WO2024109671A1

WO2024109671A1 - Cas9 protein, variants, or homologues thereof-specific protac degraders and uses thereof

Info

Publication number: WO2024109671A1
Application number: PCT/CN2023/132513
Authority: WO
Inventors: Xiaobao Yang; Baoxu PANG; Renhong SUN; Shengnan SUN
Original assignee: Gluetacs Therapeutics (Shanghai) Co., Ltd.; ACADEMISCH ZIEKENHUIS LEIDEN (h.o.d.n. LUMC)
Priority date: 2022-11-22
Filing date: 2023-11-20
Publication date: 2024-05-30

Abstract

Disclosed are Cas9 protein, variants or homologues thereof-specific PROTAC degrader(s) of Formula (I) or a salt, an enantiomer, a stereoisomer, a solvate, or a polymorph thereof, composition comprising the same, and uses thereof. The said compounds can effectively degrade Cas9 protein, variants or homologues thereof or complexes comprising the same, and reduce unwanted off-target effects made by CRISPR/Cas9 protein, variants or homologues thereof system to the minimum, thereby increasing the precision (or accuracy) of gene editing, and thus providing new methods and tools for genome engineering.

Description

Cas9 protein, variants, or homologues thereof-specific PROTAC degraders and uses thereof

Technical Field

The present disclosure relates to Cas9 protein, variants or homologues thereof-specific PROTAC degraders of Formula (I) or a salt, an enantiomer, a stereoisomer, a solvate, or a polymorph thereof, and uses thereof, especially their use for degrading Cas9 protein, variants or homologues thereof utilized in a CRISPR/Cas9 protein, variants or homologues thereof system which mediates genome editing, transcriptional regulation, genome imaging, epigenetic modification, gene therapy (e.g., for preventing and/or treating a genetic disease in a subject) , establishing disease models, genome-wide genetic screening, and drug design and screening; and is used as a molecular diagnostic tool for diseases, e.g., infectious diseases.

Background

Traditional gene therapy uses wild-type genes to compensate for the function of mutant genes, but it still has problems such as gene silencing and random insertion. The successful development of genome editing tools makes it possible to repair genes in situ. Genome editing tools include zinc finger nucleases (ZFNs) , transcriptional activator like effector nucleases (TALENs) , and the recently discovered clustered spaced short palindrome repeats and Cas protein-based DNA endonucleases system (Clustered regulatory interspaced short palindromic repeats (CRISPR) /Cas based RNA guided DNA endonucleases) (Fruman DA et al., Cancer: a targeted treatment with off-target risks. Nature, 2017, 542 (7642) : 424–425) .

CRISPR/Cas system comprises Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and CRISPR-associated (Cas) proteins. CRISPR is an adaptive immune system present in many bacteria and archaea that can provides protection against mobile genetic elements (viruses, transposable elements and conjugative plasmids) , and be used against exogenous DNA (D. Rath, et al., Biochimie, 117: 119-128, 2015) . There are at least 45 distinct proteins in bacterial and archaeal genomes which have been identified to be associated with CRISPR loci (K. S. Makarova, et al., Biol Direct 6: 38, 2011) . CRISPR/Cas system can be classified as Type I, II, or III, depending on the Cas proteins including Cas1 to Cas10 and relatively rare types such as Cas8a1, Cas12a, and Cas13a (Makarova K. S, et al., [J] . Nature Reviews Microbiology, 2011, 9 (6) : 467-477) . Type II CRISPR/Cas system, which is marked by Cas9 (a dual RNA-guided DNA endonuclease) , have been successfully used in genome engineering (Makarova K. S, et al., [J] . Cell, 2017, 168 (1-2) : 328-328e) .

CRISPR/Cas9-mediated genome editing technology utilizes archaeal and bacterial Cas9 nucleases to introduce double-stranded breaks in DNA at targeted sites. These breaks can be used to remove, replace, or add pieces of DNA (Julie M. Crudele et al., Cas9 immunity creates challenges for CRISPR gene editing therapies. Nat Commun 9, 3497 (2018) ) . The key of genome editing technology is the use of sequence-specific nucleases to identify specific DNA sequences and generate targeted sites with double-stranded DNA breaks (DSBs) (Progress in Molecular Biology and Translational Science, 2020, Pages37-69) . Usually, CRISPR/Cas9-mediated genome editing is done by delivering Cas9 proteins, guide RNAs (gRNA) , and repair-templates together into the target cells. The whole machinery is working in the cells till either Cas9 or guide RNAs are degraded by different types of machinery present in the cells. By making precise editing in the genome, pathological traits could be restored to healthy conditions. Promising clinical trials have been developed to treat different genetic diseases including blood disorders such as beta-thalassemia and sickle cell disease.

So far, CRISPR/Cas9 system has been widely applied in many fields. CRISPR/Cas9 system has been used for transcriptional regulation, genome imaging and epigenetic modification, which may be helpful to further understand eukaryotic gene expression (Xin Xiong, et al., “CRISPR/Cas9 for Human Genome Engineering and Disease Research” , Annu Rev Genomics Hum Genet, 2016 Aug 31, 17: 131-54) . CRISPR/Cas9 system has also accelerated the improvement of crop varieties, shortened the years of crop breeding, and greatly alleviated the global food crisis. CRISPR/Cas9 system shows great potential in medical applications to cure the difficult miscellaneous diseases that have plagued human beings for a long time, and has been widely used for establishing disease models, genome-wide genetic screening, drug design and screening, and as a molecular diagnostic tool for diseases (e.g., infectious diseases) , etc.

However, alongside the on-target modifications, unwanted off-target changes could also be made by CRISPR/Cas9 system. In this regard, while the CRISPR/Cas9 system recognizes and cleaves the target site, it also cleaves the DNA sequence similar to the target site, that is, off targets. Off-target effects may destroy important genes in cells, sometimes even resulting in the loss of a whole chromosome in human embryos, thus leading to other diseases (Fruman DA et al., Cancer: a targeted treatment with off-target risks. Nature, 2017, 542 (7642) : 424–425) . Such off-target effects need to be addressed before the safe application of genome editing in medicine.

There are potentially multiple ways to disable the CRISPR/Cas9 system. For instance, small proteins, also known as anti-CRISPRs (Acrs) , that inhibit the RNA-guided DNA targeting activity of Cas enzymes have been identified in bacteriophages or bacteria. However, these small proteins are still not suitable to be administered into cells and human bodies, and the activity of these inhibitors is also dependent on their own protein half-lives. Recently, there are also small molecule inhibitors that have been identified. These small molecule inhibitors could potentially be used to block the activity of Cas9 proteins. Nonetheless, often such inhibitors are non-covalently bound to the Cas9 proteins; therefore, the inhibitory effects are reversible. There have not been any small molecules developed yet that could lead to the complete removal of the CRISPR/Cas9 system.

Summary of the Invention

Designing a degrader that targets specific proteins is a new mode of drug development. PROTAC (proteolysis targeting chimera) is a ternary complex, in which the first part is small molecule which can bind to specifical protein of interest; the second part is linker with different length; and the third part is E3 ligase ligand with ubiquitination function. We used the PROTAC technology platform and have developed small molecule PROTAC degraders (CASPROTAC) that could target Cas9 proteins, variants or homologues thereof or complexes comprising the same (including Cas9 protein, Cas9 nuclease dimers, Cas9 nuclease fusion proteins, Cas9 nuclease fragments, minimized Cas9 nucleases, Cas9 variants without a cleavage domain, Cas9 variants without a gRNA domain, and Cas9-recombinase fusions, and complexes comprising any of these Cas proteins, e.g., deactivated Cas9 (dCas9) proteins, variants of dCas9, Cas9 nicknase (or D10A nickase) , SaCas9, Cas9 nuclease from Streptococcus pyogenes (SpCas9) , SpCas9n, saCas9, High Fidelity Cas9 (HiFi Cas9) , Cas9-H840A, and FokI-dCas9, and any of these Cas proteins fused with other engineered proteins, and ribonucleoprotein complexes comprising Cas9 protein) for fast degradation. The designed CASPROTAC compounds of formula (I) of the present disclosure can target Cas9 proteins, variants or homologues thereof or complexes comprising the same and recruit E3 ubiquitination ligase through the E3ligase ligand ULM, so that the target Cas9 proteins, variants or homologues thereof or complexes comprising the same is connected to the E3ubiquitination ligase through the CASPROTAC compounds, and ubiquitinated by the E3ubiquitination ligase, and finally degraded under the action of the proteasome, thereby removing the Cas9 proteins, variants or homologues thereof of the CRISPR/Cas9 proteins, variants or homologues thereof system. In this way, the timing of the genome editing could be controlled to maintain on-target editing whilst reducing off-target effects to the minimum. The CASPROTAC compounds of the present invention have great potential to be used in various applications/fields where the CRISPR/Cas9 proteins, variants or homologues thereof system is required, such as genome editing techniques, gene expression regulation (transcriptional activation/inhibition) , genome imaging, epigenetic modification, genomic medicine applications, research applications, disease models establishing, genome-wide genetic screening, genome engineering (for crop or plant) , CRISPR/Cas9 protein, variants or homologues thereof-based molecular diagnostic tool for diseases, and drug design and screening applications. These molecules could also prevent potential biohazards caused by CRISPR/Cas9 protein, variants or homologues thereof-mediated genome editing in the human population.

Therefore, it is an objective of the present disclosure to provide a Cas9 protein, variants or homologues thereof-specific PROTAC degrader (s) , i.e., a compound of Formula (I) , or a salt, an enantiomer, a stereoisomer, a solvate, or a polymorph thereof, preparation method and use thereof to remove the above-mentioned disadvantages and solve the problems in the prior art.

In order to achieve the above-mentioned objectives and other related objectives, in one aspect of the present disclosure, there is provided a compound of Formula (I) :

or a salt, an enantiomer, a stereoisomer, a solvate, or a polymorph thereof;

wherein:

R represents C (O) , S (O) ₂, CH₂, CH₂C (O) , or C (O) CH₂;

R¹ represents C_1-4 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, cyano, amino, and any combination thereof;

R² represents H or C_1-4 alkyl;

(R³) _n1 indicates that phenyl where (R³) _n1 is attached to is optionally substituted with n1 R³ group (s) , wherein n1represents an integer of 0, 1, 2, or 3, and each R³ group independently represents halogen, hydroxyl, cyano, amino, C_1-4 alkyl, halogenated C_1-4 alkyl, or C_1-3 alkoxy;

ring A represents aryl, heteroaryl, heterocyclyl, or cycloalkyl;

(R⁴) _n2 indicates that the ring A where (R⁴) _n2 is attached to is optionally substituted with n2 R⁴ group (s) , wherein n2 represents an integer of 0, 1, 2, 3, 4, or 5, and each R⁴ group independently represents halogen, hydroxyl, cyano, amino, C_1-4 alkyl, halogenated C_1-4 alkyl, C_1-3 alkoxy, or C_3-6 cycloalkyl;

W represents:

-U₁-#

wherein U₁ represents ethynylene or vinylene; or

wherein W₁ represents ethynylene or vinylene, or W₁ represent a bond; and

ring B represents arylene, heteroarylene, heterocyclylene, or cycloalkylene;

(R⁵) _n3 indicates that the ring B where (R⁵) _n3is attached to is optionally substituted with n3 R⁵group (s) , wherein n3 represents an integer of 0, 1, 2, 3, 4, or 5, and each R⁵ group independently represents halogen, hydroxyl, cyano, amino, C_1-4 alkyl, halogenated C_1-4 alkyl, C_1-3 alkoxy, C (O) N (C_1-3 alkyl) ₂, or C_3-6cycloalkyl; and

symbol#indicates the point of attachment to the U₂; or

W represent a bond;

U₂ represents C (O) NH, NHC (O) , C (O) O, OC (O) , NH, O, or ethynylene, or U₂ represent a bond;

L (linker) represents an optionally substituted linear or branched alkylene group, wherein one or more groups selected from the group consisting of R_a, R_b, and any combination thereof are optionally inserted between one or more pairs of adjacent carbon atoms of the backbone carbon chain of the linear or branched alkylene group, wherein each R_a is independently selected from the group consisting of O, C (O) , OC (O) , S, S (O) , S (O) ₂, S (O) ₂N (R⁶) , N (R⁶) S (O) ₂, C (O) N (R⁶) , N (R⁶) C (O) , N (R⁶) , and N (R⁶) C (O) N (R⁶) , where each R⁶independently represents H or C_1-3 alkyl, and in case that two or more groups R_a are inserted into the backbone carbon chain of the linear or branched alkylene group, the two or more groups R_a are not directly connected to each other; and wherein each R_bis independently selected from the group consisting of optionally substituted cycloalkylene, optionally substituted arylene, optionally substituted heterocyclylene, optionally substituted heteroarylene, and any combination thereof; and

ULM (Ubiquitin Ligase binding moiety) represents a E3 ubiquitinated ligase ligand which is covalently bonded to the L.

In one aspect, the present disclosure provides a composition or preparation comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof of the present disclosure, and at least one physiologically acceptable carrier.

In a further aspect, the present disclosure provides a kit comprising the compound of Formula (I)or a pharmaceutically acceptable salt thereof of the present disclosure or the composition or preparation of the present disclosure that degrades Cas9 protein, variants or homologues thereof or complexes comprising the same.

In a further aspect, the present disclosure also provides the compound of Formula (I) or a salt, an enantiomer, a stereoisomer, a solvate, or a polymorph thereof for use as a degrader for degrading Cas9 protein, variants or homologues thereof or complexes comprising the same which include Cas9 protein, Cas9 nuclease dimers, Cas9 nuclease fusion proteins, Cas9 nuclease fragments, minimized Cas9 nucleases, Cas9 variants without a cleavage domain, Cas9 variants without a gRNA domain, and Cas9-recombinase fusions, and complexes comprising any of these Cas proteins, e.g., deactivated Cas9 (dCas9) proteins, variants of dCas9, Cas9 nicknase (or D10A nickase) , SaCas9, Cas9 nuclease from Streptococcus pyogenes (SpCas9) , SpCas9n, saCas9, High Fidelity Cas9 (HiFi Cas9) , Cas9-H840A, and FokI-dCas9, and any of these Cas proteins fused with other engineered proteins, and ribonucleoprotein complexes comprising Cas9 protein.

In yet a further aspect, the present disclosure also provides the compound of Formula (I) or a salt, an enantiomer, a stereoisomer, a solvate, or a polymorph thereof for use as a degrader, which is used, in combination with a CRISPR/Cas9 protein, variants or homologues thereof system, for modulating CRISPR/Cas9 protein, variants or homologues thereof-mediated genome editing, transcriptional regulation, genome imaging, epigenetic modification, gene therapy, disease models establishing, genome-wide genetic screening, or drug design and screening; or for modulating CRISPR/Cas9 protein, variants or homologues thereof-based molecular diagnostic tool for diseases.

In yet a further aspect, the present disclosure also provides the compound of Formula (I) or a salt, an enantiomer, a stereoisomer, a solvate, or a polymorph thereof for use as a degrader, which is used in combination with CRISPR/Cas9 protein, variants or homologues thereof-mediated gene therapy for the prevention and/or treatment of a genetic disease in a subject.

In yet a further aspect, the present disclosure also provides the compound of Formula (I) or a salt, an enantiomer, a stereoisomer, a solvate, or a polymorph thereof for use in the modulation of CRISPR/Cas9 protein, variants or homologues thereof-mediated genome editing of the target DNA in a cell.

In still a further aspect, the present disclosure also provides use of the compound of Formula (I) or a salt, an enantiomer, a stereoisomer, a solvate, or a polymorph thereof or the composition of the present disclosure for the manufacture of a degrader for degrading Cas9 protein, variants or homologues thereof or complexes comprising the same which include Cas9 protein, Cas9 nuclease dimers, Cas9 nuclease fusion proteins, Cas9 nuclease fragments, minimized Cas9 nucleases, Cas9 variants without a cleavage domain, Cas9 variants without a gRNA domain, and Cas9-recombinase fusions, and complexes comprising any of these Cas proteins, e.g., deactivated Cas9 (dCas9) proteins, variants of dCas9, Cas9 nicknase (or D10A nickase) , SaCas9, SpCas9, SpCas9n, saCas9, High Fidelity Cas9 (HiFi Cas9) , Cas9-H840A, and FokI-dCas9, and any of these Cas proteins fused with other engineered proteins, and ribonucleoprotein complexes comprising Cas9 protein.

In still a further aspect, the present disclosure also provides use of the compound of Formula (I) or a salt, an enantiomer, a stereoisomer, a solvate, or a polymorph thereof or the pharmaceutical composition of the present disclosure for the manufacture of a modulator for the modulation of CRISPR/Cas9 protein, variants or homologues thereof-mediated genome editing of the target DNA in a cell.

In a further aspect, the present disclosure also provides a method for treating or preventing a genetic disease in a subject, comprising (a) applying to the subject genome therapy adopting a CRISPR/Cas9 protein, variants or homologues thereof-mediated genome editing using a CRISPR/Cas9 protein, variants or homologues thereof system comprising a Cas9 protein, variants or homologues thereof, and guide RNAs (gRNA) in a sufficient amount to correct a mutation in a target gene associated with the genetic disease; (b) administering to the subject the compound of Formula (I) , or a pharmaceutically acceptable salt thereof, or the composition of the present disclosure in a sufficient amount to degrade the Cas9 protein, variants or homologues thereof simultaneously or after applying the CRISPR/Cas9 protein, variants or homologues thereof-mediated genome editing.

In a further aspect, the present disclosure also provides a method for modulating CRISPR/Cas9 protein, variants or homologues thereof-mediated genome editing of a target DNA in a cell, comprising contacting the cell with the compound of Formula (I) , or a pharmaceutically acceptable salt thereof, or the composition or preparation of the present disclosure.

Brief Description of Drawings

Figures1A-1D: The CASPROTAC molecules of the present disclosure exhibited degradation efficacy. Fig. 1A-1B: Western blotting was used to test the efficacy of the first batch of CASPROTACs in degrading Cas9 proteins. K562 cells were electroporated with60pmol Cas9 protein, followed by incubation with compound GT-02631 (1μM) , CASPROTAC (1μM) GT-02591, GT-02590, GT-02592, and GT-02593for 24h. The intensity of the staining was quantified in Fig. 1B. Fig. 1C-1D: Western blotting for GT-02592, GT-02593 in wild type K562 cells after electroporated with 60 pmol Cas9 protein, followed by incubation with GT-02592, GT-02593 in a dose-dependent manner. The intensity of the staining was quantified in Fig. 1D. Anti-HA antibody was used to detect the level of recombinant Cas9-HA proteins. Anti-b-actin was used as the loading control (Ctr. ) . Bars show mean value ± s.e.m. and significance was calculated using Student’s t-test (n=2 or 3) . *p<0.05, **p<0.005, and***p<0.0001 (versus the control) .

Figures 2A-2H: Optimized CASPROTAC molecules degraded both of Cas9, and dead Cas9 efficiently. Fig. 2A-2B: Western blotting was used to test the efficacy of the optimized CASPROTAC molecules in degrading Cas9 proteins. K562 cells were electroporated with 60 pmol Cas9 protein, followed by incubation with CASPROTAC (1μM) GT-03390, GT-03391, GT-03392, GT-03393, GT-03394, GT-03395 for 24 h. The intensity of the staining was quantified in Fig. 2B. Fig. 2C-2D: Optimized CASPROTAC molecules led to dose-dependent degradation of Cas9 proteins. Western blotting was used to test the degradation of Cas9 proteins by CASPROTAC GT-03391, GT-03395. K562 cells were electroporated with 60 pmol Cas9 protein, followed by incubation with GT-03391, GT-03395 in a dose-dependent manner for 24 h. The intensity of the staining was quantified in Fig. 2D. Fig. 2E-2F: Western blotting was used to test the degradation of Cas9 proteins by CASPROTAC GT-03391 in different time points. K562 cells were electroporated with 60 pmol Cas9 protein were followed at the respective time points with and without GT-03391 treatment. Relative quantification was made between the treated and non-treated cells in Fig. 2F. Anti-HA antibody was used to detect the level of recombinant Cas9-HA proteins. Anti-b-actin was used as the loading control (Ctr. ) . Fig. 2G-2H: Optimized CASPROTAC molecule GT-03391degraded dCas9 proteins. HEK293 Tet-On 3G cells with stable integration of Cas9-APEX2 were pretreated with doxycycline (500ng/mL) for 9 h to the simultaneous expression of Cas9-APEX2 protein complex, 15 hrs after removing doxycycline, GT-03391 was added for 24 h in a dose. Protein level of dCas9-APEX2 was monitored by Western blotting and quantified in Fig. 2H. Anti-Flag antibody was used to detect the level dCas9-HA proteins. Anti-b-actin was used as the loading control (Ctr. ) . Bars show mean value ± s.e.m. and significance was calculated using Student’s t-test (n=2 or 3) . *p<0.05, **p< 0.005, and***p<0.0001 (versus the control) .

Figures 3A-3E: The optimized CASPROTAC molecule degrade Cas9 via the proteasome system, and could degrade Cas9-guide-RNA complex. Fig. 3A-3C: The proteasome inhibitor MG132blocked the degradation of electroporated Cas9 protein by GT-03391in K562 cells. Western blotting was used to test GT-03391 in K562 cells after electroporated with 60 pmol Cas9 protein, followed by incubation with compound GT-03391 (1μM) and MG132 (CAS No.: 133407-82-6; a proteasome inhibitor) (500nM) for 24 h. The intensity of the staining was quantified in Fig. 3B and Fig. 3C. Fig. 3D-3E: GT-03391degraded CRISPR ribonucleoprotein complexes efficiently. Mix the EGFP-guide RNA and Cas9 protein components at a 1: 1.2 molar ratio (60 pmol Cas9+72pmol guide RNA-EGFP) in PBS, incubating at room temperature for 20 min to allow formation of the CRISPR ribonucleoprotein complexes. Western blotting for GT-03391 in K562 cells after electroporated with 60 pmol Cas9 protein or Ribonucleoproteins (RNP) , followed by incubation with GT-03391 for 24h; The intensity of the staining was quantified in Fig. 3E. Anti-HA antibody was used to detect the level of recombinant Cas9-HA proteins. Anti-b-actin was used as the loading control (Ctr. ) . Anti-ubiquitin antibody was used to test the general ubiquitin levels of proteins. Bars show mean value ± s.e.m. and significance was calculated using Student’s t-test (n=2 or 3) . *p< 0.05, **p<0.005, and***p<0.0001 (versus the control) .

Detailed Description of the Invention

The following detailed description is provided as exemplary specific embodiments to assist those skilled in the art in understanding and practicing the present disclosure. It should be appreciated, however, that such description is not intended to limit the scope of the present disclosure, and that various modifications and changes may be made to the specific embodiments described in the present disclosure without departing from the spirit and scope of the present disclosure. Such changes and modifications are to be understood as being included within the scope of the present invention as defined by the appended claims.

I. Definitions

Unless otherwise specified, the following words, phrases and symbols used herein generally have the meanings as described below.

In general, the nomenclature used herein (including the IUPAC nomenclature) and the laboratory procedures described below (including those used in cell culture, organic chemistry, analytical chemistry, and pharmacology, etc. ) are those well known and commonly used in the art. Unless otherwise defined, all scientific and technical terms used herein in connection with the present disclosure described herein have the same meaning as commonly understood by one skill in the art. In addition, the use of the word “a” or “an” when used in conjunction with the term “comprising” or a noun in the claims and/or the specification may mean “one” , but it is also consistent with the meaning of “one or more” , “at least one” , and “one or more than one” . Similarly, the terms "another" or "other" can mean at least a second or more.

It should be understood that whenever the term "comprise" or "include" is used herein to describe various aspects, other similar aspects described by "consisting of" and/or "consisting essentially of" are also provided.

As used herein, the terms “CASPROTAC” , “CASPROTAC compounds” , “CASPROTAC molecules” , “Cas9 protein, variants or homologues thereof-specific PROTAC degrader (s) ” , “degrader” , “the compound (s) of the present invention” , “the compound of formula (I) ” , and “modulator” can be used interchangeably, and used alone or in combination refers to the compound (s) of Formula (I) of the present invention.

As used herein, the term "about" used alone or in combination refers to approximately, roughly, nearly, or around. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the stated numerical value. In general, the term "about" can modify a numerical value above and below the stated value by an upward or downward (increasing or decreasing) variation, e.g., 10%, 5%, 2%, or 1%.

As used herein, the wording "... represents a bond" used alone or in combination means that the referenced group is a bond linker (that is, the referenced group is absent, and two groups respectively connected to the referenced group in the compound can be directly linked each other) . For example, when U₂ presents a bond, the L of the compound of Formula (I) is directly connected to W of the compound of Formula (I) .

As used herein, the term "optionally substituted" , used alone or in combination, means that the referenced group may be unsubstituted or substituted with one or more substituents as defined herein. Herein, the terms "optionally substituted" and "unsubstituted or substituted" can be used interchangeably. The term "substituted" generally means that one or more hydrogens in the referenced group are replaced with the same or different specified substituents. The number of substituents is in principle not limited in any way, or is automatically limited by the size of the building unit (i.e., the total number of replaceable hydrogen atoms of the building unit) , or as explicitly defined herein.

As used herein, the term “inserted” of the expression “one or more groups selected from the group consisting of R_a, R_b, and any combination thereof are optionally inserted between one or more pairs of adjacent carbon atoms of the backbone carbon chain of the linear or branched C_1-40 alkylene group” , used alone or in combination, can mean that the referenced one or more pairs of adjacent carbon atoms of the backbone carbon chain of the linear or branched C_1-40 alkylene group are optionally connected to each other through the referenced one or more groups selected from the group consisting of R_a, R_b, and any combination thereof. Herein, non-limiting examples of the above-mentioned expression "one or more groups selected from the group consisting of R_a, R_b, and any combination thereof are optionally inserted between one or more pairs of adjacent carbon atoms of the backbone carbon chain of the linear or branched C_1-40 alkylene group" may include, but are not limited to, that one or more (e.g., 1-30, 1-20, or 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1-2, or 1)groups R_aas defined herein and/or one or more (e.g., 1-30, 1-20, or 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1-2, or 1) groups R_b as defined herein and/or one or more (e.g., 1-30, 1-20, or 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1-2, or 1) combinations of R_a with R_b are optionally inserted between one or more (e.g., 1-30, 1-20, or 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1-2, or 1) pairs of adjacent carbon atoms of the backbone carbon chain of the linear or branched C_1-40 alkylene group, and the resulting backbone chain group conforms to the covalent bond theory. In case that two or more groups R_a are inserted into the backbone carbon chain of the linear or branched C_1-40 alkylene group, the two or more groups R_a are not directly connected to each other. For example, the expression "one or more groups selected from the group consisting of R_a, R_b, and any combination thereof are inserted between one or more pairs of adjacent carbon atoms of the backbone carbon chain of the linear or branched C_1-40 alkylene group" can refer to that one or more (e.g., 1-30, 1-20, or 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1-2, or 1) groups R_a as defined herein and/or one or more (e.g., 1-30, 1-20, or 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1-2, or 1) groups R_b as defined herein and/or one or more (e.g., 1-30, 1-20, or 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1-2, or 1) combinations ofR_a with R_b are inserted between one or more (e.g., 1-30, 1-20, or 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1-2, or 1) pairs of adjacent carbon atoms of the backbone carbon chain of the linear or branched C_1-40 alkylene group, such that a linear or branched C_1-40 alkylene group containing one or more (e.g., 1-30, 1-20, or 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1-2, or 1) fragments "-CH₂-R_a-CH₂-" and/or one or more (e.g., 1-30, 1-20, or 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1-2, or 1) fragments "-CH₂- (R_b) _m9-CH₂-" and/or one or more (e.g., 1-30, 1-20, or 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1-2, or 1) fragments "-CH₂- (R_a- (R_b) _m9) _m10-CH₂-" is formed, wherein each R_aare the same or different, each R_bare the same or different, and are as defined herein, and m9and m10each independently represent for example an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9or 10.

As used herein, the expression "one or more hydrogens of one or more CH₂of the linear or branched C_x-yalkylene is replaced by a substituent (s) selected from the group consisting of... " , used alone or in combination, means that any one or more hydrogens of one or more CH₂of the linear or branched C_x-yalkylene is replaced by a substituent (s) as defined herein. Herein, the term "one or more" of "one or more hydrogens of one or more CH₂of groups-CH₂-; - (CH₂) ₂-; - (CH₂) ₃-; - (CH₂) ₄-; - (CH₂) ₅-; - (CH₂) ₆-; - (CH₂) ₇-; - (CH₂) ₈-; - (CH₂) ₉-; - (CH₂) ₁₀-; - (CH₂) ₁₁-; - (CH₂) ₁₂-; - (CH₂) ₁₃-; - (CH₂) ₁₄-; - (CH₂) ₁₅-; - (CH₂) ₁₆-; - (CH₂) ₁₇-; - (CH₂) ₁₈-; - (CH₂) ₁₉-; or- (CH₂) ₂₀-" may refer to part or all hydrogens of each referenced alkylene group, including but not limited to 1-80 hydrogens. In some embodiments, the expression "one or more hydrogens of one or more CH₂" may refer to part or all of the hydrogens of the referenced alkylene group, including but not limited to 1-30, such as1-25, 1-20, 1-15, 1-10, 1-5, 1-4, 1-3, 1-2 or 1 hydrogens. In some embodiments, the expression "one or more hydrogens of one or more CH₂" may include 1-3 of the plurality of hydrogens of the referenced alkylene group. The number of hydrogens to be replaced is in principle not limited in any way, or is automatically limited by the size of the building unit (i.e., the total number of replaceable hydrogen atoms of the building unit) , or as explicitly defined herein.

As used herein, the term "oxo" refers to=O.

As used herein, the term "C (O) " or "C (=O) " or "C=O" used alone or in combination refer to a carbonyl group.

Herein, a bond interrupted by a wavy line shows the point of attachment of the radical depicted. For example, the group depicted below

represents the chemical fragment ULM represented by formula (II-1) , which is connected to the linking group L of the compound of formula (I) .

Although the symbol "*" in the linking group L herein is defined to indicate the point of attachment of the group L to the group U₂, the present invention also encompasses an embodiment where the symbol "*" in the group L indicates the point of attachment of the group L to the chemical fragment ULM.

As used herein, the term "halogen atom" or "halogen" , used alone or in combination, refers to fluorine (F) , chlorine (Cl) , bromine (Br) , or iodine (I) .

As used herein, the term "alkyl" , used alone or in combination, refers to a linear or branched alkyl group. The term "C_x-C_y alkyl" or "C_x-y alkyl" (x and y each being an integer) refers to a linear or branched alkyl group containing from x to y carbon atoms. The term "C_1-6 alkyl" used alone or in combination in the present disclosure refers to a linear or branched alkyl group containing from 1 to 6 carbon atoms. Non-limiting examples of the C_1-6 alkyl of the present disclosure may include a C_1-5 alkyl, such as C_1-4 alkyl, and C_1-3 alkyl. Representative examples of C_1-6 alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, and hexyl. The term "C_1-4 alkyl" in the present disclosure refers to an alkyl group containing from 1 to 4 carbon atoms, and representative examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. In the present disclosure, the "alkyl" is optionally substituted by one or more selected from the group consisting of halogen, hydroxyl, cyano, amino, and mercapto.

As used herein, the term "alkylene" (which is used interchangeably with "alkylene chain" ) , used alone or in combination, refers to a linear or branched divalent saturated hydrocarbon group composed of carbon and hydrogen atoms. The term "C_x-C_y alkylene" or "C_x-y alkylene" (x and y each being an integer) refers to a linear or branched alkylene group containing from x to y carbon atoms. Non-limiting examples of the C₁-C₄₀ alkylene in the present disclosure may include C₁-C₃₅ alkylene, C₁-C₃₀ alkylene, C₁-C₂₉ alkylene, C₁-C₂₈ alkylene, C₁-C₂₇ alkylene, C₁-C₂₆ alkylene, C₁-C₂₅ alkylene, C₁-C₂₄ alkylene, C₁-C₂₃ alkylene, C₁-C₂₂ alkylene, C₁-C₂₁ alkylene, C₁-C₂₀ alkylene, C₁-C₁₉ alkylene, C₁-C₁₈ alkylene, C₁-C₁₇ alkylene, C₁-C₁₆ alkylene, C₁-C₁₅ alkylene, C₁-C₁₄ alkylene, C₁-C₁₃ alkylene, C₁-C₁₂ alkylene, C₁-C₁₁ alkylene, C₁-C₁₀ alkylene, C₁-C₉ alkylene, C₁-C₈ alkylene, C₁-C₇ alkylene, C₁-C₆ alkylene, C₁-C₅ alkylene, C₁-C₄ alkylene, C₁-C₃ alkylene, and C₁-C₂ alkylene. Representative examples include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, tert-butylene, n-pentylene, isopentylene, neopentylidene, tert-pentylene, hexylene, heptylene, octylene, nonylene, decylene, undecylene, dodecylene, tridecylene, tetradecylene, pentadecylene, hexadecylene, heptadecylene, octadecylene, nonadecylene, eicosylene, heneicosylene, docosylene, tricosylene, tetracosylene, pentacosylene, hexacosylene, peptacosylene, octacosylene, nonacosylene, and triacontylene. In the present invention, the "alkylene" is optionally substituted by one or more selected from halogen, hydroxyl, cyano, amino, mercapto, C_1-3 alkyl, C_1-3 alkoxy, halogenated C_1-4 alkyl, C_5-10 aryl, C_5-10 heteroaryl, C_3-12 cycloalkyl, 4-to 12-membered heterocyclyl, or any combination thereof.

As used herein, the term "halogenated alkyl" or "haloalkyl" , used alone or in combination, refers to a linear or branched alkyl group substituted with one or more halogens, wherein one or more hydrogen atom (s) of the alkyl group is replaced with one or more halogens. The term "halogenated C_x-Cyalkyl" or "halogenated C_x-yalkyl" (x and y are each an integer) refers to a linear or branched alkyl containing from x to y carbon atoms substituted with one or more halogens. The term "halogenated C_1-4 alkyl" used alone or in combination in the present invention refers to a linear or branched alkyl group containing from 1 to 4 carbon atoms substituted with one or more halogens. Non-limiting examples of the halogenated C_1-4 alkyl group of the present invention include halogenated C_1-4 alkyl group, halogenated C_1-3 alkyl, halogenated C_1-2alkyl, and halogenated methyl. Representative examples include halomethyl, haloethyl, halo-n-propyl, haloisopropyl, halo-n-butyl, haloisobutyl, halo-sec-butyl, and halo-tert-butyl. The term "halo-C_1-3 alkyl" of the present invention refers to an alkyl group containing from 1 to 3 carbon atoms substituted by one or more halogens, and its representative examples include halomethyl, haloethyl, halo-n-propyl and haloisopropyl.

As used herein, the term "alkoxy" , used alone or in combination, refers to a linear or branched alkoxy group having structural formula of-O-alkyl. Optionally, the alkyl portion of the alkoxy group may contain1-10 carbon atoms. Representative examples of "alkoxy" include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, 2-pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, 2-hexyloxy, 3-hexyloxy, 3-methylpentyloxy, etc. The term "C₁-C₃ alkoxy" or "C_1-3 alkoxy" refers to a linear or branched alkoxy group containing from 1 to 3 carbon atoms. Representative examples of C_1-3 alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, and isopropoxy. Optional Representative examples of C_1-3 alkoxy are methoxy and ethoxy.

As used herein, the term "cycloalkyl" , used alone or in combination, refers to a saturated or partially unsaturated (i.e., containing one or more double bonds, but not having a fully conjugatedπ-electron system) monocyclic or bicyclic or polycyclic cyclic hydrocarbon radical, which in some embodiments contains from 3 to 20 carbon atoms (i.e., C_3-20 cycloalkyl) , or from 3 to 15carbon atoms (i.e., C_3-15 cycloalkyl) , or from 3 to 12 carbon atoms (i.e., C_3-12 cycloalkyl) , or from 3 to 11 carbon atoms (i.e., C_3-11 cycloalkyl) , or from 3 to 10 carbon atoms (i.e., C_3-10 cycloalkyl) , or from 3 to8 carbon atoms (i.e., C_3-8 cycloalkyl) , or from 3 to 7 carbon atoms (i.e., C_3-7 cycloalkyl) , or from 3 to 6 carbon atoms (i.e., C_3-6 cycloalkyl) . The term "cycloalkyl" includes monocyclic, bicyclic, tricyclic or polycyclic cyclic hydrocarbon radical having from 3 to 20 carbon atoms. Representative examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicyclic and tricyclic and polycyclic cycloalkyl groups include bridged cycloalkyl, fused cycloalkyl and spiro-cycloalkyl groups such as, but not limited to, decalinyl, octahydropentalenyl, octahydro-1H-indenyl, spiro-cycloalkyl (including C_5-20 spiro-cycloalkyl and C_5-15 spiro-cycloalkyl) , adamantanyl, noradamantanyl, bornyl, norbornyl (also named as bicyclo [2.2.1] heptyl by the IUPAC system) . As used herein, the "cycloalkyl" is optionally mono-or poly-substituted, such as, but not limited to, 2, 2-, 2, 3-, 2, 4-, 2, 5-, or 2, 6-disubstituted cyclohexyl. The substituents of the substituted "cycloalkyl" can be optionally one or more (e.g., 1-5, 1-4, 1-3, 1-2, or 1) selected from halogen, hydroxyl, cyano, amino, mercapto, oxo, C_1-3 alkyl, C_1-3 alkoxy, halogenated C_1-4 alkyl, C_5-10 aryl, C_5-10 heteroaryl, C_3-12 cycloalkyl, 4-to 12-membered heterocyclyl, or any combination thereof.

As used herein, the term "C_x-y spiro-cycloalkyl" (x and y each being an integer) , used alone or in combination, refers to a spiro-cycloalkyl group containing from x to y carbon atoms. As used herein, the term "C_7-11 spiro-cycloalkyl" , used alone or in combination, refers to a spiro-cycloalkyl group containing from 7 to 11 (e.g., 7-10, 7-9) carbon atoms. Representative examples of the term "C_7-11 spiro-cycloalkyl" include, but are not limited to, spiro [3.3] heptyl, spiro [2.5] octyl, spiro [3.5] nonyl, spiro [4.4] nonyl, spiro [4.5] decyl, or spiro [5.5] undecyl. The "C_7-11 spiro-cycloalkyl" is optionally further substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, cyano, amino, mercapto, oxo, C_1-3 alkyl, C_1-3 alkoxy, halogenated C_1-4 alkyl, C_5-10 aryl, C_5-10 heteroaryl, C_3-12 cycloalkyl, 4-to 12-membered heterocyclyl, or any combination thereof.

As used herein, the term "C_x-y bridged cycloalkyl" (x and y each being an integer) , used alone or in combination, refers to a bridged cycloalkyl group containing from x to y carbon atoms. As used herein, the term "C_7-15 bridged cycloalkyl" , used alone or in combination, refers to bridged cycloalkyl containing from 7 to 15 (e.g., 7-11, 7-10, 7-9, 7-8) carbon atoms. Representative examples of the term "C_7-15 bridged cycloalkyl" include, but are not limited to, adamantanyl, noradamantanyl, bornyl, norbornyl (also named as bicyclo [2.2.1] heptyl by the IUPAC system) . The "bridged cycloalkyl" is optionally substituted with1 to 10substituents selected from the group consisting of halogen, hydroxyl, cyano, amino, mercapto, oxo, C_1-3 alkyl, C_1-3 alkoxy, halogenated C_1-4 alkyl, C_5-10 aryl, C_5-10 heteroaryl, C_3-12 cycloalkyl, 4-to 12-membered heterocyclyl, or any combination thereof.

As used herein, the term "cycloalkylene" , used alone or in combination, is a group formed by removing one hydrogen from the cycloalkyl, and refers to a saturated or partially unsaturated (i.e., containing one or more double bonds, but not having a fully conjugated π-electron system) monocyclic or bicyclic or polycyclic divalent cyclic hydrocarbon radical, which in some embodiments contains from 3 to 20 carbon atoms (i.e., C_3-20 cycloalkylene) , or from 3 to 15 carbon atoms (i.e., C_3-15 cycloalkylene) , or from 3 to 12 carbon atoms (i.e., C_3-12 cycloalkylene) , or from 3 to 11 carbon atoms (i.e., C_3-11 cycloalkylene) , or from 3 to 10 carbon atoms (i.e., C_3-10 cycloalkylene) , or from 3 to 8 carbon atoms (i.e., C_3-8cycloalkylene) , or from 3 to 7 carbon atoms (i.e., C_3-7 cycloalkylene) , or from 3 to 6 carbon atoms (i.e., C_3-6 cycloalkylene) . The term "cycloalkylene" includes monocyclic, bicyclic or tricyclic or polycyclic cycloalkylene having from 3 to 20 carbon atoms. Representative examples of monocyclic cycloalkylene groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenylene, cyclohexylene, cyclohexenylene, cycloheptylene, and cyclooctylene. Bicyclic, tricyclic and polycyclic cycloalkylene groups include bridged cycloalkylene, fused cycloalkylene and spiro-cycloalkylene groups such as, but not limited to, decalinylene, octahydropentalenylene, octahydro-1H-indenylene, spiro-cycloalkylene (including C_5-20 spiro-cycloalkylene and C_5-15 spiro-cycloalkylene) , adamantanylene, noradamantanylene, bornylene, and norbornylene (also known as norcamphanylene) . As used herein, the "cycloalkylene" is optionally mono-or poly-substituted, such as, but not limited to, 2, 2-, 2, 3-, 2, 4-, 2, 5-, or 2, 6-disubstituted cyclohexylene. The substituents of the substituted "cycloalkylene" can be optionally one or more (e.g., 1-5, 1-4, 1-3, 1-2, or 1) selected from the group consisting of halogen, hydroxyl, cyano, amino, mercapto, oxo, C_1-3 alkyl, C_1-3 alkoxy, halogenated C_1-4 alkyl, C_5-10 aryl, C_5-10 heteroaryl, C_3-12 cycloalkyl, 4-to 12-membered heterocyclyl, or any combination thereof.

As used herein, the term "aryl" used alone or in combination refers to a monovalent aromatic hydrocarbon group containing from 5 to 20 (including from 5 to 14) carbon atoms and optionally one or more fused rings, such as phenyl, naphthyl or fluorenyl. In the present disclosure, the "aryl" is optionally mono-or poly-substituted. The substituents of the substituted "aryl" can be optionally one or more (e.g., 1-5, 1-4, 1-3, 1-2, or 1) selected from halogen, hydroxyl, cyano, amino, mercapto, C_1-3 alkyl, C_1-3 alkoxy, halogenated C_1-4 alkyl, C_5-10 aryl, C_5-10 heteroaryl, C_3-12 cycloalkyl, 4-to 12-membered heterocyclyl, or any combination thereof.

As used herein, the term "arylene" used alone or in combination is a group formed by removing one hydrogen from the aryl, and refers to a divalent aromatic hydrocarbon group containing from5to 20 (including from5to 14) carbon atoms and optionally one or more fused rings, such as phenylene, naphthylene or fluorenylene. In the present disclosure, the "arylene" is optionally mono-or poly-substituted. The substituents of the substituted "arylene" can be optionally one or more (e.g., 1-4, 1-3, 1-2, or 1) selected from the group consisting of halogen, hydroxyl, cyano, amino, mercapto, C_1-3 alkyl, C_1-3 alkoxy, halogenated C_1-4 alkyl, C_5-10 aryl, C_5-10 heteroaryl, C_3-12 cycloalkyl, 4-to 12-membered heterocyclyl, or any combination thereof.

As used herein, the term "heterocyclyl" or "heterocyclic group" , used alone or in combination, refers to a 3-to 20-membered (e.g., 3-to 15-membered, 3-to 9-membered, 4-to 20-membered, 4-to 15-membered, or 4-to 9-membered) saturated or partially unsaturated (i.e., containing one or more double bonds, but not having a fully conjugatedπ-electron system) monocyclic, bicyclic, tricyclic or polycyclic cyclic hydrocarbon group containing one or more (e.g., from 1 to 5, or from 1 to 4, from 1 to 3, from 1 to 2, or 1) heteroatoms independently selected from sulfur, oxygen, and nitrogen. In some embodiments, non-limiting examples of "heterocyclyl" may preferably include a 3-to 20-membered (e.g., 3-to 15-membered, 3-to 14-membered, 3-to 12-membered, 3-to 11-membered, 3-to 10-membered, 3-to 9-membered, 3-to 8-membered, 3-to 7-membered, 3-to 6-membered, 3-to 5-membered, 4-to 20-membered, 4-to 15-membered, or 4-to 9-membered) saturated or partially unsaturated (i.e., containing one or more double bonds, but not having a fully conjugatedπ-electron system) monocyclic cyclic hydrocarbon group containing one or more heteroatoms independently selected from sulfur, oxygen, and nitrogen. Representative examples of the monocyclic heterocyclyl include, but are not limited to, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolidyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxacyclohexyl, azacycloheptyl, azacyclooctyl, diazacycloheptanyl (e.g., 1, 4-diazacycloheptan-1-yl) , and diazacyclooctyl. Bicyclic and tricyclic and polycyclic heterocyclyl groups include bridged heterocyclyl, fused heterocyclyl and spiro-heterocyclyl groups such as, but not limited to, 6-azabicyclo [3.1.1] heptan-3-yl, 2, 5-diazabicyclo [2.2.1] heptan-2-yl, 3, 6-diazabicyclo [3.1.1] heptan-3-yl, 3-azabicyclo [3.2.1] octan-8-yl, 3, 8-diazabicyclo [3.2.1] octan-8-yl, 3, 8-diazabicyclo [3.2.1] octan-3-yl, 2, 5-diazabicyclo [2.2.2] octan-2-yl, and azaspirocycloalkyl (including3-azaspiro [5.5] undecan-3-yl) . The heterocyclyl may be unsubstituted or substituted as explicitly defined (e.g., mono-, di-, tri-, or poly-substituted) , and the substituent (s) of the heterocyclyl can be as defined above, or be optionally selected from the group consisting of halogen, hydroxyl, cyano, amino, mercapto, oxo, C_1-3 alkyl, C_1-3 alkoxy, halogenated C_1-4 alkyl, C_5-10 aryl, C_5-10 heteroaryl, C_3-12 cycloalkyl, 4-to 12-membered heterocyclyl, or any combination thereof.

As used herein, the term "heterocyclylene" , used alone or in combination, is a group formed by removing one hydrogen from the heterocyclyl, and refers to a 3-to 20-membered (e.g., 3-to 15-membered, 3-to 9-membered, 4-to 20-membered, 4-to 15-membered, or 4-to 9-membered) saturated or partially unsaturated (i.e., containing one or more double bonds, but not having a fully conjugated π-electron system) monocyclic, bicyclic, tricyclic or polycyclic bivalent cyclic hydrocarbon group containing one or more (e.g., from 1 to 5, or from 1 to 4, from 1 to 3, from 1 to 2, or 1) heteroatoms independently selected from sulfur, oxygen, and nitrogen. In some embodiments, non-limiting examples of "heterocyclylene" may preferably include a 3-to 20-membered (e.g., 3-to 15-membered, 3-to 14-membered, 3-to 12-membered, 3-to 11-membered, 3-to 10-membered, 3-to 9-membered, 3-to 8-membered, 3-to 7-membered, 3-to 6-membered, 3-to 5-membered, 4-to 20-membered, 4-to 15-membered, or 4-to 9-membered) saturated or partially unsaturated (i.e., containing one or more double bonds, but not having a fully conjugated π-electron system) monocyclic bivalent cyclic hydrocarbon group containing one or more heteroatoms independently selected from sulfur, oxygen, and nitrogen. Representative examples of the monocyclic heterocyclylene include, but are not limited to, azetidinylene, oxetanylene, pyrrolidinylene, imidazolidinylene, pyrazolidylene, tetrahydrofuranylene, tetrahydropyranylene, tetrahydrothienylene, tetrahydrothiopyranylene, oxazolidinylene, thiazolidinylene, piperidinylene, piperazinylene, morpholinylene, thiomorpholinylene, dioxacyclohexylene, azacycloheptylene, azacyclooctylene, diazacycloheptanylene (e.g., 1, 4-diazacycloheptan-1-ylene) , and diazacyclooctylene. Bicyclic and tricyclic and polycyclic heterocyclylene groups include bridged heterocyclylene, fused heterocyclylene and spiro-heterocyclylene groups such as, but not limited to, 6-azabicyclo [3.1.1] heptan-3-ylene, 2, 5-diazabicyclo [2.2.1] heptan-2-ylene, 3, 6-diazabicyclo [3.1.1] heptan-3-ylene, 3-azabicyclo [3.2.1] octan-8-ylene, 3, 8-diazabicyclo [3.2.1] octan-8-ylene, 3, 8-diazabicyclo [3.2.1] octan-3-ylene, 2, 5-diazabicyclo [2.2.2] octan-2-ylene, and azaspirocycloalkylene (especially3-azaspiro [5.5] undecan-3-ylene) . The heterocyclylene may be unsubstituted or substituted as explicitly defined (e.g., mono-, di-, tri-, or poly-substituted) , and the substituent (s) of the heterocyclylene can be as defined above, or be optionally selected from the group consisting of halogen, hydroxyl, cyano, amino, mercapto, oxo, C_1-3 alkyl, C_1-3 alkoxy, halogenated C_1- ₄ alkyl, C_5-10 aryl, C_5-10 heteroaryl, C_3-12 cycloalkyl, 4-to 12-membered heterocyclyl, or any combination thereof.

As used herein, the term "heteroaryl" used alone or in combination refers to a 5-to 20-membered (e.g., 5-to 15-membered, 5-to 12-membered, 5-to 11-membered, 5-to 10-membered, 5-to 9-membered, 5-to 8-membered, 5-to 7-membered, 5-to 6-membered, 6-to 15-membered, or 6-to 9-membered) monocyclic, bicyclic, tricyclic or polycyclic monovalent aromatic ring group containing one or more (e.g., from 1 to 6, or from 1 to 5, or from 1 to 4, or from 1 to 3) heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur. Bicyclic or polycyclic heteroaryl groups include bicyclic, tricyclic or tetracyclic heteroaryl groups, which contain one aromatic ring having one or more heteroatoms independently selected from O, S and N, and the remaining rings may be a saturated, partially unsaturated or aromatic ring and can be carbocyclic ring or contain one or more heteroatoms independently selected from O, S and N. Non-limiting examples of monocyclic heteroaryl groups include, but are not limited to, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, tetrazolyl, and triazinyl. Non-limiting examples of bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, isoindolinyl, benzofuranyl, isobenzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, benzo [2, 1, 3] oxadiazolyl, benzo [2, 1, 3] thiadiazolyl, benzo [1, 2, 3] thiadiazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, oxazolopyridyl, furopyridyl, pteridyl, purinyl, pyridopyridyl, pyrazolo [1, 5-a] pyridyl, pyrazolo [1, 5-a] pyrimidinyl, imidazo [1, 2a] pyridyl, 1H-pyrrolo [3, 2-b] pyridyl, 1H-pyrrolo [2, 3-b] pyridyl, pyrrolo [2, 1-b] thiazolyl and imidazo [2, 1-b] thiazolyl. Non-limiting examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, and xanthyl. The heteroaryl group may be unsubstituted or substituted as explicitly defined (e.g., mono-, di-, tri-, or poly-substituted) , and the substituent (s) of the heteroaryl can be as defined above, or be optionally selected from the group consisting of halogen, hydroxyl, cyano, amino, mercapto, C_1-3 alkyl, C_1-3 alkoxy, halogenated C_1-4 alkyl, C_5-10 aryl, C_5-10 heteroaryl, C_3-12 cycloalkyl, 4-to 12-membered heterocyclyl, or any combination thereof.

As used herein, the term "heteroarylene" used alone or in combination is a group formed by removing one hydrogen from the heteroaryl, and refers to a 5-to 20-membered (e.g., 5-to 15-membered, 5-to 12-membered, 5-to 11-membered, 5-to 10-membered, 5-to 9-membered, 5-to 8-membered, 5-to 7-membered, 5-to 6-membered, 6-to 15-membered, or 6-to 9-membered) monocyclic, bicyclic, tricyclic or polycyclic bivalent aromatic ring group containing one or more (e.g., from 1 to 6, or from 1 to 5, or from 1 to 4, or from 1 to 3) heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur. Bicyclic or polycyclic heteroarylene groups include bicyclic, tricyclic or tetracyclic heteroarylene groups, which contain one aromatic ring having one or more heteroatoms independently selected from O, S and N, and the remaining ring (s) may be a saturated, partially unsaturated or aromatic ring and can be carbocyclic ring or contain one or more heteroatoms independently selected from O, S and N. Non-limiting examples of monocyclic heteroarylene groups include, but are not limited to, furanylene, oxazolylene, isoxazolylene, oxadiazolylene, thienylene, thiazolylene, isothiazolylene, thiadiazolylene, pyrrolylene, imidazolylene, pyrazolylene, triazolylene, pyridylene, pyrimidinylene, pyridazinylene, pyrazinylene, tetrazolylene, and triazinylene. Non-limiting examples of bicyclic heteroarylene groups include, but are not limited to, indolylene, isoindolylene, isoindolinylene, benzofuranylene, isobenzofuranylene, benzothienylene, indazolylene, benzimidazolylene, benzoxazolylene, benzisoxazolylene, benzothiazolylene, benzisothiazolylene, benzotriazolylene, benzo [2, 1, 3] oxadiazolylene, benzo [2, 1, 3] thiadiazolylene, benzo [1, 2, 3] thiadiazolylene, quinolinylene, isoquinolinylene, naphthyridinylene, cinnolinylene, quinazolinylene, quinoxalinylene, phthalazinylene, oxazolopyridylene, furopyridylene, pteridylene, purinylene, pyridopyridylene, pyrazolo [1, 5-a] pyridylene, pyrazolo [1, 5-a] pyrimidinylene, imidazo [1, 2a] pyridylene, 1H-pyrrolo [3, 2-b] pyridylene, 1H-pyrrolo [2, 3-b] pyridylene, pyrrolo [2, 1-b] thiazolylene, and imidazo [2, 1-b] thiazolylene. Non-limiting examples of tricyclic heteroarylene groups include, but are not limited to, acridinylene, benzindolylene, carbazolylene, dibenzofuranylene, and xanthylene. The heteroarylene group may be unsubstituted or substituted as explicitly defined (e.g., mono-, di-, tri-, or poly-substituted) , and the substituent (s) of the heteroarylene can be as defined above, or be optionally selected from the group consisting of halogen, hydroxyl, cyano, amino, mercapto, C_1-3 alkyl, C_1-3 alkoxy, halogenated C_1-4 alkyl, C_5-10 aryl, C_5-10 heteroaryl, C_3-12 cycloalkyl, 4-to 12-membered heterocyclyl, or any combination thereof.

As used herein, the term "alkynylene" , used alone or in combination, refers to a linear or branched divalent hydrocarbon group containing from 2 to 8 (e.g., from 2 to 6, from 2 to 5, from 2 to 4, or 2) carbon atoms and having one or more (e.g., from 1 to 3, from 1 to 2, or 1) carbon-carbon triple bonds. Examples of alkynylene include, but are not limited to, ethynylene, 1-propynylene, 1- butynylene, and 1, 3-diynylene.

As used herein, the term "alkenylene" , used alone or in combination, refers to a linear or branched divalent hydrocarbon group containing from 2 to 8 (e.g., from 2 to 6, from 2 to 5, from 2 to 4, or 2) carbon atoms and having one or more (e.g., from 1 to 3, from 1 to 2, or 1) carbon-carbon double bonds. Examples of alkenylene groups include, but are not limited to, vinylene (e.g., -CH=CH-) , 1-propenylene, allylidene, 1-butenylene, 2-butenylene, 3-butenylene, isobutenylene, pentenylene, n-pent-2, 4-dienylene, 1-methyl-but-1-enylene, 2-methyl-but-1-enylene, 3-methyl-but-1-enylene, 1-methyl-but-2-enylene, 2-methyl-but-2-enylene, 3-methyl-but-2-enylene, 1-methyl-but-3-enylene, 2-methyl-but-3-enylene, 3-methyl-but-3-enylene, and hexenylene.

The compound of formula (I) of the present invention may include an enantiomer depending on the presence of a chiral center or an isomer depending on the presence of a double bond (for example, Z, E) . Salts or pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs of the compounds of Formula (I) of the present disclosure are also encompassed within the scope of the present invention as defined by the appended claims.

As used herein, the term "stereoisomer" refers to compounds having the same chemical structure, but different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers) , geometric isomers (including cis/trans isomers) , atropisomers, etc.

In the present invention, the term "solvate" generally refers to any form of the active compound according to the present invention bonded to another molecule (usually a polar solvent, including H₂O, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid and ethanolamine) through a non-covalent bond, and the obtained substance may specifically include but not limited to hydrates and alcoholates, such as methanolates.

As used herein, the term "chiral" refers to a molecule that has the property of being non-superimposable with its mirror image; and "achiral" refers to a molecule that can overlap with its mirror image.

As used herein, the term "enantiomer" refers to two non-superimposable but mirror-image isomers of a compound.

As used herein, the term "diastereomer" refers to a stereoisomer of a compound having two or more chiral centers that is not a mirror image of another stereoisomer of the same compound. Diastereomers have different physical properties such as melting point, boiling point, spectral properties and reactivity. Diastereomeric mixtures can be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.

In all embodiments of the present disclosure, the salts or pharmaceutically acceptable salts of the compounds of Formula (I) refer to non-toxic inorganic or organic acid and/or base addition salts. Non-limiting examples include, but are not limited to, sulfate, hydrochloride, citrate, maleate, sulfonate, citrate, lactate, tartrate, fumarate, phosphate, dihydrogenphosphate, pyrophosphate, metaphosphate, oxalate, malonate, benzoate, mandelate, succinate, glycolate, or p-toluenesulfonate of the compound of Formula (I) , etc.

As used herein, the term "Pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, such as a filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, with which the useful compounds according to the present disclosure are carried or transported into or administered to a patient so that they can perform their intended function. Generally, such constructs are carried or transported from one organ or part of the body to another organ or part of the body. The carrier is compatible with the other ingredients of the formulation, including the compounds useful in the present disclosure, and is not harmful to the patient, and the carrier must be "acceptable" . Some examples of materials that can be used as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; surfactant phosphate buffer solution; and other common non-toxic compatible substances used in pharmaceutical formulations.

As used herein, the term “physiologically acceptable carriers” include "pharmaceutically acceptable carrier" , and refer to those known to be usable in the pharmaceutical technology sectors and adjacent areas, in particular those listed in relevant pharmacopeias (e.g., ChP, DAB, Ph. Eur., BP, NF, USP) , as well as other auxiliary agents (excipients) whose properties do not impair a physiological use.

As used herein, the term “patient” or “subject” or “host” refers to animal, for example mammal, including but not limited to primate (such as human being) , cow, sheep, goat, horse, dog, cat, rabbit, guinea pig, rat, mice, etc. ”

As used herein, the term "therapeutically effective amount" of a compound or a pharmaceutical composition of the present disclosure means an amount of a compound that, when administered to a subject for treating a disease, is sufficient to provide a therapeutic benefit.

As used herein, the terms "genome editing" or “gene editing” has a definition known to those skilled in the art, that is, it refers to an accurate genetic engineering technology or process that can modify specific target genes of organism genome, in which DNA is inserted, replaced, modified or removed from a target DNA, e.g., the genome of a cell, by using e.g., one or more Cas9 protein, variants or homologues thereof including Cas9 nucleases, Cas9 nuclease dimers, Cas9 nuclease fusion proteins, Cas9 nuclease fragments, minimized Cas9 nucleases, Cas9 variants without a cleavage domain, Cas9 variants without a gRNA domain, and Cas9-recombinase fusions, e.g., dCas9 proteins, variants of dCas9, Cas9 nickases (or D10A nickase) , SaCas9, SpCas9, SpCas9n, saCas9, High Fidelity Cas9 (HiFi Cas9) , Cas9-H840A, FokI-dCas9, and any of these Cas proteins fused with other engineered proteins.

As used herein, the terms “epigenetic editing” or “epigenetic modification” refer to an accurate genetic engineering technology or process that can modify specific histones, up-or down-regulated specific genes, using any of the Cas9 proteins, variants or homologues thereof fused with engineered proteins, e.g., VP64, VPR, KRAB, p300, LSD1, Dnmt3 a and Tet1 (see, e.g., M. Nakamura, et al., Nature Cell Biology, vol. 23, pages11-22, January2021) , the entire contents of which is incorporated herein by reference for all purposes as if fully set forth herein.

As used herein, the term "CRISPR/Cas9 protein, variants or homologues thereof system" refers to a tool comprising Cas9 endonuclease protein, variants or homologues thereof and guide RNAs (gRNA) and repair-templates, which can be used for genome editing, transcriptional regulation, genome imaging, epigenetic modification, gene therapy, disease models establishing, genome-wide genetic screening, or drug design and screening, or molecular diagnostic tool for diseases. In some embodiments, the system comprises Cas9 endonuclease protein, functional variants or homologues thereof and gRNA for genome editing, which can cut a specific piece of DNA, alter it in the desired way, and modify gene function. Cas9 endonucleases acts like a scissor cutting the genomic DNA at a particular location, thus, facilitating the addition or deletion of DNA base pairs. gRNA is a small piece of a pre-designed RNA sequence (about 20 nucleotide bases long) located within a longer RNA scaffold, and consists of CRISPR RNA or (crRNA) and tracrRNA. gRNA guides the Cas9 endonucleases to the specific target location where the cut is needed (See, e.g., WO2019143677, WO2015048557, the entire contents of which is hereby incorporated by reference) . In some embodiments, the system comprises dCas9 protein (a Cas9 variant) and gRNA for transcriptional regulation, which can regulate endogenous gene expression by gRNA guiding the fusion of dCas9 with effector domains to bind to the specific target DNA sequences either to activate or to repress gene expression. In some embodiments, the system comprises dCas9 protein and gRNA, which can form a dCas9 epigenetic editing system, wherein dCas9 is used as an epigenetic modulator, and fuses with epigenetic modifiers (e.g., epigenetic enzyme) or engineered proteins (e.g., VP64, VPR, KRAB, p300, LSD1, Dnmt3a and Tet1) for epigenetic modification (see, e.g., M. Nakamura, et al., Nature Cell Biology, vol. 23, pages 11-22, January2021) , the entire contents of which is incorporated herein by reference for all purposes as if fully set forth herein. In some embodiments, epigenetic modification includes DNA methylation, histone methylation, histone acetylation, histone phosphorylation and so on.

As used herein, the term “Cas9” or “Cas9 nuclease” or "Cas9 protein" refers to RNA-guided endonuclease proteins in bacterial and archaeal genomes which have been identified to be associated with CRISPR loci, including an RNA-guided double-stranded DNA-binding nuclease protein (Cas9 protein) , or a fragment thereof (e.g., a protein comprising an active or inactive DNA cleavage domain of Cas9, and/or the gRNA binding domain of Cas9) . A Cas9 protein is also known as a CRISPR-associated nuclease Cas9, and formerly named as a Csn1nuclease. Cas9 protein is predominantly present in type II bacterial CRISPR systems. Wild-type Cas9 nuclease has two functional domains, e.g., RuvC and HNH, that cut different DNA strands. Cas9 protein recognizes a short motif in the CRISPR repeat sequences (the PAM or protospacer adjacent motif) and the gRNA base pairs with the complementary target DNA sequence. When the gRNA/Cas9 complex binds to the target site, the Cas9 introduces a blunt-ended, double-stranded cut, 3 bases upstream of the PAM site. Cas9 protein can induce double-strand breaks in genomic DNA (target DNA) when both functional domains are active. Cas9 nuclease sequences and structures are well known to those skilled in the art (see, e.g., US2016/0215276A1; WO2019143677; WO2015048557; “Complete genome sequence of an M1 strain of Streptococcus pyogenes. ” Ferretti, J. J. et al., Proceedings of the National Academy of Sciences, 98: 4658-4663 (2001) ; “CRISPR RNA maturation by trans-encoded small RNA and host factor RNase III. ” Deltcheva E. et al., Nature 471: 602-607 (2011) ; and “A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. ” Jinek M., et al., Science 337: 816-821 (2012) , the entire contents of each of which are incorporated herein by reference) . Cas9 orthologs have been described in various species, including, but not limited to, S. pyogenes and S. thermophilus. Additional suitable Cas9 nucleases and sequences will be apparent to those skilled in the art, and include Cas9 sequences from the organisms and loci disclosed in Chylinski, Rhun, and Charpentier, “The tracrRNA and Cas9 families of type II CRISPR-Cas immunity systems” , RNA Biology, 2013, 10 (5) : 726-737; and US2016/0215276A1; the entire contents of which are incorporated herein by reference. Many variants and homologues of Cas9 nuclease have been engineered and developed, and include, but are not limited to, Cas9 nuclease dimers, Cas9 nuclease fusion proteins, Cas9 nuclease fragments, minimized Cas9 nucleases, Cas9 variants without a cleavage domain, Cas9 variants without a gRNA domain, Cas9-recombinase fusions, etc., especially deactivated Cas9 (dCas9) proteins, variants of dCas9, Cas9 nicknase (or D10A nickase) , SaCas9, Cas9 nuclease from Streptococcus pyogenes (SpCas9) , SpCas9n, saCas9, High Fidelity Cas9 (HiFi Cas9) , Cas9-H840A, and FokI-dCas9, as described in many publications, e.g., US2016/0215276A1; WO2019143677; WO2015048557; Anzalone, A.V., et al., “Genome editing with CRISPR-Cas nucleases, base editors, transposases and prime editors” , Nature Biotechnology, 2020, 38 (7) , 824-844; Xinhui Xu et al., “Gene activation by a CRISPR-assisted trans enhancer” , eLife, 2019; 8: e45973; and Nakamura, M., et al, “CRISPR technologies for precise epigenome editing” , Nature Cell Biology, January 2021, vol. 23, pages 11-22; the entire contents of which are incorporated herein by reference.

The Cas9 variant dCas9 is generated by inactivation of both catalytic domains (D10A for HNH and H840A for RuvC in S. pyogenes Cas9) so that it still binds to DNA based on sgRNA specificity but is not able to cleave the DNA. This variant has several applications, such as regulation of endogenous gene expression by the fusion of dCas9 with effector domains either to activate or to repress gene expression. When dCas9 is fused to a repressor domain, the approach is called CRISPRi (CRISPR interference) (gene silencing) , and when it is fused to an activation domain, it is called CRISPRa (gene activation) . dCas9 is also used as an epigenetic modulator through the fusion of dCas9 with epigenetic modifiers. dCas9 can even be used for in vivo imaging when fused to a fluorescent protein and in live cells for targeting specific genomic loci. See, “Chapter 34-Modeling Cancer Using CRISPR-Cas9 Technology” , Animal Models for the Study of Human Disease, (2^ndEdition) , edited by: P. Michael Conn, 2017, Pages 905-924; the entire contents of which are incorporated herein by reference.

As used herein, the term “complexes comprising Cas9 protein, variants or homologues thereof” refers to complexes assembled by Cas9 protein, variants or homologues thereof with any assemblies involved during the gene engineering where the CRISPR/Cas9 proteins, variants or homologues thereof system is required, e.g., guide RNAs. Non-limiting examples of “complexes comprising Cas9 protein, variants or homologues thereof” include, but are not limited to, complexes comprising any of these Cas proteins as described above, e.g., complexes assembled by Cas9 protein, variants or homologues thereof with guide RNAs, e.g., ribonucleoprotein complexes (RNP) assembled by Cas9 protein, variants or homologues thereof with guide RNAs.

The term "room temperature" used herein refers to the ambient temperature, such as a temperature of 20-30℃.

II. Compounds

The present disclosure provides the compound of Formula (I) :

wherein the R, R¹, R², (R³) _n1, ring A, (R⁴) _n2, W, U₂, L, and ULM are as defined above in the Summary of the Invention.

In some embodiments, R represents C (O) , S (O) ₂, CH₂, CH₂C (O) , or C (O) CH₂. In a sub-embodiment, R represents CH₂. In a sub-embodiment, R represents C (O) . In a sub-embodiment, R represents S (O) ₂. In a sub-embodiment, R represents CH₂C (O) . In a sub-embodiment, R represents C (O) CH₂.

In some embodiments, the ring A represents C_5-20 aryl, 5-to 20-membered heteroaryl, 4-to 20-membered heterocyclyl, or C_3-20 cycloalkyl.

In some embodiments, the ring A represents C_5-20 aryl. Non-limiting examples of "C_5-20 aryl" include C_5-15 aryl, for example, phenyl, and naphthyl.

In some embodiments, the ring A represents 5-to 20-membered heteroaryl. Non-limiting examples of "5-to 20-membered heteroaryl" include 5-to 15-membered heteroaryl, for example, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, benzo [2, 1, 3] oxadiazolyl, benzo [2, 1, 3] thiadiazolyl, benzo [1, 2, 3] thiadiazolyl, quinolyl, isoquinolyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrazolo [1, 5-a] pyridyl, pyrazolo [1, 5-a] pyrimidyl, imidazo [1, 2-a] pyridyl, 1H-pyrrolo [3, 2-b] pyridyl, 1H-pyrrolo [2, 3-b] pyridyl, 4H-fluoro [3, 2-b] pyrrolyl, pyrrolo [2, 1-b] thiazolyl, imidazo [2, 1-b] thiazolyl, and triazolyl.

In some embodiments, the ring A represents 4-to 20-membered heterocyclyl. Non-limiting examples of "4-to 20-membered heterocyclyl" include 4-to 15-membered heterocyclyl, for example, azetidinyl, pyrrolidinyl, 2-oxopyrrolidin-1-yl, imidazolidinyl, pyrazolidyl, , tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, piperidinyl, 2-oxopiperidin-1-yl, piperazinyl, morpholinyl, thiomorpholinyl, dioxacyclohexyl, 3-azabicyclo [3.1.0] hexyl, 3-azabicyclo [4.1.0] heptyl, 1, 4-diazacycloheptan-1-yl, 3, 8-diazabicyclo [3.2.1] octan-3-yl, 2, 5-diazabicyclo [2.2.2] octan-2-yl, 1, 4-diazepan-1-yl, 1, 4-diazabicyclo [3.2.1] octan-4-yl, 2-azabicyclo [3.2.1] octan-2-yl, tetrahydro-2H-pyran-2-yl, azepanyl, azacyclooctanyl, 5-azaspiro [2.4] heptan-5-yl, 5-azaspiro [2.4] heptan-5-yl, 6-azaspiro [2.5] octan-6-yl, 2-oxa-7-azaspiro [3.5] nonan-7-yl, 3-azabicyclo [3.1.0] hexan-3-yl, and3-azabicyclo [4.1.0] heptan-3-yl.

In some embodiments, the ring A represents C_3-20 cycloalkyl. Non-limiting examples of "C_3-20 cycloalkyl" include C_3-15 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, decalinyl, octahydropentalenyl, octahydro-1H-indenyl, 2, 3-dihydro-1H-indenyl, spiro [3.3] heptyl, spiro [2.5] octyl, spiro [3.5] nonyl, spiro [4.4] nonyl, spiro [4.5] decyl, spiro [5.5] undecyl, quinuclidinyl, adamantanyl, nordamantanyl, norcamphanyl, bicyclo [2.2.1] heptyl, 2-oxobicyclo [2.2.1] heptyl, or 2-oxobicyclo [2.2.1] heptenyl.

In some embodiments, the ring A is optionally substituted with n2 R⁴ group (s) , wherein n2 represents an integer of 0, 1, 2, 3, 4, or 5, and each R⁴ group independently represents halogen, hydroxyl, cyano, amino, C_1-4 alkyl, halogenated C_1-4 alkyl, C_1-3 alkoxy, or C_3-6 cycloalkyl.

In some embodiments, the ring A is unsubstituted.

In some embodiments, the ring A is substituted with n2 R⁴ group (s) , wherein n2 represents an integer of 1, 2, 3, 4, or 5, and each R⁴ group independently represents halogen (e.g., fluorine, chlorine, bromine, or iodine) , hydroxyl, cyano, amino, C_1-4 alkyl (e.g., methyl or ethyl) , halogenated C_1-4 alkyl (e.g., trifluoromethyl) , C_1-3 alkoxy (e.g., methoxy) , or C_3-6 cycloalkyl (e.g., cyclopropyl) .

In some embodiments, the ring A is imidazolyl, pyridinyl, phenyl or cyclohexyl, which are optionally substituted with from 1 to 3 substituents R⁴ selected from the group consisting of methyl, halogen (e.g., fluorine, chlorine, bromine, or iodine) , hydroxyl, cyano, amino, methoxy, and trifluoromethyl.

In some embodiments, W represents a bond.

In some embodiments, W represents: -U₁-#, wherein U₁ represents ethynylene or vinylene, or U₁ represent a bond; and symbol#indicates the point of attachment to the U₂.

In some sub-embodiments, U₁ represents ethynylene. In some sub-embodiments, U₁ represents vinylene. In some sub-embodiments, U₁ represent a bond.

In some embodiments, W represents:

wherein W₁ represents ethynylene or vinylene, or W₁ represent a bond;the ring B represents C_5-20 arylene, 5-to 20-membered heteroarylene, 4-to 20-membered heterocyclylene, or C_3-20 cycloalkylene;

(R⁵) _n3 indicates that the ring B where (R⁵) _n3is attached to is optionally substituted with n3 R⁵ group (s) , wherein n3represents an integer of 0, 1, 2, 3, 4, or 5, and each R⁵ group independently represents halogen, hydroxyl, cyano, amino, C_1-4 alkyl, halogenated C_1-4 alkyl, C_1-3 alkoxy, C (O) N (C_1-3 alkyl) ₂, or C_3-6 cycloalkyl; and symbol#indicates the point of attachment to the U₂.

Herein the ring B is a divalent group as depicted in the structure of the group W of the compound of formula (I) .

In some embodiments, the ring B represents C_5-20 arylene. Non-limiting examples of "C_5-20 arylene" include C_5-15 arylene, forexample, phenylene (e.g., ) , andnaphthylene.

In some embodiments, the ring B represents 5-to 20-membered heteroarylene. Non-limiting examples of “5-to 20-membered heteroarylene” include 5-to 15-membered heteroarylene, for example, furanylene, oxazolylene, isoxazolylene, oxadiazolylene, thienylene, thiazolylene, isothiazolylene, thiadiazolylene, pyrrolylene, imidazolylene, pyrazolylene, triazolylene, pyridylene, pyrimidinylene, pyridazinylene, pyrazinylene, indolylene, isoindolylene, benzofuranylene, isobenzofuranylene, benzothienylene, indazolylene, benzimidazolylene, benzoxazolylene, benzoisoxazolylene, benzothiazolylene, benzoisothiazolylene, benzotriazolylene, benzo [2, 1, 3] oxadiazolylene, benzo [2, 1, 3] thiadiazolylene, benzo [1, 2, 3] thiadiazolylene, quinolinylene, isoquinolinylene, naphthyridinylene, cinnolinylene, quinazolinylene, quinoxalinylene, phthalazinylene, pyrazolo [1, 5-a] pyridylene, pyrazolo [1, 5-a] pyrimidinylene, imidazo [1, 2-a] pyridylene, 1H-pyrrolo [3, 2-b] pyridylene, 1H-pyrrolo [2, 3-b] pyridylene, pyrrolo [2, 1-b] thiazolylene, and imidazo [2, 1-b] thiazolylene.

In some embodiments, the ring B represents 4-to 20-membered heterocyclylene. Non-limiting examples of "4-to 20-membered heterocyclylene" include 4-to 15-membered heterocyclylene, for example, azetidinylene, pyrrolidinylene, 2-oxopyrrolidin-1-ylene, imidazolidinylene, pyrazolidylene, tetrahydrofuranylene, tetrahydropyranylene, tetrahydrothienylene, tetrahydrothiopyranylene, oxazolidinylene, thiazolidinylene, piperidinylene, 2-oxopiperidin-1-ylene, piperazinylene, morpholinylene, thiomorpholinylene, dioxacyclohexylene, 3-azabicyclo [3.1.0] hexylene, 3-azabicyclo [4.1.0] heptylene, 1, 4-diazacycloheptan-1-ylene, 3, 8-diazabicyclo [3.2.1] octan-3-ylene, 2, 5-diazabicyclo [2.2.2] octan-2-ylene, 1, 4-diazepan-1-ylene, 1, 4-diazabicyclo [3.2.1] octan-4-ylene, 2-azabicyclo [3.2.1] octan-2-ylene, tetrahydro-2H-pyran-2-ylene, azepanylene, azacyclooctanylene, 5-azaspiro [2.4] heptan-5-ylene, 5-azaspiro [2.4] heptan-5-ylene, 6-azaspiro [2.5] octan-6-ylene, 2-oxa-7-azaspiro [3.5] nonan-7-ylene, 3-azabicyclo [3.1.0] hexan-3-ylene, and3-azabicyclo [4.1.0] heptan-3-ylene.

In some embodiments, the ring B represents C_3-20 cycloalkylene. Non-limiting examples of "C_3-20 cycloalkylene" include C_3-15 cycloalkylene, for example, cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenylene, cyclohexylene, cyclohexenylene, cycloheptylene, cyclooctylene, decalinylene, octahydropentalenylene, octahydro-1H-indenylene, 2, 3-dihydro-1H-indenylene, spiro [3.3] heptylene, spiro [2.5] octylene, spiro [3.5] nonylene, spiro [4.4] nonylene, spiro [4.5] decylene, spiro [5.5] undecylene, quinuclidinylene, adamantanylene, noradamantanylene, bornylene, norbornylene (also known as norcamphanyl) , bicyclo [2.2.1] heptylene, 2-oxobicyclo [2.2.1] heptylene, or 2-oxobicyclo [2.2.1] heptenylene.

In some embodiments, the ring B is optionally substituted with n3 R⁵ group (s) , wherein n3 represents an integer of 0, 1, 2, 3, 4, or 5, and each R⁵ group independently represents halogen, hydroxyl, cyano, amino, C_1-4 alkyl, halogenated C_1-4 alkyl, C_1-3 alkoxy, C (O) N (C_1-3 alkyl) ₂, or C_3-6 cycloalkyl.

In some embodiments, the ring B is unsubstituted.

In some embodiments, the ring B is substituted with n3 R⁵ group (s) , wherein n3 represents an integer of 1, 2, 3, 4, or 5, and each R⁵ group independently represents halogen (e.g., fluorine, chlorine, bromine, or iodine) , hydroxyl, cyano, amino, C_1-4 alkyl (e.g., methyl or ethyl) , halogenated C_1-4 alkyl (e.g., trifluoromethyl) , C_1-3 alkoxy (e.g., methoxy) , C (O) N (C_1-3 alkyl) ₂ (e.g., C (O) N (CH₃) ₂) , or C_3-6 cycloalkyl (e.g., cyclopropyl) ) .

In some embodiments, the ring B is phenylene or pyridinylene, which are optionally substituted with from 1 to 3 substituents R⁵ selected from the group consisting of methyl, halogen (e.g., fluorine, chlorine, bromine, or iodine) , hydroxyl, cyano, amino, methoxy, C (O) N (CH₃) ₂, and trifluoromethyl.

In some embodiments, W₁ represents ethynylene.

In some embodiments, W₁ represents vinylene.

In some embodiments, W₁ a bond.

In some embodiments, non-limiting examples of compounds of Formula (I) include:

wherein in formula (I-1) , (I-2) , (I-3) , (I-4) , (I-5) , (I-6) , (I-7) , and (I-8) the R, R¹, R², (R³) _n1, ring A, (R⁴) _n2, (R⁵) _n3, U₂, L, and ULM are as defined herein.

Insomeembodiments, non-limitingexamplesof fragmentofinclude:

In some embodiments, non-limiting examples of W include:

wherein symbol#indicates the point of attachment to U₂.

In some embodiments, non-limiting examples of compounds of Formula (I) include:

wherein in formula (IA) , (IB) , (IC) , (ID) , (IE) , (IF) , (IG) , and (IH) , the R, R², (R³) _n1, ring A, (R⁴) _n2, W, U₂, L, and ULM are as defined herein.

In some embodiments, non-limiting examples of compounds of Formula (I) include:

wherein in formula (I-1-1) , (I-1-2) , (I-1-3) , (I-1-4) , (I-1-5) , (I-1-6) , (I-1-7) , (I-1-8) , (I-1-9) , (I-1-10) , (I-1-11) , (I-1-12) , (I-1-13) , (I-1-14) , (I-1-15) , (I-1-16) , (I-1-17) , (I-1-18) , (I-1-19) , (I-1-20) , (I-1-21) , (I-1-22) , (I-1-23) , (I-1-24) , (I-1-25) , (I-1-26) , (I-1-27) , (I-1-28) , (I-1-29) , (I-1-30) , (I-1-31) , (I-2-1) , (I-2-2) , (I-4-1) , (I-4-2) , (I-4-3) , (I-5-1) , (I-6-1) , (I-7-1) , and (I-8-1) , the U₂, L, and ULM are as defined herein.

In some embodiments, U₂ represents C (O) NH, NHC (O) , C (O) O, OC (O) , NH, O, or ethynylene.

In some embodiments, U₂ represents C (O) NH.

In some embodiments, U₂ represents NHC (O) .

In some embodiments, U₂ represents C (O) O.

In some embodiments, U₂ represents OC (O) .

In some embodiments, U₂ represents NH.

In some embodiments, U₂ represents O.

In some embodiments, U₂ represents ethynylene.

In some embodiments, U₂ represents a bond.

In some embodiments, R¹ represents C_1-4 alkyl (e.g., methyl, ethyl, or propyl) optionally substituted with one or more (e.g., 1-6, 1-5, 1-4, 1-3, 1-2, or 1) substituents selected from the group consisting of halogen, hydroxyl, cyano, amino, and any combination thereof. In some sub-embodiments, R¹ represents methyl substituted with a substituent selected from the group consisting of halogen, hydroxyl, cyano, amino, and any combination thereof.

In some embodiments, R² represents H or C_1-4 alkyl (e.g., methyl, ethyl, or propyl) .

In some embodiments, ULM represents a E3 ubiquitinated ligase ligand which is covalently bonded to the L.

In some embodiments, ULM represents:

wherein:

X represents C (O) or CH₂;

W₂ represents S, S (O) , S (O) ₂, O, ethynylene, vinylene, or N (R⁷) , where R⁷ represents H or C_1-3 alkyl, or W₂ represents a bond; and

(R⁸) _n4 indicates that phenyl where (R⁸) _n4 is attached to is optionally substituted with n4 R⁸ group (s) , wherein n4 represents an integer of 0, 1, 2, or 3, and each R⁸ group independently represents halogen (e.g., fluorine, chlorine, bromine, or iodine) , hydroxyl, cyano, amino, C_1-4 alkyl (e.g., methyl, and ethyl) , halogenated C_1-4 alkyl (e.g., trifluoromethyl) , or C_1-3 alkoxy (e.g., methoxy) .

In some embodiments, ULM represents:

wherein Z₁ represents H or CH₃.

In some embodiments, ULM represents:

wherein Z₁ represents H or CH₃.

In some embodiments, ULM represents:

wherein (R⁹) _a1 indicates that each phenyl where (R⁹) _a1 is attached to is independently optionally substituted with a1 R⁹ group (s) , wherein a1 represents an integer of 0, 1, 2, 3, 4, or 5, and each R⁹ group independently represents halogen (e.g., fluorine, chlorine, bromine, or iodine) , hydroxyl, cyano, amino, C_1-4 alkyl (e.g., methyl) , halogenated C_1-4 alkyl (e.g., trifluoromethyl) , or C_1-3 alkoxy (e.g., methoxy, ethoxy, propoxy, or isopropoxy) .

In some embodiments, ULM represents:

wherein Z₂ represents O or NH.

In some embodiments, non-limiting examples of ULM include:

wherein (R⁸) _n4 indicates that phenyl where (R⁸) _n4 is attached to is optionally substituted with n4 R⁸ group (s) , wherein n4 represents an integer of 0, 1, 2, or 3, and each R ⁸group independently represents halogen, hydroxyl, cyano, amino, C_1-4 alkyl, halogenated C_1-4 alkyl, or C_1-3 alkoxy.

In some embodiments, the L represents an optionally substituted linear or branched alkylene group, wherein one or more groups selected from the group consisting ofR_a, R_b, and any combination thereof are optionally inserted between one or more pairs of adjacent carbon atoms of the backbone carbon chain of the linear or branched alkylene group, wherein each R_a is independently selected from the group consisting of O, C (O) , OC (O) , S, S (O) , S (O) ₂, S (O) ₂N (R⁶) , N (R⁶) S (O) ₂, C (O) N (R⁶) , N (R⁶) C (O) , N (R⁶) , and N (R⁶) C (O) N (R⁶) , where each R⁶independently represents H or C_1-3 alkyl, and in case that two or more groups R_a are inserted into the backbone carbon chain of the linear or branched alkylene group, the two or more groups R_a are not directly connected to each other; and wherein each R_b is independently selected from the group consisting of optionally substituted cycloalkylene, optionally substituted arylene, optionally substituted heterocyclylene, optionally substituted heteroarylene, and any combination thereof. In some sub-embodiments, the linear or branched alkylene group is optionally substituted with (e.g., 1-15, 1-12, 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, or 1) substituents selected from the group consisting of halogen, hydroxyl, cyano, amino, mercapto, C_1-3 alkyl, C_1-3 alkoxy, halogenated C_1-4 alkyl, C_5-10 aryl, C_5-10 heteroaryl, C_3-12 cycloalkyl, 4-to 12-membered heterocyclyl, or any combination thereof. In some sub-embodiments, each R_b is independently selected from the group consisting of optionally substituted cycloalkylene, optionally substituted arylene, optionally substituted heterocyclylene, optionally substituted heteroarylene, and any combination thereof, wherein the cycloalkylene and heterocyclylene are each independently optionally substituted with a substituent (s) selected from the group consisting of halogen, hydroxyl, cyano, amino, mercapto, oxo, C_1-3 alkyl, C_1-3 alkoxy, halogenated C_1-4 alkyl, C_5-10 aryl, C_5-10 heteroaryl, C_3-12 cycloalkyl, 4-to 12-membered heterocyclyl, or any combination thereof; and the arylene and heteroarylene are each independently optionally substituted with a substituent (s) selected from the group consisting of halogen, hydroxyl, cyano, amino, mercapto, C_1-3 alkyl, C_1-3 alkoxy, halogenated C_1-4 alkyl, C_5-10 aryl, C_5-10 heteroaryl, C_3-12 cycloalkyl, 4-to 12-membered heterocyclyl, or any combination thereof.

In some embodiments, the L represents an optionally substituted linear or branched C_1-40 alkylene group (including C_1-30 alkylene, C_1-20 alkylene, C_1-15 alkylene, or C_1-10 alkylene) , wherein one or more groups selected from the group consisting of R_a, R_b, and any combination thereof are optionally inserted between one or more pairs of adjacent carbon atoms of the backbone carbon chain of the linear or branched C_1-40 alkylene group, wherein each R_a is independently selected from the group consisting of O, C (O) , OC (O) , S, S (O) , S (O) ₂, S (O) ₂N (R⁶) , N (R⁶) S (O) ₂, C (O) N (R⁶) , N (R⁶) C (O) , N (R⁶) , and N (R⁶) C (O) N (R⁶) , where each R⁶independently represents H or C_1-3 alkyl, and in case that two or more groups R_a are inserted into the backbone carbon chain of the linear or branched C_1-40 alkylene group, the two or more groups R_a are not directly connected to each other; and wherein each R_b is independently selected from the group consisting of optionally substituted C_3- ₂₀ cycloalkylene, optionally substituted C_5-20 arylene, optionally substituted 4-to 20-membered heterocyclylene, optionally substituted 5-to 20-membered heteroarylene, and any combination thereof. In some sub-embodiments, the linear or branched C_1-40 alkylene group is optionally substituted with one or more (e.g., 1-15, 1-12, 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, or 1) substituents selected from the group consisting of halogen, hydroxyl, cyano, amino, mercapto, C_1-3 alkyl, C_1-3 alkoxy, halogenated C_1-4 alkyl, C_5-10 aryl, C_5-10 heteroaryl, C_3-12 cycloalkyl, 4-to 12-membered heterocyclyl, or any combination thereof. In some sub-embodiments, each R_bis independently selected from the group consisting of optionally substituted C_3-20 cycloalkylene, optionally substituted C_5-20 arylene, optionally substituted 4-to 20-membered heterocyclylene, optionally substituted 5-to 20-membered heteroarylene, and any combination thereof, wherein the C_3- ₂₀ cycloalkylene and4-to 20-membered heterocyclylene are each independently optionally substituted with a substituent (s) selected from the group consisting of halogen, hydroxyl, cyano, amino, mercapto, oxo, C_1-3 alkyl, C_1-3 alkoxy, halogenated C_1-4 alkyl, C_5-10 aryl, C_5-10 heteroaryl, C_3-12 cycloalkyl, 4-to 12-membered heterocyclyl, or any combination thereof; and the C_5-20 arylene and 5-to 20-membered heteroarylene are each independently optionally substituted with a substituent (s) selected from the group consisting of halogen, hydroxyl, cyano, amino, mercapto, C_1-3 alkyl, C_1-3 alkoxy, halogenated C_1-4 alkyl, C_5-10 aryl, C_5-10 heteroaryl, C_3-12 cycloalkyl, 4-to 12-membered heterocyclyl, or any combination thereof.

In some embodiments, the L represents an optionally substituted linear or branched C_2-40 alkylene group (including C_2-30 alkylene, C_2-20 alkylene, C_2-15 alkylene, or C_2-10 alkylene) or methylene, wherein one or more groups selected from the group consisting of R_a, R_b, and any combination thereof are optionally inserted between one or more pairs of adjacent carbon atoms of the backbone carbon chain of the linear or branched C_2-40 alkylene group, wherein each R_a is independently selected from the group consisting of O, C (O) , OC (O) , S, S (O) , S (O) ₂, S (O) ₂N (R⁶) , N (R⁶) S (O) ₂, C (O) N (R⁶) , N (R⁶) C (O) , N (R⁶) , and N (R⁶) C (O) N (R⁶) , where each R⁶independently represents H or C_1-3 alkyl, and in case that two or more groups R_a are inserted into the backbone carbon chain of the linear or branched C_2-40 alkylene group, the two or more groups R_a are not directly connected to each other; and wherein each R_b is independently selected from the group consisting of optionally substituted C_3-20 cycloalkylene, optionally substituted C_5-20 arylene, optionally substituted 4-to 20-membered heterocyclylene, optionally substituted 5-to 20-membered heteroarylene, and any combination thereof. In some sub-embodiments, the linear or branched C_2-40 alkylene group and methylene are each independently optionally substituted with one or more (e.g., 1-15, 1-12, 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, or 1) substituents selected from the group consisting of halogen, hydroxyl, cyano, amino, mercapto, C_1-3 alkyl, C_1-3 alkoxy, halogenated C_1-4 alkyl, C_5-10 aryl, C_5-10 heteroaryl, C_3-12 cycloalkyl, 4-to 12-membered heterocyclyl, or any combination thereof. In some sub-embodiments, each R_b is independently selected from the group consisting of optionally substituted C_3-20 cycloalkylene, optionally substituted C_5-20 arylene, optionally substituted 4-to 20-membered heterocyclylene, optionally substituted 5-to 20-membered heteroarylene, and any combination thereof, wherein the C_3-20 cycloalkylene and 4-to 20-membered heterocyclylene are each independently optionally substituted with a substituent (s) selected from the group consisting of halogen, hydroxyl, cyano, amino, mercapto, oxo, C_1-3 alkyl, C_1-3 alkoxy, halogenated C_1-4 alkyl, C_5-10 aryl, C_5-10 heteroaryl, C_3-12 cycloalkyl, 4-to 12-membered heterocyclyl, or any combination thereof; and the C_5-20 arylene and 5-to 20-membered heteroarylene are each independently optionally substituted with a substituent (s) selected from the group consisting of halogen, hydroxyl, cyano, amino, mercapto, C_1-3 alkyl, C_1-3 alkoxy, halogenated C_1-4 alkyl, C_5-10 aryl, C_5-10 heteroaryl, C_3-12 cycloalkyl, 4-to 12-membered heterocyclyl, or any combination thereof.

In some embodiments, the L represents a linear or branched C_1-40 alkylene (including C_1-30 alkylene, C_1-20 alkylene, C_1-15 alkylene, or C_1-10 alkylene) , wherein one or more (e.g., 1-15, 1-12, 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, or 1) hydrogens of one or more (e.g., 1-15, 1-12, 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, or 1) CH₂of the linear or branched C_1-40 alkylene are optionally further replaced by one or more (e.g., 1-15, 1-12, 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, or 1) substituents selected from the group consisting of halogen, hydroxyl, cyano, amino, mercapto, C_1-3 alkyl, C_1-3 alkoxy, halogenated C_1-4 alkyl, C_5-10 aryl, C_5-10 heteroaryl, C_3-12 cycloalkyl, 4-to 12-membered heterocyclyl, or any combination thereof.

In some embodiments, the L represents-CH₂-; - (CH₂) ₂-; - (CH₂) ₃-; - (CH₂) ₄-; - (CH₂) ₅-; - (CH₂) ₆-; - (CH₂) ₇-; - (CH₂) ₈-; - (CH₂) ₉-; - (CH₂) ₁₀-; - (CH₂) ₁₁-; - (CH₂) ₁₂-; - (CH₂) ₁₃-; - (CH₂) ₁₄-; - (CH₂) ₁₅-; - (CH₂) ₁₆-; - (CH₂) ₁₇-; - (CH₂) ₁₈-; - (CH₂) ₁₉-; or- (CH₂) ₂₀-; wherein one or more hydrogens (e.g., 1-15, 1-12, 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, or 1) of one or more (e.g., 1-15, 1-12, 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, or 1) CH₂ of the groups are optionally further replaced by a substituent (s) selected from the group consisting of halogen, hydroxyl, cyano, amino, mercapto, C_1-3 alkyl, C_1-3 alkoxy, halogenated C_1-4 alkyl, C_5-10 aryl, C_5-10 heteroaryl, C_3-12 cycloalkyl, 4-to 12-membered heterocyclyl, or any combination thereof.

In some embodiments, the L represents-CH₂-; - (CH₂) ₂-; - (CH₂) ₃-; - (CH₂) ₄-; - (CH₂) ₅-; - (CH₂) ₆-; - (CH₂) ₇-; - (CH₂) ₈-; - (CH₂) ₉-; - (CH₂) ₁₀-; - (CH₂) ₁₁-; - (CH₂) ₁₂-; - (CH₂) ₁₃-; - (CH₂) ₁₄-; - (CH₂) ₁₅-; - (CH₂) ₁₆-; - (CH₂) ₁₇-; - (CH₂) ₁₈-; - (CH₂) ₁₉-; or- (CH₂) ₂₀-.

In some embodiments, the L represents:

*- (C (R_a1) (R_a2) ) _m1- (R_a- (C (R_a3) (R_a4) ) _m2) _m3-;

*- (C (R_a1) (R_a2) ) _m1- (R_a- (C (R_a3) (R_a4) ) _m2) _m3- (R_a- (C (R_a5) (R_a6) ) _m4) _m5-;

*- (C (R_a1) (R_a2) ) _m1- (R_a- (C (R_a3) (R_a4) ) _m2) _m3- (R_a- (C (R_a5) (R_a6) ) _m4) _m5- (R_a- (C (R_a7) (R_a8) ) _m6) _m7-;

*- (C (R_a1) (R_a2) ) _m1- (R_b- (C (R_a3) (R_a4) ) _m2) _m3-;

*- (C (R_a1) (R_a2) ) _m1- (R_b- (C (R_a3) (R_a4) ) _m2) _m3- (R_b- (C (R_a5) (R_a6) ) _m4) _m5-;

*- (C (R_a1) (R_a2) ) _m1- (R_b- (C (R_a3) (R_a4) ) _m2) _m3- (R_b- (C (R_a5) (R_a6) ) _m4) _m5- (R_b- (C (R_a7) (R_a8) ) _m6) _m7-;

*- (C (R_a1) (R_a2) ) _m1- (R_a-R_b- (C (R_a3) (R_a4) ) _m2) _m3-;

*- (C (R_a1) (R_a2) ) _m1- (R_a- (C (R_a3) (R_a4) ) _m2) _m3- (R_b- (C (R_a5) (R_a6) ) _m4) _m5-;

*- (C (R_a1) (R_a2) ) _m1- (R_b-R_a- (C (R_a3) (R_a4) ) _m2) _m3-; or

*- (C (R_a1) (R_a2) ) _m1- (R_b- (C (R_a3) (R_a4) ) _m2) _m3- (R_a- (C (R_a5) (R_a6) ) _m4) _m5-; or

wherein symbol*indicates the point of attachment to the U₂;

each R_ais independently selected from the group consisting of O, C (O) , OC (O) , S, S (O) , S (O) ₂, S (O) ₂N (R⁶) , N (R⁶) S (O) ₂, C (O) N (R⁶) , N (R⁶) C (O) , N (R⁶) , and N (R⁶) C (O) N (R⁶) , where each R⁶ independently represents H or C_1-3 alkyl;

each R_b is independently selected from the group consisting of optionally substituted C_3-20 cycloalkylene, optionally substituted C_5-20 arylene, optionally substituted 4-to 20-membered heterocyclylene, optionally substituted 5-to 20-membered heteroarylene, and any combination thereof;

R_a1, R_a2, R_a3, R_a4, R_a5, R_a6, R_a7, and R_a8 each independently represent hydrogen, halogen, hydroxyl, cyano, amino, mercapto, C_1-3 alkyl, C_1-3 alkoxy, halogenated C_1-4 alkyl, C_5-10 aryl, C_5-10 heteroaryl, C_3- ₁₂ cycloalkyl, or 4-to 12-membered heterocyclyl; and

m1, m2, m3, m4, m5, m6, and m7 each independently represent an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some sub-embodiments, the C_3-20 cycloalkylene and 4-to 20-membered heterocyclylene are each independently optionally substituted with a substituent (s) selected from the group consisting of halogen, hydroxyl, cyano, amino, mercapto, oxo, C_1-3 alkyl, C_1-3 alkoxy, halogenated C_1-4 alkyl, C_5-10 aryl, C_5-10 heteroaryl, C_3-12 cycloalkyl, 4-to 12-membered heterocyclyl, or any combination thereof; and the C_5-2 ₀ arylene and 5-to 20-membered heteroarylene are each independently optionally substituted with a substituent (s) selected from the group consisting of halogen, hydroxyl, cyano, amino, mercapto, C_1-3 alkyl, C_1-3 alkoxy, halogenated C_1-4 alkyl, C_5-10 aryl, C_5-10 heteroaryl, C_3-12 cycloalkyl, 4-to 12-membered heterocyclyl, or any combination thereof.

In some embodiments, the L represents:

*- (C (R_a1) (R_a2) ) _m1- (C_5-20 arylene- (C (R_a3) (R_a4) ) _m2) _m3-;

*- (C (R_a1) (R_a2) ) _m1- (C_5-20 arylene- (C (R_a3) (R_a4) ) _m2) _m3- (C_5-20 arylene- (C (R_a5) (R_a6) ) _m4) _m5-;

*- (C (R_a1) (R_a2) ) _m1- (C_5-20 arylene- (C (R_a3) (R_a4) ) _m2) _m3- (C_5-20 arylene- (C (R_a5) (R_a6) ) _m4) _m5- (C_5-20 arylene- (C (R_a7) (R_a8) ) _m6) _m7-;

*- (C (R_a1) (R_a2) ) _m1- (5-to 20-membered heteroarylene- (C (R_a3) (R_a4) ) _m2) _m3-;

*- (C (R_a1) (R_a2) ) _m1- (5-to 20-membered heteroarylene- (C (R_a3) (R_a4) ) _m2) _m3- (5-to 20-membered heteroarylene- (C (R_a5) (R_a6) ) _m4) _m5-;

*- (C (R_a1) (R_a2) ) _m1- (5-to 20-membered heteroarylene- (C (R_a3) (R_a4) ) _m2) _m3- (5-to 20-membered heteroarylene- (C (R_a5) (R_a6) ) _m4) _m5- (5-to 20-membered heteroarylene- (C (R_a7) (R_a8) ) _m6) _m7-;

*- (C (R_a1) (R_a2) ) _m1- (4-to 20-membered heterocyclylene- (C (R_a3) (R_a4) ) _m2) _m3-;

*- (C (R_a1) (R_a2) ) _m1- (4-to 20-membered heterocyclylene- (C (R_a3) (R_a4) ) _m2) _m3- (4-to 20-membered heterocyclylene- (C (R_a5) (R_a6) ) _m4) _m5-;

*- (C (R_a1) (R_a2) ) _m1- (C_3-20 cycloalkylene- (C (R_a3) (R_a4) ) _m2) _m3-;

*- (C (R_a1) (R_a2) ) _m1- (C_3-20 cycloalkylene- (C (R_a3) (R_a4) ) _m2) _m3- (C_3-20 cycloalkylene- (C (R_a5) (R_a6) ) _m4) _m5-;

*- (C (R_a1) (R_a2) ) _m1- (C_3-20 cycloalkylene-N (R₆) - (C (R_a3) (R_a4) ) _m2) _m3-;

*- (C (R_a1) (R_a2) ) _m1- (O- (C (R_a3) (R_a4) ) _m2) _m3-;

*- (C (R_a1) (R_a2) ) _m1- (O- (C (R_a3) (R_a4) ) _m2) _m3- (O- (C (R_a5) (R_a6) ) _m4) _m5-;

*- (C (R_a1) (R_a2) ) _m1- (O- (C (R_a3) (R_a4) ) _m2) _m3- (O- (C (R_a5) (R_a6) ) _m4) _m5- (O- (C (R_a7) (R_a8) ) _m6) _m7-;

*- (C (R_a1) (R_a2) ) _m1- (S- (C (R_a3) (R_a4) ) _m2) _m3-;

*- (C (R_a1) (R_a2) ) _m1- (S- (C (R_a3) (R_a4) ) _m2) _m3- (S- (C (R_a5) (R_a6) ) _m4) _m5-;

*- (C (R_a1) (R_a2) ) _m1- (S- (C (R_a3) (R_a4) ) _m2) _m3- (S- (C (R_a5) (R_a6) ) _m4) _m5- (S- (C (R_a7) (R_a8) ) _m6) _m7-;

*- (C (R_a1) (R_a2) ) _m1- (S (O) - (C (R_a3) (R_a4) ) _m2) _m3-;

*- (C (R_a1) (R_a2) ) _m1- (S (O) ₂- (C (R_a3) (R_a4) ) _m2) _m3-;

*- (C (R_a1) (R_a2) ) _m1- (S- (C (R_a3) (R_a4) ) _m2) _m3-;

*- (C (R_a1) (R_a2) ) _m1- (S (O) ₂N (R⁶) - (C (R_a3) (R_a4) ) _m2) _m3-;

*- (C (R_a1) (R_a2) ) _m1- (N (R⁶) S (O) ₂- (C (R_a3) (R_a4) ) _m2) _m3-;

*- (C (R_a1) (R_a2) ) _m1- (C (O) N (R⁶) - (C (R_a3) (R_a4) ) _m2) _m3-;

*- (C (R_a1) (R_a2) ) _m1- (N (R⁶) C (O) - (C (R_a3) (R_a4) ) _m2) _m3-;

*- (C (R_a1) (R_a2) ) _m1- (N (R⁶) - (C (R_a3) (R_a4) ) _m2) _m3-; or

*- (C (R_a1) (R_a2) ) _m1- (N (R⁶) C (O) N (R⁶) - (C (R_a3) (R_a4) ) _m2) _m3-;

wherein symbol*indicates the point of attachment to the U₂;

R_a1, R_a2, R_a3, R_a4, R_a5, R_a6, R_a7, and R_a8 each independently represent hydrogen, halogen, hydroxyl, cyano, amino, mercapto, C_1-3 alkyl, C_1-3 alkoxy, halogenated C_1-4 alkyl, C_5-10 aryl, C_5-10 heteroaryl, C_3- ₁₂ cycloalkyl, or4-to 12-membered heterocyclyl;

m1, m2, m3, m4, m5, m6, and m7 each independently represent an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20;

each R⁶ independently represents H or C_1-3 alkyl;

the C_5-20 arylene and 5-to 20-membered heteroarylene are each independently optionally further substituted with a substituent (s) selected from the group consisting of halogen, hydroxyl, cyano, amino, mercapto, C_1-3 alkyl, C_1-3 alkoxy, halogenated C_1-4 alkyl, C_5-10 aryl, C_5-10 heteroaryl, C_3-12 cycloalkyl, 4-to 12-membered heterocyclyl, or any combination thereof; and

the 4-to 20-membered heterocyclylene and C_3-20 cycloalkylene are each independently optionally further substituted with a substituent (s) selected from the group consisting of halogen, hydroxyl, cyano, amino, mercapto, oxo, C_1-3 alkyl, C_1-3 alkoxy, halogenated C_1-4 alkyl, C_5-10 aryl, C_5-10 heteroaryl, C_3-12 cycloalkyl, 4-to 12-membered heterocyclyl, or any combination thereof.

In some embodiments, the L represents:

a linear or branched C_1-40 alkylene, *- (CH₂) _m1- (O- (CH₂) _m2) _m3-, *- (CH₂) _m1- (O- (CH₂) _m2) _m3- (O- (CH₂) _m4) _m5-, *- (CH₂) _m1- (O- (CH₂) _m2) _m3- (O- (CH₂) _m4) _m5- (O- (CH₂) _m6) _m7-, *- (CH₂) _m1-C (O) N (R⁶) - (CH₂) _m2-, *- (CH₂) _m1- (C (O) N (R⁶) - (CH₂) _m2) _m3-, *- (CH₂) _m1-N (R⁶) C (O) - (CH₂) _m2-, *- (CH₂) _m1- (N (R⁶) C (O) - (CH₂) _m2) _m3-, *- (CH₂) _m1-N (R⁶) C (O) N (R⁶) - (CH₂) _m2-, *- (CH₂) _m1-S- (CH₂) _m2-, *- (CH₂) _m1-S (O) - (CH₂) _m2-, *- (CH₂) _m1-S (O) ₂- (CH₂) _m2-, *- (CH₂) _m1-N (R⁶) S (O) ₂- (CH₂) _m2-, *- (CH₂) _m1-S (O) ₂N (R⁶) - (CH₂) _m2-, *- (CH₂) _m1-N (R⁶) - (CH₂) _m2-, *- (CH₂) _m1-phenylene- (CH₂) _m2-, *- (CH₂) _m1-phenylene- (CH₂) _m2-N (R⁶) - (CH₂) _m3-, *- (CH₂) _m1-piperazinylene- (CH₂) _m2-, *- (CH₂) _m1-piperidinylene- (CH₂) _m2-, *- (CH₂) _m1-piperidinylene-N (R⁶) - (CH₂) _m2-, *- (CH₂) _m1-cyclohexylene- (CH₂) _m2-, *- (CH₂) _m1-cyclohexylene-N (R⁶) - (CH₂) _m2-, *- (CH₂) _m1-furanylene- (CH₂) _m2-, *- (CH₂) _m1-furanylene- (CH₂) _m2-N (R⁶) - (CH₂) _m3-, *- (CH₂) _m1-thiazolylene- (CH₂) _m2-, *- (CH₂) _m1-thiazolylene-C (O) N (R⁶) - (CH₂) _m2-, *- (CH₂) _m1-thiazolylene- (CH₂) _m2-N (R⁶) - (CH₂) _m3-, *- (CH₂) _m1-triazolylene- (CH₂) _m2-, *- (CH₂) _m1-triazolylene-C (O) N (R⁶) - (CH₂) _m2-, *- (CH₂) _m1-triazolylene- (CH₂) _m2-N (R⁶) - (CH₂) _m3-, *- (CH₂) _m1-pyridylene- (CH₂) _m2-, *- (CH₂) _m1-pyridylene-C (O) N (R⁶) - (CH₂) _m2-, or*- (CH₂) _m1-pyridylene- (CH₂) _m2-N (R⁶) - (CH₂) _m3-,

wherein one or more hydrogens of one or more CH₂of the linear or branched C_1-40 alkylene are optionally further replaced by a substituent (s) selected from the group consisting of halogen, hydroxyl, cyano, amino, mercapto, C_1-3 alkyl, C_1-3 alkoxy, halogenated C_1-4 alkyl, C_5-10 aryl, C_5-10 heteroaryl, C_3- ₁₂ cycloalkyl, 4-to 12-membered heterocyclyl, or any combination thereof;

the symbol*indicates the point of attachment to the U₂;

each R⁶independently represents H or C_1-3 alkyl;

the phenylene, furanylene, thiazolylene, triazolylene, and pyridylene are each independently optionally further substituted with a substituent (s) selected from the group consisting of halogen, hydroxyl, cyano, amino, mercapto, C_1-3 alkyl, C_1-3 alkoxy, halogenated C_1-4 alkyl, C_5-10 aryl, C_5-10 heteroaryl, C_3-12 cycloalkyl, 4-to 12-membered heterocyclyl, or any combination thereof; and

the piperidinylene, piperazinylene, and cyclohexylene are each independently optionally further substituted with a substituent (s) selected from the group consisting of halogen, hydroxyl, cyano, amino, mercapto, oxo, C_1-3 alkyl, C_1-3 alkoxy, halogenated C_1-4 alkyl, C_5-10 aryl, C_5-10 heteroaryl, C_3-12 cycloalkyl, 4-to 12-membered heterocyclyl, or any combination thereof.

In some embodiments, the L represents one of the following groups:

-CH₂-; - (CH₂) ₂-; - (CH₂) ₃-; - (CH₂) ₄-; - (CH₂) ₅-; - (CH₂) ₆-; - (CH₂) ₇-; - (CH₂) ₈-; - (CH₂) ₉-; - (CH₂) ₁₀-; - (CH₂) ₁₁-; - (CH₂) ₁₂-; - (CH₂) ₁₃-; - (CH₂) ₁₄-; - (CH₂) ₁₅-; - (CH₂) ₁₆-; - (CH₂) ₁₇-; - (CH₂) ₁₈-; - (CH₂) ₁₉-; or- (CH₂) ₂₀-;

*-CH₂OCH₂CH₂-; *-CH₂- (OCH₂CH₂) ₂-; *-CH₂- (OCH₂CH₂) ₃-; *-CH₂- (OCH₂CH₂) ₄-; *-CH₂- (OCH₂CH₂) ₅-; *-CH₂- (OCH₂CH₂) ₆-; *-CH₂- (OCH₂CH₂) ₇-; *-CH₂- (OCH₂CH₂) ₈-; *-CH₂- (OCH₂CH₂) ₉-; *-CH₂- (OCH₂CH₂) ₁₀-; *- (CH₂CH₂O) ₁-CH₂-; *- (CH₂CH₂O) ₂-CH₂-; *- (CH₂CH₂O) ₃-CH₂-; *- (CH₂CH₂O) ₄-CH₂-; *- (CH₂CH₂O) ₅-CH₂-; *- (CH₂CH₂O) ₆-CH₂-; *- (CH₂CH₂O) ₇-CH₂-; *- (CH₂CH₂O) ₈-CH₂-; *- (CH₂CH₂O) ₉-CH₂-; *- (CH₂CH₂O) ₁₀-CH₂-; *- (CH₂) ₂-OCH₂CH₂-; *- (CH₂) ₂- (OCH₂CH₂) ₂-; *- (CH₂) ₂- (OCH₂CH₂) ₃-; *- (CH₂) ₂- (OCH₂CH₂) ₄-; *- (CH₂) ₂- (OCH₂CH₂) ₅-; *- (CH₂) ₂- (OCH₂CH₂) ₆-; *- (CH₂) ₂- (OCH₂CH₂) ₇-; *- (CH₂) ₂- (OCH₂CH₂) ₈-; *- (CH₂) ₂- (OCH₂CH₂) ₉-; *- (CH₂) ₂- (OCH₂CH₂) ₁₀-; *-CH₂CH₂O (CH₂) ₂-; *- (CH₂CH₂O) ₂- (CH₂) ₂-; *- (CH₂CH₂O) ₃- (CH₂) ₂-; *- (CH₂CH₂O) ₄- (CH₂) ₂-; *- (CH₂CH₂O) ₅- (CH₂) ₂-; *- (CH₂CH₂O) ₆- (CH₂) ₂-; *- (CH₂CH₂O) ₇- (CH₂) ₂-; *- (CH₂CH₂O) ₈- (CH₂) ₂-; *- (CH₂CH₂O) ₉ (CH₂) ₂-; *- (CH₂CH₂O) ₁₀ (CH₂) ₂-; *- (CH₂) ₃-OCH₂CH₂-; *- (CH₂) ₃- (OCH₂CH₂) ₂-; *- (CH₂) ₃- (OCH₂CH₂) ₃-; *- (CH₂) ₃- (OCH₂CH₂) ₄-; *- (CH₂) ₃- (OCH₂CH₂) ₅-; *- (CH₂) ₃- (OCH₂CH₂) ₆-; *- (CH₂) ₃- (OCH₂CH₂) ₇-; *- (CH₂) ₃- (OCH₂CH₂) ₈-; *- (CH₂) ₃- (OCH₂CH₂) ₉-; *- (CH₂) ₃- (OCH₂CH₂) ₁₀-; *-CH₂CH₂O (CH₂) ₃-; *- (CH₂CH₂O) ₂- (CH₂) ₃-; *- (CH₂CH₂O) ₃- (CH₂) ₃-; *- (CH₂CH₂O) ₄- (CH₂) ₃-; *- (CH₂CH₂O) ₅- (CH₂) ₃-; *- (CH₂CH₂O) ₆- (CH₂) ₃-; *- (CH₂CH₂O) ₇- (CH₂) ₃-; *- (CH₂CH₂O) ₈- (CH₂) ₃-; *- (CH₂CH₂O) ₉ (CH₂) ₃-; *- (CH₂CH₂O) ₁₀ (CH₂) ₃-; *-CH₂CH₂OCH₂CH₂CH₂OCH₂-; *-CH₂CH₂OCH₂CH₂CH₂O- (CH₂) ₂-; *-CH₂CH₂OCH₂CH₂CH₂O- (CH₂) ₃-; *- (CH₂CH₂O) ₂ (CH₂CH₂CH₂O) (CH₂) ₃-; *- (CH₂CH₂O) ₂ (CH₂CH₂CH₂O) ₂ (CH₂) ₃-; *- (CH₂) ₁O (CH₂) ₁-; *- (CH₂) ₂O (CH₂) ₂-; *- (CH₂) ₂O (CH₂) ₃-; *- (CH₂) ₂O (CH₂) ₄-; *- (CH₂) ₂O (CH₂) ₅-; *- (CH₂) ₂O (CH₂) ₆-; *- (CH₂) ₃O (CH₂) ₁-; *- (CH₂) ₃O (CH₂) ₂-; *- (CH₂) ₃O (CH₂) ₃-; *- (CH₂) ₄O (CH₂) ₁-; *- (CH₂) ₄O (CH₂) ₂-; *- (CH₂) ₄O (CH₂) ₃-; *- (CH₂) ₅O (CH₂) ₁-; *- (CH₂) ₅O (CH₂) ₂-; *- (CH₂) ₅O (CH₂) ₃-; *- (CH₂) ₅O (CH₂) ₄-; or*- (CH₂) ₅O (CH₂) ₅-;

*-(CH₂) ₁-NH- (CH₂) ₁-; *- (CH₂) ₂-NH- (CH₂) ₁-; *- (CH₂) ₂-NH- (CH₂) ₂-; *- (CH₂) ₂-NH- (CH₂) ₃-; *- (CH₂) ₂-NH- (CH₂) ₄-; *- (CH₂) ₂-NH- (CH₂) ₅-; *- (CH₂) ₂-NH- (CH₂) ₆-; *- (CH₂) ₂-NH- (CH₂) ₇-; *- (CH₂) ₂- NH-(CH₂) ₈-; *- (CH₂) ₂-NH- (CH₂) ₉-; *- (CH₂) ₂-NH- (CH₂) ₁₀-; *- (CH₂) ₂-NH- (CH₂) ₁₁-; *- (CH₂) ₂-NH- (CH₂) ₁₂-; *- (CH₂) ₃-NH- (CH₂) ₁-; *- (CH₂) ₃-NH- (CH₂) ₂-; *- (CH₂) ₃-NH- (CH₂) ₃-; *- (CH₂) ₄-NH- (CH₂) ₁-; *- (CH₂) ₄-NH- (CH₂) ₂-; *- (CH₂) ₅-NH- (CH₂) ₃-; *- (CH₂) ₅-NH- (CH₂) ₁-; *- (CH₂) ₅-NH- (CH₂) ₂-; *- (CH₂) ₈-NH-(CH₂) ₂-; *- (CH₂) ₅-NH- (CH₂) ₃-; *- (CH₂) ₅-NH- (CH₂) ₄-; *- (CH₂) ₅-NH- (CH₂) ₅-; *- (CH₂) ₁-N (CH₃) - (CH₂) ₈-; *- (CH₂) ₂-N (CH₃) - (CH₂) ₁-; *- (CH₂) ₃-N (CH₃) - (CH₂) ₁-; *- (CH₂) ₄-N (CH₃) - (CH₂) ₁-; *- (CH₂) ₅-N (CH₃) - (CH₂) ₁-; *- (CH₂) ₆-N (CH₃) - (CH₂) ₁-; *- (CH₂) ₂-N (CH₃) - (CH₂) ₂-; *- (CH₂) ₂-N (CH₃) - (CH₂) ₃-; *- (CH₂) ₂-N (CH₃) - (CH₂) ₄-; *- (CH₂) ₂-N (CH₃) - (CH₂) ₅-; *- (CH₂) ₂-N (CH₃) - (CH₂) ₆-; *- (CH₂) ₂-N (CH₃) -(CH₂) ₇-; *- (CH₂) ₂-N (CH₃) - (CH₂) ₈-; *- (CH₂) ₂-N (CH₃) - (CH₂) ₉-; *- (CH₂) ₂-N (CH₃) - (CH₂) ₁₀-; *- (CH₂) ₂-N (CH₃) - (CH₂) ₁₁-; *- (CH₂) ₂-N (CH₃) - (CH₂) ₁₂-; *- (CH₂) ₂-NHC (O) -CH₂-; *- (CH₂) ₂-NHC (O) - (CH₂) ₂-; *- (CH₂) ₂-NHC (O) - (CH₂) ₃-; *- (CH₂) ₂-NHC (O) - (CH₂) ₄-; *- (CH₂) ₂-NHC (O) - (CH₂) ₅-; *- (CH₂) ₂-NHC (O) - (CH₂) ₆-; *- (CH₂) ₂-NHC (O) - (CH₂) ₇-; *- (CH₂) ₂-NHC (O) - (CH₂) ₈-; *- (CH₂) ₂-NHC (O) - (CH₂) ₉-; *- (CH₂) ₂-NHC (O) - (CH₂) ₁₀-; *- (CH₂) ₂-NHC (O) - (CH₂) ₁₁-; *- (CH₂) ₂-NHC (O) - (CH₂) ₁₂-; *- (CH₂) ₂-NHC (O) - (CH₂) ₁₃-; *- (CH₂) ₂-NHC (O) - (CH₂) ₁₄-; *- (CH₂) ₂-NHC (O) - (CH₂) ₁₅-; *- (CH₂) ₃-NHC (O) -CH₂-; *- (CH₂) ₃-NHC (O) - (CH₂) ₂-; *- (CH₂) ₃-NHC (O) - (CH₂) ₃-; *- (CH₂) ₃-NHC (O) - (CH₂) ₄-; *- (CH₂) ₃-NHC (O) - (CH₂) ₅-; *- (CH₂) ₃-NHC (O) - (CH₂) ₆-; *- (CH₂) ₃-NHC (O) - (CH₂) ₇-; *- (CH₂) ₃-NHC (O) - (CH₂) ₈-; *- (CH₂) ₃-NHC (O) - (CH₂) ₉-; *- (CH₂) ₃-NHC (O) - (CH₂) ₁₀-; *- (CH₂) ₃-NHC (O) - (CH₂) ₁₁-; *- (CH₂) ₃-NHC (O) - (CH₂) ₁₂-; *- (CH₂) ₃-NHC (O) - (CH₂) ₁₃-; *- (CH₂) ₃-NHC (O) - (CH₂) ₁₄-; *- (CH₂) ₃-NHC (O) - (CH₂) ₁₅-; *- (CH₂) ₄NHC (O) (CH₂) ₁-; *- (CH₂) ₄NHC (O) (CH₂) ₂-; *- (CH₂) ₄NHC (O) (CH₂) ₃-; *- (CH₂) ₄NHC (O) (CH₂) ₄-; *- (CH₂) ₄NHC (O) (CH₂) ₅-; *- (CH₂) ₄NHC (O) (CH₂) ₆-; *- (CH₂) ₄NHC (O) (CH₂) ₇-; *- (CH₂) ₄NHC (O) (CH₂) ₈-; *- (CH₂) ₄NHC (O) (CH₂) ₉-; *- (CH₂) ₄NHC (O) (CH₂) ₁₀-; *- (CH₂) ₅NHC (O) (CH₂) ₁-; *- (CH₂) ₈NHC (O) (CH₂) ₂-; *- (CH₂) ₂-N (CH₃) C (O) -CH₂-; *- (CH₂) ₂-N (CH₃) C (O) - (CH₂) ₂-; *- (CH₂) ₂-N (CH₃) C (O) - (CH₂) ₃-; *- (CH₂) ₂-N (CH₃) C (O) - (CH₂) ₄-; *- (CH₂) ₂-N (CH₃) C (O) - (CH₂) ₅-; *- (CH₂) ₂-N (CH₃) C (O) - (CH₂) ₆-; *- (CH₂) ₂-N (CH₃) C (O) - (CH₂) ₇-; *- (CH₂) ₂-N (CH₃) C (O) - (CH₂) ₈-; *- (CH₂) ₂-N (CH₃) C (O) - (CH₂) ₉-; *- (CH₂) ₂-N (CH₃) C (O) - (CH₂) ₁₀-; *- (CH₂) ₂-N (CH₃) C (O) - (CH₂) ₁₁-; *- (CH₂) ₂-N (CH₃) C (O) - (CH₂) ₁₂-; *- (CH₂) ₂-N (CH₃) C (O) - (CH₂) ₁₃-; *- (CH₂) ₂-N (CH₃) C (O) - (CH₂) ₁₄-; *- (CH₂) ₂-N (CH₃) C (O) - (CH₂) ₁₅-; *- (CH₂) ₂-C (O) NH-CH₂-; *- (CH₂) ₂-C (O) NH- (CH₂) ₂-; *- (CH₂) ₂-C (O) NH- (CH₂) ₃-; *- (CH₂) ₂-C (O) NH- (CH₂) ₄-; *- (CH₂) ₂-C (O) NH- (CH₂) ₅-; *- (CH₂) ₂-C (O) NH- (CH₂) ₆-; *- (CH₂) ₂-C (O) NH- (CH₂) ₇-; *- (CH₂) ₂-C (O) NH- (CH₂) ₈-; *- (CH₂) ₂-C (O) NH- (CH₂) ₉-; *- (CH₂) ₂-C (O) NH- (CH₂) ₁₀-; *- (CH₂) ₂-C (O) NH- (CH₂) ₁₁-; *- (CH₂) ₂-C (O) NH- (CH₂) ₁₂-; *- (CH₂) ₂-C (O) NH- (CH₂) ₁₃-; *- (CH₂) ₂-C (O) NH- (CH₂) ₁₄-; *- (CH₂) ₂-C (O) NH- (CH₂) ₁₅-; *- (CH₂) ₃-C (O) NH-CH₂-; *- (CH₂) ₃-C (O) NH- (CH₂) ₂-; *- (CH₂) ₃-C (O) NH- (CH₂) ₃-; *- (CH₂) ₃-C (O) NH- (CH₂) ₄-; *- (CH₂) ₃-C (O) NH- (CH₂) ₅-; *- (CH₂) ₃-C (O) NH- (CH₂) ₆-; *- (CH₂) ₃-C (O) NH- (CH₂) ₇-; *- (CH₂) ₃-C (O) NH- (CH₂) ₈-; *- (CH₂) ₃-C (O) NH- (CH₂) ₉-; *- (CH₂) ₃-C (O) NH- (CH₂) ₁₀-; *- (CH₂) ₃- C (O) NH- (CH₂) ₁₁-; *- (CH₂) ₃-C (O) NH- (CH₂) ₁₂-; *- (CH₂) ₃-C (O) NH- (CH₂) ₁₃-; *- (CH₂) ₃-C (O) NH- (CH₂) ₁₄-; *- (CH₂) ₃-C (O) NH- (CH₂) ₁₅-; *- (CH₂) ₄C (O) NH (CH₂) ₁-; *- (CH₂) ₄C (O) NH (CH₂) ₂-; *- (CH₂) ₄C (O) NH (CH₂) ₃-; *- (CH₂) ₄C (O) NH (CH₂) ₄-; *- (CH₂) ₄C (O) NH (CH₂) ₅-; *- (CH₂) ₄C (O) NH (CH₂) ₆-; *- (CH₂) ₄C (O) NH (CH₂) ₇-; *- (CH₂) ₄C (O) NH (CH₂) ₈-; *- (CH₂) ₄C (O) NH (CH₂) ₉-; *- (CH₂) ₄C (O) NH (CH₂) ₁₀-; *- (CH₂) ₂-C (O) N (CH₃) -CH₂-; *- (CH₂) ₂-C (O) N (CH₃) - (CH₂) ₂-; *- (CH₂) ₂-C (O) N (CH₃) - (CH₂) ₃-; *- (CH₂) ₂-C (O) N (CH₃) - (CH₂) ₄-; *- (CH₂) ₂-C (O) N (CH₃) - (CH₂) ₅-; *- (CH₂) ₂-C (O) N (CH₃) - (CH₂) ₆-; *- (CH₂) ₂-C (O) N (CH₃) - (CH₂) ₇-; *- (CH₂) ₂-C (O) N (CH₃) - (CH₂) ₈-; *- (CH₂) ₂-C (O) N (CH₃) - (CH₂) ₉-; *- (CH₂) ₂-C (O) N (CH₃) - (CH₂) ₁₀-; *- (CH₂) ₂-C (O) N (CH₃) - (CH₂) ₁₁-; *- (CH₂) ₂-C (O) N (CH₃) - (CH₂) ₁₂-; *- (CH₂) ₂-C (O) N (CH₃) - (CH₂) ₁₃-; *- (CH₂) ₂-C (O) N (CH₃) - (CH₂) ₁₄-; *- (CH₂) ₂-C (O) N (CH₃) - (CH₂) ₁₅-; *- (CH₂) ₂-NHC (O) NH- (CH₂) ₄-; *- (CH₂) ₄-NHC (O) NH- (CH₂) ₂-; *-CH₂-NHC (O) NH- (CH₂) ₂-; *- (CH₂) ₂-NHC (O) NH-CH₂-; *- (CH₂) ₂-NHC (O) NH- (CH₂) ₂-; *- (CH₂) ₂-NHC (O) NH- (CH₂) ₃-; *- (CH₂) ₃-NHC (O) NH- (CH₂) ₂-; *-CH₂-piperazinylene-CH₂-; *- (CH₂) ₂-piperazinylene- (CH₂) ₂-; *- (CH₂) ₂-piperazinylene- (CH₂) ₃-; *- (CH₂) ₂-piperazinylene- (CH₂) ₄-; *- (CH₂) ₂-piperazinylene- (CH₂) ₅-; *- (CH₂) ₃-piperazinylene-CH₂-; *- (CH₂) ₃-piperazinylene- (CH₂) ₂-; *- (CH₂) ₃-piperazinylene- (CH₂) ₃-; *- (CH₂) ₄-piperazinylene-CH₂-; *- (CH₂) ₄-piperazinylene- (CH₂) ₂-; *- (CH₂) ₄-piperazinylene- (CH₂) ₃-; *- (CH₂) ₈-piperazinylene-CH₂-; *- (CH₂) ₈-piperazinylene- (CH₂) ₂-; *- (CH₂) ₈-piperazinylene- (CH₂) ₃-; *- (CH₂) ₈-piperazinylene- (CH₂) ₄-; *- (CH₂) ₈-piperazinylene- (CH₂) ₅-; *- (CH₂) ₈-piperazinylene- (CH₂) ₆-; *- (CH₂) ₈-piperazinylene- (CH₂) ₇-; *- (CH₂) ₈-piperazinylene- (CH₂) ₈-; *-CH₂-piperazinylene- (CH₂) ₈-; *- (CH₂) ₂-piperazinylene- (CH₂) ₈-; *- (CH₂) ₃-piperazinylene- (CH₂) ₈-; *- (CH₂) ₄-piperazinylene- (CH₂) ₈-; *- (CH₂) ₅-piperazinylene- (CH₂) ₈-; *- (CH₂) ₆-piperazinylene- (CH₂) ₈-; *- (CH₂) ₇-piperazinylene- (CH₂) ₈-; *-CH₂-phenylene-CH₂-; *- (CH₂) ₁-phenylene- (CH₂) ₂-; *- (CH₂) ₁-phenylene- (CH₂) ₃-; *- (CH₂) ₁-phenylene- (CH₂) ₄-; *- (CH₂) ₁-phenylene- (CH₂) ₅-; *- (CH₂) ₂-phenylene- (CH₂) ₁-; *- (CH₂) ₂-phenylene- (CH₂) ₂-; *- (CH₂) ₂-phenylene- (CH₂) ₃-; *- (CH₂) ₂-phenylene- (CH₂) ₄-; *- (CH₂) ₂-phenylene- (CH₂) ₅-; *- (CH₂) ₃-phenylene-CH₂-; *- (CH₂) ₃-phenylene- (CH₂) ₂-; *- (CH₂) ₃-phenylene- (CH₂) ₃-; *- (CH₂) ₄-phenylene-CH₂-; *- (CH₂) ₄-phenylene- (CH₂) ₂-; *- (CH₂) ₄-phenylene- (CH₂) ₃-; *- (CH₂) ₅-phenylene- (CH₂) ₃-; *- (CH₂) ₆-phenylene- (CH₂) ₃-; *- (CH₂) ₇-phenylene- (CH₂) ₃-; *- (CH₂) ₈-phenylene-CH₂-; *- (CH₂) ₈-phenylene- (CH₂) ₂-; *- (CH₂) ₈-phenylene- (CH₂) ₃-; *- (CH₂) ₈-phenylene- (CH₂) ₄-; *- (CH₂) ₈-phenylene- (CH₂) ₅-; *- (CH₂) ₈-phenylene- (CH₂) ₆-; *- (CH₂) ₈-phenylene- (CH₂) ₇-; *- (CH₂) ₈-phenylene- (CH₂) ₈-; *-CH₂-phenylene- (CH₂) ₈-; *- (CH₂) ₂-phenylene- (CH₂) ₈-; *- (CH₂) ₃-phenylene- (CH₂) ₈-; *- (CH₂) ₄-phenylene- (CH₂) ₈-; *- (CH₂) ₅-phenylene- (CH₂) ₈-; *- (CH₂) ₆-phenylene- (CH₂) ₈-; *- (CH₂) ₇-phenylene- (CH₂) ₈-; *-CH₂-piperidinylene-CH₂-; *- (CH₂) ₂-piperidinylene- (CH₂) ₂-; *- (CH₂) ₂-piperidinylene- (CH₂) ₃-; *- (CH₂) ₂-piperidinylene- (CH₂) ₄-; *- (CH₂) ₂-piperidinylene- (CH₂) ₅-; *- (CH₂) ₃-piperidinylene-CH₂-; *- (CH₂) ₃-piperidinylene- (CH₂) ₂-; *- (CH₂) ₃-piperidinylene- (CH₂) ₃-; *- (CH₂) ₄-piperidinylene-CH₂-; *- (CH₂) ₄-piperidinylene- (CH₂) ₂-; *- (CH₂) ₄-piperidinylene- (CH₂) ₃-; *- (CH₂) ₅-piperidinylene- (CH₂) ₃-; *- (CH₂) ₆-piperidinylene- (CH₂) ₃-; *- (CH₂) ₇-piperidinylene- (CH₂) ₃-; *- (CH₂) ₈-piperidinylene-CH₂-; *- (CH₂) ₈-piperidinylene- (CH₂) ₂-; *- (CH₂) ₈-piperidinylene- (CH₂) ₃-; *- (CH₂) ₈-piperidinylene- (CH₂) ₄-; *- (CH₂) ₈-piperidinylene- (CH₂) ₅-; *- (CH₂) ₈-piperidinylene- (CH₂) ₆-; *- (CH₂) ₈-piperidinylene- (CH₂) ₇-; *- (CH₂) ₈-piperidinylene- (CH₂) ₈-; *-CH₂-piperidinylene- (CH₂) ₈-; *- (CH₂) ₂-piperidinylene- (CH₂) ₈-; *- (CH₂) ₃-piperidinylene- (CH₂) ₈-; *- (CH₂) ₄-piperidinylene- (CH₂) ₈-; *- (CH₂) ₅-piperidinylene- (CH₂) ₈-; *- (CH₂) ₆-piperidinylene- (CH₂) ₈-; *- (CH₂) ₇-piperidinylene- (CH₂) ₈-; *-CH₂-cyclohexylene-CH₂-; *- (CH₂) ₂-cyclohexylene- (CH₂) ₂-; *- (CH₂) ₂-cyclohexylene- (CH₂) ₃-; *- (CH₂) ₂-cyclohexylene- (CH₂) ₄-; *- (CH₂) ₂-cyclohexylene- (CH₂) ₅-; *- (CH₂) ₃-cyclohexylene-CH₂-; *- (CH₂) ₃-cyclohexylene- (CH₂) ₂-; *- (CH₂) ₃-cyclohexylene- (CH₂) ₃-; *- (CH₂) ₄-cyclohexylene-CH₂-; *- (CH₂) ₄-cyclohexylene- (CH₂) ₂-; *- (CH₂) ₄-cyclohexylene- (CH₂) ₃-; *- (CH₂) ₅-cyclohexylene- (CH₂) ₃-; *- (CH₂) ₆-cyclohexylene- (CH₂) ₃-; *- (CH₂) ₇-cyclohexylene- (CH₂) ₃-; *- (CH₂) ₈-cyclohexylene-CH₂-; *- (CH₂) ₈-cyclohexylene- (CH₂) ₂-; *- (CH₂) ₈-cyclohexylene- (CH₂) ₃-; *- (CH₂) ₈-cyclohexylene- (CH₂) ₄-; *- (CH₂) ₈-cyclohexylene- (CH₂) ₅-; *- (CH₂) ₈-cyclohexylene- (CH₂) ₆-; *- (CH₂) ₈-cyclohexylene- (CH₂) ₇-; *- (CH₂) ₈-cyclohexylene- (CH₂) ₈-; *-CH₂-cyclohexylene- (CH₂) ₈-; *- (CH₂) ₂-cyclohexylene- (CH₂) ₈-; *- (CH₂) ₃-cyclohexylene- (CH₂) ₈-; *- (CH₂) ₄-cyclohexylene- (CH₂) ₈-; *- (CH₂) ₅-cyclohexylene- (CH₂) ₈-; *- (CH₂) ₆-cyclohexylene- (CH₂) ₈-; *- (CH₂) ₇- cyclohexylene- (CH₂) ₈-; *-CH₂-cyclohexylene-NH-CH₂-; *- (CH₂) ₂-cyclohexylene-NH- (CH₂) ₂-; *- (CH₂) ₂-cyclohexylene-NH- (CH₂) ₃-; *- (CH₂) ₂-cyclohexylene-NH- (CH₂) ₄-; *- (CH₂) ₂-cyclohexylene-NH- (CH₂) ₅-; *- (CH₂) ₃-cyclohexylene-NH-CH₂-; *- (CH₂) ₃-cyclohexylene-NH- (CH₂) ₂-; *- (CH₂) ₃-cyclohexylene-NH- (CH₂) ₃-; *- (CH₂) ₄-cyclohexylene-NH-CH₂-; *- (CH₂) ₄-cyclohexylene-NH- (CH₂) ₂-; *- (CH₂) ₄-cyclohexylene-NH- (CH₂) ₃-; *- (CH₂) ₅-cyclohexylene-NH- (CH₂) ₃-; *- (CH₂) ₆-cyclohexylene-NH-(CH₂) ₃-; *- (CH₂) ₇-cyclohexylene-NH- (CH₂) ₃-; *- (CH₂) ₈-cyclohexylene-NH-CH₂-; *- (CH₂) ₈-cyclohexylene-NH- (CH₂) ₂-; *- (CH₂) ₈-cyclohexylene-NH- (CH₂) ₃-; *- (CH₂) ₈-cyclohexylene-NH- (CH₂) ₄-; *- (CH₂) ₈-cyclohexylene-NH- (CH₂) ₅-; *- (CH₂) ₈-cyclohexylene-NH- (CH₂) ₆-; *- (CH₂) ₈-cyclohexylene-NH- (CH₂) ₇-; *- (CH₂) ₈-cyclohexylene-NH- (CH₂) ₈-; *-CH₂-cyclohexylene-NH- (CH₂) ₈-; *- (CH₂) ₂-cyclohexylene-NH- (CH₂) ₈-; *- (CH₂) ₃-cyclohexylene-NH- (CH₂) ₈-; *- (CH₂) ₄-cyclohexylene-NH- (CH₂) ₈-; *- (CH₂) ₅-cyclohexylene-NH- (CH₂) ₈-; *- (CH₂) ₆-cyclohexylene-NH- (CH₂) ₈-; *- (CH₂) ₇-cyclohexylene-NH- (CH₂) ₈-; *-CH₂-triazolylene-CH₂-; *- (CH₂) ₁-triazolylene- (CH₂) ₂-; *- (CH₂) ₁-triazolylene- (CH₂) ₃-; *- (CH₂) ₂-triazolylene- (CH₂) ₁-; *- (CH₂) ₂-triazolylene- (CH₂) ₂-; *- (CH₂) ₂-triazolylene- (CH₂) ₃-; *- (CH₂) ₂-triazolylene- (CH₂) ₄-; *- (CH₂) ₂-triazolylene- (CH₂) ₅-; *- (CH₂) ₃-triazolylene-CH₂-; *- (CH₂) ₃-triazolylene- (CH₂) ₂-; *- (CH₂) ₃-triazolylene- (CH₂) ₃-; *- (CH₂) ₄-triazolylene-CH₂-; *- (CH₂) ₄-triazolylene- (CH₂) ₂-; *- (CH₂) ₄-triazolylene- (CH₂) ₃-; *- (CH₂) ₅-triazolylene- (CH₂) ₃-; *- (CH₂) ₆-triazolylene- (CH₂) ₃-; *- (CH₂) ₇-triazolylene- (CH₂) ₃-; *- (CH₂) ₈-triazolylene-CH₂-; *- (CH₂) ₈-triazolylene- (CH₂) ₂-; *- (CH₂) ₈-triazolylene- (CH₂) ₃-; *- (CH₂) ₈-triazolylene- (CH₂) ₄-; *- (CH₂) ₈-triazolylene- (CH₂) ₅-; *- (CH₂) ₈-triazolylene- (CH₂) ₆-; *- (CH₂) ₈-triazolylene- (CH₂) ₇-; *- (CH₂) ₈-triazolylene- (CH₂) ₈-; *-CH₂-triazolylene- (CH₂) ₈-; *- (CH₂) ₂-triazolylene- (CH₂) ₈-; *- (CH₂) ₃-triazolylene- (CH₂) ₈-; *- (CH₂) ₄-triazolylene- (CH₂) ₈-; *- (CH₂) ₅-triazolylene- (CH₂) ₈-; *- (CH₂) ₆-triazolylene- (CH₂) ₈-; *- (CH₂) ₇-triazolylene- (CH₂) ₈-; *-CH₂-pyridylene-CH₂-; *- (CH₂) ₂-pyridylene- (CH₂) ₂-; *- (CH₂) ₂-pyridylene- (CH₂) ₃-; *- (CH₂) ₂-pyridylene- (CH₂) ₄-; *- (CH₂) ₂-pyridylene- (CH₂) ₅-; *- (CH₂) ₃-pyridylene-CH₂-; *- (CH₂) ₃-pyridylene- (CH₂) ₂-; *- (CH₂) ₃-pyridylene- (CH₂) ₃-; *- (CH₂) ₄-pyridylene-CH₂-; *- (CH₂) ₄-pyridylene- (CH₂) ₂-; *- (CH₂) ₄-pyridylene- (CH₂) ₃-; *- (CH₂) ₅-pyridylene- (CH₂) ₃-; *- (CH₂) ₆-pyridylene- (CH₂) ₃-; *- (CH₂) ₇-pyridylene- (CH₂) ₃-; *- (CH₂) ₈-pyridylene-CH₂-; *- (CH₂) ₈-pyridylene- (CH₂) ₂-; *- (CH₂) ₈-pyridylene- (CH₂) ₃-; *- (CH₂) ₈-pyridylene- (CH₂) ₄-; *- (CH₂) ₈-pyridylene- (CH₂) ₅-; *- (CH₂) ₈-pyridylene- (CH₂) ₆-; *- (CH₂) ₈-pyridylene- (CH₂) ₇-; *- (CH₂) ₈-pyridylene- (CH₂) ₈-; *-CH₂-pyridylene- (CH₂) ₈-; *- (CH₂) ₂-pyridylene- (CH₂) ₈-; *- (CH₂) ₃-pyridylene- (CH₂) ₈-; *- (CH₂) ₄-pyridylene- (CH₂) ₈-; *- (CH₂) ₅-pyridylene- (CH₂) ₈-; *- (CH₂) ₆-pyridylene- (CH₂) ₈-; *- (CH₂) ₇-pyridylene- (CH₂) ₈-; *- (CH₂) ₁S (CH₂) ₁-; *- (CH₂) ₂S (CH₂) ₂-; *- (CH₂) ₂S (CH₂) ₁-; *- (CH₂) ₁S (CH₂) ₂-; *- (CH₂) ₁S (CH₂) ₃-; *- (CH₂) ₁S (CH₂) ₄-; *- (CH₂) ₂S (CH₂) ₃-; *- (CH₂) ₂S (CH₂) ₄-; *- (CH₂) ₂S (CH₂) ₅-; *- (CH₂) ₃S (CH₂) ₁-; *- (CH₂) ₃S (CH₂) ₂-; *- (CH₂) ₃S (CH₂) ₃-; *- (CH₂) ₄S (CH₂) ₁-; *- (CH₂) ₄S (CH₂) ₂-; *- (CH₂) ₄S (CH₂) ₃-; *- (CH₂) ₅S (CH₂) ₁-; *- (CH₂) ₅S (CH₂) ₂-; *- (CH₂) ₅S (CH₂) ₃-; *- (CH₂) ₆S (CH₂) ₁-; *- (CH₂) ₆S (CH₂) ₂-; *- (CH₂) ₆S (CH₂) ₃-; *- (CH₂) ₇S (CH₂) ₁-; *- (CH₂) ₇S (CH₂) ₂-; *- (CH₂) ₇S (CH₂) ₃-; *- (CH₂) ₈S (CH₂) ₁-; *- (CH₂) ₈S (CH₂) ₂-; *- (CH₂) ₈S (CH₂) ₃-; *- (CH₂) ₉S (CH₂) ₁-; *- (CH₂) ₉S (CH₂) ₂-; *- (CH₂) ₉S (CH₂) ₃-; *- (CH₂) ₁S (O) (CH₂) ₁-; *- (CH₂) ₂S (O) (CH₂) ₂-; *- (CH₂) ₂S (O) (CH₂) ₁-; *- (CH₂) ₁S (O) (CH₂) ₂-; *- (CH₂) ₁S (O) (CH₂) ₃-; *- (CH₂) ₁S (O) (CH₂) ₄-; *- (CH₂) ₂S (O) (CH₂) ₃-; *- (CH₂) ₂S (O) (CH₂) ₄-; *- (CH₂) ₂S (O) (CH₂) ₅-; *- (CH₂) ₃S (O) (CH₂) ₁-; *- (CH₂) ₃S (O) (CH₂) ₂-; *- (CH₂) ₃S (O) (CH₂) ₃-; *- (CH₂) ₄S (O) (CH₂) ₁-; *- (CH₂) ₄S (O) (CH₂) ₂-; *- (CH₂) ₄S (O) (CH₂) ₃-; *- (CH₂) ₅S (O) (CH₂) ₁-; *- (CH₂) ₅S (O) (CH₂) ₂-; *- (CH₂) ₅S (O) (CH₂) ₃-; *- (CH₂) ₆S (O) (CH₂) ₁-; *- (CH₂) ₆S (O) (CH₂) ₂-; *- (CH₂) ₆S (O) (CH₂) ₃-; *- (CH₂) ₇S (O) (CH₂) ₁-; *- (CH₂) ₇S (O) (CH₂) ₂-; *- (CH₂) ₇S (O) (CH₂) ₃-; *- (CH₂) ₈S (O) (CH₂) ₁-; *- (CH₂) ₈S (O) (CH₂) ₂-; *- (CH₂) ₈S (O) (CH₂) ₃-; *- (CH₂) ₉S (O) (CH₂) ₁-; *- (CH₂) ₉S (O) (CH₂) ₂-; *- (CH₂) ₉S (O) (CH₂) ₃-; *- (CH₂) ₁S (O) ₂ (CH₂) ₁-; *- (CH₂) ₂S (O) ₂ (CH₂) ₂-; *- (CH₂) ₂S (O) ₂ (CH₂) ₁-; *- (CH₂) ₁S (O) ₂ (CH₂) ₂-; *- (CH₂) ₁S (O) ₂ (CH₂) ₃-; *- (CH₂) ₁S (O) ₂ (CH₂) ₄-; *- (CH₂) ₂S (O) ₂ (CH₂) ₃-; *- (CH₂) ₂S (O) ₂ (CH₂) ₄-; *- (CH₂) ₂S (O) ₂ (CH₂) ₅-; *- (CH₂) ₃S (O) ₂ (CH₂) ₁-; *- (CH₂) ₃S (O) ₂ (CH₂) ₂-; *- (CH₂) ₃S (O) ₂ (CH₂) ₃-; *- (CH₂) ₄S (O) ₂ (CH₂) ₁-; *- (CH₂) ₄S (O) ₂ (CH₂) ₂-; *- (CH₂) ₄S (O) ₂ (CH₂) ₃-; *- (CH₂) ₅S (O) ₂ (CH₂) ₁-; *- (CH₂) ₅S (O) ₂ (CH₂) ₂-; *- (CH₂) ₅S (O) (CH₂) ₃-; *- (CH₂) ₆S (O) ₂ (CH₂) ₁-; *- (CH₂) ₆S (O) ₂ (CH₂) ₂-; *- (CH₂) ₆S (O) ₂ (CH₂) ₃-; *- (CH₂) ₇S (O) ₂ (CH₂) ₁-; *- (CH₂) ₇S (O) ₂ (CH₂) ₂-; *- (CH₂) ₇S (O) ₂ (CH₂) ₃-; *- (CH₂) ₈S (O) ₂ (CH₂) ₁-; *- (CH₂) ₈S (O) ₂ (CH₂) ₂-; *- (CH₂) ₈S (O) ₂ (CH₂) ₃-; *- (CH₂) ₉S (O) ₂ (CH₂) ₁-; *- (CH₂) ₉S (O) ₂ (CH₂) ₂-; or*- (CH₂) ₉S (O) ₂ (CH₂) ₃-;

*-(CH₂) ₆-NH- (CH₂) ₁-; *- (CH₂) ₆-NH- (CH₂) ₃-; *- (CH₂) ₆-NH- (CH₂) ₄-; *- (CH₂) ₆-NH- (CH₂) ₅-; *- (CH₂) ₇-NH- (CH₂) ₁-; *- (CH₂) ₇-NH- (CH₂) ₂-; *- (CH₂) ₇-NH- (CH₂) ₃-; *- (CH₂) ₇-NH- (CH₂) ₄-; *- (CH₂) ₆-NH-CH (CH₃) -; *- (CH₂) ₅-NH-CH (CH₃) -; *- (CH₂) ₄-NH-CH (CH₃) -; *- (CH₂) ₃-NH-CH (CH₃) -; *- (CH₂) ₂-NH-CH (CH₃) -; *- (CH₂) ₇-NH-CH (CH₃) -; *- (CH₂) ₈-NH-CH (CH₃) -; *- (CH₂) ₇-NH-CH (CF₃) -; *- (CH₂) ₆-NH-CH (CF₃) -; *- (CH₂) ₅-NH-CH (CF₃) -; *- (CH₂) ₄-NH-CH (CF₃) -; *- (CH₂) ₃-NH-CH (CF₃) -; *- (CH₂) ₂-NH-CH (CF₃) -; *- (CH₂) ₈-NH-CH (CF₃) -; *-CH₂-C (O) NH- (CH₂) ₄-; *-CH₂-C (O) NH- (CH₂) ₂-; *-CH₂-C (O) NH- (CH₂) ₃-; *-CH₂-C (O) NH- (CH₂) ₅-; *-CH₂-phenylene-CH₂-NH-CH (CH₃) -; *-CH₂-phenylene- (CH₂) ₂-NH-CH (CH₃) -; *-CH₂-phenylene-CH₂-NH-CH₂-; *-CH₂-phenylene- (CH₂) ₂-NH-CH₂-; *- (CH₂) ₁-furanylene- (CH₂) ₁-; *- (CH₂) ₁-furanylene- (CH₂) ₂-; *- (CH₂) ₁-furanylene- (CH₂) ₃-; *- (CH₂) ₂-furanylene- (CH₂) ₁-; *- (CH₂) ₂-furanylene- (CH₂) ₂-; *- (CH₂) ₃-furanylene- (CH₂) ₁-; *- (CH₂) ₃-furanylene- (CH₂) ₂-; or*-CH₂-triazolylene-CH₂-NH-CH₂-;

wherein one or more hydrogen of one or more CH₂ of the groups are optionally further replaced by a substituent (s) selected from the group consisting of halogen, hydroxyl, cyano, amino, mercapto, C_1-3 alkyl, C_1-3 alkoxy, halogenated C_1-4 alkyl, C_5-10 aryl, C_5-10 heteroaryl, C_3-12 cycloalkyl, 4-to 12-membered heterocyclyl, or any combination thereof;

the symbol*indicates the point of attachment to the U₂;

the piperazinylene, piperidinylene, and cyclohexylene are each independently optionally further substituted with a substituent (s) selected from the group consisting of halogen, hydroxyl, cyano, amino, mercapto, oxo, C_1-3 alkyl, C_1-3 alkoxy, halogenated C_1-4 alkyl, C_5-10 aryl, C_5-10 heteroaryl, C_3-12 cycloalkyl, 4-to 12-membered heterocyclyl, or any combination thereof; and

the phenylene, triazolylene, pyridylene, and furanylene are each independently optionally further substituted with a substituent (s) selected from the group consisting of halogen, hydroxyl, cyano, amino, mercapto, C_1-3 alkyl, C_1-3 alkoxy, halogenated C_1-4 alkyl, C_5-10 aryl, C_5-10 heteroaryl, C_3-12 cycloalkyl, 4-to 12-membered heterocyclyl, or any combination thereof.

In some embodiments, the L represents the following groups:

wherein the symbol*indicates the point of attachment to the U₂.

It will be understood by those skilled in the art that the present invention encompasses compounds resulting from any combination of the various embodiments. Embodiments obtained by combining technical features or preferred technical features of one embodiment with technical features or preferred technical features of another embodiment are also encompassed within the scope of the present invention as defined by the appended claims.

Particularly preferred are the compounds of the present invention in Table 1 and their salts (especially pharmaceutically acceptable salts, such as hydrochloride, etc. ) , enantiomers, stereoisomers, solvates, or polymorphs:

Table 1. Compounds of the present invention

III. Other Forms of Compounds (including salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs, or polymorphs of compounds)

The compounds of the present disclosure have the structures of any one of formula (I) , formula (I-1) , formula (I-2) , formula (I-3) , formula (I-4) , formula (I-5) , formula (I-6) , or formula (I-1-1) , (I-1-2) , (I-1-3) , (I-1-4) , (I-1-5) , (I-1-6) , (I-1-7) , (I-1-8) , (I-1-9) , (I-1-10) , (I-1-11) , (I-1-12) , (I-1-13) , (I-1-14) , (I-1-15) , (I-1-16) , (I-1-17) , (I-1-18) , (I-1-19) , (I-1-20) , (I-1-21) , (I-1-22) , (I-1-23) , (I-1-24) , (I-1-25) , (I-1-26) , (I-1-27) , (I-1-28) , (I-1-29) , (I-1-30) , (I-1-31) , (I-2-1) , (I-2-2) , (I-4-1) , (I-4-2) , (I-4-3) , (I-5-1) , (I-6-1) , (I-7) , or (I-8) . Unless otherwise specified, all references to the compound of the present disclosure also include compounds of any one of formula (I) , formula (I-1) , formula (I-2) , formula (I-3) , formula (I-4) , formula (I-5) , formula (I-6) , or formula (I-1-1) , (I-1-2) , (I-1-3) , (I-1-4) , (I-1-5) , (I-1-6) , (I-1-7) , (I-1-8) , (I-1-9) , (I-1-10) , (I-1-11) , (I-1-12) , (I-1-13) , (I-1-14) , (I-1-15) , (I-1-16) , (I-1-17) , (I-1-18) , (I-1-19) , (I-1-20) , (I-1-21) , (I-1-22) , (I-1-23) , (I-1-24) , (I-1-25) , (I-1-26) , (I-1-27) , (I-1-28) , (I-1-29) , (I-1-30) , (I-1-31) , (I-2-1) , (I-2-2) , (I-4-1) , (I-4-2) , (I-4-3) , (I-5-1) , (I-6-1) , (I-7) , or (I-8) and specific compounds within the scope of these general formulae.

The compound of formula I of the present invention may include an enantiomer depending on the presence of a chiral center or an isomer depending on the presence of a double bond (for example, Z, E) . Single isomer, enantiomers, diastereomers, or cis-trans isomers, and mixtures thereof are also encompassed within the scope of the present invention.

It should be recognized that compounds of the present disclosure (including formula (I) , formula (I-1) , formula (I-2) , formula (I-3) , formula (I-4) , formula (I-5) , formula (I-6) , or formula (I-1-1) , (I-1-2) , (I-1-3) , (I-1-4) , (I-1-5) , (I-1-6) , (I-1-7) , (I-1-8) , (I-1-9) , (I-1-10) , (I-1-11) , (I-1-12) , (I-1-13) , (I-1-14) , (I-1-15) , (I-1-16) , (I-1-17) , (I-1-18) , (I-1-19) , (I-1-20) , (I-1-21) , (I-1-22) , (I-1-23) , (I-1-24) , (I-1-25) , (I-1-26) , (I-1-27) , (I-1-28) , (I-1-29) , (I-1-30) , (I-1-31) , (I-2-1) , (I-2-2) , (I-4-1) , (I-4-2) , (I-4-3) , (I-5-1) , (I-6-1) , (I-7) , or (I-8) ) may have a stereo-configuration and thus can exist in more than one stereoisomeric form. The present disclosure also relates to optically enriched compounds having a stereo-configuration, e.g., greater than about 90%enantiomeric/diastereomeric excess ( "ee" ) , such as about 95%ee or 97%ee, or greater than 99%ee, and mixtures thereof, including racemic mixtures. As used herein, "optically enriched" means that a mixture of enantiomers consists of a significantly greater proportion of one enantiomer, and can be described by enantiomeric excess (ee%) . Purification of isomers and separation of mixtures of isomers can be accomplished by standard techniques known in the art (e.g., column chromatography, preparative TLC, preparative HPLC, asymmetric synthesis (e.g., by using chiral intermediates) and/or or chiral resolution, etc. ) .

In some embodiments, polymorph forms or salts of the compounds of the present disclosure are also provided. Salts of the compounds of the present disclosure can be pharmaceutically acceptable salts including, but not limited to, sulfate, hydrochloride, citrate, maleate, sulfonate, citrate, lactate, tartrate, fumarate, phosphate, dihydrogenphosphate, pyrophosphate, metaphosphate, oxalate, malonate, benzoate, mandelate, succinate, glycolate, or p-toluenesulfonate, etc. The compounds of the present disclosure can exist as non-solvated or solvated forms in pharmaceutically acceptable solvents such as water, ethanol, and the like. In some embodiments, compounds of the present disclosure can be prepared as prodrugs or precursor drugs. Prodrugs can be converted into parent drugs in the body to play their role. In some embodiments, isotopically-labeled compounds of the present disclosure are also provided, examples of which include deuterium (D or ²H) .

IV. Genome editing

The compounds of formula (I) of the present disclosure can modulate CRISPR/Cas9 protein, variants or homologues thereof-mediated genome editing of a target DNA in a sample (e.g., a cell) . The CASPROTAC compounds of formula (I) of the present disclosure can target Cas9 proteins, variants or homologues thereof or complexes comprising the same (including Cas9 protein, Cas9 nuclease dimers, Cas9 nuclease fusion proteins, Cas9 nuclease fragments, minimized Cas9 nucleases, Cas9 variants without a cleavage domain, Cas9 variants without a gRNA domain, and Cas9-recombinase fusions, and complexes comprising any of these Cas proteins, e.g., deactivated Cas9 (dCas9) proteins, variants of dCas9, Cas9nicknase (or D10A nickase) , SaCas9, Cas9 nuclease from Streptococcus pyogenes (SpCas9) , SpCas9n, saCas9, High Fidelity Cas9 (HiFi Cas9) , Cas9-H840A, and FokI-dCas9, and any of these Cas proteins fused with other engineered proteins, and ribonucleoprotein complexes comprising Cas9 protein) and recruit E3ubiquitination ligase through the E3 ligase ligand, so that the target Cas9 protein, variants or homologues thereof or complexes comprising the same is connected to the E3 ubiquitination ligase through the CASPROTAC compounds, and ubiquitinated by the E3 ligase, thereby being degraded under the action of the proteasome. In this way, the timing of the genome editing could be controlled to maintain on-target editing whilst reducing off-target effects to the minimum, improving the precision (or accuracy) of the genome editing, and thus the safety of the genome editing-based therapies.

In some embodiments, the Cas9 protein, variants or homologues thereof or complexes comprising the same includes, but is not limited to, Cas9 protein, Cas9 nuclease dimers, Cas9 nuclease fusion proteins, Cas9 nuclease fragments, minimized Cas9 nucleases, Cas9 variants without a cleavage domain, Cas9 variants without a gRNA domain, and Cas9-recombinase fusions, and complexes comprising any of these Cas proteins, e.g., dCas9 protein (deactivated Cas9 protein) , variants of dCas9, Cas9nicknase (a D10A mutant of Cas9 protein) , SaCas9, Cas9 nuclease from Streptococcus pyogenes (SpCas9) , SpCas9n, saCas9, High Fidelity Cas9 (HiFi Cas9) , Cas9-H840A, and FokI-dCas9, and any of these Cas proteins fused with other engineered proteins, and ribonucleoprotein complexes comprising Cas9 protein (e.g., ribonucleoprotein complexes (RNP) assembled by Cas9 proteins with guide RNA) .

In some embodiments, the CRISPR/Cas9 protein, variants or homologues thereof system for implementation of CRISPR/Cas9 protein, variants or homologues thereof-mediated genome editing technique includes, but is not limited to, Cas9 proteins, variants or homologues thereof (including Cas9 protein, Cas9 nuclease dimers, Cas9 nuclease fusion proteins, Cas9 nuclease fragments, minimized Cas9 nucleases, Cas9 variants without a cleavage domain, Cas9 variants without a gRNA domain, and Cas9-recombinase fusions, e.g., deactivated Cas9 (dCas9) proteins, variants of dCas9, Cas9nicknase (a D10A mutant of Cas9 protein) , SaCas9, Cas9 nuclease from Streptococcus pyogenes (SpCas9) , SpCas9n, saCas9, High Fidelity Cas9 (HiFi Cas9) , Cas9-H840A, and FokI-dCas9, and any of these Cas proteins fused with other engineered proteins) or a nucleic acid comprising a nucleotide sequence encoding the Cas9 protein, variants or homologues thereof, guide RNAs (gRNA) , and repair-templates, which are those common elements in the art and well-known to those skilled in the art. See, for example, WO2019143677, WO2015048557.

In some embodiments, the CRISPR/Cas9 protein, variants or homologues thereof system can be delivered by one or more vectors. In some embodiments, the one or more vectors include, but are not limited to, viral vectors, plasmids, or ssDNAs. In some embodiments, the viral vectors include, but are not limited to, retroviral, lentiviral, adenoviral, adeno-associated and herpes simplex viral vectors. In some embodiments, the CRISPR/Cas9 protein, variants or homologues thereof system can be delivered by synthetic RNA or a nanoformulation.

In some embodiments, the genome editing can include, but is not limited to, in vivo genome editing, in vitro genome editing, or combination thereof.

In some embodiments, the genome editing can aim at a gene, e.g., pathogenic genes, tumor related genes (such as oncogenes) , immune related genes (such as genes related to autoimmunity) , and vision related genes.

In some embodiments, the sample for the genome editing includes, but is not limited to, cell, tissue, organ, or combination thereof. In some embodiments, the sample can be from animal, plant, microorganism (including bacteria, archaea and virus) . In some embodiments, non-limiting examples of the cell include primary cells; passage cells; somatic cells; germ cells; stem cells (e.g., pluripotent stem cells, pluripotent stem cells (e.g., induced pluripotent stem cells) , and specialized stem cells) . In some embodiments, the cell includes embryonic stem cells, adipose stem cells, hematopoietic stem cells, and immune cells (such as T cells, NK cells) .

V. Compositions/Formulations/Preparations

The present disclosure provides a composition comprising the compound of Formula (I) of the present disclosure or a salt, an enantiomer, a stereoisomer, a solvate, or a polymorph thereof, and at least one physiologically acceptable carrier. In some embodiments, the composition or preparation can be used as a degrader composition or preparation for degrading Cas9 protein, variants or homologues thereof or complexes comprising the same which include Cas9 protein, Cas9 nuclease dimers, Cas9 nuclease fusion proteins, Cas9 nuclease fragments, minimized Cas9 nucleases, Cas9 variants without a cleavage domain, Cas9 variants without a gRNA domain, and Cas9-recombinase fusions, and complexes comprising any of these Cas proteins, e.g., deactivated Cas9 (dCas9) proteins, variants of dCas9, Cas9 nicknase (or D10A nickase) , SaCas9, SpCas9, SpCas9n, saCas9, High Fidelity Cas9 (HiFi Cas9) , Cas9-H840A, and FokI-dCas9, and any of these Cas proteins fused with other engineered proteins, and ribonucleoprotein complexes comprising Cas9 protein (e.g., ribonucleoprotein complexes (RNP) assembled by Cas9 proteins with guide RNAs) .

In some embodiments, the composition or preparation of the present disclosure can be used to modulate CRISPR/Cas9 protein, variants or homologues thereof-mediated genome editing, transcriptional regulation, genome imaging, epigenetic modification, gene therapy, disease models establishing, genome-wide genetic screening, or drug design and screening; or modulate CRISPR/Cas9 protein, variants or homologues thereof-based molecular diagnostic tool for diseases (e.g., infectious diseases) .

In some embodiments, the composition or preparation of the present disclosure can be used, in combination with a CRISPR/Cas9 protein, variants or homologues thereof system, for modulating CRISPR/Cas9 protein, variants or homologues thereof-mediated genome editing, transcriptional regulation, genome imaging, epigenetic modification, gene therapy, disease models establishing, genome-wide genetic screening, or drug design and screening; or for modulating CRISPR/Cas9 protein, variants or homologues thereof-based molecular diagnostic tool for diseases (e.g., infectious diseases) .

Herein, in some embodiments, the composition of the present disclosure can be used to control the timing of the genome editing (including gene knock-in, gene replacement and gene-specific point modifications) to maintain on-target editing whilst reducing off-target effects to the minimum, and thus improving the precision (or accuracy) of the genome editing, and the safety of the genome editing-based therapies. Therefore, the composition of the present disclosure could potentially be used for genomic medicine applications and to prevent potential biohazards caused by CRISPR/Cas9 protein, variants or homologues thereof-mediated genome editing in the human population. In some embodiments, the degrader composition of the present disclosure can be used in combination with CRISPR/Cas9 protein, variants or homologues thereof-mediated gene therapy for the prevention and/or treatment of a genetic disease in a subject.

In some embodiments, the composition or preparation of the present disclosure can be used as a reagent composition (e.g., for scientific research, genome editing, gene expression regulation (transcriptional activation/inhibition) , genome imaging, epigenetic modification, disease models establishing, genome-wide genetic screening, molecular diagnostic tool for diseases, and drug design and screening system etc. ) .

The reagent composition as provided herein comprises (i) as a modulator the compound of Formula (I) of the present disclosure or a pharmaceutically acceptable salt, an enantiomer, astereoisomer, a solvate, or a polymorph thereof, and (ii) at least one pharmaceutically/physiologically acceptable carrier.

The reagent composition as provided herein can further comprise (i) as a modulator the compound of Formula (I) of the present disclosure or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer, a solvate, or a polymorph thereof, and optionally at least one pharmaceutically/physiologically acceptable carrier; and (ii) reagents for implementing the CRISPR/Cas protein-mediated genome editing or epigenetic modification (such as the CRISPR/Cas system, e.g., the CRISPR/Cas9 protein, variants or homologues thereof system) .

In some embodiments, the reagent composition can be used as a modulator for the modulation of CRISPR/Cas9 protein, variants or homologues thereof-mediated genome editing of a target DNA in a cell. In some embodiments, the genome editing adopts a CRISPR/Cas9 protein, variants or homologues thereof system comprising Cas9 nucleases, variants or homologues thereof, gRNA, and repair-templates.

The present disclosure also provides a pharmaceutical composition comprising as an active ingredient the compound of Formula (I) of the present disclosure or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer, a solvate, or a polymorph thereof, and at least one pharmaceutically acceptable carrier.

In some embodiments, pharmaceutically acceptable carriers include, but are not limited to, fillers, stabilizers, dispersants, suspending agents, diluents, excipients, thickeners, solvents, or encapsulating materials, with which the useful compounds according to the present disclosure are carried or transported into or administered to a patient so that they can perform their intended function. Generally, such constructs are carried or transported from one organ or part of the body to another organ or part of the body. The carrier is compatible with the other ingredients of the formulation, including the compounds useful in the present disclosure, and is not harmful to the patient, and the carrier must be "acceptable" . Some examples of materials that can be used as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; surfactant phosphate buffer solution; saline; Sterile water; and other common non-toxic compatible substances used in pharmaceutical formulations.

The pharmaceutical composition of the present disclosure can further comprise at least one second therapeutic agent, such as a therapeutic agent for treating or preventing a disease, e.g., genetic disease. The second therapeutic agent may be used in combination with the compound of Formula (I) described in the present disclosure to treat the diseases or conditions described in the present disclosure. The second therapeutic agent includes, but is not limited to, chemotherapeutic agents, immunotherapeutic agents, gene therapy agents, anti-angiogenic agents, immunomodulatory agents, and the like.

The pharmaceutical composition of the present invention comprising, as an active ingredient, the compound of Formula (I) of the present invention or a pharmaceutically acceptable salt thereof can be formulated into any suitable formulations such as sprays, patches, tablets (such as conventional tablets, dispersible tablets, orally disintegrating tablets) , capsules (such as soft capsules, hard capsules, enteric-coated capsules) , dragees, troches, powders, granules, powder injections, or liquid formulations (such as suspensions (e.g., aqueous or oily suspensions) , solutions, emulsions, or syrups) , or conventional injection dosage forms such as injectable solutions (e.g., sterile injectable solutions formulated according to methods known in the art using water, Ringer's solution, or isotonic sodium chloride solution or the like as a vehicle or solvent) or lyophilized injectable formulation and the like, depending upon a suitable route of administration (including, but not limited to, nasal administration, inhalation administration, topical administration, oral administration, oral mucosal administration, rectal administration, intrapleural administration, intraperitoneal administration, vaginal administration, intramuscular administration, subcutaneous administration, transdermal administration, epidural administration, intrathecal administration, and intravenous administration) . Those skilled in the art can also formulate the compound of formula (I) of the present disclosure into conventional, dispersible, chewable, orally disintegrating or rapidly dissolving formulations, or sustained-release capsules or controlled-release capsules as needed.

The compound of Formula (I) as described in the present disclosure as an active ingredient can be contained in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver a therapeutically effective amount of the compound of Formula (I) to the subject for treating the diseases or conditions without causing serious toxic effects in the treated subjects. For all diseases or conditions mentioned herein, the active compound of Formula (I) of the present disclosure is administered at a dose of, for example, about 5 ng/kg body weight/day to about 500 mg/kg body weight/day, about 10 ng/kg body weight/day to about 300 mg/kg body weight/day, e.g., from about 0.1 to 100 mg/kg body weight per day, or from about 0.5 to 25 mg/kg body weight per day.

The compounds of formula (I) of the present disclosure, or a pharmaceutically acceptable salt thereof, may be conveniently administered in any suitable formulation having specifications including, but not limited to, less than 1 mg, 1 mg to 3000 mg, 5mg to 1000 mg, e.g., 5 to 500 mg, 25 to 250 mg of active ingredient per dosage units.

VI. Kits/Packaged Products

The compounds of formula (I) of the present disclosure, or pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, or polymorphs thereof, can be used as a degrader or modulator that can degrade Cas9 protein, variants or homologues thereof or complexes comprising the same including Cas9 protein, Cas9 nuclease dimers, Cas9 nuclease fusion proteins, Cas9 nuclease fragments, minimized Cas9 nucleases, Cas9 variants without a cleavage domain, Cas9 variants without a gRNA domain, and Cas9-recombinase fusions, and complexes comprising any of these Cas proteins, e.g., deactivated Cas9 (dCas9) proteins, variants of dCas9, Cas9 nicknase (or D10A nickase) , SaCas9, Cas9 nuclease from Streptococcus pyogenes (SpCas9) , SpCas9n, saCas9, High Fidelity Cas9 (HiFi Cas9) , Cas9-H840A, and FokI-dCas9, and any of these Cas proteins fused with other engineered proteins, and ribonucleoprotein complexes comprising Cas9 protein. The degrader or modulator can be used, in combination with a CRISPR/Cas9 protein, variants or homologues thereof system, to modulate CRISPR/Cas9 protein, variants or homologues thereof-mediated genome editing, transcriptional regulation, genome imaging, epigenetic modification, gene therapy, disease models establishing, genome-wide genetic screening, or drug design and screening; or for modulating CRISPR/Cas9 protein, variants or homologues thereof-based molecular diagnostic tool for diseases (e.g., infectious diseases) . CRISPR based molecular diagnostic tools are well known, and include those described by e.g., Seohyun Kim et al., CRISPR as a Diagnostic Tool, Biomolecules, 2021Aug; 11(8) : 1162. In some embodiments, the degrader or modulator can be used to control the timing of the CRISPR/Cas9 protein, variants or homologues thereof-mediated genome editing to improve the precision (or accuracy) of the genome editing and thus the safety of the genome editing-based therapies, thereby treating or preventing a genetic disease in a subject. In some embodiments, the degrader or medicament of the present disclosure or the composition of the present disclosure may be presented in a kit/packaged product. The kit/packaged product may include a package or container including, but not limited to, ampoules, blister packs, pharmaceutical plastic bottles, vials, pharmaceutical glass bottles, containers, syringes, laminated flexible packaging, co-extruded film infusion containers, test tubes and dispensing devices, and the like. The kit/packaged product may contain instructions for use of the product. In some embodiments, the kit/packaged product may further include a genome editing system, such as the CRISPR/Cas system, e.g., the CRISPR/Cas9 protein, variants or homologues thereof system as described herein. In some embodiments, the kit/packaged product can be used to modulate CRISPR/Cas9 protein, variants or homologues thereof-mediated genome editing, transcriptional regulation, genome imaging, epigenetic modification, gene therapy, disease models establishing, genome-wide genetic screening, or drug design and screening; or to modulate CRISPR/Cas9 protein, variants or homologues thereof-based molecular diagnostic tool for diseases (e.g., infectious diseases) .

The compounds of formula (I) of the present disclosure, or pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, or polymorphs thereof, can also be used as a modulator that modulate CRISPR/Cas9 protein, variants or homologues thereof-mediated genome editing of a target DNA in sample (e.g., a cell) . The modulator of the present disclosure may enhance precise genome editing to knock-in a gene, knock-out a gene, replace a gene, modify a gene, or correct a mutation in the target gene by modulating CRISPR/Cas9 protein, variants or homologues thereof-mediated genome editing of the target DNA, and thus increasing the precision (or accuracy) of CRISPR/Cas9 protein, variants or homologues thereof-mediated genome editing and the safety of the genome editing-based therapies. The modulator of the present disclosure may be presented in a kit/packaged product. The kit/packaged product may include a package or container including, but not limited to, ampoules, blister packs, pharmaceutical plastic bottles, vials, pharmaceutical glass bottles, containers, syringes, laminated flexible packaging, co-extruded film infusion containers, test tubes and dispensing devices, and the like. The kit/packaged product may contain instructions for use of the product. In some embodiments, the kit/packaged product may further include a genome editing system, such as the CRISPR/Cas system, e.g., the CRISPR/Cas9 protein, variants or homologues thereof system as described herein.

The compounds of formula (I) of the present disclosure, or pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, or polymorphs thereof, can also be used as a modulator that modulate CRISPR/Cas9 protein, variants or homologues thereof-mediated epigenetic editing. The modulator of the present disclosure may enhance precise epigenetic editing to modify specific histones, up-or down-regulated specific genes by modulating (e.g., degrading) the Cas9 proteins, variants or homologues thereof fused with engineered proteins (e.g., VP64, VPR, KRAB, p300, LSD1, Dnmt3a and Tet1) , and thus reducing unwanted off-target effects made by CRISPR/Cas9 protein, variants or homologues thereof system to the minimum, thereby increasing the precision (or accuracy) of CRISPR/Cas9 protein, variants or homologues thereof-mediated epigenetic editing and the safety of the epigenetic editing-based therapies. The modulator of the present disclosure may be presented in a kit/packaged product. The kit/packaged product may include a package or container including, but not limited to, ampoules, blister packs, pharmaceutical plastic bottles, vials, pharmaceutical glass bottles, containers, syringes, laminated flexible packaging, co-extruded film infusion containers, test tubes and dispensing devices, and the like. The kit/packaged product may contain instructions for use of the product. In some embodiments, the kit/packaged product may further include an epigenetic editing system, such as the CRISPR/Cas system, e.g., the CRISPR/Cas9 protein, variants or homologues thereof system as described herein.

VII. Methods and Uses

The combination of the compounds of formula (I) of the present disclosure, or salts, enantiomers, stereoisomers, solvates, or polymorphs thereof with the reagents for genome editing or epigenetic editing (such as the CRISPR/Cas system, e.g., the CRISPR/Cas9 protein, variants or homologues thereof system as described herein) can precisely control the timing of the genome editing or epigenetic editing and improve the precision/accuracy of the genome editing or epigenetic editing, so it has revolutionary potential in various fields where the CRISPR/Cas9 proteins, variants or homologues thereof system is required, such as therapeutic application, research application, drug screening, disease models establishing, and CRISPR/Cas9 protein, variants or homologues thereof-based molecular diagnostic tool, etc.

In some embodiments, the compounds of formula (I) of the present disclosure, or salts, enantiomers, stereoisomers, solvates, or polymorphs thereof can be used as a modulator. Especially, the compounds of Formula (I) of the present disclosure, or pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, or polymorphs thereof, can be used to manufacture a modulator for the modulation of CRISPR/Cas9 protein, variants or homologues thereof-mediated genome editing of a target DNA in a sample (e.g., a cell) or a subject (e.g., subject as described herein) . The modulator of the present disclosure can be used in various fields where the CRISPR/Cas9 proteins, variants or homologues thereof system is required, such as the therapeutic application, research application, drug screening, disease models establishing, and CRISPR/Cas9 protein, variants or homologues thereof-based molecular diagnostic tool, etc.

A method for modulating CRISPR/Cas9 protein, variants or homologues thereof-mediated genome editing of a target DNA in a cell is also provided, the method comprising: contacting the cell with the compound of Formula (I) or pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, or polymorphs thereof of the present disclosure, or the composition of the present disclosure. The compound of Formula (I) or pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, or polymorphs thereof of the present disclosure, or the composition of the present disclosure is used in an amount e.g., sufficient to degrading Cas9 proteins, variants or homologues thereof or complexes comprising the same (including Cas9 protein, Cas9 nuclease dimers, Cas9 nuclease fusion proteins, Cas9 nuclease fragments, minimized Cas9 nucleases, Cas9 variants without a cleavage domain, Cas9 variants without a gRNA domain, and Cas9-recombinase fusions, and complexes comprising any of these Cas proteins, e.g., deactivated Cas9 (dCas9) proteins, variants of dCas9, Cas9 nicknase (or D10A nickase) , SaCas9, Cas9 nuclease from Streptococcus pyogenes (SpCas9) , SpCas9n, saCas9, High Fidelity Cas9 (HiFi Cas9) , Cas9-H840A, and FokI-dCas9, and any of these Cas proteins fused with other engineered proteins, and ribonucleoprotein complexes comprising Cas9 protein) in the cell, thereby keeping on-target effects of CRISPR/Cas9 protein-mediated genome editing while minimizing off-target effects. The method for modulating CRISPR/Cas protein, variants or homologues thereof-mediated genome editing of the present disclosure can provide precise genome editing to precisely knock-in a gene, knock-out a gene, replace a gene, modify a gene, or correct a mutation in the target DNA, and increase the safety of gene editing-based therapies.

In some embodiments, the method for modulating CRISPR/Cas9 protein, variants or homologues thereof-mediated genome editing of the present disclosure can be performed in vivo, in vitro, or combination thereof.

In some embodiments, the contacting the cell with the compound of Formula (I) or pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, or polymorphs thereof of the present disclosure, or the pharmaceutical composition of the present disclosure can be performed simultaneously or after the CRISPR/Cas9 protein, variants or homologues thereof system is delivery to the target DNA. CRISPR/Cas9 protein, variants or homologues thereof system comprising Cas9 nucleases, guide RNAs (gRNA) and repair-templates is well-known to those in the art as described herein. In some embodiments, the CRISPR/Cas9 protein, variants or homologues thereof system comprises Cas9 nucleases, variants or homologues thereof, guide RNAs (gRNA) and repair-templates as described herein.

In some embodiments, the method for modulating CRISPR/Cas9 protein, variants or homologues thereof-mediated genome editing of the present disclosure can be therapeutic or non- therapeutic, or diagnostic.

The compounds of formula (I) of the present disclosure, or salts, enantiomers, stereoisomers, solvates, or polymorphs thereof can precisely control the timing of the genome editing and improve the safety of the genome editing-based therapies, and thus can be used to treat or prevent a genetic disease in a subject.

In some embodiments, the compounds of formula (I) of the present disclosure, or pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, or polymorphs thereof, can be used as a medicament, modulator or a degrader. Especially, the compounds of Formula (I) of the present disclosure, or pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, or polymorphs thereof, can be used to manufacture a medicament or modulator or degrader for the prevention and/or treatment of a genetic disease in a subject. In some embodiments, the medicament or modulator or degrader can be used in combination with CRISPR/Cas9 protein, variants or homologues thereof-mediated gene therapy for the prevention and/or treatment of a genetic disease in a subject.

Also provided herein are methods for preventing or treating a genetic disease in a subject, comprising (a) applying to the subject a genome therapy adopting a CRISPR/Cas9 protein, variants or homologues thereof-mediated genome editing or epigenetic modification using a CRISPR/Cas9 protein, variants or homologues thereof system comprising a Cas9 protein, variants or homologues thereof, and guide RNAs (gRNA) ; (b) administering to the subject a therapeutically effective amount of the compound of Formula (I) or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, or polymorph thereof of the present disclosure, or the pharmaceutical composition of the present disclosure. The compound of Formula (I) or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, or polymorph thereof of the present disclosure, or the pharmaceutical composition of the present disclosure is administered in a sufficient amount to degrade the Cas9 protein, variants or homologues thereof or complexes comprising the same simultaneously or after applying the CRISPR/Cas9 protein, variants or homologues thereof-mediated genome editing. The methods for preventing or treating a genetic disease in a subject can enhance precise genome editing to correct a mutation in a target gene associated with the genetic disease.

In some embodiments, the administering to the subject a therapeutically effective amount of the compound of Formula (I) or pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, or polymorphs thereof of the present disclosure, or the pharmaceutical composition of the present disclosure can be performed simultaneously or after the CRISPR/Cas9 protein, variants or homologues thereof system is delivery to the subject. The CRISPR/Cas9 protein, variants or homologues thereof system includes, but is not limited to Cas9 nucleases, variants or homologues thereof, guide RNAs (gRNA) and repair-templates, which is known to those skilled in the art. The compound of Formula (I) or pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, or polymorphs thereof of the present disclosure, or the pharmaceutical composition of the present disclosure can be administered to the subject via any suitable route of administration (including, but not limited to, nasal administration, inhalation administration, topical administration, oral administration, oral mucosal administration, rectal administration, intrapleural administration, intraperitoneal administration, vaginal administration, intramuscular administration, subcutaneous administration, transdermal administration, epidural administration, intrathecal administration, and intravenous administration) and at doses or amounts sufficient to enhance the effect (e.g., improve the genome editing efficiency) of the Cas9 nuclease-based gene therapy.

The diseases that may be treated by the method include, but are not limited to, genetic diseases which includes, but is not limited to, blood disorders such as sickle cell anemia and thalassemia; X-linked dominant genetic diseases, such as vitamin D resistant rickets and hereditary nephritis; X-linked recessive genetic diseases, such as red green blindness, hemophilia, and congenital deafness; neoplasia; cancer; age-related macular degeneration; schizophrenia; trinucleotide repeat disorders; prion-related disorders; amyotrophic lateral sclerosis; autism; Alzheimer's disease; Parkinson's disease; immune-related diseases; metabolic diseases, such as diabetes; hypertension; bronchial asthma; glaucoma; cleft lip and palate; deformed feet; epilepsy; spina bifida; neural tube defects; congenital myotonia; and progressive muscular dystrophy.

The term "treatment" or "treating" refers to the administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof according to the present disclosure, or the pharmaceutical composition containing, as an active ingredient, the compound of Formula I or a pharmaceutically acceptable salt thereof, to a subject to mitigate (alleviate) undesirable diseases or conditions, such as the development of a cancer or tumor. The beneficial or desired clinical results of the present disclosure include, but are not limited to: alleviating symptoms, reducing the severity of the disease, stabilizing the state of the disease, slowing down or delaying the progression of the disease, improving or alleviating the condition, and alleviating the disease.

A "therapeutic effective amount" of the compound of the present disclosure depends on a variety of factors, including the activity of the specific compound used, the metabolic stability of the compound and the duration of its action, the age, sex and weight of the patient, the patient's current medical condition, the route and duration of administration, the excretion rate, the combined administration of additional drugs, and the progression of the diseases or conditions of the patient being treated. Those skilled in the art will be able to determine appropriate dosages based on these and other factors.

It is to be understood that the choice of using one or more active compounds and/or compositions and their dosage depends on the basic situations of the individual (which should generally render the individual situation to achieve the best effect) . Dosing and dosing regimens should be within the ability of those skilled in the art, and the appropriate dosage depends on many factors including the knowledge and ability of the physicians, veterinarians or researchers (Jun Li (chief editor) , "Clinical Pharmacology" , 4th edition, People’s Public Health Press, 2008) .

Beneficial Effects of the Present Invention

The invention provides for the first time a small molecule CASPROTAC compound that can modulate CRISPR/Cas9 protein, variants or homologues thereof-mediated genome editing, which is particularly effective for precise modulation of CRISPR/Cas9 protein, variants or homologues thereof -mediated genome editing or epigenetic modification of a target DNA in a cell.

The small molecule CASPROTAC compound also can modulate CRISPR/Cas9 protein, variants or homologues thereof-mediated transcriptional regulation, genome imaging, epigenetic modification, gene therapy, disease models establishing, genome-wide genetic screening, or drug design and screening; or modulate CRISPR/Cas9 protein, variants or homologues thereof-based molecular diagnostic tool for diseases (e.g., infectious diseases) .

The combination of the CASPROTAC compound of formula (I) of the present invention and CRISPR/Cas9 protein, variants or homologues thereof system (the reagents for genome editing or epigenetic modification) provides a simple, precise, safe and efficient strategy for genome editing or epigenetic modification. The CASPROTAC compounds of the present invention have great potential to be used in various applications/fields where the CRISPR/Cas9 proteins, variants or homologues thereof system is required, such as genome editing techniques, gene expression regulation (transcriptional activation/inhibition) , genome imaging, epigenetic modification, genomic medicine applications, research applications, disease models establishing, genome-wide genetic screening, genome engineering (for crop or plant) , CRISPR/Cas9 protein, variants or homologues thereof-based molecular diagnostic tool for diseases, and drug design and screening applications.

Examples

In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present disclosure. The present disclosure may be practiced without some or all of these specific details. The experimental methods in the Biological Activity Assay without specifying specific conditions usually can be carried out according to conventional conditions, such as the conditions described in Michael R. Green et al., Molecular Cloning: A Laboratory Manual, New York: Cold Spring Harbor Laboratory Press, 4th edition, 2012, or the conditions recommended by the manufacturer. In other cases, well-known process operations have not been described in detail in order not to unnecessarily obscure the present disclosure. Although the present disclosure will be described in conjunction with specific embodiments, it should be understood that this is not intended to limit the present disclosure to these embodiments.

The following abbreviations are used throughout the description and examples:
BnCl                     benzyl chloride
Bipy                     bipyridine
Boc                      t-Butyloxy carbonyl
BPO                      benzoyl peroxide
Cbz                      benzyloxycarbonyl
CRBN                     Cereblon protein
DCM                      dichloromethane
DIPEA or DIEA            N, N-diisopropylethylamine
DMF                      N, N-dimethylformamide
DMAP                     N, N-dimethylpyridin-4-amine
DMSO                     dimethyl sulfoxide
dppf                     1, 1'-bis (diphenylphosphino) ferrocene
equiv                    equivalent
EDCI                     1- (3-dimethylaminopropyl) -3-ethylcarbodiimide
ESI                      electrospray ionization
EtOH                     ethanol
EtONa                    sodium ethoxide
HATU                     2- (7-Azabenzotriazol-1-yl) -N, N, N', N'-tetramethyluronium
                         hexafluorophosphate
HOAc or AcOH             acetic acid
HOAT                     1-Hydroxy-7-azabenzotriazole
HOBT                     1-hydroxybenzotriazole
HPLC                     high performance liquid chromatography
HRMS                     high resolution mass spectrometry
LC-MS                    liquid chromatography-mass spectrometry
LRMS                     low resolution mass spectrometry
LC                       liquid chromatography
MsO                      methylsulfonyloxy
MW                       microwave
NBS                      N-bromosuccinimide
NMP                      N-methylpyrrolidone
¹H NMR                   Proton nuclear magnetic resonance
rt                       room temperature
TEA                      triethylamine
TFA                      trifluoroacetic acid
TfO                      trifluoromethylsulfonyloxy
THF                      tetrahydrofuran
TLC                      thin layer chromatography
TMS                      trimethylsilyl
TsOH                     p-toluenesulfonic acid
TsO-                     p-toluenesulfonyloxy
VHL                      von Hippel-Lindau protein

In the present disclosure, the ¹H NMR spectrum was recorded on a Bruker-500MHz nuclear magnetic resonance instrument, by using, as a solvent, CD₃OD (δ=3.31 ppm) containing 0.1%TMS (as an internal standard) ; or using, as a solvent, CDCl₃ (δ=7.26 ppm) containing 0.1%TMS (as an internal standard) ; or using, as a solvent, DMSO-d₆ (δ=2.50 ppm) containing 0.03%TMS (as an internal standard) . HRMS spectrum was recorded on an AB Triple 4600 mass spectrometer, HPLC preparation was measured on a SHIMADZU LC-20AP type instrument, and HPLC purity was measured on a SHIMADZU LC-30AP or Waters 1525 type instrument. Unless otherwise specified, all reactions were performed in the air atmosphere. The reactions were followed by TLC or LC-MS, intermediates were isolated and purified by column chromatography using e.g., an ISCO or Biotage, and the designed and synthesized target products were separated and purified by the Waters 2767 preparative HPLC.

Solvents and reagents are processed as follows:

The solvents used in the reactions such as DCM, DMF, anhydrous EtOH, and anhydrous MeOH were commercially available, e.g., from Chinese Sinopharm Group; Preparative grade CH₃CN and deionized water were used in HPLC preparation; Other reagents and medicines were commercially available and used directly without special instructions.

Unless otherwise specified, various carbon chain link units with different lengths (i.e., compounds used to form the groups represented by L) , as well as other reaction substrates, reagents and drugs were commercially available.

Unless otherwise specified, the materials and reagents used in the following examples can be purchased from commercial sources for direct use, or can be synthesized by using methods known in the art.

General synthesis methods

Compounds and/or pharmaceutically acceptable salts thereof of the present disclosure can be synthesized using commercially available raw materials by synthetic techniques known in the art. The synthetic schemes described below illustrate the preparation of most compounds. The starting materials or reagents used in each scheme can be purchased from commercial sources or prepared by methods known to those skilled in the art. One skilled in the art can prepare the salt, racemate, enantiomer, phosphate, sulfate, hydrochloride and prodrug forms of the compounds of formula (I) of the present disclosure according to routine techniques in the art.

General synthesis method (I) for compounds of Formula (I) of the present invention:

In Scheme 1, the R, R¹, R², (R³) _n1, rings A and B, (R⁴) _n2, (R⁵) _n3, U₁, L, X, W, (R⁸) _n4, Z₁, and (R⁹) _a1 are as defined in the embodiments or sub-embodiments of the compounds of Formula (I) herein.

The reaction in Scheme 1 can be condensation, which can be carried out under a conventional condition known to those skilled in the art. For example, the condensation can be carried out in the presence of HATU, DIPEA and DMF, or HOAt, EDCI, TEA and DCM at room temperature to 80℃.

For example, to a solution of amine substrate 1 (i.e., derivatives of CRISPR-Cas9 inhibitors) (1.0 eq. ) and acid substrate 2 (i.e., intermediates HOOC-L-ULM) (1.05eq. ) in DMF were added HATU (1.5 eq. ) and DIPEA (3.0 eq. ) . The reaction solution was stirred at 50℃ for 1-24 hours. The reaction was completed as monitored by LCMS detection. The reaction solution was filtered, and the filtrate was subjected to preparative HPLC for separation and purification to give the desired target compound.

Non-limiting examples of intermediates HOOC-L-ULM include:

wherein the X, Z₁, and (R⁹) _a1 are as defined in the embodiments or sub-embodiments of the compounds of Formula (I) herein.

General synthesis method (II) for compounds of Formula (I) of the present invention:

In Scheme 2, the R, R¹, R², (R³) _n1, ring A, (R⁴) _n2, (R⁵) _n3, U₁, L, X, W, (R⁸) _n4, Z₁, and (R⁹) _a1 are as defined in the embodiments or sub-embodiments of the compounds of Formula (I) herein, U₃ represents Br, Cl, I, OMs, OTs, or ONs.

The reaction in Scheme 2 can be amine alkylation, which can be carried out under a conventional condition known to those skilled in the art. For example, the amine alkylation can be carried out in the presence of DIEA and sodium iodide, or triethylamine and sodium iodide at room temperature to 80℃.

For example, to a solution of substrate 1 (i.e., derivatives of CRISPR-Cas9 inhibitors) (1.3 eq. ) and substrate 2 (i.e., intermediates U₃-L-ULM) (1.0 eq. ) in DMF were added triethylamine (3.0 eq. ) and sodium iodide (1.0 eq. ) . The reaction solution was stirred at 50℃ for 0.5-24 hours. The reaction was completed as monitored by LCMS detection. The reaction solution was filtered, and the filtrate was subjected to preparative HPLC for separation and purification to give the desired target compound.

Non-limiting examples of intermediates U₃-L-ULM include:

General synthesis method for HOOC-alkylene-thio-CRBN ligand:

In Scheme 3, X represents C (O) or CH₂.

General synthesis method for HOOC-PEG_n-thio-CRBN ligand:

In Scheme 4, X represents C (O) or CH₂.

General synthesis method for Br-alkylene-thio-CRBN ligand:

In Scheme 5, X represents C (O) or CH₂.

General synthesis method for HOOC-L-NH-CRBN ligand:

In Scheme 6, X represent C (O) or CH₂.

Step 1: a 30 mL microwave reaction tube was charged with fluorinated substrate (1 equiv) , corresponding raw amine (1.2 equiv) and N, N-diisopropylethylamine (5 equiv) , followed by addition of NMP (8 mL) . The reaction mixture was stirred at room temperature for 10 minutes. Then argon gas was slowly blown into the microwave reaction tube. The microwave reaction tube was placed into a microwave reactor, and heated to 110 ℃. The reaction mixture was stirred for 2 h. The reaction solution was cooled to room temperature, and poured into 90%brine. The resulting mixture was extract it with ethyl acetate (4 x 50 mL) . Organic phases were combined, washed with water (2 x 30 mL) and saturated brine (50 mL) , and dried over anhydrous Na₂SO₄, and evaporated under reduced pressure to remove the solvent. The obtained crude products were purified by column chromatography (eluent (v/v) : petroleum ether/ethyl acetate=1: 1) to give Boc protected intermediates.

Step 2: a 50 mL single-necked flask was charged with the Boc protected intermediate from step 1 and 20 mL of 88%formic acid. The reaction mixture was stirred at room temperature for 12 h, and evaporated under reduced pressure to remove the reaction solvent. The resulting residue was added with water and lyophilized to obtain the corresponding final target compound.

General synthesis method for HOOC-alkylene-NH-CRBN ligand:

In Scheme 7, X represent C (O) or CH₂.

Step 1: a 50 mL single-necked flask was charged with amine substrate (1 equiv. ) , NMP (8 mL) , corresponding substrate brominated tert butyl ester (1.2 equiv. ) and N, N-diisopropylethylamine (3 equiv. ) . The reaction solution was reacted at 110 ℃ for 12 h, cooled to room temperature, and subjected to a C18 reverse phase column for separation and purification, to give the corresponding intermediate tert butyl ester.

Step 2: a single-necked flask was charged with the intermediate tert butyl ester from step 1, DCM (6 mL) and TFA (2 mL) . The reaction mixture was stirred at room temperature for 1h, and evaporated under reduced pressure to remove the reaction solvent. The resulting residue was added with water and lyophilized to obtain the corresponding final target compound.

General synthesis method for MsO-alkylene-alkynyl-CRBN ligand:

In Scheme 8, X represent C (O) or CH₂.

Step 1: a solution of brominated substrate (1 equiv. ) in DMF (5mL) was bubbled with argon gas for 5 min, followed by sequentially addition of corresponding alkynol substrate (2 equiv. ) , Pd (PPh₃) ₂Cl₂ (0.1 equiv. ) and CuI (0.2 equiv. ) . The reaction mixture was stirred for 5min, and then triethylamine (2.5mL) was added thereto. The resulting mixture was heated to 80 ℃, and reacted overnight. The mixture was cooled to room temperature, quenched with 50 mL water, and extracted with ethyl acetate (3 x 50 mL) . Organic phases were combined, washed with water (2 x 30 mL) and saturated brine (50 mL) , dried over anhydrous Na₂SO₄, and evaporated under reduced pressure to remove the solvent. The obtained crude products were purified by column chromatography (eluent (v/v) : DCM/MeOH=5/1) to give the corresponding alcohol intermediate.

Step 2: to a solution of the corresponding alcohol intermediate from step 1in DCM (15 mL) were sequentially added triethylamine (3 equiv. ) and methyl sulfonyl chloride (1.5 equiv. ) . The reaction system become clear and reacted overnight. The reaction solution was washed with saturated brine, and evaporated under reduced pressure to remove the solvent. The resulting residue was purified by column chromatography (eluent (v/v) : DCM/MeOH=5/1) to give the corresponding target compound.

General synthesis method for MsO-alkylene-CRBN ligand:

In Scheme 9, X represent C (O) or CH₂.

Step 1: to a solution of the alkynol substrate (1 equiv. ) in ethanol (10 mL) were added 10%Pd/C (5 mg) and PtO₂ (5 mg) as catalysts under hydrogen atmosphere. The resulting mixture was reacted for 12 h at 50 ℃ under normal pressure under hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was evaporated under reduced pressure to remove the solvent. The resulting crude product was directly used in the next step.

Step 2: to a solution of the reduction product from step 1 in DCM (15 mL) were sequentially added triethylamine (3 equiv. ) and methyl sulfonyl chloride (1.5 equiv. ) . The reaction system become clear and reacted overnight. The reaction solution was washed with saturated brine, and evaporated under reduced pressure to remove the solvent. The resulting residue was purified by column chromatography (eluent (v/v) : DCM/MeOH=5/1) to give the corresponding target compound.

General synthesis method for Br-alkylene-oxy-CRBN ligand:

In Scheme 10, X represent C (O) or CH₂.

General synthesis method for HOOC-alkylene-oxy-CRBN ligand:

In Scheme 11, X represent C (O) or CH₂.

Step 1: to a solution of alcohol substrate (1 equiv. ) in DMF (20 mL) were added K₂CO₃ (3 equiv. ) and corresponding tert-butyl brominated alkanoate (1.2 equiv. ) . The reaction mixture was reacted at room temperature for 2h. The reaction solution was poured into 50 mL water, and the resulting mixture was extracted with dichloromethane twice. Organic phases were combined, washed with saturated brine, and evaporated under reduced pressure to remove the solvent. The resulting residue was purified by silica gel column chromatography (eluent (v/v) : DCM to DCM/MeOH (10/1) ) to give tert-butyl ester intermediate.

Step 2: to a 25 mL egg shaped flask were added the tert-butyl ester intermediate from step 1, TFA (5 mL) and DCM (10 mL) . The reaction mixture was stirred at room temperature for 12h, and evaporated under reduced pressure. The resulting residue was added with water and lyophilized to obtain the corresponding final target compound.

General synthesis method for HOOC-PEG_n-VHL ligand or HOOC-alkylene-VHL ligand:

In Scheme 12, Z₁ represents H or CH₃.

A 250 mL three necked flask was charged with the corresponding dicarboxylic acid substrate (2.5 equiv. ) , anhydrous DMF (10 mL) and anhydrous dichloromethane (150 mL) , followed by sequentially addition of DIPEA (10.0 mmol, 5 equiv) , VHL ligand substrate (2 mmol, 1 equiv) , HOAT (2.4 mmol, 1.2 equiv) and EDCI (2.4 mmol, 1.2 equiv) in ice water bath with stirring. After addition, the reaction mixture was stirred in ice water bath for 5 h, and then warmed up to room temperature and stirred overnight. After the reaction was complete, the reaction was quenched with 1 mL of deionized water. The mixture was evaporated under reduced pressure to remove dichloromethane. The resulting residue was subjected to a C18 reverse phase column for separation and purification. The collected fractions were evaporated under reduced pressure to remove acetonitrile, and the resulting residue was lyophilized to obtain the corresponding target compound.

General synthesis method for derivatives of CRISPR-Cas9 inhibitors

Depending upon the target compounds, the above schemes and their reaction substrates, reaction conditions (including reaction dosage, temperature, duration, etc. ) , work up, etc. can be appropriately modified and adjusted by techniques and methods well known to those skilled in the art to obtain the desired target compounds. The obtained target compounds can be further modified by the substituents and the like to obtain subsequent target compounds through methods well known to those skilled in the art.

Intermediate preparation examples

Intermediate preparation example 1: preparation of 16- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -16-oxohexadecanoic acid

Referring to the method of Scheme 12, the target compound was prepared under appropriate conditions that will be recognized by one skilled in the art, except that the diacid substrate used was hexadecane diacid. The target compound was obtained as white solid (0.88 g, yield 67%) . ESI[M+H] ⁺699.

Intermediate preparation example 1: preparation of ( (3aR, 4S, 9bR) -8- (3-aminophenyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-4-yl) methanol (GT-02631)

Referring to the method of Scheme 13, ( (3aR, 4S, 9bR) -8- (3-aminophenyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-4-yl) methanol (GT-02631) was prepared.

Step 1: preparation of 1-benzyl5- (tert-butyl) (3aS, 4S, 9bR) -8- (3- ( (tert-butoxycarbonyl) amino) phenyl) -4- (hydroxymethyl) -2, 3, 3a, 9b-tetrahydro-1H-pyrrolo [3, 2-c] quinoline-1, 5 (4H) -dicarboxylate

A mixture of benzyl (3aR, 4S, 9bR) -8- (3- ( (tert-butoxycarbonyl) amino) phenyl) -4- (hydroxymethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinoline-1-carboxylate (3g, 5.66mmol, 1 eq; CAS RN: 2225903-56-8) , (Boc) ₂O (1.36 g, 6.23mmol, 1.43 mL, 1.1 eq) , Et₃N (687.81 mg, 6.80 mmol, 946.09 uL, 1.2 eq) and DMAP (69.20 mg, 566.44umol, 0.1 eq) in DCM (30 mL) was stirred at 25 ℃ for 0.5 hr under N₂ atmosphere. LC-MS showed about 41.11%of desired compound mass was detected. The reaction mixture was quenched with water 40 mL and extracted with DCM 150 mL (50 mL×3) . The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=3/1) to give 1-benzyl5- (tert-butyl) (3aS, 4S, 9bR) -8- (3- ( (tert-butoxycarbonyl) amino) phenyl) -4- (hydroxymethyl) -2, 3, 3a, 9b-tetrahydro-1H-pyrrolo [3, 2-c] quinoline-1, 5 (4H) -dicarboxylate as a yellow solid (2.5 g, yield 65.79%) . LCMS: MS (M+H⁺) =630.5.

Step2: preparation of tert-butyl (3aS, 4S, 9bR) -8- (3- ( (tert-butoxycarbonyl) amino) phenyl) -4- (hydroxymethyl) -1, 2, 3, 3a, 4, 9b-hexahydro-5H-pyrrolo [3, 2-c] quinoline-5-carboxylate

A mixture of 1-benzyl5- (tert-butyl) (3aS, 4S, 9bR) -8- (3- ( (tert-butoxycarbonyl) amino) phenyl) -4- (hydroxymethyl) -2, 3, 3a, 9b-tetrahydro-1H-pyrrolo [3, 2-c] quinoline-1, 5 (4H) -dicarboxylate (2.5 g, 3.97 mmol, 1eq) , Pd/C (250 mg, 10%purity) in MeOH (25mL) was degassed and purged with H₂ for 3 times, and then the mixture was stirred at 25 ℃ for 2 hr under H₂atmosphere at 50 psi. LC-MS showed about 83.56%of desired compound mass was detected. The mixture was filtered on a celite pad and then the filtrate was concentrated under reduced pressure to give a crude product as a white solid (2 g, crude) . The crude product was used to the next step without further purification. LCMS: MS (M+H⁺) =496.5

Step 3: preparation of tert-butyl (3aS, 4S, 9bR) -8- (3- ( (tert-butoxycarbonyl) amino) phenyl) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -1, 2, 3, 3a, 4, 9b-hexahydro-5H-pyrrolo [3, 2-c] quinoline-5-carboxylate

A mixture of the crude product from step2 (1.9 g, 3.83 mmol, 1 eq) , pyridine-4-carbaldehyde (410.62 mg, 3.83 mmol, 360.20 μL, 1 eq) and AcOH (230.21 mg, 3.83 mmol, 219.25 μL, 1 eq) in DCM (38 mL) was stirred at 25 ℃ for 1 hr, then to the solution was added NaBH (OAc) ₃ (2.44 g, 11.50 mmol, 3 eq) and the mixture was stirred at 25 ℃ for another 3 hr. LC-MS showed about 79.80%of desired compound mass was detected. The residue was diluted with 30 mL DCM, quenched with a saturate NaHCO₃ aqueous solution (50 mL) , then was extracted with DCM (30 mL×3) . The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC. The target compound tert-butyl (3aS, 4S, 9bR) -8- (3- ( (tert-butoxycarbonyl) amino) phenyl) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -1, 2, 3, 3a, 4, 9b-hexahydro-5H-pyrrolo [3, 2-c] quinoline-5-carboxylate (1.1 g, yield 48.90%) was obtained as a white solid. LCMS: MS (M+H⁺) =587.4

Step 4: preparation of the target compound ( (3aR, 4S, 9bR) -8- (3-aminophenyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-4-yl) methanol hydrochloride

To a solution of tert-butyl (3aS, 4S, 9bR) -8- (3- ( (tert-butoxycarbonyl) amino) phenyl) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -1, 2, 3, 3a, 4, 9b-hexahydro-5H-pyrrolo [3, 2-c] quinoline-5-carboxylate (1.1 g, 1.87 mmol, 1 eq) in MeOH (11 mL) was added dropwise HCl/MeOH (4 M) at 20 ℃, and then the mixture was stirred for 3 hr. LC-MS showed about 99.10%of desired compound mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was used without further purification. LC-MS showed about 99.48%of desired compound mass was detected. HPLC showed about 97.30%purity. The target compound (1.1 g, yield 96.94%, 6HCl) was obtained as a yellow solid. ¹H NMR: (400MHz, D₂O) δ 8.67 (br d, J= 5.50 Hz, 2H) , 8.03 (br d, J=3.38Hz, 2H) , 7.57 (br d, J=7.38Hz, 3H) , 7.50 (s, 1H) , 7.45-7.35 (m, 1H) , 7.31 (br d, J=7.13Hz, 1H) , 6.94 (d, J=8.63Hz, 1H) , 5.03-4.87 (m, 2H) , 4.81 (br s, 1H) , 3.77 (dd, J=11.82, 3.31Hz, 1H) , 3.70-3.52 (m, 3H) , 3.33 (dt, J=5.44, 2.53Hz, 1H) , 2.84-2.73 (m, 1H) , 2.59 (br dd, J=14.38, 6.63Hz, 1H) , 2.22 (br s, 1H) .

Examples

Example 1: preparation of 2- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide (GT-03390)

Referring to the method of Scheme 1, the target compound (GT-03390) was prepared as a white solid (4.8 mg, yield 25%) . LCMS (ESI) m/z: cal. C₃₉H₃₉N₆O₅S⁺ [M+H] ⁺, 703.27; found, 703.3. ¹H NMR (400MHz, MeOD) δ8.81 (s, 2H) , 8.20 (s, 2H) , 7.82 (d, J=7.6Hz, 2H) , 7.69–7.60 (m, 1H) , 7.55–7.40 (m, 3H) , 7.36–7.28 (m, 2H) , 7.24–7.14 (m, 1H) , 6.89 (d, J=8.4Hz, 1H) , 5.23–5.01 (m, 2H) , 4.50 (s, 2H) , 3.84 (s, 2H) , 3.83–3.75 (m, 1H) , 3.67–3.32 (m, 5H) , 2.92–2.64 (m, 4H) , 2.61–2.49 (m, 1H) , 2.43–2.13 (m, 2H) , 2.06–1.92 (m, 1H) .

Example 2: preparation of 7- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H- pyrrolo [3, 2-c] quinolin-8-yl) phenyl) heptanamide (GT-03391)

Referring to the method of Scheme 1, the target compound (GT-03391) was prepared as a white solid (5.7 mg, yield 27%) . LCMS (ESI) m/z: cal. C₄₄H₄₉N₆O₅S⁺ [M+H] ⁺, 773.35; found, 773.3.

Example 3: preparation of 8- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-

pyrrolo [3, 2-c] quinolin-8-yl) phenyl) octanamide (GT-03392)

Referring to the method of Scheme 1, the target compound (GT-03392) was prepared as a yellow solid (6.9 mg, yield 32%) . LCMS (ESI) m/z: cal. C₄₅H₅₁N₆O₅S⁺ [M+H] ⁺, 787.36; found, 787.3.¹H NMR (400MHz, MeOD) δ 8.78 (s, 2H) , 8.06–7.85 (m, 3H) , 7.58 (t, J=7.2Hz, 2H) , 7.53 –7.42 (m, 3H) , 7.38–7.21 (m, 3H) , 6.89 (d, J=8.8Hz, 1H) , 5.13 (dd, J=13.2, 2.9Hz, 1H) , 5.07–4.98 (m, 1H) , 4.46–4.31 (m, 2H) , 3.78 (d, J=8.1Hz, 1H) , 3.62 (dd, J=11.1, 6.3Hz, 1H) , 3.58–3.39 (m, 2H) , 3.04 (t, J=7.1Hz, 2H) , 2.93–2.81 (m, 1H) , 2.80–2.70 (m, 2H) , 2.59–2.43 (m, 2H) , 2.39 (t, J=7.3Hz, 2H) , 2.27–2.09 (m, 2H) , 1.73–1.61 (m, 4H) , 1.51–1.37 (m, 6H) .

Example 4: preparation of 9- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) decanamide (GT-03393)

Referring to the method of Scheme 1, the target compound (GT-03393) was prepared as a yellow solid (7.6 mg, yield 35%) . LCMS (ESI) m/z: cal. C₄₆H₅₃N₆O₅S⁺ [M+H] ⁺, 801.38; found, 801.3. ¹H NMR (400MHz, MeOD) δ8.75 (s, 2H) , 8.02–7.84 (m, 3H) , 7.60 (d, J=7.6Hz, 2H) , 7.54–7.43 (m, 3H) , 7.38–7.21 (m, 3H) , 6.88 (d, J=8.3Hz, 1H) , 5.14 (dd, J=13.4, 5.0Hz, 1H) , 5.04–4.96 (m, 1H) , 4.47–4.32 (m, 2H) , 3.83–3.73 (m, 1H) , 3.65–3.57 (m, 1H) , 3.53–3.36 (m, 2H) , 3.02 (t, J=7.0Hz, 2H) , 2.94–2.82 (m, 1H) , 2.81–2.68 (m, 2H) , 2.58–2.46 (m, 2H) , 2.38 (t,J=7.3Hz, 2H) , 2.25–2.11 (m, 2H) , 1.77–1.59 (m, 4H) , 1.50–1.33 (m, 8H) .

Example 5: preparation of 10- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) decanamide (GT-03394)

Referring to the method of Scheme 1, the target compound (GT-03394) was prepared as a yellow solid (5.3 mg, yield 24%) . LCMS (ESI) m/z: cal. C₄₇H₅₅N₆O₅S⁺ [M+H] ⁺, 815.39; found, 815.3. ¹H NMR (400MHz, MeOD) δ8.78–8.63 (m, 2H) , 8.04–7.83 (m, 3H) , 7.64–7.43 (m, 5H) , 7.35–7.20 (m, 3H) , 6.88 (d, J=8.6Hz, 1H) , 5.18–5.09 (m, 1H) , 5.05–4.97 (m, 1H) , 4.46–4.33 (m,2H) , 3.82–3.76 (m, 1H) , 3.62 (dd, J=11.2, 6.4Hz, 1H) , 3.54–3.38 (m, 2H) , 3.01 (t, J=7.0Hz, 2H) , 2.91–2.81 (m, 1H) , 2.80–2.68 (m, 2H) , 2.59–2.47 (m, 2H) , 2.39 (t, J=7.4Hz, 2H) , 2.26–2.11 (m, 2H) , 1.76–1.57 (m, 4H) , 1.37–1.27 (m, 10H) .

Example 6: preparation of 11- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H- pyrrolo [3, 2-c] quinolin-8-yl) phenyl) undecanamide (GT-03395)

Referring to the method of Scheme 1, the target compound (GT-03395) was prepared as a yellow solid (4.7 mg, yield 21%) . LCMS (ESI) m/z: cal. C₄₈H₅₇N₆O₅S⁺ [M+H] ⁺, 829.41; found, 829.3. ¹H NMR (400MHz, MeOD) δ 8.69 (s, 2H) , 7.96 (s, 1H) , 7.86–7.73 (m, 2H) , 7.66–7.57 (m, 2H) , 7.52–7.44 (m, 3H) , 7.37–7.21 (m, 3H) , 6.88 (d, J=7.6Hz, 1H) , 5.19–5.09 (m, 1H) , 5.01–4.96 (m, 1H) , 4.46–4.37 (m, 2H) , 3.81–3.73 (m, 1H) , 3.65–3.59 (m, 1H) , 3.50–3.44 (m, 2H) , 3.02 (t, J=7.4Hz, 2H) , 2.90–2.82 (m, 1H) , 2.79–2.68 (m, 2H) , 2.55–2.44 (m, 2H) , 2.39 (t, J= 7.4Hz, 2H) , 2.22–2.13 (m, 2H) , 1.79–1.55 (m, 6H) , 1.34–1.23 (m, 10H) .

Example 7: preparation of 6- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) hexanamide (GT-02593)

Referring to the method of Scheme 1, the target compound (GT-02593) was prepared as a white solid (6.2 mg, yield 30%) . LCMS (ESI) m/z: cal. C₄₃H₄₇N₆O₅S⁺ [M+H] ⁺, 759.33; found, 759.4. ¹H NMR (400MHz, DMSO) δ 10.98 (s, 1H) , 9.91 (s, 1H) , 8.69 (d, J=5.8Hz, 2H) , 7.86 (s, 1H) , 7.69 (d, J=5.2Hz, 2H) , 7.62 (d, J=8.5Hz, 1H) , 7.57–7.48 (m, 2H) , 7.47–7.39 (m, 3H) , 7.32–7.23 (m, 2H) , 6.90 (d, J=8.5Hz, 1H) , 5.12 (dd, J=13.3, 5.2Hz, 1H) , 4.83–4.58 (m, 2H) , 4.34 (d, J=17.4 Hz, 1H) , 4.20 (d, J=17.4Hz, 1H) , 3.68–3.61 (m, 1H) , 3.54–3.50 (m, 1H) , 3.23–3.03 (m, 7H) , 2.98–2.82 (m, 2H) , 2.71–2.56 (m, 3H) , 2.38–2.29 (m, 4H) , 2.09–1.90 (m, 2H) , 1.72–1.55 (m, 5H) , 1.55–1.40 (m, 2H) .

Example 8: preparation of 5- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) pentanamide (GT-02592)

Referring to the method of Scheme 1, the target compound (GT-02592) was prepared as a white solid (8.5 mg, yield 42%) . LCMS (ESI) m/z: cal. C₄₂H₄₅N₆O₅S⁺ [M+H] ⁺, 745.32; found, 745.3. ¹H NMR (400MHz, DMSO) δ 10.98 (s, 1H) , 9.93 (s, 1H) , 8.66 (s, 2H) , 7.85 (s, 1H) , 7.66–7.58 (m, 3H) , 7.55 (d, J=6.7Hz, 1H) , 7.51–7.36 (m, 4H) , 7.33–7.23 (m, 2H) , 6.94–6.87 (m, 1H) , 5.11 (dd, J=13.2, 5.1Hz, 1H) , 4.82–4.50 (m, 2H) , 4.35 (d, J=17.5Hz, 1H) , 4.21 (d, J=17.5Hz, 1H) , 3.68–3.61 (m, 1H) , 3.54–3.47 (m, 1H) , 3.20–3.08 (m, 7H) , 2.95–2.83 (m, 3H) , 2.69–2.64 (m, 2H) , 2.37–2.30 (m, 3H) , 2.08–1.93 (m, 2H) , 1.82–1.60 (m, 4H) .

Example 9: preparation of 3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) propanamide (GT-02590)

Referring to the method of Scheme 1, the target compound (GT-02590) was prepared as a white solid (6.4mg, yield32%) . LCMS (ESI) m/z: cal. C₄₀H₄₁N₆O₅S₂ ⁺ [M+H] ⁺, 717.29; found, 717.3. ¹H NMR (400MHz, DMSO) δ 10.97 (s, 1H) , 10.05 (s, 1H) , 8.70 (d, J=6.0Hz, 2H) , 7.84 (s, 1H) , 7.74–7.68 (m, 3H) , 7.61–7.53 (m, 2H) , 7.46–7.38 (m, 3H) , 7.35–7.25 (m, 2H) , 6.90 (d, J=8.5 Hz, 1H) , 5.10 (dd, J=13.3, 5.1Hz, 1H) , 4.82–4.75 (m, 1H) , 4.67–4.53 (m, 1H) , 4.35 (d, J=17.7 Hz, 1H) , 4.21 (d, J=17.5Hz, 1H) , 3.68–3.61 (m, 2H) , 3.31–3.11 (m, 10H) , 2.71–2.66 (m, 2H) , 2.39–2.29 (m, 3H) , 2.02–1.90 (m, 2H) .

Example 10: preparation of 4- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide (GT-02591)

Referring to the method of Scheme 1, the target compound (GT-02591) was prepared as a white solid (5.5 mg, yield 28%) . LCMS (ESI) m/z: cal. C₄₁H₄₃N₆O₅S₂ ⁺ [M+H] ⁺, 731.30; found, 731.3. ¹H NMR (500MHz, DMSO) δ 10.99 (s, 1H) , 10.06 (s, 1H) , 8.76 (d, J=5.9Hz, 2H) , 7.90–7.84 (m, 3H) , 7.68–7.64 (m, 1H) , 7.57 (d, J=6.7Hz, 1H) , 7.55–7.50 (m, 1H) , 7.47–7.38 (m, 3H) , 7.32–7.24 (m, 2H) , 6.89 (d, J=8.5Hz, 1H) , 5.12 (dd, J=13.3, 5.1Hz, 1H) , 4.85 (d, J=13.2Hz, 1H) , 4.74 –4.57 (m, 1H) , 4.36 (d, J=17.3Hz, 1H) , 4.22 (d, J=17.3Hz, 1H) , 3.68–3.62 (m, 2H) , 3.31–3.22 (m,7H) , 3.15 (t, J=7.2Hz, 3H) , 2.95–2.83 (m, 2H) , 2.42–2.29 (m, 2H) , 2.04–1.87 (m, 5H) .

Example 11: preparation of 7- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) thio) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) heptanamide (GT-03675)

Referring to the method of Scheme 1, the target compound (GT-03675) was prepared as a white solid (8.6mg, yield42%) . LCMS (ESI) m/z: cal. C₄₄H₄₇N₆O₆S⁺ [M+H] ⁺, 787.32; found, 787.30.

Example 12: preparation of 7- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) heptanamide (GT-03680)

Referring to the method of Scheme 1, the target compound (GT-03680) was prepared as a white solid (7.3 mg, yield 37%) . LCMS (ESI) m/z: cal. C₄₄H₄₉N₆O₆ ⁺ [M+H] ⁺, 757.36; found, 757.40.

Example 13: preparation of 7- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) heptanamide (GT-03681)

Referring to the method of Scheme 1, the target compound (GT-03681) was prepared as a white solid (7.9 mg, yield40%) . LCMS (ESI) m/z: cal. C₄₄H₅₀N₇O₅ ⁺ [M+H] ⁺, 756.38; found, 756.40.

Example 14: preparation of 2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) ethoxy) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide (GT-03682)

Referring to the method of Scheme 1, the target compound (GT-03682) was prepared as a white solid (7.0 mg, yield 36%) . LCMS (ESI) m/z: cal. C₄₁H₄₃N₆O₆S⁺ [M+H] ⁺, 747.29; found, 747.30.

Example 15: preparation of 2- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) ethoxy) ethoxy) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide (GT-03683)

Referring to the method of Scheme 1, the target compound (GT-03683) was prepared as a white solid (6.8 mg, yield 33%) . LCMS (ESI) m/z: cal. C₄₃H₄₇N₆O₇S⁺ [M+H] ⁺, 791.31; found, 791.30.

Example 16: preparation of 2- (2- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) ethoxy) ethoxy) ethoxy) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide (GT-03684)

Referring to the method of Scheme 1, the target compound (GT-03684) was prepared as a white solid (10.0 mg, yield 46%) . LCMS (ESI) m/z: cal. C₄₅H₅₁N₆O₈S⁺ [M+H] ⁺, 835.34; found, 835.40.

Example 17: preparation of 17- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) -3, 6, 9, 12, 15-pentaoxaheptadecanamide (GT-03686)

Referring to the method of Scheme 1, the target compound (GT-03686) was prepared as a white solid (11.5 mg, yield 48%) . LCMS (ESI) m/z: cal. C₄₉H₅₉N₆O₁₀S⁺ [M+H] ⁺, 923.39; found, 923.40.

Biological activity assay

Experimental materials:

Cas9 proteins were made from plasmid from Addgene#53261 at the Department of Cell and Chemical Biology, Leiden University Medical Center (LUMC) .

Methods

Cell Culture

K562 cells were cultured in RPMI 1640 with L-glutamine, 10%fetal bovine serum (FBS) and1%Pen-Strep. HEK 293T cells were cultured in DMEM, 10%FBS and 1%Pen-Strep. Cell density and culture conditions were maintained according to the ENCODE (the Encyclopedia of DNA Elements) Cell Culture Guidelines (www. encodeproject. org) .

Electroporation

One million K562 cells were washed once by PBS and resuspended in 50 μl of Gene Pulser Electroporation Buffer (Bio-Rad, #1652676) , containing 60 pmol of Cas9 protein (made in the Department of Cell and Chemical Biology, LUMC) . Cells were then transferred into the Gene Pulser/MicroPulser Electroporation Cuvettes (Bio-Rad, #1652089) , and pulsed at 60V voltage, 500μF capacitance, ∞ sample resistance using a Gene Pulser X cell electroporator (Bio-Rad) . Cells were then cultured in 6-well plates.

Assembly of guide RNA and Cas9 protein into RNP complexes in vitro

The guide RNA targeting GFP and Cas9 proteins were mixed at a 1: 1.2 molar ratio (60 pmol of Cas9 protein +72 pmol of guide RNA targeting GFP) in PBS, and incubated at room temperature for 20 min to allow the formation of the RNP complexes. The RNP complexes were kept on ice until electroporation.

Guide RNA in vitro synthesis

The templates DNA for guide RNA synthesis were prepared usingHigh-Fidelity 2X PCR Master Mix (New England Biolabs, #M0544) , T7-EGFP gRNA primer (10μM) and common scaffold primer (10μM) . The procedures were: 95 ℃ for 2 min, 60 ℃ for 1 min, 72 ℃ for 3 min. The products were cleaned up using ISOLATE II PCR and Gel Kit (Bioline, BIO-52060) .

T7-EGFP gRNA primers (SEQ ID NO: 1) :

common scaffold primer (SEQ ID NO: 2) :

Guide RNAs were transcribed from the DNA template using the Guide RNA in vitro synthesis Kit (Agilent Technologies, 5190-7714, 5190-7719) according to the manufacturer’s procedure.

Stable cell line generation and the protein induction

293T cells were grown in 6 well plate at 50%confluency before transfection. For each well of 293T cells grown in 2 ml of fresh medium, 1 μg of inducible-dCas9-APEX2-EGFP plasmids (from Addgene#97421) and 1μg of PiggyBac plasmid and 2.4 μl ofPolyethylenimine Transfection Reagent (MERCK, 919012) were mixed in 50 μl of serum-free medium and used for transfection. Medium was refreshed one day after transfection. To select for transfected cells, 2 μg/ml of puromycin (Thermofisher, #A1113803) was added two days after transfection and kept for another 2days. Then cell clones were generated by limiting dilution. The successful knock-out clones were confirmed by PCR and sanger sequencing.

To induce the expression of dCas9-APEX2 protein, 500 ng/ml of doxycycline was added to the inducible-dCas9-APEX2-EGFP cell line for one day.

Western blotting

Cells were lysed directly in 1X RIPA buffer (Merck, 20-188) . All buffers were supplemented with the 50X protease inhibitor cocktail (Roche) . Lysates were quantified using an enhanced bicinchoninic acid (BCA) protein assay kit (Thermofisher Scientific, 23225) , and equal amounts of proteins were analyzed by SDS-PAGE for subsequent western blotting analysis. The separated proteins were transferred to a nitrocellulose membrane, blocked with5% (wt/vol) nonfat milk in PBST for 1h at room temperature, probed with the respective primary antibodies overnight at 4℃. The membrane was washed with PBST three times, incubated with the secondary antibodies (1: 5000 dilution) for 1 h at room temperature, and then washed with PBST three times. The Pierce enhanced chemiluminescence (ECL) Plus Western Blotting Substrate (Thermo Scientific, 32106) was used as the substrates and the signal was quantified with BioRad ChemiDoc Imaging System.

DC₅₀ value (the drug concentration required for degrading proteins by 50%, abbreviated as DC₅₀) reads method: comparing the gray values of the Western blotting bands for the drug treatment with the gray values of the Western blotting band for the DMSO control, and reading the drug concentration range corresponding to the gray value of the Western blotting bands for the drug treatment which is equal to half of the gray value of the Western blotting band for the DMSO control.

DC₅₀ value could also be calculated as follows: using software ImageJ to quantify the gray values of the Western blotting bands for the drug treatment, fitting the relationship curve between drug concentrations and gray values, and from the fitted curve, calculating the drug concentration corresponding to half of the gray value of the Western blotting band for the DMSO control.

Western-blot (WB) determination of half-degradation concentration (DC₅₀) of the compounds of the present invention to target proteins (e.g., Cas9 proteins, or dCas9, or RNP complexes comprising Cas9 proteins)

WB assay 1:

The effects of the compounds of the present invention (including those in table 1 and examples) were tested in K562 cells.

K562 cells were electroporated with 60 pmol of recombinant Cas9 proteins, the concentration of which is often used in genome editing experiments. 24 hr post electroporation, cells were treated with1μM of the respective CASPROTACs compounds of the present invention for another 24 hrs, before the level of the recombinant Cas9 proteins was tested. Results were showed in Figures 1A and 1B.

WB assay 2:

To better test the optimal concentration of these CASPROTAC compounds, K562 cells transfected with recombinant Cas9 proteins were treated with a serial dilution of CASPROTAC compounds GT-02592 and GT-02593. Results were showed in Figures 1C and 1D.

WB assay 3:

To better test the optimal linker length of the compounds of the present invention (including those in table 1 and examples) , these compounds were tested again on K562 cells transfected with Cas9 proteins first with a fixed concentration of 1μM for 24 hrs. Around 50%of protein reduction was observed from two compounds GT-03391 and GT-03395 among 5 other molecules, indicating these two compounds could degrade Cas9 proteins efficiently (Figures 2A and 2B) . A serial dilution of the GT-03391 and GT-03395 was tested, again these two compounds showed a Cas9 degradation profiles similar to other PROTAC molecules, with the optimal concentration of 1μM (Figures 2C and 2D) . As CASPROTAC compound GT-03391 showed the most effective Cas9 degradation profile, further tests were focused on it. To test the optimal duration to apply CASPROTAC compound GT-03391, time course experiments were performed on K562 cells transfected with Cas9 proteins. Atime dependent degradation of Cas9 proteins was observed, with 24 hr time point giving the highest degradation efficiency (Figure 2E) . It should be noted that at 36-hr time point, the Cas9 protein level between compound GT-03391-treated cells and control ones dropped (Figure2F) . One possibility is that detection limited of western blotting was reached to distinguish the differences in protein levels.

WB assay 4:

Besides Cas9 proteins that are able to make DNA breaks for genome editing, catalytic dead Cas9 proteins (dCas9) that could only bind DNA but not make DNA breaks are also broadly used in both basic research and clinical trials. In order to test if CASPROTAC compound GT-03391 could also degrade dCas9 proteins, 293T cells that express dCas9-APEX were used. The expression of the dCas9-APEX2 is driven by a tetracycline-controlled Tet-On inducible gene expression system. These cells will only start to express the dCas9-APEX2 protein complex once doxycycline (dox) is added, and the transcription would stop if dox is removed. 293T/dCas9-APEX2 cells were treated with dox for 24 hours. After dox was removed and cells were washed extensively, the protein level of dCas9-APEX2 was monitored. Transcription of the dCas9-APEX2 proteins stopped after dox removal. Therefore, no new dCas9-APEX will be produced when treated with CASPROTAC compound GT-03391, to better monitor the degradation efficiency of dCas9 proteins. The results showed that CASPROTAC compound GT-03391 degraded dCas9 by 50%after 24 hrs with 1μM concentration, which is as efficiently as degrading Cas9 proteins (Figures 2G and 2H) . Furthermore, a dose dependent degradation of dCas9 proteins was also observed (Figures 2G and 2H) .

WB assay 5:

PROTAC molecules use the proteasome degradation system to remove the target proteins. To further confirm that CASPROTAC molecules degrade Cas9 proteins via the endogenous proteasome systems within the cells, K562 cells transfected with Cas9 proteins were co-treated with proteasome inhibitor MG132 (500 nM) and CASPROTAC compound GT-03391 for 24 hrs. The degradation of Cas9 proteins were stopped completed when the activity of proteasome was blocked, as shown by the accumulation of poly-ubiquitinated species in the cell lysate (Figures 3A, 3B and 3C) , indicating that CASPROTAC compound GT-03391 function as a bona fide PROTAC.

WB assay 6:

As Cas9 proteins need to assemble with guide RNAs into the ribonucleoprotein complexes (RNP) before it could function, we also tested if CASPROTAC compound GT-03391 is capable to degrade the more relevant RNP complexes. As shown in Figures 3D and 3E, CASPROTAC compound GT-03391 could degrade RNP complex as efficient as Cas9 proteins, indicating that this molecule could target the Cas9 proteins in different forms.

In general, the results showed that the series PROTAC molecules of the present invention could target the CRISPR system, and degrade Cas9, dCas9 and RNP complexes by 50%. We expect these PROTAC molecules of the present invention could be used in genome medicine for a more precise genome editing with few off-target effects. These molecules have great potential to be used in various applications/fields where the CRISPR/Cas9 proteins, variants or homologues thereof system is required, such as genome editing techniques, gene expression regulation (transcriptional activation/inhibition) , genome imaging, epigenetic modification, genomic medicine applications, research applications, disease models establishing, genome-wide genetic screening, genome engineering (for crop or plant) , CRISPR/Cas9 protein, variants or homologues thereof-based molecular diagnostic tool for diseases, and drug design and screening applications.

The basic principles, main features and advantages of the present disclosure are shown and described above. Those skilled in the art should understand that the present disclosure is not limited by the foregoing embodiments, and they can make various changes, substitutions and alterations herein without departing from the spirit and scope of the present disclosure. These changes, substitutions and alterations fall within the scope of the present disclosure. The claimed scope of the present disclosure is defined by the appended claims and their equivalents.

Claims

A compound of Formula (I)

or a salt, an enantiomer, a stereoisomer, a solvate, or a polymorph thereof;

wherein:

R represents C (O) , S (O) ₂, CH₂, CH₂C (O) , or C (O) CH₂;

R¹ represents C_1-4 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, cyano, amino, and any combination thereof;

R² represents H or C_1-4 alkyl;

(R³) _n1 indicates that phenyl where (R³) _n1 is attached to is optionally substituted with n1 R³ group (s) , wherein n1 represents an integer of 0, 1, 2, or 3, and each R³ group independently represents halogen, hydroxyl, cyano, amino, C_1-4 alkyl, halogenated C_1-4 alkyl, or C_1-3 alkoxy;

ring A represents aryl, heteroaryl, heterocyclyl, or cycloalkyl;

(R⁴) _n2 indicates that the ring A where (R⁴) _n2 is attached to is optionally substituted with n2 R⁴ group (s) , wherein n2 represents an integer of 0, 1, 2, 3, 4, or 5, and each R⁴ group independently represents halogen, hydroxyl, cyano, amino, C_1-4 alkyl, halogenated C_1-4 alkyl, C_1-3 alkoxy, or C_3-6 cycloalkyl;

W represents:
-U₁-#

wherein U₁ represents ethynylene or vinylene; or

wherein W₁ represents ethynylene or vinylene, or W₁ represents a bond; and

ring B represents arylene, heteroarylene, heterocyclylene, or cycloalkylene;

(R⁵) _n3 indicates that the ring B where (R⁵) _n3 is attached to is optionally substituted with n3 R⁵ group (s) , wherein n3 represents an integer of 0, 1, 2, 3, 4, or 5, and each R⁵ group independently represents halogen, hydroxyl, cyano, amino, C_1-4 alkyl, halogenated C_1-4 alkyl, C_1-3 alkoxy, C (O) N (C_1-3 alkyl) ₂, or C_3-6 cycloalkyl; and

symbol#indicates the point of attachment to the U₂; or

W represents a bond;

U₂ represents C (O) NH, NHC (O) , C (O) O, OC (O) , NH, O, or ethynylene, or U₂ represents a bond;

L represents an optionally substituted linear or branched alkylene group, wherein one or more groups selected from the group consisting of R_a, R_b, and any combination thereof are optionally inserted between one or more pairs of adjacent carbon atoms of the backbone carbon chain of the linear or branched alkylene group, wherein each R_a is independently selected from the group consisting of O, C (O) , OC (O) , S, S (O) , S (O) ₂, S (O) ₂N (R⁶) , N (R⁶) S (O) ₂, C (O) N (R⁶) , N (R⁶) C (O) , N (R⁶) , and N (R⁶) C (O) N (R⁶) , where each R⁶ independently represents H or C_1-3 alkyl, and in case that two or more groups R_a are inserted into the backbone carbon chain of the linear or branched alkylene group, the two or more groups R_a are not directly connected to each other; and wherein each R_b is independently selected from the group consisting of optionally substituted cycloalkylene, optionally substituted arylene, optionally substituted heterocyclylene, optionally substituted heteroarylene, and any combination thereof; and

ULM represents a E3 ubiquitinated ligase ligand which is covalently bonded to the L.
The compound of Formula (I) or a salt, an enantiomer, a stereoisomer, a solvate, or a polymorph thereof as claimed in claim 1, wherein

the ring A represents C_5-20 aryl, 5-to 20-membered heteroaryl, 4-to 20-membered heterocyclyl, or C_3-20 cycloalkyl; and/or

W represents:
-U₁-#

wherein U₁ represents ethynylene or vinylene, or U₁ represents a bond; or

wherein W₁ represents ethynylene or vinylene, or W₁ represents a bond; and

the ring B represents C_5-20 arylene, 5-to 20-membered heteroarylene, 4-to 20-membered heterocyclylene, or C_3-20 cycloalkylene; and

symbol#indicates the point of attachment to the U₂; or

W represent a bond; and/or

the L represents an optionally substituted linear or branched C_1-40 alkylene group, wherein one or more groups selected from the group consisting of R_a, R_b, and any combination thereof are optionally inserted between one or more pairs of adjacent carbon atoms of the backbone carbon chain of the linear or branched C_1-40 alkylene group, wherein each R_a is independently selected from the group consisting of O, C (O) , OC (O) , S, S (O) , S (O) ₂, S (O) ₂N (R⁶) , N (R⁶) S (O) ₂, C (O) N (R⁶) , N (R⁶) C (O) , N (R⁶) , and N (R⁶) C (O) N (R⁶) , where each R⁶ independently represents H or C_1-3 alkyl, and in case that two or more groups R_a are inserted into the backbone carbon chain of the linear or branched C_1-40 alkylene group, the two or more groups R_a are not directly connected to each other; and wherein each R_b is independently selected from the group consisting of optionally substituted C_3-20 cycloalkylene, optionally substituted C_5-20 arylene, optionally substituted 4-to 20-membered heterocyclylene, optionally substituted 5-to 20-membered heteroarylene, and any combination thereof.
The compound of Formula (I) or a salt, an enantiomer, a stereoisomer, a solvate, or a polymorph thereof as claimed in claim 1, wherein

the ring A represents: phenyl, naphthyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, benzo [2, 1, 3] oxadiazolyl, benzo [2, 1, 3] thiadiazolyl, benzo [1, 2, 3] thiadiazolyl, quinolyl, isoquinolyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrazolo [1, 5-a] pyridyl, pyrazolo [1, 5-a] pyrimidyl, imidazo [1, 2-a] pyridyl, 1H-pyrrolo [3, 2-b] pyridyl, 1H-pyrrolo [2, 3-b] pyridyl, 4H-fluoro [3, 2-b] pyrrolyl, pyrrolo [2, 1-b] thiazolyl, imidazo [2, 1-b] thiazolyl, azetidinyl, pyrrolidinyl, 2-oxopyrrolidin-1-yl, imidazolidinyl, pyrazolidyl, triazolyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, piperidinyl, 2-oxopiperidin-1-yl, piperazinyl, morpholinyl, thiomorpholinyl, dioxacyclohexyl, 3-azabicyclo [3.1.0] hexyl, 3-azabicyclo [4.1.0] heptyl, 1, 4-diazacycloheptan-1-yl, 3, 8-diazabicyclo [3.2.1] octan-3-yl, 2, 5-diazabicyclo [2.2.2] octan-2-yl, 1, 4-diazepan-1-yl, 1, 4-diazabicyclo [3.2.1] octan-4-yl, 2-azabicyclo [3.2.1] octan-2-yl, tetrahydro-2H-pyran-2-yl, azepanyl, azacyclooctanyl, 5-azaspiro [2.4] heptan-5-yl, 5-azaspiro [2.4] heptan-5-yl, 6-azaspiro [2.5] octan-6-yl, 2-oxa-7-azaspiro [3.5] nonan-7-yl, 3-azabicyclo [3.1.0] hexan-3-yl, 3-azabicyclo [4.1.0] heptan-3-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, decalinyl, octahydropentalenyl, octahydro-1H-indenyl, 2, 3-dihydro-1H-indenyl, spiro [3.3] heptyl, spiro [2.5] octyl, spiro [3.5] nonyl, spiro [4.4] nonyl, spiro [4.5] decyl, spiro [5.5] undecyl, quinuclidinyl, adamantanyl, nordamantanyl, bornyl, norbornyl, bicyclo [2.2.1] heptyl, 2-oxobicyclo [2.2.1] heptyl, or 2-oxobicyclo [2.2.1] heptenyl; and/or

the ring B represents: phenylene, naphthylene, furanylene, oxazolylene, isoxazolylene, oxadiazolylene, thienylene, thiazolylene, isothiazolylene, thiadiazolylene, pyrrolylene, imidazolylene, pyrazolylene, triazolylene, pyridylene, pyrimidinylene, pyridazinylene, pyrazinylene, indolylene, isoindolylene, benzofuranylene, isobenzofuranylene, benzothienylene, indazolylene, benzimidazolylene, benzoxazolylene, benzoisoxazolylene, benzothiazolylene, benzoisothiazolylene, benzotriazolylene, benzo [2, 1, 3] oxadiazolylene, benzo [2, 1, 3] thiadiazolylene, benzo [1, 2, 3] thiadiazolylene, quinolinylene, isoquinolinylene, naphthyridinylene, cinnolinylene, quinazolinylene, quinoxalinylene, phthalazinylene, pyrazolo [1, 5-a] pyridylene, pyrazolo [1, 5-a] pyrimidinylene, imidazo [1, 2-a] pyridylene, 1H-pyrrolo [3, 2-b] pyridylene, 1H-pyrrolo [2, 3-b] pyridylene, pyrrolo [2, 1-b] thiazolylene, imidazo [2, 1-b] thiazolylene, azetidinylene, pyrrolidinylene, 2-oxopyrrolidin-1-ylene, imidazolidinylene, pyrazolidylene, tetrahydrofuranylene, tetrahydropyranylene, tetrahydrothienylene, tetrahydrothiopyranylene, oxazolidinylene, thiazolidinylene, piperidinylene, 2-oxopiperidin-1-ylene, piperazinylene, morpholinylene, thiomorpholinylene, dioxacyclohexylene, 3-azabicyclo [3.1.0] hexylene, 3-azabicyclo [4.1.0] heptylene, 1, 4-diazacycloheptan-1-ylene, 3, 8-diazabicyclo [3.2.1] octan-3-ylene, 2, 5-diazabicyclo [2.2.2] octan-2-ylene, 1, 4-diazepan-1-ylene, 1, 4-diazabicyclo [3.2.1] octan-4-ylene, 2-azabicyclo [3.2.1] octan-2-ylene, tetrahydro-2H-pyran-2-ylene, azepanylene, azacyclooctanylene, 5-azaspiro [2.4] heptan-5-ylene, 5-azaspiro [2.4] heptan-5-ylene, 6-azaspiro [2.5] octan-6-ylene, 2-oxa-7-azaspiro [3.5] nonan-7-ylene, 3-azabicyclo [3.1.0] hexan-3-ylene, 3-azabicyclo [4.1.0] heptan-3-ylene, cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenylene, cyclohexylene, cyclohexenylene, cycloheptylene, cyclooctylene, decalinylene, octahydropentalenylene, octahydro-1H-indenylene, 2, 3-dihydro-1H-indenylene, spiro [3.3] heptylene, spiro [2.5] octylene, spiro [3.5] nonylene, spiro [4.4] nonylene, spiro [4.5] decylene, spiro [5.5] undecylene, quinuclidinylene, adamantanylene, noradamantanylene, bornylene, norbornylene, bicyclo [2.2.1] heptylene, 2-oxobicyclo [2.2.1] heptylene, or 2-oxobicyclo [2.2.1] heptenylene.
The compound of Formula (I) or a salt, an enantiomer, a stereoisomer, a solvate, or a polymorph thereof as claimed in any one of claims 1-3, wherein the compound of formula (I) is also of formula (I-1) , (I-2) , (I-3) , (I-4) , (I-5) , (I-6) , (I-7) , or (I-8) :

wherein the R, R¹, R², (R³) _n1, ring A, (R⁴) _n2, (R⁵) _n3, U₂, L and ULM are as defined in claim 1.
The compound of Formula (I) or a salt, an enantiomer, a stereoisomer, a solvate, or a polymorph thereof as claimed in any one of claims 1-4, wherein the ULM represents:

wherein:

X represents C (O) or CH₂;

W₂ represents S, S (O) , S (O) ₂, O, ethynylene, vinylene, or N (R⁷) , where R⁷ represents H or C_1-3 alkyl, or W₂ represents a bond;

(R⁸) _n4 indicates that phenyl where (R⁸) _n4 is attached to is optionally substituted with n4 R⁸ group (s) , wherein n4 represents an integer of 0, 1, 2, or 3, and each R⁸ group independently represents halogen, hydroxyl, cyano, amino, C_1-4 alkyl, halogenated C_1-4 alkyl, or C_1-3 alkoxy;

Z₁ represents H or CH₃;

(R⁹) _a1 indicates that phenyl where (R⁹) _a1 is attached to is optionally substituted with a1 R⁹ group (s) , wherein a1 represents an integer of 0, 1, 2, 3, 4, or 5, and each R⁹ group independently represents halogen, hydroxyl, cyano, amino, C_1-4 alkyl, halogenated C_1-4 alkyl, or C_1-3 alkoxy; and

Z₂ represents O or NH.
The compound of Formula (I) or a salt, an enantiomer, a stereoisomer, a solvate, or a polymorph thereof as claimed in any one of claims 1-5, wherein the ULM represents:

wherein (R⁸) _n4 indicates that phenyl where (R⁸) _n4 is attached to is optionally substituted with n4 R⁸ group (s) , wherein n4 represents an integer of 0, 1, 2, or 3, and each R⁸ group independently represents halogen, hydroxyl, cyano, amino, C_1-4 alkyl, halogenated C_1-4 alkyl, or C_1-3 alkoxy.
The compound of Formula (I) or a salt, an enantiomer, a stereoisomer, a solvate, or a polymorph thereof as claimed in any one of claims 1-6, wherein the L represents:

a linear or branched C_1-40 alkylene;

*- (C (R_a1) (R_a2) ) _m1- (R_a- (C (R_a3) (R_a4) ) _m2) _m3-;

*- (C (R_a1) (R_a2) ) _m1- (R_a- (C (R_a3) (R_a4) ) _m2) _m3- (R_a- (C (R_a5) (R_a6) ) _m4) _m5-;

*- (C (R_a1) (R_a2) ) _m1- (R_a- (C (R_a3) (R_a4) ) _m2) _m3- (R_a- (C (R_a5) (R_a6) ) _m4) _m5- (R_a- (C (R_a7) (R_a8) ) _m6) _m7-;

*- (C (R_a1) (R_a2) ) _m1- (R_b- (C (R_a3) (R_a4) ) _m2) _m3-;

*- (C (R_a1) (R_a2) ) _m1- (R_b- (C (R_a3) (R_a4) ) _m2) _m3- (R_b- (C (R_a5) (R_a6) ) _m4) _m5-;

*- (C (R_a1) (R_a2) ) _m1- (R_b- (C (R_a3) (R_a4) ) _m2) _m3- (R_b- (C (R_a5) (R_a6) ) _m4) _m5- (R_b- (C (R_a7) (R_a8) ) _m6) _m7-;

*- (C (R_a1) (R_a2) ) _m1- (R_a-R_b- (C (R_a3) (R_a4) ) _m2) _m3-;

*- (C (R_a1) (R_a2) ) _m1- (R_a- (C (R_a3) (R_a4) ) _m2) _m3- (R_b- (C (R_a5) (R_a6) ) _m4) _m5-;

*- (C (R_a1) (R_a2) ) _m1- (R_b-R_a- (C (R_a3) (R_a4) ) _m2) _m3-; or

*- (C (R_a1) (R_a2) ) _m1- (R_b- (C (R_a3) (R_a4) ) _m2) _m3- (R_a- (C (R_a5) (R_a6) ) _m4) _m5-;

wherein symbol*indicates the point of attachment to the U₂;

one or more hydrogens of one or more CH₂ of the linear or branched C_1-40 alkylene are optionally further replaced by a substituent (s) selected from the group consisting of halogen, hydroxyl, cyano, amino, mercapto, C_1-3 alkyl, C_1-3 alkoxy, halogenated C_1-4 alkyl, C_5-10 aryl, C_5-10 heteroaryl, C_3-12 cycloalkyl, 4-to 12-membered heterocyclyl, or any combination thereof;

each R_a is independently selected from the group consisting of O, C (O) , OC (O) , S, S (O) , S (O) ₂, S (O) ₂N (R⁶) , N (R⁶) S (O) ₂, C (O) N (R⁶) , N (R⁶) C (O) , N (R⁶) , and N (R⁶) C (O) N (R⁶) , where each R⁶ independently represents H or C_1-3 alkyl;

each R_b is independently selected from the group consisting of optionally substituted C_3-20 cycloalkylene, optionally substituted C_5-20 arylene, optionally substituted 4-to 20-membered heterocyclylene, optionally substituted 5-to 20-membered heteroarylene, and any combination thereof;

R_a1, R_a2, R_a3, R_a4, R_a5, R_a6, R_a7, and R_a8 each independently represent hydrogen, halogen, hydroxyl, cyano, amino, mercapto, C_1-3 alkyl, C_1-3 alkoxy, halogenated C_1-4 alkyl, C_5-10 aryl, C_5-10 heteroaryl, C_3- ₁₂ cycloalkyl, or 4-to 12-membered heterocyclyl; and

m1, m2, m3, m4, m5, m6, and m7 each independently represent an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
The compound of Formula (I) or a salt, an enantiomer, a stereoisomer, a solvate, or a polymorph thereof as claimed in any one of claims 1-6, wherein the L represents:

*- (C (R_a1) (R_a2) ) _m1- (C_5-20 arylene- (C (R_a3) (R_a4) ) _m2) _m3-;

*- (C (R_a1) (R_a2) ) _m1- (C_5-20 arylene- (C (R_a3) (R_a4) ) _m2) _m3- (C_5-20 arylene- (C (R_a5) (R_a6) ) _m4) _m5-;

*- (C (R_a1) (R_a2) ) _m1- (C_5-20 arylene- (C (R_a3) (R_a4) ) _m2) _m3- (C_5-20 arylene- (C (R_a5) (R_a6) ) _m4) _m5- (C_5-20 arylene- (C (R_a7) (R_a8) ) _m6) _m7-;

*- (C (R_a1) (R_a2) ) _m1- (5-to 20-membered heteroarylene- (C (R_a3) (R_a4) ) _m2) _m3-;

*- (C (R_a1) (R_a2) ) _m1- (5-to 20-membered heteroarylene- (C (R_a3) (R_a4) ) _m2) _m3- (5-to 20-membered heteroarylene- (C (R_a5) (R_a6) ) _m4) _m5-;

*- (C (R_a1) (R_a2) ) _m1- (5-to 20-membered heteroarylene- (C (R_a3) (R_a4) ) _m2) _m3- (5-to 20-membered heteroarylene- (C (R_a5) (R_a6) ) _m4) _m5- (5-to 20-membered heteroarylene- (C (R_a7) (R_a8) ) _m6) _m7-;

*- (C (R_a1) (R_a2) ) _m1- (4-to 20-membered heterocyclylene- (C (R_a3) (R_a4) ) _m2) _m3-;

*- (C (R_a1) (R_a2) ) _m1- (4-to 20-membered heterocyclylene- (C (R_a3) (R_a4) ) _m2) _m3- (4-to 20-membered heterocyclylene- (C (R_a5) (R_a6) ) _m4) _m5-;

*- (C (R_a1) (R_a2) ) _m1- (C_3-20cycloalkylene- (C (R_a3) (R_a4) ) _m2) _m3-;

*- (C (R_a1) (R_a2) ) _m1- (C_3-20cycloalkylene- (C (R_a3) (R_a4) ) _m2) _m3- (C_3-20cycloalkylene- (C (R_a5) (R_a6) ) _m4) _m5-;

*- (C (R_a1) (R_a2) ) _m1- (C_3-20cycloalkylene-N (R₆) - (C (R_a3) (R_a4) ) _m2) _m3-;

*- (C (R_a1) (R_a2) ) _m1- (O- (C (R_a3) (R_a4) ) _m2) _m3-;

*- (C (R_a1) (R_a2) ) _m1- (O- (C (R_a3) (R_a4) ) _m2) _m3- (O- (C (R_a5) (R_a6) ) _m4) _m5-;

*- (C (R_a1) (R_a2) ) _m1- (O- (C (R_a3) (R_a4) ) _m2) _m3- (O- (C (R_a5) (R_a6) ) _m4) _m5- (O- (C (R_a7) (R_a8) ) _m6) _m7-;

*- (C (R_a1) (R_a2) ) _m1- (S- (C (R_a3) (R_a4) ) _m2) _m3-;

*- (C (R_a1) (R_a2) ) _m1- (S- (C (R_a3) (R_a4) ) _m2) _m3- (S- (C (R_a5) (R_a6) ) _m4) _m5-;

*- (C (R_a1) (R_a2) ) _m1- (S- (C (R_a3) (R_a4) ) _m2) _m3- (S- (C (R_a5) (R_a6) ) _m4) _m5- (S- (C (R_a7) (R_a8) ) _m6) _m7-;

*- (C (R_a1) (R_a2) ) _m1- (S (O) - (C (R_a3) (R_a4) ) _m2) _m3-;

*- (C (R_a1) (R_a2) ) _m1- (S (O) ₂- (C (R_a3) (R_a4) ) _m2) _m3-;

*- (C (R_a1) (R_a2) ) _m1- (S- (C (R_a3) (R_a4) ) _m2) _m3-;

*- (C (R_a1) (R_a2) ) _m1- (S (O) ₂N (R⁶) - (C (R_a3) (R_a4) ) _m2) _m3-;

*- (C (R_a1) (R_a2) ) _m1- (N (R⁶) S (O) ₂- (C (R_a3) (R_a4) ) _m2) _m3-;

*- (C (R_a1) (R_a2) ) _m1- (C (O) N (R⁶) - (C (R_a3) (R_a4) ) _m2) _m3-;

*- (C (R_a1) (R_a2) ) _m1- (N (R⁶) C (O) - (C (R_a3) (R_a4) ) _m2) _m3-;

*- (C (R_a1) (R_a2) ) _m1- (N (R⁶) - (C (R_a3) (R_a4) ) _m2) _m3-; or

*- (C (R_a1) (R_a2) ) _m1- (N (R⁶) C (O) N (R⁶) - (C (R_a3) (R_a4) ) _m2) _m3-;

wherein symbol*indicates the point of attachment to the U₂;

R_a1, R_a2, R_a3, R_a4, R_a5, R_a6, R_a7, and R_a8 each independently represent hydrogen, halogen, hydroxyl, cyano, amino, mercapto, C_1-3 alkyl, C_1-3 alkoxy, halogenated C_1-4 alkyl, C_5-10 aryl, C_5-10 heteroaryl, C_3- ₁₂ cycloalkyl, or 4-to 12-membered heterocyclyl;

m1, m2, m3, m4, m5, m6, and m7 each independently represent an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20;

each R⁶ independently represents H or C_1-3 alkyl;

the C_5-20 arylene and 5-to 20-membered heteroarylene are each independently optionally further substituted with a substituent (s) selected from the group consisting of halogen, hydroxyl, cyano, amino, mercapto, C_1-3 alkyl, C_1-3 alkoxy, halogenated C_1-4 alkyl, C_5-10 aryl, C_5-10 heteroaryl, C_3-12 cycloalkyl, 4-to 12-membered heterocyclyl, or any combination thereof; and

the 4-to 20-membered heterocyclylene and C_3-20cycloalkylene are each independently optionally further substituted with a substituent (s) selected from the group consisting of halogen, hydroxyl, cyano, amino, mercapto, oxo, C_1-3 alkyl, C_1-3 alkoxy, halogenated C_1-4 alkyl, C_5-10 aryl, C_5-10 heteroaryl, C_3-12 cycloalkyl, 4-to 12-membered heterocyclyl, or any combination thereof.
The compound of Formula (I) or a salt, an enantiomer, a stereoisomer, a solvate, or a polymorph thereof as claimed in any one of claims 1-6, wherein the L represents:

a linear or branched C_1-40 alkylene, *- (CH₂) _m1- (O- (CH₂) _m2) _m3-, *- (CH₂) _m1- (O- (CH₂) _m2) _m3- (O- (CH₂) _m4) _m5-, *- (CH₂) _m1- (O- (CH₂) _m2) _m3- (O- (CH₂) _m4) _m5- (O- (CH₂) _m6) _m7-, *- (CH₂) _m1-C (O) N (R⁶) - (CH₂) _m2-, *- (CH₂) _m1- (C (O) N (R⁶) - (CH₂) _m2) _m3-, *- (CH₂) _m1-N (R⁶) C (O) - (CH₂) _m2-, *- (CH₂) _m1- (N(R⁶) C (O) - (CH₂) _m2) _m3-, *- (CH₂) _m1-N (R⁶) C (O) N (R⁶) - (CH₂) _m2-, *- (CH₂) _m1-S- (CH₂) _m2-, *- (CH₂) _m1-S (O) - (CH₂) _m2-, *- (CH₂) _m1-S (O) ₂- (CH₂) _m2-, *- (CH₂) _m1-N (R⁶) S (O) ₂- (CH₂) _m2-, *- (CH₂) _m1-S (O) ₂N (R⁶) - (CH₂) _m2-, *- (CH₂) _m1-N (R⁶) - (CH₂) _m2-, *- (CH₂) _m1-phenylene- (CH₂) _m2-, *- (CH₂) _m1-phenylene- (CH₂) _m2-N (R⁶) - (CH₂) _m3-, *- (CH₂) _m1-piperazinylene- (CH₂) _m2-, *- (CH₂) _m1-piperidinylene- (CH₂) _m2-, *- (CH₂) _m1-piperidinylene-N (R⁶) - (CH₂) _m2-, *- (CH₂) _m1-cyclohexylene- (CH₂) _m2-, *- (CH₂) _m1-cyclohexylene-N (R⁶) - (CH₂) _m2-, *- (CH₂) _m1-furanylene- (CH₂) _m2-, *- (CH₂) _m1-furanylene- (CH₂) _m2-N (R⁶) - (CH₂) _m3-, *- (CH₂) _m1-thiazolylene- (CH₂) _m2-, *- (CH₂) _m1-thiazolylene-C (O) N (R⁶) - (CH₂) _m2-, *- (CH₂) _m1-thiazolylene- (CH₂) _m2-N (R⁶) - (CH₂) _m3-, *- (CH₂) _m1-triazolylene- (CH₂) _m2-, *- (CH₂) _m1-triazolylene-C (O) N (R⁶) - (CH₂) _m2-, *- (CH₂) _m1-triazolylene- (CH₂) _m2-N (R⁶) - (CH₂) _m3-, *- (CH₂) _m1-pyridylene- (CH₂) _m2-, *- (CH₂) _m1-pyridylene-C (O) N (R⁶) - (CH₂) _m2-, or*- (CH₂) _m1-pyridylene- (CH₂) _m2-N (R⁶) - (CH₂) _m3-,

wherein one or more hydrogens of one or more CH₂ of the linear or branched C_1-40 alkylene are optionally further replaced by a substituent (s) selected from the group consisting of halogen, hydroxyl, cyano, amino, mercapto, C_1-3 alkyl, C_1-3 alkoxy, halogenated C_1-4 alkyl, C_5-10 aryl, C_5-10 heteroaryl, C_3- ₁₂ cycloalkyl, 4-to 12-membered heterocyclyl, or any combination thereof;

the symbol*indicates the point of attachment to the U₂;

each R⁶ independently represents H or C_1-3 alkyl;

m1, m2, m3, m4, m5, m6, and m7 each independently represent an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20;

the phenylene, furanylene, thiazolylene, triazolylene, and pyridylene are each independently optionally further substituted with a substituent (s) selected from the group consisting of halogen, hydroxyl, cyano, amino, mercapto, C_1-3 alkyl, C_1-3 alkoxy, halogenated C_1-4 alkyl, C_5-10 aryl, C_5-10 heteroaryl, C_3-12 cycloalkyl, 4-to 12-membered heterocyclyl, or any combination thereof; and

the piperidinylene, piperazinylene, and cyclohexylene are each independently optionally further substituted with a substituent (s) selected from the group consisting of halogen, hydroxyl, cyano, amino, mercapto, oxo, C_1-3 alkyl, C_1-3 alkoxy, halogenated C_1-4 alkyl, C_5-10 aryl, C_5-10 heteroaryl, C_3-12 cycloalkyl, 4-to 12-membered heterocyclyl, or any combination thereof.
The compound of Formula (I) or a salt, an enantiomer, a stereoisomer, a solvate, or a polymorph thereof as claimed in any one of claims 1-6, wherein the L represents the following groups:

-CH₂-; - (CH₂) ₂-; - (CH₂) ₃-; - (CH₂) ₄-; - (CH₂) ₅-; - (CH₂) ₆-; - (CH₂) ₇-; - (CH₂) ₈-; - (CH₂) ₉-; - (CH₂) ₁₀-; - (CH₂) ₁₁-; - (CH₂) ₁₂-; - (CH₂) ₁₃-; - (CH₂) ₁₄-; - (CH₂) ₁₅-; - (CH₂) ₁₆-; - (CH₂) ₁₇-; - (CH₂) ₁₈-; - (CH₂) ₁₉-; or- (CH₂) ₂₀-;

*-CH₂OCH₂CH₂-; *-CH₂- (OCH₂CH₂) ₂-; *-CH₂- (OCH₂CH₂) ₃-; *-CH₂- (OCH₂CH₂) ₄-; *-CH₂- (OCH₂CH₂) ₅-; *-CH₂- (OCH₂CH₂) ₆-; *-CH₂- (OCH₂CH₂) ₇-; *-CH₂- (OCH₂CH₂) ₈-; *-CH₂- (OCH₂CH₂) ₉-; *-CH₂- (OCH₂CH₂) ₁₀-; *- (CH₂CH₂O) ₁-CH₂-; *- (CH₂CH₂O) ₂-CH₂-; *- (CH₂CH₂O) ₃-CH₂-; *- (CH₂CH₂O) ₄-CH₂-; *- (CH₂CH₂O) ₅-CH₂-; *- (CH₂CH₂O) ₆-CH₂-; *- (CH₂CH₂O) ₇-CH₂-; *- (CH₂CH₂O) ₈-CH₂-; *- (CH₂CH₂O) ₉-CH₂-; *- (CH₂CH₂O) ₁₀-CH₂-; *- (CH₂) ₂-OCH₂CH₂-; *- (CH₂) ₂- (OCH₂CH₂) ₂-; *- (CH₂) ₂- (OCH₂CH₂) ₃-; *- (CH₂) ₂- (OCH₂CH₂) ₄-; *- (CH₂) ₂- (OCH₂CH₂) ₅-; *- (CH₂) ₂- (OCH₂CH₂) ₆-; *- (CH₂) ₂- (OCH₂CH₂) ₇-; *- (CH₂) ₂- (OCH₂CH₂) ₈-; *- (CH₂) ₂- (OCH₂CH₂) ₉-; *- (CH₂) ₂- (OCH₂CH₂) ₁₀-; *-CH₂CH₂O (CH₂) ₂-; *- (CH₂CH₂O) ₂- (CH₂) ₂-; *- (CH₂CH₂O) ₃- (CH₂) ₂-; *- (CH₂CH₂O) ₄- (CH₂) ₂-; *- (CH₂CH₂O) ₅- (CH₂) ₂-; *- (CH₂CH₂O) ₆- (CH₂) ₂-; *- (CH₂CH₂O) ₇- (CH₂) ₂-; *- (CH₂CH₂O) ₈- (CH₂) ₂-; *- (CH₂CH₂O) ₉ (CH₂) ₂-; *- (CH₂CH₂O) ₁₀ (CH₂) ₂-; *- (CH₂) ₃-OCH₂CH₂-; *- (CH₂) ₃- (OCH₂CH₂) ₂-; *- (CH₂) ₃- (OCH₂CH₂) ₃-; *- (CH₂) ₃- (OCH₂CH₂) ₄-; *- (CH₂) ₃- (OCH₂CH₂) ₅-; *- (CH₂) ₃- (OCH₂CH₂) ₆-; *- (CH₂) ₃- (OCH₂CH₂) ₇-; *- (CH₂) ₃- (OCH₂CH₂) ₈-; *- (CH₂) ₃- (OCH₂CH₂) ₉-; *- (CH₂) ₃- (OCH₂CH₂) ₁₀-; *-CH₂CH₂O (CH₂) ₃-; *- (CH₂CH₂O) ₂- (CH₂) ₃-; *- (CH₂CH₂O) ₃- (CH₂) ₃-; *- (CH₂CH₂O) ₄- (CH₂) ₃-; *- (CH₂CH₂O) ₅- (CH₂) ₃-; *- (CH₂CH₂O) ₆- (CH₂) ₃-; *- (CH₂CH₂O) ₇- (CH₂) ₃-; *- (CH₂CH₂O) ₈- (CH₂) ₃-; *- (CH₂CH₂O) ₉ (CH₂) ₃-; *- (CH₂CH₂O) ₁₀ (CH₂) ₃-; *-CH₂CH₂OCH₂CH₂CH₂OCH₂-; *- CH₂CH₂OCH₂CH₂CH₂O- (CH₂) ₂-; *-CH₂CH₂OCH₂CH₂CH₂O- (CH₂) ₃-; *-(CH₂CH₂O) ₂ (CH₂CH₂CH₂O) (CH₂) ₃-; *- (CH₂CH₂O) ₂ (CH₂CH₂CH₂O) ₂ (CH₂) ₃-; *- (CH₂) ₁O (CH₂) ₁-; *- (CH₂) ₂O (CH₂) ₂-; *- (CH₂) ₂O (CH₂) ₃-; *- (CH₂) ₂O (CH₂) ₄-; *- (CH₂) ₂O (CH₂) ₅-; *- (CH₂) ₂O (CH₂) ₆-; *- (CH₂) ₃O (CH₂) ₁-; *- (CH₂) ₃O (CH₂) ₂-; *- (CH₂) ₃O (CH₂) ₃-; *- (CH₂) ₄O (CH₂) ₁-; *- (CH₂) ₄O (CH₂) ₂-; *- (CH₂) ₄O (CH₂) ₃-; *- (CH₂) ₅O (CH₂) ₁-; *- (CH₂) ₅O (CH₂) ₂-; *- (CH₂) ₅O (CH₂) ₃-; *- (CH₂) ₅O (CH₂) ₄-; or*- (CH₂) ₅O (CH₂) ₅-;

*- (CH₂) ₁-NH- (CH₂) ₁-; *- (CH₂) ₂-NH- (CH₂) ₁-; *- (CH₂) ₂-NH- (CH₂) ₂-; *- (CH₂) ₂-NH- (CH₂) ₃-; *- (CH₂) ₂-NH- (CH₂) ₄-; *- (CH₂) ₂-NH- (CH₂) ₅-; *- (CH₂) ₂-NH- (CH₂) ₆-; *- (CH₂) ₂-NH- (CH₂) ₇-; *- (CH₂) ₂-NH- (CH₂) ₈-; *- (CH₂) ₂-NH- (CH₂) ₉-; *- (CH₂) ₂-NH- (CH₂) ₁₀-; *- (CH₂) ₂-NH- (CH₂) ₁₁-; *- (CH₂) ₂-NH- (CH₂) ₁₂-; *- (CH₂) ₃-NH- (CH₂) ₁-; *- (CH₂) ₃-NH- (CH₂) ₂-; *- (CH₂) ₃-NH- (CH₂) ₃-; *- (CH₂) ₄-NH- (CH₂) ₁-; *- (CH₂) ₄-NH- (CH₂) ₂-; *- (CH₂) ₅-NH- (CH₂) ₃-; *- (CH₂) ₅-NH- (CH₂) ₁-; *- (CH₂) ₅-NH- (CH₂) ₂-; *- (CH₂) ₈-NH- (CH₂) ₂-; *- (CH₂) ₅-NH- (CH₂) ₃-; *- (CH₂) ₅-NH- (CH₂) ₄-; *- (CH₂) ₅-NH- (CH₂) ₅-; *- (CH₂) ₁-N (CH₃) - (CH₂) ₈-; *- (CH₂) ₂-N (CH₃) - (CH₂) ₁-; *- (CH₂) ₃-N (CH₃) - (CH₂) ₁-; *- (CH₂) ₄-N (CH₃) - (CH₂) ₁-; *- (CH₂) ₅-N(CH₃) - (CH₂) ₁-; *- (CH₂) ₆-N (CH₃) - (CH₂) ₁-; *- (CH₂) ₂-N (CH₃) - (CH₂) ₂-; *- (CH₂) ₂-N (CH₃) - (CH₂) ₃-; *- (CH₂) ₂-N (CH₃) - (CH₂) ₄-; *- (CH₂) ₂-N (CH₃) - (CH₂) ₅-; *- (CH₂) ₂-N (CH₃) - (CH₂) ₆-; *- (CH₂) ₂-N (CH₃) - (CH₂) ₇-; *- (CH₂) ₂-N (CH₃) - (CH₂) ₈-; *- (CH₂) ₂-N (CH₃) - (CH₂) ₉-; *- (CH₂) ₂-N (CH₃) - (CH₂) ₁₀-; *- (CH₂) ₂-N(CH₃) - (CH₂) ₁₁-; *- (CH₂) ₂-N (CH₃) - (CH₂) ₁₂-; *- (CH₂) ₂-NHC (O) -CH₂-; *- (CH₂) ₂-NHC (O) - (CH₂) ₂-; *- (CH₂) ₂-NHC (O) - (CH₂) ₃-; *- (CH₂) ₂-NHC (O) - (CH₂) ₄-; *- (CH₂) ₂-NHC (O) - (CH₂) ₅-; *- (CH₂) ₂-NHC (O) - (CH₂) ₆-; *- (CH₂) ₂-NHC (O) - (CH₂) ₇-; *- (CH₂) ₂-NHC (O) - (CH₂) ₈-; *- (CH₂) ₂-NHC (O) - (CH₂) ₉-; *- (CH₂) ₂-NHC (O) - (CH₂) ₁₀-; *- (CH₂) ₂-NHC (O) - (CH₂) ₁₁-; *- (CH₂) ₂-NHC (O) - (CH₂) ₁₂-; *- (CH₂) ₂-NHC(O) - (CH₂) ₁₃-; *- (CH₂) ₂-NHC (O) - (CH₂) ₁₄-; *- (CH₂) ₂-NHC (O) - (CH₂) ₁₅-; *- (CH₂) ₃-NHC (O) -CH₂-; *- (CH₂) ₃-NHC (O) - (CH₂) ₂-; *- (CH₂) ₃-NHC (O) - (CH₂) ₃-; *- (CH₂) ₃-NHC (O) - (CH₂) ₄-; *- (CH₂) ₃-NHC(O) - (CH₂) ₅-; *- (CH₂) ₃-NHC (O) - (CH₂) ₆-; *- (CH₂) ₃-NHC (O) - (CH₂) ₇-; *- (CH₂) ₃-NHC (O) - (CH₂) ₈-; *- (CH₂) ₃-NHC (O) - (CH₂) ₉-; *- (CH₂) ₃-NHC (O) - (CH₂) ₁₀-; *- (CH₂) ₃-NHC (O) - (CH₂) ₁₁-; *- (CH₂) ₃-NHC(O) - (CH₂) ₁₂-; *- (CH₂) ₃-NHC (O) - (CH₂) ₁₃-; *- (CH₂) ₃-NHC (O) - (CH₂) ₁₄-; *- (CH₂) ₃-NHC (O) - (CH₂) ₁₅-; *- (CH₂) ₄NHC (O) (CH₂) ₁-; *- (CH₂) ₄NHC (O) (CH₂) ₂-; *- (CH₂) ₄NHC (O) (CH₂) ₃-; *- (CH₂) ₄NHC (O) (CH₂) ₄-; *- (CH₂) ₄NHC (O) (CH₂) ₅-; *- (CH₂) ₄NHC (O) (CH₂) ₆-; *- (CH₂) ₄NHC (O) (CH₂) ₇-; *- (CH₂) ₄NHC (O) (CH₂) ₈-; *- (CH₂) ₄NHC (O) (CH₂) ₉-; *- (CH₂) ₄NHC (O) (CH₂) ₁₀-; *- (CH₂) ₅NHC (O) (CH₂) ₁-; *- (CH₂) ₈NHC (O) (CH₂) ₂-; *- (CH₂) ₂-N (CH₃) C (O) -CH₂-; *- (CH₂) ₂-N (CH₃) C (O) - (CH₂) ₂-; *- (CH₂) ₂-N (CH₃) C (O) - (CH₂) ₃-; *- (CH₂) ₂-N (CH₃) C (O) - (CH₂) ₄-; *- (CH₂) ₂-N (CH₃) C (O) - (CH₂) ₅-; *- (CH₂) ₂-N (CH₃) C (O) - (CH₂) ₆-; *- (CH₂) ₂-N (CH₃) C (O) - (CH₂) ₇-; *- (CH₂) ₂-N (CH₃) C (O) - (CH₂) ₈-; *- (CH₂) ₂-N (CH₃) C (O) - (CH₂) ₉-; *- (CH₂) ₂-N (CH₃) C (O) - (CH₂) ₁₀-; *- (CH₂) ₂-N (CH₃) C (O) - (CH₂) ₁₁-; *- (CH₂) ₂-N (CH₃) C (O) - (CH₂) ₁₂-; *- (CH₂) ₂-N (CH₃) C (O) - (CH₂) ₁₃-; *- (CH₂) ₂-N (CH₃) C (O) - (CH₂) ₁₄-; *- (CH₂) ₂-N (CH₃) C (O) - (CH₂) ₁₅-; *- (CH₂) ₂-C (O) NH-CH₂-; *- (CH₂) ₂-C (O) NH- (CH₂) ₂-; *- (CH₂) ₂-C (O) NH- (CH₂) ₃-; *- (CH₂) ₂-C (O) NH- (CH₂) ₄-; *- (CH₂) ₂-C (O) NH- (CH₂) ₅-; *- (CH₂) ₂-C (O) NH- (CH₂) ₆-; *- (CH₂) ₂-C (O) NH- (CH₂) ₇-; *- (CH₂) ₂-C (O) NH- (CH₂) ₈-; *- (CH₂) ₂-C (O) NH- (CH₂) ₉-; *- (CH₂) ₂-C (O) NH- (CH₂) ₁₀-; *- (CH₂) ₂-C (O) NH- (CH₂) ₁₁-; *- (CH₂) ₂-C (O) NH- (CH₂) ₁₂-; *- (CH₂) ₂-C (O) NH- (CH₂) ₁₃-; *- (CH₂) ₂-C (O) NH- (CH₂) ₁₄-; *- (CH₂) ₂-C (O) NH- (CH₂) ₁₅-; *- (CH₂) ₃-C (O) NH-CH₂-; *- (CH₂) ₃-C (O) NH- (CH₂) ₂-; *- (CH₂) ₃-C (O) NH- (CH₂) ₃-; *- (CH₂) ₃-C (O) NH- (CH₂) ₄-; *- (CH₂) ₃-C (O) NH- (CH₂) ₅-; *- (CH₂) ₃-C (O) NH- (CH₂) ₆-; *- (CH₂) ₃-C (O) NH- (CH₂) ₇-; *- (CH₂) ₃-C (O) NH- (CH₂) ₈-; *- (CH₂) ₃-C (O) NH- (CH₂) ₉-; *- (CH₂) ₃-C (O) NH- (CH₂) ₁₀-; *- (CH₂) ₃- C (O) NH- (CH₂) ₁₁-; *- (CH₂) ₃-C (O) NH- (CH₂) ₁₂-; *- (CH₂) ₃-C (O) NH- (CH₂) ₁₃-; *- (CH₂) ₃-C (O) NH- (CH₂) ₁₄-; *- (CH₂) ₃-C (O) NH- (CH₂) ₁₅-; *- (CH₂) ₄C (O) NH (CH₂) ₁-; *- (CH₂) ₄C (O) NH (CH₂) ₂-; *- (CH₂) ₄C (O) NH (CH₂) ₃-; *- (CH₂) ₄C (O) NH (CH₂) ₄-; *- (CH₂) ₄C (O) NH (CH₂) ₅-; *- (CH₂) ₄C (O) NH (CH₂) ₆-; *- (CH₂) ₄C (O) NH (CH₂) ₇-; *- (CH₂) ₄C (O) NH (CH₂) ₈-; *- (CH₂) ₄C (O) NH (CH₂) ₉-; *- (CH₂) ₄C (O) NH (CH₂) ₁₀-; *- (CH₂) ₂-C (O) N (CH₃) -CH₂-; *- (CH₂) ₂-C (O) N (CH₃) - (CH₂) ₂-; *- (CH₂) ₂-C (O) N (CH₃) - (CH₂) ₃-; *- (CH₂) ₂-C (O) N (CH₃) - (CH₂) ₄-; *- (CH₂) ₂-C (O) N (CH₃) - (CH₂) ₅-; *- (CH₂) ₂-C (O) N (CH₃) - (CH₂) ₆-; *- (CH₂) ₂-C (O) N (CH₃) - (CH₂) ₇-; *- (CH₂) ₂-C (O) N (CH₃) - (CH₂) ₈-; *- (CH₂) ₂-C (O) N (CH₃) - (CH₂) ₉-; *- (CH₂) ₂-C (O) N (CH₃) - (CH₂) ₁₀-; *- (CH₂) ₂-C (O) N (CH₃) - (CH₂) ₁₁-; *- (CH₂) ₂-C (O) N (CH₃) - (CH₂) ₁₂-; *- (CH₂) ₂-C (O) N (CH₃) - (CH₂) ₁₃-; *- (CH₂) ₂-C (O) N (CH₃) - (CH₂) ₁₄-; *- (CH₂) ₂-C (O) N (CH₃) - (CH₂) ₁₅-; *- (CH₂) ₂-NHC (O) NH- (CH₂) ₄-; *- (CH₂) ₄-NHC (O) NH- (CH₂) ₂-; *-CH₂-NHC (O) NH- (CH₂) ₂-; *- (CH₂) ₂-NHC (O) NH-CH₂-; *- (CH₂) ₂-NHC (O) NH- (CH₂) ₂-; *- (CH₂) ₂-NHC (O) NH- (CH₂) ₃-; *- (CH₂) ₃-NHC (O) NH- (CH₂) ₂-; *-CH₂-piperazinylene-CH₂-; *- (CH₂) ₂-piperazinylene- (CH₂) ₂-; *- (CH₂) ₂-piperazinylene- (CH₂) ₃-; *- (CH₂) ₂-piperazinylene- (CH₂) ₄-; *- (CH₂) ₂-piperazinylene- (CH₂) ₅-; *- (CH₂) ₃-piperazinylene-CH₂-; *- (CH₂) ₃-piperazinylene- (CH₂) ₂-; *- (CH₂) ₃-piperazinylene- (CH₂) ₃-; *- (CH₂) ₄-piperazinylene-CH₂-; *- (CH₂) ₄-piperazinylene- (CH₂) ₂-; *- (CH₂) ₄-piperazinylene- (CH₂) ₃-; *- (CH₂) ₈-piperazinylene-CH₂-; *- (CH₂) ₈-piperazinylene- (CH₂) ₂-; *- (CH₂) ₈-piperazinylene- (CH₂) ₃-; *- (CH₂) ₈-piperazinylene- (CH₂) ₄-; *- (CH₂) ₈-piperazinylene- (CH₂) ₅-; *- (CH₂) ₈-piperazinylene- (CH₂) ₆-; *- (CH₂) ₈-piperazinylene- (CH₂) ₇-; *- (CH₂) ₈-piperazinylene- (CH₂) ₈-; *-CH₂-piperazinylene- (CH₂) ₈-; *- (CH₂) ₂-piperazinylene- (CH₂) ₈-; *- (CH₂) ₃-piperazinylene- (CH₂) ₈-; *- (CH₂) ₄-piperazinylene- (CH₂) ₈-; *- (CH₂) ₅-piperazinylene- (CH₂) ₈-; *- (CH₂) ₆-piperazinylene- (CH₂) ₈-; *- (CH₂) ₇-piperazinylene- (CH₂) ₈-; *-CH₂-phenylene-CH₂-; *- (CH₂) ₁-phenylene- (CH₂) ₂-; *- (CH₂) ₁-phenylene- (CH₂) ₃-; *- (CH₂) ₁-phenylene- (CH₂) ₄-; *- (CH₂) ₁-phenylene- (CH₂) ₅-; *- (CH₂) ₂-phenylene- (CH₂) ₁-; *- (CH₂) ₂-phenylene- (CH₂) ₂-; *- (CH₂) ₂-phenylene- (CH₂) ₃-; *- (CH₂) ₂-phenylene- (CH₂) ₄-; *- (CH₂) ₂-phenylene- (CH₂) ₅-; *- (CH₂) ₃-phenylene-CH₂-; *- (CH₂) ₃-phenylene- (CH₂) ₂-; *- (CH₂) ₃-phenylene- (CH₂) ₃-; *- (CH₂) ₄-phenylene-CH₂-; *- (CH₂) ₄-phenylene- (CH₂) ₂-; *- (CH₂) ₄-phenylene- (CH₂) ₃-; *- (CH₂) ₅-phenylene- (CH₂) ₃-; *- (CH₂) ₆-phenylene- (CH₂) ₃-; *- (CH₂) ₇-phenylene- (CH₂) ₃-; *- (CH₂) ₈-phenylene-CH₂-; *- (CH₂) ₈-phenylene- (CH₂) ₂-; *- (CH₂) ₈-phenylene- (CH₂) ₃-; *- (CH₂) ₈-phenylene- (CH₂) ₄-; *- (CH₂) ₈-phenylene- (CH₂) ₅-; *- (CH₂) ₈-phenylene- (CH₂) ₆-; *- (CH₂) ₈-phenylene- (CH₂) ₇-; *- (CH₂) ₈-phenylene- (CH₂) ₈-; *-CH₂-phenylene- (CH₂) ₈-; *- (CH₂) ₂-phenylene- (CH₂) ₈-; *- (CH₂) ₃-phenylene- (CH₂) ₈-; *- (CH₂) ₄-phenylene- (CH₂) ₈-; *- (CH₂) ₅-phenylene- (CH₂) ₈-; *- (CH₂) ₆-phenylene- (CH₂) ₈-; *- (CH₂) ₇-phenylene- (CH₂) ₈-; *-CH₂-piperidinylene-CH₂-; *- (CH₂) ₂-piperidinylene- (CH₂) ₂-; *- (CH₂) ₂-piperidinylene- (CH₂) ₃-; *- (CH₂) ₂-piperidinylene- (CH₂) ₄-; *- (CH₂) ₂-piperidinylene- (CH₂) ₅-; *- (CH₂) ₃-piperidinylene-CH₂-; *- (CH₂) ₃-piperidinylene- (CH₂) ₂-; *- (CH₂) ₃-piperidinylene- (CH₂) ₃-; *- (CH₂) ₄-piperidinylene-CH₂-; *- (CH₂) ₄-piperidinylene- (CH₂) ₂-; *- (CH₂) ₄-piperidinylene- (CH₂) ₃-; *- (CH₂) ₅-piperidinylene- (CH₂) ₃-; *- (CH₂) ₆-piperidinylene- (CH₂) ₃-; *- (CH₂) ₇-piperidinylene- (CH₂) ₃-; *- (CH₂) ₈-piperidinylene-CH₂-; *- (CH₂) ₈-piperidinylene- (CH₂) ₂-; *- (CH₂) ₈-piperidinylene- (CH₂) ₃-; *- (CH₂) ₈-piperidinylene- (CH₂) ₄-; *- (CH₂) ₈-piperidinylene- (CH₂) ₅-; *- (CH₂) ₈-piperidinylene- (CH₂) ₆-; *- (CH₂) ₈-piperidinylene- (CH₂) ₇-; *- (CH₂) ₈-piperidinylene- (CH₂) ₈-; *-CH₂-piperidinylene- (CH₂) ₈-; *- (CH₂) ₂-piperidinylene- (CH₂) ₈-; *- (CH₂) ₃-piperidinylene- (CH₂) ₈-; *- (CH₂) ₄-piperidinylene- (CH₂) ₈-; *- (CH₂) ₅-piperidinylene- (CH₂) ₈-; *- (CH₂) ₆-piperidinylene- (CH₂) ₈-; *- (CH₂) ₇-piperidinylene- (CH₂) ₈-; *-CH₂-cyclohexylene-CH₂-; *- (CH₂) ₂-cyclohexylene- (CH₂) ₂-; *- (CH₂) ₂-cyclohexylene- (CH₂) ₃-; *- (CH₂) ₂-cyclohexylene- (CH₂) ₄-; *- (CH₂) ₂-cyclohexylene- (CH₂) ₅-; *- (CH₂) ₃-cyclohexylene-CH₂-; *- (CH₂) ₃-cyclohexylene- (CH₂) ₂-; *- (CH₂) ₃-cyclohexylene- (CH₂) ₃-; *- (CH₂) ₄-cyclohexylene-CH₂-; *- (CH₂) ₄-cyclohexylene- (CH₂) ₂-; *- (CH₂) ₄-cyclohexylene- (CH₂) ₃-; *- (CH₂) ₅-cyclohexylene- (CH₂) ₃-; *- (CH₂) ₆-cyclohexylene- (CH₂) ₃-; *- (CH₂) ₇-cyclohexylene- (CH₂) ₃-; *- (CH₂) ₈-cyclohexylene-CH₂-; *- (CH₂) ₈-cyclohexylene- (CH₂) ₂-; *- (CH₂) ₈-cyclohexylene- (CH₂) ₃-; *- (CH₂) ₈-cyclohexylene- (CH₂) ₄-; *- (CH₂) ₈-cyclohexylene- (CH₂) ₅-; *- (CH₂) ₈-cyclohexylene- (CH₂) ₆-; *- (CH₂) ₈-cyclohexylene- (CH₂) ₇-; *- (CH₂) ₈-cyclohexylene- (CH₂) ₈-; *-CH₂-cyclohexylene- (CH₂) ₈-; *- (CH₂) ₂-cyclohexylene- (CH₂) ₈-; *- (CH₂) ₃-cyclohexylene- (CH₂) ₈-; *- (CH₂) ₄-cyclohexylene- (CH₂) ₈-; *- (CH₂) ₅-cyclohexylene- (CH₂) ₈-; *- (CH₂) ₆-cyclohexylene- (CH₂) ₈-; *- (CH₂) ₇-cyclohexylene- (CH₂) ₈-; *-CH₂-cyclohexylene-NH-CH₂-; *- (CH₂) ₂-cyclohexylene-NH- (CH₂) ₂-; *- (CH₂) ₂-cyclohexylene-NH- (CH₂) ₃-; *- (CH₂) ₂-cyclohexylene-NH- (CH₂) ₄-; *- (CH₂) ₂-cyclohexylene-NH- (CH₂) ₅-; *- (CH₂) ₃-cyclohexylene-NH-CH₂-; *- (CH₂) ₃-cyclohexylene-NH- (CH₂) ₂-; *- (CH₂) ₃-cyclohexylene-NH- (CH₂) ₃-; *- (CH₂) ₄-cyclohexylene-NH-CH₂-; *- (CH₂) ₄-cyclohexylene-NH- (CH₂) ₂-; *- (CH₂) ₄-cyclohexylene-NH- (CH₂) ₃-; *- (CH₂) ₅-cyclohexylene-NH- (CH₂) ₃-; *- (CH₂) ₆-cyclohexylene-NH- (CH₂) ₃-; *- (CH₂) ₇-cyclohexylene-NH- (CH₂) ₃-; *- (CH₂) ₈-cyclohexylene-NH-CH₂-; *- (CH₂) ₈-cyclohexylene-NH- (CH₂) ₂-; *- (CH₂) ₈-cyclohexylene-NH- (CH₂) ₃-; *- (CH₂) ₈-cyclohexylene-NH- (CH₂) ₄-; *- (CH₂) ₈-cyclohexylene-NH- (CH₂) ₅-; *- (CH₂) ₈-cyclohexylene-NH- (CH₂) ₆-; *- (CH₂) ₈-cyclohexylene-NH- (CH₂) ₇-; *- (CH₂) ₈-cyclohexylene-NH- (CH₂) ₈-; *-CH₂-cyclohexylene-NH- (CH₂) ₈-; *- (CH₂) ₂-cyclohexylene-NH- (CH₂) ₈-; *- (CH₂) ₃-cyclohexylene-NH- (CH₂) ₈-; *- (CH₂) ₄-cyclohexylene-NH- (CH₂) ₈-; *- (CH₂) ₅-cyclohexylene-NH- (CH₂) ₈-; *- (CH₂) ₆-cyclohexylene-NH- (CH₂) ₈-; *- (CH₂) ₇-cyclohexylene-NH- (CH₂) ₈-; *-CH₂-triazolylene-CH₂-; *- (CH₂) ₁-triazolylene- (CH₂) ₂-; *- (CH₂) ₁-triazolylene- (CH₂) ₃-; *- (CH₂) ₂-triazolylene- (CH₂) ₁-; *- (CH₂) ₂-triazolylene- (CH₂) ₂-; *- (CH₂) ₂-triazolylene- (CH₂) ₃-; *- (CH₂) ₂-triazolylene- (CH₂) ₄-; *- (CH₂) ₂-triazolylene- (CH₂) ₅-; *- (CH₂) ₃-triazolylene-CH₂-; *- (CH₂) ₃-triazolylene- (CH₂) ₂-; *- (CH₂) ₃-triazolylene- (CH₂) ₃-; *- (CH₂) ₄-triazolylene-CH₂-; *- (CH₂) ₄-triazolylene- (CH₂) ₂-; *- (CH₂) ₄-triazolylene- (CH₂) ₃-; *- (CH₂) ₅-triazolylene- (CH₂) ₃-; *- (CH₂) ₆-triazolylene- (CH₂) ₃-; *- (CH₂) ₇-triazolylene- (CH₂) ₃-; *- (CH₂) ₈-triazolylene-CH₂-; *- (CH₂) ₈-triazolylene- (CH₂) ₂-; *- (CH₂) ₈-triazolylene- (CH₂) ₃-; *- (CH₂) ₈-triazolylene- (CH₂) ₄-; *- (CH₂) ₈-triazolylene- (CH₂) ₅-; *- (CH₂) ₈-triazolylene- (CH₂) ₆-; *- (CH₂) ₈-triazolylene- (CH₂) ₇-; *- (CH₂) ₈-triazolylene- (CH₂) ₈-; *-CH₂-triazolylene- (CH₂) ₈-; *- (CH₂) ₂-triazolylene- (CH₂) ₈-; *- (CH₂) ₃-triazolylene- (CH₂) ₈-; *- (CH₂) ₄-triazolylene- (CH₂) ₈-; *- (CH₂) ₅-triazolylene- (CH₂) ₈-; *- (CH₂) ₆-triazolylene- (CH₂) ₈-; *- (CH₂) ₇-triazolylene- (CH₂) ₈-; *-CH₂-pyridylene-CH₂-; *- (CH₂) ₂-pyridylene- (CH₂) ₂-; *- (CH₂) ₂-pyridylene- (CH₂) ₃-; *- (CH₂) ₂-pyridylene- (CH₂) ₄-; *- (CH₂) ₂-pyridylene- (CH₂) ₅-; *- (CH₂) ₃-pyridylene-CH₂-; *- (CH₂) ₃-pyridylene- (CH₂) ₂-; *- (CH₂) ₃-pyridylene- (CH₂) ₃-; *- (CH₂) ₄-pyridylene-CH₂-; *- (CH₂) ₄-pyridylene- (CH₂) ₂-; *- (CH₂) ₄-pyridylene- (CH₂) ₃-; *- (CH₂) ₅-pyridylene- (CH₂) ₃-; *- (CH₂) ₆-pyridylene- (CH₂) ₃-; *- (CH₂) ₇-pyridylene- (CH₂) ₃-; *- (CH₂) ₈-pyridylene-CH₂-; *- (CH₂) ₈-pyridylene- (CH₂) ₂-; *- (CH₂) ₈-pyridylene- (CH₂) ₃-; *- (CH₂) ₈-pyridylene- (CH₂) ₄-; *- (CH₂) ₈-pyridylene- (CH₂) ₅-; *- (CH₂) ₈-pyridylene- (CH₂) ₆-; *- (CH₂) ₈-pyridylene- (CH₂) ₇-; *- (CH₂) ₈-pyridylene- (CH₂) ₈-; *-CH₂-pyridylene- (CH₂) ₈-; *- (CH₂) ₂-pyridylene- (CH₂) ₈-; *- (CH₂) ₃-pyridylene- (CH₂) ₈-; *- (CH₂) ₄-pyridylene- (CH₂) ₈-; *- (CH₂) ₅-pyridylene- (CH₂) ₈-; *- (CH₂) ₆-pyridylene- (CH₂) ₈-; *- (CH₂) ₇-pyridylene- (CH₂) ₈-; *- (CH₂) ₁S (CH₂) ₁-; *- (CH₂) ₂S (CH₂) ₂-; *- (CH₂) ₂S (CH₂) ₁-; *- (CH₂) ₁S (CH₂) ₂-; *- (CH₂) ₁S (CH₂) ₃-; *- (CH₂) ₁S (CH₂) ₄-; *- (CH₂) ₂S (CH₂) ₃-; *- (CH₂) ₂S (CH₂) ₄-; *- (CH₂) ₂S (CH₂) ₅-; *- (CH₂) ₃S (CH₂) ₁-; *- (CH₂) ₃S (CH₂) ₂-; *- (CH₂) ₃S (CH₂) ₃-; *- (CH₂) ₄S (CH₂) ₁-; *- (CH₂) ₄S (CH₂) ₂-; *- (CH₂) ₄S (CH₂) ₃-; *- (CH₂) ₅S (CH₂) ₁-; *- (CH₂) ₅S (CH₂) ₂-; *- (CH₂) ₅S (CH₂) ₃-; *- (CH₂) ₆S (CH₂) ₁-; *- (CH₂) ₆S (CH₂) ₂-; *- (CH₂) ₆S (CH₂) ₃-; *- (CH₂) ₇S (CH₂) ₁-; *- (CH₂) ₇S (CH₂) ₂-; *- (CH₂) ₇S (CH₂) ₃-; *- (CH₂) ₈S (CH₂) ₁-; *- (CH₂) ₈S (CH₂) ₂-; *- (CH₂) ₈S (CH₂) ₃-; *- (CH₂) ₉S (CH₂) ₁-; *- (CH₂) ₉S (CH₂) ₂-; *- (CH₂) ₉S (CH₂) ₃-; *- (CH₂) ₁S (O) (CH₂) ₁-; *- (CH₂) ₂S (O) (CH₂) ₂-; *- (CH₂) ₂S (O) (CH₂) ₁-; *- (CH₂) ₁S (O) (CH₂) ₂-; *- (CH₂) ₁S (O) (CH₂) ₃-; *- (CH₂) ₁S (O) (CH₂) ₄-; *- (CH₂) ₂S (O) (CH₂) ₃-; *- (CH₂) ₂S (O) (CH₂) ₄-; *- (CH₂) ₂S (O) (CH₂) ₅-; *- (CH₂) ₃S (O) (CH₂) ₁-; *- (CH₂) ₃S (O) (CH₂) ₂-; *- (CH₂) ₃S (O) (CH₂) ₃-; *- (CH₂) ₄S (O) (CH₂) ₁-; *- (CH₂) ₄S (O) (CH₂) ₂-; *- (CH₂) ₄S (O) (CH₂) ₃-; *- (CH₂) ₅S (O) (CH₂) ₁-; *- (CH₂) ₅S (O) (CH₂) ₂-; *- (CH₂) ₅S (O) (CH₂) ₃-; *- (CH₂) ₆S (O) (CH₂) ₁-; *- (CH₂) ₆S (O) (CH₂) ₂-; *- (CH₂) ₆S (O) (CH₂) ₃-; *- (CH₂) ₇S (O) (CH₂) ₁-; *- (CH₂) ₇S (O) (CH₂) ₂-; *- (CH₂) ₇S (O) (CH₂) ₃-; *- (CH₂) ₈S (O) (CH₂) ₁-; *- (CH₂) ₈S (O) (CH₂) ₂-; *- (CH₂) ₈S (O) (CH₂) ₃-; *- (CH₂) ₉S (O) (CH₂) ₁-; *- (CH₂) ₉S (O) (CH₂) ₂-; *- (CH₂) ₉S (O) (CH₂) ₃-; *- (CH₂) ₁S (O) ₂ (CH₂) ₁-; *- (CH₂) ₂S (O) ₂ (CH₂) ₂-; *- (CH₂) ₂S (O) ₂ (CH₂) ₁-; *- (CH₂) ₁S (O) ₂ (CH₂) ₂-; *- (CH₂) ₁S (O) ₂ (CH₂) ₃-; *- (CH₂) ₁S (O) ₂ (CH₂) ₄-; *- (CH₂) ₂S (O) ₂ (CH₂) ₃-; *- (CH₂) ₂S (O) ₂ (CH₂) ₄-; *- (CH₂) ₂S (O) ₂ (CH₂) ₅-; *- (CH₂) ₃S (O) ₂ (CH₂) ₁-; *- (CH₂) ₃S (O) ₂ (CH₂) ₂-; *- (CH₂) ₃S (O) ₂ (CH₂) ₃-; *- (CH₂) ₄S (O) ₂ (CH₂) ₁-; *- (CH₂) ₄S (O) ₂ (CH₂) ₂-; *- (CH₂) ₄S (O) ₂ (CH₂) ₃-; *- (CH₂) ₅S (O) ₂ (CH₂) ₁-; *- (CH₂) ₅S (O) ₂ (CH₂) ₂-; *- (CH₂) ₅S (O) (CH₂) ₃-; *- (CH₂) ₆S (O) ₂ (CH₂) ₁-; *- (CH₂) ₆S (O) ₂ (CH₂) ₂-; *- (CH₂) ₆S (O) ₂ (CH₂) ₃-; *- (CH₂) ₇S (O) ₂ (CH₂) ₁-; *- (CH₂) ₇S (O) ₂ (CH₂) ₂-; *- (CH₂) ₇S (O) ₂ (CH₂) ₃-; *- (CH₂) ₈S (O) ₂ (CH₂) ₁-; *- (CH₂) ₈S (O) ₂ (CH₂) ₂-; *- (CH₂) ₈S (O) ₂ (CH₂) ₃-; *- (CH₂) ₉S (O) ₂ (CH₂) ₁-; *- (CH₂) ₉S (O) ₂ (CH₂) ₂-; or*- (CH₂) ₉S (O) ₂ (CH₂) ₃-;

*- (CH₂) ₆-NH- (CH₂) ₁-; *- (CH₂) ₆-NH- (CH₂) ₃-; *- (CH₂) ₆-NH- (CH₂) ₄-; *- (CH₂) ₆-NH- (CH₂) ₅-; *- (CH₂) ₇-NH- (CH₂) ₁-; *- (CH₂) ₇-NH- (CH₂) ₂-; *- (CH₂) ₇-NH- (CH₂) ₃-; *- (CH₂) ₇-NH- (CH₂) ₄-; *- (CH₂) ₆-NH-CH (CH₃) -; *- (CH₂) ₅-NH-CH (CH₃) -; *- (CH₂) ₄-NH-CH (CH₃) -; *- (CH₂) ₃-NH-CH (CH₃) -; *- (CH₂) ₂-NH-CH (CH₃) -; *- (CH₂) ₇-NH-CH (CH₃) -; *- (CH₂) ₈-NH-CH (CH₃) -; *- (CH₂) ₇-NH-CH (CF₃) -; *- (CH₂) ₆-NH-CH (CF₃) -; *- (CH₂) ₅-NH-CH (CF₃) -; *- (CH₂) ₄-NH-CH (CF₃) -; *- (CH₂) ₃-NH-CH (CF₃) -; *- (CH₂) ₂-NH-CH (CF₃) -; *- (CH₂) ₈-NH-CH (CF₃) -; *-CH₂-C (O) NH- (CH₂) ₄-; *-CH₂-C (O) NH- (CH₂) ₂-; *-CH₂-C (O) NH- (CH₂) ₃-; *-CH₂-C (O) NH- (CH₂) ₅-; *-CH₂-phenylene-CH₂-NH-CH (CH₃) -; *-CH₂-phenylene- (CH₂) ₂-NH-CH (CH₃) -; *-CH₂-phenylene-CH₂-NH-CH₂-; *-CH₂-phenylene- (CH₂) ₂-NH-CH₂-; *- (CH₂) ₁-furanylene- (CH₂) ₁-; *- (CH₂) ₁-furanylene- (CH₂) ₂-; *- (CH₂) ₁-furanylene- (CH₂) ₃-; *- (CH₂) ₂-furanylene- (CH₂) ₁-; *- (CH₂) ₂-furanylene- (CH₂) ₂-; *- (CH₂) ₃-furanylene- (CH₂) ₁-; *- (CH₂) ₃-furanylene- (CH₂) ₂-; or*-CH₂-triazolylene-CH₂-NH-CH₂-;

wherein one or more hydrogen of one or more CH₂ of the groups are optionally further replaced by a substituent (s) selected from the group consisting of halogen, hydroxyl, cyano, amino, mercapto, C_1-3 alkyl, C_1-3 alkoxy, halogenated C_1-4 alkyl, C_5-10 aryl, C_5-10 heteroaryl, C_3-12 cycloalkyl, 4-to 12-membered heterocyclyl, or any combination thereof;

the symbol*indicates the point of attachment to the U₂;

the piperazinylene, piperidinylene, and cyclohexylene are each independently optionally further substituted with a substituent (s) selected from the group consisting of halogen, hydroxyl, cyano, amino, mercapto, oxo, C_1-3 alkyl, C_1-3 alkoxy, halogenated C_1-4 alkyl, C_5-10 aryl, C_5-10 heteroaryl, C_3-12 cycloalkyl, 4-to 12-membered heterocyclyl, or any combination thereof; and

the phenylene, triazolylene, pyridylene, and furanylene are each independently optionally further substituted with a substituent (s) selected from the group consisting of halogen, hydroxyl, cyano, amino, mercapto, C_1-3 alkyl, C_1-3 alkoxy, halogenated C_1-4 alkyl, C_5-10 aryl, C_5-10 heteroaryl, C_3-12 cycloalkyl, 4-to 12-membered heterocyclyl, or any combination thereof.
The compound of Formula (I) or a salt, an enantiomer, a stereoisomer, a solvate, or a polymorph thereof as claimed in any one of claims 1-6, wherein the L represents the following groups:

wherein the symbol*indicates the point of attachment to the U₂.
The compound of Formula (I) or a salt, an enantiomer, a stereoisomer, a solvate, or a polymorph thereof as claimed in claim 1, which is selected from:

2- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) propenamide;

4- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

5- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) pentanamide;

6- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) hexanamide;

7- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) heptanamide;

8- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) octanamide;

9- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) nonanamide;

10- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) decanamide;

11- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) undecanamide;

N¹- (4- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) butyl) -N⁶- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) adipamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) propyl) phenyl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) propyl) -2-fluorophenyl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) propyl) piperazin-1-yl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) propyl) -2-oxopiperazin-1-yl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) propyl) piperidin-1-yl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) propyl) cyclohexyl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- ( (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) ethyl) amino) cyclohexyl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (1- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) propyl) -1H-1, 2, 3-triazol-4-yl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (5- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) propyl) pyridin-2-yl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) thio) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) thio) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) propenamide;

4- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) thio) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

5- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) thio) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) pentanamide;

6- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) thio) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) hexanamide;

7- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) thio) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) heptanamide;

8- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) thio) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) octanamide;

N¹- (4- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) thio) butyl) -N⁶- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) adipamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) thio) propyl) phenyl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) thio) propyl) -2-fluorophenyl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) thio) propyl) piperazin-1-yl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) thio) propyl) -2-oxopiperazin-1-yl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) thio) propyl) piperidin-1-yl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) thio) propyl) cyclohexyl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- ( (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) thio) ethyl) amino) cyclohexyl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (1- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) thio) propyl) -1H-1, 2, 3-triazol-4-yl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (5- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) thio) propyl) pyridin-2-yl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

3- (4- ( (5- ( (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) pentyl) thio) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;

3- (4- ( (6- ( (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) hexyl) thio) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;

3- (4- ( (7- ( (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) heptyl) thio) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;

3- (4- ( (8- ( (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) octyl) thio) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;

3- (6-fluoro-4- ( (5- ( (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) pentyl) thio) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;

3- (6-fluoro-4- ( (6- ( (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) hexyl) thio) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;

3- (6-fluoro-4- ( (7- ( (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) heptyl) thio) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;

3- (6-fluoro-4- ( (8- ( (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) octyl) thio) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;

2- (2, 6-dioxopiperidin-3-yl) -4- ( (5- ( (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) pentyl) thio) isoindoline-1, 3-dione;

2- (2, 6-dioxopiperidin-3-yl) -4- ( (6- ( (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) hexyl) thio) isoindoline-1, 3-dione;

2- (2, 6-dioxopiperidin-3-yl) -4- ( (7- ( (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) heptyl) thio) isoindoline-1, 3-dione;

2- (2, 6-dioxopiperidin-3-yl) -4- ( (8- ( (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) octyl) thio) isoindoline-1, 3-dione;

2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-4- ( (5- ( (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) pentyl) thio) isoindoline-1, 3-dione;

2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-4- ( (6- ( (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) hexyl) thio) isoindoline-1, 3-dione;

2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-4- ( (7- ( (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) heptyl) thio) isoindoline-1, 3-dione;

2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-4- ( (8- ( (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) octyl) thio) isoindoline-1, 3-dione;

2- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) propenamide;

5- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) pentanamide;

7- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) heptanamide;

8- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) octanamide;

N¹- (4- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) butyl) -N⁶- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) adipamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) propyl) phenyl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) propyl) -2-fluorophenyl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) propyl) piperazin-1-yl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) propyl) -2-oxopiperazin-1-yl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) propyl) piperidin-1-yl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) propyl) cyclohexyl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- ( (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) ethyl) amino) cyclohexyl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (1- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) propyl) -1H-1, 2, 3-triazol-4-yl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (5- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) propyl) pyridin-2-yl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) propenamide;

5- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) pentanamide;

7- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) heptanamide;

8- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) octanamide;

N¹- (4- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) butyl) -N⁶- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) adipamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) propyl) phenyl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) propyl) -2-fluorophenyl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) propyl) piperazin-1-yl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) propyl) -2-oxopiperazin-1-yl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) propyl) piperidin-1-yl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) propyl) cyclohexyl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- ( (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) ethyl) amino) cyclohexyl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (1- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) propyl) -1H-1, 2, 3-triazol-4-yl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (5- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) propyl) pyridin-2-yl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

2- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) propenamide;

5- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) pentanamide;

7- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) heptanamide;

8- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) octanamide;

N¹- (4- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) butyl) -N⁶- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) adipamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) propyl) phenyl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) propyl) -2-fluorophenyl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) propyl) piperazin-1-yl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) propyl) -2-oxopiperazin-1-yl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) propyl) piperidin-1-yl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) propyl) cyclohexyl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- ( (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) ethyl) amino) cyclohexyl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (1- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) propyl) -1H-1, 2, 3-triazol-4-yl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (5- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) propyl) pyridin-2-yl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) propenamide;

5- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) pentanamide;

7- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) heptanamide;

8- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) octanamide;

N¹- (4- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) butyl) -N⁶- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) adipamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) propyl) phenyl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) propyl) -2-fluorophenyl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) propyl) piperazin-1-yl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) propyl) -2-oxopiperazin-1-yl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) propyl) piperidin-1-yl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) propyl) cyclohexyl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- ( (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethyl) amino) cyclohexyl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (1- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) propyl) -1H-1, 2, 3-triazol-4-yl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (5- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) propyl) pyridin-2-yl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) ethoxy) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

2- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) ethoxy) ethoxy) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

2- (2- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) ethoxy) ethoxy) ethoxy) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

17- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) -3, 6, 9, 12, 15-pentaoxaheptadecanamide;

2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) thio) ethoxy) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

2- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) thio) ethoxy) ethoxy) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

2- (2- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) thio) ethoxy) ethoxy) ethoxy) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

17- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) thio) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) -3, 6, 9, 12, 15-pentaoxaheptadecanamide;

2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) ethoxy) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

2- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) ethoxy) ethoxy) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

2- (2- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) ethoxy) ethoxy) ethoxy) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

17- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) -3, 6, 9, 12, 15-pentaoxaheptadecanamide;

2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) ethoxy) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

2- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) ethoxy) ethoxy) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

2- (2- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) ethoxy) ethoxy) ethoxy) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

17- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) -3, 6, 9, 12, 15-pentaoxaheptadecanamide;

2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) ethoxy) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

2- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) ethoxy) ethoxy) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

2- (2- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) ethoxy) ethoxy) ethoxy) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

17- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) -3, 6, 9, 12, 15-pentaoxaheptadecanamide;

2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethoxy) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

2- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethoxy) ethoxy) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

2- (2- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethoxy) ethoxy) ethoxy) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

17- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) -3, 6, 9, 12, 15-pentaoxaheptadecanamide;

2- (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

3- (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) propenamide;

4- (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

6- (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) hexanamide;

8- (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) octanamide;

2- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

3- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) propenamide;

6- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) hexanamide;

8- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) octanamide;

2- (2- (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) ethoxy) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

2- (2- (2- (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) ethoxy) ethoxy) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

2- (2- (2- (2- (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) ethoxy) ethoxy) ethoxy) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

17- (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) -3, 6, 9, 12, 15-pentaoxaheptadecanamide;

2- (2- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) ethoxy) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

2- (2- (2- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) ethoxy) ethoxy) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

2- (2- (2- (2- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) ethoxy) ethoxy) ethoxy) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

17- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) -3, 6, 9, 12, 15-pentaoxaheptadecanamide;

3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl 2- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) acetate;

3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl 4- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) butanoate;

3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl 6- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) hexanoate;

3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) glycinate;

3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) glycinate;

3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl 6- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) hexanoate;

3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl 6- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) hexanoate;

3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl 2- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) acetate;

3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl 2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) acetate;

3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl 6- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) hexanoate;

3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl 6- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) hexanoate;

3- (4- ( (3- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) prop-2-yn-1-yl) oxy) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;

3- (4- ( (7- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) hept-6-yn-1-yl) oxy) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;

2- (2, 6-dioxopiperidin-3-yl) -4- ( (3- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) prop-2-yn-1-yl) oxy) isoindoline-1, 3-dione;

2- (2, 6-dioxopiperidin-3-yl) -4- ( (7- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) hept-6-yn-1-yl) oxy) isoindoline-1, 3-dione;

3- (4- ( (3- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) prop-2-yn-1-yl) thio) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;

3- (4- ( (7- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) hept-6-yn-1-yl) thio) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;

2- (2, 6-dioxopiperidin-3-yl) -4- ( (3- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) prop-2-yn-1-yl) thio) isoindoline-1, 3-dione;

2- (2, 6-dioxopiperidin-3-yl) -4- ( (7- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) hept-6-yn-1-yl) thio) isoindoline-1, 3-dione;

3- (4- ( (3- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) prop-2-yn-1-yl) amino) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;

3- (4- ( (7- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) hept-6-yn-1-yl) amino) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;

2- (2, 6-dioxopiperidin-3-yl) -4- ( (3- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) prop-2-yn-1-yl) amino) isoindoline-1, 3-dione;

2- (2, 6-dioxopiperidin-3-yl) -4- ( (7- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) hept-6-yn-1-yl) amino) isoindoline-1, 3-dione;

3- (4- ( (5- ( (4-fluoro-3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1-picolinoyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) pentyl) thio) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;

3- (4- ( (6- ( (4-fluoro-3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1-picolinoyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) hexyl) thio) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;

3- (4- ( (7- ( (4-fluoro-3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1-picolinoyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) heptyl) thio) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;

3- (4- ( (8- ( (4-fluoro-3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1-picolinoyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) octyl) thio) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;

2- (2, 6-dioxopiperidin-3-yl) -4- ( (5- ( (4-fluoro-3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1-picolinoyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) pentyl) thio) isoindoline-1, 3-dione;

2- (2, 6-dioxopiperidin-3-yl) -4- ( (6- ( (4-fluoro-3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1-picolinoyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) hexyl) thio) isoindoline-1, 3-dione;

2- (2, 6-dioxopiperidin-3-yl) -4- ( (7- ( (4-fluoro-3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1-picolinoyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) heptyl) thio) isoindoline-1, 3-dione;

2- (2, 6-dioxopiperidin-3-yl) -4- ( (8- ( (4-fluoro-3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1-picolinoyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) octyl) thio) isoindoline-1, 3-dione;

3- (4- ( (5- ( (4-fluoro-3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -5-methyl-1- ( (4-methyl-4H-imidazol-2-yl) sulfonyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) pentyl) thio) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;

3- (4- ( (6- ( (4-fluoro-3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -5-methyl-1- ( (4-methyl-4H-imidazol-2-yl) sulfonyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) hexyl) thio) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;

3- (4- ( (7- ( (4-fluoro-3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -5-methyl-1- ( (4-methyl-4H-imidazol-2-yl) sulfonyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) heptyl) thio) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;

3- (4- ( (8- ( (4-fluoro-3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -5-methyl-1- ( (4-methyl-4H-imidazol-2-yl) sulfonyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) octyl) thio) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;

2- (2, 6-dioxopiperidin-3-yl) -4- ( (5- ( (4-fluoro-3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -5-methyl-1- ( (4-methyl-4H-imidazol-2-yl) sulfonyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) pentyl) thio) isoindoline-1, 3-dione;

2- (2, 6-dioxopiperidin-3-yl) -4- ( (6- ( (4-fluoro-3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -5-methyl-1- ( (4-methyl-4H-imidazol-2-yl) sulfonyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) hexyl) thio) isoindoline-1, 3-dione;

2- (2, 6-dioxopiperidin-3-yl) -4- ( (7- ( (4-fluoro-3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -5-methyl-1- ( (4-methyl-4H-imidazol-2-yl) sulfonyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) heptyl) thio) isoindoline-1, 3-dione;

2- (2, 6-dioxopiperidin-3-yl) -4- ( (8- ( (4-fluoro-3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -5-methyl-1- ( (4-methyl-4H-imidazol-2-yl) sulfonyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) octyl) thio) isoindoline-1, 3-dione;

3- (4- ( (5- ( (4-fluoro-3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) pentyl) thio) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;

3- (4- ( (6- ( (4-fluoro-3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) hexyl) thio) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;

3- (4- ( (7- ( (4-fluoro-3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) heptyl) thio) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;

3- (4- ( (8- ( (4-fluoro-3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) octyl) thio) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;

2- (2, 6-dioxopiperidin-3-yl) -4- ( (5- ( (4-fluoro-3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) pentyl) thio) isoindoline-1, 3-dione;

2- (2, 6-dioxopiperidin-3-yl) -4- ( (6- ( (4-fluoro-3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) hexyl) thio) isoindoline-1, 3-dione;

2- (2, 6-dioxopiperidin-3-yl) -4- ( (7- ( (4-fluoro-3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) heptyl) thio) isoindoline-1, 3-dione;

2- (2, 6-dioxopiperidin-3-yl) -4- ( (8- ( (4-fluoro-3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) octyl) thio) isoindoline-1, 3-dione;

3- (4- ( (5- ( (5- ( ( (3aS, 4S, 9bR) -1- (cyclohexanecarbonyl) -4- (hydroxymethyl) -5-methyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) ethynyl) pyridin-2-yl) amino) pentyl) thio) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;

3- (4- ( (6- ( (5- ( ( (3aS, 4S, 9bR) -1- (cyclohexanecarbonyl) -4- (hydroxymethyl) -5-methyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) ethynyl) pyridin-2-yl) amino) hexyl) thio) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;

3- (4- ( (7- ( (5- ( ( (3aS, 4S, 9bR) -1- (cyclohexanecarbonyl) -4- (hydroxymethyl) -5-methyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) ethynyl) pyridin-2-yl) amino) heptyl) thio) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;

3- (4- ( (8- ( (5- ( ( (3aS, 4S, 9bR) -1- (cyclohexanecarbonyl) -4- (hydroxymethyl) -5-methyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) ethynyl) pyridin-2-yl) amino) octyl) thio) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;

4- ( (5- ( (5- ( ( (3aS, 4S, 9bR) -1- (cyclohexanecarbonyl) -4- (hydroxymethyl) -5-methyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) ethynyl) pyridin-2-yl) amino) pentyl) thio) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;

4- ( (6- ( (5- ( ( (3aS, 4S, 9bR) -1- (cyclohexanecarbonyl) -4- (hydroxymethyl) -5-methyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) ethynyl) pyridin-2-yl) amino) hexyl) thio) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;

4- ( (7- ( (5- ( ( (3aS, 4S, 9bR) -1- (cyclohexanecarbonyl) -4- (hydroxymethyl) -5-methyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) ethynyl) pyridin-2-yl) amino) heptyl) thio) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;

4- ( (8- ( (5- ( ( (3aS, 4S, 9bR) -1- (cyclohexanecarbonyl) -4- (hydroxymethyl) -5-methyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) ethynyl) pyridin-2-yl) amino) octyl) thio) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;

N¹- ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) -N³- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) malonamide;

N¹- ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) -N⁴- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) succinimide;

N¹- ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) -N⁵- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) glutaramide;

N¹- ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) -N⁷- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) heptanediamide;

(2S, 4R) -4-hydroxy-1- ( (S) -2- (3- (2- ( (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) -2-oxoethoxy) propanamido) -3, 3-dimethylbutanoyl) -N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide;

(2S, 4R) -4-hydroxy-1- ( (S) -2- (3- (2- (2- ( (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) -2-oxoethoxy) ethoxy) propanamido) -3, 3-dimethylbutanoyl) -N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide;

(2S, 4R) -4-hydroxy-1- ( (S) -2- (4- (4- (4- ( (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) -4-oxobutyl) phenyl) butanamido) -3, 3-dimethylbutanoyl) -N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide;

(2S, 4R) -1- ( (S) -2- (4- (3-fluoro-4- (4- ( (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) -4-oxobutyl) phenyl) butanamido) -3, 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide;

(2S, 4R) -4-hydroxy-1- ( (S) -2- (4- (4- (4- ( (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) -4-oxobutyl) piperazin-1-yl) butanamido) -3, 3-dimethylbutanoyl) -N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide;

(2S, 4R) -4-hydroxy-1- ( (S) -2- (4- (1- (4- ( (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) -4-oxobutyl) piperidin-4-yl) butanamido) -3, 3-dimethylbutanoyl) -N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide;

(2S, 4R) -4-hydroxy-1- ( (S) -2- (4- (4- (4- ( (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) -4-oxobutyl) cyclohexyl) butanamido) -3, 3-dimethylbutanoyl) -N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide;

(2S, 4R) -4-hydroxy-1- ( (S) -2- (3- (4- (4- ( (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) -4-oxobutyl) -1H-1, 2, 3-triazol-1-yl) propanamido) -3, 3-dimethylbutanoyl) -N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide;

(2S, 4R) -4-hydroxy-1- ( (S) -2- (4- (6- (4- ( (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) -4-oxobutyl) pyridin-3-yl) butanamido) -3, 3-dimethylbutanoyl) -N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide;

(2S, 4R) -4-hydroxy-1- ( (S) -2- (4- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) but-3-ynamido) -3, 3-dimethylbutanoyl) -N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide;

(2S, 4R) -4-hydroxy-1- ( (S) -2- (6- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) hex-5-ynamido) -3, 3-dimethylbutanoyl) -N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide;

3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl 2- (3- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -3-oxopropoxy) acetate;

(2S, 4R) -4-hydroxy-1- ( (S) -2- (3- (2- ( (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) ethoxy) propanamido) -3, 3-dimethylbutanoyl) -N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide;

2- (4- ( (4R, 5S) -4, 5-bis (4-chlorophenyl) -2- (2-isopropoxy-4-methoxyphenyl) -4, 5-dihydro-1H-imidazole-1-carbonyl) -2-oxopiperazin-1-yl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

4- (4- ( (4R, 5S) -4, 5-bis (4-chlorophenyl) -2- (2-isopropoxy-4-methoxyphenyl) -4, 5-dihydro-1H-imidazole-1-carbonyl) -2-oxopiperazin-1-yl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

6- (4- ( (4R, 5S) -4, 5-bis (4-chlorophenyl) -2- (2-isopropoxy-4-methoxyphenyl) -4, 5-dihydro-1H-imidazole-1-carbonyl) -2-oxopiperazin-1-yl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) hexanamide;

4- (4- (3- (4- ( (4R, 5S) -4, 5-bis (4-chlorophenyl) -2- (2-isopropoxy-4-methoxyphenyl) -4, 5-dihydro-1H-imidazole-1-carbonyl) -2-oxopiperazin-1-yl) propyl) phenyl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (5- (3- (4- ( (4R, 5S) -4, 5-bis (4-chlorophenyl) -2- (2-isopropoxy-4-methoxyphenyl) -4, 5-dihydro-1H-imidazole-1-carbonyl) -2-oxopiperazin-1-yl) propyl) pyridin-2-yl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- (4- ( (4R, 5S) -4, 5-bis (4-chlorophenyl) -2- (2-isopropoxy-4-methoxyphenyl) -4, 5-dihydro-1H-imidazole-1-carbonyl) -2-oxopiperazin-1-yl) propyl) piperazin-1-yl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- (4- ( (4R, 5S) -4, 5-bis (4-chlorophenyl) -2- (2-isopropoxy-4-methoxyphenyl) -4, 5-dihydro-1H-imidazole-1-carbonyl) -2-oxopiperazin-1-yl) propyl) piperidin-1-yl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- (4- ( (4R, 5S) -4, 5-bis (4-chlorophenyl) -2- (2-isopropoxy-4-methoxyphenyl) -4, 5-dihydro-1H-imidazole-1-carbonyl) -2-oxopiperazin-1-yl) propyl) cyclohexyl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (1- (3- (4- ( (4R, 5S) -4, 5-bis (4-chlorophenyl) -2- (2-isopropoxy-4-methoxyphenyl) -4, 5-dihydro-1H-imidazole-1-carbonyl) -2-oxopiperazin-1-yl) propyl) -1H-1, 2, 3-triazol-4-yl) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

2- (2- (4- ( (4R, 5S) -4, 5-bis (4-chlorophenyl) -2- (2-isopropoxy-4-methoxyphenyl) -4, 5-dihydro-1H-imidazole-1-carbonyl) -2-oxopiperazin-1-yl) ethoxy) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

2- (2- (2- (4- ( (4R, 5S) -4, 5-bis (4-chlorophenyl) -2- (2-isopropoxy-4-methoxyphenyl) -4, 5-dihydro-1H-imidazole-1-carbonyl) -2-oxopiperazin-1-yl) ethoxy) ethoxy) -N- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

4- ( (4R, 5S) -4, 5-bis (4-chlorophenyl) -2- (2-isopropoxy-4-methoxyphenyl) -4, 5-dihydro-1H-imidazole-1-carbonyl) -1- (3- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) prop-2-yn-1-yl) piperazin-2-one;

4- ( (4R, 5S) -4, 5-bis (4-chlorophenyl) -2- (2-isopropoxy-4-methoxyphenyl) -4, 5-dihydro-1H-imidazole-1-carbonyl) -1- (5- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) pent-4-yn-1-yl) piperazin-2-one;

4- ( (4R, 5S) -4, 5-bis (4-chlorophenyl) -2- (2-isopropoxy-4-methoxyphenyl) -4, 5-dihydro-1H-imidazole-1-carbonyl) -1- (7- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) hept-6-yn-1-yl) piperazin-2-one;

4- ( (4R, 5S) -4, 5-bis (4-chlorophenyl) -2- (2-isopropoxy-4-methoxyphenyl) -4, 5-dihydro-1H-imidazole-1-carbonyl) -1- (2- ( (3- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) prop-2-yn-1-yl) oxy) ethyl) piperazin-2-one;

4- ( (4R, 5S) -4, 5-bis (4-chlorophenyl) -2- (2-isopropoxy-4-methoxyphenyl) -4, 5-dihydro-1H-imidazole-1-carbonyl) -1- (2- (2- ( (3- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) prop-2-yn-1-yl) oxy) ethoxy) ethyl) piperazin-2-one;

4- ( (4R, 5S) -4, 5-bis (4-chlorophenyl) -2- (2-isopropoxy-4-methoxyphenyl) -4, 5-dihydro-1H-imidazole-1-carbonyl) -1- (2- ( (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) ethyl) piperazin-2-one;

4- ( (4R, 5S) -4, 5-bis (4-chlorophenyl) -2- (2-isopropoxy-4-methoxyphenyl) -4, 5-dihydro-1H-imidazole-1-carbonyl) -1- (4- ( (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) butyl) piperazin-2-one;

4- ( (4R, 5S) -4, 5-bis (4-chlorophenyl) -2- (2-isopropoxy-4-methoxyphenyl) -4, 5-dihydro-1H-imidazole-1-carbonyl) -1- (6- ( (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) hexyl) piperazin-2-one;

4- ( (4R, 5S) -4, 5-bis (4-chlorophenyl) -2- (2-isopropoxy-4-methoxyphenyl) -4, 5-dihydro-1H-imidazole-1-carbonyl) -1- (2- ( ( (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) methoxy) ethyl) piperazin-2-one;

4- ( (4R, 5S) -4, 5-bis (4-chlorophenyl) -2- (2-isopropoxy-4-methoxyphenyl) -4, 5-dihydro-1H-imidazole-1-carbonyl) -1- (2- (2- ( ( (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) methoxy) ethoxy) ethyl) piperazin-2-one;

3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl 2- (4- ( (4R, 5S) -4, 5-bis (4-chlorophenyl) -2- (2-isopropoxy-4-methoxyphenyl) -4, 5-dihydro-1H-imidazole-1-carbonyl) -2-oxopiperazin-1-yl) acetate;

3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl 4- (4- ( (4R, 5S) -4, 5-bis (4-chlorophenyl) -2- (2-isopropoxy-4-methoxyphenyl) -4, 5-dihydro-1H-imidazole-1-carbonyl) -2-oxopiperazin-1-yl) butanoate;

3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl 6- (4- ( (4R, 5S) -4, 5-bis (4-chlorophenyl) -2- (2-isopropoxy-4-methoxyphenyl) -4, 5-dihydro-1H-imidazole-1-carbonyl) -2-oxopiperazin-1-yl) hexanoate;

3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl 2- (2- (4- ( (4R, 5S) -4, 5-bis (4-chlorophenyl) -2- (2-isopropoxy-4-methoxyphenyl) -4, 5-dihydro-1H-imidazole-1-carbonyl) -2-oxopiperazin-1-yl) ethoxy) acetate;

3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl 2- (2- (2- (4- ( (4R, 5S) -4, 5-bis (4-chlorophenyl) -2- (2-isopropoxy-4-methoxyphenyl) -4, 5-dihydro-1H-imidazole-1-carbonyl) -2-oxopiperazin-1-yl) ethoxy) ethoxy) acetate;

2- ( (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) -2-oxoethyl ( (2S, 3R) -3-amino-2-hydroxy-4-phenylbutanoyl) -L-leucinate;

4- ( (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) -4-oxobutyl ( (2S, 3R) -3-amino-2-hydroxy-4-phenylbutanoyl) -L-leucinate;

6- ( (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) -6-oxohexyl ( (2S, 3R) -3-amino-2-hydroxy-4-phenylbutanoyl) -L-leucinate;

2- (3- ( (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) -3-oxopropoxy) ethyl ( (2S, 3R) -3-amino-2-hydroxy-4-phenylbutanoyl) -L-leucinate;

2- (2- (2- ( (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) -2-oxoethoxy) ethoxy) ethyl ( (2S, 3R) -3-amino-2-hydroxy-4-phenylbutanoyl) -L-leucinate;

4- (4- ( (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) -4-oxobutyl) phenethyl ( (2S, 3R) -3-amino-2-hydroxy-4-phenylbutanoyl) -L-leucinate;

2- (6- (4- ( (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) -4-oxobutyl) pyridin-3-yl) ethyl ( (2S, 3R) -3-amino-2-hydroxy-4-phenylbutanoyl) -L-leucinate;

2- (4- (4- ( (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) -4-oxobutyl) piperazin-1-yl) ethyl ( (2S, 3R) -3-amino-2-hydroxy-4-phenylbutanoyl) -L-leucinate;

2- (1- (4- ( (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) -4-oxobutyl) piperidin-4-yl) ethyl ( (2S, 3R) -3-amino-2-hydroxy-4-phenylbutanoyl) -L-leucinate;

2- (4- (4- ( (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) -4-oxobutyl) cyclohexyl) ethyl ( (2S, 3R) -3-amino-2-hydroxy-4-phenylbutanoyl) -L-leucinate;

2- (4- (4- ( (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) -4-oxobutyl) -1H-1, 2, 3-triazol-1-yl) ethyl ( (2S, 3R) -3-amino-2-hydroxy-4-phenylbutanoyl) -L-leucinate;

3- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) prop-2-yn-1-yl ( (2S, 3R) -3-amino-2-hydroxy-4-phenylbutanoyl) -L-leucinate;

5- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) pent-4-yn-1-yl ( (2S, 3R) -3-amino-2-hydroxy-4-phenylbutanoyl) -L-leucinate;

7- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) hept-6-yn-1-yl ( (2S, 3R) -3-amino-2-hydroxy-4-phenylbutanoyl) -L-leucinate;

2- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenoxy) -2-oxoethyl ( (2S, 3R) -3-amino-2-hydroxy-4-phenylbutanoyl) -L-leucinate;

4- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenoxy) -4-oxobutyl ( (2S, 3R) -3-amino-2-hydroxy-4-phenylbutanoyl) -L-leucinate;

3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl 6- ( ( ( (2S, 3R) -3-amino-2-hydroxy-4-phenylbutanoyl) -L-leucyl) oxy) hexanoate;

2- (3- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenoxy) -3-oxopropoxy) ethyl ( (2S, 3R) -3-amino-2-hydroxy-4-phenylbutanoyl) -L-leucinate;

2- (2- (2- (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenoxy) -2-oxoethoxy) ethoxy) ethyl ( (2S, 3R) -3-amino-2-hydroxy-4-phenylbutanoyl) -L-leucinate;

2- ( (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) ethyl ( (2S, 3R) -3-amino-2-hydroxy-4-phenylbutanoyl) -L-leucinate;

4- ( (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) butyl ( (2S, 3R) -3-amino-2-hydroxy-4-phenylbutanoyl) -L-leucinate;

2- ( ( (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) methoxy) ethyl ( (2S, 3R) -3-amino-2-hydroxy-4-phenylbutanoyl) -L-leucinate;

2- (2- (2- ( (3- ( (3aR, 4S, 9bR) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) ethoxy) ethoxy) ethyl ( (2S, 3R) -3-amino-2-hydroxy-4-phenylbutanoyl) -L-leucinate;

2- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) propenamide;

4- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

5- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) pentanamide;

6- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) hexanamide;

7- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) heptanamide;

8- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) octanamide;

9- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) nonanamide;

10- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) decanamide;

11- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) undecanamide;

N¹- (4- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) butyl) -N⁶- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) adipamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) propyl) phenyl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) propyl) -2-fluorophenyl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) propyl) piperazin-1-yl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) propyl) -2-oxopiperazin-1-yl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) propyl) piperidin-1-yl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) propyl) cyclohexyl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- ( (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) ethyl) amino) cyclohexyl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (1- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) propyl) -1H-1, 2, 3-triazol-4-yl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (5- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) propyl) pyridin-2-yl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) thio) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) thio) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) propenamide;

4- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) thio) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

5- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) thio) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) pentanamide;

6- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) thio) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) hexanamide;

7- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) thio) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) heptanamide;

8- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) thio) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) octanamide;

N¹- (4- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) thio) butyl) -N⁶- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) adipamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) thio) propyl) phenyl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) thio) propyl) -2-fluorophenyl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) thio) propyl) piperazin-1-yl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) thio) propyl) -2-oxopiperazin-1-yl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) thio) propyl) piperidin-1-yl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) thio) propyl) cyclohexyl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- ( (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) thio) ethyl) amino) cyclohexyl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (1- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) thio) propyl) -1H-1, 2, 3-triazol-4-yl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (5- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) thio) propyl) pyridin-2-yl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

3- (4- ( (5- ( (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) pentyl) thio) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;

3- (4- ( (6- ( (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) hexyl) thio) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;

3- (4- ( (7- ( (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) heptyl) thio) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;

3- (4- ( (8- ( (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) octyl) thio) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;

3- (6-fluoro-4- ( (5- ( (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) pentyl) thio) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;

3- (6-fluoro-4- ( (6- ( (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) hexyl) thio) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;

3- (6-fluoro-4- ( (7- ( (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) heptyl) thio) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;

3- (6-fluoro-4- ( (8- ( (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) octyl) thio) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;

2- (2, 6-dioxopiperidin-3-yl) -4- ( (5- ( (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) pentyl) thio) isoindoline-1, 3-dione;

2- (2, 6-dioxopiperidin-3-yl) -4- ( (6- ( (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) hexyl) thio) isoindoline-1, 3-dione;

2- (2, 6-dioxopiperidin-3-yl) -4- ( (7- ( (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) heptyl) thio) isoindoline-1, 3-dione;

2- (2, 6-dioxopiperidin-3-yl) -4- ( (8- ( (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) octyl) thio) isoindoline-1, 3-dione;

2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-4- ( (5- ( (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) pentyl) thio) isoindoline-1, 3-dione;

2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-4- ( (6- ( (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) hexyl) thio) isoindoline-1, 3-dione;

2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-4- ( (7- ( (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) heptyl) thio) isoindoline-1, 3-dione;

2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-4- ( (8- ( (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) octyl) thio) isoindoline-1, 3-dione;

2- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) propenamide;

5- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) pentanamide;

7- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) heptanamide;

8- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) octanamide;

N¹- (4- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) butyl) -N⁶- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) adipamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) propyl) phenyl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) propyl) -2-fluorophenyl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) propyl) piperazin-1-yl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) propyl) -2-oxopiperazin-1-yl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) propyl) piperidin-1-yl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) propyl) cyclohexyl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- ( (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) ethyl) amino) cyclohexyl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (1- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) propyl) -1H-1, 2, 3-triazol-4-yl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (5- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) propyl) pyridin-2-yl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) propenamide;

5- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) pentanamide;

7- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) heptanamide;

8- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) octanamide;

N¹- (4- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) butyl) -N⁶- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) adipamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) propyl) phenyl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) propyl) -2-fluorophenyl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) propyl) piperazin-1-yl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) propyl) -2-oxopiperazin-1-yl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) propyl) piperidin-1-yl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) propyl) cyclohexyl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- ( (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) ethyl) amino) cyclohexyl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (1- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) propyl) -1H-1, 2, 3-triazol-4-yl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (5- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) propyl) pyridin-2-yl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

2- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) propenamide;

5- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) pentanamide;

7- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) heptanamide;

8- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) octanamide;

N¹- (4- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) butyl) -N⁶- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) adipamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) propyl) phenyl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) propyl) -2-fluorophenyl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) propyl) piperazin-1-yl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) propyl) -2-oxopiperazin-1-yl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) propyl) piperidin-1-yl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) propyl) cyclohexyl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- ( (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) ethyl) amino) cyclohexyl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (1- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) propyl) -1H-1, 2, 3-triazol-4-yl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (5- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) propyl) pyridin-2-yl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) propenamide;

5- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) pentanamide;

7- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) heptanamide;

8- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) octanamide;

N¹- (4- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) butyl) -N⁶- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) adipamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) propyl) phenyl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) propyl) -2-fluorophenyl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) propyl) piperazin-1-yl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) propyl) -2-oxopiperazin-1-yl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) propyl) piperidin-1-yl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) propyl) cyclohexyl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (4- ( (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethyl) amino) cyclohexyl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (1- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) propyl) -1H-1, 2, 3-triazol-4-yl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

4- (5- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) propyl) pyridin-2-yl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) ethoxy) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

2- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) ethoxy) ethoxy) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

2- (2- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) ethoxy) ethoxy) ethoxy) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

17- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) -3, 6, 9, 12, 15-pentaoxaheptadecanamide;

2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) thio) ethoxy) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

2- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) thio) ethoxy) ethoxy) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

2- (2- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) thio) ethoxy) ethoxy) ethoxy) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

17- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) thio) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) -3, 6, 9, 12, 15-pentaoxaheptadecanamide;

2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) ethoxy) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

2- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) ethoxy) ethoxy) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

2- (2- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) ethoxy) ethoxy) ethoxy) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

17- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) -3, 6, 9, 12, 15-pentaoxaheptadecanamide;

2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) ethoxy) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

2- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) ethoxy) ethoxy) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

2- (2- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) ethoxy) ethoxy) ethoxy) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

17- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) -3, 6, 9, 12, 15-pentaoxaheptadecanamide;

2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) ethoxy) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

2- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) ethoxy) ethoxy) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

2- (2- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) ethoxy) ethoxy) ethoxy) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

17- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) -3, 6, 9, 12, 15-pentaoxaheptadecanamide;

2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethoxy) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

2- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethoxy) ethoxy) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

2- (2- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethoxy) ethoxy) ethoxy) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

17- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) -3, 6, 9, 12, 15-pentaoxaheptadecanamide;

2- (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

3- (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) propenamide;

4- (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide;

6- (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) hexanamide;

8- (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) octanamide;

2- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

3- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) propenamide;

6- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) hexanamide;

8- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) octanamide;

2- (2- (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) ethoxy) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

2- (2- (2- (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) ethoxy) ethoxy) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

2- (2- (2- (2- (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) ethoxy) ethoxy) ethoxy) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

17- (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) -3, 6, 9, 12, 15-pentaoxaheptadecanamide;

2- (2- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) ethoxy) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

2- (2- (2- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) ethoxy) ethoxy) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

2- (2- (2- (2- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) ethoxy) ethoxy) ethoxy) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

17- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) -N- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) -3, 6, 9, 12, 15-pentaoxaheptadecanamide;

3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl 2- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) acetate;

3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl 4- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) butanoate;

3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl 6- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) hexanoate;

3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) glycinate;

3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) glycinate;

3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl 6- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) hexanoate;

3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl 6- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) hexanoate;

3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl 2- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) acetate;

3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl 2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) acetate;

3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl 6- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) hexanoate;

3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl 6- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) hexanoate;

3- (4- ( (3- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) prop-2-yn-1-yl) oxy) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;

3- (4- ( (7- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) hept-6-yn-1-yl) oxy) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;

2- (2, 6-dioxopiperidin-3-yl) -4- ( (3- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) prop-2-yn-1-yl) oxy) isoindoline-1, 3-dione;

2- (2, 6-dioxopiperidin-3-yl) -4- ( (7- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) hept-6-yn-1-yl) oxy) isoindoline-1, 3-dione;

3- (4- ( (3- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) prop-2-yn-1-yl) thio) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;

3- (4- ( (7- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) hept-6-yn-1-yl) thio) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;

2- (2, 6-dioxopiperidin-3-yl) -4- ( (3- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) prop-2-yn-1-yl) thio) isoindoline-1, 3-dione;

2- (2, 6-dioxopiperidin-3-yl) -4- ( (7- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) hept-6-yn-1-yl) thio) isoindoline-1, 3-dione;

3- (4- ( (3- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) prop-2-yn-1-yl) amino) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;

3- (4- ( (7- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) hept-6-yn-1-yl) amino) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;

2- (2, 6-dioxopiperidin-3-yl) -4- ( (3- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) prop-2-yn-1-yl) amino) isoindoline-1, 3-dione;

2- (2, 6-dioxopiperidin-3-yl) -4- ( (7- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) hept-6-yn-1-yl) amino) isoindoline-1, 3-dione;

N¹- ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) -N³- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) malonamide;

N¹- ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) -N⁴- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) succinimide;

N¹- ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) -N⁵- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) glutaramide;

N¹- ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) -N⁷- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) heptanediamide;

(2S, 4R) -4-hydroxy-1- ( (S) -2- (3- (2- ( (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) -2-oxoethoxy) propanamido) -3, 3-dimethylbutanoyl) -N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide;

(2S, 4R) -4-hydroxy-1- ( (S) -2- (3- (2- (2- ( (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) -2-oxoethoxy) ethoxy) propanamido) -3, 3-dimethylbutanoyl) -N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide;

(2S, 4R) -4-hydroxy-1- ( (S) -2- (4- (4- (4- ( (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) -4-oxobutyl) phenyl) butanamido) -3, 3-dimethylbutanoyl) -N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide;

(2S, 4R) -1- ( (S) -2- (4- (3-fluoro-4- (4- ( (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) -4-oxobutyl) phenyl) butanamido) -3, 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide;

(2S, 4R) -4-hydroxy-1- ( (S) -2- (4- (4- (4- ( (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) -4-oxobutyl) piperazin-1-yl) butanamido) -3, 3-dimethylbutanoyl) -N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide;

(2S, 4R) -4-hydroxy-1- ( (S) -2- (4- (1- (4- ( (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) -4-oxobutyl) piperidin-4-yl) butanamido) -3, 3-dimethylbutanoyl) -N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide;

(2S, 4R) -4-hydroxy-1- ( (S) -2- (4- (4- (4- ( (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) -4-oxobutyl) cyclohexyl) butanamido) -3, 3-dimethylbutanoyl) -N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide;

(2S, 4R) -4-hydroxy-1- ( (S) -2- (3- (4- (4- ( (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) -4-oxobutyl) -1H-1, 2, 3-triazol-1-yl) propanamido) -3, 3-dimethylbutanoyl) -N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide;

(2S, 4R) -4-hydroxy-1- ( (S) -2- (4- (6- (4- ( (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) -4-oxobutyl) pyridin-3-yl) butanamido) -3, 3-dimethylbutanoyl) -N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide;

(2S, 4R) -4-hydroxy-1- ( (S) -2- (4- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) but-3-ynamido) -3, 3-dimethylbutanoyl) -N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide;

(2S, 4R) -4-hydroxy-1- ( (S) -2- (6- (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) hex-5-ynamido) -3, 3-dimethylbutanoyl) -N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide;

3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl 2- (3- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -3-oxopropoxy) acetate;

(2S, 4R) -4-hydroxy-1- ( (S) -2- (3- (2- ( (3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) ethoxy) propanamido) -3, 3-dimethylbutanoyl) -N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide;

2- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) -N- (4-fluoro-3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) acetamide;

7- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) -N- (4-fluoro-3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) heptanamide;

8- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) -N- (4-fluoro-3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) octanamide;

9- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) -N- (4-fluoro-3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) nonanamide;

10- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) -N- (4-fluoro-3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) decanamide;

11- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) -N- (4-fluoro-3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) undecanamide;

3- (5- ( ( (4-fluoro-3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;

6- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) -N- (4-fluoro-3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) hexanamide;

5- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) -N- (4-fluoro-3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) pentanamide;

4- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) -N- (4-fluoro-3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) butanamide; or

3- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) thio) -N- (4-fluoro-3- ( (3aR, 4R, 9bR) -4- (hydroxymethyl) -1-tosyl-2, 3, 3a, 4, 5, 9b-hexahydro-1H-pyrrolo [3, 2-c] quinolin-8-yl) phenyl) propanamide.
The compound of Formula (I) or a salt, an enantiomer, a stereoisomer, a solvate, or a polymorph thereof as claimed in any one of claims 1-12, which is a salt of the compound of Formula (I) , e.g., sulfate, hydrochloride, citrate, maleate, sulfonate, citrate, lactate, tartrate, fumarate, phosphate, dihydrogenphosphate, pyrophosphate, metaphosphate, oxalate, malonate, benzoate, mandelate, succinate, glycolate, or p-toluenesulfonate of the compound of Formula (I) .
A composition or preparation comprising the compound of Formula (I) as claimed in any one of claims 1-13 or a salt thereof, and at least one physiologically acceptable carrier.
The composition or preparation as claimed in claim 14, wherein the composition or preparation is used for degrading Cas9 protein, variants or homologues thereof or complexes comprising the same, which include Cas9 protein, Cas9 nuclease dimers, Cas9 nuclease fusion proteins, Cas9 nuclease fragments, minimized Cas9 nucleases, Cas9 variants without a cleavage domain, Cas9 variants without a gRNA domain, Cas9-recombinase fusions, and complexes comprising any of these Cas proteins, e.g., deactivated Cas9 (dCas9) proteins, variants of dCas9, Cas9 nicknase (or D10A nickase) , SaCas9, Cas9 nuclease from Streptococcus pyogenes (SpCas9) , SpCas9n, saCas9, High Fidelity Cas9 (HiFi Cas9) , Cas9-H840A, FokI-dCas9, and any of these Cas proteins fused with other engineered proteins, and ribonucleoprotein complexes comprising Cas9 protein.
The composition or preparation as claimed in claim 15, wherein the composition or preparation is used for modulating CRISPR/Cas9 protein, variants or homologues thereof-mediated genome editing, transcriptional regulation, genome imaging, epigenetic modification, gene therapy, disease models establishing, genome-wide genetic screening, or drug design and screening; or for modulating CRISPR/Cas9 protein, variants or homologues thereof-based molecular diagnostic tool for diseases.
The composition or preparation as claimed in any one of claims 14-16, wherein the composition or preparation is a degrader composition or preparation.
A kit comprising the compound of formula (I) as claimed in any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof or the composition or preparation as claimed in any one of claims 14-17.
The kit as claimed in claim 18, wherein the kit further comprises a CRISPR/Cas9 protein, variants or homologues thereof system comprising Cas9 nucleases, variants or homologues thereof, and guide RNAs (gRNA) .
The kit as claimed in claim 19, wherein the kit is used for modulating CRISPR/Cas9 protein, variants or homologues thereof-mediated genome editing, transcriptional regulation, genome imaging, epigenetic modification, gene therapy, disease models establishing, genome-wide genetic screening, or drug design and screening; or for modulating CRISPR/Cas9 protein, variants or homologues thereof-based molecular diagnostic tool for diseases.
Use of the compound of Formula (I) as claimed in any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof or the composition or preparation as claimed in any one of claims 14-17 for the manufacture of a degrader for degrading Cas9 protein, variants or homologues thereof or complexes comprising the same including Cas9 protein, Cas9 nuclease dimers, Cas9 nuclease fusion proteins, Cas9 nuclease fragments, minimized Cas9 nucleases, Cas9 variants without a cleavage domain, Cas9 variants without a gRNA domain, Cas9-recombinase fusions, and complexes comprising any of these Cas proteins, e.g., deactivated Cas9 (dCas9) proteins, variants of dCas9, Cas9 nicknase (or D10A nickase) , SaCas9, Cas9 nuclease from Streptococcus pyogenes (SpCas9) , SpCas9n, saCas9, High Fidelity Cas9 (HiFi Cas9) , Cas9-H840A, and FokI-dCas9, any of these Cas proteins fused with other engineered proteins, and ribonucleoprotein complexes comprising Cas9 protein.
The use as claimed in claim 21, wherein the degrader is used, in combination with a CRISPR/Cas9 protein, variants or homologues thereof system, for modulating CRISPR/Cas9 protein, variants or homologues thereof-mediated genome editing, transcriptional regulation, genome imaging, epigenetic modification, gene therapy, disease models establishing, genome-wide genetic screening, or drug design and screening; or for modulating CRISPR/Cas9 protein, variants or homologues thereof-based molecular diagnostic tool for diseases.
The use as claimed in claim 21, wherein the degrader is used in combination with CRISPR/Cas9 protein, variants or homologues thereof-mediated gene therapy for the prevention and/or treatment of a genetic disease in a subject; or as a modulator for the modulation of CRISPR/Cas9 protein, variants or homologues thereof-mediated genome editing of a target DNA in a cell.
The use as claimed in claim 23, wherein the CRISPR/Cas9 protein, variants or homologues thereof-mediated genome editing adopts a CRISPR/Cas9 protein, variants or homologues thereof system comprising Cas9 nucleases, variants or homologues thereof, and guide RNAs (gRNA) .
The use as claimed in claim 23, wherein the genetic disease is selected from the group consisting of blood disorders such as sickle cell anemia and thalassemia; X-linked dominant genetic diseases, such as vitamin D resistant rickets and hereditary nephritis; X-linked recessive genetic diseases, such as red green blindness, hemophilia, and congenital deafness; neoplasia; cancer; age-related macular degeneration; schizophrenia; trinucleotide repeat disorders; prion-related disorders; amyotrophic lateral sclerosis; autism; Alzheimer's disease; Parkinson's disease; immune-related diseases; metabolic diseases, such as diabetes; hypertension; bronchial asthma; glaucoma; cleft lip and palate; deformed feet; epilepsy; spina bifida; neural tube defects; congenital myotonia; and progressive muscular dystrophy.
The compound of Formula (I) as claimed in any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, for use as a degrader for degrading Cas9 protein, variants or homologues thereof or complexes comprising the same, which include Cas9 protein, Cas9 nuclease dimers, Cas9 nuclease fusion proteins, Cas9 nuclease fragments, minimized Cas9 nucleases, Cas9 variants without a cleavage domain, Cas9 variants without a gRNA domain, Cas9-recombinase fusions and complexes comprising any of these Cas proteins, e.g., deactivated Cas9 (dCas9) proteins, variants of dCas9, Cas9 nicknase (or D10A nickase) , SaCas9, Cas9 nuclease from Streptococcus pyogenes (SpCas9) , SpCas9n, saCas9, High Fidelity Cas9 (HiFi Cas9) , Cas9-H840A, and FokI-dCas9, and any of these Cas proteins fused with other engineered proteins, and ribonucleoprotein complexes comprising Cas9 protein.
The compound of Formula (I) as claimed in claim 26, for use in modulating CRISPR/Cas9 protein, variants or homologues thereof-mediated genome editing, transcriptional regulation, genome imaging, epigenetic modification, gene therapy, disease models establishing, genome-wide genetic screening, or drug design and screening; or modulating CRISPR/Cas9 protein, variants or homologues thereof-based molecular diagnostic tool for diseases.
The compound of Formula (I) as claimed in claim 27, wherein the degrader is used in combination with CRISPR/Cas9 protein, variants or homologues thereof-mediated gene therapy for the prevention and/or treatment of a genetic disease in a subject; or as a modulator for the modulation of CRISPR/Cas9 protein, variants or homologues thereof-mediated genome editing of a target DNA in a cell, wherein the Cas9 protein, variants or homologues thereof comprises Cas9 protein, Cas9 nuclease dimers, Cas9 nuclease fusion proteins, Cas9 nuclease fragments, minimized Cas9 nucleases, Cas9 variants without a cleavage domain, Cas9 variants without a gRNA domain, and Cas9-recombinase fusions, e.g., deactivated Cas9 (dCas9) proteins, variants of dCas9, Cas9 nicknase (or D10A nickase) , SaCas9, Cas9 nuclease from Streptococcus pyogenes (SpCas9) , SpCas9n, saCas9, High Fidelity Cas9 (HiFi Cas9) , Cas9-H840A, and FokI-dCas9, and any of these Cas proteins fused with other engineered proteins.
The compound of Formula (I) as claimed in claim 28, or a pharmaceutically acceptable salt thereof, wherein the genetic disease is selected from the group consisting of blood disorders such as sickle cell anemia and thalassemia; X-linked dominant genetic diseases, such as vitamin D resistant rickets and hereditary nephritis; X-linked recessive genetic diseases, such as red green blindness, hemophilia, and congenital deafness; neoplasia; cancer; age-related macular degeneration; schizophrenia; trinucleotide repeat disorders; prion-related disorders; amyotrophic lateral sclerosis; autism; Alzheimer's disease; Parkinson's disease; immune-related diseases; metabolic diseases, such as diabetes; hypertension; bronchial asthma; glaucoma; cleft lip and palate; deformed feet; epilepsy; spina bifida; neural tube defects; congenital myotonia; and progressive muscular dystrophy.
A method for treating or preventing a genetic disease in a subject, comprising:

(a) applying to the subject a genome therapy adopting a CRISPR/Cas9 protein, variants or homologues thereof-mediated genome editing or epigenetic modification using a CRISPR/Cas9 protein, variants or homologues thereof system comprising a Cas9 protein, variants or homologues thereof, and guide RNAs (gRNA) ;

(b) administering to the subject the compound of Formula (I) as claimed in any one of claims 1-13, or a pharmaceutically acceptable salt thereof, or the composition or preparation as claimed in any one of claims 14-17 in a sufficient amount to degrade the Cas9 protein, variants or homologues thereof or complexes comprising the same simultaneously or after applying the CRISPR/Cas9 protein, variants or homologues thereof-mediated genome editing.
The method as claimed in claim 30, wherein the genetic disease is selected from the group consisting of blood disorders such as sickle cell anemia and thalassemia; X-linked dominant genetic diseases, such as vitamin D resistant rickets and hereditary nephritis; X-linked recessive genetic diseases, such as red green blindness, hemophilia, and congenital deafness; neoplasia; cancer; age-related macular degeneration; schizophrenia; trinucleotide repeat disorders; prion-related disorders; amyotrophic lateral sclerosis; autism; Alzheimer's disease; Parkinson's disease; immune-related diseases; metabolic diseases, such as diabetes; hypertension; bronchial asthma; glaucoma; cleft lip and palate; deformed feet; epilepsy; spina bifida; neural tube defects; congenital myotonia; and progressive muscular dystrophy.
A method for modulating CRISPR/Cas9 protein, variants or homologues thereof-mediated genome editing of a target DNA in a cell, comprising contacting the cell with the compound of Formula (I) as claimed in any one of claims 1-13, or a pharmaceutically acceptable salt thereof, or the composition or preparation as claimed in any one of claims 14-17.
The method as claimed in claim 32, wherein the contacting is performed simultaneously or after a CRISPR/Cas9 protein, variants or homologues thereof system for genome editing is delivery to the target DNA.
The method as claimed in claim 33, wherein the CRISPR/Cas9 protein, variants or homologues thereof system comprises a Cas9 protein, variants or homologues thereof, and guide RNAs (gRNA) .
The method as claimed in claim 30 or 32, wherein the Cas9 protein, variants or homologues thereof comprises Cas9 protein, Cas9 nuclease dimers, Cas9 nuclease fusion proteins, Cas9 nuclease fragments, minimized Cas9 nucleases, Cas9 variants without a cleavage domain, Cas9 variants without a gRNA domain, and Cas9-recombinase fusions, e.g., deactivated Cas9 (dCas9) proteins, variants of dCas9, Cas9 nicknase (or D10A nickase) , SaCas9, Cas9 nuclease from Streptococcus pyogenes (SpCas9) , SpCas9n, saCas9, High Fidelity Cas9 (HiFi Cas9) , Cas9-H840A, and FokI-dCas9, and any of these Cas proteins fused with other engineered proteins.