Novel compounds and pharmaceutical compositions containing the same

Abstract

The present invention relates to a novel urea compound, its optical isomer, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, and the novel compound exhibits NAMPT inhibitory activity and can effectively prevent or treat cancer.

Description

[Technical Field]

[0001] The present invention relates to a compound represented by the following chemical formula I, an optical isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof, and uses thereof. [Background technology]

[0002] Nicotinamide phosphoribosyltransferase (NAMPT) is an enzyme that induces nicotinamide mononucleotide (NMN) synthesis from nicotinamide (NAM) and 5'phosphoribosyl-1'-pyrophosphate (PRPP) and plays a key role in the cyclic biosynthetic pathway of nicotinamide adenine dinucleotide (NAD+). NAD is essential for multiple signaling pathways, including mono-ADP-ribosylation in both the immune system and G-protein-coupled receptor signaling, among other poly-ADP-ribosylation in DNA repair. NAD is also essential for the deacetylase activity of sirtuins.

[0003] NAD+ is produced by two distinct biosynthetic pathways: salvage and de novo. As the rate-limiting enzyme in the NAD+ salvage pathway, NAMPT is biologically essential and has been implicated in a number of diverse diseases.

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

[0005] [Patent Document 1] Korean Patent Publication No. 10-2015-0014250 Summary of the Invention [Problem to be solved by the invention]

[0006] The present invention provides a novel urea compound, an optical isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

[0007] The present invention provides a pharmaceutical composition comprising a novel urea compound, an optical isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

[0008] The present invention provides a method for producing a novel urea compound, an optical isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

[0009] The present invention provides a pharmaceutical composition for preventing or treating a disease (e.g., cancer) that can be treated by inhibiting NAMPT, comprising a novel urea compound, its optical isomer, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient.

[0010] Another object of the present invention is to provide a method for preventing or treating a disease (e.g., cancer) that can be treated by inhibiting NAMPT, comprising the step of administering to an individual a novel urea compound, its optical isomer, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

[0011] Another object of the present invention is to provide a novel urea compound, its optical isomer, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof for the prevention or treatment of a disease (e.g., cancer) that can be treated by inhibiting NAMPT.

[0012] Another object of the present invention is to provide a use of a novel urea compound, its optical isomer, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof for the manufacture of a drug for the prevention or treatment of a disease (e.g., cancer) that can be treated by inhibiting NAMPT. [Means for solving the problem]

[0013] The present inventors have identified compounds with novel structures that have NAMPT inhibitory activity, and have completed the present invention by using these compounds to prevent and / or treat diseases that can be treated by inhibiting NAMPT.

[0014] The present invention will be described in more detail below. All combinations of the various elements disclosed in the present invention fall within the scope of the present invention. In addition, the following specific descriptions are not intended to limit the scope of the present invention.

[0015] The present invention provides a urea compound represented by the following chemical formula I, an optical isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof:

[0016] [ka] In the above formula I, R1 is NHYx (the above Y x may be a 3- to 6-membered heteroaryl, wherein at least one H of the heteroaryl may be substituted), an aryl (wherein at least one —H of the aryl and heteroaryl may be substituted with a substituent), or a heteroaryl (wherein at least one —H of the aryl and heteroaryl may be substituted with a substituent); R2 is any substituent other than H (any substituents except -H), and is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocycloalkyl, bicycloalkyl, biheterocycloalkyl, alkylamine, C 1-10 Amides of C 1-10or phenoxy, wherein the R2 group may be unsubstituted or substituted with at least one H; Ak is -(CH2)n- or C 3-6 wherein -(CH)- or -H in the cycloalkylene group is unsubstituted, or at least one -H is independently substituted with a substituent, and n is 0 to 5; X1, X2, and X3 are each independently -CH- or -N-; R3 is Aryl or heteroaryl (at least one -H of the aryl or heteroaryl may be substituted with another substituent).

[0017] In this specification, when a functional group is represented as "Cx", x represents the number of carbon atoms (C), and Cx-y means an integer having a carbon number of x or more and y or less.

[0018] As used herein, the term "substituted" refers to a moiety having a substituent replacing an -H at one or more carbons (-C-) or nitrogens (-N-) in the backbone. "Substituted" or "substituted with" is defined to include the implicit proviso that such substitution, subject to the substituted atom and the permissible valence of the substituent, leads to a stable compound, e.g., a compound that does not spontaneously deform by rearrangement, cyclization, elimination, etc.

[0019] In this specification, the term "single bond" refers to a direct bond between adjacent atoms or atomic groups.

[0020] As used herein, unless otherwise specified, "alkyl" means a linear or branched saturated hydrocarbon group, which may be one or more selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and n-heptyl, and the like, but is not limited to these.

[0021] In the present invention, unless otherwise specified, "alkylene" refers to a divalent functional group derived from alkyl as defined above. For example, C alkylene is methylene (-CH-).

[0022] As used herein, unless otherwise specified, "alkenyl" refers to an unsaturated hydrocarbon group containing at least one double bond between carbon atoms, and can refer to unsaturated hydrocarbon groups that are straight-chain or branched, and include cis and trans configurations, unless otherwise specified. As used herein, "alkylene" refers to a divalent functional group derived from alkyl as defined above, unless otherwise specified.

[0023] As used herein, unless otherwise specified, "alkynyl" means an unsaturated hydrocarbon group containing at least one triple bond between carbon atoms.

[0024] In this specification, unless otherwise specified, "aryl" includes monocyclic aromatic, bicyclic aromatic, or polycyclic aromatic, and may include cases in which one or more of the two or more rings are aromatic, and may be one or more selected from phenyl, biphenyl, naphthalenyl, and the like, but is not limited thereto.

[0025] As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic, or polycyclic heterocycle in which at least one carbon atom in the aryl group is replaced with nitrogen (N), oxygen (O), or sulfur (S), or a polycyclic structure in which two or more rings share one or more pairs of atoms, and may include cases in which one or more of the two or more rings are aromatic. Heteroaryl can be one or more selected from, but is not limited to, pyridinyl, pyrimidinyl, furanyl, thiophenyl, triazolyl, tetrazolyl, benzothiazolyl, benzothiophenyl, quinolinyl, indolyl, isoindolyl, benzofuranyl, benzopyrrolyl, furanyl, pyrrolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxazolyl, imidazolyl, isoxazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, isoquinolinyl, benzoxazolyl, benzimidazolyl, dihydrobenzothiophenyl, purinyl, indolizinyl, pyrrolyl, quinazolyl, imidazopyridinyl, benzoxazolyl, imidazoimidazolyl, imidazotriazolyl, and chromenyl.

[0026] As used herein, "cycloalkyl" refers to a saturated hydrocarbon ring having three or more specified carbon atoms, including the ring, and the saturated hydrocarbon ring refers to both monocyclic and polycyclic structures, including bicycloalkyl. "Bicycloalkyl" refers to a saturated hydrocarbon ring generally having three or more specified carbon atoms, including the ring, in which two or more rings share one or more pairs of carbon atoms, and includes cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. [ka] The compound may be one or more selected from the above, but is not limited to this.

[0027] As used herein, "heterocycloalkyl" refers to saturated mono- and polycyclic heterocycles containing 1 to 5 heteroatoms independently selected from nitrogen (N), oxygen (O), and sulfur (S), or polycyclic structures in which two or more rings share one or more pairs of carbon atoms. Heterocycloalkyl may be one or more selected from, but is not limited to, oxiranyl, oxetanyl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, azabicyclohexanyl, azabicycloheptanyl, tetrahydrothiopyranyl, and the like.

[0028] 1) The present invention provides a urea compound represented by the following chemical formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof:

[0029] [ka] In the compound represented by Formula I, R1, R2, R3, Ak, X1, X2, and X3 may each be as follows: In an embodiment of the present invention, R1 is 6- to 12-membered aryl (e.g., C 6-12 aryl); or It may be a 5- to 12-membered heteroaryl containing at least one heteroatom selected from the group consisting of N, O and S.

[0030] wherein each —H in the aryl or heteroaryl represented by R1 is independently unsubstituted, or at least one H is independently —NH2, —(C 1-5 alkyl)NH2, -NH-(C 1-5 alkyl), -N(C 1-5 alkyl)2, -OH, -NO2, C 1-5 It may be substituted with alkyl, -F, -Cl, -Br, or -I.

[0031] 2) In the above 1), specifically, R1 is [ka] wherein Z1 to Z 22 may each independently be -CH-, -CH2, -N-, -NH, -O- or -S-, wherein -H in the above group listed for R1 is unsubstituted or at least one H is each independently -NH2, -(C 1-5 alkyl)NH2, -NH(C 1-5 alkyl), -N(C 1-5 alkyl)2-OH, -NO2, -C 1-5 It may be substituted with alkyl, -F, -Cl, -Br, or -I.

[0032] 3) In the above 1) or 2), specifically, R1 is [ka] wherein Z1 to Z 22 may each independently be -CH, -CH2, -N-, -NH-, -O- or -S-, wherein -H in the above group listed for R1 is each independently unsubstituted, or at least one H is each independently substituted with -NH2, -(C 1-5 alkyl)NH2, -NH-(C 1-5 alkyl), -N(C 1-5 alkyl)2-OH, -NO2, C 1-5 It may be substituted with alkyl, -F, -Cl, -Br, or -I.

[0033] 4) In any one of the above 1) to 3), more specifically, R1 is [ka] wherein each —H in the group listed above for R1 is independently unsubstituted, or at least one —H is independently —NH2, —(C 1-5 alkyl)NH2, -NH-(C1-5 alkyl), -N(C 1-5 alkyl)2, -OH, -NO2, C 1-5 It may be substituted with alkyl, -F, -Cl, -Br, or -I.

[0034] 5) In any one of the above 1) to 4), more specifically, R1 is [ka] wherein -H in the group listed above for R1 is unsubstituted, or at least one -H is independently -NH2, -(C 1-5 alkyl)NH2, -NH(C 1-5 alkyl), -N(C 1-5 alkyl)2, -OH, -NO2, C 1-5 It may be substituted with alkyl, -F, -Cl, -Br, or -I.

[0035] 6) In any one of 1) to 5), according to an embodiment of the present invention, R2 is [ka] (The above Rx1 is C 1-5 Alkyl; C 2-5 Alkenyl; 6- to 12-membered aryl (e.g., C 6-12 aryl); 3- to 10-membered cycloalkyl (e.g., C 3-10 a 3- to 10-membered heterocycloalkyl containing at least one heteroatom selected from the group consisting of N, O, and S; or a 5- to 12-membered heteroaryl containing at least one heteroatom selected from the group consisting of N, O, and S; -NRx2Rx3 (wherein Rx2 or Rx3 are each independently H or C) 1-6 alkyl); 6- to 12-membered aryl (e.g., C 6-12aryl); 5- to 12-membered heteroaryl containing at least one heteroatom selected from the group consisting of N, O, and S; -ORx4 (Rx4 is 3- to 7-membered aryl); 3- to 10-membered heterocycloalkyl containing at least one heteroatom selected from the group consisting of N, O, and S; 3- to 10-membered cycloalkyl (e.g., C 3-10 cycloalkyl); [ka] (Za may be a single bond, -NH or -CH2-, and Rx5 is a 5- to 12-membered heteroaryl containing at least one heteroatom selected from the group consisting of N, O and S, a 6- to 12-membered aryl (e.g., C 6-12 aryl), 3- to 10-membered cycloalkyl (e.g., C 3-10 cycloalkyl), or a 3- to 10-membered heterocycloalkyl containing at least one heteroatom selected from the group consisting of N, O, and S, or -NYaYb {Ya or Yb are each independently H or C 1-6 alkyl}); [ka] (Zb may be a single bond, -NH, -NHCH2-, -NH(CH2)2-CH2-, -(CH2)2-, -(CH2)3-, or -CH2NH-; Rx6 is a 5- to 12-membered heteroaryl containing at least one heteroatom selected from the group consisting of N, O, and S, a 6- to 12-membered aryl (e.g., C 6-12 aryl), 3- to 10-membered heterocycloalkyl containing at least one heteroatom selected from the group consisting of N, O, and S, -NYcYd {Yc or Yd are each independently H, C 1-6 Alkyl or C 3-6 cycloalkyl} or 3- to 10-membered cycloalkyl (e.g., C 3-10 wherein b is an integer of 0 to 4; [ka] may be.

[0036] wherein each —H in each group of R2 is independently unsubstituted, or at least one —H is independently C 1-5 alkyl (wherein -H of said alkyl may be unsubstituted or at least one -H may be independently substituted with one selected from the group consisting of phenyl, pyridinyl, morpholinyl, piperazine, and piperidine); -(C 1-5 alkyl)NH2;-NH2;-NH(C 1-5 alkyl);-N(C 1-5 alkyl)2, -NHCH3; -N(CH3)2; -NHCH2CH3; -OH; -NO2; -F; -Cl; -Br; -I; -CHF2; -CF3; -C 1-5 Alkoxy; -C(=O)N(CH3)2; -C(=O)NHCH3; -C(=O)NH2; -NHC(=O)CH3; -C(=O)CH2CH3; 6- to 12-membered aryl (e.g., C 6-12 aryl), wherein -H of the aryl is unsubstituted or at least one -H is replaced with -C 1-3 alkyl and -CF3; 5- to 12-membered heteroaryl containing at least one heteroatom selected from the group consisting of N, O and S (-H of the heteroaryl is unsubstituted or at least one -H is replaced with -C 1-3 alkyl and -CF3; 3- to 10-membered cycloalkyl (e.g., C 3-10 a 3- to 10-membered heterocycloalkyl containing at least one heteroatom selected from the group consisting of N, O, and S (wherein -H in the heterocycloalkyl is unsubstituted or at least one -H is replaced with -C 1-3 optionally substituted with one selected from the group consisting of alkyl and -CF3; 3- to 10-membered cycloalkoxy; -S(=O)2NHCH3; -S(=O)2, -S(=O)2-CH3, -C(=O)NH2; [ka] (The Ra1 and Ra2 are each independently H, F, Cl, Br, I, or -C 1-5 alkyl, and Y1 may be one selected from -CH2, -NH, -, and -O-; [ka] (The above Ra3 is -H, -C 1-5 may be alkyl or -CF3); [ka] may be substituted with one selected from the group consisting of:

[0037] 7) In any one of 1) to 6), according to an embodiment of the present invention, R2 is [ka] where Rx1 may be -C 1-5 Alkyl, -C 2-5 Alkenyl; 6- to 12-membered aryl (e.g., C 6-12 aryl); 3- to 10-membered cycloalkyl (e.g., C 3-10 a cycloalkyl having at least one heteroatom selected from the group consisting of N, O, and S; a 3- to 10-membered heterocycloalkyl having at least one heteroatom selected from the group consisting of N, O, and S; or a 5- to 12-membered heteroaryl having at least one heteroatom selected from the group consisting of N, O, and S. [ka] -H is unsubstituted or at least one -H is each independently -C 1-5alkyl (wherein -H of said alkyl is unsubstituted or at least one -H may each independently be substituted with one selected from the group consisting of phenyl, pyridinyl, morpholinyl, piperazine, and piperidine), -morpholinyl, piperazinyl, piperidinyl, -phenyl (wherein -H of said -morpholinyl, -piperazinyl, -piperidinyl, and -phenyl is unsubstituted or at least one -H may each independently be substituted with one selected from the group consisting of -C 1-3 and a may be 0, 1, 2, 3, or 4.

[0038] 8) In any one of 1) to 6), according to an embodiment of the present invention, R2 may be -NRx2Rx3, where Rx2 or Rx3 are each independently H or C. 1-6 When Rx2 or Rx3 is alkyl, -H of Rx2 and Rx3 is not substituted, or at least one -H is each independently selected from the group consisting of C 1-6 It may be substituted with alkyl, -F, -Cl, -Br or -I.

[0039] 9) In any one of the above 1) to 6), according to an embodiment of the present invention, R2 is a 6- to 12-membered aryl (for example, C 6-12 The -H of the aryl may be unsubstituted or at least one -H may be independently selected from C 1-5 alkyl (wherein -H of said alkyl is unsubstituted or at least one -H may each independently be substituted with one selected from the group consisting of phenyl, pyridinyl, morpholinyl, piperazine, and piperidine), F, -Cl, -Br, -I, -morpholinyl, -piperazinyl, piperidinyl (wherein -H of said -morpholinyl, -piperazinyl, and -piperidinyl is unsubstituted or at least one -H may each independently be substituted with one selected from the group consisting of -C 1-3-cyclobutoxy, -cyclopropoxy, -cyclopentoxy, [ka] (The Ra1 and Ra2 are each independently -H, -F, -Cl, -Br-, -I, or -C 1-5 alkyl, and Y1 may be one selected from -CH2, -NH, -, and -O-; [ka] , -C 1-3 It may be substituted with one selected from the group consisting of alkoxy, -C(=O)-N(CH3)2 and -C(=O)NH2.

[0040] 10) In any one of 1) to 6), according to an embodiment of the present invention, R2 may be a 5- to 12-membered heteroaryl containing at least one heteroatom selected from the group consisting of N, O, and S. The -H of the heteroaryl may be unsubstituted or at least one -H may be independently substituted with -C 1-5 Alkyl, -F, -Cl, -Br, -I, -NH2, -NH(C 1-5 alkyl), -N(C 1-5 and -C(=O)NH(CH).

[0041] 11) In any one of 1) to 6), according to an embodiment of the present invention, R2 may be -ORx4. Rx4 may be a 6- to 7-membered aryl (e.g., C such as phenyl). 6-7 aryl), and each of the -H in the -ORx is unsubstituted, or at least one -H is independently -C 1-5 Alkyl, F, -Cl, -Br, -I, -NH2, -NH(C 1-5alkyl), -N(C 1-5 and -C(=O)NH(CH3).

[0042] 12) In any one of 1) to 6), according to an embodiment of the present invention, R2 may be a 3- to 10-membered heterocycloalkyl containing at least one heteroatom selected from the group consisting of N, O, and S. Here, -H in the heterocycloalkyl is unsubstituted or at least one -H is each independently substituted with -C 1-5 alkyl (wherein -H of said alkyl is unsubstituted or at least one -H may each independently be substituted with one selected from the group consisting of phenyl, pyridinyl, morpholinyl, piperazine, and piperidine), pyridinyl, phenyl (wherein -H of said pyridinyl and phenyl is unsubstituted or at least one or more -H may each independently be substituted with one selected from the group consisting of C 1-3 optionally substituted with one selected from the group consisting of alkyl and -CF3, [ka] , -NHC(=O)CH3, -C(=O)CH2CH3, [ka] (The above Ra3 is H, -C 1-3 -C(═O)CH, -NH, -NH(C 1-5 alkyl), -N(C 1-5 It may be substituted with one selected from the group consisting of -N(CH3)2, -NHCH3, -N(CH3)2, and -NHCH2CH3.

[0043] 13) In any one of the above 1) to 6), according to an embodiment of the present invention, R2 is a 3- to 10-membered cycloalkyl (for example, C 3-10cycloalkyl).

[0044] 14) In any one of 1) to 6), according to an embodiment of the present invention, R2 is [ka] wherein Za may be a single bond, -NH or -CH2-, and Rx5 may be a 5- to 12-membered heteroaryl containing at least one heteroatom selected from the group consisting of N, O and S, a 6- to 10-membered aryl (e.g., C 6-12 aryl), 3- to 10-membered cycloalkyl, or 5- to 12-membered heterocycloalkyl containing at least one heteroatom selected from the group consisting of N, O, and S; -NYaYb (Ya or Yb are each independently H or C); 1-6 alkyl). [ka] -H is unsubstituted or at least one -H is each independently 1-5 alkyl (wherein -H of said alkyl may be unsubstituted or at least one -H may be each independently substituted with one selected from the group consisting of phenyl, pyridinyl, morpholinyl, piperazine, and piperidine), -CF3, [ka] , pyridinyl, pyrimidinyl, piperazinyl, morpholinyl, piperidinyl (wherein -H of the pyridinyl, pyrimidinyl, piperidinyl, piperazinyl, and morpholinyl is not substituted or at least one -H is -C 1-3 and -CF3) [ka] , -NH2, -F, -Cl, -Br or -I. 15) In any one of 1) to 6), according to an embodiment of the present invention, R2 is [ka] wherein Zb may be a single bond, -NH, -NHCH2-, -NH(CH2)2-CH2-, -(CH2)2-, -(CH2)3-, or -CH2NH-, and Rx6 may be a 5- to 12-membered heteroaryl containing at least one heteroatom selected from the group consisting of N, O, and S, a 6- to 10-membered aryl (e.g., C aryl such as phenyl), or 6-12 aryl), 3- to 10-membered heterocycloalkyl containing at least one heteroatom selected from the group consisting of N, O, and S, -NYcYd (Yc or Yd are each independently H, -C 1-6 Alkyl or C 3-6 cycloalkyl), or 3- to 10-membered cycloalkyl (e.g., C 3-10 cycloalkyl), and b may be an integer of 0 to 4. [ka] -H is unsubstituted or at least one -H is each independently -C 1-5 alkyl (wherein -H of said alkyl may be unsubstituted or at least one -H may be each independently substituted with one selected from the group consisting of phenyl, pyridinyl, morpholinyl, piperazine, and piperidine), -CF3, [ka] , pyridinyl, pyrimidinyl, piperidinyl, piperazinyl, -morpholinyl (in pyridinyl, pyrimidinyl, piperidinyl, piperazinyl, and morpholinyl, -H is unsubstituted or at least one or more -H is each independently -C 1-3 optionally substituted with one selected from the group consisting of alkyl and —CF3, [ka] , -NH2, -F, -Cl, -Br or -I.

[0045] 16) In any one of 1) to 6), according to an embodiment of the present invention, R2 is [ka] wherein the -H in the group is unsubstituted or at least one -H is independently selected from the group 1-5 Alkyl, -NH2, -NHCH2CH3, -(C 1-5 It may be substituted with one selected from the group consisting of alkyl)NH2, -F, -Cl, -Br, and -I.

[0046] 17) In any one of 1) to 16), according to an embodiment of the present invention, R2 is [ka] wherein the -H in the group is unsubstituted or at least one -H is each independently -C 1-5 It may be substituted with one selected from the group consisting of alkyl, -NH2, -NHCH2CH3, -F, -Cl, -Br, and -I.

[0047] 18) In any one of the above 1) to 17), according to an embodiment of the present invention, R3 is a 6- to 12-membered aryl (for example, C 6-12 aryl); 5- to 12-membered heteroaryl containing at least one heteroatom selected from the group consisting of N, O, and S; 3- to 10-membered heterocycloalkyl containing at least one heteroatom selected from the group consisting of N, O, and S; or 3- to 10-membered cycloalkyl (e.g., C 3-10 Heterocycloalkyl). The above groups listed in R3 are each independently unsubstituted, or at least one H is each independently -NH2, -OH, -NO2, C 1-3 Alkyl, -F, -Cl, -Br, -I, -C 1-3 alkylamine, 6- to 12-membered aryl, 5- to 10-membered heteroaryl containing at least one heteroatom selected from the group consisting of N, O, and S, or 3- to 10-membered heterocycloalkyl containing at least one heteroatom selected from the group consisting of N, O, and S, C 5-12 It may be substituted with a bicycloalkyl, a 3- to 8-membered cycloalkyl, -CHF2, or -CF3.

[0048] 19) In any one of 1) to 18), according to an embodiment of the present invention, each -H in each of the groups listed in R3 may be independently unsubstituted, or at least one -H may be independently substituted with a group selected from the group consisting of the following 1) to 18): 1) C 1-5 alkyl; 2) -F, -Cl, -Br, or -I 3) [ka] , where Rx7 is C 1-3 may be alkyl or -CF3; 4) [ka] , where c is 0, 1, 2, or 3, and Rx8 is C 1-5 Alkyl, -NH2, -NHCH3, -N(CH3)2, piperidinyl, piperazinyl, morpholinyl, [ka] (wherein Rb1 may be —NH2 or —CH2OH), [ka] (wherein Rb2 may be -CH2-, -NH- or -O-, and Rb3 and Rb4 may each independently be -H, -F, -Cl, -Br or -I), pyridinyl, pyrimidinyl or pyrrolyl, and Rx9 may be -H or C 1-5 may be alkyl; 5)-COOH; 6)-NRx 10 Rx 11 , where Rx 10 or Rx 11 may each independently be -H or -CH3; 7)-CF3; 8)-CN; 9) morpholinyl or one or more -H are each independently selected from C 1-5 morpholidinyl substituted with alkyl, -F, -Cl, -Br, I, -C(=O)NHCH3, -C(=O)CH3, or -C(=O)CH=CH2; 10) piperidinyl or one or more -H are each independently C 1-5 piperidinyl substituted with alkyl, -F, -Cl, -Br, I, -C(=O)NHCH3, -C(=O)CH3, or -C(=O)CH=CH2; 11) piperazinyl or one or more -H are each independently C 1-5 piperazinyl substituted with alkyl, -F, -Cl, -Br, I, -C(=O)NHCH3, -C(=O)CH3, or -C(=O)CH=CH2; 12)-ORx 12 , where R 12 Rx 12 is -CF3;C 1-3 may be alkyl; 13)-OH; 14) [ka] , where d can be 0, 1, 2 or 3; Rx 13may be -NH2, -NH(CH3), -N(CH3)2 pyrazolyl, methylpyrazolyl, pyrazolyl, piperazinyl, piperidinyl, or morpholinyl; 15) [ka] , where Rx 14 may be -CH2-, -NH or -O-, and Rx 15 -H, C 1-5 may be alkyl, -NH2, -F, -Cl, -Br, or -I; 16) [ka] , where Rx 16 is C 1-5 may be alkyl or -CH2CH2N(CH3)2; 17) [ka] ;or 18)-(C 1-3 alkyl)-NH2.

[0049] 20) In any one of 1) to 19), according to an embodiment of the present invention, R3 may be a 6- to 8-membered aryl, and -H of the aryl may be unsubstituted or at least one -H may each independently be substituted with a group selected from the group consisting of 1) to 18).

[0050] 21) In any one of 1) to 20), according to an embodiment of the present invention, R3 may be phenyl, and the -H of the aryl may be unsubstituted, or at least one -H may be each independently substituted with a group selected from the group consisting of 1) to 18).

[0051] 22) In any one of 1) to 21), according to an embodiment of the present invention, Ak is -(CH2)n-, or [ka] wherein said -(CH2)n- or [ka] each -H is independently unsubstituted, or at least one -H is independently selected from NH2, -OH, -NO2, -C 1-5 It may be substituted with alkyl, -CH2NH2, -CF3, OCF3, -CN, -F, -Cl, -Br, or -I, and n may be 1, 2, or 3.

[0052] 23) In any one of 1) to 22) above, according to an embodiment of the present invention, X1, X2, and X3 in the chemical formula I may each independently be —CH or —N.

[0053] 24) In any one of 1) to 23), according to an embodiment of the present invention, the urea compound represented by the chemical formula I may be a compound represented by the following chemical formula I-1: [ka]

[0054] In an embodiment of the present invention, in the compound represented by Formula I or Formula I-1, R1, R2, R3, Ak, X1, X2, and X3 may be respectively as follows: In an embodiment of the present invention, R1 is Pyridinyl; pyrimidinyl; pyrazolyl; imidazolyl; pyrrolyl; furanyl; phenyl; phenolic; [ka] wherein each group of R1 listed above is independently -H is unsubstituted or at least one H is independently -NH2, -(C 1-3 alkyl)NH2, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)2, -OH, -NO2, C 1-5 It may be substituted with alkyl, -F, -Cl, -Br, or -I.

[0055] In an embodiment of the present invention, R2 is Pyridinyl; pyrimidinyl; phenyl; piperidinyl; piperazinyl; morpholinyl; pyrazolyl, imidazolyl, phenolic, phenyl; -CH2C(=O)NH2; -C(=O)NH2; -C(=O)NHCH2CH3; -CH2NHC(=O)CH2CH3; -NH2; -NHCH3, -NHCH2CH2CH3; [ka] [ka] [ka] In this case, each of the -H groups in each of the R2 groups listed above may be independently unsubstituted, or at least one -H may be independently selected from -NH2, -NH(C 1-5 alkyl), -N(C 1-5 alkyl)2, -NHCH3, -N(CH3)2, -NHCH2CH3, -OH, -NO2, -S(=O)2CH3, C 1-5alkyl (wherein -H of said alkyl is unsubstituted or at least one -H may each independently be substituted with one selected from the group consisting of phenyl, pyridinyl, morpholinyl, piperazine, and piperidine), -morpholidinyl-piperidinyl, -piperazinyl, phenyl, pyridinyl, pyrimidinyl (wherein -H of said -morpholidinyl, -piperidinyl, -piperazinyl, -phenyl, -pyridinyl, and -pyrimidinyl is unsubstituted or at least one -H may each independently be substituted with one selected from the group consisting of -C 1-3 cyclohexyl, -cyclobutoxy, -cyclopropoxy, -cyclopentoxy, -F, -Cl, -Br, -I, -CHF2, -CF3, -C) optionally substituted with one selected from the group consisting of alkyl and -CF3 1-3 Alkoxy, -NHC(=O)CH3, -C(=O)CH2CH3, -C(=O)N(CH3)2, -C(=O)NH(CH3), -C(=O)NH2, -S(=O)2NHCH3; -S(=O)2, -S(=O)2CH3, -trifluoromethylphenyl, [ka] (The Ra1 and Ra2 are each independently H, F, Cl, Br-, I, or -C 1-5 alkyl, and Y1 may be one selected from -CH2, -NH, -, and -O-; [ka] (The above Ra3 is -H, -C 1-5 alkyl or -CF3), [ka] may be substituted with

[0056] R3 may be phenyl, wherein each -H in each of the groups of R3 listed above may be independently unsubstituted, or at least one -H may be independently substituted with a group selected from the group consisting of the following 1) to 18): 1) C 1-5 alkyl; 2) -F, -Cl, -Br, or -I 3) [ka] , wherein Rx7 may be -CF3; 4) [ka] , Here, if c is 0 (in this case, Rx8 is directly bonded to -N), Rx8 is C 1-5 Rx9 may be alkyl or piperidine; 1-5 may be alkyl; If c is 1, Rx8 is [ka] (wherein Rb1 may be -NH2 or -CH2OH), and Rx9 is -H or C 1-5 may be alkyl; If c is 2, Rx8 is C 1-3 Alkyl, -NH2, -NHCH3, -N(CH3)2, piperidinyl, difluoropiperidinyl, piperazinyl, morpholinyl, [ka] (Said Rb1 may be -NH2 or -CH2OH), pyridinyl, pyrrolyl, and Rx9 may be -H or C 1-5 may be alkyl; 5)-COOH; 6)-NRx 10 Rx 11 , where Rx10 and Rx 11 may each independently be -H or -CH3; 7)-CF3; 8)-CN; 9) morpholidinyl or one or more -H are each independently selected from C 1-3 morpholidinyl substituted with alkyl, -F, -Cl, -Br, -I, -C(=O)NHCH3, -C(=O)CH3, or -C(=O)CH=CH2; 10) piperidinyl or one or more -H are each independently C 1-3 piperidinyl substituted with alkyl, -F, -Cl, -Br, -I, -C(=O)NHCH3, -C(=O)CH3, or -C(=O)CH=CH2; 11) piperazinyl or one or more -H are each independently C 1-3 piperazinyl substituted with alkyl, -F, -Cl, -Br, I, -C(=O)NHCH3, -C(=O)CH3, or -C(=O)CH=CH2; 12)-ORx 12 , where R 12 Rx 12 is -CF3;C 1-3 may be alkyl; 13)-OH; 14) [ka] , where d can be 1, 2, or 3; Rx 13 may be -NH2, -NH(CH3), -N(CH3)2 pyrazolyl, methylpyrazolyl, pyrazolyl, piperazinyl, piperidinyl, or morpholinyl; 15) [ka] , where Rx 14 may be -CH2-, NH- or -O-; Rx 15 -H, C 1-5 may be alkyl, -NH2, -F, -Cl, -Br, or I; 16) [ka] , where Rx 16 is C 1-5 may be alkyl or -CH2CH2N(CH3)2; 17) [ka] ;or 18) Ethylamine. Ak is -CH2-, -(CH2)2--(CH2)3- or [ka] may be -CH2-, -(CH2)2-, -(CH2)3- or [ka] Each -H is independently unsubstituted, or at least one -H is independently -NH2, -OH, -NO2, C 1-5 optionally substituted with alkyl, -CH2NH2, -CF3, OCF3, -CN, -F, -Cl, -Br, or -I; X1, X2 and X3 may be -CH-.

[0057] 25) In any one of 1) to 24), according to an embodiment of the present invention, specifically, in the above chemical formula I or chemical formula I-1, R1, R2, R3, Ak, X1, X2, and X3 may be respectively as follows: In an embodiment of the present invention, in the formula I or formula I-1, R1 may be one of the groups in Table 1 below: [Table 1]

[0058] [Table 2]

[0059] The -H in the groups listed in Table 1 above is unsubstituted or at least one H is each independently selected from -NH2, -OH, -NO2, -CH2NH2, -CF3, OCF3, -CN, -C 1-5 It may be substituted with alkyl, -F, -Cl, -Br, or -I.

[0060] In an embodiment of the present invention, in the formula I or formula I-1, R2 may be one of the groups in the following table:

[0061] [Table 3]

[0062] [Table 4]

[0063] [Table 5]

[0064] [Table 6]

[0065] [Table 7]

[0066] The groups listed in Table 2 above may be unsubstituted or at least one H may be independently replaced by -NH2, -OH, NO2, -C 1-5 It may be substituted with alkyl, -CH2NH2, -CF3, -OCF3, -CN, -F, -Cl, -Br, or -I.

[0067] In an embodiment of the present invention, in the formula I or formula I-1, R3 may be one of the groups in the following table:

[0068] [Table 8]

[0069] [Table 9]

[0070] [Table 10]

[0071] The groups listed in Table 3 above may be unsubstituted or at least one H may be independently replaced by -NH, -OH, -NO, -C 1-5 It may be substituted with alkyl, -CH2NH2, -CF3, -OCF3, -CN, -F, -Cl, -Br, or -I.

[0072] In an embodiment of the present invention, in the formula I or formula I-1, Ak is -(CH2)n-, or [ka] (wherein the —(CH)— or [ka] Each -H is independently unsubstituted, or at least one -H is independently -NH2, -OH, -NO2, C 1-5 It may be substituted with alkyl, -CH2NH2, -CF3, OCF3, -CN, -F, -Cl, -Br, or -I, and n may be 1, 2, or 3.

[0073] In the present embodiment, X1, X2 and X3 may each independently be -CH- or -N-, specifically -CH-.

[0074] 26) In any one of 1) to 25) above, according to an embodiment of the present invention, the urea compound represented by the chemical formula I-1 may be a compound represented by the following chemical formula I-2:

[0075] [ka] In the above chemical formula I-2, R1, R2 and Ak are as defined above in Formula II; A urea compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein Za and Zb are each independently -H or one selected from the group consisting of the following 1) to 18): 1) C 1-5 alkyl; 2) -F, -Cl, -Br, or -I 3) [ka] , where Rx7 is C 1-5 may be alkyl or -CF3; 4) [ka] , where c is 0, 1, 2, or 3, and Rx8 is C 1-5 Alkyl, -NH2, -NHCH3, -N(CH3)2, piperidinyl, piperazinyl, morpholinyl, [ka] (wherein Rb1 may be —NH2 or —CH2OH), or [ka] (wherein Rb2 may be -CH2-, -NH- or -O-, and Rb3 and Rb4 may each independently be -H, -F, -Cl, -Br or -I), pyrimidinyl or pyrrolyl, and Rx9 may be -H or C 1-5 may be alkyl; 5)-COOH; 6)-NRx 10 Rx 11 , where Rx 10 or Rx 11 may each independently be -H or -CH3; 7)-CF3; 8)-CN; 9) morpholinyl or one or more -H are each independently selected from C 1-5 morpholidinyl substituted with alkyl, -F, -Cl, -Br, I, -C(=O)NHCH3, -C(=O)CH3, or -C(=O)CH=CH2; 10) piperidinyl or one or more -H are each independently C 1-5 piperidinyl substituted with alkyl, -F, -Cl, -Br, I, -C(=O)NHCH3, -C(=O)CH3, or -C(=O)CH=CH2; 11) piperazinyl or one or more -H are each independently C 1-5 piperazinyl substituted with alkyl, -F, -Cl, -Br, I, -C(=O)NHCH3, -C(=O)CH3, or -C(=O)CH=CH2; 12)-ORx 12 , where R 12 Rx 12 is -CF3;C 1-3 may be alkyl; 13)-OH; 14) [ka] , where d can be 0, 1, 2 or 3; Rx 13may be -NH2, -NH(CH3), -N(CH3)2 pyrazolyl, methylpyrazolyl, pyrazolyl, piperazinyl, piperidinyl, or morpholinyl; 15) [ka] , where Rx 14 may be -CH2-, NH or -O-, and Rx 15 -H, straight or branched chain C 1-5 may be alkyl, -NH2, -F, -Cl, -Br, or -I; 16) [ka] , where Rx 16 is C 1-5 may be alkyl or -CH2CH2N(CH3)2; 17) [ka] ;or 18)-(C 1-3 alkyl)-NH2.

[0076] 27) In any one of 1) to 25) above, according to an embodiment of the present invention, there is provided a urea compound represented by the following chemical formula I-2, an optical isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof:

[0077] [ka] In the above chemical formula I-2, R1 is Pyridinyl; Pyrimidinyl; Imidazolyl; Pyrazolyl; Phenyl; [ka] wherein each —H in R is independently unsubstituted, or at least one —H is independently morpholinyl, piperidinyl, piperazinyl, —NH, —(C 1-3 alkyl)NH2, -NH-(C 1-3 alkyl), -N(C 1-3 alkyl)2, -OH, -NO2, C 1-5 optionally substituted with alkyl, -F, -Cl, -Br, or -I; R2 is Pyridinyl; Pyrimidinyl; Phenyl; Piperazinyl; Piperidinyl; [ka] wherein p1, p2, p3, or p4 is each independently an integer of 0 to 3, and wherein -H in R2 is each independently unsubstituted, or at least one -H is each independently morpholinyl, piperidinyl, piperazinyl, -NH2, -(C 1-3 alkyl)NH2, -NH-(C 1-3 alkyl), -N(C 1-3 alkyl)2, -OH, -NO2, -C 1-5 optionally substituted with alkyl, -F, -Cl, -Br, or -I; Za or Zb each independently represent -H, morpholinyl, piperidinyl, piperazinyl, -NHC(=O)(C 1-3 alkyl), -NH2, -(C 1-3 alkyl)NH2, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)2, -OH, -NO2, -C 1-5 Alkyl, -F, -Cl, -Br, -I, [ka] wherein q1 and q2 each independently represent an integer of 0 to 3, and wherein each of Za and Zb is independently unsubstituted, or at least one of Za and Zb is independently -C 1-5Alkyl, -NH2, -(C 1-3 alkyl)NH2, -NH-(C 1-3 alkyl), or -N(C 1-3 alkyl)2, The Ak-(CH2)n-, wherein n may be 1, 2 or 3. 28) In any one of the above 1) to 26), the present invention provides compounds 1 to 189, their optical isomers, their pharmaceutically acceptable salts, or their hydrates or solvates, as shown in Table 4 below:

[0078] [Table 11]

[0079] [Table 12]

[0080] [Table 13]

[0081] [Table 14]

[0082] [Table 15]

[0083] [Table 16]

[0084] [Table 17]

[0085] [Table 18]

[0086] Table 19

[0087] Table 20

[0088] Table 21

[0089] Table 22

[0090] Table 23

[0091] Table 24

[0092] Table 25

[0093] Table 26

[0094] Table 27

[0095] Table 28

[0096] Table 29

[0097] Table 30

[0098] Table 31

[0099] Table 32

[0100] Table 33

[0101] Table 34

[0102] Table 35

[0103] Table 36

[0104] Table 37

[0105] Table 38

[0106] Table 39

[0107] Table 40

[0108] Table 41

[0109] Table 42

[0110] Table 43

[0111] Table 44

[0112] Table 45

[0113] Table 46

[0114] Table 47

[0115] Table 48

[0116] Table 49

[0117] Table 50

[0118] Table 51

[0119] Table 52

[0120] Table 53

[0121] Table 54

[0122] Table 55

[0123] Table 56

[0124] Table 57

[0125] Table 58

[0126] Table 59

[0127] [Table 60]

[0128] [Table 61]

[0129] [Table 62]

[0130] [Table 63]

[0131] [Table 64]

[0132] [Table 65]

[0133] [Table 66]

[0134] The compounds of the present invention represented by the chemical formula I, the compounds represented by the chemical formula I-1, the compounds represented by the chemical formula I-2, compounds 1 to 189 in Table 4, their optical isomers, pharmaceutically acceptable salts thereof, or hydrates or solvates thereof exhibit NAMPT inhibitory activity.

[0135] The compounds of the present invention represented by Chemical Formula I, compounds represented by Chemical Formula I-1, compounds represented by Chemical Formula I-2, compounds 1 to 189 in Table 4, their optical isomers, pharmaceutically acceptable salts, or hydrates or solvates thereof can effectively inhibit NAMPT at low concentrations and can effectively prevent or treat diseases that can be treated by inhibiting NAMPT.

[0136] The compounds of the present invention represented by the chemical formula I, the compounds represented by the chemical formula I-1, the compounds represented by the chemical formula I-2, compounds 1 to 189 in Table 4, their optical isomers, pharmaceutically acceptable salts thereof, or hydrates or solvates thereof can sufficiently lower NAD concentration in cells.

[0137] The compounds of the present invention represented by chemical formula I, compounds represented by chemical formula I-1, compounds represented by chemical formula I-2, compounds 1 to 189 in Table 4, their optical isomers, pharmaceutically acceptable salts thereof, or hydrates or solvates thereof exhibit high cytotoxicity to cancer cells and can sufficiently kill cancer cells at low concentrations.

[0138] The compounds of the present invention represented by chemical formula I, compounds represented by chemical formula I-1, compounds represented by chemical formula I-2, compounds 1 to 189 in Table 4, their optical isomers, pharmaceutically acceptable salts, or hydrates or solvates thereof exhibit high cytotoxicity against gastric cancer cells or colon cancer cells and can sufficiently kill gastric cancer cells or colon cancer cells at low concentrations.

[0139] The compounds of the present invention, including compounds represented by Formula I, I-1, I-2, compounds 1 to 189 in Table 4, their optical isomers, pharmaceutically acceptable salts, and hydrates or solvates thereof, have little or no side effects and exhibit excellent pharmacokinetic properties. For example, the compounds of Formula I, I-1, I-2, compounds 1 to 188 in Table 4, their optical isomers, pharmaceutically acceptable salts, and hydrates or solvates thereof, exhibit excellent absorption rates (e.g., high bioavailability), are appropriately distributed to various tissues upon administration, and exhibit desired pharmacological effects (e.g., preventive or therapeutic effects for diseases that can be treated by inhibiting NAMPT) in each tissue, and are effectively metabolized in the body.

[0140] In the present invention, optical isomers include not only enantiomers but also mixtures of enantiomers and racemates.

[0141] In the present invention, the term "pharmaceutically acceptable salt" refers to a salt commonly used in the pharmaceutical industry, such as an inorganic ion salt prepared with calcium, potassium, sodium, magnesium, or the like; an inorganic acid salt prepared with hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid, sulfuric acid, or the like; an inorganic acid salt prepared with 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, acetic ... Examples of suitable salts include organic acid salts prepared with arginic acid, ascorbic acid, carboxylic acid, or vanillic acid; sulfonate salts prepared with methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or naphthalenesulfonic acid; amino acid salts prepared with glycine, arginine, or lysine; and amine salts prepared with trimethylamine, triethylamine, ammonia, pyridine, or picoline. However, the types of salts intended in the present invention are not limited to these listed salts.

[0142] The "hydrate" of the present invention is a compound represented by the above chemical formula I, a compound represented by the chemical formula I-1, a compound represented by the chemical formula I-2, or compounds 1 to 189 in Table 4, which is bound to water by non-covalent intermolecular forces, and may contain a stoichiometric or non-stoichiometric amount of water. Specifically, the hydrate may contain water in a molar ratio of about 0.25 mol to about 10 mol per mol of the active ingredient, more specifically, 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.

[0143] The "solvate" of the present invention is a compound represented by the above chemical formula I, the compound represented by the chemical formula I-1, the compound represented by the chemical formula I-2, or compounds 1 to 189 in Table 4, which is bound to a solvent other than water by intermolecular forces, and may contain the solvent in a stoichiometric or non-stoichiometric amount. Specifically, the solvate may contain about 0.25 to about 10 moles of solvent molecules per mole of the active ingredient, more specifically, about 0.5 moles, about 1 mole, about 1.5 moles, about 2 moles, about 2.5 moles, about 3 moles, about 5 moles, etc.

[0144] The present invention provides a pharmaceutical composition comprising the compound represented by chemical formula I, the compound represented by chemical formula I-1, the compound represented by chemical formula I-2, compounds 1 to 189 in Table 4, an optical isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

[0145] Pharmaceutical compositions containing the compounds represented by formula I, I-1, I-2, compounds 1 to 189 in Table 4, their optical isomers, pharmaceutically acceptable salts, or hydrates or solvates thereof exhibit NAMPT inhibitory activity and can be used for the prevention or treatment of diseases that can be treated by inhibiting NAMPT.

[0146] The pharmaceutical composition of the present invention, comprising the compound represented by chemical formula I, the compound represented by chemical formula I-1, the compound represented by chemical formula I-2, compounds 1 to 189 in Table 4, their optical isomers, their pharmaceutically acceptable salts, or their hydrates or solvates, can exhibit a preventive or therapeutic effect on cancer.

[0147] In embodiments of the present invention, the cancer may be a solid cancer or a blood cancer, and the cancer may be a cancer of the blood and bone marrow, such as skin cancer (e.g., melanoma), lymph node cancer, breast cancer, cervical cancer, uterine cancer, gastrointestinal tract 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, larynx cancer, nasal cavity cancer, AIDS-related cancer, esophageal cancer, gastrointestinal cancer, stomach cancer, colorectal cancer, virus-related cancer (e.g., 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, e.g., lymphoblastic leukemia, myeloid leukemia, lymphocytic leukemia, and myelocytic leukemia.

[0148] The pharmaceutical composition of the present invention may further contain pharmaceutically acceptable additives. The pharmaceutically acceptable additives are additives commonly used in the pharmaceutical field and can be appropriately selected by those skilled in the art. For example, the pharmaceutically acceptable additives include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. In addition to the above ingredients, the composition may further contain lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents, preservatives, etc.

[0149] The pharmaceutical compositions of the present invention may be formulated using pharmaceutically acceptable carriers and excipients into oral dosage forms such as tablets, powders, granules, pills, capsules, suspensions, emulsions, oral solutions, emulsions, syrups, and the like, topical preparations, suppositories, or sterile injection solutions, and may be prepared in unit dose forms or in multi-dose containers. The preparations may be prepared by conventional methods used in the art or by methods disclosed in Remington's Pharmaceutical Science (19th ed., 1995), and may be formulated in various formulations depending on the disease or component.

[0150] The pharmaceutical compositions of the present invention may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically) depending on the intended method. The dosage varies depending on the patient's condition and weight, the severity of the disease, the drug form, and the route and time of administration, and may be appropriately selected by those skilled in the art. Specifically, the daily dosage of the compound represented by formula I, the compound represented by formula I-1, the compound represented by formula I-2, compounds 1 to 189 in Table 4, their optical isomers, their pharmaceutically acceptable salts, or their hydrates or solvates may be about 0.1 to about 1,000 mg / kg based on the weight of the compound represented by formula I, and may be administered once or in divided doses per day.

[0151] The pharmaceutical composition of the present invention may further contain one or more components that exhibit the same or similar effects or that can bring about synergistic efficacy when used in combination with the compound represented by chemical formula I, the compound represented by chemical formula I-1, the compound represented by chemical formula I-2, compounds 1 to 189 in Table 4, their optical isomers, their pharmaceutically acceptable salts, or hydrates or solvates thereof.

[0152] The present invention provides use of the compounds represented by chemical formula I, compounds represented by chemical formula I-1, compounds represented by chemical formula I-2, compounds 1 to 189 in Table 4, optical isomers thereof, pharmaceutically acceptable salts thereof, hydrates or solvates thereof for the prevention or treatment of diseases (e.g., cancer) that can be treated by inhibiting NAMPT.

[0153] The present invention provides use of the compound represented by Chemical Formula I, the compound represented by Chemical Formula I-1, the compound represented by Chemical Formula I-2, compounds 1 to 189 in Table 4, their optical isomers, pharmaceutically acceptable salts, or hydrates or solvates thereof for use in the manufacture of a medicament for preventing or treating a disease (e.g., cancer) that can be treated by inhibiting NAMPT.

[0154] The present invention provides a method for preventing or treating a disease (e.g., cancer) that can be treated by inhibiting NAMPT, comprising the step of administering to an individual a compound represented by the above-mentioned chemical formula I, a compound represented by the above-mentioned chemical formula I-1, a compound represented by the above-mentioned chemical formula I-2, compounds 1 to 189 in Table 4, an optical isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof.

[0155] The compounds of the present invention represented by Chemical Formula I, compounds represented by Chemical Formula I-1, compounds represented by Chemical Formula I-2, compounds 1 to 189 in Table 4, optical isomers thereof, pharmaceutically acceptable salts thereof, hydrates or solvates thereof can be administered in a therapeutically effective amount.

[0156] In the present invention, the term "therapeutically effective amount" refers to an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to any medical treatment, and the effective dose level may be determined depending on factors including the type and severity of the patient's disease, the activity of the drug, sensitivity to the drug, the time of administration, the route of administration and excretion rate, the duration of treatment, concurrently used drugs, and other factors well known in the medical field. Specifically, it refers to an amount effective for preventing or treating a disease (e.g., cancer) that can be treated by inhibiting NAMPT.

[0157] In the present invention, the term "individual" refers to a subject for disease prevention or treatment, and more specifically, may refer to mammals such as humans, monkeys, mice, dogs, cats, horses, and cows, but is not limited thereto.

[0158] The term "prevention" as used herein means any action of suppressing or delaying a disease (e.g., cancer) that can be treated by inhibiting NAMPT through the administration of a compound according to the present invention.

[0159] The term "treatment" as used herein means any action that improves, beneficially alters, or slows the progression of a disease (e.g., cancer) that can be treated by inhibiting NAMPT through the administration of a compound according to the present invention.

[0160] The items mentioned in each section of the present invention, i.e., urea compounds, uses, compositions, and treatment methods, are all applied identically unless they contradict each other, and other terms and abbreviations used in the present specification have their original meanings unless otherwise defined. [Effects of the Invention]

[0161] The urea compound of the present invention, its optical isomer, their pharmaceutically acceptable salt, or their hydrate or solvate can inhibit NAMPT and have a significantly excellent preventive or therapeutic effect on NAMPT-related diseases. Therefore, the urea compound of the present invention, its optical isomer, their pharmaceutically acceptable salt, or their hydrate or solvate can be effectively used for the prevention or treatment of diseases (e.g., cancer) that can be treated by inhibiting NAMPT. DETAILED DESCRIPTION OF THE INVENTION

[0162] The present invention will be described in more detail below using Production Examples and Examples, which are provided for illustrative purposes only and are not intended to limit the scope of the present invention.

[0163] Each of the compounds according to the present invention can be synthesized by the methods described below, and methods conventional to those skilled in the art can be used that are derived by combining the specific synthesis methods below.

[0164] The compounds used in the synthesis were either purchased from external companies or synthesized using organic synthesis methods known to those skilled in the art and used without further purification. The compounds in each example were identified through 400MHz H-NMR (BRUKER, 400-MR) and LC-Mass (Waters, SQD2) analysis.

[0165] Example 1: Synthesis of Compound 1 (Synthetic Reaction Scheme 1) Synthesis of 1-(3-((4-fluorophenyl)ethynyl)-4-(pyridin-4-yl)phenyl)-3-(2-(pyridin-3-yl)ethyl)urea [ka] [ka] Reaction Scheme 1. (a) 4-pyridine boronic acid, Pd[PPh3]4, sodium carbonate (Na2CO3), toluene, ethanol (EtOH), reflux, 1-3 hours; (b) sodium nitrite (NaNO2), KI, HCl, water, 0°C, 1 hour; (c) Pd[PPh3]4, CuI, TEA, ACN, room temperature (rt), 1 hour; (d) Fe, AcOH, 80°C, 2 hours; (e) phenyl chloroformate (f) 2-(pyridin-3-yl)ethan-1-amine, TEA, THF, reflux, 24 h

[0166] <Step 1(a) Synthesis of 5-nitro-2-(pyridin-4-yl)aniline> A mixture of 2-bromo-5-nitroaniline (3 g, 13.8 mmol, 1.0 eq) and 4-pyridine boronic acid (2.55 g, 1.5 eq) in toluene (40 mL) and ethanol (EtOH) was rapidly added to a mixture of Pd[PPh3]4 (3.15 g, 0.2 eq) and aqueous sodium carbonate (Na2CO3) (2 M, 16.5 mL, 2.4 eq) in toluene (40 mL) and ethanol (EtOH) (30 mL). 16.5 mL of distilled water was added to the reaction mixture, which was refluxed under nitrogen for 1-3 hours, cooled to room temperature, and concentrated under reduced pressure. The resulting residue was dissolved and diluted with distilled water and EA and filtered through Celite. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, 30-70% hexane / ethyl acetate) to give the title compound (2.77 g) (yellow solid, 93% yield).

[0167] <Step 2(b) Synthesis of 4-(2-iodo-4-nitrophenyl)pyridine> A solution of sodium nitrite (0.48 g, 1.5 eq) in water (13 mL) was slowly added dropwise to a suspension of 5-nitro-2-(pyridin-4-yl)aniline (1 g, 4.65 mmol, 1 eq) in concentrated aqueous hydrochloric acid (12 mL) and water (12 mL) at 0 °C. The reaction mixture became clear at the end of the addition of the sodium nitrite solution. After the addition, the reaction mixture was stirred at 0 °C for 10 min. Then, a solution of potassium iodide (2.31 g, 2.0 eq) in water (12 mL) was added to the mixture at 0 °C. A very viscous reddish-brown mixture was formed, which turned dark brown. The reaction mixture was stirred at room temperature for 1 h, treated with saturated aqueous potassium carbonate (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, hexane / ethyl acetate, 1:1) to give the title compound (0.84 g, yield 55%).

[0168] <Step 3(c) Synthesis of 4-(2-((4-fluorophenyl)ethynyl)-4-nitrophenyl)pyridine> Triethylamine (0.1 mL, 3 eq), CuI (1.5 mg, 3 mol%), and Pd[PPh3]4 (9.2 mg, 3 mol%) were added to a solution of 4-(2-iodo-4-nitrophenyl)pyridine (87 mg, 0.27 mmol, 1.0 eq) in MeCN (2 mL). The mixture was stirred at room temperature under a N2 atmosphere for 5 min. 4-Fluorophenylacetylene (38 mg, 1.2 eq) was then added. The reaction mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, hexane / ethyl acetate) to give the desired compound (82 mg, 96.5% yield).

[0169] <Step 4(d) Synthesis of 3-((4-fluorophenyl)ethynyl)-4-(pyridin-4-yl)aniline> A mixture of 4-(2-((4-fluorophenyl)ethynyl)-4-nitrophenyl)pyridine (0.08 g, 0.25 mmol, 1.0 eq), iron (0.14 g, 10 eq), and AcOH (2 mL) was stirred at 80°C for 1-2 hours. The catalyst was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure. The resulting black viscous oil residue was basified with aqueous potassium carbonate, extracted with ethyl acetate, and the organic layer was concentrated under reduced pressure. The target compound was obtained as a crude product.

[0170] Step 5(e) Synthesis of benzyl(3-((4-fluorophenyl)ethynyl)-4-(pyridin-4-yl)phenyl)carbamate 3-((4-Fluorophenyl)ethynyl)-4-(pyridin-4-yl)aniline (90 mg, 1.0 eq) and pyridine (40 uL, 2 eq) were dissolved in tetrahydrofuran (2 mL). The reaction solution was then cooled on ice, and phenyl chloroformate (47 uL, 1.5 eq) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, water (0.1 mL) was added to the reaction mixture, and the reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with water and ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The target compound was obtained as a crude product.

[0171] Step 6(f) Synthesis of 1-(3-((4-fluorophenyl)ethynyl)-4-(pyridin-4-yl)phenyl)-3-(2-(pyridin-3-yl)ethyl)urea A mixture of benzyl (3-((4-fluorophenyl)ethynyl)-4-(pyridin-4-yl)phenyl)carbamate (1.0 eq), 3-(2-aminoethyl)pyridine (2 eq), and triethylamine (3 eq) in THF (4 mL) was heated at 80° C. for 24 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (silica gel, 0-5% dichloromethane / methanol) to give the title compound. 1 H NMR (400 MHz, CDCl3) 8.65-8.66 (m, 2H), 8.44-8.45 (m, 2H), 7.66 (d, J=2.1 Hz, 1H), 7.60 (dt, J = 7.8, 1.8 Hz, 2H), 7.54 (m, 2H), 7.27-7.37 (m, 5H), 6.97-7.02 (m, 2H), 6.94 (s, 1H), 5.08 (t, J = 5.8 Hz, 1H), 3.61 (q, J = 6.4 Hz, 2H), 2.91 (t, J = 6.6 Hz, 2H); MS(ESI) m / z MH + 437.

[0172] Compounds 12, 103, 104, 105, 106, 107, 108, 109, 111, 112, 113, 146, 151, 154, 159, 163, 164, 165, 167, and 173 can be synthesized using substantially the same synthetic method as in Example 1 above, but changing the reactants.

[0173] Example 2: Synthesis of Compound 3 Synthesis of 1-(2-(1H-imidazol-1-yl)ethyl)-3-(3-((4-fluorophenyl)ethynyl)-4-(pyridin-4-yl)phenyl)urea [ka]

[0174] Compound 3 was prepared in substantially the same manner as in the synthesis of compound 1 in Example 1, except that 1H-Imidazole-1-ethanamine was used instead of 3-(2-aminoethyl)pyridine in step 6). 1 H NMR (400 MHz, MeOD) δ 8.59-8.61 (m, 2H), 7.78 (d, J = 2.1 Hz, 1H), 7.74-7.66 (m, 3H), 7.36-7.48 (m, 4H), 7.19 (m, 1H), 7.10 (m, 2H), 7.00 (m, 1H), 4.20 (t, J = 6.0 Hz, 2H), 3.58 (t, J = 6.0 Hz, 2H); MS(ESI) m / z MH + 426.

[0175] Example 3: Synthesis of Compound 4 Synthesis of 1-(3-((4-fluorophenyl)ethynyl)-4-(pyridin-4-yl)phenyl)-3-(imidazo[1,2-a]pyridin-7-ylmethyl)urea [ka]

[0176] Compound 4 was prepared in substantially the same manner as in the synthesis of compound 1 in Example 1, except that 1-{imidazo[1,2-a]pyridin-7-yl}methanamine dihydrochloride was used instead of 3-(2-aminoethyl)pyridine in step 6). 1 H NMR (400 MHz, MeOD) δ 8.59-8.61 (m, 2H), 8.40 (d, J = 7.0 Hz, 1H), 7.83 (d, J = 2.2 Hz, 1H), 7.79 (m, 1H), 7.71-7.72 (m, 2H), 7.51-7.54 (m, 2H), 7.43-7.48 (m, 2H), 7.35-7.39 (m, 2H), 7.07-7.11 (m, 2H), 6.93 (dd, J = 7.0, 1.6 Hz, 1H), 4.49 (s, 2H); MS(ESI) m / z MH + 462.

[0177] Example 4: Synthesis of Compound 5 Synthesis of 1-(3-((4-fluorophenyl)ethynyl)-4-(pyridin-4-yl)phenyl)-3-(3-hydroxyphenethyl)urea [ka]

[0178] Compound 5 was prepared in substantially the same manner as in the synthesis of compound 1 in Example 1, except that 3-(2-aminoethyl)phenol hydrobromide was used instead of 3-(2-aminoethyl)pyridine in step 6). 1 H NMR (400 MHz, MeOD) δ 8.60 (d, J = 6.1 Hz, 2H), 7.79 (d, J = 2.2 Hz, 1H), 7.71-7.72 (m, 2H), 7.36-7.46 (m, 4H), 7.08-7.15 (m, 2H), 6.70-6.75 (m, 2H), 6.65 (dd, J = 8.1, 2.1 Hz, 1H), 3.46 (t, J = 7.1 Hz, 2H), 2.78 (t, J = 7.0 Hz, 2H); MS(ESI) m / z MH + 452.

[0179] Example 5: Synthesis of Compound 6 Synthesis of 1-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-3-(3-((4-fluorophenyl)ethynyl)-4-(pyridin-4-yl)phenyl)urea [ka]

[0180] Compound 6 was prepared in substantially the same manner as in the synthesis of compound 1 in Example 1, except that 1-{1H-pyrrolo[3,2-c]pyridin-2-yl}methanamine dihydrochloride was used instead of 3-(2-aminoethyl)pyridine in step 6). 1 H NMR (400 MHz, DMSO) δ 11.45 (s, 1H), 9.05 (s, 1H), 8.75 (s, 1H), 8.65-8.67 (m, 2H), 8.12 (d, J = 5.7 Hz, 1H), 7.93 (d, J = 1.9 Hz, 1H), 7.64-7.68 (m, 2H), 7.44-7.52 (m, 4H), 7.35 (d, J = 5.7 Hz, 1H), 7.24-7.28 (m, 2H), 6.85 (t, J = 5.8 Hz, 1H), 6.45 (s, 1H), 4.49 (d, J = 5.7 Hz, 2H); MS(ESI) m / z MH + 462.

[0181] Example 6: Synthesis of Compound 8 [ka]

[0182] Synthesis of 1-(3-((4-fluorophenyl)ethynyl)-4-(pyridin-4-yl)phenyl)-3-(2-(2-nitro-1H-imidazol-1-yl)ethyl)urea Compound 8 (0.044 g, 38%) was prepared in substantially the same manner as in the synthesis of compound 1, except that 2-(2-nitro-1H-imidazol-1-yl)ethan-1-amine hydrochloride was used instead of 3-(2-aminoethyl)pyridine in step 6) of compound 1 in Example 1. 1 H NMR (400 MHz, CDCl3) δ 8.52 (d, J = 5.4 Hz, 2H), 8.19 (s, 1H), 7.67 (s, 1H), 7.44 (d, J = 5.4 Hz, 2H), 7.27 (s, 1H), 7.21-7.16 (m, 3H), 7.09 (s, 1H), 7.02 (s, 1H), 6.88 (t, J = 8.6 Hz, 2H), 6.10 (t, J = 5.7 Hz, 1H), 4.52 (t, J = 5.7 Hz, 2H), 3.53 (q, J = 5.8 Hz, 2H). MS(ESI) m / z MH + 471

[0183] Example 7: Synthesis of Compound 2 (Synthetic Reaction Scheme 2) Synthesis of 1-(4'-(4,4-difluoropiperidine-1-carbonyl)-2-((4-fluorophenyl)ethynyl)-[1,1'-biphenyl]-4-yl)-3-(2-(pyridin-3-yl)ethyl)urea [ka] [ka] Reaction Scheme 2. (a) 4,4-difluoropiperidine hydrochloride, HATU, TEA, DCM, room temperature (RT), 2 hours (2 h); (b) 2-bromo-5-nitroaniline, PdCl2(dppf), K2CO3, dioxane:water (3:1 (v / v)), 90 °C, 2 hours (2 h); (c) sodium carbonate (NaCO2), KI, HCl, water, 0 °C, 1 hour (1 h); (d) PdCl2(PPh3)2, CuI, TEA, ACN, 90 °C, 3 hours (3 h); (e) Fe, AcOH, reflux, 1 hour (1 h); (f) phenyl chloroformate (g) 2-(pyridin-3-yl)ethan-1-amine, TEA, THF, 80°C, 4 hours

[0184] <Step 1(a) Synthesis of (4-(4,4-difluoropiperidine-1-carbonyl)phenyl)boronic acid> 4-Carboxyphenylboronic acid (0.5 g, 3 mmol, 1.0 eq) was dissolved in DCM (15 ml, 0.2 M), followed by the addition of 4,4-difluoropiperidine hydrochloride (0.57 g, 3.6 mmol, 1.2 eq), HATU (1.48 g, 3.9 mmol, 1.3 eq), and TEA (1.7 ml, 12 mmol). The mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate (NaHCO3) was added and the mixture was extracted with DCM. The organic layer was concentrated under reduced pressure and then subjected to the reaction as in step 2) without separation.

[0185] <Step 2(b) Synthesis of (2'-amino-4'-nitro-[1,1'-biphenyl]-4-yl)(4,4-difluoropiperidin-1-yl)methanone> 2-Bromo-5-nitroaniline (0.5 g, 2.3 mmol, 1.0 eq) was dissolved in 1,4-dioxane:water (3:1 (v / v)) (12 ml, 0.2 M), followed by the addition of (4-(4,4-difluoropiperidine-1-carbonyl)phenyl)boronic acid (0.8 g, 3 mmol, 1.3 eq), PdCl2 (dppf) (0.34 g, 0.46 mmol, 0.2 eq), and K2CO3 (0.7 g, 5.06 mmol, 2.2 eq). The mixture was stirred at 90 °C for 2 hours. After cooling to room temperature and filtering, the filtrate was mixed with water and ethyl acetate (EA) to extract the organic layer. The organic layer was dried over MgSO4, filtered, concentrated, and purified by column chromatography (silica gel, EA / HX) to give the title compound (1.226 g, 68%).

[0186] <Step 3(c) Synthesis of (4,4-difluoropiperidin-1-yl)(2'-iodo-4'-nitro-[1,1'-biphenyl]-4-yl)methanone> To (2'-amino-4'-nitro-[1,1'-biphenyl]-4-yl)(4,4-difluoropiperidin-1-yl)methanone (0.311 g, 0.861 mmol, 1 eq), 0.9 ml of water and 0.9 ml of concentrated HCl (conc. HCl) were added. At 0°C, NaNO2 (0.059 g, 0.861 mmol, 1 eq) dissolved in 0.9 ml of water and KI (0.143 g, 0.861 mmol, 1 eq) dissolved in 0.9 ml of water were added and stirred for 1 hour. The mixture was neutralized with saturated aqueous sodium bicarbonate (Sat. NaHCO3) and extracted with EA. The organic layer was dried over MgSO4, filtered, concentrated, and purified by column chromatography (silica Purification by column chromatography (gel, EA / HX) gave the title compound (0.089 g, 22%).

[0187] Step 4(d) Synthesis of (4,4-difluoropiperidin-1-yl)(2'-((4-fluorophenyl)ethynyl)-4'-nitro-[1,1'-biphenyl]-4-yl)methanone (4,4-Difluoropiperidin-1-yl)(2'-iodo-4'-nitro-[1,1'-biphenyl]-4-yl)methanone (0.089 g, 0.188 mmol, 1 eq) was dissolved in ACN (acetonitrile, 2 ml, 0.1 M), followed by the addition of TEA (triethylamine, 0.06 ml, 0.414 mmol, 2.2 eq), PdCl2(PPh3)2 (4 mg, 0.006 mmol, 3 mol%), and CuI (2 mg, 0.008 mmol, 4 mol%). The mixture was stirred at room temperature for 5 minutes. 1-ethynyl-4-fluorobenzene (0.032 ml, 0.283 mmol, 1.5 eq) was added and the mixture was stirred at 90°C for 3 hours. After cooling to room temperature, the mixture was concentrated and purified by column chromatography (silica gel, EA / HX) to give the title compound (0.075 g, 86%).

[0188] <Step 5(e) Synthesis of (4'-amino-2'-((4-fluorophenyl)ethynyl)-[1,1'-biphenyl]-4-yl)(4,4-difluoropiperidin-1-yl)methanone> (4,4-Difluoropiperidin-1-yl)(2'-((4-fluorophenyl)ethynyl)-4'-nitro-[1,1'-biphenyl]-4-yl)methanone (0.075 g, 0.161 mmol, 1 eq) was dissolved in AcOH (acetic acid, 1.3 ml, 0.13 M), and then Fe (0.090 g, 1.61 mmol, 10 eq) was added and refluxed for 1 hour. After cooling to room temperature, the mixture was filtered through a Celite filter. Water was added to the filtrate and extracted with DCM (dichloromethane). The organic layer was dried over MgSO4, filtered, concentrated, and purified by column chromatography (silica gel, EA / HX) to give the title compound (0.030 g, 43%).

[0189] Step 6(f) Synthesis of phenyl(4'-(4,4-difluoropiperidine-1-carbonyl)-2-((4-fluorophenyl)ethynyl)-[1,1'-biphenyl]-4-yl)carbamate (4'-amino-2'-((4-fluorophenyl)ethynyl)-[1,1'-biphenyl]-4-yl)(4,4-difluoropiperidin-1-yl)methanone (0.030 g, 0.069 mmol, 1 eq) was dissolved in THF (tetrahydrofuran, 1 ml, 0.1 M), and then pyridine (0.011 ml, 0.138 mmol, 2 eq) and phenyl chloroformate (0.013 ml, 0.104 mmol, 1.5 eq) were added at 0°C, followed by stirring at room temperature for 2 hours. 0.1 ml of water was added and the mixture was stirred for 10 minutes, then concentrated and purified by column chromatography (silica gel, EA / HX) to give the title compound (0.027 g, 71%).

[0190] Step 7(g) Synthesis of 1-(4'-(4,4-difluoropiperidine-1-carbonyl)-2-((4-fluorophenyl)ethynyl)-[1,1'-biphenyl]-4-yl)-3-(2-(pyridin-3-yl)ethyl)urea Phenyl(4'-(4,4-difluoropiperidine-1-carbonyl)-2-((4-fluorophenyl)ethynyl)-[1,1'-biphenyl]-4-yl)carbamate (0.027 g, 0.049 mmol, 1 eq) was dissolved in THF (1 ml, 0.06 M), followed by addition of 2-(pyridin-3-yl)ethan-1-amine (0.011 ml, 0.097 mmol, 2 eq) and TEA (0.02 ml, 0.147 mmol, 3 eq) and stirring at 80 °C for 4 hours. The reaction mixture was concentrated and purified by column chromatography (silica gel, MC / MeOH) to give the title compound (0.020 g, 70%). 1 H NMR (400 MHz, MeOD) δ 8.47 (s, 1H), 8.41 (d, J = 4.8 Hz, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.74 (s, 1H), 7.72 (s, 2H), 7.57-7.52 (m, 2H), 7.44-7.39 (m, 2H), 7.38-7.32 (m, 3H), 7.08 (t, J = 8.7 Hz, 2H), 3.98-3.57 (m, 4H), 3.50 (t, J = 7.0 Hz, 2H), 2.92 (t, J = 6.9 Hz, 2H), 2.07 (s, 4H). MS(ESI) m / z MH + 583

[0191] Compounds 22, 29, 58, 59, 67, and 68 can be synthesized by changing the reactants in substantially the same manner as in Example 7 above.

[0192] Example 8: Synthesis of Compound 7 (Synthetic Reaction Scheme 3) Synthesis of N-(2-(piperidin-1-yl)ethyl)-4-((5-(3-(2-(pyridin-3-yl)ethyl)ureido)-2-(pyridin-4-yl)phenyl)ethynyl)benzamide [ka] [ka] Scheme 3. Reagents and conditions: (a) 2-(piperidin-1-yl)ethan-1-amine, HATU, DIPEA, DMF, room temperature (rt), overnight; (b) NaNO, KI, HCl, HO, 5°C, 1 hour; (c) PdCl(PPh), CuI, TEA, ACN, 60°C, 5 hours; (d) Zn, NH, Cl, 1,4-dioxane, water (HO), room temperature (rt), overnight; (e) phenyl chloroformate. (f) 2-(pyridin-3-yl)ethan-1-amine, TEA, THF, rt, overnight; (f) 2-(pyridin-3-yl)ethan-1-amine, TEA, THF, rt, overnight

[0193] <Step 1(a) Synthesis of 4-ethynyl-N-(2-(piperidin-1-yl)ethyl)benzamide> 4-Ethynylbenzoic acid (0.5 g, 3.42 mmol, 1 eq) was dissolved in DMF (11 mL, 0.3 M). 2-(piperidin-1-yl)ethan-1-amine (0.657 g, 5.13 eq, 1.5 eq), HATU (1.950 g, 5.13 mmol, 1.5 eq), and DIPEA (1.326 g, 10.26 mmol, 3 eq) were added and stirred overnight at room temperature. Extraction with EA and HO was performed. The organic layer was dried over MgSO, filtered, concentrated, and purified by column chromatography (silica gel, MeOH / DCM) to give the title compound (0.788 g, 89.7%).

[0194] <Step 2(b) Synthesis of 4-(2-iodo-4-nitrophenyl)pyridine> 5-nitro-2-(pyridin-4-yl)aniline (1.00 g, 4.64 mmol, 1 eq) was added to 4.5 mL of water and 4.5 mL of concentrated HCl (conc. HCl). NaNO (0.326 g, 4.73 mmol, 1.0 eq) dissolved in 4.5 mL of water was slowly added dropwise at 5°C and stirred. After stirring for 10 minutes, KI (1.464 g, 8.82 mmol, 2 eq) dissolved in 4.5 mL of water was added. The mixture was then warmed to room temperature and stirred for 30 minutes. The mixture was neutralized to pH 8 or higher with saturated KCO (Sat.KCO) solution and extracted with DCM. The organic layer was dried over MgSO4, filtered, concentrated, and purified by column chromatography (silica gel, EA / Hex) to give the title compound (0.952 g, 62.9%).

[0195] <Step 3(c) Synthesis of 4-((5-nitro-2-(pyridin-4-yl)phenyl)ethynyl)-N-(2-(piperidin-1-yl)ethyl)benzamide> A solution of 4-(2-iodo-4-nitrophenyl)pyridine (0.5 g, 1.53 mmol, 1 eq), 4-ethynyl-N-(2-(piperidin-1-yl)ethyl)benzamide (0.588 g, 2.295 mmol, 1.5 eq), PdCl2(PPh3)2 (0.0322 g, 0.046 mmol, 0.03 eq), and CuI (0.00876 g, 0.046 mmol, 0.03 eq) was added and degassed with nitrogen gas (N2 gas). ACN (3.06 ml, 0.5 M) and TEA (0.309 g, 3.06 mmol, 2 eq) were then added, followed by stirring at 60°C for 5 hours. After completion of the reaction, the mixture was extracted with EA and HO. The organic layer was dried over MgSO, filtered, concentrated, and purified by column chromatography (silica gel, MeOH / DCM) to give the title compound (0.29 g, 41.7%).

[0196] <Step 4(d) Synthesis of 4-((5-amino-2-(pyridin-4-yl)phenyl)ethynyl)-N-(2-(piperidin-1-yl)ethyl)benzamide> 4-((5-nitro-2-(pyridin-4-yl)phenyl)ethynyl)-N-(2-(piperidin-1-yl)ethyl)benzamide (0.29 g, 0.64 mmol, 1 eq) was dissolved in 1,4-dioxane:water (HO) (3:1 (v / v)) (1.5 mL, 0.4 M), Zn (0.418 g, 6.4 mmol, 10 eq) and NHCl (0.342 g, 6.4 mmol, 10 eq) were added, and the mixture was stirred at room temperature overnight. The mixture was washed with MeOH and filtered under reduced pressure. The filtrate was concentrated and used in the reaction described in Step 5) without further purification.

[0197] Step 5(e) Synthesis of phenyl(3-((4-((2-(piperidin-1-yl)ethyl)carbamoyl)phenyl)ethynyl)-4-(pyridin-4-yl)phenyl)carbamate 4-((5-amino-2-(pyridin-4-yl)phenyl)ethynyl)-N-(2-(piperidin-1-yl)ethyl)benzamide (0.272 g, 0.64 mmol, 1 eq) was dissolved in THF (3 mL, 0.2 M), followed by the addition of pyridine (0.063 g, 0.8 mmol, 1.25 eq). After cooling to 0 °C, phenyl chloroformate (0.180 g, 1.152 mmol, 1.8 eq) was added dropwise. The mixture was gradually heated to room temperature and stirred for 2 hours. After the reaction was completed, the mixture was concentrated, neutralized with 1N NaOH, and extracted with EA and water (HO). The organic layer was dried over MgSO4, filtered, concentrated, and purified by column chromatography (silica gel, MeOH / DCM) to give the title compound (0.115 g, 31.9%).

[0198] Step 6(f) Synthesis of N-(2-(piperidin-1-yl)ethyl)-4-((5-(3-(2-(pyridin-3-yl)ethyl)ureido)-2-(pyridin-4-yl)phenyl)ethynyl)benzamide Phenyl(3-((4-((2-(piperidin-1-yl)ethyl)carbamoyl)phenyl)ethynyl)-4-(pyridin-4-yl)phenyl)carbamate (0.115 g, 0.21 mmol, 1 eq) was dissolved in THF (2 ml, 0.1 M), and then 2-(pyridin-3-yl)ethan-1-amine (0.0513 g, 0.42 mmol, 2 eq) and TEA (0.064 g, 0.63 mmol, 3 eq) were added, followed by stirring at room temperature overnight. After the reaction was completed, the mixture was concentrated and purified by reverse phase column chromatography (0.1% formic acid in H2O / ACN) to obtain the title compound (0.016 g, 13.7%). 1 H NMR (400 MHz, DMSO) δ 8.91 (s, 1H), 8.68 (s, 2H), 8.57-8.42 (m, 3H), 8.20 (s, 1H), 7.94 (s, 1H), 7.86 (d, J = 8.0 Hz, 2H), 7.72-7.63 (m, 3H), 7.53-7.43 (m, 4H), 7.39-7.33 (m, 1H), 6.42 (s, 1H), 3.41 (m, 4H), 2.82 (t, J = 6.6 Hz, 2H), 2.55 (m, 5H), 1.54 (m, 4H), 1.41 (m, 2H); MS(ESI) m / z MH + 573.1

[0199] Compounds 19, 20, 44, 45, 46, 54, 64, 33, 34, 36, 41, 48, 61, 62, 84, 85, and 92 can be synthesized by changing the reactants in substantially the same manner as in Example 8 above.

[0200] Example 9: Synthesis of Compound 9 (Synthetic Reaction Scheme 4) Synthesis of 1-(2-((4-fluorophenyl)ethynyl)-3'-morpholino-[1,1'-biphenyl]-4-yl)-3-(2-(pyridin-3-yl)ethyl)urea [ka] [ka] Scheme 4. Reagents and conditions: (a) 1-ethynyl-4-fluorobenzene, TEA, CuI, PdCl2(PPh3)2, ACN, reflux, 1 hour; (b) phenyl chloroformate, pyridine, THF, 0°C, 2 hours; (c) 2-(pyridin-3-yl)ethan-1-amine, TEA, THF, 80°C, 2 hours; (d) Fe, AcOH, reflux, 1 hour; (e) NaNO2, KI, pTSA, ACN, 5°C, 1 hour; (f) (3-morpholinophenyl)boronic acid acid), PdCl2(dppf), K2CO3, 1,4-dioxane, H2O, 90℃, 4 hours (4h)

[0201] <Step 1(a) Synthesis of 3-((4-fluorophenyl)ethynyl)-4-nitroaniline> 3-Bromo-4-nitroaniline (2.17 g, 0.01 mol, 1 eq) was dissolved in ACN (100 mL, 0.1 M) and then TEA (3 mL, 0.22 mol, 2.2 eq), PdCl2(PPh3)2 (210 mg, 0.3 mmol, 3 mol%), and CuI (80 mg, 0.4 mmol, 4 mol%) were added and stirred at room temperature for 5 minutes. 1-Ethynyl-4-fluorobenzene (1.72 mL, 0.015 mmol, 1.5 eq) was added and stirred at 90 °C for 1 hour. After cooling to room temperature, the solution was concentrated and purified by column chromatography (silica gel, EA / HX) to give the title compound (1.44 g, 56%).

[0202] <Step 2(b) Synthesis of phenyl(3-((4-fluorophenyl)ethynyl)-4-nitrophenyl)carbamate> 3-((4-fluorophenyl)ethynyl)-4-nitroaniline (1.436 g, 5.60 mmol, 1 eq) was dissolved in THF (56 ml, 0.1 M). Pyridine (0.9 ml, 11.2 mmol, 2 eq) and phenyl chloroformate (1.06 ml, 8.41 mmol, 1.5 eq) were added dropwise at 0°C and the mixture was stirred at room temperature for 2 hours. Water was added and the mixture was stirred for 10 minutes. The mixture was concentrated and purified by column chromatography (silica gel, EA / HX) to give the title compound (1.968 g, 93.4%).

[0203] Step 3(c) Synthesis of 1-(3-((4-fluorophenyl)ethynyl)-4-nitrophenyl)-3-(2-(pyridin-3-yl)ethyl)urea Phenyl(3-((4-fluorophenyl)ethynyl)-4-nitrophenyl)carbamate (1 g, 2.66 mmol, 1 eq) was dissolved in THF (1 mL, 0.06 M), followed by addition of 2-(pyridin-3-yl)ethan-1-amine (0.62 mL, 5.32 mmol, 2 eq) and TEA (1.11 mL, 7.98 mmol, 3 eq) and stirring at 80 °C for 4 h. The reaction mixture was concentrated and purified by column chromatography (silica gel, MC / MeOH) to give the title compound (0.954 g, 96%).

[0204] Step 4(d) Synthesis of 1-(4-amino-3-((4-fluorophenyl)ethynyl)phenyl)-3-(2-(pyridin-3-yl)ethyl)urea 1-(3-((4-fluorophenyl)ethynyl)-4-nitrophenyl)-3-(2-(pyridin-3-yl)ethyl)urea (0.954 g, 2.55 mmol, 1 eq) was dissolved in AcOH (20 mL, 0.13 M), and then Fe (1.42 g, 25.5 mmol, 10 eq) was added and refluxed for 1 hour. After cooling to room temperature, the mixture was filtered through a Celite filter. Water was added to the filtrate and extracted with DCM. The organic layer was dried over MgSO4, filtered, concentrated, and purified by column chromatography (silica gel, EA / HX) to give the title compound (0.859 g, 90%). 1H NMR (400 MHz, DMSO) δ 8.46 (d, J = 1.5 Hz, 1H), 8.43 (d, J = 3.9 Hz, 1H), 8.06 (s, 1H), 7.39-7.31 (m, 2H), 7.26 (t, J = 8.8 Hz, 2H), 6.98 (dd, J = 8.7, 2.4 Hz, 1H), 6.64 (d, J = 8.7 Hz, 1H), 6.06-5.99 (m, 1H), 5.18 (s, 2H), 3.36-3.30 (m, 2H), 2.77 (t, J = 7.0 Hz, 2H).

[0205] Step 5(e) Synthesis of 1-(3-((4-fluorophenyl)ethynyl)-4-iodophenyl)-3-(2-(pyridin-3-yl)ethyl)urea 1-(4-amino-3-((4-fluorophenyl)ethynyl)phenyl)-3-(2-(pyridin-3-yl)ethyl)urea (0.05 g, 0.134 mmol, 1 eq) was dissolved in ACN (1.34 mL, 0.1 M) and then p-TSA (p-toluenesulfonic acid, 0.069 g, 0.402 mmol, 3 eq) was added. Then, NaNO (0.01 g, 0.136 mmol, 1.02 eq) dissolved in 0.15 mL of water and KI (0.045 g, 0.268 mmol, 2 eq) dissolved in 0.15 mL of water were added at 0 °C. After reacting at room temperature for 1 hour, the mixture was neutralized to pH 8 or higher with saturated aqueous sodium bicarbonate (Sat.NaHCO3) and extracted with EA. The organic layer was dried over MgSO4, filtered, concentrated, and purified by column chromatography (silica gel, MeOH / DCM) to give the title compound (0.038 g, 58.4%).

[0206] Step 6(f) Synthesis of 1-(2-((4-fluorophenyl)ethynyl)-3'-morpholino-[1,1'-biphenyl]-4-yl)-3-(2-(pyridin-3-yl)ethyl)urea 1-(3-((4-fluorophenyl)ethynyl)-4-iodophenyl)-3-(2-(pyridin-3-yl)ethyl)urea (0.05 g, 0.1 mmol, 1 eq) was dissolved in 1,4-dioxane:water (HO) (3:1 (v / v)) (0.5 ml, 0.2 M) and then (3-morpholinophenyl)boronic acid was obtained. After adding PdCl(dppf) (0.0146 g, 0.02 mmol, 0.2 eq), KCO (0.0304 g, 0.22 mmol, 2.2 eq), the mixture was heated to 90 °C and stirred for 4 hours. After the reaction was completed, the mixture was washed with EA, filtered through a Celite filter, and extracted with EA and HO. The organic layer was dried over MgSO, filtered, concentrated, and filtered through prep-LC (0.1% formic acid in HO / ACN) to give the title compound (0.078 g, 15.0%). 1H NMR (400 MHz, DMSO) δ 8.74 (s, 1H), 8.48 (s, 1H), 8.45 (d, J = 4.4 Hz, 1H), 7.84 (m, 1H), 7.69 (m, 1H), 7.42 (dd, J = 8.3, 5.6 Hz, 2H), 7.37 (s, 2H), 7.33 (m, 2H), 7.26 (t, J = 8.8 Hz, 2H), 7.18 (s, 1H), 7.04 (d, J = 7.4 Hz, 1H), 6.96 (d, J = 8.6 Hz, 1H), 6.30 (t, J = 5.5 Hz, 1H), 3.74-3.70 (m, MS(ESI) m / z MH- 519.48

[0207] Compounds 49, 50, 51, 56, 131, 132, 134, 142, 143, 144, 145, 179 and 180 can be synthesized by substantially the same method as in Example 9 above, but by changing the reactants.

[0208] Example 10: Synthesis of Compound 13 (Synthetic Reaction Scheme 5) Synthesis of 1-(2-((4-fluorophenyl)ethynyl)-4'-(piperazin-1-yl)-[1,1'-biphenyl]-4-yl)-3-(2-(pyridin-3-yl)ethyl)urea [ka] [ka] Reaction Scheme 5. (a) PdCl2(dppf), K2CO3, 1,4-dioxane, water (HO), 90 °C, 4 h; (b) TFA, DCM, room temperature (rt), overnight.

[0209] Step 1(a) Synthesis of tert-butyl 4-(2'-((4-fluorophenyl)ethynyl)-4'-(3-(2-(pyridin-3-yl)ethyl)ureido)-[1,1'-biphenyl]-4-yl)piperazine-1-carboxylate 1-(3-((4-fluorophenyl)ethynyl)-4-iodophenyl)-3-(2-(pyridin-3-yl)ethyl)urea (0.05 g, 0.1 mmol, 1 eq) was dissolved in 1,4-dioxane:water (HO) (3:1 (v / v)) (0.5 ml, 0.2 M) and then the resulting solution was treated with (4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)boronic acid. After adding PdCl(dppf) (0.0146 g, 0.02 mmol, 0.2 eq), KCO (0.0304 g, 0.22 mmol, 2.2 eq), the mixture was heated to 90 °C and stirred for 4 hours. After the reaction was completed, the mixture was washed with EA, filtered through a Celite filter, and extracted with EA and HO. The organic layer was dried over MgSO, filtered, concentrated, and purified by column chromatography (silica gel, MeOH / DCM) to give the title compound (0.043 g, 69.4%).

[0210] <Step 2(b) Synthesis of 1-(2-((4-fluorophenyl)ethynyl)-4'-(piperazin-1-yl)-[1,1'-biphenyl]-4-yl)-3-(2-(pyridin-3-yl)ethyl)urea> tert-Butyl 4-(2'-((4-fluorophenyl)ethynyl)-4'-(3-(2-(pyridin-3-yl)ethyl)ureido)-[1,1'-biphenyl]-4-yl)piperazine-1-carboxylate (0.047 g, 0.075 mmol, 1 eq) was dissolved in DCM (0.5 mL), and then trifluoroacetic acid (0.083 g, 0.75 mmol, 10 eq) was added and the mixture was stirred at room temperature overnight. After the reaction was completed, the mixture was concentrated and purified by reverse phase column chromatography (0.1% formic acid in H2O / acetonitrile) to obtain the title compound (0.017 g, 43.6%). 1H NMR (400 MHz, DMSO) δ 8.76 (s, 1H), 8.47 (d, J = 15.1 Hz, 2H), 7.81 (s, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.52 (d, J = 8.2 Hz, 2H), 7.48-7.43 (m, 2H), 7.35 (d, J = 7.6 Hz, 2H), 7.26 (dd, J = 16.4, 8.2 Hz, 3H), 7.04 (d, J = 8.1 Hz, 2H), 6.38 (s, 1H), 3.42-3.35 (m, 3H), 3.26 (s, 4H), 3.07 (s, 4H), 2.81 (t, J = 6.7 Hz, 2H).; MS(ESI) m / z MH- 518.45

[0211] Example 11: Synthesis of Compound 14 (Synthetic Reaction Scheme 6) Synthesis of 1-(3-((4-fluorophenyl)ethynyl)-4-(2-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)phenyl)-3-(2-(pyridin-3-yl)ethyl)urea [ka] [ka] Reaction Scheme 6. (a) PdCl2(dppf), bis(pinacolato)diboron, KOAc, dioxane, 60°C, 16 hours; (b) PdCl2(dppf), K2CO3, 1,4-dioxane, water (HO), 90°C, 4 hours

[0212] <Step 1(a) Synthesis of 2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4(3H)-one> 7-Bromo-2-methylquinazolin-4(3H)-one (0.24 g, 1 mmol, 1 eq) was dissolved in dioxane (10 mL, 0.1 M), followed by the addition of bis(pinacolato)diboron (0.5 g, 2 mmol, 2 eq), potassium acetate (0.2 g, 2 mmol, 2 eq), and PdCl(dppf) (0.15 g, 0.2 mmol, 0.2 eq) and stirring at 60 °C for 16 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (silica gel, EA / HX) to give the title compound (0.075 g, 26%).

[0213] <Step 2(b) Synthesis of 1-(3-((4-fluorophenyl)ethynyl)-4-(2-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)phenyl)-3-(2-(pyridin-3-yl)ethyl)urea> The title compound (7.38 mg, 22%) was obtained in substantially the same manner as in Step 6) of Compound 9 in Example 9, except that 2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4(3H)-one was used instead of (3-morpholinophenyl)boronic acid in Step 6). 1 H NMR (400 MHz, MeOD) δ 8.50 (s, 1H), 8.43 (d, J = 4.5 Hz, 1H), 8.26 (d, J = 8.3 Hz, 1H), 7.90 (s, 1H), 7.85-7.76 (m, 3H), 7.48-7.41 (m, MS(ESI) m / z MH + 518

[0214] Example 12: Synthesis of Compound 11 (Synthetic Reaction Scheme 7) Synthesis of 1-(2-(benzo[d]oxazol-5-yl)ethyl)-3-(3-((4-fluorophenyl)ethynyl)-4-(pyridin-4-yl)phenyl)urea [ka] [ka] Reaction Scheme 7. (a) potassium(2-((tert-butoxycarbonyl)amino)ethyl)trifluoroborate, Cs2CO3, Pd(OAc)2, RuPhos, toluene / water; (b) TFA, DCM; (c) TEA, THF, 24 h, reflux

[0215] <Step 1(a) Synthesis of tert-butyl(2-(benzo[d]oxazol-5-yl)ethyl)carbamate> A mixture of 5-bromobenzo[d]oxazole (0.2 g, 1 eq), potassium (2-((tert-butoxycarbonyl)amino)ethyl)trifluoroborate (0.28 g, 1.1 eq), and cesium carbonate (0.977 g, 3 eq) in toluene (6 mL) and water (2 mL) was degassed twice with nitrogen. Subsequently, palladium(II) acetate (11 mg, 0.05 eq) and RuPhos (46 mg, 0.1 eq) were added, and the mixture was heated at 95 °C under nitrogen overnight. The reaction was cooled to room temperature, and water was added. The mixture was extracted twice with EtOAc. The combined organic layers were then washed with brine, dried over anhydrous MgSO, filtered, and concentrated under reduced pressure. Subsequent purification with hexane / ethyl acetate (1 / 5) afforded the title compound (40 mg, 15% yield).

[0216] Step 2(b) Synthesis of 2-(benzo[d]oxazol-5-yl)ethan-1-amine To a solution of tert-butyl (2-(benzo[d]oxazol-5-yl)ethyl)carbamate (0.04 g, 1 eq) in DCM (5 mL) was added TFA (0.11 mL, 10 eq) and the mixture was stirred at room temperature for 2 h. The reaction was then concentrated under reduced pressure to give crude 2-(benzo[d]oxazol-5-yl)ethan-1-amine, which was further dried under high vacuum.

[0217] Step 3(c) Synthesis of 1-(2-(benzo[d]oxazol-5-yl)ethyl)-3-(3-((4-fluorophenyl)ethynyl)-4-(pyridin-4-yl)phenyl)urea The title compound was obtained in substantially the same manner as in the synthesis of compound 1 in Example 1, except that 2-(benzo[d]oxazol-5-yl)ethan-1-amine was used instead of 3-(2-aminoethyl)pyridine in step 6). 1 H NMR (400 MHz, MeOD) δ 8.60 (d, J = 5.1 Hz, 2H), 8.45 (s, 1H), 7.77-7.61 (m, 5H), 7.45-7.34 (m, 5H), 7.10 (t, J = 8.6 Hz, 2H), 3.53 (t, J = 7.0 Hz, 2H), 3.01 (t, J = 7.0 Hz, 2H).

[0218] Example 13: Synthesis of Compound 118 (Synthetic Reaction Scheme 8) Synthesis of 1-(3-((4-fluorophenyl)ethynyl)-4-(piperazin-1-yl)phenyl)-3-(2-(pyridin-3-yl)ethyl)urea [ka] [ka] Reaction Scheme 8. (a) tert-butyl piperazine-1-carboxylate, Cs2CO3, DMF, 80°C, 24 hours (24 h); (b) 1-ethynyl-4-fluorobenzene, PdCl2(PPh3)2, CuI, TEA, ACN, 90°C, 2 hours (2 h); (c) Zn, NHCl, 1,4-dioxane, water (HO), room temperature (rt), 1 hour (1 h); (d) phenyl chloroformate (e) 2-(pyridin-3-yl)ethan-1-amine, TEA, THF, reflux, 24 h; (f) 4N HCl in dioxane, 1,4-dioxane, room temperature (rt), 24 h.

[0219] Step 1(a) Synthesis of tert-butyl 4-(2-iodo-4-nitrophenyl)piperazine-1-carboxylate 1-Fluoro-2-iodo-4-nitrobenzene (0.1 g, 0.375 mmol, 1.0 eq) was dissolved in DMF (1 mL), followed by the addition of CsCO (0.15 g, 0.45 mmol, 1.2 eq) and tert-butyl piperazine-1-carboxylate (0.07 g, 0.375 mmol, 1.0 eq). The mixture was stirred at 80 °C overnight. After completion of the reaction, the mixture was extracted with EA and HO. The organic layer was dried over MgSO, filtered, concentrated, and purified by column chromatography (silica gel, EA / HX) to give the title compound (0.114 g, 70.4%). 1 H NMR (400 MHz, CDCl3) δ 8.71 (d, J = 2.2 Hz, 1H), 8.21 (dd, J = 8.8, 2.2 Hz, 1H), 7.00 (d, J = 8.8 Hz, 1H), 3.70-3.61 (m, 4H), 3.11-3.03 (m, 4H), 1.49 (s, 9H).

[0220] Step 2(b) Synthesis of tert-butyl 4-(2-((4-fluorophenyl)ethynyl)-4-nitrophenyl)piperazine-1-carboxylate tert-Butyl 4-(2-iodo-4-nitrophenyl)piperazine-1-carboxylate (0.114 g, 0.263 mmol, 1 eq) was dissolved in ACN (3 mL, 0.1 M), followed by the addition of TEA (0.08 mL, 0.579 mmol, 2.2 eq), PdCl2(PPh3)2 (5.5 mg, 0.008 mmol, 3 mol%), and CuI (2 mg, 0.011 mmol, 4 mol%). The mixture was stirred at room temperature for 5 min. 1-ethynyl-4-fluorobenzene (0.045 mL, 0.395 mmol, 1.5 eq) was added and stirred at 90 °C for 2 h. After cooling to room temperature, the mixture was concentrated and purified by column chromatography (silica gel, EA / HX) to give the title compound (0.109 g, 97.3%). 1 H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 2.5 Hz, 1H), 8.15 (dd, J = 9.1, 2.6 Hz, 1H), 7.52 (dd, J = 8.4, 5.4 Hz, 2H), 7.12 (t, J = 8.6 Hz, 2H), 6.95 (d, J = 9.1 Hz, 1H), 3.72-3.65 (m, 4H), 3.47-3.38 (m, 4H), 1.52 (s, 8H).

[0221] Step 3(c) Synthesis of tert-butyl 4-(4-amino-2-((4-fluorophenyl)ethynyl)phenyl)piperazine-1-carboxylate tert-Butyl 4-(2-((4-fluorophenyl)ethynyl)-4-nitrophenyl)piperazine-1-carboxylate (0.109 g, 0.256 mmol, 1 eq) was dissolved in 1,4-dioxane:water (HO) (3:1 (v / v)) (3 mL, 0.4 M). Zn (0.14 g, 2.56 mmol, 10 eq) and NHCl (0.137 g, 2.56 mmol, 10 eq) were added and stirred at room temperature for 1 h. The mixture was washed with MeOH and filtered under reduced pressure. The filtrate was concentrated and extracted with EA and HO. The organic layer was dried over MgSO, filtered, concentrated, and used in the reaction as in step 4) without further purification. 1 H NMR (400 MHz, CDCl3) δ 7.47 (dd, J = 8.2, 5.6 Hz, 2H), 7.26-7.26 (m, 1H), 7.05 (t, J = 8.5 Hz, 2H), 6.90 (s, 1H), 6.68 (d, J = 6.2 Hz, 1H), 3.64 (s, 4H), 3.09 (s, 4H), 1.48 (s, 9H).

[0222] Step 4(d) Synthesis of tert-butyl 4-(2-((4-fluorophenyl)ethynyl)-4-((phenoxycarbonyl)amino)phenyl)piperazine-1-carboxylate tert-Butyl 4-(4-amino-2-((4-fluorophenyl)ethynyl)phenyl)piperazine-1-carboxylate (0.114 g, 0.256 mmol, 1 eq) was dissolved in THF (3 mL, 0.1 M). Pyridine (0.04 mL, 0.512 mmol, 2 eq) and phenyl chloroformate (0.049 mL, 0.384 mmol, 1.5 eq) were added at 0 °C and the mixture was stirred at room temperature for 2 hours. Water was added and the mixture was stirred for 10 minutes. The mixture was concentrated and purified by column chromatography (silica gel, EA / HX) to give the title compound (0.093 g, 70.5%). 1 H NMR (400 MHz, CDCl3) δ 7.66 (s, 1H), 7.51-7.44 (m, 2H), 7.44-7.35 (m, 3H), 7.25-7.22 (m, 2H), 7.19 (d, J = 7.8 Hz, 3H), 7.06 (t, J = 8.6 Hz, 2H), 6.87 (s, 1H), 3.67 (s, 4H), 3.18 (s, 4H), 1.48 (s, 9H).

[0223] Step 5(e) Synthesis of tert-butyl 4-(2-((4-fluorophenyl)ethynyl)-4-(3-(2-(pyridin-3-yl)ethyl)ureido)phenyl)piperazine-1-carboxylate tert-Butyl 4-(2-((4-fluorophenyl)ethynyl)-4-((phenoxycarbonyl)amino)phenyl)piperazine-1-carboxylate (0.093 g, 0.180 mmol, 1 eq) was dissolved in THF (2 ml, 0.1 M), and then 2-(pyridin-3-yl)ethan-1-amine (0.042 ml, 0.36 mmol, 2 eq) and TEA (0.075 ml, 0.54 mmol, 3 eq) were added and the mixture was stirred at 80°C for 4 hours. The reaction mixture was concentrated and purified by column chromatography (silica gel, MC / MeOH) to give the title compound (0.089 g, 90.8%). 1 H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 8.43 (d, J = 4.2 Hz, 1H), 7.62 (d, J = 7.7 Hz, 1H), 7.51-7.44 (m, 2H), 7.41 (s, 1H), 7.30 (d, J = 6.9 Hz, 1H), 7.17 (d, J = 7.8 Hz, 1H), 7.06 (t, J = 8.6 Hz, 2H), 6.84 (d, J = 8.7 Hz, 1H), 6.63 (s, 1H), 5.02 (s, 1H), 3.61 (s, 4H), 3.56-3.47 (m, 2H), 3.10 (s, 4H), 2.87 (t, J = 6.5 Hz, 2H), 1.48 (s, 9H).

[0224] Step 6(f) Synthesis of 1-(3-((4-fluorophenyl)ethynyl)-4-(piperazin-1-yl)phenyl)-3-(2-(pyridin-3-yl)ethyl)urea tert-Butyl 4-(2-((4-fluorophenyl)ethynyl)-4-(3-(2-(pyridin-3-yl)ethyl)ureido)phenyl)piperazine-1-carboxylate (0.089 g, 0.164 mmol, 1 eq) was dissolved in 1,4-dioxane (2 ml, 0.1 M), and then 4N HCl (0.16 ml, 0.655 mmol, 4 eq) was added to the dioxane and stirred overnight. After washing with 1,4-dioxane and filtration under reduced pressure, the compound was obtained. 1 H NMR (400 MHz, MeOD) δ 8.45 (s, 1H), 8.39 (d, J = 4.4 Hz, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.56-7.48 (m, 3H), 7.39 (dd, J = 7.6, 5.0 Hz, 1H), 7.24 (dd, J = 8.7, 2.4 Hz, 1H), 7.14 (t, J = 8.7 Hz, 2H), 6.95 (d, J = 8.8 Hz, 1H), 3.46 (t, J = 6.9 Hz, 2H), 3.15-3.09 (m, 4H), 3.05-2.99 (m, 4H), 2.89 (t, J = 6.9 Hz, 2H).

[0225] Compounds 25, 26, 27, 28, 30, 31, 32, 42, 114, 115, 116, 117, 119, 120, 121, 169, and 171 can be synthesized by changing the reactants in substantially the same manner as in Example 13 above.

[0226] Example 14: Synthesis of Compound 52 (Synthetic Reaction Scheme 9) Synthesis of 1-(4-(4-(3-aminobenzoyl)piperazin-1-yl)-3-((4-fluorophenyl)ethynyl)phenyl)-3-(2-(pyridin-3-yl)ethyl)urea [ka] [ka] Scheme 9. (a) 3-((tert-butoxycarbonyl)amino)benzoic acid, DIPEA, HATU, DCM, room temperature (rt), 24 hours (24 h); (b) 4N HCl in dioxane, 1,4-dioxane, room temperature (rt), 24 hours (24 h);

[0227] Step 1(a) Synthesis of tert-butyl(3-(4-(2-((4-fluorophenyl)ethynyl)-4-(3-(2-(pyridin-3-yl)ethyl)ureido)phenyl)piperazine-1-carbonyl)phenyl)carbamate 3-((tert-butoxycarbonyl)amino)benzoic acid (0.024 g, 0.1 mmol, 1 eq) was dissolved in DCM (1 ml, 0.3 M), followed by the addition of HATU (0.046 g, 0.12 mmol, 1.2 eq), DIPEA (0.05 ml, 0.3 mmol, 3 eq), and 1-(3-((4-fluorophenyl)ethynyl)-4-(piperazin-1-yl)phenyl)-3-(2-(pyridin-3-yl)ethyl)urea (0.044 g, 0.1 mmol, 1 eq). The mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated and purified by column chromatography (silica gel, EA) (0.022 g, 33.3%). 1 H NMR (400 MHz, CDCl3) δ 8.64-8.42 (m, 2H), 8.02 (s, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.72 (s, 2H), 7.52 (s, J = 8.4 Hz, 1H), 7.49-7.33 (m, 8H), 7.20 (d, J = 7.6 Hz, 1H), 7.11-7.03 (m, 4H), 6.93 (s, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.68 (d, J = 12.4 Hz, 2H), 5.07 (s, 1H), 3.98 (s, 2H), 3.64 (s, 2H), 3.55 (s, 2H), 3.24 (s, 2H), 3.13 (s, 2H), 2.92 (s, 2H), 1.54 (s, 9H).

[0228] Step 2(b) Synthesis of 1-(4-(4-(3-aminobenzoyl)piperazin-1-yl)-3-((4-fluorophenyl)ethynyl)phenyl)-3-(2-(pyridin-3-yl)ethyl)urea tert-Butyl (3-(4-(2-((4-fluorophenyl)ethynyl)-4-(3-(2-(pyridin-3-yl)ethyl)ureido)phenyl)piperazine-1-carbonyl)phenyl)carbamate (0.05 g, 0.075 mmol, 1 eq) was dissolved in 1,4-dioxane (1 ml), and then 4N HCl in dioxane (0.1 ml, 0.377 mmol, 5 eq) was added and stirred overnight. The mixture was neutralized with saturated aqueous sodium bicarbonate (NaHCO3) and extracted with EA. The organic layer was dried over MgSO4, filtered, concentrated, and purified by column chromatography (silica gel, MeOH / DCM) to give the title compound (0.018 g, 42.8%). 1H NMR (400 MHz, MeOD) δ 8.46 (s, 1H), 8.41 (d, J = 4.2 Hz, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.61-7.52 (m, 3H), 7.44-7.39 (m, 1H), 7.27 (dd, J = 8.8, 2.6 Hz, 1H), 7.22-7.12 (m, 3H), 7.01-6.97 (m, 1H), 6.80 (dd, J = 7.7, 1.9 Hz, 1H), 6.77-6.74 (m, 1H), 6.72-6.68 (m, 1H), 3.95 (s, 2H), 3.67 (s, 2H), 3.48 (t, J = 7.0 Hz, 2H), 3.24 (s, 2H), 3.13 (s, 2H), 2.90 (t, J = 7.0 Hz, 2H).

[0229] Example 15: Synthesis of Compound 186 (Synthetic Reaction Scheme 10) Synthesis of 1-(4-(3-(2-aminoethyl)-2-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)-3-((4-fluorophenyl)ethynyl)phenyl)-3-(2-(pyridin-3-yl)ethyl)urea [ka] [ka] Scheme 10. (a) tert-butyl(2-bromoethyl)carbamate, Cs2CO3, DMF, 80 °C, 24 h; (b) 4 N HCl in dioxane, 1,4-dioxane, room temperature (rt), 24 h

[0230] Step 1(a) Synthesis of tert-butyl(2-(7-(2-((4-fluorophenyl)ethynyl)-4-(3-(2-(pyridin-3-yl)ethyl)ureido)phenyl)-2-methyl-4-oxoquinazolin-3(4H)-yl)ethyl)carbamate 1-(3-((4-fluorophenyl)ethynyl)-4-(2-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)phenyl)-3-(2-(pyridin-3-yl)ethyl)urea (n-3-yl)ethyl)urea (0.064 g, 0.124 mmol, 1.0 eq) was dissolved in DMF (1 mL), followed by the addition of Cs2CO3 (0.081 g, 0.248 mmol, 1.2 eq) and tert-butyl(2-bromoethyl)carbamate (0.033 g, 0.15 mmol, 1.2 eq) and stirring at 80 °C overnight. After completion of the reaction, the mixture was extracted with EA and HO. The organic layer was dried over MgSO4, filtered, concentrated, and purified by column chromatography (silica gel, DCM / MeOH) to give the title compound (0.049 g, 59.8%). 11H NMR (400 MHz, CDCl3) δ 8.49 (s, 2H), 8.24 (d, J = 8.3 Hz, 1H), 7.84 (s, 1H), 7.77 (d, J = 9.5 Hz, 1H), 7.68 (s, 2H), 7.54 - 7.48 (m, 1H), 7.37 (s, 2H), 7.35 - 7.29 (m, 3H), 7.04 (t, J = 8.7 Hz, 1H), 7.00 - 6.92 (m, 3H), 5.22 (s, 1H), 5.00 (t, J = 5.9 Hz, 1H), 4.27 (t, J = 6.0 Hz, 2H), 3.58 (s, 2H), 3.54 - 3.47 (m, 2H), 2.92 - 2.84 (m, 2H), 2.72 (s, 3H), 1.39 (s, 9H).

[0231] <Synthesis of 1-(4-(3-(2-aminoethyl)-2-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)-3-((4-fluorophenyl)ethynyl)phenyl)-3-(2-(pyridin-3-yl)ethyl)urea (Step 2(b))> tert-Butyl (2-(7-(2-((4-fluorophenyl)ethynyl)-4-(3-(2-(pyridin-3-yl)ethyl)ureido)phenyl)-2-methyl-4-oxoquinazolin-3(4H)-yl)ethyl)carbamate (0.05 g, 0.075 mmol, 1 eq) was dissolved in 1,4-dioxane (1 ml), followed by 4N HCl in dioxane (0.1 ml, 0.377 mmol, 5 eq) and stirring overnight. The mixture was neutralized with saturated aqueous sodium bicarbonate (Sat. NaHCO3) and extracted with EA. The organic layer was dried over MgSO4, filtered, concentrated, and purified by preparative HPLC (0.1% formic acid / acetonitrile) to give the title compound (0.002 g, 0.5%). 1 H NMR (400 MHz, MeOD) δ 8.50 (s, 5H), 8.44 (s, 1H), 8.30 (d, J = 8.3 Hz, 1H), 7.93 (s, 1H), 7.80 (dd, J = 12.0, 5.0 Hz, 3H), 7.51-7.36 (m, 5H), 7.08 (t, J = 8.7 Hz, 2H), 4.49 (t, J = 6.2 Hz, 2H), 3.62 (s, 1H), 3.53 (t, J = 7.0 Hz, 2H), 3.41-3.36 (m, 2H), 2.94 (t, J = 6.9 Hz, 2H), 2.73 (s, 3H).

[0232] Example 16: Synthesis of Compound 40 (Synthetic Reaction Scheme 11) Synthesis of N-(2-(3-aminopiperidin-1-yl)ethyl)-4-((5-(3-(2-(pyridin-3-yl)ethyl)ureido)-2-(pyridin-4-yl)phenyl)ethynyl)benzamide [ka] [ka] Scheme 11. Reagents and conditions: (a) HATU, DIPEA, DMF, room temperature (rt), overnight; (b) phenyl chloroformate, pyridine, THF, 0°C, 2 hours (2 h); (c) 2-(pyridin-3-yl)ethan-1-amine, TEA, THF, reflux, 24 hours (24 h); (d) PdCl2(PPh3)2, CuI, TEA, ACN, 60°C, 5 hours (5 h); (e) 4N HCl in dioxane, 1,4-dioxane, room temperature (rt), 2 hours (2 h).

[0233] <Step 1(a) Synthesis of tert-butyl(1-(2-(4-ethynylbenzamido)ethyl)piperidin-3-yl)carbamate> 4-Ethynylbenzoic acid (0.15 g, 1 mmol, 1 eq) was dissolved in DMF (3 mL, 0.3 M), followed by the addition of tert-butyl(1-(2-aminoethyl)piperidin-3-yl)carbamate (0.243 g, 1 mmol, 1.5 eq), HATU (0.456 g, 1.2 mmol, 1.2 eq), and DIPEA (0.52 mL, 3 mmol, 3 eq). The mixture was stirred overnight at room temperature, washed with water, and filtered to give the title compound (0.371 g, 74%). 1 H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 8.3 Hz, 2H), 7.55 (d, J = 8.3 Hz, 2H), 6.76 (s, 1H), 4.72 (s, 1H), 3.72 (s, 1H), 3.53 (dt, J = 10.5, 5.3 Hz, 2H), 2.75 (s, 1H), 2.56 (t, J = 5.3 Hz, 2H), 2.36-2.09 (m, 2H), 1.84-1.69 (m, 3H), 1.43 (s, 9H).

[0234] <Step 2(b) Synthesis of phenyl(3-iodo-4-(pyridin-4-yl)phenyl)carbamate> 3-iodo-4-(pyridin-4-yl)aniline (0.592 g, 2 mmol, 1 eq) was dissolved in THF (20 mL, 0.1 M), and then pyridine (0.32 mL, 4 mmol, 2 eq) and phenyl chloroformate (0.38 mL, 3 mmol, 1.5 eq) were added dropwise at 0 °C and stirred. After the reaction was complete, the mixture was concentrated and extracted with EA and HO. The organic layer was dried over MgSO and used in step 3 without further purification. 1H NMR (400 MHz, CDCl3) δ 8.79 (d, J = 6.0 Hz, 2H), 8.20 (s, 1H), 7.91 (d, J = 6.2 Hz, 2H), 7.63 (d, J = 8.0 Hz, 1H), 7.38-7.33 (m, 3H), 7.24 (d, J = 8.6 Hz, 1H), 7.13 (d, J = 7.6 Hz, 2H).

[0235] <Step 3(c) Synthesis of 1-(3-iodo-4-(pyridin-4-yl)phenyl)-3-(2-(pyridin-3-yl)ethyl)urea> Phenyl(3-iodo-4-(pyridin-4-yl)phenyl)carbamate (1.14 g, 2 mmol, 1 eq) was dissolved in THF (20 mL, 0.1 M), followed by the addition of 2-(pyridin-3-yl)ethan-1-amine (0.47 mL, 4 mmol, 2 eq) and TEA (0.84 mL, 6 mmol, 3 eq) and stirring at 80 °C for 4 h. The reaction mixture was concentrated and purified by column chromatography (silica gel, MC / MeOH) to give the title compound (0.552 g, 62%). 1 H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 5.9 Hz, 2H), 8.40 (s, 2H), 7.93 (d, J = 2.0 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.51 (s, 1H), 7.41 (dd, J = 8.4, 2.1 Hz, 1H), 7.31-7.27 (m, 1H), 7.24 (s, 1H), 7.12 (d, J = 8.3 Hz, 1H), 5.42 (t, J = 5.6 Hz, 1H), 3.58 (q, J = 6.2 Hz, 2H), 2.89 (t, J = 6.5 Hz, 2H).

[0236] Step 4(d) Synthesis of tert-butyl(1-(2-(4-((5-(3-(2-(pyridin-3-yl)ethyl)ureido)-2-(pyridin-4-yl)phenyl)ethynyl)benzamido)ethyl)piperidin-3-yl)carbamate 1-(3-iodo-4-(pyridin-4-yl)phenyl)-3-(2-(pyridin-3-yl)ethyl)urea (0.044 g, 0.1 mmol, 1 eq) was dissolved in ACN (1 ml, 0.1 M), followed by addition of TEA (0.03 ml, 0.22 mmol, 2.2 eq), PdCl2(PPh3)2 (2.1 mg, 0.003 m tert-butyl(1-(2-(4-ethynylbenzamido)ethyl)piperidin-3-yl)carbamate (0.045 g, 0.12 mmol, 1.2 eq) was added and stirred at room temperature for 5 minutes. After cooling to room temperature, the mixture was concentrated and purified by column chromatography (silica gel, EA / HX) to give the title compound (0.109 g, 97.3%). 11H NMR (400 MHz, CDCl3) δ 8.57 (s, 4H), 8.00 (s, 1H), 7.67 (d, J = 8.1 Hz, 2H), 7.62 (t, J = 8.2 Hz, 2H), 7.45 (s, 3H), 7.31 (s, 1H), 7.25 - 7.19 (m, 4H), 5.94 (s, 1H), 5.05 (s, 1H), 3.80 (s, 1H), 3.68 - 3.50 (m, 5H), 3.03 (s, 1H), 2.91 (t, J = 6.5 Hz, 2H), 2.82 (s, 3H), 2.51 (s, 2H), 2.02 (s, 10H), 1.83 (s, 3H), 1.72 (s, 2H), 1.42 (d, J = 19.1 Hz, 12H), 1.25 (s, 2H).

[0237] <Synthesis of N-(2-(3-aminopiperidin-1-yl)ethyl)-4-((5-(3-(2-(pyridin-3-yl)ethyl)ureido)-2-(pyridin-4-yl)phenyl)ethynyl)benzamide (Step 5(e))> tert-Butyl (1-(2-(4-((5-(3-(2-(pyridin-3-yl)ethyl)ureido)-2-(pyridin-4-yl)phenyl)ethynyl)benzamido)ethyl)piperidin-3-yl)carbamate (0.03 g, 0.044 mmol, 1 eq) was dissolved in 1,4-dioxane (1 ml), and then 4N HCl in dioxane (0.1 ml, 0.436 mmol, 10 eq) was added and stirred at room temperature for 2 hours. Washing with 1,4-dioxane and vacuum filtration gave the title compound (0.014 g, 50%). 1 H NMR (400 MHz, MeOD) δ 8.89 (s, 2H), 8.86 (s, 1H), 8.75 (s, 1H), 8.60 (d, J = 8.1 Hz, 1H), 8.41 (d, J = 5.3 Hz, 2H), 8.08-8.02 (m, 1H), 7.97 (s, 1H), 7.96-7.94 (m, 2H), 7.68-7.64 (m, 1H), 7.63-7.59 (m, 1H), 7.59-7.55 (m, 2H), 3.90 (s, 1H), 3.85 (t, J = 5.6 Hz, 2H), 3.73 (s, 2H), 3.61 (t, J = 6.8 Hz, 2H), 3.49 (t, J = 5.7 Hz, 2H), 3.14 (t, J = 6.7 Hz, 3H), 2.26-2.13 (m, 2H), 2.09-1.96 (m, 1H), 1.80-1.66 (m, 1H), 1.44 (s, 1H).

[0238] Example 17: Synthesis of Compound 188 (Synthetic Reaction Scheme 12) [ka] [ka] Scheme 12. (a) Pd(dppf)Cl2, K2CO3, 1,4-dioxane, water (HO), 90 °C, overnight; (b) tert-butyl(2-bromoethyl)carbamate, Cs2CO3, DMF, 80 °C, 24 h; (c) 4 N HCl in dioxane, 1,4-dioxane, room temperature (rt), 24 h

[0239] <Step 1(a) Synthesis of 1-(3-((4-fluorophenyl)ethynyl)-4-(2-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)phenyl)-3-(imidazo[1,2-a]pyridin-7-ylmethyl)urea> The title compound (0.034 g, 31.2%) was prepared in substantially the same manner as in Step 6) of compound 14 in Example 11, except that 1-(3-((4-fluorophenyl)ethynyl)-4-iodophenyl)-3-(imidazo[1,2-a]pyridin-7-ylmethyl)urea was used instead of 1-(3-((4-fluorophenyl)ethynyl)-4-iodophenyl)-3-(2-(pyridin-3-yl)ethyl)urea in Step 2). 11H NMR (400 MHz, MeOD) δ 8.43 (d, J = 7.1 Hz, 1H), 8.26 (d, J = 8.3 Hz, 1H), 7.91 (s, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.82 (s, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.57 - 7.50 (m, 3H), 7.49 - 7.45 (m, 1H), 7.36 (dd, J = 8.6, 5.5 Hz, 2H), 7.07 (t, J = 8.8 Hz, 2H), 6.97 (d, J = 7.1 Hz, 1H), 4.52 (s, 2H), 2.50 (s, J = 5.9 Hz, 3H).

[0240] <Synthesis of tert-butyl(2-(7-(2-((4-fluorophenyl)ethynyl)-4-(3-(imidazo[1,2-a]pyridin-7-ylmethyl)ureido)phenyl)-2-methyl-4-oxoquinazolin-3(4H)-yl)ethyl)carbamate> Compared to the synthesis of compound 186 in Example 15, in step 1) 1-(3-((4-fluorophenyl)ethynyl)-4-(2-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)phenyl)-3-(2-(pyridin-3-yl)ethyl)urea) was replaced with 1-(3-((4- The title compound (23 mg, 56.1%) was obtained in substantially the same manner as in the synthesis of compound 186 in Step 1) of Example 15, except that 1-(3-((4-fluorophenyl)ethynyl)-4-(2-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)phenyl)-3-(imidazo[1,2-a]pyridin-7-ylmethyl)urea was used.

[0241] Step 3(c) Synthesis of 1-(4-(3-(2-aminoethyl)-2-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)-3-((4-fluorophenyl)ethynyl)phenyl)-3-(imidazo[1,2-a]pyridin-7-ylmethyl)urea Compared to the synthesis of compound 186 in Example 15, in step 2, tert-butyl(2-(7-(2-((4-fluorophenyl)ethynyl)-4-(3-(2-(pyridin-3-yl)ethyl)ureido)phenyl)-2-methyl-4-oxoquinazolin-3(4H)-yl)ethyl)carbamate was replaced with tert-butyl(2-(7-(2-((4-fluorophenyl)ethynyl)-4-(3-(2-(pyridin-3-yl)ethyl)ureido)phenyl)-2-methyl-4-oxoquinazolin-3(4H)-yl)ethyl)carbamate. The title compound (10 mg, 86.3%) was obtained in essentially the same manner as in the synthesis of compound 186 in Example 15, Step 2), except that tert-butyl(2-(7-(2-((4-fluorophenyl)ethynyl)-4-(3-(imidazo[1,2-a]pyridin-7-ylmethyl)ureido)phenyl)-2-methyl-4-oxoquinazolin-3(4H)-yl)ethyl)carbamate was used. 1 H NMR (400 MHz, MeOD) δ 8.79 (d, J = 7.0 Hz, 1H), 8.43 (d, J = 8.3 Hz, 1H), 8.21 (s, 1H), 8.07-8.00 (m, 2H), 7.98 (s, 1H), 7.92 (d, J = 1.9 Hz, 1H), 7.88 (s, 1H), 7.62-7.57 (m, 1H), 7.57-7.47 (m, 2H), 7.45-7.35 (m, 2H), 7.11 (t, J = 8.7 Hz, 2H), 4.67 (s, 2H), 4.60 (t, J = 6.1 Hz, 2H), 3.48 (t, J = 6.0 Hz, 2H), 2.99 (s, 3H).

[0242] Example 18: Synthesis of Compound 110 (Synthetic Reaction Scheme 13) Synthesis of 1-(3-(1H-pyrazol-4-yl)propyl)-3-(3-((4-fluorophenyl)ethynyl)-4-(pyridin-4-yl)phenyl)urea [ka] [ka] Reaction Scheme 13. (a) 3-(1H-pyrazol-4-yl)propan-1-amine, TEA, THF, reflux, 3 hours; (b) 1-ethynyl-4-fluorobenzene, PdCl2(PPh3)2, CuI, TEA, ACN, 90°C, 24 hours;

[0243] <Step 1(a) Synthesis of 1-(3-(1H-pyrazol-4-yl)propyl)-3-(3-iodo-4-(pyridin-4-yl)phenyl)urea> This was prepared in essentially the same manner as in the synthesis of compound 40 in Example 16, except that 3-(1H-pyrazol-4-yl)propan-1-amine was used instead of 2-(pyridin-3-yl)ethan-1-amine in step 3). (0.1 g, 93.5%) 1H NMR (400 MHz, MeOD) δ 8.60 (d, J = 5.5 Hz, 2H), 8.21 (d, J = 2.1 Hz, 1H), 7.53-7.42 (m, 5H), 7.24 (d, J = 8.4 Hz, 1H), 3.37 (s, 1H), 3.28-3.26 (m, 2H), 2.61 (t, J = 7.6 Hz, 2H), 1.90-1.78 (m, 2H).

[0244] <Step 2(b) Synthesis of 1-(3-(1H-pyrazol-4-yl)propyl)-3-(3-((4-fluorophenyl)ethynyl)-4-(pyridin-4-yl)phenyl)urea> 1-(3-(1H-pyrazol-4-yl)propyl)-3-(3-iodo-4-(pyridin-4-yl)phenyl)urea (0.1 g, 0.22 mmol, 1 eq) was dissolved in ACN (2 ml, 0.1 M), followed by the addition of TEA (0.07 ml, 0.48 mmol, 2.2 eq), PdCl2(PPh3)2 (4.6 mg, 0.007 mmol, 3 mol%), and CuI (2 mg, 0.009 mmol, 4 mol%). The mixture was stirred at room temperature for 5 minutes. 1-ethynyl-4-fluorobenzene (0.030 ml, 0.27 mmol, 1.2 eq) was added and the mixture was stirred at 90° C. for 2 hours. After cooling to room temperature, the mixture was concentrated and purified by column chromatography (C18, 0.1% formic acid in HO / acetonitrile) to give the title compound (2.8 mg, 3%). 1H NMR (400 MHz, MeOD) δ 8.62 (s, 2H), 7.82 (d, J = 2.2 Hz, 1H), 7.74 (d, J = 6.0 Hz, 2H), 7.70-7.63 (m, 2H), 7.61-7.57 (m, 1H), 7.53-7.49 (m, 1H), 7.47-7.44 (m, 1H), 7.42-7.38 (m, 2H), 7.12 (t, J = 8.8 Hz, 2H), 3.28 (t, J = 7.0 Hz, 2H), 2.62 (t, J = 7.5 Hz, 2H), 1.90-1.81 (m, 2H).

[0245] Example 19: Synthesis of Compound 57 (Synthetic Reaction Scheme 14) Synthesis of 1-(3-((4-fluorophenyl)ethynyl)-4-(isoquinolin-6-yl)phenyl)-3-(2-(pyridin-3-yl)ethyl)urea [ka] [ka] Reaction Scheme 14. (a) NaCO2, KI, pTSA, ACN, 0°C, 1 h; (b) Pd(dppf)Cl2, K2CO3, 1,4-dioxane, water (HO), 90°C, 3 h; (c) Fe, NHCl, EtOH, water (HO), reflux, 1 h; (d) phenyl chloroformate, pyridine, THF, 0°C to room temperature (rt), 2 h; (e) 2-(pyridin-3-yl)ethan-1-amine, TEA, THF, room temperature (rt), reflux.

[0246] <Step 1(a) Synthesis of 2-((4-fluorophenyl)ethynyl)-1-iodo-4-nitrobenzene> 2-((4-fluorophenyl)ethynyl)-4-nitroaniline (0.1 g, 0.39 mmol, 1 eq) was dissolved in ACN (4 mL, 0.1 M) and then pTSA (0.2 g, 1.17 mmol, 3 eq) was added. NaNO (0.03 g, 0.408 mmol, 1.02 eq) dissolved in 0.15 mL of water and KI (0.13 g, 0.78 mmol, 2 eq) dissolved in 0.15 mL of water were added at 0 °C. After reacting at room temperature for 1 hour, the mixture was neutralized to pH 8 or higher with saturated aqueous sodium bicarbonate (NaHCO) and extracted with EA. The organic layer was dried over MgSO, filtered, and concentrated to obtain the target compound as a crude product. 1 H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 2.6 Hz, 1H), 8.07 (d, J = 8.7 Hz, 1H), 7.83 (dd, J = 8.7, 2.7 Hz, 1H), 7.64-7.59 (m, 2H), 7.10 (t, J = 8.6Hz, 2H)

[0247] <Step 2(b) Synthesis of 6-(2-((4-fluorophenyl)ethynyl)-4-nitrophenyl)isoquinoline> 2-((4-fluorophenyl)ethynyl)-1-iodo-4-nitrobenzene (0.14 g, 0.38 mmol, 1 eq) was dissolved in 1,4-dioxane:water (HO) (3:1 (v / v), 2 mL, 0.2 M), followed by the addition of isoquinolin-6-ylboronic acid (0.066 g, 0.38 mmol, 1 eq), Pd(dppf)Cl (0.056 g, 0.076 mmol, 0.2 eq), and KCO (0.116 g, 0.836 mmol, 2.2 eq). The mixture was then degassed with nitrogen gas (N). The reaction mixture was heated to 90°C and stirred for 3 hours. After completion of the reaction, the mixture was filtered through a Celite filter and extracted with EA and H2O. The organic layer was dried over MgSO4, filtered, concentrated, and purified by column chromatography (silica gel, EA / HX) to give the title compound (0.032 g, 23%). 1 H NMR (400 MHz, MeOD) δ 9.37 (s, 1H), 8.58-8.52 (m, 2H), 8.38 (d, J = 8.5 Hz, 1H), 8.31 (s, 2H), 8.06 (d, J = 8.5 Hz, 1H), 7.97 (d, J = 5.7 MS(ESI) m / z MH + 369

[0248] <Step 3(c) Synthesis of 3-((4-fluorophenyl)ethynyl)-4-(isoquinolin-6-yl)aniline> A mixture of 6-(2-((4-fluorophenyl)ethynyl)-4-nitrophenyl)isoquinoline (0.032 g, 0.087 mmol, 1.0 eq), Fe (0.024 g, 0.434 mmol, 5 eq), and NHCl (0.023 g, 0.434 mmol, 5 eq) was stirred at 80 °C for 1 hour. The catalyst was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure. Water was added and the mixture was extracted with EA, and the organic layer was concentrated under reduced pressure. The target compound was obtained as a crude product.

[0249] Step 4(d) Synthesis of phenyl(3-((4-fluorophenyl)ethynyl)-4-(isoquinolin-6-yl)phenyl)carbamate The title compound was prepared in substantially the same manner as in the synthesis of step 5) of compound 1 in Example 1, except that, in comparison with the synthesis of compound 1 in Example 1, 6-(2-((4-fluorophenyl)ethynyl)-4-nitrophenyl)isoquinoline was used instead of 3-((4-fluorophenyl)ethynyl)-4-(pyridin-4-yl)aniline in step 5). MS(ESI) m / z MH + 459

[0250] Step 5(e) Synthesis of 1-(3-((4-fluorophenyl)ethynyl)-4-(isoquinolin-6-yl)phenyl)-3-(2-(pyridin-3-yl)ethyl)urea The title compound was prepared in substantially the same manner as in the synthesis of Step 6) of compound 1 in Example 1, except that, in comparison with the synthesis of compound 1 in Example 1, phenyl(3-((4-fluorophenyl)ethynyl)-4-(isoquinolin-6-yl)phenyl)carbamate was used instead of phenyl(3-((4-fluorophenyl)ethynyl)-4-(pyridin-4-yl)phenyl)carbamate in Step 6). 1 H NMR (400 MHz, MeOD) δ 9.29 (s, 1H), 8.53-8.46 (m, 2H), 8.43 (s, 1H), 8.23-8.16 (m, 2H), 8.02 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 5.3 Hz, 1H), 7.86-7.79 (m, 2H), 7.54-7.47 (m, 2H), 7.47-7.40 (m, 1H), 7.34-7.26 (m, 2H), 7.05 (t, J = 8.2 Hz, 2H), 3.54 (t, J = 6.8 Hz, 2H), 2.95 (t, J = 6.4 Hz, 2H). MS(ESI) m / z MH + 487

[0251] Example 20: Synthesis of Compound 182 (Synthetic Reaction Scheme 15) Synthesis of 1-(3-((4-fluorophenyl)ethynyl)-4-(pyridin-4-yl)phenyl)-3-(2-(6-nitropyridin-3-yl)ethyl)urea [ka] [ka] Scheme 15. Reagents and conditions: (a) Pd(dppf)Cl2, Cs2CO3, toluene, water (HO), 80 °C, 16 h; (b) 4 N HCl in dioxane, 1,4-dioxane, room temperature (rt), 4 h; (c) triethylamine (TEA), THF, room temperature (rt), overnight.

[0252] <Step 1(a) Synthesis of tert-butyl(2-(6-nitropyridin-3-yl)ethyl)carbamate> 5-Bromo-2-nitro-pyridine (1 g, 4.93 mmol, 1.0 eq) was dissolved in toluene (20 mL, 0.25 M) and water (5 mL, 1 M H2O). Potassium 2-(Boc-aminoethyl)trifluoroborate (1.36 g, 5.41 mmol, 1.1 eq), Pd(dppf)Cl2 (0.302 g, 0.369 mmol, 0.07 eq), and Cs2CO3 (4.82 g, 14.8 mmol, 3 eq) were added. The reaction mixture was heated to 80 °C and stirred for 16 h. After completion of the reaction, the mixture was cooled to room temperature and extracted with EA and H2O. The organic layer was dried over MgSO4, filtered, concentrated, and purified by column chromatography (silica gel, EA / HX) to give the title compound (0.842 g, 64%).

[0253] <Step 2(b) Synthesis of 2-(6-nitropyridin-3-yl)ethan-1-amine> tert-Butyl (2-(6-nitropyridin-3-yl)ethyl)carbamate (0.84 g, 3.15 mmol, 1 eq) was dissolved in 1,4-dioxane (1,4-dioxane, 6 mL, 0.5 M), and then 4N HCl (4N HCl in dioxane, 8 mL, 31.5 mmol, 10 eq) was added to the dioxane and stirred at room temperature for 16 hours. After the reaction was completed, the mixture was concentrated and diluted with diethyl ether. The resulting crystals were washed with ether and filtered under reduced pressure to give the title compound (0.507 g, 79%).

[0254] Step 3(c) Synthesis of 1-(3-((4-fluorophenyl)ethynyl)-4-(pyridin-4-yl)phenyl)-3-(2-(6-nitropyridin-3-yl)ethyl)urea Phenyl(3-((4-fluorophenyl)ethynyl)-4-(pyridin-4-yl)phenyl)carbamate (0.081 g, 0.20 mmol, 1 eq) was dissolved in THF (1 mL, 0.2 M), followed by the addition of 2-(6-nitropyridin-3-yl)ethan-1-amine (0.082 mg, 0.4 mmol, 2 eq) and TEA (0.84 mL, 0.6 mmol, 3 eq). The mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was concentrated and purified by column chromatography (silica gel, MeOH / DCM) to give the title compound (0.113 g, 23%). 1H NMR (400 MHz, CDCl3) δ 8.67 (d, J = 4.2 Hz, 2H), 8.49 (s, 1H), 8.17 (d, J = 8.2 Hz, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.74 (s, 1H), 7.64 (d, J = 5.1 Hz, 3H), 7.39 (d, J = 8.5 Hz, 1H), 7.31 (d, J = 8.2 Hz, 2H), 6.99 (t, J = 8.2 Hz, 2H), 5.77 (s, 1H), 3.65 (d, J = 6.1 Hz, 2H), 3.08 (t, J = 6.3 Hz, 2H); MS(ESI) MH + 482.4

[0255] Example 21: Synthesis of Compound 10 (Synthetic Reaction Scheme 16) Synthesis of 1-(2-(6-aminopyridin-3-yl)ethyl)-3-(3-((4-fluorophenyl)ethynyl)-4-(pyridin-4-yl)phenyl)urea [ka] Reaction Scheme 16. Reagents and conditions: (a) Zn, NH₄Cl, 1,4-dioxane, water (HO), room temperature (rt), overnight

[0256] 1-(3-((4-fluorophenyl)ethynyl)-4-(pyridin-4-yl)phenyl)-3-(2-(6-nitropyridin-3-yl)ethyl)urea (0.048 g, 0.1 mmol, 1 eq) was dissolved in 1,4-dioxane:water (HO) (3:1 (v / v)) (0.5 mL, 0.2 M), and then Zn (0.065 g, 1 mmol, 10 eq) and NHCl (0.053 g, 1 mmol, 10 eq) were added and the mixture was stirred at room temperature overnight. After washing with MeOH and filtering under reduced pressure, the mixture was concentrated and purified by reverse phase column chromatography (0.1% formic acid in H2O / ACN) to give the title compound (0.001 g, 2.4%). 1 H NMR (400 MHz, MeOD) δ 8.62 (s, 2H), 7.80 (s, 2H), 7.73 (d, J = 4.5 Hz, 2H), 7.61 (d, J = 8.7 Hz, 1H), 7.46 (dd, J = 18.2, 8.6 Hz, 2H), MS MH - 450.39

[0257] Example 22: Synthesis of Compound 47 (Synthetic Reaction Scheme 17) Synthesis of N-(2-(piperazin-1-yl)ethyl)-4-((5-(3-(2-(pyridin-3-yl)ethyl)ureido)-2-(pyridin-4-yl)phenyl)ethynyl)benzamide [ka] [ka] Scheme 17. Reagents and conditions: (a) tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate, HATU, DIPEA, DMF, rt, overnight; (b) NaNO, KI, HCl, HO, 5 °C, 1 h; (c) PdCl(PPh), CuI, TEA, ACN, 60 °C, 5 h; (d) Zn, NH, Cl, 1,4-dioxane, HO, rt, overnight; (e) phenyl chloroformate. (f) 2-(pyridin-3-yl)ethan-1-amine, TEA, THF, rt, overnight; (g) TFA, DCM, rt, overnight.

[0258] Step 1(a) Synthesis of tert-butyl 4-(2-(4-ethynylbenzamido)ethyl)piperazine-1-carboxylate 4-Ethynylbenzoic acid (0.25 g, 1.71 mmol, 1 eq) was dissolved in DMF (11 mL, 0.3 M). tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate (0.589 g, 2.57 eq, 1.5 eq), HATU (0.977 g, 2.57 mmol, 1.5 eq), and DIPEA (0.663 g, 5.13 mmol, 3 eq) were added and stirred overnight at room temperature. Extraction with EA and HO was performed. The organic layer was dried over MgSO, filtered, concentrated, and purified by column chromatography (silica gel, MeOH / DCM) to give the title compound (0.382 g, 63%).

[0259] <Step 2(b) Synthesis of 4-(2-iodo-4-nitrophenyl)pyridine> To 5-nitro-2-(pyridin-4-yl)aniline (1.00 g, 4.64 mmol, 1 eq) was added 4.5 mL of water and 4.5 mL of conc. HCl. At 5°C, NaNO (0.326 g, 4.73 mmol, 1.0 eq) dissolved in 4.5 mL of water was slowly added dropwise and stirred. After stirring for 10 minutes, KI (1.464 g, 8.82 mmol, 2 eq) dissolved in 4.5 mL of water was added. The mixture was then warmed to room temperature and stirred for 30 minutes. The mixture was neutralized to pH 8 or higher with aqueous KCO and extracted with DCM. The organic layer was dried over MgSO, filtered, concentrated, and purified by column chromatography (silica gel, Hex / EA) to give the title compound (0.952 g, 62.9%).

[0260] Step 3(c) Synthesis of tert-butyl 4-(2-(4-((5-nitro-2-(pyridin-4-yl)phenyl)ethynyl)benzamido)ethyl)piperazine-1-carboxylate 4-(2-iodo-4-nitrophenyl)pyridine (0.232 g, 0.71 mmol, 1 eq), tert-butyl 4-(2-(4-ethynylbenzamido)ethyl)piperazine-1-carboxylate 4-(2-(4-ethynylbenzamido)ethyl)piperazine-1-carboxylate (0.382 g, 1.07 mmol, 1.5 eq), PdCl2(PPh3)2 (0.014 g, 0.02 mmol, 0.03 eq), CuI (0.0038 g, 0.02 mmol, 0.03 eq), and TEA (0.144 g, 1.42 mmol, 2 eq) were dissolved in ACN (2 mL, 0.3 M) and degassed with nitrogen gas (N2 gas). The reaction mixture was heated to 60 °C and stirred for 5 h. After completion of the reaction, the mixture was extracted with EA and HO. The organic layer was dried over MgSO4, filtered, concentrated, and purified by column chromatography (silica gel, DCM / MeOH) to give the title compound (0.25 g, 65%).

[0261] Step 4(d) Synthesis of tert-butyl 4-(2-(4-((5-amino-2-(pyridin-4-yl)phenyl)ethynyl)benzamido)ethyl)piperazine-1-carboxylate tert-Butyl 4-(2-(4-((5-nitro-2-(pyridin-4-yl)phenyl)ethynyl)benzamido)ethyl)piperazine-1-carboxylate (0.255 g, 0.46 mmol, 1 eq) was dissolved in 1,4-dioxane:water (HO) (3:1 (v / v)) (4.6 mL, 0.1 M), Zn (0.3 g, 4.6 mmol, 10 eq) and NHCl (0.246 g, 4.6 mmol, 10 eq) were added, and the mixture was stirred at room temperature overnight. The mixture was washed with MeOH and filtered under reduced pressure. The filtrate was concentrated and used in the reaction described in Step 5 without further purification.

[0262] Step 5(e) Synthesis of tert-butyl 4-(2-(4-((5-((phenoxycarbonyl)amino)-2-(pyridin-4-yl)phenyl)ethynyl)benzamido)ethyl)piperazine-1-carboxylate tert-Butyl 4-(2-(4-((5-amino-2-(pyridin-4-yl)phenyl)ethynyl)benzamido)ethyl)piperazine-1-carboxylate (0.023 g, 0.043 mmol, 1 eq)) was dissolved in DMF (0.3 mL, 0.1 M), followed by the addition of pyridine (0.01 g, 0.129 mmol, 3 eq). After cooling to 0°C, phenyl chloroformate (0.007 g, 0.0473 mmol, 1.1 eq) was added dropwise. The mixture was gradually heated to room temperature and stirred for 2 hours. After the reaction was completed, the mixture was concentrated and neutralized with 1N NaOH, followed by extraction with EA and H 2 O. The organic layer was dried over MgSO 4 , filtered, concentrated, and purified by column chromatography (silica gel, DCM / MeOH) to give the title compound (0.020 g, 72%).

[0263] Step 6(f) Synthesis of tert-butyl 4-(2-(4-((5-(3-(2-(pyridin-3-yl)ethyl)ureido)-2-(pyridin-4-yl)phenyl)ethynyl)benzamido)ethyl)piperazine-1-carboxylate tert-Butyl 4-(2-(4-((5-((phenoxycarbonyl)amino)-2-(pyridin-4-yl)phenyl)ethynyl)benzamido)ethyl)piperazine-1-carboxylate (0.030 g, 0.046 mmol, 1 eq)) was dissolved in THF (1 ml, 0.05 M), and then 2-(pyridin-3-yl)ethan-1-amine (0.011 g, 0.092 mmol, 2 eq) and TEA (0.014 g, 0.138 mmol, 3 eq) were added, followed by stirring at room temperature overnight. After the reaction was completed, the mixture was concentrated and purified by column chromatography (silica gel, DCM / MeOH) to obtain the title compound (0.021 g, 70%).

[0264] Step 7(g) Synthesis of N-(2-(piperazin-1-yl)ethyl)-4-((5-(3-(2-(pyridin-3-yl)ethyl)ureido)-2-(pyridin-4-yl)phenyl)ethynyl)benzamide tert-Butyl 4-(2-(4-((5-(3-(2-(pyridin-3-yl)ethyl)ureido)-2-(pyridin-4-yl)phenyl)ethynyl)benzamido)ethyl)piperazine-1-carboxylate (0.064 g, 0.094 mmol, 1 eq) was dissolved in DCM (1 ml, 0.1 M), and then TFA (0.107 g, 0.94 mmol, 10 eq) was added and the mixture was stirred at room temperature overnight. After the reaction was completed, the mixture was concentrated and purified by reverse phase column chromatography (0.1% formic acid in H2O / ACN) to obtain the title compound (0.021 g, 40%). 1 H NMR (400 MHz, MeOD) δ 8.63 (d, J = 4.4 Hz, 2H), 8.49 (s, 1H), 8.43 (s, 1H), 7.88 (s, 1H), 7.82 (d, J = 7.9 Hz, 4H), 7.74 (d, J = 4.7 Hz, 2H), 7.45 (d, J = 7.3 Hz, 5H), 3.55 (d, J = 10.7 Hz, 4H), 3.23 (s, 4H), 2.94 (t, J = 6.8 Hz, 2H), 2.79 (s, 4H), 2.69 (t, J = 6.5 Hz, 2H).

[0265] Example 23: Synthesis of Compound 95 (Synthetic Reaction Scheme 18) Synthesis of N-phenyl-2-((4-((2-(piperidin-1-yl)ethyl)carbamoyl)phenyl)ethynyl)-4-(3-(2-(pyridin-3-yl)ethyl)ureido)benzamide [ka] [ka] Scheme 18. Reagents and conditions: (a) Aniline, EDC, DMAP, DMF, overnight; (b) PdCl2(PPh3)2, CuI, TEA, ACN, 60 °C, 5 h; (c) Zn, NH4Cl, 1,4-dioxane, water (HO), rt, overnight; (d) phenyl chloroformate, pyridine, THF, 0 °C to rt, overnight; (e) 2-(pyridin-3-yl)ethan-1-amine, TEA, THF, rt, overnight.

[0266] <Step 1(a) Synthesis of 2-iodo-4-nitro-N-phenylbenzamide> 2-Iodo-4-nitrobenzoic acid (0.5 g, 1.71 mmol, 1 eq) was dissolved in DMF (7 mL, 0.25 M). Aniline (0.159 g, 1.71 mmol, 1 eq), EDC (0.392 g, 2.05 mmol, 1.2 eq), and DMAP (0.417 g, 3.42 mmol, 2 eq) were added under nitrogen gas (N2 gas) and stirred at room temperature for 16 h. After completion of the reaction, 5% aqueous LiCl solution (100 mL) was added and stirred. The mixture was extracted with DCM. The organic layer was dried over MgSO4, filtered, concentrated, and purified by column chromatography (silica gel, Hex / EA) to give the title compound (0.341 g, 54%).

[0267] <Step 2(b) Synthesis of 4-nitro-N-phenyl-2-((4-((2-(piperidin-1-yl)ethyl)carbamoyl)phenyl)ethynyl)benzamide> 2-iodo-4-nitro-N-phenylbenzamide (0.34 g, 0.92 mmol, 1 eq), 4-ethynyl-N-(2-(piperidin-1-yl)ethyl)benzamide (0.353 g, 1.38 mmol, 1.5 eq), PdCl2(PPh3)2 (0.019 g, 0.03 mmol, 0.03 eq), CuI (0.005 g, 0.03 mmol, 0.03 eq), and TEA (0.186 g, 1.84 mmol, 2 eq) were dissolved in ACN (4 mL, 0.25 M) and degassed with nitrogen gas (N2 gas). The reaction mixture was heated to 60°C and stirred for 5 hours. After completion of the reaction, the mixture was extracted with EA and H2O. The organic layer was dried over MgSO4, filtered, concentrated, and purified by column chromatography (silica gel, MeOH / DCM) to give the title compound (0.276 g, 60%).

[0268] <Step 3(c) Synthesis of 4-amino-N-phenyl-2-((4-((2-(piperidin-1-yl)ethyl)carbamoyl)phenyl)ethynyl)benzamide> tert-Butyl 4-(2-(4-((5-nitro-2-(pyridin-4-yl)phenyl)ethynyl)benzamido)ethyl)piperazine-1-carboxylate (0.1 g, 0.20 mmol, 1 eq) was dissolved in 1,4-dioxane:water (HO) (3:1 (v / v)) (2 mL, 0.1 M), Zn (0.13 g, 2 mmol, 10 eq) and NHCl (0.106 g, 2 mmol, 10 eq) were added, and the mixture was stirred at room temperature overnight. The mixture was washed with MeOH and filtered under reduced pressure. The filtrate was concentrated and used in the reaction described in Step 4) without further purification.

[0269] Step 4(d) Synthesis of phenyl(4-(phenylcarbamoyl)-3-((4-((2-(piperidin-1-yl)ethyl)carbamoyl)phenyl)ethynyl)phenyl)carbamate 4-amino-N-phenyl-2-((4-((2-(piperidin-1-yl)ethyl)carbamoyl)phenyl)ethynyl)benzamide (0.093 g, 0.2 mmol, 1 eq) was dissolved in THF (2 mL, 0.1 M), and pyridine (0.02 g, 0.25 mmol, 1.25 eq) was added. After cooling to 0 °C, phenyl chloroformate (0.056 g, 0.36 mmol, 1.8 eq) was added dropwise. The mixture was gradually heated to room temperature and stirred for 2 hours. After the reaction was completed, the mixture was concentrated, neutralized with 1N NaOH, and extracted with EA and HO. The organic layer was dried over MgSO4, filtered, concentrated, and purified by column chromatography (silica gel, MeOH / DCM) to give the title compound (0.052 g, 44%).

[0270] Step 5(e) Synthesis of N-phenyl-2-((4-((2-(piperidin-1-yl)ethyl)carbamoyl)phenyl)ethynyl)-4-(3-(2-(pyridin-3-yl)ethyl)ureido)benzamide Phenyl(4-(phenylcarbamoyl)-3-((4-((2-(piperidin-1-yl)ethyl)carbamoyl)phenyl)ethynyl)phenyl)carbamate (0.052 g, 0.089 mmol, 1 eq) was dissolved in THF (1 ml, 0.1 M), and then 2-(pyridin-3-yl)ethan-1-amine (0.022 g, 0.178 mmol, 2 eq) and TEA (0.027 g, 0.267 mmol, 3 eq) were added, followed by stirring at room temperature overnight. After the reaction was completed, the mixture was concentrated and purified by column chromatography (silica gel, MeOH / DCM) to obtain the title compound (0.033 g, 60%). 1 H NMR (400 MHz, MeOD) δ 8.45 (d, J = 22.7 Hz, 2H), 8.18 (s, 1H), 7.96 (d, J = 8.0 Hz, 2H), 7.92 (s, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.62 (t, J = 7.4 Hz, 2H), 7.56 (d, J = 7.0 Hz, 3H), 7.46 (d, J = 6.5 Hz, 4H), 7.33 (d, J = 8.9 Hz, 1H), 6.23 (s, 1H), 3.83 (s, 2H), 3.51 (t, J = 6.5 Hz, 2H), 3.37 (s, 4H), 2.92 (t, J = 6.5 Hz, 2H), 1.93 (s, 4H), 1.72 (s, 2H)

[0271] Compounds 87, 88, 90, 127, 128, 168, and 176 can be synthesized by changing the reactants in substantially the same manner as in Example 23 above.

[0272] Example 24: Synthesis of Compound 184 (Synthetic Reaction Scheme 19) Synthesis of 4-((2-(3-aminopiperidin-1-yl)-5-(3-(2-(pyridin-3-yl)ethyl)ureido)phenyl)ethynyl)-N-(2-(piperidin-1-yl)ethyl)benzamide [ka] [ka] Scheme 19. Reagents and conditions: (a) tert-butyl piperidin-3-ylcarbamate, Cs2CO3, DMF, 80°C, overnight; (b) PdCl2(PPh3)2, CuI, TEA, ACN, 60°C, 5h; (c) Zn, NH4Cl, 1,4-dioxane, water (HO), rt, overnight; (d) phenyl chloroformate (e) 2-(pyridin-3-yl)ethan-1-amine, TEA, THF, 55°C, overnight; (f) TFA, DCM, rt, overnight.

[0273] Step 1(a) Synthesis of tert-butyl(1-(2-iodo-4-nitrophenyl)piperidin-3-yl)carbamate 1-Fluoro-2-iodo-4-nitrobenzene (0.5 g, 1.87 mmol, 1 eq) was dissolved in DMF (3.74 mL, 0.5 M), followed by the addition of tert-butyl piperidin-3-ylcarbamate (0.412 g, 2.057 mmol, 1.1 eq) and CsCO (0.670 g, 2.057 mmol, 1.1 eq). The mixture was heated and stirred at 80 °C for 16 hours. After the reaction was complete, the mixture was gradually cooled to room temperature and extracted with EA and HO. The organic layer was dried over MgSO, filtered, concentrated, and purified by column chromatography (silica gel, Hex / EA) to give the title compound (0.614 g, 73%).

[0274] Step 2(b) Synthesis of tert-butyl(1-(4-nitro-2-((4-((2-(piperidin-1-yl)ethyl)carbamoyl)phenyl)ethynyl)phenyl)piperidin-3-yl)carbamate tert-butyl(1-(2-iodo-4-nitrophenyl)piperidin-3-yl)carbamate (0.614 g, 1.37 mmol, 1 eq), 4-ethynyl-N-(2-(piperidin-1-yl)ethyl)benzamide (n-1-yl)ethyl)benzamide (0.527 g, 2.06 mmol, 1.5 eq), PdCl2(PPh3)2 (0.028 g, 0.04 mmol, 0.03 eq), CuI (0.008 g, 0.04 mmol, 0.03 eq), and TEA (0.38 g, 2.74 mmol, 2 eq) were dissolved in ACN (13.7 mL, 0.1 M) and degassed with nitrogen gas (N2 gas). The reaction mixture was heated to 60 °C and stirred for 5 h. After completion of the reaction, the mixture was extracted with EA and HO. The organic layer was dried over MgSO4, filtered, concentrated, and purified by column chromatography (silica gel, MeOH / DCM) to give the title compound (0.277 g, 35%).

[0275] Step 3(c) Synthesis of tert-butyl(1-(4-amino-2-((4-((2-(piperidin-1-yl)ethyl)carbamoyl)phenyl)ethynyl)phenyl)piperidin-3-yl)carbamate tert-Butyl (1-(4-nitro-2-((4-((2-(piperidin-1-yl)ethyl)carbamoyl)phenyl)ethynyl)phenyl)piperidin-3-yl)carbamate (0.277 g, 0.48 mmol, 1 eq) was dissolved in 1,4-dioxane:HO (3:1) (4.8 mL, 0.1 M), followed by addition of Zn (0.314 g, 4.8 mmol, 10 eq) and NHCl (0.257 g, 4.8 mmol, 10 eq). The mixture was stirred overnight at room temperature. The mixture was washed with MeOH and filtered under reduced pressure. The filtrate was concentrated and then used in the following reaction without further purification.

[0276] Step 4(d) Synthesis of tert-butyl(1-(4-((phenoxycarbonyl)amino)-2-((4-((2-(piperidin-1-yl)ethyl)carbamoyl)phenyl)ethynyl)phenyl)piperidin-3-yl)carbamate tert-Butyl (1-(4-amino-2-((4-((2-(piperidin-1-yl)ethyl)carbamoyl)phenyl)ethynyl)phenyl)piperidin-3-yl)carbamate (0.209 g, 0.38 mmol, 1 eq) was dissolved in THF (3.8 mL, 0.1 M), and pyridine (0.09 g, 1.14 mmol, 3 eq) was added. After cooling to 0°C, phenyl chloroformate (0.107 g, 0.68 mmol, 1.8 eq) was added dropwise. The mixture was gradually heated to room temperature and stirred for 2 hours. After the reaction was completed, the mixture was concentrated and neutralized with 1N NaOH, followed by extraction with EA and H 2 O. The organic layer was dried over MgSO 4 , filtered, concentrated, and purified by column chromatography (silica gel, MeOH / DCM) to give the title compound (0.052 g, 44%).

[0277] Step 5(e) Synthesis of tert-butyl(1-(2-((4-((2-(piperidin-1-yl)ethyl)carbamoyl)phenyl)ethynyl)-4-(3-(2-(pyridin-3-yl)ethyl)ureido)phenyl)piperidin-3-yl)carbamate tert-butyl(1-(4-((phenoxycarbonyl)amino)-2-((4-((2-(piperidin-1-yl)ethyl)carbamoyl)phenyl)ethynyl)phenyl)piperidin-3-yl)carbamate (2-(pyridin-3-yl)ethan-1-amine, 0.054 g, 0.45 mmol, 3 eq) and TEA (0.045 g, 0.45 mmol, 3 eq) were added to the solution, which was then stirred overnight at 55°C. After completion of the reaction, the mixture was concentrated and purified by column chromatography (silica gel, MeOH / DCM) to give the title compound (0.070 g, 67%).

[0278] Step 6(f) Synthesis of 4-((2-(3-aminopiperidin-1-yl)-5-(3-(2-(pyridin-3-yl)ethyl)ureido)phenyl)ethynyl)-N-(2-(piperidin-1-yl)ethyl)benzamide tert-Butyl (1-(2-((4-((2-(piperidin-1-yl)ethyl)carbamoyl)phenyl)ethynyl)-4-(3-(2-(pyridin-3-yl)ethyl)ureido)phenyl)piperidin-3-yl)carbamate (0.030 g, 0.043 mmol, 1 eq) was dissolved in DCM (1 ml, 0.05 M), and then TFA (0.025 g, 0.215 mmol, 5 eq) was added and the mixture was stirred at room temperature overnight. After the reaction was completed, the mixture was concentrated and purified by reverse phase column chromatography (0.1% formic acid in H2O / ACN) to obtain the title compound (0.0947 g, 37%). 1 H NMR (400 MHz, MeOD) δ 8.46 (s, 2H), 7.91 (d, J = 6.9 Hz, 2H), 7.78 (d, J = 7.5 Hz, 1H), 7.65 (d, J = 6.9 Hz, 2H), 7.59 (s, 1H), 7.41 (s, 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.01 (d, J = 8.8 Hz, 1H), 3.75 (s, 2H), 3.49 (dd, J = 19.1, 12.4 Hz, 4H), 3.32 (s, 2H), 3.21 (s, 5H), 2.89 (t, J = 6.7 Hz, 4H), 2.66 (s, 1H), 2.10 (s, 1H), 1.99 (s, 1H), 1.85 (s, 5H), 1.66 (s, 3H).

[0279] Example 25: Synthesis of Compound 43 (Synthetic Reaction Scheme 20) Synthesis of 4-((3'-(3-aminopyrrolidine-1-carbonyl)-4-(3-(2-(pyridin-3-yl)ethyl)ureido)-[1,1'-biphenyl]-2-yl)ethynyl)-N-(2-(piperidin-1-yl)ethyl)benzamide [ka] [ka] Scheme 20. Reagents and conditions: (a) tert-butyl pyrrolidin-3-ylcarbamate, EDC, HOBT, TEA, DCM, room temperature (rt), overnight; (b) Pd(dppf)Cl2, K2CO3, 1,4-dioxane, water (HO), 90 °C, overnight; (c) 10% aqueous p-TSA solution (P-TSA), NaNO2, KI, HO, ACN, 0 °C, 1 h; (d) PdCl2(PPh3)2, CuI, TEA, ACN, 60 °C, 5 h; (e) Zn, NH4Cl, 1,4-dioxane, water (HO), rt, overnight; (f); (g) 2-(pyridin-3-yl)ethan-1-amine, TEA, THF, rt, overnight; (h) TFA, DCM, rt, overnight.

[0280] <Step 1(a) Synthesis of tert-butyl(1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)pyrrolidin-3-yl)carbamate> 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (2 g, 8.06 mmol, 1 eq) was dissolved in DCM (80 mL, 0.1 M), followed by the addition of tert-butyl pyrrolidin-3-ylcarbamate (1.8 g, 9.67 mmol, 1.2 eq), EDC (1.853 g, 9.67 mmol, 1.2 eq), HOBT (1.306 g, 9.67 mmol, 1.2 eq), and TEA (1.63 g, 16.12 mmol, 2 eq). The mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was extracted with MC and HO. The organic layer was dried over MgSO4, filtered, concentrated, and purified by column chromatography (silica gel. EA / Hex) to give the title compound (2.1 g, 98%).

[0281] <Step 2(b) Synthesis of tert-butyl(1-(2'-amino-4'-nitro-[1,1'-biphenyl]-3-carbonyl)pyrrolidin-3-yl)carbamate> 2-iodo-5-nitroaniline (0.7 g, 2.65 mmol, 1 eq) was dissolved in 1,4-dioxane:water (HO) (3:1 (v / v), 13 ml, 0.14 M), and then tert-butyl (1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)benzoyl)pyrrolidin-3-yl)carbamate (tert-butyl(1- (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)pyrrolidin-3-yl)carbamate (1.65 g, 3.97 mmol, 1.5 eq), Pd(dppf)Cl (0.387 g, 0.53 mmol, 0.2 eq), and KCO (0.805 g, 5.83 mmol, 2.2 eq) were added and degassed with nitrogen gas (N gas). The reaction mixture was heated to 90 °C and stirred overnight. After completion of the reaction, the mixture was filtered through a Celite filter and extracted with EA and HO. The organic layer was dried over MgSO, filtered, concentrated, and purified by column chromatography (silica gel, EA / Hex) to give the title compound (1.1 g, 97%).

[0282] Step 3(c) Synthesis of tert-butyl(1-(2'-iodo-4'-nitro-[1,1'-biphenyl]-3-carbonyl)pyrrolidin-3-yl)carbamate tert-Butyl (1-(2'-amino-4'-nitro-[1,1'-biphenyl]-3-carbonyl)pyrrolidin-3-yl)carbamate (0.6 g, 1.4 mmol, 1 eq) was dissolved in ACN (14 mL, 0.1 M). 10% aqueous p-TSA (1.687 g, 9.8 mmol, 7 eq) was added, followed by the dropwise addition of 0.1 M aqueous NaNO (0.106 g, 1.54 mmol, 1.1 eq) over 0.5 hours. 0.1 M NaI (0.419 g, 2.8 mmol, 2 eq) was added all at once to the reaction mixture at 0 °C and stirred for 0.5 hours. After the reaction was completed, water (HO) was added to the reaction mixture, which was then extracted with EA and HO. The organic layer was dried over MgSO, filtered, concentrated, and purified by column chromatography (silica gel, EA / Hex) to give the title compound (0.671 g, 89%).

[0283] Step 4(d) Synthesis of tert-butyl(1-(4'-nitro-2'-((4-((2-(piperidin-1-yl)ethyl)carbamoyl)phenyl)ethynyl)-[1,1'-biphenyl]-3-carbonyl)pyrrolidin-3-yl)carbamate tert-butyl(1-(2'-iodo-4'-nitro-[1,1'-biphenyl]-3-carbonyl)pyrrolidin-3-yl)carbamate, 0.3 g, 0.56 mmol, 1 eq), 4-ethynyl-N-(2-(piperidin-1-yl)ethyl)benzamide Hynyl-N-(2-(piperidin-1-yl)ethyl)benzamide (0.215 g, 0.84 mmol, 1.5 eq), PdCl2(PPh3)2 (0.012 g, 0.017 mmol, 0.03 eq), CuI (0.003 g, 0.017 mmol, 0.03 eq), and TEA (0.113 g, 1.12 mmol, 2 eq) were dissolved in ACN (5.6 mL, 0.1 M) and degassed with nitrogen gas (N2 gas). The reaction mixture was heated to 60 °C and stirred for 5 h. After completion of the reaction, the mixture was extracted with EA and HO. The organic layer was dried over MgSO4, filtered, concentrated, and purified by column chromatography (silica gel, MeOH / DCM) to give the title compound (0.316 g, 85%).

[0284] Step 5(e) Synthesis of tert-butyl(1-(4'-amino-2'-((4-((2-(piperidin-1-yl)ethyl)carbamoyl)phenyl)ethynyl)-[1,1'-biphenyl]-3-carbonyl)pyrrolidin-3-yl)carbamate tert-butyl(1-(4'-nitro-2'-((4-((2-(piperidin-1-yl)ethyl)carbamoyl)phenyl)ethynyl)-[1,1'-biphenyl]-3-carbonyl)pyrrolidin-3-yl)carbamate [1,1'-biphenyl]-3-carbonyl)pyrrolidin-3-yl)carbamate (0.2 g, 0.3 mmol, 1 eq) was dissolved in 1,4-dioxane (1,4-dioxane:water (HO) (3:1 (v / v)) (3 ml, 0.1 M), Zn (0.196 g, 3 mmol, 10 eq) and NHCl (0.16 g, 3 mmol, 10 eq) were added, and the mixture was stirred overnight at room temperature. The mixture was washed with MeOH and filtered under reduced pressure. The filtrate was concentrated and used in the reaction described in Step 6) without further purification.

[0285] Step 6(f) Synthesis of tert-butyl(1-(4'-((phenoxycarbonyl)amino)-2'-((4-((2-(piperidin-1-yl)ethyl)carbamoyl)phenol)ethynyl)-[1,1'-biphenyl]-3-carbonyl)pyrrolidin-3-yl)carbamate tert-Butyl (1-(4'-amino-2'-((4-((2-(piperidin-1-yl)ethyl)carbamoyl)phenyl)ethynyl)-[1,1'-biphenyl]-3-carbonyl)pyrrolidin-3-yl)carbamate (0.19 g, 0.3 mmol, 1 eq) was dissolved in THF (3 ml, 0.1 M), and pyridine (0.07 g, 0.9 mmol, 3 eq) was added. After cooling to 0°C, phenyl chloroformate (0.084 g, 0.54 mmol, 1.8 eq) was added dropwise. The mixture was gradually heated to room temperature and stirred for 2 hours. After the reaction was complete, the mixture was concentrated, neutralized with 1N NaOH, and extracted with EA and HO. The organic layer was dried over MgSO, filtered, concentrated, and purified by column chromatography (silica gel, MeOH / DCM) to give the title compound (0.083 g, 33%).

[0286] Step 7(g) Synthesis of tert-butyl(1-(2'-((4-((2-(piperidin-1-yl)ethyl)carbamoyl)phenyl)ethynyl)-4'-(3-(2-(pyridin-3-yl)ethyl)ureido)-[1,1'-biphenyl]-3-carbonyl)pyrrolidin-3-yl)carbamate tert-butyl(1-(4'-((phenoxycarbonyl)amino)-2'-((4-((2-(piperidin-1-yl)ethyl)carbamoyl)phenol)ethynyl)-[1,1'-biphenyl]-3-carbonyl)pyrrolidin-3-yl)carbamate (pyridin-3-yl)-[1,1'-biphenyl]-3-carbonyl)pyrrolidin-3-yl)carbamate (0.083 g, 0.1 mmol, 1 eq) was dissolved in THF (1 ml, 0.1 M), and then 2-(pyridin-3-yl)ethan-1-amine (0.024 g, 0.2 mmol, 2 eq) and TEA (0.030 g, 0.3 mmol, 3 eq) were added and stirred overnight at 55 °C. After completion of the reaction, the mixture was concentrated and purified by column chromatography (silica gel, MeOH / DCM) to give the title compound (0.049 g, 62%).

[0287] Step 8(h) Synthesis of 4-((3'-(3-aminopyrrolidine-1-carbonyl)-4-(3-(2-(pyridin-3-yl)ethyl)ureido)-[1,1'-biphenyl]-2-yl)ethynyl)-N-(2-(piperidin-1-yl)ethyl)benzamide tert-butyl(1-(2'-((4-((2-(piperidin-1-yl)ethyl)carbamoyl)phenyl)ethynyl)-4'-(3-(2-(pyridin-3-yl)ethyl)ureido)-[1,1'-biphenyl]-3-carbonyl)pyrrolidin-3-yl)carbamate (enyl)ethynyl)-4'-(3-(2-(pyridin-3-yl)ethyl)ureido)-[1,1'-biphenyl]-3-carbonyl)pyrrolidin-3-yl)carbamate (0.049 g, 0.062 mmol, 1 eq) was dissolved in DCM (1 mL, 0.05 M), and then TFA (0.035 g, 0.31 mmol, 5 eq) was added and stirred overnight at room temperature. After the reaction was completed, the mixture was concentrated and purified by reverse-phase column chromatography (0.1% formic acid in HO / ACN) to give the title compound (0.014 g, 33%). 1 H NMR (400 MHz, MeOD) δ 8.39 (s, 2H), 8.28 (s, 1H), 7.94 (d, J = 5.5 Hz, 2H), 7.85 (d, J = 7.8 Hz, 1H), 7.79-7.71 (m, 1H), 7.65-7.45 (m, 6H), 7.38 (s, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.30-7.22 (m, 1H), 4.05-3.88 (m, 2H), 3.78 (d, J = 22.7 Hz, 5H), 3.63 (s, 1H), 3.53-3.33 (m, 6H), 3.21 (dd, J = 14.6, 7.3 Hz, 1H), 2.87-2.77 (m, 2H), 2.66 (s, 1H), 2.40 (s, 1H), 2.16 (s, 1H), 1.95-1.86 (m, 4H), 1.69 (s, 2H), 1.33 (dd, J = 16.2, 8.9 Hz, 1H).

[0288] <Example 26: Synthesis of Compound 185 (Synthetic Reaction Scheme 21)> Synthesis of 1-(2-((4-fluorophenyl)ethynyl)-4'-(piperazin-1-yl)-[1,1'-biphenyl]-4-yl)-3-(imidazo[1,2-a]pyridin-7-ylmethyl)urea [ka] [ka] Scheme 21. Reagents and conditions: (a) phenyl chloroformate, pyridine, THF, 0 °C to rt, overnight; (b) imidazo[1,2-a]pyridin-7-ylmethanamine*HCl, TEA, THF, reflux, overnight; (c) Pd(dppf)Cl2, K2CO3, 1,4-dioxane, water (HO), 90 °C, overnight; (d) TFA, DCM, rt, overnight.

[0289] <Step 1(a) Synthesis of phenyl(3-((4-fluorophenyl)ethynyl)-4-iodophenyl)carbamate> 3-((4-fluorophenyl)ethynyl)-4-iodoaniline (1 g, 2.97 mmol, 1 eq) was dissolved in THF (10 mL, 0.3 M), and then pyridine (0.329 g, 41.58 mmol, 14 eq) and phenyl chloroformate (0.558 g, 3.564 mmol, 1.2 eq) were added dropwise at 0 °C and stirred. After completion of the reaction, the mixture was concentrated and extracted with EA and water (HO). The organic layer was dried over MgSO, filtered, concentrated, and purified by column chromatography (silica gel, EA / Hex) to give the title compound (1.3 g, 96%).

[0290] <Step 2(b) Synthesis of 1-(3-((4-fluorophenyl)ethynyl)-4-iodophenyl)-3-(imidazo[1,2-a]pyridin-7-ylmethyl)urea> Phenyl(3-((4-fluorophenyl)ethynyl)-4-iodophenyl)carbamate (1 g, 2.18 mmol, 1 eq) was dissolved in THF (21.8 mL, 0.1 M). Imidazo[1,2-a]pyridin-7-ylmethanamine*HCl salt (0.8 g, 4.36 mmol, 2 eq) and TEA (0.662 g, 6.54 mmol, 3 eq) were added, and the mixture was refluxed overnight. After the reaction was complete, the mixture was concentrated and crystallized using Hexamethylcyclohexane (MC). The crystals were washed three times with HO and filtered to give the title compound (0.85 g, 76%).

[0291] Step 3(c) Synthesis of tert-butyl 4-(2'-((4-fluorophenyl)ethynyl)-4'-(3-(imidazo[1,2-a]pyridin-7-ylmethyl)ureido)-[1,1'-biphenyl]-4-yl)piperazine-1-carboxylate 1-(3-((4-fluorophenyl)ethynyl)-4-iodophenyl)-3-(imidazo[1,2-a]pyridin-7-ylmethyl)urea (0.1 g, 0.19 mmol, 1 eq) was dissolved in 1,4-dioxane:water (HO) (3:1 (v / v), 0.8 ml, 0.25 M) and the resulting solution was treated with (4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)boronic acid. After adding Pd(dppf)Cl (0.027 g, 0.038 mmol, 0.2 eq), and KCO (0.058 g, 0.418 mmol, 2.2 eq), the mixture was degassed with nitrogen gas (N). The reaction mixture was heated to 90 °C and stirred overnight. After completion of the reaction, the mixture was filtered through a Celite filter and extracted with EA and H2O. The organic layer was dried over MgSO4, filtered, concentrated, and purified by column chromatography (silica gel, MeOH / DCM) to give the title compound (0.024 g, 19%).

[0292] Step 4(d) Synthesis of 1-(2-((4-fluorophenyl)ethynyl)-4'-(piperazin-1-yl)-[1,1'-biphenyl]-4-yl)-3-(imidazo[1,2-a]pyridin-7-ylmethyl)urea tert-Butyl 4-(2'-((4-fluorophenyl)ethynyl)-4'-(3-(imidazo[1,2-a]pyridin-7-ylmethyl)ureido)-[1,1'-biphenyl]-4-yl)piperazine-1-carboxylate (0.024 g, 0.037 mmol, 1 eq) was dissolved in DCM (1 ml, 0.03 M), and TFA (0.021 g, 0.185 mmol, 5 eq) was added and the mixture was stirred at room temperature overnight. After the reaction was completed, the mixture was concentrated and purified by reverse phase column chromatography (0.1% formic acid in H2O / ACN) to obtain the title compound (0.007 g, 35%). 1 H NMR (400 MHz, MeOD) δ 8.42 (s, 1H), 7.83 (s, 1H), 7.72 (s, 1H), 7.61-7.49 (m, 4H), 7.45-7.31 (m, 4H), 7.08 (d, J = 6.9 Hz, 4H), 6.97 (d, J = 6.6 Hz, 1H), 4.51 (s, 2H), 3.62 (s, 4H), 3.21 (s, 4H).

[0293] Example 27: Synthesis of Compound 187 (Synthetic Reaction Scheme 22) Synthesis of 1-(imidazo[1,2-a]pyridin-7-ylmethyl)-3-(3-((4-(piperidin-4-yl)phenyl)ethynyl)-4-(pyridin-4-yl)phenyl)urea [ka] [ka] Reaction Scheme 22. Reagents and conditions: (a) trimethylsilylacetylene, PdCl2(PPh3)2, CuI, TEA, toluene, 100°C, 12 hours (12 h); (b) K2CO3, MeOH, room temperature (rt), 2 hours (2 h); (c) PdCl2(PPh3)2, CuI, TEA, ACN, 60°C, 1 hour (1 h); (d) phenyl chloroformate (e) imidazo[1,2-a]pyridin-7-ylmethanamine, TEA, THF, 80°C, overnight; (f) TFA, DCM, rt, overnight.

[0294] Step 1(a) Synthesis of tert-butyl 4-(4-((trimethylsilyl)ethynyl)phenyl)piperidine-1-carboxylate tert-Butyl 4-(4-bromophenyl)piperidine-1-carboxylate (0.5 g, 1.47 mmol, 1 eq) was dissolved in toluene (7.4 mL, 0.2 M). Trimethylsilylacetylene (0.216 g, 2.2 mmol, 1.5 eq), PdCl(PPh) (0.103 g, 0.147 mmol, 0.1 eq), CuI (0.027 g, 0.147 mmol, 0.1 eq), and TEA (0.594 g, 5.88 mmol, 4 eq) were added and the mixture was degassed with nitrogen gas (N). The reaction mixture was heated to 100 °C and stirred for 12 h. After the reaction was completed, the 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 title compound (0.196 g, 37%).

[0295] <Step 2(b) Synthesis of tert-butyl 4-(4-ethynylphenyl)piperidine-1-carboxylate> tert-Butyl 4-(4-((trimethylsilyl)ethynyl)phenyl)piperidine-1-carboxylate (0.196 g, 0.55 mmol, 1 eq) was dissolved in MeOH (5.5 ml, 0.1 M), followed by addition of K2CO3 (0.38 g, 2.75 mmol, 5 eq) and stirring at room temperature for 2 hours. After completion of the reaction, the mixture was filtered, concentrated, and purified by column chromatography (silica gel, EA / Hex) to give the title compound (0.156 g, 100%).

[0296] Step 3(c) Synthesis of tert-butyl 4-(4-((5-amino-2-(pyridin-4-yl)phenyl)ethynyl)phenyl)piperidine-1-carboxylate 3-iodo-4-(pyridin-4-yl)aniline (0.1 g, 0.37 mmol, 1 eq), tert-butyl 4-(4-ethynylphenyl)piperidine-1-carboxylate (0.157 g, 0.55 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) were dissolved in ACN (3.7 ml, 0.1 M) and degassed with nitrogen gas (N2 gas). The reaction mixture was heated to 60°C and stirred for 1 hour. After completion of the reaction, the mixture was extracted with EA and H2O. The organic layer was dried over MgSO4, filtered, concentrated, and purified by column chromatography (silica gel, MeOH / DCM) to give the title compound (0.075 g, 43%).

[0297] Step 4(d) Synthesis of tert-butyl 4-(4-((5-((phenoxycarbonyl)amino)-2-(pyridin-4-yl)phenyl)ethynyl)phenyl)piperidine-1-carboxylate tert-Butyl 4-(4-((5-amino-2-(pyridin-4-yl)phenyl)ethynyl)phenyl)piperidine-1-carboxylate (0.075 g, 0.16 mmol, 1 eq) was dissolved in THF (1.6 ml, 0.1 M), and then pyridine (0.177 g, 2.24 mmol, 14 eq) and phenyl chloroformate (0.030 g, 0.192 mmol, 1.2 eq) were added dropwise at 0 °C and stirred. After the reaction was complete, the mixture was concentrated and extracted with EA and HO. The organic layer was dried over MgSO4, filtered, concentrated, and purified by column chromatography (silica gel, MeOH / DCM) to give the title compound (0.06 g, 63%).

[0298] Step 5(e) Synthesis of tert-butyl 4-(4-((5-(3-(imidazo[1,2-a]pyridin-7-ylmethyl)ureido)-2-(pyridin-4-yl)phenyl)ethynyl)phenyl)piperidine-1-carboxylate tert-Butyl 4-(4-((5-((phenoxycarbonyl)amino)-2-(pyridin-4-yl)phenyl)ethynyl)phenyl)piperidine-1-carboxylate (0.060 g, 0.1 mmol, 1 eq)) was dissolved in THF (1 ml, 0.1 M). To the solution was added imidazo[1,2-a]pyridin-7-ylmethanamine*HCl salt (0.037 g, 0.2 mmol, 2 eq) and TEA (0.030 g, 0.3 mmol, 3 eq). The mixture was heated at reflux and stirred overnight. After the reaction was completed, the mixture was concentrated and the reaction was carried out as in step 6) without further purification.

[0299] Step 6(f) Synthesis of 1-(imidazo[1,2-a]pyridin-7-ylmethyl)-3-(3-((4-(piperidin-4-yl)phenyl)ethynyl)-4-(pyridin-4-yl)phenyl)urea tert-Butyl 4-(4-((5-(3-(imidazo[1,2-a]pyridin-7-ylmethyl)ureido)-2-(pyridin-4-yl)phenyl)ethynyl)phenyl)piperidine-1-carboxylate (0.063 g, 0.1 mmol, 1 eq) was dissolved in DCM (1 ml, 0.1 M), and then TFA (0.057 g, 0.5 mmol, 5 eq) was added and the mixture was stirred at room temperature overnight. After the reaction was completed, the mixture was concentrated and purified by reverse phase column chromatography (0.1% formic acid in H2O / ACN) to obtain the title compound (0.021 g, 40%). 1 H NMR (400 MHz, MeOD) δ 8.60 (d, J = 5.4 Hz, 2H), 8.56 (d, J = 6.9 Hz, 1H), 8.21 (s, 1H), 7.97 (s, 1H), 7.88 (d, J = 1.7 Hz, 1H), 7.76-7.71 (m, 3H), 7.68 (s, 1H), 7.53 (dd, J = 8.4, 1.9 Hz, 1H), 7.44 (d, J = 8.5 Hz, 1H), 7.32 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 8.2 Hz, 2H), 7.20 (d, J = 6.8 Hz, 1H), 4.58 (s, 2H), 3.51 (d, J = 12.6 Hz, 2H), 3.14 (t, J = 11.8 Hz, 2H), 2.92 (t, J = 12.2 Hz, 1H), 2.07 (d, J = 13.6 Hz, 2H), 1.92 (t, J = 11.8 Hz, 2H); MS MH + 527.25

[0300] Example 28: Synthesis of Compound 35 (Synthetic Reaction Scheme 23) Synthesis of N-(2-(2,8-diazaspiro[4.5]decan-8-yl)ethyl)-4-((5-(3-(2-(pyridin-3-yl)ethyl)ureido)-2-(pyridin-4-yl)phenyl)ethynyl)benzamide [ka] [ka] Scheme 23. Reagents and conditions: (a) HATU, DIPEA, DMF, room temperature (rt), overnight; (b) PdCl2(PPh3)2, CuI, TEA, ACN, 60 °C, 5 h; (c) TFA, DCM, room temperature (rt), overnight.

[0301] Step 1(a) Synthesis of tert-butyl 8-(2-(4-ethynylbenzamido)ethyl)-2,8-diazaspiro[4.5]decane-2-carboxylate 4-Ethynylbenzoic acid (0.05 g, 0.34 mmol, 1 eq) was dissolved in DMF (3.4 ml, 0.1 M), followed by addition of HATU (0.193 g, 0.51 mmol, 1.5 eq) and stirring at room temperature for 10 minutes. tert-butyl 8-(2-aminoethyl)-2,8-diazaspiro[4.5]decane-2-carboxylate (0.149 g, 0.51 mmol, 1.5 eq) and DIPEA (0.131 g, 1.02 mmol, 3 eq) were added to the reaction mixture and stirred overnight at room temperature. After completion of the reaction, the mixture was extracted with EA and HO. The organic layer was dried over MgSO4, filtered, concentrated, and purified by column chromatography (silica gel, MeOH / DCM) to give the title compound (0.118 g, 84%).

[0302] Step 2(b) Synthesis of tert-butyl 8-(2-(4-((5-(3-(2-(pyridin-3-yl)ethyl)ureido)-2-(pyridin-4-yl)phenyl)ethynyl)benzamido)ethyl)-2,8-diazaspiro[4.5]decane-2-carboxylate 1-(3-iodo-4-(pyridin-4-yl)phenyl)-3-(2-(pyridin-3-yl)ethyl)urea, 0.05g, 0.11mmol, 1eq), tert-butyl 8-(2-(4-ethynylbenzamido)ethyl)-2,8-diazospiro[4.5]decane-2-carboxylate 8-(2-(4-ethynylbenzamido)ethyl)-2,8-diazaspiro[4.5]decane-2-carboxylate (0.068 g, 0.165 mmol, 1.5 eq), PdCl2(PPh3)2 (0.002 g, 0.0033 mmol, 0.03 eq), CuI (0.00063 g, 0.0033 mmol, 0.03 eq), and TEA (0.022 g, 0.22 mmol, 2 eq) were dissolved in ACN (1.1 ml, 0.1 M) and degassed with nitrogen gas (N2 gas). The reaction mixture was heated to 60 °C and stirred for 5 h. After completion of the reaction, the mixture was extracted with DCM:MeOH (9:1 (v / v)) and water (HO). The organic layer was dried over MgSO4, filtered, concentrated, and purified by column chromatography (silica gel, MeOH / DCM) to give the title compound (0.052 g, 65%).

[0303] Step 3(c) Synthesis of N-(2-(2,8-diazaspiro[4.5]decan-8-yl)ethyl)-4-((5-(3-(2-(pyridin-3-yl)ethyl)ureido)-2-(pyridin-4-yl)phenyl)ethynyl)benzamide tert-Butyl 8-(2-(4-((5-(3-(2-(pyridin-3-yl)ethyl)ureido)-2-(pyridin-4-yl)phenyl)ethynyl)benzamido)ethyl)-2,8-diazaspiro[4.5]decane-2-carboxylate (0.052 g, 0.071 mmol, 1 eq) was dissolved in DCM (1 ml, 0.07 M), and TFA (0.04 g, 0.36 mmol, 5 eq) was added and the mixture was stirred at room temperature overnight. After the reaction was completed, the mixture was concentrated and purified by reverse phase column chromatography (0.1% formic acid in H2O / ACN) to obtain the title compound (0.015 g, 34%). 1 H NMR (400 MHz, MeOD) δ 8.59 (d, J = 3.9 Hz, 2H), 8.48 (s, 1H), 8.40 (s, 1H), 8.33 (s, 1H), 7.84 (dd, J = 21.1, 10.8 Hz, 4H), 7.70 (d, J = 4.5 Hz, 2H), 7.47 (d, J = 8.5 Hz, 1H), 7.42 (d, J = 7.1 Hz, 3H), 3.73 (s, 2H), 3.51 (t, J = 6.5 Hz, 2H), 3.41 (s, 2H), 3.15 (d, J = 29.0 Hz, 8H), 2.92 (t, J = 6.5 Hz, 2H), 2.05-1.79 (m, 6H); MS MH + 628.5

[0304] Example 29: Synthesis of Compound 39 (Synthetic Reaction Scheme 24) Synthesis of N-(2-(3-aminopyrrolidin-1-yl)ethyl)-4-((5-(3-(2-(pyridin-3-yl)ethyl)ureido)-2-(pyridin-4-yl)phenyl)ethynyl)benzamide [ka] [ka] Scheme 24. Reagents and conditions: (a) HATU, DIPEA, DMF, room temperature (rt), overnight; (b) PdCl2(PPh3)2, CuI, TEA, ACN, 60 °C, 5 h; (c) TFA, DCM, room temperature (rt), overnight.

[0305] <Step 1(a) Synthesis of tert-butyl(1-(2-(4-ethynylbenzamido)ethyl)pyrrolidin-3-yl)carbamate> 4-Ethynylbenzoic acid (0.05 g, 0.34 mmol, 1 eq) was dissolved in DMF (3.4 ml, 0.1 M), followed by addition of HATU (0.193 g, 0.51 mmol, 1.5 eq) and stirring at room temperature for 10 minutes. tert-butyl(1-(2-aminoethyl)pyrrolidin-3-yl)carbamate (0.117 g, 0.51 mmol, 1.5 eq) and DIPEA (0.131 g, 1.02 mmol, 3 eq) were added to the reaction mixture and stirred overnight at room temperature. After completion of the reaction, the mixture was extracted with EA and HO. The organic layer was dried over MgSO4, filtered, concentrated, and purified by column chromatography (silica gel, MeOH / DCM) to give the title compound (0.063 g, 26%).

[0306] Step 2(b) Synthesis of tert-butyl(1-(2-(4-((5-(3-(2-(pyridin-3-yl)ethyl)ureido)-2-(pyridin-4-yl)phenyl)ethynyl)benzamido)ethyl)pyrrolidin-3-yl)carbamate 1-(3-iodo-4-(pyridin-4-yl)phenyl)-3-(2-(pyridin-3-yl)ethyl)urea, 0.053 g, 0.12 mmol, 1 eq), tert-butyl(1-(2-(4-ethynylbenzamido)ethyl)pyrrolidin-3-yl)carbamate (Ibenzamido)ethyl)pyrrolidin-3-yl)carbamate (0.063 g, 0.176 mmol, 1.5 eq), PdCl2(PPh3)2 (0.003 g, 0.0036 mmol, 0.03 eq), CuI (0.00069 g, 0.0036 mmol, 0.03 eq), and TEA (0.024 g, 0.24 mmol, 2 eq) were dissolved in ACN (1.2 mL, 0.1 M) and degassed with nitrogen gas (N2 gas). The reaction mixture was heated to 60 °C and stirred for 5 h. After completion of the reaction, the mixture was extracted with DCM:MeOH (9:1 (v / v)) and water (HO). The organic layer was dried over MgSO4, filtered, concentrated, and purified by column chromatography (silica gel, MeOH / DCM) to give the title compound (0.036 g, 44%).

[0307] Step 3(c) Synthesis of N-(2-(3-aminopyrrolidin-1-yl)ethyl)-4-((5-(3-(2-(pyridin-3-yl)ethyl)ureido)-2-(pyridin-4-yl)phenyl)ethynyl)benzamide tert-Butyl (1-(2-(4-((5-(3-(2-(pyridin-3-yl)ethyl)ureido)-2-(pyridin-4-yl)phenyl)ethynyl)benzamido)ethyl)pyrrolidin-3-yl)carbamate (0.036 g, 0.053 mmol, 1 eq) was dissolved in DCM (1 ml, 0.05 M), and then TFA (0.06 g, 0.53 mmol, 10 eq) was added and the mixture was stirred at room temperature overnight. After the reaction was completed, the mixture was concentrated and purified by reverse phase column chromatography (0.1% formic acid in H2O / ACN) to obtain the title compound (0.020 g, 66%). 1 H NMR (400 MHz, MeOD) δ 8.61 (d, J = 5.9 Hz, 1H), 8.48 (s, 1H), 8.41 (d, J = 4.4 Hz, 1H), 8.12 (s, 2H), 7.85 (dt, J = 22.1, 7.8 Hz, 4H), 7.73 (d, J = 5.9 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.46-7.39 (m, 4H), 3.83 (s, 1H), 3.65-3.55 (m, 2H), 3.51 (t, J = 7.0 Hz, 2H), 3.19 (s, 1H), 3.12-3.01 (m, 1H), 2.96-2.84 (m, 5H), 2.62 (dd, J = 17.1, 9.1 Hz, 2H), 2.38 (s, 1H), 1.90 (s, 1H).

[0308] Example 30: Synthesis of Compound 139 (Synthetic Reaction Scheme 25) Synthesis of 1-(3-((3-aminophenyl)ethynyl)-4-(pyridin-4-yl)phenyl)-3-(2-(pyridin-3-yl)ethyl)urea [ka] Reaction Scheme 25. Reagents and conditions: (a) 3-ethynylaniline, PdCl2(PPh3)2, CuI, TEA, ACN, 80°C, 3 hours

[0309] 1-(3-iodo-4-(pyridin-4-yl)phenyl)-3-(2-(pyridin-3-yl)ethyl)urea, 0.050 g, 0.11 mmol, 1 eq), 3-ethynylaniline , 0.019 g, 0.165 mmol, 1.5 eq), PdCl2(PPh3)2 (0.007 g, 0.011 mmol, 0.1 eq), CuI (0.002 g, 0.011 mmol, 0.1 eq), and TEA (0.044 g, 0.44 mmol, 4 eq) were dissolved in ACN (1.1 mL, 0.1 M) and degassed with nitrogen gas (N2 gas). The reaction mixture was heated to 80 °C and stirred for 3 h. After completion of the reaction, the mixture was extracted with DCM:MeOH (9:1 (v / v)) and HO. The organic layer was dried over MgSO4, filtered, concentrated, and purified by column chromatography (silica gel, MeOH / DCM) to give the title compound (15 mg, 32%). 1H NMR (400 MHz, DMSO) δ 8.79 (s, 1H), 8.66 (s, 2H), 8.46 (d, J = 13.7 Hz, 2H), 7.83 (s, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.64 (d, J = 5.4 Hz, 2H), 7.43 (d, J = 1.1 Hz, 2H), 7.35 (dd, J = 7.6, 4.8 Hz, 1H), 7.02 (dd, J = 8.4, 7.5 Hz, 1H), 6.58 (dd, J = 8.6, 1.1 Hz, 2H), 6.53 (d, J = 7.5 Hz, 1H), 6.31 (t, J = 5.7 Hz, 1H), 5.26 (s, 2H), 3.39 (dd, J = 12.8, 6.8 Hz, 2H), 2.80 (t, J = 7.0 Hz, 2H).

[0310] Compounds 15, 16, 17, 18, 21, 37, 38, 53, 55, 129, 133, 135, 137, 140, 141, 156, 157, 158, 160, 162, and 172 can be synthesized in substantially the same manner as in Example 30, except for varying the reactants.

[0311] Example 31: Synthesis of Compound 89 (Synthetic Reaction Scheme 26) [ka] [ka] Reaction Scheme 26: (a) SOCl2, MeOH, room temperature (rt); (b) NaH, MeI, DMF, 4 hours (4 h); (c) NaOH, HO, MeOH, reflux, 4 hours (4 h); (d) TBTU, TEA, cyclohexanamine, DCM, 24 hours (24 h); (e) Pd[PPh3]4, CuI, TEA, 4-ethynyl-N-(2-(piperidin-1-yl)ethyl)benzamide, ACN, room temperature (rt), 1 hour (1 h); (f) Fe, NHCl, EtOH, HO, 90 °C, 2 hours (2 h); (g) phenyl chloroformate chloroformate, pyridine, THF, room temperature (RT), 2 h; (h) 2-(pyridin-3-yl)ethan-1-amine, TEA, THF, reflux, 24 h

[0312] <Step 1(a) Synthesis of methyl 2-(2-iodo-4-nitrophenyl)acetate> 2-(2-iodo-4-nitrophenyl)acetic acid (1 g, 3.26 mmol, 1 eq) was dissolved in MeOH (0.25 M) and the reaction mixture was cooled on ice, and SOCl (7.8 mL) was slowly added dropwise. After stirring at room temperature, the reaction mixture was concentrated under reduced pressure to give the title compound.

[0313] <Step 2(b) Synthesis of methyl 2-(2-iodo-4-nitrophenyl)propanoate> Methyl 2-(2-iodo-4-nitrophenyl)acetate (3.25 mmol) was dissolved in DMF (6 mL) and then MeI (0.24 mL, 1.2 eq) was added. The reaction solution was cooled on ice, and 60% NaH (0.14 g, 3.58 mmol, 1.1 eq) was added in portions, followed by stirring for 4 hours. Water was added to the reaction mixture, which was then extracted with EA. The organic layer was washed with saturated aqueous ammonium chloride, dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (1.2 g).

[0314] <Step 3(c) Synthesis of 2-(2-iodo-4-nitrophenyl)propanoic acid> A mixture of methyl 2-(2-iodo-4-nitrophenyl)propanoate (36 g, 2.98 mmol, 1 eq), NaOH (0.3 g, 7.5 mmol, 2.5 eq) in water (0.2 M) and MeOH (0.1 M) was stirred at 60 °C for 2-4 hours. After the reaction was confirmed by TLC and the reaction was complete, the pH of the reaction mixture was adjusted to 1 with 1N aqueous HCl and extracted with EA. The organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (1 g).

[0315] Step 4(d) Synthesis of N-cyclohexyl-2-(2-iodo-4-nitrophenyl)propenamide 2-(2-iodo-4-nitrophenyl)propanoic acid (1 g, 3 mmol), TBTU (1.4 g, 4.5 mmol, 1.5 eq) and 30 mL of DCM were added and stirred at room temperature for 50 minutes. TEA (0.83 mL, 6 mmol, 2 eq) and cyclohexanamine (41 mL, 3.6 mmol, 1.2 eq) were added to the reaction mixture and stirred at room temperature for 24 hours. Water was added to the reaction mixture and the mixture was extracted with EA. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography to give the title compound (1.4 g).

[0316] Step 5(e) Synthesis of 4-((2-(1-(cyclohexylamino)-1-oxopropan-2-yl)-5-nitrophenyl)ethynyl)-N-(2-(piperidin-1-yl)ethyl)benzamide TEA (0.1 mL, 3 eq), CuI (1.4 mg, 3 mol%), and Pd[PPh3]4 (5.3 mg, 3 mol%) were added to a solution of N-cyclohexyl-2-(2-iodo-4-nitrophenyl)propenamide in MeCN (2 mL). The mixture was stirred at room temperature under a nitrogen atmosphere for 5 min. Subsequently, 4-ethynyl-N-(2-(piperidin-1-yl)ethyl)benzamide (7 mg, 0.3 mmol, 1.0 eq) was added. The reaction mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. The resulting residue was purified by column chromatography to give the desired compound (0.15 g).

[0317] Step 6(f) Synthesis of 4-((5-amino-2-(1-(cyclohexylamino)-1-oxopropan-2-yl)phenyl)ethynyl)-N-(2-(piperidin-1-yl)ethyl)benzamide A mixture of 4-((2-(1-(cyclohexylamino)-1-oxopropan-2-yl)-5-nitrophenyl)ethynyl)-N-(2-(piperidin-1-yl)ethyl)benzamide (0.26 g, 0.49 mmol, 1.0 eq), Fe (0.27 g, 10 eq), NHCl (0.24 g, 10 eq), EtOH (0.1 M), and HO (0.1 M) was added and stirred at 90 °C for 2 h. The reaction mixture became a black suspension. After completion of the reaction, the reaction mixture was washed with water and extracted with DCM. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give the target compound as a crude product.

[0318] Step 7(g) Synthesis of phenyl(4-(1-(cyclohexylamino)-1-oxopropan-2-yl)-3-((4-((2-(piperidin-1-yl)ethyl)carbamoyl)phenyl)ethynyl)phenyl)carbamate 4-((5-amino-2-(1-(cyclohexylamino)-1-oxopropan-2-yl)phenyl)ethynyl)-N-(2-(piperidin-1-yl)ethyl)benzamide (0.24 g, 0.48 mmol, 1.0 eq) and pyridine (0.087 ml, 2 eq) were dissolved in THF (10 mL). The reaction solution was cooled on ice, and phenyl chloroformate (0.091 ml, 1.5 eq) was added. The mixture was stirred at room temperature for 2 hours. After completion of the reaction, water (0.2 mL) was added to the reaction mixture, and the reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with water and EA. The organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (silica gel, 0-5% MeOH / DCM) to give the target compound.

[0319] Step 8(h) Synthesis of 4-((2-(1-(cyclohexylamino)-1-oxopropan-2-yl)-5-(3-(2-(pyridin-3-yl)ethyl)ureido)phenyl)ethynyl)-N-(2-(piperidin-1-yl)ethyl)benzamide A mixture of phenyl(4-(1-(cyclohexylamino)-1-oxopropan-2-yl)-3-((4-((2-(piperidin-1-yl)ethyl)carbamoyl)phenyl)ethynyl)phenyl)carbamate (0.08 g, 0.13 mmol, 1.0 eq), 3-(2-aminoethyl)pyridine (0.031 g, 0.25 mmol, 2 eq), and TEA (0.054 ml, 3 eq) in THF (2 mL) was heated at 80 °C for 24 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (silica gel, 0-5% MeOH / DCM) to give the target compound. 1 H NMR (400 MHz, MeOD) δ 8.47 (d, J = 1.4 Hz, 1H), 8.42 (dd, J = 4.8, 1.2 Hz, 1H), 7.89 (d, J = 8.3 Hz, 2H), 7.81-7.79 (m, 1H), 7.69-7.67 (m, 3H), 7.50 (d, J = 7.8 Hz, 1H), 7.42 (dd, J = 7.6, 4.9 Hz, 1H), 7.36-7.34 (m, 1H), 7.28-7.27 (m, 1H), 4.13 (q, J = 7.2 Hz, 1H), 3.64-3.61 (m, 3H), 3.50 (t, J = 7.0 Hz, 2H), 3.37 (s, 1H), 2.92 (t, J = 6.9 Hz, 2H), 2.76-2.71 (m, 6H), 1.86-1.83 (m, 1H), 1.71-1.65 (m, 10H), 1.51 (d, J = 7.1 Hz, 3H), 1.39-1.00 (m, 6H).

[0320] Compound 101 can be synthesized by substantially the same method as in Example 31, except for changing the reactants.

[0321] Example 32: Synthesis of Compound 69 (Synthetic Reaction Scheme 27) [ka] [ka] Reaction Scheme 27. (a) Na2S, DMF, rt; (b) 3-(chloromethyl)-1-methyl-1H-pyrazole, K2CO3, DMF, rt, 16 h; (c) mCPBA, DCM, rt, 16 h; (d) PdCl2[PPh3]2, CuI, TEA, ACN, rt, 16 h; (e) Fe, AcOH, 80 °C, 2 h; (f) phenyl chloroformate (g) 2-(pyridin-3-yl)ethan-1-amine, TEA, THF, reflux, 24 h

[0322] <Step 1(a) Synthesis of 2-iodo-4-nitrobenzenethiol> 1-Fluoro-2-iodo-4-nitrobenzene (5 g, 0.019 mol, 1 eq) was dissolved in DMF (25 mL), sodium disulfide (1.6 g, 0.021 mol, 1.1 eq) was added, and the mixture was stirred at room temperature for 16 hours. After the reaction was complete, 200 mL of water was added to the reaction mixture, the pH was adjusted to 5 with 1N HCl, and the mixture was extracted multiple times with DCM. 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 obtain the target compound (4 g, 0.014 mol, 73%).

[0323] <Step 2(b) Synthesis of 3-(((2-iodo-4-nitrophenyl)thio)methyl)-1-methyl-1H-pyrazole> 2-iodo-4-nitrobenzenethiol (4 g, 0.014 mol, 1 eq) was dissolved in DMF (40 mL) and K2CO3 (3.9 g, 0.028 mol, 2 eq) was added and stirred. 3-(chloromethyl)-1-methyl-1H-pyrazole (1.85 g, 0.014 mol, 1 eq) was added to the reaction mixture and stirred for 16 hours. After confirming the reaction by TLC, water was added to the reaction mixture and the resulting precipitate was filtered to obtain the desired compound (4.9 g, 0.013 mol, 93%).

[0324] <Step 3(c) Synthesis of 3-(((2-iodo-4-nitrophenyl)sulfonyl)methyl)-1-methyl-1H-pyrazole> 3-(((2-iodo-4-nitrophenyl)thio)methyl)-1-methyl-1H-pyrazole (4.5 g, 0.012 mmol, 1 eq) was dissolved in DCM (200 mL), mCPBA (metachloroperoxybenzoic acid, 8.3 g, 0.048 mol, 4 eq) was added, and the mixture was stirred for 2 days. The reaction was monitored by TLC, and either further mCPBA was added or the reaction was complete. The mixture was diluted with water, neutralized with saturated aqueous NaHCO3, and extracted multiple times with DCM. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and recrystallized (MeOH / MC) to give the desired compound (3 g, 0.0074 mol, 62%).

[0325] Step 4(d) Synthesis of 3-(((2-((4-fluorophenyl)ethynyl)-4-nitrophenyl)sulfonyl)methyl)-1-methyl-1H-pyrazole 3-(((2-iodo-4-nitrophenyl)sulfonyl)methyl)-1-methyl-1H-pyrazole (3 g, 0.0074 mol, 1 eq) was dissolved in MeCN (30 mL) and TEA (3 mL, 0.022 mol, 3 eq) was added. The reaction mixture was charged with PdCl2[PPh3]2 (155 mg, 3 mol%) and CuI (42 mg, 3 mol%) and stirred at room temperature under a nitrogen atmosphere for 5 min. 4-Fluorophenylacetylene (1 g, 0.0088 mol, 1.2 eq) was then 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 (silica gel, 4% MeOH / DCM) to give the desired compound (2 g, 0.005 mmol, 68%).

[0326] <Step 5(e) Synthesis of 3-((4-fluorophenyl)ethynyl)-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)aniline> 3-(((2-((4-fluorophenyl)ethynyl)-4-nitrophenyl)sulfonyl)methyl)-1-methyl-1H-pyrazole (2 g, 0.005 mol, 1 eq) was added with AcOH (30 mL) and iron (2.8 g, 0.05 mol, 10 eq) and stirred at 85°C for 2-3 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 and extracted with EA. The organic layer was then concentrated under reduced pressure to obtain the target compound as a crude product.

[0327] Step 6(f) Synthesis of phenyl(3-((4-fluorophenyl)ethynyl)-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)phenyl)carbamate 3-((4-fluorophenyl)ethynyl)-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)aniline (1.3 g, 0.0035 mol, 1 eq) and pyridine (0.56 mL, 0.0053 mol, 2 eq) were dissolved in THF. The reaction solution was cooled on ice, and phenyl chloroformate (0.66 mL, 0.0053 mol, 1.5 eq) was added. The mixture was stirred at room temperature for 3–4 h. After completion of the reaction, water (0.1 mL) was added to the reaction mixture, which was then concentrated under reduced pressure. The resulting residue was poured into 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, 4-6% MeOH / DCM) to give the desired compound (0.8 g, 0.0016 mol, 46%).

[0328] Step 7(g) Synthesis of 1-(3-((4-fluorophenyl)ethynyl)-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)phenyl)-3-(2-(pyridin-3-yl)ethyl)urea (Compound 69)) A mixture of phenyl(3-((4-fluorophenyl)ethynyl)-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)phenyl)carbamate (0.1 g, 0.2 mmol, 1.0 eq), 3-(2-aminoethyl)pyridine (2 eq), and TEA (3 eq) in THF (4 mL) was heated at 80 °C for 24 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (silica gel, 0-5% MeOH / DCM) to give the target compound. 1 H NMR (400 MHz, MeOD) δ 8.48 (s, 1H), 8.42 (m, 1H), 7.90 (s, 1H), 7.81 (d, J = 7.7 Hz, 1H), 7.74-7.71 (m, 3H), 7.47-7.38 (m, 3H), 7.22 (t, J = 8.1 Hz, 2H), 6.13 (s, 1H), 4.75 (s, 2H), 3.77 (s, 3H), 3.52 (t, J = 6.7 Hz, 2H), 2.93 (t, J = 6.5 Hz, 2H). MS(ESI) m / e MH + 518.4

[0329] Compounds 23, 24, 70, 71, 77, 78, 79, 80, 81, 93, 98, 100, and 150 can be synthesized by changing the reactants in substantially the same manner as in Example 32 above.

[0330] Example 33: Synthesis of Compound 183 Synthesis of 1-(3-((4-fluorophenyl)ethynyl)-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)phenyl)-3-(imidazo[1,2-a]pyridin-7-ylmethyl)urea [ka]

[0331] Compound 183 was prepared in substantially the same manner as in the synthesis of compound 69 in Example 32, except that 1-{imidazo[1,2-a]pyridin-7-yl}methanamine dihydrochloride was used instead of 3-(2-aminoethyl)pyridine in step 7). 1H NMR (400 MHz, DMSO) δ 9.41 (s, 1H), 8.50 (d, J = 6.9 Hz, 1H), 8.17 (s, 1H), 8.00 (s, 1H), 7.89 (s, 1H), 7.75 (m, 2H), 7.67 (d, J = 8.8 Hz, 1H), 7.58 (s, 1H), 7.52 (s, 1H), 7.46 (d, J = 8.7 Hz, 1H), 7.41 (s, 1H), 7.35 (t, J = 8.5 Hz, 2H), 7.12 (m, 1H), 6.86 (d, J = 6.9 Hz, 1H), 6.03 (s, 1H), 4.72 (s, 2H), 4.36 (d, J = 4.8 Hz, 2H), 3.73 (s, 3H). MS(ESI) m / e MH + 543.4

[0332] Example 34: Synthesis of Compound 177 (Synthetic Reaction Scheme 28) Synthesis of 3-amino-N-(2-((4-fluorophenyl)ethynyl)-4-(3-(2-(pyridin-3-yl)ethyl)ureido)phenyl)benzamide [ka] [ka] Scheme 28. Reactants and conditions: (a) 3-((tert-butoxycarbonyl)amino)benzoic acid, DIPEA, HATU, DCM, room temperature (rt), 24 hours (24 h); (b) 4N HCl in dioxane, 1,4-dioxane, room temperature (rt), 24 hours (24 h).

[0333] Step 1(a) Synthesis of tert-butyl(3-((2-((4-fluorophenyl)ethynyl)-4-(3-(2-(pyridin-3-yl)ethyl)ureido)phenyl)carbamoyl)phenyl)carbamate 1-(4-amino-3-((4-fluorophenyl)ethynyl)phenyl)-3-(2-(pyridin-3-yl)ethyl)urea (0.05 g, 0.134 mmol, 1 eq) was dissolved in DCM (0.5 mL), followed by 3-((tert-butoxycarbonyl)amino)benzoic acid (0.032 g, 0.134 mmol, 1 eq), DIPEA (0.07 mL, 3 eq), and HATU (0.061 g, 1.2 eq) and stirred at room temperature for 24 hours. The reaction mixture was concentrated and purified by reverse-phase column chromatography to afford the title compound (0.047 g, 59.5%).

[0334] <Step 2(b) Synthesis of 3-amino-N-(2-((4-fluorophenyl)ethynyl)-4-(3-(2-(pyridin-3-yl)ethyl)ureido)phenyl)benzamide> tert-Butyl (3-((2-((4-fluorophenyl)ethynyl)-4-(3-(2-(pyridin-3-yl)ethyl)ureido)phenyl)carbamoyl)phenyl)carbamate, 0.047 g, 0.079 mmol, 1 eq) was dissolved in 1,4-dioxane (1,4-Dioxane, 0.9 ml, 0.2 M), followed by 4N HCl in dioxane * 4N HCl in dioxane, 0.2 ml, 0.79 mmol, 10 eq) and stirring at room temperature for 24 hours. The reaction mixture was concentrated and purified by reverse phase column chromatography to give the title compound (2.62 mg, 7%). 1 H NMR (400 MHz, MeOD) δ 8.44 (d, J = 21.9 Hz, 2H), 7.82-7.74 (m, 2H), 7.68 (d, J = 2.3 Hz, 1H), 7.54-7.46 (m, 2H), 7.44-7.37 (m, 1H), 7.32 (dd, J = 8.8, 2.3 Hz, 1H), 7.29-7.19 (m, 3H), 7.11 (t, J = 8.7 Hz, 2H), 6.94-6.88 (m, 1H), 3.49 (t, J = 7.0 Hz, 2H), 2.91 (t, J = 6.9Hz,2H).

[0335] Compounds 123, 125, and 166 can be synthesized by changing the reactants in substantially the same manner as in Example 34 above.

[0336] Example 35: Synthesis of Compound 124 (Synthetic Reaction Scheme 29) Synthesis of 4-fluoro-N-(2-((4-fluorophenyl)ethynyl)-4-(3-(2-(pyridin-3-yl)ethyl)ureido)phenyl)benzamide [ka] Reaction Scheme 29. Reactants and conditions: (a) 4-fluorobenzoic acid, DIPEA, HATU, DCM, room temperature (rt), 24 hours (24h);

[0337] 1-(4-amino-3-((4-fluorophenyl)ethynyl)phenyl)-3-(2-(pyridin-3-yl)ethyl)urea (0.05 g, 0.134 mmol, 1 eq) was dissolved in DCM (0.5 mL), followed by 4-fluorobenzoic acid (0.019 g, 0.134 mmol, 1 eq), DIPEA (0.07 mL, 3 eq), and HATU (0.061 g, 1.2 eq). The mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated and purified by reverse-phase column chromatography to give the title compound (0.047 g, 59.5%). 1 H NMR (400 MHz, MeOD) δ 8.46 (d, J = 24.0 Hz, 2H), 8.12-8.03 (m, 2H), 7.81 (d, J = 7.8 Hz, 1H), 7.72 (d, J = 2.4 Hz, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.55-7.46 (m, 2H), 7.45-7.39 (m, 1H), 7.36 (dd, J = 8.8, 2.5 Hz, 1H), 7.28 (t, J = 8.7 Hz, 2H), 7.12 (t, J = 8.8 Hz, 2H), 3.51 (t, J = 7.0 Hz, 2H), 2.93 (t, J = 6.9 Hz, 2H).

[0338] Example 36: Synthesis of Compound 122 (Synthetic Reaction Scheme 30) Synthesis of N-(2-((4-fluorophenyl)ethynyl)-4-(3-(2-(pyridin-3-yl)ethyl)ureido)phenyl)propionamide [ka] Reaction Scheme 30. Reagents and conditions: (a) propionic acid, DIPEA, HATU, DCM, room temperature (rt), 24 hours (24h);

[0339] 1-(4-amino-3-((4-fluorophenyl)ethynyl)phenyl)-3-(2-(pyridin-3-yl)ethyl)urea (0.05 g, 0.134 mmol, 1 eq) was dissolved in DCM (0.5 mL). Propionic acid (0.01 mL, 0.134 mmol, 1 eq), DIPEA (0.07 mL, 3 eq), and HATU (0.061 g, 1.2 eq) were added and stirred at room temperature for 24 hours. The reaction mixture was concentrated and purified by column chromatography (silica gel, DCM / MeOH) to give the title compound (0.039 g, 67%). 1H NMR (400 MHz, DMSO) δ 9.30 (s, 1H), 8.58 (s, 1H), 8.47 (d, J = 1.7 Hz, 1H), 8.44 (dd, J = 4.7, 1.4 Hz, 1H), 7.73 (d, J = 2.4 Hz, 1H), 7.70-7.62 (m, 3H), 7.52 (d, J = 8.7 Hz, 1H), 7.37-7.28 (m, 3H), 7.22 (dd, J = 8.8, 2.4 Hz, 1H), 6.23 (t, J = 5.7 Hz, 1H), 3.37 (dd, J = 13.0, 6.9 Hz, 2H), 2.79 (t, J = 7.0 Hz, 2H), 2.42-2.35 (m, 2H), 1.11 (t, J = 7.5 Hz, 3H).

[0340] Example 37: Compound 74 (Synthesis Scheme 31) Synthesis of 1-(3-((4-fluorophenyl)ethynyl)-4-(2-oxo-2-(piperidin-1-yl)ethyl)phenyl)-3-(2-(pyridin-3-yl)ethyl)urea [ka] [ka] Reaction Scheme 31: (a) TBTU, piperidine, TEA, DCM; (b) Pd[PPh3]4, CuI, TEA, 1-ethynyl-4-fluorobenzene, ACN, room temperature (rt), 1 hour; (c) Zn, NHCl, 1,4-dioxane, water (HO); (d) phenyl chloroformate, pyridine, THF, room temperature (RT), 2 hours; (e) 2-(pyridin-3-yl)ethan-1-amine, TEA, THF, reflux, 24 hours.

[0341] <Step 1(a): Synthesis of 2-(2-iodo-4-nitrophenyl)-1-(piperidin-1-yl)ethan-1-one> 2-(2-iodo-4-nitrophenyl)acetic acid (1 g, 3.26 mmol) was added to 20 ml of DCM and TBTU (1.57 g, 1.5 eq) and stirred at room temperature for 50 minutes. TEA (0.9 ml, 2 eq) and piperidine (0.38 ml, 1.2 eq) were added and stirred for 24 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give the desired compound (1.1 g, 90%).

[0342] Step 2(b): Synthesis of 2-(2-((4-fluorophenyl)ethynyl)-4-nitrophenyl)-1-(piperidin-1-yl)ethan-1-one Triethylamine (1.22 mL, 3 eq), CuI (17 mg, 3 mol%), and Pd[PPh3]4 (62 mg, 3 mol%) were added to a solution of 2-(2-iodo-4-nitrophenyl)-1-(piperidin-1-yl)ethan-1-one (1.1 g, 2.94 mmol) in ACN (30 mL). The mixture was stirred at room temperature under a nitrogen atmosphere for 5 min. 1-ethynyl-4-fluorobenzene (0.42 mg, 1.2 eq) was then added. The reaction mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. The resulting residue was purified by column chromatography (30% EA / HX) to give the desired compound (0.84 g, 78%).

[0343] Step 3(c): Synthesis of 2-(4-amino-2-((4-fluorophenyl)ethynyl)phenyl)-1-(piperidin-1-yl)ethan-1-one 2-(2-((4-fluorophenyl)ethynyl)-4-nitrophenyl)-1-(piperidin-1-yl)ethan-1-one (0.84 g, 2.3 mmol, 1.0 eq), Zn (1.5 g, 10 eq), NH4Cl (1.37 g, 10 eq), and dioxane:water (HO) (12 mL, 3:1 (v:v), 0.02 M) were added and stirred at room temperature for 24 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to remove the dioxane. The reaction mixture was washed with water and saturated NaHCO3 solution and then extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give the title compound as a crude product.

[0344] Step 4(d): Synthesis of phenyl(3-((4-fluorophenyl)ethynyl)-4-(2-oxo-2-(piperidin-1-yl)ethyl)phenyl)carbamate 2-(4-amino-2-((4-fluorophenyl)ethynyl)phenyl)-1-(piperidin-1-yl)ethan-1-one (1.0 eq) and pyridine (0.42 ml, 2 eq) were dissolved in tetrahydrofuran (10 ml). The reaction solution was cooled on ice, and phenyl chloroformate (0.44 ml, 1.5 eq) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, water (0.2 ml) was added to the reaction mixture, and the reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with water and 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, 0-5% methanol / dichloromethane) to give the target compound.

[0345] Step 5(e): Synthesis of 1-(3-((4-fluorophenyl)ethynyl)-4-(2-oxo-2-(piperidin-1-yl)ethyl)phenyl)-3-(2-(pyridin-3-yl)ethyl)urea A mixture of phenyl(3-((4-fluorophenyl)ethynyl)-4-(2-oxo-2-(piperidin-1-yl)ethyl)phenyl)carbamate (0.2 g, 0.44 mmol, 1.0 eq), 3-(2-aminoethyl)pyridine (0.1 g, 2 eq), and triethylamine (0.18 mL, 3 eq) in THF (8 mL) was heated at 80 °C for 24 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (silica gel, 0-5% methanol / dichloromethane) to give the target compound. 1 H NMR (400 MHz, DMSO) δ 8.59 (s, 1H), 8.47 (d, J = 1.8 Hz, 1H), 8.44 (dd, J = 4.7, 1.5 Hz, 1H), 7.71 (d, J = 2.2 Hz, 1H), 7.68 (dt, J = 7.6, 1.7 Hz, 1H), 7.64-7.57 (m, 2H), 7.37-7.27 (m, 3H), 7.23 (dd, J = 8.4, 2.3 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 6.25 (t, J = 5.6 Hz, 1H), 3.80 (s, 2H), 3.47-3.42 (m, 4H), 3.37 (dd, J = 12.9, 6.8 Hz, 2H), 2.79 (t, J = 7.0 Hz, 2H), 1.54-1.52 (m, J = 5.1 Hz, 2H), 1.39 (s, 4H).

[0346] Compounds 99, 75, and 76 can be synthesized by changing the reactants in substantially the same manner as in Example 37 above.

[0347] Example 38: Compound 66 (Synthesis Reaction Scheme 32) Synthesis of N-(piperidin-4-yl)-4-((5-(3-(2-(pyridin-3-yl)ethyl)ureido)-2-(pyridin-4-yl)phenyl)ethynyl)benzamide [ka] [ka] Reaction Scheme 32. Reagents and conditions: (a) HATU, DIPEA, DCM, 0 °C to room temperature (rt), overnight; (b) PdCl2(PPh3)2, CuI, TEA, ACN, 60 °C, overnight; (c) TFA, DCM, room temperature (rt), overnight.

[0348] Step 1(a): Synthesis of tert-butyl 4-(4-ethynylbenzamido)piperidine-1-carboxylate 4-Ethynylbenzoic acid (0.5 g, 3.42 mmol, 1 eq) was dissolved in DCM (34.2 mL, 0.1 M), followed by addition of HATU (1.55 g, 4.1 mmol, 1.5 eq) and stirring at room temperature for 10 minutes. tert-butyl 4-aminopiperidine-1-carboxylate (0.821 g, 4.1 mmol, 1.5 eq) and DIPEA (1.326 g, 10.26 mmol, 3 eq) were added to the reaction mixture and stirred overnight at room temperature. After completion of the reaction, the mixture was extracted with EA and water (HO). The organic layer was dried over MgSO, filtered, concentrated, and purified by column chromatography (silica gel, MeOH / DCM) to give the title compound (0.769 g, 68.4%).

[0349] Step 2(b) Synthesis of tert-butyl 4-(4-((5-(3-(2-(pyridin-3-yl)ethyl)ureido)-2-(pyridin-4-yl)phenyl)ethynyl)benzamido)piperidine-1-carboxylate 1-(3-iodo-4-(pyridin-4-yl)phenyl)-3-(2-(pyridin-3-yl)ethyl)urea, 0.05g, 0.11mmol, 1eq), tert-butyl 4-(4-ethynylbenzamido)piperidine-1-carboxylate 4-(4-ethynylbenzamido)piperidine-1-carboxylate (0.054 g, 0.165 mmol, 1.5 eq), PdCl2(PPh3)2 (0.002 g, 0.0033 mmol, 0.03 eq), CuI (0.00063 g, 0.0033 mmol, 0.03 eq), and TEA (0.022 g, 0.22 mmol, 2 eq) were dissolved in ACN (1.1 ml, 0.1 M) and degassed with nitrogen gas (N2 gas). The reaction mixture was heated to 60 °C and stirred overnight. After completion of the reaction, the mixture was extracted with DCM and water (HO). The organic layer was dried over MgSO4, filtered, concentrated, and purified by column chromatography (silica gel, MeOH / DCM) to give the title compound (0.021 g, 29.6%).

[0350] <Step 3(c) Synthesis of N-(piperidin-4-yl)-4-((5-(3-(2-(pyridin-3-yl)ethyl)ureido)-2-(pyridin-4-yl)phenyl)ethynyl)benzamide> tert-Butyl 4-(4-((5-(3-(2-(pyridin-3-yl)ethyl)ureido)-2-(pyridin-4-yl)phenyl)ethynyl)benzamido)piperidine-1-carboxylate (0.021 g, 0.032 mmol, 1 eq) was dissolved in DCM (1 mL, 0.07 M), followed by addition of TFA (0.036 g, 0.32 mmol, 10 eq) and stirring overnight at room temperature. After completion of the reaction, the mixture was concentrated and purified by reverse-phase column chromatography (0.1% formic acid in HO / ACN) (0.008 g, 49.3%). 1 H NMR (400 MHz, DMSO) δ 9.22 (s, 1H), 8.66 (d, J = 5.6 Hz, 2H), 8.45 (dd, J = 11.1, 6.4 Hz, 3H), 8.33 (s, 1H), 7.95 (s, 1H), 7.87 (d, J = 8.2 Hz, 2H), 7.67 (dd, J = 12.2, 6.7 Hz, 3H), 7.46 (dd, J = 14.7, 8.4 Hz, 4H), 7.38-7.30 (m, 1H), 6.76 (s, 1H), 3.96 (s, 1H), 3.44-3.34 (m, 5H), 2.85-2.77 (m, 3H), 1.93-1.85 (m, 2H), 1.68-1.58 (m, 2H).

[0351] Example 39: Compound 65 (Synthesis Reaction Scheme 33) Synthesis of 1-(3-((4-(4-aminopiperidine-1-carbonyl)phenyl)ethynyl)-4-(pyridin-4-yl)phenyl)-3-(2-(pyridin-3-yl)ethyl)urea [ka] [ka] Reaction Scheme 33. Reagents and conditions: (a) HATU, DIPEA, DCM, 0 °C to room temperature (rt), overnight; (b) PdCl2(PPh3)2, CuI, TEA, ACN, 60 °C, overnight; (c) TFA, DCM, room temperature (rt), overnight.

[0352] <Step 1(a) Synthesis of tert-butyl(1-(4-ethynylbenzoyl)piperidin-4-yl)carbamate> 4-Ethynylbenzoic acid (0.5 g, 3.42 mmol, 1 eq) was dissolved in DCM (34.2 ml, 0.1 M), followed by addition of HATU (1.55 g, 4.1 mmol, 1.5 eq) and stirring at room temperature for 10 minutes. tert-Butyl piperidin-4-ylcarbamate (0.821 g, 4.1 mmol, 1.5 eq) and DIPEA (1.326 g, 10.26 mmol, 3 eq) were added to the reaction mixture and stirred overnight at room temperature. After completion of the reaction, the mixture was extracted with EA and water (HO). The organic layer was dried over MgSO, filtered, concentrated, and purified by column chromatography (silica gel, MeOH / DCM) to give the title compound (0.640 g, 57%).

[0353] Step 2(b) Synthesis of tert-butyl(1-(4-((5-(3-(2-(pyridin-3-yl)ethyl)ureido)-2-(pyridin-4-yl)phenyl)ethynyl)benzoyl)piperidin-4-yl)carbamate 1-(3-iodo-4-(pyridin-4-yl)phenyl)-3-(2-(pyridin-3-yl)ethyl)urea, 0.1 g, 0.23 mmol, 1 eq), tert-butyl(1-(4-ethynylbenzoyl)piperidin-4-yl)carbamate (enzoyl)piperidin-4-yl)carbamate (0.113 g, 0.345 mmol, 1.5 eq), PdCl2(PPh3)2 (0.005 g, 0.0069 mmol, 0.03 eq), CuI (0.0013 g, 0.0069 mmol, 0.03 eq), and TEA (0.047 g, 0.46 mmol, 2 eq) were dissolved in ACN (2.3 mL, 0.1 M) and degassed with nitrogen gas (N2 gas). The reaction mixture was heated to 60 °C and stirred overnight. After completion of the reaction, the mixture was extracted with DCM and water (HO). The organic layer was dried over MgSO4, filtered, concentrated, and purified by column chromatography (silica gel, MeOH / DCM) to give the title compound (0.075 g, 50.6%).

[0354] Step 3(c) Synthesis of 1-(3-((4-(4-aminopiperidine-1-carbonyl)phenyl)ethynyl)-4-(pyridin-4-yl)phenyl)-3-(2-(pyridin-3-yl)ethyl)urea tert-Butyl (1-(4-((5-(3-(2-(pyridin-3-yl)ethyl)ureido)-2-(pyridin-4-yl)phenyl)ethynyl)benzoyl)piperidin-4-yl)carbamate (0.068 g, 0.1 mmol, 1 eq) was dissolved in DCM (1 ml, 0.1 M), and then TFA (0.114 g, 1 mmol, 10 eq) was added and the mixture was stirred at room temperature overnight. After the reaction was completed, the mixture was concentrated and purified by reverse phase column chromatography (0.1% formic acid in H2O / ACN) to obtain the title compound (0.0337 g, 61.9%). 1 H NMR (400 MHz, DMSO) δ 8.94 (s, 1H), 8.68 (s, 2H), 8.48 (d, J = 13.5 Hz, 2H), 7.97-7.90 (m, 3H), 7.73 (d, J = 7.8 Hz, 1H), 7.68 (d, J = 5.3 Hz, 2H), 7.50-7.44 (m, 4H), 7.41-7.36 (m, 3H), 6.46 (t, J = 5.6 Hz, 1H), 4.57-4.27 (m, 1H), 3.58 (s, 2H), 3.39 (dd, J = 12.7, 6.7 Hz, 3H), 3.13 (s, 1H), 2.81 (t, J = 6.9 Hz, 2H), 2.02-1.81 (m, 2H), 1.43 (s, 2H); MS MH + 545.13

[0355] Example 40: Compound 126 (Synthesis Scheme 34) Synthesis of N-(4-((5-(3-(2-(pyridin-3-yl)ethyl)ureido)-2-(pyridin-4-yl)phenyl)ethynyl)phenyl)acetamide [ka] [ka] Scheme 34. Reagents and conditions: (a) acetic anhydride, DCM, rt, overnight; (b) PdCl2(PPh3)2, CuI, TEA, ACN, 60 °C, overnight

[0356] <Step 1(a) Synthesis of N-(4-ethynylphenyl)acetamide> 4-Ethynylaniline (0.5 g, 4.26 mmol, 1 eq) was dissolved in DCM (12.78 ml, 0.3 M), and then acetic anhydride (0.477 g, 4.68 mmol, 1.1 eq) was added and stirred at room temperature. After the reaction was complete, the mixture was extracted with DCM and water (HO). The organic layer was dried over MgSO, filtered, concentrated, and purified by column chromatography (silica gel, EA / HEX) to obtain the title compound.

[0357] <Step 2(b) Synthesis of N-(4-((5-(3-(2-(pyridin-3-yl)ethyl)ureido)-2-(pyridin-4-yl)phenyl)ethynyl)phenyl)acetamide> 1-(3-iodo-4-(pyridin-4-yl)phenyl)-3-(2-(pyridin-3-yl)ethyl)urea, 0.1 g, 0.23 mmol, 1 eq), N-(4-ethynylphenyl)acetamide etamide (0.055 g, 0.345 mmol, 1.5 eq), PdCl2(PPh3)2 (0.005 g, 0.0069 mmol, 0.03 eq), CuI (0.0013 g, 0.0069 mmol, 0.03 eq), and TEA (0.047 g, 0.46 mmol, 2 eq) were dissolved in ACN (2.3 mL, 0.1 M) and degassed with nitrogen gas (N2 gas). The reaction mixture was heated to 60 °C and stirred overnight. After completion of the reaction, the mixture was extracted with DCM and water (HO). The organic layer was dried over MgSO4, filtered, concentrated, and purified by column chromatography (silica gel, MeOH / DCM) to give the title compound (0.047 mg, 43%). 1 H NMR (400 MHz, DMSO) δ 10.12 (s, 1H), 8.81 (s, 1H), 8.66 (d, J = 6.0 Hz, 2H), 8.50-8.41 (m, 2H), 7.85 (s, 1H), 7.64 (ddd, J = 14.3, 13.3, 8.2 Hz, 5H), 7.42 (s, 2H), 7.37-7.31 (m, 3H), 6.34 (t, J = 5.6 Hz, 1H), 3.39 (dd, J = 12.8, 6.7 Hz, 2H), 2.80 (t, J = 7.0 Hz, 2H), 2.06 (s, 3H); MS MH + 476.2

[0358] Compound 60 can be synthesized by substantially the same method as in Example 40, but by changing the reactants.

[0359] Example 41: Compound 189 (Synthesis Scheme 35) Synthesis of 1-(4-(6-aminopyridin-3-yl)-3-((4-fluorophenyl)ethynyl)phenyl)-3-(2-(pyridin-3-yl)ethyl)urea [ka] [ka] Scheme 35. Reagents and conditions: (a) PdCl2(dppf)2, K2CO3, 1,4-dioxane, H2O, 90°C, 1 hour (1 h).

[0360] 1-(3-((4-fluorophenyl)ethynyl)-4-iodophenyl)-3-(2-(pyridin-3-yl)ethyl)urea (0.1 g, 0.20 mmol, 1 eq) was dissolved in 1,4-dioxane:water (HO) (3:1 (v:v), 2 ml, 0.1 M) and then (6-aminopyridin-3-yl)boronic acid was obtained. After adding PdCl(dppf) (0.029 g, 0.04 mmol, 0.2 eq), KCO (0.061 g, 0.44 mmol, 2.2 eq), the mixture was degassed with nitrogen gas (N). The reaction mixture was heated to 90 °C and stirred for 1 hour. After completion of the reaction, the mixture was filtered through a Celite filter and extracted with EA and water (HO). The organic layer was dried over MgSO, filtered, concentrated, and purified by column chromatography (silica gel, MeOH / DCM) to give the title compound (0.053 g, 58.8%). 1H NMR (400 MHz, MeOD) δ 8.47 (d, J = 1.5 Hz, 1H), 8.42-8.38 (m, 1H), 8.16 (d, J = 2.1 Hz, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.74 (dd, J = 8.6, 2.3 Hz, 1H), 7.68 (d, J = 2.2 Hz, 1H), 7.42-7.34 (m, 4H), 7.28 (d, J = 8.5 Hz, 1H), 7.08 (t, J = 8.8 Hz, 2H), 6.67 (d, J = 8.6 Hz, 1H), 3.50 (t, J = 7.0 Hz, 2H), 2.91 (t, J = 7.0 Hz, 2H); MS MH + 452.08

[0361] Example 42: Compound 138 (Synthetic Reaction Scheme 36) Synthesis of 1-(3-((4-aminophenyl)ethynyl)-4-(pyridin-4-yl)phenyl)-3-(2-(pyridin-3-yl)ethyl)urea [ka] [ka] Scheme 36. Reagents and conditions: (a) Dimethyl 1-diazo-2-oxopropylphosphate, K2CO3, methanol (MeOH), room temperature (rt), 3 hours (3 h); (b) PdCl2(PPh3)2, CuI, Et3N, ACN, 90 °C, 2 h; (c) Zn, NH4Cl, 1,4-dioxane, HO, room temperature (rt), overnight.

[0362] <Step 1(a) Synthesis of 1-ethynyl-4-nitrobenzene> 4-Nitrobenzaldehyde (0.3 g, 1.99 mmol, 1 eq) was dissolved in methanol (MeOH) (8 mL, 0.25 M), followed by the addition of dimethyl 1-diazo-2-oxopropylphosphate (0.458 g, 2.388 mmol, 1.2 eq) and K2CO3 (0.55 g, 3.98 mmol, 2 eq). The mixture was stirred at room temperature for 3 h. After the reaction was complete, the mixture was concentrated, diluted with EA (ethyl acetate), and extracted with brine and water. The organic layer was dried over MgSO4, filtered, concentrated, and purified by column chromatography (silica gel, EA / HEX) to give the title compound (0.25 g, 85%).

[0363] <Step 2(b) Synthesis of 1-(3-((4-nitrophenyl)ethynyl)-4-(pyridin-4-yl)phenyl)-3-(2-(pyridin-3-yl)ethyl)urea> 1-(3-iodo-4-(pyridin-4-yl)phenyl)-3-(2-(pyridin-3-yl)ethyl)urea (0.2 g, 0.45 mmol, 1 eq) was dissolved in acetonitrile (ACN, 4.5 ml, 0.1 M) and then 1-ethynyl-4-nitrobenzaldehyde was added. 1-ethynyl-4-nitrobenzene (0.099 g, 0.675 mmol, 1.5 eq), PdCl(PPh) (0.009 g, 0.0135 mmol, 0.03 eq), CuI (0.002 g, 0.0135 mmol, 0.03 eq), and EtN (0.091 g, 0.9 mmol, 2 eq) were added and degassed with nitrogen gas (N). The reaction mixture was heated to 90 °C and stirred for 2 h. After completion of the reaction, the mixture was filtered through Celite and extracted with EA and H2O. The organic layer was dried over MgSO4, filtered, concentrated, and purified by column chromatography (silica gel, MeOH / DCM) to give the title compound (0.109 g, 52%).

[0364] Step 3(c) Synthesis of 1-(3-((4-aminophenyl)ethynyl)-4-(pyridin-4-yl)phenyl)-3-(2-(pyridin-3-yl)ethyl)urea 1-(3-((4-nitrophenyl)ethynyl)-4-(pyridin-4-yl)phenyl)-3-(2-(pyridin-3-yl)ethyl)urea (0.020 g, 0.043 mmol, 1 eq) was dissolved in 1,4-dioxane:water (HO) (3:1 (v / v)) (2 mL, 0.02 M), Zn (0.028 g, 0.43 mmol, 10 eq) and NHCl (0.023 g, 0.43 mmol, 10 eq) were added, and the mixture was stirred overnight at room temperature. The mixture was washed with methanol and filtered under reduced pressure. The filtrate was concentrated and extracted with DCM:MeOH (9:1 (v / v)) and HO. The organic layer was dried over MgSO, filtered, concentrated, and purified by column chromatography (silica gel, MeOH / DCM) to give the title compound (0.013 g, 69%). 1 H NMR (400 MHz, MeOD) δ 8.56 (s, 2H), 8.43 (d, J = 25.2 Hz, 2H), 7.78 (d, J = 7.8 Hz, 1H), 7.70 (d, J = 4.3 Hz, 2H), 7.67 (d, J = 2.0 Hz, 1H), 7.39 (dt, J = 16.2, 5.2 Hz, 3H), 7.06 (d, J = 8.4 Hz, 2H), 6.61 (d, J = 8.4 Hz, 2H), 3.49 (t, J = 7.0 Hz, 2H), 2.90 (t, J = 7.0 Hz, 2H).

[0365] <Experimental Example 1> NAMPT enzyme inhibition assay Ability of compound to inhibit NAMPT enzyme activity (IC 50The NAMPT Inhibitor Screening Assay Kit (#7176-1) from BPS Biosciences was used to evaluate the activity of NAMPT. Recombinant NAMPT protein was added to each well of a black 96-well plate, and dilution buffer was added to blank wells instead of NAMPT protein. A 5x concentrated compound solution was added and pre-incubated at room temperature (approximately 22°C) for 30 minutes before the start of the reaction to allow the compound to bind to the protein prior to the enzymatic reaction. The NAMPT protein concentration was adjusted depending on the enzymatic activity of each protein lot, ranging from 4-10 ng / μl. Test compounds were serially diluted 1:3 from 1000 nM to 1 nM, with approximately seven concentrations tested in duplicate. A 2x 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 2 hours. The fluorescence of the resulting reaction product was measured at excitation 340 nm and emission 460 nM. NAMPT enzyme activity (%) was calculated by subtracting the measurement value of the blank well without NAMPT protein from the measurement values ​​of all wells, and then setting the measurement value of the control well without compound as 100%, and the IC 50 was calculated using GraphPad Prism 9 software and the results are shown in Table 5 below.

[0366] In Table 5 below, A, B, and C are as follows. A:NAMPT IC 50 ≦0.5μM (0.5μM or less) B: 0.5 μM <NAMPT IC 50 ≦1μM (over 0.5μM, ≦1μM) C:NAMPT IC 50 >1μM (over 1μM)

[0367] [Table 67]

[0368] [Table 68]

[0369] [Table 69]

[0370] [Table 70]

[0371] [Table 71]

[0372] [Table 72]

[0373] [Table 73]

[0374] [Table 74]

[0375] As can be seen from the above table, the compounds of the present invention exhibit excellent inhibitory activity against NAMPT, and exhibit sufficient inhibitory activity even at low concentrations. Therefore, the compounds of the present invention have excellent preventive or therapeutic effects on NAMPT-related diseases.

[0376] <Experimental Example 2> Cellular NAD measurement assay The reduction of intracellular NAD+ and NADH levels due to the inhibition of NAMPT enzyme activity by compounds was assessed in HCT-116 cells using Promega's NAD / NADH-Glo™ Assay (Promega, G9072). Cells were cultured in DMEM (Gibco, 11995-065) medium supplemented with 10% FBS. HCT-116 cells were cultured for 24 hours at a density of 2,500 cells per well in a 96-well plate and then treated with drugs using serum-free DMEM. Compounds were first dissolved in 100% DMSO (dimethyl sulfoxide) and then diluted into culture medium to a final DMSO concentration of 0.5%. The final compound concentrations ranged from 0.1 nM to 100 nM. Cells were then cultured for an additional 24 hours at 37°C and 5% CO2. To perform the NAD / NADH-Glo™ Assay, the drug-treated cell culture medium was removed, and 50 μL of DPBS was added per well and allowed to stand at room temperature for 5 minutes. The required amount of NAD / NADH-Glo™ Detection Reagent (1 mL of Reconstituted Luciferin Detection Reagent, 5 μL of Reductase, 5 μL of Reductase Substrate, 5 μL of NAD Cycling Enzyme, and 25 μL of NAD Cycling Substrate) was prepared according to the manufacturer's instructions, and 50 μL was added per well. Cells were lysed by incubating at 400 rpm for 2 minutes on a plate shaker, followed by incubation at room temperature for 30 minutes and measuring luminescence. NAD+ / NADH levels were calculated by subtracting the values ​​from blank wells without cells from the values ​​from all wells, and then using the 0.5% DMSO-treated control group as a reference group (IC). 50 was calculated using GraphPad Prism 9 software and the results are shown in Table 6 below.

[0377] In Table 6 below, A, B and C are as follows: A: NAD IC 50 ≦10nM (10nM or less) B: 10 nM <NAD IC 50 ≦1μM μM (more than 10nM, less than 1μM) C:NAD IC 50 >1μM (over 1μM)

[0378] [Table 75]

[0379] [Table 76]

[0380] As can be seen from the above table, the compounds of the present invention significantly inhibited NAD production in the HCT-116 cell line, and even at low concentrations, they sufficiently inhibited the intracellular NAD concentration. Therefore, the compounds of the present invention can inhibit NAMPT and sufficiently reduce the concentration of NAD in cells even at low concentrations, thereby having excellent preventive or therapeutic effects on diseases (e.g., cancer) that can be treated through the inhibition of NAMPT.

[0381] <Experimental Example 3> Tumor cytotoxicity assay The anticancer efficacy of compounds was evaluated using the MTT assay in two cell lines, HCT-116 (colon cancer) and NCI-N87 (gastric cancer). HCT-116 cells were cultured in DMEM (Gibco, 11995-065) supplemented with 10% FBS, and NCI-N87 cells were cultured in RPMI Medium 1640 (Gibco, 11875-093) supplemented with 10% FBS and 25 mM HEPES. HCT-116 cells were seeded into a 96-well plate at a density of 2,500 cells per well, and NCI-N87 cells at a density of 10,000 cells per well. After 24 hours of culture, the cells were treated with drugs in FBS-free medium. Compounds were first prepared in 100% DMSO (dimethyl sulfoxide) at concentrations of 0.02 μM–200 μM. Then, the compounds were diluted in culture medium to a final DMSO concentration of 0.5%. The final compound concentrations ranged from 0.1 nM–1000 nM. The cells were then cultured for an additional 72 hours at 37°C and 5% CO2. To confirm cytotoxicity, MTT (Sigma-Aldrich, M2128) was treated for 2 or 4 hours. Formazan, generated by reduction by mitochondrial enzymes in viable cells, was measured using a Spark® Multimode Microplate Reader with a TECAN instrument. Cell viability (%) was determined by subtracting the reference 650 nm absorbance (Optical density, OD) from the 570 nm absorbance (OD) and setting the 0.5% DMSO-treated control group as 100%. Results were plotted as a function of compound concentration using GraphPad Prism 9 software, and CC was calculated. 50 The (50% cytotoxic concentration) values ​​were calculated, and the results are shown in Table 7 below.

[0382] In Table 7 below, A, B and C are as follows: A:CC 50 ≦30nM (30nM or less) B: 30nM <CC 50 ≦100nM (over 30nM, ≦100nM) C:CC 50>1μM (over 1μM)

[0383] [Table 77]

[0384] [Table 78]

[0385] [Table 79]

[0386] [Table 80]

[0387] [Table 81]

[0388] As can be seen from the above table, the compounds of the present invention exhibit excellent cytotoxicity against colon cancer cell lines and gastric cancer cell lines even at low concentrations. Therefore, it is clear that the compounds of the present invention inhibit NAMPT and have excellent preventive or therapeutic effects against various diseases, such as cancer. Although the present invention has been described with reference to one embodiment thereof, those skilled in the art will understand that various modifications and variations of the present invention can be made without departing from the spirit and scope of the present invention as set forth in the claims below.

Claims

1. A urea compound represented by the following chemical formula I, an optical isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof: 【Chemistry 1】 R １ is a 6- to 12-membered aryl (e.g., C ６－１２ or a 5- to 12-membered heteroaryl containing at least one heteroatom selected from the group consisting of N, O, and S, wherein １ Each —H of the aryl or heteroaryl is independently unsubstituted, or at least one —H is independently —NH ２ , -(C １－５ alkyl)NH ２ , —NH—(C １－５ alkyl), -N(C １－５ alkyl) ２ , —OH, —NO ２ , C １－５ optionally substituted with alkyl, —F, —Cl, —Br, or —I; R ２ teeth, 【Chemistry 2】 (The Rx １ is C １－５ Alkyl; C ２－５ alkenyl; 6- to 12-membered aryl; 3- to 10-membered cycloalkyl; 3- to 10-membered heterocycloalkyl containing at least one heteroatom selected from the group consisting of N, O, and S; or 5- to 12-membered heteroaryl containing at least one heteroatom selected from the group consisting of N, O, and S; -NRx ２ Rx ３ (Rx ２ or Rx ３ are each independently H or C １－６ alkyl); 6- to 12-membered aryl; 5- to 12-membered heteroaryl containing at least one heteroatom selected from the group consisting of N, O, and S; -ORx ４ (Rx ４ is a 3- to 7-membered aryl); a 3- to 10-membered heterocycloalkyl containing at least one heteroatom selected from the group consisting of N, O, and S; a 3- to 10-membered cycloalkyl; 【Transformation 3】 (Za is a single bond, —NH or —CH ２ -, and Rx ５ is a 5- to 12-membered heteroaryl containing at least one heteroatom selected from the group consisting of N, O, and S, a 6- to 12-membered aryl, a 3- to 10-membered cycloalkyl, or a 3- to 10-membered heterocycloalkyl containing at least one heteroatom selected from the group consisting of N, O, and S, or -NYaYb {Ya or Yb are each independently H or C １－６ alkyl}); 【Chemistry 4】 (Zb is a single bond, —NH, —NHCH ２ -, -NH(CH ２ ) ２ -CH ２ -, -(CH ２ ) ２ -, -(CH ２ ) ３ - or -CH ２ NH-, and Rx ６ represents a 5- to 12-membered heteroaryl containing at least one heteroatom selected from the group consisting of N, O, and S; a 6- to 12-membered aryl; a 3- to 10-membered heterocycloalkyl containing at least one heteroatom selected from the group consisting of N, O, and S; -NYcYd {Yc or Yd are each independently -H, -C １－６ Alkyl or C ３－６ cycloalkyl} or 3- to 10-membered cycloalkyl, where b is an integer from 0 to 4); 【Transformation 5】 and Here, the R ２ Each —H in each group is independently unsubstituted, or at least one —H is independently substituted １－５ alkyl (wherein the -H of the alkyl may be unsubstituted or at least one -H may be independently substituted with one selected from the group consisting of phenyl, pyridinyl, morpholinyl, piperazine, and piperidine); -(C １－５ alkyl)NH ２ ; -NH ２ -NH(C １－５ alkyl); -N(C １－５ alkyl) ２ ;-NHCH ３ ; -N(CH ３ ) ２ ;-NHCH ２ CH ３ -OH; -NO ２ ;-F; -Cl;-Br;-I;-CHF ２ ;-CF ３ ;-C １－５ Alkoxy; -C(=O)N(CH ３ ) ２ ;-C(=O)NHCH ３ -C(=O)NH ２ ;-NHC(=O)CH ３ -C(=O)CH ２ CH ３ 6- to 12-membered aryl (wherein the -H of the aryl is unsubstituted or at least one -H is -C １－３ Alkyl and —CF ３ 5- to 12-membered heteroaryl containing at least one heteroatom selected from the group consisting of N, O, and S (wherein the —H of said heteroaryl is unsubstituted or at least one —H is replaced by —C １－３ Alkyl and —CF ３ 3- to 10-membered cycloalkyl; 3- to 10-membered heterocycloalkyl containing at least one heteroatom selected from the group consisting of N, O and S (wherein -H of said heterocycloalkyl is unsubstituted or at least one -H is replaced by -C １－３ Alkyl and —CF ３ 3- to 10-membered cycloalkoxy; -S(=O) ２ NHCH ３ -S(=O) ２ , -S(=O) ２ -CH ３ , —C(═O)NH ２ ; 【Transformation 6】 (The above Ra １ and Ra ２ are each independently H, F, Cl, Br—, I, or —C １－５ may be alkyl, and Y １ is -CH ２ , -NH, -, and -O-), 【Transformation 7】 (The above Ra ３ is -H, -C １－５ Alkyl or —CF ３ may be); 【Transformation 8】 may be substituted with one selected from the group consisting of: R ３ is a 6- to 12-membered aryl; a 5- to 12-membered heteroaryl containing at least one heteroatom selected from the group consisting of N, O, and S; a 3- to 10-membered heterocycloalkyl containing at least one heteroatom selected from the group consisting of N, O, and S; or a 3- to 10-membered cycloalkyl; Here, R ３ Each -H may be independently unsubstituted, or at least one -H may be independently substituted with one selected from the group consisting of 1) to 18) below: 1) C １－５ Alkyl; 2) —F, —Cl, —Br, or —I ３） 【Chemistry 9】 , where Rx ７ is C １－３ Alkyl or -CF3 で There may be; ４） 【Chemistry 10】 , where c is 0, 1, 2 or 3; Rx ８ is C １－５ Alkyl, —NH ２ , -NHCH ３ , -N(CH ３ ) ２ , piperidinyl, piperazinyl, morpholinyl, 【Chemistry 11】 (The above Rb １ is -NH ２ , or -CH ２ OH), 【Chemistry 12】 (The above Rb ２ is -CH ２ -, -NH- or -O-; Rb ３ and Rb ４ each independently may be —H, —F, —Cl, —Br, or —I), pyridinyl, pyrimidinyl, or pyrrolyl; Rx ９ is -H or C １－５ may be alkyl; 5) -COOH; 6) -NRx １０ Rx １１ , where Rx １０ or Rx １１ are each independently —H or —CH ３ may be; 7)-CF ３ ; 8)-CN; 9) morpholinyl or one or more —H are each independently selected from C １－５ Alkyl, —F, —Cl, —Br, I, —C(═O)NHCH ３ , —C(═O)CH ３ or -C(=O)CH=CH ２ morpholidinyl substituted with; 10) piperidinyl or one or more —H are each independently C １－５ Alkyl, —F, —Cl, —Br, I, —C(═O)NHCH ３ , —C(═O)CH ３ or -C(=O)CH=CH ２ piperidinyl substituted with; 11) piperazinyl or one or more -H are each independently C １－５ Alkyl, —F, —Cl, —Br, I, —C(═O)NHCH ３ , —C(═O)CH ３ or -C(=O)CH=CH ２ piperazinyl substituted with; 12) -ORx １２ , where R １２ is Rx １２ is -CF ３ ; C １－３ may be alkyl; 13) —OH; １４） 【Chemistry 13】 , where d can be 0, 1, 2 or 3; Rx １３ is -NH ２ , -NH(CH ３ ), -N(CH ３ ) ２ It may be pyrazolyl, methylpyrazolyl, pyrazolyl, piperazinyl, piperidinyl, or morpholinyl; １５） 【Chemistry 14】 , where Rx １４ is -CH ２ -, -NH or -O-, and Rx １５ is -H, C １－５ Alkyl, —NH ２ , —F, —Cl, —Br, or —I; １６） 【Chemistry 15】 , where Rx １６ is C １－５ Alkyl or -CH ２ CH ２ N (CH ３ ) ２ may be １７） 【Chemistry 16】 ;or 18)-(C １－３ alkyl)-NH ２ and Ak is -(CH ２ ) n-, or 【Chemistry 17】 wherein the -(CH ２ ) n- or [Chemistry 18] each —H is independently unsubstituted, or at least one —H is independently substituted ２ , —OH, —NO ２ , -C １－５ Alkyl, —CH ２ NH ２ , -CF ３ , OCF ３ , —CN, —F, —Cl, —Br, or —I, where n is 1, 2, or 3; and X １ ~X ３ are each independently —CH— or —N—.

2. The R ３ is a 3- to 8-membered aryl; 2. The urea compound according to claim 1, an optical isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

3. The R １ teeth, 【Chemistry 19】 wherein Z １ ~Z ２２ are each independently —CH—, —CH ２ , —N—, —NH, —O—, or —S—, wherein R １ each —H is independently unsubstituted, or at least one —H is independently —NH ２ , -(C １－５ alkyl)NH ２ , —NH—(C １－５ alkyl), -N(C １－５ alkyl) ２ -OH, -NO ２ , C １－５ 3. The urea compound according to claim 1 or 2, which is optionally substituted with alkyl, -F, -Cl, -Br, or -I, an optical isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

4. The R １ teeth, 【Chemistry 20】 wherein R １ each —H is independently unsubstituted, or at least one —H is independently —NH ２ , -(C １－５ alkyl)NH ２ , —NH—(C １－５ alkyl), -N(C １－５ alkyl) ２ , —OH, —NO ２ , C １－５ The urea compound according to claim 3, an optical isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, which is optionally substituted with alkyl, -F, -Cl, -Br, or -I.

5. The R ２ teeth, 【Chemistry 21】 and Here, Rx １ is -C １－５ Alkyl; -C ２－５ alkenyl; 6- to 12-membered aryl; 3- to 10-membered cycloalkyl; 3- to 10-membered heterocycloalkyl containing at least one heteroatom selected from the group consisting of N, O, and S; or 5- to 12-membered heteroaryl containing at least one heteroatom selected from the group consisting of N, O, and S; Here, the 【Chemistry 22】 is unsubstituted, or at least one —H is independently —C １－５ alkyl (wherein -H of said alkyl is unsubstituted or at least one -H may each independently be substituted with one selected from the group consisting of phenyl, pyridinyl, morpholinyl, piperazine, and piperidine), -morpholinyl, piperazinyl, piperidinyl, phenyl (wherein -H of said -morpholinyl, -piperazinyl, -piperidinyl, and -phenyl is unsubstituted or at least one -H may each independently be substituted with one selected from the group consisting of -C １－３ Alkyl and —CF ３ may be substituted with one selected from the group consisting of —NH ２ 2. The urea compound according to claim 1, its optical isomer, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, wherein a is optionally substituted with -F, -Cl, -Br, or -I, and a is 0, 1, 2, 3, or 4.

6. The R ２ is a 6- to 12-membered aryl; The —H of the aryl is unsubstituted or at least one —H is independently C １－５ alkyl (wherein —H of the alkyl is unsubstituted or at least one —H may each independently be substituted with one selected from the group consisting of phenyl, pyridinyl, morpholinyl, piperazine, and piperidine), F, —Cl, —Br, —I, -morpholinyl, -piperazinyl, and -piperidinyl (wherein —H of the -morpholinyl, -piperazinyl, and -piperidinyl is unsubstituted or at least one —H may each independently be substituted with one selected from the group consisting of —C １－３ Alkyl and —CF ３ -cyclobutoxy, -cyclopropoxy, -cyclopentoxy, 【Chemistry 23】 (The above Ra １ and Ra ２ are each independently —H, —F, —Cl, —Br—, —I, or —C １－５ may be alkyl, and Y １ is -CH ２ , -NH, -, and -O-), 【Chemistry 24】 , -C １－３ Alkoxy, —C(═O)—N(CH ３ ) ２ and —C(═O)NH ２ The urea compound according to claim 1, its optical isomer, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, which may be substituted with one selected from the group consisting of:

7. The R ２ is -NRx ２ Rx ３ and Rx ２ or Rx ３ are each independently —H or a straight or branched chain C １－６ and Rx may be an alkyl group represented by the formula: ２ or Rx ３ is alkyl, ２ and Rx ３ -H in the formula (I) is unsubstituted or at least one -H is independently selected from the group consisting of C １－６ The urea compound according to claim 1, an optical isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, which is optionally substituted with alkyl, -F, -Cl, -Br, or -I.

8. The R ２ is -ORx ４ and Here, Rx ４ may be a 6- to 7-membered aryl; wherein -H of said -ORx is not substituted, or at least one -H is independently -C １－５ Alkyl, -F, -Cl, -Br, -I, -NH ２ , —NH(C １－５ alkyl), -N(C １－５ alkyl) ２ , -NHCH ３ , -N(CH ３ ) ２ , -NHCH ２ CH ３ , —C(═O)NH ２ , -C(=O)N(CH ３ ) ２ and -C(=O)NH(CH ３ 2. The urea compound according to claim 1, its optical isomer, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, wherein the urea compound is optionally substituted with one selected from the group consisting of:

9. The R ２ is a 5- to 12-membered heteroaryl containing at least one heteroatom selected from the group consisting of N, O, and S; The —H of the heteroaryl is unsubstituted, or at least one —H is independently —C １－５ Alkyl, -F, -Cl, -Br, -I, -NH ２ , —NH(C １－５ alkyl), -N(C １－５ alkyl) ２ , -NHCH ３ , -N(CH ３ ) ２ , -NHCH ２ CH ３ , —C(═O)NH ２ , -C(=O)N(CH ３ ) ２ , and —C(═O)NH(CH ３ 2. The urea compound according to claim 1, its optical isomer, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, wherein the urea compound is optionally substituted with one selected from the group consisting of:

10. R ２ is a 3- to 10-membered heterocycloalkyl containing at least one heteroatom selected from the group consisting of N, O, and S; wherein the —H of the heterocycloalkyl is unsubstituted, or at least one —H is independently —C １－５ alkyl (wherein -H of said alkyl is unsubstituted or at least one -H is each independently substituted with one selected from the group consisting of phenyl, pyridinyl, morpholinyl, piperazine, and piperidine), pyridinyl, phenyl (wherein -H of said pyridinyl and phenyl is unsubstituted or at least one -H is each independently substituted with one selected from the group consisting of C １－３ Alkyl and —CF ３ may be substituted with one selected from the group consisting of 【Chemistry 25】 、-NHCC(=O)CH ３ 、-C(=O)CH ２ CH ３ 、 【Chemistry 26】 (The above Ra ３ is H, -C １－３ Alkyl or —CF ３ may be), —OH, —S(═O) ２ CH ３ , -NH ２ , —NH(C １－５ alkyl), -N(C １－５ alkyl) ２ , -NHCH ３ , -N(CH ３ ) ２ , and -NHCH ２ CH ３ The urea compound according to claim 1, its optical isomer, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, which may be substituted with one selected from the group consisting of:

11. The R ２ teeth, 【Chemistry 27】 and Here, Za is a single bond, —NH or —CH ２ - may be, Rx ５ is a 5- to 12-membered heteroaryl containing at least one heteroatom selected from the group consisting of N, O, and S; a 6- to 10-membered aryl (e.g., C ６－１２ aryl), 3- to 10-membered cycloalkyl, or 5- to 12-membered heterocycloalkyl containing at least one heteroatom selected from the group consisting of N, O, and S; -NYaYb (Ya and Yb are each independently H or C); １－６ alkyl), Here, the 【Chemistry 28】 -H in the formula (I) is unsubstituted or at least one -H is independently selected from the group consisting of C １－５ alkyl (wherein the —H of the alkyl may be unsubstituted or at least one —H may be independently substituted with one selected from the group consisting of phenyl, pyridinyl, morpholinyl, piperazine, and piperidine); —CF ３ , 【Chemistry 29】 , pyridinyl, pyrimidinyl, piperidinyl, piperazinyl, morpholinyl (wherein -H of said pyridinyl, pyrimidinyl, piperidinyl, piperazinyl, and morpholinyl is not substituted or at least one -H is replaced by -C １－３ Alkyl and —CF ３ may be substituted with one selected from the group consisting of 【Transformation 30】 , -NH ２ 2. The urea compound according to claim 1, an optical isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, which may be substituted with -F, -Cl, -Br, or -I.

12. The R ２ teeth, 【Chemistry 31】 and Here, Zb is a single bond, —NH, or —NHCH ２ -, -NH(CH ２ ) ２ -CH ２ -, -(CH ２ ) ２ -, -(CH ２ ) ３ -, -CH ２ may be NH—, Rx ６ represents a 5- to 12-membered heteroaryl containing at least one heteroatom selected from the group consisting of N, O, and S; a 6- to 10-membered aryl; a 3- to 10-membered heterocycloalkyl containing at least one heteroatom selected from the group consisting of N, O, and S; -NYcYd (Yc and Yd are each independently -H, -C １－６ alkyl or C ３－６ cycloalkyl), or 3- to 10-membered cycloalkyl; b is an integer from 0 to 4; Here, the 【Chemistry 32】 is unsubstituted, or at least one —H is independently —C １－５ alkyl (wherein the —H of the alkyl may be unsubstituted or at least one —H may be independently substituted with one selected from the group consisting of phenyl, pyridinyl, morpholinyl, piperazine, and piperidine); —CF ３ , 【Transformation 33】 , pyridinyl, pyrimidinyl, piperidinyl, piperazinyl, -morpholinyl (wherein -H in said pyridinyl, pyrimidinyl, piperidinyl, piperazinyl, and morpholinyl is unsubstituted, or at least one or more -H is each independently -C １－３ Alkyl and —CF ３ may be substituted with one selected from the group consisting of 【Transformation 34】 , -NH ２ 2. The urea compound according to claim 1, an optical isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, which may be substituted with -F, -Cl, -Br, or -I.

13. The R ２ teeth, 【Chemistry 35】 and Here, the R ２ is unsubstituted, or at least one —H is independently selected from C １－５ Alkyl, —NH ２ , -NHCH ２ CH ３ , -(C １－５ alkyl)NH ２ 2. The urea compound according to claim 1, its optical isomer, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, wherein the urea compound is optionally substituted by one selected from the group consisting of -F, -Cl, -Br, and -I.

14. A urea compound represented by the following chemical formula I-1, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof: 【Transformation 36】 R １ is pyridinyl; pyrimidinyl; pyrazolyl; imidazolyl; pyrrolyl; furanyl; phenyl; phenolic; 【Chemistry 37】 wherein R １ is unsubstituted or at least one —H is independently —NH ２ , -(C １－３ alkyl)NH ２ , —NH(C １－３ alkyl), -N(C １－３ alkyl) ２ , —OH, —NO ２ , C １－５ optionally substituted with alkyl, —F, —Cl, —Br, or —I; R ２ is pyridinyl; pyrimidinyl; phenyl; piperidinyl; piperazinyl; morpholinyl; pyrazolyl, imidazolyl, phenolic, phenyl; ２ C(=O)NH ２ -C(=O)NH ２ ;-C(=O)NHCH ２ CH ３ ;-CH ２ NHC(=O)CH ２ CH ３ ; -NH ２ ;-NHCH ３ , -NHCH ２ CH ２ CH ３ , 【Transformation 38】 【Chemistry 39】 【Chemistry 40】 wherein R ２ each —H is independently unsubstituted, or at least one —H is independently —NH ２ , —NH(C １－５ alkyl), -N(C １－５ alkyl) ２ , -NHCH ３ , -N(CH ３ ) ２ , -NHCH ２ CH ３ , —OH, —NO ２ , -S(=O) ２ CH ３ , C １－５ alkyl (wherein -H of said alkyl is unsubstituted or at least one -H may each independently be substituted with one selected from the group consisting of phenyl, pyridinyl, morpholinyl, piperazine, and piperidine), -morpholidinyl, -piperidinyl, -piperazinyl, phenyl, -pyridinyl, -pyrimidinyl (wherein -H of said -morpholidinyl, -piperidinyl, piperazinyl, phenyl, -pyridinyl, and -pyrimidinyl is unsubstituted or at least one -H may each independently be substituted with one selected from the group consisting of -C １－３ Alkyl and —CF ３ -cyclohexyl, -cyclobutoxy, -cyclopropoxy, -cyclopentoxy, -F, -Cl, -Br, -I, -CHF ２ , -CF ３ , -C １－３ Alkoxy, —NHC(═O)CH ３ , —C(═O)CH ２ CH ３ , -C(=O)N(CH ３ ) ２ , -C(=O)NH(CH ３ ), -C(=O)NH ２ , -S(=O) ２ NHCH ３ -S(=O) ２ , -S(=O) ２ CH ３ , -trifluoromethylphenyl, 【Chemistry 41】 (The above Ra １ and Ra ２ are each independently H, F, Cl, Br—, I, or —C １－５ may be alkyl, and Y １ is -CH ２ , -NH, -, and -O-), 【Chemistry 42】 (The above Ra ３ is -H, -C １－５ Alkyl or —CF ３ may be), 【Chemistry 43】 may be substituted with R ３ is phenyl, wherein said R ３ -H in the formula (I) may be unsubstituted, or at least one -H may be independently substituted with one group selected from the group consisting of 1) to 18) below: 1) C １－５ Alkyl; 2) —F, —Cl, —Br, or —I ３） 【Chemistry 44】 , where Rx ７ is -CF ３ may be; ４） 【Chemistry 45】 where c is 0 (in this case, Rx ８ is directly bonded to -N), then Rx ８ is C １－５ Rx may be alkyl or piperidine; ９ is -H, C １－５ may be alkyl; If c is 1, then Rx ８ teeth, 【Chemistry 46】 (The above Rb １ is -NH ２ , or -CH ２ OH), and Rx ９ is -H or C １－５ may be alkyl; If c is 2, then Rx ８ is C １－５ Alkyl, —NH ２ , -NHCH ３ , -N(CH ３ ) ２ , piperidinyl, difluoropiperidinyl, piperazinyl, morpholinyl, 【Chemistry 47】 (The above Rb １ is -NH ２ , or -CH ２ OH), pyridinyl, pyrrolyl, and Rx ９ is -H or C １－５ may be alkyl; 5) -COOH; 6) -NRx １０ Rx １１ , where Rx １０ and Rx １１ are each independently —H or —CH ３ may be; 7)-CF ３ ; 8)-CN; 9) morpholidinyl or one or more —H are each independently C １－５ Alkyl, -F, -Cl, -Br, -I, -C(=O)NHCH ３ , —C(═O)CH ３ or -C(=O)CH=CH ２ morpholidinyl substituted with; 10) piperidinyl or one or more —H are each independently C １－５ Alkyl, -F, -Cl, -Br, -I, -C(=O)NHCH ３ , —C(═O)CH ３ or -C(=O)CH=CH ２ piperidinyl substituted with; 11) piperazinyl or one or more -H are each independently C １－５ Alkyl, —F, —Cl, —Br, I, —C(═O)NHCH ３ , —C(═O)CH ３ or -C(=O)CH=CH ２ piperazinyl substituted with; 12) -ORx １２ , where R １２ is Rx １２ is -CF ３ ; C １－３ may be alkyl; 13) —OH; １４） 【Chemistry 48】 、 where d can be 1, 2, or 3, and Rx １３ is -NH ２ , -NH(CH ３ ), -N(CH ３ ) ２ It may be pyrazolyl, methylpyrazolyl, pyrazolyl, piperazinyl, piperidinyl, or morpholinyl; １５） 【Chemistry 49】 , where Rx １４ is -CH ２ -, NH- or -O-; Rx １５ is -H, C １－５ Alkyl, —NH ２ , —F, —Cl, —Br, or I; １６） [Transformation 50] , where Rx １６ is C １－５ Alkyl or -CH ２ CH ２ N (CH ３ ) ２ may be; １７） 【Chemistry 51】 ;or 18) Ethylamine, Ak is -CH ２ -, -(CH ２ ) ２ -, -(CH ２ ) ３ -or 【Chemistry 52】 and -CH ２ -, -(CH ２ ) ２ -, -(CH ２ ) ３ -or 【Chemistry 53】 each —H is independently unsubstituted, or at least one —H is independently —NH ２ , —OH, —NO ２ , C １－５ Alkyl, —CH ２ NH ２ , -CF ３ , OCF ３ , -CN, -F, -Cl, -Br, or -I, an optical isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

15. A urea compound represented by the following chemical formula I-1, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof: 【Chemistry 54】 In the formula I-1, R １ is a functional group in Table 1, and R １ In the formula, -H is unsubstituted or at least one H is independently -NH ２ , —OH, —NO ２ , -CH ２ NH ２ , -CF ３ , -OCF ３ , -CN, -C １－５ optionally substituted with alkyl, —F, —Cl, —Br, or —I; R ２ is a functional group in Table 2, and R ２ In the formula, -H is unsubstituted or at least one H is independently -NH ２ , -OH, NO ２ , -C １－５ Alkyl, —CH ２ NH ２ , -CF ３ , -OCF ３ , —CN, —F, —Cl, —Br, or —I; R ３ is a functional group in Table 3, and the R ３ In the formula, -H is unsubstituted or at least one H is independently -NH ２ , -NHCH ３ , —OH, —NO ２ , -C １－３ Alkyl, —CH ２ NH ２ , -CF ３ , -OCF ３ , —CN, —F, —Cl, —Br, or —NH ２ , —OH, —NO ２ , -C １－５ Alkyl, —CH ２ NH ２ , -CF ３ , -OCF ３ , —CN, —F, —Cl, —Br, or —II; Table 1 Table 2 Table 3 Table 4 Table 5 Table 6 Table 7 Table 8 Table 9 Table 10 Ak is -CH ２ -, -(CH ２ ) ２ -, -(CH ２ ) ３ -or 【Transformation 55】 may be -CH ２ -, -(CH ２ ) ２ -, -(CH ２ ) ３ -or 【Transformation 56】 each —H is independently unsubstituted, or at least one —H is independently —NH ２ , —OH, —NO ２ , C １－５ Alkyl, —CH ２ NH ２ , -CF ３ , OCF ３ , —CN, —F, —Cl, —Br, or —I.

16. A urea compound represented by the following chemical formula I-2, an optical isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof: 【Chemistry 57】 In the above chemical formula I-2, R １ , R ２ and Ak is as defined in claim 14, Za and Zb are each independently —H or one selected from the group consisting of the following 1) to 18): a urea compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof: 1) C １－５ Alkyl; 2) —F, —Cl, —Br, or —I ３） 【Chemistry 58】 , where Rx ７ is C １－５ Alkyl or —CF ３ may be; ４） 【Chemistry 59】 , where c is 0, 1, 2 or 3; Rx ８ is C １－５ Alkyl, —NH ２ , -NHCH ３ , -N(CH ３ ) ２ , piperidinyl, piperazinyl, morpholinyl, 【Transformation 60】 (The above Rb １ is -NH ２ , or -CH ２ OH), 【Chemistry 61】 (The above Rb ２ is -CH ２ -, -NH- or -O-; Rb ３ and Rb ４ each independently may be —H, —F, —Cl, —Br, or —I), pyrimidinyl, or pyrrolyl; ９ is -H or C １－５ may be alkyl; 5) -COOH; 6) -NRx １０ Rx １１ , where Rx １０ or Rx １１ are each independently —H or —CH ３ may be; 7)-CF ３ ; 8)-CN; 9) morpholinyl or one or more —H are each independently selected from C １－５ Alkyl, —F, —Cl, —Br, I, —C(═O)NHCH ３ , —C(═O)CH ３ or -C(=O)CH=CH ２ morpholidinyl substituted with; 10) piperidinyl or one or more —H are each independently C １－５ Alkyl, —F, —Cl, —Br, I, —C(═O)NHCH ３ , —C(═O)CH ３ or -C(=O)CH=CH ２ piperidinyl substituted with; 11) piperazinyl or one or more -H are each independently C １－５ Alkyl, —F, —Cl, —Br, I, —C(═O)NHCH ３ , —C(═O)CH ３ or -C(=O)CH=CH ２ piperazinyl substituted with; 12) -ORx １２ , where R １２ is Rx １２ is -CF ３ ; C １－３ may be alkyl; 13) —OH; １４） 【Transformation 62】 , where d can be 0, 1, 2 or 3; Rx １３ is -NH ２ , -NH(CH ３ ), -N(CH ３ ) ２ It may be pyrazolyl, methylpyrazolyl, pyrazolyl, piperazinyl, piperidinyl, or morpholinyl; １５） 【Transformation 63】 , where Rx １４ is -CH ２ -, NH or -O-, and Rx １５ is -H, straight or branched chain C １－５ Alkyl, —NH ２ , —F, —Cl, —Br, or —I; １６） 【Chemistry 64】 , where Rx １６ is C １－５ Alkyl or -CH ２ CH ２ N (CH ３ ) ２ may be １７） 【Transformation 65】 ;or 18)-(C １－３ alkyl)-NH ２ .

17. The following compounds 1 to 189, their optical isomers, their pharmaceutically acceptable salts, or their hydrates or solvates: Table 11 Table 12 Table 13 Table 14 Table 15 Table 16 Table 17 Table 18 Table 19 Table 20 Table 21 Table 22 Table 23 Table 24 Table 25 Table 26 Table 27 Table 28 Table 29 Table 30 Table 31 Table 32 Table 33 Table 34 Table 35 Table 36 Table 37 Table 38 Table 39 Table 40 Table 41 Table 42 Table 43 Table 44 Table 45 Table 46 Table 47 Table 48 Table 49 Table 50 Table 51 Table 52 Table 53 Table 54 Table 55 Table 56 Table 57 。

18. A urea compound represented by the following chemical formula I-2, an optical isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof: 【Chemical Formula 66】 In the above chemical formula I-2, R １ teeth, Pyridinyl; Pyrimidinyl; Imidazolyl; Pyrazolyl; Phenyl; 【Transformation 67】 where R １ each —H is independently unsubstituted, or at least one —H is independently morpholinyl, piperidinyl, piperazinyl, —NH ２ , -(C １－３ alkyl)NH ２ , —NH—(C １－３ alkyl), -N(C １－３ alkyl) ２ , —OH, —NO ２ , C １－５ optionally substituted with alkyl, —F, —Cl, —Br, or —I; R ２ is pyridinyl; pyrimidinyl; phenyl; piperazinyl; piperidinyl; 【Transformation 68】 wherein p1, p2, p3, or p4 is each independently an integer of 0 to 3, and wherein R ２ each —H is independently unsubstituted, or at least one —H is independently morpholinyl, piperidinyl, piperazinyl, —NH ２ , -(C １－３ alkyl)NH ２ , —NH—(C １－３ alkyl), -N(C １－３ alkyl) ２ , —OH, —NO ２ , -C １－５ optionally substituted with alkyl, —F, —Cl, —Br, or —I; Za and Zb each independently represent —H, morpholinyl, piperidinyl, piperazinyl, —NHC(═O)(C １－３ alkyl), -NH ２ , -(C １－３ alkyl)NH ２ , —NH(C １－３ alkyl), -N(C １－３ alkyl) ２ , —OH, —NO ２ , -C １－５ Alkyl, -F, -Cl, -Br, -I, 【Transformation 69】 wherein q1 or q2 may each independently represent an integer of 0 to 3, and wherein each of Za or Zb is independently unsubstituted, or at least one of -H is independently -C １－５ Alkyl, —NH ２ , -(C １－３ alkyl)NH ２ , —NH—(C １－３ alkyl), or —N(C １－３ alkyl) ２ may be substituted with The Ak-(CH ２ ) n-, where n can be 1, 2, or 3.

19. A pharmaceutical composition comprising the urea compound according to any one of claims 1 to 18, an optical isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

20. 20. The pharmaceutical composition of claim 19, wherein the pharmaceutical composition exhibits NAMPT inhibitory activity.

21. The pharmaceutical composition of claim 19, wherein the pharmaceutical composition is for preventing or treating cancer.

22. 20. The pharmaceutical composition of claim 19, wherein the cancer is a solid cancer or a blood cancer.

23. 20. The pharmaceutical composition of claim 19, wherein the cancer is selected from the group consisting of skin cancer, melanoma, lymph node cancer, breast cancer, cervical cancer, uterine cancer, gastrointestinal tract 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, larynx cancer, nasal cavity cancer, AIDS-related cancer, esophageal cancer, gastrointestinal cancer, stomach cancer, colorectal cancer, virus-related cancer, nasopharyngeal cancer, vaginal cancer, vulva cancer, penile cancer, Kaposi's sarcoma, Burkitt's lymphoma, T-cell lymphoma, and Merkel cell carcinoma, multiple myeloma, acute and chronic leukemia, lymphoblastic leukemia, myeloid leukemia, lymphocytic leukemia, and myelocytic leukemia.

24. A method for preventing or treating cancer, comprising administering to an individual the urea compound according to any one of claims 1 to 18, an optical isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

25. Use of the urea compound according to any one of claims 1 to 18, an optical isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof for preventing or treating cancer.

26. Use of the urea compound according to any one of claims 1 to 18, an optical isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof for use in the manufacture of a medicament for preventing or treating cancer.

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