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

Abstract

1. A compound of formula (I): [MCL-1 ligand site]-[linker]-[ligase ligand site] (I), or a salt, solvate, hydrate, isomer, or prodrug thereof, wherein [MCL-1 ligand site] is a compound of formula (A), or [MCL-1 ligand site] is a compound of formula (A1), (A2), (A3), or (A4), and use thereof in the treatment of cancer. [Formula 1] JPEG2025540970000791.jpg126170

Description

[Technical Field]

[0001] The present invention relates to a bifunctional compound that can bind to both a ubiquitin ligase and a target protein, thereby bringing the target protein into proximity with the ubiquitin ligase and inducing its degradation. [Background technology]

[0002] The ubiquitin-proteasome system (UPS) is responsible for maintaining a healthy and balanced proteome. During the ubiquitination process, ubiquitin units are covalently attached to proteins to form polyubiquitin chains, which mark 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, thereby 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 (US2002173049A1 (PROTEINIX INC) November 21, 2002). One approach for TPD relies on the use of bifunctional molecules that simultaneously bind to a ubiquitin ligase and a target protein, thereby enabling efficient ubiquitin transfer to the latter. This concept was first described by Sakamoto KM et al. (Proc Natl Acad Sci USA. 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 stresses, such as DNA damage, can result in programmed cell death, a cellular response aimed at preventing 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 a BH3 domain. These proteins bind to the effector Bcl-2 proteins Bak and Bax (via their BH3 domains) and prevent their pro-apoptotic activity. Inhibition of the BH3 domain-BH3 pocket binding interface is a well-known approach for cancer therapy (Leber B, Kale J, Andrews DW. Cancer Discov. 2018 Dec;8(12):1511-1514).

[0006] Inducible high expression of myeloid leukemia cell differentiation protein-1 (MCL-1) is observed in many human cancers and is associated with resistance to cytotoxic drugs. Studies have shown that inhibition of MCL-1 protein in some malignant tumors results in the release of proapoptotic proteins and the induction of apoptosis. Therefore, targeting MCL-1 may be applied as a therapeutic strategy in these MCL-1-dependent cancer types, such as 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). Furthermore, treatment with Bcl-2 and MEK inhibitors often induces MCL-1 dependency, and subsequent inactivation of MCL-1 leads to 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 promotes adaptive survival of tumor cells treated with oncogene-targeting therapy, and therefore, MCL-1-targeting drugs are likely to overcome cancer resistance to these therapeutic agents.

[0007] Along with efforts focused on MCL-1 inhibition, targeted degradation is considered an attractive therapeutic option. Both 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 demonstrated degradation of the MCL-1 protein. However, the efficacy of previously reported compounds in terms of cell degradation and apoptosis induction remains suboptimal. Therefore, alternative chemical species with improved potency are needed to develop therapeutically applicable MCL-1 degrading drugs.

[0008] One of the challenges in developing MCL-1-targeting therapeutics is safety. This is because MCL-1 has been shown to be essential for cardiac homeostasis in adult mouse models, and its absence led to cardiomyocyte loss. Several clinical trials using MCL-1 inhibitors are currently on hold to evaluate safety signals for cardiac toxicity (Wei AH et al. Blood Rev. 2020 Nov;44:100672). Summary of the Invention

[0009] According to a first aspect of the present invention, a compound of formula (I) [MCL-1 ligand site]-linker-[ligase ligand site] (I) or a salt, solvate, hydrate, isomer or prodrug thereof, In the formula, [ligase ligand site] is [ka] (In the formula, M is O, S, or NH, or absent; [ka] is the linker R 18 indicates binding to; R 22 is hydrogen, halogen, -OMe, 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 moiety] is a compound of formula (A1), (A2), (A3) or (A4): [ka] (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; when Z2 is C, [ka] is a double bond; Each R 9 are independently —C(O)OH, —C(O)OC-Calkyl, —C(O)NH, or P(O)(OH), 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 of the groups is H and R 10 and R 30 The other of these 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 teeth, [ka] and Each R 33 are independently, H, R19 or C1-C6 alkyl optionally substituted with morpholine or piperazine; R 31 -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 are independently, H, [ka] and where R 20 are Me, -CH2-OMe, -(CH2CH2O) p (C1-C6 alkyl), or -CH2-O-bromobenzaldehyde (wherein 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 teeth, [ka] and; R 19 is the linker R 14 and each of formula (A1), formula (A2), formula (A3) and formula (A4) is a bond connected to a single R 19 containing [Linker] is a group represented by the following formula: R 14 -R 15 -R 16 -R 17 -R 18 wherein R 14 -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 a 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 -C 1-6 Alkyl, -C(O)-C 1-6 alkyl-, -C(O)-, -C(O)-NH-, -C(O)O-, -CH2-C(O)-, -CH2-C(O)-NH-, -CH2-C(O)O-, or absent; R 17 is -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 -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 these exists.

[0010] In some embodiments, the ligase ligand site is [ka] is.

[0011] In some embodiments, R 29 is Me. In other embodiments, R 29 is hydrogen.

[0012] In some embodiments, the ligase ligand site is [ka] is.

[0013] In another embodiment, the ligase ligand site is [ka] is.

[0014] In some embodiments, R 22 is hydrogen, halogen, -OMe, -NH, -NHMe, -NMe, or piperidine. In some such embodiments, R 22 is hydrogen, -OMe, -NH, -NHMe, -NMe, or piperidine. In some embodiments, R 22 is hydrogen.

[0015] In some embodiments, L' is hydrogen.

[0016] In some embodiments, M is O or NH, or absent.

[0017] In some embodiments, the ligase ligand site is [ka] [ka] is.

[0018] In some embodiments, the ligase ligand site is [ka] is.

[0019] In some embodiments, the ligase ligand site is [ka] is.

[0020] In some embodiments, R 16 -C 1-6 alkyl, -C(O)-, -C(O)-NH-, -C(O)O-, -CH2-C(O)-, -CH2-C(O)-NH-, -CH2-C(O)O-, or absent; R 17 is -CH2(C2H4-O) y , -(C2H4-O) x , -(C3H6-O) x , or absent, R 18 -C 1-6 It is alkyl, cycloalkyl, -CH2-NH-C(O)-, heterocycloalkyl, or absent.

[0021] In some embodiments, R 14 -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 alkynyl, —C(O)—, —SO—, or absent. In some embodiments, R 14 -C 1-6 It is alkyl.

[0022] In some embodiments, R 15 is a cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 In some such embodiments, R is alkyl-NH-, -cycloalkyl-NH-, or absent. 15 is heterocycloalkyl or absent. In some embodiments, R 15 is piperazine, bridged piperazine, piperazine N-oxide, piperazine cation, [ka] or absent, [ka] is R 14 indicates the bond to [ka] is R 16 The bond to

[0023] In some embodiments, R 15 is piperazine, [ka] Or absent.

[0024] In some embodiments, R 16 -C 1-6 alkyl, -CH2-C(O)-NH-, -CH2-C(O)-, -C(O)-, or absent.

[0025] In some embodiments, R 17 is absent.

[0026] In some embodiments, R 18 -C 1-6 alkyl, cyclobutyl, CH2-NH-C(O)-, piperazine, or absent.

[0027] In some embodiments, the linker is [ka] is selected from During the ceremony, [ka] indicates binding to the MCL-1 ligand site, [ka] indicates binding to the [ligase ligand site].

[0028] In some embodiments, the linker is [ka] is selected from.

[0029] In some embodiments, the [MCL-1 ligand moiety] has formula (A1): [ka] It is of the type.

[0030] In some embodiments, the [MCL-1 ligand moiety] has formula (A2): [ka] It is of the type.

[0031] In some embodiments, the [MCL-1 ligand moiety] has formula (A3): [ka] It is of the type.

[0032] In some embodiments, the [MCL-1 ligand moiety] has formula (A4): [ka] It is of the type.

[0033] In some embodiments, in each of Formula (A1) and Formula (A4), R 10 and R 30 One of the groups is H and R 10 and R 30 The other of these is -C 2-5 Alkyl-OR 13 , or -OC 2-5 Alkyl-R 13 where R 13 is phenyl or naphthyl, said phenyl or said naphthyl being optionally substituted with at least one substituent selected from halogen and C1-C6 alkyl.

[0034] In some embodiments, R of formula (A1) 12 teeth, [ka] is.

[0035] In some embodiments, R of formula (A4) 35 teeth, [ka] is.

[0036] In some embodiments, R of formula (A2) 31 -C 2-5 Alkyl-OR 13 or -OC 2-5 Alkyl-R 13 where R 13 is phenyl or naphthyl, said phenyl or said naphthyl being optionally substituted with at least one substituent selected from halogen and C1-C6 alkyl.

[0037] In some embodiments, R of formula (A3) 34 -C 2-5Alkyl-OR 13 or -OC 2-5 Alkyl-R 13 where R 13 is phenyl or naphthyl, said phenyl or said naphthyl being optionally substituted with at least one substituent selected from halogen and C1-C6 alkyl.

[0038] In some embodiments, Z2 is C; [ka] is a double bond.

[0039] In some embodiments, each R 9 are independently —C(O)OH or —P(O)(OH)2.

[0040] In some embodiments, R 11 is a halogen.

[0041] In some embodiments, each R 20 is Me or -(CH2CH2O)2Me.

[0042] In some embodiments, the C1-C6 alkyl substituted with morpholine or piperazine is [ka] is.

[0043] In some embodiments, the [MCL-1 ligand site] is [ka] [ka] is selected from.

[0044] In some embodiments, the compound is selected from the following: [ka]

[0045] According to a second aspect of the present invention, there is provided a compound of formula (I) [MCL-1 ligand site]-[linker]-[ligase ligand site] (I) or a salt, solvate, hydrate, isomer or prodrug thereof, In the formula, [ligase ligand site] is (a) Formula (IV) or (IVa) [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 , -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)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;-OR 21 , -NH-R 21 , -C(O)-NH-R 21 , or -CH2-NH-C(O)-R 21 and; Each R' 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. -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 b2. -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; and Each R b are independently hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl; R 21 is the linker R 18 and formula (IV) is a bond connected to a single R 21 containing); (b) Formula (VIIa), (VIIb), (VIIc) or (VIId): [ka] (In the formula, Each of X1 and X2 is independently O or S; Each of Q1 and Q2 is independently 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 independently represents hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, or -NHR. b , -NRb 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)2Rb , -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 linker R 18 and each of formula (VIIa), formula (VIIb) and formula (VIIc) is a bond connected to a single R 21 containing); (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; R1, R2, and R3 each independently represent 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 b are independently hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl; R 21 is the linker R 18 and formula (VIII) is a bond connected to a single R 21 containing); 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 is independently N or CR, and at least one of Q1, Q2, Q3, Q4, and Q5 is N; Each R independently represents hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, or -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 , 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 bare independently hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl; R 21 is the linker R 18 and formula (IX) is a bond connected to a single R 21 containing [MCL-1 ligand moiety] is a compound of formula (A1), (A2), (A3) or (A4): [ka] (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; when Z2 is C, [ka] is a double bond; Each R 9 are independently —C(O)OH, —C(O)OC-Calkyl, —C(O)NH, or —P(O)(OH), 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 of the groups is H and R 10 and R 30 The other of these 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 teeth, [ka] and Each R 33 are independently, H, R 19 or C1-C6 alkyl optionally substituted with morpholine or piperazine; R 31 -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 are independently, H, [ka] and where R 20 are Me, -CH2-OMe, -(CH2CH2O) p (C1-C6 alkyl), -CH2-O-bromobenzaldehyde, or [ka] (wherein 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 teeth, [ka] and; R 19 is the linker R 14 and each of formula (A1), formula (A2), formula (A3) and formula (A4) is a bond connected to a single R 19 containing [Linker] is a group represented by the following formula: R 14 -R 15 -R 16 -R 17 -R 18 wherein R 14 -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 a 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 -C1-6 Alkyl, -C(O)-, -C(O)-C 1-6 alkyl-, -C(O)-NH-, -C(O)O-, -CH2-C(O)-, -CH2-C(O)-NH-, -CH2-C(O)O-, or absent; R 17 is -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 -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 these exists.

[0046] In some embodiments of the second aspect, R 16 -C 1-6 alkyl, -C(O)-, -C(O)-NH-, -C(O)O-, -CH2-C(O)-, -CH2-C(O)-NH-, -CH2-C(O)O-, or absent; R 17 is -CH2(C2H4-O) y , (C2H4-O) x , (C3H6-O) x , or absent; R 18 -C 1-6 It is alkyl, cycloalkyl, CH2-NH-C(O)-, heterocycloalkyl, or absent.

[0047] In some embodiments of the second aspect, [linker] is [ka] wherein: [ka] indicates binding to the MCL-1 ligand site, [ka] indicates binding to the [ligase ligand site].

[0048] In some embodiments of the second aspect, the [MCL-1 ligand site] is [ka] is.

[0049] In some embodiments of the second aspect, the [ligase ligand site] is [ka] is.

[0050] In some embodiments of the second aspect, the compound is [ka] is.

[0051] In some embodiments of the second aspect, the [ligase ligand site] is [ka] is.

[0052] In some embodiments of the second aspect, the compound is [ka] is.

[0053] According to a third aspect of the present invention, there is provided a compound of formula (I) [MCL-1 ligand site]-[linker]-[ligase ligand site] (I) or a salt, solvate, hydrate, isomer or prodrug thereof, In the formula, [ligase ligand site] is (a) Formula (Va) or (Vb): [ka] 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; Each of Y5, Y6, Y7, and Y8 independently represents 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'''', -CH2C(O)OR'''', -C(O)OR'''', -C(O)NH2, -C(O)NHR'''', -C(O)NR''''2, -OR'''', -NR''''2, or -S(O)2R''''; Each R 7are 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 linker R 18 and formula (Va) and formula (Vb) each represent a single R 21 Contains; If Z1 is O, Y6 is CR 7 and When the compound is a compound 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) if Z1 is S, then 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, then Y6 is not CH, C-aryl, or CC(O)OR''''; and (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′′′; when Y7 is C—NH2, C—NHR′′′, or C—NR′′′′2, Y5 is CH; When the compound is a compound 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] (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] indicates a single or double bond, where: [ka] When each of W1, W2, W3 and W4 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; [ka] When each of W1, W2, W3 and W4 is a single bond, W1, W2, W3 and W4 are each CR a 2 and 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 independently represents hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, or -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 h2, -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 and; 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 Rh 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; and R 1 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; R 21 is the linker R 18 and formula (IIa) and formula (IIb) each represent a single R 21 Contains; [ka] each of which is a double bond and Z is NR 2 and R 2 is hydrogen, and each R a is hydrogen, W4 is CRa is) is; [MCL-1 ligand moiety] is a compound of formula (A1), (A2), (A3) or (A4): [ka] (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; when Z2 is C, [ka] is a double bond; Each R 9 are independently —C(O)OH, —C(O)OC-Calkyl, —C(O)NH, or —P(O)(OH), 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 of the groups is H and R 10 and R 30 The other of these 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 teeth, [ka] and Each R 33 are independently, H, R 19 or C1-C6 alkyl optionally substituted with morpholine or piperazine; R 31 -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 are independently, H, [ka] and where R 20 are Me, -CH2-OMe, -(CH2CH2O) p (C1-C6 alkyl), -CH2-O-bromobenzaldehyde, or [ka] (wherein 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 teeth, [ka] and; R 19 is the linker R 14 and each of formula (A1), formula (A2), formula (A3) and formula (A4) is a bond connected to a single R 19 containing [Linker] is a group represented by the following formula: R 14 -R 15 -R 16 -R 17 -R 18 wherein R 14 -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 a 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 -C1-6 Alkyl, -C(O)-, -C(O)-C 1-6 alkyl-, -C(O)-NH-, -C(O)O-, -CH2-C(O)-, -CH2-C(O)-NH-, -CH2-C(O)O-, or absent; R 17 is -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 -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 these exists.

[0054] According to a fourth aspect of the present invention, there is provided a compound of formula (I) [MCL-1 ligand site]-[linker]-[ligase ligand site] (I) or a salt, solvate, hydrate, isomer or prodrug thereof, In the formula, [ligase ligand site] is (a) Formula (VIa) or (VIb): [ka] (In the formula, M is O, S, or NH, or absent; [ka] is the linker R 18 indicates binding to; R 22 is hydrogen, halogen, -OMe, amino group, 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 teeth, [ka] is selected from, where: [ka] indicates binding to T, Z3 is O, S or NR 3 and; U, O, S, NR b or CR i 2 and; Each of Y1, Y2 and Y3 independently represents N or CR d and; Each R dare 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)-R 21 and; Each R i are independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR b , -NRb 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 and; 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 linker R 18 and formula (II) is a bond connected to a single R 21 Contains; 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 teeth, [ka] is selected from, where: [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 each independently represent N or CR c and Each of Y1 and Y2 independently represents N or CR f and Each R fare 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-R 21 , or -CH2-NH-C(O)-R 21 or Y1 and Y2 are CR f If R fforms, together with the carbon atom to which it is attached, a five- or six-membered ring; 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-R 21 , or -CH2-NH-C(O)-R 21 and; Each R 4are 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 linker R 18 and formula (III) is a bond connected to a single R 21 Contains; where n=2 and each R c is hydrogen, and each of G1, G2, G3 and G4 is CR c When C=X1 may be 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 R2 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] rather than; (v)R x but [ka] and Z4 is NR 4 and when Y1 or Y2 is N, R 4 is not alkyl; (vi)R x but [ka] where n=1 or 2; and (vii)R x but [ka] where Z4=O or S; [MCL-1 ligand moiety] is a compound of formula (A1), (A2), (A3) or (A4): [ka] (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; when Z2 is C, [ka] is a double bond; Each R 9 are independently —C(O)OH, —C(O)OC-Calkyl, —C(O)NH, or —P(O)(OH), 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 of the groups is H and R 10 and R 30 The other of these 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 teeth, [ka] and Each R 33 are independently, H, R 19 or C1-C6 alkyl optionally substituted with morpholine or piperazine; R 31 -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 are independently, H, [ka] and where R 20 are Me, -CH2-OMe, -(CH2CH2O) p (C1-C6 alkyl), -CH2-O-bromobenzaldehyde, or [ka] (wherein 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 teeth, [ka] and; R 19 is the linker R 14 and each of formula (A1), formula (A2), formula (A3) and formula (A4) is a bond connected to a single R 19 containing [Linker] is a group represented by the following formula: R 14 -R 15 -R 16 -R 17 -R 18 wherein R 14 -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 a 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 -C 1-6 Alkyl, -C(O)-, -C(O)-C 1-6 alkyl-, -C(O)-NH-, -C(O)O-, -CH2-C(O)-, -CH2-C(O)-NH-, -CH2-C(O)O-, or absent; R 17 is -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 -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 these exists.

[0055] In some embodiments of the fourth aspect, the [ligase ligand site] is [ka] is.

[0056] In some embodiments of the fourth aspect, R 16 -C 1-6 alkyl, -C(O)-, -C(O)-NH-, -C(O)O-, -CH2-C(O)-, -CH2-C(O)-NH-, -CH2-C(O)O-, or absent; R 17 is -CH2(C2H4-O) y , (C2H4-O) x , (C3H6-O) x , or absent; R 18 -C 1-6 It is alkyl, cycloalkyl, CH2-NH-C(O)-, heterocycloalkyl, or absent.

[0057] In some embodiments of the fourth aspect, [linker] is [ka] wherein: [ka] indicates binding to the MCL-1 ligand site, [ka] indicates binding to the [ligase ligand site].

[0058] In some embodiments of the fourth aspect, the [MCL-1 ligand site] is [ka] is.

[0059] In some embodiments of the fourth aspect, the compound is [ka] is.

[0060] In some embodiments of the fourth aspect, the [ligase ligand site] has formula (III): [ka] is.

[0061] In some embodiments of the fourth aspect, the [ligase ligand site] is [ka] is.

[0062] According to a fifth aspect of the present invention, there is provided a compound of formula (I) [MCL-1 ligand site]-linker-[ligase ligand site] (I) or a salt, solvate, hydrate, isomer or prodrug thereof, In the formula, [ligase ligand site] is [ka] (In the formula, M is O, S, or NH, or absent; [ka] is the linker R 18 indicates binding to; R 22 is hydrogen, halogen, -OMe, amino group, heterocycloalkyl, or unsubstituted C1-C6 alkyl; R 29 is hydrogen or Me, L' is hydrogen, alkyl, benzyl, acetyl, or pivaloyl; The MCL-1 ligand moiety is a compound of formula (A): [ka] (In the formula, [ka] is a single or double bond; R 8 H, R 19 or C1-C6 alkyl optionally substituted with morpholine or piperazine; R 9 is —C(O)OH, —C(O)OC1-C6 alkyl, —C(O)NH2, or —P(O)(OH)2; R 10 and R 30 One of the groups is H and R 10 and R 30 The other of these 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 11 is H, halogen, or C1-C6 alkyl; R 12 H, [ka] and where R 20 are Me, -CH2-OMe, -(CH2CH2O) p (C1-C6 alkyl), or -CH2-O-bromobenzaldehyde (wherein p is 1 to 5); Or, R 12 but [ka] and R 10 is -O-naphthyl substituted with -O- or -S-, R 20 teeth [ka] (In the formula, [ka] is R 10 (representing a bond to -O- or -S-); and, R 19 is the linker R 14 is a bond connected to; Z2 is N or C, and when Z2 is N, [ka] is a single bond; when Z2 is C, [ka] is a double bond, Formula (A) is a single R 19 containing [Linker] is a group represented by the following formula: R 14 -R 15 -R 16 -R 17 -R 18 wherein R 14 -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6Alkynyl, C 1-6 Alkyl-N(C 1-6 alkyl)-, -C(O)-, -SO2-, or absent; R 15 is a 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 -C 1-6 Alkyl, -C(O)-, -C(O)-C 1-6 alkyl-, -C(O)-NH-, -C(O)O-, -CH2-C(O)-, -CH2-C(O)-NH-, -CH2-C(O)O-, or absent; R 17 is -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 -C 1-6 It is alkyl-C(O)-, cycloalkyl, or -CH2-NH-C(O)-.

[0063] In some embodiments of the fifth aspect, the [ligase ligand site] is [ka] is.

[0064] In some embodiments of the fifth aspect, R 16 -C 1-6 alkyl, -C(O)-, -C(O)-NH-, -C(O)O-, -CH2-C(O)-, -CH2-C(O)-NH-, -CH2-C(O)O-, or absent; R 17 is -CH2(C2H4-O)y , (C2H4-O) x , (C3H6-O) x , or absent, R 18 is cycloalkyl or —CH—NH—C(O)—.

[0065] In some embodiments of the fifth aspect, R 14 -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 alkynyl, —C(O)—, —SO—, or absent. In some embodiments, R 14 -C 1-6 It is alkyl.

[0066] In some embodiments of the fifth aspect, R 15 is heterocycloalkyl. In some such embodiments, R 15 is piperazine, [ka] where: [ka] is R 14 indicates the bond to [ka] is R 16 The bond to

[0067] In some embodiments of the fifth aspect, R 16 -C 1-6 alkyl, -CH2-C(O)-, or -C(O)-.

[0068] In some embodiments of the fifth aspect, R 17 is absent.

[0069] In some embodiments of the fifth aspect, R 18 is cyclobutyl.

[0070] In some embodiments of the fifth aspect, the [MCL-1 ligand site] is [ka] is.

[0071] According to a sixth aspect of the present invention, there is provided a compound of formula (I) [MCL-1 ligand site]-[linker]-[ligase ligand site] (I) or a salt, solvate, hydrate, isomer or prodrug thereof, In the formula, [ligase ligand site] is (a) Formula (IV) or (IVa) [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 , -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' 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. -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, -SRb , -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; and Each R b are independently hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl; R 21 is the linker R 18 and formula (IV) is a bond connected to a single R 21 containing); (b) Formula (VIIa), (VIIb), (VIIc) or (VIId): [ka] (In the formula, Each of X1 and X2 is independently O or S; Each of Q1 and Q2 is independently 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 independently represents hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, or -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 b are independently hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl; R 21 is the linker R 18 and each of formula (VIIa), formula (VIIb) and formula (VIIc) is a bond connected to a single R 21 containing); (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; R1, R2, and R3 each independently represent 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 b are independently hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl; R 21 is the linker R 18 and formula (VIII) is a bond connected to a single R 21 containing); 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 is independently N or CR, and at least one of Q1, Q2, Q3, Q4, and Q5 is N; Each R independently represents hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, or -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 , 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)-R21 and Each R b are independently hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl; R 21 is the linker R 18 and formula (IX) is a bond connected to a single R 21 containing The MCL-1 ligand moiety is a compound of formula (A): [ka] (In the formula, [ka] is a single or double bond; R 8 H, R 19 or C1-C6 alkyl optionally substituted with morpholine or piperazine; R 9 is —C(O)OH, —C(O)OC1-C6 alkyl, —C(O)NH2, or —P(O)(OH)2; R 10 and R 30 One of the groups is H and R 10 and R 30 The other of these 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 11 is H, halogen, or C1-C6 alkyl; R 12 H, [ka] and where R 20 are Me, -CH2-OMe, -(CH2CH2O) p (C1-C6 alkyl), -CH2-O-bromobenzaldehyde, or [ka] or (wherein p is 1 to 5); Or, R 12 but [ka] and R 10 is -O-naphthyl substituted with -O- or -S-, R 20 teeth [ka] (In the formula, [ka] is R 10 (representing a bond to -O- or -S-); and, R 19 is the linker R 14 is a bond connected to; Z2 is N or C, and when Z2 is N, [ka] is a single bond; when Z2 is C, [ka] is a double bond, Formula (A) is a single R 19 containing [Linker] is a group represented by the following formula: R 14-R 15 -R 16 -R 17 -R 18 wherein R 14 -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 a 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 -C 1-6 Alkyl, -C(O)-, -C(O)-C 1-6 alkyl-, -C(O)-NH-, -C(O)O-, -CH2-C(O)-, -CH2-C(O)-NH-, -CH2-C(O)O-, or absent; R 17 is -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 -C 1-6 It is alkyl-C(O)-, cycloalkyl, or -CH2-NH-C(O)-.

[0072] In some embodiments of the sixth aspect, the [ligase ligand site] has formula (IV): [ka] is.

[0073] In some embodiments of the sixth 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)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 is.

[0074] In some embodiments of the sixth aspect, each R b is independently hydrogen, alkyl, cycloalkyl, or aryl.

[0075] In some embodiments of the sixth aspect, the aryl is substituted with one or more groups selected from halogen, alkyl, and O-haloalkyl, where optionally the halogen is Cl, the alkyl is methyl, and the O-haloalkyl is O—CF 3 .

[0076] In some embodiments of the sixth 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 embodiments, E1 is N, and E2, E3, and E4 are CR'. In other embodiments, E2 is N, and E1, E3, and E4 are CR'. In other embodiments, E3 is N, and E1, E2, and E4 are CR'. In other embodiments, E4 is N, and E1, E2, and E3 are CR'.

[0077] In some embodiments of the sixth aspect, E1, E2, E3, and E4 are each CR', and optionally, E1, E2, E3, and E4 are each CH.

[0078] In some embodiments of the sixth aspect, 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)2ORb , 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 In some such embodiments, 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.

[0079] In some embodiments of the sixth aspect, two of E1, E2, E3, and E4 are N, and the remaining two of E1, E2, E3, and E4 are each CR'.

[0080] In some embodiments of the sixth aspect, three of E1, E2, E3, and E4 are N, and the remaining one of E1, E2, E3, and E4 is CR'.

[0081] In some embodiments of the sixth aspect, 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.

[0082] In some embodiments of the sixth aspect, R 16 -C 1-6 alkyl, -C(O)-, -C(O)-NH-, -C(O)O-, -CH2-C(O)-, -CH2-C(O)-NH-, -CH2-C(O)O-, or absent; R 17 is -CH2(C2H4-O) y , (C2H4-O) x , (C3H6-O)x , or absent; R 18 is cycloalkyl or —CH—NH—C(O)—.

[0083] In some embodiments of the sixth aspect, R 14 -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 alkynyl, —C(O)—, —SO—, or absent. In some embodiments, R 14 -C 1-6 It is alkyl.

[0084] In some embodiments of the sixth aspect, R 15 is a cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 alkyl-NH-, -cycloalkyl-NH-, or absent. In some embodiments, R 15 is heterocycloalkyl or absent. In some embodiments, R 15 is piperazine.

[0085] In some embodiments of the sixth aspect, R 16 is -C(O)-.

[0086] In some embodiments of the sixth aspect, R 17 is absent.

[0087] In some embodiments of the sixth aspect, R 18 is -CH2-NH-C(O)-.

[0088] In some embodiments of the sixth aspect, [linker] is [ka] wherein: [ka] indicates binding to the MCL-1 ligand site, [ka] indicates binding to the [ligase ligand site].

[0089] In some embodiments of the sixth aspect, the [MCL-1 ligand site] is [ka] is.

[0090] In some embodiments of the sixth aspect, the compound is selected from the following: [ka]

[0091] In some embodiments, the compound is selected from compounds 6, 146, and 148.

[0092] In some embodiments of the sixth aspect, the compound is [ka] is.

[0093] According to a seventh aspect of the present invention, there is provided a compound of formula (I) [MCL-1 ligand site]-[linker]-[ligase ligand site] (I) or a salt, solvate, hydrate, isomer or prodrug thereof, In the formula, [ligase ligand site] is (a) Formula (Va) or (Vb): [ka] 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; Each of Y5, Y6, Y7, and Y8 independently represents 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'''', -CH2C(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, -OR21 , -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 6 is 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 linker R 18 and formula (Va) and formula (Vb) each represent a single R 21 Contains; If Z1 is O, Y6 is CR 7 and When the compound is a compound 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) if Z1 is S, then 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, then Y6 is not CH, C-aryl, or CC(O)OR''''; and (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′′′; when Y7 is C—NH2, C—NHR′′′, or C—NR′′′′2, Y5 is CH; When the compound is a compound 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] (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] indicates a single or double bond, where: [ka] When each of W1, W2, W3 and W4 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; [ka] When each of W1, W2, W3 and W4 is a single bond, W1, W2, W3 and W4 are each CR a 2 and 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 independently represents hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, or -NHR. h , -NR h 2, -NR h C(O)R h , -NR h C(O)CH2R h , -NR hC(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 and; 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)2ORh , -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; and R 1 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; R 21 is the linker R 18and formula (IIa) and formula (IIb) each represent a single R 21 Contains; [ka] each of which is a double bond and Z is NR 2 and R 2 is hydrogen, and each R a is hydrogen, W4 is CR a is) is; The MCL-1 ligand moiety is a compound of formula (A): [ka] (In the formula, [ka] is a single or double bond; R 8 H, R 19 or C1-C6 alkyl optionally substituted with morpholine or piperazine; R 9 is —C(O)OH, —C(O)OC1-C6 alkyl, —C(O)NH2, or —P(O)(OH)2; R 10 and R 30 One of the groups is H and R 10 and R 30 The other of these 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—; R11 is H, halogen, or C1-C6 alkyl; R 12 H, [ka] and where R 20 are Me, -CH2-OMe, -(CH2CH2O) p (C1-C6 alkyl), -CH2-O-bromobenzaldehyde, or [ka] or (wherein p is 1 to 5); Or, R 12 but [ka] and R 10 is -O-naphthyl substituted with -O- or -S-, R 20 teeth [ka] (In the formula, [ka] is R 10 (representing a bond to -O- or -S-); and, R 19 is the linker R 14 is a bond connected to; Z2 is N or C, and when Z2 is N, [ka] is a single bond; when Z2 is C, [ka] is a double bond, Formula (A) is a single R 19 containing [Linker] is a group represented by the following formula: R 14 -R 15 -R 16 -R 17 -R 18 wherein R 14 -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 a 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 -C 1-6 Alkyl, -C(O)-, -C(O)-C 1-6 alkyl-, -C(O)-NH-, -C(O)O-, -CH2-C(O)-, -CH2-C(O)-NH-, -CH2-C(O)O-, or absent; R 17 is -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 -C 1-6 It is alkyl-C(O)-, cycloalkyl, or CH2-NH-C(O)-.

[0094] According to an eighth aspect of the present invention, there is provided a compound of formula (I) [MCL-1 ligand site]-[linker]-[ligase ligand site] (I) or a salt, solvate, hydrate, isomer or prodrug thereof, In the formula, [ligase ligand site] is (a) Formula (VIa) or (VIb): [ka] (In the formula, M is O, S, or NH, or absent; [ka] is the linker R 18 indicates binding to; R 22 is hydrogen, halogen, -OMe, amino group, 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 teeth, [ka] is selected from, where: [ka] indicates binding to T, Z3 is O, S or NR 3 and; U, O, S, NR b or CR i 2 and; 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)-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 and; Each R 3are 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 linker R 18 and formula (II) is a bond connected to a single R 21 Contains; 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 teeth, [ka] is selected from, where: [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 each independently represent N or CR c and Each of Y1 and Y2 independently represents 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)2Rb , -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, together with the carbon atom to which it is attached, a five- or six-membered ring; 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, -SRb , -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)-R 21 and Each R b is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; R 21 is the linker R 18 and formula (III) is a bond connected to a single R 21 Contains; where n=2 and each R c is hydrogen, and each of G1, G2, G3 and G4 is CR c When C=X1 may be 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] rather than; (v)R x but [ka] and Z4 is NR 4 and when Y1 or Y2 is N, R 4 is not alkyl; (vi)R x but [ka] where n=1 or 2; and (vii)R x but [ka] where Z4=O or S; The MCL-1 ligand moiety is a compound of formula (A): [ka] (In the formula, [ka] is a single or double bond; R 8 H, R 19 or C1-C6 alkyl optionally substituted with morpholine or piperazine; R 9 is —C(O)OH, —C(O)OC1-C6 alkyl, —C(O)NH2, or —P(O)(OH)2; R 10 and R 30 One of the groups is H and R 10 and R 30 The other of these 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 11 is H, halogen, or C1-C6 alkyl; R 12 H, [ka] and where R 20are Me, -CH2-OMe, -(CH2CH2O) p (C1-C6 alkyl), -CH2-O-bromobenzaldehyde, or [ka] wherein p is 1 to 5; or R 12 but [ka] and R 10 is -O-naphthyl substituted with -O- or -S-, R 20 teeth [ka] (In the formula, [ka] is R 10 (representing a bond to -O- or -S-); and, R 19 is the linker R 14 is a bond connected to; Z2 is N or C, and when Z2 is N, [ka] is a single bond; when Z2 is C, [ka] is a double bond, Formula (A) is a single R 19 containing [Linker] is a group represented by the following formula: R 14 -R 15 -R 16 -R 17 -R 18 wherein R 14 -C 1-6 Alkyl, -C2-6 Alkenyl, -C 2-6 Alkynyl, C 1-6 Alkyl-N(C 1-6 alkyl)-, -C(O)-, -SO2-, or absent; R 15 is a 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 -C 1-6 Alkyl, -C(O)-, -C(O)-C 1-6 alkyl-, -C(O)-NH-, -C(O)O-, -CH2-C(O)-, -CH2-C(O)-NH-, -CH2-C(O)O-, or absent; R 17 is -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 -C 1-6 It is alkyl-C(O)-, cycloalkyl, or CH2-NH-C(O)-.

[0095] In some embodiments of the seventh and eighth aspects, R 16 -C 1-6 alkyl, -C(O)-, C(O)-NH-, -C(O)O-, -CH2-C(O)-, -CH2-C(O)-NH-, -CH2-C(O)O-, or absent; R 17 is -CH2(C2H4-O) y , (C2H4-O) x , (C3H6-O) x , or absent; R 18is cycloalkyl or CH2-NH-C(O)-.

[0096] In some embodiments of any of the fifth through eighth aspects, R 10 and R 30 One of the groups is H and R 10 and R 30 The other of these is -C 2-5 Alkyl-OR 13 where R 13 is phenyl, naphthyl, or tetralin, wherein the phenyl, the naphthyl, or the tetralin is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl, and —O(C1-C6 alkyl); or the naphthyl is optionally substituted with —O— or —S—.

[0097] In some embodiments of any of the fifth through eighth aspects, R 30 is H.

[0098] In some embodiments of any of the fifth through eighth aspects, R 12 H, [ka] is.

[0099] In some embodiments of any of the fifth through eighth aspects, R 20 is Me, -CH2-O-bromobenzaldehyde, or [ka] is.

[0100] In some embodiments of any of the fifth through eighth aspects, Z2 is C; [ka] is a double bond.

[0101] In some embodiments of any of the fifth through eighth aspects, R 11 is hydrogen. In other embodiments, R 11 is a halogen.

[0102] In some embodiments of any of the fifth to eighth aspects, the [MCL-1 ligand site] is [ka] is.

[0103] According to a ninth aspect of the present invention, there is provided a compound of formula (I) [MCL-1 ligand site]-linker-[ligase ligand site] (I) or a salt, solvate, hydrate, isomer or prodrug thereof, In the formula, [ligase ligand site] is [ka] (In the formula, M is O, S, or NH, or absent; [ka] is the linker R 18 indicates binding to; R 24 is -OMe or heterocycloalkyl; R 22 is hydrogen, halogen, -OMe, amino group, heterocycloalkyl, or unsubstituted C1-C6 alkyl; R 29 is hydrogen or Me; and L' is hydrogen, alkyl, benzyl, acetyl, or pivaloyl; The MCL-1 ligand moiety is a compound of formula (A): [ka] (In the formula, [ka] is a single or double bond; R 8 H, R 19 or C1-C6 alkyl optionally substituted with morpholine or piperazine; R 9 is —C(O)OH, —C(O)OC1-C6 alkyl, —C(O)NH2, or —P(O)(OH)2; R 10 and R 30 One of the groups is H and R 10 and R 30 The other of these 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 11 is H, halogen, or C1-C6 alkyl; R 12 H, [ka] and where R 20 are Me, -CH2-OMe, -(CH2CH2O) p (C1-C6 alkyl), or -CH2-O-bromobenzaldehyde (wherein p is 1 to 5); Or, R 12 but [ka] and R 10is -O-naphthyl substituted with -O- or -S-, R 20 teeth [ka] (In the formula, [ka] is R 10 (representing a bond to -O- or -S-); and, R 19 is the linker R 14 is a bond connected to; Z2 is N or C, and when Z2 is N, [ka] is a single bond; when Z2 is C, [ka] is a double bond, Formula (A) is a single R 19 containing [Linker] is a group represented by the following formula: R 14 -R 15 -R 16 -R 17 -R 18 wherein R 14 -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 a 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 -C 1-6 Alkyl, -C(O)-, -C(O)-C 1-6 alkyl-, -C(O)-NH-, -C(O)O-, -CH2-C(O)-, -CH2-C(O)-NH-, -CH2-C(O)O-, or absent; R 17 is -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 -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 these exists.

[0104] In some embodiments of the ninth aspect, L' is hydrogen or methyl. In some embodiments, L' is hydrogen.

[0105] In some embodiments of the ninth aspect, M is O or NH, or absent.

[0106] In some embodiments of the ninth aspect, the [ligase ligand site] is [ka] is.

[0107] In some embodiments of the ninth aspect, R 16 -C 1-6 alkyl, -C(O)-, -C(O)-NH-, -C(O)O-, -CH2-C(O)-, -CH2-C(O)-NH-, -CH2-C(O)O-, or absent; R17 is -CH2(C2H4-O) y , (C2H4-O) x , (C3H6-O) x , or absent; R 18 is C 1-6 It is alkyl, cycloalkyl, CH2-NH-C(O)-, heterocycloalkyl, or absent.

[0108] In some embodiments of the ninth aspect, R 14 -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 alkynyl, —C(O)—, —SO—, or absent. In some embodiments, R 14 -C 1-6 It is alkyl.

[0109] In some embodiments of the ninth aspect, R 15 is a cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 alkyl-NH-, -cycloalkyl-NH-, or absent. In some embodiments, R 15 is heterocycloalkyl, or absent. In some such embodiments, R 15 is piperazine, bridged piperazine, piperazine N-oxide, piperazine cation, [ka] or absent; [ka] is R 14 indicates the bond to [ka] is R 16 In some embodiments, R 15 is piperazine, [ka] Or absent.

[0110] In some embodiments of the ninth aspect, R 16 -C 1-6 alkyl, -CH2-C(O)-NH-, -CH2-C(O)-, -C(O)-, or absent.

[0111] In some embodiments of the ninth aspect, R 17 is absent.

[0112] In some embodiments of the ninth aspect, R 18 -C 1-6 alkyl, cyclobutyl, CH2-NH-C(O)-, piperazine, or absent.

[0113] In some embodiments of the ninth aspect, [linker] is [ka] is selected from During the ceremony, [ka] indicates binding to the MCL-1 ligand site, [ka] indicates binding to the [ligase ligand site].

[0114] In some embodiments of the ninth aspect, [linker] is [ka] is selected from.

[0115] In some embodiments of the ninth aspect, the [MCL-1 ligand site] is [ka] is selected from.

[0116] In some embodiments of the ninth aspect, the compound is selected from the following: [ka]

[0117] In some embodiments of the ninth aspect, the compound is selected from compounds 7, 15, 23, 22, and 21. In some embodiments, the compound is compound 22.

[0118] According to a tenth aspect of the present invention, there is provided a compound of formula (I) [MCL-1 ligand site]-[linker]-[ligase ligand site] (I) or a salt, solvate, hydrate, isomer or prodrug thereof, wherein [ligase ligand site] is represented by formula (VIa) or (VIb): [ka] (In the formula, M is O, S, or NH, or absent; [ka] is the linker R 18 indicates binding to; R 22 is hydrogen, halogen, -OMe, amino group, heterocycloalkyl, or unsubstituted C1-C6 alkyl; L' is hydrogen, alkyl, benzyl, acetyl, or pivaloyl; The MCL-1 ligand moiety is a compound of formula (A): [ka] (In the formula, [ka] is a single or double bond; R 8 H, R 19 or C1-C6 alkyl optionally substituted with morpholine or piperazine; R 9 is —C(O)OH, —C(O)OC1-C6 alkyl, —C(O)NH2, or —P(O)(OH)2; R 10 and R 30 One of the groups is H and R 10 and R 30 The other of these 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 11 is H, halogen, or C1-C6 alkyl; R 12 H, [ka] and where R 20 are Me, -CH2-OMe, -(CH2CH2O) p (C1-C6 alkyl), -CH2-O-bromobenzaldehyde, or [ka] wherein p is 1 to 5; or R 12 but [ka] and R 10 is -O-naphthyl substituted with -O- or -S-, R 20 teeth [ka] (In the formula, [ka] is R 10 (representing a bond to -O- or -S-); and, R 19 is the linker R 14 is a bond connected to; Z2 is N or C, and when Z2 is N, [ka] is a single bond; when Z2 is C, [ka] is a double bond, Formula (A) is a single R 19 containing [Linker] is a group represented by the following formula: R 14 -R 15 -R 16 -R 17 -R 18 wherein R 14 -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 a cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1-6 Alkyl-NH-, -C 1-6 Alkyl-N(C1-6 alkyl)-, -cycloalkyl-NH-, -heterocycloalkyl-NH-, or absent; R 16 -C 1-6 Alkyl, -C(O)-, -C(O)-C 1-6 alkyl-, -C(O)-NH-, -C(O)O-, -CH2-C(O)-, -CH2-C(O)-NH-, -CH2-C(O)O-, or absent; R 17 is -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 -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 these exists.

[0119] In some embodiments of the tenth aspect, the [ligase ligand site] is [ka] is.

[0120] In some embodiments of the tenth aspect, R 16 -C 1-6 alkyl, -C(O)-, -C(O)-NH-, -C(O)O-, -CH2-C(O)-, -CH2-C(O)-NH-, -CH2-C(O)O-, or absent; R 17 is -CH2(C2H4-O) y , (C2H4-O) x , (C3H6-O) x , or absent; R18 -C 1-6 It is alkyl, cycloalkyl, CH2-NH-C(O)-, heterocycloalkyl, or absent.

[0121] In some embodiments of the tenth aspect, R 14 -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 alkynyl, —C(O)—, —SO—, or absent. In some embodiments, R 14 -C 1-6 It is alkyl.

[0122] In some embodiments of the tenth aspect, R 15 is a cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 alkyl-NH-, -cycloalkyl-NH-, or absent. In some embodiments, R 15 is heterocycloalkyl or absent. In some embodiments, R 15 is piperazine.

[0123] In some embodiments of the tenth aspect, R 16 is -C(O)-.

[0124] In some embodiments of the tenth aspect, R 17 is absent.

[0125] In some embodiments of the tenth aspect, R 18 -C 1-6 It is alkyl.

[0126] In some embodiments of the tenth aspect, [linker] is [ka] is.

[0127] In some embodiments of the tenth aspect, the [MCL-1 ligand site] is [ka] is.

[0128] In some embodiments of the tenth aspect, the compound is [ka] is.

[0129] In some embodiments of any of the first through tenth aspects, T is C=O.

[0130] In some embodiments of any of the first through tenth 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.

[0131] In some embodiments of any of the first through tenth aspects, n is 1.

[0132] In some embodiments of any of the first through tenth aspects, unless otherwise specified, each alkyl, alkenyl, alkynyl, aryl, heteroaryl, and benzyl is unsubstituted.

[0133] In an eleventh aspect of the present invention, there is provided a compound selected from: [ka]

[0134] In a twelfth aspect of the present invention, there is provided a compound selected from: [ka] [ka]

[0135] In some embodiments of the twelfth aspect, the compound is selected from compounds 1, 2, 3, 4, 10, 11, 12, 13, and 26.

[0136] In some embodiments of the twelfth aspect, the compound is selected from compounds 1, 2, 3, 4, 10, 11, and 12. In some embodiments, the compound is compound 12.

[0137] In a twelfth aspect of the invention, there is provided a pharmaceutical composition comprising a compound of the invention.

[0138] In a thirteenth aspect of the invention, there is provided a compound or pharmaceutical composition of the invention for use in medicine.

[0139] In a fourteenth aspect of the present invention, there is provided a method of treating cancer in a subject in need thereof, comprising administering to said subject an effective amount of a compound or pharmaceutical composition of the present invention.

[0140] 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 some embodiments, the cancer is multiple myeloma acute myeloid leukemia.

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

[0142] In some embodiments, the method further comprises 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] In a fifteenth aspect of the present invention, there is provided a method of reversing resistance to chemotherapy or targeted cancer therapy in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound or pharmaceutical composition of the present invention.

[0144] In a sixteenth aspect of the invention, there is provided a combined preparation of a compound of the invention and at least one additional active agent for simultaneous, separate or sequential use in therapy.

[0145] 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 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.

[0146] In some embodiments, the therapy is the treatment of cancer.

[0147] In a seventeenth aspect of the present invention, there is provided a method of reducing cardiac cytotoxicity of an MCL-1 inhibitor, comprising coupling a cereblon-binding site to the MCL-1 inhibitor, wherein the cereblon-binding site is a "ligase ligand site" as defined in any of the embodiments of any one of the first to tenth aspects, and the MCL-1 inhibitor is an "MCL-1 ligand site" as defined in any of the embodiments of any one of the first to tenth aspects.

[0148] As used herein, the term "alkyl" is intended to include both unsubstituted alkyl groups and alkyl groups that are 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, -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 alkyl group is C-C 12 Alkyl, C1-C 10 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 an -OH, -OR W , -NH2, -NHR W , -NR W 2. -SO2R W , -C(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 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.

[0149] 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 alkyl group such as -OH, -OR, -O, or -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 alkenyl group is C-C 12 Alkenyl, 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, -NHRW , -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 -R is a branched alkenyl group substituted with one or more groups selected from -CN, -NO, and -NO, W is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.

[0150] 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, C2-C 10In 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.

[0151] 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, the cycloalkyl group is an unsubstituted cycloalkyl group. In some embodiments, the 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, C4-C 12 Cycloalkyl, C5-C 12 Cycloalkyl, C3-C 10 Cycloalkyl, C4-C 10 Cycloalkyl, C5-C 10 cycloalkyl, C3-C8 cycloalkyl, C4-C8 cycloalkyl, C5-C8 cycloalkyl, C3-C6 cycloalkyl, C4-C6 cycloalkyl, C5-C6 cycloalkyl, C3-C4 cycloalkyl, or C4-C5 cycloalkyl group.

[0152] 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, C5-C 12 Cycloalkenyl, C4-C 10Cycloalkenyl, C5-C 10 cycloalkenyl, C4-C8 cycloalkenyl, C5-C8 cycloalkenyl, C4-C6 cycloalkenyl, C5-C6 cycloalkenyl, or C4-C5 cycloalkenyl group.

[0153] 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 selected from the group consisting of -R W , -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 -CH2- groups of the heterocycloalkyl ring can be replaced with a -C(O)- group, and in some embodiments, the heterocycloalkyl group can be a C3-C 12 Heterocycloalkyl, C4-C 12 Heterocycloalkyl, C5-C 12 Heterocycloalkyl, C3-C 10 Heterocycloalkyl, C4-C 10 Heterocycloalkyl, C5-C 10heterocycloalkyl, C3-C8 heterocycloalkyl, C4-C8 heterocycloalkyl, C5-C8 heterocycloalkyl, C3-C6 heterocycloalkyl, C4-C6 heterocycloalkyl, C5-C6 heterocycloalkyl, C3-C4 heterocycloalkyl, or C4-C5 heterocycloalkyl group.

[0154] 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 , —CN, and —NO2, wherein each R W is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. In some embodiments, an aryl group is a C-C 10 aryl, C6-C8 aryl, or C6 aryl.

[0155] 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 Wis unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. In some embodiments, the heteroaryl group is C-C 10 heteroaryl, C6-C9 heteroaryl, C6-C8 heteroaryl, or C6 heteroaryl.

[0156] 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 is a heteroaryl ring, and the two rings share two adjacent atoms. Of the two adjacent atoms shared by the two rings, both may be carbon atoms, both may be heteroatoms (e.g., independently O, N, or S), or one may be a 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.

[0157] 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 , -NRW 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] 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. DETAILED DESCRIPTION OF THE INVENTION

[0159] As mentioned above, the present invention provides a compound of formula (I) [MCL-1 ligand site]-linker-[ligase ligand site] (I) or a salt, solvate, hydrate, isomer or prodrug thereof.

[0160] Ligase ligand site Ligase ligand site with a thalidomide-type structure According to the first and fifth aspects of the present invention, the [ligase ligand site] is [ka] wherein: M is O, S, or NH, or absent; [ka] is the linker R 18 indicates binding to; R 22 is hydrogen, halogen, -OMe, amino group, heterocycloalkyl, or unsubstituted C1-C6 alkyl; R 29 is hydrogen or Me; and L' is hydrogen, alkyl, benzyl, acetyl, or pivaloyl.

[0161] In some embodiments of the first and fifth aspects of the invention, L' is hydrogen or methyl. In some embodiments, L' is hydrogen.

[0162] In some embodiments of the first and fifth aspects of the invention, M is O or NH, or absent.

[0163] In some embodiments of the first and fifth aspects of the invention, R 29 is Me. In other embodiments, R 29 is hydrogen.

[0164] Examples of the above ligase ligand sites are shown in Table 1 below. [Table 1] [Table 2] [Table 3]

[0165] In some embodiments of the first and fifth aspects of the invention, the [ligase ligand site] is [ka] [ka] is.

[0166] In a further embodiment of the first and fifth aspects of the invention, the [ligase ligand site] is [ka] is.

[0167] In a further embodiment of the first and fifth aspects of the invention, the [ligase ligand site] is [ka] is.

[0168] In a ninth aspect of the present invention, the [ligase ligand site] is [ka] wherein: M is O, S, or NH, or absent; [ka] is the linker R 18 indicates binding to; R 24 is -OMe or heterocycloalkyl; R 22 is hydrogen, halogen, -OMe, amino group, heterocycloalkyl, or unsubstituted C1-C6 alkyl; R 29 is hydrogen or Me; and L' is hydrogen, alkyl, benzyl, acetyl, or pivaloyl.

[0169] In some embodiments of the ninth aspect of the invention, L' is hydrogen or methyl. In some embodiments, L' is hydrogen.

[0170] In some embodiments of the ninth aspect of the invention, M is O or NH, or absent.

[0171] In some embodiments of the ninth aspect of the invention, R 29 is Me. In other embodiments, R 29 is hydrogen.

[0172] Examples of the above ligase ligand sites are shown in Table 2 below. [Table 4]

[0173] Ligase ligand moieties of formula (II) and formula (III) In the fourth and eighth aspects of the invention, the ligase ligand site may be of formula (II) or formula (III). The synthesis of the ligase ligand site of formula (II) and formula (III) (as defined above) can be summarized as follows: [ka]

[0174] Examples of ligase ligand moieties of Formula (II) and Formula (III) are shown below in Table 3. Many of these compounds can be modified to allow attachment to a [linker] (e.g., by bromination of the aromatic ring followed by attachment via palladium coupling of the [linker] itself or of a functional group to which the [linker] can be attached). [Table 5] [Table 6] [Table 7]

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

[0176] Examples of ligase ligand moieties of formula (IV) are shown in Table 4 below. For example: [ka] can be modified to allow attachment to [linker] (e.g., by nucleophilic aromatic substitution or by exchange of fluorine for bromine followed by attachment by palladium coupling of [linker] itself or of a functional group to which [linker] can be attached). [Table 8] [Table 9]

[0177] In the second and sixth aspects of the invention, the ligase ligand site may be of formula (VIIa), (VIIb), (VIIc) or (VIId). Examples of ligase ligand sites of formula (VIIa, (VIIb), (VIIc) and (VIId) are shown in Table 5 below. [Table 10]

[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)3]2Cl2 (0.2 equiv.) under inert gas, and the reaction mixture was stirred at 130 °C for 48 hours (h). The reaction mixture was filtered through Celite, concentrated under reduced pressure, and purified by flash column chromatography to give the appropriate aryl tert-butyl acetate.

[0180] Step 2: [ka] To a solution of the appropriate tert-butyl 2-(quinolin-3-yl)acetate (1 equiv.) in DMF was added K2CO3 (1 equiv.), benzyltriethylammonium chloride (1 equiv.), and acrylonitrile (1 equiv.), and the reaction mixture was stirred at RT 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 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 RT 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 at 80° C. for 2-48 hours. 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 the third and seventh aspects of the invention, the ligase ligand moiety may be of formula (Va), (Vb), (IIa) and (IIb) (as defined above). The synthesis of ligase ligand moieties of formula (Va), (Vb), (IIa) and (IIb) can be summarized in the following general procedure (carried out under synthesis conditions D, E, F or G set out below). [ka]

[0184] Synthesis condition D A solution of 3-aminopiperidine-2,6-dione (1 equivalent) and N-hydroxybenzotriazole (1.2 equivalents) in DMF (0.5 M) was treated with an appropriate acid (R in the above reaction scheme). x COOH (1.1 equiv.), DMAP (0.04 equiv.), and EDC (1.2 equiv.) were added. The reaction mixture was stirred at room temperature (20-25 °C) overnight. Water (2 x DMF volume) was added, and the resulting solution was extracted with dichloromethane (3 x 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 solution of 3-aminopiperidine-2,6-dione (hydrochloride, 1.1 equiv.), triethylamine (1.2 equiv.), and N-hydroxybenzotriazole (1.2 equiv.) in DMA (0.5 M) was treated with an appropriate acid (R in the reaction scheme above). x COOH) (1 eq.) and EDC (1.2 eq.) were added. The reaction mixture was stirred at room temperature overnight. Water (2x DMA volume) was added and the resulting mixture was extracted with dichloromethane (3x DMA volume). 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) xTo a solution of (COOH) (1 equiv.) and HATU (1.5 equiv.) in anhydrous DMF was added 3-aminopiperidine-2,6-dione (hydrochloride, 1.2 equiv.) and DIPEA (3 equiv.). 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) x To a solution of (COOH) (1 equiv.), 3-aminopiperidine-2,6-dione (hydrochloride, 1.2 equiv.), and DMAP (0.1 equiv.) in anhydrous DMF under an inert atmosphere was added DIPEA (2.2 equiv.) and HATU (1.5 equiv.) in anhydrous DMF. The reaction mixture was stirred at room temperature overnight. The crude product was purified by preparative HPLC and / or preparative TLC.

[0188] Exemplary Method 1: R x COOH (or its ester R x COOR y ) Chlorination R x Formation of the base To a solution of the appropriate starting material (1 equiv.) in DMF (0.5 M) was added NCS (1.1 equiv.), and the reaction mixture was stirred at room temperature (20–25°C) for 2 h. The reaction mixture was poured into water (2x the volume of DMF), 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 To a solution of the appropriate ester (1 equiv.) in a THF:water mixture (3:1 or 5:1, 85 mM) was added LiOH (1.1 equiv.), and the resulting mixture was stirred at room temperature (20–25 °C) overnight. The mixture was concentrated under reduced pressure, diluted with water, and acidified to pH = 2–3 with concentrated HCl. The precipitate was filtered, washed with water, and dried in vacuo to give the desired carboxylic acid.

[0190] Exemplary Method 3: R xCOOR 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× volume of dioxane) and extracted with EtOAc (3× volume of dioxane). The organic layer was washed with water, brine, dried over NaSO, and evaporated to dryness to give 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 6. Many of these compounds can be modified (e.g., by C—H bond activation) to allow attachment to a [linker]. [Table 11] [Table 12]

[0192] Examples of ligase ligand moieties of Formula (IIa) and Formula (IIb) are shown below in Table 7. Many of these compounds can be modified (e.g., by C—H bond activation) to allow attachment to a [linker]. [Table 13]

[0193] Ligase ligand moieties of formula (VIa) and formula (VIb) In the fourth, eighth and tenth aspects of the invention, the ligase ligand site may be of formula (VIa) or (VIb): [ka] During the ceremony, M is O, S, or NH, or absent; [ka] is the linker R 18 indicates binding to; R 22 is hydrogen, halogen, -OMe, 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 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 8 below, where: [ka] is the linker R 18 (showing the bond to [Table 14]

[0197] Linker In the first, second, third, fourth, ninth and tenth aspects of the invention, [linker] is a group of formula R 14 -R 15 -R 16 -R 17 -R 18 and During the ceremony, R 14 -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; R15 is a 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 -C 1-6 Alkyl, -C(O)-C 1-6 alkyl-, -C(O)-, -C(O)-NH-, -C(O)O-, -CH2-C(O)-, -CH2-C(O)-NH-, -CH2-C(O)O-, or absent; R 17 is -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 -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 these exists.

[0198] In some embodiments of the first, second, third, fourth, ninth, and tenth aspects of the invention, R 16 -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 is -CH2(C2H4-O) y , -(C2H4-O) x , -(C3H6-O) x , or absent;R 18 -C 1-6It is alkyl, cycloalkyl, -CH2-NH-C(O)-, heterocycloalkyl, or absent.

[0199] In some embodiments of the first, second, third, fourth, ninth, and tenth aspects of the invention, R 14 -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 alkynyl, —C(O)—, —SO—, or absent. In some such embodiments, R 14 -C 1-6 It is alkyl.

[0200] In some embodiments of the first, second, third, fourth, ninth, and tenth aspects of the invention, R 15 is a cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 In some such embodiments, R is alkyl-NH-, -cycloalkyl-NH-, or absent. 15 is heterocycloalkyl, or absent. In some such embodiments, R 15 is piperazine, bridged piperazine, piperazine N-oxide, piperazine cation, [ka] or absent, [ka] is R 14 indicates the bond to [ka] is R 16 The bond to

[0201] In some embodiments of the first, second, third, fourth, ninth, and tenth aspects of the invention, R 15 is piperazine, [ka] Or absent.

[0202] In some embodiments of the first, second, third, fourth, ninth, and tenth aspects of the invention, R 16 -C 1-6 alkyl, -CH2-C(O)-NH-, -CH2-C(O)-, -C(O)-, or absent.

[0203] In some embodiments of the first, second, third, fourth, ninth, and tenth aspects of the invention, R 17 is absent.

[0204] In some embodiments of the first, second, third, fourth, ninth, and tenth aspects of the invention, R 18 -C 1-6 alkyl, cyclobutyl, CH2-NH-C(O)-, piperazine, or absent.

[0205] In some embodiments of the first, second, third, fourth, ninth, and tenth aspects of the invention, R 14 -C 1-6 Alkyl, -C 1-6 alkyl-N(Me)-, -SO2-, or absent; R 15 is piperazine, bridged piperazine, piperazine N-oxide, piperazine cation, [ka] or absent, [ka] is R 14 indicates the bond to [ka] is R 16 indicates the bond to R 16 -C 1-6alkyl, -CH2-C(O)-NH-, -CH2-C(O)-, -C(O)-, or absent; R 17 is -CH2(C2H4-O) y , (C2H4-O) x , (C3H6-O) x or absent (wherein x is 1 to 6 and y is 2 to 6); R 18 -C 1-6 Alkyl, piperazine, [ka] cyclobutyl, -CH2-NH-C(O)-, or absent, wherein [ka] is R 17 (showing the bond to And R 14 ~R 18 At least one of these exists.

[0206] In some embodiments of the first, second, third, fourth, ninth, and tenth aspects of the invention, R 14 -C 1-6 is alkyl, R 15 is piperazine, [ka] or absent, R 16 -C 1-6 alkyl, -CH2-C(O)-NH-, -CH2-C(O)-, -C(O)-, or absent; R 17 is absent, R 18 -C 1-6 alkyl, cyclobutyl, CH2-NH-C(O)-, piperazine, or absent.

[0207] In some embodiments of the first, second, third, fourth, ninth, and tenth aspects of the invention, [linker] is [ka] is selected from During the ceremony, [ka] indicates binding to the MCL-1 ligand site, [ka] indicates binding to the [ligase ligand site].

[0208] In some embodiments of the first, second, third, fourth, ninth, and tenth aspects of the invention, [linker] is [ka] is selected from.

[0209] In some embodiments of the first, second, third, fourth, ninth, and tenth aspects of the invention, [linker] is [ka] is selected from.

[0210] In the fifth, sixth, seventh and eighth aspects of the invention, the [linker] is a group of the formula: R 14 -R 15 -R 16 -R 17 -R 18 wherein R 14 -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; R15 is a 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 -C 1-6 Alkyl, -C(O)-, C(O)-C 1-6 alkyl-, -C(O)-NH-, -C(O)O-, -CH2-C(O)-, -CH2-C(O)-NH-, -CH2-C(O)O-, or absent; R 17 is -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 -C 1-6 It is alkyl-C(O)-, cycloalkyl, or CH2-NH-C(O)-.

[0211] In some embodiments of the fifth, sixth, seventh, and eighth aspects of the invention, R 16 -C 1-6 alkyl, -C(O)-, C(O)-NH-, -C(O)O-, -CH2-C(O)-, -CH2-C(O)-NH-, -CH2-C(O)O-, or absent; R 17 is -CH2(C2H4-O) y , (C2H4-O) x , (C3H6-O) x , or absent;R 18 is cycloalkyl or CH2-NH-C(O)-.

[0212] In some embodiments of the fifth, sixth, seventh, and eighth aspects of the invention, R 14 -C 1-6 Alkyl, -C 2-6 Alkenyl, -C2-6 alkynyl, —C(O)—, —SO—, or absent. In some such embodiments, R 14 -C 1-6 It is alkyl.

[0213] In some embodiments of the fifth, sixth, seventh, and eighth aspects of the invention, R 15 is a cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 In some such embodiments, R is alkyl-NH-, -cycloalkyl-NH-, or absent. 15 is heterocycloalkyl or absent. In some embodiments, R 15 is heterocycloalkyl. In some embodiments, R 15 is piperazine, bridged piperazine, piperazine N-oxide, piperazine cation, [ka] or absent, [ka] is R 14 indicates the bond to [ka] is R 16 The bond to

[0214] In some embodiments of the fifth, sixth, seventh, and eighth aspects of the invention, R 15 is piperazine, [ka] and [ka] is R 14 indicates the bond to [ka] is R 16 In some embodiments, R 15 is piperazine.

[0215] In some embodiments of the fifth, sixth, seventh, and eighth aspects of the invention, R 16 -C 1-6 alkyl, —CH—C(O)—NH—, —CH—C(O)—, —C(O)—, or absent. In some embodiments, R 16 -C 1-6 alkyl, —CH—C(O)—, or —C(O)—. In some embodiments, R 16 is -C(O)-.

[0216] In some embodiments of the fifth, sixth, seventh, and eighth aspects of the invention, R 17 is absent.

[0217] In some embodiments of the fifth, sixth, seventh, and eighth aspects of the invention, R 18 is cycloalkyl. In some such embodiments, R 18 is cyclobutyl. In another embodiment, R 18 or —CH—NH—C(O)—.

[0218] In other embodiments of the fifth, sixth, seventh and eighth aspects of the invention, [linker] is [ka] wherein: [ka] indicates binding to the MCL-1 ligand site, [ka] indicates binding to the [ligase ligand site].

[0219] The linkers used in the compounds of the invention can be synthesized according to standard methods.

[0220] Most of the alkyl and polyethylene glycol (PEG) linkers were commercially available or prepared according to literature procedures.

[0221] Examples of commercially available linkers include: [ka]

[0222] The synthesis of non-commercially available linkers is described in the Examples.

[0223] Linkers containing piperazine modifications were prepared according to the following scheme. [ka]

[0224] MCL-1 ligand site In the first, second, third and fourth aspects of the present invention, the [MCL-1 ligand site] is a compound of formula (A1), (A2), (A3) or (A4): [ka] wherein: [ka] is a single or double bond; Each Z2 is independently N or C, and when Z2 is N, [ka] is a single bond; when Z2 is C, [ka] is a double bond; Each R 9are independently —C(O)OH, —C(O)OC-Calkyl, —C(O)NH, or P(O)(OH), 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 of the groups is H and R 10 and R 30 The other of these 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 teeth, [ka] and Each R 33 are independently, H, R 19 or C1-C6 alkyl optionally substituted with morpholine or piperazine; R 31 -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 are independently, H, [ka] and where 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 teeth, [ka] and; R 19 is the linker R 14 and each of formula (A1), formula (A2), formula (A3) and formula (A4) is a bond connected to a single R 19 Contains:

[0225] In some embodiments of the first, second, third and fourth aspects of the invention, the [MCL-1 ligand moiety] has the formula (A1): [ka] It is of the type.

[0226] In other embodiments of the first, second, third and fourth aspects of the invention, the [MCL-1 ligand moiety] has formula (A2): [ka] It is of the type.

[0227] In other embodiments of the first, second, third and fourth aspects of the invention, the [MCL-1 ligand moiety] has formula (A3): [ka] It is of the type.

[0228] In other embodiments of the first, second, third and fourth aspects of the invention, the [MCL-1 ligand moiety] has formula (A4): [ka] It is of the type.

[0229] In some embodiments of the first, second, third, and fourth aspects of the present invention, in each of Formula (A1) and Formula (A4), R 10 and R 30 One of the groups is H and R 10 and R 30 The other of these is -C 2-5 Alkyl-OR 13 , or -OC 2-5 Alkyl-R 13 where R 13 is phenyl or naphthyl, said phenyl or said naphthyl being optionally substituted with at least one substituent selected from halogen and C1-C6 alkyl.

[0230] In some embodiments of the first, second, third, and fourth aspects of the present invention, R in formula (A1) 12 teeth [ka] is.

[0231] In some embodiments of the first, second, third, and fourth aspects of the present invention, R of formula (A4) 35 teeth [ka] is.

[0232] In some embodiments of the first, second, third, and fourth aspects of the present invention, R of formula (A2) 31 -C 2-5 Alkyl-OR 13 or -OC 2-5 Alkyl-R 13 where R 13 is phenyl or naphthyl, said phenyl or said naphthyl being optionally substituted with at least one substituent selected from halogen and C1-C6 alkyl.

[0233] In some embodiments of the first, second, third, and fourth aspects of the present invention, R of formula (A3) 34 -OC 2-5 Alkyl-R 13 where R 13 is phenyl or naphthyl, said phenyl or said naphthyl being optionally substituted with at least one substituent selected from halogen and C1-C6 alkyl.

[0234] In some embodiments of the first, second, third, and fourth aspects of the invention, Z2 is C; [ka] is a double bond.

[0235] In some embodiments of the first, second, third, and fourth aspects of the invention, each R 9 are independently —C(O)OH or —P(O)(OH)2.

[0236] In some embodiments of the first, second, third, and fourth aspects of the invention, R 11 is a halogen.

[0237] In some embodiments of the first, second, third, and fourth aspects of the invention, each R 20 is Me.

[0238] In some embodiments of the first, second, third and fourth aspects of the invention, the [MCL-1 ligand site] is [ka] [ka] is selected from.

[0239] In the fifth, sixth, seventh, eighth, ninth and tenth aspects of the present invention, the [MCL-1 ligand site] is a compound of formula (A): [ka] wherein: [ka] is a single or double bond; R 8 H, R 19 or C1-C6 alkyl optionally substituted with morpholine or piperazine; R 9 is —C(O)OH, —C(O)OC1-C6 alkyl, —C(O)NH2, or —P(O)(OH)2; R 10 and R 30 One of the groups is H and R 10 and R 30 The other of these is -C2-5 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 11 is H, halogen, or C1-C6 alkyl; R 12 H, [ka] and where R 20 are Me, -CH2-OMe, -(CH2CH2O) p (C1-C6 alkyl), -CH2-O-bromobenzaldehyde, or [ka] wherein p is 1 to 5; or R 12 but [ka] and R 10 is -O-naphthyl substituted with -O- or -S-, R 20 teeth [ka] (In the formula, [ka] is R 10 (representing a bond to -O- or -S-); and, R 19 is the linker R 14 is a bond connected to; Z2 is N or C, and when Z2 is N, [ka] is a single bond; when Z2 is C, [ka] is a double bond, Formula (A) is a single R 19 Contains:

[0240] In some embodiments of the fifth, sixth, seventh, eighth, ninth, and tenth aspects of the invention, R 10 and R 30 One of the groups is H and R 10 and R 30 The other of these is -C 2-5 Alkyl-OR 13 where R 13 is phenyl, naphthyl, or tetralin, wherein the phenyl, the naphthyl, or the tetralin is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl, and —O(C1-C6 alkyl); or the naphthyl is optionally substituted with —O— or —S—.

[0241] In some embodiments of the fifth, sixth, seventh, eighth, ninth, and tenth aspects of the invention, R 30 is H.

[0242] In some embodiments of the fifth, sixth, seventh, eighth, ninth, and tenth aspects of the invention, R 13 is phenyl or naphthyl, said phenyl or said naphthyl being optionally substituted with at least one substituent selected from halogen and C1-C6 alkyl.

[0243] In some embodiments of the fifth, sixth, seventh, eighth, ninth, and tenth aspects of the invention, R 12 H, [ka] is.

[0244] In some embodiments of the fifth, sixth, seventh, eighth, ninth, and tenth aspects of the invention, R 12 teeth, [ka] In some such embodiments, R 20 is Me.

[0245] In some embodiments of the fifth, sixth, seventh, eighth, ninth, and tenth aspects of the invention, R 20 is Me, -CH2-O-bromobenzaldehyde, or [ka] is.

[0246] In some embodiments of the fifth, sixth, seventh, eighth, ninth, and tenth aspects of the invention, Z2 is C; [ka] is a double bond.

[0247] In some embodiments of the fifth, sixth, seventh, eighth, ninth, and tenth aspects of the invention, R 11 is hydrogen. In other embodiments, R 11 is a halogen. In some such embodiments, R 11 is Cl.

[0248] In some embodiments of the fifth, sixth, seventh, eighth, ninth, and tenth aspects of the invention, R 9 is -C(O)OH.

[0249] In some embodiments of the fifth, sixth, seventh, eighth, ninth and tenth aspects of the invention, the [MCL-1 ligand site] is [ka] is selected from.

[0250] In some embodiments of the fifth, sixth, seventh, eighth, ninth and tenth aspects of the invention, the [MCL-1 ligand site] is [ka] is. [Example]

[0251] There are several ways in which the bifunctional compound [MCL-1 ligand moiety]-[linker]-[ligase ligand moiety] of the present application can be synthesized.

[0252] 1. Coupling of [Mcl-1 ligand moiety] to linker A followed by coupling to [ligase ligand moiety]-linker B [ka] where X is halogen or OMs, OTs; linker AN-Boc corresponds to linker A terminating in a Boc-protected primary or secondary amine; linker A-NH corresponds to linker A terminating in a primary or secondary amine; R 11 ~R 13 and [Linker] is as defined herein; [Linker] is, in the above synthesis, -LinkerA-NHR w It is formed by the reaction of the linker B-COOH with

[0253] An example of this method is provided below.

[0254] (a) R of [MCL-1 ligand site] 8and coupling of linker A and linker B via an amide bond: [ka] where X is halogen or OMs, OTs; linker AN-Boc corresponds to linker A terminating in a Boc-protected primary or secondary amine; linker A-NH corresponds to linker A terminating in a primary or secondary amine; R5 is succinimidyl or pentafluorophenyl; R 11 ~R 13 is as defined herein; linker A-NHC(O)-linker B corresponds to [linker].

[0255] (b) R of [MCL-1 ligand site] 8 and coupling of linker A and linker B by alkylation or reductive amination [ka] where X is halogen or OMs, OTs; linker AN-Boc corresponds to linker A terminating in a Boc-protected primary or secondary amine; linker A-NH corresponds to linker A terminating in a primary or secondary amine; R 11 ~R 13 is as defined herein; linker A N - linker B corresponds to [linker].

[0256] 2. [Mcl-1 ligand site] is coupled to linker A, followed by linker B, followed by coupling to [ligase ligand site] [ka] where X is halogen or OMs, OTs; linker AN-Boc corresponds to linker A terminating in a Boc-protected primary or secondary amine; linker A-NH corresponds to linker A terminating in a primary or secondary amine; R11 ~R 13 is as defined herein; linker A N - linker B corresponds to [linker].

[0257] 3. Coupling the [Mcl-1 ligand site]-[linker] to the [ligase ligand site] [ka]

[0258] 4. Coupling the [Mcl-1 ligand site] to the [linker]-[ligase ligand site] [ka]

[0259] 5. [Mcl-1 ligand site]-[linker]-R v is coupled with 3-aminopiperidine-2,6-dione [ka] In the formula, R 11 ~R 13 is as defined herein; R v -TR x , -TR y , [ka] is.

[0260] The bifunctional compounds of the present invention were prepared as follows.

[0261] Example 1: 6-chloro-1-(2-(4-(2-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-7-fluoro-2-methyl-1H-benzo[d]imidazol-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 (Compound 1) [ka] [ka] Step A 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 KCO (1.859 g, 13.471 mmol). The mixture was deoxygenated with argon, and to it was added Pd(dppf)Cl (0.369 g, 0.505 mmol) under an argon atmosphere. The reaction mixture was then heated under reflux for 16 h. After the starting material was completely consumed (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 / 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] +

[0262] Step B 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. It was then diluted with water and washed with EtOAc. The aqueous layer was carefully acidified to pH = 3 using 1 M HCl and extracted with EtOAc (x3). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to afford 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] +

[0263] Step C 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 for 16 hours under nitrogen. After complete consumption of the starting material (monitored by TLC and LCMS), the reaction mixture was then diluted with EtOAc and washed successively with sodium bicarbonate (saturated aqueous solution), 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 / 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% over two steps) as a brownish liquid. LCMS (ESI): 561.9 m / z [M+H] +

[0264] Step D 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 at 90° C. 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 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 / 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] +

[0265] Step E 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 / dioxane at 0° C., and the mixture was stirred at the same temperature for 2 hours under nitrogen. 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 / 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] +

[0266] Step F To a solution of methyl 7-fluoro-2-methyl-1H-benzo[d]imidazole-4-carboxylate (400 mg, 1.923 mmol) in THF (15 mL) was added sodium hydride (60%, 69.23 mg, 2.885 mmol) in portions at 0 °C under nitrogen, followed by tert-butyl bromoacetate (0.315 mL, 4.615 mmol), and the reaction mixture was stirred under nitrogen for 2 h. After complete consumption of the starting material (monitored by LC-MS and TLC), 5 mL of cold water was added to the reaction mixture to quench unreacted sodium hydride, and the reaction mixture was then extracted with ethyl acetate. The combined organic layers were washed with water, saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude compound, which was then purified by column chromatography (SiO, 60% EtOAc / DCM) to give methyl 1-(2-(tert-butoxy)-2-oxoethyl)-7-fluoro-2-methyl-1H-benzo[d]imidazole-4-carboxylate (450 mg, 1.39 mmol, 72%) as a brown solid. LCMS (ESI): 322.5 m / z [M+H] + .

[0267] Step G To a stirred solution of methyl 1-(2-(tert-butoxy)-2-oxoethyl)-7-fluoro-2-methyl-1H-benzo[d]imidazole-4-carboxylate (200 mg, 0.621 mmol) in HO (1 mL) and MeCN (9 mL) was added LiBr (1618.32 mg, 18.63 mmol) followed by EtN (1.723 mL, 12.42 mmol) at room temperature. The mixture was stirred at room temperature for 24 h. After complete consumption of the starting material (monitored by LCMS and TLC), the reaction mixture was concentrated under reduced pressure at low temperature. The residue was dissolved in water and washed with EtO. The aqueous layer was carefully acidified to pH = 7 using 1 M HCl at 0 °C. The product was extracted with EtOAc, washed with brine, dried over NaSO, filtered, and evaporated under reduced pressure. The crude product was purified by trituration with Et2O to give 1-(2-(tert-butoxy)-2-oxoethyl)-7-fluoro-2-methyl-1H-benzo[d]imidazole-4-carboxylic acid (130 mg, 0.421 mmol, 68%) as an off-white solid. LCMS (ESI): 309.2 m / z [M+H] +

[0268] Step H 1-(2-(tert-butoxy)-2-oxoethyl)-7-fluoro-2-methyl-1H-benzo[d]imidazole-4-carboxylic acid (30.0 mg, 0.097 mmol), 3-aminopiperidine-2,6-dione hydrochloride (19.2 mg, 0.117 mmol), and HATU (74.0 mg, 0.195 mmol) were dissolved in anhydrous DMF (1.2 mL) under an argon atmosphere. DIPEA (0.051 mL, 0.292 mmol) was added, and the reaction (monitored by LCMS) was stirred at room temperature under argon for 15 minutes. After complete conversion of the starting material, the reaction was diluted with DMSO (3 mL). The crude product was purified by preparative HPLC (C18, HO:MeCN+0.1% FA) to give tert-butyl 2-{4-[(2,6-dioxopiperidin-3-yl)carbamoyl]-7-fluoro-2-methyl-1H-1,3-benzodiazol-1-yl}acetate (28.1 mg, 0.067 mmol, 69.0%) as a white solid. LCMS (ESI): 419.7 m / z [M+H] +

[0269] Step I tert-Butyl 2-{4-[(2,6-dioxopiperidin-3-yl)carbamoyl]-7-fluoro-2-methyl-1H-1,3-benzodiazol-1-yl}acetate (28.1 mg, 0.067 mmol) was dissolved in anhydrous DCM under an argon atmosphere, and TFA (0.500 mL, 6.529 mmol) was added. The reaction (monitored by LCMS) was stirred at room temperature for 4 hours under argon. After complete consumption of the starting material, the reaction mixture was concentrated in vacuo. To the resulting residue was added 1 M aqueous HCl (1 mL) and concentrated to dryness under reduced pressure. The procedure of adding and evaporating 1 M HCl was repeated twice. The reaction product was dry frozen to give 2-{4-[(2,6-dioxopiperidin-3-yl)carbamoyl]-7-fluoro-2-methyl-1H-1,3-benzodiazol-1-yl}acetic acid hydrochloride (25.8 mg, 0.065 mmol, 96.4%) as a white solid. LCMS (ESI): 363.0 m / z [M+H] +

[0270] Step J 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 (25.0 mg, 0.037 mmol) and 2-{4-[(2,6-dioxopiperidin-3-yl)carbamoyl]-7-fluoro-2-methyl-1H-1,3-benzodiazol-1-yl}acetic acid hydrochloride (17.7 mg, 0.044 mmol) were dissolved in anhydrous DMF (0.6 mL) under an argon atmosphere, and DIPEA (0.019 mL, 0.111 mmol) was added. HATU (14.8 mg, 0.039 mmol) was added as a DMF solution (0.6 mL). The reaction (monitored by LCMS) was stirred at room temperature under argon for 25 minutes. After complete consumption of the starting material, the solution was diluted to 10 mL with DCM and washed with saturated aqueous NaHCO (10 mL) and brine (2 × 10 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness to afford crude tert-butyl 6-chloro-1-{2-[4-(2-{4-[(2,6-dioxopiperidin-3-yl)carbamoyl]-7-fluoro-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 (46.3 mg) as a yellow oil, which was used in the next step without further purification. LCMS (ESI): 1118.8 m / z [M+H] +

[0271] Step K Crude tert-butyl 6-chloro-1-{2-[4-(2-{4-[(2,6-dioxopiperidin-3-yl)carbamoyl]-7-fluoro-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 (46.3 mg, 0.045 mmol) was dissolved in anhydrous DCM (0.489 mL) under an argon atmosphere, and TFA (0.489 mL, 6.391 mmol) was added. The reaction (monitored by LCMS) was stirred at room temperature under argon for 16 hours. After complete consumption of the starting material, the mixture was concentrated to dryness under reduced pressure. The resulting residue was dissolved in DMSO and 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)-7-fluoro-2-methyl-1H-benzo[d]imidazol-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 (18.7 mg, 0.019 mmol, 51.3% over two steps) as a white solid. LCMS (ESI): 962.20 m / z [M+H] + 1H NMR (500 MHz, DMSO, 353 K) δ 10.58 (s, 1H), 9.98 (d, J = 7.1 Hz, 1H), 8.25 (dd, J = 9.2, 5.9 Hz, 1H), 7.85 (dd, J = 8.5, 5.0 Hz, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.58 (dd, J = 10.4, 2.6 Hz, 1H), 7.46 - 7.39 (m, 2H), 7.32 (ddd, J = 9.3, 8.6, 2.6 Hz, 1H), 7.23 (d, J = 8.5 Hz, 1H), 7.07 (dd, J = 11.3, 8.5 Hz, 1H), 6.88 (dd, J = 5.4, 3.3 Hz, 1H), 5.25 (s, 2H), 4.85 (ddd, J = 12.3, 7.2, 5.2 Hz, 1H), 4.37 - 4.15 (m, 4H), 3.78 (s, 3H), 3.48 - 3.36 (m, 4H), 3.32 - 3.27 (m, 2H), 2.80 (ddd, J = 17.5, 13.1, 5.5 Hz, 1H), 2.65 - 2.56 (m, 1H), 2.52 (s, 3H), 2.35 - 2.29 (m, 1H), 2.29 - 2.22 (m, 2H), 2.22 - 2.06 (m, 7H), 2.03 (s, 3H), 1.90 (s, 3H).

[0272] Example 2: 6-chloro-1-(2-{4-[3-({4-[(2,6-dioxopiperidin-3-yl)carbamoyl]-2-methyl-1H-1,3-benzodiazol-6-yl}oxy)propanoyl]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 (Compound 3) [ka] Step A To a stirred solution of methyl 6-bromo-2-methyl-1H-benzo[d]imidazole-4-carboxylate (2.5 g, 9.29 mmol) in DMF (50 mL) at 0° C., SEM chloride (3.29 mL, 18.6 mmol) and DIPEA (4.85 mL, 27.88 mmol) were added sequentially under nitrogen. The reaction mixture was stirred at 80° C. for 16 h under nitrogen. After complete consumption of the starting material (confirmed by TLC), the reaction was diluted with EtOAc, washed successively with cold water and brine, dried over Na2SO4, and evaporated under reduced pressure to give the crude material, which was purified by column chromatography (SiO2, 50% EtOAc / DCM) to give methyl 6-bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-4-carboxylate (2 g, 5.0 mmol, 54%) as a yellowish gummy solid. LCMS (ESI): 401.0 m / z [M+H] +

[0273] Step B To a well-stirred solution of methyl 6-bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-4-carboxylate (3 g, 7.5 mmol) in dioxane (50 mL) was added Pd(dppf)Cl (0.550 g, 0.75 mmol) at RT under nitrogen. It was stirred at 90 °C for 15 min. The reaction mixture was then cooled to RT. Bispinacolatodiborane (3.82 g, 15.04 mmol) and KOAc (1.476 g, 15.04 mmol) were added sequentially at RT under nitrogen. The resulting mixture was stirred 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 solution. The organic layer was dried over Na2SO4 and evaporated under reduced pressure to give the crude compound, which was purified by column chromatography (SiO2, 40-50% EtOAc / DCM) to give methyl 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-4-carboxylate (2.5 g, 5.6 mmol, 74%) as a yellowish liquid. LCMS (ESI): 447.0 m / z [M+H] +

[0274] Step C To a stirred solution of methyl 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-4-carboxylate (4 g, 8.96 mmol) in MeOH (80 mL) and water (40 mL) was added mCPBA (1.697 g, 9.86 mmol) at 0 °C. The resulting reaction mixture was stirred at RT for 6 h. After complete consumption of the starting material (monitored by TLC and LCMS), the reaction mixture was concentrated under reduced pressure, which was then diluted with EtOAc and washed successively with saturated NaHCO solution, water, and brine. The organic layer was dried over anhydrous NaSO and evaporated under reduced pressure to give the crude compound, which was purified by column chromatography (SiO, 60% EtOAc / DCM) to give methyl 6-hydroxy-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-4-carboxylate (2.3 g, 6.84 mmol, 76%) as a white solid. LCMS (ESI): 337.0 m / z [M+H] +

[0275] Step D To a stirred solution of methyl 6-hydroxy-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-4-carboxylate (400 mg, 1.19 mmol) in DCM (15 mL) was added DMAP (436 mg, 3.57 mmol) and tert-butyl propionate (0.326 mL, 2.381 mmol) sequentially at 0° C. under nitrogen. The resulting reaction mixture was stirred at RT for 1 h. After complete consumption of the starting material (monitored by TLC), the reaction was diluted with DCM and washed with water. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude compound, which was purified by column chromatography (SiO2, 30% EtOAc / DCM) to give methyl (E)-6-((3-(tert-butoxy)-3-oxoprop-1-en-1-yl)oxy)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-4-carboxylate (480 mg, 1.04 mmol, 87%) as a white solid. LCMS (ESI): 463.0 m / z [M+H] +

[0276] Step E A stirred solution of methyl (E)-6-((3-(tert-butoxy)-3-oxoprop-1-en-1-yl)oxy)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-4-carboxylate (450 mg, 0.97 mmol) in MeOH (10 mL) was degassed with argon for 15 min, and then Pd(OH) (10 wt%, 450 mg) was slowly added. The reaction mixture was then stirred at room temperature under H balloon pressure (15 PSI) for 16 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 to give the crude material, which was purified by column chromatography (SiO, 20%-30% EtOAc / DCM) to give methyl 6-(3-(tert-butoxy)-3-oxopropoxy)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-4-carboxylate (180 mg, 0.387 mmol, 40%) as an off-white solid. LCMS (ESI): 465.0 m / z [M+H] +

[0277] Step F To a stirred suspension of methyl 6-(3-(tert-butoxy)-3-oxopropoxy)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-4-carboxylate (1.1 g, 2.37 mmol) in DCM (6 mL) was added TFA (4 mL) dropwise at 0 °C under nitrogen. The mixture was allowed to stir at RT for 16 h. After complete consumption of the starting material (monitored by TLC and LCMS), the volatiles were evaporated under reduced pressure to give the crude compound (3-((4-(methoxycarbonyl)-2-methyl-1H-benzo[d]imidazol-6-yl)oxy)propanoic acid (1 g crude), which was then triturated with EtO and pentane and used directly in the next step without further purification. LCMS (ESI): 279.0 m / z [M+H] +

[0278] Step G (3-((4-(Methoxycarbonyl)-2-methyl-1H-benzo[d]imidazol-6-yl)oxy)propanoic acid (550 mg, crude) was dissolved in toluene (20 mL) and a solution of 1,1-di-tert-butoxy-N,N-dimethylmethanamine (3.79 mL, 15.82 mmol) was added. The mixture was stirred at 110° C. for 3 h. After complete consumption of the starting material (monitored by TLC and LCMS), the reaction mixture was diluted with EtOAc. The organic layer was dried over NaSO and evaporated under reduced pressure to give the crude compound, which was then purified by column chromatography (SiO, 20%-30% EtOAc / hexanes) to give methyl 6-(3-(tert-butoxy)-3-oxopropoxy)-2-methyl-1H-benzo[d]imidazole-4-carboxylate (150 mg, 0.449 mmol, 34% over two steps) as a white solid. LCMS (ESI): 335.2 m / z [M+H] +

[0279] Step H To a solution of methyl 6-[3-(tert-butoxy)-3-oxopropoxy]-2-methyl-1H-1,3-benzodiazole-4-carboxylate (75.0 mg, 0.224 mmol) in HO (1.0 mL) and MeCN (5.0 mL) was added LiBr (389.6 mg, 4.486 mmol) and EtN (0.313 mL, 2.243 mmol). The mixture was stirred at RT for 3 days. The crude material was concentrated in vacuo and purified by reverse-phase flash chromatography (C18, HO:MeCN with 0.1% FA) to give 6-[3-(tert-butoxy)-3-oxopropoxy]-2-methyl-1H-1,3-benzodiazole-4-carboxylic acid (41.6 mg, 0.130 mmol, 57.9%) as a white solid. LCMS (ESI): 321.0 m / z [M+H] +

[0280] Step I To a solution of 6-[3-(tert-butoxy)-3-oxopropoxy]-2-methyl-1H-1,3-benzodiazole-4-carboxylic acid (41.6 mg, 0.130 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (25.7 mg, 0.156 mmol) in DMF was added DIPEA (0.068 mL, 0.390 mmol) and HATU (98.9 mg, 0.260 mmol). The mixture was stirred at RT for 30 min. The crude material was then purified by reverse-phase flash chromatography (C18, HO:MeCN+0.1% FA) to afford tert-butyl 3-({4-[(2,6-dioxopiperidin-3-yl)carbamoyl]-2-methyl-1H-1,3-benzodiazol-6-yl}oxy)propanoate (22.0 mg, 0.051 mmol, 39.3%) as a white solid. LCMS (ESI): 431.3 m / z [M+H] +

[0281] Step J To a solution of tert-butyl 3-({4-[(2,6-dioxopiperidin-3-yl)carbamoyl]-2-methyl-1H-1,3-benzodiazol-6-yl}oxy)propanoate in DCM was added TFA, and the mixture was stirred at RT for the next 18 h. The crude material was then concentrated in vacuo and dissolved in 1 M HCl / water. The solvent was evaporated under reduced pressure, redissolved in water, and lyophilized to afford 3-({4-[(2,6-dioxopiperidin-3-yl)carbamoyl]-2-methyl-1H-1,3-benzodiazol-6-yl}oxy)propanoic acid hydrochloride (18.3 mg, 0.045 mmol, 87.2%) as an off-white solid. LCMS (ESI): 375.1 m / z [M+H] +

[0282] Step K To a solution of 3-({4-[(2,6-dioxopiperidin-3-yl)carbamoyl]-2-methyl-1H-1,3-benzodiazol-6-yl}oxy)propanoic acid hydrochloride (18.3 mg, 0.044 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 (20.0 mg, 0.030 mmol), and HATU (22.6 mg, 0.059 mmol) in anhydrous DMF (2.0 mL) was added DIPEA (0.026 mL, 0.148 mmol). The mixture was stirred at RT for 30 min. The crude material was diluted with DCM and washed with brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give 33.5 mg of crude tert-butyl 6-chloro-1-(2-{4-[3-({4-[(2,6-dioxopiperidin-3-yl)carbamoyl]-2-methyl-1H-1,3-benzodiazol-6-yl}oxy)propanoyl]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 in the next step without further purification. LCMS (ESI): 1030.5 m / z [M+H] +

[0283] Step L To a solution of tert-butyl 6-chloro-1-(2-{4-[3-({4-[(2,6-dioxopiperidin-3-yl)carbamoyl]-2-methyl-1H-1,3-benzodiazol-6-yl}oxy)propanoyl]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 (33.5 mg, crude) in DCM (1.0 mL) was added TFA (1.0 mL, 13.059 mmol). The reaction mixture was stirred at RT for 18 h. The crude material was concentrated in vacuo and purified by preparative HPLC (C18, HO:MeCN+0.1% FA) to afford 6-chloro-1-(2-{4-[3-({4-[(2,6-dioxopiperidin-3-yl)carbamoyl]-2-methyl-1H-1,3-benzodiazol-6-yl}oxy)propanoyl]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 (9.9 mg, 0.010 mmol, 33% over two steps) as a white solid. LCMS (ESI): 974.2 m / z [M+H] + 1H NMR (500 MHz, DMSO, 353 K) δ 12.65 (s, 1H), 10.55 (s, 1H), 10.19 (s, 1H), 8.25 (dd, J = 9.3, 5.9 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.61 - 7.54 (m, 1H), 7.45 - 7.37 (m, 3H), 7.32 (td, J = 8.9, 2.6 Hz, 1H), 7.24 - 7.15 (m, 2H), 6.87 (dd, J = 6.2, 2.4 Hz, 1H), 4.87 - 4.78 (m, 1H), 4.40 - 4.15 (m, 6H), 3.75 (s, 3H), 3.41 - 3.35 (m, 4H), 3.30 - 3.24 (m, 2H), 2.85 - 2.70 (m, 4H), 2.66 - 2.56 (m, 1H), 2.54 (s, 3H), 2.29 - 2.20 (m, 2H), 2.19 - 2.06 (m, 7H), 2.01 (d, J = 2.6 Hz, 3H), 1.90 - 1.86 (m, 3H).

[0284] Example 3: 6-chloro-1-(2-(4-(2-((4-((2,6-dioxopiperidin-3-yl)carbamoyl)-2-methyl-1H-benzo[d]imidazol-6-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 (Compound 2) [ka] Step A To a solution of methyl 6-[2-(tert-butoxy)-2-oxoethoxy]-2-methyl-1H-1,3-benzodiazole-4-carboxylate (50.0 mg, 0.156 mmol) in HO (0.500 mL) and MeCN (2.5 mL) was added LiBr (271.1 mg, 3.122 mmol) and EtN (0.218 mL, 1.561 mmol). The mixture was stirred at room temperature for 6 days. The crude material was concentrated under reduced pressure and purified by reverse-phase chromatography (C18, HO:MeCN with 0.1% FA) to give 6-[2-(tert-butoxy)-2-oxoethoxy]-2-methyl-1H-1,3-benzodiazole-4-carboxylic acid (9.4 mg, 0.031 mmol, 19.7%) as a white solid. LCMS (ESI): 307.1 m / z [M+H] +

[0285] Step B 6-[2-(tert-butoxy)-2-oxoethoxy]-2-methyl-1H-1,3-benzodiazole-4-carboxylic acid (9.4 mg, 0.031 mmol), 3-aminopiperidine-2,6-dione hydrochloride (6.1 mg, 0.037 mmol), and HATU (17.5 mg, 0.046 mmol) were dissolved in anhydrous DMF (1.0 mL) under an argon atmosphere, and DIPEA (0.016 mL, 0.092 mmol) was added. The reaction (monitored by LCMS) was stirred at room temperature for 15 minutes under argon. After complete consumption of the starting material, the solution was diluted to 10 mL with DCM and washed with aqueous NaHCO (10 mL), brine (10 mL), and water (10 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness to give tert-butyl 2-({4-[(2,6-dioxopiperidin-3-yl)carbamoyl]-2-methyl-1H-1,3-benzodiazol-6-yl}oxy)acetate (10.1 mg, 0.24 mmol, 78.7%) as a yellow oil. The reaction product was used in the next step without further purification. LCMS (ESI): 417.4 m / z [M+H] +

[0286] Step C tert-Butyl 2-({4-[(2,6-dioxopiperidin-3-yl)carbamoyl]-2-methyl-1H-1,3-benzodiazol-6-yl}oxy)acetate (10.1 mg, 0.024 mmol) was dissolved in anhydrous DCM (0.250 mL) under an argon atmosphere and TFA (0.250 mL, 3.265 mmol) was added. The reaction was stirred at room temperature under argon for 16 hours. Once LCMS showed complete consumption of the starting material, the solution was concentrated under reduced pressure. 1 M aqueous HCl (1 mL) was added and the solution was concentrated in vacuo. The addition of HCl followed by evaporation was repeated twice. The product was dry-frozen to give crude 2-({4-[(2,6-dioxopiperidin-3-yl)carbamoyl]-2-methyl-1H-1,3-benzodiazol-6-yl}oxy)acetic acid hydrochloride (8.0 mg, 0.020 mmol, 83.3%) as a white solid. LCMS (ESI): 361.0 m / z [M+H] +

[0287] Step D 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 (11.3 mg, 0.017 mmol) and {4-[(2,6-dioxopiperidin-3-yl)carbamoyl]-2-methyl-1H-1,3-benzodiazol-6-yl}oxy)acetic acid hydrochloride (8.0 mg, 0.020 mmol) were dissolved in anhydrous DMF (0.8 mL) under an argon atmosphere, and DIPEA (0.009 mL, 0.050 mmol) was added, followed by HATU (6.7 mg, 0.018 mmol). The reaction (monitored by LCMS) was stirred under argon at room temperature for 20 hours. After complete consumption of the starting material, the mixture was diluted to 10 mL with DCM and washed with saturated aqueous NaHCO (10 mL), brine (10 mL), and water (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to afford crude tert-butyl 6-chloro-1-(2-{4-[2-({4-[(2,6-dioxopiperidin-3-yl)carbamoyl]-2-methyl-1H-1,3-benzodiazol-6-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 (14.2 mg) as a yellow oil, which was used in the subsequent step without further purification. LCMS (ESI): 1016.1 m / z [M+H] +

[0288] Step E Crude tert-butyl 6-chloro-1-(2-{4-[2-({4-[(2,6-dioxopiperidin-3-yl)carbamoyl]-2-methyl-1H-1,3-benzodiazol-6-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 (14.2 mg, 0.014 mmol) was dissolved in anhydrous DCM (0.500 mL) under an argon atmosphere, and TFA (0.500 mL, 6.529 mmol) was added. The reaction (monitored by LCMS) was stirred at room temperature for 16 hours under argon. After complete conversion of the starting material, the solution was concentrated to dryness under reduced pressure and purified by reverse-phase 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-benzo[d]imidazol-6-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 (7.3 mg, 0.008 mmol, 47% over two steps) as a white solid. LCMS (ESI): 960.1 m / z [M+H] + 1H NMR (500 MHz, DMSO, 353 K) δ 12.34 (s, 1H), 10.58 (s, 1H), 10.20 (s, 1H), 8.26 (dd, J = 9.2, 5.9 Hz, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.60 (dd, J = 10.4, 2.6 Hz, 1H), 7.51 - 7.38 (m, 3H), 7.34 (td, J = 8.9, 2.6 Hz, 1H), 7.22 (d, J = 8.5 Hz, 1H), 7.21 - 7.16 (m, 1H), 6.88 (dd, J = 5.9, 2.8 Hz, 1H), 4.91 - 4.81 (m, 1H), 4.79 (s, 2H), 4.36 - 4.24 (m, 3H), 4.21 (ddd, J = 14.0, 7.9, 5.8 Hz, 1H), 3.76 (s, 3H), 3.45 - 3.36 (m, 4H), 3.34 - 3.25 (m, 2H), 2.81 (ddd, J = 17.5, 13.0, 5.6 Hz, 1H), 2.65 - 2.59 (m, 1H), 2.55 (s, 3H), 2.35 - 2.21 (m, 3H), 2.20 - 2.05 (m, 7H), 2.02 (s, 3H), 1.90 (s, 3H).

[0289] Example 4: 6-chloro-1-{2-[4-(2-{[3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin-6-yl]formamido}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 (compound 5). [ka] Step A To a stirred solution of 2-amino-5-bromobenzaldehyde (5.8 g, 28.99 mmol) in MeOH (140 mL) was added 4-oxopentanoic acid (10.34 mL, 101.48 mmol) followed by 2(N) aqueous sodium hydroxide (20 mL) dropwise at 0 °C. The resulting reaction mixture was then refluxed for 18 h. After complete consumption of the starting material (monitored by TLC and LCMS), the reaction mixture was concentrated under reduced pressure. The residue was dissolved in a minimum amount of water and washed with EtO. The aqueous layer was then neutralized with acetic acid, and the resulting precipitate was filtered and washed with ether and pentane to give 2-(6-bromo-2-methylquinolin-3-yl)acetic acid (5 g, crude) as a yellow solid, which was used directly in the next step without further purification. LCMS (ESI): 280.0 m / z [M+H] +

[0290] Step B To a cooled solution of DCC (8.55 g, 41.43 mmol) in DCM (100 mL) was added DMAP (3.29 g, 26.93 mmol) at 0 °C, followed by 2-(6-bromo-2-methylquinolin-3-yl)acetic acid (5 g, crude), and the resulting mixture was stirred at 0 °C for 5 min. tert-Butanol (3.071 mL, 103.57 mmol) was then added, and the reaction was allowed to stir at room temperature under nitrogen for 12 h. After complete consumption of the starting material (monitored by TLC and LCMS), the solvent was evaporated under reduced pressure to give the crude compound, which 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, 30-40% EtOAc / hexanes) to give tert-butyl 2-(6-bromo-2-methylquinolin-3-yl)acetate (4 g, 11.9 mmol, 41% over two steps) as an off-white solid. LCMS (ESI): 335.4 m / z [M+H] +

[0291] Step C To a stirred solution of tert-butyl 2-(6-bromo-2-methylquinolin-3-yl)acetate (4 g, 11.9 mmol) in DMF (50 mL) was added KCO (1.81 g, 13.095 mmol) followed by TEBAC (2.712 g, 11.905 mmol) under a nitrogen atmosphere at 0 °C. Acrylonitrile (0.858 mL, 13.095 mmol) was then added, and the resulting mixture was allowed to stir at room temperature under nitrogen for 3 h. After complete consumption of the starting material (monitored by TLC and LCMS), the reaction mixture was diluted with EtOAc and washed successively with cold 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, 30-50% EtOAc / hexanes) to give tert-butyl 2-(6-bromo-2-methylquinolin-3-yl)-4-cyanobutanoate (1.4 g, 3.6 mmol, 30%) as a pale yellow sticky solid. LCMS (ESI): 387.4 m / z [M−H] -

[0292] Step D To a solution of tert-butyl 2-(6-bromo-2-methylquinolin-3-yl)-4-cyanobutanoate (1.4 g, 3.6 mmol) in MeOH (18 mL) was added HO (1.5 mL, 3.6 mmol) followed by KCO (995 mg, 7.21 mmol) under a nitrogen atmosphere at 0 °C. The reaction mixture was then stirred at room temperature under nitrogen for 16 h. After the starting material was consumed (monitored by TLC and LCMS), the reaction mixture was concentrated under reduced pressure to give the crude compound, which was then purified by column chromatography (SiO, 2-3% MeOH / DCM) to give tert-butyl 5-amino-2-(6-bromo-2-methylquinolin-3-yl)-5-oxopentanoate (700.0 mg, 1.72 mmol, 48%) as a white solid. LCMS (ESI): 409.1 m / z [M+H] +

[0293] Step E To a stirred solution of tert-butyl 5-amino-2-(6-bromo-2-methylquinolin-3-yl)-5-oxopentanoate (700 mg, 1.72 mmol) in MeCN (10.0 mL) was added PTSA (980 g, 5.15 mmol) at room temperature, and the reaction mixture was refluxed for 16 h. After complete consumption of the starting material (monitored by LC-MS and TLC), the reaction mixture was neutralized by adding EtN at 0 °C and then evaporated to give the crude compound, which was then purified by column chromatography (SiO, 5% MeOH / DCM) to give 3-(6-bromo-2-methylquinolin-3-yl)piperidine-2,6-dione (350 mg, 1.05 mmol, 61%) as a white solid. LCMS (ESI): 335.0 m / z [M+H] +

[0294] Step F To a solution of 3-(6-bromo-2-methylquinolin-3-yl)piperidine-2,6-dione (350.0 mg, 1.05 mmol) in DMF (5.0 mL), HO (3 mL), and MeCN (5 mL) was added BINAP (65.34 mg, 0.105 mmol), Mo(CO) (277.32 mg, 1.05 mmol), and CsF (160 mg, 1.05 mmol) at room temperature. The reaction mixture was deoxygenated with argon for 10 minutes, and then Pd(OAc) (11.8 mg, 0.053 mmol) was added to it. The reaction mixture was stirred at 90 °C for 16 hours. After complete consumption of the starting material (monitored by TLC and LCMS), the reaction mixture was filtered through a pad of Celite, and the filtrate was purified by preparative HPLC (C18, HO:MeCN+0.1% FA) to give 3-(2,6-dioxopiperidin-3-yl)-2-methylquinoline-6-carboxylic acid (130 mg, 0.436 mmol, 41.5%) as a white solid. LCMS (ESI): 299.2 m / z [M+H] +

[0295] Step G To a solution of 3-(2,6-dioxopiperidin-3-yl)-2-methylquinoline-6-carboxylic acid (30.0 mg, 0.101 mmol) and tert-butyl 2-aminoacetate hydrochloride (25.3 mg, 0.151 mmol) in anhydrous DMF (2.0 mL) was added HATU (76.5 mg, 0.201 mmol) and DIPEA (0.088 mL, 0.503 mmol). The reaction was stirred at room temperature for 15 minutes. The crude material was purified by reverse-phase flash chromatography (C18, HO:MeCN with 0.1% FA) to afford tert-butyl 2-{[3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin-6-yl]formamide}acetate (39.0 mg, 0.095 mmol, 94%) as a white solid. LCMS (ESI): 412.1 m / z [M+H] +

[0296] Step H To a solution of tert-butyl 2-{[3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin-6-yl]formamide}acetate (39.0 mg, 0.095 mmol) in DCM (1.0 mL) was added TFA (1.0 mL). The mixture was stirred at room temperature for 5 hours. The crude material was concentrated under reduced pressure and dissolved in HO. HCl was added to the solution, which was then evaporated. The product, 2-{[3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin-6-yl]formamide}acetic acid hydrochloride (37.0 mg, 0.094 mmol, 99.6%), was isolated as a white solid. LCMS (ESI): 356.0 m / z [M+H] +

[0297] Step I To a solution of 2-{[3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin-6-yl]formamide}acetic acid hydrochloride (10.5 mg, 0.027 mmol) and 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 (15.0 mg, 0.022 mmol) in anhydrous DMF (2.0 mL) was added HATU (16.9 mg, 0.044 mmol) and DIPEA (0.019 mL, 0.111 mmol). The reaction was stirred at room temperature for 15 minutes. The crude material was diluted in DCM and washed with brine. The organic layer was dried over MgSO, filtered, and concentrated under reduced pressure to afford tert-butyl 6-chloro-1-{2-[4-(2-{[3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin-6-yl]formamido}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 (43.8 mg, crude) as a yellow oil, which was used in the next step without further purification. LCMS (ESI): 1011.5 m / z [M+H] +

[0298] Step J To a solution of tert-butyl 6-chloro-1-{2-[4-(2-{[3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin-6-yl]formamido}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 (43.8 mg, crude) in DCM (1.0 mL) was added TFA (1.0 mL, 13.059 mmol). The reaction mixture was stirred at room temperature for 18 hours. The crude material was concentrated in vacuo and purified by preparative HPLC (C18, HO:MeCN+0.1% FA) to afford 6-chloro-1-{2-[4-(2-{[3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin-6-yl]formamido}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 (2.2 mg, 0.002 mmol, 9% over two steps) as a solid. LCMS (ESI): 955.2 m / z [M+H] + 1H NMR (500 MHz, DMSO, 353 K) δ 10.61 (s, 1H), 8.41 (d, J = 2.0 Hz, 1H), 8.36 (t, J = 5.6 Hz, 1H), 8.25 (dd, J = 9.2, 5.9 Hz, 1H), 8.18 (s, 1H), 8.10 (dd, J = 8.8, 2.0 Hz, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.58 (dd, J = 10.4, 2.6 Hz, 1H), 7.45 - 7.39 (m, 2H), 7.32 (td, J = 8.9, 2.7 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 6.87 (dd, J = 5.8, 2.8 Hz, 1H), 4.35 - 4.27 (m, 2H), 4.24 (t, J = 6.4 Hz, 2H), 4.23 - 4.16 (m, 1H), 4.14 (d, J = 5.5 Hz, 2H), 3.77 (s, 3H), 3.42 - 3.36 (m, 4H), 3.30 - 3.23 (m, 2H), 2.83 (ddd, J = 17.6, 12.5, 5.5 Hz, 1H), 2.70 (s, 3H), 2.69 - 2.61 (m, 1H), 2.48 - 2.36 (m, 1H), 2.29 - 2.07 (m, 9H), 2.02 (s, 3H), 1.89 (s, 3H).

[0299] Example 5: 6-chloro-1-(2-(4-((3-(2,6-dioxopiperidin-3-yl)-2-methylquinoline-7-carbonyl)glycyl)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 (Compound 6) [ka] Step A To a solution of 3-(7-bromo-2-methylquinolin-3-yl)piperidine-2,6-dione (1.0 g, 3.012 mmol), Mo(CO) (0.795 g, 3.012 mmol) in MeCN (10 mL), DMF (10 mL), and water (8.0 mL) was added cesium fluoride (0.457 g, 3.012 mmol). The reaction mixture was then deoxygenated with argon for 10 minutes. BINAP (0.187 g, 0.301 mmol) was added followed by Pd(OAc) (0.034 g, 0.151 mmol) to the reaction mixture, which was stirred at 90 °C for 16 hours. After complete consumption of the starting material (monitored by TLC and LCMS), the mixture was filtered through Celite and washed with MeCN. The filtrate was concentrated under reduced pressure and the crude material was purified by reverse-phase preparative HPLC (C18, 10 mM ammonium acetate / HO:MeCN) to afford 3-(2,6-dioxopiperidin-3-yl)-2-methylquinoline-7-carboxylic acid (325 mg, 1.1 mmol, 36.5%) as an off-white solid. LCMS (ESI): 299.0 m / z [M+H] +

[0300] Step B 3-(2,6-Dioxopiperidin-3-yl)-2-methylquinoline-7-carboxylic acid (30.0 mg, 0.101 mmol), tert-butyl 2-aminoacetate hydrochloride (25.3 mg, 0.151 mmol), and HATU (76.5 mg, 0.201 mmol) were dissolved in anhydrous DMF (2.0 mL) under an argon atmosphere, and DIPEA (0.088 mL, 0.503 mmol) was added. The reaction (monitored by LCMS) was stirred for 30 min. After complete consumption of the starting material, the solution was diluted to 10 mL with DCM and washed with brine (2 × 10 mL) and water (2 × 10 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was dissolved in DMSO and purified by preparative HPLC (C18, HO:MeCN+0.1% FA) to afford tert-butyl 2-{[3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin-7-yl]formamide}acetate (34.9 mg, 0.085 mmol, 84.4%) as a white solid. LCMS (ESI): 412.1 m / z [M+H] +

[0301] Step C tert-Butyl 2-{[3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin-7-yl]formamide}acetate (34.9 mg, 0.085 mmol) was dissolved in anhydrous DCM (0.5 mL) under an argon atmosphere, and TFA (0.500 mL, 6.529 mmol) was added. The reaction (monitored by LCMS) was stirred at room temperature under argon for 16 hours. After complete consumption of the starting material, the solution was concentrated under reduced pressure. The resulting residue was dissolved in 1 M HCl (1.0 mL), and the solution was concentrated to dryness. The addition and evaporation of aqueous HCl was repeated twice, and the resulting product was freeze-dried to give 2-{[3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin-7-yl]formamide}acetic acid hydrochloride (29.5 mg, 0.075 mmol, 88.7%) as a white solid. LCMS (ESI): 356.0 m / z [M+H] +

[0302] Step D 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 (23.5 mg, 0.035 mmol) and 2-{[3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin-7-yl]formamide}acetic acid hydrochloride (15.0 mg, 0.038 mmol) were dissolved in anhydrous DMF (1.0 mL) and DIPEA (0.018 mL, 0.105 mmol) was added. HATU (13.9 mg, 0.037 mmol) was added as a DMF solution (1.0 mL), and the reaction (monitored by LCMS) was stirred at room temperature for 40 minutes. After complete consumption of the starting material, the solution was diluted to 10 mL with DCM and washed with brine (2 × 10 mL) and water (2 × 10 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude tert-butyl 6-chloro-1-{2-[4-(2-{[3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin-7-yl]formamido}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) obtained as a yellow oil was used in the next step without further purification. LCMS (ESI): 1011.47 m / z [M+H] +

[0303] Step E Crude tert-butyl 6-chloro-1-{2-[4-(2-{[3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin-7-yl]formamido}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, 0.044 mmol) was dissolved in anhydrous DCM (0.5 mL) under an argon atmosphere. To this was added TFA (0.500 mL, 6.529 mmol), and the reaction (monitored by LCMS) was stirred at room temperature under argon for 16 hours. After complete consumption of the starting material, the mixture was concentrated under reduced pressure. The resulting residue was dissolved in DMSO and purified by reverse-phase preparative HPLC (C18, HO:MeCN+0.1% FA) to afford 6-chloro-1-(2-(4-((3-(2,6-dioxopiperidin-3-yl)-2-methylquinoline-7-carbonyl)glycyl)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 (14.4 mg, 0.015 mmol, 42.8% over two steps) as a white solid. LCMS (ESI): 955.2 m / z [M+H] + 1H NMR (500 MHz, DMSO, 353 K) δ 10.62 (s, 1H), 8.54 - 8.40 (m, 2H), 8.24 (dd, J = 9.2, 5.8 Hz, 1H), 8.14 (s, 1H), 7.94 (s, 2H), 7.71 (d, J = 8.6 Hz, 1H), 7.59 (dd, J = 10.4, 2.8 Hz, 1H), 7.47 - 7.38 (m, 2H), 7.33 (td, J = 8.9, 2.7 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 6.88 (dd, J = 5.5, 3.0 Hz, 1H), 4.38 - 4.08 (m, 7H), 3.78 (s, 3H), 3.43 - 3.38 (m, 4H), 3.29 (t, J = 7.4 Hz, 2H), 2.83 (ddd, J = 17.4, 12.5, 5.3 Hz, 1H), 2.71 (s, 3H), 2.69 - 2.62 (m, 1H), 2.47 - 2.35 (m, 1H), 2.30 - 2.06 (m, 9H), 2.02 (s, 3H), 1.89 (s, 3H).

[0304] Example 6: 6-chloro-1-{2-[4-(2-{[3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin-8-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, formate salt (Compound 4) [ka] Step A To a stirred solution of ethyl 2-(8-methoxy-2-methylquinolin-3-yl)acetate (4.2 g, 16.2 mmol) in DCM (70 mL) at 0 °C, 1 (M) BBr3 / DCM solution (65 mL, 64.8 mmol) was added. The mixture was stirred at the same temperature for 4 h. After complete consumption of the starting material (monitored by TLC and LCMS), the reaction mixture was poured into water at 0 °C and extracted with DCM. The aqueous portion was then diluted with saturated NaHCO3 solution and then extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (SiO2, 30% EtOAc / hexanes) to give ethyl 2-(8-hydroxy-2-methylquinolin-3-yl)acetate (2.3 g, 9.38 mmol, 58%) as a white solid. LCMS (ESI): 245.8 m / z [M+H] +

[0305] Step B To a suspension of ethyl 2-(8-hydroxy-2-methylquinolin-3-yl)acetate (2.3 g, 9.38 mmol) in MeCN (40 mL) was added KCO (2.5 g, 18.77 mmol) followed by benzyl bromide (0.7 mL, 12.20 mmol) at 0 °C. The reaction mixture was stirred at room temperature under nitrogen for 18 h. After complete consumption of the starting material (monitored by TLC and LCMS), the volatiles were evaporated under reduced pressure. The resulting residue was diluted with EtOAc and washed with cold water and brine. The organic layer was dried over NaSO and evaporated under reduced pressure to give the crude compound, which was then purified by column chromatography (SiO, 40% EtOAc / hexane) to give ethyl 2-(8-(benzyloxy)-2-methylquinolin-3-yl)acetate (1.75 g, 5.22 mmol, 56%) as a brown solid. LCMS (ESI): 335.8 m / z [M+H] +

[0306] Step C To a solution of ethyl 2-(8-(benzyloxy)-2-methylquinolin-3-yl)acetate (1.75 g, 5.22 mmol) in DMF (25 mL) was added KCO (1.4 g, 10.44 mmol) followed by TEBAC (1.2 g, 5.22 mmol) under a nitrogen atmosphere at 0° C. Then, acrylonitrile (0.45 mL, 6.791 mmol) was added, and the mixture was allowed to stir at room temperature under nitrogen for 2 hours. After complete consumption of the starting material (monitored by TLC and LCMS), the reaction mixture was diluted with EtOAc and washed with cold water and brine. The organic layer was dried over anhydrous NaSO and evaporated under reduced pressure to give the crude compound, which was then purified by column chromatography (SiO, 40% EtOAc / hexanes) to give ethyl 2-(8-(benzyloxy)-2-methylquinolin-3-yl)-4-cyanobutanoate (800 mg, 2.06 mmol, 39%) as a brown viscous liquid. LCMS (ESI): 388.8 m / z [M+H] +

[0307] Step D To a solution of ethyl 2-(8-(benzyloxy)-2-methylquinolin-3-yl)-4-cyanobutanoate (800 mg, 2.06 mmol) in MeOH (10 mL) was added HO (0.3 mL, 10.31 mmol) followed by KCO (56 mg, 0.412 mmol) under a nitrogen atmosphere at 0 °C. The mixture was allowed to stir at room temperature under nitrogen for 16 h. After complete consumption of the starting material (monitored by TLC and LCMS), the volatiles were removed under reduced pressure to give crude ethyl 5-amino-2-(8-(benzyloxy)-2-methylquinolin-3-yl)-5-oxopentanoate, which was used directly in the next step without further purification. LCMS (ESI): 407.3 m / z [M+H] +

[0308] Step E Ethyl 5-amino-2-(8-(benzyloxy)-2-methylquinolin-3-yl)-5-oxopentanoate (crude product from Step D) was dissolved in EtOH (10 mL), and a solution of LiOH (177 mg, 7.389 mmol) in water (2 mL) was added to it. The reaction mixture was stirred for 16 h. After complete consumption of the starting material (monitored by TLC and LCMS), the volatiles were evaporated under reduced pressure. The crude 5-amino-2-(8-(benzyloxy)-2-methylquinolin-3-yl)-5-oxopentanoic acid was used in the next step without further purification. LCMS (ESI): 379.0 m / z [M+H] +

[0309] Step F The crude 5-amino-2-(8-(benzyloxy)-2-methylquinolin-3-yl)-5-oxopentanoic acid from the previous step was dissolved in MeCN (20 mL), p-toluenesulfonic acid monohydrate (3.4 g, 19.84 mmol) was added, and the resulting reaction mixture was stirred at 80 °C for 16 h. After the reaction (monitored by TLC and LCMS) was completed, the mixture was concentrated under reduced pressure. The crude compound was purified by column chromatography (SiO, 70% EtOAc / DCM) to give 3-(8-(benzyloxy)-2-methylquinolin-3-yl)piperidine-2,6-dione (280 mg, 0.78 mmol, 38% over three steps) as a brown solid. LCMS (ESI): 361.1 m / z [M+H] +

[0310] Step G 3-(8-(benzyloxy)-2-methylquinolin-3-yl)piperidine-2,6-dione (280 mg, 0.78 mmol) was dissolved in MeCN (10 mL) and 140 mg of Pd(OH) (50 wt%) was added. The reaction vessel was backfilled with hydrogen, and the reaction mixture was stirred under a hydrogen atmosphere for 8 hours. After complete consumption of the starting material (monitored by TLC and LCMS), the reaction mixture was filtered through a Celite pad and washed thoroughly with MeCN. The combined filtrate was evaporated under reduced pressure to give the crude compound, which was then purified by trituration with ether and pentane to give 3-(8-hydroxy-2-methylquinolin-3-yl)piperidine-2,6-dione (115 mg, 0.43 mmol, 55%) as a white solid. LCMS (ESI): 271.1 m / z [M+H] +

[0311] Step H 3-(8-Hydroxy-2-methylquinolin-3-yl)piperidine-2,6-dione (25.0 mg, 0.092 mmol) was dissolved in DMF (2.0 mL) and KI (15.4 mg, 0.092 mmol), KHCO (27.8 mg, 0.277 mmol), and tert-butyl bromoacetate (0.016 mL, 0.111 mmol) were added. The reaction was stirred at 60 °C for 6 h. The crude material was directly injected into reverse-phase flash chromatography (C18, HO:MeCN + 0.1% FA) to afford the corresponding tert-butyl 2-{[3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin-8-yl]oxy}acetate (14.6 mg, 0.038 mmol, 41%) as a white solid. LCMS (ESI): 385.2 m / z [M+H] +

[0312] Step I To a solution of tert-butyl 2-{[3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin-8-yl]oxy}acetate (14.6 mg, 0.038 mmol) in DCM (1.0 mL) was added TFA (1.0 mL, 13.059 mmol). The mixture was stirred at room temperature for 5 hours. The crude material was concentrated in vacuo and dissolved in HO. HCl was added to the solution, which was then evaporated. 2-{[3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin-8-yl]oxy}acetic acid hydrochloride (12.6 mg, 0.035 mmol, 91.0%) was isolated as a greenish solid. LCMS (ESI): 329.0 m / z [M+H] +

[0313] Step J To a solution of 2-{[3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin-8-yl]oxy}acetic acid hydrochloride (9.7 mg, 0.027 mmol) and 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 (15.0 mg, 0.022 mmol) in anhydrous DMF (2.0 mL) was added HATU (16.9 mg, 0.044 mmol) and DIPEA (0.012 mL, 0.067 mmol). The reaction was stirred at room temperature for 15 minutes. The crude material was diluted in DCM and washed with brine. The organic layer was dried over MgSO, filtered, and concentrated in vacuo to afford tert-butyl 6-chloro-1-(2-{4-[(2-{[3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin-8-yl]oxy}acetyl)oxy]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 (37.5 mg, crude) as a yellow oil, which was used in the next step without further purification. LCMS (ESI): 984.5 m / z [M+H]+

[0314] Step K To a solution of tert-butyl 6-chloro-1-{2-[4-(2-{[3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin-8-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 (37.5 mg, crude) in DCM (1.0 mL) was added TFA (1.0 mL, 13.059 mmol). The reaction mixture was stirred at room temperature for 18 hours. The crude material was concentrated in vacuo and purified by preparative HPLC (C18, HO:MeCN+0.1% FA) to afford 6-chloro-1-{2-[4-(2-{[3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin-8-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 (formate) (10.3 mg, 0.011 mmol, 50% over two steps) as a yellow solid. LCMS (ESI): 928.2 m / z [M+H] + 1H NMR (500 MHz, DMSO, 353 K) δ 10.59 (s, 1H), 8.24 (dd, J = 9.2, 5.9 Hz, 1H), 8.02 (s, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.57 (dd, J = 10.4, 2.6 Hz, 1H), 7.44 (dd, J = 8.2, 1.3 Hz, 1H), 7.42 - 7.36 (m, 3H), 7.32 (ddd, J = 9.3, 8.7, 2.6 Hz, 1H), 7.19 (d, J = 8.5 Hz, 1H), 7.09 (dd, J = 7.7, 1.3 Hz, 1H), 6.86 (dd, J = 5.4, 3.2 Hz, 1H), 4.98 - 4.93 (m, 2H), 4.33 - 4.21 (m, 4H), 4.18 (ddd, J = 13.8, 7.9, 5.8 Hz, 1H), 3.72 (d, J = 3.3 Hz, 3H), 3.52 - 3.39 (m, 4H), 3.30 - 3.23 (m, 2H), 2.81 (ddd, J = 17.6, 12.5, 5.4 Hz, 1H), 2.67 - 2.61 (m, 4H), 2.43 - 2.31 (m, 1H), 2.28 - 2.19 (m, 2H), 2.19 - 2.04 (m, 7H), 2.00 (d, J = 2.0 Hz, 3H), 1.88 (s, 3H).

[0315] Example 7: 6-chloro-1-{2-[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-5-methoxy-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 (Compound 7) [ka] Step A To a solution of methyl 2-formyl-3-hydroxy-4-methoxybenzoate (550 mg, 2.62 mmol) in DMF (15 mL) was added KCO (398 mg, 2.88 mmol) under a nitrogen atmosphere at 0° C. Then, tert-butyl 2-bromoacetate (768 mg, 3.93 mmol) was added to the reaction mixture at room temperature. The resulting mixture was then stirred at room temperature 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 with cold water and brine. The organic layer was dried over anhydrous NaSO and evaporated under reduced pressure to give the crude compound, which was then purified by column chromatography (SiO, 30% EtOAc / hexane) to give methyl 3-(2-(tert-butoxy)-2-oxoethoxy)-2-formyl-4-methoxybenzoate (600 mg, 1.85 mmol, 70%) as a white viscous liquid. LCMS (ESI): 325.0 m / z [M+H] +

[0316] Step B To a solution of methyl 3-(2-(tert-butoxy)-2-oxoethoxy)-2-formyl-4-methoxybenzoate (600 mg, 1.85 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (610 mg, 3.7 mmol) in DCE (10 mL) was added acetic acid (0.1 mL, 1.85 mmol). The pH of the reaction mixture was adjusted to 7, and the reaction mixture was stirred at reflux in a sealed tube for 4 hours. Sodium triacetoxyborohydride (1.9 g, 9.26 mmol) was then added, and the mixture was stirred at 90° C. for 16 hours. After complete consumption of the starting material (monitored by TLC and LCMS), the volatiles were evaporated under reduced pressure to give the crude compound, which was purified by column chromatography (SiO, 80% EtOAc / DCM) to give tert-butyl 2-((2-(2,6-dioxopiperidin-3-yl)-5-methoxy-1-oxoisoindolin-4-yl)oxy)acetate (310 mg, 0.77 mmol, 42%) as a brown solid. LCMS (ESI): 405.0 m / z [M+H] +

[0317] Step C To a stirred suspension of tert-butyl 2-((2-(2,6-dioxopiperidin-3-yl)-5-methoxy-1-oxoisoindolin-4-yl)oxy)acetate (310 mg, 0.77 mmol) in DCM (5 mL) was added TFA (5 mL) dropwise at 0° C. under nitrogen. The mixture was allowed to stir at room temperature for 16 hours. After complete consumption of the starting material (monitored by TLC and LCMS), the volatiles were evaporated under reduced pressure to give the crude compound, which was then purified by trituration with ether and pentane to give 2-((2-(2,6-dioxopiperidin-3-yl)-5-methoxy-1-oxoisoindolin-4-yl)oxy)acetic acid (220 mg, 0.63 mmol, 81%) as a black solid. LCMS (ESI): 349.2 m / z [M+H] +

[0318] Step D To a mixture of 2-{[2-(2,6-dioxopiperidin-3-yl)-5-methoxy-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}acetic acid (9.3 mg, 0.027 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 (15.0 mg, 0.022 mmol), and HATU (16.9 mg, 0.044 mmol) in anhydrous DMF (2.0 mL) was added DIPEA (0.012 mL, 0.067 mmol), and the reaction was stirred at room temperature for 30 minutes. After complete consumption of the starting material, the crude material was diluted with DCM and washed with brine. The organic layer was dried over MgSO, filtered, and concentrated in vacuo to give tert-butyl 6-chloro-1-{2-[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-5-methoxy-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 (33.5 mg crude), which was used in the next step without further purification. LCMS (ESI): 1004.3 m / z [M+H] +

[0319] Step E To a solution of tert-butyl 6-chloro-1-{2-[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-5-methoxy-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 (33.5 mg, crude) in DCM (1.0 mL) was added TFA (1.0 mL, 13.059 mmol, 391.588 equiv). The reaction mixture was stirred at room temperature for 18 hours. The crude material was concentrated in vacuo and purified by preparative HPLC (C18, HO:MeCN+0.1% FA) to afford 6-chloro-1-{2-[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-5-methoxy-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 (13.5 mg, 0.014 mmol, 64% over two steps) as a white solid. LCMS (ESI): 948.2 m / z [M+H] + 1H NMR (500 MHz, DMSO, 353 K) δ 10.62 (s, 1H), 8.24 (dd, J = 9.2, 5.9 Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.58 (dd, J = 10.3, 2.7 Hz, 1H), 7.44 - 7.39 (m, 3H), 7.32 (td, J = 8.9, 2.7 Hz, 1H), 7.23 - 7.16 (m, 2H), 6.87 (dd, J = 5.7, 2.9 Hz, 1H), 5.00 (dd, J = 13.0, 5.2 Hz, 1H), 4.83 - 4.76 (m, 2H), 4.46 (dd, J = 16.8, 2.3 Hz, 1H), 4.38 (dd, J = 16.8, 2.9 Hz, 1H), 4.31 - 4.23 (m, 3H), 4.22 - 4.15 (m, 1H), 3.89 (s, 3H), 3.75 (s, 3H), 3.37 - 3.32 (m, 4H), 3.31 - 3.24 (m, 2H), 2.87 (ddd, J = 17.1, 13.5, 5.5 Hz, 1H), 2.66 - 2.59 (m, 1H), 2.46 - 2.35 (m, 1H), 2.27 - 2.21 (m, 2H), 2.16 - 2.00 (m, 10H), 1.88 (s, 3H).

[0320] Example 8: 6-chloro-1-(2-(4-(2-((5-(dimethylamino)-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 (Compound 10) [ka] Step A To a solution of methyl 4-bromo-2-formyl-3-hydroxybenzoate (1.2 g, 4.631 mmol) in DMF (20 mL) was added potassium bicarbonate (1.926 g, 13.953 mmol), potassium iodide (772 mg, 4.651 mmol), and tert-butyl bromoacetate (0.684 mL, 4.651 mmol) at room temperature under nitrogen. The reaction mixture was stirred at 60° C. for 1 hour. After complete consumption of the starting material (monitored by TLC and LCMS), the reaction mixture was diluted with ethyl acetate 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 then purified by column chromatography (SiO, 20-30% EtOAc / DCM) to give methyl 4-bromo-3-(2-(tert-butoxy)-2-oxoethoxy)-2-formylbenzoate (1.6 g, 4.28 mmol, 92%) as an off-white solid. LCMS (ESI): 373.0 m / z [M+H] +

[0321] Step B To a stirred solution of methyl 4-bromo-3-(2-(tert-butoxy)-2-oxoethoxy)-2-formylbenzoate (500 mg, 1.344 mmol) in DCE (10 mL) was added 3-aminopiperidine-2,6-dione hydrochloride (443.54 mg, 2.688 mmol) and acetic acid (0.077 mL, 1.344 mmol) at room temperature. The mixture was stirred at 80° C. for 4 hours. The reaction mixture was then cooled to room temperature, and sodium triacetoxyborohydride (0.7 g, 11.11 mol) was added. The resulting mixture was then stirred at 80° C. for 16 hours. After complete consumption of the starting material (monitored by TLC and LCMS), the volatiles were evaporated under reduced pressure. The crude compound was purified by column chromatography (SiO, 70% to 100% EtOAc / DCM) to afford tert-butyl 2-((5-bromo-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetate (200 mg, 0.44 mmol, 33%) as an off-white solid. LCMS (ESI): 453.0 m / z [M+H] +

[0322] Step C To a stirred solution of tert-butyl 2-((5-bromo-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetate (200 mg, 0.442 mmol) in dioxane (10 mL) was added dimethylamine / THF (2 M) (3.3 mL, 0.6618 mmol) and cesium carbonate (121.546 mg, 0.126 mmol). The mixture was deoxygenated with argon, and Pd-PEPPSI-IHeptCl (121.546 mg, 0.126 mmol) was added under an argon atmosphere. The reaction mixture was then irradiated in a microwave at 120° C. for 2 hours. 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. The crude material was purified by preparative TLC (SiO2, 100% EtOAc) to afford tert-butyl 2-((5-(dimethylamino)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetate (40 mg, 0.096 mmol, 21.7%) as a yellow solid. LCMS (ESI): 418.3 m / z [M+H] +

[0323] Step D To a stirred solution of tert-butyl 2-((5-(dimethylamino)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetate (40 mg, 0.096 mmol) in DCM (5 mL) was added TFA (3 mL) dropwise to the reaction mixture at 0° C. The reaction mixture was then allowed to stir at ambient temperature for 16 hours under nitrogen. After complete consumption of the starting material (monitored by TLC and LCMS), the volatiles were evaporated under reduced pressure. The crude compound was purified by trituration with diethyl ether and n-pentane to give 2-((5-(dimethylamino)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetic acid (26 mg, 0.072 mmol, 75%) as an off-white solid. LCMS (ESI): 362.3 m / z [M+H] +

[0324] Step E 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 (17.0 mg, 0.025 mmol) and 2-((5-(dimethylamino)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetic acid (10.0 mg, 0.028 mmol) were dissolved in anhydrous DMF (1.0 mL) under an argon atmosphere, and DIPEA (0.013 mL, 0.076 mmol) was added, followed by HATU (10.1 mg, 0.026 mmol). The reaction (monitored by LCMS) was stirred at room temperature under argon for 40 minutes. After complete consumption of the starting material, the mixture was diluted with DCM and washed with brine (2 × 10 mL) and water (2 × 10 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness to afford crude tert-butyl 6-chloro-1-{2-[4-(2-{[5-(dimethylamino)-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 as a yellow oil, which was used directly in the next step without further purification. LCMS (ESI): 1017.2 m / z [M+H] +

[0325] Step F The crude tert-butyl 6-chloro-1-(2-(4-(2-((5-(dimethylamino)-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 from the previous step was dissolved in anhydrous DCM (0.500 mL) under an argon atmosphere and TFA (0.500 mL, 6.529 mmol) 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-((5-(dimethylamino)-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 (6.9 mg, 0.007 mmol, 28% over two steps) as a white solid. LCMS (ESI): 961.2 m / z [M+H] + 1H NMR (500 MHz, DMSO, 353 K) δ 10.65 (s, 1H), 8.24 (dd, J = 9.2, 5.9 Hz, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.58 (dd, J = 10.3, 2.6 Hz, 1H), 7.44 - 7.39 (m, 2H), 7.36 (d, J = 8.1 Hz, 1H), 7.32 (ddd, J = 9.2, 8.6, 2.6 Hz, 1H), 7.20 (d, J = 8.5 Hz, 1H), 7.05 (d, J = 8.2 Hz, 1H), 6.87 (dd, J = 5.7, 3.0 Hz, 1H), 4.99 (ddd, J = 13.0, 5.2, 1.0 Hz, 1H), 4.76 (dd, J = 13.9, 2.7 Hz, 1H), 4.72 (dd, J = 13.8, 3.4 Hz, 1H), 4.46 (dd, J = 16.7, 2.6 Hz, 1H), 4.36 (dd, J = 16.6, 3.6 Hz, 1H), 4.31 - 4.21 (m, 3H), 4.21 - 4.13 (m, 1H), 3.75 (d, J = 1.0 Hz, 3H), 3.37 - 3.29 (m, 4H), 3.29 - 3.23 (m, 2H), 2.92 - 2.82 (m, 7H), 2.67 - 2.58 (m, 1H), 2.45 - 2.34 (m, 1H), 2.27 - 2.19 (m, 2H), 2.16 - 1.98 (m, 10H), 1.88 (s, 3H).

[0326] Example 9: 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-6-(methylamino)-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 (Compound 12) [ka] Step A To a solution of methyl 5-bromo-3-hydroxy-2-methylbenzoate (8 g, 32.78 mmol) in DMF (150 mL) was added KCO (5 g, 36.066 mmol) under a nitrogen atmosphere at 0 °C. Then, tert-butyl 2-bromoacetate (10 g, 51.48 mmol) was added to the reaction mixture at RT, and the reaction mixture was stirred at RT for 16 h under nitrogen. After complete consumption of the starting material (monitored by TLC and LCMS), the reaction mixture was diluted with ethyl acetate and washed with cold water and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was then purified by column chromatography (SiO, 30% EtOAc / hexane) to give methyl 5-bromo-3-(2-(tert-butoxy)-2-oxoethoxy)-2-methylbenzoate (6 g, 16.75 mmol, 51%) as a white sticky solid. LCMS (ESI): 304.5 m / z [M-tBu+H] +

[0327] Step B To a solution of methyl 5-bromo-3-(2-(tert-butoxy)-2-oxoethoxy)-2-methylbenzoate (6 g, 16.75 mmol) in anhydrous CCl4 (100 mL) was added NBS (3.5 g, 20.1 mmol) followed by AIBN (0.55 g, 3.35 mmol) at 0 °C under nitrogen. The reaction mixture was then allowed to stir at 70 °C for 3 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 anhydrous Na2SO4 and evaporated under reduced pressure to give 6 g of crude methyl 5-bromo-2-(bromomethyl)-3-(2-(tert-butoxy)-2-oxoethoxy)benzoate, which was then used in the next step without further purification.

[0328] Step C To a solution of methyl 5-bromo-2-(bromomethyl)-3-(2-(tert-butoxy)-2-oxoethoxy)benzoate (6 g, 13.761 mmol) in MeCN (70 mL) was added 3-aminopiperidine-2,6-dione (3 g, 17.89 mmol) followed by DIPEA (7.2 mL, 41.284 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at 70° C. for 16 h. The reaction was monitored by LCMS and TLC. After complete consumption of the starting material, the reaction mass was concentrated and the crude material was purified by flash column chromatography (SiO, 70% EtOAc / DCM) to afford tert-butyl 2-((6-bromo-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetate (3.5 g, 7.74 mmol, 46% over two steps) as a black solid. LCMS (ESI): 454.9 m / z [M+H] +

[0329] Step D To a solution of tert-butyl 2-((6-bromo-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetate (200 mg, 0.442 mmol) in dioxane (8 mL) was added methylamine (1 M in THF, 9 mL, 8.85 mmol), followed by CsCO (360 mg, 1.106 mmol). The mixture was deoxygenated with argon, and to it was added Pd-PEPPSI-IHeptCl (172 mg, 0.177 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 pad of Celite and the solvent was evaporated under reduced pressure to give crude tert-butyl 2-((2-(2,6-dioxopiperidin-3-yl)-6-(methylamino)-1-oxoisoindolin-4-yl)oxy)acetate, which was used in the next step without further purification. LCMS (ESI): 404.1 m / z [M+H] +

[0330] Step E To a solution of tert-butyl 2-((2-(2,6-dioxopiperidin-3-yl)-6-(methylamino)-1-oxoisoindolin-4-yl)oxy)acetate (175 mg, 0.434 mmol) in DCM (10 mL) was added TFA (2 mL) dropwise at 0° C. and the reaction mixture was allowed to stir under nitrogen at ambient temperature for 16 hours. After complete consumption of the starting material (monitored by TLC and LCMS), the volatiles were evaporated under reduced pressure to give the crude compound, which was purified by preparative HPLC (C18, HO:MeCN+0.1% FA) to give 2-{[2-(2,6-dioxopiperidin-3-yl)-6-(methylamino)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}acetic acid (18 mg, 12% in two steps, 0.0518 mmol) as a brown solid. LCMS (ESI): 348.2 m / z [M+H] +

[0331] 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 (13.0 mg, 0.019 mmol) and 2-{[2-(2,6-dioxopiperidin-3-yl)-6-(methylamino)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}acetic acid (7.4 mg, 0.021 mmol) were dissolved in anhydrous DMF (0.6 mL), and DIPEA (0.010 mL, 0.058 mmol) was added, followed by the addition of HATU (7.7 mg, 0.020 mmol) as a DMF solution (0.6 mL). The reaction (monitored by LCMS) was stirred at room temperature for 1 hour. After complete consumption of the starting material, the solution was diluted to 10 mL with DCM and washed with brine and water. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Crude tert-butyl 6-chloro-1-{2-[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-6-(methylamino)-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 (22.5 mg) was obtained as a yellow oil and was carried on to the next step without further purification. LCMS (ESI): 1003.2 m / z [M+H] +

[0332] Step G Crude tert-butyl 6-chloro-1-{2-[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-6-(methylamino)-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 was dissolved in anhydrous DCM (0.500 mL) under an argon atmosphere, and TFA (0.500 mL, 6.529 mmol) was added. The reaction (monitored by LCMS) was stirred for 16 hours at room temperature. After complete consumption of the starting material, the solution was concentrated under reduced pressure. The resulting residue was dissolved in DMSO and purified by preparative HPLC (C18, HO:MeCN+0.1% FA) to afford 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-6-(methylamino)-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 (7.0 mg, 0.007 mmol, 53.8% over two steps) as a white solid. LCMS (ESI): 947.2 m / z [M+H] + 1H NMR (500 MHz, DMSO, 353 K) δ 10.63 (s, 1H), 8.24 (dd, J = 9.2, 5.9 Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.59 (dd, J = 10.4, 2.6 Hz, 1H), 7.44 - 7.39 (m, 2H), 7.33 (ddd, J = 9.3, 8.7, 2.7 Hz, 1H), 7.21 (d, J = 8.5 Hz, 1H), 6.87 (dd, J = 5.8, 2.9 Hz, 1H), 6.46 (d, J = 1.7 Hz, 1H), 6.35 (d, J = 1.8 Hz, 1H), 4.99 (ddd, J = 13.1, 5.2, 1.1 Hz, 1H), 4.77 (s, 2H), 4.34 - 4.11 (m, 6H), 3.75 (d, J = 1.9 Hz, 3H), 3.40 - 3.33 (m, 4H), 3.31 - 3.25 (m, 2H), 2.86 (ddd, J = 17.4, 13.4, 5.5 Hz, 1H), 2.73 (s, 3H), 2.64 - 2.57 (m, 1H), 2.44 - 2.35 (m, 1H), 2.28 - 2.20 (m, 2H), 2.16 - 1.97 (m, 10H), 1.88 (s, 3H).

[0333] Example 10: 1-{2-[4-(2-{[6-amino-2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}acetyl)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-carboxylic acid (Compound 11) [ka] Step A To a solution of tert-butyl 2-((6-bromo-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetate (200 mg, 0.44 mmol) in dioxane (8 mL) was added benzylamine (0.1 mL, 0.885 mmol) and CsCO (360 mg, 1.106 mmol). The mixture was deoxygenated with argon, and to it was added Pd-PEPPSI-IHeptCl (129 mg, 0.133 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 pad of Celite and the solvent was evaporated under reduced pressure to give crude tert-butyl 2-((6-(benzylamino)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetate, which was used in the next step without further purification. LCMS (ESI): 480.4 m / z [M+H] +

[0334] Step B To a solution of tert-butyl 2-((6-(benzylamino)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetate (200 mg, crude) in DCM (10 mL) was added TFA (2 mL) dropwise at 0° C., and the reaction mixture was stirred at ambient temperature for 16 h under nitrogen. After complete consumption of the starting material (monitored by TLC and LCMS), the volatiles were evaporated under reduced pressure to give the crude compound, which was then purified by preparative HPLC (C18, 10 mM ammonium acetate / water:MeCN) to give 2-((6-(benzylamino)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetic acid (55 mg, 0.13 mmol, 29% over two steps) as an off-white solid. LCMS (ESI): 424.3 m / z [M+H] +

[0335] Step C To a solution of 2-{[6-(benzylamino)-2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}acetic acid (18.8 mg, 0.044 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 (25.0 mg, 0.037 mmol), and HATU (21.1 mg, 0.056 mmol) in anhydrous DMF (2.0 mL) was added DIPEA (0.019 mL, 0.111 mmol). The mixture was stirred at room temperature for 30 minutes. The crude material was diluted with DCM and washed with brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give 55.2 mg of crude tert-butyl 1-{2-[4-(2-{[6-(benzylamino)-2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}acetyl)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 as a yellow oil, which was used in the next step without further purification. LCMS (ESI): 1079.4 m / z [M+H] +

[0336] Step D To a solution of tert-butyl 1-{2-[4-(2-{[6-(benzylamino)-2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}acetyl)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 (55.2 mg, crude) in EtOH (10.0 mL) was added Pd / C (10 mg), and the reaction mixture was degassed with argon for 15 minutes. Hydrogen was then bubbled through the reaction mixture at room temperature for 1 day. The reaction mixture was filtered, concentrated under reduced pressure, dissolved in DMSO, and purified by preparative HPLC (C18, HO:MeCN+0.1% FA) to give tert-butyl 1-{2-[4-(2-{[6-amino-2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}acetyl)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 (38.2 mg, crude). LCMS (ESI): 989.5 m / z [M+H] +

[0337] Step E To a solution of tert-butyl 1-{2-[4-(2-{[6-amino-2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}acetyl)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 (38.2 mg, crude) in DCM (1.0 mL) was added TFA (1.0 mL, 13.059 mmol). The mixture was stirred at room temperature for 18 hours. The crude material was concentrated in vacuo, dissolved in DMSO, and purified by preparative HPLC (C18, HO:MeCN+0.1% FA) to afford 1-{2-[4-(2-{[6-amino-2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}acetyl)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-carboxylic acid (9.5 mg, 0.010 mmol, 27% over 3 steps) as a white solid. LCMS (ESI): 933.2 m / z [M+H] + 1H NMR (500 MHz, DMSO, 353 K) δ 10.60 (s, 1H), 8.24 (dd, J = 9.2, 5.9 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.58 (dd, J = 10.4, 2.6 Hz, 1H), 7.44 - 7.40 (m, 2H), 7.32 (td, J = 8.9, 2.6 Hz, 1H), 7.20 (d, J = 8.5 Hz, 1H), 6.87 (dd, J = 5.9, 2.7 Hz, 1H), 6.56 (d, J = 1.7 Hz, 1H), 6.39 (d, J = 1.7 Hz, 1H), 4.97 (ddd, J = 13.0, 5.2, 1.2 Hz, 1H), 4.73 (s, 2H), 4.32 - 4.17 (m, 5H), 4.14 (dd, J = 16.2, 2.1 Hz, 1H), 3.75 (d, J = 1.8 Hz, 3H), 3.39 - 3.33 (m, 4H), 3.30 - 3.25 (m, 2H), 2.89 - 2.80 (m, 1H), 2.65 - 2.57 (m, 1H), 2.44 - 2.34 (m, 1H), 2.27 - 2.20 (m, 2H), 2.16 - 2.06 (m, 6H), 2.05 - 1.98 (m, 4H), 1.88 (s, 3H).

[0338] Example 11: 6-chloro-1-{2-[4-(2-{[6-(dimethylamino)-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 (Compound 13) [ka] Step A To a solution of tert-butyl 2-((6-bromo-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetate (200 mg, 0.44 mmol) in dioxane (8 mL) was added dimethylamine (1 (M) in THF; 9 mL, 8.85 mmol), followed by CsCO (360 mg, 1.106 mmol). The mixture was deoxygenated with argon, and to it was added Pd-PEPPSI-IHeptCl (129 mg, 0.133 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 pad of Celite and the solvent was evaporated under reduced pressure to give crude tert-butyl 2-((6-(dimethylamino)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetate, which was used in the next step without further purification. LCMS (ESI): 418.2 m / z [M+H] +

[0339] Step B To a solution of tert-butyl 2-((6-(dimethylamino)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetate (180 mg, crude) in DCM (10 mL) was added TFA (2 mL) dropwise at 0° C. The reaction mixture was stirred at ambient temperature for 16 h under nitrogen. After complete consumption of the starting material (monitored by TLC and LCMS), the volatiles were evaporated under reduced pressure to give the crude compound, which was then purified by preparative HPLC (C18, HO:MeCN+0.1% FA) to give the desired molecule, 2-((6-(dimethylamino)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetic acid (17 mg, 0.047 mmol, 11% over two steps) as an off-white solid. LCMS (ESI): 362.3 m / z [M+H] +

[0340] Step C To a solution of 2-{[6-(dimethylamino)-2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}acetic acid (6.4 mg, 0.018 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 (10.0 mg, 0.015 mmol), and HATU (8.5 mg, 0.022 mmol) in anhydrous DMF (2.0 mL) was added DIPEA (0.008 mL, 0.044 mmol). The mixture was stirred at room temperature for 30 minutes. The crude material was diluted with DCM and washed with brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give 21.8 mg of crude tert-butyl 6-chloro-1-{2-[4-(2-{[6-(dimethylamino)-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 as a yellow oil, which was used in the next step without further purification. LCMS (ESI): 1017.1 m / z [M+H] +

[0341] Step D To a solution of tert-butyl 6-chloro-1-{2-[4-(2-{[6-(dimethylamino)-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 (21.8 mg, crude) in DCM (1.0 mL) was added TFA (1.0 mL, 13.059 mmol). The mixture was stirred at RT for 18 h. The crude material was concentrated in vacuo and purified by preparative HPLC (C18, HO:MeCN+0.1% FA) to afford 6-chloro-1-{2-[4-(2-{[6-(dimethylamino)-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 (6.5 mg, 0.007 mmol, 47% over two steps) as a white solid. LCMS (ESI): 961.2 m / z [M+H] + 1H NMR (600 MHz, DMSO, 353 K) δ 10.68 (s, 1H), 8.24 (dd, J = 9.2, 5.9 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.59 (dd, J = 10.4, 2.6 Hz, 1H), 7.43 - 7.39 (m, 2H), 7.33 (ddd, J = 9.2, 8.6, 2.6 Hz, 1H), 7.20 (d, J = 8.5 Hz, 1H), 6.87 (dd, J = 5.8, 2.8 Hz, 1H), 6.60 (d, J = 2.0 Hz, 1H), 6.49 (d, J = 2.0 Hz, 1H), 5.02 (dd, J = 13.8, 5.0 Hz, 1H), 4.84 (s, 2H), 4.31 - 4.25 (m, 2H), 4.24 (t, J = 6.3 Hz, 2H), 4.21 - 4.15 (m, 2H), 3.74 (d, J = 3.0 Hz, 3H), 3.40 - 3.34 (m, 4H), 3.29 - 3.24 (m, 2H), 2.94 (d, J = 0.7 Hz, 6H), 2.87 (ddd, J = 17.3, 13.5, 5.5 Hz, 1H), 2.63 - 2.57 (m, 1H), 2.44 - 2.37 (m, 1H), 2.26 - 2.20 (m, 2H), 2.13 - 2.01 (m, 7H), 2.00 (s, 3H), 1.88 (s, 3H).

[0342] Example 12: 6-chloro-1-{2-[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-6-(piperidin-1-yl)-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 (Compound 14) [ka] Step A To a solution of tert-butyl 2-((6-bromo-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetate (200 mg, 0.44 mmol) in dioxane (8 mL) was added piperidine (0.1 mL, 0.885 mmol), followed by CsCO (360 mg, 1.106 mmol). The mixture was deoxygenated with argon, and to it was added Pd-PEPPSI-IHeptCl (86 mg, 0.088 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 pad of Celite and the solvent was evaporated under reduced pressure to give crude tert-butyl 2-((2-(2,6-dioxopiperidin-3-yl)-1-oxo-6-(piperidin-1-yl)isoindolin-4-yl)oxy)acetate, which was used in the next step without further purification. LCMS (ESI): 458.0 m / z [M+H] +

[0343] Step B To a solution of tert-butyl 2-((2-(2,6-dioxopiperidin-3-yl)-1-oxo-6-(piperidin-1-yl)isoindolin-4-yl)oxy)acetate (200 mg, crude) in DCM (10 mL) was added TFA (2 mL) dropwise at 0° C. The reaction mixture was allowed to stir at ambient temperature under nitrogen for 16 hours. After complete consumption of the starting material (monitored by TLC and LCMS), the volatiles were evaporated under reduced pressure to give the crude compound, which was then purified by preparative HPLC (C18, 10 mM ammonium acetate / water:MeCN) to give 2-((2-(2,6-dioxopiperidin-3-yl)-1-oxo-6-(piperidin-1-yl)isoindolin-4-yl)oxy)acetic acid (44 mg, 0.11 mmol, 25% over two steps) as an off-white solid. LCMS (ESI): 402.3 m / z [M+H] +

[0344] Step C To a solution of 2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-6-(piperidin-1-yl)-2,3-dihydro-1H-isoindol-4-yl]oxy}acetic acid (10.7 mg, 0.027 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 (15.0 mg, 0.022 mmol), and HATU (12.7 mg, 0.033 mmol) in anhydrous DMF (2.0 mL) was added DIPEA (0.012 mL, 0.067 mmol). The mixture was stirred at room temperature for 30 minutes. The crude material was diluted with DCM and washed with brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give 35.8 mg of crude tert-butyl 6-chloro-1-{2-[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-6-(piperidin-1-yl)-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 as a yellow oil, which was used in the next step without further purification. LCMS (ESI): 1057.6 m / z [M+H] +

[0345] Step D To a solution of tert-butyl 6-chloro-1-{2-[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-6-(piperidin-1-yl)-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 (35.8 mg, crude) in DCM (0.3 mL) was added TFA (0.3 mL). The mixture was stirred at RT for 18 h. The crude material was concentrated in vacuo and purified by preparative HPLC (C18, HO:MeCN+0.1% FA) to afford 6-chloro-1-{2-[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-6-(piperidin-1-yl)-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 (6.5 mg, 0.006 mmol, 22% over two steps) as a white solid. LCMS (ESI): 1001.2 m / z [M+H] + 1H NMR (600 MHz, DMSO, 353 K) δ 10.68 (s, 1H), 8.24 (dd, J = 9.2, 5.9 Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.59 (dd, J = 10.3, 2.6 Hz, 1H), 7.44 - 7.39 (m, 2H), 7.33 (ddd, J = 9.3, 8.6, 2.6 Hz, 1H), 7.21 (d, J = 8.5 Hz, 1H), 6.87 (dd, J = 5.9, 2.7 Hz, 1H), 6.77 (d, J = 1.9 Hz, 1H), 6.71 - 6.68 (m, 1H), 5.02 (dd, J = 13.0, 5.2 Hz, 1H), 4.84 (s, 2H), 4.30 - 4.15 (m, 6H), 3.75 (d, J = 2.5 Hz, 3H), 3.39 - 3.33 (m, 4H), 3.31 - 3.25 (m, 2H), 3.21 - 3.16 (m, 4H), 2.87 (ddd, J = 17.4, 13.5, 5.5 Hz, 1H), 2.63 - 2.58 (m, 1H), 2.45 - 2.36 (m, 1H), 2.26 - 2.20 (m, 2H), 2.13 - 2.00 (m, 10H), 1.88 (s, 3H), 1.65 - 1.60 (m, 4H), 1.59 - 1.54 (m, 2H).

[0346] Example 13: 6-chloro-1-{2-[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-3-methyl-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 (Compound 15) [ka] Step A To a solution of 2-ethyl-3-methoxybenzoic acid (4.23 g, 23.5 mmol) in MeOH (120 mL) was added sulfuric acid (2.00 mL, 37.6 mmol), and the reaction was stirred at reflux for 16 h. The reaction was cooled to room temperature, and the solvent was removed in vacuo. The residue was dissolved in EtO, and saturated aqueous NaHCO and water were added. The layers were separated, and the aqueous layer was extracted twice with EtO. The combined organic layers were washed with brine, dried over NaSO, and concentrated in vacuo. The crude residue was eluted with a mixture of cyclohexane / EtO (3:2). The filtrate was concentrated to give methyl 2-ethyl-3-methoxybenzoate (3.67 g, 18.9 mmol, 80%) as a colorless oil.

[0347] Step B Methyl 2-ethyl-3-methoxybenzoate (2.67 g, 13.7 mmol) was dissolved in EtOAc (55.0 mL), and N-bromosuccinimide (2.81 g, 15.8 mmol) and benzoyl peroxide (166 mg, 0.69 mmol) were added sequentially. The reaction mixture was refluxed for 16 hours. The reaction was cooled to room temperature, and saturated aqueous NaHCO3 was added. The layers were separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude methyl 2-(1-bromoethyl)-3-methoxybenzoate was used in the next step without further purification.

[0348] Step C The impure fractions containing methyl 2-(1-bromoethyl)-3-methoxybenzoate (500 mg, crude) were dissolved in MeCN (9.2 mL). DIPEA (957 mL, 5.49 mmol) was added, followed by 3-aminopiperidine-2,6-dione hydrochloride (452.0 mg). The resulting solution was stirred under reflux for 14 hours. The reaction was cooled to room temperature, and the solvent was removed in vacuo. The residue was dissolved in EtOAc, and 1 M aqueous HCl was added. The layers were separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (SiO2, 0-20% EtOAc / cyclohexane) to afford the impure fraction of 3-(4-methoxy-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione.

[0349] Step D The impure fractions containing 3-(4-methoxy-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (40.0 mg, crude) were dissolved in DCM (1.4 mL) and cooled to 0 °C. BBr (1.0 M in DCM, 832 mL, 832 mmol) was added dropwise, and the reaction was stirred at room temperature for 2 hours. At 0 °C, saturated aqueous NaHCO was added dropwise and diluted with DCM. The layers were separated, and the aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over NaSO, and concentrated in vacuo. The crude 3-(4-hydroxy-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (38.0 mg) was used directly in the next step without further purification.

[0350] Step E 3-(4-Hydroxy-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (38.0 mg, crude) was dissolved in DMF (1.4 mL). KHCO (28.0 mg, 278 mmol) and KI (11.5 mg, 69.5 mmol) were added sequentially. tert-Butyl bromoacetate (31 mL, 208 mmol) was then added, and the reaction was heated to 70 °C for 12 h. The reaction was cooled to room temperature, and water followed by EtOAc was added. The layers were separated, and the organic layer was washed three times with water and then three times with brine. The organic fraction was dried over NaSO and concentrated in vacuo. The crude tert-butyl 2-((2-(2,6-dioxopiperidin-3-yl)-3-methyl-1-oxoisoindolin-4-yl)oxy)acetate was used directly in the next step without further purification.

[0351] Step F To a solution of tert-butyl 2-((2-(2,6-dioxopiperidin-3-yl)-3-methyl-1-oxoisoindolin-4-yl)oxy)acetate (54.0 mg, crude) in DCM (2.8 mL) at 0° C. was added TFA (0.428 mL, 3.60 mmol). The mixture was allowed to warm to room temperature and stirred for 5 h. The volatiles were removed in vacuo. The crude residue was dissolved in MeOH and concentrated in vacuo. This procedure was repeated three times to remove residual TFA. The crude residue was purified by reverse phase (C18, HO:MeCN+0.1% FA) to give the desired product (11.5 mg, 0.035 mmol, 25% over 3 steps) as a 2:1 mixture of diastereomers of 2-((2-(2,6-dioxopiperidin-3-yl)-3-methyl-1-oxoisoindolin-4-yl)oxy)acetic acid as a white solid. LCMS (ESI): 333.0 m / z [M+H] +

[0352] Step G To a solution of 2-((2-(2,6-dioxopiperidin-3-yl)-3-methyl-1-oxoisoindolin-4-yl)oxy)acetic acid (5.0 mg, 0.015 mmol) and 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 (8.5 mg, 0.013 mmol) in anhydrous DMF (2.0 mL) was added HATU (9.6 mg, 0.025 mmol) and DIPEA (0.007 mL, 0.038 mmol). The reaction was stirred at RT for 20 min. The crude material was diluted in DCM and washed with brine. The organic layer was dried over MgSO, filtered, and concentrated in vacuo to afford tert-butyl 6-chloro-1-{2-[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-3-methyl-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 (37.5 mg, crude) as a yellow oil, which was used in the next step without further purification. LCMS: (ESI) 989.1 m / z [M+H]+

[0353] Step H To a solution of tert-butyl 6-chloro-1-{2-[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-3-methyl-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 (37.5 mg, crude) in DCM (1.0 mL) was added TFA (1.0 mL, 13.059 mmol). The reaction mixture was stirred at RT for 18 h. The crude material was concentrated in vacuo and purified by preparative HPLC (C18, HO:MeCN+0.1% FA) to afford 6-chloro-1-{2-[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-3-methyl-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 (6.7 mg, 0.007 mmol, 19.1%) as a yellow solid. LCMS (ESI): 932.2 m / z [M+H] + 1H NMR (500 MHz, DMSO, 353 K) δ 10.59 (s, 0.6 H), 10.56 (s, 0.4 H), 8.24 (dd, J = 9.3, 5.9 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.58 (dd, J = 10.4, 2.6 Hz, 1H), 7.44 - 7.39 (m, 3H), 7.32 (td, J = 8.9, 2.6 Hz, 1H), 7.28 - 7.25 (m, 1H), 7.21 (d, J = 8.5 Hz, 1H), 7.16 - 7.12 (m, 1H), 6.87 (dd, J = 5.7, 2.9 Hz, 1H), 4.88 (s, 2H), 4.82 - 4.75 (m, 0.4 H), 4.73 - 4.63 (m, 1.6 H), 4.31 - 4.23 (m, 3H), 4.22 - 4.16 (m, 1H), 3.76 (s, 3H), 3.40 - 3.34 (m, 4H), 3.30 - 3.26 (m, 2H), 2.87 - 2.55 (m, 3H), 2.27 - 2.21 (m, 2H), 2.16 - 2.03 (m, 7H), 2.01 (s, 3H), 1.89 (s, 3H), 1.52 (d, J = 6.6 Hz, 1H), 1.50 (d, J = 6.6 Hz, 2H).

[0354] Example 14: 6-chloro-1-(2-(4-(2-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-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 (Compound 21) [ka] Step A 9-Hydroxy-2-azatricyclo[6.3.1.0 4 , 12]dodeca-1(11),4,6,8(12),9-pentaen-3-one (25.1 mg, 0.135 mmol) was dissolved in anhydrous DMF (1.4 mL) under an argon atmosphere and Cs2CO3 (132.3 mg, 0.406 mmol) was added. The reaction was stirred at room temperature for 10 minutes, and tert-butyl 2-bromoacetate (0.020 mL, 0.135 mmol) was added. The reaction (monitored by LCMS) was stirred at room temperature under argon for 90 minutes. After complete consumption of the starting material, DCM (10 mL) was added and the solution was washed with brine and water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The resulting residue was dissolved in DMSO and purified by reverse-phase preparative HPLC to give tert-butyl 2-({3-oxo-2-azatricyclo[6.3.1.0]. 4 , 12 ]dodeca-1(11),4,6,8(12),9-pentaen-9-yl}oxy)acetate (25.3 mg, 0.085 mmol, 62.4%) was obtained. LCMS (ESI): 300.1 m / z [M+H] +

[0355] Step B tert-Butyl 2-({3-oxo-2-azatricyclo[6.3.1.0 4 , 12To a well-stirred solution of ]dodeca-1(11),4,6,8(12),9-pentaen-9-yl}oxy)acetate (25.3 mg, 0.085 mmol) in DMF (2 mL), NaH (50.7 mg, 1.268 mmol) was added 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 (162.3 mg, 0.845 mmol) in DMF (2 mL) was slowly added dropwise to the reaction mixture at 0° C. and the reaction mass was stirred at the same temperature for 5 minutes. The mixture was then heated to 80° C. and the reaction (monitored by TLC (SiO2, 70% ethyl acetate / isohexane) continued for 2 h under nitrogen. The reaction was cooled to −80° C. and quenched with solid ammonium chloride. The mixture was slowly allowed to warm to room temperature and diluted with DCM. The mixture was filtered through a Schott funnel and the separated solid was washed with DCM. The filtrate was concentrated and dried under reduced pressure. The crude product was purified by preparative TLC (SiO2, 70% EtOAc / isohexane) to give tert-butyl 2-{[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2-azatricyclo[6.3.1.0] 4 , 12 ]dodeca-1(11),4,6,8(12),9-pentaen-9-yl]oxy}acetate (10.6 mg, 0.026 mmol, 30.4%) as a yellow solid. LCMS (ESI): 411.0 m / z [M+H] +

[0356] Step C tert-Butyl 2-{[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2-azatricyclo[6.3.1.0 4 , 12]dodeca-1(11),4,6,8(12),9-pentaen-9-yl]oxy}acetate (10.6 mg, 0.026 mmol) was dissolved in anhydrous DCM (0.50 mL) under an argon atmosphere, and TFA (0.500 mL, 6.529 mmol) was added. The reaction was stirred at room temperature under argon. After 16 h, LCMS indicated complete consumption of the starting material. The solution was concentrated to dryness under reduced pressure. The resulting residue was dissolved twice in 1 M aqueous HCl (1 mL) and concentrated under vacuum. 2-{[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2-azatricyclo[6.3.1.0 4 , 12 ]dodeca-1(11),4,6,8(12),9-pentaen-9-yl]oxy}acetic acid (9.0 mg, 0.025 mmol, 98.8%) was obtained as a yellow solid. The reaction product was used in the next step without further purification. LCMS (ESI): 355.3 m / z [M+H] +

[0357] Step D 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 (14.3 mg, 0.021 mmol) and 2-{[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2-azatricyclo[6.3.1.0 4 , 12[Dodeca-1(11),4,6,8(12),9-pentaen-9-yl]oxy}acetic acid (9.0 mg, 0.025 mmol) was dissolved in anhydrous DMF (1.0 mL) under an argon atmosphere. To this was added DIPEA (0.011 mL, 0.064 mmol), followed by the dropwise addition of HATU (8.5 mg, 0.022 mmol) as a DMF solution (1.0 mL). The reaction (monitored by LCMS) was stirred at room temperature for 20 minutes under argon. After complete consumption of the starting material, the solution was diluted to 10 mL with DCM and washed with brine and water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure to give crude tert-butyl 6-chloro-1-(2-(4-(2-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-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 (22.5 mg) as a yellow oil. The reaction product was used in the next step without further purification. LCMS (ESI): 1010.2 m / z [M+H] +

[0358] Step E Crude tert-butyl 6-chloro-1-(2-(4-(2-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-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 (22.5 mg) was dissolved in anhydrous DCM (0.50 mL) under an argon atmosphere and TFA (0.50 mL) was added. The reaction (monitored by LCMS) was stirred at room temperature under argon for 16 hours. After complete consumption of the starting material, the solution was concentrated under reduced pressure. The resulting residue was dissolved in DMSO and purified by reverse-phase HPLC (C18, HO:MeCN+0.1% FA) to afford 6-chloro-1-(2-(4-(2-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-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 (9.1 mg, 0.010 mmol, 47.6% over two steps) as a yellow solid. LCMS (ESI): 954.15 m / z [M+H] + 1H NMR (500 MHz, DMSO, 353 K) δ 10.77 (s, 1H), 8.29 (dd, J = 8.2, 0.7 Hz, 1H), 8.24 (dd, J = 9.2, 5.9 Hz, 1H), 8.08 (dd, J = 7.1, 0.6 Hz, 1H), 7.83 (dd, J = 8.2, 7.0 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.58 (dd, J = 10.4, 2.6 Hz, 1H), 7.45 - 7.37 (m, 2H), 7.32 (ddd, J = 9.2, 8.6, 2.6 Hz, 1H), 7.20 (d, J = 8.5 Hz, 1H), 6.97 (d, J = 7.8 Hz, 1H), 6.91 - 6.81 (m, 2H), 5.35 (dd, J = 12.6, 5.5 Hz, 1H), 4.91 (s, 2H), 4.33 - 4.22 (m, 3H), 4.18 (ddd, J = 13.9, 7.9, 5.8 Hz, 1H), 3.74 (s, 3H), 3.47 - 3.35 (m, 4H), 3.32 - 3.23 (m, 2H), 2.93 (ddd, J = 16.7, 12.9, 5.4 Hz, 1H), 2.79 - 2.65 (m, 2H), 2.28 - 2.20 (m, 2H), 2.18 - 2.02 (m, 7H), 1.99 (s, 3H), 1.88 (s, 3H).

[0359] Example 15: 6-chloro-1-{2-[4-(2-{3-[(2,6-dioxopiperidin-3-yl)carbamoyl]-2-ethylphenoxy}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 (Compound 24) [ka] Step A To a well-stirred solution of 2-ethyl-3-hydroxybenzoic acid (600 mg, 3.614 mmol) in DMF (12 mL) was added HATU (1.643 g, 4.337 mmol) and DIPEA (1.26 mL, 7.23 mmol) sequentially under nitrogen at RT. The reaction mixture was then stirred at RT for 15 minutes. 3-Aminopiperidine-2,6-dione (873 mg, 5.422 mmol) was added to the reaction mixture, and the resulting reaction mixture was stirred at RT for an additional hour. After complete consumption of the starting material (monitored by LC-MS), the reaction mixture was quenched by adding ice water, evaporated in vacuo, diluted with DCM, washed with saturated sodium bicarbonate solution, water, and brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to give the crude compound, which was purified by column chromatography (SiO2, 50-60% ethyl acetate / DCM) to give N-(2,6-dioxopiperidin-3-yl)-2-ethyl-3-hydroxybenzamide (400 mg, 1.45 mmol, 40%) as a white solid. LCMS (ESI): 278.8 m / z [M+H] +

[0360] Step B To a well-stirred solution of N-(2,6-dioxopiperidin-3-yl)-2-ethyl-3-hydroxybenzamide (400 mg, 1.45 mmol) in DMF (5 mL) was added potassium bicarbonate (435 mg, 4.34 mmol) and tert-butyl bromoacetate (0.213 mL, 1.45 mmol) sequentially at room temperature under nitrogen. The reaction mixture was stirred at 60° C. for 1 hour. After complete consumption of the starting material, the reaction mixture was diluted with ethyl acetate and washed successively with water and brine. The organic layer was dried over sodium sulfate and evaporated under reduced pressure to give the crude compound, which was then purified by preparative HPLC (10 mM ammonium acetate:ACN) to give tert-butyl 2-(3-((2,6-dioxopiperidin-3-yl)carbamoyl)-2-ethylphenoxy)acetate (80 mg, 0.204 mmol, 14%) as a white solid. LCMS (ESI): 391.27 m / z [M+H] +

[0361] Step C To a stirred solution of tert-butyl 2-(3-((2,6-dioxopiperidin-3-yl)carbamoyl)-2-ethylphenoxy)acetate (70 mg, 0.179 mmol) in dichloromethane (3 ml), TFA (1 ml) was added dropwise to the reaction mixture at 0° C., and the reaction mixture was allowed to stir at ambient temperature for 16 hours under nitrogen. After complete consumption of the starting material, 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-{3-[(2,6-dioxopiperidin-3-yl)carbamoyl]-2-ethylphenoxy}acetic acid (55 mg, 0.164 mmol, 91.6%) as an off-white solid. LCMS (ESI): 333.2 m / z [M+H] +

[0362] Step D To a solution of 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-{3-[(2,6-dioxopiperidin-3-yl)carbamoyl]-2-ethylphenoxy}acetic acid (11.9 mg, 0.036 mmol), and HATU (16.9 mg, 0.044 mmol) in anhydrous DMF (2.0 mL) was added DIPEA (0.026 mL, 0.148 mmol). The mixture was stirred at RT for 30 minutes. The crude material was diluted with DCM and washed with brine. The organic layer was dried over MgSO, filtered, and concentrated in vacuo to afford 38.9 mg of crude tert-butyl 6-chloro-1-{2-[4-(2-{3-[(2,6-dioxopiperidin-3-yl)carbamoyl]-2-ethylphenoxy}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 in the next step without further purification. LCMS (ESI): 991.0 m / z [M+H] +

[0363] Step E To a solution of tert-butyl 6-chloro-1-{2-[4-(2-{3-[(2,6-dioxopiperidin-3-yl)carbamoyl]-2-ethylphenoxy}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 (38.9 mg, crude) in DCM (1.0 mL) was added TFA (1.0 mL, 13.059 mmol). The mixture was stirred at RT for 18 h. The crude material was concentrated in vacuo and purified by preparative HPLC (HO:ACN+0.1% FA) to afford 6-chloro-1-{2-[4-(2-{3-[(2,6-dioxopiperidin-3-yl)carbamoyl]-2-ethylphenoxy}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 (11.0 mg, 0.012 mmol, 30.0%) as a white solid. LCMS (ESI): 934.2 m / z [M+H] + 1H NMR (500 MHz, DMSO, 353 K) δ 10.48 (s, 1H), 8.24 (dd, J = 9.2, 5.9 Hz, 2H), 7.69 (d, J = 8.4 Hz, 1H), 7.58 (dd, J = 10.3, 2.8 Hz, 1H), 7.45 - 7.39 (m, 2H), 7.33 (td, J = 8.9, 2.7 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.16 (t, J = 7.9 Hz, 1H), 6.98 - 6.92 (m, 2H), 6.87 (dd, J = 5.8, 2.9 Hz, 1H), 4.75 (s, 2H), 4.69 (ddd, J = 11.3, 8.3, 5.6 Hz, 1H), 4.31 - 4.23 (m, 3H), 4.22 - 4.15 (m, 1H), 3.76 (s, 3H), 3.41 - 3.36 (m, 4H), 3.30 - 3.24 (m, 2H), 2.80 - 2.71 (m, 3H), 2.61 - 2.54 (m, 1H), 2.27 - 2.21 (m, 2H), 2.15 - 2.04 (m, 8H), 2.01 (s, 3H), 1.89 (s, 3H), 1.12 (t, J = 7.3 Hz, 3H).

[0364] Example 16: 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 (Compound 22) [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 material was purified by flash column chromatography (SiO, 50% EtOAc / hexanes) to afford tert-butyl 2-(3-(methylamino)-4-nitrophenoxy)acetate (400 mg, 1.418 mmol, 77%) as a brown liquid. LCMS (ESI): 283.2 m / z [M+H] +

[0365] 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) was then 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 reaction product was purified by column chromatography (SiO, 70% EtOAc / 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] +

[0366] 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 the reaction was complete, the volatiles were evaporated and the crude material was purified by column chromatography (SiO, 50-60% EtOAc / hexane) to give 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] +

[0367] 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) portionwise at 0° C. under nitrogen. The reaction mixture was allowed to stir 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., and the reaction mixture was allowed to stir at the same temperature for 5 minutes. The mixture was then heated to 80° C. and stirred under nitrogen for the next 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 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 three times with EtOAc. The combined organic layers were washed with brine and evaporated under reduced pressure to give crude tert-butyl 2-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oxy)acetate. The product was purified by preparative TLC (SiO, 60% EtOAc / 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] +

[0368] 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 allowed to stir under nitrogen at ambient temperature for 16 h. 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 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] +

[0369] 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 anhydrous DMF (0.989 mL) under an argon atmosphere, and DIPEA (0.016 mL, 0.089 mmol) followed by HATU (11.8 mg, 0.031 mmol) were added. 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 (2 × 10 mL) and water (2 × 10 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness to afford 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] +

[0370] 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 anhydrous DCM (0.500 mL) under an argon atmosphere and TFA (0.500 mL) was added. The reaction (monitored by LCMS) 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-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] + 1H NMR (500 MHz, DMSO, 353 K) δ 10.77 (s, 1H), 8.24 (dd, J = 9.2, 5.9 Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.58 (dd, J = 10.4, 2.6 Hz, 1H), 7.45 - 7.38 (m, 2H), 7.32 (td, J = 8.9, 2.6 Hz, 1H), 7.21 (d, J = 8.5 Hz, 1H), 6.96 (d, J = 8.6 Hz, 1H), 6.87 (dd, J = 5.8, 2.8 Hz, 1H), 6.82 (d, J = 2.4 Hz, 1H), 6.62 (dd, J = 8.6, 2.5 Hz, 1H), 5.25 (dd, J = 12.5, 5.5 Hz, 1H), 4.69 (s, 2H), 4.36 - 4.22 (m, 3H), 4.18 (ddd, J = 13.9, 7.8, 5.9 Hz, 1H), 3.75 (s, 3H), 3.40 - 3.35 (m, 4H), 3.30 (s, 3H), 3.29 - 3.25 (m, 2H), 2.92 - 2.83 (m, 1H), 2.73 - 2.61 (m, 2H), 2.28 - 2.20 (m, 2H), 2.17 - 2.01 (m, 7H), 2.01 (s, 3H), 1.88 (s, 3H).

[0371] Example 17: 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 (Compound 23) [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 to the reaction mixture, which was then stirred at 60 °C for 5 hours under nitrogen. 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 evaporated under reduced pressure to give the crude compound, which was then purified by column chromatography (SiO, 0-10% EtOAc / hexane) to give tert-butyl 2-(2-fluoro-3-nitrophenoxy)acetate (1.6 g, 5.90 mmol, 92%) as a yellow solid.

[0372] 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 allowed to stir at 50° C. for 2 h. After complete consumption of the starting material, the volatiles were removed under reduced pressure, and the crude material was purified by column chromatography (SiO, 50% EtOAc / 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] +

[0373] 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 minutes. Pd / C (370 mg) was then added slowly under argon. 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. The crude material was purified by column chromatography (SiO, 70% EtOAc / 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] +

[0374] 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. After the reaction was complete, the volatiles were removed under reduced pressure, and the crude material was purified by column chromatography (SiO, 50-60% EtOAc / hexanes) to give 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] +

[0375] Step E To a well-dissolved 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), NaH (388 mg, 8.1 mmol) was added portionwise at 0° C. under nitrogen, 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., which was stirred for 5 minutes. The mixture was then heated to 80° C., and the reaction was continued for 2 hours under nitrogen. After complete consumption of the starting material (monitored by LCMS), the reaction mixture was cooled to −78° C., diluted with EtOAc, and stirred for another 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 2-3 times with EtOAc. The combined organic layers were washed with brine and evaporated under reduced pressure. The crude compound was purified by preparative TLC (SiO, 60% EtOAc / 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] +

[0376] 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) was added TFA (1 mL) dropwise at 0° C., and the reaction mixture was stirred at ambient temperature for 16 h under nitrogen. After complete consumption of the starting material, 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] +

[0377] 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) and 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) were dissolved in anhydrous DMF (1.0 mL) under an argon atmosphere, and DIPEA (0.016 mL, 0.089 mmol) followed by HATU (11.8 mg, 0.031 mmol) were added as a DMF solution (1.0 mL). The reaction (monitored by LCMS) was stirred at room temperature for 15 minutes under argon. After complete conversion of the starting material, the solution was diluted to 10 mL with DCM. The resulting solution was washed with brine (2 × 10 mL) and water (2 × 10 mL), dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. 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] +

[0378] 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 anhydrous 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] + 1H NMR (500 MHz, DMSO, 353 K) δ 10.75 (s, 1H), 8.24 (dd, J = 9.3, 5.9 Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.58 (dd, J = 10.4, 2.6 Hz, 1H), 7.46 - 7.38 (m, 2H), 7.32 (td, J = 8.9, 2.6 Hz, 1H), 7.21 (d, J = 8.5 Hz, 1H), 6.93 (t, J = 8.2 Hz, 1H), 6.87 (dd, J = 5.6, 3.0 Hz, 1H), 6.78 - 6.67 (m, 2H), 5.31 - 5.23 (m, 1H), 4.84 (s, 2H), 4.35 - 4.12 (m, 4H), 3.75 (s, 3H), 3.57 (s, 3H), 3.41 - 3.33 (m, 4H), 3.31 - 3.25 (m, 2H), 2.92 - 2.85 (m, 1H), 2.74 - 2.62 (m, 2H), 2.28 - 2.20 (m, 2H), 2.16 - 2.02 (m, 7H), 2.01 (s, 3H), 1.88 (s, 3H).

[0379] Example 18: 6-chloro-1-(2-{4-[({[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]methyl}carbamoyl)methyl]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 (Compound 26) [ka] Step A To a solution of 3-[5-(aminomethyl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione hydrochloride (50.0 mg, 0.161 mmol) in DMF (1.5 mL) was added DIPEA (0.042 mL, 0.242 mmol) followed by chloroacetyl chloride (0.014 mL, 0.178 mmol). The mixture was stirred at RT overnight. DMF was evaporated, and the resulting residue was partitioned between EtOAc and HO. The organic layer was further washed with brine, dried over NaSO, filtered, and evaporated. 2-Chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)acetamide (60.0 mg, 0.161 mmol, 99.8%) was obtained as an orange-colored solid. LCMS (ESI): 349.9 m / z [M+H] +

[0380] Step B 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 (35.0 mg, 0.052 mmol) and 2-chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)acetamide (23.6 mg, 0.067 mmol) were dissolved in DMF (1.0 mL). Then, KI (8.6 mg, 0.052 mmol) and DIPEA (0.027 mL, 0.156 mmol) were added, and the mixture was stirred at 70 °C for 24 hours. After the reaction was completed, DMF was evaporated, and the resulting residue was partitioned between EtOAc and water. The organic layer was further washed with brine, dried over sodium sulfate, filtered, and evaporated. The desired product was purified by preparative TLC (SiO, 10% MeOH / DCM). tert-Butyl 6-chloro-1-(2-(4-(2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)amino)-2-oxoethyl)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 (13.0 mg, 0.012 mmol, 22.3%) was obtained as an orange oil. LCMS (ESI): 986.9 m / z [M+H] +

[0381] Step C To a stirred solution of tert-butyl 6-chloro-1-(2-(4-(2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)amino)-2-oxoethyl)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 (16.0 mg, 0.016 mmol) in DCM (1.0 mL) at 0° C. was added TFA (1.0 mL) dropwise, and the resulting reaction mixture was stirred at room temperature for 1 day. After complete consumption of the starting material, the reaction mixture was concentrated under reduced pressure. The crude material was then purified by reverse-phase column chromatography (C18, HO:MeCN+0.1% FA) to afford 6-chloro-1-(2-{4-[({[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]methyl}carbamoyl)methyl]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 (4.9 mg, 0.005 mmol, 32.5%) as a white solid. LCMS (ESI): 931.2 m / z [M+H] + 1H NMR (500 MHz, DMSO) δ = 10.97 (s, 1H), 8.30 (t, J=6.3, 1H), 8.24 (dd, J=9.2, 5.9, 1H), 7.72 - 7.61 (m, 3H), 7.47 - 7.40 (m, 3H), 7.40 - 7.32 (m, 2H), 7.18 (d, J=8.5, 1H), 6.87 (dd, J=5.2, 3.5, 1H), 5.10 (dd, J=13.3, 5.1, 1H), 4.46 - 4.35 (m, 3H), 4.33 - 4.23 (m, 2H), 4.19 (t, J=6.2, 2H), 4.16 - 4.09 (m, 1H), 3.70 (d, J=3.7, 3H), 3.22 (t, J=7.6, 2H), 2.97 - 2.84 (m, 3H), 2.62 - 2.55 (m, 1H), 2.53 - 2.51 (m, 1H), 2.44 - 2.29 (m, 5H), 2.25 - 2.11 (m, 6H), 2.11 - 2.04 (m, 1H), 2.03 - 1.96 (m, 4H), 1.86 (s, 3H).

[0382] Example 19: 6-chloro-3-[3-(4-chloro-3,5-dimethylphenoxy)propyl]-1-(2-{4-[({[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]methyl}carbamoyl)methyl]piperazin-1-yl}ethyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (Compound 27) [ka] Step A 6-Chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (3.3 g, 6.613 mmol) was suspended in toluene (30 mL) and the mixture was heated to reflux under nitrogen. N,N-Dimethylformamide di-tert-butyl acetal (12.655 mL, 52.906 mmol) was added dropwise to the refluxing mixture. The mixture was heated at reflux for 16 hours under nitrogen. After complete consumption of the starting material, the reaction mixture was diluted with ethyl acetate and washed successively with sodium bicarbonate (saturated), water, and brine; the organic layer was dried over sodium sulfate and evaporated under reduced pressure to give the crude compound, which was then purified by column chromatography on (SiO, 70% ethyl acetate / hexanes) to give tert-butyl 6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (2.3 g, 4.136 mmol, 62.49%) as a light brown solid. LCMS (ESI): 556.1 m / z [M+H] +

[0383] Step B To a well-stirred solution of tert-butyl 6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (1.6 g, 2.883 mmol) in DMF (20 ml) was added the compound tert-butyl 4-(2-chloroethyl)piperazine-1-carboxylate (1.435 g, 5.766 mmol), followed by cesium carbonate (4.685 g, 14.414 mmol) in DMF (20 ml), and the mixture was stirred at 90° C. for 16 hours under nitrogen. After complete consumption of the starting material, the reaction mixture was diluted with ethyl acetate and washed successively with water and brine, the organic layer was dried over sodium sulfate and evaporated under reduced pressure to give the crude compound, which was then purified by column chromatography (SiO, ethyl acetate / hexanes) to give tert-butyl 1-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)-6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (1.6 g, 2.083 mmol, 72.19%) as an off-white solid. LCMS (ESI): 768.6 m / z [M+H] +

[0384] Step C tert-Butyl 1-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)-6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (0.5 g, 0.652 mmol) was dissolved in 10 ml of 4 M HCl / dioxane at 0° C., and the mixture was stirred at the same temperature for 2 hours under nitrogen. After complete consumption of the starting material, the reaction mixture was poured into cold 1 M NaOH solution and extracted several times with dichloromethane. The combined organics were dried over sodium sulfate and concentrated in vacuo to give the crude compound, which was then purified by column chromatography (SiO, 10% methanol / dichloromethane) to give tert-butyl 6-chloro-3-[3-(4-chloro-3,5-dimethylphenoxy)propyl]-1-[2-(piperazin-1-yl)ethyl]-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (0.2 g, 0.299 mmol, 45.88%) as an off-white solid. LCMS (ESI): 668.2 m / z [M+H] +

[0385] Step D Tert-butyl 6-chloro-3-[3-(4-chloro-3,5-dimethylphenoxy)propyl]-1-[2-(piperazin-1-yl)ethyl]-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (35.0 mg, 0.052 mmol) and 2-chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)acetamide (23.8 mg, 0.068 mmol) were dissolved in DMF (1.0 mL). Then, KI (8.7 mg, 0.052 mmol) and DIPEA (0.027 mL, 0.157 mmol) were added, and the mixture was stirred at 70 °C for 24 h. After the reaction was completed, DMF was evaporated, and the resulting residue was partitioned between EtOAc and HO. The organic layer was further washed with brine, dried over Na2SO4, filtered, and evaporated. The desired product was purified by preparative TLC (SiO2, 5% MeOH / DCM). tert-Butyl 6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1-(2-(4-(2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)amino)-2-oxoethyl)piperazin-1-yl)ethyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (16.0 mg, 0.014 mmol, 27.4%) was obtained as an orange sticky oil, which was used in the next step without further purification. LCMS (ESI): 980.99 m / z [M+H] +

[0386] Step E To a solution of tert-butyl 6-chloro-3-[3-(4-chloro-3,5-dimethylphenoxy)propyl]-1-(2-{4-[({[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]methyl}carbamoyl)methyl]piperazin-1-yl}ethyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (16.0 mg, 0.016 mmol) in DCM (0.815 mL) at 0° C., TFA (1.0 mL, 13.059 mmol) was added dropwise, and the resulting reaction mixture was stirred at room temperature for 1 day. After complete consumption of the starting material, the reaction mixture was concentrated under reduced pressure. The crude material was then purified by reverse-phase column chromatography (C18, HO:MeCN+0.1% FA) to afford 6-chloro-3-[3-(4-chloro-3,5-dimethylphenoxy)propyl]-1-(2-{4-[({[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]methyl}carbamoyl)methyl]piperazin-1-yl}ethyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (6.0 mg, 0.006 mmol, 39.6%) as a white solid. LCMS (ESI): 925.25 m / z [M+H] + 1H NMR (500 MHz, DMSO) δ = 10.97 (s, 1H), 8.30 (t, J=6.3, 1H), 7.70 - 7.60 (m, 2H), 7.44 (s, 1H), 7.38 (d, J=7.8, 1H), 7.22 (d, J=8.5, 1H), 6.73 (s, 2H), 5.10 (dd, J=13.3, 5.1, 1H), 4.47 - 4.33 (m, 3H), 4.33 - 4.22 (m, 2H), 4.18 - 4.06 (m, 1H), 3.96 (t, J=6.5, 2H), 3.71 (d, J=3.5, 3H), 3.09 (t, J=7.4, 2H), 2.97 - 2.84 (m, 3H), 2.64 - 2.55 (m, 1H), 2.54 - 2.50 (m, 1H), 2.46 - 2.29 (m, 5H), 2.26 (s, 6H), 2.23 - 2.05 (m, 5H), 2.05 - 1.96 (m, 6H), 1.87 (s, 3H).

[0387] Example 20: 6-chloro-1-{2-[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}acetyl)-2,6-dimethylpiperazin-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 (Compound 28) [ka] Step A tert-Butyl 4-(2-hydroxyethyl)-3,5-dimethylpiperazine-1-carboxylate (52 mg, 0.201 mmol) was dissolved in DCM (4.0 mL), EtN (0.084 mL, 0.604 mmol) and DMAP (2.5 mg, 0.020 mmol) were added, and the reaction mixture was cooled to 0 °C. MsCl (0.031 mL, 0.403 mmol) was then added dropwise, and the reaction mixture was allowed to stir at RT for 2 h. The crude material was washed with brine, dried over MgSO, filtered, and concentrated in vacuo. The isolated product, tert-butyl 4-[2-(methanesulfonyloxy)ethyl]-3,5-dimethylpiperazine-1-carboxylate (45 mg, crude), was an orange oil.

[0388] Step B 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 (25.0 mg, 0.044 mmol), tert-butyl 4-[2-(methanesulfonyloxy)ethyl]-3,5-dimethylpiperazine-1-carboxylate (45 mg, crude), and CsCO (58.0 mg, 0.178 mmol) were dissolved in anhydrous DMF (2.0 mL) under an inert atmosphere and stirred at 60° C. for 18 h. After complete consumption of the starting material, the reaction was dissolved in DCM and washed with brine. The organic layer was dried over MgSO, filtered, and concentrated in vacuo to give 35.0 mg crude tert-butyl 1-(2-{4-[(tert-butoxy)carbonyl]-2,6-dimethylpiperazin-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 as a yellow oil. LCMS (ESI): 802.4 m / z [M+H] +

[0389] Step C To a solution of tert-butyl 1-(2-{4-[(tert-butoxy)carbonyl]-2,6-dimethylpiperazin-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 (35 mg, crude) in THF (4.0 mL) was added 4 M HCl in dioxane (2.0 mL, 8.000 mmol) at 0 °C. The mixture was stirred at RT for 40 h. The solvent was evaporated to give tert-butyl 6-chloro-1-[2-(2,6-dimethylpiperazin-1-yl)ethyl]-3-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate hydrochloride (28.9 mg, crude) as a yellow solid, which was used in the next step without further purification. LCMS (ESI): 702.4 m / z [M+H] +

[0390] Step D To a solution of tert-butyl 6-chloro-1-[2-(2,6-dimethylpiperazin-1-yl)ethyl]-3-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate hydrochloride (28.9 mg, crude), 2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}acetic acid (14.9 mg, 0.047 mmol) in anhydrous DMF (1.8 mL) was added HATU (29.7 mg, 0.078 mmol) and DIPEA (0.020 mL, 0.117 mmol). The mixture was stirred at RT for 25 min. The crude material was purified by preparative HPLC (C18, HO:MeCN+0.1% FA) to afford 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)-2,6-dimethylpiperazin-1-yl]ethyl}-3-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (8.0 mg, 0.008 mmol, 19% over 3 steps) as a white powder. LCMS (ESI): 1002.3 m / z [M+H] +

[0391] Step E A solution of 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)-2,6-dimethylpiperazin-1-yl]ethyl}-3-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (8.0 mg, 0.008 mmol) in FA (1.0 mL, 23.400 mmol) was stirred at 55° C. for 14 hours. The crude material was then concentrated in vacuo 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)-2,6-dimethylpiperazin-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 (5.5 mg, 0.006 mmol, 72.8%) as a white solid. LCMS (ESI): 946.2 m / z [M+H] + 1H NMR (500 MHz, DMSO, 353 K) δ 10.64 (s, 1H), 8.26 (dd, J = 9.2, 5.9 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.59 (dd, J = 10.4, 2.6 Hz, 1H), 7.47 - 7.40 (m, 3H), 7.37 - 7.29 (m, 2H), 7.23 (d, J = 8.5 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 6.88 (dd, J = 5.2, 3.4 Hz, 1H), 5.05 (dd, J = 13.0, 5.2 Hz, 1H), 4.90 (s, 2H), 4.39 (d, J = 17.1 Hz, 1H), 4.34 - 4.26 (m, 2H), 4.28 - 4.18 (m, 3H), 3.76 (s, 3H), 3.30 - 3.23 (m, 2H), 2.88 (ddd, J = 17.4, 13.4, 5.5 Hz, 1H), 2.67 - 2.59 (m, 1H), 2.39 - 2.34 (m, 1H), 2.29 - 2.20 (m, 2H), 2.09 - 1.98 (m, 5H), 1.91 (s, 3H), 1.34 - 1.25 (m, 4H), 0.69 (d, J = 6.3 Hz, 3H), 0.66 (d, J = 6.3 Hz, 3H). Three protons in the aliphatic region overlap with DMSO.

[0392] Example 21: 6-chloro-1-{2-[4-({[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]carbamoyl}methyl)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 (Compound 29) [ka] Step A To a solution of 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 (106.0 mg, 0.157 mmol) in THF (1.0 mL) was added 4 M HCl in dioxane (2.1 mL, 61.053 mmol). The mixture was stirred at room temperature for 18 h and then at 40° C. for 18 h. The crude material was concentrated in vacuo and dissolved in 1M HCl to give 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-carboxylic acid hydrochloride (107.0 mg, 0.163 mmol, quantitative) as a white solid. LCMS (ESI): 618.3 m / z [M+H] +

[0393] Step B To a stirred solution of 2-chloro-N-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]acetamide (16.2 mg, 0.048 mmol) and DIPEA (0.024 mL, 0.137 mmol) in DMF (0.600 mL) was added 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-carboxylic acid hydrochloride (30.0 mg, 0.046 mmol). The mixture was stirred at 70 °C overnight. The solvent was removed under reduced pressure, and the desired product was purified using flash chromatography (SiO, DCM:MeOH gradient with 0-10% MeOH) followed by preparative HPLC (HO:MeCN+0.1% FA) to afford 6-chloro-1-{2-[4-({[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]carbamoyl}methyl)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 (1.3 mg, 0.001 mmol, 3.2%) as a white solid. LCMS (ESI): 917.2 m / z [M+H] + 1H NMR (500 MHz, DMSO, 353 K) δ = 10.68 (s, 1H), 9.43 (s, 1H), 8.25 (dd, J=9.3, 5.9, 1H), 7.80 (ddd, J=7.7, 3.5, 1.3, 1H), 7.67 (d, J=8.5, 1H), 7.58 (dd, J=10.3, 2.6, 1H), 7.55 - 7.45 (m, 2H), 7.45 - 7.38 (m, 2H), 7.33 (td, J=9.0, 2.6, 1H), 7.19 (d, J=8.5, 1H), 6.87 (dd, J=5.4, 3.3, 1H), 5.07 (ddd, J=13.0, 5.2, 2.4, 1H), 4.40 (d, J=4.0, 2H), 4.33 - 4.19 (m, 3H), 4.23 - 4.13 (m, 1H), 3.75 (s, 3H), 3.32 - 3.21 (m, 2H), 3.11 (s, 2H), 2.93 - 2.83 (m, 1H), 2.68 - 2.60 (m, 1H), 2.43 - 2.34 (m, 1H), 2.28 - 2.08 (m, 8H), 2.11 - 2.03 (m, 1H), 2.02 (s, 3H), 1.89 (s, 3H). Note: Four protons in the aliphatic region overlap with signals from the solvent.

[0394] Example 22: 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-7-(2-ethyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-3-yl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-1H-indole-2-carboxylic acid (Compound 36) [ka] Step A To a stirred solution of 4-bromo-3-ethyl-1H-pyrazole (6 g, 34.28 mmol) in MeCN (150 mL) was added dropwise CsCO (16.711 g, 51.42 mmol) followed by a solution of (2-bromoethoxy)(tert-butyl)dimethylsilane (8.19 mL, 37.70 mmol) at ambient temperature under nitrogen. The reaction mixture was allowed to stir at room temperature 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 washed with diethyl ether (50 mL). The filtrate was concentrated, and the resulting residue was purified by column chromatography (SiO, 0-5% EtOAc / n-hexane) to give 4-bromo-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-ethyl-1H-pyrazole (5.5 g, 16.51 mmol) as a colorless oil. LCMS (ESI): 334.9 m / z [M+H] +

[0395] Step B To a well-stirred solution of 2M LDA (18.61 mL, 36.32 mmol) in THF, a THF solution (50 mL) of 4-bromo-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-ethyl-1H-pyrazole (5.5 g, 16.51 mmol) was added dropwise at −78° C. under nitrogen. The reaction mixture was stirred at the same temperature for 30 minutes. To this mixture, DMF (6.356 mL, 82.55 mmol) was added dropwise at −78° C., and the resulting reaction mixture was stirred at the same temperature for another hour. After complete consumption of the starting material (monitored by TLC and LCMS), the excess LDA was quenched with saturated ammonium chloride. The reaction mixture was diluted with ethyl acetate 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 then purified by column chromatography (SiO, 15-20% EtOAc / n-hexane) to give 4-bromo-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-ethyl-1H-pyrazole-5-carbaldehyde (3 g, 8.31 mmol, 50%) as a white sticky solid. LCMS (ESI): 362.9 m / z [M+H] +

[0396] Step C To a stirred solution of 4-bromo-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-ethyl-1H-pyrazole-5-carbaldehyde (3 g, 8.31 mmol) in 2-methyl THF (6 mL) and water (6 mL) was added TFA (12 mL) dropwise at RT under nitrogen. The reaction mixture was allowed to stir at RT for 1 h. After complete consumption of the starting material (monitored by TLC and LCMS), the volatiles were evaporated under reduced pressure. The crude mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution, water, and brine. The organic layer was dried over sodium sulfate and evaporated under reduced pressure to give crude 3-bromo-2-ethyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-4-ol (1.8 g) as a white solid, which was then used directly in the next step without further purification. LCMS (ESI): 249.0 m / z [M+H] +

[0397] Step D To a well-stirred solution of crude 3-bromo-2-ethyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-4-ol (1.8 g, 7.28 mmol) in DCM (35 mL) was added TFA (4.98 mL, 43.725 mmol) and triethylsilane (2.53 mL, 21.86 mmol) at 0 °C under nitrogen. The reaction mixture was stirred at 0 °C for 1 h. Then, trifluoroacetic acid (4.98 mL, 43.72 mmol) and triethylsilane (2.53 mL, 21.86 mmol) were added again in succession, and the reaction mixture was stirred at RT for 16 h. After complete consumption of the starting material (monitored by TLC and LCMS), the volatiles of the reaction mixture were evaporated under reduced pressure. The crude mass was diluted with DCM and washed with saturated bicarbonate solution and brine. The organic layer was dried over sodium sulfate and evaporated under reduced pressure to give the crude compound, which was then purified by column chromatography (SiO, 30-40% EtOAc / n-hexane) to give 3-bromo-2-ethyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine (1.5 g, 6.64 mmol, 80% in two steps) as an off-white powder. LCMS (ESI): 232.7 m / z [M+H] +

[0398] Step E To a well-stirred solution of 3-bromo-2-ethyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine (1.534 g, 6.64 mmol) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.17 mL, 33.2 mmol) in THF (30 mL) was added n-butyllithium (2 M THF solution, 7.3 mL, 14.60 mmol) at −78° C. under argon. The resulting mixture was then allowed to stir at −78° C. for 2 h. The mixture was slowly warmed to RT and stirred for an additional 30 min. After complete consumption of the starting material (monitored by TLC and LCMS), excess butyllithium was quenched by the addition of saturated ammonium chloride. The solution was diluted with ethyl acetate 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 then purified by column chromatography (SiO, 10-20% EtOAc / n-hexane) to give 2-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine (270 mg, 0.96 mmol, 15%) as a white solid. LCMS (ESI): 279.0 m / z [M+H] +

[0399] Step F To a stirred solution of ethyl 7-bromo-6-chloro-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-1H-indole-2-carboxylate (270 mg, 0.53 mmol) in dioxane (2.5 mL) and water (0.25 mL) was added 2-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine (270 mg, 0.96 mmol) and KPO (337.5 mg, 1.59 mmol) at room temperature under nitrogen. The mixture was deoxygenated with argon, and to it was added Pd(dtbpf)Cl (69.29 mg, 0.106 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 filtrate was evaporated under reduced pressure to give a residue, which was then diluted with ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate and evaporated under reduced pressure to give crude ethyl 6-chloro-7-(2-ethyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-3-yl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-1H-indole-2-carboxylate (270 mg) as a brown sticky solid, which was then used directly in the next step without further purification. LCMS (ESI): 576.0 m / z [M+H] +

[0400] Step G To a well-stirred solution of ethyl 6-chloro-7-(2-ethyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-3-yl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-1H-indole-2-carboxylate (270 mg, 0.469 mmol) in DMF (3 mL) was added tert-butyl 4-(2-chloroethyl)piperazine-1-carboxylate (174.37 mg, 0.703 mmol) followed by cesium carbonate (229.092 mg, 0.703 mmol) at RT under nitrogen. The resulting mixture was allowed to stir at 90° C. for 16 h under nitrogen. After complete consumption of the starting material (monitored by TLC and LCMS), the reaction mixture was diluted with ethyl acetate 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 then purified by column chromatography (SiO, 100% EtOAc) to give ethyl 1-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)-6-chloro-7-(2-ethyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-3-yl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-1H-indole-2-carboxylate (160 mg, 0.20 mmol, 38% over two steps) as a brown sticky solid. LCMS (ESI): 788.4 m / z [M+H] +

[0401] Step H Ethyl 1-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)-6-chloro-7-(2-ethyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-3-yl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-1H-indole-2-carboxylate (160 mg, 0.20 mmol) was dissolved in EtOH (2 mL) and a solution of NaOH (32.529 mg, 0.813 mmol) in water (0.5 mL) was added. 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. The residue was diluted with water and washed with ethyl acetate. The aqueous layer was carefully acidified to pH = 3 using 1 M HCl, extracted with ethyl acetate (3 × 50 mL), dried over NaSO, filtered, and concentrated in vacuo to give crude 1-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)-6-chloro-7-(2-ethyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-3-yl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-1H-indole-2-carboxylic acid (135 mg) as a light brown gummy solid, which was used directly in the next step without further purification. LCMS (ESI): 760.4 m / z [M+H] +

[0402] Step I Crude 1-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)-6-chloro-7-(2-ethyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-3-yl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-1H-indole-2-carboxylic acid (135 mg) was dissolved in 4 M HCl / dioxane (12 mL) at 0° C., and the mixture was stirred at room temperature for 2 hours under nitrogen. When LCMS showed the reaction was complete, the volatiles were concentrated in vacuo to give the crude compound, which was then purified by trituration with diethyl ether and n-pentane to give 6-chloro-7-(2-ethyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-3-yl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-1-(2-(piperazin-1-yl)ethyl)-1H-indole-2-carboxylic acid hydrochloride (55 mg, 0.08 mmol, 41% over two steps) as an off-white solid. LCMS (ESI): 660.4 m / z [M+H] +

[0403] Step J 2-{[2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}acetic acid (12.3 mg, 0.039 mmol) and HATU (13.1 mg, 0.034 mmol) were dissolved in anhydrous DMF (2.7 mL) under an argon atmosphere, and DIPEA (0.011 mL, 0.064 mmol) was added. The reaction was stirred at room temperature for 1 hour. 6-Chloro-7-{2-ethyl-4H,6H,7H-pyrazolo[3,2-c][1,4]oxazin-3-yl}-3-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-1-[2-(piperazin-1-yl)ethyl]-1H-indole-2-carboxylic acid hydrochloride (15.0 mg, 0.022 mmol) and DIPEA (0.011 mL, 0.064 mmol) were dissolved in DMSO in a separate vial and added dropwise to the reaction mixture. The reaction (monitored by LCMS) was stirred for the next 20 minutes. After complete consumption of the starting material, the reaction mixture was passed through a syringe filter and directly purified by reverse-phase preparative HPLC (HO / MeCN with 0.1% FA) to afford 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-7-(2-ethyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-3-yl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-1H-indole-2-carboxylic acid (7.1 mg, 0.007 mmol, 34.4%) as a white solid. LCMS (ESI): 960.1 m / z [M+H] + 1H NMR (500 MHz, DMSO, 353 K) δ 10.64 (s, 1H), 8.22 (dd, J = 9.2, 5.9 Hz, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.58 (dd, J = 10.4, 2.6 Hz, 1H), 7.50 - 7.36 (m, 3H), 7.36 - 7.26 (m, 2H), 7.20 (d, J = 8.6 Hz, 1H), 7.14 (d, J = 8.1 Hz, 1H), 6.86 (dd, J = 5.9, 2.7 Hz, 1H), 5.04 (dd, J = 13.0, 5.2 Hz, 1H), 4.88 (s, 2H), 4.56 (d, J = 15.0 Hz, 1H), 4.52 (d, J = 14.9 Hz, 1H), 4.45 - 4.36 (m, 2H), 4.31 (d, J = 17.1 Hz, 1H), 4.23 (t, J = 6.2 Hz, 2H), 4.21 - 4.14 (m, 1H), 4.14 - 4.04 (m, 4H), 3.39 - 3.34 (m, 4H), 3.29 - 3.25 (m, 2H), 2.87 (ddd, J = 17.3, 13.4, 5.5 Hz, 1H), 2.66 - 2.59 (m, 1H), 2.48 - 2.40 (m, 1H), 2.37 - 2.28 (m, 1H), 2.26 - 2.20 (m, 3H), 2.19 - 2.08 (m, 6H), 2.07 - 2.01 (m, 1H), 1.00 (t, J = 7.5 Hz, 3H).

[0404] Example 23: 6-chloro-1-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-3-methyl-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 (Compound 145) [ka] Step A To a solution of methyl 2-bromo-4-fluorobenzoate (800 mg, 3.43 mmol) in DMSO (5 mL) was added DIPEA (1.1 mL, 6.93 mmol) and benzyl piperazine-1-carboxylate (1.34 mL, 6.93 mmol). The resulting solution was stirred at 110 °C for 16 h. The reaction mixture was then diluted with ethyl acetate and washed with cold water and brine. The organic layer was dried over NaSO and evaporated to give the crude compound. Benzyl 4-(3-bromo-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (1.1 g, 2.53 mmol, 74%) was purified by column chromatography (SiO, 40-50% EtOAc / DCM). LCMS (ESI): 435.0 m / z [M+H] + .

[0405] Step B To a solution of benzyl 4-(3-bromo-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (500 mg, 1.16 mmol) in toluene (5 mL) was added tributyl(1-ethoxyvinyl)stannane (0.19 mL, 0.56 mmol) at room temperature, and the mixture was bubbled with argon for 15 minutes. Tetrakis(triphenylphosphine)palladium(0) (26.75 mg, 0.023 mmol) was added, and the reaction mixture was stirred at 110 °C overnight. After complete consumption of the starting material (monitored by TLC and LCMS), the reaction mixture was filtered through a Celite bed, and the filtrate was evaporated to give the crude intermediate, which was immediately dissolved in THF (6 mL) and 1 M HCl (3 mL) and stirred at room temperature for 3 hours. After completion (monitored by TLC and LCMS), the volatiles were evaporated, and the residue was taken up in water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and evaporated. Benzyl 4-(3-acetyl-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (300 mg, 0.75 mmol, 65%) was purified by column chromatography (SiO2, 10-20% EtOAc / hexane). LCMS (ESI): 397.2 m / z [M+H] + .

[0406] Step C To a stirred solution of benzyl 4-(3-acetyl-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (300 mg, 0.75 mmol) in THF (6 mL) and water (3 mL), NaOH (241.6 mg, 6.04 mmol) was added at 0 °C, and the reaction mixture was stirred for 3 h. After complete consumption of the starting material (monitored by TLC and LCMS), the volatiles were evaporated, and the resulting residue was dissolved in water and acidified to pH 5–6 with 1 M HCl at 0 °C. The mixture was extracted with ethyl acetate. The combined organic phases were washed with brine and dried over Na SO to afford crude 2-acetyl-4-(4-((benzyloxy)carbonyl)piperazin-1-yl)benzoic acid (200 mg) as a white solid, which was used directly in the next step without further purification. LCMS (ESI): 383.1 m / z [M+H] + .

[0407] Step D To a solution of crude 2-acetyl-4-(4-((benzyloxy)carbonyl)piperazin-1-yl)benzoic acid (200 mg) in DMF (3 mL) was added 3-aminopiperidine-2,6-dione hydrochloride (171.8 g, 1.044 mmol) and DIPEA (0.177 mL, 1.044 mmol) at room temperature under nitrogen. The reaction mixture was stirred under the same conditions for 15 min. HATU (296.75 mg, 0.78 mmol) was added and the resulting mixture was stirred at room temperature for 1 h. After complete consumption of the starting material (monitored by TLC and LCMS), the reaction mixture was quenched with ice water and the volatiles were evaporated. The crude reaction mass was diluted with DCM, washed with saturated NaHCO3 solution, water and brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to give crude benzyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-hydroxy-3-methyl-1-oxoisoindolin-5-yl)piperazine-1-carboxylate (200 mg) as a yellow sticky solid, which was used directly in the next step. LCMS (ESI): m / z not detected.

[0408] Step E To a solution of crude benzyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-hydroxy-3-methyl-1-oxoisoindolin-5-yl)piperazine-1-carboxylate (200 mg) in DCM (2 mL) was added TFA (0.186 mL, 2.436 mmol) and triethylsilane (0.036 mL, 1.22 mmol) at 0 °C under nitrogen. The reaction mixture was stirred at 0 °C for 1 h. Additional portions of TFA (0.19 mL, 2.44 mmol) and triethylsilane (0.036 mL, 1.22 mmol) were added. After complete consumption of the starting material (monitored by TLC and LCMS), the reaction mixture was evaporated, and the residue was taken up in DCM and washed with saturated NaHCO3 solution and brine. The organic layer was dried over Na2SO4 and filtered. The filtrate was evaporated to give the crude compound, which was purified by silica gel chromatography (SiO, 3% to 5% MeOH / DCM) to give 100 mg (0.21 mmol, 28% over 3 steps) of benzyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-methylene-1-oxoisoindolin-5-yl)piperazine-1-carboxylate as a yellow solid. LCMS (ESI): 475.1 m / z [M+H] + .

[0409] Step F A solution of benzyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-methylene-1-oxoisoindolin-5-yl)piperazine-1-carboxylate (100 mg, 0.21 mmol) in acetic acid (3 mL) was purged with argon at room temperature for 10 minutes, and then Pd / C (100 mg, 10% w / w) was added. The reaction mixture was stirred at room temperature under a hydrogen atmosphere (balloon pressure) for 5 hours. After the starting material was consumed (monitored by LCMS and TLC), the reaction mixture was filtered through a Celite pad, and the filtrate was evaporated to give 60 mg (0.175 mmol, 83%) of 3-(3-methyl-1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione as a brownish-yellow solid. LCMS (ESI): 343.2 m / z [M+H] + .

[0410] Step G To a solution of 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 (100 mg, 0.14 mmol) in DCM (5 mL) and methanol (1 mL) was added acetic acid (0.008 mL, 0.14 mmol) followed by 3-(3-methyl-1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (58.14 mg, 0.17 mmol), and the reaction mixture was stirred at room temperature for 4 hours. Sodium triacetoxyborohydride (149.81 mg, 0.71 mmol) was then added. The reaction mixture was stirred at 80° C. overnight. After complete consumption of the starting material (monitored by TLC and LCMS), the reaction mixture was filtered through a pad of Celite and the solvent was evaporated to give the crude material, which was then purified by preparative TLC (SiO, 10% MeOH / DCM) to remove some amount of unreacted 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 This gave 70 mg of tert-butyl 6-chloro-1-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-3-methyl-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 as an off-white solid. This mixture was carried on to the next step.

[0411] 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 was prepared as described in WO2022 / 253713A1. LCMS (ESI): 1027.7 m / z [M+H] + .

[0412] Step H To a crude solution of tert-butyl 6-chloro-1-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-3-methyl-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 (70 mg) in DCM (2 mL) was added TFA (1 mL) dropwise at 0° C. under nitrogen and the reaction mixture was stirred at room temperature for 3 h. After complete consumption of the starting material (monitored by TLC and LCMS), the volatiles were evaporated. The crude compound was purified by reverse-phase preparative HPLC (C18, 10 mM NHOAc / HO:MeCN) to afford 12 mg (0.012 mmol, 8% over two steps) of 6-chloro-1-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-3-methyl-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 as a white solid as a mixture of two stereoisomers. LCMS (ESI): 971.9 m / z [M+H] + . 1H NMR (500 MHz, DMSO, 353 K) δ 10.56 - 10.47 (m, 1H), 8.26 (dd, J = 9.2, 5.8 Hz, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.58 (dd, J = 10.4, 2.7 Hz, 1H), 7.47 - 7.38 (m, 3H), 7.32 (td, J = 8.9, 2.7 Hz, 1H), 7.18 (d, J = 8.5 Hz, 1H), 6.99 (s, 1H), 7.00 - 6.94 (m, 1H), 6.87 (dd, J = 5.3, 3.4 Hz, 1H), 4.71 - 4.51 (m, 2H), 4.31 - 4.21 (m, 3H), 4.21 - 4.14 (m, 1H), 3.76 (s, 3H), 3.28 - 3.19 (m, 6H), 2.82 - 2.67 (m, 1H), 2.62 - 2.54 (m, 2H), 2.48 - 2.43 (m, 4H), 2.34 - 2.20 (m, 5H), 2.19 - 2.13 (m, 2H), 2.11 (d, J = 7.1 Hz, 2H), 2.06 - 1.94 (m, 4H), 1.91 (s, 1H), 1.89 (s, 3H), 1.66 - 1.56 (m, 2H), 1.56 - 1.47 (m, 1H), 1.43 (dd, J = 13.4, 6.6 Hz, 3H), 1.20 - 1.09 (m, 2H).

[0413] Example 24: 6-chloro-1-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-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 (Compound 144) [ka] Step A To a solution of 4-bromo-5-fluoro-2-methylbenzoic acid (2.5 g, 10.73 mmol) in a mixture of EtOAc:HO (110 mL, 6 / 5 v / v) was added NaBrO (4.88 g, 32.33 mmol) followed by NaHSO (3.36 g, 32.33 mmol) at 0 °C. The reaction was stirred at room temperature for 48 h. Upon completion, the reaction was extracted with ethyl acetate, and the combined organic phase was washed with water and brine, dried over anhydrous NaSO, and concentrated. The crude product was purified by column chromatography (SiO, 5-10% EtOAc / hexanes) to afford 1.5 g (6.49 mmol, 60%) of 5-bromo-6-fluoroisobenzofuran-1(3H)-one as a white solid. LCMS (ESI): 233.2 m / z [M+H] + .

[0414] Step B To a solution of 5-bromo-6-fluoroisobenzofuran-1(3H)-one (1.5 g, 6.49 mmol) in dioxane (40 mL) was added tert-butyl piperazine-1-carboxylate (2.42 g, 12.92 mmol), followed by CsCO (6.33 g, 19.48 mmol) and Xantphos (375 mg, 0.65 mmol). The mixture was purged with argon, and Pddba (297 mg, 0.33 mmol) was added under argon. The reaction mixture was then stirred at 100 °C for 16 h. After complete consumption of the starting material (monitored by TLC and LCMS), the solvent was evaporated. The resulting residue was diluted with ethyl acetate and washed with water and brine. The combined organic phases were dried over Na2SO4 and evaporated to give the crude compound, which was then purified by column chromatography (SiO2, 20-30% EtOAc / hexanes) to give 700 mg (2.08 mmol, 32%) of tert-butyl 4-(6-fluoro-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazine-1-carboxylate as an off-white solid. LCMS (ESI): 337.1 m / z [M+H] + .

[0415] Step C To a solution of tert-butyl 4-(6-fluoro-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazine-1-carboxylate (700 mg, 2.08 mmol) in THF (4 mL), methanol (4 mL), and water (4 mL) was added NaOH (333 mg, 8.33 mmol), and the reaction was stirred at room temperature for 1 h. After complete consumption of the starting material (monitored by TLC and LCMS), the reaction mixture was acidified with 1 M HCl and extracted with ethyl acetate. The organic phase was dried over Na2SO4 and evaporated to give crude 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-fluoro-2-(hydroxymethyl)benzoic acid (600 mg) as an off-white solid, which was used in the next step without further purification. LCMS (ESI): 355.4 m / z [M+H] + .

[0416] Step D To a solution of crude 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-fluoro-2-(hydroxymethyl)benzoic acid (600 mg) in methanol (6 mL) and ethyl acetate (6 mL) was added trimethylsilyldiazomethane (2 M in hexane, 5.3 mL, 10.59 mmol) under an argon atmosphere at −10° C. The reaction mixture was then stirred at the same temperature under an argon atmosphere for 30 minutes. After complete consumption of the starting material (monitored by TLC and LCMS), the solution was quenched with water and extracted with ethyl acetate. The organic phase was dried over NaSO and concentrated under reduced pressure to give crude tert-butyl 4-(2-fluoro-5-(hydroxymethyl)-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (500 mg), which was used in the next step without further purification. LCMS (ESI): 369.2 m / z [M+H] + .

[0417] Step E To a solution of crude tert-butyl 4-(2-fluoro-5-(hydroxymethyl)-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (500 mg) in DCM (12 mL) was added Dess-Martin periodinane (1.72 g) at 0 °C under nitrogen. The reaction mixture was stirred at room temperature for 2 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was quenched with cold water and extracted with DCM. The combined organic layers were dried over Na2SO4 and evaporated to give the crude product. tert-Butyl 4-(2-fluoro-5-formyl-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (500 mg, 1.37 mmol, 65% over 3 steps) was purified by column chromatography (SiO2, 20% EtOAc / hexanes).

[0418] Step F To a solution of tert-butyl 4-(2-fluoro-5-formyl-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (500 mg, 1.37 mmol) in DCE (10 mL) was added 3-aminopiperidine-2,6-dione hydrochloride (450 mg, 2.74 mmol), acetic acid (1.1 mL, 19.13 mmol), and DIPEA (0.6 mL, 3.42 mmol) at room temperature under nitrogen. The reaction mixture was stirred at 80 °C for 4 hours and cooled to room temperature. Sodium triacetoxyborohydride (868 mg, 2.73 mmol) was added under nitrogen, and the reaction was refluxed for 12 hours. After complete consumption of the starting material (monitored by TLC and LCMS), the volatiles were evaporated, and the residue was diluted with ethyl acetate and washed with water and brine. The organic phase was dried over Na2SO4 and concentrated to give the crude compound, which was then purified by column chromatography (SiO2, 5-10% MeOH / DCM) to give 210 mg (0.47 mmol, 34%) of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazine-1-carboxylate as an off-white solid. LCMS (ESI): 447.3 m / z [M+H] + .

[0419] Step G To a solution of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazine-1-carboxylate (210 mg, 0.47 mmol) in DCM (5 mL) was added TFA (3 mL) dropwise at 0° C. The reaction was stirred at room temperature under nitrogen for 16 h. After complete consumption of the starting material (monitored by TLC and LCMS), the volatiles were evaporated and the residue was triturated with diethyl ether and n-pentane to afford 150 mg (0.33 mmol, 69%) of 3-(6-fluoro-1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione trifluoroacetate as an off-white solid. LCMS (ESI): 347.0 m / z [M+H] + .

[0420] Step H To a solution of 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 (100 mg, 0.14 mmol) in DCM / methanol (10 mL, 4:1 v / v), 3-(6-fluoro-1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione trifluoroacetate (99 mg, 0.22 mmol) was added at room temperature under nitrogen. Acetic acid (8 μL, 0.14 mmol) was added to the reaction mixture at 0 ° C, followed by the addition of sodium triacetoxyborohydride (151 mg, 0.71 mmol). The reaction was stirred at room temperature under nitrogen for 16 hours. After complete consumption of the starting material (monitored by TLC and LCMS), the solvent was evaporated to give the crude material. The residue was taken up in ethyl acetate and washed with water and brine. The organic phase was dried over Na2SO4 and concentrated. The residue was triturated with diethyl ether and n-pentane to give 80 mg of crude tert-butyl 6-chloro-1-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-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 as an off-white solid, which was used directly in the next step without purification.

[0421] 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 was prepared as described in WO2022 / 253713A1. LCMS (ESI): 1031.7 m / z [M+H] + .

[0422] Step I To a solution of crude tert-butyl 6-chloro-1-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-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 (80 mg, 0.077 mmol) in DCM (2 mL) was added TFA (1 mL) dropwise at 0° C. under nitrogen and the reaction mixture was stirred at room temperature for 3 hours. After complete consumption of the starting material, the volatiles were evaporated. The residue was purified by reverse-phase preparative HPLC (C18, HO:MeCN+0.1% FA) to afford 18 mg of 6-chloro-1-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-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 (0.018 mmol, 13.1% over two steps) as a white solid. LCMS (ESI): 976.7 m / z [M+H] + 1H NMR (500 MHz, DMSO) δ 10.95 (s, 1H), 8.25 (dd, J = 9.3, 5.9 Hz, 1H), 7.69 - 7.60 (m, 2H), 7.46 - 7.33 (m, 4H), 7.20 (d, J = 8.5 Hz, 1H), 7.16 (d, J = 7.5 Hz, 1H), 6.89 - 6.83 (m, 1H), 5.06 (dd, J = 13.3, 5.1 Hz, 1H), 4.35 (d, J = 17.1 Hz, 1H), 4.30 - 4.05 (m, 5H), 3.75 (s, 3H), 3.20 - 3.15 (m, 2H), 3.06 - 2.97 (m, 4H), 2.90 (ddd, J = 17.3, 13.7, 5.4 Hz, 1H), 2.63 - 2.56 (m, 1H), 2.43 - 2.31 (m, 8H), 2.24 - 2.14 (m, 2H), 2.06 - 1.93 (m, 7H), 1.88 (s, 3H), 1.67 - 1.56 (m, 2H), 1.55 - 1.47 (m, 1H), 1.33 - 1.23 (m, 2H), 1.18 - 1.05 (m, 2H).

[0423] Example 25: 6-chloro-1-(2-(4-(2-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-ethylphenoxy)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 (Compound 25) [ka] Step A To a stirred solution of 2-ethyl-4-methoxybenzoic acid (750 mg, 4.17 mmol) in DMF (12 mL) was added HATU (1.90 g, 5.0 mmol) and DIPEA (1.46 mL, 8.33 mmol) at room temperature under nitrogen. The reaction mixture was stirred for 15 minutes, and 3-aminopiperidine-2,6-dione hydrochloride (1.03 g, 6.24 mmol) was added. The reaction was stirred at room temperature for 1 hour. After complete conversion (monitored by LCMS), the reaction was quenched with ice water. The mixture was concentrated in vacuo, diluted with DCM, and washed with saturated NaHCO3 solution, water, and brine. The organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the crude product was purified by column chromatography (SiO 2 , 50-60% EtOAc / DCM) to afford 500 mg (1.72 mmol, 41%) of N-(2,6-dioxopiperidin-3-yl)-2-ethyl-4-methoxybenzamide as a white solid. LCMS (ESI): 291.1 m / z [M+H] + .

[0424] Step B To a solution of N-(2,6-dioxopiperidin-3-yl)-2-ethyl-4-methoxybenzamide (500 mg, 1.72 mmol) in DCM (12.0 mL) was added 1 M BBr / DCM solution (8.6 mL, 8.6 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 3 h and allowed to warm slowly to room temperature. After the starting material was consumed, the mixture was concentrated under reduced pressure, and the resulting residue was purified by flash chromatography (SiO, 3% MeOH / DCM) to give N-(2,6-dioxopiperidin-3-yl)-2-ethyl-4-hydroxybenzamide (400 mg, 1.45 mmol, 84%) as a white solid. LCMS (ESI): 277.1 m / z [M+H] + .

[0425] Step C To a solution of N-(2,6-dioxopiperidin-3-yl)-2-ethyl-4-hydroxybenzamide (400 mg, 1.45 mmol) in DMF (5 mL) was added KHCO (435 mg, 4.34 mmol), tert-butyl bromoacetate (0.21 mL, 1.45 mmol), and KI (72.17 mg, 0.44 mmol) at room temperature under nitrogen. The reaction mixture was stirred at 60 °C for 1 h. After complete consumption of the starting material (monitored by TLC and LCMS), the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was dried over Na SO and concentrated under reduced pressure. The crude material was purified by reverse-phase preparative HPLC (C18, 10 mM NH4Cl / HO:MeCN) to afford 110 mg (0.282 mmol, 19.4%) of tert-butyl 2-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-ethylphenoxy)acetate as a white solid. LCMS (ESI): 391.1 m / z [M+H] + .

[0426] Step D To a solution of tert-butyl 2-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-ethylphenoxy)acetate (100 mg, 0.26 mmol) in DCM (3 mL) was added TFA (1 mL) dropwise at 0° C. The reaction mixture was stirred at room temperature under nitrogen for 16 h. After complete conversion (monitored by TLC and LCMS), the solution was concentrated under reduced ...

Claims

1. Compounds of formula (I) [MCL-1 ligand site]-linker-[ligase ligand site] (I) or a salt, solvate, hydrate, isomer or prodrug thereof (wherein, [ligase ligand site] is 【Chemistry 1】 (In the formula, M is O, S, or NH, or absent; 【Chemistry 2】 is R of the linker １８ indicates a bond to 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; The [MCL-1 ligand site] is a compound of formula (A1), (A2), (A3) or (A4): 【Transformation 3】 (In the formula, 【Chemistry 4】 is a single or double bond; Each Z ２ are independently N or C, and Z ２ If is N, then 【Transformation 5】 is a single bond; Z ２ If is C, then 【Transformation 6】 is a double bond; Each R ９ are independently —C(O)OH, —C(O)OC １ -C ６ Alkyl, —C(O)NH ２ , or P(O)(OH) ２ and 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 which is H and R １０ and R ３０ The other of them is -C ２－５ Alkyl-O-R １３ , —O—C ２－５ Alkyl-R １３ , or -C ２－５ Alkyl-NMe-R １３ where 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 said tetralin is optionally substituted with at least one substituent selected from a bridged —CH ２ - group; or said naphthyl is optionally substituted by -O- or -S- group; R １２ teeth, 【Transformation 7】 and Each R ３３ are independently H, R １９ or C optionally substituted with morpholine or piperazine １ -C ６ is alkyl; R ３１ is -C ２－５ Alkyl-O-R １３ , —O—C ２－５ Alkyl-R １３ , or -C ２－５ Alkyl-NMe-R １３ where 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 said tetralin is optionally substituted with at least one substituent selected from a bridged —CH ２ - group; or said naphthyl is optionally substituted with -O- or -S-; Each R ３２ are independently, H, 【Transformation 8】 and Here, R ２０ is Me, -CH ２ -OMe, -(CH ２ CH ２ O) ｐ (C １ -C ６ alkyl), or —CH ２ -O-bromobenzaldehyde, where p is 1 to 5; R ３４ is C ２－５ Alkyl-O-R １３ or -O-C ２－５ Alkyl-R １３ where 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 said tetralin is optionally substituted with at least one substituent selected from a bridged —CH ２ - group; or said naphthyl is optionally substituted with -O- or -S-; R ３５ teeth, 【Chemistry 9】 and 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 containing [Linker] is a group represented by the following formula: R １４ -R １５ -R １６ -R １７ -R １８ wherein R １４ is -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 a 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 is -C １－６ Alkyl, —C(O)—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 is -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 is -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

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

3. R ２９ The compound according to claim 1 or 2, wherein is Me.

4. R ２９ The compound of claim 1 or 2, wherein is hydrogen.

5. The compound of claim 1, wherein the [ligase ligand site] is: 【Chemistry 11】

6. The compound of claim 1, wherein the [ligase ligand site] is: 【Chemistry 12】

7. R ２２ is hydrogen, halogen, -OMe, -NH ２ , -NHMe, -NMe ２ or piperidine; optionally, R ２２ is hydrogen, -OMe, -NH ２ , -NHMe, -NMe ２ or piperidine.

8. R ２２ The compound of claim 7 , wherein is hydrogen.

9. The compound of any one of claims 1 to 8, wherein L' is hydrogen.

10. The compound of any one of claims 1 to 9, wherein M is O or NH, or absent.

11. The compound of claim 1, wherein the [ligase ligand site] is: 【Chemistry 13】 【change】

12. The compound of claim 1, wherein the [ligase ligand site] is: 【Chemistry 14】

13. The compound of claim 1, wherein the [ligase ligand site] is: 【Chemistry 15】

14. R １６ is -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 is -CH ２ (C ２ H ４ -O) ｙ , -(C ２ H ４ -O) ｘ , -(C ３ H ６ -O) ｘ , or absent, R １８ is -C １－６ Alkyl, cycloalkyl, -CH ２ The compound of any one of claims 1 to 13, wherein -NH-C(O)-, heterocycloalkyl, or absent.

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

16. R １４ is -C １－６ 16. The compound of claim 15, wherein the compound is alkyl.

17. R １５ is a cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C １－６ The compound of any one of claims 1 to 16, which is alkyl-NH-, -cycloalkyl-NH-, or absent.

18. R １５ is heterocycloalkyl or absent.

19. R １５ is piperazine, bridged piperazine, piperazine N-oxide, piperazine cation, 【Chemistry 16】 or absent; 【Chemistry 17】 is R １４ indicates the bond to [Chemistry 18] is R １６ 20. The compound of claim 18, wherein the compound exhibits binding to

20. R １５ is piperazine, 【Chemistry 19】 or absent.

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

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

23. R １８ is -C １－６ Alkyl, cyclobutyl, CH ２ The compound of any one of claims 1 to 22, which is -NH-C(O)-, piperazine, or absent.

24. The compound according to any one of claims 1 to 23, wherein the linker is selected from the following: 【Chemistry 20】 [In the formula, 【Chemistry 21】 indicates binding to the [MCL-1 ligand site], 【Chemistry 22】 indicates binding to [ligase ligand site]]

25. 25. The compound of claim 24, wherein [linker] is selected from the following: 【Chemistry 23】

26. [MCL-1 ligand site] is represented by formula (A1): 【Chemistry 24】 The compound according to any one of claims 1 to 25,

27. [MCL-1 ligand site] is represented by formula (A2): 【Chemistry 25】 The compound according to any one of claims 1 to 25,

28. [MCL-1 ligand site] is represented by formula (A3): 【Chemistry 26】 The compound according to any one of claims 1 to 25,

29. [MCL-1 ligand site] is represented by formula (A4): 【Chemistry 27】 The compound according to any one of claims 1 to 25,

30. In each of formula (A1) and formula (A4), R １０ and R ３０ one of which is H and R １０ and R ３０ The other of the two is -C ２－５ Alkyl-O-R １３ , or —O—C ２－５ Alkyl-R １３ where R １３ is phenyl or naphthyl, and the phenyl or naphthyl is selected from halogen and C １ -C ６ 30. The compound of any one of claims 1 to 29, optionally substituted with at least one substituent selected from alkyl.

31. R in formula (A1) １２ is the following: 【Chemistry 28】 The compound according to any one of claims 1 to 30.

32. R in formula (A4) ３５ is the following: 【Chemistry 29】 A compound according to any one of claims 1 to 31.

33. R in formula (A2) ３１ is -C ２－５ Alkyl-O-R １３ or -O-C ２－５ Alkyl-R １３ where R １３ is phenyl or naphthyl, and the phenyl or naphthyl is selected from halogen and C １ -C ６ 33. The compound of any one of claims 1 to 32, optionally substituted with at least one substituent selected from alkyl.

34. R in formula (A3) ３４ is C ２－５ Alkyl-O-R １３ or -O-C ２－５ Alkyl-R １３ where R １３ is phenyl or naphthyl, and the phenyl or naphthyl is selected from halogen and C １ -C ６ 34. The compound of any one of claims 1 to 33, optionally substituted with at least one substituent selected from alkyl.

35. Z ２ is C, 【Transformation 30】 The compound according to any one of claims 1 to 34, wherein is a double bond.

36. Each R ９ are independently —C(O)OH or —P(O)(OH) ２ The compound according to any one of claims 1 to 35,

37. R １１ The compound according to any one of claims 1 to 36, wherein is a halogen.

38. Each R ２０ is Me or -(CH ２ CH ２ O) ２ The compound of any one of claims 1 to 37, wherein Me.

39. C substituted with morpholine or piperazine １ -C ６ 39. The compound of any one of claims 1 to 38, wherein alkyl is: 【Chemistry 31】

40. [MCL-1 ligand site] is 【Chemistry 32】 【change】 40. The compound according to any one of claims 1 to 39, selected from:

41. 2. The compound of claim 1 selected from the following: Table 1

42. (a) compound 144 or 147; or (b) Compound 147 42. The compound of claim 41, wherein:

43. Compounds of formula (I) [MCL-1 ligand site]-[linker]-[ligase ligand site] (I) or a salt, solvate, hydrate, isomer or prodrug thereof (wherein, [ligase ligand site] is (a) Formula (IV) or (IVa) 【Transformation 33】 (In the formula, X １ and X ２ each is independently O or S; Q １ and Q ２ each independently represents 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 is independently 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 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 connected to a single R ２１ containing (b) Formula (VIIa), (VIIb), (VIIc) or (VIId): 【Transformation 34】 (In the formula, X １ and X ２ each is independently 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 independently represents 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 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 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 connected to a single R ２１ containing (c) Formula (VIII): 【Chemistry 35】 (In the formula, X １ and X ２ each 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)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 connected to a single R ２１ containing (d) Formula (IX): 【Transformation 36】 (In the formula, X １ and X ２ each 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)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 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 , 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 connected to a single R ２１ containing The [MCL-1 ligand site] is a compound of formula (A1), (A2), (A3) or (A4): 【Chemistry 37】 (In the formula, 【Transformation 38】 is a single or double bond; Each Z ２ are independently N or C, and Z ２ If is N, then 【Chemistry 39】 is a single bond; Z ２ If is C, then 【Chemistry 40】 is a double bond; Each R ９ are independently —C(O)OH, —C(O)OC １ -C ６ Alkyl, —C(O)NH ２ , or -P(O)(OH) ２ and 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 which is H and R １０ and R ３０ The other of the two is -C ２－５ Alkyl-O-R １３ , —O—C ２－５ Alkyl-R １３ , or -C ２－５ Alkyl-NMe-R １３ where 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 said tetralin is optionally substituted with at least one substituent selected from a bridged —CH ２ - group; or said naphthyl is optionally substituted by -O- or -S- group; R １２ teeth, 【Chemistry 41】 and Each R ３３ are independently H, R １９ or C optionally substituted with morpholine or piperazine １ -C ６ is alkyl; R ３１ is -C ２－５ Alkyl-O-R １３ , —O—C ２－５ Alkyl-R １３ , or -C ２－５ Alkyl-NMe-R １３ where 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 said tetralin is optionally substituted with at least one substituent selected from a bridged —CH ２ - group; or said naphthyl is optionally substituted with -O- or -S-; Each R ３２ are independently, H, 【Chemistry 42】 and Here, R ２０ is Me, -CH ２ -OMe, -(CH ２ CH ２ O) ｐ (C １ -C ６ alkyl), -CH ２ —O-bromobenzaldehyde, or 【Chemistry 43】 wherein p is 1 to 5; R ３４ is C ２－５ Alkyl-O-R １３ or -O-C ２－５ Alkyl-R １３ where 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 said tetralin is optionally substituted with at least one substituent selected from a bridged —CH ２ - group; or said naphthyl is optionally substituted with -O- or -S-; R ３５ teeth, 【Chemistry 44】 and 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 containing [Linker] is a group represented by the following formula: R １４ -R １５ -R １６ -R １７ -R １８ wherein R １４ is -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 a 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 is -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 is -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 is -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

44. R １６ is -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 is -CH ２ (C ２ H ４ -O) ｙ , (C ２ H ４ -O) ｘ , (C ３ H ６ -O) ｘ , or absent; R １８ is -C １－６ Alkyl, cycloalkyl, CH ２ 44. The compound of claim 43, which is -NH-C(O)-, heterocycloalkyl, or absent.

45. [Linker] is 【Chemistry 45】 wherein: 【Chemistry 46】 indicates binding to the [MCL-1 ligand site], 【Chemistry 47】 indicates binding to the [ligase ligand site].

46. The compound according to any one of claims 43 to 45, wherein [MCL-1 ligand site] is: 【Chemistry 48】

47. The compound according to any one of claims 44 to 46, wherein the [ligase ligand site] is: 【Chemistry 49】

48. 48. The compound of claim 47, wherein: [Transformation 50]

49. The compound according to any one of claims 43 to 46, wherein the [ligase ligand site] is: 【Chemistry 51】

50. 50. The compound of claim 49, wherein: 【Chemistry 52】

51. Compounds of formula (I) [MCL-1 ligand site]-[linker]-[ligase ligand site] (I) or a salt, solvate, hydrate, isomer or prodrug thereof (wherein, [ligase ligand site] is (a) Formula (Va) or (Vb): 【Chemistry 53】 or a pharmaceutically acceptable salt or tautomer thereof (In the formula, X １ and X ２ each is independently 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 independently represents 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 Formula (Va) and Formula (Vb) each represent a single R ２１ Contains; Z １ is O, then Y ６ is CR ７ and When the compound is a compound of formula (Va), (i) Y ５ , Y ６ and Y ７ Each of these is CR ７ If R ７ at least one of 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 NR''''C(O)OR'''' not; (v) Z １ is S and Y ５ If N, then Y ６ is not C—H, C-aryl, or C—C(O)OR″″; and (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 a compound of formula (Vb), (vii) Y ５ , Y ６ and Y ８ Each of these is CR ７ If R ７ at least one of 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 54】 (In the formula, X １ and X ２ each is independently 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 55】 indicates a single or double bond, where: 【Transformation 56】 When each of W is a double bond, １ , W ２ , W ３ and W ４ each independently represents N or CR ａ and W １ , W ２ , W ３ and W ４ is N; 【Chemistry 57】 When each of 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 independently represents 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 is 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 formula (IIa) and formula (IIb) each represent a single R ２１ Contains; 【Chemistry 58】 each of which 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 ) and The [MCL-1 ligand site] is a compound of formula (A1), (A2), (A3) or (A4): 【Chemistry 59】 (In the formula, 【Transformation 60】 is a single or double bond; Each Z ２ are independently N or C, and Z ２ If is N, then 【Chemistry 61】 is a single bond; Z ２ If is C, then 【Transformation 62】 is a double bond; Each R ９ are independently —C(O)OH, —C(O)OC １ -C ６ Alkyl, —C(O)NH ２ , or -P(O)(OH) ２ and 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 which is H and R １０ and R ３０ The other of the two is -C ２－５ Alkyl-O-R １３ , —O—C ２－５ Alkyl-R １３ , or -C ２－５ Alkyl-NMe-R １３ where 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 said tetralin is optionally substituted with at least one substituent selected from a bridged —CH ２ - group; or said naphthyl is optionally substituted by -O- or -S- group; R １２ teeth, 【Transformation 63】 and Each R ３３ are independently H, R １９ or C optionally substituted with morpholine or piperazine １ -C ６ is alkyl; R ３１ is -C ２－５ Alkyl-O-R １３ , —O—C ２－５ Alkyl-R １３ , or -C ２－５ Alkyl-NMe-R １３ where 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 said tetralin is optionally substituted with at least one substituent selected from a bridged —CH ２ - group; or said naphthyl is optionally substituted with -O- or -S-; Each R ３２ are independently, H, 【Chemistry 64】 and Here, R ２０ is Me, -CH ２ -OMe, -(CH ２ CH ２ O) ｐ (C １ -C ６ alkyl), -CH ２ —O-bromobenzaldehyde, or 【Transformation 65】 wherein p is 1 to 5; R ３４ is C ２－５ Alkyl-O-R １３ or -O-C ２－５ Alkyl-R １３ where 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 said tetralin is optionally substituted with at least one substituent selected from a bridged —CH ２ - group; or said naphthyl is optionally substituted with -O- or -S-; R ３５ teeth, 【Chemical Formula 66】 and 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 containing [Linker] is a group represented by the following formula: R １４ -R １５ -R １６ -R １７ -R １８ wherein R １４ is -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 a 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 is -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 is -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 is -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

52. Compounds of formula (I) [MCL-1 ligand site]-[linker]-[ligase ligand site] (I) or a salt, solvate, hydrate, isomer or prodrug thereof (wherein, [ligase ligand site] is (a) Formula (VIa) or (VIb): 【Transformation 67】 (In the formula, M is O, S, or NH, or absent; 【Transformation 68】 is R of the linker １８ indicates a bond to 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): 【Transformation 69】 (In the formula, X １ and X ２ each is independently 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 teeth, 【Transformation 70】 is selected from, where: 【Chemistry 71】 indicates binding 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 independently represents 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 connected to a single R ２１ Contains; During the ceremony, (i) R ｙ but 【Chemistry 72】 If Y ２ is CR ｄ and (ii) R ｙ but 【Transformation 73】 If ｉ ２ R ｉ is not hydrogen) or (c) Formula (III): 【Chemistry 74】 (In the formula, X １ and X ２ each is independently 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 teeth, 【Chemistry 75】 is selected from, where: 【Transformation 76】 indicates binding 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 independently represents N or CR ｃ and Y １ and Y ２ each independently represents 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 together with the carbon atom to which it is attached form a 5- or 6-membered ring; 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 connected to a single R ２１ Contains; where 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 【Chemical 77】 and Z ４ When is NH, L １ is hydrogen, -CH ２ C(O)OR ｂ , or -OR ｂ and (ii) R ｘ but 【Transformation 78】 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 【Transformation 79】 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 【Chemistry 80】 rather than; (v) R ｘ but 【Chemistry 81】 and Z ４ NR ４ and Y １ or Y ２ If is N, then R ４ is not alkyl; (vi)R ｘ が 【Chemistry 82】 where n=1 or 2; and (vii) R ｘ but 【Chemistry 83】 If Z ４ =O or S), The [MCL-1 ligand site] is a compound of formula (A1), (A2), (A3) or (A4): 【Chemical 84】 (In the formula, 【Chemical 85】 is a single or double bond; Each Z ２ are independently N or C, and Z ２ If is N, then 【Chemical 86】 is a single bond; Z ２ If is C, then 【Transformation 87】 is a double bond; Each R ９ are independently —C(O)OH, —C(O)OC １ -C ６ Alkyl, —C(O)NH ２ , or -P(O)(OH) ２ and 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 which is H and R １０ and R ３０ The other of the two is -C ２－５ Alkyl-O-R １３ , —O—C ２－５ Alkyl-R １３ , or -C ２－５ Alkyl-NMe-R １３ where 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 said tetralin is optionally substituted with at least one substituent selected from a bridged —CH ２ - group; or said naphthyl is optionally substituted by -O- or -S- group; R １２ teeth, 【Chemical 88】 and Each R ３３ are independently H, R １９ or C optionally substituted with morpholine or piperazine １ -C ６ is alkyl; R ３１ is -C ２－５ Alkyl-O-R １３ , —O—C ２－５ Alkyl-R １３ , or -C ２－５ Alkyl-NMe-R １３ where 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 said tetralin is optionally substituted with at least one substituent selected from a bridged —CH ２ - group; or said naphthyl is optionally substituted with -O- or -S-; Each R ３２ are independently, H, 【Chemical 89】 and Here, R ２０ is Me, -CH ２ -OMe, -(CH ２ CH ２ O) ｐ (C １ -C ６ alkyl), -CH ２ —O-bromobenzaldehyde, or 【Chemistry 90】 wherein p is 1 to 5; R ３４ is C ２－５ Alkyl-O-R １３ or -O-C ２－５ Alkyl-R １３ where 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 said tetralin is optionally substituted with at least one substituent selected from a bridged —CH ２ - group; or said naphthyl is optionally substituted with -O- or -S-; R ３５ teeth, 【Chemistry 91】 and 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 containing [Linker] is a group represented by the following formula: R １４ -R １５ -R １６ -R １７ -R １８ wherein R １４ is -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 a 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 is -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 is -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 is -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

53. [ligase ligand site] is 【Chemistry 92】 53. The compound of claim 52, wherein:

54. R １６ is -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 is -CH ２ (C ２ H ４ -O) ｙ , (C ２ H ４ -O) ｘ , (C ３ H ６ -O) ｘ , or absent; R １８ is -C １－６ Alkyl, cycloalkyl, CH ２ 54. The compound of any one of claims 51 to 53, which is -NH-C(O)-, heterocycloalkyl, or absent.

55. [Linker] is 【Chemistry 93】 wherein: 【Chemical 94】 indicates binding to the [MCL-1 ligand site], 【Chemical 95】 55. The compound of claim 53 or 54, wherein: indicates binding to a [ligase ligand site].

56. The compound according to any one of claims 51 to 55, wherein the [MCL-1 ligand site] is: 【Chemistry 96】

57. 57. The compound of claim 56, wherein: 【Chemistry 97】

58. The [ligase ligand site] has the formula (III): 【Chem.98】 53. The compound of claim 52, wherein:

59. The compound of claim 58, wherein the [ligase ligand site] is: 【Chem.99】

60. Compounds of formula (I) [MCL-1 ligand site]-linker-[ligase ligand site] (I) or a salt, solvate, hydrate, isomer or prodrug thereof (wherein, [ligase ligand site] is 【Chemistry 100】 (In the formula, M is O, S, or NH, or absent; 【Chemistry 101】 is R of the linker １８ indicates a bond to 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; The MCL-1 ligand site is a compound of formula (A): 【Chemical Engineering 102】 (In the formula, 【Chemistry 103】 is a single or double bond; R ８ is H, R １９ or C optionally substituted with morpholine or piperazine １ -C ６ is alkyl; R ９ is -C(O)OH, -C(O)OC １ -C ６ Alkyl, —C(O)NH ２ , or -P(O)(OH) ２ and R １０ and R ３０ one of which is H and R １０ and R ３０ The other of the two is -C ２－５ Alkyl-O-R １３ , —O—C ２－５ Alkyl-R １３ , or -C ２－５ Alkyl-NMe-R １３ where 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 said tetralin is optionally substituted with at least one substituent selected from a bridged —CH ２ - group; or said naphthyl is optionally substituted by -O- or -S- group; R １１ is H, halogen, or C １ -C ６ is alkyl, R １２ H, 【Chemical 104】 and Here, R ２０ is Me, -CH ２ -OMe, -(CH ２ CH ２ O) ｐ (C １ -C ６ alkyl), or -CH ２ -O-bromobenzaldehyde, where p is 1 to 5; Or, R １２ but 【Chemistry 105】 and R １０ is —O-naphthyl substituted with —O— or —S—, R ２０ teeth 【Chemistry 106】 (In the formula, 【Chemistry 107】 is R １０ represents a bond to —O— or —S—; and, R １９ is R of the linker １４ is a bond connected to; Z ２ is N or C, and Z ２ If is N, then 【Chemistry 108】 is a single bond; Z ２ If is C, then 【Chemistry 109】 is a double bond, Formula (A) is a single R １９ containing [Linker] is a group represented by the following formula: R １４ -R １５ -R １６ -R １７ -R １８ wherein R １４ is -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 a 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 is -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 is -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 is -C １－６ Alkyl-C(O)-, cycloalkyl, or —CH ２ -NH-C(O)-).

61. [ligase ligand site] is 【Chemical 110】 61. The compound of claim 60, wherein:

62. R １６ is -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 is -CH ２ (C ２ H ４ -O) ｙ , (C ２ H ４ -O) ｘ , (C ３ H ６ -O) ｘ , or absent, R １８ is cycloalkyl or —CH ２ 62. The compound of claim 60 or 61, which is -NH-C(O)-.

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

64. R １４ is -C １－６ 64. The compound of claim 63, which is alkyl.

65. R １５ The compound of any one of claims 60 to 64, wherein is heterocycloalkyl.

66. R １５ is piperazine, 【Chemistry 111】 and 【Chemistry 112】 is R １４ indicates the bond to 【Chemistry 113】 is R １６ 66. The compound of claim 65, wherein the compound exhibits binding to

67. R １６ is -C １－６ Alkyl, —CH ２ The compound according to any one of claims 60 to 66, which is -C(O)- or -C(O)-.

68. R １７ 68. The compound of any one of claims 60 to 67, wherein is absent.

69. R １８ The compound of any one of claims 60 to 68, wherein is cyclobutyl.

70. The compound according to any one of claims 59 to 69, wherein the [MCL-1 ligand site] is: 【Chemistry 114】

71. Compounds of formula (I) [MCL-1 ligand site]-[linker]-[ligase ligand site] (I) or a salt, solvate, hydrate, isomer or prodrug thereof (wherein, [ligase ligand site] is (a) Formula (IV) or (IVa) 【Chemical 115】 (In the formula, X １ and X ２ each is independently O or S; Q １ and Q ２ each independently represents 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 is independently 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 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 connected to a single R ２１ containing (b) Formula (VIIa), (VIIb), (VIIc) or (VIId): 【Chemistry 116】 (In the formula, X １ and X ２ each is independently 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 independently represents 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 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 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 connected to a single R ２１ containing (c) Formula (VIII): 【Chemistry 117】 (In the formula, X １ and X ２ each 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)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 connected to a single R ２１ containing (d) Formula (IX): 【Chemistry 118】 (In the formula, X １ and X ２ each 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)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 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 , 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 connected to a single R ２１ containing The MCL-1 ligand site is a compound of formula (A): 【Chemical 119】 (In the formula, 【Chemical 120】 is a single or double bond; R ８ is H, R １９ or C optionally substituted with morpholine or piperazine １ -C ６ is alkyl; R ９ is -C(O)OH, -C(O)OC １ -C ６ Alkyl, —C(O)NH ２ , or -P(O)(OH) ２ and R １０ and R ３０ one of which is H and R １０ and R ３０ The other of the two is -C ２－５ Alkyl-O-R １３ , —O—C ２－５ Alkyl-R １３ , or -C ２－５ Alkyl-NMe-R １３ where 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 said tetralin is optionally substituted with at least one substituent selected from a bridged —CH ２ - group; or said naphthyl is optionally substituted by -O- or -S- group; R １１ is H, halogen, or C １ -C ６ is alkyl, R １２ H, 【Chemistry 121】 and Here, R ２０ is Me, -CH ２ -OMe, -(CH ２ CH ２ O) ｐ (C １ -C ６ alkyl), -CH ２ -O-bromobenzaldehyde, or 【Chemistry 122】 or wherein p is 1 to 5; Or, R １２ but 【Chemical 123】 and R １０ is —O-naphthyl substituted with —O— or —S—, R ２０ teeth 【Chemistry 124】 (In the formula, 【Chemistry 125】 is R １０ represents a bond to —O— or —S—; and, R １９ is R of the linker １４ is a bond connected to; Z ２ is N or C, and Z ２ If is N, then 【Chemistry 126】 is a single bond; Z ２ If is C, then 【Chemistry 127】 is a double bond, Formula (A) is a single R １９ containing [Linker] is a group represented by the following formula: R １４ -R １５ -R １６ -R １７ -R １８ wherein R １４ is -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 a 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 is -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 is -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 is -C １－６ Alkyl-C(O)-, cycloalkyl, or —CH ２ -NH-C(O)-).

72. The [ligase ligand site] has the formula (IV): 【Chemistry 128】 72. The compound of claim 71, wherein:

73. 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 73. The compound of claim 71 or 72, wherein:

74. Each R ｂ is independently hydrogen, alkyl, cycloalkyl, or aryl.

75. The 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 75. The compound of claim 74, wherein:

76. E １ , E ２ , E ３ , and E ４ One of them is N and E １ , E ２ , E ３ , and E ４ the remaining three of which are each CR'; As appropriate, (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 The compound of any one of claims 71 to 75, wherein is CR'.

77. E １ , E ２ , E ３ and E ４ are each CR', and where appropriate, E １ , E ２ , E ３ and E ４ 76. The compound of any one of claims 71 to 75, wherein each is CH.

78. 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 78. The compound of claim 77, wherein:

79. (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 79. The compound of claim 78, wherein each is CH.

80. E １ , E ２ , E ３ , and E ４ Two of them are N and E １ , E ２ , E ３ , and E ４ The compound according to any one of claims 71 to 77, wherein the remaining two of are each CR'.

81. 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 71 to 77, wherein the remaining one of is CR'.

82. (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 appropriately, Q １ is C—H or C-alkyl, and optionally, Q １ is C-H or C-Me.

83. R １６ is -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 is -CH ２ (C ２ H ４ -O) ｙ , (C ２ H ４ -O) ｘ , (C ３ H ６ -O) ｘ , or absent; R １８ is cycloalkyl or —CH ２ The compound according to any one of claims 71 to 82, which is -NH-C(O)-.

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

85. R １４ is -C １－６ 85. The compound of claim 84, which is alkyl.

86. R １５ is a cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C １－６ 86. The compound of any one of claims 71 to 85, which is alkyl-NH-, -cycloalkyl-NH-, or absent.

87. R １５ 87. The compound of claim 86, wherein is heterocycloalkyl or absent.

88. R １５ 88. The compound of claim 87, wherein is piperazine.

89. R １６ The compound of any one of claims 71 to 88, wherein is -C(O)-.

90. R １７ The compound of any one of claims 71 to 89, wherein is absent.

91. R １８ is -CH ２ The compound according to any one of claims 71 to 90, which is -NH-C(O)-.

92. [Linker] is: 【Chemistry 129】 During the ceremony, 【Chemistry 130】 indicates binding to the [MCL-1 ligand site], 【Chemistry 131】 The compound according to any one of claims 71 to 91, wherein indicates binding to a [ligase ligand site].

93. The compound according to any one of claims 71 to 92, wherein the [MCL-1 ligand site] is: 【Chemistry 132】

94. 72. The compound of claim 71, wherein the compound is selected from the following: Table 2

95. 95. The compound of claim 94, wherein the compound is selected from the following: Table 3

96. 72. The compound of claim 71, wherein: 【Chemistry 133】

97. Compounds of formula (I) [MCL-1 ligand site]-[linker]-[ligase ligand site] (I) or a salt, solvate, hydrate, isomer or prodrug thereof (wherein, [ligase ligand site] is (a) Formula (Va) or (Vb): 【Chemistry 134】 or a pharmaceutically acceptable salt or tautomer thereof (In the formula, X １ and X ２ each is independently 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 independently represents 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 Formula (Va) and Formula (Vb) each represent a single R ２１ Contains; Z １ is O, then Y ６ is CR ７ and When the compound is a compound of formula (Va), (i) Y ５ , Y ６ and Y ７ Each of these is CR ７ If R ７ at least one of 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 NR''''C(O)OR'''' not; (v) Z １ is S and Y ５ If N, then Y ６ is not C—H, C-aryl, or C—C(O)OR″″; and (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 a compound of formula (Vb), (vii) Y ５ , Y ６ and Y ８ Each of these is CR ７ If R ７ at least one of 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 135】 (In the formula, X １ and X ２ each is independently 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 136】 indicates a single or double bond, where: 【Chemistry 137】 When each of W is a double bond, １ , W ２ , W ３ and W ４ each independently represents N or CR ａ and W １ , W ２ , W ３ and W ４ is N; 【Chemistry 138】 When each of 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 independently represents 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 is 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 formula (IIa) and formula (IIb) each represent a single R ２１ Contains; 【Chemistry 139】 each of which 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 ) and The MCL-1 ligand site is a compound of formula (A): [Chemistry 140] (In the formula, 【Chemistry 141】 is a single or double bond; R ８ is H, R １９ or C optionally substituted with morpholine or piperazine １ -C ６ is alkyl; R ９ is -C(O)OH, -C(O)OC １ -C ６ Alkyl, —C(O)NH ２ , or -P(O)(OH) ２ and R １０ and R ３０ one of which is H and R １０ and R ３０ The other of the two is -C ２－５ Alkyl-O-R １３ , —O—C ２－５ Alkyl-R １３ , or -C ２－５ Alkyl-NMe-R １３ where 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 said tetralin is optionally substituted with at least one substituent selected from a bridged —CH ２ - group; or said naphthyl is optionally substituted by -O- or -S- group; R １１ is H, halogen, or C １ -C ６ is alkyl, R １２ H, 【Chemistry 142】 and Here, R ２０ is Me, -CH ２ -OMe, -(CH ２ CH ２ O) ｐ (C １ -C ６ alkyl), -CH ２ -O-bromobenzaldehyde, or 【Chemistry 143】 or wherein p is 1 to 5; Or, R １２ but 【Chemistry 144】 and R １０ is —O-naphthyl substituted with —O— or —S—, R ２０ teeth 【Chemistry 145】 (In the formula, 【Chemistry 146】 is R １０ represents a bond to —O— or —S—; and, R １９ is R of the linker １４ is a bond connected to; Z ２ is N or C, and Z ２ If is N, then 【Chemistry 147】 is a single bond; Z ２ If is C, then 【Chemistry 148】 is a double bond, Formula (A) is a single R １９ containing [Linker] is a group represented by the following formula: R １４ -R １５ -R １６ -R １７ -R １８ wherein R １４ is -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 a 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 is -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 is -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 is -C １－６ Alkyl-C(O)-, cycloalkyl, or CH ２ -NH-C(O)-).

98. Compounds of formula (I) [MCL-1 ligand site]-[linker]-[ligase ligand site] (I) or a salt, solvate, hydrate, isomer or prodrug thereof (wherein, [ligase ligand site] is (a) Formula (VIa) or (VIb): 【Chemistry 149】 (In the formula, M is O, S, or NH, or absent; [Chemical 150] is R of the linker １８ indicates a bond to 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 151】 (In the formula, X １ and X ２ each is independently 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 teeth, 【Chemistry 152】 is selected from, where: 【Chemistry 153】 indicates binding 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 independently represents 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 connected to a single R ２１ Contains; During the ceremony, (i) R ｙ but 【Chemistry 154】 If Y ２ is CR ｄ and (ii) R ｙ but 【Chemistry 155】 If ｉ ２ R ｉ is not hydrogen) or (c) Formula (III): 【Chemistry 156】 (In the formula, X １ and X ２ each is independently 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 teeth, 【Chemistry 157】 is selected from, where: 【Chemistry 158】 indicates binding 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 independently represents N or CR ｃ and Y １ and Y ２ each independently represents 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 together with the carbon atom to which it is attached form a 5- or 6-membered ring; 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 connected to a single R ２１ Contains; where 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 159】 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 160] 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 161】 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 【Chemistry 162】 rather than; (v) R ｘ but 【Chemistry 163】 and Z ４ NR ４ and Y １ or Y ２ If is N, then R ４ is not alkyl; (vi)R ｘ が 【Chemistry 164】 where n=1 or 2; and (vii) R ｘ but 【Chemistry 165】 If Z ４ =O or S), The MCL-1 ligand site is a compound of formula (A): 【Chemistry 166】 (In the formula, 【Chemistry 167】 is a single or double bond; R ８ is H, R １９ or C optionally substituted with morpholine or piperazine １ -C ６ is alkyl; R ９ is -C(O)OH, -C(O)OC １ -C ６ Alkyl, —C(O)NH ２ , or -P(O)(OH) ２ and R １０ and R ３０ one of which is H and R １０ and R ３０ The other of them is -C ２－５ Alkyl-O-R １３ , —O—C ２－５ Alkyl-R １３ , or -C ２－５ Alkyl-NMe-R １３ where 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 said tetralin is optionally substituted with at least one substituent selected from a bridged —CH ２ - group; or said naphthyl is optionally substituted by -O- or -S- group; R １１ is H, halogen, or C １ -C ６ is alkyl, R １２ H, 【Chemical 168】 and Here, R ２０ is Me, -CH ２ -OMe, -(CH ２ CH ２ O) ｐ (C １ -C ６ alkyl), -CH ２ -O-bromobenzaldehyde, or 【Chemistry 169】 wherein p is 1 to 5; or R １２ but 【Chemistry 170】 and R １０ is —O-naphthyl substituted with —O— or —S—, R ２０ teeth 【Chemistry 171】 (In the formula, 【Chemistry 172】 is R １０ represents a bond to —O— or —S—; and, R １９ is R of the linker １４ is a bond connected to; Z ２ is N or C, and Z ２ If is N, then 【Chemistry 173】 is a single bond; Z ２ If is C, then 【Chemistry 174】 is a double bond, Formula (A) is a single R １９ containing [Linker] is a group represented by the following formula: R １４ -R １５ -R １６ -R １７ -R １８ wherein R １４ is -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 a 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 is -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 is -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 is -C １－６ Alkyl-C(O)-, cycloalkyl, or CH ２ -NH-C(O)-).

99. R １６ is -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 is -CH ２ (C ２ H ４ -O) ｙ , (C ２ H ４ -O) ｘ , (C ３ H ６ -O) ｘ , or absent; R １８ is cycloalkyl or CH ２ The compound of claim 97 or 98, which is -NH-C(O)-.

100. R １０ and R ３０ one of which is H and R １０ and R ３０ The other of them is -C ２－５ Alkyl-O-R １３ where 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 99. The compound of claim 58, wherein the naphthyl is optionally substituted with at least one substituent selected from -O- or -S-.

101. R ３０ The compound of any one of claims 59 to 100, wherein is H.

102. R １２ H, 【Chemistry 175】 The compound according to any one of claims 59 to 101,

103. R ２０ is Me, -CH ２ —O-bromobenzaldehyde, or 【Chemistry 176】 The compound according to any one of claims 59 to 102,

104. Z ２ is C, 【Chemistry 177】 The compound according to any one of claims 59 to 103, wherein is a double bond.

105. R １１ The compound of any one of claims 59 to 104, wherein is hydrogen.

106. R １１ The compound of any one of claims 59 to 104, wherein is halogen.

107. The compound according to any one of claims 59 to 106, wherein the [MCL-1 ligand site] is: 【Chemistry 178】

108. Compounds of formula (I) [MCL-1 ligand site]-linker-[ligase ligand site] (I) or a salt, solvate, hydrate, isomer or prodrug thereof (wherein, [ligase ligand site] is 【Chemistry 179】 (In the formula, M is O, S, or NH, or absent; 【Chemistry 180】 is R of the linker １８ indicates a bond to R ２４ is —OMe or heterocycloalkyl; R ２２ is hydrogen, halogen, —OMe, an amino group, heterocycloalkyl, or unsubstituted C １ -C ６ is alkyl; R ２９ is hydrogen or Me; and L' is hydrogen, alkyl, benzyl, acetyl, or pivaloyl; The MCL-1 ligand site is a compound of formula (A): 【Chemistry 181】 (In the formula, 【Chemistry 182】 is a single or double bond; R ８ is H, R １９ or C optionally substituted with morpholine or piperazine １ -C ６ is alkyl; R ９ is -C(O)OH, -C(O)OC １ -C ６ Alkyl, —C(O)NH ２ , or -P(O)(OH) ２ and R １０ and R ３０ one of which is H and R １０ and R ３０ The other of them is -C ２－５ Alkyl-O-R １３ , —O—C ２－５ Alkyl-R １３ , or -C ２－５ Alkyl-NMe-R １３ where 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 said tetralin is optionally substituted with at least one substituent selected from a bridged —CH ２ - group; or said naphthyl is optionally substituted by -O- or -S- group; R １１ is H, halogen, or C １ -C ６ is alkyl, R １２ H, 【Chemistry 183】 and Here, R ２０ is Me, -CH ２ -OMe, -(CH ２ CH ２ O) ｐ (C １ -C ６ alkyl), or -CH ２ -O-bromobenzaldehyde, where p is 1 to 5; Or, R １２ but 【Chemistry 184】 and R １０ is —O-naphthyl substituted with —O— or —S—, R ２０ teeth 【Chemistry 185】 (In the formula, 【Chemistry 186】 is R １０ represents a bond to —O— or —S—; and, R １９ is R of the linker １４ is a bond connected to; Z ２ is N or C, and Z ２ If is N, then 【Chemistry 187】 is a single bond; Z ２ If is C, then 【Chemical 188】 is a double bond, Formula (A) is a single R １９ containing [Linker] is a group represented by the following formula: R １４ -R １５ -R １６ -R １７ -R １８ wherein R １４ is -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 a 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 is -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 is -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 is -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

109. 109. The compound of claim 108, wherein L' is hydrogen or methyl.

110. 110. The compound of claim 109, wherein L' is hydrogen.

111. 110. The compound of any one of claims 108 to 109, wherein M is O or NH, or absent.

112. The compound of claim 108, wherein the [ligase ligand site] is: 【Chemical 189】

113. R １６ is -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 is -CH ２ (C ２ H ４ -O) ｙ , (C ２ H ４ -O) ｘ , (C ３ H ６ -O) ｘ , or absent; R １８ is C １－６ Alkyl, cycloalkyl, CH ２ 113. The compound of any one of claims 108 to 112, which is -NH-C(O)-, heterocycloalkyl, or absent.

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

115. R １４ is -C １－６ 115. The compound of claim 114, which is alkyl.

116. R １５ is a cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C １－６ 116. The compound of any one of claims 108 to 115, which is alkyl-NH-, -cycloalkyl-NH-, or absent.

117. R １５ is heterocycloalkyl or absent.

118. R １５ is piperazine, bridged piperazine, piperazine N-oxide, piperazine cation, 【Chemistry 190】 or absent; 【Chemistry 191】 is R １４ indicates the bond to 【Chemistry 192】 is R １６ 118. The compound of claim 117, wherein the compound exhibits binding to

119. R １５ is piperazine, 【Chemistry 193】 or absent.

120. R １６ is -C １－６ Alkyl, —CH ２ -C(O)-NH-, -CH ２ 120. The compound of any one of claims 108 to 119, which is -C(O)-, -C(O)-, or absent.

121. R １７ The compound of any one of claims 108 to 120, wherein is absent.

122. R １８ is -C １－６ Alkyl, cyclobutyl, CH ２ 122. The compound of any one of claims 108 to 121, which is -NH-C(O)-, piperazine, or absent.

123. [Linker] is 【Chemistry 194】 is selected from During the ceremony, 【Chemistry 195】 indicates binding to the [MCL-1 ligand site], 【Chemistry 196】 The compound according to any one of claims 108 to 122, wherein indicates binding to a [ligase ligand site].

124. The compound of claim 123, wherein the linker is selected from the following: 【Chemistry 197】

125. The compound according to any one of claims 108 to 124, wherein the MCL-1 ligand site is selected from the following: 【Chemistry 198】

126. 109. The compound of claim 108, selected from the following: Table 4 Table 5

127. The compound of claim 108, wherein the compound is compound 22.

128. Compounds of formula (I) [MCL-1 ligand site]-[linker]-[ligase ligand site] (I) or a salt, solvate, hydrate, isomer or prodrug thereof wherein [ligase ligand site] is represented by formula (VIa) or (VIb): 【Chemistry 199】 (In the formula, M is O, S, or NH, or absent; 【Chemistry 200】 is R of the linker １８ indicates a bond to 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; The MCL-1 ligand site is a compound of formula (A): 【Chemical Engineering 201】 (In the formula, 【Chemical Engineering 202】 is a single or double bond; R ８ is H, R １９ or C optionally substituted with morpholine or piperazine １ -C ６ is alkyl; R ９ is -C(O)OH, -C(O)OC １ -C ６ Alkyl, —C(O)NH ２ , or -P(O)(OH) ２ and R １０ and R ３０ one of which is H and R １０ and R ３０ The other of the two is -C ２－５ Alkyl-O-R １３ , —O—C ２－５ Alkyl-R １３ , or -C ２－５ Alkyl-NMe-R １３ where 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 said tetralin is optionally substituted with at least one substituent selected from a bridged —CH ２ - group; or said naphthyl is optionally substituted by -O- or -S- group; R １１ is H, halogen, or C １ -C ６ is alkyl, R １２ H, 【Chemical 203】 and Here, R ２０ is Me, -CH ２ -OMe, -(CH ２ CH ２ O) ｐ (C １ -C ６ alkyl), -CH ２ -O-bromobenzaldehyde, or 【Chemical 204】 wherein p is 1 to 5; or R １２ but 【Chemical 205】 and R １０ is —O-naphthyl substituted with —O— or —S—, R ２０ teeth 【Chemical 206】 (In the formula, 【Chemical 207】 is R １０ represents a bond to —O— or —S—; and, R １９ is R of the linker １４ is a bond connected to; Z ２ is N or C, and Z ２ If is N, then 【Chemical 208】 is a single bond; Z ２ If is C, then 【Chemical Engineering 209】 is a double bond, Formula (A) is a single R １９ containing [Linker] is a group represented by the following formula: R １４ -R １５ -R １６ -R １７ -R １８ wherein R １４ is -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 a 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 is -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 is -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 is -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

129. The compound of claim 128, wherein the [ligase ligand site] is: 【Chemical 210】

130. R １６ is -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 is -CH ２ (C ２ H ４ -O) ｙ , (C ２ H ４ -O) ｘ , (C ３ H ６ -O) ｘ , or absent; R １８ is -C １－６ Alkyl, cycloalkyl, CH ２ 130. The compound of claim 128 or 129, which is -NH-C(O)-, heterocycloalkyl, or absent.

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

132. R １４ is -C １－６ 132. The compound of claim 131, which is alkyl.

133. R １５ is a cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C １－６ 133. The compound of any one of claims 128 to 132, which is alkyl-NH-, -cycloalkyl-NH-, or absent.

134. R １５ is heterocycloalkyl or absent.

135. R １５ is piperazine.

136. R １６ The compound according to any one of claims 128 to 135, wherein is -C(O)-.

137. R １７ The compound of any one of claims 128 to 136, wherein is absent.

138. R １８ is -C １－６ The compound of any one of claims 128 to 137, which is alkyl.

139. The compound according to any one of claims 128 to 138, wherein [Linker] is: 【Chemistry 211】

140. The compound according to any one of claims 128 to 139, wherein the [MCL-1 ligand site] is: 【Chemical Engineering 212】

141. 141. The compound of claim 140, wherein: 【Chemistry 213】

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; (b) X １ is O and X ２ Is S? (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 1.

145. 145. The compound of any one of claims 1 to 144, wherein each alkyl, alkenyl, alkynyl, aryl, heteroaryl, and benzyl is unsubstituted unless otherwise specified.

146. A compound selected from: Table 6

147. A compound selected from: Table 7

148. Selected from the following: Table 8 Table 9 Optionally, the compound of claim 147 is compound 12.

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

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

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

152. 152. The method of claim 151, 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.

153. 152. The method of claim 151, wherein the cancer is multiple myeloma acute myeloid leukemia.

154. 154. The method of any one of claims 151 to 153, wherein the administration does not result in cytotoxicity in the subject's cardiomyocytes.

155. 155. The method of any one of claims 151 to 154, further comprising administering to the subject at least one additional active agent.

156. The method of claim 155, 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.

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

158. A combined preparation of a compound according to any one of claims 1 to 148 and at least one additional active agent for simultaneous, separate or sequential use in therapy.

159. The combination preparation of claim 158, 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.

160. 160. The combined preparation of claim 158 or 159, wherein the therapy is the treatment of cancer.

161. A method for reducing cardiac cell toxicity of an MCL-1 inhibitor, comprising the step of binding a cereblon binding site to an MCL-1 inhibitor, wherein the cereblon binding site is a [ligase ligand site] as defined in any one of claims 1 to 148, and the MCL-1 inhibitor is an [MCL-1 ligand site] as defined in any one of claims 1 to 148.

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