Targeted protein degradation using prodrugs of bifunctional compounds binding to ubiquitin ligase and target MCL-1 protein

Abstract

Compounds of formula (I): [MCL-1 ligand prodrug moiety]-[linker]-[ligase ligand moiety] (I), or salts, solvates, hydrates or isomers thereof, where [MCL-1 ligand prodrug moiety] is e.g. A compound of the formula, and their use for the treatment of cancer. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to prodrugs of bifunctional compounds that are capable of binding to a ubiquitin ligase and also capable of binding to a target protein, such that the target protein is placed in proximity to the ubiquitin ligase to induce its degradation. Background Art

[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 proteins for degradation via the proteasome. Ubiquitination is central to the regulation of almost all cellular processes and is itself strictly regulated. Ubiquitin ligases promote ubiquitination of different proteins in vivo and contribute to the precise regulation of the system. Once recognized, ubiquitin ligases mediate the attachment of the ubiquitin moiety to the target protein, which marks the target protein for degradation by the proteasome.

[0003] The idea of ​​selective target protein degradation (TPD) regulated by the UPS was first proposed in 1999 (US2002173049 A1 (PROTEINIX INC), November 21, 2002). One approach to TPD is to use bifunctional molecules that simultaneously bind to ubiquitin ligases and target proteins, enabling efficient transfer of ubiquitin to the latter. This concept was first proposed by Skamoto KM et al. (Proc Natl Acad Sci US A. 2001 Jul 17; 98(15): 8554-9) and recently reviewed by Burslem GM and Crews CM (Cell. 2020 Apr 2; 181(1): 102-114).

[0004] Oncogenic stress, such as DNA damage, can lead to programmed cell death, a cellular response designed to prevent oncogenic transformation. This mechanism relies on the interplay between pro-apoptotic and anti-apoptotic Bcl-2 proteins, and the balance of these proteins is crucial for normal cellular function.

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

[0006] High expression of myeloid leukemia cell differentiation protein (MCL-1) has been observed in many human cancers and is associated with resistance to cytotoxic drugs. Studies have shown that inhibition of MCL-1 protein in some malignancies leads to the release of pro-apoptotic proteins and induction of apoptosis. Therefore, targeting MCL-1 could be a therapeutic strategy for 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). In addition, treatment with Bcl-2 inhibitors 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 is a driver of adaptive survival of tumor cells treated with oncogene-targeted therapies, and therefore MCL-1-targeted drugs may overcome cancer resistance to these therapies.

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

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

[0009] It is also desirable to develop prodrugs for MCL-1 targeted therapies. Some potential advantages of prodrugs may be that the bioavailability of the active therapeutic compound may be increased, thereby allowing for administration of lower doses. The risk of adverse side effects of the active therapeutic compound may also be reduced. Summary of the Invention

[0010] According to a first aspect of the present invention, there is provided a compound of formula (I):

[0011] [MCL-1 ligand prodrug moiety]-linker-[ligase ligand moiety] (I) or a salt, solvate, hydrate or isomer thereof,

[0012] Wherein, [ligase ligand part] is:

[0013]

[0014] in:

[0015] M is O, S or NH, or does not exist;

[0016] represents R connected to the linking group 18 ;

[0017] R 22 is hydrogen, halogen, -OMe, amino, heterocycloalkyl, or unsubstituted C1-C6 alkyl; and

[0018] R 29 is hydrogen or Me;

[0019] L' is hydrogen, alkyl, benzyl, acetyl or pivaloyl;

[0020] wherein [MCL-1 ligand prodrug moiety] is a compound of formula (A1), formula (A2), formula (A3) or formula (A4):

[0021]

[0022] in:

[0023] is a single bond or a double bond;

[0024] Each Z2 is independently N or C, wherein when Z2 is N, then is a single bond; when Z2 is C, is a double bond;

[0025] Each R 11 are independently H, halogen or C1-C6 alkyl,

[0026] R 8 is a C1-C6 alkyl group substituted with piperazine;

[0027] In each of formula (A1) and formula (A4), R 10 and R 30 One of them is H, R 10 and R 30 The other one 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 tetrahydronaphthyl, wherein the phenyl, naphthyl or tetrahydronaphthyl is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl and -O(C1-C6 alkyl); or wherein the tetrahydronaphthyl is optionally substituted with a bridging -CH2- group; or wherein the naphthyl is optionally substituted with -O- or -S-,

[0028] R 12 for

[0029] R 31 Yes-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 tetrahydronaphthyl, wherein the phenyl, naphthyl or tetrahydronaphthyl is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl and -O(C1-C6 alkyl); or wherein the tetrahydronaphthyl is optionally substituted with a bridged -CH2- group; or wherein the naphthyl is optionally substituted with -O- or -S-;

[0030] Each R 32 are independently H,

[0031] Each R 33 Independently R 19 or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with morpholine or piperazine;

[0032] R 20 Me, -CH2-OMe, -(CH2CH2O) p (C1-C6 alkyl) or -CH2-O-bromobenzaldehyde, wherein p is 1-5;

[0033] R 34 It is C2-5 Alkyl-OR 13 or -OC 2-5 Alkyl-R 13 , where R 13 is phenyl, naphthyl or tetrahydronaphthyl, wherein the phenyl, naphthyl or tetrahydronaphthyl is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl and -O(C1-C6 alkyl); or wherein the tetrahydronaphthyl is optionally substituted with a bridged -CH2- group; or wherein the naphthyl is optionally substituted with -O- or -S-;

[0034] R 35 for

[0035] R 19 is the R of the linking group 14 wherein each of Formula (A1), Formula (A2), Formula (A3) and Formula (A4) contains a single R 19 ;

[0036] and

[0037] (i)R 9 is -C(O)O(C1-C6 alkyl), -C(O)O cycloalkyl, -C(O)O heterocycloalkyl, -C(O)O aryl or -P(O)(OR p ) 2, wherein the C1-C6 alkyl group is substituted by one or more groups selected from the following: -OC(O) (unsubstituted C1-C6 alkyl), -OC(O) (substituted by at least one R 10 substituted C1-C6 alkyl), -OC(O)cycloalkyl, -OC(O)heterocycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, -OC(O)(CH2) m O(CH2) m O(unsubstituted C1-C6 alkyl), -OC(O)(CH2) m O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(unsubstituted C1-C6 alkyl), -OC(O)O(substituted by at least one R 10 Substituted C1-C6 alkyl), -OC(O)O cycloalkyl, -OC(O)O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2CH2O) m (C1-C6 alkyl substituted with OP(O)(OH)2), -OC(O)O(CH2CH2S) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2) mS(O)(unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)2(unsubstituted C1-C6 alkyl), -OC(O)NH(C1-C6 alkyl substituted by OMe), -OC(O)NMe(C1-C6 alkyl substituted by OMe), -P(O)(OH)2, -OP(O)(OH)2, -C(O)heterocycloalkyl, -C(O)N(unsubstituted C1-C6 alkyl)2, heteroaryl, heterocycloalkyl, -S(unsubstituted C1-C6 alkyl), -S(O)(unsubstituted C1-C6 alkyl), -N + (unsubstituted C1-C6 alkyl)3, -N + (Unsubstituted C1-C6 alkyl)2-cycloalkyl, N-(unsubstituted C1-C6 alkyl)piperidine Cation, N-(unsubstituted C1-C6 alkyl)morpholine Cation and N-(unsubstituted C1-C6 alkyl) imidazole cation;

[0038] Among them, each R 10 are independently -OH, -O(unsubstituted C1-C6 alkyl), -OBn, -NH2, -NMe2, -NHC(O)(unsubstituted C1-C6 alkyl), -NHC(O)O(unsubstituted C1-C6 alkyl), heterocycloalkyl, heteroaryl, aryl, -C(O)NMe2;

[0039] Each R p are independently -(CH2) m OC(O) (unsubstituted C1-C6 alkyl), and

[0040] Each m is independently 1, 2, 3 or 4;

[0041] or

[0042] (ii)R 9 is -C(O)O(CH2) p NMe2, -C(O)O(CH2) p NHMe, -C(O)OCH2CH(OH)CH2OH, -C(O)OCH2CH2CMe2OH, or -C(O)OCH2CH2SO2Me, wherein each p is independently 2, 3, 4, 5, or 6;

[0043] and wherein [linking group] has the formula:

[0044] R 14 -R 15 -R 16 -R 17 -R 18

[0045] in:

[0046] 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;

[0047] R 15 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 Alkyl-NH-, -C 1-6 Alkyl-N(C 1-6 alkyl)-, -cycloalkyl-NH-, -heterocycloalkyl-NH- or absent;

[0048] 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;

[0049] R 17 -CH2(C2H4-O) y 、-(CH2O) x 、-(C2H4-O) x 、-(C3H6-O) x or does not exist;

[0050] x is 1-10;

[0051] y is 2-10;

[0052] R 18 -C 1-6 Alkyl, -C 1-6 Alkyl-C(O)-, cycloalkyl, -CH2-NH-C(O)-, heterocycloalkyl or absent;

[0053] where R 14 -R 18 At least one of exists.

[0054] In some embodiments, [ligase ligand moiety] is:

[0055]

[0056] In some embodiments, [ligase ligand moiety] is:

[0057]

[0058] In some embodiments, [ligase ligand moiety] is:

[0059]

[0060] In some embodiments, R 22 For hydrogen.

[0061] In some embodiments, L' is hydrogen.

[0062] In some embodiments, M is O or NH, or is absent.

[0063] In some embodiments, [ligase ligand moiety] is

[0064] In some embodiments, [ligase ligand moiety] is:

[0065] In some embodiments, [ligase ligand moiety] is:

[0066]

[0067]

[0068] In some embodiments, [ligase ligand moiety] is:

[0069] In some embodiments, [ligase ligand moiety] is:

[0070] In some embodiments, [the ligase ligand moiety] is

[0071]

[0072] In some embodiments, [ligase ligand moiety] is:

[0073]

[0074] In some embodiments:

[0075] 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;

[0076] R 17 is -CH2(C2H4-O) y 、-(C2H4-O) x 、-(C3H6-O) x or does not exist;

[0077] R 18 Yes-C 1-6 Alkyl, cycloalkyl, -CH2-NH-C(O)-, heterocycloalkyl or absent.

[0078] In some embodiments, R 14 -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 In some such embodiments, R 14 Yes-C 1-6 alkyl.

[0079] In some embodiments, R 15 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 In some embodiments, R 15 In some such embodiments, R 15 is piperazine, bridged piperazine, piperazine N-oxide, piperazine cation,

[0080]

[0081] in, Indicates connection to R 14 , Indicates connection to R 16 In some such embodiments, R 15 Is piperazine or

[0082] In other embodiments, R 15 Does not exist.

[0083] In some embodiments, R 16 Yes-C 1-6 In some such embodiments, R 16 Yes-C 1-6 Alkyl or -C(O)-.

[0084] In some embodiments, R 17 Does not exist.

[0085] In some embodiments, R18 -C 1-6 In some embodiments, R 18 Yes-C 1-6 In some such embodiments, R 18 Yes-C 1-6 Alkyl or piperazine.

[0086] In some embodiments, R 18 Does not exist.

[0087] In some embodiments, [linking group] is selected from:

[0088]

[0089] in

[0090] represents attachment to [MCL-1 ligand prodrug moiety]; and

[0091] Indicates attachment to [ligase ligand moiety].

[0092] In some embodiments, [linking group] is selected from:

[0093]

[0094] in:

[0095] represents attachment to [MCL-1 ligand prodrug moiety]; and

[0096] Indicates attachment to [ligase ligand moiety].

[0097] In some embodiments, in each of Formula (A1) and Formula (A4), R 10 and R 30 One of them is H, R 10 and R 30 The other one is -C 2-5 Alkyl-OR 13 or -OC 2-5 Alkyl-R 13 , where R 13 is phenyl or naphthyl, wherein the phenyl or naphthyl is optionally substituted with at least one substituent selected from halogen and C1-C6 alkyl.

[0098] In some embodiments, in Formula (A1), R 12 for

[0099] In some embodiments, in Formula (A4), R 35 for

[0100] In some embodiments, in Formula (A2), R 31 -C 2-5 Alkyl-OR 13 or -OC 2-5 Alkyl-R 13 , where R 13 is phenyl or naphthyl, wherein the phenyl or naphthyl is optionally substituted with at least one substituent selected from halogen and C1-C6 alkyl.

[0101] In some embodiments, in Formula (A3), R 34 It is C 2-5 Alkyl-OR 13 or -OC 2-5 Alkyl-R 13 , where R 13 is phenyl or naphthyl, wherein the phenyl or naphthyl is optionally substituted with at least one substituent selected from halogen and C1-C6 alkyl.

[0102] In some embodiments, Z2 is C and For double bonds.

[0103] In some embodiments, [MCL-1 ligand prodrug moiety] is:

[0104]

[0105] in:

[0106] R 11 It is a halogen;

[0107] R 13a is a halogen; and

[0108] R 20 is Me, -CH2-OMe or -(CH2CH2O) p (C1-C6 alkyl), wherein p is 1-5.

[0109] In some embodiments, R 9 is -C(O)O(C1-C6 alkyl), -C(O)O cycloalkyl, -C(O)O heterocycloalkyl, -C(O)O aryl or -P(O)(OR p ) 2, wherein the C1-C6 alkyl group is substituted by one or more groups selected from the following: -OC(O) (unsubstituted C1-C6 alkyl), -OC(O) (substituted by at least one R 10substituted C1-C6 alkyl), -OC(O)cycloalkyl, -OC(O)heterocycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, -OC(O)(CH2) m O(CH2) m O(unsubstituted C1-C6 alkyl), -OC(O)(CH2) m O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(unsubstituted C1-C6 alkyl), -OC(O)O(substituted by at least one R 10 Substituted C1-C6 alkyl), -OC(O)O cycloalkyl, -OC(O)O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2CH2O) m (C1-C6 alkyl substituted with OP(O)(OH)2), -OC(O)O(CH2CH2S) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)(unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)2(unsubstituted C1-C6 alkyl), -OC(O)NH(C1-C6 alkyl substituted by OMe), -OC(O)NMe(C1-C6 alkyl substituted by OMe), -P(O)(OH)2, -OP(O)(OH)2, -C(O)heterocycloalkyl, -C(O)N(unsubstituted C1-C6 alkyl)2, heteroaryl, heterocycloalkyl, -S(unsubstituted C1-C6 alkyl), -S(O)(unsubstituted C1-C6 alkyl), -N + (unsubstituted C1-C6 alkyl)3, -N + (Unsubstituted C1-C6 alkyl)2-cycloalkyl, N-(unsubstituted C1-C6 alkyl)piperidine Cation, N-(unsubstituted C1-C6 alkyl)morpholine cation and N-(unsubstituted C1-C6 alkyl)imidazolyl cation.

[0110] In some embodiments, R 9 is -C(O)O(C1-C6 alkyl), -C(O)O cycloalkyl, -C(O)O heterocycloalkyl, -C(O)O aryl or -P(O)(OR p ) 2, wherein the C1-C6 alkyl group is substituted by one or more groups selected from the group consisting of: -OC(O)Me, -OC(O)Et, -OC(O) iPr, -OC(O)C(CH3)3, -OC(O)CH2OH, -OC(O)CH(CH3)OH, -OC(O)C(CH3)2OH, -OC(O)CH2CH2OH, -OC(O)CH(OH)CHMe2, -OC(O)CH(OH)CH2CHMe2, -OC(O)CH2CH(OH)Me, -OC(O)CH2C(OH)Me2, -OC(O)CH(CH2OH)(NHC(O)Me), -OC(O)CH(NHC(O)Me)(isobutyl), -OC(O)CH(OH)aryl, -OC(O)CH(OH)CH2aryl, -OC(O)heterocycloalkyl, -OC(O)cycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, -OC(O)CH2CH2aryl, -OC(O)CH(NH2) i Pr, -OC(O)CH( i Pr)NHC(O)O t Bu, -OC(O)CH2OCH2CH2OMe, -OC(O)CH2(OCH2CH2)2OMe, -OC(O)OMe, -OC(O)OEt, -OC(O)O i Pr, -OC(O)Ocycloalkyl, -OC(O)OCH2CH2OEt, -OC(O)O(CH2CH2O)2Et, -OC(O)O(CH2CH2O)3Et, -OC(O)O(CH2CH2O)3CH2CH2OP(O)(OH)2, -OC(O)OCH2CH2SMe, -OC(O)OCH2CH2S(O)Me, -OC(O)OCH2CH2S(O)2Me, -OC(O)OCH2heteroaryl, -OC(O)OCH2heterocycloalkyl, -OC (O)OCH2CH2OCH2aryl-OC(O)OCH2CH2C(O)NMe2、-OC(O)O(CH2)6NH2、-OC(O)O(CH2)6NMe2、-OC(O)OCH(CH2OEt)2、-OC(O)NHCH2CH2OMe、-OC(O)NMeCH2CH2OMe、-SMe、-S(O)Me、-P(O)(OH)2、-OP(O)(OH)2、-C(O)NMe2、-C(O)heterocycloalkyl、heteroaryl、heterocycloalkyl、-N + (Me)3, -N + (Me)2 cycloalkyl, N-methylmorpholine Cation, N-methylpiperidine Cation and N-methylimidazole In some such embodiments, R 9It is -C(O)O(C1-C6 alkyl), wherein the C1-C6 alkyl is substituted by one or more groups selected from -O(CO)C(CH3)3, -OC(O)CH2CH2OH, -OC(O)C(CH3)2OH, -OC(O)heterocycloalkyl, -OC(O)CH2OCH2CH2OMe, -OC(O)OiPr, -OC(O)Ocycloalkyl, -OC(O)O(CH2CH2O)2Et, -OP(O)(OH)2, heteroaryl or heterocycloalkyl.

[0111] In other embodiments, R 9 is -C(O)OCH2OC(O)C(CH3)3, -C(O)OCH2OC(O)Me, -C(O)OCH(Me)OC(O)Me, -C(O)OCH2OC(O)CH2CH2OH, -C(O)OCH2OC(O)C(CH3)2OH, -C(O)OCH2OC(O)piperidine, -C(O)OCH2OC(O)CH2OCH2CH2OMe, -C(O)OCH2OC(O)OiPr, -C(O)OCHMeOC(O)OiPr, -C(O)OCHMeOC(O)Ocyclohexyl, -C(O)OCHMeOC(O)O(CH2CH2O)2Et, -C(O)OCH2CH2OP(O)(OH)2, -C(O)OCH2(N-methylimidazole) cation), -C(O)OCH2(N-methylpiperidin cation), -C(O)OCH2 dioxolane, -C(O)OCH2CH2 morpholine, -C(O)OCH2CH2 piperazine, -C(O)OCH2CH2CH2 piperazine or -P(O)(OCH2OC(O)C(CH3)3)2. In some such embodiments, R 9 -C(O)OCH2OC(O)C(CH3)3, -C(O)OCH2OC(O)Me, -C(O)OCH(Me)OC(O)Me, -C(O)OCH2OC(O)CH2CH2OH, -C(O)OCH2OC(O)C(CH3)2OH, -C(O)OCH2OC(O)piperidine, -C(O)OCH2OC(O)CH2OCH2CH2OMe, -C(O)OCH2OC(O)OiPr, -C(O)OCHMeOC(O)OiPr, -C(O)OCHMeOC(O)Ocyclohexyl, -C(O)OCHMeOC(O)O(CH2CH2O)2Et, -C(O)OCH2CH2OP(O)(OH)2, -C(O)OCH2(N-methylimidazole) cation), -C(O)OCH2(N-methylpiperidin cation), -C(O)OCH2dioxolane, -C(O)OCH2CH2morpholine, -C(O)OCH2CH2piperazine or -C(O)OCH2CH2CH2piperazine.

[0112] In some embodiments, R 9 is -C(O)O(CH2) p NMe2, -C(O)O(CH2) p NHMe, -C(O)OCH2CH(OH)CH2OH, C(O)OCH2CH2CMe2OH, or -C(O)OCH2CH2SO2Me, wherein each p is independently 2, 3, 4, 5, or 6. In some such embodiments, R 9 It is -C(O)OCH2CH2NMe2, -C(O)OCH2CH(OH)CH2OH or -C(O)OCH2CH2SO2Me.

[0113] In some embodiments, R 20 It is Me or -(CH2CH2O)2Me.

[0114] In some embodiments, R 33 It is R 19 In other embodiments, R 33 It is a C1-C6 alkyl group substituted by morpholine or piperazine.

[0115] In some embodiments, the C1-C6 alkyl group substituted with morpholine or piperazine is In some embodiments, R 11 For Cl.

[0116] In some embodiments, R 13a For F.

[0117] (c) In some embodiments, [MCL-1 ligand prodrug moiety] is:

[0118]

[0119] In some embodiments, [MCL-1 ligand prodrug moiety] is:

[0120]

[0121] In some embodiments, [linking group] is [Ligase ligand portion] is

[0122] and

[0123] [MCL-1 ligand prodrug moiety] is a compound of formula (A3), wherein:

[0124] R 32 yes and

[0125] R 9 It is C(O)O(straight chain C1-C6 alkyl)OC(O)C(CH3)3, C(O)O(straight chain C1-C6 alkyl)OC(O)heterocycloalkyl, C(O)O(straight chain C1-C6 alkyl)OC(O)CH2CH2OH, C(O)O(straight chain C1-C6 alkyl)OC(O)CH2OCH2CH2OMe, C(O)O(straight chain C1-C6 alkyl)OC(O)Me, C(O)O(branched C1-C6 alkyl)OC(O)OiPr, C(O)O(branched C1-C6 alkyl)OC(O)Ocycloalkyl, C(O)O(branched C1-C6 alkyl)OC(O)O(CH2CH2O)2Et or C(O)O(branched C1-C6 alkyl)OC(O)Me.

[0126] In some embodiments, [linking group] is [Ligase ligand portion] is and

[0127] [MCL-1 ligand prodrug moiety] is a compound of formula (A3),

[0128] in

[0129] R 32 yes and

[0130] R 9 It is C(O)O(straight-chain C1-C6 alkyl)OC(O)C(CH3)3, C(O)O(branched C1-C6 alkyl)OC(O)OiPr, C(O)O(branched C1-C6 alkyl)OC(O)Ocycloalkyl, C(O)O(branched C1-C6 alkyl)OC(O)O(CH2CH2O)2Et or C(O)O(branched C1-C6 alkyl)OC(O)Me.

[0131] In some embodiments, [linking group] is

[0132] [Ligase ligand portion] is

[0133] and

[0134] [MCL-1 ligand prodrug moiety] is a compound of formula (A3), wherein:

[0135] R 32 yes and

[0136] R 9 It is C(O)O(straight-chain C1-C6 alkyl)OC(O)C(CH3)3, C(O)O(straight-chain C1-C6 alkyl)OC(O)CH2CH2OH, C(O)O(straight-chain C1-C6 alkyl)OC(O)Me, C(O)OCH2CH2heterocycloalkyl or C(O)O(branched C1-C6 alkyl)OC(O)O(CH2CH2O)2Et.

[0137] In some embodiments, [linking group] is

[0138] [Ligase ligand portion] is

[0139] and

[0140] [MCL-1 ligand prodrug moiety] is a compound of formula (A3), wherein

[0141] R 32 yes and

[0142] R 9 is C(O)O(straight-chain C1-C6 alkyl)OC(O)C(CH3)3, C(O)O(straight-chain C1-C6 alkyl)OC(O)CH2CH2OH, C(O)O(straight-chain C1-C6 alkyl)OC(O)Me or C(O)OCH2CH2heterocycloalkyl;

[0143] Among them, when R 9 When it is C(O)O(straight-chain C1-C6 alkyl)OC(O)C(CH3)3, then [ligase ligand part] is

[0144]

[0145] In some embodiments, the compound is selected from:

[0146]

[0147]

[0148]

[0149]

[0150] In some embodiments, the compound is selected from Compound 43, 55, 57, 69, 71, 99, 100, 101, 129, 131, 133, 137, and 140. In other embodiments, the compound is selected from Compound 107 and Compound 124.

[0151] In some embodiments, the compound is selected from compounds 69, 99, 100, 107, 124, and 140.

[0152] In some embodiments, the compound is selected from the group consisting of compounds 41, 43, 55, 57, 69, 71, 73, 74, 75, 99, 100, 101, and 124. In some embodiments, the compound is selected from the group consisting of compounds 41, 43, 55, 57, 69, 71, 73, 74, 75, 99, 100, and 101. In some embodiments, the compound is selected from the group consisting of compounds 69, 75, 99, 100, 101, and 124. In some embodiments, the compound is selected from the group consisting of compounds 69, 75, 99, 100, and 101.

[0153] In some embodiments, the compound is selected from the group consisting of compounds 41, 43, 69, 73, 74, 101, 129, and 133. In some embodiments, the compound is selected from the group consisting of compounds 41, 43, 73, 74, 129, and 133.

[0154] In some embodiments, wherein, unless otherwise specified, each alkyl, alkenyl, alkynyl, aryl, heteroaryl, and benzyl group is unsubstituted.

[0155] According to a second aspect of the present invention, there is provided a compound of formula (I)

[0156] [MCL-1 ligand prodrug moiety]-[linker]-[ligase ligand moiety] (I) or a salt, solvate, hydrate or isomer thereof,

[0157] Wherein, [ligase ligand part] is:

[0158] (a) Formula (IV) or Formula (IVa)

[0159]

[0160] in:

[0161] Each of X1 and X2 is independently O or S;

[0162] Each of Q1 and Q2 is independently N or CR 5 , wherein at least one of Q1 and Q2 is N;

[0163] Each of E1, E2, E3 and E4 is independently N or CR';

[0164] n is 0, 1, or 2;

[0165] 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 2or-S(O)2R b ;

[0166] 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)2NR b 2. -OR 21 、-NH-R 21 、-C(O)-NH-R 21 or -CH2-NH-C(O)-R 21 ;

[0167] Each R' is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR b 、-NR b 2. -NR b C(O)R b 、-NR b C(O)OR b 、-NO2、-CN、-C(O)Rb 、-C(O)OR b 、-C(O)NH2、-C(O)NHR b 、-C(O)NR b 2. -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)2NR 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 ;

[0168] and

[0169] Each R b are independently hydrogen, alkyl, alkenyl, aryl, heteroaryl or benzyl;

[0170] Among them, R 21 is the R of the linking group 18 and wherein Formula (IV) comprises a single R 21 ;

[0171] (b) Formula (VIIa), Formula (VIIb), Formula (VIIc) or Formula (VIId):

[0172]

[0173] in:

[0174] Each of X1 and X2 is independently O or S;

[0175] Each of Q1 and Q2 is independently N or CR, wherein at least one of Q1 and Q2 is N;

[0176] Each of W1, W2 and W3 is independently N or CR a ;

[0177] Z is O, S or NR e ;

[0178] n is 0, 1, or 2;

[0179] 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 2or-S(O)2R b ;

[0180] 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)2NR 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 ;

[0181] 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)2NR 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 ;

[0182] 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 ;

[0183] Each R b are independently hydrogen, alkyl, alkenyl, aryl, heteroaryl or benzyl;

[0184] Among them, R 21 is the R of the linking group 18 and wherein each of Formula (VIIa), Formula (VIIb) and Formula (VIIc) contains a single R21 ;

[0185] (c) Formula (VIII):

[0186]

[0187] in

[0188] Each of X1 and X2 is independently O or S;

[0189] n is 0, 1, or 2;

[0190] 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 2or-S(O)2R b ;

[0191] Each of R1, R2 and R3 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)2NR 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 ;as well as

[0192] Each R b are independently hydrogen, alkyl, alkenyl, aryl, heteroaryl or benzyl;

[0193] Among them, R 21 is the R of the linking group 18 and wherein Formula (VIII) comprises a single R 21 ;or

[0194] (d) Formula (IX):

[0195]

[0196] in,

[0197] Each of X1 and X2 is independently O or S;

[0198] 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 2or-S(O)2R b ;

[0199] Each of Q1, Q2, Q3, Q4 and Q5 is independently N or CR, wherein at least one of Q1, Q2, Q3, Q4 and Q5 is N;

[0200] 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)2NR 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 ;as well as

[0201] Each R b are independently hydrogen, alkyl, alkenyl, aryl, heteroaryl or benzyl;

[0202] Among them, R 21 is the R of the linking group 18 The bond is connected, and wherein Formula (IX) contains a single R 21 ;

[0203] wherein [MCL-1 ligand prodrug moiety] is a compound of formula (A1), formula (A2), formula (A3) or formula (A4):

[0204]

[0205] in:

[0206] is a single bond or a double bond;

[0207] Each Z2 is independently N or C, wherein when Z2 is N, then is a single bond; when Z2 is C, is a double bond;

[0208] Each R 11 are independently H, halogen or C1-C6 alkyl,

[0209] R 8 is a C1-C6 alkyl group substituted with piperazine;

[0210] In each of formula (A1) and formula (A4), R 10 and R 30 One of them is H, R 10 and R 30 The other one 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 tetrahydronaphthyl, wherein the phenyl, naphthyl or tetrahydronaphthyl is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl and -O(C1-C6 alkyl); or wherein the tetrahydronaphthyl is optionally substituted with a bridging -CH2- group; or wherein the naphthyl is optionally substituted with -O- or -S-,

[0211] R 12 for

[0212] R 31 Yes-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 tetrahydronaphthyl, wherein the phenyl, naphthyl or tetrahydronaphthyl is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl and -O(C1-C6 alkyl); or wherein the tetrahydronaphthyl is optionally substituted with a bridged -CH2- group; or wherein the naphthyl is optionally substituted with -O- or -S-;

[0213] Each R 32 are independently H,

[0214] Each R 33 Independently R 19 or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with morpholine or piperazine;

[0215] R 20 Me, -CH2-OMe, -(CH2CH2O) p (C1-C6 alkyl) or -CH2-O-bromobenzaldehyde, wherein p is 1-5;

[0216] R 34 It is C 2-5 Alkyl-OR 13 or -OC 2-5 Alkyl-R 13 , where R 13is phenyl, naphthyl or tetrahydronaphthyl, wherein the phenyl, naphthyl or tetrahydronaphthyl is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl and -O(C1-C6 alkyl); or wherein the tetrahydronaphthyl is optionally substituted with a bridged -CH2- group; or wherein the naphthyl is optionally substituted with -O- or -S-;

[0217] R 35 for

[0218] R 19 is the R of the linking group 14 wherein each of Formula (A1), Formula (A2), Formula (A3) and Formula (A4) contains a single R 19 ;and

[0219] (i)R 9 is -C(O)O(C1-C6 alkyl), -C(O)O cycloalkyl, -C(O)O heterocycloalkyl, -C(O)O aryl or -P(O)(OR p ) 2, wherein the C1-C6 alkyl group is substituted by one or more groups selected from the following: -OC(O) (unsubstituted C1-C6 alkyl), -OC(O) (substituted by at least one R 10 substituted C1-C6 alkyl), -OC(O)cycloalkyl, -OC(O)heterocycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, -OC(O)(CH2) m O(CH2) m O(unsubstituted C1-C6 alkyl), -OC(O)(CH2) m O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(unsubstituted C1-C6 alkyl), -OC(O)O(substituted by at least one R 10 Substituted C1-C6 alkyl), -OC(O)O cycloalkyl, -OC(O)O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2CH2O) m (C1-C6 alkyl substituted with OP(O)(OH)2), -OC(O)O(CH2CH2S) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)(unsubstituted C1-C6 alkyl), -OC(O)O(CH2) mS(O)2(unsubstituted C1-C6 alkyl), -OC(O)NH(C1-C6 alkyl substituted by OMe), -OC(O)NMe(C1-C6 alkyl substituted by OMe), -P(O)(OH)2, -OP(O)(OH)2, -C(O)heterocycloalkyl, -C(O)N(unsubstituted C1-C6 alkyl)2, heteroaryl, heterocycloalkyl, -S(unsubstituted C1-C6 alkyl), -S(O)(unsubstituted C1-C6 alkyl), -N + (unsubstituted C1-C6 alkyl)3, -N + (Unsubstituted C1-C6 alkyl)2-cycloalkyl, N-(unsubstituted C1-C6 alkyl)piperidine Cation, N-(unsubstituted C1-C6 alkyl)morpholine Cation and N-(unsubstituted C1-C6 alkyl) imidazole cation;

[0220] Among them, each R 10 are independently -OH, -O(unsubstituted C1-C6 alkyl), -OBn, -NH2, -NMe2, -NHC(O)(unsubstituted C1-C6 alkyl), -NHC(O)O(unsubstituted C1-C6 alkyl), heterocycloalkyl, heteroaryl, aryl, -C(O)NMe2;

[0221] Each R p are independently -(CH2) m OC(O) (unsubstituted C1-C6 alkyl), and

[0222] Each m is independently 1, 2, 3 or 4;

[0223] or

[0224] (ii)R 9 is -C(O)O(CH2) p NMe2, -C(O)O(CH2) p NHMe, -C(O)OCH2CH(OH)CH2OH, -C(O)OCH2CH2CMe2OH, or -C(O)OCH2CH2SO2Me, wherein each p is independently 2, 3, 4, 5, or 6;

[0225] and wherein [linking group] has the formula:

[0226] R 14 -R 15 -R 16 -R 17 -R 18

[0227] in:

[0228] 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;

[0229] R 15 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 Alkyl-NH-, -C 1-6 Alkyl-N(C 1-6 alkyl)-, -cycloalkyl-NH-, -heterocycloalkyl-NH- or absent;

[0230] 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;

[0231] R 17 -CH2(C2H4-O) y 、-(CH2O) x 、-(C2H4-O) x 、-(C3H6-O) x or does not exist;

[0232] x is 1-10;

[0233] y is 2-10;

[0234] R 18 -C 1-6 Alkyl, -C 1-6 Alkyl-C(O)-, cycloalkyl, -CH2-NH-C(O)-, heterocycloalkyl or absent;

[0235] where R 14 -R 18 At least one of exists.

[0236] In some embodiments of the second aspect, unless otherwise specified, each alkyl, alkenyl, alkynyl, aryl, heteroaryl, and benzyl group is unsubstituted.

[0237] In some embodiments of the second aspect, each R' is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR b 、-NRb 2. -NR b C(O)R b 、-NRbC(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 )2 NHR b 、-S(O)2NR b 2. -R 21 、-OR 21 、-NH-R 21 、-C(O)-R 21 、-C(O)-NH-R 21 or -CH2-NH-C(O)-R 21 In some such embodiments, each R b is independently hydrogen, alkyl, cycloalkyl or aryl. In some such embodiments, the aryl is substituted with one or more substituents selected from halogen, alkyl and O-haloalkyl, optionally wherein the halogen is Cl, the alkyl is methyl and the O-haloalkyl is O-CF3.

[0238] In some embodiments of the second aspect, one of E1, E2, E3, and E4 is N, and the remaining three of E1, E2, E3, and E4 are each CR'. In some such embodiments, E1 is N, and E2, E3, and E4 are CR'. In other such embodiments, E2 is N, and E1, E3, and E4 are CR'. In other such embodiments, E3 is N, and E1, E2, and E4 are CR'. In other such embodiments, E4 is N, and E1, E2, and E3 are CR'.

[0239] In some embodiments of the second aspect, E1, E2, E3, and E4 are each CR', optionally wherein each of E1, E2, E3, and E4 is CH. In some such embodiments, three of E1, E2, E3, and E4 are CH, and one of E1, E2, E3, and E4 is C-halogen, C-alkyl, C-alkenyl, C-alkynyl, C-aryl, C-heteroaryl, C-benzyl, C-haloalkyl, C-haloalkenyl, C-NH2, C-NHR b 、C-NR b 2. C-NR b C(O)R b 、C-NRbC(O)OR b 、C-NO2、C-CN、CC(O)R b 、CC(O)OR b 、CC(O)NH2、CC(O)NHR b 、CC(O)NR b 2. CC(O)NHCHR b 2. C-CHR b NHC(O)NHR b 、C-CHR b NHC(O)C(Halogen)2R b 、C-OR b 、C-OC(O)R b 、C-OC(O)OR b 、C-OC(O)NH2、C-OC(O)NHR b 、C-OC(O)NR b 2. C-SR b 、CS(O)2R b 、CS(O)2OR b 、CS(O)2NH2、CS(O)2NHR b 、CS(O)2NR b 2. C-NHS(O)2R b 、-R 21 、-OR 21 、-NH-R 21 、-C(O)-R 21 、-C(O)-NH-R 21 or -CH2-NH-C(O)-R 21 .

[0240] In some embodiments of the second aspect, E2, E3, and E4 are each CH. In other embodiments, E1, E3, and E4 are each CH. In other embodiments, E1, E2, and E4 are each CH.

[0241] In some embodiments of the second aspect, two of E1, E2, E3, and E4 are N, and the remaining two of E1, E2, E3, and E4 are each CR'.

[0242] In some embodiments of the second aspect, three of E1, E2, E3, and E4 are N, and the remaining one of E1, E2, E3, and E4 is CR'.

[0243] In some embodiments of the second aspect, one of W1, W2, and W3 is N, and the others of W1, W2, and W3 are CR a In some such embodiments, R a For H.

[0244] In some embodiments of the second aspect, W1, W2, and W3 are each CR a .

[0245] In some embodiments of the second aspect, W1 is C-NH2, C-NHR b or C-NR b 2, optionally C-NH2.

[0246] In some embodiments of the second aspect, W1, W2, and W3 are each N.

[0247] In some embodiments of the second aspect, Z is NH or N-alkyl, optionally NH or N-Me.

[0248] In some embodiments of the second aspect, in Formula (IV), Formula (VIIa), Formula (VIIb), and Formula (VIIc), Q 1 is N and Q 2 is CR. In other embodiments, Q 1 is N and Q 2 is N. In other embodiments, Q 1 is CR and Q 2 is N. In some such embodiments, Q 1 is CH or C-alkyl. In some such embodiments, Q 1 is CH or C-Me.

[0249] In some embodiments of the second aspect, in Formula (IX), one of Q1, Q2, Q3, Q4, and Q5 is N, and the remaining four of Q1, Q2, Q3, Q4, and Q5 are each CR. In some such embodiments, Q1 is N. In other embodiments, Q2 is N. In other embodiments, Q3 is N.

[0250] In some embodiments of the second aspect, in Formula (IX), two of Q1, Q2, Q3, Q4, and Q5 are N, and the remaining three of Q1, Q2, Q3, Q4, and Q5 are each CR. In some such embodiments, Q1 and Q2 are N, and Q3, Q4, and Q5 are each CR. In other embodiments, Q2 and Q3 are N, and Q1, Q4, and Q5 are each CR. In other embodiments, Q1 and Q3 are N, and Q2, Q4, and Q5 are each CR. In other embodiments, Q2 and Q4 are N, and Q1, Q3, and Q5 are each CR. In other embodiments, Q1 and Q4 are N, and Q2, Q3, and Q5 are each CR.

[0251] In some embodiments of the second aspect, in Formula (IX), three of Q1, Q2, Q3, Q4, and Q5 are N, and the remaining two of Q1, Q2, Q3, Q4, and Q5 are each CR.

[0252] In some embodiments of the second aspect, the [ligase ligand moiety] is:

[0253]

[0254] In some embodiments of the second aspect, [ligase ligand moiety] is

[0255]

[0256] In some embodiments of the second aspect, the [ligase ligand moiety] is:

[0257]

[0258] According to a third aspect of the present invention, there is provided a compound of formula (I)

[0259] [MCL-1 ligand prodrug moiety]-[linker]-[ligase ligand moiety] (I) or a salt, solvate, hydrate or isomer thereof,

[0260] Wherein, [ligase ligand part] is:

[0261] (a) Formula (Va) or Formula (Vb):

[0262]

[0263] or a pharmaceutically acceptable salt or tautomer thereof,

[0264] in

[0265] Each of X1 and X2 is independently O or S;

[0266] Z1 is O, S or NR 6 ;

[0267] T is C=O or SO2;

[0268] R 1 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl;

[0269] Each of Y5, Y6, Y7 and Y8 is independently N or CR 7 ,

[0270] wherein 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 ;

[0271] n is 0, 1, or 2;

[0272] 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", -OR", -NR", or -S(O)2R";

[0273] Each R 7 are independently hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR", -NR", -CH2NR", -NR", C(O)R", -NR", C(O)CH2NR", -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 ;

[0274] each R"" is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl;

[0275] R 6 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR", -NR", -NR", -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)N HR"", -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 ;

[0276] Among them, R 21 is the R of the linking group 18 and wherein Formula (Va) and Formula (Vb) each contain a single R 21 ;

[0277] Among them, when Z1 is O, then Y6 is CR 7 ,and

[0278] Wherein, when the compound is a compound of formula (Va), then

[0279] (i) When each of Y5, Y6 and Y7 is CR 7 When at least one R 7 Not H;

[0280] (ii) When Z1 is NR 6 When Y6 and Y7 are CR 7 ;

[0281] (iii) when Z1 is S, then Y5 is not C-OMe and Y6 is not C-OMe;

[0282] (iv) when Z1 is S and Y5 is C-NHCOMe, then Y7 is not C-CH2NR""C(O)OR"";

[0283] (v) when Z1 is S and Y5 is N, then Y6 is not CH, C-aryl or CC(O)OR""; and

[0284] (vi) when Z1 is S and Y6 is N, then Y7 is C-NH2, C-NHR", C-NR", C-NR""2, C-NR""C(O)OR", C-CH2NR""C(O)OR"", C-haloalkyl, C-tert-butyl, C-OR", C-COOR"" or C-SR""; wherein, when Y7 is C-NH2, C-NHR"" or C-NR""2, then Y5 is CH;

[0285] And when the compound is a compound of formula (Vb), then:

[0286] (vii) When each of Y5, Y6 and Y8 is CR 7 When at least one R 7 Not H;

[0287] (viii) when Z1 is S, then Y5 is not C-COOH or C-NHC(O)Me, and Y8 is not C-Br;

[0288] (ix) When Z1 is S and Y6 is C-Br, then Y8 is C-OR"";

[0289] (x) When Z1 is S, Y5 is N and Y6 is CH or C-NH2, then Y8 is not CH;

[0290] (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 When Y5, Y6 and Y8 are CR 7 ;

[0291] or

[0292] (b) Formula (IIa) or (IIb):

[0293]

[0294] in

[0295] Each of X1 and X2 is independently O or S;

[0296] Z is O, S or NR 2 ;

[0297] T is C=O or SO2;

[0298] Y3 is N or CR;

[0299] Y4 is N or CR;

[0300] represents a single bond or a double bond, where:

[0301] When each When a double bond is present, each of W1, W2, W3 and W4 is independently N or CR a , wherein at least one of W1, W2, W3 and W4 is N, and

[0302] When each When it is a single bond, W1, W2, W3 and W4 are each CR a 2, and Y4 is CR;

[0303] n is 0, 1, or 2;

[0304] 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 2or-S(O)2R h ;

[0305] Each R is independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR h 、-NR h 2. -NR h C(O)R h 、-NR h C(O)CH2R h 、-NR h C(O)CH(OH)R h 、-NR h C(O)OR h 、-NR h SO2R h 、-NO2、-CN、-C(O)R h 、-C(O)OR h 、-C(O)NH2、-C(O)NHR h 、-C(O)NR h 2. -OR h 、-OC(O)R h 、-OC(O)OR h 、-OC(O)NH2、-OC(O)NHR h 、-OC(O)NR h 2. -SRh , or -S(O)2R h 、-S(O)2OR h 、-S(O)2NH2、-S(O)2NHR h , or -S(O)2NR h 2;

[0306] 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)2NR h 2. -OR 21 、-NH-R 21 、-C(O)-NH-R 21 or -CH2-NH-C(O)-R 21 ;

[0307] Each R h is independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl;

[0308] R 2 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR h 、-NRh 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 , or -S(O)2R h 、-S(O)2OR h 、-S(O)2NH2、-S(O)2NHR h , or -S(O)2NR h 2; and

[0309] R 1 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl;

[0310] R 21 is the R of the linking group 18 wherein Formula (IIa) and Formula (IIb) each contain a single R 21 ;

[0311] Among them, when each is a double bond, Z is NR 2 , R 2 is hydrogen, and each R a When it is hydrogen, W4 is CR a ;

[0312] wherein [MCL-1 ligand prodrug moiety] is a compound of formula (A1), (A2), (A3) or (A4):

[0313]

[0314] in:

[0315] is a single bond or a double bond;

[0316] Each Z2 is independently N or C, wherein when Z2 is N, then is a single bond; when Z2 is C, is a double bond;

[0317] Each R 11 are independently H, halogen or C1-C6 alkyl,

[0318] R 8 is a C1-C6 alkyl group substituted with piperazine;

[0319] In each of formula (A1) and formula (A4), R 10 and R 30 One of them is H, R 10 and R 30 The other one 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 tetrahydronaphthyl, wherein the phenyl, naphthyl or tetrahydronaphthyl is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl and -O(C1-C6 alkyl); or wherein the tetrahydronaphthyl is optionally substituted with a bridging -CH2- group; or wherein the naphthyl is optionally substituted with -O- or -S-,

[0320] R 12 for

[0321] R 31 Yes-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 tetrahydronaphthyl, wherein the phenyl, naphthyl or tetrahydronaphthyl is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl and -O(C1-C6 alkyl); or wherein the tetrahydronaphthyl is optionally substituted with a bridged -CH2- group; or wherein the naphthyl is optionally substituted with -O- or -S-;

[0322] Each R 32 are independently H,

[0323] Each R 33 Independently R 19 or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with morpholine or piperazine;

[0324] R20 Me, -CH2-OMe, -(CH2CH2O) p (C1-C6 alkyl) or -CH2-O-bromobenzaldehyde, wherein p is 1-5;

[0325] R 34 It is C 2-5 Alkyl-OR 13 or -OC 2-5 Alkyl-R 13 , where R 13 is phenyl, naphthyl or tetrahydronaphthyl, wherein the phenyl, naphthyl or tetrahydronaphthyl is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl and -O(C1-C6 alkyl); or wherein the tetrahydronaphthyl is optionally substituted with a bridged -CH2- group; or wherein the naphthyl is optionally substituted with -O- or -S-;

[0326] R 35 for

[0327] R 19 is the R of the linking group 14 wherein each of Formula (A1), Formula (A2), Formula (A3) and Formula (A4) contains a single R 19 ;and

[0328] (i)R 9 is -C(O)O(C1-C6 alkyl), -C(O)O cycloalkyl, -C(O)O heterocycloalkyl, -C(O)O aryl or -P(O)(OR p ) 2, wherein the C1-C6 alkyl group is substituted by one or more groups selected from the following: -OC(O) (unsubstituted C1-C6 alkyl), -OC(O) (substituted by at least one R 10 substituted C1-C6 alkyl), -OC(O)cycloalkyl, -OC(O)heterocycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, -OC(O)(CH2) m O(CH2) m O(unsubstituted C1-C6 alkyl), -OC(O)(CH2) m O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(unsubstituted C1-C6 alkyl), -OC(O)O(substituted by at least one R 10 Substituted C1-C6 alkyl), -OC(O)O cycloalkyl, -OC(O)O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2CH2O) m(C1-C6 alkyl substituted with OP(O)(OH)2), -OC(O)O(CH2CH2S) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)(unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)2(unsubstituted C1-C6 alkyl), -OC(O)NH(C1-C6 alkyl substituted by OMe), -OC(O)NMe(C1-C6 alkyl substituted by OMe), -P(O)(OH)2, -OP(O)(OH)2, -C(O)heterocycloalkyl, -C(O)N(unsubstituted C1-C6 alkyl)2, heteroaryl, heterocycloalkyl, -S(unsubstituted C1-C6 alkyl), -S(O)(unsubstituted C1-C6 alkyl), -N + (unsubstituted C1-C6 alkyl)3, -N + (Unsubstituted C1-C6 alkyl)2-cycloalkyl, N-(unsubstituted C1-C6 alkyl)piperidine Cation, N-(unsubstituted C1-C6 alkyl)morpholine Cation and N-(unsubstituted C1-C6 alkyl) imidazole cation;

[0329] Among them, each R 10 are independently -OH, -O(unsubstituted C1-C6 alkyl), -OBn, -NH2, -NMe2, -NHC(O)(unsubstituted C1-C6 alkyl), -NHC(O)O(unsubstituted C1-C6 alkyl), heterocycloalkyl, heteroaryl, aryl, -C(O)NMe2;

[0330] Each R p are independently -(CH2) m OC(O) (unsubstituted C1-C6 alkyl), and

[0331] Each m is independently 1, 2, 3 or 4;

[0332] or

[0333] (ii)R 9 is -C(O)O(CH2) p NMe2, -C(O)O(CH2) p NHMe, -C(O)OCH2CH(OH)CH2OH, -C(O)OCH2CH2CMe2OH, or -C(O)OCH2CH2SO2Me, wherein each p is independently 2, 3, 4, 5, or 6;

[0334] and wherein [linking group] has the formula:

[0335] R 14 -R 15 -R 16 -R 17 -R 18

[0336] in:

[0337] 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;

[0338] R 15 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 Alkyl-NH-, -C 1-6 Alkyl-N(C 1-6 alkyl)-, -cycloalkyl-NH-, -heterocycloalkyl-NH- or absent;

[0339] 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;

[0340] R 17 -CH2(C2H4-O) y 、-(CH2O) x 、-(C2H4-O) x 、-(C3H6-O) x or does not exist;

[0341] x is 1-10;

[0342] y is 2-10;

[0343] R 18 -C 1-6 Alkyl, -C 1-6 Alkyl-C(O)-, cycloalkyl, -CH2-NH-C(O)-, heterocycloalkyl or absent;

[0344] where R 14 -R 18 At least one of exists.

[0345] In some embodiments of the third aspect, unless otherwise specified, each alkyl, alkenyl, alkynyl, aryl, heteroaryl, and benzyl group is unsubstituted.

[0346] In some embodiments of the third aspect, when Z1 in formula (Vb) is S, then Y5 is not C-NHC(O)R"" or -C(O)OR"".

[0347] In some embodiments of the third aspect, Z1 is NR 6 .

[0348] In some embodiments of the third aspect, each R is independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR", -NR""2, -NR""C(O)R", -NR""C(O)CH(OH)R", -NR""C(O)OR", -NR""S2R", -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)N HR"", -OC(O)NR""2, -SR"" or -S(O)2R"", -S(O)2OR"", -S(O)2NH2, -S(O)2NHR"", -S(O)2NR""2, -OR 21 、-NH-R 21 、-C(O)-NH-R 21 or -CH2-NH-C(O)-R 21 .

[0349] In some embodiments of the third aspect, R 1 It's hydrogen.

[0350] In some embodiments of the third aspect, R 6 For hydrogen.

[0351] In some embodiments of the third aspect, [ligase ligand moiety] is a compound of formula (Va), and Y5, Y6, and Y7 are each CR 7 In some such embodiments, Y5 is -C-NHC(O)R"", Y6 is CH, and Y7 is CH or CCl. In some such embodiments, L3 is hydrogen, Z1 is S, R 1 is hydrogen, T is C=O, and Y7 is CH.

[0352] In some embodiments of the third aspect, the compound is of formula (Vb), and Y5, Y6, and Y8 are each CR7 In some such embodiments:

[0353] L3 is hydrogen;

[0354] Z1 is S;

[0355] R 1 is H;

[0356] T is C=O;

[0357] Y5 is CH, C-OR", CCl, C-CN or C-NHC(O)R"";

[0358] Y6 is CH, CCl, C-alkyl, C-cycloalkyl or C-haloalkyl; and

[0359] Y8 is CH, C-OR", C-NHC(O)R", C-NHC(O)OR", C-NHR", C-NH2 or C-NHSO2R",

[0360] wherein, when Y is CCl, then Y is CH, C-alkyl, C-cycloalkyl, or C-haloalkyl. In some such embodiments, each R" is independently alkyl, cycloalkyl, aryl, or benzyl. In some embodiments, Y is CH, Y is CH or CCl, and Y is C-OR" or C-NH, optionally C-OMe or C-NH.

[0361] In some embodiments of the third aspect, Z is NR 2 In other embodiments, Z is S.

[0362] In some embodiments of the third aspect, each For double bonds.

[0363] In some embodiments of the third aspect, L is hydrogen.

[0364] In some embodiments of the third aspect, one of W1, W2, W3, and W4 is N, and the remaining three of W1, W2, W3, and W4 are each CR a In some such embodiments, W4 is CR a .

[0365] In some embodiments of the third aspect, two of W1, W2, W3, and W4 are N, and the remaining two of W1, W2, W3, and W4 are each CR. a .

[0366] In some embodiments of the third aspect, one of W1, W2, W3, and W4 is CR a, the remaining three of W1, W2, W3 and W4 are each N.

[0367] In some embodiments of the third aspect, each R is independently hydrogen, halogen, or -NR h C(O)R h .

[0368] According to a fourth aspect of the present invention, there is provided a compound of formula (I)

[0369] [MCL-1 ligand prodrug moiety]-[linker]-[ligase ligand moiety] (I) or a salt, solvate, hydrate or isomer thereof,

[0370] Wherein [ligase ligand part] is:

[0371] (a) Formula (VIa) or Formula (VIb):

[0372]

[0373] in:

[0374] M is O, S or NH, or does not exist;

[0375] represents R connected to the linking group 18 ;

[0376] R 22 is hydrogen, halogen, -OMe, amino, heterocycloalkyl, or unsubstituted C1-C6 alkyl; and

[0377] L' is hydrogen, alkyl, benzyl, acetyl or pivaloyl;

[0378] (b) Formula (II):

[0379]

[0380] in:

[0381] Each of X1 and X2 is independently O or S;

[0382] T is C=O or SO2;

[0383] R 1 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl;

[0384] n is 0, 1, or 2;

[0385] L4 is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)H, -C(O)R b 、-C(O)OH、-C(O)ORb 、-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 ;

[0386] R y Selected from

[0387]

[0388] in, Indicates connection to T,

[0389] Z3 is O, S or NR 3 ;

[0390] U is O, S, NR b or CR i 2;

[0391] Each of Y1, Y2 and Y3 is independently N or CR d ;

[0392] 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)2NR b 2. -OR 21 、-NH-R 21 、-C(O)-NH-R 21 or -CH2-NH-C(O)-R 21 ;

[0393] 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)2NR b 2;

[0394] 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)2NR b 2. -R 21 、-C(O)-NH-R 21 or -CH2-NH-C(O)-R 21 ;

[0395] Each R b are independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl or benzyl;

[0396] R 21 is the R of the linking group 18 The bond connected, wherein formula (II) contains a single R 21 ;

[0397] in:

[0398] (i) When R y for When Y2 is CR d ;as well as

[0399] (ii) When R y for When CR i R in 2 i It’s not hydrogen;

[0400] or

[0401] (c) Formula (III):

[0402]

[0403] in:

[0404] Each of X1 and X2 is independently O or S;

[0405] T is C=O or SO2;

[0406] R 1 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl;

[0407] n is 0, 1, or 2;

[0408] 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 ;

[0409] R x Selected from

[0410]

[0411] in, Indicates connection to T,

[0412] Z4 is O, S or NR 4 ;

[0413] V is CR f 2. NR 4 or S;

[0414] Each of G1, G2, G3 and G4 is independently N or CR c ;

[0415] Each of Y1 and Y2 is independently N or CR f ;

[0416] 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, -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)2NHRb 、-S(O)2NR b 2. -R 21 、-OR 21 、-NH-R 21 、-C(O)-NH-R 21 or -CH2-NH-C(O)-R 21 ; or when Y1 and Y2 are CR f When each R f Together with the carbon atom to which it is attached, it forms a 5-membered or 6-membered ring;

[0417] Each R c are independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, substituted by 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)2NR b 2. -OR21 、-NH-R 21 、-C(O)-NH-R 21 or -CH2-NH-C(O)-R 21 ;

[0418] 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 ;as well as

[0419] Each R b are independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl or benzyl;

[0420] R 21 is the R of the linking group 18 The bond connected, wherein formula (III) contains a single R 21 ;

[0421] Among them, when n=2, each R c is hydrogen, and each of G1, G2, G3 and G4 is CR c When , C=X1 can be replaced by CH;

[0422] And among them:

[0423] (i) When R x for When Z4 is NH, L1 is hydrogen, -CH2C(O)OR b OR b ;

[0424] (ii) When R x for Z4 to NR 4 , Y1 is CR f , and when Y2 is N, then R 4 is not an alkyl group, and R 2 and at least one of R is not H;

[0425] (iii) When R x for Z4 to NR 4 , and Y1 and Y2 are CR f When , at least one of G1, G2 and G3 is N;

[0426] (iv) When Z4 is NR 4 , and Y1 and Y2 are CR f When R x no

[0427] (v) When R x for Z4 to NR 4 , and when Y1 or Y2 is N, then R 4 Not an alkyl group;

[0428] (vi) When R x for When , n = 1 or 2; and

[0429] (vii) When R x for When Z4=O or S;

[0430] wherein [MCL-1 ligand prodrug moiety] is a compound of formula (A1), formula (A2), formula (A3) or formula (A4):

[0431]

[0432]

[0433] in:

[0434] is a single bond or a double bond;

[0435] Each Z2 is independently N or C, wherein when Z2 is N, then is a single bond; when Z2 is C, is a double bond;

[0436] Each R 11 are independently H, halogen or C1-C6 alkyl,

[0437] R 8 is a C1-C6 alkyl group substituted with piperazine;

[0438] In each of formula (A1) and formula (A4), R 10 and R 30 One of them is H, R 10 and R30 The other one 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 tetrahydronaphthyl, wherein the phenyl, naphthyl or tetrahydronaphthyl is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl and -O(C1-C6 alkyl); or wherein the tetrahydronaphthyl is optionally substituted with a bridging -CH2- group; or wherein the naphthyl is optionally substituted with -O- or -S-,

[0439] R 12 for

[0440] R 31 Yes-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 tetrahydronaphthyl, wherein the phenyl, naphthyl or tetrahydronaphthyl is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl and -O(C1-C6 alkyl); or wherein the tetrahydronaphthyl is optionally substituted with a bridged -CH2- group; or wherein the naphthyl is optionally substituted with -O- or -S-;

[0441] Each R 32 are independently H,

[0442] Each R 33 Independently R 19 or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with morpholine or piperazine;

[0443] R 20 Me, -CH2-OMe, -(CH2CH2O) p (C1-C6 alkyl) or -CH2-O-bromobenzaldehyde, wherein p is 1-5;

[0444] R 34 It is C 2-5 Alkyl-OR 13 or -OC 2-5 Alkyl-R 13 , where R 13is phenyl, naphthyl or tetrahydronaphthyl, wherein the phenyl, naphthyl or tetrahydronaphthyl is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl and -O(C1-C6 alkyl); or wherein the tetrahydronaphthyl is optionally substituted with a bridged -CH2- group; or wherein the naphthyl is optionally substituted with -O- or -S-;

[0445] R 35 for

[0446] R 19 is the R of the linking group 14 wherein each of Formula (A1), Formula (A2), Formula (A3) and Formula (A4) contains a single R 19 ;and

[0447] (i)R 9 is -C(O)O(C1-C6 alkyl), -C(O)O cycloalkyl, -C(O)O heterocycloalkyl, -C(O)O aryl or -P(O)(OR p ) 2, wherein the C1-C6 alkyl group is substituted by one or more groups selected from the following: -OC(O) (unsubstituted C1-C6 alkyl), -OC(O) (substituted by at least one R 10 substituted C1-C6 alkyl), -OC(O)cycloalkyl, -OC(O)heterocycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, -OC(O)(CH2) m O(CH2) m O(unsubstituted C1-C6 alkyl), -OC(O)(CH2) m O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(unsubstituted C1-C6 alkyl), -OC(O)O(substituted by at least one R 10 Substituted C1-C6 alkyl), -OC(O)O cycloalkyl, -OC(O)O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2CH2O) m (C1-C6 alkyl substituted with OP(O)(OH)2), -OC(O)O(CH2CH2S) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)(unsubstituted C1-C6 alkyl), -OC(O)O(CH2) mS(O)2(unsubstituted C1-C6 alkyl), -OC(O)NH(C1-C6 alkyl substituted by OMe), -OC(O)NMe(C1-C6 alkyl substituted by OMe), -P(O)(OH)2, -OP(O)(OH)2, -C(O)heterocycloalkyl, -C(O)N(unsubstituted C1-C6 alkyl)2, heteroaryl, heterocycloalkyl, -S(unsubstituted C1-C6 alkyl), -S(O)(unsubstituted C1-C6 alkyl), -N + (unsubstituted C1-C6 alkyl)3, -N + (Unsubstituted C1-C6 alkyl)2-cycloalkyl, N-(unsubstituted C1-C6 alkyl)piperidine Cation, N-(unsubstituted C1-C6 alkyl)morpholine Cation and N-(unsubstituted C1-C6 alkyl) imidazole cation;

[0448] Among them, each R 10 are independently -OH, -O(unsubstituted C1-C6 alkyl), -Obn, -NH2, -NMe2, -NHC(O)(unsubstituted C1-C6 alkyl), -NHC(O)O(unsubstituted C1-C6 alkyl), heterocycloalkyl, heteroaryl, aryl, -C(O)NMe2;

[0449] Each R p are independently -(CH2) m OC(O) (unsubstituted C1-C6 alkyl), and

[0450] Each m is independently 1, 2, 3 or 4;

[0451] or

[0452] (ii)R 9 is -C(O)O(CH2) p NMe2, -C(O)O(CH2) p NHMe, -C(O)OCH2CH(OH)CH2OH, -C(O)OCH2CH2CMe2OH, or -C(O)OCH2CH2SO2Me, wherein each p is independently 2, 3, 4, 5, or 6;

[0453] and wherein [linking group] has the formula:

[0454] R 14 -R 15 -R 16 -R 17 -R 18

[0455] in:

[0456] 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;

[0457] R 15 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 Alkyl-NH-, -C 1-6 Alkyl-N(C 1-6 alkyl)-, -cycloalkyl-NH-, -heterocycloalkyl-NH- or absent;

[0458] 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;

[0459] R 17 -CH2(C2H4-O) y 、-(CH2O) x 、-(C2H4-O) x 、-(C3H6-O) x or does not exist;

[0460] x is 1-10;

[0461] y is 2-10;

[0462] R 18 -C 1-6 Alkyl, -C 1-6 Alkyl-C(O)-, cycloalkyl, -CH2-NH-C(O)-, heterocycloalkyl or absent;

[0463] where R 14 -R 18 At least one of exists.

[0464] In some embodiments of the fourth aspect, unless otherwise specified, each alkyl, alkenyl, alkynyl, aryl, heteroaryl, and benzyl group is unsubstituted.

[0465] In some embodiments of the fourth aspect, in Formula (III):

[0466] Each of X1 and X2 is 0;

[0467] T is C=O;

[0468] R 1 It's hydrogen,

[0469] L1 is hydrogen,

[0470] R x yes

[0471] Z4 to NR 4 ;

[0472] Each of G1, G2 and G4 is CR c ,

[0473] Y1 is N, and

[0474] Y2 is CR f , where R f Not hydrogen.

[0475] In some embodiments of the fourth aspect, [ligase ligand moiety] is of formula (III):

[0476]

[0477] In some embodiments of the fourth aspect, R c One of the -OR 21 、-NH-R 21 、-C(O)-NH-R 21 or -CH2-NH-C(O)-R 21 In other embodiments, G1 is COR 21 、C-NH-R 21 、CC(O)-NH-R 21 or C-CH2-NH-C(O)-R 21 In other embodiments, G2 is COR 21 、C-NH-R 21 、CC(O)-NH-R 21 or C-CH2-NH-C(O)-R 21 In other embodiments, R 4 It is R 21 、-C(O)-NH-R 21 or -CH2-NH-C(O)-R 21 In other embodiments, R f One of them is -R 21 、-OR 21 、-NH-R 21 、-C(O)-NH-R 21 or -CH2-NH-C(O)-R 21.

[0478] In some embodiments of the fourth aspect, Y2 is CR 21 、CO-R 21 、C-NH-R 21 、CC(O)-NH-R 21 or C-CH2-NH-C(O)-R 21 .

[0479] In some embodiments of the fourth aspect, [ligase ligand moiety] is selected from the group consisting of:

[0480]

[0481]

[0482] In some embodiments of the fourth aspect, [ligase ligand moiety] is selected from the group consisting of:

[0483]

[0484]

[0485]

[0486] In some embodiments of the fourth aspect, [ligase ligand moiety] is

[0487]

[0488] In some embodiments of the fourth aspect, [ligase ligand moiety] is

[0489]

[0490] In some embodiments of any one of the second, third, and fourth aspects:

[0491] 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;

[0492] R 17 is -CH2(C2H4-O) y 、-(C2H4-O) x 、-(C3H6-O) x Or does not exist.

[0493] R 18 Yes-C 1-6Alkyl, cycloalkyl, -CH2-NH-C(O)-, heterocycloalkyl or absent.

[0494] In some embodiments of any one of the second, third, and fourth aspects, R 14 -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 In some embodiments, R 14 Yes-C 1-6 alkyl.

[0495] In some embodiments of any one of the second, third, and fourth aspects, R 15 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 In some such embodiments, R 15 In some such embodiments, R 15 is piperazine, bridged piperazine, piperazine N-oxide, piperazine cation,

[0496]

[0497] in, Indicates connection to R 14 , Indicates connection to R 16 In some such embodiments, R 15 Is piperazine or In other embodiments, R 15 Does not exist.

[0498] In some embodiments of the second, third, and fourth aspects, R 16 Yes-C 1-6 In some such embodiments, R 16 Yes-C 1-6 Alkyl or -C(O)-.

[0499] In some embodiments of any one of the second, third, and fourth aspects, R 17 Does not exist.

[0500] In some embodiments of any one of the second, third, and fourth aspects, R 18 -C 1-6 In some such embodiments, R 18 Yes-C 1-6 In some such embodiments, R 18Yes-C 1-6 In other embodiments, R 18 Does not exist.

[0501] In some embodiments of any one of the second, third, and fourth aspects, [linking group] is selected from:

[0502]

[0503] in:

[0504] represents attachment to [MCL-1 ligand prodrug moiety]; and

[0505] Indicates attachment to [ligase ligand moiety].

[0506] In some embodiments of any one of the second, third, and fourth aspects, in each of Formula (A1) and Formula (A4), R 10 and R 30 One of them is H, R 10 and R 30 The other one is -C 2-5 Alkyl-OR 13 or -OC 2-5 Alkyl-R 13 , where R 13 is phenyl or naphthyl, wherein the phenyl or naphthyl is optionally substituted with at least one substituent selected from halogen and C1-C6 alkyl.

[0507] In some embodiments of any one of the second, third, and fourth aspects, in Formula (A1), R 12 for

[0508] In some embodiments of any one of the second, third, and fourth aspects, in Formula (A4), R 35 for

[0509] In some embodiments of any one of the second, third, and fourth aspects, in Formula (A2), R 31 -C 2-5 Alkyl-OR 13 or -OC 2-5 Alkyl-R 13 , where R 13 is phenyl or naphthyl, wherein the phenyl or naphthyl is optionally substituted with at least one substituent selected from halogen and C1-C6 alkyl.

[0510] In some embodiments of any one of the second, third, and fourth aspects, in Formula (A3), R34 It is C 2-5 Alkyl-OR 13 or -OC 2-5 Alkyl-R 13 , where R 13 is phenyl or naphthyl, wherein the phenyl or naphthyl is optionally substituted with at least one substituent selected from halogen and C1-C6 alkyl.

[0511] In some embodiments of any one of the second, third, and fourth aspects, Z2 is C and For double bonds.

[0512] In some embodiments of any one of the second, third, and fourth aspects, [MCL-1 ligand prodrug moiety] is:

[0513]

[0514] in:

[0515] R 11 It is a halogen;

[0516] R 13a is a halogen; and

[0517] R 20 is Me, -CH2-OMe or -(CH2CH2O) p (C1-C6 alkyl), wherein p is 1-5.

[0518] In some embodiments of any one of the second, third, and fourth aspects, R 9 is -C(O)O(C1-C6 alkyl), -C(O)O cycloalkyl, -C(O)O heterocycloalkyl, -C(O)O aryl or -P(O)(OR p ) 2, wherein the C1-C6 alkyl group is substituted by one or more groups selected from the following: -OC(O) (unsubstituted C1-C6 alkyl), -OC(O) (substituted by at least one R 10 substituted C1-C6 alkyl), -OC(O)cycloalkyl, -OC(O)heterocycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, -OC(O)(CH2) m O(CH2) m O(unsubstituted C1-C6 alkyl), -OC(O)(CH2) m O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(unsubstituted C1-C6 alkyl), -OC(O)O(substituted by at least one R 10 Substituted C1-C6 alkyl), -OC(O)O cycloalkyl, -OC(O)O(CH2CH2O)m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2CH2O) m (C1-C6 alkyl substituted with OP(O)(OH)2), -OC(O)O(CH2CH2S) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)(unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)2(unsubstituted C1-C6 alkyl), -OC(O)NH(C1-C6 alkyl substituted by OMe), -OC(O)NMe(C1-C6 alkyl substituted by OMe), -P(O)(OH)2, -OP(O)(OH)2, -C(O)heterocycloalkyl, -C(O)N(unsubstituted C1-C6 alkyl)2, heteroaryl, heterocycloalkyl, -S(unsubstituted C1-C6 alkyl), -S(O)(unsubstituted C1-C6 alkyl), -N + (unsubstituted C1-C6 alkyl)3, -N + (Unsubstituted C1-C6 alkyl)2-cycloalkyl, N-(unsubstituted C1-C6 alkyl)piperidine Cation, N-(unsubstituted C1-C6 alkyl)morpholine cation and N-(unsubstituted C1-C6 alkyl)imidazolyl cation.

[0519] In some embodiments of any one of the second, third, and fourth aspects, R 9 is -C(O)O(C1-C6 alkyl), -C(O)O cycloalkyl, -C(O)O heterocycloalkyl, -C(O)O aryl or -P(O)(OR p ) 2, wherein the C1-C6 alkyl group is substituted by one or more groups selected from the group consisting of: -OC(O)Me, -OC(O)Et, -OC(O) iPr, -OC(O)C(CH3)3, -OC(O)CH2OH, -OC(O)CH(CH3)OH, -OC(O)C(CH3)2OH, -OC(O)CH2CH2OH, -OC(O)CH(OH)CHMe2, -OC(O)CH(OH)CH2CHMe2, -OC(O)CH2CH(OH)Me, -OC(O)CH2C(OH)Me2, -OC(O)CH(CH2OH)(NHC(O)Me), -OC(O)CH(NHC(O)Me)(isobutyl), -OC(O)CH(OH)aryl, -OC(O)CH(OH)CH2aryl, -OC(O)heterocycloalkyl, -OC(O)cycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, -OC(O)CH2CH2aryl, -OC(O)CH(NH2) i Pr, -OC(O)CH( i Pr)NHC(O)O t Bu, -OC(O)CH2OCH2CH2OMe, -OC(O)CH2(OCH2CH2)2OMe, -OC(O)OMe, -OC(O)OEt, -OC(O)O i Pr, -OC(O)Ocycloalkyl, -OC(O)OCH2CH2OEt, -OC(O)O(CH2CH2O)2Et, -OC(O)O(CH2CH2O)3Et, -OC(O)O(CH2CH2O)3CH2CH2OP(O)(OH)2, -OC(O)OCH2CH2SMe, -OC(O)OCH2CH2S(O)Me, -OC(O)OCH2CH2S(O)2Me, -OC(O)OCH2heteroaryl, -OC(O)OCH2heterocycloalkyl, -OC (O)OCH2CH2OCH2aryl-OC(O)OCH2CH2C(O)NMe2、-OC(O)O(CH2)6NH2、-OC(O)O(CH2)6NMe2、-OC(O)OCH(CH2OEt)2、-OC(O)NHCH2CH2OMe、-OC(O)NMeCH2CH2OMe、-SMe、-S(O)Me、-P(O)(OH)2、-OP(O)(OH)2、-C(O)NMe2、-C(O)heterocycloalkyl、heteroaryl、heterocycloalkyl、-N + (Me)3, -N + (Me)2 cycloalkyl, N-methylmorpholine Cation, N-methylpiperidine Cation and N-methylimidazole cation.

[0520] In some embodiments of any one of the second, third, and fourth aspects, R 9 is -C(O)O(C1-C6 alkyl), wherein the C1-C6 alkyl is substituted with one or more groups selected from -O(CO)C(CH3)3, -OC(O)CH2CH2OH, -OC(O)C(CH3)2OH, -OC(O)heterocycloalkyl, -OC(O)CH2OCH2CH2OMe, -OC(O)OiPr, -OC(O)Ocycloalkyl, -OC(O)O(CH2CH2O)2Et, -OP(O)(OH)2, heteroaryl, or heterocycloalkyl. In some such embodiments, R 9 is -C(O)O(C1-C6 alkyl), wherein the C1-C6 alkyl is substituted with -O(CO)C(CH3)3. 9 It is -C(O)OCH2OC(O)C(CH3)3.

[0521] In some embodiments of any one of the second, third, and fourth aspects, R 9 is -C(O)OCH2OC(O)C(CH3)3, -C(O)OCH2OC(O)Me, -C(O)OCH(Me)OC(O)Me, -C(O)OCH2OC(O)CH2CH2OH, -C(O)OCH2OC(O)C(CH3)2OH, -C(O)OCH2OC(O)piperidine, -C(O)OCH2OC(O)CH2OCH2CH2OMe, -C(O)OCH2OC(O)OiPr, -C(O)OCHMeOC(O)OiPr, -C(O)OCHMeOC(O)Ocyclohexyl, -C(O)OCHMeOC(O)O(CH2CH2O)2Et, -C(O)OCH2CH2OP(O)(OH)2, -C(O)OCH2(N-methylimidazole) cation), -C(O)OCH2(N-methylpiperidin cation), -C(O)OCH2 dioxolane, -C(O)OCH2CH2 morpholine, -C(O)OCH2CH2 piperazine, -C(O)OCH2CH2CH2 piperazine or -P(O)(OCH2OC(O)C(CH3)3)2.

[0522] In some embodiments of any one of the second, third, and fourth aspects, R 20 It is Me or -(CH2CH2O)2Me.

[0523] In some embodiments of any one of the second, third, and fourth aspects, R 33 It is R 19 In other embodiments, R33 It is a C1-C6 alkyl group substituted by morpholine or piperazine.

[0524] In some embodiments of any one of the second, third, and fourth aspects, the C1-C6 alkyl substituted with morpholine or piperazine is

[0525] In some embodiments of any one of the second, third, and fourth aspects, [MCL-1 ligand prodrug moiety] is:

[0526]

[0527]

[0528] In some embodiments of any one of the second, third, and fourth aspects, [MCL-1 ligand prodrug moiety] is:

[0529]

[0530]

[0531] In some embodiments of the fourth aspect, the compound is:

[0532]

[0533] In some embodiments of any of the aforementioned aspects, T is C=O.

[0534] In some embodiments of any of the aforementioned 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.

[0535] In some embodiments of any of the aforementioned aspects, n is 0. In other embodiments, n is 1 or 2. In some embodiments, n is 1. In other embodiments, n is 2.

[0536] According to a fifth aspect of the present invention, there is provided a pharmaceutical composition comprising a compound according to any embodiment of any one of the first, second, third or fourth aspects.

[0537] According to a sixth aspect of the present invention, there is provided a compound according to any embodiment of any one of the first, second, third or fourth aspects or a pharmaceutical composition according to the fifth aspect for use in medicine.

[0538] According to a seventh aspect of the present invention, there is provided a compound of any embodiment of any aspect of the first, second, third or fourth aspects for the purposes of treating cancer or a pharmaceutical composition of the fifth aspect. In some embodiments, the cancer is selected from breast cancer, triple-negative breast cancer, colorectal cancer, pancreatic cancer, skin cancer, melanoma, ovarian cancer, kidney cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, lymphoma, non-Hodgkin's lymphoma, multiple myeloma, cervical cancer, leukemia, chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), bladder cancer and prostate cancer. In certain embodiments, cancer is multiple myeloma or acute myeloid leukemia.

[0539] According to an eighth aspect of the present invention, there is provided a method for treating the cancer of a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of any embodiment of any aspect of the first, second, third or fourth aspects or the pharmaceutical composition of the fifth aspect. In some embodiments, the cancer is selected from breast cancer, triple-negative breast cancer, colorectal cancer, pancreatic cancer, skin cancer, melanoma, ovarian cancer, kidney cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, lymphoma, non-Hodgkin's lymphoma, multiple myeloma, cervical cancer, leukemia, chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), bladder cancer and prostate cancer. In certain embodiments, the cancer is multiple myeloma or acute myeloid leukemia.

[0540] In some embodiments of the eighth aspect, the administering does not result in cytotoxicity to cardiomyocytes of the subject.

[0541] In some embodiments of the eighth aspect, 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 anticancer agent selected from the group consisting of 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; anthracyclines; taxane compounds; and hypomethylating agents.

[0542] According to a ninth aspect of the present invention, there is provided a compound according to any embodiment of any one of the first, second, third or fourth aspects or a pharmaceutical composition according to the fifth aspect for use in reversing resistance to chemotherapy or targeted cancer therapy.

[0543] According to a tenth 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 according to any one of claims 1 to 147 or a pharmaceutical composition according to claim 148.

[0544] According to an eleventh aspect of the present invention there is provided a combined preparation of a compound according to any embodiment of any of the first, second, third or fourth aspects and at least one additional active agent for simultaneous, separate or sequential use in therapy.

[0545] In some embodiments of the eleventh aspect, the at least one additional active agent is an anticancer agent selected from the group consisting of 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; pidilimumab; carfilzomib; venetoclax; cytarabine; anthracyclines; taxane compounds; and a hypomethylating agent.

[0546] In some embodiments of the eleventh aspect, the therapy is treatment of cancer.

[0547] According to a twelfth aspect of the present invention, there is provided a method for reducing the cardiotoxicity of an MCL-1 inhibitor, comprising coupling a cereblon binding moiety to the MCL-1 inhibitor, wherein the cereblon binding moiety is a [ligase ligand moiety] as defined in any embodiment of any one of the first, second, third or fourth aspects, and the MCL-1 inhibitor is a [MCL-1 ligand prodrug moiety] as defined in any embodiment of any one of the first, second, third or fourth aspects.

[0548] As used herein, the term "alkyl" is intended to include both straight-chain and branched-chain alkyl groups, both of which may be unsubstituted or substituted with one or more additional groups. In some embodiments, the alkyl group is an unsubstituted alkyl group. In some embodiments, the alkyl group is substituted with one or more groups selected from -OH, -OR W 、-NH2、-NHR W 、-NR W 2. -SO2R W 、-C(O)R W , -CN and -NO2, wherein each RW is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. In some embodiments, the alkyl group is C1-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 substituted by one or more of -OH, -OR W 、-NH2、-NHR W 、-NR W 2. -SO2R W 、-C(O)R W , -CN and -NO2, wherein each R W is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl or benzyl. In some embodiments, the alkyl group is a branched alkyl group. In some embodiments, the alkyl group is an unsubstituted branched alkyl group. In some embodiments, the alkyl group is substituted by one or more of -OH, -OR W 、-NH2、-NHR W 、-NR W 2. -SO2R W 、-C(O)R W , -CN and -NO2 substituted branched alkyl groups, wherein each R W is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl or benzyl.

[0549] As used herein, the term "alkenyl" is intended to include unsubstituted alkenyl groups and alkenyl groups substituted with one or more additional groups. In some embodiments, the alkenyl group is an unsubstituted alkenyl group. In some embodiments, the alkenyl group is selected from -OH, -OR W 、-NH2、-NHR W 、-NR W 2. -SO2R W 、-C(O)R W , -CN and -NO2, wherein each R W is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. In some embodiments, the alkenyl group is C2-C 12 Alkenyl, C2-C 10In 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 selected from -OH, -OR W 、-NH2、-NHR W 、-NR W 2. -SO2R W 、-C(O)R W , -CN and -NO2, wherein each R W is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl or benzyl. In some embodiments, the alkenyl group is a branched alkenyl group. In some embodiments, the alkenyl group is an unsubstituted branched alkenyl group. In some embodiments, the alkenyl group is selected from -OH, -OR W 、-NH2、-NHR W 、-NR W 2. -SO2R W 、-C(O)R W , -CN and -NO2 one or more groups substituted branched alkenyl group, wherein each R W are all unsubstituted and are independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl or benzyl.

[0550] As used herein, the term "alkynyl" is intended to include unsubstituted alkynyl groups and alkynyl groups substituted with one or more additional groups. In some embodiments, the alkynyl group is an unsubstituted alkynyl group. In some embodiments, the alkynyl group is substituted with one or more groups selected from -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 C2-C 12 Alkynyl, C2-C 10 In some embodiments, the alkynyl group is a straight chain alkynyl group. In some embodiments, the alkynyl group is an unsubstituted straight chain alkynyl group. In some embodiments, the alkynyl group is selected from -OH, -OR 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. 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 selected from -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.

[0551] As used herein, the term "cycloalkyl" is intended to include unsubstituted cycloalkyl groups and cycloalkyl groups substituted by 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 -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 cycloalkyl group is C3-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.

[0552] As used herein, the term "cycloalkenyl" is intended to include unsubstituted cycloalkenyl groups and cycloalkenyl groups substituted with one or more additional groups. In some embodiments, the cycloalkenyl group is an unsubstituted cycloalkenyl group. In some embodiments, the cycloalkenyl group is selected from -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 cycloalkenyl group is C4-C 12 Cycloalkenyl, C5-C 12 Cycloalkenyl, C4-C 10 Cycloalkenyl, C5-C 10 Cycloalkenyl, C4-C8 cycloalkenyl, C5-C8 cycloalkenyl, C4-C6 cycloalkenyl, C5-C6 cycloalkenyl or C4-C5 cycloalkenyl group.

[0553] As used herein, the term "heterocycloalkyl" is intended to include unsubstituted heterocycloalkyl groups and heterocycloalkyl groups substituted by one or more additional groups. The term "heterocycloalkyl" is also intended to include monocyclic and bicyclic ring systems (including spirocyclic ring systems, wherein the two rings share a single atom; fused bicyclic ring systems, wherein the two rings share two adjacent atoms; and bridged bicyclic ring systems, wherein the two rings share three or more atoms). In some embodiments, the heterocycloalkyl group is a monocyclic ring system, a spirocyclic ring system, or a fused bicyclic ring system. In some embodiments, the heterocycloalkyl group is an unsubstituted heterocycloalkyl group. In some embodiments, the heterocycloalkyl group is selected from -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 by a -C(O)- group. In some embodiments, the heterocycloalkyl group is C3-C 12 Heterocycloalkyl, C4-C 12 Heterocycloalkyl, C5-C 12 Heterocycloalkyl, C3-C10 Heterocycloalkyl, C4-C 10 Heterocycloalkyl, C5-C 10 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.

[0554] As used herein, the term "aryl" is intended to include unsubstituted aryl groups and aryl groups substituted with one or more additional groups. In some embodiments, the aryl group is an unsubstituted aryl group. In some embodiments, the aryl group is selected from -OH, -OR W 、-NH2、-NHR W 、-NR W 2. -SO2R W 、-C(O)R W 、-OC(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 aryl group is C6-C 10 aryl, C6-C8 aryl or C6 aryl.

[0555] As used herein, the term "heteroaryl" is intended to include unsubstituted heteroaryl groups as well as heteroaryl groups substituted with one or more additional groups. In some embodiments, the heteroaryl group is an unsubstituted heteroaryl group. In some embodiments, the heteroaryl group is selected from -OH, -OR W 、-NH2、-NHR W 、-NR W 2. -SO2R W 、-C(O)R W , -CN and -NO2, wherein each R W is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. In some embodiments, one or more -NH- groups of a heteroaryl ring may be replaced by -NR W In some embodiments, the heteroaryl group is C6-C 10 heteroaryl, C6-C9 heteroaryl, C6-C8 heteroaryl or C6 heteroaryl.

[0556] 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 wherein the two rings share two adjacent atoms. Of the two adjacent atoms shared by the two rings, both can be carbon atoms; both can be heteroatoms (e.g., independently O, N, or S); or one can be a carbon atom and the other a heteroatom (e.g., O, N, or S). The fused heterocycloalkyl-heteroaryl can 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 selected from -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.

[0557] As used herein, the term "benzyl" is intended to include unsubstituted benzyl groups as well as benzyl groups substituted with one or more additional groups. In some embodiments, the benzyl group is an unsubstituted benzyl group. In some embodiments, the benzyl group is selected from -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.

[0558] In some embodiments of any of the aforementioned aspects of the invention, all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, and benzyl groups in the compound are unsubstituted. BRIEF DESCRIPTION OF THE DRAWINGS

[0559] Figure 1 Shown are representative Western blots demonstrating MCL-1 protein degradation in MV4-11 cells treated for 6 hours with compound 69 of the present invention. Loading control: total protein (SF - no staining).

[0560] Figure 2Representative Western blots are shown showing MCL-1 protein degradation in the presence of apoptosis inhibitors in MV4-11 cells treated for 6 hours with compounds of WO2022 / 253713A1 and compound 41 of the present invention. Loading control: total protein (SF - no staining). DETAILED DESCRIPTION

[0561] As mentioned above, the present invention provides a compound of formula (I)

[0562] [MCL-1 ligand prodrug moiety]-linker-[ligase ligand moiety] (I) or a salt, solvate, hydrate or isomer thereof.

[0563] Prodrugs of bifunctional compounds according to the present invention that bind to ubiquitin ligases and target the MCL-1 protein have the potential to improve bioavailability and, therefore, require fewer administrations while maintaining good therapeutic efficacy due to their extended half-life. Reducing the therapeutic dose compared to administering the drug itself as the active compound can also have the effect of reducing side effects and toxicity. Furthermore, some prodrugs of the present invention may have improved water solubility compared to the active compound.

[0564] Ligase ligand part

[0565] Ligase ligand moiety with a thalidomide-type structure

[0566] In the first aspect of the present invention, the [ligase ligand moiety] is:

[0567]

[0568] in:

[0569] M is O, S or NH, or does not exist;

[0570] represents R connected to the linking group 18 ;

[0571] R 22 is hydrogen, halogen, -OMe, amino, heterocycloalkyl or unsubstituted C1-C6 alkyl;

[0572] R 29 is hydrogen or Me; and

[0573] L' is hydrogen, alkyl, benzyl, acetyl or pivaloyl.

[0574] In some embodiments of the first aspect of the present invention, M is O or NH, or is absent.

[0575] In some embodiments of the first aspect of the present invention, R 22 For hydrogen.

[0576] In some embodiments of the first aspect of the present invention, L' is hydrogen or methyl. In some embodiments, L' is hydrogen.

[0577] In some embodiments of the first aspect of the present invention, R 29 For hydrogen.

[0578] In some embodiments of the first aspect of the invention, [ligase ligand moiety] is:

[0579]

[0580] In some embodiments of the first aspect of the invention, [ligase ligand moiety] is:

[0581]

[0582] In some embodiments of the first aspect of the invention, [ligase ligand moiety] is:

[0583]

[0584] In some embodiments of the first aspect of the invention, [ligase ligand moiety] is

[0585]

[0586] In some embodiments of the first aspect of the invention, [ligase ligand moiety] is

[0587]

[0588] Examples of the above-mentioned ligase ligand moieties are shown in Table 1 below:

[0589] Table 1:

[0590]

[0591]

[0592]

[0593]

[0594] Many of the compounds in Table 1 above are commercially available in the forms shown below.

[0595]

[0596] Formula (IV) and Formula (IVa); Formula (VIIa), Formula (VIIb), Formula (VIIc) and Formula (VIId); Formula (VIII) and Formula (IX) The ligase ligand portion

[0597] In the second aspect of the invention, [ligase ligand moiety] may be a ligase ligand moiety of formula (IV) or (IVa); (VIIa), (VIIb), (VIIc), or (VIId); or (VIII); or (IX). The synthesis of the ligase ligand moiety of formula (IV) (defined above) may be summarized as follows:

[0598]

[0599] Exemplary ligase ligand moieties of formula (IV) and formula (IVa) are shown in Table 2 below. For example, Modifications may be made to allow attachment to [linker] (e.g., by nucleophilic aromatic substitution; or by exchanging fluorine with bromine followed by palladium coupling to attach [linker] itself or a functional group to which [linker] can be attached).

[0600] Table 2:

[0601]

[0602]

[0603] Exemplary ligase ligand moieties of Formula (VIIa), Formula (VIIb), Formula (VIIc), and Formula (VIId) are shown below in Table 3:

[0604] Table 3:

[0605]

[0606] The synthesis of these compounds is summarized in steps 1-4 as follows:

[0607] Step 1:

[0608]

[0609] Under inert gas, dibromoaryl hydrocarbon (1 equivalent) To the oxane solution were added KOAc (2 equivalents), ((1-(tert-butoxy)vinyl)oxy)(tert-butyl)dimethylsilane (4 equivalents), and Pd[P(o-toluene)3]2Cl2 (0.2 equivalents), and the reaction mixture was stirred at 130°C for 48 hours. The reaction mixture was filtered through Celite, concentrated under reduced pressure, and purified by flash column chromatography to give the corresponding tert-butyl arylacetate.

[0610] Step 2:

[0611]

[0612] To a solution of the appropriate amount of tert-butyl 2-(quinolin-3-yl)acetate (1 equivalent) in DMF were added KCO (1 equivalent), benzyltriethylammonium chloride (1 equivalent), and acrylonitrile (1 equivalent), and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water, and the product was extracted with ethyl acetate. The combined organic phases were dried over NaSO, concentrated under reduced pressure, and purified by flash column chromatography.

[0613] Step 3:

[0614]

[0615] To an ice-cold solution of the appropriate tert-butyl 4-cyano-2-(quinolin-3-yl)butanoate (1 equiv) in DMSO was added H2O2 (5 equiv) and K2CO3 (0.1 equiv). The reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was diluted with water and the product was extracted with ethyl acetate. The organic phases were combined, dried over Na2SO4, concentrated under reduced pressure, and purified by flash column chromatography.

[0616] Step 4:

[0617]

[0618] The appropriate tert-butyl 5-amino-2-(2-methylquinolin-3-yl)-5-oxopentanoate (1 equivalent), p-toluenesulfonic acid (5-10 equivalents) and ACN were placed in a vial, 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.

[0619] Linker ligand moieties of formula (Va) and (Vb) and formula (IIa) and (IIb)

[0620] In the third aspect of the present invention, [ligase ligand moiety] can be a ligase ligand moiety of formula (Va), formula (Vb), or a ligase ligand moiety of formula (IIa) and formula (IIb). The synthesis of the ligase ligand moieties of formula (Va), formula (Vb), formula (IIa) and (IIb) (as defined above) can be summarized in the following general steps (performed under synthesis conditions D, E, F or G), as described below:

[0621]

[0622] Reaction Scheme 2: General Steps

[0623] Synthesis conditions D

[0624] To a DMF solution (0.5 M) of 3-aminopiperidine-2,6-dione (1 eq.) and N-hydroxybenzotriazole (1.2 eq.) was added the appropriate acid (R in the above reaction scheme). xThe mixture was stirred at room temperature (20-25° C.) overnight. Water (2×DMF volume) was added and the resulting solution was extracted with dichloromethane (3×DMF volume). The combined organic layers were washed with water, dried over Na 2 SO 4 , and concentrated under reduced pressure. The crude product was purified by preparative HPLC or column chromatography.

[0625] Synthesis conditions E

[0626] To a 0.5 M solution of 3-aminopiperidine-2,6-dione (hydrochloride, 1.1 eq.), triethylamine (1.2 eq.) and N-hydroxybenzotriazole (1.2 eq.) in DMA was added the appropriate acid (R in the above reaction scheme). x The mixture was stirred at room temperature overnight. Water (2 × DMA volume) was added and the resulting mixture was extracted with dichloromethane (3 × DMA volume). The combined organic layers were washed with water, dried over Na2SO4, and concentrated under reduced pressure. The crude product was separated by preparative HPLC or column chromatography.

[0627] Synthesis Condition F

[0628] To a suitable acid (R in the above reaction scheme x To a solution of 3-aminopiperidine-2,6-dione (hydrochloride, 1.2 equiv) and DIPEA (3 equiv) in anhydrous DMF were added 1,2-dione (hydrochloride, 1.2 equiv) and 1,2-dione (3 equiv). The reaction mixture was stirred at room temperature overnight. The crude product was purified by preparative HPLC and / or by preparative TLC.

[0629] Synthesis Condition G

[0630] Under an inert atmosphere, add an appropriate acid (R x To a solution of 2-[4-[ ...

[0631] Exemplary Method 1: Formation of R x COOH (or its ester R x COOR y ) of chloro R x Group

[0632] To a 0.5 M solution of the appropriate starting material (1 eq) in DMF was added NCS (1.1 eq). The reaction mixture was stirred at room temperature (20-25°C) for 2 hours. The reaction mixture was poured into water (2 x the volume of DMF) and the precipitate was filtered. The solid was washed with water and dried under vacuum to yield the acid ROOH.

[0633] Exemplary method 2: From the corresponding ester R x COOR y Synthetic R x COOH

[0634] To a solution of the appropriate ester (1 equivalent) in THF:water (3:1 or 5:1, 85 mM) was added LiOH (1.1 equivalents), 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 under vacuum to yield the desired carboxylic acid.

[0635] Exemplary Method 3: R x COOR y Acetylated R x Group formation

[0636] The appropriate amine (1 eq.), Ac2O (3 eq.) and DMAP (0.2 eq.) were mixed in a The mixture was heated to 80°C for 2 hours. After completion, the mixture was cooled to room temperature (20-25°C) and concentrated under reduced pressure. The residue was washed with water (1× distilled water). dilution with ethyl acetate (3 × dioxane) The organic layer was washed with water, brine, dried over Na2SO4 and evaporated to dryness to give the acylated product, which was usually used without further purification.

[0637] Exemplary ligase ligand moieties of Formula (Va) and Formula (Vb) are shown below in Table 4. Many of these compounds can be modified to allow for attachment to [linking group] (e.g., via CH bond activation).

[0638] Table 4:

[0639]

[0640]

[0641] Exemplary ligase ligand moieties of Formula (IIa) and Formula (IIb) are shown below in Table 5. Many of these compounds can be modified to allow for attachment to a [linking group] (e.g., via CH bond activation).

[0642] Table 5:

[0643]

[0644]

[0645] Ligase ligand moieties of formula (VIa) and formula (VIb)

[0646] In a fourth aspect of the invention, the ligase ligand moiety may be a ligase ligand moiety of formula (VIa) or formula (VIb):

[0647]

[0648] in:

[0649] M is O, S or NH, or does not exist;

[0650] represents R connected to the linking group 18 ;

[0651] R 22 is hydrogen, halogen, -OMe, amino, heterocycloalkyl, or unsubstituted C1-C6 alkyl; and

[0652] L' is hydrogen, alkyl, benzyl, acetyl or pivaloyl.

[0653] In some embodiments, L' is hydrogen. In some embodiments, M is O. In some embodiments, R 22 It is an unsubstituted C1-C6 alkyl group.

[0654] The synthesis of the ligase ligand moieties of Formula (VIa) and Formula (VIb) is described in the Examples section below.

[0655] Exemplary ligase ligand moieties of formula (VIa) and formula (VIb) are shown in Table 6 below, wherein R represents the linker group 18 :

[0656] Table 6:

[0657]

[0658] Ligase ligand moieties of formula (II) and formula (III)

[0659] In the fourth aspect of the present invention, the [ligase ligand moiety] may alternatively be a ligase ligand moiety of formula (II) or formula (III). The synthesis of the ligase ligand moieties of formula (II) and formula (III) (as defined above) can be summarized as follows:

[0660]

[0661] Reaction Scheme 1

[0662] (R z R x or R y )

[0663] Exemplary ligase ligand moieties of formula (II) and formula (III) are shown below in Table 7. Many of these compounds can be modified to allow for attachment to [linker] (e.g., by bromination of the aromatic ring followed by palladium coupling to the [linker] itself or to a functional group to which the [linker] can be attached).

[0664] Table 7:

[0665]

[0666]

[0667]

[0668] Exemplary ligase ligand moieties of formula (III) are shown below in Table 8, where the linkage to the linker group (R 21 is the R of the linking group 18 Connected keys):

[0669] Table 8:

[0670]

[0671]

[0672]

[0673] Linking group

[0674] In the first, second, third and fourth aspects of the invention, the [linking group] has the formula:

[0675] R 14 -R 15 -R 16 -R 17 -R 18

[0676] in

[0677] 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;

[0678] R15 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 Alkyl-NH-, -C 1-6 Alkyl-N(C 1-6 alkyl)-, -cycloalkyl-NH-, -heterocycloalkyl-NH- or absent;

[0679] 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;

[0680] R 17 -CH2(C2H4-O) y 、-(CH2O) x 、-(C2H4-O) x 、-(C3H6-O) x or does not exist;

[0681] x is 1-10;

[0682] y is 2-10;

[0683] R 18 -C 1-6 Alkyl, -C 1-6 Alkyl-C(O)-, cycloalkyl, -CH2-NH-C(O)-, heterocycloalkyl or absent;

[0684] where R 14 -R 18 At least one of exists.

[0685] In some embodiments, R 14 -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 In some such embodiments, R 14 Yes-C 1-6 alkyl.

[0686] In some embodiments, R 15 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 In some such embodiments, R 15 Is heterocycloalkyl or absent. In some embodiments, R 15 In some such embodiments, R 15is piperazine, bridged piperazine, piperazine N-oxide, piperazine cation,

[0687]

[0688] in, Indicates connection to R 14 , Indicates connection to R 16 .

[0689] In some embodiments, R 15 Is piperazine or

[0690] In some embodiments, R 16 Yes-C 1-6 alkyl, -CH2-C(O)-NH-, -CH2-C(O)-, -C(O)-, or absent. In some embodiments, R 16 Yes-C 1-6 In some embodiments, R 16 Yes-C 1-6 Alkyl or -C(O)-.

[0691] In some embodiments, R 17 Does not exist.

[0692] In some embodiments, R 18 -C 1-6 In some embodiments, R 18 Yes-C 1-6 In some embodiments, R 18 Yes-C 1-6 Alkyl or piperazine.

[0693] In some embodiments,

[0694] R 14 -C 1-6 Alkyl, -C 1-6 Alkyl-N(Me)-, -SO2- or absent;

[0695] R 15 is piperazine, bridged piperazine, piperazine N-oxide, piperazine cation,

[0696] or does not exist, where Indicates connection to R 14 , Indicates connection to R 16 ;

[0697] R16 -C 1-6 Alkyl, -CH2-C(O)-NH-, -CH2-C(O)-, -C(O)-, or absent;

[0698] R 17 is -CH2(C2H4-O) y 、(C2H4-O) x 、(C3H6-O) x or absent, where x is 1-6 and y is 2-6; and

[0699] R 18 Yes-C 1-6 Alkyl, piperazine, or does not exist, where Indicates connection to R 17 ,

[0700] And where R 14 -R 18 At least one of exists.

[0701] In some embodiments,

[0702] R 14 -C 1-6 alkyl,

[0703] R 15 Is piperazine or

[0704] R 16 Yes-C 1-6 Alkyl or -C(O)-,

[0705] R 17 does not exist,

[0706] R 18 Yes-C 1-6 Alkyl or piperazine.

[0707] In some embodiments, [linking group] is selected from:

[0708]

[0709] in

[0710] represents attachment to [MCL-1 ligand prodrug moiety]; and Indicates attachment to [ligase ligand moiety].

[0711] In some embodiments, [linking group] is selected from:

[0712]

[0713] in:

[0714] represents attachment to [MCL-1 ligand prodrug moiety]; and

[0715] Indicates attachment to [ligase ligand moiety].

[0716] The linking groups used in the compounds of the present invention can be synthesized according to standard methods.

[0717] Most alkyl and polyethylene glycol (PEG) linking groups are commercially available or can be prepared according to procedures described in the literature.

[0718] Examples of commercially available linking groups include:

[0719]

[0720] The synthesis of linkers that are not commercially available is described in the Examples.

[0721] The piperazine-modified linker was prepared according to the following scheme:

[0722]

[0723] MCL-1 ligand prodrug moiety

[0724] In the first, second, third and fourth aspects of the present invention, the [MCL-1 ligand prodrug moiety] is a compound of formula (A1), formula (A2), formula (A3) or formula (A4):

[0725]

[0726] in:

[0727] is a single bond or a double bond;

[0728] Each Z2 is independently N or C, wherein when Z2 is N, then is a single bond; when Z2 is C, is a double bond;

[0729] Each R 11 are independently H, halogen or C1-C6 alkyl,

[0730] R 8 is a C1-C6 alkyl group substituted with piperazine;

[0731] In each of formula (A1) and formula (A4), R 10 and R 30 One of them is H, R 10 and R30 The other one 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 tetrahydronaphthyl, wherein the phenyl, naphthyl or tetrahydronaphthyl is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl and -O(C1-C6 alkyl); or wherein the tetrahydronaphthyl is optionally substituted with a bridging -CH2- group; or wherein the naphthyl is optionally substituted with -O- or -S-,

[0732] R 12 for

[0733] R 31 Yes-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 tetrahydronaphthyl, wherein the phenyl, naphthyl or tetrahydronaphthyl is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl and -O(C1-C6 alkyl); or wherein the tetrahydronaphthyl is optionally substituted with a bridged -CH2- group; or wherein the naphthyl is optionally substituted with -O- or -S-;

[0734] Each R 32 are independently H,

[0735] Each R 33 Independently R 19 or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with morpholine or piperazine;

[0736] R 20 Me, -CH2-OMe, -(CH2CH2O) p (C1-C6 alkyl) or -CH2-O-bromobenzaldehyde, wherein p is 1-5;

[0737] R 34 It is C 2-5 Alkyl-OR 13 or -OC 2-5 Alkyl-R 13 , where R 13is phenyl, naphthyl or tetrahydronaphthyl, wherein the phenyl, naphthyl or tetrahydronaphthyl is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl and -O(C1-C6 alkyl); or wherein the tetrahydronaphthyl is optionally substituted with a bridged -CH2- group; or wherein the naphthyl is optionally substituted with -O- or -S-;

[0738] R 35 for

[0739] R 19 is the R of the linking group 14 wherein each of Formula (A1), Formula (A2), Formula (A3) and Formula (A4) contains a single R 19 ;and

[0740] (i)R 9 is -C(O)O(C1-C6 alkyl), -C(O)O cycloalkyl, -C(O)O heterocycloalkyl, -C(O)O aryl or -P(O)(OR p ) 2, wherein the C1-C6 alkyl group is substituted by one or more groups selected from the following: -OC(O) (unsubstituted C1-C6 alkyl), -OC(O) (substituted by at least one R 10 substituted C1-C6 alkyl), -OC(O)cycloalkyl, -OC(O)heterocycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, -OC(O)(CH2) m O(CH2) m O(unsubstituted C1-C6 alkyl), -OC(O)(CH2) m O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(unsubstituted C1-C6 alkyl), -OC(O)O(substituted by at least one R 10 Substituted C1-C6 alkyl), -OC(O)O cycloalkyl, -OC(O)O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2CH2O) m (C1-C6 alkyl substituted with OP(O)(OH)2), -OC(O)O(CH2CH2S) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)(unsubstituted C1-C6 alkyl), -OC(O)O(CH2) mS(O)2(unsubstituted C1-C6 alkyl), -OC(O)NH(C1-C6 alkyl substituted by OMe), -OC(O)NMe(C1-C6 alkyl substituted by OMe), -P(O)(OH)2, -OP(O)(OH)2, -C(O)heterocycloalkyl, -C(O)N(unsubstituted C1-C6 alkyl)2, heteroaryl, heterocycloalkyl, -S(unsubstituted C1-C6 alkyl), -S(O)(unsubstituted C1-C6 alkyl), -N + (unsubstituted C1-C6 alkyl)3, -N + (Unsubstituted C1-C6 alkyl)2-cycloalkyl, N-(unsubstituted C1-C6 alkyl)piperidine Cation, N-(unsubstituted C1-C6 alkyl)morpholine Cation and N-(unsubstituted C1-C6 alkyl) imidazole cation;

[0741] Among them, each R 10 are independently -OH, -O(unsubstituted C1-C6 alkyl), -Obn, -NH2, -NMe2, -NHC(O)(unsubstituted C1-C6 alkyl), -NHC(O)O(unsubstituted C1-C6 alkyl), heterocycloalkyl, heteroaryl, aryl, -C(O)NMe2;

[0742] Each R p are independently -(CH2) m OC(O) (unsubstituted C1-C6 alkyl), and

[0743] Each m is independently 1, 2, 3 or 4;

[0744] or

[0745] (ii)R 9 is -C(O)O(CH2) p NMe2, -C(O)O(CH2) p NHMe, -C(O)OCH2CH(OH)CH2OH, -C(O)OCH2CH2CMe2OH or -C(O)OCH2CH2SO2Me, wherein each p is independently 2, 3, 4, 5 or 6.

[0746] In some embodiments, [MCL-1 ligand prodrug moiety] is:

[0747]

[0748] in:

[0749] R 11 It is a halogen;

[0750] R 13a is a halogen; and

[0751] R 20 is Me, -CH2-OMe or -(CH2CH2O) p (C1-C6 alkyl), wherein p is 1-5.

[0752] In some embodiments, R 9 is -C(O)O(C1-C6 alkyl), -C(O)O cycloalkyl, -C(O)O heterocycloalkyl, -C(O)O aryl or -P(O)(OR p ) 2, wherein the C1-C6 alkyl group is substituted by one or more groups selected from the following: -OC(O) (unsubstituted C1-C6 alkyl), -OC(O) (substituted by at least one R 10 substituted C1-C6 alkyl), -OC(O)cycloalkyl, -OC(O)heterocycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, -OC(O)(CH2) m O(CH2) m O(unsubstituted C1-C6 alkyl), -OC(O)(CH2) m O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(unsubstituted C1-C6 alkyl), -OC(O)O(substituted by at least one R 10 Substituted C1-C6 alkyl), -OC(O)O cycloalkyl, -OC(O)O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2CH2O) m (C1-C6 alkyl substituted with OP(O)(OH)2), -OC(O)O(CH2CH2S) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)(unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)2(unsubstituted C1-C6 alkyl), -OC(O)NH(C1-C6 alkyl substituted by OMe), -OC(O)NMe(C1-C6 alkyl substituted by OMe), -P(O)(OH)2, -OP(O)(OH)2, -C(O)heterocycloalkyl, -C(O)N(unsubstituted C1-C6 alkyl)2, heteroaryl, heterocycloalkyl, -S(unsubstituted C1-C6 alkyl), -S(O)(unsubstituted C1-C6 alkyl), -N + (unsubstituted C1-C6 alkyl)3, -N +(Unsubstituted C1-C6 alkyl)2-cycloalkyl, N-(unsubstituted C1-C6 alkyl)piperidine Cation, N-(unsubstituted C1-C6 alkyl)morpholine In some such embodiments, R 9 is -C(O)O(C1-C6 alkyl), -C(O)O cycloalkyl, -C(O)O heterocycloalkyl, -C(O)O aryl or -P(O)(OR p ) 2, wherein the C1-C6 alkyl group is substituted by one or more groups selected from the group consisting of: -OC(O)Me, -OC(O)Et, -OC(O) i Pr, -OC(O)C(CH3)3, -OC(O)CH2OH, -OC(O)CH(CH3)OH, -OC(O)C(CH3)2OH, -OC(O)CH2CH2OH, -OC(O)CH(OH)CHMe2, -OC(O)CH(OH)CH2CHMe2, -OC(O)CH2CH(OH)Me, -OC(O)CH2C(OH)Me2, -OC(O)CH(CH2OH)(NHC(O)Me), -OC(O)CH(NHC(O)Me)(isobutyl), -OC(O)CH(OH)aryl, -OC(O)CH(OH)CH2aryl, -OC(O)heterocycloalkyl, -OC(O)cycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, -OC(O)CH2CH2aryl, -OC(O)CH(NH2) i Pr, -OC(O)CH( i Pr)NHC(O)O t Bu, -OC(O)CH2OCH2CH2OMe, -OC(O)CH2(OCH2CH2)2OMe, -OC(O)OMe, -OC(O)OEt, -OC(O)O iPr, -OC(O)Ocycloalkyl, -OC(O)OCH2CH2OEt, -OC(O)O(CH2CH2O)2Et, -OC(O)O(CH2CH2O)3Et, -OC(O)O(CH2CH2O)3CH2CH2OP(O)(OH)2, -OC(O)OCH2CH2SMe, -OC(O)OCH2CH2S(O)Me, -OC(O)OCH2CH2S(O)2Me, -OC(O)OCH2heteroaryl, -OC(O)OCH2heterocycloalkyl, -OC (O)OCH2CH2OCH2aryl-OC(O)OCH2CH2C(O)NMe2、-OC(O)O(CH2)6NH2、-OC(O)O(CH2)6NMe2、-OC(O)OCH(CH2OEt)2、-OC(O)NHCH2CH2OMe、-OC(O)NMeCH2CH2OMe、-SMe、-S(O)Me、-P(O)(OH)2、-OP(O)(OH)2、-C(O)NMe2、-C(O)heterocycloalkyl、heteroaryl、heterocycloalkyl、-N + (Me)3, -N + (Me)2 cycloalkyl, N-methylmorpholine Cation, N-methylpiperidine Cation and N-methylimidazole cation.

[0753] In some embodiments, R 9 is -C(O)O(C1-C6 alkyl), wherein the C1-C6 alkyl is substituted with one or more groups selected from -OC(O)C(CH3)3, -OC(O)CH2CH2OH, -OC(O)C(CH3)2OH, -OC(O)heterocycloalkyl, -OC(O)CH2OCH2CH2OMe, -OC(O)OiPr, -OC(O)Ocycloalkyl, -OC(O)O(CH2CH2O)2Et, -OP(O)(OH)2, heteroaryl, or heterocycloalkyl. In some such embodiments, R 9 It is -C(O)O(C1-C6 alkyl), wherein the C1-C6 alkyl is substituted by -OC(O)C(CH3)3.

[0754] In some embodiments, R 9is -C(O)OCH2OC(O)C(CH3)3, -C(O)OCH2OC(O)Me, -C(O)OCH(Me)OC(O)Me, -C(O)OCH2OC(O)CH2CH2OH, -C(O)OCH2OC(O)C(CH3)2OH, -C(O)OCH2OC(O)piperidine, -C(O)OCH2OC(O)CH2OCH2CH2OMe, -C(O)OCH2OC(O)OiPr, -C(O)OCHMeOC(O)OiPr, -C(O)OCHMeOC(O)Ocyclohexyl, -C(O)OCHMeOC(O)O(CH2CH2O)2Et, -C(O)OCH2CH2OP(O)(OH)2, -C(O)OCH2(N-methylimidazole) cation), -C(O)OCH2(N-methylpiperidin cation), -C(O)OCH2 dioxolane, -C(O)OCH2CH2 morpholine, -C(O)OCH2CH2 piperazine, -C(O)OCH2CH2CH2 piperazine or -P(O)(OCH2OC(O)C(CH3)3)2.

[0755] In some embodiments, R 9 It is -C(O)OCH2OC(O)C(CH3)3.

[0756] In some embodiments, [MCL-1 ligand prodrug moiety] is:

[0757]

[0758] Example

[0759] The bifunctional compound [MCL-1 ligand prodrug portion]-[linker]-[ligase ligand prodrug portion] of the present application can be synthesized in a variety of ways:

[0760] 1. [MCL-1 ligand prodrug moiety] is coupled to linker A and subsequently to [ligase ligand moiety]-linker B Coupling

[0761]

[0762] wherein X is a halogen or OMs, OTs; the linker AN-Boc corresponds to the linker A terminated with a primary or secondary amine protected by Boc; the linker A-NH corresponds to the linker A terminated with a primary or secondary amine; R 11 -R 13 and [Linker] is as defined herein; wherein [Linker] is represented in the above synthesis by -Linker A-NHR w Reaction with the -linking group B-COOH forms.

[0763] 2. [MCL-1 ligand prodrug moiety] is coupled to linker A, followed by linker B, and then to [linker enzyme-ligand moiety] coupling

[0764]

[0765] wherein X is a halogen or OMs, OTs; the linker AN-Boc corresponds to the linker A terminated with a primary or secondary amine protected by Boc; the linker A-NH corresponds to the linker A terminated with a primary or secondary amine; R 11 -R 13 as defined herein; and wherein Linker AN-Linker B corresponds to [Linker].

[0766] 3. [MCL-1 ligand prodrug moiety]-[linker] coupled to [ligase ligand moiety]

[0767]

[0768] 4. [MCL-1 ligand prodrug moiety] coupled to [linker]-[ligase ligand moiety]

[0769]

[0770] 5. [MCL-1 ligand prodrug moiety]-[linker]-R v Coupling with 3-aminopiperidine-2,6-dione

[0771]

[0772] The preparation method of the bifunctional compound of the present invention is as follows:

[0773] Example 1: (2-(2-methoxy base 6-Chloro-1-(2-(4-(2-(2-(2,6-dioxy)acetoxy)methyl (3-((6-fluoronaphthalene-1-yl)-3-((6-fluoronaphthalene-1-yl)-1-oxoisoindolin-4-yl)-1-oxoisoindolin-4-yl)-1-oxoisoindolin-3-yl)-1-oxoisoindolin-4 ... (4-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate) (Compound 57)

[0774]

[0775]

[0776] Step A

[0777] To a solution of 2-(2-methoxyethoxy)acetic acid (250 mg, 1.86 mmol) in DMF (4 mL) at room temperature under nitrogen was added chloroiodomethane (0.172 mL, 2.052 mmol), followed by KHCO (554 mg, 5.6 mmol). The resulting mixture was stirred at 60° C. under nitrogen for 1 hour. After complete consumption of the starting material (monitored by TLC), the reaction mixture was cooled to room temperature and filtered through a sintered funnel. The filtrate of chloromethyl 2-(2-methoxyethoxy)acetate in DMF was used without further purification.

[0778] Step B

[0779] To ethyl 7-bromo-6-chloro-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-1H-indole-2-carboxylate (1.7 g, 3.368 mmol) was added dibromo-6-chloro-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-1H-indole-2-carboxylate (1.7 g, 3.368 mmol) in di To a stirred solution of 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.386 g, 10.103 mmol) and K2CO3 (1.859 g, 13.471 mmol) in oxane (20 mL) and water (5 mL) was added. The mixture was deoxygenated with argon and Pd(dppf)Cl2 (0.369 g, 0.505 mmol) was added under an argon atmosphere. The reaction mixture was then heated at reflux 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 solvent evaporated under reduced pressure to give the crude product. It was then diluted with ethyl acetate and washed sequentially 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 (silica, 50% ethyl acetate in hexanes) 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.

[0780] LCMS (ESI): 534.2 m / z [M+H] + .

[0781] Step C

[0782] 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 ethanol (20 mL) and a solution of sodium hydroxide (0.315 g, 7.88 mmol) in water (10 mL) was added. The mixture was heated at 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 mixture was evaporated. The solvent was evaporated under reduced pressure to obtain a crude reaction mixture. It was then diluted with water and washed with ethyl acetate. The aqueous layer was carefully acidified to pH = 3 with 1M hydrochloric acid and extracted with ethyl acetate (x3). The organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum to obtain 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 product) as a brown liquid, which was used in the next step without further purification.

[0783] LCMS (ESI): 506.3 m / z [M+H] + .

[0784] Step D

[0785] 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 to reflux under nitrogen for 16 hours. After the starting material was completely consumed (monitored by TLC and LCMS), The reaction mixture was diluted with ethyl acetate and washed sequentially with sodium bicarbonate (saturated aqueous solution), 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 (silica, 70% ethyl acetate in hexanes) to give tert-butyl 6-chloro-3-((3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (0.772 g, 1.373 mmol, 61% yield over two steps) as a slightly brown liquid.

[0786] LCMS (ESI): 561.9 m / z [M+H] + .

[0787] Step E

[0788] 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 a solution of 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. When the starting material was completely consumed (by TLC and LC After 4 hours, the reaction mixture was diluted with ethyl acetate and washed with water and then 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 (silica, 30% ethyl acetate in hexanes) to give tert-butyl 1-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)-6-chloro-3-3-((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.

[0789] LCMS (ESI): 774.6m / z[M+H] + .

[0790] Step F

[0791] 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 hydrochloric acid in distilled water at 0°C. The mixture was stirred in an oxane solution under nitrogen at the same temperature for 2 hours. After complete consumption of the starting material (monitored by TLC and LCMS), the reaction mixture was poured into cold 1 M sodium hydroxide solution and extracted several times with dichloromethane. The organic phases were combined, dried over sodium sulfate, and concentrated in vacuo to afford the crude compound, which was then purified by column chromatography (aminoSiO2, 10% methanol in DCM) to afford 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.

[0792] LCMS (ESI): 674.4 m / z [M+H] + .

[0793] Step G

[0794] Under an argon atmosphere, 2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}acetic acid (18.3 mg, 0.058 mmol) was dissolved in anhydrous DMF (1.0 mL), and DIPEA (0.025 mL, 0.144 mmol) was added, followed by 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 tert-butyl ester (32.3 mg, 0.048 mmol). After the solution was cooled to 0°C, HATU (21.9 mg, 0.058 mmol) was added dropwise as a 0.2 mL anhydrous DMF solution. The reaction is stirred under an argon atmosphere and is allowed to warm to room temperature. After 15 minutes, complete conversion (monitored by LCMS) is observed. The solution is diluted with DCM, washed with salt solution, sodium bicarbonate (saturated), and washed with salt solution and water again. The organic layer is dried over anhydrous MgSO4, filtered, concentrated under reduced pressure and dried to give 6- chloro- 1- {2- [4- (2- { [2- (2,6- dioxopiperidin-3-yl) -1- oxygen -2,3- dihydro -1H- isoindole -4- base] oxygen} acetyl) piperazine-1- base] ethyl} -3- {3- [(6- fluoronaphthalene -1- base) oxygen] propyl group} -7- (1,3,5- trimethyl -1H- pyrazole -4- base) -1H- indole -2- carboxylic acid tert-butyl ester (44.7mg, crude product), which is an orange oil. The product is used in the next step without further purification.

[0795] LCMS (ESI): 974.6m / z[M+H] + .

[0796] Step H

[0797] Under argon atmosphere, tert-butyl 6-chloro-1-{2-[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}acetyl)piperazin-1-yl]ethyl}-3-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (44.7 mg, crude) was dissolved in anhydrous DCM (0.351 mL). TFA (0.351 mL, 4.584 mmol) was added and the reaction was stirred at room temperature for 18 hours. DCM and TFA were evaporated under reduced pressure, and the resulting residue was dissolved in DMSO and purified by preparative HPLC (water:MeCN+0.1% FA) to give 6-chloro-1-{2-[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}acetyl)piperazin-1-yl]ethyl}-3-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (12.6 mg, 0.014 mmol, 29% yield over two steps) as a white solid.

[0798] LCMS (ESI): 917.6 m / z [M+H] + .

[0799] Step I

[0800] To a solution of 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (120 mg, 0.13 mmol) in DMF (3 mL) was added KHCO (26 mg, 0.26 mmol) at room temperature under nitrogen, followed by a DMF solution of chloromethyl 2-(2-methoxyethoxy)acetate obtained in the previous step. The resulting mixture was stirred at 60° C. under nitrogen for 2 hours. After complete consumption of the starting material, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate and evaporated under reduced pressure to give the crude compound which was purified twice by preparative TLC (silica, 10% methanol in DCM then 50% acetone in DCM) to give (2-(2-methoxyethoxy)acetoxy)methyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (20 mg, 0.0188 mmol, 14.4%) as a white solid.

[0801] LCMS (ESI): 1065.0 m / z [M+H] + .

[0802] 11H NMR (500 MHz, DMSO) δ = 10.67 (s, 1H), 8.23 (dd, J = 9.2, 5.8, 1H), 7.77 (d, J = 8.6, 1H), 7.59 (dd, J = 10.4, 2.7, 1H), 7.49 - 7.40 (m, 3H), 7.37 - 7.30 (m, 2H), 7.26 (d, J = 8.6, 1H), 7.14 (d, J = 8.1, 1H), 6.88 (dd, J = 5.6, 3.0, 1H), 6.03 (d, J = 0.9, 2H), 5.05 (dd, J = 13.1, 5.2, 1H), 4.89 (s, 2H), 4.40 (d, J = 17.1, 1H), 4.32 (dd, J = 17.2, 1.6, 1H), 4.29 - 4.11 (m, 6H), 3.76 (d, J = 1.9, 3H), 3.60 - 3.57 (m, 2H), 3.44 - 3.40 (m, 2H), 3.38 - 3.30 (m, 4H), 3.29 - 3.24 (m, 2H), 3.20 (s, 2H), 2.88 (ddd, J = 17.4, 13.4, 5.5, 1H), 2.64 - 2.59 (m, 1H), 2.46 - 2.39 (m, 2H), 2.26 - 2.18 (m, 2H), 2.15 - 2.02 (m, 7H), 2.01 (s, 3H), 1.88 (s, 3H).

[0803] Example 2: ((piperidine-4-carbonyl)oxy)methyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidine-3- (6-fluoronaphthalen-1-yl)oxy)propyl 1H- 吡 oxazol-4-yl)-1H-indole-2-carboxylate (TFA salt) (Compound 55)

[0804]

[0805] Step A

[0806] To a solution of 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (150 mg, 0.163 mmol) in DMF (2 mL) at room temperature under nitrogen was added KCO (45 mg, 0.327 mmol), followed by a DMF solution of crude 1-(tert-butyl)-4-(chloromethyl)piperidine-1,4-dicarboxylate. The resulting mixture was stirred at 70°C under nitrogen for 2 hours. After complete consumption of the starting material (monitored by TLC and LCMS), the mixture was concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (silica, 3-4% methanol in DCM). 1-(tert-butyl)-4-(((6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonyl)oxy)methyl)piperidine-1,4-dicarboxylate (110 mg, 0.095 mmol, 58%) was obtained as a white solid.

[0807] LCMS (ESI): 1157.1m / z[MH] - .

[0808] Step B

[0809] To a solution of 1-(tert-butyl)-4-(((6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonyl)oxy)methyl)piperidine-1,4-dicarboxylate (110 mg, 0.095 mmol) in DCM (3 mL) was added TFA (2 mL) dropwise under nitrogen at 0° C. The reaction mixture was stirred at ambient temperature under nitrogen for 3 hours. After complete consumption of the starting material, the volatiles were removed under reduced pressure and the crude product was purified by trituration with diethyl ether and n-pentane to give ((piperidine-4-carbonyl)oxy)methyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (100 mg, 0.085 mmol, 89%) as a TFA salt (white solid).

[0810] LCMS (ESI): 1060.1m / z[M+H] + .

[0811] 11H NMR (500 MHz, DMSO, 353 K) δ 10.69 (s, 1H), 8.42 (bs, 1H), 8.25 (dd, J = 9.3, 5.9 Hz, 1H), 8.14b (s, 1H), 7.80 (d, J = 8.6 Hz, 1H), 7.63 (dd, J = 10.4, 2.5 Hz, 1H), 7.50 - 7.42 (m, 3H), 7.40 - 7.32 (m, 2H), 7.29 (d, J = 8.6 Hz, 1H), 7.16 (d, J = 8.2 Hz, 1H), 6.90 (dd, J = 6.2, 2.5 Hz, 1H), 6.04 (d, J = 5.9 Hz, 1H), 6.03 (d, J = 5.9 Hz, 1H), 5.08 (dd, J = 13.0, 5.2 Hz, 1H), 4.92 (s, 2H), 4.42 (d, J = 17.2 Hz, 1H), 4.33 (dd, J = 17.1, 1.6 Hz, 1H), 4.31 - 4.23 (m, 3H), 4.23 - 4.14 (m, 1H), 3.78 (d, J = 2.0 Hz, 3H), 3.39 - 3.35 (m, 4H), 3.31 - 3.26 (m, 2H), 3.26 - 3.19 (m, 3H), 2.96 - 2.85 (m, 2H), 2.78 (tt, J = 10.8, 4.0 Hz, 1H), 2.68 - 2.62 (m, 1H), 2.49 - 2.41 (m, 1H), 2.28 - 2.20 (m, 2H), 2.15 (s, 6H), 2.10 - 1.98 (m, 6H), 1.89 (s, 3H), 1.77 (dtd, J = 14.7, 11.1, 4.0 Hz, 2H).

[0812] Example 3: (6-chloro-1-{2-[4-(2-{4-[(2,6-dioxopiperidin-3-yl)carbamoyl]-2-methyl- 1H-1,3-benzodiazol-1-yl}acetyl)piperazin-1-yl]ethyl}-3-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-7-(1, 3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonyloxy)methyl 2,2-dimethylpropanoate (Compound 70)

[0813]

[0814] Step A

[0815] To a solution of 1-[2-(tert-butyl)-2-oxoethyl]-2-methyl-1H-1,3-benzodiazole-4-carboxylic acid methyl ester (152.0 mg, 0.499 mmol) in water (0.500 mL) and MeCN (5.0 mL) was added LiBr (867.4 mg, 9.989 mmol) and Et3N (0.695 mL, 4.994 mmol). The mixture was stirred at room temperature for 4 days. The crude product was concentrated in vacuo and purified by reverse phase flash chromatography (water:MeCN + 0.1% FA) to give 1-[2-(tert-butyloxy)-2-oxoethyl]-2-methyl-1H-1,3-benzodiazole-4-carboxylic acid (75.0 mg, 0.233 mmol, 47%) as a yellow solid.

[0816] LCMS (ESI): 291.0 m / z [M+H] + .

[0817] Step B

[0818] To a solution of 1-[2-(tert-butoxy)-2-oxoethyl]-2-methyl-1H-1,3-benzodiazole-4-carboxylic acid (100.0 mg, 0.344 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (68.0 mg, 0.413 mmol) in anhydrous DMF (2.0 mL) was added DIPEA (0.300 mL, 1.722 mmol) and HATU (196.5 mg, 0.517 mmol). The mixture was stirred at room temperature for 18 hours. After this time, the crude product was concentrated in vacuo and the residue was dissolved in DCM and purified by flash chromatography (silica, methanol:DCM, 0-50%) to isolate tert-butyl 2-{4-[(2,6-dioxopiperidin-3-yl)carbamoyl]-2-methyl-1H-1,3-benzodiazol-1-yl}acetate (74.0 mg, 0.185 mmol, 54%) as a yellow solid.

[0819] LCMS (ESI): 401.1m / z[M+H] + .

[0820] Step C

[0821] To a solution of tert-butyl 2-{4-[(2,6-dioxopiperidin-3-yl)carbamoyl]-2-methyl-1H-1,3-benzodiazol-1-yl}acetate (64.5 mg, 0.161 mmol) in DCM (2.0 mL) was added TFA (1.0 mL, 13.059 mmol). The mixture was stirred at room temperature for 18 hours. The crude product was concentrated in vacuo and dissolved in water. To this solution was added 1 M aqueous hydrochloric acid solution and then evaporated. The product, 2-{4-[(2,6-dioxopiperidin-3-yl)carbamoyl]-2-methyl-1H-1,3-benzodiazol-1-yl}acetic acid hydrochloride (58.8 mg, 0.154 mmol, 96%), was isolated as a beige solid.

[0822] LCMS (ESI): 344.8 m / z [M+H] + .

[0823] Step D

[0824] 2-{4-[(2,6-dioxopiperidin-3-yl)carbamoyl]-2-methyl-1H-1,3-benzodiazol-1-yl}acetic acid hydrochloride (37.3 mg, 0.098 mmol), 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 tert-butyl ester (55.0 mg, 0.082 mmol) and HATU (62.0 mg, 0.163 mmol) were dissolved in anhydrous DMF (2.0 mL), and DIPEA (0.071 mL, 0.408 mmol) was added to the mixture. The reaction was stirred at room temperature for 2 hours. The solvent was evaporated. The residue was dissolved in DCM and washed with brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give tert-butyl (6-chloro-1-{2-[4-(2-{4-[(2,6-dioxopiperidin-3-yl)carbamoyl]-2-methyl-1H-1,3-benzodiazol-1-yl}acetyl)piperazin-1-yl]ethyl}-3-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (102.2 mg, crude) which was used in the next step without further purification.

[0825] LCMS (ESI): 1001.3 m / z [M+H] + .

[0826] Step E

[0827] To a solution of tert-butyl (6-chloro-1-{2-[4-(2-{4-[(2,6-dioxopiperidin-3-yl)carbamoyl]-2-methyl-1H-1,3-benzodiazol-1-yl}acetyl)piperazin-1-yl]ethyl}-3-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (102.2 mg, crude) in DCM (1.0 mL) was added TFA (0.500 mL, 6.529 mmol). The mixture was stirred at room temperature for 18 hours. The crude product was concentrated in vacuo and purified by preparative HPLC (water:MeCN + 0.1% The product was purified by HPLC (5% yield 5-nitropropane-2-yl)-2-nitropropane-1-yl)-4-nitropropane-2-yl)-6-nitropropane-1-yl)-2-nitropropane-2-yl)-6-nitropropane-1-yl)-2-nitropropane-2-yl)-6-nitropropane-1-yl)-2-nitropropane-2-yl)-6-nitropropane-1-yl)-2-nitropropane-2-yl)-6-nitropropane-1-yl)-2-nitropropane-2-yl)-6-nitropropane-1-yl)-2-nitropropane-2-yl)-6-nitropropane-1-yl)-2-nitropropane-2-yl)-6-nitropropane-1-yl)-2-nitropropane-2-yl)-6-nitropropane-1-yl)-2-nitropropane-2-yl)-6-nitropropane-1-yl)-

[0828] LCMS (ESI): 944.3 m / z [M+H] + .

[0829] Step F

[0830] To a solution of 6-chloro-1-{2-[4-(2-{4-[(2,6-dioxopiperidin-3-yl)carbamoyl]-2-methyl-1H-1,3-benzodiazol-1-yl}acetyl)piperazin-1-yl]ethyl}-3-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (20.0 mg, 0.021 mmol) in anhydrous DMF (1.2 mL) was added EtN (0.030 mL, 0.212 mmol) and chloromethyl 2,2-dimethylpropanoate (0.009 mL, 0.064 mmol). The reaction mixture was stirred at 60° C. for the next 18 hours. The crude product was then purified by preparative HPLC (C18, H2O:MeCN + 0.1% FA) to give (6-chloro-1-{2-[4-(2-{4-[(2,6-dioxopiperidin-3-yl)carbamoyl]-2-methyl-1H-1,3-benzodiazol-1-yl}acetyl)piperazin-1-yl]ethyl}-3-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonyloxy)methyl 2,2-dimethylpropanoate (16.6 mg, 0.016 mmol, 74%) as a white solid.

[0831] LCMS(ESI): 1058.2 m / z [M+H] + 。

[0832] 1 H NMR(500 MHz, DMSO) δ 10.91 (s, 1H), 10.23 (d, J = 7.3 Hz, 1H), 8.22 (dd, J = 9.2, 5.9 Hz, 1H), 7.84 (dd, J = 7.6, 1.1 Hz, 1H), 7.81 (d, J = 8.6 Hz, 1H), 7.67 - 7.62 (m, 2H), 7.46 - 7.43 (m, 2H), 7.36 (td, J = 8.9, 2.6 Hz, 1H), 7.31 - 7.27 (m, 2H), 6.90 - 6.86 (m, 1H), 6.01 (s, 2H), 5.29 (s, 2H), 4.88 (ddd, J = 12.6, 7.4, 5.3 Hz, 1H), 4.29 - 4.20 (m, 3H), 4.19 - 4.12 (m, 1H), 3.77 (s, 3H), 3.48 - 3.43 (m, 2H), 3.28 - 3.20 (m, 4H), 2.82 (ddd, J = 17.2, 13.5, 5.6 Hz, 1H), 2.61 - 2.52 (m, 1H), 2.47 (s, 3H), 2.27 - 2.02 (m, 13H), 1.88 (s, 3H), 1.14 (s, 9H).

[0833] Example 4: (Pivaloyloxy)methyl (S)-6-chloro-1-(2-(4-((4-(2-(2,6-dioxopiperidine-3- (3-((6-fluoronaphthalen-1-yl)oxy)-1-((6-fluoronaphthalen-1-yl)methyl)piperidin-1-yl)ethyl)-1-((6-fluoronaphthalen-1-yl)oxy)-2-((6-fluoronaphthalen-1-yl)methyl)piperidin-1-yl)ethyl)-1-((6-fluoronaphthalen-1-yl)oxy) propyl)-7-1,3,5-trimethyl-1H- 吡 Oxazol-4-yl-1H-indole-2-carboxylate (Compound 71)

[0834]

[0835] Step A

[0836] To a stirred solution of 4-(dimethoxymethyl)piperidine (0.4 g, 2.51 mmol) in DMF (10 mL) was added anhydrous (washed with n-hexane) sodium hydride (0.18 g, 7.5 mmol) in portions at 0 ° C. under nitrogen. The reaction mixture was stirred at room temperature for 30 min. Subsequently, the reaction mixture was cooled to 0 ° C. again, and 1-bromo-2-chloroethane (2.08 mL, 25.1 mmol) was added dropwise. The resulting reaction mixture was stirred at room temperature for 4 hours under nitrogen. The excess sodium hydride was then quenched by adding ice water and diluted with ethyl acetate. The organic layer was washed with ice water and brine, dried over sodium sulfate, and evaporated under reduced pressure. The crude compound was purified by column chromatography (silica, 30-40% ethyl acetate in hexane) to give 1-(2-chloroethyl)-4-(dimethoxymethyl)piperidine (300 mg, 1.35 mmol, 54%) as a light brown viscous solid.

[0837] LCMS (ESI): 222.2 m / z [M+H] + .

[0838] Step B

[0839] To a well-stirred solution of tert-butyl 6-chloro-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (350 mg, 0.62 mmol) in DMF (3 mL) was added 1-(2-chloroethyl)-4-(dimethoxymethyl)piperidine (276 mg, 1.24 mmol) followed by CsCO (304 mg, 0.93 mmol) and the mixture was stirred at 100 ° C. under nitrogen for 16 hours. 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 (silica, 60-70% EtOAc in DCM) to give tert-butyl 6-chloro-1-(2-(4-(dimethoxymethyl)piperidin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (120 mg, 0.16 mmol, 26%) as a light pink solid.

[0840] LCMS (ESI): 747.6m / z[M+H] + .

[0841] Step C

[0842] 6-Chloro-1-{2-[4-(dimethoxymethyl)piperidin-1-yl]ethyl}-3-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid tert-butyl ester (10.0 mg, 0.013 mmol) was dissolved in THF (0.535 mL) and 2M aqueous sulfuric acid solution (0.268 mL, 0.535 mmol) was added. The reaction was stirred at 70 ° C for 1 hour in a sealed vial. When the raw material was completely converted, 1M NaOH aqueous solution was added to pH = 7, and the reaction product was extracted with DCM. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and dried under reduced pressure. Crude tert-butyl 6-chloro-3-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-1-[2-(4-formylpiperidin-1-yl)ethyl]-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (7.5 mg) was obtained as an off-white solid and used directly in the next step.

[0843] LCMS (ESI): 701.4 m / z [M+H] + .

[0844] Step D

[0845] Under argon, crude tert-butyl 6-chloro-3-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-1-[2-(4-formylpiperidin-1-yl)ethyl]-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (7.5 mg) and (3S)-3-[1-oxo-5-(piperazin-1-yl)-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (4.8 mg, 0.015 mmol) were dissolved in anhydrous DCM (0.531 mL) and MeOH (0.133 mL). STAB (14.2 mg, 0.067 mmol) and AcOH (0.001 mL, 0.017 mmol) were added and the reaction was stirred at room temperature under argon for 16 hours. After the starting material was completely consumed, the mixture was diluted with DCM and washed with saturated aqueous sodium bicarbonate solution, brine and water. The organic layer was dried over anhydrous magnesium sulfate, filtered and dried under reduced pressure to give (S)-6-chloro-1-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy]propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid tert-butyl ester (8.4 mg, crude product) as a beige film. The crude product was entered into the next step without further purification.

[0846] LCMS (ESI): 1013.3 m / z [M+H] + .

[0847] Step E

[0848] Under argon atmosphere, (S)-tert-butyl 6-chloro-1-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy]propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (8.4 mg, crude) was dissolved in anhydrous DCM (0.300 mL) and TFA (0.300 mL, 3.918 mmol) was added. The reaction was stirred at room temperature under argon for 16 hours. After complete consumption of the starting material, the solution was concentrated to dryness under reduced pressure and dissolved in DMSO. The crude product was purified by preparative HPLC (C18, H2O:MeCN + 0.1% The reaction mixture was purified by 4% FA to afford (S)-6-chloro-1-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (2.8 mg, 0.003 mmol, 23% over 3 steps) as a white solid.

[0849] LCMS (ESI): 957.25 m / z [M+H] + .

[0850] Step F

[0851] To a well-stirred solution of (S)-6-chloro-1-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (150 mg, 0.157 mmol) in DMF (3 ml) was added chloromethyl pivalate (0.027 mL, 0.188 mmol) followed by potassium carbonate (21 mg, 0.157 mmol), and the mixture was stirred at 60° C. under nitrogen for 2 hours. After complete consumption of the starting material, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the crude compound, which was then purified by preparative HPLC (10 mM ammonium acetate in water:MeCN) to give (pivaloyloxy)methyl (S)-6-chloro-1-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-1,3,5-trimethyl-1H-pyrazol-4-yl-1H-indole-2-carboxylate (15 mg, 0.014 mmol, 9%) as a white solid.

[0852] LCMS (ESI): 1071.2 m / z [M+H] + .

[0853] 11H NMR (500 MHz, DMSO) δ = 10.93 (s, 1H), 8.20 (dd, J = 9.3, 5.9, 1H), 7.80 (d, J = 8.6, 1H), 7.65 (dd, J = 10.3, 2.7, 1H), 7.59 - 7.48 (m, 1H), 7.48 - 7.40 (m, 2H), 7.36 (td, J = 8.9, 2.6, 1H), 7.27 (d, J = 8.5, 1H), 7.15 - 6.96 (m, 2H), 6.94 - 6.80 (m, 1H), 5.98 (s, 2H), 5.04 (dd, J = 13.3, 5.2, 1H), 4.32 (d, J = 16.9, 1H), 4.28 - 4.14 (m, 4H), 4.14 - 4.01 (m, 1H), 3.75 (s, 3H), 3.26 - 3.14 (m, 6H), 2.90 (ddd, J = 17.8, 13.6, 5.4, 1H), 2.62 - 2.55 (m, 1H), 2.47 - 2.24 (m, 6H), 2.24 - 2.15 (m, 2H), 2.14 - 1.92 (m, 7H), 1.91 - 1.80 (m, 5H), 1.80 - 1.60 (m, 3H), 1.60 - 1.42 (m, 2H), 1.14 (s, 9H), 1.01 - 0.78 (m, 2H).

[0854] Example 5: (6-chloro-1-{2-[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H- Isoindol-4-yl]oxy}acetyl)piperazin-1-yl]ethyl}-3-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-7-(1,3,5-trifluoromethyl)piperazin-1-yl]ethyl Methyl-1H-pyrazol-4-yl)-1H-indole-2-carbonyloxy)methyl 2,2-dimethylpropanoate (Compound 69)

[0855]

[0856] Step A

[0857] 6-Chloro-1-{2-[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}acetyl)piperazin-1-yl]ethyl}-3-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (100.0 mg, 0.109 mmol) was dissolved in DMF (6.3 mL) and triethylamine (0.076 mL, 0.544 mmol) was added, followed by chloromethyl pivalate (0.031 mL, 0.218 mmol). The mixture was stirred at room temperature overnight and then at 80° C. for the next two days. The solvent was removed under reduced pressure and the desired product was purified using flash chromatography (silica, 5% methanol in DCM) to give the corresponding (6-chloro-1-{2-[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}acetyl)piperazin-1-yl]ethyl}-3-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonyloxy)methyl 2,2-dimethylpropanoate (66.0 mg, 0.064 mmol, 58.7%) as a white solid.

[0858] LCMS (ESI): 1032.2 m / z [M+H] + .

[0859] 11H NMR (500 MHz, DMSO, 353 K) δ = 10.64 (s, 1H), 8.21 (dd, J = 9.3, 5.8, 1H), 7.77 (d, J = 8.6, 1H), 7.58 (dd, J = 10.4, 2.6, 1H), 7.47 - 7.38 (m, 3H), 7.35 - 7.28 (m, 2H), 7.26 (d, J = 8.6, 1H), 7.14 (d, J = 8.1, 1H), 6.87 (dd, J = 6.1, 2.6, 1H), 5.99 (s, 2H), 5.05 (dd, J = 13.0, 5.2, 1H), 4.89 (s, 2H), 4.40 (d, J = 17.1, 1H), 4.32 (d, J = 16.9, 1H), 4.28 - 4.19 (m, 3H), 4.20 - 4.11 (m, 1H), 3.76 (d, J = 1.9, 3H), 3.37 - 3.30 (m, 4H), 3.30 - 3.23 (m, 2H), 2.88 (ddd, J = 17.2, 13.4, 5.5, 1H), 2.64 - 2.56 (m, 1H), 2.48 - 2.38 (m, 1H), 2.27 - 2.18 (m, 2H), 2.14 - 2.02 (m, 7H), 2.01 (s, 3H), 1.88 (s, 3H), 1.16 (s, 9H).

[0860] Example 6: 4-oxo-3,5,8,11-tetraoxatridecan-2-yl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxo- (3-((6-fluoronaphthalene-1-yl)-3-((6-fluoronaphthalene-1-yl)-1-oxoisoindolin-4-yl)-1-oxoisoindolin-4-yl)-1-oxoisoindolin-3-yl)-1-oxoisoindolin-4 ... (4-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate) (Compound 101)

[0861]

[0862] Step A

[0863] To a well stirred solution of 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (100 mg, 0.109 mmol) in DMF (1 mL) was added KCO (45 mg, 0.327 mmol) followed by 1-chloroethyl (2-(2-ethoxyethoxy)ethyl) carbonate (100 mg, 0.417 mmol) and the reaction mixture was stirred at 60° C. under nitrogen for 2 h. After complete consumption of the starting material, the solvent was concentrated under reduced pressure and the target molecule was purified by preparative HPLC (10 mM ammonium acetate buffer:MeCN) to give 4-oxo-3,5,8,11-tetraoxatridecan-2-yl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (45 mg, 0.04 mmol, 37%) as a white solid.

[0864] LCMS (ESI): 1120.84 m / z [MH] - .

[0865] 11H NMR (500 MHz, DMSO, 353 K) δ 10.66 (s, 1H), 8.24 (dd, J = 9.2, 5.9 Hz, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.59 (dd, J = 10.4, 2.6 Hz, 1H), 7.48 - 7.38 (m, 3H), 7.37 - 7.30 (m, 2H), 7.26 (d, J = 8.6 Hz, 1H), 7.17 - 7.11 (m, 1H), 7.00 - 6.93 (m, 1H), 6.89 (dd, J = 5.8, 2.9 Hz, 1H), 5.05 (dd, J = 13.0, 5.2 Hz, 1H), 4.89 (s, 2H), 4.40 (d, J = 17.1 Hz, 1H), 4.31 (dd, J = 17.0, 1.6 Hz, 1H), 4.29 - 4.11 (m, 6H), 3.76 (d, J = 2.2 Hz, 3H), 3.63 - 3.58 (m, 2H), 3.51 - 3.45 (m, 2H), 3.43 - 3.40 (m, 2H), 3.38 (q, J = 7.0 Hz, 2H), 3.35 - 3.31 (m, 4H), 3.30 - 3.25 (m, 2H), 2.88 (ddd, J = 17.4, 13.5, 5.5 Hz, 1H), 2.64 - 2.59 (m, 1H), 2.47 - 2.39 (m, 1H), 2.28 - 2.20 (m, 2H), 2.18 - 2.02 (m, 7H), 2.01 (d, J = 1.7 Hz, 3H), 1.88 (d, J = 1.5 Hz, 3H), 1.63 (dd, J = 5.4, 1.6 Hz, 3H), 1.04 (t, J = 7.0 Hz, 3H).

[0866] Example 7: 1-{[(Propan-2-yloxy)carbonyl]oxy}ethyl 6-chloro-1-{2-[4-(2-{[2-(2,6-dioxo [(6-fluoro-1-[(1-[(piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy]acetyl]piperazin-1-yl]ethyl]-3- Naphthalen-1-yl)oxy]propyl}-7-(1,3,5-trimethyl-1H- 吡 oxazol-4-yl)-1H-indole-2-carboxylate (Compound 99)

[0867]

[0868] Step A

[0869] To a solution of 6-chloro-1-{2-[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}acetyl)piperazin-1-yl]ethyl}-3-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (40.0 mg, 0.044 mmol) in DMF (2.5 mL) was added triethylamine (17.6 mg, 0.174 mmol) and 1-chloroethyl isopropyl carbonate (7.6 mg, 0.046 mmol). The reaction was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure and the desired product was purified using flash chromatography (silica, DCM:methanol gradient from 5% to 20% methanol) to give 1-{[(propan-2-yloxy)carbonyl]oxy}ethyl 6-chloro-1-{2-[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}acetyl)piperazin-1-yl]ethyl}-3-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (21.1 mg, 0.020 mmol, 46.2%) as a white solid.

[0870] LCMS (ESI): 1046.1m / z[MH] - .

[0871] 11H NMR (500 MHz, DMSO, 353 K) δ = 10.67 (s, 1H), 8.24 (dd, J = 9.2, 5.9, 1H), 7.77 (d, J = 8.6, 1H), 7.59 (dd, J = 10.3, 2.6, 1H), 7.47 - 7.39 (m, 3H), 7.36 - 7.29 (m, 2H), 7.26 (d, J = 8.6, 1H), 7.16 - 7.11 (m, 1H), 6.96 - 6.91 (m, 1H), 6.88 (dd, J = 6.1, 2.5, 1H), 5.05 (dd, J = 13.0, 5.2, 1H), 4.89 (s, 2H), 4.84 - 4.75 (m, 1H), 4.40 (d, J = 17.2, 1H), 4.31 (dd, J = 17.0, 1.6, 1H), 4.26 (t, J = 6.3, 2H), 4.24 - 4.20 (m, 1H), 4.20 - 4.12 (m, 1H), 3.76 (d, J = 2.0, 3H), 3.38 - 3.31 (m, 4H), 3.31 - 3.21 (m, 2H), 2.88 (ddd, J = 17.4, 13.5, 5.5, 1H), 2.65 - 2.59 (m, 1H), 2.47 - 2.38 (m, 1H), 2.27 - 2.20 (m, 2H), 2.16 - 2.02 (m, 7H), 2.01 (s, 3H), 1.88 (d, J = 1.1, 3H), 1.62 (dd, J = 5.4, 1.7, 3H), 1.22 (d, J = 6.2, 3H), 1.19 (dd, J = 6.2, 1.4, 3H).

[0872] Example 8: 1-(((cyclohexyloxy)carbonyl)oxy)ethyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperazine) (3-((6-fluoronaphthalen-1-yl)oxy)-3-((6-fluoronaphthalen-1-yl)piperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy) propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (Compound 100)

[0873]

[0874] Step A

[0875] 6-Chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (30.0 mg, 0.033 mmol) was dissolved in anhydrous MeCN (1.0 mL) and Et3N (0.046 mL, 0.327 mmol), followed by the addition of 1-chloroethylcyclohexyl carbonate (8.1 mg, 0.039 mmol). The reaction mixture (monitored by LCMS) was stirred at 60 ° C in a sealed vial for 96 hours. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure and then dissolved in DCM. The organic phase was washed with brine and water, dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (silica, 5% to 20% methanol in DCM) to give 1-(((cyclohexyloxy)carbonyl)oxy)ethyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (17.2 mg, 0.016 mmol, 48.5%) as a white solid.

[0876] LCMS (ESI): 1088.2 m / z [M+H] + .

[0877] 11H NMR (500 MHz, DMSO, 353 K) δ 10.67 (s, 1H), 8.24 (dd, J = 9.2, 5.9 Hz, 1H), 7.78 (d, J = 8.6 Hz, 1H), 7.59 (dd, J = 10.4, 2.6 Hz, 1H), 7.50 - 7.38 (m, 3H), 7.36 - 7.29 (m, 2H), 7.26 (d, J = 8.6 Hz, 1H), 7.14 (dt, J = 8.2, 0.7 Hz, 1H), 6.94 (q, J = 5.4 Hz, 1H), 6.88 (dd, J = 6.1, 2.5 Hz, 1H), 5.05 (dd, J = 13.1, 5.2 Hz, 1H), 4.89 (s, 2H), 4.62 - 4.52 (m, 1H), 4.40 (d, J = 17.1 Hz, 1H), 4.31 (dd, J = 17.2, 1.5 Hz, 1H), 4.29 - 4.11 (m, 4H), 3.76 (d, J = 2.0 Hz, 3H), 3.38 - 3.31 (m, 4H), 3.31 - 3.20 (m, 2H), 2.88 (ddd, J = 17.4, 13.5, 5.5 Hz, 1H), 2.67 - 2.59 (m, 1H), 2.44 (qd, J = 13.1, 4.9 Hz, 1H), 2.28 - 2.19 (m, 2H), 2.17 - 2.03 (m, 7H), 2.01 (d, J = 1.3 Hz, 3H), 1.88 (d, J = 1.6 Hz, 3H), 1.85 - 1.73 (m, 2H), 1.62 (dd, J = 5.4, 1.7 Hz, 3H), 1.61 - 1.49 (m, 2H), 1.45 - 1.30 (m, 4H), 1.26 - 1.10 (m, 2H).

[0878] Example 9: 2-(Phosphonooxy)ethyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1- (6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1, 3,5-Trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (Compound 131)

[0879]

[0880]

[0881] Step A

[0882] To a solution of 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (200 mg, 0.218 mmol) in DMF (1 mL) at room temperature under nitrogen was added HATU (165.5 mg, 0.436 mmol) and EtN (0.092 mL, 0.654 mmol), and the reaction was stirred for 15 minutes. 2-Bromoethane-1-ol (0.08 mL, 1.089 mmol) was added, and the resulting mixture was stirred at room temperature for an additional 4 hours. Once the starting material was completely consumed, the reaction was quenched by the addition of ice water. The mixture was concentrated in vacuo, diluted with DCM, and washed with saturated sodium bicarbonate solution (2 x 50 mL), water (50 mL), and brine (50 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated. The crude compound was purified by column chromatography (SiO, 3-5% methanol in DCM) to afford 2-bromoethyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (150 mg, 0.146 mmol, 67%) as a white solid.

[0883] LCMS (ESI): 1026.1m / z[M+H] + .

[0884] Step B

[0885] To a solution of 2-bromoethyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (150 mg, 0.146 mmol) in DMF (1 mL) was added potassium di-tert-butyl phosphate (72.5 mg, 0.293 mmol) at room temperature under nitrogen. The resulting mixture was stirred at 100° C. under nitrogen for 16 hours. After complete consumption of the starting material, the solvent was concentrated under reduced pressure, diluted with ethyl acetate, and washed with cold water and brine. The organic layer was dried over sodium sulfate and evaporated under reduced pressure to give crude 2-((di-tert-butoxyphosphoryl)oxy)ethyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (120 mg) as an off-white solid which was used in the next step without further purification.

[0886] LCMS (ESI): 1154.4 m / z [M+H] + .

[0887] Step C

[0888] To a solution of 2-((di-tert-butoxyphosphoryl)oxy)ethyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (120 mg, 0.104 mmol) in DCM (3 mL) at 0°C under nitrogen was added TFA (2 mL) dropwise and the reaction mixture was stirred at ambient temperature for 3 hours. After complete consumption of the starting material, the volatiles were removed under reduced pressure to give the crude product, which was then purified by preparative HPLC (10 mM ammonium acetate buffer:MeCN) to give 2-(phosphonooxy)ethyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (13 mg, 0.0124 mmol, 8.4% yield over two steps) as a white solid.

[0889] LCMS(ESI): 1040.1 m / z [M-H] - .

[0890] 1 H NMR (400 MHz, DMSO, 372 K) δ 10.57 (s, 1H), 8.22 (dd, J = 9.3, 5.9 Hz, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.57 (dd, J = 10.3, 2.8 Hz, 1H), 7.47 - 7.38 (m, 3H), 7.37 - 7.29 (m, 2H), 7.23 (dd, J = 8.6, 1.6 Hz, 1H), 7.15 (d, J = 8.1 Hz, 1H), 6.93 - 6.85 (m, 1H), 5.04 (dd, J = 13.5, 5.2 Hz, 1H), 4.89 (s, 2H), 4.53 - 4.44 (m, 2H), 4.41 (d, J = 17.1 Hz, 1H), 4.32 (d, J = 16.9 Hz, 1H), 4.30 - 4.12 (m, 6H), 3.80 - 3.72 (m, 3H), 3.38 - 3.35 (m, 4H), 3.31 - 3.27 (m, 2H), 2.87 (ddd, J = 18.2, 13.7, 5.8 Hz, 1H), 2.68 - 2.59 (m, 1H), 2.47 - 2.38 (m, 1H), 2.29 - 2.21 (m, 2H), 2.19 - 2.03 (m, 7H), 2.01 (s, 3H), 1.88 (s, 3H).

[0891] Example 10: 3-(4-methylpiperazin-1-yl)propyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidine- (3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propane 1H- 吡 oxazol-4-yl)-1H-indole-2-carboxylate (Compound 137)

[0892]

[0893] Step A

[0894] Under argon, 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (20.0 mg, 0.022 mmol) and HATU (9.1 mg, 0.024 mmol) were dissolved in anhydrous DMF (1.0 mL) and DIPEA (0.011 mL, 0.065 mmol) was added. The reaction was stirred at room temperature under argon for 20 minutes, and 3-(4-methylpiperazin-1-yl)propan-1-ol (4.1 mg, 0.026 mmol) was added. The reaction was stirred at room temperature for the next 16 hours (monitored by LCMS). Subsequently, additional portions of HATU (9.1 mg, 0.024 mmol), DIPEA (0.011 mL, 0.065 mmol), and 3-(4-methylpiperazin-1-yl)propan-1-ol (4.1 mg, 0.026 mmol) were added. The reaction was continued at room temperature under argon for 2 hours. Upon complete consumption of the starting material, the solution was concentrated under reduced pressure, diluted with DMSO, and purified by reverse phase preparative HPLC (C18, H2O:MeCN + 0.1% FA). 3-(4-Methylpiperazin-1-yl)propyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (6.5 mg, 0.006 mmol, 28.3%) was obtained as a white solid.

[0895] LCMS (ESI): 1058.2 m / z [M+H] + .

[0896] 11H NMR (500 MHz, DMSO, 353 K) δ 10.68 (s, 1H), 8.22 (dd, J = 9.2, 5.9 Hz, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.60 (dd, J = 10.4, 2.6 Hz, 1H), 7.47 - 7.40 (m, 3H), 7.36 - 7.30 (m, 2H), 7.25 (d, J = 8.6 Hz, 1H), 7.16 - 7.12 (m, 1H), 6.88 (dd, J = 6.4, 2.3 Hz, 1H), 5.05 (dd, J = 13.1, 5.1 Hz, 1H), 4.89 (s, 2H), 4.40 (d, J = 17.1 Hz, 1H), 4.35 - 4.28 (m, 3H), 4.28 - 4.10 (m, 4H), 3.76 (d, J = 2.1 Hz, 3H), 3.39 - 3.30 (m, 4H), 3.30 - 3.24 (m, 2H), 2.88 (ddd, J = 17.3, 13.4, 5.5 Hz, 1H), 2.66 - 2.59 (m, 1H), 2.44 (qd, J = 13.3, 4.6 Hz, 1H), 2.39 - 2.34 (m, 2H), 2.34 - 2.29 (m, 4H), 2.28 - 2.19 (m, 6H), 2.15 - 2.10 (m, 1H), 2.10 (s, 3H), 2.09 - 2.02 (m, 6H), 2.01 (s, 3H), 1.88 (s, 3H), 1.85 (p, J = 6.8 Hz, 2H).

[0897] Example 11: 2-(Dimethylamino)ethyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1- (1,2-(6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1-((6-fluoronaphthalen-1-yl)oxy)propyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-4-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1, 3,5-Trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (Compound 107)

[0898]

[0899] Step A

[0900] 6-Chloro-1-{2-[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}acetyl)piperazin-1-yl]ethyl}-3-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (40.0 mg, 0.044 mmol) was dissolved in DMF (0.8 mL). DIPEA (0.023 mL, 0.131 mmol), HATU (19.9 mg, 0.052 mmol), and 2-dimethylaminoethanol (7.8 mg, 0.087 mmol) were added. The mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure and the desired product was purified using flash chromatography (silica, DCM:MeOH gradient from 0 to 20% MeOH) to give 2-(dimethylamino)ethyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (33.0 mg, 0.033 mmol, 76.6%) as a white solid.

[0901] LCMS (ESI): 989.25 m / z [M+H] + .

[0902] 1H NMR (500MHz, DMSO, 353K) δ = 10.70 (s, 1H), 8.22 (dd, J = 9.2, 5.8, 1H), 7.74 ( d, J = 8.5, 1H), 7.60 ( dd, J = 10.4, 2.7, 1H), 7.48-7.39 ( m, 3H), 7. 37-7.29(m,2H),7.24(d,J=8.5,1H),7.14(d,J=8.1,1H),6.88(dd,J=5.6,3.0,1H),5.05(dd,J=13.1,5.2,1H),4.89(s,2H),4.39(d,J=17. 2,1H), 4.37-4.28 (m, 3H), 4.28-4.20 (m, 3H), 4.19-4.11 (m, 1H), 3.75 (d, J=2.1, 3H), 3.36-3.31 (m, 4H), 3.30-3.26 (m, 2H), 2.93-2.84 (m, 1H), 2.62-2.57 (m, 2H), 2.46-2.38 (m, 1H), 2.28-2.21 (m, 2H), 2.18 (s, 6H), 2.13-2.02 (m, 7H), 2.01 (s, 3H), 1.88 (s, 3H). One proton in the aliphatic region overlapped with the solvent.

[0903] Example 12: 2-(Methylsulfonyl)ethyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1- (6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1, 3,5-Trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (Compound 124)

[0904]

[0905] Step A

[0906] Under argon atmosphere, 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (20.0 mg, 0.022 mmol) and HATU (9.1 mg, 0.024 mmol) were dissolved in anhydrous DMF (2.0 mL). EtN (0.011 mL, 0.065 mmol) was added and the reaction was stirred at room temperature for 20 min. 2-(methylsulfonyl)ethane-1-ol (3.2 mg, 0.026 mmol) was then added and the reaction (monitored by LCMS) was stirred at room temperature under argon for 3.5 hours. A second portion of HATU (9.1 mg, 0.024 mmol) and EtN (0.011 mL, 0.065 mmol) in DMF (1.0 mL) was then added and the reaction was continued at room temperature under argon for the next 16 hours. When the starting material was completely consumed, the solution was diluted with DCM (to 10 mL) and washed with salt solution and water. The organic layer was dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure. The resulting residue was dissolved in DCM and purified by column chromatography (silica, 1% to 40% methanol in DCM) to give 2-(methylsulfonyl)ethyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (11.4 mg, 0.011 mmol, 51.1%) as a white solid.

[0907] LCMS (ESI): 1024.1m / z[M+H] + .

[0908] 1H NMR (500MHz, DMSO, 353K) δ10.64 (s, 1H), 8.23 ​​(dd, J = 9.2, 5.9Hz, 1H), 7.74 (d, J=8.6Hz,1H),7.59(dd,J=10.4,2.6Hz,1H),7.47-7.39(m,3H),7.38-7.30(m, 2H), 7.25 (d, J=8.6Hz, 1H), 7.14 (d, J=8.1Hz, 1H), 6.89 (dd, J=5.5, 3.2Hz, 1H) ,5.05(dd,J=13.1,5.2Hz,1H),4.89(s,2H),4.69(t,J=6.1Hz,2H), 4.40(d,J= 17.1Hz,1H),4.32(d,J=17.0Hz,1H),4.30-4.20(m,3H),4.20-4.10(m,1H),3. 76(d,J=2.1Hz,3H),3.64(t,J=6.1Hz,2H),3.36-3.32(m,4H),3.32-3.28(m,2 H), 3.02 (s, 3H), 2.88 (ddd, J = 17.2, 13.5, 5.5Hz, 1H), 2.67-2.60 (m, 1H), 2.48 -2.40(m,1H),2.29-2.21(m,2H),2.15-2.02(m,7H),2.01(s,3H),1.88(s,3H).

[0909] Example 13: 2-(4-methylpiperazin-1-yl)ethyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidine- (3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propane 1H- 吡 oxazol-4-yl)-1H-indole-2-carboxylate (Compound 133)

[0910]

[0911] Step A

[0912] Under argon atmosphere, 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (20.0 mg, 0.022 mmol), EDC-HCl (6.3 mg, 0.033 mmol) and DMAP (0.8 mg, 0.007 mmol) were added to the mixture.

[0913] Dissolve in anhydrous DMF (1.0 mL) and add DIPEA (0.011 mL, 0.065 mmol), followed by 2-(4-methylpiperazin-1-yl)ethan-1-ol (3.8 mg, 0.026 mmol). The reaction is stirred at room temperature under argon for 16 hours. HATU (8.3 mg, 0.022 mmol) is then added and the reaction is continued for another 45 minutes. The mixture is then diluted with DCM, and the solution is washed with brine and water. The organic layer is dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure. The resulting residue was dissolved in DCM and purified by flash column chromatography (silica, 1% to 40% methanol in DCM) to give 2-(4-methylpiperazin-1-yl)ethyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (5.8 mg, 0.006 mmol, 25.6%) as a white powder.

[0914] LCMS (ESI): 1044.2 m / z [M+H] + .

[0915] 11H NMR (500 MHz, DMSO, 353 K) δ 10.65 (s, 1H), 8.22 (dd, J = 9.3, 5.9 Hz, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.59 (dd, J = 10.4, 2.6 Hz, 1H), 7.47 - 7.39 (m, 3H), 7.37 - 7.30 (m, 2H), 7.25 (d, J = 8.9 Hz, 1H), 7.14 (d, J = 8.1 Hz, 1H), 6.87 (dd, J = 6.3, 2.3 Hz, 1H), 5.05 (dd, J = 13.0, 5.2 Hz, 1H), 4.89 (s, 2H), 4.43 - 4.35 (m, 3H), 4.32 (d, J = 17.0 Hz, 1H), 4.29 - 4.20 (m, 3H), 4.19 - 4.09 (m, 1H), 3.76 (d, J = 2.0 Hz, 3H), 3.37 - 3.31 (m, 4H), 3.31 - 3.27 (m, 2H), 2.88 (ddd, J = 18.9, 13.5, 5.6 Hz, 1H), 2.68 (t, J = 5.8 Hz, 2H), 2.66 - 2.53 (m, 2H), 2.49 - 2.44 (m, 4H), 2.43 - 2.37 (m, 4H), 2.30 - 2.23 (m, 2H), 2.19 (s, 3H), 2.14 - 2.03 (m, 7H), 2.01 (s, 3H), 1.88 (s, 3H).

[0916] Example 14: 2-morpholinoethyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoiso (indolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-triazol-1-yl) Methyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (Compound 129)

[0917]

[0918] Step A

[0919] 6-Chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (30.0 mg, 0.033 mmol) was suspended in MeCN (1.0 mL) and 4-(2-bromoethyl)morpholine hydrobromide (18.0 mg, 0.065 mmol) was added followed by Et3N (0.046 mL, 0.327 mmol). The reaction (monitored by LCMS) was stirred at 60°C for 96 hours. The solution was concentrated to dryness under reduced pressure and purified by flash column chromatography (silica, 0% to 40% methanol in DCM) and reverse phase preparative HPLC (C18, H2O:MeCN + 0.1% FA) to give 2-morpholinoethyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (17.5 mg, 0.017 mmol, 51.8%) as a white solid.

[0920] LCMS (ESI): 1031.2 m / z [M+H] + .

[0921] 1H NMR (500MHz, DMSO, 353K) δ10.65(s,1H),8.21(dd,J=9.2,5.8Hz,1H),7.75(d,J=8.7Hz,1H),7.59(dd,J=10.4,2.6Hz,1H),7.48-7.37(m,3H),7.37- 7.28(m,2H),7.24(d,J=8.5Hz,1H),7.14(d,J=8.1Hz,1H),6.87(dd,J=6. 3,2.3Hz,1H),5.05(dd,J=13.0,5.2Hz,1H),4.89(s,2H),4.46-4.35(m,3H ),4.32(dd,J=17.1,1.6Hz,1H),4.29-4.12(m,4H),3.76(d,J=2.0Hz,3H) ,3.57-3.48(m,4H),3.38-3.31(m,4H),3.31-3.27(m,2H),2.88(ddd,J=17 .2,13.5,5.5Hz,1H),2.67(t,J=5.8Hz,2H),2.65-2.60(m,1H),2.47-2.3 9(m,5H),2.30-2.23(m,2H),2.15-2.02(m,7H),2.01(s,3H),1.88(s,3H).

[0922] Example 15: 3-(((6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindole (1,3,5-trimethylol)-7-((1,3,5-trimethoxy)-1-[(1,3,5 ... (1H-pyrazol-4-yl)-1H-indole-2-carbonyl)oxy)methyl)-1-methyl-1H-imidazole-3- Iodide (compound 140)

[0923]

[0924] Step A

[0925] 1-Methyl-1H-imidazole (0.097 mL, 1.218 mmol) and chloroiodomethane (0.093 mL, 1.279 mmol) were placed in a vial and stirred at room temperature for 48 hours. Afterwards, the reaction product was washed three times with ether and dried under reduced pressure to obtain a crude product of 3-(chloromethyl)-1-methyl-1H-imidazole-3- Iodide (135.1 mg) as a white solid.

[0926] Step B

[0927] 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (5.0 mg, 0.005 mmol), crude 3-(chloromethyl)-1-methyl-1H-imidazole-3- Iodide (3.1 mg), KI (4.5 mg, 0.027 mmol) and Et3N (0.004 mL, 0.027 mmol) were dissolved in anhydrous DMF and stirred at 60°C for 3 hours. The mixture was diluted with DCM and washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtered and dried under reduced pressure. The resulting residue was purified by preparative TLC (aluminum oxide, 20% methanol in DCM) to give 3-(((6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonyl)oxy)methyl)-1-methyl-1H-imidazole-3-yl)-1-nitro-1H-imidazol ... Iodide (2.6 mg, 0.002 mmol, 41.9%) as a beige solid.

[0928] LCMS (ESI): 1012.2 m / z [M+H] + .

[0929] 1H NMR (500MHz, DMSO, 353K) δ10.68 (s, 1H), 9.43-9.38 (m, 1H), 8.19 (dd, J = 9.3, 5.9Hz, 1H) ,7.93(t,J=1.9Hz,1H),7.78(d,J=8.7Hz,1H),7.72(t,J=1.8Hz,1H),7.61(dd,J=10.3, 2.6Hz, 1H), 7.47-7.41 (m, 3H), 7.38-7.31 (m, 2H), 7.27 (d, J=8.6Hz, 1H), 7.15 (d, J=8.1 Hz, 1H), 6.87 (dd, J = 6.3, 2.4Hz, 1H), 6.43 (d, J = 10.7Hz, 1H), 6.40 (d, J = 10.7Hz, 1H), 5.0 6(dd,J=13.0,5.3Hz,1H),4.96-4.85(m,2H),4.40(d,J=17.1Hz,1H),4.32(dd,J=17.1, 1.6Hz,1H),4.29-4.19(m,3H),4.19-4.10(m,1H),3.88(s,3H),3.76(d,J=2.2Hz,3H),3. 35-3.28(m,4H),3.28-3.24(m,2H),2.89(ddd,J=17.3,13.4,5.5Hz,1H),2.67-2.59(m, 1H),2.46-2.38(m,1H),2.23-2.15(m,2H),2.15-2.02(m,7H),2.01(s,3H),1.87(s,3H).

[0930] Example 16: (Pivaloyloxy)methyl 6-chloro-1-(2-(4-(2-((1-(2,6-dioxopiperidin-3-yl)-3- (methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoro (1-naphthalene)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (Compound 74)

[0931]

[0932] Step A

[0933] To a solution of tert-butyl 2-(3-fluoro-4-nitrophenoxy)acetate (500 mg, 1.844 mmol) in ethanol (10 mL) was added aqueous methylamine (0.41 mL, 9.22 mmol, 40% in water) at room temperature, and the reaction mixture was stirred at 50° C. for 2 hours. After complete consumption of the starting material (monitored by TLC and LCMS), the volatiles were removed and the crude product was purified by flash column chromatography (silica, 50% ethyl acetate in hexanes) to give tert-butyl 2-(3-(methylamino)-4-nitrophenoxy)acetate (400 mg, 1.418 mmol, 77%) as a brown liquid.

[0934] Tert-butyl 2-(3-fluoro-4-nitrophenoxy)acetate was prepared as described in US 2009 / 163552 A1.

[0935] LCMS (ESI+): 283.2 m / z [M+H] + .

[0936] Step B

[0937] A solution of tert-butyl 2-(3-(methylamino)-4-nitrophenoxy)acetate (400 mg, 1.418 mmol) in methanol (10 mL) was degassed with argon for 15 min. Pd / C (400 mg, 10 wt %) was slowly added at room temperature under nitrogen. The reaction mixture was then stirred at room temperature under hydrogen balloon pressure for 4 hours. After complete consumption of the starting material, the reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to afford the crude product. The product was purified by column chromatography (silica, 70% ethyl acetate in hexanes) to afford tert-butyl 2-(4-amino-3-(methylamino)phenoxy)acetate (250 mg, 0.992 mmol, 70%) as a brown liquid.

[0938] LCMS (ESI+): 253.1m / z[M+H] + .

[0939] Step C

[0940] 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 nitrogen. The reaction mixture was stirred at 70 ° C for 4 hours and monitored by LCMS and TLC. After completion, the volatiles were evaporated and the crude product was purified by column chromatography (silica, 50-60% ethyl acetate in hexanes) 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.

[0941] LCMS (ESI+): 278.9 m / z [M+H] + .

[0942] Step D

[0943] 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) at 0°C under nitrogen was added NaH (388 mg, 8.1 mmol, 60% in mineral oil) portionwise. The reaction mixture was stirred at the same temperature for 30 minutes. Subsequently, a solution of 3-bromopiperidine-2,6-dione (1.026 g, 5.4 mmol) in DMF (2 mL) was added dropwise at 0°C over 5 minutes. The mixture was then heated at 80°C under nitrogen for 2 hours. After complete consumption of the starting material (monitored by LCMS), the reaction mixture was cooled to -78°C, diluted with ethyl acetate, and stirred for the next 5 minutes. A saturated solution of NH4Cl was then added dropwise to the reaction mixture to quench the excess sodium hydride. The organic layer was separated from the solidified aqueous phase, and the solid was washed with ethyl acetate. The combined organic phases were washed with brine and evaporated under reduced pressure to give the crude product. The product was purified by preparative TLC (SiO2, 60% ethyl acetate in hexanes) to give tert-butyl 2-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oxy)acetate (60 mg, 0.154 mmol, 28%) as an off-white solid.

[0944] LCMS (ESI+): 390.1m / z[M+H] + .

[0945] Step E

[0946] To a solution of tert-butyl 2-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oxy)acetate (60 mg, 0.154 mmol) in DCM (2 mL) was added TFA (1 mL) dropwise at 0° C., and the reaction mixture was stirred at room temperature under nitrogen for 16 hours. After complete consumption of the starting material (reaction monitored by TLC and LCMS), the volatiles were evaporated under reduced pressure to give the crude compound, which was subsequently purified by trituration with diethyl ether and n-pentane to give 2-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oxy)acetic acid (45 mg, 0.135 mmol, 87%) as an off-white solid.

[0947] LCMS (ESI+): 334.2 m / z [M+H] + .

[0948] Step F

[0949] Under argon atmosphere, 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) and DIPEA (0.016 mL, 0.089 mmol) was added, followed by HATU (11.8 mg, 0.031 mmol). The reaction (monitored by LCMS) was stirred under argon for 20 minutes. After the raw material is completely consumed, the mixture is diluted with DCM and washed with salt water and water. The organic layer is dried over anhydrous MgSO4, filtered and dried under reduced pressure to give a crude product of 6-chloro-1-(2-(4-(2-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxygen-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oxy)acetyl)piperazine-1-yl)ethyl)-3-(3-((6-fluoronaphthalene-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazole-4-yl)-1H-indole-2-carboxylic acid tert-butyl ester, a yellow oil, which is used directly in the next step.

[0950] LCMS (ESI+): 989.0 m / z [M+H] + .

[0951] Step G

[0952] Under argon atmosphere, 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 (0.5 mL) and TFA (0.5 mL) was added. The reaction (monitored by LCMS) was stirred under argon for 16 hours. When the starting material was completely consumed, the solution was concentrated under reduced pressure and the residue was purified by preparative HPLC (C18, water:MeCN + 0.1% FA) to give 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% yield over two steps) as a white solid.

[0953] LCMS (ESI+): 933.15 m / z [M+H] + .

[0954] Step H

[0955] To a solution of 6-chloro-1-(2-(4-(2-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (13.0 mg, 0.014 mmol) in MeCN (500 μL) was added EtN (10 μL, 0.070 mmol). The reaction was stirred for 15 min and chloromethyl pivalate (2 μL, 0.017 mmol) was added. The reaction was allowed to proceed at room temperature overnight. A second portion of chloromethyl pivalate (2 μL, 0.017 mmol) was added and the mixture was stirred at 60° C. for 48 hours. The solvent was removed under reduced pressure and the mixture was diluted with DCM and brine. The aqueous layer was extracted with DCM. The combined organic layers were dried over sodium sulfate and concentrated under vacuum to give the corresponding (pivaloyloxy)methyl 6-chloro-1-(2-(4-(2-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (13.5 mg, 0.013 mmol, 92%) as a white solid.

[0956] LCMS (ESI): 1047.25 m / z [M+H] + .

[0957] 1H NMR (500MHz, DMSO, 353K) δ10.76(s,1H),8.21(dd,J=9.2,5.9Hz,1H),7.77(d,J=8.6Hz,1H),7.59(dd,J=10.4,2.6Hz,1H),7.45-7.38(m,2H),7.32( td, J=8.9, 2.6Hz, 1H), 7.26 (d, J=8.6Hz, 1H), 6.96 (d, J=8.6Hz, 1H), 6.86 (dd, J=6.1, 2.6Hz, 1H), 6.82 (d, J=2.4Hz, 1H), 6.62 (dd, J=8.6, 2.5Hz, 1H) ,5.99(s,2H),5.25(dd,J=12.5,5.4Hz,1H),4.69(s,2H),4.28-4.20(m,3 H),4.20-4.12(m,1H),3.75(s,3H),3.38-3.32(m,4H),3.30(s,3H),3.28- 3.23(m,2H),2.91-2.84(m,1H),2.72-2.63(m,1H),2.54-2.51(m,1H),2.2 6-2.19(m,2H),2.14-2.01(m,7H),2.00(s,3H),1.87(s,3H),1.15(s,9H).

[0958] Example 17: (Pivaloyloxy)methyl 6-chloro-1-(2-(4-(2-((1-(2,6-dioxopiperidin-3-yl)-3- (methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoro (1-naphthalene)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (Compound 73)

[0959]

[0960] Step A

[0961] 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. Subsequently, tert-butyl bromoacetate (1.691 ml, 11.458 mmol) was added dropwise and the reaction mixture was stirred at 60° C. under nitrogen for 5 hours. After complete consumption of the starting material, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate and evaporated to give the crude compound, which was then purified by column chromatography (silica, 0-10% ethyl acetate in hexanes) to give tert-butyl 2-(2-fluoro-3-nitrophenoxy)acetate (1.6 g, 5.90 mmol, 92%) as a yellow solid.

[0962] Step B

[0963] To a solution of tert-butyl 2-(2-fluoro-3-nitrophenoxy)acetate (400 mg, 1.476 mmol) in ethanol (8 mL) was added an aqueous solution of methylamine (0.33 mL, 7.378 mmol, 40% in water) at room temperature, and the reaction mixture was stirred for 2 hours at 50° C. After complete consumption of the starting material, the volatiles were removed under reduced pressure, and the crude product was purified by column chromatography (silica, 50% ethyl acetate in hexanes) to give tert-butyl 2-(2-(methylamino)-3-nitrophenoxy)acetate (370 mg, 1.31 mmol, 88%) as a brown liquid.

[0964] LCMS (ESI+): 283.2 m / z [M+H] + .

[0965] Step C

[0966] A solution of tert-butyl 2-(2-(methylamino)-3-nitrophenoxy)acetate (370 mg, 1.312 mmol) in methanol (10 mL) was degassed with argon for 15 minutes. Pd / C (370 mg, 10 wt %) was slowly added under argon. The reaction mixture was then stirred at room temperature under hydrogen balloon pressure for 4 hours. After complete consumption of the starting material, the reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica, 70% ethyl acetate in hexanes) to give tert-butyl 2-(3-amino-2-(methylamino)phenoxy)acetate (225 mg, 0.892 mmol, 68%) as a brown liquid.

[0967] LCMS (ESI+): 253.0 m / z [M+H] + .

[0968] Step D

[0969] 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 nitrogen. The reaction mixture was stirred at 60°C for 4 hours. The volatiles were removed under reduced pressure, and the crude product was purified by column chromatography (silica, 50-60% ethyl acetate in 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.

[0970] LCMS (ESI+): 279.2 m / z [M+H] + .

[0971] Step E

[0972] To a solution of tert-butyl 2-((3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)acetate (150 mg, 0.54 mmol) in DMF (4 mL) was added portionwise NaH (388 mg, 8.1 mmol, 60% in mineral oil) at 0°C under nitrogen, and the reaction mixture was stirred at the same temperature for 30 minutes. Subsequently, a solution of 3-bromopiperidine-2,6-dione (1.026 g, 5.4 mmol) in DMF (2 mL) was added dropwise at 0°C over 5 minutes. The mixture was then heated to 80°C under nitrogen for 2 hours. After complete consumption of the starting material (monitored by LCMS), the reaction mixture was cooled to -78°C, diluted with ethyl acetate, and stirred for 5 minutes. A saturated ammonium chloride solution was then added dropwise to the reaction mixture to quench the excess sodium hydride. The organic layer was separated from the solidified aqueous layer, and the solid was washed with ethyl acetate. The combined organic phases were washed with brine and evaporated. The crude compound was purified by preparative TLC (SiO2, 60% ethyl acetate in hexanes) to afford 60 mg (0.154 mmol, 28%) of tert-butyl 2-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)acetate as an off-white solid.

[0973] LCMS (ESI+): 390.2 m / z [M+H] + .

[0974] Step F

[0975] 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 room temperature under nitrogen for 16 hours. After complete consumption of the starting material, the volatiles were removed under reduced pressure to afford the crude compound, which was subsequently purified by trituration with diethyl ether and n-pentane to afford 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.

[0976] LCMS (ESI+): 334.2 m / z [M+H] + .

[0977] Step G

[0978] Under argon, tert-butyl 6-chloro-3-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-1-[2-(piperazin-1-yl)ethyl]-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (20.0 mg, 0.030 mmol), 2-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)acetic acid (10.9 mg, 0.033 mmol), and DIPEA (0.016 mL, 0.089 mmol) were dissolved in anhydrous DMF (1.0 mL). A solution of HATU (11.8 mg, 0.031 mmol) in DMF (1.0 mL) was added. The reaction was stirred at room temperature under argon for 15 minutes. After complete conversion, the solution was diluted to 10mL with DCM. The resulting solution was washed with brine and water, and dried over anhydrous MgSO4, filtered and dried under reduced pressure. Crude product 6-chloro-1-{2-[4-(2-{[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxygen-2,3-dihydro-1H-1,3-benzodiazol-4-yl] oxygen}acetyl)piperazine-1-yl] ethyl}-3-{3-[(6-fluoronaphthalene-1-yl) oxygen] propyl}-7-(1,3,5-trimethyl-1H-pyrazole-4-yl)-1H-indole-2-carboxylic acid tert-butyl ester (41.8mg) was obtained as a yellow oil.

[0979] LCMS (ESI+): 989.2 m / z [M+H] + .

[0980] Step H

[0981] Under argon atmosphere, 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) 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 residue was purified by preparative HPLC (C18, H2O: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% yield over two steps) as a white solid.

[0982] LCMS (ESI+): 933.2 m / z [M+H] + .

[0983] Step I

[0984] To a solution of 6-chloro-1-(2-(4-(2-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (17.7 mg, 0.019 mmol) in anhydrous MeCN (0.95 mL) was added EtN (0.013 mL, 0.095 mmol) followed by chloromethyl pivalate (0.030 mL, 0.021 mmol). The reaction was stirred at room temperature for 3 hours. Add another portion of chloromethyl pivalate (0.027mL, 0.019mmol), and the mixture is stirred at 60 ℃ for 16 hours. Then add chloromethyl pivalate (0.014mL, 0.010mmol) again, and the reaction continues for another 16 hours. After the raw material is completely consumed, the mixture is concentrated to dryness under reduced pressure. The gained residue is diluted with DCM and washed with water. The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting solid was freeze-dried to give (pivaloyloxy)methyl 6-chloro-1-(2-(4-(2-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (15.4 mg, 0.015 mmol, 77%) as a white solid.

[0985] LCMS (ESI): 1047.25 m / z [M+H] + .

[0986] 11H NMR (500 MHz, DMSO, 353 K) δ 10.77 (s, 1H), 8.21 (dd, J = 9.2, 5.9 Hz, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.59 (dd, J = 10.4, 2.6 Hz, 1H), 7.45 - 7.39 (m, 2H), 7.32 (ddd, J = 9.2, 8.6, 2.6 Hz, 1H), 7.26 (d, J = 8.5 Hz, 1H), 6.93 (t, J = 8.2 Hz, 1H), 6.87 (dd, J = 5.9, 2.7 Hz, 1H), 6.75 (dd, J = 8.0, 0.8 Hz, 1H), 6.72 (dd, J = 8.4, 0.8 Hz, 1H), 5.99 (s, 2H), 5.27 (dd, J = 12.4, 5.5 Hz, 1H), 4.84 (s, 2H), 4.31 - 4.19 (m, 3H), 4.19 - 4.09 (m, 1H), 3.75 (s, 3H), 3.57 (s, 3H), 3.40 - 3.30 (m, 4H), 3.30 - 3.21 (m, 2H), 2.95 - 2.81 (m, 1H), 2.74 - 2.61 (m, 2H), 2.26 - 2.18 (m, 2H), 2.14 - 2.01 (m, 7H), 2.01 (s, 3H), 1.87 (s, 3H), 1.15 (s, 9H).

[0987] Example 18: Acetoxymethyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisothiazolin-2-yl)-1-oxoisothiazolin ...iso (indolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-triazol-1-yl) Methyl-1H- 吡 oxazol-4-yl)-1H-indole-2-carboxylate (Compound 41)

[0988]

[0989] Step A

[0990] To a solution of 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (10.0 mg, 0.011 mmol) in DMF (0.31 mL) was added DIPEA (0.009 mL, 0.054 mmol) followed by chloromethyl acetate (0.001 mL, 0.016 mmol). The reaction was stirred at 55 °C for 16 hours. Upon completion, the solution was evaporated. The resulting residue was dissolved in DMSO and purified by reverse phase preparative HPLC (C18, H2O:MeCN + 0.1% FA) to give acetoxymethyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (6.6 mg, 0.007 mmol, 61%) as a white solid.

[0991] LCMS (ESI): 990.25 m / z [M+H] + .

[0992] 11H NMR (500 MHz, DMSO, 353 K) δ 10.66 (s, 1H), 8.23 (dd, J = 9.2, 5.8 Hz, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.59 (dd, J = 10.4, 2.6 Hz, 1H), 7.50 - 7.38 (m, 3H), 7.38 - 7.29 (m, 2H), 7.26 (d, J = 8.6 Hz, 1H), 7.14 (d, J = 8.1 Hz, 1H), 6.88 (dd, J = 5.6, 3.0 Hz, 1H), 5.96 (d, J = 6.0 Hz, 1H), 5.95 (d, J = 6.1 Hz, 1H), 5.05 (dd, J = 13.0, 5.2 Hz, 1H), 4.89 (s, 2H), 4.40 (d, J = 17.1 Hz, 1H), 4.31 (dd, J = 17.2, 1.4 Hz, 1H), 4.28 - 4.19 (m, 3H), 4.19 - 4.10 (m, 1H), 3.76 (d, J = 1.8 Hz, 3H), 3.36 - 3.30 (m, 4H), 3.30 - 3.24 (m, 2H), 2.88 (ddd, J = 17.3, 13.5, 5.5 Hz, 1H), 2.66 - 2.59 (m, 1H), 2.48 - 2.39 (m, 1H), 2.26 - 2.18 (m, 2H), 2.15 - 2.02 (m, 10H), 2.01 (s, 3H), 1.88 (s, 3H).

[0993] Example 19: 1-acetoxyethyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxopiperidin- (isoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5- Trimethyl-1H- 吡 oxazol-4-yl)-1H-indole-2-carboxylate (Compound 75)

[0994]

[0995] Step A

[0996] 6-Chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid (20.0 mg, 0.022 mmol) was dissolved in anhydrous DMF (0.73 mL) and DIPEA (0.019 mL, 0.109 mmol), followed by the addition of 1-bromoethyl acetate (4.4 mg, 0.026 mmol). The reaction was stirred at 55° C. under argon for 24 hours. A second portion of 1-bromoethyl acetate (3.6 mg, 0.022 mmol) was added, and the reaction continued at 55° C. under argon for the next 48 hours. Upon completion, the solution was concentrated under reduced pressure, diluted with DMSO, and purified by reverse phase preparative HPLC (C18, H2O:MeCN + 0.1% FA) to give 1-acetoxyethyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (10.9 mg, 0.011 mmol, 49%) as a white solid.

[0997] LCMS (ESI): 1004.1m / z[M+H] + .

[0998] 11H NMR (500 MHz, DMSO, 353 K) δ 10.66 (s, 1H), 8.24 (dd, J = 9.2, 5.8 Hz, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.59 (dd, J = 10.4, 2.6 Hz, 1H), 7.47 - 7.38 (m, 3H), 7.37 - 7.29 (m, 2H), 7.26 (d, J = 8.6 Hz, 1H), 7.14 (d, J = 8.1 Hz, 1H), 7.08 - 7.00 (m, 1H), 6.90 (dd, J = 5.9, 2.7 Hz, 1H), 5.05 (dd, J = 13.1, 5.2 Hz, 1H), 4.89 (s, 2H), 4.40 (d, J = 17.0 Hz, 1H), 4.32 (dd, J = 17.1, 1.6 Hz, 1H), 4.27 (t, J = 6.3 Hz, 2H), 4.25 - 4.20 (m, 1H), 4.20 - 4.11 (m, 1H), 3.76 (d, J = 2.1 Hz, 3H), 3.37 - 3.32 (m, 4H), 3.32 - 3.24 (m, 2H), 2.88 (ddd, J = 17.4, 13.5, 5.5 Hz, 1H), 2.67 - 2.58 (m, 1H), 2.48 - 2.40 (m, 1H), 2.27 - 2.20 (m, 2H), 2.17 - 2.04 (m, 7H), 2.03 (d, J = 1.5 Hz, 3H), 2.01 (d, J = 1.1 Hz, 3H), 1.88 (s, 3H), 1.59 (dd, J = 5.5, 2.1 Hz, 3H).

[0999] Example 20: (Pivaloyloxy)methyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1- (6-(1-(6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1- (2-(2-methoxy group (Ethoxy)ethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (Compound 149)

[1000]

[1001]

[1002] Step A

[1003] To a solution of 4-bromo-3,5-dimethyl-1H-pyrazole (5 g, 28.57 mmol) in DMF (50 mL) at room temperature under nitrogen was added 1-bromo-2-(2-methoxyethoxy)ethane (5.07 mL, 37.14 mmol) followed by Cs2CO3 (18.57 g, 57.14 mmol). The reaction mixture was stirred at room temperature for 2 hours. After the starting material was completely consumed, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was triturated with diethyl ether and n-pentane to give 4.8 g (17.33 mmol, 60%) of 4-bromo-1-(2-(2-methoxyethoxy)ethyl)-3,5-dimethyl-1H-pyrazole as an off-white solid.

[1004] LCMS (ESI): 276.8m / z[M+H] + .

[1005] Step B

[1006] To a solution of 4-bromo-1-(2-(2-methoxyethoxy)ethyl)-3,5-dimethyl-1H-pyrazole (1 g, 3.61 mmol) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.70 mL, 18.12 mmol) in THF (20 mL) was added n-butyllithium (2M in hexane, 4.5 mL, 9.058 mmol) at -78°C under nitrogen. The reaction mixture was stirred at the same temperature for 2 hours. After complete conversion, the excess n-butyllithium was quenched with a saturated solution of NH4Cl at -78°C, and the reaction mixture was extracted with ethyl acetate. The combined organic fractions were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude 1-(2-(2-methoxyethoxy)ethyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1 g) was used in the next step without further purification.

[1007] LCMS (ESI): 325.0 m / z [M+H] + .

[1008] Step C

[1009] To tert-butyl 7-bromo-6-chloro-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-1H-indole-2-carboxylate (300 mg, 0.57 mmol) was added dibromo-6-chloro-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-1H-indole-2-carboxylate (300 mg, 0.57 mmol) in dibromo- Crude 1-(2-(2-methoxyethoxy)ethyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (734 mg) and Cs2CO3 (552 mg, 1.70 mmol) were added to a solution of 2-(2-methoxyethoxy)ethyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in dextrin (4 mL) and water (1 mL). The mixture was deoxygenated with argon, and PdCl2(dtbpf) (36 mg, 0.056 mmol) was added under a nitrogen atmosphere. The reaction mixture was stirred at 100°C for 1 hour until the starting material was completely consumed. The reaction mixture was diluted with ethyl acetate and washed sequentially with water and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. Tert-butyl 6-chloro-3-(3-((6-fluoronaphthalen-l-yl)oxy)propyl)-7-(l-(2-(2-methoxyethoxy)ethyl)-3,5-dimethyl-lH-pyrazol-4-yl)-lH-indole-2-carboxylate (240 mg, 0.37 mmol, 65%) was purified by column chromatography (silica, 20% ethyl acetate in hexanes).

[1010] LCMS (ESI): 650.4 m / z [M+H] + .

[1011] Step D

[1012] To a solution of tert-butyl 6-chloro-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1-(2-(2-methoxyethoxy)ethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (240 mg, 0.37 mmol) in DMF (5 mL) was added tert-butyl 4-(2-chloroethyl)piperazine-1-carboxylate (275 mg, 1.11 mmol) and CsCO (360 mg, 1.11 mmol) at room temperature. The reaction mixture was stirred at 90° C. under nitrogen for 16 hours. After complete consumption of the starting material, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica, 30% ethyl acetate in hexanes) to give 240 mg (0.28 mmol, 75%) of tert-butyl 1-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)-6-chloro-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1-(2-(2-methoxyethoxy)ethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate as a white solid.

[1013] LCMS (ESI): 862.8 m / z [M+H] + .

[1014] Step E

[1015] At 0°C under nitrogen, tert-butyl 1-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)-6-chloro-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1-(2-(2-methoxyethoxy)ethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (240 mg, 0.28 mmol) was added to the mixture in distilled water. To the solution in oxane (3 mL), 6 mL of 4 M hydrochloric acid in dioxane was added. The reaction mixture was cooled to 0 ° C under nitrogen and stirred for 2 hours. After the raw material was completely consumed (monitored by TLC and LCMS), the reaction mixture was poured into a cold 1M sodium hydroxide solution and extracted with dichloromethane. The combined organic portion was dried over sodium sulfate and concentrated under vacuum. The crude compound was purified by trituration with diethyl ether and n-pentane to give 200 mg (0.26 mmol, 94%) of 6-chloro-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1-(2-(2-methoxyethoxy)ethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-(2-(piperazin-1-yl)ethyl)-1H-indole-2-carboxylic acid tert-butyl ester as a white solid.

[1016] LCMS (ESI): 762.6m / z[M+H] + .

[1017] Step F

[1018] To a solution of tert-butyl 6-chloro-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1-(2-(2-methoxyethoxy)ethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-(2-(piperazin-1-yl)ethyl)-1H-indole-2-carboxylate (180 mg, 0.24 mmol) in DMF (5 mL) was added 2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetic acid (75 mg, 0.24 mmol), HATU (134 mg, 0.36 mmol), and DIPEA (0.082 mL, 0.47 mmol) at room temperature under nitrogen. The mixture was stirred at room temperature under nitrogen for 1 hour. After completion of the reaction, the mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude compound was purified by column chromatography (silica, 10% methanol in DCM) to afford 100 mg (0.094 mmol, 39%) of tert-butyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1-(2-(2-methoxyethoxy)ethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate as an off-white solid.

[1019] LCMS (ESI): 1062.4 m / z [M+H] + .

[1020] Step G

[1021] To a solution of tert-butyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1-(2-(2-methoxyethoxy)ethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (100 mg, 0.094 mmol) in DCM (5 mL) at 0° C. under nitrogen was added TFA (1 mL) dropwise. The mixture was stirred at room temperature under nitrogen for 16 hours. After complete consumption of the starting material (monitored by TLC and LCMS), the volatiles were evaporated. The crude compound was purified by trituration with diethyl ether and n-pentane to give 93 mg (0.083 mmol, 83%) of 1-(2-(2-carboxy-6-chloro-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1-(2-(2-methoxyethoxy)ethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1H-indol-1-yl)ethyl-4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazine-1-yl Trifluoroacetate, a white solid.

[1022] LCMS (ESI): 1006.6m / z[M+H] + .

[1023] Step H

[1024] To a solution of 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1-(2-(2-methoxyethoxy)ethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid trifluoroacetate (16.8 mg, 0.015 mmol) in DMF (75 μL) and DIPEA (16 μL, 0.089 mmol) was added chloromethyl 2,2-dimethylpropanoate (4 μL, 0.030 mmol). The reaction was stirred at room temperature for 24 hours. An additional portion of chloromethyl 2,2-dimethylpropanoate (4 μL, 0.030 mmol) was added and the reaction mixture was stirred for 48 hours at 55° C. The solvent was removed under reduced pressure and the product was purified by flash chromatography (silica, 5-10% methanol in DCM) to give (pivaloyloxy)methyl 6-chloro-1-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)ethyl)-3-(3-((6-fluoronaphthalen-1-yl)oxy)propyl)-7-(1-(2-(2-methoxyethoxy)ethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate (2.1 mg, 0.002 mmol, 12%) as a white solid.

[1025] LCMS (ESI): 1120.5 m / z [M+H] + .

[1026] 1H NMR (500MHz, DMSO, 353K) δ10.66(s,1H),8.21(dd,J=9.3,5.9,1H),7.77(d,J=8.6,1H),7.59(dd,J=10.3,2.6,1H),7.46-7.40(m,3H),7.35-7.2 9(m,2H),7.26(d,J=8.6,1H),7.13(dd,J=8.1,3.0,1H),6.87(dd,J=6.1 ,2.6,1H),5.99(s,2H),5.15-5.03(m,2H),4.88(s,2H),4.40(dd,J=17. 1,4.5,1H),4.31(d,J=17.1,1H),4.26-4.17(m,6H),3.81-3.78(m,2H), 3.54(dd,J=5.8,4.1,2H),3.46-3.43(m,2H),3.33-3.29(m,4H),3.28-3 .23(m,5H),2.88(ddd,J=18.5,13.3,5.5,1H),2.46-2.38(m,1H),2.25- 2.19(m,2H),2.12-2.02(m,7H),2.01(s,3H),1.91(s,3H),1.15(s,9H).

[1027] Example 21: Cell viability assay of MV4-11 and ARH-77 cells

[1028] The effects of various compounds of the present invention on the viability of MV4-11 and ARH-77 cell lines were investigated using the CTG protocol described below.

[1029] The MV4-11 cell line is derived from acute myeloid leukemia and has been described in the literature as an MCL-1-dependent cell line, in contrast to the lymphoblastoid ARH-77 cell line, which has been described as MCL-1-independent (Tron AE et al. Nat Commun. 2018;9:5341; Caenepeel S et al. Cancer Discov. 2018 Dec;8(12):1582-1597).

[1030] Cells (MV4-11 or ARH-77) were plated in 348-well plates in growth medium containing 1% FBS. Subsequently, compound stocks were pre-diluted in DMSO and added directly to the cell culture medium (final DMSO concentration: 0.5%). Compound concentrations used in this assay were: 1 / 3 dilutions (9 to 12 points) starting from 30 μM. After 24 hours of incubation, the cells were incubated with Cell viability was assessed using a luminescent cell viability assay (Promega, cat# G7572). Luminescent signals were measured using a CLARIOstar Plus multi-function microplate reader (574-590 nm).

[1031] Results were normalized to DMSO control and collected data were analyzed using GraphPad Prism to calculate pCC 50 Value (ie CC 50 negative logarithm of the value). CC 50 (50% cytotoxic concentration) refers to the effective concentration of a cytotoxic compound that causes 50% of the maximal possible cell death (i.e., the concentration of compound required to reduce cell viability by 50%). In cytotoxicity assays, CC is often used. 50 Not IC 50 .

[1032] Table 9: Effects of various compounds of the present invention on the viability of MV4-11 and ARH-77 cell lines

[1033]

[1034]

[1035] As shown in Table 9, the compounds of the present invention can reduce the viability of acute myeloid leukemia cells and are therefore useful for cancer treatment. Furthermore, the compounds of the present invention have little or no effect on the viability of ARH-77, further supporting the specific MCL-1-dependent activity of the compounds.

[1036] dMCL-1-2 is a MCL-1 degrader described in Papatzimas et al., J. Med. Chem. 2019, 62, 5522-5540.

[1037] Example 22: MV4-11 cells: MCL-1 protein degradation, Western blot

[1038] The effects of various compounds of the present invention on MCL-1 protein degradation in the MV4-11 cell line were investigated using the following degradation assay protocol.

[1039] MV4-11 cells were maintained in IMDM medium supplemented with penicillin / streptomycin and 10% fetal bovine serum (FBS). MV4-11 cells were harvested, centrifuged (250 rcf, 5 min), resuspended in growth medium containing 10% FBS, and counted. The cell suspension was then adjusted to 1×10 cells / mL using growth medium containing 10% FBS. 6 cells / mL. Subsequently, 0.5×10 6Cells were seeded into 24-well plates with 0.5 mL of culture medium per well. Immediately after inoculation, the cells were pretreated with DMSO or the pan-caspase inhibitor Q-VD-Oph for 30 minutes. Subsequently, the compound from the stock solution pre-diluted with DMSO was added directly to the cell culture medium at an appropriate concentration (the final concentration of DMSO was 0.5%). After 6 hours of treatment with the compound, the cells were collected from the plate, resuspended in lysis buffer (2% SDS, 50 mM Tris, pH 8.0, 100 U / ml Pierce Cell Lysis Universal Nuclease, EDTA-free complete protease inhibitor cocktail), and incubated on ice for 45 minutes. The amount of protein was determined by BCA assay, and equal amounts of each sample were loaded onto precast gels for protein separation. After antibody staining for MCL-1, α-tubulin, and cleaved forms of PARP and caspase 3, the membrane was washed and the signal was developed.

[1040] Densitometry values ​​for MCL-1 were normalized to total protein levels (unstained membranes) and the protein reduction [%] was calculated compared to cells treated with DMSO (representing 0%).

[1041] Table 10: Results of MCL-1 protein degradation in MV4-11 cells after treatment with exemplary compounds. The table shows density values ​​normalized to the loading control and calculated as % of the DMSO control.

[1042]

[1043] A-MCL-1 protein amount ≤ 25%, calculated as % of DMSO control

[1044] B-MCL-1 protein amount >25% and ≤50%, calculated as % of DMSO control

[1045] The amount of C-MCL-1 protein was >50% and <75%, calculated as % of DMSO control

[1046] The amount of D-MCL-1 protein was ≥75%, calculated as % of DMSO control

[1047] As shown in Table 10 and Figure 1As shown in Table 9, the exemplary compounds of the present invention induced dose-dependent degradation of MCL-1 protein in MV4-11 cells, resulting in strong apoptosis induction. Therefore, complete degradation of MCL-1 protein was observed at the highest tested dose. When apoptosis was blocked, the exemplary compounds induced the expected incomplete MCL-1 degradation, which may help protect MCL-1 independent cells (e.g., normal cells) from death. This hypothesis is supported by the results from ARH-77 cells shown in Table 9, which show that the exemplary compounds lack cytotoxic activity in MCL-1 independent leukemia cells.

[1048] Example 23: Determination of Cell Permeability and Target Binding

[1049] NanoBRET-Intracellular CRBN Target Binding Assay

[1050] The commercially available NanoBRET In-cell CRBN target binding assay (NanoBRET CRBN TE Assay), which employs NanoLuc CRBN HEK293 cells and NanoBRET In-cell CRBN tracers (N2910, N2912, PROMEGA), was used to determine the cell membrane permeability of the prodrugs of MCL-1 degraders.

[1051] The assay was performed in 96-well plates (cat. 3600, Corning). NanoLuc CRBN HEK293 cells were treated with CRBN tracer and compounds. Briefly, a cell suspension (0.17 × 10 6cells / ml). Cells were treated with CRBN tracer (20x concentrated, 5 μl / well; for live cell mode: final concentration 0.8 μM; for lytic mode: final concentration 0.17 μM) or DMSO vehicle control (20x concentrated, 5 μl / well). Prepared cells were seeded onto compounds (100x concentrated, 1 μl / well; 11 points, 2-fold dilution) pre-plated on the wells of a 96-well plate with the help of an Echo 555 sonic dispenser (Labcyte). For lytic mode assays, digitonin (0.05 mg / ml, 10x concentrated, 10 μl / well) was additionally added. In the live cell mode assay, the plate was incubated at 37°C, 5% carbon dioxide for 2 hours and then incubated at room temperature for 15 minutes to cool. In the lytic mode assay, no incubation was performed. According to the manufacturer's recommendations, 3x complete NanoBRET reagent (50 μl / well) was prepared for both live cell and lysis modes. The plate was incubated at room temperature for 2 minutes, and then luminescence and fluorescence readings were recorded using a CLARIOstar multi-function microplate reader (donor emission is RLU-450 nm; acceptor emission is RFU-610 nm). The RBA value is an indicator of cell membrane permeability (lower is better), which is determined by the live cell mode (pIC 50 living cells) and lysis pattern assays (pIC 50 Absolute pIC 50 (When converted to moles, the absolute IC 50 The negative logarithm of the value is calculated.

[1052] RBA xi=10^(-absolute pIC 50 Live cells xi) / 10^(-absolute pIC 50 Crackingxi)

[1053] Table 11. NanoBRET pIC values ​​of bifunctional compounds tested in intact and lysed cells 50 [M] value.

[1054]

[1055]

[1056] Based on the evidence presented herein, prodrugs of MCL-1 degraders are cell membrane permeable. Importantly, the permeability of the prodrug-modified degraders is 4-2600 times higher than that of the unmodified dMCL-1-2 degraders, indicating that the prodrugs have enhanced cell membrane permeability.

[1057] Abbreviations and Definitions

[1058] Shown below is a list of abbreviations used in this application:

[1059]

[1060] As used herein, "room temperature" refers to a temperature of 20°C to 25°C.

[1061] The present invention is further described with reference to the following clauses:

[1062] 1. Compounds of formula (I)

[1063] [MCL-1 ligand prodrug moiety]-linker-[ligase ligand moiety] (I) or a salt, solvate, hydrate or isomer thereof,

[1064] Wherein, [ligase ligand part] is:

[1065]

[1066] in:

[1067] M is O, S or NH, or does not exist;

[1068] represents R connected to the linking group 18 ;

[1069] R 22 is hydrogen, halogen, -OMe, amino, heterocycloalkyl, or unsubstituted C1-C6 alkyl; and

[1070] R 29 is hydrogen or Me;

[1071] L' is hydrogen, alkyl, benzyl, acetyl or pivaloyl;

[1072] Wherein, [MCL-1 ligand prodrug moiety] is:

[1073]

[1074] in:

[1075] R 11 It is a halogen;

[1076] R 13 It is a halogen;

[1077] R 19 is the R of the linking group 14 connected keys;

[1078] and

[1079] (i)R 9is -C(O)O(C1-C6 alkyl), -C(O)O cycloalkyl, -C(O)O heterocycloalkyl, -C(O)O aryl or -P(O)(OR p ) 2, wherein the C1-C6 alkyl group is substituted by one or more groups selected from the following: -OC(O) (unsubstituted C1-C6 alkyl), -OC(O) (substituted by at least one R 10 substituted C1-C6 alkyl), -OC(O)cycloalkyl, -OC(O)heterocycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, -OC(O)(CH2) m O(CH2) m O(unsubstituted C1-C6 alkyl), -OC(O)(CH2) m O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(unsubstituted C1-C6 alkyl), -OC(O)O(substituted by at least one R 10 Substituted C1-C6 alkyl), -OC(O)O cycloalkyl, -OC(O)O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2CH2O) m (C1-C6 alkyl substituted with OP(O)(OH)2), -OC(O)O(CH2CH2S) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)(unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)2(unsubstituted C1-C6 alkyl), -OC(O)NH(C1-C6 alkyl substituted by OMe), -OC(O)NMe(C1-C6 alkyl substituted by OMe), -P(O)(OH)2, -OP(O)(OH)2, -C(O)heterocycloalkyl, -C(O)N(unsubstituted C1-C6 alkyl)2, heteroaryl, heterocycloalkyl, -S(unsubstituted C1-C6 alkyl), -S(O)(unsubstituted C1-C6 alkyl), -N + (unsubstituted C1-C6 alkyl)3, -N + (Unsubstituted C1-C6 alkyl)2-cycloalkyl, N-(unsubstituted C1-C6 alkyl)piperidine Cation, N-(unsubstituted C1-C6 alkyl)morpholine Cation and N-(unsubstituted C1-C6 alkyl) imidazole cation;

[1080] Among them, each R 10are independently -OH, -O(unsubstituted C1-C6 alkyl), -OBn, -NH2, -NMe2, -NHC(O)(unsubstituted C1-C6 alkyl), -NHC(O)O(unsubstituted C1-C6 alkyl), heterocycloalkyl, heteroaryl, aryl, -C(O)NMe2;

[1081] Each R p are independently -(CH2) m OC(O) (unsubstituted C1-C6 alkyl), and

[1082] Each m is independently 1, 2, 3 or 4;

[1083] or

[1084] (ii)R 9 is -C(O)O(CH2) p NMe2, -C(O)O(CH2) p NHMe, -C(O)OCH2CH(OH)CH2OH, -C(O)OCH2CH2CMe2OH, or -C(O)OCH2CH2SO2Me, wherein each p is independently 2, 3, 4, 5, or 6;

[1085] and wherein [linking group] has the formula:

[1086] R 14 -R 15 -R 16 -R 17 -R 18

[1087] in:

[1088] 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;

[1089] R 15 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 Alkyl-NH-, -C 1-6 Alkyl-N(C 1-6 alkyl)-, -cycloalkyl-NH-, -heterocycloalkyl-NH- or absent;

[1090] R 16 -C 1-6Alkyl, -C(O)-, -C(O)-NH-, -C(O)O-, -CH2-C(O)-, -CH2-C(O)-NH-, -CH2-C(O)O-, or absent;

[1091] R 17 -CH2(C2H4-O) y 、-(C2H4-O) x 、-(C3H6-O) x or does not exist;

[1092] x is 1-10;

[1093] y is 2-10;

[1094] R 18 -C 1-6 Alkyl, cycloalkyl, -CH2-NH-C(O)-, heterocycloalkyl or absent;

[1095] where R 14 -R 18 At least one of exists.

[1096] 2. The compound of clause 1, wherein [ligase ligand moiety] is:

[1097]

[1098] 3. The compound of clause 1, wherein [ligase ligand moiety] is:

[1099]

[1100] 4. A compound according to any one of the preceding clauses, wherein R 22 For hydrogen.

[1101] 5. The compound of any one of the preceding clauses, wherein L' is hydrogen.

[1102] 6. The compound of any one of the preceding clauses, wherein M is O or NH, or is absent.

[1103] 7. The compound of any one of clauses 1-2 and 4-6, wherein [ligase ligand moiety] is

[1104]

[1105] 8. The compound of clause 7, wherein [ligase ligand moiety] is

[1106]

[1107] 9. A compound according to any one of the preceding clauses, wherein R 14 -C 1-6Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C(O)-, -SO2- or absent.

[1108] 10. The compound according to item 9, wherein R 14 Yes-C 1-6 alkyl.

[1109] 11. The compound of any one of the preceding clauses, wherein R 15 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 Alkyl-NH-, -cycloalkyl-NH- or not present.

[1110] 12. The compound of clause 11, wherein R 15 It is a heterocycloalkyl group.

[1111] 13. The compound of clause 12, wherein R 15 is piperazine, bridged piperazine, piperazine N-oxide, piperazine cation,

[1112]

[1113] in, Indicates connection to R 14 , Indicates connection to R 16 .

[1114] 14. The compound of clause 13, wherein R 15 Is piperazine or

[1115] 15. The compound of any one of the preceding clauses, wherein R 16 Yes-C 1-6 Alkyl, -CH2-C(O)-NH- or -C(O)-.

[1116] 16. The compound of any one of the preceding clauses, wherein R 16 Yes-C 1-6 Alkyl or -C(O)-.

[1117] 17. The compound of any one of the preceding clauses, wherein R 17 Does not exist.

[1118] 18. The compound of any one of the preceding clauses, wherein R 18 -C 1-6 Alkyl, heterocycloalkyl or not present.

[1119] 19. The compound according to clause 18, wherein R 18 Yes-C 1-6 Alkyl or heterocycloalkyl.

[1120] 20. The compound of clause 19, wherein R 18 Yes-C 1-6 Alkyl or piperazine.

[1121] 21. The compound of any one of the preceding clauses, wherein [Linking Group] is selected from:

[1122]

[1123] in:

[1124] represents attachment to [MCL-1 ligand prodrug moiety]; and

[1125] Indicates attachment to [ligase ligand moiety].

[1126] 22. The compound of any one of the preceding clauses, wherein R 9 is -C(O)O(C1-C6 alkyl), -C(O)O cycloalkyl, -C(O)O heterocycloalkyl, -C(O)O aryl or -P(O)(OR p ) 2, wherein the C1-C6 alkyl group is substituted by one or more groups selected from the following: -OC(O) (unsubstituted C1-C6 alkyl), -OC(O) (substituted by at least one R 10 substituted C1-C6 alkyl), -OC(O)cycloalkyl, -OC(O)heterocycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, -OC(O)(CH2) m O(CH2) m O(unsubstituted C1-C6 alkyl), -OC(O)(CH2) m O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(unsubstituted C1-C6 alkyl), -OC(O)O(substituted by at least one R 10 Substituted C1-C6 alkyl), -OC(O)O cycloalkyl, -OC(O)O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2CH2O) m (C1-C6 alkyl substituted with OP(O)(OH)2), -OC(O)O(CH2CH2S) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)(unsubstituted C1-C6 alkyl), -OC(O)O(CH2) mS(O)2(unsubstituted C1-C6 alkyl), -OC(O)NH(C1-C6 alkyl substituted by OMe), -OC(O)NMe(C1-C6 alkyl substituted by OMe), -P(O)(OH)2, -OP(O)(OH)2, -C(O)heterocycloalkyl, -C(O)N(unsubstituted C1-C6 alkyl)2, heteroaryl, heterocycloalkyl, -S(unsubstituted C1-C6 alkyl), -S(O)(unsubstituted C1-C6 alkyl), -N + (unsubstituted C1-C6 alkyl)3, -N + (Unsubstituted C1-C6 alkyl)2-cycloalkyl, N-(unsubstituted C1-C6 alkyl)piperidine Cation, N-(unsubstituted C1-C6 alkyl)morpholine cation and N-(unsubstituted C1-C6 alkyl)imidazolyl cation.

[1127] 23. The compound of clause 22, wherein R 9 is -C(O)O(C1-C6 alkyl), -C(O)O cycloalkyl, -C(O)O heterocycloalkyl, -C(O)O aryl or -P(O)(OR p ) 2, wherein the C1-C6 alkyl group is substituted by one or more groups selected from the group consisting of: -OC(O)Me, -OC(O)Et, -OC(O) i Pr, -OC(O)C(CH3)3, -OC(O)CH2OH, -OC(O)CH(CH3)OH, -OC(O)C(CH3)2OH, -OC(O)CH2CH2OH, -OC(O)CH(OH)CHMe2, -OC(O)CH(OH)CH2CHMe2, -OC(O)CH2CH(OH)Me, -OC(O)CH2C(OH)Me2, -OC(O)CH(CH2OH)(NHC(O)Me), -OC(O)CH(NHC(O)Me)(isobutyl), -OC(O)CH(OH)aryl, -OC(O)CH(OH)CH2aryl, -OC(O)heterocycloalkyl, -OC(O)cycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, -OC(O)CH2CH2aryl, -OC(O)CH(NH2) i Pr, -OC(O)CH( i Pr)NHC(O)O t Bu, -OC(O)CH2OCH2CH2OMe, -OC(O)CH2(OCH2CH2)2OMe, -OC(O)OMe, -OC(O)OEt, -OC(O)O iPr, -OC(O)Ocycloalkyl, -OC(O)OCH2CH2OEt, -OC(O)O(CH2CH2O)2Et, -OC(O)O(CH2CH2O)3Et, -OC(O)O(CH2CH2O)3CH2CH2OP(O)(OH)2, -OC(O)OCH2CH2SMe, -OC(O)OCH2CH2S(O)Me, -OC(O)OCH2CH2S(O)2Me, -OC(O)OCH2heteroaryl, -OC(O)OCH2heterocycloalkyl, -OC (O)OCH2CH2OCH2aryl-OC(O)OCH2CH2C(O)NMe2、-OC(O)O(CH2)6NH2、-OC(O)O(CH2)6NMe2、-OC(O)OCH(CH2OEt)2、-OC(O)NHCH2CH2OMe、-OC(O)NMeCH2CH2OMe、-SMe、-S(O)Me、-P(O)(OH)2、-OP(O)(OH)2、-C(O)NMe2、-C(O)heterocycloalkyl、heteroaryl、heterocycloalkyl、-N + (Me)3, -N + (Me)2 cycloalkyl, N-methylmorpholine Cation, N-methylpiperidine Cation and N-methylimidazole cation.

[1128] 24. The compound of clause 23, wherein R 9 It is -C(O)O(C1-C6 alkyl), wherein the C1-C6 alkyl is substituted by one or more groups selected from -O(CO)C(CH3)3, -OC(O)CH2CH2OH, -OC(O)C(CH3)2OH, -OC(O)heterocycloalkyl, -OC(O)CH2OCH2CH2OMe, -OC(O)OiPr, -OC(O)Ocycloalkyl, -OC(O)O(CH2CH2O)2Et, -OP(O)(OH)2, heteroaryl or heterocycloalkyl.

[1129] 25. The compound of clause 24, wherein R 9-C(O)OCH2OC(O)C(CH3)3, -C(O)OCH2OC(O)CH2CH2OH, -C(O)OCH2OC(O)C(CH3)2OH, -C(O)OCH2OC(O)piperidine, -C(O)OCH2OC(O)CH2OCH2CH2OMe, -C(O)OCH2OC(O)OiPr, -C(O)OCHMeOC(O)OiPr, -C(O)OCHMeOC(O)Ocyclohexyl, -C(O)OCHMeOC(O)O(CH2CH2O)2Et, -C(O)OCH2CH2OP(O)(OH)2, -C(O)OCH2(N-methylimidazole) cation), -C(O)OCH2(N-methylpiperidin cation), -C(O)OCH2 dioxolane, -C(O)OCH2CH2 morpholine, -C(O)OCH2CH2 piperazine, -C(O)OCH2CH2CH2 piperazine.

[1130] 26. The compound of any one of clauses 1 to 21, wherein R 9 is -C(O)O(CH2) p NMe2, -C(O)O(CH2) p NHMe, -C(O)OCH2CH(OH)CH2OH, C(O)OCH2CH2CMe2OH or -C(O)OCH2CH2SO2Me, wherein each p is independently 2, 3, 4, 5 or 6.

[1131] 27. The compound of clause 26, wherein R 9 It is -C(O)OCH2CH2NMe2, -C(O)OCH2CH(OH)CH2OH or -C(O)OCH2CH2SO2Me.

[1132] 28. A compound according to any one of the preceding clauses, wherein R 11 For Cl.

[1133] 29. The compound of any one of the preceding clauses, wherein R 13 For F.

[1134] 30. The compound of clause 1, which is selected from:

[1135]

[1136]

[1137]

[1138] 31. The compound of clause 30, which is selected from:

[1139]

[1140]

[1141] 32. The compound of clause 30, which is selected from:

[1142]

[1143] 33. The compound of clause 30, which is selected from:

[1144]

[1145] 34. The compound of any of the preceding clauses, wherein, unless otherwise specified, each alkyl, alkenyl, alkynyl, aryl, heteroaryl, and benzyl group is unsubstituted.

[1146] 35. Compounds of formula (I)

[1147] [MCL-1 ligand prodrug moiety]-[linker]-[ligase ligand moiety] (I) or a salt, solvate, hydrate or isomer thereof,

[1148] Wherein, [ligase ligand part] is:

[1149] (a) Formula (IV):

[1150]

[1151] in:

[1152] Each of X1 and X2 is independently O or S;

[1153] Each of Q1 and Q2 is independently N or CR 5 , wherein at least one of Q1 and Q2 is N;

[1154] Each of E1, E2, E3 and E4 is independently N or CR';

[1155] n is 0, 1, or 2;

[1156] 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 2or-S(O)2R b ;

[1157] Each R5 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)2NR b 2. -OR 21 、-NH-R 21 、-C(O)-NH-R 21 or -CH2-NH-C(O)-R 21 ;

[1158] Each R' is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR b 、-NR b 2. -NR b C(O)R b 、-NR b C(O)OR b 、-NO2、-CN、-C(O)R b 、-C(O)OR b 、-C(O)NH2、-C(O)NHR b 、-C(O)NR b 2. -C(O)NHCHR b 2. -CHR b NHC(O)NHR b 、-CHR b NHC(O)C(Halogen)2R b 、-OR b 、-OC(O)Rb 、-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)2NR 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 ;

[1159] and

[1160] Each R b are independently hydrogen, alkyl, alkenyl, aryl, heteroaryl or benzyl;

[1161] Among them, R 21 is the R of the linking group 18 and wherein Formula (IV) comprises a single R 21 ;

[1162] (b) Formula (VIIa), Formula (VIIb) or Formula (VIIc)

[1163]

[1164] in:

[1165] Each of X1 and X2 is independently O or S;

[1166] Each of Q1 and Q2 is independently N or CR, wherein at least one of Q1 and Q2 is N;

[1167] Each of W1, W2 and W3 is independently N or CR a ;

[1168] Z is O, S or NR e ;

[1169] n is 0, 1, or 2;

[1170] L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)R b 、-C(O)ORb 、-C(O)NH2、-C(O)NHR b 、-C(O)NR b 2. -OR b 、-NR b 2or-S(O)2R b ;

[1171] 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)2NR 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 ;

[1172] 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)2NR 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 ;as well as

[1173] 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 ;

[1174] Each R b are independently hydrogen, alkyl, alkenyl, aryl, heteroaryl or benzyl;

[1175] Among them, R 21 is the R of the linking group 18 and wherein each of Formula (VIIa), Formula (VIIb) and Formula (VIIc) contains a single R 21 ;

[1176] (c) Formula (VIII):

[1177]

[1178] in

[1179] Each of X1 and X2 is independently O or S;

[1180] n is 0, 1, or 2;

[1181] 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 2or-S(O)2R b ;

[1182] Each of R1, R2 and R3 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)2NR 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 ;as well as

[1183] Each R b are independently hydrogen, alkyl, alkenyl, aryl, heteroaryl or benzyl;

[1184] Among them, R 21 is the R of the linking group 18 and wherein Formula (VIII) comprises a single R 21 ;or

[1185] (d) Formula (IX):

[1186]

[1187] in,

[1188] Each of X1 and X2 is independently O or S;

[1189] 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 2or-S(O)2R b ;

[1190] Each of Q1, Q2, Q3, Q4 and Q5 is independently N or CR, wherein at least one of Q1, Q2, Q3, Q4 and Q5 is N;

[1191] 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 , or -S(O)2NR 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 ;as well as

[1192] Each R b are independently hydrogen, alkyl, alkenyl, aryl, heteroaryl or benzyl;

[1193] Among them, R 21 is the R of the linking group 18 The bond is connected, and wherein Formula (IX) contains a single R 21 ;

[1194] Wherein, [MCL-1 ligand prodrug moiety] is:

[1195]

[1196] in:

[1197] R 11 It is a halogen;

[1198] R 13 It is a halogen;

[1199] R 19 is the R of the linking group 14 connected keys;

[1200] and

[1201] (i)R 9 is -C(O)O(C1-C6 alkyl), -C(O)O cycloalkyl, -C(O)O heterocycloalkyl, -C(O)O aryl or -P(O)(OR p ) 2, wherein the C1-C6 alkyl group is substituted by one or more groups selected from the following: -OC(O) (unsubstituted C1-C6 alkyl), -OC(O) (substituted by at least one R 10 substituted C1-C6 alkyl), -OC(O)cycloalkyl, -OC(O)heterocycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, -OC(O)(CH2) m O(CH2) m O(unsubstituted C1-C6 alkyl), -OC(O)(CH2) m O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(unsubstituted C1-C6 alkyl), -OC(O)O(substituted by at least one R 10 Substituted C1-C6 alkyl), -OC(O)O cycloalkyl, -OC(O)O(CH2CH2O) m(unsubstituted C1-C6 alkyl), -OC(O)O(CH2CH2O) m (C1-C6 alkyl substituted with OP(O)(OH)2), -OC(O)O(CH2CH2S) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)(unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)2(unsubstituted C1-C6 alkyl), -OC(O)NH(C1-C6 alkyl substituted by OMe), -OC(O)NMe(C1-C6 alkyl substituted by OMe), -P(O)(OH)2, -OP(O)(OH)2, -C(O)heterocycloalkyl, -C(O)N(unsubstituted C1-C6 alkyl)2, heteroaryl, heterocycloalkyl, -S(unsubstituted C1-C6 alkyl), -S(O)(unsubstituted C1-C6 alkyl), -N + (unsubstituted C1-C6 alkyl)3, -N + (Unsubstituted C1-C6 alkyl)2-cycloalkyl, N-(unsubstituted C1-C6 alkyl)piperidine Cation, N-(unsubstituted C1-C6 alkyl)morpholine Cation and N-(unsubstituted C1-C6 alkyl) imidazole cation;

[1202] Among them, each R 10 are independently -OH, -O(unsubstituted C1-C6 alkyl), -OBn, -NH2, -NMe2, -NHC(O)(unsubstituted C1-C6 alkyl), -NHC(O)O(unsubstituted C1-C6 alkyl), heterocycloalkyl, heteroaryl, aryl, -C(O)NMe2;

[1203] Each R p are independently -(CH2) m OC(O) (unsubstituted C1-C6 alkyl), and

[1204] Each m is independently 1, 2, 3 or 4;

[1205] or

[1206] (ii)R 9 is -C(O)O(CH2) p NMe2, -C(O)O(CH2) p NHMe, -C(O)OCH2CH(OH)CH2OH, -C(O)OCH2CH2CMe2OH, or -C(O)OCH2CH2SO2Me, wherein each p is independently 2, 3, 4, 5, or 6;

[1207] and wherein [linking group] has the formula:

[1208] R 14 -R 15 -R 16 -R 17 -R 18

[1209] in:

[1210] 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;

[1211] R 15 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 Alkyl-NH-, -C 1-6 Alkyl-N(C 1-6 alkyl)-, -cycloalkyl-NH-, -heterocycloalkyl-NH- or absent;

[1212] 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;

[1213] R 17 -CH2(C2H4-O) y 、-(C2H4-O) x 、-(C3H6-O) x or does not exist;

[1214] x is 1-10;

[1215] y is 2-10;

[1216] R 18 -C 1-6 Alkyl, cycloalkyl, -CH2-NH-C(O)-, heterocycloalkyl or absent;

[1217] where R 14 -R 18 At least one of exists.

[1218] 36. The compound of clause 35, wherein, unless otherwise specified, each alkyl, alkenyl, alkynyl, aryl, heteroaryl, and benzyl group is unsubstituted.

[1219] 37. The compound of clause 36, wherein 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)2NR 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 .

[1220] 38. The compound of clause 37, wherein each R b are independently hydrogen, alkyl, cycloalkyl or aryl.

[1221] 39. The compound of clause 38, wherein the aryl group is substituted with one or more groups selected from halogen, alkyl and O-haloalkyl, optionally wherein the halogen is Cl, the alkyl is methyl and the O-haloalkyl is O-CF3.

[1222] 40. The compound of any one of clauses 35-39, wherein one of E1, E2, E3, and E4 is N, and the remaining three of E1, E2, E3, and E4 are each CR'.

[1223] 41. The compound of clause 40, wherein:

[1224] (a) E1 is N, and E2, E3 and E4 are CR'; or

[1225] (b) E2 is N, and E1, E3 and E4 are CR'; or

[1226] (c) E3 is N, and E1, E2 and E4 are CR'; or

[1227] (d) E4 is N, and E1, E2, and E3 are CR'.

[1228] 42. The compound of any one of clauses 35-39, wherein E1, E2, E3 and E4 are each CR', optionally wherein E1, E2, E3 and E4 are each CH.

[1229] 43. The compound of clause 42, wherein three of E1, E2, E3 and E4 are CH, and one of E1, E2, E3 and E4 is C-halogen, C-alkyl, C-alkenyl, C-alkynyl, C-aryl, C-heteroaryl, C-benzyl, C-haloalkyl, C-haloalkenyl, C-NH2, C-NHR b 、C-NR b 2. C-NR b C(O)R b 、C-NR b C(O)OR b 、C-NO2、C-CN、CC(O)R b 、CC(O)OR b 、CC(O)NH2、CC(O)NHR b 、CC(O)NR b 2. CC(O)NHCHR b 2. C-CHR b NHC(O)NHR b 、C-CHR b NHC(O)C(Halogen)2R b 、C-OR b 、C-OC(O)R b 、C-OC(O)OR b 、C-OC(O)NH2、C-OC(O)NHR b 、C-OC(O)NR b 2. C-SR b 、CS(O)2R b 、CS(O)2OR b 、CS(O)2NH2、CS(O)2NHR b 、CS(O)2NR b 2. C-NHS(O)2R b 、-R21 、-OR 21 、-NH-R 21 、-C(O)-R 21 、-C(O)-NH-R 21 or -CH2-NH-C(O)-R 21 .

[1230] 44. The compound of clause 43, wherein:

[1231] (a) E2, E3 and E4 are each CH; or

[1232] (b) E1, E3 and E4 are each CH; or

[1233] (c) E1, E2 and E4 are each CH.

[1234] 45. The compound of any one of clauses 35-39, wherein two of E1, E2, E3, and E4 are N, and the remaining two of E1, E2, E3, and E4 are each CR'.

[1235] 46. ​​The compound of any one of clauses 35-39, wherein three of E1, E2, E3, and E4 are N, and the remaining one of E1, E2, E3, and E4 is CR'.

[1236] 47. The compound of any one of clauses 35-46, wherein one of W1, W2 and W3 is N, and the others of W1, W2 and W3 are CR a , optionally, wherein R a For H.

[1237] 48. The compound of any one of clauses 35-46, wherein W1, W2 and W3 are each CR a .

[1238] 49. The compound of any one of clauses 35-48, wherein W1 is C-NH2, C-NHR b or C-NR b 2, optionally C-NH2.

[1239] 50. The compound of any one of clauses 35-46, wherein W1, W2, and W3 are each N.

[1240] 51. The compound of any one of clauses 35-50, wherein Z is NH or N-alkyl, optionally NH or N-Me.

[1241] 52. The compound of any one of clauses 35-51, wherein, in Formula (IV), Formula (VIIa), Formula (VIIb) and Formula (VIIc):

[1242] (a) Q1 is N and Q2 is CR; or

[1243] (b) Q1 is N and Q2 is N; or

[1244] (c) Q1 is CR and Q2 is N, optionally, wherein Q1 is CH or C-alkyl, further optionally, wherein Q1 is CH or C-Me.

[1245] 53. The compound of any one of clauses 35-52, wherein, in formula (IX), one of Q1, Q2, Q3, Q4, and Q5 is N, and the remaining four of Q1, Q2, Q3, Q4, and Q5 are each CR.

[1246] 54. The compound of clause 53, wherein:

[1247] (a) Q1 is N; or

[1248] (b) Q2 is N; or

[1249] (c)Q3 is N.

[1250] 55. The compound of any one of clauses 35-52, wherein, in formula (IX), two of Q1, Q2, Q3, Q4, and Q5 are N, and the remaining three of Q1, Q2, Q3, Q4, and Q5 are each CR.

[1251] 56. The compound of clause 55, wherein:

[1252] (a) Q1 and Q2 are N, and Q3, Q4, and Q5 are each CR; or

[1253] (b) Q2 and Q3 are N, and Q1, Q4, and Q5 are each CR; or

[1254] (c) Q1 and Q3 are N, and Q2, Q4, and Q5 are each CR; or

[1255] (d) Q2 and Q4 are N, and Q1, Q3, and Q5 are each CR; or

[1256] (e) Q1 and Q4 are N, and Q2, Q3, and Q5 are each CR.

[1257] 57. The compound of any one of clauses 35-52, wherein, in formula (IX), three of Q1, Q2, Q3, Q4, and Q5 are N, and the remaining two of Q1, Q2, Q3, Q4, and Q5 are each CR.

[1258] 58. Compounds of formula (I)

[1259] [MCL-1 ligand prodrug moiety]-[linker]-[ligase ligand moiety] (I) or a salt, solvate, hydrate or isomer thereof,

[1260] Wherein, [ligase ligand part] is:

[1261] (a) Formula (Va) or Formula (Vb):

[1262]

[1263] or a pharmaceutically acceptable salt or isomer thereof,

[1264] in

[1265] Each of X1 and X2 is independently O or S;

[1266] Z1 is O, S or NR 6 ;

[1267] T is C=O or SO2;

[1268] R 1 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl;

[1269] Each of Y5, Y6, Y7 and Y8 is independently N or CR 7 ,

[1270] wherein 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 ;

[1271] n is 0, 1, or 2;

[1272] 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", -OR", -NR", or -S(O)2R";

[1273] Each R 7are independently hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR", -NR", -CH2NR", -NR", C(O)R", -NR", C(O)CH2NR", -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 ;

[1274] each R"" is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl;

[1275] R 6 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR", -NR", -NR", -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)N HR"", -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 ;

[1276] Among them, R 21 is the R of the linking group 18and wherein Formula (Va) and Formula (Vb) each contain a single R 21 ;

[1277] Among them, when Z1 is O, then Y6 is CR 7 ,and

[1278] Wherein, when the compound is a compound of formula (Va), then

[1279] (i) When each of Y5, Y6 and Y7 is CR 7 When at least one R 7 Not H;

[1280] (ii) When Z1 is NR 6 When Y6 and Y7 are CR 7 ;

[1281] (iii) when Z1 is S, then Y5 is not C-OMe and Y6 is not C-OMe;

[1282] (iv) when Z1 is S and Y5 is C-NHCOMe, then Y7 is not C-CH2NR""C(O)OR"";

[1283] (v) when Z1 is S and Y5 is N, then Y6 is not CH, C-aryl or CC(O)OR""; and

[1284] (vi) when Z1 is S and Y6 is N, then Y7 is C-NH2, C-NHR", C-NR", C-NR""2, C-NR""C(O)OR", C-CH2NR""C(O)OR"", C-haloalkyl, C-tert-butyl, C-OR", C-COOR"" or C-SR""; wherein, when Y7 is C-NH2, C-NHR"" or C-NR""2, then Y5 is CH;

[1285] And when the compound is a compound of formula (Vb), then:

[1286] (vii) When each of Y5, Y6 and Y8 is CR 7 When at least one R 7 Not H;

[1287] (viii) when Z1 is S, then Y5 is not C-COOH or C-NHC(O)Me, and Y8 is not C-Br;

[1288] (ix) When Z1 is S and Y6 is C-Br, then Y8 is C-OR"";

[1289] (x) When Z1 is S, Y5 is N and Y6 is CH or C-NH2, then Y8 is not CH;

[1290] (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 When Y5, Y6 and Y8 are CR 7 ;

[1291] or

[1292] (b) Formula (IIa) or (IIb):

[1293]

[1294] in

[1295] Each of X1 and X2 is independently O or S;

[1296] Z is O, S or NR 2 ;

[1297] T is C=O or SO2;

[1298] Y3 is N or CR;

[1299] Y4 is N or CR;

[1300] represents a single bond or a double bond, where:

[1301] When each When a double bond is present, each of W1, W2, W3 and W4 is independently N or CR a , wherein at least one of W1, W2, W3 and W4 is N, and

[1302] When each When it is a single bond, W1, W2, W3 and W4 are each CR a 2, and Y4 is CR;

[1303] n is 0, 1, or 2;

[1304] 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 2or-S(O)2R h ;

[1305] Each R is independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR h 、-NR h 2. -NR h C(O)R h 、-NR h C(O)CH2R h 、-NR h C(O)CH(OH)R h 、-NR h C(O)OR h 、-NR h SO2R h 、-NO2、-CN、-C(O)R h 、-C(O)OR h 、-C(O)NH2、-C(O)NHR h 、-C(O)NR h 2. -OR h 、-OC(O)R h 、-OC(O)OR h 、-OC(O)NH2、-OC(O)NHR h 、-OC(O)NR h 2. -SR h , or -S(O)2R h 、-S(O)2OR h 、-S(O)2NH2、-S(O)2NHR h , or -S(O)2NR h 2;

[1306] 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. -ORh 、-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)2NR h 2. -OR 21 、-NH-R 21 、-C(O)-NH-R 21 or -CH2-NH-C(O)-R 21 ;

[1307] Each R h is independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl;

[1308] 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 , or -S(O)2R h 、-S(O)2OR h 、-S(O)2NH2、-S(O)2NHR h , or -S(O)2NR h 2; and

[1309] R 1is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl;

[1310] R 21 is the R of the linking group 18 wherein Formula (IIa) and Formula (IIb) each contain a single R 21 ;

[1311] Among them, when each is a double bond, Z is NR 2 , R 2 is hydrogen, and each R a When it is hydrogen, W4 is CR a ;

[1312] Wherein, [MCL-1 ligand prodrug moiety] is:

[1313]

[1314] in:

[1315] R 11 It is a halogen;

[1316] R 13 It is a halogen;

[1317] R 19 is the R of the linking group 14 connected keys;

[1318] and

[1319] (i)R 9 is -C(O)O(C1-C6 alkyl), -C(O)O cycloalkyl, -C(O)O heterocycloalkyl, -C(O)O aryl or -P(O)(OR p ) 2, wherein the C1-C6 alkyl group is substituted by one or more groups selected from the following: -OC(O) (unsubstituted C1-C6 alkyl), -OC(O) (substituted by at least one R 10 substituted C1-C6 alkyl), -OC(O)cycloalkyl, -OC(O)heterocycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, -OC(O)(CH2) m O(CH2) m O(unsubstituted C1-C6 alkyl), -OC(O)(CH2) m O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(unsubstituted C1-C6 alkyl), -OC(O)O(substituted by at least one R 10 Substituted C1-C6 alkyl), -OC(O)O cycloalkyl, -OC(O)O(CH2CH2O)m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2CH2O) m (C1-C6 alkyl substituted with OP(O)(OH)2), -OC(O)O(CH2CH2S) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)(unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)2(unsubstituted C1-C6 alkyl), -OC(O)NH(C1-C6 alkyl substituted by OMe), -OC(O)NMe(C1-C6 alkyl substituted by OMe), -P(O)(OH)2, -OP(O)(OH)2, -C(O)heterocycloalkyl, -C(O)N(unsubstituted C1-C6 alkyl)2, heteroaryl, heterocycloalkyl, -S(unsubstituted C1-C6 alkyl), -S(O)(unsubstituted C1-C6 alkyl), -N + (unsubstituted C1-C6 alkyl)3, -N + (Unsubstituted C1-C6 alkyl)2-cycloalkyl, N-(unsubstituted C1-C6 alkyl)piperidine Cation, N-(unsubstituted C1-C6 alkyl)morpholine Cation and N-(unsubstituted C1-C6 alkyl) imidazole cation;

[1320] Among them, each R 10 are independently -OH, -O(unsubstituted C1-C6 alkyl), -OBn, -NH2, -NMe2, -NHC(O)(unsubstituted C1-C6 alkyl), -NHC(O)O(unsubstituted C1-C6 alkyl), heterocycloalkyl, heteroaryl, aryl, -C(O)NMe2;

[1321] Each R p are independently -(CH2) m OC(O) (unsubstituted C1-C6 alkyl), and

[1322] Each m is independently 1, 2, 3 or 4;

[1323] or

[1324] (ii)R 9 is -C(O)O(CH2) p NMe2, -C(O)O(CH2) pNHMe, -C(O)OCH2CH(OH)CH2OH, -C(O)OCH2CH2CMe2OH, or -C(O)OCH2CH2SO2Me, wherein each p is independently 2, 3, 4, 5, or 6;

[1325] and wherein [linking group] has the formula:

[1326] R 14 -R 15 -R 16 -R 17 -R 18

[1327] in:

[1328] 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;

[1329] R 15 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 Alkyl-NH-, -C 1-6 Alkyl-N(C 1-6 alkyl)-, -cycloalkyl-NH-, -heterocycloalkyl-NH- or absent;

[1330] 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;

[1331] R 17 -CH2(C2H4-O) y 、-(C2H4-O) x 、-(C3H6-O) x or does not exist;

[1332] x is 1-10;

[1333] y is 2-10;

[1334] R 18 -C 1-6 Alkyl, cycloalkyl, -CH2-NH-C(O)-, heterocycloalkyl or absent;

[1335] where R 14 -R 18At least one of exists.

[1336] 59. The compound of clause 58, wherein, unless otherwise specified, each alkyl, alkenyl, alkynyl, aryl, heteroaryl, and benzyl group is unsubstituted.

[1337] 60. The compound of any one of clauses 58-59, wherein, when Z1 in formula (Vb) is S, then Y5 is not C-NHC(O)R"" or -C(O)OR"".

[1338] 61. The compound of any one of clauses 58-60, wherein Z1 is NR 6 .

[1339] 62. The compound of any one of clauses 58-61, wherein each R is independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR", -NR""2, -NR""C(O)R", -NR""C(O)CH(OH)R", -NR""C(O)OR", -NR""S2R", -NO2, -CN, -C(O)R", -C(O)OR””, -C(O)NH2, -C(O)NHR””, -C(O)NR””2, -OR””, -OC(O)R””, -OC(O)OR””, -OC(O)NH2, -OC(O )NHR””, -OC(O)NR””2, -SR”” or -S(O)2R””, -S(O)2OR””, -S(O)2NH2, -S(O)2NHR””, -S(O)2NR””2, -OR 21 、-NH-R 21 、-C(O)-NH-R 21 or -CH2-NH-C(O)-R 21 .

[1340] 63. The compound of any one of clauses 58-62, wherein R 1 It's hydrogen.

[1341] 64. The compound of any one of clauses 58-63, wherein R 6 For hydrogen.

[1342] 65. The compound of any one of clauses 58-64, wherein [ligase ligand moiety] is a compound of formula (Va), and Y5, Y6, and Y7 are each CR 7 .

[1343] 66. The compound of clause 65, wherein:

[1344] Y5 is -C-NHC(O)R"",

[1345] Y6 is CH, and

[1346] Y7 is CH or CCl.

[1347] 67. The compound of clause 66, wherein:

[1348] L3 is hydrogen;

[1349] Z1 is S;

[1350] R 1 It is hydrogen;

[1351] T is C=O; and

[1352] Y7 is CH.

[1353] 68. The compound of any one of clauses 58-64, wherein the compound is of formula (Vb), and Y5, Y6, and Y8 are each CR 7 .

[1354] 69. The compound of clause 68, wherein:

[1355] L3 is hydrogen;

[1356] Z1 is S;

[1357] R 1 is H;

[1358] T is C=O;

[1359] Y5 is CH, C-OR", CCl, C-CN or C-NHC(O)R"";

[1360] Y6 is CH, CCl, C-alkyl, C-cycloalkyl or C-haloalkyl; and

[1361] Y8 is CH, C-OR", C-NHC(O)R", C-NHC(O)OR", C-NHR", C-NH2 or C-NHSO2R",

[1362] wherein, when Y5 is CCl, then Y6 is CH, C-alkyl, C-cycloalkyl or C-haloalkyl;

[1363] Optionally, wherein each R"" is independently alkyl, cycloalkyl, aryl or benzyl.

[1364] 70. The compound of clause 69, wherein:

[1365] Y5 is CH;

[1366] Y6 is CH or CCl; and

[1367] Y8 is C-OR"" or C-NH2, optionally C-OMe or C-NH2.

[1368] 71. The compound of any one of clauses 58 to 70, wherein:

[1369] (a) Z is NR 2 ;or

[1370] (b) Z is S.

[1371] 72. The compound of any one of clauses 58-71, wherein each For double bonds.

[1372] 73. The compound of any one of clauses 58-72, wherein L is hydrogen.

[1373] 74. The compound of clause 72 or 73, wherein one of W1, W2, W3 and W4 is N, and the remaining three of W1, W2, W3 and W4 are each CR a ; Optionally, wherein W4 is CR a .

[1374] 75. The compound of any one of clauses 58-72, wherein two of W1, W2, W3 and W4 are N, and the remaining two of W1, W2, W3 and W4 are each CR a .

[1375] 76. The compound of any one of clauses 58-72, wherein one of W1, W2, W3 and W4 is CR a , the remaining three of W1, W2, W3 and W4 are each N.

[1376] 77. The compound of any one of clauses 58-76, wherein each R is independently hydrogen, halogen, or -NR h C(O)R h .

[1377] 78. Compounds of formula (I)

[1378] [MCL-1 ligand prodrug moiety]-[linker]-[ligase ligand moiety] (I) or a salt, solvate, hydrate or isomer thereof,

[1379] Wherein [ligase ligand part] is:

[1380] (a) Formula (VIa) or Formula (VIb):

[1381]

[1382] in:

[1383] M is O, S or NH, or does not exist;

[1384] represents R connected to the linking group 18 ;

[1385] R 22 is hydrogen, halogen, -OMe, amino, heterocycloalkyl, or unsubstituted C1-C6 alkyl; and

[1386] L' is hydrogen, alkyl, benzyl, acetyl or pivaloyl;

[1387] (b) Formula (II):

[1388]

[1389] in:

[1390] Each of X1 and X2 is independently O or S;

[1391] T is C=O or SO2;

[1392] R 1 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl;

[1393] n is 0, 1, or 2;

[1394] 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 ;

[1395] R y Selected from

[1396]

[1397] in, Indicates connection to T,

[1398] Z3 is O, S or NR 3 ;

[1399] U is O, S, NR b or CR i 2;

[1400] Each of Y1, Y2 and Y3 is independently N or CR d ;

[1401] 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)2NR b 2. -OR 21 、-NH-R 21 、-C(O)-NH-R 21 or -CH2-NH-C(O)-R 21 ;

[1402] Each R i are independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHRb 、-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)2NR b 2;

[1403] 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 、-NRb 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)2NR b 2. -R 21 、-C(O)-NH-R 21 or -CH2-NH-C(O)-R 21 ;

[1404] Each R b are independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl or benzyl;

[1405] R 21 is the R of the linking group 18 The bond connected, wherein formula (II) contains a single R 21 ;

[1406] in:

[1407] (i) When R y for When Y 2 It's CR d ;as well as

[1408] (ii) When R y for When CR i R in 2 i It’s not hydrogen;

[1409] or

[1410] (c) Formula (III):

[1411]

[1412] in:

[1413] Each of X1 and X2 is independently O or S;

[1414] T is C=O or SO2;

[1415] R 1 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl;

[1416] n is 0, 1, or 2;

[1417] 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 ;

[1418] R x Selected from

[1419]

[1420] in, Indicates connection to T,

[1421] Z4 is O, S or NR 4 ;

[1422] V is CR f 2. NR 4 or S;

[1423] Each of G1, G2, G3 and G4 is independently N or CR c ;

[1424] Each of Y1 and Y2 is independently N or CR f ;

[1425] 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, -NH2, -NHR b 、-NR b 2. -NHC(O)Rb 、-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)2NR b 2. -R 21 、-OR 21 、-NH-R 21 、-C(O)-NH-R 21 or -CH2-NH-C(O)-R 21 ; or when Y1 and Y2 are CR f When each R f Together with the carbon atom to which it is attached, it forms a 5-membered or 6-membered ring;

[1426] Each R c are independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, substituted by 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)Rb 、-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)2NR b 2. -OR 21 、-NH-R 21 、-C(O)-NH-R 21 or -CH2-NH-C(O)-R 21 ;

[1427] 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 21or -CH2-NH-C(O)-R 21 ;as well as

[1428] Each R b are independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl or benzyl;

[1429] R 21 is the R of the linking group 18 The bond connected, wherein formula (III) contains a single R 21 ;

[1430] Among them, when n=2, each R c is hydrogen, and each of G1, G2, G3 and G4 is CR c When , C=X1 can be replaced by CH;

[1431] And among them:

[1432] (i) When R x for When Z4 is NH, L1 is hydrogen, -CH2C(O)OR b OR b ;

[1433] (ii) When R x for Z4 to NR 4 , Y1 is CR f , and when Y2 is N, then R 4 is not an alkyl group, and R 2 and at least one of R is not H;

[1434] (iii) When R x for Z4 to NR 4 , and Y1 and Y2 are CR f When , at least one of G1, G2 and G3 is N;

[1435] (iv) When Z4 is NR 4 , and Y1 and Y2 are CR f When R x no

[1436] (v) When R x for Z4 to NR 4 , and when Y1 or Y2 is N, then R 4 Not an alkyl group;

[1437] (vi) When R x for When , n = 1 or 2; and

[1438] (vii) When R x for When Z4=O or S;

[1439] Wherein, [MCL-1 ligand prodrug moiety] is:

[1440]

[1441] in:

[1442] R 11 It is a halogen;

[1443] R 13 It is a halogen;

[1444] R 19 is the R of the linking group 14 connected keys;

[1445] and

[1446] (i)R 9 is -C(O)O(C1-C6 alkyl), -C(O)O cycloalkyl, -C(O)O heterocycloalkyl, -C(O)O aryl or -P(O)(OR p ) 2, wherein the C1-C6 alkyl group is substituted by one or more groups selected from the following: -OC(O) (unsubstituted C1-C6 alkyl), -OC(O) (substituted by at least one R 10 substituted C1-C6 alkyl), -OC(O)cycloalkyl, -OC(O)heterocycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, -OC(O)(CH2) m O(CH2) m O(unsubstituted C1-C6 alkyl), -OC(O)(CH2) m O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(unsubstituted C1-C6 alkyl), -OC(O)O(substituted by at least one R 10 Substituted C1-C6 alkyl), -OC(O)O cycloalkyl, -OC(O)O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2CH2O) m (C1-C6 alkyl substituted with OP(O)(OH)2), -OC(O)O(CH2CH2S) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)(unsubstituted C1-C6 alkyl), -OC(O)O(CH2) mS(O)2(unsubstituted C1-C6 alkyl), -OC(O)NH(C1-C6 alkyl substituted by OMe), -OC(O)NMe(C1-C6 alkyl substituted by OMe), -P(O)(OH)2, -OP(O)(OH)2, -C(O)heterocycloalkyl, -C(O)N(unsubstituted C1-C6 alkyl)2, heteroaryl, heterocycloalkyl, -S(unsubstituted C1-C6 alkyl), -S(O)(unsubstituted C1-C6 alkyl), -N + (unsubstituted C1-C6 alkyl)3, -N + (Unsubstituted C1-C6 alkyl)2-cycloalkyl, N-(unsubstituted C1-C6 alkyl)piperidine Cation, N-(unsubstituted C1-C6 alkyl)morpholine Cation and N-(unsubstituted C1-C6 alkyl) imidazole cation;

[1447] Among them, each R 10 are independently -OH, -O(unsubstituted C1-C6 alkyl), -OBn, -NH2, -NMe2, -NHC(O)(unsubstituted C1-C6 alkyl), -NHC(O)O(unsubstituted C1-C6 alkyl), heterocycloalkyl, heteroaryl, aryl, -C(O)NMe2;

[1448] Each R p are independently -(CH2) m OC(O) (unsubstituted C1-C6 alkyl), and

[1449] Each m is independently 1, 2, 3 or 4;

[1450] or

[1451] (ii)R 9 is -C(O)O(CH2) p NMe2, -C(O)O(CH2) p NHMe, -C(O)OCH2CH(OH)CH2OH, -C(O)OCH2CH2CMe2OH, or -C(O)OCH2CH2SO2Me, wherein each p is independently 2, 3, 4, 5, or 6;

[1452] and wherein [linking group] has the formula:

[1453] R 14 -R 15 -R 16 -R 17 -R 18

[1454] in:

[1455] 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;

[1456] R 15 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 Alkyl-NH-, -C 1-6 Alkyl-N(C 1-6 alkyl)-, -cycloalkyl-NH-, -heterocycloalkyl-NH- or absent;

[1457] 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;

[1458] R 17 -CH2(C2H4-O) y 、-(C2H4-O) x 、-(C3H6-O) x or does not exist;

[1459] x is 1-10;

[1460] y is 2-10;

[1461] R 18 -C 1-6 Alkyl, cycloalkyl, -CH2-NH-C(O)-, heterocycloalkyl or absent; wherein R 14 -R 18 At least one of exists.

[1462] 79. The compound of clause 78, wherein, unless otherwise specified, each alkyl, alkenyl, alkynyl, aryl, heteroaryl, and benzyl group is unsubstituted.

[1463] 80. The compound of any one of clauses 78-79, wherein in formula (III):

[1464] Each of X1 and X2 is 0;

[1465] T is C=O;

[1466] R 1 It's hydrogen,

[1467] L1 is hydrogen,

[1468] R x yes

[1469] Z4 to NR 4 ;

[1470] Each of G1, G2 and G4 is CR c ,

[1471] Y1 is N, and

[1472] Y2 is CR f , where R f Not hydrogen.

[1473] 81. The compound of any one of clauses 78 to 80, wherein [ligase ligand moiety] is of formula (III):

[1474]

[1475] 82. The compound of any one of clauses 78 to 81, wherein:

[1476] (a)R c One of -OR 21 、-NH-R 21 、-C(O)-NH-R 21 or -CH2-NH-C(O)-R 21 ;

[1477] (b) G1 is COR 21 、C-NH-R 21 、CC(O)-NH-R 21 or C-CH2-NH-C(O)-R 21 ;

[1478] (c) G2 is COR 21 、C-NH-R 21 、CC(O)-NH-R 21 or C-CH2-NH-C(O)-R 21 ;

[1479] (d)R 4 It is R 21 、-C(O)-NH-R 21 or -CH2-NH-C(O)-R 21 ;or

[1480] (e)R f One of them is -R 21 、-OR 21 、-NH-R 21 、-C(O)-NH-R21 or -CH2-NH-C(O)-R 21 .

[1481] 83. The compound of any one of clauses 78-81, wherein Y2 is CR 21 、CO-R 21 、C-NH-R 21 、CC(O)-NH-R 21 or C-CH2-NH-C(O)-R 21 .

[1482] 84. The compound of any one of clauses 78 to 83, wherein [ligase ligand moiety] is selected from:

[1483]

[1484]

[1485] 85. The compound of clause 84, wherein [ligase ligand moiety] is

[1486]

[1487] 86. The compound of any one of clauses 35-85, wherein R 14 -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C(O)-, -SO2- or absent.

[1488] 87. The compound of clause 86, wherein R 14 Yes-C 1-6 alkyl.

[1489] 88. The compound of any one of clauses 35-87, wherein R 15 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 Alkyl-NH-, -cycloalkyl-NH- or not present.

[1490] 89. The compound of clause 88, wherein R 15 It is a heterocycloalkyl group.

[1491] 90. The compound of clause 89, wherein R 15 is piperazine, bridged piperazine, piperazine N-oxide, piperazine cation,

[1492]

[1493] in, Indicates connection to R 14 , Indicates connection to R 16 .

[1494] 91. The compound of clause 90, wherein R 15 Is piperazine or

[1495] 92. The compound of any one of clauses 35-91, wherein R 16 Yes-C 1-6 Alkyl, -CH2-C(O)-NH- or -C(O)-.

[1496] 93. The compound of clause 92, wherein R 16 Yes-C 1-6 Alkyl or -C(O)-.

[1497] 94. The compound of any one of clauses 35-93, wherein R 17 Does not exist.

[1498] 95. The compound of any one of clauses 35-94, wherein R 18 -C 1-6 Alkyl, heterocycloalkyl or not present.

[1499] 96. The compound of clause 95, wherein R 18 Yes-C 1-6 Alkyl or heterocycloalkyl.

[1500] 97. The compound of clause 96, wherein R 18 Yes-C 1-6 Alkyl or piperazine.

[1501] 98. The compound of any one of clauses 35-97, wherein [Linking Group] is selected from:

[1502]

[1503] in:

[1504] represents attachment to [MCL-1 ligand prodrug moiety]; and

[1505] Indicates attachment to [ligase ligand moiety].

[1506] 99. The compound of any one of clauses 35-98, wherein R 9 is -C(O)O(C1-C6 alkyl), -C(O)O cycloalkyl, -C(O)O heterocycloalkyl, -C(O)O aryl or -P(O)(OR p) 2, wherein the C1-C6 alkyl group is substituted by one or more groups selected from the following: -OC(O) (unsubstituted C1-C6 alkyl), -OC(O) (substituted by at least one R 10 substituted C1-C6 alkyl), -OC(O)cycloalkyl, -OC(O)heterocycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, -OC(O)(CH2) m O(CH2) m O(unsubstituted C1-C6 alkyl), -OC(O)(CH2) m O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(unsubstituted C1-C6 alkyl), -OC(O)O(substituted by at least one R 10 Substituted C1-C6 alkyl), -OC(O)O cycloalkyl, -OC(O)O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2CH2O) m (C1-C6 alkyl substituted with OP(O)(OH)2), -OC(O)O(CH2CH2S) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)(unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)2(unsubstituted C1-C6 alkyl), -OC(O)NH(C1-C6 alkyl substituted by OMe), -OC(O)NMe(C1-C6 alkyl substituted by OMe), -P(O)(OH)2, -OP(O)(OH)2, -C(O)heterocycloalkyl, -C(O)N(unsubstituted C1-C6 alkyl)2, heteroaryl, heterocycloalkyl, -S(unsubstituted C1-C6 alkyl), -S(O)(unsubstituted C1-C6 alkyl), -N + (unsubstituted C1-C6 alkyl)3, -N + (Unsubstituted C1-C6 alkyl)2-cycloalkyl, N-(unsubstituted C1-C6 alkyl)piperidine Cation, N-(unsubstituted C1-C6 alkyl)morpholine cation and N-(unsubstituted C1-C6 alkyl)imidazolyl cation.

[1507] 100. The compound of clause 99, wherein R 9 is -C(O)O(C1-C6 alkyl), -C(O)O cycloalkyl, -C(O)O heterocycloalkyl, -C(O)O aryl or -P(O)(OR p) 2, wherein the C1-C6 alkyl group is substituted by one or more groups selected from the group consisting of: -OC(O)Me, -OC(O)Et, -OC(O) i Pr, -OC(O)C(CH3)3, -OC(O)CH2OH, -OC(O)CH(CH3)OH, -OC(O)C(CH3)2OH, -OC(O)CH2CH2OH, -OC(O)CH(OH)CHMe2, -OC(O)CH(OH)CH2CHMe2, -OC(O)CH2CH(OH)Me, -OC(O)CH2C(OH)Me2, -OC(O)CH(CH2OH)(NHC(O)Me), -OC(O)CH(NHC(O)Me)(isobutyl), -OC(O)CH(OH)aryl, -OC(O)CH(OH)CH2aryl, -OC(O)heterocycloalkyl, -OC(O)cycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, -OC(O)CH2CH2aryl, -OC(O)CH(NH2) i Pr, -OC(O)CH( i Pr)NHC(O)O t Bu, -OC(O)CH2OCH2CH2OMe, -OC(O)CH2(OCH2CH2)2OMe, -OC(O)OMe, -OC(O)OEt, -OC(O)O i Pr, -OC(O)Ocycloalkyl, -OC(O)OCH2CH2OEt, -OC(O)O(CH2CH2O)2Et, -OC(O)O(CH2CH2O)3Et, -OC(O)O(CH2CH2O)3CH2CH2OP(O)(OH)2, -OC(O)OCH2CH2SMe, -OC(O)OCH2CH2S(O)Me, -OC(O)OCH2CH2S(O)2Me, -OC(O)OCH2heteroaryl, -OC(O)OCH2heterocycloalkyl, -OC (O)OCH2CH2OCH2aryl-OC(O)OCH2CH2C(O)NMe2、-OC(O)O(CH2)6NH2、-OC(O)O(CH2)6NMe2、-OC(O)OCH(CH2OEt)2、-OC(O)NHCH2CH2OMe、-OC(O)NMeCH2CH2OMe、-SMe、-S(O)Me、-P(O)(OH)2、-OP(O)(OH)2、-C(O)NMe2、-C(O)heterocycloalkyl、heteroaryl、heterocycloalkyl、-N + (Me)3, -N + (Me)2 cycloalkyl, N-methylmorpholine Cation, N-methylpiperidine Cation and N-methylimidazole cation.

[1508] 101. The compound of clause 100, wherein R 9 It is -C(O)O(C1-C6 alkyl), and the C1-C6 alkyl is substituted by one or more groups selected from -O(CO)C(CH3)3, -OC(O)CH2CH2OH, -OC(O)C(CH3)2OH, -OC(O)heterocycloalkyl, -OC(O)CH2OCH2CH2OMe, -OC(O)OiPr, -OC(O)Ocycloalkyl, -OC(O)O(CH2CH2O)2Et, -OP(O)(OH)2, heteroaryl or heterocycloalkyl.

[1509] 102. The compound of clause 101, wherein R 9 It is -C(O)O(C1-C6 alkyl), wherein the C1-C6 alkyl is substituted by -O(CO)C(CH3)3.

[1510] 103. The compound of clause 101, wherein R 9 -C(O)OCH2OC(O)C(CH3)3, -C(O)OCH2OC(O)CH2CH2OH, -C(O)OCH2OC(O)C(CH3)2OH, -C(O)OCH2OC(O)piperidine, -C(O)OCH2OC(O)CH2OCH2CH2OMe, -C(O)OCH2OC(O)OiPr, -C(O)OCHMeOC(O)OiPr, -C(O)OCHMeOC(O)Ocyclohexyl, -C(O)OCHMeOC(O)O(CH2CH2O)2Et, -C(O)OCH2CH2OP(O)(OH)2, -C(O)OCH2(N-methylimidazole) cation), -C(O)OCH2(N-methylpiperidin cation), -C(O)OCH2 dioxolane, -C(O)OCH2CH2 morpholine, -C(O)OCH2CH2 piperazine, -C(O)OCH2CH2CH2 piperazine.

[1511] 104. The compound of clause 103, wherein R 9 It is -C(O)OCH2OC(O)C(CH3)3.

[1512] 105. The compound of any one of clauses 35-104, wherein [MCL-1 ligand prodrug moiety] is:

[1513]

[1514] 106. The compound of clause 78, wherein the compound is:

[1515]

[1516] 107. The compound of any one of the preceding clauses, wherein T is C=O.

[1517] 108. The compound of any one of the preceding clauses, wherein:

[1518] (a) X1 and X2 are O;

[1519] (b) X1 is O, X2 is S;

[1520] (c) X1 is S and X2 is O; or

[1521] (d) X1 and X2 are S.

[1522] 109. The compound of any one of the preceding clauses, wherein n is 0.

[1523] 110. The compound of any one of clauses 1-108, wherein n is 1 or 2.

[1524] 111. The compound of clause 110, wherein n is 1.

[1525] 112. The compound of clause 110, wherein n is 2.

[1526] 113. A pharmaceutical composition comprising a compound according to any one of clauses 1-112.

[1527] 114. A compound according to any one of clauses 1 to 112 or a pharmaceutical composition according to clause 113 for use in medicine.

[1528] 115. A compound according to any one of clauses 1 to 112 or a pharmaceutical composition according to clause 113 for use in treating cancer.

[1529] 116. The compound or pharmaceutical composition for use according to clause 115, wherein the cancer is selected from breast cancer, triple-negative breast cancer, colorectal cancer, pancreatic cancer, skin cancer, melanoma, ovarian cancer, kidney cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, lymphoma, non-Hodgkin lymphoma, multiple myeloma, cervical cancer, leukemia, chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), bladder cancer and prostate cancer.

[1530] 117. The compound or pharmaceutical composition for use according to clause 116, wherein the cancer is multiple myeloma or acute myeloid leukemia.

[1531] 118. A method for treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of clauses 1-112 or a pharmaceutical composition according to clause 113.

[1532] 119. The method of clause 118, wherein the cancer is selected from breast cancer, triple-negative breast cancer, colorectal cancer, pancreatic cancer, skin cancer, melanoma, ovarian cancer, renal cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, lymphoma, non-Hodgkin lymphoma, multiple myeloma, cervical cancer, leukemia, chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), bladder cancer, and prostate cancer.

[1533] 120. The method of clause 119, wherein the cancer is multiple myeloma or acute myeloid leukemia.

[1534] 121. The method of any one of clauses 118-120, wherein the administration does not result in cytotoxicity to cardiomyocytes of the subject.

[1535] 122. The method of any one of clauses 118-121, further comprising administering to the subject at least one additional active agent.

[1536] 123. The method of clause 122, wherein the at least one additional active agent is an anticancer agent selected from the group consisting of 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; pidilimumab; carfilzomib; venetoclax; cytarabine; anthracyclines; taxane compounds; and hypomethylating agents.

[1537] 124. A compound according to any one of clauses 1 to 112 or a pharmaceutical composition according to clause 112 for use in reversing resistance to chemotherapy or targeted cancer therapy.

[1538] 125. 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 according to any one of clauses 1-112 or a pharmaceutical composition according to clause 113.

[1539] 126. A combined preparation of a compound according to any one of clauses 1 to 112 and at least one additional active agent, for simultaneous, separate or sequential use in therapy.

[1540] 127. The combination preparation of clause 126, wherein the at least one additional active agent is an anticancer agent selected from the group consisting of 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; pidilimumab; carfilzomib; venetoclax; cytarabine; anthracyclines; taxane compounds; and a hypomethylating agent.

[1541] 128. The combined preparation of any one of clauses 126-127, wherein the therapy is the treatment of cancer.

[1542] 129. A method of reducing the cardiotoxicity of an MCL-1 inhibitor comprising coupling a cereblon binding moiety to the MCL-1 inhibitor, wherein the cereblon binding moiety is a [ligase ligand moiety] as defined in any one of clauses 1-112, and the MCL-1 inhibitor is a [MCL-1 ligand prodrug moiety] as defined in any one of clauses 1-112.

Claims

1. Compounds of formula (I) [MCL-1 ligand prodrug moiety]-linker-[ligase ligand moiety] (I) or a salt, solvate, hydrate or isomer thereof, in, [Ligase ligand part] is: in: M is O, S or NH, or does not exist; represents R connected to the linking group 18 ; R 22 is hydrogen, halogen, -OMe, amino, heterocycloalkyl, or unsubstituted C1-C6 alkyl; and R 29 is hydrogen or Me; L' is hydrogen, alkyl, benzyl, acetyl or pivaloyl; wherein [MCL-1 ligand prodrug moiety] is a compound of formula (A1), formula (A2), formula (A3) or formula (A4): in: is a single bond or a double bond; Each Z2 is independently N or C, wherein when Z2 is N, then is a single bond; when Z2 is C, is a double bond; Each R 11 are independently H, halogen or C1-C6 alkyl, R 8 is a C1-C6 alkyl group substituted with piperazine; In each of formula (A1) and formula (A4), R 10 and R 30 One of them is H, R 10 and R 30 The other one 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 tetrahydronaphthyl, wherein the phenyl, naphthyl or tetrahydronaphthyl is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl and -O(C1-C6 alkyl); or wherein the tetrahydronaphthyl is optionally substituted with a bridging -CH2- group; or wherein the naphthyl is optionally substituted with -O- or -S-, R 12 for R 31 Yes-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 tetrahydronaphthyl, wherein the phenyl, naphthyl or tetrahydronaphthyl is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl and -O(C1-C6 alkyl); or wherein the tetrahydronaphthyl is optionally substituted with a bridged -CH2- group; or wherein the naphthyl is optionally substituted with -O- or -S-; Each R 32 are independently H, Each R 33 Independently R 19 or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with morpholine or piperazine; R 20 Me, -CH2-OMe, -(CH2CH2O) p (C1-C6 alkyl) or -CH2-O-bromobenzaldehyde, wherein p is 1-5; R 34 It is C 2-5 Alkyl-OR 13 or -OC 2-5 Alkyl-R 13 , where R 13 is phenyl, naphthyl or tetrahydronaphthyl, wherein the phenyl, naphthyl or tetrahydronaphthyl is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl and -O(C1-C6 alkyl); or wherein the tetrahydronaphthyl is optionally substituted with a bridged -CH2- group; or wherein the naphthyl is optionally substituted with -O- or -S-; R 35 for R 19 is the R of the linking group 14 wherein each of Formula (A1), Formula (A2), Formula (A3) and Formula (A4) contains a single R 19 ; and (i)R 9 is -C(O)O(C1-C6 alkyl), -C(O)O cycloalkyl, -C(O)O heterocycloalkyl, -C(O)O aryl or -P(O)(OR p ) 2, wherein the C1-C6 alkyl group is substituted by one or more groups selected from the following: -OC(O) (unsubstituted C1-C6 alkyl), -OC(O) (substituted by at least one R 10 substituted C1-C6 alkyl), -OC(O)cycloalkyl, -OC(O)heterocycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, -OC(O)(CH2) m O(CH2) m O(unsubstituted C1-C6 alkyl), -OC(O)(CH2) m O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(unsubstituted C1-C6 alkyl), -OC(O)O(substituted by at least one R 10 Substituted C1-C6 alkyl), -OC(O)O cycloalkyl, -OC(O)O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2CH2O) m (C1-C6 alkyl substituted with OP(O)(OH)2), -OC(O)O(CH2CH2S) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)(unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)2(unsubstituted C1-C6 alkyl), -OC(O)NH(C1-C6 alkyl substituted by OMe), -OC(O)NMe(C1-C6 alkyl substituted by OMe), -P(O)(OH)2, -OP(O)(OH)2, -C(O)heterocycloalkyl, -C(O)N(unsubstituted C1-C6 alkyl)2, heteroaryl, heterocycloalkyl, -S(unsubstituted C1-C6 alkyl), -S(O)(unsubstituted C1-C6 alkyl), -N + (unsubstituted C1-C6 alkyl)3, -N + (Unsubstituted C1-C6 alkyl)2-cycloalkyl, N-(unsubstituted C1-C6 alkyl)piperidine Cation, N-(unsubstituted C1-C6 alkyl)morpholine Cation and N-(unsubstituted C1-C6 alkyl) imidazole cation; Among them, each R 10 are independently -OH, -O(unsubstituted C1-C6 alkyl), -OBn, -NH2, -NMe2, -NHC(O)(unsubstituted C1-C6 alkyl), -NHC(O)O(unsubstituted C1-C6 alkyl), heterocycloalkyl, heteroaryl, aryl, -C(O)NMe2; Each R p are independently -(CH2) m OC(O) (unsubstituted C1-C6 alkyl), and Each m is independently 1, 2, 3 or 4; or (ii)R 9 is -C(O)O(CH2) p NMe2, -C(O)O(CH2) p NHMe, -C(O)OCH2CH(OH)CH2OH, -C(O)OCH2CH2CMe2OH, or -C(O)OCH2CH2SO2Me, wherein each p is independently 2, 3, 4, 5, or 6; and wherein [linking group] has the formula: R 14 -R 15 -R 16 -R 17 -R 18 in: 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 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 -CH2(C2H4-O) y 、-(CH2O) x 、-(C2H4-O) x 、-(C3H6-O) x or does not exist; x is 1-10; y is 2-10; R 18 -C 1-6 Alkyl, -C 1-6 Alkyl-C(O)-, cycloalkyl, -CH2-NH-C(O)-, heterocycloalkyl or absent; where R 14 -R 18 At least one of exists.

2. The compound of claim 1, wherein [ligase ligand moiety] is:

3. The compound of claim 1, wherein [ligase ligand moiety] is:

4. The compound of claim 3, wherein [ligase ligand moiety] is:

5. A compound according to any one of the preceding claims, wherein R 22 For hydrogen.

6. A compound according to any one of the preceding claims, wherein L' is hydrogen.

7. A compound according to any one of the preceding claims, wherein M is O or NH, or is absent.

8. The compound of any one of claims 1-2 and 4-7, wherein [ligase ligand moiety] is 9. The compound of claim 8, wherein [ligase ligand moiety] is:

10. The compound of any one of the preceding claims, wherein: (a) [Ligase ligand moiety] is: or (b) [Ligase ligand moiety] is: or (c) [ligase ligand moiety] is:

11. The compound of any one of the preceding claims, wherein: (a) [Ligase ligand portion] is or (b) [Ligase ligand moiety] is:

12. The compound of any one of the preceding claims, wherein: 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 does not exist; R 18 Yes-C 1-6 Alkyl, cycloalkyl, -CH2-NH-C(O)-, heterocycloalkyl or absent.

13. A compound according to any one of the preceding claims, wherein R 14 -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C(O)-, -SO2- or absent.

14. The compound of claim 13, wherein R 14 Yes-C 1-6 alkyl.

15. A compound according to any one of the preceding claims, wherein R 15 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 Alkyl-NH-, -cycloalkyl-NH- or not present.

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

17. The compound of claim 16, wherein R 15 is piperazine, bridged piperazine, piperazine N-oxide, piperazine cation, in, Indicates connection to R 14 , Indicates connection to R 16 .

18. The compound of claim 17, wherein R 15 Is piperazine or 19. The compound of claim 15, wherein R 15 Does not exist.

20. A compound according to any one of the preceding claims, wherein R 16 Yes-C 1-6 Alkyl, -CH2-C(O)-NH- or -C(O)-.

21. The compound of claim 20, wherein R 16 Yes-C 1-6 Alkyl or -C(O)-.

22. A compound according to any one of the preceding claims, wherein R 17 Does not exist.

23. A compound according to any one of the preceding claims, wherein R 18 -C 1-6 Alkyl, heterocycloalkyl or not present.

24. The compound of claim 23, wherein R 18 Yes-C 1-6 Alkyl or heterocycloalkyl, optionally -C 1-6 Alkyl or piperazine.

25. The compound of claim 23, wherein R 18 Does not exist.

26. The compound of any one of the preceding claims, wherein [Linking Group] is selected from: in represents attachment to [MCL-1 ligand prodrug moiety]; as well as indicates attachment to [ligase ligand moiety]; Optionally, wherein [linking group] is selected from: in: represents attachment to [MCL-1 ligand prodrug moiety]; and Indicates attachment to [ligase ligand moiety].

27. A compound according to any one of the preceding claims, wherein In each of formula (A1) and formula (A4), R 10 and R 30 One of them is H, R 10 and R 30 The other one is -C 2-5 Alkyl-OR 13 or -OC 2-5 Alkyl-R 13 , where R 13 is phenyl or naphthyl, wherein the phenyl or naphthyl is optionally substituted with at least one substituent selected from halogen and C1-C6 alkyl.

28. The compound of any one of the preceding claims, wherein in formula (A1), R 12 for 29. A compound according to any one of the preceding claims, wherein in formula (A4), R 35 for 30. A compound according to any one of the preceding claims, wherein in formula (A2), R 31 -C 2-5 Alkyl-OR 13 or -OC 2-5 Alkyl-R 13 , where R 13 is phenyl or naphthyl, wherein the phenyl or naphthyl is optionally substituted with at least one substituent selected from halogen and C1-C6 alkyl.

31. A compound according to any one of the preceding claims, wherein in formula (A3), R 34 It is C 2-5 Alkyl-OR 13 or -OC 2-5 Alkyl-R 13 , where R 13 is phenyl or naphthyl, wherein the phenyl or naphthyl is optionally substituted with at least one substituent selected from halogen and C1-C6 alkyl.

32. A compound according to any one of the preceding claims, wherein Z2 is C and For double bonds.

33. The compound of any one of the preceding claims, wherein [MCL-1 ligand prodrug moiety] is: in: R 11 It is a halogen; R 13a is a halogen; and R 20 is Me, -CH2-OMe or -(CH2CH2O) p (C1-C6 alkyl), wherein p is 1-5.

34. A compound according to any one of the preceding claims, wherein R 9 is -C(O)O(C1-C6 alkyl), -C(O)O cycloalkyl, -C(O)O heterocycloalkyl, -C(O)O aryl or -P(O)(OR p ) 2, wherein the C1-C6 alkyl group is substituted by one or more groups selected from the following: -OC(O) (unsubstituted C1-C6 alkyl), -OC(O) (substituted by at least one R 10 substituted C1-C6 alkyl), -OC(O)cycloalkyl, -OC(O)heterocycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, -OC(O)(CH2) m O(CH2) m O(unsubstituted C1-C6 alkyl), -OC(O)(CH2) m O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(unsubstituted C1-C6 alkyl), -OC(O)O(substituted by at least one R 10 Substituted C1-C6 alkyl), -OC(O)O cycloalkyl, -OC(O)O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2CH2O) m (C1-C6 alkyl substituted with OP(O)(OH)2), -OC(O)O(CH2CH2S) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)(unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)2(unsubstituted C1-C6 alkyl), -OC(O)NH(C1-C6 alkyl substituted by OMe), -OC(O)NMe(C1-C6 alkyl substituted by OMe), -P(O)(OH)2, -OP(O)(OH)2, -C(O)heterocycloalkyl, -C(O)N(unsubstituted C1-C6 alkyl)2, heteroaryl, heterocycloalkyl, -S(unsubstituted C1-C6 alkyl), -S(O)(unsubstituted C1-C6 alkyl), -N + (unsubstituted C1-C6 alkyl)3, -N + (Unsubstituted C1-C6 alkyl)2-cycloalkyl, N-(unsubstituted C1-C6 alkyl)piperidine Cation, N-(unsubstituted C1-C6 alkyl)morpholine cation and N-(unsubstituted C1-C6 alkyl)imidazolyl cation.

35. The compound of claim 34, wherein R 9 is -C(O)O(C1-C6 alkyl), -C(O)O cycloalkyl, -C(O)O heterocycloalkyl, -C(O)O aryl or -P(O)(OR p ) 2, wherein the C1-C6 alkyl group is substituted by one or more groups selected from the group consisting of: -OC(O)Me, -OC(O)Et, -OC(O) i Pr, -OC(O)C(CH3)3, -OC(O)CH2OH, -OC(O)CH(CH3)OH, -OC(O)C(CH3)2OH, -OC(O)CH2CH2OH, -OC(O)CH(OH)CHMe2, -OC(O)CH(OH)CH2CHMe2, -OC(O)CH2CH(OH)Me, -OC(O)CH2C(OH)Me2, -OC(O)CH(CH2OH)(NHC(O)Me), -OC(O)CH(NHC(O)Me)(isobutyl), -OC(O)CH(OH)aryl, -OC(O)CH(OH)CH2aryl, -OC(O)heterocycloalkyl, -OC(O)cycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, -OC(O)CH2CH2aryl, -OC(O)CH(NH2) i Pr, -OC(O)CH( i Pr)NHC(O)O t Bu, -OC(O)CH2OCH2CH2OMe, -OC(O)CH2(OCH2CH2)2OMe, -OC(O)OMe, -OC(O)OEt, -OC(O)O i Pr, -OC(O)Ocycloalkyl, -OC(O)OCH2CH2OEt, -OC(O)O(CH2CH2O)2Et, -OC(O)O(CH2CH2O)3Et, -OC(O)O(CH2CH2O)3CH2CH2OP(O)(OH)2, -OC(O)OCH2CH2SMe, -OC(O)OCH2CH2S(O)Me, -OC(O)OCH2CH2S(O)2Me, -OC(O)OCH2heteroaryl, -OC(O)OCH2heterocycloalkyl, -OC (O)OCH2CH2OCH2aryl-OC(O)OCH2CH2C(O)NMe2、-OC(O)O(CH2)6NH2、-OC(O)O(CH2)6NMe2、-OC(O)OCH(CH2OEt)2、-OC(O)NHCH2CH2OMe、-OC(O)NMeCH2CH2OMe、-SMe、-S(O)Me、-P(O)(OH)2、-OP(O)(OH)2、-C(O)NMe2、-C(O)heterocycloalkyl、heteroaryl、heterocycloalkyl、-N + (Me)3, -N + (Me)2 cycloalkyl, N-methylmorpholine Cation, N-methylpiperidine Cation and N-methylimidazole cation.

36. The compound of claim 35, wherein R 9 It is -C(O)O(C1-C6 alkyl), and the C1-C6 alkyl is substituted by one or more groups selected from -O(CO)C(CH3)3, -OC(O)CH2CH2OH, -OC(O)C(CH3)2OH, -OC(O)heterocycloalkyl, -OC(O)CH2OCH2CH2OMe, -OC(O)OiPr, -OC(O)Ocycloalkyl, -OC(O)O(CH2CH2O)2Et, -OP(O)(OH)2, heteroaryl or heterocycloalkyl.

37. The compound of claim 35, wherein R 9 is -C(O)OCH2OC(O)C(CH3)3, -C(O)OCH2OC(O)Me, -C(O)OCH(Me)OC(O)Me, -C(O)OCH2OC(O)CH2CH2OH, -C(O)OCH2OC(O)C(CH3)2OH, -C(O)OCH2OC(O)piperidine, -C(O)OCH2OC(O)CH2OCH2CH2OMe, -C(O)OCH2OC(O)OiPr, -C(O)OCHMeOC(O)OiPr, -C(O)OCHMeOC(O)Ocyclohexyl, -C(O)OCHMeOC(O)O(CH2CH2O)2Et, -C(O)OCH2CH2OP(O)(OH)2, -C(O)OCH2(N-methylimidazole) cation), -C(O)OCH2(N-methylpiperidin cation), -C(O)OCH2 dioxolane, -C(O)OCH2CH2 morpholine, -C(O)OCH2CH2 piperazine, -C(O)OCH2CH2CH2 piperazine or -P(O)(OCH2OC(O)C(CH3)3)2; Optionally, wherein R 9 -C(O)OCH2OC(O)C(CH3)3, -C(O)OCH2OC(O)Me, -C(O)OCH(Me)OC(O)Me, -C(O)OCH2OC(O)CH2CH2OH, -C(O)OCH2OC(O)C(CH3)2OH, -C(O)OCH2OC(O)piperidine, -C(O)OCH2OC(O)CH2OCH2CH2Ome, -C(O)OCH2OC(O)OiPr, -C(O)OCHMeOC(O)OiPr-C(O)OCHMeOC(O)Ocyclohexyl, -C(O)OCHMeOC(O)O(CH2CH2O)2Et, -C(O)OCH2CH2OP(O)(OH)2, -C(O)OCH2(N-methylimidazole) cation), -C(O)OCH2(N-methylpiperidin cation), -C(O)OCH2dioxolane, -C(O)OCH2CH2morpholine, -C(O)OCH2CH2piperazine, or -C(O)OCH2CH2CH2piperazine.

38. The compound of any one of claims 1 to 33, wherein R 9 is -C(O)O(CH2) p NMe2, -C(O)O(CH2) p NHMe, -C(O)OCH2CH(OH)CH2OH, C(O)OCH2CH2CMe2OH or -C(O)OCH2CH2SO2Me, wherein each p is independently 2, 3, 4, 5 or 6.

39. The compound of claim 38, wherein R 9 It is -C(O)OCH2CH2NMe2, -C(O)OCH2CH(OH)CH2OH or -C(O)OCH2CH2SO2Me.

40. A compound according to any one of the preceding claims, wherein R 20 It is Me or -(CH2CH2O)2Me.

41. A compound according to any one of the preceding claims, wherein R 33 It is R 19 .

42. The compound of any one of claims 1 to 40, wherein R 33 It is a C1-C6 alkyl group substituted by morpholine or piperazine.

43. A compound according to any one of the preceding claims, wherein the C1-C6 alkyl group substituted by morpholine or piperazine is 44. A compound according to any one of the preceding claims, wherein R 11 For Cl.

45. A compound according to any one of the preceding claims, wherein R 13a For F.

46. ​​A compound according to any one of the preceding claims, wherein: (a) [MCL-1 ligand prodrug portion] is: or (b) [MCL-1 ligand prodrug moiety] is:

47. The compound of claim 26, wherein: (a) [Linking group] is [Ligase ligand portion] is and [MCL-1 ligand prodrug moiety] is a compound of formula (A3), wherein: R 32 yes and R 9 is C(O)O(straight-chain C1-C6 alkyl)OC(O)C(CH3)3, C(O)O(straight-chain C1-C6 alkyl)OC(O)heterocycloalkyl, C(O)O(straight-chain C1-C6 alkyl)OC(O)CH2CH2OH, C(O)O(straight-chain C1-C6 alkyl)OC(O)CH2OCH2CH2OMe, C(O)O(straight-chain C1-C6 alkyl)OC(O)Me, C(O)O(branched C1-C6 alkyl)OC(O)OiPr, C(O)O(branched C1-C6 alkyl)OC(O)Ocycloalkyl, C(O)O(branched C1-C6 alkyl)OC(O)O(CH2CH2O)2Et or C(O)O(branched C1-C6 alkyl)OC(O)Me; or (b) [Linking group] is [Ligase ligand portion] is and [MCL-1 ligand prodrug moiety] is a compound of formula (A3), in R 32 yes and R 9 is C(O)O(straight-chain C1-C6 alkyl)OC(O)C(CH3)3, C(O)O(branched C1-C6 alkyl)OC(O)OiPr, C(O)O(branched C1-C6 alkyl)OC(O)Ocycloalkyl, C(O)O(branched C1-C6 alkyl)OC(O)O(CH2CH2O)2Et or C(O)O(branched C1-C6 alkyl)OC(O)Me; or (c) [Linking group] is [Ligase ligand portion] is and [MCL-1 ligand prodrug moiety] is a compound of formula (A3), wherein: R 32 yes and R 9 is C(O)O(straight-chain C1-C6 alkyl)OC(O)C(CH3)3, C(O)O(straight-chain C1-C6 alkyl)OC(O)CH2CH2OH, C(O)O(straight-chain C1-C6 alkyl)OC(O)Me, C(O)OCH2CH2heterocycloalkyl or C(O)O(branched C1-C6 alkyl)OC(O)O(CH2CH2O)2Et; or (d) [Linking group] is [Ligase ligand portion] is and [MCL-1 ligand prodrug moiety] is a compound of formula (A3), wherein R 32 yes and R 9 is C(O)O(straight-chain C1-C6 alkyl)OC(O)C(CH3)3, C(O)O(straight-chain C1-C6 alkyl)OC(O)CH2CH2OH, C(O)O(straight-chain C1-C6 alkyl)OC(O)Me or C(O)OCH2CH2heterocycloalkyl; Among them, when R 9 When it is C(O)O(straight-chain C1-C6 alkyl)OC(O)C(CH3)3, then [ligase ligand part] is 48. The compound of claim 1 selected from the group consisting of:

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

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

52. A compound according to any one of the preceding claims, wherein Unless otherwise specified, each alkyl, alkenyl, alkynyl, aryl, heteroaryl, and benzyl group is unsubstituted.

53. Compounds of formula (I) [MCL-1 ligand prodrug moiety]-[linker]-[ligase ligand moiety] (I) or a salt, solvate, hydrate or isomer thereof, in, [Ligase ligand part] is: (a) Formula (IV) or Formula (IVa) in: Each of X1 and X2 is independently O or S; Each of Q1 and Q2 is independently N or CR 5 , wherein 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 2or-S(O)2R b ; 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)2NR b 2. -OR 21 、-NH-R 21 、-C(O)-NH-R 21 or -CH2-NH-C(O)-R 21 ; Each R' is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR b 、-NR b 2. -NR b C(O)R b 、-NR b C(O)OR b 、-NO2、-CN、-C(O)R b 、-C(O)OR b 、-C(O)NH2、-C(O)NHR b 、-C(O)NR b 2. -C(O)NHCHR b 2. -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)2NR b 2. -NHS(O)2R b 、-R 21 、-OR 21 、-NH-R 21 、-C(O)-R 21 、-C(O)-NH-R 21 or -CH2-NH-C(O)-R 21 ; and Each R b are independently hydrogen, alkyl, alkenyl, aryl, heteroaryl or benzyl; Among them, R 21 is the R of the linking group 18 and wherein Formula (IV) comprises a single R 21 ; (b) Formula (VIIa), Formula (VIIb), Formula (VIIc) or Formula (VIId): in: Each of X1 and X2 is independently O or S; Each of Q1 and Q2 is independently N or CR, wherein at least one of Q1 and Q2 is N; Each of W1, W2 and W3 is independently N or CR a ; Z is O, S or NR e ; 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 2or-S(O)2R b ; 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)2NR 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 ; 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)2NR 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 ; Each R b are independently hydrogen, alkyl, alkenyl, aryl, heteroaryl or benzyl; Among them, R 21 is the R of the linking group 18 and wherein each of Formula (VIIa), Formula (VIIb) and Formula (VIIc) contains a single R 21 ; (c) Formula (VIII): in 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 2or-S(O)2R b ; Each of R1, R2 and R3 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)2NR 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 ;as well as Each R b are independently hydrogen, alkyl, alkenyl, aryl, heteroaryl or benzyl; Among them, R 21 is the R of the linking group 18 and wherein Formula (VIII) comprises a single R 21 ;or (d) Formula (IX): in, 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 2or-S(O)2R b ; Each of Q1, Q2, Q3, Q4 and Q5 is independently N or CR, wherein at least one of Q1, Q2, Q3, Q4 and Q5 is N; Each R is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR b 、-NR b 2. -NR b C(O)R b 、-NR b C(O)OR b 、-NO2、-CN、-C(O)R b 、-C(O)OR b 、-C(O)NH2、-C(O)NHR b 、-C(O)NR b 2. -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)2NR 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 ;as well as Each R b are independently hydrogen, alkyl, alkenyl, aryl, heteroaryl or benzyl; Among them, R 21 is the R of the linking group 18 The bond is connected, and wherein Formula (IX) contains a single R 21 ; wherein [MCL-1 ligand prodrug moiety] is a compound of formula (A1), formula (A2), formula (A3) or formula (A4): in: is a single bond or a double bond; Each Z2 is independently N or C, wherein when Z2 is N, then is a single bond; when Z2 is C, is a double bond; Each R 11 are independently H, halogen or C1-C6 alkyl, R 8 is a C1-C6 alkyl group substituted with piperazine; In each of formula (A1) and formula (A4), R 10 and R 30 One of them is H, R 10 and R 30 The other one 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 tetrahydronaphthyl, wherein the phenyl, naphthyl or tetrahydronaphthyl is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl and -O(C1-C6 alkyl); or wherein the tetrahydronaphthyl is optionally substituted with a bridging -CH2- group; or wherein the naphthyl is optionally substituted with -O- or -S-, R 12 for R 31 Yes-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 tetrahydronaphthyl, wherein the phenyl, naphthyl or tetrahydronaphthyl is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl and -O(C1-C6 alkyl); or wherein the tetrahydronaphthyl is optionally substituted with a bridged -CH2- group; or wherein the naphthyl is optionally substituted with -O- or -S-; Each R 32 are independently H, Each R 33 Independently R 19 or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with morpholine or piperazine; R 20 Me, -CH2-OMe, -(CH2CH2O) p (C1-C6 alkyl) or -CH2-O-bromobenzaldehyde, wherein p is 1-5; R 34 It is C 2-5 Alkyl-OR 13 or -OC 2-5 Alkyl-R 13 , where R 13 is phenyl, naphthyl or tetrahydronaphthyl, wherein the phenyl, naphthyl or tetrahydronaphthyl is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl and -O(C1-C6 alkyl); or wherein the tetrahydronaphthyl is optionally substituted with a bridged -CH2- group; or wherein the naphthyl is optionally substituted with -O- or -S-; R 35 for R 19 is the R of the linking group 14 wherein each of Formula (A1), Formula (A2), Formula (A3) and Formula (A4) contains a single R 19 ;and (i)R 9 is -C(O)O(C1-C6 alkyl), -C(O)O cycloalkyl, -C(O)O heterocycloalkyl, -C(O)O aryl or -P(O)(OR p ) 2, wherein the C1-C6 alkyl group is substituted by one or more groups selected from the following: -OC(O) (unsubstituted C1-C6 alkyl), -OC(O) (substituted by at least one R 10 substituted C1-C6 alkyl), -OC(O)cycloalkyl, -OC(O)heterocycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, -OC(O)(CH2) m O(CH2) m O(unsubstituted C1-C6 alkyl), -OC(O)(CH2) m O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(unsubstituted C1-C6 alkyl), -OC(O)O(substituted by at least one R 10 Substituted C1-C6 alkyl), -OC(O)O cycloalkyl, -OC(O)O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2CH2O) m (C1-C6 alkyl substituted with OP(O)(OH)2), -OC(O)O(CH2CH2S) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)(unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)2(unsubstituted C1-C6 alkyl), -OC(O)NH(C1-C6 alkyl substituted by OMe), -OC(O)NMe(C1-C6 alkyl substituted by OMe), -P(O)(OH)2, -OP(O)(OH)2, -C(O)heterocycloalkyl, -C(O)N(unsubstituted C1-C6 alkyl)2, heteroaryl, heterocycloalkyl, -S(unsubstituted C1-C6 alkyl), -S(O)(unsubstituted C1-C6 alkyl), -N + (unsubstituted C1-C6 alkyl)3, -N + (Unsubstituted C1-C6 alkyl)2-cycloalkyl, N-(unsubstituted C1-C6 alkyl)piperidine Cation, N-(unsubstituted C1-C6 alkyl)morpholine Cation and N-(unsubstituted C1-C6 alkyl) imidazole cation; Among them, each R 10 are independently -OH, -O(unsubstituted C1-C6 alkyl), -OBn, -NH2, -NMe2, -NHC(O)(unsubstituted C1-C6 alkyl), -NHC(O)O(unsubstituted C1-C6 alkyl), heterocycloalkyl, heteroaryl, aryl, -C(O)NMe2; Each R p are independently -(CH2) m OC(O) (unsubstituted C1-C6 alkyl), and Each m is independently 1, 2, 3 or 4; or (ii)R 9 is -C(O)O(CH2) p NMe2, -C(O)O(CH2) p NHMe, -C(O)OCH2CH(OH)CH2OH, -C(O)OCH2CH2CMe2OH, or -C(O)OCH2CH2SO2Me, wherein each p is independently 2, 3, 4, 5, or 6; and wherein [linking group] has the formula: R 14 -R 15 -R 16 -R 17 -R 18 in: 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 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 -CH2(C2H4-O) y 、-(CH2O) x 、-(C2H4-O) x 、-(C3H6-O) x or does not exist; x is 1-10; y is 2-10; R 18 -C 1-6 Alkyl, -C 1-6 Alkyl-C(O)-, cycloalkyl, -CH2-NH-C(O)-, heterocycloalkyl or absent; where R 14 -R 18 At least one of exists.

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

55. The compound of claim 53 or 54, wherein 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)2NR 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 .

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

57. The compound of claim 56, wherein The aryl group is substituted with one or more groups selected from halogen, alkyl and O-haloalkyl, optionally wherein the halogen is Cl, the alkyl is methyl and the O-haloalkyl is O-CF3.

58. The compound of any one of claims 53 to 57, wherein one of E1, E2, E3 and E4 is N, and the remaining three of E1, E2, E3 and E4 are each CR'.

59. The compound of claim 58, wherein: (a) E1 is N, and E2, E3 and E4 are CR'; or (b) E2 is N, and E1, E3 and E4 are CR'; or (c) E3 is N, and E1, E2 and E4 are CR'; or (d) E4 is N, and E1, E2, and E3 are CR'.

60. The compound of any one of claims 53-57, wherein E1, E2, E3 and E4 are each CR', optionally wherein E1, E2, E3 and E4 are each CH.

61. The compound of claim 60, wherein three of E1, E2, E3, and E4 are CH, and one of E1, E2, E3, and E4 is C-halogen, C-alkyl, C-alkenyl, C-alkynyl, C-aryl, C-heteroaryl, C-benzyl, C-haloalkyl, C-haloalkenyl, C-NH2, C-NHR b 、C-NR b 2. C-NR b C(O)R b 、C-NR b C(O)OR b 、C-NO2、C-CN、CC(O)R b 、CC(O)OR b 、CC(O)NH2、CC(O)NHR b 、CC(O)NR b 2. CC(O)NHCHR b 2. C-CHR b NHC(O)NHR b 、C-CHR b NHC(O)C(Halogen)2R b 、C-OR b 、C-OC(O)R b 、C-OC(O)OR b 、C-OC(O)NH2、C-OC(O)NHR b 、C-OC(O)NR b 2. C-SR b 、CS(O)2R b 、CS(O)2OR b 、CS(O)2NH2、CS(O)2NHR b 、CS(O)2NR b 2. C-NHS(O)2R b 、-R 21 、-OR 21 、-NH-R 21 、-C(O)-R 21 、-C(O)-NH-R 21 or -CH2-NH-C(O)-R 21 .

62. The compound of claim 61, wherein: (a) E2, E3 and E4 are each CH; or (b) E1, E3 and E4 are each CH; or (c) E1, E2 and E4 are each CH.

63. The compound of any one of claims 53-57, wherein two of E1, E2, E3, and E4 are N, and the remaining two of E1, E2, E3, and E4 are each CR'.

64. The compound of any one of claims 53-57, wherein three of E1, E2, E3, and E4 are N, and the remaining one of E1, E2, E3, and E4 is CR'.

65. The compound of any one of claims 53 to 64, wherein one of W1, W2 and W3 is N, and the others of W1, W2 and W3 are CR a , optionally, wherein R a For H.

66. The compound of any one of claims 53-64, wherein W1, W2, and W3 are each CR a .

67. The compound of any one of claims 53-66, wherein W1 is C-NH2, C-NHR b or C-NR b 2, optionally C-NH2.

68. The compound of any one of claims 53-64, wherein W1, W2 and W3 are each N.

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

70. The compound of any one of claims 53-69, wherein in Formula (IV), Formula (VIIa), Formula (VIIb), and Formula (VIIc): (a) Q1 is N and Q2 is CR; or (b) Q1 is N and Q2 is N; or (c) Q1 is CR and Q2 is N, optionally, wherein Q1 is CH or C-alkyl, further optionally, wherein Q1 is CH or C-Me.

71. The compound of any one of claims 53-70, wherein in formula (IX), one of Q1, Q2, Q3, Q4 and Q5 is N, and the remaining four of Q1, Q2, Q3, Q4 and Q5 are each CR.

72. The compound of claim 71, wherein: (a) Q1 is N; or (b) Q2 is N; or (c)Q3 is N.

73. The compound of any one of claims 53-70, wherein in formula (IX), two of Q1, Q2, Q3, Q4 and Q5 are N, and the remaining three of Q1, Q2, Q3, Q4 and Q5 are each CR.

74. The compound of claim 73, wherein: (a) Q1 and Q2 are N, and Q3, Q4, and Q5 are each CR; or (b) Q2 and Q3 are N, and Q1, Q4, and Q5 are each CR; or (c) Q1 and Q3 are N, and Q2, Q4, and Q5 are each CR; or (d) Q2 and Q4 are N, and Q1, Q3, and Q5 are each CR; or (e) Q1 and Q4 are N, and Q2, Q3, and Q5 are each CR.

75. The compound of any one of claims 53-70, wherein in formula (IX), three of Q1, Q2, Q3, Q4 and Q5 are N, and the remaining two of Q1, Q2, Q3, Q4 and Q5 are each CR.

76. The compound of any one of claims 53-70, wherein [ligase ligand moiety] is: (a) or (b) 77. The compound of any one of claims 53-70, wherein [ligase ligand moiety] is:

78. Compounds of formula (I) [MCL-1 ligand prodrug moiety]-[linker]-[ligase ligand moiety] (I) or a salt, solvate, hydrate or isomer thereof, in, [Ligase ligand part] is: (a) Formula (Va) or Formula (Vb): or a pharmaceutically acceptable salt or tautomer thereof, in Each of X1 and X2 is independently O or S; Z1 is O, S or NR 6 ; 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 is independently N or CR 7 , wherein 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 ; 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", -OR", -NR", 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", -CH2NR", -NR", C(O)R", -NR", C(O)CH2NR", -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 ; 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", -NR", -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)N HR"", -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 ; Among them, R 21 is the R of the linking group 18 and wherein Formula (Va) and Formula (Vb) each contain a single R 21 ; Among them, when Z1 is O, then Y6 is CR 7 ,and Wherein, when the compound is a compound of formula (Va), then (i) When each of Y5, Y6 and Y7 is CR 7 When at least one R 7 Not H; (ii) When Z1 is NR 6 When Y6 and Y7 are CR 7 ; (iii) when 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, then 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, then Y7 is C-NH2, C-NHR", C-NR", C-NR""2, C-NR""C(O)OR", C-CH2NR""C(O)OR"", C-haloalkyl, C-tert-butyl, C-OR", C-COOR"" or C-SR""; wherein, when Y7 is C-NH2, C-NHR"" or C-NR""2, then Y5 is CH; And when the compound is a compound of formula (Vb), then: (vii) When each of Y5, Y6 and Y8 is CR 7 When at least one R 7 Not H; (viii) when Z1 is S, then 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, then 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 When Y5, Y6 and Y8 are CR 7 ; or (b) Formula (IIa) or (IIb): in Each of X1 and X2 is independently O or S; Z is O, S or NR 2 ; T is C=O or SO2; Y3 is N or CR; Y4 is N or CR; represents a single bond or a double bond, where: When each When a double bond is present, each of W1, W2, W3 and W4 is independently N or CR a , wherein at least one of W1, W2, W3 and W4 is N, and When each When it 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 2or-S(O)2R h ; Each R is independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR h 、-NR h 2. -NR h C(O)R h 、-NR h C(O)CH2R h 、-NR h C(O)CH(OH)R h 、-NR h C(O)OR h 、-NR h SO2R h 、-NO2、-CN、-C(O)R h 、-C(O)OR h 、-C(O)NH2、-C(O)NHR h 、-C(O)NR h 2. -OR h 、-OC(O)R h 、-OC(O)OR h 、-OC(O)NH2、-OC(O)NHR h 、-OC(O)NR h 2. -SR h , or -S(O)2R h 、-S(O)2OR h 、-S(O)2NH2、-S(O)2NHR h , or -S(O)2NR h 2; Each R a are independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR h 、-NR h 2. -NR h C(O)R h 、-NR h C(O)CH(OH)R h 、-NR h C(O)OR h 、-NR h SO2R h 、-NO2、-CN、-C(O)R h 、-C(O)OR h 、-C(O)NH2、-C(O)NHR h 、-C(O)NR h 2. -OR h 、-OC(O)R h 、-OC(O)OR h 、-OC(O)NH2、-OC(O)NHR h 、-OC(O)NR h 2. -SR h 、-S(O)2R h 、-S(O)2OR h 、-S(O)2NH2、-S(O)2NHR h 、-S(O)2NR h 2. -OR 21 、-NH-R 21 、-C(O)-NH-R 21 or -CH2-NH-C(O)-R 21 ; 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, -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 , or -S(O)2R h 、-S(O)2OR h 、-S(O)2NH2、-S(O)2NHR h , or -S(O)2NR h 2; and R 1 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; R 21 is the R of the linking group 18 wherein Formula (IIa) and Formula (IIb) each contain a single R 21 ; Among them, when each is a double bond, Z is NR 2 , R 2 is hydrogen, and each R a When it is hydrogen, W4 is CR a ; wherein [MCL-1 ligand prodrug moiety] is a compound of formula (A1), (A2), (A3) or (A4): in: is a single bond or a double bond; Each Z2 is independently N or C, wherein when Z2 is N, then is a single bond; when Z2 is C, is a double bond; Each R 11 are independently H, halogen or C1-C6 alkyl, R 8 is a C1-C6 alkyl group substituted with piperazine; In each of formula (A1) and formula (A4), R 10 and R 30 One of them is H, R 10 and R 30 The other one 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 tetrahydronaphthyl, wherein the phenyl, naphthyl or tetrahydronaphthyl is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl and -O(C1-C6 alkyl); or wherein the tetrahydronaphthyl is optionally substituted with a bridging -CH2- group; or wherein the naphthyl is optionally substituted with -O- or -S-, R 12 for R 31 Yes-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 tetrahydronaphthyl, wherein the phenyl, naphthyl or tetrahydronaphthyl is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl and -O(C1-C6 alkyl); or wherein the tetrahydronaphthyl is optionally substituted with a bridged -CH2- group; or wherein the naphthyl is optionally substituted with -O- or -S-; Each R 32 are independently H, Each R 33 Independently R 19 or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with morpholine or piperazine; R 20 Me, -CH2-OMe, -(CH2CH2O) p (C1-C6 alkyl) or -CH2-O-bromobenzaldehyde, wherein p is 1-5; R 34 It is C 2-5 Alkyl-OR 13 or -OC 2-5 Alkyl-R 13 , where R 13 is phenyl, naphthyl or tetrahydronaphthyl, wherein the phenyl, naphthyl or tetrahydronaphthyl is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl and -O(C1-C6 alkyl); or wherein the tetrahydronaphthyl is optionally substituted with a bridged -CH2- group; or wherein the naphthyl is optionally substituted with -O- or -S-; R 35 for R 19 is the R of the linking group 14 wherein each of Formula (A1), Formula (A2), Formula (A3) and Formula (A4) contains a single R 19 ;and (i)R 9 is -C(O)O(C1-C6 alkyl), -C(O)O cycloalkyl, -C(O)O heterocycloalkyl, -C(O)O aryl or -P(O)(OR p ) 2, wherein the C1-C6 alkyl group is substituted by one or more groups selected from the following: -OC(O) (unsubstituted C1-C6 alkyl), -OC(O) (substituted by at least one R 10 substituted C1-C6 alkyl), -OC(O)cycloalkyl, -OC(O)heterocycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, -OC(O)(CH2) m O(CH2) m O(unsubstituted C1-C6 alkyl), -OC(O)(CH2) m O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(unsubstituted C1-C6 alkyl), -OC(O)O(substituted by at least one R 10 Substituted C1-C6 alkyl), -OC(O)O cycloalkyl, -OC(O)O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2CH2O) m (C1-C6 alkyl substituted with OP(O)(OH)2), -OC(O)O(CH2CH2S) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)(unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)2(unsubstituted C1-C6 alkyl), -OC(O)NH(C1-C6 alkyl substituted by OMe), -OC(O)NMe(C1-C6 alkyl substituted by OMe), -P(O)(OH)2, -OP(O)(OH)2, -C(O)heterocycloalkyl, -C(O)N(unsubstituted C1-C6 alkyl)2, heteroaryl, heterocycloalkyl, -S(unsubstituted C1-C6 alkyl), -S(O)(unsubstituted C1-C6 alkyl), -N + (unsubstituted C1-C6 alkyl)3, -N + (Unsubstituted C1-C6 alkyl)2-cycloalkyl, N-(unsubstituted C1-C6 alkyl)piperidine Cation, N-(unsubstituted C1-C6 alkyl)morpholine Cation and N-(unsubstituted C1-C6 alkyl) imidazole cation; Among them, each R 10 are independently -OH, -O(unsubstituted C1-C6 alkyl), -OBn, -NH2, -NMe2, -NHC(O)(unsubstituted C1-C6 alkyl), -NHC(O)O(unsubstituted C1-C6 alkyl), heterocycloalkyl, heteroaryl, aryl, -C(O)NMe2; Each R p are independently -(CH2) m OC(O) (unsubstituted C1-C6 alkyl), and Each m is independently 1, 2, 3 or 4; or (ii)R 9 is -C(O)O(CH2) p NMe2, -C(O)O(CH2) p NHMe, -C(O)OCH2CH(OH)CH2OH, -C(O)OCH2CH2CMe2OH, or -C(O)OCH2CH2SO2Me, wherein each p is independently 2, 3, 4, 5, or 6; and wherein [linking group] has the formula: R 14 -R 15 -R 16 -R 17 -R 18 in: 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 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 -CH2(C2H4-O) y 、-(CH2O) x 、-(C2H4-O) x 、-(C3H6-O) x or does not exist; x is 1-10; y is 2-10; R 18 -C 1-6 Alkyl, -C 1-6 Alkyl-C(O)-, cycloalkyl, -CH2-NH-C(O)-, heterocycloalkyl or absent; where R 14 -R 18 At least one of exists.

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

80. The compound of any one of claims 78-79, wherein when Z1 in formula (Vb) is S, then Y5 is not C-NHC(O)R"" or -C(O)OR"".

81. The compound of any one of claims 78-80, wherein Z1 is NR 6 .

82. The compound of any one of claims 78-81, wherein each R is independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR", -NR""2, -NR""C(O)R", -NR""C(O)CH(OH)R"", -NR""C(O)OR", -NR""S2R"", -NO2, -CN, -C(O)R"" , -C(O)OR””, -C(O)NH2, -C(O)NHR””, -C(O)NR””2, -OR””, -OC(O)R””, -OC(O)OR””, -OC(O)NH2, -OC( O)NHR””, -OC(O)NR””2, -SR”” or -S(O)2R””, -S(O)2OR””, -S(O)2NH2, -S(O)2NHR””, -S(O)2NR””2, -OR 21 、-NH-R 21 、-C(O)-NH-R 21 or -CH2-NH-C(O)-R 21 .

83. The compound of any one of claims 78-82, wherein R 1 It's hydrogen.

84. The compound of any one of claims 78-83, wherein R 6 For hydrogen.

85. The compound of any one of claims 78-84, wherein [ligase ligand moiety] is a compound of formula (Va), and Y5, Y6, and Y7 are each CR 7 .

86. The compound of claim 85, wherein Y5 is -C-NHC(O)R"", Y6 is CH, and Y7 is CH or CCl.

87. The compound of claim 86, wherein: L3 is hydrogen; Z1 is S; R 1 It is hydrogen; T is C=O; and Y7 is CH.

88. The compound of any one of claims 78 to 84, wherein the compound is of formula (Vb), and Y5, Y6, and Y8 are each CR 7 .

89. The compound of claim 88, wherein: L3 is hydrogen; Z1 is S; R 1 is H; T is C=O; Y5 is CH, C-OR", CCl, C-CN or C-NHC(O)R""; Y6 is CH, CCl, C-alkyl, C-cycloalkyl or C-haloalkyl; and Y8 is CH, C-OR", C-NHC(O)R", C-NHC(O)OR", C-NHR", C-NH2 or C-NHSO2R", wherein, when Y5 is CCl, then Y6 is CH, C-alkyl, C-cycloalkyl or C-haloalkyl; Optionally, wherein each R"" is independently alkyl, cycloalkyl, aryl or benzyl.

90. The compound of claim 89, wherein: Y5 is CH; Y6 is CH or CCl; and Y8 is C-OR"" or C-NH2, optionally C-OMe or C-NH2.

91. The compound of any one of claims 78-90, wherein: (a) Z is NR 2 ;or (b) Z is S.

92. The compound of any one of claims 78-91, wherein each For double bonds.

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

94. The compound of claim 92 or 93, wherein one of W1, W2, W3 and W4 is N, and the remaining three of W1, W2, W3 and W4 are each CR a ; Optionally, wherein W4 is CR a .

95. The compound of any one of claims 78 to 92, wherein two of W1, W2, W3 and W4 are N, and the remaining two of W1, W2, W3 and W4 are each CR a .

96. The compound of any one of claims 78-92, wherein one of W1, W2, W3 and W4 is CR a , the remaining three of W1, W2, W3 and W4 are each N.

97. The compound of any one of claims 78-96, wherein each R is independently hydrogen, halogen, or -NR h C(O)R h .

98. Compounds of formula (I) [MCL-1 ligand prodrug moiety]-[linker]-[ligase ligand moiety] (I) or a salt, solvate, hydrate or isomer thereof, Wherein [ligase ligand part] is: (a) Formula (VIa) or Formula (VIb): in: M is O, S or NH, or does not exist; represents R connected to the linking group 18 ; R 22 is hydrogen, halogen, -OMe, amino, heterocycloalkyl, or unsubstituted C1-C6 alkyl; and L' is hydrogen, alkyl, benzyl, acetyl or pivaloyl; (b) Formula (II): in: 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 ; R y Selected from in, Indicates connection to T, Z3 is O, S or NR 3 ; U is O, S, NR b or CR i 2; Each of Y1, Y2 and Y3 is independently N or CR d ; 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)2NR b 2. -OR 21 、-NH-R 21 、-C(O)-NH-R 21 or -CH2-NH-C(O)-R 21 ; 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)2NR b 2; Each R 3 are independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR b 、-NR b 2. -NHC(O)R b 、-NR b C(O)R b 、-NHC(O)CH(OH)R b 、-NR b C(O)CH(OH)R b 、-NHC(O)OR b 、-NR b C(O)OR b 、-NHSO2R b 、-NR b SO2R b , -NO2, -CN, -C(O)H, -C(O)R b 、-C(O)OH、-C(O)OR b 、-C(O)NH2、-C(O)NHR b 、-C(O)NR b 2. -OH, -OR b 、-OC(O)H、-OC(O)R b 、-OC(O)OH、-OC(O)OR b 、-OC(O)NH2、-OC(O)NHR b 、-OC(O)NR b 2. -SH, -SR b 、-S(O)2H、-S(O)2R b 、-S(O)2OH、-S(O)2OR b 、-S(O)2NH2、-S(O)2NHR b 、-S(O)2NR b 2. -R 21 、-C(O)-NH-R 21 or -CH2-NH-C(O)-R 21 ; Each R b are independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl or benzyl; R 21 is the R of the linking group 18 The bond connected, wherein formula (II) contains a single R 21 ; in: (i) When R y for When Y 2 It's CR d ;as well as (ii) When R y for When CR i R in 2 i It is not hydrogen; or (c) Formula (III): in: 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 ; R x Selected from in, Indicates connection to T, Z4 is O, S or NR 4 ; V is CR f 2. NR 4 or S; Each of G1, G2, G3 and G4 is independently N or CR c ; Each of Y1 and Y2 is independently N or CR f ; 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, -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)2NR b 2. -R 21 、-OR 21 、-NH-R 21 、-C(O)-NH-R 21 or -CH2-NH-C(O)-R 21 ; or when Y1 and Y2 are CR f When each R f Together with the carbon atom to which it is attached, it forms a 5-membered or 6-membered ring; Each R c are independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, substituted by 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)2NR b 2. -OR 21 、-NH-R 21 、-C(O)-NH-R 21 or -CH2-NH-C(O)-R 21 ; 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 ;as well as Each R b are independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl or benzyl; R 21 is the R of the linking group 18 The bond connected, wherein formula (III) contains a single R 21 ; Among them, when n=2, each R c is hydrogen, and each of G1, G2, G3 and G4 is CR c When , C=X1 can be replaced by CH; And among them: (i) When R x for When Z4 is NH, L1 is hydrogen, -CH2C(O)OR b OR b ; (ii) When R x for Z4 to NR 4 , Y1 is CR f , and when Y2 is N, then R 4 is not an alkyl group, and R 2 and at least one of R is not H; (iii) When R x for Z4 to NR 4 , and Y1 and Y2 are CR f When , at least one of G1, G2 and G3 is N; (iv) When Z4 is NR 4 , and Y1 and Y2 are CR f When R x no (v) When R x for Z4 to NR 4 , and when Y1 or Y2 is N, then R 4 Not an alkyl group; (vi) When R x for When , n = 1 or 2; and (vii) When R x for When Z4=O or S; wherein [MCL-1 ligand prodrug moiety] is a compound of formula (A1), formula (A2), formula (A3) or formula (A4): in: is a single bond or a double bond; Each Z2 is independently N or C, wherein when Z2 is N, then is a single bond; when Z2 is C, is a double bond; Each R 11 are independently H, halogen or C1-C6 alkyl, R 8 is a C1-C6 alkyl group substituted with piperazine; In each of formula (A1) and formula (A4), R 10 and R 30 One of them is H, R 10 and R 30 The other one 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 tetrahydronaphthyl, wherein the phenyl, naphthyl or tetrahydronaphthyl is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl and -O(C1-C6 alkyl); or wherein the tetrahydronaphthyl is optionally substituted with a bridging -CH2- group; or wherein the naphthyl is optionally substituted with -O- or -S-, R 12 for R 31 Yes-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 tetrahydronaphthyl, wherein the phenyl, naphthyl or tetrahydronaphthyl is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl and -O(C1-C6 alkyl); or wherein the tetrahydronaphthyl is optionally substituted with a bridged -CH2- group; or wherein the naphthyl is optionally substituted with -O- or -S-; Each R 32 are independently H, Each R 33 Independently R 19 or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with morpholine or piperazine; R 20 Me, -CH2-OMe, -(CH2CH2O) p (C1-C6 alkyl) or -CH2-O-bromobenzaldehyde, wherein p is 1-5; R 34 It is C 2-5 Alkyl-OR 13 or -OC 2-5 Alkyl-R 13 , where R 13 is phenyl, naphthyl or tetrahydronaphthyl, wherein the phenyl, naphthyl or tetrahydronaphthyl is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl and -O(C1-C6 alkyl); or wherein the tetrahydronaphthyl is optionally substituted with a bridged -CH2- group; or wherein the naphthyl is optionally substituted with -O- or -S-; R 35 for R 19 is the R of the linking group 14 wherein each of Formula (A1), Formula (A2), Formula (A3) and Formula (A4) contains a single R 19 ;and (i)R 9 is -C(O)O(C1-C6 alkyl), -C(O)O cycloalkyl, -C(O)O heterocycloalkyl, -C(O)O aryl or -P(O)(OR p ) 2, wherein the C1-C6 alkyl group is substituted by one or more groups selected from the following: -OC(O) (unsubstituted C1-C6 alkyl), -OC(O) (substituted by at least one R 10 substituted C1-C6 alkyl), -OC(O)cycloalkyl, -OC(O)heterocycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, -OC(O)(CH2) m O(CH2) m O(unsubstituted C1-C6 alkyl), -OC(O)(CH2) m O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(unsubstituted C1-C6 alkyl), -OC(O)O(OP(O)(OH)2(substituted by at least one R 10 Substituted C1-C6 alkyl), -OC(O)O cycloalkyl, -OC(O)O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2CH2O) m substituted C1-C6 alkyl), -OC(O)O(CH2CH2S) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)(unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)2(unsubstituted C1-C6 alkyl), -OC(O)NH(C1-C6 alkyl substituted by OMe), -OC(O)NMe(C1-C6 alkyl substituted by OMe), -P(O)(OH)2, -OP(O)(OH)2, -C(O)heterocycloalkyl, -C(O)N(unsubstituted C1-C6 alkyl)2, heteroaryl, heterocycloalkyl, -S(unsubstituted C1-C6 alkyl), -S(O)(unsubstituted C1-C6 alkyl), -N + (unsubstituted C1-C6 alkyl)3, -N + (Unsubstituted C1-C6 alkyl)2-cycloalkyl, N-(unsubstituted C1-C6 alkyl)piperidine Cation, N-(unsubstituted C1-C6 alkyl)morpholine Cation and N-(unsubstituted C1-C6 alkyl) imidazole cation; Among them, each R 10 are independently -OH, -O(unsubstituted C1-C6 alkyl), -Obn, -NH2, -NMe2, -NHC(O)(unsubstituted C1-C6 alkyl), -NHC(O)O(unsubstituted C1-C6 alkyl), heterocycloalkyl, heteroaryl, aryl, -C(O)NMe2; Each R p are independently -(CH2) m OC(O) (unsubstituted C1-C6 alkyl), and Each m is independently 1, 2, 3 or 4; or (ii)R 9 is -C(O)O(CH2) p NMe2, -C(O)O(CH2) p NHMe, -C(O)OCH2CH(OH)CH2OH, -C(O)OCH2CH2CMe2OH, or -C(O)OCH2CH2SO2Me, wherein each p is independently 2, 3, 4, 5, or 6; and wherein [linking group] has the formula: R 14 -R 15 -R 16 -R 17 -R 18 in: 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 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 -CH2(C2H4-O) y 、-(CH2O) x 、-(C2H4-O) x 、-(C3H6-O) x or does not exist; x is 1-10; y is 2-10; R 18 -C 1-6 Alkyl, -C 1-6 Alkyl-C(O)-, cycloalkyl, -CH2-NH-C(O)-, heterocycloalkyl or absent; where R 14 -R 18 At least one of exists.

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

100. The compound of any one of claims 98-99, wherein in formula (III): Each of X1 and X2 is 0; T is C=O; R 1 It's hydrogen, L1 is hydrogen, R x yes Z4 to NR 4 ; Each of G1, G2 and G4 is CR c , Y1 is N, and Y2 is CR f , where R f Not hydrogen.

101. The compound of any one of claims 98-100, wherein [ligase ligand moiety] is of formula (III):

102. The compound of any one of claims 98-101, wherein: (a)R c One of -OR 21 、-NH-R 21 、-C(O)-NH-R 21 or -CH2-NH-C(O)-R 21 ; (b) G1 is COR 21 、C-NH-R 21 、CC(O)-NH-R 21 or C-CH2-NH-C(O)-R 21 ; (c) G2 is COR 21 、C-NH-R 21 、CC(O)-NH-R 21 or C-CH2-NH-C(O)-R 21 ; (d)R 4 It is R 21 、-C(O)-NH-R 21 or -CH2-NH-C(O)-R 21 ;or (e)R f One of them is -R 21 、-OR 21 、-NH-R 21 、-C(O)-NH-R 21 or -CH2-NH-C(O)-R 21 .

103. The compound of any one of claims 98-102, wherein Y2 is CR 21 、CO-R 21 、C-NH-R 21 、CC(O)-NH-R 21 or C-CH2-NH-C(O)-R 21 .

104. The compound of any one of claims 98-103, wherein: (a) [Ligase ligand moiety] is selected from: or (b) [Ligase ligand moiety] is selected from:

105. The compound of claim 104, wherein [ligase ligand moiety] is 106. The compound of any one of claims 98-99, wherein [ligase ligand moiety] is 107. The compound of any one of claims 53-106, wherein: 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 does not exist; R 18 Yes-C 1-6 Alkyl, cycloalkyl, -CH2-NH-C(O)-, heterocycloalkyl or absent.

108. The compound of any one of claims 53-107, wherein R 14 -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C(O)-, -SO2- or absent.

109. The compound of claim 108, wherein R 14 Yes-C 1-6 alkyl.

110. The compound of any one of claims 53-109, wherein R 15 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 Alkyl-NH-, -cycloalkyl-NH- or not present.

111. The compound of claim 110, wherein R 15 It is a heterocycloalkyl group.

112. The compound of claim 111, wherein R 15 is piperazine, bridged piperazine, piperazine N-oxide, piperazine cation, in, Indicates connection to R 14 , Indicates connection to R 16 .

113. The compound of claim 112, wherein R 15 Is piperazine or 114. The compound of claim 110, wherein R 15 Does not exist.

115. The compound of any one of claims 53-114, wherein R 16 Yes-C 1-6 Alkyl, -CH2-C(O)-NH- or -C(O)-.

116. The compound of claim 115, wherein R 16 Yes-C 1-6 Alkyl or -C(O)-.

117. The compound of any one of claims 53-116, wherein R 17 Does not exist.

118. The compound of any one of claims 53-117, wherein R 18 -C 1-6 Alkyl, heterocycloalkyl or not present.

119. The compound of claim 118, wherein R 18 Yes-C 1-6 Alkyl or heterocycloalkyl.

120. The compound of claim 119, wherein R 18 Yes-C 1-6 Alkyl or piperazine.

121. The compound of claim 118, wherein R 18 Does not exist.

122. The compound of any one of claims 53-121, wherein [Linking Group] is selected from the group consisting of: in: represents attachment to [MCL-1 ligand prodrug moiety]; as well as Indicates attachment to [ligase ligand moiety].

123. The compound of any one of claims 53-122, wherein In each of formula (A1) and formula (A4), R 10 and R 30 One of them is H, R 10 and R 30 The other one is -C 2-5 Alkyl-OR 13 or -OC 2-5 Alkyl-R 13 , where R 13 is phenyl or naphthyl, wherein the phenyl or naphthyl is optionally substituted with at least one substituent selected from halogen and C1-C6 alkyl.

124. The compound of any one of claims 53-123, wherein In formula (A1), R 12 for 125. The compound of any one of claims 53-124, wherein In formula (A4), R 35 for 126. The compound of any one of claims 53-125, wherein In formula (A2), R 31 -C 2-5 Alkyl-OR 13 or -OC 2-5 Alkyl-R 13 , where R 13 is phenyl or naphthyl, wherein the phenyl or naphthyl is optionally substituted with at least one substituent selected from halogen and C1-C6 alkyl.

127. The compound of any one of claims 53-126, wherein In formula (A3), R 34 It is C 2-5 Alkyl-OR 13 or -OC 2-5 Alkyl-R 13 , where R 13 is phenyl or naphthyl, wherein the phenyl or naphthyl is optionally substituted with at least one substituent selected from halogen and C1-C6 alkyl.

128. The compound of any one of claims 53-127, wherein Z2 is C and For double bonds.

129. The compound of any one of claims 53-128, wherein [MCL-1 ligand prodrug moiety] is: in: R 11 It is a halogen; R 13a is a halogen; and R 20 is Me, -CH2-OMe or -(CH2CH2O) p (C1-C6 alkyl), wherein p is 1-5.

130. The compound of any one of claims 53-129, wherein R 9 is -C(O)O(C1-C6 alkyl), -C(O)O cycloalkyl, -C(O)O heterocycloalkyl, -C(O)O aryl or -P(O)(OR p ) 2, wherein the C1-C6 alkyl group is substituted by one or more groups selected from the following: -OC(O) (unsubstituted C1-C6 alkyl), -OC(O) (substituted by at least one R 10 substituted C1-C6 alkyl), -OC(O)cycloalkyl, -OC(O)heterocycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, -OC(O)(CH2) m O(CH2) m O(unsubstituted C1-C6 alkyl), -OC(O)(CH2) m O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(unsubstituted C1-C6 alkyl), -OC(O)O(substituted by at least one R 10 Substituted C1-C6 alkyl), -OC(O)O cycloalkyl, -OC(O)O(CH2CH2O) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2CH2O) m (C1-C6 alkyl substituted with OP(O)(OH)2), -OC(O)O(CH2CH2S) m (unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)(unsubstituted C1-C6 alkyl), -OC(O)O(CH2) m S(O)2(unsubstituted C1-C6 alkyl), -OC(O)NH(C1-C6 alkyl substituted by OMe), -OC(O)NMe(C1-C6 alkyl substituted by OMe), -P(O)(OH)2, -OP(O)(OH)2, -C(O)heterocycloalkyl, -C(O)N(unsubstituted C1-C6 alkyl)2, heteroaryl, heterocycloalkyl, -S(unsubstituted C1-C6 alkyl), -S(O)(unsubstituted C1-C6 alkyl), -N + (unsubstituted C1-C6 alkyl)3, -N + (Unsubstituted C1-C6 alkyl)2-cycloalkyl, N-(unsubstituted C1-C6 alkyl)piperidine Cation, N-(unsubstituted C1-C6 alkyl)morpholine cation and N-(unsubstituted C1-C6 alkyl)imidazolyl cation.

131. The compound of claim 130, wherein R 9 is -C(O)O(C1-C6 alkyl), -C(O)O cycloalkyl, -C(O)O heterocycloalkyl, -C(O)O aryl or -P(O)(OR p ) 2, wherein the C1-C6 alkyl group is substituted by one or more groups selected from the group consisting of: -OC(O)Me, -OC(O)Et, -OC(O) i Pr, -OC(O)C(CH3)3, -OC(O)CH2OH, -OC(O)CH(CH3)OH, -OC(O)C(CH3)2OH, -OC(O)CH2CH2OH, -OC(O)CH(OH)CHMe2, -OC(O)CH(OH)CH2CHMe2, -OC(O)CH2CH(OH)Me, -OC(O)CH2C(OH)Me2, -OC(O)CH(CH2OH)(NHC(O)Me), -OC(O)CH(NHC(O)Me)(isobutyl), -OC(O)CH(OH)aryl, -OC(O)CH(OH)CH2aryl, -OC(O)heterocycloalkyl, -OC(O)cycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, -OC(O)CH2CH2aryl, -OC(O)CH(NH2) i Pr, -OC(O)CH( i Pr)NHC(O)O t Bu, -OC(O)CH2OCH2CH2OMe, -OC(O)CH2(OCH2CH2)2OMe, -OC(O)OMe, -OC(O)OEt, -OC(O)O i Pr, -OC(O)Ocycloalkyl, -OC(O)OCH2CH2OEt, -OC(O)O(CH2CH2O)2Et, -OC(O)O(CH2CH2O)3Et, -OC(O)O(CH2CH2O)3CH2CH2OP(O)(OH)2, -OC(O)OCH2CH2SMe, -OC(O)OCH2CH2S(O)Me, -OC(O)OCH2CH2S(O)2Me, -OC(O)OCH2heteroaryl, -OC(O)OCH2heterocycloalkyl, -OC (O)OCH2CH2OCH2aryl-OC(O)OCH2CH2C(O)NMe2、-OC(O)O(CH2)6NH2、-OC(O)O(CH2)6NMe2、-OC(O)OCH(CH2OEt)2、-OC(O)NHCH2CH2OMe、-OC(O)NMeCH2CH2OMe、-SMe、-S(O)Me、-P(O)(OH)2、-OP(O)(OH)2、-C(O)NMe2、-C(O)heterocycloalkyl、heteroaryl、heterocycloalkyl、-N + (Me)3, -N + (Me)2 cycloalkyl, N-methylmorpholine Cation, N-methylpiperidine Cation and N-methylimidazole cation.

132. The compound of claim 131, wherein R 9 It is -C(O)O(C1-C6 alkyl), and the C1-C6 alkyl is substituted by one or more groups selected from -O(CO)C(CH3)3, -OC(O)CH2CH2OH, -OC(O)C(CH3)2OH, -OC(O)heterocycloalkyl, -OC(O)CH2OCH2CH2OMe, -OC(O)OiPr, -OC(O)Ocycloalkyl, -OC(O)O(CH2CH2O)2Et, -OP(O)(OH)2, heteroaryl or heterocycloalkyl.

133. The compound of claim 132, wherein R 9 It is -C(O)O(C1-C6 alkyl), wherein the C1-C6 alkyl is substituted by -O(CO)C(CH3)3.

134. The compound of claim 133, wherein R 9 It is -C(O)OCH2OC(O)C(CH3)3.

135. The compound of claim 131, wherein R 9 is -C(O)OCH2OC(O)C(CH3)3, -C(O)OCH2OC(O)Me, -C(O)OCH(Me)OC(O)Me, -C(O)OCH2OC(O)CH2CH2OH, -C(O)OCH2OC(O)C(CH3)2OH, -C(O)OCH2OC(O)piperidine, -C(O)OCH2OC(O)CH2OCH2CH2OMe, -C(O)OCH2OC(O)OiPr, -C(O)OCHMeOC(O)OiPr, -C(O)OCHMeOC(O)Ocyclohexyl, -C(O)OCHMeOC(O)O(CH2CH2O)2Et, -C(O)OCH2CH2OP(O)(OH)2, -C(O)OCH2(N-methylimidazole) cation), -C(O)OCH2(N-methylpiperidin cation), -C(O)OCH2 dioxolane, -C(O)OCH2CH2 morpholine, -C(O)OCH2CH2 piperazine, -C(O)OCH2CH2CH2 piperazine or -P(O)(OCH2OC(O)C(CH3)3)2.

136. The compound of any one of claims 53-135, wherein R 20 It is Me or -(CH2CH2O)2Me.

137. The compound of any one of claims 53-136, wherein R 33 It is R 19 .

138. The compound of any one of claims 53-136, wherein R 33 It is a C1-C6 alkyl group substituted by morpholine or piperazine.

139. A compound according to any one of claims 53 to 138, wherein the C1-C6 alkyl group substituted with morpholine or piperazine is 140. The compound of any one of claims 53-139, wherein: (a) [MCL-1 ligand prodrug portion] is: or (b) [MCL-1 ligand prodrug moiety] is:

141. The compound of claim 98, wherein the compound is:

142. The compound of any one of the preceding claims, wherein T is C=O.

143. The compound of any one of the preceding claims, wherein: (a) X1 and X2 are O; (b) X1 is O, and X2 is S; (c) X1 is S and X2 is O; or (d) X1 and X2 are S.

144. The compound of any one of the preceding claims, wherein n is 0.

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

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

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

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

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

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

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

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

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

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

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

156. The method of any one of claims 153-155, wherein the administering does not result in cytotoxicity to cardiomyocytes of the subject.

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

158. The method of claim 157, wherein the at least one additional active agent is an anticancer agent selected from the group consisting of eribulin; fulvestrant; midostaurin; an immune checkpoint inhibitor selected from the group consisting of an anti-PD-1 antibody, an anti-PD-L1 antibody, and an anti-PD-1 / PD-L1 interaction inhibitor; nivolumab; pembrolizumab; atezolizumab; pidilimumab; carfilzomib; venetoclax; cytarabine; anthracyclines; taxane compounds; and a hypomethylating agent.

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

160. 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 according to any one of claims 1-147 or a pharmaceutical composition according to claim 148.

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

162. The combined preparation of claim 161, wherein the at least one additional active agent is an anticancer agent selected from the group consisting of eribulin; fulvestrant; midostaurin; an immune checkpoint inhibitor selected from the group consisting of an anti-PD-1 antibody, an anti-PD-L1 antibody, and an anti-PD-1 / PD-L1 interaction inhibitor; nivolumab; pembrolizumab; atezolizumab; pidilimumab; carfilzomib; venetoclax; cytarabine; anthracyclines; taxane compounds; and a hypomethylating agent.

163. The combined preparation of any one of claims 161-162, wherein the therapy is the treatment of cancer.

164. A method of reducing the cardiotoxicity of an MCL-1 inhibitor comprising coupling a cereblon binding moiety to the MCL-1 inhibitor, wherein the cereblon binding moiety is a [ligase ligand moiety] as defined in any one of claims 1-147 and the MCL-1 inhibitor is a [MCL-1 ligand prodrug moiety] as defined in any one of claims 1-147.

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