Hemiasterlin derivatives and their antibody-drug conjugates

Abstract

The present invention provides a hemiasterlin derivative that specifically inflicts cytotoxicity on target cells while suppressing cytotoxicity to normal cells, an antibody-drug conjugate thereof, and a synthetic intermediate for the antibody-drug conjugate. [Solution] Formula (1): TIFF2023036829000176.tif35149 [wherein AA is a specific amino acid residue or C 1-6 It represents an alkyl ester, and when there are a plurality of AA, each AA may be the same or different, and the AA are bonded to each other via an amide bond, and (AA) m The N-terminal nitrogen atom of the formula (I) forms an amide bond with the carbonyl (a), Q represents an unsubstituted phenyl group or a specific cyclic group, and R 1a and R 1b are each independently a hydrogen atom or C 1-6 represents an alkyl group, and m represents an integer of 1 to 10, or a salt thereof.

Description

[Technical field]

[0001] The present invention relates to a hemiasterlin derivative, an antibody-drug conjugate thereof, and a synthetic intermediate for the antibody-drug conjugate. [Background technology]

[0002] Hemiasterlin is a natural compound having a tripeptide structure isolated from a marine sponge, and is involved in microtubule depolymerization and mitotic arrest in cells (Non-Patent Document 1).

[0003] To date, several groups have modified the structure of hemiasterlin derivatives and reported structure-activity relationships (Patent Documents 1 to 5, Non-Patent Documents 2 to 5). Hemiasterlin derivatives that exhibit strong cytotoxicity (cytotoxicity) based on antimitotic activity have been found for the treatment of diseases such as cancer. However, it has been reported that these hemiasterlin derivatives exhibit cytotoxicity not only to target cells but also to normal cells, causing side effects (Non-Patent Document 6).

[0004] In addition, antibody-drug conjugates containing hemiasterlin derivatives that exhibit cytotoxic activity in antigen-expressing cells have been reported (Patent Documents 4, 6 to 9). [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Publication No. 2004 / 026293 [Patent Document 2] WO 96 / 33211 [Patent Document 3] U.S. Patent No. 7,579,323 [Patent Document 4] International Publication No. 2014 / 144871 [Patent Document 5] International Publication No. 2003 / 082268 [Patent Document 6] International Publication No. 2016 / 123582 [Patent Document 7] International Publication No. 2015 / 095952 [Patent Document 8] International Publication No. 2015 / 095953 [Patent Document 9] International Publication No. 2013 / 173393 [Non-patent literature]

[0006] [Non-Patent Document 1] Talpir, R. et al., Tetrahedron Lett., 1994, 35, 4453-4456. [Non-Patent Document 2] Zask,A. et. al.,Bioorg.Med.Chem.Lett., 2004, 14, 4353-4358. [Non-Patent Document 3] Zask, A. et. al., J. Med. Chem., 2004, 47, 4774-4786. [Non-Patent Document 4] Yamashita, A. et. al., Bioorg.Med.Chem.Lett.,2004,14,5317-5322. [Non-Patent Document 5] Nieman, JA et. al., J, Nat. Prod., 2003, 66, 183-199. [Non-Patent Document 6] Rocha-Lima,CM et. al.,Cancer,2012,118,4262-4270. [Non-Patent Document 7] Toki et. al.,2002,J.Org.Chem.67,1866-1872. Summary of the Invention [Problem to be solved by the invention]

[0007] The objective of the present invention is to provide a hemiasterlin derivative that is bound to an antibody to form an antibody-drug conjugate, and thereby specifically inflicts cytotoxicity on target cells while suppressing cytotoxicity to normal cells, as well as an antibody-drug conjugate thereof, and a synthetic intermediate for the antibody-drug conjugate. [Means for solving the problem]

[0008] As a result of intensive research, the inventors have found that an antibody-drug conjugate formed between a hemiasterlin derivative represented by formula (1) or formula (1a) and an antibody exhibits strong antitumor activity while having low cytotoxicity to normal cells, and have thus completed the present invention.

[0009] That is, the present invention is as follows. [Section 1] Formula (1): [ka] [In the formula, AA is a glutamic acid residue (Glu), an aspartic acid residue (Asp), a lysine residue (Lys), a cysteine ​​residue (Cys), a phosphotyrosine residue, a phosphoserine residue, or a cysteic acid residue, or a C 1-6 represents an alkyl ester, and when there are a plurality of AA, each AAs may be the same or different, and AAs are bonded to each other via an amide bond, (AA) m The N-terminal nitrogen atom of forms an amide bond with the carbonyl (a), Q is represented by formula (Q-1), formula (Qa-2), formula (Qa-3), formula (Qa-4), formula (Qa-5), formula (Qa-6) or formula (Qa-7): [ka] (In the formula, R 2a , R 2b , R 2c , R 2d and R 2eeach independently represents a hydrogen atom, a halogen atom, or C optionally substituted with 1 to 5 fluorine atoms; 1-6 C optionally substituted with an alkyl group or 1 to 5 fluorine atoms 1-6 represents an alkoxy group, R 2f is a hydrogen atom or C 1-6 represents an alkyl group, R aa , R ab and R ac each independently represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, an amino group, a carboxyl group, a phenyl group, or C optionally substituted with 1 to 3 fluorine atoms 1-6 Alkyl group, C 1-6 Alkoxy group or C 1-6 represents an alkyl ester group) represents a group represented by R 1a and R 1b are each independently a hydrogen atom or C 1-6 represents an alkyl group, m represents an integer from 1 to 10. Represented by A compound or a salt thereof.

[0010] [Section 2] Formula (1): [ka] [In the formula, AA is a glutamic acid residue (Glu), an aspartic acid residue (Asp), a lysine residue (Lys), or a cysteine ​​residue (Cys), or 1-6 represents an alkyl ester, and when there are a plurality of AA, each AAs may be the same or different, and AAs are bonded to each other via an amide bond, (AA) m The N-terminal nitrogen atom of forms an amide bond with the carbonyl (a), Q is an unsubstituted phenyl group or a group represented by formula (Q-1): [ka] (In the formula, R 2a , R 2b , R 2c , R 2d and R 2e each independently represents a hydrogen atom, a halogen atom, or C optionally substituted with 1 to 5 fluorine atoms; 1-6 C optionally substituted with an alkyl group or 1 to 5 fluorine atoms 1-6 represents an alkoxy group, R 2f is a hydrogen atom or C 1-6 represents an alkyl group) represents a group represented by R 1a and R 1b are each independently a hydrogen atom or C 1-6 represents an alkyl group, m represents an integer from 1 to 10. Item 1. The compound or a salt thereof according to item 1.

[0011] [Section 3] Q is a formula (Q-2): [ka] (In the formula, R 2b and R 2c are each independently a hydrogen atom, a halogen atom, or C 1-6 Alkyl group or C 1-6 represents an alkoxy group) Item 3. The compound or salt thereof according to item 1 or 2, wherein R is a group represented by the following formula:

[0012] [Section 4] Q is a formula (Q-2): [ka] (In the formula, R 2b and R 2c each independently represents a hydrogen atom, a fluorine atom, or a methoxy group), or a salt thereof.

[0013] [Section 5] R 2b and R 2c and each represents a hydrogen atom, or a salt thereof.

[0014] [Section 6] R 1a is a methyl group, and R 1b 6. The compound or salt thereof according to any one of items 1 to 5, wherein is a hydrogen atom.

[0015] [Section 7] Formula (1a): [ka] [In the formula, AA is a glutamic acid residue (Glu), an aspartic acid residue (Asp), a lysine residue (Lys), a cysteine ​​residue (Cys), a phosphotyrosine residue, a phosphoserine residue, or a cysteic acid residue, or a C 1-6 represents an alkyl ester, and when there are a plurality of AA, each AAs may be the same or different, and AAs are bonded to each other via an amide bond, (AA) m The N-terminal nitrogen atom of forms an amide bond with the carbonyl (a), R ad is a hydrogen atom or C 1-6 represents an alkyl group, m represents an integer from 1 to 10. A compound or a salt thereof represented by the formula:

[0016] [Section 8] 8. The compound or salt thereof according to any one of items 1 to 7, wherein m is an integer of 1 to 5.

[0017] [Section 9] m is an integer from 2 to 10; (AA) m Item 8. The compound or salt thereof according to any one of Items 1 to 7, wherein is a linear peptide residue.

[0018] [Section 10] m is an integer from 3 to 10; (AA) m is a branched peptide residue having one or two branching points, or a salt thereof according to any one of items 1 to 7.

[0019] [Section 11] (AA) m But, formula (A-1): [ka] (wherein AA1, AA2 and AA3 each independently represent Glu, Asp or Lys) is a group represented by the formula (1), or a salt thereof according to any one of items 1 to 7.

[0020] [Section 12] 11. The compound or salt thereof according to any one of items 1 to 10, wherein AA is D-Glu, L-Glu, D-Asp or L-Asp, and when there are a plurality of AAs, each AAs may be the same or different from each other.

[0021] [Section 13] Item 3. The compound or salt thereof according to item 1 or 2, selected from the following compounds: [ka]

[0022] [Section 14] Formula (2): [ka] [In the formula, mAb stands for antibody; q represents an integer from 1 to 8; h represents an integer from 1 to 5; G represents an alanine residue (Ala), an arginine residue (Arg), an asparagine residue (Asn), an aspartic acid residue (Asp), a cysteine ​​residue (Cys), a glutamine residue (Gln), a glutamic acid residue (Glu), a glycine residue (Gly), a histidine residue (His), an isoleucine residue (Ile), a leucine residue (Leu), a lysine residue (Lys), a methionine residue (Met), a phenylalanine residue (Phe), a proline residue (Pro), a serine residue (Ser), a threonine residue (Thr), a tryptophan residue (Trp), a tyrosine residue (Tyr), a valine residue (Val), or a citrulline residue (Cit); when there are a plurality of Gs, each G may be the same or different from the others, and Gs are bonded to each other via an amide bond; g represents an integer from 1 to 4; Y is a single bond or a group represented by the formula (Y-1): [ka] (In the formula, Y' represents a single bond or a carbonyl group; R 3 is a C optionally substituted with a halogen atom, a cyano group, or 1 to 5 fluorine atoms; 1-6 C optionally substituted with an alkyl group or 1 to 5 fluorine atoms 1-6 represents an alkoxy group, R 3 If there are multiple R 3 may be the same or different, f represents an integer between 0 and 2. is a group represented by The group represented by formula (Y-1) 1 The end is bound to Z, Z is a group represented by the formula (Z-1), (Z-2), (Z-3), (Z-4), (Z-5), (Z-6), (Za-1), (Za-2), (Za-3), (Za-4), (Za-5), (Za-6), (Za-7), (Za-8), (Za-9), or (Za-10): [ka] [ka] [ka] (In these formulas, AA is Glu, Asp, Lys, Cys, a phosphotyrosine residue, a phosphoserine residue, or a cysteic acid residue, or any of these C 1-6 represents an alkyl ester, and when there are a plurality of AA, each AAs may be the same or different, and AAs are bonded to each other via an amide bond, (AA) m The N-terminal nitrogen atom of forms an amide bond with the carbonyl group (a), (AA) n The N-terminal nitrogen atom of forms an amide bond with the carbonyl group (a), Q is represented by formula (Q-1), formula (Qa-2), formula (Qa-3), formula (Qa-4), formula (Qa-5), formula (Qa-6) or formula (Qa-7): [ka] (In the formula, R 2a , R 2b , R 2c , R 2d and R 2e each independently represents a hydrogen atom, a halogen atom, or C optionally substituted with 1 to 5 fluorine atoms; 1-6 C optionally substituted with an alkyl group or 1 to 5 fluorine atoms 1-6 represents an alkoxy group, R 2f is a hydrogen atom or C 1-6 represents an alkyl group, R aa , R ab and R ac each independently represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, an amino group, a carboxyl group, a phenyl group, or C optionally substituted with 1 to 3 fluorine atoms1-6 Alkyl group, C 1-6 Alkoxy group or C 1-6 represents an alkyl ester group) represents a group represented by R 1a and R 1b are each independently a hydrogen atom or C 1-6 represents an alkyl group, R ad is a hydrogen atom or C 1-6 represents an alkyl group, m represents an integer from 1 to 10; n represents an integer of 0 to 4; R 4 is -(CH2) u -COR 7 represents u represents 1 or 2; R 5 and R 7 are each independently -OR 8 Or - (AB) p represents R 6 and R 8 are each independently a hydrogen atom or C 1-6 represents an alkyl group, AB represents Glu, Asp, or Lys, and when there are a plurality of AB, each AB may be the same or different, and AB are bonded to each other via an amide bond; p represents an integer of 1 to 4; However, R 5 or R 7 Ga-(AB) p When n and p are the same, the sum of n and p is an integer between 1 and 5. is a group represented by provided that when Y' is a single bond, Z is a group represented by formula (Z-2), formula (Z-3), formula (Z-4), formula (Za-1), formula (Za-2), formula (Za-3), formula (Za-7) or formula (Za-8). An antibody-drug conjugate or a pharma- ceutically acceptable salt thereof,

[0023] [Section 15] Formula (2): [ka] [In the formula, mAb stands for antibody; q represents an integer from 1 to 8; h represents an integer from 1 to 5; G represents an alanine residue (Ala), an arginine residue (Arg), an asparagine residue (Asn), an aspartic acid residue (Asp), a cysteine ​​residue (Cys), a glutamine residue (Gln), a glutamic acid residue (Glu), a glycine residue (Gly), a histidine residue (His), an isoleucine residue (Ile), a leucine residue (Leu), a lysine residue (Lys), a methionine residue (Met), a phenylalanine residue (Phe), a proline residue (Pro), a serine residue (Ser), a threonine residue (Thr), a tryptophan residue (Trp), a tyrosine residue (Tyr), a valine residue (Val), or a citrulline residue (Cit); when there are a plurality of Gs, each G may be the same or different from the others, and Gs are bonded to each other via an amide bond; g represents an integer from 1 to 4; Y is a single bond or a group represented by the formula (Y-1): [ka] (In the formula, Y' represents a single bond or a carbonyl group; R 3 is a C optionally substituted with a halogen atom, a cyano group, or 1 to 5 fluorine atoms; 1-6 C optionally substituted with an alkyl group or 1 to 5 fluorine atoms 1-6 represents an alkoxy group, R 3 If there are multiple R 3 may be the same or different, f represents an integer between 0 and 2. is a group represented by The group represented by formula (Y-1) 1 The end is bound to Z, Z is represented by formula (Z-1), formula (Z-2), formula (Z-3), formula (Z-4), formula (Z-5) or formula (Z-6): [ka] (In these formulas, AA is Glu, Asp, Lys, or Cys, or any of these C 1-6 represents an alkyl ester, and when there are a plurality of AA, each AAs may be the same or different, and AAs are bonded to each other via an amide bond, (AA) m The N-terminal nitrogen atom of forms an amide bond with the carbonyl group (a), (AA) n The N-terminal nitrogen atom of forms an amide bond with the carbonyl group (a), Q is an unsubstituted phenyl group or a group represented by formula (Q-1): [ka] (In the formula, R 2a , R 2b , R 2c , R 2d and R 2e each independently represents a hydrogen atom, a halogen atom, or C optionally substituted with 1 to 5 fluorine atoms; 1-6 C optionally substituted with an alkyl group or 1 to 5 fluorine atoms 1-6 represents an alkoxy group, R 2f is a hydrogen atom or C 1-6 represents an alkyl group), R 1a and R 1b are each independently a hydrogen atom or C 1-6 represents an alkyl group, m represents an integer from 1 to 10; n represents an integer of 0 to 4; R 4 is -(CH2) u -COR 7 represents u represents 1 or 2; R 5 and R 7 are each independently -OR 8 Or - (AB) p represents R 6 and R 8 are each independently a hydrogen atom or C 1-6 represents an alkyl group, AB represents Glu, Asp, or Lys, and when there are a plurality of AB, each AB may be the same or different, and AB are bonded to each other via an amide bond; p represents an integer of 1 to 4; However, R 5 or R 7 Ga-(AB) p When n and p are the same, the sum of n and p is an integer between 1 and 5. is a group represented by However, when Y' is a single bond, Z is a group represented by formula (Z-2), formula (Z-3) or formula (Z-4). Item 15. The antibody-drug conjugate or a pharma- ceutical acceptable salt thereof according to Item 14, wherein

[0024] [Section 16] The mAbs are brentuximab, trastuzumab, inotuzumab, gemtuzumab, glembatumumab, labetuzumab, sacituzumab, rifastuzumab, indusatuzumab, polatuzumab, pinatuzumab, cortuximab, indatuximab, milatuzumab, rovalpituzumab, anetuzumab, tisotumab, miabetuximab, lorvotuzumab, rituximab, depatuxizumab, denintuzumab, tersotuzumab, enfortumab, bundletuzumab, sofituzumab, borsetuzumab, mirvetuximab, naratuximab, cantuzumab, and laprituximab. , bivatuzumab, vadastuximab, rupartumab, apurutumab, abagovomab, abciximab, avituzumab, abrilumab, actoxumab, adalibumab, adecatumumab, aducanumab, afacevicumab, afelimomab, alacizumab, alemtuzumab, alirocumab, altumomab, amatuximab, anatumomab, anifrolumab, anrukinzumab, apolizumab, arcitumomab, asclinbacumab, acelizumab, atezolizumab, atinumab, atorlimumab, avelumab, azintuxizumab, bapineuzumab, basilicumab Cimab, bavituximab, bectumomab, begelomab, belimumab, benralizumab, bertilimumab, besilesomab, bevacizumab, bezlotoxumab, biciromab, bimagrumab, bimekizumab, bleselumab, blinatumomab, brontuzumab, brosozumab, bococizumab, brazikumab, briakinumab, brodalumab, brolucizumab, broticutuzumab, burosumab, cabilalizumab, camrelizumab, caplacizumab, capromab, carlumab, carotuximab, catumazomab, cedelizumab, certolizumab, cetuximab, sitat Zumab, sikisumumab, serenoliximab, clivatuzumab, codrituzumab, conatumumab, concizumab, cosfrobiximab, crenezumab, crizanlizumab, cloteduumab, dacetuzumab, daclizumab, dalotuzumab, dapirorizumab, daratumumab, dectrekumab, demcizumab, denosumab, detumomab, dezamizumab, dinutuximab, zilidamab, domagurozumab, dorlimomab, drozitumab, durigotuzumab, dupilumab, durvalumab, dusigitumab, duvortuxizumab, ecromeximab, eculizumab,Edobacomab, edrecolomab, efalizumab, efungumab, eldelumab, elezamumab, elotuzumab, ersilimomab, emactuzumab, emapalumab, emibetuzumab, emicizumab, enavatuzumab, enlimomab, enoblitzumab, enokizumab, enoticumab, encituximab, epitumomab, epratuzumab, eptinezumab, erenumab, erlizumab, ertumaxomab, etaracizumab, etrolizumab, evinacumab, evolocumab, exbivirumab, faralimomab, farletuzumab, fasinumab, felvisumab , fezakinumab, ficlatuzumab, figitumumab, filibumab, flavotumab, fretikumab, fontolizumab, foralumab, foravirumab, fremanezumab, fresolimumab, fulnevetomab, fullanumab, futuximab, galcanezumab, galiximab, ganitumab, gantenerumab, gatipotuzumab, gavilimomab, gedivumab, gevokizumab, gilvetumab, girentuximab, golimumab, guselkumab, ibalizumab, ibritumomab, icrucumab, idarucizumab, ifavotuzumab, igovomab, imalumab, im Ciromab, Imgatuzumab, Inclacumab, Inebilizumab, Infliximab, Inolimomab, Intetumumab, Ipilimumab, Iratumumab, Isatuximab, Itolizumab, Ixekizumab, Keliximab, Lacnotumab, Lampalizumab, Lanadelumab, Landgrozumab, Ralcaviximab, Lebrikizumab, Remaresomab, Lenzilumab, Lerdelimumab, Lesofabutumab, Letolizumab, Lexatumumab, Ribililumab, Rifatuzumab, Ligelizumab, Rilotomab, Lintuzumab, Lirilumab, Rodericizumab, Loxobetomab, Rovo ... Zumab, rosatuximab, lucatumumab, lurizumab, lumuletuzumab, rutikizumab, mapatumumab, margetuximab, masalimoab, matuzumab, mavrilimumab, mepolizumab, metelimumab, minitelumomab, mitumomab, modotuximab, mogamulizumab, monalizumab, morolizumab, motavizumab, moxetumomab, muromonab, nacolomab, namilumab, naptumomab, narnalumab, natalizumab, navicixizumab, nabivumab, nebacumab, necitumumab, nemolizumab, nerelimomab, nesbacumab, nimotuzumab, nivolumab,Oviltoxaximab, obinutuzumab, ocaratuzumab, ocrelizumab, odulimomab, ofatumumab, olaratumab, oleculumab, orendalizumab, olokizumab, omalizumab, onartuzumab, ontuxizumab, opicinumab, oportuzumab, oregovomab, oreticumab, olticumab, otelixizumab, otlertuzumab, oxelumab, ozanezumab, ozoralizumab, pagibaximab, palivizumab, pamrevlumab, panitumumab, panobacumab, palsatuzumab, pascolizumab, pasotuxizumab, pateclizumab , patritumab, pembrolizumab, perakizumab, pertuzumab, pexelizumab, pidilizumab, placumab, prozalizumab, ponezumab, polgabiximab, prezalumab, priliximab, plitoxaximab, pritumumab, quilizumab, racotumomab, radletumab, rafivirumab, ralpancizumab, ramucirumab, ranevetomab, ranibizumab, raxibacumab, refanezumab, regavirumab, lemtolumab, reslizumab, rilotumumab, linikumab, risankizumab, rivavazumab, lobatumumab, romotumab, romosoz ... zumab, rontalizumab, rosmantuzumab, rovelizumab, rozanolixizumab, ruplizumab, sacituzumab, samalizumab, sarilumab, satralizumab, satumomab, secukinumab, cericlerumab, celeribantumab, setoxaximab, sevirumab, sibrotuzumab, sifalimumab, siltuximab, simtuzumab, siplizumab, sirukumab, solanezumab, solitomab, sontuzumab, stamulumab, sulesomab, sumtavumab, subizumab, subratocumab, tabalumab, tadocizumab, talizumab, tamtubetomab, tanezumab, ta Pritumomab, talexuzumab, taborixizumab, fanolesomab, nofetumomab, pintumomab, tefibazumab, terimomab, telisozumab, tenatumomab, teneliximab, teplizumab, teprotumumab, tesidolumab, tezepelumab, tigatuzumab, tildrakizumab, timigtuzumab, timolumab, tocilizumab, tomzotuximab, toralizumab, tosatoxumab, tositumomab, tobetumab, tralokinumab, tregalizumab, tremelimumab, trevoglumab, tucotuzumab, tuvilumab, ublituximab, urocuplumab,Item 16. The antibody-drug conjugate or a pharmaceutically acceptable salt thereof according to Item 14 or 15, which is an antibody selected from the group consisting of urelumab, urtoxazumab, ustekinumab, utomilumab, vanticutumab, vanucizumab, bapaliximab, valisacumab, varlilumab, batelizumab, vedolizumab, beltuzumab, beparimomab, besencumab, visilizumab, bovalilizumab, volociximab, bonlerolizumab, votumumab, bunakizumab, tacatuzumab, zaltuzumab, zanolimumab, diralimumab, zolimomab, camidanlumab, cofetuzumab, radilatuzumab, loncastuzumab, terisotuzumab, enapotamab, and AMG595, or an anti-emvidin antibody.

[0025] [Section 17] Item 17. The antibody-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of Items 14 to 16, wherein the mAb is brentuximab, trastuzumab, inotuzumab, gemtuzumab, labetuzumab, polatuzumab, cortuximab, indatuximab, anetuzumab, rituximab, denintuzumab, laprituximab, vadastuximab, glembatumumab, cetuximab, alemtuzumab, depatuxizumab, or an anti-emvidin antibody.

[0026] [Section 18] Item 18. The antibody-drug conjugate or a pharma- ceutically acceptable salt thereof according to any one of Items 14 to 17, wherein the mAb is brentuximab, trastuzumab, rituximab, or an anti-emvidin antibody.

[0027] [Section 19] Item 19. The antibody-drug conjugate or a pharma- ceutically acceptable salt thereof according to any one of items 14 to 18, wherein h is 5.

[0028] [Section 20] (G) g but,* 2 -Gly-,* 2 -Gly-Gly-,* 2 -Lys-, * 2 -Lys-Phe-,* 2 -Lys-Val-, * 2 -Lys-Ala-, *2 -Cit-Val-,* 2 -Cit-Phe-,* 2 -Cit-Leu-,* 2 -Arg-Phe-,* 2 -Cit-Ile-,* 2 -Cit-Trp-,* 2 -Lys-Phe-Phe-,* 2 -Lys-Phe-Ala-, * 2 -Lys-Phe-Gly-,* 2 -Asn-, * 2 -Asn-Ala-, * 2 -Asn-Ala-Ala-, * 2 -Asn-Ala-Thr-, * 2 -Asn-Ala-Pro-, * 2 -Asn-Ala-Val-, * 2 -Asn-Ala-Phe-, * 2 -Asn-Ala-Tyr-, * 2 -Asn-Ala-Leu-,* 2 -Asn-Ala-Gly-, * 2 -Asn-Thr-Ala-, * 2 -Asn-Thr-Pro-, * 2 -Asn-Thr-Thr-, * 2 -Gly-Phe-Gly-Gly-,* 2 -Gly-Leu-Phe-Gly- or * 2 -Leu-Ala-Leu-Ala- (G) g of* 2 20. The antibody-drug conjugate or a pharma- ceutically acceptable salt thereof according to any one of items 14 to 19, wherein the terminal is bound to Y.

[0029] [Section 21] (G) g Formula (G-1), Formula (G-2), Formula (G-3) or Formula (G-4): [ka] is a group represented by (G) g of*2 20. The antibody-drug conjugate or a pharma- ceutically acceptable salt thereof according to any one of items 14 to 19, wherein the terminal is bound to Y.

[0030] [Section 22] R 3 Fluorine atom, C 1-3 Alkyl group or C 1-3 is an alkoxy group, R 3 If there are multiple R 3 and may be the same or different from each other, or a pharma- ceutical drug conjugate or a pharma- ceutical acceptable salt thereof according to any one of items 14 to 21.

[0031] [Section 23] 22. The antibody-drug conjugate or a pharma- ceutically acceptable salt thereof according to any one of items 14 to 21, wherein f is 0.

[0032] [Section 24] Z is a group represented by formula (Z-2), formula (Z-3) or formula (Z-4), Q is an unsubstituted phenyl group or a group represented by formula (Q-2): [ka] (In the formula, R 2b and R 2c each independently represents a hydrogen atom, a fluorine atom, or a methoxy group. is a group represented by R 5 and R 7 is -OH, 24. The antibody-drug conjugate or a pharma- ceutically acceptable salt thereof according to any one of items 14 to 23, wherein n is 1 or 2.

[0033] [Section 25] Z is a group represented by formula (Z-2), formula (Z-3) or formula (Z-4), Q is an unsubstituted phenyl group or a group represented by formula (Q-2): [ka] (In the formula, R 2b and R 2c each independently represents a hydrogen atom, a fluorine atom, or a methoxy group. is a group represented by R 5 and R 7 But -(AB) p and 24. The antibody-drug conjugate or a pharma- ceutically acceptable salt thereof according to any one of items 14 to 23, wherein n is 0 and p is 2, or n and p are each 1.

[0034] [Section 26] ZY is represented by the formula (ZY-1): [ka] [In the formula, AA and m are as defined above, Q is an unsubstituted phenyl group or a formula (Q-2): [ka] (In the formula, R 2b and R 2c each independently represents a hydrogen atom, a fluorine atom, or a methoxy group. is a group represented by the formula: 22. The antibody-drug conjugate or a pharma- ceutically acceptable salt thereof according to any one of items 14 to 21, wherein the antibody-drug conjugate is a group represented by the following formula:

[0035] [Section 27] ZY is represented by the formula (ZY-2): [ka] [In the formula, AA, R 1a , R 1b , R 6 and n is as defined above, Q is an unsubstituted phenyl group or a formula (Q-2): [ka] (In the formula, R 2b and R 2c each independently represents a hydrogen atom, a fluorine atom, or a methoxy group. is a group represented by the formula: 22. The antibody-drug conjugate or a pharma- ceutically acceptable salt thereof according to any one of items 14 to 21, wherein the antibody-drug conjugate is a group represented by the following formula:

[0036] [Section 28] Formula (2) is formula (YG-1), formula (YG-2), formula (YG-3) or formula (YG-4): [ka] (In the formula, mAb, Z, Y', h and q are as defined above.) 20. The antibody-drug conjugate or a pharma- ceutically acceptable salt thereof according to any one of items 14 to 19,

[0037] [Section 29] Formula (3-1) or Formula (3-2): [ka] [In the formula, h represents an integer from 1 to 5; G represents an alanine residue (Ala), an arginine residue (Arg), an asparagine residue (Asn), an aspartic acid residue (Asp), a cysteine ​​residue (Cys), a glutamine residue (Gln), a glutamic acid residue (Glu), a glycine residue (Gly), a histidine residue (His), an isoleucine residue (Ile), a leucine residue (Leu), a lysine residue (Lys), a methionine residue (Met), a phenylalanine residue (Phe), a proline residue (Pro), a serine residue (Ser), a threonine residue (Thr), a tryptophan residue (Trp), a tyrosine residue (Tyr), a valine residue (Val), or a citrulline residue (Cit); when there are a plurality of Gs, each G may be the same or different from the others, and Gs are bonded to each other via an amide bond; g represents an integer from 1 to 4; Y is a single bond or a group represented by the formula (Y-1): [ka] (In the formula, Y' represents a single bond or a carbonyl group; R 3 is a C optionally substituted with a halogen atom, a cyano group, or 1 to 5 fluorine atoms; 1-6 C optionally substituted with an alkyl group or 1 to 5 fluorine atoms 1-6 represents an alkoxy group, R 3 If there are multiple R 3 may be the same or different, f represents an integer between 0 and 2. is a group represented by * in formula (Y-1) 1 The end is bound to Z, Z is a group represented by the formula (Z-1), (Z-2), (Z-3), (Z-4), (Z-5), (Z-6), (Za-1), (Za-2), (Za-3), (Za-4), (Za-5), (Za-6), (Za-7), (Za-8), (Za-9), or (Za-10): [ka] [ka] [ka] (In these formulas, AA is Glu, Asp, Lys, Cys, a phosphotyrosine residue, a phosphoserine residue, or a cysteic acid residue, or any of these C 1-6 represents an alkyl ester, and when there are a plurality of AA, each AAs may be the same or different, and AAs are bonded to each other via an amide bond, (AA) mThe N-terminal nitrogen atom of forms an amide bond with the carbonyl group (a), (AA) n The N-terminal nitrogen atom of forms an amide bond with the carbonyl group (a), Q is represented by formula (Q-1), formula (Qa-2), formula (Qa-3), formula (Qa-4), formula (Qa-5), formula (Qa-6) or formula (Qa-7): [ka] (In the formula, R 2a , R 2b , R 2c , R 2d and R 2e each independently represents a hydrogen atom, a halogen atom, or C optionally substituted with 1 to 5 fluorine atoms; 1-6 C optionally substituted with an alkyl group or 1 to 5 fluorine atoms 1-6 represents an alkoxy group, R 2f is a hydrogen atom or C 1-6 represents an alkyl group, R aa , R ab and R ac each independently represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, an amino group, a carboxyl group, a phenyl group, or C optionally substituted with 1 to 3 fluorine atoms 1-6 Alkyl group, C 1-6 Alkoxy group or C 1-6 represents an alkyl ester group) represents a group represented by R 1a and R 1b are each independently a hydrogen atom or C 1-6 represents an alkyl group, R ad is a hydrogen atom or C 1-6 represents an alkyl group, m represents an integer from 1 to 10; n represents an integer of 0 to 4; R 4 is -(CH2) u -COR 7 represents u represents 1 or 2; R 5 and R 7 are each independently -OR 8 Or - (AB) p represents R 6 and R 8 are each independently a hydrogen atom or C 1-6 represents an alkyl group, AB represents Glu, Asp, or Lys, and when there are a plurality of AB, each AB may be the same or different, and AB are bonded to each other via an amide bond; p represents an integer of 1 to 4; However, R 5 or R 7 Ga-(AB) p when the sum of n and p is an integer from 1 to 5, i represents an integer from 1 to 12; provided that when Y' is a single bond, Z is a group represented by formula (Z-2), formula (Z-3), formula (Z-4), formula (Za-1), formula (Za-2), formula (Za-3), formula (Za-7) or formula (Za-8). A compound or a salt thereof represented by the formula:

[0038] [Section 30] Formula (3-1) or Formula (3-2): [ka] [In the formula, h represents an integer from 1 to 5; G represents an alanine residue (Ala), an arginine residue (Arg), an asparagine residue (Asn), an aspartic acid residue (Asp), a cysteine ​​residue (Cys), a glutamine residue (Gln), a glutamic acid residue (Glu), a glycine residue (Gly), a histidine residue (His), an isoleucine residue (Ile), a leucine residue (Leu), a lysine residue (Lys), a methionine residue (Met), a phenylalanine residue (Phe), a proline residue (Pro), a serine residue (Ser), a threonine residue (Thr), a tryptophan residue (Trp), a tyrosine residue (Tyr), a valine residue (Val), or a citrulline residue (Cit); when there are a plurality of Gs, each G may be the same or different from the others, and Gs are bonded to each other via an amide bond; g represents an integer from 1 to 4; Y is a single bond or a group represented by the formula (Y-1): [ka] (In the formula, Y' represents a single bond or a carbonyl group; R 3 is a C optionally substituted with a halogen atom, a cyano group, or 1 to 5 fluorine atoms; 1-6 C optionally substituted with an alkyl group or 1 to 5 fluorine atoms 1-6 represents an alkoxy group, R 3 If there are multiple R 3 may be the same or different, f represents an integer between 0 and 2. is a group represented by * in formula (Y-1) 1 The end is bound to Z, Z is represented by formula (Z-1), formula (Z-2), formula (Z-3), formula (Z-4), formula (Z-5) or formula (Z-6): [ka] (In these formulas, AA is Glu, Asp, Lys, or Cys, or any of these C 1-6represents an alkyl ester, and when there are a plurality of AA, each AAs may be the same or different, and AAs are bonded to each other via an amide bond, (AA) m The N-terminal nitrogen atom of forms an amide bond with the carbonyl group (a), (AA) n The N-terminal nitrogen atom of forms an amide bond with the carbonyl group (a), Q is an unsubstituted phenyl group or a group represented by formula (Q-1): [ka] (In the formula, R 2a , R 2b , R 2c , R 2d and R 2e each independently represents a hydrogen atom, a halogen atom, or C optionally substituted with 1 to 5 fluorine atoms; 1-6 C optionally substituted with an alkyl group or 1 to 5 fluorine atoms 1-6 represents an alkoxy group, R 2f is a hydrogen atom or C 1-6 represents an alkyl group) represents a group represented by R 1a and R 1b are each independently a hydrogen atom or C 1-6 represents an alkyl group, m represents an integer from 1 to 10; n represents an integer of 0 to 4; R 4 is -(CH2) u -COR 7 represents u represents 1 or 2; R 5 and R 7 are each independently -OR 8 Or - (AB) p represents R 6 and R 8 are each independently a hydrogen atom or C 1-6represents an alkyl group, AB represents Glu, Asp, or Lys, and when there are a plurality of AB, each AB may be the same or different, and AB are bonded to each other via an amide bond; p represents an integer of 1 to 4; However, R 5 or R 7 Ga-(AB) p When the sum of n and p is an integer from 1 to 5, i represents an integer from 1 to 12; However, when Y' is a single bond, Z is a group represented by formula (Z-2), formula (Z-3) or formula (Z-4). Represented by Item 30. The compound or salt thereof according to item 29.

[0039] [Section 31] Item 31. The compound or salt thereof according to item 29 or 30, which is represented by formula (3-1):

[0040] [Section 32] Item 32. The compound or salt thereof according to any one of items 29 to 31, wherein h is 5.

[0041] [Section 33] Item 31. The compound or salt thereof according to item 29 or 30, wherein i is 2.

[0042] [Section 34] (G) g but,* 2 -Gly-,* 2 -Gly-Gly-,* 2 -Lys-, * 2 -Lys-Phe-,* 2 -Lys-Val-, * 2 -Lys-Ala-, * 2 -Cit-Val-,* 2 -Cit-Phe-,* 2 -Cit-Leu-,* 2 -Arg-Phe-,* 2 -Cit-Ile-,* 2 -Cit-Trp-,* 2 -Lys-Phe-Phe-,*2 -Lys-Phe-Ala-, * 2 -Lys-Phe-Gly-,* 2 -Asn-, * 2 -Asn-Ala-, * 2 -Asn-Ala-Ala-, * 2 -Asn-Ala-Thr-, * 2 -Asn-Ala-Pro-, * 2 -Asn-Ala-Val-, * 2 -Asn-Ala-Phe-, * 2 -Asn-Ala-Tyr-, * 2 -Asn-Ala-Leu-,* 2 -Asn-Ala-Gly-, * 2 -Asn-Thr-Ala-, * 2 -Asn-Thr-Pro-, * 2 -Asn-Thr-Thr-, * 2 -Gly-Phe-Gly-Gly-,* 2 -Gly-Leu-Phe-Gly- or * 2 -Leu-Ala-Leu-Ala- (G) g of* 2 Item 34. The compound or salt thereof according to any one of Items 29 to 33, wherein the terminal is bonded to Y.

[0043] [Section 35] (G) g Formula (G-1), Formula (G-2), Formula (G-3) or Formula (G-4): [ka] is a group represented by (G) g of* 2 Item 34. The compound or salt thereof according to any one of Items 29 to 33, wherein the terminal is bonded to Y.

[0044] [Section 36] R 3 Fluorine atom, C 1-3 Alkyl group or C 1-3 is an alkoxy group, R 3If there are multiple R 3 and may be the same or different from each other, the compound or salt thereof according to any one of items 29 to 35.

[0045] [Section 37] Item 36. The compound or salt thereof according to any one of items 29 to 35, wherein f is 0.

[0046] [Section 38] Z is a group represented by formula (Z-2), formula (Z-3) or formula (Z-4), Q is an unsubstituted phenyl group or a group represented by formula (Q-2): [ka] (In the formula, R 2b and R 2c each independently represents a hydrogen atom, a fluorine atom, or a methoxy group. is a group represented by R 5 and R 7 is -OH, Item 38. The compound or salt thereof according to any one of items 29 to 37, wherein n is 1 or 2.

[0047] [Section 39] Z is a group represented by formula (Z-2), formula (Z-3) or formula (Z-4), Q is an unsubstituted phenyl group or a group represented by formula (Q-2): [ka] (In the formula, R 2b and R 2c each independently represents a hydrogen atom, a fluorine atom, or a methoxy group. is a group represented by R 5 and R 7 But -(AB) p and Item 38. The compound or salt thereof according to any one of items 29 to 37, wherein n is 0 and p is 2, or n and p are each 1.

[0048] [Section 40] ZY is represented by the formula (ZY-1): [ka] [In the formula, AA and m are as defined above. Q is an unsubstituted phenyl group or a formula (Q-2): [ka] (In the formula, R 2b and R 2c each independently represents a hydrogen atom, a fluorine atom, or a methoxy group. is a group represented by the formula: 36. The compound or salt thereof according to any one of items 29 to 35, wherein R is a group represented by the following formula:

[0049] [Section 41] ZY is represented by the formula (ZY-2): [ka] [In the formula, A.A., R. 1a , R 1b , R 6 and n is as defined above, Q is an unsubstituted phenyl group or a formula (Q-2): [ka] (In the formula, R 2b and R 2c each independently represents a hydrogen atom, a fluorine atom, or a methoxy group. is a group represented by the formula: 36. The compound or salt thereof according to any one of items 29 to 35, wherein R is a group represented by the following formula:

[0050] [Section 42] Formula (3-1) is Formula (MDF-1), Formula (MDF-2), Formula (MDF-3) or Formula (MDF-4): [ka] (In the formula, h, Y′, and Z are as defined above.) Item 33. The compound or salt thereof according to any one of items 29 to 32,

[0051] [Section 43] A pharmaceutical composition comprising the antibody-drug conjugate or a pharma- ceutically acceptable salt thereof according to any one of items 14 to 28.

[0052] [Section 44] The antibody-drug conjugate or a pharma- ceutical acceptable salt thereof according to any one of items 14 to 28, and one or more anticancer compounds selected from the group consisting of anticancer alkylating agents, anticancer antimetabolites, anticancer antibiotics, anticancer platinum coordination compounds, anticancer camptothecin derivatives, anticancer tyrosine kinase inhibitors, anticancer serine threonine kinase inhibitors, anticancer phospholipid kinase inhibitors, anticancer monoclonal antibodies, interferons, biological response modifiers, hormones, immune checkpoint inhibitors, epigenetics-related molecule inhibitors, and protein post-translational modification inhibitors, or pharma- ceutical compositions comprising the above-mentioned anticancer compounds and ...

[0053] [Section 45] 29. An anticancer agent comprising the antibody-drug conjugate or a pharma- ceutically acceptable salt thereof according to any one of items 14 to 28.

[0054] [Section 46] Item 46. The anticancer agent according to Item 45, wherein the cancer is breast cancer, stomach cancer, lung cancer, liver cancer, cervical cancer, colorectal cancer, rectal cancer, colon cancer, glioma, lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, urothelial cancer, skin cancer, thyroid cancer, bladder cancer, head and neck cancer, uterine cancer, mesothelioma, melanoma, multiple myeloma, or leukemia.

[0055] [Section 47] A method for treating cancer, comprising administering the antibody-drug conjugate or a pharma- ceutically acceptable salt thereof according to any one of items 14 to 28 to a patient in need of such treatment.

[0056] [Section 48] Item 14. Use of the compound or a salt thereof according to any one of items 1 to 13 for the production of an anticancer agent.

[0057] [Section 49] 30. Use of the antibody-drug conjugate or a pharma- ceutically acceptable salt thereof according to any one of items 14 to 28 for the manufacture of an anticancer agent.

[0058] [Section 50] Item 43. Use of the compound or a salt thereof according to any one of Items 29 to 42 for the production of an anticancer agent.

[0059] [Section 51] Item 30. The antibody-drug conjugate or a pharma- ceutically acceptable salt thereof according to any one of items 14 to 28, for use in the treatment of cancer.

[0060] [Section 52] Item 29. The antibody-drug conjugate or a pharma- ceutical acceptable salt thereof according to any one of Items 14 to 28, for use in combination with one or more anticancer compounds selected from the group consisting of anticancer alkylating agents, anticancer antimetabolites, anticancer antibiotics, anticancer platinum coordination compounds, anticancer camptothecin derivatives, anticancer tyrosine kinase inhibitors, anticancer serine-threonine kinase inhibitors, anticancer phospholipid kinase inhibitors, anticancer monoclonal antibodies, interferons, biological response modifiers, hormonal agents, immune checkpoint inhibitors, epigenetics-related molecule inhibitors, and protein post-translational modification inhibitors, for treating cancer. Effect of the Invention

[0061] The antibody-drug conjugate formed between the hemiasterlin derivative of the present invention and an antibody exhibits specific cytotoxic activity against antigen-expressing cells and has low cytotoxicity in cells other than antigen-expressing cells, and therefore can be used as an anticancer drug with excellent safety. [Brief description of the drawings]

[0062] [Figure 1] A figure showing the polymerization inhibitory activity of porcine tubulin in Examples 4, 9, 23, 28, 43 and 44. [Diagram 2] A figure showing the polymerization inhibitory activity of porcine tubulin in Examples 14, 24 and 27. [Diagram 3] FIG. 1 shows the therapeutic effects of Example ADC1 and Example ADC2 on Karpas-299 xenograft tumors (CD30 antigen positive) transplanted into SCID mice. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0063] <Hemiasterlin derivatives> The compound represented by formula (1) or formula (1a) or a salt thereof (hereinafter sometimes referred to as the "hemiasterlin derivative of the present invention") is as follows. [ka]

[0064] AA is a glutamic acid residue, an aspartic acid residue, a lysine residue, a cysteine ​​residue, a phosphotyrosine residue, a phosphoserine residue, or a cysteic acid residue, or 1-6 It represents an alkyl ester.

[0065] In this specification, unless otherwise necessary, the following three-letter abbreviations may be used to represent both α-amino acids and the corresponding amino acid residues. In addition, the optical activity of α-amino acids may include any of DL-, D-, or L-isomers unless otherwise specified. For example, "glutamic acid" or "Glu" represents DL-glutamic acid or a residue thereof, D-glutamic acid or a residue thereof, or L-glutamic acid or a residue thereof. Ala…alanine, Arg…arginine, Asn…asparagine, Asp…aspartic acid, Cit…citrulline, Cys…cysteine, Gln…glutamine, Glu…glutamic acid, Gly…glycine, His…histidine, Ile…isoleucine, Leu…leucine, Lys…lysine, Met…methionine, Phe…phenylalanine, Pro…proline, Ser…serine, Trp…tryptophan, Thr…threonine, Tyr…tyrosine, Val…valine

[0066] When AA is an amino acid residue, the hemiasterlin derivative contains a given amino acid residue: (AA) m Having this structure, cell membrane permeability is reduced, and even if free hemiasterlin derivatives are present in the blood, they are less likely to be taken up by cells, thereby suppressing cytotoxicity to normal cells.

[0067] The amino acid residue AA is preferably Glu or Asp, more specifically, D-Glu, L-Glu, D-Asp or L-Asp. When there are multiple AA, each AA may be the same or different.

[0068] On the other hand, AA is the amino acid residue C 1-6 When the hemiasterlin derivative is an alkyl ester, the cell membrane permeability of the derivative is higher than when AA is an amino acid residue. However, when administered as a drug, the ester bond is quickly hydrolyzed by enzymes such as esterases present in the blood. Therefore, the C of a specific amino acid residue 1-6 Contains alkyl esters (AA) mThe hemiasterlin derivative having the structure contains a specific amino acid residue (AA) in blood. m Since it becomes a hemiasterlin derivative having the structure, its cell membrane permeability is reduced, and cytotoxicity to normal cells is suppressed.

[0069] "C 1-6 An "alkyl ester" is an ester (-COOR') in which R' is 1-6 The term "alkyl group" refers to an ester of the group "alkyl group."

[0070] "C 1-6 The term "alkyl group" means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. 1-6 As the alkyl group, preferably "C 1-4 More preferably, "C 1-3 Preferred examples include an alkyl group, a methyl group, an ethyl group, a propyl group, or an isopropyl group, and particularly preferred examples include a methyl group or an ethyl group.

[0071] "C 1-3 Specific examples of the alkyl group include a methyl group, an ethyl group, a propyl group, and an isopropyl group. 1-4 Specific examples of the alkyl group include, for example, "C 1-3 In addition to the specific examples of the alkyl group, examples of the alkyl group include a butyl group, a 1,1-dimethylethyl group, a 1-methylpropyl group, and a 2-methylpropyl group. 1-6 Specific examples of the alkyl group include "C 1-4 In addition to those given as specific examples of "alkyl group," examples include a pentyl group, a 3-methylbutyl group, a 2-methylbutyl group, a 2,2-dimethylpropyl group, a 1-ethylpropyl group, a 1,1-dimethylpropyl group, a hexyl group, a 4-methylpentyl group, a 3-methylpentyl group, a 2-methylpentyl group, a 1-methylpentyl group, a 3,3-dimethylbutyl group, a 2,2-dimethylbutyl group, a 1,1-dimethylbutyl group, and a 1,2-dimethylbutyl group.

[0072] "C 1-6As the "alkyl ester", preferably "C 1-4 More preferably, "C 1-3 Preferred examples include methyl ester, ethyl ester, isopropyl ester, and tertiary butyl ester, and particularly preferred examples include methyl ester and ethyl ester.

[0073] "C 1-3 Specific examples of "alkyl ester" include, for example, methyl ester, ethyl ester, propyl ester, and isopropyl ester. 1-4 Specific examples of "alkyl esters" include "C 1-3 In addition to the specific examples of "alkyl esters," butyl esters, tertiary butyl esters, etc. are also included. 1-6 Specific examples of "alkyl esters" include "C 1-4 In addition to the specific examples of "alkyl ester," examples thereof include pentyl ester, 3-methylbutyl ester, 2-methylbutyl ester, 2,2-dimethylpropyl ester, 1-ethylpropyl ester, 1,1-dimethylpropyl ester, hexyl ester, 4-methylpentyl ester, 3-methylpentyl ester, 2-methylpentyl ester, 1-methylpentyl ester, 3,3-dimethylbutyl ester, 2,2-dimethylbutyl ester, 1,1-dimethylbutyl ester, and 1,2-dimethylbutyl ester.

[0074] m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment, m is an integer from 1 to 5 or an integer from 1 to 3, and in another embodiment, m is an integer from 2 to 10 or an integer from 3 to 10.

[0075] When there are a plurality of AA, each AA may be the same or different from the others, and the AA are bonded to each other via an amide bond. 1-6 The carboxyl group of the alkyl ester and other amino acids or their C1-6 This means that the amino group of the alkyl ester is condensed with the amino group of the alkyl ester to form an amide bond. For example, in the formula (1), when m is 2 and both AA are Glu, the nitrogen atom (d) of one Glu and the carbonyl group (c) of the other Glu may be linked to each other by forming an amide bond as shown in the following formula: [ka]

[0076] In one embodiment, m is an integer from 2 to 10, and (AA) m In another embodiment, m is an integer of 3 to 10, and (AA) m is a branched peptide residue having one or two branch points.

[0077] The term "linear peptide residue" refers to 2 to 10 amino acids or their Cs independently selected from the group consisting of Glu, Asp, Lys, Cys, phosphotyrosine, phosphoserine, and cysteic acid. 1-6 The alkyl ester is an amino acid or its C 1-6 The carboxyl group of the alkyl ester and other amino acids or their C 1-6 This means that an amide bond (-CONH-) is formed by condensing with the amino group of the alkyl ester to form a single-chain amino acid linked structure. The "linear peptide residue" preferably includes a linear peptide residue composed of 3 to 7 amino acid residues, more preferably a linear peptide residue composed of 3 to 5 amino acid residues, and even more preferably a linear peptide residue composed of 3 amino acid residues.

[0078] The term "branched peptide residue having one or two branching points" refers to a peptide having 3 to 10 amino acids independently selected from the group consisting of Glu, Asp, Lys, Cys, phosphotyrosine, phosphoserine, and cysteic acid, each of which is connected to one amino acid or its C. 1-6 The carboxyl group of the alkyl ester and other amino acids or their C 1-6This means that an amide bond is formed by condensing with the amino group of the alkyl ester, resulting in an amino acid linked structure having one or two branched positions in the structure. The "branched peptide residue having one or two branching points" preferably includes a branched peptide group having one or two branching points composed of 3 to 7 amino acid residues, more preferably a branched peptide residue having one or two branching points composed of 3 to 5 amino acid residues, and even more preferably a branched peptide residue having one branching point composed of 3 amino acid residues.

[0079] (AA) m is expressed by the formula (A-1): [ka] (In the formula, AA1, AA2, and AA3 each independently represent Glu, Asp, or Lys.) It is preferable that AA2-AA1-AA3 is a group represented by the following formula: AA2-AA1-AA3 is preferably Glu-Glu-Glu.

[0080] (AA) m The N-terminal nitrogen atom of AA forms an amide bond together with the carbonyl group (a). For example, when AA is Asp, the nitrogen atom (b) and the carbonyl group (a) of Asp are linked together by forming an amide bond as shown in the following formula: [ka]

[0081] R 1a and R 1b are each independently a hydrogen atom or C 1-6 Represents an alkyl group. 1a and R 1b are preferably each independently a hydrogen atom or C 1-3An alkyl group is preferable, a hydrogen atom, a methyl group, or an ethyl group is more preferable, and a hydrogen atom or a methyl group is particularly preferable. 1a is a methyl group, and R 1b is a hydrogen atom.

[0082] In this specification, a hydrogen atom is 1 Even if it is H. 2 H(D). That is, for example, one or more compounds represented by formula (1) 1 H 2 Deuterium converted to H(D) is also included in the compound represented by formula (1).

[0083] R ad is a hydrogen atom or C 1-6 Represents an alkyl group. ad is preferably a hydrogen atom, a methyl group, an ethyl group, a propyl group or an isopropyl group.

[0084] Q is represented by formula (Q-1), formula (Qa-2), formula (Qa-3), formula (Qa-4), formula (Qa-5), formula (Qa-6) or formula (Qa-7): [ka] It represents a group represented by the following formula:

[0085] In formula (Q-1), R 2a , R 2b , R 2c , R 2d and R 2e each independently represents a hydrogen atom, a halogen atom, or C optionally substituted with 1 to 5 fluorine atoms; 1-6 C optionally substituted with an alkyl group or 1 to 5 fluorine atoms 1-6 represents an alkoxy group, R 2f is a hydrogen atom or C 1-6 In formula (Qa-2), R aa , R ab and R aceach independently represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, an amino group, a carboxyl group, a phenyl group, or C optionally substituted with 1 to 3 fluorine atoms 1-6 Alkyl group, C 1-6 Alkoxy group or C 1-6 Represents an alkyl ester group.

[0086] "C 1-6 The term "alkyl group" has the same meaning as above. The number of substituents in a group defined as "optionally substituted" is not particularly limited as long as it is substitutable, unless otherwise specified. In addition, unless otherwise specified, the explanation of each group also applies to the case where the group is a part or a substituent of another group.

[0087] "C 1-6 An alkoxy group is a 1-6 "C" means an oxy group substituted with an alkyl group. 1-6 As the "alkoxy group", preferably "C 1-4 An alkoxy group is preferably used. 1-3 Preferred examples include an alkoxy group, a methoxy group, an ethoxy group, a propoxy group, or a 1-methylethoxy group, and particularly preferred examples include a methoxy group or an ethoxy group.

[0088] "C 1-3 Specific examples of the "alkoxy group" include a methoxy group, an ethoxy group, a propoxy group, and a 1-methylethoxy group. 1-4 Specific examples of the "alkoxy group" include "C 1-3 In addition to the specific examples of the "alkoxy group," examples of the "alkoxy group" include a butoxy group, a 1,1-dimethylethoxy group, a 1-methylpropoxy group, and a 2-methylpropoxy group. 1-6 Specific examples of the "alkoxy group" include "C 1-4In addition to the examples given as specific examples of the "alkoxy group," examples include a pentyloxy group, a 3-methylbutoxy group, a 2-methylbutoxy group, a 2,2-dimethylpropoxy group, a 1-ethylpropoxy group, a 1,1-dimethylpropoxy group, a hexyloxy group, a 4-methylpentyloxy group, a 3-methylpentyloxy group, a 2-methylpentyloxy group, a 1-methylpentyloxy group, a 3,3-dimethylbutoxy group, a 2,2-dimethylbutoxy group, a 1,1-dimethylbutoxy group, and a 1,2-dimethylbutoxy group.

[0089] The term "halogen atom" includes a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. Preferably, a fluorine atom or a chlorine atom is used, and more preferably, a fluorine atom is used.

[0090] R 2a , R 2b , R 2c , R 2d and R 2e are preferably each independently a hydrogen atom, a halogen atom, or C optionally substituted with 1 to 5 fluorine atoms. 1-3 C optionally substituted with an alkyl group or 1 to 5 fluorine atoms 1-3 An alkoxy group is preferable, and a hydrogen atom, a fluorine atom, a chlorine atom, or a C 1-3 Alkyl group or C 1-3 An alkoxy group is preferably a hydrogen atom, a fluorine atom, or a C 1-3 R is preferably an alkoxy group, more preferably a hydrogen atom, a fluorine atom or a methoxy group, and most preferably a hydrogen atom. 2a , R 2b , R 2c , R 2d and R 2e may be the same or different.

[0091] R 2f is preferably a hydrogen atom or C 1-3 Examples of the alkyl group include an alkyl group, more preferably a hydrogen atom, a methyl group, or an ethyl group, particularly preferably a hydrogen atom or a methyl group, and most preferably a methyl group.

[0092] R aa , R ab and R ac are preferably each independently a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, a cyano group, a carboxyl group, a phenyl group, a trifluoromethyl group, a methyl group, a methoxy group, a methyl ester group, an ethyl ester group, or a tert-butyl ester group, and more preferably all are a hydrogen atom.

[0093] Q may be a group represented by formula (Qa-2) or formula (Q-1), may be an unsubstituted phenyl group or a group represented by formula (Q-1), and may be a group represented by formula (Q-2): [ka] In formula (Q-2), R 2b and R 2c are preferably each independently a hydrogen atom, a halogen atom, or C 1-6 Alkyl group or C 1-6 Each of them is preferably an alkoxy group, more preferably each of them is independently a hydrogen atom, a fluorine atom or a methoxy group, and further preferably each of them is a hydrogen atom.

[0094] One embodiment of the hemiasterlin derivative of the present invention is the following (1-A). (1-A) In formula (1), AA is Glu or Asp; Q is a group represented by formula (Q-2), R 1a is a methyl group, R 1b is a hydrogen atom, R 2b and R 2c is a hydrogen atom, m is 1 or 2; A compound or a salt thereof.

[0095] One embodiment of the hemiasterlin derivative of the present invention is the following (1-B). (1-B) In formula (1), AA is Glu or Asp; Q is an unsubstituted phenyl group; R 1a is a methyl group, R 1b is a hydrogen atom, m is 1 or 2; A compound or a salt thereof.

[0096] One embodiment of the hemiasterlin derivative of the present invention is the following (1-C). (1-C) In formula (1), AA is Glu, Asp, Lys or Cys; Q is a group represented by formula (Q-2), R 1a is a methyl group, R 1b is a hydrogen atom, R 2b and R 2c is a hydrogen atom, m is 1, A compound or a salt thereof.

[0097] One embodiment of the hemiasterlin derivative of the present invention is the following (1-D). (1-D) In formula (1), AA is Glu, Asp, Lys or Cys; Q is an unsubstituted phenyl group; R 1a is a methyl group, R 1b is a hydrogen atom, m is 1, A compound or a salt thereof.

[0098] An embodiment of the hemiasterlin derivative of the present invention includes the following compound. [ka]

[0099] <Antibody-drug conjugates> The antibody-drug conjugate represented by formula (2) or a pharma- ceutically acceptable salt thereof (hereinafter sometimes referred to as the "antibody-drug conjugate of the present invention") is a conjugate in which an antibody moiety derived from an antibody molecule and a drug moiety derived from a drug molecule are covalently bonded via a linker, as shown below. In this specification, the "antibody-drug conjugate" is also referred to as an "ADC." [ka]

[0100] "Z" in the drug moiety is a group represented by formula (Z-1), (Z-2), (Z-3), (Z-4), (Z-5), (Z-6), (Za-1), (Za-2), (Za-3), (Za-4), (Za-5), (Za-6), (Za-7), (Za-8), (Za-9) or (Za-10) below. [ka] [ka] [ka] However, when Y' described later is a single bond, Z is a group represented by formula (Z-2), formula (Z-3), formula (Z-4), formula (Za-1), formula (Za-2), formula (Za-3), formula (Za-7) or formula (Za-8).

[0101] In these formulas, AA and (AA) m , Q, R 1a , R 1b , R adThe details of (AA) are the same as those of the compound of formula (1) or (1a) above, unless otherwise specified. n The N-terminal nitrogen atom of the compound (AA) forms an amide bond together with the carbonyl group (a). m This is equivalent to the N-terminal nitrogen atom of the above forming an amide bond together with the carbonyl group (a).

[0102] An embodiment of Z includes a group represented by formula (Z-1), formula (Z-5) or formula (Z-6), and another embodiment includes a group represented by formula (Z-2), formula (Z-3) or formula (Z-4).

[0103] n is 0, 1, 2, 3, or 4. One embodiment of n is an integer of 0 to 2, another embodiment is 0 or 1, another embodiment is 1 or 2, another embodiment is an integer of 1 to 3, and another embodiment is 0.

[0104] R 4 is -(CH2) u -COR 7 where u represents 1 or 2. 5 and R 7 are each independently -OR 8 Or - (AB) p AB represents Glu, Asp or Lys, and when there are a plurality of AB, each AB may be the same or different, and AB are bonded to each other via an amide bond.

[0105] p is 1, 2, 3, or 4. One embodiment of p is 1 or 2, another embodiment is 1, another embodiment is 2, another embodiment is an integer from 1 to 3, and another embodiment is 3.

[0106] R 5 or R 7 Ga-(AB) pIn the above embodiment, the sum of n and p is 1, 2, 3, 4, or 5. One embodiment of the sum of n and p is an integer of 1 to 4, another embodiment is an integer of 1 to 3, and another embodiment is 1 or 2.

[0107] R 6 and R 8 are each independently a hydrogen atom or C 1-6 Represents an alkyl group. 6 and R 8 are preferably each independently a hydrogen atom or C 1-3 Examples of the alkyl group include an alkyl group, more preferably a hydrogen atom, a methyl group, or an ethyl group, particularly preferably a hydrogen atom or a methyl group, and most preferably a hydrogen atom.

[0108] Y, which is part of the linker moiety and is attached to the drug moiety Z, is a single bond or a group represented by formula (Y-1), and * of the group represented by formula (Y-1) 1 The end is bound to Z. [ka]

[0109] In formula (Y-1), Y' represents a single bond or a carbonyl group, and R 3 is a C optionally substituted with a halogen atom, a cyano group, or 1 to 5 fluorine atoms; 1-6 C optionally substituted with an alkyl group or 1 to 5 fluorine atoms 1-6 represents an alkoxy group, R 3 If there are multiple R 3 may be the same or different. 3 As an embodiment of the above, a fluorine atom, C 1-3 Alkyl group or C 1-3 R is an alkoxy group. 3 If there are multiple R 3 may be the same or different. f is an integer of 0 to 2, and one embodiment of f is 0, another embodiment is 1, and another embodiment is 2.

[0110] (G) is part of the linker and is attached to Y. g In the formula (G), G represents Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Val, or Cit. When there are multiple Gs, each G may be the same or different from the others, and Gs are bonded to each other via an amide bond, and (G) g of* 2 The end is bound to Y.

[0111] (G) g As one aspect of 2 -Gly-,* 2 -Gly-Gly-,* 2 -Lys-, * 2 -Lys-Phe-,* 2 -Lys-Val-, * 2 -Lys-Ala-, * 2 -Cit-Val-,* 2 -Cit-Phe-,* 2 -Cit-Leu-,* 2 -Arg-Phe-,* 2 -Cit-Ile-,* 2 -Cit-Trp-,* 2 -Lys-Phe-Phe-,* 2 -Lys-Phe-Ala-, * 2 -Lys-Phe-Gly-,* 2 -Asn-, * 2 -Asn-Ala-, * 2 -Asn-Ala-Ala-, * 2 -Asn-Ala-Thr-, * 2 -Asn-Ala-Pro-, * 2 -Asn-Ala-Val-, * 2 -Asn-Ala-Phe-, * 2 -Asn-Ala-Tyr-, * 2 -Asn-Ala-Leu-,* 2 -Asn-Ala-Gly-, * 2 -Asn-Thr-Ala-, * 2-Asn-Thr-Pro-, * 2 -Asn-Thr-Thr-, * 2 -Gly-Phe-Gly-Gly-,* 2 -Gly-Leu-Phe-Gly- or * 2 -Leu-Ala-Leu-Ala-, (G) g of* 2 An embodiment in which the end is bound to Y is given.

[0112] The antibody-drug conjugate of the present invention is first reacted in vivo with the compound represented by the formula (2) Y-(G) g It is presumed that the bond between Z and Y is cleaved, and then the bond between Z and Y is cleaved, thereby releasing the drug moiety Z.

[0113] Y-(G) g The bond is cleaved by an intracellular peptidase, protease (eg, lysosomal protease or endosomal protease), etc., present in the intracellular environment (eg, within a lysosome, endosome, or caveolea).

[0114] As a protease present in the intracellular environment, for example, cathepsin B is known. Y-(G) by cathepsin B g The cleavage of the bond is described in Dubowchik GM, et. al., 1998, Bioorg. Med. Chem. Lett., 8:3341-3346, etc. Y-(G) bond cleaved by cathepsin B g Specific examples include Y-Lys-Phe, Y-Lys-Val, Y-Lys-Ala, Y-Lys-Phe-Phe, Y-Lys-Phe-Ala, Y-Lys-Ph. Examples include e-Gly, Y-Lys, Y-Cit-Val, Y-Cit-Phe, Y-Cit-Leu, Y-Cit-Ile, Y-Cit-Trp, Y-Arg-Phe, and the like.

[0115] Aspartic endopeptidase is known as another protease present in the intracellular environment.g The cleavage of the bond is described in Dando M. P., et. al., 1999, Biochem. J. 339: 743-749, etc. Y-(G) bond cleaved by asparagine endopeptidase g Specific examples include Y-Asn-Ala-Ala, Y-Asn-Ala-Thr, Y-Asn-Ala-Val, Y-Asn-Ala-Pro, Y-Asn-Ala-Phe, Y-Asn-Ala-Tyr, Y-Asn-Ala-Leu, and Y-Asn-Ala-Gly.

[0116] The hypothesized mechanisms of drug release from the antibody-drug conjugate of the present invention, in which Y is a group represented by formula (Y-1), in an intracellular environment are shown below. These drug release mechanisms are based on the report by Toki et al. (Non-Patent Document 7). [ka]

[0117] (G) g One aspect of the above is as follows: 2 -Lys-Phe-,* 2 -Lys-Val-, * 2 -Lys-Ala-, * 2 -Lys-Phe-Phe-,* 2 -Lys-Phe-Ala-, * 2 -Lys-Phe-Gly-,* 2 -Lys-, * 2 -Cit-Val-,* 2 -Cit-Phe-,* 2 -Cit-Leu-,* 2 -Cit-Ile-,* 2 -Cit-Trp-, and * 2 -Arg-Phe-. Also, (G) g Another embodiment of the present invention is 2 -Asn-Ala-Ala-, * 2 -Asn-Ala-Tyr-, * 2 -Asn-Ala-Val-, * 2 -Asn-Ala-Pro-, * 2-Asn-Ala-Phe-, * 2 -Asn-Ala-Leu-, and * 2 -Asn-Ala-Gly-.

[0118] (G) g Another embodiment of the formula (G-1), (G-2), (G-3) or (G-4) is a group represented by the formula (G-1), (G-2), (G-3) or (G-4). 2 " means (G) g This shows the end that is bound to Y. That is, (G) g is Y and * 2 It is joined at the side. [ka]

[0119] g is 1, 2, 3, or 4. One embodiment of g is an integer of 1 to 3, and another embodiment is 2 or 3.

[0120] h is 1, 2, 3, 4, or 5. One embodiment of h is an integer from 2 to 5, another embodiment is an integer from 3 to 5, and another embodiment is 4 or 5.

[0121] One embodiment of the antibody-drug conjugate of the present invention is represented by the formula (2): Z is a group represented by formula (Z-2), formula (Z-3) or formula (Z-4), Q is an unsubstituted phenyl group or a group represented by formula (Q-2), R 5 and R 7 is -OH, n is 0 or 1; The antibody-drug conjugate or a pharma- ceutically acceptable salt thereof.

[0122] One embodiment of the antibody-drug conjugate of the present invention is represented by the formula (2): Z is a group represented by formula (Z-2), formula (Z-3) or formula (Z-4), Q is an unsubstituted phenyl group or a group represented by formula (Q-2), R 5 and R 7 Ga-(AB) p and n is 0 and p is 2, or n and p are each 1; The antibody-drug conjugate or a pharma- ceutically acceptable salt thereof.

[0123] One embodiment of ZY in the antibody-drug conjugate of the present invention is a group represented by the following formula (ZY-1): [ka] (In the formula, AA and m are defined as above, and Q is an unsubstituted phenyl group or a group represented by formula (Q-2).)

[0124] One embodiment of ZY in the drug-antibody-drug conjugate of the present invention is a group represented by the following formula (ZY-2): [ka] (In the formula, AA, R 1a , R 1b , R 6 and n are as defined above, and Q is an unsubstituted phenyl group or a group represented by formula (Q-2).

[0125] q indicates the drug antibody ratio (also referred to as Drug Antibody Ratio, or DAR) in the antibody-drug conjugate molecule represented by formula (2). The drug antibody ratio q means the number of drug molecules per antibody molecule in one antibody-drug conjugate molecule, i.e., per antibody-drug conjugate molecule. Note that an antibody-drug conjugate obtained by chemical synthesis is often a mixture of multiple antibody-drug conjugate molecules that may have different drug antibody ratios q. In this specification, the overall drug antibody ratio in such a mixture of antibody-drug conjugates (i.e., the average value of the drug antibody ratios q of each antibody-drug conjugate) is referred to as the "average drug antibody ratio" or "average DAR".

[0126] q is 1, 2, 3, 4, 5, 6, 7, or 8. One embodiment of q is an integer from 2 to 8, another embodiment is an integer from 2 to 6, another embodiment is an integer from 4 to 8, another embodiment is 2 or 4, another embodiment is 6 or 8, and another embodiment is 8.

[0127] One embodiment of the average DAR is 2 to 8, another embodiment is 3.5 to 4.5, and another embodiment is 1 to 2, 2 to 3, 3 to 4, 4 to 5, 5 to 6, 6 to 7, or 7 to 8. The average DAR can be determined by a method commonly used for determining the average DAR, such as SDS-PAGE, mass spectrometry, ELISA (enzyme-linked immunosorbent assay), HPLC (high performance liquid chromatography), etc. An antibody-drug conjugate having a specific DAR can be separated, purified, and characterized from a mixture of antibody-drug conjugates having different DARs by a method such as hydrophobic interaction column chromatography (HIC) HPLC, reversed-phase HPLC, electrophoresis, etc.

[0128] The antibody mAb is not particularly limited as long as it is an antibody capable of recognizing an antigen present on the surface of a target cell. The target cell may be any cell that requires treatment with a hemiasterlin derivative, and is preferably a cancer cell. The antigen present on the surface of the target cell is preferably an antigen specific to the target cell that is not expressed or is expressed in a small amount in normal cells. One embodiment of the mAb includes the known antibodies listed above, and another embodiment includes brentuximab, trastuzumab, inotuzumab, gemtuzumab, glembatumumab, labetuzumab, sacituzumab, rifastuzumab, indusatuzumab, polatuzumab, pinatuzumab, cortuximab, indatuximab, milatuzumab, rovalpituzumab, anetuzumab, tisotumab, miabetuximab, lorvotuzumab, rituximab, depatuxizumab, denintuzumab, Tersotuzumab, Bundletuzumab, Sofituzumab, Borsetuzumab, Mirvetuximab, Naratuximab, Cantuzumab, Laprituximab, Bivatuzumab, Vadastuximab, Rupartumab, Apurutuzumab, Avagovomab, Abciximab, Avituzumab, Abrilumab, Actoxumab, Adalivumab, Adecatumumab, Aducanumab, Afacevicumab, Afelimomab, Alacizumab, Alemtuzumab, Alirocumab, Altumomab, Amatuximab, A Natumomab, anifrolumab, anrukinzumab, apolizumab, arcitumomab, asclinbacumab, acelizumab, atezolizumab, atinumab, atorolimumab, avelumab, azintuxizumab, bapinezumab, basiliximab, bavituximab, bectumomab, begelomab, belimumab, benralizumab, bertilimumab, besilesomab, bevacizumab, bezlotoxumab, biciromab, bimagrumab, bimekizumab, bleselumab, blinatumomab, bro Ntubetumab, brosozumab, bococizumab, brazikumab, briakinumab, brodalumab, brolucizumab, brontixutuzumab, burosumab, cabilalizumab, camrelizumab, caplacizumab, capromab, carlumab, carotuximab, catumazomab, cedelizumab, certolizumab, cetuximab, sitatuzumab, sikisumab, serenoliximab, clivatuzumab, codrituzumab, conatumumab, concizumab, cosfrobiximab, crenezumab,Crizanlizumab, Clotedumab, Dacetuzumab, Daclizumab, Dalotuzumab, Dapirorizumab, Daratumumab, Dectrecumab, Demcizumab, Denosumab, Detumomab, Desamizumab, Dinutuximab, Zilidabumab, Domaglozumab, Dorlimomab, Drozitumab, Durigotuzumab, Dupilumab, Durvalumab, Dusigitumab, Duvortuxizumab, Eclomeximab, Eculizumab, Edobacomab, Edrecolomab, Efalizumab, Efungumab, Eldelumab, Elezamumab, Elotuzumab, Elclimomab, Elclimomab, Emactuzumab , emapalumab, emibetuzumab, emicizumab, enavatuzumab, enlimomab, enoblitzumab, enokizumab, enoticumab, encituximab, epitumomab, epratuzumab, eptinezumab, erenumab, erlizumab, ertumaxomab, etaracizumab, etrolizumab, evinacumab, evolocumab, exbivirumab, faralimomab, farletuzumab, fasinumab, felvizumab, fezakinumab, ficlatuzumab, figitumumab, filibumab, flavotumab, fretikumab, fontolizumab, foralumab, f Folavirumab, fremanezumab, fresolimumab, furunevetomab, furanumab, futuximab, galcanezumab, galiximab, ganitumab, gantenerumab, gatipotuzumab, gavilimomab, gedivumab, gevokizumab, gilvetomab, girentuximab, golimumab, guselkumab, ibalizumab, ibritumomab, icrucumab, idarucizumab, ifavotuzumab, igovomab, imalumab, imciromab, imgatuzumab, inlacumab, inebilizumab, infliximab, inolimomab, intetumumab, ipilimumab, iratum Mab, isatuximab, itolizumab, ixekizumab, keliximab, lakunotumab, lampalizumab, lanadelumab, landgrozumab, ralcaviciximab, lebrikizumab, remaresomab, lenzilumab, lerdelimumab, lesofabumab, letolizumab, lexatumumab, ribililumab, rifatuzumab, ligelizumab, rilotomab, lintuzumab, lirilumab, roderucizumab, lokivetomab, rolovotuzumab, rosatuximab, lucatumumab, lurizumab, lumuletuzumab, rutikizumab, mapatumumab, margetuximab, masalimoumab,Matuzumab, mavrilimumab, mepolizumab, metelimu- mab, minitherumomab, mitumomab, modotuximab, mogamulizumab, monalizumab, morolizumab, motavizumab, moxetumomab, muromonab, nacolomab, namilumab, naptumomab, narnalumab, natalizumab, navicixizumab, nabivumab, nebacumab, necitumumab, nemolizumab, nerelimomab, nesbacumab, nimotuzumab, nivolumab, obiltoxaximab, obinutuzumab, ocralizumab, ocrelizumab, odulimomab, ofatumumab, olaratumab, orek lumab, orendalizumab, olokizumab, omalizumab, onartuzumab, ontuxizumab, opicinumab, oportuzumab, oregovomab, oreticumab, olticumab, otelixizumab, otlertuzumab, oxelumab, ozanezumab, ozoralizumab, pagibaximab, palivizumab, pamrevlumab, panitumumab, panobacumab, palsatuzumab, pascolizumab, pasotuxizumab, pateclizumab, patritumab, pembrolizumab, perakizumab, pertuzumab, pexelizumab, pidilizumab, placumab, prozalizumab , ponezumab, polgabiximab, prezalumab, priliximab, plitoxaximab, pritumumab, quilizumab, racotumomab, radletumab, rafivirumab, ralpancizumab, ramucirumab, ranevetomab, ranibizumab, raxibacumab, refanezumab, regavirumab, lemtolumab, reslizumab, rilotumumab, linikumab, risankizumab, rivavazumab, lobatumumab, loredumab, romosozumab, rontalizumab, rosmantuzumab, rovelizumab, rozanolixizumab, ruplizumab, samalizumab, sarilumab, sat Ralizumab, satumomab, secukinumab, cericlerumab, seribantumab, setoxaximab, sevirumab, sibrotuzumab, sifalimumab, siltuximab, simtuzumab, siplizumab, sirukumab, solanezumab, solitomab, sontuzumab, stamulumab, sulesomab, sumtabumab, subizumab, subratocumab, tabalumab, tadocizumab, talizumab, tamtubetomab, tanezumab, taplitumomab, talexuzumab, tablitumomab, tabolixizumab, fanolesomab, nofetumomab, pintumomab, tefibazumab, terimomab, telisozumab,Tenatumomab, teneliximab, teplizumab, teprotumumab, tesidolumab, tezepelumab, tigatuzumab, tildrakizumab, timigtuzumab, timolumab, tocilizumab, tomzotuximab, toralizumab, tosatoxumab, tositumomab, tobetumab, tralokinumab, tregalizumab, tremelimumab, trevoglumab, tukoglumab Tuzumab, tuvilumab, ublituximab, urocupulumab, urelumab, urtoxazumab, ustekinumab, utomilumab, vanticutumab, vanucizumab, bapaliximab, valisacumab, varlilumab, batelizumab, vedolizumab, beltuzumab, bepalimomab, besencumab, visilizumab, bovalilizumab, volociximab, bon Examples of the antibody include lerolizumab, votumumab, bunakizumab, tacatuzumab, zaltuzumab, zanolimumab, diralimumab, zolimomab, or an anti-envidin antibody; another embodiment includes brentuximab, trastuzumab, inotuzumab, gemtuzumab, labetuzumab, polatuzumab, cortuximab, indatuximab, anetumab, rituximab, denintuzumab, laprituximab, vadastuximab, glembatumumab, cetuximab, alemtuzumab, depatuxizumab, or an anti-envidin antibody; another embodiment includes brentuximab, trastuzumab, rituximab, or an anti-envidin antibody; another embodiment includes brentuximab or trastuzumab.

[0129] Another embodiment of the mAb includes anti-19A antibody, anti-AXL antibody, anti-BCMA antibody, anti-C4.4a antibody, anti-CA6 antibody, anti-CA9 antibody, anti-CA-125 antibody, anti-cadherin-6 antibody, anti-CD166 antibody, anti-CD 19 antibodies, anti-CD20 antibodies, anti-CD22 antibodies, anti-CD25 antibodies, anti-CD27 antibodies, anti-CD30 antibodies, anti-CD33 antibodies, anti-CD37 antibodies, anti-CD40 antibodies, anti-CD41 antibodies, anti-CD44v6 antibodies, anti-CD51 Antibodies, anti-CD52 antibody, anti-CD56 antibody, anti-CD70 antibody, anti-CD74 antibody, anti-CD79 antibody, anti-CD79b antibody, anti-CEACAM5 antibody, anti-c-Met antibody, anti-DLL3 antibody, anti-DPEP3 antibody, anti-E GFR antibody, anti-EGFRvIII antibody, anti-ENPP3 antibody, anti-EpCAM antibody, anti-EphA4 antibody, anti-FGFR2 antibody, anti-FGFR3 antibody, anti-FTL3 antibody, anti-folate receptor α antibody, anti-glypican-3 antibody, anti- gpNMB antibody, anti-HER2 antibody, anti-HER3 antibody, anti-IL-3RA antibody, anti-LAMP1 antibody, anti-LIV-1 antibody, anti-LRRC15 antibody, anti-Ly6E antibody, anti-mesothelin antibody, anti-MUC-16 antibody, anti-N aPi2b antibody, anti-Nectin-4 antibody, anti-CD352 antibody, anti-P-cadherin antibody, anti-PMSA antibody, anti-protein tyrosine kinase 7 antibody, anti-SLITRK antibody, anti-STEAP1 antibody, anti-CD138 antibody , anti-tissue factor antibody, anti-CD71 antibody, anti-TIM-1 antibody, anti-Trop2 antibody, anti-5T4 antibody, anti-B7-H3 antibody, anti-CD163 macrophage receptor antibody, anti-CD38 antibody, anti-CD48 antibody, anti-cKit antibody, anti-guanylate cyclase C antibody, anti-gastrin releasing peptide antibody, anti-solute transporter antibody, anti-tumor-associated MUC-1 antibody, anti-GD2 antibody, anti-α4β7 integrin antibody, or anti-embodiin antibody. Another embodiment of the mAb includes anti-CD19 antibody, anti-CD20 antibody, anti-CD22 antibody, anti-CD30 antibody, anti-CD33 antibody, anti-CD52 antibody, anti-CD70 antibody, anti-CD79b antibody, anti-CEACAM5 antibody, anti-EGFR antibody, anti-EGFRvIII antibody, anti-gpNMB antibody, anti-HER2 antibody, anti-mesothelin antibody, anti-CD138 antibody, anti-CD38 antibody, or anti-GD2 antibody.Another embodiment of the mAb includes an anti-CD19 antibody, an anti-CD20 antibody, an anti-CD22 antibody, an anti-CD30 antibody, an anti-CD33 antibody, an anti-CD52 antibody, an anti-CD79b antibody, an anti-CEACAM5 antibody, an anti-EGFR antibody, an anti-EGFRvIII antibody, an anti-gpNMB antibody, an anti-HER2 antibody, an anti-mesothelin antibody, or an anti-CD138 antibody.

[0130] Here, the "antibody" may be any antibody that contains at least a heavy chain variable domain and a light chain variable domain, and may be a complete antibody or an antigen-binding fragment of a complete antibody that has an antigen recognition site. A complete antibody has two full-length light chains and two full-length heavy chains, and each light chain and heavy chain are linked by a disulfide bond. Complete antibodies include IgA, IgD, IgE, IgM, and IgG, and IgG includes IgG1, IgG2, IgG3, and IgG4 as subtypes. In addition, the antibody is preferably a monoclonal antibody. The antibody portion and the linker portion are bonded via a sulfhydryl group obtained by reducing a disulfide bond in the antibody.

[0131] Furthermore, the antibodies are not limited to human antibodies, but also include antibodies from monkeys, mice, rats, goats, rabbits, and the like.

[0132] "AMG595 antibody" refers to an anti-EGFRvIII antibody obtained by the method described in Mol. Cancer Ther., 2015, 14, 1614-1624.

[0133] One embodiment of the antibody-drug conjugate of the present invention includes the following (2-A). (2-A) In formula (2), the mAb is brentuximab or trastuzumab; q is an integer from 1 to 8; h is 2, 3, 4 or 5; (G) g is a group represented by formula (G-1), Y is a group represented by formula (Y-1), Y' is a carbonyl group; f is 0, Z is a group represented by formula (Z-1), Q is an unsubstituted phenyl group or a group represented by formula (Q-2), R 1a is a methyl group, R 2b and R 2c is a hydrogen atom, AA is Glu or Asp; m is 1 or 2; An antibody-drug conjugate or a pharma- ceutically acceptable salt thereof.

[0134] One embodiment of the antibody-drug conjugate of the present invention includes the following (2-B). (2-B) In formula (2), the mAb is brentuximab or trastuzumab; q is an integer from 1 to 8; h is 2, 3, 4 or 5; (G) g is a group represented by formula (G-2), formula (G-3) or formula (G-4), Y is a group represented by formula (Y-1), Y' is a carbonyl group; f is 0, Z is a group represented by formula (Z-1), Q is an unsubstituted phenyl group or a group represented by formula (Q-2), R 1a is a methyl group, R 2b and R 2c is a hydrogen atom, AA is Glu or Asp; m is 1 or 2; An antibody-drug conjugate or a pharma- ceutically acceptable salt thereof.

[0135] One embodiment of the antibody-drug conjugate of the present invention includes the following (2-C). (2-C) In formula (2), the mAb is brentuximab or trastuzumab; q is an integer from 1 to 8; (G) g is a group represented by formula (G-1), h is 2, 3, 4 or 5; Y is a group represented by formula (Y-1), Y' is a carbonyl group; f is 0, Z is a group represented by formula (Z-5) or formula (Z-6), Q is an unsubstituted phenyl group or a group represented by formula (Q-2), R 1a is a methyl group, R 1b is a hydrogen atom, R 2b and R 2c is a hydrogen atom, AA is Glu or Asp; n is 1, R 6 is a hydrogen atom, An antibody-drug conjugate or a pharma- ceutically acceptable salt thereof.

[0136] One embodiment of the antibody-drug conjugate of the present invention includes the following (2-D). (2-D) In formula (2), the mAb is brentuximab or trastuzumab; q is an integer from 1 to 8; h is 2, 3, 4 or 5; (G) g is a group represented by formula (G-2), formula (G-3) or formula (G-4), Y is a group represented by formula (Y-1), Y' is a carbonyl group; f is 0, Z is a group represented by formula (Z-5) or formula (Z-6), Q is an unsubstituted phenyl group or a group represented by formula (Q-2), R 1a is a methyl group, R 1b is a hydrogen atom, R 2b and R 2c is a hydrogen atom, AA is Glu or Asp; n is 1, R 6 is a hydrogen atom, An antibody-drug conjugate or a pharma- ceutically acceptable salt thereof.

[0137] One embodiment of the antibody-drug conjugate of the present invention includes the following (2-E). (2-E) In formula (2), the mAb is brentuximab or trastuzumab; q is an integer from 1 to 8; h is 2, 3, 4 or 5; (G) g is a group represented by formula (G-2), formula (G-3) or formula (G-4), Y is a single bond, Z is a group represented by formula (Z-1), Q is an unsubstituted phenyl group or a group represented by formula (Q-2), R 1a is a methyl group, R 2b and R 2c is a hydrogen atom, AA is Glu or Asp; m is 1 or 2; An antibody-drug conjugate or a pharma- ceutically acceptable salt thereof.

[0138] One embodiment of the antibody-drug conjugate of the present invention is shown below in (2-F). (2-F) In formula (2), the mAb is brentuximab or trastuzumab; q is an integer from 1 to 8; h is 2, 3, 4 or 5; (G) g is a group represented by formula (G-2), formula (G-3) or formula (G-4), Y is a single bond, Z is a group represented by formula (Z-5) or formula (Z-6), Q is an unsubstituted phenyl group or a group represented by formula (Q-2), R 1a is a methyl group, R 1b is a hydrogen atom, R 2b and R 2c is a hydrogen atom, AA is Glu or Asp; n is 1, R 6 is a hydrogen atom, An antibody-drug conjugate or a pharma- ceutically acceptable salt thereof.

[0139] One embodiment of the antibody-drug conjugate of the present invention is the following (2- G ) are mentioned. (2-G) In formula (2), the mAb is inotuzumab, gemtuzumab, labetuzumab, polatuzumab, cortuximab, indatuximab, anetuzumab, rituximab, denintuzumab, laprituximab, vadastuximab, glembatumumab, cetuximab, alemtuzumab, depatuxizumab or an anti-emvidin antibody; q is an integer from 1 to 8; h is 2, 3, 4 or 5; (G) g is a group represented by formula (G-1), Y is a group represented by formula (Y-1), Y' is a carbonyl group; f is 0, Z is a group represented by formula (Z-1), Q is an unsubstituted phenyl group or a group represented by formula (Q-2), R 1a is a methyl group, R 2b and R 2c is a hydrogen atom, AA is Glu or Asp; m is 1 or 2; An antibody-drug conjugate or a pharma- ceutically acceptable salt thereof.

[0140] One embodiment of the antibody-drug conjugate of the present invention includes an antibody-drug conjugate represented by the following formula (YG-1), formula (YG-2), formula (YG-3) or formula (YG-4), or a pharma- ceutically acceptable salt thereof. [ka] (In the formula, mAb, Z, Y', h and q are as defined above.)

[0141] In general, antibody-drug conjugates can be produced and analyzed by any method known to those skilled in the art, such as those described in Antibody-Drug Conjugates (edited by Laurent Ducry, published by Humana Press, 2013).

[0142] The antibody-drug conjugate of the present invention can be formed, for example, by reducing disulfide bonds in an antibody to sulfhydryl groups and reacting the sulfhydryl groups with an ADC intermediate, which is obtained by binding a linker compound containing a maleimide group to a hemiasterlin derivative.

[0143] It is assumed that the antibody-drug conjugate is specifically delivered to a specific antigen-expressing cell by intracellular uptake utilizing the antibody-antigen reaction, and then the drug moiety is released by the above-mentioned mechanism, thereby exerting its medicinal effect only in the specific cell. Since the antibody-drug conjugate can be specifically taken up by cancer cells, it is expected to exert a strong medicinal effect on cancer cells.

[0144] On the one hand, it is considered that the antibody-drug conjugate may be decomposed by proteases and the like contained in the blood before being delivered to the target cells, and the drug moiety may be released in the blood. In that case, in the case of the conventional antibody-drug conjugate, since the cell membrane permeability of the drug moiety is high, the drug released into the blood is also passively diffused into and taken up by normal cells. Therefore, it results in unintended systemic exposure and is likely to cause side effects, which is not preferable.

[0145] On the other hand, since the drug moiety of the antibody-drug conjugate of the present invention has low cell membrane permeability, even if the drug moiety is released in the blood before reaching the target cells, the drug is less likely to be passively diffused into normal cells and is rapidly metabolized and excreted. Therefore, it can be expected that there are few side effects due to systemic exposure.

[0146] Furthermore, when a compound with low membrane permeability is used as the drug moiety, the drug moiety released in the target cells can be suppressed from flowing out of the cells through the cell membrane. Therefore, it is expected that the drug can stay in the target cells for a long time and exhibit good drug efficacy.

[0147] That is, since the antibody-drug conjugate of the present invention has a hemiasterlin derivative with low cell membrane permeability as the drug moiety, it is expected to exhibit drug efficacy specifically against cancer cells and have little effect on normal cells and high safety.

[0148] <ADC intermediate> The synthetic intermediate for synthesizing the antibody-drug conjugate of the present invention (hereinafter, also referred to as "the ADC intermediate of the present invention") is a compound or a salt thereof represented by the following formula (3-1) or formula (3-2).

Chemical formula

[0149] Regarding the details of each symbol in the above formula, unless otherwise specified, it has the same meaning as the description in the compounds of the above formula (1) or formula (1a) and formula (2). i is an integer from 1 to 12.

[0150] The ADC intermediate of the present invention preferably includes a compound represented by formula (MDF-1), formula (MDF-2), formula (MDF-3) or formula (MDF-4) or a salt thereof. [ka] (In the formula, h, Y′, and Z are as defined above.)

[0151] One embodiment of the ADC intermediate of the present invention is the following (3-1-A). (3-1-A) In formula (3-1), (G) g is a group represented by formula (G-1), h is 2, 3, 4 or 5; Y is a group represented by formula (Y-1), Y' is a carbonyl group; f is 0, Z is a group represented by formula (Z-1), Q is an unsubstituted phenyl group or a group represented by formula (Q-2), R 1a is a methyl group, R 2b and R 2c is a hydrogen atom, AA is Glu or Asp; m is 1 or 2; A compound or a salt thereof.

[0152] One embodiment of the ADC intermediate of the present invention is the following (3-1-B). (3-1-B) In formula (3-1), (G) g is a group represented by formula (G-2), formula (G-3) or formula (G-4), h is 2, 3, 4 or 5; Y is a group represented by formula (Y-1), Y' is a carbonyl group; f is 0, Z is a group represented by formula (Z-1), Q is an unsubstituted phenyl group or a group represented by formula (Q-2), R 1a is a methyl group, R 2b and R 2c is a hydrogen atom, AA is Glu or Asp; m is 1 or 2; A compound or a salt thereof.

[0153] One embodiment of the ADC intermediate of the present invention is the following (3-1-C). (3-1-C) In formula (3-1), (G) g is a group represented by formula (G-1), h is 2, 3, 4 or 5; Y is a group represented by formula (Y-1), Y' is a carbonyl group; f is 0, Z is a group represented by formula (Z-5) or formula (Z-6), Q is an unsubstituted phenyl group or a group represented by formula (Q-2), R 1a is a methyl group, R 1b is a hydrogen atom, R 2b and R 2c is a hydrogen atom, AA is Glu or Asp; n is 1, R 6 is a hydrogen atom, A compound or a salt thereof.

[0154] One embodiment of the ADC intermediate of the present invention is the following (3-1-D). (3-1-D) In formula (3-1), (G) g is a group represented by formula (G-2), formula (G-3) or formula (G-4), h is 2, 3, 4 or 5; Y is a group represented by formula (Y-1), Y' is a carbonyl group; f is 0, Z is a group represented by formula (Z-5) or formula (Z-6), Q is an unsubstituted phenyl group or a group represented by formula (Q-2), R 1a is a methyl group, R 1b is a hydrogen atom, R 2b and R 2c is a hydrogen atom, AA is Glu or Asp; n is 1, R 6 is a hydrogen atom, A compound or a salt thereof.

[0155] One embodiment of the ADC intermediate of the present invention is the following (3-1-E). (3-1-E) In formula (3-1), (G) g is a group represented by formula (G-2), formula (G-3) or formula (G-4), h is 2, 3, 4 or 5; Y is a single bond, Z is a group represented by formula (Z-1), Q is an unsubstituted phenyl group or a group represented by formula (Q-2), R 1a is a methyl group, R 2b and R 2c is a hydrogen atom, AA is Glu or Asp; m is 1 or 2; A compound or a salt thereof.

[0156] One embodiment of the ADC intermediate of the present invention is the following (3-1-F). (3-1-F) In formula (3-1), (G) g is a group represented by formula (G-2), formula (G-3) or formula (G-4), h is 2, 3, 4 or 5; Y is a single bond, Z is a group represented by formula (Z-5) or formula (Z-6), Q is an unsubstituted phenyl group or a group represented by formula (Q-2), R 1a is a methyl group, R 1b is a hydrogen atom, R 2b and R 2c is a hydrogen atom, AA is Glu or Asp; n is 1, R 6 is a hydrogen atom, A compound or a salt thereof.

[0157] The "salt" is a suitable salt of the hemiasterlin derivative and ADC intermediate of the present invention and a salt acceptable as a pharmaceutical raw material, preferably a conventional non-toxic salt. As the "salt", for example, an acid addition salt such as an organic acid salt (e.g., acetate, trifluoroacetate, maleate, fumarate, citrate, tartrate, methanesulfonate, benzenesulfonate, formate, or p-toluenesulfonate, etc.) and an inorganic acid salt (e.g., hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, or phosphate, etc.), a salt with an amino acid (e.g., arginine, aspartic acid, or glutamic acid, etc.), a metal salt such as an alkali metal salt (e.g., sodium salt, potassium salt, etc.) and an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), an ammonium salt, or an organic base salt (e.g., trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, or N,N'-dibenzylethylenediamine salt, etc.), etc., and other appropriate salts can be appropriately selected by those skilled in the art.

[0158] The "pharmaceutical acceptable salt" includes acid addition salts and base addition salts. For example, the acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, and phosphate, and organic acid salts such as citrate, oxalate, phthalate, fumarate, maleate, succinate, malate, acetate, formate, propionate, benzoate, trifluoroacetate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, and camphorsulfonate. In addition, the base addition salts include inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt, barium salt, and aluminum salt, and organic base salts such as trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris(hydroxymethyl)methylamine], tert-butylamine, cyclohexylamine, dicyclohexylamine, and N,N-dibenzylethylamine. Furthermore, the "pharmaceutically acceptable salt" also includes salts with basic or acidic amino acids such as arginine, lysine, ornithine, aspartic acid, glutamic acid, etc. (amino acid salts).

[0159] When it is desired to obtain a salt of the hemiasterlin derivative, antibody-drug conjugate, or ADC intermediate of the present invention, if the target compound is obtained in the form of a salt, it can be purified as is, or if it is obtained in the free form, it can be dissolved or suspended in an appropriate organic solvent, and an acid or base can be added to form a salt by a conventional method.

[0160] The hemiasterlin derivatives, antibody-drug conjugates, and ADC intermediates of the present invention may exist in the form of hydrates and / or solvates with various solvents (such as ethanol solvates), and these hydrates and / or solvates are also included in the hemiasterlin derivatives, antibody-drug conjugates, and ADC intermediates of the present invention. Furthermore, the present invention also includes all forms of crystal forms of the hemiasterlin derivatives, antibody-drug conjugates, and ADC intermediates of the present invention.

[0161] Among the hemiasterlin derivatives, antibody-drug conjugates, and ADC intermediates of the present invention, there may exist optical isomers based on optically active centers, atropisomers based on axial or planar chirality resulting from restricted intramolecular rotation, and all other stereoisomers, tautomers, and geometric isomers, and all possible isomers, including these, are included in the scope of the present invention.

[0162] In particular, optical isomers and atropisomers can be obtained as racemates, or as optically active isomers when optically active starting materials or intermediates are used. If necessary, at an appropriate stage of the following production method, the corresponding racemates of the starting materials, intermediates or final products can be physically or chemically optically resolved into their optical antipodes by known separation methods such as a method using an optically active column or a fractional crystallization method. Specifically, for example, in the diastereomeric method, two diastereomers are formed from a racemate by a reaction using an optically active resolving agent. These different diastereomers generally have different physical properties, and can therefore be optically resolved by known methods such as fractional crystallization.

[0163] The method for producing the hemiasterlin derivative of the present invention is described below. The hemiasterlin derivative of the present invention represented by formula (1) or formula (1a) can be produced, for example, by the following Production Methods A to F, LP, T, or W.

[0164] Manufacturing method A When Q is a group represented by formula (Q-1), the compound represented by formula (1) can be produced, for example, by the following production method. [ka] (In the formula, R 1a , R 1b , Q, AA and m are as defined in Item 2, R a , R x , R y and R z are each independently 1-6 represents an alkyl group or a benzyl group, PX means a protecting group for an amino group.)

[0165] Above P X Examples of the protecting group for the amino group represented by the formula (I) include protecting groups described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999).

[0166] Compound a1 can be prepared by the method described in, for example, J. Med. Chem., 2007, 50, 4329-4339, etc., or can be purchased as a commercial product. Compound a15 can be prepared by the method described in, for example, Tetrahedron Lett., 1997, 38, 317-320, etc., or can be purchased as a commercial product.

[0167] [A-1 process] Compound a2 can be produced by reacting compound a1 with various methylating reagents in a suitable solvent in the presence of a suitable base. Examples of the methylating reagent include methyl halides, and preferably methyl iodide, methyl bromide, and methyl chloride. Examples of the base include potassium hexamethyldisilazide. Examples of the solvent include tetrahydrofuran. The reaction time is usually 5 minutes to 48 hours, and preferably 10 minutes to 2 hours. The reaction temperature is usually -78°C to 100°C, and preferably -78°C to 10°C. This step can be carried out in accordance with the method described in J. Nat. Prod. 2003, 66, 183-199, etc.

[0168] [A-2 process] Compound a3 can be produced from compound a2 according to the method described in step A-1 above.

[0169] [A-3 process] Compound a4 can be produced by reacting compound a3 with a suitable reducing agent in a suitable solvent. The reducing agent is appropriately selected from reducing agents used in ordinary organic synthesis reactions, and preferably includes diisobutylaluminum hydride. The solvent is preferably diethyl ether. The reaction time is usually 5 minutes to 48 hours, and preferably 10 minutes to 24 hours. The reaction temperature is usually -78°C to 100°C, and preferably -78°C to 50°C. This step can be carried out in accordance with the method described in J. Nat. Prod. 2003, 66, 183-199, etc.

[0170] [A-4 process] Compound a5 can be produced by oxidizing compound a4 using a suitable oxidizing agent in a suitable solvent. The oxidizing agent can be appropriately selected from oxidizing agents used in normal organic synthesis reactions, and preferably includes tetrapropylammonium perruthenate. The solvent preferably includes dichloromethane. The reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours. The reaction temperature is usually -78°C to 100°C, preferably -78°C to 50°C. This step can be carried out in accordance with the method described in J. Nat. Prod. 2003, 66, 183-199, etc.

[0171] [A-5 process] Compound a6 can be produced by α-aminocyanating the aldehyde of compound a5 in a suitable solvent. Preferred examples of the solvent include toluene and dichloromethane. The reaction time is usually 5 minutes to 96 hours, preferably 24 hours to 72 hours. The reaction temperature is usually 0°C to 200°C, preferably 0°C to 100°C. This step can be carried out in accordance with the method described in Org. Lett. 2002, 4, 695-697, etc.

[0172] [A-6 process] Compound a7 can be produced by using a suitable oxidizing agent in a suitable solvent in the presence or absence of a suitable base from compound a6. The oxidizing agent can be appropriately selected from oxidizing agents used in normal organic synthesis reactions, and preferably includes hydrogen peroxide. The base preferably includes potassium carbonate. The solvent preferably includes methanol. The reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours. The reaction temperature is usually 0°C to 200°C, preferably 0°C to 60°C. This step can be carried out in accordance with the method described in J. Org. Chem. 2001, 66, 7355-7364, etc.

[0173] [A-7 process] Compound a8 can be produced by reducing compound a7 with a suitable reducing agent in a suitable solvent in the presence of a suitable catalyst. The reducing agent can be appropriately selected from reducing agents used in ordinary organic synthesis reactions, and preferably includes hydrogen, formic acid salts such as ammonium formate, or hydrazine. The catalyst includes transition metals such as palladium, nickel, rhodium, cobalt, platinum, salts thereof, complexes thereof, or the above transition metals supported on carriers such as polymers. The solvent is preferably ethanol or methanol. The reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours. The reaction temperature is usually 0°C to 200°C, preferably 0°C to 100°C. This step can be carried out in accordance with the method described in J. Org. Chem. 2001, 66, 7355-7364, etc.

[0174] [A-8 process] Compound a9 is prepared by converting the amino group of compound a8 into a protecting group P X This step can be carried out in accordance with the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, John Wiley & Sons, Inc., 1999).

[0175] [A-9 process] Compound A11 can be produced by reacting Compound A9 with various acylating reagents (e.g., Compound A10) in a suitable solvent in the presence or absence of a suitable base. Examples of the acylating reagent include carboxylic acid halides and carboxylic acid anhydrides, and preferably di-tert-butyl dicarbonate. A preferred example of the base is diisopropylethylamine. A preferred example of the solvent is chloroform. The reaction time is usually 5 minutes to 72 hours, and preferably 30 minutes to 24 hours. The reaction temperature is usually 0°C to 200°C, and preferably 0°C to 50°C.

[0176] [A-10 process] Compound a12 can be produced by reacting compound a11 with an appropriate alkali metal alkoxide in an appropriate solvent. The alkali metal alkoxide can be appropriately selected from alkali metal alkoxides used in normal organic synthesis reactions, and preferably includes lithium methoxide or lithium ethoxide. The solvent is preferably methanol or ethanol. The reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 6 hours. The reaction temperature is usually -78°C to 200°C, preferably -78°C to 50°C.

[0177] [A-11 process] Compound a13 can be produced by reacting compound a12 with various alkylating reagents in the presence of a suitable base in a suitable solvent. Examples of alkylating reagents include alkyl halides, and preferably alkyl iodides, alkyl bromides, and alkyl chlorides. Examples of bases include sodium hydride. Examples of solvents include tetrahydrofuran. The reaction time is usually 5 minutes to 48 hours, and preferably 10 minutes to 2 hours. The reaction temperature is usually -78°C to 100°C, and preferably -78°C to 10°C.

[0178] [A-12 process] Compound a14 can be produced by hydrolyzing the ester of compound a13 in the presence of a suitable base in a suitable solvent. The base is preferably lithium hydroxide. The solvent is preferably water or methanol. The reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours. The reaction temperature is usually 0°C to 200°C, preferably 0°C to 100°C.

[0179] [A-13 process] Compound a16 can be produced by condensing compound a14 and compound a15 in a suitable solvent in the presence of a suitable base using various condensing agents. As the condensing agent, various condensing agents used in normal organic synthesis reactions can be used, and preferably (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide or bromotripyrrolidinophosphonium hexafluorophosphate can be used. If necessary, a carbonyl activating agent such as 1-hydroxybenzotriazole can be used together to improve the efficiency of the condensation reaction. As the base, preferably diisopropylethylamine can be used. As the solvent, preferably N,N-dimethylformamide can be used. The reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours. The reaction temperature is usually -78°C to 200°C, preferably 0°C to 100°C. This step can be carried out in accordance with the method described in Tetrahedron Lett., 1997, 38, 317-320, etc.

[0180] [A-14 process] Compound a17 can be produced by hydrolyzing the ester of compound a16 in accordance with the method described in step A-12 above. This step can be carried out in accordance with the method described in Tetrahedron Lett., 1997, 38, 317-320, etc.

[0181] [A-15 process] Compound a18 can be produced by reacting compound a17 with N-hydroxysuccinimide in a suitable solvent in the presence of a suitable base using various condensing agents. As the condensing agent, various condensing agents used in normal organic synthesis reactions can be used, and preferably (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, bromotripyrrolidinophosphonium hexafluorophosphate, or O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate can be used. If necessary, a carbonyl activating agent such as 1-hydroxybenzotriazole can be used together to improve the efficiency of the reaction. As a base, preferably, diisopropylethylamine can be used. As a solvent, preferably, N,N-dimethylformamide can be used. The reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours. The reaction temperature is usually -78°C to 200°C, preferably 0°C to 100°C.

[0182] [A-16 process] Compound a19 can be prepared by reacting compound a18 with -(AA) in the presence of a suitable base in a suitable solvent. m The compound can be produced by reacting with an amino acid or peptide, which is a raw material for the group. A preferable example of the base is diisopropylethylamine. A preferable example of the solvent is N,N-dimethylformamide. The reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours. The reaction temperature is usually 0°C to 200°C, preferably 0°C to 100°C.

[0183] [A-17 process] Compound A1 is a compound a19 having a protecting group P XThis step can be carried out in accordance with the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, John Wiley & Sons, Inc., 1999). m When contains an ester, the ester can be hydrolyzed in this deprotection step, if necessary.

[0184] [A-18 process] Compound A2 can be produced by reacting Compound A1 with an alkyl aldehyde in a suitable solvent together with a suitable reducing agent. As the solvent, acetonitrile is preferable. As the reducing agent, various reducing agents used in normal organic synthesis reactions can be used, and sodium triacetoxyborohydride is preferable. The reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours. The reaction temperature is usually 0°C to about 200°C, preferably 0°C to 100°C.

[0185] Manufacturing method B R 1a and R 1b When is a hydrogen atom, the compound represented by formula (1) can be produced, for example, by the following production method. [ka] (Wherein, Q, AA and m are as defined in Item 2, R a , R x and P x is the same as above.)

[0186] Compound b2 can be produced, for example, by the method described in Tetrahedron Lett., 1997, 38, 317-320, or can be purchased as a commercially available product.

[0187] [B-1 process] Compound b1 can be produced from compound a12 according to the method described in step A-12 above.

[0188] [B-2 process] Compound b3 can be produced from compound b1 and compound b2 according to the method described in step A-13 above.

[0189] [B-3 process] Compound b4 can be produced from compound b3 according to the method described in step A-14 above.

[0190] [B-4 process] Compound b5 can be produced from compound b4 according to the method described in step A-15 above.

[0191] [B-5 process] Compound b6 can be produced from compound b5 according to the method described in step A-16 above.

[0192] [B-6 process] Compound B1 can be produced from compound b6 according to the method described in step A-17 above.

[0193] Manufacturing method C The compound represented by formula (1) can be produced, for example, by the following process. [ka] (In the formula, R 1a , R 1b , Q, AA and m are as defined in Item 2, and P X is the same as above.)

[0194] [C-1 process] Compound c1 can be prepared by reacting compound a17 with -(AA) according to the method described in step A-13 above. m The compound can be produced by reacting amino acids or peptides that serve as raw materials for the group.

[0195] [C-2 process] Compound C1 can be produced from compound c1 according to the method described in step A-17 above.

[0196] [C-3 process] Compound C2 can be produced from compound C1 according to the method described in step A-18 above.

[0197] Manufacturing method D The compound represented by formula (1) can be produced, for example, by the following process. [ka] (In the formula, R 1a , R 1b , Q, AA, and m are as defined in item 2, and k represents an integer of 1 to 8, where m>k; (AA) m-k is (AA) m This means that there are k fewer AAs than P X is the same as above.)

[0198] [D-1 process] Compound d1 can be produced from compound a18 according to the method described in step A-16 above.

[0199] [D-2 process] Compound d2 can be produced from compound d1 by reacting it with a peptide having k amino acid residues (or with an amino acid when k=1) in accordance with the method described in step A-13 above.

[0200] [D-3 process] Compound D1 can be produced from compound d2 according to the method described in step A-17 above.

[0201] [D-4 process] Compound D2 can be produced from compound D1 according to the method described in step A-18 above.

[0202] Manufacturing method E The compound represented by formula (1) can be produced, for example, by the following process. [ka] (In the formula, R 1a , R 1b , Q, AA and m are as defined in Item 2, R a and P X is the same as above.)

[0203] Compound e1 can be prepared by the method described in, for example, Tetrahedron Lett., 1997, 38, 317-320, etc., or can be purchased as a commercial product. Compound e5 can be prepared by the method described in, for example, J. Nat. Prod. 2003, 66, 183-199, J. Med. Chem., 2004, 47, 4774-4786, etc., or can be purchased as a commercial product.

[0204] [E-1 process] Compound e2 can be produced from compound e1 according to the method described in step A-12 above.

[0205] [E-2 process] Compound e3 can be produced by reacting compound e2 with -(AA) according to the method described in step A-13 above. m The compound can be produced by reacting amino acids or peptides that serve as raw materials for the group.

[0206] [E-3 process] Compound e4 can be produced from compound e3 according to the method described in step A-17 above.

[0207] [E-4 process] Compound e6 can be produced from compound e4 and compound e5 according to the method described in step A-13 above.

[0208] [E-5 process] Compound E1 can be produced from compound e6 according to the method described in step A-17 above.

[0209] [E-6 process] Compound E2 can be produced from compound E1 according to the method described in step A-18 above.

[0210] Manufacturing method F When Q is an unsubstituted phenyl group, the compound represented by formula (1) can be produced, for example, by the following production method. [ka] (In the formula, R 1a , R 1b , AA and m are as defined in Item 2, and R a , R x and P X is the same as above.)

[0211] Compound f1 can be purchased, for example, as a commercially available product. Compound f11 can be prepared, for example, by the method described in Tetrahedron Lett., 1997, 38, 317-320, or can be purchased as a commercially available product.

[0212] [F-1 process] Compound f2 can be produced by reacting compound f1 with benzene in the presence of various Lewis acids. Examples of Lewis acids include boron halides, aluminum halides, gallium halides, iron halides, titanium halides, and the like, and aluminum chloride and iron chloride are preferred. The reaction time is usually 5 minutes to 48 hours, and preferably 30 minutes to 4 hours. The reaction temperature is usually -78°C to 200°C, and preferably 50°C to 150°C. This step can be carried out in accordance with the method described in J. Nat. Prod. 2003, 66, 183-199, and the like.

[0213] [F-2 process] Compound f3 can be produced by reacting compound f2 with various carboxylic acid halides in a suitable solvent in the presence of a suitable base, and then reacting with an alkali metal 4-alkyl-2-oxazolidinone. As the base, preferably, triethylamine or diisopropylethylamine is used. As the solvent, preferably, tetrahydrofuran is used. As the carboxylic acid halides, for example, carboxylic acid chlorides and the like are used, and preferably, pivaloyl chloride and the like are used. As the alkali metal 4-alkyl-2-oxazolidinones, 4-alkyl-2-oxazolidinone lithium, 4-alkyl-2-oxazolidinone sodium and the like are used, and preferably, 4-isopropyl-2-oxazolidinone lithium is used. The reaction time is usually 5 minutes to 48 hours, and preferably 10 minutes to 24 hours. The reaction temperature is usually -78°C to 100°C, and preferably -78°C to 50°C. This step can be carried out in accordance with the method described in J. Nat. Prod. 2003, 66, 183-199, etc.

[0214] [F-3 process] Compound f4 can be produced by reacting compound f3 with various azidation reagents in a suitable solvent in the presence of a suitable base. Examples of the azidation reagent include sodium azide, trimethylsilyl azide, diphenylphosphoryl azide, and the like, and preferably trimethylsilyl azide. Examples of the base include potassium hexamethyldisilazide. Examples of the solvent include tetrahydrofuran. The reaction time is usually 5 minutes to 72 hours, and preferably 30 minutes to 24 hours. The reaction temperature is usually -78°C to 200°C, and preferably -78°C to 75°C. This step can be carried out in accordance with the method described in J. Nat. Prod. 2003, 66, 183-199, etc.

[0215] [F-4 process] Compound f5 can be produced from compound f4 according to the method described in step A-7 above.

[0216] [F-5 process] Compound f6 can be produced from compound f5 according to the method described in step A-8 above.

[0217] [F-6 process] Compound f7 can be produced by using a suitable oxidizing agent from compound f6 in a suitable solvent in the presence of a suitable base. The base is preferably lithium hydroxide. The solvent is preferably methanol, tetrahydrofuran or water. The oxidizing agent can be appropriately selected from oxidizing agents used in normal organic synthesis reactions, and preferably hydrogen peroxide. The reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours. The reaction temperature is usually 0°C to 200°C, preferably 0°C to 60°C. This step can be carried out in accordance with the method described in J. Nat. Prod. 2003, 66, 183-199, etc.

[0218] [F-7 process] Compound f8 can be produced by reacting compound f7 with various alkylating reagents in the presence of a suitable base in a suitable solvent. Examples of alkylating reagents include alkyl halides, and preferably alkyl iodides, alkyl bromides, and alkyl chlorides. Examples of bases include sodium carbonate and potassium carbonate. Examples of solvents include N,N-dimethylformamide. The reaction time is usually 5 minutes to 48 hours, and preferably 10 minutes to 2 hours. The reaction temperature is usually -78°C to 100°C, and preferably -10°C to 25°C. This step can be carried out according to the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999), and the like.

[0219] [F-8 process] Compound f9 can be produced from compound f8 according to the method described in step A-11 above.

[0220] [F-9 process] Compound f10 can be produced from compound f9 according to the method described in step A-12 above.

[0221] [F-10 process] Compound f12 can be produced from compound f10 and compound f11 according to the method described in step A-13 above.

[0222] [F-11 process] Compound f13 can be produced by hydrolyzing the ester of compound f12 in accordance with the method described in step A-12 above.

[0223] [F-12 process] Compound f14 can be produced from compound f13 according to the method described in step A-15 above.

[0224] [F-13 process] Compound f15 can be produced from compound f14 according to the method described in step A-16 above.

[0225] [F-14 process] Compound F1 can be produced from compound f15 according to the method described in step A-17 above.

[0226] [F-15 process] Compound F2 can be produced from compound F1 according to the method described in step A-18 above.

[0227] Manufacturing method L Compound l6 is a production intermediate of the compound represented by formula (1) in which Q is a group represented by formula (Q-1), formula (Qa-2), formula (Qa-3), formula (Qa-4), formula (Qa-5) or formula (Qa-6). Compound l6 can be produced, for example, by the following production method. Compound L1 can be produced from compound l6 in accordance with the production method described in steps A-16 to A-18 of production method A. [ka] (In the formula, R 1a , R 1b , AA, m and (a) are as defined in item 1, and R a is C 1-6 represents an alkyl group.

[0228] Compound l1 can be purchased as a commercial product, for example. Compound a15 can be produced, for example, by the method described in Production Method A.

[0229] [L-1 process] Compound 12 can be produced, for example, according to the method described in Bioorg. Med. Chem. Lett. 14 (2004) 5317-5322.

[0230] [L-2 process] Compound l3 can be produced, for example, according to the method described in Bioorg. Med. Chem. Lett. 14 (2004) 5317-5322.

[0231] [L-3 process] Compound 14 can be produced, for example, according to the method described in Bioorg. Med. Chem. Lett. 14 (2004) 5317-5322.

[0232] [L-4 process] Compound l5 can be produced from compound l4 according to step A-14 of production method A.

[0233] [L-5 process] Compound l6 can be produced from compound l5 according to step A-15 of production method A.

[0234] Manufacturing method M Compound m7 is a production intermediate of the compound represented by formula (1) in which Q is a group represented by formula (Qa-7). Compound m7 can be produced, for example, by the following production method. Compound Ma1 can be produced from compound m7 in accordance with the production method described in steps A-16 to A-18 of Production Method A. [ka] (In the formula, R 1a , R 1b , AA, m and (a) are as defined in item 1, and R a is C 1-6 represents an alkyl group.

[0235] Compound m1 can be purchased as a commercial product, for example. Compound a15 can be produced, for example, by the method described in Production Method A.

[0236] [M-1 process] Compound m2 can be produced, for example, according to the method described in Bioorg. Med. Chem. Lett. 14 (2004) 5317-5322 or the like.

[0237] [M-2 process] Compound m3 can be produced, for example, according to the method described in Bioorg. Med. Chem. Lett. 14 (2004) 5317-5322 or the like.

[0238] [M-3 process] Compound m4 can be produced, for example, according to the method described in J. Med. Chem. 2004, 47, 4774-4786.

[0239] [M-4 process] Compound m5 can be produced, for example, according to the method described in Bioorg. Med. Chem. Lett. 14 (2004) 5317-5322 or the like.

[0240] [M-5 process] Compound m6 can be produced from compound m5 according to step A-14 of Production Method A.

[0241] [M-6 process] Compound m7 can be produced from compound m6 according to step A-15 of Production Method A.

[0242] Manufacturing method N Compound n5 is a production intermediate of the compound represented by formula (1a). Compound n5 can be produced, for example, by the following production method. Compound N1 can be produced from compound n5 in accordance with the production method described in steps A-16 to A-17 of production method A. [ka] (In the formula, R ad , AA, m and (a) are as defined in Section 7, and R a is C 1-6 represents an alkyl group.

[0243] Compound n1 can be purchased as a commercial product, for example. Compound a15 can be produced, for example, by the method described in Production Method A.

[0244] [N-1 process] Compound n2 can be produced, for example, according to the method described in WO 2003 / 082268.

[0245] [N-2 process] Compound n3 can be produced from compound n2 according to the method described in step A-13.

[0246] [N-3 process] Compound n4 can be produced from compound n3 according to the method described in step A-14.

[0247] [N-4 process] Compound n5 can be produced from compound n4 according to step A-15 of production method A.

[0248] Manufacturing method O Compounds O1, O2, O3 and O4 each include a compound represented by formula (Qa-2): aa , R ab or R ac is a carboxyl group or C 1-6 The compounds O1, O2, O3 and O4 are alkyl ester groups and are represented by the formula (1). Compounds O1, O2, O3 and O4 can be produced, for example, by the following production method. [ka] (In the formula, AA, R 1a , R 1b and m are as defined in item 1, EL represents a chlorine atom, a bromine atom, an iodine atom, a trifluoromethylsulfonyl group, or a tosyl group, R zz is a hydrogen atom or -COOR a represents P x represents a protecting group for an amino group, and R a , R y and R z is C 1-6 represents an alkyl group)

[0249] Compound o1 can be prepared by the method described in, for example, WO 2004 / 026293, WO 2016 / 123582, etc., or can be purchased commercially. Compound a15 can be prepared by the method described in Production Method A, for example.

[0250] [O-1 process] Compound o2 can be produced from compound o1 according to the methods described in, for example, WO 2004 / 026293, Bioorg. Med. Chem. Lett. 14 (2004) 5317-5322, and the like.

[0251] [O-2 process] Compound o3 can be produced from compound o2 according to the method described in step A-8 above.

[0252] [O-3 process] Compound o4 can be produced from compound o3 according to the method described in step A-11 above.

[0253] [O-4 process] Compound o5 can be produced from compound o4 by, for example, the method described in WO 2004 / 026293.

[0254] [O-5 process] Compound o6 can be produced from compound o5 by the method described in, for example, WO 2004 / 026293.

[0255] [O-6 process] Compound o7 can be produced from compound o6 by the method described in, for example, WO2004026293A2.

[0256] [O-7 process] Compound o8 can be produced by esterifying the carboxyl group of compound o7. This step can be carried out in accordance with the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, John Wiley & Sons, Inc., 1999).

[0257] [O-8 process] Compound o9 can be produced from compound o8 according to the method described in step A-12 above.

[0258] [O-9 process] Compound o10 can be produced from compound o9 according to the method described in step A-13 above.

[0259] [O-10 process] Compound o11 can be produced from compound o10 according to the method described in step A-14 above.

[0260] [O-11 process] Compound o12 can be produced from compound o11 according to the method described in step A-15 above.

[0261] [O-12 process] Compound o13 can be produced from compound o12 according to the method described in step A-16 above.

[0262] [O-13 process] Compound O1 is obtained by removing the protecting group P from compound o13. x This step can be carried out in accordance with the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, John Wiley & Sons, Inc., 1999). m In the case where has an ester or a protected amino group, after the condensation reaction, hydrolysis of the ester and deprotection of the protecting group of the amino group can be carried out, if necessary, in accordance with the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999).

[0263] [O-14 process] Compound O2 can be produced from compound O1 according to the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, John Wiley & Sons, Inc., 1999).

[0264] [O-15 process] Compound O3 can be produced from compound O2 according to the methods described in Step A-11 and Step A-18 above. [O-16 process] Compound O4 can be produced from compound O3 according to the method described in step O-13 above.

[0265] Manufacturing method P In the compounds P1 and P2, Q is a group represented by formula (Qa-2), and R aa , R ab or R ac is a hydroxyl group. Compounds P1 and P2 can be produced, for example, by the following production method. [ka] (In the formula, AA, m, R 1a and R 1b is as defined in Item 1, and P x represents a protecting group for an amino group, P z represents a protecting group for a hydroxyl group, and R a is C 1-6 represents an alkyl group)

[0266] Compound p1 can be purchased as a commercial product, for example. Compound a15 can be produced, for example, by the method described in Production Method A.

[0267] [P-1 process] Compound p2 can be produced from compound p1 according to the method described in, for example, WO 2004 / 026293.

[0268] [P-2 process] Compound p3 is obtained by removing the protecting group P from compound p2. z This step can be carried out in accordance with the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, John Wiley & Sons, Inc., 1999), or the like.

[0269] [P-3 process] Compound p4 can be produced from compound p3 according to the method described in, for example, WO 2004 / 026293.

[0270] [P-4 process] Compound p5 is prepared by converting the amino group and hydroxyl group of compound p4 into a protecting group P x and a protecting group P z This step can be carried out in accordance with the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, John Wiley & Sons, Inc., 1999).

[0271] [P-5 process] Compound p6 is obtained by removing the protecting group P from compound p5. z This step can be carried out in accordance with the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, John Wiley & Sons, Inc., 1999) or Tetrahedron Lett. 45 (2004) 495-499.

[0272] [P-6 process] Compound p7 can be produced from compound p6 according to the method described in step A-13.

[0273] [P-7 process] Compound p8 can be produced from compound p7 according to the method described in step A-18 above.

[0274] [P-8 process] Compound P1 can be produced from compound p8 by condensation according to the method described in step A-13 above. m In the case where has an ester or a protected amino group, after the condensation reaction, hydrolysis of the ester and deprotection of the protecting group of the amino group can be carried out, if necessary, in accordance with the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999).

[0275] [P-9 process] Compound P2 can be produced from compound P1 according to the method described in step A-18 above.

[0276] Manufacturing method T Compound T1 and Compound T2 each have a structure in which Q is a group represented by formula (Qa-2), and R aa , R ab or R ac is an amino group. Compounds T1 and T2 can be produced, for example, by the following production method. [ka] (In the formula, AA, m, R 1a and R 1b is as defined in item 1, EL represents a chlorine atom, a bromine atom, an iodine atom, a trifluoromethylsulfonyl group, or a tosyl group, P x and P yrepresents a protecting group for an amino group, and R a is C 1-6 represents an alkyl group)

[0277] Compound t1 can be produced, for example, by the methods described in WO2004026293A2, WO2016123582A1, etc., or can be purchased as a commercial product. Compound a15 can be produced, for example, by the method described in Production Method A.

[0278] [T-1 process] Compound t2 can be produced from compound t1 according to the methods described in, for example, International Publication No. 2004 / 026293, Bioorg. Med. Chem. Lett. 14 (2004) 5317-5322, and the like.

[0279] [T-2 process] Compound t3 can be produced from compound t2 according to the method described in step A-8 above.

[0280] [T-3 process] Compound t4 can be produced from compound t3 by, for example, the method described in International Publication No. 2016 / 123582.

[0281] [T-4 process] Compound t5 is a compound t4 having an amino group protected by a protecting group P y This step can be carried out in accordance with the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, John Wiley & Sons, Inc., 1999).

[0282] [T-5 process] Compound t6 can be produced from compound t5 according to the method described in the above step A-13.

[0283] [T-6 process] Compound t7 can be produced from compound t6 according to the method described in step A-14 above.

[0284] [T-7 process] Compound t8 can be produced from compound t7 according to the method described in the above step A-13.

[0285] [T-8 process] Compound T1 is a protecting group P of compound t8. x and P y This step can be carried out in accordance with the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, John Wiley & Sons, Inc., 1999), Tetrahedron Lett. 45 (2004) 495-499, etc. m When has an ester or a protected amino group, hydrolysis of the ester and deprotection of the protecting group of the amino group can be carried out in this deprotection step, if necessary.

[0286] [T-9 process] Compound T2 can be produced from compound T1 according to the method described in step A-18 above.

[0287] Manufacturing method W R ad Compound W1 represented by formula (1a) in which is a hydrogen atom can be prepared, for example, by the following process. [ka] (Wherein, AA and m are as defined in Section 7, P x represents a protecting group for an amino group, and R a is C 1-6 represents an alkyl group)

[0288] Compound w1 can be purchased as a commercial product, for example. Compound a15 can be produced, for example, by the method described in Production Method A.

[0289] [W-1 process] Compound w2 is prepared by converting the amino group of compound w1 into a protecting group P x This step can be carried out in accordance with the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, John Wiley & Sons, Inc., 1999).

[0290] [W-2 process] Compound w3 can be produced from compound w2 according to the method described in the above step A-13.

[0291] [W-3 process] Compound w4 can be produced from compound w3 according to the method described in the above step A-14.

[0292] [W-4 process] Compound w5 can be produced from compound w4 according to the method described in the above step A-13.

[0293] [W-5 process] Compound W1 is a protecting group P of compound w5. x This step can be carried out in accordance with the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, John Wiley & Sons, Inc., 1999), Tetrahedron Lett. 45 (2004) 495-499, etc. m When has an ester or a protected amino group, hydrolysis of the ester and deprotection of the protecting group of the amino group can be carried out in this deprotection step, if necessary.

[0294] The compound represented by formula (3-1) can be produced, for example, by the following production methods MA, MB, MC, MD, ME, MF, MG, MH or MI.

[0295] Manufacturing method MA When Y is a group represented by formula (Y-1), Y' is a carbonyl group, and Z is a group represented by formula (Z-1), the compound represented by formula (3-1) can be produced, for example, by the following production method. [ka] (In the formula, Q, R 1a , A.A., m, R 3 , f, G, g and h are as described in item 30, R a , R x and P X is the same as above.)

[0296] Compound g1 can be purchased, for example, as a commercially available product. Compound g4 can be prepared, for example, by the method described in J. Nat. Prod. 2003, 66, 183-199, J. Med. Chem., 2004, 47, 4774-4786, etc., or can be purchased, for example, as a commercially available product. Compound g7 can be prepared, for example, by the method described in Tetrahedron Lett., 1997, 38, 317-320, etc., or can be purchased, for example, as a commercially available product.

[0297] [G-1 process] Compound g2 is the product of compound g1 and -(G) gThe compound can be produced by condensing an amino acid or peptide, which is a raw material of the group, with various condensing agents in an appropriate solvent in the presence of an appropriate base. As the condensing agent, various condensing agents used in normal organic synthesis reactions can be used, and preferably 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) can be used. If necessary, a carbonyl activating agent such as 1-hydroxybenzotriazole can be used together to improve the efficiency of the condensation reaction. As the base, preferably diisopropylethylamine can be used. As the solvent, preferably dichloromethane can be used. The reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours. The reaction temperature is usually -78°C to 200°C, preferably 0°C to 50°C. This step can be carried out in accordance with the method described in Bioconjugate Chem. 2002, 13, 855-869, etc.

[0298] [G-2 process] Compound g3 can be produced by reacting compound g2 with various p-nitrophenyl carbonate esterification reagents in the presence of a suitable base in a suitable solvent. Examples of p-nitrophenyl carbonate esterification reagents include 4-nitrophenyl chloroformate, bis(4-nitrophenyl) carbonate, and the like, and preferably bis(4-nitrophenyl) carbonate. A preferred example of the base is N,N-diisopropylethylamine. A preferred example of the solvent is tetrahydrofuran, dichloromethane, or N,N-dimethylformamide. The reaction time is usually 5 minutes to 72 hours, and preferably 1 hour to 24 hours. The reaction temperature is usually -78°C to 200°C, and preferably 10°C to 50°C. This step can be carried out in accordance with the methods described in Bioconjugate Chem. 2002, 13, 855-869 and BioconjugateChem.2015, 26, 650-659, and the like.

[0299] [G-3 process] Compound g5 can be produced by reacting compound g3 with compound g4 in the presence of a suitable base in a suitable solvent. If necessary, a carbonyl activating reagent such as 1-hydroxy-7-benzotriazole can be used together to improve the efficiency of the condensation reaction. As the base, preferably, triethylamine, diisopropylethylamine, and 2,6-lutidine can be used. As the solvent, preferably, N,N-dimethylformamide can be used. The reaction time is usually 5 minutes to 72 hours, preferably 1 hour to 24 hours. The reaction temperature is usually -78°C to 200°C, preferably 10°C to 50°C. This step can be carried out in accordance with the method described in Bioconjugate Chem. 2002, 13, 855-869 and BioconjugateChem.2015, 26, 650-659.

[0300] [G-4 process] Compound g6 can be prepared by hydrolyzing the ester of compound g5 according to the method described in step A-12 above.

[0301] [G-5 process] Compound g8 can be produced from compound g6 and compound g7 according to the method described in step A-13 above.

[0302] [G-6 process] Compound g9 can be prepared by hydrolyzing the ester of compound g8 according to the method described in step A-12 above.

[0303] [G-7 process] Compound g10 can be produced from compound g9 according to the method described in step A-15 above.

[0304] [G-8 process] Compound g11 can be produced from compound g10 according to the method described in step A-16 above.

[0305] [G-9 process] Compound g12 can be produced from compound g11 according to the method described in step A-17 above.

[0306] [G-10 process] Compound G1 can be produced from compound g12 according to the method described in the above step A-13 or step A-16.

[0307] Manufacturing method MB When Y is a group represented by formula (Y-1), Y' is a carbonyl group, and Z is a group represented by formula (Z-1), the compound represented by formula (3-2) can be produced, for example, by the following production method. [ka] (In the formula, Q, R 1a , A.A., m, R 3 , f, G, g, and i are as defined in Section 30.

[0308] [H-1 process] Compound H1 can be produced from compound g12 according to the method described in the above step A-13 or step A-16.

[0309] Manufacturing method MC When Y is a group represented by formula (Y-1), Y' is a single bond, and Z is a group represented by formula (Z-2), formula (Z-3) or formula (Z-4), the compound represented by formula (3-1) can be produced, for example, by the following production method. [ka] (In the formula, Q, R 1a , R 1b , A-A, n, h, G, g, R 3 and f are as defined in paragraph 30; P X is the same as above, and P Y means a protecting group for an amino group.)

[0310] [J-1 process] Compound j1 can be produced by condensing compound g2 with an amino acid derivative in the presence of a suitable sulfonylating reagent and imidazoles in a suitable solvent. Examples of the sulfonylating reagent include methylsulfonyl chloride and p-toluenesulfonyl chloride, and preferably p-toluenesulfonyl chloride. Examples of the imidazoles include imidazole and 1-methylimidazole, and preferably 1-methylimidazole. A preferred solvent is acetonitrile. The reaction time is usually 5 minutes to 72 hours, and preferably 30 minutes to 24 hours. The reaction temperature is usually -78°C to 200°C, and preferably 0°C to 50°C.

[0311] [J-2 process] Compound j2 can be produced from compound j1 according to the method described in step A-17 above.

[0312] [J-3 process] Compound j3 can be produced from compound j2 according to the method described in the above Step A-13 or Step A-16.

[0313] [J-4 process] Compound j4 can be produced from compound j3 according to the method described in step A-17 above.

[0314] [J-5 process] Compound J1 can be produced from compound j4 according to the method described in the above step A-13 or step A-16.

[0315] Manufacturing method MD When Y is a group represented by formula (Y-1), Y' is a carbonyl group, and Z is a group represented by formula (Z-5) or formula (Z-6), the compound represented by formula (3-1) can be produced, for example, by the following production method. [ka] (In the formula, Q, R 1a , R 1b and AA, n, h, G, g, R 3 and f are as defined in paragraph 30; P X is the same as above.)

[0316] [K-1 process] Compound k3 can be produced from compound k1 and compound k2 according to the method described in step G-3 above.

[0317] [K-2 process] Compound k4 can be produced from compound k3 according to the method described in step A-17 above.

[0318] [K-3 process] Compound K1 can be produced from compound k4 according to the method described in the above step A-13 or step A-16.

[0319] Manufacturing method ME When Y is a group represented by formula (Y-1), Y' is a single bond, and Z is a group represented by formula (Za-1), formula (Za-2) or formula (Za-3), the compound represented by formula (3-1) can be produced, for example, by the following production method. [ka] (In the formula, R ad , A-A, m, h, G, g, R 3 and f are as defined in paragraph 29; P X is the same as above.)

[0320] [JJ-1 process] Compound jj1 can be produced from compound j2 according to the method described in the above Step A-13 or Step A-16.

[0321] [JJ-2 process] Compound jj2 can be produced from compound jj1 according to the method described in step A-17 above.

[0322] [JJ-3 process] Compound JJ1 can be produced from compound jj2 according to the method described in Step A-13 or Step A-16 above.

[0323] Manufacturing method MF When Y is a group represented by formula (Y-1), Y' is a carbonyl group, and Z is a group represented by formula (Za-4) or formula (Za-5), the compound represented by formula (3-1) can be produced, for example, by the following production method. [ka] (In the formula, R ad , A-A, n, h, G, g, R 3 and f are as defined in paragraph 29; P X is the same as above.)

[0324] [KK-1 process] Compound kk2 can be produced from compound k1 and compound kk2 according to the method described in step G-3 above.

[0325] [KK-2 process] Compound kk3 can be produced from compound kk2 according to the method described in step A-17 above.

[0326] [KK-3 process] Compound KK1 can be produced from compound kk3 according to the method described in the above step A-13 or step A-16.

[0327] Manufacturing method MG When Y is a group represented by formula (Y-1), Y' is a carbonyl group, and Z is a group represented by formula (Za-6), the compound represented by formula (3-1) can be produced, for example, by the following production method. [ka] (In the formula, AA, m, h, G, g, R 3 and f are as defined in paragraph 29; P X is the same as above.)

[0328] [KKK-1 process] Compound kkk2 can be produced from compound k1 and compound kkk1 according to the method described in step G-3 above.

[0329] [KKK-2 process] Compound kkk3 can be produced from compound kkk2 according to the method described in step A-17 above.

[0330] [KKK-3 process] Compound KKK1 can be produced from compound kkk3 according to the method described in the above step A-13 or step A-16.

[0331] Manufacturing method MH When Y is a group represented by formula (Y-1), Y' is a single bond, and Z is a group represented by formula (Za-7) or formula (Za-8), the compound represented by formula (3-1) can be produced, for example, by the following production method. [ka] (In the formula, R 1a , R 1b , A-A, m, h, G, g, R 3 and f are as defined in paragraph 29; P X is the same as above.)

[0332] [JJJ-1 process] Compound jjj1 can be produced from compound g2 and compound O2 or compound O4 according to the method described in step J-1 above.

[0333] [JJJ-2 process] Compound jjj2 can be produced from compound jjj1 according to the method described in step A-17 above.

[0334] [JJJ-3 process] Compound JJJ1 can be produced from compound jjj2 according to the method described in Step A-13 or Step A-16 above.

[0335] Manufacturing method MI When Y is a group represented by formula (Y-1), Y' is a carbonyl group, and Z is a group represented by formula (Za-9) or formula (Za-10), the compound represented by formula (3-1) can be produced, for example, by the following production method. [ka] (In the formula, R 1a , R 1b and AA, m, h, G, g, R 3 and f are as defined in paragraph 29; P X is the same as above.)

[0336] [JJJJ-1 process] Compound jjjj1 can be produced from compound k1 and compound T1 or compound T2 according to the method described in step G-3 above.

[0337] [JJJJ-2 process] Compound jjjj2 can be produced from compound jjjj1 according to the method described in step A-17 above.

[0338] [JJJJ-3 process] Compound JJJJ1 can be produced from compound jjjj2 according to the method described in Step A-13 or Step A-16 above.

[0339] The antibody-drug conjugate of the present invention represented by formula (2) can be produced, for example, by the following Production Method AA.

[0340] Manufacturing method AA [ka] (In the formula, mAb, q, h, G, g, Y, and Z are defined as in item 14, mAb' represents a mAb whose disulfide bond has been reduced, and qq represents an integer of 1 to 8.)

[0341] [P-1 process] Compound p2 can be produced by reacting compound p1 with an appropriate disulfide reducing agent in an appropriate buffer solution. Examples of disulfide reducing agents include dithiothreitol, mercaptoethanol, tris(2-carboxyethyl)phosphine, and the like, preferably tris(2-carboxyethyl)phosphine. Examples of buffer solutions include Tris-HCl, PBS, HEPES, acetate-based, borate-based, phosphate-based, and carbonate-based buffer solutions, preferably Tris-HCl and PBS. The pH during the reaction is usually 2 to 12, and preferably 4 to 9. The reaction time is usually 5 minutes to 24 hours, and preferably 5 minutes to 5 hours. The reaction temperature is usually -10°C to 50°C, and preferably 0°C to 40°C.

[0342] [P-2 process] Compound P1 can be produced by reacting compound p2 with compound p3 in an appropriate buffer solution. Examples of the buffer solution include Tris-HCl, PBS, HEPES, acetate, borate, phosphate, and carbonate buffer solutions, and preferably Tris-HCl and PBS. The pH during the reaction is usually 2 to 12, and preferably 4 to 9. The reaction time is usually 5 minutes to 72 hours, and preferably 30 minutes to 24 hours. The reaction temperature is usually -78°C to 200°C, and preferably 0°C to 25°C.

[0343] The appropriate base used in each step of each of the above-mentioned production methods should be appropriately selected depending on the type of reaction or raw material compound, and examples thereof include alkali bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali carbonates such as sodium carbonate and potassium carbonate; metal hydrides such as sodium hydride and potassium hydride; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal alkoxides such as sodium methoxide and sodium t-butoxide; organometallic bases such as butyllithium and lithium diisopropylamide; and organic bases such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine (DMAP), and 1,8-diazabicyclo[5.4.0]-7-undecene (DBU).

[0344] The appropriate solvent used in each step of the above-mentioned production methods should be selected appropriately depending on the type of reaction and raw material compound, and examples of the solvent include alcohols such as methanol, ethanol, isopropanol, etc.; ketones such as acetone, methyl ketone, etc.; halogenated hydrocarbons such as methylene chloride, chloroform, etc.; ethers such as tetrahydrofuran (THF), dioxane, etc.; aromatic hydrocarbons such as toluene, benzene, etc.; aliphatic hydrocarbons such as hexane, heptane, etc.; esters such as ethyl acetate, propyl acetate, etc.; amides such as N,N-dimethylformamide (DMF), N-methyl-2-pyrrolidone, etc.; sulfoxides such as dimethyl sulfoxide (DMSO), etc.; nitriles such as acetonitrile, etc.; distilled water, etc., and these solvents can be used alone or in combination of two or more. Depending on the type of reaction, organic bases such as triethylamine, diisopropylethylamine, pyridine, etc. may be used as a solvent.

[0345] The hemiasterlin derivative, antibody-drug conjugate, and ADC intermediate of the present invention can be separated and purified by methods known to those skilled in the art, such as extraction, distribution, reprecipitation, column chromatography (e.g., silica gel column chromatography, ion exchange column chromatography, or preparative liquid chromatography), or recrystallization.

[0346] Examples of recrystallization solvents that can be used include alcohol-based solvents such as methanol, ethanol, and 2-propanol; ether-based solvents such as diethyl ether; ester-based solvents such as ethyl acetate; aromatic hydrocarbon-based solvents such as benzene and toluene; ketone-based solvents such as acetone; halogen-based solvents such as dichloromethane and chloroform; hydrocarbon-based solvents such as hexane; aprotic solvents such as dimethylformamide, acetonitrile; water; or a mixture of these solvents.

[0347] Other purification methods that can be used include the methods described in Experimental Chemistry Lectures (edited by the Chemical Society of Japan, Maruzen), Vol. 1, etc. In addition, the molecular structures of the hemiasterlin derivatives, antibody-drug conjugates, and ADC intermediates of the present invention can be easily determined by spectroscopic methods such as nuclear magnetic resonance, infrared absorption, and circular dichroism spectroscopy, or mass spectrometry, with reference to the structures derived from the respective raw material compounds.

[0348] In addition, the intermediate or final product in the above-mentioned production method can be led to another compound included in the present invention by appropriately converting its functional group, particularly by extending various side chains using amino groups, hydroxyl groups, carbonyl groups, halogen atoms, etc. as a foothold, and by protecting and deprotecting the functional groups as necessary. The conversion of functional groups and the extension of side chains can be carried out by a commonly used general method (see, for example, Comprehensive Organic Transformations, RC Larock, John Wiley & Sons Inc. (1999), etc.).

[0349] The hemiasterlin derivative, antibody-drug conjugate, and ADC intermediate of the present invention may have asymmetry or a substituent with an asymmetric carbon, and such compounds have optical isomers. Optical isomers can be produced according to a conventional method. Examples of the production method include a method using a raw material with an asymmetric center or a method introducing asymmetry at an intermediate stage. For example, in the case of optical isomers, optical isomers can be obtained by using optically active raw materials or by performing optical resolution at an appropriate stage of the production process. For example, when the hemiasterlin derivative of the present invention or an intermediate thereof has a basic functional group, the optical resolution method includes a diastereomeric method in which a salt is formed using an optically active acid (e.g., monocarboxylic acid such as mandelic acid, N-benzyloxyalanine, lactic acid, etc.; dicarboxylic acid such as tartaric acid, o-diisopropylidene tartaric acid, malic acid, etc.; sulfonic acid such as camphorsulfonic acid, bromocamphorsulfonic acid, etc.) in an inert solvent (e.g., alcoholic solvents such as methanol, ethanol, 2-propanol, etc.; ether solvents such as diethyl ether; ester solvents such as ethyl acetate; hydrocarbon solvents such as toluene; aprotic solvents such as acetonitrile; or a mixed solvent of two or more of the above solvents). When the hemiasterlin derivative, antibody-drug conjugate, or ADC intermediate of the present invention has an acidic functional group such as a carboxyl group, an optically active amine (e.g., organic amines such as 1-phenylethylamine, quinine, quinidine, cinchonidine, cinchonine, strychnine, etc.) is used to form a salt, and optical resolution can also be performed.

[0350] The temperature at which the salt is formed may range from -50°C to the boiling point of the solvent, preferably from 0°C to the boiling point, more preferably from room temperature to the boiling point of the solvent. In order to improve the optical purity, it is desirable to once raise the temperature to near the boiling point of the solvent. When filtering out the precipitated salt, the yield can be improved by cooling as necessary. The amount of the optically active acid or amine used may range from about 0.5 to about 2.0 equivalents relative to the substrate, preferably about 1 equivalent. If necessary, the crystals may be recrystallized in an inert solvent (e.g., alcohol-based solvents such as methanol, ethanol, and 2-propanol; ether-based solvents such as diethyl ether; ester-based solvents such as ethyl acetate; hydrocarbon-based solvents such as toluene; aprotic solvents such as acetonitrile; or a mixed solvent of two or more of the above solvents) to obtain a high-purity optically active salt. If necessary, the optically resolved salt may be treated with an acid or base by a conventional method to obtain a free form.

[0351] Among the raw materials or intermediates in each of the above-mentioned production methods, those for which the production method is not particularly described are commercially available compounds or can be synthesized from commercially available compounds by methods known to those skilled in the art or methods similar thereto.

[0352] The antibody-drug conjugate of the present invention, and a pharmaceutical composition containing the antibody-drug conjugate or a pharma- ceutically acceptable salt thereof, are useful as anticancer agents (e.g., therapeutic agents for breast cancer, stomach cancer, lung cancer, liver cancer, cervical cancer, colorectal cancer, rectal cancer, colon cancer, glioma, lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, urothelial cancer, skin cancer, thyroid cancer, bladder cancer, head and neck cancer, uterine cancer, mesothelioma, melanoma, multiple myeloma, leukemia, etc.).

[0353] The antibody-drug conjugate of the present invention can be administered orally or parenterally, either directly or after preparation using an appropriate dosage form. Examples of dosage forms include, but are not limited to, solutions, suspensions, injections, etc. These preparations are produced by known methods using pharma- ceutically acceptable additives.

[0354] As additives, excipients, disintegrants, binders, fluidizing agents, lubricants, coating agents, solubilizers, solubilizing aids, thickeners, dispersants, stabilizers, sweeteners, flavors, etc. can be used depending on the purpose. Specific examples include lactose, mannitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, corn starch, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl alcohol, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide, talc, etc.

[0355] Examples of the "anticancer compound" that can be used in combination with or in conjunction with the antibody-drug conjugate of the present invention include one or more anticancer compounds selected from the group consisting of anticancer alkylating agents, anticancer antimetabolites, anticancer antibiotics, anticancer platinum coordination compounds, anticancer camptothecin derivatives, anticancer tyrosine kinase inhibitors, anticancer serine threonine kinase inhibitors, anticancer phospholipid kinase inhibitors, anticancer monoclonal antibodies, interferons, biological response modifiers, hormones, immune checkpoint inhibitors, epigenetics-related molecule inhibitors, protein post-translational modification inhibitors, and other antitumor agents. Specific examples of "anticancer compounds" that can be used in combination or in combination with other compounds include, for example, azacitidine, vorinostat, decitabine, romidepsin, idarubicin, daunorubicin, doxorubicin, enocitabine, cytarabine, mitoxantrone, thioguanine, etoposide, ifosfamide, cyclophosphamide, dacarbazine, temozolomide, nimustine, busulfan, procarbazine, melphalan, ranimustine, all-trans retinoic acid, tamibarotene, cisplatin, carboplatin, oxaliplatin, irinotecan, bleomycin, mitomycin C, methotrexate, paclitaxel, docetaxel, gemcitabine, tamoxifen, thiotepa, tegafur, fluorouracil, and the like. Rasil, everolimus, temsirolimus, gefitinib, erlotinib, imatinib, crizotinib, osimertinib, afatinib, dasatinib, bosutinib, vandetanib, sunitinib, axitinib, pazopanib, lenvatinib, lapatinib, nilotinib, ibrutinib, ceritinib, alectinib, tofacitinib, baricitinib, ruxolitinib These include nib, olaparib, sorafenib, vemurafenib, dabrafenib, trametinib, palbociclib, bortezomib, carfilzomib, rituximab, cetuximab, trastuzumab, bevacizumab, panitumumab, nivolumab, atezolizumab, mogamulizumab, alemtuzumab, ofatumumab, ipilimumab, ramucirumab, brentuximab vedotin, trastuzumab emtansine, gemtuzumab ozogamicin, and inotuzumab ozogamicin.

[0356] From the above, the antibody-drug conjugate of the present invention and the pharmaceutical composition containing the same can be used for the treatment of cancer. That is, one aspect of the present invention can be said to be a method for treating cancer, which comprises administering the antibody-drug conjugate or the pharmaceutical composition containing the same to a subject suffering from cancer. The subject suffering from cancer may be a human patient or a non-human animal.

[0357] The present invention will be described in more detail below with reference examples, examples and test examples, but the present invention is not limited thereto. Note that the compound names shown in the following reference examples and examples do not necessarily conform to the IUPAC nomenclature.

[0358] The compounds of the Reference Examples and Examples may be obtained as acid addition salts such as TFA salts by post-reaction treatment or other methods.

[0359] In order to simplify the description of the specification, the following abbreviations may be used in the Reference Examples, Examples, and Tables in the Examples. As abbreviations used as substituents, Me means methyl group, Et means ethyl group, Boc means tert-butoxycarbonyl group, Fmoc means 9-fluorenylmethyloxycarbonyl group, trt means trityl group, Ph means phenyl group, and tBu means tert-butyl group. Alko means p-alkoxybenzyl alcohol, and PEG means polyethylene glycol. TFA means trifluoroacetic acid, DMF means N,N-dimethylformamide, TCEP means tris(2-carboxyethyl)phosphine, Tris-HCl means trishydroxymethylaminomethane hydrochloride, PBS means phosphate buffered saline, HEPES means 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid, and PIPES means piperazine-1,4-bis(2-ethanesulfonic acid). NMR means nuclear magnetic resonance. The symbols used in NMR are s for singlet, d for doublet, dd for doublet of doublets, t for triplet, q for quartet, m for multiplet, br for broad, brs for broad singlet, brd for broad doublet, brm for broad multiplet, and J for coupling constant.

[0360] The measurement conditions for the high-performance liquid chromatography mass spectrometer (LCMS) were as follows, and the observed mass spectrometry values ​​[MS (m / z)] were defined as [M+nH] n+ / n, [M+Na] + , [M-nH] n- / n, and retention time is Rt(min). For each measured value, the measurement conditions used are noted with A to G or J.

[0361] Measurement condition A Detection equipment: Shimadzu LCMS-IT-TOF Column: Phenomenex Kinetex(1.7μm C18,50mm×2.10mm) Solvent: A liquid: 0.1%HCOOH / CH3CN, B liquid: 0.1%HCOOH / H2O Gradient Condition: 0.0 minutes;A / B=1:99 0.0-1.4minLinear gradient from A 1% to 95% 1.4-1.6 minutes; A / B=95:5 1.6-2.0 minutes;A / B=1:99 Flow rate: 1.2mL / min UV: 220 / 254nm Column temperature: 40℃

[0362] Measurement condition B Detection equipment: Shimadzu LCMS-IT-TOF Column: Phenomenex Kinetex(1.7μm C18,50mm×2.10mm) Solvent: A liquid: 0.1%HCOOH / CH3CN, B liquid: 0.1%HCOOH / H2O Gradient Condition: 0.0 minutes;A / B=10:90 0.0-1.4min Linear gradient from A 10% to 90% 1.4-1.6 minutes; A / B=90:10 1.6-2.0 minutes;A / B=10:90 Flow rate:1.2mL / min UV:220 / 254nm カラムTemperature:40℃

[0363] Measurement conditions C Detection equipment: Shimadzu LCMS-IT-TOF Column:Phenomenex Kinetex(1.7μm C8,50mm×2.10mm) Solvent: Solution A: 0.1% HCOOH / CH3CN, Solution B: 0.1% HCOOH / H2O Gradient Condition: 0.0 points; A / B=1:99 0.0-1.4 points Linear gradient from A 1% to 95% 1.4-1.6 points; A / B=95:5 1.6-2.0 points; A / B=1:99 Flow rate:1.2mL / min UV:220 / 254nm カラムTemperature:40℃

[0364] Measurement condition D Detection equipment: Shimadzu LCMS-IT-TOF Column:Phenomenex Kinetex(1.7μm C8,50mm×2.10mm) Solvent: Solution A: 0.1% HCOOH / CH3CN, Solution B: 0.1% HCOOH / H2O Gradient Condition: 0.0 points; A / B=10:90 0.0-1.4 points Linear gradient from A 10% to 90% 1.4-1.6 points; A / B=90:10 1.6-2.0 points; A / B=10:90 Flow rate:1.2mL / min UV:220 / 254nm カラムTemperature:40℃

[0365] Measurement condition E Detection equipment: ACQUITY (registered trademark) SQdetector (Waters) HPLC: ACQUITY® system Column: Waters ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm, 2.1 mm × 30 mm) Solvent: Solution A: 0.06% formic acid / CH3CN, Solution B: 0.06% formic acid / H2O Gradient Condition:0.0-1.3min Linear gradient from A 2% to 96% Flow rate: 0.8mL / min UV: 220 / 254nm Column temperature: 25℃

[0366] Measurement condition F Detection equipment: Perkin-Elmer Sciex API 150EX Mass spectrometer HPLC: Shimadzu LC 10ATVP Column:Shiseido CAPCELL PAK C18 ACR (S-5μm,4.6mm×50mm) Solvent: Solution A: 0.035% TFA / CH3CN, Solution B: 0.05% TFA / H2O Gradient Condition: 0.0-0.5 min A solution 10%, 0.5-4.8 min A solution Linear gradient from A 10% to 99%, 4.8-5.0 min Flow rate:3.5mL / min A solution 99% UV: 220 / 254nm Column temperature: 25℃

[0367] Measurement condition G Detection equipment: Perkin-Elmer Sciex API 150EX Mass spectrometer (40 eV) HPLC: Shimadzu LC 10ATVP Column:Shiseido CAPCELL PAK C18 ACR(S-5μm,4.6mm×50mm) Solvent: Solution A: 0.035% TFA / CH3CN, Solution B: 0.05% TFA / H2O Gradient Condition: 0.0-0.5 min. A solution 40%, 0.5-4.8 min. A solution Linear gradient from A 40% to 99%, 4.8-5.0 min. Flow rate:3.5mL / min A solution 99% UV: 220 / 254nm Column temperature: 25℃

[0368] Measurement condition J Detection equipment: Shimadzu LCMS-IT-TOF Column: Phenomenex Kinetex(1.7μm C8,50mm×2.10mm) Solvent: A liquid: 0.1%HCOOH / CH3CN, B liquid: 0.1%HCOOH / H2O Gradient Condition: 0.0 minutes;A / B=10:90 0.0-1.4min Linear gradient from A 10% to 95% 1.4-1.6 minutes; A / B=95:5 1.6-2.0 minutes;A / B=10:90 Flow rate: 1.2mL / min UV: 220 / 254nm Column temperature: 40℃

[0369] High performance liquid chromatograph: The measurement conditions for determining the average DAR are as follows, and the retention time is indicated as Rt (min). For each measured value, the measurement conditions used for the measurement are indicated with H or I.

[0370] Measurement condition H HPLC: Shimadzu LC-10A series Column:nonporousTSKgel Butyl-NPR column(TosohBioscience,2.5μm,35mm×4.6mm) Solvent: Solution A: 1.5 mol / L ammonium sulfate, 25 mmol / L sodium phosphate aqueous solution (pH 6.95), Solution B: 25% isopropanol / 25 mmol / L sodium phosphate aqueous solution (pH 6.95) Gradient Condition: 0.0 minutes;A / B=100:0 0.0-12.0min Linear gradient from B 0% to 100% 12.1-18.0 minutes;A / B=100:0 Flow rate: 0.8mL / min UV: 230nm Column temperature: 25℃

[0371] Measurement condition I HPLC: Shimadzu LC-10A series Column:nonporousTSKgel Butyl-NPR column(TosohBioscience,2.5μm,35mm×4.6mm) Solvent: Solution A: 1.5 mol / L ammonium sulfate, 25 mmol / L sodium phosphate aqueous solution (pH 6.95), Solution B: 25% isopropanol / 25 mmol / L sodium phosphate aqueous solution (pH 6.95) Gradient Condition: 0.0 minutes;A / B=100:0 0.0-24.0min Linear gradient from B 0% to 100% 24.1-60.0 minutes;A / B=100:0 Flow rate: 0.8mL / min UV: 230nm Column temperature: 25℃ EXAMPLES

[0372] Reference example 1 Methyl N-(tert-butoxycarbonyl)-N,β,β,1-tetramethyl-L-tryptophanate [ka]

[0373] a) Preparation of methyl 2-(1-methyl-1H-indol-3-yl)propanoate (compound Q1) Under a nitrogen atmosphere, potassium hexamethyldisilazide (1 mol / L tetrahydrofuran solution, 65.5 mL) was added dropwise to a solution of indole-3-acetic acid methyl ester (3.8 g) in tetrahydrofuran (87 mL) at -78°C, and the mixture was stirred at 0°C for 2 hours. The reaction solution was cooled to -78°C, and methyl iodide (23 g) was added dropwise, and the mixture was stirred at 0°C for 3 hours. After the reaction was completed, water was added and the mixture was extracted with diethyl ether. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate) to obtain compound Q1 (3.95 g). 1 H-NMR(400 MHz, CDCl3):1.60 (3H, d, J =7.1 Hz),3.67 (3H, s), 3.76 (3H,s),4.02 (1H, q, J = 7.1 Hz), 7.00 (1H, s), 7.12 (1H, t,J = 7.8 Hz), 7.23 (1H, t,J= 7.8 Hz), 7.29(1H, d,J = 7.8 Hz),7.66(1H, d, J= 7.8 Hz).

[0374] b) Preparation of methyl 2-methyl-2-(1-methyl-1H-indol-3-yl)propanoate (compound Q2) Under a nitrogen atmosphere, potassium hexamethyldisilazide (1 mol / L tetrahydrofuran solution, 27.7 mL) was added dropwise to a solution of compound Q1 (3.94 g) in tetrahydrofuran (200 mL) at -78°C, and the mixture was stirred at 0°C for 2 hours. The reaction solution was cooled to -78°C, and methyl iodide (15.4 g) was added dropwise, and the mixture was stirred at 0°C for 3 hours. After the reaction was completed, water was added and the mixture was extracted with diethyl ether. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate) to obtain compound Q2 (3.59 g). 1 H-NMR(400MHz, CDCl3):1.66 (6H,s), 3.61 (3H,s), 3.73 (3H,s), 6.91 (1H,s), 7.06(1H, t,J = 8.0 Hz), 7.19 (1H, t,J = 8.0 Hz), 7.27(1H, d,J = 8.0 Hz), 7.61 (1H,d,J = 7.9 Hz).

[0375] c) Preparation of 2-methyl-2-(1-methyl-1H-indol-3-yl)propan-1-ol (compound Q3) Under a nitrogen atmosphere, diisobutylaluminum hydride (1 mol / L n-hexane solution, 38.8 mL) was added dropwise to a solution of compound Q2 (3.59 g) in diethyl ether (169 mL) and dichloromethane (47 mL) at -78°C, and the mixture was stirred at 0°C for 1 hour. After the reaction was completed, water was added, and then a saturated aqueous solution of potassium sodium tartrate was added to the reaction mixture at 25°C, followed by extraction with diethyl ether. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate) to obtain compound Q3 (3.14 g). 1H-NMR(400MHz, CDCl3):1.42 (6H,s), 3.74 (3H,s), 3.77 (2H,s), 6.87 (1H,s), 7.07(1H,t, J = 7.9 Hz), 7.20 (1H,t, J = 7.9 Hz), 7.29(1H,d, J = 8.0 Hz), 7.75(1H,d,J = 8.0 Hz).

[0376] d) Preparation of 2-methyl-2-(1-methyl-1H-indol-3-yl)propanal (compound Q4) Under a nitrogen atmosphere, a mixture of compound Q3 (3.14 g), tetrapropylammonium perruthenate (271 mg), N-methylmorpholine-N-oxide (3.26 g), and molecular sieve 4A (7.7 g) in dichloromethane (110 mL) was stirred for 1 hour at 25° C. After the reaction was completed, the mixture was filtered through Celite, the solvent was distilled off, and the residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate) to obtain compound Q4 (2.4 g). 1 H-NMR(400 MHz, CDCl3):1.53 (6H,s), 3.77 (3H,s), 6.94 (1H,s), 7.07 (1H,t,J = 8.0 Hz), 7.22 (1H,t, J = 8.0 Hz), 7.30(1H,d, J = 8.0 Hz), 7.53 (1H,d,J =8.0 Hz), 9.47 (1H,s).

[0377] e) Preparation of (2S)-2-{[(1R)-2-hydroxy-1-phenylethyl]amino}-3-methyl-3-(1-methyl-1H-indol-3-yl)butanenitrile (Compound Q5) Under a nitrogen atmosphere, a solution of compound Q4 (2.4 g) and (R)-(-)-2-phenylglycinol (1.63 g) in toluene (47 mL) was heated to reflux for 1.5 hours, water was removed using a Dean-Stark apparatus, and the solvent was removed. Under a nitrogen atmosphere, dichloromethane (69 mL) was added to the residue at 0°C, followed by trimethylsilyl cyanide (2.36 g) and stirring at 25°C for 96 hours. Tetra-n-butylammonium fluoride (1 mol / L tetrahydrofuran solution, 1 mL) was added to the reaction solution, which was then stirred for another 30 minutes, after which water was added and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate) to obtain compound Q5 (2.74 g). 1 H-NMR(400MHz, CDCl3):1.64 (3H,s), 1.65 (3H,s), 3.49-3.55 (1H,m), 3.73 (1H,dd,J = 10.9, 4.2 Hz), 3.79 (1H,s), 3.80 (3H,s), 4.05 (1H,dd, J = 7.9, 3.6 Hz),6.96-7.00 (2H,m), 7.11(2H,d, J = 8.0 Hz), 7.21-7.40 (6H,m).

[0378] f) Preparation of Nα-[(1R)-2-hydroxy-1-phenylethyl]-β,β,1-trimethyl-L-tryptophanamide (Compound Q6) To a suspension of compound Q5 (2.74 g), dimethyl sulfoxide (6.16 g), and potassium carbonate (10.9 g) in methanol (50 mL) and water (2.1 mL), 30% hydrogen peroxide (8.94 mL) was added at 0°C, and the mixture was stirred at 45°C for 1.5 hours. After the reaction was completed, a saturated aqueous solution of sodium thiosulfate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: chloroform:methanol) to obtain compound Q6 (2.32 g). 1H-NMR(400MHz, CDCl3):1.49 (3H,s),1.51 (3H, s), 2.06-2.14 (1H, br), 2.37(1H,dd, J = 6.0, 6.0 Hz), 3.44-3.50 (1H, m),3.50-3.54 (1H, m), 3.56-3.63(m,2H), 3.75 (3H, s), 5.52 (1H, brs), 6.14 (1H, brs), 6.71-6.73 (2H, m),6.81-6.85(2H, m), 6.97-7.00 (2H, m), 7.10-7.18 (2H, m), 7.24-7.28 (2H, m).

[0379] g) Preparation of β,β,1-trimethyl-L-tryptophanamide (Compound Q7) Palladium hydroxide / carbon (2.8 g) was added to a solution of compound Q6 (2.32 g) in methanol (65 mL), and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. After filtration through Celite, the solvent was removed, and the residue was purified by silica gel column chromatography (elution solvent: chloroform:methanol) to obtain compound Q7 (1.27 g). 1 H-NMR(400 MHz, DMSO-d6):1.24 (2H, brs), 1.28 (3H, s), 1.42 (3H, s), 3.68 (1H, s),3.71 (3H,s), 6.93-7.00 (2H, m), 7.06 (1H, s), 7.11 (1H, t, J = 7.7 Hz), 7.29(1H, brs),7.36 (1H, d, J = 8.3 Hz), 7.88 (1H, d, J = 8.2 Hz).

[0380] h) Preparation of Nα-(tert-butoxycarbonyl-β,β,1-trimethyl-L-tryptophanamide (Compound Q8) A mixture of compound Q7 (1.27 g), sodium hydrogen carbonate (522 mg), di-tert-butyl dicarbonate (1.35 g), tetrahydrofuran (13 mL), chloroform (13 mL) and water (6.5 mL) was stirred at 25° C. for 16 hours. After the reaction was completed, water was added and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: chloroform:methanol) to obtain compound Q8 (1.80 g). 1 H-NMR(400 MHz, CDCl3):1.33 (3H, s), 1.47 (9H, s), 1.50 (3H, s), 3.73 (3H,d, J = 1.3 Hz),4.51 (1H, brs), 4.86 (1H, brs), 5.02 (1H, brd, J = 8.2 Hz), 5.59(1H, brd, J =6.4 Hz), 6.83 (1H, d, J = 1.8 Hz), 7.15 (1H, t, J = 7.3 Hz),7.21-7.25 (1H, m),7.30 (1H, d, J = 8.2 Hz), 8.05 (1H, brd, J = 7.3 Hz). LC-MS: 346 (M+H) + (1.211 min, measurement condition A).

[0381] i) Preparation of N,N,Nα-tris(tert-butoxycarbonyl)-β,β,1-trimethyl-L-tryptophanamide (Compound Q9) A mixture of compound Q8 (1.79 g), di-tert-butyl dicarbonate (2.8 g), N,N-diisopropylethylamine (2.68 g), 4-dimethylaminopyridine (0.19 g) and chloroform (20 mL) was stirred at 25° C. for 2.5 hours. After the reaction was completed, water was added and the mixture was extracted with chloroform. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate) to obtain compound Q9 (1.99 g). 1H-NMR(400 MHz, CDCl3):1.08-1.58 (33H, m), 3.70 (3H, s), 4.67-4.90 (0.2H,m), 5.25-5.45(0.8H, m), 6.00-6.03 (1H, m), 6.81-6.87 (1H, m), 7.04-7.09 (1H, m), 7.13-7.18(1H. m), 7,21-7,27 (1H, m), 7.91-7.94 (1H, m). LC-MS: 546 (M+H) + (1.630 min, measurement condition A)

[0382] j) Preparation of methyl N-(tert-butoxycarbonyl)-β,β,1-trimethyl-L-tryptophanate (compound Q10) Lithium methoxide (176 mg) was added to a methanol solution (21 mL) of compound Q9 (2.29 g) under a nitrogen atmosphere at 0°C, and the mixture was stirred at 25°C for 2 hours. After the reaction was completed, a saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate) to obtain compound Q10 (927 mg). 1 H-NMR(400 MHz, CDCl3):1.17-1.59 (15H, m), 3.45 and 3.58 (3H, 2brs), 3.71(3H, s), 4.56-4.73 (1.2H,m), 5.06 (0.8H, brd, J = 7.3 Hz), 6.81-6.82 (1H, m),7.05-7.10 (1H, m),7.16-7.21 (1H, m), 7.24-7.29 (1H, m), 7.73-7.80 (1H, m). LC-MS: 361 (M+H) + (1.379 min, measurement condition A).

[0383] k) Preparation of methyl N-(tert-butoxycarbonyl)-N,β,β,1-tetramethyl-L-tryptophanate (Reference Example 1) Under a nitrogen atmosphere, 60% sodium hydride (168 mg) was added to a solution (13 mL) of compound Q10 (927 mg) in N,N-dimethylformamide at 0°C, and the mixture was stirred at 25°C for 15 minutes. After the reaction suspension was cooled to 0°C, methyl iodide (1.1 g) was added, and the mixture was stirred at 25°C for 1 hour. After the reaction was completed, water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate) to obtain Reference Example 1 (915 mg). 1 H-NMR(400 MHz, CDCl3):1.42(9H, s), 1.52 and 1.64 (6H, 2s), 2.80 and 2.86(3H, 2s), 3.46 (3H, s), 3.71 (3H,s), 5.27 and 5.52 (1H, 2s), 6.85 (1H, s),7.07-7.27(3H, m), 7.78 and 7.92 (1H, 2d,J = 7.88 Hz). LC-MS: 397 (M+Na) + (1.406 min, measurement condition B)

[0384] Reference example 2 N-(tert-butoxycarbonyl)-N,β,β,1-tetramethyl-L-tryptophyl-N-{(3S,4E)-6-[(2,5-dioxopyrrolidin-1-yl)oxy]-2,5-dimethyl-6-oxohex-4-en-3-yl}-N,3-dimethyl-L-valinamide [ka]

[0385] a) Preparation of N-(tert-butoxycarbonyl)-N,β,β,1-tetramethyl-L-tryptophan (Compound A11) 1 mol / L lithium hydroxide (13.5 mL) was added to a water (11 mL)-methanol (44 mL) solution of Reference Example 1 (639 mg), and the mixture was stirred at 60° C. for 24 hours. After the reaction was completed, a 1 mol / L aqueous oxalic acid solution was added to adjust the reaction solution to pH 4, and then water was added and the mixture was extracted with chloroform. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: chloroform:methanol) to obtain compound A11 (610 mg). 1 H-NMR(400 MHz, CDCl3):1.43(9H, s), 1.53 (3H, s), 1.63 (3H, s), 2.76 and2.89 (3H, 2s), 3.71 (3H, s), 5.36and 5.44 (1H, 2s), 6.85 and 6.87 (1H, 2s),7.02-7.11 (1H, m), 7.18 (1H, t, J =7.3 Hz), 7.24-7.27 (1H, m), 7.81 and 7.96(1H, 2d, J = 7.9 Hz). LC-MS: 361 (M+H) + , 359 (MH) - (1.300 min, measurement condition A).

[0386] b) Preparation of N-(tert-butoxycarbonyl)-N,β,β,1-tetramethyl-L-tryptophyl-N-[(3S,4E)-6-ethoxy-2,5-dimethyl-6-oxohex-4-en-3-yl]-N,3-dimethyl-L-valinamide (Compound A12) A mixture of compound A11 (500 mg), ethyl (2E,4S)-2,5-dimethyl-4-[methyl(3-methyl-L-valyl)amino]hex-2-enoate (520 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (399 mg), 1-hydroxy-1H-benzotriazole monohydrate (425 mg) and N,N-dimethylformamide (5 mL) was stirred at 25°C for 16 hours. After the reaction was completed, water was added and the mixture was extracted with chloroform. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate) to obtain compound A12 (759 mg). LC-MS: 655 (M+H) + (1.714 min, measurement condition A)

[0387] c) Preparation of N-(tert-butoxycarbonyl)-N,β,β,1-tetramethyl-L-tryptophyll-N-[(3S,4E)-5-carboxy-2-methylhex-4-en-3-yl]-N,3-dimethyl-L-valinamide (Compound A13) To a solution of compound A12 (127 mg) in water (1.55 mL)-methanol (4.65 mL), 1 mol / L lithium hydroxide (1.65 mL) was added and stirred at 25° C. for 24 hours. After the reaction was completed, a 1 mol / L aqueous oxalic acid solution was added to adjust the reaction solution to pH 4, water was added, and the solution was extracted with chloroform. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: chloroform:methanol) to obtain compound A13 (93 mg). LC-MS: 627 (M+H) + (1.508 min, measurement condition A)

[0388] d) Preparation of N-(tert-butoxycarbonyl)-N,β,β,1-tetramethyl-L-tryptophyl-N-{(3S,4E)-6-[(2,5-dioxopyrrolidin-1-yl)oxy]-2,5-dimethyl-6-oxohex-4-en-3-yl}-N,3-dimethyl-L-valinamide (Reference Example 2) A mixture of Compound A13 (185 mg), N-hydroxysuccinimide (97 mg), bromotripyrrolidinophosphonium hexafluorophosphate (391 mg), 4-dimethylaminopyridine (102 mg), N,N-diisopropylethylamine (108 mg) and N,N-dimethylformamide (2.8 mL) was stirred at 25° C. for 4 hours. After the reaction was completed, water was added and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: chloroform:methanol) to obtain Reference Example 2 (166 mg). 1 H-NMR(400 MHz, CDCl3):8.27 and 7.96 (1H, 2d, J = 7.9 Hz), 7.16-7.04 (4H,m), 6.88 (1H, d, J = 9.1Hz), 6.17 and 6.09 (1H, 2d, J = 8.5 Hz), 5.96 and 5.66(1H, 2s), 5.07 (1H, t, J= 9.3 Hz), 4.45 and 3.87 (1H, 2d, J = 8.6 Hz), 3.74 and3.73 (3H, 2s), 2.99(3H, s), 2.95 (3H, s), 2.83 (4H, brs), 1.97 (3H, s),1.92-1.86 (1H, m),1.57-1.42 (14H, m), 0.89 (3H, d, J = 6.1 Hz), 0.83-0.80 (3H,m), 0.48 and 0.41(9H, 2s). LC-MS: 724 (M+H) + (1.573 min, measurement condition A)

[0389] Reference example 3 (6S,9S,12S,13E,17R)-9-tert-butyl-17-(ethoxycarbonyl)-2,2,5,11,14-pentamethyl-6-[2-(1-methyl-1H-indol-3-yl)propan-2-yl]-4,7,10,15-tetraoxo-12-(propan-2-yl)-3-oxa-5,8,11,16-tetraazaicos-13-ene-20-carboxylic acid [ka] A mixture of Reference Example 2 (160 mg), α-ethyl D-glutamic acid ester trifluoroacetate (122 mg), N,N-diisopropylethylamine (100 mg) and N,N-dimethylformamide (2.2 mL) was stirred at 25°C for 6 hours. After the reaction was completed, the pH was adjusted to 4 with 1 mol / L aqueous oxalic acid solution and extracted with chloroform. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: chloroform:methanol) to obtain Reference Example 3 (155 mg). 1H-NMR(400 MHz, CDCl3):8.26 and 7.97 (1H, 2d, J = 7.9 Hz), 7.32-7.05 (4H,m), 6.71 (1H, t, J = 6.7 Hz),6.45 (1H, d, J = 8.6 Hz), 6.31-6.26 (1H, m), 5.95and 5.63 (1H, 2s), 4.94-4.82(1H, m), 4.64-4.59 (1H, m), 4.51 and 4.41 (1H, 2d,J = 9.1 Hz), 4.21 (2H, q, J= 7.3 Hz), 3.75 and 3.74 (3H, 2s), 3.00 (3H, s),2.97 and 2.95 (3H, 2s),2.52-2.38 (2H, m), 2.29-2.20 (1H, m), 2.10-2.00 (1H, m),1.98-1.90 (1H, m),1.90 (3H, s), 1.57-1.45 (14H, m), 1.28 (3H, t, J = 7.3 Hz), 0.88 (3H, d, J =6.1 Hz), 0.82 (3H, d, J = 6.7 Hz), 0.53 and 0.46 (9H, 2s). LC-MS: 784 (M+H) + , 782 (MH) - (1.472 min, measurement condition A)

[0390] Reference example 4 N-(tert-Butoxycarbonyl)-N,β,β,1-tetramethyl-L-tryptophyll-N-[(3S,4E)-6-{[(1R)-1,3-dicarboxypropyl]amino}-2,5-dimethyl-6-oxohex-4-en-3-yl]-N,3-dimethyl-L-valinamide [ka] To a solution of Reference Example 3 (103 mg) in water (0.8 mL)-methanol (3.3 mL), 1 mol / L lithium hydroxide (1 mL) was added and stirred for 16 hours at 25° C. After completion of the reaction, a 1 mol / L aqueous oxalic acid solution was added to adjust the reaction solution to pH 4, and then the solution was purified by silica gel column chromatography (elution solvent: chloroform:methanol) to obtain Reference Example 4 (100 mg). LC-MS: 756 (M+H) + , 754 (MH) - (1.388 min, measurement condition A)

[0391] Reference example 5 N-[(2E,4S)-4-{[N-(tert-butoxycarbonyl)-N,β,β,1-tetramethyl-L-tryptophyll-3-methyl-L-valyl](methyl)amino}-2,5-dimethylhex-2-enoyl]-L-α-aspartyl-L-α-aspartyl-L-α-aspartyl-L-α-aspartic acid [ka] A mixture of Reference Example 2 (20 mg), L-α-aspartyl-L-α-aspartyl-L-α-aspartyl-L-α-aspartyl-L-α-aspartic acid (16 mg), N,N-diisopropylethylamine (10 mg) and N,N-dimethylformamide (1 mL) was stirred for 68 hours at 25° C. After completion of the reaction, the reaction solution was purified by reverse phase column chromatography (elution solvent: 0.1% TFA acetonitrile:water) to obtain Reference Example 5 (16 mg). LC-MS: 1200 (MH) - (1.304 min, measurement condition D)

[0392] Reference example 6 N-(tert-butoxycarbonyl)-N,β,β,1-tetramethyl-L-tryptophyll-N-[(3S,4E)-6-({(2R)-1-tert-butoxy-6-[(tert-butoxycarbonyl)amino]-1-oxohexan-2-yl}amino)-2,5-dimethyl-6-oxohex-4-en-3-yl]-N,3-dimethyl-L-valinamide [ka] Reference Example 6 (57 mg) was obtained from Compound A13 (50 mg) in the same manner as in Reference Example 2-b). LC-MS: 911 (M+H) + (1.756 min, measurement condition D)

[0393] Reference example 7 tert-Butyl N-[(2E,4S)-4-{[N-(tert-butoxycarbonyl)-N,β,β,1-tetramethyl-L-tryptophyll-3-methyl-L-valyl](methyl)amino}-2,5-dimethylhex-2-enoyl]-D-γ-glutamyl-N 6 -(tert-Butoxycarbonyl)-D-lysinate [ka]

[0394] a) Preparation of 22-tert-butyl 17-ethyl (6S,9S,12S,13E,17R,22R)-9-tert-butyl-2,2,5,11,14,30,30-heptamethyl-6-[2-(1-methyl-1H-indol-3-yl)propan-2-yl]-4,7,10,15,20,28-hexaoxo-12-(propan-2-yl)-3,29-dioxa-5,8,11,16,21,27-hexaazahentriacont-13-ene-17,22-dicarboxylate (compound G1) Compound G1 (54 mg) was obtained from Reference Example 3 (40 mg) in the same manner as in Reference Example 2-b). LC-MS: 1068 (M+H)+ (1.751min, measurement condition D).

[0395] b) tert-Butyl N-[(2E,4S)-4-{[N-(tert-butoxycarbonyl)-N,β,β,1-tetramethyl-L-tryptophyll-3-methyl-L-valyl](methyl)amino}-2,5-dimethylhex-2-enoyl]-D-γ-glutamyl-N 6 Preparation of -(tert-butoxycarbonyl)-D-lysinate (Reference Example 7) In the same manner as in Reference Example 4, Reference Example 7 (37 mg) was obtained from Compound G1 (54 mg). LC-MS: 1038 (MH) - (1.672min, measurement condition D).

[0396] Reference example 8 Diethyl (2R)-2-{[(6S,9S,12S,13E)-9-tert-butyl-2,2,11,14-tetramethyl-6-[2-(1-methyl-1H-indol-3-yl)propan-2-yl]-4,7,10,15-tetraoxo-12-(propan-2-yl)-3-oxa-5,8,11-triazapentadec-13-en-15-yl]amino}pentane diester [ka]

[0397] a) Preparation of N-(tert-butoxycarbonyl)-β,β,1-trimethyl-L-tryptophan (Compound B1) Compound B1 (38 mg) was obtained from compound Q10 (40 mg) in the same manner as in Reference Example 2-a). 1H-NMR(400 MHz, CDCl3):1.34 (9H, s), 1.48 (3H, s), 1.53 (3H, s), 3.72 (3H,s), 4.88 (1H,brd, J = 4.3 Hz), 5.11 (1H, brd, J = 6.7 Hz), 6.85 (1H, s), 7.09(1H, t, J =7.3Hz), 7.20 (1H, t, J = 8.5 Hz), 7.28 (1H, d, J = 8.0 Hz), 7.88(1H, brd, J =7.3 Hz).

[0398] b) Preparation of diethyl (2R)-2-{[(6S,9S,12S,13E)-9-tert-butyl-2,2,11,14-tetramethyl-6-[2-(1-methyl-1H-indol-3-yl)propan-2-yl]-4,7,10,15-tetraoxo-12-(propan-2-yl)-3-oxa-5,8,11-triazapentadec-13-en-15-yl]amino}pentane diester (Reference Example 8) Reference Example 8 (80 mg) was obtained from Compound B1 (38 mg) in the same manner as in Reference Example 2-b). LC-MS: 798 (M+H) + (1.606 min, measurement condition D)

[0399] Reference example 9 Diethyl (2S)-2-{[(6S,9S,12S,13E)-9-tert-butyl-2,2,5,11,14-pentamethyl-4,7,10,15-tetraoxo-6-(2-phenylpropan-2-yl)-12-(propan-2-yl)-3-oxa-5,8,11-triazapentadec-13-en-15-yl]amino}pentane diester [ka]

[0400] a) Preparation of 3-methyl-3-phenylbutanoic acid (compound J1) To a solution of 3-methyl-2-butenoic acid (15 g) in benzene (100 mL), aluminum chloride (24.1 g) was added at 10° C., and the mixture was stirred for 30 minutes and then at 40° C. for 1 hour. After cooling to 0° C., ice water was added, the mixture was extracted with tert-butyl methyl ether, and concentrated to a certain extent, and the organic layer was extracted with a saturated aqueous solution of sodium bicarbonate. The aqueous layer was adjusted to pH 2 with concentrated hydrochloric acid, and extracted with tert-butyl methyl ether. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain compound J1 (26.3 g). 1 H-NMR(400 MHz, CDCl3):1.46 (6H, s), 2.65 (2H, s), 7.20 (1H, t, J = 7.2Hz), 7.31 (1H, t, J= 7.2 Hz), 7.37 (2H, d, J = 7.2 Hz).

[0401] b) Preparation of (4S)-3-(3-methyl-3-phenylbutanoyl)-4-(propan-2-yl)-1,3-oxazolidin-2-one (compound J2) To a THF solution (900 mL) of compound J1 (17.2 g), triethylamine (23.7 mL) and pivaloyl chloride (15.3 mL) were added at -78°C. The mixture was heated to 0°C and stirred for 1 hour. Separately, n-butyllithium (89.8 mL of 1.64 mol / L hexane solution) was added to a THF solution (760 mL) of (S)-isopropyloxazolidinone (19.5 g) at -78°C and stirred for 30 minutes to prepare a lithium salt. The reaction solution was cooled to -78°C, the lithium salt was added dropwise, and the mixture was stirred for 1 hour, then heated to 0°C and stirred for another 30 minutes, after which water was added and the mixture was extracted with tert-butyl methyl ether. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane: tert-butyl methyl ether) to obtain compound J2 (27.0 g). 1H-NMR(400 MHz, CDCl3):0.723 (3H, d, J = 6.8 Hz), 0.80 (3H, d, J = 6.8Hz), 1.49 (s, 6H),2.13-2.18 (m, 1H), 3.36 (s, 3H), 3.99-4.09 (m, 2H), 4.20-4.23(m, 1H),7.16-7.20 (m, 1H), 7.28-7.32 (m, 2H), 7.38-7.40 (m, 2H).

[0402] c) Preparation of (4S)-3-[(2S)-2-azido-3-methyl-3-phenylbutanoyl]-4-(propan-2-yl)-1,3-oxazolidin-2-one (compound J3) A suspension of compound J2 (27.0 g) in THF (560 mL) was cooled to -78°C, potassium hexamethyldisilazide (1.06 mol / L tetrahydrofuran solution, 99.5 mL) was added, and the mixture was stirred for 1.5 hours. A solution of 2,4,6-triisopropylbenzenesulfonyl azide (40 g) in THF (330 mL) at -78°C was added, and after 10 minutes, acetic acid (24.5 mL) was added, and the mixture was heated to 40°C and stirred for 1 hour. Saturated saline was added, and the mixture was extracted with tert-butyl methyl ether. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and saturated saline, and then the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane:chloroform) to obtain compound J3 (16.4 g). 1 H-NMR(400 MHz, CDCl3):0.80 (3H, d, J = 6.8 Hz), 0.84 (3H, d, J = 7.2 Hz),1.54 (3H, s),1.56 (3H, s), 2.28-2.33 (1H, m), 3.54-3.59 (1H, m), 3.87-3.90 (1H, m), 3.95-3.98 (1H, m), 5.66 (1H, s), 7.23-7.420 (5H, m).

[0403] d) Preparation of tert-butyl {(2S)-3-methyl-1-oxo-1-[(4S)-2-oxo-4-(propan-2-yl)-1,3-oxazolidin-3-yl]-3-phenylbutan-2-yl}carbamate (compound J4) To a solution (1200 mL) of compound J3 (16.4 g) in ethyl acetate, di-tert-butyl dicarbonate (24.0 g) and 10% Pd-C (11.6 g, 50% wet) were added, and the mixture was stirred under a hydrogen atmosphere for 2 hours. The mixture was filtered through Celite and washed with ethyl acetate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane: tert-butyl methyl ether) to obtain compound J4 (16.1 g). 1 H-NMR(400 MHz, CDCl3):0.77 (3H, d, J = 6.8 Hz), 0.82 (3H, d, J = 6.8 Hz),1.42 (3H, s),1.43 (9H, s), 1.48 (3H, s), 2.20-2.29 (1H, m), 3.45 (1H, t, J =8.8 Hz),3.80-3.83 (1H, m), 3.89-3.92 (1H, dd, J = 2.0 Hz, J = 8.4 Hz), 5.16(1H, brs),6.13 (1H, d, J = 9.6 Hz), 7.21-7.26 (1H, m), 7.29-7.33 (2H, m). 7.42(2H, d, J= 7.2 Hz).

[0404] e) Preparation of N-(tert-butoxycarbonyl)-β,β-dimethyl-L-phenylalanine (Compound J5) To a solution of compound J4 (16.1 g) in THF (468 mL) and water (117 mL), 30% hydrogen peroxide solution (32.5 mL) and lithium hydroxide solution (1 mol / L, 119 mL) were added at 0° C., the temperature was raised to 25° C., and the mixture was stirred for 3 hours. An aqueous sodium hydrogen sulfate solution (1.5 mol / L, 470 mL) was added at 0° C., the temperature was raised to 25° C., and the mixture was stirred for 1 hour. The pH was adjusted to 3 with an aqueous citric acid solution (1 mol / L), and the mixture was extracted with tert-butyl methyl ether. The organic layer was washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain compound J5 (14.2 g). 1 H-NMR(400 MHz, CDCl3):1.38 (9H, s), 1.44 (3H, s), 1.46 (3H, s), 4.56 (1H,brd, J = 11.6Hz), 4.94 (1H,brd, J = 14.4Hz), 7.21-7.38 (5H, m).

[0405] f) Preparation of methyl N-(tert-butoxycarbonyl)-β,β-dimethyl-L-phenylalanine ester (Compound J6) Sodium carbonate (8.44 g) and methyl iodide (9.91 mL) were added to a solution (84 mL) of compound J5 (14.2 g) in N,N-dimethylformamide, and the mixture was stirred at 25° C. for 15 hours. After cooling to 0° C., cold water was added and the mixture was extracted with tert-butyl methyl ether. The organic layer obtained was washed with saturated saline and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane: tert-butyl methyl ether) to obtain compound J6 (11.1 g). 1 H-NMR(400 MHz, CDCl3):1.36 (9H, s), 1.37 (3H, s), 1.41 (3H, s), 3.48 (3H,brs), 4.49 (1H,brd, J = 9.8 Hz), 4.98 (1H,brd, J = 9.1 Hz), 7.18-7.22 (1H, m),7.27-7.33 (4H, m).

[0406] g) Preparation of methyl N-(tert-butoxycarbonyl)-N,β,β-trimethyl-L-phenylalanine ester (Compound J7) Compound J7 (245 mg) was obtained from compound J6 (307 mg) in the same manner as in Reference Example 1-k). LC-MS: 344 (M+Na) + (1.589 min, measurement condition C)

[0407] h) Preparation of N-(tert-butoxycarbonyl)-N,β,β-trimethyl-L-phenylalanine (Compound J8) Compound J8 (195 mg) was obtained from compound J7 (235 mg) in the same manner as in Reference Example 2-a). LC-MS: 330 (M+Na) + (1.420 min, measurement condition C)

[0408] i) Preparation of N-(tert-butoxycarbonyl)-N,β,β-trimethyl-L-phenylalanyl-N-[(3S,4E)-6-ethoxy-2,5-dimethyl-6-oxohex-4-en-3-yl]-N,3-dimethyl-L-valinamide (Compound J9) Compound J9 (307 mg) was obtained from compound J8 (195 mg) in the same manner as in Reference Example 2-b). LC-MS: 624 (M+Na) + (1.797 min, measurement condition C)

[0409] j) Preparation of N-(tert-butoxycarbonyl)-N,β,β-trimethyl-L-phenylalanyl-N-[(3S,4E)-5-carboxy-2-methylhex-4-en-3-yl]-N,3-dimethyl-L-valinamide (Compound J10) Compound J10 (286 mg) was obtained from compound J9 (307 mg) in the same manner as in Reference Example 2-c). LC-MS: 596 (M+Na) + , 572 (MH) - (1.596 min, measurement condition C)

[0410] k) Preparation of N-(tert-butoxycarbonyl)-N,β,β-trimethyl-L-phenylalanyl-N-{(3S,4E)-6-[(2,5-dioxopyrrolidin-1-yl)oxy]-2,5-dimethyl-6-oxohex-4-en-3-yl}-N,3-dimethyl-L-valinamide (Compound J11) Compound J11 (227 mg) was obtained from compound J10 (286 mg) in the same manner as in Reference Example 2-d). LC-MS: 693 (M+Na) + (1.658 min, measurement condition C)

[0411] l) Preparation of diethyl (2S)-2-{[(6S,9S,12S,13E)-9-tert-butyl-2,2,5,11,14-pentamethyl-4,7,10,15-tetraoxo-6-(2-phenylpropan-2-yl)-12-(propan-2-yl)-3-oxa-5,8,11-triazapentadec-13-en-15-yl]amino}pentane diester (Reference Example 9) In the same manner as in Reference Example 3, Reference Example 9 (232 mg) was obtained from Compound J11 (227 mg). LC-MS: 781 (M+Na) + (1.707 min, measurement condition C)

[0412] Reference example 10 The compounds shown in the table below were synthesized by reactions and treatments according to the method described in Molecules 2015, 20(6), 10004-10031. [Table 1]

[0413] Reference example 11 Tetraethyl 2,2'-(((S)-2-aminopentanedioyl)bis(azanediyl))(2S,2'S)-diglutarate [ka]

[0414] a) Preparation of (2S,2'S)-tetraethyl 2,2'-(((S)-2-((tert-butoxycarbonyl)amino)pentanedioyl)bis(azanediyl))dipentanedioate In the same manner as in Reference Example 2-b), (2S,2'S)-tetraethyl 2,2'-(((S)-2-((tert-butoxycarbonyl)amino)pentanedioyl)bis(azanediyl))dipentanedioate (741 mg) was obtained from (S)-2-((tert-butoxycarbonyl)amino)pentanedioic acid (500 mg). LC-MS: 618 (M+H) + / 1.267min, measurement condition C

[0415] b) Preparation of tetraethyl 2,2'-(((S)-2-aminopentanedioyl)bis(azanediyl))(2S,2'S)-diglutarate (Reference Example 11) Reference Example 11 (450 mg) was obtained in the same manner as in Reference Example 101-a). LC-MS: 518 (M+H) + / 1.263min, measurement condition C

[0416] Reference examples 12~15 The peptides shown in the table below were synthesized by solid-phase synthesis using the Fmoc method, starting from Fmoc-Glu(OtBu)-Alko-PEG resin (1.00 g, Watanabe Chemical; 0.23 mmol / g, 0.23 mmol). The Fmoc method can be performed by the method described in Fundamentals and Experiments of Peptide Synthesis (by Nobuo Izumiya, Tetsuo Kato, Haruhiko Aoyagi, and Michinori Waki, published by Maruzen Co., Ltd., 1985). For solid-phase synthesis, a CS336X peptide synthesizer manufactured by CS Bio was used. The Fmoc group was deprotected by treating with a 20% piperidine solution in DMF for 25 minutes. The coupling reaction for peptide synthesis was carried out by reacting a DMF solution of Fmoc-protected amino acid (1.05 mmol), O-(benzotriazol-1-yl)-N,N,N'N'-tetramethyluronium hexafluorophosphate (1 mmol) and N,N-diisopropylethylamine (2 mmol) with the amino acid or peptide (0.23 mmol) on the resin for 1 hour. The resulting resin was washed with DMF and ether and then dried under reduced pressure to obtain a peptide resin. A mixture (10 mL) of TFA / water / triisopropylsilane (volume ratio: 95 / 2.5 / 2.5) was added to this peptide resin and shaken at room temperature for 2 hours. After filtering off the resin, the reaction solution was concentrated under reduced pressure. The reaction solution was cooled on ice and diethyl ether (50 mL) was added. The resulting precipitate was collected by filtration, washed with diethyl ether, and then dried under reduced pressure to obtain a crude peptide. The resulting crude peptide was dissolved in a mixture of 20% aqueous acetic acid and acetonitrile (volume ratio 1 / 1) and purified by reverse-phase HPLC (mobile phase: 0.1% v / v TFA in water and 0.035% v / v TFA in acetonitrile) to obtain the peptides shown in the table below.

[0417] [Table 2]

[0418] Reference example 16 Diethyl ((S,E)-4-((S)-2-amino-N,3,3-trimethylbutanamido)-2,5-dimethylhex-2-enoyl)-D-glutamate [ka]

[0419] a) Preparation of (S,E)-4-((S)-2-((tert-butoxycarbonyl)amino)-N,3,3-trimethylbutanamido)-2,5-dimethylhex-2-enoic acid In the same manner as in Reference Example 2-c), (S,E)-4-((S)-2-((tert-butoxycarbonyl)amino)-N,3,3-trimethylbutanamido)-2,5-dimethylhex-2-enoic acid (1.55 g) was obtained from ethyl (S,E)-4-((S)-2-((tert-butoxycarbonyl)amino)-N,3,3-trimethylbutanamido)-2,5-dimethylhex-2-enoate (1.64 g). LC-MS: 385 (M+H) + / 0.986min, measurement condition E

[0420] b) Preparation of diethyl((S,E)-4-((S)-2-((tert-butoxycarbonyl)amino)-N,3,3-trimethylbutanamido)-2,5-dimethylhex-2-enoyl)-D-glutamic acid By a method similar to that of Reference Example 2-b), diethyl ((S,E)-4-((S)-2-((tert-butoxycarbonyl)amino)-N,3,3-trimethylbutanamido)-2,5-dimethylhex-2-enoyl)-D-glutamate (500 mg) was obtained from (S,E)-4-((S)-2-((tert-butoxycarbonyl)amino)-N,3,3-trimethylbutanamido)-2,5-dimethylhex-2-enoic acid (376 mg).

[0421] c) Preparation of diethyl((S,E)-4-((S)-2-amino-N,3,3-trimethylbutanamido)-2,5-dimethylhex-2-enoyl)-D-glutamic acid (Reference Example 16) In the same manner as in Reference Example 101-a), Reference Example 16 (515 mg) was obtained from diethyl ((S,E)-4-((S)-2-((tert-butoxycarbonyl)amino)-N,3,3-trimethylbutanamido)-2,5-dimethylhex-2-enoyl)-D-glutamate (528 mg). LC-MS: 470 (M+H) + / 1.223min, measurement condition C

[0422] Reference example 17 Diethyl ((R)-2-((S,E)-4-((S)-2-amino-N,3,3-trimethylbutanamido)-2,5-dimethylhex-2-enamido)-5-methoxy-5-oxopentanoyl)-D-glutamate [ka]

[0423] a) Preparation of 2,5-dioxopyrrolidin-1-yl (S,E)-4-((S)-2-((tert-butoxycarbonyl)amino)-N,3,3-trimethylbutanamido)-2,5-dimethylhex-2-enolate In the same manner as in Reference Example 2-d), 2,5-dioxopyrrolidin-1-yl (S,E)-4-((S)-2-((tert-butoxycarbonyl)amino)-N,3,3-trimethylbutanamido)-2,5-dimethylhex-2-enolate (220 mg) was obtained from (S,E)-4-((S)-2-((tert-butoxycarbonyl)amino)-N,3,3-trimethylbutanamido)-2,5-dimethylhex-2-enoic acid (192 mg). LC-MS: 482 (M+H) + / 1.404min, measurement condition C

[0424] b) Preparation of diethyl ((R)-2-((S,E)-4-((S)-2-((tert-butoxycarbonyl)amino)-N,3,3-trimethylbutanamido)-2,5-dimethylhex-2-enamido)-5-methoxy-5-oxopentanoyl)-D-glutamic acid Using a method similar to that used in Reference Example 3, diethyl ((R)-2-((S,E)-4-((S)-2-((tert-butoxycarbonyl)amino)-N,3,3-trimethylbutanamido)-2,5-dimethylhex-2-enamido)-5-methoxy-5-oxopentanoyl)-D-glutamic acid (51.2 mg) was obtained from 2,5-dioxopyrrolidin-1-yl (S,E)-4-((S)-2-((tert-butoxycarbonyl)amino)-N,3,3-trimethylbutanamido)-2,5-dimethylhex-2-enolate (48 mg). LC-MS: 735 (M+Na) + / 1.469min, measurement condition J

[0425] c) Preparation of diethyl ((R)-2-((S,E)-4-((S)-2-amino-N,3,3-trimethylbutanamido)-2,5-dimethylhex-2-enamido)-5-methoxy-5-oxopentanoyl)-D-glutamic acid (Reference Example 17) In the same manner as in Reference Example 101-a), Reference Example 17 (41.2 mg) was obtained from diethyl ((R)-2-((S,E)-4-((S)-2-((tert-butoxycarbonyl)amino)-N,3,3-trimethylbutanamido)-2,5-dimethylhex-2-enamido)-5-methoxy-5-oxopentanoyl)-D-glutamate (51.2 mg). LC-MS: 613 (M+H) + / 1.066min, measurement condition J

[0426] Reference example 18 The corresponding starting compounds were used and reacted and treated in the same manner as in Reference Examples 1 and 2 to obtain the compounds shown in the table below. [Table 3]

[0427] Reference examples 19~21 The corresponding starting compounds were used and reacted and treated in the same manner as in Reference Examples 1 and 2 to obtain the compounds shown in the table below. [Table 4]

[0428] Reference example 22 tert-Butyl ((S)-3-methyl-1-(((S)-1-((4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-1-oxobutan-2-yl)carbamate [ka]

[0429] a) Preparation of 2,5-dioxopyrrolidin-1-yl (tert-butoxycarbonyl)-L-valinate In the same manner as in Reference Example 2-d), 2,5-dioxopyrrolidin-1-yl(tert-butoxycarbonyl)-L-valinate (4.9 g) was obtained from (tert-butoxycarbonyl)-L-valine (3.72 g). 1 H-NMR(400MHz, CDCl3): 1.01(3H,d,J=7.2Hz), 1.05(3H,d,J=6.8Hz), 1.44(9H,s),2.28(1H,m), 2.82(4H,s), 4.58(1H,m), 4.97(1H,m)

[0430] b) Preparation of (S)-2-((S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanamido)-5-ureidopentanoic acid Using a method similar to that of Reference Example 3, (S)-2-((S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanamido)-5-ureidopentanoic acid (5.31 g) was obtained from 2,5-dioxopyrrolidin-1-yl (tert-butoxycarbonyl)-L-valinate (4.9 g). LC-MS: 375 (M+H) + / 0.972min, measurement condition C

[0431] c) Preparation of tert-butyl ((S)-1-(((S)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate A mixture of (S)-2-((S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanamido)-5-ureidopentanoic acid (701 mg), 4-aminobenzyl alcohol (461 mg), ethyl 2-ethoxyquinoline-1(2H)-carboxylate (926 mg), methanol (10 mL) and dichloromethane (20 mL) was stirred at room temperature for 24 hours under light shielding. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: chloroform:methanol) to obtain tert-butyl ((S)-1-(((S)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (243 mg). LC-MS: 480 (M+H) + / 1.583min, measurement condition J

[0432] d) Preparation of tert-butyl ((S)-3-methyl-1-(((S)-1-((4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-1-oxobutan-2-yl)carbamate (Reference Example 22) A mixture of tert-butyl ((S)-1-(((S)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (2.0 g), bis(4-nitrophenyl)carbonate (3.81 g), N,N-diisopropylethylenediamine (2.179 mL) and N,N-dimethylformamide was stirred at room temperature for 2 hours. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography (elution solvent: chloroform:methanol) to obtain Reference Example 22 (2.1 g). LC-MS: 645 (M+H)+ / 1.225min, measurement condition J

[0433] Reference example 23 tert-Butyl ((S)-3-methyl-1-(((S)-1-((4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-1-oxopropan-2-yl)amino)-1-oxobutan-2-yl)carbamate [ka]

[0434] a) Preparation of (tert-butoxycarbonyl)-L-valyl-L-alanine In the same manner as in Reference Example 3, (tert-butoxycarbonyl)-L-valyl-L-alanine (676 mg) was obtained from 2,5-dioxopyrrolidin-1-yl (tert-butoxycarbonyl)-L-valinate (1.0 g). LC-MS: 278 (M-H) - / 0.925min, measurement condition J

[0435] b) Preparation of tert-butyl ((S)-1-(((S)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate In the same manner as in step c) of Reference Example 22, tert-butyl ((S)-1-(((S)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (400 mg) was obtained from (tert-butoxycarbonyl)-L-valyl-L-alanine (676 mg). LC-MS: 394 (M+H) + / 0.974min, measurement condition J

[0436] c) Preparation of tert-butyl ((S)-3-methyl-1-(((S)-1-((4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-1-oxopropan-2-yl)amino)-1-oxobutan-2-yl)carbamate (Reference Example 23) In the same manner as in step d) of Reference Example 22, tert-butyl ((S)-1-(((S)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (400 mg) was used to obtain Reference Example 23 (567 mg). LC-MS: 559 (M+H) + / 1.217min, measurement condition J

[0437] Reference examples 24~26 The compounds shown in the table below were obtained by reacting and treating the corresponding starting compounds in the same manner as in Reference Example 103 using intermediate F3 of Reference Example 103. [Table 5]

[0438] Reference examples 27~45 The corresponding starting compounds were used and treated in the same manner as in Reference Example 3 to obtain the compounds shown in the table below. [Table 6-1] [Table 6-2] [Table 6-3]

[0439] Reference examples 46~49 The corresponding starting compounds were used and treated in the same manner as in step b) of Reference Example 2 to give the compounds shown in the table below. [Table 7]

[0440] Reference examples 50~56 The corresponding starting compounds were used and treated in the same manner as in step b) of Reference Example 2 to give the compounds shown in the table below. [Table 8-1] [Table 8-2]

[0441] Reference example 59 The corresponding starting compounds were used in the same manner as in step f) of Reference Example 9 to give the compounds shown in the table below. [Table 9]

[0442] Reference examples 60~69 The corresponding starting compounds were used and reacted and treated in the same manner as in Example 2 to obtain the compounds shown in the table below. [Table 10-1] [Table 10-2]

[0443] Synthesis of Reference Examples 70 to 76 The corresponding starting compounds were used and reacted and treated in the same manner as in Example 1 to obtain the compounds shown in the table below. [Table 11-1] [Table 11-2]

[0444] Reference example 77 E11 described in Reference Example 101 and the corresponding starting compounds were used and reacted and treated in the same manner as in Reference Example 101 to give the compounds shown in the table below. [Table 12]

[0445] Reference example 101 Diethyl (2R)-2-{[(5S,8S,11S,12E)-1-(4-{[(2S)-2-{[(2S)-2-amino-3-methylbutanoyl]amino}-5-(carbamoylamino)pentanoyl]amino}phenyl)-8-tert-butyl-4,10,13-trimethyl-5-[2-(1-methyl-1H-indol-3-yl)propan-2-yl]-3,6,9,14-tetraoxo-11-(propan-2-yl)-2-oxa-4,7,10-triazatetradec-12-en-14-yl]amino}pentanedioate [ka]

[0446] a) Preparation of methyl N,β,β,1-tetramethyl-L-tryptophan ester (compound E11) Trifluoroacetic acid (1 mL) was added to a solution of Reference Example 1 (402 mg) in chloroform (5 mL), and the mixture was stirred for 45 minutes at 25° C. After completion of the reaction, the reaction solution was purified by silica gel column chromatography (elution solvent: methanol:chloroform) to obtain compound E11 (306 mg). 1H-NMR(400 MHz, CDCl3):1.47-1.48(6H, m), 2.21 (3H, d, J = 1.8 Hz), 3.61(3H, d, J = 2.3 Hz), 3.71 (1H, d, J =1.8 Hz), 3.72 (3H, d, J = 1.8 Hz), 6.83(1H, d, J = 1.8 Hz), 7.08 (1H, t, J =8.2 Hz), 7.19 (1H, t, J = 8.2 Hz), 7.27(1H, d, J = 8.2 Hz), 7.81 (1H, d, J =8.2 Hz). LC-MS: 275 (M+H) + (0.856 min, measurement condition D)

[0447] b) N-(tert-butoxycarbonyl)-L-valyl-N 5 Preparation of -carbamoyl-N-{4-[({[(2S)-1-methoxy-3-methyl-3-(1-methyl-1H-indol-3-yl)-1-oxobutan-2-yl](methyl)carbamoyl}oxy)methyl]phenyl}-L-ornithinamide (Compound E12) Compound E11 (306 mg), N-(tert-butoxycarbonyl)-L-valyl-N 5 A mixture of N-carbamoyl-N-[4-({[(4-nitrophenoxy)carbonyl]oxy}methyl)phenyl]-L-ornithineamide (791 mg), 1-hydroxy-7-benzotriazole (101 mg), 2,6-lutidine (663 mg) and N,N-dimethylformamide (5.5 mL) was stirred at 45° C. for 8 hours. After the reaction was completed, water was added and the mixture was extracted with chloroform. The organic layer was washed with water and saturated sodium bicarbonate, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: chloroform:methanol) to obtain compound E12 (516 mg). LC-MS: 780 (M+H) + (1.369 min, measurement condition D)

[0448] c) N-(tert-butoxycarbonyl)-L-valyl-N 5 Preparation of -carbamoyl-N-{4-[({[(1S)-1-carboxy-2-methyl-2-(1-methyl-1H-indol-3-yl)propyl](methyl)carbamoyl}oxy)methyl]phenyl}-L-ornithinamide (Compound E13) Compound E13 (175 mg) was obtained from compound 12 (516 mg) in the same manner as in Reference Example 2-a). LC-MS: 766 (M+H) + , 764 (MH) - (1.285 min, measurement condition D)

[0449] d) N-(tert-butoxycarbonyl)-L-valyl-N-{4-[(5S,8S,11S,12E)-8-tert-butyl-4,10,13-trimethyl-5-[2-(1-methyl-1H-indol-3-yl)propan-2-yl]-3,6,9,14-tetraoxo-11-(propan-2-yl)-2,15-dioxa-4,7,10-triazaheptadec-12-en-1-yl]phenyl}-N 5 -Preparation of Carbamoyl-L-ornithineamide (Compound E14) Compound E14 (146 mg) was obtained from compound E13 (130 mg) in the same manner as in Reference Example 2-b). LC-MS: 1060 (M+H) + (1.380 min, measurement condition D)

[0450] e) N-(tert-butoxycarbonyl)-L-valyl-N-{4-[(5S,8S,11S,12E)-8-tert-butyl-13-carboxy-4,10-dimethyl-5-[2-(1-methyl-1H-indol-3-yl)propan-2-yl]-3,6,9-trioxo-11-(propan-2-yl)-2-oxa-4,7,10-triazatetradec-12-en-1-yl]phenyl}-N 5 -Preparation of Carbamoyl-L-ornithineamide (Compound E15) Compound E15 (145 mg) was obtained from compound E14 (148 mg) in the same manner as in Reference Example 2-c). LC-MS: 1032 (M+H) + (1.231 min, measurement condition D)

[0451] f) N-(tert-butoxycarbonyl)-L-valyl-N-{4-[(5S,8S,11S,12E)-8-tert-butyl-14-[(2,5-dioxopyrrolidin-1-yl)oxy]-4,10,13-trimethyl-5-[2-(1-methyl-1H-indol-3-yl)propan-2-yl]-3,6,9,14-tetraoxo-11-(propan-2-yl)-2-oxa-4,7,10-triazatetradec-12-en-1-yl]phenyl}-N 5 -Preparation of Carbamoyl-L-ornithineamide (Compound E16) Compound E16 (139 mg) was obtained from compound E15 (145 mg) in the same manner as in Reference Example 2-d). LC-MS: 1129 (M+H) + (1.271 min, measurement condition D)

[0452] g) Preparation of diethyl (2R)-2-{[(5S,8S,11S,12E)-1-(4-{[(2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoyl}amino)-5-(carbamoylamino)pentanoyl]amino}phenyl)-8-tert-butyl-4,10,13-trimethyl-5-[2-(1-methyl-1H-indol-3-yl)propan-2-yl]-3,6,9,14-tetraoxo-11-(propan-2-yl)-2-oxa-4,7,10-triazatetradec-12-en-14-yl]amino}pentanedioate (compound E17) In the same manner as in Reference Example 3, compound E17 (154 mg) was obtained from compound E16 (139 mg). LC-MS: 1217 (M+H) + (1.533 min, measurement condition D)

[0453] h) Preparation of diethyl (2R)-2-{[(5S,8S,11S,12E)-1-(4-{[(2S)-2-{[(2S)-2-amino-3-methylbutanoyl]amino}-5-(carbamoylamino)pentanoyl]amino}phenyl)-8-tert-butyl-4,10,13-trimethyl-5-[2-(1-methyl-1H-indol-3-yl)propan-2-yl]-3,6,9,14-tetraoxo-11-(propan-2-yl)-2-oxa-4,7,10-triazatetradec-12-en-14-yl]amino}pentanedioate (Reference Example 101) Reference Example 101 (87 mg) was obtained from Compound E17 (92 mg) in the same manner as in Reference Example 101-a). LC-MS: 1117 (M+H) + (1.279 min, measurement condition D)

[0454] Reference example 102 L-valyl-N-{4-[(5S,8S,11S,12E,16R)-8-tert-butyl-16,18-dicarboxy-4,10,13-trimethyl-5-[2-(1-methyl-1H-indol-3-yl)propan-2-yl]-3,6,9,14-tetraoxo-11-(propan-2-yl)-2-oxa-4,7,10,15-tetraazaoctadec-12-en-1-yl]phenyl}-N 5 -Carbamoyl-L-ornithine amide [ka] Synthesis was carried out in the same manner as in Reference Example 2-c), and purification was carried out by reverse phase column chromatography (elution solvent: 0.1% TFA acetonitrile:water) to obtain Reference Example 102 (79 mg) from Reference Example 101 (87 mg). LC-MS: 1061 (M+H) + (1.124 min, measurement condition D)

[0455] Reference example 103 L-Prolyl-L-alanyl-N 1-(4-{[(N-{(2E,4S)-2,5-dimethyl-4-[methyl(N,β,β,1-tetramethyl-L-tryptophyll-3-methyl-L-valyl)amino]hex-2-enoyl}-L-α-glutamyl)oxy]methyl}phenyl)-L-aspartamide [ka]

[0456] a) Preparation of 9H-fluoren-9-ylmethyl [(2S)-1-{[4-(hydroxymethyl)phenyl]amino}-1,4-dioxo-4-(tritylamino)butan-2-yl]carbamate (compound F1) N 2 -[(9H-fluoren-9-ylmethoxy)carbonyl]-N-trityl-L-asparagine (Fmoc-Asn(Trt)-OH, 18 g) and p-aminobenzyl alcohol (3.9 g) in THF solution (150 mL) were added with 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) (8.6 g) and stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and ethyl acetate was added to the resulting residue and stirred at room temperature. The resulting solid was collected by filtration, washed with ethyl acetate, and dried under reduced pressure. The same washing was repeated once more to obtain compound F1 (19.2 g). LC-MS: 702 (M+H) + (3.36 min, measurement condition G)

[0457] b)N 1 -[4-(hydroxymethyl)phenyl]-N 4 - Preparation of trityl-L-aspartamide (compound F2) Compound F1 (3.0 g) was added with 30% piperidine-THF solution and stirred at room temperature for 5 hours. Concentrated under reduced pressure, diethyl ether was added to the obtained residue, washed, and the solid was collected by filtration. The obtained solid was washed with diethyl ether and dried. The same washing process was carried out again to obtain compound F2 (1.82 g). LC-MS: 480 (M+H) + (3.00 min, measurement condition F)

[0458] c) L-alanyl-N 1 -[4-(hydroxymethyl)phenyl]-N 4 -Preparation of trityl-L-aspartamide (compound F3) Compound F2 (1.5 g), N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-alanine (Fmoc-Ala-OH, 1.23 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (714 mg), and 1-hydroxy-1H-benzotriazole monohydrate (505 mg) in N,N-dimethylformamide (15 mL) were stirred at room temperature overnight. After adding ethyl acetate, the organic solvent layer was collected and washed with saturated ammonium chloride aqueous solution and saturated saline, and dried over sodium sulfate. After removing sodium sulfate, the solution was concentrated, and the obtained amorphous was purified by short column chromatography (elution solvent; methanol:chloroform). A 30% piperidine-THF solution was added to the obtained amorphous, and the mixture was stirred at room temperature for 5 hours. The mixture was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (elution solvent; methanol:chloroform) to obtain compound F3 (562 mg). LC-MS: 551 (M+H) + (2.89 min, measurement condition F)

[0459] d) 1-(tert-butoxycarbonyl)-L-prolyl-L-alanyl-N 1 -[4-(hydroxymethyl)phenyl]-N 4 - Preparation of trityl-L-aspartamide (compound F4) Compound F3 (275 mg), 1-(tert-butoxycarbonyl)-L-proline (Boc-Pro-OH, 118 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (714 mg), and 1-hydroxy-1H-benzotriazole monohydrate (505 mg) in N,N-dimethylformamide (15 mL) were stirred overnight at room temperature. After adding ethyl acetate, the organic solvent layer was collected and washed with saturated ammonium chloride aqueous solution and saturated saline, and dried over sodium sulfate. After removing sodium sulfate, the mixture was concentrated, and the resulting amorphous was purified by column chromatography (elution solvent: methanol:chloroform) to obtain compound F4 (321 mg). LC-MS: 748 (M+H) + (2.42 min, measurement condition G)

[0460] e) Preparation of 1-(4-{[(2S)-2-{[(2S)-2-({[(2S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl]carbonyl}amino)propanoyl]amino}-4-oxo-4-(tritylamino)butanoyl]amino}benzyl) 5-tert-butyl(2S)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}pentanedioate (Compound F5) Compound F4 (242 mg), (2S)-5-tert-butoxy-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-5-oxopentanoic acid·monohydrate (Fmoc-Glu(OtBu)-OH·HO, 150 mg), and paratoluenesulfonyl chloride (TsCl) (65 mg) were dissolved in acetonitrile (5.0 mL) and cooled to 0°C. 1-Methylimidazole (0.06 mL) was added to the acetonitrile solution, and the mixture was stirred overnight while returning to room temperature. After adding ethyl acetate, the organic solvent layer was collected and dried over sodium sulfate after washing with a saturated aqueous ammonium chloride solution and saturated saline. After removing sodium sulfate, the mixture was concentrated, and the obtained amorphous was purified by column chromatography (elution solvent; methanol:chloroform) to obtain compound F5 (342 mg). LC-MS: 1155 (M+H) +(4.60 min, measurement condition G)

[0461] f) Preparation of 1-(4-{[(2S)-2-{[(2S)-2-({[(2S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl]carbonyl}amino)propanoyl]amino}-4-oxo-4-(tritylamino)butanoyl]amino}benzyl) 5-tert-butyl(2S)-2-aminopentanedioate (Compound F6) Compound F6 (110 mg) was obtained from compound F5 (342 mg) in the same manner as in Reference Example 103-b). LC-MS: 933 (M+H) + (2.23 min, measurement condition G)

[0462] g) Preparation of 1-(4-{[(2S)-2-{[(2S)-2-({[(2S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl]carbonyl}amino)propanoyl]amino}-4-oxo-4-(tritylamino)butanoyl]amino}benzyl) 5-tert-butyl(2S)-2-{[(6S,9S,12S,13E)-9-tert-butyl-2,2,5,11,14-pentamethyl-6-[2-(1-methyl-1H-indol-3-yl)propan-2-yl]-4,7,10,15-tetraoxo-12-(propan-2-yl)-3-oxa-5,8,11-triazapentadec-13-en-15-yl]amino}pentanedioate (Compound F7) Compound F6 (30 mg), compound A13 (22 mg), bromotripyrrolidinophosphonium hexafluorophosphate (20 mg), and 4-dimethylaminopyridine (5 mg) were dissolved in N,N-dimethylformamide (5.0 mL) and cooled to 0°C. N-diisopropylethylamine (0.017 mL) was added dropwise to the mixed solution, and the mixture was stirred overnight while returning to room temperature. Ethyl acetate was added, and the mixture was washed with a saturated aqueous ammonium chloride solution and saturated saline, and dried over sodium sulfate. After removing sodium sulfate, the mixture was concentrated, and the obtained amorphous was purified by silica gel column chromatography (elution solvent: methanol:chloroform) to obtain compound F7 (42 mg). LC-MS: 1541 (M+H) + (5.23 min, measurement condition G)

[0463] h) L-Prolyl-L-alanyl-N 1 Preparation of -(4-{[(N-{(2E,4S)-2,5-dimethyl-4-[methyl(N,β,β,1-tetramethyl-L-tryptophyll-3-methyl-L-valyl)amino]hex-2-enoyl}-L-α-glutamyl)oxy]methyl}phenyl)-L-aspartamide (Reference Example 103) Synthesis was carried out in the same manner as in Reference Example 101-a) and purification was carried out by reverse phase column chromatography (elution solvent: 0.1% TFA acetonitrile:water) to obtain Reference Example 103 (10.3 mg) from Compound F7 (42 mg). LC-MS: 1043 (M+H) + (2.79 min, measurement condition F)

[0464] Reference examples 104~106 The corresponding starting compounds were used and reacted and treated in the same manner as in Example 1 and Reference Example 12 to give the compounds shown in the table below. [Table 13]

[0465] Reference examples 108~110 The corresponding starting compounds were used and treated in a similar manner to step b) of Reference Example 101 to give the compounds shown in the table below. [Table 14]

[0466] Reference examples 111~121 The compounds shown in the table below were obtained according to the methods described in Bioorg. Med. Chem. Lett. 2004 Nov1;14(21):5317-22, J. Med. Chem. 2004 Sep9;47(19):4774-86, WO 2003 / 082268, WO 2016 / 123582, and the like. [Table 15-1] [Table 15-2]

[0467] Reference example 122 N,3,3-trimethyl-2-((S)-3-methyl-2-(methylamino)-3-(m-tolyl)butanamide)hexa-2-enoic acid [ka] A mixture of (S,E)-4-((S)-2-((S)-3-(3-bromophenyl)-3-methyl-2-(methylamino)butanamido)-N,3,3-trimethylbutanamido)-2,5-dimethylhex-2-enoic acid (62.5 mg), tetrakis(triphenylphosphine)palladium(0) (13.07 mg), dimethylzinc (0.113 mL) and tetrahydrofuran (5 mL) was stirred at 60° C. for 2.5 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: chloroform:methanol) to obtain Reference Example 122 (29.7 mg). LC-MS: 488 (M+H) + / 0.68min, measurement condition E

[0468] Reference example 123 (S,E)-4-((S)-2-((S)-3-(3-cyanophenyl)-3-methyl-2-(methylamino)butanamido)-N,3,3-trimethylbutanamido)-2,5-dimethylhex-2-enoic acid [ka] A mixture of (S,E)-4-((S)-2-((S)-3-(3-bromophenyl)-3-methyl-2-(methylamino)butanamido)-N,3,3-trimethylbutanamido)-2,5-dimethylhex-2-enoic acid (76.1 mg), tetrakis(triphenylphosphine)palladium(0) (15.92 mg), zinc (18.01 mg), zinc cyanide (32.3 mg) and N,N-dimethylformamide (1 mL) was stirred at 120° C. for 1 hour under microwave irradiation. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was roughly purified by silica gel chromatography (elution solvent: chloroform:methanol), and then the product of Reference Example 123 (53.5 mg) was obtained by reverse phase HPLC (mobile phase: 0.1% TFA water / 0.035% TFA acetonitrile solvent). LC-MS: 499 (M+H) + / 0.99min, measurement condition E

[0469] Reference example 124 (S,E)-4-((S)-2-((S)-3-([1,1'-biphenyl]-3-yl)-3-methyl-2-(methylamino)butanamido)-N,3,3-trimethylbutanamido)-2,5-dimethylhex-2-enoic acid [ka] A mixture of (S,E)-4-((S)-2-((S)-3-(3-bromophenyl)-3-methyl-2-(methylamino)butanamido)-N,3,3-trimethylbutanamido)-2,5-dimethylhex-2-enoic acid (64.3 mg), tetrakis(triphenylphosphine)palladium(0) (13.45 mg), phenylboronic acid (28.4 mg), sodium carbonate (24.67 mg) and tetrahydrofuran (5 mL) was stirred at 80° C. for 3.5 hours. The solvent was distilled off under reduced pressure. Reference Example 124 (10.7 mg) was obtained by reverse phase HPLC (mobile phase: 0.1% TFA water / 0.035% TFA acetonitrile solvent). LC-MS: 550 (M+H) + / 0.88min, measurement condition E

[0470] Reference example 125 (S,E)-4-((S)-2-((S)-3-(4-(tert-butoxycarbonyl)phenyl)-3-methyl-2-(methoxyamino)butanamido)-N,3,3-trimethylbutanamido)-2,5-dimethylhex-2-enoic acid [ka]

[0471] a) Preparation of tert-butyl 4-((S)-4-(((S)-1-(((S,E)-6-ethoxy-2,5-dimethyl-6-oxohex-4-en-3-yl)(methyl)amino)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-methyl-3-(methylamino)-4-oxobutan-2-yl)benzoate To a mixture of 4-(4-(((S)-1-(((S,E)-6-ethoxy-2,5-dimethyl-6-oxohex-4-en-3-yl)(methyl)amino)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-methyl-3-(methylamino)-4-oxobutan-2-yl)benzoic acid (104.0 mg) and toluene (1 mL), N,N-dimethylfluoroamide-di-tert-butyl acetate (0.456 mL) was added and the mixture was heated to reflux for 14 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography to obtain tert-butyl 4-((S)-4-(((S)-1-(((S,E)-6-ethoxy-2,5-dimethyl-6-oxohex-4-en-3-yl)(methyl)amino)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-methyl-3-(methylamino)-4-oxobutan-2-yl)benzoate (21.0 mg). LC-MS: 602 (M+H) + / 1.47min, Measurement condition E

[0472] b) Preparation of (S,E)-4-((S)-2-((S)-3-(4-(tert-butoxycarbonyl)phenyl)-3-methyl-2-(methoxyamino)butanamido)-N,3,3-trimethylbutanamido)-2,5-dimethylhex-2-enoic acid (Reference Example 125) tert-Butyl 4-((S)-4-(((S)-1-(((S,E)-6-ethoxy-2,5-dimethyl-6-oxohex-4-en-3-yl)(methyl)amino)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-methyl-3-(methylamino)-4-oxobutan-2-yl)benzoate (10.5 mg), methanol (3 mL) and water (1 mL) were mixed and added with lithium hydroxide (4.39 mg), and stirred at room temperature for 2 days. The solvent was distilled off under reduced pressure, and the residue was purified by reverse phase HPLC (mobile phase was 0.1% TFA water / 0.035% TFA acetonitrile solvent) to obtain Reference Example 125 (7.0 mg). LC-MS: 574 (M+H) + / 1.49min, Measurement condition E

[0473] Reference example 126 4-((S)-4-(((S)-1-(((S,E)-5-carboxy-2-methylhex-4-en-3-yl)(methyl)amino)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-methyl-3-(methylamino)-4-oxobutan-2-yl)benzoic acid [ka] tert-Butyl 4-((S)-4-(((S)-1-(((S,E)-6-ethoxy-2,5-dimethyl-6-oxohex-4-en-3-yl)(methyl)amino)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-methyl-3-(methylamino)-4-oxobutan-2-yl)benzoate (10.5 mg), methanol (3 mL) and water (1 mL) were mixed and added with lithium hydroxide (4.39 mg) and stirred at room temperature for 5 days. After the solvent was distilled off under reduced pressure, the residue was dissolved in chloroform (4 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 17 hours. After the solvent was distilled off under reduced pressure, the residue was purified by reverse phase HPLC (mobile phase was 0.1% TFA water / 0.035% TFA acetonitrile solvent) to obtain Reference Example 126 (7.40 mg). LC-MS: 518 (M+H) + / 1.08min, measurement condition E

[0474] Reference example 127 (4S,E)-4-((2S)-2-(3-(4-hydroxyphenyl)-3-methyl-2-(methylamino)butyl)-N,3,3-trimethylbutanamido)-2,5-dimethylhex-2-enoic acid [ka]

[0475] a) Preparation of 3-(4-hydroxyphenyl)-3-methyl-2-(methylamino)butanoic acid Under a nitrogen atmosphere, a solution of 3-(4-hydroxyphenyl)-3-methyl-2-oxobutanoic acid (54.9 g) in anhydrous tetrahydrofuran (480 mL) was ice-cooled, and methylamine (280 mL) (2 mol / L tetrahydrofuran solution) was added dropwise. After stirring at room temperature for 1 hour, borane-pyridine complex (27.5 mL) was added dropwise, and the mixture was stirred at 55°C for 2.5 hours. Methanol (240 mL) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 2 hours. After the solvent was distilled off under reduced pressure, tetrahydrofuran was added, and the suspension was suction-filtered. The powder was washed with tetrahydrofuran to obtain 3-(4-hydroxyphenyl)-3-methyl-2-(methylamino)butanoic acid (40.7 g).

[0476] b) Preparation of 2-((tert-butoxycarbonyl)(methyl)amino)-3-(4-((tert-butoxycarbonyl)oxy)phenyl)-3-methylbutanoic acid Under a nitrogen atmosphere, di-tert-butyl carbonate (39.9 g) and potassium carbonate (25.4 g) were added to a suspension of 3-(4-hydroxyphenyl)-3-methyl-2-(methylamino)butanoic acid (10.2 g) in 1,4-dioxane / water (1:1) (160 mL), and the mixture was stirred at 40° C. overnight. Ethyl acetate and water were added to the reaction solution, and the pH was adjusted to 2-3 with a 1 mol / L aqueous potassium hydrogen sulfate solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: chloroform:methanol) to obtain 2-((tert-butoxycarbonyl)(methyl)amino)-3-(4-((tert-butoxycarbonyl)oxy)phenyl)-3-methylbutanoic acid.

[0477] c) Preparation of (S)-2-((tert-butoxycarbonyl)(methyl)amino)-3-(4-hydroxyphenyl)-3-methylbutanoic acid (153.7 mg), ethyl (S,E)-4-((S)-2-amino-N,3,3-trimethylbutanamido)-2,5-dimethylhex-2-enoate hydrochloride Under a nitrogen atmosphere, 2-((tert-butoxycarbonyl)(methyl)amino)-3-(4-((tert-butoxycarbonyl)oxy)phenyl)-3-methylbutanoic acid (15.7 g) was dissolved in dichloromethane (370 mL), and 28% sodium methoxide methanol solution (15.8 g) and methanol (14 mL) were added, followed by stirring at room temperature for 1.5 hours. Ethyl acetate and a 4% aqueous potassium hydrogen sulfate solution were added to the reaction liquid for extraction. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: chloroform:methanol) to give (S)-2-((tert-butoxycarbonyl)(methyl)amino)-3-(4-hydroxyphenyl)-3-methylbutanoic acid (153.7 mg) and ethyl (S,E)-4-((S)-2-amino-N,3,3-trimethylbutanamide)-2,5-dimethylhex-2-enoate hydrochloride (9.73 g).

[0478] d) Preparation of ethyl (9S,12S,E)-9-(tert-butyl)-6-(2-(4-hydroxyphenyl)propan-2-yl)-12-isopropyl-2,2,5,11,14-pentamethyl-4,7,10-trioxo-3-oxa-5,8,11-triazapentadec-13-en-15-oate A suspension of (S)-2-((tert-butoxycarbonyl)(methyl)amino)-3-(4-hydroxyphenyl)-3-methylbutanoic acid (153.7 mg), ethyl (S,E)-4-((S)-2-amino-N,3,3-trimethylbutanamido)-2,5-dimethylhex-2-enoate hydrochloride (117.6 mg), N-ethyl-N-isopropylpropan-2-amine (0.172 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (129 mg), 1-hydroxybenzotriazole (103 mg) and DMF (5 mL) was stirred at room temperature for 17 hours. After the solvent was distilled off under reduced pressure, chloroform was added, the organic layer was washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane:ethyl acetate) to give ethyl (9S,12S,E)-9-(tert-butyl)-6-(2-(4-hydroxyphenyl)propan-2-yl)-12-isopropyl-2,2,5,11,14-pentamethyl-4,7,10-trioxo-3-oxa-5,8,11-triazapentadec-13-en-15-oate (206.3 mg). LC-MS: 618 (M+H) + / 1.69min, measurement condition E

[0479] e) Preparation of ethyl (4S,E)-4-((2S)-2-(3-(4-hydroxyphenyl)-3-methyl-2-(methylamino)butanamido)-N,3,3-trimethylbutanamido)-2,5-dimethylhex-2-enoate TFA (1mL) was added to a mixture of ethyl (9S,12S,E)-9-(tert-butyl)-6-(2-(4-hydroxyphenyl)propan-2-yl)-12-isopropyl-2,2,5,11,14-pentamethyl-4,7,10-trioxo-3-oxa-5,8,11-triazapentadec-13-en-15-oate (189.2mg) and chloroform (4mL), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. Chloroform was added, and the organic layer was washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane:ethyl acetate) to give ethyl (4S,E)-4-((2S)-2-(3-(4-hydroxyphenyl)-3-methyl-2-(methylamino)butanamido)-N,3,3-trimethylbutanamido)-2,5-dimethylhex-2-enoate (110.1 mg). LC-MS: 518 (M+H) + / 1.09min, measurement condition E

[0480] f) Preparation of (4S,E)-4-((2S)-2-(3-(4-hydroxyphenyl)-3-methyl-2-(methylamino)butyl)-N,3,3-trimethylbutanamido)-2,5-dimethylhex-2-enoic acid (Reference Example 127) Ethyl (4S,E)-4-((2S)-2-(3-(4-hydroxyphenyl)-3-methyl-2-(methylamino)butanamido)-N,3,3-trimethylbutanamido)-2,5-dimethylhex-2-enoate (110.1 mg), methanol (3 mL) and water (1 mL) were mixed, and lithium hydroxide (35.7 mg) was added under ice cooling and stirred at room temperature for 2 days. The solvent was distilled off under reduced pressure, and the residue was purified by reverse phase HPLC (mobile phase: 0.1% TFA water / 0.035% TFA acetonitrile solvent) to obtain Reference Example 127 (113.2 mg). LC-MS: 490 (M+H) + / 1.03min, measurement condition E

[0481] Reference examples 128~131 The corresponding starting compounds were used in the same manner as in step d) of Reference Example 2 to give the compounds shown in the table below. [Table 16]

[0482] Reference examples 132~143 The corresponding starting compounds were used and treated in the same manner as in step b) of Reference Example 2 to give the compounds shown in the table below. [Table 17-1] [Table 17-2]

[0483] Example 1 Diethyl (2R)-2-{[(2E,4S)-4-{[(2S)-2-{[(2S)-2-amino-3-methyl-3-(1-methyl-1H-indol-3-yl)butanoyl]amino}-3,3-dimethylbutanoyl](methyl)amino}-2,5-dimethylhex-2-enoyl]amino}pentane diester [ka] Trifluoroacetic acid (0.2 mL) was added to a chloroform solution (1.0 mL) of Reference Example 8 (70 mg), and the mixture was stirred for 2 hours at 25° C. After completion of the reaction, the reaction solution was purified by silica gel column chromatography (elution solvent: methanol:chloroform) to obtain Example 1 (47 mg). LC-MS: 698 (M+H) + (1.205min, measurement condition D)

[0484] Example 2 β,β,1-trimethyl-L-tryptophyl-N-[(3S,4E)-6-{[(1R)-1,3-dicarboxypropyl]amino}-2,5-dimethyl-6-oxohex-4-en-3-yl]-N,3-dimethyl-L-valinamide [ka] To a methanol solution (1.0 mL) of Example 1 (42 mg), 1 mol / L lithium hydroxide (0.36 mL) was added and stirred for 12 hours at 25° C. After completion of the reaction, the reaction mixture was purified by silica gel column chromatography (elution solvent: chloroform:methanol) to obtain Example 2 (28 mg). LC-MS: 642 (M+H) + 640(MH) - (1.056min, measurement condition D)

[0485] Example 3 N-{(2E,4S)-2,5-dimethyl-4-[methyl(N,β,β,1-tetramethyl-L-tryptophyll-3-methyl-L-valyl)amino]hex-2-enoyl}-L-α-aspartyl-L-α-aspartyl-L-α-aspartyl-L-α-aspartic acid [ka] Trifluoroacetic acid (0.2 mL) was added to a chloroform solution (0.8 mL) of Reference Example 5 (16 mg), and the mixture was stirred for 2 hours at 25° C. After completion of the reaction, the reaction solution was purified by reverse phase column chromatography (elution solvent: 0.1% TFA acetonitrile:water) to obtain Example 3 (8.9 mg). LC-MS: 1102 (M+H) + ,1100(MH) - (0.986min, measurement condition D)

[0486] Examples 4 to 51 The corresponding starting compounds were used in the same manner as in Example 1, 2 or 3 to obtain the compounds shown in Tables 18 to 20 below.

[0487] [Table 18-1] [Table 18-2] [Table 18-3]

[0488] [Table 19]

[0489] [Table 20]

[0490] Alternative synthesis of Examples 22-23 In accordance with the synthesis method described in J. Med. Chem. 2006, 49, 4392-4408, Reference Example 31 or 60 was used as a raw material compound, and treated with a dithiothreitol phosphate solution and a triethylamine tetraacetic acid phosphate solution in a mixed solvent of methanol and ethyl acetate to obtain the compounds shown in the table below. [Table 21]

[0491] Example 52 Using Reference Example 19, reactions and treatments were carried out in the same manner as in Reference Example 3 and Example 1 to obtain the compounds shown in the table below. [Table 22]

[0492] Examples 53 to 54 Using J11 of Reference Example 9 and the corresponding starting compounds, reactions and treatments were carried out in a similar manner to Reference Example 9 to give the compounds shown in the table below. [Table 23]

[0493] Examples 55 to 66 The corresponding starting compounds were used and treated in the same manner as in step a) of Reference Example 2 to give the compounds shown in the table below. [Table 24-1] [Table 24-2]

[0494] Examples 67 to 69 The corresponding starting compounds were used and treated in the same manner as in Reference Example 3 to obtain the compounds shown in the table below. [Table 25]

[0495] Example 70 Using Reference Example 125, reactions and treatments were carried out in a similar manner to step a) of Reference Example 2 and step a) of Reference Example 101 to give the compounds shown in the table below. [Table 26]

[0496] Example 71 Example 66 was used for the same reaction and treatment as in Example 1 to obtain the compounds shown in the table below. [Table 27]

[0497] Examples 72 to 73 The compounds shown in the table below were obtained by carrying out reactions and treatments similar to those in Reference Examples 2 and 3. [Table 28]

[0498] Example M1 Diethyl (2R)-2-{[(5S,8S,11S,12E)-8-tert-butyl-1-(4-{[(2S)-5-(carbamoylamino)-2-{[(2S)-2-{[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]amino}-3-methylbutanoyl]amino}pentanoyl]amino}phenyl)-4,10,13-trimethyl-5-[2-(1-methyl-1H-indol-3-yl)propan-2-yl]-3,6,9,14-tetraoxo-11-(propan-2-yl)-2-oxa-4,7,10-triazatetradec-12-en-14-yl]amino}pentanedioate [ka] A mixture of Reference Example 101 (14 mg), N-succinimidyl 6-maleimidohexanoate (4.7 mg) and N,N-dimethylformamide (1 mL) was stirred for 48 hours at 25° C. After completion of the reaction, the reaction solution was purified by reverse phase column chromatography (elution solvent: 0.1% TFA acetonitrile:water) to obtain Example M1 (5.8 mg). LC-MS: 1310 (M+H) + (1.398min, measurement condition D)

[0499] Examples M2 to M12 The corresponding starting compounds were reacted and treated in the same manner as in Examples 1, 3 or M1 to give the compounds shown in Tables 29 and 30 below.

[0500] [Table 29]

[0501] [Table 30]

[0502] Example M13 The corresponding starting compounds were reacted and treated in the same manner as in Example M1 to give the following compounds. N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]-L-valyl-N-{4-[(5S,8S,11S,12E,16R)-8-tert-butyl-16,18-dicarboxy-4,10,13-trimethyl-3,6,9,14-tetraoxo-5-(2-phenylpropan-2-yl)-11-(propan-2-yl)-2-oxa-4,7,10,15-tetraazaoctadec-12-en-1-yl]phenyl}-N 5 -Carbamoyl-L-ornithine amide [ka] LC-MS: 1201 (M+H) + (1.110min, measurement condition D)

[0503] Example M14 The corresponding starting compounds were used in the same manner as in Example M1 to obtain the compounds shown in the following table. [Table 31]

[0504] The NMR data for Examples 4, 32, 53-60, 65-69 and 71 are shown in the table below. [Table 32-1] [Table 32-2]

[0505] The antibodies used in the example ADCs are either commercially available or can be prepared according to the references shown in the table below. [Table 33]

[0506] Example ADC1 Brentuximab-Example M2 Complex (mean DAR: 7.41) [ka] To a phosphate buffered saline solution (3.77 mL, pH 7.4) of brentuximab (91 mg), 1 mmol / L tris(2-carboxyethyl)phosphine (TCEP) in trishydroxymethylaminomethane hydrochloride buffer (12.2 mL, pH 7.5) was added, and incubated at 37°C for 45 minutes. The antibody solution was cooled to 0°C, and then treated with a PD-10 desalting column pre-equilibrated with phosphate buffered saline solution (pH 7.4) to obtain a phosphate buffered saline solution (pH 7.4) of reduced anti-CD30 antibody (brentuximab). After cooling to 0°C, a 1 mmol / L DMSO solution of Example M2 (12.2 mL), diluted 10-fold with phosphate buffered saline solution (pH 7.4), was added as a modifying agent, thoroughly mixed, and incubated at 4°C for 16 hours. The mixture was then purified using a PD-10 desalting column pre-equilibrated with a phosphate buffered saline solution (pH 7.4), and then concentrated by centrifugation to obtain Example ADC1 (78.2 mg).

[0507] The average DAR of the obtained ADC was measured by reducing or non-reducing SDS-PAGE or HPLC-HIC. The average DAR can also be qualitatively or quantitatively measured by ultraviolet-visible absorption spectroscopy (UV-Vis), reducing or non-reducing SDS-PAGE, HPLC-HIC, SEC, RP-HPLC, LC-MS, etc. These methods are described in Antibody Drug Conjugates, Methods in Molecular Biology vol.1045,2013.pp267-284.L.Ducry,Ed.

[0508] When the average drug-antibody ratio of an ADC prepared from a human IgG1 antibody is 8, the production of the ADC can also be estimated from the results of reducing and non-reducing SDS-PAGE. Specifically, when the example ADC is subjected to SDS-PAGE analysis under disulfide non-reducing conditions using SeeBlue (registered trademark) Plus2 (Thermo Fisher Scientific) as a marker, if bands at molecular weights of about 50 kDa and 25 kDa are strongly detected, this indicates that the modifying agent has been conjugated to cysteine ​​residues involved in the disulfide bonds between the light and heavy chains of the antibody and in the hinge, i.e., it means that an ADC with an average drug-antibody ratio of 8 has been obtained.

[0509] The average DAR of Example ADC1 determined by HPLC-HIC analysis was 7.41.

[0510] Example ADC2 Brentuximab-Example M2 Complex (mean DAR: 3.76) [ka] In the protocol of Example ADC1, the DAR of ADC can be adjusted by changing the amount of TCEP or modifying agent added. Example ADC2 was obtained by using 4 equimolar amounts of TCEP according to the protocol of Example ADC1.

[0511] Examples ADC3 to 22 The corresponding antibodies and modifying agents were used and reacted and treated in the same manner as in Example ADC1 to obtain the ADCs shown in the following Table 34. The average DAR of these ADCs was calculated or estimated from UV-Vis, HPLC-HIC, or SDS-PAGE analysis in the same manner as in Example ADC1. [ka] [Table 34]

[0512] Examples ADC23 to 39 The corresponding antibody and modifying agent (the compound of the Example) were reacted and treated in the same manner as in Example ADC1 to obtain the Example ADC shown in the table below. [Table 35]

[0513] The Rt(min) of the ADC of the examples in the above table is that of the peak of the ADC with a DAR of 8 observed by HPLC-HIC analysis (measurement condition H).

[0514] Test Example Below, pharmacological test results for specific examples of the hemiasterlin derivatives, antibody-drug conjugates, and ADC intermediates of the present invention are shown and their pharmacological effects are explained, but the present invention is not limited to the compounds or antibody-drug conjugates shown in these test examples.

[0515] Test Example 1: Evaluation of microtubule polymerization inhibitory activity using porcine tubulin (1) The polymerization inhibitory activity of the compound of the Example at a concentration of 0.91 μM was evaluated using a tubulin polymerization inhibition assay kit (catalog number: BK006P) purchased from Cytoskeleton, following the protocol attached to the kit. In summary, 10 μL of 80 mM PIPES pH 6.9, 2 mM MgCl, 0.5 mM EGTA, and 5% DMSO buffer of the compound to be evaluated was added to a 96-well microplate, and 100 μL of 3 mg / mL porcine tubulin 80 mM PIPES pH 6.9, 2 mM MgCl, 0.5 mM EGTA, 1 mM GTP, and 10.2% glycerol solution was added to each of them. To examine the polymerization of tubulin over time, the absorbance at 340 nm was measured at 37° C. using a microplate reader. As the polymerization of tubulin progresses, the absorbance at 340 nm increases. The results are shown in Figures 1 and 2.

[0516] 1, in the microtubule polymerization inhibition evaluation test, Examples 4, 9, 23, 28, 43 and 44 exhibited microtubule polymerization inhibitory activity. In particular, Example 4 exhibited stronger polymerization inhibitory activity.

[0517] 2, Examples 14, 24 and 27 exhibited microtubule polymerization inhibitory activity in the microtubule polymerization inhibition evaluation test. Example 14 exhibited polymerization inhibitory activity in a concentration-dependent manner.

[0518] Test Example 2 : Evaluation of microtubule polymerization inhibitory activity using porcine tubulin (2) The polymerization inhibitory activity of the compounds of the examples was evaluated using a tubulin polymerization inhibition assay kit (catalog number: BK006P) purchased from Cytoskeleton, following the protocol attached to the kit. 10 μL of 80 mM PIPES pH 6.9, 2 mM MgCl, 0.5 mM EGTA, and 5% DMSO buffer of the compound to be evaluated was added to a 96-well microplate, and 100 μL of 3 mg / mL porcine tubulin 80 mM PIPES pH 6.9, 2 mM MgCl, 0.5 mM EGTA, 1 mM GTP, and 10.2% glycerol solution was added to each. In order to examine the polymerization of tubulin over time, the absorbance at 340 nm was measured at 37° C. using a microplate reader. As the polymerization of tubulin progresses, the absorbance at 340 nm increases.

[0519] The tubulin polymerization inhibitory activity was evaluated based on the percentage of polymerized tubulin 60 minutes after the start of the assay. Specifically, the absorbance of polymerized tubulin in the wells to which the compound was added was divided by the absorbance of polymerized tubulin in the wells to which the compound was not added, and the result was multiplied by 100 to calculate the microtubule polymerization rate (%). [Table 36]

[0520] A lower value of the microtubule polymerization rate indicates that the compound inhibits microtubule polymerization more strongly.

[0521] As shown by the results of Test Examples 1 and 2, it was revealed that the hemiasterlin derivatives of the present invention exhibit tubulin polymerization inhibitory activity.

[0522] Test Example 3: Cytotoxicity test (1) Human lymphoma cell lines, SU-DHL-1 cells (American Type Culture Collection, hereinafter referred to as ATCC) and Karpas-299 cells (European Collection of Authenticated Cell Cultures, hereinafter referred to as ECACC), were cultured in RPMI1640 (GIBCO) containing 10% fetal bovine serum (MP Biomedicals) (hereinafter referred to as "medium" in this test). SU-DHL-1 cells and Karpas-299 cells were cultured at 2 × 10 6 The cells / mL were prepared and added at 50 μL per well to a 96-well cell culture microplate. 50 μL per well of the compound of the example or hemiasterlin diluted 4-fold in 8 steps with medium was added to the microplate. 50 μL per well of medium was added to wells to which the test substance was not added. These were cultured at 37°C and under 5% CO2 for 4 days. After culture, the microplate was removed from the incubator and left to stand at room temperature for 10 minutes. 50 μL of CellTiter-Glo Luminescent Cell Viability Assay (Promega) was added to each well and stirred. This mixture was incubated in the dark for 20 minutes. The cell viability was calculated for each concentration of the test substance by measuring the luminescence in each well using a microplate luminometer. The IC 50 The results are shown in Tables 37 and 38.

[0523] I C 50 The value was calculated using the following formula. I C 50 (nM) = antilog(LOG 10 (a÷b)×(ed)÷(cd)+LOG 10 b) a: concentration of test substance a b: concentration of test substance b c: Cell viability when test substance at concentration a was added d: Cell viability when test substance at concentration b was added e: The mean value between the maximum and minimum cell viability when each concentration of the test substance was added. (a and b are concentrations that straddle the cell viability e, and a>b represents the concentration.)

[0524] The cell viability at each concentration was calculated using the following formula. Cell viability (%)=a'÷b'×100 a': Average luminescence intensity of wells to which the test substance was added (n=6) b': Average luminescence intensity in wells to which no test substance was added (n=6) (n represents the number of evaluations performed per concentration of the test substance)

[0525] [Table 37] [Table 38]

[0526] Test Example 4: Cytotoxicity test (2) SK-BR-3 cells (ATCC), a human breast cancer cell line, were cultured in McCoy's 5A (GIBCO) containing 10% fetal bovine serum (MP Biomedicals) (hereinafter referred to as "medium" in this study). SK-BR-3 cells were cultured at 2 × 10 6 The wells were cultured at 37°C and 5% CO2 for 3 days. After that, 50 μL of the compound of the example or hemiasterlin diluted 4-fold with medium was added to the wells. 50 μL of medium was added to the wells to which the test substance was not added. These were cultured at 37°C and 5% CO2 for 3 days. After the culture, the microplate was removed from the incubator and left to stand at room temperature for 10 minutes. 50 μL of CellTiter-Glo Luminescent Cell Viability Assay (Promega) was added and stirred. This mixture was incubated in the dark for 20 minutes. The cell viability was calculated for each concentration of the test substance by measuring the luminescence in each well using a microplate luminometer. IC 50The values ​​were calculated according to the method described in Test Example 3. The results are shown in Table 39.

[0527] [Table 39]

[0528] As shown in Tables 37 to 39 above, the compounds shown in Test Examples 1 and 2 to exhibit microtubule polymerization inhibitory activity equivalent to that of hemiasterlin showed activity different from that of hemiasterlin in the cytotoxicity test.

[0529] Test Example 5: Membrane permeability test The membrane permeability of the compounds of the examples was tested by the artificial membrane permeability test (PAMPA) as follows. 200 μL of system solution (pION inc.) containing the compound of the examples and 4 μL of GIT Lipid-0 (pION inc.) were added to the donor plate. 200 μL of Acceptor Sink Buffer (pION inc.) was added to the acceptor plate. Both plates were overlaid and incubated at 37° C. for 4 hours, after which the UV of the solutions on the acceptor side and the donor side was measured using a UV plate reader (190-500 nm). Compounds with poor UV absorption were measured using LC-MS. The permeability coefficient P of the drug e (10 -6 The velocity (cm / sec) was calculated using the following formula. The results are shown in Tables 40 and 41.

number

[0530] [Table 40] [Table 41]

[0531] From the results of Test Examples 3 to 5, it is presumed that the compounds of the Examples, which have the same microtubule polymerization inhibitory activity as hemiasterlin, showed lower activity than hemiasterlin in the cytotoxicity test due to the difference in cell membrane permeability between these compounds. That is, the activity in the cytotoxicity test was lower than the activity in the polymerization inhibitory activity evaluation because the compounds of the Examples had low cell membrane permeability, which suppressed the migration of the compounds of the Examples into cells.

[0532] Test Example 6: Cytotoxicity test of ADC (1) CD30 antigen-positive cells, SU-DHL-1 cells (ATCC) and CD30 antigen-positive cells, Karpas-299 cells (ECACC), were cultured in RPMI1640 (GIBCO) containing 10% fetal bovine serum (MP Biomedicals) (hereinafter referred to as "medium A" in this test). CD30 antigen-negative cells, SK-BR-3 cells (ATCC), were cultured in McCoy's 5A (GIBCO) containing 10% fetal bovine serum (MP Biomedicals) (hereinafter referred to as "medium B" in this test). SU-DHL-1 cells, Karpas-299 cells, and SK-BR-3 cells were cultured in medium A or medium B at a concentration of 2 × 10 6 The ADC was prepared to 100 μL / mL and added to a 96-well cell culture microplate at 50 μL each. After addition, SK-BR-3 cells were cultured overnight at 37°C and 5% CO2. 50 μL each of the diluted ADCs, which were diluted 4-fold in eight stages with medium A or medium B, was added to the microplate at 50 μL each. 50 μL each of medium A or medium B was added to wells to which ADC was not added, and SU-DHL-1 cells and Karpas-299 cells were cultured for 4 days and SK-BR-3 cells for 3 days at 37°C and 5% CO2. After culture, the microplate was removed from the incubator and left to stand at room temperature for 10 minutes. 50 μL of CellTiter-Glo Luminescent Cell Viability Assay (Promega) was added to each well and stirred. This mixture was incubated in the dark for 20 minutes. The cell viability was calculated for each ADC concentration by measuring luminescence using a microplate luminometer. IC 50The values ​​were calculated according to the method described in Test Example 3. The results are shown in Table 42.

[0533] [Table 42]

[0534] As shown in Table 42 above, Examples ADC1, ADC3, and ADC4, which are antibody-drug conjugates of Examples 4, 9, and 14 and brentuximab, respectively, selectively exhibited cytotoxic activity against CD30 antigen-positive cells. This result indicates that even a compound with weak cytotoxicity due to low membrane permeability exhibits strong cytotoxic activity by forming a complex with an antibody. Furthermore, antibody-drug conjugates other than Examples ADC1, ADC3, and ADC4 also exhibited strong cytotoxic activity.

[0535] Test Example 7: Pharmacokinetic evaluation test using mice Example 4 was administered intravenously once to mice at a dose of 1.0 mg / kg, and a pharmacokinetic evaluation test was performed. A calibration curve was created from the measured values ​​of Example 4, whose concentrations were known, and the measured values ​​of each sample were interpolated to calculate the amount of compound contained per unit volume in each plasma using LC-MS. The pharmacokinetics of compound 14 and hemiasterlin were also evaluated in the same manner. The results are shown in Tables 43 and 44.

[0536] [Table 43]

[0537] [Table 44] (In the table, nd means less than the detection limit (0.5 ng / mL).)

[0538] The half-life of each compound was determined, and the half-life of Example 4 was less than 0.5 hours, the half-life of Example 14 was less than 0.5 hours, and the half-life of hemiasterlin was 13.1 hours. It is considered that Example 14 was hydrolyzed in the body to produce mainly Example 4 and disappear. These results show that the hemiasterlin derivative of the present invention disappears quickly when released into the blood.

[0539] Test Example 8: Efficacy test of antibody-drug conjugates in Karpas-299 tumor type using CB-17 SCID mice This test is a representative test for evaluating the antitumor activity of drugs. The Karpas human anaplastic large cell lymphoma model is performed in CB-17 SCID mice at 5 × 10 6 The tumor model was created by subcutaneously transplanting 100 cells. 3 Treatment was initiated after the average volume was reached. Mice were given a single intravenous injection of Example ADC1 in phosphate buffered saline. Tumor volume was calculated using the formula: 0.5(longest dimension x perpendicular dimension) 2 ) was used to calculate the tumor size. 3 When the tumor size reached 0.001 mm, the mice were removed from the study and the average tumor size was not plotted thereafter. The efficacy of the mixture of Example ADC2 and Example 4 with Brentuximab was also tested in the same manner. The method of this test is described in Hamblett KJ et.al. Clin.Cancer Res., 2004, 10, 7063-7070, etc.

[0540] The results are shown in Figure 3. Mice administered Example ADC1 or Example ADC2 showed good tumor regression, whereas mice administered a mixture of substantially equal amounts of Example 4 and brentuximab showed tumor progression.

[0541] Test Example 9: Toxicity (safety) test of drugs or antibody-drug conjugates using Sprague-Dawley rats This test is a typical test to evaluate the toxicity (safety) of drugs or antibody-drug conjugates. Toxicity can be confirmed by administering drugs or antibody-drug conjugates to Sprague-Dawley rats once or repeatedly into the tail vein, and then observing general symptoms, hematological tests, blood biochemistry tests, bone marrow tests, autopsy, organ weights, histopathological tests, etc. This test is described in New Edition Toxicology, edited by the Education Committee of the Japanese Society of Toxicology, Asakura Publishing (2009), and in the Brentuximab Vetotin Application Document Summary, Pharmaceuticals and Medical Devices Agency, etc.

[0542] Test Example 10: Cytotoxicity test of ADC (2) The cell viability was measured using the ADC of the Example according to the method described in Test Example 6. The cell viability was calculated as a percentage of the average luminescence intensity (n=3) of wells to which an ADC of the Example was added at a certain concentration relative to the luminescence intensity (n=1) of a well to which an antibody of the same concentration was added. The results are shown in the table below. [Table 45]

[0543] As shown in Test Example 10, when the ADC of the Example was used, a more significant decrease in cell count was observed compared to when the antibody portion thereof was used, demonstrating that the ADC of the present invention exhibits stronger cytotoxicity than the antibody itself.

[0544] From the above results, it was found that the compounds of the Examples showed lower activity than the compounds of the Comparative Examples in the cytotoxicity test. On the other hand, the compounds of the Examples did not lose the tubulin polymerization inhibitory activity derived from the hemiasterlin structure. In addition, the antibody-drug conjugate obtained by binding the compounds of the Examples to the antibody showed high activity in the cytotoxicity test. From these results, it is presumed that the difference in cytotoxicity between the compounds of the Comparative Examples and the compounds of the Examples is based on the difference in cell membrane permeability. That is, it is considered that the compounds of the Examples showed weaker cytotoxicity than the compounds of the Comparative Examples because the compounds of the Examples had low cell membrane permeability and the migration of the compounds of the Examples into cells was suppressed. Therefore, it was suggested that the antibody-drug conjugates containing the compounds of the Examples could suppress the migration of the compounds of the Examples, which have low cell membrane permeability, into normal cells even if reversible dissociation between the antibody portion and the drug portion occurs in the systemic blood, thereby reducing side effects. [Industrial Applicability]

[0545] As explained above, the antibody-drug conjugate of the present invention selectively exhibits cytotoxic activity in antigen-expressing cells and has low cytotoxicity in normal cells, and is therefore expected to become an anticancer drug with excellent safety.

Claims

1. Formula (3-1): 【Chemistry 1】 [In the formula, h represents an integer from 1 to 5; (G) g is * 2 -Lys-, * 2 -Lys-Phe-, * 2 -Lys-Val-, * 2 -Lys-Ala-, * 2 -Cit-Val-, * 2 -Cit-Phe-, * 2 -Cit-Leu-, * 2 -Arg-Phe-, * 2 -Cit-Ile-, * 2 -Cit-Trp-, * 2 -Lys-Phe-Phe-, * 2 -Lys-Phe-Ala-, * 2 -Lys-Phe-Gly-, * 2 -Asn-, * 2 -Asn-Ala-, * 2 -Asn-Ala-Ala-, *2 -Asn-Ala-Thr-, *2-Asn-Ala-Pro-, *2-Asn-Ala-Val-, *2-Asn-Ala-Phe-, *2-Asn-Ala-Tyr-, *2-Asn-Ala-Leu-, *2-Asn-Ala-Gly-, *2-Gly-Phe-Gly-Gly-, *2-Gly-Leu-Phe-Gly- or *2-Leu-Ala-Leu-Ala-, and the *2 end of (G)g is bonded to Y, Y is represented by the formula (Y-1): 【Chemistry 2】 (In the formula, Y′ represents a carbonyl group; R ３ is a C optionally substituted with a halogen atom, a cyano group, or 1 to 5 fluorine atoms. １－６ C optionally substituted with an alkyl group or 1 to 5 fluorine atoms １－６ represents an alkoxy group; R ３ If there are multiple R ３ may be the same or different, f represents an integer of 0 to 2. is a group represented by In formula (Y-1), * １ The end is bound to Z, Z is represented by the formula (Z-1): 【Chemistry 3】 (In the formula, AA represents Glu, Asp, Lys, Cys, or a C1-3 alkyl ester thereof, and when there are a plurality of AAs, each AAs may be the same or different from each other, and AAs are bonded to each other via an amide bond; (AA) ｍ The N-terminal nitrogen atom of the formula (I) forms an amide bond with the carbonyl group (a), Q is represented by formula (Q-1) or formula (Qa-2): 【Chemistry 4】 (In the formula, R 2a and R 2e each represent a hydrogen atom; R ２ｂ , R ２ｃ and R2d each independently represent a hydrogen atom, a halogen atom, or a C 1-3 alkoxy group; R ２ｆ represents a methyl group or an ethyl group, R ａａ , R ａｂ and R ａｃ each independently represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a carboxyl group, a C1-3 alkyl group optionally substituted with 1 to 3 fluorine atoms, a C1-3 alkoxy group, or a C1-4 alkyl ester group. represents a group represented by R1a represents a hydrogen atom or a C1-3 alkyl group; m represents an integer from 1 to 10. represents a group represented by the formula: A compound or a salt thereof represented by the formula:

2. Formula (3-1): 【Chemistry 5】 [In the formula, h represents an integer from 1 to 5; (G) g is * 2 -Lys-, * 2 -Lys-Phe-, * 2 -Lys-Val-, * 2 -Lys-Ala-, * 2 -Cit-Val-, * 2 -Cit-Phe-, * 2 -Cit-Leu-, * 2 -Arg-Phe-, * 2 -Cit-Ile-, * 2 -Cit-Trp-, * 2 -Lys-Phe-Phe-, * 2 -Lys-Phe-Ala-, * 2 -Lys-Phe-Gly-, * 2 -Asn-, * 2 -Asn-Ala-, * 2 -Asn-Ala-Ala-, *2 -Asn-Ala-Thr-, *2-Asn-Ala-Pro-, *2-Asn-Ala-Val-, *2-Asn-Ala-Phe-, *2-Asn-Ala-Tyr-, *2-Asn-Ala-Leu-, *2-Asn-Ala-Gly-, *2-Gly-Phe-Gly-Gly-, *2-Gly-Leu-Phe-Gly- or *2-Leu-Ala-Leu-Ala-, and the *2 end of (G)g is bonded to Y, Y is represented by the formula (Y-1): 【Chemistry 6】 (In the formula, Y′ represents a carbonyl group; R ３ is a C optionally substituted with a halogen atom, a cyano group, or 1 to 5 fluorine atoms. １－６ C optionally substituted with an alkyl group or 1 to 5 fluorine atoms １－６ represents an alkoxy group; R ３ If there are multiple R ３ may be the same or different, f represents an integer of 0 to 2. is a group represented by In the formula (Y-1), * １ The end is bound to Z, Z is represented by the formula (Z-1): 【Chemistry 7】 (In the formula, AA represents Glu, Asp, Lys, or Cys, or a C1-3 alkyl ester thereof, and when there are a plurality of AAs, each AAs may be the same or different, and AAs are bonded to each other via an amide bond; (AA) ｍ The N-terminal nitrogen atom of the formula (I) forms an amide bond with the carbonyl group (a), Q is an unsubstituted phenyl group or a group represented by formula (Q-1): 【Chemistry 8】 (In the formula, R 2a and R 2e each represent a hydrogen atom; R ２ｂ , R ２ｃ and R2d each independently represent a hydrogen atom, a halogen atom, or a methoxy group; R ２ｆ represents a methyl group) represents a group represented by R1a represents a hydrogen atom, a methyl group, or an ethyl group; m represents an integer of 1 to 10. Represented by The compound according to claim 1 or a salt thereof.

3. 3. The compound or salt thereof according to claim 1 or 2, wherein h is 5.

4. (G) ｇ is * ２ -Lys-Val-, * ２ -Cit-Val-, * ２ -Cit-Phe-, * ２ -Cit-Leu-, * ２ -Asn-, * ２ -Asn-Ala-, * ２ -Asn-Ala-Ala-, * ２ -Asn-Ala-Pro-, * ２ -Asn-Ala-Val-, * ２ -Asn-Ala-Gly-, or * ２ -Gly-Phe-Gly-Gly- and (G) ｇ of* ２ The compound or salt thereof according to any one of claims 1 to 3, wherein the terminal is bonded to Y.

5. (G) ｇ Formula (G-1), Formula (G-2) or Formula (G-4): 【Chemistry 9】 is a group represented by (G) ｇ of* ２ The compound or salt thereof according to any one of claims 1 to 3, wherein the terminal is bonded to Y.

6. R ３ is a fluorine atom, C １－３ Alkyl group or C １－３ is an alkoxy group, R ３ If there are multiple R ３ and may be the same or different, the compound or salt thereof according to any one of claims 1 to 5.

7. The compound or salt thereof according to any one of claims 1 to 5, wherein f is 0.

8. Z-Y is a compound represented by the formula (ZY-1): 【Chemistry 10】 [In the formula, AA and m are as defined above. Q is an unsubstituted phenyl group or a group represented by formula (Q-2): 【Chemistry 11】 (In the formula, R ２ｂ and R ２ｃ each independently represents a hydrogen atom, a fluorine atom, or a methoxy group. is a group represented by the formula: The compound or salt thereof according to any one of claims 1 to 5, wherein the compound is a group represented by:

9. Formula (3-1) is formula (MDF-1), formula (MDF-2) or formula (MDF-4): 【Chemistry 12】 (In the formula, h, Y′, and Z are defined as above.) The compound or salt thereof according to any one of claims 1 to 3,

10. 2. The compound according to claim 1, which is the compound or a salt thereof shown below: 【Chemistry 13】

11. 2. The compound according to claim 1, which is the compound or a salt thereof shown below: 【Chemistry 14】

12. 2. The compound according to claim 1, which is the compound or a salt thereof shown below: 【Chemistry 15】

13. 2. The compound according to claim 1, which is the compound or a salt thereof shown below: 【Chemistry 16】

14. 2. The compound according to claim 1, which is the compound or a salt thereof shown below: 【Chemistry 17】

15. 2. The compound according to claim 1, which is the compound or a salt thereof shown below: 【Chemistry 18】

16. Use of the compound or a salt thereof according to any one of claims 1 to 15 for the manufacture of an anticancer agent.

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