Targeted protein degradation using bifunctional prodrugs that bind to ubiquitin ligase and target MCL-1 protein

Abstract

Compounds of formula (I) [MCL-1 ligand prodrug moiety]-[linker]-[ligase ligand moiety] (I) or a salt, solvate, hydrate or isomer thereof wherein the MCL-1 ligand prodrug moiety is, for example, [Formula 1] JPEG2025540250000453.jpg91170] and its use in the treatment of cancer.

Description

[Technical Field]

[0001] The present invention relates to prodrugs of bifunctional compounds that can bind to ubiquitin ligase and also to target proteins so as to bring the target proteins into proximity with the ubiquitin ligase and induce degradation of the target proteins. [Background technology]

[0002] The ubiquitin-proteasome system (UPS) is involved in maintaining a healthy and balanced proteome. During the ubiquitination process, ubiquitin units are covalently attached to proteins to form polyubiquitin chains, marking the proteins for degradation by the proteasome. Ubiquitination is central to the regulation of nearly all cellular processes and is itself tightly regulated. Ubiquitin ligases facilitate the ubiquitination of various proteins in vivo, contributing to the precise regulation of the system. Upon recognition, ubiquitin ligases mediate the attachment of ubiquitin moieties to target proteins, marking them for degradation by the proteasome.

[0003] The concept of selective targeted protein degradation (TPD) through modulation of the UPS was first described in 1999 (US Patent Application Publication No. 2002173049A1 (PROTEINIX INC); November 21, 2002). One approach to TPD involves the use of bifunctional molecules that simultaneously bind to a ubiquitin ligase and a target protein, enabling efficient ubiquitin transfer to the latter. This concept was first described by Sakamoto KM et al. (Proc Natl Acad Sci U S A. 2001 Jul 17;98(15):8554-9) and more recently reviewed by Burslem GM and Crews CM (Cell. 2020 Apr 2;181(1):102-114).

[0004] Oncogenic stress (e.g., DNA damage) can result in programmed cell death, a cellular response intended to prevent oncogenic transformation. This mechanism relies on the interplay between pro- and anti-apoptotic Bcl-2 proteins, the balance of which is essential for proper cellular function.

[0005] BCL-2, BCL-xL, and MCL-1 are anti-apoptotic proteins containing the BH3 domain. These proteins bind (via the BH3 domain) to the effector Bcl-2 proteins Bak and Bax, preventing their pro-apoptotic activity. Inhibition of the BH3 domain-BH3 pocket binding interface is a well-known approach to cancer therapy (Leber B, Kale J, Andrews DW. Cancer Discov. 2018 Dec;8(12):1511-1514).

[0006] High expression of induced myeloid leukemia cell differentiation protein (MCL-1) has been observed in many human cancers and is associated with resistance to cytotoxic drugs. Studies have shown that inhibition of MCL-1 in several malignancies induces apoptosis through the release of proapoptotic proteins. Therefore, targeting MCL-1 may be applied as a therapeutic strategy in MCL-1-dependent cancer types (e.g., multiple myeloma, acute myeloid leukemia, chronic myeloid leukemia, B-cell acute lymphoblastic leukemia, hepatocellular carcinoma, and non-small cell lung cancer). This concept has been confirmed in vitro and in vivo (Tron AE et al. Nat Commun. 2018 Dec 17;9(1):5341). Treatment with Bcl-2 and MEK inhibitors also induces MCL-1 dependence, and subsequent inactivation of MCL-1 often results in synthetic lethality (Leber B, Kale J, Andrews DW. Cancer Discov. 2018 Dec;8(12):1511-1514). As demonstrated by Montero, J. et al. (Nat. Commun. 10, 5157(2019)) and Sale, MJ et al. (Nat. Commun. 10, 5167(2019)), MCL-1 is a driver of adaptive survival in tumor cells treated with targeted oncogene therapy, and therefore, drugs targeting MCL-1 may overcome cancer resistance to these therapeutic agents.

[0007] In parallel with efforts focused on MCL-1 inhibition, targeted degradation appears to be an attractive therapeutic option. Papatzimas et al. (J. Med. Chem. 2019, 62, 11, 5522-5540) and Wang Z et al. (J. Med. Chem. 2019, 62, 17, 8152-8163) have both demonstrated degradation of the MCL-1 protein. However, the efficacy of the reported compounds remains suboptimal in terms of their ability to induce cell destruction and apoptosis. Therefore, alternative chemical species with improved potency are needed to develop therapeutically applicable MCL-1 degraders.

[0008] One of the challenges in developing MCL-1-targeted therapeutics is safety, because MCL-1 has been shown to be essential for cardiac homeostasis in adult mouse models, and its absence leads to cardiomyocyte loss. Currently, several clinical trials involving MCL-1 inhibitors are on hold to evaluate safety signals for cardiotoxicity (Wei AH et al. Blood Rev. 2020 Nov; 44: 100672).

[0009] It is also desirable to develop prodrugs of MCL-1 targeting therapeutic agents. Some potential advantages of prodrugs include increasing the bioavailability of the active therapeutic compound, thereby allowing for administration at lower doses. The risk of adverse side effects of the active therapeutic compound may also be reduced. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] US Patent Application Publication No. 2002173049 A1 [Non-patent literature]

[0011] [Non-Patent Document 1] Sakamoto KM et al. (Proc Natl Acad Sci US A. 2001 Jul 17;98(15):8554-9) [Non-patent document 2] Burslem GM and Crews CM (Cell. 2020 Apr 2;181(1):102-114) [Non-patent document 3] Leber B, Kale J, Andrews DW. Cancer Discov. 2018 Dec;8(12):1511-1514 [Non-patent document 4] Tron AE et al. Nat Commun. 2018 Dec 17;9(1):5341 [Non-Patent Document 5] Montero, J. et al. (Nat. Commun. 10, 5157 (2019)) [Non-patent document 6] Sale, MJ et al. (Nat. Commun. 10, 5167 (2019)) [Non-Patent Document 7] Papatzimas et al. (J. Med. Chem. 2019, 62, 11, 5522-5540) [Non-patent document 8] Wang Z et al. (J. Med. Chem. 2019, 62, 17, 8152-8163) [Non-Patent Document 9] Wei AH et al. Blood Rev. 2020 Nov; 44: 100672 Summary of the Invention [Means for solving the problem]

[0012] According to a first aspect of the present invention, a compound of formula (I) [MCL-1 ligand prodrug moiety]-linker-[ligase ligand moiety] (I) or a salt, solvate, hydrate or isomer thereof, wherein [ligase ligand moiety] is: [ka] [In the formula, M is O, S, or NH, or absent; [ka] is the R of the linker 18 shows the bond with R 22 is hydrogen, halogen, -OMe, an amino group, heterocycloalkyl, or unsubstituted C1-C6 alkyl; R 29 is hydrogen or Me, L' is hydrogen, alkyl, benzyl, acetyl, or pivaloyl. [MCL-1 ligand prodrug moiety] is a compound of formula (A1), (A2), (A3) or (A4), [ka] (A1) (A2) (A3) JPEG2025540250000005.jpg33170(A4) [In the formula, [ka] is a single or double bond, Each Z2 is independently N or C, and when Z2 is N, [ka] is a single bond, and when Z2 is C, [ka] is a double bond, Each R 11 are independently H, halogen, or C1-C6 alkyl; R 8 is a C1-C6 alkyl substituted with piperazine; In each of formula (A1) and formula (A4), R 10 and R 30 One side is H and the other side is R 10 and R 30 The other is -C 2-5 Alkyl-OR 13 , -OC 2-5 Alkyl-R 13 or -C 2-5 Alkyl-NMe-R 13 where R 13 is phenyl, naphthyl, or tetralin, wherein the phenyl, naphthyl, or tetralin is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl, and —O(C1-C6 alkyl), or the tetralin is optionally substituted with a bridging —CH2— group, or the naphthyl is optionally substituted with —O— or —S—; R 12 is as follows: [ka] R 31 Ha-C 2-5 Alkyl-OR 13 , -OC 2-5 Alkyl-R 13 or -C 2-5 Alkyl-NMe-R 13 where R 13 is phenyl, naphthyl, or tetralin, wherein the phenyl, naphthyl, or tetralin is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl, and —O(C1-C6 alkyl), or the tetralin is optionally substituted with a bridging —CH2— group, or the naphthyl is optionally substituted with —O— or —S—; Each R 32 is independently H, [ka] and Each R 33 is independently R 19or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with morpholine or piperazine; R 20 are Me, -CH2-OMe, -(CH2CH2O) p (C1-C6 alkyl), or —CH2—O-bromobenzaldehyde, where p is 1 to 5; R 34 is C 2-5 Alkyl-OR 13 or -OC 2-5 Alkyl-R 13 where R 13 is phenyl, naphthyl, or tetralin, wherein the phenyl, naphthyl, or tetralin is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl, and —O(C1-C6 alkyl), or the tetralin is optionally substituted with a bridging —CH2— group, or the naphthyl is optionally substituted with —O— or —S—; R 35 is as follows: [ka] R 19 is the R of the linker 14 and each of formula (A1), formula (A2), formula (A3) and formula (A4) is a bond connected to a single R 19 Including, (i)R 9 is -C(O)O(C1-C6 alkyl), -C(O)Ocycloalkyl, -C(O)Oheterocycloalkyl, -C(O)Oaryl or -P(O)(OR p )2, and the C1-C6 alkyl is -OC(O)(unsubstituted C1-C6 alkyl), -OC(O)(at least one R 10 C1-C6 alkyl substituted with), -OC(O)cycloalkyl, -OC(O)heterocycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, -OC(O)(CH2) m O(CH2) m O(unsubstituted C1-C6 alkyl), -OC(O)(CH2) mO(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(unsubstituted C1-C6 alkyl), -OC(O)O(at least one R 10 C1-C6 alkyl substituted with -OC(O)Ocycloalkyl, -OC(O)O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2CH2O) m (C1-C6 alkyl substituted with OP(O)(OH)2), -OC(O)O(CH2CH2S) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)(unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)2 (unsubstituted C1-C6 alkyl), -OC(O)NH (C1-C6 alkyl substituted with OMe), -OC(O)NMe (C1-C6 alkyl substituted with OMe), -P(O)(OH)2, -OP(O)(OH)2, -C(O)heterocycloalkyl, -C(O)N(unsubstituted C1-C6 alkyl)2, heteroaryl, heterocycloalkyl, -S(unsubstituted C1-C6 alkyl), -S(O)(unsubstituted C1-C6 alkyl), -N + (unsubstituted C1-C6 alkyl)3, -N + substituted with one or more groups selected from (unsubstituted C1-C6 alkyl)cycloalkyl, N-(unsubstituted C1-C6 alkyl)piperidinium cation, N-(unsubstituted C1-C6 alkyl)morpholinium cation, and N-(unsubstituted C1-C6 alkyl)imidazolium cation; Each R 10 are independently -OH, -O(unsubstituted C-C alkyl), -OBn, -NH, -NMe, -NHC(O)(unsubstituted C-C alkyl), -NHC(O)O(unsubstituted C-C alkyl), heterocycloalkyl, heteroaryl, aryl, -C(O)NMe; Each R p are independently -(CH2) m OC(O) (unsubstituted C1-C6 alkyl), each m is independently 1, 2, 3, or 4; or (ii)R 9 is -C(O)O(CH2) p NMe2, -C(O)O(CH2) p NHMe, -C(O)OCH2CH(OH)CH2OH, -C(O)OCH2CH2CMe2OH, or -C(O)OCH2CH2SO2Me, and each p is independently 2, 3, 4, 5, or 6. [Linker] has the formula: R 14 -R 15 -R 16 -R 17 -R 18 [In the formula, R 14 Ha-C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 1-6 Alkyl-N(C 1-6 alkyl)-, -C(O)-, -SO2- or absent; R 15 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 Alkyl-NH-, -C 1-6 Alkyl-N(C 1-6 alkyl)-, -cycloalkyl-NH-, -heterocycloalkyl-NH- or absent; R 16 Ha-C 1-6 Alkyl, -C(O)-, -C(O)-C 1-6 alkyl-, —C(O)—NH—, —C(O)O—, —CH—C(O)—, —CH—C(O)—NH—, —CH—C(O)O— or absent; R 17 -CH2(C2H4-O) y , -(CHO) x , -(C2H4-O) x , -(C3H6-O) x , or absent, x is 1 to 10, y is between 2 and 10; R 18 Ha-C 1-6 Alkyl, -C 1-6alkyl-C(O)-, cycloalkyl, -CH2-NH-C(O)-, heterocycloalkyl, or absent; R 14 ~R 18 At least one of the following is present] The compound, or a salt, solvate, hydrate, or isomer thereof, is provided.

[0013] In some embodiments, the ligase ligand moiety is: [ka]

[0014] In some embodiments, the ligase ligand moiety is: [ka]

[0015] In some embodiments, the ligase ligand moiety is: [ka]

[0016] In some embodiments, R 22 is hydrogen.

[0017] In some embodiments, L' is hydrogen.

[0018] In some embodiments, M is O or NH, or absent.

[0019] In some embodiments, the ligase ligand moiety is: [ka]

[0020] In some embodiments, the ligase ligand moiety is: [ka]

[0021] In some embodiments, the ligase ligand moiety is: [ka] JPEG2025540250000018.jpg58170

[0022] In some embodiments, the ligase ligand moiety is: [ka]

[0023] In some embodiments, the ligase ligand moiety is: [ka]

[0024] In some embodiments, the ligase ligand moiety is: [ka]

[0025] In some embodiments, the ligase ligand moiety is: [ka]

[0026] In some embodiments, R 16 Ha-C 1-6 alkyl, —C(O)—, —C(O)—NH—, —C(O)O—, —CH—C(O)—, —CH—C(O)—NH—, —CH—C(O)O— or absent; R17 -CH2(C2H4-O) y , -(C2H4-O) x , -(C3H6-O) x , or absent, R 18 Ha-C 1-6 It is alkyl, cycloalkyl, -CH2-NH-C(O)-, heterocycloalkyl, or absent.

[0027] In some embodiments, R 14 Ha-C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 alkynyl, —C(O)—, —SO—, or absent. In some such embodiments, R 14 Ha-C 1-6 It is alkyl.

[0028] In some embodiments, R 15 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 alkyl-NH-, -cycloalkyl-NH-, or absent. In some embodiments, R 15 is heterocycloalkyl. In some such embodiments, R 15 are piperazine, bridged piperazine, piperazine N-oxide, piperazine cation, [ka] and During the ceremony, [ka] is R 14 shows the bond with [ka] is R 16 In some such embodiments, R 15 is piperazine or [ka] is.

[0029] In other embodiments, R 15 is absent.

[0030] In some embodiments, R 16 Ha-C 1-6 alkyl, —CH—C(O)—NH—, or —C(O)—. In some such embodiments, R 16 Ha-C 1-6 It is alkyl or -C(O)-.

[0031] In some embodiments, R 17 is absent.

[0032] In some embodiments, R 18 Ha-C 1-6 In some embodiments, R is alkyl, heterocycloalkyl, or absent. 18 Ha-C 1-6 In some such embodiments, R 18 Ha-C 1-6 It is an alkyl or piperazine.

[0033] In some embodiments, R 18 is absent.

[0034] In some embodiments, the linker is selected from: [ka] [In the formula, [ka] indicates binding to the [MCL-1 ligand prodrug moiety], [ka] indicates binding to [ligase ligand moiety]]

[0035] In some embodiments, the linker is selected from: [ka] [In the formula, [ka] indicates binding to the [MCL-1 ligand prodrug moiety], [ka] indicates binding to [ligase ligand moiety]]

[0036] In some embodiments, in each of Formula (A1) and Formula (A4), R 10 and R 30 One side is H and the other side is R 10 and R 30 The other is -C 2-5 Alkyl-OR 13 or -OC 2-5 Alkyl-R 13 where R 13 is phenyl or naphthyl, and the phenyl or naphthyl may be substituted with at least one substituent selected from halogen and C1-C6 alkyl.

[0037] In some embodiments, in Formula (A1), R 12 is as follows: [ka]

[0038] In some embodiments, in Formula (A4), R 35 is as follows: [ka]

[0039] In some embodiments, in Formula (A2), R31 Ha-C 2-5 Alkyl-OR 13 or -OC 2-5 Alkyl-R 13 where R 13 is phenyl or naphthyl, and the phenyl or naphthyl may be substituted with at least one substituent selected from halogen and C1-C6 alkyl.

[0040] In some embodiments, in Formula (A3), R 34 Ha-C 2-5 Alkyl-OR 13 or -OC 2-5 Alkyl-R 13 where R 13 is phenyl or naphthyl, and the phenyl or naphthyl may be substituted with at least one substituent selected from halogen and C1-C6 alkyl.

[0041] In some embodiments, Z2 is C; [ka] is a double bond.

[0042] In some embodiments, the MCL-1 ligand prodrug moiety is: [ka] [In the formula, R 11 is a halogen, R 13a is a halogen, R 20 is Me, -CH2-OMe, or -(CH2CH2O) p (C1-C6 alkyl), and p is 1 to 5.

[0043] In some embodiments, R 9is -C(O)O(C1-C6 alkyl), -C(O)Ocycloalkyl, -C(O)Oheterocycloalkyl, -C(O)Oaryl or -P(O)(OR p )2, and the C1-C6 alkyl is -OC(O)(unsubstituted C1-C6 alkyl), -OC(O)(at least one R 10 C1-C6 alkyl substituted with), -OC(O)cycloalkyl, -OC(O)heterocycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, -OC(O)(CH2) m O(CH2) m O(unsubstituted C1-C6 alkyl), -OC(O)(CH2) m O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(unsubstituted C1-C6 alkyl), -OC(O)O(at least one R 10 C1-C6 alkyl substituted with -OC(O)Ocycloalkyl, -OC(O)O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2CH2O) m (C1-C6 alkyl substituted with OP(O)(OH)2), -OC(O)O(CH2CH2S) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)(unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)2 (unsubstituted C1-C6 alkyl), -OC(O)NH (C1-C6 alkyl substituted with OMe), -OC(O)NMe (C1-C6 alkyl substituted with OMe), -P(O)(OH)2, -OP(O)(OH)2, -C(O)heterocycloalkyl, -C(O)N(unsubstituted C1-C6 alkyl)2, heteroaryl, heterocycloalkyl, -S(unsubstituted C1-C6 alkyl), -S(O)(unsubstituted C1-C6 alkyl), -N + (unsubstituted C1-C6 alkyl)3, -N +It is substituted with one or more groups selected from (unsubstituted C1-C6 alkyl)2 cycloalkyl, N-(unsubstituted C1-C6 alkyl) piperidinium cation, N-(unsubstituted C1-C6 alkyl) morpholinium cation, and N-(unsubstituted C1-C6 alkyl) imidazolyl cation.

[0044] In some embodiments, R 9 is -C(O)O(C1-C6 alkyl), -C(O)Ocycloalkyl, -C(O)Oheterocycloalkyl, -C(O)Oaryl, or -P(O)(OR p )2, and the C1-C6 alkyl is -OC(O)Me, -OC(O)Et, -OC(O) i Pr, -OC(O)C(CH3)3, -OC(O)CH2OH, -OC(O)CH(CH3)OH, -OC(O)C(CH3)2OH, -OC(O)CH2CH2OH, -OC(O)CH(OH)CHMe2, -OC(O)CH(OH)CH2CHMe2, -OC(O)CH2CH(OH)Me, -OC(O)CH2C(OH)Me2, -OC(O)CH(CH2OH)(NHC(O)Me), -OC(O)CH(NHC(O)Me)(isobutyl), -OC(O)CH(OH)aryl, -OC(O)CH(OH)CH2aryl, -OC(O)heterocycloalkyl, -OC(O)cycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, -OC(O)CH2CH2aryl, -OC(O)CH(NH2) i Pr, -OC(O)CH( i Pr)NHC(O)O t Bu, -OC(O)CH2OCH2CH2OMe, -OC(O)CH2(OCH2CH2)2OMe, -OC(O)OMe, -OC(O)OEt, -OC(O)O iPr, -OC(O)Ocycloalkyl, -OC(O)OCH2CH2OEt, -OC(O)O(CH2CH2O)2Et, -OC(O)O(CH2CH2O)3Et, -OC(O)O(CH2CH2O)3CH2CH2OP(O)(OH)2, -OC(O)OCH2CH2SMe, -OC(O)OCH2CH2S(O)Me, -OC(O)OCH2CH2S(O)2Me, -OC(O)OCH2heteroaryl, -OC(O)OCH2heterocycloalkyl, -OC(O) OCH2CH2OCH2aryl, -OC(O)OCH2CH2C(O)NMe2, -OC(O)O(CH2)6NH2, -OC(O)O(CH2)6NMe2, -OC(O)OCH(CHOEt)2, -OC(O)NHCH2CH2OMe, -OC(O)NMeCH2CH2OMe, -SMe, -S(O)Me, -P(O)(OH)2, -OP(O)(OH)2, -C(O)NMe2, -C(O)heterocycloalkyl, heteroaryl, heterocycloalkyl, -N + (Me)3, -N + (Me) is substituted with one or more groups selected from cycloalkyl, N-methylmorpholinium cation, N-methylpiperidinium cation, and N-methylimidazolium cation. In some such embodiments, R 9 is —C(O)O(C1-C6 alkyl), wherein the C1-C6 alkyl is substituted with one or more groups selected from —OC(O)C(CH3)3, —OC(O)CH2CH2OH, —OC(O)C(CH3)2OH, —OC(O)heterocycloalkyl, —OC(O)CHOCH2CHOMe, —OC(O)OiPr, —OC(O)Ocycloalkyl, —OC(O)O(CH2CHO)2Et, —OP(O)(OH)2, heteroaryl, or heterocycloalkyl.

[0045] In other embodiments, R 9is -C(O)OCH2OC(O)C(CH3)3, -C(O)OCH2OC(O)Me, -C(O)OCH(Me)OC(O)Me, -(O)OCH2OC(O)CH2CH2OH, -C(O)OCH2OC(O)C(CH3)2OH, - C(O)OCH2OC(O)piperidine, -C(O)OCH2OC(O)CH2OCH2CH2OMe, -C(O)OCH2OC(O)OiPr, -C(O)OCHMeOC(O)OiPr, -C(O)OCHMeOC(O)Ocyclohexyl sil, -C(O)OCHMeOC(O)O(CHCHO)Et, -C(O)OCHCHOP(O)(OH), -C(O)OCH(N-methylimidazolium cation), -C(O)OCH(N-methylpiperidinium cation), -C(O)OCHdioxolane, -C(O)OCHCHmorpholine, -C(O)OCHCHpiperazine, -C(O)OCHCHCHpiperazine, or -P(O)(OCHOC(O)C(CH)). In some such embodiments, R 9 is -C(O)OCH2OC(O)C(CH3)3, -C(O)OCH2OC(O)Me, -C(O)OCH(Me)OC(O)Me, -(O)OCH2OC(O)CH2CH2OH, -C(O)OCH2OC(O)C(CH 3)2OH, -C(O)OCH2OC(O)piperidine, -C(O)OCH2OC(O)CH2OCH2CH2OMe, -C(O)OCH2OC(O)OiPr, -C(O)OCHMeOC(O)OiPr, -C(O)OCH MeOC(O)Ocyclohexyl, -C(O)OCHMeOC(O)O(CHCHO)Et, -C(O)OCHCHOP(O)(OH), -C(O)OCH(N-methylimidazolium cation), -C(O)OCH(N-methylpiperidinium cation), -C(O)OCHdioxolane, -C(O)OCHCHmorpholine, -C(O)OCHCHpiperazine, or -C(O)OCHCHCHpiperazine.

[0046] In some embodiments, R 9 is -C(O)O(CH2) p NMe2, -C(O)O(CH2) pNHMe, —C(O)OCHCH(OH)CHOH, C(O)OCHCHCMeOH, or —C(O)OCHCHSOMe, and each p is independently 2, 3, 4, 5, or 6. In some such embodiments, R 9 is —C(O)OCH2CH2NMe2, —C(O)OCH2CH(OH)CH2OH or —C(O)OCH2CH2SO2Me.

[0047] In some embodiments, R 20 is Me or -(CH2CH2O)2Me.

[0048] In some embodiments, R 33 is R 19 In another embodiment, R 33 is a C1-C6 alkyl substituted with morpholine or piperazine.

[0049] In some embodiments, the C1-C6 alkyl substituted with morpholine or piperazine is: [ka]

[0050] In some embodiments, R 11 is Cl.

[0051] In some embodiments, R 13a is F.

[0052] In some embodiments, the MCL-1 ligand prodrug moiety is: [ka]

[0053] In some embodiments, the MCL-1 ligand prodrug moiety is: [ka]

[0054] In some embodiments, [Linker] is: [ka] [ligase ligand portion] is: [ka] [MCL-1 ligand prodrug moiety] is a compound of formula (A3), wherein: R 32 is as follows: [ka] R 9 is C(O)O(linear C1-C6 alkyl)OC(O)C(CH3)3, C(O)O(linear C1-C6 alkyl)OC(O)heterocycloalkyl, C(O)O(linear C1-C6 alkyl)OC(O)CH2CH2OH, C(O)O(linear C1-C6 alkyl)OC(O)CHOCH2CHOMe, C(O)O(linear C1-C6 alkyl)OC(O)Me, C(O)O(branched C1-C6 alkyl)OC(O)OiPr, C(O)O(branched C1-C6 alkyl)OC(O)Ocycloalkyl, C(O)O(branched C1-C6 alkyl)OC(O)O(CH2CHO)2Et, or C(O)O(branched C1-C6 alkyl)OC(O)Me.

[0055] In some embodiments, [Linker] is: [ka] [ligase ligand portion] is: [ka] [MCL-1 ligand prodrug moiety] is a compound of formula (A3): During the ceremony, R32 is as follows: [ka] R 9 is C(O)O(linear C1-C6 alkyl)OC(O)C(CH3)3, C(O)O(branched C1-C6 alkyl)OC(O)OiPr, C(O)O(branched C1-C6 alkyl)OC(O)Ocycloalkyl, C(O)O(branched C1-C6 alkyl)OC(O)O(CH2CHO)2Et, or C(O)O(branched C1-C6 alkyl)OC(O)Me.

[0056] In some embodiments, [Linker] is: [ka] [ligase ligand portion] is: [ka] [MCL-1 ligand prodrug moiety] is a compound of formula (A3), wherein: R 32 is as follows: [ka] R 9 is C(O)O(linear C1-C6 alkyl)OC(O)C(CH3)3, C(O)O(linear C1-C6 alkyl)OC(O)CH2CH2OH, C(O)O(linear C1-C6 alkyl)OC(O)Me, C(O)OCH2CH2 heterocycloalkyl, or C(O)O(branched C1-C6 alkyl)OC(O)O(CH2CH2O)2Et.

[0057] In some embodiments, [Linker] is: [ka] [ligase ligand portion] is: [ka] [MCL-1 ligand prodrug moiety] is a compound of formula (A3), wherein: R 32 is as follows: [ka] R 9 is C(O)O(linear C-C alkyl)OC(O)C(CH), C(O)O(linear C-C alkyl)OC(O)CHCHOH, C(O)O(linear C-C alkyl)OC(O)Me, or C(O)OCHCHheterocycloalkyl; R 9 is C(O)O(linear C1-C6 alkyl)OC(O)C(CH3)3, then the [ligase ligand moiety] is [ka]

[0058] In some embodiments, the compound is selected from the following: [Table 1] JPEG2025540250000054.jpg148170 JPEG2025540250000055.jpg233170

[0059] In some embodiments, the compound is selected from Compounds 43, 55, 57, 69, 71, 99, 100, 101, 129, 131, 133, 137, and 140. In other embodiments, the compound is selected from Compound 107 and Compound 124.

[0060] In some embodiments, the compound is selected from compounds 69, 99, 100, 107, 124, and 140.

[0061] In some embodiments, the compound is selected from compounds 41, 43, 55, 57, 69, 71, 73, 74, 75, 99, 100, 101, and 124. In some embodiments, the compound is selected from compounds 41, 43, 55, 57, 69, 71, 73, 74, 75, 99, 100, and 101. In some embodiments, the compound is selected from compounds 69, 75, 99, 100, 101, and 124. In some embodiments, the compound is selected from compounds 69, 75, 99, 100, and 101.

[0062] In some embodiments, the compound is selected from compounds 41, 43, 69, 73, 74, 101, 129, and 133. In some embodiments, the compound is selected from compounds 41, 43, 73, 74, 129, and 133.

[0063] In some embodiments, unless otherwise specified, each alkyl, alkenyl, alkynyl, aryl, heteroaryl, and benzyl is unsubstituted.

[0064] According to a second aspect of the present invention, there is provided a compound of formula (I) [MCL-1 ligand prodrug moiety]-[linker]-[ligase ligand moiety] (I) or a salt, solvate, hydrate or isomer thereof, wherein [ligase ligand moiety] is: (a) Formula (IV) or (IVa) [ka] (IV) (IVa) [In the formula, Each of X1 and X2 is independently O or S; Each of Q1 and Q2 is independently N or CR 5 and at least one of Q1 and Q2 is N; Each of E1, E2, E3, and E4 is independently N or CR'; n is 0, 1 or 2; L2 is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)R b , -C(O)OR b , -C(O)NH2, -C(O)NHR b , -C(O)NR b 2, -OR b , -NR b 2, or -S(O)2R b and Each R 5 are independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR b , -NR b 2, -NR b C(O)R b , -NR b C(O)OR b , -NO2, -CN, -C(O)R b , -C(O)OR b , -C(O)NH2, -C(O)NHR b , -C(O)NR b 2, -OR b , -OC(O)R b , -OC(O)OR b , -OC(O)NH2, -OC(O)NHR b , -OC(O)NR b 2, -SR b , -S(O)2R b , -S(O)2OR b , -S(O)2NH2, -S(O)2NHR b , -S(O)NR b 2;-OR 21 , -NH-R 21 , -C(O)-NH-R 21 , or -CH2-NH-C(O)-R 21 and Each R' is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR b , -NR b 2, -NR b C(O)R b , -NRb C(O)OR b , -NO2, -CN, -C(O)R b , -C(O)OR b , -C(O)NH2, -C(O)NHR b , -C(O)NR b 2. -C(O)NHCHR b 2. -CHR b NHC(O)NHR b , -CHR b NHC(O)C(halogen)2R b , -OR b , -OC(O)R b , -OC(O)OR b , -OC(O)NH2, -OC(O)NHR b , -OC(O)NR b 2, -SR b , -S(O)2R b , -S(O)2OR b , -S(O)2NH2, -S(O)2NHR b , -S(O)NR b 2. -NHS(O)2R b , -R 21 , -OR 21 , -NH-R 21 , -C(O)-R 21 , -C(O)-NH-R 21 , or -CH2-NH-C(O)-R 21 and Each R b are independently hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl; R 21 is the R of the linker 18 and formula (IV) is a bond connecting to a single R 21 [including (b) Formula (VIIa), (VIIb), (VIIc) or (VIId) [ka] (VIIa) (VIIb) JPEG2025540250000058.jpg33170(VIIc) (VIId) [In the formula, Each of X1 and X2 is independently O or S; each of Q1 and Q2 independently represents N or CR, and at least one of Q1 and Q2 is N; Each of W1, W2, and W3 is independently N or CR a and Z is O, S, or NR e and n is 0, 1 or 2; L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)R b , -C(O)OR b , -C(O)NH2, -C(O)NHR b , -C(O)NR b 2, -OR b , -NR b 2, or -S(O)2R b and Each R is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR b , -NR b 2, -NR b C(O)R b , -NR b C(O)OR b , -NO2, -CN, -C(O)R b , -C(O)OR b , -C(O)NH2, -C(O)NHR b , -C(O)NR b 2, -OR b , -OC(O)R b , -OC(O)OR b , -OC(O)NH2, -OC(O)NHR b , -OC(O)NR b 2, -SR b , -S(O)2R b , -S(O)2OR b , -S(O)2NH2, -S(O)2NHR b , -S(O)NR b 2, -R 21 , -OR 21, -NH-R 21 , -C(O)-R 21 , -C(O)-NH-R 21 , or -CH2-NH-C(O)-R 21 and Each R a are independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR b , -NR b 2, -NR b C(O)R b , -NR b C(O)OR b , -NO2, -CN, -C(O)R b , -C(O)OR b , -C(O)NH2, -C(O)NHR b , -C(O)NR b 2, -OR b , -OC(O)R b , -OC(O)OR b , -OC(O)NH2, -OC(O)NHR b , -OC(O)NR b 2, -SR b , -S(O)2R b , -S(O)2OR b , -S(O)2NH2, -S(O)2NHR b , -S(O)NR b 2, -R 21 , -OR 21 , -NH-R 21 , -C(O)-R 21 , -C(O)-NH-R 21 , or -CH2-NH-C(O)-R 21 and Each R e are independently hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, -R 21 , -OR 21 , -NH-R 21 , -C(O)-R 21 , -C(O)-NH-R 21 , or -CH2-NH-C(O)-R 21 and Each R bare independently hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl; R 21 is the R of the linker 18 and each of formula (VIIa), formula (VIIb) and formula (VIIc) is a bond connecting to a single R 21 [including (c) Formula (VIII) [ka] [In the formula, Each of X1 and X2 is independently O or S; n is 0, 1 or 2; L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)R b , -C(O)OR b , -C(O)NH2, -C(O)NHR b , -C(O)NR b 2, -OR b , -NR b 2, or -S(O)2R b and Each of R1, R2, and R3 independently represents hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR b , -NR b 2, -NR b C(O)R b , -NR b C(O)OR b , -NO2, -CN, -C(O)R b , -C(O)OR b , -C(O)NH2, -C(O)NHR b , -C(O)NR b 2, -OR b , -OC(O)R b , -OC(O)OR b , -OC(O)NH2, -OC(O)NHR b , -OC(O)NR b 2, -SR b , S(O)2R b , -S(O)2ORb , -S(O)2NH2, -S(O)2NHR b , -S(O)NR b 2, -R 21 , -OR 21 , -NH-R 21 , -C(O)-R 21 , -C(O)-NH-R 21 , or -CH2-NH-C(O)-R 21 and Each R b are independently hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl; R 21 is the R of the linker 18 and formula (VIII) is a bond connecting to a single R 21 including] or (d) Formula (IX) [ka] [In the formula, Each of X1 and X2 is independently O or S; L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)R b , -C(O)OR b , -C(O)NH2, -C(O)NHR b , -C(O)NR b 2, -OR b , -NR b 2, or -S(O)2R b and each of Q1, Q2, Q3, Q4, and Q5 independently represents N or CR, and at least one of Q1, Q2, Q3, Q4, and Q5 is N; Each R is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR b , -NR b 2, -NR b C(O)R b , -NR b C(O)OR b , -NO2, -CN, -C(O)Rb , -C(O)OR b , -C(O)NH2, -C(O)NHR b , -C(O)NR b 2, -OR b , -OC(O)R b , -OC(O)OR b , -OC(O)NH2, -OC(O)NHR b , -OC(O)NR b 2, -SR b , -S(O)2R b , -S(O)2OR b , -S(O)2NH2, -S(O)2NHR b , or -S(O)NR b 2, -R 21 , -OR 21 , -NH-R 21 , -C(O)-R 21 , -C(O)-NH-R 21 , or -CH2-NH-C(O)-R 21 and Each R b are independently hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl; R 21 is the R of the linker 18 and formula (IX) is a bond connecting to a single R 21 [including [MCL-1 ligand prodrug moiety] is a compound of formula (A1), (A2), (A3) or (A4), [ka] (A1) (A2) (A3) JPEG2025540250000062.jpg33170(A4) [In the formula, [ka] is a single or double bond, Each Z2 is independently N or C, and when Z2 is N, [ka] is a single bond, and when Z2 is C, [ka] is a double bond, Each R 11 are independently H, halogen, or C1-C6 alkyl; R 8 is a C1-C6 alkyl substituted with piperazine; In each of formula (A1) and formula (A4), R 10 and R 30 One side is H and the other side is R 10 and R 30 The other is -C 2-5 Alkyl-OR 13 , -OC 2-5 Alkyl-R 13 or -C 2-5 Alkyl-NMe-R 13 where R 13 is phenyl, naphthyl, or tetralin, wherein the phenyl, naphthyl, or tetralin is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl, and —O(C1-C6 alkyl), or the tetralin is optionally substituted with a bridging —CH2— group, or the naphthyl is optionally substituted with —O— or —S—; R 12 is as follows: [ka] R 31 Ha-C 2-5 Alkyl-OR 13 , -OC 2-5 Alkyl-R 13 or -C 2-5 Alkyl-NMe-R 13 where R 13is phenyl, naphthyl, or tetralin, wherein the phenyl, naphthyl, or tetralin is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl, and —O(C1-C6 alkyl), or the tetralin is optionally substituted with a bridging —CH2— group, or the naphthyl is optionally substituted with —O— or —S—; Each R 32 is independently H, [ka] and Each R 33 is independently R 19 or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with morpholine or piperazine; R 20 are Me, -CH2-OMe, -(CH2CH2O) p (C1-C6 alkyl), or —CH2—O-bromobenzaldehyde, where p is 1 to 5; R 34 is C 2-5 Alkyl-OR 13 or -OC 2-5 Alkyl-R 13 where R 13 is phenyl, naphthyl, or tetralin, wherein the phenyl, naphthyl, or tetralin is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl, and —O(C1-C6 alkyl), or the tetralin is optionally substituted with a bridging —CH2— group, or the naphthyl is optionally substituted with —O— or —S—; R 35 is as follows: [ka] R 19 is the R of the linker 14 and each of formula (A1), formula (A2), formula (A3) and formula (A4) is a bond connected to a single R 19 Including, (i)R9 is -C(O)O(C1-C6 alkyl), -C(O)Ocycloalkyl, -C(O)Oheterocycloalkyl, -C(O)Oaryl or -P(O)(OR p )2, and the C1-C6 alkyl is -OC(O)(unsubstituted C1-C6 alkyl), -OC(O)(at least one R 10 C1-C6 alkyl substituted with), -OC(O)cycloalkyl, -OC(O)heterocycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, -OC(O)(CH2) m O(CH2) m O(unsubstituted C1-C6 alkyl), -OC(O)(CH2) m O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(unsubstituted C1-C6 alkyl), -OC(O)O(at least one R 10 C1-C6 alkyl substituted with -OC(O)Ocycloalkyl, -OC(O)O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2CH2O) m (C1-C6 alkyl substituted with OP(O)(OH)2), -OC(O)O(CH2CH2S) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)(unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)2 (unsubstituted C1-C6 alkyl), -OC(O)NH (C1-C6 alkyl substituted with OMe), -OC(O)NMe (C1-C6 alkyl substituted with OMe), -P(O)(OH)2, -OP(O)(OH)2, -C(O)heterocycloalkyl, -C(O)N(unsubstituted C1-C6 alkyl)2, heteroaryl, heterocycloalkyl, -S(unsubstituted C1-C6 alkyl), -S(O)(unsubstituted C1-C6 alkyl), -N + (unsubstituted C1-C6 alkyl)3, -N +substituted with one or more groups selected from (unsubstituted C1-C6 alkyl)cycloalkyl, N-(unsubstituted C1-C6 alkyl)piperidinium cation, N-(unsubstituted C1-C6 alkyl)morpholinium cation, and N-(unsubstituted C1-C6 alkyl)imidazolium cation; Each R 10 are independently -OH, -O(unsubstituted C-C alkyl), -OBn, -NH, -NMe, -NHC(O)(unsubstituted C-C alkyl), -NHC(O)O(unsubstituted C-C alkyl), heterocycloalkyl, heteroaryl, aryl, C(O)NMe; Each R p are independently -(CH2) m OC(O) (unsubstituted C1-C6 alkyl), each m is independently 1, 2, 3, or 4; or (ii)R 9 is -C(O)O(CH2) p NMe2, -C(O)O(CH2) p NHMe, -C(O)OCH2CH(OH)CH2OH, -C(O)OCH2CH2CMe2OH, or -C(O)OCH2CH2SO2Me, and each p is independently 2, 3, 4, 5, or 6. [Linker] has the formula: R 14 -R 15 -R 16 -R 17 -R 18 [In the formula, R 14 Ha-C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 1-6 Alkyl-N(C 1-6 alkyl)-, -C(O)-, -SO2- or absent; R 15 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 Alkyl-NH-, -C 1-6 Alkyl-N(C 1-6alkyl)-, -cycloalkyl-NH-, -heterocycloalkyl-NH- or absent; R 16 Ha-C 1-6 Alkyl, -C(O)-, -C(O)-C 1-6 alkyl-, —C(O)—NH—, —C(O)O—, —CH—C(O)—, —CH—C(O)—NH—, —CH—C(O)O— or absent; R 17 -CH2(C2H4-O) y , -(CHO) x , -(C2H4-O) x , -(C3H6-O) x , or absent, x is 1 to 10, y is between 2 and 10; R 18 Ha-C 1-6 Alkyl, -C 1-6 alkyl-C(O)-, cycloalkyl, -CH2-NH-C(O)-, heterocycloalkyl, or absent; R 14 ~R 18 At least one of the following is present] The compound, or a salt, solvate, hydrate, or isomer thereof, is provided.

[0065] In some embodiments of the second aspect, unless otherwise specified, each alkyl group, alkenyl group, alkynyl group, aryl group, heteroaryl group, and benzyl group is unsubstituted.

[0066] In some embodiments of the second aspect, each R' is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR b , -NR b 2, -NR b C(O)R b , -NR b C(O)OR b , -NO2, CN, -C(O)R b , -C(O)OR b , -C(O)NH2, -C(O)NHRb , -C(O)NR b 2, -OR b , -OC(O)R b , -OC(O)OR b , -OC(O)NH2, -OC(O)NHR b , -OC(O)NR b 2, -SR b , -S(O)2R b , -S(O)2OR b , S(O)2NH2, -S(O)2NHR b , -S(O)NR b 2, -R 21 , -OR 21 , -NH-R 21 , -C(O)-R 21 , -C(O)-NH-R 21 , or -CH2-NH-C(O)-R 21 In some such embodiments, each R b is independently hydrogen, alkyl, cycloalkyl, or aryl. In some such embodiments, aryl is substituted with one or more groups selected from halogen, alkyl, and O-haloalkyl, and optionally, the halogen is Cl, the alkyl is methyl, and the O-haloalkyl is O—CF.

[0067] In some embodiments of the second aspect, one of E1, E2, E3, and E4 is N, and the remaining three of E1, E2, E3, and E4 are each CR'. In some such embodiments, E1 is N, and E2, E3, and E4 are CR'. In other such embodiments, E2 is N, and E1, E3, and E4 are CR'. In other such embodiments, E3 is N, and E1, E2, and E4 are CR'. In other such embodiments, E4 is N, and E1, E2, and E3 are CR'.

[0068] In some embodiments of the second aspect, E1, E2, E3, and E4 are each CR', and optionally E1, E2, E3, and E4 are each CH. In some such embodiments, three of E1, E2, E3, and E4 are CH, and one of E1, E2, E3, and E4 is C-halogen, C-alkyl, C-alkenyl, C-alkynyl, C-aryl, C-heteroaryl, C-benzyl, C-haloalkyl, C-haloalkenyl, C-NH, C-NHR. b , C-NR b 2. C-NR b C(O)R b , C-NR b C(O)OR b , C-NO2, C-CN, CC(O)R b , CC(O)OR b , CC(O)NH2, CC(O)NHR b , CC(O)NR b 2. CC(O)NHCHR b 2. C-CHR b NHC(O)NHR b , C-CHR b NHC(O)C(halogen)2R b , C-OR b , C-OC(O)R b , C-OC(O)OR b , C-OC(O)NH2, C-OC(O)NHR b , C-OC(O)NR b 2. C-SR b , CS(O)2R b , CS(O)2OR b , CS(O)2NH2, CS(O)2NHR b , CS(O)2NR b 2. C-NHS(O)2R b , -R 21 , -OR 21 , -NH-R 21 , -C(O)-R 21 , -C(O)-NH-R 21 , or -CH2-NH-C(O)-R 21 is.

[0069] In some embodiments of the second aspect, E2, E3, and E4 are each CH. In other embodiments, E1, E3, and E4 are each CH. In other embodiments, E1, E2, and E4 are each CH.

[0070] In some embodiments of the second aspect, two of E1, E2, E3, and E4 are N, and the remaining two of E1, E2, E3, and E4 are each CR'.

[0071] In some embodiments of the second aspect, three of E1, E2, E3, and E4 are N, and the remaining one of E1, E2, E3, and E4 is CR'.

[0072] In some embodiments of the second aspect, one of W1, W2, and W3 is N and the other of W1, W2, and W3 is CR a In some such embodiments, R a is H.

[0073] In some embodiments of the second aspect, W1, W2, and W3 are each CR a is.

[0074] In some embodiments of the second aspect, W1 is C-NH2, C-NHR b or C-NR b 2, and may be C—NH2.

[0075] In some embodiments of the second aspect, W1, W2, and W3 are each N.

[0076] In some embodiments of the second aspect, Z is NH or N-alkyl, and may be NH or N-Me.

[0077] In some embodiments of the second aspect, in Formula (IV), Formula (VIIa), Formula (VIIb), and Formula (VIIc), Q1 is N and Q2 is CR. In other embodiments, Q1 is N and Q2 is N. In other embodiments, Q1 is CR and Q2 is N. In some such embodiments, Q1 is CH or C-alkyl. In some such embodiments, Q1 is CH or C-Me.

[0078] In some embodiments of the second aspect, in Formula (IX), one of Q1, Q2, Q3, Q4, and Q5 is N, and the remaining four of Q1, Q2, Q3, Q4, and Q5 are each CR. In some such embodiments, Q1 is N, and in other embodiments, Q2 is N. In other embodiments, Q3 is N.

[0079] In some embodiments of the second aspect, in formula (IX), two of Q1, Q2, Q3, Q4, and Q5 are N, and the remaining three of Q1, Q2, Q3, Q4, and Q5 are each CR. In some such embodiments, Q1 and Q2 are N, and Q3, Q4, and Q5 are each CR. In other embodiments, Q2 and Q3 are N, and Q1, Q4, and Q5 are each CR. In other embodiments, Q1 and Q3 are N, and Q2, Q4, and Q5 are each CR. In other embodiments, Q2 and Q4 are N, and Q1, Q3, and Q5 are each CR. In other embodiments, Q1 and Q4 are N, and Q2, Q3, and Q5 are each CR. In other embodiments, Q1 and Q4 are N, and Q2, Q3, and Q5 are each CR.

[0080] In some embodiments of the second aspect, in formula (IX), three of Q1, Q2, Q3, Q4, and Q5 are N, and the remaining two of Q1, Q2, Q3, Q4, and Q5 are each CR.

[0081] In some embodiments of the second aspect, the [ligase ligand moiety] is: [ka]

[0082] In some embodiments of the second aspect, the [ligase ligand moiety] is: [ka]

[0083] In another embodiment of the second aspect, the [ligase ligand moiety] is: [ka]

[0084] According to a third aspect of the present invention, there is provided a compound of formula (I) [MCL-1 ligand prodrug moiety]-[linker]-[ligase ligand moiety] (I) or a salt, solvate, hydrate or isomer thereof, wherein [ligase ligand moiety] is: (a) Formula (Va) or (Vb) [ka] (Va) (Vb) or a pharmaceutically acceptable salt or tautomer thereof [In the formula, Each of X1 and X2 is independently O or S; Z1 is O, S, or NR 6 and T is C=O or SO2, R 1 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; Y5, Y6, Y7 and Y8 each independently represent N or CR 7 and At least one of Y5, Y6 and Y7 in formula (Va) is CR 7 and at least one of Y5, Y5 and Y8 in formula (Vb) is CR 7and n is 0, 1 or 2; L3 is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)R'''', -CHC(O)OR'''', -C(O)OR'''', -C(O)NH2, -C(O)NHR'''', -C(O)NR''''2, -OR'''', -NR''''2, or -S(O)2R'''', Each R 7 are independently hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR'''', -NR''''2, -CH2NR''''2, -NR''''C(O)R'''', -NR''''C(O)CH2NR''''2, -NR''''C(O)CH2-heterocycloalkyl, -NR''''C(O)CH(OH)R'''', -CH2NR''''C(O)OR'''', -NR''''C(O)OR' ''', -NR''''SO2R'''', -NO2, -CN, -C(O)R'''', -C(O)OR'''', -C(O)NH2, -C(O)NHR'''', -C(O)NR''''2, -OR'''', -OC(O)R'''', -OC(O)OR'''', -OC(O )NH2, -OC(O)NHR'''', -OC(O)NR''''2, -NHC(S)NHR'''', SR'''', or -S(O)2R'''', -S(O)2OR'''', -S(O)2NH2, -S(O)2NHR'''', -S(O)2NR''''2, -OR 21 , -NH-R 21 , -C(O)-NH-R 21 , or -CH2-NH-C(O)-R 21 and each R"" is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; R 6is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR'''', -NR''''2, -NR''''C(O)R'''', -N[C(O)R'''']2, -NR''''C(O)OR'''', -NO2, -CN, -C(O)R'''', -C(O)OR'''', -C( O)NH2, -C(O)NHR'''', -C(O)NR''''2, -OR'''', -OC(O)R'''', -OC(O)OR'''', -OC(O)NH2, -OC(O)NHR'''', - OC(O)NR''''2, -SR'''', or -S(O)2R'''', -S(O)2OR'''', -S(O)2NH2, -S(O)2NHR'''', -S(O)2NR''''2, -R 21 , -C(O)-NH-R 21 , or -CH2-NH-C(O)-R 21 and R 21 is the R of the linker 18 and each of formula (Va) and formula (Vb) is a bond connecting to a single R 21 Including, If Z1 is O, Y6 is CR 7 and When the compound is of formula (Va): (i) Y5, Y6, and Y7 are each CR 7 If R 7 At least one of them is not H, (ii) Z1 is NR 6 If Y6 and Y7 are CR 7 and (iii) When Z1 is S, Y5 is not C-OMe and Y6 is not C-OMe; (iv) When Z1 is S and Y5 is C-NHCOMe, Y7 is not C-CH2NR''''C(O)OR''''; (v) When Z1 is S and Y5 is N, Y6 is not CH, C-aryl or CC(O)OR''''; (vi) When Z1 is S and Y6 is N, Y7 is C-NH2, C-NHR'''', C-NR''''2, C-NR''''C(O)OR'''', C-CH2NR''''C(O)OR'''', C-haloalkyl, C- t butyl, C—OR′′′, C—COOR′′′ or C—SR′′′ and when Y7 is C—NH2, C—NHR′′′ or C—NR′′′′2, then Y5 is CH; When the compound is of formula (Vb): (vii) Y5, Y6, and Y8 are each CR 7 If R 7 At least one of them is not H, (viii) when Z1 is S, Y5 is not C-COOH or C-NHC(O)Me, and Y8 is not C-Br; (ix) When Z1 is S and Y6 is C-Br, Y8 is C-OR'''', (x) When Z1 is S, Y5 is N, and Y6 is CH or C—NH2, then Y8 is not CH; (xi) when Z1 is S and Y5 is N, then Y6 is not C-halogen, C-alkyl, C-cycloalkyl, C-aryl, C-heteroaryl, C-CH2NH2, C-COOalkyl, or C-NHC(O)alkyl; (xii) when Z1 is NR 6 If Y5, Y6 and Y8 are CR 7 is], or (b) Formula (IIa) or (IIb) [ka] (IIa) (IIb) [In the formula, Each of X1 and X2 is independently O or S; Z is O, S, or NR 2 and T is C=O or SO2, Y3 is N or CR; Y4 is N or CR; [ka] represents a single bond or a double bond, each [ka] is a double bond, each of W1, W2, W3 and W4 independently represents N or CR a and at least one of W1, W2, W3, and W4 is N; each [ka] is a single bond, W1, W2, W3 and W4 are each CR a 2, Y4 is CR, n is 0, 1 or 2; L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)R h , -C(O)OR h , -C(O)NH2, -C(O)NHR h , -C(O)NR h 2, -OR h , -NR h 2, or -S(O)2R h and Each R is independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR h , -NR h 2, -NR h C(O)R h , -NR h C(O)CH2R h , -NR h C(O)CH(OH)R h , -NR h C(O)OR h , -NR h SO2R h , -NO2, -CN, -C(O)R h , -C(O)OR h, -C(O)NH2, -C(O)NHR h , -C(O)NR h 2, -OR h , -OC(O)R h , -OC(O)OR h , -OC(O)NH2, -OC(O)NHR h , -OC(O)NR h 2, -SR h , or -S(O)2R h , -S(O)2OR h , -S(O)2NH2, -S(O)2NHR h , or -S(O)NR h 2, Each R a are independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR h , -NR h 2, -NR h C(O)R h , -NR h C(O)CH(OH)R h , -NR h C(O)OR h , -NR h SO2R h , -NO2, -CN, -C(O)R h , -C(O)OR h , -C(O)NH2, -C(O)NHR h , -C(O)NR h 2, -OR h , -OC(O)R h , -OC(O)OR h , -OC(O)NH2, -OC(O)NHR h , -OC(O)NR h 2, -SR h , -S(O)2R h , -S(O)2OR h , -S(O)2NH2, -S(O)2NHR h , -S(O)NR h 2, -OR 21 , -NH-R 21 , -C(O)-NH-R 21, or -CH2-NH-C(O)-R 21 and Each R h are independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; R 2 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR h , -NR h 2, -NR h C(O)R h , -N[C(O)R h ]2, -NR h C(O)OR h , -NO2, -CN, -C(O)R h , -C(O)OR h , -C(O)NH2, -C(O)NHR h , -C(O)NR h 2, -OR h , -OC(O)R h , -OC(O)OR h , -OC(O)NH2, -OC(O)NHR h , -OC(O)NR h 2, -SR h , -S(O)2R h , -S(O)2OR h , -S(O)2NH2, -S(O)2NHR h , or -S(O)NR h 2, R 1 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; R 21 is the R of the linker 18 and each of formula (IIa) and formula (IIb) is a bond connecting to a single R 21 Including, each [ka] is a double bond and Z is NR2 and R 2 is hydrogen, and each R a is hydrogen, W4 is CR a is] [MCL-1 ligand prodrug moiety] is a compound of formula (A1), (A2), (A3) or (A4), [ka] (A1) (A2) (A3) JPEG2025540250000079.jpg33170(A4) [In the formula, [ka] is a single or double bond, Each Z2 is independently N or C, and when Z2 is N, [ka] is a single bond, and when Z2 is C, [ka] is a double bond, Each R 11 are independently H, halogen, or C1-C6 alkyl; R 8 is a C1-C6 alkyl substituted with piperazine; In each of formula (A1) and formula (A4), R 10 and R 30 One side is H and the other side is R 10 and R 30 The other is -C 2-5 Alkyl-OR 13 , -OC 2-5 Alkyl-R 13 or -C 2-5 Alkyl-NMe-R 13 where R 13is phenyl, naphthyl, or tetralin, wherein the phenyl, naphthyl, or tetralin is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl, and —O(C1-C6 alkyl), or the tetralin is optionally substituted with a bridging —CH2— group, or the naphthyl is optionally substituted with —O— or —S—; R 12 is as follows: [ka] R 31 Ha-C 2-5 Alkyl-OR 13 , -OC 2-5 Alkyl-R 13 or -C 2-5 Alkyl-NMe-R 13 where R 13 is phenyl, naphthyl, or tetralin, wherein the phenyl, naphthyl, or tetralin is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl, and —O(C1-C6 alkyl), or the tetralin is optionally substituted with a bridging —CH2— group, or the naphthyl is optionally substituted with —O— or —S—; Each R 32 is independently H, [ka] and Each R 33 is independently R 19 or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with morpholine or piperazine; R 20 are Me, -CH2-OMe, -(CH2CH2O) p (C1-C6 alkyl), or —CH2—O-bromobenzaldehyde, where p is 1 to 5; R 34 is C 2-5 Alkyl-OR 13 or -OC 2-5 Alkyl-R13 where R 13 is phenyl, naphthyl, or tetralin, wherein the phenyl, naphthyl, or tetralin is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl, and —O(C1-C6 alkyl), or the tetralin is optionally substituted with a bridging —CH2— group, or the naphthyl is optionally substituted with —O— or —S—; R 35 is as follows: [ka] R 19 is the R of the linker 14 and each of formula (A1), formula (A2), formula (A3) and formula (A4) is a bond connected to a single R 19 Including, (i)R 9 is -C(O)O(C1-C6 alkyl), -C(O)Ocycloalkyl, -C(O)Oheterocycloalkyl, -C(O)Oaryl or -P(O)(OR p )2, and the C1-C6 alkyl is -OC(O)(unsubstituted C1-C6 alkyl), -OC(O)(at least one R 10 C1-C6 alkyl substituted with), -OC(O)cycloalkyl, -OC(O)heterocycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, -OC(O)(CH2) m O(CH2) m O(unsubstituted C1-C6 alkyl), -OC(O)(CH2) m O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(unsubstituted C1-C6 alkyl), -OC(O)O(at least one R 10 C1-C6 alkyl substituted with -OC(O)Ocycloalkyl, -OC(O)O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2CH2O) m (C1-C6 alkyl substituted with OP(O)(OH)2), -OC(O)O(CH2CH2S) m(unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)(unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)2 (unsubstituted C1-C6 alkyl), -OC(O)NH (C1-C6 alkyl substituted with OMe), -OC(O)NMe (C1-C6 alkyl substituted with OMe), -P(O)(OH)2, -OP(O)(OH)2, -C(O)heterocycloalkyl, -C(O)N(unsubstituted C1-C6 alkyl)2, heteroaryl, heterocycloalkyl, -S(unsubstituted C1-C6 alkyl), -S(O)(unsubstituted C1-C6 alkyl), -N + (unsubstituted C1-C6 alkyl)3, -N + substituted with one or more groups selected from (unsubstituted C1-C6 alkyl)cycloalkyl, N-(unsubstituted C1-C6 alkyl)piperidinium cation, N-(unsubstituted C1-C6 alkyl)morpholinium cation, and N-(unsubstituted C1-C6 alkyl)imidazolium cation; Each R 10 are independently -OH, -O(unsubstituted C-C alkyl), -OBn, -NH, -NMe, -NHC(O)(unsubstituted C-C alkyl), -NHC(O)O(unsubstituted C-C alkyl), heterocycloalkyl, heteroaryl, aryl, -C(O)NMe; Each R p are independently -(CH2) m OC(O) (unsubstituted C1-C6 alkyl), each m is independently 1, 2, 3, or 4; or (ii)R 9 is -C(O)O(CH2) p NMe2, -C(O)O(CH2) p NHMe, -C(O)OCH2CH(OH)CH2OH, -C(O)OCH2CH2CMe2OH, or -C(O)OCH2CH2SO2Me, and each p is independently 2, 3, 4, 5, or 6. [Linker] has the formula: R 14 -R 15 -R 16 -R17 -R 18 [In the formula, R 14 Ha-C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 1-6 Alkyl-N(C 1-6 alkyl)-, -C(O)-, -SO2- or absent; R 15 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 Alkyl-NH-, -C 1-6 Alkyl-N(C 1-6 alkyl)-, -cycloalkyl-NH-, -heterocycloalkyl-NH- or absent; R 16 Ha-C 1-6 Alkyl, -C(O)-, -C(O)-C 1-6 alkyl-, —C(O)—NH—, —C(O)O—, —CH—C(O)—, —CH—C(O)—NH—, —CH—C(O)O— or absent; R 17 -CH2(C2H4-O) y , -(CHO) x , -(C2H4-O) x , -(C3H6-O) x , or absent, x is 1 to 10, y is between 2 and 10; R 18 Ha-C 1-6 Alkyl, -C 1-6 alkyl-C(O)-, cycloalkyl, -CH2-NH-C(O)-, heterocycloalkyl, or absent; R 14 ~R 18 At least one of the following is present] The compound, or a salt, solvate, hydrate, or isomer thereof, is provided.

[0085] In some embodiments of the third aspect, unless otherwise specified, each alkyl group, alkenyl group, alkynyl group, aryl group, heteroaryl group, and benzyl group is unsubstituted.

[0086] In some embodiments of the third aspect, when Z 1 is S in formula (Vb), Y 5 is not —C—NHC(O)R″″ or —C(O)OR″″.

[0087] In some embodiments of the third aspect, Z is NR 6 is.

[0088] In some embodiments of the third aspect, each R is independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, —NH2, —NHR″″, —NR″″2, —NR″″C(O)R″″, —NR″″C(O)CH(OH)R″″, —NR″″C(O)OR″″, —NR″″S02R″″, —NO2, —C N, -C(O)R'''', -C(O)OR'''', -C(O)NH2, -C(O)NHR'''', -C(O)NR''''2, -OR'''', -OC(O)R'''', -OC(O)OR'''', -OC(O)NH2, -OC(O)NHR'''', -OC(O)NR''''2, -SR'''', or -S(O)2R'''', -S(O)2OR'''', -S(O)2NH2, -S(O)2NHR'''', -S(O)2NR''''2, -OR 21 , -NH-R 21 , -C(O)-NH-R 21 , or -CH2-NH-C(O)-R 21 is.

[0089] In some embodiments of the third aspect, R 1 is hydrogen.

[0090] In some embodiments of the third aspect, R 6 is hydrogen.

[0091] In some embodiments of the third aspect, the [ligase ligand moiety] is of formula (Va), and Y5, Y6, and Y7 are each CR 7 In some such embodiments, Y5 is -C-NHC(O)R'''', Y6 is CH, and Y7 is CH or CCl. In some such embodiments, L3 is hydrogen, Z1 is S, and R 1 is hydrogen, T is C=O, and Y7 is CH.

[0092] In some embodiments of the third aspect, the compound is of Formula (Vb), and Y5, Y6, and Y8 are each CR 7 In some such embodiments, L3 is hydrogen, Z1 is S, R 1 is H, T is C=O, Y5 is CH, C-OR'', CCl, C-CN, or C-NHC(O)R'', Y6 is CH, CCl, C-alkyl, C-cycloalkyl, or C-haloalkyl; Y8 is CH, C-OR'''', C-NHC(O)R'''', C-NHC(O)OR'''', C-NHR'''', C-NH2, or C-NHSO2R'''', When Y5 is CCl, Y6 is CH, C-alkyl, C-cycloalkyl, or C-haloalkyl. In some such embodiments, each R"" is independently alkyl, cycloalkyl, aryl, or benzyl. In some embodiments, Y5 is CH, Y6 is CH or CCl, and Y8 is C-OR"" or C-NH2, and may be C-OMe or C-NH2.

[0093] In some embodiments of the third aspect, Z is NR 2 In other embodiments, Z is S.

[0094] In some embodiments of the third aspect, each [ka] is a double bond.

[0095] In some embodiments of the third aspect, L is hydrogen.

[0096] In some embodiments of the third aspect, one of W1, W2, W3, and W4 is N, and the remaining three of W1, W2, W3, and W4 are each CR a In some such embodiments, W4 is CR a is.

[0097] In some embodiments of the third aspect, two of W1, W2, W3, and W4 are N, and the remaining two of W1, W2, W3, and W4 are each CR a is.

[0098] In some embodiments of the third aspect, one of W1, W2, W3, and W4 is CR a and the remaining three of W1, W2, W3 and W4 are each N.

[0099] In some embodiments of the third aspect, each R is independently hydrogen, halogen, or —NR h C(O)R h is.

[0100] According to a fourth aspect of the present invention, there is provided a compound of formula (I) [MCL-1 ligand prodrug moiety]-[linker]-[ligase ligand moiety] (I) or a salt, solvate, hydrate or isomer thereof, wherein [ligase ligand moiety] is: (a) Formula (VIa) or (VIb) [ka] (VIa) (VIb) [In the formula, M is O, S, or NH, or absent; [ka] is the R of the linker 18 shows the bond with R 22 is hydrogen, halogen, -OMe, amino, heterocycloalkyl, or unsubstituted C1-C6 alkyl; L' is hydrogen, alkyl, benzyl, acetyl, or pivaloyl. (b) Formula (II) [ka] [In the formula, Each of X1 and X2 is independently O or S; T is C=O or SO2, R 1 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; n is 0, 1 or 2; L4 is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)H, -C(O)R b , -C(O)OH, -C(O)OR b , -C(O)NH2, -C(O)NHR b , -C(O)NR b 2, -OH, -OR b , -NH2, -NHR b , -NR b 2. -S(O)2H or -S(O)2R b and R y is selected from the following: [ka] During the ceremony, [ka] indicates binding to T, Z3 is O, S, or NR 3 and U is O, S, NR b or CR i 2, Each of Y1, Y2 and Y3 independently represents N or CR d and Each R d are independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR b , -NR b 2. -NHC(O)R b , -NR b C(O)R b , NHC(O)CH(OH)R b , -NR b C(O)CH(OH)R b , -NHC(O)OR b , -NR b C(O)OR b , -NHSO2R b , -NR b SO2R b , -NO2, -CN, -C(O)H, C(O)R b , -C(O)OH, -C(O)OR b , -C(O)NH2, -C(O)NHR b , -C(O)NR b 2, -OH, -OR b , -OC(O)H, -OC(O)R b , -OC(O)OH, -OC(O)OR b , -OC(O)NH2, -OC(O)NHR b , -OC(O)NR b 2, -SH, -SR b , -S(O)2H, -S(O)2R b , -S(O)2OH, -S(O)2OR b , -S(O)2NH2, -S(O)2NHR b , -S(O)NR b 2, -OR 21 , -NH-R 21 , -C(O)-NH-R 21 , or -CH2-NH-C(O)-R21 and Each R i are independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR b , -NR b 2. -NHC(O)R b , -NR b C(O)R b , -NHC(O)CH(OH)R b , -NR b C(O)CH(OH)R b , -NHC(O)OR b , -NR b C(O)OR b , -NHSO2R b , -NR b SO2R b , -NO2, -CN, -C(O)H, C(O)R b , -C(O)OH, -C(O)OR b , -C(O)NH2, -C(O)NHR b , -C(O)NR b 2, -OH, -OR b , -OC(O)H, -OC(O)R b , -OC(O)OH, -OC(O)OR b , -OC(O)NH2, -OC(O)NHR b , -OC(O)NR b 2, -SH, -SR b , -S(O)2H, -S(O)2R b , -S(O)2OH, -S(O)2OR b , -S(O)2NH2, -S(O)2NHR b , or -S(O)NR b 2, Each R 3 are independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR b , -NR b 2. -NHC(O)R b , -NR b C(O)R b, NHC(O)CH(OH)R b , -NR b C(O)CH(OH)R b , -NHC(O)OR b , -NR b C(O)OR b , -NHSO2R b , -NR b SO2R b , -NO2, -CN, -C(O)H, C(O)R b , -C(O)OH, -C(O)OR b , -C(O)NH2, -C(O)NHR b , -C(O)NR b 2, -OH, -OR b , -OC(O)H, -OC(O)R b , -OC(O)OH, -OC(O)OR b , -OC(O)NH2, -OC(O)NHR b , -OC(O)NR b 2, -SH, -SR b , -S(O)2H, -S(O)2R b , -S(O)2OH, -S(O)2OR b , -S(O)2NH2, -S(O)2NHR b , -S(O)NR b 2, -R 21 , -C(O)-NH-R 21 , or -CH2-NH-C(O)-R 21 and Each R b is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; R 21 is the R of the linker 18 and formula (II) is a bond connecting to a single R 21 Including, During the ceremony, (i)R y but [ka] If Y2 is CR d and (ii)R y but [ka] If CR i R of 2 i is not hydrogen] or (c) Formula (III) [ka] [In the formula, Each of X1 and X2 is independently O or S; T is C=O or SO2, R 1 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; n is 0, 1 or 2; L1 is hydrogen, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)H, -C(O)R b , -C(O)OH, -C(O)OR b , -CH2C(O)OR b , -C(O)NH2, -C(O)NHR b , -C(O)NR b 2, -OH, -OR b , -NH2, -NHR b , -NR b 2. -S(O)2H or -S(O)2R b and R x is selected from the following: [ka] During the ceremony, [ka] indicates binding to T, Z4 is O, S, or NR 4 and V is CR f 2. NR 4 Or S, G1, G2, G3 and G4 are each independently N or CR c and Each of Y1 and Y2 is independently N or CR f and Each R f are independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, fused aryl-cycloalkyl, fused aryl-heterocycloalkyl, heteroaryl, heteroaryl substituted with at least one aryl group, benzyl, haloalkyl, haloalkenyl, -NH, -NHR b , -NR b 2. -NHC(O)R b , -NR b C(O)R b , -NHC(O)CH(OH)R b , -NR b C(O)CH(OH)R b , -NHC(O)OR b , -NR b C(O)OR b , -NHSO2R b , -NR b SO2R b , -NO2, -CN, -C(O)H, -C(O)R b , -C(O)OH, -C(O)OR b , -C(O)NH2, -C(O)NHR b , -C(O)NR b 2, -OH, -OR b , -OC(O)H, -OC(O)R b , -OC(O)OH, -OC(O)OR b , -OC(O)NH2, -OC(O)NHR b , -OC(O)NR b 2, -SH, -SR b , -S(O)2H, -S(O)2R b , -S(O)2OH, -S(O)2OR b , -S(O)2NH2, -S(O)2NHR b , -S(O)NR b 2, -R 21 , -OR 21 , -NH-R 21 , -C(O)-NH-R21 , or -CH2-NH-C(O)-R 21 Or Y1 and Y2 are CR f If R f forms a 5- or 6-membered ring together with the carbon atom to which it is attached, Each R c are independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, at least one -OR b substituted aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR b , -NR b 2, -CH2NH2, -NHC(O)R b , -NR b C(O)R b , -NHC(O)CH(OH)R b , -NR b C(O)CH(OH)R b , -NHC(O)OR b , -NR b C(O)OR b , -NHSO2R b , -NR b SO2R b , -NO2, -CN, -C(O)H, -C(O)R b , -C(O)OR b , -C(O)NH2, -C(O)NHR b , -C(O)NR b 2, -OH, -OR b , -OC(O)H, -OC(O)R b , -OC(O)OH, -OC(O)OR b , -OC(O)NH2, -OC(O)NHR b , -OC(O)NR b 2, -SH, -SR b , -S(O)2H, -S(O)2R b , -S(O)2OH, -S(O)2OR b , -S(O)2NH2, -S(O)2NHR b , -S(O)NR b 2, -OR 21 , -NH-R 21 , -C(O)-NH-R21 , or -CH2-NH-C(O)-R 21 and Each R 4 are independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)H, C(O)R b , -C(O)OH, -C(O)OR b , -C(O)NH2, -C(O)NHR b , -C(O)NR b 2, -OH, -OR b , -NH2, -NHR b , -NR b 2, -S(O)2H, -S(O)2R b , -R 21 , -C(O)-NH-R 21 , or -CH2-NH-C(O)-R 21 and Each R b is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; R 21 is the R of the linker 18 and formula (III) is a bond connecting to a single R 21 Including, n=2, and each R c is hydrogen, and each of G1, G2, G3 and G4 is CR c When C=X1 is optionally replaced by CH, During the ceremony, (i)R x but [ka] and when Z4 is NH, L1 is hydrogen, -CH2C(O)OR b , or -OR b and (ii)R x but [ka] and Z4 is NR4 and Y1 is CR f and when Y2 is N, R 4 is not an alkyl, but R 2 and at least one of R is not H; (iii)R x but [ka] and Z4 is NR 4 and Y1 and Y2 are CR f then at least one of G1, G2 and G3 is N; (iv) Z4 is NR 4 and Y1 and Y2 are CR f If R x teeth [ka] Instead, (v)R x but [ka] and Z4 is NR 4 and when Y1 or Y2 is N, R 4 is not an alkyl, (vi)R x but [ka] where n=1 or 2, (vii)R x but [ka] If Z4=O or S, [MCL-1 ligand prodrug moiety] is a compound of formula (A1), (A2), (A3) or (A4), [ka] (A1) (A2) (A3) JPEG2025540250000105.jpg33170(A4) [In the formula, [ka] is a single or double bond, Each Z2 is independently N or C, and when Z2 is N, [ka] is a single bond, and when Z2 is C, [ka] is a double bond, Each R 11 are independently H, halogen, or C1-C6 alkyl; R 8 is a C1-C6 alkyl substituted with piperazine; In each of formula (A1) and formula (A4), R 10 and R 30 One side is H and the other side is R 10 and R 30 The other is -C 2-5 Alkyl-OR 13 , -OC 2-5 Alkyl-R 13 or -C 2-5 Alkyl-NMe-R 13 where R 13 is phenyl, naphthyl, or tetralin, wherein the phenyl, naphthyl, or tetralin is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl, and —O(C1-C6 alkyl), or the tetralin is optionally substituted with a bridging —CH2— group, or the naphthyl is optionally substituted with —O— or —S—; R 12 is as follows: [ka] R 31 Ha-C 2-5 Alkyl-OR 13, -OC 2-5 Alkyl-R 13 or -C 2-5 Alkyl-NMe-R 13 where R 13 is phenyl, naphthyl, or tetralin, wherein the phenyl, naphthyl, or tetralin is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl, and —O(C1-C6 alkyl), or the tetralin is optionally substituted with a bridging —CH2— group, or the naphthyl is optionally substituted with —O— or —S—; Each R 32 is independently H, [ka] and Each R 33 is independently R 19 or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with morpholine or piperazine; R 20 are Me, -CH2-OMe, -(CH2CH2O) p (C1-C6 alkyl), or —CH2—O-bromobenzaldehyde, where p is 1 to 5; R 34 is C 2-5 Alkyl-OR 13 or -OC 2-5 Alkyl-R 13 where R 13 is phenyl, naphthyl, or tetralin, wherein the phenyl, naphthyl, or tetralin is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl, and —O(C1-C6 alkyl), or the tetralin is optionally substituted with a bridging —CH2— group, or the naphthyl is optionally substituted with —O— or —S—; R 35 is as follows: [ka] R 19 is the R of the linker14 and each of formula (A1), formula (A2), formula (A3) and formula (A4) is a bond connected to a single R 19 Including, (i)R 9 is -C(O)O(C1-C6 alkyl), -C(O)Ocycloalkyl, -C(O)Oheterocycloalkyl, -C(O)Oaryl or -P(O)(OR p )2, and the C1-C6 alkyl is -OC(O)(unsubstituted C1-C6 alkyl), -OC(O)(at least one R 10 C1-C6 alkyl substituted with), -OC(O)cycloalkyl, -OC(O)heterocycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, -OC(O)(CH2) m O(CH2) m O(unsubstituted C1-C6 alkyl), -OC(O)(CH2) m O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(unsubstituted C1-C6 alkyl), -OC(O)O(at least one R 10 C1-C6 alkyl substituted with -OC(O)Ocycloalkyl, -OC(O)O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2CH2O) m (C1-C6 alkyl substituted with OP(O)(OH)2), -OC(O)O(CH2CH2S) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)(unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)2 (unsubstituted C1-C6 alkyl), -OC(O)NH (C1-C6 alkyl substituted with OMe), -OC(O)NMe (C1-C6 alkyl substituted with OMe), -P(O)(OH)2, -OP(O)(OH)2, -C(O)heterocycloalkyl, -C(O)N(unsubstituted C1-C6 alkyl)2, heteroaryl, heterocycloalkyl, -S(unsubstituted C1-C6 alkyl), -S(O)(unsubstituted C1-C6 alkyl), -N + (unsubstituted C1-C6 alkyl)3, -N +substituted with one or more groups selected from (unsubstituted C1-C6 alkyl)cycloalkyl, N-(unsubstituted C1-C6 alkyl)piperidinium cation, N-(unsubstituted C1-C6 alkyl)morpholinium cation, and N-(unsubstituted C1-C6 alkyl)imidazolium cation; Each R 10 are independently -OH, -O(unsubstituted C-C alkyl), -Obn, -NH, -Nme, -NHC(O)(unsubstituted C-C alkyl), -NHC(O)O(unsubstituted C-C alkyl), heterocycloalkyl, heteroaryl, aryl, -C(O)Nme; Each R p are independently -(CH2) m OC(O) (unsubstituted C1-C6 alkyl), each m is independently 1, 2, 3, or 4; or (ii)R 9 is -C(O)O(CH2) p Nme2, -C(O)O(CH2) p NHMe, -C(O)OCH2CH(OH)CH2OH, -C(O)OCH2CH2CMe2OH, or -C(O)OCH2CH2SO2Me, and each p is independently 2, 3, 4, 5, or 6. [Linker] has the formula: R 14 -R 15 -R 16 -R 17 -R 18 [In the formula, R 14 Ha-C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, C 1-6 Alkyl-N(C 1-6 alkyl)-, -C(O)-, -SO2- or absent; R 15 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 Alkyl-NH-, -C 1-6 Alkyl-N(C 1-6alkyl)-, -cycloalkyl-NH-, -heterocycloalkyl-NH- or absent; R 16 Ha-C 1-6 Alkyl, -C(O)-, -C(O)-C 1-6 alkyl-, —C(O)—NH—, —C(O)O—, —CH—C(O)—, —CH—C(O)—NH—, —CH—C(O)O— or absent; R 17 -CH2(C2H4-O) y , -(CHO) x , -(C2H4-O) x , -(C3H6-O) x , or absent, x is 1 to 10, y is between 2 and 10; R 18 Ha-C 1-6 Alkyl, -C 1-6 alkyl-C(O)-, cycloalkyl, -CH2-NH-C(O)-, heterocycloalkyl, or absent; R 14 ~R 18 At least one of the following is present] The compound, or a salt, solvate, hydrate, or isomer thereof, is provided.

[0101] In some embodiments of the fourth aspect, unless otherwise specified, each alkyl, alkenyl, alkynyl, aryl, heteroaryl, and benzyl is unsubstituted.

[0102] In some embodiments of the fourth aspect, in Formula (III): Each of X1 and X2 is O; T is C=O, R 1 is hydrogen, L1 is hydrogen, R x teeth [ka] and The Z4 is NR4 and Each of G1, G2 and G4 is CR c and Y1 is N, Y2 is CR f and R f is not hydrogen.

[0103] In some embodiments of the fourth aspect, the [ligase ligand moiety] has formula (III): [ka] is.

[0104] In some embodiments of the fourth aspect, R c One of them is -OR 21 , -NH-R 21 , -C(O)-NH-R 21 , or -CH2-NH-C(O)-R 21 In another embodiment, G1 is COR 21 , C-NH-R 21 , CC(O)-NH-R 21 , or C—CH—NH—C(O)—R 21 In another embodiment, G2 is COR 21 , C-NH-R 21 , CC(O)-NH-R 21 , or C—CH—NH—C(O)—R 21 In another embodiment, R 4 is R 21 , -C(O)-NH-R 21 , or -CH2-NH-C(O)-R 21 In another embodiment, R f One of them is -R 21 , -OR 21 , -NH-R 21 , -C(O)-NH-R 21 , or -CH2-NH-C(O)-R 21 is.

[0105] In some embodiments of the fourth aspect, Y2 is CR21 , CO-R 21 , C-NH-R 21 , CC(O)-NH-R 21 , or C—CH—NH—C(O)—R 21 is.

[0106] In some embodiments of the fourth aspect, the ligase ligand moiety is selected from: [ka] JPEG2025540250000115.jpg177170

[0107] In some embodiments of the fourth aspect, the ligase ligand moiety is selected from: [ka] JPEG2025540250000117.jpg144170

[0108] In some embodiments of the fourth aspect, the [ligase ligand moiety] is: [ka]

[0109] In some embodiments of the fourth aspect, the [ligase ligand moiety] is: [ka]

[0110] In some embodiments of any of the second, third, and fourth aspects, R 16 Ha-C 1-6 alkyl, —C(O)—, —C(O)—NH—, —C(O)O—, —CH—C(O)—, —CH—C(O)—NH—, —CH—C(O)O— or absent; R 17-CH2(C2H4-O) y , -(C2H4-O) x , -(C3H6-O) x , or absent, R 18 Ha-C 1-6 It is alkyl, cycloalkyl, -CH2-NH-C(O)-, heterocycloalkyl, or absent.

[0111] In some embodiments of any of the second, third, and fourth aspects, R 14 Ha-C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 alkynyl, —C(O)—, —SO—, or absent. In some embodiments, R 14 Ha-C 1-6 It is alkyl.

[0112] In some embodiments of the second, third and fourth aspects, R 15 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 In some such embodiments, R 15 is heterocycloalkyl. In some such embodiments, R 15 are piperazine, bridged piperazine, piperazine N-oxide, piperazine cation, [ka] and During the ceremony, [ka] is R 14 shows the bond with [ka] is R 16 In some such embodiments, R 15 is piperazine or [ka] In another embodiment, R 15 is absent.

[0113] In some embodiments of the second, third and fourth aspects, R 16 is C 1-6 alkyl, —CH—C(O)—NH—, or —C(O)—. In some such embodiments, R 16 Ha-C 1-6 It is alkyl or -C(O)-.

[0114] In some embodiments of any of the second, third, and fourth aspects, R 17 is absent.

[0115] In some embodiments of any of the second, third, and fourth aspects, R 18 Ha-C 1-6 In some such embodiments, R is alkyl, heterocycloalkyl, or absent. 18 Ha-C 1-6 In some such embodiments, R 18 Ha-C 1-6 alkyl or piperazine. In other embodiments, R 18 is absent.

[0116] In some embodiments of any of the second, third, and fourth aspects, [linker] is selected from: [ka] [In the formula, [ka] indicates binding to the [MCL-1 ligand prodrug moiety], [ka] indicates binding to [ligase ligand moiety]]

[0117] In some embodiments of any of the second, third, and fourth aspects, in each of Formula (A1) and Formula (A4), R 10 and R 30 One side is H and the other side is R 10 and R 30 The other is -C 2-5 Alkyl-OR 13 or -OC 2-5 Alkyl-R 13 where R 13 is phenyl or naphthyl, and the phenyl or naphthyl may be substituted with at least one substituent selected from halogen and C1-C6 alkyl.

[0118] In some embodiments of any of the second, third, and fourth aspects, in formula (A1), R 12 is as follows: [ka]

[0119] In some embodiments of any of the second, third, and fourth aspects, in formula (A4), R 35 is as follows: [ka]

[0120] In some embodiments of any of the second, third, and fourth aspects, in formula (A2), R 31 Ha-C 2-5 Alkyl-OR 13 or -OC 2-5 Alkyl-R 13 where R 13 is phenyl or naphthyl, and the phenyl or naphthyl may be substituted with at least one substituent selected from halogen and C1-C6 alkyl.

[0121] In some embodiments of any of the second, third, and fourth aspects, in formula (A3), R 34 Ha-C 2-5 Alkyl-OR 13 or -OC 2-5 Alkyl-R 13 where R 13 is phenyl or naphthyl, and the phenyl or naphthyl may be substituted with at least one substituent selected from halogen and C1-C6 alkyl.

[0122] In some embodiments of any of the second, third, and fourth aspects, Z2 is C; [ka] is a double bond.

[0123] In some embodiments of any of the second, third and fourth aspects, the [MCL-1 ligand prodrug moiety] is: [ka] [In the formula, R 11 is a halogen, R 13a is a halogen, R 20 is Me, -CH2-OMe, or -(CH2CH2O) p (C1-C6 alkyl), and p is 1 to 5.

[0124] In some embodiments of any of the second, third, and fourth aspects, R 9 is -C(O)O(C1-C6 alkyl), -C(O)Ocycloalkyl, -C(O)Oheterocycloalkyl, -C(O)Oaryl or -P(O)(OR p )2, and the C1-C6 alkyl is -OC(O)(unsubstituted C1-C6 alkyl), -OC(O)(at least one R 10C1-C6 alkyl substituted with), -OC(O)cycloalkyl, -OC(O)heterocycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, -OC(O)(CH2) m O(CH2) m O(unsubstituted C1-C6 alkyl), -OC(O)(CH2) m O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(unsubstituted C1-C6 alkyl), -OC(O)O(at least one R 10 C1-C6 alkyl substituted with -OC(O)Ocycloalkyl, -OC(O)O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2CH2O) m (C1-C6 alkyl substituted with OP(O)(OH)2), -OC(O)O(CH2CH2S) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)(unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)2 (unsubstituted C1-C6 alkyl), -OC(O)NH (C1-C6 alkyl substituted with OMe), -OC(O)NMe (C1-C6 alkyl substituted with OMe), -P(O)(OH)2, -OP(O)(OH)2, -C(O)heterocycloalkyl, -C(O)N(unsubstituted C1-C6 alkyl)2, heteroaryl, heterocycloalkyl, -S(unsubstituted C1-C6 alkyl), -S(O)(unsubstituted C1-C6 alkyl), -N + (unsubstituted C1-C6 alkyl)3, -N + It is substituted with one or more groups selected from (unsubstituted C1-C6 alkyl)2 cycloalkyl, N-(unsubstituted C1-C6 alkyl) piperidinium cation, N-(unsubstituted C1-C6 alkyl) morpholinium cation, and N-(unsubstituted C1-C6 alkyl) imidazolyl cation.

[0125] In some embodiments of any of the second, third, and fourth aspects, R 9is -C(O)O(C1-C6 alkyl), -C(O)Ocycloalkyl, -C(O)Oheterocycloalkyl, -C(O)Oaryl, or -P(O)(OR p )2, and the C1-C6 alkyl is -OC(O)Me, -OC(O)Et, -OC(O) i Pr, -OC(O)C(CH3)3, -OC(O)CH2OH, -OC(O)CH(CH3)OH, -OC(O)C(CH3)2OH, -OC(O)CH2CH2OH, -OC(O)CH(OH)CHMe2, -OC(O)CH(OH)CH2CHMe2, -OC(O)CH2CH(OH)Me, -OC(O)CH2C(OH)Me2, -OC(O)CH(CH2OH)(NHC(O)Me), -OC(O)CH(NHC(O)Me)(isobutyl), -OC(O)CH(OH)aryl, -OC(O)CH(OH)CH2aryl, -OC(O)heterocycloalkyl, -OC(O)cycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, -OC(O)CH2CH2aryl, -OC(O)CH(NH2) i Pr, -OC(O)CH( i Pr)NHC(O)O tBu, -OC(O)CH2OCH2CH2OMe, -OC(O)CH2(OCH2CH2)2OMe, -OC(O)OMe, -OC(O)OEt, -OC(O)OiPr, -OC(O)Ocycloalkyl, -OC(O)OCH2CH2OEt, -OC(O)O(CH2CH2O )2Et, -OC(O)O(CH2CH2O)3Et, -OC(O)O(CH2CH2O)3CH2CH2OP(O)(OH)2, -OC(O)OCh2CH2SMe, -OC(O)OCH2CH2S(O)Me, -OC(O)OCH2CH2S(O)2Me, -OC(O)OC H2heteroaryl, -OC(O)OCH2heterocycloalkyl, -OC(O)OCH2CH2OCH2aryl, -OC(O)OCH2CH2C(O)NMe2, -OC(O)O(CH2)6NH2, -OC(O)O(CH2)6NMe2, -OC(O)OCH(CHOEt)2, -OC(O)NHCH2CH2OMe, -OC(O)NMeCH2CH2OMe, -SMe, -S(O)Me, -P(O)(OH)2, -OP(O)(OH)2, -C(O)NMe2, -C(O)heterocycloalkyl, heteroaryl, heterocycloalkyl, -N + (Me)3, -N + (Me)2 is substituted with one or more groups selected from cycloalkyl, N-methylmorpholinium cation, N-methylpiperidinium cation, and N-methylimidazolium cation.

[0126] In some embodiments of any of the second, third, and fourth aspects, R 9 is —C(O)O(C1-C6 alkyl), wherein the C1-C6 alkyl is substituted with one or more groups selected from —OC(O)C(CH3)3, —OC(O)CH2CH2OH, —OC(O)C(CH3)2OH, —OC(O)heterocycloalkyl, —OC(O)CHOCH2CH2OMe, —OC(O)OiPr, —OC(O)Ocycloalkyl, —OC(O)O(CH2CHO)2Et, —OP(O)(OH)2, heteroaryl, or heterocycloalkyl. In some such embodiments, R 9is —C(O)O(C1-C6 alkyl), wherein the C1-C6 alkyl is substituted with —OC(O)C(CH3)3. In some embodiments, R 9 is -C(O)OCH2OC(O)C(CH3)3.

[0127] In some embodiments of any of the second, third, and fourth aspects, R 9 -C(O)OCH2OC(O)C(CH3)3, -C(O)OCH2OC(O)Me, -C(O)OCH(Me)OC(O)Me, -C(O)OCH2OC(O)CH2CH2OH, -C(O)OCH2OC(O)C(CH3)2OH, -C(O)OCH2OC(O)piperidine, -C(O)OCH2OC(O)CH2OCH2CH2OMe, -C(O)OCH2OC(O)OiPr, -C(O)OCHMeOC(O)OiPr, -C(O)OCHMeOC(O)Ocyclohe -C(O)OCH2CH2P(O)(OH)2, -C(O)OCH2(N-methylimidazolium cation), -C(O)OCH2(N-methylpiperidinium cation), -C(O)OCH2 dioxolane, -C(O)OCH2CH2 morpholine, -C(O)OCH2CH2 piperazine, -C(O)OCH2CH2CH2 piperazine, or -P(O)(OCH2OC(O)C(CH3)3)2.

[0128] In some embodiments of any of the second, third, and fourth aspects, R 20 is Me or -(CH2CH2O)2Me.

[0129] In some embodiments of any of the second, third, and fourth aspects, R 33 is R 19 In another embodiment, R 33 is a C1-C6 alkyl substituted with morpholine or piperazine.

[0130] In some embodiments of any of the second, third, and fourth aspects, the C1-C6 alkyl substituted with morpholine or piperazine is: [ka]

[0131] In some embodiments of any of the second, third and fourth aspects, the [MCL-1 ligand prodrug moiety] is: [ka]

[0132] In some embodiments of any of the second, third and fourth aspects, the [MCL-1 ligand prodrug moiety] is: [ka]

[0133] In some embodiments of the fourth aspect, the compound is: [ka] compound 70

[0134] In some embodiments of any of the above aspects, T is C=O.

[0135] In some embodiments of any of the above aspects, X1 and X2 are O. In other embodiments, X1 is O and X2 is S. In other embodiments, X1 is S and X2 is O. In other embodiments, X1 and X2 are S.

[0136] In some embodiments of any of the above aspects, n is 0. In other embodiments, n is 1 or 2. In some embodiments, n is 1. In other embodiments, n is 2.

[0137] According to a fifth aspect of the present invention there is provided a pharmaceutical composition comprising a compound of any embodiment of any one of the first, second, third or fourth aspects.

[0138] According to a sixth aspect of the invention there is provided a compound of any embodiment of any one of the first, second, third or fourth aspects or a pharmaceutical composition of the fifth aspect for use in medicine.

[0139] According to a seventh aspect of the present invention, there is provided a compound of any embodiment of any one of the first, second, third, or fourth aspects or a pharmaceutical composition of the fifth aspect for use in treating cancer. In some embodiments, the cancer is selected from breast cancer, triple-negative breast cancer, colon cancer, pancreatic cancer, skin cancer, melanoma, ovarian cancer, kidney cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, lymphoma, non-Hodgkin's lymphoma, multiple myeloma, cervical cancer, leukemia, chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), bladder cancer, and prostate cancer. In certain embodiments, the cancer is multiple myeloma or acute myeloid leukemia.

[0140] According to an eighth aspect of the present invention, there is provided a method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of the first, second, third, or fourth aspects or a pharmaceutical composition of the fifth aspect. In some embodiments, the cancer is selected from breast cancer, triple-negative breast cancer, colon cancer, pancreatic cancer, skin cancer, melanoma, ovarian cancer, kidney cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, lymphoma, non-Hodgkin's lymphoma, multiple myeloma, cervical cancer, leukemia, chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), bladder cancer, and prostate cancer. In certain embodiments, the cancer is multiple myeloma or acute myeloid leukemia.

[0141] In some embodiments of the eighth aspect, the administration does not result in cytotoxicity in the subject's cardiomyocytes.

[0142] In some embodiments of the eighth aspect, the method further includes administering to the subject at least one additional active agent. In some embodiments, the at least one additional active agent is an anti-cancer agent selected from eribulin; fulvestrant; midostaurin; an immune checkpoint inhibitor selected from an anti-PD-1 antibody, an anti-PD-L1 antibody, and an anti-PD-1 / PD-L1 interaction inhibitor; nivolumab; pembrolizumab; atezolizumab; pidilizumab; carfilzomib; venetoclax; cytarabine; an anthracycline; a taxane compound; and a hypomethylating agent.

[0143] According to a ninth aspect of the invention there is provided a compound of any embodiment of any one of the first, second, third or fourth aspects or a pharmaceutical composition of the fifth aspect for use in reversing resistance to chemotherapy or targeted cancer therapy.

[0144] According to a tenth aspect of the present invention there is provided a method for reversing resistance to chemotherapy or targeted cancer therapy in a subject in need thereof, said method comprising the step of administering to said subject an effective amount of a compound according to any one of claims 1 to 147 or a pharmaceutical composition according to claim 148.

[0145] According to an eleventh aspect of the invention there is provided a combined preparation of a compound of any embodiment of any one of the first, second, third or fourth aspects together with at least one additional active agent for simultaneous, separate or sequential use in therapy.

[0146] In some embodiments of the eleventh aspect, the at least one additional active agent is an anti-cancer agent selected from eribulin; fulvestrant; midostaurin; an immune checkpoint inhibitor selected from an anti-PD-1 antibody, an anti-PD-L1 antibody, and an anti-PD-1 / PD-L1 interaction inhibitor; nivolumab; pembrolizumab; atezolizumab; pidilizumab; carfilzomib; venetoclax; cytarabine; an anthracycline; a taxane compound; and a hypomethylating agent.

[0147] In some embodiments of the eleventh aspect, the therapy is treatment of cancer.

[0148] According to a twelfth aspect of the present invention, there is provided a method of reducing cardiac cytotoxicity of an MCL-1 inhibitor, comprising the step of conjugating a cereblon-binding moiety to an MCL-1 inhibitor, wherein the cereblon-binding moiety is a "ligase ligand moiety" as defined in any embodiment of any one of the first, second, third and fourth aspects, and the MCL-1 inhibitor is an "MCL-1 ligand prodrug moiety" as defined in any embodiment of any one of the first, second, third and fourth aspects.

[0149] As used herein, the term "alkyl" is intended to include both straight-chain and branched alkyl groups, any of which may be unsubstituted or substituted with one or more additional groups. In some embodiments, an alkyl group is an unsubstituted alkyl group. In some embodiments, an alkyl group is an alkyl group selected from the group consisting of -OH, -OR ... W , -NH2, -NHR W , -NR W 2. -SO2R W , -C(O)R W , —CN, and —NO2, wherein each R W is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. In some embodiments, the alkyl group is C-C 12 Alkyl groups, C1-C10 In some embodiments, the alkyl group is a straight-chain alkyl group. In some embodiments, the alkyl group is an unsubstituted straight-chain alkyl group. In some embodiments, the alkyl group is -OH, -OR W , -NH2, -NHR W , -NR W 2. -SO2R W , -C(O)R W , -CN, and -NO2, wherein each R W is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. In some embodiments, the alkyl group is a branched alkyl group. In some embodiments, the alkyl group is an unsubstituted branched alkyl group. In some embodiments, the alkyl group is an -OH, -OR W , -NH2, -NHR W , -NR W 2. -SO2R W , -C(O)R W , —CN, and —NO2, wherein each R W is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.

[0150] As used herein, the term "alkenyl" is intended to include both unsubstituted alkenyl groups and alkenyl groups substituted with one or more additional groups. In some embodiments, an alkenyl group is an unsubstituted alkenyl group. In some embodiments, an alkenyl group is an -OH, -OR W , -NH2, -NHR W , -NR W 2. -SO2R W , -C(O)R W, —CN, and —NO2, wherein each R W is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. In some embodiments, the alkenyl group is C-C 12 Alkenyl groups, C2-C 10 In some embodiments, the alkenyl group is a straight-chain alkenyl group. In some embodiments, the alkenyl group is an unsubstituted straight-chain alkenyl group. In some embodiments, the alkenyl group is an -OH, -OR W , -NH2, -NHR W , -NR W 2. -SO2R W , -C(O)R W , -CN, and -NO2, wherein each R W is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. In some embodiments, the alkenyl group is a branched alkenyl group. In some embodiments, the alkenyl group is an unsubstituted branched alkenyl group. In some embodiments, the alkenyl group is an -OH, -OR W , -NH2, -NHR W , -NR W 2. -SO2R W , -C(O)R W , —CN, and —NO2, wherein each R W is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.

[0151] As used herein, the term "alkynyl" is intended to include both unsubstituted alkynyl groups and alkynyl groups substituted with one or more additional groups. In some embodiments, an alkynyl group is an unsubstituted alkynyl group. In some embodiments, an alkynyl group is an alkynyl group selected from the group consisting of -OH, -OR, -O, -O- ... W , -NH2, -NHR W , -NR W 2. -SO2R W , -C(O)R W , —CN, and —NO2, wherein each R W is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. In some embodiments, the alkynyl group is C-C 12 Alkynyl groups, C2-C 10 In some embodiments, the alkynyl group is a straight-chain alkynyl group. In some embodiments, the alkynyl group is an unsubstituted straight-chain alkynyl group. In some embodiments, the alkynyl group is an -OH, -OR W , -NH2, -NHR W , -NR W 2. -SO2R W , -C(O)R W , -CN, and -NO2, wherein each R W is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. In some embodiments, the alkynyl group is a branched alkynyl group. In some embodiments, the alkynyl group is an unsubstituted branched alkynyl group. In some embodiments, the alkynyl group is an -OH, -OR W , -NH2, -NHR W , -NR W 2. -SO2R W , -C(O)R W, -CN, and -NO2, wherein each R W is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.

[0152] As used herein, the term "cycloalkyl" is intended to include both unsubstituted cycloalkyl groups and cycloalkyl groups substituted with one or more additional groups. The term "cycloalkyl" is also intended to include monocyclic and bicyclic ring systems, including spirocyclic ring systems in which two rings share a single atom, fused bicyclic ring systems in which two rings share two adjacent atoms, and bridged bicyclic ring systems in which two rings share three or more atoms. In some embodiments, a cycloalkyl group is an unsubstituted cycloalkyl group. In some embodiments, a cycloalkyl group is selected from the group consisting of -OH, -OR, -O, -O- ... W , -NH2, -NHR W , -NR W 2. -SO2R W , -C(O)R W , —CN, and —NO2, wherein each R W is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. In some embodiments, the cycloalkyl group is C-C 12 Cycloalkyl groups, C4-C 12 Cycloalkyl groups, C5-C 12 Cycloalkyl groups, C3-C 10 Cycloalkyl groups, C4-C 10 Cycloalkyl groups, C5-C 10 cycloalkyl group, a C3-C8 cycloalkyl group, a C4-C8 cycloalkyl group, a C5-C8 cycloalkyl group, a C3-C6 cycloalkyl group, a C4-C6 cycloalkyl group, a C5-C6 cycloalkyl group, a C3-C4 cycloalkyl group, or a C4-C5 cycloalkyl group.

[0153] As used herein, the term "cycloalkenyl" is intended to include both unsubstituted cycloalkenyl groups and cycloalkenyl groups substituted with one or more additional groups. In some embodiments, a cycloalkenyl group is an unsubstituted cycloalkenyl group. In some embodiments, a cycloalkenyl group is selected from the group consisting of -OH, -OR, -O, -O- ... W , -NH2, -NHR W , -NR W 2. -SO2R W , -C(O)R W , —CN, and —NO2, wherein each R W is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. In some embodiments, the cycloalkenyl group is C-C 12 Cycloalkenyl groups, C5-C 12 Cycloalkenyl group, C4-C 10 Cycloalkenyl groups, C5-C 10 It is a cycloalkenyl group, a C4-C8 cycloalkenyl group, a C5-C8 cycloalkenyl group, a C4-C6 cycloalkenyl group, a C5-C6 cycloalkenyl group, or a C4-C5 cycloalkenyl group.

[0154] As used herein, the term "heterocycloalkyl" is intended to include both unsubstituted heterocycloalkyl groups and heterocycloalkyl groups substituted with one or more additional groups. The term "heterocycloalkyl" is also intended to include monocyclic and bicyclic ring systems, including spirocyclic ring systems in which two rings share a single atom, fused bicyclic ring systems in which two rings share two adjacent atoms, and bridged bicyclic ring systems in which two rings share three or more atoms. In some embodiments, a heterocycloalkyl group is a monocyclic ring system, a spirocyclic ring system, or a fused bicyclic ring system. In some embodiments, a heterocycloalkyl group is an unsubstituted heterocycloalkyl group. In some embodiments, a heterocycloalkyl group is an -R W , -OH, -ORW , -NH2, -NHR W , -NR W 2. -SO2R W , -C(O)R W , —CN, and —NO2, wherein each R W is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. In some embodiments, one or more -CH2- groups of the heterocycloalkyl ring may be replaced with a -C(O)- group. In some embodiments, the heterocycloalkyl group is a C3-C 12 Heterocycloalkyl groups, C4-C 12 Heterocycloalkyl groups, C5-C 12 Heterocycloalkyl groups, C3-C 10 Heterocycloalkyl groups, C4-C 10 Heterocycloalkyl groups, C5-C 10 heterocycloalkyl group, a C3-C8 heterocycloalkyl group, a C4-C8 heterocycloalkyl group, a C5-C8 heterocycloalkyl group, a C3-C6 heterocycloalkyl group, a C4-C6 heterocycloalkyl group, a C5-C6 heterocycloalkyl group, a C3-C4 heterocycloalkyl group, or a C4-C5 heterocycloalkyl group.

[0155] As used herein, the term "aryl" is intended to include both unsubstituted aryl groups and aryl groups substituted with one or more additional groups. In some embodiments, an aryl group is an unsubstituted aryl group. In some embodiments, an aryl group is an aryl group selected from the group consisting of -OH, -OR, -O, -O- ... W , -NH2, -NHR W , -NR W 2. -SO2R W , -C(O)R W , -OC(O)R W , —CN, and —NO2, wherein each R Wis unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. In some embodiments, the aryl group is C-C 10 aryl, C6-C8 aryl, or C6 aryl.

[0156] As used herein, the term "heteroaryl" is intended to include both unsubstituted heteroaryl groups and heteroaryl groups substituted with one or more additional groups. In some embodiments, a heteroaryl group is an unsubstituted heteroaryl group. In some embodiments, a heteroaryl group is an -OH, -OR W , -NH2, -NHR W , -NR W 2. -SO2R W , -C(O)R W , —CN, and —NO2, wherein each R W is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. In some embodiments, one or more -NH- groups on the heteroaryl ring are -NR W In some embodiments, the heteroaryl group may be substituted with a C-C 10 heteroaryl, C6-C9 heteroaryl, C6-C8 heteroaryl, or C6 heteroaryl.

[0157] As used herein, the term "fused heterocycloalkyl-heteroaryl" is intended to mean a bicyclic ring system in which one ring is a heterocycloalkyl ring and the other ring is a heteroaryl ring, and the two rings share two adjacent atoms. The two adjacent atoms shared by the two rings may both be carbon atoms, both heteroatoms (e.g., independently O, N, or S), or one carbon atom and the other a heteroatom (e.g., O, N, or S). The fused heterocycloalkyl-heteroaryl may be unsubstituted or substituted with one or more additional groups. In some embodiments, the fused heterocycloalkyl-heteroaryl group is an unsubstituted cycloalkenyl group. In some embodiments, the fused heterocycloalkyl-heteroaryl group is an -OH, -OR W , -NH2, -NHR W , -NR W 2. -SO2R W , -C(O)R W , —CN, and —NO2, wherein each R W is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.

[0158] As used herein, the term "benzyl" is intended to include both unsubstituted benzyl groups and benzyl groups substituted with one or more additional groups. In some embodiments, a benzyl group is an unsubstituted benzyl group. In some embodiments, a benzyl group is selected from the group consisting of -OH, -OR, -O, -O- ... W , -NH2, -NHR W , -NR W 2. -SO2R W , -C(O)R W , —CN, and —NO2, wherein each R W is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.

[0159] In some embodiments of any of the above aspects of the invention, all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, and benzyl groups in the compound are unsubstituted. [Brief explanation of the drawings]

[0160] [Figure 1] Figure 1 shows a representative Western blotting membrane demonstrating MCL-1 protein degradation in MV4-11 cells treated for 6 hours with compound 69 of the present invention. Loading control: total protein (SF (stain free) - unstained). [Figure 2] Figure 1 shows a representative Western blot membrane demonstrating MCL-1 protein degradation in MV4-11 cells treated for 6 hours with compounds of WO 2022 / 253713 and compound 41 of the present invention in the presence of an apoptosis inhibitor. Loading control: total protein (SF - unstained). DETAILED DESCRIPTION OF THE INVENTION

[0161] As explained above, the present invention provides compounds of formula (I) [MCL-1 ligand prodrug moiety]-linker-[ligase ligand moiety] (I) or a salt, solvate, hydrate or isomer thereof.

[0162] Prodrugs of bifunctional compounds that bind to ubiquitin ligase and target MCL-1 protein according to the present invention are believed to potentially improve bioavailability, thereby requiring less frequent administration while maintaining favorable efficacy by extending half-life. A reduction in therapeutic dose can also have an impact in terms of reducing side effects and toxicity compared to administration of the drug itself as an active compound. Furthermore, some prodrugs of the present invention can have improved aqueous solubility compared to the active compound.

[0163] Ligase ligand moiety Ligase ligand moiety with a thalidomide-type structure In a first embodiment of the present invention, the [ligase ligand moiety] is: [ka] [In the formula, M is O, S, or NH, or absent; [ka] is the linker R 18 shows the bond with R 22 is hydrogen, halogen, -OMe, an amino group, heterocycloalkyl, or unsubstituted C1-C6 alkyl; R 29 is hydrogen or Me, L' is hydrogen, alkyl, benzyl, acetyl, or pivaloyl.

[0164] In some embodiments of the first aspect of the invention, M is O or NH, or absent.

[0165] In some embodiments of the first aspect of the present invention, R 22 is hydrogen.

[0166] In some embodiments of the first aspect of the present invention, L' is hydrogen or methyl. In some embodiments, L' is hydrogen.

[0167] In some embodiments of the first aspect of the present invention, R 29 is hydrogen.

[0168] In some embodiments of the first aspect of the invention, the [ligase ligand moiety] is: [ka]

[0169] In some embodiments of the first aspect of the invention, the [ligase ligand moiety] is: [ka]

[0170] In some embodiments of the first aspect of the invention, the [ligase ligand moiety] is: [ka]

[0171] In some embodiments of the first aspect of the invention, the [ligase ligand moiety] is: [ka]

[0172] In some embodiments of the first aspect of the invention, the [ligase ligand moiety] is: [ka]

[0173] Examples of such ligase ligand moieties are shown in Table 1 below. [Table 2] JPEG2025540250000143.jpg213170 JPEG2025540250000144.jpg210170 JPEG2025540250000145.jpg149170

[0174] Many of the compounds in Table 1 above are commercially available in the forms shown below. [ka]

[0175] Ligase ligand moieties of formula (IV) and (IVa); formula (VIIa), (VIIb), (VIIc) and (VIId); formula (VIII) and formula (IX) In a second aspect of the invention, the ligase ligand moiety may be of formula (IV) or (IVa); formula (VIIa), (VIIb), (VIIc) or (VIId); or formula (VIII); or formula (IX). The synthesis of a ligase ligand moiety of formula (IV) (defined above) can be summarized as follows: [ka]

[0176] Examples of ligase ligand moieties of formula (IV) and (IVa) are shown in Table 2 below. For example: [ka] can be modified to allow for coupling to [linker] (e.g., by nucleophilic aromatic substitution, or by exchanging the fluorine for a bromine, followed by palladium coupling to attach either [linker] itself or a functional group that can be coupled to [linker]). [Table 3] JPEG2025540250000150.jpg244170 JPEG2025540250000151.jpg37170

[0177] Examples of ligase ligand moieties of formula (VIIa), (VIIb), (VIIc) and (VIId) are shown in Table 3 below. [Table 4] JPEG2025540250000153.jpg30170

[0178] The synthesis of these compounds is summarized in steps 1-4 below.

[0179] Step 1: [ka] To a solution of bromoallene (1 equiv.) in dioxane was added KOAc (2 equiv.), ((1-(tert-butoxy)vinyl)oxy)(tert-butyl)dimethylsilane (4 equiv.), and Pd[P(o-Tol)]Cl (0.2 equiv.) under inert gas, and the reaction mixture was stirred at 130° C. for 48 h. The reaction mixture was filtered through Celite, concentrated under reduced pressure, and purified by flash column chromatography to give the appropriate tert-butyl aryl acetate.

[0180] Step 2: [ka] To a solution of the appropriate tert-butyl 2-(quinolin-3-yl)acetate (1 equivalent) in DMF was added K2CO3 (1 equivalent), benzyltriethylammonium chloride (1 equivalent), and acrylonitrile (1 equivalent), and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water, and the product was extracted with ethyl acetate. The combined organic phases were dried over Na2SO4, concentrated under reduced pressure, and purified by flash column chromatography.

[0181] Step 3: [ka] To an ice-cold solution of the appropriate tert-butyl 4-cyano-2-(quinolin-3-yl)butanoate (1 equiv.) in DMSO was added HO (5 equiv.) and KCO (0.1 equiv.). The reaction mixture was warmed to room temperature and stirred for 16 h. The reaction mixture was diluted with water, and the product was extracted with ethyl acetate. The combined organic phases were dried over NaSO, concentrated under reduced pressure, and purified by flash column chromatography.

[0182] Step 4: [ka] A vial was charged with the appropriate tert-butyl 5-amino-2-(2-methylquinolin-3-yl)-5-oxopentanoate (1 equivalent), p-toluenesulfonic acid (5-10 equivalents), and ACN, and the reaction mixture was stirred for 2-48 hours at 80° C. The mixture was concentrated under reduced pressure and purified by flash column chromatography or preparative HPLC.

[0183] Ligase ligand moieties of formula (Va) and formula (Vb), and formula (IIa) and formula (IIb) In a third aspect of the invention, the [ligase ligand moiety] may be of formula (Va) or (Vb), or may be of formula (IIa) or (IIb). The synthesis of ligase ligand moieties of formula (Va), (Vb), (IIa) and (IIb) (defined above) can be summarized in the following general procedure (carried out under synthesis conditions D, E, F or G shown below): [ka]

[0184] Reaction Scheme 2: General Procedure Synthesis condition D A suitable acid (R in the above reaction scheme) x COOH) (1.1 equiv.), DMAP (0.04 equiv.), and EDC (1.2 equiv.) were added to a solution of 3-aminopiperidine-2,6-dione (1 equiv.) and N-hydroxybenzotriazole (1.2 equiv.) in DMF (0.5 M). The reaction mixture was stirred at room temperature (20-25 °C) overnight. Water (2 × DMF volume) was added, and the resulting solution was extracted with dichloromethane (3 × DMF volume). The combined organic layers were washed with water, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by preparative HPLC or column chromatography.

[0185] Synthesis Condition E A suitable acid (R in the above reaction scheme) xCOOH) (1 eq.) and EDC (1.2 eq.) were added to a solution of 3-aminopiperidine-2,6-dione (hydrochloride, 1.1 eq.), triethylamine (1.2 eq.), and N-hydroxybenzotriazole (1.2 eq.) in DMA (0.5 M). The reaction mixture was stirred overnight at room temperature. Water (2× DMA volumes) was added, and the resulting mixture was extracted with dichloromethane (3× DMA volumes). The combined organic layers were washed with water, dried over Na2SO4, and concentrated under reduced pressure. The crude product was isolated by preparative HPLC or column chromatography.

[0186] Synthesis condition F A suitable acid (R in the above reaction scheme) x To a solution of (COOH) (1 eq.) and HATU (1.5 eq.) in dry DMF was added 3-aminopiperidine-2,6-dione (hydrochloride, 1.2 eq.) and DIPEA (3 eq.). The reaction mixture was stirred at room temperature overnight. The crude product was purified by preparative HPLC or / and preparative TLC.

[0187] Synthesis condition G A suitable acid (R in the above reaction scheme) under an inert atmosphere x To a solution of (COOH) (1 eq.), 3-aminopiperidine-2,6-dione (hydrochloride, 1.2 eq.), and DMAP (0.1 eq.) in dry DMF was added DIPEA (2.2 eq.) and HATU (1.5 eq.) in dry DMF. The reaction mixture was stirred at room temperature overnight. The crude product was purified by preparative HPLC or / and preparative TLC.

[0188] Exemplary Method 1: R x COOH (or its ester R x COOR y ) Chlorination R x Formation of the base NCS (1.1 equiv.) was added to a solution of the appropriate starting material (1 equiv.) in DMF (0.5 M), and the reaction mixture was stirred at room temperature (20-25 °C) for 2 h. The reaction mixture was poured into water (2 × DMF volume), and the resulting precipitate was filtered. The solid was washed with water and dried in vacuo to give the acid ROOH.

[0189] Exemplary Method 2: Synthesis of the Corresponding Ester R x COOR y From R x Synthesis of COOH LiOH (1.1 equiv.) was added to a solution of the appropriate ester (1 equiv.) in a THF:water mixture (3:1 or 5:1, 85 mM), and the resulting mixture was stirred overnight at room temperature (20-25 °C). The mixture was concentrated under reduced pressure, diluted with water, and acidified with concentrated HCl to pH = 2-3. The precipitate was filtered, washed with water, and dried in vacuo to give the target carboxylic acid.

[0190] Exemplary Method 3: R x COOR y Acetylation of R x Formation of the base A mixture of the appropriate amine (1 equiv.), AcO (3 equiv.), and DMAP (0.2 equiv.) in dioxane (0.2 M) was heated to 80 °C for 2 h. Upon completion, the mixture was cooled to room temperature (20-25 °C) and concentrated under reduced pressure. The residue was diluted with water (1 × dioxane volume) and extracted with EtOAc (3 × dioxane volumes). The organic layer was washed with water, brine, dried over NaSO, and evaporated to dryness to afford the acylated product, which was typically used without further purification.

[0191] Examples of ligase ligand moieties of formula (Va) and formula (Vb) are shown below in Table 4. Many of these compounds could be modified to allow for conjugation with [linker] (e.g., via C—H bond activity). [Table 5] JPEG2025540250000160.jpg242170 JPEG2025540250000161.jpg190170

[0192] Examples of ligase ligand moieties of Formula (IIa) and Formula (IIb) are shown below in Table 5. Many of these compounds could be modified to allow for conjugation with [Linker] (e.g., via C—H bond activity). [Table 6] JPEG2025540250000163.jpg74170

[0193] Ligase ligand moieties of formula (VIa) and formula (VIb) In a fourth aspect of the invention, the ligase ligand moiety may be of formula (VIa) or (VIb): [ka] (VIa) (VIb) [In the formula, M is O, S, or NH, or absent; [ka] is the linker R 18 shows the bond with R 22 is hydrogen, halogen, -OMe, an amino group, heterocycloalkyl, or unsubstituted C1-C6 alkyl; L' is hydrogen, alkyl, benzyl, acetyl, or pivaloyl.

[0194] In some embodiments, L' is hydrogen. In some embodiments, M is O. In some embodiments, R 22 is unsubstituted C1-C6 alkyl.

[0195] The synthesis of the ligase ligand moieties of formula (VIa) and (VIb) is provided in the Examples section below.

[0196] Examples of ligase ligand moieties of formula (VIa) and formula (VIb) are shown in Table 6 below: [ka] is the R of the linker 18 This shows the bond with [Table 7] JPEG2025540250000168.jpg32170

[0197] Ligase Ligand Moieties of Formula (II) and Formula (III) In a fourth aspect of the invention, the ligase ligand moiety may alternatively be of formula (II) or formula (III). The synthesis of the ligase ligand moieties of formula (II) and formula (III) (defined above) can be summarized as follows: [ka] Reaction Scheme 1 (R z is R x or R y is)

[0198] Examples of ligase ligand moieties of Formula (II) and Formula (III) are shown below in Table 7. Many of these compounds could be modified to allow for conjugation to [Linker] (e.g., by brominating the aromatic ring and then attaching a functional group that can be attached to either [Linker] itself or to [Linker] via palladium coupling). [Table 8] JPEG2025540250000171.jpg228170 JPEG2025540250000172.jpg232170 JPEG2025540250000173.jpg55170

[0199] Examples of ligase ligand moieties of formula (III) showing attachment to the linker (R 21 is the R of the linker 18 (the bond connecting to the ) are shown in Table 8 below. [Table 9] JPEG2025540250000175.jpg211170 JPEG2025540250000176.jpg135170

[0200] Linker In the first, second, third and fourth aspects of the invention, [linker] has the formula: R 14 -R 15 -R 16 -R 17 -R 18 [In the formula, R 14 Ha-C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 1-6 Alkyl-N(C 1-6 alkyl)-, -C(O)-, -SO2- or absent; R 15 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 Alkyl-NH-, -C 1-6 Alkyl-N(C 1-6 alkyl)-, -cycloalkyl-NH-, -heterocycloalkyl-NH- or absent; R 16 Ha-C 1-6 Alkyl, -C(O)-, -C(O)-C 1-6 alkyl-, —C(O)—NH—, —C(O)O—, —CH—C(O)—, —CH—C(O)—NH—, —CH—C(O)O— or absent; R 17 -CH2(C2H4-O) y , -(CHO) x , -(C2H4-O) x , -(C3H6-O) x , or absent, x is 1 to 10, y is between 2 and 10; R 18 Ha-C 1-6 Alkyl, -C 1-6 alkyl-C(O)-, cycloalkyl, -CH2-NH-C(O)-, heterocycloalkyl, or absent; R 14 ~R 18 At least one of the following is present]

[0201] In some embodiments, R 14 Ha-C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 alkynyl, —C(O)—, —SO—, or absent. In some such embodiments, R 14 Ha-C 1-6 It is alkyl.

[0202] In some embodiments, R 15 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 In some such embodiments, R 15 is heterocycloalkyl or absent. In some embodiments, R 15 is heterocycloalkyl. In some such embodiments, R 15 are piperazine, bridged piperazine, piperazine N-oxide, piperazine cation, [ka] is. [In the formula, [ka] is R 14 shows the bond with [ka] is R 16 ]

[0203] In some embodiments, R 15 is piperazine or [ka] is.

[0204] In some embodiments, R 16Ha-C 1-6 alkyl, —CH—C(O)—NH—, —CH—C(O)—, —C(O)—, or absent. In some embodiments, R 16 is C 1-6 alkyl, -CH-C(O)-NH-, or -C(O)-. In some embodiments, R 16 Ha-C 1-6 It is alkyl or -C(O)-.

[0205] In some embodiments, R 17 is absent.

[0206] In some embodiments, R 18 Ha-C 1-6 In some embodiments, R is alkyl, heterocycloalkyl, or absent. 18 Ha-C 1-6 In some embodiments, R is alkyl or heterocycloalkyl. 18 Ha-C 1-6 It is an alkyl or piperazine.

[0207] In some embodiments, R 14 Ha-C 1-6 Alkyl, -C 1-6 alkyl-N(Me)-, -SO2- or absent; R 15 are piperazine, bridged piperazine, piperazine N-oxide, piperazine cation, [ka] or absent, [In the formula, [ka] is R 14 shows the bond with [ka] is R 16 ] R16 Ha-C 1-6 alkyl, —CH—C(O)—NH—, —CH—C(O)—, —C(O)— or absent; R 17 -CH2(C2H4-O) y , (C2H4-O) x , (C3H6-O) x or absent, x is 1 to 6, and y is 2 to 6; R 18 Ha-C 1-6 Alkyl, piperazine, [ka] or absent, wherein [ka] is R 17 shows the bond with R 14 ~R 18 At least one of the following is present:

[0208] In some embodiments, R 14 Ha-C 1-6 is alkyl, R 15 is piperazine or [ka] and R 16 Ha-C 1-6 alkyl or —C(O)—; R 17 is absent, R 18 Ha-C 1-6 It is an alkyl or piperazine.

[0209] In some embodiments, the linker is selected from: [ka] [In the formula, [ka] indicates binding to the [MCL-1 ligand prodrug moiety], [ka] indicates binding to [ligase ligand moiety]]

[0210] In some embodiments, the linker is selected from: [ka] [In the formula, [ka] indicates binding to the [MCL-1 ligand prodrug moiety], [ka] indicates binding to [ligase ligand moiety]]

[0211] The linkers used in the compounds of the invention can be synthesized according to standard methods.

[0212] Most of the alkyl and polyethylene glycol (PEG) linkers are commercially available or prepared by literature procedures.

[0213] Examples of commercially available linkers include: (2225148-49-0 Sigma Aldrich) [ka] (2140807-17-4 Sigma Aldrich) [ka] (2375194-37-7 Sigma Aldrich) [ka]

[0214] The synthesis of non-commercially available linkers is described in the Examples.

[0215] Linkers containing piperazine modifications were prepared according to the following scheme: [ka]

[0216] MCL-1 ligand prodrug moiety In the first, second, third and fourth aspects of the present invention, the [MCL-1 ligand prodrug moiety] is a compound of formula (A1), (A2), (A3) or (A4). [ka] (A1) (A2) (A3) JPEG2025540250000198.jpg33170(A4) [In the formula, [ka] is a single or double bond, Each Z2 is independently N or C, and when Z2 is N, [ka] is a single bond, and when Z2 is C, [ka] is a double bond, Each R 11 are independently H, halogen, or C1-C6 alkyl; R 8 is a C1-C6 alkyl substituted with piperazine; In each of formula (A1) and formula (A4), R 10 and R30 One side is H and the other side is R 10 and R 30 The other is -C 2-5 Alkyl-OR 13 , -OC 2-5 Alkyl-R 13 or -C 2-5 Alkyl-NMe-R 13 where R 13 is phenyl, naphthyl, or tetralin, wherein the phenyl, naphthyl, or tetralin is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl, and —O(C1-C6 alkyl), or the tetralin is optionally substituted with a bridging —CH2— group, or the naphthyl is optionally substituted with —O— or —S—; R 12 is as follows: [ka] R 31 Ha-C 2-5 Alkyl-OR 13 , -OC 2-5 Alkyl-R 13 or -C 2-5 Alkyl-NMe-R 13 where R 13 is phenyl, naphthyl, or tetralin, wherein the phenyl, naphthyl, or tetralin is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl, and —O(C1-C6 alkyl), or the tetralin is optionally substituted with a bridging —CH2— group, or the naphthyl is optionally substituted with —O— or —S—; Each R 32 is independently H, [ka] and Each R 33 is independently R 19 or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with morpholine or piperazine; R20 are Me, -CH2-OMe, -(CH2CH2O) p (C1-C6 alkyl), or —CH2—O-bromobenzaldehyde, where p is 1 to 5; R 34 is C 2-5 Alkyl-OR 13 or -OC 2-5 Alkyl-R 13 where R 13 is phenyl, naphthyl, or tetralin, wherein the phenyl, naphthyl, or tetralin is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl, and —O(C1-C6 alkyl), or the tetralin is optionally substituted with a bridging —CH2— group, or the naphthyl is optionally substituted with —O— or —S—; R 35 is as follows: [ka] R 19 is the R of the linker 14 and each of formula (A1), formula (A2), formula (A3) and formula (A4) is a bond connected to a single R 19 Including, (i)R 9 is -C(O)O(C1-C6 alkyl), -C(O)Ocycloalkyl, -C(O)Oheterocycloalkyl, -C(O)Oaryl or -P(O)(OR p )2, and the C1-C6 alkyl is -OC(O)(unsubstituted C1-C6 alkyl), -OC(O)(at least one R 10 C1-C6 alkyl substituted with), -OC(O)cycloalkyl, -OC(O)heterocycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, -OC(O)(CH2) m O(CH2) m O(unsubstituted C1-C6 alkyl), -OC(O)(CH2) m O(CH2CH2O) m(unsubstituted C1-C6 alkyl), -OC(O)O(unsubstituted C1-C6 alkyl), -OC(O)O(at least one R 10 C1-C6 alkyl substituted with -OC(O)Ocycloalkyl, -OC(O)O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2CH2O) m (C1-C6 alkyl substituted with OP(O)(OH)2), -OC(O)O(CH2CH2S) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)(unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)2 (unsubstituted C1-C6 alkyl), -OC(O)NH (C1-C6 alkyl substituted with OMe), -OC(O)NMe (C1-C6 alkyl substituted with OMe), -P(O)(OH)2, -OP(O)(OH)2, -C(O)heterocycloalkyl, -C(O)N(unsubstituted C1-C6 alkyl)2, heteroaryl, heterocycloalkyl, -S(unsubstituted C1-C6 alkyl), -S(O)(unsubstituted C1-C6 alkyl), -N + (unsubstituted C1-C6 alkyl)3, -N + substituted with one or more groups selected from (unsubstituted C1-C6 alkyl)cycloalkyl, N-(unsubstituted C1-C6 alkyl)piperidinium cation, N-(unsubstituted C1-C6 alkyl)morpholinium cation, and N-(unsubstituted C1-C6 alkyl)imidazolium cation; Each R 10 are independently -OH, -O(unsubstituted C-C alkyl), -OBn, -NH, -NMe, -NHC(O)(unsubstituted C-C alkyl), -NHC(O)O(unsubstituted C-C alkyl), heterocycloalkyl, heteroaryl, aryl, -C(O)NMe; Each R p are independently -(CH2) m OC(O) (unsubstituted C1-C6 alkyl), each m is independently 1, 2, 3, or 4; or (ii)R 9is -C(O)O(CH2) p NMe2, -C(O)O(CH2) p NHMe, -C(O)OCH2CH(OH)CH2OH, -C(O)OCH2CH2CMe2OH, or -C(O)OCH2CH2SO2Me, and each p is independently 2, 3, 4, 5, or 6.

[0217] In some embodiments, the MCL-1 ligand prodrug moiety is: [ka] [In the formula, R 11 is a halogen, R 13a is a halogen, R 20 is Me, -CH2-OMe, or -(CH2CH2O) p (C1-C6 alkyl), and p is 1 to 5.

[0218] In some embodiments, R 9 is -C(O)O(C1-C6 alkyl), -C(O)Ocycloalkyl, -C(O)Oheterocycloalkyl, -C(O)Oaryl or -P(O)(OR p )2, and the C1-C6 alkyl is -OC(O)(unsubstituted C1-C6 alkyl), -OC(O)(at least one R 10 C1-C6 alkyl substituted with), -OC(O)cycloalkyl, -OC(O)heterocycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, -OC(O)(CH2) m O(CH2) m O(unsubstituted C1-C6 alkyl), -OC(O)(CH2) m O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(unsubstituted C1-C6 alkyl), -OC(O)O(at least one R 10 C1-C6 alkyl substituted with -OC(O)Ocycloalkyl, -OC(O)O(CH2CH2O) m(unsubstituted C1-C6 alkyl), -OC(O)O(CH2CH2O) m (C1-C6 alkyl substituted with OP(O)(OH)2), -OC(O)O(CH2CH2S) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)(unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)2 (unsubstituted C1-C6 alkyl), -OC(O)NH (C1-C6 alkyl substituted with OMe), -OC(O)NMe (C1-C6 alkyl substituted with OMe), -P(O)(OH)2, -OP(O)(OH)2, -C(O)heterocycloalkyl, -C(O)N(unsubstituted C1-C6 alkyl)2, heteroaryl, heterocycloalkyl, -S(unsubstituted C1-C6 alkyl), -S(O)(unsubstituted C1-C6 alkyl), -N + (unsubstituted C1-C6 alkyl)3, -N + It is substituted with one or more groups selected from (unsubstituted C1-C6 alkyl)2 cycloalkyl, N-(unsubstituted C1-C6 alkyl) piperidinium cation, N-(unsubstituted C1-C6 alkyl) morpholinium cation, and N-(unsubstituted C1-C6 alkyl) imidazolyl cation.

[0219] In some such embodiments, R 9 is -C(O)O(C1-C6 alkyl), -C(O)Ocycloalkyl, -C(O)Oheterocycloalkyl, -C(O)Oaryl, or -P(O)(OR p )2, and the C1-C6 alkyl is -OC(O)Me, -OC(O)Et, -OC(O) iPr, -OC(O)C(CH3)3, -OC(O)CH2OH, -OC(O)CH(CH3)OH, -OC(O)C(CH3)2OH, -OC(O)CH2CH2OH, -OC(O)CH(OH)CHMe2, -OC(O)CH(OH)CH2CHMe2, -OC(O)CH2CH(OH)Me, -OC(O)CH2C(OH)Me2, -OC(O)CH(CH2OH)(NHC(O)Me), -OC(O)CH(NHC(O)Me)(isobutyl), -OC(O)CH(OH)aryl, -OC(O)CH(OH)CH2aryl, -OC(O)heterocycloalkyl, -OC(O)cycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, -OC(O)CH2CH2aryl, -OC(O)CH(NH2) i Pr, -OC(O)CH( i Pr)NHC(O)O t Bu, -OC(O)CH2OCH2CH2OMe, -OC(O)CH2(OCH2CH2)2OMe, -OC(O)OMe, -OC(O)OEt, -OC(O)OiPr, -OC(O)Ocycloalkyl, -OC(O)OCH2CH2OEt, -OC(O)O(CH2CH2O )2Et, -OC(O)O(CH2CH2O)3Et, -OC(O)O(CH2CH2O)3CH2CH2OP(O)(OH)2, -OC(O)OCH2CH2SMe, -OC(O)OCH2CH2S(O)Me, -OC(O)OCH2CH2S(O)2Me, -OC(O)OC H2heteroaryl, -OC(O)OCH2heterocycloalkyl, -OC(O)OCH2CH2OCH2aryl, -OC(O)OCH2CH2C(O)NMe2, -OC(O)O(CH2)6NH2, -OC(O)O(CH2)6NMe2, -OC(O)OCH(CHOEt)2, -OC(O)NHCH2CH2OMe, -OC(O)NMeCH2CH2OMe, -SMe, -S(O)Me, -P(O)(OH)2, -OP(O)(OH)2, -C(O)NMe2, -C(O)heterocycloalkyl, heteroaryl, heterocycloalkyl, -N + (Me)3, -N +(Me)2 is substituted with one or more groups selected from cycloalkyl, N-methylmorpholinium cation, N-methylpiperidinium cation, and N-methylimidazolium cation.

[0220] In some embodiments, R 9 is —C(O)O(C1-C6 alkyl), wherein the C1-C6 alkyl is substituted with one or more groups selected from —OC(O)C(CH3)3, —OC(O)CH2CH2OH, —OC(O)C(CH3)2OH, —OC(O)heterocycloalkyl, —OC(O)CHOCH2CH2OMe, —OC(O)OiPr, —OC(O)Ocycloalkyl, —OC(O)O(CH2CHO)2Et, —OP(O)(OH)2, heteroaryl, or heterocycloalkyl. In some such embodiments, R 9 is —C(O)O(C1-C6 alkyl), wherein the C1-C6 alkyl is substituted with —OC(O)C(CH3)3.

[0221] In some embodiments, R 9 -C(O)OCH2OC(O)C(CH3)3, -C(O)OCH2OC(O)Me, -C(O)OCH(Me)OC(O)Me, -C(O)OCH2OC(O)CH2CH2OH, -C(O)OCH2OC(O)C(CH3)2OH, -C(O)OCH2OC(O)piperidine, -C(O)OCH2OC(O)CH2OCH2CH2OMe, -C(O)OCH2OC(O)OiPr, -C(O)OCHMeOC(O)OiPr, -C(O)OCHMeOC(O)Ocyclohe -C(O)OCH2CH2P(O)(OH)2, -C(O)OCH2(N-methylimidazolium cation), -C(O)OCH2(N-methylpiperidinium cation), -C(O)OCH2 dioxolane, -C(O)OCH2CH2 morpholine, -C(O)OCH2CH2 piperazine, -C(O)OCH2CH2CH2 piperazine or -P(O)(OCH2OC(O)C(CH3)3)2.

[0222] In some embodiments, R 9 is -C(O)OCH2OC(O)C(CH3)3.

[0223] In some embodiments, the MCL-1 ligand prodrug moiety is: [ka] [Example]

[0224] There are several ways in which the bifunctional compounds [MCL-1 ligand prodrug moiety]-[linker]-[ligase ligand prodrug moiety] of the present application can be synthesized.

[0225] 1. [Mcl-1 ligand prodrug moiety] is coupled to linker A, which is then coupled to [ligase ligand moiety]-linker B. [Mcl-1 ligand moiety] -リンカーA +[ligase ligand moiety] -リンカーB [ka] wherein X is halogen or OM, OT; linker AN-Boc corresponds to linker A terminated with a Boc-protected primary or secondary amine; linker A-NH corresponds to linker A terminated with a primary or secondary amine; R 11 ~R 13 and [Linker] is as defined herein, and [Linker] is -LinkerA-NHR in the above synthesis. w and -formed by reaction of linker B-COOH]

[0226] 2. [MCL-1 ligand prodrug moiety] is coupled to linker A, which is then coupled to linker B, which is then coupled to the [ligase ligand moiety]. [ka] wherein X is halogen or OM, OT; linker AN-Boc corresponds to linker A terminated with a Boc-protected primary or secondary amine; linker A-NH corresponds to linker A terminated with a primary or secondary amine; R 11 ~R 13 are as defined herein, and Linker A N - Linker B correspond to [Linker]]

[0227] 3. [MCL-1 ligand prodrug moiety]-[linker] is coupled to [ligase ligand moiety]. [ka]

[0228] 4. The [MCL-1 ligand prodrug moiety] is coupled to the [linker]-[ligase ligand moiety]. [ka]

[0229] 5. [MCL-1 ligand prodrug moiety]-[linker]-R v is coupled with 3-aminopiperidine-2,6-dione. [ka]

[0230] The bifunctional compounds of the present invention were prepared as follows. [Example]

[0231] (2-(2-Methoxyethoxy)acetoxy)methyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (Compound 57) [ka] Step A To a solution of 2-(2-methoxyethoxy)acetic acid (250 mg, 1.86 mmol) in DMF (4 mL) was added chloroiodomethane (0.172 mL, 2.052 mmol) at room temperature under nitrogen, followed by KHCO (554 mg, 5.6 mmol). The resulting mixture was stirred at 60 °C under nitrogen for 1 hour. After complete consumption of the starting material (monitored by TLC), the reaction mixture was cooled to room temperature and filtered through a sintered funnel. The filtrate of chloromethyl 2-(2-methoxyethoxy)acetate in DMF was used without further purification.

[0232] Step B To a stirred solution of ethyl 7-bromo-6-chloro-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-1H-indole-2-carboxylate (1.7 g, 3.368 mmol) in dioxane (20 mL) and water (5 mL) was added 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.386 g, 10.103 mmol) and K2CO3 (1.859 g, 13.471 mmol). The mixture was deoxygenated with argon, and to this was added Pd(dppf)Cl2 (0.369 g, 0.505 mmol) under an argon atmosphere. The reaction mixture was then heated under reflux for 16 h. After complete consumption of the starting material (monitored by TLC and LCMS), the reaction mixture was filtered through a Celite pad, and the solvent was evaporated under reduced pressure to give a crude material, which was then diluted with EtOAc and washed successively with water and brine. The organic layer was dried over Na2SO4 and evaporated under reduced pressure to give a crude compound, which was then purified by column chromatography (SiO2, 50% EtOAc in hexane) to give ethyl 6-chloro-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (1.2 g, 2.247 mmol, 66.72%) as a brown solid. LCMS(ESI):534.2 m / z [M+H] +

[0233] Step C Ethyl 6-chloro-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (1.2 g, 2.251 mmol) was dissolved in EtOH (20 mL), and a solution of NaOH (0.315 g, 7.88 mmol) in water (10 mL) was added to it. The mixture was heated under reflux for 16 h. After complete consumption of the starting material (monitored by TLC and LCMS), the reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure to give the crude reaction mixture. This was then diluted with water and washed with EtOAc. The aqueous layer was carefully acidified to pH = 3 with 1 M HCl and extracted with EtOAc (x3). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give 6-chloro-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (0.9 g, crude) as a brown liquid, which was used in the next step without further purification. LCMS(ESI):506.3 m / z [M+H] +

[0234] Step D 6-Chloro-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (1.2 g, 2.376 mmol) was suspended in toluene (20 mL) and the mixture was heated to reflux under nitrogen. N,N-Dimethylformamide di-tert-butyl acetal (4.547 mL, 19.01 mmol) was added dropwise to the refluxing mixture. The mixture was heated under reflux under nitrogen for 16 hours. After complete consumption of the starting material (monitored by TLC and LCMS), the reaction mixture was diluted with EtOAc and washed successively with sodium bicarbonate (aqueous, saturated), water, and brine. The organic layer was dried over Na2SO4 and evaporated under reduced pressure to give the crude compound, which was then purified by column chromatography (SiO2, 70% EtOAc in hexanes) to give tert-butyl 6-chloro-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (0.772 g, 1.373 mmol, 61% for two steps) as a brownish liquid. LCMS(ESI):561.9 m / z [M+H] +

[0235] Step E To a solution of tert-butyl 6-chloro-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (0.555 g, 0.989 mmol) in DMF (10 mL) was added tert-butyl 4-(2-chloroethyl)piperazine-1-carboxylate (0.492 g, 1.979 mmol), followed by cesium carbonate (1.607 g, 4.947 mmol) in DMF (5 mL), and the mixture was stirred under nitrogen at 90° C. for 16 h. After complete consumption of the starting material (monitored by TLC and LCMS), the reaction mixture was diluted with EtOAc and washed successively with water and brine. The organic layer was dried over Na2SO4 and evaporated under reduced pressure to give the crude compound, which was then purified by column chromatography (SiO2, 30% EtOAc in hexanes) to give tert-butyl 1-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)-6-chloro-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (0.5 g, 0.645 mmol, 65.27%) as an off-white solid. LCMS(ESI):774.6 m / z [M+H] +

[0236] Step F tert-Butyl 1-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)-6-chloro-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (0.3 g, 0.388 mmol) was dissolved in 20 mL of 4 M HCl in dioxane at 0° C., and the mixture was stirred under nitrogen at the same temperature for 2 h. After complete consumption of the starting material (monitored by TLC and LCMS), the reaction mixture was poured into cold 1 M NaOH solution and extracted several times with DCM. The combined organics were dried over Na2SO4 and concentrated in vacuo to give the crude compound, which was then purified by column chromatography (amine SiO2, 10% MeOH in DCM) to give tert-butyl 6-chloro-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-1-(2-(piperazin-1-yl)ethyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (0.165 g, 0.244 mmol, 62.98%) as an off-white solid. LCMS(ESI):674.4 m / z [M+H] +

[0237] Step G 2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}acetic acid (18.3 mg, 0.058 mmol) was dissolved in dry DMF (1.0 mL) under an argon atmosphere, DIPEA (0.025 mL, 0.144 mmol) was added, followed by tert-butyl 6-chloro-3-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-1-[2-(piperazin-1-yl)ethyl]-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (32.3 mg, 0.048 mmol). The solution was cooled to 0 ° C., and HATU (21.9 mg, 0.058 mmol) was added dropwise as a solution in 0.2 mL of dry DMF. The reaction was stirred under an argon atmosphere and allowed to warm to room temperature. After 15 minutes, complete conversion was observed (monitored by LCMS). The solution was diluted with DCM and washed with brine, NaHCO (saturated), and again with brine and water. The organic layer was dried over anhydrous MgSO, filtered, concentrated, and dried under reduced pressure to give tert-butyl 6-chloro-1-{2-[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}acetyl)piperazin-1-yl]ethyl}-3-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (44.7 mg, crude) as an orange oil. The product was used in the next step without further purification. LCMS(ESI):974.6 m / z [M+H] +

[0238] Step H Tert-butyl 6-chloro-1-{2-[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}acetyl)piperazin-1-yl]ethyl}-3-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (44.7 mg, crude) was dissolved in dry DCM (0.351 mL) under an argon atmosphere. TFA (0.351 mL, 4.584 mmol) was added and the reaction was stirred at room temperature for 18 hours. DCM and TFA were evaporated under reduced pressure, and the resulting residue was dissolved in DMSO and purified by preparative HPLC (HO:MeCN+0.1% FA) to afford 6-chloro-1-{2-[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}acetyl)piperazin-1-yl]ethyl}-3-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (12.6 mg, 0.014 mmol, 29% over two steps) as a white solid. LCMS(ESI):917.6 m / z [M+H] +

[0239] Step I To a solution of 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (120 mg, 0.13 mmol) in DMF (3 mL) was added KHCO (26 mg, 0.26 mmol) at room temperature under a nitrogen atmosphere, followed by a solution of chloromethyl 2-(2-methoxyethoxy)acetate in DMF obtained in the previous step. The resulting mixture was stirred under nitrogen at 60° C. for 2 hours. After complete consumption of the starting material, the reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over sodium sulfate and evaporated under reduced pressure to give the crude compound, which was purified twice by preparative TLC (SiO, 10% MeOH in DCM, then 50% acetone in DCM) to give (2-(2-methoxyethoxy)acetoxy)methyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (20 mg, 0.0188 mmol, 14.4%) as a white solid. LCMS(ESI): 1065.0 m / z [M+H] + . 1H NMR(500MHz,DMSO)δ=10.67(s,1H), 8.23(dd,J=9.2,5.8,1H), 7.77(d,J=8.6,1H), 7.59(dd,J=10.4,2.7,1H), 7.49~7.40(m,3H), 7.37~7.30(m,2H) , 7.26(d,J=8.6,1H), 7.14(d,J=8.1,1H), 6.88(dd,J=5.6,3.0,1H), 6.03( d,J=0.9,2H), 5.05(dd,J=13.1,5.2,1H), 4.89(s,2H), 4.40(d,J=17.1,1H ), 4.32(dd,J=17.2,1.6,1H), 4.29~4.11(m,6H), 3.76(d,J=1.9,3H), 3.60 ~3.57(m,2H), 3.44~3.40(m,2H), 3.38~3.30(m,4H), 3.29~3.24(m,2H), 3. 20(s,2H), 2.88(ddd,J=17.4,13.4,5.5,1H), 2.64~2.59(m,1H), 2.46~2.3 9(m,2H), 2.26~2.18(m,2H), 2.15~2.02(m,7H), 2.01(s,3H), 1.88(s,3H). [Example]

[0240] ((Piperidine-4-carbonyl)oxy)methyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (TFA salt) (Compound 55) [ka] Step A To a solution of 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (150 mg, 0.163 mmol) in DMF (2 mL) under nitrogen at room temperature was added KCO (45 mg, 0.327 mmol), followed by a solution of crude 1-(tert-butyl)4-(chloromethyl)piperidine-1,4-dicarboxylate in DMF. The resulting mixture was stirred under nitrogen at 70° C. for 2 hours. After complete consumption of the starting material (monitored by TLC and LCMS), the mixture was concentrated under reduced pressure. The resulting residue was diluted with EtOAc and washed with water and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (SiO, 3-4% MeOH in DCM). 1-(tert-butyl) 4-(((6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonyl)oxy)methyl)piperidine-1,4-dicarboxylate (110 mg, 0.095 mmol, 58%) was obtained as a white solid. LCMS(ESI): 1157.1 m / z [M−H] - .

[0241] Step B To a solution of 1-(tert-butyl) 4-(((6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonyl)oxy)methyl)piperidine-1,4-dicarboxylate (110 mg, 0.095 mmol) in DCM (3 mL) under nitrogen at 0° C. was added TFA (2 mL) dropwise. The reaction mixture was stirred under nitrogen at ambient temperature for 3 hours. After complete consumption of the starting material, the volatiles were removed under reduced pressure and the crude was purified by triturating with diethyl ether and n-pentane to afford ((piperidine-4-carbonyl)oxy)methyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (100 mg, 0.085 mmol, 89%) as a TFA salt (white solid). LCMS(ESI):1060.1m / z[M+H] + 1H NMR(500MHz,DMSO,353K)δ10.69(s,1H), 8.42(bs,1H), 8.25(dd,J=9.3,5.9Hz,1H), 8.14 b(s,1H), 7.80(d,J=8.6Hz,1H), 7.63(dd,J=10.4,2.5Hz,1H), 7.50~7.42(m,3H), 7.40~7. 32(m,2H), 7.29(d,J=8.6Hz,1H), 7.16(d,J=8.2Hz,1H), 6.90(dd,J=6.2,2.5Hz,1H), 6.0 4(d,J=5.9Hz,1H), 6.03(d,J=5.9Hz,1H), 5.08(dd,J=13.0,5.2Hz,1H), 4.92(s,2H), 4.42 (d,J=17.2Hz,1H), 4.33(dd,J=17.1,1.6Hz,1H), 4.31~4.23(m,3H), 4.23~4.14(m,1H), 3 .78(d,J=2.0Hz,3H), 3.39~3.35(m,4H), 3.31~3.26(m,2H), 3.26~3.19(m,3H), 2.96~2.85 (m,2H), 2.78(tt,J=10.8,4.0Hz,1H), 2.68~2.62(m,1H), 2.49~2.41(m,1H), 2.28~2.20( m,2H), 2.15(s,6H), 2.10~1.98(m,6H), 1.89(s,3H), 1.77(dtd,J=14.7,11.1,4.0Hz,2H). [Example]

[0242] (6-chloro-1-{2-[4-(2-{4-[(2,6-dioxopiperidin-3-yl)carbamoyl]-2-methyl-1H-1,3-benzodiazol-1-yl}acetyl)piperazin-1-yl]ethyl}-3-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonyloxy)methyl 2,2-dimethylpropanoate (Compound 70) [ka] Step A To a solution of methyl 1-[2-(tert-butoxy)-2-oxoethyl]-2-methyl-1H-1,3-benzodiazole-4-carboxylate (152.0 mg, 0.499 mmol) in HO (0.500 mL) and MeCN (5.0 mL) was added LiBr (867.4 mg, 9.989 mmol) and EtN (0.695 mL, 4.994 mmol). The mixture was stirred at room temperature for 4 days. The crude product was concentrated in vacuo and purified by reverse-phase flash chromatography (HO:MeCN + 0.1% FA) to afford 1-[2-(tert-butoxy)-2-oxoethyl]-2-methyl-1H-1,3-benzodiazole-4-carboxylic acid (75.0 mg, 0.233 mmol, 47%) as a yellow solid. LCMS(ESI):291.0 m / z [M+H] +

[0243] Step B To a solution of 1-[2-(tert-butoxy)-2-oxoethyl]-2-methyl-1H-1,3-benzodiazole-4-carboxylic acid (100.0 mg, 0.344 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (68.0 mg, 0.413 mmol) in dry DMF (2.0 mL) was added DIPEA (0.300 mL, 1.722 mmol) and HATU (196.5 mg, 0.517 mmol). The mixture was stirred at room temperature for 18 hours. The crude was then concentrated in vacuo and the residue was dissolved in DCM and purified by flash chromatography (SiO, MeOH:DCM, 0–50%) to isolate tert-butyl 2-{4-[(2,6-dioxopiperidin-3-yl)carbamoyl]-2-methyl-1H-1,3-benzodiazol-1-yl}acetate (74.0 mg, 0.185 mmol, 54%) as a yellow solid. LCMS(ESI):401.1 m / z [M+H] +

[0244] Step C To a solution of tert-butyl 2-{4-[(2,6-dioxopiperidin-3-yl)carbamoyl]-2-methyl-1H-1,3-benzodiazol-1-yl}acetate (64.5 mg, 0.161 mmol) in DCM (2.0 mL) was added TFA (1.0 mL, 13.059 mmol). The mixture was stirred at room temperature for 18 hours. The crude was concentrated in vacuo and dissolved in H2O. 1 M HCl in water was added to the solution, which was then evaporated. The product, 2-{4-[(2,6-dioxopiperidin-3-yl)carbamoyl]-2-methyl-1H-1,3-benzodiazol-1-yl}acetic acid hydrochloride (58.8 mg, 0.154 mmol, 96%), was isolated as a beige solid. LCMS(ESI):344.8 m / z [M+H] +

[0245] Step D 2-{4-[(2,6-dioxopiperidin-3-yl)carbamoyl]-2-methyl-1H-1,3-benzodiazol-1-yl}acetic acid hydrochloride (37.3 mg, 0.098 mmol), tert-butyl 6-chloro-3-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-1-[2-(piperazin-1-yl)ethyl]-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (55.0 mg, 0.082 mmol), and HATU (62.0 mg, 0.163 mmol) were dissolved in dry DMF (2.0 mL), and DIPEA (0.071 mL, 0.408 mmol) was added to the mixture. The reaction was stirred at room temperature for 2 hours. The solvent was evaporated. The residue was dissolved in DCM and washed with brine. The organic layer was dried over NaSO, filtered, and concentrated in vacuo to afford tert-butyl 6-chloro-1-{2-[4-(2-{4-[(2,6-dioxopiperidin-3-yl)carbamoyl]-2-methyl-1H-1,3-benzodiazol-1-yl}acetyl)piperazin-1-yl]ethyl}-3-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (102.2 mg, crude), which was used in the next step without further purification. LCMS(ESI):1001.3 m / z [M+H] +

[0246] Step E To a solution of tert-butyl 6-chloro-1-{2-[4-(2-{4-[(2,6-dioxopiperidin-3-yl)carbamoyl]-2-methyl-1H-1,3-benzodiazol-1-yl}acetyl)piperazin-1-yl]ethyl}-3-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (102.2 mg, crude) in DCM (1.0 mL) was added TFA (0.500 mL, 6.529 mmol). The mixture was stirred at room temperature for 18 hours. The crude was concentrated in vacuo and purified by preparative HPLC (HO:MeCN+0.1% FA) to afford 6-chloro-1-{2-[4-(2-{4-[(2,6-dioxopiperidin-3-yl)carbamoyl]-2-methyl-1H-1,3-benzodiazol-1-yl}acetyl)piperazin-1-yl]ethyl}-3-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (32.3 mg, 0.034 mmol, 35%) as a white solid. LCMS(ESI):944.3 m / z [M+H] +

[0247] Step F To a solution of 6-chloro-1-{2-[4-(2-{4-[(2,6-dioxopiperidin-3-yl)carbamoyl]-2-methyl-1H-1,3-benzodiazol-1-yl}acetyl)piperazin-1-yl]ethyl}-3-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (20.0 mg, 0.021 mmol) in dry DMF (1.2 mL) was added EtN (0.030 mL, 0.212 mmol) and chloromethyl 2,2-dimethylpropanoate (0.009 mL, 0.064 mmol). The reaction mixture was stirred at 60 °C for the next 18 hours. The crude material was then purified by preparative HPLC (C18, HO:MeCN+0.1% FA) to afford (6-chloro-1-{2-[4-(2-{4-[(2,6-dioxopiperidin-3-yl)carbamoyl]-2-methyl-1H-1,3-benzodiazol-1-yl}acetyl)piperazin-1-yl]ethyl}-3-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonyloxy)methyl 2,2-dimethylpropanoate (16.6 mg, 0.016 mmol, 74%) as a white solid. LCMS(ESI):1058.2m / z[M+H] + 1H NMR(500MHz,DMSO)δ10.91(s,1H), 10.23(d,J=7.3Hz,1H), 8.22(dd,J=9.2,5.9Hz,1H), 7.84(dd,J=7.6,1.1Hz,1H), 7.81(d,J=8 .6Hz,1H), 7.67~7.62(m,2H), 7.46~7.43(m,2H), 7.36(td,J=8.9,2.6Hz,1H), 7.31~7.27(m,2H), 6.90~6.86(m,1H), 6.01(s,2H) , 5.29(s,2H), 4.88(ddd,J=12.6,7.4,5.3Hz,1H), 4.29~4.20(m,3H), 4.19~4.12(m,1H), 3.77(s,3H), 3.48~3.43(m,2H), 3.28~3 .20(m,4H), 2.82(ddd,J=17.2,13.5,5.6Hz,1H), 2.61~2.52(m,1H), 2.47(s,3H), 2.27~2.02(m,13H), 1.88(s,3H), 1.14(s,9H). [Example]

[0248] (Pivaloyloxy)methyl (S)-6-chloro-1-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (Compound 71) [ka] Step A To a stirred solution of 4-(dimethoxymethyl)piperidine (0.4 g, 2.51 mmol) in DMF (10 mL) under nitrogen at 0 °C, dry sodium hydride (washed with n-hexane) (0.18 g, 7.5 mmol) was added portionwise. The reaction mixture was stirred at room temperature for 30 min. Next, the reaction mixture was cooled again to 0 °C, and 1-bromo-2-chloroethane (2.08 mL, 25.1 mmol) was added dropwise. The resulting reaction mixture was stirred under nitrogen at room temperature for 4 h. The excess sodium hydride was then quenched by adding ice water and diluted with EtOAc. The organic layer was washed with ice water and brine, dried over Na2SO4, and evaporated under reduced pressure. The crude compound was purified by column chromatography (SiO2, 30–40% EtOAc in hexane) to give 1-(2-chloroethyl)-4-(dimethoxymethyl)piperidine (300 mg, 1.35 mmol, 54%) as a light brown sticky solid. LCMS(ESI):222.2 m / z [M+H] +

[0249] Step B To a well-stirred solution of tert-butyl 6-chloro-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (350 mg, 0.62 mmol) in DMF (3 mL) was added 1-(2-chloroethyl)-4-(dimethoxymethyl)piperidine (276 mg, 1.24 mmol), followed by CsCO (304 mg, 0.93 mmol), and the mixture was stirred under nitrogen at 100° C. for 16 h. After complete consumption of the starting material (monitored by TLC and LCMS), the reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over Na2SO4 and evaporated under reduced pressure to give the crude compound, which was then purified by column chromatography (SiO2, 60-70% EtOAc in DCM) to give tert-butyl 6-chloro-1-(2-(4-(dimethoxymethyl)piperidin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (120 mg, 0.16 mmol, 26%) as a pale pink solid. LCMS(ESI):747.6 m / z [M+H] +

[0250] Step C tert-Butyl 6-chloro-1-{2-[4-(dimethoxymethyl)piperidin-1-yl]ethyl}-3-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (10.0 mg, 0.013 mmol) was dissolved in THF (0.535 mL) and a 2 M aqueous solution of H2SO4 (0.268 mL, 0.535 mmol) was added. The reaction was stirred in a sealed vial at 70 °C for 1 h. After complete conversion of the starting material, 1 M aqueous NaOH was added to pH = 7, and the reaction product was extracted with DCM. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and dried under reduced pressure. Crude tert-butyl 6-chloro-3-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-1-[2-(4-formylpiperidin-1-yl)ethyl]-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (7.5 mg) was obtained as an off-white solid and used directly in the next step. LCMS(ESI):701.4 m / z [M+H] +

[0251] Step D Crude tert-butyl 6-chloro-3-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-1-[2-(4-formylpiperidin-1-yl)ethyl]-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (7.5 mg) and (3S)-3-[1-oxo-5-(piperazin-1-yl)-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (4.8 mg, 0.015 mmol) were dissolved in dry DCM (0.531 mL) and MeOH (0.133 mL) under an argon atmosphere. To this was added STAB (14.2 mg, 0.067 mmol) and AcOH (0.001 mL, 0.017 mmol), and the reaction was stirred under argon at room temperature for 16 h. After complete consumption of the starting material, the mixture was diluted with DCM and washed with saturated aqueous NaHCO, brine, and water. The organic layer was dried over anhydrous MgSO, filtered, and dried under reduced pressure to give tert-butyl (S)-6-chloro-1-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (8.4 mg, crude) as a beige film. The crude product was carried on to the next step without further purification. LCMS(ESI):1013.3 m / z [M+H] +

[0252] Step E tert-Butyl (S)-6-chloro-1-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (8.4 mg, crude) was dissolved in dry DCM (0.300 mL) under an argon atmosphere and TFA (0.300 mL, 3.918 mmol) was added. The reaction was stirred under argon at room temperature for 16 hours. After complete consumption of the starting material, the solution was concentrated to dryness under reduced pressure and dissolved in DMSO. The crude product was purified by preparative HPLC (C18, HO:MeCN+0.1% FA) to afford (S)-6-chloro-1-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (2.8 mg, 0.003 mmol, 23% over 3 steps) as a white solid. LCMS(ESI):957.25 m / z [M+H] +

[0253] Step F To a well-stirred solution of (S)-6-chloro-1-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (150 mg, 0.157 mmol) in DMF (3 ml) was added chloromethyl pivalate (0.027 ml, 0.188 mmol), followed by potassium carbonate (21 mg, 0.157 mmol), and the mixture was stirred under nitrogen at 60° C. for 2 hours. After complete consumption of the starting material, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the crude compound, which was then purified by preparative HPLC (10 mM ammonium acetate in HO:MeCN) to give (pivaloyloxy)methyl (S)-6-chloro-1-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (15 mg, 0.014 mmol, 9%) as a white solid. LCMS(ESI):1071.2m / z[M+H] + 1H NMR(500MHz,DMSO)δ=10.93(s,1H), 8.20(dd,J=9.3,5.9,1H), 7.80(d,J=8.6,1H), 7.65(dd,J=10.3,2.7,1H), 7.59~7.48(m,1H), 7.48~7.40( m,2H), 7.36(td,J=8.9,2.6,1H), 7.27(d,J=8.5,1H), 7.15~6.96(m,2H ), 6.94~6.80(m,1H), 5.98(s,2H), 5.04(dd,J=13.3,5.2,1H), 4.32(d,J =16.9,1H), 4.28~4.14(m,4H), 4.14~4.01(m,1H), 3.75(s,3H), 3.26~3 .14(m,6H), 2.90(ddd,J=17.8,13.6,5.4,1H), 2.62~2.55(m,1H), 2.47 ~2.24(m,6H), 2.24~2.15(m,2H), 2.14~1.92(m,7H), 1.91~1.80(m,5H) , 1.80~1.60(m,3H), 1.60~1.42(m,2H), 1.14(s,9H), 1.01~0.78(m,2H). [Example]

[0254] (6-chloro-1-{2-[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}acetyl)piperazin-1-yl]ethyl}-3-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonyloxy)methyl 2,2-dimethylpropanoate (Compound 69) [ka] Step A 6-Chloro-1-{2-[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}acetyl)piperazin-1-yl]ethyl}-3-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (100.0 mg, 0.109 mmol) was dissolved in DMF (6.3 mL), and triethylamine (0.076 mL, 0.544 mmol) was added, followed by chloromethyl pivalate (0.031 mL, 0.218 mmol). The mixture was stirred at room temperature overnight and then at 80° C. for the next 2 days. The solvent was removed under reduced pressure, and the desired product was purified using flash chromatography (SiO, 5% MeOH in DCM) to afford the corresponding (6-chloro-1-{2-[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}acetyl)piperazin-1-yl]ethyl}-3-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonyloxy)methyl 2,2-dimethylpropanoate (66.0 mg, 0.064 mmol, 58.7%) as a white solid. LCMS(ESI):1032.2m / z[M+H] + 1H NMR(500MHz,DMSO,353K)δ=10.64(s,1H), 8.21(dd,J=9.3,5.8,1H), 7.77(d,J=8.6,1H), 7.58(dd,J=10.4,2.6,1H), 7.47~7.38(m,3H), 7.35~ 7.28(m,2H), 7.26(d,J=8.6,1H), 7.14(d,J=8.1,1H), 6.87(dd,J=6.1, 2.6,1H), 5.99(s,2H), 5.05(dd,J=13.0,5.2,1H), 4.89(s,2H), 4.40(d ,J=17.1,1H), 4.32(d,J=16.9,1H), 4.28~4.19(m,3H), 4.20~4.11(m,1 H), 3.76(d,J=1.9,3H), 3.37~3.30(m,4H), 3.30~3.23(m,2H), 2.88(dd d,J=17.2,13.4,5.5,1H), 2.64~2.56(m,1H), 2.48~2.38(m,1H), 2.27~ 2.18(m,2H), 2.14~2.02(m,7H), 2.01(s,3H), 1.88(s,3H), 1.16(s,9H). [Example]

[0255] 4-Oxo-3,5,8,11-tetraoxatridecan-2-yl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (Compound 101) [ka] Step A To a well-stirred solution of 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (100 mg, 0.109 mmol) in DMF (1 mL) was added KCO (45 mg, 0.327 mmol) followed by 1-chloroethyl(2-(2-ethoxyethoxy)ethyl)carbonate (100 mg, 0.417 mmol) and the reaction mixture was stirred under nitrogen at 60° C. for 2 h. After complete consumption of the starting material, the solvent was concentrated under reduced pressure and the target molecule was purified by preparative HPLC (10 mM ammonium acetate buffer: MeCN) to give 4-oxo-3,5,8,11-tetraoxatridecan-2-yl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (45 mg, 0.04 mmol, 37%) as a white solid. LCMS(ESI): 1120.84 m / z [M−H] - 1H NMR(500MHz,DMSO,353K)δ10.66(s,1H), 8.24(dd,J=9.2,5.9Hz,1H),7.77(d,J=8.6Hz,1H ), 7.59(dd,J=10.4,2.6Hz,1H), 7.48~7.38(m,3H), 7.37~7.30(m,2H), 7.26(d,J=8.6Hz,1 H), 7.17~7.11(m,1H), 7.00~6.93(m,1H), 6.89(dd,J=5.8,2.9Hz,1H), 5.05(dd,J=13.0,5 .2Hz,1H), 4.89(s,2H), 4.40(d,J=17.1Hz,1H), 4.31(dd,J=17.0,1.6Hz,1H), 4.29~4.11( m,6H), 3.76(d,J=2.2Hz,3H), 3.63~3.58(m,2H), 3.51~3.45(m,2H), 3.43~3.40(m,2H), 3. 38(q,J=7.0Hz,2H), 3.35~3.31(m,4H), 3.30~3.25(m,2H), 2.88(ddd,J=17.4,13.5,5.5Hz ,1H), 2.64~2.59(m,1H), 2.47~2.39(m,1H), 2.28~2.20(m,2H), 2.18~2.02(m,7H), 2.01(d ,J=1.7Hz,3H), 1.88(d,J=1.5Hz,3H), 1.63(dd,J=5.4,1.6Hz,3H), 1.04(t,J=7.0Hz,3H). [Example]

[0256] 1-{[(propan-2-yloxy)carbonyl]oxy}ethyl 6-chloro-1-{2-[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}acetyl)piperazin-1-yl]ethyl}-3-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (Compound 99) [ka] Step A To a solution of 6-chloro-1-{2-[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}acetyl)piperazin-1-yl]ethyl}-3-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (40.0 mg, 0.044 mmol) in DMF (2.5 mL) was added triethylamine (17.6 mg, 0.174 mmol) and 1-chloroethyl isopropyl carbonate (7.6 mg, 0.046 mmol). The reaction was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure, and the desired product was purified using flash chromatography (SiO, DCM:MeOH, 5 to 20% MeOH gradient) to afford 1-{[(propan-2-yloxy)carbonyl]oxy}ethyl 6-chloro-1-{2-[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}acetyl)piperazin-1-yl]ethyl}-3-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (21.1 mg, 0.020 mmol, 46.2%) as a white solid. LCMS(ESI):1046.1m / z[MH] - . 1H NMR(500MHz,DMSO,353K)δ=10.67(s,1H), 8.24(dd,J=9.2,5.9,1H), 7.77(d,J=8.6,1 H), 7.59(dd,J=10.3,2.6,1H), 7.47~7.39(m,3H), 7.36~7.29(m,2H), 7.26(d,J=8.6, 1H), 7.16~7.11(m,1H), 6.96~6.91(m,1H), 6.88(dd,J=6.1,2.5,1H), 5.05(dd,J=13. 0,5.2,1H), 4.89(s,2H), 4.84~4.75(m,1H), 4.40(d,J=17.2,1H), 4.31(dd,J=17.0,1. 6,1H), 4.26(t,J=6.3,2H), 4.24~4.20(m,1H), 4.20~4.12(m,1H), 3.76(d,J=2.0,3H) , 3.38~3.31(m,4H), 3.31~3.21(m,2H), 2.88(ddd,J=17.4,13.5,5.5,1H), 2.65~2.59( m,1H), 2.47~2.38(m,1H), 2.27~2.20(m,2H), 2.16~2.02(m,7H), 2.01(s,3H), 1.88(d ,J=1.1,3H), 1.62(dd,J=5.4,1.7,3H), 1.22(d,J=6.2,3H), 1.19(dd,J=6.2,1.4,3H). [Example]

[0257] 1-(((cyclohexyloxy)carbonyl)oxy)ethyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (Compound 100) [ka] Step A 6-Chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (30.0 mg, 0.033 mmol) was dissolved in dry MeCN (1.0 mL) and EtN (0.046 mL, 0.327 mmol), followed by 1-chloroethylcyclohexyl carbonate (8.1 mg, 0.039 mmol). The reaction mixture (monitored by LCMS) was stirred in a sealed vial at 60° C. for 96 hours. After complete reaction, the mixture was concentrated to dryness under reduced pressure and dissolved in DCM. The organic phase was washed with brine and water, dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (SiO, 5% to 20% MeOH in DCM) to afford 1-(((cyclohexyloxy)carbonyl)oxy)ethyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (17.2 mg, 0.016 mmol, 48.5%) as a white solid. LCMS(ESI):1088.2m / z[M+H] + . 1H NMR(500MHz,DMSO,353K)δ10.67(s,1H), 8.24(dd,J=9.2,5.9Hz,1H), 7.78(d,J=8.6Hz,1H) , 7.59(dd,J=10.4,2.6Hz,1H), 7.50~7.38(m,3H), 7.36~7.29(m,2H), 7.26(d,J=8.6Hz,1H), 7.14(dt,J=8.2,0.7Hz,1H), 6.94(q,J=5.4Hz,1H), 6.88(dd,J=6.1,2.5Hz,1H), 5.05(dd,J= 13.1,5.2Hz,1H), 4.89(s,2H), 4.62~4.52(m,1H), 4.40(d,J=17.1Hz,1H), 4.31(dd,J=17.2, 1.5Hz,1H), 4.29~4.11(m,4H), 3.76(d,J=2.0Hz,3H), 3.38~3.31(m,4H), 3.31~3.20(m,2H) , 2.88(ddd,J=17.4,13.5,5.5Hz,1H), 2.67~2.59(m,1H), 2.44(qd,J=13.1,4.9Hz,1H), 2.28 ~2.19(m,2H), 2.17~2.03(m,7H), 2.01(d,J=1.3Hz,3H), 1.88(d,J=1.6Hz,3H), 1.85~1.73(m ,2H), 1.62(dd,J=5.4,1.7Hz,3H), 1.61~1.49(m,2H), 1.45~1.30(m,4H), 1.26~1.10(m,2H). [Example]

[0258] (2-(Phosphonooxy)ethyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (Compound 131) [ka] Step A To a solution of 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (200 mg, 0.218 mmol) in DMF (1 mL) under nitrogen at room temperature was added HATU (165.5 mg, 0.436 mmol) and EtN (0.092 mL, 0.654 mmol), and the reaction was stirred for 15 minutes. To this was added 2-bromoethan-1-ol (0.08 mL, 1.089 mmol), and the resulting mixture was then stirred at room temperature for an additional 4 hours. After complete consumption of the starting material, the reaction was quenched by adding ice water. The mixture was concentrated in vacuo, diluted with DCM, and washed with saturated sodium bicarbonate solution (2 x 50 mL), water (50 mL), and brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The crude compound was purified by column chromatography (SiO, 3-5% MeOH in DCM) to give 2-bromoethyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (150 mg, 0.146 mmol, 67%) as a white solid. LCMS(ESI):1026.1 m / z [M+H] + .

[0259] Step B To a solution of 2-bromoethyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (150 mg, 0.146 mmol) in DMF (1 mL) was added potassium di-tert-butylphosphate (72.5 mg, 0.293 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100° C. for 16 hours under nitrogen. After complete consumption of the starting material, the solvent was concentrated under reduced pressure, diluted with EtOAc, and washed with cold water and brine. The organic layer was dried over sodium sulfate and evaporated under reduced pressure to give crude 2-((di-tert-butoxyphosphoryl)oxy)ethyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (120 mg) as an off-white solid, which was used directly in the next step without further purification. LCMS(ESI):1154.4 m / z [M+H] +

[0260] Step C To a solution of 2-((di-tert-butoxyphosphoryl)oxy)ethyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (120 mg, 0.104 mmol) in DCM (3 mL) under nitrogen at 0° C. was added TFA (2 mL) dropwise and the reaction mixture was stirred at ambient temperature for 3 hours. After complete consumption of the starting material, the volatiles were removed under reduced pressure to give the crude product, which was then purified by preparative HPLC (10 mM ammonium acetate buffer:MeCN) to give 2-(phosphonooxy)ethyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (13 mg, 0.0124 mmol, 8.4% over two steps) as a white solid. LCMS(ESI):1040.1m / z[MH] - 1H NMR(400MHz,DMSO,372K)δ10.57(s,1H), 8.22(dd,J=9.3,5.9Hz,1H), 7.73(d,J=8.5Hz,1H), 7.57(dd,J=10.3,2.8Hz,1H), 7.47~7.38(m,3H) ), 7.37~7.29(m,2H), 7.23(dd,J=8.6,1.6Hz,1H), 7.15(d,J=8.1Hz,1H), 6.93~6.85(m,1H), 5.04(dd,J=13.5,5.2Hz,1H), 4.89(s,2H), 4.53 ~4.44(m,2H), 4.41(d,J=17.1Hz,1H), 4.32(d,J=16.9Hz,1H), 4.30~4.12(m,6H), 3.80~3.72(m,3H), 3.38~3.35(m,4H), 3.31~3.27(m,2H), 2.87(ddd,J=18.2,13.7,5.8Hz,1H), 2.68~2.59(m,1H), 2.47~2.38(m,1H), 2.29~2.21(m,2H), 2.19~2.03(m,7H), 2.01(s,3H), 1.88(s,3H). [Example]

[0261] 3-(4-Methylpiperazin-1-yl)propyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (Compound 137) [ka] Step A 6-Chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (20.0 mg, 0.022 mmol) and HATU (9.1 mg, 0.024 mmol) were dissolved in dry DMF (1.0 mL) under an argon atmosphere, and DIPEA (0.011 mL, 0.065 mmol) was added. The reaction was stirred under argon at room temperature for 20 minutes, and 3-(4-methylpiperazin-1-yl)propan-1-ol (4.1 mg, 0.026 mmol) was added. The reaction (monitored by LCMS) was stirred at room temperature for the next 16 hours. After that, additional amounts of HATU (9.1 mg, 0.024 mmol), DIPEA (0.011 mL, 0.065 mmol), and 3-(4-methylpiperazin-1-yl)propan-1-ol (4.1 mg, 0.026 mmol) were added. The reaction was continued under argon at room temperature for 2 hours. After complete consumption of the starting material, the solution was concentrated under reduced pressure, diluted with DMSO, and purified by reverse-phase preparative HPLC (C18, HO:MeCN+0.1% FA). 3-(4-Methylpiperazin-1-yl)propyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (6.5 mg, 0.006 mmol, 28.3%) was obtained as a white solid. LCMS(ESI):1058.2m / z[M+H] + . 1H NMR(500MHz,DMSO,353K)δ10.68(s,1H), 8.22(dd,J=9.2,5.9Hz,1H), 7.75(d,J= 8.6Hz,1H), 7.60(dd,J=10.4,2.6Hz,1H), 7.47~7.40(m,3H), 7.36~7.30(m,2H), 7.25(d,J=8.6Hz,1H), 7.16~7.12(m,1H), 6.88(dd,J=6.4,2.3Hz,1H), 5.05(dd, J=13.1,5.1Hz,1H), 4.89(s,2H), 4.40(d,J=17.1Hz,1H), 4.35~4.28(m,3H), 4.2 8~4.10(m,4H), 3.76(d,J=2.1Hz,3H), 3.39~3.30(m,4H), 3.30~3.24(m,2H), 2.8 8(ddd,J=17.3,13.4,5.5Hz,1H), 2.66~2.59(m,1H), 2.44(qd,J=13.3,4.6Hz,1H ), 2.39~2.34(m,2H), 2.34~2.29(m,4H), 2.28~2.19(m,6H), 2.15~2.10(m,1H), 2 .10(s,3H), 2.09~2.02(m,6H), 2.01(s,3H), 1.88(s,3H), 1.85(p,J=6.8Hz,2H). [Example]

[0262] 2-(Dimethylamino)ethyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (Compound 107) [ka] Step A 6-Chloro-1-{2-[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}acetyl)piperazin-1-yl]ethyl}-3-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (40.0 mg, 0.044 mmol) was dissolved in DMF (0.8 mL). DIPEA (0.023 mL, 0.131 mmol), HATU (19.9 mg, 0.052 mmol), and 2-dimethylaminoethanol (7.8 mg, 0.087 mmol) were added. The mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure and the desired product was purified using flash chromatography (SiO, DCM:MeOH, 0 to 20% MeOH gradient) to afford 2-(dimethylamino)ethyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (33.0 mg, 0.033 mmol, 76.6%) as a white solid. LCMS(ESI): 989.25m / z[M+H] + 1H NMR(500MHz,DMSO,353K)δ=10.70(s,1H), 8.22(dd,J=9.2,5.8,1H), 7.74(d,J=8.5,1H), 7.60(dd,J=10.4,2.7,1H), 7.48~7.39(m,3H) ), 7.37~7.29(m,2H), 7.24(d,J=8.5,1H), 7.14(d,J=8.1,1H), 6.88(dd,J=5.6,3.0,1H), 5.05(dd,J=13.1,5.2,1H), 4.89(s,2H), 4.39 (d, J = 17.2, 1H), 4.37-4.28 (m, 3H), 4.28-4.20 (m, 3H), 4.19-4.11 (m, 1H), 3.75 (d, J = 2.1, 3H), 3.36-3.31 (m, 4H), 3.30-3.26 (m, 2H), 2.93-2.84 (m, 1H), 2.62-2.57 (m, 2H), 2.46-2.38 (m, 1H), 2.28-2.21 (m, 2H), 2.18 (s, 6H), 2.13-2.02 (m, 7H), 2.01 (s, 3H), 1.88 (s, 3H). One proton in the aliphatic region overlaps with the solvent. [Example]

[0263] 2-(Methylsulfonyl)ethyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (Compound 124) [ka] Step A 6-Chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (20.0 mg, 0.022 mmol) and HATU (9.1 mg, 0.024 mmol) were dissolved in dry DMF (2.0 mL) under an argon atmosphere. To this was added EtN (0.011 mL, 0.065 mmol), and the reaction was stirred at room temperature for 20 minutes. 2-(Methylsulfonyl)ethan-1-ol (3.2 mg, 0.026 mmol) was then added, and the reaction (monitored by LCMS) was stirred under argon at room temperature for 3.5 hours. A second portion of HATU (9.1 mg, 0.024 mmol) containing EtN (0.011 mL, 0.065 mmol) in DMF (1.0 mL) was then added, and the reaction was continued under argon at room temperature for the next 16 hours. After complete consumption of the starting material, the solution was diluted with DCM (up to 10 mL) and washed with brine and water. The organic layer was dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure. The resulting residue was dissolved in DCM and purified by column chromatography (SiO, 1% to 40% MeOH in DCM) to afford 2-(methylsulfonyl)ethyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (11.4 mg, 0.011 mmol, 51.1%) as a white solid. LCMS(ESI):1024.1m / z[M+H] + 1H NMR(500MHz,DMSO,353K)δ10.64(s,1H), 8.23(dd,J=9.2,5.9Hz,1H), 7.74(d, J=8.6Hz,1H), 7.59(dd,J=10.4,2.6Hz,1H), 7.47~7.39(m,3H), 7.38~7.30(m, 2H), 7.25(d,J=8.6Hz,1H), 7.14(d,J=8.1Hz,1H), 6.89(dd,J=5.5,3.2Hz,1H) , 5.05(dd,J=13.1,5.2Hz,1H), 4.89(s,2H), 4.69(t,J=6.1Hz,2H), 4.40(d,J= 17.1Hz,1H), 4.32(d,J=17.0Hz,1H), 4.30~4.20(m,3H), 4.20~4.10(m,1H), 3. 76(d,J=2.1Hz,3H), 3.64(t,J=6.1Hz,2H), 3.36~3.32(m,4H), 3.32~3.28(m,2 H), 3.02(s,3H), 2.88(ddd,J=17.2,13.5,5.5Hz,1H), 2.67~2.60(m,1H), 2.48 ~2.40(m,1H), 2.29~2.21(m,2H), 2.15~2.02(m,7H), 2.01(s,3H), 1.88(s,3H). [Example]

[0264] 2-(4-Methylpiperazin-1-yl)ethyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (Compound 133) [ka] Step A 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (20. To a mixture of 1.0 mL of HCl (6.0 mg, 0.022 mmol), EDC-HCl (6.3 mg, 0.033 mmol), and DMAP (0.8 mg, 0.007 mmol) in dry DMF (1.0 mL) under an argon atmosphere, DIPEA (0.011 mL, 0.065 mmol) was added, followed by 2-(4-methylpiperazin-1-yl)ethan-1-ol (3.8 mg, 0.026 mmol). The reaction was stirred under argon at room temperature for 16 hours. HATU (8.3 mg, 0.022 mmol) was then added, and the reaction was continued for the next 45 minutes. The mixture was then diluted with DCM, and the solution was washed with brine and water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and dried under reduced pressure. The resulting residue was dissolved in DCM and purified by flash column chromatography (SiO, 1% to 40% MeOH in DCM) to afford 2-(4-methylpiperazin-1-yl)ethyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (5.8 mg, 0.006 mmol, 25.6%) as a white powder. LCMS(ESI):1044.2m / z[M+H] + 1H NMR(500MHz,DMSO,353K)δ10.65(s,1H), 8.22(dd,J=9.3,5.9Hz,1H), 7.75(d ,J=8.6Hz,1H), 7.59(dd,J=10.4,2.6Hz,1H), 7.47~7.39(m,3H), 7.37~7.30( m,2H), 7.25(d,J=8.9Hz,1H), 7.14(d,J=8.1Hz,1H), 6.87(dd,J=6.3,2.3Hz, 1H), 5.05(dd,J=13.0,5.2Hz,1H), 4.89(s,2H), 4.43~4.35(m,3H), 4.32(d,J= 17.0Hz,1H), 4.29~4.20(m,3H), 4.19~4.09(m,1H), 3.76(d,J=2.0Hz,3H), 3. 37~3.31(m,4H), 3.31~3.27(m,2H), 2.88(ddd,J=18.9,13.5,5.6Hz,1H), 2.6 8(t,J=5.8Hz,2H), 2.66~2.53(m,2H), 2.49~2.44(m,4H), 2.43~2.37(m,4H), 2.30~2.23(m,2H), 2.19(s,3H), 2.14~2.03(m,7H), 2.01(s,3H), 1.88(s,3H). [Example]

[0265] 2-Morpholinoethyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (Compound 129) [ka] Step A 6-Chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (30.0 mg, 0.033 mmol) was suspended in MeCN (1.0 mL) and 4-(2-bromoethyl)morpholine hydrobromide (18.0 mg, 0.065 mmol), followed by the addition of EtN (0.046 mL, 0.327 mmol). The reaction (monitored by LCMS) was stirred at 60° C. for 96 h. The solution was concentrated to dryness under reduced pressure and purified by flash column chromatography (SiO, 0% to 40% MeOH in DCM) and reverse-phase preparative HPLC (C, HO:MeCN+0.1% FA) to afford 2-morpholinoethyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (17.5 mg, 0.017 mmol, 51.8%) as a white solid. LCMS(ESI): 1031.2m / z[M+H] + 1H NMR(500MHz,DMSO,353K)δ10.65(s,1H), 8.21(dd,J=9.2,5.8Hz,1H), 7.75(d,J=8.7Hz,1H), 7.59(dd,J=10.4,2.6Hz,1H), 7.48~7.37(m,3H), 7.37~ 7.28(m,2H), 7.24(d,J=8.5Hz,1H), 7.14(d,J=8.1Hz,1H), 6.87(dd,J=6. 3,2.3Hz,1H), 5.05(dd,J=13.0,5.2Hz,1H), 4.89(s,2H), 4.46~4.35(m,3H) ), 4.32(dd,J=17.1,1.6Hz,1H), 4.29~4.12(m,4H), 3.76(d,J=2.0Hz,3H) , 3.57~3.48(m,4H), 3.38~3.31(m,4H), 3.31~3.27(m,2H), 2.88(ddd,J=17 .2,13.5,5.5Hz,1H), 2.67(t,J=5.8Hz,2H), 2.65~2.60(m,1H), 2.47~2.3 9(m,5H), 2.30~2.23(m,2H), 2.15~2.02(m,7H), 2.01(s,3H), 1.88(s,3H). [Example]

[0266] 3-(((6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonyl)oxy)methyl)-1-methyl-1H-imidazol-3-ium iodide (Compound 140) [ka] Step A 1-Methyl-1H-imidazole (0.097 mL, 1.218 mmol) and chloroiodomethane (0.093 mL, 1.279 mmol) were placed in a vial and stirred at room temperature for 48 h. The reaction product was then washed three times with EtO and dried under reduced pressure to give crude 3-(chloromethyl)-1-methyl-1H-imidazol-3-ium iodide (135.1 mg) as a white solid.

[0267] Step B 6-Chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (5.0 mg, 0.005 mmol), crude 3-(chloromethyl)-1-methyl-1H-imidazol-3-ium iodide (3.1 mg), KI (4.5 mg, 0.027 mmol), and EtN (0.004 mL, 0.027 mmol) were dissolved in dry DMF and stirred at 60° C. for 3 hours. The mixture was diluted with DCM and washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and dried under reduced pressure. The resulting residue was purified by preparative TLC (AlO, 20% MeOH in DCM) to give 3-(((6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonyl)oxy)methyl)-1-methyl-1H-imidazol-3-ium iodide (2.6 mg, 0.002 mmol, 41.9%) as a beige solid. LCMS(ESI):1012.2m / z[M+H] + 1H NMR(500MHz,DMSO,353K)δ10.68(s,1H), 9.43~9.38(m,1H), 8.19(dd,J=9.3,5.9Hz,1H) , 7.93(t,J=1.9Hz,1H), 7.78(d,J=8.7Hz,1H), 7.72(t,J=1.8Hz,1H), 7.61(dd,J=10.3, 2.6Hz,1H), 7.47~7.41(m,3H), 7.38~7.31(m,2H), 7.27(d,J=8.6Hz,1H), 7.15(d,J=8.1 Hz,1H), 6.87(dd,J=6.3,2.4Hz,1H), 6.43(d,J=10.7Hz,1H), 6.40(d,J=10.7Hz,1H), 5.0 6(dd,J=13.0,5.3Hz,1H), 4.96~4.85(m,2H), 4.40(d,J=17.1Hz,1H), 4.32(dd,J=17.1, 1.6Hz,1H), 4.29~4.19(m,3H), 4.19~4.10(m,1H), 3.88(s,3H), 3.76(d,J=2.2Hz,3H), 3. 35~3.28(m,4H), 3.28~3.24(m,2H), 2.89(ddd,J=17.3,13.4,5.5Hz,1H), 2.67~2.59(m, 1H), 2.46~2.38(m,1H), 2.23~2.15(m,2H), 2.15~2.02(m,7H), 2.01(s,3H), 1.87(s,3H). [Example]

[0268] (Pivaloyloxy)methyl 6-chloro-1-(2-(4-(2-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (Compound 74) [ka] Step A To a solution of tert-butyl 2-(3-fluoro-4-nitrophenoxy)acetate (500 mg, 1.844 mmol) in EtOH (10 mL) was added an aqueous solution of methylamine (0.41 ml, 9.22 mmol, 40% in HO) at room temperature, and the reaction mixture was stirred for 2 h at 50° C. After complete consumption of the starting material (monitored by TLC and LCMS), the volatiles were removed and the crude was purified by flash column chromatography (SiO, 50% EtOAc in hexanes) to give tert-butyl 2-(3-(methylamino)-4-nitrophenoxy)acetate (400 mg, 1.418 mmol, 77%) as a brown liquid. tert-Butyl 2-(3-fluoro-4-nitrophenoxy)acetate was prepared as described in US Patent Application Publication No. 2009 / 163552. LCMS(ESI+):283.2 m / z [M+H] + .

[0269] Step B A solution of tert-butyl 2-(3-(methylamino)-4-nitrophenoxy)acetate (400 mg, 1.418 mmol) in MeOH (10 mL) was degassed with argon for 15 minutes. Pd / C (400 mg, 10% w / w) was added slowly at room temperature under nitrogen. The reaction mixture was then stirred at room temperature under H balloon pressure for 4 hours. After complete consumption of the starting material, the reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to give the crude material. The product was purified by column chromatography (SiO, 70% EtOAc in hexanes) to give tert-butyl 2-(4-amino-3-(methylamino)phenoxy)acetate (250 mg, 0.992 mmol, 70%) as a brown liquid. LCMS(ESI+):253.1 m / z [M+H] + .

[0270] Step C To a solution of tert-butyl 2-(4-amino-3-(methylamino)phenoxy)acetate (250 mg, 0.992 mmol) in THF (6 mL) was added CDI (290 mg, 1.785 mmol) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at 70 °C for 4 h and monitored by LCMS and TLC. After completion, the volatiles were evaporated and the crude material was purified by column chromatography (SiO, 50-60% EtOAc in hexanes) to afford tert-butyl 2-((3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oxy)acetate (150 mg, 0.539 mmol, 55%) as a white solid. LCMS(ESI+):278.9 m / z [M+H] + .

[0271] Step D To a solution of tert-butyl 2-((3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oxy)acetate (150 mg, 0.54 mmol) in DMF (4 mL) was added NaH (388 mg, 8.1 mmol, 60% in mineral oil) portionwise at 0° C. under nitrogen. The reaction mixture was stirred at the same temperature for 30 minutes. Then, a solution of 3-bromopiperidine-2,6-dione (1.026 g, 5.4 mmol) in DMF (2 mL) was added dropwise to the reaction at 0° C. over a period of 5 minutes. The mixture was then heated at 80° C. under nitrogen for 2 hours. After complete consumption of the starting material (monitored by LCMS), the reaction mixture was cooled to −78° C., diluted with ethyl acetate, and stirred for the next 5 minutes. A saturated solution of NH4Cl was then added dropwise to the reaction mixture to quench excess sodium hydride. The organic layer was separated from the solidified aqueous layer, and the solid was washed with ethyl acetate. The combined organic phases were washed with brine and evaporated under reduced pressure to give the crude product. The product was purified by preparative TLC (SiO, 60% EtOAc in hexanes) to give tert-butyl 2-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oxy)acetate (60 mg, 0.154 mmol, 28%) as an off-white solid. LCMS(ESI+):390.1 m / z [M+H] + .

[0272] Step E To a solution of tert-butyl 2-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oxy)acetate (60 mg, 0.154 mmol) in DCM (2 mL) was added TFA (1 mL) dropwise at 0° C. and the reaction mixture was stirred at room temperature under nitrogen for 16 hours. After complete consumption of the starting material (the reaction was monitored by TLC and LCMS), the volatiles were evaporated under reduced pressure to give the crude compound, which was then purified by trituration with diethyl ether and n-pentane to give 2-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oxy)acetic acid (45 mg, 0.135 mmol, 87%) as an off-white solid. LCMS(ESI+):334.2 m / z [M+H] + .

[0273] Step F tert-Butyl 6-chloro-3-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-1-[2-(piperazin-1-yl)ethyl]-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (20.0 mg, 0.030 mmol) and 2-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oxy)acetic acid (10.9 mg, 0.033 mmol) were dissolved in dry DMF (0.989 mL) under an argon atmosphere, and DIPEA (0.016 mL, 0.089 mmol) was added, followed by HATU (11.8 mg, 0.031 mmol). The reaction (monitored by LCMS) was stirred under argon for 20 minutes. After complete consumption of the starting material, the mixture was diluted with DCM and washed with brine and water. The organic layer was dried over anhydrous MgSO, filtered, and dried under reduced pressure to give crude tert-butyl 6-chloro-1-(2-(4-(2-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate as a yellow oil, which was used directly in the next step. LCMS(ESI+):989.0 m / z [M+H] + .

[0274] Step G Crude tert-butyl 6-chloro-1-(2-(4-(2-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate was dissolved in dry DCM (0.5 mL) under an argon atmosphere and TFA (0.5 mL) was added. The reaction (monitored by LCMS) was stirred under argon for 16 h. After complete consumption of the starting material, the solution was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (C18, HO:MeCN+0.1% FA) to afford 6-chloro-1-(2-(4-(2-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (10.5 mg, 0.011 mmol, 36.7% over two steps) as a white solid. LCMS(ESI+):933.15 m / z [M+H] + .

[0275] Step H To a solution of 6-chloro-1-(2-(4-(2-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (13.0 mg, 0.014 mmol) in MeCN (500 μL) was added EtN (10 μL, 0.070 mmol). The reaction was stirred for 15 minutes and chloromethyl pivalate (2 μL, 0.017 mmol) was added. The reaction was carried out at room temperature overnight. A second amount of chloromethyl pivalate (2 μL, 0.017 mmol) was added and the mixture was stirred at 60° C. for 48 h. The solvent was removed under reduced pressure and the mixture was diluted with DCM and brine. The aqueous layer was extracted with DCM. The combined organic layers were dried over NaSO and concentrated in vacuo to give the corresponding (pivaloyloxy)methyl 6-chloro-1-(2-(4-(2-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (13.5 mg, 0.013 mmol, 92%) as a white solid. LCMS(ESI): 1047.25m / z[M+H] + . 1H NMR(500MHz,DMSO,353K)δ10.76(s,1H), 8.21(dd,J=9.2,5.9Hz,1H), 7.77(d,J=8.6Hz,1H), 7.59(dd,J=10.4,2.6Hz,1H), 7.45~7.38(m,2H), 7.32( td,J=8.9,2.6Hz,1H), 7.26(d,J=8.6Hz,1H), 6.96(d,J=8.6Hz,1H), 6.86(dd,J=6.1,2.6Hz,1H), 6.82(d,J=2.4Hz,1H), 6.62(dd,J=8.6,2.5Hz,1H) , 5.99(s,2H), 5.25(dd,J=12.5,5.4Hz,1H), 4.69(s,2H), 4.28~4.20(m,3 H), 4.20~4.12(m,1H), 3.75(s,3H), 3.38~3.32(m,4H), 3.30(s,3H), 3.28~ 3.23(m,2H), 2.91~2.84(m,1H), 2.72~2.63(m,1H), 2.54~2.51(m,1H), 2.2 6~2.19(m,2H), 2.14~2.01(m,7H), 2.00(s,3H), 1.87(s,3H), 1.15(s,9H). [Example]

[0276] (Pivaloyloxy)methyl 6-chloro-1-(2-(4-(2-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (Compound 73) [ka] Step A 2-Fluoro-3-nitrophenol (1 g, 6.365 mmol) was dissolved in DMF (20 mL) and KI (317 mg, 1.91 mmol) and KHCO (764 mg, 7.638 mmol) were added. tert-Butyl bromoacetate (1.691 mL, 11.458 mmol) was then added dropwise, and the reaction mixture was stirred under nitrogen at 60 °C for 5 h. After complete consumption of the starting material, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over NaSO and evaporated to give the crude compound, which was then purified by column chromatography (SiO, 0–10% EtOAc in hexanes) to give tert-butyl 2-(2-fluoro-3-nitrophenoxy)acetate (1.6 g, 5.90 mmol, 92%) as a yellow solid.

[0277] Step B To a solution of tert-butyl 2-(2-fluoro-3-nitrophenoxy)acetate (400 mg, 1.476 mmol) in EtOH (8 mL) was added an aqueous solution of methylamine (0.33 mL, 7.378 mmol, 40% in HO) at room temperature, and the reaction mixture was stirred at 50° C. for 2 h. After complete consumption of the starting material, the volatiles were removed under reduced pressure, and the crude was purified by column chromatography (SiO, 50% EtOAc in hexanes) to afford tert-butyl 2-(2-(methylamino)-3-nitrophenoxy)acetate (370 mg, 1.31 mmol, 88%) as a brown liquid. LCMS(ESI+):283.2 m / z [M+H] + .

[0278] Step C A solution of tert-butyl 2-(2-(methylamino)-3-nitrophenoxy)acetate (370 mg, 1.312 mmol) in MeOH (10 mL) was degassed with argon for 15 min. Pd / C (370 mg, 10% w / w) was added slowly under argon. The reaction mixture was then stirred at room temperature under H balloon pressure for 4 h. After complete consumption of the starting material, the reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography (SiO, 70% EtOAc in hexanes) to afford tert-butyl 2-(3-amino-2-(methylamino)phenoxy)acetate (225 mg, 0.892 mmol, 68%) as a brown liquid. LCMS(ESI+):253.0 m / z [M+H] + .

[0279] Step D To a solution of tert-butyl 2-(3-amino-2-(methylamino)phenoxy)acetate (225 mg, 0.892 mmol) in THF (12 mL) was added CDI (261 mg, 1.606 mmol) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at 60 °C for 4 h. The volatiles were removed under reduced pressure, and the crude material was purified by column chromatography (SiO, 50-60% EtOAc in hexanes) to afford tert-butyl 2-((3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)acetate (150 mg, 0.539 mmol, 60%) as a white solid. LCMS(ESI+):279.2 m / z [M+H] + .

[0280] Step E To a solution of tert-butyl 2-((3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)acetate (150 mg, 0.54 mmol) in DMF (4 mL) was added NaH (388 mg, 8.1 mmol, 60% in mineral oil) portionwise under nitrogen at 0° C., and the reaction mixture was stirred at the same temperature for 30 minutes. Then, a solution of 3-bromopiperidine-2,6-dione (1.026 g, 5.4 mmol) in DMF (2 mL) was added dropwise to the reaction mixture at 0° C. over a period of 5 minutes. The mixture was then heated to 80° C. under nitrogen for 2 hours. After complete consumption of the starting material (monitored by LCMS), the reaction mixture was cooled to −78° C., diluted with EtOAc, and stirred for 5 minutes. A saturated solution of ammonium chloride was then added dropwise to the reaction mixture to quench the excess sodium hydride. The organic layer was separated from the solidified aqueous layer, and the solid was washed with EtOAc. The combined organic phases were washed with brine and evaporated. The crude compound was purified by preparative TLC (SiO, 60% EtOAc in hexanes) to afford 60 mg (0.154 mmol, 28%) of tert-butyl 2-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)acetate as an off-white solid. LCMS(ESI+):390.2 m / z [M+H] + .

[0281] Step F To a solution of tert-butyl 2-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)acetate (60 mg, 0.154 mmol) in DCM (2 mL) at 0° C. was added TFA (1 mL) dropwise, and the reaction mixture was stirred at room temperature under nitrogen for 16 hours. After complete consumption of the starting material, the volatiles were removed under reduced pressure to give the crude compound, which was then purified by trituration with diethyl ether and n-pentane to give 2-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)acetic acid (30 mg, 0.09 mmol, 58%) as an off-white solid. LCMS(ESI+):334.2 m / z [M+H] + .

[0282] Step G Tert-butyl 6-chloro-3-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-1-[2-(piperazin-1-yl)ethyl]-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (20.0 mg, 0.030 mmol), 2-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)acetic acid (10.9 mg, 0.033 mmol), and DIPEA (0.016 mL, 0.089 mmol) were dissolved in dry DMF (1.0 mL) under an argon atmosphere. HATU (11.8 mg, 0.031 mmol) in DMF (1.0 mL) was added. The reaction was stirred under argon at room temperature for 15 minutes. After complete conversion, the solution was diluted with DCM to a maximum of 10 mL. The resulting solution was washed with brine and water, dried over anhydrous MgSO4, filtered, and dried under reduced pressure. Crude tert-butyl 6-chloro-1-{2-[4-(2-{[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-4-yl]oxy}acetyl)piperazin-1-yl]ethyl}-3-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (41.8 mg) was obtained as a yellow oil. LCMS(ESI+):989.2 m / z [M+H] + .

[0283] Step H Crude tert-butyl 6-chloro-1-{2-[4-(2-{[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-4-yl]oxy}acetyl)piperazin-1-yl]ethyl}-3-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (41.8 mg) was dissolved in dry DCM (0.500 mL) under an argon atmosphere, and TFA (0.500 mL, 6.529 mmol) was added. The reaction was stirred under argon for 16 hours. After complete consumption of the starting material, the solution was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (C18, HO:MeCN+0.1% FA) to afford 6-chloro-1-(2-(4-(2-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (13.9 mg, 0.015 mmol, 50% over two steps) as a white solid. LCMS(ESI+):933.2 m / z [M+H] + .

[0284] Step I To a solution of 6-chloro-1-(2-(4-(2-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (17.7 mg, 0.019 mmol) in dry MeCN (0.95 mL) was added EtN (0.013 mL, 0.095 mmol) followed by chloromethyl pivalate (0.030 mL, 0.021 mmol). The reaction was stirred at room temperature for 3 hours. An additional amount of chloromethyl pivalate (0.027 mL, 0.019 mmol) was added, and the mixture was stirred at 60° C. for 16 hours. Then, chloromethyl pivalate (0.014 mL, 0.010 mmol) was added again, and the reaction was continued for another 16 hours. After complete consumption of the starting material, the mixture was concentrated to dryness under reduced pressure. The resulting residue was diluted with DCM and washed with water. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated. The resulting solid was lyophilized to give (pivaloyloxy)methyl 6-chloro-1-(2-(4-(2-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (15.4 mg, 0.015 mmol, 77%) as a white solid. LCMS(ESI): 1047.25m / z[M+H] + . 1H NMR(500MHz,DMSO,353K)δ10.77(s,1H), 8.21(dd,J=9.2,5.9Hz,1H), 7.77(d,J=8.6Hz,1H), 7.59(dd,J=10.4,2.6Hz,1H), 7.45~7.39(m,2H), 7.3 2(ddd,J=9.2,8.6,2.6Hz,1H), 7.26(d,J=8.5Hz,1H), 6.93(t,J=8.2Hz,1H), 6.87(dd,J=5.9,2.7Hz,1H), 6.75(dd,J=8.0,0.8Hz,1H), 6.72(dd,J= 8.4,0.8Hz,1H), 5.99(s,2H), 5.27(dd,J=12.4,5.5Hz,1H), 4.84(s,2H), 4.31~4.19(m,3H), 4.19~4.09(m,1H), 3.75(s,3H), 3.57(s,3H), 3.40~3. 30(m,4H), 3.30~3.21(m,2H), 2.95~2.81(m,1H), 2.74~2.61(m,2H), 2.26 ~2.18(m,2H), 2.14~2.01(m,7H), 2.01(s,3H), 1.87(s,3H), 1.15(s,9H). [Example]

[0285] Acetoxymethyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (Compound 41) [ka] Step A To a solution of 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (10.0 mg, 0.011 mmol) in DMF (0.31 mL) was added DIPEA (0.009 mL, 0.054 mmol) followed by chloromethyl acetate (0.001 mL, 0.016 mmol). The reaction was stirred at 55° C. for 16 hours. After completion, the solution was evaporated. The resulting residue was dissolved in DMSO and purified by reverse-phase preparative HPLC (C18, HO:MeCN+0.1% FA) to afford acetoxymethyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (6.6 mg, 0.007 mmol, 61%) as a white solid. LCMS(ESI): 990.25m / z[M+H] + . 1H NMR(500MHz,DMSO,353K)δ10.66(s,1H), 8.23(dd,J=9.2,5.8Hz,1H), 7.77(d ,J=8.6Hz,1H), 7.59(dd,J=10.4,2.6Hz,1H), 7.50~7.38(m,3H), 7.38~7.29(m ,2H), 7.26(d,J=8.6Hz,1H), 7.14(d,J=8.1Hz,1H), 6.88(dd,J=5.6,3.0Hz,1 H), 5.96(d,J=6.0Hz,1H), 5.95(d,J=6.1Hz,1H), 5.05(dd,J=13.0,5.2Hz,1H) , 4.89(s,2H), 4.40(d,J=17.1Hz,1H), 4.31(dd,J=17.2,1.4Hz,1H), 4.28~4. 19(m,3H), 4.19~4.10(m,1H), 3.76(d,J=1.8Hz,3H), 3.36~3.30(m,4H), 3.30~ 3.24(m,2H), 2.88(ddd,J=17.3,13.5,5.5Hz,1H), 2.66~2.59(m,1H), 2.48~2 .39(m,1H), 2.26~2.18(m,2H), 2.15~2.02(m,10H), 2.01(s,3H), 1.88(s,3H). [Example]

[0286] 1-Acetoxyethyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (Compound 75) [ka] Step A 6-Chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (20.0 mg, 0.022 mmol) was dissolved in dry DMF (0.73 mL) and DIPEA (0.019 mL, 0.109 mmol), followed by ethyl 1-bromoacetate (4.4 mg, 0.026 mmol). The reaction was stirred under argon at 55° C. for 24 hours. A second amount of ethyl 1-bromoacetate (3.6 mg, 0.022 mmol) was added, and the reaction was continued under argon at 55° C. for another 48 h. After completion, the solution was concentrated under reduced pressure, diluted with DMSO, and purified by reverse-phase preparative HPLC (C18, HO:MeCN+0.1% FA) to afford 1-acetoxyethyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (10.9 mg, 0.011 mmol, 49%) as a white solid. LCMS(ESI):1004.1m / z[M+H] + . 1H NMR(500MHz,DMSO,353K)δ10.66(s,1H), 8.24(dd,J=9.2,5.8Hz,1H), 7.77(d,J=8.6 Hz,1H), 7.59(dd,J=10.4,2.6Hz,1H), 7.47~7.38(m,3H), 7.37~7.29(m,2H), 7.26(d ,J=8.6Hz,1H), 7.14(d,J=8.1Hz,1H), 7.08~7.00(m,1H), 6.90(dd,J=5.9,2.7Hz,1H ), 5.05(dd,J=13.1,5.2Hz,1H), 4.89(s,2H), 4.40(d,J=17.0Hz,1H), 4.32(dd,J=17. 1,1.6Hz,1H), 4.27(t,J=6.3Hz,2H), 4.25~4.20(m,1H), 4.20~4.11(m,1H), 3.76(d, J=2.1Hz,3H), 3.37~3.32(m,4H), 3.32~3.24(m,2H), 2.88(ddd,J=17.4,13.5,5.5Hz, 1H), 2.67~2.58(m,1H), 2.48~2.40(m,1H), 2.27~2.20(m,2H), 2.17~2.04(m,7H), 2. 03(d,J=1.5Hz,3H), 2.01(d,J=1.1Hz,3H), 1.88(s,3H), 1.59(dd,J=5.5,2.1Hz,3H). [Example]

[0287] (Pivaloyloxy)methyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1-(2-(2-methoxyethoxy)ethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (Compound 149) [ka] Step A To a solution of 4-bromo-3,5-dimethyl-1H-pyrazole (5 g, 28.57 mmol) in DMF (50 mL) under nitrogen at room temperature was added 1-bromo-2-(2-methoxyethoxy)ethane (5.07 mL, 37.14 mmol), followed by CsCO (18.57 g, 57.14 mmol). The reaction mixture was stirred at room temperature for 2 hours. After complete consumption of the starting material, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over NaSO and concentrated under reduced pressure. The residue was triturated with diethyl ether and n-pentane to give 4.8 g (17.33 mmol, 60%) of 4-bromo-1-(2-(2-methoxyethoxy)ethyl)-3,5-dimethyl-1H-pyrazole as an off-white solid. LCMS(ESI):276.8 m / z [M+H] + .

[0288] Step B To a solution of 4-bromo-1-(2-(2-methoxyethoxy)ethyl)-3,5-dimethyl-1H-pyrazole (1 g, 3.61 mmol) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.70 ml, 18.12 mmol) in THF (20 mL) was added n-butyllithium (2 M in hexanes, 4.5 mL, 9.058 mmol) under nitrogen at −78° C. The reaction mixture was stirred at the same temperature for 2 h. After complete conversion, excess n-butyllithium was quenched with saturated NH4Cl solution at −78° C., and the reaction was extracted with ethyl acetate. The combined organic fractions were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude 1-(2-(2-methoxyethoxy)ethyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1 g) was used in the next step without further purification. LCMS(ESI):325.0 m / z [M+H] + .

[0289] Step C To a solution of tert-butyl 7-bromo-6-chloro-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-1H-indole-2-carboxylate (300 mg, 0.57 mmol) in dioxane (4 mL) and water (1 mL) was added crude 1-(2-(2-methoxyethoxy)ethyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (734 mg) and CsCO (552 mg, 1.70 mmol). The mixture was deoxygenated with argon, and PdCl(dtbpf) (36 mg, 0.056 mmol) was added under a nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 1 h until the starting material was completely consumed. The reaction mixture was diluted with ethyl acetate and washed successively with water and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. tert-Butyl 6-chloro-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1-(2-(2-methoxyethoxy)ethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (240 mg, 0.37 mmol, 65%) was purified by column chromatography (SiO2, 20% EtOAc in hexanes). LCMS(ESI):650.4 m / z [M+H] + .

[0290] Step D To a solution of tert-butyl 6-chloro-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1-(2-(2-methoxyethoxy)ethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (240 mg, 0.37 mmol) in DMF (5 mL) at room temperature was added tert-butyl 4-(2-chloroethyl)piperazine-1-carboxylate (275 mg, 1.11 mmol) and CsCO (360 mg, 1.11 mmol). The reaction mixture was stirred under nitrogen at 90° C. for 16 hours. After complete consumption of the starting material, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over NaSO and concentrated under reduced pressure. The crude material was purified by column chromatography (SiO, 30% EtOAc in hexanes) to afford 240 mg (0.28 mmol, 75%) of tert-butyl 1-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)-6-chloro-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1-(2-(2-methoxyethoxy)ethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate as a white solid. LCMS(ESI):862.8 m / z [M+H] + .

[0291] Step E To a solution of tert-butyl 1-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)-6-chloro-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1-(2-(2-methoxyethoxy)ethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (240 mg, 0.28 mmol) in dioxane (3 mL) under nitrogen at 0° C. was added 6 mL of 4 M HCl in dioxane. The reaction mixture was stirred under nitrogen with cooling at 0° C. for 2 hours. After complete consumption of the starting material (monitored by TLC and LCMS), the reaction mixture was poured into cold 1 M NaOH solution and extracted with dichloromethane. The combined organic fractions were dried over Na2SO4 and concentrated in vacuo. The crude compound was purified by trituration with diethyl ether and n-pentane to give 200 mg (0.26 mmol, 94%) of tert-butyl 6-chloro-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1-(2-(2-methoxyethoxy)ethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-(2-(piperazin-1-yl)ethyl)-1H-indole-2-carboxylate as a white solid. LCMS(ESI):762.6 m / z [M+H] + .

[0292] Step F To a solution of tert-butyl 6-chloro-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1-(2-(2-methoxyethoxy)ethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-(2-(piperazin-1-yl)ethyl)-1H-indole-2-carboxylate (180 mg, 0.24 mmol) in DMF (5 mL) was added 2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetic acid (75 mg, 0.24 mmol), HATU (134 mg, 0.36 mmol), and DIPEA (0.082 mL, 0.47 mmol) at room temperature under nitrogen. The mixture was stirred at room temperature under nitrogen for 1 hour. After the reaction was completed, the mixture was poured into ice-cold water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The crude compound was purified by column chromatography (SiO, 10% MeOH in DCM) to give 100 mg (0.094 mmol, 39%) of tert-butyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1-(2-(2-methoxyethoxy)ethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate as an off-white solid. LCMS(ESI):1062.4 m / z [M+H] + .

[0293] Step G To a solution of tert-butyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1-(2-(2-methoxyethoxy)ethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (100 mg, 0.094 mmol) in DCM (5 mL) under nitrogen was added TFA (1 mL) dropwise at 0° C. The mixture was stirred under nitrogen at room temperature for 16 hours. After complete consumption of the starting material (monitored by TLC and LCMS), the volatiles were evaporated. The crude compound was purified by trituration with diethyl ether and n-pentane to give 93 mg (0.083 mmol, 83%) of 1-(2-(2-carboxy-6-chloro-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1-(2-(2-methoxyethoxy)ethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1H-indol-1-yl)ethyl)-4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-ium trifluoroacetate as a white solid. LCMS(ESI):1006.6 m / z [M+H] + .

[0294] Step H To a solution of 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1-(2-(2-methoxyethoxy)ethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid trifluoroacetate (16.8 mg, 0.015 mmol) in DMF (75 μL) and DIPEA (16 μL, 0.089 mmol) was added chloromethyl 2,2-dimethylpropanoate (4 μL, 0.030 mmol). The reaction was stirred at room temperature for 24 hours. An additional amount of chloromethyl 2,2-dimethylpropanoate (4 μL, 0.030 mmol) was added, and the reaction mixture was stirred at 55° C. for 48 h. The solvent was removed under reduced pressure, and the product was purified using flash chromatography (SiO, 5–10% MeOH in DCM) to afford (pivaloyloxy)methyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1-(2-(2-methoxyethoxy)ethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (2.1 mg, 0.002 mmol, 12%) as a white solid. LCMS(ESI):1120.5m / z[M+H] + . 1H NMR(500MHz,DMSO,353K)δ10.66(s,1H), 8.21(dd,J=9.3,5.9,1H), 7.77(d,J=8.6,1H), 7.59(dd,J=10.3,2.6,1H), 7.46~7.40(m,3H), 7.35~7.2 9(m,2H), 7.26(d,J=8.6,1H), 7.13(dd,J=8.1,3.0,1H), 6.87(dd,J=6.1 ,2.6,1H), 5.99(s,2H), 5.15~5.03(m,2H), 4.88(s,2H), 4.40(dd,J=17. 1,4.5,1H), 4.31(d,J=17.1,1H), 4.26~4.17(m,6H), 3.81~3.78(m,2H), 3.54(dd,J=5.8,4.1,2H), 3.46~3.43(m,2H), 3.33~3.29(m,4H), 3.28~3 .23(m,5H), 2.88(ddd,J=18.5,13.3,5.5,1H), 2.46~2.38(m,1H), 2.25~ 2.19(m,2H), 2.12~2.02(m,7H), 2.01(s,3H), 1.91(s,3H), 1.15(s,9H). [Example]

[0295] Cell viability assay: MV4-11, ARH-77 cells The effect of various compounds of the present invention on the viability of MV4-11 and ARH-77 cell lines was investigated using the CTG protocol described below.

[0296] The MV4-11 cell line is derived from acute myeloid leukemia, and both cell lines have been described in the literature as MCL-1-dependent cell lines, whereas the lymphoblastoid ARH-77 cell line has been described as MCL-1-independent (Tron AE et al. Nat Commun. 2018;9:5341; Caenepeel S et al. Cancer Discov. 2018 Dec;8(12):1582-1597).

[0297] Cells (MV4-11 or ARH-77) were seeded in 348-well plates containing growth medium containing 1% FBS. Compound stocks were then pre-diluted in DMSO and added directly to the cell culture medium (final DMSO concentration: 0.5%). Compound concentrations used in this assay were 1 / 3 dilutions (9–12 points) starting from 30 μM. After 24 h of incubation, cell viability was assessed using the CellTiter-Glo® Luminescent Cell Viability Assay (Promega, Cat. No. G7572). Luminescent signals were measured using a CLARIOstar Plus multimode microplate reader (574–590 nm).

[0298] Results were normalized to the DMSO control. Collected data was analyzed using GraphPad Prism to determine pCC 50 value (i.e. CC 50 The negative logarithm of the CC value was calculated. 50 The IC (50% cytotoxic concentration) is the effective concentration of a cytotoxic compound that results in 50% of the maximum possible cell death (i.e., the concentration of compound required to reduce cell viability by 50%). 50 Rather than CC 50 is often used.

[0299] [Table 10] JPEG2025540250000233.jpg119170

[0300] As shown in Table 9, compounds of the present invention have the ability to reduce the viability of acute myeloid leukemia cells and may therefore be useful in the treatment of cancer. At the same time, compounds of the present invention have no / little effect on the viability of ARH-77 cells, further supporting the specific MCL-1-dependent activity of the compounds.

[0301] dMCL-1-2 is an MCL-1 degrader described in Papatzimas et al., J. Med. Chem. 2019, 62, 5522-5540. [Example]

[0302] MV4-11 cells: MCL-1 protein degradation, Western blot The following degradation assay protocol was used to examine the effect of various compounds of the present invention on MCL-1 protein degradation in the MV4-11 cell line.

[0303] MV4-11 cells were maintained in IMDM medium (supplemented with penicillin / streptomycin and 10% fetal bovine serum (FBS)). MV4-11 cells were harvested, centrifuged (250 rcf, 5 min), resuspended in growth medium containing 10% FBS, and counted. The cell suspension was then diluted to 1 × 10 cells / well using growth medium containing 10% FBS. 6 The culture was adjusted to 0.5 × 10 cells / ml. 6 Cells were seeded into 24-well plates containing 0.5 mL of medium per well. Immediately after seeding, cells were pretreated with DMSO or the pan-caspase inhibitor Q-VD-Oph for 30 minutes. Compounds from stocks pre-diluted in DMSO were then added directly to the cell culture medium at the appropriate concentrations (final DMSO concentration was 0.5%). After 6 hours of compound treatment, cells were harvested from the plates and suspended in lysis buffer (2% SDS, 50 mM Tris, pH 8.0, 100 U / mL Pierce Universal Nuclease for Cell Lysis, complete EDTA-free protease inhibitor cocktail) and incubated on ice for 45 minutes. Protein amounts were determined by BCA assay, and equal amounts of each sample were loaded onto precast gels for protein separation. After antibody staining for MCL-1, α-tubulin, and cleaved forms of PARP and caspase-3, the membranes were washed and signals were developed.

[0304] Densitometry values ​​for MCL-1 were normalized to total protein levels (unstained membranes). The percentage of protein reduction is calculated relative to DMSO-treated cells (0% reduction).

[0305] [Table 11] JPEG2025540250000235.jpg56170JPEG2025540250000236.jpg28170

[0306] As shown in Table 10 and Figure 1, exemplified compounds of the present invention induced dose-dependent degradation of MCL-1 protein in MV4-11 cells, resulting in potent apoptosis induction. Consequently, complete degradation of MCL-1 protein was observed at the highest tested dose. When apoptosis is blocked, exemplified compounds induce the expected incomplete MCL-1 degradation, which may prevent MCL-1-independent cells (e.g., normal cells) from dying. This hypothesis is supported by the results from ARH-77 cells shown in Table 9, which demonstrate the lack of cytotoxic activity of exemplified compounds in MCL-1-independent leukemia cells. [Example]

[0307] Determination of cell permeability and target engagement NanoBRET-in-cell CRBN target engagement assay The cell membrane permeability of prodrugs of MCL-1 degraders was determined using a commercially available NanoBRET intracellular CRBN target engagement assay (NanoBRET CRBN TE Assay) using NanoLuc CRBN HEK293 cells and NanoBRET intracellular CRBN tracers (N2910, N2912, PROMEGA).

[0308] The assay was performed in a 96-well plate format (Corning Catalog 3600). NanoLuc CRBN HEK293 cells were treated with CRBN tracer and compounds. Briefly, cells were suspended (0.17 x 10) in Opti-MEM without phenol red (Life Technologies). 6 Cells were treated with CRBN tracer (20x concentrated, 5 μl / well; final concentrations of 0.8 μM for live mode and 0.17 μM for lysis) or DMSO vehicle control (20x concentrated, 5 μl / well). The cells thus prepared were seeded into wells of a 96-well plate on top of pre-seeded compound (100x concentrated, 1 μl / well; 11-point 2-fold dilutions) using an Echo 555 acoustic dispenser (Labcyte). For lysis mode assays, digitonin (0.05 mg / ml, 10x concentrated, 10 μl / well) was additionally added. For live mode assays, plates were incubated at 37°C and 5% CO for 2 hours, then incubated at room temperature for 15 minutes before cooling. For lysis mode assays, no incubation was performed. 3x complete NanoBRET reagent (50 μl / well) was prepared appropriately for live mode and lysis mode according to the manufacturer's recommendations. Plates were incubated at room temperature for 2 minutes and luminescence and fluorescence readings were taken using a CLARIOstar multimode plate reader (donor emission RLU - 450 nm; acceptor emission RFU - 610 nm). RBA values ​​were calculated using the live mode assay (pIC 50 Live) and lytic mode assays (pIC 50 Absolute pIC of lysis 50 It is an index of cell membrane permeability (lower is better) calculated from the negative logarithm of the absolute IC50 value when converted to molar. RBA xi=10 Λ (-absolute pIC 50 Live xi) / 10 Λ (-absolute pIC 50 dissolution xi)

[0309] [Table 12] JPEG2025540250000238.jpg94170

[0310] Based on the evidence, the prodrugs of the MCL-1 degraders presented herein have cell membrane permeability. Importantly, the permeability of the prodrug-modified degraders is 4-2600 times higher than that of the unmodified dMCL-1-2 degraders, demonstrating improved cell membrane permeability for the prodrugs.

[0311] Abbreviations and Definitions Below is a list of abbreviations used in this application: [Table 13]

[0312] As used herein, the term "room temperature" means a temperature between 20°C and 25°C.

[0313] The present invention is further described with reference to the following clauses. 1. Compounds of formula (I) [MCL-1 ligand prodrug moiety]-linker-[ligase ligand moiety] (I) or a salt, solvate, hydrate or isomer thereof, wherein [ligase ligand moiety] is: [ka] [In the formula, M is O, S, or NH, or absent; [ka] is the R of the linker 18 shows the bond with R 22 is hydrogen, halogen, -OMe, an amino group, heterocycloalkyl, or unsubstituted C1-C6 alkyl; R 29 is hydrogen or Me, L' is hydrogen, alkyl, benzyl, acetyl, or pivaloyl. [MCL-1 ligand prodrug moiety] is: [ka] [In the formula, R 11 is a halogen, R 13 is a halogen, R 19 is the R of the linker 14 is the bond that connects to (i)R 9 is -C(O)O(C1-C6 alkyl), -C(O)Ocycloalkyl, -C(O)Oheterocycloalkyl, -C(O)Oaryl or -P(O)(OR p )2, and the C1-C6 alkyl is -OC(O)(unsubstituted C1-C6 alkyl), -OC(O)(at least one R 10 C1-C6 alkyl substituted with), -OC(O)cycloalkyl, -OC(O)heterocycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, -OC(O)(CH2) m O(CH2) m O(unsubstituted C1-C6 alkyl), -OC(O)(CH2) m O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(unsubstituted C1-C6 alkyl), -OC(O)O(at least one R 10 C1-C6 alkyl substituted with -OC(O)Ocycloalkyl, -OC(O)O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2CH2O) m (C1-C6 alkyl substituted with OP(O)(OH)2), -OC(O)O(CH2CH2S) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)(unsubstituted C1-C6 alkyl), -OC(O)O(CH2) mS(O)2 (unsubstituted C1-C6 alkyl), -OC(O)NH (C1-C6 alkyl substituted with OMe), -OC(O)NMe (C1-C6 alkyl substituted with OMe), -P(O)(OH)2, -OP(O)(OH)2, -C(O)heterocycloalkyl, -C(O)N(unsubstituted C1-C6 alkyl)2, heteroaryl, heterocycloalkyl, -S(unsubstituted C1-C6 alkyl), -S(O)(unsubstituted C1-C6 alkyl), -N + (unsubstituted C1-C6 alkyl)3, -N + substituted with one or more groups selected from (unsubstituted C1-C6 alkyl)cycloalkyl, N-(unsubstituted C1-C6 alkyl)piperidinium cation, N-(unsubstituted C1-C6 alkyl)morpholinium cation, and N-(unsubstituted C1-C6 alkyl)imidazolium cation; Each R 10 are independently -OH, -O(unsubstituted C-C alkyl), -OBn, -NH, -NMe, -NHC(O)(unsubstituted C-C alkyl), -NHC(O)O(unsubstituted C-C alkyl), heterocycloalkyl, heteroaryl, aryl, -C(O)NMe; Each R p are independently -(CH2) m OC(O) (unsubstituted C1-C6 alkyl), each m is independently 1, 2, 3, or 4; or (ii)R 9 is -C(O)O(CH2) p NMe2, -C(O)O(CH2) p NHMe, -C(O)OCH2CH(OH)CH2OH, -C(O)OCH2CH2CMe2OH, or -C(O)OCH2CH2SO2Me, and each p is independently 2, 3, 4, 5, or 6. [Linker] has the formula: R 14 -R 15 -R 16 -R 17 -R 18 [In the formula, R 14 Ha-C1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 1-6 Alkyl-N(C 1-6 alkyl)-, -C(O)-, -SO2- or absent; R 15 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 Alkyl-NH-, -C 1-6 Alkyl-N(C 1-6 alkyl)-, -cycloalkyl-NH-, -heterocycloalkyl-NH- or absent; R 16 Ha-C 1-6 alkyl, —C(O)—, —C(O)—NH—, —C(O)O—, —CH—C(O)—, —CH—C(O)—NH—, —CH—C(O)O— or absent; R 17 -CH2(C2H4-O) y , -(C2H4-O) x , -(C3H6-O) x , or absent, x is 1 to 10, y is between 2 and 10; R 18 Ga-C 1-6 alkyl, cycloalkyl, —CH—NH—C(O)—, heterocycloalkyl, or absent; R 14 ~R 18 At least one of the following is present] The compound, or a salt, solvate, hydrate or isomer thereof. 2. The compound of clause 1, wherein [ligase ligand moiety] is: [ka] 3. The compound of clause 1, wherein [ligase ligand moiety] is: [ka] 4.R 22 4. The compound according to any one of clauses 1 to 3, wherein is hydrogen. 5. The compound according to any one of clauses 1 to 4, wherein L' is hydrogen. 6. The compound according to any one of clauses 1 to 5, wherein M is O or NH, or absent. 7. The compound according to any one of clauses 1, 2 and 4-6, wherein the [ligase ligand moiety] is: [ka] 8. The compound of clause 7, wherein [ligase ligand moiety] is: [ka] 9.R 14 Ga-C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 The compound according to any one of clauses 1 to 8, wherein the group is alkynyl, -C(O)-, -SO2- or absent. 10.R 14 Ga-C 1-6 The compound according to clause 9, wherein the aryl group is alkyl. 11.R 15 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 11. The compound according to any one of clauses 1 to 10, wherein alkyl-NH-, -cycloalkyl-NH- or absent. 12.R 15 12. The compound according to clause 11, wherein is heterocycloalkyl. 13.R 15 piperazine, bridged piperazine, piperazine N-oxide, piperazine cation, [ka] and During the ceremony, [ka] is R 14 shows the bond with [ka] is R16 13. The compound according to clause 12, exhibiting a bond with 14.R 15 is piperazine or [ka] 14. The compound according to clause 13, wherein 15.R 16 Ga-C 1-6 15. The compound according to any one of clauses 1 to 14, wherein the alkyl is -CH2-C(O)-NH- or -C(O)-. 16.R 16 Ga-C 1-6 16. The compound according to clauses 1 to 15, wherein the group is alkyl or -C(O)-. 17.R 17 17. The compound according to any one of clauses 1 to 16, wherein 18.R 18 Ga-C 1-6 18. The compound according to any one of clauses 1 to 17, wherein said alkyl, heterocycloalkyl or absent. 19.R 18 Ga-C 1-6 The compound according to clause 18, wherein the alkyl or heterocycloalkyl. 20.R 18 Ga-C 1-6 20. The compound according to clause 19, which is an alkyl or piperazine. 21. The compound according to any one of clauses 1 to 20, wherein [Linker] is selected from the following: [ka] [In the formula, [ka] indicates binding to the [MCL-1 ligand prodrug moiety], [ka] indicates binding to [ligase ligand moiety]] 22.R 9is -C(O)O(C1-C6 alkyl), -C(O)Ocycloalkyl, -C(O)Oheterocycloalkyl, -C(O)Oaryl or -P(O)(OR p )2, wherein the C1-C6 alkyl is -OC(O)(unsubstituted C1-C6 alkyl), -OC(O)(at least one R 10 C1-C6 alkyl substituted with), -OC(O)cycloalkyl, -OC(O)heterocycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, -OC(O)(CH2) m O(CH2) m O(unsubstituted C1-C6 alkyl), -OC(O)(CH2) m O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(unsubstituted C1-C6 alkyl), -OC(O)O(at least one R 10 C1-C6 alkyl substituted with -OC(O)Ocycloalkyl, -OC(O)O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2CH2O) m (C1-C6 alkyl substituted with OP(O)(OH)2), -OC(O)O(CH2CH2S) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)(unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)2 (unsubstituted C1-C6 alkyl), -OC(O)NH (C1-C6 alkyl substituted with OMe), -OC(O)NMe (C1-C6 alkyl substituted with OMe), -P(O)(OH)2, -OP(O)(OH)2, -C(O)heterocycloalkyl, -C(O)N(unsubstituted C1-C6 alkyl)2, heteroaryl, heterocycloalkyl, -S(unsubstituted C1-C6 alkyl), -S(O)(unsubstituted C1-C6 alkyl), -N + (unsubstituted C1-C6 alkyl)3, -N +22. The compound of any one of clauses 1 to 21, substituted with one or more groups selected from (unsubstituted C1-C6 alkyl)2 cycloalkyl, N-(unsubstituted C1-C6 alkyl) piperidinium cation, N-(unsubstituted C1-C6 alkyl) morpholinium cation, and N-(unsubstituted C1-C6 alkyl) imidazolyl cation. 23.R 9 is -C(O)O(C1-C6 alkyl), -C(O)Ocycloalkyl, -C(O)Oheterocycloalkyl, -C(O)Oaryl, or -P(O)(OR p )2, wherein the C1-C6 alkyl is -OC(O)Me, -OC(O)Et, -OC(O) i Pr, -OC(O)C(CH3)3, -OC(O)CH2OH, -OC(O)CH(CH3)OH, -OC(O)C(CH3)2OH, -OC(O)CH2CH2OH, -OC(O)CH(OH)CHMe2, -OC(O)CH(OH)CH2CHMe2, -OC(O)CH2CH(OH)Me, -OC(O)CH2C(OH)Me2, -OC(O)CH(CH2OH)(NHC(O)Me), -OC(O)CH(NHC(O)Me)(isobutyl), -OC(O)CH(OH)aryl, -OC(O)CH(OH)CH2aryl, -OC(O)heterocycloalkyl, -OC(O)cycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, -OC(O)CH2CH2aryl, -OC(O)CH(NH2) i Pr, -OC(O)CH( i Pr)NHC(O)O t Bu, -OC(O)CH2OCH2CH2OMe, -OC(O)CH2(OCH2CH2)2OMe, -OC(O)OMe, -OC(O)OEt, -OC(O)O iPr, -OC(O)Ocycloalkyl, -OC(O)OCH2CH2OEt, -OC(O)O(CH2CH2O)2Et, -OC(O)O(CH2CH2O)3Et, -OC(O)O(CH2CH2O)3CH2CH2OP(O)(OH)2, -OC(O)OCH2CH2SMe, -OC(O)OCH2CH2S(O)Me, -OC(O)OCH2CH2S(O)2Me, -OC(O)OCH2heteroaryl, -OC(O)OCH2heterocycloalkyl, -OC(O) OCH2CH2OCH2aryl, -OC(O)OCH2CH2C(O)NMe2, -OC(O)O(CH2)6NH2, -OC(O)O(CH2)6NMe2, -OC(O)OCH(CHOEt)2, -OC(O)NHCH2CH2OMe, -OC(O)NMeCH2CH2OMe, -SMe, -S(O)Me, -P(O)(OH)2, -OP(O)(OH)2, -C(O)NMe2, -C(O)heterocycloalkyl, heteroaryl, heterocycloalkyl, -N + (Me)3, -N + 23. The compound of clause 22, substituted with one or more groups selected from (Me)2 cycloalkyl, N-methylmorpholinium cation, N-methylpiperidinium cation and N-methylimidazolium cation. 24.R 9 24. The compound of clause 23, wherein is —C(O)O(C1-C6 alkyl), wherein the C1-C6 alkyl is substituted with one or more groups selected from —OC(O)C(CH3)3, —OC(O)CH2CH2OH, —OC(O)C(CH3)2OH, —OC(O)heterocycloalkyl, —OC(O)CHOCH2CHOMe, —OC(O)OiPr, —OC(O)Ocycloalkyl, —OC(O)O(CH2CHO)2Et, —OP(O)(OH)2, heteroaryl, or heterocycloalkyl. 25.R 9-C(O)OCH2OC(O)C(CH3)3, -C(O)OCH2OC(O)CH2CH2OH, -C(O)OCH2OC(O)C(CH3)2OH, -C(O)OCH2OC(O)piperidine, -C(O)OCH2OC(O)CH2OCH2CH2OMe, -C(O)OCH2OC(O)OiPr, -C(O)OCHMeOC(O)OiPr, -C(O)OCHMeOC(O)Ocyclohexyl, -C(O)OC 25. The compound according to clause 24, which is HMeOC(O)O(CH2CHO)2Et, -C(O)OCH2CH2OP(O)(OH)2, -C(O)OCH2(N-methylimidazolium cation), -C(O)OCH2(N-methylpiperidinium cation), -C(O)OCH2 dioxolane, -C(O)OCH2CH2 morpholine, -C(O)OCH2CH2 piperazine, -C(O)OCH2CH2CH2 piperazine. 26.R 9 -C(O)O(CH2) p NMe2, -C(O)O(CH2) p 22. The compound of any of clauses 1-21, wherein the compound is NHMe, —C(O)OCH2CH(OH)CH2OH, C(O)OCH2CH2CMe2OH, or —C(O)OCH2CH2SO2Me, and each p is independently 2, 3, 4, 5, or 6. 27.R 9 27. The compound according to clause 26, wherein is —C(O)OCH2CH2NMe2, —C(O)OCH2CH(OH)CH2OH or —C(O)OCH2CH2SO2Me. 28.R 11 28. The compound according to any one of clauses 1 to 27, wherein is Cl. 29.R 13 29. The compound according to any one of clauses 1 to 28, wherein is F. 30. [Table 14] JPEG2025540250000255.jpg148170. 31. [Table 15] 31. The compound according to clause 30, selected from: JPEG2025540250000257.jpg140170. 32. [Table 16] 31. The compound according to clause 30, selected from: 33. [Table 17] 31. The compound according to clause 30, selected from: 34. The compound according to any one of clauses 1 to 33, wherein, unless otherwise specified, each alkyl, alkenyl, alkynyl, aryl, heteroaryl and benzyl is unsubstituted. 35. Compound of formula (I) [MCL-1 ligand prodrug moiety]-[linker]-[ligase ligand moiety] (I) or a salt, solvate, hydrate or isomer thereof, wherein [ligase ligand moiety] is: (a) Formula (IV) [ka] [In the formula, Each of X1 and X2 is independently O or S; Each of Q1 and Q2 is independently N or CR 5 and at least one of Q1 and Q2 is N; Each of E1, E2, E3, and E4 is independently N or CR'; n is 0, 1 or 2; L2 is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)R b , -C(O)OR b , -C(O)NH2, -C(O)NHR b , -C(O)NR b 2, -OR b , -NRb 2, or -S(O)2R b and Each R 5 are independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR b , -NR b 2, -NR b C(O)R b , -NR b C(O)OR b , -NO2, -CN, -C(O)R b , -C(O)OR b , -C(O)NH2, -C(O)NHR b , -C(O)NR b 2, -OR b , -OC(O)R b , -OC(O)OR b , -OC(O)NH2, -OC(O)NHR b , -OC(O)NR b 2, -SR b , -S(O)2R b , -S(O)2OR b , -S(O)2NH2, -S(O)2NHR b , -S(O)NR b 2;-OR 21 , -NH-R 21 , -C(O)-NH-R 21 , or -CH2-NH-C(O)-R 21 and Each R' is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR b , -NR b 2, -NR b C(O)R b , -NR b C(O)OR b , -NO2, -CN, -C(O)R b , -C(O)OR b , -C(O)NH2, -C(O)NHR b , -C(O)NR b 2. -C(O)NHCHR b 2. -CHRb NHC(O)NHR b , -CHR b NHC(O)C(halogen)2R b , -OR b , -OC(O)R b , -OC(O)OR b , -OC(O)NH2, -OC(O)NHR b , -OC(O)NR b 2, -SR b , -S(O)2R b , -S(O)2OR b , -S(O)2NH2, -S(O)2NHR b , -S(O)NR b 2. -NHS(O)2R b , -R 21 , -OR 21 , -NH-R 21 , -C(O)-R 21 , -C(O)-NH-R 21 , or -CH2-NH-C(O)-R 21 and Each R b are independently hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl; R 21 is the R of the linker 18 and formula (IV) is a bond connecting to a single R 21 [including (b) Formula (VIIa), (VIIb), or (VIIc) [ka] (VIIa) (VIIb) JPEG2025540250000262.jpg35170(VIIc) [In the formula, Each of X1 and X2 is independently O or S; each of Q1 and Q2 independently represents N or CR, and at least one of Q1 and Q2 is N; Each of W1, W2, and W3 is independently N or CR a and Z is O, S, or NRe and n is 0, 1 or 2; L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)R b , -C(O)OR b , -C(O)NH2, -C(O)NHR b , -C(O)NR b 2, -OR b , -NR b 2, or -S(O)2R b and Each R is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR b , -NR b 2, -NR b C(O)R b , -NR b C(O)OR b , -NO2, -CN, -C(O)R b , -C(O)OR b , -C(O)NH2, -C(O)NHR b , -C(O)NR b 2, -OR b , -OC(O)R b , -OC(O)OR b , -OC(O)NH2, -OC(O)NHR b , -OC(O)NR b 2, -SR b , -S(O)2R b , -S(O)2OR b , -S(O)2NH2, -S(O)2NHR b , -S(O)NR b 2, -R 21 , -OR 21 , -NH-R 21 , -C(O)-R 21 , -C(O)-NH-R 21 , or -CH2-NH-C(O)-R 21 and Each R aare independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR b , -NR b 2, -NR b C(O)R b , -NR b C(O)OR b , -NO2, -CN, -C(O)R b , -C(O)OR b , -C(O)NH2, -C(O)NHR b , -C(O)NR b 2, -OR b , -OC(O)R b , -OC(O)OR b , -OC(O)NH2, -OC(O)NHR b , -OC(O)NR b 2, -SR b , -S(O)2R b , -S(O)2OR b , -S(O)2NH2, -S(O)2NHR b , -S(O)NR b 2, -R 21 , -OR 21 , -NH-R 21 , -C(O)-R 21 , -C(O)-NH-R 21 , or -CH2-NH-C(O)-R 21 and Each R e are independently hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, -R 21 , -OR 21 , -NH-R 21 , -C(O)-R 21 , -C(O)-NH-R 21 , or -CH2-NH-C(O)-R 21 and Each R b are independently hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl; R 21 is the R of the linker 18and each of formula (VIIa), formula (VIIb) and formula (VIIc) is a bond connecting to a single R 21 [including (c) Formula (VIII) [ka] [In the formula, Each of X1 and X2 is independently O or S; n is 0, 1 or 2; L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)R b , -C(O)OR b , -C(O)NH2, -C(O)NHR b , -C(O)NR b 2, -OR b , -NR b 2, or -S(O)2R b and Each of R1, R2, and R3 independently represents hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR b , -NR b 2, -NR b C(O)R b , -NR b C(O)OR b , -NO2, -CN, -C(O)R b , -C(O)OR b , -C(O)NH2, -C(O)NHR b , -C(O)NR b 2, -OR b , -OC(O)R b , -OC(O)OR b , -OC(O)NH2, -OC(O)NHR b , -OC(O)NR b 2, -SR b , S(O)2R b , -S(O)2OR b , -S(O)2NH2, -S(O)2NHR b , -S(O)NR b 2, -R 21 , -OR21 , -NH-R 21 , -C(O)-R 21 , -C(O)-NH-R 21 , or -CH2-NH-C(O)-R 21 and Each R b are independently hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl; R 21 is the R of the linker 18 and formula (VIII) is a bond connecting to a single R 21 including] or (d) Formula (IX) [ka] [In the formula, Each of X1 and X2 is independently O or S; L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)R b , -C(O)OR b , -C(O)NH2, -C(O)NHR b , -C(O)NR b 2, -OR b , -NR b 2, or -S(O)2R b and each of Q1, Q2, Q3, Q4, and Q5 independently represents N or CR, and at least one of Q1, Q2, Q3, Q4, and Q5 is N; Each R is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR b , -NR b 2, -NR b C(O)R b , -NR b C(O)OR b , -NO2, -CN, -C(O)R b , -C(O)OR b , -C(O)NH2, -C(O)NHR b , -C(O)NR b 2, -ORb , -OC(O)R b , -OC(O)OR b , -OC(O)NH2, -OC(O)NHR b , -OC(O)NR b 2, -SR b , -S(O)2R b , -S(O)2OR b , -S(O)2NH2, -S(O)2NHR b , or -S(O)NR b 2, -R 21 , -OR 21 , -NH-R 21 , -C(O)-R 21 , -C(O)-NH-R 21 , or -CH2-NH-C(O)-R 21 and Each R b are independently hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl; R 21 is the R of the linker 18 and formula (IX) is a bond connecting to a single R 21 [including [MCL-1 ligand prodrug moiety] is: [ka] [In the formula, R 11 is a halogen, R 13 is a halogen, R 19 is the R of the linker 14 is the bond that connects to (i)R 9 is -C(O)O(C1-C6 alkyl), -C(O)Ocycloalkyl, -C(O)Oheterocycloalkyl, -C(O)Oaryl or -P(O)(OR p )2, and the C1-C6 alkyl is -OC(O)(unsubstituted C1-C6 alkyl), -OC(O)(at least one R 10C1-C6 alkyl substituted with), -OC(O)cycloalkyl, -OC(O)heterocycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, -OC(O)(CH2) m O(CH2) m O(unsubstituted C1-C6 alkyl), -OC(O)(CH2) m O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(unsubstituted C1-C6 alkyl), -OC(O)O(at least one R 10 C1-C6 alkyl substituted with -OC(O)Ocycloalkyl, -OC(O)O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2CH2O) m (C1-C6 alkyl substituted with OP(O)(OH)2), -OC(O)O(CH2CH2S) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)(unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)2 (unsubstituted C1-C6 alkyl), -OC(O)NH (C1-C6 alkyl substituted with OMe), -OC(O)NMe (C1-C6 alkyl substituted with OMe), -P(O)(OH)2, -OP(O)(OH)2, -C(O)heterocycloalkyl, -C(O)N(unsubstituted C1-C6 alkyl)2, heteroaryl, heterocycloalkyl, -S(unsubstituted C1-C6 alkyl), -S(O)(unsubstituted C1-C6 alkyl), -N + (unsubstituted C1-C6 alkyl)3, -N + substituted with one or more groups selected from (unsubstituted C1-C6 alkyl)cycloalkyl, N-(unsubstituted C1-C6 alkyl)piperidinium cation, N-(unsubstituted C1-C6 alkyl)morpholinium cation, and N-(unsubstituted C1-C6 alkyl)imidazolium cation; Each R 10are independently -OH, -O(unsubstituted C-C alkyl), -OBn, -NH, -NMe, -NHC(O)(unsubstituted C-C alkyl), -NHC(O)O(unsubstituted C-C alkyl), heterocycloalkyl, heteroaryl, aryl, C(O)NMe; Each R p are independently -(CH2) m OC(O) (unsubstituted C1-C6 alkyl), each m is independently 1, 2, 3, or 4; or (ii)R 9 is -C(O)O(CH2) p NMe2, -C(O)O(CH2) p NHMe, -C(O)OCH2CH(OH)CH2OH, -C(O)OCH2CH2CMe2OH, or -C(O)OCH2CH2SO2Me, and each p is independently 2, 3, 4, 5, or 6. [Linker] has the formula: R 14 -R 15 -R 16 -R 17 -R 18 [In the formula, R 14 Ha-C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 1-6 Alkyl-N(C 1-6 alkyl)-, -C(O)-, -SO2- or absent; R 15 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 Alkyl-NH-, -C 1-6 Alkyl-N(C 1-6 alkyl)-, -cycloalkyl-NH-, -heterocycloalkyl-NH- or absent; R 16 Ha-C 1-6 alkyl, —C(O)—, —C(O)—NH—, —C(O)O—, —CH—C(O)—, —CH—C(O)—NH—, —CH—C(O)O— or absent; R 17 -CH2(C2H4-O) y , -(C2H4-O) x , -(C3H6-O) x , or absent, x is 1 to 10, y is between 2 and 10; R 18 Ga-C 1-6 alkyl, cycloalkyl, -CH2-NH-C(O)-, heterocycloalkyl, or absent; R 14 ~R 18 At least one of the following is present] The compound, or a salt, solvate, hydrate or isomer thereof. 36. The compound according to clause 35, wherein each alkyl group, alkenyl group, alkynyl group, aryl group, heteroaryl group and benzyl group is unsubstituted unless otherwise specified. 37. Each R' is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR b , -NR b 2, -NR b C(O)R b , -NR b C(O)OR b , -NO2, CN, -C(O)R b , -C(O)OR b , -C(O)NH2, -C(O)NHR b , -C(O)NR b 2, -OR b , -OC(O)R b , -OC(O)OR b , -OC(O)NH2, -OC(O)NHR b , -OC(O)NR b 2, -SR b , -S(O)2R b , -S(O)2OR b , S(O)2NH2, -S(O)2NHR b , -S(O)NR b 2, -R 21 , -OR 21 , -NH-R 21, -C(O)-R 21 , -C(O)-NH-R 21 , or -CH2-NH-C(O)-R 21 37. The compound according to clause 35 or 36, wherein 38.Each R b 38. The compound of clause 37, wherein is independently hydrogen, alkyl, cycloalkyl, or aryl. 39. The compound according to clause 38, wherein aryl is substituted with one or more groups selected from halogen, alkyl and O-haloalkyl, optionally wherein the halogen is Cl, the alkyl is methyl and the O-haloalkyl is O-CF3. 40. The compound according to any one of clauses 35 to 39, wherein one of E1, E2, E3 and E4 is N, and the remaining three of E1, E2, E3 and E4 are each CR'. 41.(a) E1 is N and E2, E3 and E4 are CR', or (b) E2 is N and E1, E3 and E4 are CR'; or (c) E3 is N and E1, E2 and E4 are CR', or (d) E4 is N, and E1, E2 and E3 are CR'; A compound according to clause 40. 42. The compound according to any one of clauses 35-39, wherein E1, E2, E3 and E4 are each CR', and optionally E1, E2, E3 and E4 are each CH. 43. Three of E1, E2, E3 and E4 are CH, and one of E1, E2, E3 and E4 is C-halogen, C-alkyl, C-alkenyl, C-alkynyl, C-aryl, C-heteroaryl, C-benzyl, C-haloalkyl, C-haloalkenyl, C-NH2, C-NHR b , C-NR b 2. C-NR b C(O)R b , C-NR b C(O)OR b , C-NO2, C-CN, CC(O)R b , CC(O)OR b , CC(O)NH2, CC(O)NHR b, CC(O)NR b 2. CC(O)NHCHR b 2. C-CHR b NHC(O)NHR b , C-CHR b NHC(O)C(halogen)2R b , C-OR b , C-OC(O)R b , C-OC(O)OR b , C-OC(O)NH2, C-OC(O)NHR b , C-OC(O)NR b 2. C-SR b , CS(O)2R b , CS(O)2OR b , CS(O)2NH2, CS(O)2NHR b , CS(O)2NR b 2. C-NHS(O)2R b , -R 21 , -OR 21 , -NH-R 21 , -C(O)-R 21 , -C(O)-NH-R 21 , or -CH2-NH-C(O)-R 21 43. The compound according to clause 42, wherein 44.(a) E2, E3 and E4 are each CH or (b) E1, E3 and E4 are each CH; or (c) E1, E2 and E4 are each CH; A compound according to clause 43. 45. The compound according to any one of clauses 35 to 39, wherein two of E1, E2, E3 and E4 are N, and the remaining two of E1, E2, E3 and E4 are each CR'. 46. ​​The compound according to any one of clauses 35 to 39, wherein three of E1, E2, E3 and E4 are N and the remaining one of E1, E2, E3 and E4 is CR'. 47. One of W1, W2 and W3 is N and the remaining W1, W2 and W3 are CR a and optionally R a 47. The compound according to any one of clauses 35 to 46, wherein is H. 48.W1, W2 and W3 are each CR a 47. The compound according to any one of clauses 35 to 46, wherein 49.W1 is C-NH2, C-NHR b or C-NR b 2, optionally C—NH2. 50. The compound according to any one of clauses 35-46, wherein W1, W2 and W3 are each N. 51. The compound according to any one of clauses 35 to 50, wherein Z is NH or N-alkyl, optionally NH or N-Me. 52. In the formula (IV), formula (VIIa), formula (VIIb) and formula (VIIc), (a) Q1 is N and Q2 is CR, or (b) Q1 is N and Q2 is N, or (c) Q1 is CR and Q2 is N, optionally Q1 is CH or C-alkyl, and further optionally Q1 is CH or C-Me; 52. A compound according to any one of clauses 35 to 51. 53. The compound according to any one of clauses 35 to 52, wherein in formula (IX), one of Q1, Q2, Q3, Q4 and Q5 is N, and the remaining four of Q1, Q2, Q3, Q4 and Q5 are each CR. 54.(a) Whether Q1 is N or (b) Q2 is N, or (c) Q3 is N; A compound according to clause 53. 55. The compound according to any one of clauses 35 to 52, wherein in formula (IX), two of Q1, Q2, Q3, Q4 and Q5 are N, and the remaining three of Q1, Q2, Q3, Q4 and Q5 are each CR. 56.(a) Q1 and Q2 are N and Q3, Q4 and Q5 are each CR, or (b) Q2 and Q3 are N and Q1, Q4 and Q5 are each CR; (c) Q1 and Q3 are N, and Q2, Q4, and Q5 are each CR, or (d) Q2 and Q4 are N and Q1, Q3 and Q5 are each CR; or (e) Q1 and Q4 are N, and Q2, Q3, and Q5 are each CR; 55. A compound according to clause 55. 57. The compound according to any one of clauses 35 to 52, wherein in formula (IX), three of Q1, Q2, Q3, Q4 and Q5 are N, and the remaining two of Q1, Q2, Q3, Q4 and Q5 are each CR. 58. Compound of formula (I) [MCL-1 ligand prodrug moiety]-[linker]-[ligase ligand moiety] (I) or a salt, solvate, hydrate or isomer thereof, wherein [ligase ligand moiety] is: (a) Formula (Va) or (Vb) [ka] (Va) (Vb) or a pharmaceutically acceptable salt or tautomer thereof [In the formula, Each of X1 and X2 is independently O or S; Z1 is O, S, or NR 6 and T is C=O or SO2, R 1 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; Y5, Y6, Y7 and Y8 each independently represent N or CR 7 and At least one of Y5, Y6 and Y7 in formula (Va) is CR 7 and at least one of Y5, Y5 and Y8 in formula (Vb) is CR 7 and n is 0, 1 or 2; L3 is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)R'''', -CHC(O)OR'''', -C(O)OR'''', -C(O)NH2, -C(O)NHR'''', -C(O)NR''''2, -OR'''', -NR''''2, or -S(O)2R'''', Each R 7 are independently hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR'''', -NR''''2, -CH2NR''''2, -NR''''C(O)R'''', -NR''''C(O)CH2NR''''2, -NR''''C(O)CH2-heterocycloalkyl, -NR''''C(O)CH(OH)R'''', -CH2NR''''C(O)OR'''', -NR''''C(O)OR' ''', -NR''''SO2R'''', -NO2, -CN, -C(O)R'''', -C(O)OR'''', -C(O)NH2, -C(O)NHR'''', -C(O)NR''''2, -OR'''', -OC(O)R'''', -OC(O)OR'''', -OC(O )NH2, -OC(O)NHR'''', -OC(O)NR''''2, -NHC(S)NHR'''', SR'''', or -S(O)2R'''', -S(O)2OR'''', -S(O)2NH2, -S(O)2NHR'''', -S(O)2NR''''2, -OR 21 , -NH-R 21 , -C(O)-NH-R 21 , or -CH2-NH-C(O)-R 21 and each R"" is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; R 6is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR'''', -NR''''2, -NR''''C(O)R'''', -N[C(O)R'''']2, -NR''''C(O)OR'''', -NO2, -CN, -C(O)R'''', -C(O)OR'''', -C( O)NH2, -C(O)NHR'''', -C(O)NR''''2, -OR'''', -OC(O)R'''', -OC(O)OR'''', -OC(O)NH2, -OC(O)NHR'''', - OC(O)NR''''2, -SR'''', or -S(O)2R'''', -S(O)2OR'''', -S(O)2NH2, -S(O)2NHR'''', -S(O)2NR''''2, -R 21 , -C(O)-NH-R 21 , or -CH2-NH-C(O)-R 21 and R 21 is the R of the linker 18 and each of formula (Va) and formula (Vb) is a bond connecting to a single R 21 Including, If Z1 is O, Y6 is CR 7 and When the compound is of formula (Va): (i) Y5, Y6, and Y7 are each CR 7 If R 7 At least one of them is not H, (ii) Z1 is NR 6 If Y6 and Y7 are CR 7 and (iii) When Z1 is S, Y5 is not C-OMe and Y6 is not C-OMe; (iv) When Z1 is S and Y5 is C-NHCOMe, Y7 is not C-CH2NR''''C(O)OR''''; (v) When Z1 is S and Y5 is N, Y6 is not CH, C-aryl or CC(O)OR''''; (vi) When Z1 is S and Y6 is N, Y7 is C-NH2, C-NHR'''', C-NR''''2, C-NR''''C(O)OR'''', C-CH2NR''''C(O)OR'''', C-haloalkyl, C- t butyl, C—OR′′′, C—COOR′′′ or C—SR′′′ and when Y7 is C—NH2, C—NHR′′′ or C—NR′′′′2, then Y5 is CH; When the compound is of formula (Vb): (vii) Y5, Y6, and Y8 are each CR 7 If R 7 At least one of them is not H, (viii) when Z1 is S, Y5 is not C-COOH or C-NHC(O)Me, and Y8 is not C-Br; (ix) When Z1 is S and Y6 is C-Br, Y8 is C-OR'''', (x) When Z1 is S, Y5 is N, and Y6 is CH or C—NH2, then Y8 is not CH; (xi) when Z1 is S and Y5 is N, then Y6 is not C-halogen, C-alkyl, C-cycloalkyl, C-aryl, C-heteroaryl, C-CH2NH2, C-COOalkyl, or C-NHC(O)alkyl; (xii) when Z1 is NR 6 If Y5, Y6 and Y8 are CR 7 is], or (b) Formula (IIa) or (IIb) [ka] (IIa) (IIb) [In the formula, Each of X1 and X2 is independently O or S; Z is O, S, or NR 2 and T is C=O or SO2, Y3 is N or CR; Y4 is N or CR; [ka] represents a single bond or a double bond, each [ka] is a double bond, each of W1, W2, W3 and W4 independently represents N or CR a and at least one of W1, W2, W3, and W4 is N; each [ka] is a single bond, W1, W2, W3 and W4 are each CR a 2, Y4 is CR, n is 0, 1 or 2; L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)R h , -C(O)OR h , -C(O)NH2, -C(O)NHR h , -C(O)NR h 2, -OR h , -NR h 2, or -S(O)2R h and Each R is independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR h , -NR h 2, -NR h C(O)R h , -NR h C(O)CH2R h , -NR h C(O)CH(OH)R h , -NR h C(O)OR h , -NR h SO2R h , -NO2, -CN, -C(O)R h , -C(O)OR h, -C(O)NH2, -C(O)NHR h , -C(O)NR h 2, -OR h , -OC(O)R h , -OC(O)OR h , -OC(O)NH2, -OC(O)NHR h , -OC(O)NR h 2, -SR h , or -S(O)2R h , -S(O)2OR h , -S(O)2NH2, -S(O)2NHR h , or -S(O)NR h 2, Each R a are independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR h , -NR h 2, -NR h C(O)R h , -NR h C(O)CH(OH)R h , -NR h C(O)OR h , -NR h SO2R h , -NO2, -CN, -C(O)R h , -C(O)OR h , -C(O)NH2, -C(O)NHR h , -C(O)NR h 2, -OR h , -OC(O)R h , -OC(O)OR h , -OC(O)NH2, -OC(O)NHR h , -OC(O)NR h 2, -SR h , -S(O)2R h , -S(O)2OR h , -S(O)2NH2, -S(O)2NHR h , -S(O)NR h 2, -OR 21 , -NH-R 21 , -C(O)-NH-R 21, or -CH2-NH-C(O)-R 21 and Each R h are independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; R 2 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR h , -NR h 2, -NR h C(O)R h , -N[C(O)R h ]2, -NR h C(O)OR h , -NO2, -CN, -C(O)R h , -C(O)OR h , -C(O)NH2, -C(O)NHR h , -C(O)NR h 2, -OR h , -OC(O)R h , -OC(O)OR h , -OC(O)NH2, -OC(O)NHR h , -OC(O)NR h 2, -SR h , -S(O)2R h , -S(O)2OR h , -S(O)2NH2, -S(O)2NHR h , or -S(O)NR h 2, R 1 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; R 21 is the R of the linker 18 and each of formula (IIa) and formula (IIb) is a bond connecting to a single R 21 Including, each [ka] is a double bond and Z is NR2 and R 2 is hydrogen, and each R a is hydrogen, W4 is CR a is] [MCL-1 ligand prodrug moiety] is: [ka] [In the formula, R 11 is a halogen, R 13 is a halogen, R 19 is the R of the linker 14 is the bond that connects to (i)R 9 is -C(O)O(C1-C6 alkyl), -C(O)Ocycloalkyl, -C(O)Oheterocycloalkyl, -C(O)Oaryl or -P(O)(OR p )2, and the C1-C6 alkyl is -OC(O)(unsubstituted C1-C6 alkyl), -OC(O)(at least one R 10 C1-C6 alkyl substituted with), -OC(O)cycloalkyl, -OC(O)heterocycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, -OC(O)(CH2) m O(CH2) m O(unsubstituted C1-C6 alkyl), -OC(O)(CH2) m O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(unsubstituted C1-C6 alkyl), -OC(O)O(at least one R 10 C1-C6 alkyl substituted with -OC(O)Ocycloalkyl, -OC(O)O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2CH2O) m (C1-C6 alkyl substituted with OP(O)(OH)2), -OC(O)O(CH2CH2S) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)(unsubstituted C1-C6 alkyl), -OC(O)O(CH2) mS(O)2 (unsubstituted C1-C6 alkyl), -OC(O)NH (C1-C6 alkyl substituted with OMe), -OC(O)NMe (C1-C6 alkyl substituted with OMe), -P(O)(OH)2, -OP(O)(OH)2, -C(O)heterocycloalkyl, -C(O)N(unsubstituted C1-C6 alkyl)2, heteroaryl, heterocycloalkyl, -S(unsubstituted C1-C6 alkyl), -S(O)(unsubstituted C1-C6 alkyl), -N + (unsubstituted C1-C6 alkyl)3, -N + substituted with one or more groups selected from (unsubstituted C1-C6 alkyl)cycloalkyl, N-(unsubstituted C1-C6 alkyl)piperidinium cation, N-(unsubstituted C1-C6 alkyl)morpholinium cation, and N-(unsubstituted C1-C6 alkyl)imidazolium cation; Each R 10 are independently -OH, -O(unsubstituted C-C alkyl), -OBn, -NH, -NMe, -NHC(O)(unsubstituted C-C alkyl), -NHC(O)O(unsubstituted C-C alkyl), heterocycloalkyl, heteroaryl, aryl, -C(O)NMe; Each R p are independently -(CH2) m OC(O) (unsubstituted C1-C6 alkyl), each m is independently 1, 2, 3, or 4; or (ii)R 9 is -C(O)O(CH2) p NMe2, -C(O)O(CH2) p NHMe, -C(O)OCH2CH(OH)CH2OH, -C(O)OCH2CH2CMe2OH, or -C(O)OCH2CH2SO2Me, and each p is independently 2, 3, 4, 5, or 6. [Linker] has the formula: R 14 -R 15 -R 16 -R 17 -R 18 [In the formula, R 14 Ha-C1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 1-6 Alkyl-N(C 1-6 alkyl)-, -C(O)-, -SO2- or absent; R 15 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 Alkyl-NH-, -C 1-6 Alkyl-N(C 1-6 alkyl)-, -cycloalkyl-NH-, -heterocycloalkyl-NH- or absent; R 16 Ha-C 1-6 alkyl, —C(O)—, —C(O)—NH—, —C(O)O—, —CH—C(O)—, —CH—C(O)—NH—, —CH—C(O)O— or absent; R 17 -CH2(C2H4-O) y , -(C2H4-O) x , -(C3H6-O) x , or absent, x is 1 to 10, y is between 2 and 10; R 18 Ga-C 1-6 alkyl, cycloalkyl, -CH2-NH-C(O)-, heterocycloalkyl, or absent; R 14 ~R 18 At least one of the following is present] The compound, or a salt, solvate, hydrate or isomer thereof. 59. The compound according to clause 58, wherein each alkyl group, alkenyl group, alkynyl group, aryl group, heteroaryl group and benzyl group is unsubstituted unless otherwise specified. 60. The compound according to clause 58 or 59, wherein when Z1 is S of formula (Vb), then Y5 is not -C-NHC(O)R'''' or -C(O)OR''''. 61.Z1 is NR 6 61. The compound according to any one of clauses 58 to 60, wherein 62. Each R is independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR'''', -NR''''2, -NR''''C(O)R'''', -NR''''C(O)CH(OH)R'''', -NR''''C(O)OR'''', -NR''''S02R'''', -NO2, -CN, -C(O)R' ''', -C(O)OR''', -C(O)NH2, -C(O)NHR'''', -C(O)NR''''2, -OR'''', -OC(O)R'''', -OC(O)OR''', -OC(O)NH2, -OC(O )NHR'''', -OC(O)NR''''2, -SR'''', or -S(O)2R'''', -S(O)2OR'''', -S(O)2NH2, -S(O)2NHR'''', -S(O)2NR''''2, -OR 21 , -NH-R 21 , -C(O)-NH-R 21 , or -CH2-NH-C(O)-R 21 62. The compound according to any one of clauses 58 to 61, wherein 63.R 1 63. The compound according to any one of clauses 58 to 62, wherein is hydrogen. 64.R 6 64. The compound according to any one of clauses 58 to 63, wherein is hydrogen. 65. [ligase ligand moiety] is formula (Va), and Y5, Y6, and Y7 are each CR 7 65. The compound according to any one of clauses 58 to 64, wherein 66.Y5 is -C-NHC(O)R'''', Y6 is CH, Y7 is CH or CCl; A compound according to clause 65. 67.L3 is hydrogen, Z1 is S, R 1 is hydrogen, T is C=O, Y7 is CH, A compound according to clause 66. 68. Formula (Vb), wherein Y5, Y6 and Y8 are each CR 7 65. The compound according to any one of clauses 58 to 64, wherein 69.L3 is hydrogen, Z1 is S, R 1 is H, T is C=O, Y5 is CH, C—OR″″, CCl, C—CN, or C—NHC(O)R″″; Y6 is CH, CCl, C-alkyl, C-cycloalkyl, or C-haloalkyl; Y8 is CH, C-OR'''', C-NHC(O)R'''', C-NHC(O)OR'''', C-NHR'''', C-NH2, or C-NHS02R'''', when Y5 is CCl, Y6 is CH, C-alkyl, C-cycloalkyl, or C-haloalkyl; optionally, each R"" is independently alkyl, cycloalkyl, aryl, or benzyl; A compound according to clause 68. 70.Y5 is CH, Y6 is CH or CCl; Y8 is C-OR'''' or C-NH2, and may be C-OMe or C-NH2; 69. A compound according to clause 69. 71.(a) Z is NR 2 or (b) Z is S; A compound according to any one of clauses 58 to 70. 72.Each [ka] 72. The compound according to any one of clauses 58 to 71, wherein is a double bond. 73. The compound according to any one of clauses 58 to 72, wherein L is hydrogen. 74. One of W1, W2, W3 and W4 is N, and the remaining three W1, W2, W3 and W4 are CR a and optionally W4 is CR a74. The compound according to clause 72 or 73, wherein 75. Two of W1, W2, W3 and W4 are N, and the remaining two W1, W2, W3 and W4 are CR. a 73. The compound according to any one of clauses 58 to 72, wherein 76. One of W1, W2, W3 and W4 is CR a and the remaining three W1, W2, W3 and W4 are each N. 77. Each R is independently hydrogen, halogen, or -NR h C(O)R h 77. The compound according to any one of clauses 58 to 76, wherein 78. Compound of formula (I) [MCL-1 ligand prodrug moiety]-[linker]-[ligase ligand moiety] (I) or a salt, solvate, hydrate or isomer thereof, wherein [ligase ligand moiety] is: (a) Formula (VIa) or (VIb) [ka] (VIa) (VIb) [In the formula, M is O, S, or NH, or absent; [ka] is the R of the linker 18 shows the bond with R 22 is hydrogen, halogen, -OMe, amino, heterocycloalkyl, or unsubstituted C1-C6 alkyl; L' is hydrogen, alkyl, benzyl, acetyl, or pivaloyl. (b) Formula (II) [ka] [In the formula, Each of X1 and X2 is independently O or S; T is C=O or SO2, R 1 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; n is 0, 1 or 2; L4 is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)H, -C(O)R b , -C(O)OH, -C(O)OR b , -C(O)NH2, -C(O)NHR b , -C(O)NR b 2, -OH, -OR b , -NH2, -NHR b , -NR b 2. -S(O)2H or -S(O)2R b and R y is selected from the following: [ka] During the ceremony, [ka] indicates binding to T, Z3 is O, S, or NR 3 and U is O, S, NR b or CR i 2, Each of Y1, Y2 and Y3 independently represents N or CR d and Each R d are independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR b , -NR b 2. -NHC(O)R b , -NR b C(O)R b , NHC(O)CH(OH)R b , -NR b C(O)CH(OH)Rb , -NHC(O)OR b , -NR b C(O)OR b , -NHSO2R b , -NR b SO2R b , -NO2, -CN, -C(O)H, C(O)R b , -C(O)OH, -C(O)OR b , -C(O)NH2, -C(O)NHR b , -C(O)NR b 2, -OH, -OR b , -OC(O)H, -OC(O)R b , -OC(O)OH, -OC(O)OR b , -OC(O)NH2, -OC(O)NHR b , -OC(O)NR b 2, -SH, -SR b , -S(O)2H, -S(O)2R b , -S(O)2OH, -S(O)2OR b , -S(O)2NH2, -S(O)2NHR b , -S(O)NR b 2, -OR 21 , -NH-R 21 , -C(O)-NH-R 21 , or -CH2-NH-C(O)-R 21 and Each R i are independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR b , -NR b 2. -NHC(O)R b , -NR b C(O)R b , -NHC(O)CH(OH)R b , -NR b C(O)CH(OH)R b , -NHC(O)OR b , -NR b C(O)OR b , -NHSO2R b , -NR b SO2R b, -NO2, -CN, -C(O)H, C(O)R b , -C(O)OH, -C(O)OR b , -C(O)NH2, -C(O)NHR b , -C(O)NR b 2, -OH, -OR b , -OC(O)H, -OC(O)R b , -OC(O)OH, -OC(O)OR b , -OC(O)NH2, -OC(O)NHR b , -OC(O)NR b 2, -SH, -SR b , -S(O)2H, -S(O)2R b , -S(O)2OH, -S(O)2OR b , -S(O)2NH2, -S(O)2NHR b , or -S(O)NR b 2, Each R 3 are independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR b , -NR b 2. -NHC(O)R b , -NR b C(O)R b , NHC(O)CH(OH)R b , -NR b C(O)CH(OH)R b , -NHC(O)OR b , -NR b C(O)OR b , -NHSO2R b , -NR b SO2R b , -NO2, -CN, -C(O)H, C(O)R b , -C(O)OH, -C(O)OR b , -C(O)NH2, -C(O)NHR b , -C(O)NR b 2, -OH, -OR b , -OC(O)H, -OC(O)R b , -OC(O)OH, -OC(O)OR b , -OC(O)NH2, -OC(O)NHRb , -OC(O)NR b 2, -SH, -SR b , -S(O)2H, -S(O)2R b , -S(O)2OH, -S(O)2OR b , -S(O)2NH2, -S(O)2NHR b , -S(O)NR b 2, -R 21 , -C(O)-NH-R 21 , or -CH2-NH-C(O)-R 21 and Each R b is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; R 21 is the R of the linker 18 and formula (II) is a bond connecting to a single R 21 Including, During the ceremony, (i)R y but [ka] If Y2 is CR d and (ii)R y but [ka] If CR i R of 2 i is not hydrogen] or (c) Formula (III) [ka] [In the formula, Each of X1 and X2 is independently O or S; T is C=O or SO2, R 1 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; n is 0, 1 or 2; L1 is hydrogen, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)H, -C(O)R b , -C(O)OH, -C(O)OR b , -CH2C(O)OR b , -C(O)NH2, -C(O)NHR b , -C(O)NR b 2, -OH, -OR b , -NH2, -NHR b , -NR b 2. -S(O)2H or -S(O)2R b and R x is selected from the following: [ka] During the ceremony, [ka] indicates binding to T, Z4 is O, S, or NR 4 and V is CR f 2. NR 4 Or S, G1, G2, G3 and G4 are each independently N or CR c and Each of Y1 and Y2 is independently N or CR f and Each R f are independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, fused aryl-cycloalkyl, fused aryl-heterocycloalkyl, heteroaryl, heteroaryl substituted with at least one aryl group, benzyl, haloalkyl, haloalkenyl, -NH, -NHR b , -NR b 2. -NHC(O)R b , -NR b C(O)R b , -NHC(O)CH(OH)R b , -NR b C(O)CH(OH)Rb , -NHC(O)OR b , -NR b C(O)OR b , -NHSO2R b , -NR b SO2R b , -NO2, -CN, -C(O)H, -C(O)R b , -C(O)OH, -C(O)OR b , -C(O)NH2, -C(O)NHR b , -C(O)NR b 2, -OH, -OR b , -OC(O)H, -OC(O)R b , -OC(O)OH, -OC(O)OR b , -OC(O)NH2, -OC(O)NHR b , -OC(O)NR b 2, -SH, -SR b , -S(O)2H, -S(O)2R b , -S(O)2OH, -S(O)2OR b , -S(O)2NH2, -S(O)2NHR b , -S(O)NR b 2, -R 21 , -OR 21 , -NH-R 21 , -C(O)-NH-R 21 , or -CH2-NH-C(O)-R 21 Or Y1 and Y2 are CR f If R f forms a 5- or 6-membered ring together with the carbon atom to which it is attached, Each R c are independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, at least one -OR b substituted aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR b , -NR b 2, -CH2NH2, -NHC(O)R b , -NR b C(O)R b , -NHC(O)CH(OH)R b , -NRb C(O)CH(OH)R b , -NHC(O)OR b , -NR b C(O)OR b , -NHSO2R b , -NR b SO2R b , -NO2, -CN, -C(O)H, -C(O)R b , -C(O)OR b , -C(O)NH2, -C(O)NHR b , -C(O)NR b 2, -OH, -OR b , -OC(O)H, -OC(O)R b , -OC(O)OH, -OC(O)OR b , -OC(O)NH2, -OC(O)NHR b , -OC(O)NR b 2, -SH, -SR b , -S(O)2H, -S(O)2R b , -S(O)2OH, -S(O)2OR b , -S(O)2NH2, -S(O)2NHR b , -S(O)NR b 2, -OR 21 , -NH-R 21 , -C(O)-NH-R 21 , or -CH2-NH-C(O)-R 21 and Each R 4 are independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)H, C(O)R b , -C(O)OH, -C(O)OR b , -C(O)NH2, -C(O)NHR b , -C(O)NR b 2, -OH, -OR b , -NH2, -NHR b , -NR b 2, -S(O)2H, -S(O)2R b , -R 21 , -C(O)-NH-R 21 , or -CH2-NH-C(O)-R21 and Each R b is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; R 21 is the R of the linker 18 and formula (III) is a bond connecting to a single R 21 Including, n=2, and each R c is hydrogen, and each of G1, G2, G3 and G4 is CR c When C=X1 is optionally replaced by CH, During the ceremony, (i)R x but [ka] and when Z4 is NH, L1 is hydrogen, -CH2C(O)OR b , or -OR b and (ii)R x but [ka] and Z4 is NR 4 and Y1 is CR f and when Y2 is N, R 4 is not an alkyl, but R 2 and at least one of R is not H; (iii)R x but [ka] and Z4 is NR 4 and Y1 and Y2 are CR f then at least one of G1, G2 and G3 is N; (iv) Z4 is NR 4 and Y1 and Y2 are CR f If R x teeth [ka] Instead, (v)R x but [ka] and Z4 is NR 4 and when Y1 or Y2 is N, R 4 is not an alkyl, (vi)R x but [ka] where n=1 or 2, (vii)R x but [ka] If Z4=O or S, [MCL-1 ligand prodrug moiety] is: [ka] [In the formula, R 11 is a halogen, R 13 is a halogen, R 19 is the R of the linker 14 is the bond that connects to (i)R 9 is -C(O)O(C1-C6 alkyl), -C(O)Ocycloalkyl, -C(O)Oheterocycloalkyl, -C(O)Oaryl or -P(O)(OR p )2, and the C1-C6 alkyl is -OC(O)(unsubstituted C1-C6 alkyl), -OC(O)(at least one R 10 C1-C6 alkyl substituted with), -OC(O)cycloalkyl, -OC(O)heterocycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, -OC(O)(CH2) m O(CH2) mO(unsubstituted C1-C6 alkyl), -OC(O)(CH2) m O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(unsubstituted C1-C6 alkyl), -OC(O)O(at least one R 10 C1-C6 alkyl substituted with -OC(O)Ocycloalkyl, -OC(O)O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2CH2O) m (C1-C6 alkyl substituted with OP(O)(OH)2), -OC(O)O(CH2CH2S) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)(unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)2 (unsubstituted C1-C6 alkyl), -OC(O)NH (C1-C6 alkyl substituted with OMe), -OC(O)NMe (C1-C6 alkyl substituted with OMe), -P(O)(OH)2, -OP(O)(OH)2, -C(O)heterocycloalkyl, -C(O)N(unsubstituted C1-C6 alkyl)2, heteroaryl, heterocycloalkyl, -S(unsubstituted C1-C6 alkyl), -S(O)(unsubstituted C1-C6 alkyl), -N + (unsubstituted C1-C6 alkyl)3, -N + substituted with one or more groups selected from (unsubstituted C1-C6 alkyl)cycloalkyl, N-(unsubstituted C1-C6 alkyl)piperidinium cation, N-(unsubstituted C1-C6 alkyl)morpholinium cation, and N-(unsubstituted C1-C6 alkyl)imidazolium cation; Each R 10 are independently -OH, -O(unsubstituted C-C alkyl), -Obn, -NH, -Nme, -NHC(O)(unsubstituted C-C alkyl), -NHC(O)O(unsubstituted C-C alkyl), heterocycloalkyl, heteroaryl, aryl, -C(O)Nme; Each R p are independently -(CH2) m OC(O) (unsubstituted C1-C6 alkyl), each m is independently 1, 2, 3, or 4; or (ii)R 9 is -C(O)O(CH2) p Nme2, -C(O)O(CH2) p NHMe, -C(O)OCH2CH(OH)CH2OH, -C(O)OCH2CH2CMe2OH, or -C(O)OCH2CH2SO2Me, and each p is independently 2, 3, 4, 5, or 6. [Linker] has the formula: R 14 -R 15 -R 16 -R 17 -R 18 [In the formula, R 14 Ha-C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, C 1-6 Alkyl-N(C 1-6 alkyl)-, -C(O)-, -SO2- or absent; R 15 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 Alkyl-NH-, -C 1-6 Alkyl-N(C 1-6 alkyl)-, -cycloalkyl-NH-, -heterocycloalkyl-NH- or absent; R 16 Ha-C 1-6 alkyl, —C(O)—, —C(O)—NH—, —C(O)O—, —CH—C(O)—, —CH—C(O)—NH—, —CH—C(O)O— or absent; R 17 -CH2(C2H4-O) y , -(C2H4-O) x , -(C3H6-O) x , or absent, x is 1 to 10, y is between 2 and 10; R 18 Ga-C 1-6alkyl, cycloalkyl, —CH—NH—C(O)—, heterocycloalkyl, or absent; R 14 ~R 18 At least one of the following is present] The compound, or a salt, solvate, hydrate or isomer thereof. 79. The compound according to clause 78, wherein each alkyl, alkenyl, alkynyl, aryl, heteroaryl and benzyl is unsubstituted unless otherwise specified. 80. In formula (III), Each of X1 and X2 is O; T is C=O, R 1 is hydrogen, L1 is hydrogen, R x but [ka] and Z4 is NR 4 and Each of G1, G2 and G4 is CR c and Y1 is N, Y2 is CR f and R f is not hydrogen, 79. A compound according to clause 78 or 79. 81. The compound of any one of clauses 78-80, wherein the [ligase ligand moiety] is of formula (III). [ka] 82.(a)R c One of the is -OR 21 , -NH-R 21 , -C(O)-NH-R 21 , or -CH2-NH-C(O)-R 21 Or (b) G1 is COR 21 , C-NH-R 21 , CC(O)-NH-R 21, or C—CH2—NH—C(O)—R 21 Or (c) G2 is COR 21 , C-NH-R 21 , CC(O)-NH-R 21 , or C—CH2—NH—C(O)—R 21 Or (d)R 4 R 21 , -C(O)-NH-R 21 , or -CH2-NH-C(O)-R 21 or (e)R f One of them is -R 21 , -OR 21 , -NH-R 21 , -C(O)-NH-R 21 , or -CH2-NH-C(O)-R 21 That is, A compound according to any one of clauses 78 to 81. 83.Y2 is CR 21 , CO-R 21 , C-NH-R 21 , CC(O)-NH-R 21 , or C—CH—NH—C(O)—R 21 82. The compound according to any one of clauses 78 to 81, wherein 84. The compound according to any one of clauses 78 to 83, wherein the [ligase ligand moiety] is selected from: [ka] JPEG2025540250000295.jpg12617085.The compound of clause 84, wherein [ligase ligand moiety] is: [ka] 86.R 14 Ga-C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 86. The compound according to any one of clauses 35 to 85, wherein the group is alkynyl, -C(O)-, -SO2- or absent. 87.R 14 Ga-C 1-6 87. The compound according to clause 86, wherein the aryl group is alkyl. 88.R 15 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 88. The compound according to any one of clauses 35 to 87, wherein alkyl-NH-, -cycloalkyl-NH- or absent. 89.R 15 89. The compound according to clause 88, wherein is heterocycloalkyl. 90.R 15 piperazine, bridged piperazine, piperazine N-oxide, piperazine cation, [ka] and During the ceremony, [ka] is R 14 shows the bond with [ka] is R 16 89. The compound according to clause 89, which exhibits a bond with 91.R 15 is piperazine or [ka] 91. The compound according to clause 90, wherein 92.R 16 Ga-C 1-6 92. The compound according to any one of clauses 35 to 91, wherein the alkyl is -CH2-C(O)-NH- or -C(O)-. 93.R 16 Ga-C 1-6 93. The compound according to clause 92, wherein the alkyl is alkyl or -C(O)-. 94.R 17 94. The compound according to any one of clauses 35 to 93, wherein is absent. 95.R 18 Ga-C 1-6The compound of any one of clauses 35 to 94, wherein the alkyl, heterocycloalkyl or absent. 96.R 18 Ga-C 1-6 The compound according to clause 95, wherein the alkyl or heterocycloalkyl. 97.R 18 Ga-C 1-6 97. The compound according to clause 96, which is an alkyl or piperazine. 98. The compound according to any one of clauses 35 to 97, wherein [Linker] is selected from the following: [ka] [In the formula, [ka] indicates binding to the [MCL-1 ligand prodrug moiety], [ka] indicates binding to [ligase ligand moiety]] 99.R 9 is -C(O)O(C1-C6 alkyl), -C(O)Ocycloalkyl, -C(O)Oheterocycloalkyl, -C(O)Oaryl or -P(O)(OR p )2, wherein the C1-C6 alkyl is -OC(O)(unsubstituted C1-C6 alkyl), -OC(O)(at least one R 10 C1-C6 alkyl substituted with), -OC(O)cycloalkyl, -OC(O)heterocycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, -OC(O)(CH2) m O(CH2) m O(unsubstituted C1-C6 alkyl), -OC(O)(CH2) m O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(unsubstituted C1-C6 alkyl), -OC(O)O(at least one R 10 C1-C6 alkyl substituted with -OC(O)Ocycloalkyl, -OC(O)O(CH2CH2O) m(unsubstituted C1-C6 alkyl), -OC(O)O(CH2CH2O) m (C1-C6 alkyl substituted with OP(O)(OH)2), -OC(O)O(CH2CH2S) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)(unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)2 (unsubstituted C1-C6 alkyl), -OC(O)NH (C1-C6 alkyl substituted with OMe), -OC(O)NMe (C1-C6 alkyl substituted with OMe), -P(O)(OH)2, -OP(O)(OH)2, -C(O)heterocycloalkyl, -C(O)N(unsubstituted C1-C6 alkyl)2, heteroaryl, heterocycloalkyl, -S(unsubstituted C1-C6 alkyl), -S(O)(unsubstituted C1-C6 alkyl), -N + (unsubstituted C1-C6 alkyl)3, -N + The compound of any one of clauses 35 to 98, substituted with one or more groups selected from (unsubstituted C1-C6 alkyl)2cycloalkyl, N-(unsubstituted C1-C6 alkyl)piperidinium cation, N-(unsubstituted C1-C6 alkyl)morpholinium cation, and N-(unsubstituted C1-C6 alkyl)imidazolyl cation. 100.R 9 is -C(O)O(C1-C6 alkyl), -C(O)Ocycloalkyl, -C(O)Oheterocycloalkyl, -C(O)Oaryl, or -P(O)(OR p )2, wherein the C1-C6 alkyl is -OC(O)Me, -OC(O)Et, -OC(O) iPr, -OC(O)C(CH3)3, -OC(O)CH2OH, -OC(O)CH(CH3)OH, -OC(O)C(CH3)2OH, -OC(O)CH2CH2OH, -OC(O)CH(OH)CHMe2, -OC(O)CH(OH)CH2CHMe2, -OC(O)CH2CH(OH)Me, -OC(O)CH2C(OH)Me2, -OC(O)CH(CH2OH)(NHC(O)Me), -OC(O)CH(NHC(O)Me)(isobutyl), -OC(O)CH(OH)aryl, -OC(O)CH(OH)CH2aryl, -OC(O)heterocycloalkyl, -OC(O)cycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, -OC(O)CH2CH2aryl, -OC(O)CH(NH2) i Pr, -OC(O)CH( i Pr)NHC(O)O t Bu, -OC(O)CH2OCH2CH2OMe, -OC(O)CH2(OCH2CH2)2OMe, -OC(O)OMe, -OC(O)OEt, -OC(O)OiPr, -OC(O)Ocycloalkyl, -OC(O)OCH2CH2OEt, -OC(O)O(CH2CH2O )2Et, -OC(O)O(CH2CH2O)3Et, -OC(O)O(CH2CH2O)3CH2CH2OP(O)(OH)2, -OC(O)OCh2CH2SMe, -OC(O)OCH2CH2S(O)Me, -OC(O)OCH2CH2S(O)2Me, -OC(O)OC H2heteroaryl, -OC(O)OCH2heterocycloalkyl, -OC(O)OCH2CH2OCH2aryl, -OC(O)OCH2CH2C(O)NMe2, -OC(O)O(CH2)6NH2, -OC(O)O(cH2)6NMe2, -OC(O)OCH(CHOEt)2, -OC(O)NHCH2CH2OMe, -OC(O)NMeCH2CH2Ome, -SMe, -S(O)Me, -P(O)(OH)2, -OP(O)(OH)2, -C(O)NMe2, -C(O)heterocycloalkyl, heteroaryl, heterocycloalkyl, -N + (Me)3, -N +The compound according to clause 99, substituted with one or more groups selected from (Me)2 cycloalkyl, N-methylmorpholinium cation, N-methylpiperidinium cation and N-methylimidazolium cation. 101.R 9 is —C(O)O(C1-C6 alkyl), wherein the C1-C6 alkyl is substituted with one or more groups selected from —OC(O)C(CH3)3, —OC(O)CH2CH2OH, —OC(O)C(CH3)2OH, —OC(O)heterocycloalkyl, —OC(O)CHOCH2CHOMe, —OC(O)OiPr, —OC(O)Ocycloalkyl, —OC(O)O(CH2CHO)2Et, —OP(O)(OH)2, heteroaryl, or heterocycloalkyl. 102.R 9 is —C(O)O(C1-C6 alkyl), wherein said C1-C6 alkyl is substituted with —OC(O)C(CH3)3. 103.R 9 -C(O)OCH2OC(O)C(CH3)3, -C(O)OCH2OC(O)CH2CH2OH, -C(O)OCH2OC(O)C(CH3)2OH, -C(O)OCH2OC(O)piperidine, -C(O)OCH2OC(O)CH2OCH2CH2OMe, -C(O)OCH2OC(O)OiPr, -C(O)OCHMeOC(O)OiPr, -C(O)OCHMeOC(O)Ocyclohexyl, -C(O)OCH 102. The compound according to clause 101, which is MeOC(O)O(CH2CHO)2Et, -C(O)OCH2CH2OP(O)(OH)2, -C(O)OCH2(N-methylimidazolium cation), -C(O)OCH2(N-methylpiperidinium cation), -C(O)OCH2 dioxolane, -C(O)OCH2CH2 morpholine, -C(O)OCH2CH2 piperazine, -C(O)OCH2CH2CH2 piperazine. 104.R 9 104. The compound according to clause 103, wherein is —C(O)OCH2OC(O)C(CH3)3. 105. The compound according to any one of clauses 35 to 104, wherein [MCL-1 ligand prodrug moiety] is: [ka] 106. A compound according to clause 78, which is: [ka] 70 107. The compound according to any one of clauses 1 to 106, wherein T is C=O. 108.(a) X1 and X2 are O or (b) X1 is O and X2 is S, or (c) X1 is S and X2 is O, or (d) X1 and X2 are S; 108. A compound according to any one of clauses 1 to 107. 109. The compound according to any one of clauses 1 to 108, wherein n is 0. 110. A compound according to any one of clauses 1 to 108, wherein n is 1 or 2. 111. The compound according to clause 110, wherein n is 1. 112. The compound according to clause 110, wherein n is 2. 113. A pharmaceutical composition comprising a compound according to any one of clauses 1 to 112. 114. A compound according to any one of clauses 1 to 112 or a pharmaceutical composition according to clause 113 for use in medicine. 115. A compound according to any one of clauses 1 to 112 or a pharmaceutical composition according to clause 113 for use in the treatment of cancer. 116. The compound or composition for use according to clause 115, wherein the cancer is selected from breast cancer, triple-negative breast cancer, colon cancer, pancreatic cancer, skin cancer, melanoma, ovarian cancer, kidney cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, lymphoma, non-Hodgkin's lymphoma, multiple myeloma, cervical cancer, leukemia, chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bladder cancer, and prostate cancer. 117. The compound or composition for use according to clause 116, wherein the cancer is multiple myeloma or acute myeloid leukemia. 118. A method for treating cancer in a subject in need thereof, comprising administering to said subject an effective amount of a compound according to any one of clauses 1 to 112 or a pharmaceutical composition according to clause 113. 119. The method of clause 118, wherein the cancer is selected from breast cancer, triple-negative breast cancer, colon cancer, pancreatic cancer, skin cancer, melanoma, ovarian cancer, kidney cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, lymphoma, non-Hodgkin's lymphoma, multiple myeloma, cervical cancer, leukemia, chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), bladder cancer, and prostate cancer. 120. The method according to clause 119, wherein the cancer is multiple myeloma or acute myeloid leukemia. 121. The method of any of clauses 118-120, wherein the administration does not result in cytotoxicity in the subject's cardiomyocytes. 122. The method of any of clauses 118-121, further comprising administering to the subject at least one additional active agent. 123. The method of clause 122, wherein the at least one additional active agent is an anti-cancer agent selected from eribulin; fulvestrant; midostaurin; an immune checkpoint inhibitor selected from anti-PD-1 antibodies, anti-PD-L1 antibodies, and anti-PD-1 / PD-L1 interaction inhibitors; nivolumab; pembrolizumab; atezolizumab; pidilizumab; carfilzomib; venetoclax; cytarabine; anthracyclines; taxane compounds; and hypomethylating agents. 124. A compound according to any one of clauses 1 to 112 or a pharmaceutical composition according to clause 113 for use in reversing resistance to chemotherapy or targeted cancer therapy. 125. A method for reversing resistance to chemotherapy or targeted cancer therapy in a subject in need thereof, said method comprising administering to said subject an effective amount of a compound according to any of clauses 1 to 112 or a pharmaceutical composition according to clause 113. 126. A combined preparation of a compound according to any of clauses 1 to 112 with at least one additional active agent for simultaneous, separate or sequential use in therapy. 127. The combination preparation according to clause 126, wherein at least one additional active agent is an anticancer agent selected from eribulin; fulvestrant; midostaurin; an immune checkpoint inhibitor selected from anti-PD-1 antibodies, anti-PD-L1 antibodies, and anti-PD-1 / PD-L1 interaction inhibitors; nivolumab; pembrolizumab; atezolizumab; pidilizumab; carfilzomib; venetoclax; cytarabine; anthracyclines; taxane compounds; and hypomethylating agents. 128. The combined preparation according to clause 126 or 127, wherein the therapy is the treatment of cancer. 129. A method for reducing cardiac cytotoxicity of an MCL-1 inhibitor, comprising the step of conjugating a cereblon-binding moiety to an MCL-1 inhibitor, wherein the cereblon-binding moiety is a [ligase ligand moiety] as defined in any one of clauses 1 to 112, and the MCL-1 inhibitor is an [MCL-1 ligand prodrug moiety] as defined in any one of clauses 1 to 112.

Claims

1. Compounds of formula (I) [MCL-1 ligand prodrug moiety]-linker-[ligase ligand moiety] (I) or a salt, solvate, hydrate or isomer thereof, wherein the [ligase ligand moiety] is: 【Chemistry 1】 [In the formula, M is O, S, or NH, or absent; 【Chemistry 2】 is the R of the linker １８ shows the bond with R ２２ is hydrogen, halogen, —OMe, an amino group, heterocycloalkyl, or unsubstituted C １ -C ６ is alkyl, R ２９ is hydrogen or Me, L' is hydrogen, alkyl, benzyl, acetyl, or pivaloyl. [MCL-1 ligand prodrug moiety] is a compound of formula (A1), (A2), (A3) or (A4), 【Transformation 3】 (A1) (A2) (A3) 【change】 (A4) [In the formula, 【Chemistry 4】 is a single or double bond, Each Z ２ are independently N or C, Z ２ If is N, then 【Transformation 5】 is a single bond, and Z ２ If is C, then 【Transformation 6】 is a double bond, Each R １１ are independently H, halogen or C １ -C ６ is alkyl, R ８ is a piperazine-substituted C １ -C ６ is alkyl, In each of formula (A1) and formula (A4), R １０ and R ３０ One of the groups is H, and the other is R １０ and R ３０ The other is -C ２－５ Alkyl-O-R １３ , —O—C ２－５ Alkyl-R １３ or -C ２－５ Alkyl-NMe-R １３ wherein R １３ is phenyl, naphthyl, or tetralin, and the phenyl, naphthyl, or tetralin is not halogen, C １ -C ６ Alkyl and —O(C １ -C ６ or the tetralin is substituted with at least one substituent selected from a bridged —CH ２ - group, or the naphthyl may be substituted by -O- or -S-; R １２ is as follows: 【Transformation 7】 R ３１ Ha-C ２－５ Alkyl-O-R １３ , —O—C ２－５ Alkyl-R １３ or -C ２－５ Alkyl-NMe-R １３ wherein R １３ is phenyl, naphthyl, or tetralin, wherein the phenyl, naphthyl, or tetralin is halogen, C １ -C ６ Alkyl and —O(C １ -C ６ or the tetralin is substituted with at least one substituent selected from a bridged —CH ２ - group, or the naphthyl may be substituted by -O- or -S-; Each R ３２ is independently H, 【Transformation 8】 and Each R ３３ is independently R １９ or C １ -C ６ alkyl, １ -C ６ The alkyl may be substituted with morpholine or piperazine; R ２０ is Me, -CH ２ -OMe, -(CH ２ CH ２ O) ｐ (C １ -C ６ alkyl), or —CH ２ -O-bromobenzaldehyde, p is 1 to 5; R ３４ is C ２－５ Alkyl-O-R １３ or -O-C ２－５ Alkyl-R １３ wherein R １３ is phenyl, naphthyl, or tetralin, and the phenyl, naphthyl, or tetralin is not halogen, C １ -C ６ Alkyl and —O(C １ -C ６ or the tetralin is substituted with at least one substituent selected from a bridged —CH ２ - group, or the naphthyl may be substituted by -O- or -S-; R ３５ is as follows: 【Chemistry 9】 R １９ is R of the linker １４ and each of formula (A1), formula (A2), formula (A3) and formula (A4) is a bond connected to a single R １９ Including, (i) R ９ is -C(O)O(C １ -C ６ alkyl), —C(O)Ocycloalkyl, —C(O)Oheterocycloalkyl, —C(O)Oaryl or —P(O)(OR ｐ ) ２ and said C １ -C ６ Alkyl is —OC(O)(unsubstituted C １ -C ６ alkyl), —OC(O) (at least one R １０ C substituted with １ -C ６ alkyl), —OC(O)cycloalkyl, —OC(O)heterocycloalkyl, —OC(O)aryl, —OC(O)heteroaryl, —OC(O)(CH ２ ) ｍ O (CH ２ ) ｍ O (unsubstituted C １ -C ６ alkyl), —OC(O)(CH ２ ) ｍ O (CH ２ CH ２ O) ｍ (Unsubstituted C １ -C ６ alkyl), —OC(O)O(unsubstituted C １ -C ６ alkyl), —OC(O)O (at least one R １０ C substituted with １ -C ６ alkyl), —OC(O)Ocycloalkyl, —OC(O)O(CH ２ CH ２ O) ｍ (Unsubstituted C １ -C ６ alkyl), —OC(O)O(CH ２ CH ２ O) ｍ (OP(O)(OH) ２ C substituted with １ -C ６ alkyl), —OC(O)O(CH ２ CH ２ S) ｍ (Unsubstituted C １ -C ６ alkyl), —OC(O)O(CH ２ ) ｍ S(O) (unsubstituted C １ -C ６ alkyl), —OC(O)O(CH ２ ) ｍ S (O) ２ (Unsubstituted C １ -C ６ alkyl), —OC(O)NH(C substituted with OMe １ -C ６ alkyl), —OC(O)NMe (C substituted with OMe １ -C ６ alkyl), -P(O)(OH) ２ , -OP(O)(OH) ２ , —C(O)heterocycloalkyl, —C(O)N(unsubstituted C １ -C ６ alkyl) ２ , heteroaryl, heterocycloalkyl, -S(unsubstituted C １ -C ６ alkyl), —S(O)(unsubstituted C １ -C ６ alkyl), -N ＋ (Unsubstituted C １ -C ６ alkyl) ３ , -N ＋ (Unsubstituted C １ -C ６ alkyl) ２ Cycloalkyl, N-(unsubstituted C １ -C ６ alkyl)piperidinium cation, N-(unsubstituted C １ -C ６ alkyl)morpholinium cation, and N-(unsubstituted C １ -C ６ substituted with one or more groups selected from the group consisting of alkyl)imidazolium cations, Each R １０ are independently —OH, —O(unsubstituted C １ -C ６ alkyl), -OBn, -NH ２ , -NMe ２ , -NHC(O) (unsubstituted C １ -C ６ alkyl), —NHC(O)O(unsubstituted C １ -C ６ alkyl), heterocycloalkyl, heteroaryl, aryl, —C(O)NMe ２ and Each R ｐ are independently -(CH ２ ) ｍ OC(O) (unsubstituted C １ -C ６ alkyl), each m is independently 1, 2, 3, or 4; or (ii) R ９ is -C(O)O(CH ２ ) ｐ NMe ２ , -C(O)O(CH ２ ) ｐ NHMe, -C(O)OCH ２ CH(OH)CH ２ OH, -C(O)OCH ２ CH ２ CMe ２ OH, or —C(O)OCH ２ CH ２ SO ２ Me, and each p is independently 2, 3, 4, 5, or 6. [Linker] has the formula: R １４ -R １５ -R １６ -R １７ -R １８ [In the formula, R １４ Ha-C １－６ Alkyl, —C ２－６ Alkenyl, -C ２－６ Alkynyl, —C １－６ Alkyl-N(C １－６ alkyl)-, —C(O)-, —SO ２ -or absent, R １５ is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C １－６ Alkyl-NH-, -C １－６ Alkyl-N(C １－６ alkyl)-, -cycloalkyl-NH-, -heterocycloalkyl-NH- or absent; R １６ Ha-C １－６ Alkyl, —C(O)—, —C(O)—C １－６ Alkyl-, —C(O)—NH—, —C(O)O—, —CH ２ -C(O)-, -CH ２ -C(O)-NH-, -CH ２ -C(O)O- or absent, R １７ Ha-CH ２ (C ２ H ４ -O) ｙ , -(CH ２ O) ｘ , -(C ２ H ４ -O) ｘ , -(C ３ H ６ -O) ｘ , or absent, x is 1 to 10; y is 2 to 10; R １８ Ha-C １－６ Alkyl, —C １－６ Alkyl-C(O)-, cycloalkyl, -CH ２ -NH-C(O)-, heterocycloalkyl, or absent; R １４ ~R １８ At least one of The compound, or a salt, solvate, hydrate or isomer thereof.

2. 2. The compound of claim 1, wherein the [ligase ligand moiety] is: 【Chemistry 10】

3. 2. The compound of claim 1, wherein the [ligase ligand moiety] is: 【Chemistry 11】

4. The compound of claim 3, wherein the [ligase ligand moiety] is: 【Chemistry 12】

5. R ２２ The compound according to any one of claims 1 to 4, wherein is hydrogen.

6. The compound of any one of claims 1 to 5, wherein L' is hydrogen.

7. The compound of any one of claims 1 to 6, wherein M is O or NH, or absent.

8. The compound according to any one of claims 1, 2 and 4 to 7, wherein the [ligase ligand portion] is: 【Chemistry 13】

9. 9. The compound of claim 8, wherein the [ligase ligand portion] is: 【Chemistry 14】

10. (a) [ligase ligand moiety] is: 【Chemistry 15】 【change】 , 【change】 , or 【change】 or (b) [ligase ligand moiety] is: 【Chemistry 16】 or 【change】 or (c) [ligase ligand moiety] is: 【Chemistry 17】 The compound according to any one of claims 1 to 9.

11. (a) [ligase ligand moiety] is: [Chemistry 18] 【change】 or 【change】 or (b) [ligase ligand moiety] is: 【Chemistry 19】 The compound according to any one of claims 1 to 10.

12. R １６ Ga-C １－６ Alkyl, —C(O)—, —C(O)—NH—, —C(O)O—, —CH ２ -C(O)-, -CH ２ -C(O)-NH-, -CH ２ -C(O)O- or absent, R １７ Ga-CH ２ (C ２ H ４ -O) ｙ , -(C ２ H ４ -O) ｘ , -(C ３ H ６ -O) ｘ , or absent, R １８ Ga-C １－６ Alkyl, cycloalkyl, -CH ２ -NH-C(O)-, heterocycloalkyl, or absent; The compound according to any one of claims 1 to 11.

13. R １４ Ga-C １－６ Alkyl, —C ２－６ Alkenyl, -C ２－６ Alkynyl, —C(O)—, —SO ２ - or absent.

14. R １４ Ga-C １－６ 14. The compound of claim 13, wherein the compound is alkyl.

15. R １５ is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C １－６ The compound according to any one of claims 1 to 14, which is alkyl-NH-, -cycloalkyl-NH- or absent.

16. R １５ 16. The compound of claim 15, wherein is heterocycloalkyl.

17. R １５ piperazine, bridged piperazine, piperazine N-oxide, piperazine cation, 【Chemistry 20】 and During the ceremony, 【Chemistry 21】 is R １４ shows the bond with 【Chemistry 22】 is R １６ 17. The compound of claim 16, wherein the compound exhibits a bond with

18. R １５ is piperazine or 【Chemistry 23】 18. The compound of claim 17, wherein:

19. R １５ 16. The compound of claim 15, wherein is absent.

20. R １６ Ga-C １－６ Alkyl, —CH ２ The compound according to any one of claims 1 to 19, which is -C(O)-NH- or -C(O)-.

21. R １６ Ga-C １－６ The compound of claim 20, which is alkyl or -C(O)-.

22. R １７ The compound of any one of claims 1 to 21, wherein is absent.

23. R １８ Ga-C １－６ The compound of any one of claims 1 to 22, wherein the aryl group is alkyl, heterocycloalkyl, or absent.

24. R １８ Ga-C １－６ alkyl or heterocycloalkyl, １－６ 24. The compound of claim 23, which may be an alkyl or piperazine.

25. R １８ 24. The compound of claim 23, wherein is absent.

26. The compound according to any one of claims 1 to 25, wherein [Linker] is selected from the following: 【Chemistry 24】 [In the formula, 【Chemistry 25】 indicates a bond to the [MCL-1 ligand prodrug moiety], 【Chemistry 26】 indicates binding to the [ligase ligand moiety], Optionally, [linker] is selected from: 【Chemistry 27】 [In the formula, 【Chemistry 28】 indicates a bond to the [MCL-1 ligand prodrug moiety], 【Chemistry 29】 indicates binding to the [ligase ligand moiety].

27. In each of formula (A1) and formula (A4), R １０ and R ３０ is H, and R １０ and R ３０ The other side is -C ２－５ Alkyl-O-R １３ or -O-C ２－５ Alkyl-R １３ wherein R １３ is phenyl or naphthyl, and the phenyl or naphthyl is halogen and C １ -C ６ The compound according to any one of claims 1 to 26, which is optionally substituted with at least one substituent selected from alkyl.

28. In formula (A1), R １２ but 【Transformation 30】 The compound according to any one of claims 1 to 27,

29. In formula (A4), R ３５ but 【Chemistry 31】 The compound according to any one of claims 1 to 28,

30. In formula (A2), R ３１ Ga-C ２－５ Alkyl-O-R １３ or -O-C ２－５ Alkyl-R １３ wherein R １３ is phenyl or naphthyl, and the phenyl or naphthyl is halogen and C １ -C ６ The compound according to any one of claims 1 to 29, which is optionally substituted with at least one substituent selected from alkyl.

31. In formula (A3), R ３４ is C ２－５ Alkyl-O-R １３ or -O-C ２－５ Alkyl-R １３ wherein R １３ is phenyl or naphthyl, and the phenyl or naphthyl is halogen and C １ -C ６ The compound according to any one of claims 1 to 30, which is optionally substituted with at least one substituent selected from alkyl.

32. Z ２ is C, 【Chemistry 32】 The compound according to any one of claims 1 to 31, wherein is a double bond.

33. The compound of any one of claims 1 to 32, wherein the [MCL-1 ligand prodrug moiety] is: 【Transformation 33】 [In the formula, R １１ is a halogen, R １３ａ is a halogen, R ２０ is Me, -CH ２ -OMe, or -(CH ２ CH ２ O) ｐ (C １ -C ６ alkyl), and p is 1 to 5.

34. R ９ -C(O)O(C １ -C ６ alkyl), —C(O)Ocycloalkyl, —C(O)Oheterocycloalkyl, —C(O)Oaryl or —P(O)(OR ｐ ) ２ and said C １ -C ６ The alkyl is —OC(O)(unsubstituted C １ -C ６ alkyl), —OC(O) (at least one R １０ C substituted with １ -C ６ alkyl), —OC(O)cycloalkyl, —OC(O)heterocycloalkyl, —OC(O)aryl, —OC(O)heteroaryl, —OC(O)(CH ２ ) ｍ O (CH ２ ) ｍ O (unsubstituted C １ -C ６ alkyl), —OC(O)(CH ２ ) ｍ O (CH ２ CH ２ O) ｍ (Unsubstituted C １ -C ６ alkyl), —OC(O)O(unsubstituted C １ -C ６ alkyl), —OC(O)O (at least one R １０ C substituted with １ -C ６ alkyl), —OC(O)Ocycloalkyl, —OC(O)O(CH ２ CH ２ O) ｍ (Unsubstituted C １ -C ６ alkyl), —OC(O)O(CH ２ CH ２ O) ｍ (OP(O)(OH) ２ C substituted with １ -C ６ alkyl), —OC(O)O(CH ２ CH ２ S) ｍ (Unsubstituted C １ -C ６ alkyl), —OC(O)O(CH ２ ) ｍ S(O) (unsubstituted C １ -C ６ alkyl), —OC(O)O(CH ２ ) ｍ S (O) ２ (Unsubstituted C １ -C ６ alkyl), —OC(O)NH(C substituted with OMe １ -C ６ alkyl), —OC(O)NMe (C substituted with OMe １ -C ６ alkyl), -P(O)(OH) ２ , -OP(O)(OH) ２ , —C(O)heterocycloalkyl, —C(O)N(unsubstituted C １ -C ６ alkyl) ２ , heteroaryl, heterocycloalkyl, -S(unsubstituted C １ -C ６ alkyl), —S(O)(unsubstituted C １ -C ６ alkyl), -N ＋ (Unsubstituted C １ -C ６ alkyl) ３ , -N ＋ (Unsubstituted C １ -C ６ alkyl) ２ Cycloalkyl, N-(unsubstituted C １ -C ６ alkyl)piperidinium cation, N-(unsubstituted C １ -C ６ alkyl)morpholinium cation, and N-(unsubstituted C １ -C ６ 34. The compound of any one of claims 1 to 33, wherein the compound is substituted with one or more groups selected from the group consisting of alkyl)imidazolyl cations.

35. R ９ -C(O)O(C １ -C ６ alkyl), —C(O)Ocycloalkyl, —C(O)Oheterocycloalkyl, —C(O)Oaryl, or —P(O)(OR ｐ ) ２ and said C １ -C ６ Alkyl is -OC(O)Me, -OC(O)Et, -OC(O) ｉ Pr, -OC(O)C(CH ３ ) ３ , —OC(O)CH ２ OH, -OC(O)CH(CH ３ )OH, -OC(O)C(CH ３ ) ２ OH, -OC(O)CH ２ CH ２ OH, -OC(O)CH(OH)CHMe ２ , -OC(O)CH(OH)CH ２ CHMe ２ , —OC(O)CH ２ CH(OH)Me, -OC(O)CH ２ C(OH)Me ２ , -OC(O)CH(CH ２ OH)(NHC(O)Me), —OC(O)CH(NHC(O)Me)(isobutyl), —OC(O)CH(OH)aryl, —OC(O)CH(OH)CH ２ Aryl, —OC(O)heterocycloalkyl, —OC(O)cycloalkyl, —OC(O)aryl, —OC(O)heteroaryl, —OC(O)CH ２ CH ２ Aryl, —OC(O)CH(NH ２ ) ｉ Pr, -OC(O)CH( ｉ Pr)NHC(O)O ｔ Bu, -OC(O)CH ２ OCH ２ CH ２ OMe, -OC(O)CH ２ (OCH ２ CH ２ ) ２ OMe, -OC(O)OMe, -OC(O)OEt, -OC(O)O ｉ Pr, —OC(O)Ocycloalkyl, —OC(O)OCH ２ CH ２ OEt, -OC(O)O(CH ２ CH ２ O) ２ Et, -OC(O)O(CH ２ CH ２ O) ３ Et, -OC(O)O(CH ２ CH ２ O) ３ CH ２ CH ２ OP(O)(OH) ２ , -OC(O)OCH ２ CH ２ SMe, -OC(O)OCH ２ CH ２ S(O)Me, -OC(O)OCH ２ CH ２ S (O) ２ Me, -OC(O)OCH ２ Heteroaryl, —OC(O)OCH ２ Heterocycloalkyl, —OC(O)OCH ２ CH ２ OCH ２ Aryl, —OC(O)OCH ２ CH ２ C(O)NMe ２ , -OC(O)O(CH ２ ) ６ NH ２ , -OC(O)O(CH ２ ) ６ NMe ２ , -OC(O)OCH(CH ２ OEt) ２ , -OC(O)NHCH ２ CH ２ OMe, -OC(O)NMeCH ２ CH ２ OMe, -SMe, -S(O)Me, -P(O)(OH) ２ , -OP(O)(OH) ２ , —C(O)NMe ２ , —C(O)heterocycloalkyl, heteroaryl, heterocycloalkyl, —N ＋ (Me) ３ , -N ＋ (Me) ２ 35. The compound of claim 34, substituted with one or more groups selected from cycloalkyl, N-methylmorpholinium cation, N-methylpiperidinium cation, and N-methylimidazolium cation.

36. R ９ -C(O)O(C １ -C ６ alkyl), and １ -C ６ Alkyl is -OC(O)C(CH ３ ) ３ , —OC(O)CH ２ CH ２ OH, -OC(O)C(CH ３ ) ２ OH, —OC(O)heterocycloalkyl, —OC(O)CH ２ OCH ２ CH ２ OMe, —OC(O)OiPr, —OC(O)Ocycloalkyl, —OC(O)O(CH ２ CH ２ O) ２ Et, -OP(O)(OH) ２ 36. The compound of claim 35, substituted with one or more groups selected from: heteroaryl, or heterocycloalkyl.

37. R ９ -C(O)OCH ２ OC(O)C(CH ３ ) ３ , —C(O)OCH ２ OC(O)Me, -C(O)OCH(Me)OC(O)Me, -C(O)OCH ２ OC(O)CH ２ CH ２ OH, -C(O)OCH ２ OC(O)C(CH ３ ) ２ OH, -C(O)OCH ２ OC(O)piperidine, —C(O)OCH ２ OC(O)CH ２ OCH ２ CH ２ OMe, -C(O)OCH ２ OC(O)OiPr, -C(O)OCHMeOC(O)OiPr, -C(O)OCHMeOC(O)Ocyclohexyl, -C(O)OCHMeOC(O)O(CH ２ CH ２ O) ２ Et, -C(O)OCH ２ CH ２ OP(O)(OH) ２ , —C(O)OCH ２ (N-methylimidazolium cation), —C(O)OCH ２ (N-methylpiperidinium cation), —C(O)OCH ２ Dioxolane, —C(O)OCH ２ CH ２ Morpholine, —C(O)OCH ２ CH ２ Piperazine, —C(O)OCH ２ CH ２ CH ２ Piperazine or -P(O)(OCH ２ OC(O)C(CH ３ ) ３ ) ２ and Optionally R ９ -C(O)OCH ２ OC(O)C(CH ３ ) ３ , —C(O)OCH ２ OC(O)Me, -C(O)OCH(Me)OC(O)Me, -C(O)OCH ２ OC(O)CH ２ CH ２ OH, -C(O)OCH ２ OC(O)C(CH ３ ) ２ OH, -C(O)OCH ２ OC(O)piperidine, —C(O)OCH ２ OC(O)CH ２ OCH ２ CH ２ Ome, -C(O)OCH ２ OC(O)OiPr, -C(O)OCHMeOC(O)OiPr, -C(O)OCHMeOC(O)Ocyclohexyl, -C(O)OCHMeOC(O)O(CH ２ CH ２ O) ２ Et, -C(O)OCH ２ CH ２ OP(O)(OH) ２ , —C(O)OCH ２ (N-methylimidazolium cation), —C(O)OCH ２ (N-methylpiperidinium cation), —C(O)OCH ２ Dioxolane, —C(O)OCH ２ CH ２ Morpholine, —C(O)OCH ２ CH ２ Piperazine, or —C(O)OCH ２ CH ２ CH ２ Piperazine, 36. The compound of claim 35.

38. R ９ -C(O)O(CH ２ ) ｐ NMe ２ , -C(O)O(CH ２ ) ｐ NHMe, -C(O)OCH ２ CH(OH)CH ２ OH,C(O)OCH ２ CH ２ CMe ２ OH or -C(O)OCH ２ CH ２ SO ２ 34. The compound of any one of claims 1 to 33, wherein Me is Me and each p is independently 2, 3, 4, 5, or 6.

39. R ９ -C(O)OCH ２ CH ２ NMe ２ , —C(O)OCH ２ CH(OH)CH ２ OH or -C(O)OCH ２ CH ２ SO ２ 39. The compound of claim 38, wherein Me.

40. R ２０ is Me or -(CH ２ CH ２ O) ２ The compound of any one of claims 1 to 39, wherein Me is

41. R ３３ is R １９ The compound according to any one of claims 1 to 40,

42. R ３３ is substituted with morpholine or piperazine １ -C ６ The compound of any one of claims 1 to 40, which is alkyl.

43. C substituted with morpholine or piperazine １ -C ６ 43. The compound of any one of claims 1 to 42, wherein alkyl is: 【Transformation 34】

44. R １１ The compound of any one of claims 1 to 43, wherein is Cl.

45. R １３ａ The compound of any one of claims 1 to 44, wherein is F.

46. (a) [MCL-1 ligand prodrug moiety] is: 【Chemistry 35】 or (b) [MCL-1 ligand prodrug moiety] is: 【Transformation 36】 A compound according to any one of claims 1 to 45.

47. (a) [Linker] is: 【Chemistry 37】 [ligase ligand portion] is 【Transformation 38】 [MCL-1 ligand prodrug moiety] is a compound of formula (A3), R ３２ is as follows: 【Chemistry 39】 R ９ is C(O)O (linear C １ -C ６ alkyl)OC(O)C(CH ３ ) ３ , C(O)O (linear C １ -C ６ alkyl)OC(O)heterocycloalkyl, C(O)O(linear C １ -C ６ alkyl)OC(O)CH ２ CH ２ OH, C(O)O (linear C １ -C ６ alkyl)OC(O)CH ２ OCH ２ CH ２ OMe, C(O)O (linear C １ -C ６ alkyl)OC(O)Me, C(O)O(branched C １ -C ６ alkyl)OC(O)OiPr, C(O)O(branched C １ -C ６ alkyl)OC(O)Ocycloalkyl, C(O)O(branched C １ -C ６ alkyl)OC(O)O(CH ２ CH ２ O) ２ Et, or C(O)O (branched C １ -C ６ alkyl)OC(O)Me] or (b) [Linker] is: 【Chemistry 40】 [ligase ligand portion] is 【Chemistry 41】 [MCL-1 ligand prodrug moiety] is a compound of formula (A3), [In the formula, R ３２ is as follows: 【Chemistry 42】 R ９ is C(O)O (linear C １ -C ６ alkyl)OC(O)C(CH ３ ) ３ , C(O)O (branched C １ -C ６ alkyl)OC(O)OiPr, C(O)O(branched C １ -C ６ alkyl)OC(O)Ocycloalkyl, C(O)O(branched C １ -C ６ alkyl)OC(O)O(CH ２ CH ２ O) ２ Et, or C(O)O (branched C １ -C ６ alkyl)OC(O)Me] or (c) [Linker] is: 【Chemistry 43】 [ligase ligand portion] is 【Chemistry 44】 [MCL-1 ligand prodrug moiety] is a compound of formula (A3), R ３２ is as follows: 【Chemistry 45】 R ９ is C(O)O (linear C １ -C ６ alkyl)OC(O)C(CH ３ ) ３ , C(O)O (linear C １ -C ６ alkyl)OC(O)CH ２ CH ２ OH, C(O)O (linear C １ -C ６ alkyl)OC(O)Me, C(O)OCH ２ CH ２ Heterocycloalkyl, or C(O)O (branched C １ -C ６ alkyl)OC(O)O(CH ２ CH ２ O) ２ Et] or (d) [Linker] is: 【Chemistry 46】 [ligase ligand portion] is 【Chemistry 47】 [MCL-1 ligand prodrug moiety] is a compound of formula (A3), R ３２ is as follows: 【Chemistry 48】 R ９ is C(O)O (linear C １ -C ６ alkyl)OC(O)C(CH ３ ) ３ , C(O)O (linear C １ -C ６ alkyl)OC(O)CH ２ CH ２ OH, C(O)O (linear C １ -C ６ alkyl)OC(O)Me, or C(O)OCH ２ CH ２ is heterocycloalkyl, R ９ is C(O)O (linear C １ -C ６ alkyl)OC(O)C(CH ３ ) ３ then the [ligase ligand moiety] is 【Chemistry 49】 27. The compound of claim 26, wherein: 【Request Item 48】 【Table 1】 2. The compound of claim 1 selected from:

49. (a) Table 2 or (b) Table 3 or (c) Table 4 49. The compound of claim 48, selected from:

50. (a) compounds 41, 43, 55, 57, 69, 71, 73, 74, 75, 99, 100, 101, and 124; or (b) compounds 41, 43, 55, 57, 69, 71, 73, 74, 75, 99, 100, and 101; or (c) compounds 69, 75, 99, 100, 101 and 124; or (d) Compounds 69, 75, 99, 100 and 101 49. The compound of claim 48, selected from:

51. (a) compounds 41, 43, 69, 73, 74, 101, 129 and 133; or (b) Compounds 41, 43, 73, 74, 129 and 133 49. The compound of claim 48, selected from:

52. 52. The compound of any one of claims 1 to 51, wherein each alkyl, alkenyl, alkynyl, aryl, heteroaryl and benzyl is unsubstituted unless otherwise specified.

53. Compounds of formula (I) [MCL-1 ligand prodrug moiety]-[linker]-[ligase ligand moiety] (I) or a salt, solvate, hydrate or isomer thereof, wherein the [ligase ligand moiety] is: (a) Formula (IV) or (IVa) [Transformation 50] (IV) (IVa) [In the formula, X １ and X ２ each independently is O or S; Q １ and Q ２ Each of the groups is independently N or CR ５ and Q １ and Q ２ at least one of is N; E １ , E ２ , E ３ and E ４ each independently is N or CR'; n is 0, 1 or 2; L ２ is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, —C(O)R ｂ , -C(O)OR ｂ , —C(O)NH ２ , —C(O)NHR ｂ , —C(O)NR ｂ ２ , -OR ｂ , -NR ｂ ２ , or -S(O) ２ R ｂ and Each R ５ are independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH ２ , -NHR ｂ , -NR ｂ ２ , -NR ｂ C(O)R ｂ , -NR ｂ C(O)OR ｂ , -NO ２ , -CN, -C(O)R ｂ , -C(O)OR ｂ , —C(O)NH ２ , —C(O)NHR ｂ , —C(O)NR ｂ ２ , -OR ｂ , -OC(O)R ｂ , -OC(O)OR ｂ , —OC(O)NH ２ , -OC(O)NHR ｂ , —OC(O)NR ｂ ２ , -SR ｂ , -S(O) ２ R ｂ , -S(O) ２ OR ｂ , -S(O) ２ NH ２ , -S(O) ２ NHR ｂ , -S(O) ２ NR ｂ ２ ;-O-R ２１ , -NH-R ２１ , -C(O)-NH-R ２１ , or -CH ２ -NH-C(O)-R ２１ and Each R' is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH ２ , -NHR ｂ , -NR ｂ ２ , -NR ｂ C(O)R ｂ , -NR ｂ C(O)OR ｂ , -NO ２ , -CN, -C(O)R ｂ , -C(O)OR ｂ , —C(O)NH ２ , —C(O)NHR ｂ , —C(O)NR ｂ ２ , -C(O)NHCHHR ｂ ２ , -CHR ｂ NHC(O)NHR ｂ , -CHR ｂ NHC(O)C(halogen) ２ R ｂ , -OR ｂ , -OC(O)R ｂ , -OC(O)OR ｂ , —OC(O)NH ２ , -OC(O)NHR ｂ , —OC(O)NR ｂ ２ , -SR ｂ , -S(O) ２ R ｂ , -S(O) ２ OR ｂ , -S(O) ２ NH ２ , -S(O) ２ NHR ｂ , -S(O) ２ NR ｂ ２ , -NHS(O) ２ R ｂ , -R ２１ , -O-R ２１ , -NH-R ２１ , —C(O)—R ２１ , -C(O)-NH-R ２１ , or -CH ２ -NH-C(O)-R ２１ and Each R ｂ are independently hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl; R ２１ is R of the linker １８ and formula (IV) is a bond connecting to a single R ２１ Including (b) Formula (VIIa), (VIIb), (VIIc) or (VIId) 【Chemistry 51】 (VIIa) (VIIb) 【change】 (VIIc) (VIId) [In the formula, X １ and X ２ each independently is O or S; Q １ and Q ２ Each of is independently N or CR, and Q １ and Q ２ at least one of is N; W １ , W ２ and W ３ Each of the groups is independently N or CR ａ and Z is O, S, or NR ｅ and n is 0, 1 or 2; L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)R ｂ , -C(O)OR ｂ , —C(O)NH ２ , —C(O)NHR ｂ , —C(O)NR ｂ ２ , -OR ｂ , -NR ｂ ２ , or -S(O) ２ R ｂ and Each R is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH ２ , -NHR ｂ , -NR ｂ ２ , -NR ｂ C(O)R ｂ , -NR ｂ C(O)OR ｂ , -NO ２ , -CN, -C(O)R ｂ , -C(O)OR ｂ , —C(O)NH ２ , —C(O)NHR ｂ , —C(O)NR ｂ ２ , -OR ｂ , -OC(O)R ｂ , -OC(O)OR ｂ , —OC(O)NH ２ , -OC(O)NHR ｂ , —OC(O)NR ｂ ２ , -SR ｂ , -S(O) ２ R ｂ , -S(O) ２ OR ｂ , -S(O) ２ NH ２ , -S(O) ２ NHR ｂ , -S(O) ２ NR ｂ ２ , -R ２１ , -O-R ２１ , -NH-R ２１ , —C(O)—R ２１ , -C(O)-NH-R ２１ , or -CH ２ -NH-C(O)-R ２１ and Each R ａ are independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH ２ , -NHR ｂ , -NR ｂ ２ , -NR ｂ C(O)R ｂ , -NR ｂ C(O)OR ｂ , -NO ２ , -CN, -C(O)R ｂ , -C(O)OR ｂ , —C(O)NH ２ , —C(O)NHR ｂ , —C(O)NR ｂ ２ , -OR ｂ , -OC(O)R ｂ , -OC(O)OR ｂ , —OC(O)NH ２ , -OC(O)NHR ｂ , —OC(O)NR ｂ ２ , -SR ｂ , -S(O) ２ R ｂ , -S(O) ２ OR ｂ , -S(O) ２ NH ２ , -S(O) ２ NHR ｂ , -S(O) ２ NR ｂ ２ , -R ２１ , -O-R ２１ , -NH-R ２１ , —C(O)—R ２１ , -C(O)-NH-R ２１ , or -CH ２ -NH-C(O)-R ２１ and Each R ｅ are independently hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, -R ２１ , -O-R ２１ , -NH-R ２１ , —C(O)—R ２１ , -C(O)-NH-R ２１ , or -CH ２ -NH-C(O)-R ２１ and Each R ｂ are independently hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl; R ２１ is R of the linker １８ and each of formula (VIIa), formula (VIIb) and formula (VIIc) is a bond connecting to a single R ２１ Including (c) Formula (VIII) 【Chemistry 52】 [In the formula, X １ and X ２ each independently is O or S; n is 0, 1 or 2; L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)R ｂ , -C(O)OR ｂ , —C(O)NH ２ , —C(O)NHR ｂ , —C(O)NR ｂ ２ , -OR ｂ , -NR ｂ ２ , or -S(O) ２ R ｂ and R １ , R ２ and R ３ each independently represents hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH ２ , -NHR ｂ , -NR ｂ ２ , -NR ｂ C(O)R ｂ , -NR ｂ C(O)OR ｂ , -NO ２ , -CN, -C(O)R ｂ , -C(O)OR ｂ , —C(O)NH ２ , —C(O)NHR ｂ , —C(O)NR ｂ ２ , -OR ｂ , -OC(O)R ｂ , -OC(O)OR ｂ , —OC(O)NH ２ , -OC(O)NHR ｂ , —OC(O)NR ｂ ２ , -SR ｂ , S(O) ２ R ｂ , -S(O) ２ OR ｂ , -S(O) ２ NH ２ , -S(O) ２ NHR ｂ , -S(O) ２ NR ｂ ２ , -R ２１ , -O-R ２１ , -NH-R ２１ , —C(O)—R ２１ , -C(O)-NH-R ２１ , or -CH ２ -NH-C(O)-R ２１ and Each R ｂ are independently hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl; R ２１ is R of the linker １８ and formula (VIII) is a bond connecting to a single R ２１ or (d) Formula (IX) 【Chemistry 53】 [In the formula, X １ and X ２ each independently is O or S; L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)R ｂ , -C(O)OR ｂ , —C(O)NH ２ , —C(O)NHR ｂ , —C(O)NR ｂ ２ , -OR ｂ , -NR ｂ ２ , or -S(O) ２ R ｂ and Q １ , Q ２ , Q ３ , Q ４ and Q ５ Each of is independently N or CR, and Q １ , Q ２ , Q ３ , Q ４ and Q ５ at least one of is N; Each R is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH ２ , -NHR ｂ , -NR ｂ ２ , -NR ｂ C(O)R ｂ , -NR ｂ C(O)OR ｂ , -NO ２ , -CN, -C(O)R ｂ , -C(O)OR ｂ , —C(O)NH ２ , —C(O)NHR ｂ , —C(O)NR ｂ ２ , -OR ｂ , -OC(O)R ｂ , -OC(O)OR ｂ , —OC(O)NH ２ , -OC(O)NHR ｂ , —OC(O)NR ｂ ２ , -SR ｂ , -S(O) ２ R ｂ , -S(O) ２ OR ｂ , -S(O) ２ NH ２ , -S(O) ２ NHR ｂ , or -S(O) ２ NR ｂ ２ , -R ２１ , -O-R ２１ , -NH-R ２１ , —C(O)—R ２１ , -C(O)-NH-R ２１ , or -CH ２ -NH-C(O)-R ２１ and Each R ｂ are independently hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl; R ２１ is R of the linker １８ and formula (IX) is a bond connecting to a single R ２１ Including [MCL-1 ligand prodrug moiety] is a compound of formula (A1), (A2), (A3) or (A4), 【Chemistry 54】 (A1) (A2) (A3) 【change】 (A4) [In the formula, 【Transformation 55】 is a single or double bond, Each Z ２ are independently N or C, Z ２ If is N, then 【Transformation 56】 is a single bond, and Z ２ If is C, then 【Chemistry 57】 is a double bond, Each R １１ are independently H, halogen or C １ -C ６ is alkyl, R ８ is a piperazine-substituted C １ -C ６ is alkyl, In each of formula (A1) and formula (A4), R １０ and R ３０ One of the groups is H, and the other is R １０ and R ３０ The other is -C ２－５ Alkyl-O-R １３ , —O—C ２－５ Alkyl-R １３ or -C ２－５ Alkyl-NMe-R １３ wherein R １３ is phenyl, naphthyl, or tetralin, and the phenyl, naphthyl, or tetralin is not halogen, C １ -C ６ Alkyl and —O(C １ -C ６ or the tetralin is substituted with at least one substituent selected from a bridged —CH ２ - group, or the naphthyl may be substituted by -O- or -S-; R １２ is as follows: 【Transformation 58】 R ３１ Ha-C ２－５ Alkyl-O-R １３ , —O—C ２－５ Alkyl-R １３ or -C ２－５ Alkyl-NMe-R １３ wherein R １３ is phenyl, naphthyl, or tetralin, and the phenyl, naphthyl, or tetralin is halogen, C １ -C ６ Alkyl and —O(C １ -C ６ or the tetralin is substituted with at least one substituent selected from a bridged —CH ２ - group, or said naphthyl may be substituted by -O- or -S-; Each R ３２ is independently H, 【Chemistry 59】 and each R ３３ is independently R １９ or C １ -C ６ alkyl, １ -C ６ The alkyl may be substituted with morpholine or piperazine; R ２０ is Me, -CH ２ -OMe, -(CH ２ CH ２ O) ｐ (C １ -C ６ alkyl), or —CH ２ -O-bromobenzaldehyde, p is 1 to 5; R ３４ is C ２－５ Alkyl-O-R １３ or -O-C ２－５ Alkyl-R １３ wherein R １３ is phenyl, naphthyl, or tetralin, and the phenyl, naphthyl, or tetralin is not halogen, C １ -C ６ Alkyl and —O(C １ -C ６ or the tetralin is substituted with at least one substituent selected from a bridged —CH ２ - group, or the naphthyl may be substituted by -O- or -S-; R ３５ is as follows: 【Transformation 60】 R １９ is R of the linker １４ and each of formula (A1), formula (A2), formula (A3) and formula (A4) is a bond connected to a single R １９ Including, (i) R ９ is -C(O)O(C １ -C ６ alkyl), —C(O)Ocycloalkyl, —C(O)Oheterocycloalkyl, —C(O)Oaryl or —P(O)(OR ｐ ) ２ and said C １ -C ６ Alkyl is —OC(O)(unsubstituted C １ -C ６ alkyl), —OC(O) (at least one R １０ C substituted with １ -C ６ alkyl), —OC(O)cycloalkyl, —OC(O)heterocycloalkyl, —OC(O)aryl, —OC(O)heteroaryl, —OC(O)(CH ２ ) ｍ O (CH ２ ) ｍ O (unsubstituted C １ -C ６ alkyl), —OC(O)(CH ２ ) ｍ O (CH ２ CH ２ O) ｍ (Unsubstituted C １ -C ６ alkyl), —OC(O)O(unsubstituted C １ -C ６ alkyl), —OC(O)O (at least one R １０ C substituted with １ -C ６ alkyl), —OC(O)Ocycloalkyl, —OC(O)O(CH ２ CH ２ O) ｍ (Unsubstituted C １ -C ６ alkyl), —OC(O)O(CH ２ CH ２ O) ｍ (OP(O)(OH) ２ C substituted with １ -C ６ alkyl), —OC(O)O(CH ２ CH ２ S) ｍ (Unsubstituted C １ -C ６ alkyl), —OC(O)O(CH ２ ) ｍ S(O) (unsubstituted C １ -C ６ alkyl), —OC(O)O(CH ２ ) ｍ S (O) ２ (Unsubstituted C １ -C ６ alkyl), —OC(O)NH(C substituted with OMe １ -C ６ alkyl), —OC(O)NMe (C substituted with OMe １ -C ６ alkyl), -P(O)(OH) ２ , -OP(O)(OH) ２ , —C(O)heterocycloalkyl, —C(O)N(unsubstituted C １ -C ６ alkyl) ２ , heteroaryl, heterocycloalkyl, -S(unsubstituted C １ -C ６ alkyl), —S(O)(unsubstituted C １ -C ６ alkyl), -N ＋ (Unsubstituted C １ -C ６ alkyl) ３ , -N ＋ (Unsubstituted C １ -C ６ alkyl) ２ Cycloalkyl, N-(unsubstituted C １ -C ６ alkyl)piperidinium cation, N-(unsubstituted C １ -C ６ alkyl)morpholinium cation, and N-(unsubstituted C １ -C ６ substituted with one or more groups selected from the group consisting of alkyl)imidazolium cations, Each R １０ are independently —OH, —O(unsubstituted C １ -C ６ alkyl), -OBn, -NH ２ , -NMe ２ , -NHC(O) (unsubstituted C １ -C ６ alkyl), —NHC(O)O(unsubstituted C １ -C ６ alkyl), heterocycloalkyl, heteroaryl, aryl, C(O)NMe ２ and Each R ｐ are independently -(CH ２ ) ｍ OC(O) (unsubstituted C １ -C ６ alkyl), each m is independently 1, 2, 3, or 4; or (ii) R ９ is -C(O)O(CH ２ ) ｐ NMe ２ , -C(O)O(CH ２ ) ｐ NHMe, -C(O)OCH ２ CH(OH)CH ２ OH, -C(O)OCH ２ CH ２ CMe ２ OH, or —C(O)OCH ２ CH ２ SO ２ Me, and each p is independently 2, 3, 4, 5, or 6. [Linker] has the formula: R １４ -R １５ -R １６ -R １７ -R １８ [In the formula, R １４ Ha-C １－６ Alkyl, —C ２－６ Alkenyl, -C ２－６ Alkynyl, —C １－６ Alkyl-N(C １－６ alkyl)-, —C(O)-, —SO ２ -or absent, R １５ is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C １－６ Alkyl-NH-, -C １－６ Alkyl-N(C １－６ alkyl)-, -cycloalkyl-NH-, -heterocycloalkyl-NH- or absent; R １６ Ha-C １－６ Alkyl, —C(O)—, —C(O)—C １－６ Alkyl-, —C(O)—NH—, —C(O)O—, —CH ２ -C(O)-, -CH ２ -C(O)-NH-, -CH ２ -C(O)O- or absent, R １７ Ha-CH ２ (C ２ H ４ -O) ｙ , -(CH ２ O) ｘ , -(C ２ H ４ -O) ｘ , -(C ３ H ６ -O) ｘ , or absent, x is 1 to 10; y is 2 to 10; R １８ Ha-C １－６ Alkyl, —C １－６ Alkyl-C(O)-, cycloalkyl, -CH ２ -NH-C(O)-, heterocycloalkyl, or absent; R １４ ~R １８ At least one of The compound, or a salt, solvate, hydrate or isomer thereof.

54. 54. The compound of claim 53, wherein, unless otherwise specified, each alkyl, alkenyl, alkynyl, aryl, heteroaryl, and benzyl group is unsubstituted.

55. Each R' is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH ２ , -NHR ｂ , -NR ｂ ２ , -NR ｂ C(O)R ｂ , -NR ｂ C(O)OR ｂ , -NO ２ , CN, -C(O)R ｂ , -C(O)OR ｂ , —C(O)NH ２ , —C(O)NHR ｂ , —C(O)NR ｂ ２ , -OR ｂ , -OC(O)R ｂ , -OC(O)OR ｂ , —OC(O)NH ２ , -OC(O)NHR ｂ , —OC(O)NR ｂ ２ , -SR ｂ , -S(O) ２ R ｂ , -S(O) ２ OR ｂ , S(O) ２ NH ２ , -S(O) ２ NHR ｂ , -S(O) ２ NR ｂ ２ , -R ２１ , -O-R ２１ , -NH-R ２１ , —C(O)—R ２１ , -C(O)-NH-R ２１ , or -CH ２ -NH-C(O)-R ２１ 55. The compound of claim 53 or 54, wherein:

56. Each R ｂ 56. The compound of claim 55, wherein is independently hydrogen, alkyl, cycloalkyl, or aryl.

57. Aryl is substituted with one or more groups selected from halogen, alkyl, and O-haloalkyl, and optionally, the halogen is Cl, the alkyl is methyl, and the O-haloalkyl is O-CF ３ 57. The compound of claim 56, wherein:

58. E １ , E ２ , E ３ and E ４ One of the two is N, and the other is E. １ , E ２ , E ３ and E ４ The compound according to any one of claims 53 to 57, wherein the remaining three of are each CR'.

59. (a) E １ is N and E ２ , E ３ and E ４ is CR', or (b) E ２ is N and E １ , E ３ and E ４ is CR', or (c) E ３ is N and E １ , E ２ and E ４ is CR', or (d) E ４ is N and E １ , E ２ and E ３ is CR', 59. The compound of claim 58.

60. E １ , E ２ , E ３ and E ４ are each CR', and optionally E １ , E ２ , E ３ and E ４ 58. The compound of any one of claims 53 to 57, wherein each is CH.

61. E １ , E ２ , E ３ and E ４ Three of them are CH, and E １ , E ２ , E ３ and E ４ one of which is C-halogen, C-alkyl, C-alkenyl, C-alkynyl, C-aryl, C-heteroaryl, C-benzyl, C-haloalkyl, C-haloalkenyl, C-NH ２ , C-NHR ｂ , C-NR ｂ ２ , C-NR ｂ C(O)R ｂ , C-NR ｂ C(O)OR ｂ , C-NO ２ , C-CN, C-C(O)R ｂ , C-C(O)OR ｂ , C—C(O)NH ２ , C-C(O)NHR ｂ , C-C(O)NR ｂ ２ , C-C(O)NHCHHR ｂ ２ , C-CHR ｂ NHC(O)NHR ｂ , C-CHR ｂ NHC(O)C(halogen) ２ R ｂ , C-OR ｂ , C-OC(O)R ｂ ,C-OC(O)OR ｂ ,C-OC(O)NH ２ ,C-OC(O)NHR ｂ ,C-OC(O)NR ｂ ２ , C-SR ｂ , C-S(O) ２ R ｂ , C-S(O) ２ OR ｂ , C-S(O) ２ NH ２ , C-S(O) ２ NHR ｂ , C-S(O) ２ NR ｂ ２ , C-NHS(O) ２ R ｂ , -R ２１ , -O-R ２１ , -NH-R ２１ , —C(O)—R ２１ , -C(O)-NH-R ２１ , or -CH ２ -NH-C(O)-R ２１ 61. The compound of claim 60, wherein:

62. (a) E ２ , E ３ and E ４ are each CH, or (b) E １ , E ３ and E ４ are each CH, or (c) E １ , E ２ and E ４ are each CH, 62. The compound of claim 61.

63. E １ , E ２ , E ３ and E ４ Two of them are N and E １ , E ２ , E ３ and E ４ and the remaining two of are each CR'.

64. E １ , E ２ , E ３ and E ４ Three of them are N and E １ , E ２ , E ３ and E ４ The compound according to any one of claims 53 to 57, wherein the remaining one of is CR'.

65. W １ , W ２ and W ３ One of the two is N and the other is W １ , W ２ and W ３ is CR ａ and optionally R ａ The compound of any one of claims 53 to 64, wherein is H.

66. W １ , W ２ and W ３ Each is CR ａ The compound according to any one of claims 53 to 64,

67. W １ is C-NH ２ , C-NHR ｂ or C-NR ｂ ２ and C—NH ２ The compound according to any one of claims 53 to 66,

68. W １ , W ２ and W ３ The compound of any one of claims 53 to 64, wherein each is N.

69. 69. The compound of any one of claims 53 to 68, wherein Z is NH or N-alkyl, and may be NH or N-Me.

70. In formula (IV), formula (VIIa), formula (VIIb) and formula (VIIc), (a) Q １ is N and Q ２ is CR, or (b) Q １ is N and Q ２ is N, or (c) Q １ is CR and Q ２ is N, and optionally Q １ is C—H or C-alkyl, and optionally Q １ is C—H or C-Me; A compound according to any one of claims 53 to 69.

71. In formula (IX), Q １ , Q ２ , Q ３ , Q ４ and Q ５ One of the １ , Q ２ , Q ３ , Q ４ and Q ５ The compound according to any one of claims 53 to 70, wherein the remaining four of are each CR.

72. (a) Q １ is N, or (b) Q ２ is N, or (c) Q ３ is N, 72. The compound of claim 71.

73. In formula (IX), Q １ , Q ２ , Q ３ , Q ４ and Q ５ Two of them are N and Q １ , Q ２ , Q ３ , Q ４ and Q ５ The compound according to any one of claims 53 to 70, wherein the remaining three of are each CR.

74. (a) Q １ and Q ２ is N and Q ３ , Q ４ and Q ５ are each CR, or (b) Q ２ and Q ３ is N and Q １ , Q ４ and Q ５ are each CR, or (c) Q １ and Q ３ is N and Q ２ , Q ４ and Q ５ are each CR, or (d) Q ２ and Q ４ is N and Q １ , Q ３ and Q ５ are each CR, or (e) Q １ and Q ４ is N and Q ２ , Q ３ and Q ５ are each CR, 74. The compound of claim 73.

75. In formula (IX), Q １ , Q ２ , Q ３ , Q ４ and Q ５ Three of them are N and Q １ , Q ２ , Q ３ , Q ４ and Q ５ and the remaining two of are each CR.

76. The compound according to any one of claims 53 to 70, wherein the [ligase ligand portion] is: 【Chemistry 61】 【change】 , 【change】 or 【change】 or (b) 【change】

77. The compound according to any one of claims 53 to 70, wherein the [ligase ligand portion] is: 【Transformation 62】

78. Compounds of formula (I) [MCL-1 ligand prodrug moiety]-[linker]-[ligase ligand moiety] (I) or a salt, solvate, hydrate or isomer thereof, wherein the [ligase ligand moiety] is: (a) Formula (Va) or (Vb) 【Transformation 63】 (Va) (Vb) or a pharmaceutically acceptable salt or tautomer thereof [In the formula, X １ and X ２ each independently is O or S; Z １ is O, S, or NR ６ and T is C=O or SO ２ and R １ is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; Y ５ , Y ６ , Y ７ and Y ８ Each of the groups is independently N or CR ７ and Y in formula (Va) ５ , Y ６ and Y ７ At least one of the following is CR ７ and Y in formula (Vb) ５ , Y ５ and Y ８ At least one of the following is CR ７ and n is 0, 1 or 2; L ３ is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, —C(O)R″″, —CH ２ C(O)OR'''', -C(O)OR'''', -C(O)NH ２ , -C(O)NHR'''', -C(O)NR'''' ２ , -OR'''', -NR'''' ２ , or -S(O) ２ R'''', Each R ７ are independently hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH ２ , -NHR'''', -NR'''' ２ , -CH ２ NR'''' ２ , -NR''''C(O)R'''', -NR''''C(O)CH ２ NR'''' ２ , -NR''''C(O)CH ２ -heterocycloalkyl, -NR""C(O)CH(OH)R"", -CH ２ NR''''C(O)OR'''', -NR''''C(O)OR'''', -NR''''SO ２ R'''', -NO ２ , -CN, -C(O)R'''', -C(O)OR'''', -C(O)NH ２ , -C(O)NHR'''', -C(O)NR'''' ２ , -OR''', -OC(O)R''', -OC(O)OR''', -OC(O)NH ２ , -OC(O)NHR'''', -OC(O)NR'''' ２ , -NHC(S)NHR'', SR'', or -S(O) ２ R"", -S(O) ２ OR'''', -S(O) ２ NH ２ , -S(O) ２ NHR'''', -S(O) ２ NR'''' ２ , -O-R ２１ , -NH-R ２１ , -C(O)-NH-R ２１ , or -CH ２ -NH-C(O)-R ２１ and each R"" is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; R ６ is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH ２ , -NHR'''', -NR'''' ２ , -NR''''C(O)R'''', -N[C(O)R''''] ２ , -NR''''C(O)OR'''', -NO ２ , -CN, -C(O)R'''', -C(O)OR'''', -C(O)NH ２ , -C(O)NHR'''', -C(O)NR'''' ２ , -OR''', -OC(O)R''', -OC(O)OR''', -OC(O)NH ２ , -OC(O)NHR'''', -OC(O)NR'''' ２ , -SR'''', or -S(O) ２ R"", -S(O) ２ OR'''', -S(O) ２ NH ２ , -S(O) ２ NHR'''', -S(O) ２ NR'''' ２ , -R ２１ , -C(O)-NH-R ２１ , or -CH ２ -NH-C(O)-R ２１ and R ２１ is R of the linker １８ and each of formula (Va) and formula (Vb) is a bond connecting to a single R ２１ Including, Z １ is O, then Y ６ is CR ７ and When the compound is of formula (Va): (i) Y ５ , Y ６ and Y ７ Each of these is CR ７ If R ７ At least one of them is not H, (ii) Z １ NR ６ If Y ６ and Y ７ is CR ７ and (iii) Z １ If S, then Y ５ is not C-OMe, but Y ６ is not C-OMe, (iv) Z １ is S and Y ５ When Y is C-NHCOMe, ７ is C-CH ２ Not NR''''C(O)OR'''', (v) Z １ is S and Y ５ If N, then Y ６ is not C—H, C-aryl or C—C(O)OR″″, (vi) Z １ is S and Y ６ If N, then Y ７ is C-NH ２ , C-NHR'''', C-NR'''' ２ , C-NR''''C(O)OR'''', C-CH ２ NR''''C(O)OR'''', C-haloalkyl, C- ｔ butyl, C—OR′′′, C—COOR′′′ or C—SR′′′; Y ７ is C-NH ２ , C-NHR'''' or C-NR'''' ２ If Y ５ is C—H, When the compound is of formula (Vb), (vii) Y ５ , Y ６ and Y ８ Each of these is CR ７ If R ７ At least one of them is not H, (viii) Z １ If S, then Y ５ is not C-COOH or C-NHC(O)Me, but Y ８ is not C-Br, (ix) Z １ is S and Y ６ When Y is C—Br, ８ is C-OR'''', (x)Z １ is S and Y ５ is N and Y ６ is C—H or C—NH ２ If Y ８ is not C-H, (xi) Z １ is S and Y ５ If N, then Y ６ is C-halogen, C-alkyl, C-cycloalkyl, C-aryl, C-heteroaryl, C-CH ２ NH ２ , C—COOalkyl, or C—NHC(O)alkyl; (xii) Z １ NR ６ If Y ５ , Y ６ and Y ８ is CR ７ is], or (b) Formula (IIa) or (IIb) 【Chemistry 64】 (IIa) (IIb) [In the formula, X １ and X ２ each independently is O or S; Z is O, S, or NR ２ and T is C=O or SO ２ and Y ３ is N or CR, Y ４ is N or CR, 【Transformation 65】 represents a single bond or a double bond, each 【Chemical Formula 66】 is a double bond, W １ , W ２ , W ３ and W ４ Each of the groups is independently N or CR ａ and W １ , W ２ , W ３ and W ４ at least one of is N; each 【Transformation 67】 When W is a single bond, １ , W ２ , W ３ and W ４ are CR ａ ２ and Y ４ is CR, n is 0, 1 or 2; L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)R ｈ , -C(O)OR ｈ , —C(O)NH ２ , —C(O)NHR ｈ , —C(O)NR ｈ ２ , -OR ｈ , -NR ｈ ２ , or -S(O) ２ R ｈ and Each R is independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH ２ , -NHR ｈ , -NR ｈ ２ , -NR ｈ C(O)R ｈ , -NR ｈ C(O)CH ２ R ｈ , -NR ｈ C(O)CH(OH)R ｈ , -NR ｈ C(O)OR ｈ , -NR ｈ SO ２ R ｈ , -NO ２ , -CN, -C(O)R ｈ , -C(O)OR ｈ , —C(O)NH ２ , —C(O)NHR ｈ , —C(O)NR ｈ ２ , -OR ｈ , -OC(O)R ｈ , -OC(O)OR ｈ , —OC(O)NH ２ , -OC(O)NHR ｈ , —OC(O)NR ｈ ２ , -SR ｈ , or -S(O) ２ R ｈ , -S(O) ２ OR ｈ , -S(O) ２ NH ２ , -S(O) ２ NHR ｈ , or -S(O) ２ NR ｈ ２ and Each R ａ are independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH ２ , -NHR ｈ , -NR ｈ ２ , -NR ｈ C(O)R ｈ , -NR ｈ C(O)CH(OH)R ｈ , -NR ｈ C(O)OR ｈ , -NR ｈ SO ２ R ｈ , -NO ２ , -CN, -C(O)R ｈ , -C(O)OR ｈ , —C(O)NH ２ , —C(O)NHR ｈ , —C(O)NR ｈ ２ , -OR ｈ , -OC(O)R ｈ , -OC(O)OR ｈ , —OC(O)NH ２ , -OC(O)NHR ｈ , —OC(O)NR ｈ ２ , -SR ｈ , -S(O) ２ R ｈ , -S(O) ２ OR ｈ , -S(O) ２ NH ２ , -S(O) ２ NHR ｈ , -S(O) ２ NR ｈ ２ , -O-R ２１ , -NH-R ２１ , -C(O)-NH-R ２１ , or -CH ２ -NH-C(O)-R ２１ and Each R ｈ are independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; R ２ is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH ２ , -NHR ｈ , -NR ｈ ２ , -NR ｈ C(O)R ｈ , -N[C(O)R ｈ ] ２ , -NR ｈ C(O)OR ｈ , -NO ２ , -CN, -C(O)R ｈ , -C(O)OR ｈ , —C(O)NH ２ , —C(O)NHR ｈ , —C(O)NR ｈ ２ , -OR ｈ , -OC(O)R ｈ , -OC(O)OR ｈ , —OC(O)NH ２ , -OC(O)NHR ｈ , —OC(O)NR ｈ ２ , -SR ｈ , -S(O) ２ R ｈ , -S(O) ２ OR ｈ , -S(O) ２ NH ２ , -S(O) ２ NHR ｈ , or -S(O) ２ NR ｈ ２ and R １ is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; R ２１ is R of the linker １８ and each of formula (IIa) and formula (IIb) is a bond connecting to a single R ２１ Including, each 【Transformation 68】 is a double bond, and Z is NR ２ and R ２ is hydrogen, and each R ａ is hydrogen, W ４ is CR ａ is] [MCL-1 ligand prodrug moiety] is a compound of formula (A1), (A2), (A3) or (A4), 【Transformation 69】 (A1) (A2) (A3) 【change】 (A4) [In the formula, 【Transformation 70】 is a single or double bond, Each Z ２ are independently N or C, Z ２ If is N, then 【Chemistry 71】 is a single bond, and Z ２ If is C, then 【Chemistry 72】 is a double bond, Each R １１ are independently H, halogen or C １ -C ６ is alkyl, R ８ is a piperazine-substituted C １ -C ６ is alkyl, In each of formula (A1) and formula (A4), R １０ and R ３０ One of the groups is H, and the other is R １０ and R ３０ The other is -C ２－５ Alkyl-O-R １３ , —O—C ２－５ Alkyl-R １３ or -C ２－５ Alkyl-NMe-R １３ wherein R １３ is phenyl, naphthyl, or tetralin, and the phenyl, naphthyl, or tetralin is not halogen, C １ -C ６ Alkyl and —O(C １ -C ６ or the tetralin is substituted with at least one substituent selected from a bridged —CH ２ - group, or the naphthyl may be substituted by -O- or -S-; R １２ is as follows: 【Transformation 73】 R ３１ Ha-C ２－５ Alkyl-O-R １３ , —O—C ２－５ Alkyl-R １３ or -C ２－５ Alkyl-NMe-R １３ wherein R １３ is phenyl, naphthyl, or tetralin, and the phenyl, naphthyl, or tetralin is halogen, C １ -C ６ Alkyl and —O(C １ -C ６ or the tetralin is substituted with at least one substituent selected from a bridged —CH ２ - group, or said naphthyl may be substituted by -O- or -S-; Each R ３２ is independently H, 【Chemistry 74】 and Each R ３３ is independently R １９ or C １ -C ６ alkyl, １ -C ６ The alkyl may be substituted with morpholine or piperazine; R ２０ is Me, -CH ２ -OMe, -(CH ２ CH ２ O) ｐ (C １ -C ６ alkyl), or —CH ２ -O-bromobenzaldehyde, p is 1 to 5; R ３４ is C ２－５ Alkyl-O-R １３ or -O-C ２－５ Alkyl-R １３ wherein R １３ is phenyl, naphthyl, or tetralin, and the phenyl, naphthyl, or tetralin is not halogen, C １ -C ６ Alkyl and —O(C １ -C ６ or the tetralin is substituted with at least one substituent selected from a bridged —CH ２ - group, or the naphthyl may be substituted by -O- or -S-; R ３５ is as follows: 【Chemistry 75】 R １９ is R of the linker １４ and each of formula (A1), formula (A2), formula (A3) and formula (A4) is a bond connected to a single R １９ Including, (i) R ９ is -C(O)O(C １ -C ６ alkyl), —C(O)Ocycloalkyl, —C(O)Oheterocycloalkyl, —C(O)Oaryl or —P(O)(OR ｐ ) ２ and said C １ -C ６ Alkyl is —OC(O)(unsubstituted C １ -C ６ alkyl), —OC(O) (at least one R １０ C substituted with １ -C ６ alkyl), —OC(O)cycloalkyl, —OC(O)heterocycloalkyl, —OC(O)aryl, —OC(O)heteroaryl, —OC(O)(CH ２ ) ｍ O (CH ２ ) ｍ O (unsubstituted C １ -C ６ alkyl), —OC(O)(CH ２ ) ｍ O (CH ２ CH ２ O) ｍ (Unsubstituted C １ -C ６ alkyl), —OC(O)O(unsubstituted C １ -C ６ alkyl), —OC(O)O (at least one R １０ C substituted with １ -C ６ alkyl), —OC(O)Ocycloalkyl, —OC(O)O(CH ２ CH ２ O) ｍ (Unsubstituted C １ -C ６ alkyl), —OC(O)O(CH ２ CH ２ O) ｍ (OP(O)(OH) ２ C substituted with １ -C ６ alkyl), —OC(O)O(CH ２ CH ２ S) ｍ (Unsubstituted C １ -C ６ alkyl), —OC(O)O(CH ２ ) ｍ S(O) (unsubstituted C １ -C ６ alkyl), —OC(O)O(CH ２ ) ｍ S (O) ２ (Unsubstituted C １ -C ６ alkyl), —OC(O)NH(C substituted with OMe １ -C ６ alkyl), —OC(O)NMe (C substituted with OMe １ -C ６ alkyl), -P(O)(OH) ２ , -OP(O)(OH) ２ , —C(O)heterocycloalkyl, —C(O)N(unsubstituted C １ -C ６ alkyl) ２ , heteroaryl, heterocycloalkyl, -S(unsubstituted C １ -C ６ alkyl), —S(O)(unsubstituted C １ -C ６ alkyl), -N ＋ (Unsubstituted C １ -C ６ alkyl) ３ , -N ＋ (Unsubstituted C １ -C ６ alkyl) ２ Cycloalkyl, N-(unsubstituted C １ -C ６ alkyl)piperidinium cation, N-(unsubstituted C １ -C ６ alkyl)morpholinium cation, and N-(unsubstituted C １ -C ６ substituted with one or more groups selected from the group consisting of alkyl)imidazolium cations, Each R １０ are independently —OH, —O(unsubstituted C １ -C ６ alkyl), -OBn, -NH ２ , -NMe ２ , -NHC(O) (unsubstituted C １ -C ６ alkyl), —NHC(O)O(unsubstituted C １ -C ６ alkyl), heterocycloalkyl, heteroaryl, aryl, —C(O)NMe ２ and Each R ｐ are independently -(CH ２ ) ｍ OC(O) (unsubstituted C １ -C ６ alkyl), each m is independently 1, 2, 3, or 4; or (ii) R ９ is -C(O)O(CH ２ ) ｐ NMe ２ , -C(O)O(CH ２ ) ｐ NHMe, -C(O)OCH ２ CH(OH)CH ２ OH, -C(O)OCH ２ CH ２ CMe ２ OH, or —C(O)OCH ２ CH ２ SO ２ Me, and each p is independently 2, 3, 4, 5, or 6. [Linker] has the formula: R １４ -R １５ -R １６ -R １７ -R １８ [In the formula, R １４ Ha-C １－６ Alkyl, —C ２－６ Alkenyl, -C ２－６ Alkynyl, —C １－６ Alkyl-N(C １－６ alkyl)-, —C(O)-, —SO ２ -or absent, R １５ is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C １－６ Alkyl-NH-, -C １－６ Alkyl-N(C １－６ alkyl)-, -cycloalkyl-NH-, -heterocycloalkyl-NH- or absent; R １６ Ha-C １－６ Alkyl, —C(O)—, —C(O)—C １－６ Alkyl-, —C(O)—NH—, —C(O)O—, —CH ２ -C(O)-, -CH ２ -C(O)-NH-, -CH ２ -C(O)O- or absent, R １７ Ha-CH ２ (C ２ H ４ -O) ｙ , -(CH ２ O) ｘ , -(C ２ H ４ -O) ｘ , -(C ３ H ６ -O) ｘ , or absent, x is 1 to 10; y is 2 to 10; R １８ Ha-C １－６ Alkyl, —C １－６ Alkyl-C(O)-, cycloalkyl, -CH ２ -NH-C(O)-, heterocycloalkyl, or absent; R １４ ~R １８ At least one of The compound, or a salt, solvate, hydrate or isomer thereof.

79. 79. The compound of claim 78, wherein each alkyl, alkenyl, alkynyl, aryl, heteroaryl, and benzyl group is unsubstituted unless otherwise specified.

80. Z １ is S in formula (Vb), Y ５ is not —C—NHC(O)R″″ or —C(O)OR″″.

81. Z １ NR ６ The compound according to any one of claims 78 to 80,

82. Each R is independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH ２ , -NHR'''', -NR'''' ２ , -NR'''C(O)R''', -NR'''C(O)CH(OH)R''', -NR'''C(O)OR''', -NR'''SO ２ R'''', -NO ２ , -CN, -C(O)R'''', -C(O)OR'''', -C(O)NH ２ , -C(O)NHR'''', -C(O)NR'''' ２ , -OR''', -OC(O)R''', -OC(O)OR''', -OC(O)NH ２ , -OC(O)NHR'''', -OC(O)NR'''' ２ , -SR'''', or -S(O) ２ R"", -S(O) ２ OR'''', -S(O) ２ NH ２ , -S(O) ２ NHR'''', -S(O) ２ NR'''' ２ , -O-R ２１ , -NH-R ２１ , -C(O)-NH-R ２１ , or -CH ２ -NH-C(O)-R ２１ The compound according to any one of claims 78 to 81,

83. R １ The compound of any one of claims 78 to 82, wherein is hydrogen.

84. R ６ The compound of any one of claims 78 to 83, wherein is hydrogen.

85. [ligase ligand moiety] is of formula (Va), and Y ５ , Y ６ and Y ７ Each is CR ７ The compound according to any one of claims 78 to 84,

86. Y ５ is —C-NHC(O)R″″; Y ６ is CH, Y ７ is CH or CCl; 86. The compound of claim 85.

87. L ３ is hydrogen, Z １ is S, R １ is hydrogen, T is C=O; Y ７ is CH, 87. The compound of claim 86.

88. is a compound of formula (Vb), ５ , Y ６ and Y ８ Each is CR ７ The compound according to any one of claims 78 to 84,

89. L ３ is hydrogen, Z １ is S, R １ is H, T is C=O; Y ５ is CH, C—OR″″, CCl, C—CN, or C—NHC(O)R″″; Y ６ is CH, CCl, C-alkyl, C-cycloalkyl, or C-haloalkyl; Y ８ is CH, C-OR'''', C-NHC(O)R'''', C-NHC(O)OR'''', C-NHR'''', C-NH ２ , or C-NHSO ２ R'''', Y ５ When is CCl, Y ６ is CH, C-alkyl, C-cycloalkyl, or C-haloalkyl; optionally, each R"" is independently alkyl, cycloalkyl, aryl, or benzyl; 89. The compound of claim 88.

90. Y ５ is CH, Y ６ is CH or CCl, Y ８ is C-OR'''' or C-NH ２ and C-OMe or C-NH ２ may be, 90. The compound of claim 89.

91. (a) Z is NR ２ or (b) Z is S; The compound according to any one of claims 78 to 90.

92. each 【Transformation 76】 The compound according to any one of claims 78 to 91, wherein is a double bond.

93. 93. The compound of any one of claims 78 to 92, wherein L is hydrogen.

94. W １ , W ２ , W ３ and W ４ One of the two is N, and W １ , W ２ , W ３ and W ４ The remaining three are CR ａ and optionally W ４ is CR ａ 94. The compound of claim 92 or 93, wherein:

95. W １ , W ２ , W ３ and W ４ Two of them are N and W １ , W ２ , W ３ and W ４ The remaining two are CR ａ The compound according to any one of claims 78 to 92,

96. W １ , W ２ , W ３ and W ４ One of them is CR ａ and W １ , W ２ , W ３ and W ４ The compound according to any one of claims 78 to 92, wherein the remaining three of are each N.

97. Each R is independently hydrogen, halogen, or —NR ｈ C(O)R ｈ The compound according to any one of claims 78 to 96,

98. Compounds of formula (I) [MCL-1 ligand prodrug moiety]-[linker]-[ligase ligand moiety] (I) or a salt, solvate, hydrate or isomer thereof, wherein the [ligase ligand moiety] is: (a) Formula (VIa) or (VIb) 【Chemical 77】 (VIa) (VIb) [In the formula, M is O, S, or NH, or absent; 【Transformation 78】 is the R of the linker １８ shows the bond with R ２２ is hydrogen, halogen, —OMe, an amino group, heterocycloalkyl, or unsubstituted C １ -C ６ is alkyl, L' is hydrogen, alkyl, benzyl, acetyl, or pivaloyl. (b) Formula (II) 【Chemistry 79】 [In the formula, X １ and X ２ each independently is O or S; T is C=O or SO ２ and R １ is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; n is 0, 1 or 2; L ４ is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, —C(O)H, —C(O)R ｂ , -C(O)OH, -C(O)OR ｂ , —C(O)NH ２ , —C(O)NHR ｂ , —C(O)NR ｂ ２ , —OH, —OR ｂ , -NH ２ , -NHR ｂ , -NR ｂ ２ , -S(O) ２ H or -S(O) ２ R ｂ and R ｙ is selected from the following: 【Chemistry 80】 During the ceremony, 【Chemistry 81】 indicates a bond to T, Z ３ is O, S, or NR ３ and U is O, S, NR ｂ Or CR ｉ ２ and Y １ , Y ２ and Y ３ Each of the groups is independently N or CR ｄ and Each R ｄ are independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH ２ , -NHR ｂ , -NR ｂ ２ , -NHC(O)R ｂ , -NR ｂ C(O)R ｂ ,NHC(O)CH(OH)R ｂ , -NR ｂ C(O)CH(OH)R ｂ , -NHC(O)OR ｂ , -NR ｂ C(O)OR ｂ , -NHSO ２ R ｂ , -NR ｂ SO ２ R ｂ , -NO ２ , -CN, -C(O)H, C(O)R ｂ , -C(O)OH, -C(O)OR ｂ , —C(O)NH ２ , —C(O)NHR ｂ , —C(O)NR ｂ ２ , —OH, —OR ｂ , -OC(O)H, -OC(O)R ｂ , -OC(O)OH, -OC(O)OR ｂ , —OC(O)NH ２ , -OC(O)NHR ｂ , —OC(O)NR ｂ ２ , -SH, -SR ｂ , -S(O) ２ H, -S(O) ２ R ｂ , -S(O) ２ OH, -S(O) ２ OR ｂ , -S(O) ２ NH ２ , -S(O) ２ NHR ｂ , -S(O) ２ NR ｂ ２ , -O-R ２１ , -NH-R ２１ , -C(O)-NH-R ２１ , or -CH ２ -NH-C(O)-R ２１ and Each R ｉ are independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH ２ , -NHR ｂ , -NR ｂ ２ , -NHC(O)R ｂ , -NR ｂ C(O)R ｂ , -NHC(O)CH(OH)R ｂ , -NR ｂ C(O)CH(OH)R ｂ , -NHC(O)OR ｂ , -NR ｂ C(O)OR ｂ , -NHSO ２ R ｂ , -NR ｂ SO ２ R ｂ , -NO ２ , -CN, -C(O)H, C(O)R ｂ , -C(O)OH, -C(O)OR ｂ , —C(O)NH ２ , —C(O)NHR ｂ , —C(O)NR ｂ ２ , —OH, —OR ｂ , -OC(O)H, -OC(O)R ｂ , -OC(O)OH, -OC(O)OR ｂ , —OC(O)NH ２ , -OC(O)NHR ｂ , —OC(O)NR ｂ ２ , -SH, -SR ｂ , -S(O) ２ H, -S(O) ２ R ｂ , -S(O) ２ OH, -S(O) ２ OR ｂ , -S(O) ２ NH ２ , -S(O) ２ NHR ｂ , or -S(O) ２ NR ｂ ２ and Each R ３ are independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH ２ , -NHR ｂ , -NR ｂ ２ , -NHC(O)R ｂ , -NR ｂ C(O)R ｂ ,NHC(O)CH(OH)R ｂ , -NR ｂ C(O)CH(OH)R ｂ , -NHC(O)OR ｂ , -NR ｂ C(O)OR ｂ , -NHSO ２ R ｂ , -NR ｂ SO ２ R ｂ , -NO ２ , -CN, -C(O)H, C(O)R ｂ , -C(O)OH, -C(O)OR ｂ , —C(O)NH ２ , —C(O)NHR ｂ , —C(O)NR ｂ ２ , —OH, —OR ｂ , -OC(O)H, -OC(O)R ｂ , -OC(O)OH, -OC(O)OR ｂ , —OC(O)NH ２ , -OC(O)NHR ｂ , —OC(O)NR ｂ ２ , -SH, -SR ｂ , -S(O) ２ H, -S(O) ２ R ｂ , -S(O) ２ OH, -S(O) ２ OR ｂ , -S(O) ２ NH ２ , -S(O) ２ NHR ｂ , -S(O) ２ NR ｂ ２ , -R ２１ , -C(O)-NH-R ２１ , or -CH ２ -NH-C(O)-R ２１ and Each R ｂ is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; R ２１ is R of the linker １８ and formula (II) is a bond connecting to a single R ２１ Including, During the ceremony, (i) R ｙ but 【Chemistry 82】 If Y ２ is CR ｄ and (ii) R ｙ but 【Chemistry 83】 If ｉ ２ R ｉ is not hydrogen] or (c) Formula (III) 【Chemical 84】 [In the formula, X １ and X ２ each independently is O or S; T is C=O or SO ２ and R １ is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; n is 0, 1 or 2; L １ is hydrogen, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, —C(O)H, —C(O)R ｂ , -C(O)OH, -C(O)OR ｂ , -CH ２ C(O)OR ｂ , —C(O)NH ２ , —C(O)NHR ｂ , —C(O)NR ｂ ２ , —OH, —OR ｂ , -NH ２ , -NHR ｂ , -NR ｂ ２ , -S(O) ２ H or -S(O) ２ R ｂ and R ｘ is selected from the following: 【Chemical 85】 During the ceremony, 【Chemical 86】 indicates a bond to T, Z ４ is O, S, or NR ４ and V is CR ｆ ２ , N.R. ４ Or S, G １ , G ２ , G ３ and G ４ Each of the groups is independently N or CR ｃ and Y １ and Y ２ Each of the groups is independently N or CR ｆ and Each R ｆ are independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, fused aryl-cycloalkyl, fused aryl-heterocycloalkyl, heteroaryl, heteroaryl substituted with at least one aryl group, benzyl, haloalkyl, haloalkenyl, -NH ２ , -NHR ｂ , -NR ｂ ２ , -NHC(O)R ｂ , -NR ｂ C(O)R ｂ , -NHC(O)CH(OH)R ｂ , -NR ｂ C(O)CH(OH)R ｂ , -NHC(O)OR ｂ , -NR ｂ C(O)OR ｂ , -NHSO ２ R ｂ , -NR ｂ SO ２ R ｂ , -NO ２ , -CN, -C(O)H, -C(O)R ｂ , -C(O)OH, -C(O)OR ｂ , —C(O)NH ２ , —C(O)NHR ｂ , —C(O)NR ｂ ２ , —OH, —OR ｂ , -OC(O)H, -OC(O)R ｂ , -OC(O)OH, -OC(O)OR ｂ , —OC(O)NH ２ , -OC(O)NHR ｂ , —OC(O)NR ｂ ２ , -SH, -SR ｂ , -S(O) ２ H, -S(O) ２ R ｂ , -S(O) ２ OH, -S(O) ２ OR ｂ , -S(O) ２ NH ２ , -S(O) ２ NHR ｂ , -S(O) ２ NR ｂ ２ , -R ２１ , -O-R ２１ , -NH-R ２１ , -C(O)-NH-R ２１ , or -CH ２ -NH-C(O)-R ２１ or Y １ and Y ２ is CR ｆ If ｆ forms a 5- or 6-membered ring together with the carbon atom to which it is attached, Each R ｃ are independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, at least one -OR ｂ aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH ２ , -NHR ｂ , -NR ｂ ２ , -CH ２ NH ２ , -NHC(O)R ｂ , -NR ｂ C(O)R ｂ , -NHC(O)CH(OH)R ｂ , -NR ｂ C(O)CH(OH)R ｂ , -NHC(O)OR ｂ , -NR ｂ C(O)OR ｂ , -NHSO ２ R ｂ , -NR ｂ SO ２ R ｂ , -NO ２ , -CN, -C(O)H, -C(O)R ｂ , -C(O)OR ｂ , —C(O)NH ２ , —C(O)NHR ｂ , —C(O)NR ｂ ２ , —OH, —OR ｂ , -OC(O)H, -OC(O)R ｂ , -OC(O)OH, -OC(O)OR ｂ , —OC(O)NH ２ , -OC(O)NHR ｂ , —OC(O)NR ｂ ２ , -SH, -SR ｂ , -S(O) ２ H, -S(O) ２ R ｂ , -S(O) ２ OH, -S(O) ２ OR ｂ , -S(O) ２ NH ２ , -S(O) ２ NHR ｂ , -S(O) ２ NR ｂ ２ , -O-R ２１ , -NH-R ２１ , -C(O)-NH-R ２１ , or -CH ２ -NH-C(O)-R ２１ and Each R ４ are independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, —C(O)H, C(O)R ｂ , -C(O)OH, -C(O)OR ｂ , —C(O)NH ２ , —C(O)NHR ｂ , —C(O)NR ｂ ２ , —OH, —OR ｂ , -NH ２ , -NHR ｂ , -NR ｂ ２ , -S(O) ２ H, -S(O) ２ R ｂ , -R ２１ , -C(O)-NH-R ２１ , or -CH ２ -NH-C(O)-R ２１ and Each R ｂ is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; R ２１ is R of the linker １８ and formula (III) is a bond connecting to a single R ２１ Including, n=2, and each R ｃ is hydrogen, and G １ , G ２ , G ３ and G ４ Each of these is CR ｃ If C=X １ may be replaced by CH; During the ceremony, (i) R ｘ but 【Chemistry 87】 and Z ４ When is NH, L １ is hydrogen, -CH ２ C(O)OR ｂ , or -OR ｂ and (ii) R ｘ but 【Chemical 88】 and Z ４ NR ４ and Y １ is CR ｆ and Y ２ If is N, then R ４ is not alkyl, R ２ and at least one of R is not H; (iii) R ｘ but 【Chemistry 89】 and Z ４ NR ４ and Y １ and Y ２ is CR ｆ If G １ , G ２ and G ３ at least one of is N; (iv) Z ４ NR ４ and Y １ and Y ２ is CR ｆ If R ｘ teeth [Chemical 90] Instead, (v) R ｘ but 【Chemistry 91】 and Z ４ NR ４ and Y １ Or Y ２ If is N, then R ４ is not an alkyl, (we)R ｘ が 【Chemistry 92】 where n=1 or 2; (vii) R ｘ but 【Chemistry 93】 If Z ４ = O or S] [MCL-1 ligand prodrug moiety] is a compound of formula (A1), (A2), (A3) or (A4), 【Chemical 94】 (A1) (A2) (A3) 【change】 (A4) [In the formula, 【Chemical 95】 is a single or double bond, Each Z ２ are independently N or C, Z ２ If is N, then 【Chemistry 96】 is a single bond, and Z ２ If is C, then 【Chemistry 97】 is a double bond, Each R １１ are independently H, halogen or C １ -C ６ is alkyl, R ８ is a piperazine-substituted C １ -C ６ is alkyl, In each of formula (A1) and formula (A4), R １０ and R ３０ One of the groups is H, and the other is R １０ and R ３０ The other is -C ２－５ Alkyl-O-R １３ , —O—C ２－５ Alkyl-R １３ or -C ２－５ Alkyl-NM^e-R １３ wherein R １３ is phenyl, naphthyl, or tetralin, and the phenyl, naphthyl, or tetralin is not halogen, C １ -C ６ Alkyl and —O(C １ -C ６ or the tetralin is substituted with at least one substituent selected from a bridged —CH ２ - group, or the naphthyl may be substituted by -O- or -S-; R １２ is as follows: 【Chem.98】 R ３１ Ha-C ２－５ Alkyl-O-R １３ , —O—C ２－５ Alkyl-R １３ or -C ２－５ Alkyl-NMe-R １３ wherein R １３ is phenyl, naphthyl, or tetralin, and the phenyl, naphthyl, or tetralin is halogen, C １ -C ６ Alkyl and —O(C １ -C ６ or the tetralin is substituted with at least one substituent selected from a bridged —CH ２ - group, or said naphthyl may be substituted by -O- or -S-; Each R ３２ is independently H, 【Chem.99】 and Each R ３３ is independently R １９ or C １ -C ６ alkyl, １ -C ６ The alkyl may be substituted with morpholine or piperazine; R ２０ is Me, -CH ２ -OMe, -(CH ２ CH ２ O) ｐ (C １ -C ６ alkyl), or —CH ２ -O-bromobenzaldehyde, p is 1 to 5; R ３４ is C ２－５ Alkyl-O-R １３ or -O-C ２－５ Alkyl-R １３ wherein R １３ is phenyl, naphthyl, or tetralin, and the phenyl, naphthyl, or tetralin is not halogen, C １ -C ６ Alkyl and —O(C １ -C ６ or the tetralin is substituted with at least one substituent selected from a bridged —CH ２ - group, or the naphthyl may be substituted by -O- or -S-; R ３５ is as follows: 【Chemistry 100】 R １９ is R of the linker １４ and each of formula (A1), formula (A2), formula (A3) and formula (A4) is a bond connected to a single R １９ Including, (i) R ９ is -C(O)O(C １ -C ６ alkyl), —C(O)Ocycloalkyl, —C(O)Oheterocycloalkyl, —C(O)Oaryl or —P(O)(OR ｐ ) ２ and said C １ -C ６ Alkyl is —OC(O)(unsubstituted C １ -C ６ alkyl), —OC(O) (at least one R １０ C substituted with １ -C ６ alkyl), —OC(O)cycloalkyl, —OC(O)heterocycloalkyl, —OC(O)aryl, —OC(O)heteroaryl, —OC(O)(CH ２ ) ｍ O (CH ２ ) ｍ O (unsubstituted C １ -C ６ alkyl), —OC(O)(CH ２ ) ｍ O (CH ２ CH ２ O) ｍ (Unsubstituted C １ -C ６ alkyl), —OC(O)O(unsubstituted C １ -C ６ alkyl), —OC(O)O (at least one R １０ C substituted with １ -C ６ alkyl), —OC(O)Ocycloalkyl, —OC(O)O(CH ２ CH ２ O) ｍ (Unsubstituted C １ -C ６ alkyl), —OC(O)O(CH ２ CH ２ O) ｍ (OP(O)(OH) ２ C substituted with １ -C ６ alkyl), —OC(O)O(CH ２ CH ２ S) ｍ (Unsubstituted C １ -C ６ alkyl), —OC(O)O(CH ２ ) ｍ S(O) (unsubstituted C １ -C ６ alkyl), —OC(O)O(CH ２ ) ｍ S (O) ２ (Unsubstituted C １ -C ６ alkyl), —OC(O)NH(C substituted with OMe １ -C ６ alkyl), —OC(O)NMe (C substituted with OMe １ -C ６ alkyl), -P(O)(OH) ２ , -OP(O)(OH) ２ , —C(O)heterocycloalkyl, —C(O)N(unsubstituted C １ -C ６ alkyl) ２ , heteroaryl, heterocycloalkyl, -S(unsubstituted C １ -C ６ alkyl), —S(O)(unsubstituted C １ -C ６ alkyl), -N ＋ (Unsubstituted C １ -C ６ alkyl) ３ , -N ＋ (Unsubstituted C １ -C ６ alkyl) ２ Cycloalkyl, N-(unsubstituted C １ -C ６ alkyl)piperidinium cation, N-(unsubstituted C １ -C ６ alkyl)morpholinium cation, and N-(unsubstituted C １ -C ６ substituted with one or more groups selected from the group consisting of alkyl)imidazolium cations, Each R １０ are independently —OH, —O(unsubstituted C １ -C ６ alkyl), -Obn, -NH ２ , -Nme ２ , -NHC(O) (unsubstituted C １ -C ６ alkyl), —NHC(O)O(unsubstituted C １ -C ６ alkyl), heterocycloalkyl, heteroaryl, aryl, —C(O)Nme ２ and Each R ｐ are independently -(CH ２ ) ｍ OC(O) (unsubstituted C １ -C ６ alkyl), each m is independently 1, 2, 3, or 4; or (ii) R ９ is -C(O)O(CH ２ ) ｐ Nme ２ , -C(O)O(CH ２ ) ｐ NHMe, -C(O)OCH ２ CH(OH)CH ２ OH, -C(O)OCH ２ CH ２ CMe ２ OH, or —C(O)OCH ２ CH ２ SO ２ Me, and each p is independently 2, 3, 4, 5, or 6. [Linker] has the formula: R １４ -R １５ -R １６ -R １７ -R １８ [In the formula, R １４ Ha-C １－６ Alkyl, —C ２－６ Alkenyl, -C ２－６ Alkynyl, C １－６ Alkyl-N(C １－６ alkyl)-, —C(O)-, —SO ２ -or absent, R １５ is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C １－６ Alkyl-NH-, -C １－６ Alkyl-N(C １－６ alkyl)-, -cycloalkyl-NH-, -heterocycloalkyl-NH- or absent; R １６ Ha-C １－６ Alkyl, —C(O)—, —C(O)—C １－６ Alkyl-, —C(O)—NH—, —C(O)O—, —CH ２ -C(O)-, -CH ２ -C(O)-NH-, -CH ２ -C(O)O- or absent, R １７ Ha-CH ２ (C ２ H ４ -O) ｙ , -(CH ２ O) ｘ , -(C ２ H ４ -O) ｘ , -(C ３ H ６ -O) ｘ , or absent, x is 1 to 10; y is 2 to 10; R １８ Ha-C １－６ Alkyl, —C １－６ Alkyl-C(O)-, cycloalkyl, -CH ２ -NH-C(O)-, heterocycloalkyl, or absent; R １４ ~R １８ At least one of The compound, or a salt, solvate, hydrate or isomer thereof.

99. 99. The compound of claim 98, wherein each alkyl, alkenyl, alkynyl, aryl, heteroaryl, and benzyl is unsubstituted unless otherwise specified.

100. In formula (III), X １ and X ２ each of which is O; T is C=O; R １ is hydrogen, L １ is hydrogen, R ｘ but 【Chemistry 101】 and Z ４ NR ４ and G １ , G ２ and G ４ Each of these is CR ｃ and Y １ is N, Y ２ is CR ｆ and R ｆ is not hydrogen, 100. The compound of claim 98 or 99.

101. The compound according to any one of claims 98 to 100, wherein the [ligase ligand portion] is formula (III). 【Chemical Engineering 102】

102. (a) R ｃ One of them is -O-R ２１ , -NH-R ２１ , -C(O)-NH-R ２１ , or -CH ２ -NH-C(O)-R ２１ Or (b) G １ is C-O-R ２１ , C-NH-R ２１ , C-C(O)-NH-R ２１ , or C-CH ２ -NH-C(O)-R ２１ Or (c) G ２ is C-O-R ２１ , C-NH-R ２１ , C-C(O)-NH-R ２１ , or C-CH ２ -NH-C(O)-R ２１ Or (d) R ４ is R ２１ , -C(O)-NH-R ２１ , or -CH ２ -NH-C(O)-R ２１ or (e) R ｆ One of them is -R ２１ , -O-R ２１ , -NH-R ２１ , -C(O)-NH-R ２１ , or -CH ２ -NH-C(O)-R ２１ That is, The compound according to any one of claims 98 to 101.

103. Y ２ is C-R ２１ , CO-R ２１ , C-NH-R ２１ , C-C(O)-NH-R ２１ , or C-CH ２ -NH-C(O)-R ２１ The compound according to any one of claims 98 to 102,

104. (a) the [ligase ligand moiety] is selected from: 【Chemistry 103】 【change】 or (b) the [ligase ligand moiety] is selected from: 【Chemical 104】 【change】 The compound according to any one of claims 98 to 103.

105. The compound of claim 104, wherein the [ligase ligand portion] is: 【Chemistry 105】

106. 100. The compound of claim 98 or 99, wherein the [ligase ligand portion] is: 【Chemistry 106】

107. R １６ Ga-C １－６ Alkyl, —C(O)—, —C(O)—NH—, —C(O)O—, —CH ２ -C(O)-, -CH ２ -C(O)-NH-, -CH ２ -C(O)O- or absent, R １７ Ga-CH ２ (C ２ H ４ -O) ｙ , -(C ２ H ４ -O) ｘ , -(C ３ H ６ -O) ｘ , or absent, R １８ Ga-C １－６ Alkyl, cycloalkyl, -CH ２ -NH-C(O)-, heterocycloalkyl, or absent; The compound according to any one of claims 53 to 106.

108. R １４ Ga-C １－６ Alkyl, —C ２－６ Alkenyl, -C ２－６ Alkynyl, —C(O)—, —SO ２ - or absent.

109. R １４ Ga-C １－６ 109. The compound of claim 108, which is alkyl.

110. R １５ is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C １－６ The compound of any one of claims 53 to 109, which is alkyl-NH-, -cycloalkyl-NH-, or absent.

111. R １５ is heterocycloalkyl.

112. R １５ piperazine, bridged piperazine, piperazine N-oxide, piperazine cation, 【Chemistry 107】 and During the ceremony, 【Chemistry 108】 is R １４ shows the bond with 【Chemistry 109】 is R １６ 112. The compound of claim 111, wherein the compound exhibits a bond with

113. R １５ is piperazine or 【Chemical 110】 113. The compound of claim 112, wherein:

114. R １５ 111. The compound of claim 110, wherein is absent.

115. R １６ Ga-C １－６ Alkyl, —CH ２ The compound according to any one of claims 53 to 114, which is -C(O)-NH- or -C(O)-.

116. R １６ Ga-C １－６ 116. The compound of claim 115, which is alkyl or -C(O)-.

117. R １７ The compound of any one of claims 53 to 116, wherein is absent.

118. R １８ Ga-C １－６ 118. The compound of any one of claims 53 to 117, wherein the alkyl, heterocycloalkyl, or absent.

119. R １８ Ga-C １－６ 119. The compound of claim 118, which is alkyl or heterocycloalkyl.

120. R １８ Ga-C １－６ 120. The compound of claim 119, which is an alkyl or piperazine.

121. R １８ 119. The compound of claim 118, wherein is absent.

122. The compound according to any one of claims 53 to 121, wherein the linker is selected from the following: 【Chemistry 111】 [In the formula, 【Chemistry 112】 indicates a bond to the [MCL-1 ligand prodrug moiety], 【Chemistry 113】 indicates binding to [ligase ligand moiety]]

123. In each of formula (A1) and formula (A4), R １０ and R ３０ is H, and R １０ and R ３０ The other side is -C ２－５ Alkyl-O-R １３ or -O-C ２－５ Alkyl-R １３ wherein R １３ is phenyl or naphthyl, and the phenyl or naphthyl is halogen and C １ -C ６ The compound according to any one of claims 53 to 122, optionally substituted with at least one substituent selected from alkyl.

124. In formula (A1), R １２ but 【Chemical 114】 The compound according to any one of claims 53 to 123,

125. In formula (A4), R ３５ but 【Chemical 115】 The compound according to any one of claims 53 to 124,

126. In formula (A2), R ３１ Ga-C ２－５ Alkyl-O-R １３ or -O-C ２－５ Alkyl-R １３ wherein R １３ is phenyl or naphthyl, and the phenyl or naphthyl is halogen and C １ -C ６ The compound according to any one of claims 53 to 125, optionally substituted with at least one substituent selected from alkyl.

127. In formula (A3), R ３４ is C ２－５ Alkyl-O-R １３ or -O-C ２－５ Alkyl-R １３ wherein R １３ is phenyl or naphthyl, and the phenyl or naphthyl is halogen and C １ -C ６ The compound according to any one of claims 53 to 126, optionally substituted with at least one substituent selected from alkyl.

128. Z ２ is C, 【Chemistry 116】 The compound according to any one of claims 53 to 127, wherein is a double bond.

129. The compound of any one of claims 53 to 128, wherein the [MCL-1 ligand prodrug moiety] is: 【Chemistry 117】 [In the formula, R １１ is a halogen, R １３ａ is a halogen, R ２０ is Me, -CH ２ -OMe, or -(CH ２ CH ２ O)p(C １ -C ６ alkyl), and p is 1 to 5.

130. R ９ -C(O)O(C １ -C ６ alkyl), —C(O)Ocycloalkyl, —C(O)Oheterocycloalkyl, —C(O)Oaryl or —P(O)(OR ｐ ) ２ and said C １ -C ６ The alkyl is —OC(O)(unsubstituted C １ -C ６ alkyl), —OC(O) (at least one R １０ C substituted with １ -C ６ alkyl), —OC(O)cycloalkyl, —OC(O)heterocycloalkyl, —OC(O)aryl, —OC(O)heteroaryl, —OC(O)(CH ２ ) ｍ O (CH ２ ) ｍ O (unsubstituted C １ -C ６ alkyl), —OC(O)(CH ２ ) ｍ O (CH ２ CH ２ O) ｍ (Unsubstituted C １ -C ６ alkyl), —OC(O)O(unsubstituted C １ -C ６ alkyl), —OC(O)O (at least one R １０ C substituted with １ -C ６ alkyl), —OC(O)Ocycloalkyl, —OC(O)O(CH ２ CH ２ O) ｍ (Unsubstituted C １ -C ６ alkyl), —OC(O)O(CH ２ CH ２ O) ｍ (OP(O)(OH) ２ C substituted with １ -C ６ alkyl), —OC(O)O(CH ２ CH ２ S) ｍ (Unsubstituted C １ -C ６ alkyl), —OC(O)O(CH ２ ) ｍ S(O) (unsubstituted C １ -C ６ alkyl), —OC(O)O(CH ２ ) ｍ S (O) ２ (Unsubstituted C １ -C ６ alkyl), —OC(O)NH(C substituted with OMe １ -C ６ alkyl), -C(O)NMe (C substituted with OMe １ -C ６ alkyl), -P(O)(OH) ２ , -OP(O)(OH) ２ , —C(O)heterocycloalkyl, —C(O)N(unsubstituted C １ -C ６ alkyl) ２ , heteroaryl, heterocycloalkyl, -S(unsubstituted C １ -C ６ alkyl), —S(O)(unsubstituted C １ -C ６ alkyl), -N ＋ (Unsubstituted C １ -C ６ alkyl) ３ , -N ＋ (Unsubstituted C １ -C ６ alkyl) ２ Cycloalkyl, N-(unsubstituted C １ -C ６ alkyl)piperidinium cation, N-(unsubstituted C １ -C ６ alkyl)morpholinium cation, and N-(unsubstituted C １ -C ６ 130. The compound of any one of claims 53 to 129, wherein the compound is substituted with one or more groups selected from the group consisting of alkyl)imidazolyl cations.

131. R ９ -C(O)O(C １ -C ６ alkyl), —C(O)Ocycloalkyl, —C(O)Oheterocycloalkyl, —C(O)Oaryl, or —P(O)(OR ｐ ) ２ and said C １ -C ６ Alkyl is -OC(O)Me, -OC(O)Et, -OC(O) ｉ Pr, -OC(O)C(CH ３ ) ３ , —OC(O)CH ２ OH, -OC(O)CH(CH ３ )OH, -OC(O)C(CH ３ ) ２ OH, -OC(O)CH ２ CH ２ OH, -OC(O)CH(OH)CHMe ２ , -OC(O)CH(OH)CH ２ CHMe ２ , —OC(O)CH ２ CH(OH)Me, -OC(O)CH ２ C(OH)Me ２ , -OC(O)CH(CH ２ OH)(NHC(O)Me), —OC(O)CH(NHC(O)Me)(isobutyl), —OC(O)CH(OH)aryl, —OC(O)CH(OH)CH ２ Aryl, —OC(O)heterocycloalkyl, —OC(O)cycloalkyl, —OC(O)aryl, —OC(O)heteroaryl, —OC(O)CH ２ CH ２ Aryl, —OC(O)CH(NH ２ ) ｉ Pr, -OC(O)CH( ｉ Pr)NHC(O)O ｔ Bu, -OC(O)CH ２ OCH ２ CH ２ OMe, -OC(O)CH ２ (OCH ２ CH ２ ) ２ OMe, -OC(O)OMe, -OC(O)OEt, -OC(O)O ｉ Pr, —OC(O)Ocycloalkyl, —OC(O)OCH ２ CH ２ OEt, -OC(O)O(CH ２ CH ２ O) ２ Et, -OC(O)O(CH ２ CH ２ O) ３ Et, -OC(O)O(CH ２ CH ２ O) ３ CH ２ CH ２ OP(O)(OH) ２ , -OC(O)OCH ２ CH ２ SMe, -OC(O)OCH ２ CH ２ S(O)Me, -OC(O)OCH ２ CH ２ S (O) ２ Me, -OC(O)OCH ２ Heteroaryl, —OC(O)OCH ２ Heterocycloalkyl, —OC(O)OCH ２ CH ２ OCH ２ Aryl, —OC(O)OCH ２ CH ２ C(O)NMe ２ , -OC(O)O(CH ２ ) ６ NH ２ , -OC(O)O(CH ２ ) ６ NMe ２ , -OC(O)OCH(CH ２ OEt) ２ , -OC(O)NHCH ２ CH ２ OMe, -oC(O)NMeCH ２ CH ２ OMe, -SMe, -S(O)Me, -P(O)(OH) ２ , -OP(O)(OH) ２ , —C(O)NMe ２ , —C(O)heterocycloalkyl, heteroaryl, heterocycloalkyl, —N ＋ (Me) ３ , -N ＋ (Me) ２ 131. The compound of claim 130, substituted with one or more groups selected from cycloalkyl, N-methylmorpholinium cation, N-methylpiperidinium cation, and N-methylimidazolium cation.

132. R ９ -C(O)O(C １ -C ６ alkyl), and １ -C ６ Alkyl is -OC(O)C(CH ３ ) ３ , —OC(O)CH ２ CH ２ OH, -OC(O)C(CH ３ ) ２ OH, —OC(O)heterocycloalkyl, —OC(O)CH ２ OCH ２ CH ２ OMe, —OC(O)OiPr, —OC(O)Ocycloalkyl, —OC(O)O(CH ２ CH ２ O) ２ Et, -OP(O)(OH) ２ 132. The compound of claim 131, substituted with one or more groups selected from: heteroaryl, or heterocycloalkyl.

133. R ９ -C(O)O(C １ -C ６ alkyl), and １ -C ６ Alkyl is -OC(O)C(CH ３ ) ３ 133. The compound of claim 132, substituted with:

134. R ９ -C(O)OCH ２ OC(O)C(CH ３ ) ３ 134. The compound of claim 133, wherein:

135. R ９ -C(O)OCH ２ OC(O)C(CH ３ ) ３ , —C(O)OCH ２ OC(O)Me, -C(O)OCH(Me)OC(O)Me, -C(O)OCH ２ OC(O)CH ２ CH ２ OH, -C(O)OCH ２ OC(O)C(CH ３ ) ２ OH, -C(O)OCH ２ OC(O)piperidine, —C(O)OCH ２ OC(O)CH ２ OCH ２ CH ２ OMe, -C(O)OCH ２ OC(O)OiPr, -C(O)OCHMeOC(O)OiPr, -C(O)OCHMeOC(O)Ocyclohexyl, -C(O)OCHMeOC(O)O(CH ２ CH ２ O) ２ Et, -C(O)OCH ２ CH ２ OP(O)(OH) ２ , —C(O)OCH ２ (N-methylimidazolium cation), —C(O)OCH ２ (N-methylpiperidinium cation), —C(O)OCH ２ Dioxolane, —C(O)OCH ２ CH ２ Morpholine, —C(O)OCH ２ CH ２ Piperazine, —C(O)OCH ２ CH ２ CH ２ Piperazine or -P(O)(OCH ２ OC(O)C(CH ３ ) ３ ) ２ 132. The compound of claim 131, wherein:

136. R ２０ is Me or -(CH ２ CH ２ O) ２ The compound of any one of claims 53 to 135, which is Me.

137. R ３３ is R １９ The compound according to any one of claims 53 to 136,

138. R ３３ is substituted with morpholine or piperazine １ -C ６ The compound of any one of claims 53 to 136, which is alkyl.

139. C substituted with morpholine or piperazine １ -C ６ The compound of any one of claims 53 to 138, wherein alkyl is: 【Chemistry 118】

140. (a) [MCL-1 ligand prodrug moiety] is: 【Chemical 119】 【change】 or 【change】 or (b) The compound of any one of claims 53 to 139, wherein [MCL-1 ligand prodrug moiety] is: 【Chemical 120】

141. 99. The compound of claim 98, wherein: 【Chemistry 121】 compound 70

142. The compound of any one of claims 1 to 141, wherein T is C=O.

143. (a) X １ and X ２ is O or (b) X １ is O and X ２ is S or (c) X １ is S and X ２ is O, or (d) X １ and X ２ is S, A compound according to any one of claims 1 to 142.

144. The compound of any one of claims 1 to 143, wherein n is 0.

145. The compound of any one of claims 1 to 143127, wherein n is 1 or 2.

146. 146. The compound of claim 145, wherein n is 1.

147. 146. The compound of claim 145, wherein n is 2.

148. A pharmaceutical composition comprising a compound according to any one of claims 1 to 147.

149. A compound according to any one of claims 1 to 147 or a pharmaceutical composition according to claim 148 for use in medicine.

150. A compound according to any one of claims 1 to 147 or a pharmaceutical composition according to claim 148 for use in the treatment of cancer.

151. 151. The compound or composition for use of claim 150, wherein the cancer is selected from breast cancer, triple-negative breast cancer, colon cancer, pancreatic cancer, skin cancer, melanoma, ovarian cancer, kidney cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, lymphoma, non-Hodgkin's lymphoma, multiple myeloma, cervical cancer, leukemia, chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), bladder cancer, and prostate cancer.

152. 152. The compound or composition for use of claim 151, wherein the cancer is multiple myeloma or acute myeloid leukemia.

153. 149. A method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any of claims 1-147 or a pharmaceutical composition of claim 148.

154. 154. The method of claim 153, wherein the cancer is selected from breast cancer, triple-negative breast cancer, colon cancer, pancreatic cancer, skin cancer, melanoma, ovarian cancer, kidney cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, lymphoma, non-Hodgkin's lymphoma, multiple myeloma, cervical cancer, leukemia, chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), bladder cancer, and prostate cancer.

155. The method of claim 154, wherein the cancer is multiple myeloma or acute myeloid leukemia.

156. 156. The method of any of claims 153-155, wherein administration does not result in cytotoxicity in the subject's cardiomyocytes.

157. 157. The method of any of claims 153-156, further comprising administering to the subject at least one additional active agent.

158. The method of claim 157, wherein the at least one additional active agent is an anti-cancer agent selected from eribulin; fulvestrant; midostaurin; an immune checkpoint inhibitor selected from anti-PD-1 antibodies, anti-PD-11 antibodies, and anti-PD-1 / PD-11 interaction inhibitors; nivolumab; pembrolizumab; atezolizumab; pidilizumab; carfilzomib; venetoclax; cytarabine; anthracyclines; taxane compounds; and hypomethylating agents.

159. A compound according to any one of claims 1 to 147 or a pharmaceutical composition according to claim 148 for use in reversing resistance to chemotherapy or targeted cancer therapy.

160. 149. A method of reversing resistance to chemotherapy or targeted cancer therapy in a subject in need thereof, comprising administering to said subject an effective amount of a compound of any of claims 1-147 or a pharmaceutical composition of claim 148.

161. A combined preparation of a compound according to any one of claims 1 to 147 with at least one additional active agent for simultaneous, separate or sequential use in therapy.

162. The combination preparation of claim 161, wherein the at least one additional active agent is an anti-cancer agent selected from eribulin; fulvestrant; midostaurin; an immune checkpoint inhibitor selected from anti-PD-1 antibodies, anti-PD-11 antibodies, and anti-PD-1 / PD-11 interaction inhibitors; nivolumab; pembrolizumab; atezolizumab; pidilizumab; carfilzomib; venetoclax; cytarabine; anthracyclines; taxane compounds; and hypomethylating agents.

163. 163. The combined preparation of claim 161 or 162, wherein the therapy is the treatment of cancer.

164. 147. A method for reducing cardiac cytotoxicity of an MCL-1 inhibitor, comprising the step of attaching a cereblon-binding moiety to an MCL-1 inhibitor, wherein the cereblon-binding moiety is a "ligase ligand moiety" as defined in any one of claims 1 to 147, and the MCL-1 inhibitor is an "MCL-1 ligand prodrug moiety" as defined in any one of claims 1 to 147.

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