TW202341983A - Compounds for mutant kras protein degradation and uses thereof - Google Patents

Abstract

The present disclosure provides a bifunctional compound of formula (I): RB─Linker─ULM (I), which binds more preferentially to mutant KRAS proteins than to wild KRAS protein and promotes degradation of KRAS protein via recruitment of an E3 ubiquitin ligase. Pharmaceutical compositions comprising the bifunctional compound and uses thereof are also provided.

Description

Compounds for degrading mutant KRAS proteins and their applications

The present invention generally relates to bifunctional compounds that preferentially bind to mutant KRAS proteins compared to wild-type KRAS proteins and promote degradation of KRAS proteins by recruiting E3 ubiquitin ligases and the use of such compounds for the treatment of diseases associated with KRAS mutations. .

Proteolysis ta rgeting c himera (PROTAC) technology was first described in 2001 (Sakamoto et al., “Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation”, Proceedings of the National Academy of Sciences of the United States of America . 98 (15): 8554-9). PROTACs are two-headed heterobifunctional molecules that remove unwanted proteins by inducing selective intracellular proteolysis. The PROTAC system consists of two protein-binding moieties: one for binding E3 ubiquitin ligase and the other for binding to the target protein. PROTAC brings the target protein to an E3 ligase by binding two proteins, causing ubiquitination of the target protein for subsequent degradation by the proteasome (Bondeson et al., "Lessons in PROTAC design from selective degradation with a promiscuous warhead." ” Cell Chem Biol. 25(1): 78-87, 2018). PROTAC technology has been used for several targets: AR, ER, STAT3, BTK, FLT-3, EGFR, BCR-ABL, BET, BRD7/9, CDK4/6, CK2, ALK, PI3K, MCL-1, PARP1 and c- MET.

RAS proteins are proto-oncogenes and are encoded by three RAS genes: HRAS , Kirsten ras sarcoma protein (KRas or KRAS) , and NRAS . The role of RAS protein in the signaling pathway is to act as a binary switch to control cell growth and differentiation, thereby converting the inactive GDP-bound state into the active GTP-bound state. Mutations usually occur at codons 12, 13, and 61, which cause the inherent GTPase activity of the RAS protein to weaken, or prevent GAP binding, activate downstream signaling pathways, and promote tumor formation and maintenance. (Chang et al., "Detection of N-, H-, and KRAS codons 12, 13, and 61 mutations with universal RAS primer multiplex PCR and N-, H-, and KRAS-specific primer extension" Clin Biochem. 43(3 ):296-301, 2010.) RAS gene mutations are commonly found in a variety of malignancies, including pancreatic cancer (90%), colorectal cancer (45%), and lung cancer (35%). In cellular and animal models, many tumor types have been shown to be associated with the persistent expression of oncogenic mutations in RAS. Because RAS has picomole affinity for GTP and GDP, and because RAS lacks well-defined pockets for high-affinity small molecule binding, it is difficult to target RAS pharmacologically, and is therefore often called "undruggable" ( Cox et al., “Drugging the undruggable Ras: mission possible?” Nat Rev Drug Discov. 13(11): 828-851, 2014.).

Currently, AMG510 (Sotorasib), a small molecule inhibitor targeting the KRAS ^G12C mutant, has passed clinical trials and was approved for marketing by the US FDA on May 28, 2021. Strategies targeting mutated KRAS proteins have been shown to be therapeutically effective.

Michael J. Bond et al., "Targeted Degradation of Oncogenic KRAS ^G12C by VHL-Recruiting PROTACs" ACS Cent. Sci. 2020, 6, 8, 1367-1375; US 2019/0315732 A1; WO2019195609A2 and WO2021/207172 A1 reveal the use of KRAS ^G12C inhibitors act as binders to produce degraders, thus providing a different therapeutic strategy than inhibitors. However, both KRAS ^G12C inhibitors and KRAS ^G12C degraders are only effective against KRAS ^G12C and are not effective against other variants such as G12D, G12V, G13D, G12R, G12S and Q61H.

There is a continuing need in this technology for effective treatments of KRAS-related diseases and conditions, such as pancreatic, colorectal, colorectal, lung and non-small cell lung cancer, biliary malignancies, endometrial cancer, and cervical cancer. , bladder cancer, liver cancer, myeloid leukemia and breast cancer.

This invention describes heterobifunctional compounds and methods of making and using them for recruiting KRAS, such as mutant or gain-of-function KRAS, to E3 ubiquitin ligases for targeting ubiquitination and subsequent proteasomal degradation. In addition, the present description provides methods of treating or ameliorating disease conditions, such as KRAS-related diseases or disorders, such as accumulation of KRAS protein or mutant or gain-of-function KRAS proteins or misfolded KRAS proteins, using an effective amount of a bifunctional compound of the invention. Hyperactivity, pancreatic cancer, colorectal cancer, colorectal cancer, lung cancer, non-small cell lung cancer, biliary malignancies, endometrial cancer, cervical cancer, bladder cancer, liver cancer, myeloid leukemia and breast cancer.

In one aspect, the invention describes a bifunctional compound of formula (I): RB-linker-ULM (I) or a pharmaceutically acceptable salt, tautomer, stereoisomer, solvate thereof substance, hydrate, polymorph, isotope-enriched derivative or prodrug, where: ULM is the E3 ubiquitin ligase binding part or the chaperone complex binding part; the linker is covalently bonded to the RB and ULM part of the group; and RB is the RAS protein binding part, and is represented by the formula RB-I: Where: X ₁ is H, NR ^X1 R ^X2 , SO ₂ NR ^X1 R ^X2 , OR ^X1 , CHR ^X1 R ^X2 , NH(C=O)R ^X3 or ^CN ; ^R Or linear ^or branched C _1-4 alkyl, which is optionally substituted by one or more halo groups, or ^R or _a 4- to 8-membered ring system substituted by multiple C _1-4 alkyl groups; ^R Linear or branched C _1-10 alkoxy groups substituted by multiple halo groups, or 4 containing 0 to 2 heteroatoms and optionally substituted by one or more halo groups, CF ₃ , NH ₂ , OH or CN to 8-membered ring system; W ₁ is a bond, C _1-6 alkyl, alicyclic, heterocyclic, bicyclic or diheterocyclic, each substituted by one, two or three R ^W1 as appropriate, and each R ^W1 Independently H, halo, OH, NH ₂ , NMe ₂ , NEt ₂ , CN, C _1-4 alkyl optionally substituted with one or more F or C ₁ optionally substituted with one or more F _-3 alkoxy; R ₁ is CH, C-Me, C-halogen or N; is aryl, heteroaryl or indazole, which is independently substituted with: one or more halo, CF ₃ , OCF ₃ , OR ^{A1 -RA2} , hydroxyl, nitro, CN, C≡CH, as appropriate Straight-chain or branched-chain C _1-6 alkyl substituted by one or more halo groups or C _1-6 alkoxy groups, optionally straight-chain or branched chain C _1-6 alkyl substituted by one or more halo groups Oxygen group, C _2-6 alkenyl group, C _2-6 alkynyl group or 4 to 7 membered saturated or partially unsaturated heterocyclic ring containing 1-2 heteroatoms, R ^A1 is C _1-6 alkyl group, R ^A2 is a heteroaryl group containing 1 to 2 heteroatoms and optionally substituted with one or more halo groups; X ₂ is CH ₂ or C=O; It is a 4- to 8-membered alicyclic system having 0 to 4 ^heteroatoms , optionally substituted by 0 to 4 ^R Chain or branched chain C _1-6 alkyl, or 2 ^RQ groups and the atoms to which they are connected together form a 3- to 8-membered ring system containing 0 to 2 heteroatoms; Z ₁ is H, C _1-4 Alkyl, C _1-4 alkoxy, halogen, OH, CN or C _2-4 alkynyl; and the dashed line indicates the point of attachment to the linker.

The bifunctional compound of formula (I) can induce ubiquitination of KRAS protein and promote its degradation in cells. An advantage of the bifunctional compounds of formula (I) provided herein is that a wide range of pharmacological activities can exist.

In another aspect, the present invention provides pharmaceutical compositions comprising an effective amount of a bifunctional compound as described herein and a pharmaceutically acceptable carrier.

In another aspect, the present invention provides a pharmaceutical composition for preventing, ameliorating and/or treating KRAS mutation-related diseases in an individual in need thereof, comprising an effective amount of a bifunctional compound and one or more pharmaceutical Acceptable excipients.

definition

In order that the present invention may be fully understood, the following embodiments are set forth. The following terms are used in the instructions:

It must be noted that, as used herein, the singular forms "a/an" and "the" include plural referents unless the context clearly dictates otherwise. Therefore, unless the context otherwise requires, singular terms shall include the plural and plural terms shall include the singular.

Generally, ranges are expressed herein as from "about" one particular value and/or to "about" another particular value. When such a range is stated, an embodiment includes a range from one particular value and/or to another particular value. Likewise, when a value is expressed as an approximation by use of the word "about," it is understood that the particular value forms another embodiment. It will be further understood that the endpoints of each range are meaningful both in relation to and independently of the other endpoint. As used herein, the term "about" means ±20%, preferably ±10%, and even better ±5%.

The term "and/or" is used to refer to two things or either of the two things mentioned.

The terms "treatment", "treating" and "treat" generally refer to obtaining a desired pharmacological and/or physiological effect. The effect may be prophylactic in terms of complete or partial prevention of the disease, disorder, or symptoms thereof, and therapeutic in terms of partial or complete cure of the disease, disorder, and/or symptoms attributable thereto. "Treatment" as used herein encompasses any treatment of a disease in a mammal, preferably a human, and includes (1) inhibiting the progression of a disease, disorder, or symptoms thereof in an individual, or (2) alleviating or ameliorating a disease, condition, or condition in an individual, disease or its symptoms.

The terms "preventing" or "prevention" are recognized in the art, and when used in connection with a condition, include the administration of an agent before the onset of the condition, relative to an individual who does not receive the agent Specifically, the agent reduces the frequency or severity of, or delays the onset of, symptoms of a medical condition in an individual.

The terms "individual", "subject" and "patient" are used interchangeably herein and refer to any mammalian individual in need of diagnosis, treatment or therapy.

The term "effective amount" of an active ingredient as provided herein means a sufficient amount of the ingredient required to provide the desired function. As will be noted below, the precise amounts required will vary with each individual, depending on the individual's disease condition, physical condition, age, gender, species and body weight, the specific characteristics and formulation of the composition, and the like. Dosage regimens can be adjusted to induce an optimal therapeutic response. For example, several divided doses may be administered daily, or the dose may be proportionally reduced as indicated by the exigencies of the treatment situation. Therefore, it is impossible to specify a precise "effective amount." However, one skilled in the art can determine an appropriate effective amount using no more than routine experimentation.

Unless otherwise stated, as used herein, the term "alkyl" refers to a monovalent saturated straight or branched chain hydrocarbon radical containing 1 to 12 carbon atoms. The alkyl group is preferably C ₁ -C ₈ alkyl. The alkyl group is more preferably C ₁ -C ₆ alkyl. Alkyl groups may be substituted or unsubstituted. Examples of C ₁ -C ₆ alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl, pentyl (including all isomeric forms) and hexyl (including all isomeric forms), heptyl (including all isomeric forms) and octyl (including all isomeric forms).

Heteroatoms such as oxygen, sulfur and nitrogen (in the form of tertiary amine moieties) may be present in the alkylene group, resulting in "heteroalkyl groups". Examples of heteroalkyl groups include, but are not limited to -CH ₂ CH ₂ N(CH ₃ ) ₂ and -CH ₂ CH ₂ OCH ₂ CH ₃ .

Unless otherwise stated, as used herein, the term "alkoxy" refers to a group of the general formula -O-(alkyl), where alkyl is as defined above. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, secondary butoxy, tertiary butoxy, n- Pentyloxy and n-hexyloxy.

As used herein, the term "aryl" refers to an all-carbon monocyclic or fused-cyclic polycyclic aromatic group having a conjugated pi electron system. Aryl groups can have 6 to 14 carbon atoms in the ring. Exemplary aryl groups include, but are not limited to, phenyl, biphenyl, and naphthyl.

As used herein, the term "cycloalkyl" refers to an all-carbon monocyclic or fused ring (i.e., a ring sharing a pair of adjacent carbon atoms) groups in which one or more rings do not have fully conjugated π electrons system. Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, 1-methylcyclopropyl, 2-methylcyclopentyl base and 2-methylcyclooctyl.

As used herein, the terms "heterocycle" and "heterocyclyl" are used interchangeably. The term "heterocycle" or "heterocyclyl" means a ring having 3 to 14 atoms, alternatively 3 to 12 atoms, alternatively 3 to 10 atoms, alternatively 3 to 8 atoms, alternatively 4 to 7 atoms, alternatively 5 Or a monocyclic, bicyclic or polycyclic structure of 6 atoms; one or more atoms, such as 1, 2 or 3 atoms, are independently selected from the group consisting of N, O and S, and the remaining ring atoms are carbon atoms . The ring structure may be saturated or unsaturated, but not aromatic. Exemplary heterocycles include, but are not limited to, imidazolyl, imidazolinolyl, imidazolidinyl, quinolinyl, isoquinolinyl, indolyl, indazolyl, indazolinyl, perhydropyridinyl, dazolinyl Pyridazyl, pyridyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyridyl, quinolinyl, piperidinyl, piperanyl, pyrazolinyl, piperazyl, pyrimidine base, pyridazinyl, pyridazinyl, thiophenyl, furyl, thienyl, triazolyl, thiazolyl, carboline, tetrazolyl, thiazolidinyl, benzofuranyl, thiazolyl 𠰌Linyltribenzoyl, ethazolyl, benzothiazolyl, lateral oxypiperidinyl, lateral oxypyrrolidinyl, lateral oxyazazolyl, azazolyl, isothiazolyl, isothiazolyl , furanyl, tetrahydropyranyl, tetrahydrofuranyl, thiadiazolyl, dioxolyl, dioxanyl, oxothiolanyl, benzodioxane Pentenyl, dithiolanyl, thienyl, tetrahydrothienyl, cyclobutanyl, dioxanyl, dioxolanyl, tetrahydrofuranodihydrofuranyl, tetrahydropyranodi Hydrofuryl, dihydropyranyl, tetrahydrofuranyl and tetrahydropyranyl.

As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic or tricyclic aryl group containing 1 to 4 heteroatoms selected from S, N and O, and includes those having a direct bond through a covalent bond. A group consisting of two such monocyclic rings or one such monocyclic ring and a monocyclic aromatic ring. The heteroaryl group may have 5 to 14 ring atoms, including 1 to 13 ring carbon atoms and 1 to 8 ring heteroatoms each independently selected from O, S and N. Exemplary heteroaryl groups include, but are not limited to, thienyl, benzothienyl, furyl, benzofuryl, pyrrolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isothiazolyl, benzo Isothiazolyl, pyrazolyl, thiazolyl, benzotiazolyl, isothiazolyl, benzisothiazolyl, isothiazolyl, triazolyl, benzotriazolyl, thiadiazolyl, 㗁Diazolyl, pyridyl, pyridinyl, pyrimidinyl, pyridinyl, trizoyl, indolyl and indazolyl.

As used herein, the term "heterocycloalkyl" refers to a monocyclic or polycyclic ring (including two or more rings fused together, including spiro, fused or bridged systems, such as bicyclic systems) saturated or The unsaturated non-aromatic 4- to 15-membered ring system includes 1 to 14 ring-forming carbon atoms and 1 to 10 ring-forming heteroatoms each independently selected from O, S and N. Examples of heterocycloalkyl groups include, but are not limited to, azetidinyl, tetrahydrofuran, dihydrofuran, dioxane, cyclohexyl, and the like.

As used herein, the term "ring system" refers to one or more rings (e.g., monocyclic or polycyclic) of atoms, which may be saturated, unsaturated, or aromatic, and the atoms may be carbon only or may include heteroatoms (e.g. N, S, O). For example, ring systems may include, but are not limited to, aryl (eg, phenyl, heterophenyl, naphthyl), alicyclic, heterocyclic, bicyclic (including spiro, fused, and bridged), and biheterocyclic structures.

As used herein, the terms "halide" and "halo" are used interchangeably and include fluorine, chlorine, bromine and iodine.

compound

In one aspect, the present specification provides an E3 ubiquitin ligase binding moiety ("ULM") covalently coupled to a protein targeting moiety (RB) via a chemical linkage group (linker) according to structure (I) Heterobifunctional compounds: RB─Connector─ULM (I) or its pharmaceutically acceptable salts, solvates, hydrates, polymorphs, tautomers, stereoisomers, isotopically enriched derivatives or prodrugs, in: The linker is a group covalently bonded to RB and the ULM moiety, RB is the RAS protein binding moiety that binds to mutant or wild-type KRAS protein; and ULM includes all E3 ubiquitin ligase binding moieties or chaperone complex binding moieties .

The bifunctional compounds described herein preferentially interact with KRAS mutant proteins compared to KRAS wild-type proteins. As described herein, the therapeutic effect may be the result of degradation, modulation, binding or modification of the KRAS protein by a compound described herein. Without wishing to be bound by any particular theory, the therapeutic effect may be the result of the compounds described herein modulating, targeting, binding or modifying E3 ubiquitin ligases. The therapeutic effect may be the result of compounds that modulate, target, bind, or modify E3 ubiquitin ligases to recruit E3 ubiquitin ligases to ubiquitinated RAS proteins and tag them for proteasomal degradation. Specifically, the bifunctional compound of formula (I) is suitable for treating and/or preventing RAS mutation-related diseases in an individual in need thereof.

ULM

ULM is an E3 ubiquitin ligase binding part or a chaperone complex binding part, and can be Cereblon E3 ubiquitin ligase binding part (CLM), Von Hippel-Lindau (VHL) ) E3 ubiquitin ligase-binding portion (VLM), DDB1-related and CUL4-associated factor 16 (DCAF16) E3 ubiquitin ligase-binding portion (DLM), IAP E3 ubiquitin ligase-binding portion (ILM), mouse double microbody 2 (MDM2) homolog E3 ubiquitin ligase binding part (MLM), Kelch-like ECH-associated protein-1 (KEAP1) E3 ubiquitin ligase binding part, DCAF15 E3 ubiquitin ligase binding part , RNF4 E3 ubiquitin ligase binding portion, RNF114 E3 ubiquitin ligase binding portion, aryl hydrocarbon receptor (AhR) E3 ubiquitin ligase binding portion, or other E3 ubiquitin described in SLAS Discovery, 1-19, 2020 Ligase binding moiety. ULMs include all moieties that bind, can bind, or form covalent bonds with any E3 ubiquitin ligase. For example, in certain embodiments, ULMs are capable of binding E3 ubiquitin ligases, such as Celebrobron or Vanhippe-Lindau (VHL). In certain embodiments, ULM is capable of forming a covalent bond with an E3 ubiquitin ligase, such as DCAF16. In certain embodiments, ULM is capable of binding to multiple different E3 ubiquitin ligases. In certain embodiments, ULM binds to cereblon. In certain embodiments, ULM binds to VHL. In certain embodiments, ULM forms a covalent bond with DCAF16.

Celeblon is an E3 ubiquitin ligase, and it forms an E3 ubiquitin ligase complex with damaged DNA-binding protein 1 (DDB1), clustin-4A (CUL4A) and clustin regulatory factor 1 (ROC1). This complex ubiquitinates a variety of proteins.

In certain embodiments, the ULM is a celeblon E3 ligase binding moiety (CLM) selected from the group consisting of thalidomide, lenalidomide, pomalidomide, and A group consisting of analogs, isosteres thereof or derivatives thereof; preferably having the following formulas CLM-a and CLM-b: CLM-a wherein: W is selected from CH ₂ and C=O; and Q ₁ , Q ₂ , Q ₃ and Q ₄ are each independently C, N or C-halogen, and wherein Q ₁ , Q ₂ , Q ₃ and one of Q ₄ covalently linked to the linker; CLM-b where the dashed lines represent the connection points to the linker.

In some embodiments, the ULM is ; where the dashed line represents the connection point to the linker; and X _CLM is halogen.

Vanhippe-Lindau (VHL) is an E3 ubiquitin ligase. VHL contains the receptor recognition subunit/E3 ubiquitin ligase complex VCB including extensin B and C, and a complex including tarnin-2 and Rbxl. The main substrates of VHL are hypoxia-inducible factor 1 (HIF-la), a transcription factor that upregulates genes in response to low oxygen levels, such as the pro-angiogenic growth factor VEGF, and the erythropoietin, an interleukin that induces red blood cells. VCB is a known target in cancer, chronic anemia and ischemia. In one embodiment, the ULM is a VHL E3 ubiquitin ligase binding moiety and can be hydroxyproline or a derivative thereof.

In certain embodiments, ULMs comprise peptide backbone structures. In certain embodiments, ULM has a chemical structure represented by the following formula: Among them: R ₅ is H or a linear or branched chain C _1-3 alkyl group; R ₆ is CN or a 5-membered heteroaryl group with one or two heteroatoms selected from N, S or O, which is optionally Methyl substitution (e.g., , the dotted line indicates the connection point to the benzene ring); Z ₂ is F or CN; and the dotted line indicates the connection point to the linker.

As described in Xiaoyu Zhang et al., Nature Chemical Biology , vol. 15, 2019, p73791og, DDB1-associated and CUL4-associated factor 16 (DCAF16) is an uncharacterized substrate recognition component of the CUL4-DDB1 E3 ubiquitin ligase. The DCAF16 protein has eight cysteine residues and can covalently bond to the DCAF16 binding moiety of the heterobifunctional degrader at the cysteine residues and subsequently promote protein degradation.

In certain embodiments, the ULM is a DCAF16 ligase binding moiety (DLM) and has the chemical structure represented by D16-a: D16-a wherein: R ₇ is H, halogen, C _1-4 alkyl, C _1-4 alkoxy; Y ₁ is O or S or NH; R ^m is a covalent electrophile, and is selected from the following Group: , the dashed line indicates the connection point to the nitrogen atom; and the dashed line to Y indicates the connection point to the linker.

In certain embodiments, the ULM is a DLM represented by: ; The dotted line represents the connection point with the connector.

In certain embodiments, ULM binds an E3 ubiquitin ligase with a _K value of less than about 10,000 nM, less than about 5,000 nM, less than about 1,000 nM, less than about 500 nM, less than about 100 nM, less than about 50 nM.

In certain embodiments, ULM binds Thaler with a K _D value of less than about 50 μM, less than about 10,000 nM, less than about 5,000 nM, less than about 1,000 nM, less than about 500 nM, less than about 100 nM, less than about 50 nM. Bron.

In certain embodiments, ULM binds VHL with a _K value of less than about 50 μM, less than about 10,000 nM, less than about 5,000 nM, less than about 1,000 nM, less than about 500 nM, less than about 100 nM, less than about 50 nM.

RB

In certain embodiments, RB is represented by formula RB-I: , where: X ₁ is H, NR ^X1 R ^{X2 ,} SO ₂ ^{NR X1} R ^X2 , ^{OR X1} , CHR ^X1 R ^X2 , NH(C=O)R OH or C _1-4 alkyl (straight chain or branched chain, optionally substituted with ¹ or ^more halogen groups), or R to an 8-membered ring system (optionally substituted with one or more C _1-4 alkyl groups) _; ^R C _1-10 alkoxy (straight chain or branched chain, optionally substituted with 1 or more halo groups), or aryl or alicyclic (4- to 8-membered ring system containing 0 to 2 heteroatoms, depending on substituted by 1 or more halo groups, CF ₃ , NH ₂ , OH or CN); W ₁ is a bond, C _1-6 alkyl, alicyclic, heterocyclic, bicyclic or biheterocyclic, each of which is substituted by 1 as appropriate One, 2 or 3 R ^W1 are substituted; and each R ^W1 is independently halo, C _1-4 alkyl (optionally substituted with 1 or more F), C _1-3 alkoxy (optionally substituted with 1 or more F substituted), OH, NH ₂ , NMe ₂ , NEt ₂ or CN; R ₁ is CH, C-Me, C-halogen or N; is an aryl or heteroaryl group, which is independently substituted by: 1 or more OR ^{A1 -RA2} , halo, CF ₃ , OCF ₃ , hydroxyl, nitro, CN, C≡CH, C _1-6 alkane group (straight chain or branched chain, optionally substituted by 1 or more halogen groups, C _1-6 alkoxy group), C _1-6 alkoxy group (straight chain or branched chain, optionally substituted by 1 or more halogen groups) group substituted), C _2-6 alkenyl, C _2-6 alkynyl, or a 4- to 7-membered saturated or partially unsaturated heterocyclic ring with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, R ^A1 is C _1-6 alkyl, R ^A2 is a heteroaryl group containing 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and optionally substituted with 1 or more halo groups; X ₂ is CH ₂ or C=O; It is a 4- to 8-membered alicyclic ring with 0 to 4 heteroatoms, which is optionally substituted by 0 to 4 ^RQ , each ^RQ is independently OH, or C _1-6 alkyl (straight chain or branched chain , optionally substituted with 1 or more halo groups), or the 2 R ^Q groups together with the atoms to which they are connected form a 3- to 8-membered ring system containing 0 to 2 heteroatoms; Z ₁ is H, C _{1 -4} alkyl, C _1-4 alkoxy, halogen, OH, CN or C _2-4 alkynyl; and the dashed line indicates the point of attachment to the linker.

In certain embodiments, the heteroatoms in ^RX1 and ^RX3 are independently selected from nitrogen, oxygen, and sulfur. Preferably, the heteroatom is nitrogen.

^{In certain embodiments ,} _X1 ^{is H ,} _NR ^{_ _ _} is H or C _1-4 alkyl ^, _or ^R aryl, _alicyclic or bicyclic; _and ^R chain, optionally substituted with 1 or more halo groups) or aryl or alicyclic (4 to 8 membered ring systems containing 0 to 2 heteroatoms independently selected from nitrogen and oxygen, optionally substituted with 1 or Multiple halo, _CF or NH _{substitutions} ).

In certain embodiments, W ₁ is a bond or C _1-4 alkyl optionally substituted with C _1-3 alkoxy.

In some embodiments, is phenyl, heterophenyl, naphthyl or indazole, which is independently passed through 1 or more O-CH ₂ ^-RA2 , halo, CF ₃ , OCF ₃ , hydroxyl, CN, C _1-6 alkyl, C _1-6 alkoxy substituted, R ^A2 is a heteroaryl group having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur and optionally substituted with 1 or more halo groups.

In some embodiments, is phenyl or indazole, which is independently substituted by 1 or more O-CH ₂ ^-RA2 , halo, CF ₃ , OCF ₃ , CN, C _1-6 alkyl, C _1-6 alkoxy, R ^A2 is a heteroaryl group having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur and optionally substituted with 1 or more halo groups.

In some embodiments, The heteroatoms in are independently selected from nitrogen, oxygen and sulfur. Preferably, the heteroatom is nitrogen.

In some embodiments, It is a 4- to 6-membered alicyclic ring with 1 to 2 heteroatoms, which is optionally substituted by 0 to 4 ^RQ , each ^RQ is independently H or C _1-6 alkyl (linear or branched chain) , or the two ^RQ groups and the atoms to which they are connected together form a 4- to 5-membered ring system containing 0 to 2 heteroatoms, and the heteroatom is nitrogen.

In certain embodiments, Formula RB-I is selected from the group consisting of RB-1 to RB-7: . The dotted line represents the connection point with the connector.

In certain embodiments, Formula RB-I is represented by: ; The dotted line represents the connection point with the connector.

In some embodiments of the invention, RB-I is selected from the group consisting of: ; The dotted line represents the connection point with the connector.

In some embodiments of the invention, the bifunctional compound is selected from Formula Ia to Formula Ig: .

In certain embodiments, the RB binding moiety is present at less than about 100 μM, less than about 50 μM, less than about 10 μM, less than about 5 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, or less than about 50 nM. K _D value for binding to KRAS protein.

In certain embodiments, the RB binding moiety selectively binds a mutant KRAS protein relative to a wild-type KRAS protein. In some embodiments, compounds of Formula (I) selectively bind mutant KRAS protein relative to wild-type KRAS protein. In certain embodiments, the selectivity is between about 2-fold and about 5-fold. In certain embodiments, the selectivity is between about 5-fold and about 10-fold. In certain embodiments, the selectivity is between about 10-fold and about 20-fold.

Connector

The linker is a bivalent moiety that connects RB and ULM; preferably, the linker covalently couples RB to ULM. In certain embodiments, the linker comprises the following chemical structure , where: The dotted line of the linker is the connection point with RB or ULM; Y ^L2 is a bond, or an unsubstituted or substituted straight-chain or branched C _1-4 alkyl or alkoxy group (for example, by halogen as appropriate) , C _1-3 alkyl, methyl or ethyl substitution); W ^L3 is a bond, -C=OCH ₂ - or a 3- to 7-membered ring system (such as a 4- to 6-membered cycloalkyl, heterocycloalkyl or aryl) or an 8- to 12-membered spirocyclic ring, each having 0 to 4 heteroatoms (e.g., 0 to 4 heteroatoms independently selected from N, O, and S) and optionally substituted with halogen or methyl; Y ^L3 is a bond or C _1-32 alkyl alkenyl or alkynyl group, in which one or more C atoms are optionally separated by O, Or NH replacement, and each carbon is optionally substituted by halogen, =O, methyl or ethyl, and each nitrogen is optionally substituted by methyl or ethyl; Y ^L4 is a bond, O or unsubstituted or substituted straight Chain or branched C _1-6 alkyl, one or more carbons of which are optionally replaced by O, NH or _NCH3 , and optionally substituted by halogen or methyl; W ^L4 is a 3- to 8-membered ring system (e.g. 4- to 6-membered cycloalkyl or heterocycloalkyl, aryl or ) or a 5- to 8-membered spirocyclic ring, each having 0 to 4 heteroatoms (e.g., 0 to 4 heteroatoms independently selected from N, O, and S) and optionally modified by a halogen (e.g., F, Cl, Br) or methyl substituted; and Y ^L5 is a bond or an unsubstituted or substituted C _1-6 alkyl group, in which one or more C atoms are optionally replaced by O and optionally replaced by a halo group (such as F, Cl, Br ) or methyl substitution.

In certain embodiments, Y ^L2 is a bond or C _1-4 alkyl; preferably, it is a bond or CH ₂ .

In certain embodiments, W ^L3 is a bond, -C=OCH ₂ -, a 4- to 6-membered heterocycloalkyl group containing 0 to 2 nitrogens, or an 8- to 12-membered spirocyclic ring, each ring containing 0 to 1 nitrogen.

In certain embodiments, Y ^L3 is a bond or C _1-8 alkyl or alkynyl group, wherein one or more C atoms are optionally replaced with O, and each carbon is optionally substituted with =O.

In certain embodiments, Y ^L4 is a bond or C _1-4 alkyl; preferably a bond or CH ₂ .

In certain embodiments, W ^L4 is an aryl group optionally substituted with halogen (eg, F, Cl, Br) or a 4- to 6-membered heterocycloalkyl group containing 0 to 2 nitrogens.

In certain embodiments, Y ^L5 is a bond or C _1-4 alkyl; preferably a bond or CH ₂ .

In certain embodiments, the linker is selected from the group consisting of: ; The dotted line of the connector is the connection point with RB or ULM.

In certain embodiments, the ring system of the linker and the ring system of RB can share one or more atoms (carbon atoms or heteroatoms, preferably carbon atoms) to form a bicyclic structure. For example, the ring system of the linker and the ring system of the RB may share 1 atom to form a spirocyclic structure, 2 atoms to form a fused bicyclic structure, or 3 atoms to form a bridged bicyclic structure.

The RB group and the ULM group can be covalently linked to the linker via any group that is suitable and stable for the chemistry of the linker. In illustrative aspects of the invention, the linker in certain embodiments is independently via an amide, ester, thioester, ketone, carbamate (urethane), carbon or ether covalent bond To the RB group and the ULM group, each of these groups can be inserted into any position on the RB group and the ULM group, so that the ULM group on the ubiquitin ligase and the target protein to be degraded The RB group produces maximum binding.

WO 2021/222138 also discloses bifunctional compounds that bind to mutant KRAS proteins. In certain embodiments of the invention, while not wishing to be bound by any particular theory, it is believed that due to the linker attaching to RB-I , and/or because the molecular weight of the bifunctional compounds is relatively small (less than the molecular weight of WO 2021/222138), these bifunctional compounds provide improved pharmacokinetic properties and improved therapeutic effects.

As used herein, the phrase "substituted or unsubstituted" means that substitution is optional. Where substitution is required, such substitution means that any number of hydrogens on a designated atom are selectively replaced by a group selected from the designated group, subject to the proviso that the normal valency of the designated atom is not exceeded and that the substitution results in a stable compound. For example, when the substituent is a ketone group (ie =O), two hydrogens on the atom are replaced. Examples of substituents for "substituted" groups are those found in the exemplary compounds and examples disclosed herein, and may include, for example, halogen, -OH, _-CF3 , -CN, _-NO2 , alkyl , alkenyl, alkynyl, cycloalkyl, alkoxy, haloalkyl, alkylamino, aminoalkyl, dialkylamino, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, Alkoxyalkoxy, aminoalkoxy, alkylaminoalkoxy, alkylaminoalkyl and aryl groups and the like.

As used herein, the term "pharmaceutically acceptable salts" refers to compounds according to the invention used in the form of salts derived from inorganic or organic acids and bases. Acid salts include, for example, the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate , camphor sulfonate, cyclopentane propionate, digluconate, lauryl sulfate, ethanesulfonate, fumarate, fluoroheptanoate, glycerophosphate, hemisulfate , Enanthate, caproate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethane sulfonate, lactate, maleate, methanesulfonate, 2-naphthalene Sulfonate, nicotinate, oxalate, pamoate, pectate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinic acid Salt, tartrate, thiocyanate, tosylate and undecanoate. Salts derived from suitable bases include alkali metals (eg sodium), alkaline earth metals (eg magnesium), ammonium and NW ⁴⁺ (where W is C _1-4 alkyl).

As used herein, "prodrug" is intended to include any covalently bonded carrier that, when such prodrug is administered to an individual, is released via physiological effects in vivo (such as hydrolysis, metabolism, and the like) according to the formula ( The active parent drug of I). Those skilled in the art are generally familiar with the applicability and techniques involved in preparing and using prodrugs. Prodrugs of compounds of formula (I) (the parent compound) can be prepared by modifying functional groups present in the compound such that the modification is cleaved to the parent compound during routine procedures or in vivo. "Prodrugs" include compounds of formula (I) in which a hydroxyl, amine or sulfhydryl group is bonded to any group that is cleaved to form a free hydroxyl, free amine or sulfhydryl group, respectively, when the prodrug is administered to an individual. Free sulfhydryl group. Examples of prodrugs include, but are not limited to, derivatives and metabolites of compounds of formula (I) including biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable Carbonates, biohydrolyzable ureas and biohydrolyzable phosphate analogs. In certain embodiments, prodrugs of compounds of Formula (I) having carboxyl functionality are lower alkyl (eg, C ₁ -C ₆ ) esters of carboxylic acids. Carboxylic acid esters are preferably formed by esterifying any carboxylic acid moiety present on the molecule.

The compounds of the present invention may exist in the form of solvates. As used herein and unless otherwise specified, the term "solvate" means a compound of formula (I) or a pharmaceutically acceptable salt thereof further including stoichiometric or non-stoichiometric forms bound by non-covalent intermolecular forces. of solvent. If the solvent is water, the solvate may be appropriately called "hydrate", such as hemihydrate, monohydrate, sesquihydrate, dihydrate, trihydrate, etc.

As used herein, the term "tautomers" refers to compounds whose structures differ significantly in the arrangement of atoms but which readily and rapidly reach equilibrium, and it is understood that the compounds provided herein may be characterized as different tautomers , and when a compound has tautomeric forms, all tautomeric forms are intended to be within the scope of the present invention, and the naming of the compound does not exclude any tautomers. Exemplary tautomerizations include, but are not limited to, amide-imine; enamine-imine; enamine-(different)enamine tautomerization; and keto-enol.

The term "stereoisomers" refers to compounds that have the same chemical structure but different arrangements of atoms or groups in space. Stereoisomers include diastereomers, mirror image isomers, conformational isomers and the like.

The term "polymorph" refers to the crystalline form of a compound (or a salt, hydrate or solvate thereof). All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors can make one crystal form dominant. Various polymorphs of a compound can be prepared by crystallization under different conditions.

As used herein, an "isotopically enriched derivative" refers to a compound containing at least one atom having an isotopic composition other than that atom's natural isotopic composition. "Isotope enrichment" may be expressed in terms of the percentage of a given amount of a specific isotope incorporated at a given atom in a molecule, rather than in terms of the natural abundance of the isotope at that atom.

The bifunctional compound of the present invention can be one or more specific geometric, optical, enantiomers, diastereomers, epimers, hysteretic isomers, stereoisomers, tautomers, and configurations. Isomers or mutator forms exist, including but not limited to cis and trans; E- and Z-forms; c-, t- and r-forms; endo- and exo-forms; R-, S - and meso-forms; D- and L-forms; d- and I-forms; (+) and (-) forms; keto-, enol- and enolate-forms; cis- and reverse -forms; syncline- and anticline-forms; alpha- and beta-forms; axial and equatorial forms; navicular-, chair-, torsional-, capsular- and semi-chair-forms; and combinations thereof.

In certain embodiments, the bifunctional compound is selected from compounds (cpd) 1-72: 4-Amino-N-(3-(5-((4-(4-((4-(2-(2,6-bisoxypiperidin-3-yl))-1,3-bis Oxyisoindolin-5-yl)piperidine-1-yl)methyl)benzyl)piperidine-1-yl)methyl)-3-(4-(trifluoromethoxy)phenyl )-1H-indol-1-yl)propyl)piperidine-4-methamide (cpd 1); 4-Amino-N-(3-(5-((4-(4-((4-(2-(2,6-bisoxypiperidin-3-yl))-1,3-bis Oxyisoindolin-5-yl)piperidine-1-yl)methyl)benzyl)piperidine-1-yl)methyl)-3-(4-(trifluoromethoxy)phenyl )-1H-indol-1-yl)propyl)piperidine-4-methamide (cpd 2); 5-(4-((4-((1-(3-aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl) Piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxypiperidin-3-yl)isoindoline-1,3-dione (cpd 3 ); 5-(4-((4-((1-(3-aminopropyl))-3-(4-hydroxyphenyl)-1H-indol-5-yl)methyl)piperidine-1-yl )Methyl)piperidin-1-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline-1,3-dione (cpd 4); 5-(4-((1-((1-(3-aminopropyl))-3-(4-hydroxyphenyl)-1H-indol-5-yl)methyl)piperidin-4-yl )Methyl)piperidin-1-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline-1,3-dione (cpd 5); 5-(4-((1-((1-(3-aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl) Piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline-1,3-dione (cpd 6 ); 5-(4-((4-((1-(3-aminopropyl))-3-(4-fluorophenyl)-1H-indol-5-yl)methyl)piperidine-1-yl )Methyl)piperidin-1-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline-1,3-dione (cpd 7); 5-(4-((1-(3-Aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl)piperidine-1 -yl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline-1,3-dione (cpd 8); 1-(4-((1-(3-Aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl)piperidine-1 -yl)-2-((1-(2-chloroacetyl)-1,2,3,4-tetrahydroquinolin-6-yl)oxy)ethan-1-one (cpd 9); 5-(4-((4-((1-(3-aminopropyl))-3-(4-methoxyphenyl)-1H-indol-5-yl)methyl)piperidine-1 -yl)methyl)piperidin-1-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline-1,3-dione (cpd 10); 4-(1-(3-aminopropyl)-5-((4-((4-(2-(2,6-bisoxypiperidin-3-yl))-1,3-bis Oxyisoindolin-5-yl)piperidin-1-yl)methyl)piperidin-1-yl)methyl)-1H-indol-3-yl)benzonitrile (cpd 11); 5-(4-((1-((1-(3-aminopropyl))-3-(6-methoxypyridin-3-yl)-1H-indol-5-yl)methyl)piper (Din-4-yl)methyl)piperidin-1-yl)-2-(2,6-bis-oxypiperidin-3-yl)isoindoline-1,3-dione (cpd 12) ; 3-(1-(3-aminopropyl)-5-((4-((4-(2-(2,6-bisoxypiperidin-3-yl))-1,3-bis Oxyisoindolin-5-yl)piperidin-1-yl)methyl)piperidin-1-yl)methyl)-1H-indol-3-yl)benzonitrile (cpd 13); 5-(4-((1-((1-(3-aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-7-yl)methyl) Piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline-1,3-dione (cpd 14 ); 5-(4-((1-((1-(3-aminopropyl)-3-(2-fluoro-4-methoxyphenyl)-1H-indol-5-yl)methyl) Piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline-1,3-dione (cpd 15 ); 5-(4-((1-((1-(3-aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-6-yl)methyl) Piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline-1,3-dione (cpd 16 ); 5-(4-((1-((1-(3-aminopropyl))-3-(2-methoxypyridin-3-yl)-1H-indol-5-yl)methyl)piper (Din-4-yl)methyl)piperidin-1-yl)-2-(2,6-bis-oxypiperidin-3-yl)isoindoline-1,3-dione (cpd 17) ; 5-(4-((1-((1-(3-aminopropyl))-3-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)methyl)piper (Din-4-yl)methyl)piperidin-1-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline-1,3-dione (cpd 18) ; 5-(4-((1-((1-(3-aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-4-yl)methyl) Piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline-1,3-dione (cpd 19 ); 4-(4-((1-((1-(3-aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl) Piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline-1,3-dione (cpd 20 ); (3-(5-((4-(((4-(2-(2,6-di-oxypiperidin-3-yl))-1,3-di-oxyisoindolin-5-yl )piperidin-1-yl)methyl)piperidin-1-yl)methyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-1-yl)propyl) Tertiary butyl carbamate (cpd 21); 5-(3-((1-((1-(3-aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl) Piperidin-4-yl)oxy)prop-1-yn-1-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline-1,3-dione (cpd 22); 5-(3-((1-((1-(3-aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl) Piperidin-4-yl)oxy)propyl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline-1,3-dione (cpd 23); 5-(4-(2-(4-((1-(3-aminopropyl))-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl yl)piperidin-1-yl)ethyl)piperidine-1-yl)-2-(2,6-bis-oxypiperidin-3-yl)isoindoline-1,3-dione (cpd 24); 5-(4-((1-((1-(3-aminopropyl)-3-(3-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl) Piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-dioxypiperidin-3-yl)isoindoline-1,3-dione (Cpd 25 ); 5-(4-((1-(1-(3-aminopropyl))-3-(4-(trifluoromethoxy)phenyl)-1H-indole-5-carbonyl)piperidine-4 -Methyl)piperidin-1-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline-1,3-dione (Cpd 26); 5-(4-((1-((1-(3-aminopropyl))-3-(3-hydroxynaphthalen-1-yl)-1H-indol-5-yl)methyl)piperidine- 4-yl)methyl)piperidin-1-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline-1,3-dione (Cpd 27); 5-(4-((1-((1-(azetidin-3-ylmethyl))-3-(4-(trifluoromethoxy)phenyl)-1H-indole-5- yl)methyl)piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-di-oxypiperidin-3-yl)isoindoline-1,3- Dione (Cpd 28); 5-(4-((1-((1-(3-aminopropyl))-3-(5-chloro-6-methyl-1H-indazol-4-yl)-1H-indole-5 -yl)methyl)piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline-1,3 -Diketone (Cpd 29); 5-(4-((1-((1-(3-aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl) Piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline-1,3-dione (Cpd 30 ); (2S)-N-(2-(3-(4-((1-(3-aminopropyl))-3-(4-(trifluoromethoxy)phenyl)-1H-indole-5 -yl)methyl)piperidine-1-yl)propoxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclic Propane-1-formamide)-3,3-dimethylbutyl)-4-hydroxypyrrolidine-2-formamide (Cpd 31); 5-(4-((1-((1-(3-aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl) Piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-dioxypiperidin-3-yl)-6-fluoroisoindoline-1,3-di Ketone (Cpd 32); 2-(2,6-Dilateral oxypiperidin-3-yl)-5-(4-((1-((1-(3-(methylamino)propyl))-3-(4- (Trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl)piperidin-4-yl)methyl)piperidin-1-yl)isoindoline-1,3-di Ketone (Cpd 33); 5-(7-((1-(3-Aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl)-2,7 -Diazaspiro[3.5]non-2-yl)-2-(2,6-bis-oxypiperidin-3-yl)isoindoline-1,3-dione (Cpd 34); 5-(4-((1-((1-(3-aminopropyl))-3-(2-fluoro-4-((3-fluoropyridin-2-yl)methoxy)phenyl)- 1H-indol-5-yl)methyl)piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindol Doline-1,3-dione (Cpd 35); 5-(4-(1-((1-(3-aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl)nitrogen Heterocyclobutan-3-yl)piperidin-1-yl)-2-(2,6-dioxypiperidin-3-yl)isoindoline-1,3-dione (Cpd 36) ; 5-(4-((1-((1-(3-(dimethylamino)propyl))-3-(4-(trifluoromethoxy)phenyl)-1H-indole-5- yl)methyl)piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-di-oxypiperidin-3-yl)isoindoline-1,3- Dione (Cpd 37); 5-(4-((1-((1-(5-aminopentyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl) Piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-dioxypiperidin-3-yl)isoindoline-1,3-dione (Cpd 38 ); 5-(7-((1-((1-(3-aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl) Piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindole Phenoline-1,3-dione (Cpd 39); N-(3-(5-((4-((4-(2-(2,6-dioxypiperidin-3-yl))-1,3-dioxyisoindoline-5 -yl)piperidin-1-yl)methyl)piperidin-1-yl)methyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-1-yl)propan Acetamide (Cpd 40); 4-(5-((4-((4-(2-(2,6-Dilateral oxypiperidin-3-yl)-1,3-Dilateral oxyisoindolin-5-yl) Piperidin-1-yl)methyl)piperidin-1-yl)methyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-1-yl)butanenitrile (Cpd 41); 2-(2,6-Dilateral oxypiperidin-3-yl)-5-(4-((1-((1-((1-methyl-1H-imidazol-5-yl)methyl) -3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl)piperidin-4-yl)methyl)piperidin-1-yl)isoindoline -1,3-dione (Cpd 42); 2-(2,6-Dilateral oxypiperidin-3-yl)-5-(4-((1-((1-(3-methoxypropyl))-3-(4-(trifluoro Methoxy)phenyl)-1H-indol-5-yl)methyl)piperidin-4-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione (Cpd 43); 2-(2,6-Dilateral oxypiperidin-3-yl)-5-(4-((1-((1-(3-(2,2,2-trifluoroethoxy))propyl )-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl)piperidin-4-yl)methyl)piperidin-1-yl)isoindole Phenoline-1,3-dione (Cpd 44); N-(3-(5-((4-((4-(2-(2,6-dioxypiperidin-3-yl))-1,3-dioxyisoindoline-5 -yl)piperidin-1-yl)methyl)piperidin-1-yl)methyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-1-yl)propan (Cpd 45)-1H-pyrrole-2-methamide (Cpd 45); 3-((4-(1-((1-(3-aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl) Piperidin-4-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (Cpd 46); N-(3-(5-((4-((4-(2-(2,6-dioxypiperidin-3-yl))-1,3-dioxyisoindoline-5 -yl)piperidin-1-yl)methyl)piperidin-1-yl)methyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-1-yl)propan methyl)-3-(trifluoromethyl)benzamide (Cpd 47); N-(3-(5-((4-((4-(2-(2,6-dioxypiperidin-3-yl))-1,3-dioxyisoindoline-5 -yl)piperidin-1-yl)methyl)piperidin-1-yl)methyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-1-yl)propan (Cpd 48)-4-fluorobenzamide (Cpd 48); 3-((4-(4-((1-((1-(3-aminopropyl))-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl )methyl)piperidin-4-yl)methyl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (Cpd 49); 5-(4-((1-((1-butyl-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl)piperidin-4-yl )Methyl)piperidin-1-yl)-2-(2,6-dioxypiperidin-3-yl)isoindoline-1,3-dione (Cpd 50); 2-(2,6-Dilateral oxypiperidin-3-yl)-5-(4-((1-((3-(4-(trifluoromethoxy)phenyl))-1H-indole -5-yl)methyl)piperidin-4-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione (Cpd 51); 5-(4-((1-((1-((2,3-dihydrobenzo[b][1,4]dioxen-2-yl)methyl))-3-(4 -(Trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl)piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-di Pendant oxypiperidin-3-yl)isoindoline-1,3-dione (Cpd 52); 2-(2,6-Dilateral oxypiperidin-3-yl)-5-(4-((1-((1-(pyridin-2-ylmethyl))-3-(4-(trifluoro Methoxy)phenyl)-1H-indol-5-yl)methyl)piperidin-4-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione (Cpd 53); 3-((4-(1'-((1-(3-aminopropyl))-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl )-[4,4'-dipiperidin]-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (Cpd 54); 3-((4-(4-((1-((1-butyl-3-(4-(trifluoromethoxy)phenyl))-1H-indol-5-yl)methyl)piperidine -4-yl)methyl)piperidine-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (Cpd 55); 5-(4-((1-((1-((1,3-dioxolane-2-yl)methyl)methyl)-3-(4-(trifluoromethoxy)phenyl)-1H- Indol-5-yl)methyl)piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline -1,3-dione (Cpd 56); 2-(2,6-Dilateral oxypiperidin-3-yl)-5-(4-((1-((1-(4-methylpentyl))-3-(4-(trifluoromethyl Oxy)phenyl)-1H-indol-5-yl)methyl)piperidin-4-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione (Cpd 57 ); 3-((4-(4-((1-((1-(3-(dimethylamino)propyl))-3-(4-(trifluoromethoxy)phenyl)-1H-indino Indo-5-yl)methyl)piperidin-4-yl)methyl)piperidine-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (Cpd 58); 5-(1'-((1-(3-Aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl)-[4 ,4'-dipiperidin]-1-yl)-2-(2,6-di-oxypiperidin-3-yl)isoindoline-1,3-dione (Cpd 59); 3-((4-(1'-((1-(3-(dimethylamino)propyl))-3-(4-(trifluoromethoxy)phenyl)-1H-indole-5 -yl)methyl)-[4,4'-dipiperidin]-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (Cpd 60); 4-Amino-N-(3-(5-((4-((4-(4-((2,6-bisoxypiperidin-3-yl)amino))-2-fluorophenyl )piperidin-1-yl)methyl)piperidin-1-yl)methyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-1-yl)propyl) Piperidine-4-methamide (Cpd 61); 5-((4-((4-(2-(2,6-bisoxypiperidin-3-yl)-1,3-bisoxy-2,3-dihydro-1H-indene- 5-yl)piperidin-1-yl)methyl)piperidin-1-yl)methyl)-N,N-dimethyl-3-(4-(trifluoromethoxy)phenyl)-1H -Indole-1-sulfonamide (Cpd 62); 3-((3-Fluoro-4-(4-((1-((1-(4-methylpentyl))-3-(4-(trifluoromethoxy)phenyl)-1H-indole -5-yl)methyl)piperidin-4-yl)methyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione (Cpd 63); 3-((4-fluoro-3-(4-((1-((3-(4-(trifluoromethoxy)phenyl))-1H-indol-5-yl)methyl)piperidine- 4-yl)methyl)piperidine-1-yl)phenyl)amino)piperidine-2,6-dione (Cpd 64); 3-((3-Fluoro-4-(1'-((3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl)-[4,4' -Dipiperidin]-1-yl)phenyl)amino)piperidine-2,6-dione (Cpd 65); 5-(5-((1-(3-Aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl)hexahydropyrrolo [3,4-c]pyrrole-2(1H)-yl)-2-(2,6-bis-oxypiperidin-3-yl)isoindoline-1,3-dione (Cpd 66) ; 3-((4-(5-((1-(3-aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl) Hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (Cpd 67); 5-(4-((1-((1-(3,3-dimethoxypropyl))-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl )Methyl)piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline-1,3-di Ketone (Cpd 68); 5-(5-((1-(3-(dimethylamino)propyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl )Hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline-1,3-di Ketone (Cpd 69); 5-(1'-((1-(3-aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl)-[3 ,3'-azazetidin]-1-yl)-2-(2,6-bis-oxypiperidin-3-yl)isoindoline-1,3-dione (Cpd 70); 5-(1'-((1-(3-(dimethylamino)propyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl Cpd 71); (2R,4S)-1-((R)-2-(2-(4-((1-((1-(3-aminopropyl))-3-(4-(trifluoromethoxy) Phenyl)-1H-indol-5-yl)methyl)piperidin-4-yl)methyl)piperidin-1-yl)acetyl)-3,3-dimethylbutyl)-4 -Hydroxy-N-((R)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-methamide (Cpd 72); or its pharmaceutically acceptable salts, solvates, hydrates, polymorphs, tautomers, stereoisomers, isotopically enriched derivatives or prodrugs.

In certain embodiments, bifunctional compounds as described herein are present at less than about 100 μM, less than about 50 μM, less than about 10 μM, less than about 5 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM. Or bind KRAS protein with a _KD value less than about 50 nM.

In certain embodiments, bifunctional compounds as described herein selectively bind mutant KRAS protein relative to wild-type KRAS protein. In some embodiments, compounds of Formula (I) selectively bind mutant KRAS protein relative to wild-type KRAS protein. In certain embodiments, the selectivity is between about 2-fold and about 5-fold. In certain embodiments, the selectivity is between about 5-fold and about 10-fold. In certain embodiments, the selectivity is between about 10-fold and about 20-fold.

In certain embodiments, bifunctional compounds as described herein are present at less than about 50 μM, less than about 10,000 nM, less than about 5,000 nM, less than about 1,000 nM, less than about 500 nM, less than about 100 nM, less than about 50 nM. The K _D value of binding E3 ubiquitin ligase.

In certain embodiments, bifunctional compounds as described herein are present at 20 μM or less, 10 μM or less, 5 μM or less, 1,000 nM or less, 500 nM or less, 100 nM or less. Promote degradation of mutant KRAS protein by up to 10%, up to 20%, up to 30%, up to 40%, up to 50%, up to 60%, up to 70%, up to 70%, up to 10% at low, 50 nM or lower, 10 nM or lower concentrations 80%, at most 90%, at most 100%.

Pharmaceutical compositions and applications

Bifunctional compounds as described herein may be administered therapeutically as pure chemicals, although administration of the compounds in the form of pharmaceutical compositions or formulations may be suitable. Therefore, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a bifunctional compound as described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, or hydrate thereof , polymorphs, isotopically enriched derivatives or prodrugs, and one or more pharmaceutically acceptable excipients.

Pharmaceutical compositions may be administered in a variety of dosage forms, including but not limited to solid or liquid dosage forms, oral dosage forms, parenteral dosage forms, intranasal dosage forms, suppositories, buccal tablets, dragees, buccal tablets, controlled release dosage forms, pulse release dosage forms , immediate-release dosage forms, intravenous solutions, suspensions, or combinations thereof. Pharmaceutical compositions may be administered, for example, by oral or parenteral routes, including intravenous, intramuscular, intraperitoneal, subcutaneous, transdermal, respiratory (aerosol), rectal, vaginal, and surface (including intrabuccal and lingual) (below) investment.

"Excipient" generally refers to a substance, often an inert substance, that is added to a pharmacological composition or otherwise serves as a vehicle to further facilitate administration of the compound. Examples of excipients include, but are not limited to, inert diluents, disintegrating agents, binders, lubricants, sweeteners, flavoring agents, colorants, preservatives, foaming mixtures, and adsorbents. Suitable inert diluents include, but are not limited to, sodium and calcium carbonate, sodium and calcium phosphate, lactose and the like. Suitable disintegrants include, but are not limited to, starches (such as corn starch), cross-linked polyvinylpyrrolidone, agar, alginic acid or salts thereof (such as sodium alginate), and the like. Binders may include, but are not limited to, magnesium aluminum silicate, starch (such as corn, wheat, or rice starch), gelatin, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, and the like. The lubricant, if present, will usually be magnesium and calcium stearate, stearic acid, talc or hydrogenated vegetable oil. If necessary, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption from the gastrointestinal tract. The composition may also be formulated as a chewable lozenge, for example, by using a substance such as mannitol in the formulation.

The term "therapeutically effective amount" refers to an amount of a bifunctional compound as described herein that provides the desired effect in a subject treated when administered to the subject in single or multiple doses, alone or in combination with an anti-cancer agent.

The bifunctional compounds described herein are effective in treating or ameliorating KRAS mutation-related diseases. When the target protein is positioned adjacent to the E3 ubiquitin ligase, degradation of the target protein will occur, thereby degrading/inhibiting the target protein and controlling protein content. The control of protein levels achieved by the present invention provides for the treatment of disease conditions or conditions that are modulated by reducing protein levels in the patient's cells via the target protein. "KRAS mutation-related disease" may be cancer, autoimmune disease, infectious disease, or vasoproliferative disorder. The cancer may be lung cancer (eg, non-small cell lung cancer), colorectal cancer, colorectal cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, bladder cancer, stomach cancer, kidney cancer, salivary gland cancer, ovarian cancer, uterine corpus cancer, cervix cancer cancer, oral cancer, skin cancer, brain cancer, lymphoma, leukemia, biliary malignancy, endometrial cancer or myeloid leukemia.

Bifunctional compounds as described herein can be administered as the sole active agent, or administered separately, sequentially, or together with one or more other anti-cancer agents. Unless otherwise stated, as used herein, the term "anticancer agent" refers to an agent capable of inhibiting or preventing the growth of neoplasms or examining the maturation and proliferation of malignant cells (cancer cells). Anti-cancer agents suitable for use in combination with compounds of formula (I) include, but are not limited to, targeted cancer drugs such as trastuzumab, ramucirumab, vismodegib, soni sonidegib, bevacizumab, everolimus, tamoxifen, toremifene, fulvestrant, anastrozole anastrozole), exemestane, lapatinib, letrozole, pertuzumab, trastuzumab-metansin conjugate (ado- trastuzumab emtansine), palbociclib, cetuximab, panitumumab, ziv-aflibercept, regorafenib, lmatinib mesylate, lanreotide acetate, sunitinib, denosumab, alitretinoin, sorafenib sorafenib), pazopanib, temsirolimus, everolimus, tretinoin, dasatinib, nilotinib, bosutinib, rituximab, alemtuzumab, ofatumumab, obinutuxumab, ibrutinib, Aide Idelalisib, blinatumomab, soragenib, crizotinib, erlotinib, gefitinib, dimethonine afatinib dimaleate, ceritnib, ramucirumab, nivolumab, pembrolizumab, osimertinib (osimertinib) and necitumumab; alkylating agents such as busulfan, chlorambucil, cyclophosphamide, iphosphamide ), melphalan, nitrogen mustard, streptozocin, thiotepa, uracil nitrogen mustard, triethylenemelamine , temozolomide and 2-chloroethyl-3-sarcosinamide-1-nitrosourea (SarCNU); antibiotics or plant alkaloids, such as actinomycin-D, bole Bleomycin, cryptophycins, daunorubicin, doxorubicin, idarubicin, irinotecan, L-aspartase (L-asparaginase), mitomycin-C (mitomycin-C), mitramycin, navelbine, paclitaxel, docetaxel, topote topotecan, vinblastine, vincristine, teniposide (VM-26), and etoposide (VP-16); hormones or steroids, such as 5α- Reductase inhibitors, aminoglutethimide, anastrozole, bicalutamide, chlorotrianisene, diethylstilbestrol (DES), dromostanolone ), estramustine, ethinyl estradiol, flutamide, fluoxymesterone, goserelin, hydroxyprogesterone, trazole, leuprolide, medroxyprogesterone acetate, megestrol acetate, methyl prednisolone, methyltestosterone (methyltestosterone), mitotane, nilutamide, prednisolone, arzoxifene (SERM-3), tamoxifen, testolactone Testolactone, testosterone, triamcinolone, and zoladex; synthetics, such as all-trans retinoic acid, carmustine (BCNU), carboplatin (carboplatin) (CBDCA), lomustine (CCNU), cis-diamine dichloroplatin (cisplatin), dacarbazine (dacarbazine), gliadel (gliadel), hexamethylmelamine (hexamethylmelamine) , hydroxyurea, levamisole, mitoxantrone, o,p'-dichlorodiphenyldichloroethane (o,p'-DDD) (also known as hydroxyurea) (lysodren or mitotane), oxaliplatin, porfimer sodium, procarbazine and imatinib mesylate (Gleevec ^® ) ;Antimetabolites such as chlorodeoxyadenosine, cytosine arabinoside, 2'-deoxycoformycin, fludarabine phosphate ), 5-fluorouracil (5-FU), 5-fluoro-2'-deoxyuridine (5-FUdR), gemcitabine (gemcitabine), camptothecin (camptothecin), 6-mercaptopurine (6-mercaptopurine), methotrexate, 4-methylthioamphetamine (4-MTA), and thioguanine; and biological agents, such as alpha interferon, Bacillus Calmette-Guerin (BCG) , granule colony-stimulating factor (G-CSF), granule-macrophage colony-stimulating factor (GM-CSF), interleukin-2 and herceptin.

Furthermore, the present invention provides a method for preventing, ameliorating and/or treating a disease associated with a KRAS mutation in an individual in need thereof, comprising administering to the individual a bifunctional compound as described herein or a pharmaceutical combination comprising the same things.

In addition, the present invention provides a therapeutically effective amount of a bifunctional compound for use in the manufacture of a medicament for preventing, ameliorating and/or treating KRAS mutation-related diseases in an individual in need thereof.

In another aspect, the present invention provides a method of ubiquitinating and degrading a target protein in a cell by contacting the target protein with a bifunctional compound according to Formula (I) as described herein.

For a more complete understanding of the invention described herein, the following examples are set forth. The examples described in this application are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein and should not be construed as limiting their scope in any way.

Example

Abbreviation

ACN: acetonitrile; AcOH: acetic acid; Boc: tertiary butoxycarbonyl; DCM: dichloromethane DMA: dimethylacetamide; DMF: dimethylformamide; DMSO: dimethyltrisoxide; DMAC/DMA : Dimethylacetamide; DIPEA/DIEA: N,N-diisopropylethylamine; EtOAc/EA: ethyl acetate; EtOH: ethanol; FA: formic acid; HPLC: high pressure liquid chromatography; LAH: hydrogenation Aluminum lithium; LCMS or LC-MS: liquid chromatography/mass spectrometry; NBS: N-bromosuccinimide; NCS: N-chlorosuccinimide; NMR: nuclear magnetic resonance; NMP: N- Methyl-2-pyrrolidone; MeOH: methanol; MPLC: medium pressure liquid chromatography; RT or r.t.: room temperature; TEA: triethylamine; THF: tetrahydrofuran; TFA: trifluoroacetic acid; TLC: thin layer layer analysis.

General synthesis method

The synthesis and optimization of bifunctional molecules described in this article can be carried out step by step or in a modular manner. In the case of RB and ULM, one skilled in the art can combine them with or without chemical linking groups using known synthetic methods. Chemical linking groups can be synthesized with a range of compositions, lengths, and flexibility and functionalized so that RB and ULM groups can be sequentially attached to the termini of the linker. In some cases, protecting group strategies and/or functional group interconversions (FGIs) may be required to prepare the desired material. Such chemical processes are well known to synthetic organic chemists, and many of them can be found in textbooks or books.

Example 1 cpd 1 synthesis

cpd 1 can be prepared using the synthetic scheme and procedures described in detail below.

Synthesis of (B)

Sodium triacetyloxyborohydride (NaBH(OAc) ₃ , 32.3 mg, 0.415 mmol, 2 eq) was added to 2-(2,6-bisoxypiperidin-3-yl)-5-(piperidine 𠯤-1-yl)isoindoline-1,3-dione (Compound A, 100 mg, 0.228 mmol, 1.1 eq) and 4-(4-methanoylbenzyl)piperidine-1-carboxylic acid tris A solution of grade butyl ester (63.0 mg, 0.207 mmol, 1.0 eq) in DCM (2.2 ml) was stirred for 2 h. Upon completion, the solvent was removed in vacuo, and the crude material was purified by silica gel chromatography (0 to 5% MeOH/DCM) to afford Boc-intermediate (89.2 mg, 62%). To the solution of Boc-intermediate was added TFA (155 μL, 2.02 mmol, 15 eq). The reaction mixture was stirred at room temperature for 2 hours. After completion, the solvent was removed by rotary evaporator, and the crude material was purified by silica gel chromatography (0 to 20% MeOH/DCM) to obtain compound (B), 2-(2,6-bis-oxypiperidine -3-yl)-5-(4-(4-(piperidine-1-ylmethyl)benzyl)piperidine-1-yl)isoindoline-1,3-dione (71.5 mg, 99%). ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 11.10 (s, 1H), 8.68 (s, 2H), 7.75 (s, 1H), 7.42-7.32 (m, 6H), 5.09 (dd, J = 12.9 , 5.4 Hz, 1H), 4.38-4.22 (m, 3H), 3.59 (s, 2H), 3.11 (s, 4H), 2.92-2.85 (m, 1H), 2.62 - 2.52 (m, 6H), 2.06 - 1.98 (m, 1H). LC-MS (m/z): [M] ⁺ calculated for C ₂₉ H ₃₄ N ₆ O ₄ 530.63, found 531.52.

(D) synthesis

Compound B (71.5 mg, 0.135 mmol, 1 eq) was added to (3-(5-methanoyl-3-(4-(trifluoromethoxy)phenyl)-1H-indol-1-yl) A solution of tert-butylpropyl)carbamate (Compound C, 62.4 mg, 0.135 mmol, 1 eq) in DMF (1.3 ml) was stirred for 30 min. Sodium triacetoxyborohydride (NaBH(OAc) ₃ , 57.2 mg, 0.27 mmol, 2 eq) was added and stirred for an additional 16 hours. Upon completion, the solvent was removed in vacuo, and the crude material was purified by silica gel chromatography (0 to 7% MeOH/DCM) to obtain compound (D), (3-(5-((4-(4-((4- (2-(2,6-dioxypiperidin-3-yl)-1,3-dioxyisoindolin-5-yl)piperidin-1-yl)methyl)benzyl )(piperidine-1-yl)methyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-1-yl)propyl)carbamic acid tertiary butyl ester (66.0 mg , 50%). ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 11.09 (s, 1H), 7.82 - 7.73 (m, 3H), 7.67 (d, J = 8.5 Hz, 1H), 7.49 (s, 1H), 7.46 - 7.41 (m, 2H), 7.32 (d, J = 2.2 Hz, 1H), 7.30 - 7.20 (m, 5H), 7.18 (s, 1H), 7.00 (t, J = 5.6 Hz, 1H), 5.07 (dd , J = 12.9, 5.4 Hz, 1H), 4.21 (t, J = 6.9 Hz, 2H), 3.49 (s, 2H), 3.43 (m, 5H), 2.96 - 2.85 (m, 3H), 2.62 - 2.52 ( m, 2H), 2.47 (br, 4H), 2.36 (br, 4H), 2.04 - 1.98 (m, 1H), 1.91-1.88 (m, 4H), 1.37 (s, 9H). LC-MS (m/z): [M] ⁺ calculated for C ₅₃ H ₅₉ F ₃ N ₈ O ₇ 977.10, found 977.59.

Synthesis of cpd 1

To a solution of compound D ₍ 63 mg, 0.0644 mmol) in _CH2Cl2 (0.2 mL) was added TFA (100 μL, 1.29 mmol, 20 eq). The reaction mixture was stirred at room temperature for 2 hours. Upon completion, the solvent was removed by rotary evaporator, and the crude material was purified by silica gel chromatography (0 to 20% MeOH/DCM) to obtain cpd 1,5-(4-(4-((4-((1 -(3-Aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl)piperidine-1-yl)methyl)benzyl (yl)piperidin-1-yl)-2-(2,6-dioxypiperidin-3-yl)isoindoline-1,3-dione (55.9 mg, 98%). ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 11.10 (s, 1H), 7.89-7.69 (m, 8H), 7.46-7.34 (m, 8H), 5.08 (q, J = 6.0 Hz, 1H), 4.45-4.11 (m, 7H), 3.56 (br, 2H), 3.17 (s, 4H), 3.09-3.07 (br, 2H), 2.91-2.89 (m, 2H), 2.82-2.81 (m, 2H), 2.61-2.57 (m, 2H), 2.32 (br, 2H), 2.08 (m, J = 7.2 Hz, 2H), 2.02 (t, J = 5.4 Hz, 1H). LC-MS (m/z): [M] ⁺ calculated for C ₄₈ H ₅₁ F ₃ N ₈ O ₅ 876.39, found 877.38.

Example 2 cpd 2 synthesis

cpd 2 can be prepared using the synthetic scheme and procedures described in detail below.

Synthesis of (E)

1-(tertiary butoxycarbonyl)-4-((tertiary butoxycarbonyl)amino)piperidine-4-carboxylic acid (14 mg, 0.04 mmol) with HBTU (21 mg, 0.056 mmol), DMF ( 0.4 mL) and DIPEA (0.026 mL, 0.15 mmol) were added together, and the solution was stirred at 25°C for 10 min under an Ar atmosphere. Add 5-(4-(4-((4-((1-(3-aminopropyl))-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl )Methyl)piperidine-1-yl)methyl)benzyl)piperidine-1-yl)-2-(2,6-di-oxypiperidin-3-yl)isoindoline-1 , 3-diketone (33 mg, 0.038 mmol), and the resulting mixture was stirred at 25°C for 2 hours. The reaction mixture was diluted to 10 mL with acetonitrile and purified via preparative HPLC and concentrated to afford the title compound (8 mg, 18%). LC-MS (m/z): C ₆₄ H ₇₇ F ₃ N ₁₀ O ₁₀ of [M] ⁺ calculated value 1203.37, found value 1203.75. ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 11.11 (s, 1H), 9.98 (s, 1H), 9.42 (s, 1H), 8.03 (s, 1H), 7.89 (s, 1H), 7.77 ( m, 3H), 7.69 (s, 1H), 7.46 (m, 6H), 7.37 - 7.27 (m, 2H), 7.07 (s, 1H), 5.10 (dd, J = 12.9, 5.4 Hz, 1H), 4.42 (d, J = 42.2 Hz, 4H), 4.24 (s, 4H), 3.61 (s, 4H), 3.10 (m, 4H), 2.95 - 2.88 (m, 2H), 2.07 - 1.96 (m, 3H), 1.96 - 1.82 (m, 4H), 1.80 - 1.73 (m, 2H), 1.39 (s, 9H).

Synthesis of cpd 2

To 4-((tertiary butoxycarbonyl)amino)-4-((3-(5-((4-(4-((4-(2-(2,6-bisoxypiperidine) -3-yl)-1,3-bis-oxyisoindolin-5-yl)piperidine-1-yl)methyl)benzyl)piperidine-1-yl)methyl)-3- (4-(Trifluoromethoxy)phenyl)-1H-indol-1-yl)propyl)aminomethyl)piperidine-1-carboxylic acid tertiary butyl ester (5 mg, 0.04 mmol) in CH To a solution in ₂ Cl ₂ (0.1 mL) was added TFA (0.05 mL, 0.62 mmol). The reaction mixture was stirred at room temperature for 1 hour. The mixture was neutralized with _{NaHCO3 (sat)} and _diluted with _CH2Cl2 . The CH ₂ Cl ₂ was dried over MgSO ₄ and concentrated, and the crude material was concentrated to give cpd 2,4-amino-N-(3-(5-((4-(4-((4-(2-(2, 6-Dipedoxypiperidin-3-yl)-1,3-Dipedoxyisoindolin-5-yl)piperidin-1-yl)methyl)benzyl)piperidine-1- methyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-1-yl)propyl)piperidine-4-carboxamide (4 mg, 96%). ¹ H NMR (600 MHz, methanol- d ₄ ) δ 8.02 (s, 1H), 7.81 - 7.76 (m, 1H), 7.73 - 7.68 (m, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.38 (m, 4H), 7.26 (dd, J = 8.6, 2.4 Hz, 1H), 5.36 (ddd, J = 5.7, 4.4, 1.1 Hz, 2H), 5.09 (dd, J = 12.8, 5.5 Hz, 1H) , 4.64 (s, 6H), 4.34 (t, J = 6.9 Hz, 1H), 3.77 (d, J = 25.0 Hz, 2H), 3.69 - 3.65 (m, 1H), 3.53 (s, 2H), 3.30 - 3.26 (m, 2H), 2.92 - 2.71 (m, 5H), 2.23 - 2.19 (m, 2H), 2.16 - 2.10 (m, 2H), 2.07 - 2.03 (m, 4H), 1.66 - 1.59 (m, 4H ). LC-MS (m/z): [M] ⁺ calculated for C ₅₄ H ₆₁ F ₃ N ₁₀ O ₆ 1003.14, found 1003.59.

Example 3 cpd 3 to 72 synthesis

cpd 3 can be prepared using the synthetic scheme and procedures described in detail below.

Synthesis of (G)

Compound F (70 mg, 0.147 mmol, 1 eq) was added to (3-(5-methanoyl-3-(4-(trifluoromethoxy)phenyl)-1H-indol-1-yl) A solution of propyl)tert-butylcarbamate (Compound C, 67.9 mg, 0.147 mmol, 1 eq) in DMF (1.4 ml) was stirred for 30 min. Sodium triacetoxyborohydride (NaBH(OAc) ₃ , 62.3 mg, 0.294 mmol, 2 eq) was added and stirred for a further 16 hours. After completion, the solvent was removed in vacuo, and the crude material was purified by silica gel chromatography (0 to 5% MeOH/DCM) to obtain compound (G) (3-(5-((4-((1-(2-() 2,6-bis-oxypiperidin-3-yl)-1,3-bis-bis-oxyisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-1-yl) Methyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-1-yl)propyl)carbamic acid tertiary butyl ester (52.8 mg, 41%). ¹ H NMR (600 MHz, methanol- d ₄ ) δ 7.92 (d, J = 1.5 Hz, 1H), 7.79 - 7.74 (m, 2H), 7.64 (d, J = 8.5 Hz, 1H), 7.60 (s, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.36 - 7.29 (m, 3H), 7.27 (dd, J = 8.5, 1.6 Hz, 1H), 7.18 (dd, J = 8.7, 2.4 Hz, 1H ), 5.05 (dd, J = 12.7, 5.5 Hz, 1H), 4.28 (t, J = 6.9 Hz, 2H), 4.04 - 3.95 (m, 4H), 3.07 (t, J = 6.7 Hz, 2H), 2.99 - 2.92 (m, 3H), 2.91 - 2.80 (m, 4H), 2.76 - 2.65 (m, 4H), 2.32 (d, J = 6.7 Hz, 2H), 2.13 - 2.06 (m, 1H), 2.03 (p , J = 6.8 Hz, 2H), 1.94 (s, 3H), 1.88-1.85 (m, 3H), 1.44 (s, 9H), 1.30 - 1.22 (m, 2H). LC-MS (m/z): [M] ⁺ calculated for C ₄₇ H ₅₄ F ₃ N ₇ O ₇ 885.99, found 886.45.

Synthesis of cpd 3

To a solution _of compound G (40 mg, 0.0451 mmol) in _CH2Cl2 (0.15 mL) was added TFA (69.1 μL, 0.903 mmol, 20 eq). The reaction mixture was stirred at room temperature for 2 hours. Upon completion, the solvent was removed by rotary evaporator, and the crude material was purified by silica gel chromatography (0 to 20% MeOH/DCM) to obtain cpd3,5-(4-(((4-((1-(3- Aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl)piperidin-1-yl)methyl)piperidin-1-yl )-2-(2,6-Dimensyloxypiperidin-3-yl)isoindoline-1,3-dione (13.0 mg, 37%). ¹ H NMR (600 MHz, MeOD- d ₄ ) δ 7.84 (s, 1H), 7.76-7.74 (m, 2H), 7.63 (d, J = 8.6 Hz, 1H), 7.55 (s, 1H), 7.47 ( d, J = 8.6 Hz, 1H), 7.33-7.31 (m, 3H), 7.23 (dd, J = 1.4, 8.5 Hz, 1H), 7.18 (dd, J = 2.4, 8.7 Hz, 1H), 5.05 (dd , J = 5.5, 12.7 Hz, 1H), 4.61 (br, 3H), 4.31 (t, J = 6.9 Hz, 2H), 4.01 (d, J = 13.1 Hz, 2H), 3.66 (br, 2H), 2.97 -2.93 (m, 2H), 2.85-2.81 (m, 1H), 2.74-2.68 (m, 4H), 2.54 (br, 6H), 2.23 (d, J = 6.8 Hz, 2H), 2.10-2.04 (m , 3H), 1.88-1.82 (m, 3H), 1.28-1.26 (m, 3H). LC-MS (m/z): [M] ⁺ calculated for C ₄₂ H ₄₆ F ₃ N ₇ O ₅ 785.87, found 786.36.

Example 4 cpd twenty four synthesis

cpd 24 can be prepared using the synthetic scheme and procedures described in detail below.

(H-2) synthesis

To a solution of compound C (400 mg, 0.865 mmol, 1.1 eq) and ethyl piperazoacetate (129.2 μL, 0.786 mmol, 1.0 eq) in DMF (3.93 mL) was added sodium triacetyloxyborohydride ( NaBH(OAc) ₃ , 733.3 mg, 3.46 mmol, 4 eq) and stirred at room temperature for 18 hours. Upon completion, the solvent was removed in vacuo, and the crude material was purified by silica gel chromatography (0 to 5% MeOH/DCM) to afford the ester intermediate (H-2), 2-(4-((1-(3-( (tertiary butoxycarbonyl)amino)propyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl)piperidine-1-yl) Ethyl acetate (357.5 mg, 67%). LC-MS (m/z): [M] ⁺ calculated for C ₃₂ H ₄₁ F ₃ N ₄ O ₅ 618.70, found 619.07.

Synthesis of (H-3)

To a solution of compound H-2 (70 mg, 0.113 mmol, 1.0 eq) in THF/EtOH (0.6 mL/0.2 mL) was added lithium hydroxide (LiOH, 14.2 mg, 0.339 mmol, 3.0 eq) in H ₂ O (0.2 ml) solution and stirred at room temperature for 4 hours. Upon completion, adjust the mixture to pH 4-5 with 1 N HCl in an ice bath. The solid was collected by filtration and washed with _H2O to give (H-3), 2-(4-((1-(3-((tertiary butoxycarbonyl)amino)propyl))-3-( 4-(Trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl)piperidine-1-yl)acetic acid (37.3 mg, 55.9%). LC-MS (m/z): [M] ⁺ calculated for C ₃₀ H ₃₇ F ₃ N ₄ O ₅ 590.64, found 590.92.

Synthesis of (H-4)

To a solution of H-3 (37.0 mg, 0.0626 mmol) in DMF (0.3 mL) was added HBTU (28.5 mg, 0.0751 mmol, 1.2 eq) and DIPEA (0.016 mL, 0.113 mmol, 1.8 eq) and at room temperature The solution was stirred for 10 min under Ar atmosphere. Add 2-(2,6-dilateral oxypiperidin-3-yl)-5-(piperidin-1-yl)isoindoline-1,3-dione (23.6 mg, 0.0689 mmol, 1.1 eq ) and the resulting mixture was stirred at room temperature for 16 hours. After completion, the solvent was removed in vacuo, and the crude material was purified by silica gel chromatography (0 to 6% MeOH/DCM) to obtain compound (H-4), (3-(5-((4-(2-(4) -(2-(2,6-Dilateral oxypiperidin-3-yl)-1,3-Dilateral oxyisoindolin-5-yl)piperidin-1-yl)-2-Pendant oxy Tertiary butyl ethyl)piperidine-1-yl)methyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-1-yl)propyl)carbamate (21.3 mg, 37.2%). LC-MS (m/z): C ₄₇ H ₅₃ F ₃ N ₈ O ₈ of [M] ⁺ calculated value 914.98, experimental value 915.26

Synthesis of cpd 24

To compound H-4 (20 mg, 0.0219 mmol) was added 4N HCl in dihexane (0.24 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted to 1 mL with acetonitrile and purified via preparative HPLC and concentrated to give cpd 24,5-(4-(2-(4-((1-(3-aminopropyl))-3-(4- (Trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl)piperidine-1-yl)acetyl)piperidine-1-yl)-2-(2,6-di Pendant oxypiperidin-3-yl)isoindoline-1,3-dione (4.4 mg, 24.7%). LC-MS (m/z): [M] ⁺ calculated for C ₄₂ H ₄₅ F ₃ N ₈ O ₆ 814.87, found 815.66. ¹ H NMR (500 MHz, methanol- d ₄ ) δ 8.04 (d, J = 1.6 Hz, 1H), 7.79 - 7.73 (m, 2H), 7.71 (d, J = 8.5 Hz, 1H), 7.68 - 7.61 ( m, 2H), 7.41 - 7.32 (m, 4H), 7.25 (dd, J = 8.6, 2.4 Hz, 1H), 5.08 (dd, J = 12.6, 5.5 Hz, 1H), 4.48 - 4.33 (m, 4H) , 3.79 - 3.67 (m, 4H), 3.56 - 3.45 (m, 6H), 3.03 - 2.91 (m, 3H), 2.91-2.81 (m, 2H), 2.79 - 2.65 (m, 2H), 2.24 (p, J = 7.1 Hz, 2H), 2.15-2.07 (m, 1H).

Example 5 cpd 26 synthesis

cpd 26 can be prepared using the synthetic scheme and procedures described in detail below.

Synthesis of (J)

To a solution of compound F (90 mg, 0.188 mmol, 1.0 eq.), HBTU (82 mg, 0.216 mmol) and DIPEA (49 mg, 0.376 mmol) in DMF (1.25 mL) was added compound I (121 mg, 0.226 mmol, 1.2 eq.) and stirred for 16 hours. After completion, the solvent was removed in vacuo, and the crude material was purified by silica gel chromatography (0 to 5% MeOH/DCM) to obtain compound (J) (3-(5-(4-((4-(2-(2) ,6-di-oxypiperidin-3-yl)-1,3-di-oxyisoindolin-5-yl)piperidin-1-yl)methyl)piperidine-1-carbonyl)- 3-(4-(Trifluoromethoxy)phenyl)-1H-indol-1-yl)propyl)carbamic acid tertiary butyl ester (39 mg, 80%). LC-MS (m/z): [M] + calculated for C ₄₇ H ₅₂ F ₃ N ₇ O ₈ 899.97, found 900.59.

Synthesis of cpd 26

To a solution of compound J (55 mg, 0.061 mmol) in ethyl acetate (0.61 mL) was added TFA (1.23 mL, 20 eq). The reaction mixture was stirred at room temperature for 2 hours. Upon completion, the solvent was removed by rotary evaporator, and the crude material was purified by silica gel chromatography (0 to 20% MeOH/DCM) to afford cpd 26, 5-(4-((1-(1-(3- Aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indole-5-carbonyl)piperidin-4-yl)methyl)piperidine-1-yl)-2 -(2,6-Dimensyloxypiperidin-3-yl)isoindoline-1,3-dione (39 mg, 80%). ¹ H NMR (500 MHz, methanol- d ₄ ) δ 7.99 (d, J = 1.1 Hz, 1H), 7.82 - 7.75 (m, 3H), 7.73 (s, 1H), 7.71 - 7.65 (m, 1H), 7.51 (d, J = 2.4 Hz, 1H), 7.43 - 7.35 (m, 4H), 5.12 (dd, J = 12.5, 5.5 Hz, 1H), 4.46 (t, J = 6.9 Hz, 2H), 4.19 (d , J = 13.9 Hz, 2H), 3.82 - 3.75 (m, 2H), 3.48 (t, J = 12.9 Hz, 2H), 3.33 - 3.28 (m, 2H), 3.24 (d, J = 6.9 Hz, 2H) , 3.03 - 2.96 (m, 2H), 2.95 - 2.84 (m, 1H), 2.82 - 2.68 (m, 2H), 2.39 - 2.25 (m, 3H), 2.19 - 2.10 (m, 1H), 2.04 (s, 1H), 1.92 - 1.88 (m, 1H), 1.51 - 1.36 (m, 2H), 1.27 (t, J = 7.2 Hz, 1H). LC-MS (m/z): [M] ⁺ calculated for C ₄₂ H ₄₄ F ₃ N ₇ O ₆ 799.85, found 800.43.

Example compounds 4-72 in Table 1 were prepared in a manner similar to compound 3 using the corresponding aldehyde starting materials (eg, cpd C) and amines (eg, cpd F).

surface 1 cpd number Structure and chemical name Mass/NMR 1 5-(4-(4-((4-((1-(3-aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl) Methyl)piperidin-1-yl)methyl)benzyl)piperidin-1-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline-1, 3-diketone LC-MS (m/z): [M] ⁺ calculated for C ₅₃ H ₅₉ F ₃ N ₈ O ₇ 977.10, found 977.59. ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 11.09 (s, 1H), 7.82 - 7.73 (m, 3H), 7.67 (d, J = 8.5 Hz, 1H), 7.49 (s, 1H), 7.46 - 7.41 (m, 2H), 7.32 (d, J = 2.2 Hz, 1H), 7.30 - 7.20 (m, 5H), 7.18 (s, 1H), 7.00 (t, J = 5.6 Hz, 1H), 5.07 (dd , J = 12.9, 5.4 Hz, 1H), 4.21 (t, J = 6.9 Hz, 2H), 3.49 (s, 2H), 3.43 (m, 5H), 2.96 - 2.85 (m, 3H), 2.62 - 2.52 ( m, 2H), 2.47 (br, 4H), 2.36 (br, 4H), 2.04 - 1.98 (m, 1H), 1.91-1.88 (m, 4H), 1.37 (s, 9H). 2 4-Amino-N-(3-(5-((4-(4-((4-(2-(2,6-bisoxypiperidin-3-yl))-1,3-bis Oxyisoindolin-5-yl)piperidine-1-yl)methyl)benzyl)piperidine-1-yl)methyl)-3-(4-(trifluoromethoxy)phenyl )-1H-indol-1-yl)propyl)piperidine-4-methamide LC-MS (m/z): [M] ⁺ calculated for C ₅₄ H ₆₁ F ₃ N ₁₀ O ₆ 1003.14, found 1003.59. ¹ H NMR (600 MHz, methanol- d ₄ ) δ 8.02 (s, 1H), 7.81 - 7.76 (m, 1H), 7.73 - 7.68 (m, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.38 (m, 4H), 7.26 (dd, J = 8.6, 2.4 Hz, 1H), 5.36 (ddd, J = 5.7, 4.4, 1.1 Hz, 2H), 5.09 (dd, J = 12.8, 5.5 Hz, 1H) , 4.64 (s, 6H), 4.34 (t, J = 6.9 Hz, 1H), 3.77 (d, J = 25.0 Hz, 2H), 3.69 - 3.65 (m, 1H), 3.53 (s, 2H), 3.30 - 3.26 (m, 2H), 2.92 - 2.71 (m, 5H), 2.23 - 2.19 (m, 2H), 2.16 - 2.10 (m, 2H), 2.07 - 2.03 (m, 4H), 1.66 - 1.59 (m, 4H ). 3 5-(4-((4-((1-(3-aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl) Piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline-1,3-dione LC-MS (m/z): [M] ⁺ calculated for C ₄₂ H ₄₆ F ₃ N ₇ O ₅ 785.87, found 786.36. ¹ H NMR (600 MHz, MeOD- d ₄ ) δ 7.84 (s, 1H), 7.76-7.74 (m, 2H), 7.63 (d, J = 8.6 Hz, 1H), 7.55 (s, 1H), 7.47 ( d, J = 8.6 Hz, 1H), 7.33-7.31 (m, 3H), 7.23 (dd, J = 1.4, 8.5 Hz, 1H), 7.18 (dd, J = 2.4, 8.7 Hz, 1H), 5.05 (dd , J = 5.5, 12.7 Hz, 1H), 4.61 (br, 3H), 4.31 (t, J = 6.9 Hz, 2H), 4.01 (d, J = 13.1 Hz, 2H), 3.66 (br, 2H), 2.97 -2.93 (m, 2H), 2.85-2.81 (m, 1H), 2.74-2.68 (m, 4H), 2.54 (br, 6H), 2.23 (d, J = 6.8 Hz, 2H), 2.10-2.04 (m , 3H), 1.88-1.82 (m, 3H), 1.28-1.26 (m, 3H). 4 5-(4-((4-((1-(3-aminopropyl))-3-(4-hydroxyphenyl)-1H-indol-5-yl)methyl)piperidine-1-yl )Methyl)piperidin-1-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline-1,3-dione LC-MS (m/z): [M] ⁺ calculated for C ₄₁ H ₄₇ N ₇ O ₅ 718.87, found 718.31. ¹ H NMR (500 MHz, methanol- d ₄ ) δ 8.01 (d, J = 1.6 Hz, 1H), 7.68 (d, J = 8.6 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.50 (m, 3H), 7.36 (m, 2H), 7.22 (dd, J = 8.7, 2.4 Hz, 1H), 6.95 - 6.87 (m, 2H), 5.08 (dd, J = 12.6, 5.5 Hz, 1H), 4.44 - 4.36 (m, 4H), 4.06 (d, J = 13.1 Hz, 2H), 3.08 - 2.94 (m, 6H), 2.87 (m, 2H), 2.80 - 2.70 (m, 2H), 2.63 (d, J = 7.0 Hz, 2H), 2.24 (m, 2H), 2.16 - 2.07 (m, 1H), 1.91 (m, 3H), 1.39 - 1.28 (m, 2H). 5 5-(4-((1-((1-(3-aminopropyl))-3-(4-hydroxyphenyl)-1H-indol-5-yl)methyl)piperidin-4-yl )Methyl)piperidin-1-yl)-2-(2,6-dioxypiperidin-3-yl)isoindoline-1,3-dione LC-MS (m/z): [M] ⁺ calculated for C ₄₁ H ₄₇ N ₇ O ₅ 718.87, found 718.61. ¹ H NMR (600 MHz, methanol- d ₄ ) δ 8.03 (d, J = 1.7 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.53 - 7.47 (m, 4H), 7.36 (ddd, J = 8.5, 4.2, 2.0 Hz, 2H), 6.93 - 6.88 (m, 2H), 5.11 (dd, J = 12.8, 5.4 Hz, 1H), 4.47 (s , 2H), 4.40 (t, J = 6.9 Hz, 2H), 3.59 (d, J = 12.4 Hz, 2H), 3.15 (s, 1H), 3.12 - 3.05 (m, 2H), 3.00 - 2.94 (m, 2H), 2.88 (m, 1H), 2.80 - 2.68 (m, 2H), 2.25 (m, 3H), 2.16 - 2.10 (m, 3H), 1.59 (m, 2H). 6 5-(4-((1-((1-(3-aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl) Piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-dioxypiperidin-3-yl)isoindoline-1,3-dione LC-MS (m/z): [M] ⁺ calculated for C ₄₂ H ₄₆ F ₃ N ₇ O ₅ 785.87, found 786.27. ¹ H NMR (500 MHz, methanol- d ₄ ) δ 7.86 (d, J = 1.5 Hz, 1H), 7.79 - 7.73 (m, 2H), 7.67 (d, J = 8.5 Hz, 1H), 7.56 (s, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.34-7.32 (m, 3H), 7.25-7.19 (m, 2H), 5.06 (dd, J = 12.5, 5.4 Hz, 1H), 4.60 (br , 1H), 4.31 (t, J = 7.0 Hz, 2H), 3.68 (s, 2H), 3.44 (t, J = 6.9 Hz, 4H), 2.99 (d, J = 11.5 Hz, 2H), 2.91 - 2.80 (m, 1H), 2.78 - 2.64 (m, 4H), 2.56 (t, J = 5.1 Hz, 4H), 2.28-2.25 (m, 2H), 2.14 - 2.01 (m, 5H), 1.83 - 1.76 (m , 2H), 1.65-1.61 (m, 1H), 1.31 - 1.22 (m, 4H). 7 5-(4-((4-((1-(3-aminopropyl))-3-(4-fluorophenyl)-1H-indol-5-yl)methyl)piperidine-1-yl )Methyl)piperidin-1-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline-1,3-dione LC-MS (m/z): [M+H] ⁺ calculated for C ₄₁ H ₄₆ FN ₇ O ₄ 719.86, found 720.56. ¹ H NMR (500 MHz, MeOD) δ 7.77 (s, 1H), 7.66 - 7.58 (m, 3H), 7.40 - 7.33 (m, 1H), 7.33 - 7.20 (m, 3H), 7.16 - 7.10 (m, 2H), 7.06 (dd, J = 8.7, 2.4 Hz, 1H), 4.27 (td, J = 6.8 Hz, 2H), 4.06 - 3.91 (m, 4H), 3.67 (s, 2H), 3.01 - 2.90 (m , 2H), 2.82 - 2.73 (m, 4H), 2.64 - 2.39 (m, 8H), 2.23 (d, J = 6.8 Hz, 2H), 2.14 - 2.08 (m, 2H), 1.91 - 1.84 (m, 2H ), 0.90 - 0.81 (m, 3H). 8 5-(4-((1-(3-Aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl)piperidine-1 -yl)-2-(2,6-di-oxypiperidin-3-yl)isoindoline-1,3-dione LC-MS (m/z): [M] ⁺ calculated for C ₃₆ H ₃₅ F ₃ N ₆ O ₅ 688.71, found 689.2. ¹ H NMR (500 MHz, methanol- d ₄ ) δ 8.11 (d, J = 1.7 Hz, 1H), 7.81 - 7.78 (m, 2H), 7.75 (d, J = 8.5 Hz, 1H), 7.72 - 7.66 ( m, 2H), 7.48 - 7.41 (m, 2H), 7.41 - 7.36 (m, 2H), 7.33 (dd, J = 8.6, 2.4 Hz, 1H), 5.10 (dd, J = 12.6, 5.5 Hz, 1H) , 4.51 (s, 2H), 4.44 (t, J = 7.0 Hz, 2H), 3.41 (s, 4H), 3.03 - 2.96 (m, 2H), 2.87 (ddd, J = 17.4, 13.9, 5.2 Hz, 1H ), 2.80 - 2.66 (m, 2H), 2.32 - 2.22 (m, 2H), 2.17 - 2.08 (m, 1H). 9 1-(4-((1-(3-Aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl)piperidine-1 -yl)-2-((1-(2-chloroacetyl)-1,2,3,4-tetrahydroquinolin-6-yl)oxy)ethan-1-one LC-MS (m/z): [M] ⁺ calculated for C ₃₆ H ₃₉ ClF ₃ N ₅ O ₄ 698.18, found 698.16. ¹ H NMR (500 MHz, methanol- d ₄ ) δ 8.10 - 8.06 (m, 1H), 7.80 - 7.73 (m, 2H), 7.71 - 7.65 (m, 2H), 7.43 - 7.34 (m, 3H), 6.84 (s, 2H), 4.52 (s, 2H), 4.42 (t, J = 7.0 Hz, 2H), 4.29 (s, 1H), 3.76 (t, J = 6.5 Hz, 2H), 2.97 (t, J = 7.9 Hz, 2H), 2.71 (s, 1H), 2.25 (dt, J = 14.8, 7.1 Hz, 2H), 1.96 (s, 2H), 1.29 (s, 1H). 10 5-(4-((4-((1-(3-aminopropyl))-3-(4-methoxyphenyl)-1H-indol-5-yl)methyl)piperidine-1 -yl)methyl)piperidin-1-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline-1,3-dione LC-MS (m/z): [M] ⁺ calculated for C ₄₂ H ₄₉ N ₇ O ₅ 731.90, found 731.30. ¹ H NMR (500 MHz, MeOD) δ 7.91 (d, J = 1.3 Hz, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.55 - 7.45 (m, 3H), 7.37 (s, 1H), 7.32 - 7.24 (m, 2H), 7.09 (dd, J = 8.7, 2.4 Hz, 1H), 7.05 - 6.93 (m, 2H), 4.99 - 4.91 (m, 1H), 4.37 - 4.25 (m, 4H), 3.96 (d, J = 13.1 Hz, 2H), 3.84 (s, 3H), 3.29 - 3.16 (m, 3H), 3.01 - 2.87 (m, 6H), 2.80 - 2.70 (m, 3H), 2.53 (d, J = 6.7 Hz, 2H), 2.27 - 2.17 (m, 2H), 2.14 - 2.06 (m, 1H), 1.87 (d, J = 10.8 Hz, 3H), 1.39 - 1.19 (m, 5H). 11 4-(1-(3-aminopropyl)-5-((4-((4-(2-(2,6-bisoxypiperidin-3-yl))-1,3-bis Oxyisoindolin-5-yl)piperidin-1-yl)methyl)piperidin-1-yl)methyl)-1H-indol-3-yl)benzonitrile LC-MS (m/z): [M] ⁺ calculated for C ₄₂ H ₄₆ N ₈ O ₄ 726.88, found 727.25. ¹ H NMR (500 MHz, methanol- d ₄ ) δ 8.16 (d, J = 1.6 Hz, 1H), 7.94 - 7.88 (m, 2H), 7.87 (s, 1H), 7.85 - 7.76 (m, 3H), 7.71 (d, J = 8.5 Hz, 1H), 7.49 (d, J = 2.3 Hz, 1H), 7.44 (dd, J = 8.6, 1.7 Hz, 1H), 7.36 (dd, J = 8.3, 2.3 Hz, 1H ), 5.11 (dd, J = 12.5, 5.4 Hz, 1H), 4.52 - 4.42 (m, 3H), 3.78 (s, 4H), 3.61 (d, J = 12.6 Hz, 2H), 3.51 (q, J = 7.0 Hz, 2H), 3.19 (d, J = 7.1 Hz, 1H), 3.11 (t, J = 12.7 Hz, 2H), 3.03 - 2.97 (m, 2H), 2.94 - 2.83 (m, 1H), 2.81 - 2.67 (m, 2H), 2.27 (m, 2H), 2.17 - 2.10 (m, 2H), 1.63 (m, 2H), 1.20 (t, J = 7.0 Hz, 1H). 12 5-(4-((1-((1-(3-aminopropyl))-3-(6-methoxypyridin-3-yl)-1H-indol-5-yl)methyl)piper (Din-4-yl)methyl)piperidin-1-yl)-2-(2,6-bis-oxypiperidin-3-yl)isoindoline-1,3-dione LC-MS (m/z): [M] ⁺ calculated for C ₄₁ H ₄₈ N ₈ O ₅ 732.89, found 733.39. ¹ H NMR (500 MHz, methanol- d ₄ ) δ 8.38 - 8.33 (m, 1H), 7.91 (dd, J = 8.6, 2.4 Hz, 1H), 7.88 (m, 1H), 7.68 (d, J = 8.6 Hz, 1H), 7.61 (m, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.49 (s, 1H), 7.36 - 7.29 (m, 2H), 7.15 (dd, J = 8.6, 2.3 Hz , 1H), 6.89 (dd, J = 8.6, 0.8 Hz, 1H), 4.98 (dd, J = 12.2, 5.5 Hz, 1H), 4.38 - 4.32 (m, 4H), 3.95 (s, 3H), 3.50 ( m, 5H), 2.99 - 2.89 (m, 4H), 2.84 - 2.70 (m, 6H), 2.48 (s, 1H), 2.23 (p, J = 7.2 Hz, 2H), 2.14 - 2.07 (m, 1H) , 2.05 (d, J = 14.5 Hz, 2H), 1.95 (s, 1H), 1.51-1.44 (m, 2H), 1.24 (m, 1H). 13 3-(1-(3-aminopropyl)-5-((4-((4-(2-(2,6-bisoxypiperidin-3-yl))-1,3-bis Oxyisoindolin-5-yl)piperidin-1-yl)methyl)piperidin-1-yl)methyl)-1H-indol-3-yl)benzonitrile LC-MS (m/z): [M] ⁺ calculated for C ₄₂ H ₄₆ N ₈ O ₄ 726.88, found 726.39. ¹ H NMR (600 MHz, MeOD) δ 7.99 (s, 1H), 7.98 - 7.91 (m, 2H), 7.76 (d, J = 8.5 Hz, 1H), 7.64 (s, 1H), 7.63 - 7.60 (m , 2H), 7.60 - 7.57 (m, 2H), 7.40 (d, J = 2.2 Hz, 1H), 7.37 (dd, J = 8.5, 1.5 Hz, 1H), 7.25 (dd, J = 8.5, 2.2 Hz, 1H), 5.13 - 4.97 (m, 1H), 4.43 - 4.35 (m, 4H), 3.72 (s, 3H), 3.52 (d, J = 12.5 Hz, 2H), 3.49 - 3.37 (m, 3H), 3.11 (d, J = 6.6 Hz, 2H), 3.07 - 2.97 (m, 2H), 2.97 - 2.92 (m, 2H), 2.87 - 2.72 (m, 3H), 2.35 - 2.21 (m, 3H), 2.18 - 2.12 (m, 1H), 2.09 (d, J = 13.9 Hz, 2H), 1.70 - 1.59 (m, 2H), 1.26 (s, 2H). 14 5-(4-((1-((1-(3-aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-7-yl)methyl) Piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-dioxypiperidin-3-yl)isoindoline-1,3-dione LC-MS (m/z): [M] ⁺ calculated for C ₄₂ H ₄₆ F ₃ N ₇ O ₅ 785.87, found 786.15. ¹ H NMR (500 MHz, methanol- d ₄ ) δ 8.00 (d, J = 8.1 Hz, 1H), 7.77 - 7.68 (m, 3H), 7.59 (s, 1H), 7.44-7.43 (m, 1H), 7.40 - 7.34 (m, 3H), 7.34 - 7.26 (m, 2H), 5.09 (dd, J = 12.6, 5.5 Hz, 1H), 4.60 (t, J = 6.8 Hz, 2H), 3.63 (s, 2H) , 3.48 (br, 2H), 3.17 (br, 2H), 2.92 - 2.81 (m, 5H), 2.79 - 2.66 (m, 2H), 2.18 - 2.07 (m, 4H), 2.06-2.03 (m, 2H) , 1.52 (br, 2H), 1.29 (s, 1H). 15 5-(4-((1-((1-(3-aminopropyl)-3-(2-fluoro-4-methoxyphenyl)-1H-indol-5-yl)methyl) Piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-dioxypiperidin-3-yl)isoindoline-1,3-dione LC-MS (m/z): [M] ⁺ calculated for C ₄₂ H ₄₈ FN ₇ O ₅ 749.89, found 750.25. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 11.09 (s, 1H), 7.80 - 7.67 (m, 7H), 7.59 (t, J = 8.8 Hz, 1H), 7.49 (s, 1H), 7.34 ( d, J = 8.5 Hz, 1H), 7.00 (dd, J = 12.5, 2.6 Hz, 1H), 6.92 (dd, J = 8.4, 2.6 Hz, 1H), 5.09 (dd, J = 13.0, 5.4 Hz, 1H ), 4.42 - 4.33 (m, 4H), 4.22 (s, 1H), 3.83 (s, 3H), 3.61 (s, 2H), 3.18 (m, 4H), 2.95 - 2.80 (m, 4H), 2.61 - 2.58 (m, 2H), 2.06 (m, 3H), 1.95 (d, J = 13.3 Hz, 2H), 1.82 (s, 1H), 1.37 (s, 2H), 1.10 (t, J = 7.0 Hz, 1H ). 16 5-(4-((1-((1-(3-aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-6-yl)methyl) Piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-dioxypiperidin-3-yl)isoindoline-1,3-dione LC-MS (m/z): [M] ⁺ calculated for C ₄₂ H ₄₆ F ₃ N ₇ O ₅ 785.87, found 786.2. ¹ H NMR (500 MHz, methanol- d ₄ ) δ 8.00 (s, 1H), 7.77 (m, 2H), 7.76 (d, J = 2.1 Hz, 1H), 7.72 (s, 1H), 7.49 (d, J = 2.4 Hz, 1H), 7.40 - 7.36 (m, 2H), 7.31 (dd, J = 8.3, 1.5 Hz, 1H), 5.11 (dd, J = 12.5, 5.5 Hz, 1H), 4.52 - 4.42 (m , 3H), 3.63 (d, J = 12.4 Hz, 2H), 3.51 (m, 2H), 3.20 (d, J = 6.7 Hz, 1H), 3.12 (m, 1H), 3.03 - 2.96 (m, 3H) , 2.92 - 2.83 (m, 2H), 2.81 - 2.68 (m, 2H), 2.28 (m, 2H), 2.16 (m, 2H), 1.68 (m, 2H), 1.31 (s, 1H), 1.20 (t , J = 7.0 Hz, 2H). 17 5-(4-((1-((1-(3-aminopropyl))-3-(2-methoxypyridin-3-yl)-1H-indol-5-yl)methyl)piper (Din-4-yl)methyl)piperidin-1-yl)-2-(2,6-bis-oxypiperidin-3-yl)isoindoline-1,3-dione LC-MS (m/z): [M] ⁺ calculated for C ₄₁ H ₄₈ N ₈ O ₅ 732.89, found 733.25. ¹ H NMR (500 MHz, methanol- d ₄ ) δ 8.09 (dd, J = 5.0, 1.8 Hz, 1H), 7.99 (dd, J = 7.3, 1.9 Hz, 1H), 7.90 (d, J = 1.7 Hz, 1H), 7.77 - 7.71 (m, 2H), 7.65 (d, J = 8.5 Hz, 1H), 7.44 (d, J = 2.3 Hz, 1H), 7.38 (dd, J = 8.6, 1.7 Hz, 1H), 7.31 (dd, J = 8.6, 2.3 Hz, 1H), 7.08 (dd, J = 7.3, 5.0 Hz, 1H), 5.08 (dd, J = 12.6, 5.5 Hz, 1H), 4.46 - 4.39 (m, 4H) , 3.99 (s, 3H), 3.69 (br, 2H), 3.56 (d, J = 12.4 Hz, 2H), 3.35 (s, 1H), 3.05 (t, J = 12.8 Hz, 2H), 3.01 - 2.94 ( m, 3H), 2.87-2.82 (m, 1H), 2.79 - 2.65 (m, 2H), 2.29 - 2.15 (m, 3H), 2.12-2.09 (m, 3H), 1.59-.151 (m, 2H) . 18 5-(4-((1-((1-(3-aminopropyl))-3-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)methyl)piper (Din-4-yl)methyl)piperidin-1-yl)-2-(2,6-bis-oxypiperidin-3-yl)isoindoline-1,3-dione LC-MS (m/z): [M] ⁺ calculated for C ₄₂ H ₄₆ F ₃ N ₇ O ₄ 769.87, found 770.15. ¹ H NMR (500 MHz, methanol- d ₄ ) δ 8.13 (d, J = 1.6 Hz, 1H), 7.88 (d, J = 8.0 Hz, 2H), 7.80 (s, 1H), 7.77-7.73 (m, 3H), 7.68 (d, J = 8.5 Hz, 1H), 7.47 (d, J = 2.3 Hz, 1H), 7.41 (dd, J = 8.5, 1.7 Hz, 1H), 7.34 (dd, J = 8.6, 2.4 Hz, 1H), 5.09 (dd, J = 12.6, 5.5 Hz, 1H), 4.48 (s, 2H), 4.43 (t, J = 7.0 Hz, 2H), 3.77 (br, 2H), 3.59 (d, J = 12.5 Hz, 2H), 3.49 (s, 2H), 3.18 (d, J = 6.9 Hz, 2H), 3.13 - 3.04 (m, 2H), 3.02 - 2.95 (m, 2H), 2.92 - 2.81 (m, 1H), 2.79 - 2.65 (m, 2H), 2.29-2.23 (m, 3H), 2.14-2.09 (m, 3H), 1.65-1.57 (m, 2H). 19 5-(4-((1-((1-(3-aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-4-yl)methyl) Piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-dioxypiperidin-3-yl)isoindoline-1,3-dione LC-MS (m/z): [M] ⁺ calculated for C ₄₂ H ₄₆ F ₃ N ₇ O ₅ 785.87, found 787.09. ¹ H NMR (600 MHz, methanol- d ₄ ) δ 7.80 - 7.74 (m, 2H), 7.70 - 7.63 (m, 2H), 7.53 - 7.45 (m, 4H), 7.42 (t, J = 7.8 Hz, 1H ), 7.35 (dd, J = 8.4, 2.3 Hz, 1H), 7.31 (d, J = 7.3 Hz, 1H), 5.11 (dd, J = 12.8, 5.5 Hz, 1H), 4.51 - 4.35 (m, 4H) , 3.75 (bs, 4H), 3.40 (bs, 4H), 3.09 (d, J = 6.8 Hz, 2H), 3.04 - 2.97 (m, 4H), 2.88 (m, 1H), 2.80 - 2.66 (m, 4H ), 2.29 - 2.21 (m, 2H), 2.17 - 2.05 (m, 2H), 1.94 (d, J = 14.3 Hz, 2H), 1.43 (m, 2H). 20 4-(4-((1-((1-(3-aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl) Piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-dioxypiperidin-3-yl)isoindoline-1,3-dione LC-MS (m/z): [M] ⁺ calculated for C ₄₂ H ₄₆ F ₃ N ₇ O ₅ 785.87, found 785.87. ¹ H NMR (500 MHz, methanol- d ₄ ) δ 8.06 (d, J = 1.7 Hz, 1H), 7.78 - 7.74 (m, 2H), 7.73 - 7.64 (m, 3H), 7.45 (d, J = 7.2 Hz, 1H), 7.40 - 7.32 (m, 4H), 5.10 (dd, J = 12.7, 5.5 Hz, 1H), 4.44-4.40 (m, 4H), 3.55-3.53 (m, 4H), 3.05 (t, J = 12.7 Hz, 2H), 3.00 - 2.93 (m, 3H), 2.90 - 2.81 (m, 2H), 2.78 - 2.66 (m, 2H), 2.29 - 2.22 (m, 2H), 2.14-2.08 (m, 3H), 1.56-1.48 (m, 1H). twenty one (3-(5-((4-(((4-(2-(2,6-di-oxypiperidin-3-yl))-1,3-di-oxyisoindolin-5-yl )piperidin-1-yl)methyl)piperidin-1-yl)methyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-1-yl)propyl) Tertiary butyl carbamate LC-MS (m/z): [M] ⁺ calculated for C ₄₇ H ₅₄ F ₃ N ₇ O ₇ 885.99, found 886.31. ¹ H NMR (600 MHz, methanol- d ₄ ) δ 8.03 (d, J = 1.6 Hz, 1H), 7.79 - 7.74 (m, 2H), 7.66 (t, J = 4.3 Hz, 2H), 7.59 (d, J = 8.5 Hz, 1H), 7.36 - 7.31 (m, 4H), 7.20 (dd, J = 8.6, 2.4 Hz, 1H), 5.06 (dd, J = 12.8, 5.4 Hz, 1H), 4.61 (br, 2H ), 4.40 (s, 2H), 4.30 (t, J = 6.9 Hz, 2H), 3.48 (s, 2H), 3.43 (t, J = 5.0, 4H), 3.34 (s, 2H), 3.06 (t, J = 6.7 Hz, 2H), 3.00 (br, 2H), 2.89 - 2.80 (m, 1H), 2.76 - 2.64 (m, 2H), 2.57 (t, J = 5.1 Hz, 4H), 2.29-2.28 (m , 2H), 2.12 - 1.99 (m, 5H), 1.91 (s, 1H), 1.43 (s, 9H). twenty two 5-(3-((1-((1-(3-aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl) Piperidin-4-yl)oxy)prop-1-yn-1-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline-1,3-dione LC-MS (m/z): [M] ⁺ calculated for C ₄₀ H ₃₈ F ₃ N ₅ O ₆ 741.77, found 743.67. ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 11.15 (d, J = 2.3 Hz, 1H), 9.39 (s, 1H), 8.07 (dd, J = 24.9, 1.6 Hz, 1H), 7.93 (dd, J = 7.7, 5.1 Hz, 1H), 7.90 (d, J = 2.9 Hz, 1H), 7.82 - 7.68 (m, 8H), 7.50 - 7.45 (m, 2H), 7.36 (ddd, J = 25.9, 8.5, 1.6 Hz, 1H), 6.82 - 6.75 (m, 1H), 6.06 (m, H), 5.17 (m, 1H), 4.44 (dd, J = 22.1, 5.3 Hz, 2H), 4.38 - 4.33 (m, 2H ), 4.31 (dd, J = 6.2, 1.8 Hz, 2H), 3.77 (s, 1H), 3.39 (m, 3H), 3.21 (d, J = 12.3 Hz, 1H), 3.16 - 3.07 (m, 1H) , 3.02 - 2.96 (m, 1H), 2.90 (m, 1H), 2.81 (m, 2H), 2.18 (d, J = 13.3 Hz, 1H), 2.11 - 1.98 (m, 4H), 1.79 (t, J = 14.1 Hz, 1H), 1.61 - 1.54 (m, 1H), 1.10 (t, J = 7.0 Hz, 1H). twenty three 5-(3-((1-((1-(3-aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl) Piperidin-4-yl)oxy)propyl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline-1,3-dione LC-MS (m/z): [M] ⁺ calculated for C ₄₀ H ₄₂ F ₃ N ₅ O ₆ 745.80, found 746.48. ¹ H NMR (600 MHz, methanol- d ₄ ) δ 8.09 (s, 1H), 7.83 - 7.77 (m, 4H), 7.70 (m, 2H), 7.68 - 7.62 (m, 3H), 7.45 - 7.35 (m , 4H), 5.18 - 5.15 (m, 1H), 4.46 (d, J = 2.8 Hz, 2H), 4.44 (t, J = 7.4 Hz, 1H), 4.36 (t, J = 7.1 Hz, 2H), 3.69 (s, 1H), 3.55 - 3.51 (m, 2H), 3.49 (t, J = 5.8 Hz, 2H), 3.24 - 3.18 (m, 2H), 3.07 (t, J = 12.6 Hz, 1H), 3.00 - 2.96 (m, 2H), 2.92 - 2.86 (m, 2H), 2.83 - 2.74 (m, 4H), 2.25 (m, 4H), 2.16 (m, 1H), 2.09 (d, J = 15.5 Hz, 2H) , 2.00 - 1.91 (m, 3H), 1.86 (t, J = 14.1 Hz, 2H), 1.66 (m, 1H). twenty four 5-(4-(2-(4-((1-(3-aminopropyl))-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl yl)piperidin-1-yl)ethyl)piperidine-1-yl)-2-(2,6-bis-oxypiperidin-3-yl)isoindoline-1,3-dione LC-MS (m/z): [M] ⁺ calculated for C ₄₂ H ₄₅ F ₃ N ₈ O ₆ 814.87, found 815.66. ¹ H NMR (500 MHz, methanol- d ₄ ) δ 8.04 (d, J = 1.6 Hz, 1H), 7.79 - 7.73 (m, 2H), 7.71 (d, J = 8.5 Hz, 1H), 7.68 - 7.61 ( m, 2H), 7.41 - 7.32 (m, 4H), 7.25 (dd, J = 8.6, 2.4 Hz, 1H), 5.08 (dd, J = 12.6, 5.5 Hz, 1H), 4.48 - 4.33 (m, 4H) , 3.79 - 3.67 (m, 4H), 3.56 - 3.45 (m, 6H), 3.03 - 2.91 (m, 3H), 2.91-2.81 (m, 2H), 2.79 - 2.65 (m, 2H), 2.24 (p, J = 7.1 Hz, 2H), 2.15-2.07 (m, 1H). 25 ​ 5-(4-((1-((1-(3-aminopropyl)-3-(3-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl) Piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-dioxypiperidin-3-yl)isoindoline-1,3-dione LC-MS (m/z): [M] ⁺ calculated for C ₄₂ H ₄₆ F ₃ N ₇ O ₅ 785.35, found 786.34. ¹ H NMR (600 MHz, methanol-d4) δ 8.13 - 8.11 (m, 1H), 7.79 - 7.77 (m, 3H), 7.72 (dd, J = 8.6, 0.6 Hz, 1H), 7.60 - 7.57 (m, 2H), 7.50 (m, 2H), 7.37 (dd, J = 8.6, 2.4 Hz, 1H), 7.23 (ddt, J = 8.2, 2.3, 1.1 Hz, 1H), 5.13 - 5.10 (m, 1H), 4.51 (s, 2H), 4.46 (t, J = 7.0 Hz, 2H), 4.26 - 4.13 (m, 2H), 3.77 (s, 2H), 3.59 (d, J = 12.4 Hz, 2H), 3.53 - 3.43 ( m, 2H), 3.39 - 3.35 (m, 1H), 3.29 (s, 1H), 3.24 - 3.20 (m, 2H), 3.15 (m, 2H), 3.01 -2.97 (m, 2H), 2.88 (m, 1H), 2.78 (m, 2H), 2.34 (m, 1H), 2.30 - 2.25 (m, 2H), 2.21 - 2.16 (m, 2H), 2.16 -2.11 (m, 1H), 1.72 - 1.63 (m, 2H). 26 ​ 5-(4-((1-(1-(3-aminopropyl))-3-(4-(trifluoromethoxy)phenyl)-1H-indole-5-carbonyl)piperidine-4 -Methyl)piperidin-1-yl)-2-(2,6-dioxypiperidin-3-yl)isoindoline-1,3-dione LC-MS (m/z): [M] ⁺ calculated for C ₄₂ H ₄₄ F ₃ N ₇ O ₆ 799.85, found 800.43. ¹ H NMR (500 MHz, methanol- d ₄ ) δ 7.99 (d, J = 1.1 Hz, 1H), 7.82 - 7.75 (m, 3H), 7.73 (s, 1H), 7.71 - 7.65 (m, 1H), 7.51 (d, J = 2.4 Hz, 1H), 7.43 - 7.35 (m, 4H), 5.12 (dd, J = 12.5, 5.5 Hz, 1H), 4.46 (t, J = 6.9 Hz, 2H), 4.19 (d , J = 13.9 Hz, 2H), 3.82 - 3.75 (m, 2H), 3.48 (t, J = 12.9 Hz, 2H), 3.33 - 3.28 (m, 2H), 3.24 (d, J = 6.9 Hz, 2H) , 3.03 - 2.96 (m, 2H), 2.95 - 2.84 (m, 1H), 2.82 - 2.68 (m, 2H), 2.39 - 2.25 (m, 3H), 2.19 - 2.10 (m, 1H), 2.04 (s, 1H), 1.92 - 1.88 (m, 1H), 1.51 - 1.36 (m, 2H), 1.27 (t, J = 7.2 Hz, 1H). 27 ​ 5-(4-((1-((1-(3-aminopropyl))-3-(3-hydroxynaphthalen-1-yl)-1 H -indol-5-yl)methyl)piperidine -4-yl)methyl)piperidin-1-yl)-2-(2,6-dioxypiperidin-3-yl)isoindoline-1,3-dione LC-MS (m/z): [M] ⁺ calculated for C ₄₅ H ₄₉ N ₇ O ₅ 767.93, found 768.25. ¹ H NMR (600 MHz, MeOD) δ 7.84 (d, J = 8.5 Hz, 1H), 7.76 (dd, J = 17.6, 8.7 Hz, 3H), 7.64 (s, 1H), 7.60 (s, 1H), 7.51 - 7.47 (m, 2H), 7.42 (t, J = 7.5 Hz, 1H), 7.37 (d, J = 8.5 Hz, 1H), 7.25 - 7.20 (m, 2H), 7.19 (d, J = 2.2 Hz , 1H), 5.12 (dd, J = 12.8, 5.4 Hz, 1H), 4.53 (t, J = 6.9 Hz, 2H), 4.40 (s, 2H), 4.21 - 4.13 (m, 2H), 3.80 - 3.71 ( m, 2H), 3.59 - 3.42 (m, 4H), 3.31 - 3.23 (m, 2H), 3.20 (d, J = 6.8 Hz, 2H), 3.11 - 3.00 (m, 4H), 2.93 - 2.84 (m, 1H), 2.81 - 2.66 (m, 2H), 2.40 - 2.22 (m, 3H), 2.21 - 2.08 (m, 3H), 1.70 - 1.54 (m, 2H) 28 ​ 5-(4-((1-((1-(azetidin-3-ylmethyl))-3-(4-(trifluoromethoxy)phenyl)-1H-indole-5- yl)methyl)piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-di-oxypiperidin-3-yl)isoindoline-1,3- diketone LC-MS (m/z): [M] + calculated for C ₄₃ H ₄₆ F ₃ N ₇ O ₅ 797.88, found 798.65. ¹ H NMR (600 MHz, methanol-d ₄ ) δ 8.16 (d, J = 1.6 Hz, 1H), 7.87 - 7.80 (m, 2H), 7.79 - 7.72 (m, 3H), 7.52 - 7.46 (m, 2H ), 7.40 (d, J = 8.2 Hz, 2H), 7.38 - 7.33 (m, 1H), 5.11 (dd, J = 12.8, 5.4 Hz, 1H), 4.55 - 4.44 (m, 4H), 3.78 (dd, J = 12.1, 3.8 Hz, 1.39 - 1.24 (m, 8H), 0.92 (t, J = 7.0 Hz, 1H).3.60 - 3.54 (m, 3H), 3.29 (dd, J = 13.3, 8.4 Hz, 2H) , 3.15 (t, J = 12.7 Hz, 2H), 3.10 (dd, J = 13.3, 5.0 Hz, 2H), 2.88 (ddd, J = 17.5, 14.4, 5.6 Hz, 2H), 2.80 - 2.68 (m, 2H ), 2.20 - 2.10 (m, 3H), 2.05 (q, J = 6.5 Hz, 1H), 1.73 - 1.59 (m, 2H), 1H). 29 ​ 5-(4-((1-((1-(3-aminopropyl))-3-(5-chloro-6-methyl- 1H -indazol-4-yl) -1H -indole -5-yl)methyl)piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline-1 ,3-diketone LC-MS (m/z): [M] ⁺ calculated for C ₄₃ H ₄₈ ClN ₉ O ₄ 790.37, found 790.40. ¹ H NMR (600 MHz, MeOD) δ 7.86 - 7.75 (m, 3H), 7.73 (s, 1H), 7.59 - 7.47 (m, 4H), 7.37 (dd, J = 8.5, 2.2 Hz, 1H), 5.12 (dd, J = 12.8, 5.5 Hz, 1H), 4.59 - 4.49 (m, 2H), 4.43 (s, 2H), 4.24 - 4.12 (m, 2H), 3.84 - 3.71 (m, 2H), 3.60 - 3.43 (m, 4H), 3.31 - 3.24 (m, 2H), 3.21 (d, J = 6.7 Hz, 2H), 3.15 - 2.98 (m, 4H), 2.94 - 2.85 (m, 1H), 2.81 - 2.69 (m , 2H), 2.61 (s, 3H), 2.39 - 2.25 (m, 3H), 2.21 - 2.10 (m, 3H), 1.71 - 1.56 (m, 2H). 30 ​ 5-(4-((1-((1-(3-aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl) Piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-dioxypiperidin-3-yl)isoindoline-1,3-dione LC-MS (m/z): [M] ⁺ calculated for C ₄₂ H ₄₆ F ₃ N ₇ O ₅ 785.87, found 786.20. ¹ H NMR (600 MHz, MeOD) δ 8.13 (d, J = 1.1 Hz, 1H), 7.83 - 7.80 (m, 2H), 7.75 (d, J = 8.5 Hz, 1H), 7.72 - 7.66 (m, 2H ), 7.46 (dd, J = 8.6, 1.7 Hz, 2H), 7.39 - 7.32 (m, 3H), 5.09 (dd, J = 12.7, 5.5 Hz, 1H), 4.48 (s, 2H), 4.43 (t, J = 7.0 Hz, 2H), 4.15 (d, J = 12.6 Hz, 2H), 3.75 (br, 2H), 3.56 (d, J = 12.7 Hz, 2H), 3.52 - 3.41 (m, 2H), 3.35 ( s, 1H), 3.27 (s, 1H), 3.20 (d, J = 6.3 Hz, 2H), 3.14 (t, J = 12.0 Hz, 2H), 3.00 - 2.95 (m, 2H), 2.89-2.83 (m , 1H), 2.76-2.67 (m, 2H), 2.35-2.30 (m, 1H), 2.28 - 2.22 (m, 2H), 2.17 (d, J = 14.0 Hz, 2H), 2.11-2.09 (m, 1H ), 1.72-1.65 (m, 2H). 31 ​ (2S)-N-(2-(3-(4-((1-(3-aminopropyl))-3-(4-(trifluoromethoxy)phenyl)-1H-indole-5 -yl)methyl)piperidine-1-yl)propoxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclic Propane-1-formamide)-3,3-dimethylbutyl)-4-hydroxypyrrolidine-2-formamide LC-MS (m/z): [M] ⁺ calculated value for C ₅₂ H ₆₄ F ₄ N ₈ O ₆ S 1005.19, experimental value 1005.6. ¹ H NMR (600 MHz, DMSO) δ 8.99 (s, 1H), 8.55 - 8.48 (m, 1H), 7.87 - 7.69 (m, 7H), 7.58 (d, J = 8.3 Hz, 1H), 7.45 (d , J = 8.2 Hz, 2H), 7.40 (s, 1H), 7.27 (d, J = 8.9 Hz, 1H), 6.99 (s, 2H), 5.19 (d, J = 3.5 Hz, 1H), 4.58 (d , J = 9.2 Hz, 1H), 4.50 (t, J = 8.2 Hz, 1H), 4.43 (s, 1H), 4.34 (s, 3H), 4.26 (s, 2H), 4.14 - 4.05 (m, 2H) , 3.69 - 3.57 (m, 3H), 3.54 - 3.48 (m, 1H), 3.10 - 2.99 (m, 3H), 2.98 - 2.91 (m, 1H), 2.81 (s, 2H), 2.45 (s, 3H) , 2.34 (s, 1H), 2.30 - 2.23 (m, 1H), 2.13 (s, 1H), 2.11 - 2.03 (m, 3H), 1.93 - 1.84 (m, 2H), 1.39 - 1.30 (m, 2H) , 1.25 - 1.19 (m, 3H), 0.92 (s, 9H). 32 ​ 5-(4-((1-((1-(3-aminopropyl))-3-(4-(trifluoromethoxy)phenyl) -1H -indol-5-yl)methyl )piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-di-oxypiperidin-3-yl)-6-fluoroisoindoline-1,3- diketone LC-MS (m/z): [M] ⁺ calculated for C ₄₂ H ₄₅ F ₄ N ₇ O ₅ 803.86, found 804.30. ¹ H NMR (600 MHz, MeOD) δ 8.16 (s, 1H), 7.84 (d, J = 8.6 Hz, 2H), 7.74 (s, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.67 ( d, J = 10.7 Hz, 1H), 7.62 (d, J = 7.2 Hz, 1H), 7.49 (d, J = 8.5 Hz, 1H), 7.40 (d, J = 8.3 Hz, 2H), 5.14 (dd, J = 12.9, 5.4 Hz, 1H), 4.51 (s, 2H), 4.46 (t, J = 6.9 Hz, 2H), 3.82 (dd, J = 32.8, 12.4 Hz, 4H), 3.60 (d, J = 12.8 Hz, 2H), 3.49 (t, J = 12.4 Hz, 2H), 3.41 - 3.35 (m, 2H), 3.25 (d, J = 6.7 Hz, 2H), 3.16 (t, J = 12.1 Hz, 2H), 3.04 - 2.97 (m, 2H), 2.93 - 2.86 (m, 1H), 2.82 - 2.69 (m, 2H), 2.40 - 2.32 (m, 1H), 2.31 - 2.25 (m, 2H), 2.22 - 2.10 (m , 3H), 1.76 - 1.66 (m, 2H). 33 ​ 2-(2,6-Dilateral oxypiperidin-3-yl)-5-(4-((1-((1-(3-(methylamino)propyl))-3-(4- (Trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl)piperidin-4-yl)methyl)piperidin-1-yl)isoindoline-1,3-di ketone LC-MS (m/z): [M] + calculated for C ₄₃ H ₄₆ F ₃ N ₇ O ₅ 799.90, found 800.60. ¹ H NMR (600 MHz, MeOD) δ 8.14 (s, 1H), 7.82 (d, J = 8.6 Hz, 2H), 7.77 - 7.71 (m, 2H), 7.69 (d, J = 8.5 Hz, 1H), 7.50 - 7.44 (m, 2H), 7.39 - 7.32 (m, 3H), 5.09 (dd, J = 12.8, 5.4 Hz, 1H), 4.48 (s, 2H), 4.44 (t, J = 6.9 Hz, 2H) , 4.15 (d, J = 14.2 Hz, 2H), 3.76 (d, J = 11.4 Hz, 2H), 3.56 (d, J = 12.9 Hz, 2H), 3.51 - 3.43 (m, 2H), 3.27 (t, J = 11.2 Hz, 2H), 3.21 (d, J = 6.7 Hz, 2H), 3.14 (t, J = 12.1 Hz, 2H), 3.07 - 3.01 (m, 2H), 2.90 - 2.82 (m, 1H), 2.77 - 2.70 (m, 2H), 2.37 - 2.25 (m, 3H), 2.17 (d, J = 13.9 Hz, 2H), 2.13 - 2.08 (m, 1H), 1.74 - 1.64 (m, 2H). 34 ​ 5-(7-((1-(3-Aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl)-2,7 -Diazaspiro[3.5]nonan-2-yl)-2-(2,6-bis-oxypiperidin-3-yl)isoindoline-1,3-dione LC-MS (m/z): [M] ⁺ calculated for C ₃₉ H ₃₉ F ₃ N ₆ O ₅ 728.77, found 729.1. ¹ H NMR (600 MHz, MeOD) δ 8.10 (d, J = 5.2 Hz, 1H), 7.80 - 7.79 (m, 2H), 7.71 - 7.69 (m, 2H), 7.55 (dd, J = 8.4, 2.8 Hz , 1H), 7.37 (t, J = 7.1 Hz, 4H), 7.10 (d, J = 2.1 Hz, 1H), 6.98 (dd, J = 8.4, 2.2 Hz, 1H), 6.84 (d, J = 2.0 Hz , 1H), 6.68 (dd, J = 8.3, 2.1 Hz, 1H), 5.07 - 5.02 (m, 2H), 4.47 (d, J = 12.5 Hz, 3H), 3.93 (d, J = 15.8 Hz, 4H) , 3.49 (d, J = 13.1 Hz, 1H), 3.17 - 3.11 (m, 2H), 3.01 - 2.96 (m, 4H), 2.86 - 2.83 (m, 1H), 2.74 - 2.70 (m, 2H), 2.26 - 2.24 (m, 3H), 2.09 - 2.07 (m, 2H). 35 ​ 5-(4-((1-((1-(3-aminopropyl))-3-(2-fluoro-4-((3-fluoropyridin-2-yl)methoxy)phenyl)- 1H-indol-5-yl)methyl)piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindol Doline-1,3-dione LC-MS (m/z): [M] ⁺ calculated for C ₄₇ H ₅₀ F ₂ N ₈ O ₅ 844.97, found 845.6. ¹ H NMR (600 MHz, MeOD) δ 8.45 (d, J = 4.7 Hz, 1H), 7.86 (s, 1H), 7.71-7.75 (m, 2H), 7.64 (d, J = 8.5 Hz, 1H), 7.57-7.61 (m, 2H), 7.51-7.54 (m, 1H), 7.45 (s, 1H), 7.37 (dd, J = 1.2, 8.5 Hz, 1H), 7.32-7.33 (m, 1H), 6.95- 6.99 (m, 2H), 5.30 (d, J = 1.8 Hz, 2H), 5.09 (dd, J = 5.1, 12.7 Hz, 1H), 4.39-4.43 (m, 4H), 3.98 (s, 2H), 3.80 (br, 2H), 3.53-3.56 (m, 4H), 3.49 (br, 2H), 3.17 (d, J = 6.8 Hz, 2H), 3.04-3.08 (m, 2H), 2.95-2.97 (m, 2H ), 2.82-2.88 (m, 1H), 2.67-2.75 (m, 2H), 2.21-2.27 (m, 3H), 2.09-2.11 (m, 3H), 1.55-1.62 (m, 2H). 36 ​ 5-(4-(1-((1-(3-aminopropyl)-3-(4-(trifluoromethoxy)phenyl) -1H -indol-5-yl)methyl) Azetidin-3-yl)piperidin-1-yl)-2-(2,6-bis-oxypiperidin-3-yl)isoindoline-1,3-dione LC-MS (m/z): [M] ⁺ calculated for C ₃₉ H ₄₀ F ₃ N ₇ O ₅ 743.79, found 744.50. ¹ H NMR (600 MHz, MeOD) δ 8.09 (s, 1H), 7.83 - 7.79 (m, 2H), 7.75 - 7.70 (m, 2H), 7.69 (d, J = 8.5 Hz, 1H), 7.44 - 7.37 (m, 4H), 7.28 (dd, J = 8.6, 2.2 Hz, 1H), 5.11 (dd, J = 12.8, 5.5 Hz, 1H), 4.57 (s, 2H), 4.44 (t, J = 7.0 Hz, 2H), 4.30 - 4.23 (m, 2H), 4.20 - 4.13 (m, 2H), 3.56 - 3.50 (m, 4H), 3.46 (p, J = 6.7 Hz, 1H), 3.03 - 2.97 (m, 2H) , 2.93 - 2.85 (m, 1H), 2.81 - 2.69 (m, 2H), 2.67 - 2.59 (m, 4H), 2.31 - 2.23 (m, 2H), 2.16 - 2.10 (m, 1H). 37 ​ 5-(4-((1-((1-(3-(dimethylamino)propyl))-3-(4-(trifluoromethoxy)phenyl)-1H-indole-5- yl)methyl)piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-di-oxypiperidin-3-yl)isoindoline-1,3- diketone LC-MS (m/z): [M] ⁺ calculated for C ₄₄ H ₅₀ F ₃ N ₇ O ₅ 813.92, found 814.4. ¹ H NMR (600 MHz, MeOD) δ 7.91 (d, J = 0.9 Hz, 1H), 7.79 - 7.73 (m, 2H), 7.66 (d, J = 8.5 Hz, 1H), 7.59 (s, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.36 - 7.31 (m, 3H), 7.27 (dd, J = 8.5, 1.5 Hz, 1H), 7.20 (dd, J = 8.6, 2.3 Hz, 1H), 5.06 (dd, J = 12.7, 5.5 Hz, 1H), 4.30 (t, J = 6.9 Hz, 2H), 3.87 (s, 2H), 3.46 - 3.39 (m, 4H), 3.15 - 3.07 (m, 2H), 2.88 - 2.81 (m, 1H), 2.76 - 2.67 (m, 2H), 2.59 - 2.52 (m, 4H), 2.39 - 2.30 (m, 4H), 2.26 (s, 6H), 2.11 - 2.05 (m, 3H ), 1.86 (d, J = 12.4 Hz, 2H), 1.72 - 1.66 (m, 1H), 1.35 - 1.27 (m, 4H). 38 ​ 5-(4-((1-((1-(5-aminopentyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl) Piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-dioxypiperidin-3-yl)isoindoline-1,3-dione LC-MS (m/z): [M] ⁺ calculated for C ₄₄ H ₅₀ F ₃ N ₇ O ₅ 813.38; found: 814. ¹ H NMR (600 MHz, DMSO ): δ 11.11 (s, 1H), 8.05 (s, 1H), 7.89 (s, 1H), 7.81-7.76 (m, 3H), 7.75-7.66 (m, 3H), 7.49 (s, 1H), 7.46 (d, J = 7.8 Hz, 2H), 7.39-7.32 (m, 2H), 5.08 (dd, J = 13.2 Hz, 5.4 Hz, 1H), 4.18 (s, 1H), 4.25 (t, J = 6.6 Hz, 2H), 3.06 (m, 5H), 2.95-2.88(m, 3H), 2.78 (m, 2H), 2.02 (m, 2H), 1.97 (m, 2H), 1.84 (m, 2H), 1.58 (m, 2H), 1.33 (m, 4H), 1.23 (m, 4H). 39 ​ 5-(7-((1-((1-(3-aminopropyl))-3-(4-(trifluoromethoxy)phenyl) -1H -indol-5-yl)methyl )piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindole Doline-1,3-dione LC-MS (m/z): [M] ⁺ calculated for C ₄₅ H ₅₀ F ₃ N ₇ O ₅ 825.93, found 825.50. ¹ H NMR (600 MHz, MeOD) δ 8.09 (d, J = 1.2 Hz, 1H), 7.82 - 7.76 (m, 2H), 7.72 (s, 1H), 7.68 (dd, J = 8.4, 4.7 Hz, 2H ), 7.42 (dd, J = 8.5, 1.6 Hz, 1H), 7.39 (d, J = 8.0 Hz, 2H), 6.88 (d, J = 2.1 Hz, 1H), 6.72 (dd, J = 8.4, 2.1 Hz , 1H), 5.09 (dd, J = 12.7, 5.5 Hz, 1H), 4.49 (s, 2H), 4.45 (t, J = 7.0 Hz, 2H), 3.92 (d, J = 47.5 Hz, 4H), 3.70 - 3.54 (m, 4H), 3.17 - 3.04 (m, 5H), 3.03 - 2.97 (m, 2H), 2.92 - 2.84 (m, 1H), 2.80 - 2.68 (m, 2H), 2.36 - 2.21 (m, 5H), 2.21 - 2.07 (m, 5H), 1.67 - 1.56 (m, 2H). 40 ​ N-(3-(5-((4-((4-(2-(2,6-dioxypiperidin-3-yl))-1,3-dioxyisoindoline-5 -yl)piperidin-1-yl)methyl)piperidin-1-yl)methyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-1-yl)propan acetamide LC-MS (m/z): [M] ⁺ calculated for C ₄₄ H ₄₈ F ₃ N ₇ O ₆ 827.91, found 828.7. ¹ H NMR (600 MHz, MeOD) δ 8.02 (d, J = 1.0 Hz, 1H), 7.81 - 7.76 (m, 2H), 7.69 - 7.65 (m, 2H), 7.59 (d, J = 8.5 Hz, 1H ), 7.37 - 7.31 (m, 4H), 7.21 (dd, J = 8.6, 2.3 Hz, 1H), 5.07 (dd, J = 12.7, 5.5 Hz, 1H), 4.34 - 4.26 (m, 4H), 3.47 - 3.36 (m, 6H), 3.22 - 3.17 (m, 3H), 2.93 - 2.80 (m, 3H), 2.77 - 2.67 (m, 2H), 2.61 - 2.53 (m, 4H), 2.29 (d, J = 7.1 Hz, 2H), 2.13 - 2.06 (m, 3H), 2.02 (d, J = 13.5 Hz, 2H), 1.93 (s, 3H), 1.88 (br, 1H), 1.46 - 1.36 (m, 2H). 41 ​ 4-(5-((4-((4-(2-(2,6-Dilateral oxypiperidin-3-yl)-1,3-Dilateral oxyisoindolin-5-yl) Piperidin-1-yl)methyl)piperidin-1-yl)methyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-1-yl)butyronitrile LC-MS (m/z): [M] ⁺ calculated for C ₄₃ H ₄₄ F ₃ N ₇ O ₅ 795.86, found 796.4. ¹ H NMR (600 MHz, MeOD) δ 8.05 (d, J = 1.3 Hz, 1H), 7.80 - 7.75 (m, 2H), 7.69 - 7.63 (m, 3H), 7.40 - 7.31 (m, 4H), 7.22 (dd, J = 8.6, 2.4 Hz, 1H), 5.07 (dd, J = 12.7, 5.5 Hz, 1H), 4.44 - 4.38 (m, 4H), 3.52 - 3.40 (m, 6H), 3.01 (t, J = 10.4 Hz, 2H), 2.88 - 2.81 (m, 1H), 2.76 - 2.67 (m, 2H), 2.63 - 2.54 (m, 4H), 2.46 (t, J = 7.1 Hz, 2H), 2.30 (d, J = 6.9 Hz, 2H), 2.24 (p, J = 7.0 Hz, 2H), 2.12 - 2.02 (m, 3H), 1.94 - 1.87 (m, 1H), 1.43 (br, 2H). 42 ​ 2-(2,6-Dilateral oxypiperidin-3-yl)-5-(4-((1-((1-((1-methyl-1H-imidazol-5-yl)methyl) -3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl)piperidin-4-yl)methyl)piperidin-1-yl)isoindoline -1,3-dione LC-MS (m/z): [M] ⁺ calculated for C ₄₄ H ₄₅ F ₃ N ₈ O ₅ 822.35, found: 823.8. ¹ H NMR (600 MHz, DMSO) δ 11.10 (s, 1H), 8.01 (br, 1H), 7.87 (s, 1H), 7.78 (d, J = 9.0 Hz, 2H), 7.75 (br. 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.59 (s, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.33 (d, 2H), 7.25 (dd, J = 7.2 Hz, 1.8 Hz, 1H), 7.05 (s, 1H), 5.52 (s, 2H), 5.06 (dd, J = 13.2 Hz, 5.4 Hz, 1H), 4.36 (br, 1H), 3.55 (s, 3H), 2.87 (m, 2H), 2.47 (br, 4H), 2.16 (br. 2H), 2.01 (m, 2H), 1.91 (s, 4H), 1.76 (br, 2H), 1.23 (br, 4H). 43 ​ 2-(2,6-Dilateral oxypiperidin-3-yl)-5-(4-((1-((1-(3-methoxypropyl))-3-(4-(trifluoro Methoxy)phenyl)-1H-indol-5-yl)methyl)piperidin-4-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione LC-MS (m/z): [M] ⁺ calculated value for C ₄₃ H ₄₇ F ₃ N ₆ O ₆ 800.88, found value 801.9. ¹ H NMR (600 MHz, MeOD) δ 7.93 (s, 1H), 7.75-7.78 (m, 2H), 7.66 (d, J = 8.3 Hz, 1H), 7.56 (s, 1H), 7.51 (d, J = 8.3 Hz, 1H), 7.33-7.34 (m, 3H), 7.27 (dd, J = 1.3, 8.3 Hz, 1H), 7.20 (dd, J = 2.3, 8.6 Hz, 1H), 5.06 (dd, J = 5.3, 12.6 Hz, 1H), 4.34 (t, J = 6.9 Hz, 2H), 3.97 (br, 2H), 3.42-3.44 (m, 4H), 3.32 (s, 3H), 3.17-3.21 (m, 2H ), 2.82-2.88 (m, 1H), 2.66-2.75 (m, 2H), 2.55-2.57 (m, 4H), 2.47 (br, 2H), 2.27 (d, J = 7.3 Hz, 2H), 2.07- 2.12 (m, 3H), 1.89-1.91 (m, 2H), 1.74-1.77 (m, 1H), 1.28-1.36 (m, 4H) 44 ​ 2-(2,6-Dilateral oxypiperidin-3-yl)-5-(4-((1-((1-(3-(2,2,2-trifluoroethoxy))propyl )-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl)piperidin-4-yl)methyl)piperidin-1-yl)isoindole pholine-1,3-dione LC-MS (m/z): [M] ⁺ calculated value for C ₄₄ H ₄₆ F ₆ N ₆ O ₆ 868.34; experimental value: 869.5. ¹ H NMR (600 MHz, DMSO) δ 11.10 (s, 1H), 8.01 (br, 1H), 7.84 (s, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.4 Hz, 1H), 7.61 (br., 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.33 (m, 2H), 7.25 (d, J = 9.0 Hz, 1H), 5.05 (dd, J = 12.6 Hz, 5.4 Hz, 1H), 4.31 (t, J = 6.6 Hz, 2H), 4.05 (q, J = 9.6 Hz, 2H), 3.58 (t, J = 6.6 Hz, 3H), 2.88 (m, 2H ), 2.47 (m, 4H), 2.17 (br,2H), 2.10 (m, 4H), 2.02 (m, 2H), 1.91 (s, 4H), 1.76 (br, 2H), 1.23 (br, 4H) . 45 ​ N-(3-(5-((4-((4-(2-(2,6-dioxypiperidin-3-yl))-1,3-dioxyisoindoline-5 -yl)piperidin-1-yl)methyl)piperidin-1-yl)methyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-1-yl)propan base)-1H-pyrrole-2-methamide LC-MS (m/z): [M] ⁺ calculated for C ₄₇ H ₄₉ F ₃ N ₈ O ₆ 878.95, found 879.6. ¹ H NMR (600 MHz, MeOD) δ 8.04 (d, J = 1.2 Hz, 1H), 7.78 - 7.75 (m, 2H), 7.72 - 7.71 (m, 1H), 7.70 - 7.66 (m, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.35 - 7.34 (m, 2H), 6.90 (dd, J = 2.5, 1.4 Hz, 1H), 6.74 (dd, J = 3.7, 1.4 Hz, 1H), 6.15 ( dd, J = 3.7, 2.6 Hz, 1H), 5.07 (dd, J = 12.7, 5.5 Hz, 1H), 4.42 (s, 2H), 4.37 (t, J = 6.9 Hz, 2H), 3.72 (dt, J = 13.3, 6.6 Hz, 4H), 3.51 (br, 1H), 3.47 - 3.43 (m, 4H), 3.38 (t, J = 6.8 Hz, 2H), 3.23 (q, J = 7.4 Hz, 4H), 2.88 - 2.82 (m, 1H), 2.77 - 2.67 (m, 2H), 2.62 (s, 4H), 2.17 (p, J = 6.8 Hz, 2H), 2.13 - 2.03 (m, 3H). 46 ​ 3-((4-(1-((1-(3-aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl) Piperidin-4-yl)-3-fluorophenyl)amino)piperidine-2,6-dione LC-MS (m/z): [M] + calculated for C ₃₅ H ₃₇ F ₄ N ₅ O ₃ 651.71, found 652.3. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 10.81 (s, 1H), 9.55 (s, 1H), 8.08 (s, 1H), 7.91 (s, 1H), 7.81 - 7.79 (m, 3H), 7.73 (d, J = 8.5 Hz, 1H), 7.50 - 7.46 (m, 2H), 7.39 - 7.36 (m, 1H), 6.92 (t, J = 8.8 Hz, 1H), 6.49 - 6.43 (m, 2H) , 6.11 (d, J = 7.8 Hz, 1H), 4.44 (s, 2H), 4.36 (t, J = 6.9 Hz, 2H), 4.31 (m, 1H), 3.43 (d, J = 11.7 Hz, 2H) , 3.11 (d, J = 11.5 Hz, 2H), 2.89 (s, 1H), 2.85 - 2.80 (m, 2H), 2.73 (m, 1H), 2.07 (m, 4H), 1.92 - 1.82 (m, 5H ), 1.24 (d, J = 3.3 Hz, 2H). 47 ​ N-(3-(5-((4-((4-(2-(2,6-dioxypiperidin-3-yl))-1,3-dioxyisoindoline-5 -yl)piperidin-1-yl)methyl)piperidin-1-yl)methyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-1-yl)propan methyl)-3-(trifluoromethyl)benzamide LC-MS (m/z): [M] ⁺ calculated value for C ₅₀ H ₄₉ F ₆ N ₇ O ₆ 957.98, found value 958.4. ¹ H NMR (500 MHz, MeOD) δ 8.07 (s, 2H), 8.00 (d, J = 7.8 Hz, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.78 - 7.74 (m, 3H), 7.73 (s, 1H), 7.67 - 7.61 (m, 2H), 7.47 (d, J = 2.3 Hz, 1H), 7.38 (dd, J = 8.5, 1.6 Hz, 1H), 7.36 - 7.30 (m, 3H) , 5.09 (dd, J = 12.6, 5.5 Hz, 1H), 4.46 (s, 2H), 4.41 (t, J = 6.7 Hz, 2H), 4.14 (s, 2H), 3.74 (s, 2H), 3.57 ( d, J = 12.8 Hz, 2H), 3.49 - 3.39 (m, 4H), 3.35 (s, 2H), 3.20 (d, J = 6.8 Hz, 2H), 3.11 (t, J = 12.0 Hz, 2H), 2.89 - 2.82 (m, 1H), 2.78 - 2.67 (m, 2H), 2.33 - 2.22 (m, 3H), 2.19 - 2.07 (m, 3H), 1.70 - 1.58 (m, 2H). 48 ​ N-(3-(5-((4-((4-(2-(2,6-dioxypiperidin-3-yl))-1,3-dioxyisoindoline-5 -yl)piperidin-1-yl)methyl)piperidin-1-yl)methyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-1-yl)propan methyl)-4-fluorobenzamide LC-MS (m/z): [M] ⁺ calculated for C ₄₉ H ₄₉ F ₄ N ₇ O ₆ 907.97, found 908.4. ¹ H NMR (600 MHz, MeOD) δ 8.08 (d, J = 1.1 Hz, 1H), 7.83 - 7.72 (m, 6H), 7.63 (d, J = 8.5 Hz, 1H), 7.46 (d, J = 2.2 Hz, 1H), 7.39 - 7.32 (m, 4H), 7.19 - 7.12 (m, 2H), 5.09 (dd, J = 12.8, 5.5 Hz, 1H), 4.46 (s, 2H), 4.40 (t, J = 6.8 Hz, 2H), 4.20 - 4.10 (m, 2H), 3.74 (br, 2H), 3.56 (d, J = 12.8 Hz, 2H), 3.43 (t, J = 6.8 Hz, 4H), 3.29 - 3.18 ( m, 4H), 3.14 - 3.06 (m, 2H), 2.90 - 2.82 (m, 1H), 2.77 - 2.67 (m, 2H), 2.34 - 2.26 (m, 1H), 2.22 (p, J = 6.8 Hz, 2H), 2.18 - 2.08 (m, 3H), 1.64 (td, J = 15.0, 3.5 Hz, 2H). 49 ​ 3-((4-(4-((1-((1-(3-aminopropyl))-3-(4-(trifluoromethoxy)phenyl) -1H -indole-5- Base)methyl)piperidin-4-yl)methyl)piperidine-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione LC-MS (m/z): [M] ⁺ calculated for C ₄₀ H ₄₇ F ₄ N ₇ O ₃ 749.86, found 750.30. ¹ H NMR (600 MHz, MeOD) δ 8.16 (d, J = 1.1 Hz, 1H), 7.87 - 7.82 (m, 2H), 7.74 (s, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.49 (dd, J = 8.5, 1.5 Hz, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.06 (t, J = 9.1 Hz, 1H), 6.78 - 6.71 (m, 2H), 4.50 (s , 2H), 4.46 (t, J = 7.0 Hz, 2H), 4.40 (dd, J = 12.2, 5.0 Hz, 1H), 3.79 - 3.70 (m, 2H), 3.69 (s, 3H), 3.58 (d, J = 12.8 Hz, 2H), 3.49 - 3.42 (m, 2H), 3.32 - 3.26 (m, 3H), 3.21 (d, J = 6.9 Hz, 2H), 3.20 - 3.13 (m, 2H), 3.02 - 2.98 (m, 2H), 2.85 - 2.72 (m, 2H), 2.38 - 2.23 (m, 4H), 2.17 (d, J = 14.3 Hz, 2H), 1.75 - 1.65 (m, 2H). 50 ​ 5-(4-((1-((1-butyl-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl)piperidin-4-yl )Methyl)piperidin-1-yl)-2-(2,6-dioxypiperidin-3-yl)isoindoline-1,3-dione LC-MS (m/z): [M] ⁺ calculated for C ₄₃ H ₄₇ N ₆ O ₅ 784.36; found: 785.3. ¹ H NMR (600 MHz, DMSO ) δ 11.10 (s, 1H), 8.04 (br, 1H), 7.89 (s, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.67 (t, J = 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.32 (br, 2H), 7.25 (d, 1H), 5.06 (dd, J = 13.2 Hz, 5.4Hz, 1H), 4.38 (s, 1H), 4.26 (t, J = 7.2 Hz 2H), 2.91 (m, 3H), 2.61 (m, 2H), 2.47 (s, 3H), 2.17 (s, 2H), 2.01 (m, 2H), 1.91 (m, 3H), 1.80 (m, 4H), 1.28 (m, 7H), 1.18 (br, 2H), 0.91 (t, J = 7.2 Hz, 3H). 51 ​ 2-(2,6-Dilateral oxypiperidin-3-yl)-5-(4-((1-((3-(4-(trifluoromethoxy)phenyl))-1 H -indole Indolin-5-yl)methyl)piperidin-4-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione LC-MS (m/z): [M] ⁺ calculated for C ₃₉ H ₃₉ F ₃ N ₆ O ₅ 728.77, found 729.20. ¹ H NMR (600 MHz, MeOD) δ 8.07 (s, 1H), 7.82 - 7.78 (m, 3H), 7.68 (s, 1H), 7.60 (d, J = 8.3 Hz, 1H), 7.50 (d, J = 2.3 Hz, 1H), 7.40 - 7.35 (m, 3H), 7.34 (dd, J = 8.4, 1.5 Hz, 1H), 5.12 (dd, J = 12.8, 5.5 Hz, 1H), 4.49 (s, 2H) , 3.62 (d, J = 13.0 Hz, 2H), 3.58 - 3.44 (m, 3H), 3.20 (d, J = 6.9 Hz, 2H), 3.13 - 3.07 (m, 2H), 2.92 - 2.85 (m, 1H ), 2.81 - 2.70 (m, 2H), 2.33 - 2.23 (m, 1H), 2.19 - 2.11 (m, 3H), 1.68 - 1.54 (m, 2H). 52 ​ 5-(4-((1-((1-((2,3-dihydrobenzo[b][1,4]dioxen-2-yl)methyl))-3-(4 -(Trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl)piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-di Pendant oxypiperidin-3-yl)isoindoline-1,3-dione LC-MS (m/z): [M] ⁺ calculated for C ₄₈ H ₄₇ F ₃ N ₆ O ₇ 876.93, found 877.3. ¹ H NMR (600 MHz, MeOD) δ 8.04 (d, J = 1.3 Hz, 1H), 7.79 - 7.75 (m, 2H), 7.69 - 7.62 (m, 3H), 7.38 - 7.32 (m, 4H), 7.21 (dd, J = 8.6, 2.3 Hz, 1H), 6.87 - 6.78 (m, 4H), 5.07 (dd, J = 12.8, 5.5 Hz, 1H), 4.62 - 4.59 (m, 4H), 4.40 (s, 2H ), 4.36 - 4.32 (m, 1H), 3.96 (dd, J = 11.5, 5.7 Hz, 1H), 3.51 - 3.41 (m, 6H), 3.04 - 2.95 (m, 2H), 2.87 - 2.82 (m, 1H ), 2.76 - 2.68 (m, 2H), 2.60 - 2.55 (m, 4H), 2.29 (d, J = 6.9 Hz, 2H), 2.12 - 2.02 (m, 3H), 1.91 (br, 1H), 1.43 ( br, 2H). 53 ​ 2-(2,6-Dilateral oxypiperidin-3-yl)-5-(4-((1-((1-(pyridin-2-ylmethyl))-3-(4-(trifluoro Methoxy)phenyl)-1H-indol-5-yl)methyl)piperidin-4-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione LC-MS (m/z): [M] ⁺ calculated for C ₄₅ H ₄₄ F ₃ N ₇ O ₅ 819.34; found: 820. ¹ H NMR (600 MHz, DMSO) δ 11.09 (s, 1H), 8.53 (m, 1H), 8.01 (br, 2H), 7.81 (d, J =8.4 Hz, 2H), 7.76 (t, J =6.0 Hz, 1H), 7.67 (d, J =8.4 Hz, 1H), 7.62 (br, 1H), 7.46 (d, J =7.8 Hz 2H), 7.31 (m, 3H), 7.25 (d, J =8.4 Hz , 1H), 7.22 (d, J =8.4 Hz, 1H), 5.59 (s, 2H), 5.07 (dd, J =13.2 Hz, 5.4 Hz, 1H), 4.37 (br, 1H), 3.36 (m, 4H ), 2.87 (m, 2H), 2.52 (m, 2H), 2.46 (br, 4H), 2.16 (br,2H), 2.02 (m, 2H), 1.89 (br, 2H), 1.76 (br, 2H) , 1.23 (br, 4H). 54 ​ 3-((4-(1'-((1-(3-aminopropyl))-3-(4-(trifluoromethoxy)phenyl) -1H -indol-5-yl)methyl (yl)-[4,4'-dipiperidin]-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione LC-MS (m/z): [M] ⁺ calculated for C ₄₀ H ₄₆ F ₄ N ₆ O ₃ 734.84, found 735.40. ¹ H NMR (500 MHz, MeOD) δ 8.10 (d, J = 1.2 Hz, 1H), 7.82 - 7.76 (m, 2H), 7.71 (s, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.47 - 7.35 (m, 4H), 6.70 (ddd, J = 11.9, 11.5, 2.5 Hz, 2H), 4.51 - 4.35 (m, 5H), 3.75 - 3.66 (m, 2H), 3.66 - 3.52 (m, 4H ), 3.09 - 2.95 (m, 4H), 2.88 - 2.70 (m, 2H), 2.34 - 2.23 (m, 3H), 2.14 - 1.94 (m, 5H), 1.86 - 1.74 (m, 2H), 1.67 - 1.49 (m, 4H). 55 ​ 3-((4-(4-((1-((1-butyl-3-(4-(trifluoromethoxy)phenyl))-1H-indol-5-yl)methyl)piperidine -4-yl)methyl)piperidine-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione LC-MS (m/z): [M] ⁺ calculated for C ₄₁ H ₄₈ F ₄ N ₆ O ₃ 748.37; found: 749.6. ¹ H NMR (600 MHz, d ⁴ -MeOD) δ 8.03 (s, 1H), 7.78 (d, 2H), 7.66 (s, 1H), 7.60 (d, J = 8.4Hz, 1H), 7.36 (d, J = 7.8 Hz, 2H), 7.33 (m, 1H), 6.91 (t., J = 9.0 Hz, 1H), 6.55 (dd, J = 14.4 Hz, 2.4 Hz,1H), 6.50 (d, J = 8.4 Hz,1H), 4.35 (br, 2H), 4.30 (t, J = 7.2 Hz, 2H), 4.25 (dd, J = 12.0 Hz, 4.8Hz, 1H), 3.49 (br, 2H), 2.98 (br, 6H), 2.80 (m, 1H), 2.74 (m, 1H), 2.62 (br, 4H), 2.32 (br, 3H), 2.04 (d, J = 12.9 Hz, 2H), 1.96 (s, 1H), 1.88 (m, 4H), 1.39 (m, 4H), 0.99 (t, J = 7.2 Hz 3H). 56 ​ 5-(4-((1-((1-((1,3-dioxolane-2-yl)methyl)methyl)-3-(4-(trifluoromethoxy)phenyl)-1H- Indol-5-yl)methyl)piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline -1,3-dione LC-MS (m/z): [M] for C ₄₃ H ₄₅ F ₃ N ₆ O ₇ ⁺ calculated value 814.86, found value 815.3 ¹ H NMR (600 MHz, MeOD) δ 8.02 (br, J = 1.3 Hz, 1H), 7.78 - 7.75 (m, 2H), 7.67 (dd, J = 8.5, 6.0 Hz, 2H), 7.63 (s, 1H), 7.38 - 7.32 (m, 4H), 7.22 (dd, J = 8.6, 2.3 Hz, 1H), 5.24 (t, J = 3.2 Hz, 1H), 5.07 (dd, J = 12.8, 5.5 Hz, 1H), 4.44 (d, J = 3.2 Hz, 2H), 4.41 (s, 2H) , 3.83 - 3.78 (m, 2H), 3.76 - 3.71 (m, 2H), 3.54 - 3.41 (m, 6H), 3.06 - 2.98 (m, 2H), 2.88 - 2.81 (m, 1H), 2.76 - 2.68 ( m, 2H), 2.62 - 2.55 (m, 4H), 2.30 (d, J = 6.4 Hz, 2H), 2.12 - 2.02 (m, 3H), 1.92 (s, 1H), 1.42 (br, 2H), 1.34 - 1.27 (m, 1H). 57 ​ 2-(2,6-Dilateral oxypiperidin-3-yl)-5-(4-((1-((1-(4-methylpentyl))-3-(4-(trifluoromethyl Oxy)phenyl)-1H-indol-5-yl)methyl)piperidin-4-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione LC-MS (m/z): [M] ⁺ calculated for C ₄₆ H ₅₂ F ₃ N ₅ O ₅ 811.95; found: 813.3. ¹ H NMR (600 MHz, d ⁴ -MeOD ) δ 8.06 (s, 1H), 7.79 (d, 2H), 7.69 (d, 1H), 7.67 (s, 1H), 7.62 (d, J =8.46 Hz, 1H), 7.37 (m, 4H), 7.24 (m, 1H), 5.09 (dd, J =13.2 Hz, 5.46 Hz, 1H), 4.43 (s, 2H), 4.29 (t, J =7.02 Hz, 2H) , 3.46 (br, 4H), 3.03 (br, 2H), 2.87 (m, 1H), 2.74 (m, 2H), 2.61 (br, 4H), 2.32 (br, 2H), 2.09 (m, 3H), 1.99 (s, 1H), 1.92 (m, 3H), 1.60 (m, 1H), 1.32 (br, 3H), 1.26 (m, 2H), 0.91 (s, 3H), 0.90 (s, 3H). 58 ​ 3-((4-(4-((1-((1-(3-(dimethylamino)propyl))-3-(4-(trifluoromethoxy)phenyl)-1 H - Indol-5-yl)methyl)piperidin-4-yl)methyl)piperidine-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione LC-MS (m/z): [M] ⁺ calculated for C ₄₂ H ₅₁ F ₄ N ₇ O ₃ 777.91, found 778.50. ¹ H NMR (600 MHz, MeOD) δ 8.10 (d, J = 1.1 Hz, 1H), 7.83 - 7.77 (m, 2H), 7.73 (s, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.43 (dd, J = 8.5, 1.5 Hz, 1H), 7.39 (d, J = 8.0 Hz, 2H), 6.95 (t, J = 9.1 Hz, 1H), 6.61 - 6.51 (m, 2H), 4.49 (s , 2H), 4.44 (t, J = 7.0 Hz, 2H), 4.28 (dd, J = 11.9, 4.9 Hz, 1H), 3.79 - 3.63 (m, 2H), 3.59 (m, 2H), 3.43 - 3.36 ( m, 2H), 3.33 - 3.25 (m, 2H), 3.25 - 3.13 (m, 6H), 3.10 (dd, J = 12.9, 10.8 Hz, 2H), 2.91 (s, 6H), 2.87 - 2.71 (m, 2H), 2.40 - 2.23 (m, 4H), 2.13 (d, J = 13.2 Hz, 2H), 1.97 (ddd, J = 25.4, 12.6, 4.8 Hz, 1H), 1.67 - 1.57 (m, 2H). 59 ​ 5-(1'-((1-(3-Aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl)-[4 ,4'-dipiperidin]-1-yl)-2-(2,6-dioxypiperidin-3-yl)isoindoline-1,3-dione LC-MS (m/z): C ₄₂ H ₄₅ F ₃ N ₆ O ₅ of [M] ⁺ calculated value 770.85, found value 771.3 ¹ H NMR (600 MHz, MeOD) δ 8.09 (d, J = 1.1 Hz, 1H), 7.82 - 7.78 (m, 2H), 7.69 (dd, J = 17.0, 8.3 Hz, 3H), 7.44 - 7.40 (m, 2H), 7.37 (d, J = 8.1 Hz, 2H), 7.29 (dd , J = 8.6, 2.2 Hz, 1H), 5.07 (dd, J = 12.8, 5.5 Hz, 1H), 4.44 - 4.39 (m, 4H), 4.04 (d, J = 13.1 Hz, 2H), 3.52 (d, J = 12.7 Hz, 2H), 3.03 - 2.95 (m, 6H), 2.88 - 2.82 (m, 1H), 2.77 - 2.68 (m, 2H), 2.28 - 2.22 (m, 2H), 2.12 - 2.07 (m, 1H), 2.05 - 2.00 (m, 2H), 1.87 (d, J = 12.1 Hz, 2H), 1.57 - 1.45 (m, 4H), 1.43 - 1.35 (m, 2H). 60 ​ 3-((4-(1'-((1-(3-(dimethylamino)propyl))-3-(4-(trifluoromethoxy)phenyl)-1H-indole-5 -yl)methyl)-[4,4'-dipiperidin]-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione LC-MS (m/z): [M] for C ₄₂ H ₅₀ F ₄ N ₆ O ₃ ⁺ calculated value 762.89, found value 763.4 ¹ H NMR (600 MHz, MeOD) δ 8.06 (d, J = 1.1 Hz, 1H), 7.81 - 7.76 (m, 2H), 7.70 (s, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.40 - 7.34 (m, 3H), 6.91 (t, J = 9.2 Hz, 1H ), 6.54 - 6.45 (m, 2H), 4.41 - 4.35 (m, 4H), 4.22 (dd, J = 11.8, 4.9 Hz, 1H), 3.48 (d, J = 12.1 Hz, 2H), 3.25 (d, J = 11.5 Hz, 2H), 2.98 - 2.91 (m, 4H), 2.82 - 2.76 (m, 1H), 2.73 - 2.71 (m, 1H), 2.68 (s, 6H), 2.57 (t, J = 11.8 Hz , 2H), 2.32 - 2.24 (m, 3H), 2.00 (d, J = 12.9 Hz, 2H), 1.80 (d, J = 12.6 Hz, 2H), 1.53 - 1.40 (m, 5H), 1.32 - 1.22 ( m, 3H). 61 ​ 4-Amino-N-(3-(5-((4-((4-(4-((2,6-bisoxypiperidin-3-yl)amino))-2-fluorophenyl )piperidin-1-yl)methyl)piperidin-1-yl)methyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-1-yl)propyl) Piperidine-4-methamide LC-MS (m/z): C ₄₆ H ₅₇ F ₄ N ₉ O ₄ of [M] ⁺ calculated value 876.01, found value 876.5 ¹ H NMR (600 MHz, MeOD) δ 8.12 (d, J = 1.1 Hz, 1H), 7.85 - 7.79 (m, 3H), 7.67 (d, J = 8.5 Hz, 1H), 7.43 (dd, J = 8.5, 1.5 Hz, 1H), 7.36 (d, J = 8.0 Hz, 2H), 7.10 (t, J = 9.0 Hz, 1H), 6.90 - 6.81 (m, 2H), 4.50 - 4.43 (m, 3H), 4.38 (t, J = 6.9 Hz, 2H), 3.76 - 3.68 (m, 2H) , 3.56 (d, J = 13.2 Hz, 2H), 3.51 - 3.41 (m, 4H), 3.39 - 3.34 (m, 5H), 3.19 (d, J = 6.8 Hz, 2H), 3.16 - 3.08 (m, 2H ), 2.79 - 2.67 (m, 4H), 2.34 - 2.26 (m, 1H), 2.23 - 2.11 (m, 7H), 2.03 - 1.95 (m, 3H), 1.72 - 1.62 (m, 2H), 1.41 - 1.34 (m, 2H). 62 ​ 5-((4-((4-(2-(2,6-bisoxypiperidin-3-yl)-1,3-bisoxy-2,3-dihydro-1H-indene- 5-yl)piperidin-1-yl)methyl)piperidin-1-yl)methyl)-N,N-dimethyl-3-(4-(trifluoromethoxy)phenyl)-1H -indole-1-sulfonamide LC-MS (m/z): [M] ⁺ calculated value for C ₄₂ H ₄₅ F ₃ N ₆ O ₇ S: 834.91; experimental value: 836.3. ¹ H NMR (600 MHz, d ⁴ -MeOD ) δ 8.12 (d, J =8.4 Hz, 1H), 8.00 (s, 1H), 7.90 (s, 1H), 7.83 (m, 2H), 7.70 (d, J =8.4 Hz, 1H), 7.50 (dd, J =7.2 Hz, 1.2 Hz, 1H), 7.45 (d, J =7.8 Hz,2H), 7.37 (d, J =2.4 Hz,1H), 7.24 (dd , J = 9.0 Hz, 2.4 Hz, 1H), 5.09 (dd, J =12.6 Hz, 5.4 Hz,, 1H), 4.63 (br, 1H), 4.25 (br, 1H), 3.46 (t, J =5.4 Hz ,, 4H), 3.36 (m, 2H), 2.86 (m, 1H), 2.76 (m, 4H), 2.61 (t, J =4.8Hz, 4H), 2.32 (d, J =7.2 Hz, 2H), 2.12 (m, 1H), 2.01 (d, J =14.4 Hz, 2H), 1.98 (s, 1H), 1.87 (br, 1H), 1.41 (m, 2H), 1.32 (m, 4H). 63 ​ 3-((3-Fluoro-4-(4-((1-((1-(4-methylpentyl))-3-(4-(trifluoromethoxy)phenyl)-1H-indole -5-yl)methyl)piperidin-4-yl)methyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione LC-MS (m/z): [M] ⁺ calculated for C ₄₃ H ₅₂ F ₄ N ₆ O ₃ 776.24; found: 777.5. ¹ H NMR (600 MHz, d ⁴ -MeOD ) δ 8.05 (s, 1H), 7.79 (d, J = 6.6 Hz, 2H), 7.67 (s, 1H), 7.61 (d, J = 8.4 Hz, 1H) , 7.36 (m, 3H), 6.90 (t, J =9.0Hz, 1H), 6.55 (dd, J = 14.4 Hz, 2.58 Hz, 1H), 6.50 (d, J = 8.64 Hz, 6.06 Hz, 1H), 4.41 (br, 2H), 4.29 (t, J =7.0 Hz, 2H), 4.25 (dd, J = 11.8 Hz, 4.86 Hz, 1H), 3.50 (m, 2H), 2.99 (br, 5H), 2.83- 2.78 (m, 1H), 2.75-2.70 (m, 1H), 2.64 (br, 3H), 2.38-2.28 (m, 3H), 2.07 (br, 1H), 2.04 (br, 1H), 1.99 (s, 2H), 1.92 (m, 4H), 1.60 (m, 1H), 1.43 (m, 2H), 1.32 (br, 2H), 1.26 (m, 2H), 0.91 (s, 3H), 0.90 (s, 3H ). 64 ​ 3-((4-fluoro-3-(4-((1-((3-(4-(trifluoromethoxy)phenyl))-1H-indol-5-yl)methyl)piperidine- 4-yl)methyl)piperidine-1-yl)phenyl)amino)piperidine-2,6-dione LC-MS (m/z): Calculated for C ₃₇ H ₄₀ F ₄ N ₆ O ₃ of [M] ⁺ 692.31: Experimental: 693.6. ¹ H NMR (600 MHz, d ⁴ -MeOD ) δ 8.05 (s, 1H), 7.80 (d, J =8.4 Hz, 1H), 7.66 (s, 1H), 7.58 (d, 1H), 7.37 (d, J =8.4 Hz, 2H), 7.31 (d, J =7.8 Hz, 1H), 6.91 (t, J =9.6 Hz, 1H), 6.55 (dd, J =13.08 Hz, 2.4 Hz, 1H), 6.50 (d , J =8.4 Hz, 1H), 4.42 (s, 2H), 4.24 (dd, J = 11.4 Hz, 4.8 Hz, 1H), 3.50 (br, 2H), 3.00 (br, 6H), 2.83-2.29 (m , 6H), 2.36 (br, 2H), 2.31 (m, 1H), 2.06 (d, 2H), 1.99 (s, 1H), 1.94 (m, 2H), 1.43 (br, 2H), 1.31 (br, 2H). 65 ​ 3-((3-Fluoro-4-(1'-((3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl)-[4,4' -Dipiperidin]-1-yl)phenyl)amino)piperidine-2,6-dione LC-MS (m/z): [M] ⁺ calculated for C ₃₇ H ₃₉ F ₄ N ₅ O ₃ 677.30; found: 678.2. ¹ H NMR (600 MHz, d ⁴ -MeOD ) δ 8.05 (d, J = 0.6 Hz, 1H), 7.80 (d, J = 6.6 Hz, 2H), 7.66 (s, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 7.8 Hz, 2H), 7.31 (dd, J = 8.4 Hz, 1.2 Hz, 1H), 6.92 (t, J = 9.0 Hz, 1H), 6.54 (dd, J = 14.4 Hz, 2.4 Hz, 1H), 6.49 (dd, J = 8.4 Hz, 2.4 Hz 1H), 4.04 (s, 2H), 4.24 (dd, J = 12.0 Hz, 4.8 Hz 1H), 3.52 (d, J = 12Hz, 2H), 3.27 (br, 2H), 3.00 (br, 2H), 2.85-2.77 (m, 1H), 2.72 (m, 1H), 2.59 (t, J = 12 Hz, 2H), 2.31 ( m, 1H), 2.04 (br, 2H), 1.98 (s, 2H), 1.93 (m, 1H), 1.81 (br, 2H), 1.56-1.42 (m, 5H), 1.33-1.22 (m, 2H) . 66 ​ 5-(5-((1-(3-Aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl)hexahydropyrrolo [3,4-c]pyrrole-2(1H)-yl)-2-(2,6-bis-oxypiperidin-3-yl)isoindoline-1,3-dione LC-MS (m/z): C ₃₈ H ₃₇ F ₃ N ₆ O ₅ of [M] ⁺ calculated 714.75, found 715.1 ¹ H NMR (600 MHz, MeOD) δ 8.07 (br, 1H), 7.79 - 7.75 (m, 2H), 7.68 (s, 1H), 7.65 (dd, J = 8.4, 2.9 Hz, 2H), 7.43 (dd, J = 8.5, 1.2 Hz, 1H), 7.34 (d, J = 8.1 Hz , 2H), 7.05 (d, J = 2.1 Hz, 1H), 6.93 (dd, J = 8.5, 2.1 Hz, 1H), 5.07 (dd, J = 12.8, 5.5 Hz, 1H), 4.62 (s, 4H) , 4.46 - 4.37 (m, 4H), 3.66 - 3.48 (m, 6H), 3.19 (s, 2H), 3.00 - 2.94 (m, 2H), 2.89 - 2.82 (m, 1H), 2.77 - 2.67 (m, 2H), 2.28 - 2.21 (m, 2H), 2.13 - 2.07 (m, 1H). 67 ​ 3-((4-(5-((1-(3-aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl) Hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)-3-fluorophenyl)amino)piperidine-2,6-dione LC-MS (m/z): [M] ⁺ calculated for C ₃₆ H ₃₈ F ₄ N ₆ O ₃ 678.73, found 679.2. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 10.81 (s, 1H), 8.21 - 8.15 (m, 1H), 8.02 - 7.93 (m, 4H), 7.85 (dd, J = 8.9, 2.3 Hz, 2H ), 7.73 (dd, J = 12.5, 8.5 Hz, 1H), 7.52 - 7.42 (m, 3H), 6.78 (s, 1H), 6.58 (d, J = 15.5 Hz, 1H), 6.46 (s, 1H) , 4.52 (d, J = 5.6 Hz, 2H), 4.44 (s, 1H), 4.39 (d, J = 6.8 Hz, 2H), 4.28 (d, J = 11.1 Hz, 1H), 3.21 (s, 2H) , 2.93 (d, J = 31.9 Hz, 4H), 2.80 (m, 4H), 2.15 - 2.07 (m, 3H), 1.90 - 1.82 (m, 1H). 68 ​ 5-(4-((1-((1-(3,3-dimethoxypropyl))-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl )Methyl)piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline-1,3-di ketone LC-MS (m/z): [M] ⁺ calculated for C ₄₄ H ₄₉ F ₃ N ₆ O ₇ 830.36; found: 831.4. ¹ H NMR (600 MHz, d ⁴ -MeOD ) δ 8.04 (s, 1H), 7.79 (d, J = 9.0 Hz, 2H), 7.69 (d, J = 8.4 Hz, 1H), 7.66 (s, 1H) , 7.61 (d, J = 8.4 Hz, 1H), 7.37 (m, 4H), 7.24 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 5.09 (dd, J = 12.6 Hz, 5.4 Hz, 1H), 4.63 (s, 1H), 4.38-4.31 (m, 5H), 3.46 (br, 6H), 3.34 (st, 6H), 2.78 (m, 1H), 2.74 (m, 1H), 2.60 (br, 4H) , 2.32 (d, J =6.6Hz, 1H), 2.17 (m, 2H), 2.12 (m, 1H), 2.05 (br, 2H), 1.96 (s, 1H), 1.32 (br, 4H). 69 ​ 5-(5-((1-(3-(dimethylamino)propyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl )Hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline-1,3-di ketone LC-MS (m/z): C ₄₀ H ₄₁ F ₃ N ₆ O ₅ of [M] ⁺ calculated 742.80, found 743.2 ¹ H NMR (600 MHz, MeOD) δ 7.99 (s, 1H), 7.76 - 7.72 (m, 2H), 7.65 (d, J = 8.6 Hz, 2H), 7.58 (d, J = 8.5 Hz, 1H), 7.35 (dd, J = 8.5, 1.5 Hz, 1H), 7.31 (d, J = 8.1 Hz, 2H), 7.03 (d, J = 2.2 Hz, 1H), 6.91 (dd, J = 8.5, 2.2 Hz, 1H), 5.06 (dd, J = 12.8, 5.5 Hz, 1H), 4.36 (t , J = 6.9 Hz, 2H), 4.25 (s, 2H), 3.55 - 3.48 (m, 4H), 3.47 - 3.41 (m, 2H), 3.22 (s, 2H), 3.05 - 2.95 (m, 4H), 2.87 - 2.82 (m, 1H), 2.77 - 2.74 (m, 1H), 2.72 (s, 6H), 2.29 - 2.23 (m, 2H), 2.12 - 2.07 (m, 1H). 70 ​ 5-(1'-((1-(3-aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl)-[3 ,3'-azazetidin]-1-yl)-2-(2,6-di-oxypiperidin-3-yl)isoindoline-1,3-dione LC-MS (m/z): C ₃₈ H ₃₇ F ₃ N ₆ O ₅ of [M] ⁺ calculated value 714.75, found value 715.1 ¹ H NMR (600 MHz, MeOD) δ 8.00 (s, 1H), 7.76 ( dd, J = 8.8, 2.1 Hz, 2H), 7.69 - 7.68 (m, 1H), 7.58 (d, J = 8.3 Hz, 1H), 7.38 - 7.34 (m, 3H), 7.30 (ddd, J = 8.4, 5.5, 1.5 Hz, 1H), 7.01 (t, J = 1.9 Hz, 1H), 6.87 (dd, J = 8.4, 2.1 Hz, 1H), 5.07 (ddd, J = 12.8, 5.5, 2.4 Hz, 1H), 4.43 - 4.39 (m, 4H), 4.22 - 4.12 (m, 3H), 4.07 - 4.02 (m, 1H), 3.71 - 3.67 (m, 2H), 2.99 - 2.93 (m, 3H), 2.88 - 2.83 (m , 2H), 2.76 - 2.68 (m, 2H), 2.56 - 2.50 (m, 1H), 2.26 - 2.20 (m, 3H), 2.11 - 2.07 (m, 1H). 71 ​ 5-(1'-((1-(3-(dimethylamino)propyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl yl)-[4,4'-dipiperidin]-1-yl)-2-(2,6-di-oxypiperidin-3-yl)isoindoline-1,3-dione LC-MS (m/z): C ₄₄ H ₄₉ F ₃ N ₆ O ₅ of [M] ⁺ calculated value 798.91, found value 799.4 ¹ H NMR (600 MHz, MeOD) δ 8.07 - 8.04 (m, 1H), 7.79 - 7.75 (m, 2H), 7.70 (s, 1H), 7.65 (dd, J = 8.5, 5.7 Hz, 2H), 7.40 - 7.34 (m, 3H), 7.32 (d, J = 2.3 Hz, 1H) , 7.19 (dd, J = 8.7, 2.3 Hz, 1H), 5.06 (dd, J = 12.8, 5.5 Hz, 1H), 4.43 - 4.36 (m, 4H), 4.07 (d, J = 13.3 Hz, 2H), 3.50 (d, J = 11.0 Hz, 2H), 3.14 - 3.08 (m, 2H), 3.00 - 2.90 (m, 4H), 2.90 - 2.83 (m, 1H), 2.81 (s, 6H), 2.77 - 2.68 ( m, 2H), 2.34 - 2.27 (m, 2H), 2.12 - 2.07 (m, 1H), 2.01 (d, J = 12.0 Hz, 2H), 1.85 (d, J = 12.3 Hz, 2H), 1.46 (s , 4H), 1.37 - 1.29 (m, 2H). 72 ​ (2R,4S)-1-((R)-2-(2-(4-((1-((1-(3-aminopropyl))-3-(4-(trifluoromethoxy) Phenyl)-1H-indol-5-yl)methyl)piperidin-4-yl)methyl)piperidin-1-yl)acetyl)-3,3-dimethylbutyl)-4 -Hydroxy-N-((R)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-methamide LC-MS (m/z): C ₄₄ H ₄₉ F ₃ N ₆ O ₅ of [M] ⁺ calculated value 1013.52, found value 1014.7 ¹ H NMR (600 MHz, DMSO-d6) δ 9.67 (s, 1H), 9.00 (s, 1H), 8.45 - 8.38 (m, 1H), 8.06 (s, 1H), 7.91 (d, J = 2.6 Hz, 1H), 7.88 - 7.75 (m, 5H), 7.71 (dd, J = 8.3, 3.8 Hz, 1H), 7.49 - 7.33 (m, 6H), 4.92 - 4.89 (m, 1H), 4.53 (d, J = 9.2 Hz, 1H), 4.41 (t, J = 6.6 Hz, 3H), 4.36 (t, J = 7.1 Hz, 2H), 4.30 (s, 2H), 3.97 (s, 2H), 3.64 - 3.61 (m, 2H), 3.55 (d, J = 10.8 Hz, 2H), 3.43 (s , 2H), 2.94 - 2.86 (m, 3H), 2.83 (d, J = 7.2 Hz, 2H), 2.46 (s, 3H), 2.10 (d, J = 7.7 Hz, 2H), 1.92 (d, J = 13.4 Hz, 2H), 1.79 (m, 1H), 1.38 (d, J = 7.0 Hz, 4H), 0.95 (s, 9H).

Example 6 biological activity

Test the specificity and ability of multiple RAS-PROTACs to degrade target proteins. A brief description of the different analyzes is described below.

Western blot assay to assess the cellular efficacy of RAS-PROTAC in KRAS protein degradation

In Western blot experiments, BT-474 (KRAS ^WT ) and MIA PaCa-2 (KRAS ^G12C ) cells were cultured in DMEM medium with 10% FBS. BxPC3 (KRAS ^WT ) and KLM-1 (KRAS ^G12D ) cells were cultured in DMEM medium with 10% FBS. MDA-MB-231 (KRAS ^G13D ) cells were cultured in L15 medium with 10% FBS. BT-474, MIA PaCa-2, BxPC3 and MDA-MB-231 have been established by the American Type Culture Collection. KLM-1 has been built by ExPASy. On the day of analysis, two hundred thousand cells were pretreated with each test compound for 24 hours. After 24 hours, whole cell lysates were collected by adding 2× SDS sample buffer. Proteins were separated by SDS-PAGE electrophoresis and transferred to PVDF membrane. Use the immunoblot method to detect protein expression using various primary and secondary antibodies and following standard protocols. Antibodies against KRAS were purchased from Abcam (Cambridge, UK). Anti-rabbit IgG, HRP-linked secondary antibody system was purchased from Cell Signaling Technology (Danvers, MA). Antibodies against actin were purchased from Millipore (Burlington, MA). Immunoblots were visualized by chemiluminescence (SuperSignal™ West Femto Maximum Sensitivity Substrate, Thermo Fisher, Waltham, MA) and detected by a ChemiDoc ^™ MP Imaging System (Bio-Rad, Hercules, CA). The ribbon intensity of Western ink dots was also quantified by the ChemiDoc ^TM MP imaging system. The relative intensity of the color band corresponding to the drug-treated group was compared to the intensity of the untreated group.

The preliminary screening results of bifunctional compounds 1-21 degrading KRAS protein in Calu-1, H358, H441, KLM-1, MDA-MB-231 and HCT-116 cell lines are shown in Table 2, which are listed above. Tested under the conditions described.

Table 2 DC50 G12C G12V G12D G13D G12S cpd number MW(Da) Calu-1 H358 H441 KLM-1 MDA-MB-231 HCT-116 A549 1 876.98 ++ + + ++ 2 1003.14 - - - - - 3 785.87 ++ + ++ ++ ++ ++ 4 717.87 - - - - - 5 717.87 - - - - - 6 785.87 ++ + ++ ++ ++ ++ 7 719.86 ++ - + + + + 8 688.71 + + + + + 9 698.18 ++ + + + + 10 731.9 + + + + + + 11 726.88 - - - - - - 12 732.89 - - - - - 13 726.88 - + - - + 14 785.87 + + + + + + 15 749.89 + + + + + 16 785.87 + + + + + 17 732.89 - - - - - - 18 769.87 + + + + + + 19 785.87 + + + + + + 20 785.87 ++ + Not measured Not measured Not measured Not measured twenty one 885.99 + + + - - + twenty two 741.77 + + + + + + 30 785.87 +++ ++ ++ ++ ++ ++ +++ 37 813.92 ++ ++ ++ ++ ++ ++ ++ 49 749.86 ++ ++ ++ ++ ++ ++ ++ 54 734.84 +++ +++ +++ +++ +++ +++ +++ 59 770.85 ++ ++ ++ ++ ++ ++ ++ "ND" means not measured, "++++" ＜ 0.3 µM, 0.3 µM ≤ "+++" ＜ 1.0 µM, 1.0 µM ≤ "++" ＜ 3.0 µM, 3 µM ≤ "+" ＜ 10.0 µM, "━" means ≥ 10 µM.

Example 7 antiproliferative activity

As mentioned above, the KRAS-PROTAC of the present invention can be used to treat diseases or conditions with specific KRAS mutations. Such diseases may be cancer, autoimmune diseases, infectious diseases or vasoproliferative disorders. The cancer may be lung cancer (eg, non-small cell lung cancer), colorectal cancer, colorectal cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, bladder cancer, stomach cancer, kidney cancer, salivary gland cancer, ovarian cancer, uterine corpus cancer, cervix cancer cancer, oral cancer, skin cancer, brain cancer, lymphoma, leukemia, biliary malignancy, endometrial cancer or myeloid leukemia. The CellTiter ^™ -96 assay was used to measure the inhibition of cell growth by the KRAS-PROTAC of the present invention. Evaluate the cytotoxicity of KRAS-PROTAC in lung cancer cell lines, breast cancer cell lines, and pancreatic cancer cell lines with different RAS mutations. The results are shown in Table 3.

table 3 IC ₅₀ (µM) G12C G12V G12D G13D G12S cpd number Calu-1 H358 H441 KLM-1 MDA-MB-231 HCT-116 A549 1 ++ + ++ ++ ++ 2 - - - - - 3 ++ ++ + ++ + + 4 - - - - - - 5 - - - - - - 6 ++ ++ + ++ + ++ 7 + + + + + + 8 + + + + + + 9 ++ ++ ++ ++ ++ ++ 10 ++ + + ++ + ++ 11 + + + + + + 12 + - - - + + 13 + + + + + + 14 ++ + + + + ++ 15 ++ + + + + + 16 ++ + + + + ++ 17 - - - - - - 18 ++ + + + + + 19 ++ + + + + + 20 ++ + + ++ ++ ++ twenty one ++ + + + + ++ twenty two ++ + + ++ + ++ twenty three + + - + + + twenty four + - - + + + 25 ++ ++ + ++ ++ ++ 26 ++ + + + + ++ 27 - - - + + + 28 ++ ++ + ++ + ++ 29 + + + + + + 30 ++ ++ ++ ++ ++ ++ +++ 31 + + + ++ ++ ++ 32 ++ ++ + ++ + ++ 33 ++ ++ ++ ++ ++ +++ 34 ++ + + ++ + ++ 35 + + - + + + 36 + + + + + + 37 ++ ++ ++ ++ ++ +++ 38 + ++ + ++ + ++ 39 ++ ++ + ++ + ++ 40 + + + - 41 + + + + 42 + + + - 43 + + ++ + 44 + + + + 45 + + + - 46 + + + + 47 + - + + 48 + - + + 49 ++ ++ + ++ ++ +++ ++ 50 ++ + ++ + 51 ++ + + ++ 52 ++ - + ++ 53 + + + + 54 +++ ++ ++++ ++++ ++ ++ ++++ 55 ++ + ++ + 56 + + + + 57 ++ + ++ + 58 ++ + ++ ++ 59 ++ ++ ++ ++ ++ ++ ++ 60 ++ + ++ ++ 61 + + + + 62 + - + + 63 ++ + ++ ++ 64 ++ + ++ ++ 65 ++ + ++ ++ 66 ++ + ++ ++ 67 ++ + ++ + 68 ++ + + + 69 +++ + ++ + 70 - - + + 71 ++ + ++ ++ 72 + ++ + ++ ++ ++ "ND" means not measured, "++++" ＜ 0.3 µM, 0.3 µM ≤ "+++" ＜ 1.0 µM, 1.0 µM ≤ "++" ＜ 3.0 µM, 3 µM ≤ "+" ＜ 10.0 µM, "━" means ≥ 10 µM.

Example 8 Ras-PROTAC xenograft model ( lung cancer )

The goal of this study was to evaluate the in vivo anti-tumor efficacy of Ras-PROTAC in the Calu-1 human lung cancer xenograft model in male NOD SCID mice.

The test substance Cpd 6 and the corresponding vehicle were prepared and injected intratumorally (IT) into mice once a day for 14 consecutive days. Calu-1 cells were maintained in vitro as a monolayer culture in RPMI-1640 medium supplemented with 10% fetal calf serum at 37°C in an air atmosphere containing 5% _CO2 . Tumor cells were subcultured by trypsin-EDTA treatment in a conventional manner, twice a week. Growing cells in the exponential growth phase were collected and counted for tumor seeding. Male NOD SCID mice aged 6-7 weeks were purchased from BioLasco Taiwan and isolated for one week. Six mice were housed in each cage. All animals were housed in animal facilities at 19-25°C with a 12-hour light/12-hour dark cycle. Animals had free access to rodent pellet food and water ad libitum. Calu-1 cells were subcutaneously (SC) implanted into the right flank of male NOD SCID mice (1:1 PBS/Matrigel mixture containing 5 × 10 ⁶ cells, 0.1 mL per mouse). ^When the average tumor volume reached 170 mm, the mice were randomly divided into 2 groups (N=6 in each group). Vehicle or Cpd 6 (10 mg/kg) was administered by intratumoral (IT) injection once daily for 14 days. Tumor volume, body weight, mortality, and obvious signs of toxicity were monitored three times a week for 28 days. Tumor volume (mm ³ ) was measured three times a week using a caliper and calculated according to the following formula: tumor volume = ( w ² × l )/2, where w = tumor width and l = tumor diameter length (mm). The percentage of tumor growth inhibition (TGI) was calculated using the following formula: %TGI = [1 - (T/C)] × 100%, where T and C represent the average tumor volume of the treatment group and control group, respectively. The results are shown in Table 4 and Figures 1 and 2. Student's t test was used to compare the vehicle treatment group and the test substance treatment group. *When P<0.05, the difference is considered significant. Animals were weighed three times per week until study completion. Weight change was calculated as percent weight gain compared to initial weight.

Table 4 Calu-1 xenograft model processing TGI% (1-T/C) D0 D3 D5 D7 D10 D12 D14 D17 D19 D21 D24 D26 D28 Medium, IT, QD×14 0 0 0 0 0 0 0 0 0 0 0 0 0 Cpd6, 10 mpk, IT, QD×14 0 56 80 82 90 93 91 93 93 93 89 87 86

Figure 1 shows the tumor growth curve of Calu-1 implanted male NOD SCID mice. The test substance Cpd 6 at 10 mg/kg significantly reduced Calu-1 tumor growth from day 3 to day 28, with TGI values ranging from 56% to 93%, and was considered to be very effective against Calu-1 xenografts.

Figure 2 shows the body weight changes of male NOD SCID mice implanted with Calu-1. No weight loss was observed throughout the experimental period.

The KRAS-PROTAC of the present invention is a promising new therapeutic agent for cancer patients with KRAS mutations.

This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated by reference. In the event of a conflict between any incorporated reference and this specification, this specification shall control. In addition, specific embodiments of the present invention that belong to the prior art may be expressly excluded from any one or more of the claims. Because such embodiments are considered to be known to those of ordinary skill in the art, they may be excluded, even if the exclusion is not expressly stated herein. Any particular embodiment of the invention may be excluded from the scope of any claim for any reason, whether or not related to the existence of prior art.

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. The scope of the embodiments of the invention described herein is not intended to be limited by the above description, but rather is set forth in the appended claims. Those skilled in the art will appreciate that various changes and modifications can be made in this specification without departing from the spirit or scope of the invention as defined by the following claims.

without

Figure 1 shows the tumor growth curve of Calu-1 implanted male NOD SCID mice.

Figure 2 shows the body weight changes of male NOD SCID mice implanted with Calu-1.

Claims (21)

A bifunctional compound of formula (I): RB─linker─ULM (I) or its pharmaceutically acceptable salt, solvate, hydrate, polymorph, tautomer, stereoisomer , isotope enriched derivatives, prodrugs, wherein: ULM is the E3 ubiquitin ligase binding part or the chaperone complex binding part; the linker is a group covalently bonded to the RB and ULM part; and RB is RAS Protein binding part, and represented by formula RB-I: Where: X ₁ is H, NR ^X1 R ^X2 , SO ₂ NR ^X1 R ^X2 , OR ^X1 , CHR ^X1 R ^X2 , NH(C=O)R ^X3 or ^CN ; ^R Or linear ^or branched C _1-4 alkyl, which is optionally substituted by one or more halo groups, or ^R or a 4- to 8-membered _ring system substituted by multiple C _1-4 alkyl groups; ^R Linear or branched C _1-10 alkoxy groups substituted by multiple halo groups, or 4 containing 0 to 2 heteroatoms and optionally substituted by one or more halo groups, CF ₃ , NH ₂ , OH or CN to 8-membered ring system; W ₁ is a bond, C _1-6 alkyl, alicyclic, heterocyclic, bicyclic or diheterocyclic, each substituted by one, two or three R ^W1 as appropriate, and each R ^W1 Independently H, halo, OH, NH ₂ , NMe ₂ , NEt ₂ , CN, C _1-4 alkyl optionally substituted with one or more F or C ₁ optionally substituted with one or more F _-3 alkoxy; R ₁ is CH, C-Me, C-halogen or N; is aryl, heteroaryl or indazole, which is independently substituted with: one or more halo, CF ₃ , OCF ₃ , OR ^{A1 -RA2} , hydroxyl, nitro, CN, C≡CH, as appropriate Straight-chain or branched-chain C _1-6 alkyl substituted by one or more halo groups or C _1-6 alkoxy groups, optionally straight-chain or branched chain C _1-6 alkyl substituted by one or more halo groups Oxygen group, C _2-6 alkenyl group, C _2-6 alkynyl group or 4 to 7 membered saturated or partially unsaturated heterocyclic ring containing 1-2 heteroatoms, R ^A1 is C _1-6 alkyl group, R ^A2 is a heteroaryl group containing 1 to 2 heteroatoms and optionally substituted with one or more halo groups; X ₂ is CH ₂ or C=O; It is a 4- to 8-membered alicyclic ring with 0 to 4 heteroatoms, which is optionally substituted by 0 to 4 ^RQ , each ^RQ is independently OH, or optionally substituted by one or more halo groups. Chain or branched chain C _1-6 alkyl, or 2 ^RQ groups and the atoms to which they are connected together form a 3- to 8-membered ring system containing 0 to 2 heteroatoms; Z ₁ is H, C _1-4 Alkyl, C _1-4 alkoxy, halogen, OH, CN or C _2-4 alkynyl; and the dashed line indicates the point of attachment to the linker. Such as the bifunctional compound of claim 1, wherein ULM is Cereblon E3 ubiquitin ligase binding part (CLM), Von Hippel-Lindau (VHL) E3 ubiquitin ligase binding part (VLM), DDB1-associated and CUL4-associated factor 16 (DCAF16) E3 ubiquitin ligase-binding portion (DLM), IAP E3 ubiquitin ligase-binding portion (ILM), mouse double microbody 2 (MDM2) homolog E3 Ubiquitin ligase binding portion (MLM), Kelch-like ECH-associated protein-1 (KEAP1) E3 ubiquitin ligase binding portion, DCAF15 E3 ubiquitin ligase binding portion, RNF4 E3 ubiquitin ligase binding moiety, the RNF114 E3 ubiquitin ligase-binding portion, or the aryl hydrocarbon receptor (AhR) E3 ubiquitin ligase-binding portion. The bifunctional compound of claim 1, wherein the ULM is a CLM having a chemical structure represented by CLM-a or CLM-b: CLM-a wherein: W is selected from CH ₂ and C=O; and Q ₁ , Q ₂ , Q ₃ and Q ₄ are each independently C, N or C-halogen, and wherein Q ₁ , Q ₂ , Q ₃ and one of Q ₄ covalently linked to the linker; CLM-b where the dashed lines represent the connection points to the linker. For example, the bifunctional compound of claim 3, wherein the ULM is the CLM represented by: ; where: the dashed line indicates the connection point to the linker; and X _CLM is halogen. The bifunctional compound of claim 1, wherein the ULM is a VLM having a chemical structure represented by one of the following chemical structures: Among them: R ₅ is H or a linear or branched chain C _1-3 alkyl group; R ₆ is CN or a 5-membered heteroaryl group with one or two heteroatoms selected from N, S or O, which is optionally Methyl substitution; _Z2 is F or CN; and the dashed line indicates the point of attachment to the linker. The bifunctional compound of claim 1, wherein the ULM is a DLM having a chemical structure represented by D16-a: D16-a where: the dashed line connected to Y represents the point of attachment to the linker; R ₇ is H, halogen, C _1-4 alkyl or C _1-4 alkoxy; Y ₁ is O or S or NH; and R ^m is a covalent electrophile and is selected from . For example, the bifunctional compound of claim 1, wherein the ULM is a DLM represented by: ; The dotted line represents the connection point with the connector. The bifunctional compound of claim 1, wherein the RB-I is selected from the group consisting of formulas RB-1 to RB-7: ; The dotted line represents the connection point with the connector. Such as the bifunctional compound of claim 1, wherein the RB-I is represented by the following: ; The dotted line represents the connection point with the connector. Such as the bifunctional compound of claim 1, wherein the RB-I is selected from the group consisting of: ; The dotted line represents the connection point with the connector. Such as the bifunctional compound of claim 1, which is selected from formula Ia to formula Ig: . For example, the bifunctional compound of claim 1, wherein the linker contains the following chemical structure: , where: the dotted line of the linker is the connection point with RB or ULM; Y ^L2 is a bond, or a straight or branched chain C _1-4 substituted by halogen, C _1-3 alkyl, methyl or ethyl as appropriate. Alkyl or alkoxy; W ^L3 is a bond, -C=OCH ₂ -, aryl or a 3- to 7-membered ring system or an 8- to 12-membered spirocyclic ring, each containing 0 to 4 heteroatoms and optionally Halogen or methyl substitution; Y ^L3 is a bond or C _1-32 alkyl alkenyl or alkynyl group, in which one or more C atoms are optionally replaced by O, Or NH replacement, and each carbon is optionally substituted by halogen, =O, methyl or ethyl, and each nitrogen is optionally substituted by methyl or ethyl; Y _L4 is a bond, O or unsubstituted or substituted straight Chain or branched chain C _1-6 alkyl, one or more carbons of which are optionally replaced by O, NH or NCH ₃ , and optionally substituted by halogen or methyl; W ^L4 is a 3- to 8-membered ring system or 5 to 8-membered spirocyclic rings, each having 0 to 4 heteroatoms and optionally substituted with halogen or methyl; and Y ^L5 is a bond or C _1-6 alkyl group, in which one or more C atoms are optionally substituted with O and optionally substituted by halo or methyl. The bifunctional compound of claim 12, wherein the linker has a chemical structure represented by: ; The dotted line of the connector is the connection point with RB or ULM. A bifunctional compound selected from the group consisting of compounds (cpd) 1-72: 4-Amino-N-(3-(5-((4-(4-((4-(2-(2,6-bisoxypiperidin-3-yl))-1,3-bis Oxyisoindolin-5-yl)piperidine-1-yl)methyl)benzyl)piperidine-1-yl)methyl)-3-(4-(trifluoromethoxy)phenyl )-1H-indol-1-yl)propyl)piperidine-4-methamide (cpd 1); 4-Amino-N-(3-(5-((4-(4-((4-(2-(2,6-bisoxypiperidin-3-yl))-1,3-bis Oxyisoindolin-5-yl)piperidine-1-yl)methyl)benzyl)piperidine-1-yl)methyl)-3-(4-(trifluoromethoxy)phenyl )-1H-indol-1-yl)propyl)piperidine-4-methamide (cpd 2); 5-(4-((4-((1-(3-aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl) Piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxypiperidin-3-yl)isoindoline-1,3-dione (cpd 3 ); 5-(4-((4-((1-(3-aminopropyl))-3-(4-hydroxyphenyl)-1H-indol-5-yl)methyl)piperidine-1-yl )Methyl)piperidin-1-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline-1,3-dione (cpd 4); 5-(4-((1-((1-(3-aminopropyl))-3-(4-hydroxyphenyl)-1H-indol-5-yl)methyl)piperidin-4-yl )Methyl)piperidin-1-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline-1,3-dione (cpd 5); 5-(4-((1-((1-(3-aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl) Piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline-1,3-dione (cpd 6 ); 5-(4-((4-((1-(3-aminopropyl))-3-(4-fluorophenyl)-1H-indol-5-yl)methyl)piperidine-1-yl )Methyl)piperidin-1-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline-1,3-dione (cpd 7); 5-(4-((1-(3-Aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl)piperidine-1 -yl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline-1,3-dione (cpd 8); 1-(4-((1-(3-Aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl)piperidine-1 -yl)-2-((1-(2-chloroacetyl)-1,2,3,4-tetrahydroquinolin-6-yl)oxy)ethan-1-one (cpd 9); 5-(4-((4-((1-(3-aminopropyl))-3-(4-methoxyphenyl)-1H-indol-5-yl)methyl)piperidine-1 -yl)methyl)piperidin-1-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline-1,3-dione (cpd 10); 4-(1-(3-aminopropyl)-5-((4-((4-(2-(2,6-bisoxypiperidin-3-yl))-1,3-bis Oxyisoindolin-5-yl)piperidin-1-yl)methyl)piperidin-1-yl)methyl)-1H-indol-3-yl)benzonitrile (cpd 11); 5-(4-((1-((1-(3-aminopropyl))-3-(6-methoxypyridin-3-yl)-1H-indol-5-yl)methyl)piper (Din-4-yl)methyl)piperidin-1-yl)-2-(2,6-bis-oxypiperidin-3-yl)isoindoline-1,3-dione (cpd 12) ; 3-(1-(3-aminopropyl)-5-((4-((4-(2-(2,6-bisoxypiperidin-3-yl))-1,3-bis Oxyisoindolin-5-yl)piperidin-1-yl)methyl)piperidin-1-yl)methyl)-1H-indol-3-yl)benzonitrile (cpd 13); 5-(4-((1-((1-(3-aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-7-yl)methyl) Piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline-1,3-dione (cpd 14 ); 5-(4-((1-((1-(3-aminopropyl)-3-(2-fluoro-4-methoxyphenyl)-1H-indol-5-yl)methyl) Piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline-1,3-dione (cpd 15 ); 5-(4-((1-((1-(3-aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-6-yl)methyl) Piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline-1,3-dione (cpd 16 ); 5-(4-((1-((1-(3-aminopropyl))-3-(2-methoxypyridin-3-yl)-1H-indol-5-yl)methyl)piper (Din-4-yl)methyl)piperidin-1-yl)-2-(2,6-bis-oxypiperidin-3-yl)isoindoline-1,3-dione (cpd 17) ; 5-(4-((1-((1-(3-aminopropyl))-3-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)methyl)piper (Din-4-yl)methyl)piperidin-1-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline-1,3-dione (cpd 18) ; 5-(4-((1-((1-(3-aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-4-yl)methyl) Piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline-1,3-dione (cpd 19 ); 4-(4-((1-((1-(3-aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl) Piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline-1,3-dione (cpd 20 ); (3-(5-((4-(((4-(2-(2,6-di-oxypiperidin-3-yl))-1,3-di-oxyisoindolin-5-yl )piperidin-1-yl)methyl)piperidin-1-yl)methyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-1-yl)propyl) Tertiary butyl carbamate (cpd 21); 5-(3-((1-((1-(3-aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl) Piperidin-4-yl)oxy)prop-1-yn-1-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline-1,3-dione (cpd 22); 5-(3-((1-((1-(3-aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl) Piperidin-4-yl)oxy)propyl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline-1,3-dione (Cpd 23); 5-(4-(2-(4-((1-(3-aminopropyl))-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl yl)piperidin-1-yl)ethyl)piperidine-1-yl)-2-(2,6-bis-oxypiperidin-3-yl)isoindoline-1,3-dione (cpd 24); 5-(4-((1-((1-(3-aminopropyl)-3-(3-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl) Piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-dioxypiperidin-3-yl)isoindoline-1,3-dione (Cpd 25 ); 5-(4-((1-(1-(3-aminopropyl))-3-(4-(trifluoromethoxy)phenyl)-1H-indole-5-carbonyl)piperidine-4 -Methyl)piperidin-1-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline-1,3-dione (Cpd 26); 5-(4-((1-((1-(3-aminopropyl))-3-(3-hydroxynaphthalen-1-yl)-1H-indol-5-yl)methyl)piperidine- 4-yl)methyl)piperidin-1-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline-1,3-dione (Cpd 27); 5-(4-((1-((1-(azetidin-3-ylmethyl))-3-(4-(trifluoromethoxy)phenyl)-1H-indole-5- yl)methyl)piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-di-oxypiperidin-3-yl)isoindoline-1,3- Dione (Cpd 28); 5-(4-((1-((1-(3-aminopropyl))-3-(5-chloro-6-methyl-1H-indazol-4-yl)-1H-indole-5 -yl)methyl)piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline-1,3 -Diketone (Cpd 29); 5-(4-((1-((1-(3-aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl) Piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline-1,3-dione (Cpd 30 ); (2S)-N-(2-(3-(4-((1-(3-aminopropyl))-3-(4-(trifluoromethoxy)phenyl)-1H-indole-5 -yl)methyl)piperidine-1-yl)propoxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclic Propane-1-formamide)-3,3-dimethylbutyl)-4-hydroxypyrrolidine-2-formamide (Cpd 31); 5-(4-((1-((1-(3-aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl) Piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-dioxypiperidin-3-yl)-6-fluoroisoindoline-1,3-di Ketone (Cpd 32); 2-(2,6-Dilateral oxypiperidin-3-yl)-5-(4-((1-((1-(3-(methylamino)propyl))-3-(4- (Trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl)piperidin-4-yl)methyl)piperidin-1-yl)isoindoline-1,3-di Ketone (Cpd 33); 5-(7-((1-(3-Aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl)-2,7 -Diazaspiro[3.5]non-2-yl)-2-(2,6-bis-oxypiperidin-3-yl)isoindoline-1,3-dione (Cpd 34); 5-(4-((1-((1-(3-aminopropyl))-3-(2-fluoro-4-((3-fluoropyridin-2-yl)methoxy)phenyl)- 1H-indol-5-yl)methyl)piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindol Doline-1,3-dione (Cpd 35); 5-(4-(1-((1-(3-aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl)nitrogen Heterocyclobutan-3-yl)piperidin-1-yl)-2-(2,6-dioxypiperidin-3-yl)isoindoline-1,3-dione (Cpd 36) ; 5-(4-((1-((1-(3-(dimethylamino)propyl))-3-(4-(trifluoromethoxy)phenyl)-1H-indole-5- yl)methyl)piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-di-oxypiperidin-3-yl)isoindoline-1,3- Dione (Cpd 37); 5-(4-((1-((1-(5-aminopentyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl) Piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-dioxypiperidin-3-yl)isoindoline-1,3-dione (Cpd 38 ); 5-(7-((1-((1-(3-aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl) Piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindole Phenoline-1,3-dione (Cpd 39); N-(3-(5-((4-((4-(2-(2,6-dioxypiperidin-3-yl))-1,3-dioxyisoindoline-5 -yl)piperidin-1-yl)methyl)piperidin-1-yl)methyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-1-yl)propan Acetamide (Cpd 40); 4-(5-((4-((4-(2-(2,6-Dilateral oxypiperidin-3-yl)-1,3-Dilateral oxyisoindolin-5-yl) Piperidin-1-yl)methyl)piperidin-1-yl)methyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-1-yl)butanenitrile (Cpd 41); 2-(2,6-Dilateral oxypiperidin-3-yl)-5-(4-((1-((1-((1-methyl-1H-imidazol-5-yl)methyl) -3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl)piperidin-4-yl)methyl)piperidin-1-yl)isoindoline -1,3-dione (Cpd 42); 2-(2,6-Dilateral oxypiperidin-3-yl)-5-(4-((1-((1-(3-methoxypropyl))-3-(4-(trifluoro Methoxy)phenyl)-1H-indol-5-yl)methyl)piperidin-4-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione (Cpd 43); 2-(2,6-Dilateral oxypiperidin-3-yl)-5-(4-((1-((1-(3-(2,2,2-trifluoroethoxy))propyl )-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl)piperidin-4-yl)methyl)piperidin-1-yl)isoindole Phenoline-1,3-dione (Cpd 44); N-(3-(5-((4-((4-(2-(2,6-dioxypiperidin-3-yl))-1,3-dioxyisoindoline-5 -yl)piperidin-1-yl)methyl)piperidin-1-yl)methyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-1-yl)propan (Cpd 45)-1H-pyrrole-2-methamide (Cpd 45); 3-((4-(1-((1-(3-aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl) Piperidin-4-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (Cpd 46); N-(3-(5-((4-((4-(2-(2,6-dioxypiperidin-3-yl))-1,3-dioxyisoindoline-5 -yl)piperidin-1-yl)methyl)piperidin-1-yl)methyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-1-yl)propan methyl)-3-(trifluoromethyl)benzamide (Cpd 47); N-(3-(5-((4-((4-(2-(2,6-dioxypiperidin-3-yl))-1,3-dioxyisoindoline-5 -yl)piperidin-1-yl)methyl)piperidin-1-yl)methyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-1-yl)propan (Cpd 48)-4-fluorobenzamide (Cpd 48); 3-((4-(4-((1-((1-(3-aminopropyl))-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl )methyl)piperidin-4-yl)methyl)piperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (Cpd 49); 5-(4-((1-((1-butyl-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl)piperidin-4-yl )Methyl)piperidin-1-yl)-2-(2,6-dioxypiperidin-3-yl)isoindoline-1,3-dione (Cpd 50); 2-(2,6-Dilateral oxypiperidin-3-yl)-5-(4-((1-((3-(4-(trifluoromethoxy)phenyl))-1H-indole -5-yl)methyl)piperidin-4-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione (Cpd 51); 5-(4-((1-((1-((2,3-dihydrobenzo[b][1,4]dioxen-2-yl)methyl))-3-(4 -(Trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl)piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-di Pendant oxypiperidin-3-yl)isoindoline-1,3-dione (Cpd 52); 2-(2,6-Dilateral oxypiperidin-3-yl)-5-(4-((1-((1-(pyridin-2-ylmethyl))-3-(4-(trifluoro Methoxy)phenyl)-1H-indol-5-yl)methyl)piperidin-4-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione (Cpd 53); 3-((4-(1'-((1-(3-aminopropyl))-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl )-[4,4'-dipiperidin]-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (Cpd 54); 3-((4-(4-((1-((1-butyl-3-(4-(trifluoromethoxy)phenyl))-1H-indol-5-yl)methyl)piperidine -4-yl)methyl)piperidine-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (Cpd 55); 5-(4-((1-((1-((1,3-dioxolane-2-yl)methyl)methyl)-3-(4-(trifluoromethoxy)phenyl)-1H- Indol-5-yl)methyl)piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline -1,3-dione (Cpd 56); 2-(2,6-Dilateral oxypiperidin-3-yl)-5-(4-((1-((1-(4-methylpentyl))-3-(4-(trifluoromethyl Oxy)phenyl)-1H-indol-5-yl)methyl)piperidin-4-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione (Cpd 57 ); 3-((4-(4-((1-((1-(3-(dimethylamino)propyl))-3-(4-(trifluoromethoxy)phenyl)-1H-indino Indo-5-yl)methyl)piperidin-4-yl)methyl)piperidine-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (Cpd 58); 5-(1'-((1-(3-Aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl)-[4 ,4'-dipiperidin]-1-yl)-2-(2,6-di-oxypiperidin-3-yl)isoindoline-1,3-dione (Cpd 59); 3-((4-(1'-((1-(3-(dimethylamino)propyl))-3-(4-(trifluoromethoxy)phenyl)-1H-indole-5 -yl)methyl)-[4,4'-dipiperidin]-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (Cpd 60); 4-Amino-N-(3-(5-((4-((4-(4-((2,6-bisoxypiperidin-3-yl)amino))-2-fluorophenyl )piperidin-1-yl)methyl)piperidin-1-yl)methyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-1-yl)propyl) Piperidine-4-methamide (Cpd 61); 5-((4-((4-(2-(2,6-bisoxypiperidin-3-yl)-1,3-bisoxy-2,3-dihydro-1H-indene- 5-yl)piperidin-1-yl)methyl)piperidin-1-yl)methyl)-N,N-dimethyl-3-(4-(trifluoromethoxy)phenyl)-1H -Indole-1-sulfonamide (Cpd 62); 3-((3-Fluoro-4-(4-((1-((1-(4-methylpentyl))-3-(4-(trifluoromethoxy)phenyl)-1H-indole -5-yl)methyl)piperidin-4-yl)methyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione (Cpd 63); 3-((4-fluoro-3-(4-((1-((3-(4-(trifluoromethoxy)phenyl))-1H-indol-5-yl)methyl)piperidine- 4-yl)methyl)piperidine-1-yl)phenyl)amino)piperidine-2,6-dione (Cpd 64); 3-((3-Fluoro-4-(1'-((3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl)-[4,4' -Dipiperidin]-1-yl)phenyl)amino)piperidine-2,6-dione (Cpd 65); 5-(5-((1-(3-Aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl)hexahydropyrrolo [3,4-c]pyrrole-2(1H)-yl)-2-(2,6-bis-oxypiperidin-3-yl)isoindoline-1,3-dione (Cpd 66) ; 3-((4-(5-((1-(3-aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl) Hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (Cpd 67); 5-(4-((1-((1-(3,3-dimethoxypropyl))-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl )Methyl)piperidin-4-yl)methyl)piperidin-1-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline-1,3-di Ketone (Cpd 68); 5-(5-((1-(3-(dimethylamino)propyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl )Hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)-2-(2,6-bisoxypiperidin-3-yl)isoindoline-1,3-di Ketone (Cpd 69); 5-(1'-((1-(3-aminopropyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl)-[3 ,3'-azazetidin]-1-yl)-2-(2,6-bis-oxypiperidin-3-yl)isoindoline-1,3-dione (Cpd 70); 5-(1'-((1-(3-(dimethylamino)propyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indol-5-yl)methyl Cpd 71); (2R,4S)-1-((R)-2-(2-(4-((1-((1-(3-aminopropyl))-3-(4-(trifluoromethoxy) Phenyl)-1H-indol-5-yl)methyl)piperidin-4-yl)methyl)piperidin-1-yl)acetyl)-3,3-dimethylbutyl)-4 -Hydroxy-N-((R)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-methamide (Cpd 72); or its pharmaceutically acceptable salts, solvates, hydrates, polymorphs, tautomers, stereoisomers, isotopically enriched derivatives or prodrugs. A pharmaceutical composition comprising an effective amount of a bifunctional compound as claimed in any one of claims 1 to 14 and one or more pharmaceutically acceptable excipients. A pharmaceutical composition for preventing, improving and/or treating diseases related to KRAS mutations in individuals in need, which contains an effective amount of a bifunctional compound as claimed in any one of claims 1 to 14 and one or more medicines Scientifically acceptable excipients. The pharmaceutical composition of claim 16, wherein the bifunctional compound is administered separately, sequentially or together with one or more other anti-cancer agents. For example, the pharmaceutical composition of claim 17, wherein the other anti-cancer agents are selected from the group consisting of: trastuzumab, ramucirumab, vismodegib, Sonidegib, bevacizumab, everolimus, tamoxifen, toremifene, fulvestrant, anastrozole (anastrozole), exemestane (exemestane), lapatinib (lapatinib), letrozole (letrozole), pertuzumab (pertuzumab), trastuzumab-metansin conjugate (ado) -trastuzumab emtansine), palbociclib, cetuximab, panitumumab, ziv-aflibercept, regorafenib , lmatinib mesylate, lanreotide acetate, sunitinib, denosumab, alitretinoin, sorafenib (sorafenib), pazopanib, temsirolimus, everolimus, tretinoin, dasatinib, nilotinib, bosutinib, rituximab, alemtuzumab, ofatumumab, obinutuxumab, ibrutinib, idelalisib, blinatumomab, soragenib, crizotinib, erlotinib, gefitinib, distal afatinib dimaleate, ceritnib, ramucirumab, nivolumab, pembrolizumab, osimertin osimertinib, necitumumab, busulfan, chlorambucil, cyclophosphamide, iphosphamide, chlorambucil Melphalan, nitrogen mustard, streptozocin, thiotepa, uracil nitrogen mustard, triethylenemelamine, temozolomide ), 2-chloroethyl-3-sarcosinamide-1-nitrosourea (SarCNU), actinomycin-D, bleomycin, cryptophycins ), daunorubicin, doxorubicin, idarubicin, irinotecan, L-asparaginase, mitomycin- C (mitomycin-C), mitramycin, navelbine, paclitaxel, docetaxel, topotecan, vinblastine, Vincristine, teniposide (VM-26), etoposide (VP-16), 5α-reductase inhibitor, aminoglutethimide, anastrozole (anastrozole), bicalutamide, chlorotrianisene, diethylstilbestrol (DES), dromostanolone, estramustine, ethinyl estradiol ), flutamide, fluoxymesterone, goserelin, hydroxyprogesterone, letrozole, leuprolide, methyl acetate medroxyprogesterone acetate, megestrol acetate, methyl prednisolone, methyltestosterone, mitotane, nilutamide nilutamide), prednisolone, arzoxifene (SERM-3), tamoxifen, testolactone, testosterone, triamcinolone ( triamicnolone), zoladex, all-trans retinoic acid, carmustine (BCNU), carboplatin (CBDCA), lomustine (CCNU), cis- Diamine dichloroplatinum (cisplatin), dacarbazine, gliadel, hexamethylmelamine, hydroxyurea, levamisole, mitoxantrone , o,p'-dichlorodiphenyldichloroethane (o,p'-DDD) (also known as lysodren or mitotane), oxaliplatin, Porfimer sodium, procarbazine, imatinib mesylate, chlorodeoxyadenosine, cytosine arabinoside, 2'-deoxy Metamycin (2'-deoxycoformycin), fludarabine phosphate, 5-fluorouracil (5-FU), 5-fluoro-2'-deoxyuridine (5-FUdR), gemcitabine ( gemcitabine), camptothecin, 6-mercaptopurine, methotrexate, 4-methylthioamphetamine (4-MTA), thioguanine ( thioguanine), alpha interferon, Bacillus Calmette-Guerin (BCG), granule colony-stimulating factor (G-CSF), granule-macrophage colony-stimulating factor (GM-CSF), interleukin-2, and Herceptin. The pharmaceutical composition of claim 16, wherein the disease is cancer, autoimmune disease, infectious disease or vascular proliferative disease. The pharmaceutical composition of claim 19, wherein the cancer is selected from the group consisting of: lung cancer, colorectal cancer, colorectal cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, bladder cancer, gastric cancer, kidney cancer, salivary gland cancer , ovarian cancer, uterine corpus cancer, cervical cancer, oral cancer, skin cancer, brain cancer, lymphoma, leukemia, biliary malignant tumors, endometrial cancer and myeloid leukemia. The pharmaceutical composition of claim 20, wherein the cancer is pancreatic cancer, colorectal cancer, lung cancer or non-small cell lung cancer.