Antibody-drug conjugate comprising benzamide derivative compound

Abstract

The present invention relates to an immunoconjugate comprising a cytotoxic drug having NAMPT inhibitory activity and, specifically, to a drug-linker conjugate comprising a cytotoxic drug having NAMPT inhibitory activity and a linker, an immunoconjugate comprising the drug-linker conjugate and an antibody or antigen-binding fragment thereof, and a composition for preventing or treating cancer, the composition comprising the immunoconjugate or a pharmaceutically acceptable salt thereof. The immunoconjugate according to the present invention exhibits an excellent anticancer effect compared to a cytotoxic drug alone and has almost no side effects, and thus can be very advantageously used to prevent or treat cancer.

Description

[0001]

Description of the Invention

[0002]

Title of Invention

[0003]

Technical Field

[0004]

Background Techniques

[0005] NAMPT (Nicotinamide phosphor ibosyl transferase) is nicotinamide

[0006] As an enzyme that induces the synthesis of nicotinamide mononucleotide (NMN) from nicotinamide (NAM) and 5'-phosphoribosyl-1'-pyrophosphate (PRPP), it plays a crucial role in the cyclic biosynthetic pathway of NAD+ (nicotinamide adenine dinucleotide). Among other polyADP-ribosylations in DNA repair, NAD is essential for several signaling pathways, including mono-ADP-ribosylation in both the immune system and G-protein-coupled receptor signaling, and is also essential for the diacetylase activity of sirtuins. NAD+ is generated by two distinct biosynthetic pathways: the recovery and neogenesis pathways. As a rate-limiting enzyme in the NAD+ recovery pathway, NAMPT is biologically indispensable and may be associated with a number of diverse diseases. In particular, cancer cells must continuously resynthesize NAD+ to avoid NAD+ depletion and subsequent apoptosis. Increased expression of NAMPT has been reported in various cancers, including colorectal, breast, and ovarian cancers (Garten, A. et al., Nat. Rev. Endocrinol. 2015, 11: 535-546; Sampath, D. et al., Pharmacol. Ther. 2015, 151: 16-31). However, various NAMPT inhibitors have shown disappointing results in clinical trials due to dose-limiting toxicities such as thrombocytopenia, retinal toxicity, and cardiotoxicity (Ghanem, MS et al., Nutrients, 2021, 13: 1665).

[0007] Antibody-drug conjugates (ADCs) are immunoconjugates formed by combining a drug and an antibody via a linker. Because they move to a target site via the antibody to release the drug, they are attracting attention as a new class of drugs due to their targeted nature and fewer side effects compared to using the drug alone. The inventors developed a payload possessing novel NAMPT inhibitory activity and completed the present invention by confirming that it exhibits excellent anticancer effects when applied to an ADC. Prior Art Literature Patent Literature Korean Patent Application Publication No. 10-2015-0014250 Non-Patent Literature

[0008] Garten, A. et al. , Nat. Rev. Endocrinol. 2015, 11:535-546

[0009] Sampath, D. et al. , Pharmacol. Ther. 2015, 151:16-31 Ghanem, M. S. et al. , Nutr ients , 2021 , 13 : 1665

[0010]

Description of the Invention

[0011]

Technical Problem

Technical Solution

[0012] [Chemical Formula I]

[0013] Ab-(L-D) p In the above formula, D is a cytotoxic drug moiety;

[0014] L is a linker moiety connecting Ab and D;

[0015] Ab is an antibody or an antigen-binding fragment thereof; and D is an integer from 1 to 10. Another aspect of the present invention is a drug-linker conjugate represented by the following Chemical Formula II or a pharmaceutically acceptable salt thereof.

[0016] [Chemical Formula II]

[0017] L-D In the above formula, D is a cytotoxic drug moiety;

[0018] L is a linker moiety connected to [the element]. In the present invention, the term "immunoconjugate" refers to a complex in which a cytotoxic drug-linker conjugate is connected to an antibody or its antigen-binding fragment. In the present invention, the term "drug-linker conjugate" refers to a material for the preparation of an immunoconjugate in which an antibody or its antigen-binding fragment is not connected, and may be combined with any antibody or its antigen-binding fragment to be used as an immunoconjugate depending on the purpose. When the immunoconjugate is administered in vivo, the antibody or its antigen-binding fragment, which is one of its components, binds to a target antigen and then releases the drug, thereby allowing the drug to act on target cells and / or surrounding cells, so that excellent efficacy and reduced side effects can be expected as a targeted drug. A person skilled in the art may appropriately adjust the Drug-Antibody Ratio (DAR) of the immunoconjugate according to the form of the linker or the ratio of the antibody to the linker (or drug-linker conjugate) when preparing the immunoconjugate, and in the immunoconjugate of the present invention, the DAR may be 1 to 10. In one embodiment, in the immunoconjugate of the present invention, DAR may be 2 to 10, for example, 2 to 4, 4 to 6, 6 to 8, and specifically 2, 4, 6, 8, or 10, but is not limited thereto. The immunoconjugate of the present invention comprises an antibody or its antigen-binding fragment, a cytotoxic drug moiety according to any one of (1) to (5) described below, and one or more of (6) to (12) described below as a linker moiety. Additionally, the immunoconjugate of the present invention may have a drug-linker conjugate represented by any one of (13) to (21) described below connected to the antibody or its antigen-binding fragment. Those skilled in the art will readily recognize that the structure of each moiety may be partially modified as a result of the reaction during the conjugation process, and such modified structures also fall within the scope of the present invention.Hereinafter, the composition of each of the immunoconjugate and drug-linker conjugate of the present invention will be described in detail. Cytotoxic drug moiety The present invention provides a compound according to any one of (1) to (5) below, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof as a cytotoxic drug moiety.

[0019] (1) Benzoamide derivative compounds represented by the following chemical formula III, stereoisomers thereof, pharmaceutically acceptable salts thereof or hydrates thereof or solvates thereof:

[0020] [Chemical Formula III] I or one or more of the above are each independently a halogen, - NH2, - NO2, - NHCHs, - N(CH3)2 or -

[0021] It can be substituted with 0H;

[0022] Li is methylene (-CH『), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), isopropylene (-CH(CH3)CH『), n-butylene (-CH2CH2CH2CH2-), sec-butylene (-CH(CH3)CH2CH2-), isobutylene (-CH2CH(CH3)CH2-), tert-butylene (-C(CH3)2CH『), n-pentylene (-CH2CH2CH2CH2CH2-), or n~hexylene (-CH2CH2CH2CH2CH2CH2-);

[0023] V stands for unity, One or more of the groups may each be independently substituted with -C1-C6 alkyl, -halogen, -OH, -NO2, -C1-C6 alkoxy, or -CF3; the group 2 is a single bond, -(CH2)-, -(CH2)『, -(CH2)『, -(CH2)4-, -(CH2)5-, -(C=0)-NH(CH2) n-, -NH(C=O)-(CH2)n-, or -(C=O)-, where n is 0, 1, 2, 3, or 4; 平.--•、、 nr 斗 i j

[0024] '、.、,NH

[0025] R2 is -H, -OH, -halogen, -C1-C6 alkyl, -C1-C6 alkoxy, -NH2, H where the -C1-C6 alkyl, -C1-C6 alkoxy,, or are unsubstituted or each independently may be substituted with -halogen, -C1-C6 alkoxy,, -

[0026] NH2 or -C1-C6 alkyl; 匕3 is a single bond, -(CH2)-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, _ NH“, -NHCH『, -

[0027] NH(CH2)2 - or -NH(CH2)『, where the interior of L3 is unsubstituted or at least one interior of L3 may each independently be substituted with -C1-C6 alkyl; where the interior of R3 is unsubstituted or at least one interior of R3 may each independently be substituted with -C1-C6 alkyl, -C1-C6 alkoxy, -NH2, -CFs, -OCFs or halogen.

[0028] (2) In the above (1), the formula III may be a compound represented by the following formula III-1.

[0029] Li is methylene (-CH『), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), isopropylene (-

[0030] CH(CH3)CH2-), n-butylene (-CH2CH2CH2CH2-), n-pentylene (-CH2CH2CH2CH2CH2-), or n-hexylene (-CH2CH2CH2CH2CH2CH2—);

[0031] A-, r>s are, zs, and in this case, the -H of the above five is unsubstituted or one or more -H are each independently substituted with halogen;

[0032] L2 is a single bond; R2 is -H, -halogen or -NH2;

[0033] L3 is - (CH2)-, - (CH2)2-, - (CH2)3, - (CH2)4 - or - (CH2)5 -; At this time, at least one of the above R3s may be each independently substituted with -Cl-C6 alkyl.

[0034] (4) In any one of the above (1) to (3), the compound represented by the above formula III may be the following Compound 1 to Compound 43.

[0035] (5) In any one of the above (1) to (4), the compound may be a compound represented by the following formulas IV-1 to IV-5.

[0036] [Formula IV-1]

[0037] N-(3-(1H-pyrazol-4-yl)propyl )-3-((4-fluorophenyl)ethynyl )-4-(((1-methyl-1H-pyrazol-3-yl)methyl )sulfonyl )benzamide (su ( 3— ( IH-pyrazol 1 — 4— y 1 )propy 1 ) —3—((4— fluorophenyl )ethynyl ) —4—( ((1— methyl— 1H— pyrazol— 3— yl)methyl)sulfonyl)benzamide)

[0038] N- (3- (1H-pyrazol-4-yl)propyl)- 3- ((4-fluorophenyl)ethynyl)- 4- (((1-(pyridin-4-yl)- 1H-pyrazol-3-yl)methyl)sulfonyl) benzamide (N-(3-(1H-pyrazol-4-yl)propyl)-3-((4-fluorophenyl)ethynyl)— 4— (((1— (pyridin— 4— yl)— 1H— pyrazol— 3— yl )methyl)sulfonyl ) benzamide)

[0039] [Chemical Formula IV-3]

[0040] 3-((4-aminophenyl)ethynyl )-N-(imidazo[1,2-a]pyridine-7-ylmethyl )-4-(((1-methyl-

[0041] 1H-pyrazol-3-yl)methyl)sulfonyl)benzamide (3-((4-aminophenyl )ethyny 1)-N-(imidazot 1,2-a]pyridin—7—ylmethyl )—4—((1—methyl—IH—pyrazol—3—yl)methyl)sulfonyl)benzamide)

[0042] [Chemical Formula IV-4]

[0043] 3-((4-amino-3-fluorophenyl)ethynyl)-N-(imidazo[1,2-a]pyridine-7-ylmethyl)-4-

[0044] (((1-methyl- 1H-pyrazole- 3-yl)methyl)sulfonyl )benzamide (3— ((4— amino— 3— f luorophenyl)ethynyl)— N—( imidazo[ 1,2— a] pyridin— 7— ylmethyl)— 4—( ((1— methyl— 1H— pyr azo 1-3-yl )methyl)sulfonyl ) benzamide)

[0045] [Chemical Formula IV-5] 3—( (4—amino— 3-chlorophenyl)ethynyl)- N- (imidazo[ 1 , 2- a]pyridin-7-ylmethyl)- 4- (((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl) benzamide (3-((4-amino-3-chlorophenyl )ethynyl )— N— ( imidazo[l , 2— a]pyridin—7—ylmethyl )—4—(((l—methyl—lH— pyrazol—3—yl )methyl )sulfonyl )benzamide) linker moiety

[0046] L is a linker moiety connecting Ab and any one of (1) to (5) above. The linker moiety of the present invention may include one or more of (6) to (12) below. In light of common technical knowledge, a person skilled in the art can easily understand what form the linker moiety will exist in the final product, the immunoconjugate or drug-linker conjugate, when used in the manufacture of the immunoconjugate or drug-linker conjugate of the present invention. Therefore, not only the linker moiety below but also obvious manufacturing variations of the linker moiety below are all included within the scope of the present invention.

[0047] (6) A linker capable of cutting or a linker that is not capable of cutting

[0048] (7) A linker containing a cleavable peptide unit such as a dipeptide, tripeptide, or tetrapeptide (e.g., GGFG).

[0049] (8) Glucuronid linker

[0050] (9) Linker containing PEG group

[0051] (10) MC-Branched PEG24—VC—PABC, MP—E(PEG) m iVA— PAB, MP— E(PEG) m iVK— PAB, MP- E(PEG) m iGCit— PAB, MP— K(PEG) m i— PEG m 2— VA— PAB, MP-K(PEG) m i-PEG m2 -VK-PAB , MC-VK(PEG) mi -

[0052] PAB, MC- FK(PEG) m i-PAB, MP-K(PEG) mi -B-VA-PAB (Glue) and MP-K (PEG) m Any one linker selected from the group consisting of i- B- VK- PAB(Gluc), where ml and m2 are each independently integers from 1 to 10.

[0053] (11) Linker represented by the following chemical formula V:

[0054] [Chemical Formula V]

[0055] Ly is a single bond, or -valine-citrulline- or -glycine-glycine-phenylalanine-glycine-, and Lx and Ly cannot be single bonds simultaneously;

[0056] Lz is a PABC (para-aminobenzyl carbamate), PAB (para-aminobenzyl), or glucuronide moiety; e is an integer from 1 to 6; h and j are each independently integers from 1 to 3; at least two of f, g and i are 0, and when f, g or gu is not 0, f or g is an integer from 2 to 16, and gu may be an integer from 16 to 30.

[0057] (12) Any one linker selected from the following formulas V-1 to V-8

[0058] [Chemical Formula V-1]

[0059] [Chemical Formula V-4]

[0060]

[0061] [Chemical Formula V-8] The drug-linker conjugate of the present invention may be a compound represented by any one of (13) to (21) below.

[0062] ( 13) 4-( (2S , 5S)- 37- (2 , 5 -dioxo- 2 , 5 -dihydro- 1H-pyrrole- 1-yl)- 5 -isopropyl-

[0063] 4,7,35 -trioxo- 2- (3-ureidopropyl)- 10 ,13,16,19,22,25,28,31 -octaoxa- 3 ,6,34 - triazahepta triacon tanamido) benzyl 4- (3- (3- ((4-fluorophenyl)ethynyl)- 4- (((1-methyl-

[0064] 1H-pyrazole-3-yl)methyl)sulfonyl)benzamido)propyl)-1H-pyrazole-1-carboxylate (4-

[0065] ((2S,5S)— 37— (2,5— dioxo— 2,5— dihydro—lH— pyrrol— 1—yl)— 5— isopropyl— 4,7,35— trioxo— 2— (3-ureidopropyl )-10,13,16,19,22,25,28, 31— octaoxa— 3 , 6 , 34— tri azaheptatri acontanamido)benzyl 4-(3-(3-( (4-f luoropheny 1 )ethyny 1 )-4-( ( (1- methyl— 1H— pyrazol— 3— yl )methyl)sulfonyl ) benz ami do) propyl )—lH—pyr azole— 1— carboxylate)

[0066] ( 14) 4-( (2S , 5S)- 37- (2 , 5-dioxo- 2 , 5-dihydro- 1H-pyrrole- 1-yl)- 5-isopropyl- 4.7.35 -trioxo- 2- (3-ureidopropyl)- 10 ,13 ,16 ,19 ,22 ,25 ,28 , 31 -octaoxa- 3 ,6 , 34 - triaza heptatriacon tanamido) benzyl 4- (3- (3-( 4-fluorophenyl )ethynyl )- 4- ( ( (1-

[0067] (pyridine-4-yl)-1H-pyrazole-3-yl)methyl)sulfonyl)benzamido)propyl)-1H-pyrazole-1-carboxylate (4-((2S,5S)-37-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-y1)-5-isopropyl-

[0068] 4.7.35- trioxo- 2-(3- ureidopropyl)- 10,13,16,19,22,25,28,31- octaoxa- 3,6,34- tri azaheptatri acontanamido)benzyl 4-(3-(3-( (4-f luoropheny 1 )ethyny 1 )-4-(((l-

[0069] (pyr idin-4-yl ) -IH-pyr azo 1 -3-y 1 )methyl)sulfonyl ) benz ami do) propyl )—lH—pyr azole— 1— carboxylate)

[0070] ( 15) 4-( (2S , 5S)-37-(2, 5-dioxo- 2 , 5-dihydro- 1H-pyrrole- 1-yl)- 5-isopropyl-

[0071] 4,7,35 -trioxo- 2- (3-ureidopropyl)- 10 ,13,16,19,22,25,28,31 -octaoxa- 3 ,6,34 - triazahepta triacon tanamido)benzyl (4- ((5-((imidazo[1,2-a]pyridin-7-ylmethyl)carbamoyl)- 2-( (( 1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)phenyl)ethynyl)phenyl)carbamate (4-((2S,5S)-37-(2,5-dioxo-2,5-dihydro— 1H— pyrrol— 1— y 1)—5— isopropyl— 4,7,35— trioxo— 2—(3— ureidopropyl)—

[0072] 10, 13, 16, 19,22,25,28,31— octaoxa— 3,6,34— tri azaheptatri acontanamido)benzyl (4—((5— ( (imidazotl, 2-a]pyri di n-7-ylmethyl) carbamoyl )-2-( ((1-methyl-lH-pyr azo 1-3- yl )methyl)sulfonyl )phenyl )ethynyl )phenyl )carbamate)

[0073] (16) 4-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl)hexanamido)-3-methylbutanamide)-5-ureidopentanamide)benzyl 4-(3-(3-(4-fluorophenyl)ethynyl)-4-

[0074] ( ( (1-methyl- 1H-pyrazole- 3-yl)methyl)sulfonyl)benzamido)propyl) -1H-pyrazole- 1-carboxylate (4— ( (S)— 2— ( (S)— 2— (6— (2 ,5-di oxo-2 ,5— dihydro— 1H— pyrrol— 1—yl )hexanamido)-3- methyl hy 1 bu t anam i do ) -5-ur ei dopen t anam i do ) benzy 1 4— (3— (3—((4— f luorophenyl )ethynyl )—4— (((1— methyl— IH—pyr azol— 3— yl )methyl)sulfonyl ) benzamido) propyl )— IH—pyr azole— 1— carboxylate)

[0075] (17) (2S, 3S, 4S, 5R, 6S)-6-(2-(3-(6-(2, 5-dioxo-2, 5-dihydro-1H-pyrrole-1-yl)hexanamido)propanamido)-4-( ((4-((5-((imidazo[1, 2-a]pyridin-7-ylmethyl)carbamoyl)-2-( ( (1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)phenyl)ethinyl)phenyl)carbamoyl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid ((2S, 3S, 4S, 5R, 6S)-6- (2- (3- (6 - (2,5— dioxo— 2,5— dihydro— 1H— pyrrol— 1—yl )hexanamido)propan amido)— 4— ((((4— ((5 —

[0076] ((imidazo[l,2— a]pyridin— 7— y Imethyl) carbamoyl )—2— (((1— methyl— IH—pyr azol— 3— yl)methyl)sulfonyl)phenyl)ethynyl)phenyl)carbamoyl)oxy)methyl)phenoxy)-3,4,5- tr ihydr oxytetr ahydro—2H— pyran— 2— carboxyl ic acid)

[0077] (18) 4- ((78S,81S,84S)- 78- (3- (2,5-dioxo-2,5-dihydro-lH-pyrrole-l-yl)propaneamido)- 81-isopropyl- 75 , 79 , 82-trioxo- 84- (3-ureidopropyl)-

[0078] 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71- Tetracosa oxa- 74, 80, 83 -Triazapentaoctacon Tan- 85 -Amido)Benzyl (4-((5-

[0079] ((Imidazo [1,2-a]pyridine-7-ylmethyl)carbamoyl)-2-(((1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)phenyl)ethinyl)phenyl)carbamate (4-((78S,81S,84S)-78-(3-(2,5-dioxo-

[0080] 2,5— dihydro—lH— pyrrol— l—yl)propanamido)— 81— isopropyl— 75,79,82— trioxo— 84— (3— ureidopropyl )-

[0081] 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71- tetracosaoxa— 74,80,83— tri azapentaoct acontan— 85— amido)benzyl (4-( (5-(( imidazot 1,2- a]pyr idin-7-ylmethyl )carbamoyl )-2-( ((1-methyl -IH-pyr azo 1-3- yl )methyl)sulfonyl )phenyl )ethynyl )phenyl )carbamate)

[0082] (19) (S)- 4- (5-benzyl- 55- (2,5-dioxo- 2,5-dihydro- 1H-pyrrole- 1-yl)-

[0083] 4, 7, 10, 13, 53 -pentaoxo- 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49 -dodecaoxa- 3, 6, 9, 12,52- pentazapentapentacontanamido)benzyl (4-( (5-( (imidazo[ 1 ,2-a]pyridin-7-ylmethyl)carbamoyl)- 2-( ( (1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)phenyl)ethynyl)phenyl)carbamate ( ( S ) - 4- ( 5-benzyl -55 - (2,5-di oxo-2 ,5-di hydr o-lH-pyr ro 1-1-yl )-4, 7, 10, 13, 53-pent aoxo-

[0084] 16,19,22,25,28,31,34,37,40,43,46, 49- dodecaoxa- 3 ,6,9,12, 52- pent aaz apent apent acont an am i do ) benzy 1 ( 4— ( ( 5— ( ( imi dazo [1,2-a] pyr idin~7~ ylmethyl ) carbamoyl )— 2— (((1— methyl— 1H— pyr azol— 3— yl )methyl)sulfonyl )phenyl )ethynyl )phenyl )carbamate)

[0085] (20) 4-( (78S , 87S)- 87 -benzyl- 78- (3-(2 , 5 -dioxo- 2 , 5 -dihydro- 1H-pyrrole- 1-yl)propaneamido)- 75 ,79 ,82 ,85 , 88 -pentaoxo- 2,5 ,8 ,11 ,14 ,17 ,20 ,23 ,26 ,29 ,32 ,35 ,38 ,41 ,44 ,47 ,50 ,53 ,56 ,59 ,62 ,65 ,68 ,71- tetracosaoxa- 74 ,80 ,83 ,86 , 89 -pentazahennocontan- 91-amido)benzyl (2 ,-fluoro- 4-( (5 - ((imidazo [1,2- a]pyridine- 7-ylmethyl)carbamoyl)-2-(((1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)phenyl)ethynyl)phenyl)carbamate (4-((78S,87S)-87-benzyl-78-(3-(2,5-dioxo—2,5—dihydro—1H—pyrrol—1—yl )propan amido)—75,79,82,85,88—pentaoxo—

[0086] 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71- tetracosaoxa-74,80,83,86, 89— pentaazahennocontan— 91— amido)benzy 1 (2-f luoro—4—((5—

[0087] ( (imidazotl, 2-a]pyri di n-7-ylmethyl) carbamoyl)-2-( ((1-methyl-lH-pyr azo 1-3- yl)methyl)sulfonyl) phenyl)ethynyl)phenyl)carbamate)

[0088] (21) 4- ((78S,87S)- 87 -benzyl- 78- (3- (2,5-dioxo-2,5-dihydro-lH-pyrrole-l-yl)propaneamido)- 75 ,79,82,85, 88 -pentaoxo-

[0089] 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71- Tetracosaoxa- 74, 80, 83, 86, 89 -Pentazahennonacontan- 91-Amido)benzyl (2 -Chloro- 4-((5-

[0090] ((Imidazo [1,2-a]pyridine-7-ylmethyl)carbamoyl)-2-(((1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)phenyl)ethynyl)phenyl)carbamate (4-((78S,87S)-87-benzyl-78-(3-(2,5-dioxo—2,5—dihydro—1H—pyrrol—1—yl )propan amido)—75,79,82,85,88—pentaoxo—

[0091] 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71- tetracosaoxa— 74,80,83,86,89— pent aazahennonacont an— 91— ami do)benzyl (2—chloro—4—

[0092] ( (5-( ( imi dazo [ 1, 2~a] pyr i di n-7-y Imethyl) carbamoyl )-2-( ((1-methyl-lH-pyr azo 1-3- yl )methyl)sulfonyl ) phenyl )ethynyl )phenyl )carbamate) An antibody or its antigen-binding fragment may be prepared by attaching a suitable antibody or its antigen-binding fragment, as described below, to a drug-linker conjugate of the present invention as intended (i.e., a drug-linker conjugate comprising or having one or more linker moieties of any one of (1) to (5) and any one of (6) to (12); or a drug-linker conjugate of any one of (13) to (21)), and the antibody or its antigen-binding fragment of the immunoconjugate may recognize a target site and bind thereto to deliver the cytotoxic drug of the present invention into or around the cell. In the present invention, the term "antibody" refers to a protein molecule that acts as a ligand specifically recognizes an antigen, comprising an immunoglobulin molecule having immunological reactivity with a specific antigen, and includes polyclonal antibodies, monoclonal antibodies, and whole antibodies. Additionally, the above terms include chimeric antibodies and bivalent or bispecific molecules, diabodies, triabodyes, and tetrabodies. The above terms further include short-chain antibodies possessing binding function to FcRn, scapps, derivatives of antibody constant regions, and artificial antibodies based on protein scaffolds. The total antibody has a structure having two full-length light chains and two full-length heavy chains, each light chain being connected to the heavy chain by a disulfide bond. The total antibody includes IgA, IgD, IgE, IgM, and IgG, and IgG includes subtypes IgG1, IgG2, IgG3, and IgG4. In the present invention, the terms “fragment,” “antibody fragment,” and “antigen-binding fragment” are used interchangeably to refer to any fragment of the antibody of the present invention possessing the antigen-binding function of the antibody. Exemplary antigen-binding fragments include Fab, Fab', F(ab')2, Fd, dsFv, and scFv, but,The above Fab is not limited thereto. The above Fab has a structure comprising variable regions of the light and heavy chains, a constant region of the light chain, and a first constant region of the heavy chain (CH1 domain), and has one antigen-binding site. An antigen-binding fragment of an antibody molecule or an antibody fragment refers to a fragment possessing antigen-binding function, and Fab' differs from Fab in that it has a hinge region containing one or more cysteine ​​residues at the C-terminus of the heavy chain CH1 domain. The F(ab')2 antibody is generated when the cysteine ​​residues in the hinge region of Fab' form disulfide bonds. Fd refers to the heavy chain portion contained in the Fab fragment. Fv (variable fragment) refers to the smallest antibody fragment having only the heavy chain variable region and the light chain variable region. In double disulfide Fv (dsFv), the heavy chain variable region and the light chain variable region are connected by a disulfide bond, and in short chain Fv (scFv), the heavy chain variable region and the short chain variable region are generally connected by a covalent bond via a peptide linker or directly at the C-terminus, forming a structure similar to a dimer. Although not limited thereto, such antibody fragments can be obtained using proteolytic enzymes (for example, restriction cleavage of the whole antibody with papain yields Fab, and cleavage with pepsin yields the F(ab')2 fragment), or can be produced through genetic recombination technology. In the present invention, although not limited thereto, the antibody may target an antigen specific to cancer cells. Through this, the immune conjugate administered in vivo may migrate to the vicinity of cancer cells and be internalized within the cancer cells, after which the drug is released, or the drug may be spontaneously released due to the acidic environment surrounding the cancer cells. The above cancer cell-specific antigens are, for example, 5T4, ABL, ABCF1, ACVR1, ACVR1B, ACVR2, ACVR2B, ACVRL1, AD0RA2A,AFP, Aggrecan, AGR2, AICDA, AIF1, AIGI, AKAP1, AKAP2, ALCAM, ALK, AMH, AMHR2, ANGPT1, ANGPT2, ANGPTL3, ANGPTL4, ANPEP, APC, APOCI, AR, aromatase, ASPH, ATX, AX1, AXL, AZGP1 (zinc-α-glycoprotein), B4GALNT1, B7, B7.1, B7.2, B7-H1, B7-H3, B7-H4, B7-H6, BAD, BAFF, BAG1, BAI1, BCR, BCL2, BCL6, BCMA, BDNF, BLNK, BLR1 (MDR15), BlyS, BMP1, BMP2, BMP3B (GDF10), BMP4, BMP6, BMP8, BMP10, BMPR1A, BMPR1B, BMPR2, BPAG1 (plectin), BRCA1, C19orf10 (IL27w), C3, C4A, C5, C5R1, CA6, CA9, CANT1, CAPRIN-1, CASP1, CASP4, CAV1, CCBP2 (D6 / JAB61), CCL1 (1-309), CCL11 (eotaxin), CCL13 (MCP-4), CCL15 (MIP-1d), CCL16 (HCC-4), CCL17 (TARC), CCL18 (PARC), CCL19 (MIP-3b), CCL2 (MCP-1), MCAF, CCL20 (MIP-3a), CCL21 (MEC-2), SLC, exodus-2, CCL22 (MDC / STC-1), CCL23 (MPIF-1), CCL24 (MPIF-2 / eotaxin-2), CCL25 (TECK), CCL26 (eotaxin-3), CCL27 (CTACK / ILC), CCL28, CCL3 (MIP-1a), CCL4 (MIP-1b), CCL5 (RANTES), CCL7 (MCP-3), CCL8 (mcp-2), CCNA1, CCNA2, CCND1, CCNE1, CCNE2, CCR1 (CKR1 / HM145),CCR2 (mcp-IRB / RA) , CCR3 (CKR3 / CMKBR3) , CCR4, CCR5(CMKBR5 / ChemR13) , CCR6 (CMKBR6 / CKR-L3 / STRL22 / DRY6) , CCR7 (CKR7 / EBI1), CCR8 또는 CDwl98 (CMKBR8 / TERI / CKR-L1) , CCR9 (GPR-9-6) , CCRL1 (VSHK1), CCRL2 (L-CCR) , CD13, CD164, CD19, CDH6, CDIC, CD2, CD20, CD21, CD200, CD22, CD23, CD24, CD27,

[0093] CD28, CD29, CD3, CD33, CD35, CD37, CD38, CD3E, CD3G, CD3Z, CD4, CD40, CD40L, CD44, CD45RB, CD47, CD52, CD56, CD69, CD70, CD72, CD74, CD79A, CD79B, CD8, CD80, CD81, CD83, CD86, CD97, CD99, CD117, CD125, CD137, CD147, CD179b, CD223, CD279, CDH1 (E-card herin), CDH10, CDH12, CDH13, CDH18, CDH19, CDH20, CDH3, CDH5, CDH7, CDH8, CDH9, CDH17, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK9, CDKN1A (p21Wapl / Cipl), CDKN1B (p27Kipl), CDKN1C, CDKN2A (pl6INK4a), CDKN2B, CDKN2C, CDKN3, CEA, CEACAM5, CEACAM6, CEBPB, CERI, CFC1B, CHGA, CHGB, Chitinase] CHST10, CIK, CKLFSF2, CKLFSF3, CKLFSF4, CKLFSF5, CKLFSF6, CKLFSF7, CKLFSF8, CLDN3, CLDN6, CLDN7 (claudin-7), CLDN18, CLEC5A, CLEC6A, CLEC11A, CLEC14A, CLN3, CLU (claudin), CMKLR1, CMK0R1 (RDC1), CNR1, C-MET, C0L18A1, C0LIA1, C0L4A3, C0L6A1, CR2, Cripto, CRP, CSF1 (M-CSF), CSF2 (GM-CSF), CSF3 (GCSF), CTAG1B (NY-ESO-1), CTLA4, CTL8, CTNNB1 (b—catenin), CTSB (catechin B), CX3CL1 (SCYD1), CX3CR1 (V28), CXCL1 (GR01), CXCL10 (IP-IO), CXCLI1 (l-TAC / IP-9),CXCL12 (SDF1), CXCL13, CXCL14, CXCL16, CXCL2 (GR02), CXCL3 (GR03), CXCL5 (ENA-78 / LIX), CXCL6 (GCP-2), CXCL9 (MIG), CXCR3 (GPR9 / CKR-L2), CXCR4, CXCR6 (TYMSTR / STRL33 / Bonzo) , CYB5, CYC1, CYSLTR1 , DAB2IP, DES, DKFZp451J0118, DLK1, DNCL1 , DPP4, E2F1, Engel, Edge, Fennel, EFNA3, EFNB2, EGF, EGFR, ELAC2, ENG, Enola, EN02, EN03, EpCAM, EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHA9, EPHA10, EPHB1, EPHB2, EPHB3, EPHB4, EPHB5, EPHB6, EPHRIN-A1, EPHRIN-A2, EPHRINA3, EPHRIN-A4, EPHRIN-A5, EPHRIN-A6, EPHRIN-B1, EPHRIN-B2, EPHRIN-B3, EPHB4, EPG, ERBB2 (HER-2), ERBB3, ERBB4, EREG, ERK8, 에스트로겐 수용체 (Ear 1과 ESR2), F3 (TF), FADD, FAP, 파 르네 실트란 스 퍼 라저] , FasL, FASNf, FCER1A, FCER2, FCGR3A, FGF, FGF1 (aFGF), FGF10, FGF11, FGF12, FGF12B, FGF13, FGF14, FGF16, FGF17, FGF18, FGF19, FGF2 (bFGF), FGF20,

[0094] FGF21, FGF22, FGF23, FGF3 (int-2), FGF4 (HST), FGF5, FGF6 (HST-2), FGF7 (KGF), FGF8, FGF9, FGFR1, FGFR2, FGFR3, FGFR4, FIGF (VEGFD), FILl(EPSILON), FBL1 (ZETA) , FL J 12584, FLJ25530, FLRT1 (flavonoid), FLT1, FLT-3 , FOLR1(FR-link), FOS, FOSLl(FRA-l), FY (DARC) , GABRP (MARKET) , GAGEB1 , GAGECI , GALNAC4S-6ST , GATA3 , GD2, GD3, GDF5, GFI1, GFRA1, GGT1, GM-CSF, GNAS1 , GNRH1 , GPC1, GPC3, GPNB, GPR2 (CCR10) , GPR31, GPR44, GPR81 (FKSG80) , GRCC10 (CIO), GRP, GSN (Gelsolin), GSTP1 , GUCY2C,

[0095] HAVCR1 , HAVCR2, HDAC, HDAC4, HDAC5, HDAC7A, HDAC9, Hedgehog, HGF, HIF1A, HIP1, 히 스타민 및 히스타민 수용체 , HLA-A, HLA-DR, HLA-DRA, HLA-E, HM74, HMOXI, HSP90, HUMCYT2A, ICEBERG, ICOSL, ID2, IFN-a, IFNA1, IFNA2, IFNA4, IFNA5, EFNA6, BFNA7, IFNB1, IFN감마, IFNW1, IGBP1, IGF1, IGFIR, IGF2, IGFBP2, IGFBP3, IGFBP6, DL-1, ILIO, ILIORA, ILIORB, IL-1, IL1R1(CD121a), ILlR2(CD121b), IL-IRA, IL-2, IL2RA(CD25), IL2RB(CD122), IL2RG(CD132), IL-4, IL- 4R(CD123), IL-5, IL5RA(CD125), IL3RB(CD131), IL-6, IL6RA, (CD126) , IR6RB(CD130) , IL-7, IL7RA(CD127) , IL-8, CXCR1 (IL8RA), CXCR2, (IL8RB / CD128) , IL-9, IL9R(CD129) , IL-10, IL10RA(CD210), IL10RB(CDW210B), IL-11, IL11RA, IL-12, IL-12A, IL-12B, IL-12RB1, IL-12RB2, IL-13, IL13RA1, IL13RA2, IL14, IL15, IL15RA, IL16, IL17, IL17A, IL17B, IL17C, IL17R, IL18, IL18BP, IL18R1, IL18RAP, IL19, ILIA, ILIB, ILIF10, ILIF5, IL1F6, ILIF7, IL1F8, DL1F9, ILIHYI, ILIR1, IL1R2, ILIRAP, ILIRAPLI, ILIRAPL2, ILIRL1, IL1RL2, ILIRN, IL2, IL20, IL20RA, IL21R, IL22, IL22R,IL22RA2, IL23, DL24, IL25, IL26, IL27, IL28A, IL28B, IL29, IL2RA, IL2RB, IL2RG, IL3, IL30, IL3RA, IL4, 1L4, IL6ST (glycoprotein 130), ILK, INHA, INHBA, INSL3, INSL4, IRAKI, IRAK2, ITGA1, ITGA2, ITGA3, ITGA6 (a6 integrin), ITGAV, ITGB3, ITGB4 (heart4 integrin), JAG1, JAK1, JAK3, JTB, JUN, K6HF, KAI1, KDR, KIT, KITLG, KLF5 (GC Box BP), KLF6, KLK10, KLK12, KLK13, KLK14, KLK15, KLK3, KLK4, KLK5, KLK6, KLK9, KRT1, KRT19 (Keratin 19), KRT2A, KRTHB6 (Hair-specific Type II Keratin), L1CAM, LAG3, LAMA5, LAMP1, LEP (Leptin), Lewis Y Antigen (LeY), LILRB1, Lingo-p75, Lingo-Troy, LGALS3BP, LRRC15, LPS, LTA (TNF-β), LTB, LTB4R (GPR16), LTB4R2, LTBR, ​​LY75, LYPD3, MACMARCKS, MAG or OMgp, MAGEA3, MAGEA6, MAP2K7 (c-Jun), MDK, MIB1, midkine, MIF, MISRII, MJP-2, MLSN, MK, MKI67 (Ki-67), MMP2, MMP9, MSMB, MT3 (metallothionectin—UI), mTOR, MTSS1, MUC1 (mucin), MUC16, MYC, MYD88, NCK2, NCR3LG1, neurocan, NFKBI, NFKB2, NGFB (NGF), NGFR, NgR-Lingo, NgRNogo66, (Nogo), NgR—p75, NgR-Troy, NMEI (NM23A), NOTCH, N0TCH1, N0TCH3,N0X5, NPPB, NR0B1, NR0B2, NRID1, NR1D2, NR1H2, NR1H3, NR1H4, NR112, NR113, NR2C1, NR2C2, NR2E1, NR2E3, NR2F1, NR2F2, NR2F6, NR3C1, NR3C2, NR4A1, NR4A2, NR4A3, NR5A1, NR5A2, NR6A1, NRP1, NRP2, NT5E, NTN4, NYES01, ODZI, OPRDI, P2RX7, PAP, PARTI, PATE, PAWR, P-card herin, PCA3, PCD1, PDL1, PCDGF, PCNA, PDGFA, PDGFB, PDGFRA, PDGFRB, PECAMI, Ll-CAM, peg-{heart asparagus}, PF4 (CXCL4), PGF, PGR, phosphacan, PIAS2, PI3 kinase, PIK3CG, PLAU (uPA), PLG, PLXDCI, PKC, PKC-beta, PPBP (CXCL7), PPID, PR1, PRAME, PRKCQ, PRKD1, PRL, PROC, PR0K2, PSAP, PSCA, PSMA, PTAFR, PTEN, PTHR2, PTGS2 (COX-2), PTN, PVRIG, RAC2 (P21Rac2), RANK, RANK ligand, RARE, RGS1, RGS13, RGS3, RNFI10 (ZNF144), Ron, R0B02, R0R1, RXR, S100A2, SCGB1D2 (lipophilin B), SCGB2A1 (mammaglobin 2), SCGB2A2 (mammaglobin 1), SCYE1 (endothelial mononuclear cell-activating cytokine), SDF2, SERPENA1, SERPINA3, SERPINB5 (maspin), SERPINEI (PAID, SERPINFI, SHIP-1, SHIP-2, SHB1, SHB2, SHBG, SfcAZ, SLC2A2, SLC33A1, SLC43A1, SLC44A4, SLC34A2, SLIT2, SPP1, SPRR1B (Sprl) It should be noted that there are some unclear or potentially incorrect terms in the original text, such as "peg—心}스파라기 나저]" which seems to be an incorrect or unrecognized expression. This might affect the overall comprehensibility of the text.ST6GAL1 , ST8SIA1, STAB1 , STATE, STEAP, STEAP2, TB4R2, TBX21 , TCP10, TDGF1 , TEK, TGFA, TGFB1 , TGFB1I1, TGFB2, TGFB3 , TGFBI , TGFBR1 , TGFBR2, TGFBR3 , THIL, THBS1 (Thrombospondin-1), THBS2, THBS4, THPO, TIE (Tie-1), TIMP3, tissue factor, TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TNF, TNFa, TNFAIP2 (B94), TNFAIP3, TNFRSFI1A, TNFRSF1A, TNFRSF1B, TNFRSF21, TNFRSF5, TNFRSF6 (Fas), TNFRSF7, TNFRSF8, TNFRSF9, TNFSF10 (TRAIL), TNFRSF10A, TNFRSF10B, TNFRSF12A, TNFRSF17, TNFSF11 (TRANCE), TNFSF12 (AP03L), TNFSF13 (April), TNFSF13B, TNFSF14 (HVEM-L), TNFRSF14 (HVEM), TNFSF15 (VEGI), TNFSF18, TNFSF4 (0X40 ligand), TNFSF5 (CD40 ligand), TNFSF6 (FasL), TNFSF7 (CD27 ligand), TNFSF8 (CD30 ligand), TNFSF9 (4-1BB Ligand), TOLLIP, Toll-like receptor, T0P2A (Topoisomerasase Ila), TP53, TPM1, TPM2, TRADD, TRAF1, TRAF2, TRAF3, TRAF4, TRAF5, TRAF6, TRKA, TREM1, TREM2, TR0P2, TRPC6, TSLP, TWEAK, Tyrosinase), uPAR, VEGF, VEGFB, VEGFC, Versican, VHL C5, VLA-4, WT1, Wnt-1,XCL1 (lymphotactin), XCL2 (SCM-Ib), XCR1 (GPR5 / CCXCR1), YY1, ZFPM2, CLEC4C (BDCA-2, DLEC, CD303, CDH6, CLECSF7), CLEC4D (MCL, CLECSF8), CLEC4E (Mincle), CLEC6A (dectin-2), CLEC5A (MDL-1, CLECSF5), CLEC1B (CLEC-2), CLEC9A (DNGR-1), CLEC7A (dectin-1), CLEC11A, PDGFRa, SLAMF7, GP6 (GPVI), LILRA1 (CD85I), LILRA2 (CD85H, ILT1), LILRA4 (CD85G, ILT7), LILRA5 (CD85F, ILT11), LILRA6 (CD85b, ILT8), LILRB1, NCR1 (CD335, LY94, NKp46), NCR3 (CD335, LY94, NKp46), NCR3 (CD337, NKp30), OSCAR, TARM1, CD30, CD300C, CD300E, CD300LB (CD300B), CD300LD (CD300D), KIR2DL4 (CD158D), KIR2DS, KLRC2 (CD159C, NKG2C), KLRK1 (CD314, NKG2D), NCR2 (CD336, NKp44), PILRB, SIGLEC1 (CD169, SN), SIGLEC5, SIGLEC6, SIGLEC7, SIGLEC8, SIGLEC9, SIGLEC10, SIGLEC11, SIGLEC12, SIGLEC14, SIGLEC15 (CD33L3), SIGLEC16, SIRPA, SIRPB1 (CD172B), TREM1 (CD354), TREM2, KLRF1 (NKp80), 17-1A, SLAM7,

[0096] MSLN, CTAG1B / NY-ES0-1, MAGEA3 / A6, ATP5I (Q06185), OAT (P29758), AIFM1 (Q9Z0X1), AGFA (Q64133), MTDC (P18155), CMC1 (Q8BH59), PREP (Q8K411), YMEL1 (088967), LPPRC (Q6PB66), LONM (Q8CGK3), ACON (Q99KI0), 0D01 (Q60597), IDHP (P54071), ALDH2

[0097] (P47738), ATPB (P56480), AATM (P05202), TMM93 (Q9CQW0), ERG I 3 (Q9CQE7), RTN4

[0098] (Q99P72), CL041 (Q8BQR4), ERLN2 (Q8BFZ9), TERA (Q01853), DADI (P61804), CALX

[0099] (P35564), CALU (035887), VAPA (Q9WV55), MOGS (Q80UM7), GANAB (Q8BHN3), ER01A

[0100] (Q8R180), UGGG1 (Q6P5E4), P4HA1 (Q60715), HYEP (Q9D379), CALR (P14211), AT2A2

[0101] (055143), PDIA4 (P08003), PDIA1 (P09103), PDIA3 (P27773), PDIA6 (Q922R8), CLH

[0102] (Q68FD5) , PPIB (P24369) , TCPG (P80318) , M0T4 (P57787) , NICA (P57716) , BAS I (P18572) , VAPA (Q9WV55) , ENV2 (P11370) , VAT1 (Q62465) , 4F2 (P10852) , ENOA (P17182) , ILK (055222) , GPNMB (Q99P91) , ENV1 (P10404) , ER01A (Q8R180) , CLH (Q68FD5) , DSG1A (Q61495) , AT1A1 (Q8VDN2) , HY0U1 (Q9JKR6), TRAP1 It may be (Q9CQN1), GRP75 (P38647), ENPL (P08113), CH60 (P63038), or CH10 (Q64433), but is not limited thereto. In one embodiment, the antibody of the present invention or its antigen-binding fragment may target HER2, and specifically may be trastuzumab, but is not limited thereto. Use of an immunoconjugate or a pharmaceutically acceptable salt thereof and a treatment method using the same. Another embodiment of the present invention is a pharmaceutical composition for the prevention or treatment of cancer comprising the above immunoconjugate or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition of the present invention exhibits NAMPT inhibitory activity, thereby having an excellent anticancer effect, and is effectively delivered to target cells, resulting in almost no side effects compared to the case where a cytotoxic drug is administered alone. The above cancer includes, but is not limited to, all cancers treatable by inhibition of NAMPT, and may be solid tumors or blood cancers.For example, pseudomyxoma, intrahepatic biliary cancer, hepatic capillary tumor, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, mycosis fungoides, acute myeloid leukemia, acute lymphocytic leukemia, basal cell carcinoma, ovarian epithelial carcinoma, ovarian germ cell carcinoma, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla of Vater cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, paraparasinus cancer, non-small cell lung cancer, tongue cancer, gonadal follicle tumor, small cell lung cancer, pediatric brain cancer, pediatric lymphoma, pediatric leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal pelvis cancer, kidney cancer, heart It may be one or more selected from the group consisting of cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, primary gastric cancer, gastric lymphoma, gastric cancer, gastric carcinoma, gastrointestinal stromal cancer, Wilms cancer, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational trophoblastic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid tumor, vaginal cancer, spinal cord cancer, acoustic neuromuscular tumor, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, blood cancer, and thymic cancer, but is not limited thereto. In addition, the above cancer includes not only primary cancer but also metastatic cancer. Although not limited thereto, the above cancer may be a cancer in which NAMPT is overexpressed or overactivated. In addition, it may be a HER2-positive or mutant cancer, such as HER2-positive or mutant breast cancer, gastric cancer, or ovarian cancer, but is not limited thereto.In addition, the immunoconjugate of the present invention has excellent efficacy even in cancer resistant to the FDA-approved drug ENHERTU® (trastuzumab-deruxtecan). Therefore, the immunoconjugate of the present invention can show excellent anticancer effects when administered to patients who do not respond to ADCs based on HER2 antibodies and topoisomerase inhibitors, or who have relapsed after receiving treatment with said ADCs. In the present invention, pharmaceutically acceptable salts are salts commonly used in the pharmaceutical industry, for example, 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, L-ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, (+)-campphoric acid, (+)-campphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid , D-glucoheptonic acid, D-gluconic acid, D-glucuronic acid, glutamic acid, glutaric acid, glyceroic acid, glycolic acid, hipfuric acid, hydrobromide, hydrochloric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, L-malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, parmolic acid, phosphoric acid, proprionic acid, L-pyroglutamic acid, salicylic acid, sebactic acid, stearic acid, succinic acid, sulfuric acid, L-tartaric acid, thiocyanic acid, toluenesulfonic acid, undecylenic acid, or other acids that can be used It may refer to acid salts produced from compounds, but is not limited thereto.For administration, the pharmaceutical composition of the present invention may additionally contain at least one type of pharmaceutically acceptable carrier in addition to the immunoconjugate, and may also be used with other conventional additives such as antioxidants, buffer solutions, antibacterial agents, etc., as needed. Additionally, such pharmaceutical compositions may be formulated by further adding diluents, dispersants, surfactants, binders, and lubricants. The composition of the present invention may be administered orally or parenterally according to the intended method (e.g., intravenously, subcutaneously, intraperitoneally, or topically), wherein the dosage varies within the range depending on the patient's body weight, age, sex, health status and dietary habits, time of administration, method of administration, excretion rate, severity of the disease, etc. The daily dosage of the immunoconjugate of the present invention is about 0.001 to 1000 mg / kg and may be administered once or in divided doses per day. In addition to the immunoconjugate of the present invention, the pharmaceutical composition of the present invention may additionally contain at least one therapeutic agent as an active ingredient that exhibits the same or similar medical effects. The therapeutic agent may be selected from the group consisting of chemotherapy agents, radiotherapy agents, immunotherapy agents, and tumor microenvironment modulators. According to one specific embodiment of the present invention, the present invention provides a method for preventing or treating cancer, comprising the step of administering a therapeutically effective amount of the immunoconjugate to an individual in need thereof. The method for preventing or treating cancer according to the present invention includes not only treating the cancer itself before the onset of symptoms, but also suppressing or avoiding such symptoms by administering the immunoconjugate of the present invention. According to one specific embodiment of the present invention, the present invention provides a use of the immunoconjugate of the present invention in the manufacture of a drug for preventing or treating cancer.To prepare a medicament, the immunoconjugate of the present invention can be combined with acceptable adjuvants, diluents, carriers, etc., and can be prepared as a complex preparation together with other active agents (therapeutic agents) to have a synergistic effect of the active components. As used herein, "subject" means a mammal including a human, and "administration" means providing a predetermined substance to a patient by any appropriate method. As used herein, the term "therapeutically effective amount" refers to the amount of the immunoconjugate of the present invention effective for preventing or treating cancer. The matters mentioned in the uses, compositions, and treatment methods of the present invention are equally applicable as long as they do not conflict with each other. Embodiments of the present invention can be modified in various other forms, and the scope of the present invention is not limited to the embodiments described below. In addition, the embodiments of the present invention are provided to more fully explain the present invention to those of ordinary skill in the art. Furthermore, throughout the specification, stating that a component "comprises" means that it can include other components rather than excluding other components unless specifically stated to the contrary. Specific embodiments of the present invention are as follows, but the scope of the present invention is not limited to these embodiments.

[0103] (1) The immunoconjugate according to the present invention or a pharmaceutically acceptable salt thereof is represented by the following Chemical Formula I:

[0104] [Chemical Formula I]

[0105] Ab-(L-D) p In Chemical Formula I above, 日 is a cytotoxic drug moiety represented by the following Chemical Formula III,

[0106] [Chemical Formula III] 나 or one or more 내 are each independently halogen, -NH2, -NO2, -NHCHs, -N(CH3)2 or -

[0107] is replaced by 0H;

[0108] Li is -CH2-, - CH2CH2- , - CH2CH2CH2- , - CH(CH3)CH2- , -CH2CH2CH2CH2-, -CH(CH3)CH2CH2-,

[0109] -CH2CH(CH3)CH2-, -C(CH3)2CH2-, -CH2CH2CH2CH2CH2 - or - CH2CH2CH2CH2CH2CH2-;

[0110] V is a single bond, or one or more of which are each independently substituted by -C1-C6 alkyl, -halogen, -OH, -NO2, -C1-C6 alkoxy or -CF3;匕2 is a single bond, - (CH2)-, - (CH2)『, - (CH2)『, - (CH2)4-, -(CH2)5-, -(C=0)-NH(CH2) n -, -NH(C=0)-(CH2)n-, or - (C=o)-, where n is 0, 1, 2, 3 or 4;平.--•、、nr 斗 i j

[0111] '、.、,NH

[0112] R2 is - H, -OH, -halogen, -Ci-C6 alkyl, -Ci-C6 alkoxy, - NH2, lip is substituted by -halogen, - Ci-C6 alkoxy, -

[0113] NH2, or -Ci-C6 alkyl; 匕3 is a single bond, - (CH2)-, - (CH2)2-, - (CH2)3-, - (CH2)4-, -(CH2)5-, _ NH“, - NHCH『, -

[0114] NH(CH2)2 - or - NH(CH2)3 -, where the interior of L3 is unsubstituted or at least one of the interior of L3 is each independently substituted by -C1-C6 alkyl; At this time, the inside of Rs is not substituted or at least one of the insides of R3 is each independently substituted with -C1-C6 alkyl, -C1-C6 alkoxy, -NH2, -CFs, -OCFs or halogen;

[0115] L is a linker moiety that connects Ab and 日;

[0116] Ab is an antibody or an antigen-binding fragment thereof; and

[0117] P is an integer from 1 to 10.

[0118] (2) In the above (1), the formula III may be represented by the following formula III-1: Li is -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)CH2-, -CH2CH2CH2CH2-, -

[0119] CH2CH2CH2CH2CH2 - or -CH2CH2CH2CH2CH2CH2 -; and at this time, the inside of the above 오 is not substituted or one or more

[0120] -H is each independently substituted with halogen; 匕2 is a single bond;

[0121] 『2 is H, halogen or -NH2; 느3 is - (CH2)-, - (CH2)2-, - (CH2)『, - (CH2)4 - or - (CH2)5 -; At this time, at least one -H of the above R3 may be each independently substituted with -Cl-C6 alkyl.

[0122] (4) In any one of the above (1) to (3), the compound represented by the formula III may be any one of the following compounds 1 to compound 43: (5) In any one of (1) to (4) above, the cytotoxic drug moiety represented by the above formula III may be any one of the following formulas IV-1 to IV-5:

[0123] [Chemical Formula IV-1] [Chemical Formula IV-5]

[0124] (6) In any one of (1) to (5) above,

[0125] L may be represented by the following chemical formula V:

[0126] [Chemical Formula V] Ly is a single bond, or -valine-citrulline- or -glycine-glycine-phenylalanine-glycine-, and Lx and Ly cannot be single bonds simultaneously;

[0127] Lz is a PABC (para-aminobenzyl carbamate), PAB (para-aminobenzyl), or glucuronide moiety; e is an integer from 1 to 6; h and j are each independently integers from 1 to 3; at least two of f, g and i are 0, and when f, g or i is not 0, f or g is an integer from 2 to 16, and gu is an integer from 16 to 30.

[0128] (7) In any one of (1) to (6) above,

[0129] L may be represented by any one of the following chemical formulas V-1 to V-8:

[0130] [Chemical Formula V-1]

[0131] [Chemical Formula V-3] [Chemical Formula V-8]

[0132] (8) In any one of (1) to (7) above,

[0133] L - D may be represented by any one of the following Chemical Formulas VI-1 to VI-9:

[0134] [Chemical Formula VI-1] [Chemical Formula VI-4]

[0135] [Chemical Formula VI-7]

[0136] (9) In any one of (1) to (8) above, the antibody may target a cancer cell-specific antigen, and the cancer cell-specific antigen is 5T4, ABL, ABCF1, ACVR1, ACVR1B, ACVR2, ACVR2B, ACVRL1, AD0RA2A, AFP, Aggrecan, AGR2, AICDA, AIF1, AIGI, AKAP1, AKAP2, ALCAM, ALK, AMH, AMHR2, ANGPT1, ANGPT2, ANGPTL3, ANGPTL4, ANPEP, APC, APOCI, AR, aromatase, ASPH, ATX, AX1, AXL, AZGP1 (zinc—a—glycoprotein), B4GALNT1, B7, B7.1,

[0137] B7.2, B7-H1, B7-H3, B7-H4, B7-H6, BAD, BAFF, BAG1, BAI1, BCR, BCL2, BCL6, BCMA,

[0138] BDNF, BLNK, BLR1 (MDR15), BlyS, BMP1, BMP2, BMP3B (GDFIO), BMP4, BMP6, BMP8, BMP10, BMPR1A, BMPR1B, BMPR2, BPAG1 (plectin), BRCA1, C19orfl0 (IL27w), C3, C4A, C5, C5R1,

[0139] CA6, CA9, CANT1 , CAPRIN-1, CASP1 , CASP4, CAV1, CCBP2 (D6 / JAB61), CCL1 (1—309), CCLI1 (에오탁신) , CCL13 (MCP-4) , CCL15 (MIP-Id), CCL16 (HCC-4) , CCL17 (TARC) , CCL18 (PARC) , CCL19 (MIP-3b), CCL2 (MCP-1), MCAF, CCL20 (MIP- 3a) , CCL21 (MEP-2) , SLC, exodus-2, CCL22(MDC / STC-I), CCL23 (MPIF-I), CCL24 (MPIF- 2 / 에오탁신- 2) , CCL25 (TECK) , CCL26(에오탁신- 3), CCL27 (CTACK / ILC) , CCL28, CCL3 (MIP-Ia), CCL4 (MIPIb), CCL5(RANTES) , CCL7 (MCP-3), CCL8 (mcp-2) , CCNA1 , CCNA2, CCND1 , CCNE1 , CCNE2, CCR1 (CKR1 / HM145) , CCR2 (mcp-IRB / RA) , CCR3 (CKR3 / CMKBR3) , CCR4, CCR5(CMKBR5 / ChemR13) , CCR6 (CMKBR6 / CKR-L3 / STRL22 / DRY6) , CCR7 (CKR7 / EBI1), CCR8 또는 CDwl98 (CMKBR8 / TERI / CKR-L1) , CCR9 (GPR-9-6) , CCRL1 (VSHK1), CCRL2 (L-CCR) , CD13, CD164, CD19, CDH6, CDIC, CD2, CD20, CD21, CD200, CD22, CD23, CD24, CD27, CD28, CD29, CD3, CD33, CD35, CD37, CD38, CD3E, CD3G, CD3Z, CD4, CD40, CD40L, CD44, CD45RB, CD47, CD52, CD56, CD69, CD70, CD72, CD74, CD79A, CD79B, CD8, CD80, CD81, CD83, CD86, CD97, CD99, CD117, CD125,CD137, CD147, CD179b, CD223 , CD279, CDH1 (E-카드헤린), CDH10, CDH12, CDH13 , CDH18, CDH19, CDH20, CDH3, CDH5, CDH7, CDH8, CDH9, CDH17, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK9, CDKN1A (p21Wapl / Cipl) , CDKN1B (p27Kipl), CDKN1C, CDKN2A (pl6INK4a) , CDKN2B, CDKN2C, CDKN3 , CEA, CEACAM5, CEACAM6, CEBPB, CERI, CFC1B, CHGA, CHGB, 키티나제 (Chitinase), CHST10, CIK, CKLFSF2, CKLFSF3 , CKLFSF4, CKLFSF5, CKLFSF6, CKLFSF7, CKLFSF8, CLDN3 , CLDN6, CLDN7 (클라우딘- 7), CLDN18, CLEC5A, CLEC6A, CLEC11A, CLEC14A, CLN3, CLU (클러스테린), CMKLR1 , CMK0R1 (RDC1), CNR1, C-MET, C0L18A1 , C0LIA1, C0L4A3 , C0L6A1 , CR2, Cripto, CRP, CSF1 (M- CSF), CSF2 (GM-CSF) , CSF3 (GCSF) , CTAG1B (NY-ESO-1), CTLA4, CTL8, CTNNB1 (b—가테닌), CTSB (가텝신 B), CX3CL1 (SCYD1), CX3CR1 (V28) , CXCL1 (GR01), CXCL10 (IP-IO), CXCLI1,

[0140] (l-TAC / IP-9), CXCL12 (SDF1), CXCL13 , CXCL14, CXCL16, CXCL2 (GR02), CXCL3 (GR03), CXCL5 (ENA-78 / LIX), CXCL6 (GCP-2), CXCL9 (MIG), CXCR3 (GPR9 / CKR-L2), CXCR4, CXCR6 (TYMSTR / STRL33 / Bonzo) , CYB5, CYC1, CYSLTR1 , DAB2IP, DES, DKFZp451J0118, DLK1, DNCL1 , DPP4, E2F1, Engel, Edge, Fennel, EFNA3, EFNB2, EGF, EGFR, ELAC2, ENG, Enola, EN02, EN03, EpCAM, EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHA9, EPHA10, EPHB1, EPHB2, EPHB3, EPHB4, EPHB5, EPHB6, EPHRIN-A1, EPHRIN-A2, EPHRINA3, EPHRIN-A4, EPHRIN-A5, EPHRIN-A6, EPHRIN-B1, EPHRIN-B2, EPHRIN-B3, EPHB4, EPG, ERBB2 (HER-2), ERBB3, ERBB4, EREG, ERK8, 에스트로겐 수용체 (Ear 1과 ESR2), F3 (TF) FADD, FAP, 파 르네 실트란 스 퍼 라저] , FasL, FASNf, FCER1A, FCER2, FCGR3A, FGF, FGF1 (aFGF), FGF10, FGF11, FGF12, FGF12B, FGF13, FGF14, FGF16, FGF17, FGF18, FGF19, FGF2 (bFGF), FGF20, FGF21, FGF22, FGF23, FGF3 (int-2), FGF4 (HST), FGF5, FGF6 (HST-2), FGF7 (KGF), FGF8, FGF9, FGFR1, FGFR2, FGFR3, FGFR4, FIGF (VEGFD), FILl(EPSILON) ,FBL1 (ZETA), FL J 12584, FLJ25530, FLRT1 (fibronectin), FLT1, FLT-3, FOLR1 (FR-alpha), FOS, FOSLl (FRA-l), FY (DARC), GABRP (GABAa), GAGEB1, GAGECI, GALNAC4S-6ST, GATA3, GD2, GD3, GDF5, GFI1, GFRA1, GGT1, GM-CSF, GNAS1, GNRH1, GPC1, GPC3, GPNB, GPR2 (CCR10), GPR31, GPR44, GPR81 (FKSG80), GRCC10 (CIO), GRP, GSN (Gelsolin), GSTP1, GUCY2C, HAVCR1, HAVCR2, HDAC, HDAC4, HDAC5, HDAC7A, HDAC9, Hedgehog, HGF, HIF1A, HIP1, Histamine and Histamine Receptor, HLA-A, HLA-DR, HLA-DRA, HLA-E, HM74, HMOXI, HSP90, HUMCYT2A, ICEBERG, ICOSL, ID2, IFN-α, IFNA1, IFNA2, IFNA4, IFNA5, EFNA6, BFNA7, IFNB1, IFN-Gamma, IFNW1, IGBP1, IGF1, IGFIR, IGF2, IGFBP2, IGFBP3, IGFBP6, DL-1, ILIO, ILIORA, ILIORB, IL-1, IL1R1 (CD121a), IL1R2(CD121b), IL-IRA, IL-2, IL2RA (CD25), IL2RB(CD122), IL2RG(CD132), IL-4, IL-4R(CD123), IL-5, IL5RA(CD125),

[0141] IL3RB(CD131), IL-6, IL6RA, (CD126), IR6RB(CD130), IL-7, IL7RA(CD127), IL-8, CXCR1

[0142] (IL8RA), CXCR2, (IL8RB / CD128) , IL-9, IL9R(CD129) , IL-10, IL10RA(CD210) ,

[0143] IL10RB(CDW210B) , IL-11, IL11RA, IL-12, IL-12A, IL-12B, IL-12RB1, IL-12RB2, IL-13,

[0144] IL13RA1, IL13RA2, IL14, IL15, IL15RA, IL16, IL17, IL17A, IL17B, IL17C, IL17R, IL18, IL18BP, IL18R1, IL18RAP, IL19, ILIA, ILIB, ILIF10, ILIF5, IL1F6, ILIF7, IL1F8, DL1F9, ILIHYI, ILIR1, IL1R2, ILIRAP, ILIRAPLI, ILIRAPL2, ILIRL1, IL1RL2, ILIRN, IL2, IL20, IL20RA, IL21R, IL22, IL22R, IL22RA2, IL23, DL24, IL25, IL26, IL27, IL28A, IL28B, IL29, IL2RA, IL2RB, IL2RG, IL3, IL30, IL3RA, IL4, 1L4, IL6ST (Protein 130), ILK, INHA, INHBA, INSL3, INSL4, IRAKI, IRAK2, ITGA1, ITGA2, ITGA3, ITGA6 (alpha6 integrin), ITGAV, ITGB3, ITGB4 (beta4 integrin), JAG1, JAK1, JAK3, JTB, JUN, K6HF, KAI1, KDR, KIT, KITLG, KLF5 (GC Box BP), KLF6, KLK10, KLK12, KLK13, KLK14, KLK15, KLK3, KLK4, KLK5, KLK6, KLK9, KRT1, KRT19 (Keratin 19), KRT2A, KRTHB6 (Hair-specific type II keratin), L1CAM, LAG3, LAMA5, LAMP1, LEP (Leptin), Lewis Y antigen (LeY), LILRB1, Lingo-p75, Lingo-Troy, LGALS3BP, LRRC15, LPS, LTA (TNF-b), LTB, LTB4R (GPR16), LTB4R2, LTBR, LY75, LYPD3, MACMARCKS, MAG or OMgp, MAGEA3, MAGEA6, MAP2K7 (c-Jun), MDK, MIB1, midkine, MIF,MISRII, MJP-2, MLSN, MK, MKI67 (Ki-67), MMP2, MMP9, MSMB, MT3 (메탈로티오넥 틴 — UI), mTOR, MTSS1, MUC1 (mucin), MUC16, MYC, MYD88, NCK2, NCR3LG1, 뉴로칸 (neurocan) , NFKBI , NFKB2, NGFB (NGF) , NGFR, NgR-Lingo, NgRNogo66, (Nogo) , NgR—p75, NgR-Troy, NMEI (NM23A) , NOTCH, N0TCH1 , N0TCH3 , N0X5, NPPB, NR0B1, NR0B2, NRID1, NR1D2, NR1H2, NR1H3, NR1H4, NR112, NR113, NR2C1, NR2C2, NR2E1, NR2E3, NR2F1, NR2F2, NR2F6, NR3C1, NR3C2, NR4A1, NR4A2, NR4A3, NR5A1, NR5A2, NR6A1, NRP1, NRP2, NT5E, NTN4, NYES01, ODZI, OPRDI, P2RX7, PAP, PARTI, PATE, PAWR

[0145] P-card herin, PCA3, PCD1, PDL1, PCDGF, PCNA, PDGFA, PDGFB, PDGFRA, PDGFRB, PECAMI, Ll-CAM, peg—{asparaginase}, PF4 (CXCL4), PGF, PGR, phosphacan, PIAS2, PI3 kinase, PIK3CG, PLAU (uPA), PLG, PLXDCI, PKC, PKC-beta, PPBP (CXCL7), PPID, PR1, PRAME, PRKCQ, PRKD1, PRL, PROC, PROK2, PSAP, PSCA, PSMA, PTAFR, PTEN, PTHR2, PTGS2 (COX-2), PTN, PVRIG, RAC2 (P21Rac2), RANK, RANK ligand, RARE, RGS1, RGS13, RGS3, RNFI10 (ZNF144), Ron, ROB02, ROR1, RXR, S100A2, SCGB1D2 (lipophilin B), SCGB2A1 (mammaglobin 2), SCGB2A2 (mammaglobin 1), SCYE1 (endothelial mononuclear cell-activating cytokine), SDF2, SERPENA1, SERPINA3, SERPINB5 (maspin), SERPINEI (PAID, SERPINFI, SHIP-1, SHIP-2, SHB1, SHB2, SHBG, SfcAZ, SLC2A2, SLC33A1, SLC43A1, SLC44A4, SLC34A2, SLIT2, SPP1, SPRR1B (Sprl), ST6GAL1, ST8SIA1, STAB1, STATE, STEAP, STEAP2, TB4R2, TBX21, TCP10, TDGF1, TEK, TGFA, TGFB1, TGFB1I1, TGFB2, TGFB3, TGFBI, TGFBR1, TGFBR2, TGFBR3, THIL, THBS1 (thrombospondin-1), THBS2, THBS4, THPO, TIE (Tie-1), TIMP3, tissue factor, TLR1, TLR2, TLR3, TLR4, TLR5TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TNF, TNFa, TNFAIP2 (B94), TNFAIP3, TNFRSFI1A, TNFRSF1A, TNFRSF1B, TNFRSF21, TNFRSF5, TNFRSF6 (Fas), TNFRSF7, TNFRSF8, TNFRSF9, TNFSF10 (TRAIL), TNFRSF10A, TNFRSF10B, TNFRSF12A, TNFRSF17, TNFSF11 (TRANCE), TNFSF12 (AP03L), TNFSF13 (April), TNFSF13B, TNFSF14 (HVEM-L), TNFRSF14 (HVEM), TNFSF15 (VEGI), TNFSF18, TNFSF4 (0X40 LI) Gand), TNFSF5 (CD40 ligand), TNFSF6 (FasL), TNFSF7 (CD27 ligand), TNFSF8 (CD30 ligand), TNFSF9 (4-1BB ligand), TOLLIP, Toll-like receptor, T0P2A (Topoisomerasase Ila), TP53, TPM1, TPM2, TRADD, TRAF1, TRAF2, TRAF3, TRAF4, TRAF5, TRAF6, TRKA, TREM1, TREM2, TR0P2, TRPC6, TSLP, TWEAK, Tyrosinase), uPAR, VEGF, VEGFB, VEGFC, Versican, VHL C5, VLA-4, WT1, Wnt-1, XCL1 (Lympotactin), XCL2 (SCM-,

[0146] Ib), XCRI (GPR5 / CCXCR1), YY1, ZFPM2, CLEC4C (BDCA-2, DLEC, CD303, CDH6, CLECSF7), CLEC4D (MCL, CLECSF8), CLEC4E (Mincle), CLEC6A (Dectin-2), CLEC5A (MDL-1, CLECSF5), CLEC1B (CLEC-2), CLEC9A (DNGR-1), CLEC7A (Dectin-1), CLEC11A, PDGFRa, SLAMF7, GP6 (GPVI), LILRA1 (CD85I), LILRA2 (CD85H, ILT1), LILRA4 (CD85G, ILT7), LILRA5 (CD85F, ILT11), LILRA6 (CD85b, ILT8), LILRB1, NCR1 (CD335, LY94, NKp46), NCR3 (CD335, LY94, NKp46), NCR3 (CD337, NKp30), OSCAR, TARM1, CD30, CD300C, CD300E, CD300LB (CD300B), CD300LD (CD300D), KIR2DL4 (CD158D), KIR2DS, KLRC2 (CD159C, NKG2C), KLRK1 (CD314, NKG2D), NCR2 (CD336, NKp44), PILRB, SIGLEC1 (CD169, SN), SIGLEC5, SIGLEC6, SIGLEC7, SIGLEC8, SIGLEC9, SIGLEC10, SIGLEC11, SIGLEC12, SIGLEC14, SIGLEC15 (CD33L3), SIGLEC16, SIRPA, SIRPB1 (CD172B), TREM1 (CD354), TREM2, KLRF1 (NKp80), 17-1A, SLAM7, MSLN, CTAG1B / NY-ESO-1, MAGEA3 / A6, ATP5I (Q06185), OAT (P29758), AIFM1 (Q9Z0X1), AGFA (Q64133), MTDC (P18155), CMC1 (Q8BH59), PREP (Q8K411), YMEL1 (088967),LPPRC (Q6PB66), LONM (Q8CGK3), ACON (Q99KI0), 0D01 (Q60597), IDHP (P54071), ALDH2 (P47738), ATPB (P56480), AATM (P05202), TMM93 (Q9CQW0), ERG I 3 (Q9CQE7) , RTN4 (Q99P72) , CL041 (Q8BQR4) , ERLN2 (Q8BFZ9) , TERA (Q01853), DADI (P61804) , CALX (P35564) , CALU (035887) , VAPA (Q9WV55) , MOGS (Q80UM7) , GANAB (Q8BHN3), ER01A (Q8R180), UGGG1 (Q6P5E4), P4HA1 (Q60715), HYEP (Q9D379), CALR (P14211), AT2A2 (055143), PDIA4 (P08003), PDIA1 (P09103), PDIA3 (P27773), PDIA6 (Q922R8), CLH (Q68FD5), PPIB (P24369), TCPG (P80318), M0T4 (P57787), NICA (P57716), BAS I (P18572), VAPA (Q9WV55), ENV2 (P11370), VAT1 (Q62465), An immunoconjugate or a pharmaceutically acceptable salt thereof, any one or more selected from the group consisting of 4F2 (P10852), ENOA (P17182), ILK (055222), GPNMB (Q99P91), ENV1 (P10404), ER01A (Q8R180), CLH (Q68FD5), DSG1A (Q61495), AT1A1 (Q8VDN2), HY0U1 (Q9JKR6), TRAP1 (Q9CQN1), GRP75 (P38647), ENPL (P08113), CH60 (P63038), and CH10 (Q64433).

[0147] (10) In any one of (1) to (9) above, the antibody may target HER2.

[0148] (11) A pharmaceutical composition for the prevention or treatment of cancer according to the present invention comprises any one of (1) to (10) an immunoconjugate or a pharmaceutically acceptable salt thereof as an active ingredient.

[0149] (12) A method for preventing or treating cancer according to the present invention comprises the step of administering a therapeutically effective amount of any one of (1) to (10) of an immunoconjugate or a pharmaceutically acceptable salt thereof to an individual in need thereof.

[0150] (13) One use according to the present invention is the use of any one of (1) to (10) of the immunoconjugate or a pharmaceutically acceptable salt thereof for preventing or treating cancer.

[0151] (14) Another use according to the present invention is the use of any one of (1) to (10) of the immunoconjugate or the pharmaceutically acceptable salt thereof in the manufacture of a drug for preventing or treating cancer.

[0152] (15) In any one of (11) to (14) above, the cancer may be a cancer in which NAMPT is overexpressed or overactivated.

[0153] (16) In any one of (11) to (14) above, the cancer may be HER2-positive or mutant cancer. (17) A drug-linker conjugate according to the present invention or a pharmaceutically acceptable salt thereof is represented by the following formula II:

[0154] [Chemical Formula II]

[0155] In the above chemical formula II, LD is a cytotoxic drug moiety represented by the following chemical formula III, and

[0156] [Chemical Formula III] I or one or more -bos are each independently -halogen, -NH2, -NO2, -NHCHs, _N(CH3)2 or -

[0157] Substituted with OH; Li is -CH2-CH2CH2-, -CH2CH2CH2-, -CH(CH3)CH2-, -CH2CH2CH2CH2-, -CH(CH3)CH2CH2-,

[0158] -CH2CH(CH3)CH2-, -C(CH3)2CH2-, -CH2CH2CH2CH2CH2 - or - CH2CH2CH2CH2CH2CH2- and; One or more of the groups are each independently substituted with -C1-C6 alkyl, -halogen, -OH, -NO2, -C1-C6 alkoxy, or -CF3; the group 2 is a single bond, -(CH2)-, -(CH2)『, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(C=0)-NH(CH2)n-, -NH(C=0)-(CH2)n-, or -(C=o)-, where n is 0, 1, 2, 3, or 4; At this time, the above - Cl- C6 alkyl, - Cl- C6 alkoxy, The inner part is unsubstituted or is independently substituted with -halogen, -Cl- C6 alkoxy, -NH2, or -C1-C6 alkyl; the 3 is a single bond, -(CH2)-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, _ NH“ , - NHCH『 , -

[0159] NH(CH2)2 - or -NH(CH2)』, wherein the inner part of L3 is not substituted or at least one inner part of L3 is independently substituted with -Ci-C6alkyl; At this time, the inside of Rs is unsubstituted or at least one of R3s is each independently substituted with -C1-C6 alkyl, -C1-C6 alkoxy, -NH2, -CF3, -OCF3 or -halogen;

[0160] L is a linker moiety connected to the day.

[0161] (18) In the above (17), the formula III may be a compound represented by the following formula III-1:

[0162] (19) In the above (17) or (18), Y is C-OC-X-LW; Ri is

[0163] Li is -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)CH2-, -CH2CH2CH2CH2-, -

[0164] CH2CH2CH2CH2CH2 - or -CH2CH2CH2CH2CH2CH2 -; and at this time, the inside of the above five is unsubstituted or one or more

[0165] -H is each independently substituted with -halogen;

[0166] L2 is a single bond; R2 is -H, -halogen or -NH2, and

[0167] L3 is - (CH2)-, - (C 썻시읗짜.H2)2-, - (CH2) 『, - (CH2)4 - or - (CH2)5 -;

[0168] —S N 즈、.、슈-' ijj

[0169] \、、 /

[0170] R3 is " or ", and at this time, at least one -H of the above R3 may be each independently substituted with -C1-C6 alkyl.

[0171] (20) In any one of (17) to (19) above, the cytotoxic drug moiety represented by the formula III may be any one of the following compounds 1 to 43:

[0172]

[0173]

[0174]

[0175]

[0176] (21) In any one of (17) to (20) above, the cytotoxic drug moiety represented by the above formula III may be any one of the following formulas IV-1 to IV-5:

[0177] [Chemical Formula IV-1] [Chemical Formula IV-5]

[0178] (22) In any one of the above (17) to (21),

[0179] L may be represented by the following chemical formula V:

[0180] [Chemical Formula V] Ly is a single bond, or -valine-citrulline- or -glycine-glycine-phenylalanine-glycine-, and Lx and Ly cannot be single bonds simultaneously;

[0181] Lz is a PABC (para-aminobenzyl carbamate), PAB (para-aminobenzyl), or glucuronide moiety; e is an integer from 1 to 6; h and j are each independently integers from 1 to 3; at least two of f, g and i are 0, and when f, g or i is not 0, f or g is an integer from 2 to 16, and gu is an integer from 16 to 30.

[0182] (23) In any one of the above (17) to (22),

[0183] L may be represented by any one of the following chemical formulas V-1 to V-8:

[0184] [Chemical Formula V-1]

[0185] [Chemical Formula V-3] [Chemical Formula V-8]

[0186] (24) In any one of (17) to (23) above, the drug-linker conjugate or the pharmaceutically acceptable salt thereof may be represented by any one of the following formulas VI-1 to VI-9:

[0187] [Chemical Formula VI-1]

[0188] [Chemical Formula VI-3]

[0189]

[0190] [Chemical Formula VI-6] (25) A benzamide compound according to the present invention, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof may be represented by any one of the following formulas VII-1 to VI 1-8:

[0191] [Chemical Formula VII-1]

[0192] [Chemical Formula VII-5]

[0193]

Effects of the Invention

[0194] [Brief Description of Drawings] Fig. 1 is the result of confirming the enzymatic cleavage of the immunoconjugate of the present invention containing a VC (Vai ine-Citrul 1 ine) linker. Fig. 2 is the result of confirming the enzymatic cleavage of the immunoconjugate of the present invention containing a VC (Vai ine-Citrul 1 ine) linker. Fig. 3 is the result of confirming the enzymatic cleavage of the immunoconjugate of the present invention containing a GGFG (Glycine-Glycine-Pheny lalanine-Glycine) linker. Fig. 4 is the result of confirming the enzymatic cleavage of the immunoconjugate of the present invention containing a GGFG (Glycine-Glycine-Pheny lalanine-Glycine) linker. Fig. 5 is the result of confirming the enzymatic cleavage of the immunoconjugate of the present invention containing a P-glucuronide linker. Fig. 6 is the result of confirming the pharmacokinetics of total antibodies of the immunoconjugate of the present invention in rat plasma. Figure 7 shows the results of confirming the pharmacokinetics of total antibodies of the immunoconjugate of the present invention in rat plasma. Figure 8 shows the results of confirming the stability of total antibodies of the immunoconjugate of the present invention in plasma and buffer solution. Figure 10 shows the results of confirming the stability of total antibodies of the immunoconjugate of the present invention in plasma and buffer solution. Figure 11 shows the results of confirming the stability of total antibodies of the immunoconjugate of the present invention in plasma and buffer solution. Figure 12 shows the results of confirming the antigen binding ability of the immunoconjugate of the present invention through HER2 extracellular domain competitive ELISA. Figure 13 shows the results of confirming the antigen binding ability of the immunoconjugate of the present invention through flow cytometry cell binding ability test. Figure 14 shows the results of confirming the internalization ability of the immunoconjugate of the present invention through incucyte cell internalization analysis.Figure 15 is the result of confirming the anticancer effect of the immunoconjugate of the present invention in an NCI-N87 xenograft animal model. Figure 16 is the result of confirming the anticancer effect of the immunoconjugate of the present invention in an NCI-N87 xenograft animal model. Figure 17 is the result of confirming the body weight of mice administered the immunoconjugate of the present invention in an NCI-N87 xenograft animal model. Figure 18 is the result of confirming the body weight of mice administered the immunoconjugate of the present invention in an NCI-N87 xenograft animal model.

[0195]

Forms for Carrying Out the Invention

[0196] <1. Preparation of Cytotoxic Drugs > Example 1: Synthesis of N-(3-(1H-pyrazol-4-yl)propyl)-3-((4-fluorophenyl)ethynyl)-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide QV~(3-(1H-pyrazol-4-y1)propy1)-3-((4-fluorophenyl)ethynyl)—4—((1—methyl—lH—pyrazol-1—3—yl)methyl)sulfonyl)benzamide, Compound 1). Reagents and conditions. (a) Na2S, DMF, room temperature (rt), 16 hours (16h) (b) 3-(chloromethyl)-1-methyl-1H-pyrazole, K2CO3, DMF, room temperature (rt), 16 hours (16h) (c) mCPBA, DCM, room temperature (rt) 16 hours (16h) (d) Fe, AcOH, 80 °C, 2 hours (2h) (e) HC1, NaNO2, KI, H2O, 0°C to room temperature (0°C- rt),

[0197] 1 hour (lh) (f) PdC12[PPh3]2, Cui, TEA, ACN, room temperature (rt), 16 hours (16h) (g) NaOH, H2O, MeOH, 55 °C, 2 hours (2h) (h) 3-(1H-pyrazol-4-yl)propane-1-amine dihydrochloride (3-(1H-pyrazol-

[0198] Step 1) Synthesis of methyl 4-mercapto-3-nitrobenzoate Methyl 4-fluoro-3-nitrobenzoate (10 g, 46.4 mmol, 1 eq) was dissolved in DMF (80 ml), sodium sulfide (4.32 g, 55.3 mmol, 1.2 eq) was added, and the mixture was stirred at room temperature for 16 hours. After the reaction was finished, 200 ml of water was added to the reaction mixture, and the pH was adjusted to 5 using HC1 while stirring. The yellow solid formed during stirring was filtered and washed with a suspension of 25% EA / HX to obtain the target compound (6.13 g, 28.7 mmol, 62%). Step 2) Methyl 4-(((1-methyl-1H-pyrazole-3-yl)methyl)thio)-3-nitrobenzoate

[0199] Synthesis of (methyl 4-(((1-methyl-1H-pyrazol-3-yl )methyl )thio)-3-nitrobenzoate): Methyl 4-mercapto-3-nitrobenzoate (4 g, 18.8 mmol, 1 eq) was dissolved in DMF (40 ml), K2CO3 (5.18 g, 37.52 mmol, 2 eq) was added, and the mixture was stirred. When the reaction mixture turned dark red, 3-(chloromethyl)-1-methyl-1H-pyrazole (2.45 g, 18.8 mmol, 1 eq) was added to the reaction mixture and the mixture was stirred for 16 hours. The reaction was confirmed by TLC, and once the reaction was finished, water was added to the reactants and the resulting precipitate was filtered to obtain the target compound (5.14 g, 16.7 mmol, 89%). Step 3) Synthesis of methyl 4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)-3-nitrobenzoate methyl 4-(((1-methyl-1H-pyrazol-3-yl)methyl)thio)-3-nitrobenzoate (5.14 g, 16.7 mmol, 1 eq) was dissolved in DCM (100 ml), mCPBA (12.2 g, 50.2 mmol, 3 eq) was added, and the mixture was stirred for 16 hours. The reaction was monitored by TLC, and once the reaction was complete, water was added to dilute the mixture, it was neutralized with a saturated aqueous NaHCOs solution, and extracted several times with DCM. The organic layer was dried with magnesium sulfate and concentrated under reduced pressure to obtain the unpurified target compound.Step 4) Synthesis of methyl 3-amino-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzoate (methyl 3-amino-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)-3-nitrobenzoate (methyl 4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)-3-nitrobenzoate, 16.7 mmol, 1 eq) was mixed with AcOH (100 ml) and iron (9.32 g, 167 mmol, 10 eq) and stirred at 80°C for 2 hours. The catalyst was removed by Celite filtration, and the filtrate was concentrated under reduced pressure. The residue was basicized with an aqueous potassium carbonate solution and extracted with ethyl acetate, after which the organic layer was concentrated under reduced pressure. The target compound was obtained as a crude product. Step 5) Methyl 3-iodo-4-(((1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)benzoate.

[0200] A solution of sodium nitrite (1.73 g, 25 mmol, 1.5 eq) dissolved in a synthesis of (methyl 3-iodo-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzoate) (40 ml) was slowly added dropwise at 0°C to a suspension of methyl 3-amino-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzoate (16.7 mmol, 1 eq) in an aqueous solution of concentrated hydrochloric acid (40 ml) and water (40 ml). The mixture was stirred in an ice bath for 30 minutes, and a solution of potassium iodide (8.3 g, 50 mmol, 3 eq) dissolved in water (40 mL) was added to the mixture at 0°C. The reaction mixture was stirred at room temperature for 1 hour, treated with an aqueous solution of saturated potassium carbonate (pH > 8), and extracted with ethyl acetate. The organic layer was washed with water, dried with magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, 30-50% EA / HX) to obtain the target compound (3.24 g, 3 steps [(c), (d), (e)] yield 46%). Step 6) Synthesis of methyl 3-((4-fluorophenyl)ethynyl)-4-(( (1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzoate (methyl 3-iodo-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzoate (methyl 3— iodo— 4— (((1— methyl— 1H— pyrazol— 3— yl)methyl)sulfonyl)benzoate, 0.MeCN (10 ml, 0.2 M) and TEA (0.84 ml, 6 mmol, 3 eq) were added to 84 g (2 mmol, 1 eq). PdC12[PPh3]2 (42 mg, 3 mol%) and Cul (2 mg, 3 mol%) were added to the reaction mixture and stirred at room temperature for 5 minutes under a nitrogen atmosphere. Subsequently, 4-fluorophenylacetylene (0.29 g, 2.4 mmol, 1.2 eq) was added. The reaction mixture was stirred at room temperature for 16 hours and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, 40-50% EA / HX) to obtain the target compound (1.7 mmol, 85%). Step 7) Synthesis of 3-((4-fluorophenyl)ethynyl)-4-(( (1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzoic acid (3-((4-fluorophenyl)ethynyl )-4-( ( ( 1-methyl-1H-pyrazol-3-yl)methyl )sulfonyl )benzoate (methyl 3-( (4-fluorophenyl)ethynyl )-4-( ( (1-methyl-1H-pyrazol-3-yl)methyl )sulfonyl )benzoate , MeOH (17 ml, 0.1 M), H2O (8.5 ml, 0.2 M), and NaOH (0.17 g, 4.3 mmol, 2.5 eq) were added to 0.7 g, 1.7 mmol, 1 eq, and the mixture was stirred at 55°C for 2 hours. The reaction was monitored by TLC; upon completion, the pH of the reaction mixture was adjusted to 1 using an aqueous solution of INHC1, and extracted with a Toyo extractor. The organic layer was washed with water, dried with magnesium sulfate, and concentrated under reduced pressure to obtain the target compound (0.62 g, 92%).Step 8) Synthesis of N-(3-(1H-pyrazole-4-yl)propyl)-3-((4-fluorophenyl)ethynyl)-4-(((1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)benzamide G¥(3-(lH-pyrazol-4-yl)propyl)-3-((4-fluorophenyl)ethynyl)—4—(((1-methyl-1-lH-pyrazol-1-3-yl)methyl)sulfonyl)benzamide).

[0201] DCM (5 ml) and TBTU (0.14 g, 0.45 mmol, 1.5 eq) were added to 3-((4-fluorophenyl)ethynyl)-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzoic acid (3-(4-fluorophenyl)ethynyl )-4-(((1-methyl-1H-pyrazol-3-yl)methyl )sulfonyl )benzoic acid, 0.12 g, 0.3 mmol, 1 eq) and stirred at room temperature for 50 minutes. Next, TEA (0.15 ml, 1.11 mmol, 3.7 eq) and 3-(1H-pyrazol-4-yl)propan-1-amine dihydrochloride (71 mg, 0.36 mmol, 1.2 eq) were added to the reaction mixture and stirred for 12 hours. Water was added to the reaction mixture and extracted with a Toyo. After drying the organic layer with magnesium sulfate and concentrating under reduced pressure, the resulting residue was purified by column chromatography (silica gel, 3-4% MeOH / DCM) to obtain the target compound (0.1 g, 0.20 mmol, 66%). P NMR (400 MHz, CDCls) 8 8.01 (d, J = 1.6 Hz, 1H) , 7.94 (d, J = 8.2 Hz, 1H), 7.73 - 7.66 (m, 3H) , 7.49 (s, 2H) , 7.23 (d, J = 2.2 Hz, 1H) , 7.13 (t, J= 8.7 Hz, 2H), 6.35 — 6.32 (m, 1H) , 6.17 (d, J= 2.2 Hz, 1H) , 4.79 (s, 2H) , 3.79 (s, 3H) , 3.55 (q, J = 6.4 Hz, 2H) , 2.66 (t, J = 7.4 Hz, 2H) , 1.97 (p, J = 7.4 Hz, 2H) .

[0202] MS(ESI) m / z MH +506.2 Example 2: 3 - ((4 - fluorophenyl) ethynyl)-N - (imidazo[1,2 - a]pyridin - 7 - ylmethyl)-4 - (((1 - methyl - 1H - pyrazol - 3 - yl)methyl)sulfonyl)benz 0}White]d (3 - ((4 - fluorophenyl)ethynyl)-N - (imidazo[1,2 - a]pyridin - 7 - ylmethyl)-4 - (((1 - methyl - 1H - pyrazol - 3 - yl)methyl)sulfonyl)benzamide, Compound 2) synthesis

[0203] 1 - {imidazo[1,2 - a]pyridin - 7 - yl}methanamine dihydrochloride was used to synthesize the target compound in the same manner as in step 8) of Example 1. Among them, NMR (400 MHz, DMSO - d6) δ 9.47 - 9.44 (m, 1H), 8.52 (d, J = 7.1 Hz, 1H),

[0204] 8.33 (s, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.97 - 7.88 (m, 2H), 7.82 - 7.76 (m, 2H),

[0205] 7.60 (s, 1H), 7.54 (s, 1H), 7.46 (s, 1H), 7.39 (t, J = 8.4 Hz, 2H), 6.89 (d, J =

[0206] 6.7 Hz, 1H), 6.10 (s, 1H), 4.88 (s, 2H), 4.55 (d, J = 5.4 Hz, 2H), 3.72 (s, 3H).

[0207] MS(ESI) m / z MH +528.4 Example 3: Synthesis of N-(2-(1H-pyrrolo[3,2-c]pyridin-3-yl)ethyl)-3-((4-fluorophenyl)ethynyl)-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide (N-(2-(1H-pyrrolo[3,2-c]pyridin-3-yl)ethyl)-3-((4-fluorophenyl)ethyny 1)-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide, Compound 3).

[0208] The target compound was synthesized using 1-{1H-pyrrolo[3,2-c]pyridin-2-yl}methanamine dihydrochloride in the same manner as in Step 8 of Example 1. P NMR (400 MHz, MeOD) 5 8.91 (s, 1H), 8.15 (d, J = 5.8 Hz, 1H), 8.10 (s, 1H), 7.90 (d, J = 8.3 Hz, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.78–7.72 (m, 2H), 7.45

[0209] (m, 2H), 7.32 (s, 1H), 7.24 (t, J = 8.3 Hz, 2H), 6.17 (s, 1H), 4.83 (s, 2H), 3.78

[0210] - 3.72 (m, 5H), 3.19 (t, J = 7.1 Hz, 2H). 540.4 Example 4: 3-(chloromethyl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole (3-

[0211] Synthesis of (chloromethyl )—1— (4— (tri fluoromethyl )phenyl )— 1H— pyrazole) Reactants and Conditions (Reagent and condition). (a) 1-iodo-4-

[0212] (a) (1-iodo-4-(trifluoromethyl)benzene), Cui, K3PO4, (1S,2S)-(+)-N,N'-dimethylcyclohexane-1,2-diamine, 110 °C, 16 hours (16h) (b) LiAlH4 (1.0M L1AIH4 in THF), THF, 0 °C to room temperature (0 °C -rt), 1 hour (1h) (c) SOCI2, DCM, room temperature (rt), 12 hours (12h) Step 1) Methyl 1-(4-(trifluoromethyl)phenyl)-IH-pyrazole-3-carboxylate

[0213] Synthesis of (methyl 1-(4-(trifluoromethyl)phenyl)-lH-pyrazole-3-carboxylate) methyl IH-pyrazole-3-carboxylate (methyl IH-pyrazole 1 e-3~carboxylate, 1 g, 7.9 mmol, 1 eq), 1-iodo-4-(trifluoromethyl)benzene (l-iodo-4-

[0214] ( tr if luoromethy 1 )benzene , 2.15 g, 1 eq), Cui (0.24 g, 1.27 mmo 1 , 0.16 eq), (1S,2S)— (+)- N,N'-dimethylcyclohexane- 1,2-diamine ((1S,2S)-(+)-N,N'- Dimethylcyclohexane- 1,2- diamine, 0.28 ml , 1.7 mmo 1 , 0.22 eq), K3PO4 (4 g, 19 mmol , 2.4 eq), and toluene (10 ml, 0.8 M) were placed in a pressure tube and stirred at 110°C for 16 hours. The reaction mixture was cooled to room temperature, water and oil were added, and the mixture was separated. After drying the organic layer with magnesium sulfate and concentrating under reduced pressure, the resulting residue was purified by column chromatography (silica gel, 10% EA / HX) to obtain the target compound (1.4 g, 5.2 mmol, 65%). Step 2) (1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-yl)methanol ((1-(4-

[0215] Synthesis of (trifluoromethyl)phenyl)-IH-pyrazole-3-carboxylate (methyl 1-(4-(trifluoromethyl)phenyl)-IH-pyrazole-3-carboxylate, 1 g, 3.7 mmol, 1 eq) was dissolved in anhydrous THF, and lithium aluminum hydride solution (1.0 M in THF solution, 3.7 ml) was added dropwise at 0°C. After stirring at room temperature for 1 hour, the reaction mixture was cooled to 0°C. Water (1 ml), aqueous NaOH solution (1 ml), and water (2 ml) were added to the reactants in sequence, and after the reaction was completed, the solution was filtered through Celite. The filtrate was concentrated under reduced pressure to obtain the unpurified target compound. Step 3) 3-(chloromethyl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole (3-

[0216] Synthesis of (chloromethyl )-1- (4- (tri fluoromethyl )phenyl)-1H-pyrazole)

[0217] (1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-yl)methanol ((1-(4-

[0218] N-(3-(1H-pyrazol-4-yl)propyl)-3-((4-fluorophenyl)ethynyl)-4-(((1-(4-(trifluoromethyl)phenyl)phenyl)-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide (N-(3-(1H-pyrazol-4-yl)propyl )-3-((4-fluorophenyl)ethynyl)-4-(( (1-(4-(trifluoromethyl)phenyl)phenyl)-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide (N-(3-(1H-pyrazol-4-yl)propyl )-3-((4-fluorophenyl)ethynyl )ethyny )-4-( ( (1-(4-(trifluoromethyl)phenyl)phenyl)-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide

[0219] Synthesis of (trifluoromethyl)phenyl)-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide, compound 4)

[0220] Reactants and conditions. (a) Na2S, DMF, reflux,

[0221] 2 hours (2h) (b) 3-(chloromethyl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole (3-

[0222] (chloromethyl)- 1-(4- (tri fluoromethyl )phenyl)-lH- pyrazole), K2CO3, DMF, room temperature (rt),

[0223] 0.5 hours (0.5h) (c) mCPBA, DCM, room temperature (rt), 16 hours (16h) (d) PdCMPPhzh, Cui, TEA,

[0224] ACN, room temperature (rt), 16 hours (16h) (e) NaOH, H2O, MeOH, 60 °C, 12 hours (12h) (f) 3-(1H-pyrazol-4-yl)propan-1-amine dihydrochloride (3-(1H-pyrazol-4-yl)propan-1-amine dihydrochloride), TBTU, TEA, DCM, 12 hours (12h) Step 1) Synthesis of methyl 3-iodo-4-mercaptobenzoate Methyl 4-fluoro-3-iodobenzoate (5 g, 17.8 mmol, 1 eq) was dissolved in DMF (20 ml) and sodium sulfide Sodium sulfide (1.53 g, 19.6 mmol, 1.1 eq) was added and stirred under reflux for 2 hours. Water was added to the reaction mixture, acidified with HC1, and extracted several times with oil. The organic layer was dried with magnesium sulfate, and the residue obtained by concentration under reduced pressure was used as the crude product to obtain the target compound. Step 2) Synthesis of methyl 3-iodo-4-(((1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)methyl)thio)benzoate.

[0225] 3-(chloromethyl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole (94 mg, 0.36 mmol, 1 eq) was dissolved in DMF (2 ml), and methyl 3-iodo-4-mercaptobenzoate (0.36 mmol, 0.1 g) was added to the reaction mixture containing K2CO3 (0.098 g, 0.71 mmol, 2 eq) and stirred for 30 minutes. Water was added to the reaction mixture and extracted several times with oil. The organic layer was washed with a saturated aqueous NH4Cl solution, separated, dried with magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 10% EA / HX) to obtain the target compound (78 mg, 0.15 mmol, 42%). Step 3) Synthesis of methyl 3-iodo-4-(((1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)methyl)sulfonyl)benzoate (methyl 3-iodo-4-(((1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)methyl)thio)benzoate (methyl 3-iodo-4-(((1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)methyl)thio)benzoate (methyl 3-iodo-4-(((1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)methyl)thio)benzoate, 0.1 g, 0.61 mmol, 1 eq) in DCM (30 ml). The mixture was dissolved, and mCPBA (0.45 g, 1.83 mmol, 3 eq) was added and stirred for 16 hours. The reaction was monitored by TLC, and once the reaction was complete, water was added to dilute it, the solution was neutralized with a saturated aqueous solution of NaHCOs, and extracted several times with DCM.After drying the organic layer with magnesium sulfate and concentrating it under reduced pressure, the resulting residue was purified by column chromatography (silica gel, 25% EA / HX) to obtain the target compound (0.19 g, 0.34 mmol, 57%). Step 4) Synthesis of methyl 3-((4-fluorophenyl)ethynyl)-4-(((1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)methyl)sulfonyl)benzoate MeCN (1 ml, 0.2 M) was added to sulfonyl benzoate (0.1 g, 0.19 mmol, leq), followed by TEA (0.078 ml, 0.56 mmol, 3 eq). PdCldPPhzh (4 mg, 3 mol%) and Cul (1 mg, 3 mol%) were added to the reaction mixture and stirred at room temperature under a nitrogen atmosphere for 5 minutes. Subsequently, 4-fluoropenylacetylene (27 mg, 0.22 mmol, 1.2 eq) was added. The reaction mixture was stirred at room temperature for 16 hours and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, 30% EA / HX) to obtain the target compound (86 mg, 0.16 mmol, 85%).Step 5) 3-((4-fluorophenyl)ethynyl)-4-(((1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-yl)methyl)sulfonyl)benzoic acid (3-( (4-fluorophenyl )ethynyl )-4-( ( ( 1-(4-.

[0226] Synthesis of (trifluoromethyl)phenyl)-1H-pyrazol-3-yl)methyl)sulfonyl)benzoic acid)methyl 3-((4-fluorophenyl)ethynyl)-4-(((1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)methyl)sulfonyl)benzoate (methyl 3-((4-fluorophenyl)ethynyl)-4-(((l-(4-(trifluoromethyl)phenyl)phenyl)-lH-pyrazol-1-3-yl)methyl)sulfonyl)benzoate, 0.085 g, 0.16 mmol, 1 eq) in MeOH (1 ml, 0.1 M), H2O (0.5 ml, 0.2 M), NaOH (0.016 g, 0.4 mmol, 2.5 eq) was added and stirred at 60°C for 2 hours. NaOH (0.016 g, 0.4 mmol, 2.5 eq) was additionally added and stirred for 12 hours. The reaction was monitored by TLC; once the reaction was complete, the pH of the reaction mixture was adjusted to 1 using an aqueous solution of INHC1 and extracted with a Toyo extractor. The organic layer was washed with water, separated, dried with magnesium sulfate, and concentrated under reduced pressure to obtain the target compound (0.075 g, 90%). Step 6) Synthesis of N-(3-(1H-pyrazol-4-yl)propyl)-3-((4-fluorophenyl)ethynyl)-4-(((1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide (N-(3-(1H-pyrazol-4-yl)propyl )—3—((4-fluorophenyl )ethynyl )—4—((((1-(4-(trifluoromethyl )phenyl )—1H-pyrazol-3-yl )methyl )sulfonyl )benzamide).

[0227] 3-( (4-fluorophenyl)ethynyl)- 4-( ( (1-(4-(trifluoromethyl)phenyl)- 1H-pyrazole- 3- yl) methyl) sulfonyl) benzoic acid (3- ( (4- fluorophenyl )ethynyl )-4-( ( (l-(4-

[0228] DCM (2.5 ml) and TBTU (0.037 g, 0.21 mmol, 1.5 eq) were added to (tr if luoromethyl )phenyl )-lH-pyrazo 1-3-yl )methyl )sulfonyl )benzoic acid, 0.075 g, 0.14 mmol, 1 eq) and stirred at room temperature for 50 minutes. Then, TEA (0.072 ml, 0.52 mmol, 3.7 eq) and 3-(1H-pyrazol-4-yl)propan-1-amine dihydrochloride (3-(1H-pyrazol-4-yl )propan-1-amine dihydrochloride, 0.034 g, 0.17 mmol, 1.2 eq) were added to the reaction mixture and stirred for 12 hours. Water was added to the reactants and extracted using a Toyo extractor. The organic layer was dried with magnesium sulfate, and the residue obtained by concentration under reduced pressure was purified by column chromatography (silica gel, 2% MeOH / DCM) to obtain the target compound. P NMR (400 MHz, MeOD) 5 8.25–8.22 (m, 2H), 7.98 (d, J = 8.1 Hz, 1H).

[0229] 7.87 (d, J = 8.1 Hz, 1H), 7.73 (m, 6H), 7.49 (m, 2H), 7.20 (t, J = 8.5 Hz, 2H),

[0230] 6.53 (s, 1H), 4.99 (s, 2H), 3.45 (d, J = 6.8 Hz, 2H), 2.63 (t, J = 7.4 Hz, 2H),

[0231] 1.98 - 1.92 (m, 2H).

[0232] MS(ESI) m / z [MH]' 634.4 Example 6: N-(3-(1H-pyrazole-4-yl)propyl)-4-((2,3-dimethylbenzyl)sulfonyl)-3-((4-fluorphenyl)ethinyl)benz 6 Synthesis of}White]d ( N— ( 3— ( 1H— pyr azo 1 — 4— y 1 )pr opy 1 ) —4 — ((2,3— dimethylbenzyl)sulfonyl)— 3— ((4— fluorophenyl )ethynyl)benzamide, compound 5) Reagents and Conditions (a) 1-(bromomethyl)-2,3-dimethylbenzene, K2CO3, DMF, room temperature (rt), 0.5 hours (0.5h) (b) mCPBA, DCM, room temperature (rt), 16 hours (16h) (c) PdCl2[PPh3]2, Cui, TEA, ACN, room temperature (rt), 16 hours (16h)

[0233] (d) NaOH, H2O, MeOH, 55 °C, 12 hours (12h) (e) 3-(1H-pyrazol-4-yl)propan-1-amine dihydrochloride), TBTU, TEA, DCM, 12 hours (12h) Step 1) Synthesis of methyl 4-((2,3-dimethylbenzyl)thio)-3-iodobenzoate

[0234] 1-(bromomethyl)-2,3-dimethylbenzene (0.07 g, 0.36 mmol, 1 eq) was dissolved in DMF (2 ml), and methyl 3-iodo-4-mercaptobenzomate (0.1 g, 0.36 mmol, 1 eq) was added to the reaction mixture containing K2CO3 (0.098 g, 0.71 mmol, 2 eq) and stirred for 30 minutes. Water was added to the reaction mixture and extracted several times with a sieve. The organic layer was washed with a saturated aqueous NH4Cl solution, separated, dried with magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 10% EA / HX) to obtain the target compound. Step 2) Synthesis of methyl 4-((2,3-dimethylbenzyl)sulfonyl)-3-iodobenzoate. Methyl 4-((2,3-dimethylbenzyl)thio)-3-iodobenzoate (0.31 g, 0.75 mmol, 1 eq) was dissolved in DCM (30 ml), and mCPBA (0.55 g, 2.3 mmol, 3 eq) was added and stirred for 16 hours. The reaction was monitored by TLC, and once the reaction was complete, water was added to dilute it, neutralized with a saturated aqueous NaHCOs solution, and extracted several times with DCM. After drying the organic layer with magnesium sulfate and concentrating it under reduced pressure, the resulting residue was purified by column chromatography (silica gel, 20% EA / HX) to obtain the target compound (0.17 g, 0.39 mmol, 52%).Step 3) Synthesis of methyl 4-((2,3-dimethylbenzyl)sulfonyl)-3-((4-fluorophenyl)ethynyl)benzoate (methyl 4-((2,3-dimethylbenzyl)sulfonyl)-3-((4-fluorophenyl)ethynyl)benzoate) methyl 4-((2,3-dimethylbenzyl)sulfonyl)-3-iodobenzoate (methyl 4-((2,3-dimethylbenzyl)sulfonyl)-3-iodobenzoate, 0.17 g, 0.38 mmol, 3 eq) was mixed with MeCN (2 ml, 0.2 M) and TEA (0.16 ml, 1.15 mmol, 3 eq). PdCMPPhyh (8 mg, 3 mol%) and Cui (2 mg, 3 mol%) were added to the reaction mixture and stirred at room temperature under a nitrogen atmosphere for 5 minutes. Subsequently, 4-fluorophenylacetylene (55 mg, 0.45 mmol 1, 1.2 eq) was added. The reaction mixture was stirred at room temperature for 16 hours and concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain the target compound (0.165 g, 0.38 mmol, 99%). Step 4) Synthesis of 4-((2,3-dimethylbenzyl)sulfonyl)-3-((4-fluorophenyl)ethynyl)benzoic acid (4-((2,3-dimethylbenzyl)sulfonyl)-3-((4-fluorophenyl)ethynyl)benzoate.

[0235] (methyl 4—((2, 3-dimethy Ibenzy 1 )sulf ony 1 )—3—( (4— f 1 uor opheny 1 )ethynyl )benzoate,

[0236] MeOH (1 ml, 0.1 M), H2O (0.5 ml, 0.2 M), and NaOH (0.016 g, 0.4 mmol, 2.5 eq) were added to 0.165 g, 0.38 nmol, 1 eq, and the mixture was stirred at 85°C for 12 hours. The reaction was monitored by TLC; upon completion, the pH of the reaction mixture was adjusted to 1 using an aqueous solution of INHC1, and the mixture was extracted with a Toyo extractor. The organic layer was washed with water, separated, dried with magnesium sulfate, and concentrated under reduced pressure to obtain the target compound as the crude product. Step 5) Synthesis of N-(3-(1H-pyrazol-4-yl)propyl)-4-((2,3-dimethylbenzyl)sulfonyl)-3-((4-fluoropenyl)ethynyl)benzamide (N-(3-(1H-pyrazol-4-yl)propyl)-4-((2,3-dimethylbenzyl)sulfonyl)-3-((4-fluoropenyl)ethynyl)benzamide).

[0237] 4 - ((2, 3 - Dimethylbenzyl)sulfonyl)-3 - ((4 - fluorophenyl)ethynyl)benzoic acid (0.15 g, 0.35 mmol, 1 eq) was added to DCM (5 ml) and TBTU (0.17 g, 0.53 mmol, 1.5 eq), and the mixture was stirred at room temperature for 50 minutes. Subsequently, TEA (0.18 ml, 1.3 mmol, 3.7 eq) and 3 - (1H - pyrazol - 4 - yl)propan - 1 - amine dihydrochloride (0.083 g, 0.42 mmol, 1.2 eq) were added to the reaction mixture, and it was stirred for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with toluene. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue obtained was purified by column chromatography (silica gel, 3 - 5% MeOH / DCM) to obtain the target compound (0.07 g, 0.13 mmol, 38%). 1H NMR (400 MHz, DMSO - d6) δ 12.51 (s, 1H), 8.83 (m, 1H), 8.27 (s, 1H), 8.00 (d, J = 8.3 Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.77 - 7.70 (m, 2H), 7.52 (br, 1H), 7.37 (d, J = 8.5 Hz, 2H), 7.10 (d, J = 7.4 Hz, 1H), 6.95 (t, J = 7.5 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 4.91 (s, 2H), 3.32 (m, 2H), 2.48 (m, 2H), 2.19 (s, 6H), 1.80 (p, J = 7.0 Hz, 2H).

[0238] MS(ESI) m / z [MH]' 528.4 Example 7: N-(3-(1H-pyrazole-4-yl)propyl)-3-((4-fluorophenyl)ethynyl)-4-(N-methylsulfamoyl)benz 0} 1 Synthesis of (N— (3— ( 1H— pyr azo 1— 4— y 1 )propyl)—3—((4— f luorophenyQethynyl)- 4- (N- methylsulfamoyl)benzamide, compound 6) Reagents and Conditions (a) Na₂S, DMF, room temperature (rt), 16 hours (16h) (b) n-chlorosuccinimide, 2N HC₃(aq.), MeCN, room temperature (rt.t), 16 hours (16h) (c) methylamine, EtOH, MeCN, room temperature (rt), 1 hour (Ih) (d) Fe, AcOH, 80 °C, 1 hour (Ih) (e) HC₃, NaNO₂, KI, H₂O, 0 °C, room temperature (rt), 1 hour (Ih) (f) PdCMPPhzk Cui, TEA, ACN, room temperature (rt), 1 hour (Ih) (g) NaOH, H₂O, MeOH, 55 °C, 4 hours (4h) (h) Step 1) Synthesis of methyl 4-mercapto-3-nitrobenzoate methyl 4-fluoro-3-nitrobenzoate (10 g, 46.4 mmol, 1 eq) was dissolved in DMF (80 ml), sodium sulfide (4.32 g, 55.3 mmol, 1.2 eq) was added, and the mixture was stirred at room temperature for 16 hours. After the reaction was finished, 200 ml of water was added to the reaction mixture, and the mixture was stirred while adjusting the pH to 5 using IN HC1. The yellow solid formed during stirring was filtered, and after washing the suspension with 25% EA / HX, the target compound (6.13 g, 28.7 mmol, 62%) was obtained.Step 2) Synthesis of methyl 4-(chlorosulfonyl)-3-nitrobenzoate. Methyl 4-mercapto-3-nitrobenzoate (1 g, 4.9 mmol, 1 eq) was added to the reaction mixture of n-chlorosuccinimide (3.3 g, 24.5 mmol, 5 eq), 2N HC1 aqueous solution (5.2 ml, 2 eq), and MeCN (50 ml) in an ice bath and stirred at room temperature for 16 hours. After the reaction was complete, 20 ml of water was added and the MeCN was concentrated under reduced pressure. The residue was extracted several times with a Toyo and washed several times with a saturated aqueous NaHCOs solution and brine. The organic layer was dried with magnesium sulfate and concentrated under reduced pressure to obtain the residue, from which the target compound was obtained as the crude product. Step 3) Synthesis of methyl 4-(N-methylsulfamoyl)-3-nitrobenzoate. Methyl 4-(chlorosulfonyl)-3-nitrobenzoate (0.2 g, 0.71 mmol, 1 eq) was dissolved in MeCN, then a methylamine solution (33 wt.% in absolute ethanol) was added and stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the residue obtained by concentrating MeCN under reduced pressure was extracted several times with a Toyo. The organic layer was dried with magnesium sulfate and concentrated under reduced pressure, and the resulting residue was purified by column chromatography (silica gel, 20-50% EA / HX) to obtain the target compound (0.13 g, 0.47 mmol, 66%).Step 4) Synthesis of methyl 3-amino-4-(N-methylsulfamoyl)benzoate. AcOH (5 ml) and iron (0.26 g, 4.67 mmol, 10 eq) were added to methyl 4-(N-methylsulfamoyl)-3-nitrobenzoate (0.128 g, 0.47 mmol, 1 eq) and stirred at 80 °C for 1 hour. The catalyst was removed by Celite filtration, and the filtrate was concentrated under reduced pressure. The residue was basicized with an aqueous potassium carbonate solution and extracted with ethyl acetate; afterward, the organic layer was concentrated under reduced pressure to obtain the target compound as a crude product. Step 5) A solution of sodium nitrite (0.03 g, 0.4 mmol, 1.5 eq) dissolved in the synthesized product of methyl 3-iodo-4-(N-methylsulfamoyl)benzoate (1 ml) was slowly added dropwise at 0 °C to a suspension of methyl 3-amino-4-(N-methylsulfamoyl)benzoate (0.065 g, 0.27 mmol, 1 eq), concentrated aqueous hydrochloric acid (1 ml), and water (1 ml). The mixture was stirred in an ice bath for 30 minutes, and a solution of potassium iodide (0.13 g, 0.8 mmol, 3 eq) dissolved in water (1 mL) was added to the mixture at 0 °C. The reaction mixture was stirred at room temperature for 1 to 2 hours and extracted with ethyl acetate by treatment with an aqueous solution of saturated potassium carbonate (pH > 8). The organic layer was dried with magnesium sulfate and concentrated under reduced pressure; the resulting residue was purified by column chromatography (silica gel, 20–60% EA / HX) to obtain the target compound (0.0.6 g, 0.17 mmol, 63%) was obtained. Step 6) Methyl 3-((4-fluorophenyl)ethinyl)-4-(N-methylsulfamoyl)benzoate.

[0239] Synthesis of (methyl 3-( (4-f luorophenyl )ethynyl ) -4 - ( N-methyl t hy 1 su 1 f amoy 1 )benzoate): MeCN (1 ml) was added to methyl 3-iodo-4-(N-methylsulfamoyl )benzoate (0.06 g, 0.17 mmol, 1 eq) and TEA (0.071 ml, 0.51 mol, 3 eq). PdCLdPPhzh (0.0036 mg, 3 mol%) and Cui (0.001 mg, 3 mol%) were added to the reaction mixture and stirred at room temperature under a nitrogen atmosphere for 5 minutes. Next, 4-fluoropenyl-acetylene (0.024 g, 0.2 mmol, 1.2 eq) was added. The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, 40% EA / HX) to obtain the target compound (0.059 g, 0.17 mmol, 99%). Step 7) Synthesis of 3-((4-fluorophenyl)ethynyl)-4-(N-methylsulfamoyl)benzoic acid (3-((4-fluorophenyl)ethynyl)-4-(N-methylsulfamoyl)benzoate (0.089 g, 0.26 mmol, 1 eq) in MeOH (2.6 ml, 0.1 M), H2O (1.3 ml, 0.2 M), NaOH (0.026 g, 0.64 mmol, 2.5 ml) eq) was added and stirred at 55 °C for 4 hours. The reaction was monitored by TLC, and once the reaction was complete, the pH of the reaction product was adjusted to 1 with an aqueous solution of IN HC1 and extracted with Toyo.The organic layer was washed with water, separated, dried with magnesium sulfate, and concentrated under reduced pressure to obtain the target compound as a crude product. Step 8) Synthesis of N-(3-(1H-pyrazol-4-yl)propyl)-3-((4-fluorophenyl)ethynyl)-4-(N-methylsulfamoyl)benzamide (N-(3-(lH-pyrazol-4-yl)propyl)-3-((4-fluorophenyl)ethynyl)-4-(N-methylsulfamoyl)benzamide).

[0240] DCM (5 ml) and TBTU (0.12 g, 0.38 mmol, 1.5 eq) were added to 3-((4-fluorophenyl)ethynyl)-4-(N-methylsulfamoyl)benzoic acid (3-((4-fluorophenyl)ethynyl)-4-(N-methyl sul f amoyl)benzoic acid, 0.084 g, 0.25 mmol, 1 eq) and stirred at room temperature for 50 minutes. Next, TEA (0.13 ml, 0.93 mmol, 3.7 eq) and 3-(1H-pyrazol-4-yl)propan-1-amine dihydrochloride (3-(1H-pyrazol-4-yl)propan-1-amine dihydrochloride, 0.060 g, 0.3 mmol, 1.2 eq) were added to the reaction mixture and stirred for 12 hours. Water was added to the reaction mixture and extracted with a Toyo extractor. After drying the organic layer with magnesium sulfate and concentrating it under reduced pressure, the resulting residue was purified by reverse-phase column chromatography (C18 Aq, 40% ACN / 0.1% formic acid in water) to obtain the target compound (0.02 g, 0.045 mmol, 18%). P NMR (400 MHz, MeOD) 5 8.42 (s, 1H) , 8.05 — 7.92 (m, 2H) , 7.56 — 7.48 (m, 4H), 7.18 (t, J = 8.8 Hz, 2H) , 6.95 (s, 1H) , 3.47 (t, J = 7.1 Hz, 2H), 2.94 (s, 3H), 2.63 (t, J = 7.5 Hz, 2H), 1.94 (p, J = 7.3 Hz, 2H).

[0241] MS(ESI) m / z MH +441.2 Example 8: Synthesis of 3-((4-fluorophenyl)ethynyl)-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)-N-(2-(6-nitropyridin-3-yl)ethyl)benzamide (3-((4-fluorophenyl )ethynyl )—4—( (1-methyl-1H-pyrazol-3-yl)methyl )sulfonyl )—N-(2-(6-nitropyridin-3-yl)ethyl)benzamide, Compound 7). Reagent and Condition (a) Potassium tert-butyl N-[2-(trifluoroboranudyl)ethyl]carbamate (Potassium tert-butyl N-[2-

[0242] (tr if luoroboranuidyl )ethyl ] carbamate), Pd(dppf )C12 • CH2Cl2, CS2CO3, H2O, toluene, 80 °C, overnight; (b) 4N HC1 in dioxane, room temperature (rt), overnight; (c) TBTU, TEA, DCM, room temperature (rt), overnight Step 1) Synthesis of tert-butyl (2-(6-nitropyridin-3-yl)ethyl)carbamate

[0243] After dissolving 5-bromo-2-nitropyridine (1 g, 4.93 mmol, 1.0 eq) in toluene (20 ml, 0.25 MH), potassium tert-butyl N-[2-(trifluoroboranonuidyl)ethyl]carbamate (1.36 g, 5.41 mmol, 1.1 eq), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) [1,1'-

[0244] [Bi s (di phenylphosphino) ferrocene] di chi or opal ladium(II) , complex with di chloromethane, 0.302 g, 0.369 mmol, 0.07 eq), CS2CO3 (4.815 g, 14.8 mmol, 3 eq), and H2O (5 ml) were added and heated to 80 °C while stirring overnight. After cooling to room temperature, water and oil were added to extract the organic layer. The organic layer was dried with MgSO₄, filtered, concentrated, and then purified by column chromatography (silica gel, EA / HX). (0.842 g, 64%) Step 2) Synthesis of 2-(6-nitropyridin-3-yl)ethan-1-amine. Tert-butyl (2-(6-nitropyridin-3-yl)ethyl)carbamate (0.842 g, 3.15 mmol, 1 eq) was dissolved in 4N HC1 (4N HC1 in dioxane, 8 ml, 31.5 mmol, 10 eq) and stirred overnight at room temperature. The reaction mixture was concentrated, diethyl ether was added, and precipitation was performed. The precipitated solid was washed with diethyl ether and filtered under reduced pressure. (0.507 g, 79%) Step 3) Synthesis of 3-((4-fluorophenyl)ethynyl)-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)-N-(2-(6-nitropyridin-3-yl)ethyl)benzamide (3-((4-fluorophenyl)ethynyl)-4-(((l-methyl-lH-pyrazol-1-3-yl)methyl)sulfonyl)-N-(2-(6-nitropyridin-3-yl)ethyl)benzamide).

[0245] 3-((4-fluorophenyl)ethynyl)-4-(((1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)benzoic acid (0.1 g, 0.25 mmol, 1 eq) was dissolved in DCM (0.5 ml, 0.5 M), then 2-(6-nitropyridin-3-yl)ethynyl-1-amine (0.057 g, 0.28 mmol, 1.1 eq), TBTU (0.12 g, 0.375 mmol, 1.5 eq), TEA (0.076 ml, 0.55 mmol, 2.2 eq) were added, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted in DCM, and the organic layer was extracted by adding a saturated aqueous NaHCOs solution, H2O, and brine. The organic layer was dried with MgSO4, filtered, concentrated, and then precipitated by adding Sun. The precipitated solid was washed with MC and filtered under reduced pressure. (0.052 g, 38%) P NMR (400 MHz, MeOD) 5 8.51 (s, 1H) , 8.27 (d, J = 8.3 Hz, 1H) , 8.10 (d, J = 12.5 Hz, 2H), 7.88 (d, J = 8.2 Hz, 1H) , 7.79 (d, J = 8.2 Hz, 1H) , 7.75 - 7.69 (m, 2H), 7.43 (s, 1H) , 7.21 (t, J = 8.4 Hz, 2H) , 6.15 (s, 1H) , 4.81 (s, 2H) , 3.76 — 3.70 (m, 5H), 3.14 (t, J= 6.8 Hz, 2H) . ; MS(ESI) m / z MH + 548.4 Example 9: N-(2-(6-aminopyridine-3-yl)ethyl)-3-((4-fluorophenyl)ethynyl)-4~

[0246] Synthesis of (((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide (N-(2-(6-aminopyridin-3-yl)ethyl )—3—((4—f luorophenyl )ethynyl )—4—((l—methyl—lH—pyrazol—3—yl)methyl)sulfonyl)benzamide, compound 8). Reactants and Conditions (a) Zn, NH4Cl, 1,4-dioxane,

[0247] H2O, room temperature (rt), overnight (overnight)

[0248] 3-( (4-fluorophenyl )ethynyl )- 4-( ( (1-methyl- 1H-pyrazole- 3-yl )methyl )sulfonyl ) -N- (2-

[0249] (6-nitropyridin-3-yl)ethyl)benzamide (3-((4-fluorophenyl)ethynyl)-4-(((1-methyl-IH-pyr azol-3-yl)methyl)sulfony 1)—N-(2-(6-nitr opyr idin-3-yl)ethyl 1)et hy 1)benzamide, 0.046 g, 0.084 mmol, 1 eq) was dissolved in 1,4-dioxane:water (H2O) (3:l(v / v)(l ml, 0.084 M), then Zn (0.055 g, 0.84 mmol, 10 eq) and NH4Cl (0.045 g, 0.84 mmol, 10 eq) were added, and at room temperature Stirred overnight. The reaction mixture was washed with MeOH and filtered under reduced pressure through Celite. The filtrate was concentrated and purified by reverse-phase column chromatography (0.1% formic acid in H2O / Acetonitrile). (0.021 g, 47%) p NMR (400 MHz, MeOD) 5 8.13 (s, 1H), 7.90 (d, J = 8.6 Hz, 2H), 7.83 (d, J = 8.3 Hz, 1H), 7.78 - 7.73 (m, 2H), 7.63 (d, J = 8.6 Hz, 1H), 7.45 (s, 1H), 7.23 (t, J = 8.3 Hz, 2H), 6.74 (d, J = 8.8 Hz, 1H), 6.16 (s, 1H) , 4.84 (s, 2H) , 3.74 (s, 3H), 3.60 (t, J= 6.7 Hz, 2H) , 2.82 (t, J= 6.7 Hz, 2H) . MS(ESI) m / z MH +518.4 Example 10: N— (3— (1H—pyrazol-4—yl)propyl)- 3— ((4—fluorophenyl)ethynyl)- 4~((3~ (trifluoromethyl)benzyl)sulfonyl)benzamide (N- (3- (1H-pyrazol-4-yQpropyl)- 3- ((4- fluorophenyl )ethyny 1 )—4—( (3—( tr if fluoromethyl 1 )benzyl )sulfonyl 1 )benzamide , compound

[0250] Synthesis of 9)

[0251] Reagents and Conditions (a) 1-(chloromethyl)-3-(trifluoromethyl)benzene, TEA, ACN, reflux, 1 hour (Ih); (b) mCPBA, MC, room temperature (RT), overnight; (c) Fe, NH4Cl, EtOH, water (H2O), reflux, 1 hour (Ih); (d) Sodium nitrite (NaNO2), potassium iodide (KI), pTSA, ACN, 0 °C, 1 hour (1 h); (e) 1-ethynyl-4-fluorobenzene, TEA, Cu, PdC12(PPh3)2 ACN, reflux (ref lux), 1 hour (Ih); (f) NaOH, EtOH, H2O, reflux (ref lux), 1 hour (Ih); (g) 3-(IH-pyrazol-4-yl)propan-1-amine dihydrochloride (3-(IH-pyrazol-4-yl)propan-1-amine dihydrochloride), TBTU, TEA, MC, room temperature (rt), overnight (overnight) Step 1) Methyl 3-nitro-4-((3-(trifluoromethyl)benzyl)thio)benzoate (methyl

[0252] Synthesis of 3-nitro-4-((3-(tr if luoromethyl ) benzyl )thio)benzoate): methyl 4-mercapto-3-nitrobenzoate (methyl 4-mercapto-3-nitrobenzoate, 0.1 g, 0.469 mmol, 1 eq) was dissolved in ACN (5 ml, 0.1 M), and then 1-(chloromethyl)-3-

[0253] (trifluoromethyl)benzene (1—(chloromethyl)—3—(trifluoromethyl)benzene, 0.07 ml, 0.469 mmol, leq) and TEA (0.09 ml, 0.61 mmol, 1.3 eq) were added, and the mixture was refluxed and stirred for 1 hour. After the reaction was complete, the mixture was concentrated, water was added, and the extract was extracted with a Toyo. The organic layer was dried with MgSO4, filtered, and concentrated to obtain the crude product. (0.15g, 85%) p NMR (400 MHz, CDCls) 8 8.90 (s, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.71 (s, 1H), 7.64 (dd, J = 16.9, 7.6 Hz, 2H), 7.52 (t, J = 8.6 Hz, 2H), 4.32 (s, 2H), 3.99 (s, 3H). Step 2) Methyl 3-nitro-4-((3-(trifluoromethyl)benzyl)sulfonyl)benzoate

[0254] Synthesis of (methyl 3-nitro-4-((3-(trifluoromethyl)benzyl)sulfonyl)benzoate): Methyl 3-nitro-4-((3-(trifluoromethyl)benzyl)thio)benzoate (0.15 g, 0.4 mmol, leq) was dissolved in MC (2 ml, 0.2 M), then mCPBA (0.68 g, 3.96 mmol, 10 eq) was added and stirred overnight. After the reaction was complete, a saturated aqueous solution of NaHCOs was added and extracted with MC. The organic layer was dried with MgSO₄, filtered, and concentrated to obtain the crude product. (0.138 g, 86%) p NMR (400 MHz, CDCls) 8 8.43 (s, 1H), 8.16 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.56 - 7.51 (m, 2H), 7.45 (t, J = 7.6 Hz, 1H), 4.89 (s, 2H), 4.00 (s, 3H). Step 3) Methyl 3-amino-4-((3-(trifluoromethyl)benzyl)sulfonyl)benzoate

[0255] Synthesis of methyl 3-nitro-4-((3-(trifluoromethyl)benzyl)sulfonyl)benzoate)methyl 3-nitro-4-((3-(trifluoromethyl)benzyl)sulfonyl)benzoate (0.14 g, 0.342 mmol, 1 eq) was dissolved in ethanol (EtOH):water (H2O) (7 ml, 4:l (v:v), 0.05 M), then Fe (0.1 g, 1.71 mmol, 5 eq) and NH4Cl (0.091 g, 1.71 mmol, 5 eq) were added and the mixture was refluxed and stirred for 1 hour. After cooling to room temperature and filtering with Celite, water was added to the filtrate, and extraction was performed using a Toyo extractor. The organic layer was dried with MgSO4, filtered, and concentrated to obtain the unpurified product. (0.12 g, 93.8%) NMR (400 MHz, CDCI3) 8 7.57 (d, J = 7.4 Hz, 1H), 7.44–7.32 (m, 4H), 7.28 (d, J = 6.1 Hz, 2H), 5.12 (s, 2H), 4.43 (s, 2H), 3.92 (s, 3H). Step 4) Synthesis of methyl 3-iodo-4-((3-(trifluoromethyl)benzyl)sulfonyl)benzoate methyl 3-amino-4-((3-(trifluoromethyl)benzyl)sulfonyl)benzoate (0.373 g, 1 mmol, 1 eq) was dissolved in ACN (10 ml, 0.1 M), then pTSA (0.517 g, 3 mmol, 3 eq) was added, followed by sodium nitrite (0.07 g, 1.07 g) dissolved in 1 ml of water at 0 °C.0.2 nmol, 1.02 eq) and KI (0.169 g, 1.02 mmol, 1.02 eq) dissolved in 1 ml of water were added. After reacting at room temperature for 1 hour, a saturated aqueous NaHCOs solution was added and the pH was neutralized to above 8, followed by extraction with a Toyo. The organic layer was dried with MgSO4, filtered, concentrated, and then purified by column chromatography (silica gel, EA / HX). (0.175 g, 36%) p NMR (400 MHz, CDCI3) 8 8.77 (s, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.59 (d, J = 5.0 Hz, 1H), 7.44 (d, J = 6.3 Hz, 3H), 4.75 (s, 2H), 3.99 (s, 3H). Step 5) Methyl 3-((4-fluorophenyl)ethynyl)-4-((3-.

[0256] Synthesis of (trifluoromethyl)benzyl)sulfonyl)benzoate (methyl 3-iodo-4-((3-(trifluoromethyl)benzyl)sulfonyl)benzoate)0.194 g, 0.4 mmol, 1 eq) was dissolved in ACN (4 ml, 0.1 M) and then TEA (0.12 ml, 0.88 mmol, 2.2 eq), PdC12(PPh3)2 (8.4 mg, 0.012 mmol, 3 mol%) and Cui (3 mg, 0.016 mmol, 4 mol%) were added and stirred at room temperature for 5 minutes. After adding 1-ethynyl-4-fluorobenzene (0.07 ml, 0.6 mmol, 1, 1.5 eq), the mixture was stirred at 90 °C for 1 hour. After cooling to room temperature and concentrating, the solution was purified by column chromatography (silica gel, EA / HX). (0.183 g, 96.3 %) p NMR (400 MHz, CDCls) 8 8.40 (s, 1H), 8.01 (d, J = 8.1 Hz, 1H), 7.87 (d, J = 8.3 Hz, 1H), 7.71 (t, J = 6.1 Hz, 2H), 7.57 (d, J = 7.1 Hz, 1H), 7.47–7.38 (m, 3H), 7.17 (t, J = 7.9 Hz, 2H), 4.76 (s, 2H), 4.01 (s, 3H). Step 6) 3-((4-fluorophenyl)ethynyl)-4-((3-

[0257] (Trifluoromethyl)benzyl)sulfonyl)benzoic acid (3-((4-fluorophenyl )ethynyl )-4-( (3-

[0258] (Synthesis of (trifluoromethyl)benzyl)sulfonyl)benzoic acid) Methyl 3-((4-fluorophenyl)ethynyl)-4-((3-

[0259] (trifluoromethyl)benzyl)sulfonyl)benzoate, 0.183 g, 0.396 mmol, 1 eq) was dissolved in EtOH (8 ml, 0.05 M), and then NaOH (0.079 g, 1.98 mmol, 5 eq) dissolved in H2O (0.8 ml) was added, and the mixture was refluxed and stirred for 1 hour. After cooling to room temperature, it was concentrated and then diluted with water. After adjusting the pH to 5-6 with 1 N HCl, the resulting solid was filtered, washed with water, and dried. (0.14 g,

[0260] 76.5%) 1H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.80 - 7.73 (m, 2H), 7.68 (d, J = 7.6 Hz, 1H), 7.58 - 7.51

[0261] (m, 1H), 7.51 - 7.47 (m, 1H), 7.45 (s, 1H), 7.38 (t, J = 8.5 Hz, 2H), 5.03 (s, 2H). Step 7) Synthesis of N-(3-(1H-pyrazol-4-yl)propyl)-3-((4-fluorophenyl)ethynyl)-4-((3-(trifluoromethyl)benzyl)sulfonyl)benzamide (N-(3-(1H-pyrazol-4-yl)propyl)-3-((4-fluorophenyl)ethynyl)-4-((3-(trifluoromethyl)benzyl)sulfonyl)benzamide)

[0262] After dissolving 3-((4-fluorophenyl)ethynyl)-4-((3-(trifluoromethyl)benzyl)sulfonyl)benzoic acid (0.046 g, 0.1 mmol, 1 eq) in MC, TBTU (0.048 g, 0.15 mmol, 1.5 eq), TEA (0.03 ml, 0.22 mmol, 2.2 eq), and 3-(1H-pyrazol-4-yl)propan-1-amine dihydrochloride (0.022 g, 0.11 mmol, 1.1 eq) were added, and at room temperature Stirring was performed overnight. After the reaction was complete, a saturated aqueous NaHCOs solution was added for neutralization, followed by extraction with MC. The organic layer was dried with MgSO4, filtered, concentrated, and purified by column chromatography (silica gel, EA 100%). (35.7 mg, 62.7 %) p NMR (400 MHz, CDCls) 8 8.05 (s, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.69–7.63 (m, 2H), 7.61 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 6.4 Hz, 1H), 7.45 (s, 2H), 7.41–7.34 (m, 3H), 7.13 (t, J = 8.1 Hz, 2H) , 6.35 (s, 1H) , 4.70 (s, 2H) , 3.51 (dd, J = 12.6, 6.3 Hz, 2H) , 2.62 (t, J = 7.2 Hz, 2Hff), 1.99 - 1.89 (m, 2H) . m / z MH +570.1 Example 11: Synthesis of N-(3-(1H-pyrazol-4-yl)propyl)-3-((4-fluorophenyl)ethynyl)-4-(( (1-(pyridin-4-yl)-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide (N-(3-(1H-pyrazol-4-y1)propyl )—3—( (4-fluorophenyl )ethyny 1 )—4—( ( ( 1-(pyridin-4-y1 )—1H-pyrazol-3-yl)methyl)sulfonyl)benzamide, Compound 10). Reagents and Conditions (a) 4-iodopyridine,

[0263] (a) K3PO4, Cui, 1,2-transdimethylaminocyclohexane, 110 °C, 16 hours (16h); (b) 1.0 M L1AIH4 (in THF), THF, 0 °C, 1 hour (Ih); (c) SOC12, MC, reflux at 0 °C overnight; (d) methyl 4-mercapto-3-nitrobenzoate, K2CO3, DMF, room temperature (rt), overnight; (e) mCPBA, MC, room temperature (RT), overnight; (f) Fe, NH4Cl, ethanol (EtOH), water (H2O), reflux, 1 hour (Ih); (g) Sodium nitrite (NaNO), KI, pTSA, ACN, 0 °C, 1 h: (h) 1-ethynyl-4-fluorobenzene, TEA, Cui, PdC12(PPh3)2, ACN, reflux, 1 h; (i) NaOH, EtOH, H2O, reflux, 1 h; (j) 3-(1H-pyrazol-4-yl)propan-1-amine dihydrochloride, TBTU, TEA, MC, room temperature, overnight. Step 1) Ethyl 1-(pyridine-4-yl)- Synthesis of 1H-pyrazole-3-carboxylate (ethyl 1-(pyridin-4-yl)-1H-pyrazole-3-carboxylate): Add ethyl 1H-pyrazole-3-carboxylate (lg, 7.2 mmol, leq) to a pressure tube and toluene (Toluene, 30 ml, 0.After dissolving in 2 M, 4-iodopyridine (1.54 g, 7.56 mmol, 1.05 eq), K3PO4 (3.8 g, 18 mmol, 2.5 eq), Cui (0.14 g, 0.72 mmol, 0.1 eq), and 1,2-transdimethylaminocyclohexane (0.22 ml, 1.44 mmol, 0.2 eq) were added, and the mixture was stirred at 110 °C for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, water was added, and the mixture was extracted with oil. The organic layer was dried with MgSO4, filtered, concentrated, and then purified by column chromatography (silica gel, EA / HX). (1.1 g, 70.5%) Na NMR (400 MHz, CDCI3) 6 8.71 (d, J = 4.9 Hz, 2H), 8.06 (s, 1H), 7.72 (d, J = 4.9 Hz, 2H), 7.04 (s, 1H), 4.46 (q, J = 6.8 Hz, 2H), 1.43 (t, J = 6.9 Hz, 3H). Step 2) Synthesis of (1-(pyridin-4-yl)-1H-pyrazol-3-yl)methanol ((l-(pyridin-4-yl)-lH-pyrazol-3-yl)methanol) ethyl 1-(pyridin-4-yl)-1H-pyrazol-3-carboxylate (ethyl 1-(pyridin-4-y 1 )-1H-pyrazol-3-carboxylate, 1.1 g, 5.06 mmol, 1 eq) was dissolved in anhydrous THF (50 ml, 0.1 M), and then 1.0 M L1AIH4 (in THF, 7.6 ml, 7.60 mmol, 1.5 eq) was slowly added dropwise at 0 °C and stirred for 1 hour. After the reaction was completed, water and oil were added, the solid was filtered, and the filtrate was concentrated to obtain the unpurified product. (0.89 g, 100%) NMR (400 MHz, MeOD) 6 8.59 (d, J = 5.3 Hz, 2H), 8.42 (s, 1H), 7.87 (d,.

[0264] J = 5.4 Hz, 2H), 6.63 (s, 1H), 4.70 (s, 2H). Step 3) Synthesis of 4-(3-(chloromethyl)-1H-pyrazol-1-yl)pyridine.

[0265] 1-(pyridine-4-yl)-1H-pyrazole-3-yl)methanol (0.89 g, 5.06 mmol, leq) was dissolved in MC (25 ml, 0.2 M), after which SOC12 (1.1 ml, 15.2 mmol, 3 eq) was slowly added dropwise at 0 °C and stirred overnight under reflux. After the reaction was complete, the solution was concentrated under reduced pressure and obtained as an unpurified product. (1.42 g, 100%) NMR (400 MHz, MeOD) 5 8.62 (d, J = 5.3 Hz, 2H), 8.45 (s, 1H), 7.89 (d, J = 5.4 Hz, 2H) 2H), 6.69 (s, 1H), 4.73 (s, 2H). Step 4) Synthesis of methyl 3-nitro-4-(((1-(pyridin-4-yl)-1H-pyrazol-3-yl)methyl)thio)benzoate.

[0266] 4-(3-(chloromethyl)-1H-pyrazol-1-yl)pyridine (0.091 g, 0.47 mmol, leq) was dissolved in DMF (5 ml, 0.1 M), followed by the addition of K2CO3 (0.13 g, 0.94 mmol, 2 eq). Methyl 4-mercapto-3-nitrobenzoate (0.1 g, 0.47 mmol, leq) dissolved in DMF (5 ml, 0.1 M) was then slowly added, and the mixture was stirred overnight at room temperature. After the reaction was complete, water was added, and the resulting solid was filtered and dried to obtain the crude product. (0.09 g, 52%) p NMR (400 MHz, MeOD) 5 8.77 (s, 1H), 8.60 (d, J = 5.3 Hz, 2H), 8.42 (s, 1H), 8.21 (d, J= 8.6 Hz, 1H), 7.98 (d, J= 8.6 Hz, 1H), 7.87 (d, J= 5.5 Hz, 2H), 6.67 (s, 1H), 4.49 (s, 2H), 3.96 (s, 3H). Step 5) Methyl 3-nitro-4-(((1-(pyridin-4-yl)-1H-pyrazole-3-yl)methyl)sulfonyl)benzoate (methyl 3-nitro-4-(((1-(pyridin-4-4- Synthesis of y 1 )- 1H- pyrazol- 3- yl)methyl)sulfonyl)benzoate) methyl 3-nitro- 4-( ( (1-(pyridin- 4-yl)- 1H-pyrazol- 3-yl)methyl)thio)benzoate

[0267] 0.61 g, 1.65 mmol, 1 eq)methyl 3-nitro-4-(((1- (pyr idin-4- yl)-1H-pyrazol-3-yl)methyl)thio)benzoate was dissolved in MC (8 ml, 0.2 M), then mCPBA (2.8 g, 16.46 mmol, 10 eq) was added and stirred overnight. After the reaction was complete, a saturated aqueous solution of NaHCOs was added and extracted with MC. The organic layer was dried with MgSO4, filtered, and concentrated to obtain the crude product. (0.685g, 100%) P NMR (400 MHz, MeOD) 5 8.50 (s, 1H) , 8.43 (s, 1H) , 8.36 (d, J = 6.5 Hz, 2H), 8.28 (d, J = 7.9 Hz, 1H) , 7.99 (s, 1H) , 7.95 (d, J = 7.9 Hz, 2H) , 7.86 (d, J = 6.6 Hz, 2H), 7.60 (d, J = 7.8 Hz, 1H) , 7.47 (t, J = 7.9 Hz, 1H) , 6.72 (s, 1H) , 5.11 (s, 2H), 4.00 (s, 3H). Step 6) Synthesis of methyl 3-amino-4-(((1-(pyridin-4-yl)-1H-pyrazol-3-yl)methyl)sulfonyl)benzoate (methyl 3-amino-4-(((1-(pyridin-4-yl)-1H-pyrazol-3-yl)methyl)sulfonyl)benzoate (methyl 3-nitro-4-(((1-(pyridin-4-yl)-1H-pyrazol-3-yl)methyl)sulfonyl)benzoate (0.385 g, 0.96 mmol, 1 eq) in ethanol (EtOH):water After dissolving in [H2O] (10 ml, 4:l(v:v), 0.1 MH], Fe (0.27 g, 4.78 mmol, 5 eq), NH4Cl (0.26 g, 4.78 mmol (5 eq) was added and refluxed for 1 hour. After cooling to room temperature, the mixture was filtered using a Celite filter, water was added to the filtrate, and the mixture was extracted using a Toyo extractor. The organic layer was dried with MgSO4, filtered, concentrated, and then purified by column chromatography (silica gel, EA / HX). (0.085 g, 24%) P NMR (400 MHz, MeOD) 5 8.55 (d, J = 4.9 Hz, 2H) , 8.38 (s, 1H) , 7.71 (d, J= 5.1 Hz, 2H), 7.51 (s, 1H) , 7.46 (d, J= 8.2 Hz, 1H) , 7.16 (d, J= 8.2 Hz, 1H) , 6.53 (s, 1H), 4.68 (s, 2H) , 3.90 (s, 3H) . Step 7) Synthesis of methyl 3-iodo-4-(((1-(pyridin-4-yl)-1H-pyrazole-3-yl)methyl)sulfonyl)benzoate (methyl 3-iodo-4-(((1-(pyr idi n-4-y 1 )-lH-pyr azol-3-yl)methyl)sulfonyl)benzoate (methyl 3-amino-4-( ( (1-(pyridin-4-yl)-1H-pyrazole-3-yl)methyl)sulfonyl)benzoate (methyl 3-ami no-4-( ( ( 1-(pyr idi n-4-y 1 )-IH-pyr azo 1-3-y 1 )met hy 1 ) su 1 f ony 1 )benzoate e , 0.159 g, 0.427 mmol, 1 eq) was dissolved in ACN (4 ml, 0.1 M), and then pTSA (0.22 g, 1.28 mmol, 3 eq) was added. Subsequently, sodium nitrite (NaNO, 0.03 g, 0.436 mmol, 1.02 eq) dissolved in 0.4 ml of water at 0 °C and KI (0.142 g, 0.854 mmol, 2 eq) dissolved in 0.8 ml of water were added. After reacting at room temperature for 1 hour, a saturated aqueous solution of NaHCOs was added to neutralize the pH to 8 or higher, and then the mixture was extracted with Toyo.The organic layer was dried with MgSO4, filtered, and concentrated to obtain the crude product. (0.2 g, 100%) NMR (400 MHz, CDCls) 8 8.75 (s, 1H), 8.61 (d, J = 4.9 Hz, 2H), 8.00 (s, 2H), 7.92 (s, 1H), 7.43 (d, J = 4.9 Hz, 2H), 6.55 (s, 1H), 4.88 (s, 2H), 3.95 (s, 3H). Step 8) Synthesis of methyl 3-((4-fluorophenyl)ethynyl )-4-(((1-(pyridin-4-yl)-1H-pyrazol-3-yl)methyl)sulfonyl)benzoate (methyl 3-( (4-fluorophenyl )ethynyl )-4-( ( ( 1-(pyridin-4-yl )-1H-pyrazo 1-3-yl )methyl )sulfonyl )benzoate (methyl 3-iodo-4-( ( (1-(pyridin-4-yl)-1H-pyrazol-3-yl)methyl)sulfonyl)benzoate (methyl 3-iodo-4-( ( (1-(pyridin-4-yl)-1H-pyrazol-3-yl)methyl)sulfonyl)benzoate (methyl 3-iodo-4-( ( (1-(pyridin-4-yl)-1H-pyrazol-3-yl)methyl)sulfonyl)benzoate 1 f ony 1 )benzoat e ,.

[0268] 0.2 g (0.414 mmol, 1 eq) was dissolved in ACN (4 ml, 0.1 M), then TEA (0.13 ml, 0.92 mmol, 2.2 eq), PdC12(PPhs)2 (8.7 mg, 0.012 mmol, 3 mol%), and Cui (3.2 mg, 0.017 mmol, 4 mol%) were added and stirred at room temperature for 5 minutes. After adding 1-ethynyl-4-fluorobenzene (0.071 ml, 0.62 mmol, 1.5 eq), the mixture was stirred at 90 °C for 1 hour. After cooling to room temperature and concentrating, the solution was purified by column chromatography (silica gel, EA / HX). (0.104 g, 51.5%) P NMR (400 MHz, CDCls) 8 8.61 (s, 2H), 8.38 (s, 1H), 8.01 (s, 2H), 7.91 (s, 1H), 7.73 — 7.65 (m, 3H), 7.43 (s, 2H), 7.11 (t, J = 8.2 Hz, 2H), 6.55 (s, 1H), 4.89 (s, 2H), 3.98 (s, 3H). Step 9) Synthesis of 3-((4-fluorophenyl)ethynyl)-4-(((1-(pyridin-4-yl)-1H-pyrazol-3-yl)methyl)sulfonyl)benzoic acid (3-((4-fluorophenyl)ethynyl)-4-(((l-(pyridin-4-yl)-lH-pyrazol-3-yl)methyl)sulfonyl)benzoic acid)methyl 3-((4-fluorophenyl)ethynyl)-4-(((1-(pyridin-4-yl)-1H-pyrazol-3-yl)methyl)sulfonyl)benzoate (methyl 3-((4-fluorophenyl)ethynyl)-4-(((l-(pyridin-4-yl)-lH-pyrazol-3-yl)methyl)sulfonyl)benzoate 1-3-yl )methyl )sul fonyl )benzoate, 0.104 g, 0.212 mmol, 1 eq) was dissolved in EtOH (4 ml, 0.05 M), then NaOH (0.042 g, 1.062 mmol, 5 eq) dissolved in H2O (0.4 ml) was added, and the mixture was refluxed and stirred for 1 hour. After cooling to room temperature, the mixture was concentrated and diluted with water. The pH was adjusted to 5–6 using HC1, and the resulting solid was filtered, washed with water, and dried. (0.039 g, 40%) Step 10) Synthesis of N-(3-(1H-pyrazol-4-yl)propyl)-3-((4-fluorophenyl)ethynyl)-4-(( (1-(pyridin-4-yl)-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide (N-(3-(1H-pyrazol-4-yl)propyl)-3-((4-fluorophenyl)ethynyl)—4—(((l-(pyridin-4-yl)-lH-pyrazol-1-3-yl)methyl)sulfonyl)benzamide).

[0269] After dissolving 3-( (4-fluorophenyl )ethynyl )-4-( ( (1-(pyridin-4-yl )-1H-pyrazol-3-yl)methyl)sulfonyl )benzoic acid (3-( (4-fluorophenyl )ethynyl )-4-( ( (1-(pyridin-4-y 1 )-1H-pyrazol-1-3-yl )methyl )sulfonyl )benzoic acid, 0.039g, 0.08mmo 1, 1 eq) in [MOI]

[0270] TBTU (0.039 g, 0.12 mmol, 1.5 eq), TEA (0.025 ml, 0.176 mmol, 2.2 eq), and 3-(1H-pyrazol-4-yl)propan-1-amine dihydrochloride (0.0174 g, 0.088 mmol, 1.1 eq) were added and stirred overnight at room temperature. After the reaction was complete, a saturated aqueous solution of NaHCOs was added and neutralized, followed by extraction with MC. The organic layer was dried with MgSO₄, filtered, concentrated, and purified by column chromatography (silica gel, MeOH / MC). (16.2 mg, 35.6 %) Blood NMR (400 MHz, MeOD) 5 8.53 (d, J = 5.2 Hz, 2H) , 8.35 (s, 1H) , 8.21 (s, 1H), 7.98 (d, J= 8.3 Hz, 1H) , 7.86 (d, J= 8.3 Hz, 1H) , 7.77 — 7.70 (m, 2H) , 7.64 (d, J = 5.3 Hz, 2H), 7.49 (s, 2H) , 7.21 (t, J = 8.2 Hz, 2H) , 6.57 (s, 1H) , 4.99 (s, 2H), 3.45 (t, J = 7.2 Hz, 2H) , 2.62 (t, J = 7.2 Hz, 2H) , 1.93 (p, J = 6.8 Hz, 2H). MS(ESI) m / z MH +569.2 Example 12: Synthesis of N-(3-(1H-pyrazole-4-yl)propyl)-4-(( (1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)-3-((4-(piperidin-4-yl)phenyl)ethynyl)benzamide hydrochloride (N-(3-(1H-pyrazole-4-yl)propyl)-4-(((1-methyl-pyrazole-3-yl)methyl)sulfonyl)-3-((4-(piperidin-4-yl)phenyl)ethynyl)benzamide hydrochloride, Compound 11).

[0271] Reaction Scheme 10. (a) Trimethylsilylacetylene, PdCMPPhyh, Cui, TEA, toluene, 100 °C, 12 hours (12h); (b) K2CO3, MeOH, room temperature (rt). (c) PdChLPPhsh, Cui, TEA, ACN, reflux, 12 hours (12h); (d) NaOH, H2O, MeOH, 55 °C; 2 hours (2h); (e) (IH-pyrazol-4-yl)propan-1-amine dihydrochloride), TBTU, TEA, DCM, room temperature (rt), 12 hours (12h); (f) 4N HC1 in dioxane, 1,4-dioxane, room temperature (rt). 12 Hours (12h) Step 1) Synthesis of tert-butyl 4-(4-((trimethylsilyl)ethynyl)phenyl)piperidine-1-carboxylate; after dissolving tert-butyl 4-(4-bromophenyl)piperidine-1-carboxylate (tert-butyl 4-(4-bromophenyl)piperidine-1-carboxylate, 0.34 g, 1 mmol, leq) and trimethylsilylacetylene (0.24 ml, 1.5 mmol, 1.5 eq) in toluene (Toluene, 0.1 M, 10 ml), PdCl2[PPh3]2 (0.07 g, 0.1 mmol, 0.leq), Cui (0.019 g, 0.1 mmol, 0.leq), and trithylamine (0.6 ml, 4 mmol, 4 eq) were added and stirred at 100 °C for 12 hours. The reaction mixture was extracted with DCM.After drying the organic layer with MgS04, the residue obtained by concentrating under reduced pressure was used in the next reaction without purification. Step 2) Synthesis of tert-butyl 4-(4-ethynylphenyl)piperidine-1-carboxylate. Tert-butyl 4-(4-((trimethylsilyl)ethynyl)phenyl)piperidine-1-carboxylate (tert-butyl 4—(4— ((trimethylsilyl)ethynyl)phenyl)piperidine—1—carboxylate, 0.31 g, 0.87 mmol, leq) was dissolved in methanol (4.35 ml, 0.2 M), then K2CO3 (0.6 g, 4.33 mmol, 5 eq) was added and stirred at room temperature for 1 hour. After the reaction was completed, the mixture was filtered and concentrated, and purified by column chromatography (silica gel, 10% EA / HX) to obtain the target compound (0.266 g). Step 3) Synthesis of tert-butyl 4-(4-((5-(methoxycarbonyl)-2-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)phenyl)ethynyl)phenyl)piperidine—l—carboxylate (tert-butyl 4-(4-((5-(methoxycarbonyl 1 )-2-((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzoate (methyl 3—iodo—4—((1—methyl—1H—pyrazol—3— MeCN (2 ml, 0.1 M) and TEA (0.074 ml, 0.53 mmol, 2.2 eq) were added to yl)methyl)sulfonyl)benzoate, 0.1 g, 0.24 mmol, leq).PdC12[PPh3]2 (5 mg, 3 mol%) and Cul (2 mg, 4 mol%) were added to the reaction mixture and stirred at room temperature for 5 minutes under a nitrogen atmosphere. Subsequently, tert-butyl 4-(4-ethynylphenyl)piperidin-1-carboxylate (tert-butyl 4-(4-ethyny 1pheny 1)piperidin-1-carboxylate, 0.1 g, 1.5 eq) was added. The reaction mixture was stirred at 90 °C for 12 hours and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, 40-50% EA / HX) to obtain the target compound (0.1 g). P NMR (400 MHz, CDCls) 8 8.35 (d, J= 1.1 Hz, 1H) , 7.97 (dd, J= 11.4, 4.8.

[0272] Hz, 3H), 7.63 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 2.0 Hz, 2H), 6.13 (d, J = 2.1 Hz,

[0273] 1H), 4.81 (s, 2H), 4.26 (s, 2H), 3.98 (s, 3H), 3.76 (s, 3H), 2.81 (t, J= 12.2 Hz,

[0274] 2H), 2.69 (t, J = 12.2 Hz, 1H), 1.83 (d, J = 13.0 Hz, 2H), 1.65 (d, J = 12.4 Hz,

[0275] 2H), 1.49 (s, 9H). Step 4) Synthesis of 3-((4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)ethynyl)-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzoic acid (3-((4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)ethynyl)—4—(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzoic acid) tert-butyl 4-(4-((5-(methoxycarbonyl)-2-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)phenyl)ethynyl)phenyl)piperidin-carboxylate (tert-butyl 4- (4-((5- (met hoxy car bony 1 )— 2— (((1— methyl— 1H— pyrazol— 3— yl )methyl)sulfonyl ) phenyl )ethynyl ) phenyl )piper idine—1— carboxylate , 0.1g,

[0276] Ethanol (3 ml, 0.05 M), H2O (0.5 ml), and NaOH (0.035 g, 0.87 mmol, 5 eq) were added to 0.173 mmol, leq, and the mixture was stirred at 100 °C for 1 hour. The reaction was monitored by TLC, and once complete, the pH of the reaction mixture was adjusted to 1 using an aqueous solution of H1N1 and extracted with a Toyo extractor. The organic layer was washed with water, dried with magnesium sulfate, and concentrated under reduced pressure to obtain the target compound (0.082 g, 84%). Step 5) Synthesis of tertbutyl 4-((5-((3-(1H-pyrazol-4-yl)propyl)carbamoyl)-2-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)phenyl)ethynyl)phenyl)piperidine—1-carboxylate

[0277] 3- ((4- (1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)ethynyl)-4- (((1-methyl-1H-pyrazole—3-yl)methyl)sulfonyl)benzoic acid (3—(4—(l—(tert—butoxycarbonyl)piperidin—4—yl)phenyl)ethynyl)—4— (((1—methyl—IH—pyr azol—3—yl)methyl 1)sulfonyl )benzoic acid,

[0278] TBTU (0.071 g, 0.22 mmol, 1.5 eq), TEA (0.045 ml, 0.32 mmol, 2.2 eq), and 3-(1H-pyrazol-4-yl)propan-1-amine dihydrochloride (32 mg, 0.16 mmol, 1.1 eq) were added to DCM (2 ml) and 0.082 g (0.145 mmol, 1 eq), and stirred for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with oil. After drying the organic layer with magnesium sulfate, the residue obtained by concentration under reduced pressure was purified by column chromatography (silica gel, 100% EA) to obtain the target compound (0.02 g, 21%). Step 6) Synthesis of N-(3-(1H-pyrazol-4-yl)propyl)-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)-3-((4-(piperidin-4-yl)phenyl)ethynyl)benzamide hydrochloride (N-(3-(lH-pyrazol-4-yl)propyl)—4—( (1—methyl—1H—pyrazol—3—yl)methyl)sulfonyl)—3—( (4-(piperidin—4—y1)pheny1)ethynyl)benzamide hydrochloride)tert-butyl 4-(4-((5-((3-(1H-pyrazol-4-yl)propyl)carbamoyl)-2- (((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)phenyl)ethynyl)phenyl)piperidine-1-carboxylate (tert-butyl 4- (4— ((5—((3— (1H—pyrazol—4—yl)propyl)carbamoyl)—2— (((1—methyl—1H—pyrazol—3—yl)methyl)sulfonyl)phenyl)ethynyl)phenyl)piperidine—l—carboxylate, 0.02g,

[0279] O.OSmmol, leq) was dissolved in 1,4-dioxane (1 ml, 0.03 M), then 4N HC1 (4N HC1 in 1,4-dioxane, 0.015 ml, 0.06 mmol, 1, 2 eq) was added under dioxane and stirred at room temperature for 12 hours. After the reaction was complete, the resulting solid was filtered and washed with 1,4-dioxane to obtain the target compound (0.0066 g, 39%). P NMR (400 MHz, MeOD) 5 8.20 (s, 3H) , 7.96 — 7.86 (m, 3H) , 7.70 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 1.9 Hz, 1H) , 7.42 (d, J = 8.1 Hz, 2H) , 6.18 (d, J = 2.0 Hz, 1H), 4.86 (s, 2H), 3.74 (s, 3H), 3.55 (d, J = 12.5 Hz, 2H), 3.51 - 3.44 (m,

[0280] 3H), 3.19 (t, J = 12.6 Hz, 2H), 3.09 - 2.98 (m, 2H), 2.73 (dd, J = 14.4, 7.3 Hz,

[0281] 3H), 2.14 (d, J = 14.3 Hz, 2H), 2.02 - 1.97 (m, 3H). Example 13: 4-ethynyl-N-(2-(piperidin-1-yl)ethyl)benzamide (4-ethynyl-N-(2-

[0282] Synthesis of (piper idin—l—yl )ethyl )benzamide)

[0283] DMF (20 ml), HATU (7.8 g, 20.5 mmol, 1.5 eq), DI PEA (7 ml, 41.1 mmol, 3), and 2-(piperidin-1-yl)ethan-1-amine (2.7 ml, 15.4 mmol, 1.1 eq) were added to 4-ethynyl benzoic acid (2.0 g, 13.7 mmol, 1 eq) and stirred for 12 hours. Water was added to the reaction mixture, and the organic layer extracted three times with a clay oven was washed with an aqueous NH4Cl solution and dried with magnesium sulfate. The residue obtained by concentrating under reduced pressure was purified by column chromatography (silica gel, 10% MeOH / DCM) to obtain the target compound. P NMR (400 MHz, CDC13) 57.81 (d, J= 7.9 Hz, 2H) , 7.58 (d, J= 7.8 Hz, 2H) , 7.39 (s, 1H), 3.68 (m, 2H) , 3.23 (s, 1H) , 2.89-2.99 (m, 6H) , 1.80 (m, 4H) , 1.62 (s, 2H). Example 14: Synthesis of 3-((4-fluorophenyl)ethynyl)-N-(imidazo[1,2-a]pyridin-7-ylmethyl)-4-(N-((l-methyl-1H-pyrazol-3-yl)methyl)sulfamoyl)benzamide (3-((4-fluorophenyl)ethynyl)—N—(imidazo[l,2-a]pyridin-7-ylmethyl)—4—(N—((1-methyl-1H-pyrazol-3-yl)methyl)sulfamoyl)benzamide, Compound 12). Reagents and conditions: (a) NCS, 2N HC1 (aq), ACN, 0 °C to room temperature (0 °C to rt), overnight; (b) ACN, 4 hours (4 h), room temperature (rt); (c) Zn, NH4Cl, 1,4-dioxane, H2O, room temperature (rt), overnight; (d) NaNC)2, KI, HC1, H2O, 0 °C to room temperature (0 °C to rt), 2 hours (2 h); (e) PdC12(PPh3)2, Cui, TEA, ACN, 60 °C,

[0284] 4 hours (4 h); (f) in NaOH, EtOH, 60 °C, overnight; (g) 1-{imidazo[1,2-a]pyridin-7-yl}methaneamine dihydrochloride (l-{imidazo[l,2-a]pyridin-7-yl Imethanamine dihydrochloride}), TBTU, TEA, DCM, room temperature (rt), overnight. Step 1) Methyl 4-(chlorosulfonyl)-3-nitrobenzoate (methyl 4-

[0285] Synthesis of (chlorosulfonyl)-3-nitr obenzoate

[0286] NCS (3.131 g, 23.45 mmol, 5 eq) and 2N HC1 aqueous solution (4.69 ml, 9.38 mmol, 2 eq) were mixed with ACN (46 ml, 0.1 MH) and stirred at 0 °C for 30 minutes. Methyl 4-mercapto-3-nitrobenzoate (1 g, 4.69 mmol, 1 eq) was added, and the mixture was stirred overnight at room temperature. After the reaction was complete, the solution was concentrated, the concentrate was diluted with Toyo, and then extracted sequentially with an aqueous NaHCOs solution and an aqueous NaCl solution. The organic layer was dried with MgSO4, filtered, and concentrated to obtain the target compound as an unpurified product. Step 2) Methyl 4-(N-((l-methyl-1H-pyrazole-3-yl)methyl)sulfamoyl)- Synthesis of 3-nitrobenzoate (methyl 4- (N-((l-methyl- lH-pyr azo 1-3-yl )methyl ) sulfamoyl )-3-nitrobenzoate)

[0287] (1-methyl-1H-pyrazole-3-yl)methaneamine ((1-methyl-1H-pyrazole-1-3-yl)me than amine,

[0288] 1.042 g, 9.38 mmol, 2 eq) was dissolved in ACN (20 ml, 0.23 M), and methyl 4-(chlorosulfonyl)-3-nitrobenzoate (methyl 4-(chlorosulfonyl 1)-3-nitr obenzoate, 1.311 g, 4.69 mmol, 1 eq) dissolved in ACN (26 ml, 0.18 M) was added dropwise to the reaction mixture. After the reaction was complete, the mixture was extracted with EA and water. The organic layer was dried with MgSO4, filtered, concentrated, and purified by column chromatography (silica gel, EA / HEX) to obtain the target compound (0.3 g, 18.4%). Step 3) Methyl 3-amino-4-(N-((1-methyl-1H-pyrazole-3-yl)methyl)sulfamoyl)benzoate Synthesis of methyl 4-(N-((l-methyl-1H-pyrazol-3-yl)methyl)sulfamoyl)benzoate (methyl 4—(N—(1—methyl—1H—pyrazol-3-yl)methyl)sulfamoyl)-3-nitrobenzoate (methyl 4—(N—(1—methyl—1H—pyrazol-1—3—yl )methhy1)su1famoy1)—3—nitrobenzoate, 0.296 g, 0.835 mmol, 1 eq) was dissolved in 1,4-dioxane:H2O(3:l(v / v))(8.3 ml, 0.1 M), and then Zn (0.546 g, 8.35 mmol, 10 eq) and NH4C1 (0.447 g, 8.35 mmol, 10 eq) were added and stirred overnight at room temperature. The target compound was obtained as an unpurified product by washing with MeOH, filtering under reduced pressure, and concentrating.Step 4) Synthesis of methyl 3-iodo-4-(N-((1-methyl-1H-pyrazole-3-yl)methyl)sulfamoyl)benzoate (methyl 3-iodo-4-(N-((1-methyl-1H-pyrazole-3-yl)methyl)sulfamoyl)benzoate).

[0289] (methyl (3-amino- 4- (N-((l- methyl- 1H- pyr azo 1-3- yl ) me t hy 1 ) su 1 f amoy 1 )benzoate, 0.255 g, 0.79 mmol, 1 eq), HC1 (7 ml, 0.1 M) was dissolved in H2O (7 ml, 0.1 M) and stirred at 0 °C. NaNO2 (0.082 g, 1.185 mmol, 1.5 eq) dissolved in H2O (7 ml, 0.1 M) was added dropwise. After stirring the reaction mixture at 0 °C for 30 minutes, KI (0.393 g, 2.37 mmol, 3 eq) dissolved in H2O (7 ml, 0.1 M) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours, and NaHCOs After neutralizing to a pH of 8 or higher with an aqueous solution, extraction was performed using EA and water. The organic layer was dried with MgSO4, filtered, concentrated, and purified by column chromatography (silica gel, EA / HEX) to obtain the target compound (0.167 g, 48.6%). Step 5) Synthesis of methyl 3-((4-fluorophenyl)ethynyl)-4-(N-((l-methyl-1H-pyrazole-3-yl)methyl)sulfamoyl)benzoate.

[0290] After dissolving (methyl 3-iodo-4-(N- ((1-methyl-1H-pyrazol-3-yl )me t hy 1 )su 1 f amoy 1 )benzoate, 0.167 g, 0.38 mmol, 1 eq) in ACN (7.6 ml, 0.05 M), 1-ethynyl-4-fluorobenzene (1-ethynyl-4-fluorobenzene, 0.068 g, 0.57 mmol, 1.5 eq), PdC12(PPh3)2 (0.008 g, 0.01 mmol, 0.03 eq), Cui (0.002 g, 0.01 mmol, 0.03 eq), and TEA (0.077 g, 0.76 mmol, 2 eq) were added, followed by nitrogen gas (dead The mixture was degassed with gas. The reaction solution was heated to 60 °C and stirred for 4 hours. After the reaction was complete, it was filtered through Celite and extracted with oil. The organic layer was washed with water, separated, dried with MgSO₄, filtered, and concentrated to obtain the target compound as an unpurified product. Step 6) Synthesis of 3-((4-fluorophenyl)ethynyl)-4-(N-((1-methyl-1H-pyrazol-3-yl)methyl)sulfamoyl)benzoic acid (3-((4-fluorophenyl)ethynyl)-4-(N-((l-methyl-1H-pyrazol-3-yl)methyl)sulfamoyl)benzoate (methyl 3-((4-fluorophenyl)ethynyl)-4-(N-((1-methyl-1H-pyrazol-3-yl)methyl)sulfamoyl)benzoate, 0.187 g, 0.438 mmol, 1 eq) in EtOH (8 ml, 0.05 M), H2O (4.38 ml, 0.1 M), NaOH (0.175 g, 4.38 mmol (10 eq) was added and stirred overnight at 60 °C. After the reaction was complete, the pH of the reaction mixture was adjusted to 1 with an aqueous solution of HC1 and extracted with oil. The organic layer was washed with water, separated, dried with MgSO4, filtered, and concentrated to obtain the target compound as an unpurified product. Step 7) Synthesis of 3-((4-fluorophenyl)ethynyl)-N-(imidazo[1,2-a]pyridin-7-ylmethyl)-4-(N-((l-methyl-1H-pyrazol-3-yl)methyl)sulfamoyl)benzamide (3-((4-fluorophenyl )ethynyl)-N-(imidazo[l,2-a]pyridin-7-ylmethyl )-4-(N-((l-methyl-1H-pyrazol-3-yl )methyl )sulfamoyl )benzamide).

[0291] 3-( (4-fluorophenyl)ethynyl)- 4- (N- ( ( 1-methyl- 1H-pyrazole- 3-yl) methyl) sulfamoyl) benzoic acid (3- ( (4- fluorophenyl )ethynyl )- 4- (N-( (1- methyl- 1H-pyrazole- 3-yl) methyl- 1H-pyrazole-

[0292] DCM (3.2 ml, 0.1 M) and TBTU (0.154 g, 0.48 mmol, 1.5 eq) were added to 3-yl )methyl )sulfamoyl )benzoic acid (0.131 g, 0.32 mmol, 1 eq) and stirred at room temperature for 30 minutes. Subsequently, TEA (0.070 g, 0.7 mmol, 2.2 eq) and 1-{imidazō [1,2-a]pyridin-7-yl}methanamine dihydrochloride (1-{imidazō [1,2-a]pyridin-7-yl}methanamine dihydrochloride, 0.077 g, 0.352 mmol, 1.1 eq) were added to the reaction mixture and stirred for 12 hours. Water was added to the reaction mixture and extracted with DCM. The organic layer was dried with MgSO4, filtered, concentrated, and purified by column chromatography (silica gel, MeOH / DCM) to obtain the title compound (0.03 g, 17.3%). Particle NMR (400 MHz, DMSO-based) 5 9.36 (s, 1H), 8.54 (s, 1H), 8.51 (d, J = 6.9

[0293] Hz, 1H), 8.12 (dd, J= 19.3, 8.1 Hz, 2H), 7.90 (s, 1H), 7.55 (dd, J= 8.3, 5.7 Hz,

[0294] 3H), 7.47 (s, 1H), 7.42 (d, J = 1.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 2H), 7.10 (s,

[0295] 1H), 6.89 (d, J = 6.2 Hz, 1H), 5.81 (d, J = 1.9 Hz, 1H), 4.57 (s, 2H), 3.62 (s,

[0296] 3H); MS MH +543.6 Example 15: Synthesis of N-(imidazo[1,2-a]pyridin-7-ylmethyl)-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)-3-((4-((2-(piperazin-1-yl)ethyl)carbamoyl)phenyl)ethynyl)benzamide (N— ( imidazo[1,2-a]pyridin-7-ylmethyl )— 4— (((1-methyl-1H-pyrazol-3-yl )methyl )sulfonyl )—3—( (4—((2-(piperazin-1-yl )ethyl )carbamoyl )phenyl )ethynyl )benzamide (Compound 13) Reagents and conditions: (a) PdC12(PPh3)2, Cui, TEA, ACN, 60 °C, 1 h; (b) IN NaOH, EtOH, 60 °C, 1 h; (c) TBTU, TEA, DCM, room temperature (rt), overnight; (d) TFA, DCM, room temperature (rt), overnight. Step 1) Tert-butyl 4-(2-(4-((5-(methoxycarbonyl)-2-(((1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)phenyl)ethynyl)benzamido)ethyl)piperazine-1-carboxylate (tert-butyl 4-(2-(4-((5-(methoxycarbonyl )-2-(((1-methyl-1H-pyrazole-3-yl)methyl- Synthesis of lH-pyrazol-3-yl )methyl )sulfonyl )phenyl )ethynyl )benzamido)ethyl )piperazine—l—carboxylate): methyl 3-iodo-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzoate (0.26 g, 0.52 mmO 1, 1 eq) was dissolved in ACN (3 ml, 0.2 M), and then tert-butyl 4-(2-(4-ethynylbenzamido)ethyl)piperazine-1-carboxylate was prepared. )piperazi ne- 1-car boxy late, 0.336 g, 0.84 mmol, 1.5 eq),

[0297] After adding PdC12(PPhs)2 (0.013 g, 0.0186 mmol, 0.03 eq), Cui (0.0035 g, 0.0186 mmol, 0.03 eq), and TEA (0.125 g, 1.24 mmol, 1.2 eq), the mixture was degassed with nitrogen gas (N2 gas). The reaction mixture was heated to 60 °C and stirred for 1 hour. After the reaction was complete, the mixture was filtered through Celite and extracted with Toyo. The organic layer was washed with water, separated, dried with MgSO4, filtered, and concentrated to obtain the target compound as an unpurified product. Step 2) Synthesis of 3-((4-((2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)carbamoyl)phenyl)ethynyl)-4-(((1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)benzoic acid (3-((4-((2-(4-(tert-butoxycarbonyl)piperazin—1-yl)ethyl)carbamoyl)phenyl)ethynyl)—4-(((1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)benzoic acid) tert-butyl 4-(2-(4-((5-(methoxycarbonyl)-2-(((1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)phenyl) EtOH (12 ml, 0.05 M), H2O (3.1 ml, 0.2 M), and NaOH (0.120 g, 3.1 mmol, 5 eq) were added to tert-butyl benzamido ethyl piperazine-1-carboxylate (tert-butyl 4-(2-(4-((5-(methoxycarbonyl )-2-(((1-methyl-1H-pyrazol-3-yl )methyl )sulfonyl )phenyl )ethynyl )benzamido)ethyl )piperazine-1-carboxylate, 0.403 g, 0.62 mmol, 1 eq) and stirred at 60 °C for 1 hour.The reaction was monitored by TLC, and once the reaction was complete, the pH of the reactants was adjusted to 1 with an aqueous solution of IN HC1 and extracted with Toyo. The organic layer was washed with water, separated, dried with MgS04, filtered, and concentrated to obtain the target compound as an unpurified product. Step 3) Synthesis of tert-butyl 4-(2-(4-((5-((imidazo[1,2-a]pyridin-7-ylmethyl)carbamoyl)-2-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)phenyl)ethynyl)benzamido)ethyl)piperazine-1-carboxylate.

[0298] 3-((4-((2-(4-(tert-butoxycarbonyl)piperazine-1-yl)ethyl)carbamoyl)phenyl)ethynyl)-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzoic acid (3-((4-((2-(4-(t-butoxycarbonyl)piperazin—1—yl)ethyl)carbamoyl)phenyl)ethynyl)—4—(((1—methyl—IH—pyrazol—3—yl)methyl)sulfonyl)benzoic acid, 0.394g, 0.62 mmol, 1 eq) in DCM (3 ml, 0.2M) and TBTU (0.298 g, 0.93 mmol, 1.5 eq) was added and stirred at room temperature for 50 minutes. Then, TEA (0.137 g, 1.36 mmol, 2.2 eq) and 1-{imidazo[1,2-a]pyridin-7-yl}methane amine dihydrochloride (0.150 g, 0.682 mmol, 1.1 eq) were added to the reaction mixture and stirred for 12 hours. Water was added to the reaction mixture and extracted with DCM. The organic layer was dried with MgSO₄, filtered, concentrated, and then purified by column chromatography (silica gel, MeOH / DCM) to obtain the compound of the title (0.27 g, 56.4%).Step 4) Synthesis of N-(imidazo[1,2-a]pyridin-7-ylmethyl)-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)-3-((4-((2-(piperazin-1-yl)ethyl)carbamoyl)phenyl)ethynyl)benzamide (N-(imidazo[1,2-a]pyridin-7-ylmethyl )-4-(((1-methyl-1H-pyrazol-3-yl )methyl )sulfonyl )-3-((4-((2-(piperazin-1-yl )ethyl )carbamoyl )phenyl )ethynyl )benzamide) a]pyridin- 7-ylmethyl)carbamoyl)- 2- (((1-methyl- 1H-pyrazol- 3-yl)methyl)sulfonyl) phenyl)ethynyl)benzamido)ethyl)piperazine-1-carboxylate (tert-butyl 4— (2— (4— ((5— ((imidazo[l,2— a]pyridin— 7— ylmethyl )carbamoyl )— 2— (((1— methyl— 1H— pyrazol— 3— yl )methyl)sulfonyl ) phenyl )ethynyl )benzamido)ethyl )piperazine—l— carboxylate ,.

[0299] 0.150 g, 0.196 mmol, leq) was dissolved in DCM (2 ml, 0.1 M), and then TFA (0.223 g, 1.96 mmol,

[0300] 10 eq) was added and stirred overnight at room temperature. After the reaction was complete, the solution was concentrated and purified by reverse-phase column chromatography (0.1% formic acid in H2O / ACN) to obtain the compound of the title (0.067 g,

[0301] 51.5%) was obtained. p NMR (400 MHz, MeOD) 5 8.51 s, 1H), 8.28 (s, 1H), 8.23 ​​s, 1H), 7.96 (s,

[0302] 1H), 7.91 (d, J = 5.1 Hz, 3H), 7.78 (d, J = 7.5 Hz, 2H), 7.66 (s, 1H), 7.59 (s,

[0303] 1H), 7.44 (s, 1H), 7.10 (d, J = 6.7 Hz, 1H), 6.17 (s, 1H), 4.85 - 4.83 (m, 2H),

[0304] 4.70 s, 2H), 3.72 (s, 3H), 3.57 (s, 3H), 3.50 (s, 1H), 3.22 (s, 2H), 2.79 (s, 2H),

[0305] 2.75 — 2.57 (m, 4H); MS MH + 665.58 Example 16: 3-((4-aminophenyl)ethynyl)-N-(imidazo[1,2-a]pyridine-7-ylmethyl)-4-(((1-methyl—1H-pyrazol—3-yl)methyl)sulfonyl)benz 0} 13 ]d (3— ((4— ami nopheny 1 ) et hyny 1 ) —N—

[0306] Synthesis of (imidazo[l,2—a]pyridin—7—ylmethyl)—4—(((l—methyl—lH—pyrazol—3— yl)methyl)sulfonyl)benzamide, compound 14) Reagents and conditions: 4-ethynylaniline,

[0307] TEA, Cui, PdCh(PPh3)2, ACN, Reflux (ref lux), 1 hour (Ih)

[0308] N-(imidazo[1,2-a]pyridin-7-ylmethyl)-3-iodo-4-(((l-methyl—IH—pyrazol—3—yl)methyl)sulfonyl)benzamide (0.535 g, 1 mmol, 1 eq) was dissolved in ACN (10 ml, 0.1 M), then TEA (0.3 ml, 2.2 mmol, 2.2 eq), PdC12(PPh3)2 (21 mg, 0.03 mmol, 3 mol%), and Cui (8 mg, 0.04 mmol, 4 mol%) were added, and the mixture was stirred at room temperature for 5 minutes. 4-ethynylaniline (0.14 g, 1.2 mmol, 1.5 eq) was added and stirred at 90 °C for 1 hour. After cooling to room temperature and concentrating, it was purified by column chromatography (silica gel, EA / HX). (0.193 g, 37%) or NMR (400 MHz, CD30D) 6 8.41 (d, J = 7.0 Hz, 1H), 8.16–8.12 (m, 1H),

[0309] 7.87 (d, J = 8.3 Hz, 1H), 7.84 - 7.79 (m, 2H), 7.53 (s, 1H), 7.48 (s, 1H), 7.44 -

[0310] 7.37 (m, 3H), 6.95 (dd, J = 7.1, 1.5 Hz, 1H), 6.69 (d, J = 8.7 Hz, 2H), 6.12 (d,

[0311] J = 2.2 Hz, 1H), 4.85 (s, 2H), 4.64 (s, 2H), 3.72 (s, 3H). Example 17: 3-((3-aminophenyl)ethynyl)-N-(imidazo[1,2-a]pyridine-7-ylmethyl)-4-(((1—methyl—1na—pyrazole—3—yl)methyl)sulfonyl)benz0} 13 ]d (3~((3~aminopheny! )ethynyl )~N~

[0312] Synthesis of (imidazo[l,2— a]pyr idin— 7— ylmethyl )—4—(((l—methyl—lH—pyrazol—3— yl)methyl)sulfonyl)benzamide, compound 15) Reagents and conditions: (a) 3-ethylnylaniline, PdC12(PPh3)2, Cui, TEA, ACN, 60 °C, 4 h) N-(imidazoo[1,2-a]pyridin-7-ylmethyl)-3-iodo-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide (N-(imidazoo[1,2-a]pyridin-7-ylmethyl)3-iodo-4-(((1-methyl—1H—pyrazol—3—yl)methyl)sulfonyl)benzamide, 0.050 g, 0.093 mmol, 1 eq) in ACN (1 After dissolving in ml (0.1 M), 3-ethylnylaniline (0.016 g, 0.139 mmol, 1.5 eq), PdC12(PPhs)2 (0.006 g, 0.01 mmol, 0.1 eq), Cui (0.002 g, 0.01 mmol, 0.1 eq), and TEA (0.037 g, 0.37 mmol, 4 eq) were added, followed by degassing with nitrogen gas. The reaction mixture was heated to 60 °C and stirred for 4 hours. After the reaction was complete, the mixture was filtered through Celite and extracted with Toyo. The organic layer was washed with water, separated, dried with MgSO4, filtered, concentrated, and purified by column chromatography (silica gel, MeOH / DCM) to obtain the title compound (0.002 g, 4%). Particle NMR (400 MHz, MeOD) 5 8.43 (d, J = 7.0 Hz, 1H), 8.23 ​​(s, 1H), 7.92 (d, J = 0.7 Hz, 2H), 7.82 (s, 1H), 7.56 (s, 1H), 7.51 (s, 1H), 7.44 (d, J = 2.2 Hz, 1H), 7.17 (t, J = 7.8 Hz, 1H), 7.02 (d, J = 1.8 Hz, 1H), 6.98 (dd, J = 11.8, 4.6 Hz, 2H), 6.81 (dd, J = 8.1, 1.5 Hz, 1H), 6.15 (d, J = 2.2 Hz, 1H), 4.67 (s, 2H), 3.74 (s, 3H). Example 18: N-(imidazo[1,2-a]pyridine-7-ylmethyl)-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)-3-((3-(piperazine-1-carbonyl)phenyl)ethynyl)benzamide (N-.

[0313] Synthesis of (imidazo[l,2— a]pyridin— 7— y Imethy 1)—4— (((1— methyl— 1H— pyrazol— 3— yl )methyl )sulfonyl )—3— ((3— (piperazine— 1— carbonyl )phenyl )ethynyl )benzamide, compound 16) Reagents and conditions: (a) N-Boc-piperazine, EDOHCl, HOBt, TEA, DCM, room temperature (rt), overnight; (b) PdCl2(PPh3)2, Cui, TEA, ACN, reflux, 1 hour (1 h); (c) TFA, DCM, room temperature (rt), 3 hours (3 h). Step 1) Synthesis of tert-butyl 4-(3-ethynylbenzoyl)piperazine-1-carboxylate

[0314] 3-ethynylbenzoic acid (0.2 g, 1.37 mmol, 1 eq), EDOHCl (0.393 g, 2.05 mmol, 1.5 eq), and HOBt (0.296 g, 2.192 mmol, 1.6 eq) were added to DCM (13 ml, 0.1 M) and stirred at room temperature for 15 minutes. N-Boc-piperazine (0.331 g, 1.781 mmol, 1.3 eq) and TEA (0.416 g, 4.11 mmol, 3 eq) were added and stirred overnight at room temperature. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by column chromatography (silica gel, EA / HEX) to obtain the target compound (0.25 g, 58%). Step 2) Synthesis of tert-butyl 4-(3-((5-((imidazo[1,2-a]pyridin-7-ylmethyl)carbamoyl)-2-(((1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)phenyl)ethynyl)benzoyl)piperazine-1-carboxylate

[0315] N-(imidazoc[1,2-a]pyridin-7-ylmethyl)-3-iodo-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide (N-(imidazoc[1,2-a]pyrazol-3-yl)methyl)sulfonyl)benzamide, 0.1g, 0.19 mmol, 1 eq) was dissolved in ACN (1.9 ml, 0.1 M), and then tert-butyl 4-(3-ethynylbenzoyl)piperazine-1-carboxylate was prepared. After adding carboxylate (0.089 g, 0.285 mmol, 1.5 eq), PdC12(PPhs)2 (0.013 g, 0.02 mmol, 0.1 eq), Cui (0.004 g, 0.02 mmol, 0.1 eq), and TEA (0.077 g, 0.76 mmol, 4 eq), the mixture was degassed with nitrogen gas. The reaction mixture was stirred for 1 hour under reflux. After the reaction was complete, the mixture was filtered through Celite and extracted with a Toyo. The organic layer was washed with water, separated, dried with MgSO4, filtered, concentrated, and purified by column chromatography (silica gel, MeOH / DCM) to obtain the target compound (0.052 g, 37.9%). Step 3) N-(imidazo[1,2-a]pyridine-7-ylmethyl)-4-(((1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)-3-((3-(piperazine-1-carbonyl)phenyl)ethynyl)benzamide(N-

[0316] Synthesis of (imidazo[l,2-a]pyridin-7-ylmethyl )-4-( ( (1-methyl 1-lH-pyridin-7-ylmethyl)carbamoyl )-3-( (3-(piperazine-l-carbony 1 )phenyl )ethynyl )benzamide) tert-butyl 4-(3-((5-((imidazo[1,2-a]pyridin-7-ylmethyl)carbamoyl)-2-(((1-methyl-1H-pyridin-3-yl)methyl)sulfonyl)phenyl)ethynyl)benzoyl)piperazine-1-carboxylate (tert-butyl 4— (3—(5— ((imidazo[l,2—a]pyridin— 7— ylmethyl 1)carbamoyl )— 2—(( (1— methyl- IH-pyr azo 1-3-yl )methyl)sulfonyl ) phenyl )ethynyl )benzoyl )piperazine—l— carboxylate , 0.050 g, 0.069 mmol, leq) was dissolved in DCM (1 ml, 0.07 M), after which TFA (0.079 g, 0.69 mmol, 10 eq) was added and stirred overnight at room temperature. After the reaction was complete, the solution was concentrated and purified by reverse-phase column chromatography (0.1% formic acid in H2O / ACN) to obtain the compound of the title (0.013 g,

[0317] 32.5%). The 1H NMR (400 MHz, DMSO-d6) δ 9.45 (d, J = 5.5 Hz, 1H), 8.51 (d, J = 6.6 Hz, 1H), 8.34 (s, 1H), 8.16 (s, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.97 - 7.88 (m, 2H), 7.79 (d, J = 7.5 Hz, 1H), 7.75 (s, 1H), 7.60 (t, J = 7.4 Hz, 2H), 7.55 (d, J = 7.2 Hz, 2H), 7.46 (s, 1H), 6.89 (d, J = 6.9 Hz, 1H), 6.09 (s, 1H), 4.88 (s, 2H), 4.54 (d, J = 5.3 Hz, 2H), 3.70 (s, 3H), 3.43 (s, 4H), 2.96 (s, 4H). Example 19: Synthesis of N-(imidazo[1,2-a]pyridin-7-ylmethyl)-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)-3-((1,2,3,4-tetrahydroisoquinolin-6-yl)ethynyl)benzamide (Compound 17) Reagents and conditions: (a) Dimethyl (1-diazo-2-oxopropyl)phosphate, K2CO3, MeOH, room temperature (rt), overnight; (b) PdC12(PPhs)2, Cui, TEA, ACN, reflux, 1 h; (c) TFA, 4N HC1 in 1,4-dioxane, DCM, room temperature (rt), overnight. Step 1) Tert-butyl 6-ethynyl-3,4-dihydroisoquinoline-2(1H)-carboxylate

[0318] Synthesis of (tert-butyl 6-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate): tert-butyl 6-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.25 g, 0.96 mmol, 1 eq) was diluted in MeOH (4 ml, 0.24 M), dimethyl (1-diazo-2-oxopropyl)phosphate (0.221 g, 1.152 mmol, 1.2 eq) and K2CO3 (0.265 g, 1.92 mmol, 2 eq) were added, and at room temperature Stirring was performed overnight. After the reaction was complete, extraction was performed with DCM and water. The organic layer was washed with an aqueous NaCl solution, separated, dried with MgSO₄, filtered, and concentrated to obtain the target compound as an unpurified product. Step 2) Synthesis of tert-butyl 6-((5-((imidazo[1,2-a]pyridin-7-ylmethyl)carbamoyl)-2-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)phenyl)ethynyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[0319] N-(imidazo[1,2-a]pyridin-7-ylmethyl)-3-iodo-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide (0.1g, 0.19 mmol, 1 eq) was dissolved in ACN (1.9 ml, 0.1 M), and then tert-butyl 6-ethynyl-3,4-dihydroisoquinoline-2(1H)-carboxylate After adding 2(1H)-carboxylate (0.072 g, 0.281 mmol, 1.5 eq), PdC12(PPh3)2 (0.013 g, 0.02 mmol, 0.1 eq), Cui (0.004 g, 0.02 mmol, 0.1 eq), and TEA (0.076 g, 0.75 mmol, 4 eq), the mixture was degassed with nitrogen gas (N2 gas). The reaction mixture was stirred for 1 hour under reflux. After the reaction was complete, the mixture was filtered through Celite and extracted with Toyo. The organic layer was washed with water, separated, dried with MgSO4, filtered, concentrated, and purified by column chromatography (silica gel, MeOH / DCM) to obtain the target compound (0.046 g, 36.9%). Step 3) N-(imidazo[1,2-a]pyridine-7-ylmethyl)-4-(((1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)-3-((1,2,3,4-tetrahydroisoquinoline-6-yl)ethinyl)benzamide(N-

[0320] Synthesis of (imidazo[l,2-a]pyridin-7-ylmethyl )-4-( ( (1-methyl 1-lH-pyridin-7-ylmethyl)methyl )sulfonyl )— 3— ((1,2,3,4— tetrahydroisoquinol in-6-yl )ethynyl )benzamide) tert-butyl 6- ((5-((imidazo[1,2-a]pyridin-7-ylmethyl)carbamoyl)-2- (((1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)phenyl)ethynyl)-3,4-dihydroisoquinoline -2(1H)-carboxylate (tert-butyl 6-( (5-( ( imidazo[l , 2~a ] pyr idi n-7-y 1 me t hy 1)carbamoy 1)-2- ( ( (1—methyl—1H—pyr azo 1—3—yl )methyl)sulfonyl )phenyl )ethynyl )—3,4—dihydroisoquinol ine-2(1H)-carbamoy late, 0.046 g, 0.069 mmol, leq) was dissolved in DCM (1 ml, 0.07 M), then TFA (0.079 g, 0.69 mmol, 10 eq) was added and stirred overnight at room temperature. After concentrating the reaction mixture, 4N HC1 (in 1,4-dioxane, 0.34 ml, 1.38 mmol, 20 eq) was added and stirred at room temperature for 3 hours. After the reaction was complete, the reaction product was concentrated and purified by reverse-phase column chromatography (0.1% formic acid in H2O / ACN) to obtain the compound of the title (0.013 g, 33%). Particle NMR (400 MHz, DMSO-based) 9.47 (s, 1H), 8.67 (s, 1H), 8.32 (s, 1H), 8.05 (d, J= 8.0 Hz, 1H), 7.93 (d, J= 8.0 Hz, 1H), 7.61 (s, 1H), 7.52 (d, J= 13.1 Hz, 3H), 7.28 (s, 1H), 6.90 (d, J= 6.3 Hz, 1H) , 6.10 (s, 1H) , 4.90 (s, 2H) , 4.53 (s,.

[0321] 2H), 3.90 (s, 3H), 3.72 (s, 3H), 2.92 (s, 3H). Example 20: 3-((3-(aminomethyl)phenyl)ethinyl)-N-(imidazo[1,2-a]pyridine-7~ylmethyl)-4-(((1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)benzamide (3-((3-

[0322] (aminomethyl)phenyl)ethynyl)—N—(imidazo[l,2—a]pyridin— 7— ylmethyl)— 4—(( (1— methyl—

[0323] Synthesis of 1H— pyrazol— 3— yl)methyl)sulfonyl)benzamide, compound 18) Reagents and conditions: (a) B0C2O, DCM, 0 °C to room temperature (0 °C to rt), overnight; (b) PdC12(PPh3)2, Cui, TEA, ACN, reflux, 4 h; (c) 4N HC1 in dioxane, room temperature (rt), overnight. Step 1) Synthesis of tert-butyl (3-ethynyl benzyl)carbamate

[0324] (3-ethynylphenyl)methanamine (0.1 g, 0.76 mmol, 1 eq) was diluted in DCM (1.4 ml, 0.5 M), di-tert-butyl dicarbonate (0.183 g, 0.84 mmol, 1.1 eq) was added at 0 °C, and the mixture was stirred overnight while gradually increasing the temperature to room temperature. After the reaction was complete, the mixture was extracted with DCM. The organic layer was dried with MgSO₄, filtered, concentrated, and purified by column chromatography (silica gel, EA / HEX) to obtain the target compound (0.15 g, 85%). Step 2) Tert-butyl (3- ((5-((imidazo[1,2-a]pyridin-7-ylmethyl)carbamoyl)-2- (((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)phenyl)ethynyl)benzyl)carbamate (tert-butyl)

[0325] Synthesis of (3— ((5— ((imidazo[l,2— a]pyridin— 7— ylmethyl )carbamoyl)— 2— (((1— methyl— IH—pyr azo 1—3— yl )methyl )sulfonyl )phenyl )ethynyl )benzyl )carbamate)

[0326] After dissolving N-(imidazo[1,2-a]pyridin-7-ylmethyl)-3-iodo-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide (0.2g, 0.37 mmol, 1 eq) in ACN (3.7 ml, 0.1 M), tert-butyl(3-ethynylbenzyl)carbamate (0.128 g, 0.56 mmol, 1.5 eq), After adding PdC12(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), the mixture was degassed with nitrogen gas (N2 gas). The reaction mixture was stirred for 4 hours under reflux. After the reaction was complete, the mixture was filtered through Celite and extracted with oil. The organic layer was washed with water, separated, dried with MgSO4, filtered, concentrated, and purified by column chromatography (silica gel, MeOH / DCM) to obtain the target compound (0.15 g, 63.5%). Step 3) 3-((3-(aminomethyl)phenyl)ethinyl)-N-(imidazo[1,2-a]pyridine-7-ylmethyl)-4-(((1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)benzamide (3-((3-

[0327] Synthesis of (aminomethyl)phenyl)ethynyl)—N—(imidazo[l,2—a]pyridin—7—ylmethyl)—4—((1—methyl—IH-pyr azo 1-3-yl )methyl )sulfonyl )benzamide) tert-butyl (3-((5-((imidazo[1,2-a]pyridin-7-ylmethyl)carbamoyl)-2-(((1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)phenyl)ethynyl)benzyl)carbamate (tert-butyl (3-((5-

[0328] ( (imidazotl, 2-a]pyri di n-7-ylmethyl) carbamoyl )-2-( ((1-methyl-lH-pyr azo 1-3- yl )methyl )sul f onyl )phenyl )ethynyl )benzyl )carbamate , 0.05 g, 0.078 mmol , leq) was dissolved in 1,4-dioxane (1 ml, 0.07 M), and then 4N HC1 (4N HC1 in 1,4-di oxane, ) was dissolved in 1,4-dioxane.

[0329] 0.58 mL, 2.34 mmol, 30 eq) was added and stirred at room temperature overnight. After completion of the reaction, the reaction mixture was concentrated and purified by reverse-phase column chromatography (0.1% formic acid in H2O / ACN). The purified product was added with 4N HCl in dioxane (0.058 mL, 0.3 M) under 1,4-dioxane at room temperature and stirred overnight. The resulting solid was washed with diethyl ether and filtered under reduced pressure to obtain the title compound (0.017 g, 42.3%). 1H NMR (400 MHz, DMSO-d6) δ 9.84 (t, J = 5.6 Hz, 1H), 8.88 (d, J = 6.9 Hz, 1H), 8.50 (s, 2H), 8.38 (d, J = 1.4 Hz, 1H), 8.34 (d, J = 1.6 Hz, 1H), 8.17 (d, J = 1.9 Hz, 1H), 8.09 (dd, J = 8.3, 1.5 Hz, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.87 (s, 1H), 7.82 (s, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.65 (d, J = 7.7 Hz, 1H), 7.61 - 7.55 (m, 2H), 7.52 (d, J = 7.0 Hz, 1H), 6.09 (d, J = 2.1 Hz, 1H), 4.91 (s, 2H), 4.71 (d, J = 5.5 Hz, 2H), 4.10 (d, J = 5.6 Hz, 2H), 3.70 (s, 3H); MS MH+ 537.05 Example 21: Synthesis of 4-(((1-(4-aminophenyl)-1H-pyrazol-3-yl)methyl)sulfonyl)-3-((4-fluorophenyl)ethynyl)-N-(imidazo[1,2-a]pyridin-7-ylmethyl)benzamide (4-(((1-(4-aminophenyl)—1H-pyrazol—3-yl)methyl)sulfonyl)—3—((4-fluorophenyl)ethynyl)—N—(imidazo[l,2-a]pyridin—7-ylmethyl)benzamide, compound 19).

[0330] Reagents and conditions: (a) 1-fluoro-4-nitrobenzene, K2CO3, DMF, room temperature (rt), 16 hours (16h); (b) LiAlH4 in 1.0M THF, THF, 0 °C, 7 hours (7h); (c) SOCl2, MC, 0 °C—room temperature (rt); (d) methyl 3-iodo-4-mercaptobenzoate, K2CO3, DMF, room temperature (rt), 2 hours (2h); (e) mCPBA, MC, room temperature (RT), overnight; (f) 1-ethynyl-4-fluorobenzene (l-ethynyl-4-f luorobenzene), TEA, Cui, PdC12(PPh3)2, ACN, reflux, 1 hour (Ih); (g) NaOH, EtOH, H2O, reflux, 1 hour (Ih); (h) 1-{imidazo[1,2-a]pyridin-7-yl} methaneamine hydrochloride (l-{imidazo[l,2-a]pyridin-7-yl Imethanamine hydrochloride), TBTU, TEA, MC, room temperature (rt), 7 hours (7h); (i) Zn, NH4C1, 1,4-dioxane, H2O, room temperature (rt), 5 hours (5h) Step 1) Ethyl 1-(4-nitrophenyl)- Synthesis of IH-pyrazole-3-carboxylate (ethyl 1-(4-nitrophenyl )-IH-pyrazole-3-carboxylate): Ethyl IH-pyrazole-3-carboxylate (ethyl IH-pyrazole-3-carboxylate, 1.4 g, 10 mmol, leq) was dissolved in DMF (100 ml, 0.1 M), and then K2CO3 (1.66 g, 12 mmol, 1.2 eq), 1-fluoro-4-nitrobenzene (1-fluoro-4-nitrobenzene, 1.55 g, 11 mmol, l. eq) was added and stirred overnight at room temperature. After the reaction was complete, water was added and the resulting solid was filtered and dried to obtain the crude product. (1.907 g, 73%) Step 2) Synthesis of ethyl 1-(4-nitrophenyl)-1H-pyrazol-3-yl)methanol ((l-(4-nitrophenyl)-lH-pyrazol-3-yl )methanol). Ethyl 1-(4-nitrophenyl)-1H-pyrazol-3-carboxylate (ethyl l-(4-nitrophenyl)-1H-pyrazol-3-carboxylate, 1.907 g, 7.36 mmol, 1 eq) was dissolved in anhydrous THF (73 ml, 0.1 M), and then 1.0 M LiAlH4in THF (10.9 ml, 10.9 mmol, 1.5 eq) was slowly added dropwise at 0 °C and stirred for 7 hours. After the reaction was complete, water and clay were added, the solid was filtered, and the filtrate was concentrated to obtain the unpurified product (0.468 g). NMR (400 MHz, CDCls) 8 8.40–8.33 (m, 2H), 8.03 (d, J = 2.6 Hz, 1H), 7.91–7.86 (m, 2H), 6.59 (d, J = 2.6 Hz, 1H), 4.84 (s, 2H). Step 3) Synthesis of 3-(chloromethyl)-1-(4-nitrophenyl)-1H-pyrazole.

[0331] (1-(4-nitrophenyl)-1H-pyrazol-3-yl)methanol ((1-(4-nitr ophenyl)-1H-pyrazol-3-yl)methanol, 0.468 g, 2.135 mmol, leq) was dissolved in DCM (11 ml, 0.2 M), after which SOC12 (0.46 ml, 6.41 mmol, 3 eq) was slowly added dropwise at 0 °C and refluxed overnight. After the reaction was complete, the product was concentrated under reduced pressure and obtained as an unpurified product. (0.432 g, 100%) p NMR (400 MHz, CDC13) 8 8.37 — 8.30 (m, 2H), 8.00 (d, J = 2.6 Hz, 1H), 7.87 (dd, J = 6.9, 5.0 Hz, 2H), 6.63 (d, J = 2.6 Hz, 1H), 4.68 (s, 2H). Step 4) Synthesis of methyl 3-iodo-4-(((1-(4-nitrophenyl )-1H-pyrazol-3-yl)methyl)thio)benzoate.

[0332] 3-(chloromethyl)-1-(4-nitrophenyl)-1H-pyrazole (0.15 g, 0.5 mmol, leq) was dissolved in DMF (4 ml, 0.1 M), K2CO3 (0.116 g, 0.84 mmol, 2 eq) was added, and methyl 3-iodo-4-mer captobenzoate (0.15 g, 0.5 mmol, 1.2 eq) dissolved in DMF (5 ml, 0.1 M) was slowly added, followed by stirring at room temperature for 2 hours. After the reaction was complete, water was added, and the resulting solid was filtered, dried, and purified by column chromatography (silica gel, EA / HX). (0.073 g, 29.4%) p NMR (400 MHz, CDCI3) 8 8.45 (d, J = 1.8 Hz, 1H), 8.39–8.34 (m, 2H), 7.98 (dd, J = 4.6, 3.0 Hz, 2H), 7.89–7.84 (m, 2H), 7.42 (d, J = 8.4 Hz, 1H), 6.60 (d, J = 2.6 Hz, 1H), 4.33 (s, 2H), 3.92 (d, J = 2.9 Hz, 3H, step 5) methyl 3-iodo-4-(((1-(4-nitrophenyl)-1H-pyrazole-3-yl)methyl) Synthesis of methyl 3-iodo-4-(((1-(4-nitr ophenyl)-lH-pyrazol-3-yl)methyl)thio)benzoate (methyl 3-iodo-4-(((1-(4-nitrophenyl)-1H-pyrazol-3-yl)methyl)thio)benzoate (methyl 3-iodo-4-(((1-(4-nitr ophenyl)-lH-pyrazol-3-yl)methyl)thio)benzoate (methyl 3-iodo-4-(((1-(4-nitr ophenyl)-lH-pyrazol-1-3-y 1)methyl hy 1)thi 0)benzoate e, 0.073 g, 0.147 mmol, 1 eq) in MC (8 ml, 0.After dissolving in 2M, mCPBA (0.127 g, 0.735 mmol, 5 eq) was added and stirred overnight. After the reaction was complete, a saturated aqueous solution of NaHCOs was added and extracted with MC. The organic layer was dried with MgSO4, filtered, and concentrated to obtain the crude product. (0.080g, 100%) Step 6) Synthesis of methyl 3-((4-fluorophenyl)ethynyl)-4-(((1-(4-nitrophenyl)-1H-pyrazol-3-yl)methyl)sulfonyl)benzoate 0.447 g (0.859 mmol, 1 eq)sulfonyl benzoate was dissolved in ACN (8.6 ml, 0.1 M), then TEA (0.26 ml, 1.89 mmol, 2.2 eq), PdC12(PPh3)2 (18 mg, 0.025 mmol, 3 mol%), and Cui (6.5 mg, 0.034 mmol, 4 mol%) were added, and the mixture was stirred at room temperature for 5 minutes. After adding 1-ethynyl-4-fluorobenzene (0.15 ml, 1.29 mmol, 1.5 eq), the mixture was stirred at 90 °C for 1 hour. After cooling to room temperature and concentrating, the solution was purified by column chromatography (silica gel, EA / HX). (0.125 g, 28%) B NMR (400 MHz, CDC13) 6 8.38 (s, 1H), 8.28 (d, J = 9.1 Hz, 2H), 8.02 (d, J = 0.8 Hz, 2H), 7.91 (d, J = 2.4 Hz, 1H), 7.72 — 7.65 (m, 4H), 7.11 (t, J = 8.6 Hz, 2H), 6.56 (d, J = 2.4 Hz, 1H), 4.90 (s, 2H), 3.98 (s, 3H). Step 7) Synthesis of 3-((4-fluorophenyl)ethynyl)-4-(((1-(4-nitrophenyl)-1H-pyrazol-3-yl)methyl)sulfonyl)benzoic acid (3-((4-fluorophenyl)ethynyl)-4-(((1-(4-nitrophenyl)-1H-pyrazol-3-yl)methyl)sulfonyl)benzoate (methyl 3-(((4-fluorophenyl)ethynyl)-4-(((l-(4-nitrophenyl)-1H-pyrazol-3-yl)methyl)sulfonyl)benzoate )su onyl)benzoate, 0.125 g, 0.065 mmol, 1 eq) was dissolved in EtOH (1 ml, 0.05 M), then NaOH (0.005 g, 0.13 mmol, 2 eq) dissolved in H2O (0.14 ml) was added, and the mixture was refluxed for 1 hour. After cooling to room temperature, the solution was concentrated and diluted with water. The pH was adjusted to 5–6 using HC1, and the resulting solid was filtered, washed with water, and dried. (0.1 g, 82%) Step 8) Synthesis of 3-((4-fluorophenyl)ethynyl)-N-(imidazo[1,2-a]pyridin-7-ylmethyl)-4-(((1-(4-nitrophenyl)-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide (3-((4-fluorophenyl )ethynyl )-N-(imidazo[1,2-a]pyridin-7-ylmethyl )-4-(((1-(4-nitrophenyl )—1H—pyrazol—3—yl )methyl )sulfonyl )benzamide).

[0333] 3-((4-fluorophenyl)ethynyl)-4-(((1-(4-nitrophenyl)-1H-pyrazol-3-yl)methyl)sulfonyl)benzoic acid (0.1 g, 0.2 mmol, 1 eq) was dissolved in MC (2 ml, 0.1 M), then TBTU (0.1 g, 0.3 mmol, 1.5 eq), TEA (0.06 ml, 0.44 mmol, 2.2 eq), and 1-{imidazo[1,2-a]pyridine-7-yl}methaneamine hydrochloride were added. (l-{imidazo[l,2-a]pyridin-7-yl}me than amine hydrochloride, 0.04g , 0.22 mmol , 1.1 eq) was added and stirred at room temperature for 7 hours. After the reaction was complete, the mixture was concentrated and purified by column chromatography (silica gel, MeOH / MC). (51 mg, 40.2 %) Step 9) Synthesis of 4-(((1-(4-aminophenyl)-1H-pyrazol-3-yl)methyl)sulfonyl)-3-((4-fluorophenyl)ethynyl)-N-(imidazo[1,2-a]pyridin-7-ylmethyl)benzamide (4-(((1-(4-aminophenyl )—lH—pyrazol—3—yl )methyl )sulfonyl )—3—( (4—f luorophenyl )ethynyl )—N— (imidazo[l,2-a]pyridin-7-ylmethyl )benzamide).

[0334] After dissolving 3-((4-fluorophenyl)ethynyl)-N-(imidazo[1,2-a]pyridin-7-ylmethyl)-4-(((1-(4-nitrophenyl)-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide (3-((4-fluorophenyl)ethynyl)-N-(imidazo[1,2-a]pyridin-7-ylmethyl)-4-(((1-(4-nitrophenyl)-1H-pyrazol-3-yl)methyl )sulfonyl )benzamide, 0.051 g, 0.080 mmol, 1 eq) in 1,4-dioxane:H2O (3:1(v:v), 1 ml, 0.084 M), Zn (0.055 g, 0.84 mmol, 10 eq) and NH4C1 (0.045 g, 0.84 mmol, 10 eq) were added and stirred at room temperature for 5 hours. The reaction mixture was

[0335] The solution was washed with MeOH and filtered under reduced pressure through Celite. The filtrate was concentrated and purified by reverse-phase column chromatography (0.1% formic acid in IfeO / Acetonitrile). P NMR (400 MHz, MeOD) 5 8.48 (d, J = 7.1 Hz, 1H) , 8.29 (s, 1H) , 8.25 (s, 1H), 7.98 - 7.94 (m, 2H) , 7.88 (s, 1H), 7.86 (d, J = 2.4 Hz, 1H) , 7.78 - 7.73 (m, 2H), 7.63 (s, 1H), 7.57 (s, 1H) , 7.23 - 7.16 (m, 4H) , 7.04 (d, J = 7.1 Hz, 1H) , 6.71 (d, J = 8.8 Hz, 2H), 6.41 (d, J = 2.4 Hz, 1H), 4.94 (s, 2H), 4.70 (s, 2H). Example 22: Synthesis of 3-((4-fluorophenyl)ethynyl)-N-(imidazo[1,2-a]pyridin-7-ylmethyl)-4-(((1-(piperidin-4-yl)-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide (3-((4-fluorophenyl)ethynyl)—N—(imidazo[1,2-a]pyridin-7-ylmethyl)—4—((1-(piperidin-4-yl)—lH-pyrazol-3-yl)methyl)sulfonyl)benzamide (Compound 20). ((methylsulfonyl)oxy)piperidin-1-carboxylate (tert-butyl 4-

[0336] ( (methyl sulfonyl )oxy)piper idine-l-carboxylate) , K2CO3, DMF, 70 °C, overnight : (b) 1.0 M L1AIH4 in THF (1.0 M L1AIH4 in THF), THF, 0 °C, 1 hour (Ih); (c) MsCl, TEA, THF, 0 °C to room temperature (0 °C ∼ rt), 12 hours (12h) (d) methyl 3-iodo-4-mercaptobenzoate , K2CO3, DMF, room temperature (rt), 1 hour (Ih) : (e) mCPBA , MC, room temperature (RT), overnight ; (f ) 1-ethynyl-4-fluorobenzene (1-ethynyl-4- fluorobenzene, ) TEA, Cui , PdC12(PPh3)2, ACN, reflux, 1 hour (Ih); (g) NaOH, EtOH, H2O, 90 °C, 1 hour (Ih); (h) 1-{imidazotl ,2-a]pyridin-7-yl} methaneamine hydrochloride, TBTU , TEA, MC, room temperature (rt), overnight, (i) 4N HC1 under dioxane, DCM, room temperature (rt), 2 hours (2h) Step 1) Tert-butyl 4-(3-(ethoxycarbonyl)- Synthesis of 1H-pyrazole-1-yl)piperidine-1-carboxylate (tert-butyl 4-(3-(et hoxycar bony 1)-lH-pyr azo 1-1-y 1)piperidine-1-carboxylate) ethyl 1H-pyrazole-3-carboxylate (ethyl lH-pyr azo 1 e-3~carboxylate, 1.4 g, 10 mmol, 1 eq) was dissolved in DMF (50 ml, 0.2 M) and K2CO3 (1.66g, 12 mmol, 1.2. eq), tert-butyl 4-((methylsulfonyl) oxy) piperidine-1-carboxylate (tert-butyl 4-.

[0337] ((methylsulfonyDoxy)pi per idine-l-carboxylate, 3.07 g, 11 mmol, 1.1 eq) was added and stirred at 70 °C for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, water was added, and the mixture was extracted with oil. The organic layer was dried with MgSO₄, filtered, concentrated, and then purified by column chromatography (silica gel, EA / HX). (1.623 g, 50.2%) Step 2) Synthesis of tert-butyl 4-(3-(hydroxymethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate tert-butyl 4-(3-(hydroxymethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate 1.623 g, 5.02 mmol , 1 eq) was dissolved in anhydrous THF (50 ml, 0.1 M), and then 1.0 M LiAlH4 (1.0 M LiAlH4 in THF, 7.6 ml, 7.60 mmol, 1.5 eq) was slowly added dropwise at 0 °C under THF and stirred for 1 hour. After the reaction was complete, water and clay were added, the solid was filtered, and the filtrate was concentrated to obtain the crude product. (1.5 g, 100%) Step 3) Synthesis of tert-butyl 4-(3-(((methylsulfonyl)oxy)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

[0338] (tert-butyl 4-(3-(hydroxymethyl )-IH-py r az o 1-1-y 1 )piper idine-l-carboxylate, 0.2g, 0.71 mmol, leq) was dissolved in THF (4ml, 0.2 M), then TEA (0.12 ml, 0.852 mmol, 1.2 eq) and MsCl (0.06 ml, 0.781 mmol, 1.1 eq) were added and stirred overnight. After the reaction was complete, water was added and extracted with DCM. The organic layer was dried with MgSO4, filtered, and concentrated to obtain the crude product. (0.204g, 100%) Step 4) tert-butyl 4-(3-((((2-iodo-4-(methoxycarbonyl)phenyl)thio)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (tert-butyl 4-(3-(((2-iodo-4-

[0339] Synthesis of (methylsulfonyl 1-phenyl )thio)methyl )-IH-pyrazol-l-yl)piperidine-l-carboxylate: tert-butyl 4-(3-(((methylsulfonyl )oxy)methyl )-1H-pyrazol-l-yl)piperidine-l-carboxylate (0.204 g, 0.57 mmol, leq) was dissolved in DMF (5 ml, 0.1 M), then K2CO3 (0.16 g, 1.134 mmol, 2 eq) was added, and methyl 3-iodo- 4-mer captobenzoate (methyl 3-iodo-4-mer captobenzoate, 0.2 g, 0.68 mmol, 1.2 eq) was slowly added, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, water was added, and the resulting solid was filtered and dried to obtain the crude product. (0.193 g, 50.9%) P NMR (400 MHz, CDCls) 8 8.50 (d, J = 1.7 Hz, 1H), 8.00 (dd, J = 8.2, 1.8

[0340] Hz, 1H), 7.50 (d, J = 1.3 Hz, 1H) , 7.30 (s, 1H) , 7.28 (s, 1H) , 6.22 (d, J = 1.7

[0341] Hz, 1H), 4.32 (dd, J = 13.2, 8.8 Hz, 3H) , 4.24 (d, J = 5.9 Hz, 2H), 3.93 (d, J =

[0342] 4.6 Hz, 3H), 2.89 (t, J = 12.7 Hz, 2H), 2.23 (qd, J = 12.6, 4.2 Hz, 2H), 1.95 (d,

[0343] J = 12.3 Hz, 2H), 1.49 (s, 9H). Step 5) tert-butyl 4-(3-(((2-iodo-4-(methoxycarbonyl)phenyl)sulfonyl)methyl)-1H-pyrazol-1-yl)piperidine-L-carboxylate (tert-butyl 4-(3-(((2-iodo-4-

[0344] Synthesis of (methoxycarbonyl 1)phenyl )sulfonyl )methyl )-lH-pyrazol-1-1-y 1)piperidine-1-carboxylate)tert-butyl 4-(3-(((2-iodo-4-(methoxycarbonyl)phenyl)thio)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (tert-butyl 4-(3-(((2-iodo-4-

[0345] (methyl hydroxycarbony 1 )phenyl )thio)methyl ) - IH-py r az O1 - 1-y 1 )piperidine—l—carboxylate, 0.193 g, 0.346 mmol, 1 eq) was dissolved in MC (2 ml, 0.2 M), then mCPBA (0.3 g, 1.731 mmol, 5 eq) was added and stirred overnight. After the reaction was complete, a saturated aqueous solution of NaHCOs was added and extracted with MC. The organic layer was dried with MgSO4, filtered, and concentrated to obtain the crude product.

[0346] (0.183g, 100%) Step 6) Tert-butyl 4-(3-( ( (2-( (4-fluorophenyl)ethynyl )-4-

[0347] (methoxycarbonyl)phenyl)sulfonyl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (tert-butyl 4-(3-((2-((4-fluorophenyl )ethynyl )-4-

[0348] Synthesis of (methoxycarbonyl 1)phenyl)sulfonyl )methyl )-1H-pyrazol-1-1-y1)piperidine-1-carboxylate)tert-butyl 4-(3-(((2-iodo-4-(methoxycarbonyl)phenyl)sulfonyl)methyl )-1H-pyrazol-1-yl)piperidine-1-carboxylate (tert-butyl 4-(3-(((2-iodo-4-

[0349] ( methoxycarbony 1 )pheny 1 )su 1 f ony 1 )methy l)-lH-pyr azo 1-1-y Dpi peri di ne-l-carboxylate, 0.183 g, 0.31 mmol, 1 eq) was dissolved in ACN (4 ml, 0.1 M), then TEA (0.1 ml, 0.68 mmol, 2.2 eq), PdC12(PPh3)2 (6.5 mg, 0.009 mmol, 3 mol%), and Cui (2.4 mg, 0.012 mmol, 4 mol%) were added and stirred at room temperature for 5 minutes. After adding 1-ethynyl-4-fluorobenzene (l-ethynyl-4-fluorobenzene, 0.053 ml, 0.47 mmol, 1.5 eq), the mixture was stirred at 90 °C for 1 hour. After cooling to room temperature and concentrating, the mixture was purified by column chromatography (silica gel, EA / HX). (0.1 g, 55.6 %) Step 7) Synthesis of 4-(((1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-3-yl)methyl)sulfonyl)-3-((4-fluorophenyl)ethynyl)benzoic acid (4-(((l-(l-(tert-butoxycarbonyl )piperidin-4-yl )-lH-pyrazol-1-3-y 1 )methyl )sulfonyl )—3—( (4-fluorophenyl )ethynyl )benzoic acid) tert-butyl 4-(3-(((2-((4-fluorophenyl)ethynyl)-4-

[0350] (methoxycarbonyl)phenyl)sulfonyl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (tertbutyl 4-(3-(((2-((4-fluorophenyl )ethynyl )-4-

[0351] ( methoxycarbony 1 )pheny 1 ) su 1 f ony l)methyl)-lH-pyr azo 1-1-y Dpi peri di ne-l-carboxylate, 0.10 g, 0.172 mmol, 1 eq) dissolved in EtOH (4 ml, 0.05 M), then NaOH dissolved in H2O (0.1 ml).

[0352] (0.014 g, 0.344 mmol, 2 eq) was added and refluxed for 1 hour. After cooling to room temperature and concentrating, the target compound was obtained as an unpurified product. Step 8) Synthesis of tert-butyl 4-(3-(((2-((4-fluorophenyl)ethynyl)-4-((imidazotl, 2-a]pyridin-7-ylmethyl)carbamoyl)phenyl)sulfonyl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

[0353] 4- (((1-(1- (tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazole-3-yl)methyl)sulfonyl)-3- ((4-fluorophenyl)ethynyl)benzoic acid (4- (((1- (1- (tert-butoxycar bony 1 )pi per idi n-4-yl )-lH-pyr azo 1-3-yl )methyl)sulfonyl )— 3—((4— f luorophenyl )ethynyl )benzoic acid,

[0354] 0.1 g (0.172 mmol, 1 eq) was dissolved in MC, followed by the addition of TBTU (0.083 g, 0.258 mmol, 1.5 eq), TEA (0.053 ml, 0.38 mmol, 2.2 eq), and 1-{imidazotl, 2-a]pyridin-7-yl}methanamine hydrochloride (0.035 g, 0.189 mmol, 1.1 eq), and the mixture was stirred overnight at room temperature. After the reaction was complete, a saturated aqueous solution of NaHCOs was added for neutralization, followed by extraction with MC. The organic layer was dried with MgSO4, filtered, concentrated, and then purified by column chromatography (silica gel, MeOH / MC). (0.112 g, 93.3%) Step 9) Synthesis of 3-((4-fluorophenyl)ethynyl)-N-(imidazo[1,2-a]pyridin-7-ylmethyl)-4-(((1-(piperidin-4-yl)-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide (3-((4-fluorophenyl)ethynyl)—N—(imidazo[1,2-a]pyridin-7-ylmethyl)-4-(((l-(piperidin-4-yl)-lH-pyrazo-1-3-yl)methyl)sulfonyl)benzamide) tert-butyl 4-(3-(((2-((4-fluorophenyl)ethynyl)-4-((imidazo[1,2- a]pyridine-7-ylmethyl)carbamoyl)phenyl)sulfonyl)methyl)-1H-pyrazole-1-yl)piperidin-1-carboxylate

[0355] (tert-butyl 4— (3—( (2—( (4— f luorophenyl )ethynyl )-4-( ( imidazo[l , 2—a]pyridin—7— ylmethyl )carbamoyl )phenyl)sulfonyl ) methyl ) - IH-py r az o 1 - 1-y 1 )piper idine— 1— carboxylate, 0.112g, 0.16 mmol, leq) was dissolved in DCM (1ml, 0.2M), then 4N HC1 under dioxane (4N HC1 in dioxane, 0.4ml , 1.6 mmol , 10 eq) was added and stirred at room temperature for 2 hours. After the reaction was completed, the compound was concentrated and purified by reverse-phase column chromatography (0.1% formic acid in H2O / ACN) to obtain the compound of the title (0.028 g, 32.5%). P NMR (400 MHz, MeOD) 5 8.62 (s, 1H) , 8.44 (d, J = 7.0 Hz, 1H) , 8.09 (dd, J = 8.1, 1.1 Hz, 1H), 7.88 (d, J = 8.1 Hz, 1H) , 7.83 (s, 1H) , 7.76 (s, 1H) , 7.56 (s, 1H), 7.38 (d, J= 1.9 Hz, 1H) , 7.30 (dd, J= 8.7, 5.4 Hz, 2H) , 7.07 - 6.98 (m, 4H), 5.91 (d, J = 1.9 Hz, 1H) , 4.72 (s, 2H) , 4.60 - 4.50 (m, 1H), 3.22 (d, J = 12.8 Hz, 2H), 2.79 (td, J = 15.0, 4.7 Hz, 2H), 2.68 (s, 2H), 2.22 - 2.10 (m, 3H), 1.97 (d, J = 10.1 Hz, 1H). Example 23: 4-((4-aminobenzyl)sulfonyl)-3-((4-fluorophenyl)ethinyl)-N-

[0356] ( °1 1 Gidazo [ 1 , 2— a]pyridine— 7 —ylmethyl )benz 0Synthesis of}White]d (4—( (4— aminobenzyl )sul f ony 1 )—3—( (4— f luorophenyQethynyl)- N-( imidazo[ 1,2- a]pyr i din- 7- ylmethyl )benzami de, compound 2!) Reagents and conditions: (a) 1-(chloromethyl)-4-nitrobenzene, K2CO3, DMF, room temperature (r .t), 0.5 h (0.5 h) (b) mCPBA, DCM, room temperature (rt), 16 h (16 h) (c) PdCl2[PPh3]2, Cui, TEA, ACN, room temperature (rt), 16 h (16 h) (d) NaOH, H2O, MeOH, 55 °C, 2 h (2 h) (e) 1-{imidazo[1,2-a]pyridin-7-yl}methaneamine hydrochloride, TBTU, TEA, DCM, room temperature (rt), 12 hours (12h) (f) Zn, NH4Cl, Dioxane, H2O, room temperature (rt), 2 hours (2h) Step 1) Synthesis of methyl 3-iodo-4-((4-nitrobenzyl)thio)benzoate

[0357] 1-(chloromethyl)-4-nitrobenzene (0.24 g, 1.4 mmol, 1 eq) was dissolved in DMF (14 ml), and methyl 3-iodo-4-mercaptobenzoate (0.5 g, 1.70 mmol, 1.2 eq) was added to the reaction mixture containing K2CO3 (0.39 g, 2.84 mmol, 2 eq) and stirred for 30 minutes. Water was added to the reaction mixture, and it was extracted several times with oil. After drying the organic layer with magnesium sulfate, it was concentrated under reduced pressure to obtain the target compound (0.6 g, 99%) as an unpurified product. Step 2) Synthesis of methyl 3-iodo-4-((4-nitrobenzyl)sulfonyl)benzoate. Methyl 3-iodo-4-((4-nitrobenzyl)thio)benzoate (0.73 g, 1.7 mmol, eq) was dissolved in DCM (8.5 ml, 0.2 M), and mCPBA (1.47 g, 8.5 mmol, 5 eq) was added and stirred for 16 hours. The reaction was monitored by TLC; once the reaction was complete, water was added to dilute the solution, it was neutralized with a saturated aqueous NaHCOs solution, and extracted several times with DCM. The organic layer was dried with magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 40% EA / HX) to obtain the target compound (0.23 g, 29.Step 3) Synthesis of methyl 3-((4-fluorophenyl)ethynyl)-4-((4-nitrobenzyl)sulfonyl)benzoate (methyl 3-((4-fluorophenyl)ethynyl)-4-((4-nitr obenzy 1)sulfonyl)benzoate) methyl 3-iodo-4-((4-nitrobenzyl)sulfonyl)benzoate (methyl 3-iodo-4-((4-nitr obenzy 1) su 1 f ony 1) benzoate, 0.23 g, 0.5 mmol, 1 eq) was mixed with MeCN (5 ml, 0.1 M) and TEA (0.15 ml, 1.1 mmol, 2.2 eq). PdCMPPh^ (10.5 mg, 3 mol%) and Cui (4 mg, 3 mol%) were added to the reaction mixture and stirred at room temperature for 5 minutes under a nitrogen atmosphere. Subsequently, 4-fluoropenyl-acetylene (0.09 ml, 0.78 mmol, 1.5 eq) was added. The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, 40% EA / HX) to obtain the target compound (0.191 g, 84.1%). P NMR (400 MHz, CDC13) 8 8.38 (d, J = 1.6 Hz, 1H) , 8.09 (d, J = 8.7 Hz, 2H), 7.99 (dd, J = 8.3, 1.7 Hz, 1H) , 7.85 (d, J = 8.3 Hz, 1H) , 7.67 (dd, J = 8.9, 5.3 Hz, 2H), 7.36 (d, J = 8.7 Hz, 2H), 7.15 (t, J = 8.7 Hz, 2H), 4.80 (s, 2H), 3.98 (s, 3H).Step 4) Synthesis of 3-((4-fluorophenyl)ethynyl)-4-((4-nitrobenzyl)sulfonyl)benzoic acid (methyl 3-((4-fluorophenyl)ethynyl)-4-((4-nitrobenzyl)sulfonyl)benzoate (methyl 3-((4-fluorophenyl)ethynyl)-4-((4-nitrobenzyl)sulfonyl)benzoate, 0.191 g, 0.421 mmol, 1 eq) in MeOH (8 ml), H2O (0.3 ml), and NaOH (0.034 g, 0.842 mmol, 2 ml) eq) was added and stirred at 55 °C for 1 hour. The reaction was monitored by TLC; upon completion, the pH of the reaction mixture was adjusted to 1 with an aqueous solution of HC1 and extracted with a Toyo extractor. The organic layer was washed with water, dried with magnesium sulfate, and concentrated under reduced pressure to obtain the target compound (0.1 g, 56%). Step 5) Synthesis of 3-((4-fluorophenyl)ethynyl)-N-(imidazo[1,2-a]pyridin-7-ylmethyl)-4-((4-nitrobenzyl)sulfonyl)benzamide.

[0358] 3-((4-fluorophenyl)ethynyl)-4-((4-nitrobenzyl)sulfonyl)benzoic acid (3-((4- fluorophenyl)ethynyl 1 ) et hyny 1 ) -4- ( ( 4-nitr obenzy 1 ) su 1 f ony 1 ) benzoic acid, 0.1 g, 0.228 mmol , 1 eq) in DCM (2.3 ml), TBTU (0.1 g, 0.342 mmol, 1.5 eq), TEA (0.07 ml, 0.5 mmol, 2.2 eq), and 1-{imidazo[1,2-a]pyridin-7-yl}methanamine hydrochloride (l-{imidazo[l,2-a]pyridin-7-yl}methanamine hydrochloride, 0.046 g, 0.25 mmol, 1.1 eq) was added and stirred for 12 hours. The residue obtained by concentrating the reaction mixture under reduced pressure was purified by column chromatography (silica gel, 10% MeOH / DCM) to obtain the target compound (0.053 g,

[0359] 40.8%) was obtained. Step 7) 4-((4-aminobenzyl)sulfonyl)-3-((4-fluorophenyl)ethinyl)-N-

[0360] Synthesis of (imidazo[1,2-a]pyridin-7-ylmethyl)benzamide (4-((4-aminobenzyl)sulfonyl)-3-((4-fluorophenyl )ethynyl )-N-(imidazo[l,2-a]pyridin-7-ylmethyl )benzamide)

[0361] 3-((4-fluorophenyl )ethynyl )-N-(imidazot [1,2-a]pyridin-7-ylmethyl )-4-((4-nitrobenzyl)sulfonyl)benzamide (0.053 g, 0.084 mmol , leq) was dissolved in 1,4-dioxane:water (1,4-dioxane:H2O, 3:l (v:v), 1 ml), and then Zn (0.023 g, 0.42 mmol , 5 eq) and NH4Cl (0.022 g, 0.42 mmol , 5 eq) The mixture was added and stirred at room temperature for 2 hours. The reaction mixture was washed with MeOH and filtered under reduced pressure through Celite. The filtrate was concentrated and purified with prep-LC (0.1% formic acid in H2O / Acetonitrile). (0.002 g) NMR (400 MHz, MeOD) 6 8.58 (s, 1H), 8.53 (s, 7H), 8.44 (d, J = 6.8 Hz, 1H), 8.06 (d, J = 9.0 Hz, 1H), 7.84 (d, J = 8.3 Hz, 2H), 7.70 (s, 1H), 7.55 (s, 2H), 7.42 - 7.36 (m, 2H), 6.99 (dd, J = 14.3, 7.7 Hz, 5H), 6.63 (d, J = 8.6 Hz, 1H), 4.71 (s, 2H).

[0362] MS(ESI) m / z MH + 539 Example 24: 4-(((1H-pyrazol-3-yl)methyl)sulfonyl)-3-((4-fluorophenyl)ethinyl)-N-(imidazo[1,2- aSynthesis of ]pyridin-7-ylmethyl)benzamide (4-(((lH-pyrazol-3-yl)methyl)sulfonyl)—3—((4—f luorophenyl )ethynyl)—N—(imidazo[l,2~a]pyridin~7_ylmethyl )benzamide, compound 22) Reagents and conditions: (a) 3-(Chloromethyl)pyrazole hydrochloride, K2CO3, DMF, room temperature (rt), 0.5 h (0.5 h) (b) TsCl, pyridine, DCM, room temperature (rt), 12 h (12 h) (c) mCPBA, DCM, room temperature (rt), 16 h (16 h) (d) 4-fluorophenylacetylene, PdCl2[PPh3]2, Cui, TEA, ACN, room temperature (rt), 1 h (1 h) (e) NaOH, H2O, MeOH, 55 °C, 1 h (1 h) (f) 1-{Imidazō[1,2-a]pyridine-7-yl} methaneamine hydrochloride (l-imidazo[l, 2-a]pyr idin-7-yl Imethan amine hydrochloride), TBTU, TEA, DCM, 2 hours (2h) Step 1) Synthesis of methyl 4-(((IH-pyrazol-3-yl)methyl)thio)-3-iodobenzoate

[0363] 3-(Chloromethyl)pyrazole hydrochloride (0.5 g, 1.70 mmol, 1 eq) was dissolved in DMF (14 ml), and methyl 3-iodo-4-mercaptobenzoate (0.5 g, 1.70 mmol, 1.2 eq) was added to the reaction mixture containing K2CO3 (0.39 g, 2.84 mmol, 2 eq) and stirred for 30 minutes. Water was added to the reaction mixture, and the resulting solid was filtered and dried to obtain the target compound. Step 2) Synthesis of methyl 3-iodo-4-(((1-tosyl-IH-pyrazol-3-yl)methyl)thio)benzoate (methyl 4-(((1H-pyrazol-3-yl)methyl)thio)-3-iodobenzoate (0.05 g, 0.133 mmol, leq) in DCM (0.1 M,

[0364] It was dissolved in 1.33 ml of solution, pyridine (0.027 ml, 5.8 M) and TsCl (0.030 g, 0.16 mmol, 1.2 eq) were added, and the mixture was stirred at room temperature for 12 hours. After concentrating the reaction mixture, water was added and extracted with DCM. The organic layer was dried with magnesium sulfate, and the residue obtained by concentration under reduced pressure was purified by column chromatography (silica gel, 20% EA / HX) to obtain the target compound (0.041 g, 0.08 mmol, 58.6%). Step 3) Synthesis of methyl 3-iodo-4-(((1-tosyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzoate Methyl 3-iodo-4-(((1-tosyl-1H-pyrazol-3-yl)methyl)thio)benzoate (0.041 g, 0.08 mmol, 1 , leq) was dissolved in DCM (1 ml), and mCPBA (0.07 g, 0.39 mmol, 5 eq) was added The mixture was stirred for 16 hours. The reaction was monitored by TLC, and once the reaction was complete, water was added to dilute it, neutralized with a saturated aqueous NaHCOs solution, and extracted several times with DCM. After drying the organic layer with magnesium sulfate, the residue obtained by concentrating under reduced pressure was used in the next step without separation.Step 4) Synthesis of methyl 3-((4-fluorophenyl)ethynyl)-4-(((1-tosyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzoate (methyl 3-iodo-4-(((1-tosyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzoate) 0.03 g, 0.052 mmol, 1 eq) was mixed with MeCN (1 ml) and TEA (0.016 ml, 0.114 mmol, 2.2 eq) was added. PdC12[PPh3]2 (1 mg, 3 mol%) and CuI (0.4 mg, 3 mol%) were added to the reaction mixture and stirred at room temperature for 5 minutes under a nitrogen atmosphere. Subsequently, 4-fluoropenyl-acetylene (0.009 ml, 0.078 mmol, 1.5 eq) was added. The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, 40% EA / HX) to obtain the target compound (0.020 g, 69.7%). Step 5) Synthesis of 4-(((1H-pyrazol-3-yl)methyl)sulfonyl)-3-((4-fluorophenyl)ethynyl)benzoic acid (4-( ((1H-pyrazol-3-yl)methyl)sulfonyl)-3-((4-f luoropheny 1 )ethynyl )benzoic acid)methyl 3-( (4-fluorophenyl)ethynyl)-4-( ( (1-tosyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzoate (methyl 3-( (4-f luorophenyl )ethynyl )-4-(((l-tosyl-lH-pyrazol-3-yl )methyl 1 )sulfonyl )benzoate , 0.MeOH (1 ml), H2O (1 ml), and NaOH (3 mg, 0.072 mmol, 2 eq) were added to 0.20 g, 0.036 mmol, 1 eq), and stirred at 55°C for 1 hour. The reaction was monitored by TLC, and once complete, the reaction was concentrated under reduced pressure to obtain the target compound as the crude product. Step 6) 4-(((1H-pyrazole-3-yl)methyl)sulfonyl)-3-((4-fluorophenyl)ethynyl)-N-.

[0365] Synthesis of (imidazo[1,2-a]pyridin-7-ylmethyl)benzamide (4-((( IH-pyridazo 1-3-yl )methyl )sulfonyl )-3-( (4-f luorophenyl )ethynyl )— N— ( imidazo[l,2-a]pyridin-7-ylmethyl )benzamide)

[0366] 4-(((1H-pyrazol-3-yl)methyl)sulfonyl)-3-((4-fluorophenyl)ethinyl)benzoic acid (4-

[0367] DCM (1 ml), TBTU (0.027 g, 0.09 mmol, 1.5 eq), TEA (0.02 ml, 0.125 mmol, 2.2 eq), and 1-{imidazo[1,2-a]pyridin-7-yl}methanamine hydrochloride (0.012 g, 0.063 mmol, 1.1 eq) were added to ((( IH-pyr azol-3-yl )methyl )sulfony 1 )-3-((4-f 1 uoropheny 1 )et hyny 1 )benzoic acid, 0.022 g, 0.057 mmol, 1 eq) and stirred for 2 hours. The residue obtained by concentrating the reaction mixture under reduced pressure was column-coated The target compound was obtained by purification by chromatography (silica gel, 10% MeOH / DCM). Medium NMR (400 MHz, MeOD) 6 8.42 (d, J = 7.0 Hz, IH), 8.24 (s, IH), 7.89 (t, J = 6.4 Hz, 2H), 7.82 (s, IH), 7.74 (dd, J = 8.6, 5.4 Hz, 2H), 7.54 (d, J = 7.0 Hz, 2H), 7.48 (s, IH), 7.22 (t, J = 8.7 Hz, 2H), 6.96 (d, J = 7.1 Hz, IH), 6.25 (s, IH), 4.65 (s, 2H).

[0368] MS(ESI) m / z MH + 514 Example 25: Synthesis of N-(3-(1H-pyrazol-4-yl)propyl)-3-((3-methoxy-4-methylphenyl)ethynyl)-4~(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide (N-(3-(lH-pyrazol-4-yl)propyl)-3-((3-methoxy-4-methylphenyl )ethynyl )—4—((l-methyl-lH-pyrazol-3-yl)methyl)sulfonyl)benzamide, Compound 23).Reagents and conditions: (a) NaOH, H2O, MeOH, 60 °C, 2 hours (2h); (b) 3-(1H-pyrazol-4-yl)propan-1-amine dihydrochloride, TBTU, TEA, DCM, 12 hours (12h); (c) 4-ethynyl-2-methoxy-1-methylbenzene, PdChtPPhsh, Cui, TEA, ACN, room temperature (rt), 1 hour (Ih). Step 1) 3-iodo-4-(( (1-methyl-IH-pyrazol-3-yl)methyl)sulfonyl)benzoic acid Synthesis of methyl 3-iodo-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzoic acid)methyl 3-iodo-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzoate (methyl 3—iodo—4—((1—methyl—1H—pyrazol—3—yl)methyl)sulfonyl)benzoate, 1.216 g, 2.9 mmol, 1 eq) was mixed with MeOH (15 ml, 0.2 M), H2O (2 ml), and NaOH (0.23 g, 5.79 mmol, 2 eq) and stirred at 60°C for 2 hours. The reaction was monitored by TLC, and once complete, the pH of the reactants was adjusted to 1 using an aqueous solution of IN HC1 and extracted with a Toyo extractor. The organic layer was washed with water, separated, dried with magnesium sulfate, and concentrated under reduced pressure to obtain the target compound (1.18 g, 100%). P NMR (400 MHz, DMSO-based) 5 13.74 (s, 1H), 8.57 (d, J = 1.3 Hz, 1H), 8.04 (dd, J = 8.2, 1.4 Hz, 1H), 7.93 - 7.88 (m, 1H), 7.59 (d, J = 2.0 Hz, 1H), 6.06 (d, J = 2.1 Hz, 1H), 4.83 (s, 2H), 3.69 (s, 3H). Step 2) Synthesis of N-(3-(1H-pyrazol-4-yl)propyl)-3-iodo-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide (N-(3-(IH-pyrazol-4-yl)propy1)-3-iodo-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide).

[0369] DCM (10 ml), TBTU (0.48 g, 1.5 mmol, 1.5 eq), TEA (0.3 ml, 2.2 mmol, 2.2 eq), and 3-(1H-pyrazol-4-yl)methyl )sulfonyl )benzoic acid (0.4 g, 1 mmol, 1 eq) were added and stirred for 12 hours. The residue obtained by concentrating the reactants was purified by column chromatography (silica gel, 10% MeOH / DCM) to obtain the target compound. (0.16g, 31.3%) P NMR (400 MHz, MeOD) 5 8.56 (d, J = 1.4 Hz, 1H) , 7.92 (d, J = 8.2 Hz, 1H), 7.87 (dd, J= 8.2, 1.5 Hz, 1H) , 7.51 - 7.45 (m, 3H) , 6.18 (d, J= 2.2 Hz, 1H) , 4.83 (s, 2H), 3.77 (s, 3H) , 3.43 (t, J = 7.1 Hz, 2H) , 3.37 (s, 1H) , 2.83 (s, 1H) , 2.61 (t, J = 7.5 Hz, 2H), 1.91 (p, J = 7.3 Hz, 2H). Step 3) N-(3-(1H-pyrazol-4-yl)propyl)-3-((3-methoxy-4-methylphenyl)ethynyl)-4-

[0370] Synthesis of ( ( ( 1—methyl— 1H-pyrazol- 3-yl)methyl)sulfonyl )benzamide (N- (3- ( 1H-pyrazol- 4— yl )propyl )-3- ( ( 3-methyl hoxy-4-methyl hy 1pheny 1 )ethynyl )-4- ( ( (1— methyl— 1H—pyrazol— 3— yl ) methyl )sulfonyl )benzamide).

[0371] MeCN (1 ml, 0.1 M) and TEA (0.018 ml, 0.128 mmol, 2.2 eq) were added to N-(3-(1H-pyrazol-4-yl)propyl)-3-iodo-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide (N-(3-(IH-pyrazol-4-yl)propyl 1)-3-iodo-4-(((1-methyl-lH-pyrazol-3-yl)methyl )sulfonyl )benzamide, 0.03 g, 0.058 mmol 1, leq). PdCLdPPhzh (1.22 mg, 3 mol%) and Cui (0.44 mg, 3 mol%) were added to the reaction mixture and stirred at room temperature under a nitrogen atmosphere for 5 minutes. Subsequently, 4-ethynyl-2-methoxy-1-methylbenzene (4-ethynyl-2-methoxy-l-methylbenzene, 13 mg, 0.088 mmol, 1.5 eq) was added. The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, 10% MeOH / DCM) to obtain the target compound (27 mg, 87.7%). P NMR (400 MHz, CDCls) 8 8.16 (s, 1H) , 7.90 (d, J = 8.2 Hz, 1H) , 7.84 (d, J = 8.2 Hz, 1H), 7.50 (s, 2H) , 7.44 (s, 1H) , 7.19 (d, J = 4.8 Hz, 3H) , 6.16 (s, 1H), 4.86 (s, 2H), 3.89 (s, 3H) , 3.72 (s, 3H) , 3.44 (t, J = 7.0 Hz, 2H) , 2.62 (t,

[0372] J = 7.5 Hz, 2H), 2.24 (s, 3H), 1.97–1.88 (m, 2H). Example 26: Synthesis of N-(3-(1H-pyrazol-4-yl)propyl)-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)-3-((4-(trifluoromethoxy)phenyl)ethynyl)benzamide (N-(3-(1H-pyrazol-4-yl)propyl)-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)-3-((4-(trifluoromethoxy)phenyl)ethynyl)benzamide, Compound 24). Compared to the synthesis of Compound 23 in Example 25, 1-ethynyl-4- in step 3) instead of 4-ethynyl-2-methoxy-1-methylbenzene

[0373] Compound 24 was prepared in substantially the same manner as the synthesis of compound 23, except that (trifluoromethoxy)benzene (1-ethynyl-4-(trifluoromethoxy)benzene) was used. P NMR (400 MHz, CDCls) 8 8.18 (s, 1H) , 7.89 (q, J = 8.2 Hz, 2H) , 7.80 (d, J = 8.7 Hz, 2H), 7.48 (s, 2H) , 7.44 (s, 1H) , 7.39 (d, J = 8.2 Hz, 2H) , 6.16 (d, J = 2.0 Hz, 1H), 4.82 (s, 2H) , 3.72 (s, 3H) , 3.44 (t, J = 7.0 Hz, 2H) , 2.61 (t, J = 7.4 Hz, 2H), 1.97 — 1.85 (m, 2H) . Example 27: N-(3-(1H-pyrazole-4-yl)propyl)-4-(((1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)—3—(pyridine-4-ylethinyl)benz 0Synthesis of} mid (N~(3~(!H~pyrazol~4~yl)propy!)~4~ (((1— methyl— lH—pyr azo 1—3— yl )methyl )sulfonyl )— 3— (pyr idin— 4— ylethynyl )benzamide, compound 25) Compound 25 was prepared by a method substantially identical to the synthesis of Compound 23, except that 4-ethynylpyridine was used instead of 4-ethynyl-2-methoxy-1-methylbenzene in Step 3), compared to the synthesis of Compound 23 in Example 25. Medium NMR (400 MHz, MeOD) 6 8.67 (d, J = 5.9 Hz, 2H), 8.25 (s, 1H), 7.96 (s, 2H), 7.71 (d, J = 6.1 Hz, 2H), 7.50 (s, 2H), 7.46 (d, J = 2.1 Hz, 1H), 6.20 (d, J

[0374] = 2.2 Hz, 1H), 4.82 (s, 2H), 3.73 (s, 3H), 3.46 (t, J = 7.1 Hz, 2H), 2.63 (t, J =

[0375] 7.5 Hz, 2H), 1.99 — 1.89 (m, 2H), 1.33 (t, J = 7.3 Hz, 1H). Example 28: Synthesis of 3-((4-fluorophenyl)ethynyl)-N-(imidazo[1,2-a]pyrimidine-6-ylmethyl)-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide (3-((4-fluorophenyl)ethynyl)—N—(imidazo[1,2-a]pyrimidine-6-ylmethyl)-4—((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide, Compound 26). Reagents and conditions: (a) {imidazotl, 2-a]pyrimidin-6-yl}methanamine dihydrochloride,

[0376] Step 1) Synthesis of N-(imidazo[1,2-a]pyrimidin-6-ylmethyl)-3-iodo-4-(((1-methyl-lH-pyrazol-3-yl)methyl)sulfonyl)benzamide

[0377] 3-iodo-4-(((l-methyl-IH-pyrazol-3-yl)methyl)sulfonyl)benzoic acid (0.27 g, 0.67 mmol, 1 eq) was dissolved in DCM (6.7 ml, 0.1 M), and then {imidazo[1,2-a]pyrimidin-6-yl}methanamine dihydrochloride (0.147 g, 0.8 mmol, 1.2 eq), TBTU (0.257 g, 0.8 mmol, 1.2 eq), and TEA (0.37 ml, 2.68 mmol) ..., 4 eq) was added and stirred overnight at room temperature. The reaction mixture was diluted in DCM, and the organic layer was extracted by adding an aqueous solution of NaHC₂O₃, H₂O, and brine. The organic layer was dried with MgSO₄, filtered, concentrated, and purified by reverse-phase column chromatography (0.1% formic acid in H₂O / ACN) to obtain the target compound (0.092 g, 25.6%). Step 2) 3-((4-fluorophenyl)ethynyl)-N-(imidazo[1,2-a]pyrimidine-6-ylmethyl)-4-(((1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)benzamide (3-((4-fluorophenyl)ethynyl )-N-

[0378] Synthesis of (imidazo[l,2— a]pyr imidin— 6— ylmethyl )— 4— (((1— methyl— 1H— pyrazol— 3— yl )methyl )sulfonyl )benzamide)

[0379] N-(Imidazo[1,2-a]pyrimidin-6-ylmethyl)-3-iodo-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide (0.046 g, 0.08 mmol, 1 eq) was dissolved in ACN (1 ml, 0.1 M). Then, 1-ethynyl-4-fluorobenzene (0.014 g, 0.12 mmol, 1.5 eq), PdCl2(PPh3)2 (0.001 g, 0.002 mmol, 0.03 eq), CuI (0.00045 g, 0.002 mmol, 0.03 eq), and TEA (0.016 g, 0.16 mmol, 2 eq) were added, and the mixture was degassed with nitrogen gas. The reaction solution was heated to 60 °C and stirred for 1 hour. After completion of the reaction, it was filtered through celite and extracted with toluene. The organic layer was washed with water, separated, dried over MgSO4, filtered, concentrated, and purified by column chromatography (silica gel, MeOH / DCM) to obtain the target compound (0.016 g, 37.8%). 1H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 8.96 (d, J = 2.2 Hz, 1H), 8.57 (d, J = 2.4 Hz, 1H), 8.28 (d, J = 1.4 Hz, 1H), 8.01 (dd, J = 8.3, 1.6 Hz, 1H), 7.92 (dd, J = 6.6, 4.8 Hz, 2H), 7.76 (dd, J = 8.7, 5.5 Hz, 2H), 7.71 (d, J = 1.1 Hz, 1H), 7.58 (d, J = 2.1 Hz, 1H), 7.37 (t, J = 8.9 Hz, 2H), 6.07 (d, J = 2.1 Hz, 1H), 4.85 (s, 2H), 4.55 (d, J = 4.1 Hz, 2H), 3.69 (s, 3H). Example 29: 4-((3-aminobenzyl)sulfonyl)-3-((4-fluorophenyl)ethinyl)-N-.

[0380] ( °]White]Dazo [ 1 , 2— a]pyridine— 7 —ylmethyl )benz 0 Synthesis of}White]d (4—( (3— aminobenzyl )sul fonyl )—3—( (4— f luorophenyQethynyl)- N- (imidazo[l,2- a]pyridin- 7- ylmethyl)benzamide, compound 27)

[0381] Reagents and conditions: (a) 3-nitrobenzyl chloride, K2CO3, DMF, room temperature (rt), 2 hours (2 h) (b) m-CPBA, DCM, 0 °C to room temperature (0 °C to rt), overnight; (c) 1-ethynyl-4-fluorobenzene, PdC12(PPh3)2, Cui, TEA, ACN, 60 °C, 1 hour (1 h); (d) Zn, NH4C1, 1,4-dioxane, H2O, room temperature (rt), 0.5 hours (0.5 h); (e) IN NaOH(aq), THF, 70 °C, overnight; (f) 1-imidazo [1,2-a]pyridin-7-ylhnethanamine dihydrochloride (1-imidazo[l,2—a]pyridin—7—ylhnethanamine dihydrochloride), TBTU, TEA, DCM, room temperature (rt), overnight (overnight) Step 1) Synthesis of methyl 3-iodo-4-((3-nitrobenzyl)thio)benzoate

[0382] 3-nitrobenzyl chloride (0.291 g, 1.7 mmol, 1 eq) and K2CO3 (0.469 g, 3.4 mmol, 2 eq) were dissolved in DMF (3.4 ml, 0.5 M), then methyl 3-iodo-4-mercaptobenzoate (0.5 g, 1.7 mmol, leq) was added dropwise and stirred at room temperature for 2 hours. Water was added to the reaction mixture and extracted with a Toyo extractor. The organic layer was dried with MgSO4, filtered, concentrated, and then purified by column chromatography (silica gel, EA / HEX) to obtain the target compound (0.661 g, 90.5%). Step 2) Synthesis of methyl 3-iodo-4-((3-nitrobenzyl)sulfonyl)benzoate. Methyl 3-iodo-4-((3-nitrobenzyl)thio)benzoate (0.661 g, 1.54 mmol, 1 eq) was dissolved in DCM (15.4 ml, 0.1 M), and then m-CPBA (1.063 g, 6.16 mmol, 4 eq) was added dropwise at 0 °C. The reaction mixture was slowly heated to room temperature and stirred overnight. After the reaction was complete, an aqueous solution of NaHCOs was added and extracted with DCM. The organic layer was dried with MgS04, filtered, and concentrated to obtain the target compound as an unpurified product.Step 3) Synthesis of methyl 3-((4-fluorophenyl)ethynyl)-4-((3-nitrobenzyl)sulfonyl)benzoate: methyl 3-iodo-4-((3-nitrobenzyl)sulfonyl)benzoate (0.1 g, 0.22 mmol, 1 eq) was dissolved in ACN (2.2 ml, 0.1 M), and then 1-ethynyl-4-fluorobenzene (0.039 g, 0.33 mmol) After adding PdC12(PPhs)2 (0.005 g, 0.007 mmol, 0.03 eq), Cui (0.001 g, 0.007 mmol, 0.03 eq), and TEA (0.045 g, 0.44 mmol, 2 eq), the mixture was degassed with nitrogen gas. The reaction mixture was heated to 60 °C and stirred for 1 hour. After the reaction was complete, the mixture was filtered through Celite and extracted using a Toyo method. The organic layer was washed with water, separated, dried with MgSO4, filtered, concentrated, and then subjected to column chromatography (silica gel).

[0383] The target compound (0.083 g, 83%) was obtained by purification with MeOH / DCM. Step 4) Methyl 4-((3-aminobenzyl)sulfonyl)-3-((4-fluorophenyl)ethinyl)benzoate

[0384] Synthesis of (methyl 4-((3-aminobenzyl)sulfonyl)-3-((4-fluorophenyl)ethynyl)benzoate)methyl 3-((4-fluorophenyl)ethynyl)-4-((3-nitrobenzyl)sulfonyl)benzoate (methyl

[0385] 3-((4-f luorophenyl )ethynyl )-4-( (3-nitrobenzyl ) sulfonyl )benzoate, 0.083 g, 0.18 mmol, 1 eq) was dissolved in 1,4-dioxane (1,4-dioxane):0 (3:1, v / v) (1.8 ml, 0.1 M), then Zn (0.058 g, 0.9 mmol, 5 eq) and NH4Cl (0.048 g, 0.9 mmol, 5 eq) were added, and the mixture was stirred at room temperature for 0.5 hours. After the reaction was complete, the mixture was filtered and concentrated to obtain the target compound as an unpurified product. Step 5) Synthesis of 4-((3-aminobenzyl)sulfonyl)-3-((4-fluorophenyl)ethynyl)benzoic acid (4-((3-aminobenzyl)sulfonyl)-3-((4-fluorophenyl)ethynyl)benzoate (methyl

[0386] 4-((3-aminobenzyl)sulfonyl)-3-((4-fluorophenyl)ethynyl)benzoate, 0.076 g, 0.18 mmol, 1 eq) was dissolved in THF (1.8 ml, 0.1 M), after which an aqueous NaOH solution (0.36 ml, 0.36 mmol, 2 eq) was added, and the mixture was heated to 70°C and stirred overnight. After the reaction was complete, the reaction mixture was concentrated to obtain the target compound as an unpurified product. Step 6) 4-((3-aminobenzyl)sulfonyl)-3-((4-fluorophenyl)ethynyl)-N-

[0387] Synthesis of (imidazo[1,2-a]pyridin-7-ylmethyl)benzamide (4-((3-aminobenzyl)sulfonyl)-3-((4-fluorophenyl )ethynyl )-N-(imidazo[l,2-a]pyridin-7-ylmethyl )benzamide)

[0388] 4-((3-aminobenzyl)sulfonyl)-3-((4-fluorophenyl)ethynyl)benzoic acid (0.040 g, 0.098 mmol, 1.1 eq) was dissolved in DCM (1 ml, 0.1 M), and 1-{imidazo[1,2-a]pyridin-7-yl} methaneamine dihydrochloride (0.019 g, 0.108 mmol, 1.1 eq), TBTU (0.047 g, 0.147 mmol, 1.5 eq), and TEA (0.019 g, 0.196 mmol, 2 eq) was added and stirred overnight at room temperature. After the reaction was complete, water was added to the reaction solution and extracted with DCM. The organic layer was washed with water, separated, dried with MgSO4, filtered, concentrated, and purified by reverse-phase column chromatography (0.1% formic acid in H2O / ACN) to obtain the target compound (0.005 g, 9.47%). P NMR (400 MHz, MeOD) 5 8.38 (d, J = 7.1 Hz, 1H) , 8.20 (d, J = 1.4 Hz, 1H), 7.86 - 7.75 (m, 3H) , 7.69 (dd, J = 8.8, 5.4 Hz, 2H) , 7.50 (s, 1H) , 7.44 (s, 1H), 7.19 (t, J = 8.8 Hz, 2H), 6.95 - 6.84 (m, 2H) , 6.57 - 6.49 (m, 2H) , 6.40 (d, J = 7.6 Hz, 1H), 4.65 (s, 2H) , 4.61 (s, 2H) . Example 30: 3-((4-aminophenyl)ethynyl)-N-(imidazo[1,2-a]pyridine-6-ylmethyl)-4-

[0389] (((1-Methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide (3-((4-aminophenyl)ethynyl)—N—

[0390] (imidazo[1,2—a]pyridin—6—ylmethyl)—4—(((1—methyl—1H—pyrazol—3—yl)methyl)sulfonyl)benzamide, Synthesis of Compound 28) Reagents and conditions: (a) Imidazo[1,2—a]pyridin—6—ylmethanamine dihydrochloride, TBTU, TEA, DCM, room temperature (rt), overnight; (b) 4-ethynylaniline, PdCl2(PPh3)2, CuI, TEA, ACN, 60 °C, 3 h Step 1) N-(imidazo[1,2—a]pyridin—6—ylmethyl)-3-iodo-4-(((1—methyl—1H—pyrazol—3—yl)methyl)sulfonyl)benzamide

[0391] Synthesis of 4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide

[0392] 3-iodo-4-(((l-methyl-IH-pyrazol-3-yl)methyl)sulfonyl)benzoic acid (0.1 g, 0.246 mmol, 1 eq) was dissolved in DCM (2.5 ml, 0.1 M), and imidazo[1,2-a]pyridin-6-ylmethanamine dihydrochloride (0.065 g, 0.295 mmol, 1.2 eq), TBTU (0.158 g, 0.492 mmol, 2 eq), and TEA (0.074 g, 0.739 mmol, 3 eq) was added and stirred overnight at room temperature. After the reaction was complete, water was added and extracted with DCM. The organic layer was separated by washing with water, dried with MgSO4, filtered, concentrated, and purified by column chromatography (silica gel, MeOH / DCM) to obtain the target compound (0.033 g, 25%). Step 2) 3-((4-aminophenyl)ethynyl)-N-(imidazo[1,2-a]pyridine-6-ylmethyl)-4-

[0393] (((1-methyl-11<-pyrazol-3-yl)methyl)sulfonyl)benzamide (3-((4-aminophenyl1)ethynyl )-N-

[0394] Synthesis of (imidazo[l,2—a]pyr idin— 6— ylmethyl )— 4— (((1— methyl— 1H— pyrazol— 3— yl )methyl )sulfonyl )benzamide)

[0395] After dissolving N-(imidazo[1,2-a]pyridin-6-ylmethyl)-3-iodo-4-(((l-methyl—1H-pyrazol—3-yl)methyl)sulfonyl)benzamide (0.033 g, 0.062 mmol, 1 eq) in ACN (1 ml, 0.1 M), 4-ethynylaniline (0.0087 g, 0.074 mmol, 1.2 eq), PdC12(PPh3)2 (0.001 g, 0.002 mmol, After adding 0.03 eq), Cui (0.0003 g, 0.002 mmol, 0.03 eq), and TEA (0.0125 g, 0.124 mmol, 2 eq), the mixture was degassed with nitrogen gas. The reaction mixture was heated to 60°C and stirred for 3 hours. After the reaction was complete, the mixture was filtered through Celite and extracted with oil. The organic layer was washed with water, separated, dried with MgSO4, filtered, concentrated, and column chromatography (silica gel,

[0396] The target compound (0.0089 g, 27.4%) was obtained by purification with MeOH / DCM. P NMR (400 MHz, MeOD) 5 8.53 (s, 1H) , 8.10 (d, J = 1.4 Hz, 1H), 7.91 (s, 1H), 7.79 (dt, J = 8.3, 5.0 Hz, 2H) , 7.65 (s, 1H) , 7.61 (d, J = 9.4 Hz, 1H), 7.50 (d, J = 9.3 Hz, 1H), 7.38 (d, J = 2.2 Hz, 1H), 7.35 (d, J = 8.6 Hz, 2H), 6.65 (d, J = 8.6 Hz, 2H), 6.09 (d, J = 2.2 Hz, 1H) , 4.82 (s, 2H), 4.59 (s, 2H), 3.68 (s, 3H). Example 31: Synthesis of 3-((4-amino-3-fluorophenyl)ethynyl)-N-(imidazo[1,2-a]pyridin-7-ylmethyl)-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide (3-((4-amino-3-fluorophenyl)ethynyl)—N—(imidazo[1,2-a]pyridin-7-ylmethyl)—4—(((l-methyl—lH-pyrazol-3-yl)methyl)sulfonyl)benzamide (Compound 29). Reagents and conditions: (a) PdCMPPhyh, Cui, TEA, ACN, room temperature (rt), 16 hours (16h)

[0397] MeCN (1 ml, 0.2 M) and TEA (0.08 ml, 0.6 mmol, 3 eq) were added to N-(imidazo[1,2-a]pyridin-7-ylmethyl)-3-iodo-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzimide(N-(imidazo[1,2-a]pyridin-7-ylmethyl)mthy1)-3-iodo-4-(((1-methyl—1H—pyrazol—3—yl)methyl)sulfonyl)benzamide, 0.1 g, 0.2 mmol1, 1 eq). PdCldPPhzh (4 mg, 3 mol%) and Cul (1 mg, 3 mol%) were added to the reaction mixture and stirred at room temperature for 5 minutes under a nitrogen atmosphere. Subsequently, 4-ethynyl-2-fluoroaniline (35 mg, 1.2 eq) was added. The reaction mixture was stirred at room temperature for 16 hours and concentrated under reduced pressure. The resulting residue was purified by reverse-phase chromatography (water / acetonitrile) to obtain the target compound. P NMR (400 MHz, DMSO-^) 5 9.43 (t, J = 5.8 Hz, 1H) , 8.51 (d, J = 7.1 Hz, 1H), 8.23 ​​(d, J = 1.5 Hz, 1H) , 7.89-7.98 (m, 3H) , 7.61 (d, J = 2.1 Hz, 1H), 7.54 (d, J = 1.0 Hz, 1H), 7.46 (s, 1H), 7.39 (dd, J = 12.0, 1.7 Hz, 1H), 7.25 (dd, J = 8.2, 1.6 Hz, 1H), 6.89 (dd, J = 7.0, 1.5 Hz, 1H), 6.85 - 6.78 (m, 1H) , 6.10 (d, J = 2.2 Hz, 1H), 5.88 (s, 2H) , 4.87 (s, 2H) , 4.54 (d, J = 5.7 Hz, 2H) , 3.73 (s, 3H) .Example 32: Synthesis of N-(imidazo[1,2-a]pyridin-7-ylmethyl)-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)-3-((4-((2-(piperidin-1-yl)ethyl)carbamoyl)phenyl)ethynyl)benzamide (N— ( imidazo[1,2-a]pyridin—7-ylmethyl )—4— (((1-methyl—1H-pyrazol—3-yl )methyl )sulfonyl )—3—( (4—((2-(piperidin—l-yl )ethyl )carbamoyl )phenyl )ethynyl )benzamide, Compound 30). Reagents and conditions: (a) NaOH, H2O, MeOH, 80 °C, 2 hours (b) 1-{imidazo[1,2-a]pyridin-7-yl} methaneamine dihydrochloride, TBTU, TEA, DCM, room temperature, 12 hours; (c) 4-ethynyl-N-(2-(piperidin-1-yl)ethyl)benzamide, PdC12[PPh3k Cui, TEA, room temperature, 16 hours Step 1) Synthesis of 3-iodo-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzoic acid methyl 3-iodo-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzoate (methyl

[0398] MeOH (10 ml, 0.1 M), H2O (5 ml, 0.2 M), and NaOH (0.1 g, 2.5 mmol, 2.5 eq) were added to 3-iodo-4- (((1- methyl- 1H- pyrazol- 3- yl)methyl)sulfonyl)benzoate, 0.42 g, 1 mmol, 1 eq), and the mixture was stirred at 80°C for 2 hours. The reaction was monitored by TLC; upon completion, the pH of the reaction mixture was adjusted to 1 using an aqueous solution of INHC1, and the mixture was extracted with oil. The organic layer was washed with water, dried with magnesium sulfate, and concentrated under reduced pressure to obtain the target compound (0.35 g, 86%). Step 2) N-(imidazo[1,2-a]pyridin-7-ylmethyl)-3-iodo-4-(((1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)benzamide (N-(imidazo[l,2-a]pyridin-7-ylmethyl )-3-iodo-

[0399] Synthesis of 4- (((1- methyl- 1H- pyrazol- 3- yl) methyl ) sulfonyl ) benzamide)

[0400] DCM (10 ml) and TBTU (0.42 g, 1 mmol, 1.5 eq) were added to 3-iodo-4-(((l-methyl-IH-pyrazol-3-yl)methyl)sulfonyl)benzoic acid (0.35 g, 0.86 mmol, 1 eq) and stirred at room temperature for 50 minutes. Next, TEA (0.45 ml, 1.3 mmol, 3.7 eq) and 1-{imidazo[1,2-a]pyridin-7-yl} methanamine dihydrochloride (l-{imidazo[l,2-a]pyridin-7-yl Imethanamine dihydrochloride, 92 mg, 0.42 mmol, 1.2 eq) were added to the reaction mixture and stirred for 12 hours. The solid formed from the reaction mixture was filtered to obtain the target compound (0.3 g, 65%). Step 3) Synthesis of N-(imidazo[1,2-a]pyridin-7-ylmethyl)-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)-3-((4-((2-(piperidin-1-yl)ethyl)carbamoyl)phenyl)ethynyl)benzamide (N-(imidazo[1,2-a]pyridin-7-ylmethyl )-4-(((1-methyl-1H-pyrazol-3-yl )methyl )sulfonyl )-3-((4-((2-(piperidin-1-yl )ethyl )carbamoyl )phenyl )ethynyl )benzamide).

[0401] MeCN (1.4 ml, 0.2 M) and TEA (0.12 ml, 0.84 mmol, 3 eq) were added to N-(imidazo[1,2-a]pyridin-7-ylmethyl)-3-iodo-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide (N-(imidazo[1,2-a]pyr idi n-7-y 1me t hy 1)-3-iodo-4-(((1-methyl—1H—pyrazol—3—yl)methyl)sulfonyl)benzamide, 0.15 g, 0.28 mmol, 1 eq). PdC12[PPh3]2 (6 mg, 3 mol%) and Cul (1.6 mg, 3 mol%) were added to the reaction mixture and stirred at room temperature under a nitrogen atmosphere for 5 minutes. Subsequently, 4-ethynyl-N-(2-(piperidin-1-yl)ethyl)benzamide (86 mg, 0.34 mmol, 1.2 eq) was added. The reaction mixture was stirred at room temperature for 16 hours and concentrated under reduced pressure. The resulting residue was purified by prep-LC to obtain the target compound. P NMR (400 MHz, MeOD) 5 8.46 (d, J = 6.1 Hz, 2H) , 8.29 (s, 1H) , 7.97 (s, 4H), 7.88 - 7.78 (m, 3H) , 7.56 (m, 2H) , 7.46 (s, 1H) , 7.01 (d, J = 6.5 Hz, 1H) , 6.19 (s, 1H), 4.86 (s, 2H) , 4.69 (s, 2H) , 3.80 (s, 2H) , 3.74 (m, 3H) , 3.31 - 3.25 (m, 2H), 2.68 (s, 3H) , 1.90 (s, 4H) , 1.71 (s, 2H) , 1.31 (s, 1H) .Example 33: Synthesis of 3-((6-aminopyridin-3-yl)ethynyl)-N-(imidazoc[1,2-a]pyridin-7-ylmethyl)-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide (3-((6-aminopyridin-3-y1)ethynyl)—N—(imidazoc[1,2-a]pyridin—7—y1methy1)—4—(((1—methhy1—1H—pyrazoc[1—3—yl)methyl)sulfonyl)benzamide, compound 31). Reagents and conditions (a) 5-ethynylpyridin-2-amine, TEA, Cui, PdC12(PPhs)2, ACN, reflux, 3h N-(imidazoo[1,2-a]pyridin-7-ylmethyl)-3-iodo-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide, 50 mg, 0.09 mmO After dissolving 1, 1 eq) in ACN (1 ml, 0.1 M), TEA (0.025 ml, 0.18 mmol, 2 eq), PdC12(PPh3)2 (1.89 mg, 0.0027 mmol, 3 mol%), and Cui (0.51 mg, 0.0027 mmol, 3 mol%) were added, and the mixture was stirred at room temperature for 5 minutes. 5-ethynylpyridin-2-amine (22 mg, 0.186 mmol, 2 eq) was added, and the mixture was refluxed and stirred for 3 hours. After cooling to room temperature and concentrating, the solution was purified by reverse-phase column chromatography (0.1% formic acid in H2O / ACN) to obtain the compound of the title (0.004 g, 8.4%). P NMR (400 MHz, MeOD) 5 8.38 (d, J = 7.0 Hz, 1H) , 8.21 (d, J = 2.0 Hz, 1H), 8.15 (d, J = 0.9 Hz, 1H) , 7.86 (dd, J = 8.9, 4.8 Hz, 2H) , 7.78 (s, 1H) , 7.66

[0402] (dd, J = 8.7, 2.2 Hz, 1H) , 7.51 (s, 1H) , 7.46 (s, 1H) , 7.41 (d, J = 2.1 Hz, 1H) ,

[0403] 6.92 (dd, J= 7.0, 1.2 Hz, 1H) , 6.58 (d, J= 8.7 Hz, 1H) , 6.12 (d, J= 2.2 Hz, 1H) ,

[0404] 4.80 (s, 2H), 4.62 (s, 2H), 3.70 (s, 3H). Example 34: N-(3-(1H-pyrazol-4-yl)propyl)-3-((4-(dimethylamino)phenyl)ethynyl)-4-((( 1—methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide (N-(3-( 1H-pyrazol— 4— yl )propy 1 )-

[0405] Synthesis of 3— ((4— (dimethyl amino)phenyl )ethynyl )—4—(((l—methyl—lH—pyrazol—3— yl)methyl)sulfonyl)benzamide, compound 32) Compound 32 was prepared in substantially the same manner as the synthesis of Compound 23, except that 4-ethynyl-N,N-dimethylaniline was used instead of 4-ethynyl-2-methoxy-1-methylbenzene in step 3) compared to the synthesis of Compound 23 of Example 25. P NMR (400 MHz, MeOD) 5 8.11 (d, J = 1.5 Hz, 1H) , 7.87 (d, J = 8.3 Hz, 1H), 7.77 (dd, J = 8.3, 1.7 Hz, 1H) , 7.54 (d, J = 8.9 Hz, 2H) , 7.50 (s, 2H) , 7.45 (d, J = 2.1 Hz, 1H), 6.79 (d, J = 8.9 Hz, 2H) , 6.15 (d, J = 2.2 Hz, 1H) , 4.88 (s, 2H), 3.75 (s, 3H), 3.45 (t, J = 7.1 Hz, 2H), 3.05 (s, 6H), 2.63 (t, J = 7.5 Hz, 2H), 1.97 - 1.88 (m, 2H). Example 35: Synthesis of N-(3-(1H-pyrazol-4-yl)propyl)-3-(2-(4-fluorophenyl)thiazol-5-yl)-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide (N-(3-(1H-pyrazol-4-yl)propy 1 )-3—(2—(4—fluorophenyl)thiazol—5—yl)—4—((1—methyl t hy 1—1H—pyrazol—3—yl)methyl)sulfonyl)benzamide, Compound 33). Reagents and conditions: (a) NBS, DMF, room temperature (rt), 1 h (b) Bis(pinacolato)diboron, KOAc, PdC12 (dppf ), 1,2-Dimethoxyethane, 80 °C, 1.5 h (c) N-(3-(1H-pyrazole-4-yl)propyl)-3-iodo-4-(((1-methyl-IH-pyrazole-3-yl)methyl)sulfonyl)benzamide (N-(3-

[0406] (IH-pyr azol -4-yl )propyl )-3- iodo-4-(((l-methyl-lH-pyr azo 1-3-yl )methyl )sulfonyl )benzamide) , PdC12(dppf ) , K2CO3, 1,4-dioxane (1,4-dioxane) , H2O, 100 °C, 1 hr (Ih) Step 1) Synthesis of 5-bromo-2-(4-fluorophenyl)thiazole (5-bromo-2-(4-fluorophenyl )thiazole)

[0407] 2-(4-fluorophenyl)thiazole (0.27 g, 1.5 mmol, leq) was dissolved in DMF (3 ml), then N-bromosuccinimide (0.402 g) was added and stirred at room temperature for 1 hour. After the reaction was complete, water was added, filtered, and dried to obtain the target compound as an unpurified product. Step 2) Synthesis of 2-(4-fluorophenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (2-(4-fluorophenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole).

[0408] 5-bromo-2-(4-fluorophenyl)thiazole (5-bromo-2-(4-f luorophenyl ) thiazole,

[0409] After dissolving 0.05g (0.194 mmol, eq) in 1,2-Dimethoxyethane (1,2-Dimethoxyethane, 0.2M, 1ml), add Bis(pinacolato)diboron (0.058g, 0.23 mmol, 1.2eq), KOAc (0.057g, 0.582 mmol, 3eq), and PdC12(dppf) (0.014g, 0.0194 mmol, 0.1 eq).

[0410] Stirring was performed at 80°C for 1 hour and 30 minutes. After the reaction was complete, the target compound was filtered through Celite and concentrated to obtain the crude product. Step 3) Synthesis of N-(3-(1H-pyrazol-4-yl)propyl)-3-(2-(4-fluorophenyl)thiazol-5-yl)-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide.

[0411] N- (3- ( 1H-pyrazol-4-yl)propyl)-3-iodo-4-( ( ( 1-methyl- 1H-pyrazol-3-yl) methyl)sulfonyl)benzamid (N-(3-(lH-pyrazol-4-yl)propyl)-3-iodo-4-(((l-methyl-lH-pyrazol— 3— yl)methyl 1)sulfonyl )benzamid de, 0.03g, 0.058 mmol , leq) , 2- (4-fluoropenyl)-5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan- 2-yl)thiazole (2-(4- fluorophenyl)— 5— (4,4,5,5— tetramethyl— 1,3,2— di oxaborolan—2—yl)thiazole, 0.059g,

[0412] 0.194 mmol, 1.5 eq), PdC12 (dppf ) (8.5 mg, 0.011 mmol, 0.2 eq), and K2CO3 (17.6 mg, 0.128 mmol, 2.2 eq) were dissolved in 1,4-dioxane:H2O (3:l(v / v)) (0.1 M, 0.6 ml) and stirred at 100°C for 1 hour. After the reaction was complete, the solution was filtered through Celite, concentrated, and purified by column chromatography (silica gel, MeOH / DCM) to obtain the target compound. Medium NMR (400 MHz, MeOD) 6 8.11 — 8.05 (m, 2H), 8.03 (s, 1H), 7.99 (d, J = 1.8 Hz, 1H), 7.62 (d, J = 3.3 Hz, 2H), 7.45 (d, J = 2.2 Hz, 1H), 7.32 - 7.27 (m, 2H), 7.27 - 7.23 (m, 2H), 6.13 (d, J = 2.2 Hz, 1H), 4.41 (s, 2H), 3.74 (s, 3H), 3.43 (t, J = 7.2 Hz, 2H), 2.61 (t, J = 7.5 Hz, 2H), 1.95 - 1.86 (m, 2H). Example 36: 3-(3-(2-aminoethyl)-2-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)-N-

[0413] Synthesis of (imidazo[1,2-a]pyridin-7-ylmethyl)-4-(((1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)benzamide (3— (3— (2—aminoethyl )—2—methyl—4—0x0—3,4-dihydroquinazol in—7—yl )—N— (imidazo[l,2—a]pyridin—7—ylmethyl )—4—( ((1—methyl—1H—nyr az o 1-3-y 1 )me t hy 1 )su 1 f onv 1 )benz amide, compound 34) Reagents and conditions: (a) Bis(pinacolato)diboron

[0414] (Bis(pinacolato)diboron) , KOAc, Pd(dppf )C12, 1,4-dioxane (1,4-dioxane) , reflux, 0.5 h; (b) N-(imidazo[1,2-a]pyridin-7-ylmethyl)-3-iodo-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide (N-(imidazo[l,2-a]pyridin-7-ylmethyl)—3—iodo—4—((1—methyl—IH—pyrazol—3—yl)methyl)sulfonyl)benzamide) , PdCMdppf )2, K2CO3, 1,4-dioxane (1,4-dioxane) , H2O, reflux (ref (lux), overnight; (c) tert-butyl (2-bromoethyl)carbamate, Cs2CO3, DMF, 80 °C, overnight; (d) 4N HC1 in dioxane, room temperature (rt), overnight Step 1) 2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-

[0415] Synthesis of 4(3H)-one (2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4(3H)-one)

[0416] 7-bromo-2-methylquinazol in-4(3H)-one (7-bromo-2-methylquinazol in-4(3H)-one,

[0417] 0.5 g (2.1 mmol, 1.0 eq) was dissolved in 1,4-dioxane (21 ml, 0.1 M), and then bis(pinacolato)diboron (1.06 g, 4.2 mmol, 2 eq), Pd(dppf)C12 (0.307 g, 0.42 mmol, 0.2 eq), and KOAc (0.412 g, 4.2 mmol, 2 eq) were added. The reaction mixture was heated under reflux and stirred for 0.5 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated to obtain the target compound as an unpurified product. Step 2) N-(imidazo[1,2-a]pyridine-7-ylmethyl)-4-(((1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)-3-(2-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)benzamide (N-

[0418] Synthesis of (imidazo[l,2— a]pyr idin— 7— ylmethyl )— 4— (((1— methyl— 1H— pyrazol— 3— yl )methyl )sulfonyl )— 3— (2— methyl— 4— oxo— 3,4— dihydroquinazol in-7-yl )benzamide)

[0419] N-(imidazo[1,2-a]pyridin-7-ylmethyl)-3-iodo-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide (0.2 g, 0.374 mmol, 1 eq) was dissolved in 1,4-dioxane:water (1,4-dioxane:H2O, 3:1(v:v), 3 ml, 0.1 M), and then 2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)quinazolin-4(3H)-one (2-methyl-7-(4,4,5,5-tetramethyl—1,3,2—dioxaboro lan—2—yl)quinazol in—4(3H)—one, 0.214 g, 0.747 mmol, 2 eq), PdC12(dppf)2 (0.054 g, 0.075 mmol, 0.2 eq), and K2CO3 (0.114 g, 0.822 mmol, 2.2 eq) were added. The reaction mixture was heated under reflux and stirred overnight. After the reaction was complete, the mixture was filtered through Celite and extracted with oil. The organic layer was washed with water and separated

[0420] After drying with MgS04, the target compound (0.019 g, 8.9%) was obtained by filtration, concentration, and purification by reverse-phase column chromatography (0.1% formic acid in H2O / ACN). Step 3) Synthesis of tert-butyl (2-(7-(5-((imidazo[1,2-a]pyridin-7-ylmethyl)carbamoyl)-2-(((1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)phenyl)-2-methyl-4-oxoquinazolin-3(4H)-yl)ethyl)carbamate

[0421] N- (imidazo [1,2-a]pyridine-7-ylmethyl)-4- (((1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)-3- (2-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)benzamide (N-

[0422] (imidazo[l,2—a]pyridin—7—ylmethyl)4—(((1—methyl—IH—pyr azol—3—yl)methyl)sulfonyl)3—(2—methyl—4—oxo—3,4—dihydroquinazolin—7—yl)benzamide, 0.019 g, 0.03 mmol, 1.0 eq) was dissolved in DMF (1 ml, 0.03 M), after which tert-butyl (2-bromoethyl)carbamate (0.008 g, 0.036 mmol, 1.2 eq) and CS2CO3 (0.019 g, 0.06 mmol, 2 eq) were added. The reaction mixture was heated to 80 °C and stirred overnight. After the reaction was complete, the mixture was cooled to room temperature and extracted with oil. The organic layer was washed with water, separated, dried with MgSO4, filtered, and concentrated to obtain the target compound as an unpurified product. Step 4) 3-(3-(2-aminoethyl)-2-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)-N-

[0423] Synthesis of (imidazo[1,2-a]pyridin-7-ylmethyl)-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide (3-(3-(2-aminoethyl )-2-methyl-4-0x0-3,4-dihydroquinazol in-7-yl )— N— (imidazo[1,2-a]pyridin-7-ylmethyl )— 4— (((1-methyl-1H-pyrazol-3-yl )methyl )sulfonyl )benzamide) tert-butyl (2-(7-(5-((imidazo[1,2-a]pyridin-7-ylmethyl)carbamoyl)-2-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl )phenyl )-2-methyl-4-oxoquinazolin-3(4H)-yl )ethyl )carbamoyl (tert-butyl (2— (7— (5— (( imidazo[l ,2— a]pyr idin— 7— ylmethyl )carbamoyl )— 2—( ( (1— methyl— 1H— pyr azol— 3— yl )methyl)sulfonyl ) phenyl )-2-methyl-4-oxoquinazolin-3(4H)-y 1 ) et hy 1 ) carbamat e , 0.019g, 0.03 mmol , leq) was dissolved in 1,4-dioxane (1,4-dioxane, 1ml, 0.03M), and then 4N HC1 (4N HC1 in dioxane, ) was prepared under dioxane

[0424] 0.05 ml (0.2 mmol, 6.6 eq) was added and stirred overnight at room temperature. After the reaction was complete, the solution was concentrated and purified by reverse-phase column chromatography (0.1% formic acid in H2O / ACN) to obtain the compound of the title.

[0425] (0.001 g, 5.4%) was obtained. P NMR (400 MHz, MeOD) 5 8.75 (s, 1H), 8.29 (d, J = 8.1 Hz, 1H), 8.18 s,

[0426] 1H), 8.12 (s, 1H), 8.08 (d, J = 8.0 Hz, 1H), 8.03 (d, J = 8.1 Hz, 1H), 7.99 s,

[0427] 1H), 7.92 (s, 1H), 7.85 (s, 1H), 7.69 (s, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.48 (d,

[0428] J = 10.3 Hz, 2H), 6.10 (s, 1H) , 4.78 (s, 2H) , 4.72 (s, 2H) , 4.34 — 4.29 (m, 2H),

[0429] 3.76 (s, 3H), 3.41 (d, J = 6.0 Hz, 2H), 2.73 (s, 3H).

[0430] MS(ESI) m / z MH + 611.08 Example 37: N-(3-(1H-pyrazol-4-yl)propyl)-3-((4-fluorophenyl)ethinyl)-4-

[0431] Synthesis of ((oxazol-5-ylmethyl)sulfonyl)benzamide (N— (3— (1H—pyr azo 1—4—y 1) pr opy 1)—3— ( (4—f luorophenyQethynyl)-4— ((oxazol-5-ylmethyl)sulfonyl)benzamide, compound 35) Reagents and conditions: (a) oxazol-5-ylmethanol, SOCI2, DCM, 0 °C to room temperature (0 °C to RT), 2 hours (2h) (b) methyl 3-iodo-4-mercaptobenzoate, K2CO3, DMF, room temperature (RT), 1 hour (1h) (c) mCPBA, DCM, room temperature (RT), 16 hours (16h) (d) 4-fluorphenylacetylene, PdChfPPhsh, Cui, TEA, ACN, room temperature (RT), 16 hours (16h) (e) NaOH, H2O, MeOH, room temperature (rt), 4 hours (4h) (f) 3-(IH-pyrazol-4-yl)propan-l-amine dihydrochloride), TBTU, TEA, DCM, 12 hours (12h). Step 1) Synthesis of 5-(chloromethyl)oxazole. Oxazol-5-ylmethanol (1 g, 10 mmol, 1 eq) was dissolved in DCM (20 ml), and 1.0 M thionyl chloride (in dichloromethane, 11 ml, 11 eq) was slowly added dropwise in an ice bath. The temperature of the reaction mixture was raised to room temperature and stirred for 2 hours. The reactants were concentrated under reduced pressure to obtain the target compound as an unpurified product. Step 2) Synthesis of methyl 3-iodo-4-((oxazol-5-ylmethyl)thio)benzoate.

[0432] 5-(chloromethyl)oxazole (1 g, 6.5 mmol, 1 eq) was dissolved in DMF (13 ml), and methyl 3-iodo-4-mercaptobenzoate (1.9 g, 6.5 mmol, 1 eq) was added to the reaction mixture containing K2CO3 (1.79 g, 13 mmol, 2 eq) and stirred for 1 hour. Water was added to the reaction mixture, and it was extracted several times using a sieve. The organic layer was dried with magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, 40% EA / HX) to obtain the target compound (0.22 g, 9%). Step 3) Synthesis of methyl 3-iodo-4-((oxazol-5-ylmethyl)sulfonyl)benzoate. Methyl 3-iodo-4-((oxazol-5-ylmethyl)thio)benzoate (0.22 g, 0.59 mmol, eq) was dissolved in DCM (5 ml), and mCPBA (0.3 g, 1.17 mmol, 2 eq) was added and stirred for 16 hours. The reaction was monitored by TLC, and once the reaction was complete, water was added to dilute the solution, it was neutralized with a saturated aqueous solution of NaHCOs, and extracted several times with DCM. The organic layer was dried with magnesium sulfate and then concentrated under reduced pressure. The resulting residue was concentrated under reduced pressure to obtain the target compound as an unpurified product.Step 4) Synthesis of methyl 3-((4-fluorophenyl)ethynyl)-4-((oxazol-5-ylmethyl)sulfonyl)benzoate. MeCN (2 ml, 0.2 M) was added to methyl 3-iodo-4-((oxazol-5-ylmethyl)sulfonyl)benzoate (0.17 g, 0.41 mmol, 1 eq) and TEA (0.074 ml, 0.53 mmol, 0.53 eq). PdCLdPPhgh in the reactants.

[0433] (8.4 mg, 3 mol%) and Cul (2.3 mg, 3 mol%) were added and stirred at room temperature under a nitrogen atmosphere for 5 minutes. Subsequently, 4-fluorophenylacetylene (0.06 g, 0.49 mmol, 1.2 eq) was added. The reaction mixture was stirred at room temperature for 16 hours and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, 30% EA / HX) to obtain the target compound (0.05 g, 30.5%). Step 5) Synthesis of 3-((4-fluorophenyl)ethynyl)-4-((oxazole-5-ylmethyl)sulfonyl)benzoic acid (3-((4-fluorophenyl)ethynyl)-4-((oxazo-1-5-y 1methhy 1)su 1fony 1)benzoic acid) methyl 3-((4-fluorophenyl)ethynyl)-4-((oxazole-5-ylmethyl)sulfonyl)benzoate

[0434] MeOH (0.6 ml), H2O (0.3 ml), and NaOH (0.012 g, 0.31 mmol, 2.5 eq) were added to (methyl 3-((4-fluorophenyl )ethynyl )—4—((oxazol—5—y Imethyl 1)sulfony 1)benzoate, 0.05 g, 0.125 mmol, 1 eq) and stirred for 4 hours. The reaction was monitored by TLC; upon completion, the pH of the reaction mixture was adjusted to 1 using an aqueous solution of INHC1, and extracted with a Toyo extractor. The organic layer was washed with water, dried with magnesium sulfate, and concentrated under reduced pressure to obtain the target compound. Step 6) N-(3-(1H-pyrazol-4-yl)propyl)-3-((4-fluorophenyl)ethynyl)-4-

[0435] Synthesis of ((oxazol-5-ylmethyl)sulfonyl)benzamide (N-(3-(lH-pyrazol-4-yl)propy1)-3-((4-fluorophenyl)ethynyl)-4-((oxazol-5-ylmethyl)sulfonyl)benzamide).

[0436] 3-((4-fluorophenyl)ethynyl)-4-((oxazol-5-ylmethyl)sulfonyl)benzoic acid (0.05 g, 0.125 mmol, 1 eq) in DCM (2 ml), TBTU (0.06 g, 0.19 mmol, 1.5 eq), TEA (0.064 ml, 0.46 mmol, 3.7 eq), and 1-{imidazo[1,2-a]pyridin-7-yl}methanamine hydrochloride. 0.03 g (0.15 mmol, 1.2 eq) was added and stirred for 12 hours. The residue obtained by concentrating the reaction mixture under reduced pressure was purified by column chromatography (silica gel, 5-10% MeOH / DCM) to obtain the target compound (0.053 g, 40.8%). P-NMR (400 MHz, DMSO-based) 5 12.55 (s, 1H), 8.89 (t, 7 = 5.6 Hz, 1H), 8.32

[0437] (s, 1H), 8.27 (d, J = 1.2 Hz, 1H) , 8.06 - 8.00 (m, 1H) , 7.96-7.94 (m, 1H) , 7.74

[0438] (dd, J = 8.6, 5.5 Hz, 2H) , 7.53 (s, 1H) , 7.39 (t, J = 8.8 Hz, 2H) , 7.09 (s, 1H) ,

[0439] 5.19 (s, 2H), 3.34 - 3.28 (m, 2H), 2.48 (m, 2H), 1.80 (p, J = 7.2 Hz, 2H).

[0440] MS(ESI) m / z MH +493.08 Example 38. N-(3-(1H-pyrazole-4-yl)propyl)-6-(( (1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)nicotine 0 Synthesis of} mid (N_(3_(lH_pyrazol_4_yl )propyl )—6—( ((J—methyl—lH— pyrazol— 3— yl)methyl)sulfonyl)nicotinamide, compound 36)

[0441] Reagents and conditions: (a) NaSH, DMF, room temperature (rt), overnight; (b) 3-(chloromethyl)-1-methyl-1H-pyrazole, K2CO3, DMF, room temperature (rt), 2 hours (2h); (c) m-CPBA, DCM, 0 °C to room temperature (0 °C to RT), overnight; (d) IN NaOH(aq), 80 °C, 2 hours (2 h); (e) 3-(1H-pyrazole-4-yl)propan-1-amine dihydrochloride, TBTU, TEA, DCM, room temperature (rt), 5 hours (5 h). Step 1) Synthesis of methyl 6-mercaptonicotinate NaSH (2.612 g, 46.6 mmol, 4 eq) was added to DMF (22 ml, 0.5 M) in which methyl 6-chloronicotinate (2 g, 11.65 mmol, 1 eq) was dissolved, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with an oil. The organic layer was washed with brine, and

[0442] After drying with MgSO4, the target compound was obtained as an unpurified product by filtration and concentration. Step 2) Methyl 6-(((1-methyl-1H-pyrazole-3-yl)methyl)thio)nicotine (methyl 6-

[0443] Synthesis of ( ( ( l~me t hy 1 - lH-py r azo 1 -3-y 1 )methyl )thio)nicotinate)

[0444] 3-(chloromethyl)-1-methyl-1H-pyrazole (3-(chloromethyl )-1-methyl-1H-pyrazole,

[0445] 0.733 g, 5.61 nmol, 1 eq) and K2CO3 (1.552 g, 11.23 mmol, 2 eq) were dissolved in DMF (56 ml, 0.1 M), then methyl 6-mercaptonicotinate (0.95 g, 5.61 mmol, leq) was added dropwise and stirred at room temperature for 2 hours. Water was added to the reaction mixture and extracted with a sieve. The organic layer was dried with MgSO4, filtered, concentrated, and then purified by column chromatography (silica gel, EA / HEX) to obtain the target compound (0.9 g, 60.8%). Step 3) Synthesis of methyl 6-(((1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)nicotine (methyl 6-(((l-methyl-lH-pyrazole-3-yl)methyl)thio)nicotine, 0.9 g, 3.41 mmol, 1 eq) was dissolved in DCM (34 ml, 0.1 M), and then m-CPBA (2.353 g, 13.64 mmol, 4 eq) was added dropwise at 0 °C. The reactants were slowly heated to room temperature and stirred overnight. After the reaction was complete, an aqueous solution of NaHCOy was added and extracted with DCM. The organic layer was dried with MgSO4, filtered, and concentrated to obtain the target compound as an unpurified product.Step 4) Synthesis of 6-(((l-methyl-lH-pyrazol-3-yl)methyl)sulfonyl)nicotinic acid. Methyl 6-(((l-methyl-lH-pyrazol-3-yl)methyl)sulfonyl)nicotinate (1.0 g, 3.41 mmol, 1 eq) was dissolved in THF (34 ml, 0.1 M), then an aqueous solution of NaOH (10.23 ml, 10.23 mmol, 3 eq) was added and heated at 80°C for 2 hours. After the reaction was completed, the reaction mixture was adjusted to pH 4 with an aqueous solution of IN HC1 and extracted with a Toyo extractor. The organic layer was washed with water, dried with MgS04, filtered, and concentrated to obtain the target compound as an unpurified product. Step 5) Synthesis of N-(3-(1H-pyrazol-4-yl)propyl)-6-((((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)nicotinamide.

[0446] 6-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)nicotinic acid (0.317 g, 1.13 mmol, 1 eq) was dissolved in DCM (11 ml, 0.1 M), and 3-(1H-pyrazol-4-yl)propan-1-amine dihydrochloride (0.335 g, 1.69 mmol, 1.5 eq), TBTU (0.544 g, 1.69 mmol, 1.5 eq), and TEA (0.343 g, 3.39 mmol, 3 eq) were added. The mixture was stirred at room temperature for 5 hours. After the reaction was complete, water was added to the reaction solution and extracted with DCM. The organic layer was washed with water, separated, dried with MgSO4, filtered, concentrated, and purified by reverse-phase column chromatography (0.1% formic acid in H2O / ACN) to obtain the target compound (0.041 g, 9.5%). p NMR (400 MHz, MeOD) 5 9.05 (s, 1H), 8.27 (d, J = 5.4 Hz, 1H), 7.88 (d, J = 6.3 Hz, 1H), 7.39 (d, J = 10.2 Hz, 3H), 6.05 (s, 1H), 4.68 (s, 2H), 3.67 (s, 3H), 3.37 (s, 2H), 2.54 (s, 2H), 1.84 (s, 2H). Example 39.Synthesis of 3-((4-(2-hydroxyacetamido)phenyl)ethynyl)-N-(imidazo[1,2-a]pyridin-7-ylmethyl)-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide (3-((4-(2-hydroxyacetamido)phenyl)ethynyl)—N—(imidazo[l,2-a]pyridin-7-ylmethyl)—4—(((l-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide, compound 37). Step 1) Glycolic acid (0.32 g, 4.27 mmol) was dissolved in anhydrous MC (9 ml, 0.5 M), then HATU (1.95 g, 5.124 mmol), DI PEA (0.89 ml, 5.124 mmol), and Compound A (0.5 g, 4.27 mmol) were added and stirred at room temperature for 12 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (EA / MeOH) to obtain Compound B. Step 2) Compound C (0.05 g, 0.1 mmol), CuI (0.76 mg, 0.004 mmol), TEA (0.03 ml, 0.22 mmol), and PdCl2(PPh3)2 (2.1 mg, 0.003 mmol) were dissolved in acetonitrile (1 ml, 0.1 M) and stirred at room temperature for 5 minutes. Compound B (0.026 g, 0.15 mmol) was added to the reaction mixture and stirred at 80°C for 2 hours. LCMS analysis confirmed that the reaction was complete. The reaction mixture was concentrated and purified by reverse-phase column chromatography (0.1% formic acid in H2O / ACN) to obtain Compound 37. P NMR (400 MHz, MeOD) 5 8.43 (d, J = 7.1 Hz, 1H) , 8.23 ​​(s, 1H) , 7.92 (s, 2H), 7.82 (s, 1H), 7.76 (d, J = 8.6 Hz, 2H) , 7.66 (d, J = 8.6 Hz, 2H) , 7.55 (s, 1H), 7.50 (s, 1H), 7.44 (d, J = 2.1 Hz, 1H) , 6.97 (d, J = 7.0 Hz, 1H) , 6.16 (d, J = 2.2 Hz, 1H), 4.85 (s, 2H) , 4.66 (s, 2H) , 4.14 (s, 2H), 3.72 (s, 3H). Example 40. N-(imidazo[1,2-a]pyridin-7-ylmethyl)-3-iodo-4-(( (1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)benz 0Synthesis of}White'!D (N— (imidazo[l,2— a]pyr idin— 7— ylmethyl )—3—iodo— 4— (((1— methyl— 1H— pyrazol— 3— yl)methyl)sulfonyl)benzamide, compound 38) Reagents and conditions: (a) NaOH, H2O, MeOH, 80 °C, 2 hours (2h) (b) 1-{imidazo[1,2-a]pyridin-7-yl}methanamine dihydrochloride, TBTU, TEA, DCM, 12 hours (12h) Step 1) Synthesis of 3-iodo-4-(((1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)benzoic acid (3-iodo-4-(((1-methyl-1H-pyrazole-3-3-yl)methyl)sulfonyl)benzoic acid) - yl)methyl)sulfonyl)benzoate (methyl

[0447] MeOH (10 ml, 0.1 M), H2O (5 ml, 0.2 M), and NaOH (0.1 g, 2.5 mmol, 2.5 eq) were added to 3-iodo-4- (((1- methyl- 1H- pyrazol- 3- yl)methyl)sulfonyl)benzoate, 0.42 g, 1 mmol, 1 eq), and the mixture was stirred at 80°C for 2 hours. The reaction was monitored by TLC; upon completion, the pH of the reaction mixture was adjusted to 1 using an aqueous solution of INHC1, and the mixture was extracted with oil. The organic layer was washed with water, dried with magnesium sulfate, and concentrated under reduced pressure to obtain the target compound (0.35 g, 86%). Step 2) N-(imidazo[1,2-a]pyridin-7-ylmethyl)-3-iodo-4-(((1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)benzamide (N-(imidazo[l,2-a]pyridin-7-ylmethyl )-3-iodo-

[0448] Synthesis of 4-((( 1-me thyl- lH-pyr azol — 3— y 1 ) me t hy 1 ) su 1 f onyl )benz am i de )

[0449] 3-iodo-4-(((l-methyl—lH—pyrazol—3—yl)methyl)sulfonyl)benzoic acid (0.35 g, 0.86 mmol, 1 eq) was mixed with TBTU (0.42 g, 1 mmol, 1.5 eq) in 10 ml of DCM and stirred at room temperature for 50 minutes. Next, TEA (0.45 ml, 1.3 mmol, 3.7 eq) and 1-{imidazo[1,2-a]pyridin-7-yl} methanamine dihydrochloride (l-{imidazo[l,2-a]pyridin-7-yl Imethanamine dihydrochloride, 92 mg, 0.42 mmol, 1.2 eq) were added to the reaction mixture and stirred for 12 hours. The solid formed from the reaction mixture was filtered to obtain the target compound (0.3 g, 65%). Medium NMR (400 MHz, MeOD) 6 8.64 (s, 1H), 8.43 (d, J = 7.0 Hz, 1H), 7.95 (s, 2H), 7.83 (s, 1H), 7.56 (s, 1H), 7.50 - 7.47 (m, 2H), 6.96 (d, J = 7.0 Hz, 1H), 6.20 - 6.18 (m, 1H), 4.84 (s, 2H), 4.65 (s, 2H), 3.77 (s, 3H). Example 41: 3-((4-amino-3-chlorophenyl)ethynyl)-N-(imidazo[1,2-a]pyridin-7-ylmethyl)-4-(((1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)benzamide (3—((4—amino—3—chlorophenyl)ethynyl)—N—(imidazo[l,2—a]pyri7—yImethy1)—4—((1—methyl—1H— Synthesis of oyr az o 1 -3-y 1 ) me t hy 1 ) su 1 f ony 1 ) benz amide, compound 39) Reagents and conditions: (a) 2-chloro-4-ethynylaniline, PdChtPPhsh, Cui, TEA, ACN, room temperature (rt), 16 hours (16h)

[0450] N-(imidazo[1,2-a]pyridin-7-ylmethyl)-3-iodo-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide (0.1 g, 0.2 mmol, 1 eq) was charged with MeCN (1 mL, 0.2 M), and then TEA (0.08 mL, 0.6 mmol, 3 eq) was added. PdCl₂(PPh₃)₂ (4 mg, 3 mol%) and CuI (1 mg, 3 mol%) were added to the reaction mixture, and it was stirred at room temperature for 5 minutes under a nitrogen atmosphere. Subsequently, 2-chloro-4-ethynylaniline (39 mg, 1.3 eq) was added. The reaction mixture was stirred at room temperature for 16 hours and concentrated under reduced pressure. The obtained residue was purified by reverse-phase chromatography (water / acetonitrile) to obtain the target compound. ¹H NMR (400 MHz, DMSO-d₆) δ 9.46 (s, 1H), 8.52 (d, J = 7.0 Hz, 1H), 8.24 (s, 1H), 7.99 - 7.97 (m, 1H), 7.95 - 7.85 (m, 2H), 7.65 - 7.57 (m, 2H), 7.54 (s, 1H), 7.46 (s, 1H), 7.36 (d, J = 8.5 Hz, 1H), 6.90 - 6.84 (m, 2H), 6.11 (d, J = 1.8 Hz, 1H), 6.08 (s, 2H), 4.88 (s, 2H), 4.54 (d, J = 3.5 Hz, 2H), 3.75 (s, 3H). LCMS: m / z = 559.1 (M+H)+ Example 42: Synthesis of 3-((4-amino-2-(trifluoromethyl)phenyl)ethynyl)-N-(imidazo[1,2-a]pyridin-7-ylmethyl)-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide (3-((4-amino-2-(trifluoromethyl)phenyl)ethynyl)—N—(imidazo[1,2-a]pyridin-7-ylmethyl)—4—((]-methyl-lH-pyrazol-3-yl)methyl)sulfonyl)benzamide, compound 40). Reagents and conditions (a) 4-ethynyl-3-

[0451] (Triple Luoro Methyl) aniline (4-ethynyl-3-(tri fluoromethyl)ani line), TEA, Cui, PdC12(PPh3)2, ACN, reflux, 3 hours (3h) In the method for preparing compound 29 of Example 31, it was prepared in substantially the same manner except that 4-ethynyl-3-(trifluoromethyl)aniline (4-ethynyl-3-(trifluoromethyl)ani line) was used instead of 4-ethynyl-2-fluoroaniline (4-ethynyl-2-f luoroani 1 ine). 1H NMR (400 MHz, DMSO—d6) δ 9.49 (t, J = 5.7 Hz, 1H), 8.51 (d, J = 6.9 Hz, 1H), 8.14 (s, 1H), 8.02 - 7.85 (m, 3H), 7.67 - 7.57 (m, 2H), 7.54 (s, 1H), 7.45 (s, 1H), 7.00 (s, 1H), 6.92 - 6.81 (m, 2H), 6.30 (s, 2H), 6.06 (s, 1H), 4.85 (s, 2H), 4.55 (d, J = 5.5 Hz, 2H), 3.71 (s, 3H). Example 43: 3-((4-Amino-3,5-difluorophenyl)ethynyl)-N-(imidazo[1,2-a]pyridin-7-ylmethyl)-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide (3-((4-amino-3,5-difluorophenyl)ethynyl)-N-(imidazo[1,2-a]pyridin-7-ylmethyl)-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide, synthesis of compound 41) Compound 29 of Example 31 was prepared by substantially the same method, except that 4-ethynyl-2,6-difluoroaniline was substituted for 4-ethynyl-2-fluoroaniline. P-NMR (400 MHz, DMSO-based) 5 9.47 (s, 1H), 8.52 (d, J = 7.0 Hz, 1H), 8.25 (s, 1H), 8.02 (d, J = 8.3 Hz, 1H), 7.97-7.88 (m, 2H), 7.65-7.61 (m, 3H), 7.58

[0452] - 7.54 (m, 3H), 7.46 (s, 1H), 7.34 (d, J = 7.1 Hz, 2H), 6.89 (d, J = 7.0 Hz, 1H), 6.13 (s, 1H), 5.99 (s, 2H), 4.86 (s, 2H), 4.55 (s, 2H) , 3.75 (s, 3H) . Example 44: Synthesis of 3-((4-amino-3-nitrophenyl)ethynyl)-N-(imidazo[1,2-a]pyridin-7-ylmethyl)-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide (3-((4-amino-3-nitrophenyl)ethynyl)—N—(imidazo[1,2-a]pyridin-7-ylmethyl)-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide (Compound 42). In the method for preparing Compound 29 of Example 31, it was prepared in substantially the same manner except that 4-ethynyl-2-nitroaniline was used instead of 4-ethynyl-2-fluoroaniline. 1H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 8.52 (d, J = 7.2 Hz, 1H), 8.30 (s, 2H), 8.01 (d, J = 8.2 Hz, 1H), 8.02 - 7.90 (m, 4H), 7.69 - 7.41 (m, 4H), 7.12 (d, J = 8.9 Hz, 1H), 6.89 (d, J = 6.9 Hz, 1H), 6.12 (s, 1H), 4.87 (s, 2H), 4.55 (d, J = 5.3 Hz, 2H), 3.72 (s, 3H). Example 45: Synthesis of N-(imidazo[1,2-a]pyridin-7-ylmethyl)-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)-3-(piperidin-4-ylethynyl)benzamide (Compound 43) Reactants and conditions (a) tert-butyl 4-ethynylpiperidine-l-carboxylate, TEA, Cui, PdC12(PPh3)2, ACN, reflux, 3h (b) 4N HC1 in dioxane, DCM, room temperature, overnight. Step 1) Synthesis of tertbutyl 4-((5-((imidazo[1,2-a]pyridin-7-ylmethyl)carbamoyl)-2-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)phenyl)ethynyl)piperidine-1-carboxylate (tertbutyl 4—((5—((imidazo[1,2-a]pyridin—7-ylmethyl)l)carbamoy 1)—2—(((1-methyl—1H-pyrazol-3-yl)methyl)sulfonyl)phenyl)ethynyl)piperidine—1-carboxylate) in the method for preparing compound 29 of Example 31 (4-ethynyl-2-fluoroaniline) It was prepared in substantially the same way, except that tert-butyl 4-ethynylpiperidine-1-carboxylate was added instead.Step 2) Synthesis of N-(imidazo[1,2-a]pyridin-7-ylmethyl)-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)-3-(piperidin-4-ylethynyl)benzamide tert-Butyl 4-((5-((imidazo[1,2-a]pyridin-7-ylmethyl)carbamoyl)-2-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)phenyl)ethynyl)piperidine-1-carboxylate (0.2 g, 0.3 mmol, 1 eq) was dissolved in DCM (3 ml, 0.1 M), and 4N HCl in dioxane (0.05 ml, 0.2 mmol, 10 eq) was added, followed by stirring overnight at room temperature. After completion of the reaction, it was concentrated and purified by reverse-phase column chromatography (H2O / ACN) to obtain the title compound. 1H NMR (400 MHz, DMSO-d6) δ 9.49 (t, J = 5.2 Hz, 1H), 8.61 (d, J = 6.9 Hz, 1H), 8.43 (s, 2H), 8.20 (s, 1H), 8.03 - 8.01 (m, 2H), 7.89 (d, J = 8.2 Hz, 1H),

[0453] 1H), 8.43 (s, 2H), 8.20 (s, 1H), 8.03 - 8.01 (m, 2H), 7.89 (d, J = 8.2 Hz, 1H),

[0454] 7.71 (s, 1H), 7.62 (s, 1H) , 7.54 (s, 1H) , 7.05 (d, J = 7.0 Hz, 1H) , 6.08 (s, 1H) ,

[0455] 4.82 (s, 2H), 4.58 (d, J = 5.2 Hz, 2H) , 3.22 - 2.12 (m, 5H) , 2.12 - 2.09 (s, 2H),

[0456] 2.15 - 1.87 (s, 2H).

[0457] <Experimental Example 1> NAMPT Enzyme Inhibition AnalysisThe NAMPT enzyme activity inhibition ability (IC50) of the compound was evaluated using the NAMPT Inhibitor Screening Assay Kit (#7176-1) from BPS bioscience. Recombinant NAMPT protein was added to each well of a black 96-well plate, and a dilution buffer was added to the blank well instead of the NAMPT protein. After adding the 5-fold concentrated compound solution, it was pre-incubated at room temperature (about 22°C) for 30 minutes before the start of the reaction to allow the compound and the protein to bind before the enzyme reaction. At this time, the concentration of the NAMPT protein was adjusted according to the enzyme activity of each protein lot within the range of a final concentration of 4-10 ng / μl and used. The test compound was serially diluted at a ratio of 1:3 from 1000 nM to 1 nM, and the experiment was conducted with n = 2 for about 7 concentrations. A 2-fold concentrated test buffer containing ATP (final concentration 20 μM), nicotinamide (final concentration 20 μM), PRPP (Phosphoribosyl pyrophosphate, 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 an excitation of 340 nm and an emission of 460 nM. The NAMPT enzyme activity (%) was calculated by subtracting the measured value of the blank well without NAMPT protein from the measured values of all wells and using the measured value of the control well without the compound as 100%. The IC50 was calculated using GraphPad Prism 9 software, and the results are shown in Table 1 below. In Table 1 below, A, B, and C are as follows.

[0458] A: NAMPT IC50 <0.5 uM (0.5 11M or less)

[0459] B: 0.5 11M <NAMPT IC50 <1 uM(0.5 11M초과 1 yM 이하)

[0460] C: NAMPT IC50 >1 uM (1 > 11M)

[0461] [Table 1]

[0462] As confirmed in the table above, the compounds of the present invention exhibit excellent inhibitory activity against NAMPT and demonstrate sufficient inhibitory activity even at low concentrations. Therefore, the compounds of the present invention have excellent preventive or therapeutic effects against NAMPT-related diseases. <Experimental Example 2> Cellular NAD measurement assay

[0463] The reduction in intracellular NAD+ and NADH levels in HCT-116 cell lines due to the inhibition of NAMPT enzyme activity by the compound was evaluated using Promega’s NAD / NADH-G 1 o™ Assay (Promega, G9072). Cells were cultured in DMEM medium containing 10% FBS (Gibco, 11995-065). HCT-116 cells were distributed into 96-well plates at a density of 2,500 cells per well and cultured for 24 hours, after which the drug was administered using serum-free DMEM. First, the compound was dissolved in 100% DMSO (Dimethyl sulfoxide), and then the compound was diluted in the culture medium to a final DMSO concentration of 0.5% for drug administration. The final concentration range of the compound was set from 0.1 nM to 100 nM. Subsequently, the cells were cultured for an additional 24 hours at 37 °C under 25% CO2 conditions. To perform the NAD / NADH-Glo™ Assay, the culture medium of the drug-treated cells was removed, and 50 µL of DPBS was added per well and left at room temperature for 5 minutes. According to the manufacturer's manual, the required amount of NAD / NADH-Glo™ Detection Reagent (Reconstituted Luciferin Detection Reagent 1 mL, Reductase 5 µL, Reductase Substrate 5 µL, NAD Cyc 1 i ng Enzyme 5 µL, NAD Cyc 1 i ng Substrate 25 µL) was prepared, and 50 µL was added per well. For cell lysis, the cells were incubated on a plate shaker at 400 rpm for 2 minutes, followed by incubation at room temperature for 30 minutes, and luminescence was measured. The NAD+ / NADH level is calculated by subtracting the measurement from the cell-free blank well from the measurement of all wells, and then 0.Calculations were performed using the 5% DMSO-treated control group as the 100% standard, and the IC50 was calculated using GraphPad Prism 9 software. The results are shown in Table 2 below. In Table 2, A, B, and C are as follows.

[0464] A: NAD IC 50 <10 nM (10 nM or less) B: 10 nM < NAD IC5o < lyM uM (greater than 10 nM, less than or equal to 1 yM)

[0465] C: NAD IC5o >1 11M (Exceeds 1 11M)

[0466] [Table 2] As confirmed in the table above, the compounds of the present invention significantly inhibited NAD production in the HCT-116 cell line and sufficiently inhibited intracellular NAD concentration even at low concentrations. Therefore, the compounds of the present invention inhibit NAMPT and can sufficiently lower intracellular NAD concentration even at low concentrations; accordingly, they possess excellent preventive or therapeutic effects against diseases (e.g., cancer) that can be treated through the inhibition of NAMPT. <Experimental Example 3> Tumor cytotoxicity assay

[0467] The anticancer efficacy of the compound was evaluated in two cell lines, HCT-116 (colorectal cancer) and NCI-N87 (gastric cancer), using the MTT assay. HCT-116 cells were cultured in DMEM containing 10% FBS (Gibco, 11995-065), and NCI-N87 cells were cultured in RPMI Medium 1640 containing 10% FBS and 25 mM HEPES (Gibco, 22400-089). HCT-116 cells were distributed in 96-well plates at a density of 2,500 cells per well, and NCI-N87 cells at a density of 10,000 cells per well. After culturing each cell type for 24 hours, the drug was administered using a medium that did not contain FBS. First, the compound was prepared in 100% DMSO (Dimethyl sulfoxide) at concentrations ranging from 0.02 iiM to 200 iiM, and then the compound was diluted in the culture medium to achieve a final concentration of 0.5% for drug treatment. The final concentration range of the compound was set to 0.1 nM to 1000 nM. Subsequently, the cells were cultured for an additional 72 hours under 37 °C and 25% CO2 conditions. To confirm cytotoxicity, MTT (Sigma-Aldrich, M2128) was administered for 2 or 4 hours, after which formazan, produced by reduction by enzymes in the mitochondria of living cells, was measured using a Spark® Multimode Microplate Reader TECAN instrument. Cell viability (%) was determined relatively by subtracting the reference 650 nm absorbance (Optical density, OD) from the 570 nm absorbance, using the 0.5% DMSO-treated control group as the 100% standard. The CCso (50% cytotoxic concentration) values ​​were calculated by plotting the results as a function of compound concentration using GraphPad Prism 9 software, and the results are shown in Table 3 below. A, B, and C in Table 3 are as follows.

[0468] A: CC5o <30 nM (30 nM or less)

[0469] B: 30 nM < CC 50 < 300 nM (Exceeding 30 nM and up to 300 nM) C: CC5o> 300 nM (Exceeding 300 nM)

[0470] [Table 3] As confirmed in the table above, it can be seen that the compounds of the present invention exhibit excellent cytotoxicity against colorectal cancer cell lines and gastric cancer cell lines even at low concentrations. Therefore, the compounds of the present invention inhibit NAMPT and have excellent preventive or therapeutic effects against various diseases, such as cancer.

[0471] <2. Preparation of Drug-Linker Conjugates> To confirm whether the cytotoxic drug moiety of the present invention is applicable to ADCs, drug-linker conjugates were prepared as follows using the cytotoxic drug moiety of Compound 1, Compound 10, Compound 14, Compound 29, and Compound 39, by example. Example 46. Synthesis of Linker-Payload 1

[0472] Step 1) Compound A (640 mg, 1.69 mmol) of Compound B (1.00 g, 1.69 mmol)

[0473] EEDQ (835 mg, 3.37 mmol) was added to a solution of CH2C12 (25 mL) and MeOH (5 mL). The mixture was stirred at 30 °C for 6 hours. The completion of the reaction was confirmed by LCMS. The reaction mixture was concentrated under reduced pressure to obtain the residue, which was triturated with CH3CN (20 mL) and MTBE (40 mL). Compound C (1.39 g, 85.4% yield, 98.9% purity) was obtained as a white solid.

[0474] LCMS: m / z = 954.5 (M+H) +Step 2) DIEA (377 mg, 2.91 mmol, 507 μL) and pyridine (1.15 g, 14.6 mmol, 1.18 mL) were added to a solution of compound C (1.39 g, 1.46 mmol) and bis(4-nitrophenyl)carbonate (bis(4-nitr opheny 1) carbonate, 1.33 g, 4.37 mmol) dissolved in DMF (25 mL). The mixture was stirred at 50 °C for 2 hours under this atmosphere. LC-MS analysis detected the desired compound. The reaction mixture was concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography (dichloromethane:methanol = 50 / 1 to 10 / 1). Compound E (1.06 g, 62.0% yield, 95.4% purity) was obtained as a white solid.

[0475] LCMS: m / z = 1119.4 (M+H) + Step 3) DMAP (0.5 M, 80 µL, in DMF) and DIEA (77.9 mg, 603 µL, 105 µL) were added to a solution of Compound E (270 mg, 241 µmol) and Compound F (102 mg, 201 µmol) dissolved in DMF (3 mL). The mixture was stirred at 25 °C for 1 hour. LC-MS analysis detected the desired compounds. The reaction mixture was concentrated under reduced pressure to remove half of the DMF at 30 °C or below for 20 minutes, after which 1.5 mL of DMF and 0.1 mL of HOAc were added. The mixture was purified by prep-HPLC (Column: CD09-Phenomenex Gemini C18 150*30*5 µm; Mobile phase: [Water (FA)-ACN]; Gradient: 20%-50% B, 20 min). Linker-Payload 1 (20.0 mg, 6.48% yield, 96.8% purity) was obtained as a pink solid.

[0476] LCMS: m / z = 1485.5 (M+H) +P NMR (400 MHz, DMSO—o6) 5 10.06 (s, 1H) , 8.84 (t, 7= 5.6 Hz, 1H) , 8.22 (d, J = 1.2 Hz, 1H), 8.09-8.19 (m, 2H) , 8.01 (t, J = 5.6 Hz, 1H) , 7.97 (dd, J = 8.4, 1.2 Hz, 1H), 7.84-7.93 (m, 2H), 7.72-7.84 (m, 3H), 7.65 (d, J = 8.4 Hz, 2H) , 7.59 (d, J = 2.0 Hz, 1H), 7.33-7.50 (m, 4H) , 7.00 (s, 2H) , 6.08 (d, J = 2.0 Hz, 1H), 5.99 (t, J= 5.2 Hz, 1H) , 5.28-5.48 (m, 4H) , 4.86 (s, 2H) , 4.34-4.43 (m, 1H) , 4.17-4.27 (m, 1H) , 3.70 (s, 3H) , 3.59 (t, J = 7.2 Hz, 4H) , 3.48-3.52 (m, 22H) , 3.26-3.42 (m, 12H) , 3.14 (q, J= 5.6 Hz, 2H) , 2.89-3.07 (m, 2H) , 2.44-2.48 (m, 1H), 2.39 (t, J = 6.4 Hz, 1H), 2.29-2.35 (m, 2H), 1.92-2.00 (m, 1H), 1.81 (quin, J = 7.2 Hz, 2H), 1.53-1.74 (m, 2H), 1.30-1.49 (m, 2H), 0.84 (dd, J= 13.2, 6.8 Hz, 6H). Example 47. Synthesis of linker-payload 2

[0477] DMAP (0.5 M, 95 μL, DMF solution) and DIEA (92.4 mg, 715 μmol, 125 μL) were added to a solution in which , , 238 μmol) was dissolved in DMF (3 mL). The mixture was stirred at 25 °C for 1 hour. LC-MS analysis revealed the desired compound. The reaction mixture was concentrated to 1.5 mL under reduced pressure at 30 °C or below, and then diluted to 3 mL with DMF. After adding H0Ac (0.1 mL) to the solution, the mixture was purified twice using prep-HPLC (Column: CD08-Phenomenex kinetex EVO C18 150*30*5 μm; Mobile phase: [Water (FA)—ACN]; Gradient: 12%-42% B, 20 min). Linker-payload 2 (8.11 mg, 2.15% yield, 97.9% purity) was obtained as a white solid.

[0478] LCMS: m / z = 1548.5 (M+H) + P NMR: (400 MHz, DMSO—d6) 5 10.06 (s, 1H) , 8.85 (t, J= 5.6 Hz, 1H) , 8.61 (d, J = 2.8 Hz, 1H), 8.57 (d, J = 6.4 Hz, 2H) , 8.26 (s, 1H) , 8.17 (s, 1H) , 8.14

[0479] (d, J = 7.6 Hz, 1H), 8.01 (t, J = 5.2 Hz, 1H), 7.85-7.97 (m, 3H), 7.71-7.79 (m,

[0480] 3H), 7.58-7.67 (m, 4H), 7.43 (d, J = 8.4 Hz, 2H), 7.35 (t, J = 8.8 Hz, 2H), 6.99

[0481] (s, 2H), 6.51 (d, J = 2.4 Hz, 1H), 5.99 (t, J = 5.2 Hz, 1H), 5.32-5.45 (m, 4H),

[0482] 5.04 (s, 2H), 4.33-4.43 (m, 1H) , 4.18-4.26 (m, 1H) , 3.59 (t, J= 7.2 Hz, 4H) , 3.44— 3.53 (m, 33H), 3.14 (q, J = 5.6 Hz, 3H) , 2.90-3.06 (m, 3H), 2.44-2.47 (m, 1H), 2.39 (t, J = 6.4 Hz, 1H), 2.30-2.35 (m, 2H), 1.96 (dq, J = 13.2, 6. Hz, 1H), 1.81 (quin, J = 7.2 Hz, 2H), 1.56-1.73 (m, 2H) , 1.32-1.48 (m, 2H) , 0.84 (dd, J = 13.2,

[0483] 6.78 Hz, 6H). Example 48. Synthesis of linker-payload 3 Step 1) DIEA (1.72 g, 13.3 mmol, 2.32 mL) was added to a solution of Compound B (778 mg, 6.65 mmol) dissolved in THF (20.0 mL). Then, Triphosgene (493 mg, 1.66 mmol) was added under N2 at 0 °C. The mixture was stirred at 25 °C for 1 hour. A solution of Compound A (2.00 g, 3.32 mmol) dissolved in anhydrous DMF (20.0 mL) was added dropwise to freshly prepared isocyanate, and the mixture was stirred at 25 °C for 1 hour. LCMS analysis confirmed that the reaction was complete. The reaction mixture was poured into water to precipitate, filtered, and the solid was dried using a vacuum pump. The solid was purified by prep-HPLC (Column: YMC Tri art C18 70*250mm*7um; Mobile phase: [Water (TFA)-ACN]; Gradient: 35%-65% B, 22 min). Compound C (634 mg, 25.6% yield) was obtained as a white solid.

[0484] LCMS: m / z = 745.3 (M+H) +P NMR (400 MHz, DMSO- ⑦) 6 9.87-10.20 (m, 2H) , 8.05-8.17 (m, 1H) , 7.83- 7.93 (m, 2H), 7.69-7.79 (m, 2H) , 7.61 (d, J = 8.0 Hz, 2H) , 7.30-7.51 (m, 11H) , 5.97 (d, J= 5.6 Hz, 1H) , 5.29-5.54 (m, 2H) , 4.98-5.24 (m, 2H) , 4.37-4.46 (m, 1H) , 4.19-4.34 (m, 3H) , 4.02-4.11 (m, 1H) , 3.87-3.98 (m, 1H) , 2.92-3.03 (m, 2H) , 1.95- 2.02 (m, 1H), 1.58-1.72 (m, 2H) , 1.36-1.49 (m, 2H) , 0.86 (dd, J = 10.4, 6.8 Hz, 6H). Step 2) Compound 0 (208 mg, 280 nmol), Compound C (100 mg, 186 nmol), Cui (3.56 mg, 18.6 μmo 1), EtsN (56.7 mg, 560 μmol, 78.0 μL), and Pd(PPhs)4 (21.5 mg, 18.6 μmol) were mixed in DMF (3 mL), degassed three times, and replaced with this. The mixture was stirred at 40 °C for 2 hours under an N2 atmosphere. LCMS analysis confirmed that the reaction was complete. The mixture was used directly in the next step without further processing. Compound E (crude) was obtained as a brown liquid. LCMS: m / z = 1152.9 (M+H) +Step 3) Et2NH (142 mg, 1.94 mmol, 0.20 mL) was added to a solution of Compound E (215 mg, 186 μmol) dissolved in DMF (3.00 mL). The mixture was stirred at 25 °C for 1 hour. LCMS analysis confirmed that the reaction was complete. The reaction mixture was concentrated at 35 °C to obtain the residue. The residue was purified by prep-HPLC (Column: CD04-Welch Ultimate C18 150*25*7 μm; Mobile phase: [Water (TFA)-ACN]; Gradient: 12%-42% B, 14 min). Compound F (76.0 mg, 43.8% yield, Step 2) was obtained as a white solid.

[0485] LCMS: m / z = 930.5 (M+H) +P NMR (400 MHz, DMSO—⑦) 6 10.22 (s, 1H) , 10.09 (s, 1H) , 9.53-9.69 (m, 1H) , 8.83 (d, J= 6.8 Hz, 1H) , 8.68 (d, J= 7.6 Hz, 1H) , 8.29 (d, J= 6.8 Hz, 2H) , 8.08 (s, 3H), 8.01 (d, J = 8.4 Hz, 1H) , 7.93 (d, J = 8.4 Hz, 1H) , 7.79 (s, 1H) , 7.53- 7.68 (m, 7H), 7.36-7.47 (m, 3H) , 5.94-6.15 (m, 2H) , 5.48 (d, J= 1.6 Hz, 2H) , 5.12 (s, 2H), 4.89 (s, 2H), 4.69 (d, J = 4.4 Hz, 2H) , 4.41-4.57 (m, 1H) , 3.70 (s, 3H) , 3.66 (d, J= 4.4 Hz, 1H) , 2.99-3.08 (m, 2H) , 2.05-2.10 (m, 1H) , 1.60-1.74 (m, 2H) , 1.39-1.50 (m, 2H), 0.89-0.97 (m, 6H). Step 4) DIEA (13.9 mg, 107 µmol, 18.7 µL) was added to a solution of Compound F (50.0 mg, 53.7 µmol) and Compound G (44.5 mg, 64.5 µmol) dissolved in DMF (2.00 mL). The mixture was stirred at 25 °C for 2 hours. LCMS analysis confirmed that the reaction was complete. The reaction mixture was concentrated at 35 °C or below to obtain the residue. The residue was purified by prep-HPLC (Column: CD04-Welch Ultimate C18 150*25*7 µm; Mobile phase: [Water (TFA)-ACN]; Gradient: 15%-45% B, 10 min). Linker-payload 3 (8.09 mg, 99.6% purity, 9.96% yield) was obtained as a white solid. LCMS: m / z = 1505.5 (M+H) +1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 10.03 (s, 1H), 9.66 (t, J = 5.6 Hz, 1H), 8.86 (d, J = 7.6 Hz, 1H), 8.31 (dd, J = 4.4, 1.2 Hz, 2H), 8.11 - 8.17 (m, 2H), 7.99 - 8.06 (m, 2H), 7.88 - 7.95 (m, 2H), 7.83 (s, 1H), 7.58 - 7.65 (m, 7H), 7.50 (d, J = 6.8 Hz, 1H), 7.38 (d, J = 8.4 Hz, 2H), 7.00 (s, 2H), 6.09 (d, J = 2.0 Hz, 1H), 6.01 (s, 1H), 5.11 (s, 2H), 4.89 (s, 2H), 4.71 (d, J = 5.6 Hz, 2H), 4.38 (d, J = 5.6 Hz, 1H), 4.20 - 4.26 (m, 2H), 3.70 (s, 3H), 3.58 (t, J = 7.2 Hz, 4H), 3.45 - 3.51 (m, 30H), 3.35 (t, J = 5.6 Hz, 2H), 3.12 - 3.16 (m, 2H), 3.01 (s, 1H), 2.95 (d, J = 4.0 Hz, 1H), 2.39 (t, J = 6.4 Hz, 1H), 2.32 (t, J = 7.2 Hz, 2H), 1.96 (dd, J = 13.2, 6.8 Hz, 1H), 1.65 - 1.72 (m, 1H), 1.59 (d, J = 9.2 Hz, 1H), 1.32 - 1.45 (m, 2H), 0.84 (dd, J = 13.2, 6.8 Hz, 6H). Example 49. Synthesis of Linker-Payload 4

[0486] Government #흐 t>& (Government W W land) is ZT丄group, V느-으== #=--. •

[0487] B (10 mg, 20 nmol, 1.0 equivalent) was added, and DIPEA (10 u 1, 60 nmol, 3 equivalents) was added dropwise at 0 °C. After stirring the mixture overnight at room temperature, H0Bt (2.7 mg, 20 nmol, 1 equivalent) was added. The mixture was stirred overnight at room temperature. The mixture was purified by prep-HPLC (TFA conditions) to obtain linker-payload 4 (0.74 mg, 3.35% yield) as a white solid. P NMR (400 MHz, MeOD) 5 8.55 (s, 1H) , 8.14 (s, 1H) , 8.10 (s, 1H) , 7.90 (d, J = 8.3 Hz, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.75 (d, J = 10.9 Hz, 3H) , 7.64 (d, J = 8.5 Hz, 2H), 7.47 (s, 1H) , 7.45 (d, J = 2.2 Hz, 2H) , 7.23 (t, J = 8.7 Hz, 2H) , 6.79 (s, 2H), 6.16 (d, J = 2.1 Hz, 1H), 5.41 (s, 2H), 4.59 (s, 2H) , 4.51 (dd, J =

[0488] 9.1, 5.4 Hz, 2H), 4.16 (d, J = 7.3 Hz, 1H), 3.73 (s, 3H), 3.50 - 3.42 (m, 6H),

[0489] 3.13 (m, 3H), 2.62 (t, J = 7.5 Hz, 3H) , 2.28 (t, J = 7.2 Hz, 2H) , 2.11 - 2.02 (m,

[0490] 2H), 1.99 - 1.87 (m, 5H), 1.77 (m, 2H), 1.61 (m, 9H), 0.97 (dd, J = 6.6, 4.4 Hz,

[0491] 7H), 0.91 (m, 4H).

[0492] LCMS: MS cal.: 1104.23, MS observed: [M+H]+ = 1104.7 Example 50. Synthesis of Linker-Payload 5

[0493] Step 1) 4-ethynylaniline (648 mg, 5.53 mmol) was added to THF (20.0 mL), and DIEAC (1.99 g, 15.4 mmol, 2.68 mL) was added. Then, triphosgene (540 mg, 1.82 mmol) was added to the mixture under N2 at 0°C. The mixture was stirred at 0°C for 10 minutes. (2S, 3R, 4S, 5S, 6S)-2-(2-(3-(( (9H-fluorene-9-yl)methoxy)carbonyl)amino)propanamido)-4-(hydroxymethyl)phenoxy)-6-

[0494] (Methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate (2.30 g, 3.07 mmol) was dissolved in dry DMF (20.0 mL), added dropwise to the mixture, and stirred at 25°C for 1 hour. The completion of the reaction was confirmed by LC-MS. The reaction mixture was concentrated under reduced pressure to obtain the residue, which was purified by prep-HPLC (Column: F-Welch Xtimate C18 40*200mm 71; Mobile phase: [H2O(0.1% TFA)-ACN]; Gradient: 44%-84% B for 20.0 min) to obtain (2S, 3R, 4S, 5S, 6S)-2-(2-(3-(( ((9H-fluorene-9-yl)methoxy)carbonyl)amino)propanamido)-4-((((4-ethinylphenyl)carbamoyl)oxy)methyl)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate (1.50 g, yield 53.5%)> obtained as a white solid.

[0495] LCMS: m / z = 892.0 (M+H) +1H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H), 8.78 (s, 1H), 7.93 (s, 1H), 7.88

[0496] (d, J = 7.6 Hz, 2H), 7.68 (d, J = 7.6 Hz, 2H), 7.44 - 7.49 (m, 2H), 7.35 - 7.43 (m,

[0497] 5H), 7.28 - 7.34 (m, 2H), 7.19 (d, J = 8.8 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 5.60

[0498] (d, J = 7.6 Hz, 1H), 5.49 (d, J = 9.6 Hz, 1H), 5.13 - 5.24 (m, 1H), 5.02 - 5.12 (m,

[0499] 3H), 4.72 (d, J = 10.0 Hz, 1H), 4.26 - 4.33 (m, 2H), 4.17 - 4.25 (m, 1H), 4.04 (s, 1H), 3.63 (s, 3H), 3.25 - 3.34 (m, 4H), 1.95 - 2.04 (m, 9H) Step 2) N-(Imidazo[1,2-a]pyridin-7-ylmethyl)-3-iodo-4-(((1-methyl-1H-pyrazol-

[0500] 3-yl)methyl)sulfonyl)benzamide (150 mg, 280 µmol), (2S,3R,4S,5S,6S)-2-(2-(3-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)propanemid)-4-( ( ((4-ethinylphenyl)carbamoyl)oxy)methyl)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate (374 mg, 420 nmol), CuI (16.0 mg, 84.0 µmol), TEA (283 mg, 2.80 mmol) and Pd(PPh3)4 (97.1 mg, 84.0 µmol) The mixture was added to DMF (15 mL), degassed, and purged three times. The mixture was stirred at 40°C for 2 hours under a nitrogen atmosphere. The completion of the reaction was confirmed by LC-MS. The reaction mixture was concentrated under reduced pressure to obtain the residue, which was purified by prep-HPLC (Column: F-MicroPulite XP tC18 40*100 mm 10 m; Mobile phase: [H2O(0.1%TFA)-ACN]; Gradient: 20%-60% B for 25.0 min) to obtain the following. (2S,3R,4S,5S,6S)- 2- (2-(3-(( ( (9H-fluorene-9-yl)methoxy )carbonyl)amino)propaneamide)- 4-( ( ((4-((5 - ( (imidazo[ 1 ,2-a]pyridine-7-ylmethyl )carbamoyl )- 2-( ( (1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)phenyl)ethinyl)phenyl)carbamoyl)oxy)methyl)phenoxy)-6-

[0501] (Methoxycarbonyl) Tetrahydro-2H-pyran-3,4,5-triyl triacetate (100 mg, yield)

[0502] 27.4%, yellow solid)

[0503] LCMS: m / z = 1299.0 (M+H) +Step 3) Methyl (2S,3R,4S,5S,6S)-2-(2-(3-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)propanamide)-4-((((4-((5-((imidazo[1,2-a]pyridine-7-ylmethyl)carbamoyl)-2-(((1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)phenyl)ethinyl)phenyl)carbamoyl)oxy)methyl)phenoxy)-6-

[0504] LiOH·H2O (14.5 mg, 346 μmol) was added to a solution of (methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate (75.0 mg, 57.7 μmol). The mixture was stirred at 25°C for 1 hour. The completion of the reaction was confirmed by LC-MS. The reaction mixture was poured into MeCN (40 mL) to precipitate and filtered, and the cake was dried under a vacuum pump to obtain (2S, 3S, 4S, 5R, 6S)-6-(2-(3-aminopropaneamido)-4-(((4-((5-(imidazo[1, 2-a]pyridine-7-ylmethyl)carbamoyl)-2-(((1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)phenyl)ethinyl)phenyl)carbamoyl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (60.0 mg) as a yellow solid without further purification.

[0505] LCMS: m / z = 469.2 (M / 2+H)' step 4) (2S,3S,4S,5R,6S)- 6- (2- (3-aminopropaneamido)- 4- ((((4- ((5-

[0506] ( (imidazo [ 1 , 2- a ].pyridine-7-ylmethyl )carbamoyl )-2-( ( (1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)phenyl)ethinyl)phenyl)carbamoyl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (60.0 mg, 64.0 μmol) and 2,5-dioxopyrrolidine-1-yl 6-(2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl)hexanoate (23.7 mg, 76.8 μmol) were dissolved in DMF (3 mL) solution, and then DIEA (24.8 mg, 192 umol) was added and the mixture was stirred at 25°C for 1 hour. The completion of the reaction was confirmed by LC-MS. The reaction mixture was purified by prep-HPLC (Column: F-Welch Xtimate C18 40*200mm 7 ☐ ☐; Mobile phase: [H2O(0.1% TFA)-ACN]; Gradient: 2%-42% B, for 20.0 min) to obtain (2S,3S,4S,5R,6S)-6-(2-(3-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl)hexanamido)propanamido)-4-((((4-((5-((imidazo[1,2-a]pyridin-7-ylmethyl)carbamoyl)-2-(((1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)phenyl)ethinyl)phenyl)car Vamoyl(oxy)methyl(phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (20.0 mg, yield 27.1%, purity

[0507] 97.97%) was obtained as a colorless oil.

[0508] LCMS: m / z = 1130.2 (M+H) +1H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 9.63 (t, J = 5.6 Hz, 1H), 9.09 (s, 1H), 8.84 (d, J = 7.2 Hz, 1H), 8.29 (d, J = 1.6 Hz, 2H), 8.20 - 8.26 (m, 1H), 8.12

[0509] (d, J = 2.0 Hz, 1H), 7.96 - 8.03 (m, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.81 (s, 1H),

[0510] 7.63 (s, 1H), 7.52 - 7.62 (m, 5H), 7.45 - 7.52 (m, 1H), 7.05 - 7.15 (m, 2H), 6.95 (s,

[0511] 2H), 6.09 (d, J = 2.4 Hz, 1H), 5.08 (s, 2H), 4.88 (s, 2H), 4.86 (s, 1H), 4.70 (d,

[0512] J = 5.2 Hz, 2H), 3.90 (d, J = 9.6 Hz, 1H), 3.69 (s, 3H), 3.31 - 3.42 (m, 10H), 2.54 —

[0513] 2.56 (m, 2H), 2.02 (t, J = 7.2 Hz, 2H), 1.42 - 1.47 (m, 4H), 1.11 - 1.20 (m, 2H) Example 51. Synthesis of Linker - Payload 6

[0514] Step 1) To a solution of 4 - ethynylaniline (779 mg, 6.65 mmol) dissolved in THF (20 mL)

[0515] DIEA (1.72 g, 13.3 mmol, 2.32 mL) was added. Then, Triphosgene (494 mg, 1.66 mmol) was added to the mixture under N2 at 0°C. The mixture was stirred at 25°C for 1 hour. A solution of 9H-fluorene-9-ylmethyl N-[(IS)-1-[[(IS)-1-[[4-(hydroxymethyl)phenyl]carbamoyl]-4-ureido-butyl]carbamoyl]-2-methyl-propyl]carbamate (2.00 g, 3.32 mmol) dissolved in DMF (20 mL) was added dropwise at 25°C, and the mixture was stirred under N2 at 25°C for 1 hour. The completion of the reaction was confirmed by LC-MS. The reaction mixture was poured into water, and the resulting yellow precipitate was collected by filtration. The yellow solid was purified by prep-HPLC (Column: Phenomenex luna C18 250*50 mm*l (X«m; Mobile phase: [H2(〕(0.1% TFA)-ACN]; Gradient: 30%-70% B for 20.0 min) to obtain a white solid [4 - [[(2S)-2 - [[(2S)-2-(9H-fluorene-9-ylmethoxycarbonylamino)-3-methyl-butanoyl]amino]-5-ureido-pentanoyl]amino]phenyl]methyl N-(4-ethynylphenyl)carbamate (349 mg, yield 11.8%)).

[0516] LCMS: m / z = 745.1 (M+H) +Step 2) [4 - [[(2S)- 2 - [[(2S)- 2- (9H-fluorene- 9-ylmethoxycarbonylamino) -3-methyl-butanoyl ]amino] -5-ureido-pentanoyl]amino]phenyl]methyl N-(4-ethynylphenyl)carbamate (301 mg, 403 u mol), N- (imidazo[1,2-a]pyridine-7-ylmethyl)-3-iod-4-[(1-methylpyrazole-3-yl)methylsulfonyl]benzamide (180 mg, 336 u mol), Cui (6.40 mg, 33.6 u mol), Pd(PPh3)4(38.9 mg, 33.6 u mol), N- (imidazo[1,2- a]pyridine-7-ylmethyl)-3-iod-4-[(1-methylpyrazole-3-yl)methylsulfonyl]benzamide (180 mg, 336 μmol) and TEA (340 mg, 3.36 mmol, 468 μL) were added to DMF (5 mL), degassed, and purged three times. Then, the mixture was stirred at 40°C for 2 hours under an N2 atmosphere. The reaction was confirmed to be complete in LCMS. The reaction mixture was purified with prep-HPLC (column: F-Welch Xtimate C1840*200mm 71; mobile phase: [H2O(0.1%TFA)-ACN]; gradient: 0%-40%B for 20.0 min) to obtain 4-((S)-2-((S)-2-amino-3-methylbutanamido)-5-ureidopentanamido)benzyl(4-((5-((imidazo[1,2-a]pyridine-7-ylmethyl)carbamoyl)-2-(((1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)phenyl)ethynyl)phenyl)carbamate (57.2 mg, yield 17.5%, purity 95.7%) as a white solid.

[0517] LCMS: m / z = 930.2 (M+H) +Step 3) (4S)-5-tert-butoxy-4-(9H-fluoren-9-ylmethoxycarbonylamino)-5-oxo-pentanoic acid ((4S) — 5— t er t -butoxy-4 - ( 9H- f 1 uoren-9-y 1 methoxycar bony 1 amino) — 5— oxo— pentanoic acid, 350 mg, 823 u mo 1 ) # After dissolving in DMF (2 mL), HATU (375 mg, 987 u mo 1 ) ,

[0518] 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71-tetracosaoctatriheptacontan-73-amine (2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71-tetr acosaoxat ri hept acont an-73-amine ne , 895 mg, 823 u mol ) and DIEA (213 mg, 1.65 mmo 1 ,287 uL) were added. The mixture was stirred at 25°C for 1 hour. The completion of the reaction was confirmed by LCMS. The reaction mixture was purified using a reverse-phase column (Biotage: 40g Age la® C18 Flash Column; Mobile phase: [H2O-ACN]; Gradient: 10%-100% B for 20 min) to obtain tert-butyl(S)-78-(( ( (9H-fluorene-9-yl)methoxy)carbonyl)amino)-75-oxo-

[0519] 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71- Tetracosaoxa- 74 -azanona heptacontan- 79 -oate (tert- butyl (S)- 78- ((((9H- f luoren- 9-yl )methoxy)carbonyl )amino)— 75—oxo—

[0520] 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71-tetracosaoxa-74-azanonaheptacontan-79-oate, 869 mg, yield 53.2%) was obtained as a colorless oil.

[0521] LCMS: m / z = 1518.0 (M+Na) +Step 4) tert-butyl(S)-78-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-75-oxo-2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71-tetracosaoxa-74-azanohenthacontan-79-oate (tert-butyl(S)-78-((((9H-fluoren-9-yl )methoxy)carbonyl)amino)—75—oxo— 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71- tetracosaoxa— 74— azanonaheptacontan— 79— oate, 869 mg, 581 u mo 1 ) # After dissolving in CH2Cl2 (9 mL), HC1 / di oxane (2 M, 10 mL) was added. The mixture was stirred at 25°C for 8 hours. The completion of the reaction was confirmed by LCMS. The reaction mixture was concentrated and dried. The residue was purified by prep-HPLC (Column: F-Welch Xtimate C1840*200mm 71; Mobile phase: [H2O(0.05%HCl)-ACN]; Gradient: 20%-60% B for 20.0 min) to obtain (S)-78-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-75-oxo-2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71-tetracosaoxa-74-azanohanaheptacontan-79-oxan (560 mg, yield 65.3%, purity 97.5%) as a colorless oil. I got it.

[0522] LCMS: m / z = 1439.9 (M+H) +Step 5) 4-((S)-2-((S)-2-amino-3-methylbutanamido)-5-ureidopentanamido)benzyl(4-((5-((imidazo[1,2-a]pyridine-7-ylmethyl)carbamoyl)-2-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)phenyl)ethinyl)phenyl)carbamate (52.0 mg, 55.9 u mol) and (S)-78-(( ((9H-fluorene-9-yl)methoxy)carbonyl)amino)-75-oxo- 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71- Tetracosaoxa-74 -Azanonaheptacontan-79 -Osan (80.5mg, 55.9umol) dissolved in DMF (lmL), then HATU (42.5mg, 112umol) and DIEA (10.8mg, 83.9umol, 14.6 y L) was added. The mixture was stirred at 25°C for 1 hour. The completion of the reaction was confirmed by LCMS. The reaction mixture was used directly in the next step without further purification.

[0523] LCMS: m / z = 1176.2 (1 / 2M+H) +Step 6) Piperidine (47.4 mg, 557 u mol, 55.0 uL) was added to the reaction mixture from Step 5). The mixture was stirred at 25°C for 1 hour. The reaction was confirmed to be complete using LCMS. The reaction mixture was purified by prep-HPLC (Column: F-Welch Xtimate C1840*200mm 7 ☐ 1; Mobile phase: [H2O(0.1% TFA)-ACN]; Gradient: 4%-44% B for 20.0 min) to obtain 4-((78S,81S, 848)-78-amino-81-isopropyl-75,79,82-trioxo-84-(3-ureidopropyl)-2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71-tetracosaoxa-74,80,83-triazapentaoctacontan- 85 -Amido)Benzyl (4-((5-

[0524] ( (imidazo[ 1 , 2- a]pyridine-7-ylmethyl )carbamoyl )-2-( ( (1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)phenyl)ethinyl)phenyl)carbamate (80.0 mg, yield 66.3%)) was obtained as a colorless gum.

[0525] LCMS: m / z = 1065.2 (1 / 2M+H) + Step 7) 4- ((78S,81S,84S)- 78-amino- 81-isopropyl- 75,79,82-trioxo-84-(3-ureidopropyl)- 2,5,8,ll,14,^7,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71- tetracosaoxa- 74 , 80 , 83-triazapentaoctacontan- 85-amido)benzyl (4-((5-

[0526] ((Imidazo[1,2-a]pyridin-7-ylmethyl)carbamoyl)-2-((((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)phenyl)ethynyl)phenyl)carbamate (75.0 mg, 35.2 μmol) was dissolved in DMF (2 mL), and then DIEA (9.10 mg, 70.4 μmol, 12.3 μL) and (2,5-dioxopyrrolidin-1-yl) 3-(2,5-dioxopyrrol-1-yl)propanoate (10.3 mg, 38.7 μmol) were added. The mixture was stirred at 25 °C for 1 hour. It was confirmed by LC-MS that the reaction was complete. The reaction mixture was purified by prep-HPLC (column: F-Welch Xtimate C18 40*200mm 7μm; mobile phase: [H20(0.1%TFA)-

[0527] ACN]; gradient: 0%-40% B for 20.0 minutes) to obtain linker-payload 6 (57.0 mg, yield 70.4%, purity 99.3%, colorless gum).

[0528] LCMS: m / z = 1141.1 (1 / 2M+H) +

[0529] HRMS: m / z = 2280.1 (M+H) + 1H NMR (400 MHz, DMSO-d6) δ 10.08 (d, J = 13.6 Hz, 2H), 9.62 (t, J = 6.0 Hz, 1H), 8.85 (d, J = 7.2 Hz, 1H), 8.31 (t, J = 2.4 Hz, 2H), 8.13 - 8.21 (m, 3H), 7.98 - 8.03 (m, 1H), 7.92 - 7.96 (m, 1H), 7.81 - 7.88 (m, 2H), 7.75 (d, J = 8.4 Hz, 1H), 7.59 - 7.64 (m, 7H), 7.47 - 7.52 (m, 1H), 7.37 (d, J = 8.8 Hz, 2H), 6.99 (s, 2H), 6.10

[0530] (d, J = 2.0 Hz, 1H), 5.93-6.02 (m, 1H) , 5.42 (br s, 1H) , 5.11 (s, 2H) , 4.89 (s, 2H), 4.71 (d, J = 5.6 Hz, 2H) , 4.34-4.43 (m, 1H) , 4.15-4.26 (m, 2H) , 3.70 (s, 3H) , 3.64-3.69 (m, 1H) , 3.59 (t, J = 7.6 Hz, 2H) , 3.50 (s, 94H) , 3.23 (s, 3H) , 3.16- 3.20 (m, 2H), 2.93-3.04 (m, 2H), 2.38-2.42 (m, 2H), 2.05-2.14 (m, 2H), 1.94-2.00 (m, 1H), 1.80-1.88 (m, 1H), 1.64-1.73 (m, 2H), 1.54-1.62 (m, 1H), 1.34-1.47 (m, 2H), 0.84 (dd, J = 12.8, 6.8 Hz, 6H) Example 52. Synthesis of Linker-Payload 7

[0531] Step 1) 4-ethynylaniline (476 mg, 4.07 mmol) was added to THF (15 mL) and DIEM (1.46 g, 11.3 mmol, 1.97 mL) was added. Then, triphosgene (402 mg, 1.36 mmol) was added to the mixture under N2 at 0°C. The mixture was stirred at 0°C for 10 minutes. (9H-fluorene-9-yl)methyl(S)-(2-((2-((1-((2-((4-(hydroxymethyl)phenyl)amino)-2-oxoethyl)amino)-1-oxo-3-phenylpropane-2-yl)amino)-2-oxoethyl)amino)-2-oxoethyl)carbamate (1.50 g, 2.26 mmol) was dissolved in anhydrous DMF (15 mL) and then added dropwise to the above mixture. The reaction mixture was stirred at 25°C for 2 hours. The completion of the reaction was confirmed by LCMS. The reaction mixture was purified by prep-HPLC (Column: Phenomenex luna C18 250*50 mm*l (X«m; Mobile phase: [H2(](0.1% TFA)-ACN]; Gradient: 30%-80% B for 20.0 min) to obtain (S)-4-(11-benzyl-1-(9H-fluorene-9-yl)-3,6,9,12-tetraoxo-2-oxa-4,7,10,13-tetraazapentadecane-15-amido)benzyl(4-ethynylphenyl)carbamate (630 mg, yield 33.2%) as a yellow solid.

[0532] LCMS: m / z = 828.9 (M+Na) +Step 2) N-(imidazo[1,2-a]pyridine-7-ylmethyl)-3-iod-4-(((1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)benzamide (100 mg, 149 u mol), (S)-4-(11-benzyl-1-(9H-fluorene-9-yl)-3,6,9,12-tetraoxo-2-oxa-4,7,10,13-tetraazapentadecane-15-amido)benzyl(4-ethinylphenyl)carbamate (181 mg, 224 u mol), Cul (114 mg, 598 u mol), DIEA (38.6 mg, 299 u mol, 52.111 L) and Pd(PPh3)4 (121 mg, 105 u mol) was dissolved in DMF (10 mL), degassed, and purged three times. The mixture was stirred at 40°C for 1 hour under an N2 atmosphere. The completion of the reaction was confirmed by LCMS. The reaction mixture was used directly in the next step without further purification.

[0533] LCMS: m / z = 1213.8 (M+H) + Step 3) (S)-4-(11-benzyl-1-(9H-fluorene-9-yl)-3,6,9,12-tetraoxo-2-oxa-

[0534] 4, 7, 10, 13-tetrazapentadecan-15-amido)benzyl (4-((5-((imidazo [ 1 , 2-a]pyridin-7-ylmethyl)carbamoyl)-2-( ( (1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)phenyl)ethinyl)phenyl)carbamate (181 mg, 149 μmol) was dissolved in DMF (10 mL), and then DBU (22.7 mg, 149 μmol, 22.5 μL) was added. The mixture was stirred at 25°C for 1 hour. The completion of the reaction was confirmed by LCMS. The reaction mixture was purified with prep-HPLC (Column: F-Welch Xtimate C18 40*200mm 7 1; Mobile phase: [H2(0.1% TFA)-ACN]; Gradient: 0%-38% B for 20.0 min) to obtain (S)-4-(2-(2-(2-(2-aminoacetamido)acetamido)-3-phenylpropaneamido)acetamido)benzyl(4-((5-((imidazo[1,2-a]pyridine-7-ylmethyl)carbamoyl)-2-(((1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)phenyl)ethinyl)phenyl)carbamate (73.1 mg, yield 49.1%) as a yellow solid.

[0535] LCMS: m / z = 992.4 (M+H) + Step 4) (S)- 4- (2- (2- (2- (2-amino-arthr]thamido)arthr]thamido)- 3 _ Phenylpropaneamide)acetamide)benzyl (4-( (5-( (imidazo[1,2-a]pyridin-7-ylmethyl)carbamoyl)-2-( ( (1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)phenyl)ethinyl)phenyl)carbamate (73 mg, 73.6 u mol) and 2,5-dioxopyrrolidine-1-yl 1-(2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl)-3-oxo-

[0536] 7,10,13,16,19,22,25,28,31,34,37,40-dodecaoxa-4-azatritetracontan-43-oate (70.1 mg, 80.9 μmol) was dissolved in DMF (2 mL), and then DIEA (19.0 mg, 147 μmol, 25.6 μL) was added. The mixture was stirred at 25°C for 1 hour. The completion of the reaction was confirmed by LCMS. The reaction mixture was purified by prep-HPLC (Column: F-Welch Xtimate C1840*200 mm 7 ☐ 1; Mobile phase: [H2O(0.1% TFA)-ACN]; Gradient: 6%-46% B for 20.0 min) to obtain Linker-Payload 7 (55.03 mg, Yield 42.91%, Purity 100%, White Solid). LCMS: m / z = 1743.1 (M+H) +1H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 9.88 (s, 1H), 9.60 (t, J = 5.6 Hz, 1H), 8.84 (d, J = 7.2 Hz, 1H), 8.35 - 8.40 (m, 1H), 8.29 (d, J = 2.0 Hz, 2H), 8.12 - 8.18 (m, 2H), 8.10 (d, J = 1.8 Hz, 1H), 7.96 - 8.04 (m, 3H), 7.91 - 7.95 (m, 1H), 7.80 (s, 1H), 7.57 - 7.68 (m, 7H), 7.47 (d, J = 7.2 Hz, 1H), 7.39 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 4.4 Hz, 4H), 7.17 - 7.22 (m, 1H), 6.99 (s, 2H), 6.09 (d, J = 2.0 Hz, 1H), 5.12 (s, 2H), 4.88 (s, 2H), 4.70 (d, J = 5.0 Hz, 2H), 4.46 - 4.54 (m, 1H), 3.85 - 3.95 (m, 2H), 3.74 - 3.84 (m, 2H), 3.67 - 3.71 (m, 5H), 3.56 - 3.62 (m, 6H), 3.46 - 3.51 (m, 44H), 3.14 (q, J = 5.6 Hz, 2H), 3.04 - 3.10 (m, 1H), 2.80 - 2.86 (m, 1H), 2.38 (t, J = 6.4 Hz, 2H), 2.32 (t, J = 7.2 Hz, 2H) Example 53. Synthesis of Linker-Payload 8

[0537] Step 1) Synthesis of [4 - [[(2S)-2 - [[(2S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-methyl-butanoyl]amino]-5-ureido-pentanoyl]amino]phenyl]methyl N-(4-ethynyl-2-fluorophenyl)carbamate

[0538] DIEA (8.47 g, 65.54 mmol, 11.45 mL) was added to a solution of 4-ethynyl-2-fluoroaniline (3.19 g, 23.59 mmol) dissolved in THF (120 mL). Then, triphosgene (2.32 g, 7.87 mmol) was added to the mixture under N2 at 0°C. The mixture was stirred at 25°C for 1 hour. A solution of 9H-fluorene-9-ylmethyl N-[(IS)-1-[[(IS)-1-[[4-(hydroxymethyl)phenyl]carbamoyl]-4-ureido-butyl]carbamoyl]-2-methyl-propyl]carbamate (8.70 g, 13.11 mmol) dissolved in DMF (50 mL) was added dropwise at 25°C, and the mixture was stirred under N2 at 25°C for 1 hour. The completion of the reaction was confirmed by LC-MS. The reaction mixture was poured into water, and the resulting yellow precipitate was collected by filtration. The yellow solid was purified with a reverse-phase column (C18 Flash Column; mobile phase: [H2O(0.1%FA)-ACN]; gradient: 30%-70% B for 20 min) to obtain a white solid [4-[ [ (28)-2 -[[ (2S)-2-(9H-fluorene-9-ylmethoxycarbonylamino)-3-methyl-butanoyl]amino]-5-ureido-pentanoyl]amino]phenyl]methyl N-(4-ethynyl-2-fluoropenyl)carbamate (8.60 g, yield 79.5%).

[0539] LCMS: m / z = 825.5 (M+H) + Step 2) (S)- 4- (11-benzyl- 1-(9H-fluorene- 9-yl)- 3, 6, 9, 12-tetraoxo- 2-oxa-

[0540] Synthesis of 4,7,10,13-tetraazapentadecan-15-amido)benzyl (2-fluoro-4-((5-((imidazo[1,2-a]pyridin-7-ylmethyl)carbamoyl)-2-((1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)phenyl)ethinyl)phenyl)carbamate

[0541] [4 - [[(2S)- 2 - [[(2S)- 2- (9H-fluorene- 9-ylmethoxycarbonylamino) -3-methyl-butanoyl ]amino] -5-ureido-pentanoyl ]amino]phenyl] methyl N- (4-ethinyl- 2-fluoropenyl )carbamate (800mg, 0.97mmol) , N- (imidazo[ 1 ,2- a]pyridine- 7-ylmethyl )- 3-iod- 4- [(1-methylpyrazole- 3-yl)methylsulfonyl]benzamide (519mg, 0.97mmol), Cul(73.88mg, 0.39mmol ) , Pd(PPhs)4(336.22mg, DIEA (626.77 mg, 4.85 mmol) was added to DMF (5 mL) for degassing and purged three times. The mixture was then stirred at 40°C for 2 hours under an N2 atmosphere. The reaction was confirmed to be complete in LCMS. The reaction mixture was used directly in the next step without further purification.

[0542] LCMS: m / z = 1232.9 (M+H) +Step 3) Synthesis of (S)-4-(2-(2-(2-(2-amino-arthr]thamido)acetamido)3-phenylpropaneamido)acetamido)benzyl (2-fluoro-4-((5-((imidazo[1,2-a]pyridine-7-ylmethyl)carbamoyl)-2-((1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)phenyl)ethynyl)phenyl)carbamate)2-fluoro-4-(5-(imidazo[1,2-a]pyridine-7-ylmethyl)carbamoyl)2-(1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)phenyl)ethynyl)phenyl)carbamate)2-2-fluoro-4-(2-2-2-2-(1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)phenyl)ethynyl)phenyl)carbamate)2-2-2-7-2 [H2O(0.1%FA)-ACN]; purified with a gradient of 20%-30% B for 20 minutes to obtain (S)-4-(2-(2-(2-(2-aminoacetamido)acetamido)-3-phenylpropaneamido)acetamido)benzyl(2-fluoro-4-((5-((imidazo[1,2-a]pyridine-7-ylmethyl)carbamoyl)-2-((1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)phenyl)ethinyl)phenyl)carbamate (326 mg, yield 33.1%) as a colorless gum.

[0543] LCMS: m / z = 1010.6 (M+H) + Step 4) Synthesis of tert-butyl(S)-78-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-75-oxo-2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71-tetracosoxa-74-azano-heptacontan-79-oate

[0544] (4S)-5-tert-butoxy-4-(9H-fluorene-9-ylmethoxycarbonylamino)-5-oxo-pentanoic acid (2.50 g, 5.88 mmol) was dissolved in DMF (50 mL), and then HATU (3.35 g, 8.81 mmol),

[0545] 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71-tetracosaoctatriheptacontan-73-amine (7.67 g, 7.05 mmol) and DIEA (1.52 g, 11.75 mmol, 2.05 mL) were added. The mixture was stirred at 25°C for 1 hour. The reaction was confirmed to be complete using LCMS. The reaction mixture was concentrated under reduced pressure to obtain the residue, which was purified using a column (silica gel; mobile phase: [MC-MeOH] : gradient: 0%-10% B for 20 min) to obtain terto-butyl(S)-78-( ( ( (9H-fluorene-9-yl)methoxy)carbonyl)amino)-75-oxo-

[0546] 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71- Tetracosaoxa-74-azanoana heptacontan-79-oate, 8.78g (yield 99.9%) was obtained as a colorless oil.

[0547] LCMS: m / z = 1496.3 (M+H) + Step 5) (S)-78-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-75-oxo-

[0548] 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71- Tetracosaoxa-74 -azano-heptacontan-79 -synthesis of acids tert-butyl(S)-78- ( ( ( (9H-fluorene-9-yl)methoxy)carbonyl)amino)-75 -oxo-

[0549] 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71-tetracosaoxa-74-azano-heptacontan-79-oate (8.78 g, 5.87 mmol) was dissolved in dichloromethane (10 mL), and then formic acid (20 mL) was added. The mixture was stirred at 25°C for 16 hours. The completion of the reaction was confirmed by LCMS. The reaction mixture was concentrated and dried. The reaction mixture was purified using a reversed-phase column (C18 Flash Column; mobile phase: [H2O-ACN] : gradient: 10%-100% B for 20 min) to (S)-78-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-75-oxo-

[0550] 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71- Tetracosaoxa-74-azanoana heptacontan-79-acid (6.48g, yield 76.6%) was obtained as a colorless oil.

[0551] LCMS: m / z = 1439.9 (M+H) + Step 6) 4- ((78S,87S)- 78- ((((9H-fluorene- 9-yl)methoxy)carbonyl)amino) -87-benzyl- 75 , 79 , 82 , 85 , 88-pentaoxo-

[0552] 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71- Tetracosaoxa- 74 ,80,83,86, 89 -pentazahennonacontan- 91-amido) benzyl (2 -fluoro- 4-

[0553] Synthesis of ( (5-( (imidazo[ 1 , 2-a]pyridine-7-ylmethyl)carbamoyl )-2- ( (1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)phenyl)ethynyl)phenyl)carbamate)

[0554] ( S ) ~4 - (2~(2~(2~( Z -0} 13 ]paddle 0}sert] 0} 1 do) 0}sert] 0} 1 D) —3— Phenylpropaneami D)Acetami D)Benzyl (2-fluoro-4-( (5-( (imidazo[1,2-a]pyridine-7-ylmethyl)carbamoyl)-2-( (1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)phenyl)ethinyl)phenyl)carbamate (326 mg, 323 u mol) and (S)-78-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-75-oxo-

[0555] 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71- Tetracosaoxa-74 -Azanonaheptacontan-79 -Acid (464.66 mg, 323 μmol) was dissolved in DMF (5 mL), then HATU (184.13 mg, 484 μmol) and DIEA (208.58 mg, 281 uL) was added. The mixture was stirred at 25°C for 6 hours. The completion of the reaction was confirmed by LCMS. The reaction mixture was used directly in the next step without further purification.

[0556] LCMS: m / z = 1216.6 (1 / 2 M+H / Step 7) 4-( (78S , 87S)- 78-amino- 87-benzyl- 75 ,79 ,82 ,85 , 88-pentaoxo- 2,5 ,8 ,11 ,14 ,17 ,20 ,23 ,26 ,29 ,32 ,35 ,38 ,41 ,44 ,47 ,50 ,53 ,56 ,59 ,62 ,65 ,68 ,71- tetracosaoxa- 74 ,80 ,83 ,86 , 89-pentazahennonacontan- 91-amido) benzyl (2-fluoro- 4-

[0557] Piperidine (83.5 mg, 980 µ mol, 97.0 µL) was added to the reaction mixture of step 6) of the synthesis of (5-( (imidazo[1, 2-a]pyridine-7-ylmethyl)carbamoyl)-2-( (1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)phenyl)ethinyl)phenyl)carbamate). The mixture was stirred at 25°C for 1 hour. The reaction was confirmed to be complete using LCMS. The reaction mixture was purified by reverse-phase column (C18 Flash Column; mobile phase: [H2O(0.1%FA)-ACN]; gradient: 20%-40% B for 20 min) to obtain 4-((78S,87S)-78-amino-87-benzyl-75,79,82,85,88-pentaoxo-2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71-tetracosaoxa-74,80,83,86,89-pentazahennonacontan-91-amido)benzyl (2 -fluoro-4-

[0558] ( ( 5- ( (imidazo [ 1 , 2- a ]pyridine-7-ylmethyl)carbamoyl)-2- (( 1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)phenyl)ethinyl)phenyl)carbamate (146 mg, yield 20.1%) was obtained as a colorless gum.

[0559] LCMS: m / z = 1105.5 (1 / 2M+H) +Step 8) 4- ((78S,87S)- 87 -benzyl- 78- (3- (2,5-dioxo-2,5-dihydro-lH-pyrrole-l-yl )propaneamide)- 75 ,79 ,82 ,85 ,88 -pentaoxo-

[0560] Synthesis of 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71- Tetracosaoxa-74,80,83,86,89-pentazahennocontan-91-amido)benzyl (2-fluoro-4-( (5-(imidazo[1,2-a]pyridine-7-ylmethyl)carbamoyl )-2-( ( ( 1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)phenyl)ethinyl)phenyl)carbamate

[0561] 4-( (78S , 87S)- 78 -amino- 87 -benzyl- 75 ,79 ,82 ,85 , 88 -pentaoxo-

[0562] 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71- Tetracosaoxa- 74 ,80,83,86, 89 -pentazahennonacontan- 91-amido) benzyl (2 -fluoro- 4-

[0563] ( ( 5- ( (imidazo[ 1 , 2- a ]pyridin-7-ylmethyl)carbamoyl)-2-(( 1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)phenyl)ethinyl)phenyl)carbamate (146 mg, 66 μmol) and 2,5-dioxopyrrolidine-1-yl 3-(2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl)propanoate (34.9 mg, 131 μmol) were dissolved in DMF (2 mL) solution, and then DIEA (42.4 mg, 328 U(mol) was added, and the mixture was stirred at 25°C for 1 hour. The completion of the reaction was confirmed by LC-MS. The reaction mixture was purified by prep-HPLC (Column: XBridge®BEH C18 10*250mm 5; Mobile phase: [H2O(0.1%TFA)-ACN]; Gradient: 50%-70% B, for 20.0 min) to 4-((78S, 87S)-87-benzyl-78-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl)propaneamido)-75, 79, 82, 85, 88-pentaoxo-2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71-te Tracosaoxa-74,80,83,86,89-pentazahennocontan-91-amido)benzyl (2-fluoro-4-(5-((imidazo[1,2-a]pyridin-7-ylmethyl)carbamoyl)-2-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)phenyl)ethinyl)phenyl)carbamate (61.7 mg, yield 39.8%, purity 99.0%) was freeze-dried to obtain a white solid.

[0564] LCMS: m / z = 1181.1 (1 / 2M+H) +1H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 9.75 (s, 1H), 9.43 (t, J = 5.9 Hz, 1H), 8.52 (d, J = 7.0 Hz, 1H), 8.37 (t, J = 5.7 Hz, 1H), 8.25 (d, J = 1.6 Hz, 1H), 8.18 - 8.05 (m, 3H), 7.98 (dt, J = 5.4, 2.7 Hz, 2H), 7.93 (s, 1H), 7.86 (dd, J = 18.0, 8.4 Hz, 2H), 7.78 (t, J = 5.5 Hz, 1H), 7.63 - 7.51 (m, 5H), 7.47 (s, 1H), 7.44 (d, J = 9.4 Hz, 1H), 7.33 (d, J = 8.6 Hz, 2H), 7.18 (t, J = 6.5 Hz, 4H), 7.11

[0565] (dt, J = 8.6, 4.3 Hz, 1H), 6.95 (d, J = 6.8 Hz, 1H), 6.91 (s, 2H), 6.48 (s, 1H), 6.04 (d, J = 2.2 Hz, 1H), 5.06 (s, 2H), 4.80 (s, 2H), 4.51 (d, J = 5.6 Hz, 2H),

[0566] 4.49 - 4.41 (m, 1H), 4.10 (dd, J = 13.8, 7.8 Hz, 1H), 3.90 - 3.75 (m, 2H), 3.69 -

[0567] 3.59 (m, 6H), 3.55 - 3.50 (m, 2H), 3.43 (s, 90H), 3.35 (dd, J = 5.9, 3.5 Hz, 2H),

[0568] 3.31 (t, J = 6.0 Hz, 2H), 3.17 (s, 3H), 3.10 (q, J = 5.7 Hz, 2H), 3.00 (dd, J =

[0569] 13.5, 4.5 Hz, 1H), 2.75 (dd, J = 13.7, 9.7 Hz, 1H), 2.33 (t, J = 7.4 Hz, 2H), 2.02

[0570] (t, J = 7.9 Hz, 2H), 1.80 (dd, J = 14.0, 6.2 Hz, 1H), 1.71 - 1.55 (m, 1H). Example 54: Synthesis of linker-payload 9

[0571] Step 1) DI PEA (12.45 ml, 71.5 mmol) was added to a solution of 2-chloro-4-ethynylaniline (3.89 g, 25.7 mmol) dissolved in THF (100 ml). Triphosgene (2.55 g, 9 mmol) was added dropwise to the mixture at 0 °C. The mixture was stirred at 0 °C for 10 minutes. (9H-fluoren-9-yl)methyl (S)- (2- ((2- ((1-((2- ((4- (hydroxymethyl)phenyl)amino)-2-oxoethyl)amino)-1-oxo-3-phenylpropane-2-yl)amino)-2-oxoethyl)amino)-2-oxoethyl)carbamate, 9.5 g, A solution of 14.3 mmol) dissolved in DMF (100 ml) was added dropwise to the mixture. The mixture was stirred at room temperature for 2 hours. The completion of the reaction was confirmed by LC-MS. After concentrating the reaction mixture under reduced pressure, reverse-phase column chromatography (0.Purified with 1% formic acid in H2O / ACN to form (9H-fluoren-9-yl)methyl(S)-(2-((2-((1-((2-((4-((((2-chloro-4-ethynylphenyl)carbamoyl)oxy)methyl)phenyl)amino)-2-oxoethyl)amino)-1-oxo-3-phenylpropane-2-yl)amino)-2-oxoethyl)amino)-2-oxoethyl)carbamate ((9H-fluoren-9-yl )methyl(S)-(2-((2-((l-((2-((4-((((2-chloro-4-ethynylphenyl )carbamoyl )oxy)methyl )phenyl )amino)—2—oxoethyl )amino)—l—oxo—3—pheny 1 propan-2-y 1 )amino) -2-oxoethy 1 )amino) -2-oxoethy 1 )carbamat e, 2.93 g) was obtained.

[0572] LCMS: m / z = 841.5(M+H) + Step 2) (9H-fluorene-9-yl)methyl(S)-(2-((2-((1-((2-((4-((((2-chloro-4-ethynylphenyl)carbamoyl)oxy)methyl)phenyl)amino)-2-oxoethyl)amino)-1-oxo-3-phenylpropane-2-yl)amino)-2-oxoethyl)amino)-2-oxoethyl)carbamate ((9H-fluorene-9-yl )methyl(S)-(2-((2-((l-((2-((4-((((2-chloro-4-ethynylphenyl )carbamoyl )oxy)methyl )phenyl)amino)—2—oxoethyl)amino)—l—oxo—3— N-(imidazo[1,2-a]pyridin-7-ylmethyl)-3-iodo-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)benzamide (N-(imidazotl, 2-a]pyridin-7-ylmethyl )-3-iodo-4-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl )benzamide, 500 mg, 0.934 mmol), Cu (71 mg, 0.374 mmol), DI PEA (0.8 ml, After adding 4.670 mmol), Pd(PPh3)4 (323.8 mg, 0.28 mmol), the mixture was degassed three times with nitrogen gas. The mixture was stirred at 40 °C for 12 hours. The completion of the reaction was confirmed by LC-MS. The reaction mixture was used for the next reaction without purification.

[0573] LCMS: m / z = 1249.8(M+H) + Step 3) (9H-fluoren-9-yl)methyl(S)- (2-((2-((1-((2-((4-((((2-chloro-4-((5-((imidazo[1,2-a]pyridine-7-ylmethyl)carbamoyl)-2-(((1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)phenyl)ethinyl)phenyl)carbamoyl)oxy)methyl)phenyl)amino)-2-oxoethyl)amino)-1-oxo-3-phenylpropane-2-yl)amino)-2-oxoethyl)amino)-2-oxoethyl)carbamate ((9H-fluoren-9-yl)methyl Piperidine (0.3 ml, 2.80 mmol) was added to a solution of (S)-(2-((2-((l-((2-((4-((((2- chloro— 4—(5— ( (imidazo[ 1,2— a] pyr idin— 7— ylmethyl 1) carbamoyl )—2— (((1— methyl— 1H— pyr azo 1-3- yl )methyl)sulfonyl ) phenyl )ethynyl )phenyl )carbamoyl )oxy)methyl )phenyl)amino)—2— oxoethyl )amino)— 1—oxo— 3— phenylpropan— 2— yl )amino)— 2— oxoethyl )amino)— 2— oxoethyl )carbamate, 1.166 g, 0.934 mmol) dissolved in DMF (5 ml). The mixture was stirred at 25 °C for 1 hour. The completion of the reaction was confirmed by LC-MS. After concentrating the reaction mixture under reduced pressure, reverse-phase column chromatography (0.Purified with 1% formic acid in H2O / ACN) and (S)-4-(2-(2-(2-(2-aminoacetamido)acetamido)-3-phenylpropaneamido)acetamido)benzyl (2-chloro-4-((5-((imidazo[1,2-a]pyridin-7-ylmethyl)carbamoyl)-2-(((1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)phenyl)ethynyl)phenyl)carbamate (262 mg, 27% yield (2 steps)) ((S)-4-(2—(2—(2—(2—aminoacetam ido)acetamido)-3-phenylpropaneamido)acetamido)benzy 1 ( 2- chloro— 4—((5— ( (imidazo[ 1,2— a] pyridin— 7— ylmethy 1) carbamoyl )—2— (((1— methyl— 1H— pyrazol-3-yl )methyl )sul fonyl )phenyl )ethynyl )phenyl )carbamate , 262 mg, 27% yield (2 steps)) got it

[0574] LCMS: m / z = 1026.7(M+H) + step 4) (S)- 4- (2- (2- (2- (2-amino ethyl]thamido)ethyl]thamido)- 3 _Phenylpropaneamide)acetamid)benzyl (2-chloro-4-( (5-( (imidazo[1,2-a]pyridin-7-ylmethyl)carbamoyl)-2-( ( (1-methyl-1H-pyrazole-3-yl)methyl)sulfonyl)phenyl)ethynyl)phenyl)carbamate ((S)-4-(2-(2-(2-(2-aminoacetam ido )acetam ido )-3-pheny1propanam ido )acetam ido )benzy1 (2-chl oro-4-((5-((imidazo[l,2-a]pyridin-7-ylmethyl)carbamoyl )-2-( ((1-methyl-lH-pyr azo 1-3-yl )methyl (S)-78-((((9H-fluoren-9-yl)methoxy)carbonyl )amino)-75-oxo-2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71-tetracosaoxa-74-azanohanaheptacontan-79-oxo-((S)-78-(( ( (9H-fluoren-9-yl )methoxy)carbonyl )amino)— 75—oxo—

[0575] 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71- tetracosaoxa— 74— azanonaheptacontan— 79— oic acid, 367 mg, 0.255 mmo 1 ) , HATU (194 mg,

[0576] 510 mmol), DI PEA (0.07 ml, 0.383 mmol) were added. The mixture was stirred at 25 °C for 1 hour. The completion of the reaction was confirmed by LC-MS. The reaction mixture was concentrated under reduced pressure and purified by reverse-phase column chromatography (0.1% formic acid in H2O / ACN) to obtain 4-((78S,87S)-78-(( ( (9H-fluorene-9-yl)methoxy )carbonyl)amino)-87-benzyl-75,79,82,85,88-pentaoxo-

[0577] 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71- Tetracosaoxa-74,80,83,86,89-pentazahennonacontan-91-amido)benzyl (2-chloro-4-((5-((imidazo[1,2-a]pyridine-7-ylmethyl)carbamoyl)-2-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)phenyl)ethynyl)phenyl)carbamate (4-(((78S,87S)-78-((((9H-fluoren-9-yl )methoxy) car bony 1 ) ami no ) -87-benzy 1 -75 ,79,82,85, 88-pentaoxo-

[0578] 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71- tetracosaoxa-74,80,83,86, 89— pentaazahennonacontan— 91— amido)benzy 1 (2—chloro—4—

[0579] ((5— ((imidazo[l,2—a]pyridin— 7— y Imethyl) carbamoyl )—2— (((1— methyl— IH—pyrazol— 3— yl )methyl )sul fonyl )phenyl )ethynyl )phenyl )carbamate, 136 mg, 22% yield) was obtained.

[0580] LCMS: m / z = 1225.0 (1 / 2 M+H) + Step 5) 4- ((78S,87S)- 78- ((((9H-fluorene- 9-yl)methoxy)carbonyl)amino) -87-benzyl- 75 , 79 , 82 , 85 , 88-pentaoxo-

[0581] 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71- Tetracosaoxa-74,80,83,86,89-pentazahennonacontan-91-amido)benzyl (2-chloro-4-((5-((imidazo[1,2-a]pyridine-7-ylmethyl)carbamoyl)-2-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)phenyl)ethynyl)phenyl)carbamate (4-(((78S,87S)-78-((((9H-fluoren-9-yl )methoxy) car bony 1 ) ami no ) -87-benzy 1 -75,79,82,85, 88-pentaoxo- 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71- tetracosaoxa-74,80,83,86, 89— pentaazahennonacontan— 91— amido)benzy 1 (2—chloro—4—

[0582] Piperidine (0.02 ml, 0.166 mmol) was added to a solution of ((5— ((imidazo[l,2—a]pyridin— 7— y Imethyl) carbamoyl )—2— (((1— methyl— IH—pyrazol— 3— yl )methyl )sulfonyl )phenyl )ethynyl )phenyl )carbamate, 136 mg, 0.0556 mmol) dissolved in DMF (1 ml). The mixture was stirred at 25°C for 1 hour. The completion of the reaction was confirmed by LC-MS. After concentrating the reaction mixture under reduced pressure, it was purified by reverse-phase column chromatography (0.1% formic acid in H2O / ACN) to obtain 4-((78S, 87S)-78-amino-87-benzyl-75,79,82,85,88-pentaoxo-

[0583] 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71- Tetracosaoxa-74,80,83,86,89-pentazahennonacontan-91-amido)benzyl (2-chloro-4-((5-((imidazo[1,2-a]pyridine-7-ylmethyl)carbamoyl)-2-(((1-methyl-1H-pyrazol-3-yl)methyl)sulfonyl)phenyl)ethynyl)phenyl)carbamate (4-((78S,87S)-78-amino-87-benzyl-

[0584] 75,79,82,85, 88-pentaoxo-

[0585] 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71- tetracosaoxa-74,80,83,86, 89— pentaazahennonacontan— 91— ami do)benzyl (2—chloro—4—

[0586] ((5-((imidazo[l,2-a]pyr i di n-7-y Imethyl) carbamoyl )-2-( ((1-methyl-lH-pyr azo 1-3- yl )methyl )sul fonyl )phenyl )ethynyl )phenyl )carbamate, 73 mg, 59% yield) was obtained.

[0587] LCMS: m / z = 1114.0(1 / 2 M+H) + Step 6) 4- ((78S,87S)- 78 -amino- 87 -benzyl- 75, 79, 82, 85, 88 -pentaoxo-

[0588] 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71- Tetracosaoxa- 74 ,80,83,86, 89 -Pentazahennonacontan- 91-Amido)benzyl (2 -Chloro- 4-((5-

[0589] ( (imidazo[ 1 , 2- a]pyridine- 7-ylmethyl )carbamoyl )- 2-( ( (1-methyl- 1H-pyrazole- 3-yl )methyl )sulfonyl )phenyl )ethynyl )phenyl )carbamate (4-(( 78S , 87S ) -78-am i no-87-benzyl -

[0590] 75,79,82,85, 88-pentaoxo-

[0591] 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71- tetracosaoxa-74,80,83,86, 89— pentaazahennonacontan— 91— amido)benzy 1 (2—chloro—4—

[0592] ((5— ((imidazo[l,2—a]pyridin— 7— y Imethyl) carbamoyl )—2— (((1— methyl— IH—pyrazol— 3— yl )methyl )sulfonyl )phenyl )ethynyl )phenyl )carbamate , 20 mg, 0.009 mmol) dissolved in DMF (1 ml) was added to a solution of 2,5-dioxopyrrolidine- 1-yl 3-(2,5-dioxo- 2,5-dihydro- 1H-pyrrole- 1-yl )propanoate ( 2,5-dioxopyrrol idi nl-yl 3-(2,5-di oxo-2,5-d ihydro-lH-pyrrole 1-1-yl )propanoate, 3 mg, 0.011 mmol 1), DI PEA (0.005 ml, 0.027 mmol) was added. The mixture was stirred at 25 °C for 1 hour. The completion of the reaction was confirmed by LC-MS. The reaction mixture was purified by reverse-phase column chromatography (0.1% formic acid in H2O / ACN) to obtain linker-payload 9 (8 mg, 38% yield).

[0593] LCMS: m / z = 1189.6(1 / 2 M+H) + P NMR (400 MHz, DMSO—06) 5 9.92 (s, 1H) , 9.46 (t, J = 5.8 Hz, 1H) , 9.43 (s, 1H), 8.52 (d, J = 7.1 Hz, 1H) , 8.46 - 8.40 (m, 1H), 8.32 (d, J = 1.6 Hz, 1H),

[0594] 8.24 - 8.13 (m, 3H) , 8.08 - 8.00 (m, 2H) , 7.95 (d, J = 8.2 Hz, 1H) , 7.92 (s, 1H),

[0595] 7.87 - 7.81 (m, 3H) , 7.66 - 7.60 (m, 4H) , 7.55 (s, 1H) , 7.46 (s, 1H) , 7.40 (d, J = 8.6 Hz, 2H), 7.26 (d, J = 4.3 Hz, 4H) , 7.18 (dd, J = 8.5, 4.1 Hz, 1H) , 6.98 (s,

[0596] 2H), 6.90 (d, J = 5.6 Hz, 1H), 6.11 (d, J = 2.2 Hz, 1H), 5.13 (s, 2H), 4.87 (s,

[0597] 2H), 4.58 - 4.49 (m, 3H) , 4.21 - 4.11 (m, 1H) , 3.93 - 3.86 (m, 2H) , 3.77 - 3.65 (m, 7H), 3.63 - 3.56 (m, 3H) , 3.50 (s, 96H) , 3.44 - 3.36 (m, 6H) , 3.23 (s, 3H) , 3.20 - 3.13 (m, 2H) , 3.10 - 3.02 (m, 1H) , 2.87 - 2.76 (m, 1H) , 2.40 (t, J = 7.3 Hz, 2H), 2.09 (t, J = 7.9 Hz, 2H) , 1.94 - 1.81 (m, 1H) , 1.76 - 1.63 (m, 1H) .

[0598] <3. Preparation of Antibody-Drug Conjugates > Example 55-1. Preparation of Trastuzumab-Linker-Payload Summary The results of the analysis of the prepared trastuzumab-linker-payload are shown in Table 4 below.

[0599] [Table 4] Example 55-2. Trastuzumab-Linker-Payload Conjugation Experiment Procedure

[0600] 1) The conjugation of the trastuzumab-linker-payload was carried out as follows. Trastuzumab dissolved in the initial buffer (4.23 mM histidine / histidine-HC1, 55.77 mM trehalose dihydrate, 0.0085% polysorbate 20) was pipettemed into a 50 mL tube.

[0601] 2) Reduction buffer was added to make the mAb concentration 8.89-9.0 mg / mL.

[0602] 3) Reduced by adding TCEP. The reaction vial was placed in a 22°C incubator-shaker and reacted at 60 rpm for 18 hours, or at 37°C at 300 rpm for 2-3 hours.

[0603] 4) After reduction, DMA solvent was added to the sample to make the organic solvent ratio 10% (v / v).

[0604] 5) Add the linker-payload dissolved in DMA to achieve a final mAb concentration of 8 mg / ml. The mixture was reacted at 22-25 °C for 1 hour. After 1 hour, DAR was verified by LC-MS, and the samples were purified using a Zeba Spin desalting column (40K, 10mL*3) or a HighTrap Desalting column.

[0605] 6) Next, the solution was concentrated, and after performing a buffer exchange with 20 mM histidine / histidine HC1, pH 5.5 using Ami Con (50 kDa, 15 mL), the SEC purity and free drug concentration were checked. Example 55—3. ADC purification using Zeba Spin desalting column

[0606] The Zeba Spin desalting column was used after pretreatment as follows: 1) After removing the bottom plug of the column, the stock solution was removed by centrifugation (700 g, 2 min).

[0607] 2) 5 mL of 0.5 M NaOH was applied to the resin to disinfect the column, and it was left for 30 minutes.

[0608] 3) After centrifugation (700 g, 2 min), the eluent was discarded.

[0609] 4) After applying 5 ml of formulation buffer to the resin, centrifugation (700 g, 2 min) was performed, and the eluent was discarded. This step was repeated two additional times until the pH of the eluent became equal to that of the formulation buffer. Finally, centrifugation was performed for 5 minutes.

[0610] 5) Transfer the column to a new collection tube and apply the antibody-drug conjugate mixture onto the column resin.

[0611] 6) The antibody-drug conjugate was obtained by centrifugation (700 g, 4 min). Example 55—4. Purification of ADC using Ami con® UltraCentr i fugal Filter Unit. Low molecular weight substances were removed using an ultra-low molecular weight filtration membrane. It is recommended to use an ultra-low molecular weight filtration membrane with a molecular weight of 50 kDa. The Ami con UltraCentr i fugal Filter Unit was used in the following manner.

[0612] 1) The centr i fugal fi I ter uni t was washed with distilled water.

[0613] 2) Equilibrated with 20 mM histidine buffer (pH 5.5).

[0614] 3) The antibody-drug conjugate mixture was added to an Amicon® Ultra filter device and centrifuged to concentrate it to approximately 3 mL. 9 mL of 20 mM histidine buffer (pH 5.5) was added, and buffer exchanges were performed until the amount of water discarded was 63 mL to remove low molecular weight substances. The remaining solution was concentrated to obtain approximately 9 mL of the ADC composition solution.

[0615] 4) The sample was filtered through a 0.22 μm membrane. Example 55—5. ADC purification using a Hitrap desalting column

[0616] The Hitrap desalting column was used after preprocessing using the following method.

[0617] 1) A Hitrap desalting column was connected to the FPLC equipment.

[0618] 2) 20 mL of 0.5 M NaOH was applied to the resin to disinfect the column, and after washing with distilled water, the column was stabilized with 20 mM histidine / histidine HC1, 8% sucrose pH 5.5.

[0619] 3) The solution prepared in 1) was injected into the FPLC.

[0620] 4) After purifying the antibody-drug conjugate, it was concentrated using Ami con (50 kDa, 15 mL). Example 55-6. DAR measurement using LC-MS

[0621] LC-MS analysis was performed using an Agi Lent 1260 / 1290 series HPLC system with TOF / Q-TOF mass spectrometry or Waters Xevo G3 Q-TOF mass spectrometry. DAR was calculated based on the peak intensity of the deconvoluted mass. 0.1 M DTT was added to the antibody-drug conjugate solution. The mixture was incubated at 37°C for 15–30 minutes to prepare samples in which the disulfide bonds between the heavy and light chains, and between the heavy chains, of the antibody-drug conjugate were cleaved. The samples obtained in this way were used for LC-MS analysis. Example 55-7. Measurement of aggregates using SEC-HPLC

[0622] Size-exclusion chromatography was performed using a TSK gel G3000SWXL size-exclusion chromatography column (7.8 x 300 mm, 5°F). The mobile phase consisted of 78 mM KH2PO4, 122 mM K2HPO4, 250 mM KC1, 15% IPA, and a pH of 7.0. The flow rate was set to 0.75 mL / min. 40 to 50 samples were loaded per injection. Compounds were detected at 280 nm using a UV detector. The retention time of aggregate peaks was determined based on the molecular weight of the peaks, and the degree of aggregation was determined by the relative area at 280 nm.

[0623] <4. ADC Characteristics Evaluation >

[0624] <Experimental Example 4> Cathepsin B-cleavage Test Test Method:

[0625] Enzymatic cleavage of the VC (Vai ine-Citrul line) linker was evaluated by treating trastuzumab-linker-payload 3 and trastuzumab-linker-payload 6 with cathepsin. In this study, commercially available recombinant cathepsin B (Sino Biological, EC3.4.22.1) was used instead of the human-derived enzyme. This allowed for the verification of the release of the target drug, compound 14, and the formation of stable intermediates during the reaction process. Prior to use, cathepsin B (Sino Biological, Cat#10483-H08H) was activated using a cathepsin B digestion buffer solution (30 nmol / L DTT) at pH 5.0 and then diluted to a final concentration of 1 U for the reaction. The reaction mixture was reacted at 37°C, and 40 µL samples were collected at t = 0, 0.17, 0.5, 1, 2, 4, 6, and 24 hours, respectively. 100 µL of acetonitrile containing an internal standard was added to each sample and stirred for approximately 10 seconds, followed by centrifugation at 4°C under 15,000 g conditions for 10 minutes. The supernatant was used for the quantitative analysis of Compound 14 using LC-MS / MS. The test results are shown in Figures 1 and 2, which confirmed that Compound 14 is rapidly released from the ADC through a cleavage reaction following an enzymatic reaction by cathepsin. <Experimental Example 5> Cathepsin L-cleavage Test Test Method:

[0626] Enzymatic cleavage of the GGFG ( G1 yci ne - G1 yci ne - Pheny 1 a 1 an i ne - G1 yci ne ) linker was evaluated by treating trastuzumab-linker-payload 8 and trastuzumab-linker-payload 9 with human liver-derived cathepsin L (Sigma: EC 3.4.22.15). This allowed for the confirmation of the release of the desired drugs, compounds 29 and 39, and the presence of stable intermediates generated during the reaction. Prior to use, cathepsin L (Sigma, Cat# C6854) was activated in cathepsin L digestion buffer (30 mmol / L DTT) and then diluted to a final concentration of 120 nmol / L for use in the reaction. The reaction mixture was incubated at 37°C, and 40 µL samples were collected at t = 0, 0.17, 0.5, 1, 2, 4, 6, and 24 hours. 100 µL of acetonitrile containing an internal standard was added to each sample. The mixture was stirred for approximately 10 seconds, then centrifuged at 15,000 g at 4°C for 10 minutes to obtain the supernatant. Compounds 29 and 39 were quantitatively analyzed using LC-MS / MS. The test results are shown in Figures 3 and 4, and from Figures 3 and 4, it was confirmed that Compounds 29 and 39 were rapidly released from the ADC via a cleavage reaction following the enzymatic reaction by cathepsin L.

[0627] <Experimental Example 6> E. coli p-glucuronidase cleavage test Test method: Enzymatic cleavage of the p-glucuronid linker is the cysteine ​​derivative of the linker-payload 5

[0628] It was evaluated by treatment with P-glucuronidase. In this experiment, commercially available E. coli-derived P-glucuronidase (Sigma, 3.2.1.31) was used instead of human-derived enzymes. This allowed for the verification of whether the compound 14 drug was released and whether stable intermediates were formed during the reaction process. 12.5 yL of 100 mM cysteine ​​solution and 12.5 yL of 30 mM borate buffer solution at pH 9 were added to 90 µL of purified water. Subsequently, 10 µL of linker-payload dissolved in 10 mM DMSO solution was added. After 5 minutes, HPLC analysis confirmed that all linker-payloads were completely converted into cysteine-linker-payloads. 100 µL of the above-prepared cysteine-linker-payload solution was added to 880 µL of PBS, followed by the addition of 20 µL of E. colii-derived p-glucuronidase (Sigma, EC3.2.1.31 Type IX-A, 1 mg / mL PBS solution). The reaction mixture was reacted at 37°C, and 40 µL samples were taken at t = 0, 25, 60, and 90 minutes. 100 µL of acetonitrile was added to each sample and stirred for about 10 seconds, after which the mixture was centrifuged at 4°C under 15,000 g conditions for 10 minutes. The supernatant was used for the quantitative analysis of the cysteine-linker-payload and the payload using LC-MS / MS, and the analysis was performed in a manner similar to the method described in U.S. Patent No. 8,568,728 (the said patent is incorporated...

Claims

1. 276 【Claims】 【Claim 11 An immunoconjugate represented by the following formula I or a pharmaceutically acceptable salt thereof: [Formula I] Ab-(L-D) p In Formula I above, 日 is a cytotoxic drug moiety represented by the following Formula III, [Chemical Formula III] In the above formula III, Y is N, C-OC-X-LW or C- X- L『 R2 and; R1 is substituted with one or more, each independently, halogen, -NH2, -NO2, -NHCH3, -N(CH3)2 or - OH; Li은 -CH2-, -CH2CH2- , -CH2CH2CH2- , -CH(CH3)CH2- , -CH2CH2CH2CH2-, -CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -C(CH3)2CH2-, -CH2CH2CH2CH2CH2 - 또는 - CH2CH2CH2CH2CH2CH2-이고; ¬ or one or more groups are each independently substituted with -C1-C6 alkyl, -halogen, -OH, -NO2, -C1-6 alkoxy or -CF3; 2 is a single bond, -(CH2)-, -(CH2)『, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(C=0)-NH(CH2)n-, NH(C=O)-(CH2)n-, or -(C=o)-, where n is 0, 1, 2, 3 or 4; R2 is unsubstituted or each independently substituted with -halogen, -C1-C6 alkoxy, - NH2, or -C1-C6 alkyl; L3 is a single bond, - (CH2)-, - (CH2)2-, - (CH2)3-, - (CH2)4-, "(CH2)5-, "NH", -NHCH3, -H(CH2)2 - or -NH(CH2)3 -, wherein the -H of L3 is unsubstituted or at least one -H of L3 is each independently substituted with -C1-C6 alkyl; "V%H 三 广 , / 討 三 丁 닌 V_ / ‘、、...•::: •스 》 스 ==』 ''스 』 / Rs is -H, -Ci-C6 alkyl, - =, -A-, -,, wherein the R3s are unsubstituted or at least one of the R3s is each independently substituted with -C1-C6 alkyl, -C1-C6 alkoxy, -NH2, -CF3, -OCF3 or halogen; L is a linker moiety connecting Ab and P; Ab is an antibody or an antigen-binding fragment thereof; and P is an integer from 1 to 10.

2. The immunoconjugate according to claim 1, wherein the formula III is a compound represented by the following formula III-1, or a pharmaceutically acceptable salt thereof 279 <Chemical formula

3. The immunoconjugate according to claim 1, Y is C- OC- X- L『 R2 and; Li is -CH2- , -CH2CH2- , -CH2CH2CH2- , -CH(CH3)CH2- , -CH2CH2CH2CH2- , -H2CH2CH2CH2CH2- or -CH2CH2CH2CH2CH2- and is and wherein the R2s are unsubstituted or one or more of the R2s are each independently substituted with halogen; L2 is a single bond; R2 is H, halogen or -NH2; L3 is - (CH2)-, - (CH2)2, - (CH2)3, - (CH2)4 - or - (CH2)5 -; 280 wherein at least one of the R3s is each independently substituted with -C1-C6 alkyl, or a pharmaceutically acceptable salt thereof. 【Claim

4. In Claim 1, the compound represented by Formula III is an immunoconjugate or a pharmaceutically acceptable salt thereof that is any of the following compounds 1 to 43: 281 282 285 IJ86 IJ87 288

5. The cytotoxic drug moiety represented by Formula III is an immunoconjugate or a medically acceptable salt thereof, wherein the cytotoxic drug moiety is a compound of any one of Formulas IV-1 to IV-5: [Chemical Formula IV-1] 289 [Chemical Formula IV-5] 290

6. In Claim 1, L is an immunoconjugate represented by the following chemical formula V, or a pharmaceutically acceptable one thereof: [Chemical Formula V] 291 Ly is a single bond, or -valine-citrulline- or -glycine-glycine-phenylalanine-glycine-, and Lx and Ly cannot be single bonds simultaneously; Lz is a PABC (para-aminobenzyl carbamate), PAB (para-aminobenzyl), or glucuronide moiety; e is an integer from 1 to 6; h and j are each independently integers from 1 to 3; at least two of f, g and i are 0, and when f, g or i is not 0, f or g is an integer from 2 to 16, and gu is an integer from 16 to 30.

7. In Claim 1, L is an immunoconjugate or a medically acceptable salt represented by any one of the following chemical formulas V-1 to V-8: [Chemical Formula V-1] [Chemical Formula V-2] 292 [Chemical Formula V-6] 293

8. In Claim 1, L-D is an immunoconjugate or a pharmaceutically acceptable salt represented by any one of the following chemical formulas VI-1 to VI-9: [Chemical Formula VI-1] 295 [Chemical Formula VI-5] [Chemical Formula VI-9] 296 【Claim 1. The antibody targets a cancer cell-specific antigen, and the cancer cell-specific antigen is 5T4, ABL, ABCF1, ACVR1, ACVR1B, ACVR2, ACVR2B, ACVRL1, AD0RA2A, AFP, Aggrecan, AGR2, AICDA, AIF1, AIGI, AKAP1, AKAP2, ALCAM, ALK, AMH, AMHR2, ANGPT1, ANGPT2, ANGPTL3, ANGPTL4, ANPEP, APC, APOCI, AR, aromatase, ASPH, ATX, AX1, AXL, AZGP1 (zinc-α-glycoprotein), B4GALNT1, B7, B7.1, B7.2, B7-H1 , B7-H3 , B7-H4, B7-H6, BAD, BAFF, BAG1, BAI1, BCR, BCL2, BCL6, BCMA, BDNF, BLNK, BLR1 (MDR15) , BlyS, BMP1, BMP2, BMP3B (GDFIO) , BMP4, BMP6, BMP8, BMP10, BMPR1A, BMPR1B, BMPR2, BPAG1 (플렉틴), BRCA1 , C19orfl0 (IL27w), C3, C4A, C5, C5R1, CA6, CA9, CANT1 , CAPRIN-1, CASP1 , CASP4, CAV1, CCBP2 (D6 / JAB61), CCL1 (1—309), CCLI1 (에오탁신) , CCL13 (MCP-4) , CCL15 (MIP-Id), CCL16 (HCC-4) , CCL17 (TARC) , CCL18 (PARC) , CCL19 (MIP-3b), CCL2 (MCP-1), MCAF, CCL20 (MIP- 3a) , CCL21 (MEP-2) , SLC, exodus-2, CCL22(MDC / STC-I), CCL23 (MPIF-I), CCL24 (MPIF- 2 / 에오탁신- 2) , CCL25 (TECK) , CCL26(에오탁신- 3), CCL27 (CTACK / ILC) , CCL28, CCL3 (MIP-Ia), CCL4 (MIPIb),. CCL5(RANTES), CCL7 (MCP-3), CCL8 (mcp-2), CCNA1, CCNA2, CCND1, CCNE1, CCNE2, CCR1 297 (CKR1 / HM145) , CCR2 (mcp-IRB / RA) , CCR3 (CKR3 / CMKBR3) , CCR4, CCR5(CMKBR5 / ChemR13) , CCR6 (CMKBR6 / CKR-L3 / STRL22 / DRY6) , CCR7 (CKR7 / EBI1), CCR8 또는 CDwl98 (CMKBR8 / TERI / CKR-L1) , CCR9 (GPR-9-6) , CCRL1 (VSHK1), CCRL2 (L-CCR) , CD13, CD164, CD19, CDH6, CDIC, CD2, CD20, CD21, CD200, CD22, CD23, CD24, CD27, CD28, CD29, CD3, CD33, CD35, CD37, CD38, CD3E, CD3G, CD3Z, CD4, CD40, CD40L, CD44, CD45RB, CD47, CD52, CD56, CD69, CD70, CD72, CD74, CD79A, CD79B, CD8, CD80, CD81, CD83, CD86, CD97, CD99, CD117, CD125, CD137, CD147, CD179b, CD223 , CD279, CDH1 (E-카드헤린), CDH10, CDH12, CDH13 , CDH18, CDH19, CDH20, CDH3, CDH5, CDH7, CDH8, CDH9, CDH17, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK9, CDKN1A (p21Wapl / Cipl) , CDKN1B (p27Kipl), CDKN1C, CDKN2A (pl6INK4a) , CDKN2B, CDKN2C, CDKN3 , CEA, CEACAM5, CEACAM6, CEBPB, CERI, CFC1B, CHGA, CHGB, 키티나제 (Chitinase), CHST10, CIK, CKLFSF2, CKLFSF3 , CKLFSF4, CKLFSF5, CKLFSF6, CKLFSF7, CKLFSF8, CLDN3 , CLDN6, CLDN7 (클라우딘- 7), CLDN18, CLEC5A, CLEC6A, CLEC11A, CLEC14A,CLN3, CLU (클러스테린), CMKLR1 , CMK0R1 (RDC1), CNR1, C-MET, C0L18A1 , C0LIA1, C0L4A3 , C0L6A1 , CR2, Cripto, CRP, CSF1 (M- CSF), CSF2 (GM-CSF) , CSF3 (GCSF) , CTAG1B (NY-ESO-1), CTLA4, CTL8, CTNNB1 (b—가테닌), CTSB (가텝신 B), CX3CL1 (SCYD1), CX3CR1 (V28) , CXCL1 (GR01), CXCL10 (IP-IO), CXCLI1 (l-TAC / IP-9), CXCL12 (SDF1), CXCL13 , CXCL14, CXCL16, CXCL2 (GR02) , CXCL3 (GR03), CXCL5 (ENA-78 / LIX) , CXCL6 (GCP-2) , CXCL9 (MIG), CXCR3 (GPR9 / CKR-L2) , CXCR4, CXCR6 (TYMSTR / STRL33 / Bonzo) , CYB5, CYC1, CYSLTR1 , DAB2IP, DES, DKFZp451J0118, DLK1, DNCL1 , DPP4, E2F1, Engel, Edge, Fennel, EFNA3 , EFNB2, EGF, EGFR, ELAC2, ENG, Enola, EN02, EN03, EpCAM, EPHA1 , EPHA2, EPHA3 , EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHA9, EPHA10, EPHB1, EPHB2, EPHB3, EPHB4, EPHB5, EPHB6, EPHRIN-A1, EPHRIN-A2, EPHRINA3, EPHRIN- 298 A4, EPHRIN-A5, EPHRIN-A6, EPHRIN-B1, EPHRIN-B2, EPHRIN-B3, EPHB4, EPG, ERBB2 (HER- 2), ERBB3, ERBB4, EREG, ERK8, Estrogen receptor (Ear 1 and ESR2), F3 (TF), FADD, FAP, Farnesyltransferase], FasL, FASNf, FCER1A, FCER2, FCGR3A, FGF, FGF1 (aFGF), FGF10, FGF11, FGF12, FGF12B, FGF13, FGF14, FGF16, FGF17, FGF18, FGF19, FGF2 (bFGF), FGF20, FGF21, FGF22, FGF23, FGF3 (int-2), FGF4 (HST), FGF5, FGF6 (HST-2), FGF7 (KGF), FGF8, FGF9, FGFR1, FGFR2, FGFR3, FGFR4, FIGF (VEGFD), FILl(EPSILON), FBL1 (ZETA), FL J 12584, FLJ25530, FLRT1 (fibronectin), FLT1, FLT-3, FOLR1(FR-alpha), FOS, FOSLl(FRA-l), FY (DARC), GABRP (GABAa) , GAGEB1, GAGECI, GALNAC4S-6ST, GATA3, GD2, GD3, GDF5, GFI1, GFRA1, GGT1, GM-CSF, GNAS1, GNRH1, GPC1, GPC3, GPNB, GPR2 (CCR10), GPR31, GPR44, GPR81 (FKSG80), GRCC10 (CIO), GRP, GSN (Gelsolin), GSTP1 , GUCY2C, HAVCR1 , HAVCR2, HDAC, HDAC4, HDAC5, HDAC7A, HDAC9, Hedgehog, HGF, HIF1A, HIP1, Histamine and Histamine Receptor , HLA-A, HLA-DR, HLA-DRA, HLA-E, HM74, HMOXI , HSP90 , HUMCYT2A, ICEBERG, ICOSL, ID2, IFN-α, IFNA1, IFNA2, IFNA4, IFNA5, EFNA6, BFNA7, IFNB1, IFN-gamma, IFN-W1,IGBP1, IGF1, IGFIR, IGF2, IGFBP2, IGFBP3, IGFBP6, DL-1, ILIO, ILIORA, ILIORB, IL-1, IL1R1 (CD121a) , ILlR2(CD121b) , IL-IRA, IL-2, IL2RA (CD25) , IL2RB(CD122) , IL2RG(CD132) , IL-4 4R(CD123) , IL-5, IL5RA(CD125) , IL3RB(CD131), IL-6, IL6RA, (CD126) , IR6RB(CD130) , IL-7, IL7RA(CD127) , IL-8, CXCR1 (IL8RA), CXCR2, (IL8RB / CD128) , IL-9, IL9R(CD129) , IL-10, IL10RA(CD210) , IL10RB(CDW210B) , IL-11, IL11RA, IL-12, IL-12A, IL-12B, IL-12RB1, IL-12RB2, IL-13, IL13RA1, IL13RA2, IL14, IL15, IL15RA, IL16, IL17, IL17A, IL17B, IL17C, IL17R, IL18, IL18BP, IL18R1, IL18RAP, IL19, ILIA, ILIB, ILIF10, ILIF5, IL1F6, ILIF7, IL1F8, DL1F9, ILIHYI, ILIR1, IL1R2, ILIRAP, ILIRAPLI , ILIRAPL2, ILIRL1, IL1RL2, ILIRN, 299 IL2, IL20, IL20RA, IL21R, IL22, IL22R, IL22RA2, IL23, DL24, IL25, IL26, IL27, IL28A, IL28B, IL29, IL2RA, IL2RB, IL2RG, IL3, IL30, IL3RA, IL4, 1L4, IL6ST (glycoprotein 130), ILK, INHA, INHBA, INSL3, INSL4, IRAKI, IRAK2, ITGA1, ITGA2, ITGA3, ITGA6 (a6 integrin), ITGAV, ITGB3, ITGB4 (heart4 integrin), JAG1, JAK1, JAK3, JTB, JUN, K6HF, KAI1, KDR, KIT, KITLG, KLF5 (GC Box BP), KLF6, KLK10, KLK12, KLK13, KLK14, KLK15, KLK3, KLK4, KLK5, KLK6, KLK9, KRT1, KRT19 (Keratin 19), KRT2A, KRTHB6 (Hair-specific type II keratin), L1CAM, LAG3, LAMA5, LAMP1, LEP (Leptin), Lewis Y antigen (LeY), LILRB1, Lingo-p75, Lingo-Troy, LGALS3BP, LRRC15, LPS, LTA (TNF-β), LTB, LTB4R (GPR16), LTB4R2, LTBR, ​​LY75, LYPD3, MACMARCKS, MAG or OMgp, MAGEA3, MAGEA6, MAP2K7 (c-Jun), MDK, MIB1, midkine, MIF, MISRII, MJP-2, MLSN, MK, MKI67 (Ki-67), MMP2, MMP9, MSMB, MT3 (metallothionectin—UI), mTOR, MTSS1, MUC1 (mucin), MUC16, MYC, MYD88, NCK2, NCR3LG1, neurocan, NFKBI, NFKB2, NGFB (NGF), NGFR, NgR-Lingo, NgRNogo66, (Nogo), NgR—p75, NgR-Troy,NMEI (NM23A), NOTCH, NOTCH1, NOTCH3, NOX5, NPPB, NR0B1, NR0B2, NRID1, NR1D2, NR1H2, NR1H3, NR1H4, NR112, NR113, NR2C1, NR2C2, NR2E1, NR2E3, NR2F1, NR2F2, NR2F6, NR3C1, NR3C2, NR4A1, NR4A2, NR4A3, NR5A1, NR5A2, NR6A1, NRP1, NRP2, NT5E, NTN4, NYESO1, ODZI, OPRDI, P2RX7, PAP, PARTI, PATE, PAWR, P-card herrin, PCA3, PCD1, PDL1, PCDGF, PCNA, PDGFA, PDGFB, PDGFRA, PDGFRB, PECAMI, Ll-CAM, peg-{asparagus nazer}, PF4 (CXCL4), PGF, PGR, phosphacan, PIAS2, PI3 kinase, PIK3CG, PLAU (uPA), PLG, PLXDCI, PKC, PKC-beta, PPBP (CXCL7), PPID, PR1, PRAME, PRKCQ, PRKD1, PRL, PROC, PROK2, PSAP, PSCA, PSMA, PTAFR, PTEN, PTHR2, PTGS2 (COX-2), PTN, PVRIG, RAC2 (P21Rac2), RANK, RANK ligand, RARE, RGS1, RGS13, RGS3, RNFI10 (ZNF144), Ron, R0B02, R0R1, RXR, S100A2, SCGB1D2 (Lipophilin B), SCGB2A1 300 (mammaglobin 2), SCGB2A2 (mammaglobin 1), SCYE1 (endothelial monocyte-activated cytokine), SDF2, SERPENA1, SERPINA3, SERPINB5 (maspin), SERPINEI (PAID, SERPINFI, SHIP-1, SHIP-2, SHB1, SHB2, SHBG, SfcAZ, SLC2A2, SLC33A1, SLC43A1, SLC44A4, SLC34A2, SLIT2, SPP1, SPRR1B (Sprl), ST6GAL1, ST8SIA1, STAB1, STATE, STEAP, STEAP2, TB4R2, TBX21, TCP10, TDGF1, TEK, TGFA, TGFB1, TGFB1I1, TGFB2, TGFB3, TGFBI, TGFBR1, TGFBR2, TGFBR3, THIL, THBS1 (Thrombospondin-1), THBS2, THBS4, THPO, TIE (Tie-1), TIMP3, tissue factor, TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TNF, TNFa, TNFAIP2 (B94), TNFAIP3, TNFRSFI1A, TNFRSF1A, TNFRSF1B, TNFRSF21, TNFRSF5, TNFRSF6 (Fas), TNFRSF7, TNFRSF8, TNFRSF9, TNFSF10 (TRAIL), TNFRSF10A, TNFRSF10B, TNFRSF12A, TNFRSF17, TNFSF11 (TRANCE), TNFSF12 (AP03L), TNFSF13 (April), TNFSF13B, TNFSF14 (HVEM-L), TNFRSF14 (HVEM), TNFSF15 (VEGI), TNFSF18, TNFSF4 (0X40 ligand), TNFSF5 (CD40 ligand), TNFSF6 (FasL), TNFSF7 (CD27 ligand), TNFSF8 (CD30 ligand), TNFSF9 (4-1BB ligand), TOLLIP, Toll-like receptor, T0P2A (Topoisomerasase Ila), TP53, TPM1, TPM2, TRADD,TRAF1, TRAF2, TRAF3, TRAF4, TRAF5, TRAF6, TRKA, TREM1, TREM2, TR0P2, TRPC6, TSLP, TWEAK, Tyrosinase, uPAR, VEGF, VEGFB, VEGFC, versican, VHL C5, VLA-4, WT1, Wnt-1, XCL1 (lymphotactin), XCL2 (SCM-Ib), XCRI (GPR5 / CCXCR1), YY1, ZFPM2, CLEC4C (BDCA-2, DLEC, CD303, CDH6, CLECSF7), CLEC4D (MCL, CLECSF8), CLEC4E (Mincle), CLEC6A (dectin-2), CLEC5A (MDL-1, CLECSF5), CLEC1B (CLEC-2), CLEC9A (DNGR-1), CLEC7A (dectin-1), CLEC11A, PDGFRa, SLAMF7, GP6 (GPVI), LILRA1 (CD85I), LILRA2 (CD85H, ILT1), LILRA4 (CD85G, ILT7), LILRA5 (CD85F, ILT11), LILRA6 (CD85b, ILT8), LILRB1, NCR1 (CD335, LY94, NKp46), NCR3 (CD335, LY94, NKp46), NCR3 (CD337, NKp30), OSCAR, TARM1, CD30, CD300C, CD300E, CD300LB (CD300B), 301 CD300LD (CD300D), KIR2DL4 (CD158D), KIR2DS, KLRC2 (CD159C, NKG2C), KLRK1 (CD314, NKG2D), NCR2 (CD336, NKp44), PILRB, SIGLEC1 (CD169, SN), SIGLEC5, SIGLEC6, SIGLEC7, SIGLEC8, SIGLEC9, SIGLEC10, SIGLEC11, SIGLEC12, SIGLEC14, SIGLEC15 (CD33L3), SIGLEC16, SIRPA, SIRPB1 (CD172B) , TREM1 (CD354) , TREM2, KLRF1 (NKp80) . , 17-1A, SLAM7, MSLN, CTAG1B / NY-ES0-1, MAGEA3 / A6, ATP5I (Q06185), OAT (P29758), AIFM1 (Q9Z0X1), AGFA (Q64133), MTDC (P18155), CMC1 (Q8BH59), PREP (Q8K411), YMEL1 (088967), LPPRC (Q6PB66), LONM (Q8CGK3), ACON (Q99KI0), 0D01 (Q60597), IDHP (P54071), ALDH2 (P47738), ATPB (P56480), AATM (P05202), TMM93 (Q9CQW0), ERG I3 (Q9CQE7), RTN4 (Q99P72), CL041 (Q8BQR4), ERLN2 (Q8BFZ9), TERA (Q01853), DADI (P61804), CALX (P35564). CALU (035887), VAPA (Q9WV55), MOGS (Q80UM7), GANAB (Q8BHN3), ER01A (Q8R180), UGGG1 (Q6P5E4), P4HA1 (Q60715), HYEP (Q9D379), CALR (P14211), AT2A2 (055143), PDIA4 (P08003), PDIA1 (P09103), PDIA3 (P27773), PDIA6 (Q922R8), CLH (Q68FD5),PPIB (P24369) , TCPG (P80318) , M0T4 (P57787) , NICA (P57716) , BAS I (P18572) , VAPA (Q9WV55) , ENV2 (P11370) , VAT1 (Q62465) , 4F2 (P10852) , ENOA (P17182), ILK (055222), GPNMB (Q99P91), ENV1 (P10404), ER01A (Q8R180), CLH (Q68FD5), DSG1A (Q61495), AT1A1 (Q8VDN2), HY0U1 (Q9JKR6), TRAP1 (Q9CQN1), GRP75 An immunoconjugate or a pharmaceutically acceptable salt thereof, which is any one or more selected from the group consisting of (P38647), ENPL (P08113), CH60 (P63038), and CH10 (Q64433).

10. In Claim 1, 302 antibody is an immunoconjugate or a pharmaceutically acceptable salt thereof that targets HER2.

11. A pharmaceutical composition for the prevention or treatment of cancer, comprising as an active ingredient an immunoconjugate of any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof.

12. The pharmaceutical product for the prevention or treatment of cancer, wherein the cancer is a cancer in which NAMPT is overexpressed or overactivated.

13. The pharmaceutical composition for the prevention or treatment of cancer, wherein the cancer is HER2-positive or mutated cancer.

14. A method for the prevention or treatment of ¬, comprising the step of administering a therapeutically effective amount of the immunoconjugate of any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof to an individual in need thereof.

15. 303 Use of an immunoconjugate of any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof for preventing or treating cancer.

16. Use of the immunoconjugate of any of claims 1 to 10 or a pharmaceutically acceptable salt thereof in the manufacture of a drug for preventing or treating cancer.

17. A drug-linker conjugate represented by the following chemical formula II or a pharmaceutically acceptable salt thereof: [Chemical Formula II] In the above chemical formula II, LD is a cytotoxic drug moiety represented by the following chemical formula III, and [Chemical Formula III] In the above chemical formula III, Y is N, C-OC-X-LW or C- X- L『 R2 and; 304 One or more -bos are each independently substituted with -halogen, -NH2, -NO2, -NHCHS, _N(CH3)2, or _H; L1은 - CH2- , -CH2CH2-, -CH2CH2CH2-, -CH(CH3)CH2-, -CH2CH2CH2CH2-, -CH(CH3)CH2CH2-, CH2CH(CH3)CH2-, -C(CH3)2CH2-, -CH2CH2CH2CH2CH2 - 또는 - CH2CH2CH2CH2CH2CH2-이고; ¬or or one or more - H is each independently - Ci-C6 alkyl, -halogen, -OH, -NO’, - Ci-6 alkoxy or - CF3 substituted; 匕2 is a single bond, - (CH2)-, - (CH2)『, - (CH2)『, - (CH2)4-, "(CH2)5-, - (C=0)- NH(CH2)R-, NH(C=O)- (CH2)n- or - (C=o)-, where n is 0, 1, 2, 3 or 4; nr 그 i L '、、,NH R2 is - H, -OH, -halogen, -C1-C6 alkyl, -C1-C6 alkoxy, - NH2, , The inner part is unsubstituted or each is independently substituted with a -halogen, -Cl- C6 alkoxy, -H2, or -Ci-C6 alkyl; the 3 is a single bond, -(CH2)-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, _ NH" , -NHCH『 , -H(CH2)2 -or -NH(CH2)3 -, wherein the inner part of L3 is not substituted or at least one inner part of L3 is each crystallinely substituted with -C1-C6 alkyl; wherein the inside of the Rs is unsubstituted or at least one of the R3s is each independently - Cl-C6 alkyl, - Cl-C6 alkoxy, -NH2, -CFS, -OCFs or -halogen substituted; L is a linker moiety connected to 日.

18. The invention of Claim 17, wherein the formula III is a compound represented by the following formula III-1, a drug-linker conjugate or a pharmaceutically acceptable salt thereof: 【Claim 1, in claim 17, Y is C- OC- X- L『 R2 and; Li is - CH2-, - CH2CH2-, - CH2CH2CH2-, - CH(CH3)CH2-, -CH2CH2CH2CH2-, - CH2CH2CH2CH2CH2 -or - CH2CH2CH2CH2CH2CH2 -and; wherein the inside of the 오 is unsubstituted or one or more of them are each independently -halogen substituted; L2 is a single bond; 307 R2 is -H, -halogen or -NH2, and匕3 is - (CH2)-, - (CH2)2-, - (CH2)3-, - (CH2)4 - or - (CH2)5 -, wherein at least one - H of the R3s is each independently - Cl-C6 alkyl substituted, ¬water-linker conjugate or a pharmaceutically acceptable salt thereof.

20. The cytotoxic drug moiety represented by Formula III is a drug-linker conjugate or a pharmaceutically acceptable salt thereof, which is any one of the following compounds 1 to : 308 309 310 311 312 313 314 315 【Claim 21, in claim 17, the cytotoxic drug moiety represented by the formula III is a compound of any one of the following formulas IV-1¬to IV-5, a drug-linker conjugate or a pharmaceutically acceptable salt thereof: 316 [Chemical Formula iv-l] [Formula IV-5] 317 【Claim 22, in claim 17, L is represented by the following formula 두, a drug-linker conjugate or a pharmaceutically acceptable salt thereof: [Chemical Formula V] 318 Ly is a single bond or, or -valine-citrulline- or -glycine-glycine-phenylalanine-glycine-, and Lx and Ly cannot be single bonds simultaneously; Lz is a PABC (para-aminobenzyl carbamate), PAB (para-aminobenzyl), or glucuronide moiety; e is an integer from 1 to 6; h and j are each independently integers from 1 to 3; at least two of f, g and i are 0, and when f, g or i is not 0, f or g is an integer from 2 to 16, and gu is an integer from 16 to 30.

23. In Claim 17, L is a pharmaceutically acceptable salt of a drug-linker conjugate represented by any one of the following chemical formulas V-1 to V-8: [Chemical Formula V-1] [Chemical Formula V-2] 319 [Chemical Formula V-6]

24. A drug-linker conjugate or a pharmaceutically acceptable salt represented by any one of the following formulas VI-1 to VI-9: [Chemical Formula VI-1] 321 [Chemical Formula VI-2] [Chemical Formula VI-5] 322 [Chemical Formula VI-9] 323

25. A benzamide compound represented by any one of the following formulas VII-1 to VI 1-8, a stereoisomer of ¬, a pharmaceutically acceptable salt or hydrate thereof or a methyl derivative thereof: [Chemical Formula VII-1] [Chemical Formula VII-3] 324 325 [Chemical Formula VII-8]

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