, CHF2, CF3, OCF3, or halogen, and the -CH2- of the heterocycloalkenyl of R3is unsubstituted, or replaced with -(C=O)-; and each of said Ra to Rj, Rm to Ry, Rz1, and Rz2is independently H or C1-C6alkyl.

2. The benzamide derivative compound represented by the above Formula I, stereoisomer, pharmaceutically acceptable salt thereof, or hydrate or solvate thereof according to claim 1, wherein said R1is 6- to 14-membered aryl; C2-C8heterocycloalkenyl comprising at least one heteroatom or heterofunctional group selected from the group consisting of N, O, S, S(=O), and S(=O)2; or 5- to 12-membered heteroaryl comprising at least one heteroatom selected from the group consisting of N, O, and S, wherein the -H of R1is unsubstituted, or at least one H thereof is each independently substituted with halogen, -NRaRb, -NO2, or -OH; L1is C1-C6alkylene; L2is a single bond; or C2-C6alkynylene; R3is H, C1-C6alkyl, C3-C8cycloalkyl, 6- to 14-membered aryl, C1-C8heterocycloalkyl, C2-C8heterocycloalkenyl, 5- to 12-membered heteroaryl, 6- to 14-membered arlyene-C1-C8heterocycloalkyl, 6- to 14-membered arlyene-5- to 12-membered heteroaryl, 5- to 12-membered heteroarylene-6- to 14-membered aryl, 5- to 12-membered heteroarylene-C1-C8heterocycloalkyl, or 5- to 12-membered heteroarylene-5- to 12-membered heteroaryl, wherein the -H of R3is unsubstituted, or at least one -H thereof is substituted with C1-C6alkyl, C1-C6alkoxy, phenoxy, OH, (C1-C6alkylene)-OH, COOH, (C1-C6alkylene)-COOH, (C1-C6alkylene)-CN, NRoRp, (C1-C6alkylene)-NRqRr, (C=O)-(C1-C6alkyl), (C=O)-(C3-C8cycloalkyl), (C=O)-(6- to 14-membered aryl), 6- to 14-membered aryl, 6- to 14-membered heteroaryl, 6- to 14-membered heterocycloaryl, (C=O)NRsRtwhich can be substituted with halogen, (C=O)-(C1-C6alkylene)-NRuRv, NRwRx, (C=O)O-(C1-C6alkyl), NO2, CHF2, CF3, OCF3, or halogen, and the -CH2- of the heterocycloalkenyl of R3is unsubstituted, or replaced with -(C=O)-; and X is 6- to 14-membered arylene; C2-C8 heterocyclenyl comprising at least one heteroatom or heterofunctional group selected from the group consisting of N, O, S, S(=0) and S(=0)2; or 5- to 12-membered heteroarylene comprising at least one heteroatom selected from the group consisting of N, O and S, wherein when -H of X is unsubstituted, or said X is 6- to 14-membered arylene or C2-C8 heterocyclenyl, at least one -H of said X is independently substituted with C1-C6 alkyl, -CF3, halogen, -C1-C6 alkoxy or OH, and when said X is C2-C8 heterocyclenyl, -CH2- is unsubstituted, or at least one -CH2- is replaced with -(C=0)-; L3 is a single bond; C1-C6 alkylene; C2-C6 alkenylene; -C=0; -C(=0)NRc; -C(=0)NRd-(C1-C6 alkylene)-; -NRyC(=0)-(C1-C6 alkylene); -NHC(=0); or -OC(=0)-(C1-C6 alkylene); R2 is H; halogen; -NRz1Rz2; C1-C6 alkyl; C1-C6 alkoxy; C3-C8 cycloalkyl; C1-C8 heterocycloalkyl comprising at least one heteroatom or heterofunctional group selected from the group consisting of N, O, S, SO and SO2; 6- to 14-membered aryl, or 5- to 12-membered heteroaryl comprising at least one heteroatom selected from the group consisting of N, O and S, wherein -H of said R2 is unsubstituted, or at least one -H of R2 is independently substituted with -C1-C6 alkyl, -C1-C6 alkoxy, -OH, -COOH, -(C1-C6 alkylene)-NReRf, -NRgRh, -NO2, -CF3, -C(=0)NRiRj or halogen; L4 is a single bond; -C1-C6 alkylene-; -NRm-(C1-C6 alkylene)-; or -NRn-, wherein -H of said L4 is unsubstituted, or at least one -H of R2 is independently substituted with -C1-C6 alkyl; R3is H; C1-C6alkyl; C3-C8cycloalkyl; 6- to 14-membered aryl; C1-C8heterocycloalkyl comprising at least one heteroatom or heterofunctional group selected from the group consisting of N, O, S, SO, and SO2; C2-C8heterocycloalkenyl comprising at least one heteroatom selected from the group consisting of N, O, S, SO, and SO2; 5- to 12-membered heteroaryl comprising at least one heteroatom selected from the group consisting of N, O, and S; 6- to 14-membered arly-C1-C8heterocycloalkyl (wherein the heterocycloalkyl comprises at least one heteroatom or heterofunctional group selected from the group consisting of N, O, S, SO, and SO2); 6- to 14-membered arly-5- to 12-membered heteroaryl (wherein the heteroaryl comprises at least one heteroatom selected from the group consisting of N, O, and S); 5- to 12-membered heteroaryly-6- to 14-membered aryl (wherein the heteroaryly comprises at least one heteroatom selected from the group consisting of N, O, and S); 5- to 12-membered heteroaryly-C1-C8heterocycloalkyl (wherein the heteroaryly comprises at least one heteroatom selected from the group consisting of N, O, and S, and the heterocycloalkyl comprises at least one heteroatom or heterofunctional group selected from the group consisting of N, O, S, SO, and SO2); or 5- to 12-membered heteroaryly-5- to 12-membered heteroaryl (wherein the heteroaryly or heteroaryl comprises at least one heteroatom selected from the group consisting of N, O, and S), wherein the -H of R3is unsubstituted, or at least one H of R3is each independently substituted with -C1-C6alkyl, -C1-C6alkoxy, -phenoxy, -OH, -(C1-C6alkylene)-OH, -COOH, -(C1-C6alkylene)-COOH, (C1-C6alkylene)-CN, -NRoRp, (C1-C6alkylene)-NRqRr, -C(=O)-(C1-C6alkyl), -C(=O)-(C3-C8cycloalkyl), -C(=O)-(6- to 14-membered aryl), -NO2, -CHF2, -CF3, -OCF3, 6- to 14-membered aryl, 6- to 14-membered heteroaryl comprising at least one heteroatom selected from the group consisting of N, O, and S, 6- to 14-membered heterocycloaryl comprising at least one heteroatom or heterofunctional group selected from the group consisting of N, O, S, SO, and SO2, -C(=O)NRsRt(wherein the -H of -C(=O)NRsRtis unsubstituted, or at least one -H thereof is each independently substituted with halogen), -C(=O)-(C1-C6alkylene)-NRuRv, -NRwRx, or halogen, and when the R3is heterocycloalkenyl, -CH2- is unsubstituted, or at least one -CH2- is each independently replaced with -(C=O)-; and each instance of Rathrough Rj, Rmthrough Ry, Rz1, and Rz2is each independently H or C1-C6alkyl.

3. The benzamide derivative compound according to claim 1 represented by the above Formula I, a stereoisomer, a pharmaceutically acceptable salt, or a hydrate or solvate thereof, wherein R1is , , , , , , , , or , and -H of R1 is unsubstituted, or at least one -H of R1 is each independently substituted with halogen, -NRaRb, -NO2, or -OH, wherein each of Raor Rb is independently -H or C1-C6 alkyl.

4. The benzamide derivative compound represented by the above Formula I, stereoisomer, pharmaceutically acceptable salt, or hydrate or solvate thereof according to claim 3, wherein -H of R1 is unsubstituted, or at least one -H of R1 is each independently substituted with -NH2, -NO2, -NHCH3, -N(CH3)2, or -OH.

5. The benzamide derivative compound represented by the above Formula I, stereoisomer, pharmaceutically acceptable salt, or hydrate or solvate thereof according to claim 1, wherein L1 is methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), i-propylene (-CHCH3CH2), n-butylene (-CH2CH2CH2CH2-), s-butylene (-CHCH3CH2CH2-), i-butylene (-CH2CHCH3CH2-), n-butylene (-CH2CH2CH2CH2-), s-butylene (-CHCH3CH2CH2-), t-butylene (-CCH3CH3CH2-), n-pentylene (-CH2CH2CH2CH2CH2-), or n-hexylene (-CH2CH2CH2CH2CH2CH2-).

6. The benzamide derivative compound represented by the above formula I according to claim 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, wherein L2 is a single bond or ethynylene group ( ).

7. The benzamide derivative compound represented by the above Formula I, stereoisomer, pharmaceutically acceptable salt, or hydrate or solvate thereof according to claim 1 or 2, wherein X is ; ; ; ; ; ; ; ; ; ; ; ; or , wherein the -H of said X is unsubstituted, or when X is or unsubstituted, or at least one -H each independently is substituted with C1-C6alkyl, halogen, -C1-C6alkoxy, -OH, or -CF3, and when X is -CH2- is unsubstituted, or at least one -CH2- each independently is replaced with -(C=0)-.

8. The benzamide derivative compound represented by the above Formula I, stereoisomer, pharmaceutically acceptable salt, or hydrate or solvate thereof according to claim 1, wherein L3 is a single bond; C1-C6 alkylene; C2-C6 alkenylene; -(C=O)-; -(C=O)-NRc-; -C(=O)NRd-(C1-C6 alkylene)-; -NRyC(=O)-(C1-C6 alkylene); -NHC(=O); or -O(C=O)-(C1-C6 alkylene), wherein each of Rc, Rd, or Ry is independently -H or C1-C6 alkyl.

9. The benzamide derivative compound represented by the above Formula I, stereoisomer, pharmaceutically acceptable salt, or hydrate or solvate thereof according to claim 8, wherein L3 is a single bond; -(CH2)-; -(CH2)2-; -(CH2)3-; -(CH2)4-; -(CH2)5-; -(C=O)-NH(CH2)n-; -NH(C=O)-; -NH(C=O)-(CH2)m; -(C=O)NH-; -(CH=CH)-CH2-; -O(C=O)CH2; or -(C=O)-, wherein each of n and m is independently 1, 2, 3, or 4.

10. The benzamide derivative compound represented by the above formula I according to claim 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, wherein the R2 is H; halogen; C1-C6 alkyl; C1-C6 alkoxy; -OH; -NH2; ; ; ; ; ; ; ; ; ; ; ; ; ; or , wherein the -H of R2 is unsubstituted, or at least one -H of R2 is each independently substituted with halogen, -C1-C6alkoxy, -NH2, -OH, -CF3, -NO2, -C1-C6alkyl, -(CH2)3-NH2, -(CH2)2-NH2, -(CH2)-NH2, -(C=0)NH2, -NHCH3, -NHCH(CH3)2, or -COOH.

11. The benzamide derivative compound represented by the above Formula I, stereoisomer, pharmaceutically acceptable salt, or hydrate or solvate thereof according to claim 1 or 2, wherein L4 is a single bond; -C1-C6alkylene-; -NRm-(C1-C6alkylene)-; or -NRn-, wherein Rmand Rnare each independently -H or C1-C6.

12. The benzamide derivative compound represented by the above Formula I, stereoisomer, pharmaceutically acceptable salt, or hydrate or solvate thereof according to claim 11, wherein L4 is a single bond; -(CH2)-; -(CH2)2-; -(CH2)3-; -(CH2)4-; -(CH2)5-; -NH-; -NHCH2-; -NH(CH2)2-; -NH(CH2)3-; -CH(CH3)-; -CH2NH-; -(CH2)2NH-; or -(CH2)3NH-, wherein the -H of L4 is unsubstituted, or at least one -H of L4 is each independently substituted with -C1-C6alkyl.

13. The benzamide derivative compound represented by the above Formula I, stereoisomer, pharmaceutically acceptable salt, or hydrate or solvate thereof according to claim 1, wherein R3 is H; C1-C6 alkyl; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; or , wherein the -H of R3 is unsubstituted, or at least one H of R3 is each independently substituted with -C1-C6alkyl, -C1-C6alkoxy, -phenoxy, -OH, -(C1-C6alkylene)-OH, -COOH, -(C1-C6alkylene)-COOH, (C1-C6alkylene)-CN, -NRoRp, (C1-C6alkylene)-NRqRr, -C(=0)-(C1-C6alkyl), -C(=0)-(C3-C8cycloalkyl), -C(=0)-(6- to 14-membered aryl), -NO2, -CHF2, -CF3, -OCF3, -C(=0)NRsRt(wherein the -H of -C(=0)NRsRt is unsubstituted, or at least one -H thereof is each independently substituted with halogen), -C(=0)-(C1-C6alkylene)-NRuRv, -NRwRx, or halogen, and when the R3 is heterocycloalkenyl, -CH2- is unsubstituted, or at least one -CH2- is each independently replaced with -(C=0)-, wherein Ro, Rp, Rq, Rr, Rs, Rt, Ru, Rv, Rw, or Rx are each independently H or C1-C6alkyl in each instance.

14. The benzamide derivative compound represented by the above Formula I, stereoisomer, pharmaceutically acceptable salt, or hydrate or solvate thereof according to claim 1, wherein R3 is wherein the -H of R3 is unsubstituted, or at least one H of R3 is each independently substituted with -C1-C6alkyl, -C1-C6alkoxy, -phenoxy, -OH, -(C1-C6alkylene)-OH, -COOH, -(C1-C6alkylene)-COOH, (C1-C6alkylene)-CN, -NRoRp, (C1-C6alkylene)-NRqRr, -C(=0)-(C1-C6alkyl), -C(=0)-(C3-C8cycloalkyl), -C(=0)-(6- to 14-membered aryl), -NO2, -CHF2, -CF3, -OCF3, -C(=0)NRsRt(wherein the -H of -C(=0)NRsRt is unsubstituted, or at least one -H thereof is each independently substituted with halogen), -C(=0)-(C1-C6alkylene)-NRuRv, -NRwRx, or halogen, and when the R3 is heterocycloalkenyl, -CH2- is unsubstituted, or at least one -CH2- is each independently replaced with -(C=0)-, wherein Ro, Rp, Rq, Rr, Rs, Rt, Ru, Rv, Rw, or Rx are each independently H or C1-C6alkyl in each instance.

14. The benzamide derivative compound represented by Formula I above according to claim 13, its stereoisomers, their pharmaceutically acceptable salts, or their hydrates or solvates, wherein the -H of R3 is unsubstituted, or at least one -H of R3 is independently substituted by -C1-C6 alkyl, -C1-C6 alkoxy, -phenoxy, -OH, -CH2F, -CHF2, -CF3, -OCF3, halogen, -(C=O)OCH2CH3, -(C=O)CH3, -(C=O)CH(CH3)2, -(C=O)CHCH3NH2, -NH2, -NHCH3, -N(CH3)2, -COO H, -(C=O)NH2, -(C=O)NHCH3, -(C=O)N(CH3)2, -NO2, -(C=O)NHCH2CF3, -CH(CH3)OH, -CH2(CH3)OH, -CH2CN, -CH(CH3)CN, -C(CH3)CH2CN, -( CH2)2NH2, -(CH2)NH2, -(CH2)3NH2, -(CH2)4NH2, -(CH2)2OH, -(CH2)OH, -(CH2)3OH, -(CH2)4OH, -(CH2)2COOH, -(CH2)COOH, -(CH2)3COOH, , , , ,or Replace, and when said R3 is In this case, -CH2- is not substituted, or at least one -CH2- is substituted by -(C=O)-.

15. The benzamide derivative compound represented by the above formula I according to claim 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, wherein the above formula I is a compound represented by the following formula I-1: <Formula I-1> wherein in the above formula I-1, R1, L1, X, L3, R2, L4, R3 are as defined in claim 1.

16. The benzamide derivative compound represented by the above formula I according to claim 15, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, wherein the R1 is ; ; ; ; ; or wherein the -H of the R1 is unsubstituted, or each of at least one H thereof is independently substituted with halogen, -NH2, -NO2, -NHCH3, -N(CH3)2, or -OH.

17. The benzamide derivative compound represented by the above formula I according to claim 15, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, wherein L1 is methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), i-propylene (-CHCH3CH2), n-butylene (-CH2CH2CH2CH2-), s-butylene (-CHCH3CH2CH2-), i-butylene (-CH2CHCH3CH2-), t-butylene (-CCH3CH3CH2-), n-pentylene (-CH2CH2CH2CH2CH2-), n-hexylene (-CH2CH2CH2CH2CH2CH2-), and the like, specifically methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), i-propylene (-CHCH3CH2), n-butylene (-CH2CH2CH2CH2-), n-pentylene (-CH2CH2CH2CH2CH2-), or n-hexylene (-CH2CH2CH2CH2CH2CH2-).

18. The benzamide derivative compound represented by the above formula I, stereoisomer thereof, pharmaceutically acceptable salt thereof, or hydrate or solvate thereof according to claim 15, wherein X is ; ; ; or wherein the -H of X is unsubstituted, or at least one -H is each independently substituted with C1-C6 alkyl, halogen, -OH, -C1-C6 alkoxy, or -CF3.

19. The benzamide derivative compound represented by the above formula I, its stereoisomer, their pharmaceutically acceptable salts, or their hydrates or solvates according to claim 15, wherein when the X is -H is unsubstituted, or at least one -H is each independently substituted with C1-C6 alkyl, halogen, -C1-C6 alkoxy, -OH, or -CF3.

20. The benzamide derivative compound represented by the above formula I according to claim 15, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, wherein L3 is a single bond, -(CH2)-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(C=0)-NH(CH2)n-, -(C=0)NH-, or -(C=0)-, wherein n is 0, 1, 2, 3, or 4.

21. The benzamide derivative compound represented by the above formula I according to claim 15, stereoisomers thereof, pharmaceutically acceptable salts thereof, or hydrates or solvates thereof, wherein R2 is H; halogen; C1-C6 alkyl; C1-C6 alkoxy; -NH2; ; ; or , wherein the -H of said R2 is unsubstituted, or at least one -H of R2 is each independently substituted with halogen, -Ci-C6alkoxy, -NH2, or -Ci-C6alkyl.

22. The benzamide derivative compound represented by the above formula I according to claim 15, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, wherein L4 is a single bond; -(CH2)-; -(CH2)2-; -(CH2)3-; -(CH2)4-; -(CH2)5-; -NH-; -NHCH2-; -NH(CH2)2-; or -NH(CH2)3-, wherein the -H of said L4 is unsubstituted, or at least one -H of L4 is each independently substituted with -Ci-C6alkyl.

23. The benzamide derivative compound represented by the above formula I according to claim 15, stereoisomers thereof, pharmaceutically acceptable salts thereof, or hydrates or solvates thereof, wherein R3 is H; C1-C6 alkyl; ; ; ; or , wherein the -H of R3is unsubstituted, or at least one -H of R3is each independently replaced with -Ci-C6alkyl, -Ci-C6alkoxy, -NH2, -CF3, -OCF3, halogen, or substituted.

24. The benzamide derivative compound represented by the above Formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof according to claim 1, wherein the above Formula I is a compound represented by the following Formula I-2: <Formula I-2> wherein in the above Formula I-2, R1, L1, X, L3, R2, L4, R3 are as defined in claim 1.

25. The benzamide derivative compound represented by the above Formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof according to claim 24, wherein in the above Formula I-2, said R1 is or wherein said -H of R1 is unsubstituted, or at least one H thereof is each independently substituted with halogen (F, Cl, Br, or I), -NH2, -NO2, -NHCH3, -N(CH3)2, or -OH; the L1 is a C1-C6 alkylene group; said X is or wherein said -H of said X is unsubstituted, or at least one -H each independently is substituted with C1-C6 alkyl, halogen (F, Br, Cl, or I), -OH, -C1-C6 alkoxy, or -CF3, and when said X is -CH2- is unsubstituted, or at least one -CH2- each independently is replaced with -(C=0)-; the L3 is a single bond or a C1-C6 alkylene group; said R2is H, halogen, -NH2, or ; wherein the -H of said R2is unsubstituted, or at least one -H of R2is each independently substituted with halogen (F, Cl, Br, or I), -C1-C6alkoxy, -NH2, or -C1-C6alkyl; L4 is a single bond, -C1-C6 alkylene-; and said R3 is wherein said -H of R3 is unsubstituted, or at least one -H of R3 is each independently substituted with -Ci-C6alkyl, -Ci-C6alkoxy, or halogen.

26. The compound of the following Table A, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof: [Table A] 27. A pharmaceutical composition comprising the compound represented by the above Formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof according to claim 1.

28. The pharmaceutical composition according to claim 27, wherein the pharmaceutical composition has NAMPT inhibitory activity.

29. The pharmaceutical composition according to claim 28, wherein the pharmaceutical composition is used for the prevention or treatment of cancer.

30. The pharmaceutical composition according to claim 29, wherein the cancer is a solid cancer or a blood cancer.

31. The pharmaceutical composition according to claim 30, wherein the cancer is selected from one of skin cancer, melanoma, lymphoma, breast cancer, cervical cancer, uterine cancer, gastrointestinal cancer, lung cancer, ovarian cancer, prostate cancer, colorectal cancer, colon cancer, rectal cancer, oral cancer, brain cancer, head and neck cancer, throat cancer, testicular cancer, kidney cancer, pancreatic cancer, bone cancer, spleen cancer, liver cancer, bladder cancer, laryngeal cancer, nasal cancer, AIDS-related cancer, esophageal cancer, stomach cancer, gastric cancer, pancreatic cancer, colorectal cancer, virus-related cancer, nasopharyngeal cancer, vaginal cancer, vulvar cancer, penile cancer, Kaposi's sarcoma, Burkitt's lymphoma, T-cell lymphoma and Merkel cell carcinoma, multiple myeloma, acute and chronic leukemia, lymphocytic leukemia, myeloid leukemia, lymphocytic leukemia and myelocytic leukemia.

32. A method for preventing or treating cancer, the method comprising: administering the compound represented by the above Formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof according to claim 1, or the pharmaceutical composition according to claim 27 to an individual.

33. Use of the compound represented by the above Formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof according to claim 1, or the pharmaceutical composition according to claim 27 for the prevention or treatment of cancer.

34. Use of the compound represented by the above Formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof according to claim 1, or the pharmaceutical composition according to claim 27 for the manufacture of a medicament for the prevention or treatment of cancer.

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